RANZCP Practice EMQ Exam – Answers to Questions 1-6

EMQ Cluster 1  

Primary Descriptor:     Mood disorders
Secondary Descriptor: Clinical assessment
Age: Adult

The RANZCP provides a summary of the content and rough guide to the distribution of marks for the written exam in the “Basic Training Curriculum Coverage” document.

References:

American Psychiatric Association. (2013) Diagnostic and statistical manual of mental disorders (5th ed.) Washington, DC.

American Psychiatric Association. (2014) DSM-5 Handbook of Differential Diagnosis. Washington, DC.

Malhi, G. S., Bassett, D., Boyce, P., Bryant, R., Fitzgerald, P. B., Fritz, K., … Singh, A. B. (2015). Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Australian and New Zealand Journal of Psychiatry, 49(12), 1087–1206.

Do not answer questions in this booklet. Use the separate answer sheet and pencil provided.

Each question is worth 1 mark.

1. Bipolar I Disorder
2. Bipolar II Disorder
3. Cyclothymic Disorder
4. Substance/Medication-Induced Bipolar and Related Disorder
5. Bipolar and Related Disorder Due to Another Medical Condition
6. Other Specified Bipolar and Related Disorder
7. Unspecified Bipolar and Related Disorder
8. Disruptive Mood Dysregulation Disorder
9. Major Depressive Disorder, With mixed features
10. Bipolar I Disorder, With mixed features
11. Persistent Depressive Disorder
12. Substance/Medication-Induced Depressive Disorder

Select the diagnosis from the DSM-5 which most closely describes the following clinical vignettes.

Please select only ONE option for each question, BUT ANY OPTION MAY BE USED IN MORE THAN ONE QUESTION IF REQUIRED.

Question 1

A 24yo female patient who has presented to her GP multiple times since turning 21 with brief periods of mild symptoms of depression interspersed between brief periods of mild increases in energy, reduced sleep, and expansive mood.

(C)

Cyclothymic Disorder: for help with the differential diagnosis of bipolar spectrum illness, consult APA (2014), particularly Chapter 2: Differential Diagnosis by the Trees, under “Decision tree for elevated or expansive mood”.

Question 2

A 21yo male patient who reports a multiple-year history of depressed mood more days than not, accompanied by poor appetite and insomnia.

(K)

Persistent Depressive Disorder. Does not meet criteria for MDD. For help with the differential diagnosis of depressive illness, consult APA (2014), particularly Chapter 2: Differential Diagnosis by the Trees, under “Decision tree for depressed mood”.

Question 3

A 25yo female patient presents with irritable mood. She denies substance abuse or medical illness, denies history of manic/hypomanic symptoms, and you are unable to elicit evidence of clear depressive episodes. The patient does describe a pattern of frequent “out of control” behaviour characterised by anger and irritability with severe temper outbursts.

(H)

Disruptive Mood Dysregulation Disorder. Does not meet any other diagnosis. For help with the differential diagnosis of aggressive behaviour, consult APA (2014), particularly Chapter 2: Differential Diagnosis by the Trees, under “Decision tree for aggressive behavior”.

Question 4

A 28yo male patient with a history of one major depressive episode when he was 21yo and multiple presentations with hypomanic episodes lasting 2-3 days.

(F)

Other Specified Bipolar and Related Disorder (DSM-5). Presence of clinically significant hypomanic symptoms, but less than 4 days in each episode. For the criteria consult DSM-5 under “Other Specified Bipolar and Related Disorder”.

Question 5

An 18yo female patient presents with a 6 day history of elevated mood, with grandiose plans, pressured speech, and risky behaviours; she denies any other mental health history, substance abuse, or medical illness.

(F)

Other Specified Bipolar and Related Disorder. Hypomanic episode in the absence of history of depression. For the criteria consult DSM-5 under “Other Specified Bipolar and Related Disorder”.

Question 6

A 30yo male patient presents with depressed mood every day for the last two weeks, along with significant weight loss, insomnia, inappropriate guilt, poor concentration, suicidal ideation, grandiosity, pressured speech, an increase in goal-directed activity, and racing thoughts.

(I)

Major Depressive Disorder, With mixed features. Doesn’t meet criteria for manic/hypomanic episode. For the criteria of MDD and specifiers consult DSM-5 under “Depressive Disorders”.

RANZCP Practice EMQ Exam 2016 – Questions 1-6

EMQ Cluster 1  

Primary Descriptor:     Mood disorders
Secondary Descriptor: Clinical assessment
Age: Adult

References:

American Psychiatric Association. (2013) Diagnostic and statistical manual of mental disorders (5th ed.) Washington, DC.

American Psychiatric Association. (2014) DSM-5 Handbook of Differential Diagnosis. Washington, DC.

Malhi, G. S., Bassett, D., Boyce, P., Bryant, R., Fitzgerald, P. B., Fritz, K., … Singh, A. B. (2015). Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Australian and New Zealand Journal of Psychiatry, 49(12), 1087–1206.

Do not answer questions in this booklet. Use the separate answer sheet and pencil provided.

Each question is worth 1 mark.

1. Bipolar I Disorder
2. Bipolar II Disorder
3. Cyclothymic Disorder
4. Substance/Medication-Induced Bipolar and Related Disorder
5. Bipolar and Related Disorder Due to Another Medical Condition
6. Other Specified Bipolar and Related Disorder
7. Unspecified Bipolar and Related Disorder
8. Disruptive Mood Dysregulation Disorder
9. Major Depressive Disorder, With mixed features
10. Bipolar I Disorder, With mixed features
11. Persistent Depressive Disorder
12. Substance/Medication-Induced Depressive Disorder

Select the diagnosis from the DSM-5 which most closely describes the following clinical vignettes.

Please select only ONE option for each question, BUT ANY OPTION MAY BE USED IN MORE THAN ONE QUESTION IF REQUIRED.

Question 1

A 24yo female patient who has presented to her GP multiple times since turning 21 with brief periods of mild symptoms of depression interspersed between brief periods of mild increases in energy, reduced sleep, and expansive mood.

Question 2

A 21yo male patient who reports a multiple-year history of depressed mood more days than not, accompanied by poor appetite and insomnia.

Question 3

A 25yo female patient presents with irritable mood. She denies substance abuse or medical illness, denies history of manic/hypomanic symptoms, and you are unable to elicit evidence of clear depressive episodes. The patient does describe a pattern of frequent “out of control” behaviour characterised by anger and irritability with severe temper outbursts.

Question 4

A 28yo male patient with a history of one major depressive episode when he was 21yo and multiple presentations with hypomanic episodes lasting 2-3 days.

Question 5

An 18yo female patient presents with a 6 day history of elevated mood, with grandious plans, pressured speech, and risky behaviours; she denies any other mental health history, substance abuse, or medical illness.

Question 6

A 30yo male patient presents with depressed mood every day for the last two weeks, along with significant weight loss, insomnia, inappropriate guilt, poor concentration, suicidal ideation, grandiosity, pressured speech, an increase in goal-directed activity, and racing thoughts.

Answers and explanations available in separate post.

 

Interview with Gregory De Moore

Lithium, the Penicillin of Psychiatry

By Andrew Amos

The RANZCP has recently adopted a more strategic approach to recognise and encourage leaders from within its fellowship, to ensure ongoing improvement in the management of mental health and general wellbeing in Australasia. In the October 2016 podcast, I spoke with Associate Professor Greg De Moore of Westmead Hospital about his book “Finding Sanity: John Cade, lithium, and the taming of bipolar disorder”. This transcript is edited from a longer version of the interview.

AA
Professor De Moore, welcome.

GDM
Thank you very much Andrew, I look forward to it.

The self-stabbing death of Tom Wills, inventor of Australian Rules Football

AA
I was fascinated to discover that in addition to the book on John Cade you’ve also written books on Tom Wills, a 19th Century Australian Sportsman, and on the history of Australian Rules football. Do you go in search of ideas or do ideas find you?

GDM
Well, it’s interesting, the book on Tom Wills really came from my work as a consultation liaison psychiatrist. I’ve long been fascinated by the history of suicidal behaviour, and had written an article on the somewhat gruesome topic of self-stabbing. Soon after it was published I came across the extraordinary story of Tom Wills, probably Australia’s most important sportsman, but unknown by most Australians. He was the man who started the game of Australian rules football and he was also our first great cricketer.

He also created a remarkable Aboriginal cricket team which became our first international cricket team. Now, despite all of these accomplishments he tragically died at a relatively young age by stabbing himself. And when I looked into his story I became fascinated not just by the psychiatric aspects but by the broader historical aspects. As I delved into the story of his life and death in the 19th century I ditched being a full-time psychiatrist, went part-time and did a PhD in history. That led to the biography of Tom Wills, which has given me another livelihood and another life. I think from a mental health perspective what I’ve tried to do is to use his story to take issues in and around self-harm behaviour to a much broader audience than we’d normally be given privy to as psychiatrists.

We usually write journal articles for our colleagues, but when you write a book for the general public, it allows you to take incredibly important mental health issues to the public at large. So that in many ways led to the current book – it’s that same underlying philosophy: find a mental health story that would be appealing not just to colleagues but to the community as a whole.

Tom Wills…survived the biggest massacre of white settlers by Aboriginal people in Australian history

AA
Well I imagine that a sports star might be something that particularly appeals to the Australian psyche as well.

GDM
Very much so…and the story is just a phenomenal story. It’s been picked up by Channel 10 and a television documentary will come out in August. While it appeals both to the football and cricketing fraternities, it’s far more important because Tom Wills grew up with indigenous boys and girls in rural Victoria, and he also survived the biggest massacre of white settlers by Aboriginal people in Australian history, up in central Queensland. He survived, but his father was murdered. As a result Tom developed symptoms of post-traumatic stress disorder and alcoholism, yet five years after the massacre he went on to create the Indigenous cricket team which became our first international cricket team, so it is a story which started off with a mental health interest but really developed in a myriad of ways.

It has been incredibly fulfilling and it’s been an interesting story in terms of being a doctor scientist, and I’ve long been interested in that kind of discipline. I then had to really develop the craft of writing, learning how to write a book, find publishers, and then enter the public sphere, that’s been a huge story and an interest in itself. Not without some sacrifice I might add.

John Cade and the discovery of lithium for severe mental illness

AA
It sounds like writing about the transformations in other people’s lives has transformed your own. I guess that transitions nicely into the story of John Cade who is something of a half forgotten hero in the pantheon of Australian psychiatry – he is very well known to many but almost unknown to others. What led you to retell his story?

GDM
There is no doubt in my mind, no doubt whatsoever, the story of John Cade and his discovery of lithium is the single most important story in the history of Australian mental health. And the fact that you could even have an introduction and rightly say that many people know little or nothing about him is an extraordinary situation for me and it is a sad situation and reflects a lack of interest in Australian history both in the discipline but also more broadly.

For me the story goes back a long way to when I was a 5th year medical student at Royal Melbourne Hospital. I came across a very slim volume called “Mending the mind” which John Cade wrote in the last couple of years of his life. I remember thinking well here’s an Australian who uncovered one of the magical properties of lithium in treating what we called then manic depression, and yet so few people within medicine knew about him. To me it was almost like the penicillin story of mental health, because it was the very first effective medicine discovered in psychiatry, and it was an Australian discovery.

Of course then many decades went by and I got involved in medicine, and academic medicine, and then, in the last 15 years I became more interested in writing to a broader audience, and I came back to the story. I knew Anne Westmore had done a PhD on 20th century psychiatry which partly focused on the John Cade story. I discovered that Anne had some very interesting interviews with people who have since passed on, and I suggested to her that we write the complete biography of John Cade. I had little idea at the beginning just how extraordinary his life was and how many ups and downs he had to endure before fully he was finally accepted.

AA
Well, it’s a story with a long gestation period – do you have a potted history of John Cade the man?

GDM
Sure, so John Cade was born in 1912 in the country town of Horsham in Victoria. He then as a young boy travelled around with his father who was a psychiatrist to various psychiatric asylums in Melbourne and in country Victoria. There’s no doubt that during that childhood spent travelling his attitude to the mentally ill was shaped. He developed a fondness and an affinity for people afflicted with serious mental illness and you can see that in his writings.

He then went to Scotch College in Melbourne, then to Melbourne University, and was clearly a highly articulate, highly intelligent and driven individual, somewhat obsessional in nature. Once he left medical school he wanted to be a paediatrician, but while he was at the Royal Children’s Hospital in Melbourne he almost died from bilateral pneumococcal pneumonia. He eventually recovered, and the nurse that helped him recover, Jean, eventually became his wife.

Somehow during that period of great sickness there was a moment of epiphany and he decided to ditch paediatrics and become a psychiatrist. He entered into training in psychiatry but then World War II broke out, and he enlisted. He went across to Southeast Asia in 1941 and was in Malaya for a period of time and then, along with thousands of other Allied troops, was captured by the Japanese and incarcerated in Changi for 3 1/2 years.

Those 3 1/2 years in Changi were the crucible of his thinking about psychiatry.

I don’t know if you’re aware of this, but they actually set up a psychiatry unit in Changi, and John Cade was the psychiatrist that looked after patients there. He also became a consultation liaison psychiatrist and would visit the General Hospital in Changi looking at patients who had psychological disorders. He became very interested in nutritional issues which was one of the things that really shaped his thinking when he came back to Melbourne after the war. He came to believe that serious psychiatric illness such as schizophrenia and bipolar disorder should be conceived of as physical disorders, that something physically wrong was occurring with these patients.

When John Cade comes back from Changi after his three and a half years he writes an incredible letter to his wife which I think is probably the most important letter in psychiatric history in Australia. In this prescient letter, he says that he’s been thinking about ideas to do with manic-depressive insanity and schizophrenia and he has some ideas that he wants to try out when he returns home.

An extraordinary moment of foresight, he returns malnourished, returns to work at Bundura mental asylum on the northern outskirts of Melbourne and in 1946 begins in isolation a series of momentous experiments that changes the course of medicine forever.

He begins to experiment with the urine of patients with schizophrenia and manic depression, looking for some element that might affect patient’s mood. And through a series of idiosyncratic and poorly understood techniques, he injects these different patients’ urine into guinea pigs. One of the things he did was to add lithium to uric acid to create lithium urate, to make the uric acid easier to work with.

He had the idea that uric acid might have been a critical element in what made patients elevated or depressed, but as soon as he added lithium, everything changed! The guinea pigs became quiescent, they became less restless, and when he injected lithium on its own he found the same behavioural change.

In a wonderful historical moment we actually have a tape recording of his wife…recall that at that moment we’re back in the late 1940s, where John Cade has given lithium to guinea pigs, they’re lying peacefully on his palm, the palm of his hand, he calls in his wife Jean and says look at this, this is remarkable, I’ve given lithium to the guinea pigs and they’re lying on my palm.

Now because in the late 1940s there were no ethics committees, there was no impediment for him simply to cast an eye around the asylum to find a manic patient in whom he could trial lithium, and that’s what he did. Literally answering his own conscience he decided that he would try this on a range of patients and the first patient he tried was a gentleman called Bill Brand, who was a returned soldier from World War I.

Bill’s story in itself is a quintessential story of serious mental illness. In the book we were able to track down Bill’s story in minute detail and record all the trials and tribulations he went through until the experiment with lithium. So Bill has been chronically manic for five years in the asylum, he receives lithium in March 1948, and by July 1948 he’s let out to Melbourne! It is just a magical story.

John Cade and the Failure of Psychoanalysis for Schizophrenia

AA
Yes! One of the things I was interested in when when approaching the interview was the use of supplements to change what had been thought of as fairly intractable illness. This was a huge reaction against the major schools. What was the state of play in psychiatry at the time that John Cade decided to do this?

GDM
Yes, there was a deeply divided approach to the understanding of mental phenomena; on the one hand there was the powerful school of psychoanalysis, on the other hand there was a burgeoning belief that these could be seen as biological illnesses. Now prior to the Second World War John Cade read widely, and he certainly read a lot about psychotherapy and psychoanalysis in particular.

Interestingly those books that he read still survive and his underlining of Freudian thoughts make for most interesting reading. Clearly as the years went on he was greatly disaffected by psychoanalysis and thought that for the patients he was seeing at the asylum that psychoanalysis added virtually nothing. In fact he became very antagonistic towards psychoanalysis and there are a couple of moments where he underlines Freud’s lines and writes in the margin “simply not true” with exclamation marks!

He was moving very strongly towards the view that one should look at illnesses such as bipolar disorder from a biological perspective

So starting with the period just before the war, he was moving very strongly towards the view that one should look at illnesses such as bipolar disorder from a biological perspective. Now after the war and after his first use of lithium he was invited to give the Beatty Smith oration in Melbourne where he publicly denounced Freudian psychology, much to the discomfort of his fellow psychiatrists.

AA
So he was acting in opposition to what had been a very dominant paradigm. The conditions within which people with mental illness were managed changed greatly in the decades after John Cade…when I try to imagine conditions in 20th-century mental health care I picture stuffy Victorian asylums where the world kept its disturbed children out of sight, is that an accurate picture?

GDM
It is indeed. In fact one of the treasures of this research was to track down nurses and doctors who worked in asylums in the late 1940s and early 1950s. We were able to get remarkable recordings of what they remember and I think your sense of what it was like was indeed accurate, certainly a lot of thick canvas restraints, an absence of effective therapeutic medications. They were at the early stage of electroconvulsive therapy which of course was used at times indiscriminately, and of course these asylums were massive in size, there might be thousands of individuals. It wasn’t only patients with the well known psychiatric illnesses. Patients with epilepsy, developmental delay, and a whole range of neuropsychiatric conditions that we wouldn’t keep in psychiatric units today were incarcerated, all indiscriminately lumped together, often for decades.

So this was the world in which John Cade grew up and he looked at some of what he regarded as the pontification of psychoanalysis and just couldn’t see how we could bring that kind of thinking to help the patients that he was dealing with. He felt that there would be other lines of thinking, other elements that might be able to help with other disorders in the future and wrote about it quite extensively.

AA
Would you say that he initiated a paradigm shift, not just the patients like Bill with bipolar type illnesses but across the rest of psychiatry?

GDM
Without doubt, and that’s why I think this story is so important and why I think every Australian psychiatrist, and really Australians beyond psychiatry, should know the importance of what he did. The discovery of lithium predates chlorpromazine, predates tricyclics, predates benzodiazepines, and it comes back to this remarkable unlikely story of a single man doing it in isolation in an outer suburb of Melbourne.

John Cade was quite an unusual man in many ways. He was very scientific in his thinking but he was quite an eccentric and obsessional individual. For example, when he was doing his experiment in Bundura he would go and see his patients to do these experiments and when he’d finished doing his experiments he’d return home and he’d grab his rifle and go out shooting hares and rabbits and take his young boys with him. And we had these wonderful heartwarming stories of how he lived his life as he was doing these experiments because two of his boys remember the first lot of patients who received lithium, in particular Bill, and so we have their first-hand recollections of what it was like to live in the asylum in the 1940s in Melbourne.

Lithium, Psychosurgery, and Lethal Condiments

AA
Quite a different world than the one we live in. One of the strands of the October issue of Australasian psychiatry is a couple of articles by Richard White on psychosurgery, one of the few options available at the time that John Cade was working. Quite a drastic measure of course, surgical techniques of the time were not so good as now. How did the discovery of lithium and the paradigm shift into psychopharmacology affect the environment for psychosurgery?

GDM
Oh massively. So John Cade would have seen psychosurgery as an option in certain situations, as being not unreasonable even though of course some aspects we might regard as gruesome. The introduction of lithium and, in particular, the phenothiazines, really alter the landscape forever with respect to psychosurgery. I think if you look at the numbers of patients referred for psychosurgery once the psychotropic medications became more widely used the need for psychosurgery dropped enormously. John Cade describes it in his book “Mending the mind”.

AA
How was he accepted by others at the time of his discovery?

Lithium was banned in the US and wasn’t used therapeutically in psychiatry for another 20 years

GDM
Well it’s quite interesting, so he discovers this amazing effect of lithium in the treatment of mania. It was published in the Medical Journal of Australia, and that article is the single most cited article in the history of the Medical Journal of Australia. So you might think that people would celebrate it, but within the United States after the war it was noted that patients who have high blood pressure should reduce the amount of salt they take, sodium chloride. So they came across the idea that they could use lithium chloride to sprinkle on their fish and chips. And they did, completely independent of what John Cade is doing in Australia. Then several patients died and the Journal of the American Medical Association published these deaths, and lithium was banned in the US and wasn’t used therapeutically in psychiatry for well over for another 20 years or so.

AA
I guess they didn’t realise that a lethal condiment could in controlled circumstances be an effective treatment.

GDM
No, so now this effect became known in Australia but interestingly it wasn’t banned here. John Cade it is clear became very sensitive to the issue of lithium, and I don’t think he quite knew what he had unleashed. Fortunately there were other psychiatrists in Australia, particularly in Melbourne who kept experimenting with lithium and this story is also really very important. There are a couple of people in particular that that really need to be acknowledged.

Edward Trautner was an immigrant doctor, he had come from Germany originally, via England to Melbourne, and was working at Melbourne University. He, along with several others, in particular Sam Gershon, set about looking at experiments with lithium and they established safe therapeutic levels for lithium, and that’s really the second story of lithium that occurred in Australia that was critical and without that work really lithium may have died an early death.

So they kept using it in Australia, it spread to some countries but not widely and then Norm Scow in Denmark discovered some of the early Australian papers and he, particularly in the late 1950s and 1960s, was evangelical about the use of lithium, and he really brought great publicity to the therapeutic value of lithium.

Then, by the late 1960s and early 1970s it was more broadly accepted not just for the treatment of mania but the Scandinavian work also showed that it could be used in a prophylactic sense to prevent future episodes of mania and depression and once that was accepted lithium’s place in the history of psychiatry was established.

AA
Well as you say it is very important not just the initial spark of inspiration that leads to a treatment but then the translational work to get it into practice. There are some very interesting parallels between lithium being discovered, forgotten, and then rediscovered; and clozapine. I suppose these are two of our most effective treatments both going out of fashion for decades, and then being reintroduced because they are very effective, and it was found that what had been thought of as lethal side effects could be managed with appropriate treatment.

GDM
That’s an excellent example I think and there’s a lot of similarities between the two.

On the Relationship between Psychiatry and Writing

AA
I recently spoke with Nick O’Connor, chair of the section of leadership and management, from the college, about efforts in the college and in the journals to support psychiatrists looking to develop their careers in different ways. He identified that one of the great advantages of a career in psychiatry was the sheer breadth of professional interests available. Do you think there’s something about being a psychiatrist that lends itself to being a writer?

GDM
Oh yes look, that’s one of my great interests, so for example if I take the earlier work I did on Tom Wills, it started with the nidus of that discovery of someone taking their life back in 1880. By going back with my psychiatric knowledge and looking at that person’s medical notes it allowed me to really uncover his personality and aspects of psychopathology which I don’t think someone without psychiatric training could possibly do.

By the very nature of psychiatric training we are interested in social context, psychological context, spiritual context

I think also the nature of our training, Andrew, we are by the very nature of psychiatric training interested in far more than just symptoms and signs, we are interested in social context, psychological context, spiritual context; all of that was very relevant in my first book on Tom Wills and certainly with John Cade and how his personality developed; how he related to his own father. And so from a biographers perspective being a psychiatrist has been invaluable. And I’m not saying that I have overused psychiatry in these books, but it has helped underpin a lot of my understanding of an individual’s personality and the various dynamics within the family, their professions and their relationships with other people and society more generally. I think it has been a huge advantage.

AA
Yes. I recently heard heard a talk by Anne Buist an Australian perinatal psychiatrist who’s written books on forensic cases, she was talking about “Medea’s Curse” which describes as almost a hybrid work which grounded a true crime thriller in her clinical knowledge of actual cases of mothers who have killed their children. I was wondering, do you have any fictional works in progress?

GDM
Well one of the issues that people have asked me when I’ve written these books is what it takes to write a book. There’s a lot of interest in writing, and I think part of the reason for that is that we all have…well many of us have a creative desire to put something out there that is a little bit different but more broadly of appeal rather than just dealing with our colleagues…it takes a great deal of effort and sacrifice. I’ve certainly gone part-time to do this work. The research from the John Cade book being probably well over a decade of research, it required going part-time to 2-3 days a week work to support oneself financially.

Then there is the discipline of actually having to tackle it each day little bit by little bit so writing is one of those things that I think we can overly romanticise about. The reality is that it takes as much discipline as doing a PhD in a scientific discipline, and it’s something that has to be very much internally driven and you have to make enough money to support your family. So these are sort of pragmatic issues that one has to deal with, but yes, I do have some ideas about fiction and hopefully one day they’ll come to fruition.

AA
How did having collaborators and particularly Anne for the most recent work, how did that affect that equation?

GDM
Okay so that was…in this particular work that was critical. So the way it worked for the John Cade book was that although I’d been interested in John Cade for a long time I knew that Anne had done a PhD on aspects of 20th-century psychiatry in which she looked at aspects of John Cade so I contacted her seven or eight years ago and proposed the book to her. We went through the material that she had, which probably had 40 to 50% of the material needed to do a biography. Anne was involved in a couple of other major works so I resolved to do the other 50% of research that was needed.

When it got to the point of writing, about 18 months ago, I said to her that one person should write it, because it would be too difficult to have two voices coming together to write a book. So we agreed that I would write the book and as I wrote each third I would give it to her and she would make editorial comments. I would then look at those comments and add what I thought would be right in terms of my voice. So essentially I wrote the book, but as each third was done, I gave it to Anne to get feedback from her, and that was the way we were able to pull the whole thing together.

AA
Well I suppose if you had done 100% of the research you would have spent 12 to 15 years on it.

GDM
Well, collectively that’s what we did, and I guess one of the reasons stories like this don’t easily find the light of day is because it does take a lot of sacrifice at times to put that together. I think as the story has come to completion I look at it with great pride and fulfilment because I cannot think of a story in the history of Australian mental health that has so profoundly affected the course of medicine, and we should all know this story.

AA
Was there anything else that you thought was interesting or important to talk about from the book or from other aspects of your work in the history of Australian psychiatry.

GDM
I suppose I just wanted to underscore how wonderful the adventure has been. Anne and I would often talk about the story of the man, but there’s a subtext to doing work like this and it is the story of the adventure of the search itself. For example, I’ve known about the first patient to receive lithium for mania, Bill, but much of his identity was in my imagination. There was no photograph for example, of Bill, and one of the great discoveries in doing this research was to find the only known photograph of the first patient treated by John Cade.

Going through these old archives from the 1930s we were able to track down Bill’s family, and I was hoping that I could find a photograph of him. Through a circuitous series of events I was able to make contact with the family in the small town of Underpool, I’m sure you’ve never heard of…it’s in the Mallee region of north-western Victoria, and I rang this family, somewhat hesitantly introduced myself and they said well Greg, we have a photograph from 1923 of Bill on his wedding day, it’s the only known photograph of Bill Brand, would you like it? And I remember thinking “would I ever”!

I flew from Sydney to Melbourne, then I flew from Melbourne to Mildura, then I drove another couple of hours down into the desert area of the Mallee, and there was a photograph from 1923 of a fairly good-looking, boyish young man on his wedding day, really untouched by the severity of manic depression, or bipolar disorder, but I looked into his face and I thought your life is going to be so extraordinary! In some ways, awful but also hopefully to have a place in Australian history that no other person can substitute, so those kinds of discovery and then meeting people in and around the individuals involved was really very very fulfilling.

Conclusion

AA
Of course. I think your vignette of the effort that you were willing to go to to get this one photograph perfectly illustrates some of the changes from the middle of the 20th century to now where we spray hundreds of photographs on the Internet with no thought at all.

Well that brings us to the end of this edition of the Australasian psychiatry podcast. I’d like to thank Professor De Moore once again for talking with me about John Cade’s place in history of psychiatry and invite listeners to seek out his book “Finding Sanity”, as well as Richard White’s articles on psychosurgery in Sydney in the October issue of the Journal.

Critical Analysis Problems – Kaplan-Meier Survival Curves

Please read the following abstract and figure and answer the questions based on this information and your other knowledge.

Meadows GN, Shawyer F, Enticott JC, et al. (2014) Mindfulness-based cognitive therapy for recurrent depression: A translational research study with 2-year follow-up. Aus NZ J Psyc 48(8):743-755.

Objective:
While mindfulness-based cognitive therapy (MBCT) has demonstrated efficacy in reducing depressive relapse/recurrence over 12–18 months, questions remain around effectiveness, longer-term outcomes, and suitability in combination with medication. The aim of this study was to investigate within a pragmatic study design the effectiveness of MBCT on depressive relapse/recurrence over 2 years of follow-up.

Method:
This was a prospective, multi-site, single-blind trial based in Melbourne…. Non-depressed adults with a history of three or more episodes of depression were randomised to MBCT + depression relapse active monitoring (DRAM) (n=101) or control (DRAM alone) (n=102). … Relapse/recurrence of major depression was assessed over 2 years using the Composite International Diagnostic Interview 2.1.

Results:
The average number of days with major depression was 65 for MBCT participants and 112 for controls, significant with repeated-measures ANOVA (F(1,164)=4.56, p=0.03). …. Kaplan-Meier survival analysis for time to first depressive episode was non-significant, although trends favouring the MBCT group were suggested. …

Conclusions:
This work in a pragmatic design with an active control condition supports the effectiveness of MBCT in something closer to implementation in routine practice than has been studied hitherto. As expected in this translational research design, observed effects were less strong than in some previous efficacy studies but appreciable and significant differences in outcome were detected. …

Question 1:

With reference to Figure 2 and the abstract, at what month of follow-up did mindfulness-based cognitive therapy (MBCT) show a statistically significant advantage in time to relapse over depression relapse active monitoring (DRAM) alone? (1 mark)

1. 0 months
2. 5 months
3. 10 months
4. 15 months
5. 25 months
6. None of the above

Background

The name “survival curve” refers to a group of statistical techniques that were developed to estimate the effect of an intervention, exposure, or characteristic on a particular outcome over a period of time. The name derives from the fact that initially these techniques were used to provide evidence that different groups died more or less rapidly than other groups. The name persists even though these tests are now used to analyse any situation involving gradual loss of members from groups. An example of survival curve analysis from oncology might involve comparison of the rate of survival of patients with pancreatic cancer between a group given an experimental treatment at time 0, versus a group given placebo at time 0. Figure 2 shows an example from psychiatry, where the intervention is not intended to affect survival, but time to relapse of depression after a period of therapy or control management.

There are generally two main features that guide interpretation of Kaplan-Meier survival curves – a graphical plot of the survival of 2 or more different groups such as the MBCT and control groups in Figure 2; and a statistical test which estimates the probability that the curves are different from each other over the period of time being tested; although they are not named in the abstract, the Meadows et al. (2014) paper reports log-rank and Breslow tests.

It is important to realise that the plotted curves and the statistical test provide different information. A significant statistical test (such as the Breslow test) indicates that the rate of survival of the different groups is different across the whole period of time tested. The curves describe the quantitative differences between rates of survival at different times. This is different from the information given by other tests, such as t-tests, which provide information on a comparison at a single point in time.

Therefore, a survival curve analysis is appropriate to test a hypothesis such as: “the rate of relapse over the period of two years follow-up of depressed patients given MBCT will be different from those in the control group”. Tests which compare groups at a single point in time can only test hypotheses such as “the rate of relapse at 6 months follow-up of depressed patients given MBCT will be different from those in the control group”. Survival curve analysis is particularly useful in conditions such as Major Depressive Disorder and schizophrenia where most patients are expected to relapse without treatment, but there is wide variation. In these cases it can be difficult to specify a single point in time to do a comparison.

Thus, while Figure 2 appears to show that there is a difference between the MBCT and control curves at 5 months which remains roughly parallel until the end of follow-up, the phrase “Kaplan-Meier survival analysis for time to first depressive episode was non-significant, although trends favouring the MBCT group were suggested” indicates that there was no advantage in time to relapse over the period of follow-up. In addition, this type of analysis only indicates that there is a difference in time to relapse over the whole period, not at what point a difference is significant.

There is a useful series of introductory articles on Kaplan-Meier survival analysis, including sample MCQs, in the BMJ series by Sedgwick (2013a,b, 2014) for those wishing to test their knowledge further.

Answer: F

References

Meadows, G. N., Shawyer, F., Enticott, J. C., Graham, A. L., Judd, F., Martin, P. R., … Segal, Z. (2014). Mindfulness-based cognitive therapy for recurrent depression: A translational research study with 2-year follow-up. Australian and New Zealand Journal of Psychiatry, 48(8), 743–755. http://doi.org/10.1177/0004867414525841

RANZCP Committee for Examinations (2013) Guideline for Critical Analysis Problems.  https://www.ranzcp.org/Files/ranzcp-attachments/PreFellowship/Examinations/Changes_News/Guidelnes-for-CAP-130211.aspx

Sedgwick, P. (2014). How to read a Kaplan-Meier survival plot. BMJ (Clinical Research Ed.), 349(September), g5608. http://doi.org/10.1136/bmj.g5608

Sedgwick, P. (2013a). Kaplan-Meier survival analysis: types of censored observations. BMJ, 347(jul26 1), f4663–f4663. http://doi.org/10.1136/bmj.f4663

Sedgwick, P., & Joekes, K. (2013b). Kaplan-Meier survival curves: interpretation and communication of risk. Bmj, 347(nov29 1), f7118–f7118. http://doi.org/10.1136/bmj.f7118

February 2014 Transcript

February 2014 Podcast – Transcript

Highlights

Hello, I’m Andrew Amos and this is the February 2014 edition of Australian Psychatry Review. Highlights of the literature covered this month include ongoing dissection of the prospects for the ICD-11 in the ANZJP, with multiple commentaries suggesting the forthcoming edition appears unlikely to improve upon existing nosologies. The ANZJP also includes a proposal for systemic improvements required to humanely manage the growing incidence of behavioural sequelae of dementia in aged care facilities. JAMA celebrates the 50th anniversary of the US Surgeon General report linking smoking to lung cancer, which initiated largely successful public health initiatives to reduce smoking prevalence, alongside data suggesting these initiatives have been far less successful in patients with severe mental illness.

Australian Psychiatric Journals

ANZJP – February 2014

In February the Australian and New Zealand Journal of Psychiatry continues its examination of the promise and problems of the ICD-11 system for the classification of disease with three commentaries and an editorial exploring its relationship with the DSM-5. McGuffin argues that in psychiatry specificity of diagnosis is more important than sensitivity, leading them to reject single-symptom diagnoses included in the DSM-5 such as hoarding disorder.¹ They also conclude that there have not been adequate advances in psychiatric and basic science understanding to justify changing our previous diagnostic systems, and suggest working within the current systems until the advantages of change are unambiguously demonstrated.

Ghaemi also questions the empirical basis of changes to the DSM, and argues that it reflects US ‘cultural and social beliefs’ rather than the neurobiology of psychiatric phenomena, producing an invalid nosology.² Maj uses the example of the novel DSM-5 diagnosis of disruptive mood dysregulation disorder to demonstrate that DSM-5 diagnoses are not required to be reliable.³ Reinforcing Ghaemi’s argument, Maj notes that the introduction of this diagnosis to reduce overdiagnosis of bipolar disorder in adolescents reflects specific US conditions rather than a demonstrable diagnostic condition.

Malhi proceeds from the observation that the ICD is perhaps even more constrained than the DSM by its primary practical use of recording actual clinical practice, and that early indications are that the ICD-11 is unlikely to improve significantly on previous editions.⁴ Pointing to previous analyses, Malhi highlights the relatively simple but potentially dramatic improvement that would follow from including longitudinal information in psychiatric diagnoses. While some diagnoses such as schizoaffective disorder do currently include provisional longitudinal specifiers, this is not systematically applied across the nosologies, and Malhi suggests that an explicitly longitudinal perspective would facilitate both the rational evaluation of provisional diagnoses as well as eventually providing greater certainty about working diagnoses. Malhi calls for the resurrection of the system of diagnosis originally proposed by Robins and Guze in 1970, which would incorporate biomarkers linked to clinical psychopathology, family history, and genetic information, to guide both diagnosis and management.⁵

The first of a series of key reviews is included in this issue, by Phillipou on the neurobiology of anorexia nervosa.⁶ The review suggests that brain structural differences in anorexia including reduced grey matter volume persist into remission.

A viewpoint by Looi proposes a systemic approach to the management of behavioural and psychological symptoms of dementia in residential aged care facilities.⁷ They start with evidence of the overuse of psychotropic medication for behavioural control of patients with dementia, and argue that this arises from systemic mismanagement of mental health issues in aged care facilities. The widespread nature of the problem justifies more general intervention, based on structured assessment of problem behaviours and symptoms, targeted psychological and pharmacological interventions, and appropriate levels of trained and well-paid staff working within specially designed environments. Acknowledging the limitations of the literature, they review evidence that while it is true that psychotropics can be overused in the population of people with advanced dementia, there are also dangers in reflexively ceasing medications without carefully considering the indications. Looi also considers the difficulties facing GPs caring for this population, who manage extremely complex combinations of physical and mental illnesses often involving significant polypharmacy. They propose the teaching nursing home as a gold-standard model which combines excellent clinical care with the production of highly trained staff, though implicit in their viewpoint is the fact that most aged care facilities are not currently funded for such skilled workers.

Australasian Psychiatry – Awaiting February 2014

International Psychiatric Journals

AJP – January 2014

An editorial by Dickinson in the January 2014 issue of the American Journal of Psychiatry charts the recent evolution of the neurodevelopmental hypothesis of schizophrenia.⁸ Early formulations proposed congenital physiological insults with limited progression until the onset of schizophrenia around late adolescence. More recent proposals suggest ongoing interactions between biology and environment over the course of development, with evidence of marked abnormalities years before the onset of psychotic symptoms. Dickinson identifies lagging intellectual development during childhood as a particularly specific predictor of later psychosis, while motor, emotional, and social difficulties are non-specific predictors of a variety of adult psychiatric illnesses.

Meier reanalyses data from the Dunedin Multidisciplinary Health and Development Study, a birth cohort following more than 1000 people born between 1972 and 1973 in New Zealand with repeat measures of IQ and diagnosis between 3 years and 38 years of age.⁹ They report that childhood IQ was lower by 0.5 standard deviations in cohort members later diagnosed with schizophrenia. An earlier study of the same data by Reichenberg found two different developmental trajectories of IQ in patients who developed schizophrenia by age 32: a static deficit pattern with early deficits in verbal and visual knowledge acquisition and simple reasoning which did not worsen; and a dynamic deficit pattern with a lag in processing speed, working memory, and complex problem solving which worsened between 7 and 13 years of age.¹⁰ Meier extended Reichenberg’s analysis to show a widening gap in IQ scores between ages 13 and 38 years in patients who developed schizophrenia, due to declining non-verbal measures with similarities to conceptions of “fluid” intelligence.

Duelling commentaries continue the debate on the safety of high dose citalopram. Bird¹¹ criticises the recent observational study by Zivin¹² on more than 600,000 Veterans Health Administration patients treated with citalopram for depression, which concluded that doses of citalopram above 40mg were not associated with increased cardiac arrhythmias or overall mortality compared with low-dose citalopram, despite an FDA warning to avoid prescribing citalopram at 60mg per day. Bird argues that methodological shortcomings in the Zivin paper made it unlikely that they would detect differences in life-threatening arrhythmias, and that therefore the FDA warning should be heeded. They defend the FDA decision with reference to FDA data which reported increased rates of QT prolongation, which has been demonstrated, in other studies, to be associated with potentially fatal torsade de pointes, a fluctuating ventricular rhythm which can lead to ventricular fibrillation and/or sudden death. Bird argues that in the absence of adequate means of detecting torsades, it is reasonable to use proxy measures such as QT prolongation to estimate risk. They also argue that there is no evidence that increasing citalopram to 60mg improves efficacy.

Zivin notes citalopram’s first-line indication due to minimal drug interactions, safety in older adults and medically ill patients, low cost, and relative effectiveness. Zivin also refers to the absence of peer-reviewed publication of data leading to the FDA warning, along with an absence of information about the proportion of patients with QT prolongation, and torsades de pointes in the FDA data set, and suggests that the FDA data should be published and incorporated with other sources of evidence. They acknowledge the absence of evidence of increased efficacy of higher doses of citalopram but note that it is reasonable to assume this form of generalizability. Zivin concludes that, in the end, it is for individual clinicians to weigh the risks and benefits of higher doses of citalopram given the imperfect state of evidence.

Viron presents the case of a 52-year-old homeless man with schizophrenia and polysubstance abuse, with a focus on the unfortunate complication of hepatitis C infection with cirrhosis and hepatic encephalopathy.¹³ The detailed case is juxtaposed with discussion of the epidemiology, pathology, and treatment of hepatitis C, and descriptions of hepatic encephalopathy including differential diagnosis. Viron emphasises the importance for doctors dealing with patients with severe mental illness to detect hepatitis C, monitor for complications including encephalopathy, and tailor treatments for diminished hepatic capacity and to minimise further liver damage in patients with hepatitis C.

BJP – January 2014; February 2014

In the January 2014 issue of the British Journal of Psychiatry, Jauhar reported a systematic review and meta-analysis of CBT for the symptoms of psychosis.¹⁴ These authors demonstrate that previous meta-analyses which concluded that CBT could be effective in reducing symptoms of psychosis failed to consider important sources of bias. Jauhar conclude that there is evidence for a small effect size in reduction of psychotic symptoms across CBT for psychosis studies, but that this is reduced when sources of bias are considered. In particular, the authors identified masking as an important source of bias in this literature. There were no RCTs using double-blinding, which is difficult to achieve in face-to-face psychological treatments. Jauhar compared the effect size of studies which assessed patients using interviewers who were blind to treatment assignment to studies which did not specify this form of blinding, and found significantly smaller treatment effects in the appropriately blinded studies. Reanalysis using only studies at low risk of any source of bias found no significant treatment differences.

In the February 2014 issue of the British Journal of Psychiatry Duffy reports a longitudinal follow-up of the offspring of patients with bipolar disorder for up to 16 years.¹⁵ She found that high risk offspring were at increased risk of a broad range of disorders, while offspring of lithium non-responders were the only subgroup to develop psychotic disorders. The authors describe a trajectory through the clinical stages of bipolar illness which begins with non-specific psychopathology.

Menchetti reports a multi-centre randomised control trial of counselling compared with SSRIs for depression in primary care.¹⁶ Counselling achieved higher remission than SSRIs at 2 months, with subgroup analyses suggesting that patients in the first episode of depression were more likely to respond to counselling, while those in their second episode were more likely to remit with SSRIs.

Gould reported a meta-analysis of interventions to reduce benzodiazepine use in older people, which found that several interventions were effective, particularly supervised withdrawal augmented with psychotherapy.¹⁷ The authors note that limited access to resources including psychotherapy necessitate a stepped-care approach which can begin with medication review and education, progressing through to psychotherapy augmented withdrawal.

JAMA Psychiatry – January 2014

In the January 2014 issue of JAMA Psychiatry an editorial by Joshi explores possible trends in the provision of mental health services for children and adolescents in the US in the light of significant overlapping reform pressures.¹⁸ Joshi interprets the review of the evolution of mental health services between 1995 and 2010 by Olfson which shows that the mental health care of youths increased more rapidly than adults in number of contacts, prescription of psychotropic medication, and provision of psychotherapy.¹⁹ Antipsychotic medications were the fastest growing class prescribed for adolescents, including a rapid growth in antipsychotics prescribed by primary care, non-psychiatrist physicians. Olfson proposes that the rapid increase in psychotropic prescription in adolescents may be the result of systemic changes. Using the example of ADHD, the increase in stimulant prescription is likely to have occurred because of the intersection of the maturation of ADHD treatment advocacy campaigns, dissemination of practice guidelines for ADHD, and a stream of new medications approved by the US FDA. Olfson highlights the need to balance the potentially significant side effects of stimulant medications in adolescents with the demonstrated efficacy of these treatments in some patients, alongside the fact that up to half of adolescents affected by mental illness do not receive treatment. Joshi argues that the expansion of psychotropic prescription for youths has been supported by large multicenter federally funded studies including the Multimodal Treatment Study of Children with ADHD, the Treatment for Adolescents with Depression Study, the Treatment of Early Age Mania study, and the Research Units on Paediatric Psychopharmacology Autism Network study. Joshi notes much of the prescription of psychotropics for youths is provided by non-psychiatric primary care physicians due to inadequate numbers of psychiatrists, and argues that earlier identification and treatment of mental illness in youths can significantly reduce the burden of disease across the US population.

Molecular Psychiatry – Online

In the largest study of autoimmune antibody-mediated psychiatric disease to date, Molecular Psychiatry has published online an article by Hammer and colleagues, who tested 1300 healthy, 1100 schizophrenic, 260 Parkinsonian, and 150 affective disorder subjects for autoimmune antibodies to NMDA-receptors, linked to a genome wide association study comparing antibody carriers to non-carriers, and influenza antibody status.²⁰ They followed up with in vivo experiments in mice with blood-brain barrier deficiencies. Hammer was surprised to find that, while they replicated increased rates of autoimmune antibodies to NMDA receptors in schizophrenic patients of 10%, these were no different to rates in the healthy controls, which were much higher than in previous, smaller studies. They propose that it is not the presence of autoimmune antibodies that increases the probability of schizophrenia, but the interaction of autoimmune antibodies with a period of breakdown in the blood-brain barrier allowing high levels of circulating antibodies in the brain.

Biological Psychiatry – February 2014

The 15th February issue of Biological Psychiatry is a special issue devoted to the role of neuroimmune processes in schizophrenia. A review by McAllister summarises current knowledge of the mechanisms linking major histocompatibility complex I molecules to the onset of schizophrenia by their influence on brain development.²¹ The review proposes that the MHC I may alter the development of brain connections following exposure to environmental risk factors for schizophrenia. Girgis reviews evidence for the theory that cytokines may increase the risk of schizophrenia and argues that this may lead to novel treatments.²² Benros summarises evidence that a broad range of autoimmune diseases are associated with psychosis, including systemic lupus erythematosus, psoriasis and multiple sclerosis, as well as a negative association with rheumatoid arthritis.²³ They consider whether autoimmune processes cause psychosis, or whether common genetic or environmental factors such as infections could cause both autoimmune processes and psychosis, leading to non-causal associations.

A commentary by Bullmore implicitly acknowledges the false dawns of past immunologic approaches to the treatment of schizophrenia, and attempts to justify enthusiasm for current neuroimmunological methods in a hypothetical investor.²⁴ He notes the growing body of positive trials showing reduced psychotic symptoms with anti-inflammatories, plasmapheresis, and antibiotics, and refers to the possibility of immune-mediated actions of clozapine. Noting the high failure rate of past agents proposed as antipsychotics, Bullmore asks “How will it be different this time?”, answering that it is possible that the immune pathway offers objective biomarkers of disease progression, though this point is somewhat undermined by the absence of any existing biomarkers.

Neuropsychopharmacology – Awaiting March

Schizophrenia Bulletin – January 2014

A meta-analysis of long-acting injectable versus oral antipsychotics in schizophrenia by Kishimoto in the January 2014 issue of Schizophrenia Bulletin concludes that across 21 RCTs there was no evidence that long-acting injectable atypical antipsychotics could reduce relapse compared with oral medications.²⁵ There was evidence that first-generation long-acting antipsychotics, principally fluphenazine, reduced relapse, though these studies were all completed before 1991.

Journal of Clinical Psychiatry – January 2014

The Journal of Neurology, Neurosurgery, and Psychiatry – February 2014

The February 2014 issue of the Journal of Neurology, Neurosurgery, and Psychiatry is a special issue on neuropsychiatry. Among other topics, it includes several articles on somatoform disorders, including a review of neurophysiological correlates of dissociative symptoms by van der Kruijs,²⁶ a systematic review of transcranial magnetic stimulation for conversion symptoms by Pollak,²⁷ and a structural MRI study showing reduced thalamic volume in motor conversion disorder.²⁸ Of particular interest is a review which explores the value of positive signs for weakness, sensory, and gait symptoms in conversion disorder.²⁹ A related podcast cogently describes the value of these signs for explaining the nature and treatment of conversion disorder, to the patients themselves. For example, collapsing weakness is positive when a limb develops normal tone that suddenly collapses upon light pressure from the examiner’s finger. Daum explains the value of a positive sign in the physical examination of patients who may interpret negative signs as symbolic rejections of their distress.

Mainstream Medical Journals

Turning now to mainstream medical journals.

MJA – 2 February 2014

JAMA

The January 8 issue of JAMA is a special review of 50 years of public health efforts to demonstrate and manage the significant health effects of smoking cigarettes. An editorial by Cole reports that in 1962 the surgeon general of the United States, Luther Terry, released the report “Smoking and Health”, concluding on the basis of 7000 documents that “cigarette smoking is causally related to lung cancer in men; the magnitude of the effect of cigarette smoking outweighs all other factors; and the risk of developing lung cancer increases with the duration of smoking and number of cigarettes smoked per day, and diminishes by discontinuing smoking”.³⁰ Cole notes the enormous influence of the report on public health policy and legislation, industry opposition, and changing patterns of cigarette consumption.

Cahill summarises evidence on the relative efficacy of the three first-line smoking cessation treatments in the general population, nicotine replacement therapy, bupropion, and varenicline.³¹ Bupropion is a dopamine and noradrenaline reuptake inhibitor, and a nicotine antagonist. Varenicline is a partial nicotine agonist. Varenicline or nicotine replacement therapy combining patch and inhaler were the most effective treatments, and nicotine replacement monotherapy or bupropion were both more effective than placebo.

Cook uses data from nationally representative surveys of US residents to compare smoking trends in adults with and without mental illness.³² The Medical Expenditure Panel Survey sample included more than 30,000 adults with mental illness between 2004 and 2011, and showed that while smoking significantly declined among those without mental illness, from 19.2% to 16.5%, there was no statistical difference in the change among those with mental illness, from 25.3% to 24.9%. However, the surveys also showed that individuals with mental illness who received mental health treatment in the previous year were more likely to have quit smoking, 37.2% versus 33.1%. Cook and colleagues conclude that tobacco control policies and cessation interventions have not been as effective for people with mental illness. They refer to evidence that most of the excess mortality in people with mental illness leading to a 25 year difference in life expectancy can be attributed to higher prevalence and a higher intensity of smoking.

Evins and colleagues report a randomised control trial with CBT and varenicline for maintenance of smoking cessation in 87 patients with schizophrenia and bipolar disorder who had achieved at least two weeks of abstinence after a 12 week open-label trial of varenicline and CBT.³³ At 52 week follow-up 60% of the varenicline group had at least one week of abstinence versus 19% in the placebo controls, and 45% of the varenicline group maintained continuous abstinence between weeks 12 and 64 of follow-up compared with 15% of the placebo group. There were no treatment positive or negative effects on psychiatric symptoms.

A clinical education article by McDonald in the January 15 issue of JAMA describes preliminary evidence that the apolipoprotein E (or APOE) epsilon 4 allelic variant associated with Alzheimer’s disease is also associated with developmental differences in infants between 6 months and two years old.³⁴ MRI studies showed that infant carriers of the epsilon 4 variant  had lower white matter and gray matter measurements than non-carriers in multiple brain regions associated with Alzheimer’s pathology. The authors speculate on the role of the APOE gene in brain development, the relationship with subsequent Alzheimer’s pathology, and the possibility of prevention strategies.

Lancet

The January 11 issue of the Lancet includes a randomised controlled trial for German patients with anorexia nervosa by Zipfel comparing a focal psychodynamic therapy, CBT, and optimised treatment as usual combining GP and therapist care.³⁵ While all three groups gained weight over the course of the trial, contrary to the experimental hypothesis there were no significant differences in weight gain between interventions. Zipfel concludes that optimsed treatment as usual can be considered a useful baseline treatment for adult outpatients with anorexia nervosa.

The February 1 issue includes notification of a consensus statement by England’s Department of Health that reminds health-care providers about their rights and duties when communicating risks facing patients to patients’ families.³⁶ The statement addresses the balance between patient autonomy and safety, including making explicit that breaking confidentiality to disclose suicide risk can actually reduce risk in some circumstances. It is emphasised that breaking confidentiality should only adhere in cases where patients do not have the mental capacity to make their own decisions about information provision, and should only occur after discussing the provision of information with the patient.

NEJM

In the January 9 issue of the NEJM Chen reports a genetic analysis of 1761 Taiwanese patients with bipolar I which is presented as a step towards the psychopharmacogenetic goal of identifying biomarkers predicting response to lithium treatment.³⁷ Chen assessed responses to lithium and then performed a genome-wide association study (or GWAS) on a group of 294 patients. They then tested the single-nucleotide polymorphisms (or SNPs) with the strongest association with a response to lithium identified by the GWAS on another 100 patients and sequenced genetic patterns in 94 patients who had a response to lithium and 94 who did not have a response to lithium in the GWAS. They identified two SNPs with a sensitivity of 93% for predicting a treatment response to lithium and which differentiated between patients with good and poor response to treatment. On the basis of these analyses they proposed the GADL1 protein as a putative agent in BPAD pathology, and speculated that its function may be similar to that of glutamate decarboxylase, an enzyme that is important in the metabolism of the excitatory neurotransmitter glutamate.

BMJ

Nature Neuroscience

The February 2014 issue of Nature Neuroscience includes a series of reviews of recent research on the neurobiology of pain and itch.³⁸ There are reviews on the role of ions in the transmission of nociceptive pain signals; a survey of the role of endogenous lipid mediators such as endocannabinoids in the peripheral gating of nociceptive signals; a model of the organisation of the nociceptive system which incorporates evidence of cross-talk between different somatosensory pathways in normal and aberrant pain signals; and a review analysing current knowledge of genetic, epigenetic, and environmental factors involved in pain vulnerability and resilience.

Conclusion

And that’s it for the February edition of Australian Psychiatry Review. Listeners directed to the podcast from the Royal Australian and New Zealand Colleage of Psychiatry’s CPD Online page can access questions for CPD points using the password “smoke”. See you next month!

References

1. McGuffin P, Farmer A. Moving from DSM-5 to ICD-11: A joint problem? Australian and New Zealand Journal of Psychiatry. 2014;48(2):194–6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24470509. Accessed February 4, 2014.

2. Ghaemi SN. The “pragmatic” secret of DSM revisions. Australian and New Zealand Journal of Psychiatry. 2014;48(2):196–7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24470510. Accessed February 4, 2014.

3. Maj M. DSM-5, ICD-11 and “pathologization of normal conditions”. Australian and New Zealand Journal of Psychiatry. 2014;48(2):193–4. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24470508. Accessed February 4, 2014.

4. Malhi GS. ICD Future. Australian and New Zealand Journal of Psychiatry. 2014;48(2):107–9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24470507. Accessed February 4, 2014.

5. Robins E, Guze SB. Establishment of diagnostic validity in psychiatric illness: its application to schizophrenia. American Journal of Psychiatry. 1970;126(7):983–987.

6. Phillipou A, Rossell SL, Castle DJ. The neurobiology of anorexia nervosa: A systematic review. Australian and New Zealand Journal of Psychiatry. 2014;48(2):128–152. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24194589. Accessed January 26, 2014.

7. Looi JC, Byrne GJ, Macfarlane S, McKay R, O’Connor DW. Systemic approach to behavioural and psychological symptoms of dementia in residential aged care facilities. Australian and New Zealand Journal of Psychiatry. 2014;48(2):112–5. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23888078. Accessed February 4, 2014.

8. Dickinson D. Zeroing in on early cognitive development in schizophrenia. American Journal of Psychiatry. 2014;171(1):9–12. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24399421.

9. Meier MH, Caspi A, Reichenberg A, et al. Neuropsychological decline in schizophrenia from the premorbid to the postonset period: evidence from a population-representative longitudinal study. American Journal of Psychiatry. 2014;171(1):91–101. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24030246.

10. Reichenberg A, Caspi A, Harrington H, et al. Static and Dynamic Cognitive Deficits in Childhood Preceding Adult Schizophrenia: A 30-Year Study. American Journal of Psychiatry. 2010;167(2):160–169.

11. Bird ST, Crentsil V, Temple R, Pinheiro S, Demczar D, Stone M. Cardiac Safety Concerns Remain for Citalopram at Dosages Above 40 mg/Day. American Journal of Psychiatry. 2014;171(1):17–9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24399423.

12. Zivin K, Pfeiffer PN, Bohnert ASB, et al. Safety of high-dosage citalopram. American Journal of Psychiatry. 2014;171(1):20–2. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24399424.

13. Viron M, Stern AP, Keshavan MS. Schizophrenia complicated by chronic hepatitis C virus and hepatic encephalopathy. American Journal of Psychiatry. 2014;171(1):25–31. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24399426.

14. Jauhar S, McKenna PJ, Radua J, Fung E, Salvador R, Laws KR. Cognitive-behavioural therapy for the symptoms of schizophrenia: systematic review and meta-analysis with examination of potential bias. British Journal of Psychiatry. 2014;204(1):20–9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24385461. Accessed January 11, 2014.

15. Duffy A, Horrocks J, Doucette S, Keown-Stoneman C, McCloskey S, Grof P. The developmental trajectory of bipolar disorder. British Journal of Psychiatry. 2014;204(2):122–128. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24262817. Accessed January 28, 2014.

16. Menchetti M, Rucci P, Bortolotti B, et al. Moderators of remission with interpersonal counselling or drug treatment in primary care patients with depression: randomised controlled trial. British Journal of Psychiatry. 2014;204(2):144–150. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24311553. Accessed January 24, 2014.

17. Gould RL, Coulson MC, Patel N, Highton-Williamson E, Howard RJ. Interventions for reducing benzodiazepine use in older people: meta-analysis of randomised controlled trials. British Journal of Psychiatry. 2014;204(2):98–107. Available at: http://bjp.rcpsych.org/cgi/doi/10.1192/bjp.bp.113.126003. Accessed February 4, 2014.

18. Joshi PT. Mental Health Services for Children and Adolescents Challenges and Opportunities. JAMA Psychiatry. 2014;71(1):17–18.

19. Olfson M, Blanco C, Wang S, Laje G, Correll CU. National trends in the mental health care of children, adolescents, and adults by office-based physicians. JAMA Psychiatry. 2014;71(1):81–90. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24285382. Accessed January 13, 2014.

20. Hammer C, Stepniak B, Schneider A, et al. Neuropsychiatric disease relevance of circulating anti-NMDA receptor autoantibodies depends on blood-brain barrier integrity. Molecular psychiatry. 2013;Published (3 September):1–7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23999527. Accessed December 30, 2013.

21. McAllister AK. Major histocompatibility complex I in brain development and schizophrenia. Biological Psychiatry. 2014;75(4):262–8. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24199663. Accessed January 21, 2014.

22. Girgis RR, Kumar SS, Brown AS. The cytokine model of schizophrenia: emerging therapeutic strategies. Biological Psychiatry. 2014;75(4):292–9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24439555. Accessed January 21, 2014.

23. Benros ME, Eaton WW, Mortensen PB. The epidemiologic evidence linking autoimmune diseases and psychosis. Biological Psychiatry. 2014;75(4):300–6. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24199668. Accessed January 25, 2014.

24. Bullmore ET, Lynall M-E. Immunologic therapeutics and psychotic disorders. Biological Psychiatry. 2014;75(4):260–1. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24439554. Accessed February 4, 2014.

25. Kishimoto T, Robenzadeh A, Leucht C, et al. Long-Acting Injectable vs Oral Antipsychotics for Relapse Prevention in Schizophrenia: A Meta-Analysis of Randomized Trials. Schizophrenia bulletin. 2014;40(1):192–213. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23256986. Accessed February 4, 2014.

26. Van der Kruijs SJM, Bodde NMG, Carrette E, et al. Neurophysiological correlates of dissociative symptoms. Journal of Neurology, Neurosurgery, and Psychiatry. 2014;85(2):174–9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23175855. Accessed January 21, 2014.

27. Pollak TA, Nicholson TR, Edwards MJ, David AS. A systematic review of transcranial magnetic stimulation in the treatment of functional (conversion) neurological symptoms. Journal of Neurology, Neurosurgery, and Psychiatry. 2014;85(2):191–7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23303960. Accessed January 22, 2014.

28. Nicholson TR, Aybek S, Kempton MJ, et al. A structural MRI study of motor conversion disorder: evidence of reduction in thalamic volume. Journal of Neurology, Neurosurgery, and Psychiatry. 2014;85(2):227–9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24039028. Accessed January 25, 2014.

29. Daum C, Hubschmid M, Aybek S. The value of “positive” clinical signs for weakness, sensory and gait disorders in conversion disorder: a systematic and narrative review. Journal of Neurology, Neurosurgery, and Psychiatry. 2014;85(2):180–90. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23467417. Accessed January 25, 2014.

30. Cole HM, Fiore MC. The war against tobacco: 50 years and counting. JAMA. 2014;311(2):131–2. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24399546.

31. Cahill K, Stevens S, Lancaster T. Pharmacological Treatments for Smoking Cessation. JAMA. 2014;311(2):193–194.

32. Cook BL, Wayne GF, Kafali EN, Liu Z, Shu C, Flores M. Trends in Smoking Among Adults With Mental Illness and Association Between Mental Health Treatment and Smoking Cessation. JAMA. 2014;311(2):172. Available at: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2013.284985. Accessed January 9, 2014.

33. Evins AE, Cather C, Pratt S a., et al. Maintenance Treatment With Varenicline for Smoking Cessation in Patients With Schizophrenia and Bipolar Disorder. JAMA. 2014;311(2):145. Available at: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2013.285113. Accessed January 9, 2014.

34. McDonald J, Krainc D. Alzheimer Gene APOE ε4 Linked to Brain Development in Infants. JAMA. 2014;311(3):298–299.

35. Zipfel S, Wild B, Groß G, et al. Focal psychodynamic therapy, cognitive behaviour therapy, and optimised treatment as usual in outpatients with anorexia nervosa (ANTOP study): randomised controlled trial. Lancet. 2014;383(9912):127–37. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24131861. Accessed January 20, 2014.

36. Editor. Suicide: who should know? Lancet. 2014;383(February 1):384. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24485570. Accessed February 4, 2014.

37. Chen C, Lee C, Lee M, et al. Variant GADL1 and Response to Lithium Therapy in Bipolar I Disorder. New England Journal of Medicine. 2014;370(2):119–128.

38. Editor. Focus on pain. Nature Neuroscience. 2014;17(2):145–145. Available at: http://www.nature.com/doifinder/10.1038/nn.3644. Accessed January 29, 2014.

January 2014 Transcript

January 2014 Podcast – Transcript

Highlights

Hello, I’m Andrew Amos and this is the January 2014 edition of Australian Psychatry Review. The review closes with a focus section on illicit substance induced psychosis. Highlights from the literature include the ANZJP’s announcement of a series looking forward to the ICD-11, alongside the research plans of the winners of John Cade Fellowships in 2013. The AJP considers efforts to enact Kendra’s law in New York state, requiring outpatient treatment for for patients with severe mental illness. The BJP reports that parents can successfully deliver CBT to anxious minors, guided by professionals, and that community treatment orders appear to increase coercion without improving mental health. Translational Psychiatry includes a report that omega-3 fatty acids and multivitamins can worsen psychotic symptoms when added to antipsychotic medications.

Australian Psychiatric Journals

Turning now to the Australian psychiatric literature.

ANZJP

In an editorial marking the new year, Editor of the Australian and New Zealand Journal of Psychiatry Gin Malhi looks back to the journal’s series of DSM 5 digests, and heralds the arrival of the ICD-11 expected in 2015.¹ Under the rubric of “ICD Insights” the journal will feature ongoing correspondence and perspectives on the ICD-11 highlighting changes and potential improvements on the DSM-5, starting with three letters in this issue.

There are two Viewpoints by Middleton and colleagues which outline the background and framework of the Australian Royal Commission into Institutional Abuse.^2,3 The commission was triggered mainly by concern regarding abuse within religious institutions, but Middleton and colleagues note that its reach potentially involves all institutions involved in the care of children, whether they supported the abuse or did not respond appropriately to its disclosure. They propose that there has been an institutional reflex to respond to allegations of abuse by diversion, suppression, and denial, with sometimes tragic results for victims and investigators. Middleton and colleagues suggest the Commission take lessons from South Africa’s Truth and Reconciliation Commission, including granting amnesty to those willing to fully confess their transgressions, valuing the validation of victims and prevention of future wrongs over the prosecution of all perpetrators. The authors also consider the Commission a necessary first step into the broader but more difficult area of abuse within families.

Editorials by McGrath⁴ and Christensen⁵ outline the 5-year research programmes of these winners of the John Cade fellowships in 2013. Both winners focus on structuring research to achieve the best results for patients with severe mental illness. McGrath emphasises the importance of identifying and measuring modifiable risk factors. He uses vitamin D deficiency as an example, described as a potential risk factor for schizophrenia in 1999 but only this year supported by strong evidence that low prenatal vitamin D impairs brain development in rodents. McGrath proposes to use the McCade fellowship to explore the possibility that vitamin D replacement in at-risk perinatal populations may reduce the incidence or severity of neurodevelopmental disorders including schizophrenia in the same way that folate supplementation has reduced the incidence of spina bifida. He identifies the importance of leveraging research by involving international collaborators exploring related hypotheses and structuring research to test multiple risk factors as part of the same design. He aspires to combine these ambitious research endeavours with initiatives in training and systems development, such as the massive open online course platform EdX, to foster the development of a clinical research talent pool amongst Queensland clinicians.

Christensen traces her Cade fellowship proposal to the question “How could you transform the mental health of Australians?”⁵ Her answer is that “The mental health of Australians [would] be radically transformed if it were possible to implement what we already know about preventing and treating the common mental health disorders.” Christensen proposes to use internet technologies to implement evidence-based prevention strategies at the population level and facilitate appropriate help-seeking. She notes the huge numbers required to achieve population level prevention in mental illness, which cannot be implemented by traditional face-to-face mental health workers, but which appear perfect for internet-based resources which can be massively expanded with minimal cost. Her proposal includes web-based resources as well as wearable sensors, mobile apps, and social media. It is significant that both proposals address networks across clinical, professional, and educational organisations, including the goal of generating new expertise and networks across domains through novel training initiatives.

International Psychiatric Journals

Turning now to the international psychiatric literature.

AJP – December 2013

In the December issue of the American Journal of Psychiatry Drake and Colleagues report an evaluation of the US Social Security Administration’s Mental Health Treatment Study, in which disability insurance beneficiaries with psychiatric diagnoses were randomised either to usual services, or to an intensive program including supported employment, systematic medication management, complete health insurance coverage with no out-of-pocket expenses and suspension of disability reviews.⁶ Over 2000 beneficiaries with schizophrenia, bipolar disorder, or depression participated, with higher rates of paid employment in the intervention group at 60% compared with 40% in the control group, as well as greater level and duration of work. The intervention group also achieved better mental health and quality of life than controls, with lower resource use of hospital days and emergency presentations. However, a related editorial by Frank⁷ notes that only 14% of beneficiaries approached agreed to participate in the trial, and those who did participate were younger, and more motivated to find work than those who declined. Furthermore, few of the participants achieved sufficient work to leave disability insurance. Frank concludes that with the best available programs, working with the most motivated patients, vocational interventions do not substantially change patients’ lives, and recommends a focus on early intervention with the goal of maintaining work, rather than returning to work after a convalescent period.

Swanson and colleagues report a cost analysis of assisted outpatient treatment in New York City.⁸ In 1999 the New York state legislature and 41 other American states enacted Kendra’s Law authorising assisted outpatient treatment for people with serious mental illness at risk of failing to live safely in the community. This system remains controversial and unimplemented in most states, with concerns about patient coercion as well as fears of managing potentially dangerous patients outside hospital. Research suggests assisted outpatient treatment can improve outcomes but only with adequate public funding. The authors analysed more than 600 patients across NYC and five counties in NY state and compared costs from 12 months before assisted outpatient treatment was initiated and for two subsequent 12 month periods. Patients were eligible if they had a history of non-adherence resulting in hospitalisation or incarceration, or if they had committed or threatened serious acts of violence in the previous 48 months, resulting in court orders generally issued for 6 months with the potential for extension. Previous research established that this treatment reduced hospitalisation, arrests, and adherence. These authors report that the programme reduced costs by more than 40% in the first year, and more than 13% in the second year. Voluntary participation in intensive treatment was also associated with reduced costs, but assisted outpatient treatment reduced costs twice as much.

BJP – December 2013

In the December 2013 British Journal of Psychiatry Thirlwall and colleagues report a randomized controlled trial which showed superior outcomes of parent-delivered CBT for paediatric anxiety compared to wait-list controls.⁹ 194 children with a current anxiety disorder were randomised to full guided parent-delivered CBT, brief guided parent-delivered CBT, or wait-list control. The full guided CBT group achieved superior outcomes compared to wait-list controls, with 50% versus 25% levels of recovery. Thirlwall and colleagues note that outcomes were unrelated to level of therapist training and experience. A linked editorial by Cartwright-Hatton notes the prevalence of anxiety disorders in children, and highlights the importance of the Thirlwall finding, which indicates that CBT can be effectively delivered by non-professionals.¹⁰ The generalisability of the study may be limited by the exclusion of children whose primary carers were currently affected by an anxiety disorder.

Rugkasa and Dawson review the literature regarding community treatment orders, and conclude that evidence is scarce and has significant methodological limitations.¹¹ While community treatment orders are sometimes presented as a less restrictive alternative to hospitalisation for managing risk, they emphasise that current evidence does not suggest that CTOs reduce hospitalisation, and refer to literature that suggests extending involuntary treatment to the community increases rather than reduces coercion. It appears that community treatment orders are supported by patient families but opposed by patient advocates, with the central conflict between the right to autonomy and the right of receiving adequate care. Rugkasa and Dawson conclude that it is intensive community treatment, not coercion via community treatment orders, that reduces hospitalisation.

Milner and colleagues report a systematic review and meta-analysis of suicide by occupation. Previous research has suggested that medical professionals, farmers, and police are at most risk, due to access to lethal means and stressful working conditions.¹² The meta-analysis suggested that suicide rates were highest in occupations with the lowest skill levels, such as labourers, cleaners, and agricultural workers. The paper does not confirm the elevated risk for medical doctors, as it incorporates articles with both higher and lower risks of suicide for doctors. Differences in relative suicide risk between studies appears to be substantially due to the use of different comparison groups, with elevated risks in studies which used comparison groups with low suicide risk compared to whole working-age populations.

JAMA Psychiatry – December 2013

In the December 2013 issue of JAMA Psychiatry, Lane and colleagues report a novel adjunct agent which substantially improved symptoms and cognitive function in patients with schizophrenia.¹³ Using a cluster randomised, placebo-controlled, double-blind design 52 Taiwanese patients with chronic schizophrenia stabilised on antipsychotic medications for at least 3 months were randomised to receive 6 weeks of augmenting sodium benzoate or placebo. Sodium benzoate was chosen as an agent which increases NMDA receptor stimulation, putatively correcting NMDA receptor underactivation in schizophrenia. Sodium benzoate inhibits D-amino acid oxidase, which itself degrades D-serine, an NMDA coagonist. By decreasing the degradation of D-serine, sodium benzoate increases the activation of NMDA receptors. Patients receiving sodium benzoate showed a 21% improvement in PANSS total scores and small to moderate effect sizes on multiple other clinical indicators of positive and negative symptoms, function, and quality of life, as well as increased processing speed and visual learning.

Kotov and colleagues seek to define the boundaries separating psychotic and affective disorders by charting the course of symptoms and outcomes of 413 patients presenting with first-episode psychosis over 10 years.¹⁴ They note three hypotheses regarding the relationship between psychosis and psychotic mood disturbance, from Kraepelin’s separation of dementia praecox from manic-depressive insanity as two qualitatively different conditions, through the DSM’s separation of schizophrenia from schizoaffective disorder and bipolar disorder as three qualitatively different conditions, to more recent conceptualisations of a continuum of mental illness from psychotic mood disorder to non-affective schizophrenia. They based their study on Kendell and Brockington’s proposal that these three hypotheses could be tested by examining the outcomes along the spectrum from non-affective schizophrenia to bipolar disorder. Natural boundaries between two or three qualitiatively different conditions would lead to discontinuous drops in outcome along the spectrum, while a continuum of illness would show a more linear decline. Consistent with a dichotomous model, Kotov and colleagues data on longitudinal course clearly distinguished psychotic and affective disorders, but did not separate schizophrenia from schizoaffective disorder. In fact, duration of psychosis was the most important predictor of outcome across diagnoses.

A related editorial by Kendler proposes that Kotov and colleagues’ paper supports the use of the non-affective psychosis ratio as a useful prognostic indicator, with proportion of psychosis occurring outside major mood episodes associated with worse outcomes.¹⁵ Kotov and colleagues suggest that with appropriate replication, their result suggests the elimination of schizoaffective disorder from psychiatric nosologies.¹⁴

Theorising that the expression of violence in patients with psychosis may be influenced by subgroups with different developmental trajectories, Winsper and colleagues show that premorbid levels of delinquency affected violent behaviour in first episode psychosis.¹⁶ High levels of premorbid delinquent behaviour independently predicted violent behaviour during the first episode, while the effect of moderate levels was partially mediated by positive symptoms of psychosis.

Investigating the neurobiologic basis of late-life depression, Wilson and colleagues tested the hypothesis that neurodegenerative processes are related to depressive symptoms by analysing the brains of 124 people without dementia from the Rush Memory and Aging project.¹⁷ They found that neurofibrillary tangles and Lewy bodies in the monoamingergic nuclei of the brain stem correlated with depressive symptoms, while the loss of tyrosine hydroxylase positive cells in the ventral tegmental area predicted severity of depression. The association with Lewy bodies was attenuated in those receiving antidepressant treatment. Wilson and colleagues conclude that the mesolimbic dopamine system is important in late-life depression.

Sigmon and colleagues randomised primary prescription opioid abusers to 1-, 2-, or 4-week detoxification using tapering doses of the opioid partial agonist buprenorphine followed by naltrexone maintenance treatment.¹⁸ Patients and physicians were blind to the placebo condition and speed of taper. The 4-week regimen showed significantly better outcomes than the shorter schedules, with 50% versus 20% abstinent and taking naltrexone at 3 month follow-up. Sigmon and colleagues note past research found transient better outcomes in heroin addicts with a 4 week than a one week tapering period, but note that this study was open label and did not include naltrexone maintenance.

Iltis and colleagues address the difficult problem of ethical research into psychiatric risk management.¹⁹ They illustrate the problem with the fact that the presence of suicidal ideation is a common exclusion criterion in antidepressant research. This means that evidence-based treatment of depressed patients with suicidal ideation relies upon generalisation from evidence about patients without suicidal ideation. Iltis and colleagues conclude that researchers must design ethical and methodologically sound experiments that do not ignore populations only because of the difficulties involved, including risks of poor outcomes. They suggest that risks of poor outcomes, such as suicide, be treated as negative outcomes of disease in the same way as other undesirable but expected outcomes such as post-operative infection. The alternative is that risk-aversion will continue to allow high-risk groups to be harmed because of inadequate knowledge about management of their risks. Iltis and colleagues provide practical approaches to identify, communicate, manage, and justify research risks, in order to promote greater examination of these neglected populations.

Girardin and colleagues examined the prevalence of drug-induced long QT by reviewing all ECGs of all patients at the public Psychiatric Hospital of Geneva who had ECG recordings at admission between 2004 and 2009.²⁰ Patients with long QT were compared with a sample of patients with normal ECGs. Among close to 7000 patents 27% had abnormal ECGs, 1.6% had long QT, and 0.9% qualified as drug-induced long QT. There were significantly higher frequencies of hypokalaemia, hepatitis C, HIV, and abnormal T waves in patients with drug-induced long QT. Haloperidol, clotiapine, phenothiazines, citalopram, and escitalopram, were significantly more frequent in patients with drug-induced long QT even after adjustment for other factors. The paper also notes that long QT syndrome is the most common cause of marketed drug withdrawal.

Molecular Psychiatry – January 2014

The January 2014 issue of Molecular Psychiatry includes several aspirational editorials on the promise of translational psychiatry. Editor Julio Licinio and Wong declare that the time is right for a war on mental illness, with reference to the bracing effects of US President Nixon’s signing of the National Cancer Act in 1971 despite significant obstacles.²¹ They provide a useful summary of six principles of translational science, progressing through discovery, first in human studies, clinical trials, policy and guidelines, long-term effectiveness and safety, and ending with global health. They argue that there are three main translation gaps at present, in knowledge, practice, and adherence, and suggest a conceptual framework for translational psychiatry with attention to commercialisation as well as the need to manage potential conflicts of interest.

Poels and colleagues provide a systematic review of PET, SPECT, and MRS imaging evidence on the role of glutamate in schizophrenia.²² They canvas several advances in MRS and PET technologies and conclude that the evidence supports the theory of NMDA receptor hypofunction in schizophrenia, involving interaction between dopamine and glutamate systems.

Neuropsychopharmacology – January 2014

In January Neuropsychopharmacology pioneers a new segment that integrates opposing viewpoints on controversial topics by inviting comment by two leading researchers followed by a jointly written synthesis. Wise and Koob provide the first, on the development and maintenance of drug addiction, continuing their long-standing debate on whether the positive reinforcement of drug-induced euphoria or the negative reinforcement of substance use in withdrawal is more important in maintaining addictive behaviour.²³ Wise argues that whatever the negative reinforcing properties associated with avoidance of drug withdrawal, it cannot explain the acquisition of dependence which necessarily occurs before withdrawal. He describes his research in rats, where simple exposure to strongly reinforcing substances such as amphetamines appears sufficient to induce addictive behaviour in close to 100% of subjects. No negative reinforcement is needed to acquire dependence. Koob conceputalises addiction as a three stage cycle, moving from binge/intoxication, through withdrawal/negative affect, to preoccupation/anticipation, with stages worsening over time and leading from impulsive to compulsive habitual behaviour.

Translational Psychiatry

In December Translational Psychiatry published online a trial by Bentsen and colleagues which randomised adults with schizophrenia to omega-3 fatty acids, with or without multivitamins, versus placebo, for 16 weeks.²⁴ All patients also took antipsychotics. They were surprised to report that, for patients with low red blood cell fatty acid levels at baseline, adding one but not both of fatty acids or multivitamins increased patient dropout and worsened psychotic symptoms versus placebo or both agents together. Bentsen and colleagues note that theirs is the first study to show fatty acids worsening psychotic illness and adherence, and speculate that this may be because their study initiated treatment during psychotic exacerbations, which may increase oxidative stress, or because of the relatively higher dietary fatty acids of the Norwegian patients studied. Oxidative stress due to fatty acids or multivitamins could disturb neuronal and glial function, inhibit NMDA receptors, and impair dopamine modulation, worsening psychotic symptoms.

Mainstream Medical Journals

MJA

The 16th December issue of the Medical Journal of Australia includes an editorial by Gillian Triggs, President of the Australian Human Rights Commission on the mental health effects of closed detention for immigrants in Australia.²⁵ A perspective by Procter and colleagues looks more specifically at efforts to prevent suicide and self-harm for immigrants in detention, finding that suicide is the leading cause of premature death in this population,²⁶ while Deans and colleagues report the incidence of mental illness amongst asylum seekers presenting to the Royal Darwin Hospital emergency department.²⁷ Together, these articles suggest both a high incidence of mental illness amongst asylum seekers in Australia, and suggest approaches to improve outcomes, starting with improved monitoring to identify detainees at greater risk allowing selective interventions, and including increased use of community detention and bridging visas.

JAMA

In the December 25 issue of JAMA Foa and colleagues report positive results from a randomised controlled trial of prolonged exposure therapy for female adolescent survivors of sexual abuse.²⁸ 61 girls aged 13-18 years were randomised to 14 weeks of prolonged exposure therapy or supportive counselling using a block design. Prolonged exposure involved gradually increasing contact with triggers for PTSD symptoms and detailed voluntary recall of abuse events, without delay for extensive training in arousal reduction strategies. The prolonged exposure group achieved better outcomes than controls, with 83% no longer meeting criteria for PTSD compared to 54% in controls, with gains maintained at 12 months. In line with many recent studies, interventions were delivered by inexperienced therapists. A related editorial by Perrin suggests Foa and colleagues’ results are consistent with a large body of evidence justifying the use of prolonged exposure therapy as a first-line treatment for PTSD in adults.²⁹ Perrin also argues that these results should allay clinician concerns about retraumatising abused individuals, which sometimes leads to significant delays in efficacious treatment.

Lancet

In the December 7th Lancet Vincent and colleagues³⁰ comment upon the recent meta-analysis of antipsychotics by Leucht and colleagues which used a Bayesian framework to indirectly compare antipsychotics from different trials.³¹ This meta-analysis challenged the classification of antipsychotics into first- and second-generation groups, finding best efficacy in clozapine, amisulpride, and olanzapine, and worst discontinuation in haloperidol. Vincent and colleagues speculate that the finding that the five newest antipsychotics showed the least efficacy and the least discontinuation is a product of poor adherence associated with more demanding administration regimes and less tolerable side-effects prior to reaching therapeutic doses. Leucht and colleagues reinforce this point,³² and reply to the criticism by Siu and colleagues³³ that their paper does not include a complete matrix of comparisons between antipsychotic medications with the observation that they have acknowledged the limitations of their methodology, which is as complete as is currently possible.

The December 7 Lancet also includes an ambitious statement of intent by a Commission established by the journal to revisit the global case for investment in health.³⁴ The review makes the case for dramatic health gains achievable by 2035 including broad parity between countries of different incomes, with four key messages: there is an enormous payoff from investing in health; a grand convergence in health is achievable within current lifetimes; fiscal policies are a powerful and underused lever for curbing non-communicable diseases and injuries; and progressive universalism, a pathway to universal health coverage, is an efficient way to achieve health and financial protection. This 50 page document collects evidence in support of these propositions, such as the finding that reductions in mortality accounted for 11% of recent economic growth in low- and middle-income countries; and the impact on health and revenues of taxes on tobacco and other harmful substances and reducing subsidies on fossil fuels.

NEJM

An editorial by Doran and colleagues in the December 19 NEJM describes an attempt by New York state to improve population health outcomes by targetting stable accommodation for vulnerable people.³⁵ The authors note that the United States ranks first in health care spending but 25th in spending on social services, and speculate that inadequate social spending causes increased health spending, with the 1.5 million Americans who experience homelessness in any given year over-represented amongst the highest users of expensive hospital care. The intervention provides supportive housing for high-risk homeless patients in shelters and those in nursing homes for the lack of alternative accommodation, based on evidence that costs of supportive housing are offset by reduced service costs. The authors argue that the implementation of the Affordable Care Act will bring most of the United States’ homeless into the Medicaid system, which provides the opportunity to realise both cost reductions and improved health by addressing the social determinants of health.

The 26 December issue of the NEJM includes a case from the Massachusetts General Hospital on a 36 year old man presenting with agitation and paranoia shortly after ingesting bath salts.³⁶ The case report includes input from specialists in emergency medicine, psychiatry, and pathology. Along with a detailed explanation of the pathology techniques used to investigate possible toxins, the case illustrates the difficulties of accurate diagnosis and timely management of patients who present with unclear histories including novel substances which may not be detected by existing tests. The article outlines the chemical properties of bath salts, which are synthetic derivatives of cathinone, a sympathomimetic chemical found in the khat plant, itself a recreational substance used mainly in the middle east and Africa.

Focus section – Substance Induced Psychosis

This month Australian Psychiatry Review examines illicit substance induced psychosis research. Despite recent interest in this area the empirical base remains slight. Most of the research focuses on cannabis and amphetamines, because of the prevalence of cannabis use in the general population, the rapid psychotogenic potential of amphetamines, and the use of amphetamines in animal models of psychosis. The review concentrates on how illicit substance use affects the onset, course, and treatment of psychosis.

The main points to be derived from the current literature include:

• There is a high rate of substance abuse in people presenting with psychotic symptoms
• There is a high rate of transition to frank psychotic diagnoses amongst people presenting with substance induced psychoses
• Substances do not cause stable schizophreniform syndromes in the absence of other predisposing factors
• Substance abuse is associated with reduced age of onset of psychosis, non-adherence to treatment, and poor clinical and functional outcomes
• The phenomenology of acute substance-induced psychotic episodes does not reliably distinguish them from primary psychotic episodes
• There is almost no empirical basis guiding treatment of substance-induced psychosis
• Reduction of illicit substance use in patients presenting with psychosis can improve function, though this is not mediated by improved psychiatric symptoms

Outline

This review will

• outline common classes of illicit substances linked with psychosis
• review basic epidemiology
• chart the natural history of amphetamine and cannabis induced psychosis
• outline attempts to differentiate substance-induced and primary psychotic illness
• discuss evidence regarding the causal role of cannabis and amphetamines in transition to psychosis
• and examine treatment and prognostic research

To keep the podcast to a reasonable length sections on drug models of psychosis, psychosocial treatments of drug-induced psychosis, and approaches to comorbid psychosis and substance abuse have been postponed.

Classes

Murray and colleagues identify the main illicit substances associated with psychosis, including lysergic acid diethylamide (or LSD), amphetamines, ketamine, and cannabis.³⁷ Intoxication with LSD induces incapacitating hallucinations, primarily in the visual system, associated mainly with dysregulation of the serotonergic system. Amphetamines produce a reasonable approximation of acute paranoid psychosis in previously non-psychotic people, and exacerbate psychotic symptoms in ⅓ of patients with schizophrenia, associated with increased dopamine activity. The glutamate antagonists ketamine and phencyclidine induce psychotic episodes with delusions, hallucinations, and negative symptoms including impaired attention. Cannabis intoxication can be associated with psychotic episodes characterised by delusions, perceptual disturbances, disorganised thought, depersonalisation, temporal distortion, blunted affect, reduced rapport, psychomotor retardation, and emotional withdrawal, associated with activation of the endocannabinoid system.³⁸

Epidemiology

First, we will consider the basic epidemiology of illicit substance induced psychosis.

The high and increasing prevalence of substance abuse in patients with psychotic illness is demonstrated by the Survey of High Impact Psychosis (or SHIP) conducted in 2010.^39,40 The SHIP was the second national survey of psychosis in Australia, using methodology broadly similar to the first in 1998. SHIP showed that the lifetime prevalence of alcohol use disorders in patients with ICD-10 psychotic diagnoses increased from 29% in 1998 to 50% in 2010, and that the lifetime prevalence of drug use disorders increased from 30% to 56%. These high rates have been repeated in a large US-based genomic study.⁴¹

Lifetime prevalence of cannabis use in western samples at the end of secondary school has been reported to be as high as 50%, with one study finding more than 15% of senior high school students claiming to have used cannabis daily for at least a month.⁴²

A Finnish registry study on 18,000 people with substance-induced psychosis found that 85% were alcohol-induced, 4.5% were amphetamine induced, and 0.7% were cannabis-induced.⁴³

Natural history of substance induced psychoses

Now we will examine the natural history of amphetamine and cannabis-induced psychosis.

Acute methamphetamine use produces euphoria, and tolerance develops with prolonged use, leading to a binge pattern of use.⁴⁴ Initial methamphetamine intoxication is not frequently associated with psychosis, but increasing use motivated by tolerance can lead to toxicity, marked by persecutory delusions, auditory and visual hallucinations, and hypervigilance. Psychotic symptoms triggered by chronic amphetamine abuse may last for months to years after sobriety, with delusions and hallucinations quickly resolving but behavioural disturbance such as aggression more persistent. Japanese studies have shown that psychotic symptoms arise in up to 80% of active amphetamine users, on average after five years of use. Psychotic symptoms resolve within 10 days of admission and treatment in 58% of patients, within one month in 31%, and persist longer than one month in 11%. Risk factors for the development of amphetamine psychosis include neurologic disorders during childhood and genetic loading for psychotic illness.

Power and colleagues used the Survey of High Impact Psychosis to tell whether age at initiation of cannabis use or amphetamine use predicted age at onset of psychosis.⁴⁵ Their model suggested a trend towards a direct relationship of mean 7-8 years between age at onset of cannabis use and age at onset of psychosis,⁴⁶ and of mean 5.3 years between age at onset of amphetamine use and age at onset of psychosis.⁴⁵ Further modeling suggested that the amphetamine relationship was spurious, caused by the fact that almost 100% of amphetamine users had also used cannabis, with cannbis use starting 2-3 years earlier than amphetamine use. Elsewhere the same authors have suggested that the addition of each additional illicit substance reduces the age at onset of psychosis by one year.⁴⁷

While the literature often speaks of age of onset of psychosis, it is important to realise that the onset of psychosis with amphetamine is more likely to be associated with transient psychotic experiences which vary with the amphetamine dose, while cannabis is more often linked with transition to stable psychotic illness. McKetin and colleagues explored dose-related psychotic symptoms in chronic methamphetamine users in a prospective, longitudinal study.⁴⁸ They measured level of substance use and psychotic symptoms in 278 methamphetamine dependent patients without schizophrenia or history of mania over a 3 year period. McKetin and colleagues found a large dose-dependent increase in prevalence of psychotic symptoms during periods of methamphetamine use, from 7% at drug-free baseline to 48% during periods of heavy use. Prevalence was increased further with comorbid cannabis or alcohol use, up to 69%.

Differentiating substance induced psychosis and primary psychosis

Now we will consider efforts to differentiate substance-induced and primary psychosis.

Goerke and colleagues propose that DSM and ICD characterisations of substance induced psychosis and primary psychotic disorders are too simple to differentiate substance induced psychosis from a primary psychotic disorder with co-occurring substance use.⁴⁹ They report that there are instruments, such as the Psychiatric Research Interview for DSM-IV Substance and Mental Disorders (or PRISM-IV), which can reliably make this differentiation at initial presentation. However, up to 50% of patients diagnosed with substance induced psychosis at presentation transition to a primary psychotic disorder over the next few years.^43,50 Goerke and colleagues explain that the phenomenological similarity of substance-induced and primary psychosis means people presenting in the ultra-high risk phase of a developing psychotic illness will meet criteria for substance-induced psychosis, and that their diagnosis will change when the primary illness manifests. The high rate of conversion to frank psychotic illness may eliminate the usefulness of differentiating between substance-induced and primary psychotic diagnoses, leading Goerke and colleagues to recommend use of a spectrum of risk for psychotic illness in formulating an effective treatment plan, for those presenting with a substance induced psychosis.

Bramness and colleagues explore whether amphetamine induced psychosis is a separate diagnostic entity from primary psychosis, or whether it triggers primary psychosis in people predisposed to psychosis.⁵¹ They note that acute substance induced psychosis is associated with more rapid recovery that is more complete than schizophrenic controls, and that there is an increased vulnerability for acute amphetamine psychosis in people with a primary psychotic disorder. They identify genes which increase the probability of both amphetamine induced psychosis and schizophrenia, which probably lower the threshold for psychosis and increase the probability of a poorer clinical course of the disease.

Ross and Peselow provide a summary of what is known of the neurobiology underlying substance induced and primary psychosis, and use this to justify an approach to accurate diagnosis of patients presenting with psychosis and substance use.⁵² Essentially they advocate collecting detailed information regarding the pattern, intensity, and diversity of substance use, alongside the pattern and history of psychiatric symptoms, with attention to risk factors for psychotic illness and substance abuse. Temporal relationships between substance use and symptoms are important though they may not be definitive. They discuss screening, physical examination, and investigations, and incorporate these in an approach to formulation that considers the possibility of co-occurring, aetiologic, and hybrid models linking substance use and psychosis. Conceptually, associations between substance use and psychosis can arise because substance use influences psychosis, because psychosis influences substance use, or because a third factor influences both psychosis and substance use. An example of the latter would be a genetic variant which increases both the reinforcing effects of substance abuse and the probability of psychosis could lead to an non-causal association between substance use and psychosis.

Transition to psychosis

We will now turn to evidence on the rate and mechanisms of transition to primary psychotic disorder in people with a history of substance induced psychosis.

Longitudinal studies have shown high rates of transition to psychosis amongst people with substance abuse in the absence of psychosis at baseline assessment. van Os and colleagues reported a three year follow-up of 4000 psychosis free people and 60 people with psychosis in the Netherlands.⁵³ Baseline cannabis use was the best predictor of later psychosis in psychosis-free people as well as the severity of psychosis in currently psychotic people.

Rates of transition to psychosis have been best characterised in cannabis users. Goerke and colleagues review evidence that, despite high rates of psychotic symptoms among cannabis users, only a minority develop primary psychotic disorders.⁴⁹ They conclude that cannabis use alone is not sufficient to cause permanent psychotic illness, but is an additive risk factor in those with predisposing risks such as genetic vulnerability. Cannabis use may worsen the severity of psychotic disorders in those who do transition, increasing brain atrophy, and decreasing the age of onset at the first episode of psychosis.

Niemi-Pynttari and colleagues followed all 18,000 patients with a diagnosis of substance induced psychosis using the Finnish Hospital Discharge Register from first admission between 1987 and 2003.⁴³ They found an eight year cumulative risk of transition to a schizophrenia spectrum diagnosis of 46% for cannabis-induced psychosis, and 30% for amphetamine-induced psychosis. While alcohol-induced psychosis was the most common cause of acute substance-induced psychosis, only 5% made the transition to the schizophrenia spectrum over 8 years. The majority of transitions occurred during the first 3 years after the index treatment, especially for cannabis-induced psychosis.

Theories of the mechanisms linking cannabis and psychosis tend to focus on the importance of neurodevelopment in the adolescent and young adult years, when cannabis use is most prevalent, and the prefrontal cortex completes its long developmental trajectory. Bossong and colleagues suggest that adolescent exposure to THC disturbs physiological control of glutamate and GABA release, interrupting experience-dependent maturation of neural circuits involving the prefrontal cortex, and increasing the probability of psychotic illness by overpruning of the neuropil.⁵⁴

Multiple reviews of the relationship between cannabis abuse and psychosis have found that heavy cannabis use at an early age, in association with a genetic loading for psychotic illness, and exposure to environmental stressors including childhood trauma, increase the risk of psychotic outcome in later life.^55,56 Cannabis appears to increase the risk of psychosis in people with genetic or environmental vulnerabilities, though by itself it is neither a necessary nor a sufficient cause of psychosis. Parakh and Basu describe evidence against the hypothesis that predisposition to psychotic illness increases the probability of cannabis use, primarily longitudinal studies which excluded patients with psychosis at baseline but still found increased risk of psychosis in cannabis users, as well as a study which reported that age at initiation of cannabis use predicts the age at onset of psychosis, with cannabis initiation predating psychosis by 7 years.⁵⁵

Proal and colleagues studied whether familial risk for schizophrenia mediates the association between adolescent cannabis use and schizophrenia.⁵⁷ They recruited 279 people from four groups: non-psychotic groups with no drug use, non-psychotic controls with cannabis use, schizophrenia spectrum patients with no drug use, and schizophrenia spectrum patients with adolescent cannabis use in the absence of other substance use. They found an increased prevalence of schizophrenia in relatives of both cannabis-using and non-using patients with psychosis, indicating that an increased familial risk for schizophrenia may be the underlying basis for schizophrenia in cannabis users and not cannabis use per se.

Auther and colleagues compared 101 patients at high risk of psychotic illness to healthy controls on rates of substance abuse, including cannabis.⁵⁸ High risk patients had a significantly higher lifetime rate of cannabis use than healthy controls. Logistic regression analyses suggested that conversion to psychosis in high-risk patients was not related to lifetime cannabis use or the presence of attenuated positive psychotic symptoms at baseline. They discuss two previous studies which also found cannabis use did not predict psychosis, and one study which found that cannabis did predict psychosis, attributing the differences to methodological differences.

Impact on established psychotic illness

Now we will briefly consider the impact of cannabis on established psychotic disorder.

Acknowledging evidence that cannabis is a potent predictor of the earlier onset of psychosis Barrowclough and colleagues explored whether cannabis is associated with outcomes in established psychotic illness.⁵⁹ 160 patients with psychotic illness and cannabis use were compared with 167 patients who use other substances, with repeated measures at baseline, 12 months, and 24 months. Cannabis users did not differ from other substance users on measures of positive symptoms, cannabis dose was not associated with subsequent severity of positive symptoms, and change in cannabis dose did not predict change in positive symptom severity, even with abstinence. However, greater cannabis use was associated with worse function. The authors acknowledge four previous studies which did find associations between cannabis exposure and positive symptoms, which they attribute to differences in methodology and study populations, noting that their own study includes four times as many subjects as the largest of the older research. Nevertheless, they conclude that not all patients with nonaffective psychosis will show improved psychiatric symptoms with reduced cannabis use.

Treatment considerations

Finally, we will consider the treatment and prognostic implications of substance-induced psychosis. A common theme throughout this literature is the paucity of treatment evidence, often ascribed to the practice of excluding patients with comorbid substance abuse from antipsychotic trials.

In an overview of substance-induced psychosis, noting the lack of empirical guidance, Goerke and colleagues emphasise the importance of engaging families in the treatment of patients with psychotic illness of whatever cause, and recommend equal attention to the reduction of substance use and control of psychiatric symptoms.⁴⁹ Given the uncertainties of diagnosis, engagement, and treatment, they also recommend frequent contact in the early stages of illness, consistent with the early intervention paradigm.⁶⁰

Substance use is a strong predictor of disengagement from treatment and therefore has been recommended as a treatment target,⁴⁹ although there is limited evidence that interventions change engagement or outcomes.

A Cochrane review of treatment for amphetamine-induced psychosis in 2009 found only one RCT comparing 58 patients with amphetamine psychosis with olanzapine versus haloperidol treatment.⁶¹ Both showed significant improvements, with olanzapine showing significantly fewer extrapyramidal side effects.

In their prospective longitudinal study of dose-related psychotic symptoms in chronic methamphetamine users, McKetin and colleagues state that there is insufficient evidence to make clinical recommendations regarding treatment of methamphetamine psychosis, and identify the need for protocols for the emergency psychiatric management of these patients.⁴⁸ They note that most patients’ psychotic symptoms abate during periods of abstinence, though a small minority experience chronic psychosis. McKetin and colleagues were unable to conclude that amphetamine dependence causes psychotic illness.

Farnia and colleagues report a RCT of 45 patients with amphetamine induced psychotic symptoms randomised to aripiprazole 15mg daily or risperidone 4mg daily for 6 weeks.⁶² Both groups saw clinically meaningful reductions on the Scale for Assessment of Negative Symptoms and Scale for Assessment of Positive Symptoms, with risperidone more effective for positive symptoms and aripiprazole more effective for negative symptoms.

Weibell and colleagues compared Norwegian patients with substance induced psychosis to those with primary psychotic disorders with and without substance misuse, finding that those with primary psychotic illness were more often treated, and those with substance misuse were more likely to be male.⁶³ DUP was shorter in the substance-induced group, and this group had more positive symptoms on the PANSS.

Vallee and colleagues propose a novel protective therapy for cannabis intoxication from the observation that tetrahydrocannabinol, the main active agent of cannabis, substantially increases the synthesis of pregnenolone via the type 1 cannabinoid receptor (CB1).⁶⁴ Using pregnenolone as a specific inhibitor of the CB1 receptor in a feedback loop Vallee and colleagues showed that they could reduce behavioural analogs of THC intoxication in mice models.

Recent reviews of the dual diagnosis literature conclude that efficacious treatments for reducing psychiatric symptoms also work in patients with comorbid substance and psychiatric symptoms; treatments that reduce substance use also work in patients with comorbid substance and psychiatric symptoms; and the efficacy of integrated treatment that attempts to address both psychiatric symptoms and substance disorders is unclear.^65,66

Prognosis

Research on the prognosis of patients with psychosis and substance use disorders is as limited and contradictory as the rest of the field.

The combination of substance use and psychotic illness has consistently been linked with worse outcomes than psychotic illness alone, though consistent patterns are difficult to find in the literature. Reviews indicate that these patients experience worse developmental outcomes, particularly incomplete education, unemployment, depression, criminal behaviour, homelessness, re-hospitalisation, violence, and suicidal behaviour.^67,68

A recent systematic review compared patients with psychotic illness who have stopped using substances, with those who have never used substances.⁶⁹ There were no significant differences on positive or negative symptoms, depression, or global function. The same authors also compared outcomes of patients with psychotic disorders and a history of but no current substance use, to patients with psychotic disorders and ongoing substance abuse. There was evidence of improved positive symptoms, mood symptoms, and function in patients with first episode psychosis who stopped substance use, but no evidence of improvement in patients with more established psychotic illness.⁷⁰

Koola and colleagues examined the effect of substance use on mortality over 4-10 years in 762 people with psychotic disorders using public records in Maryland.⁷¹ Mortality was higher in males, but lower in cannabis users. Alcohol use was not predictive of mortality. Koola and colleagues speculate about potential protective effects of anti-inflammatory properties of the endocannabinoid system.

A systematic review by Alvarez-Jiminez and colleagues reported that while clinical and demographic variables have little effect on relapse rates after a first-episode of psychosis, persistent substance abuse disorder was ranked close to medication non-adherence as a factor increasing the probability of relapse.⁷²

Summary of Focus Section on Substance-Induced Psychosis

In summary, the literature regarding substance-induced psychosis is far from definitive. Current results suggest that there is a high rate of substance use in patients presenting with psychotic symptoms, that there is a high transition to stable psychotic disorders in these patients, and that the outcomes with comorbid substance abuse and psychosis are worse than either condition alone across clinical, social, and functional domains. Early cannabis use, and possibly polysubstance abuse, is associated with earlier age at onset of psychosis, though neither cannabis nor other substances appear to be a sufficient cause of psychotic illness in the absence of other predisposing factors. Reducing substance use appears to improve function, though probably not by improving psychiatric symptoms. Finally, treatments that work for psychosis or substance use alone appear to work for combined presentations.

Conclusion

And that’s it for the January edition of Australian Psychiatry Review. Listeners directed to the podcast from the Royal Australian and New Zealand College of Psychiatry’s CPD Online page can access questions for CPD points using the password “substance”. See you next month!

 

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72. Alvarez-Jimenez M, Priede a, Hetrick SE, et al. Risk factors for relapse following treatment for first episode psychosis: a systematic review and meta-analysis of longitudinal studies. Schizophrenia research. 2012;139(1-3):116–28. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22658527. Accessed January 1, 2014.

December 2013 Transcript

Tags

Australian Psychiatry Review

Highlights

Hello, I’m Andrew Amos, and this is the December 2013 issue of Australian Psychiatry Review. This month concludes with a focus section on early intervention in psychosis. Other highlights of the psychiatric literature this month include a collection of articles on the role of inflammation and autoimmune antibodies in psychiatric illness in the ANZJP; a review of cognitive processes underlying delusions in the British Journal of Psychiatry; a study showing that group cognitive behavioural therapy can prevent later development of depression in currently non-depressed children of parents with depression in JAMA Psychiatry; and 6 articles on UK patterns of sexual behaviour and health in the Lancet. Finally, the Journal of Clinical Psychiatry has a useful clinical practice article summarising evidence on the risks and benefits of switching antipsychotics in patients who are clinically stable but experiencing side effects. Links to all articles discussed in the podcast can be found in the podcast transcript.

Australian Psychiatric Journals

ANZJP

In December the ANZJP includes a number of articles on the role of inflammatory processes in psychiatric disease. A viewpoint by Thachil and colleagues builds on growing evidence of autoimmune aetiologies of neuropsychiatric syndromes to suggest the need for a paradigm shift in psychiatric practice.¹ Since the role of autoimmune antibodies in limbic encephalitis was first described in 2007, there has been increasing detection of antibodies which target neurotransmitter receptors in the brains of people presenting with neurological and psychiatric diseases. Thachil and colleagues argue that the overlap of presentation and care of these patients between psychiatry, neurology, and general medicine, is an opportunity to reverse the retreat of psychiatry into an institutional silo and promote its reintegration into the mainstream of clinical medicine.

Rege and Hodgkinson review the literature on immune dysregulation and autoimmunity in bipolar disorder.² They suggest that autoimmunity may have a role in bipolar disorder mediated by interactions between immune cells which damage neurons through excitotoxicity, oxidative stress, and mitochondrial dysfunction, and discuss the differential diagnosis of autoimmune encephalopathy and other neuropsychiatric syndromes such as systemic lupus erythematosus.

A commentary by Prosser and Reid revisits the ongoing controversy regarding the appropriate diagnosis of ADHD in child and adult populations.³ They note changes to the definition of ADHD in DSM-5 which substantially lower the threshold for diagnosis, including increasing the age by which symptoms must have started from 7 to 12 years, reducing the number of symptoms required for adult ADHD from 6 to 5, and removing the autism exclusion. Prosser and Reid state that these changes have not been justified by clinical research. For example, while there is no evidence to differentiate between a requirement that onset of symptoms occurs before 7 years versus 12 years, Prosser and Reid suggest that the lower age was previously preferred because it removed the confounding variables of puberty and transition to secondary school.

An editorial by Kennedy returns to the recent debate on SSRI use in pregnancy, examining how empirical results can be applied to specific patients by considering individual clinical contexts.⁴ She demonstrates the problem of blind application of decision rules by reference to the recent meta-analysis by Myles and colleagues which recommended avoiding fluoxetine and paroxetine in the first trimester of pregnancy due to small increases in birth defects.⁵ Kennedy proposes that individual circumstances must be considered, such as whether a pregnancy is planned, whether an antidepressant is being continued or initiated, and the competing risks to mother and baby of adverse effects of medication and untreated mood disorder. Kennedy suggests that the ethical concerns which prevent drug companies from participating in randomised controlled trials of SSRIs in pregnancy has led to reliance on less rigorous designs, increasing the possibility of systematic bias. Kennedy argues that odds ratios for teratogenicity in pregnancy arising from fluoxetine and paroxetine of 1.14 and 1.29 should not outweigh personal experience of antidepressant efficacy in most circumstances.

International Psychiatric Journals

AJP – November 2013

An editorial by Attia and colleagues in the November issue of the American Journal of Psychiatry considers changes to feeding and eating disorders in the DSM-5.⁶ They attribute the changes to concerns about the large minority of patients with eating disorders being diagnosed with the residual diagnosis of eating disorder not otherwise specified, and the elimination of the chapter describing disorders usually first diagnosed in infancy, childhood, or adolescence. The main new diagnosis is binge-eating disorder, excluded from the DSM-IV for its inadequate empirical basis which has now been corrected. Feeding disorder of infancy or early childhood has been renamed avoidant/restrictive food intake disorder, with expanded criteria expected to capture a larger group of patients. The diagnosis of anorexia nervosa has been modified by the removal of the requirement of amenorrhoea, provision of guidance on judging low weight. Persistent behaviour interfering with weight gain was added to criterion B of anorexia nervosa because many patients do not meet the current criterion of expressed fear of weight gain. Bulimia nervosa has reduced minimum average frequency of binge eating and inappropriate compensatory behaviour from twice to once weekly, and the purging/non-purging subtypes have been eliminated.

The November issue includes multiple articles from the Bipolar-Schizophrenia Network on Intermediate Phenotypes, or B-SNIP study. Intermediate phenotypes are analogous to endophenotypes, which are markers, such as the presence of a symptom, related to a genetic variant which mediates the manifestation of a diagnosis or disease. This idea has been pursued in psychiatric genetics since it became apparent that no single or small group of genes directly causes the majority of mental illness. It is hoped that it will be more feasible to link individual genetic variants to endophenotypes, explaining individual mechanisms which contribute to disease processes within or across pathological states, than it was to link individual genes to the presence or absence of specifc diseases.

Hill and colleagues report their findings on neuropsychological impairment from the B-SNIP study.⁷ Following recent evidence that cognitive deficits are a stable and enduring feature of bipolar disorder, Hill and colleagues’ paper treats cognitive impairment as a potential endophenotype across schizophrenia and psychotic bipolar disorder. They found that cognitive impairments increased from bipolar disorder, to schizoaffective disorder, to schizophrenia. In addition, nonpsychotic relatives of patients with schizophrenia showed significant cognitive deficits, while relatives of bipolar patients did not. Hill and colleagues conclude that cognitive dysfunction is associated with psychosis across bipolar disorder, schizoaffective disorder, schizophrenia, and the relatives of patients.

An editorial by Kern and colleagues summarises fMRI studies in people at risk of psychotic illness,⁸ to provide the context for Yaakub and colleagues,⁹ who compared fMRIs of people at risk to healthy controls during a verbal working memory test. While there were no differences between groups on speed or accuracy, at risk subjects showed less activation of left anterior insula and increased right dorsolateral prefrontal cortex. The authors speculate that, consistent with models of executive function in the dorsolateral prefrontal cortex, the at-risk patients might be compensating for impaired processing of salience in the insula by increased engagement of executive functions. Kern and colleagues acknowledge that these are interesting findings, but place these results in the context of 17 other fMRI studies in at-risk samples showing mixed patterns of hyper- and hypoactivation in multiple regions with limited cohesion. They suggest that much stronger convergence of findings is required before at-risk fMRI studies can guide clinical practice.

BJP – November 2013

The November issue of the British Journal of Psychiatry includes a review of delusions research by Garety and Freeman.¹⁰ They lament the absence of recent advances in treatments for schizophrenia, and reflect on evidence that a significant minority of the population experience subclinical psychotic symptoms without ever developing full blown psychotic illness. Along with consistent evidence that the symptoms of schizophrenia tend to arise together in distinct positive, negative, and disorganised clusters, these factors suggest that more effective treatments might arise from targeting specific symptoms or syndromes, rather than simply prescribing arbitrary antipsychotics for the single indication of schizophrenia. Garety and Freeman review empirical support for the hypothesis that disturbances in reasoning and affective processes contribute to delusions. They find evidence that a tendency to use less information to reach decisions contributes to delusion formation and persistence, but conclude that the “theory of mind” hypothesis has not been substantiated as a factor in delusions. Research into affective processes underlying delusions remains suggestive rather than conclusive. Garety and Freeman discuss the theory that individuals with low self-esteem unconsciously use paranoia as a defence mechanism, explaining negative events as the result of the hostility of others to avoid conscious awareness of negative thoughts about the self. To investigate this theory, researchers have examined discrepancies between implicit and explicit self-esteem of paranoid patients, and whether external attributions are made for negative events. Garety and Freeman also discuss a more direct model in which anxiety stimulates the threat theme of persecutory delusions, ongoing rumination elaborates and maintains the delusional content, and avoidance leads to the exclusion of evidence inconsistent with the delusional belief. They draw attention to the failure to pursue older cognitive models of delusions, including the idea that delusions are the result of attempts to explain perceptual disturbances.

Coid and colleagues review how effectively three measures of clinical risk of violence, the Historical-Clinical-Risk Management 20, the Violence Risk Assessment Guide, and Offenders Group Reconviction Scale-II, could predict future violence.¹¹ They conclude that while the instruments achieved moderate to good accuracy for released prisoners with no mental disorders, accuracy was no better than chance for psychopaths.

JAMA Psychiatry – November 2013

In the November issue of JAMA Psychiatry, Carrion and colleagues report a model that attempts to predict functional and social outcomes of people at high risk of psychotic illness from baseline clinical and neurocognitive assessment.¹² While reduced processing speed and disorganisation predicted poor social outcomes, verbal memory deficits and motor disturbances predicted poor role outcomes. Social outcomes were assessed on peer relationships, peer conflict, intimate relationships, and interactions with family members, while role outcomes were assessed on performance and support needed in specific roles such as school and work. People who converted to psychotic illness were more likely to have poor social outcomes, but not more likely to have poor role outcomes.

Simpson and colleagues randomised 100 patients with moderately severe OCD symptoms, despite 12 weeks of SSRI treatment, to augmentation with risperidone, CBT, or placebo.¹³ CBT augmentation significantly improved response on the Yale-Brown Obsessive Compulsive Scale at 8 weeks compared to risperidone, which was no different to placebo. More patients in the CBT group responded, and more CBT patients achieved minimal symptoms, than the other groups. Simpson and colleagues conclude that CBT should be offered before antipsychotics to patients with OCD who continue to experience moderate symptoms. They note that their risperidone protocol started at a lower dose and escalated more slowly than previous trials to minimise adverse effects.

To test the relative efficacy of cognitive therapy (CT) and fluoxetine continuation therapy after a primary course of CT in depressed patients, Jarrett and colleagues randomised 241 adults with MDD to 8 months of CT, fluoxetine, or placebo, with an additional 24 months of post-treatment follow-up.¹⁴ Both CT and fluoxetine were significantly less likely to relapse than the placebo controlled patients, but there were no clinical differences between CT and fluoxetine.

Beardslee and colleagues established a randomised controlled trial to test whether prophylactic group cognitive behavioural prevention (CBP) with adolescent children of depressed parents could prevent future onset of depressive episodes.¹⁵ 316 children of parents with current or past depression were randomised to 8 weekly group sessions followed by 6 monthly continuation sessions or to usual care, then followed for up to three years. 1 in 3 adolescents experienced a probable depression over the three year followup. The CBP group had significantly fewer depressive episodes with 37% versus 48% in controls. There was a significant interaction between treatment effect and parental depression at baseline, with significantly better outcomes for adolescents whose parents were not depressed at baseline, and no better outcomes when parents were depressed. The authors speculate that parental depression at baseline may be a proxy for worse genetic vulnerability, disrupted parenting, or more exposure to stressors.

Molecular Psychiatry – December 2013

In the December issue of Molecular Psychiatry Zunszain and colleagues review research on the molecular mechanisms behind the rapid antidepressant effect of the NMDA antagonist ketamine.¹⁶ They provide a useful summary of evidence for the therapeutic effects of ketamine associated synaptogenesis and immunomodulation, and contrast these with the less well established theory of glycogen synthase kinase-3 activity. Zunszain and colleagues describe how ketamine stimulates synaptogenesis via increased actions of BDNF and mTOR. They note ketamine directly and indirectly suppresses immune functions mediated by TNF-α and other cytokines.  While clinical use of ketamine is limited by its psychotomimetic and addictive properties, Zunszain and colleagues look forward to the development of related agents with fewer adverse effects; they also speculate on preliminary evidence that NMDA antagonism may have a specific anti-suicide indication which is particularly important given the rapid onset of efficacy.

Biological Psychiatry – 1 December, 15 December 2013

Nil selected

Neuropsychopharmacology – December 2013

Also exploring the mechanisms behind the rapid antidepressant effects of ketamine, in the December issue of Neuropsychopharmacology Yamamoto and colleagues investigate the effects of subanaesthetic doses of ketamine on serotonergic systems in monkey brains.¹⁷ Using microdialysis analysis and PET measurement of serotonin transporter activity in the brains of 5 monkeys they found that ketamine infusion transiently increased serotonin in the extracellular fluid of prefrontal cortex, associated with inhibited serotonin transporter activity. While transient serotonin increase is unlikely to be the sole cause of rapid antidepressant action with ketamine infusion, Yamamoto and colleagues speculate on the possible mutually reinforcing effects of serotonin transporter and NMDA receptor inhibition.

Beckley and Woodward provide a review of the science and clinical practice of volatile solvent abuse, focusing on cortico-mesolimbic circuitry.¹⁸ Volatile solvents are generally found in fuels, paints, and thinners, and are inhaled to achieve intoxication. Beckley and Woodward discuss the global epidemiology of solvent abuse and consider basic pharmacology and effects reinforcing abuse. They use toluene, the most commonly studied solvent, to show how solvents alter the mesolimbic dopamine system and the medial prefrontal cortex, with sequelae including dependence, withdrawal, and cognitive impairment.

Schizophrenia Bulletin – No December issue

Journal of Clinical Psychiatry – November 2013

The November issue of the Journal of Clinical Psychiatry includes an Academic Highlights article by Newcomer and colleagues arising from a series of teleconferences.¹⁹ The article provides a concise summary of evidence and expert consensus on when it is appropriate to change antipsychotic medications to reduce adverse effects, particularly cardiovascular risk factors. The reviewed evidence suggests elective switch from antipsychotics with high to low metabolic risk can improve weight and lipid profiles without high risk of clinical deterioration. Newcomer and colleagues also find that psychotropic switch is justified with significant EPS or hyperprolactinaemia.

International Medical Journals

JAMA 13/11/13; 20/11/13; 27/11/13

The November 6 issue of JAMA includes an article by Kravitz and colleagues which investigated attempts to correct the under-treatment of depression in primary care practices by randomising 600 patients with depression and 300 patients without depression to view a depression engagement video, complete an interactive multimedia computer program, or TAU.²⁰ The authors attempted to tailor the videos by targeting patients of particular gender and income, and the computer program was specifically designed to target characteristics, interests, and problems specific to each patient. Kravitz and colleagues found that the computer program increased the prescription of antidepressant medications and mental health referrals by primary care physicians, but neither intervention changed clinical outcomes at 12 week follow-up.

Lancet 9/11/13; 16/11/13; 23/11/13; 30/11/13

The November 9 issue of the Lancet includes articles on the global burden of drug use and mental disorders by Harvey Whiteford,²¹ Louisa Degenhardt,²² and colleagues. They report that in 2010, mental and substance use disorers accounted for 7.4% of disability adjusted life years and 22.9% of years lived with disability worldwide, as well as 0.5% of years of life lost. Years of life lost due to mental and substance use disorders may have been underestimated by coding cause of death as entirely due to physical conditions even in the context of a contributory mental illness.

A related editorial by Slim notes evidence from New Zealand that 5.4% of all deaths of people younger than 80 years were associated with alcohol use, particularly due to unintentional injury and cancer.²³ The author discusses partially implemented public health policies to address this problem, including stricter alcohol licensing, trading hours, and restrictions on beverages that target youth. Slim notes community concern that trade negotiations might reduce New Zealand’s autonomy to restrict access to particular beverages or to require mandatory warning labels.

The 30 November issue of the Lancet includes 6 articles on sexual health issues, generated by the third National Survey of Sexual Attitudes and Lifestyles in Britain, detailing prevalence of sexual practices, non-volitional sex, and relationships between sexual lifestyles and health. The authors variously emphasise the importance of changes in sexual practice, more pronounced for women than men, and particularly the extension of sexual activity into later years (Mercer et al)²⁴, as well as the heterogeneous distribution of sexually transmitted illnesses, including groups of people with STIs not accessing treatment (Sonnenberg et al).²⁵ Wellings and colleagues point out that the changing patterns of earlier ages of first intercourse and cohabitation, with later ages of childbearing and regular sexual activity has increased the period during which women seek to avert unplanned pregnancies to 30 years or more, with complex effects on physical, mental, and social wellbeing.²⁶

NEJM 7/11/13; 14/11/13; 21/11/13

An article by Gallagher and colleagues in the New England Journal of Medicine expansively discusses an ethical approach to talking with patients about errors made by other clinicians.²⁷ They’re firm about the ethical obligation to do so, but flexible in the techniques used to gather information, reduce the possibility of misunderstanding, and manage the risks of unnecessary litigation.

Volkow and Swanson provide an overview of the diagnosis, treatment, and neurobiology of adult ADHD, noting that it is a controversial topic, but also that there is compelling evidence of deficits and at least short-term benefits from appropriate medications.²⁸ The authors canvas the limitations of evidence regarding adult ADHD, particularly a lack of evidence about outcomes longer than 6 months, medication efficacy and side effects in older patients, and the use of prescription stimulants in people without ADHD both by diversion and by off-label prescription to enhance performance.

Early Intervention In Psychosis

This month Australian Psychiatry Review’s focus section looks at early intervention in psychosis research. The growing mainstream acceptance of principles of early intervention in psychosis (EIP) is illustrated by the recent declaration by Jeffrey Lieberman, current president of the American Psychiatric Association, that the early detection and treatment of psychotic illness should be the major goals underlying modern models of psychiatric care, because of the possibility of interrupting the trajectory of developmental deterioration in psychotic illness.²⁹ Current models of the EIP movement have been particularly active since the early 2000s, with prominent research centres in Australia,³⁰ North America,³¹ and Europe.^32-34

In its most basic form, EIP proposes that the earlier current or potential future psychotic illness can be identified and effective treatment implemented, the better clinical, social, and functional outcomes will be. One of the main sources of evidence supporting this view was work by Waddington³⁵ and others which showed that the longer patients with schizophrenia had experienced psychotic symptoms before entering treatment, the worse their outcomes tended to be. Initially, the preferred interpretation of this evidence was that the experience of being psychotic was itself a cause of worse pathology, including the speculation that the process of being psychotic might be toxic.³⁶ An alternative theory was that severe forms of schizophrenia might be more characterised by negative symptoms and therefore less likely to be detected early than those with acute onset of delusions and hallucinations.³⁷ This would mean that more severe psychotic illness with worse outcomes predicts longer duration of untreated psychosis, rather than longer duration of untreated psychosis predicting worse outcomes.

There are three main paradigms of EIP operating in different stages of illness and treatment. The ultra-high-risk (UHR) paradigm proposes that it may be possible to detect people who do not currently meet criteria for psychotic illness, but who are at high risk of developing psychotic illness in the future.³⁸ Various treatments including medication, nutritional supplements, and psychotherapy, have been implemented in attempts to prevent the transition from an ultra-high-risk state to frank psychotic illness. The early detection paradigm proposes that decreasing the duration of untreated psychosis (DUP) may prevent the progression of disease or prevent the damaging social effects of long periods of psychosis such as loss of relationships, delayed educational and vocational milestones, and violence or self-harm.³⁴ Finally, the early intensive treatment (EIT) paradigm suggests that, even without reducing the DUP, a concentration of treatment and support resources in the early phases of psychotic illness will lead to better outcomes.³³

Ultra-high risk of psychosis

We will consider UHR research first. Several different instruments have been developed to detect patients at high risk. The Comprehensive Assessment of At-Risk Mental States (or CAARMS) is one of the most commonly used.³⁹ Essentially this instrument predicts a high risk of future psychotic illness in three categories of people: those with ongoing psychotic symptoms that are below clinical thresholds; those with brief limited intermittent psychotic symptoms; and those with a family history of psychotic illness or personal schizotypal personality disorder combined with a recent marked drop in function. Early results with this instrument suggested that around 40% of people identified as being at high risk of psychosis would later develop psychotic illness. However, later studies suggest that only 10-15% of people at risk of psychosis transition to psychotic illness.³⁸ The high transition rates in early studies has been attributed to sampling from enriched samples, and in particular people referred to a specialist early intervention service by other health care providers who already suspected that the patient might have a psychotic illness. Later studies which sampled from general mental health presentations understandably predicted fewer transitions to frank psychosis.

To date there have been no unproblematic replications of interventions which prevent transition to psychosis in high risk samples. Antipsychotic medication, fatty acid supplements, and CBT are the main interventions tried. Of these, only the trial by Amminger and colleagues reported a convincing difference in transition rates between high risk patients randomised to receive omega-3 polyunsaturated fatty acids versus placebo for 12 weeks.⁴⁰ By 12 month follow-up 28% of placebo and 5% of PUFA patients had transitioned to frank psychotic disorder. Most recently McGorry and colleagues have reported a trial in which 115 at-risk patients were randomly assigned to low-dose risperidone, cognitive therapy, or supportive therapy, with no signficant differences in rates of transition to psychosis over 12 month follow-up.⁴¹

It should be noted that the ultra-high risk field has been subject to significant controversy, and that claims and counter-claims are best considered in the light of close attention to the published papers. For example, of five published randomised controlled trials comparing CBT to treatment as usual to prevent transition to psychosis in ultra-high-risk patients, three were negative, and two have been proposed as positive trials.⁴² Reference to the articles described as positive reveals that intention to treat analyses were negative, with no significant differences in the transition to psychotic illness in CBT groups versus treatment as usual. Each paper then re-analysed their results after excluding two patients from the CBT treated groups who had transitioned to psychosis, but who were later judged to have already made the transition to psychosis before entering the study.

Duration of untreated psychosis

The DUP paradigm is exemplified by the excellent TIPS study out of Scandinavia.³⁴ This trial was explicitly designed to test the alternative hypotheses explaining the correlation between longer duration of untreated psychosis and worse outcomes in schizophrenia.⁴³ As it is ethically untenable and practically difficult to randomise patients to shorter or longer periods of untreated psychosis, the TIPS group used a quasi-experimental design in which they implemented a public health intervention in one region and compared this to treatment as usual in a separate region.⁴⁴ The TIPS group initiated public information campaigns in the treatment regions educating the public and groups such as primary practitioners and schools about signs of psychosis and the importance of early identification and treatment. They also established rapid response teams to visit and assess potentially psychotic people. The TIPS group showed that these efforts reduced the duration of untreated psychosis from median 16 weeks to 5 weeks. It should be noted that the TIPS intervention did not change the treatment received when psychotic illness was identified, patients entering the usual mental health system in each region, but only the duration of untreated psychosis.

The TIPS study has generated results over a ten-year follow-up period, with interesting patterns throughout this time. With most relevance to the alternative hypotheses regarding the correlation between DUP and outcomes, at one year follow-up it was found that there was no difference in the time to remission between patients in the treatment and control regions,⁴⁴ and DUP did not predict outcomes at 2- and 10-year follow-up.³⁴ These results are not consistent with the theory that longer DUP causes worse outcomes. However, the reduction of the duration of untreated psychosis was associated with reduced severity of negative symptoms at 5 year follow-up.⁴⁵

Most recently, the TIPS group has reported 10-year results which showed that the early detection intervention had not sustained any clinical advantages among the original measures.³⁴ The TIPS authors took the unusual step of creating an entirely new ad-hoc measure which they described as “Recovery” and which is the only statistically significant measure favouring the early detection group at 10 year follow-up; the relevance of this measure is unclear.

Early intensive treatment of psychosis

There are two main studies investigating the effects of early intensive treatment of psychosis. This model does not specifically attempt to reduce the duration of untreated psychosis, but provides more resources to treat and support patients once they have been diagnosed with a first episode psychotic illness. The OPUS study randomised 547 patients with first-episode psychosis to two years of intensive treatment versus treatment as usual.³³ Intensive treatment involved three main components: small case loads for case managers, who each managed 10 patients rather than 25 in the mainstream mental health service, using an assertive community treatment model; family psychoeducation; and social skills training for patients. The OPUS study showed that early intensive treatment improved clinical and functional outcomes as long as intensive treatment continued, with significantly better measures of positive and negative symptoms and Global Assessment of Function scores at two years. However, the authors note that, with the end of intensive treatment and return to treatment as usual after two years, there were no differences in clinical outcomes at five years. The OPUS authors conclude that early intensive treatment does not change the course of psychotic illness, although it may be possible to sustain improved functional outcomes such as accommodation and amount of time in hospital. The other main study, the Lambeth Early Onset trial in the UK, essentially replicated these results in a smaller cohort.³²

Interpretation of results

The early intervention in psychosis movement has generated much debate in the psychiatric literature, and it is not possible to do more than adumbrate the main points here. This research has theoretical and practical implications. The main theoretical point to be made is that the research does not suggest that current treatment options change the course of psychotic illness. Each of the three paradigms contribute evidence to this conclusion. First, there is the general failure of antipsychotic medication or psychotherapy to reliably prevent transition to psychosis. The Amminger fatty acid study is promising, but awaits replication.

Second, the TIPS group has demonstrated that reducing the DUP does not change time to remission, DUP does not predict later outcomes, and no clinical or functional differences have been demonstrated prospectively over the course of 10 year follow-up.

Finally, the OPUS group has shown that intensive treatment in the first two years after psychotic illness does not permanently change clinical outcomes, although it may improve social outcomes.

On the other hand, TIPS showed that it is possible to greatly reduce the DUP, and OPUS showed that intensive treatment can improve outcomes while the intensive treatment lasts. As there is evidence that the early stages of psychosis before treatment is initiated is the time of greatest risk of violence, suicide, and other social and functional damage, the reduction of the DUP appears particularly important.

There have been diverse and sometimes stridently opposed viewpoints regarding these results. The preliminary status of UHR results was reflected in the exclusion of the proposed “attenuated psychosis syndrome” from the DSM-5 because of inadequate reliability. It is hoped that recently initiated large trials such as the Early Detection and Intervention Evaluation for people at high risk of psychosis 2 (or EDIE 2) and the PREVENT trial will have adequate power to resolve the ambiguous evidence about the prevention of transition to psychosis in high risk populations.

While it is generally acknowledged that increased resources can improve outcomes in first-episode psychosis, strong advocates have argued that the reversion to baseline after increased resources are removed at two years necessitates the extension of increased resources up to or beyond five years. Others have argued that while increasing resources for first-episode psychosis may improve outcomes for this group, increasing resources to patients with chronic schizophrenia also improves their outcomes, and it may be unethical to target one group, as well as inefficient to segregate first episode psychosis patients from general psychiatric patients.

Conclusions

In summary, there are three basic paradigms of early intervention in psychosis:

• the UHR paradigm proposes that it is possible to identify patients before they develop a full psychotic disorder and halt or delay the onset of disease, or mitigate the consequences of disease
• the ED paradigm proposes that it is possible to reduce the duration of untreated psychosis and that earlier treatment of psychosis will prevent the progression of disease
• and the EIT paradigm proposes that after psychotic disease is detected, more intensive treatment will improve clinical, functional, and social outcomes, and may change the course of disease

On balance, the evidence does not support a disease-modifying effect of current treatments for psychosis:

• only one unreplicated RCT of polyunsaturated fatty acids has shown reduced transition to psychosis amongst high risk patients over 12 months
• reducing the DUP did not change time to remission, did not change long-term outcomes, and the DUP did not predict outcomes
• and EIT did improve outcomes, but only while intensive treatment was in place, with reversion to the control outcomes after the extra support was withdrawn at two years

The current debate regarding early intervention in psychosis therefore concerns different assessments of the impact of stand-alone early intervention units:

• advocates suggest the benefits of early intervention should be extended beyond two years, and potentially throughout the course of psychotic illness
• critics suggest that the reality of current resource allocation in health care is that increased resources for first-episode psychosis are not unlikely to displace resources from other deserving patients, despite evidence that these patients are just as likely to benefit from increased resources as first-episode patients

Conclusion

And that’s it for the December edition of Australian Psychiatry Review. Listeners directed to the podcast from the Royal Australian and New Zealand College of Psychiatry’s CPD Online page can access questions for CPD points using the password “early”. See you next month!

References

Australian and New Zealand Journal of Psychiatry

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American Journal of Psychiatry

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British Journal of Psychiatry

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JAMA Psychiatry

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Molecular Psychiatry

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Neuropsychopharmacology

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Journal of Clinical Psychiatry

19. Newcomer JW, Weiden PJ, Buchanan RW. Switching Antipsychotic Medications to Reduce Adverse Event Burden in Schizophrenia: Establishing Evidence-Based Practice. J. Clin. Psychiatry. 2013; 71(11):1108-1120.

JAMA

20. Kravitz RL. Patient Engagement Programs for Recognition and Initial Treatment of Depression in Primary Care. Jama. 2013;310(17):1818.

Lancet

21. Whiteford HA, Degenhardt L, Rehm J, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet. 2013:1575–1586.

22. Degenhardt L, Whiteford HA, Ferrari AJ, et al. Global burden of disease attributable to illicit drug use and dependence: findings from the Global Burden of Disease Study 2010. Lancet. 2013;382(9904):1564–1574.

23. Slim MAM. Harmful use of alcohol in Australasia–a sobering picture. Lancet. 2013;382(9904):1542–3.

24. Mercer CH, Tanton C, Prah P, et al. Changes in sexual attitudes and lifestyles in Britain through the life course and over time: findings from the National Surveys of Sexual Attitudes and Lifestyles (Natsal). Lancet. 2013;382(9907):1781–1794.

25. Sonnenberg P, Clifton S, Beddows S, et al. Prevalence, risk factors, and uptake of interventions for sexually transmitted infections in Britain: findings from the National Surveys of Sexual Attitudes and Lifestyles (Natsal). Lancet. 2013;382(9907):1795–1806.

26. Wellings K, Jones KG, Mercer CH, et al. The prevalence of unplanned pregnancy and associated factors in Britain: findings from the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). Lancet. 2013;382(9907):1807–1816.

New England Journal of Medicine

27. Gallagher TH, Mello MM, Levinson W, et al. Talking with Patients about Other Clinicians’ Errors. N. Engl. J. Med. 2013;369(18):1752–1757.

28. Volkow ND, Swanson JM. Adult Attention Deficit–Hyperactivity Disorder. N. Engl. J. Med. 2013;369(20):1935–1944.

Focus – Early Intervention in Psychiatry

29. Lieberman JA, Dixon LB, Goldman HH. Early Detection and Intervention in Schizophrenia A New Therapeutic Model. JAMA. 2013;310(7):689–690.

30. McGorry PD, Edwards J, Mihalopoulos C, Harrigan SM, Jackson HJ. EPPIC: an evolving system of early detection and optimal management. Schizophr. Bull. 1996;22(2):305–26.

31. Addington J, Cadenhead KS, Cornblatt B a, et al. North American Prodrome Longitudinal Study (NAPLS 2): Overview and recruitment. Schizophr. Res. 2012;142(1-3):77–82.

32. Gafoor R, Nitsch D, McCrone P, et al. Effect of early intervention on 5-year outcome in non-affective psychosis. Br. J. Psychiatry. 2010;196(5):372–6.

33. Bertelsen M, Jeppesen P, Petersen L, et al. Five-year follow-up of a randomized multicenter trial of intensive early intervention vs standard treatment for patients with a first episode of psychotic illness: the OPUS trial. Arch. Gen. Psychiatry. 2008;65(7):762–71.

34. Ten Velden Hegelstad W, Larsen TK, Auestad B, et al. Long-Term Follow-up of the TIPS Early Detection in Psychosis Study: Effects on 10-Year Outcome. Am. J. Psychiatry. 2012;169(4):374–380.

35. Waddington JL, Youssef H a., Kinsella A. Sequential cross-sectional and 10-year prospective study of severe negative symptoms in relation to duration of initially untreated psychosis in chronic schizophrenia. Psychol. Med. 1995;25(4):849–857.

36. Wyatt RJ. Neuroleptics and the natural course of schizophrenia. Schizophr. Bull. 1991;17(2):325–51.

37. Verdoux H, Liraud F, Bergey C, Assens F, Abalan F, van Os J. Is the association between duration of untreated psychosis and outcome confounded? A two year follow-up study of first-admitted patients. Schizophr. Res. 2001;49(3):231–41.

38. Fusar-Poli P, Borgwardt S, Bechdolf A, et al. The Psychosis High-Risk State: A Comprehensive State-of-the-Art Review. JAMA Psychiatry. 2013;70(1):107–120.

39. Yung AR, Yuen HP, McGorry PD, et al. Mapping the onset of psychosis: the Comprehensive Assessment of At-Risk Mental States. Aust. N. Z. J. Psychiatry. 2005;39(11-12):964–71.

40. Amminger GP, Schäfer MR, Papageorgiou K, et al. Long-chain omega-3 fatty acids for indicated prevention of psychotic disorders: a randomized, placebo-controlled trial. Arch. Gen. Psychiatry. 2010;67(2):146–54.

41. McGorry PD, Nelson B, Phillips LJ, et al. Randomized controlled trial of interventions for young people at ultra-high risk of psychosis: twelve-month outcome. J. Clin. Psychiatry. 2013;74(4):349–356.

42. Van der Gaag M, Smit F, Bechdolf A, et al. Preventing a first episode of psychosis: meta-analysis of randomized controlled prevention trials of 12 month and longer-term follow-ups. Schizophr. Res. 2013;149(1-3):56–62.

43. Melle I, Larsen TK, Haahr U, et al. Reducing the Duration of Untreated First-Episode Psychosis Effects on Clinical Presentation. Arch. Gen. Psychiatry. 2004;61(2):143–150.

44. Larsen TK, Melle I, Auestad B, et al. Early detection of first-episode psychosis: the effect on 1-year outcome. Schizophr. Bull. 2006;32(4):758–64.

45. Larsen TK, Melle I, Auestad B, et al. Early detection of psychosis: positive effects on 5-year outcome. Psychol. Med. 2011;41(7):1461–9.

November 2013 Transcript

Highlights

I’m Andrew Amos, and this is the November 2013 issue of Australian Psychiatry Review. This month concludes with a focus section on psychiatric genetics, rejuvenated by recent replications of genome-wide association studies. Other highlights of the literature reviewed this month include Atigari and Healy’s suggestion that the proconvulsant effects of clozapine. lithium, and ketamine, may be a novel therapeutic principle rather than a side-effect. Jelovac and colleagues provide a systematic review showing maintenance ECT does not change relapse after a primary ECT course. Zipursky and colleagues persuasively argue against what they describe as the myth that schizophrenia is a neurodegenerative disorder. Finally, Priebe and colleagues report that small financial incentives can greatly increase treatment adherence in previously poorly adherent patients on depot antipsychotics.

ANZJP – November

In November the ANZJP includes a cognitive remediation trial by Tan and King, who randomised 70 Singaporean patients with schizophrenia to a 60-hour cognitive remediation program or physical exercise.¹ Cognitive remediation comprised computer-assisted cognitive exercises for up to 5 hours per week over 12 weeks, and fortnightly cognitive-based counselling which continued monthly after the computer assisted programme finished. Patients were paid a small amount for each hour of computer exercises or physical training they completed. They found significantly greater improvements for cognitive remediation patients on all neurocognitive measures, with better vocational and independent living skills and better functional outcomes at one year follow-up, including more wages from competitive employment; while the physical exercise patients showed better physical fitness.

Atigari and Healy draw attention to the pro-convulsant mechanism of certain psychotropic treatments.² Grounding their analysis in the initial division of psychotropics into the general therapeutic principles of sedation and stimulation in the 1950s, they trace the growing complexity of efforts to describe and understand classes of psychotropics based on structure, effects, and theoretical considerations. Atigari and Healy imply that the drive towards categorisation in late twentieth century psychiatric diagnosis with DSM-III was associated with the linkage of psychotropic medications to specific indications, ignoring evidence of more general mechanisms. An example is the creation of the idea of ‘mood stabilisers’ applied to anticonvulsants to provide a magic bullet for the target market of mania, replacing the poorly defined therapeutic principle of a general sedative action which could be applied to many states characterised by increased CNS activity. Atigari and Healy note clozapine’s unique efficacy, and the failure of attempts to reproduce its efficacy in the absence of putative side effects such as agranulocytosis and seizure diathesis. Adverting to the unique therapeutic effects associated with treatments including lithium, ketamine, and ECT, Altigari and Healy speculate that there may be a general pro-convulsant therapeutic principle analogous to the original sedative and stimulant principles.

In November, Malhi and Henderson³ debate Goldberg⁴ on the place of anxiety within psychiatry. With more than a faint echo of steps towards dimensional diagnosis in the DSM-5, Goldberg proposes the centrality of anxiety in mental disorders. He refers to evidence that anxiety is a general risk factor for psychiatric diagnoses, higher severity, and worse outcomes including suicide. Against this empirical approach Malhi and Henderson balance a structural model with unique anxiety factors, such as hyperarousal and tension, and unique depressive factors, such as anhedonia and absence of positive affect, as well as a higher-order factor called general distress comprising non-affective and affective symptoms. Noting the opposing deficiencies of treating anxiety as a diagnosis rather than as groups of symptoms, Malhi and Henderson question whether it is possible that anxiety and depression are a single entity with manifold presentations, quoting a ‘syndromal combined anxiety and depressive disorder’ called ‘cothymia’ by Tyrer.⁵ They agree with Goldberg that the DSM-5 does not adequately characterise anxiety, but differ on the important unresolved questions.

International Psychiatric Journals

AJP – October 2013

In October the American Journal of Psychiatry includes an article by Murrough and colleagues⁶ and editorial by Rush⁷ which ask whether ketamine is ready for clinical use as a rapidly acting antidepressant. Rush acknowledges that Murrough and colleagues’ two-site randomised controlled trial comparing a single infusion of ketamine versus midazolam in 73 patients with treatment resistant depression adds to evidence of a moderate to large effect size with rapid onset. They found a number needed to treat of 2.8 for significantly greater improvement on the Montgomery-Asberg Depression Rating Scale at 24 hours. This compares favourably with a number needed to treat of 6 to 7 for antidepressants in the Food and Drug Administration trials of non-treatment resistant depressed patients. This must be balanced against the relapse within a week of half the patients, with significant side effects including dissociation, anxiety, and increased or unstable blood pressure. Rush questions the generalisability of the study while noting it shares this problem with the broader depression literature, and concludes that while results are encouraging, we are not yet at the point of changing practice.

JAMA Psychiatry – October 2013

In JAMA Psychiatry in October, Bobo and colleagues⁸ described a retrospective cohort study of the Tennessee Medicaid program with close to 30,000 recent initiators of antipsychotic medications and 15,000 controls, excluding patients with a previous diagnosis of diabetes or schizophrenia. They found that those prescribed antipsychotics had a 3-fold, dose dependent increased risk of type 2 diabetes in the first year of follow-up. The risk was greater in children 6 to 17 years old, and with atypical antipsychotics.

An editorial by Heckers⁹ evaluates the challenge by Kahn and Keefe¹⁰ to the received wisdom that schizophrenia is primarily a disorder of psychosis, to argue that the primary dysfunction in schizophrenia is one of cognition. Kahn and Keefe rely on the central place of cognitive deficits in the original descriptions of dementia praecox and schizohrenia by Kraepelin and Bleuler, the enduring presence of cognitive deficits well before and long after the onset of psychosis, and argue for a specificity of cognitive deficits in schizophrenia not seen, for example, in bipolar disorder. Kahn and Keefe propose that early intervention efforts that wait until the onset of psychotic symptoms such as hallucinations and delusions are too late, given evidence of cognitive decline decades earlier. Heckers acknowledges the many associations between cognitive and functional decline and subsets of patients with schizophrenia, but notes that cognitive deficits are not ubiquitous in schizophrenia, and psychosis is far from ubiquitous amongst those with cognitive deficits. Furthermore, the evidence distinguishing cognitive outcomes in schizophrenia from those in bipolar or schizoaffective disorders is equivocal and in the process of revision. Heckers also faults Kahn and Keefe for failing to address the possibility of recovery from psychotic illness despite increasing evidence that this occurs in a substantial minority. Finally, the impractical nature of Kahn and Keefe’s proposal that the core component of schizophrenia be detected in the inability of young people to develop cognitively is demonstrated by their suggestion that this be facilitated by cognitive growth curves based on large longitudinal cognitive databases. Implicitly this acknowledges that we do not have the capacity to adequately characterise cognitive decline predictive of schizophrenia as opposed to other developmental disorders. Given these criticisms, Heckers is unwilling to accept Kahn and Keefe’s proposal that cognitive decline become a criterion for the diagnosis of schizophrenia, as well as a central target of treatment.

Biological Psychiatry – 1 November, 15 November

The 1st November edition of Biological Psychiatry includes many articles exploring the relationship between glucocorticoids, trauma, and brain development, with applications to PTSD. Steudte and colleagues showed that levels of cortisol in hair follicles but not in saliva may act as markers of trauma exposure, with increased trauma associated with sustained hypocortisolism.¹¹ They conclude that hair follicle cortisol may be a more accurate measure of chronic stress hormones than previous measures. Using MRIs in healthy 6-10 year olds, Davis and colleagues showed that foetal exposure to synthetic glucocorticoids was associated with later cortical thinning, most prominently in the anterior cingulate cortex.¹² Cortical thinning was associated with higher affective symptoms in these children.

Biological Psychiatry have published online a neuroimmunological perspective by Coutinho and colleagues which describes disturbances associated with autoantibodies targeting neuronal surface proteins and considers antibody mediated central nervous system disease.¹³ They note that the brain was originally considered immunologically privileged and not prone to autoimmune disease due to the blood brain barrier. Since 2001 multiple encephalopathic presentations have been linked with autoantibodies targeting central nervous system epitopes, including the NMDA receptor, the voltage gated potassium channel, the AMPA receptor, the GABAb receptor, and the glycine receptor. Coutinho and colleagues review evidence linking immune processes and psychosis, including increased autoimmunity in patients and relatives, inflammation-related gene involvement, and Deakin and colleagues’ paper demonstrating a small proportion of patients with clinically typical schizophrenia have autoantibodies against the NMDA receptor and other neuronal antigens.¹⁴

The 15th November issue of Biological Psychiatry includes research and editorials on speculative new treatments for depression. Dinan and colleagues review evidence on psychobiotics, defined as live organisms which, when ingested, improve psychiatric symptoms.¹⁵ While the evidence remains suggestive rather than conclusive, the authors examine biotic interactions with inflammatory cascades, infection, the hypothalamo-pituitary-adrenal axis, and neurotransmitters. Huang and colleagues report evidence from animal and human studies of the antidepressant effects of the glycine transport inhibitor sarcosine.¹⁶ They found that sarcosine decreased analogs of depressive behaviour in murine models of depression, and substantially improved scores on the Hamilton Depression Rating Scale in a six week randomised citalopram controlled trial in Taiwanese patients with major depressive disorder. They speculate that the problematic antidepressant effects of both NMDA agonists and antagonists are resolved by differential effects at synaptic and extrasynaptic NMDA receptors. Voleti and colleagues describe common mechanisms linking the rapid anti-depressant effects of ketamine and scopolamine.¹⁷ A related editorial by Monteggia and Kavalali proposes that the common mechanism of rapid antidepressant action may be increased glutamatergic synaptic efficacy.¹⁸

Neuropsychopharmacology – November 2013

An article by Jelovac and colleagues in the November Neuropsychopharmacology provides a systematic review and meta-analyses of post-ECT relapse in responders with major depressive disorder.¹⁹ They found that 50% of patients relapsed within 12 months, with 37% relapsing in the first six months. Relapse rates in the first six months after ECT were similar in patients treated with and without maintenance ECT, while antidepressant medication after ECT halved relapse rates versus placebo. The evidence base is most established for tricyclic antidepressants, with limited evidence regarding newer antidepressants or augmenting regimes.

Schizophrenia Bulletin – November 2013

In November Schizophrenia Bulletin includes a diverse set of articles. The issue opens with an editorial by Farooq and colleagues proposing the use of treatment response to subtype schizophrenia.²⁰ They base their proposal on the inadequacies of current subtypes based on polythetic symptom clusters with specifiers of course and severity, and severe deficiencies in approaches based on biomarkers and clinical staging. They compare the use of clozapine in treatment resistant schizophrenia with insulin and non-insulin dependent diabetes, and suggest three levels of schizophrenia: antipsychotic responsive schizophrenia, clozapine responsive schizophrenia, and clozapine resistant schizophrenia.

Kirkpatrick and Miller give an overview of the relationship between inflammation and schizophrenia, concluding that while the evidence is provocative, the number of studies is small and progress requires improved methodological rigor and replication studies.²¹

Selten and colleagues give an update on the social defeat hypothesis of schizophrenia, which suggests that the sustained exposure to the negative experience of exclusion from the majority group increases the risk of schizophrenia by sensitisation of the mesolimbic dopamine system.²² The literature links social defeat to 5 risk factors, with the strongest evidence for migration and childhood trauma, with insufficient evidence for urban upbringing, low intelligence, and drug abuse. Selten and colleagues note that evidence for sensitisation of the mesolimbic dopamine pathway remains preliminary, and explore criticisms, including that social defeat is a consequence of schizophrenia rather than a cause, and that social defeat is not a specific risk factor. Stilo and colleagues report an investigation of social disadvantage in schizophrenia which found an association between markers of childhood and adult disadvantage and schizophrenia.²³ Separation from or death of a parent in childhood showed the strongest association with schizophrenia. Despite the post-hoc, cross-sectional nature of the study, Stilo and colleagues propose an aetiologic role for social disadvantage in schizophrenia, and tentatively suggest that reducing social disadvantage may protect against it.

Barkhof and colleagues report a trial where 114 patients in Amsterdam who experienced a psychotic relapse in the context of treatment non-adherence in the previous year were randomly assigned to an adapted form of motivational interviewing for adherence, or an active control condition.²⁴ While motivational interviewing did not improve adherence or reduce hospitalisation overall, motivational interviewing did reduce hospitalisation rates for females, non-cannabis users, younger patients, and patients with shorter illness duration, leading Barkhof and colleagues to suggest motivational interviewing for targeted groups of patients.

Johannesen and colleagues report an effort to establish event related potentials as endophenotypes for schizophrenia.²⁵ Endophenotypes are phenotypes thought to mediate between genes and psychiatric symptoms, such as expression of the catechol-o-methyl-transferase protein thought to mediate between a gene and the negative symptoms of schizophrenia. Event related potentials are features of EEGs triggered by events such as somatosensory stimuli. Johannesen and colleagues establish that the ERPs P50, P300, and supplemental measures classified schizophrenia patients from healthy controls with 70% specificity and sensitivity, but did not differentiate schizophrenia patients from bipolar patients. The authors speculate that this is consistent with models that suggest schizophrenia and bipolar disorder share significant underlying pathophysiology.

Based on evidence linking psychosis to immune system dysfunction, a meta-analysis of adjunctive NSAIDs added to antipsychotics for patients with schizophrenia by Nitta and colleagues found little evidence of improvement.²⁶

Freeman and colleagues examine how cognitive/affective biases may play a role in maintaining paranoid delusions, with paranoia associated with greater anticipation of threat events, negative interpretations of ambiguous events, a self-focused cognitive style, and negative ideas about the self.²⁷ They conclude that treatment of emotional dysfunction should reduce psychotic experiences, including shifting attentional focus.

Jaaskelainen and colleagues report a meta-analysis that collected data from 50 studies on recovery in schizophrenia.²⁸ They found that only 1 in 7 patients improved significantly on both clinical and social measures with improvements sustained for at least 2 years. With more rigorous methodology than previous meta-analyses they found lower rates of recovery, did not find different rates of recovery for men and women, and did not find evidence of increasing rates of recovery with recent efforts at early identification and treatment of longer follow-up.

Zipursky and colleagues argue against the myth that schizophrenia is a neurodegenerative illness.²⁹ They suggest that while ¼ of patients with schizophrenia have a poor outcome, few show a progressive loss of function characteristic of neurodegeneration; MRI studies show neurodevelopmental abnormalities at first episode with ongoing volume decreases which are explicable as the effects of antipsychotic medication and substance abuse; and cognitive deficits compared to healthy controls which are present at the time of first episode psychosis but then do not deteriorate with time. They propose that individual cases of deteriorating function may be attributed to poor adherence to treatment, comorbid conditions, and social disadvantage. They conclude that most people with schizophrenia can achieve a substantial degree of recovery with appropriate treatment. Zipursky and colleagues explain clinician pessimism regarding outcomes of schizophrenia by reference to the “Clinician’s Illusion”, which suggests that doctors often attribute the characteristics and course of those currently ill to all those with an illness. As the patients being seen by psychiatrists are generally the most stably unwell, these characteristics are projected onto all people who have experienced psychotic illness, discounting the substantial proportion of people who recover some or all function.

Journal of Clinical Psychiatry – September 2013

In September the Journal of Clinical Psychiatry reported a 10 year Taiwanese registry study by Wu and colleagues that there is an increased rate of venous thromboembolism in the acute but not the chronic phase of antipsychotic prescription.³⁰

International Medical and Scientific Journals

Science

On 1st November the journal Science released a special neuroscience issue called “The Heavily Connected Brain” with articles outlining recent advances in understanding of the organising networks of the human brain. Park and Friston review network theoretical models that attempt to explain the relationships between brain structual features and functional outcomes such as cognitive processes.³¹ Turk-Browne reviews large- scale fMRI data analyses which examine functional connections between brain regions during cognitive tasks, with increasing computational power allowing the temporal correlation of millimetre scale subdivisions across the entire brain.³² Underwood provides a journalistic review of the use of deep brain stimulation for the treatment of refractory depression, with around half of 200 patients showing significant improvements.³³ The article proposes that DBS has allowed researchers to test the theory that depression is not a result of chemical imbalance, but rather of deranged brain circuits. Markov and colleagues challenge recent representations of human brains as small-world networks, reporting evidence of high-density cortical graphs that are better modelled as hierarchical networks with complex reciprocal links between a dense core and specialised periphery.³⁴

Nature Reviews Neuroscience

The November 2013 Nature Reviews Neuroscience includes a Viewpoint comparing the research advantages of the Research Domain Criteria (or RDoC) recently established by the US National Institute of Mental Health as an alternative nosology to the DSM series.³⁵ While the DSM’s polythetic categories are convenient for clinical practice, there is growing evidence of a substantial overlap in the phenomenology and pathophysiology of syndromes treated as distinct entities in the DSM, such as schizophrenia and bipolar disorder. Specifically to facilitate research, the RDoC proposes five domains representing distinct brain systems which are disturbed in different ways in different psychiatric conditions. Casey and Lee state that the RDoC is intended to facilitate the translation of basic neuroscience findings to clinical diagnosis and treatment. The Viewpoint comprises the opinions of six leading psychiatric researchers comparing the research utility of DSM and RDoC approaches. Interesting arguments are proposed, such as Hyman’s suggestion that the DSM has impeded psychiatric research because the poor reliability of DSM diagnoses weakens research grant proposals. There is general agreement that the systems-based, dimensional approach of RDoC is likely to be more successful in guiding translational research, but also that it will not completely replace the categorical approach of the DSM. Casey and Lee state that rather than trying to find the neurobiological basis of a diagnostic group as DSM based research does, the RDoC approach starts with current understanding of brain-behaviour relationships and tries to explain clinical phenomena such as symptoms and syndromes.

JAMA

The October 2nd JAMA includes an editorial by Olfson and colleagues advocating for greater investment in the expansion of collaborative care with mental health specialists colocating with primary care doctors.³⁶ They describe opportunities arising within the structures established by the Affordable Care Act for improved and more efficient outcomes for patients with severe mental illness by the provision of lithium, clozapine, and employment services by primary care doctors supported by specialist teams. Olfson and colleagues also point out that in the US specialist mental health services already struggle to meet identified needs. With the expansion of health insurance to 4 million additional people with severe mental illness by 2019, efficiencies or expanded services will be required to prevent systemic failure.

Lancet

The September 14 Lancet includes a letter by Maslen and colleagues observing that it is possible to order online brain stimulation devices such as transcranial direct-current stimulators with no regulation or oversight.³⁷ They suggest that existing medical device legislation should be extended to brain stimulation devices to prevent potential harms.

The October 5 Lancet includes an article on stem cell therapy for multiple sclerosis by Rice and colleagues which collects research regarding the remarkable ability of stem cells to produce regeneration of oligodendrocytes and myelin sheathing in multiple sclerosis patients.³⁸ Noting the work of Blakemore in the 1970s, who injected myelinating cells into demyelinated lesions in the CNS and achieved successful remyelination, they report recent work in which cells from patients’ own bone marrow infused intravenously repaired CNS lesions in multiple sclerosis. Rice and colleagues suggest that this success is probably not mediated by replacement of myelin- regenerating cells, but on the tissue repair functions of bone marrow cells by preventing damage, suppressing inflammation, reducing scarring, and promoting angiogenesis, among other mechanisms. They note the diffusion of the marrow cells throughout the body, penetrating the blood-brain-barrier and particularly collecting at sites of inflammation, increasing the possibility of repair.

The October 26 Lancet includes a comment by Banerjee on the Cognitive Functioning and Ageing Study which indicated that the prevalence of dementia in the UK had decreased from 8.3% in 1991 to 6.5% in 2011.³⁹ Banerjee attributed the decrease to changes in smoking, management of cardiovascular risk factors, and other health behaviours, and noted the possibility of increasing prevalence associated with current trends in obesity and diabetes.

BMJ

The British Medical Journal published a brief digest of Cooney and colleagues’ Cochrane review of exercise for the treatment of depression.⁴⁰ While there was a moderate effect of exercise on depression for 35 trials comparing exercise to control or no treatment, when only the six high quality trials were included there was no effect.

On 22 October the BMJ published an editorial by Kendall based on an article by Priebe and colleagues which showed that treatment adherence in people with schizophrenia treated with antipsychotics was significantly improved with financial incentives.⁴¹ Priebe and colleagues randomly allocated 73 teams with 141 patients on depot antipsychotics who had received 75% or less of their injections to the financial incentive program versus treatment as usual. Participants in the intervention group were given £15 for each depot received over 12 months. Adherence increased from 69% to 85% in the intervention group, and from 67% to 71% in the control group. While there were no differences in clinical state or hospital admissions, intervention group patients had better quality of life ratings.

COHERENCE AND PSYCHIATRIC GENETICS

In November, Australian Psychiatry Review examines recent progress in psychiatric genetics. The review uses Kendler’s review in Molecular Psychiatry as a starting point.⁴² Kendler describes growing confidence that with increasing power and demonstrated replications, results from GWAS and large-effect size rare genomic variants may lead to significant breakthroughs in understanding of psychiatric illness. He proposes that the value of this research will be determined by the level of biological coherence of genes and molecules implicated in psychiatric disease by genetic studies. This will depend upon how well the genes and molecules can be integrated into tangible mechanisms, such as metabolic pathways, neurotransmitter systems, and neurodevelopmental trajectories. If diverse sources of evidence cohere into a manageable set of molecular mechanisms which map well onto phenomenology and syndromes, Kendler is confident that psychiatric genetics will provide critical insights into the underlying biology of psychiatric syndromes and allow us to understand the disordered relationships of the brain and mind.

The section will:

• first: summarise Kendler’s framework for understanding psychiatric genetics, including the importance of biologically coherent evidence across research domains
• second: illustrate Kendler’s framework using recent studies on the genetics of schizophrenia
• third: note an effort to facilitate coherence using an open database of genetic studies of bipolar disorder by Chang and colleagues
• fourth: refer to more speculative recent studies on the genetics of ADHD
• and fifth: conclude with reference to recent efforts to explore genetic risk factors shared between multiple psychiatric disorders

Kendler breaks psychiatric genetics down by study type. In the absence of recent advances in molecular genetic techniques, early genetic studies involved family, twin, and adoption studies, which provided evidence that all psychiatric disorders aggregate in families and are heritable. He notes that these studies are unable to prove that heritable disorders are biological, and therefore cannot support a coherent neurobiological understanding of psychiatric illness.

The first generation of molecular genetic studies included linkage studies, which assess the co-segregation of particular genetic loci with the presence of disease in families.⁴³ Essentially, this type of study relies upon statistical analysis of the tendency of genes located on the same chromosome to be transmitted together from parent to child. Linkage analyses compare the frequency with which genetic markers actually occur in members of a genetically related group who are affected by a disease such as schizophrenia, to how frequently they are expected to occur.⁴⁴ Genetic markers that occur more frequently than expected in patients with the disease are putative aetiological agents. Kendler notes that linkage analyses failed to demonstrate replicable mechanisms underlying psychiatric diagnoses or phenomenology. However, they did rule out the hopeful hypothesis that a few large-effect genes could explain the aetiology of psychiatric illnesses.

The next generation within molecular genetics moved from linkage analyses to genome-wide association studies (GWAS), which compare the frequency of genetic variants between people who have a condition of interest, to those who do not have the condition.⁴³ DNA of each participant and controls is sampled and analysed using arrays capable of characterising the pattern of allelic variants for millions of genes. The huge number of tests massively increases the possibility of false positive or negative results, requiring enormous sample sizes for adequate power to confidently identify statistically signficant effects. Early GWAS did not identify replicable genetic effects due to low power. However, with increasing sample sizes, replicable effects of small size have emerged. At the same time, copy number variants (CNVs) that substantially increase risk of specific psychiatric illnesses have also been discovered. CNVs involve deletions or duplications of large sections of DNA potentially encoding multiple genes, and generally involve much larger effect sizes than single allelic variations. Kendler suggests that a substantial proportion of genetic variation in psychiatric illness results from large numbers of small effect variants. He outlines the framework for translating knowledge about individual genes and genetic copy number variants affecting multiple genes into a coherent understanding of psychiatric illness. Genes operate at a biochemical level by the production of proteins. A coherent understanding of illness described at the level of patterns of behaviour will require translation of biochemical processes, through their effect on cellular dynamics, affecting neuronal networks, which comprise brain circuits which then directly control behaviour.

Kendler examines the possibility of different levels of coherence of neurobiological models of psychiatric illness emerging out of psychiatric genetics and related fields. He proposes that it is unlikely that these efforts will lead to no coherence or high coherence, and argues that it is more likely that our developing models will achieve moderate coherence. One pathway to moderate coherence for a particular disorder such as schizophrenia would be evidence linking dysfunction in a brain circuit subserving behaviour, such as the cortico-basal ganglia-thalamic loops, to abnormalities in any of multiple neuron types associated with specific neurotransmitter systems. Moderate coherence would arise out of the fact that multiple genes affect a common pathway through multiple highly variable mechanisms also affected by individual variation and interaction with environmental exposures.

Kendler thus provides a parsimonious framework for understanding the relevance of recent psychiatric genetic research.

Recent psychiatric geneticsm research in schizophrenia

Neatly illustrating the failure of past efforts in psychiatric genetics to demonstrate coherent models of psychiatric illness, an editorial by Sullivan explores the history of the DISC1, or Disrupted in Schizophrenia structural genetic variant, first flagged as a potential causal agent in a subset of patients with schizophrenia 20 years ago.⁴⁵ First discovered in 1970, DISC1 is associated with three structural variants involving disruptions of a particular location on chromosome 1. Multiple mechanisms of action have been proposed for the disrupted genes, most commonly involving neurodevelopmental processes. Despite long intense investigation, the role of DISC1 remains equivocal, with some research groups believing it is an aetiological agent, some that it is not, and some that more data is needed to reach valid conclusions. Sullivan argues that progress in psychiatric genetics requires high quality research guided by rigorous standards, and that DISC1 is an example of research that is hopefully explored as ‘intriguing’ rather than confidently investigated with clear results.

More positively, Mowry and Gratten summarise an emerging spectrum of allelic variation in schizophrenia.⁴³ Using GWAS across international consortia with ever-larger sample sizes, Mowry and Gratten describe a research effort combining genetic insights with cellular models, animal models, and imaging genetics. They propose that the genetics of schizophrenia lie somewhere between original models, described as common disease common variant models, which posited that one or a small number of genes would explain most of the variance; and more recent models, known as common disease rare variant models, which argue for extreme genetic heterogeneity involving many rare but highly penetrant mutations. Evidence from recent GWASs and related research suggests a spectrum of illness involving the interaction of large numbers of genes of small effect in some manifestations of schizophrenia, through to a small number of rare genes of large effect in other manifestations of psychotic illness. Mowry and Gratten echo Kendler’s optimism, though both articles emphasise that most of the work remains to be done.

Bipolar genetics database

An article by Chang and colleagues in the latest Biological Psychiatry summarises genetic evidence on bipolar disorder, candidate molecular pathways, and genetic factors potentially shared between bipolar disorder, major depressive disorder, and schizophrenia.⁴⁶ Chang and colleagues note bipolar heritability of 80%, with clinical features such as psychosis and suicidality shared with depression and schizophrenia. They have constructed a publicly available database of this evidence including searchable results from 796 papers containing 797 candidate genes for bipolar disorder, with 447 genes with at least one positive finding. The most studied genes are SLC6A4, BDNF, and DRD2. They have also identified 245 pathways from GWASs, including calcium channel activity and central nervous system development. The majority of pathways were involved in synaptic transmission, membrane, and ion channel activity. Their searchable database focuses on identifying genetic factors with multiple sources of evidence, and facilitates testing of hypotheses regarding convergent pathways within and across disorders, which appears likely to foster Kendler’s idea of coherence.

Recent psychiatric genetics research in ADHD

Koenen and colleagues comment on the challenges and promise of genetic studies in post traumatic stress disorder (PTSD).⁴⁷ Noting that the tendency to PTSD is heritable, they review research that seeks to explain the vulnerability and resilience of people exposed to stress. Candidate gene studies use prior biological knowledge to identify possible genes underlying particular psychiatric phenotypes. They develop the example of Wilker and colleagues, which built on disturbed memory function in PTSD to justify the study of KIBRA, a memory-related protein.⁴⁸ Wilker and colleagues found minor alleles of two single nucleotide polymorphisms (or SNPs) encoding KIBRA reduced the lifetime risk of PTSD in genocide survivors.

GWASs do not attempt to predict candidate genes, but rely on enormous sample sizes to detect associations between phenotypic and genotypic variation. Xie and colleagues found evidence for an association between Tolloid-like 1 gene and PTSD.⁴⁹

Candidate gene studies are currently out of favour because of high false positives and low replication rates, as well as inadequate biological knowledge to identify high-probability candidate genes. GWAS have located the majority of risk variants in non-coding regions of the genome. Consistent with Kendler’s criterion of coherence, Koenen and colleagues suggest both candidate gene and GWAS can contribute to an understanding of PTSD mechanisms. To this end they have established the PTSD working group within the Psychiatric Genomics Consortium to conduct very large analyses of candidate and GWAS of PTSD. They identify five main challenges in this endeavour, including how to identify and measure trauma load, defining the PTSD phenotype, managing comorbidity, population stratification for genotype distribution by ancestry, and appropriate sampling.

Psychiatric disorders with shared psychiatric risk factors

Finally, there has been growing attention to the probability of shared genetic aetiology across psychiatric disorders. An article by the Cross-Disorder Group of the Psychiatric Genomics Consortium is a recent example, reporting GWASs showing high correlations of SNPs between schizophrenia, bipolar disorder, major depressive disorder, ADHD, and Autism Spectrum Disorder.⁵⁰ These studies promise to expose common neurobiological mechanisms underlying the substantial overlap in phenomenology between conceptually distinct entities such as schizophrenia and bipolar disorder, reflected in the hybrid schizoaffective diagnosis, and in efforts to move from a categorical to a dimensional diagnostic system. The Cross-Disorder Group of the Psychiatric Genomics Consortium concludes that their work will motivate investigation of shared pathophysiologies and common therapeutic mechanisms.

Summary

Thus, a clarifying caricature of the current state of psychiatric genetics might note the identification of ever larger numbers of common gene variants with small, non-specific effects on psychiatric dysfunction, alongside rare genetic variants with large, specific effects on particular psychiatric disorders. There is a growing move towards large international consortia to facilitate the enormous sample sizes needed to achieve adequate power in GWAS. Kendler provides a framework based on coherence with which to structure research based on psychiatric genetics, and to evaluate the results. This framework suggests that psychiatric genetics continues to promise future breakthroughs rather than deliver present understanding, though Kendler, Mowry and Gratten, and the Psychiatric Genomics Consortium papers find grounds for optimism.

Conclusion

And that’s it for the November edition of Australian Psychiatry Review. Listeners directed to the podcast from the Royal Australian and New Zealand Colleage of Psychiatry’s CPD Online page can access questions for CPD points using the password “coherence”. See you next month!

References

Australian and New Zealand Journal of Psychiatry

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JAMA Psychiatry

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Biological Psychiatry

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NEUROPSYCHOPHARMACOLOGY

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SCHIZOPHRENIA BULLETIN

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JOURNAL OF CLINICAL PSYCHIATRY

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SCIENCE

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NATURE REVIEWS. NEUROSCIENCE

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FOCUS – COHERENCE AND PSYCHIATRIC GENETICS

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October 2013 Transcript

I’m Andrew Amos, and this is the October 2013 edition of Australian Psychiatry Review. This month concludes with a focus section on cerebral organoids, an exciting new technique for exploring neurodevelopmental processes using cells taken from adults. The literature review includes Gin Malhi’s critique of the poorly defined and variably implemented diagnosis of schizoaffective disorder and evidence by Lopez and colleagues suggesting recent claims of the severe harms of prescription of antipsychotic medications for behavioural disturbances in dementia in nursing homes may be overstated. Koesters and colleagues show that agomelatine is ineffective for depression when negative unpublished data are considered, while Harrow and Jobe argue that the benefits of long-term antipsychotic therapy for schizophrenia have not been convincingly demonstrated. And now, let’s consider research in Australian psychiatric journals.

Australian Psychiatric Journals

ANZJP

In October the Australian and New Zealand Journal of Psychiatry is a themed issue on the relationship between social factors and mental health. Editors Berk and Singh note that despite importance to patients, prevention is overlooked when funding research.¹ The fact that prevention has made the greatest contribution to public health outcomes in other branches of medicine suggests similar promise in mental health. Jacka and colleagues explore modifiable risk factors and draw lessons from preventive efforts in obesity, cancer, and cardiovascular disease which demonstrate the importance of social, environmental, and behavioural factors.² Jacka and colleagues stress the primacy of public policy in achieving preventive goals.

Editor Gin Malhi describes superficial changes to the schizoaffective diagnosis in DSM-5.³ He traces the origins of the diagnosis to Kasanin in 1933, who conceptualised it as a reactive psychosis with a clear stressor and better outcome than schizophrenia. Malhi suggests the inclusion of the diagnosis in DSM-III was pragmatic, allowing diagnosis of presentations poorly described by schizophrenia or major mood categories in the Kraepelinian orthodoxy of the late 1970s. It was also hoped that more accurate diagnosis would lead to better understanding of psychosis and better treatments. Malhi points to recent evidence that schizophrenia and schizoaffective disorder exist on a spectrum of functional psychoses with myriad presentations best captured by dimensional systems rather than exclusive categories. He is puzzled by DSM-5’s retention of schizoaffective disorder, which may be attributable to inadequate data to support alternative approaches, such as dimension-based specifiers of mood symptoms. Malhi argues that the attempt to improve reliability with more rigorous criteria may only work in research settings, given the loose heuristic approach to schizoaffective disorder as a compromise diagnosis in clinical practice. He expresses hope that the ICD-11 may move beyond tweaking the schizoaffective criteria and embark on radical reform to aid future research and understanding.

There are several pieces on forensic issues. Dias and colleagues describe the high prevalence of mental comorbidity in prisoners with intellectual disability and argue for a coordinated treatment regime.⁴ Anand and Pennington-Smith analyse the complexities of compulsory treatment, with the sometimes conflicting goals of personal liberty and the right to treatment, with reference to the US legal framework.⁵ Commenting on the limitations of a previous review by Callaghan and Ryan, the authors lament the emphasis in guidelines and legislation on cognitive aspects of capacity, to the exclusion of other necessary facets such as the absence of duress, and impairments of volition by symptoms such as substance dependence, anosognosia, and apathy. They consider whether the concept of insight might be a preferable paradigm to capacity, providing a more comprehensive basis for decisions regarding treatment and management of risks to the patient and others. They also suggest that treatment and confinement are not the same, questioning whether hospitalisation is justified on the basis of incapacity or incompetence alone, without an imminent danger to self or others.

International Psychiatric Journals

AJP – September 2013

In the September issue of the American Journal of Psychiatry Lopez and colleagues partially reverse recent evidence of the harms of antipsychotic use in patients with a behavioural disturbance in dementia.⁶ The authors noted that data suggesting a link between antipsychotics and death in patients with dementia are complicated by the use of institutionalised patients with severe cognitive deficits and symptoms linked to non-specific morbidity. Lopez and colleagues retrospectively analysed a large longitudinal study to examine time to nursing home admission and time to death in 957 patients with probable Alzheimer’s disease, finding that 25% had been exposed to antipsychotics. A model including demographic, cognitive, and medical variables found only the use of conventional antipsychotics was associated with time to nursing home admission. This association was no longer significant after adjustment for psychiatric symptoms. Psychosis was strongly associated with time to nursing home admission and death. The authors conclude that psychiatric symptoms, rather than use of antipsychotics, was associated with time to admission and time to death.

Noting previous treatment resistance to SSRIs in combat-related PTSD, Raskind and colleagues report a randomised placebo controlled trial of alpha-1 adrenoceptor antagonist prazosin, most commonly used in hypertension, for combat-related PTSD in 67 US soldiers after deployments to Iraq and Afghanistan.⁷ The use of prazosin was based on the fact that arousal features of PTSD such as poor sleep and hypervigilance are mediated by excessive adrenergic activity. Raskind and colleagues found that prazosin reduced nightmares, and improved sleep quality and global function. It was well tolerated with no between-groups blood pressure differences. While the authors conclude that the improvements were clinically meaningful, they note subjects continued to experience significant levels of distress, and suggested investigation of the combination of prazosin with psychotherapy.

Jarskog and colleagues added to recent evidence that metformin can reduce weight, BMI, triglycerides, and haemoglobin A1c levels in overweight patients with schizophrenia, and suggest benefits of metformin may increase with longer treatment.⁸ A related editorial by Correll and colleagues asks when, how long, and for whom we should prescribe metformin alongside antipsychotic medications.⁹ Canvassing the modest but clinically significant reductions in weight and related risk factors, they conclude metformin should be tried in overweight patients on antipsychotics but only after lifestyle interventions have been tried.

The American Journal of Psychiatry has published online a report on antidepressant use in bipolar disorder by the International Society for Bipolar Disorder, headed by Pacchiarotti.¹⁰ The authors suggest controversy regarding the risk-benefit profile of antidepressants in bipolar depression justifies appeal to expert consensus in the absence of conclusive evidence. They used the Delphi method for achieving consensus through structured iterations, and concluded that the wide use of antidepressants in bipolar depression occurred despite a weak evidence base for efficacy and safety. They were unable to generally endorse antidepressants in bipolar depression, but suggested serotonin reuptake inhibitors and bupropion may be less likely to trigger mania than tricyclics and noradrenaline reuptake inhibitors. They also noted that antidepressant-triggered mood elevations are more likely in bipolar I, in these patients antidepressants should only be prescribed as adjuncts to mood stabilisers.

BJP – September 2013

In the September issue of the British Journal of Psychiatry Koesters and colleagues report a systematic review and meta-analysis of published and unpublished trials of agomelatine for depression.¹¹ They show that none of the negative studies were published, and that incorporation of all data suggests that it is unlikely that there is a clinically significant difference between agomelatine and placebo in the treatment of depression. Acute responses showed a statistically significant advantage over placebo of 1.5 points on the Hamilton Rating Scale for Depression in the acute phase of illness, with no difference on relapse rates. The paper suggests that differences in Hamilton scores less than 3 points are unlikely to be clinically significant, although they acknowledge this remains the subject of debate. The European Medicines Agency, which is a decentralised body that regulates medications in Europe, with some similarities to the Food and Drug administration in the US, authorised agomelatine for the treatment of depression in 2009. Koesters and colleagues recommend more rigorous procedures to prevent the licensure of ineffective medications. They also suggest agomelatine should not be used as a first-line treatment in patients with major depression, and express surprise at the extent of publication bias with agomelatine studies, with none of the negative trials being published, and effect sizes three times higher in published than unpublished studies.

An editorial by Franck Ramus with the provocative title “What’s the point of neuropsychoanalysis?” provides an aggressive critique of an obscure movement within psychiatry.¹² Tracing neuropsychoanalysis to the efforts of prominent neuroscientists to understand the mind as well as the brain, with particular reverence for Freud’s theories, Ramus suggests that another title might be simply “psychology”. Ramus identifies a tendency to attribute all psychological insights before the first world war to Freud, which is more reflective of an ignorance of the history of psychological ideas than of accurate assessment of Freud’s importance. He suggests that psychoanalysis is an outdated school of psychology whose “hypotheses were either trivial or untestable, or proved wrong”, and that its use is misleading in theory and pernicious in practice. Ramus concludes with a challenge to neuropsychoanalysts, to show that psychoanalytic concepts such as the Oedipus complex can be defined precisely enough to make testable predictions that are correct, and that they are not better explained by other, more simple theories.

Choi and colleagues review 26 double-blind, placebo-controlled studies of adjunctive medications intended to improve the cognitive performance of patients with schizophrenia.¹³ Contrary to their hypotheses, Choi and colleagues did not find any improvements on composite measures of cognition. They found cholinergic agents, such as acetylcholinesterase inhibitors donepezil, rivastigmine, and galantamine, showed a trend towards improved verbal learning and memory, with donepezil showing a moderate effect on spatial learning and memory. Glutamatergic agents, including glycine partial agonist D-cycloserine, glycine agonist D-serine, and glycine reuptake inhibitor sarcosine, as well as cholinergic agents, moderately improved negative symptoms, while 5HT1A agonists such as mianserin produced small improvements of positive symptoms. Choi and colleagues speculate that their results may suggest that cognitive impairment in schizophrenia reflects more systemic deficits with generalised grey and white matter abnormalities not remediable by alterations to specific neurotransmitters.

JAMA Psychiatry – September 2013

In September, JAMA Psychiatry includes a prospective cohort study by Kelleher and colleagues on psychotic symptoms and population risk for suicide attempts.¹⁴ They assessed 1100 school-based adolescents at baseline and 3 and 12 months for psychotic symptoms and suicide attempts. Of the 7% who reported psychotic symptoms at baseline, 7% reported a suicide attempt by 3 months compared with 1% of the cohort without baseline psychotic symptoms. Among those with other psychopathology in addition to psychotic symptoms at baseline, 14% reported a suicide attempt by 3 months, and 34% by 12 months. These differences were not explained by nonpsychotic psychiatric symptoms, or substance abuse. The authors emphasise that 80% of suicide attempts in this cohort occurred in patients who had experienced psychotic symptoms, as well as that most of the psychotic symptoms reported were hallucinations in the presence of intact reality testing. Kelleher and colleagues discuss research that may explain the increased risk of suicide attempts in people with psychotic symptoms as the result of increased sensitivity to stress, poorer coping skills, or the presence of risk factors increasing both suicide attempt and psychosis such as childhood abuse.

Das and colleagues describe the problem of bus therapy, in which indigent psychiatric patients are provided with a one-way bus ticket to another region and instructed to call local emergency services on their arrival.¹⁵ While acknowledging the right of patients with severe mental illness to decide where they live, Das and colleagues point out that bus therapy increases many risks including decompensation, poor self-care, loss of support networks, victimisation, and failure to access care. They trace the practice to deinstitutionalisation and recent reductions in health funding, using Nevada as an example of a state thought to have sent as many as 1500 patients to other states over the last five years. Das and colleagues speculate that this may bey due to an overstrained psychiatric care system, with mental health spending in Nevada in the lowest quartile even prior to the fifth largest percentile cut in funds between 2009 and 2012.

Molecular Psychiatry – October 2013

In the October Molecular Psychiatry Kendler provides an overview of the development and opportunities of genetic research into psychiatric disease.¹⁶ He outlines the elusive promise of family, twin, and adoption studies, with a summary of the early disappointments of aggregate molecular signals. Kendler then describes growing confidence that with increasing power and demonstrated replications, results from genome-wide association studies and large-effect size rare genomic variants may lead to significant breakthroughs in understanding. He proposes that the value of this research will be determined by the level of biological coherence of genes and molecules implicated in psychiatric disease by genetic studies. This will depend upon how well the genes and molecules can be integrated into tangible mechanisms, such as metabolic pathways, neurotransmitter systems, and neurodevelopmental trajectories.

An editorial by Sullivan in the same issue explores the history of the DISC1, or Disrupted in Schizophrenia structural genetic variant, first flagged as a potential causal agent in a subset of patients with schizophrenia 20 years ago.¹⁷ Despite long intense investigation, the role of DISC1 remains equivocal, with some research groups believing it is an aetiologic agent, some that it is not, and some that more data is needed to reach valid conclusions. Sullivan argues that progress in psychiatric genetics requires high quality research guided by rigorous standards, and that DISC1 is an example of research that is hopefully explored as ‘intriguing’ rather than confidently investigated with clear results.

Schizophrenia Bulletin – September 2013

The September issue of Schizophrenia Bulletin includes an editorial by Harrow and Jobe which questions whether long-term treatment of schizophrenia with antipsychotic medications facilitates recovery.¹⁸ They describe a relative absence of evidence for long-term benefits of antipsychotics, noting that better outcomes have only been demonstrated for 1 to 2 years after acute episodes. The evidence suggests that risk of relapse is high in the months immediately after discontinuation, but rapidly decreases after this. Some use this to justify the maintenance of clinical stability by blocking dopamine receptors, although it is also consistent with an increased risk of relapse induced by antipsychotic use. Antipsychotics are known to increase sensitivity to dopamine, an effect that could increase the risk of psychosis above baseline when antipsychotics are ceased. Long-term studies of patients maintained on antipsychotics show sustained psychopathology with few periods of recovery over periods as long as 20 years, while studies of patients who did not take antipsychotics over years show better outcomes. The authors acknowledge that these patterns are confounded by prognostic factors and may represent different subtypes of schizophrenia. They conclude that rigorous longitudinal studies are needed to determine the risks and benefits of long-term antipsychotic medications in different groups of patients.

International Medical Journals

Nature Reviews. Neuroscience. – October 2013

The October issue of Nature Reviews Neuroscience includes an article on neuroscientists in court by Jones and colleagues.¹⁹ They outline the growing demand for expert witnesses who can interpret neuroscientific findings in court, and suggest ways to avoid common sources of misunderstanding by judges and jurors listening to such testimony. They provide examples such as Grady Nelson, who violently murdered his wife. Nelson’s lawyer raised evidence of brain abnormalities, arguing that while this did not excuse his crime, it should mitigate his punishment. Jones and colleagues note that neuroscientific testimony is used both to support claims, as well as to argue for the irrelevance of neuroscientific evidence. Appeals to neuroscientific evidence are increasingly being made to help decide complex issues such as capacity, responsibility, and competence. Some may hope that the impressive technology of neuroscience may lend persuasive power to specious arguments, with some evidence that brain images in particular can affect judgements for extra-scientific reasons. The authors hope to show that, despite widespread reservations, neuroscience is not too complex and technical for jurors, lawyers, and judges to understand and use competently in their deliberations.

JAMA – 04/09/13; 11/09/13; 18/09/13

The 18th September JAMA includes a patient page on seizures. An editorial by O’Connor²⁰ and original research by Saitz and colleagues discusses the management of substance abuse using a chronic disease model.²¹ 563 people with substance dependence were randomised to a chronic care management system developed with medical illness involving a primary care clinician, motivational enhancement, relapse prevention, and integrated social, medical, addiction, and psychiatric treatment. While there were no differences in self-reported abstinence at 12 months, O’Connor suggests possible areas for further research.

Kuehn describes attempts to reduce the use of antipsychotic medications as chemical restraints in patients with dementia living in nursing homes in the US.²² Noting evidence that one in five nursing home residents were prescribed antipsychotic medications despite not having a diagnostic indication, the Centers for Medicare and Medicaid Services launched the Partnership to Improve Dementia Care. The initiative reported a 9% reduction in the number of nursing home residents receiving antipsychotics in 2012, short of the 15% goal. Kuehn discusses possible causes of inappropriate antipsychotic use in nursing homes, particularly severe understaffing and inability to implement behavioural management strategies. A lack of enforcement permits 99% of nursing homes to operate despite failing to meet federal requirements for assessing and developing care plans for patients prescribed antipsychotics. Funds earmarked for enforcement efforts were not delivered due to budget cuts in 2013.

NEJM – 05/09/13; 12/09/13; 19/09/13

The 19 September New England Journal of Medicine announced a new collaboration with Harvard Business Review. Until November 15 there will be free access to articles from health care and business experts on the Harvard Business Review website, www.hbr.org, focused on how to achieve a high-value health care system.

Baker charts the development of autism from Kanner’s original case-based portrayal of patients with profound autistic aloneness and obsessive insistence on the preservation of sameness, to its conceptualisation as a spectrum disorder in the DSM-5.²³

CEREBRAL ORGANOIDS

An article by Lancaster and colleagues in the 19th September issue of Nature reported a new approach to the study of brain development with exciting possibilities for the understanding of psychiatric illnesses such as schizophrenia.²⁴ The authors used induced pluripotent stem cells from adult humans to create self-organising neural tissues with properties and patterns of development similar to human brains. They described these entities as cerebral organoids.

An editorial by Brustle²⁵ contextualises Lancaster and colleagues’ work. Pluripotent stem cells are progenitor cells which can multiply and differentiate into almost all cell types of the human body. In modern research they can be harvested from embryos, which are largely composed of embryonic stem cells; or they can be created from cells which have already differentiated into specific cell types in more mature humans. Lancaster and colleagues show that human induced pluripotent stem cells which are placed in an appropriate medium proliferate, differentiate, and organise themselves into neural tissues as large as 4mm. The organising mechanisms replicate some mechanisms of the developing brain, which allows researchers to test hypotheses about brain development. Lancaster and colleagues report that where previous in vitro models of human brain used patterning growth factors to partially determine the developmental path of model tissues, they focused on improving growth conditions and allowed intrinsic signals to determine development. An important feature was a spinning reactor to improve nutrient distribution, allowing larger and more complex structures to survive.

Previous research in mice has shown that stem cells allowed to differentiate in medium generated waves of neurons resembling the sequence of neurons formed in the developing cerebral cortex. Another group showed that stem-cell derived neural cells aggregate and form concentric cell layers that release biomarkers appropriate for layers of the developing cortex. This group has shown spontaneous development of structures as complex as optic cups and stratified retinas.

Lancaster and colleagues have extended these results to show cerebral organoids can be sustained for months, developing fluid-filled cavities analogous to brain ventricles and choroid plexus. Tissue surrounding the cavities differentiates into areas expressing biomarkers characteristic of different areas of the human brain. The organoids also reproduce features of the developing human cortex including the ventricular zone, which generates neurons and radial glial cells, and the outer subventricular zone, which proliferates to generate the cerebral cortex. Immunohistochemistry demonstrated staining for markers specific for forebrain, midbrain, and hindbrain, with subregions characteristic of prefrontal cortex, frontal lobe, occipital lobe, and hippocampus.

Brustle notes limitations of the model, particularly the absence of a circulatory system and the macroscopic disorganisation of discrete brain regions. Nevertheless, Lancaster and colleagues succeeded in creating a patient-specific organoid using induced pluripotent stem cells from a patient with microcephaly, a neurodevelopmental disorder. Compared with organoids derived from the cells of healthy controls, the microcephalic model produced fewer progenitor cells and increased numbers of differentiated neurons, suggesting premature neuronal differentiation as a mechanism of microcephaly.

Application to schizophrenia

The promise of cerebral organoids can be seen as an extension of efforts to explore the neurodevelopmental theory of schizophrenia. Rapoport and colleagues recently reviewed evidence for the neurodevelopmental theory, which proposes that schizophrenia is caused by abnormal neurodevelopmental processes occuring as early as in utero.²⁶ They point to ongoing associations between schizophrenia and perinatal infection, in utero malnutrition, obstetric complications, childhood trauma, along with prospective longitudinal imaging studies showing evidence of premorbid and early childhood structural brain abnormalities in patients, high-risk groups, and siblings of patients with schizophrenia. Recent imaging has attempted to show disorganised connectivity between brain regions in patients with first episode psychosis.

Last month, Australian Psychiatry Review described a paper by Fan and colleagues which reported that multipotent stem cells derived from the olfactory mucosa of patients with schizophrenia were less adhesive and moved faster than those of healthy controls, and speculated that alterations in cell adhesion dynamics and cell motility could bias the trajectory of brain development in schizophrenia.²⁷

In the October issue of Molecular Psychiatry, Robicsek and colleagues report that they reprogrammed somatic cells from the hair follicles of three schizophrenia patients and two controls into induced pluripotent stem cells, then encouraged them to differentiate into neuronal lineages.²⁸ The cells derived from patients with schizophrenia showed severe difficulties in differentiating, while their glutamatergic cells were unable to mature. In addition, mitochondrial respiration and its inhibition by dopamine were impaired in the patient-derived cells. Robicsek and colleagues speculate that the mitochondrial dysfunction might be behind the neurodevelopmental derangement of dopaminergic and glutamatergic cells that leads to the expression of schizophrenic symptoms in adulthood.

Thus, cerebral organoids generated using stem cells from patients with schizophrenia may allow researchers to investigate specific hypotheses regarding how abnormal development of neural tissues in utero leads to stable expression of psychotic symptoms in schizophrenia decades later.

Conclusion

And that’s it for the October 2013 edition of Australian Psychiatry Review. Listeners directed to the podcast from the Royal Australian and New Zealand Colleage of Psychiatry CPD Online page can access questions for CPD points using the password “organ”. See you next month!

 

References

Australian and New Zealand Journal of Psychiatry

1. Berk M, Singh A. Contextualising the biology of psychiatry within its social environment. Aust. N. Z. J. Psychiatry. 2013;47(10):889–90.

2. Jacka FN, Reavley NJ, Jorm AF, Toumbourou JW, Lewis AJ, Berk M. Prevention of common mental disorders: What can we learn from those who have gone before and where do we go next? Aust. N. Z. J. Psychiatry. 2013;47(10):920–9.

3. Malhi GS. Making up schizoaffective disorder: Cosmetic changes to a sad creation? Aust. N. Z. J. Psychiatry. 2013;47(10):891–4.

4. Dias S, Ware RS, Kinner S a, Lennox NG. Co-occurring mental disorder and intellectual disability in a large sample of Australian prisoners. Aust. N. Z. J. Psychiatry. 2013;47(10):938–44.

5. Anand S, Pennington-Smith P a. Compulsory treatment: Rights, reforms and the role of realism. Aust. N. Z. J. Psychiatry. 2013;47(10):895–8.

6. Lopez OL, Becker JT, Chang Y, et al. The Long-Term Effects of Conventional and Atypical Antipsychotics in Patients With Probable Alzheimer’s Disease. Am. J. Psychiatry. 2013;170(9):1051–1058.

7. Raskind MA, Peterson K, Williams T, et al. A Trial of Prazosin for Combat Trauma PTSD With Nightmares in Active-Duty Soldiers Returned From Iraq and Afghanistan. Am. J. Psychiatry. 2013;170(9):1003–1010.

8. Jarskog LF, Hamer RM, Catellier DJ, et al. Metformin for Weight Loss and Metabolic Control in Overweight Outpatients With Schizophrenia and Schizoaffective Disorder. Am. J. Psychiatry. 2013;170(9):1032–1040.

9. Correll CU, Sikich L, Reeves G, Riddle M. Metformin for Antipsychotic-Related Weight Gain and Metabolic Abnormalities: When, for Whom, and for How Long? Am. J. Psychiatry. 2013;170(9):947–952.

10. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders. Am. J. Psychiatry. 2013;Published online:e1–14.

11. Koesters M, Guaiana G, Cipriani A, Becker T, Barbui C. Agomelatine efficacy and acceptability revisited: systematic review and meta-analysis of published and unpublished randomised trials. Br. J. Psychiatry. 2013;203(3):179–187.

12. Ramus F. What’s the point of neuropsychoanalysis? Br. J. Psychiatry. 2013;203(3):170–171.

13. Choi K-H, Wykes T, Kurtz MM. Adjunctive pharmacotherapy for cognitive deficits in schizophrenia: meta-analytical investigation of efficacy. Br. J. Psychiatry. 2013;203(3):172–178.

14. Kelleher I, Corcoran P, Keeley H, et al. Psychotic Symptoms and Population Risk for Suicide Attempt: A Prospective Cohort Study. JAMA Psychiatry. 2013;70(9):940–948.

15. Das S. Bus Therapy A Problematic Practice in Psychiatry. JAMA Psychiatry. 2013;September(Onlne):E1–E2.

16. Kendler KS. What psychiatric genetics has taught us about the nature of psychiatric illness and what is left to learn. Mol. Psychiatry. 2013;18(10):1058–1066.

17. Sullivan PF. Questions about DISC1 as a genetic risk factor for schizophrenia. Mol. Psychiatry. 2013;18(10):1050–1052.

18. Harrow M, Jobe TH. Does Long-Term Treatment of Schizophrenia With Antipsychotic Medications Facilitate Recovery? Schizophr. Bull. 2013;39(5):962–965.

19. Jones OD, Wagner AD, Faigman DL, Raichle ME. Neuroscientists in court. Nat. Rev. Neurosci. 2013;14(10):730–736.

20. O’Connor PG. Managing Substance Dependence as a Chronic Disease: Is the Glass Half Full or Half Empty? JAMA. 2013;310(11):1132–1134.

21. Saitz R, Cheng DM, Winter M, et al. Chronic Care Management for Dependence on Alcohol and Other Drugs: The AHEAD Randomized Trial. JAMA. 2013;310(11):1156–1157.

22. Kuehn BM. Efforts Stall to Curb Nursing Home Antipsychotic Use. JAMA. 2013;310(11):1109–1110.

23. Baker JP. Autism at 70 – Redrawing the Boundaries. N. Engl. J. Med. 2013;369(12):1089–1091.

24. Lancaster M a, Renner M, Martin C-A, et al. Cerebral organoids model human brain development and microcephaly. Nature. 2013;501(7467):373–379.

25. Brustle O. Miniature human brains. Nature. 2013;501(19 September):319–320.

26. Rapoport JL, Giedd JN, Gogtay N. Neurodevelopmental model of schizophrenia: update 2012. Mol. Psychiatry. 2012;17(12):1228–38.

27. Fan Y, Abrahamsen G, Mills R, et al. Focal adhesion dynamics are altered in schizophrenia. Biol. Psychiatry. 2013;74(6):418–26.

28. Robicsek O, Karry R, Petit I, et al. Abnormal neuronal differentiation and mitochondrial dysfunction in hair follicle-derived induced pluripotent stem cells of schizophrenia patients. Mol. Psychiatry. 2013;18:1067–1076.

September 2013 Transcript

Tags

Australian Psychiatry Review, Optogenetics, Psychiatry

I’m Andrew Amos, and this is the September edition of Australian Psychiatry Review. This month closes with a focus section on optogenetics, an exciting technique that allows scientists to control genetically determined types of neurons with millisecond accuracy. Highlights from the psychiatric literature over the last month include debate in the Australian and New Zealand Journal of Psychiatry over the legal and clinical basis of abortion justified by increased risk of adverse mental health; articles in JAMA Psychiatry and Biological Psychiatry exploring evidence linking schizophrenia with disrupted connections between specific brain regions, with Fan and colleagues in Biological Psychiatry demonstrating that olfactory stem cells taken from adults with schizophrenia show adhesion and motility dysfunction that might explain neurodevelopmental abnormalities.¹

Australian Psychiatric Journals

ANZJP – September 2013

Editor Scott Henderson opens the September 2013 issue of the Australian and New Zealand Journal of Psychiatry noting the value and uncertainty of opinions, defined as judgements resting on grounds insufficient for complete demonstration.² This is a useful reminder in an issue with evidence and interpretation of the merits and ethics of abortion. Fergusson and colleagues review evidence that abortion is unlikely to improve mental health risks of unwanted pregnancy, and may increase some risks.³ They link this to evidence that up to 90% of abortions in certain developed countries are authorised on the grounds that continuation of pregnancy would pose a serious threat to the woman’s mental health. Fergusson and colleagues draw the strong conclusion that there is no evidence to support the proposal that abortion has mental health benefits.

Separate viewpoints by Steinberg⁴ and Romans⁵ point out the limitations of necessarily descriptive data on abortion, which cannot establish causation, and likely miss relevant sub-groups at particularly high risk of poor outcomes. In his Editorial, Henderson notes that because of the ethical impossibility of controlled comparisons between women who are pregnant, and who seek, then either have, or do not have, an abortion, we will never be able to answer the question posed by Fergusson and colleagues. Steinberg highlights a paper by Gilchrist, the only extant research comparing women who underwent abortion with those who sought abortion but were denied, which found a higher rate of psychosis in women denied abortion.⁶

Berk and colleagues highlight the gap between the prevalence and treatment of serious mood disorders, and recommend public health measures supporting collaborative care in general practice settings.⁷ Noting high rates of recurrence, they question whether episode-based treatment should be discarded in favour of a chronic-disease model of the treatment of depression. Berk and colleagues also suggest access to public mental health services should be expanded from the current risk-based assessment, to include those with severe and potentially treatable disorders even in the absence of critical safety issues. They acknowledge that the high prevalence of mood disorders necessitates funding focused on primary care, but argue that inadequate systems of training and coordinated care mean substantial numbers of patients who do not respond to SSRIs or CBT are missing out on potentially helpful specialised interventions. They suggest primary care for mood disorders should be supported by specialist services focused on capacity generation and upskilling in primary care staff, with more intensive hands-on care where possible.

The ongoing debate regarding early intervention in psychosis continues, with McGorry arguing in a letter that recent pessimism regarding the possibility of predicting and preventing the transition from subclinical to syndromal psychotic illness is unfounded.⁸ An associated letter by Jorm agrees with McGorry that CBT may be the most appropriate first intervention for people at risk of psychotic illness, while highlighting that recent interventions using antipsychotics in patients at high risk of psychosis raise ethical concerns.⁹

 

International Psychiatric Journals

JAMA Psychiatry – August

An article by van den Heuvel and colleagues in the August edition of JAMA Psychiatry reports structural diffusion tensor imaging and functional magnetic resonance imaging in patients with schizophrenia and healthy controls.¹⁰ Their analysis is motivated by a dynamic model which conceptualises the brain as a large-scale network of interconnected hub regions which integrate distributed cognitive processes. They found significant interruptions in the pathways connecting midline frontal, parietal, and insular cortical areas in patients with schizophrenia. They also noted that anatomical features connecting distributed nodes in patient brains determined more of the interactions between those areas than in healthy controls, suggesting more automatic and less dynamic brain function in patients. They link these results with models of psychosis involving ineffective integration of perceptual and intellectual information distributed throughout the brain. An editorial by Bullmore and Vertes¹¹ link van den Heuvel’s work with modeling approaches, including the increasing use of graph theory to represent complex brain networks. Graph theory abstracts brain organisation as regional nodes connected by edges with measurable patterns of connectivity showing emergent properties such as small-worldness. A small-world network is one in which most nodes of the network are not connected with each other, but are reachable by a small number of intermediating nodes.

A viewpoint by Braff and Braff contrasts the rapid advances in neuroscientific knowledge with the slow pace of change in neuropsychiatric clinical practice.¹² More rapid advances in translational medicine tend to occur where diseased tissue can be directly examined, such as solid tumours, while neuropsychiatric symptoms arise from less tangible disruption of complex neural circuits. They note the promising illusion of genetic testing for neuropsychiatric disease, with its abundance of genetic factors of very small effect, placed in perspective by the ongoing failure to generate any effective treatments even from the identification of the autosomal dominant Huntington’s gene, and suggest toning down overstated claims to avoid public disappointment.

An article by Martin and colleagues published online on August 28 reanalyses data from a national US survey and concludes that the traditional truism that depressive illness is more prevalent in women is explained by different characteristic symptoms of depression in men and women.¹³ They suggest that prevalence rates of depression are equal when using scales that include externalising symptoms found at higher rates in men, including anger/aggression, substance abuse, and risk-taking. They consider different explanations of these patterns, including that men may be more willing to report externalising symptoms such as anger because they are less threatening to masculine ideals than traditional symptoms such as sadness and hopelessness.

Nelson and colleagues provide a long-term follow-up of ultra-high risk patients recruited to the PACE clinic in Melbourne, Australia between 1993 and 2006.¹⁴ Transition to psychosis was assessed in 416 patients between 2 and 15 years after presentation. The overall rate of transition was 35% over ten years, with the highest risk in the first two years. Factors associated with transition included year of presentation, duration of psychosis prior to entry, baseline function, negative symptoms, and disorders of thought content. The authors conclude that services should follow patients at risk of psychosis for at least two years, with closer monitoring for people with longer duration of symptoms and poorer functioning at presentation.

Molecular Psychiatry

In September Molecular Psychiatry published a review by Taylor and colleagues of the vascular depression hypothesis, which proposes that cerebrovascular disease may interact with geriatric depression.¹⁵ They describe well-established relationships between late-life depression, vascular risk factors, and brain imaging abnormalities, including treatment resistant depression predicted by cognitive deficits. Taylor and colleagues propose a disconnection hypothesis where the specific site of vascular damage and white matter lesions determines depressive and cognitive symptomatology, more than globally distributed damage. They refer to research linking late-life depression with damage to neural tracts including the anterior thalamic radiation, cingulum bundle, uncinate fasciculus, and superior longitudinal fasciculus. They examine how inflammatory and hypoperfusion processes might influence the development of depression.

Biological Psychiatry

The 15th September Biological Psychiatry includes two articles reviewing the potential of oxidative stress measures and cortisol as state and trait markers for schizophrenia. Flatow and colleagues provide a meta-analysis of blood oxidative stress parameters in schizophrenia, including the effects of clinical status and antipsychotic treatment.¹⁶ They identify possible state markers for acute psychosis in antioxidant status, red blood cell catalase levels, and plasma nitrite levels, all elevated during acute episodes, while red blood cell superoxide dismutase may be a trait marker for schizophrenia, as it is abnormal in both stable and acutely unwell patients.

Walker and colleagues report data from a longitudinal multicenter trial examining cortisol in people at risk of psychosis and healthy controls.¹⁷ Cortisol was higher in those at-risk of psychosis, positively correlated with baseline symptom severity, and higher in those who transitioned to psychotic-level symptoms.

Triggered by evidence from genetic association studies implicating genes involved in neural migration in the aetiology of schizophrenia, Fan and colleagues reported that olfactory neural cells derived from patients with schizophrenia were less adhesive and moved faster than those of healthy controls.¹ They biopsied the olfactory mucosa, which contains multipotent stem cells capable of neurogenesis throughout life, and used time-lapse imaging to assess cell motility and adhesion dynamics. The authors conclude that alterations in cell adhesion dynamics and cell motility could bias the trajectory of brain development in schizophrenia.

Khadka and colleagues examined functional brain connectivity in patients with schizophrenia, psychotic bipolar disorder, relatives of patients with schizophrenia or bipolar disorder, and healthy controls with no family history.¹⁸ They used resting state functional magnetic resonance imaging to assess regional interactions of brain circuits and found evidence of network abnormalities, most pronounced in schizophrenia, with a similar pattern in bipolar disorder, and less severe patterns in healthy relatives of those with mental illness. The authors speculate that there may be a continuous spectrum of circuit dysfunction from healthy controls without family history, through unaffected relatives, to those with mental illness, and discuss disrupted connections as potential endophenotypes of psychosis. They tentatively identify such endophenotypes in the disruption in three regional networks common to patients and their relatives but not healthy controls: fronto-occipital cortex, frontal/thalamic/basal ganglia, and sensorimotor networks.

Schizophrenia Bulletin – September 2013

In the September Schizophrenia Bulletin Velligan and colleagues report a trial in which 142 patients in the maintenance phase of treatment for schizophrenia were randomised to usual treatment, in-person compliance support, or an electronic medication monitor that cues medication use, warns of errors, records complaints, and alerts treatment staff of non-adherence.¹⁹ Adherence was equivalent in both active treatments at 90-92%, significantly better than treatment as usual, at 73%. Better adherence was not associated with better outcomes.

Journal of Clinical Psychiatry

The August issue of Journal of Clinical Psychiatry includes a randomised controlled trial by Trivedi and colleagues of lisdexamfetamine augmentation of major depressive disorder resistant to escitalopram treatment.²⁰ On the basis of evidence of antidepressant effects of dopaminergic agents, 129 patients were randomised to augmentation with placebo or lisdexamfetamine, a prodrug of dexamphetamine approved for ADHD in the US. The authors conclude that while there were no differences in remission rates, there was a reduction in symptoms measured by the MADRS (Montgomery–Åsberg Depression Rating Scale) based on a p-value of 9%. The most common adverse effects were headache and dry mouth.

 

International Medical Journals

JAMA

The August 7 issue of JAMA is a themed issue on violence and human rights, with multiple articles relevant to psychiatrists. An editorial by Katherine Mills examines treatment of comorbid substance dependence and PTSD.²¹ Foa and colleagues report a RCT involving 165 patients with comorbid PTSD and alcohol dependence.²² They compared naltrexone, exposure therapy, or both, with supportive therapy. They show that naltrexone can reduce dependence behaviours without exacerbating PTSD symptoms. While exposure therapy did not affect trauma outcomes at the end of treatment, it did reduce relapse over 6 month follow-up, and may improve drinking outcomes. The combination of treatments was not superior to either treatment alone.

Crosby discusses the management of a refugee from the civil war in Somalia treated in the US for weakness, pain, and PTSD.²³ She describes a multidisciplinary, culturally acceptable approach, alongside evidence-based World Health Organisation guidelines for the management of patients exposed to trauma, violence, and large-scale disasters, with attention to countries with limited resources. Crosby includes specific instructions for interviewing refugees likely to have been exposed to violence, including questions about torture and recovery. van Ommeren and colleagues recommend therapy and advise against pharmacotherapy as first-line treatments for acute stress symptoms and PTSD in the absence of moderate to severe depression.²⁴ Feder and colleagues summarise WHO recommendations regarding management of women exposed to intimate partner violence.²⁵ The recommendation against screening all women for intimate partner violence is based on evidence that screening does not reduce intimate partner violence or improve women’s outcomes.

In the August 21 JAMA, President of the APA, Jeffrey Lieberman and colleagues announce the importance of early detection and intervention approaches to schizophrenia, noting the slower pace of reform in the US compared with other developed countries, due most likely to the difficulty of financing early detection and intervention in a system highly dependent on health insurance in the absence of universal health care.²⁶

Lancet

A letter in the August 24 Lancet reports that the South Korean Neuropsychiatric Association has changed the term for schizophrenia from jungshingbunyeolbyung, or mind-split disorder, to johyeonbyung, or attunement disorder, to avoid the stigma associated with the earlier term preventing people from presenting for treatment.²⁷ The letter notes that a similar change in 2002 in Japan did lead to increased presentations with psychotic illness, and reflects that the meaning of the new term is not self-evident to Korean speakers, but requires explanation, similar to the term schizophrenia when introduced by Bleuler.

BMJ

On the 19 August the BMJ published a cluster randomised trial by Richards and colleagues on collaborative primary care for depression in the UK.²⁸ 581 adults in 51 primary care practices allocated to collaborative or usual care showed better outcomes for the collaborative care group on a Patient Health Questionaire-9 (PHQ-9) measure of depression at four and twelve months. Collaborative care was delivered by care managers under the supervision of mental health specialists.

That’s it for the monthly roundup, next we look at optogenetics in psychiatry.

Optogenetics in Psychiatry

Optogenetics is a set of novel neuroscience techniques developed over the last decade that render genes and proteins in nerve cells responsive to light. Essentially, scientists modify receptor genes expressed in specific types of neurons so that they or their protein products can be selectively activated or inhibited by the application of light. Deisseroth presents a non-technical overview in Scientific American,²⁹ while a review by Fiala and colleagues in Current Biology in 2010 describes various optogenetic techniques in more detail.³⁰ Collectively these techniques answer the major challenge for neuroscience identified by Francis Crick in 1979, the need to control one type of cell in the brain while leaving others unaltered.³¹

The main points established by this feature are:

• optogenetics combines genetic engineering of protein expression with light-sensitive protein molecules to control the firing of genetically determined sets of neurons
• particular ion channels used in optogenetics to activate or inactivate neurons include P2X2 and the channelrhodopsins
• optogenetics has most commonly been used in animal models such as drosophila melanogaster, or fruit-fly models
• by activating or inactivating specific sets of neurons, optogenetics has refined previous models of reward by identifying how specific groups of cells in the amygdala, ventral tegmental area, and nucleus accumbens interact when animals learn a conditioned fear response
• optogenetics promises control over subcellular units such as vesicles, gene transcription, and endoplasmic reticulum

Basic optogenetic techniques

Fiala and colleagues outline basic optogenetic approaches.³⁰ One technique used in research with drosophila melanogaster, a common animal model of neural mechanisms, causes an ion channel protein, P2X2, to be expressed in specific neuron populations. The channel protein remains closed until it is bound by a specific ligand, ATP. Researchers then inject ATP bound by a light sensitive molecule which prevents binding to P2X2. They are then able to selectively activate genetically defined neuron populations by opening the P2X2 channel with strong UV light, which releases ATP for binding, causing specific neurons to fire.

Another technique involves conjugating a light-sensitive molecule to an ion channel in a neuronal membrane. Varying the wavelength of light changes the conformation of the light-sensitive molecule, fixing the channel open or closed, activating or inhibiting the neuron.

A particularly common technique uses channelrhodopsins isolated from green algae. Rhodopsins are cation channels which bind to all-trans retinal, a chemical that makes the channel sensitive to blue light. This protein is particularly useful because the channel can be opened and closed with light flashes of milliseconds duration, similar to the time-frame of neuronal membranes during action potentials.

As it requires genetic modification and access to brain tissue, optogenetics research is currently limited to animal models. Nevertheless, in May Current Opinion in Neurobiology published online a review of implications of optogenetics for psychiatric diseases.³² They summarise optogenetics research on brain circuits involved in sleep, arousal, fear, and social and aggressive behaviour.

Sleep researchers have made strong use of optogenetics. Sleep and arousal arise from complex interactions between multiple populations of cells distributed throughout the brain. Optogenetic techniques have been applied to orexin secreting cells in the lateral hypothalamus and noradrenergic cells in the locus ceruleus. Both orexin and noradrenaline increase arousal. Direct optical stimulation of orexin releasing neurons increased the probability of waking in a frequency-dependent manner, while stimulation of locus ceruleus neurons caused immediate waking in sleeping animals.

Optogenetics is proving particularly useful in dissecting the neuronal pathways associated with reward seeking in animal models of addiction, including the mechanisms of brain circuit adaptations after exposure to drugs of abuse. Russo and Nestler provide a targeted review of reward circuits involved in mood disorders in Nature Reviews Neuroscience.³³ The basic reward circuit in the human brain involves dopaminergic neurons in the ventral tegmental area of the midbrain, which project to the nucleus accumbens (NAc), a ventral part of the basal ganglia. These neurons consistently release small amounts of dopamine, called tonic stimulation. Acute increases in dopamine, or phasic release, have been thought to signal rewarding or salient stimuli, allowing learning to selectively increase or decrease behaviours associated with particular stimuli.

Optogenetics has allowed researchers to demonstrate that VTA DA neurons respond to reward outcomes while VTA GABA neurons are sensitive to predicting cues. Mice self-stimulated cells in the basolateral amygdala, but not the prefrontal cortex, while silencing basolateral amygdala afferents to the NAc reduced reward associated behavioural changes. These results suggest that VTA DA neurons and glutamatergic neurons from the basolateral amygdala facilitate reward seeking by activating DA sensitive neurons in the NAc, while VTA GABA neurons and inhibitory cholinergic interneurons in the NAc decrease reward-seeking behaviour by inhibiting DA sensitive neurons in the NAc.

While traditional neuroscience techniques allowed a basic description of the brain circuits underlying fear and anxiety, optogenetics has produced a more detailed understanding.³² Researchers have examined how stimulating or inhibiting specific neurons in the amygdala interferes with fear conditioning. For example, they have shown that optogenetic activation of pyramidal neurons in the lateral amygdala paired with a sound can induce fear conditioning in the same way as pairing an aversive stimulus like footshock with a sound. Other optogenetic studies have shown that there are two populations of inhibitory GABAergic interneurons in the central nucleus of the amygdala which differentially respond to conditioned aversive stimuli, such as the tone that comes to be feared after being paired with a footshock. Interaction between these two sets of cells determines freezing behaviour in response to the tone. Taken together, these results suggest that the lateral amygdala integrates information about conditioned and unconditioned stimuli, while the central nucleus of the amygdala elicits the conditioned response of freezing.

Deisseroth and colleagues have begun to examine the mechanism of deep brain stimulation in treatment resistant depression and other psychiatric illnesses.³¹ Optogenetics allowed them to show that therapeutic effects of DBS applied to the STN are mediated by afferent axons arising from other regions rather than cell bodies in the STN.

The optogenetics repertoire continues to expand. Welberg, in Nature Reviews Neuroscience, describes new techniques allowing light-induced inhibition of vesicular release into synapses, and control of gene transcription and chromatin modifications.³⁴ Another article by Deisseroth outlines extensions of optogenetics allowing selective activation of larger sets of neurons, including neurons defined by their projections, as well as general electrical and biochemical control of all non-nervous system cells in the body.³¹ Deisseroth suggests the next step will be specific control of subcellular units such as endoplasmic reticulum, kinases, and transcription factors, leading to an unprecedented level of control of cellular and subcellular processes.

A quiz with associated Continuing Medical Education points is available to listeners accessing this podcast through the Royal Australian and New Zealand College of Psychiatrists’ Continuing Professional Development page. To access the quiz you will need to enter the word “light” and follow instructions.

And that’s it for the September edition of Australian Psychiatry Review. See you next month!

References

1. Fan Y, Abrahamsen G, Mills R, et al. Focal adhesion dynamics are altered in schizophrenia. Biol. Psychiatry. 2013;74(6):418–26.  http://www.ncbi.nlm.nih.gov/pubmed/23482246.

2. Henderson S. Opinions, data and policy. Aust. N. Z. J. Psychiatry. 2013;47(9):793–794.  http://anp.sagepub.com/lookup/doi/10.1177/0004867413501268.

3. Fergusson DM, Horwood LJ, Boden JM. Does abortion reduce the mental health risks of unwanted or unintended pregnancy? A re-appraisal of the evidence. Aust. N. Z. J. Psychiatry. 2013;47(9):819-827.  http://www.ncbi.nlm.nih.gov/pubmed/23553240.

4. Steinberg JR. Does existing research inform policies authorizing abortion for mental health reasons? Aust. N. Z. J. Psychiatry. 2013;47(9):798-801.  http://www.ncbi.nlm.nih.gov/pubmed/23859831.

5. Romans S. Asking the unanswerable: Stymied again by the impossibility of sensible controls. Aust. N. Z. J. Psychiatry. 2013;47(9):802-804.  http://www.ncbi.nlm.nih.gov/pubmed/23803898.

6. Gilchrist AC, Hannaford PC, Frank P, Kay CR. Termination of pregnancy and psychiatric morbidity. British Journal of Psychiatry. 1995;167(2):243–8.  http://www.ncbi.nlm.nih.gov/pubmed/20350638.

7. Berk M, Scott J, Macmillan I, Callaly T, Christensen HM. The need for specialist services for serious and recurrent mood disorders. Australian & New Zealand Journal of Psychiatry. 2013;47(9):815–818.  http://anp.sagepub.com/lookup/doi/10.1177/0004867413479407.

8. McGorry P. Beyond DSM: Early stages of disorder pose predictable and modifiable risk for persistent disorder. Aust. N. Z. J. Psychiatry. 2013;47(9):880-881.  http://www.ncbi.nlm.nih.gov/pubmed/23630395.

9. Jorm AF. Treatment to reduce risk of psychosis: The need to consider the potential harms as well as the benefits. Aust. N. Z. J. Psychiatry. 2013;47(9):881-882.  http://www.ncbi.nlm.nih.gov/pubmed/23744984.

10. Van den Heuvel MP, Sporns O, Collin G, et al. Abnormal Rich Club Organization and Functional Brain Dynamics in Schizophrenia. JAMA Psychiatry. 2013;70(8):783–792.  http://www.ncbi.nlm.nih.gov/pubmed/23739835.

11. Bullmore E, Vértes P. From Lichtheim to Rich Club: Brain Networks and Psychiatry. JAMA Psychiatry. 2013;70(8):780–782. http://www.ncbi.nlm.nih.gov/pubmed/23739868

12. Braff L, Braff DL. The Neuropsychiatric Translational Revolution: Still Very Early and Still Very Challenging. JAMA Psychiatry. 2013;70(8):777–779. http://www.ncbi.nlm.nih.gov/pubmed/23739986

13. Martin LA, Neighbors HW, Griffith DM. The Experience of Symptoms of Depression in Men vs Women: Analysis of the National Comorbidity Survey Replication. JAMA Psychiatry. 2013:1–7.  http://www.ncbi.nlm.nih.gov/pubmed/23986338.

14. Nelson B, Yuen HP, Wood SJ, Lin A, Spiliotacopoulos D. Long-term Follow-up of a Group at Ultra High Risk (“Prodromal”) for Psychosis. JAMA Psychiatry. 2013;70(8):793–802. http://www.ncbi.nlm.nih.gov/pubmed/23739772

15. Taylor WD, Aizenstein HJ, Alexopoulos GS. The vascular depression hypothesis: mechanisms linking vascular disease with depression. Mol. Psychiatry. 2013;18(9):963–74.  http://www.ncbi.nlm.nih.gov/pubmed/23439482.

16. Flatow J, Buckley P, Miller BJ. Meta-analysis of oxidative stress in schizophrenia. Biol. Psychiatry. 2013;74(6):400–9.  http://www.ncbi.nlm.nih.gov/pubmed/23683390.

17. Walker EF, Trotman HD, Pearce BD, et al. Cortisol levels and risk for psychosis: initial findings from the north american prodrome longitudinal study. Biol. Psychiatry. 2013;74(6):410–7.  http://www.ncbi.nlm.nih.gov/pubmed/23562006.

18. Khadka S, Meda S a, Stevens MC, et al. Is Aberrant Functional Connectivity A Psychosis Endophenotype? A Resting State Functional Magnetic Resonance Imaging Study. Biol. Psychiatry. 2013;74(6):458–466.  http://www.ncbi.nlm.nih.gov/pubmed/23746539.

19. Velligan D, Mintz J, Maples N, et al. A randomized trial comparing in person and electronic interventions for improving adherence to oral medications in schizophrenia. Schizophr. Bull. 2013;39(5):999–1007.  http://www.ncbi.nlm.nih.gov/pubmed/23086987.

20. Trivedi MH, Cutler AJ, Richards C, et al. A Randomized Controlled Trial of the Efficacy and Safety of Lisdexamfetamine Dimesylate as Augmentation Therapy in Adults With Residual Symptoms of Major Depressive Disorder After Treatment With Escitalopram. J. Clin. Psychiatry. 2013;74(08):802–809.  http://article.psychiatrist.com/?ContentType=START&ID=10008372.

21. Mills K. Treatment of Comorbid Substance Dependence and Posttraumatic Stress Disorder. JAMA. 2013;310(5):482–483. http://www.ncbi.nlm.nih.gov/pubmed/23925616

22. Foa EB, Yusko DA, McLean CP, et al. Concurrent naltrexone and prolonged exposure therapy for patients with comorbid alcohol dependence and PTSD: a randomized clinical trial. JAMA. 2013;310(5):488–95.  http://www.ncbi.nlm.nih.gov/pubmed/23925619.

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