Artwork During Recovery From Encephalitis

I recently wrote about anti-NMDA receptor encephalitis, a neurological disorder that often manifests with psychiatric symptoms, such as depression and hallucinations.

The latest American Journal of Psychiatry features a strange series of four drawings made by a 15 year old girl during an episode of the disease, which presented as psychotic symptoms but later progressed to severe insomnia and epilepsy before it was diagnosed and treated.

"As she gradually recovered we asked her to draw something. She did not know what to draw, so we suggested an animal, such as a dog, but she did not know how to start.

When we told her that a dog has four legs, a tail, two ears, two eyes, and a mouth, she drew an abstract figure that consisted of a head with four legs (A). Her next drawing, of a cat, looked exactly the same, apparently since they share the same basic features.

Two weeks later the dog now looked more recognizable but like a human, standing upright, with two arms and four legs...All body parts were listed beneath the figure in the same color as they were drawn (B).

Two months after the patient was transferred to a local rehabilitation center, the cat was catlike for the first time; it had four legs, was normally proportioned, and was correctly positioned. Colors were used adequately. However, this drawing still looked like one by a primary school child instead of a 15- year-old girl (C).

Finally, after 5 months of rehabilitation her drawing had a normal composition. She still had the urge to write down what she drew, she did not encircle the figures anymore (D)."

Esseveld MM, van de Riet EH, Cuypers L, and Schieveld JN (2013). Drawings During Neuropsychiatric Recovery From Anti-NMDA Receptor Encephalitis. The American journal of psychiatry, 170 (1), 21-2 PMID: 23288386

Mental Illness and Crime, Yet Again

As if on cue, a major study about the relationship (if any) between mental disorder and crime has appeared just when everyone's talking about that.

Although having said that, people seem to be interested in that issue most of the time nowadays, in the UK at any rate, with schizophrenia topping the list of supposedly scary syndromes.

So - should we be worried?

The new research, from Australian team Morgan et al, surveyed everyone born in the state of Western Australia between 1955 and 1969. About 1.6 million people lived there over the course of the study so this was a big project.

By linking local records of arrests over the period 1985 to 1996 to the database of psychiatric diagnosis, the researchers were able to examine disorder-crime correlations in the entire population - meaning that there was no possibility of bias.

So what happened? Here's some highlights:

• 32% of psychiatric patients had been arrested at least once. Unfortunately, it's not clear what the rate was in the general population, but that falls into the range of overall arrest rates in most countries.
• 11% of those arrested had a psychiatric diagnosis. This rose to 20% of arrests for violent offences.
• 0.8% of suspects had schizophrenia, rising to 1.7% for violent offences.
• The number of arrests in people without a disorder fell over the period 1985-1996, reflecting the well-known fact that people commit fewer crimes as they get older. However, in psychiatric patients, there was no change over time.
• For murder, 30% of suspects had a psychiatric history while 3% had a diagnosis of schizophrenia.
• Both substance abuse and personality disorders were associated with higher arrest rates than schizophrenia, but schizophrenia in turn was higher than depression, anxiety, and other miscellaneous disorders.
• Although only 1.7% of violent offenders had schizophrenia, those with the disorder were somewhat more likely to involve strangers, and to take place in public places, and less likely to target family and partners.

Overall this confirms that the great majority of crimes, including violent ones, are not committed by people with mental illness, and that your chance of getting 'murdered by a lunatic' is incredibly low. This strikes me as the only statistic that matters to most people.

There's a long-standing debate over whether people with various disorders are more likely to commit crimes than they would be if they didn't have one, the relative risk. While interesting, this is a purely academic question. What the rest of us need to know is the absolute risk, and this is low.

Morgan VA, Morgan F, Valuri G, Ferrante A, Castle D, and Jablensky A (2012). A whole-of-population study of the prevalence and patterns of criminal offending in people with schizophrenia and other mental illness. Psychological medicine, 1-12 PMID: 23234722

Neither Drugs Nor Therapy Prevent Psychosis

Neither medication nor psychotherapy is effective in improving the prognosis for youngsters considered to be at high risk of developing psychosis, according to a major study just published.

The idea of identifying and treating young people at risk of becoming psychotic - because of a family history of schizophrenia, or because they're showing some mild symptoms - has become very fashionable lately. But can we really do anything to pre-empt the disorder?

In this trial, 115 "ultra-high risk" Australian subjects were randomized to three different treatment conditions, or if they didn't agree to treatment, they were just followed up to see what happened.

The treatments didn't work. Here's the smoking gun, showing the proportion who didn't go psychotic over time:

This shows all four of the subject groups did pretty much the same in terms of their likelihood of becoming psychotic. Neither cognitive therapy, nor the antipsychotic drug risperidone (at a low dose) had any effect: those given 'supportive therapy' (basically: sympathetic chats) and a placebo pill did just as well.

There probably wasn't even a placebo effect: none of the three treatment groups did better than people who got no treatment at all (monitoring group), although people weren't randomly assigned to that group, so that's a little less clear.

Is this a surprise? Yes, if you believed the early studies to examine this question which claimed great things for drugs and therapy. But the current findings are no shock if you've been following the (much larger) recent trials - for example the British one from earlier in the year, which found zero benefit of cognitive therapy.

Early small trials have a nasty habit of not working out in the long run.

The other lesson here is that even "ultra-high risk" folks usually don't get psychotic: only about 10-20% of them, in fact, became ill in the first two years of this study; the British results I mentioned are very similar.

So is this really "ultra high"? Relatively, yes it is; even a 10% risk is far higher than the chance that a random person on the street would have. But in absolute terms, perhaps not.

A concern here is that rounding these folks up, labelling and 'treating' them might make their lives worse, or even increase the risk of psychosis. That's not just my opinion: that's what the very cognitive therapists who eagerly run these trials believe (or ought to, if they're being consistent with their own theories).

One of the key ideas in cognitive accounts of psychosis is that the belief and fear that one is 'going crazy', or that you're otherwise abnormal, is itself a major source of stress that actually leads to worsening of symptoms.

What could be scarier than being told you're at "ultra high risk"?

Preventing psychosis is a great idea in theory. But most bad ideas are.

McGorry, P., Nelson, B., Phillips, L., Yuen, H., Francey, S., Thampi, A., Berger, G., Amminger, G., Simmons, M., Kelly, D., Thompson, A., and Yung, A. (2012). Randomized Controlled Trial of Interventions for Young People at Ultra-High Risk of Psychosis The Journal of Clinical Psychiatry DOI: 10.4088/JCP.12m07785

Beware Small Positive Studies

A Letter in the prestigious American Journal of Psychiatry offers a skeptical response to a paper published there recently.

The original article claimed amazing benefits of a safe and cheap brain stimulation technique in treating schizophrenia. But Dutch letter-writers Sommer et al aren't convinced.

It's a short piece and worth quoting:

We read with interest the article by Brunelin et al. in the July issue, which described the application of transcranial direct-current stimulation (tDCS) in the treatment of both auditory hallucinations and negative symptoms simultaneously... An effect size of 1.58 was reported for refractory hallucinations, which is remarkably large when compared with the effect sizes of antipsychotic medication (0.4–0.6).

Clinical trials involving nonconvulsive brain stimulation in schizophrenia were first introduced in 1999. Initial effect sizes were very large while samples were small. Some years later, large negative studies were published. To date, 17 placebo controlled transcranial magnetic stimulation (TMS) studies on hallucinations have been published. The mean weighted effect size is now around 0.3. Yet, the negative correlation between effect size and year of publication suggests that over time, the mean effect size may become smaller.

When selective serotonin reuptake inhibitors (SSRIs) were introduced for depression, effect sizes greater than 1.0 were reported, which created their legacy as a wonder drug. Over the course of 20 years, the mean effect size of SSRIs decreased to around 0.3. A similar trend was demonstrated for cognitive-behavioral therapy.
 
This trend likely results from publication bias. A remarkably high effect size suggests the discovery of a new wonder treatment. Studies with such findings are therefore easily published in high-impact journals. In contrast, studies of similar sample size with marginally or nonsignificant findings are less likely to be accepted for publication. Usually, after some years, negative studies with large sample sizes become available. This is when meta-analyses start to detect a decrease in efficacy.

In this view, the Brunelin et al. study is exemplary of an initial placebo-controlled study applying a new technique: it included a small sample, found remarkably large effects, and is published in a high-impact journal.
 
We sincerely hope that tDCS is the exception to the rule— as a cheap, safe, and highly effective method to treat both refractory hallucinations and negative symptoms is most welcome. However, given the previous observations for other new treatments, it is realistic to expect that 10 years from now the mean weighted effect size of tDCS will be around 0.3.

Sommer et al are talking about the famous 'decline effect', in which the size of an effect mysteriously shrinks the more people study it, which I've written about before.

I suspect the authors are right in this case; playing science devil's advocate though, it's unfair and unscientific to assume that a new treatment that looks promising will eventually turn out to be mediocre, just because that's happened to other treatments before.

After all, some things look awesome because they are - penicillin, for example, was heralded as a new wonder drug... and it was.

I very much doubt that tDCS is the new penicillin. But I do think that this kind of speculation is ultimately not very useful. Rather than bemoaning the errors of the past and wondering whether they'll be repeated, we should reform science to make sure they don't.

Sommer IE, Aleman A, Slotema CM, and Schutter DJ (2012). Transcranial stimulation for psychosis: the relationship between effect size and published findings. The American Journal of Psychiatry, 169 (11) PMID: 23128925

A New Theory of Psychosis?

A team of British neuroscientists led by the (in)famous David Nutt says that magic mushrooms offer a new theory of psychosis: Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis

It's a reanalysis of a study from earlier this year, which got quite a lot of attention, in which 15 volunteers were injected with psilocybin - the major active hallucinogenic ingredient in 'magic mushrooms' - during an fMRI scan.

In a nutshell, the rather interesting proposal in the new paper is that psilocybin may cause mind-altering effects by blurring the difference between the brain networks responsible for 'internal' and 'external' thought.

Activity in the internal "default mode network" (DMN) is generally anti-correlated with the "task-positive network" (TPN) - when one is higher, the other's lower. The DMN is active when you're not doing much - hence 'default' while the TPN comes online when you're engaged in a particular mental activity.

Nutt's team say, however, that their functional connectivity fMRI data show that after psilocybin, activity in these two networks becomes positively correlated - an unusual pattern. They write:

Increased DMN-TPN coupling has been found in people at high risk of psychosis and an inability to distinguish between one’s internal world and the external environment, sometimes referred to as “disturbed ego boundaries,” is a hallmark of early psychoses and the psychedelic state.

One of our volunteers reported the following after psilocybin: “It was quite difficult at times to know where I ended and where I melted into everything around me.”

To be honest I'd need to see a replication before I put too much faith in this, because this kind of post-hoc reanalysis of fMRI data is very flexible and therefore prone to false positives, but it's an interesting idea, and at least it provides a clear theory for further research.

Carhart-Harris RL, Leech R, Erritzoe D, Williams TM, Stone JM, Evans J, Sharp DJ, Feilding A, Wise RG, and Nutt DJ (2012). Functional Connectivity Measures After Psilocybin Inform a Novel Hypothesis of Early Psychosis. Schizophrenia bulletin PMID: 23044373

Preventing Psychosis?

Can we prevent psychosis?

In a major study just published, Early detection and intervention evaluation for people at risk of psychosis, 288 young British adults who were deemed to be 'at risk of psychosis' were randomized to get cognitive therapy (CT) or a control condition. The hope was that it could prevent transition to serious psychotic illness.

The primary outcome measure was how many of them later went on to get diagnosed with full-blown psychosis. 2 years later, 7% of the CT group and 9% of the controls had, so that's no significant benefit of treatment. CT slightly reduced the level of mild psychotic-like symptoms, but not how much distress they caused.

So, in other words, no we can't prevent psychosis, not with CT alone at any rate. But there's lots more interesting stuff here...

Now a transition rate of some 8% over 2 years is lower than in previous studies and might suggest that the concept of the 'psychosis risk syndrome'  or 'at-risk mental state' (under consideration for inclusion in DSM-5) is a bit dodgy. The venerable Prof. Allen Frances thinks so. But he misses the fact that the rate was 18% when you also count the people who went psychotic during the baseline assessments (to be fair to Frances, the authors buried that bombshell quite deep in the Discussion).

Still, that's still 82% false positives. Is that too high?

We can't tell, from a study like this. As in any disease screening program, we need to know the relative costs and benefits of true and false 'hits', as well as the percentages of them.

Here's some food for thought on that note. One of the key tenets of the CT model of psychosis is that 'psychotic' symptoms are a more or less normal response to stress, and that psychosis is maintained by a cycle of thoughts and feelings in which these experiences are themselves a source of concern, because they're felt to be abnormal, pathological, or otherwise threatening, thus leading to more stress, and more symptoms, and hence more concern... and so on. CT aims to break that cycle.

Check it out (image from here, coauthored by Graham Dunn, senior author of the present work.)

If you accept that, then it seems that literally the worst possible thing you could say to someone in the 'at risk mental state' is "Watch out! You're at risk of going psychotic!" According to CT, exactly that line of thinking is the root of the whole problem.

The authors of this paper indeed write that "Key ingredients of the approach [include] a focus on normalising psychotic-like experience". But who deemed them abnormal in the first place? The patient, all by themselves... or some well-meaning professional? It's not clear.

We are told that the patients were "seeking help for symptoms", but why? Of their own accord, or after someone else raised concerns? 45 people were referred to the study but excluded because they said that they didn't want help. So there was at least some degree of professional 'railroading', driven by the idea that people with such symptoms ought to seek help

If you accept the CT account of psychosis, then I'd say you ought to think very seriously about whether this whole thing isn't equivalent to giving everyone an X-ray to detect cancers. The X-rays might end up causing more tumours than they find.

I wonder if the authors of this study considered this.

Anyway. Keith Laws of LawsNeuroBlog has a good post about the study and the rather overexcited way it's been received in the press (even, er, the BMJ...)

Despite the authors not being able to make any claims about CT positively affecting transition rates... and the lack of any medication analysis (in fact all patients were unmedicated as an entry requirement) they conclude:

"On the basis of low transition rates, high responsiveness to simple interventions such as monitoring, a specific effect of cognitive therapy on the severity of psychotic symptoms, and the toxicity associated with antipsychotic drugs, we would suggest that antipsychotics are not delivered as a first line treatment to people meeting the criteria for being in an at risk mental state"

So the article in the UK Guardian entitled Drugs not best option for people at risk of psychosis, study warns is not simply misunderstanding by a journalist, but what looks like author spinning.... The BMJ press release itself is headlined Cognitive therapy helps reduce severity of distress among psychotic patients - even though the paper (and the press release itself!) clearly states:

"Cognitive therapy did not significantly affect distress related to these psychotic experiences...nor levels of depression, social anxiety, or satisfaction with life..."

Morrison, A., French, P., Stewart, S., Birchwood, M., Fowler, D., Gumley, A., Jones, P., Bentall, R., Lewis, S., Murray, G., Patterson, P., Brunet, K., Conroy, J., Parker, S., Reilly, T., Byrne, R., Davies, L., and Dunn, G. (2012). Early detection and intervention evaluation for people at risk of psychosis: multisite randomised controlled trial BMJ, 344 (apr05 1) DOI: 10.1136/bmj.e2233

The Stigma(s) of Mental Illness

Fighting "the stigma of mental illness" is big business at the moment. But does "the stigma" really exist?

As I said back in 2010 :

There is a stigma of schizophrenia, and there's a stigma of depression, etc. but they're not the same stigma. We're told it's a myth that "the mentally ill are violent" - [but] no-one thinks depressed or anorexic people are violent. They think (roughly) that people with psychosis are. They have other equally silly opinions about each diagnosis, but there's no monolithic "stigma of mental illness".

Now a paper has come out which explores this idea in some detail: Stereotypes of mental disorders differ in competence and warmth. The title says it all : people have stereotypical views of people suffering from different mental disorders, but these stereotypes vary substantially.

The authors use the "Stereotype Content Model" framework, which despite the fancy name is very simple. On this view stereotypes are characterised by two dimensions, "competence" and "warmth". These are pretty self-explanatory. Warmth is whether you're seen as nice and friendly, or hostile and dangerous. Competence is whether you're thought to be good at it.

We all know that warmth and competence are distinct and indeed orthogonal concepts, and they crop up in other languages and in popular culture.

Anyway, in two Mechanical Turk online surveys of American adults, they first showed that respondants felt that "people with mental illness" were low on competence and (slightly) low on warmth, compared to other social and ethnic groups. That's similar to the ratings of the homeless, poor, and welfare recipients.

However in the second study, they asked about specific diagnoses, and this revealed a more complex pattern. I've shown the results above (colors are mine). There seemed to be four clusters. Mental retardation and Alzheimer's were perceived as warm, but incompetent; sociopaths and violent criminals were the opposite.

Schizophrenia clustered with homelessness and addiction in a worst-of-both-worlds category of low warmth and competence, while what could broadly be called "emotional" disorders, like bipolar, depression and anxiety, were rated more favorably. For what its worth, OCD was the least bad diagnosis.

These are interesting results. The only oddity about the method was that people weren't actually asked what they thought about these people; they were asked “In general, how much do Americans believe that..." This is, apparantly, standard procedure in this kind of stereotype research, but it seems a little strange to me.

Sadler, M., Meagor, E., and Kaye, K. (2012). Stereotypes of mental disorders differ in competence and warmth Social Science and Medicine DOI: 10.1016/j.socscimed.2011.12.019

Good Science, Bad History, in the British Journal of Psychiatry

The latest February 2012 issue of the British Journal of Psychiatry features a paper about the association between child abuse and later mental health problems. I haven't read it yet, but it looks pretty good.

However, it also includes an editorial from John Read and Richard Bentall which argues that:

Just 20 years ago, however, it would have been difficult to get the paper published. Mental health professions have been slow, even resistant, to recognise the role of childhood adversities in psychiatric disorder... Until very recently the hypothesis that abuse in childhood has a causal role in psychosis was regarded by many biologically oriented psychiatrists as heresy...

Really? I checked the BJP from exactly 20 years ago. The February 1992 issue contained:

• A paper about child sexual abuse in female psychiatric patients.
• A letter praising a different article, on the same topic.
• A review of 11 studies on psychosocial family interventions as treatments for schizophrenia.
• A paper looking at the effect of the social environment on symptoms of schizophrenia.

Four strikes and they're out. It's not true that this kind of thing wasn't being discussed 20 years ago.

Such grandstanding is bad for science. Few would deny that psychiatry in recent years has undervalued psychosocial factors and overvalued genetics and neuroscience, but it's actually quite a complicated story, not a Punch and Judy show with bad guys on one side and good guys on the other.

Rhetorical flourishes like this editorial certainly get attention but in the long run, down that road lies madness.

Read, J., and Bentall, R. (2012). Negative childhood experiences and mental health: theoretical, clinical and primary prevention implications The British Journal of Psychiatry, 200 (2), 89-91 DOI: 10.1192/bjp.bp.111.096727

Science Majors are from Mars...

According to a new study, students with a family history of autism tend to major in math and science, while substance abuse and depression are more common in the ancestors of humanities fans.

In an online survey, over 1,000 new Princeton undergrads were asked about their intended major and whether anyone in their family had been diagnosed with one of 16 neurological and psychiatric disorders. More details here.

Of the 16 maladies, 5 were so rare that there wasn't enough data to analyze. Of the remaining 11, there were significant differences between the three types of students in four. The categories being humanities, social sciences, and "technical" i.e. science, engineering and maths. Social science majors were in the middle, except for autism.

See the graph I made above.

It's an interesting study. The autism result seems tenuous though because only 24 of 1077 students reported any autism in their immediate family. That's 3% of "technical" students and 1% of others, so not very many. The authors excluded schizophrenia and epilepsy from the analysis on the grounds of being too rare - and they had 18 each. Substance abuse and depression had over 150 each, so those differences are rather more solid.

The authors note that this fits with various previous studies and they discuss their findings in Baron-Cohen-esque terms:

It has been suggested that autism represents an extreme manifestation of a ‘‘systemizing’’ nature. Since ASDs have complex inheritance, shared genetic variation between close relatives might establish a continuous phenotype which in milder forms confers interest or benefits in understanding highly structured fields... Similarly, affective disorders may represent an extreme phenotype of emotional lability that, in milder forms, is commensurate with interest in the humanities.

Hmm. OK, but does that really make sense? Sure, it fits with the popular image of the Geeky Scientist vs the Tortured Artist - but that's not science, that's stereotypes. Why would emotional lability make you favor the humanities, exactly?

Imagine if the stereotype was the Geeky Artist vs the Tortured Scientist (and there really have been plenty of both, over the years). Couldn't we rationalize that equally well? Picture the scene... -

"People with autistic traits are drawn to study the humanities because they wish to learn about humans and their emotions, something they find hard to do in day-to-day life... While emotionally volatile people like science and maths because they offer a calming sense of order and stability..."

Campbell BC, and Wang SS (2012). Familial Linkage between Neuropsychiatric Disorders and Intellectual Interests. PloS one, 7 (1) PMID: 22291951

Young, Canadian and on Antipsychotics

Antipsychotic use in Canadian children and teens is rising dramatically - prescriptions more than doubled in just 4 years, from 2005 to 2009.

That's according to a paper just out from Pringsheim et al. It's been known for a while that broadly the same is true of the USA. The data reveal that the Canadian border is no barrier to the spread of antipsychotics.

What's surprising is that while in the USA, some of these drugs are officially licensed for use in certain children and adolescent psychiatric disorders, in Canada all such use is off-label. That didn't stop there being nearly 700,000 youth prescriptions for an antipsychotic in 2009, in a country with a total population of 35 million - although bear in mind that this includes multiple prescriptions for the same person.

The growth in antipsychotics is accounted for by the second-generation "atypical" antipsychotics. Risperidone (Risperdal) was the biggest success story accounting for well over half of the total.


What's disturbing about this, as I've said before, is not so much the fact that these drugs are being used but the speed of the growth. It represents a fundamental shift in the way children and adolescent mental health problems are treated, one which has happened so fast that it's hard to believe that there was time to properly think through the consequences...

Use of SSRI antidepressants and psychostimulants (mainly ADHD drug methylphenidate, Ritalin) also rose between 05 and 09, but only by about 40%. That means that there were more antipsychotic than SSRI prescriptions in children and teens by 09, which is pretty remarkable.

Only 13% of the youth antipsychotic recommendations were actually for psychosis, the original indication of the drugs. The leading diagnosis was ADHD, which is odd, because the main drugs for ADHD, such as Ritalin, boost dopamine release, while antipsychotics block dopamine's effects via D2 receptors.


Other popular indications were mood disorders and conduct disorders. Overall, the fact that the vast majority of the antipsychotic prescriptions were not for psychosis confirms the view that the term "antipsychotic" for these drugs is misleading.

Pringsheim T, Lam D, and Patten SB (2011). The Pharmacoepidemiology of Antipsychotic Medications for Canadian Children and Adolescents: 2005-2009. Journal of child and adolescent psychopharmacology PMID: 22136092

A Psychedelic Tale of Two Neurotransmitters

An unexpected interaction between neurotransmitter systems may explain psychosis and hallucinations, according to a fascinating new paper.

Serotonin (5HT) and glutamate are two neurotransmitters. Up until now, it was thought that they acted independently. A given neuron might have receptors for both serotonin and glutamate, but they didn't interact: serotonin would never affect the glutamate receptors, and vice versa.

The new research overturns that view. Authors Miguel Fribourg and colleagues of Mount Sinai School of Medicine show, in a series of elegant experiments in mice, that different receptors can cluster together, forming a complex. The two receptors, serotonin's 5HT2A and glutamate's mGluR2, can talk to each other.

However, this doesn't seem to happen under normal conditions. Serotonin and glutamate don't seem to trigger the receptor interaction, or at least not very much. Only certain drugs can do it. And this is where it gets really interesting.

Psychedelic drugs, like LSD, have long been thought of as 5HT2A agonists, binding to the receptor and activating it. It turns out that this was only half right. They also inhibit mGluR2 transmission via the receptor complex. Serotonin itself is a 5HT2A agonist, but it doesn't do that. So psychedelics seem to be a kind of (for want of a better word) "superagonist".

It also works in reverse. The antipsychotic drugs clozapine and risperidone are known as 5HT2A antagonists. But Fribourg et al show that they also activate the mGluR2 receptor.

And the cross-talk can go in the other direction. Certain molecules that act on mGluR2 can either inhibit or promote 5HT2A. Unlike psychedelics and antipsychotics, these mGluR2 drugs have not been tested in humans yet. But these data predict that they will have psychedelic-like or antipsychotic-like effects, depending which way they work.

The interaction turns out to be all about G proteins, which are part of the chain of transmitter substances that convey signals within the cell, in response to neurotransmitters outside it. Here's a chart showing the effects of various drugs on the balance between different G proteins: the LSD-like psychedelic DOI has the opposite effect from the antipsychotics clozapine and risperidone.

This paper builds on a previous one from the same team showing that psychedelic 5HT2A "agonists" (like LSD and DOI) have different effects on G proteins from other, non-psychedelic agonists. That was interesting in itself but by adding glutamate to the picture, this new paper is really ground-breaking.

This goes a long way to explaining one of the mysteries of serotonin which is this:  if 5HT2A agonists like LSD are psychedelic, why aren't antidepressants the same? Almost all antidepressants work by increasing extracellular 5HT levels. That ought to mean that they activate 5HT2A receptors (indirectly). This explains why not - 5HT alone doesn't promote the crucial 5HT2A-mGluR2 interaction.

Taken together, these interesting results show clearly that 5HT2A and mGluR2 are hooking up and doing something exciting. Certainly in terms of how hallucinogens work.

I'm less convinced that this can directly explain antipsychotic effects though. The problem is that while newer "atypical" antipsychotics act on 5HT2A, the older antipsychotics don't, and atypicals are at best only slightly more effective on average.

What we don't yet know is whether this kind of complex receptor interactions can happen with other receptors. I'd have thought it unlikely that these two receptors were the only ones that could ever do it. The synapse looks like it's more complex than we could have imagined.

Fribourg M, et al. (2011). Decoding the Signaling of a GPCR Heteromeric Complex Reveals a Unifying Mechanism of Action of Antipsychotic Drugs. Cell, 147 (5), 1011-23 PMID: 22118459

Susan Greenfield's Dopamine Disaster

It's Susan Greenfield again.

Continuing her campaign warning of the dangers of modern technology in terms of their effects on the vulnerable brains of the young, the British neuroscientist and Baroness has written another article. This is the latest of many. None of them have been in peer reviewed academic journals.

This one's behind the Great Times Paywall so I can't link to it, but it's called Are video games taking away our identities?

The first part of the article is hard to argue against. Either you'll agree with it or you won't. Personally, videogames as Greenfield describes them bear little resemblance to any games that I've played recently. Similarly for her account of the Internet. But maybe this rings true for some:

Screen images do not depend for their impact on seeing one thing in terms of anything else. Their premium lies invariably in their raw sensory content... we are perhaps heading towards a much weaker sense of identity by engaging in a world where we are the passive recipient of senses and where there is no fixed narrative of past and future but an atomised thrill of the moment. One could even suggest that the constant self-centred readout on Twitter belies a more childlike insecurity, an existential crisis.

Greenfield then moves into discussing the brain, and this is where the science comes in. This is her "home turf" - she's Professor of physiology at Oxford. Yet it's a shambles.

There is one alarm bell ringing, which suggests that increasing 2D screen existence may be having undesirable effects: it is the threefold increase over the past decade in prescriptions for drugs for attention deficit hyperactivity disorder.

While this could be due to changes in doctors’ prescribing procedures, or indeed to a greater recognition and medicalisation of attentional problems, a third possibility could indeed be that if the young brain is exposed from the outset to a world of fast action-reaction, of instant new screen images flashing up with each press of a key, then such rapid interchange might lead to a shorter attention span.

The human condition can be basically divided into two alternating modes, first described by Euripedes... the rational “bread force”, characterised by a strong cognitive take on the world — a personalised past, present and future, in turn related to an active prefrontal cortex and lower levels of the brain chemical dopamine; and the “wine force”, more the state of young children or those adults indulging in “letting themselves go”, in situations perhaps involving wine, women and song, where a strong sensory environment demands less reflection, more passive reaction.

...An increase in physiological arousal can be linked to excessive release of dopamine. Could the screen experience be tilting this ancient balance in favour of the more infantile, senses-driven brain state?

Greenfield says that high dopamine and low prefrontal cortex activity is associated with irrationality and a deficit in attention. Video games are causing a flood of dopamine and causing ADHD. That would make sense, if ADHD was caused by too much dopamine, and if drugs for ADHD reduced dopamine release.

The problem is that it's the exact opposite. Drugs for ADHD increase dopamine release and ADHD is widely believed (although it's controversial) to be caused by a dopamine deficit.

Greenfield then says "We know too that dopamine suppresses the activity of neurons in the prefrontal cortex", but this is a serious oversimplification. Dopamine has complex effects on target neurons. It can inhibit firing, but it can also excite it. It all depends on the conditions. Here's what the authors of an influential scientific review said in 2004: "It is agreed by most researchers is that dopamine is a neuromodulator and is clearly not an excitatory or inhibitory neurotransmitter"

Some say that dopamine helps to "tune" the prefrontal by increasing the signal to noise ratio - more signal, less noise. Here's one of the most cited papers about dopamine and the PFC: Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey.

Remember that drugs for ADHD like Ritalin, which are sometimes used illicitly by students without that disorder to help them focus and concentrate, cause dopamine release. If Greenfield were right, it would be the exact opposite.

...[other] people characterised by an underactive prefrontal cortex are those with schizophrenia, this time not due to physical damage but rather a chemical imbalance, in particular an excessive amount of the transmitter dopamine. In schizophrenia, like children, the patient is easily distracted, cannot interpret proverbs, is not strong on metaphor but takes the world literally; it is a vibrant world that can implode on, and overwhelm, the fragile firewall of the schizophrenic mindset.

This again is a serious simplification. Actually, you don't need to be a neuroscientist to work that out. Just recall the earlier bit: Greenfield has said that ADHD is caused by too much dopamine leading to an underactive prefrontal cortex. Now she says that schizophrenia is the same. So why are the symptoms of ADHD completely different from schizophrenia?

Why is it, in fact, that Ritalin and similar dopamine releasing drugs help with ADHD, but can make schizophrenia worse?

As a neuroscientist, I can tell you that we don't really know what's going on with dopamine in ADHD or schizophrenia. There's decent evidence that dopamine is involved in schizophrenia, but not in any straightforward sense. Schizophrenia is now believed to be linked to reduced dopamine in the prefrontal cortex, and too much in other areas.

As for ADHD, remember: the leading theory is that it's about too little dopamine. Not too much.

The only disease that we know certainly is associated with too little dopamine is Parkinson's. Contrary to Greenfield's theory, people with Parkinson's often have cognitive and mood problems as well as the better known difficulties with movements. They're not super intelligent, prefrontal-cortex-wielding geniuses.

I appreciate that an opinion piece in the Times is never going to be a rigorously argued scientific paper, but the fact that Greenfield's article contains several claims which are the exact opposite of the truth (or at least of current scientific thinking) calls her credibility into serious question.

Mountains of Mental Disorders

This is a story about a man who lived in a house. Here it is:

The house was a lovely thatched cabin, situated in a wooded valley between two little hills, set against the spectacular scenary of a snow-capped mountain. He'd been born there, and he'd lived there all his life.

One day, there was a knock on the man's door. He opened it to find two official-looking people carrying clipboards, with serious expressions on their faces.

"Hello, sir. We are officials from the Ministry of Mountains. Sorry it took us so long."
"Oh... excuse me?", the man replied, puzzled.
"We're very sorry we didn't get here earlier."
"I'm afraid that I don't know what you mean. I wasn't expecting any..."
"Hmm. Let me explain. The Ministry of Mountains exists to help people who live on mountains. So, you see, we're here to..."
"Ask for directions to the mountain? It's about 10 miles down the road. Just look up - you can't miss it."

The official looked unamused.
"No. We're here to help you, sir."
"Help you to cope with the rigors of mountain living!" the other chimed in, helpfully.
"But... I don't live on a mountain."
"I'm afraid you do. Look - " and the first official unfolded a large map. "Do you agree that there is a mountain, here?" and she pointed to a spot 10 miles down the road.
"Yes. Actually I just told you about i..."
"...and, do you agree that you live - here?"
"Of course, but..."

"So you do live on the mountain. The very ground beneath our feet right now is part of that mountain nearby."
"No it's not." The man protested. "This is a valley, miles away. I mean just look outside. We're clearly not on a mountain now, are we?"
"How old fashioned. That's what we used to think. But, thanks to advances in geology, we now appreciate that these hills and valleys are merely a part of the mountain."
"Yes!" the other said, whipping out a textbook and becoming increasingly enthusiastic. "You see, a mountain is merely a mass of rock, and this rock extends underground for a considerable distance... It's impossible, really, to draw a line on the map and say categorically, this side is mountain, this isn't. So 'mountains' are an arbitrary construct. 'Hills' are likewise just protrusions of the underlying mountain and..."

The man was even more confused now. "Umm... well, I suppose, technically...but..."
"...so yes, so you do live on a mountain. And we know that this is very difficult. You're exposed to all kinds of dangers like blizzards, altitude sickness, avalanches..."
"Not really. It's nice here. It doesn't even snow most years."
"That's unlikely. You agree that mountains have blizzards and avalanches? Right. And you earlier agreed that there's no dividing line between you and a mountain. So logically..."
"Er..."
"So you are in danger! Don't worry, though. We're here to help. To start off with, we're going to reinforce your house with six tons of cement, to protect you against rockfalls. The construction crew will arrive tomorrow morning. Now, as for those blizzards..."
The man had had enough of this.
"This is absurd. Now look - there is a guy who really does live on top of the mountain in a rickety old shack. Old Grandpa McHermit. He might actually need your help. I don't. Get out! And if I see anyone with a bag of cement tomorrow morning, I'll shove it right up their..."

---

As you may have guess, this story is a metaphor. There is a movement in psychiatry at the moment, away from a 'categorical' view of mental illness towards a 'spectrum' view. Mental disorders are not things you either have or don't - defined according to some arbitrary cut-off. Rather, they're things that everyone has, to some degree.

This has already happened, or is happening, to autism, schizophrenia, bipolar disorder, personality disorders, and more.

Now, the "spectrum" or "dimensional" approach has much to recommend it. It's true that diagnostic cutoffs are arbitrary. It's true that the categorical approach doesn't capture the true degree of variation that real people display.

My worry is that these new "spectra" are, in practice, merely the old categories, just bigger. We still think of people as being ill or not-ill, although we may call it on the spectrum or off it. Worse, we still think of "ill" in the same way as we used to i.e. as referring to the most severe end of the spectrum. The only difference is that we've expanded the old category of "ill" to cover more people.

This is evident in the fact that we still use the old categorical labels. It's the autism (or schizophrenia or bipolar) spectrum, even though "autism", in the old sense of a discrete disorder, is now supposed to be just one extreme of that spectrum. Yet the point about an extreme is that it's unusual, so why call it that?

We don't call the rainbow the red spectrum. We don't call height the midget spectrum. We don't call hills part of the mountain spectrum.

The point is, we really think of color and height and altitude as spectra, not as approximations to an extreme point, and that's good, because they are. Now it might well be possible to think of autistic or bipolar traits in the same way - but not if we call them autistic and bipolar traits. And not if we just rename them, while keeping the mental associations the same.

Not unless we can find a way of referring to what's currently called the autism spectrum without making anyone think of autism when they hear it. Similarly for "bipolar" and all the rest. Until we get to that point, there's a real risk that "spectra" will just be big categories.

Edit: This post has been very kindly translated into Hebrew over at the alhasapa.com blog.

Mental Illness And Creativity Revisited

A new study offers support for the theory that mental illness is associated with "creative" achievement.

The idea that madness is close to creative genius is a popular one. From the nutty professor to the tortured genius, there's no end of sterotypes, and pop culture seemingly offers plenty of examples, from Van Gogh and his ear to Charlie Sheen and his bi-winning.

But is it true?

A new study says yes. Kyaga et al looked at everyone in Sweden who had been treated as an inpatient for either schizophrenia, bipolar disorder, or depression, between 1973 and 2003. In total that meant about 300,000 people (two thirds of that was depression).

They then matched this up with the Swedish national census which asks people their occupation. They looked to see whether the psychiatric cases were more likely to have been employed in a "creative" profession. They defined that as visual artists (photographers, designers, etc.) non-visual artists (musicians, actors, authors) and academics (university teachers).

Finally, they pulled up the records on the patients' relatives, to see what their jobs were. This is one of those studies that could only happen in Scandinavia, because only those countries keep such comprehensive ( rather scarily so) info about their citizens.

They found that being bipolar, or being a close relative of someone who's bipolar, was associated with having a creative job. For schizophrenia, the picture was more complex: being a schizophrenia inpatient was not linked to being a creative in itself, but being related to someone with schizophrenia was. The effects were fairly modest.

For depression (not bipolar, just plain unipolar depression), there was no link at all, or even a slightly lower level.

The correlation wasn't driven by differences in IQ (yes, they had data on that too, for males, thanks to military service records.) Creative types had higher IQs on average while psych inpatients had slightly lower IQs than others. So correcting for IQ made the associations even stronger.

So it looks as though being bipolar, at any rate, is linked to creativity, and so is having bipolar and schizophrenia in the family - if you believe these findings. Should we?

This study was huge and the data are, on the face of it, very comprehensive. However, it turns out that many people didn't state their occupation, especially the patients. Only 45% of people with schizophrenia gave a valid answer, compared to 75% of the bipolar and depressed. In the controls, it was about 80%.

That's a serious issue. The authors did try to get around this by looking at the siblings of the patients with missing data. For schizophrenia, siblings of missing data schizophrenics were more creative than for the ones with full data, and for bipolar there was no difference. So the effects are not due to nonreporting of non-creative jobs.

Another possible confound is family background and environment. Indeed, the fact that people with bipolar were no more likely to be in a creative job than their relatives who weren't bipolar (or, at least, never received inpatient treatment) rather supports this view. Maybe the relatives shared genes with the patients meaning that their creativity was associated with bipolar, but we can't know that.

One reassuring piece of evidence against the idea that these results were driven by a general correlation between psychiatric hospitalization and "middle class professions" is that there was no association with the "non-creative" job of accountancy and auditing (sorry accountants and auditors).

Overall, while this is an interesting study, and while I find the proposed link between mental illness and creativity plausible, we need more detailed research to ensure that the correlation isn't just a reflection of socioeconomic factors.

Kyaga, S., Lichtenstein, P., Boman, M., Hultman, C., Langstrom, N. Landen, M. (2011). Creativity and mental disorder: family study of 300 000 people with severe mental disorder The British Journal of Psychiatry DOI: 10.1192/bjp.bp.110.085316

Schizophrenia And The Developing World Revisited

A major international study threatens to overturn what we thought we knew about schizophrenia.

People with schizophrenia are more likely to get better if they live in poor countries: that's been known for about 25 years. In the 1980s, a series of pioneering World Health Organization (WHO) studies looked at the prognosis for people diagnosed with schizophrenia around the world.

All of the data showed that people in developed countries were less likely to recover than those from poorer areas.

This paradoxical finding sparked no end of debate. What is it about these countries that makes them a better place to get schizophrenia? Patients in richer countries tend to have access to more and "better" psychiatric care, the latest drugs, and so on. Does this mean that those treatments are useless - worse, harmful? That's been the interpretation of some people.

But is it true? Not always, says a new study, W-SOHO. It's out in the British Journal of Psychiatry.

The authors compared schizophrenia outcomes in 37 countries. They recruited outpatients who were starting, or changing, antipsychotic medication. They found that in terms of "clinical" remission - i.e. improvement in the delusions, hallucinations, and other symptoms of schizophrenia - people in the developing world did indeed fare better than those from rich countries.

Over a 3 year period, 80-85% of patients from East Asia, the Middle East, and Latin America who started off ill, showed clinical remission, compared to 60-65% in Europe. That's not new: it confirms what the old WHO data showed.

But the new study also looked at "functional" remission - essentially, being able to participate in society:

having good social functioning for a period of 6 months. Good social functioning included those participants who had: (a) a positive occupational/vocational status, i.e. paid or unpaid full- or part-time employment, being an active student in university or housewife; (b) independent living; and (c) active social interactions, i.e. having more than one social contact during the past 4 weeks or having a spouse or partner.

For functional remission, Northern Europe (e.g. the UK, France, Germany) was the best place to get sick, with 35% achieving it. Not a very high figure, but better than elsewhere: it was just 18% in the Middle East and 25% in East Asia, despite these areas having the highest chances of clinical remission. Latin America did pretty well, however, at 29%.

This is a very important finding if it's true. Is it solid?

First off, were Northern European patients just less ill to start with? Not really. They had the highest rates of suicide attempts. They tended to be older, and to have been diagnosed at a later age, which was correlated with worse functional remission. Regression analyses confirmed that region was a predictor of remission controlling for all the other variables.

However, Northern European patients did tend to have better function at baseline. They were more likely to be employed, living independently, and socially active when they entered the study. 63% were living independently which is much higher than anywhere else: it was 24% in Middle East and Latin America. 23% had a paid job compared to 17-19% in developing countries.


That's not a flaw in the study as such but it does suggest that the differences, whatever they are, are already in place before people get treated.

One concern I have is that the definition of "functional remission" may be North Europe-centric. "Living independently" is something we aspire to but in other places, with a strong tradition of the extended family household, the idea that it would be a bad thing for someone with schizophrenia to be living with their family might seem silly. If that means they'll be cared for and supported, what's wrong with it?

And in terms of paid employment, Northern Europe just has a stronger economy than most other places (erm... well, it did back in 2000 when these data were collected), so maybe it's no surprise that people with schizophrenia were more likely to have paid jobs.

In terms of the study itself, it was extremely large with over 17,000 patients enrolled. But here's the thing: this study was run by Lilly, the drug company who make olanzapine, an antipsychotic used in schizophrenia. Three of the authors on the paper are Lilly employees, and the lead author was a consultant for them. The study deliberately sampled lots of people taking olanzapine, presumably in order to find out whether they did better.

None of this necessarily means that the data aren't valid, but I'm just not sure I trust Lilly over the WHO.

Haro JM, Novick D, Bertsch J, Karagianis J, Dossenbach M, & Jones PB (2011). Cross-national clinical and functional remission rates: Worldwide Schizophrenia Outpatient Health Outcomes (W-SOHO) study. The British journal of psychiatry : the journal of mental science, 199, 194-201 PMID: 21881098