Neurology Center

The works of Sigmund Freud were enormously influential in 20th century psychiatry, but they've now been reduced to little more than a fringe belief system. Armed with the latest version of my PubMed history script, and inspired by this classic gnxp post on the death of Marxism, postmodernism, and other stupid academic fads I decided to see how this happened.

As you can see, the number of published scientific papers related to Freud-y search terms like psychoanalytic has flat-lined for the past 50 years. That represents a serious collapse of influence, given the enormous expansion in the amount of research being published over this time.

Since 1960 the number of papers on schizophrenia has risen by a factor of 10 and anxiety by a factor of 80 (sic). The peak of Freud's fame was 1968, when almost as many papers referenced psychoanalytic (721) as did schizophrenia (989), and it was more than half as popular as antidepressants (1372). Today it's just 10% of either. Proportionally speaking, psychoanalysis has gone out with a whimper, though not a bang.

The rise of Cognitive Behavioral Therapy (CBT), however, is even more dramatic. From being almost unheard until the late 80's, it overtook psychoanalytic in 1993, and it's now more popular than antipsychotics and close on the heels of antidepressants.

What's going to happen in the future? If there is to be a struggle for influence it looks set to be fought between CBT and biological psychiatry, if only because they're pretty much the only games left in town. Yet one of the reasons behind CBT's widespread appeal is that it hasn't thus far overtly challenged biology, has adopted the methods of medicine (clinical trials etc.), and has presented itself as being useful as well as medication rather than instead of it.

One of the few exceptions was Richard Bentall's book Madness Explained (2003) in which he criticized psychiatry and presented a cognitive-behavioural alternative to orthodox biological theories of schizophrenia and bipolar disorder. Bentall remains on the radical wing of the CBT community but in the coming decades this kind of thing may become more common. Only time will tell...

Important news from San Francisco neuroscientists Stuber et al: Dopaminergic Terminals in the Nucleus Accumbens But Not the Dorsal Striatum Corelease Glutamate.

The finding's right there in the title: dopamine is a neurotransmitter, and so is glutamate. Stuber et al found (in mice) that many of the cells that release dopamine also simultaneously release glutamate - specifically, almost all of the cells that project to the nucleus accumbens, involved in pleasure and motivation, also release glutamate. By contrast none of the dopaminergic neurons projecting to the nearby dorsal striatum, involved in movement regulation do this.

Previous work had provided some suggestive evidence for some degree of glutamate/dopamine co-release but this is the first hard evidence and the fact that basically all the dopamine input to the nucleus accumbens is also glutamate input is especially striking.

This is important because it overturns the idea that neurons only release one neurotransmitter each. In fact, it's been clear for a while that this isn't strictly true: there are various little-understood peptide transmitters or "neurohormones" that are known to be co-released, but their function is obscure in most cases.

Dopamine and glutamate on the other hand are both extremely well studied neurotransmitters in their own right. Glutamate's the single most common transmitter in the brain while dopamine is famous for its role in motor control, motivation, Parkinson's disease, mental illness and the action of recreational drugs, just for starters.

What exactly the glutamate does in the nucleus accumbens is completely mysterious at present but future work will no doubt shed light on this. More generally, this paper is a reminder of the fact that our knowledge of the brain is still in its infancy...

Stuber, G., Hnasko, T., Britt, J., Edwards, R., & Bonci, A. (2010). Dopaminergic Terminals in the Nucleus Accumbens But Not the Dorsal Striatum Corelease Glutamate Journal of Neuroscience, 30 (24), 8229-8233 DOI: 10.1523/JNEUROSCI.1754-10.2010

Remember the voodoo correlations and double-dipping controversies that rocked the world of fMRI last year? Well, the guys responsible have teamed up and written a new paper together. They are...

The paper is Everything you never wanted to know about circular analysis, but were afraid to ask. Our all-star team of voodoo-hunters - including Ed "Hannibal" Vul (now styled Professor Vul), Nikolaus "Howling Mad" Kriegeskorte, and Russell "B. A." Poldrack - provide a good overview of the various issues and offer their opinions on how the field should move forward.

The fuss concerns a statistical trap that it's easy for neuroimaging researchers, and certain other scientists, to fall into. Suppose you have a large set of data - like a scan of the brain, which is a set of perhaps 40,000 little cubes called voxels - and you search it for data points where there is a statistically significant effect of some kind.

Because you're searching in so many places, in order to avoid getting lots of false positives you set the threshold for significance very high. That's fine in itself, but a problem arises if you find some significant effects and then take those significant data points and use them as a measure of the size of the effects - because you have specifically selected your data points on the basis that they show the very biggest effects out of all your data. This is called the non-independence error and it can make small effects seem much bigger.

The latest paper offers little that's new in terms of theory, but it's a good read and it's interesting to get the authors' expert opinion on some hot topics. Here's what they have to say about the question of whether it's acceptable to present results that suffer from the non-independence error just to "illustrate" your statistically valid findings:

Q: Are visualizations of non-independent data helpful to illustrate the claims of a paper?

A: Although helpful for exploration and story telling, circular data plots are misleading when presented as though they constitute empirical evidence unaffected by selection. Disclaimers and graphical indications of circularity should accompany such visualizations.

Well he's not. Actually, I haven't met him, so it's always possible. But what he certainly has done is written a book called Unhinged: The Trouble with Psychiatry.

Daniel Carlat's best known online for the Carlat Psychiatry Blog and in the real world for the Carlat Psychiatry Report. Unhinged is his first book for a general audience, though he's previously written several technical works aimed at doctors. It comes hot on the heels of a number of other recent books offering more or less critical perspectives on modern psychiatry, notably these ones.

Unhinged offers a sweeping overview of the whole field. If you're looking for a detailed examination of the problems around, say, psychiatric diagnosis, you'd do well to read Crazy Like Us as well. But as an overview it's a very readable and comprehensive one, and Carlat covers many topics that readers of his blog, or indeed of this one, would expect: the medicalization of normal behaviour, to over-diagnosis, the controversy over pediatric psychopharmacology, brain imaging and the scientific state of biological psychiatry, etc.

Carlat is unique amongst authors of this mini-genre, however, in that he is himself a practising psychiatrist, and moreover, an American one. This is important, because almost everyone agrees that to the extent that there is a problem with psychiatry, American psychiatry has it worst of all: it's the country that gave us the notorious DSM-IV, where drugs are advertised direct-to-the-consumer, where children are diagnosed with bipolar and given antipsychotics, etc.

So Carlat is well placed to report from the heart of darkness and he doesn't disappoint, as he vividly reveals how dizzying sums of drug company money sway prescribing decisions and even create diseases out of thin air. His confessional account of his own time as a paid "representative" for the antidepressant Effexor (also discussed in the NYT), and of his dealings with other reps - the Paxil guy, the Cymbalta woman - have to be read to be believed. We're left with the inescapable conclusion that psychiatry, at least in America, is institutionally corrupt.

Conflict of interest is a tricky thing though. Everyone in academia and medicine has mentors, collaborators, people who work in the office next door. The social pressure against saying or publishing anything that explicitly or implicitly criticizes someone else is powerful. Of course, there are rivalries and controversies, but they're firmly the exception.

The rule is: don't rock the boat. And given that in psychiatry, all but a few of the leading figures have at least some links to industry, that means everyone's in the same boat with Pharma, even the people who don't, personally, accept drug company money. I think this is often overlooked in all the excitement over individual scandals.

For all this, Carlat is fairly conservative in his view of psychiatric drugs. They work, he says, a lot of the time, but they're rarely the whole answer. Most people need therapy, too. His conclusion is that psychiatrists need to spend more time getting to know their patients, instead of just handing out pills and then doing a 15 minute "med check" - a great way of making money when you're getting paid per patient (4 patients per hour: ker-ching!), but probably not a great way of treating people.

In other words, psychiatrists need to be psychotherapists as well as psychopharmacologists. It's not enough to just refer people to someone else for the therapy: in order to treat mental illness you need one person with the skills to address both the biological and the psychological aspects of the patient's problems. Plus, patients often find it frustrating being bounced back and forth between professionals, and it's a recipe for confusion ("My psychiatrist says this but my therapist says...")

This leads Carlat to the controversial conclusion that psychiatrists should no longer have a monopoly on prescribing medications. He supports the idea of (appropriately trained) prescribing psychologists, an idea which has taken off in a few US states but which is hotly debated.

As he puts it, for a psychiatrist, the years in medical school spent delivering babies and dissecting kidneys are rarely useful. So there's no reason why a therapist can't learn the necessary elements of psychopharmacology - which drugs do what, how to avoid dangerous drug interactions - in say one or two years.

Such a person would be at least as good as a psychiatrist at providing integrated pills-and-therapy care. In fact, he says, an even better option would be to design an entirely new type of training program to create such "integrated" mental health professionals from the ground up - neither doctors nor therapists but something combining the best aspects of both.

There does seem to be a paradox here, however: Carlat has just spent 200 pages explaining how drug companies distort the evidence and bribe doctors in order to push their latest pills at people, many of whom either don't need medication or would do equally well with older, much cheaper drugs. Now he's saying that more people should be licensed to prescribe the same pills? Whose side is he on?

In fact, Carlat's position is perfectly coherent: his concern is to give patients the best possible care, which is, he thinks, combined medication and therapy. So he is not "anti" or "pro-medication" in any simple sense. But still, if psychiatry has been corrupted by drug company money, what's to stop the exact same thing happening to psychologists as soon as they got the ability to prescribe?

I think the answer to this can only be that we must first cut the problem off at its source by legislation. We simply shouldn't allow drug companies the freedom to manipulate opinion in the way that they do. It's not inevitable: we can regulate them. The US leads the world in some areas: since 2007, all clinical trials conducted in the country must be pre-registered, and the results made available on a public website, clinicaltrials.gov.

The benefits, in terms of keeping drug manufacturer's honest, are far too many to explain here. Other places, like the European Union, are just starting to follow suit. But America suffers from a split personality in this regard. It's also one of the only countries to allow direct-to-consumer drug advertising, for example. Until the US gets serious about restraining Pharma influence in all its forms, giving more people prescribing rights might only aggravate the problem.

It's not been a great day for Germany. First, they lost to Serbia in the footy. Then German pharmaceutical company Boehringer Ingelheim suffered an equally vexing setback after their allegedly libido-boosting new drug, flibanserin, failed to get approval to be sold in the US.

The FDA panel's unanimous decision was no surprise to anyone who read their briefing report which came a few days ago (here) as it was pretty scathing about the strength of the evidence that Boehringer submitted in support of the drug's efficacy. Take this bit (from page 38)

An unexpected gem from last year's Journal of the American Psychoanalytic Association: Mind over medicine.

Surprisingly, it has nothing to do with psychoanalysis. Rutherford and colleagues performed a meta-analysis of lots of clinical trials of antidepressants. Neuroskeptic readers will be all too familiar with these. But they did an interesting thing with the data: they compared the benefits of antidepressants in trials with a placebo condition, vs. trials with no placebo arm, such as trials comparing one drug to another drug.

Why do that comparison? Because the placebo effect is likely to be stronger in trials with no placebo condition. If you volunteer for a placebo controlled trial, you'll know that you've got (say) a 50-50 chance of getting inactive sugar pills. You'll probably be uncertain whether or not you'll get better, maybe even quite worried. On the other hand if you're in a trial where you definitely will get a real drug, you can rest assured that you'll feel better - and that in itself might make your depression improve.

The paper only presents very preliminary results, but they say that:

Our group at Columbia has completed preliminary work involving metaanalyses of randomized controlled trials comparing antidepressant medications to a placebo or active comparator in geriatric outpatients with Major Depressive Disorder (Sneed et al. 2006). In placebo controlled trials, the medication response rate was 48% and the remission rate 33%, compared to a response rate of 62% and remission rate of 43% in the comparator trials (p < .05). The effect size for the comparison of response rate to medications in the comparator and placebo controlled trials was large (Cohen’s d = 1.2).

Electroconvulsive therapy (ECT) is a crude but effective treatment for depression. It consists of applying a brief alternating current to the brain in order to induce a generalized seizure, which usually lasts for less than half a minute. It looks nothing like the picture to the left.

ECT is typically given three times per week, and a dozen sessions are enough to produce a dramatic improvement in depression in most cases. However, how it works is entirely mysterious. There are plenty of theories. An important little study from Duke University psychiatrists Cassidy et al (including Bernard Carroll) has just ruled out one of them.

Monoamines are a class of neurotransmitters: serotonin, dopamine and noradrenaline. They're involved in various aspects of mood, although the picture is very complicated, and almost all antidepressant drugs target one or more monoamines. Could ECT act by increasing monoamine levels? It's as good a theory as any, and there's some evidence for it.

However, Cassidy et al's data suggest it's not the case. They took 9 volunteers who had been severely depressed, but had recently responded well to a course of ECT. They gave them combined serotonin depletion, with the tryptophan depletion method, and dopamine/noradrenaline depletion with the drug AMPT. As a placebo comparison, they used diphenhydramine, aka Benadryl, a mildly sedative antihistamine; this is because AMPT is a sedative, and they wanted to control for active placebo effects. Few psychopharmacology studies are so well controlled.

These depletion techniques, given separately, are known to cause temporary relapses in about 50% of people who've responded to antidepressants targeting the corresponding monoamine, and also in some people who used to be depressed but are no longer taking medication. If monoamines are involved in the response to ECT, depleting all of them at once should definitely cause relapse.

What happened? Nothing. No-one experienced even a partial return of their depression with either the real or the placebo treatments. These depletions don't put levels of the neurotransmitters down to zero, but Cassidy et al. used the same doses that have caused dramatic relapses in susceptible people.

This strongly suggests that monoamines are not required for the clinical response to ECT, at least not in any straightforward more-is-better way. Given that ECT works faster than antidepressants and more often (the controversial side effects are the main reason it's used only as a last resort), this is a blow for the monoamine hypothesis of depression... like I said, it is complicated.

And how does ECT work? We still don't know. This study narrows down the possibilities.

Cassidy, F., Weiner, R., Cooper, T., & Carroll, B. (2010). Combined catecholamine and indoleamine depletion following response to ECT The British Journal of Psychiatry, 196 (6), 493-494 DOI: 10.1192/bjp.bp.109.070573

Much of Britain is currently following the trial of Steven Griffiths, or as he'd like you to refer to him, the Crossbow Cannibal.

Serial killers are always newsworthy, and Griffiths has killed at least three women in cold blood. (He did use a crossbow, but I think the newspapers made up the cannibalism.) But it's Griffiths's interests that have really got people's attention.

It turns out that before he became a serial killer, he was a man obsessed with... serial killers. His Amazon wish list was full of books about murder. He has a degree in psychology, and he was working on his PhD, in Criminology. Guess what his research was about.

Griffiths is therefore a kind of real life Hannibal Lecter or Dexter, an expert in murderers who is himself one. He's also a good example of the fact that, unlike on TV, real life serial killers are never cool and sophisticated, nor even charmingly eccentric, just weird and pathetic. Not to mention lazy, given that he was still working on his PhD after 6 years...

Yet there is an interesting question: was Griffiths a good criminologist? Does he have a unique insight into serial killers? We'll probably never know, at least not until (or if) the police release some of his writings. But it seems to me that he might have done.

When the average person hears about the crimes of someone like Griffiths, we are not just shocked but confused - it seems incomprehensible. I can understand why someone would want to rob me for my wallet, because I like money too. I can understand how one guy might kill another in a drunken fight, because I've been drunk too. Of course this doesn't mean I condone either crime, but they don't leave me scratching my head; I can see how it happens.

I cannot begin to understand why Griffiths did what he did. My understanding of humanity doesn't cover him. But he is human, so all that really means is that my understanding is limited. Someone understands people like Griffiths, it can't be impossible; but it may be that the only way to understand a serial killer is to be one.

The same may be true of less dramatic mental disorders. Karl Jaspers believed that the hallmark of severe mental illness is symptoms that are impossible to understand: they just exist. I've experienced depression; I've also read an awful lot about it and published academic papers on it. My own illness taught me much more about depression than my reading. Maybe I've been reading the wrong things. I don't think so.

Prozac and suicide: what's going on?

Many people think that SSRI antidepressants do indeed cause suicide, and in recent years this idea has gained a huge amount of attention. My opinion is that, well, it's all rather complicated...

At first glance, it seems as though it should be easy to discover the truth. SSRIs are some of the most studied drugs in the world. We have data from several hundred randomized placebo-controlled trials, totaling tens of thousands of patients. Let's just look and see whether people given SSRIs are more likely to die by suicide than people given placebo.

Unfortunately, that doesn't really work. Actual suicides are extremely rare in antidepressant trials. This is partly because most trials only last 4 to 6 weeks, but also because anyone showing evidence of suicidal tendencies is excluded from the studies at the outset. There just aren't enough suicides to be able to study.

What you can do is to look at attempted suicide, and at "suicidality", meaning suicidal thoughts and self-harming behaviours. Suicidality is more common than actual suicide, so it's easier to research. Here's the bad news: the evidence from a huge number of trials is that compared to placebo, antidepressants do raise the risk of suffering suicidality(1) and of suicide attempts(1) (from 1.1 per 1000 to 2.7 per 1000), when given to people with psychiatric disorders.

There's no good evidence that SSRIs are any worse or any better than other antidepressants, or that any one SSRI stands out as particularly bad(1,2). The risk seems to be worst in younger people: compared to placebo, SSRIs raised suicidality in people below age 25, had no effect in most adults, and lowered it in the oldest age groups(1). This is why SSRIs (and all other antidepressants) now carry a "black box" in the USA, warning about the risk of suicide in young people.

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