Neurology Center

A great many neuroscientists are interested in clinical depression and antidepressants. We're still a long way from understanding depression on a biological level - and if anyone tries to tell you otherwise, they're probably trying to sell you something. I've previously discussed the controversies surrounding the neurotransmitter serotonin - according to popular belief, the brain's "happy chemical". My conclusion was that although clinical depression is not caused by "low serotonin" alone, serotonin does play an important role in mood at least in some people.

A paper published recently in Molecular Psychiatry makes a number of important contributions to the literature on depression and antidepressants; I haven't seen it discussed elsewhere, so here is make take on it. The paper is by a Portuguese research group, Bessa et. al., and it's titled The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling. The findings are right there in the title, but a little history is required in order to appreciate their significance.

For a long time, the only biological theory which attempted to explain clinical depression and how antidepressants counteract it was the monoamine hypothesis. During the early 1960s, it was noticed that early antidepressant drugs, such as imipramine, all inhibited either the breakdown or the removal (reuptake) of chemicals in the brain called monoamines, including serotonin. This led many to conclude that antidepressants improve mood by raising monoamine levels, and that depression is probably caused by some kind of monoamine deficiency. For various reasons (not all of them good ones), it was later decided that serotonin was the crucial monoamine involved in mood, although for several years another, noradrenaline, was favored by most people.

This "monoamine hypothesis" was always a little shaky, and over the past decade or so, an alternative approach has become increasingly fashionable. If you were so inclined, you might even call it a new paradigm. This is the proposal that antidepressants work by promoting the survival and proliferation of new neurones in certain areas of the brain - the "neurogenesis hypothesis". Neurogenesis, the birth of new cells from stem cells, occurs in a couple of very specific regions of the adult brain, including the elaborately named subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus. Many experiments on animals have shown that chronic stress, and injections of the "stress hormone" corticosterone, can suppress neurogenesis, while a wide range of antidepressants block this effect of stress and promote neurogenesis. (Other evidence shows that antidepressants probably do this by inducing the expression of neurotrophic signaling proteins, like BDNF.)

The literature on stress, neurogenesis, and antidepressants, is impressive and growing rapidly. For good reviews, see Duman (2004) and Duman & Monteggia (2006). However, the crucial question - do antidepressants work by boosting hippocampal neurogenesis? - remains a controversial one. The hippocampus is not an area generally thought of as being involved in mood or emotion, and damage to the human hippocampus causes amnesia, not depression. Given that the purpose (if any) of adult neurogenesis remains a mystery, it's entirely possible that neurogenesis has nothing to do with depression and mood.

To establish whether neurogenesis is involved in antidepressant action, you need to to manipulate it - for example, by blocking neurogenesis and seeing if this makes antidepressants ineffective. This is practically quite tricky, but Luca Santarelli et. al. (2003) managed to do it by irradiating the hippocampi of mice with x-rays. They found that this made two antidepressants (fluoxetine, aka Prozac, and imipramine) ineffective in protecting the animals against the detrimental effects of chronic stress. This was a landmark result, and raised a lot of interest in the neurogenesis theory.

This new paper, however, says differently. The authors gave lab rats a six-week Chronic Mild Stress treatment, a Guantanamo Bay-style program of intermittent food deprivation, sleep disruption, and confinement. Chronic stress has various effects on rats, including increased anxiety and decreased time spent grooming leading to fur deterioration. These behaviours and others can be quantified, and are treated as a rat analogue of human clinical depression - whether this is valid is obviously debatable, but I'm willing to accept it at least until a better animal model comes along.

Anyway, some of the rats were injected with antidepressants during the final two weeks of the stress procedure. As expected, these rats coped better with the stress at the end of six weeks. This graph shows the effects of stress and antidepressants on the rat's behaviour in the Forced Swim (Porsolt) Test. Higher bars indicate more "depressed" behaviour. The second pair of bars, representing the stressed rats who got placebo injections, is a lot higher than the first pair of bars representing rats who were not subjected to any stress. In other words, stress made rats "depressed" - no surprise. The other four pairs of bars are pretty much the same height as the first pair; these are rats who got antidepressants, showing that they were resistant to the effects of stress.

The crucial finding is that the white and the black bars are all pretty much the same height. The black bars represent animals who were given injections of methylazoxymethanol (MAM), a cytostatic toxin which blocks cell division (rather like cancer chemotherapy). As you can see, MAM had no effect at all on behaviour in the swim test. It had no effect on most other tests, although it did seem to make the rats more anxious in one experiment.

However, MAM powerfully inhibited neurogenesis. This second graph shows the number of hippocampal cells expressing KI-67, a protein which is a marker of neuroproliferation. As expected, stress reduced neurogenesis and antidepressants increased it. MAM (black bars again) reduced neurogenesis, and in particular, it completely blocked the ability of antidepressants to increase it.

But as we saw earlier, MAM did not stop antidepressants from protecting rats against stress. So, the authors concluded, neurogenesis is not necessary for antidepressants to work. This contradicts the landmark finding of Santarelli et. al. - why the discrepency? There are so many differences between the two experiments that there could be any number of explanations - the current study used rats, while Santarelli used mice, for one thing, and that could well be important. Whatever the reason, this result suggests at the least that neurogenesis is not the only mechanism by which antidepressants counteract the effects of stress in animals.

The most interesting aspect of this paper, to my mind, was an essentially unrelated new finding. Stress was found to reduce the volume of several areas of the rat's brain, including the hippocampus and also the medial prefrontal cortex (mPFC). Unlike the hippocampus, this is an area known to be involved in motivation and emotion. Importantly, the authors found that following stress, the mPFC did not shrink because neurones were dying or because fewer neurones were being born, but rather because the existing neurones were changing shape - stress caused atrophy of the dendritic spines which branch out from neurones. Dendrites are essential for communication between neurones.

As you can see in the drawings above, stress (the middle column) caused shrinking and stunting of the dendrites in pyrimidal neurones from three areas relative to the unstressed rats (left), while those rats recieving antidepressants as well as stress showed no such effect (right). The cytostatic MAM had no effect whatsoever on dendrites. Further work found that antidepressants increase expression of NCAM1, a protein which is involved in dendritic growth.

So what does this mean? Well, for one thing, it doesn't prove that antidepressants work by increasing dendritic branching. Cheekily, the authors come close to implying this in their choice of title for the paper, but the published evidence shows no direct evidence for this. To find out, you would have to show that blocking the effects of antidepressants on dendrites also blocks their beneficial effects. I suspect this is what the authors are now working hard to try to do, but they haven't done so yet.

It also doesn't mean that taking Prozac will change the shape of your brain cells. It might well do, but this was a study in rats given huge doses of antidepressants (by human standards), so we really don't know whether the findings apply to humans. On the other hand, if Prozac changes the shape of your cells, this study suggests that stressful situations do too - and Prozac, if anything, will put your cells back to "normal".

Finally, I don't want to suggest that the neurogenesis theory of depression is now "dead". In neuroscience, theories never live or die on the basis of single experiments (unlike in physics). But it does suggest that the much-blogged-about neurogenesis hypothesis is not the whole story. Depression isn't just a case of too little serotonin, and it isn't just a case of too little neurogenesis or too little BDNF either.


J M Bessa, D Ferreira, I Melo, F Marques, J J Cerqueira, J A Palha, O F X Almeida, N Sousa (2008). The mood-improving actions of antidepressants do not depend on neurogenesis but are associated with neuronal remodeling Molecular Psychiatry DOI: 10.1038/mp.2008.119

It was only last week that fMRI explained human hatred. Now it's revealed why some kids are horrible to others. Behold -

• "Bullying tendency wired in brain"

• "Bullies' brains may be hardwired to have sadistic tendencies"

• "Bullies' brains may be wired differently"

A better understanding of the biological basis of these things is good to have but the danger is it causes people to leap to biological solutions - drugs - rather than other behavioural solutions

For regular readers (and Google Analytics assures me I do have some - hello), this post may be a bit of a change of pace.

Many mental health blogs have alerted readers to the case of Ray Sandford, a Minnesota man who's being given ECT (electroconvulsive therapy), as an outpatient, against his wishes. Encouraging people to write to the Governor of Minnesota in protest, Philip Dawdy of the Furious Seasons said

I am officially neutral on voluntary ECT--if someone wants it, it's their brain--but involuntary ECT is barbarous and amounts to torture. If anyone would like to defend involuntary ECT, let me hear from you. If you make a good argument, I might even post it.

• Sometimes consent is a luxury
  

• ECT works

Accumulated clinical experience—later confirmed in controlled clinical trials, which included the use of simulated or “sham” ECT as a control — determined ECT to be highly effective against severe depression, some acute psychotic states, and mania. No controlled study has shown any other treatment to have superior efficacy to ECT in the treatment of depression.

• Conflicts of Interest?
  

In this excellent post, new blogger Mike Eslea (the Punk Psychologist) takes British newspapers to task for their sensationalist coverage of some new statistics about knife crime. For non-British readers, I should explain that knife crime is a hot button issue in this country at the moment, with the narrative that there's a "knife crime epidemic" in progress being widely accepted.

As Eslea explains, when the new crime statistics were released, all of the headlines talked of a "22% rise" in knife incidents. This sounds pretty dramatic, and straightforward - 22% more stabblings, oh no! But in fact the picture is much less clear - most of this rise was probably due to changes in the way such crimes are reported, and even defining knife crime is not as easy as it seems. He also notes that last year the Times managed to extract the headline "Knife Crime Doubles In Two Years", based on a report which found nothing of the sort, through careful cherry-picking of the statistics. You should read the whole of the post - it's enlightening (and if you don't, me and Eslea will stab you up.)

Anyway, what's interesting is that this is just the kind of thing that we also see in much of science journalism. Ben Goldacre's excellent Bad Science is full of examples of the way in which the media mislead in their coverage of scientific and medical research. Reporting on violence, drugs, teenage pregnancy and other social sins often misleads for exactly the same reasons - i.e. statistics are cherry-picked to support the most dramatic conclusions, caveats and methodological weaknesses are ignored, and evidence which doesn't fit with the narrative are not reported on at all (in this case the narrative is "knife crime epidemic!" but we have also had "autism epidemic!", "diet determines health!" etc. etc.) Science, medicine, or crime, the numbers get spun in the same ways.

The basic problem, as I see it, is that people just don't like doubt. We want a clear story, even if the available evidence doesn't support any firm conclusions. Look at the Daily Mail's regular headlines about something causing or preventing cancer - any epidemiologist knows that establishing risk factors for cancer is a very difficult job, and there is a huge amount of uncertainty, and a lot of the research out there is crap. For the Mail, on the other hand, one small study constitutes proof. Until the next small study comes along and proves that what we thought cured cancer actually causes it, and vice versa. Experts despair at this, but they're in a minority.

This great BBC article accuses politicians of being unwilling to admit doubt about whether policies will work. To be fair to them, though, they're in an impossible position, because the public and the media demand certainty. We know that knife crime is skyrocketing and we want someone who knows how to stop it. By which I mean that most of us do. I don't - from what I've read about knife crime, nationwide it probably isn't rising, or maybe it is a bit, but in some parts of the country and among some communities it could be rising a lot, although even if it is, we have no idea why, and we don't have any proven ways of improving things... The point is that it's complicated. There's a lot of evidence to consider and most of it's flawed in one way or another. That's true for neuroscience, and it's also true for public policy.

If you hear voices that aren't really there, are you "mad"? Maybe - auditory hallucinations, most commonly voices, are one of the characteristic symptoms of schizophrenia and are sometimes also a feature of severe depression and mania. (For more on hallucinations, try this paper. It's long, but it's worth a read because it's one of the few academic papers containing phrases like "Do YOU want a slap in the head?" and "Die, bitch".) But anyone can find themselves hearing things that others don't - it just takes a little prompting.

Via the excellent Mind Hacks, I came across this great little page by Cambridge neuroscientist Matt Davis, which gives some examples of Sine Wave Speech. Essentially, Sine Wave Speech is a voice recording which has been digitally degraded so that it's little more than a collection of beeps and bleeps (sine waves, in fact). When you first listen to it, it sounds something like R2D2 on ecstasy.

However, if you listen to the original, unaltered voice and then go back to the sine-wave version, you can hear the words - the bleeps suddenly sound like a voice. The change is striking - so much so that if you didn't know what was going on, you'd probably think you were listening to a whole new clip. This effect is one example of the brain's tendency to perceive a pattern in a stream of noise, when an expected pattern is known. We're all familiar with this in the realm of vision - if you're looking for something amongst a pile of clutter, your eye is drawn to it, but you won't even register all the other rubbish that's around it. We're not used to the same thing happening with sound, though, I suppose because we generally hear things without much difficulty.

Sine Wave Speech really is a form of voice, but the same principle can lead people to hear voices in the unlikeliest places. Hence the recent case of the Amazing Satanic Islamic Doll, also known by its Jihad name, "Little Mommy Cuddle 'n Coo". This is a kid's toy made by Fisher Price which, when hugged, plays recorded baby noises. A month or so ago a concerned parent somewhere in America decided that one of the recorded baby noises sounded like a voice with a disturbing message. Have a listen.

Did you hear any speech the first time you heard the doll's noise? Probably not, but I'd bet that after you'd heard the claim that the doll was saying "Islam is the Light", the same noise started to sound rather different. After several listens, I now can't hear the noise as anything other than a voice saying that phrase, even though intellectually I know that this is absurd (if Fisher Price were going to plant a message like that they'd be more likely to use "Buy more toys").

The doll is a post-9/11 rerun of the infamous Satanic backmasking scare. If you a play a record backwards, you'll hear various distorted sounds, some of which could be interpreted as speech, if that's what you're expecting to hear. During the 1980s, some concerned citizens (again in America) thought that they could hear Satanic or sexual messages hidden in heavy metal records when they were played backwards. Upon hearing this, several bands liked the idea and actually did put backwards messages in future songs, but most of the allegations were based on people hearing voices in noise, because that's what they expected to hear.

One man believes that the problem goes far beyond metal music and that everyone has hidden backwards messages in everything they say, messages which reveal their subconscious thoughts. Cripes. He gives a lot of examples here. Note that he helpfully tells you exactly what to expect to hear before you've heard to recordings.

Anyway, in original video above, a concerned mom argues that the Muslim message must be real because she can't believe that people across the country are "all hearing things". She doesn't understand that you don't have to be hallucinating to over-interpret noise. It happens to the best of us, and once you know what to expect you really hear the voice, clear as day, whether or not you "believe in it" or "want to hear it". It's not simply the power of suggestion.

On the other hand some psychologists have claimed that suggestion alone can make people hear things. This is generally called the "White Christmas Effect". The original experiment in support of this claim took 78 female students who were told - "in a firm and serious tone of voice" -

I want you to close your eyes and to hear a phonograph record with words and music playing White Christmas. Keep listening to the phonograph record playing White Christmas until I tell you to stop.

In a previous post, I said that I'd write about how to improve the quality of scientific research by ending the scrabbling for "positive results" at the cost of accuracy. So here we go. This is a long post, so if you'd prefer the short version, the answer is that we ought to get scientists in many fields to pre-register their research - to go on record and declare what they are looking for before they start looking for anything.

This is not my idea. Clinical trial registration is finally becoming a reality. Several organizations now offer registration services - such as Current Controlled Trials. Their site is well worth a click, if only to see the future of medical science unfolding before your eyes in the form of a list of recently registered protocols. Each of these protocols, remember, will eventually become a published scientific paper. If it doesn't, everyone will know that either the trial was never finished, or worse, it was finished and the results were never published. Without registration, a trial could be run and never published without anyone knowing what had happened - making it very easy for "inconvenient" data to never see the light of day. This is publication bias. We know it happens. Trial registration makes it all but impossible. It's important.

In fact, if someone were designing the system of clinical trials from scratch, they would, almost certainly, make registration an integral step right from the start. Unfortunately, no-one intelligently designed clinical trials. They evolved, and they're still evolving. We're not there yet. Trial registration is still a "good idea" rather than a routine part of clinical research, and while many first-class medical journals now require pre-registration and refuse to publish unregistered trials, plenty of other respectable publications have yet to catch up.

What I want to point out is that it's not just clinical trials which would benefit from registration. Registration is a way to defeat publication bias, wherever it occurs, and any field in which there are "negative results" is vulnerable to the risk that they won't be reported. In some parts of science there are no negative results - in much of physics, chemistry, and molecular biology, you either get a result, or you've failed. If you try to work out the structure of a protein, say, then you'll either come up with a structure, or give up. Of course, you might come out with the wrong structure if you mess up, but you could never "find nothing". All proteins have a structure, so there must be one to find.

But in many other areas of research there is often genuinely nothing to find. A gene might not be linked to any diseases. A treatment might have no effect. A pollutant might not cause any harm. Basically, if you're looking for a correlation between two things, or an effect of one thing upon another, you might get a negative result. Just off the top of my head, this covers almost all genetic association and linkage studies, almost all neuroimaging, most experimental psychology, much of climate science, epidemiology, sociology, criminology, and probably others I don't know about. Oh, and clinical trials, but we already knew that. People don't tend to publish negative results, for various reasons. Wherever this is a problem, trial registration would be useful.

Publication bias is known to be a problem in behavioural genetics (finding genes associated with psychological traits). For example Munafo et. al. (2007) found pretty strong evidence of publication bias in research on whether a certain allele (DRD2 Taq1A) predisposes to alcoholism. They concluded by saying that

Publication of nonsignificant results in the psychiatric genetics literature is important to protect against the existence of a biased corpus of data in the public domain.

an effective mechanism for establishment of prospective registers of proposed analyses is not feasible.

What goes on in the brains of people who are depressed? For a lot of us, the answer is remarkably straightforward - they don't have enough serotonin, innit? The belief that serotonin is somehow the brain's "happy chemical" is almost folk wisdom nowadays - I just searched for serotonin on the Guardian website and clicked on the top article, this gem which describes serotonin as "the feelgood hormone".

Now, some more informed people don't like this pop psychopharmacology. The esteemed Dr. Ben Goldacre, for example, wrote that

That’s the serotonin hypothesis. It was always shaky, and the evidence now is hugely contradictory. I’m not giving that lecture here, but as a brief illustration, there is a drug called tianeptine – a selective serotonin reuptake enhancer, not an inhibitor – and yet research shows this drug is a pretty effective treatment for depression too.

Meanwhile in popular culture the depression/serotonin theory is proven and absolute, because it was never about research, or theory, it was about marketing, and journalists who pride themselves on never pushing pills or the hegemony will still blindly push the model until the cows come home....

The serotonin hypothesis will always be a winner in popular culture, even when it has flailed in academia, because it speaks to us of a simple, abrogating explanation, and plays into our notions of a crudely dualistic world where there can only be weak people, or uncontrollable, external, molecular pressures.

A feature of particular interest was that the participants who had full relapses of symptoms described a reappearance of some of the depressive thoughts they had experienced when previously depressed. One of these participants whose previous episodes of clinical depression were associated with the loss of important friendships had, while depressed, been preoccupied with fears that she would never be able to sustain a relationship. She had not had such fears since then. She had been fully recovered and had not taken any medication for over a year. About 2 h after drinking the tryptophan-free mixture she experienced a sudden onset of sadness, despair, and uncontrollable crying. She feared that a current important relationship would end. She recognised that she was depressed but still considered that her fears were appropriate. The evening of the test day she started to feel better and the next day was fully recovered. She said that her fears about her current relationship had been unfounded and she now saw them as unrealistic.
From Smith, Cowen & Fairburn Lancet (1997)