That Antidepressants In Water Cause Autism Study

Oh dear. The newspapers this morning are reporting that

Autism 'could be triggered by very low doses of anti-depressants or other chemicals found in water supply'

Here's the study. Young fish were exposed to a combination of three drugs, two antidepressants and an epilepsy med, for 18 days.

First off, this study was tiny with an effective sample size of just 6. Three tanks of fish got exposed to the drugs, and three control tanks didn't. There were multiple fish per tank, five in fact, but those are not five independent observations, because they shared a tank. That's just tiny for a drug trial, or any scientific study really.

Next, the drug doses were much higher than in the water supply. Levels of fluoxetine (Prozac) were 700 times higher than observed in drinking water, for carbamazapine it was 400 times higher. And that's based on the authors' figures for drinking water which they admit are "the highest observed concentrations from various systems". The authors defend this by saying that in drinking water there will be other related compounds, on top of the drugs themselves, adding up to a higher dose. OK - but 400, 700 times higher? We've no idea if that's realistic. They don't justify this number.

What did the drugs actually do to the fish? After 18 days of exposure to the drugs, the fish - juvenile fathead minnows - had their brains removed and the expression levels of various genes measured using a genetic microarray.

The drugged minnows had significantly increased expression of a set of 324 genes dubbed "autism genes" ("autism_ideopathic" in the paper.) I'm not going to get into the question of whether these really are autism genes in humans, or whether fish brains are a good of model of humans. Those are hard issues. But what's easy to see is that while this set of genes were apparantly increased, so were many others. It was not specific to 'autism genes'.

The autism genes were upregulated by an average factor of +1.621... but this was only slightly more than the "Parkinson's Disease genes" at +1.56 and the "Multiple Sclerosis" ones at +1.375. Meanwhile, "Bipolar Disorder" genes were down by -1.172. So if antidepressants in the water are causing autism, they're probably also causing (or preventing!) a lot of other problems too.

The authors note that only three of the gene sets were statistically significantly altered, but that doesn't mean those sets were special, this is the fallacy of treating differences in significance levels as evidence of significant differences.

Of 10 more specific "autism gene" sets that they also examined (in the same fish), all were increased by various amounts (+1.050 to +1.537), some of which were significant - but one of those was a set of genes previously reported decreased in autistics, not increased (it was the "synapse" genes from this study).

What these changes in gene expression mean is anyone's guess. Given the small sample size they could be just noise. If not, all they really show is that levels of psychoactive medications that are quite low, but much higher than in drinking water, have affect the brains of fish. We don't know what that effect means, for the fish, let alone humans.

Early life antidepressant exposure might cause autism. I don't know. Stranger things have happened. We know that fetal anticonvulsant exposure can do it but that's when mothers are actually taking the pills. It's one giant leap from that to traces in drinking water. It's the difference between falling off your chair and falling off the Empire State Building.

Michael A. Thomas, and Rebecca D. Klaper (2012). Psychoactive Pharmaceuticals Induce Fish Gene Expression Profiles Associated with Human Idiopathic Autism PLoS ONE

Bipolar Disorder - A BRIDGE to nowhere?

Last August I blogged about a research paper that claimed that almost half of all people suffering from depression actually have features of bipolar disorder - including me: So Apparantly I'm Bipolar

It was called the BRIDGE study. I took issue with it for various reasons, including the fact that it counted as 'bipolar features' any periods of irritable or elevated mood, even if they were associated with drug treatment:

Under the new regime if you've ever been irritable, high, agitated or hyperactive, on antidepressants or not, you meet "Bipolar Specifier" criteria, so long as it was marked enough that someone else noticed it...

A cynic would say that this is a breathtaking piece of psychiatric marketing. You give people antidepressants, then you diagnose them with bipolar on the basis of their reaction to those drugs, thus justifying selling them yet more drugs.

The cynic would not be surprised to learn that this study was sponsored by pharmaceutical company Sanofi. 

Now a crack team of psychiatrists have written a Letter to the Editor criticizing BRIDGE and they say... pretty much what I said: BRIDGE Study Warrants Critique. They do make a couple of new points also.

The 8 authors of the Letter include David Allen, David Healy, Peter Parry and Jon Jureidini, all major critical voices in psychiatry. However... while this A-Team make an excellent case that BRIDGE is a step in the direction of overdiagnosis and overtreatment of bipolar, they drop the ball slightly when they say:

The article concluded with an appeal to use “mood stabilizers,” presumably atypical antipsychotics, which are less efficacious than lithium. The sponsor has a medication in this class.

Sanofi does make the atypical antipsychotic amisulpiride, but it's not generally referred to as a "mood stabilizer", and I'm not sure why you'd assume that Sanofi had amisulpiride specifically in mind. The BRIDGE team exploit this in their rebuttal letter:

Allen et al cast unseemly aspersions that the BRIDGE study was a vehicle to promote sales of an antipsychotic drug sold by sanofi-aventis. sanofi-aventis has no antipsychotic with an indication for bipolar disorder. We know of no evidence that this was the case at any stage of development and execution of the BRIDGE study.

Maybe so, but as I said in my post, Sanofi also make some popular brands of valproate/valproic acid, a prototypical "mood stabilizer" which is widely used in bipolar disorder. I'd have said that was the more likely candidate...

Fundamentally, we know that Sanofi "was involved in the study design, conduct, monitoring, data analysis, and preparation of the report." We also know that Sanofi is exists to make profit by selling drugs. So either Sanofi thought that this study would make them a profit eventually, by selling more drugs... or they threw money and time at this for no commercial reason. Hmm.

The reply concludes with the frankly bizarre statement that:

Allen et al view their position as part of a “debate” about the “ever-widening bipolar spectrum.” We consider data, not debates, as central to the progress in the scientific understanding of mood disorders...

But science is a debate about data. Data by themselves are just numbers; to be useful, they must be interpreted, and scientific debates aim at arriving at such interpretations. No-one is questioning the BRIDGE data as such, we're questioning what it means.

David M. Allen, et al (2012). BRIDGE Study Warrants Critique Archives of General Psychiatry, 69 (6) DOI: 10.1001/archgenpsychiatry.2012.118

Identical Twins, Different Lives

Virginia psychiatrists Kendler and Halberstadt describe a neat "natural experiment" into what causes depression - The road not taken: life experiences in monozygotic twin pairs discordant for major depression

They interviewed 14 pairs of identical twins. One of each pair had reported a history of depression while the other hadn't. The twins were interviewed together, and asked to describe their lives, in particular any differences between their experiences.

It's well worth reading, for the human interest stories if nothing else. Here's perhaps the most striking one:

Lisa (never depressed) and Leslie (depressed), interviewed at age 53, were identical twins... they were together constantly as children, but described their personalities as somewhat different from the start... Lisa described herself as getting quickly upset over adversity, but then rapidly changing gears and focusing on problem-solving. Leslie indicated that she had more of a temper and was more assertive, more likely to ‘mouth off’ and get into trouble than her twin.

Lisa knew she wanted to be a school teacher, attended a teacher’s college and has taught for her entire career. Leslie was less certain of her career goals and held a number of different jobs... Lisa, at 24, met her husband of nearly 30 years and had a big, traditional wedding. Leslie married the guy she dated in high school and college, invited only their parents to the wedding and divorced after 5 years, commenting "I picked the wrong man."

Late in the interview, Leslie reported (only after being asked about the most difficult time in her life) that just over 30 years ago, after drinking a modest amount of alcohol, she became pathologically intoxicated and drove onto a major highway off ramp going the wrong way. She got into the highway going against traffic and had a head-on collision, which killed the other driver - a woman with young children. Leslie was not seriously injured.

Recounting this event was clearly difficult for her as she openly wept in telling us this story even after all these years. In recounting her psychological reaction to the accident, she said, "Am I really to blame for this, and then I’ll have to live with this for the rest of my life? knowing there was somebody else whose family had been destroyed there." The depression following this episode was her most severe and she talked about her deep sense of guilt. Although manslaughter charges against her were dropped, there was evidence that Leslie was at fault.

The other stories were less extreme, but no less dramatic in their own ways. The authors conclude that, of the 14 pairs, the depressed twin got depressed because of: romantic difficulties (7); single traumatic events (2, including Lisa & Leslie); employment difficulties (1), a mixture of factors (2), and for no clear reason at all (2).

However, what we can really conclude from all this? The study specifically took identical twins, who grew up together but only one of whom reported depression, so it ruled out genetic influences and also psychological and social factors shared by both twins - things like family background, growing up in poverty, etc. That's the whole point of the study but it's important to remember that these are unusual cases.

Beyond that, it's hard to know if the differences in the twins' lives caused the depression. All we know is that they're correlated. "Leslie" for instance became seriously depressed after causing the death of a woman in a drunk driving accident. A straightforward case of cause and effect, perhaps, but then why did she drink and drive in the first place? Was depression, or something associated with it, part of the reason?

Ideally, I would want to repeat this study in identical twins both (or neither) of whom had depression to see if their lives - before the depression at any rate - were more alike than these discordant twins. However, it's still a fascinating study.

Kendler, K., and Halberstadt, L. (2012). The road not taken: life experiences in monozygotic twin pairs discordant for major depression Molecular Psychiatry DOI: 10.1038/mp.2012.55

Conference! The Game

It's conference season! That special time of year when scientists jet off to foreign shores, posters in hand, leaving the confines of the lab behind to spend three exciting days talking about... the lab.

Sadly, not everyone is lucky enough to get to go every year. So if you're feeling left out, Neuroskeptic has the answer: Conference!, a revolutionary new simulation that offers you all the best bits of a major academic summit, all from the comfort of the lab bench.

HOW TO PLAY: Print out the board. Each player has a token. Everyone starts at the Airport. Players take it in turns to roll a single six sided die, and move their token forward that many spaces (marked by circles). The player with the highest h index goes first. Follow the red arrows. If you land on a special square space, something special happens - see the text. First player to land on, or pass over, the Airport for the return journey wins.

Seeing Things in Pictures

A team of Japanese neurologists propose a new method to detect visual hallucinations - the Pareidolia Test.

Pareidolia means perceiving things that aren't there, in random or unrelated stimuli. Uchiyama et al created a set of 25 photos, each of which contains things that kind of look like faces, animals, or other objects... but not really. As you can see, the flowers and the birds look like faces. I can't work out what the leopard and the trees are meant to be, though...

The authors showed the pictures to some patients with dementia. They had one minute to describe what they saw in each image. Compared to healthy controls, patients with Alzheimer's disease did not experience any more pareidolia than controls.

But people with Lewy Body dementia - a disorder in which visual hallucinations and misclassifications are more common than in Alzheimer's - reported seeing numerous faces, people and creatures that weren't there.

They didn't just say that the images "looked like" these things: they actually thought they were pictures of the illusionary objects. This is an interesting test which might help doctors to diagnose visual hallucinations, which are often under-reported by patients. Some degree of pareidolia, especially for faces, is entirely normal, however, as the popularity of Jesus's in snacks shows. When specifically told to expect it, people can even "see" faces in random black and white patterns.

Uchiyama, M., Nishio, Y., Yokoi, K., Hirayama, K., Imamura, T., Shimomura, T., & Mori, E. (2012). Pareidolias: complex visual illusions in dementia with Lewy bodies Brain DOI: 10.1093/brain/aws126