Fat Genes Make You Happy?

Does being heavier make you happier?

An interesting new paper from a British/Danish collaboration uses a clever trick based on genetics to untangle the messy correlation between obesity and mental health.

They had a huge (53,221) sample of people from Copenhagen, Denmark. It measured people's height and weight to calculate their BMI, and asked them some simple questions about their mood, such as "Do you often feel nervous or stressed?"

Many previous studies have found that being overweight is correlated with poor mental health, or at least with unhappiness ("psychological distress"). And this was exactly what the authors found in this study, as well.

Being very underweight was also correlated with distress; perhaps these were people with eating disorders or serious medical illnesses. But if you set those small number of people aside, there was a nice linear correlation between BMI and unhappiness. When they controlled for various other variables like income, age, and smoking, the effect of BMI became smaller but it was still significant.

But that's just a correlation, and as we all know, "correlation doesn't imply causation". Actually, it does; something must be causing the correlation, it didn't just magically appear out of nowhere. The point is that shouldn't make simplistic assumptions about what the causal direction is.

It would be easy to make these assumptions. Maybe being miserable makes you fat, due to comfort eating. Or maybe being fat makes you miserable, because overweight is considered bad in our society. Or both. Or neither. We don't know.

Finding this kind of correlation and then speculating about it is where a lot of papers finish, but for these authors, it was just the start. They genotyped everyone for two different genetic variants known, from lots of earlier work, to consistently affect body weight (FTO rs9939609 and MC4R rs17782313).

They confirmed that they were indeed associated with BMI; no surprise there. But here's the surprising bit: the "fat" variants of each gene were associated with less psychological distress. The effects were very modest, but then again, their effects on weight are small too (see the graph above; the effects are in terms of z scores and anything below 0.3 is considered "small".)

The picture was very similar for the other gene.

This allows us to narrow down the possibilities about causation. Being depressed clearly can't change your genotype. Nothing short of falling into a nuclear reactor can change your genotype. It also seems unlikely that genotype was correlated with something else which protects against depression. That's not impossible; it's the problem of population stratification, and it's a serious issue with multi-ethnic samples, but this paper only included white Danish people.

So the author's conclusion is that being slightly heavier causes you to be slightly happier, even though overall, weight is strongly correlated with being less happy. This seems paradoxical, but that's what the data show.

That conclusion would fall apart, though, if these genes directly effect mood, and also, separately, make you fatter. The authors argue that this is unlikely, but I wonder. Both FTO and MC4R are active in the brain: they influence weight by making you eat more. If they can affect appetite, they might also affect mood. A quick PubMed search only turns up a couple of rather speculative papers about MC4R and its possible links to mood, so there's no direct evidence for this, but we can't rule it out.

But this paper is still an innovative and interesting attempt to use genetics to help get beneath the surface of complex correlations. It doesn't explain the observed correlation between BMI and unhappiness - it actually makes it more mysterious. But that's a whole lot better than just speculating about it.

Lawlor DA, Harbord RM, Tybjaerg-Hansen A, Palmer TM, Zacho J, Benn M, Timpson NJ, Smith GD, & Nordestgaard BG (2011). Using genetic loci to understand the relationship between adiposity and psychological distress: a Mendelian Randomization study in the Copenhagen General Population Study of 53,221 adults. Journal of internal medicine PMID: 21210875

Fat Genes Make You Happy?

Does being heavier make you happier?

An interesting new paper from a British/Danish collaboration uses a clever trick based on genetics to untangle the messy correlation between obesity and mental health.

They had a huge (53,221) sample of people from Copenhagen, Denmark. It measured people's height and weight to calculate their BMI, and asked them some simple questions about their mood, such as "Do you often feel nervous or stressed?"

Many previous studies have found that being overweight is correlated with poor mental health, or at least with unhappiness ("psychological distress"). And this was exactly what the authors found in this study, as well.

Being very underweight was also correlated with distress; perhaps these were people with eating disorders or serious medical illnesses. But if you set those small number of people aside, there was a nice linear correlation between BMI and unhappiness. When they controlled for various other variables like income, age, and smoking, the effect of BMI became smaller but it was still significant.

But that's just a correlation, and as we all know, "correlation doesn't imply causation". Actually, it does; something must be causing the correlation, it didn't just magically appear out of nowhere. The point is that shouldn't make simplistic assumptions about what the causal direction is.

It would be easy to make these assumptions. Maybe being miserable makes you fat, due to comfort eating. Or maybe being fat makes you miserable, because overweight is considered bad in our society. Or both. Or neither. We don't know.

Finding this kind of correlation and then speculating about it is where a lot of papers finish, but for these authors, it was just the start. They genotyped everyone for two different genetic variants known, from lots of earlier work, to consistently affect body weight (FTO rs9939609 and MC4R rs17782313).

They confirmed that they were indeed associated with BMI; no surprise there. But here's the surprising bit: the "fat" variants of each gene were associated with less psychological distress. The effects were very modest, but then again, their effects on weight are small too (see the graph above; the effects are in terms of z scores and anything below 0.3 is considered "small".)

The picture was very similar for the other gene.

This allows us to narrow down the possibilities about causation. Being depressed clearly can't change your genotype. Nothing short of falling into a nuclear reactor can change your genotype. It also seems unlikely that genotype was correlated with something else which protects against depression. That's not impossible; it's the problem of population stratification, and it's a serious issue with multi-ethnic samples, but this paper only included white Danish people.

So the author's conclusion is that being slightly heavier causes you to be slightly happier, even though overall, weight is strongly correlated with being less happy. This seems paradoxical, but that's what the data show.

That conclusion would fall apart, though, if these genes directly effect mood, and also, separately, make you fatter. The authors argue that this is unlikely, but I wonder. Both FTO and MC4R are active in the brain: they influence weight by making you eat more. If they can affect appetite, they might also affect mood. A quick PubMed search only turns up a couple of rather speculative papers about MC4R and its possible links to mood, so there's no direct evidence for this, but we can't rule it out.

But this paper is still an innovative and interesting attempt to use genetics to help get beneath the surface of complex correlations. It doesn't explain the observed correlation between BMI and unhappiness - it actually makes it more mysterious. But that's a whole lot better than just speculating about it.

Lawlor DA, Harbord RM, Tybjaerg-Hansen A, Palmer TM, Zacho J, Benn M, Timpson NJ, Smith GD, & Nordestgaard BG (2011). Using genetic loci to understand the relationship between adiposity and psychological distress: a Mendelian Randomization study in the Copenhagen General Population Study of 53,221 adults. Journal of internal medicine PMID: 21210875

VIAJANDO...

JA PASSAMOS-
POR LAS VEGAS, LOS ANGELES, ESTAMOS EM SAO DIEGO E SEGUINDO HOJE A NOITE PARA NOVA YORK.
ASSIM QUE CHEGAR NO BRASIL, POSTAREI AS DEMAIS FOTOS.
DEIXO UM ABRACO A TODOS.
CARINHOSAMENTE,
SANDRA

The Wheel of Peer Review

In the spirit of the 9 Circles of Scientific Hell, and inspired by the evidence showing that scientific peer reviewers agree only slightly more often than they would by chance, here's a handy tool for randomly generating your review.

Feel free to print it out and throw darts at it, or maybe make a roulette wheel kind of thing, or perhaps a ouija board. It seems to be in widespread use already, so there must be an easy way to use it.


1. The Power of Love: You love this paper! Well, you love the author. Maybe it's a romantic thing, maybe they once saved your ass by lending you their expertise/equipment/data, or maybe they bought you a drink once at a conference. Either way, they're awesome, so their paper must be fine.

2. Bee-in-your-Bonnet: You don't really care about this paper, but you do care, very strongly, about something else which is vaguely related. Many say that you're obsessed by it, though not to your face, because that would start you off talking about it. The problem with this paper is that it doesn't cover your pet idea. If the authors want it published, they'll need to change that, pronto. Major revisions are called for.

3. The Pedant: The paper is atrocious and doesn't deserve to be written on a scrap of toilet paper let alone submitted to this great Journal... in terms of spelling and formatting. Scientifically, you think it's probably pretty good, but it was hard to tell because of the amount of red ink you put all over it. English isn't the author's first language? That's their problem. Isn't that what "minor corrections" are for? No! That's what the bin is for.

4. Cite Me, Me, Me!: The problem with this paper is that it doesn't reference the right previous work... yours. Unless the authors change it to cite everything you've written in the past 10 years, they can get lost. If they do, the paper will be immediately accepted - to reject it would harm your citation count.

5. The Tortoise: You'll review this paper when you get back from holiday. And finished writing your own paper. After that conference. When you've finished your teaching for the year. Maybe. Until you submit your review, the authors are stuck in a horrible limbo, but luckily you're anonymous so they won't know who to send hate mail to.

6. The Cheerleader: This paper is awesome because it supports something that you yourself are about to publish. It's full of methodological holes? Never mind, that will only make your paper better by comparison. It's barely readable? Suggest edits to make it just about comprehensible so people can tell how well it supports you. Then accept a.s.a.p.

7. Wrong End of the Stick: You think you understand this paper, but actually you don't. So your review completely misses the point. When the authors point this out, you have two options: a) blame the paper for being confusing, and chuck it out or b) decide the whole thing is much too complicated to spend time over, and accept it.

8. The Perfect Reviewer: You are an intelligent, informed expert, new enough to the field that you have no axe to grind, and you take the time to read the paper fully, and return a constructive, perceptive review within a couple of weeks. Well done. Unfortunately, there are 1 or 2 other reviewers, and there's only a 1 in 8 chance they'll be like you...

The Wheel of Peer Review

In the spirit of the 9 Circles of Scientific Hell, and inspired by the evidence showing that scientific peer reviewers agree only slightly more often than they would by chance, here's a handy tool for randomly generating your review.

Feel free to print it out and throw darts at it, or maybe make a roulette wheel kind of thing, or perhaps a ouija board. It seems to be in widespread use already, so there must be an easy way to use it.


1. The Power of Love: You love this paper! Well, you love the author. Maybe it's a romantic thing, maybe they once saved your ass by lending you their expertise/equipment/data, or maybe they bought you a drink once at a conference. Either way, they're awesome, so their paper must be fine.

2. Bee-in-your-Bonnet: You don't really care about this paper, but you do care, very strongly, about something else which is vaguely related. Many say that you're obsessed by it, though not to your face, because that would start you off talking about it. The problem with this paper is that it doesn't cover your pet idea. If the authors want it published, they'll need to change that, pronto. Major revisions are called for.

3. The Pedant: The paper is atrocious and doesn't deserve to be written on a scrap of toilet paper let alone submitted to this great Journal... in terms of spelling and formatting. Scientifically, you think it's probably pretty good, but it was hard to tell because of the amount of red ink you put all over it. English isn't the author's first language? That's their problem. Isn't that what "minor corrections" are for? No! That's what the bin is for.

4. Cite Me, Me, Me!: The problem with this paper is that it doesn't reference the right previous work... yours. Unless the authors change it to cite everything you've written in the past 10 years, they can get lost. If they do, the paper will be immediately accepted - to reject it would harm your citation count.

5. The Tortoise: You'll review this paper when you get back from holiday. And finished writing your own paper. After that conference. When you've finished your teaching for the year. Maybe. Until you submit your review, the authors are stuck in a horrible limbo, but luckily you're anonymous so they won't know who to send hate mail to.

6. The Cheerleader: This paper is awesome because it supports something that you yourself are about to publish. It's full of methodological holes? Never mind, that will only make your paper better by comparison. It's barely readable? Suggest edits to make it just about comprehensible so people can tell how well it supports you. Then accept a.s.a.p.

7. Wrong End of the Stick: You think you understand this paper, but actually you don't. So your review completely misses the point. When the authors point this out, you have two options: a) blame the paper for being confusing, and chuck it out or b) decide the whole thing is much too complicated to spend time over, and accept it.

8. The Perfect Reviewer: You are an intelligent, informed expert, new enough to the field that you have no axe to grind, and you take the time to read the paper fully, and return a constructive, perceptive review within a couple of weeks. Well done. Unfortunately, there are 1 or 2 other reviewers, and there's only a 1 in 8 chance they'll be like you...

Antidepressants Still Don't Work In Mild Depression

A new paper has added to the growing ranks of studies finding that antidepressant drugs don't work in people with milder forms of depression: Efficacy of antidepressants and benzodiazepines in minor depression.


It's in the British Journal of Psychiatry and it's a meta-analysis of 6 randomized controlled trials on three different drugs. Antidepressants were no better than placebo in patients with "minor depressive disorder", which is like the better-known Major Depressive Disorder but... well, not as major, because you only need to have 2 symptoms instead of 5 from this list.

They also wanted to find out whether benzodiazepines (like Valium) worked in these people, but there just weren't any good studies out there.

The results look solid, and they fit with the fact that antidepressants don't work in people diagnosed with "major" depression, but who fall at the "milder" end of that range, something which several recent studies have shown. Neuroskeptic readers will, if they've been paying attention, find this entirely unsurprising.

But in fact, it's not just not news, it's positively ancient. 50 years ago, at the dawn of the antidepressant era, it was commonly said that most antidepressants don't work in everyone with "depression", they work best in people with endogenous depression, and less well, or not at all, in those with "neurotic" or "reactive" depressions (see, e.g. 1, 2, 3, but the literature goes back even further).

"Endogenous" is not strictly the same as "severe", however, in practice, these two concepts have never really been clearly seperated, and they're largely equivalent today, because the leading measure of "severity", the Hamilton Scale, measures symptoms, and arguably these symptoms are mostly (though not entirely) the symptoms of the old concept of endogenous depression. The Hamilton Scale was formulated in 1960 when modern concepts of "minor depressive disorder" and "major depressive disorder" were unknown.

Why then are we only now working out that antidepressants only work in some people? There's one obvious answer: Prozac, which arrived in 1987. Before Prozac, antidepressants were serious stuff. They could easily kill you in overdose, and they had a lot of side effects. Many of them even meant that you couldn't eat cheese. As a result, they weren't used lightly.

Prozac and the other SSRIs changed the game completely. They're much less toxic, the side effects are milder, and you can eat as much cheese as you want. So it's very easy to prescribe an SSRI - maybe it won't work, but it can't hurt, so why not try it...?

As a result, I think, the concept of "depression" broadened. Before Prozac, depression was inherently serious, because the treatments were serious. After Prozac, it didn't have to be. Drug company marketing no doubt helped this process along, but marketing has to have something to work with. Over the past 25 years, terms like "endogenous", "neurotic" etc. largely disappeared from the literature, replaced by the single construct of "Major Depression".

For nearly 1,000 years, the great scientific and philosophical work of the ancient Greeks and Romans were lost to Europeans. Only when Christian scholars rediscovered them in the libraries of the Islamic world did Europe begin to remember what it had forgotten. We call those the Dark Ages. Will the past 25 years be remembered as psychiatry's Dark Age?

Barbui, C., Cipriani, A., Patel, V., Ayuso-Mateos, J., & van Ommeren, M. (2011). Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis The British Journal of Psychiatry, 198 (1), 11-16 DOI: 10.1192/bjp.bp.109.076448

Antidepressants Still Don't Work In Mild Depression

A new paper has added to the growing ranks of studies finding that antidepressant drugs don't work in people with milder forms of depression: Efficacy of antidepressants and benzodiazepines in minor depression.


It's in the British Journal of Psychiatry and it's a meta-analysis of 6 randomized controlled trials on three different drugs. Antidepressants were no better than placebo in patients with "minor depressive disorder", which is like the better-known Major Depressive Disorder but... well, not as major, because you only need to have 2 symptoms instead of 5 from this list.

They also wanted to find out whether benzodiazepines (like Valium) worked in these people, but there just weren't any good studies out there.

The results look solid, and they fit with the fact that antidepressants don't work in people diagnosed with "major" depression, but who fall at the "milder" end of that range, something which several recent studies have shown. Neuroskeptic readers will, if they've been paying attention, find this entirely unsurprising.

But in fact, it's not just not news, it's positively ancient. 50 years ago, at the dawn of the antidepressant era, it was commonly said that most antidepressants don't work in everyone with "depression", they work best in people with endogenous depression, and less well, or not at all, in those with "neurotic" or "reactive" depressions (see, e.g. 1, 2, 3, but the literature goes back even further).

"Endogenous" is not strictly the same as "severe", however, in practice, these two concepts have never really been clearly seperated, and they're largely equivalent today, because the leading measure of "severity", the Hamilton Scale, measures symptoms, and arguably these symptoms are mostly (though not entirely) the symptoms of the old concept of endogenous depression. The Hamilton Scale was formulated in 1960 when modern concepts of "minor depressive disorder" and "major depressive disorder" were unknown.

Why then are we only now working out that antidepressants only work in some people? There's one obvious answer: Prozac, which arrived in 1987. Before Prozac, antidepressants were serious stuff. They could easily kill you in overdose, and they had a lot of side effects. Many of them even meant that you couldn't eat cheese. As a result, they weren't used lightly.

Prozac and the other SSRIs changed the game completely. They're much less toxic, the side effects are milder, and you can eat as much cheese as you want. So it's very easy to prescribe an SSRI - maybe it won't work, but it can't hurt, so why not try it...?

As a result, I think, the concept of "depression" broadened. Before Prozac, depression was inherently serious, because the treatments were serious. After Prozac, it didn't have to be. Drug company marketing no doubt helped this process along, but marketing has to have something to work with. Over the past 25 years, terms like "endogenous", "neurotic" etc. largely disappeared from the literature, replaced by the single construct of "Major Depression".

For nearly 1,000 years, the great scientific and philosophical work of the ancient Greeks and Romans were lost to Europeans. Only when Christian scholars rediscovered them in the libraries of the Islamic world did Europe begin to remember what it had forgotten. We call those the Dark Ages. Will the past 25 years be remembered as psychiatry's Dark Age?

Barbui, C., Cipriani, A., Patel, V., Ayuso-Mateos, J., & van Ommeren, M. (2011). Efficacy of antidepressants and benzodiazepines in minor depression: systematic review and meta-analysis The British Journal of Psychiatry, 198 (1), 11-16 DOI: 10.1192/bjp.bp.109.076448