Mood Is Chemistry. No Really, It Is.

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.

It's an excellent article and you should read the whole thing. Goldacre is far from alone in his skepticism towards to the serotonin hypothesis. Indeed in certain circles, the idea that the serotonin hypothesis is basically just drug company propaganda is almost folk wisdom nowadays (stop me if you've heard this one before).

Now, I'm not going to defend the idea that all depression is caused by "low serotonin".That's almost certainly wrong, and the very best you can say about it is that there's no strong evidence for it. In fact, it's not even clear, from a neurobiological perspective, what "low serotonin" means - low in which parts of the brain? Are we talking about low firing rates of serotonin neurons, or low amounts of serotonin released each time they fire, or low levels of serotonin just hanging around the synapses all the time? (And the next time someone tries to sell you a supplement or a herb or other short-cut to higher serotonin levels, just remember that there is such a thing as too much happy hormone.)

But - it's possible to be too skeptical. Serotonin does, unquestionably, play an important role in mood. Rumors of the death of the serotonin hypothesis have been greatly exaggerated. Ironically, the best evidence for the mood-relevance of serotonin doesn't come from antidepressants. Most common antidepressants, e.g. the famous Prozac, are said to work by "boosting serotonin levels", but actually it's far from clear that they do. Although these drugs inhibit the transporter protein which gets rid of serotonin after it's been released, which should in theory increase serotonin levels, in fact the picture is more complex, because serotonin inhibits the firing of the very cells that release it. Ironically, Prozac might even decrease serotonin levels in the places where they matter, at least in the short term. (For pharmacology geeks, see here).

The best evidence that mood is chemical, and that serotonin is one of the chemicals involved, comes from a foul-tasting, frothy, nausea-inducing milkshake known as the acute tryptophan depletion (ATD) mixture. The ATD mixture contains 100g of amino acids, which are what the body uses to synthesize proteins. You put the amino acids (white powders) into 200 ml of water. Some of them dissolve, some don't, so it's pretty lumpy. When (if) you manage to drink it all, interesting things happen. The influx of extra amino acids stimulates protein synthesis in your body. Some of the amino acids also get transported into the brain via certain proteins.

The key ingredient of the ATD mixture is the absence of tryptophan. Tryptophan is an amino acid, and like all amino acids it's used to make proteins, but it's also necessary for the production of serotonin in the brain. When you drink the ATD mixture - containing no tryptophan, remember - all of the tryptophan already in your blood gets used up in the burst of protein synthesis. Any that survives can't get transported into the brain, because other amino acids are already using the transporter proteins. The result is that tryptophan levels in the blood, and the brain, drop dramatically over the course of several hours.

ATD has been used in research for over a decade. The ATD procedure is unpleasant - volunteers have to consume the drink, which is truly horrible, on an empty stomach, and then not eat anything for the next 7 hours. Sometimes people vomit while trying to drink the stuff, or shortly afterwards, or two hours later. It's not much fun. But ATD has proven, to my mind, beyond any doubt, that the link between serotonin and mood is more than just a myth. The reason is that if you give ATD to people who have previously suffered clinical depression, a large proportion of them become depressed again, just for a few hours. This has been replicated several times. The effects can be dramatic (although not always, and sometimes there is no discernible effect) -

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)

Good skeptics will immediately notice that everything I've just described could be a reverse placebo effect - people are warned to expect to get depressed, and then they have to drink a god-awful mixture that makes them feel sick, so it's no surprise they feel down. This is a real concern, so for comparison there is a placebo drink - exactly the same, but with plenty of tryptophan - and everything is done double blind. The placebo drink does not produce the same effects (although occasionally there are placebo responses - sometimes very striking ones.)

So does this mean that low serotonin = depression after all? No, for the very simple reason that if you do the exact same experiments on people who have never suffered from depression, they feel fine and dandy (well, except that they feel sick.) A few people say they feel a bit down, but the reactions are nowhere near as strong as those seen in many people with a history of clinical depression. Yet the biochemical effect - reduced brain tryptophan and hence (presumably) reduced serotonin synthesis, is the same.

If we knew what made some people vulnerable to the effects of tryptophan depletion, we would be a long way towards understanding depression. We still don't. But it's something to do with serotonin. In some people, in some circumstances, serotonin is the only thing between happiness and despair. No, really.