Has the Serotonin Hypothesis Been Debunked?

The serotonin hypothesis of depression, popular from the 1990s until now, is false, and has been known to be false for a long time, and never was proven to begin with. The norepinephrine hypothesis of depression, which preceded the serotonin hypothesis in the 1960s to the 1980s, also was false, and has been known to be false for a long time, and never was proven to begin with. The same holds for the dopamine hypothesis of schizophrenia, which began in the 1960s and 1970s, and more generally for the “chemical imbalance” metaphor for all mental illness.

All of these are major oversimplifications, which most scientists realize are major oversimplifications, but which the general public and many clinicians have assumed to be true. A recent review paper merely documents the absence of much if any scientific evidence for these oversimplified false hypotheses. So it’s not new scientifically at all. The first author of the review has been a major critic of psychiatric medications in general, especially serotonin reuptake inhibitors (SRIs), and thus the main purpose of the paper may be to seek to undermine the use of SRIs. It may indeed do so for the general public and those clinicians who have believed the false concepts of chemical imbalance and/or the serotonin hypothesis of depression. But for scientists and researchers, the use of SRIs is completely unrelated to these false metaphors. The use of SRIs should be based solely on the efficacy data shown for those agents in randomized clinical trials. Those data are indeed weak, and thus, I hold the view that SRIs should be used much less than they are, and for shorter durations, but this view has nothing to do with the already known false concepts of a serotonin theory of depression.

Another feature of the paper, which usually isn’t acknowledged, is that the absence of a relationship between measures of serotonin and “depression” also is expected and routine because that is the case with any biological marker of any kind in psychiatry in the past 40 years and any DSM-based diagnosis. By “depression” these studies usually mean DSM-defined “major depressive disorder” (MDD), and almost all studies for the last 40 years find that no biological marker correlates with most DSM diagnoses (with important exceptions in schizophrenia and bipolar illness). The problem is that DSM diagnoses are not biologically valid because they are not scientifically based; they are not based solely on scientific evidence but rather are social constructions of the American psychiatric profession. Hence they are not useful for biological research and almost always produce negative results, as in this paper. The NIMH leadership acknowledged this major problem in 2013 when the DSM-5 came out and since that time the NIMH policy has been to not use DSM diagnoses for biological research. So again this review is only documenting what is already known in general: Most DSM diagnoses, like MDD, do not correlate with any biological measure, like serotonin.

More generally: It is obvious that these false views are based on backward logic. Since SRIs improved depressive symptoms somewhat in clinical trials (though much less than people believe), it was assumed that depression had a basis in “low” serotonin. This would be like saying that since aspirin is a prostaglandin inhibitor, and it reduces fever, then fever is a prostaglandin disorder. In fact, prostaglandin effects is just one way to reduce fever, and it is only a last step to reducing fever. The real way to reduce fever is to stop the cause of fever earlier in the process, as with antibiotics for the bacteria that cause infections that produce fever.

Similarly with SRIs and serotonin. SRIs are only symptomatic drugs; they reduce symptoms of depression somewhat, just as aspirin reduces symptoms of fever. Their mechanism, increasing serotonin, may have nothing at all to do with the psychiatric diseases that cause depression, such as manic-depressive illness, just as the mechanism of aspirin has nothing to do with the infectious diseases that cause fever.

Also, the brain just doesn’t work that way. It’s not about “high” this or “low” that. There are many chemicals in the brain interacting with each other in a very complex manner, with negative and positive feedback loops, so that there is no sense at all to say that anything in the brain relevant to any illness has to do with simply having too much or too little of any chemical. Further, besides the chemicals often discussed, like serotonin, norepinephrine, and dopamine, there are hundreds of other proteins, called second messengers, that relay information inside neurons related to these chemicals. And those second messengers interact with each other in a myriad of ways. If SRIs partially influence depression by their effects on serotonin – even if we accept this simple statement – those effects are then transmitted by hundreds of other proteins and second messengers in ways that are far too complex to describe.

So how should clinicians explain depression to their patients? This is what I do and recommend:

“Depression is not a disease; it is a set of symptoms, like fever, chills, and night sweats. I would be a bad doctor if I just gave you anti-fever pills and anti-chill pills and anti-night sweat pills, instead of treating the infection that caused all those symptoms. Similarly, antidepressants like SRIs improve the symptoms of depression somewhat, but don’t get at the cause. Just like aspirin and Tylenol can improve the symptoms of fever somewhat, but don’t get at the cause. We might use antidepressants short-term for symptom benefit, but we should also try to find the disease that is causing your depression, such as manic-depressive illness.”

Further, I could say: “Depression is not a ‘chemical imbalance’ because there is no ‘chemical balance.’ These are false metaphors. The brain is complex and many chemicals are active in many different directions in the brain. Your depression may be biological disease, in which chemicals are functioning abnormally, but it’s not about just having too much or too little of anything. And it’s not about getting everything into some ‘balance.’ It’s about treating the disease itself.”