The Unfriending of Serotonin

Have you heard that serotonin has been unfriended by a lot of people? It was inevitable, of course. Like all idealized love objects, serotonin was headed for heartbreak.

Richard J. Metzner, M.D.

Clinical Professor

Semel Institute for Neuroscience and Human Behavior at UCLA



It started with Prozac, the media's first serotonin MILF (Medication I'd Love To Feature), but time can be cruel to aging molecules. Those of us who started prescribing Prozac the year it came out (1987) remember how rapidly it became the cultural phenomenon we were all "listening to."  We also remember that, as good as it was, it was never even close to being a universal panacea. We knew that when we listened to patients rather than the hype about the medication, we could hear differences between people who responded to selective serotonin reuptake inhibitors (SSRIs) like Prozac and those who responded better to noradrenergic or non-selective antidepressants like the tricyclics and monoamine oxidase inhibitors. For that reason we knew that the serotonin theory of depression was as incomplete as the norepinephrine or dopamine theories of depression. We still know that these neurotransmitters matter, because the most widely used medications that alleviate depression are the ones that involve them, but we also know that they aren't the whole story.

The problem with articles like "The Serotonin Theory of Depression Is Collapsing" ( is that they are based on the false premise that serotonin ever was the whole story. SSRIs became the recommended first-line treatments for all depressed patients, mostly because of favorable side-effect profiles, but they never should have been used first for everybody. Many of us listened to symptom profiles and prescribed according to what we heard, using activating antidepressants like bupropion instead of SSRIs when called for and titrating between bupropion and an SSRI when we heard mixtures of symptoms that might benefit from both. We still do, and so does Clinapticatm.


The theory behind this individualizing approach has received support from numerous clinical studies. Quite recently, for example, a group at the University of Ulm in Germany, led by Dr. Birgit Abler, used sophisticated brain imaging techniques to show that when normal young males were exposed to erotic films, areas paralleling dopaminergic pathways associated with primary reward processing were significantly affected by the SSRI paroxetine and the NDRI bupropion, but in opposite directions. The serotonergic antidepressant decreased and the noradrenergic/dopaminergic antidepressant increased the processing of rewarding (in this case, sexual) experience. Other studies have shown that serotonin and dopamine pathways can work in opposition to each other, which would account in part for many of the side-effects of both, such as the reduction of sex drive and the blunting of emotion associated with SSRIs and the increased impulsivity and insomnia seen with NDRIs.


The important clinical lesson from studies like these is that, despite some  crosstalk between them, the serotonergic and noradrenergic/dopaminergic pathways have diverse and opposing effects that parallel in many ways the diverse and opposing symptoms of depression. Treating depression as if it were a unitary syndrome robs patients of the chance to be perceived by prescribing professionals as individuals deserving of antidepressant treatments tailored to their needs. That is the real heartbreak associated with "unfriending" serotonin or any other treatment mechanism. Friends don't abandon friends just because they aren't always right.

Copyright 2012, Scaled Psychiatric Systems, Inc. All rights reserved.