Is the low-serotonin theory of depression wrong?


The theory that depression is highly correlated with low levels of serotonin has dominated our approach to treating depression with SSRIs (selective serotonin re-uptake inhibitors) to maintain higher levels of serotonin in the synaptic cleft (rather than having the neurotransmitter re-absorbed into the post-synaptic cell). A new perspective has been proposed by authors of a recent paper published in the Neuroscience & Biobehavioral Reviews in January 2015. The paper, “Is serotonin and upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response”, makes three major claims about the role of serotonin in depression:

1024px-Serotonin-Spartan-HF-based-on-xtal-3D-balls-web1) Serotonin is elevated in states of depression; 2) The serotonergic system is an energy regulator and SSRIs disrupt energy homeostasis, often worsening symptoms of depression; 3) Symptom reduction is not achieved directly by the action of SSRIs but rather the brain’s compensatory response to restore homeostasis.

Lead author Paul Andrews from the department of Psychology, Neuroscience and Behavior at McMaster University in Ontario, says, “It’s time we rethink what we are doing. We are taking people who are suffering from the most common forms of depression, and instead of helping them, it appears we are putting an obstacle in their path to recovery.” Is it possible that the “therapeutic delay” of SSRIs is actually the result of our brain overcoming the effects of the antidepressant medication and working to bring homeostasis to the system? “We’ve seen that people report feeling worse, not better, for their first two weeks on anti-depressants,” Andrews says. “This could explain why.”

Early research suggested that monoamines (serotonin, norepinephrine, and dopamine) were implicated in depressive states and that by preventing their breakdown by enzymes or blocking the re-uptake, depressive states could be alleviated. This theory seemed to be backed up by observations that the drug reserpine, which depletes monoamines, seemed to increase depressive symptoms. Thus was born the theory that depression was caused by the reduction of monoamine neurotransmission, and later studies suggested that low serotonin was the main culprit. Researchers then looked at how to selectively increase synaptic serotonin levels which lead to the creation of the selective serotonin reuptake inhibitors (SSRIs).

There are, however, some problems with the low serotonin hypothesis that Andrews et al explain in their paper:

  • Other drugs that block serotonin reuptake are not effective in treating depression.
  • The early studies of reserpine-induced depression may not be true and reserpine may actually have antidepressant properties.
  • SSRIs can increase serotonin levels in minutes to hours, but the therapeutic effect takes weeks of continuous treatment.
  • Deliberate attempts to reduce serotonin in the non-depressed hasn’t worked.
  • Neonatal exposure to SSRI’s causes depressive symptoms in adult rodents.
  • Genetic manipulation to increase synaptic serotonin is associated with increased depressive symptoms.
  • Antidepressant medications are only modestly more effective than placebos for reducing depressive symptoms.

The serotonergic system is involved in a vast number of functions, possibly across every major system, organ, and metabolic process. Andrews et al point out the importance of serotonin in key areas of energy regulation and the need for homeostatic equilibrium of serotonin levels when there are metabolically expensive processes going on. When SSRIs are unnaturally upsetting the balance of extracellular serotonin, the brain has to work to elicit a compensatory response in an attempt to restore energy homeostasis. If the authors of this paper are correct, SSRIs may be having an opposing effect on depressive symptoms during acute and chronic treatment.

It is possible that serotonin is not the key to depression, and may be quite a distal factor in the causal pathway for depression. Serotonin is likely an important part of regulating energetically expensive states like depression (i.e. depressed states being high serotonin phenomena), but the solution for depression is probably not a simple matter of artificially tipping the balance of serotonin across the entire system.



Andrews, P. W., Bharwani, A., Lee, L. R., Fox, M., & Thomson Jr, J. A. (2015). Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response. Neuroscience & Biobehavioral Reviews, 51: 164 DOI: 10.1016/j.neubiorev.2015.01.018


See also:

New study throws into question long-held belief about depression – you can find the abstract here –

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