Intended for healthcare professionals


Serotonin and depression

BMJ 2015; 350 doi: (Published 21 April 2015) Cite this as: BMJ 2015;350:h1771

SSRI treatment for Major Depression relies on problematic assumptions

Prof Healy's editorial elucidates the history of Selective Serotonin Reuptake Inhibitors (SSRI), and casts substantial doubt on the widespread belief that SSRIs should be considered the gold-standard for treating depression. In addition to the important points raised by Prof Healy, the notion that SSRI treatment cures depression makes two important assumptions that remain largely unaddressed: (a) that depression is a distinct, consistent syndrome, and (b) that decreased serotonin levels cause depression. Both are problematic.

First, Major Depression is a highly heterogeneous disease category [1], and two patients can be diagnosed with MD without sharing a single symptom. A recent study exemplified the pronounced heterogeneity of depression by identifying over 1,000 unique symptom profiles in 3,703 depressed patients [2]. The DSM-5 not only defines a large number of disparate depression symptoms such as sadness, fatigue, concentration problems, and suicidal ideation, but encompasses symptomatic opposites like hypersomnia and insomnia, psychomotor agitation and retardation, and weight loss and weight gain. The belief that any one medication alleviates such fundamentally different problems seems controversial at best.

Second, the rationale for SSRI treatment relies on the strong causal assumption that decreased levels of serotonin in the brain trigger MD (the somewhat weaker hypothesis that depression is merely accompanied by such changes in the brain would not suffice to justify the use of SSRIs, seeing that they would target consequences and not causes). Considering that personality dimensions, adverse life events, social, and genetic factors are involved in the complex and multi-factorial etiology of MD [3], the idea that serotonin imbalances cause MD is very unlikely. For most individuals within the spectrum of the depressive syndrome, depression is not a brain disorder, but an accumulation of problems that fuel each other. People who suffer from such mental health problems deserve better than the one-size-fits-all treatment that SSRIs offer.

As Prof Healy might say: the massive over-prescription of ineffective SSRIs is anything but mostly harmless.

Eiko Fried, Ph.D.

1. Olbert CM, Gala GJ, Tupler LA (2014) Quantifying Heterogeneity Attributable to Polythetic Diagnostic Criteria : Theoretical Framework and Empirical Application. J Abnorm Psychol 123: 452–462. doi:10.1037/a0036068.
2. Fried EI, Nesse RM (2015) Depression is not a consistent syndrome: An investigation of unique symptom patterns in the STAR*D study. J Affect Disord 172: 96–102. doi:10.1016/j.jad.2014.10.010.
3. Kendler KS (2012) The dappled nature of causes of psychiatric illness: replacing the organic-functional/hardware-software dichotomy with empirically based pluralism. Mol Psychiatry 17: 377–388. doi:10.1038/mp.2011.182.
4. Fried EI (2015) Problematic assumptions have slowed down depression research: why symptoms, not syndromes are the way forward. Front Psychol 6: 1–11. doi:10.3389/fpsyg.2015.00309.

Competing interests: No competing interests

25 April 2015
Eiko I Fried
Postdoctoral Research Fellow
University of Leuven, Faculty of Psychology and Educational Sciences
Tiensestraat 102, 3000 Leuven, Belgium