SSRIs (selective serotonin reuptake inhibitors) are among the most commonly prescribed medications, used as a first-line pharmacological treatment for depression. Their basic mechanism is well-known: blocking the serotonin transporter, resulting in decreased serotonin reuptake into the neuron and thus more serotonin remains outside, allowing for more activation of serotonin receptors, and thus decreasing the depressive symptoms [1]. However, this is an oversimplification: the role of serotonin in the brain is still poorly understood.
For example, abnormally large serotonin levels in the brain may result in serotonin syndrome, a life-threatening condition characterized by neuromuscular and autonomic hyperactivity [2]. This condition may be caused by the use of drugs that act on the serotonergic system, such as SSRIs. On the other hand, serotonin deficiency may also lead to hyperactivity, as well as disrupted sleeping patterns [3].
There are also a multitude of serotonin receptors in the brain, all with different effects [1]. For instance, activation of the 5-HT1A receptor with selective agonists results in antidepressant effects [4]; however, blockade of 5-HT2C receptors with selective agonists also results in antidepressant effects, with a faster onset [5]. As well, autoreceptors modulate serotonin signalling, which further complicates the effects of increasing serotonin levels. Interestingly, the downregulation of 5-HT2C receptors appears to coincide with the onset of effects from SSRIs [6], suggesting that some abnormal signalling involving the 5-HT2C receptors may be involved in depression.
Further complicating matters is the downstream effects on serotonergic, noradrenergic, and dopaminergic pathways. It is known that NDRIs (norepinephrine/dopamine reuptake inhibitors) such as buproprion are also effective in treating depressive symptoms [7], and that activation of serotonin receptors also results in modulation of norepinephrine and dopamine signalling, such as in the case of 5-HT2C receptors [6]. This is still an active area of research, but it is still quite clear that the role of serotonin in the brain is not as simple as “serotonin = happy”.
References
[1] Sangkuhl K, Klein T, Altman R. Selective Serotonin Reuptake Inhibitors (SSRI) Pathway. Pharmacogenet Genomics. 2009;19(11):907-909. doi:10.1097/FPC.0b013e32833132cb
[2] Volpi-Abadie J, Kaye AM, Kaye AD. Serotonin Syndrome. Ochsner J. 2013;13(4):533-540.
[3] Whitney MS, Shemery AM, Yaw AM, Donovan LJ, Glass JD, Deneris ES. Adult Brain Serotonin Deficiency Causes Hyperactivity, Circadian Disruption, and Elimination of Siestas. J Neurosci. 2016;36(38):9828-9842. doi:10.1523/JNEUROSCI.1469-16.2016
[4] Kennett GA, Dourish CT, Curzon G. Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression. Eur J Pharmacol. 1987;134(3):265-274. doi:10.1016/0014-2999(87)90357-8
[5] Opal MD, Klenotich SC, Morais M, et al. Serotonin 2C receptor antagonists induce fast-onset antidepressant effects. Molecular Psychiatry. 2014;19(10):1106-1114. doi:10.1038/mp.2013.144
[6] Millan MJ. Serotonin 5-HT2C receptors as a target for the treatment of depressive and anxious states: focus on novel therapeutic strategies. Therapie. 2005;60(5):441-460. doi:10.2515/therapie:2005065
[7] Patel K, Allen S, Haque MN, Angelescu I, Baumeister D, Tracy DK. Bupropion: a systematic review and meta-analysis of effectiveness as an antidepressant. Ther Adv Psychopharmacol. 2016;6(2):99-144. doi:10.1177/2045125316629071