19.01.7 Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) demonstrate similar efficacy to TCAs in treating moderate depression, but possibly less efficacy in treating severe depression. These drugs have been shown to be very effective in reducing anxiety and agitation associated with depression. At therapeutic doses SSRIs demonstrate 50-fold selectivity for serotonin transporters over noradrenaline transporters. Owing to this highly selective blockade of the serotonin transporters, SSRIs increase levels of serotonin in the synapse. With longer-term administration, SSRIs downregulate postsynaptic 5-HT₂ receptors and, like TCAs, increase sensitivity of postsynaptic 5-HT₁ receptors in the hippocampus. Similarly to TCAs and MAOIs, SSRIs decrease the sensitivity of presynaptic 5-HT₁ autoreceptors, thus facilitating serotonin release. In this way, SSRIs enhance serotoninergic transmission by re-establishing normal firing rate, increasing serotonin output, and increasing postsynaptic (5-HT₁) receptor sensitivity in the hippocampus.

Unlike TCAs, SSRIs have little affinity for cholinergic and histaminergic receptors, and it is this purity of effect that has led to their popularity, owing to reduction in side effects. Nonetheless these drugs produce numerous 5-HT receptor-mediated side effects including nausea and vomiting, diarrhoea, agitation, insomnia, tremor, and disturbances of potency and libido. Further, a combination of SSRIs with other drugs that enhance serotoninergic transmission may lead to ‘serotonin syndrome’ resulting from serotonin toxicity. SSRIs are less dangerous in overdose than TCAs and MAOIs due to the lack of cardiotoxicity and their large therapeutic index.