Pharmacological Differences of Serotonin Reuptake Inhibitors and Possible Clinical Relevance

Summary

Depression is a heterogeneous disease state characterised by complex alterations in several CNS neurotransmitter and receptor systems. All antidepressants are thought to act by causing postsynaptic adaptive changes (e.g. in transducers or second messengers) within these systems. Thus, the mechanism of action of selective serotonin reuptake inhibitors (SSRIs) cannot simply be explained in terms of inhibition of serotonin (5-hydroxytryptamine) [5-HT] reuptake. Fluvoxamine, sertraline and fluoxetine downregulate central β-adrenoceptors, and all SSRIs are believed to normalise central 5-HT_1A- and 5-HT₂-receptor density and function in patients with depression.

SSRIs are as effective as tricyclic antidepressants in the treatment of depression, but have distinct tolerability advantages — they are not associated with anticholinergic adverse effects, cardiotoxicity, sedation or weight gain. However, gastrointestinal reactions (e.g. nausea, diarrhoea/loose stools, constipation) are relatively common during SSRI therapy. Additionally, in contrast to tricyclic antidepressants, SSRI dosage adjustments appear to be unnecessary in elderly depressed patients. Fluvoxamine has a much shorter elimination half-life than fluoxetine and its active metabolite, norfluoxetine, and therefore a reduced potential for drug interactions. Only small amounts of fluvoxamine and fluoxetine, but large quantities of paroxetine, are secreted in breast milk. Furthermore, genetic polymorphism has not been documented for fluvoxamine metabolism, whereas slow and fast metabolisers of paroxetine, and fast metabolisers of fluoxetine have been identified.

SSRIs have a better tolerability profile than tricyclic antidepressants, as indicated by lower mean rank scores for behavioural toxicity. Moreover, SSRIs are associated with a much lower incidence of fatal toxicity than tricyclics, and appear to be relatively safe in overdosage.

Thus, SSRIs represent a class of antidepressants with similar efficacy to, but major tolerability advantages over, tricyclic agents. Continued use of and experience with SSRIs will enhance our understanding of the central serotonergic system and may lead to the development of more selective drugs in the future.