The comparative pharmacology of new antidepressants

This review attempts to critically assess the evidence regarding the relationship between the specificity of antidepressants in modulating different neurotransmitter systems and their therapeutic activity. Evidence from experimental and clinical studies suggests that all antidepressants and electroconvulsive shock therapy produce qualitatively similar adaptive changes in serotonergic, adrenergic, and possibly GABAergic and dopaminergic transmission following chronic treatment. Such adaptational changes parallel the onset of the therapeutic response. The relationship between the pharmacokinetics and the therapeutic efficacy and safety of the serotonin selective reuptake inhibitors (SSRIs) is considered with particular attention to fluoxetine, fluvoxamine, sertraline, and paroxetine. The primary difference between these drugs lies in their half-lives; fluoxetine and its major active metabolite norfluoxetine have a combined half-life exceeding 7 days. All the SSRIs are well tolerated with a low incidence of life-threatening side effects. Nausea and, rarely, vomiting occur quite frequently as a consequence of increased serotonergic activity in the gastrointestinal tract and possibly via central 5-HT3 receptors. The safety and prolonged efficacy of the SSRIs render them particularly beneficial for the long-term treatment of the depressed patient. Evidence is provided that, in order to prevent relapse, depressed patients should be maintained on continuous antidepressant therapy for at least 1 year, and at the same dose as that required to treat the acute phase of the illness. The review concludes with a brief summary of the therapeutic use of the SSRIs in the treatment of panic attack, obsessive compulsive disorder, and bulimia with a brief comment on the different subtypes of serotonin receptors that may be involved.