SynopsisSertraline, a selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor (SSRI) which was initially developed as an antidepressant, has also been shown to be an effective treatment for patients with obsessive-compulsive disorder (OCD).Results of short and long term (≤ 2 years) clinical trials have shown that sertraline is an effective treatment for nondepressed adult and paediatric patients with OCD. In several placebo-controlled clinical trials conducted in patients with OCD, sertraline 50 to 200 mg/day produced significantly greater improvements than placebo on Yale-Brown Obsessive-Compulsive Scale and Clinical Global Impression Severity Scale and on various other OCD assessment scales. The efficacy of sertraline in OCD has not yet been directly compared with that of the SSRIs fluvoxamine, fluoxetine or paroxetine. However, findings of a single comparative trial indicate that sertraline is at least as effective as, and is better tolerated than, the tricyclic antidepressant (TCA) clomipramine in adults.Sertraline, like other SSRIs, is generally well tolerated. It is not associated with the anticholinergic, sedative and cardiovascular adverse effects that are characteristic of the TCAs. Headache, insomnia, nausea and diarrhoea were reported as the most common adverse events in sertraline recipients who participated in a 12-week placebo-controlled trial; the incidences of these events (except headache) decreased in patients who received sertraline treatment in a 40-week extension of this trial. Like other SSRIs, sertraline has been reported to cause sexual dysfunction in some patients.Because sertraline has a plasma elimination half-life of 25 to 26 hours, oncedaily administration is sufficient to ensure adequate plasma sertraline concentrations are achieved in patients with normal renal function. The favourable drug interaction profile of sertraline as compared with other SSRIs used to treat OCD has been partly explained by its weak inhibitory effects on some hepatic cytochrome P450 isoenzymes.In conclusion, sertraline is an effective primary treatment option for adults, adolescents and children with OCD and has broadened the range of available agents for this often disabling condition. In addition, it is better tolerated than clomipramine and thus may be preferred for the treatment of specific patient groups, particularly those susceptible to the adverse effects of TCAs.Pharmacodynamic PropertiesSertraline, a naphthylamine derivative, is one of several selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) that have demonstrated efficacy in the treatment of obsessive-compulsive disorder (OCD). The cause of OCD has not yet been conclusively established, but a dysregulation of serotonergic functioning appears to be involved.Sertraline is a potent and highly selective inhibitor of serotonin reuptake. The resultant effect is an increase in synaptic serotonin levels, enhanced serotonergic activity and subsequent downregulation of serotonergic subsystems. Although sertraline produces only minor inhibition of noradrenaline (norepinephrine) reuptake, biogenic amines other than serotonin may also be involved in mediating its therapeutic activity.CNS &sgr;1-receptors have been implicated in the pharmacological activity of sertraline and it has also been suggested that the drug may exert clinical effects via &ggr;-aminobutyric acid neuronal pathways. Sertraline shows no marked affinity for 5-HT1A, 5-HT1B, 5-HT2, histamine H1, muscarinic or dopamine D2receptors, or &agr;1-, &agr;2- or &bgr;-adrenoceptorsin vitro.Increased vigilance has been observed in healthy volunteers after single 100 to 400mg doses of the drug. Sertraline was also associated with improved cognitive performance and alertness in healthy volunteers aged 50 to 67 years.Pharmacokinetic PropertiesThe pharmacokinetics of sertraline appear to be broadly similar in male and female healthy adults, in elderly individuals aged ≥65 years and in children and adolescents. Sertraline has a linear pharmacokinetic profile after single or multiple oral doses of 50 to 200mg. It is slowly absorbed after oral administration and steady-state plasma concentrations are reached approximately 1 week after treatment initiation. The volume of distribution of sertraline (>20 L/kg) indicates that it is extensively distributed in body tissues.After absorption, sertraline undergoes substantial first-pass metabolism in the liver. Its primary metabolite is demethyl-sertraline, which subsequently undergoes oxidative deamination to produce conjugated and unconjugated metabolites. The metabolites of sertraline have been shown to have virtually no effects on serotonin reuptake. Sertraline is eliminated in approximately equal amounts in the urine and faeces. As the plasma elimination half-life of the drug is 25 to 26 hours, it is administered on a once-daily basis.The pharmacokinetics of sertraline (administered as single or multiple oral doses) are not significantly altered in patients with mild, moderate or severe renal impairment, although clearance may be reduced in patients with end-stage renal disease. Because sertraline is metabolised in the liver, its clearance is reduced in patients with hepatic disease.The favourable drug interaction profile of sertraline has been partly explained by its weak inhibitory effect on the hepatic cytochrome P450 (CYP) isoenzymes CYP2D6, CYP3A3/4, CYP2C19, CYP2C9/10 and CYP1A2. In contrast, the SSRIs fluoxetine and paroxetine have substantial inhibitory effects on CYP2D6, and fluvoxamine has marked inhibitory effects on CYP1A2 and CYP2C19. Thus, these SSRIs have a greater propensity than sertraline to interact with drugs metabolised by these enzymes. As sertraline is highly plasma protein bound, it has the potential to interact with other highly protein bound drugs. However, no reports of such interactions have yet been published.Therapeutic EfficacySeveral placebo-controlled trials in nondepressed adults with OCD have demonstrated that sertraline 50 to 200 mg/day produces significantly greater improvements than placebo on the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), Clinical Global Impression (CGI) Severity Scale and on various other OCD assessment scales. Sertraline has been shown to be effective both as short term treatment (≤16 weeks) and as longer term maintenance therapy over 1 to 2 years. In a 12-week placebo-controlled trial (n = 324 adults), 60.4 and 49% of sertraline and placebo recipients, respectively, responded to study medication. During a 40-week extension phase of this study, the clinical efficacy of sertraline was sustained, with improvements in Y-BOCS, National Institute of Mental Health Global Obsessional-Compulsive Scale (NIMH) and CGI Severity Scale scores indicating that sertraline was significantly more effective than placebo.The only study that has compared sertraline 50 to 200 mg/day with clomipramine 50 to 200 mg/day demonstrated that both agents produced significant improvements on the Y-BOCS and several other OCD assessment scales. Sertraline and clomipramine showed equal efficacy among patients completing the trial. However, intention-to-treat analysis revealed a significant advantage for sertraline over clomipramine which was explained in part by the higher treatment discontinuation rate because of adverse events in the latter group.A recent meta-analysis of data from large placebo-controlled trials revealed that sertraline, fluoxetine and fluvoxamine have similar efficacies in OCD; however, all 3 agents appeared to be significantly less effective than clomipramine. These results may be partly explained by inclusion of treatment-naive patients in earlier trials of clomipramine. In contrast, the more recent trials of SSRIs included a higher proportion of treatment-experienced patients who had not responded to previous treatment with clomipramine or with other SSRIs.In noncomparative investigations that included patients with paraphilias (classified as OCD spectrum disorders), sertraline 50 to 200 mg/day produced marked improvements on most sexuality scales and significantly decreased obsession scores.Sertraline, in dosages of 25 to 200 mg/day, has also demonstrated clinical efficacy in children and adolescents (aged 6 to 17 years) with OCD. Significant improvements in mean Children's Y-BOCS. NIMH and CGI Severity Scale scores, compared with baseline values, were evident after 5 weeks' sertraline treatment.TolerabilitySertraline 50 to 200 mg/day was generally well tolerated by adults and paediatric patients with OCD who participated in clinical trials. The incidence and severity of sertraline-related adverse events appeared to be dose related. In a placebo-controlled trial conducted in 324 nondepressed adults with OCD, the most common adverse events reported during 12 weeks' sertraline treatment (50 to 200 mg/day) were headache, insomnia, nausea, diarrhoea, decreased libido and anorexia. These events occurred with an incidence ≥10% greater than with placebo. All of the sertraline-related adverse events (except headache) decreased in incidence during a 40-week extension of the 12-week trial. There was a significantly higher incidence of insomnia, nausea, agitation and tremor in children and adolescents with OCD receiving sertraline treatment than in similar patients who received placebo.Unlike the tricyclic antidepressants (TCAs), sertraline is associated with minimal anticholinergic activity and is essentially devoid of cardiovascular effects. Moreover, in contrast to the sedative effects of the TCAs, sertraline does not generally appear to impair psychomotor performance. Results of a recent comparative study showed that there was a significantly higher treatment discontinuation rate because of adverse events in patients receiving clomipramine (25.6%) than in the sertraline treatment group (10.5%).Sertraline has a wide therapeutic index and appears to be less harmful in overdosage than the TCAs.Dosage and AdministrationThe optimal starting dosage of sertraline for treating adult and paediatric patients with OCD is 50 mg/day. Thereafter, the dosage may, if necessary, be increased in 50mg increments (over several weeks or months) to a maximum of 200 mg/day. Dosage modification is not usually required for patients with mild to moderate renal impairment, but dosage reduction is recommended for patients with hepatic disease.