Sertraline

Summary

Synopsis

Sertraline is a selective inhibitor of central serotonin reuptake. Thus, it enhances serotoninergic transmission — a property which appears to explain its antidepressant activity. Its elimination half-life (approximately 26 hours) makes it suitable for once daily administration.

Although clinical experience with sertraline is limited, it appears to possess antidepressant efficacy similar to that of amitriptyline and dothiepin, marginally better than imipramine, and significantly better than placebo. Additionally, sertraline is the only antidepressant licensed in the UK for the prevention of recurrence of depression, and preliminary findings suggest that the drug may also be effective in the treatment of obsessive-compulsive disorder.

Sertraline and other serotonin reuptake inhibitors possess tolerability advantages over tricyclic antidepressants. Sertraline has minimal anticholinergic activity, is essentially devoid of cardiovascular effects, has a wide therapeutic index and may be administered to elderly patients or those with underlying cardiovascular disorders. However, as with other serotonin reuptake inhibitors, sertraline has been associated with gastrointestinal disturbances (nausea, diarrhoea/loose stools) and male sexual dysfunction (primarily ejaculatory disturbance), although each of these effects is usually mild and transient, decreasing in frequency with continued treatment.

As a drug class, serotonin reuptake inhibitors such as sertraline appear to provide significant advantages compared with the more established antidepressant agents, particularly in terms of tolerability. Although much broader clinical experience is required before sertraline’s full therapeutic potential can be realised, if future studies confirm the encouraging initial findings, sertraline will undoubtedly become an important option in the treatment of depression.

Pharmacodynamic Properties

Sertraline inhibits serotonin uptake by rat brain synaptosomal preparations with a potency about 5, 9 and 21 times greater than fluoxetine, fluvoxamine and amitriptyline, respectively, but has little effect on dopamine and noradrenaline (norepinephrine) uptake. Sertraline also inhibits platelet serotonin uptake in healthy volunteers in a dose-dependent fashion. Acute, but not chronic, sertraline administration decreases serotonin turnover, and sertraline prevents para-chloramphetamine-induced depletion of central serotonin stores.

Sertraline has no direct effect on central noradrenergic and dopaminergic systems, but does cause down-regulation of central β-adrenoceptors. Further, sertraline has no significant affinity for central muscarinic and histamine H₁-receptors, thus explaining its lack of marked anticholinergic and sedative activity.

Single and multiple oral doses of sertraline 25 to 200mg have no significant detrimental effects on psychomotor and cognitive performance in healthy volunteers aged 25 to 75 years. Sertraline improves cognitive ability, as evidenced by increases in critical flicker fusion threshold and no significant effect on choice reaction time. In doses up to 200 mg/day, sertraline has no marked sedative activity in healthy volunteers, and significantly suppresses rapid eye movement (REM) sleep in patients with major depression. Sertraline 50 to 400 mg/day has no significant cardiovascular effects in depressed patients. In rats, sertraline markedly reduces food intake, bodyweight and voluntary ethanol consumption.

Pharmacokinetic Properties

In healthy volunteers, sertraline is slowly absorbed after oral administration — peak plasma concentrations (C_max) of about 20 to 55 μg/L occur approximately 4 to 8 hours after administration of a single 100mg dose. Sertraline pharmacokinetics are linear across the dose range 50 to 200mg; food slightly increases sertraline bioavailability and C_max increased by 25% in healthy volunteers.

Sertraline is widely distributed throughout the tissues (volume of distribution > 20 L/kg) and is extensively metabolised in the liver. Less than 0.2% of unchanged drug appears in the urine within 48 hours of administration, and the primary metabolite of sertraline — demethyl-sertraline — is considered inactive in vivo The elimination half-life of sertraline is approximately 26 hours thus making the drug suitable for once-daily administration. Peak plasma concentrations and area under the plasma concentration-time curve (AUC) values are increased, and elimination half-life is prolonged, in elderly volunteers but these changes do not appear to warrant dose adjustment in this patient group.

Therapeutic Efficacy

Sertraline 25 to 150 mg/day significantly reduced Hamilton Depression Rating Scale (HDRS) scores in a large-scale noncomparative study of patients with major depression (DSM-III) and, in large dose-ranging studies, sertraline 50 to 200 mg/day significantly improved almost all efficacy variables of depression.

In double-blind comparative studies sertraline 50 to 200 mg/day showed antidepressant efficacy similar to that of amitriptyline 50 to 150 mg/day and dothiepin 75 to 150 mg/day, but efficacy was significantly greater than that of imipramine 50 to 200 mg/day and placebo. Most studies assessed the relative antidepressant efficacy of sertraline vs amitriptyline, and response rates, based on HDRS and Clinical Global Impression (CGI) scores, ranged from 61 to 80% vs 63 to 75%, respectively. However, sertraline had a better tolerability profile than amitriptyline, as indicated by a significantly lower incidence of anticholinergic, cardiovascular and sedative effects and a lower adverse effect burden (subjective daily scores of adverse effect severity).

In terms of prevention of relapse and recurrence of depression, sertraline produced significantly lower relapse rates, based on HDRS and CGI scores, than placebo in 295 patients with major depression (7 to 13% vs 31 to 46%).

Sertraline was significantly more effective than placebo in 325 patients with obsessive-compulsive disorder: significant improvement was seen on the Yale-Brown Scale after 2 weeks, and on the CGI scale and the National Institute of Mental Health General Scale after 4 weeks.

Tolerability

Sertraline 50 to 200 mg/day has been very well tolerated in clinical trials in patients with major depression. Adverse events (i.e. events related, possibly related, or of unknown relationship to drug treatment) associated with sertraline therapy are usually dose-related, mild and transient in nature, decrease in frequency as treatment is continued, and rarely necessitate treatment withdrawal.

Pooled data from 1902 sertraline recipients showed that the most common adverse effects — gastrointestinal reactions (nausea, diarrhoea/loose stools), headache, dry mouth, insomnia, dizziness, tremor, fatigue, agitation and somnolence — occur in about 10 to 20% of patients, and cause treatment withdrawal in approximately 1 to 4% of recipients.

As a drug class, serotonin reuptake inhibitors are associated with a significantly lower incidence of anticholinergic, cardiovascular and sedative effects than tricyclic antidepressants. Thus, sertraline and other agents in its class are likely to be particularly useful in elderly patients.

Sertraline does not impair psychomotor function, or have negative effects on cardiovascular activity and haemodynamic, renal and laboratory parameters. Although sertraline has been associated with a higher incidence of male sexual dysfunction (16.5%) than amitriptyline or desipramine (8.8%), this appears to be the result of an increased incidence of ejaculatory disturbance (i.e. delayed ejaculation with occasional anorgasmia).

Dosage and Administration

For the treatment or prevention of recurrence of depression, an initial dosage of sertraline 50mg once daily is recommended. Upward titration (in 50mg increments at intervals of at least 1 week) to a maximum daily dosage of 200mg may be beneficial in patients who do not respond to a 50mg daily dose. Sertraline 50 to 200mg once daily appears to be effective for treatment of patients with obsessive-compulsive disorder.

Although dosage adjustments are not required in elderly patients, sertraline should be administered with caution in patients with renal or hepatic impairment.