Sertraline

Sertraline is a selective serotonin reuptake inhibitor (SSRI) with well established antidepressant and anxiolytic activity. Results from several well designed trials show that sertraline (50 to 200 mg/day) is effective in the treatment of major depressive disorder in elderly patients (≥60 years of age). Primary endpoints in most studies included the Hamilton Depression Rating Scale (HDRS), Clinical Global Impression (CGI) score and the Montgomery-Åsberg Depression Rating Scale (MÅDRS). Sertraline was significantly more effective than placebo, and was as effective as fluoxetine, nortriptyline and imipramine in elderly patients. During one trial, amitriptyline was significantly more effective than sertraline [mean reduction from baseline on one of six primary outcomes (HDRS)], although no quantitative data were provided. Subgroup analysis of data from a randomised, double-blind trial in elderly patients with major depressive disorder suggests that vascular morbidity, diabetes mellitus or arthritis does not affect the antidepressant effect of sertraline.

Secondary endpoints from these clinical trials suggest that sertraline has significant benefits over nortriptyline in terms of quality of life. In addition, significant differences favouring sertraline in comparison with nortriptyline and fluoxetine have been recorded for a number of cognitive functioning parameters.

Sertraline is generally well tolerated in elderly patients with major depressive disorder, and lacks the marked anticholinergic effects that characterise the adverse event profiles of tricyclic antidepressants (TCAs). The most frequently reported adverse events in patients aged ≥60 years with major depressive disorder receiving sertraline 50 to 150 mg/day were dry mouth, headache, diarrhoea, nausea, insomnia, somnolence, constipation, dizziness, sweating and taste abnormalities. The tolerability profile of sertraline is generally similar in younger and elderly patients.

Sertraline has a low potential for drug interactions at the level of the cytochrome P450 enzyme system. In addition, no dosage adjustments are warranted for elderly patients solely based on age.

Secondary outcome data from well designed clinical trials suggest that sertraline is associated with beneficial effects on cognitive functioning in patients aged ≥60 years with major depressive disorder. Significant differences favouring sertraline compared with nortriptyline have been recorded for a range of cognitive functioning parameters. In addition, patients receiving sertraline perform somewhat better on the Shopping List Task and the Digit Substitution Test than fluoxetine recipients. Sertraline appeared to have a neutral psychomotor profile in healthy volunteers aged 50 to 75 years during two randomised, double-blind, crossover studies.

The pharmacokinetic profile of sertraline in healthy volunteers aged ≥65 years does not appear to differ markedly from that in younger volunteers (aged 18 to 45 years). Maximum plasma concentrations (C_max) and the areas under the plasma concentration-time curve (AUC) were 0.14 mg/L and 2.6 mg • h/L for both age groups receiving sertraline 50 mg/day for 30 days. The pharmacokinetics of sertraline are linear up to doses of 200mg in healthy volunteers.

Sertraline is slowly absorbed: the time to C_max (t_max) is about 7 hours in both younger and elderly volunteers. Although coadministration of food appears to increase exposure by about 25% and reduce t_max from 8 to 5 hours in healthy volunteers, sertraline can be taken with or without food.

Steady-state plasma concentrations of sertraline (200 mg/day) are generally achieved within about 11 days. Plasma clearance, however, appears to be ≈40% lower in elderly patients than in younger patients. Achievement of steady-state plasma concentrations therefore takes potentially longer (by 2 to 3 weeks) in elderly patients. After administration of sertraline oral concentrate 100mg, the AUC and the C_max are 115 and 121% of those for sertraline in tablet form (100 mg). The volume of distribution of sertraline is about 20 L/kg in healthy adult volunteers and the drug is highly (98%) plasma protein bound.

Sertraline undergoes extensive first-pass metabolism by cytochrome P450 (CYP) isoenzymes to the primary metabolite N-desmethylsertraline, which is markedly less active pharmacologically. In vitro data suggest that the main CYP isoenzymes involved in the metabolism of sertraline are CYP2C19 and CYP2C9. The plasma elimination half-life of N-desmethylsertraline is between 62 to 104 hours. Less than 5% of a radiolabelled sertraline dose is detected in the urine unchanged.

Renal impairment does not seem to affect the pharmacokinetics of sertraline. In patients with mild liver impairment, however, sertraline clearance is reduced and exposure is increased by approximately 3-fold. The pharmacokinetics of sertraline have not been evaluated in patients with moderate or severe hepatic impairment.

Few clinically significant drug interactions between sertraline and other drugs have been reported. Potentially, sertraline interacts with drugs that are highly bound to plasma proteins (e.g. warfarin, digoxin), causing displacement of one of the drugs from plasma proteins. Moreover, sertraline modestly affects the pharmacokinetics of drugs that are metabolised by CYP2D6. Examples are the TCAs and some type 1C antiarrhythmics (e.g. propafenone and flecainide). In addition, sertraline has been shown to interact with cimetidine (increased systemic exposure to sertraline), diazepam (decreased clearance of diazepam) and intravenous tolbutamide (decreased clearance of tolbutamide). The clinical relevance of these interactions, however, is unknown. Drugs that have been demonstrated not to interact with sertraline are lithium, terfenadine and carbamazepine.

In comparison with other SSRIs, sertraline and citalopram have the lowest potential for drug interactions at the level of the CYP enzyme system.

Sertraline is effective in the treatment of major depressive disorder in patients aged ≥60 years as demonstrated by five randomised, double-blind trials. Decreases of 36 to 58% from baseline (mean 21.4 to 25.1) Hamilton Depression Rating Scale (HDRS) scores have been recorded after 8 to 12 weeks of sertraline (50 to 200 mg/day) administration. In addition, the number of responders to treatment (patients with ≥50% decrease in HDRS score) ranged from 46 to 73% during these trials. Sertraline was significantly more effective than placebo in a well designed trial (published as an abstract) as assessed by HDRS (p = 0.002) and Clinical Global Impression (CGI) scales (p < 0.05, primary outcomes).

No significant differences were recorded for primary efficacy parameters when sertraline 50 to 100 mg/day was compared with the SSRI fluoxetine 20 to 40 mg/day (as assessed by HDRS). Moreover, the efficacy of sertraline 50 to 150 mg/day was similar to that of the TCAs nortriptyline 25 to 100 mg/day (as assessed by HDRS) and imipramine 150 mg/day (as assessed by MÅDRS). Amitriptyline 50 to 150 mg/day, however, was significantly more effective than sertraline 50 to 200 mg/day (as assessed by HDRS, intent-to-treat analysis) on one of six primary efficacy measures in one study, although no such difference was found when only evaluable patients were used for statistical analysis.

Interestingly, subgroup analyses of two trials suggest that sertraline is more effective than fluoxetine (p < 0.05) and nortriptyline (p < 0.01) in patients aged ≥70 years, although these results await confirmation by trials primarily designed to address this difference.

Subgroup analysis of data from a randomised, double blind trial published as an abstract, suggests that medical comorbidity (vascular morbidity, diabetes mellitus or arthritis) does not affect the antidepressant effects of sertraline in elderly patients with major depressive disorder.

Secondary endpoints from well designed trials have revealed significant differences in favour of sertraline in comparison with nortriptyline on several quality-of-life parameters. No significant differences were found for quality of life when sertraline was compared with fluoxetine.

Data from a small (n = 22), but well designed trial in patients with major depressive disorder and comorbid Alzheimer’s disease suggest that sertraline 25 to 150 mg/day is superior to placebo. Significant differences (p < 0.05) in favour of sertraline were recorded on the Cornell Scale for Depression in Dementia and HDRS after 12 weeks of treatment.

Sertraline is generally well tolerated by elderly patients with major depressive disorder. The most frequently reported adverse events in patients aged ≥60 years with major depressive disorder receiving sertraline 50 to 100 mg/day were dry mouth (41% of patients), headache (34%), diarrhoea (22%), nausea (24%), insomnia (20%), somnolence (5%), constipation (15%), dizziness (9%), sweating (13%) and taste abnormalities (4%). These events occurred at a similar frequency to those with nortriptyline 25 to 150 mg/day, with the exception of dry mouth and constipation (anticholinergic adverse events), which occurred in sertraline recipients with and incidence of a half to a third of that in those receiving nortriptyline and amitriptyline 50 to 150 mg/day (p < 0.05). Nausea, however, occurred significantly more often in sertraline recipients than in patients receiving either nortriptyline or amitriptyline during these trials. The tolerability of sertraline 50 to 100 mg/day was generally similar to that of fluoxetine 20 to 40 mg/day during a randomised, double-blind trial in patients aged ≥60 years.

The adverse event profile of sertraline is generally similar for elderly and younger patients. Sertraline (like other SSRIs) has in several cases been associated with clinically significant hyponatraemia, which mainly occurred in elderly patients.

In comparison with TCAs, SSRIs like sertraline are less harmful in overdose. The most common signs and symptoms associated with sertraline overdose (nonfatal) are somnolence, vomiting, tachycardia, nausea, dizziness, agitation and tremor.

SSRIs are commonly associated with sexual dysfunction; ejaculation failure was reported by 14% of men receiving sertraline and decreased libido was reported by 6% of male and female sertraline recipients during placebo controlled trials.

In the US, sertraline is indicated for the treatment of patients with major depressive disorder, obsessive compulsive disorder, panic disorder and post-traumatic stress disorder. For the treatment of adult patients with major depressive disorder, a daily dosage of 50mg is recommended, taken with or without food. Nonetheless, dosages up to 200 mg/day have been administered during clinical trials in elderly patients with major depressive disorder. In contrast to paroxetine and citalopram, no dosage adjustments are required when sertraline is given to elderly patients. It is generally agreed that major depressive disorder requires maintenance therapy for several months or longer after an acute episode. Patients should be periodically reassessed to determine the need for maintenance treatment with sertraline.

The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied; a lower or less frequent dosage should be used when sertraline is administered to these patients. No dosage adjustments are required for patients with impaired renal function.

Sertraline should not be administered to patients receiving monoamine oxidase inhibitors (MAOIs) because of serious and sometimes fatal drug interactions. When patients are switched from sertraline to a MAOI or vice versa, at least 14 days should be allowed between the discontinuation of one drug and initiation of the next. In addition, the oral concentrate of sertraline should not be administered to patients concomitantly receiving disulfiram because of the alcohol content of the solution.