Clinical Application Research of Sertraline

Introduction

Sertraline is designated as (1S,4S)-N-methyl-4-(3,4-dichlorophenyl) -1,2,3,4- tetrahydro -1-naphthylamine and contains two asymmetric carbonatoms (Figure 1). The cis (1S,4S) enantiomer is the more potent serotonin reuptake inhibitor and is the marketed pharmaceutical form. The affinity of sertraline for other neurotransmitter receptor sites is low, and with the possible exception of binding to the dopamine transporter, are not considered to be of therapeutic consequence. Initially marketed for the treatment of depression, sertraline is also approved in the US for the treatment of obsessive-compulsive disorder (OCD), panic disorder,and post-traumatic stress disorder.

Clinical Pharmacokinetics of Sertraline

Sertraline is a naphthalenamine derivative with the predominant pharmacological action of inhibiting presynaptic reuptake of serotonin from the synaptic cleft. It was initially marketed for the treatment of major depressive disorder and is now approved for the management of panic disorder, obsessive-compulsive disorder and post-traumatic stress disorder. Sertraline is slowly absorbed following oral administration and undergoes extensive first-pass oxidation to form N-desmethyl-sertraline, a weakly active metabolite that accumulates to a greater concentration in plasma than the parent drug at steady state. Sertraline is eliminated from the body by other metabolic pathways to form a ketone and an alcohol, which are largely excreted renally as conjugates. The elimination half-life of sertraline ranges from 22-36 hours, and once-daily administration is therapeutically effective. Steady-state plasma concentrations vary widely, up to 15-fold, in patients receiving usual antidepressant dosages between 50 and 150 mg/day. However, only sparse data have been published that support useful correlations between sertraline plasma concentrations and therapeutic or adverse effects to justify therapeutic drug monitoring. Sertraline has minimal inhibitory effects on the major cytochrome P450 enzymes, and few drug-drug interactions of clinical significance have been documented. Like other selective serotonin reuptake inhibitors, sertraline is well tolerated in therapeutic dosages and relatively safe in overdosage.[1]

Brexpiprazole and Sertraline Combination Treatment in Posttraumatic Stress Disorder

To investigate the efficacy, safety, and tolerability of brexpiprazole and sertraline combination treatment (brexpiprazole + sertraline) compared with sertraline + placebo for posttraumatic stress disorder (PTSD). This was a parallel-design, double-blind, randomized clinical trial conducted from October 2019 to August 2023. The study had a 1-week, placebo run-in period followed by an 11-week, double-blind, randomized, active-controlled, parallel-arm period (with 21-day follow-up) and took place at 86 clinical trial sites in the US. Adult outpatients with PTSD were enrolled (volunteer sample). Oral brexpiprazole 2 to 3 mg per day (flexible dose) + sertraline 150 mg per day or sertraline 150 mg per day + placebo (1:1 ratio) for 11 weeks. The primary end point was change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total score (which measures the severity of 20 PTSD symptoms) from randomization (week 1) to week 10 for brexpiprazole + sertraline vs sertraline + placebo. Safety assessments included adverse events. A total of 1327 individuals were assessed for eligibility. After 878 screen failures, 416 participants (mean [SD] age, 37.4 [11.9] years; 310 female [74.5%]) were randomized. Completion rates were 137 of 214 participants (64.0%) for brexpiprazole + sertraline and 113 of 202 participants (55.9%) for sertraline + placebo. At week 10, brexpiprazole + sertraline demonstrated statistically significant greater improvement in CAPS-5 total score (mean [SD] at randomization, 38.4 [7.2]; LS mean [SE] change, -19.2 [1.2]; n=148) than sertraline + placebo (randomization, 38.7 [7.8]; change, -13.6 [1.2]; n=134), with LS mean difference, -5.59 (95% CI, -8.79 to -2.38; P< .001). All key secondary and other efficacy end points were also met. Treatment-emergent adverse events with incidence of 5% or greater for brexpiprazole + sertraline (and corresponding incidences for sertraline + placebo) were nausea (25 of 205 [12.2%] and 23 of 196 [11.7%]), fatigue (14 of 205 [6.8%] and 8 of 196 [4.1%]), weight increase (12 of 205 [5.9%] and 3 of 196 [1.5%]), and somnolence (11 of 205 [5.4%] and 5 of 196 [2.6%]). Discontinuation rates due to adverse events were 8 of 205 participants (3.9%) for brexpiprazole + sertraline and 20 of 196 participants (10.2%) for sertraline + placebo. Results of this randomized clinical trial show that brexpiprazole + sertraline combination treatment statistically significantly improved PTSD symptoms vs sertraline + placebo, indicating its potential as a new efficacious treatment for PTSD. Brexpiprazole + sertraline was tolerated by most participants, with a safety profile consistent with that of brexpiprazole in approved indications.[2]

Sertraline in the treatment of panic disorder

Sertraline has been used as a treatment for anxiety disorders since the mid 1990s and has proven itself an effective, well-tolerated and economically viable treatment for panic disorder (PD) when used in the range of 50 to 175 mg per day. Numerous short- and long-term studies have demonstrated the efficacy of sertraline in the treatment of PD. In addition, in an 80-week relapse prevention trial, sertraline was found to reduce severity and frequency of panic attacks, baseline anxiety and to confer protection from relapse for up to 36 weeks following withdrawal from medication Data on sertraline as an alternative to tricyclic antidepressants and paroxetine in terms of tolerability is presented here. The efficacy of sertraline is shown to be comparable to cognitive behavioral therapy in one study and recent attempts at adjunctive therapy for PD with atypical antipsychotics are reviewed as well. Anxiety disorders constitute the most prevalent grouping of mental illnesses in the general population. Patients with panic disorder suffer a significant degree of medical comorbidity in addition to overlap with major depressive disorder, generalized anxiety disorder and somatization disorders. Further, PD patients experience a high degree of debility as measured by public assistance, emergency room and medical service utilization and suicide risk. Epidemiological data and studies linking significant decrease in medical, emergency service and laboratory utilization in PD patients taking sertraline are also presented. When reviewed in context with the efficacy trials, a compelling argument can be made for making sertraline a first choice among the serotonin reuptake inhibitors in the treatment of PD.[3]

References

[1] DeVane CL, Liston HL, Markowitz JS. Clinical pharmacokinetics of sertraline. Clin Pharmacokinet. 2002;41(15):1247-1266. doi:10.2165/00003088-200241150-00002

[2] Davis LL, Behl S, Lee D, et al. Brexpiprazole and Sertraline Combination Treatment in Posttraumatic Stress Disorder: A Phase 3 Randomized Clinical Trial. JAMA Psychiatry. 2025;82(3):218-227. doi:10.1001/jamapsychiatry.2024.3996

[3] Hobgood CD, Clayton AH. Sertraline in the treatment of panic disorder. Drugs Today (Barc). 2009;45(5):351-361. doi:10.1358/dot.2009.45.5.1362066