What is sertraline (Selective Serotonin Reuptake Inhibitor) used for and how does it work?

Sertraline (SSRI): Mechanism of Action and Clinical Uses

Sertraline is a selective serotonin reuptake inhibitor (SSRI) that treats depression, anxiety disorders, OCD, PTSD, panic disorder, social anxiety disorder, and premenstrual dysphoric disorder by inhibiting serotonin reuptake in the brain, thereby increasing serotonin availability at the synaptic cleft. 1

Mechanism of Action

• Sertraline works primarily by inhibiting the presynaptic reuptake of serotonin in the brain, increasing serotonin availability at the synaptic cleft 1
• This blockade leads to downregulation of inhibitory serotonin autoreceptors over time, which eventually heightens serotonergic neuronal firing rate and increases serotonin release 2
• The multistep process explains the delay in onset of therapeutic effect, typically taking several weeks 2
• Sertraline has only very weak effects on norepinephrine and dopamine neuronal reuptake 1
• It has no significant affinity for adrenergic, cholinergic, GABA, dopaminergic, histaminergic, or benzodiazepine receptors 1

Pharmacokinetics

• Sertraline is slowly absorbed following oral administration and undergoes extensive first-pass metabolism 1, 3
• Peak plasma concentrations occur between 4.5 to 8.4 hours post-dosing 1
• The average terminal elimination half-life is approximately 26 hours, allowing for once-daily dosing 1, 3
• Steady-state plasma levels are achieved after approximately one week of once-daily dosing 1
• Sertraline is metabolized to N-desmethylsertraline, a weakly active metabolite that accumulates to higher concentrations than the parent drug at steady state 3
• At low doses of sertraline, twice-daily dosing may be required, particularly in youth 2

Clinical Uses

Depression

• Effective for acute treatment of major depressive disorder and prevention of relapse or recurrence 2, 4
• Recommended continuation of treatment for 4-9 months after satisfactory response in patients with first episode of major depressive disorder 2
• For patients with two or more episodes of depression, longer duration of therapy may be beneficial 2

Anxiety Disorders

• Recommended for patients 6-18 years old with social anxiety, generalized anxiety, separation anxiety, and panic disorders 2
• Effective for both acute treatment and longer-term management of social anxiety disorder, PTSD, panic disorder, and generalized anxiety disorder 4
• Improves primary anxiety symptoms (parent and clinician report), response to treatment, remission of disorder, and global function 2

Other Approved Uses

• Effective for short-term and long-term treatment of obsessive-compulsive disorder in both adults and pediatric patients 4
• Used for treatment of post-traumatic stress disorder (PTSD) 4, 5
• Approved for premenstrual dysphoric disorder (PMDD) 1, 6

Side Effects and Safety

Common Side Effects

• Most adverse effects emerge within the first few weeks of treatment 2
• Common side effects include dry mouth, nausea, diarrhea, heartburn, headache, somnolence, insomnia, dizziness, vivid dreams, changes in appetite, weight changes, fatigue, nervousness, tremor, bruxism, and diaphoresis 2
• Sertraline has a higher rate of diarrhea compared to other antidepressants 2

Serious Adverse Effects

• Potentially serious adverse effects include suicidal thinking and behavior (particularly in children, teenagers, and young adults), behavioral activation/agitation, hypomania, mania, sexual dysfunction, seizures, abnormal bleeding, and serotonin syndrome 2, 1
• Risk for nonfatal suicide attempts may be increased with SSRIs including sertraline 2
• Serotonin syndrome can be life-threatening and may include agitation, hallucinations, coma, coordination problems, racing heartbeat, blood pressure changes, fever, nausea, vomiting, diarrhea, and muscle rigidity 1

Drug Interactions

• Sertraline has minimal inhibitory effects on major cytochrome P450 enzymes, resulting in fewer drug-drug interactions compared to other SSRIs like fluoxetine, fluvoxamine, and paroxetine 3, 6
• Caution should be used when combining with blood thinners, NSAIDs, or aspirin due to increased bleeding risk 1
• Should not be taken with MAOIs, pimozide, or disulfiram (if taking liquid form) 1

Clinical Considerations

• Sertraline is generally well-tolerated with a good safety profile and low fatal toxicity 4
• Response may follow a logarithmic model with statistically significant improvement within 2 weeks, clinically significant improvement by week 6, and maximal improvement by week 12 or later 2
• This pharmacodynamic profile supports slow up-titration to avoid unintentionally exceeding the optimal medication dose 2
• In pregnancy, benefits and risks should be discussed as effects on the unborn baby are not fully known 1
• Some sertraline may pass into breast milk; consultation with healthcare provider is recommended for breastfeeding mothers 1
• Weight impact: short-term use may be associated with weight loss, while long-term use tends to be weight-neutral 2

Special Populations

• Sertraline is considered weight-neutral with long-term use, making it preferable to other antidepressants for patients with weight concerns 2
• It has a favorable side effect profile and may be administered to elderly patients or those with underlying cardiovascular disorders 7
• In children and adolescents, height and weight should be monitored during treatment 1
• Neonatal exposure to SSRIs including sertraline may lead to withdrawal symptoms including crying, irritability, tremors, feeding difficulty, sleep disturbance, and respiratory distress 2