Prescribing Sertraline

Why Sertraline Is the SSRI to Reach For First

If you had to pick one antidepressant to keep in your pocket for the widest range of patients, it would be hard to do better than sertraline. It is not the most potent antidepressant on any single axis, and it is not clearly superior to the other SSRIs for any one indication. What it is, and this is the whole point, is the SSRI with the best combination of breadth, safety, cleanliness, and evidence. It treats depression, panic, PTSD, OCD, social anxiety, GAD, and PMDD. It is among the safest psychotropics in overdose. It has the largest reproductive-safety dataset of any antidepressant. It does not meaningfully prolong the QT interval. And at standard doses it is nearly inert at the CYP450 enzymes, so it plays well with the rest of a patient's medication list.

In the landmark Cipriani network meta-analyses, sertraline consistently lands in the top tier for the combined metric that actually matters at the bedside: efficacy balanced against tolerability, and it wins outright on cost. That is why so many algorithms (Osser, and others) name it a first-line agent for depression alongside escitalopram and bupropion, and why the practical verdict in the Carlat literature is blunt: "Escitalopram and sertraline are good all-around SSRIs. Sertraline is the go-to in pregnancy and heart disease."

A word on where it came from: sertraline was one of the first-generation SSRIs to follow fluoxetine to market (Pfizer, 1991). Peter Kramer, writing about that era, captured why these drugs felt like a genuine break from what came before: "Some patients had dramatic responses and felt better than before depression, more confident, more comfortable socially, free from anxious and obsessive traits." Thirty-plus years and an enormous evidence base later, sertraline has settled into exactly that role: the dependable, broadly useful, low-drama SSRI.

Part 1: Indications: Who Is Sertraline For?

FDA-Approved Uses

• Major depressive disorder (adults)
• Obsessive-compulsive disorder (adults and children/adolescents ≥6, the pediatric approval that matters)
• Panic disorder
• Post-traumatic stress disorder (PTSD)
• Social anxiety disorder (SAD)
• Premenstrual dysphoric disorder (PMDD)

Sertraline is also used first-line and effectively for generalized anxiety disorder, which is a class effect for SSRIs even where the specific label varies. In practice, treat GAD as an on-label-equivalent use.

The Evidence-Based Clinical Picture

Major depression: the bread and butter

Sertraline is a legitimate first-line antidepressant with an NNT of roughly 8 for response, essentially indistinguishable from the other SSRIs. In fixed-dose trials, response rates run in the high 50s to low 60s percent (e.g., 58.5% at 50 mg, 62.7% at 100 mg, 58.9% at 200 mg in one classic trial, note the flat dose-response, discussed below). It performs comparably to bupropion and venlafaxine as a switch agent in STAR*D. One large Danish observational cohort (183,118 patients) even found sertraline marginally outperforming escitalopram, fluoxetine, and paroxetine over long-term treatment: modest, prescription-data-only, but consistent with its reputation as a reliable long-haul choice.

Panic disorder

Solidly effective, but with a crucial dosing implication: fixed-dose trials (Londborg 1998, Sheikh 2000) found 50 mg = 100 mg = 200 mg, all beat placebo, none beat each other. The practical corollary is start low and don't chase the dose. Panic patients are exquisitely sensitive to early SSRI activation, so a jittery first week can torpedo the whole treatment. The Carlat verdict is memorable: "In panic, the treatment is long, the dose is low."

Social anxiety disorder & GAD

First-line, dosed like depression, but with an important timeline caveat: anxiety responses are slower than depression responses. Expect 2–3 months for full effect; up to 25% of patients who look like non-responders at 8 weeks will respond by 12 weeks. Do not abandon a trial too early in an anxious patient. Continue 3–6 months (often longer) after response, since relapse on discontinuation is common.

OCD

FDA-approved in adults and in children ≥6. Like all SSRIs for OCD, it typically needs higher doses (often 150–200 mg) and longer trials (10–12 weeks) than depression, and partial response is the norm: OCD is a marathon.

PTSD

FDA-approved (sertraline and paroxetine are the only two SSRIs with this label), but be honest about the ceiling: the effect size is modest. Overall response ~58% (defined as ≥30% CAPS reduction), remission closer to 40%. NICE found sertraline did not clear its a priori effect-size threshold of 0.5. Trauma-focused psychotherapy (CBT, EMDR) is the superior first-line; sertraline is a reasonable pharmacologic adjunct or alternative. Predictors of better medication response: female sex, sexual-assault trauma, longer time since the trauma.

PMDD: a special and satisfying use

Low-dose sertraline (25–50 mg) works, and it works differently here. Beyond serotonin reuptake inhibition, sertraline accelerates the conversion of progesterone to the calming neurosteroid allopregnanolone (dropping the enzyme's Km by 10- to 30-fold). Clinically, this means onset within hours to days, not weeks, which uniquely enables luteal-phase-only (intermittent) dosing: medicate the two weeks before menses, stop with the period.

Evidence-Based Off-Label Uses

• Binge eating disorder (BED): 100–200 mg/day reduces binge frequency; a reasonable non-stimulant option, and safer than lisdexamfetamine in a bipolar patient. (For bulimia nervosa, fluoxetine 60 mg is the better-studied SSRI.)
• Behavioral/anxiety symptoms in dementia: 50–200 mg, start very low. Modest benefit for anxiety/agitation, better tolerated than citalopram, but not effective for depressive symptoms in dementia.
• Depression/anxiety in intellectual disability: first-line SSRI (with escitalopram) for its clean interaction profile and tolerability.
• Bipolar depression (adjunctive, with a mood stabilizer): ~48–63% response; comparable to bupropion and venlafaxine as an add-on. See the bipolar caution in Special Populations.

Where Sertraline Disappoints

• Subsyndromal depressive symptoms in advanced medical illness (e.g., cancer): 50 mg was no better than placebo. Treat the specific symptoms (hypnotic for insomnia, stimulant for fatigue) rather than reflexively reaching for an SSRI.
• First-ever depressive episode after an MI: in SADHART, benefit was seen only in patients with recurrent depression, not a first episode triggered by the cardiac event.

Part 2: Mechanism: The Short Version

Sertraline is a selective serotonin reuptake inhibitor: it blocks the serotonin transporter (SERT) in the brain and in peripheral tissues, including platelets (which is why SSRIs raise bleeding risk; see Part 7). That is the dominant, clinically defining action.

Two minor pharmacodynamic wrinkles distinguish it from the pack:

• Mild dopamine reuptake inhibition. Sertraline is the SSRI with the most notable (though still weak) effect at the dopamine transporter. This is a footnote clinically, but it is invoked to explain its occasional usefulness for apathy/abulia and helps distinguish it from purely serotonergic agents.
• Sigma-1 receptor activity. Sertraline binds sigma-1 receptors; the clinical meaning is uncertain but sometimes cited in discussions of its anxiety and cognitive effects.

Don't overweight these. For 95% of prescribing decisions, sertraline behaves as a clean SSRI.

Part 3: Pharmacokinetics You Actually Use

• Half-life ≈ 26 hours, comfortably supports once-daily dosing.
• Active metabolite: desmethylsertraline (norsertraline), half-life ~62–104 h. It is far less potent at SERT than the parent and contributes little clinically, so, unlike fluoxetine's norfluoxetine, you can largely ignore it.
• Steady state in ~1 week. This matters for two decisions: don't judge a dose change before a week has passed, and, importantly, sertraline clears in about a week once stopped. Contrast fluoxetine, which lingers for a month-plus.
• Take with food. Food modestly increases sertraline absorption and, more usefully, blunts the early GI upset. "Take it with a meal" is a real clinical instruction, not a throwaway.
• Metabolism: hepatic, via multiple CYP pathways. The interaction-relevant fact is its own inhibitory profile, which is dose-dependent (Part 7).

Part 4: How to Start and Dose

Formulations

Standard oral tablets (25, 50, 100 mg), and an oral concentrate/liquid (20 mg/mL) that is invaluable for the patients who need sub-25 mg starts: anxiety- and panic-prone patients, the elderly, the medication-sensitive, and anyone with swallowing difficulty. There is no clinically important extended-release version to worry about; dosing strategy is about the milligrams and the timing, not the formulation.

Starting Dose and Titration

• Unit dose is 50 mg. Titrate in 25–50 mg steps, no faster than every 1–2 weeks (in depression, wait ~2–4 weeks between meaningful increases to give each dose a fair chance).
• Usual therapeutic range: 50–200 mg/day. Most depressed patients do well at 50–100 mg. OCD and some PTSD patients live at the top of the range.
• Dose in the morning by default. If a given patient finds it sedating, move it to the evening: sertraline's activating-vs-sedating effect is idiosyncratic, so let the patient's experience decide.

The Single Most Important Dosing Insight: The Flat Dose-Response

For depression and panic, higher doses of sertraline do not buy more efficacy: they buy more side effects. The classic Fabre 1995 trial (50 vs 100 vs 200 mg) is the cautionary tale: response rates were essentially identical across all three doses, while agitation, insomnia, sedation, and nausea roughly doubled at 200 mg.

Give It a Real Trial

• First trial: 6 weeks at an adequate dose before calling it a failure.
• Second trial / partial responders: up to 12 weeks.
• Anxiety disorders: 2–3 months, with late responders at week 12 (see Part 1).

Judging sertraline at 2–3 weeks and bailing is the second great avoidable error. Under-dosing and under-timing masquerade as "sertraline didn't work."

Part 5: What to Expect & What to Monitor

The Arc of Treatment

• Week 1–2: the rocky part. Early GI upset (nausea, loose stools) and, in some, activation/jitteriness/insomnia. These are usually transient. Warn the patient in advance: forewarned is adherent.
• Weeks 2–6: anxiety and mood begin to lift; GI effects typically settle.
• Weeks 6–12: full antidepressant/anxiolytic effect declares itself, especially in anxiety disorders.

Routine Monitoring

Sertraline needs no routine bloodwork in a healthy adult, a major practical advantage over lithium or valproate. Your monitoring is clinical:

• Response and side effects at 2–3 weeks, then reassess the full trial at 6 weeks.
• Suicidality/activation, especially in patients ≤24 (boxed warning) and in the first weeks or after a dose change: closer follow-up early.
• Manic/hypomanic switch in anyone with bipolar risk; most switches occur in the first ~5 weeks.

Targeted Monitoring in At-Risk Patients

• Sodium in the elderly (≥65) or those on diuretics: check a baseline and recheck once after starting (see hyponatremia, Part 6). Median onset of SSRI hyponatremia is ~13 days.
• Bleeding risk: no lab, but take a history: NSAIDs, anticoagulants, antiplatelets, prior GI bleed (Part 7).
• QT is not a routine concern with sertraline (this is one of its selling points vs citalopram), but in a fragile elderly cardiac patient on other QT-prolonging drugs, an ECG is reasonable clinical prudence.

Part 6: Side Effects and How to Manage Them

The governing principle mirrors the SSRI class: most side effects are early and transient (GI, activation) or later and persistent (sexual dysfunction). Manage the early ones with reassurance and timing; manage the persistent ones actively rather than accepting them.

Gastrointestinal: Sertraline's Signature

Sertraline is the most diarrhea-prone SSRI (odds ratio ~2.33, the highest among antidepressants studied). This is its most distinctive tolerability quirk. Nausea is also common early.

Management:

• Take with food: the single most effective step; reduces nausea and cushions the gut.
• Reassure: GI effects are usually transient, fading over the first week or two.
• Slow the titration if GI upset is dose-driven; drop back to the last tolerated dose and re-advance more gently.
• For persistent nausea, symptomatic measures (ginger; short-term antiemetic) can bridge the adjustment window.
• For persistent, treatment-limiting diarrhea, this is a reason to consider switching SSRIs: escitalopram or citalopram are gentler on the bowel.

Sexual Dysfunction: The Most Common Persistent Complaint

Decreased libido, delayed orgasm/anorgasmia, and erectile difficulty are class effects; sertraline is not sexual-function-sparing. In patients with normal baseline function, incidence runs around 8% (vs ~1% placebo) in controlled data, though spontaneous-report figures badly underestimate the real-world rate, which is far higher when you ask directly.

Management (menu):

• Wait: a minority accommodate over weeks.
• Lower the dose: often helps, and thanks to the flat dose-response you can usually drop a depressed patient's dose without losing efficacy.
• Drug holiday: not reliable for sertraline (its half-life is too long for a weekend washout to help much; better suited to shorter agents, and not advisable in patients with adherence or relapse risk).
• Add bupropion: the best-supported augmentation for SSRI sexual dysfunction.
• Add sildenafil/tadalafil: effective for the erectile component (and has some data in women).
• Switch: to bupropion, mirtazapine, or vortioxetine, the agents least likely to cause it.

Activation, Insomnia, Jitteriness

Early over-stimulation is common, more so in anxious/panic patients and at higher doses. It is the reason we start panic and SAD patients at 25 mg or less.

Management:

• Start low, go slow (prevention beats cure).
• Move the dose to morning if insomnia is the problem.
• Short-term benzodiazepine bridge for panic patients: e.g., clonazepam 0.5 mg while the SSRI takes hold, then taper over ~4 weeks. This markedly speeds early response in panic; use judiciously given dependence risk.

Hyponatremia (SIADH)

SSRIs raise hyponatremia risk 2–3×; incidence in elderly patients can be strikingly high (studies cite 17–26%), with a median onset ~13 days. Watch for lethargy, confusion/delirium, nausea, headache, unsteadiness, easily mistaken for depression or dementia.

Management:

• Screen the elderly and those on diuretics (baseline Na, recheck ~2 weeks in).
• If symptomatic hyponatremia develops: stop the sertraline, restrict fluids (1–1.5 L/day), and it typically resolves within ~2 weeks.

GI Bleeding Risk

By blocking platelet serotonin uptake, SSRIs impair platelet aggregation and roughly double upper-GI bleed risk (baseline ~1/1,000 → ~1/500). Add an NSAID and the risk jumps ~5-fold (~1/200). Sertraline is among the more serotonergic SSRIs, so it sits at the higher end of this class risk.

Management:

• Take a bleeding history; ask specifically about NSAIDs, aspirin, anticoagulants, antiplatelets.
• In a patient with prior GI bleed or unavoidable NSAID/anticoagulant use, either co-prescribe a PPI or choose a non-serotonergic antidepressant (bupropion, mirtazapine) instead.

Bone Density

Chronic SSRI use is associated with lower bone mineral density and modestly increased fracture risk. Screen high-risk patients (older, smokers, low body weight, anorexia history) and ensure calcium/vitamin D adequacy.

Weight

Sertraline is essentially weight-neutral to minimally weight-gaining: it is the frequent reference/baseline in weight comparisons, comparable to fluoxetine and generally better than paroxetine. It offers no advantage or disadvantage over the other clean SSRIs here.

Suicidality (Boxed Warning)

Part 7: Overdose, Safety, and Drug Interactions

Overdose: One of the Safest

This is a genuine strength. Sertraline, like the SSRI class, is remarkably safe in overdose compared with TCAs (dangerous) or lithium (narrow window). Pure-SSRI overdoses are rarely lethal; the main risks are GI symptoms, sedation, and, at large ingestions or in combination with other serotonergics, serotonin syndrome and, uncommonly, seizures. And unlike citalopram, sertraline does not meaningfully prolong the QT interval, so it lacks citalopram's dose-dependent cardiac-arrhythmia liability in overdose. For a suicidal patient, this favorable overdose profile is a point in sertraline's favor.

The Interaction Headline: Clean at Low Dose, a CYP2D6 Inhibitor at High Dose

This is the one interaction fact to memorize:

• At ≤150 mg/day: sertraline is a weak CYP inhibitor, one of the "cleanest" SSRIs, in the same low-interaction tier as citalopram and escitalopram, and far cleaner than fluoxetine, paroxetine, or fluvoxamine. It does not meaningfully touch CYP3A4 or CYP2C19 at therapeutic doses.
• At ≥150 mg/day: sertraline becomes a meaningful (clinically significant) CYP2D6 inhibitor.

Practical CYP2D6 consequences at ≥150 mg:

• TCAs: sertraline can raise TCA levels; cut the TCA dose ~50% and check a serum level if combining.
• Atomoxetine and other 2D6 substrates: levels rise; adjust and monitor.
• Antipsychotics (e.g., risperidone): levels can rise via 2D6.

Serotonin Syndrome: The Hard Contraindications

• MAOIs: absolutely contraindicated together. Allow ≥14 days between stopping an MAOI and starting sertraline, and ≥14 days after stopping sertraline before starting an MAOI. Also watch other MAOI-like agents (linezolid, methylene blue).
• Other serotonergics (SNRIs, tramadol, other SSRIs, MDMA, St. John's wort, high-dose triptans, meperidine): additive serotonin-syndrome risk. Combinations are often used (e.g., an SSRI + a triptan) but warrant awareness of the symptoms: autonomic instability, hyperreflexia/clonus, agitation, hyperthermia.

Bleeding-Risk Interactions (Restated Because They Matter)

• NSAIDs + sertraline ≈ 5× GI-bleed risk. Prefer acetaminophen for pain; co-prescribe a PPI if an NSAID is unavoidable.
• Anticoagulants/antiplatelets (warfarin, DOACs, aspirin, clopidogrel): additive bleeding risk. Counsel and monitor.

What Sertraline Does Not Do

• No meaningful QT prolongation (unlike citalopram/escitalopram).
• No blood-pressure elevation (unlike venlafaxine).
• No orthostasis, no tachycardia, no anticholinergic burden of consequence.
• At standard doses, no significant 3A4 or 2C19 inhibition.

Part 8: Special Populations

Pregnancy: Sertraline Is the Reference SSRI

Sertraline has the largest reproductive-safety dataset of any antidepressant, and it is, alongside fluoxetine, the SSRI most clinicians reach for in pregnancy. The core message: for a woman who needs an antidepressant in pregnancy, sertraline is usually the right choice, because untreated depression carries real risks to mother and fetus.

The nuances to hold honestly:

• Cardiac septal defects: some data (Pedersen 2009) associate first-trimester SSRI exposure with a small absolute increase in septal defects: roughly 0.9% exposed vs 0.5% unexposed. The absolute risk is low, the literature is mixed and confounded, and exposure to multiple SSRIs carried higher risk (~2.1%) than any single agent. Counsel proportionately: a real but small signal, not a reason to leave severe depression untreated.
• Neonatal adaptation syndrome: late-pregnancy exposure can cause transient jitteriness, respiratory distress, poor tone, feeding/temperature instability, typically mild and resolving within ~4–5 days. It is a self-limited neonatal issue, not birth defect.
• PPHN (persistent pulmonary hypertension of the newborn) is a rare, much-debated late-exposure association; absolute risk is very low.

Practical approach: In most cases, continue an effective sertraline through pregnancy and delivery. The dominant risk for mother and baby is a relapse of maternal illness (which also predicts postpartum depression). Do not routinely stop or taper at term merely to spare the neonate a few days of mild adaptation symptoms; the trade (raising the mother's postpartum relapse risk) is usually the worse deal. Individualize with the patient.

Lactation: The Preferred SSRI

Sertraline is a first-choice antidepressant in breastfeeding. It passes into breast milk in very low amounts, with typically undetectable or negligible infant serum levels and an excellent safety record. When a nursing mother needs an SSRI, sertraline is the one to pick.

Elderly: Watch Sodium and Falls

Sertraline is a good choice in older adults for its cardiac cleanliness (no citalopram-style QT cap), but three risks rise with age:

• Hyponatremia (screen sodium; see Part 6),
• Falls/fractures (bone-density effect plus any hyponatremia/dizziness),
• General sensitivity.

Start low (12.5–25 mg), titrate every 1–2 weeks. Reassess whether it's helping; don't leave an ineffective SSRI running in a frail elder given these risks.

Cardiac Disease: Sertraline's Home Turf

Sertraline is the best-studied and among the safest antidepressants in cardiovascular disease. The SADHART trial (post-ACS patients, mean 70 mg/day) established its cardiac safety and showed benefit, in patients with recurrent depression (not first-episode post-MI depression). No QT prolongation, no conduction effects, no orthostasis. When a patient has heart disease, sertraline is the default.

Children & Adolescents

• FDA-approved for pediatric OCD (≥6). (For pediatric depression, fluoxetine and escitalopram hold the approvals; sertraline's peds label is OCD.)
• The boxed suicidality warning is most relevant here: monitor closely at initiation and dose changes, involve caregivers, follow up early and often.

Bipolar Disorder

• Bipolar II depression: monotherapy switch rates were ~20%, statistically no different from lithium or placebo in a controlled trial: reasonably safe, and possibly as effective as adding lithium.
• With a mood stabilizer (bipolar I/II): an acceptable adjunct for breakthrough depression.
• Rapid cyclers: avoid. Antidepressants can worsen cycling (roughly triple relapse risk in some data).
• Always watch for a manic/hypomanic switch, concentrated in the first ~5 weeks.

Hepatic and Renal Impairment

• Hepatic impairment: sertraline is hepatically metabolized, so exposure rises in liver disease. Start lower, titrate slower, and lengthen dosing intervals in significant hepatic impairment.
• Renal impairment: no specific dose adjustment is required, a modest practical advantage.

Part 9: Discontinuation: Taper, Don't Yank

Sertraline has a short-to-intermediate half-life (~26 h), which places it squarely in the middle of the SSRI discontinuation spectrum: more discontinuation symptoms than fluoxetine (whose long half-life self-tapers), but markedly fewer than paroxetine, fluvoxamine, venlafaxine, or duloxetine, the notorious offenders. It is one of the easier SSRIs to come off, but it is not free.

Discontinuation syndrome (the "FINISH" cluster: Flu-like, Insomnia, Nausea, Imbalance, Sensory disturbances, Hyperarousal) includes the classic "brain zaps" (electric-shock sensations), dizziness, anxiety, weepiness, and odd paresthesias in the hands and feet. It is uncomfortable and self-limited, not dangerous, but it is easily mistaken for relapse.

How to Stop

• Taper slowly: weeks to months, not days. The longer the patient has been on it and the higher the dose, the slower the taper.
• Go hyperbolic at the low end. Discontinuation symptoms often appear paradoxically at the lowest doses (even coming off 25 mg), because receptor occupancy falls steeply there. The liquid concentrate lets you make small final decrements (e.g., 25 → 12.5 → lower) that tablets can't.
• If brain zaps or withdrawal emerge, go back up to the last comfortable dose and taper more gradually from there.
• Prepare the patient: "For a couple of weeks you may feel anxious, weepy, dizzy, or have odd electric or tingling sensations. It's the medication leaving, not your depression returning, and it passes. Call me if it's rough, and let's tell a family member so they know what to expect." Even a well-run 2-month taper produces more transient withdrawal reports than staying on, so pace it and normalize it.

Relapse vs withdrawal: withdrawal comes on within days of a dose drop and includes physical symptoms (zaps, dizziness) that depression doesn't; relapse builds later and looks like the original illness. When in doubt, reinstate and taper slower.

A note on maintenance: after ≥2 prior depressive episodes, continuation meaningfully cuts relapse (e.g., ~39% relapse on continuation vs ~56% off over 52 weeks). Decide whether to stop before you decide how to stop.

Part 10: Sertraline vs the Alternatives

Among SSRIs, efficacy differences are small; the choice is usually driven by side effects, interactions, and safety in the specific patient. Here is where sertraline sits.

• vs Escitalopram: the two "best all-around SSRIs." Comparable efficacy and tolerability; both top-tier in Cipriani. Escitalopram may edge it in anxious depression and is arguably the single smoothest SSRI; sertraline wins on pregnancy/lactation data, cardiac safety, and cost, and avoids escitalopram's (mild) QT signal.
• vs Citalopram: similar, but citalopram carries a dose-dependent QT warning (max 40 mg/day; 20 mg in the elderly or poor 2C19 metabolizers). Sertraline has no such cap, a real advantage in cardiac and geriatric patients.
• vs Paroxetine: sertraline wins on nearly every safety axis: less sexual dysfunction, less weight gain, far less withdrawal, fewer anticholinergic effects, fewer CYP2D6 interactions, and lower congenital-malformation signal. Paroxetine is the "problem child" of the class; prefer sertraline for essentially every shared indication.
• vs Fluoxetine: the trade is half-life. Fluoxetine's very long half-life means gentler withdrawal and forgiveness of missed doses, but a 5-week washout, bad when you need to stop quickly (e.g., a newly discovered pregnancy, a planned MAOI, or an intolerable reaction). Fluoxetine also inhibits 2D6/2C19 more (more interactions). Sertraline is more maneuverable and cleaner; fluoxetine is the more forgiving.
• vs Fluvoxamine: fluvoxamine is a potent CYP inhibitor (1A2, 3A4, 2C19) with high withdrawal liability and, in the US, an OCD-only label. Sertraline is cleaner and broader.
• vs Bupropion: bupropion causes no sexual dysfunction and can aid weight loss, but it treats no anxiety and is contraindicated with seizure risk/eating disorders. Sertraline covers the anxious/OCD/PTSD spectrum bupropion can't. They are complementary (and combine well, including for SSRI sexual dysfunction).
• vs Venlafaxine/SNRIs: SNRIs are, at most, marginally more effective (a meaningful difference for perhaps 1 in 24 patients) at the cost of higher blood pressure, worse withdrawal, and more side effects. Sertraline is the gentler, cleaner starting point.
• vs Mirtazapine: mirtazapine is more sedating and weight-gaining but sexual-function-sparing and a useful augmentation partner (sertraline + mirtazapine ≈ 52% response after inadequate monotherapy).
• vs Psychotherapy/exercise: roughly comparable acute efficacy to CBT and to structured aerobic exercise in depression, and, notably, exercise showed better relapse prevention at 10 months (8% vs 38%) in one trial. Combine modalities; medication is not the only lever.

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