Antidepressant Selection & Adverse-Effect Management

Choosing the first antidepressant

Principle. Most antidepressants have similar average efficacy, so the choice rests on the patient: comorbid conditions, the side effects that matter most to them, drug interactions, overdose risk, and prior response (their own or a first-degree relative's).

SSRIs first. Blocking the serotonin transporter (SERT), SSRIs are first-line for major depression and for the anxiety disorders that often accompany it. They are inexpensive, well tolerated, and far safer in overdose than tricyclics. Sertraline and escitalopram are the usual starting choices because of tolerability and few interactions; sertraline also has safety data after myocardial infarction.

Bupropion. A norepinephrine–dopamine reuptake inhibitor, bupropion is activating, weight-neutral or weight-reducing, spares sexual function, and helps smoking cessation. It suits patients with fatigue, hypersomnia, SSRI sexual dysfunction, or tobacco use, but it does little for prominent anxiety. It lowers the seizure threshold and is contraindicated in seizure disorders, current or past anorexia or bulimia nervosa, and abrupt withdrawal from alcohol or benzodiazepines.

Mirtazapine. Presynaptic α2 blockade increases serotonin and norepinephrine release, while 5-HT2, 5-HT3, and H1 blockade produce sedation, appetite stimulation, and weight gain with little sexual or GI toxicity. It is ideal for older adults with insomnia, poor appetite, and weight loss. Sedation is often stronger at low doses (7.5–15 mg). Agranulocytosis is rare, so a CBC is warranted if fever or sore throat develops.

Comorbid pain. SNRIs treat depression and pain together. Duloxetine is used for diabetic neuropathy, fibromyalgia, and chronic musculoskeletal pain; it is avoided with liver disease, heavy alcohol use, or creatinine clearance below 30 mL/min. Venlafaxine is an alternative. Low-dose tricyclics (amitriptyline, nortriptyline) also relieve neuropathic pain and prevent migraine, but only when overdose risk is low.

SSRI adverse effects and their management

Early effects. In the first 1–2 weeks, nausea, loose stools, headache, jitteriness or anxiety, and insomnia are common and usually fade. Start low, especially in panic disorder, and give activating agents such as fluoxetine in the morning. Fluoxetine is the most activating SSRI; paroxetine is the most sedating and anticholinergic and causes the most weight gain.

Sexual dysfunction. Low libido, delayed orgasm or anorgasmia, and erectile dysfunction affect many patients on SSRIs and SNRIs and are the leading reason for stopping. Management options are lowering the dose, switching to bupropion or mirtazapine, adding bupropion, or adding a PDE5 inhibitor such as sildenafil.

Hyponatremia. SSRIs and SNRIs can cause SIADH, usually within the first weeks. Risk rises with age, female sex, low body weight, and thiazide use, so sodium should be checked in high-risk patients. With mild symptoms, stop the drug and restrict fluids; reserve hypertonic saline for seizures or obtundation. Mirtazapine or bupropion is a lower-risk replacement.

Bleeding. Platelets cannot synthesize serotonin and import it through SERT, so SSRIs deplete platelet serotonin and impair aggregation. Upper GI bleeding risk rises sharply with NSAIDs, aspirin, or anticoagulants; avoid the combination or add a proton pump inhibitor.

QT prolongation. Citalopram prolongs the QT interval in a dose-dependent way. The maximum is 40 mg/day, reduced to 20 mg/day in patients older than 60, with hepatic impairment, in CYP2C19 poor metabolizers, or with cimetidine. Obtain an ECG when cardiac disease or other QT-prolonging drugs are present. Escitalopram has a smaller effect.

Signature toxicities of other antidepressants

Venlafaxine. Norepinephrine reuptake inhibition at higher doses causes dose-dependent, sustained hypertension that is mainly diastolic, so check BP at baseline and after each increase. Its short half-life produces one of the worst discontinuation syndromes.

Trazodone. A 5-HT2A antagonist and weak SERT inhibitor, trazodone is sedating and widely used at low doses for insomnia. α1 blockade causes orthostatic hypotension, with falls in older adults, and priapism, a urologic emergency.

Tricyclics. TCAs block fast sodium channels (QRS widening beyond 100 ms, ventricular arrhythmias), muscarinic receptors (dry mouth, constipation, urinary retention, delirium), α1 receptors (orthostasis), and H1 receptors (sedation, weight gain), and they cause seizures in overdose, which can be fatal. Avoid them in suicidal patients, older adults, and patients with conduction disease. IV sodium bicarbonate treats the cardiotoxicity. Secondary amines (nortriptyline, desipramine) are less anticholinergic and orthostatic than tertiary amines (amitriptyline, imipramine).

MAOIs, serotonin syndrome, and discontinuation

MAOIs. Phenelzine, tranylcypromine, and isocarboxazid are reserved for refractory or atypical depression. Dietary tyramine, normally broken down by gut MAO, reaches the circulation and releases norepinephrine; aged cheese, cured or smoked meats, tap beer, and fermented soy can trigger a hypertensive crisis with severe occipital headache and very high BP, treated with the α-blocker phentolamine. Low-dose transdermal selegiline does not require the tyramine-restricted diet.

Serotonin syndrome. MAOIs combined with SSRIs, SNRIs, TCAs, meperidine, tramadol, dextromethorphan, linezolid, or St. John's wort produce altered mental status, autonomic instability (hyperthermia, tachycardia, diarrhea), and neuromuscular hyperactivity (clonus, hyperreflexia) within hours. Stop the offending drugs and give benzodiazepines and cyproheptadine.

Discontinuation syndrome. Abrupt cessation causes flu-like malaise, insomnia, nausea, imbalance or dizziness, sensory disturbances such as electric-shock sensations, and hyperarousal (irritability, anxiety) within days (mnemonic FINISH). It is worst with short half-life drugs (paroxetine, venlafaxine) and mildest with fluoxetine. Taper over weeks; if symptoms are severe, restart the drug and taper more slowly or cross over to fluoxetine.

Course of treatment and safety

Adequate trial and next steps. Judge a drug only after 4–6 weeks at a therapeutic dose with good adherence; switching at 2 weeks is premature. Response means at least a 50% reduction in symptoms. With partial response, increase the dose or augment with bupropion, mirtazapine, a second-generation antipsychotic such as aripiprazole, lithium, or T3. With no response or intolerance, switch agents. Failure of two or more adequate trials defines treatment-resistant depression, for which ECT, esketamine nasal spray with an oral antidepressant, and transcranial magnetic stimulation are options.

Duration. After a first episode remits, continue the full effective dose for 6–12 months, then taper. Recurrent (three or more episodes), severe, psychotic, or highly suicidal depression warrants long-term maintenance.

All antidepressants carry a boxed warning for increased suicidal thoughts and behavior in children, adolescents, and adults younger than 25, early in treatment and after dose changes. See young patients frequently in the first weeks, remembering that untreated depression is the greater danger. Before starting, screen for past mania or hypomania, because antidepressant monotherapy can switch bipolar depression into mania.

Interactions. Paroxetine, fluoxetine, and bupropion strongly inhibit CYP2D6, reducing conversion of tamoxifen to its active metabolite endoxifen and raising levels of TCAs and metoprolol. In women taking tamoxifen, venlafaxine (which also relieves hot flashes), escitalopram, or citalopram is preferred. Fluvoxamine inhibits CYP1A2, raising theophylline and clozapine levels.