Depression is linked to reduced signaling in serotonin (5-HT), norepinephrine (NE), and dopamine pathways, although the monoamine idea does not explain everything. Most antidepressants raise the amount of these transmitters in the synapse within hours, yet mood improves only after weeks. The delay reflects slower adaptive changes: receptor down-regulation, altered gene expression, and increased neuroplasticity.

Time course: early benefit in about 2–4 weeks, full effect in 6–8 weeks. After remission, treatment usually continues for at least 6–12 months to prevent relapse. Side effects often appear before benefit, which is the main reason clients stop early.

Uses include major depressive disorder, generalized anxiety and panic disorder, obsessive-compulsive disorder, PTSD, bulimia (fluoxetine), premenstrual dysphoric disorder, neuropathic pain (duloxetine, amitriptyline), smoking cessation (bupropion), and insomnia (low-dose trazodone).

Boxed warning (all antidepressants): increased suicidal thoughts and behavior in children, adolescents, and young adults under 25. The risk is highest in the first months and after dose changes. Energy may improve before mood, giving a depressed client the energy to act on suicidal plans.

SSRIs and SNRIs

• Nausea, diarrhea, headache, insomnia or drowsiness, jitteriness early in treatment (usually eases in 1–2 weeks)
• Sexual dysfunction (decreased libido, delayed orgasm) — a common reason for nonadherence
• Hyponatremia (SIADH), especially in older adults and with diuretics — confusion, falls, seizures
• Bleeding risk — serotonin is needed for platelet aggregation; increased with NSAIDs, aspirin, anticoagulants
• Weight change, bruxism, sweating; activation of mania in undiagnosed bipolar disorder
• SNRIs: sustained hypertension, sweating, urinary hesitancy

TCAs — anticholinergic effects (dry mouth, constipation, urinary retention, blurred vision, confusion), orthostatic hypotension (alpha-1 blockade), sedation and weight gain (antihistamine effect), cardiac conduction delay (QRS widening, dysrhythmias), lowered seizure threshold.

MAOIs — orthostatic hypotension (the most common effect), insomnia, weight gain, sexual dysfunction; hypertensive crisis with tyramine or sympathomimetics.

Others — bupropion: insomnia, agitation, dry mouth, seizures (dose-related); mirtazapine: sedation, increased appetite; trazodone: sedation, orthostasis, priapism.

Esketamine boxed warnings: sedation, dissociation, respiratory depression, abuse and misuse, plus the class suicidality warning. It also raises blood pressure transiently.

Zuranolone boxed warning: impaired ability to drive or do hazardous activities for at least 12 hours after each dose (CNS depression). It can also cause embryo-fetal harm.

Discontinuation syndrome after abrupt stopping (especially paroxetine and venlafaxine): dizziness, "electric shock" sensations, flu-like symptoms, irritability, insomnia, nausea. Not dangerous but distressing — taper slowly.

Serotonin syndrome — see Section 7.

Contraindications

• MAOI combined with another serotonergic drug (SSRI, SNRI, TCA, meperidine, tramadol, methadone, dextromethorphan, linezolid, IV methylene blue, St. John's wort) — serotonin syndrome
• Washout: 14 days between an MAOI and other serotonergic antidepressants in either direction; 5 weeks after stopping fluoxetine before starting an MAOI
• Bupropion: seizure disorder, bulimia or anorexia nervosa, abrupt withdrawal from alcohol, benzodiazepines, or antiseizure drugs
• TCAs: recent myocardial infarction; caution with conduction disease, narrow-angle glaucoma, prostatic hyperplasia, seizure disorder
• Pimozide or thioridazine with several SSRIs (QT prolongation)
• Esketamine: aneurysmal vascular disease (aorta, brain, or peripheral arteries), arteriovenous malformation, or history of intracerebral hemorrhage (the BP rise can be dangerous)
• Zuranolone: pregnancy — use effective contraception during treatment and for 1 week after the last dose

Major interactions

• Serotonergic combinations: triptans, tramadol, fentanyl, meperidine, lithium, linezolid, St. John's wort, tryptophan — monitor for serotonin syndrome
• Bleeding: NSAIDs, aspirin, warfarin, direct oral anticoagulants
• MAOI + sympathomimetics or tyramine: decongestants (pseudoephedrine, phenylephrine), stimulants, cocaine, aged cheese, cured meats, soy sauce, sauerkraut, tap beer, spoiled foods → hypertensive crisis
• CYP2D6 inhibition by fluoxetine, paroxetine, and bupropion: raises TCA and some beta-blocker levels; reduces conversion of tamoxifen and codeine to active forms
• QT-prolonging drugs with citalopram, escitalopram, or TCAs
• Alcohol and other CNS depressants: additive sedation

Pregnancy and lactation — untreated depression also harms mother and fetus, so decisions are individualized. Late-pregnancy SSRI exposure is linked to neonatal adaptation symptoms (jitteriness, feeding difficulty, respiratory distress) and a small risk of persistent pulmonary hypertension of the newborn. Paroxetine is generally avoided (cardiac defects). Do not stop abruptly when pregnancy is found — contact the prescriber. Sertraline is commonly preferred during breastfeeding.

Older adults — avoid TCAs such as amitriptyline (anticholinergic, falls); watch sodium with SSRIs and SNRIs.

Listed in priority order.

1. Suicide risk — assess at baseline, at every contact, and especially during the first weeks and after dose changes. Watch for sudden calm, giving away possessions, or increased energy with persistent hopelessness. Dispense limited quantities (particularly TCAs) to high-risk clients.
2. Recognize emergencies — serotonin syndrome, hypertensive crisis, TCA overdose, seizures (Section 7).
3. Vital signs — BP with SNRIs and MAOIs; BP before and after each esketamine dose, with sedation and dissociation checks for at least 2 hours; orthostatic BP with TCAs, MAOIs, and trazodone; heart rate and rhythm with TCAs.
4. Labs — serum sodium in older adults or clients on diuretics (normal 135–145 mEq/L [mmol/L]; report below 135); ECG at baseline with TCAs in older adults or cardiac disease, and with higher citalopram doses (report QTc above 500 ms or an increase over 60 ms).
5. Screen for bipolar disorder before starting — an antidepressant alone can trigger mania. Report decreased need for sleep, racing thoughts, or grandiosity.
6. Safety — fall precautions for orthostasis and sedation; seizure precautions with bupropion.
7. Adherence — explain the delayed onset; address sexual dysfunction and nausea early; plan tapering rather than abrupt stopping.
8. Administer — SSRIs and bupropion in the morning if they cause insomnia; sedating drugs (mirtazapine, trazodone, TCAs) at bedtime; SSRIs with food to reduce nausea.

• Benefit starts in 2–4 weeks; full effect takes up to 8 weeks. Keep taking the drug even after feeling better, and never stop suddenly — the dose is tapered.
• Call right away for new or worse depression, agitation, panic, or thoughts of self-harm, especially in the first weeks. Families should watch for these changes.
• Report heavy sweating, shivering, muscle twitching, confusion, or high fever (serotonin syndrome).
• Check with a pharmacist before taking cold medicines, pain medicines (tramadol), migraine drugs (triptans), or herbal products (St. John's wort).
• Avoid alcohol; do not drive until you know how the drug affects you.
• Tell the provider about easy bruising or dark stools, especially if you also take NSAIDs or anticoagulants.
• MAOIs: carry a written list of foods and drugs to avoid; continue the diet for 14 days after stopping (the lowest selegiline patch dose, 6 mg/24 h, needs no diet restriction); seek emergency care for a sudden severe headache, stiff neck, palpitations, or chest pain.
• Bupropion: do not double doses; take doses at least 8 hours apart for twice-daily forms; report seizures.
• Trazodone: an erection lasting more than 4 hours is an emergency.
• Plan pregnancy with the prescriber; do not stop the medicine on your own if you become pregnant.
• Esketamine and zuranolone: no driving until the next day after esketamine; no driving for 12 hours after each zuranolone dose.

Serotonin syndrome — rapid onset, usually within 24 hours of starting, increasing, or combining serotonergic drugs.

• Mental status: agitation, anxiety, confusion
• Autonomic: tachycardia, hypertension, hyperthermia, diaphoresis, dilated pupils, diarrhea and hyperactive bowel sounds
• Neuromuscular: clonus (inducible, ocular), hyperreflexia, myoclonus, tremor — worse in the legs
• Treatment: stop all serotonergic drugs, supportive care, IV fluids, cooling, benzodiazepines for agitation, cyproheptadine (a serotonin antagonist) for moderate cases; ICU, sedation, and paralysis for severe hyperthermia. Antipyretics do not help because the fever is from muscle activity.
• Distinguish from neuroleptic malignant syndrome (slower onset over days, lead-pipe rigidity, bradyreflexia, high CK).

TCA overdose — a leading cause of fatal antidepressant poisoning.

• Anticholinergic toxidrome (hot, dry, flushed skin; dilated pupils; urinary retention; delirium), hypotension, seizures, and QRS widening (over 100 ms signals risk of seizures and dysrhythmias)
• Treatment: airway, cardiac monitoring, IV sodium bicarbonate for QRS widening, hypotension, or dysrhythmias; benzodiazepines for seizures; activated charcoal only if the airway is protected. Flumazenil and physostigmine are avoided (seizure and asystole risk).

MAOI hypertensive crisis — severe occipital headache, stiff neck, palpitations, chest pain, sweating, nausea, very high BP.

• Hold the MAOI, place the client in semi-Fowler's or upright position with monitoring, and prepare short-acting IV antihypertensives (e.g., phentolamine or nicardipine) per protocol; watch for stroke signs.

SSRI overdose alone is usually less dangerous (vomiting, sedation, tachycardia) but can cause seizures (citalopram, escitalopram — also QT prolongation) and serotonin syndrome. Bupropion overdose causes seizures and dysrhythmias.

There is no specific antidote for any antidepressant; always screen for co-ingestants such as acetaminophen and alcohol.

• Boxed warning: suicidality under age 25 — closest monitoring in the first weeks and after dose changes
• Onset 2–4 weeks, full effect 6–8 weeks; never stop abruptly (discontinuation syndrome — paroxetine, venlafaxine)
• SSRIs: nausea, sexual dysfunction, hyponatremia in older adults, bleeding with NSAIDs or anticoagulants
• SNRIs: add raised blood pressure
• TCAs: anticholinergic, orthostatic, QRS widening — lethal overdose → sodium bicarbonate; limit supply
• MAOIs + tyramine or sympathomimetics = hypertensive crisis; 14-day washout (5 weeks after fluoxetine)
• Serotonin syndrome: rapid, clonus and hyperreflexia, diarrhea, hyperthermia → stop drugs, benzodiazepines, cyproheptadine
• Bupropion: lowers seizure threshold — contraindicated in seizure and eating disorders
• Citalopram: QT prolongation — dose limits
• Trazodone: priapism; mirtazapine: sedation and weight gain
• Screen for bipolar disorder before starting — antidepressant alone can trigger mania