Antidepressants & Mood Stabilizers
Match each antidepressant to its receptor and its signature risk, and keep lithium in its narrow window
Selective serotonin reuptake inhibitors
Mechanism and onset. Fluoxetine, sertraline, paroxetine, citalopram, escitalopram, and fluvoxamine inhibit the serotonin transporter (SERT). Synaptic serotonin rises within hours, yet mood improves only after several weeks (typically 4–6), reflecting slower receptor adaptations such as desensitization of inhibitory 5-HT1A autoreceptors. SSRIs are first-line for major depression, generalized anxiety and panic disorder, OCD, PTSD, and bulimia nervosa.
Class adverse effects. Sexual dysfunction (low libido, anorgasmia, delayed ejaculation) is common and the leading reason patients stop. Others are GI upset, insomnia or sedation, weight change, SIADH with hyponatremia (especially in older adults), and bleeding: platelets cannot synthesize serotonin and take it up through SERT, so SSRIs deplete platelet serotonin and impair aggregation, an effect amplified by NSAIDs and anticoagulants.
Boxed warning: antidepressants increase suicidal thoughts and behavior in patients younger than 25 early in treatment, so close follow-up is required. In bipolar disorder, antidepressant monotherapy can precipitate mania, so screen for prior manic episodes first.
Discontinuation syndrome. Stopping abruptly causes flu-like malaise, dizziness, electric-shock sensations ("brain zaps"), irritability, insomnia, and nausea within days. It is worst with short half-life drugs (paroxetine, venlafaxine) and mildest with fluoxetine, whose metabolite norfluoxetine lingers for weeks. Tapering prevents it.
| Drug | Distinguishing feature |
|---|---|
| Fluoxetine | Longest half-life (norfluoxetine); activating; strong CYP2D6 inhibitor; least discontinuation; approved for bulimia |
| Paroxetine | Most anticholinergic; worst discontinuation; first-trimester cardiac defects; CYP2D6 inhibitor |
| Citalopram | Dose-dependent QT prolongation |
| Sertraline | Safe after myocardial infarction; widely used in pregnancy |
| Fluvoxamine | CYP1A2 inhibitor; used for OCD |
Serotonin syndrome
Causes. Serotonin syndrome develops within hours of adding a second serotonergic drug to an SSRI or SNRI. Classic partners are MAO inhibitors (including linezolid and methylene blue, which inhibit MAO), tramadol, meperidine, dextromethorphan, MDMA, triptans (subject of an FDA warning, though the risk appears low), and St. John's wort.
Features. Three domains: altered mental status (agitation, confusion); autonomic instability (hyperthermia, tachycardia, labile blood pressure, diaphoresis, mydriasis, diarrhea); and neuromuscular hyperactivity (tremor, hyperreflexia, and inducible or ocular clonus, most marked in the legs).
Treatment. Stop all serotonergic drugs, give benzodiazepines for agitation and muscle activity, cool the patient, and give cyproheptadine, a 5-HT2A and H1 antagonist, for moderate cases. Severe hyperthermia requires sedation, paralysis with a nondepolarizing agent, and intubation.
Clonus, hyperreflexia, and diarrhea within hours point to serotonin syndrome; lead-pipe rigidity developing over days points to NMS; hot, dry, flushed skin with ileus and urinary retention points to anticholinergic toxicity.
SNRIs and tricyclic antidepressants
SNRIs. Venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran inhibit both SERT and the norepinephrine transporter. Venlafaxine raises blood pressure in a dose-dependent fashion (mainly diastolic) and has a harsh discontinuation syndrome. Duloxetine is approved for diabetic neuropathic pain, fibromyalgia, and chronic musculoskeletal pain but is avoided in chronic liver disease or heavy alcohol use. Milnacipran is used for fibromyalgia.
TCAs. Tertiary amines (amitriptyline, imipramine, clomipramine) and secondary amines (nortriptyline, desipramine) block NE and serotonin reuptake. They also block muscarinic receptors (dry mouth, constipation, urinary retention, blurred vision, confusion), H1 receptors (sedation, weight gain), and α1 receptors (orthostatic hypotension). Secondary amines are better tolerated, so nortriptyline is preferred when a TCA is needed in older adults, in whom tertiary TCAs cause delirium, falls, and urinary retention. Current uses include neuropathic pain, migraine prophylaxis, OCD (clomipramine), and enuresis (imipramine).
TCA overdose is lethal. Blockade of fast Na+ channels in the His-Purkinje system widens the QRS (above 100 ms predicts seizures, above 160 ms ventricular arrhythmias) with a tall terminal R wave in aVR, accompanied by seizures, coma, hypotension, and an anticholinergic toxidrome. IV sodium bicarbonate provides a sodium load and alkalinization that narrow the QRS. Physostigmine (asystole), flumazenil (seizures), and class IA or IC antiarrhythmics are avoided.
MAO inhibitors and atypical antidepressants
MAO inhibitors. Phenelzine, tranylcypromine, and isocarboxazid irreversibly inhibit MAO-A and MAO-B and are reserved for atypical or treatment-resistant depression. Normally, intestinal and hepatic MAO-A destroys dietary tyramine. With MAO blocked, tyramine from aged cheese, cured meats, tap beer, and fermented soy reaches sympathetic nerve terminals, displaces stored norepinephrine, and causes a hypertensive crisis with severe occipital headache. Transdermal selegiline at its lowest dose acts mainly on brain MAO and does not require the diet.
Washout and interactions. Because inhibition is irreversible, new enzyme must be synthesized: allow about 2 weeks between stopping an MAOI and starting another serotonergic antidepressant, and 5 weeks after stopping fluoxetine. MAOIs also interact dangerously with meperidine, tramadol, dextromethorphan, linezolid, and sympathomimetics such as pseudoephedrine.
| Drug | Mechanism | Signature effects and uses |
|---|---|---|
| Bupropion | NE and dopamine reuptake inhibitor | No sexual dysfunction or weight gain; smoking cessation; lowers seizure threshold, so avoid in seizure disorders, bulimia or anorexia, and abrupt alcohol or benzodiazepine withdrawal |
| Mirtazapine | α2 autoreceptor antagonist; 5-HT2, 5-HT3, H1 blocker | Sedation, increased appetite and weight gain; little sexual dysfunction or nausea; lower doses more sedating |
| Trazodone | Weak SERT inhibitor; 5-HT2A, H1, α1 antagonist | Used for insomnia; sedation, orthostasis, priapism |
| Vortioxetine | SERT inhibitor; 5-HT1A agonist, 5-HT3 antagonist | Nausea is the main side effect |
| Esketamine | NMDA receptor antagonist (intranasal) | Treatment-resistant depression or acute suicidal ideation; acts within hours; dissociation, sedation, raised blood pressure; ≥2 hours of monitoring |
Lithium
Role and mechanism. Lithium is the first-line maintenance drug for bipolar disorder, preventing both manic and depressive relapses and lowering suicide risk. Its mechanism is thought to involve inhibition of inositol monophosphatase, depleting inositol for phosphoinositide signaling, and inhibition of GSK-3.
Toxicity. A fine tremor is common at therapeutic levels. Toxic levels bring coarse tremor, ataxia, confusion, vomiting and diarrhea, and seizures; severe toxicity is treated with hemodialysis. Chronic adverse effects include nephrogenic diabetes insipidus (reduced aquaporin-2 in collecting ducts causing polyuria and polydipsia, treated with amiloride, which blocks lithium entry through ENaC), hypothyroidism and goiter, hyperparathyroidism with hypercalcemia, weight gain, acne and psoriasis flares, benign leukocytosis, and chronic kidney disease. First-trimester exposure is linked to Ebstein anomaly, with apically displaced tricuspid leaflets.
Interactions. Lithium is cleared by the kidney and reabsorbed along with sodium in the proximal tubule. Sodium or volume depletion (thiazides, dehydration, vomiting, low-salt diets) increases proximal reabsorption, and drugs that lower GFR (ACE inhibitors, ARBs, most NSAIDs) reduce clearance; both raise levels and can precipitate toxicity. Theophylline, caffeine, and acetazolamide lower levels. Monitoring includes lithium levels, creatinine, TSH, and calcium.
Anticonvulsant mood stabilizers and drug choice
Anticonvulsants. Valproate and carbamazepine treat acute mania, with valproate favored for mixed features and rapid cycling. Lamotrigine prevents bipolar depressive episodes but does not treat acute mania. Each brings its antiepileptic toxicities: valproate hepatotoxicity, pancreatitis, and neural tube defects; carbamazepine agranulocytosis and SIADH; lamotrigine SJS with rapid titration.
| Feature | Lithium | Valproate | Lamotrigine |
|---|---|---|---|
| Best use | Classic mania, maintenance, suicide prevention | Acute mania, mixed features, rapid cycling | Prevention of bipolar depression |
| Clearance | Renal | Hepatic | Hepatic glucuronidation |
| Monitoring | Levels, creatinine, TSH, calcium | Levels, LFTs, CBC with platelets | Rash surveillance during titration |
| Teratogenicity | Ebstein anomaly | Neural tube defects | Lowest of the three |
Choosing an antidepressant. Side-effect profiles guide selection: mirtazapine for insomnia with poor appetite and weight loss; bupropion for patients worried about sexual dysfunction or who want to quit smoking; duloxetine or a TCA when neuropathic pain coexists; an MAOI for refractory or atypical depression; sertraline after a recent myocardial infarction. TCAs and MAOIs are avoided when overdose risk is high because they are lethal in overdose.