Antidepressants and Antianxiety Drugs

Classification

SSRIs: fluoxetine, sertraline, paroxetine, escitalopram, citalopram. SNRIs: venlafaxine, duloxetine. TCAs: amitriptyline, imipramine, clomipramine, nortriptyline. MAOIs: phenelzine, tranylcypromine(non-selective irreversible) · moclobemide(reversible, selective MAO-A=“RIMA”). Atypical: mirtazapine(α2 antagonist), bupropion(DA/NA reuptake inhibitor), trazodone. Antianxiety: benzodiazepines, buspirone(5-HT1A partial agonist), SSRIs/SNRIs(1st-line chronic anxiety too).

Mechanism

SSRIs: selective SERT inhibition → ↑synaptic serotonin. “Selective” = relative SPARING of NA/DA transporters + TCA-type off-target receptor activity → favourable SE profile → 1st-line most depression/anxiety.

SNRIs: block BOTH SERT+NET, no off-target receptor activity(unlike TCA). Venlafaxine = DOSE-DEPENDENT selectivity — pure SSRI-like at LOW dose, gains noradrenergic activity only at HIGHER dose.

TCAs: block SERT+NET(original dual mechanism) PLUS muscarinic+histaminergic+α1 blockade(off-target, less selective structure) = source of ENTIRE TCA SE burden → displaced from 1st-line by SSRIs/SNRIs. Retained: treatment-resistant depression, chronic pain(separate lower-dose indication, descending pain-modulation), enuresis(imipramine).

MAOIs: inhibit MAO → ↑ALL THREE monoamines(5-HT,NA,DA) simultaneously. Non-selective irreversible(phenelzine, tranylcypromine): constrained by tyramine reaction+serotonin syndrome risk → last-line, specialist supervision. Moclobemide(reversible, MAO-A-selective): largely AVOIDS tyramine reaction(competitive/displaceable — tyramine still displaces drug, gets metabolized; unlike irreversible inhibition permanently removing enzyme capacity).

Mirtazapine: blocks presynaptic α2 AUTORECEPTORS(normally negative feedback on NA+indirectly 5-HT release) → DISINHIBITS release of both — indirect mechanism, distinct from reuptake blockade. Also 5-HT2/5-HT3+H1 block(H1=sedation+appetite stimulation, exploited in depression+insomnia/weight loss where SSRI’s activating/appetite-suppressing profile counterproductive).

Bupropion: DA+NA reuptake inhibition, NEGLIGIBLE serotonergic activity — distinct mechanism. Useful where SSRI sexual dysfunction is concern(minimal risk) + smoking cessation(separate indication). ↓Seizure threshold MORE than most antidepressants → CI in seizure disorder OR eating disorder(bulimia/anorexia — independently ↑seizure risk).

Buspirone: 5-HT1A PARTIAL agonist, unrelated to benzodiazepines mechanistically. Non-sedating, NO dependence/withdrawal, NO acute anxiolytic effect(onset 2-4wk, like antidepressants) → unsuitable for acute anxiety/panic, useful for CHRONIC GAD(delayed onset acceptable, no sedation/dependence advantage for long-term use).

Adverse Effects

SSRIs: GI upset(nausea, common early, improves) · sexual dysfunction(common, under-reported discontinuation reason) · SEROTONIN SYNDROME(combined with other serotonergic drug — MAOIs above all, also tramadol/triptans/other antidepressants): hyperthermia+autonomic instability+NEUROMUSCULAR HYPERACTIVITY(clonus, hyperreflexia, tremor)+altered mental status — DISTINGUISH from NMS by hyperreflexia/clonus(vs NMS rigidity/hyporeflexia) + FASTER onset; both life-threatening if unrecognized. Discontinuation syndrome(abrupt stop: dizziness, “brain zaps,” flu-like, irritability) — WORSE with short-t½ agents(paroxetine) vs long-t½(fluoxetine=self-tapering) → taper, don’t abrupt-stop.

TCAs: SE follows DIRECTLY from receptor blockade — antimuscarinic(dry mouth/blurred vision/urinary retention/constipation), antihistaminic(sedation/weight gain), α1-block(postural hypotension) + CARDIOTOXICITY IN OVERDOSE(myocardial Na+ channel blockade, SAME principle as bupivacaine — wide QRS, ventricular arrhythmia) → TCA OD = genuine emergency, major reason SSRIs became 1st-line(far safer OD profile).

MAOIs: TYRAMINE(“cheese”) REACTION — tyramine(indirect sympathomimetic, normally broken down by gut/hepatic MAO before systemic circulation) accumulates with MAO inhibited → massive NA release from sympathetic terminals → HYPERTENSIVE CRISIS with tyramine-rich foods(aged cheese, cured meats, fermented products) → dietary restriction defines MAOI use. SAME logic as other indirect sympathomimetics(Adrenergic System) — needs intact neuronal uptake/storage/MAO turnover to be normally “used up.”

Clinical Relevance

Serotonin syndrome + tyramine reaction = SAME underlying idea from opposite directions: serotonin syndrome = too much serotonergic signalling from COMBINING agents each increasing it differently(reuptake inhibition + MAO inhibition = classic dangerous combo); tyramine reaction = indirect sympathomimetic’s normal degradation pathway REMOVED, letting modest dietary exposure produce uncontrolled neurotransmitter surge. BOTH = losing a normal CLEARANCE mechanism, not simply “too much drug.”

Classification

SSRIs: fluoxetine, sertraline, paroxetine, escitalopram, citalopram
SNRIs: venlafaxine, duloxetine
Tricyclic antidepressants (TCAs): amitriptyline, imipramine, clomipramine, nortriptyline
MAO inhibitors: phenelzine, tranylcypromine (non-selective, irreversible); moclobemide (reversible, selective MAO-A — “RIMA”)
Atypical antidepressants: mirtazapine (α2 antagonist), bupropion (dopamine/noradrenaline reuptake inhibitor), trazodone
Antianxiety drugs: benzodiazepines (mechanism under Sedatives and Hypnotics), buspirone (5-HT1A partial agonist), and SSRIs/SNRIs themselves (first-line for chronic anxiety disorders, not just depression)

Mechanism of Action

SSRIs: selectively inhibit the serotonin transporter (SERT), blocking presynaptic serotonin reuptake and increasing synaptic serotonin availability — the “selective” in SSRI refers specifically to relative sparing of noradrenaline and dopamine transporters (and of the receptor-blocking off-target activity TCAs carry), not to an absence of any effect elsewhere; this selectivity is precisely what gives SSRIs their comparatively favourable adverse-effect profile relative to TCAs/MAOIs, making them first-line for most depressive and anxiety disorders today.

SNRIs: inhibit both serotonin and noradrenaline reuptake (without the additional off-target receptor activity of TCAs) — venlafaxine is dose-dependently selective, behaving essentially as a pure SSRI at low doses and gaining meaningful noradrenergic activity only at higher doses, a specific pharmacokinetic/pharmacodynamic point worth knowing rather than treating SNRIs as uniformly dual-acting at every dose.

TCAs: inhibit both serotonin and noradrenaline reuptake (the original dual-acting antidepressant mechanism, predating SNRIs), but also block muscarinic, histaminergic, and α1-adrenergic receptors as a direct consequence of their less selective structure — this off-target activity is the source of essentially the entire TCA adverse-effect burden (below) and the reason they’ve been displaced from first-line status by SSRIs/SNRIs despite comparable efficacy, retaining use today mainly in treatment-resistant depression, certain chronic pain syndromes (a genuinely separate, lower-dose indication exploiting descending pain-modulation pathways), and enuresis (imipramine).

MAO inhibitors: inhibit monoamine oxidase, the enzyme responsible for intraneuronal breakdown of serotonin, noradrenaline, and dopamine — non-selective, irreversible inhibition (phenelzine, tranylcypromine) increases levels of all three monoamines simultaneously, a broad mechanism whose clinical use is constrained almost entirely by the tyramine interaction (below) and by serotonin syndrome risk with other serotonergic drugs, pushing MAOIs to a last-line role reserved for treatment-resistant depression under specialist supervision. Moclobemide, a reversible, MAO-A-selective inhibitor, largely avoids the tyramine reaction (competitive, displaceable binding allows tyramine to still displace the drug and be metabolized, unlike irreversible inhibition which permanently removes the enzyme’s capacity) — a specific, examined distinction between reversible and irreversible MAO inhibition.

Mirtazapine: blocks presynaptic α2-adrenergic autoreceptors (which normally provide negative feedback inhibiting noradrenaline and, indirectly, serotonin release) — disinhibiting release of both, an indirect mechanism distinct from any reuptake-blocking antidepressant. Also blocks 5-HT2 and 5-HT3 receptors and H1 receptors, the latter responsible for its sedative and appetite-stimulating properties, which are exploited therapeutically (useful in depression with insomnia/weight loss, where SSRIs’ more activating, appetite-suppressing profile would be counterproductive).

Bupropion: inhibits dopamine and noradrenaline reuptake with negligible serotonergic activity — a genuinely distinct mechanism from every other class here, useful specifically where SSRI-associated sexual dysfunction is a concern (bupropion carries minimal risk of this specific adverse effect, unlike the serotonergic classes) and as a smoking-cessation aid (a separate, well-established indication). Lowers seizure threshold more than most antidepressants, a specific, examined contraindication in patients with a seizure disorder or eating disorder (bulimia/anorexia, both independently associated with seizure risk, are specific contraindications).

Buspirone: a 5-HT1A partial agonist, structurally and mechanistically unrelated to benzodiazepines — non-sedating, no dependence/withdrawal potential, and no acute anxiolytic effect (onset over 2–4 weeks, similar delay to antidepressants), making it unsuitable for acute anxiety/panic but useful for chronic generalized anxiety disorder where the delayed onset is acceptable and the absence of sedation/dependence is an advantage over benzodiazepines for long-term use.

Adverse Effects

SSRIs: GI upset (nausea, most common early adverse effect, generally improving with continued use), sexual dysfunction (a genuinely common, often under-reported reason for treatment discontinuation), and — a specific, high-yield pharmacological interaction — serotonin syndrome when combined with another serotonergic drug (MAOIs above all, but also tramadol, triptans, other antidepressants): hyperthermia, autonomic instability, neuromuscular hyperactivity (clonus, hyperreflexia, tremor) and altered mental status — distinguished from NMS by the neuromuscular hyperactivity/hyperreflexia pattern (versus NMS’s rigidity/hyporeflexia) and by faster onset, though the two syndromes are frequently confused and both are life-threatening if unrecognized. Discontinuation syndrome with abrupt cessation (dizziness, “brain zaps,” flu-like symptoms, irritability) — more pronounced with shorter-half-life agents (paroxetine) than long-half-life ones (fluoxetine, whose long half-life provides a degree of self-tapering), the pharmacokinetic reason abrupt SSRI discontinuation is generally avoided in favour of a taper.

TCAs: the adverse-effect profile follows directly from the off-target receptor blockade above — antimuscarinic (dry mouth, blurred vision, urinary retention, constipation), antihistaminic (sedation, weight gain), α1-blockade (postural hypotension) — plus cardiotoxicity in overdose (Na⁺ channel blockade in the myocardium, similar in principle to bupivacaine’s mechanism under Local Anaesthetics, producing widened QRS and ventricular arrhythmia), the specific reason TCA overdose is a genuine emergency and a major historical driver of the shift toward SSRIs as first-line (a far safer overdose profile, given SSRIs’ minimal cardiotoxicity even in substantial overdose).

MAO inhibitors: the tyramine (“cheese”) reaction — tyramine, an indirectly-acting sympathomimetic normally broken down by gut/hepatic MAO before reaching the systemic circulation, accumulates when MAO is inhibited and triggers massive noradrenaline release from sympathetic nerve terminals, producing a hypertensive crisis when tyramine-rich foods (aged cheese, cured meats, fermented products) are consumed — the mechanistic reason for the dietary restriction that defines MAOI use, and the same fundamental logic (indirect sympathomimetic requiring intact neuronal uptake/storage/MAO-mediated turnover to be “used up” normally) as other indirect sympathomimetics discussed under Adrenergic System.

Clinical Relevance

Serotonin syndrome and the tyramine reaction are both illustrations of the same underlying pharmacological idea from opposite directions: serotonin syndrome is too much serotonergic signalling from combining agents that each increase it by a different mechanism (reuptake inhibition plus MAO inhibition being the classic, most dangerous combination), while the tyramine reaction is an indirect sympathomimetic’s normal degradation pathway being removed, allowing an ordinarily modest dietary exposure to produce an uncontrolled neurotransmitter surge — both are examples of losing a normal clearance mechanism for a neurotransmitter or neurotransmitter-releasing agent, not simply “too much drug.”

Serotonin syndrome vs NMS side-by-side comparison (hyperreflexia/clonus vs rigidity/hyporeflexia, onset speed, causative drug classes).
Tyramine reaction mechanism: normal MAO-mediated tyramine breakdown vs MAOI-unmasked sympathetic surge.
TCA receptor-blockade map (muscarinic, histaminergic, α1) linked to each corresponding adverse effect.