How SSRIs are tested on Step 1

Expect a patient who stops improving or develops a side effect, a dangerous drug combination, or a question about why the drug takes weeks to work.

workspace_premium Why the delay?

SERT is blocked within hours, but mood improves over 4–8 weeks. Early extra serotonin activates inhibitory 5-HT1A autoreceptors; over weeks these desensitize, firing increases, and downstream changes such as BDNF expression follow.

Mechanism

After release, serotonin is cleared from the synapse mainly by SERT reuptake.

SERTblockedPresynaptictransporter↑Synaptic5-HTWithin hoursAutoreceptorbrake5-HT1Abriefly ↓firingBrakefadesAutoreceptorsdesensitizeover weeksClinicalresponse4–8 weeks
SSRI mechanism. Anxiety and jitteriness can transiently worsen early in treatment, before benefit appears.
AgentDistinguishing feature
FluoxetineLongest half-life (active metabolite); least discontinuation; strong CYP2D6 inhibitor
SertralineCommonly first-line; safe after MI; often used in pregnancy
ParoxetineMost anticholinergic; worst discontinuation; avoid in pregnancy (cardiac defects)
CitalopramDose-dependent QT prolongation (max dose limits)
EscitalopramS-enantiomer of citalopram; fewer interactions
FluvoxamineOCD; strong CYP1A2 inhibitor

Switching from fluoxetine to an MAOI requires a 5-week washout because of its long half-life.

Adverse effects

Serotonin acts throughout the body, so side effects are widespread but usually mild.

SSRI adverse effectsSexualLow libido,anorgasmia,delayedejaculationGINausea,diarrhea earlySIADHHyponatremia inolder adultsBleedingPlatelets loseserotonin;worse withNSAIDsOtherQT(citalopram),insomnia,weight change
SSRI adverse effects. Bupropion or mirtazapine are alternatives when sexual dysfunction is intolerable.

Serotonin syndrome vs discontinuation

Two important syndromes involve SSRIs: too much serotonin from combinations, and abrupt withdrawal.

Serotonin syndromeOnset within 24 h of a new serotonergicdrugHyperthermia, diaphoresis, tachycardiaClonus, hyperreflexia (legs > arms)Agitation, mydriasis, diarrheaTreat: stop drugs, benzodiazepines,cyproheptadineDiscontinuation syndromeDays after abrupt stopFlu-like symptoms, dizziness"Brain zaps," paresthesiasIrritability, insomnia, nauseaPrevent: taper (paroxetine worst)vs
Too much vs too little. Serotonin syndrome features clonus and hyperreflexia; neuroleptic malignant syndrome features rigidity and bradyreflexia.
Drug combined with an SSRIRisk
MAOIs (phenelzine, selegiline), linezolid, methylene blueSevere serotonin syndrome
Tramadol, meperidine, fentanyl, dextromethorphanSerotonin syndrome
Triptans, St John's wort, lithium, MDMASerotonin syndrome
NSAIDs, aspirin, warfarinGI and other bleeding
Tamoxifen (with fluoxetine, paroxetine)↓ Activation of tamoxifen by CYP2D6

Wait at least 2 weeks between stopping an MAOI and starting an SSRI (5 weeks after fluoxetine before an MAOI).

Clinical application

Serotonin syndrome is a frequent Step 1 vignette.

functions Worked example — the hospital antibiotic

A woman on sertraline is started on linezolid for VRE bacteremia. The next day she is agitated and diaphoretic with temperature 39.4 °C, heart rate 128, dilated pupils, and inducible ankle clonus. What happened, and how is it treated?

  1. Linezolid is a weak, nonselective MAO inhibitor.
  2. Combined with an SSRI, synaptic serotonin rises sharply.
  3. Rapid onset, hyperthermia, autonomic instability, and clonus are classic serotonin syndrome.

Answer. Serotonin syndrome. Stop both serotonergic drugs, give supportive care and benzodiazepines, and use cyproheptadine (a 5-HT2A antagonist); severe hyperthermia needs cooling and paralysis.