Mechanism of Action

Selectively block reuptake of serotonin at the presynaptic neuron, raising serotonin in the synaptic cleft. Reuptake blockade is immediate, but clinical response lags 4–6 weeks while downstream receptor sensitivity adjusts — a critical delay because energy and motivation can return before mood lifts, temporarily increasing suicide risk. SSRIs are first-line because they are selective: norepinephrine and dopamine reuptake are largely untouched, giving fewer cardiovascular and anticholinergic effects than TCAs or MAOIs. Fluoxetine has the longest half-life (~4–6 day active metabolite), making it the most forgiving of missed doses and least likely to cause discontinuation syndrome; paroxetine's short half-life makes it the highest-risk for it.

Common Medications

fluoxetinePrototype

longest half-life (~4–6 day metabolite); lowest discontinuation-syndrome risk; needs 5-week washout before an MAOI

sertraline

generally preferred in pregnancy

paroxetine

highest anticholinergic load; avoided in pregnancy (fetal cardiac malformation risk); shortest half-life — highest discontinuation risk

citalopram

escitalopram

fluvoxamine

Indications

major depressive disorder

first-line

generalized anxiety disorder

panic disorder

obsessive-compulsive disorder

post-traumatic stress disorder

social anxiety disorder

premenstrual dysphoric disorder

bulimia nervosa

fluoxetine specifically

Side Effects

nausea

GI upset is common early; often resolves

diarrhea

sexual dysfunction

common; can limit adherence

insomnia

drowsiness

weight changes

CNS activation / agitation

in a client under 25, new agitation may signal emerging suicidality — do not dismiss

Contraindications & Interactions

Contraindications

MAOIs

serotonin syndrome risk — washout ≥14 days; 5 weeks after fluoxetine

paroxetine in pregnancy

fetal cardiac malformation risk

Interactions

tramadol

serotonergic — additive serotonin syndrome risk

triptans

additive serotonergic activity

St. John's wort

serotonergic herbal — can precipitate serotonin syndrome

linezolid

has MAOI activity

Administration & Monitoring

obtain baseline mood and suicide assessment

documented baseline for comparison during the boxed-warning window

monitor for new/worsening suicidality

intensively in the first weeks and at each dose change, especially under 25

assess for serotonin syndrome

when serotonergic agents are combined — hyperthermia, clonus, hyperreflexia

observe the MAOI washout period

≥14 days general; 5 weeks after fluoxetine

schedule early follow-up

within 1–2 weeks of starting

no routine drug levels or LFTs

titrated to clinical response; hepatotoxicity is not a class concern

Patient Teaching

expect 4–6 weeks for full effect

do not stop early because it 'isn't working'

report new or worsening suicidal thoughts immediately

report agitation or restlessness

a possible warning sign, not just an expected side effect

do not stop abruptly

taper to avoid discontinuation syndrome

avoid serotonergic agents without provider approval

St. John's wort, tramadol, triptans

report fever with muscle twitching or confusion

serotonin syndrome — emergency

Report Nowescalate immediately

suicidality in patients under 25Black Box

FDA boxed warning; greatest risk in the first 1–4 weeks and at every dose change, when energy returns before mood lifts — it is a monitoring mandate, NOT a contraindication; obtain a baseline suicide assessment and watch for new/worsening ideation or agitation

serotonin syndrome Hallmark

life-threatening; from combining serotonergic agents (MAOIs, tramadol, triptans, St. John's wort, linezolid). Triad: altered mental status (agitation/confusion) + autonomic instability (hyperthermia, tachycardia, diaphoresis) + neuromuscular hyperactivity (clonus, hyperreflexia, tremor). Rapid onset (hours). HOT and TWITCHY — vs NMS HOT and STIFF (lead-pipe rigidity). Stop offending agents, supportive care; cyproheptadine is the serotonin antagonist

discontinuation syndrome

abrupt stop → dizziness, irritability, paresthesias ('brain zaps'), flu-like symptoms; uncomfortable but not dangerous — taper gradually (highest risk with short half-life paroxetine, lowest with fluoxetine)

Clinical Pearl

Serotonin syndrome = HOT and TWITCHY (hyperthermia, clonus, hyperreflexia); NMS = HOT and STIFF (lead-pipe rigidity, elevated CK). And in anyone under 25, watch the early weeks closely — energy can come back before the mood does, and that is the window the black box warns about.