Antidepressants — The Mood Map

The Four Classes

Every antidepressant manipulates monoamines: serotonin, norepinephrine, or dopamine. The class tells you the mechanism, the mechanism predicts the side effects.

SSRIs are first-line for depression. Why not TCAs?

TCAs work just as well as SSRIs. The problem is safety. TCAs block sodium channels in the heart → QRS widening → fatal arrhythmia in overdose. Depressed patients are at risk for overdose. Giving them a drug that kills in overdose is dangerous. SSRIs are much safer — serotonin syndrome is possible but rarely fatal. Efficacy is equal. Safety is not.

SSRIs

Selective Serotonin Reuptake Inhibitors

Block SERTThe serotonin transporter (SERT) is a protein on the presynaptic neuron that vacuums serotonin back out of the synapse. SSRIs sit on SERT and block it → more serotonin stays in the synapse → increased serotonergic transmission. Takes 4-6 weeks for downstream receptor changes to produce clinical improvement. → more serotonin in the synapse. First-line for depression, anxiety, OCD, PTSD, panic disorder.

Fluoxetine Sertraline Paroxetine Citalopram Escitalopram Fluvoxamine

Side effects: sexual dysfunction, GI upset, weight gain. Mostly serotonin-mediated.

SNRIs

Serotonin-Norepinephrine Reuptake Inhibitors

Block both SERT and NETThe norepinephrine transporter. Blocking NET increases norepinephrine in the synapse, which adds energy, focus, and pain modulation. That's why SNRIs work for both depression AND neuropathic pain / fibromyalgia.. Dual action: mood + pain.

Venlafaxine Duloxetine Desvenlafaxine

Side effects: same as SSRIs + hypertension (NE effect). Duloxetine = first-line for diabetic neuropathy and fibromyalgia.

TCAs

Tricyclic Antidepressants

Block serotonin + NE reuptake (like SNRIs) but ALSO block muscarinic, histamine, and alpha-1 receptors. The "dirty" drugs — they hit everything.

Amitriptyline Nortriptyline Imipramine Desipramine Clomipramine

Side effects: dry mouth, constipation, urinary retention (anticholinergic), sedation (antihistamine), orthostatic hypotension (alpha-1), cardiac arrhythmia in OD (Na channel block).

MAOIs

Monoamine Oxidase Inhibitors

Block MAO-A (breaks down serotonin, NE, dopamine) and/or MAO-B (dopamine). Huge monoamine increase. Effective but dangerous.

Phenelzine Tranylcypromine Selegiline

Tyramine crisis: MAO-A also breaks down tyramine in the gut. Block it → tyramine enters blood → massive NE release → hypertensive crisis. Avoid aged cheese, wine, cured meats.

The Anticholinergic Mnemonic: TCAs cause all the "anti" side effects. 🔑Can't see, can't pee, can't spit, can't sh*t. Mydriasis, urinary retention, dry mouth, constipation. All muscarinic blockade. These are the same effects you see with atropine — because TCAs have anticholinergic activity.

The Weird Ones

Not everything fits into the four main classes. These atypical antidepressants show up on boards because their unique profiles create specific clinical niches.

Bupropion (Wellbutrin)

NDRI — Norepinephrine-Dopamine Reuptake Inhibitor

The one that does NOT cause sexual dysfunction or weight gain. Used for depression, smoking cessation (Zyban), and ADHD. Lowers seizure threshold — avoid in eating disorders (electrolyte imbalance) and seizure history.

Mirtazapine (Remeron)

Alpha-2 antagonist + 5-HT2/5-HT3 antagonist + H1 antagonist

Causes sedation and weight gain as primary side effects. Board pearl: use in elderly patients with insomnia and poor appetite — the side effects become therapeutic benefits. "The one that makes you hungry and sleepy."

Trazodone

SARI — Serotonin Antagonist and Reuptake Inhibitor

At antidepressant doses it's an SSRI. At low doses it's just sedating. Boards test it as a sleep aid for patients who can't take benzos. Rare side effect: priapism (persistent erection — urologic emergency).

Vortioxetine

Multimodal — SERT inhibitor + 5-HT receptor modulator

The "cognitive" antidepressant. Improved cognitive function is part of its clinical trials data. Low sexual dysfunction. Boards may describe a depressed patient complaining of brain fog → vortioxetine.

The board question pattern: "Patient on an SSRI has sexual dysfunction. What do you switch to?" → Bupropion. It's the only major antidepressant that avoids this side effect entirely (no serotonergic activity).

Serotonin Syndrome

The single most tested antidepressant emergency. Know the triad. Know the drugs that cause it. Know how it's different from NMS.

What three findings define serotonin syndrome?

The triad: hyperthermia + clonus + altered mental status. Key distinguisher from NMS: clonus (rhythmic, involuntary jerking). NMS has lead-pipe rigidity (stiff, not jerking). Serotonin syndrome is fast onset (hours). NMS is slow (days to weeks). Both have fever and AMS. The clonus is the giveaway. 🔑Serotonin = Shaking (clonus). NMS = Not Moving (rigidity). Both hot, both confused. The muscles tell the story.

	Serotonin Syndrome	NMS
Cause	Serotonergic drugs (SSRIs, MAOIs, tramadol, linezolid, triptans)	Dopamine blockade (antipsychotics) or dopamine withdrawal (stopping L-DOPA)
Onset	Hours (fast)	Days to weeks (slow)
Key finding	Clonus, hyperreflexia, myoclonus	Lead-pipe rigidity, bradykinesia
Pupils	Dilated	Normal
Bowel sounds	Hyperactive (serotonin stimulates GI)	Normal or decreased
CK	Mildly elevated	Massively elevated (rhabdo)
Treatment	Cyproheptadine (serotonin antagonist) + supportive	Dantrolene (muscle relaxant) + bromocriptine (DA agonist)

The combos that cause it: SSRI + MAOI is the classic. But also: SSRI + tramadol, SSRI + triptans, SSRI + linezolid (weak MAOI), MAOI + meperidine, MAOI + dextromethorphan. 2-week washout required when switching between SSRIs and MAOIs. 5 weeks for fluoxetine (long half-life).

The Board Traps

⚠ TCA Overdose

Amitriptyline, Nortriptyline, etc.

Lethal in overdose. Na channel blockade → QRS widening → fatal arrhythmia. Also: seizures, anticholinergic toxicity (mydriasis, tachycardia, dry, hot). Treatment: sodium bicarbonate (alkalinizes blood, increases Na delivery to channels, increases protein binding of TCA). If the question describes a depressed patient found down with wide QRS → TCA overdose → bicarb.

⚠ MAOI + Tyramine = Hypertensive Crisis

Phenelzine, Tranylcypromine

Patient on an MAOI eats aged cheese at a wine-and-cheese party → severe hypertension, throbbing headache, diaphoresis → can progress to stroke. Tyramine (in aged/fermented foods) is normally broken down by gut MAO-A. Block that enzyme → tyramine floods the blood → massive NE release from sympathetic nerve terminals. Treat with phentolamine (alpha blocker).

⚠ SSRI Discontinuation Syndrome

Paroxetine (worst), Venlafaxine

Abruptly stopping short-acting SSRIs/SNRIs → "FINISH" symptoms: Flu-like, Insomnia, Nausea, Imbalance (dizziness), Sensory (electric shock "brain zaps"), Hyperarousal. Paroxetine is the most common culprit (shortest half-life among SSRIs). Fluoxetine almost never causes it (half-life of active metabolite = 4-16 days — self-tapers).

⚠ Pregnancy: Which Antidepressant?

Sertraline (safest data), Fluoxetine (most studied)

SSRIs as a class are generally used in pregnancy when benefits outweigh risks. Paroxetine is the exception — associated with cardiac defects in first trimester. If a pregnant patient needs an antidepressant, switch from paroxetine to sertraline. Do NOT stop antidepressants in pregnancy without replacing them — untreated depression is also harmful to the fetus.

⚠ Bupropion + Seizures

Bupropion (Wellbutrin)

Lowers the seizure threshold. Contraindicated in: eating disorders (bulimia/anorexia) — electrolyte abnormalities from purging further lower threshold. Also avoid in seizure history and alcohol withdrawal. Board setup: "patient with bulimia needs antidepressant" + bupropion in answer choices = trap.

⚠ Suicidality Black Box Warning

ALL antidepressants in patients under 25

FDA black box: antidepressants may increase suicidal ideation in children, adolescents, and young adults (under 25) during the first weeks of treatment. Mechanism theory: energy and motivation return before mood lifts → patient has the energy to act on suicidal thoughts before feeling better. This does NOT mean you don't prescribe. It means you monitor closely at treatment initiation.

Elimination Game

A 75-year-old man with depression reports poor appetite, 15-pound weight loss, and insomnia. He has benign prostatic hyperplasia (BPH).

Amitriptyline

TCA

Fluoxetine

SSRI

Bupropion

NDRI

Mirtazapine

Atypical

Clue 1: He has BPH. TCAs cause urinary retention (anticholinergic). Dangerous in BPH.

Amitriptyline is eliminated.

Clue 2: He has poor appetite and weight loss. SSRIs commonly cause GI upset and appetite suppression. Not ideal here.

Fluoxetine is eliminated.

Clue 3: He has insomnia. Bupropion is activating (NE + dopamine) — it worsens insomnia.

Bupropion is eliminated.

The Decision Tree

Patient needs an antidepressant. Which one? Follow the clinical scenario.

What's the clinical situation?

First-line → SSRI (sertraline, escitalopram)

Best safety profile, most evidence, well tolerated. Takes 4-6 weeks for full effect. If no response at adequate dose for 6-8 weeks, switch to a different SSRI or augment.

Depression + Pain → Duloxetine (SNRI)

Duloxetine is FDA-approved for MDD, GAD, diabetic neuropathy, fibromyalgia, and chronic musculoskeletal pain. The NE component provides descending pain inhibition. Two birds, one drug.

Sexual dysfunction → Switch to Bupropion

Bupropion (NDRI) has no serotonergic activity → no sexual side effects. Can also be added to an SSRI as augmentation. Alternative: mirtazapine (lower rate of sexual dysfunction than SSRIs).

Depression + Smoking → Bupropion (Wellbutrin / Zyban)

Bupropion is the only antidepressant that doubles as a smoking cessation aid. Blocks NE and dopamine reuptake, reducing cravings and withdrawal. Win-win. Just check for seizure risk factors first.

Elderly + Weight Loss + Insomnia → Mirtazapine

Side effects = treatment: sedation helps sleep, appetite stimulation helps weight. H1 and 5-HT2C blockade are the mechanisms. "The one that makes you hungry and sleepy." No anticholinergic effects (safe in elderly unlike TCAs).

Treatment-Resistant → Augmentation or MAOI

Options: (1) Add lithium or atypical antipsychotic (aripiprazole, quetiapine) to current SSRI. (2) Switch to MAOI after 2-week washout. (3) Ketamine/esketamine (Spravato) — rapid acting, works within hours. MAOIs are last resort — effective but dietary restrictions and drug interactions make them impractical.

Pregnancy → Sertraline (best safety data)

Sertraline has the most reassuring pregnancy data. Fluoxetine is also commonly used. Avoid paroxetine (cardiac defects). Do NOT stop antidepressants without replacement — untreated maternal depression harms the fetus (cortisol exposure, preterm birth, low birth weight).

The Quiz

5 patients walked into your psychiatry clinic. Try not to give anyone serotonin syndrome.