Antidepressants

MAOI dietary restriction

Avoid tyramine-rich foods (aged cheese, cured meats) to prevent hypertensive crisis [TL;DR] Washout period for MAOIs

PMDD first-line treatment

Fluoxetine or Sertraline; luteal-phase-only dosing is an option

Neuropathic pain antidepressants

SNRIs (duloxetine) and TCAs are first-line for chronic/nerve pain

Lithium drug interactions

Diuretics and NSAIDs each reduce lithium clearance by ~25%, increasing toxicity risk

Monoamine hypothesis of depression

Deficiency of serotonin and norepinephrine (small roles: cortisol, sex steroids like estrogen/testosterone)

Time to fully assess antidepressant efficacy

2-3 months

% of patients responding to initial first-line antidepressant

About 1/3 (~30%) — switching within/across classes is often needed

Maintenance therapy criteria

2+ depressive episodes within 5 years, OR 3+ episodes over lifetime

Antidepressant class-wide Black Box Warning

Increased suicidal thoughts/behavior in PEDIATRIC and YOUNG ADULT patients — applies to ALL antidepressant classes

SSRI mechanism

Selectively inhibits SERT (serotonin transporter) → increased synaptic serotonin

SSRIs — first line status

Current first-line treatment for depression

SSRI unique to have active drug AND active metabolite (long elimination)

Fluoxetine (norfluoxetine metabolite)

SSRIs with notable drug interactions (CYP inhibition)

Fluoxetine and paroxetine (CYP2D6); fluvoxamine (CYP3A4, distinct from the others)

Fluvoxamine primary indication

OCD

SSRI Pregnancy Category D (fetal cardiac defect risk)

Paroxetine — avoid in pregnancy, 1st trimester cardiac defects

SSRI with shortest half-life, highest discontinuation syndrome risk

Paroxetine

SSRI most associated with weight gain

Paroxetine (though weight gain is a general SSRI-class effect too)

SSRI side effects (general)

GI upset/nausea (early, wanes), sexual dysfunction (30-40%, persists), headache, insomnia/hypersomnia, weight gain

Why do SSRIs cause GI side effects early on?

~90% of body's serotonin is in the gut; SERT blockade there increases GI serotonin signaling

Discontinuation syndrome definition

Symptoms (dizziness, paresthesias, flu-like, irritability) 1-2 days after ABRUPT cessation; prevent by tapering

Discontinuation syndrome risk pattern

Inversely related to half-life — shorter half-life (paroxetine) = higher risk; longer half-life (fluoxetine) = lower risk

SSRIs used for PMDD

Fluoxetine and sertraline (most studied); luteal-phase-only dosing can be as effective as continuous for sertraline

SNRI mechanism

Inhibits both SERT and NET → increased serotonin AND norepinephrine

SNRI extra side effects beyond SSRI profile

Adrenergic effects — changes in BP, HR, increased anxiety/agitation

SNRI with significant hepatic metabolism (2)

Duloxetine and venlafaxine

SNRI preferred in hepatic impairment (renally excreted)

Desvenlafaxine (Pristiq) — minimal hepatic metabolism

SNRI specifically indicated for neuropathic pain/fibromyalgia

Duloxetine (Cymbalta)

Drug class overall indicated for neuropathic pain/fibromyalgia

TCAs (and duloxetine specifically among SNRIs)

TCA mechanism

SERT + NET reuptake inhibition (like SNRIs) PLUS broad off-target receptor binding (M1, H1, alpha-1)

TCA treatment line

Second to third line for depression

TCA dosing time and why

Night — due to strong sedating effects

TCA receptor → side effect: M1 (anticholinergic)

Dry mouth, constipation, urinary retention, blurred vision, confusion

TCA receptor → side effect: H1 (histamine)

Sedation (greatest of the three), weight gain

TCA receptor → side effect: alpha-1 (adrenergic)

Orthostatic hypotension

TCA with no active metabolites, wide therapeutic window, NET-selective, preferred in elderly

Desipramine / Nortriptyline

TCA repurposed at low dose for insomnia (potent H1 antagonist)

Doxepin

Strongly serotonergic TCA used for OCD

Clomipramine

Why are TCAs favored less than SNRIs today?

Same core mechanism as SNRIs, but WITHOUT the added antihistamine/alpha-blocking/anticholinergic burden — SNRIs are better tolerated

Serotonin receptor modulator mechanism

Direct agonist/antagonist action at specific 5-HT receptor SUBTYPES (not reuptake inhibition)

Trazodone mechanism and modern use

5-HT2 receptor antagonist; highly sedating; used mainly as a hypnotic (low dose) rather than for MDD today

Why do serotonin receptor modulators need multiple daily doses for depression?

Short half-lives

Why do serotonin modulators have less GI/sexual side effects than SSRI/SNRI?

More SELECTIVE for specific serotonin receptor subtypes — narrower side effect footprint

Vortioxetine mechanism

Multimodal — antagonizes 5-HT3/5-HT7/5-HT1D, partial agonist 5-HT1B, agonist 5-HT1A, also inhibits SERT

Atypical antidepressant — bupropion mechanism

NE and DA reuptake inhibition; virtually NO serotonergic activity; structurally amphetamine-like

Bupropion unique benefits

No sexual side effects; used for smoking cessation

Bupropion caution

Lowers seizure threshold (avoid in seizure disorder/eating disorders)

Mirtazapine mechanism

Antagonizes presynaptic alpha-2 autoreceptor → increases 5-HT and NE release; also blocks 5-HT2/5-HT3 and H1

Mirtazapine benefits/side effects

Least sexual side effects (with bupropion); significant sedation and weight gain (H1) — useful when sedation/appetite stimulation is desired

Atypical antidepressant unique side effects

Parkinsonian syndrome, anorexia (e.g. amoxapine — TCA-like plus D2 blockade)

MAOI mechanism

Irreversibly inhibits monoamine oxidase, the enzyme that breaks down serotonin, NE, and DA → increased monoamine availability

Why are MAOIs rarely used today?

High toxicity risk, extensive food (tyramine) and drug interactions

MAOI side effects

Orthostatic hypotension, weight gain, HIGHEST rate of sexual side effects of any antidepressant class, insomnia/restlessness (stimulant-like), discontinuation syndrome (delirium-like)

MAOI clinical role today

Reserved for refractory depression and some anxiety disorders (social anxiety, panic disorder)

Selegiline unique feature

Available transdermal/sublingual to bypass first-pass metabolism and reduce food-interaction risk

Washout period: fluoxetine to MAOI

At least 4 weeks (due to fluoxetine's long half-life/active metabolite) — risk of serotonin syndrome if overlapped

Lithium clinical use

Mood stabilizer for bipolar disorder; effective for acute mania and maintenance (prevents manic/depressive episodes)

Lithium efficacy stats

~80% remission in acute mania; ~60% success in maintenance therapy

Lithium therapeutic range

0.6-1.2 mEq/L — NARROW therapeutic index, requires frequent monitoring, dosed multiple times/day

Lithium level monitoring timing

Check ~5 days after starting (steady state) and ~5 days after any dose change

Lithium during depressive phase of bipolar

Antidepressants usually required in addition to lithium

Lithium neuro side effects (4)

Tremor (treat with propranolol/atenolol), choreoathetosis, ataxia, dysarthria, aphasia

Lithium other side effects

Edema, weight gain, increased thirst/urination, thyroid dysfunction

Lithium monitoring — thyroid

Check thyroid function every 6-12 months (lithium can impair thyroid function)

Lithium drug interactions

Diuretics and NSAIDs each reduce lithium clearance by ~25% → risk of toxicity

TCA caution in bipolar depression

Can destabilize/trigger rapid cycling

First-line for chronic/long-term anxiety maintenance

SSRIs and SNRIs

First-line for ACUTE anxiety (not long-term)

Benzodiazepines (inferior to SSRI/SNRI for long-term maintenance)