Antidepressants: SSRIs and SNRIs

Intro & MOA - Brain Chemistry 101

• Depression often linked to ↓ brain Serotonin (5-HT) & Norepinephrine (NE). Antidepressants aim to correct this imbalance.
• SSRIs (Selective Serotonin Reuptake Inhibitors):
  • MOA: Selectively block SERT (SErotonin Reuptake Transporter) on the presynaptic neuron.
  • Effect: ↑ 5-HT concentration in the synaptic cleft.
• SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors):
  • MOA: Block both SERT & NET (Norepinephrine Transporter) on the presynaptic neuron.
  • Effect: ↑ 5-HT & ↑ NE concentrations in the synaptic cleft.

⭐ Therapeutic response to SSRIs/SNRIs is typically delayed by 2-4 weeks, attributed to adaptive receptor desensitization or downregulation and other neuroplastic changes.

SSRIs In-Depth - Serotonin Select Squad

• Mechanism: Block SERT → ↑ synaptic serotonin. Generally safer with better tolerability than TCAs.
• Common SEs: GI upset (nausea, diarrhea), sexual dysfunction, headache. ⚠️ Serotonin syndrome risk (especially with MAOIs).
• Key SSRIs:

  Drug	Key Features
  Fluoxetine	Longest t½ (norfluoxetine); CYP2D6 inhibitor
  Paroxetine	Most anticholinergic; discontinuation syndrome; CYP2D6 inhibitor; weight gain
  Sertraline	GI SEs common; often preferred in cardiac disease
  Citalopram	QTc prolongation risk (max dose 40mg; 20mg in elderly)
  Escitalopram	S-enantiomer of citalopram; better tolerated, less QTc risk
  Fluvoxamine	Primarily for OCD; potent CYP1A2 & CYP2C19 inhibitor (drug interactions)

⭐ Fluoxetine's long half-life (active metabolite norfluoxetine) means less severe discontinuation symptoms and a longer washout period is required if switching to an MAOI.

SNRIs In-Depth - NorEpi & Serotonin Sidekicks

• Mechanism: Dual action (vs. SSRI's single); inhibit Serotonin (5-HT) & Norepinephrine (NE) reuptake.
• Key Agents (📌 Ven Dines During Midnight):
  • Venlafaxine: Dose-dependent NE action; discontinuation syndrome risk.
  • Desvenlafaxine: Active metabolite of Venlafaxine.
  • Duloxetine: Balanced 5-HT/NE. Uses: MDD, GAD, neuropathic pain, fibromyalgia.
  • Milnacipran: More NE > 5-HT. Primarily for fibromyalgia.
• Side Effects: SSRI-like + NE-specific (↑BP, ↑HR, sweating, dry mouth).

⭐ Duloxetine is notably used for neuropathic pain and fibromyalgia, beyond depression/anxiety.

Clinical Applications - Happy Pills Playbook

SSRIs (Selective Serotonin Reuptake Inhibitors):

• First-line: Major Depressive Disorder (MDD), Generalized Anxiety Disorder (GAD), Panic Disorder, Social Anxiety Disorder.
• Also for: Obsessive-Compulsive Disorder (OCD), Post-Traumatic Stress Disorder (PTSD).
• Specific: Fluoxetine for Bulimia Nervosa & PMDD.

SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors):

• MDD (especially with fatigue or chronic pain).
• GAD, Panic Disorder, Social Anxiety Disorder.
• Pain: Duloxetine for neuropathic pain, fibromyalgia, chronic musculoskeletal pain. Milnacipran for fibromyalgia.

⭐ Consider SNRIs (e.g., Duloxetine) when depression coexists with significant pain syndromes or fatigue.

Adverse Effects & CIs - Caution Crew Callouts

• Common (SSRIs & SNRIs):
  • GI: Nausea, diarrhea.
  • CNS: Headache, insomnia/somnolence, anxiety.
  • Sexual dysfunction (↓ libido, anorgasmia).
  • SNRIs also: ↑BP, sweating, dry mouth, constipation.
• Serious:
  • ⚠️ Serotonin Syndrome: (📌 SHIVERS - Shivering, Hyperreflexia, Increased temp, Vital instability, Encephalopathy, Restlessness, Sweating). Risk ↑ with MAOIs, triptans, linezolid.
  • Discontinuation Syndrome: (📌 FINISH - Flu-like, Insomnia, Nausea, Imbalance, Sensory disturbances, Hyperarousal). Taper slowly.
  • Suicidality: ↑ risk <25 yrs (initial phase).
  • Hyponatremia (SIADH), esp. elderly.
• Contraindications:
  • MAOIs (concurrent or within 14 days).
  • SNRIs: Uncontrolled narrow-angle glaucoma.
• Key Interactions:
  • Other serotonergic drugs (e.g., triptans, tramadol, St. John's Wort).
  • NSAIDs/Anticoagulants: ↑ bleeding risk.
  • CYP450 inhibitors/inducers.

⭐ Paroxetine has a higher risk of discontinuation syndrome due to its short half-life and anticholinergic properties.

High‑Yield Points - ⚡ Biggest Takeaways

• SSRIs are first-line for depression and anxiety disorders; common side effects include GI upset and sexual dysfunction.
• Serotonin syndrome is a critical risk, especially if co-administered with MAOIs or other serotonergic agents.
• Paroxetine is notable for anticholinergic effects, weight gain, and significant withdrawal symptoms; avoid in pregnancy.
• Fluoxetine has the longest half-life; Sertraline is often preferred in cardiac patients and breastfeeding.
• SNRIs (e.g., Venlafaxine, Duloxetine) additionally block norepinephrine reuptake, offering broader efficacy for some.
• Venlafaxine can cause dose-dependent hypertension. Duloxetine is also indicated for neuropathic pain and fibromyalgia.
• Abrupt discontinuation of most SSRIs/SNRIs (especially Paroxetine, Venlafaxine) can lead to discontinuation syndrome.