Pharmacotherapy of Mood Disorders

Antidepressants - Happy Pills Parade

• SSRIs (Selective Serotonin Reuptake Inhibitors): Fluoxetine, Sertraline.
  • Mech: Block SERT → ↑ Serotonin.
  • SE: GI upset, sexual dysfunction. 📌 SE: Stomach upset, Sexual dysfunction, Restlessness, Insomnia.
  • Fluoxetine: Longest t½.
• SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors): Venlafaxine, Duloxetine.
  • Mech: Block SERT & NET → ↑ Serotonin & NE.
  • SE: Hypertension. Duloxetine: also for neuropathic pain.
• TCAs (Tricyclic Antidepressants): Amitriptyline, Imipramine.
  • Mech: Block SERT, NET; also H1, M1, α1 receptors.
  • SE: Cardiotoxicity (QRS prolongation), anticholinergic. 📌 Three Cs: Cardiotoxicity, Convulsions, Coma.
• MAOIs (Monoamine Oxidase Inhibitors): Phenelzine, Moclobemide (RIMA).
  • Mech: Inhibit MAO → ↑ Serotonin, NE, Dopamine.
  • SE: Hypertensive crisis with tyramine-rich foods (cheese reaction).
• Atypical Antidepressants:
  • Bupropion: NDRI; for smoking cessation; ↓ seizure threshold.
  • Mirtazapine: α2 antagonist; sedation (H1 block), weight gain.
  • Trazodone: SARI; priapism (rare), sedation.

⭐ Serotonin syndrome: triad of altered mental status, autonomic hyperactivity (fever, tachycardia), neuromuscular abnormalities (clonus, hyperreflexia). High risk with SSRI/SNRI + MAOI combination.

Mood Stabilizers - Even Keel Crew

• Lithium (Li+):
  • Gold standard: Bipolar disorder (mania, maintenance).
  • MOA: ↓ IP3 & DAG, GSK-3β inhibition.
  • Therapeutic window: 0.6-1.2 mEq/L.
  • Toxicity: Tremor, ataxia, confusion. Monitor renal, thyroid.
  • 📌 LITH: Levels (0.6-1.2), Insipidus (nephrogenic DI), Teratogenic (Ebstein's anomaly), Hypothyroidism.
• Valproate (VPA):
  • Broad spectrum: Acute mania, mixed states, maintenance.
  • MOA: ↑ GABA, blocks Na+ channels.
  • SE: GI upset, weight gain, hepatotoxicity. ⚠️ Teratogenic (neural tube defects).
• Lamotrigine (LTG):
  • Bipolar depression, maintenance.
  • MOA: Blocks Na+ channels, ↓ glutamate release.
  • Slow titration: Risk of Stevens-Johnson Syndrome (SJS).
• Carbamazepine (CBZ):
  • Acute mania, maintenance.
  • MOA: Blocks Na+ channels.
  • SE: Agranulocytosis, aplastic anemia, SIADH, P450 inducer.
• Atypical Antipsychotics: Olanzapine, Risperidone, Quetiapine, Aripiprazole also used as mood stabilizers, especially in acute mania.

⭐ Lithium is the only mood stabilizer proven to reduce suicide risk in bipolar disorder.

Adjunctive & Special Use - Tricky Mood Tactics

• Treatment-Resistant Depression (TRD): Failure of ≥2 adequate antidepressant trials.
  • Augmentation: Lithium, Atypical Antipsychotics (e.g., aripiprazole, quetiapine), T3.
  • Other options: Esketamine nasal spray, ECT.

• Antipsychotics in Mood Disorders:
  • Bipolar Depression: Quetiapine, lurasidone, olanzapine-fluoxetine combination (OFC).
  • Acute Mania: Most atypicals (e.g., risperidone, olanzapine), haloperidol.
• Special Populations:
  • Pregnancy:
    • Antidepressants: Sertraline often preferred. Avoid paroxetine (1st trimester).
    • Mood Stabilizers: Lamotrigine (relatively safer). ⚠️ Valproate (high NTD risk), Carbamazepine (NTD risk). Lithium (monitor closely; Ebstein's anomaly risk).
    • ECT is a safe option.
  • Elderly: "Start low, go slow."
    • SSRIs (e.g., sertraline, escitalopram). Avoid fluoxetine (long $t_{1/2}$), paroxetine (anticholinergic).

⭐ Lithium augmentation can convert non-responders to responders in TRD for about 50% of cases.

Rapid & Novel Agents - Speedy Mood Rescuers

• Ketamine & Esketamine
  • Mechanism: NMDA antagonist.
  • Uses: Treatment-Resistant Depression (TRD), rapid ↓ suicidal thoughts.
  • Onset: Hours.
  • Ketamine: 0.5 mg/kg IV over 40 min.
  • Esketamine (Spravato): Intranasal 56mg/84mg; REMS program, monitor BP.
  • SE: Dissociation, ↑BP, abuse potential.
• Electroconvulsive Therapy (ECT)
  • Indications: Severe/psychotic depression, TRD, catatonia, acute suicidality, mania. Safe in pregnancy.
  • Mechanism: Generalized seizure induction.
  • Regimen: 2-3x/week; 6-12 sessions.
  • SE: Headache, memory loss (transient).

  ⭐ ECT is considered the most effective acute treatment for severe major depression.

• Brexanolone (Zulresso)
  • Mechanism: Allosteric modulator of GABA-A receptors.
  • Use: Postpartum depression (IV, 60-hour infusion).

High‑Yield Points - ⚡ Biggest Takeaways

• SSRIs (e.g., Fluoxetine) are first-line for depression; monitor for serotonin syndrome.
• Lithium is gold standard for bipolar disorder; requires therapeutic drug monitoring (TDM).
• Valproate is a mood stabilizer, but teratogenic; Lamotrigine risks Stevens-Johnson Syndrome (SJS).
• TCAs carry risks of cardiotoxicity and anticholinergic effects.
• MAOIs necessitate tyramine-free diet to prevent hypertensive crisis.
• Atypical antipsychotics (e.g., Olanzapine) are used for acute mania and as adjuncts.
• Esketamine for treatment-resistant depression (TRD).