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Tuesday, August 19, 2025

Antidepressants


Introduction

Antidepressants are a diverse group of psychotropic drugs used primarily for the treatment of major depressive disorder (MDD), but also for a range of other psychiatric and neurological conditions, including anxiety disorders, obsessive–compulsive disorder (OCD), post-traumatic stress disorder (PTSD), neuropathic pain, and migraine prophylaxis.

These agents act by modulating monoamine neurotransmission (serotonin, norepinephrine, dopamine) or other neurochemical systems implicated in mood regulation. Choice of antidepressant is individualized, based on efficacy, tolerability, comorbidities, risk of adverse events, and potential for drug–drug interactions.

Classification of Antidepressants

1. Selective Serotonin Reuptake Inhibitors (SSRIs)

  • Mechanism: Inhibit presynaptic serotonin transporter (SERT) → increase synaptic serotonin.

  • Generics: fluoxetine, sertraline, paroxetine, citalopram, escitalopram, fluvoxamine.

  • Uses: Major depression, anxiety disorders, OCD, PTSD, premenstrual dysphoric disorder.

  • Adverse Effects: GI upset, insomnia, sexual dysfunction, weight changes, hyponatremia (SIADH), QT prolongation (citalopram).

  • Advantages: Generally safe in overdose, well tolerated, first-line therapy.

2. Serotonin–Norepinephrine Reuptake Inhibitors (SNRIs)

  • Mechanism: Block SERT and norepinephrine transporter (NET).

  • Generics: venlafaxine, desvenlafaxine, duloxetine, levomilnacipran.

  • Uses: Depression, generalized anxiety disorder, panic disorder, neuropathic pain (duloxetine), fibromyalgia.

  • Adverse Effects: Nausea, hypertension (venlafaxine at high doses), insomnia, sexual dysfunction.

3. Tricyclic Antidepressants (TCAs)

  • Mechanism: Inhibit reuptake of serotonin and norepinephrine; also block muscarinic, H1, and α1 receptors.

  • Generics: amitriptyline, imipramine, clomipramine, nortriptyline, desipramine, doxepin.

  • Uses: Depression (less common now due to toxicity), neuropathic pain, migraine prophylaxis, nocturnal enuresis (imipramine).

  • Adverse Effects: Anticholinergic effects (dry mouth, urinary retention, blurred vision), sedation, weight gain, orthostatic hypotension, cardiac arrhythmias (QT prolongation, lethal in overdose).

  • Precautions: Avoid in elderly, cardiac disease, suicidal patients (overdose risk).

4. Monoamine Oxidase Inhibitors (MAOIs)

  • Mechanism: Inhibit monoamine oxidase (MAO-A and/or MAO-B), preventing breakdown of serotonin, norepinephrine, dopamine.

  • Generics: phenelzine, tranylcypromine, isocarboxazid, moclobemide (reversible MAOI), selegiline (selective MAO-B inhibitor, patch form for depression).

  • Uses: Atypical depression, treatment-resistant depression, certain anxiety disorders.

  • Adverse Effects: Orthostatic hypotension, insomnia, weight gain, hypertensive crisis with tyramine-containing foods (“cheese reaction”).

  • Contraindications: Concomitant use with SSRIs, SNRIs, TCAs (risk of serotonin syndrome).

5. Atypical and Novel Antidepressants

a. Bupropion

  • Mechanism: Inhibits dopamine and norepinephrine reuptake (NDRI).

  • Uses: Depression, seasonal affective disorder, smoking cessation.

  • Adverse Effects: Insomnia, dry mouth, anxiety, seizures (dose-dependent, especially in eating disorders).

  • Advantages: No sexual side effects, weight neutral or modest weight loss.

b. Mirtazapine

  • Mechanism: Antagonist at central presynaptic α2 receptors (↑ NE and serotonin release), blocks 5-HT2 and 5-HT3 receptors, H1 antagonist.

  • Uses: Depression, particularly with insomnia and poor appetite.

  • Adverse Effects: Sedation, weight gain, increased appetite.

c. Trazodone / Nefazodone

  • Mechanism: Serotonin antagonist and reuptake inhibitors (SARIs) – block 5-HT2 receptors, weakly inhibit reuptake.

  • Uses: Depression (higher doses), insomnia (trazodone in low doses).

  • Adverse Effects: Sedation, orthostatic hypotension, priapism (rare, trazodone).

  • Nefazodone: Rare severe hepatotoxicity.

d. Vortioxetine

  • Mechanism: Multimodal: SERT inhibition + partial agonist/antagonist effects on multiple serotonin receptor subtypes.

  • Uses: Major depression, with possible benefit in cognitive dysfunction.

  • Adverse Effects: Nausea, constipation, low risk of sexual dysfunction.

e. Vilazodone

  • Mechanism: SSRI and partial agonist at 5-HT1A receptors.

  • Uses: Major depression.

  • Adverse Effects: Diarrhea, insomnia, low risk of sexual dysfunction.

6. Adjunctive/Other Agents with Antidepressant Use

  • Esketamine (intranasal, NMDA receptor antagonist): Treatment-resistant depression, rapid effect on suicidal ideation.

  • Lithium, atypical antipsychotics (e.g., aripiprazole, quetiapine, brexpiprazole): Often used as augmentation agents in resistant depression.

Clinical Indications Beyond Depression

  • Anxiety disorders: SSRIs, SNRIs.

  • Obsessive–compulsive disorder (OCD): SSRIs (fluvoxamine, fluoxetine, sertraline, paroxetine, citalopram), clomipramine (TCA).

  • PTSD: SSRIs, venlafaxine.

  • Panic disorder, social anxiety disorder: SSRIs, SNRIs.

  • Neuropathic pain, fibromyalgia: TCAs, duloxetine.

  • Smoking cessation: bupropion.

  • Insomnia: trazodone, mirtazapine (low doses).

Contraindications (Class Specific)

  • SSRIs: Concomitant MAOI use (serotonin syndrome).

  • SNRIs: Uncontrolled hypertension, narrow-angle glaucoma.

  • TCAs: Cardiac conduction abnormalities, suicidal risk (overdose).

  • MAOIs: Concomitant serotonergic drugs, tyramine-rich diet.

  • Bupropion: Seizure disorders, bulimia/anorexia nervosa.

  • Mirtazapine: Severe obesity (relative).

Adverse Effects (Summary Table)

Class/DrugKey Adverse Effects
SSRIsSexual dysfunction, GI upset, insomnia, hyponatremia
SNRIsHypertension, nausea, sexual dysfunction
TCAsAnticholinergic effects, arrhythmias, weight gain, lethal overdose
MAOIsHypertensive crisis (tyramine), drug interactions
BupropionInsomnia, seizures, anxiety (no sexual side effects)
MirtazapineSedation, weight gain, increased appetite
TrazodoneSedation, priapism, hypotension
EsketamineDissociation, hypertension, abuse potential

Clinical Considerations

  1. First-line therapy: SSRIs and SNRIs are generally preferred for MDD and anxiety disorders due to safety and tolerability.

  2. Choice of agent: Based on comorbidities and symptom profile (e.g., bupropion for low energy and smoking cessation; mirtazapine for insomnia and weight loss; duloxetine for depression with neuropathic pain).

  3. Onset of action: Typically 2–4 weeks; full effect may take 6–8 weeks.

  4. Suicide risk: Monitor closely in adolescents and young adults, particularly during initiation.

  5. Treatment resistance: Defined as inadequate response to at least two adequate antidepressant trials → may require augmentation, combination therapy, or novel agents (e.g., esketamine, ECT).

  6. Discontinuation syndrome: Sudden withdrawal of SSRIs, SNRIs, TCAs may cause flu-like symptoms, insomnia, irritability; taper gradually.




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