Antidepressant Mechanisms and Effects Quiz

Nefazodone

• Pharmacologic Action: Half-life 2-4 hours, steady state in 4-5 days.
• Active Metabolites: Hydroxynefazodone and mCPP (serotonergic effects: migraine, anxiety, weight loss).
• Mechanism of Action: Inhibits serotonin and norepinephrine uptake; antagonizes 5-HT2A receptors (antidepressant/anxiolytic). Mild alpha-1 adrenergic antagonism may cause orthostatic hypotension.
• Therapeutic Indications: Major depression (300-600 mg/day), panic disorder, GAD, PMDD, PTSD, chronic pain, chronic fatigue syndrome.
• Advantages: Less sexual dysfunction than SSRIs. Improves REM sleep and sleep continuity, potential help in treatment-resistant depression.
• Limitations: Ineffective for OCD.
• Precautions and Adverse Reactions:
  • Common Adverse Effects: Sedation, nausea, dizziness, insomnia, weakness, agitation, visual trails.
  • Hepatic Risks: Potential for severe hepatic enzyme elevation and liver failure; serial liver function tests are crucial.
  • Cardiovascular Caution: Risk of postural hypotension; use cautiously in cardiac conditions, dehydration, or with antihypertensives.
  • Switching from SSRIs: May exacerbate withdrawal symptoms.
  • Overdose: Survivable above 10 g, but fatal with alcohol; symptoms include nausea, vomiting, somnolence.
• Elderly Considerations: Slower metabolism, especially in women; lower doses recommended.
• Dosage and Clinical Guidelines:
  • Initial Dosage: General population: 100 mg twice daily; Elderly or sensitive: 50 mg twice daily.
  • Maintenance Dosage: Optimal: 300-600 mg/day in two divided doses. Once-daily dosing (e.g., bedtime) might be suitable.

Trazodone

• Pharmacological Actions: Weak serotonin reuptake inhibitor; potent 5-HT2A/5-HT2C receptor antagonist. Metabolized by the liver.
• Therapeutic Indications: Depressive disorders (250-600 mg/day); improves sleep quality without influencing stage 4 sleep. Insomnia (first-line treatment due to sedative effects; 25-100 mg at bedtime). Erectile dysfunction (can enhance erections but may cause priapism). Other uses: low doses (50 mg/day) for agitation in dementia; >250 mg/day for GAD; PTSD-related insomnia and nightmares.
• Precautions and Adverse Reactions:
  • Common Side Effects: Sedation, dizziness, orthostatic hypotension, headache, nausea.
  • Serious Concerns: Priapism, arrhythmias (in predisposed individuals), orthostatic hypotension (especially with food or high doses).
  • Overdose: Symptoms include lethargy, dizziness, tachycardia, coma; supportive treatment (possible gastric lavage).
• Contraindications: Pregnancy, breastfeeding, hepatic/renal impairment.
• Drug Interactions:
  • CNS Depression: Potentiates effects of alcohol and other CNS depressants.
  • Hypotension: Increased risk with antihypertensives.
  • No Hypertensive Crisis: Safe with MAOI-associated insomnia.
  • Increased Drug Levels: May elevate digoxin, phenytoin, and warfarin.
  • CYP3A4 Inhibitors: Raise mCPP levels, increasing side effects.
• Laboratory Interference: No known lab test interferences.

Tricyclics and Tetracyclines (TCAs)

• Pharmacologic Actions: Increase serotonin and norepinephrine levels by blocking reuptake, affecting histamine and acetylcholine receptors.
• Side Effects: Anticholinergic effects (constipation, sedation, dry mouth) vary by drug; less sexual dysfunction and weight gain than SSRIs. Common: orthostatic hypotension, sedation, lightheadedness.
• Therapeutic Indications: Major depressive disorder (melancholic features, recurrent depression); not for bipolar depression; Panic disorder with agoraphobia, GAD (Doxepin, Imipramine potentially helpful*); OCD (Clomipramine is most effective); Chronic pain and migraines (Amitriptyline); Other disorders (childhood enuresis, PTSD, ADHD, narcolepsy, sleep disorders).
• Clinical Considerations: Alternative for SSRI-intolerant patients; dosage adjustments for genetic factors and interactions. Monitor for orthostatic hypotension and sedation.
• Precautions and Adverse Reactions:
  • Psychiatric Effects: May induce mania/hypomania; worsen psychotic symptoms; high plasma levels can cause confusion/delirium (especially elderly/dementia).
  • Anticholinergic Effects: Dry mouth, constipation, blurred vision, delirium, urinary retention; severe effects may lead to CNS anticholinergic syndrome. Management: sugarless gum/lozenges, bethanechol, avoid in narrow-angle glaucoma.
  • Cardiac Effects: ECG changes (tachycardia, flattened T waves, prolonged QT interval, depressed ST segments). Contraindicated in conduction defects/heart conditions unless necessary; persistent tachycardia may lead to discontinuation; overdose can cause life-threatening arrhythmias.
  • Other Autonomic Effects: Orthostatic hypotension (most common; management includes hydration, salt in diet, reducing antihypertensive meds if possible; Nortriptyline has the lowest risk). Stop TCAs days before elective surgery.
  • Sedation: Frequent effect due to anticholinergic and antihistaminergic properties.
  • Neurologic Effects: Tremors, myoclonic twitches, tremors of tongue/extremities. Rare: speech blockage, paresthesia, peroneal palsies, ataxia.
  • Drug-Specific Effects: Amoxapine (Parkinsonian symptoms, akathisia, dyskinesia, neuroleptic malignant syndrome). Maprotiline (increases seizure risk, especially with rapid dose increases). Clomipramine & amoxapine (lower seizure threshold than other TCAs).
  • Allergic and Hematologic Effects: Rashes, agranulocytosis, leukocytosis, leukopenia, eosinophilia; sore throat/fever warranting CBC testing.
  • Hepatic Effects: Mild, self-limiting increases in serum transaminases. Rare but severe: fulminant hepatitis (0.1-1%). Discontinue immediately if acute hepatitis suspected.
• Teratogenicity/Pregnancy: Crosses placenta; neonatal withdrawal syndrome (tachypnea, cyanosis, irritability, poor sucking reflex); discontinue 1 week before delivery. Breastfeeding: present in low levels (usually undetectable).
• Dosage Initiation and Titration: Starting dose 25 mg/day, gradual increase. Initial divided doses can reduce side effects, but entire dose at bedtime is possible.

Monoamine oxidase inhibitors (MAOIs)

• Pharmacologic Actions: MAO enzymes break down monoamine neurotransmitters (norepinephrine, serotonin, dopamine, tyramine).
• Mechanism: Inhibit MAO enzymes, increasing neurotransmitter levels.
• Therapeutic Indications: Depression (especially atypical depression).
• Adverse Effects and Precautions:
  • Common Side Effects: Orthostatic hypotension (manage hydration/salt, stockings, fludrocortisone), insomnia (divide doses, avoid evening dosing, benzodiazepines if necessary).
  • Neurological Effects: Paresthesias (pyridoxine deficiency), myoclonus, muscle pain, or confusion (require dosage adjustments).
• Tyramine-Induced Hypertensive Crisis: MAOIs prevent tyramine breakdown, causing severe hypertension. Symptoms: headache, stiff neck, diaphoresis, nausea, vomiting. Management: immediate medical attention, dietary restrictions for 2 weeks and avoid tyramine-rich foods and sympathomimetics.
• Overdose: Symptoms (agitation to coma with hyperthermia, hypertension, tachypnea, tachycardia, dilated pupils) emerge 1-6 hours after overdose.
• Drug interactions: CNS depressants (potentiated), serotonergic drugs (serotonin syndrome risk), opioids (fatal reactions).
• Dosage and Clinical Guidelines:
  • Phenelzine: Start 15 mg/day, gradual weekly increase to 90 mg/day.
  • Tranylcypromine & Isocarboxazid: Start 10 mg/day, increase to 10 mg TID within a week.
• Clinical Considerations: Refractory depression (combinations with other drugs possible, use cautiously).

Transdermal Selegiline

• Low doses selectively inhibit MAO-B, providing antidepressant effects. At higher doses, selectivity decreases requiring monitoring.

Thyroid Hormones

• Pharmacologic Action: T3 binds to intracellular receptors, affecting gene transcription (including neurotransmitter receptors); exact antidepressant augmentation mechanism is unknown.
• Therapeutic Indications: Adjuvant therapy in psychiatry, especially for non-responders after 6 weeks of antidepressant therapy.
• Dosage: Liothyronine (T3) 25-50 µg/day added to antidepressants.
• Precautions and Adverse Effects:
  • Adverse Effects (at 25-50 µg/day): Headache, weight loss, palpitations, nervousness, diarrhea, tremors, insomnia.
  • Serious: Osteoporosis (long-term), cardiac failure, death in overdose.
• Contraindications: Cardiac disease, angina, hypertension, thyrotoxicosis, uncorrected adrenal insufficiency, acute MI.
• Drug Interactions: Warfarin increased anticoagulant effects, Insulin & Digitalis can increase dosage requirements, Sympathomimetics, ketamine, and maprotiline can endanger cardiac function. Other antidepressants (SSRIs, tricyclics, lithium, carbamazepine) can mildly alter thyroid function (e.g., lower T4, raise TSH); regular monitoring needed.
• Thyroid Function and Diagnostic Tests: T4, TSH, FT4I; hypothyroidism common in depression patients (10%); Lithium can induce hypothyroidism or hyperthyroidism; TRH stimulation test diagnoses subclinical hypothyroidism/lithium-induced hypothyroidism (normal response is 5–25 mIU/mL TSH increase).

Test your knowledge on the pharmacology of nefazodone, trazodone, and tricyclic antidepressants. This quiz covers their mechanisms of action, benefits, potential adverse effects, and important clinical considerations. Understand how these medications differ from SSRIs and their therapeutic applications.