3.9 Psychopharmacology Foundations: Antipsychotics and Mood Stabilizers

Antipsychotics

Antipsychotics are broadly divided into First-Generation (Typical) and Second-Generation (Atypical) classes. Both classes treat the positive symptoms of schizophrenia, but SGAs are generally preferred due to their side effect profile (lower EPS risk and broader efficacy for negative and cognitive symptoms).

First-Generation Antipsychotics (FGAs)

• Mechanism of Action: Strong antagonism of Dopamine D2 receptors, particularly in the mesolimbic pathway.
• D2 Receptor Occupancy: Efficacy requires approximately 60-75% D2 receptor occupancy. Occupancy >80% significantly increases the risk of Extrapyramidal Symptoms (EPS); >60% blockade of tuberoinfundibular D2 causes hyperprolactinemia.
• Potency Classification:
  • High-potency: Haloperidol (Haldol), Fluphenazine (Prolixin) — more EPS, less sedation/orthostasis/anticholinergic burden.
  • Low-potency: Chlorpromazine (Thorazine), Thioridazine — more sedation, orthostatic hypotension, anticholinergic effects, and photosensitivity. Thioridazine carries a Black Box Warning for QT prolongation and irreversible retinal pigmentation.
• Major Risks: High risk of EPS, hyperprolactinemia (galactorrhea, amenorrhea, gynecomastia, sexual dysfunction), and Neuroleptic Malignant Syndrome (NMS).

Second-Generation Antipsychotics (SGAs)

• Mechanism of Action: Dual antagonism of Dopamine D2 and Serotonin 5-HT2A receptors. The 5-HT2A antagonism promotes dopamine release in the nigrostriatal pathway, reducing the risk of EPS.
• Examples & Subgroups:
  • D2 partial agonist (third-generation): Aripiprazole (Abilify), Brexpiprazole (Rexulti), Cariprazine (Vraylar) — stabilize dopaminergic tone, lower EPS and hyperprolactinemia risk; aripiprazole is also a 5-HT1A partial agonist.
  • Multi-receptor SGAs: Olanzapine (Zyprexa), Quetiapine (Seroquel), Risperidone (Risperdal), Paliperidone (Invega), Asenapine (Saphris), Lurasidone (Latuda), Ziprasidone (Geodon).
• Major Risks: Metabolic Syndrome (weight gain, dyslipidemia, insulin resistance/hyperglycemia). Olanzapine and clozapine carry the highest metabolic risk; Ziprasidone, aripiprazole, and lurasidone are more weight-neutral. Baseline and ongoing monitoring (BMI, waist circumference, fasting glucose, lipid panel) per ADA/APA consensus guidelines.
• Long-Acting Injectables (LAI): Risperidone (Risperdal Consta, Perseris), Paliperidone (Invega Sustenna, Trinza), Aripiprazole (Abilify Maintena, Aristada), Haloperidol decanoate, Fluphenazine decanoate. Ideal for adherence issues; oral bridge required for 2-4 weeks (except Invega Sustenna, which needs no oral overlap).

Comparison: FGAs vs SGAs

Extrapyramidal Symptoms (EPS)

EPS result from D2 blockade in the nigrostriatal pathway.

1. Acute Dystonia: Sustained muscle contractions (e.g., torticollis, oculogyric crisis, laryngospasm — airway emergency). Occurs in hours to days; highest risk in young men starting high-potency FGAs. Treatment: Anticholinergics (benztropine 1-2 mg, diphenhydramine 25-50 mg IM/IV).
2. Akathisia: Severe inner restlessness and inability to sit still; can be mistaken for agitation (do NOT increase antipsychotic). Occurs in days to weeks. Treatment: Beta-blockers (propranolol 10-30 mg TID), benzodiazepines, or reduce antipsychotic dose; consider switching to lower-EPS agent.
3. Pseudoparkinsonism: Pill-rolling tremor, cogwheel rigidity, bradykinesia, masked facies. Occurs in weeks to months. Treatment: Anticholinergics (benztropine) or amantadine.
4. Tardive Dyskinesia (TD): Involuntary, repetitive movements (lip smacking, tongue protrusion, choreoathetoid limb movements) after ≥3 months of treatment. May be irreversible. Treatment: VMAT2 inhibitors (valbenazine 40-80 mg QD, deutetrabenazine 12-24 mg BID). Stop anticholinergics, as they worsen TD. Consider switching to clozapine or quetiapine.

Neuroleptic Malignant Syndrome (NMS)

NMS is a rare but life-threatening psychiatric emergency caused by profound dopamine depletion.

• Symptoms: Remember "FALTER" - Fever (often >38.5°C/101°F), Autonomic instability (tachycardia, labile BP, incontinence), Leukocytosis, Tremor, Elevated CPK (often >1000 U/L from muscle breakdown), Rigidity (lead-pipe).
• Onset: Days to weeks after initiation or dose increase; can also occur with rapid downward titration of dopamine agents (e.g., Parkinson's patient taken off levodopa).
• Treatment: Discontinue offending agent immediately, supportive care (cooling blankets, IV fluids, electrolyte correction). Pharmacological options include Dantrolene (muscle relaxant, 1-2.5 mg/kg IV) or Bromocriptine (dopamine agonist, 2.5 mg TID, titrate up). May require ICU admission for rhabdomyolysis-induced renal failure. After resolution, restart a different antipsychetic after 2 weeks; consider ECT for refractory cases.

Clozapine Protocol

Clozapine is the gold standard for treatment-resistant schizophrenia (defined as failure of 2 adequate trials of other antipsychotics at therapeutic doses for 6-12 weeks) and for reducing suicidal behavior in schizophrenia/schizoaffective disorder.

• Black Box Warnings: Severe neutropenia (agranulocytosis, incidence ~1%), seizures (dose-related; clozapine lowers seizure threshold more than other antipsychotics), myocarditis, orthostatic hypotension, and increased mortality in elderly patients with dementia-related psychosis.
• REMS Monitoring: Strict adherence to the Clozapine REMS program. Absolute Neutrophil Count (ANC) monitored weekly for first 6 months, biweekly for next 6 months, and monthly thereafter. ANC must be ≥ 1500/μL to initiate (or ≥ 1000/μL in Benign Ethnic Neutropenia). Stop immediately if ANC < 1000 (or <500 in BEN).
• Additional Monitoring: Baseline ECG, fasting glucose, lipid panel, BMI; monitor for signs of myocarditis (chest pain, dyspnea, tachycardia, elevated troponin) within first 8 weeks. Caution with other QT-prolonging medications.

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Mood Stabilizers

Mood stabilizers are primarily used to treat Bipolar Disorder, focusing on treating acute mania, bipolar depression, and preventing mood episode recurrence.

Lithium

• Mechanism: Exact mechanism unknown, but thought to alter cation transport and influence second messenger systems (inositol triphosphate, GSK-3β, neuroprotective effects).
• Dosing: Starting 600-900 mg/day in divided doses; titrate to serum level. Target 0.6 to 1.2 mEq/L (0.8-1.0 for acute mania; 0.6-0.8 for maintenance). Draw level as 12-hour trough (consistent timing critical).
• Toxicity: Levels > 1.5 mEq/L. Early signs include severe nausea/vomiting, coarse hand tremor, ataxia, confusion, and slurred speech. Levels > 2.5 mEq/L can cause seizures, coma, and death; may require hemodialysis.
• Long-term Adverse Effects: Nephrogenic diabetes insipidus (polyuria/polydipsia — managed with amiloride), hypothyroidism (elevated TSH), hyperparathyroidism (elevated calcium), weight gain, fine hand tremor, leukocytosis (benign), T-wave flattening on ECG.
• Monitoring: Baseline and ongoing renal function (BUN/Creatinine, eGFR) and thyroid function (TSH, Free T4) at 6-12 month intervals; lithium level checked 5 days after dose change. ECG in patients > 50 or with cardiac history. Pregnancy test before initiation.
• Contraindications: Severe renal disease, severe cardiovascular disease, first trimester of pregnancy (Ebstein's anomaly — tricuspid valve displacement, risk ~1:1000 vs 1:20,000 baseline). Lithium is excreted in breast milk; caution with breastfeeding. NSAIDs, ACE inhibitors, thiazides, and dehydration raise lithium levels.

Valproate (Depakote)

• Indications: Acute mania, mixed episodes, rapid cycling bipolar disorder.
• Therapeutic Level: 50 to 125 mcg/mL.
• Black Box Warnings: Hepatotoxicity (often fatal; monitor LFTs), pancreatitis (abdominal pain, nausea — stop drug immediately and hospitalize), and teratogenicity (neural tube defects — spina bifida; absolutely contraindicated in pregnancy for migraine prophylaxis and heavily cautioned in bipolar). Avoid in women of childbearing potential without reliable contraception.
• Common Side Effects: GI upset (nausea, dyspepsia), weight gain, tremor, alopecia (dose-related; may respond to zinc/selenium supplementation), thrombocytopenia.
• Monitoring: LFTs and CBC (risk of thrombocytopenia) at baseline and periodically; valproic acid level (trough).

Carbamazepine (Tegretol)

• Indications: Acute mania and mixed episodes; second-line to lithium/valproate; also FDA-approved for trigeminal neuralgia and epilepsy.
• Therapeutic Level: 4-12 mcg/mL.
• Black Box Warnings: Aplastic anemia and agranulocytosis (monitor CBC for fever/sore throat/infection), Stevens-Johnson Syndrome (SJS/TEN) — strongly associated with HLA-B*1502 allele (screen patients of Asian ancestry before initiation).
• Major Drug Interactions: Potent CYP3A4 inducer — reduces effectiveness of oral contraceptives (use backup method), warfarin, atypical antipsychotics, other anticonvulsants. Auto-induces its own metabolism (levels fall after 3-4 weeks; recheck level). Avoid combined use with MAOIs (14-day washout).
• Monitoring: CBC, LFTs, electrolytes (risk of hyponatremia from SIADH), carbamazepine level. Baseline HLA-B*1502 in Asian patients.

Lamotrigine (Lamictal)

• Indications: FDA approved for the maintenance treatment of Bipolar I Disorder. Highly effective for bipolar depression. Not effective for acute mania.
• Black Box Warning: Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). Risk is ~1:1000 in adults; rash typically occurs in first 8 weeks.
• Titration Schedule: Standard adult titration: 25 mg/day for 2 weeks → 50 mg/day for 2 weeks → 100 mg/day for 1 week → 200 mg/day target. Halve the dose if taking valproate (valproate inhibits UGT metabolism, doubling lamotrigine levels). Double the dose if taking carbamazepine (an inducer that accelerates lamotrigine clearance). Patient education: report any rash immediately and discontinue pending evaluation.

5. Clinical Vignette

A 28-year-old male with treatment-resistant schizophrenia has failed adequate trials of risperidone (6 mg × 8 weeks) and olanzapine (20 mg × 10 weeks) due to persistent command auditory hallucinations. Baseline ANC is 5200/μL. He is started on clozapine, titrated to 300 mg/day over 3 weeks. At week 4, ANC is 1700/μL. At week 12, he presents with fever (102°F), CPK 2400 U/L, lead-pipe rigidity, and tachycardia. Plan: Stop clozapine immediately (suspected NMS — meets FALTER criteria with fever, rigidity, elevated CPK, autonomic instability). Hospitalize for supportive care; consider dantrolene and bromocriptine. Do not re-challenge with clozapine. After stabilization, consider ECT or a different SGA (e.g., aripiprazole LAI) and resume clozapine REMS once NMS resolves (with caution, after 2-week washout).