Antipsychotic and Mood Stabilizer Pharmacology

Antipsychotic and Mood Stabilizer Buzz Sheet: High-Yield Exam Pearls

• Chlorpromazine: A low-potency first-generation (typical) antipsychotic. Known for high sedation, orthostasis, and anticholinergic effects resulting from $H_1$, $M_1$, and $\alpha_1$ receptor blockade.

• Fluphenazine: A high-potency typical antipsychotic strongly associated with Extrapyramidal Symptoms (EPS) and hyperprolactinemia due to potent $D_2$ blockade.

• Haloperidol: A high-potency $D_2$ blocker used for acute psychosis and agitation. Famous for causing EPS and Neuroleptic Malignant Syndrome (NMS).

• Aripiprazole: A third-generation partial $D_2$ agonist often called a "dopamine stabilizer." It has low metabolic risk and is used for Tourette syndrome and irritability in Autism Spectrum Disorder (ASD).

• Clozapine: The most effective drug for treatment-resistant schizophrenia. It has several severe side effects: agranulocytosis (requires ANC/WBC monitoring), seizures, myocarditis, and massive weight gain. It has the lowest risk for EPS.

• Olanzapine: An atypical antipsychotic notorious for extreme weight gain, diabetes, and dyslipidemia (metabolic syndrome).

• Paliperidone Palmitate: A long-acting injectable (LAI) atypical antipsychotic useful for patients with poor treatment adherence; associated with prolactin elevation.

• Risperidone: A second-generation antipsychotic strongly associated with hyperprolactinemia, leading to galactorrhea and amenorrhea. Used for ASD irritability.

• Pimavanserin: A selective $5HT_{2A}$ inverse agonist used specifically for Parkinson disease psychosis. It does not worsen motor symptoms because it lacks $D_2$ blockade.

• Lithium (Lithobid): A mood stabilizer with a narrow therapeutic index. Toxicities include tremor, hypothyroidism, nephrogenic diabetes insipidus (DI), and SILENT syndrome (Syndrome of Irreversible Lithium-Effectuated Neurotoxicity).

• Carbamazepine (Tegretol): A mood stabilizer and anticonvulsant. Associated with aplastic anemia, agranulocytosis, SIADH (Syndrome of Inappropriate Antidiuretic Hormone), and is a potent CYP450 inducer.

• Lamotrigine (Lamictal): Used for bipolar depression; carries a risk for Stevens-Johnson syndrome (SJS) and must be titrated slowly.

• Valproic Acid (Depakote): A broad-spectrum mood stabilizer. Side effects include hepatotoxicity, pancreatitis, neural tube defects (teratogenicity), and thrombocytopenia.

Quick Reference: "If You See This → Think This"

• Agranulocytosis: Clozapine

• Massive weight gain/Obesity: Olanzapine

• Hyperprolactinemia: Risperidone

• Parkinson psychosis: Pimavanserin

• EPS/NMS: Haloperidol

• Orthostatic hypotension: Chlorpromazine

• Tourette + ASD irritability: Aripiprazole

• Stevens-Johnson syndrome: Lamotrigine

• Neural tube defects: Valproate

• Long-acting injectable: Paliperidone

• SILENT syndrome: Lithium

• CYP inducer: Carbamazepine

Schizophrenia Pathways and Symptoms

• Mesolimbic Pathway:   - Function: Reward and emotion.   - Dopamine Effect: Increased dopamine $(\uparrow DA)$.   - Manifestation: Positive symptoms (hallucinations, delusions, paranoia, disorganized thoughts).

• Mesocortical Pathway:   - Function: Cognition and executive function.   - Dopamine Effect: Decreased dopamine $(\downarrow DA)$.   - Manifestation: Negative and cognitive symptoms (flat affect, alogia, avolition, anhedonia, asociality, poor attention).

• Nigrostriatal Pathway:   - Function: Movement control.   - Dopamine Effect: Decreased dopamine $(\downarrow DA)$ via antipsychotics.   - Manifestation: Extrapyramidal Symptoms (EPS) such as rigidity, tremor, and dystonia.

• Tuberoinfundibular Pathway:   - Function: Prolactin inhibition.   - Dopamine Effect: Decreased dopamine $(\downarrow DA)$.   - Manifestation: Hyperprolactinemia leading to galactorrhea, amenorrhea, and breast engorgement.

Comparison of Antipsychotic Generations

• First Generation (Typical):   - Main Target: Strong $D_2$ blockade.   - EPS Risk: High.   - Use: Best for positive symptoms.   - Metabolic Effects: Lower risk than second generation.   - Examples: Haloperidol, Fluphenazine, Chlorpromazine, Thioridazine.

• Second Generation (Atypical):   - Main Target: $5HT_{2A} > D_2$ blockade. Serotonin antagonism offsets dopamine blockade effects to reduce EPS risk.   - EPS Risk: Lower than first generation.   - Use: Positive and negative symptoms.   - Metabolic Effects: High risk (weight gain, diabetes, dyslipidemia).   - Examples: Risperidone, Olanzapine, Clozapine, Quetiapine.

• Third Generation (Dopamine Stabilizers):   - Main Target: Partial $D_2$ agonist and $5HT_{1A}$ partial agonist. Lacks binding affinity for $H_1$, $M_1$, or $\alpha_1$.   - EPS Risk: Lowest.   - Use: Mood and psychosis.   - Metabolic Effects: Moderate to low risk.   - Example: Aripiprazole.

Extrapyramidal Symptoms (EPS) Timeline

• Acute Dystonia:   - Timing: $1-5\,\text{days}$.   - Symptoms: Muscle spasms of the neck (torticollis), jaw, face, tongue, or upward eye deviation (oculogyric crisis).   - Risk: Highest in young, drug-nave patients.   - Treatment: Benztropine or diphenhydramine.

• Pseudo-Parkinsonism:   - Timing: $5-30\,\text{days}$.   - Symptoms: Bradykinesia, rigidity (cogwheel), shuffling gait, masked face, resting tremor, and pill-rolling.   - Risk: Elderly patients at greatest risk.   - Treatment: Benztropine or amantadine.

• Akathisia:   - Timing: $5-60\,\text{days}$.   - Symptoms: Subjective and objective motor restlessness, pacing, inability to sit still.   - Treatment: Beta blockers (e.g., Propranolol).

• Tardive Dyskinesia:   - Timing: Months to years.   - Symptoms: Orofacial dyskinesia, lip smacking, tongue protrusion, chewing, or choreiform movements of limbs.   - Risk: Elderly patients at greatest risk. Often irreversible.   - Treatment: VMAT2 inhibitors.

Neuroleptic Malignant Syndrome (NMS) vs. Serotonin Syndrome

• Neuroleptic Malignant Syndrome (NMS):   - Cause: Dopamine blockade (antipsychotics).   - Onset: Days to weeks.   - Presentation: Severe "lead-pipe" muscle rigidity, hyperthermia (temp $> 40\,^{\circ}\text{C}$), autonomic instability (tachycardia, diaphoresis, labile BP), and sluggish reflexes.   - Lab findings: Elevated Creatine Kinase (CK) from rhabdomyolysis, leading to potential renal failure.   - Treatment: Discontinue offending agent, dantrolene, bromocriptine, and benzodiazepines.

• Serotonin Syndrome:   - Cause: Excess serotonin activity (SSRIs, MAOIs, etc.).   - Onset: Rapid, within $24\,\text{hours}$.   - Presentation: Hyperreflexia, clonus (especially ocular/lower limb), tremor, agitation, and severe fever.   - Treatment: Cyproheptadine, benzodiazepines.

Receptor Blockade Side Effects

• $D_2$ Blockade: Leads to EPS and hyperprolactinemia. Associated with Haloperidol and Fluphenazine.

• $H_1$ Blockade: Leads to sedation and appetite stimulation/weight gain. Associated with Olanzapine and Clozapine ("Sleepy and Hungry").

• $M_1$ Blockade: Anticholinergic effects including dry mouth, urinary retention, constipation, blurred vision, and dilated pupils. Associated with Clozapine, Chlorpromazine, and Thioridazine.

• $\alpha_1$ Blockade: Orthostatic hypotension and dizziness, increasing fall risk in the elderly. Associated with Chlorpromazine and Clozapine.

Adverse Metabolic and Cardiac Effects

• Metabolic Syndrome: High risk with Olanzapine and Clozapine. Includes dyslipidemia (elevated triglycerides) and impaired glycemic control (diabetes). Appetite stimulation is the primary mechanism. Metformin may moderate weight gain.

• Cardiac Effects: Drug-induced QT prolongation is the primary mechanism for sudden cardiac death. Antagonism of voltage-gated $Na^+$ channels can cause QRS widening and ventricular arrhythmias. Older agents like thioridazine inhibit inward rectifying $K^{+}$ channels.

Management of Specific Disorders

• Schizophrenia: Second-generation antipsychotics are first-line. Clozapine is used for treatment-resistant cases (defined as failure of two or more agents).

• Tourette Syndrome: Aripiprazole is first-line to suppress tics by reducing $D_2$ neurotransmission in the basal ganglia.

• Autism Spectrum Disorder (ASD): Risperidone and Aripiprazole are FDA-approved for irritability; they do not treat core ASD symptoms.

• Parkinson Disease Psychosis (PDP): Pimavanserin is first-line. Clozapine and Quetiapine are also used due to low $D_2$ affinity, which avoids worsening motor symptoms.

• Huntington’s Disease: Tetrabenazine (a VMAT inhibitor) is used for chorea. Haloperidol can suppress both chorea and psychosis.

• Alzheimer’s Psychosis: Acetylcholine deficiency is a hallmark; medications with high $M_1$ blockade must be avoided in elderly patients with dementia. Treatment may include low-dose Haloperidol, Risperidone, or Clozapine.

Bipolar Disorder and Mood Stabilizers

• Bipolar I: At least one manic episode (minimum 1 week); may or may not have major depressive episodes.

• Bipolar II: Hypomanic episodes (at least 4 days, no functional impairment) and major depressive episodes.

• Lithium Toxicity:   - Acute Presentation: Nausea, vomiting, diarrhea, coarse tremor, ataxia, slurred speech, confusion, and seizures.   - Cardiovascular: Arrhythmias and hypotension.   - SILENT Syndrome: Syndrome of Irreversible Lithium-Effectuated Neurotoxicity. Permanent cerebellar dysfunction, dementia, or brainstem dysfunction due to demyelination.   - Interactions: May prolong actions of local anesthetics.

• Bipolar Depression Treatment: Quetiapine, Olanzapine-Fluoxetine combinations, and Lamotrigine.

Scientific Hypotheses of Schizophrenia

• Dopamine Hypothesis: Psychosis is caused by excessive dopaminergic activity. Evidence: Amphetamines (which increase DA) worsen psychosis; $D_2$ blockers alleviate it.

• Serotonin Hypothesis: $5HT_{2A}$ and $5HT_{2C}$ receptors contribute to hallucinatory effects. Evidence: LSD and mescaline are serotonin agonists. Stimulation of $5HT_{2A}$ leads to glutamate neuron depolarization.

• Glutamate Hypothesis: Hypofunction of NMDA receptors on GABAergic interneurons leads to diminished inhibition and downstream glutamatergic hyperstimulation. Evidence: PCP and MK-801 ($NMDA$ inhibitors) exacerbate cognitive and psychotic symptoms.

Clinical Q&A Discussion

• Question 1: A 22-year-old with schizophrenia on Haloperidol develops neck stiffness and upward eye deviation after 3 days. Diagnosis? Answer: Acute dystonia (Early EPS occurring within $1-5\,\text{days}$).

• Question 2: Mechanism of fluphenazine-induced shuffling gait and tremor? Answer: Nigrostriatal dopamine blockade.

• Question 3: Appropriate treatment for severe rigidity, hyperthermia, and autonomic instability after Haloperidol? Answer: Bromocriptine (for NMS).

• Question 4: Receptor responsible for chlorpromazine-induced drowsiness and weight gain? Answer: Histamine $H_1$.

• Question 5: Pathway involved in risperidone-induced galactorrhea? Answer: Tuberoinfundibular.

• Question 6: Why do second-generation drugs have lower EPS risk? Answer: Greater $5HT_{2A}$ antagonism relative to $D_2$ blockade.

• Question 7: Repetitive lip smacking after years of use? Answer: Tardive dyskinesia.

• Question 8: Partial dopamine agonist for Tourette and ASD? Answer: Aripiprazole.

• Question 9: Olanzapine-induced hyperglycemia and high triglycerides category? Answer: Metabolic syndrome.

• Question 10: First-line for Parkinson disease psychosis? Answer: Pimavanserin.

• Question 11: Distinguishing Serotonin Syndrome from NMS? Answer: Hyperreflexia and rapid onset ($< 24\,\text{hrs}$) in Serotonin Syndrome; NMS has "lead-pipe" rigidity and develops over days/weeks.

• Question 12: Mechanism of chlorpromazine-induced dizziness when standing? Answer: Alpha-1 adrenergic blockade (vasodilation).

• Question 13: Mechanism of clozapine-induced blurry vision and constipation? Answer: $M_1$ muscarinic blockade (anticholinergic).

• Question 14: Pathway for hallucinations and delusions? Answer: Mesolimbic.

• Question 15: Diagnosis for a bipolar patient on lithium with coarse tremor, slurred speech, and ataxia? Answer: Acute lithium toxicity.