Section 6.3: Schizophrenia and Psychotic Disorders

Why Schizophrenia and Psychotic Disorders Matter for the PANCE

Psychotic disorders carry significant clinical morbidity, and their diagnostic criteria, classification timelines, and pharmacotherapy side effects are heavily tested on the PANCE. Candidates must be proficient in distinguishing psychotic disorders based on duration (Brief Psychotic Disorder vs. Schizophreniform vs. Schizophrenia), separating positive from negative symptoms, and managing critical antipsychotic-related adverse events. Specifically, life-threatening emergencies like Neuroleptic Malignant Syndrome (NMS) and highly distressing Extrapyramidal Symptoms (EPS) require rapid clinical recognition and intervention.

Schizophrenia

Pathophysiology

The primary pathophysiology of schizophrenia involves dysregulation of dopamine pathways:

• Mesolimbic Pathway: Excess dopamine activity is responsible for the positive symptoms (hallucinations, delusions).
• Mesocortical Pathway: Dopamine deficiency is responsible for the negative symptoms (flat affect, avolition, alogia) and cognitive deficits.
• Nigrostriatal Pathway: Antipsychotic D2 blockade in this pathway leads to Extrapyramidal Symptoms (EPS).
• Tuberoinfundibular Pathway: Antipsychotic D2 blockade here blocks dopamine's tonic inhibition of prolactin, leading to hyperprolactinemia (galactorrhea, gynecomastia, sexual dysfunction).

Diagnostic Criteria and Timeline

According to the DSM-5-TR, a patient must present with two or more of the following symptoms for a significant portion of time during a 1-month period (active-phase), and continuous signs of the disturbance must persist for at least 6 months:

1. Delusions (fixed, false beliefs, e.g., persecutory, grandiose, ideas of reference).
2. Hallucinations (sensory perceptions without external stimuli; auditory is most common).
3. Disorganized speech (e.g., frequent derailment, loose associations, incoherence or 'word salad').
4. Grossly disorganized or catatonic behavior.
5. Negative symptoms.

At least one of the symptoms must be delusions, hallucinations, or disorganized speech.

PANCE Timeline Trap: The diagnosis of psychotic disorders is strictly tied to the duration of symptoms:

• Brief Psychotic Disorder: Symptoms last less than 1 month with a full return to premorbid functioning.
• Schizophreniform Disorder: Symptoms last between 1 and 6 months.
• Schizophrenia: Symptoms last greater than 6 months and cause significant social or occupational dysfunction.
• Schizoaffective Disorder: Characterized by an uninterrupted period of illness during which there is a major mood episode (depressive or manic) concurrent with symptoms of schizophrenia, alongside at least 2 weeks of delusions or hallucinations in the absence of a major mood episode.

Positive vs. Negative Symptoms

• Positive Symptoms (added behaviors): Delusions, hallucinations, disorganized speech, bizarre behavior.
• Negative Symptoms (subtracted behaviors - 'The A's'):
  • Flat Affect: Lack of emotional expression.
  • Avolition: Lack of motivation or goal-directed behavior.
  • Alogia: Poverty of speech.
  • Anhedonia: Inability to experience pleasure.
  • Asociality: Social withdrawal.

Antipsychotic Pharmacotherapy

Antipsychotics are divided into first-generation (typical) and second-generation (atypical) agents.

First-Generation Antipsychotics (FGAs)

Examples include Haloperidol, Fluphenazine, and Chlorpromazine.

• Mechanism: High-potency dopamine D2 receptor antagonists.
• Target: Highly effective against positive symptoms, but poor efficacy for negative symptoms.
• Adverse Effects: High rates of EPS, hyperprolactinemia, and QT prolongation. Chlorpromazine (low-potency) is associated with corneal deposits, while Thioridazine is associated with irreversible retinitis pigmentosa.

Second-Generation Antipsychotics (SGAs)

Examples include Risperidone, Olanzapine, Quetiapine, Aripiprazole, Ziprasidone, and Clozapine.

• Mechanism: Dopamine D2 and Serotonin (5-HT2A) receptor antagonists.
• Target: Treat both positive and negative symptoms with a lower risk of EPS.
• Adverse Effects: High risk of metabolic syndrome (dyslipidemia, weight gain, hyperglycemia). Olanzapine and clozapine carry the highest metabolic risk. Ziprasidone carries a high risk of QT prolongation but has minimal metabolic side effects. Aripiprazole is a D2 partial agonist and is weight-neutral. Risperidone is notorious for causing significant hyperprolactinemia.

Clozapine: A High-Yield Exception

Clozapine is the most effective antipsychotic but is reserved for treatment-resistant schizophrenia (failure of two prior trials of different antipsychotics) due to its severe side effects.

• Agranulocytosis: Clozapine can cause life-threatening neutropenia. Patients must be enrolled in the Clozapine REMS program, requiring regular Absolute Neutrophil Count (ANC) monitoring (weekly for the first 6 months, biweekly for the next 6 months, then monthly). Treatment must be interrupted if the ANC falls below 1,500/mcL.
• Other Adverse Effects: Severe myocarditis, cardiomyopathy, seizures (lowers seizure threshold), and sialorrhea (excessive drooling).

Antipsychotic-Induced Movement Disorders (EPS)

EPS results from dopamine D2 receptor blockade in the nigrostriatal pathway.

1. Acute Dystonia:
   • Timeline: Occurs within hours to days of initiation or dose escalation.
   • Presentation: Sudden, painful, involuntary muscle spasms, most commonly involving the neck (torticollis), eyes (oculogyric crisis), or tongue.
   • Management: Intravenous or intramuscular benztropine (anticholinergic) or diphenhydramine.
2. Akathisia:
   • Timeline: Occurs within days to weeks.
   • Presentation: Intense subjective feeling of motor restlessness. The patient is unable to sit still, paces constantly, and is highly distressed.
   • Management: Beta-blockers (Propranolol) are first-line. Benzodiazepines (lorazepam) or dose reduction can also be used.
3. Drug-Induced Parkinsonism:
   • Timeline: Occurs within weeks to months.
   • Presentation: Bradykinesia, rigidity (cogwheel), resting tremor, masked facies, and shuffling gait.
   • Management: Benztropine or amantadine (a dopamine agonist that does not worsen psychosis).
4. Tardive Dyskinesia (TD):
   • Timeline: Occurs after months to years of long-term use.
   • Presentation: Involuntary, choreoathetoid movements of the face, mouth, and tongue (lip-smacking, tongue protrusion, puckering), and sometimes extremities. Caused by D2 receptor upregulation and supersensitivity.
   • Management: Discontinue or reduce the dose of the current drug, or switch to a lower-risk atypical (clozapine or quetiapine). Valbenazine or deutetrabenazine (VMAT2 inhibitors) are FDA-approved treatments. Anticholinergics (benztropine) are contraindicated as they worsen tardive dyskinesia.

Neuroleptic Malignant Syndrome (NMS)

NMS is a life-threatening, idiosyncratic reaction to dopamine antagonists (mostly antipsychotics).

Clinical Presentation

Can be remembered with the mnemonic FEVER:

• Fever: Severe hyperthermia (often >104°F or 40°C).
• Encephalopathy: Altered mental status, delirium, agitation, stupor.
• Vitals unstable: Autonomic instability (tachycardia, tachypnea, labile blood pressure, diaphoresis).
• Elevated enzymes: Markedly elevated creatine kinase (CK) (often >10,000 U/L due to muscle breakdown), leukocytosis, and transaminases.
• Rigidity: Generalized, severe 'lead-pipe' muscle rigidity.

Management

1. Immediate Action: Discontinue the offending antipsychotic immediately.
2. Supportive Care: ICU admission, aggressive cooling (cooling blankets, ice packs), IV fluids (to maintain urine output and prevent acute kidney injury from rhabdomyolysis), and correction of electrolyte abnormalities.
3. Pharmacotherapy:
   • Dantrolene: A direct-acting skeletal muscle relaxant to reduce hyperthermia and rigidity.
   • Bromocriptine: A dopamine agonist to overcome the severe dopamine blockade.

Classic PANCE Traps & Clinical Pearls

• The Benztropine Tardive Dyskinesia Trap: A common PANCE trap presents a patient with chronic schizophrenia who has developed lip-smacking after 5 years on haloperidol. The question will ask for management. Adding benztropine is a trap; it will worsen tardive dyskinesia. The correct action is to taper the drug and switch to an atypical like clozapine or quetiapine, or start a VMAT2 inhibitor.
• NMS vs. Serotonin Syndrome Rigidity: Both cause hyperthermia and autonomic instability. However, NMS presents with 'lead-pipe' rigidity and bradyreflexia, whereas Serotonin Syndrome presents with hyperreflexia and clonus. Additionally, NMS is triggered by dopamine antagonists (antipsychotics), while Serotonin Syndrome is triggered by serotonergic agents (SSRIs, SNRIs).
• Clozapine Monitoring: ANC is the parameter to watch, not total white blood cell count (WBC), although WBC is related. The registry tracks ANC specifically. Agranulocytosis refers to a severe deficiency of granulocytes (neutrophils).