4.3 Psychotic Disorders & Schizophrenia Spectrum

Pathophysiology & Dopaminergic Pathways of Psychosis

Psychotic spectrum disorders are characterized by abnormalities in one or more of five domains: delusions, hallucinations, disorganized thinking (speech), grossly disorganized or abnormal motor behavior (including catatonia), and negative symptoms. Neurochemically, psychosis is primarily linked to alterations in brain dopaminergic pathways.

Dopamine Pathway Physiology & Neuropharmacological Effects

• Mesolimbic Pathway: Hyperactivity of dopamine transmission in this pathway causes positive symptoms (hallucinations, delusions, thought disorganization). Antipsychotics block D2 receptors here to reduce positive symptoms.
• Mesocortical Pathway: Hypofunction of dopamine transmission causes negative symptoms (flat affect, avolition, alogia, asociality) and cognitive deficits. D2 blockade can potentially worsen negative symptoms.
• Nigrostriatal Pathway: Part of the extrapyramidal motor system. D2 blockade leads to Extrapyramidal Symptoms (EPS), including acute dystonia, akathisia, parkinsonism, and tardive dyskinesia.
• Tuberoinfundibular Pathway: Dopamine tonically inhibits prolactin release from the anterior pituitary. D2 blockade disinhibits prolactin, causing hyperprolactinemia (galactorrhea, amenorrhea, gynecomastia, sexual dysfunction, bone mineral density loss).

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Diagnostic Criteria for Schizophrenia Spectrum Disorders

To diagnose Schizophrenia, DSM-5 requires:

1. ≥2 Active-Phase Symptoms present for a significant portion of time during a 1-month period (or less if successfully treated). At least one of these symptoms must be item 1, 2, or 3:
   • Delusions
   • Hallucinations (most commonly auditory)
   • Disorganized speech (e.g., frequent derailment or incoherence)
   • Grossly disorganized or catatonic behavior
   • Negative symptoms (diminished emotional expression or avolition)
2. Duration: Continuous signs of the disturbance must persist for at least 6 months. This 6-month period must include at least 1 month of active-phase symptoms and may include prodromal or residual periods.
3. Functional Impairment: Marked decline in work, interpersonal relations, or self-care relative to the level achieved prior to onset.

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Time-Based Diagnostic Algorithm for Psychotic Spectrum Disorders

Time-Based Diagnostic Flowchart for Psychosis:
1. Determine total duration of psychotic symptoms (delusions, hallucinations, disorganized speech/behavior):
   - Duration <1 month with eventual full return to premorbid baseline -> Brief Psychotic Disorder.
   - Duration 1 month to 6 months -> Schizophreniform Disorder.
   - Duration >6 months (including prodromal, active phase ≥1 month, and residual phases) -> Schizophrenia.
2. Determine relationship between mood episodes (major depressive or manic) and psychotic symptoms:
   - Psychotic symptoms occur EXCLUSIVELY during mood episodes -> Major Depressive or Bipolar Disorder with Psychotic Features.
   - Psychotic symptoms present for ≥2 consecutive weeks in the ABSENCE of major mood episodes, but mood episodes are present for majority of total illness duration -> Schizoaffective Disorder.
3. Isolated non-bizarre or bizarre delusions for ≥1 month without other active schizophrenia symptoms -> Delusional Disorder.

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Differential Diagnosis of Psychotic & Affective Disorders

Distinguishing psychotic disorders relies heavily on symptom timeline and mood symptom integration.

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Antipsychotic Pharmacology & Adverse Effect Profiles

First-Generation (Typical) vs. Second-Generation (Atypical) Antipsychotics

• First-Generation Antipsychotics (FGAs) (e.g., Haloperidol, Fluphenazine, Chlorpromazine): Potent D2 receptor antagonists. Highly effective for positive symptoms but carry significant risk of extrapyramidal side effects and tardive dyskinesia.
• Second-Generation Antipsychotics (SGAs) (e.g., Olanzapine, Risperidone, Quetiapine, Aripiprazole, Clozapine): Dual 5-HT2A and D2 receptor antagonists. Serotonin blockade in the nigrostriatal pathway increases dopamine release, decreasing EPS risk. SGAs are first-line for schizophrenia, but carry variable risks for metabolic syndrome.

Clozapine Protocol & Refractory Schizophrenia

Clozapine is the most effective antipsychotic for schizophrenia. It is indicated for treatment-resistant schizophrenia (defined as failing ≥2 adequate trials of different antipsychotics, including at least one SGA) and for reducing suicidal behavior in schizophrenia. Major risks include:

1. Agranulocytosis: Potentially fatal neutropenia occurring in ~1% of patients. Mandatory blood monitoring of Absolute Neutrophil Count (ANC) is required: weekly for the first 6 months, biweekly for months 6–12, and monthly thereafter. Clozapine must be stopped if ANC drops below 1,000/mm³ (or <500/mm³ in benign ethnic neutropenia).
2. Seizures: Dose-dependent reduction in seizure threshold.
3. Myocarditis & Cardiomyopathy: Requires baseline ECG and monitoring of troponin/ESR if cardiac symptoms arise.
4. Severe Constipation / Paralytic Ileus: Due to potent anticholinergic activity.

Neurologic & Endocrine Complications of Antipsychotics

• Acute Dystonia: Sudden, painful muscle contractions (e.g., torticollis, oculogyric crisis, opisthotonos) occurring hours to days after starting FGAs. Treatment: Intravenous or intramuscular Benztropine or Diphenhydramine.
• Akathisia: Subjective feeling of inner restlessness and inability to sit still, occurring days to weeks after initiation. Treatment: Beta-blockers (Propranolol) (first-line), Lorazepam, or dose reduction.
• Parkinsonism: Bradykinesia, resting tremor, cogwheel rigidity occurring weeks to months after starting antipsychotics. Treatment: Benztropine or Amantadine.
• Tardive Dyskinesia (TD): Involuntary choreoathetoid movements of the face, tongue, lips (orofacial dyskinesia), or extremities resulting from prolonged D2 blockade and receptor up-regulation (>6 months). Treatment: Discontinue FGA or switch to Clozapine/Quetiapine; administer VMAT2 inhibitors (Valbenazine, Deutetrabenazine). Anticholinergic drugs may worsen TD.
• Neuroleptic Malignant Syndrome (NMS): Life-threatening hyperthermia, "lead-pipe" muscle rigidity, altered mental status, autonomic instability, and elevated serum creatine kinase (CK) and rhabdomyolysis. Treatment: Immediate drug withdrawal, aggressive cooling, IV fluids, and Dantrolene or Bromocriptine.