Antipsychotic Drugs and Psychosis

Jun 27, 2024

Antipsychotic Drugs and Psychosis

Introduction to Psychosis

  • Psychosis
    • Severe mental disturbances with loss of contact with reality.
    • Common in schizophrenia.
    • Other conditions with loss of reality: severe mood disorders, drug toxicity, CNS stimulant overdose.
  • Neurosis
    • Milder mental disorders where contact with reality is intact (e.g., anxiety, OCD, phobias).

Schizophrenia

  • Symptoms
    • Positive Symptoms: Hallucinations, delusions, disorganized speech, bizarre behavior.
    • Negative Symptoms: Social withdrawal, lack of motivation, flattened emotions, anhedonia, inappropriate affect.
    • Other Issues: Thought disturbances, mood abnormalities, and motor dysfunctions such as catatonia.

Biological Basis

  • Dopamine Hypothesis
    • Excessive dopaminergic activity in mesolimbic pathway → Positive symptoms.
    • Reduced dopaminergic activity in mesocortical pathway → Negative symptoms.
    • Balancing dopaminergic pathways important for normal functioning.

Antipsychotic Drugs

  • Types
    • Typical (Classical) Antipsychotics: Strong D2 receptor blockers, effective on positive symptoms, many extrapyramidal side effects (EPS).
    • Atypical (Modern) Antipsychotics: Block serotonin and some dopamine receptors, effective on both positive and negative symptoms, fewer EPS.
  • Mechanism of Action
    • Typical → Block D2 receptors strongly, affecting multiple dopamine pathways.
    • Atypical → Weaker and transient D2 blockade, more serotoninergic activity.

Side Effects

  • Extrapyramidal Side Effects (EPS)
    • Acute dystonia, Parkinson-like symptoms, akathisia, tardive dyskinesia.
    • Typical antipsychotics have a strong association with EPS.
    • Atypical antipsychotics generally have fewer EPS.
  • Neuroleptic Malignant Syndrome (NMS)
    • Life-threatening, rare, high fever, muscle rigidity, myoglobinuria, autonomic instability.
    • Stops drug, give dantrolene, dopamine agonists.
  • Other Side Effects
    • Hyperprolactinemia → Amenorrhea, galactorrhea, gynecomastia, infertility.
    • Sedation, weight gain (more common in atypicals).
    • Anticholinergic effects → Dry mouth, constipation, urinary retention, blurred vision.
    • Orthostatic hypotension (alpha-adrenergic blockade).
    • Prolonged QT interval and risk of arrhythmias.

Typical Antipsychotics

  • Phenothiazines
    • Aliphatic: Chlorpromazine.
    • Piperidine: Thioridazine (strong anticholinergic, less EPS).
    • Piperazine: Fluphenazine (Depot form).
  • Thioxanthenes
    • Thiothixene.
  • Butyrophenones
    • Haloperidol (potent, high EPS, Depot form).

Atypical Antipsychotics

  • Clozapine
    • Risk of agranulocytosis, monitor blood counts.
  • Olanzapine
    • Antipsychotic, anti-anxiety, anti-manic, effective in OCD.
  • Others
    • Quetiapine, Risperidone, Ziprasidone (Prolongs QT interval), Aripiprazole (partial agonist on D2 and 5-HT2 receptors).

Uses of Antipsychotic Drugs

  • Schizophrenia, schizoaffective disorders.
  • Severe mood disorders with psychosis.
  • Toxic psychosis, intractable hiccups, severe nausea/vomiting.
  • Tourette's syndrome, neuroleptic anesthesia.
  • Off-label for conditions like severe pruritus.

Pharmacokinetics

  • Highly lipid soluble → Good oral absorption, significant first-pass effect.
  • Crosses blood-brain barrier, placental barrier.
  • Metabolized in the liver, excreted in urine/feces.