Antipsychotic Drugs

Chapter Overview

• The Nature of Schizophrenia

• The Neurobiological Basis of Schizophrenia

• Antipsychotic Medications: Neurophysiology

• Pharmacokinetics of Antipsychotic Medications

• Effects of Antipsychotic Medications

• Tolerance; Withdrawal

Schizophrenia

• A psychiatric diagnosis affecting up to 1% of the population.

• Common manifestations include:

  • Hallucinations

  • Delusions

  • Disorganized speech and thinking

• Symptoms are categorized into three types:

  1. Positive Symptoms: Overt symptoms present that should not be, including:

  • Hallucinations

  • Delusions

  • Disorganized thoughts

  1. Negative Symptoms: Lack of characteristics that should be present, including:

  • Reduced speech (alogia), even when encouraged.

  • Lack of emotional and facial expression (affective flattening).

  • Diminished ability to begin and sustain activities (avolition).

  • Decreased ability to find pleasure in everyday activities (anhedonia).

  • Social withdrawal (asociality).

  1. Cognitive Deficits: Deficits impacting daily functioning, including:

  • Memory

  • Attention

  • Planning and decision-making

• While the underlying causes of schizophrenia are complex, it is agreed that symptoms arise partially from dysfunction in the mesocortico-limbic system:

  • Increased dopamine (DA) activity in the mesolimbic pathway is thought to contribute to positive symptoms.

  • Reduced DA functioning within the prefrontal cortex is believed responsible for negative symptoms and cognitive impairments.

The Diagnostic and Statistical Manual of Mental Disorders (DSM)

• The DSM serves as the authoritative guide for diagnosing mental disorders globally.

• Includes:

  • Descriptions

  • Symptoms

  • Diagnostic criteria for various mental disorders.

Schizophrenia’s Complex Neurobiological Profile

• Schizophrenia results from neurodevelopmental aberrations beginning long before clinical symptoms manifest, influenced by both environmental and genetic factors.

Neurobiological Basis of Schizophrenia

Dopamine Hypothesis of Schizophrenia

• Positive symptoms are thought to result from excessive dopamine release. Evidence includes:

  • Amphetamines can induce psychotic symptoms.

  • Antipsychotic drugs function as antagonists at D₂ receptors.

• However, the hypothesis does not account for negative or cognitive symptoms.

Dopamine/Glutamate Hypothesis of Schizophrenia

• Suggests diminished glutamate levels throughout the cerebral cortex may contribute to schizophrenia symptoms.

• Evidence includes:

  • Ketamine and phencyclidine lead to behaviors consistent with both positive and negative symptoms, as well as cognitive impairment.

• Diminished glutamate could explain both reduced dopamine in the prefrontal cortex and increased dopamine in the limbic system.

Discovery of Antipsychotic Medications

• The development of antipsychotic drugs stemmed from serendipity in the 1950s, initiated by Henri Laborit testing antihistamines.

• Chlorpromazine emerged as a key drug, which demonstrated dramatic effects in patients, allowing for the reduction of general anesthesia dosage during procedures.

• An important consequence was a significant decrease in the patient population within mental institutions, dropping by 80% in three decades.

Antipsychotic Medications: Neurophysiology

First Generation Antipsychotic Drugs: Typical Antipsychotic Drugs

• Also known as classical or neuroleptic antipsychotics.

• Main representatives include:

  • Phenothiazines (e.g., chlorpromazine marketed as Thorazine)

  • Butyrophenones (e.g., haloperidol marketed as Haldol)

• Mechanism:

  • Primarily function as D₂ receptor blockers.

  • Most effective for treating positive symptoms but 1/3 of patients see no improvement.

  • Side effects often include extrapyramidal symptoms (EPS), tremors, rigidity, involuntary movements.

Second Generation Antipsychotic Drugs: Atypical Antipsychotic Drugs

• Known as novel antipsychotics (e.g., olanzapine marketed as Zyprexa, risperidone marketed as Risperdal, clozapine marketed as Clozaril).

• Mechanism:

  • Weak affinity for D₂ receptors but high for D₃ and D₄ receptors.

  • Additionally antagonize serotonin 5HT₂A receptors.

Third Generation Antipsychotic Drugs

• Only one approved drug: Aripiprazole (marketed as Abilify).

• Function as a partial agonist at D₂ receptors, meaning they bind to receptors but create a lesser response than the natural neurotransmitter.

Pharmacokinetics of Antipsychotic Medications

Administration Forms for Antipsychotic Drugs

• Available primarily in pill form; patient compliance influences the exploration of alternative routes.

Pharmacokinetics: Absorption

• Generally, these drugs are readily absorbed from the digestive system with varying peak plasma concentrations.

Pharmacokinetics: Distribution

• Drugs can easily cross the blood-brain barrier (BBB).

• Significant blood protein binding occurs, and absorption into body fat can lead to slow release.

Pharmacokinetics: Metabolism/Excretion

• They undergo extensive metabolism primarily via cytochrome P450 enzymes before excretion.

• Individual variability influences both metabolism and necessary blood concentration levels; thus, finding optimal dosage can be trial-and-error.

• Half-life Details:

  • Typical antipsychotics: ≈ 24 hours; steady-state levels in 3-5 days.

  • Atypical antipsychotics: Varies widely (7-30 hours); typically stable after five days.

  • Abilify: 75 hours; about 14 days to stable state.

Effects of Antipsychotic Medications

Comparison of Typical vs. Atypical Antipsychotic Drug Effects

Adverse Effects of First Generation Antipsychotic Drugs

• May lead to:

  • Tardive Dyskinesia: A motor disorder affecting facial muscles.

  • Neuroleptic Malignant Syndrome (NMS): Flu-like symptoms, blood pressure changes, autonomic irregularities.

  • Hyperprolactinemia: High blood levels of prolactin due to dopamine inhibition at the pituitary.

Adverse Effects of Second Generation Antipsychotic Drugs

• Require monitoring for:

  • Significant weight gain and risk of type II diabetes.

  • QT interval prolongation: A change in heartbeat rhythm, leading to irregular heart signals.

  • Agranulocytosis: Low white blood cell counts, increasing infection risk.

Tolerance and Withdrawal

Tolerance

• Maintenance of therapeutic dosage is common without decreased effectiveness.

• Tolerance usually develops to sedating effects and extrapyramidal symptoms.

Withdrawal

• Physical dependence, if it occurs, is rare or mild.