Antipsychotics

Undergraduate Pharmacology: Antipsychotics

Psychosis

  • Definition: A severe mental disturbance characterized by profound misinterpretation of perceptions or loss of contact with reality.

  • Consequences:

    • Leads to inappropriate ability to interact with others or the environment.

    • Psychotic features/symptoms are present in various disorders.

Psychotic Symptoms

  • Hallucinations: Sensory experiences in the absence of an external stimulus.

  • Delusions: Fixed, false beliefs that are not based on reality (e.g., persecutory, grandiose, thought broadcasting).

  • Disorganized Speech: Speech that is incoherent, illogical, or difficult to follow.

  • Disorganized or Catatonic Behavior: Includes repetitive movements, periods of immobility, and difficulty with coordinated movement.

Schizophrenia

  • Definition: A chronic and severe mental disorder that affects how a person thinks, feels, and behaves.

Epidemiology of Schizophrenia

  • Prevalence: Approximately 1% of the US population.

  • Onset: Typically occurs from late adolescence to early adulthood, often referred to as the "First Break."

  • Gender: Affects males and females equally.

  • Ethnicity: No significant ethnic differences in prevalence.

Course of Illness

  • Ideal Case:

    • Initial psychotic episode is quickly detected and treated, preventing further illness with prophylactic treatment.

  • Chronic Relapsing Case:

    • Chronic relapsing condition where each psychotic exposure decreases global function.

    • Symptoms can persist through various ages, with a graphic depiction of age progression.

Symptoms of Schizophrenia

  • Positive Symptoms: An excess or distortion of normal mental functioning.

  • Negative Symptoms: Something taken away from a patient’s normal presentation.

  • Cognitive Symptoms: Decreased cognitive functioning.

Positive Symptoms Defined

  • Hallucinations: Sensory experiences without external stimuli.

  • Delusions: Fixed beliefs that aren't based in reality.

    • Types include persecutory, grandiose, and thought broadcasting.

  • Disorganized Speech: Characterized by incoherence and illogical connections.

  • Grossly Disorganized or Catatonic Behavior: Involves unusual movements or postures, exhibiting extremes in activity levels (e.g., immobility or excessive movement).

Negative Symptoms Defined

  • Affective Flattening: Impaired outward display of emotions.

  • Alogia: Decrease in speech fluency and productivity.

  • Avolition: Lack of motivation or drive.

  • Anhedonia: Loss of interest or pleasure in previously enjoyed activities.

  • Asociality: Deficiency in social capacity and interaction.

Cognitive Symptoms Defined

  • Poor Concentration: Inability to focus attention effectively.

  • Memory Disturbances: Issues with retaining and recalling information.

  • Inability to Plan: Difficulty in strategizing or organizing tasks.

  • Difficulty Executing Tasks: Challenges in completing daily activities.

  • Poor Abstraction: Difficulty understanding complex concepts and ideas.

  • Impaired Decision Making: Suboptimal choices due to cognitive deficits.

Clinical Presentation

  • Prodromal Phase:

    • Symptoms may include withdrawal, odd beliefs, and peculiar behavior.

  • Acute Episode:

    • Characterized by the loss of touch with reality, exhibiting hallucinations, delusions, flat or inappropriate affect, and difficulty with self-care.

Diagnosis

  • Requirements: Presence of at least two of the following symptoms for a significant portion of at least one month:

    • Delusions

    • Hallucinations

    • Disorganized speech

    • Grossly disorganized or catatonic behavior

    • Negative symptoms

  • Social/Occupational Dysfunction: Symptoms must cause significant impairment in one or more areas of functioning (e.g., work, interpersonal relations, self-care).

  • Duration of Symptoms: Continuous signs of the disorder for at least 6 months, may include prodromal or residual symptoms.

Treatment Goals

  • Prevent Harm: Ensure the safety of the individual and others.

  • Prevent Side Effects: Manage and anticipate treatment implications.

  • Social Integration: Facilitate return to community function and improvement in social interactions.

  • Medication Adherence: Encourage patients to adhere to treatment plans.

  • Prevent Relapse: Utilize strategies to minimize recurrences of psychotic episodes.

  • Quality of Life Improvement: Enhance overall patient well-being.

Pathophysiology of Schizophrenia

  • Imbalance in Dopamine: Increased dopamine activity in certain brain regions leads to the manifestation of psychotic symptoms.

  • Role of other neurotransmitters: Other chemical messengers likely contribute to the pathophysiological processes.

Mechanism of Action of Antipsychotics

  • First Generation Antipsychotics (Typical): Primarily act by dopamine blockade.

  • Second Generation Antipsychotics (Atypical): Act through blockage of both dopamine and serotonin receptors.

Dopamine (D2) Receptor Blockade

  • Therapeutic Effect: Improves positive psychotic symptoms.

  • Adverse Events:

    • May worsen negative symptoms and cognitive functioning.

    • Risk of extrapyramidal movement disorders (EPS) and tardive dyskinesia (TD).

Dopamine and Serotonin Receptor Blockade

  • Therapeutic Effect:

    • Reduced risk of EPS and TD.

    • Possible improvement in negative symptoms and cognitive function.

  • Adverse Events:

    • Included sedation and weight gain.

Treatment of Schizophrenia

  • First Generation Antipsychotics (Typical):

    • Low Potency: Chlorpromazine (Thorazine®), Thioridazine (Mellaril®)

    • Mid Potency: Perphenazine (Trilafon®), Loxapine (Loxitane®)

    • High Potency: Haloperidol (Haldol®), Fluphenazine (Prolixin®)

Extrapyramidal Symptoms (EPS)

  • Types of EPS:

    • Dystonia: Sustained muscle contractions leading to twisting/repetitive movements or abnormal postures. Usually painful and may resemble tremors or seizures. Occurs typically within 24-96 hours after administration.

    • Treatments: Diphenhydramine, benztropine (Cogentin®), benzodiazepines.

    • Pseudoparkinsonism: Includes akinesia, bradykinesia, and attenuated speech; signified by resting tremors, cogwheel rigidity, and altered gait/posture. Usually resolves within weeks upon discontinuation, but 10-40% may have persistent symptoms.

    • Treatments: Benztropine (Cogentin®), Trihexyphenidyl (Artane®).

    • Akathisia: Characterized by a motor-restlessness feeling leading to pacing and foot tapping. Occurs in 20-30% of patients treated with typical antipsychotics.

    • Treatments: Beta-blockers, benzodiazepines.

EPS Treatment Strategies

  • Methods to mitigate EPS include:

    • Decreasing the antipsychotic dose.

    • Switching from high to low-potency typical antipsychotics.

    • Transitioning from typical to atypical antipsychotics.

    • Utilizing adjunctive medication.

Tardive Dyskinesia (TD)

  • Description: Involuntary movements usually occurring after long-term antipsychotic therapy, affecting areas like the face, tongue, lips, neck, and trunk. Early signs may be reversible, but if not detected early, the condition may become irreversible despite drug discontinuation.

  • Symptoms: May interfere with verbal communication, chewing, and swallowing.

  • Treatment:

    • Prevention is the most crucial intervention.

    • Implementing early detection strategies using the AIMS scale every 3-6 months.

    • Transition to atypical antipsychotic agents.

    • Use of valbenazine (Ingrezza) and deutetrabenazine (Austedi) may help manage symptoms while also decreasing presynaptic dopamine activity. Side effects may include sedation and dry mouth in over 5% of cases.

Atypical Antipsychotic (SGA)

  • Examples:

    • Clozapine (Clozaril®)

    • Olanzapine (Zyprexa®)

    • Risperidone (Risperdal®)

    • Quetiapine (Seroquel®)

    • Ziprasidone (Geodon®)

    • Aripiprazole (Abilify®)

    • Paliperidone (Invega®)

What is “Atypical”?

  • Characteristics:

    • Reduced risk for EPS compared to typical antipsychotics.

    • Reduced risk for TD.

    • May provide better outcomes for negative symptoms and cognitive function.

    • Increased risk of metabolic adverse drug reactions (ADRs).

Clozapine (Clozaril®)

  • Unique effectiveness for treating:

    • Persistent psychotic symptoms

    • Negative symptoms

    • Suicidality

  • Caution: 1-2% chance of developing agranulocytosis, necessitating blood monitoring weekly for the first 6 months, biweekly for the next 6 months, and monthly thereafter.

  • Use: Restricted to treatment-resistant patients.

Black Box Warning

  • Increased mortality in elderly patients with dementia receiving antipsychotics prescribed for behavioral disorders.

Antipsychotics Dosage Forms

  • Oral Medications:

    • Tablets or capsules, liquids, quick dissolving formats.

  • Injection Forms:

    • Short-acting and long-acting injections are available.

Time Course of Therapy

  • Timeline of expected improvements following antipsychotic therapy:

    • Decrease in agitation, hostility, aggression/anxiety within 1-7 days.

    • Normalization of sleep and appetite within 1-2 weeks.

    • Lasting improvement in residual symptoms and increases in socialization and mood observed over 3-6 weeks or longer.

    • Gradual reduction in fixed delusions and hallucinations over time.

Summary

  • Schizophrenia is a complex disease that presents significant implications for patients and their families.

  • Antipsychotics are considered the drug of choice (DOC) for managing this disorder.

  • Typical antipsychotics are effective in decreasing positive symptoms but can lead to movement disorders.

  • Atypical antipsychotics present less risk for EPS but carry a heightened risk for serious metabolic effects.