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Antipsychotics

Overview

  • Presented by: Kavindinie Dias, B. Pharm (Hons), USJ

Psychotic Disorders

  • Definition: A mental state that is out of touch with reality, encompassing various abnormalities in perception, thought, and ideas.

  • Types of Psychotic Illnesses:

    • Schizophrenia

    • Schizoaffective disorder

    • Delusional disorders

    • Some depressive and manic illnesses

Schizophrenia

Symptoms

  • Positive Symptoms: Represent an excess or distortion of normal functions.

    • Delusions: Strongly held false beliefs.

    • Hallucinations: Sensing things that aren't present.

      • Types of Hallucinations:

      • Visual

      • Auditory

    • Disorganized speech: Incoherent or nonsensical speech patterns.

    • Agitated or repetitive movements.

  • Negative Symptoms: Indicate a reduction or loss of normal functions.

    • Flattened affect: Lack of emotional expressiveness, characterized by monotonous, almost robotic speech.

    • Anhedonia: Patients experience no pleasure from activities typically found enjoyable.

    • Extreme isolation: Reflects severe withdrawal from social interactions.

    • Resembles clinical depression.

Dopamine Synthesis

Overview

  • Tyrosine (TYR): A precursor to dopamine taken up into dopamine nerve terminals via a tyrosine transporter.

    • Conversion Process:

    • Tyrosine hydroxylase (TOH) converts TYR into DOPA.

    • DOPA decarboxylase (DDC) further converts DOPA into Dopamine (DA).

  • Storage and Release:

    • After synthesis, dopamine is packaged into synaptic vesicles via the vesicular monoamine transporter (VMAT) until released during neurotransmission.

Dopamine Pathways in the Brain

  • There are five primary dopamine pathways:

    1. Mesolimbic dopamine pathway

    2. Mesocortical dopamine pathway

    3. Nigrostriatal dopamine pathway

    4. Tubero-infundibular dopamine pathway

    5. Thalamic dopamine pathway

Key Dopamine Pathways and Brain Regions

  • Key Regions:

    • Thalamus

    • Substantia nigra

    • Dorsolateral prefrontal cortex (DLPFC)

    • Striatum

    • Nucleus accumbens

    • Tegmentum

    • Pituitary

    • Hypothalamus

    • Ventromedial prefrontal cortex (VMPFC)

Mesolimbic Dopamine Hypothesis

  • Suggests hyperactivity of dopamine neurons in the mesolimbic dopamine pathway mediates positive symptoms of psychosis such as delusions and hallucinations.

  • Also involved in pleasure, reward, and reinforcing behavior; interactions with several drugs of abuse occur here.

Mesocortical Dopamine Pathway

  • Projects from the ventral tegmental area (VTA) to the prefrontal cortex.

  • Involved in negative and cognitive symptoms of schizophrenia.

Dopamine Pathways Summary

  • Mesolimbic Pathway: Increased dopamine correlates with positive symptoms.

  • Mesocortical Pathway: Decreased dopamine relates to negative and cognitive symptoms.

  • Nigrostriatal Pathway: Blockade leads to extrapyramidal side effects.

  • Tubero-infundibular Pathway: Blockade can result in hyperprolactinemia.

Side Effects Associated with Dopamine Pathway Blocking

Nigrostriatal Pathway Blockade

  • Results in Extrapyramidal Symptoms (EPS):

    • Dopamine usually suppresses acetylcholine; with dopamine blocked, there is excessive acetylcholine.

    • Symptoms include:

    • Acute dystonia

    • Akathesia

    • Parkinsonism

    • Tardive dyskinesia due to supersensitivity of D2 receptors.

Tubero-infundibular Pathway Blockade

  • Can lead to Hyperprolactinemia: Elevated levels of prolactin due to dopamine inhibition.

Treatment of Schizophrenia

Antipsychotic Medication Classes

  1. First-Generation Antipsychotics (Typical):

    • Examples: Chlorpromazine, Haloperidol

  2. Second-Generation Antipsychotics (Atypical):

    • Examples: Clozapine, risperidone, olanzapine, quetiapine, amisulpride

Indications for Antipsychotics

  • Treatment for:

    • Hallucinations

    • Delusions

    • Agitation

  • It helps manage psychomotor excitement due to psychosis and prevent recurrences of symptoms.

Brief Psychotic Disorder Symptoms

  • Symptoms including sudden onset of:

    • Delusions

    • Hallucinations

    • Disorganized thinking

    • Functional impairments without a clear cause.

Conventional Antipsychotics

  • Mechanism: Competitive blocking of dopamine D2 receptors.

  • Associated with movement disorders, particularly with drugs that tightly bind to dopaminergic receptors like haloperidol.

  • Less likely to cause movement disorders with medications like chlorpromazine, which binds weakly.

Extrapyramidal Symptoms (EPS) / Parkinsonism

  • Characteristics:

    • Mask-like facies, tremors, rigidity, and changes in gait.

    • Occur in up to 90% of patients taking conventional neuroleptic medications if D2 receptor occupancy exceeds 70%.

  • Treatment Approaches:

    1. Anticholinergic drugs

    2. Reducing drug dosage

    3. Switching to an atypical antipsychotic

Tardive Dyskinesia (TD)

  • A late-appearing syndrome characterized by:

    • Involuntary, repetitive body movements:

    • Orofacial dyskinesia, lip smacking, tongue movements.

    • Appears after months or years of treatment.

  • Increased risk factors:

    • Elderly patients

    • Female patients (especially post-menopausal)

    • Those with organic brain damage or affective disorders.

  • Occurrence may lead to a risk when treatment is intermittently stopped.

Neuroleptic Malignant Syndrome (NMS)

  • An uncommon but severe reaction to neuroleptics; exact mechanism is unclear.

  • Incidence is between 0.5% to 1% of patients.

  • Risk may increase with combined use of lithium and antipsychotics.

Second-Generation Antipsychotics (Atypical)

  • Generally exhibit less Extrapyramidal Side Effects (EPSE) and hyperprolactinemia.

Mechanistic Insights

  • 5HT2A Receptors:

    • Located on cortical neurons, they are excitatory and enhance downstream glutamate release.

    • Control dopamine release in the striatum; antagonism at these receptors leads to increased dopamine release, resulting in reduced EPSE.

Examples of Second-Generation Antipsychotics

  • Dibenzodiazepines: Clozapine, Olanzapine

  • Dibenzothiazepines: Quetiapine

  • Substituted Benzamides: Amisulpiride, Risperidone

  • Benzisoxazole: Sulpiride

Clozapine Pharmacological Properties

  • Low affinity for D2 receptors; higher affinity for D1, D4 receptors.

  • Potency of action observed at:

    • 5-HT2

    • D4

    • D1

    • Muscarinic

    • α-adrenergic receptors.

Clozapine Side Effects

  • Common side effects include:

    • Hypersalivation

    • Weight gain

    • Tachycardia

    • Hypotension

    • Sedation (most common)

    • Neutropenia: occurs in 1 in 43 patients necessitating blood monitoring.

Clozapine's Efficacy

  • Notably superior for treating negative symptoms.

  • Recommended for patients unresponsive to at least two other conventional antipsychotics or those experiencing TD or severe EPS.

Olanzapine Pharmacological Properties

  • Structurally similar to Clozapine with:

    • Higher affinity for D2 and 5-HT2A receptors.

    • Lower affinity at D1 receptor compared to Clozapine.

Olanzapine's Efficacy

  • As effective as Haloperidol for treating positive symptoms.

  • Suggested superiority in treating negative symptoms (based on some evidence).

Olanzapine Side Effects

  • EPS incidence is no greater than placebo.

  • Common side effects:

    • Sedation

    • Significant weight gain

Quetiapine Properties

  • Binding profile similar to Clozapine with lower affinities across all receptors.

  • Tends to target cortical receptors instead of basal ganglia.

Quetiapine Side Effects

  • EPS incidence no greater than placebo across the dose range.

  • Common side effects include:

    • Somnolence

    • Dry mouth

    • Less weight gain propensity compared to Clozapine and Olanzapine.

Risperidone Efficacy

  • Effectiveness on par with conventional antipsychotics for overall symptom reduction.

  • Equally effective as Clozapine for positive symptoms in patients intolerant to typical drugs.

  • Demonstrates greater response for negative symptoms than conventional treatment.

Risperidone Side Effects

  • EPS incidence comparable to placebo.

  • Increased EPS risk at higher doses (> 8 mg).

  • Dose-related hyperprolactinaemia and related sexual side effects may arise, along with insomnia, headaches, anxiety, and weight gain.

Amisulpride Pharmacological Properties

  • Acts as a D2/D3 antagonist.

  • At low doses, blocks autoreceptors, enhancing synaptic dopamine levels, potentially improving negative symptoms.

Amisulpride Efficacy

  • Comparable effectiveness to conventional drugs for positive symptoms.

  • No additional benefits for negative symptoms at low doses when compared to Haloperidol.

Amisulpride Side Effects

  • Placebo-level EPS at low doses.

  • Increased EPS risk at higher doses, still less than conventional antipsychotics.

  • Prolactin levels elevated similarly to conventional drugs.

Long-Acting Injectable Preparations

  • Examples:

    • Haloperidol

    • Fluphenazine

    • Flupentixol

    • Clopixol

    • Risperidone

    • Paliperidone

    • Olanzapine

Conclusion

  • Thank you!