Atypical antipsychotics

• Definition

• Atypical antipsychotics, also known as second-generation antipsychotics (SGAs), are a pharmacological class primarily used to manage schizophrenia, bipolar disorder, and other mood or psychotic disorders

• They differ from first-generation (typical) antipsychotics by causing fewer extrapyramidal side effects and having broader effects on mood and cognition due to their combined dopamine and serotonin receptor activity

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• Mechanism of Action

• Antagonism of dopamine D₂ receptors in mesolimbic pathways reduces positive symptoms of psychosis

• Serotonin 5-HT₂A receptor antagonism modulates dopamine release in the nigrostriatal pathway, reducing risk of extrapyramidal symptoms and improving negative symptoms

• Additional activity on other receptors (5-HT₁A, 5-HT₂C, α₁-adrenergic, H₁ histaminergic, muscarinic cholinergic) contributes to therapeutic effects and side effect profiles

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• Common Agents

1. Clozapine – effective in treatment-resistant schizophrenia; reduces suicide risk but carries risk of agranulocytosis

2. Risperidone – treats schizophrenia, bipolar disorder, irritability in autism; higher doses may cause extrapyramidal symptoms

3. Olanzapine – effective in acute mania, bipolar maintenance, schizophrenia; associated with significant weight gain and metabolic effects

4. Quetiapine – used for schizophrenia, bipolar disorder, adjunct in major depression; sedating due to antihistamine activity

5. Aripiprazole – partial agonist at D₂ and 5-HT₁A; less sedation, lower metabolic risk; used in schizophrenia, bipolar disorder, depression augmentation

6. Ziprasidone – lower metabolic risk; prolongs QT interval; used in schizophrenia and bipolar mania

7. Paliperidone – active metabolite of risperidone; similar efficacy and side effects

8. Lurasidone – minimal metabolic effects; used in schizophrenia and bipolar depression

9. Asenapine – sublingual formulation; indicated for schizophrenia and bipolar disorder

10. Cariprazine – partial D₂/D₃ agonist; may improve negative symptoms in schizophrenia

11. Brexpiprazole – partial agonist similar to aripiprazole but with different receptor affinities

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• Therapeutic Uses

• Schizophrenia: acute and maintenance phases

• Bipolar disorder: acute mania, bipolar depression, maintenance

• Major depressive disorder: adjunct therapy (e.g., aripiprazole, quetiapine XR, brexpiprazole)

• Treatment-resistant schizophrenia (clozapine)

• Behavioral disturbances in dementia (off-label, with caution due to increased mortality risk)

• Irritability associated with autism (risperidone, aripiprazole)

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• Advantages Over Typical Antipsychotics

• Reduced risk of extrapyramidal side effects and tardive dyskinesia at therapeutic doses

• Better efficacy in treating negative symptoms of schizophrenia

• Some agents have mood-stabilizing and antidepressant properties

• Broader spectrum of efficacy across psychotic and mood disorders

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• Dosage Considerations

• Dosing varies widely between agents; individualization based on diagnosis, patient factors, and tolerability is essential

• Initiation often at low dose with gradual titration to minimize side effects

• Clozapine requires mandatory hematologic monitoring due to agranulocytosis risk

• Depot (long-acting injectable) formulations available for several agents (e.g., risperidone LAI, paliperidone palmitate, aripiprazole LAI, olanzapine pamoate) for adherence improvement

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• Contraindications

• Known hypersensitivity to the drug

• Severe CNS depression or coma

• Concomitant use with drugs causing significant QT prolongation (for ziprasidone)

• History of clozapine-induced agranulocytosis or myocarditis (for clozapine)

• Caution in dementia-related psychosis due to increased mortality risk

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• Adverse Effects

1. Metabolic

   • Weight gain, dyslipidemia, hyperglycemia, insulin resistance (most with olanzapine, clozapine)

2. Neurological

   • Extrapyramidal symptoms (less than FGAs; higher with risperidone, paliperidone)

   • Akathisia (common with aripiprazole, lurasidone, cariprazine)

   • Tardive dyskinesia (lower risk than FGAs but still possible)

3. Cardiovascular

   • Orthostatic hypotension (α₁-blockade)

   • QT prolongation (ziprasidone, iloperidone)

4. Endocrine

   • Hyperprolactinemia (especially risperidone, paliperidone)

5. Other

   • Sedation (quetiapine, clozapine, olanzapine)

   • Anticholinergic effects (clozapine, olanzapine)

   • Clozapine-specific: agranulocytosis, myocarditis, seizures

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• Precautions

• Baseline and periodic monitoring of weight, BMI, fasting glucose, lipid profile, blood pressure

• Regular CBC for clozapine per protocol

• ECG monitoring if QT prolongation risk is present

• Gradual tapering to avoid withdrawal symptoms and rebound psychosis

• Evaluate fall risk in elderly patients

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• Drug Interactions

• CYP450 metabolism:

  • Clozapine, olanzapine, quetiapine, asenapine – mainly CYP1A2, CYP3A4

  • Risperidone, paliperidone – CYP2D6, minimal hepatic metabolism for paliperidone

  • Aripiprazole, brexpiprazole, cariprazine – CYP3A4 and CYP2D6

• Strong inhibitors (e.g., ketoconazole, fluoxetine) may increase antipsychotic levels

• Inducers (e.g., carbamazepine, rifampicin, smoking with CYP1A2 substrates) may lower levels

• Additive sedation with CNS depressants

• Caution with antihypertensives (additive hypotension)

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• Monitoring Parameters

• Psychiatric symptoms and functional improvement

• Extrapyramidal symptoms and tardive dyskinesia

• Weight, waist circumference, metabolic labs at baseline, 3 months, then annually

• CBC for clozapine

• ECG when indicated

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• Resistance and Switching

• Treatment-resistant schizophrenia defined as inadequate response to at least two different antipsychotics; clozapine is drug of choice

• Cross-titration often used when switching to minimize withdrawal and symptom exacerbation

• Long-acting injectables considered in recurrent nonadherence