What are the adverse effects of atypical antipsychotics?

Adverse Effects of Atypical Antipsychotics

Atypical antipsychotics cause significant metabolic disturbances (weight gain, hyperglycemia, dyslipidemia), neurological complications (extrapyramidal symptoms, tardive dyskinesia, neuroleptic malignant syndrome), cardiovascular effects (QT prolongation, orthostatic hypotension), and hematological risks (agranulocytosis with clozapine), with metabolic effects being the most common and clinically significant problem in practice. 1, 2

Metabolic Adverse Effects

Weight gain represents the most common significant problem associated with atypical antipsychotic use and may be extreme. 1 The metabolic changes include:

• Hyperglycemia and diabetes mellitus: Monitor all patients for symptoms including polydipsia, polyuria, polyphagia, and weakness; patients with diabetes risk factors require baseline and ongoing blood glucose testing. 2

• Dyslipidemia: Undesirable alterations in lipid profiles have been observed, with elevated cholesterol and triglyceride levels documented. 2, 3

• Weight gain: Requires regular monitoring throughout treatment, with average weight gain of 12% documented in some studies. 2, 3

• Drug-specific metabolic risk: Olanzapine and clozapine carry the highest risk of metabolic syndrome, quetiapine and risperidone cause moderate alterations, while ziprasidone, lurasidone, and aripiprazole appear more metabolically tolerable. 4

Neurological Adverse Effects

Extrapyramidal Symptoms

Atypical antipsychotics cause fewer extrapyramidal side effects than typical antipsychotics, though risperidone carries the highest risk among atypicals. 1, 5

• Acute dystonia: Involuntary motor tics or spasms involving face, extraocular muscles (oculogyric crisis), neck, back, and limb muscles, typically occurring after first few doses or dose increases. 1

• Laryngeal dystonia: Rare but life-threatening, presenting as choking sensation, difficulty breathing, or stridor. 1

• Akathisia: Subjective feeling of restlessness, generally occurring within first few days of therapy. 1

• Drug-induced Parkinsonism: Early diagnosis and rapid withdrawal may improve possibility of complete recovery. 1

Tardive Dyskinesia

Tardive dyskinesia occurs in 5% of young patients per year and is more common with typical antipsychotics, though it can occur with any atypical agent. 1

• Characterized by rapid involuntary facial movements (blinking, grimacing, chewing, tongue movements) and extremity or truncal movements. 1

• Respiratory dyskinesia is often undiagnosed, can lead to recurrent aspiration pneumonia, and includes orofacial dyskinesia, dysphonia, dyspnea, and respiratory alkalosis. 1

• Monitor using the Abnormal Involuntary Movement Scale (AIMS) at least every 3 to 6 months after starting therapy. 6

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome is a potentially lethal syndrome consisting of mental status changes, fever, hypertonicity or rigidity, and autonomic dysfunction, with incidence ranging from 0.02% to 3% and mortality decreased to less than 10-15%. 1

• Caused by dopamine D2 receptor antagonism affecting hypothalamus (fever, loss of heat-dissipating mechanisms), nigrostriatal pathways (muscle rigidity, tremor), and peripheral calcium release (increased contractility, heat production, muscle breakdown). 1

• Manage with immediate discontinuation of drug and close monitoring. 2

• Risk factors include coadministration of psychotropic agents (present in over half of cases), dehydration, physical exhaustion, preexisting organic brain disease, and long-acting depot antipsychotics. 1

Seizures

Antipsychotic medications lower the seizure threshold in a dose-dependent manner, though seizures are rare (usually <1%) at therapeutic doses, except for clozapine which has a 5% incidence at high dosages. 1

Cardiovascular Adverse Effects

QT interval prolongation is a significant concern, particularly with ziprasidone, and should be avoided in patients with bradycardia, hypokalemia, hypomagnesemia, congenital QT prolongation, or when combined with other QT-prolonging drugs. 2

• Orthostatic hypotension: Common side effect requiring caution in patients with known cardiovascular or cerebrovascular disease. 1, 6, 2

• Contraindications: Do not use in patients with recent acute myocardial infarction or uncompensated heart failure. 2

• Minor electrocardiogram changes have been associated with atypical antipsychotics, raising concerns as youth may be more susceptible to cardiac effects. 1

Hematological Adverse Effects

Agranulocytosis is a potential adverse effect primarily associated with clozapine, though it can occur with any antipsychotic agent. 1

Clozapine-Specific Monitoring

• Weekly blood cell counts during first 6 months, then every 2 weeks thereafter, including 4 weeks after discontinuation. 1

• Stop immediately if WBC drops below 2,000/mm³ or absolute neutrophil count (ANC) drops below 1,000/mm³, with daily monitoring for infection. 1

• Stop immediately if WBC drops to 2,000-3,000/mm³ or ANC drops to 1,000-1,500/mm³; may resume when WBC >3,000 or ANC >1,500 without signs of infection. 1

• Biweekly monitoring if WBC between 3,000-3,500/mm³ or drops 3,000/mm³ over 1-3 weeks until WBC >3,500/mm³. 1

Leukopenia and neutropenia: Patients with pre-existing low WBC or history of leukopenia/neutropenia require frequent CBC monitoring during first few months and should discontinue at first sign of WBC decline without other causative factors. 2

Severe Cutaneous Adverse Reactions

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Stevens-Johnson syndrome have been reported with ziprasidone exposure and are sometimes fatal; discontinue immediately if suspected. 2

• Discontinue in patients who develop a rash without an identified cause. 2

Other Common Adverse Effects

• Somnolence, anxiety, agitation, oral hypoesthesia, headache, nausea, vomiting, insomnia, and tremor are documented adverse effects. 1

• Cognitive effects: Atypical antipsychotics show consistent benefits in fine motor function, memory, and executive function compared to typical antipsychotics, causing fewer cognitive difficulties. 1, 6

• Potential for cognitive and motor impairment: Patients should use caution when operating machinery. 2

Critical Monitoring Considerations

Regular clinical monitoring is essential to identify potential changes early, including baseline and follow-up laboratory tests (renal and liver function, complete blood counts, electrocardiograms) as indicated for specific agents. 1, 6

• Document any preexisting abnormal movements before initiating treatment to avoid later mislabeling them as medication side effects. 1

• Monitor for neurological side effects, especially extrapyramidal symptoms and tardive dyskinesia, particularly with long-term use. 6