What are the side effects of antipsychotic medications?

Side Effects of Antipsychotic Medications

Antipsychotic medications cause a wide range of adverse effects that vary significantly between typical (first-generation) and atypical (second-generation) agents, with typical antipsychotics carrying substantially higher risk of movement disorders while atypical agents more commonly cause metabolic complications. 1, 2

Neurological and Movement Disorders

Extrapyramidal Symptoms (EPS)

The most distinguishing feature between typical and atypical antipsychotics is their propensity to cause extrapyramidal side effects, which occur far more frequently with typical agents like haloperidol and prochlorperazine 2, 3:

• Acute dystonia involves sudden spastic muscle contractions affecting the neck, eyes, or torso, with young males at highest risk 1, 4, 5
• Laryngospasm represents a potentially life-threatening dystonic reaction requiring immediate intervention 4
• Parkinsonism manifests as bradykinesia, tremors, mask-like facies, drooling, and shuffling gait, which can be difficult to distinguish from negative symptoms of psychosis 4, 5
• Akathisia (severe restlessness) occurs in 44% of patients receiving IV prochlorperazine within one hour 4
• These symptoms are dose-related and occur more frequently with high-potency typical antipsychotics 5

Tardive Dyskinesia

• Tardive dyskinesia develops in approximately 5% of young patients per year on typical antipsychotics, characterized by involuntary facial movements and extremity/truncal movements 4
• The syndrome can appear after relatively brief treatment periods at low doses and may be irreversible even after drug discontinuation 5
• Typical antipsychotics carry substantially higher risk compared to atypical agents 2, 6
• Regular assessment should occur at least every 3-6 months using standardized measures like the Abnormal Involuntary Movement Scale 4
• Fine vermicular tongue movements may be an early warning sign 5

Neuroleptic Malignant Syndrome (NMS)

• NMS is a potentially lethal syndrome consisting of mental status changes, fever, muscle rigidity, and autonomic dysfunction 4, 5
• Mortality has decreased from 76% in the 1960s to less than 10-15% currently 4
• Risk factors include dehydration, physical exhaustion, preexisting brain disease, and concomitant psychotropic medications 4
• Immediate discontinuation of the antipsychotic and intensive supportive care are mandatory 5

Seizures

• Seizure risk is dose-related and requires gradual titration with divided doses 7
• Use with caution in patients with seizure history or risk factors 7

Cardiovascular Effects

QT Prolongation and Arrhythmias

• All antipsychotics can cause QT interval prolongation, potentially leading to torsades de pointes and sudden cardiac death 1, 4
• The American Academy of Pediatrics recommends cardiorespiratory monitoring, pulse oximetry, and/or electrocardiogram when tolerated 1, 4
• Avoid coadministration with other QT-prolonging medications including Class 1A and III antiarrhythmics, certain antibiotics (azithromycin, clarithromycin, fluoroquinolones), and antiemetics (ondansetron) 1
• Risk factors include hypokalemia, hypomagnesemia, and cardiac arrhythmia history 8

Orthostatic Hypotension and Syncope

• Orthostatic hypotension is particularly prominent with quetiapine and clozapine due to α1-adrenergic antagonist properties 8, 7
• Risk is dose-related, necessitating low starting doses (12.5 mg for clozapine) and gradual titration 7
• Can lead to falls, fractures, and other injuries, especially in elderly patients 5, 9

Myocarditis and Cardiomyopathy

• Clozapine can cause fatal myocarditis and cardiomyopathy 7
• Discontinue immediately and obtain cardiac evaluation if findings suggest these reactions 7

Metabolic Complications

Weight Gain and Obesity

• Atypical antipsychotics, especially clozapine and olanzapine, cause significant weight gain 9, 6
• Regular monitoring of BMI and waist circumference is essential 8

Diabetes and Hyperglycemia

• Both typical and atypical antipsychotics are associated with diabetes, with most reports implicating clozapine and olanzapine 6
• The American Diabetes Association recommends monitoring fasting glucose 4 weeks after initiation 8
• Monitor for symptoms including polydipsia, polyuria, polyphagia, and weakness 7

Dyslipidemia

• Long-term use is associated with insulin resistance and hypertriglyceridemia 8
• Regular lipid monitoring is necessary 8

Anticholinergic Effects

• Prominent with typical antipsychotics (especially chlorpromazine) and clozapine 9
• Manifestations include dry mouth, constipation, urinary retention, blurred vision, and cognitive impairment 1, 5
• Avoid coadministration with other anticholinergic drugs when possible 7
• Use with extreme caution in patients with prostatic hypertrophy, bladder outlet obstruction, or glaucoma 10

Gastrointestinal Complications

• Severe gastrointestinal hypomotility can occur, particularly with clozapine 7
• Constipation requires close monitoring and prompt treatment to prevent serious complications including ileus 7, 5
• Anticholinergic properties worsen these effects 1

Hematologic Effects

Severe Neutropenia

• Clozapine can cause severe neutropenia leading to serious and fatal infections 7
• Baseline absolute neutrophil count (ANC) measurement before treatment initiation and regular ANC monitoring during treatment are mandatory 7
• Available only through the restricted Clozapine REMS program 7

Eosinophilia

• Assess for organ involvement including myocarditis, pancreatitis, hepatitis, colitis, and nephritis 7
• Discontinue if organ involvement occurs 7

Cognitive and Sedative Effects

• Sedation is a hallmark effect of quetiapine and other atypical agents 8
• Cognitive blunting and memory deficits occur, especially with agents having greater anticholinergic activity 4
• Chlorpromazine may impair mental and physical abilities, especially during the first few days of therapy 5
• Caution patients about operating vehicles or machinery 5

Hepatotoxicity

• Can be fatal with clozapine 7
• Monitor for hepatotoxicity and discontinue if hepatitis or transaminase elevations combined with other symptoms occur 7

Pulmonary Complications

• Pulmonary embolism should be considered if respiratory distress, chest pain, or deep-vein thrombosis occur 7

Endocrine and Sexual Dysfunction

• Lactation, breast engorgement, amenorrhea, and gynecomastia can occur with typical antipsychotics 5
• Ejaculatory disorders, impotence, and priapism are reported 5
• All antipsychotics are associated with increased likelihood of sexual dysfunction 9

Dermatologic and Ocular Effects (Long-Term Therapy)

• Skin pigmentation ranging from imperceptible darkening to slate gray color can occur with chlorpromazine after prolonged use (typically 3+ years at 500-1500 mg daily) 5
• Ocular changes include fine particulate deposits in lens and cornea, with star-shaped opacities in advanced cases 5
• Photosensitivity reactions range from mild urticarial type to severe exfoliative dermatitis and toxic epidermal necrolysis 5
• Periodic ocular examinations are suggested for long-term patients on moderate to high dosage levels 5

Special Populations

Elderly Patients with Dementia

• Increased mortality in elderly patients with dementia-related psychosis 7
• Antipsychotics are not approved for this condition 7
• Dose reduction is mandatory in older patients, with starting doses of 25 mg recommended for quetiapine 8

Pregnancy and Neonates

• Third trimester exposure may cause extrapyramidal and/or withdrawal symptoms in neonates 7, 5
• Neonates may experience agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorders 5
• Chlorpromazine is excreted in breast milk 5

Critical Monitoring Recommendations

• Close clinical observation, cardiorespiratory monitoring, and pulse oximetry for patients receiving chemical restraint 1
• Regular assessment for tardive dyskinesia every 3-6 months using standardized measures 4
• Baseline and ongoing monitoring of ANC for clozapine 7
• Fasting glucose at 4 weeks after initiation, with regular BMI, waist circumference, and blood pressure checks 8
• Electrocardiogram monitoring when QT prolongation risk factors are present 1, 4

Common Pitfalls to Avoid

• Do not increase doses too rapidly during initial titration—allow 14-21 days between increases after initial titration to assess response 1
• Avoid combining antipsychotics with other QT-prolonging medications without careful risk assessment 1
• Do not use routine prophylactic anticholinergics; only treat extrapyramidal symptoms when they occur 10
• Assess cumulative anticholinergic burden when adding anticholinergic agents for dystonia management 10
• Do not ignore early signs of tardive dyskinesia (fine vermicular tongue movements) 5
• Avoid alcohol use due to possible additive effects and hypotension 5