Dr. Kaushik is research psychiatrist, Dr. Lindenmayer is clinical director, and Ms. Khan is research scientist at the Manhattan Psychiatric Center on Ward’s Island, New York.

Disclosures: Dr. Kaushik and Ms. Khan report no affiliation with or financial interest in any organization that may pose a conflict of interest. Dr. Lindenmayer is a consultant to Janssen; and receives grant support from AstraZeneca, Avanir, Bristol-Myers Squibb, Eli Lilly, the National Institute of Mental Health, and Pfizer.

Please direct all correspondence to: Jean-Pierre Lindenmayer, MD, Clinical Director, Manhattan Psychiatric Center, 600 E 125th St, Ward’s Island, NY 10035; Tel: 646-672-6767, ext. 6004; Fax: 646-672-6386; E-mail: Maisjll@omh.state.ny.us.


 

Focus Points

• Antipsychotic side effects significantly contribute to noncompliance and reduction of quality of life.
• Side effects differ between first- and second-generation antipsychotics.
• Extrapyramidal symptoms are the hallmark of first-generation drugs.
• Weight gain and metabolic abnormalities are the challenges of second-generation drugs.

 


 

 

Abstract

The use of antipsychotics can be extremely helpful in reducing psychotic symptoms and agitation in patients with severe mental illness. However, these drugs may produce serious side effects that can range in intensity from mild to severe. The management of these side effects should be an important part of the treatment plan, as the frequency and severity of side effects may play a role in the effectiveness and tolerability of the particular antipsychotic.  Identification of these side effects requires careful consideration of other psychiatric and medical disorders that may mimic antipsychotic-related side effects. The burden of side effects contributes to noncompliance and reduction of quality of life. Often, this burden is not fully recognized and, therefore, reduces the overall effectiveness of a given agent. Thus, side effects need to be recognized and treated effectively.

Introduction

Antipsychotics have revolutionized psychiatry by allowing significant numbers of patients in long-term hospital settings to be discharged and successfully maintained in the community. However, these medications are also associated with a range of adverse events ranging from mostly annoying to rarely dangerous. They can add a significant burden, reducing patients’ quality of life and contributing to noncompliance.1 Effective management of these unwanted effects of antipsychotics has the potential to improve patients’ compliance, quality of life, and possibly the prognosis and ultimate outcome. The aim of this article is to systematically review the management of these side effects based on the body system they affect predominantly rather than by specific antipsychotic.

 

Sedation

Sedation is a common side effect of first-generation antipsychotics (FGAs), especially low-potency agents, and several second-generation antipsychotics (SGAs) including clozapine, olanzapine, and quetiapine. Sedation appears to be mediated through histamine, dopamine, and adrenergic receptors.2,3 It is most prominent in the initial phases of treatment, when at times it can be helpful for the agitated patients. Some tolerance to somnolence develops in most patients with continued treatment. However, persistent daytime sedation and increased sleep time can interfere with patients’ social and vocational functioning.

Somnolence can be managed by decreasing the total daily dose, changing the dosing schedule to a single bedtime dose, or changing to a less sedating antipsychotic. Despite lack of systematic data, caffeine may be relatively safe and economic.4 Psychostimulants like modafinil may be useful in managing daytime sedation.5 However, there are a few case reports of clozapine toxicity at high clozapine serum levels6 and exacerbation of psychosis7 on higher-than-recommended doses of modafinil. Therefore, this combination must be used with caution.

 

Extrapyramidal Symptoms

Antipsychotic-induced extrapyramidal symptoms (EPS) can occur either acutely (eg, pseudo-parkinsonism, dystonia, akathisia) or with prolonged treatment (eg, tardive dyskinesia, tardive dystonia, neuroleptic malignant syndrome [NMS]). Greater than 60% of patients treated with FGAs develop EPS in one form or another, which is the main reason why SGAs, with their lower propensity for EPS, have become the first-line agents in treatment of psychotic disorders.8

Dystonia

The Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision, (DSM-IV-TR),9 research criteria for neuroleptic-induced acute dystonia include one or more signs or symptoms, including retrocollis or torticollis; trismus (gaping or grimacing); dysphagia (laryngeal-pharyngeal spasm or dysphonia); dysarthria or macroglossia; tongue protrusion or tongue dysfunction; oculogyric crisis; and abnormal positioning of the distal limbs or trunk, developing within 7 days of starting or raising the dose of the neuroleptic. Preferably, dystonias should be rapidly resolved with parenteral anticholinergic (eg, benztropine) or antihistaminergic (eg, diphenhydramine) medications. In patients at high risk for dystonia (eg, young black males, history of cocaine use, prior history of dystonia), prophylactic oral use of these medications should be considered with high-potency agents.

 

Neuroleptic-Induced Parkinsonism

The DSM-IV-TR research criteria for neuroleptic-induced parkinsonism include at least one of three cardinal symptoms of parkinsonian tremor, musculary rigidity, and akinesia developing within a few weeks after starting or raising the dose of a neuroleptic or reducing a medication used to treat EPS. Neuroleptic-induced parkinsonism is the most common form of acute EPS associated with FGAs,10 arises in the first few days to weeks of initiating antipsychotics, and is dose dependant.

Treatment usually involves three steps, including reduction of dose, if clinically feasible; adding an antiparkinsonian medication; or shifting to an SGA. Among these, clinicians can choose between anticholinergics (eg, benztropine, trihexyphenidyl, procyclidine, biperiden) and antihistamines (eg, diphenhydramine). The latter is more sedative, while trihexyphenidyl is more stimulating. In addition, anticholinergics have a propensity to cause cognitive impairment. Dopaminergic agonists can also be used, such as amantadine and bromocriptine, which may also be useful for the treatment of antipsychotic-induced galactorrhea. A concern with dopaminergic agonists is the possibility for an activation of psychosis by these drugs. For the treatment of acute EPS, parenteral administration of the anticholinergics or antihistamines is the preferred route.

Often, antiparkinsonian medications can be withdrawn after prolonged use (4 weeks–6 months) without return of the EPS. Some clinicians prescribe prophylactic antiparkinson medications for patients who are likely to experience disturbing EPS based on the patient’s past history of EPS sensitivity, and for those treated with relatively high doses of high-potency drugs. The risks of long-term treatment prophylaxis with its attendant adverse events should be weighed against the potential benefits.

 

Akathisia

The DSM-IV-TR research criteria for neuroleptic-induced acute akathisia include development of subjective complaints of restlessness and its observed manifestations within 4 weeks of initiating or increasing the dose of a neuroleptic. The point prevalence of akathisia has been reported to be approximately 25% in patients currently treated with FGAs.11 This side effect is frequently misdiagnosed as anxiety or agitation and is associated with poor antipsychotic response.12 As the treatment of akathisia differs from that of anxiety and agitation, it is important to diagnose it accurately. However, SGAs, particularly aripiprazole and ziprasidone, have also been reported to be associated with akathisia.

Cochrane Reviews13,14 support short-term use of benzodiazepines for managing akathisia, and a couple of double-blind studies found propranolol to be beneficial.15,16 In addition, clinical practice commonly includes neuroleptic dose reduction, switching to low EPS propensity SGAs and anticholinergics,17,18 although some authorities believe that anticholinergics are of limited value in treating akathisia.19

 

Neuroleptic Malignant Syndrome

The DSM-IV-TR research criteria for neuroleptic malignant syndrome (NMS) include the development of severe muscle rigidity and elevated temperature associated with the use of neuroleptics along with two or more signs or symptoms of diaphoresis, dysphagia, tremor, incontinence, changes in level of consciousness ranging from confusion to coma, mutism, tachycardia, elevated or labile blood pressure, leucocytosis, or elevated creatine phosphokinase. NMS is frequently misdiagnosed and can be fatal in up to 20% of patients if untreated.20

Treatment includes discontinuing the antipsychotic, supportive treatment to maintain hydration, and management of fever and other renal or cardiovascular signs and symptoms. Some case series support the use of dopamine agonists (eg, bromocriptine or amantadine) or direct muscle relaxants (eg, dantrolene).21 Based on the similarities in symptoms between catatonia and NMS, treatment with benzodiazepines (eg, lorazepam) may be helpful.22 Electroconvulsive therapy has been reported to be beneficial for treatment-resistant NMS.23 After several weeks of recovery, patients may be restarted on an antipsychotic other than the precipitating agent (preferably an SGA or a low-potency FGA) with gradual dose increase24 and careful monitoring of clinical status and lab work.

 

Tardive Dyskinesia

The American Psychiatric Association Task Force on Tardive Dyskinesia25 recommends preventing and managing tardive dyskinesia by using the lowest effective doses of antipsychotics, examining patients on a regular basis for evidence of tardive dyskinesia every 3–6 months (eg, using the Abnormal Involuntary Movement Scale [AIMS]), and considering dosage reduction and switching to another drug when tardive dyskinesia is diagnosed. As SGAs have been associated with less tardive dyskinesia than FGAs, the former should be considered when switching medications. Open-label studies have found clozapine to be effective in reducing severe tardive dyskinesia.26-28

It has been recommended that vitamin E supplementation with either vitamin E-rich foods or the use of a daily multivitamin up to the daily requirement of 30 IU of α-tocopherol, be considered a treatment option in patients with newly diagnosed tardive dyskinesia.29,30 Two well-designed, randomized, double-blind studies did not find any benefit of 1,600 IU/day vitamin E supplementation in patients with established tardive dyskinesia.31,32 Miller and colleagues33 concluded that high-dosage vitamin E supplements (defined as ≥400 IU/day) may increase all-cause mortality. Therefore, higher doses of vitamin E supplementation are not recommended. An open-label trial of tetrabenazine using raters blinded to pre- or posttreatment status found significant improvements in AIMS scores for patients with refractory tardive dyskinesia.34 A retrospective chart review found tetrabenazine to be safe and effective for long-term treatment of tardive dyskinesia.35 It is available as an orphan drug in the United States.

 

Anticholinergic and Antiadrenergic Effects

The low-potency FGAs or the high-potency FGAs given with antiparkinsonian drugs can produce a variety of peripheral nervous system side effects like dry mouth, constipation, urinary retention, and blurred vision in up to 50% of treated patients.25 These effects are also commonly seen with the SGA clozapine. While these side effects are mostly annoying, elderly patients can develop problems like worsening of benign prostatic hypertrophy.8,36 Rarely, serious complications may occur (eg, complications from an undiagnosed intestinal ileus). Susceptible patients may develop hyperthermia, especially in warm weather.

Common central nervous system (CNS) side effects include impaired cognition; CNS toxicity may result in delirium, confusion, somnolence and hallucinations, especially in the elderly and medically debilitated patients.

Patients with preexisting benign prostatic hypertrophy need careful monitoring of urinary function. Many anticholinergics, including clozapine, are contraindicated in patients with narrow angle glaucoma. Lowering or dividing the dose of anticholinergics may help alleviate some of the adverse events as they are often dose related. Parenteral physostigmine may be beneficial for anticholinergic delirium but must be given only with intensive medical monitoring.

 

Weight Gain and Metabolic Syndrome

FGAs are associated with varying degrees of weight gain, with low-potency drugs having more weight gain than high-potency drugs. Among the FGAs, molindone appears to be the antipsychotic associated with the least amount of weight gain. Among the SGAs, weight gain is often reported in the following order, from high to low: clozapine, olanzapine, quetiapine, and risperidone, with minimal or no weight gain reported with aripiprazole and ziprasidone.37,38 Weight gain is a significant issue as it is associated with diabetes mellitus, dyslipidemias, metabolic syndrome, cardiovascular disease, and osteoarthritis.39-41

The two underlying molecular mechanisms, which appear to mediate weight gain with antipsychotics, are antihistaminergic receptor-binding potency and anti-serotonin-2C receptor binding. Among the more ominous complications of weight gain is the development of the metabolic syndrome. In the Clinical Antipsychotic Trials of Intervention Effectiveness study, 43.8% of patients were classified as having the metabolic syndrome at baseline.42 At present, there are standardized criteria for diagnosing the metabolic syndrome, but these criteria are not universally accepted. The American Heart Association recommends that the metabolic syndrome be identified as the presence of three or more of the following components: elevated waist circumference ≥40 inches (102 cm) in men and 35 inches (88 cm) in women, elevated triglycerides ≥150 mg/dL, reduced high density lipoprotein (HDL) cholesterol <40 mg/dL in men and <50 mg/dL in women, elevated blood pressure ≥130/85 mm Hg, and elevated fasting glucose ≥100 mg/dL. Body mass index may also be considered when evaluating patients for metabolic syndrome risk.

Prior to starting antipsychotics, obesity-prone patients should be identified and educated about the risks of weight gain and its possible consequences. Patients should be offered dietary advice and exercise and behavior modification programs. Based on the Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes,43 it can be recommended that the metabolic parameters (fasting glucose and fasting lipid profile), abdominal girth, weight, and blood pressure be monitored at least quarterly during the first year and yearly thereafter.

Sibutramine is Food and Drug Administration-approved for the indication of weight loss. It has been reported in a double-blind placebo-controlled study to reduce weight gained by treatment with olanzapine,44 but not weight gained by clozapine.45 Orlistat is also FDA-approved for weight loss and works by inhibiting gastric and pancreatic lipases and reducing intestinal fat absorption. Common adverse events associated with its use include diarrhea, fatty stools, and dyspepsia. Other FDA-approved weight loss medications on the market include the amphetamine derivates dextroamphetamine, phentermine, diethylpropion, and phendimetrazine. With the exception of orlistat, all these drugs must be used with caution and only for the short-term treatment of obesity because of their potential for abuse and dependence. These medications should be used only with calorie-restricted diets.

One open-label study of aripiprazole add-on to a stable dose of clozapine reported significant weight loss in 4–6 weeks.46 There are reports of some success with amantadine, the histamine-2 antagonist nizatidine, metformin, and topiramate.47 One open-label study found benefit in pediatric patients with the addition of metformin.48,49 Metformin has also been found to slow the progression of insulin resistance to diabetes. Hyperlipidemias and low HDL may be managed by the use of statins, fibrates, or nicotinic acid. Hypertension may be managed by antihypertensive agents, preferably angiotensin-converting enzyme inhibitors as they may reduce the progression of diabetes, decrease coronary vascular disease, and delay the progression of microalbuminuria.

 

Diabetes Mellitus

Numerous retrospective pharmacoepidemiologic studies have reported that there may be an increased risk of diabetes type 2 during treatment with antipsychotics compared to the general population, and that exposure to SGAs may pose a higher risk than exposure to FGAs. Case series have also reported the acute emergence of diabetic keto-acidosis in the context of treatment with SGAs.50 The increased risk of diabetes mellitus type 2 and diabetic keto-acedosis may occur in the absence of significant weight gain in susceptible patients. The reports of diabetes as a complication has been highest with clozapine and olanzapine, followed by risperidone and quetiapine, with ziprasidone and aripiprazole at the lowest level. Therefore, monitoring for the occurrence of treatment-emergent type 2 diabetes mellitus is important for all patients receiving an antipsychotic, particularly if they also have any of the well-established risk factors, such as family history, non-white ethnicity, inadequate level of physical activity, and obesity. The presence of a diagnosis of schizophrenia in itself is a risk factor.

Once diabetes has developed, there should be a consideration whether the antipsychotic can be switched to one with a lesser likelihood for contributing to the disorder, such as aripiprazole or ziprasidone. If this is not possible, diabetes has to be treated as in usual medical practice.

 

Cardiovascular Adverse Events

 

Orthostasis and Tachycardia
Postural hypotension is caused by the α1-adrenergic antagonism of antipsychotics and is an important side effect of low-potency antipsychotics. Clozapine initiation and dose escalation is associated with a high risk of orthostasis and tachycardia, with rare reports of cardiovascular collapse.8 Among the FGAs, low-potency drugs are also more associated with this side effect. These adverse events limit the rate of dose increase during initial dose titration, which is generally conducted over 2–4 weeks and necessitate regular monitoring of orthostatic vital signs. Risperidone and quetiapine are also associated with orthostasis and tachycardia. Severe orthostasis can cause dizziness and syncope. Patients should be educated to not get up quickly or without support. Elderly patients are particularly sensitive to this side effect and syncopal episodes can lead to falls and hip fractures.

Management includes decreasing or dividing doses of the antipsychotic or switching to another antipsychotic without anti-adrenergic effects. Additional measures may include the use of support stockings, increasing salt intake, maintaining adequate oral hydration, or as a last resort taking fludrocortisone to increase intravascular volume by salt/fluid retention.

Tachycardia may result from anticholinergic effects or from orthostasis caused by antipsychotics. Up to 25% of patients treated with clozapine develop tachycardia unrelated to orthostasis; therefore, patients with heart disease should be monitored carefully, especially during initiation of clozapine treatment. Tachycardia caused by anticholinergic effects without orthostasis can be managed with a low dose of peripherally acting β-blockers like atenolol.51

QTc Prolongation
Corrected QT interval (QTc) measures the time interval required for cardiac ventricular repolarization and is corrected for the heart rate with which the QT interval varies. QTc >500 msec is associated with the risk for a ventricular tachyarrythmia, torsades de pointes, which can lead to ventricular fibrillation and sudden death. Thioridazine, mesoridazine, pimozide, and high-dose intravenous haloperidol are associated with risk of QTc prolongation.52 Because of the high risk of QTc prolongation with thioridazine and mesoridazine, the FDA recommends that it should be used only when treatment with other antipsychotics has not been satisfactory. Ziprasidone is associated with an average increase in QTc of 20 msec; however, arrhythmias and sudden death are not reported with its use.53 Patients treated with antipsychotics with a propensity for increasing QTc should be monitored for other risk factors for torsades de pointes, like congenital prolonged QT syndrome, bradycardia, hypokalemia, hypomagnesemia, heart failure, and medical conditions or drug interactions which may increase the serum level of the QTc prolonging medication.8,54

 

Endocrine Effects

All FGAs elevate serum prolactin by blocking the dopaminergic inhibition of anterior pituitary lactotrophic cells.55,56 Female patients are more sensitive to prolactin elevation. Risperidone may increase prolactin in a dose-dependant manner and to a greater extent than the FGAs due to its relative difficulty in crossing the blood-brain barrier and increasing exposure to the pituitary which is outside the blood-brain barrier.57 Olanzapine, quetiapine, and ziprasidone do not cause sustained prolactin elevation. Clozapine and aripiprazole do not cause prolactin elevation.

Symptoms of hyperprolactinemia include breast enlargement and tenderness, lactation, menstrual irregularities in women, and sexual dysfunction. These effects result from the effect of prolactin on the breast tissue and prolactin-related disruption of the hypothalamic-pituitary-gonal axis.58 Long-term consequences of prolonged hyperprolactinemia are unknown.
For symptomatic patients with hyperprolactinemia, the dose of the antipsychotic may be reduced or a switch to an SGA other than risperidone could be considered. If the antipsychotic needs to be continued on clinical grounds, dopamine agonists like amantadine or bromocriptine may reduce the symptoms.59

Hematologic Adverse Events

Antipsychotics may cause hematologic adverse events, including neutropenia, leucopenia, thrombocytopenia, and agranulocytosis. With chlorpromazine, benign leucopenia may occur in up to 10% of patients and agranulocytosis in 0.32% of patients.8,60 Of all the antipsychotics, clozapine appears to be associated with the highest risk of agranulocytosis (absolute neutrophil count <500/mm3), at the rate of 1.3% of patients per year of treatment with clozapine. As this can be fatal and the highest risk is during the first 6 months, the current guidelines necessitate a minimum of weekly white blood cell (WBC) count and absolute neutrophil count (ANC) monitoring for the first 6 months, biweekly for the next 6 months and monthly thereafter.61 During clozapine treatment, white blood count must remain >3,000/mm3 and ANC >1,500/mm3.

Seizures

FGAs, especially low-potency agents, can lower the seizure threshold in a dose-dependant manner which may lead to generalized tonic-clonic seizures, even though the rate of seizures is <1% for all FGAs. However, clozapine appears to be the most epileptogenic of all antipsychotics, with a cumulative risk of 10% for tonic-clonic seizures after 3.8 years of treatment (dose range 25–900 mg). This risk is dose related with the highest risk in clozapine doses >600 mg/day.62 Patients with clozapine-induced seizures may be managed by dose reduction or addition of an antiepileptic, usually allowing continuation of therapy.63

Hepatic Adverse Events

Mild, benign, and transient increase of liver enzymes infrequently occurs with both FGAs and SGAs, usually during the first 3 months of treatment.64 Jaundice is noted to occur in up to 0.5% of patients taking chlorpromazine.65 Rarely, SGAs result in symptomatic hepatotoxicity.64 Management of these cases include discontinuing the responsible antipsychotic, which results in recovery in most patients within 1 year.65

Conclusion

Although antipsychotics clearly reduce the morbidity and mortality of psychiatric illness, they may also be associated with adverse side effects, which often cause distress to the patient and may lead to non-compliance. Non-compliance can lead to a recurrence of psychotic symptoms. Thus, the recognition of these side effects and their management can lead to strategies which insure optimal care for the patient. PP

 

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