Common Side Effects: Monitoring and Management Recommendations

By | January 21, 2015

Extrapyramidal Side Effects

Antipsychotic-induced EPS may occur acutely or after long-term treatment. First-generation antipsychotics, in particular high-potency neuroleptics, are more likely than second-generation antipsychotics to cause EPS when the drugs are used at usual therapeutic doses. However, as can be noted in Table Selected side effects of commonly used antipsychotic medications, considerable variation in the incidence of EPS is seen among both the first-generation antipsychotics and the second-generation antipsychotics. Common acute EPS include akathisia, parkinsonism, and dystonia. Importantly, each of these side effects often responds to medication treatment (Table Selected medications for treating extrapyramidal side effects). Each type of acute EPS has a characteristic time of onset. Akathisia typically occurs a few hours to days after medication administration, dystonia within the first few days, and parkinsonism within a few days to weeks after starting a new drug or after a dosage increase ().

TABLE Selected side effects of commonly used antipsychotic medications

Medication EPS Prolactin elevation Weight gain Glucose abnormalities Lipid abnormalities QTc prolongation Sedation Hypotension Anticholinergic side effects
Chlorpromazine + +? +++ +? +? +? +++ +++ +++
Perphenazine ++ + +? +? +? 0 + + 0
Haloperidol +++ ++ + 0 0 0 ++ 0 0
Clozapine 0b 0 +++ +++ +++ 0 +++ +++ +++
Risperidone + +++ ++ ++ ++ + + + 0
Olanzapine + 0 +++ +++ +++ 0 +++ + +
Quetiapine + 0 ++ ++ ++ 0 +++ ++ ++
Ziprasidone + + 0 0 0 + 0 0 0
Aripiprazole + 0 0 0 0 0 + 0 0

Note. EPS=extrapyramidal side effects (includes akathisia, dystonias, and implied risk of tardive dyskinesia; TD=tardive dyskinisia; 0=no risk or rarely causes side effects at therapeutic dose; +=mild or occasionally causes side effects at therapeutic dose; ++=sometimes causes side effects at therapeutic dose; +++=frequently causes side effects at therapeutic dose; ? =data too limited to rate with confidence.

TABLE Selected medications for treating extrapyramidal side effects

Generic name Dosage (mg/day) Elimination ha If-life (hours) Targeted EPS
Benztropine mesylate 0.5-6.0 24 Akathisia, dystonia, parkinsonism
Trihexyphenidyl hydrochloride 1-15 4 Akathisia, dystonia, parkinsonism
Amantadine 100-300 10-14 Akathisia, parkinsonism
Propranolol 30-90 3-4 Akathisia
Lorazepam 1-6 12 Akathisia
Clonazepam 1-3 20-50 Akathisia
Diphenhydramine 25-50 4-8 Akathisia, dystonia, parkinsonism

 

Akathisia. Akathisia, a subjective feeling of restlessness accompanied by restless movements, usually in the legs or feet, is the most common form of EPS. Severe akathisia can be diagnosed when frequent pacing, restless foot movements, or an inability of patients to sit still is present. This condition must be differentiated from psychotic agitation, which is often a response to disturbing hallucinations or delusions, but also may represent hostility related to acute psychosis or increased motor activity associated with excited catatonia. Patients who experience milder akathisia may not have any evidence of increased motor activity but may experience an unpleasant sensation of restlessness subjectively similar to anxiety. Patients should be closely monitored for akathisia when starting a new antipsychotic drug or when the dosage is increased. Severe, unrelenting akathisia has been associated with an increased risk of suicidal behaviors. If symptoms of schizophrenia are adequately treated, lowering the antipsychotic dose is a feasible first approach to reduce akathisia. Another common approach is to change to an antipsychotic less likely to cause akathisia (e.g., a second-generation antipsychotic). Drug treatments for akathisia include P-blockers, anticholinergic agents, or benzodiazepines (Table Selected medications for treating extrapyramidal side effects). Evidence from controlled trials is inadequate to compare the efficacy of the various treatments for akathisia.

Drug-induced parkinsonism (pseudoparkinson-ism). Drug-induced parkinsonism (pseudoparkinsonism) may include the classic Parkinson’s disease symptoms of tremor, muscular rigidity, and a decrease in spontaneous movements (bradykinesia), as well as cognitive slowing and apathy. Milder forms of parkinsonism may include decreased expressive gestures, decreased facial expressiveness, or diminished arm swing. Recognition and management of parkinsonism are important because it is frequently associated with poor adherence to antipsychotic medication regimens (). The initial approach to parkinsonian side effects is to lower the dose of antipsychotic if feasible. Common drug treatments for parkinsonism include anticholinergic medications, as seen in Table Selected medications for treating extrapyramidal side effects. Another common approach is to change to an antipsychotic less likely to cause parkinsonism (e.g., a second-generation antipsychotic).

Dystonias. Dystonias are intermittent or sustained muscular spasms and abnormal postures affecting mainly the musculature of the head and neck but sometimes the trunk and lower extremities. Common forms of dystonia include abnormal positioning of the neck (torticollis), impaired swallowing (dysphagia), hypertonic or enlarged tongue, and deviations of the eyes (oculogyric crisis). These reactions usually appear within the first few days of treatment with antipsychotic drugs and sometimes occur within minutes to hours. These reactions can be painful and dramatic. They occur most commonly with high-potency first-generation antipsychotics, particularly when they are given in substantial doses (e.g., haloperidol 5-10 mg) to drug-naive patients. For this reason, prophylactic treatment with benztropine 1-2 mg is recommended if starting high-potency first-generation antipsychotics at these substantial doses, which may be required in emergency situations. Acute dystonic reactions are treated with diphenhydramine 25-50 mg or benztropine 1-2 mg. Usually, these treatments are given intramuscularly to provide rapid relief for the considerable discomfort of dystonias.

Neuroleptic malignant syndrome. Neuroleptic malignant syndrome (NMS), another neurological side effect, is characterized by rigidity, hyperthermia, mental status changes, and autonomic instability. NMS has a lifetime incidence of approximately 0.2% among antipsychotic users (). Hyperthermia and severe muscle rigidity may lead to rhabdomyolysis and renal failure. Serum levels of creatine kinase may rise dramatically. Risk factors for NMS include rapid dose escalation of high-potency first-generation antipsychotics, parenteral administration, and underlying neurological impairment. NMS is probably less common with second- than with first-generation drugs, but the incidence with first-generation antipsychotics may be decreasing because lower doses than in the past are now commonly used.

NMS may be fatal if untreated. Treatment includes discontinuation of the antipsychotic and supportive care. Temperature reduction by cooling blankets if necessary and correction of fluid imbalances are crucial. The dopamine agonist bromocriptine (2.5 mg every 8 hours) has been shown to reduce NMS duration and mortality. The muscle relaxant dantrolene (1-2.5 mg/kg intravenously every 6 hours) is also commonly used, although there is no strong evidence of its effectiveness. Electroconvulsive therapy is indicated if catatonia related to NMS persists or response is otherwise inadequate with drugs and supportive care. If NMS occurs, need for an antipsychotic medication should be carefully assessed before antipsychotic treatment is resumed. When another trial of an antipsychotic drug is attempted, second-generation antipsychotics (in particular, clozapine) are preferred. A rechallenge should begin with low doses and slow titration.

Tardive dyskinesia and other tardive syndromes. Tardive dyskinesia and other tardive (late-onset) syndromes are involuntary, repetitive, purposeless, hyperkinetic, abnormal movements of the mouth, face and tongue, trunk, and extremities that occur during or following the cessation of long-term antipsychotic drug therapy. According to DSM-IV-TR (American Psychiatric Association 2000) diagnostic criteria, the abnormal movements should be present for at least 4 weeks, and patients should have been exposed to an antipsychotic for at least 3 months. The onset of the abnormal movements should occur either while the patient is receiving an antipsychotic or within 4 weeks of discontinuing an oral or 8 weeks after the withdrawal of a long-acting injectable antipsychotic. Oral-facial movements occur in about three-fourths of TD patients and can include lip smacking, sucking, puckering, and grimacing. Other movements include irregular movements of the limbs, particularly choreoathetoid-like movements of the fingers and toes and slow, writhing movements of the trunk. When severe, TD is disfiguring. In addition to TD, tardive dystonias and tardive akathisia have been described.

Tardive dyskinesia occurs at the rate of 4%-5% per year in the adult, nongeriatric population taking a first-generation antipsychotic (). The risk may be five to six times higher in the elderly, with some data suggesting that as many as 29% of elderly patients will develop TD each year (). A systematic review of 1-year studies involving second-generation antipsychotics found a lower risk of TD in patients taking second-generation antipsychotics (annual risk=2.1%) than in patients taking the high-potency first-generation antipsychotic haloperidol (annual risk=5.2%) (). This review did not include clozapine, but clozapine-induced TD is thought to be extremely rare. Nor did the review include low- or medium-potency antipsychotics, which cause fewer acute EPS than haloperidol and may thus have a lower risk of TD. Risk factors for TD include increased age, female gender, higher dosages of antipsychotics, and longer periods of treatment.

Treatment of TD has largely been unsuccessful, but some data from controlled trials () suggest that the antioxidant vitamin E may be useful in less chronic cases. Second-generation antipsychotics (in particular, clozapine) have been used to treat TD, but there have been no methodologically rigorous trials to support this practice. The recommended clinical approach is to use the lowest possible dose of antipsychotic that is effective and to consider changing to a medication with lower risk of TD (i.e., a second-generation antipsychotic) if TD is an important concern.

Monitoring for EPS. Guidelines from the Mount Sinai Conference on Medical Monitoring () recommend an assessment of EPS prior to starting an antipsychotic and at weekly intervals until the dose has been stabilized for at least 2 weeks. Although the second-generation antipsychotics are associated with a reduced risk of EPS, it is not uncommon for patients receiving these drugs — with the possible exception of clozapine — to experience mild akathisia or rigidity.

The examination for EPS includes observing patients for restlessness movements and inquiring if the patient feels restless. Asking patients if they are having difficulty sitting still can be helpful. Parkinsonism is evaluated by observing the patient’s gait and examining for rigidity in the elbow and wrist. Dystonias usually present as urgent events reported by patients.

Regular monitoring for TD should be a component of management strategies with antipsychotics. The Mount Sinai guidelines () recommend examining patients for TD before starting an antipsychotic and at 6-month intervals for first-generation antipsychotics and yearly for second-generation antipsychotics. Patients who are at high risk, including the elderly and those who are sensitive to EPS, should be examined every 6 months. The Abnormal Involuntary Movement Scale (AIMS; 1988) provides instructions for examining patients as well as means for recording the results of the examination.

Metabolic Effects

In 2004, a joint panel of the American Diabetes Association, American Psychiatric Association, A merican Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity (2004) issued a consensus statement asking physicians to screen carefully and monitor patients who take antipsychotic drugs for signs of rapid weight gain or other problems that could lead to diabetes, obesity, and heart disease. Table Suggested monitoring protocol for patients taking second-generation antipsychotics shows the panel’s recommendation for baseline and follow-up monitoring of factors relevant to these issues. Similarly, at the Mount Sinai Conference on Medical Monitoring, a group of mental health clinicians and researchers and medical experts who convened to review data on the metabolic effects of antipsychotics developed detailed consensus recommendations for approaching metabolic side effects, which are described in the following subsections ().

TABLE Suggested monitoring protocol for patients taking second-generation antipsychotics

 

Baseline

4 weeks

8 weeks

12 weeks

Quarterly

Annually

Every 5 years

Personal or family history

X

X

Weight (body mass index)

X

X

X

X

X

Waist circumference

X

X

X

Blood pressure

X

X

X

Fasting plasma glucose

X

X

X

Fasting lipid profile

X

X

X

Note. More frequent assessments may be warranted based on clinical status.

Source. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, 2004.

 

Weight gain. Individuals with schizophrenia are more likely than the population at large to be overweight or obese (). Antipsychotics vary in their association with weight gain. A meta-analysis by Allison et al. (1999) estimated the amount of weight gain associated with moderate doses of several antipsychotics over 10 weeks. Among the drugs studied, the mean increases were 0.04 kg with ziprasidone, 0.39 kg with molindone, 0.43 kg with fluphenazine, 1.13 kg with haloperidol, 2.10 kg with risperidone, 2.58 kg with chlorpromazine, 3.19 kg with thioridazine, 4.15 kg with olanzapine, and 4.45 kg with clozapine. These differences in weight gain liabilities have been confirmed by other studies (). Quetiapine was not included in the study above but is associated with modest weight gain (American Diabetes Association, 2004). Aripiprazole, also not included in the study above and for which there are few long-term data, is associated with little or no weight gain ().

The Mount Sinai consensus recommendation is that mental health providers should monitor and chart the body mass index (BMI: weight in kg/height in m2) of every patient with schizophrenia, regardless of the antipsychotic medication prescribed (). Individuals with a BMI greater than 25 are at increased risk for diabetes, heart disease, certain cancers, and other weight-associated disorders. Patients should be weighed at every visit for the first 6 months following a medication change. BMI monitoring should be supplemented by measurement and recording of the patient’s waist circumference. A waist circumference greater than 40 inches for men or greater than 35 inches for women is a criterion of the metabolic syndrome and places a person at elevated risk for diabetes. The relative risk of weight gain for the different antipsychotic medications should be a consideration in drug selection for patients who have a BMI greater than 25. Interventions for patients who gain weight may include closer monitoring of weight, engagement in a weight management program, or a change in antipsychotic medication. If a patient is taking a medication that is associated with a high risk for weight gain, the clinician should consider switching to medication with less weight gain liability.

Diabetes. Diabetes is more prevalent in individuals with schizophrenia than in the general population (). This may be related to the high rates of obesity associated with schizophrenia or to a possible association of schizophrenia with insulin resistance (). Other evidence suggests that antipsychotics have the potential for increasing the risk of diabetes. This could be either a result of antipsychotic-associated weight gain or a direct effect of antipsychotic drugs on insulin resistance. Most attention has focused on the second-generation antipsychotics, although it is likely that the first-generation antipsychotics also differ in their tendencies to cause weight gain and diabetes. As indicated in Table Selected side effects of commonly used antipsychotic medications, the second-generation antipsychotics that are most associated with weight gain — clozapine and olanzapine — are also most associated with glucose abnormalities. The FDA, however, issued a warning that all second-generation antipsychotics increase the risk of hyperglycemia and diabetes (U.S. Food and Drug Administration, 2004).

Mental health practitioners should be aware of risk factors for diabetes and the symptoms of new-onset diabetes (including weight change, polyuria, and polydipsia) and should inform patients about these symptoms and monitor for their presence at regular intervals. Furthermore, a baseline measure of glucose should be collected for all patients before starting a new antipsychotic. A fasting glucose level is preferred, but a hemoglobin A1C level is sufficient if fasting glucose is not feasible. Patients who have significant risk factors for diabetes (family history, BMI>25, waist circumference>35 inches for women and 40 inches for men) should have fasting glucose or hemoglobin A1C levels monitored 4 months after starting an antipsychotic and then yearly. Patients who are gaining weight should have fasting glucose or hemoglobin A1C levels monitored every 4 months. Both the Mount Sinai guidelines () and the American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, et al. (2004) recommend measuring fasting blood glucose level before starting an antipsychotic, 4 months later, and then annually.

Mental health providers should ensure that patients with diagnosed diabetes are followed up by an appropriate medical provider. The patient’s psychiatrist and medical care provider should communicate when medication changes are instituted that may affect the control of the patient’s diabetes. If symptoms of diabetes are reported, a random blood glucose level should be collected, and if the level is elevated (>126 if fasting or >200 if nonfasting), the patient should be referred to a medical care provider.

Dyslipidemia. Elevated levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides may, in part, account for the high risk of coronary heart disease in schizophrenia. Studies of second-generation antipsychotics indicate that the tendency of these agents to cause weight gain is also associated with their risk for worsening serum lipid levels. Table Selected side effects of commonly used antipsychotic medications summarizes the associations between antipsychotics and dyslipidemias.

Mental health providers should be aware of the lipid profiles for all patients with schizophrenia. The National Cholesterol Education Program () and the U.S. Preventive Services Task Force (2001) guidelines provide direction for screening and treating patients who are at high risk for cardiovascular disease. If a lipid panel is not available, one should be obtained and reviewed. As noted in Table Suggested monitoring protocol for patients taking second-generation antipsychotics, the American Diabetes Association,

American Psychiatric Association, American Association of Clinical Endocrinologists, et al. (2004) recommend monitoring lipid levels before medication changes, after 12 weeks, and then every 5 years. Patients who fulfill criteria for the metabolic syndrome should be carefully monitored by a medical care provider.

Prolactin. First-generation antipsychotics and risperidone (as well as sulpiride and amisulpiride) elevate serum prolactin levels through blockade of dopamine receptors in the anterior pituitary. Consequences may include decreased libido, anorgasmia, amenorrhea, galactorrhea, and gynecomastia. Dopamine receptor antagonists, such as first-generation antipsychotics, have been associated with an increased risk of breast cancer, possibly related to elevated prolactin (). Growing evidence suggests that high levels of prolactin increase the risk of osteoporosis by reducing estrogen levels (). Aripiprazole, which has agonist effects on pituitary dopamine receptors, can be associated with decreases in serum prolactin levels that are not thought to have clinical significance.

The Mount Sinai guidelines recommend yearly monitoring of patients taking antipsychotics for symptoms of prolactin elevation, including galactorrhea, decreased libido, or menstrual disturbances in women and decreased libido or erectile or ejaculatory disturbances in men (). Patients who are receiving an agent that is associated with prolactin elevation (e.g., first-generation antipsychotics or risperidone) should be asked about symptoms of prolactin elevation at each visit after starting the agent until they are receiving a stable dose. If any symptoms of prolactin elevation are present, prolactin should be measured and, if possible, other medical causes ruled out. Consideration also should be given to a medication change to a prolactin-sparing antipsychotic. If, after a change in antipsychotic, the signs and symptoms disappear and the prolactin level declines to normal, an endocrine workup is not needed. For patients with symptomatic antipsychotic-induced hyperprolactinemia, hormone replacement therapy (estrogen/progestogen for women and testosterone in men) is considered the first choice for medication treatment (). As a last resort, treatment with a dopamine agonist (e.g., cabergoline or bromocriptine) may effectively lower prolactin levels, but psychotic exacerbation is a risk warranting careful monitoring.

Other Side Effects

Antipsychotics can also cause varying amounts of sedation and postural hypotension, as noted in Table Selected side effects of commonly used antipsychotic medications. Patients should be asked about these side effects at each visit after starting an antipsychotic until tolerance develops. If the side effects do not resolve, a change to an antipsychotic with a lower risk of sedation or hypotension is indicated.

Tachycardia may be a side effect of certain agents, particularly clozapine. In addition, mental health providers are often in the best position to diagnose hypertension. Blood pressure and pulse also should be monitored at each visit after starting an antipsychotic until the dosage is stable. Thereafter, pulse and blood pressure should be measured at least every 6 months.

Neuroleptic dysphoria, an unpleasant subjective response to antipsychotic medicines, is associated with poor adherence to antipsychotic medication regimens (). Because neuroleptic dysphoria has been associated with akathisia and parkinsonism, it may be more common with first-generation antipsychotics than with second-generation antipsychotics ().