Dr. Verovsky is a research pharmacist at the Maryland Psychiatric Research Center in the Department of Psychiatry at the University of Maryland.

Dr. Thaker is professor of psychiatry and chief of the Schizophrenia Related Disorders Program at the Maryland Psychiatric Research Center in the Department of Psychiatry at the University of Maryland.

Acknowledgments: This work was supported by grant nos. MH40279 and MH49826 from the National Institute of Health, and a grant from the Stanley Medical Research Institute. 


 

Abstract

The advent of antipsychotic drugs in the 1950s revolutionized the treatment of schizophrenia. However, serious motor side effects such as akathisia and tardive dyskinesia raised concerns. Most studies found older women to be more at risk for motor side effects. Sedation, slowed motor speed, and anticholinergic effects produced cognitive and functional problems in some patients. These side effects acted partly as a catalyst in the search for new antipsychotic agents. The new-generation antipsychotic agents are less likely to cause these troublesome motor effects but have different side effects, the most troubling of which are metabolic. Many first-generation antipsychotics and some second-generation antipsychotics affect hormones, especially prolactin. These hormonal side effects likely affect reproductivity in women. Further studies are needed to determine if gender differences affect risk and incidence rates of antipsychotic side effects.

 

Introduction

Since the 1950s, the use of antipsychotic drugs has revolutionized the treatment of patients who are chronically mentally ill. However, use of these drugs over the past 4 decades has produced significant side effects in many patients.1-6 Women exposed to antipsychotic agents are at risk for almost all of these side effects, although the risks for some of the side effects are known to vary according to gender.7 Women may be more vulnerable to the long-term motor side effects and the endocrinological side effects, which are particularly distressing to younger women.7,8 However, there is a general lack of data regarding the effects of gender on the risk, course, and management of antipsychotic drug side effects. Since many of the side effects are infrequent, large numbers of patients taking medications are needed in order to obtain reliable estimates of the prevalence rates. Many large sample studies that have examined side-effect profiles of antipsychotic agents were conducted at Veteran’s Administration facilities, which have mostly male patients.9
 

Many side effects emerge with the initiation of antipsychotic treatment, while others are more insidious in onset, perhaps emerging after years of treatment. The early-onset side effects include cardiovascular effects such as orthostatic hypotension, hypertension, and cardiac rhythm anomalies; anticholinergic effects such as dry mouth, constipation, blurred vision, urinary retention, and cognitive impairment; sedation and slowness in processing information; motor side effects such as tremors, slowness, limitation of voluntary movements and other associated parkinsonian symptoms; and motor restlessness (akathisia).10 Other side effects that may be apparent after weeks to months of antipsychotic treatment include weight gain, lactation, gynecomastia in males, breast enlargement in females, changes in libido, and disturbances in menstruation in females. Late-onset side effects occurring after months to years of antipsychotic treatment include choreoathetoid and dystonic involuntary movements of tardive dyskinesia, skin pigmentation changes, rare lenticular opacities, and morbidity secondary to weight gain. There are some rare but serious side effects associated with a particular antipsychotic drug. Examples include agranulocytosis with clozapine and cardiac conductivity changes with some low potency drugs.10
 

The side-effect profiles vary with dose and antipsychotic agent. Risks for immediate motor side effects are common with high potency first-generation antipsychotic drugs, and less common with low potency first-generation drugs. Risks for tardive dyskinesia, one of the serious adverse effects of antipsychotic drug use, are similar for all first-generation antipsychotics. Motor side effects, particularly dyskinesia, were one of the major catalysts for the search for drugs that could ameliorate psychotic symptoms with fewer side effects.11 The results were the second-generation antipsychotic agents that were introduced for clinical use: clozapine (1990), risperidone (1994), olanzapine (1996), quetiapine (1997), and ziprasidone (2001). These drugs have fewer motor side effects, but have much higher risks for weight gain, hyperlipidemia, and diabetes mellitus secondary to the weight gain or through other mechanisms, when compared to the first-generation antipsychotics. It is important to note that tardive dyskinesia only became a public health concern in the late 70s and 80s after a large number of patients took these drugs for a long time. Similarly, one would anticipate that the full impact of chronic weight gain and hyperlipidemia associated with second-generation antipsychotics will become apparent in the future as data regarding associated morbidity and mortality are compiled. Furthermore, there is considerable interindividual variability that the clinician can take advantage of when choosing a drug to treat psychosis. Side-effect vulnerability in the patient can be predicted by sex, age, or other clinical variables. In the near future, pharmacogenetic data will drive many of the drug-selection decisions made by clinicians.
 

Motor Side Effects of Antipsychotic Agents

Within hours to days of starting antipsychotic drugs, particularly high potency first-generation antipsychotic drugs, women are less vulnerable to developing acute dystonic reactions.12 Spasm and abnormal posturing of the neck muscles (torticolis), tongue, ocular muscles (oculogyric crisis), and back muscles are some of the common regions involved in acute dystonia.13 The reaction quickly responds to anticholinergic treatment. Motor symptoms mimicking Parkinson’s disease emerge within days to weeks of starting first-generation antipsychotics, and to a much lesser extent, second-generation antipsychotic treatment. Tremors affecting the extremities and other regions, hypokinesia, bradykinesia, shuffling gait, and masked facies are common clinical manifestations.13 Akathisia is perhaps one of the most troubling subchronic motor side effects associated with first-generation antipsychotics as well as some of the second-generation agents.
 

The prevalence rates of such extrapyramidal symptoms (EPS) vary from sample to sample depending on the drugs used, their doses, and duration of treatment. A large sample study (N=1,559) reported a prevalence rate of 29.4% for EPS in patients who had a long history of receiving antipsychotic drugs.7 Most common symptoms were parkinsonian (66% of those with EPS), and akathisia (32%). Least common were acute dystonia (2%). Women were at a higher risk for EPS in this study, although this has not been a consistent finding in the literature.
 

Akathisia is one of the most troubling side effects for patients and one of the leading causes of noncompliance due to the uncomfortable subjective feelings of motor restlessness.14 In addition, successful management of akathisia is difficult. In spite of high prevalence rates, parkinsonian symptoms have not been very troubling for the therapeutics of chronic psychoses because these symptoms are easily managed.9 The symptoms are reversible when the antipsychotic drug is discontinued; anticholinergic and other agents are effective in reversing the symptoms in most cases and patients develop tolerance after continued use of antipsychotic medications and reduction of parkinsonian symptoms.
 

In contrast to EPS, the recognition that the emergence of involuntary choreoathetoid and dystonic movements of tardive dyskinesia was linked to antipsychotic use in a large proportion of chronically-treated psychotic patients, caused a major public health concern. This is because dyskinetic movements are not easily reversible unless a long-term antipsychotic drug-free period is implemented, and even with that, the movements may be irreversible in some patients. Treatments of dyskinesia are difficult. The iatrogenic syndrome, although mild to moderate in most patients, progresses in a minority of patients, affecting most of the body regions and causing serious disability. Complications such as weight loss, arthritis, and disfiguring facial hypertrophy due to constant muscle spasms, dysarthria, and visual and mobility problems due to focal dystonia occur in about 15% of patients with tardive dyskinesia.15 Data from our clinic shows that the distribution of severity of dyskinesia is similar in men and women3 (Figure 1). Also, there is no effect of gender on the body distribution of dyskinetic symptoms (Figure 2).


 Several studies have found that women are at greater risk for tardive dyskinesia than men.16,17 In one of the few prospective studies, Kane and colleagues1 observed an incidence rate of about 4% to 5% per treatment year with first-generation agents. Women were at slightly increased risk, and as women aged, the risk increased. Other independent risk factors are cumulative dose of the first-generation antidepressant drugs, affective disorders, diabetes mellitus, and organic brain syndrome. The reason for the increased risk of tardive dyskinesia in women is unclear. This may be influenced by the fact that women are diagnosed with major depression and seek treatment more often than men.


 

Casey and colleagues9 examined the relationship between mood disorder and tardive dyskinesia. They noted that prevalence rates of tardive dyskinesia for those with affective disorders ranged from 30% to 83% and were consistently higher than for patients diagnosed with schizophrenia (25% to 30%). The higher risk for tardive dyskinesia in women was apparent both in affective disorders as well as nonaffective disorder cohorts.
 

Research on tardive dyskinesia has focused on the natural history of the illness and its prognostic indicators in adults.2,18 These studies have found that the course of tardive dyskinesia depend to a large extent, on the dose of antipsychotic prescribed. Switching to clozapine, and perhaps other second-generation antidepressant agents, is likely to reduce the severity of dyskinesia.19 The effects of sex on outcome have not been extensively looked at the literature. Data from a large cohort of patients that were followed for 1–15 years in our clinic showed that women show a slight but significant improvement in tardive dyskinesia, whereas men do not (Figure 3). These findings were observed even after controlling for age and duration of follow-up. With increasing use of second-generation agents to treat psychoses, new cases of tardive dyskinesia are less and less likely. However, there is still a large segment of women with psychoses who were previously treated with first-generation agents and experienced persistent tardive dyskinesia.


Treatment of tardive dyskinesia includes withdrawal from the antipsychotic agent if clinically feasible, switching to clozapine or another second-generation drug, and, in select cases, benzodiazepines to provide temporary symptom relief.20 One may want to consider Vitamin E treatment, although findings from several studies are mixed.21
 

Metabolic Side Effects of Antipsychotic Agents

While the concerns regarding tardive dyskinesia may be fading with the use of second-generation antidepressants, other side effects such as weight gain and hyperlipidemia may have serious health implications in chronic mentally ill population. Weight gain has been associated with antipsychotic treatment since chlorpromazine was introduced in the 1950s, but recent concerns about the propensity of the second-generation medications to cause obesity has promoted new interest.3,22 Obesity is a known risk factor for many health problems including diabetes mellitus, coronary artery disease, and hypertension. With the recent trend of using second-generation antidepressants in young women, not uncommonly in children and adolescents, and frequently for nonpsychotic illnesses, the complications associated with the side effects of second-generation antidepressants are likely to become a major public health issue of the future.
 

The mean weight gain associated with second-generation antidepressant treatment varies with the drug used. In general, clozapine and olanzapine are associated with about 10–20 lbs of weight gain for the first year.3 Weight gain usually plateaus by the end of the first year, but can continue, especially with clozapine, at the rate of about 4 lbs/year. Risperidone and quetiapine are less likely to cause severe weight gain, although moderate gain in the range of 5–10 lbs is not uncommon.3 Patients taking lithium and valproate concurrently with second-generation antidepressants are likely to experience two to three times the amount of weight gain as those who were not taking one of these mood stabilizers.3 Even before the advent of second-generation agents, women with schizophrenia had body mass index distributions in the overweight and obese spectrum compared to their counterparts in the general medical population.4 This trend is likely to worsen with increased use of second-generation antidepressants. Although mechanisms underlying weight gain in these patients is likely to be complex, suppression of satiety through brain neurotransmitter systems, mediated through the blockade of histamine H1 receptors and/or serotonergic 5-HT2c receptors, are likely to be implicated.
 

Following several case reports of increased triglycerides associated with second-generation antidepressants, several investigators prospectively examined the issue. Most of these were carried out based on a naturalistic study design and noted a significant increase in serum triglyceride levels.22-24 These studies had sample sizes ranging from 25 to 82 patients that were monitored for periods of 3 months to 5 years, and noted increases in triglycerides of about 60–100 mg/dL. In general, there was no significant increase in cholesterol levels. Increases in triglycerides were associated with clozapine, olanzapine, and, to a lesser extent, risperidone. In contrast to these findings, Lund and colleagues25 found no significant differences in diabetes, hyperlipidemia, or hypertension among patients treated with first-generation antidepressants or clozapine. This was a much larger sample (N>3,000), but the data set was based on medical and pharmacy claims which may not be sensitive in identifying diseases. For example, patients may experience increased serum triglycerides or glucose levels without being coded as having hyperlipidemia or diabetes. However, these authors noted an increase in relative risks of hyperlipidemia (relative risks of 2.4) and diabetes (relative risks of 2.5) associated with clozapine treatment in a young cohort (20–34 years of age).
 

Among these reports of metabolic side effects of second-generation antidepressants, the most disconcerting finding was that about one out of three patients who were initiated on clozapine were later diagnosed with adult-onset type 2 diabetes mellitus within the 5-year follow-up.24 In spite of the lack of rigorous study design, these observations based on a naturalistic study demand a closer look. The issue of type 2 diabetes mellitus and schizophrenia is complex as suggested by findings of abnormal glucose regulation in schizophrenia in the preantipsychotic drug era.26,27 The use of first-generation agents, particularly phenothiazines, may have further contributed to the risk of diabetes.28 Recently, there have been multiple reports of hyperglycemia, exacerbation of existing diabetes mellitus, and diabetic ketoacidosis with second-generation antidepressants.5,29 The increase in weight gain and abdominal adiposity associated with second-generation antidepressants may contribute to hyperglycemia by decreasing skeletal muscle insulin sensitivity. However, other independent adverse effects of these drugs are likely as numerous clinical reports have observed abnormal glucose regulation independent of weight gain.30,31 This assertion was further supported by a study by Newcomer and colleagues32 showing abnormal glucose tolerance tests in patients treated with olanzapine and clozapine. Being a female of African American ethnicity may also be risk factors for the hyperglycemic effects of second-generation antipsychotics.29
 

Hormonal Side Effects of Antipsychotic Agents

Hormonal side effects of antipsychotic agents may not have received its deserved attention from clinicians. These drugs elevate prolactin levels through blockade of dopamine D2 receptors on the lactotrophs in the anterior pituitary gland. The dopamine-inhibiting effect on prolactin release is diminished or gone, leading to hyperprolactinemia. This increase in prolactin levels is correlated with the degree of suppression of the hypothalamic pituitary axis and subsequent hypogonadal state.6 As a result, women experience serious consequences such as menstrual irregularities, sexual dysfunction, galactorrhea, and infertility. In addition, hyperprolactinemia decreases bone density directly or indirectly by decreasing ovarian estrogen secretion.33 This is a particular concern since women with schizophrenia are already candidates for osteoporosis because they tend to have other risk factors such as sedentary lifestyles, smoking, poor nutrition, and pathological water drinking.6,8,34 Another potential consequence of chronic low estrogen levels is increase in cardiovascular risk.8
 

Prolactin levels in patients with schizophrenia are generally within normal range prior to receiving treatment for the psychosis.35 Antipsychotic agents vary in their propensity to cause this side effect depending on the potency and/or transiency of D2 receptor blocking effects. In general, first-generation antipsychotics are more likely to cause serum prolactin elevations; among second-generation agents, risperidone causes hyperprolactinemia. The prolactin-elevating effect is more frequent and occurs at a lower daily dose of antipsychotic agents in women than in men.36 The effects of second-generation antipsychotics (other than risperidone) on prolactin levels are negligible. For example, in a fixed dose study in 361 patients with schizophrenia, the prolactin levels remained essentially flat from baseline to endpoint with quetiapine even at the highest dosage range, while marked elevations were found with haloperidol.37 There may be a transient increase with olanzapine in the first few weeks of use, but levels tend to remain within the normal range and then return to baseline levels or even lower.
 

Switching from typical to atypical agents can normalize prolactin levels. In addition, once the patient’s prolactin level returns to normal, the associated symptoms should resolve. In women, menses will resume, libido should increase, and fertility may return to normal for the patient’s age and health. Estrogen levels should return to age-appropriate levels, thereby reducing the risk of decreased bone mineral density and cardiovascular disease.38
 

Conclusion

Drug treatment of psychoses results in several side effects. Women, particularly those who are elderly, are more vulnerable to tardive dyskinesia and hyperprolactinemia. There is a large variability among available antipsychotic agents in their propensity to produce different side effects. Thus, clinicians should be able to switch from one medication, or one class of drugs, to another in order to manage many of these side effects. Patient characteristics, such as age, may also help in selecting a particular drug to prevent emergence of side effects. In this context, pharmacogenetics are beginning to emerge which will allow the clinicians in the near future to customize drug treatment based on genotype information.39
 

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