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Primary Care Companion Reports
A Reference for Primary Care Physicians From The Journal of Clinical Psychiatry, 2003, Vol. 3, No. 3.
Atypical Antipsychotics in Primary Care
Safety Considerations in the Use of Atypical Antipsychotics
Introduction
Today, primary care physicians are writing about 20% of the antipsychotic prescriptions being filled by pharmacies. Since many antipsychotics have the potential for serious side effects, safety is as important as efficacy in the selection of medication for patients who require antipsychotic treatment. As the rate of patients who visit primary care physicians for the treatment of mental disorders rises, these physicians are faced with the need to effectively handle potential side effects.
Atypical antipsychotics differ in side effect profiles, ranging from sedation to more serious issues such as diabetes mellitus and anticholinergic side effects. These side effects can significantly impair a patient's ability to function and return to normal social life after the resolution of psychotic symptoms. Some special groups, such as the elderly, are at a greater risk for serious side effects.
Although atypical antipsychotics have side effects, the risk of serious side effects should not prevent primary care physicians from using them to treat patients with schizophrenia. Many times, failing to treat a patient because of the risk of a potentially serious side effect places the patient at a higher risk for a far more serious problem. It is important that the physician find the right balance between adverse side effects and benefits when treating patients with atypical antipsychotics.
Reference
1. IMS Health. National Prescription Audit Plus. Fairfield, Conn: IMS Health; 2001 Joseph A. Lieberman III, M.D., M.P.H.
REPORTS
FACULTY
Chair, Joseph A. Lieberman III, M.D., M.P.H., Department of Family Medicine, Jefferson Medical College, Hockessin, Del.
Sally Berry, M.D., Medical Affairs, Janssen Pharmaceutica, Titusville, N.J.
Del Miller, Pharm.D., M.D., Psychiatry Research, University of Iowa, Iowa City
Bruce L. Saltz, M.D., Mental Health Advocates, Inc., Boca Raton, FL
Stephen M. Stahl, M.D., Ph.D., Neuroscience Education Institute, Carlsbad, Calif.
Supported by an unrestricted educational grant from Janssen Pharmaceutica, L.P.
SEDATION AND SLEEP DISTURBANCES
Sedation and sleep disturbances can impair a person's ability to function normally over the long term. These problems can effect patients who are trying to go to school, work, or normal social activities. Antipsychotics differ in their sedative properties, and sedation may be related to the dosage.
Sedation
Sedative effects of antipsychotics are often of benefit in acutely psychotic patients as these individuals frequently suffer from severe insomnia. Sedation can also help in the treatment of acutely agitated patients, although emerging evidence suggests that sedation may not be needed to treat agitation. However, sedation can also be detrimental to a patient's health over the long term, preventing normal social interactions and interfering with the patient's ability to benefit from other treatments such as psychosocial training and psychiatric rehabilitation.
Sedation is only partly related to the affinity of a drug for the histamine H receptors, since the ability of an antipsychotic drug to block the H receptors is not directly related to the sedative properties of the antipsychotic. Antipsychotic-induced sedation may also be dose related. For example, quetiapine has a lower affinity for the H receptor than risperidone or ziprasidone, but the typical dosage is 300 to 400 mg/ day, and at such a high dose, sedation can occur. In general, the high-milligram, low-potency antipsychotics, such as quetiapine and clozapine, produce more sedation than the low-milligram, high potency agents, such as risperidone.
Jibson and Tandon compared the degree of sedation caused by various antipsychotics from collected clinical data. Of the atypical antipsychotics, clozapine appears to cause the greatest amount of sedation followed by olanzapine, quetiapine, and risperidone. Ziprasidone probably causes the least amount of sedation (Table 1).
Diagnosis drug-induced sedation can be difficult since sedation is often confused with the negative symptoms of schizophrenia-avolition, amotivation, asociality, withdrawal, or anhedonia. Confusion can also arise when trying to determine if a patient's cognitive impairment is part of the illness of schizophrenia or is related to the sedative effects of an antipsychotic.
REPORTS
Although sedation affects patients of all ages, sedation among the elderly is more common and often more serious than in younger patients. Standard doses of antipsychotics may cause more sedation among elderly patients than younger patients. Sedation in the elderly tends to last longer and can impair arousal levels during the day. In addition, the risk of falls increases as elderly patients' impairment levels rise.
Effectively treating a patient's psychological challenge without overly sedating him or her can be a problem. The Expert Consensus Guidelines for the Treatment of Schizophrenia outlined several effective methods for dealing with sedation in patients treated with antipsychotics (Table 2).
First, the clinician should try to eliminate other sedating agents a patient may be taking, including tricyclic antidepressants and mood stabilizers. Second, the clinician should recommend bedtime dosing, if possible, to decrease daytime sedation, If the whole dose cannot be taken at bedtime, the majority of the dose should be taken at that time. If sedation remains a problem, physicians might consider reducing the dose of the antipsychotic. Reducing antipsychotic dosage should be done slowly and cautiously in order to maintain the drug's therapeutic effect. Another option is to switch to a less sedating antipsychotic. Physicians must also consider other medical problems patients might have, such as hypothyroidism, that may cause sedation. Lastly, the clinician could consider using caffeine, buproprion, or stimulants.
However, using stimulants to control sedation in a schizophrenic patient is highly controversial, and physicians should try to control sedation by other means. One option is to treat sedated patients with modafinil. Modafinil may improve drug-induced sedation, possibly by activating histaminergic projections to the frontal cortex from the tuberomammillary nucleus. Although modafinil is effective, it can be expensive, which may be a barrier for some patients.
PRIMARY CARE COMPANION REPORTS
October 2003 (volume 3, Number 3)
Statement of Need and Purpose
Atypical antipsychotics are increasingly being used for special populations, such as children and the elderly, and for new indications, including severe anxiety and effective disorders. This educational activity is designed to meet the needs of primary care physicians who have requested information about the use of atypical antipsychotics in their practice. There are no prerequisites for participating in this activity.
Accreditation Statement
Physicians Postgraduate Press, Inc. is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.
Credit Designation
Physicians postgraduate Press, Inc. designates this educational activity for up to 1 Category credit toward the AMA Physician's Recognition Award. Each participant should claim only those credits that he/she actually spent in the educational activity.
REPORTS
Date of Original Release/Review
This Primary Care Companion Reports was published in October 2003 and is eligible for CME credit through October 31, 2005. The latest review of this material was September 2003.
Faculty Disclosure
In the spirit of full disclosure and in compliance with all ACCME Essential Areas and Policies, the faculty for this CME activity was asked to complete a full disclosure statement. The information received is as follows:
Dr. Lieberman is a consultant for Abbott, Bristol-Myers Squibb, Cephalon, Forest, Janssen, Eli Lilly, Novo Nordisk, Organon, Ortho-McNeil, Pfizer, and Sanofi-Synthelabo; Dr. Berry is an employee of Johnson & Johnson; Dr. Miller has received grant/research support from Bristol-Myers Squibb and Eli Lilly, and is a member of the speakers/advisory boards for Bristol-Myers Squibb and Janssen; Dr. Saltz is an employee of Mental Health Advocates, Inc.; is a consultant for Solvay, Bristol-Myers Squibb, Novartis, Janssen, Johnson & Johnson, AstraZeneca, and Eli Lilly; has received grant/research support from the Small Business Innovation Research section of the National Institutes of Health; and is a member of the speakers/advisory board for Bristol-Myers Squibb; and Dr. Stahl has received grant/ research support from Asahi, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cephalon, Cypress Bioscience, Pierre Fabre, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Lundbeck, Organon, Parke-Davis, Pfizer, Pharmacia, Sanofi-Synthelabo, Solvay, Watson, Wyeth, and Yamanouchi; is a consultant for and has received honoraria from Asahi, Abbott, AstraZeneca, Aventis, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cephalon, Cypress Bioscience, Eli Lilly, Pierre Fabre, Forest, GlaxoSmithKline, Janssen, Lorex, Lundbeck, Neurocrine, Novartis, Organon, Parke-Davis, Pfizer, Pharmacia, Roche, Sanao, Sanofi-Synthelabo, Searle, Solvay, Sumitomo, Takeda Abbott, Watson, Wyeth, and Yamanouchi; and is a member of the speakers bureaus for AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Forest, GlaxoSmithKline, Janssen, Lundbeck, Organon, Parke-Davis, Pfizer, Pharmacia, Sanofi-Synthelabo, Solvay, Watson, and Wyeth.
Disclosure of Off-Label Usage
The authors have determined that, to the best of their knowledge, bupropion is not approved by the U.S. Food and Drug Administration for the treatment of stimulation and modafinil is not approved for the treatment of drug-induced sedation. If you have questions, contact the medical affairs department of the manufacturer for the most recent prescribing information.
Acknowledgement
This Primary Care Companion Reports was derived from the symposium "Using Atypical Antipsychotics in Primary Care," which was held June 2-4, 2002, in Washington, D.C., and was independently developed by the Physicians Post Graduate Press, Inc. Office of Continuing Medical Education pursuant to an unrestricted educational grant from Janssen Pharmaceutica, L.P. The opinions expressed herein are those of the authors and do not necessarily reflect the views of the CME provider and publisher or the commercial supporter.
Editor- Joseph A. Lieberman III, M.D., M.P.H.
Project Assistant- Elaina Cubine, B.A.
CME Director- Jane Eckstein, M.A.
Assistant CME Director- Becky Derych, M.A.
CME Coordinator- Diane Brunner
Print Media Manager- Erik Adamec
External CME Advisory Board
Michael H. Ebert, M.D., Chair; Richard C. Shelton, M.D., Vice Chair; Benjamin L. Beatus, Jr. M.D.; E. Sherwood Brown, Ph.D., M.D.; Stephanie C. Avanaugh, M.D.; Lawrence J. Cohen, Pharm. D.; Larry Culpepper, M.D., M.P.H.; John M. Downs, M.D.; Allen J. Gelenberg, M.D.; Radwan F. Haykal, M.D.; Paul King, M.D.; Joseph A. Lieberman, III, M.D., M.P.H.; Elizabeth H. B. Lin, M.D., M.P.H.; Frank W. Ling, M.D.; J. Sloan Manning, M.D.; Meir Steiner, M.D., Ph. D.
Sleep Disturbances
While antipsychotics can be the cause of sleep disturbances, untreated schizophrenia itself can cause problems with sleep. Although patients with schizophrenia or depression are often characterized as sleeping excessively, many individuals with schizophrenia, bipolar illness, depression, or dementia experience insomnia. It is common for patients with these disorders to have their nights and days switched around. A decrease in sleep efficacy has been observed among patients with schizophrenia when compared with healthy controls. Tandon et al. observed the sleep cycles of 20 drug-naïve schizophrenic patients, 20 schizophrenic patients previously administered antipsychotics, and 15 healthy controls. Electroencephalographic sleep was measured and sleep variables were analyzed by the Kruskal-Wallis test and that Mann-Whitney U test. Both schizophrenic groups showed significant impairment of sleep continuity and shorter rapid eye movement (REM) latency. The previously treated group displayed significantly more REM sleep and less stage two sleep than the other two groups.
Another study observed sleep measures and sleep structure in 5 haloperidol-treated and 5 risperidone-treated patients by using polysomnography. Data were analyzed with the Mann-Whitney U tests, and while no significant difference was seen in sleep variables, the duration of slow-wave sleep period was found to be significantly longer in the risperidone group, suggesting that risperidone may improve the quality of sleep among patients with schizophrenia.
Treatment guidelines for patients suffering from sleep disturbances and insomnia are similar to those for patients with severe sedation. First, the clinician should eliminate other agents that may cause sleep disturbances.
While nighttime dosing is effective with sedation, daytime dosing may be effective when treatments cause insomnia. Physicians should consider switching the patient to a more sedating antipsychotic- olanzapine, clozapine, or quetiapine- if the current antipsychotic continues to cause problems with sleep. Another consideration would be the use of sedatives; benzodiazepines, antihistamines, or chloral hydrate can be effective options.
References
1. Battaglia J., Lindborg SR, Alaka K, et al. Calming versus sedative effects of intramuscular olanzapine in agitated patients. Am J Emerg Med 2003; 21:192-198
2. Richelson E. Receptor pharmacology of neuroleptics: relation to clinical effects. J Clin Psychiatry 1999;60 (suppl 10):5-14
3. Kane JM, Schulz SC, Jeste DV, et al. Assesment of therapeutic efficacy versus sedation with antipsychotic agents. J Clin Psychiatry Intercom; June 1996
4. Jibson MD, Tandon R, New atypical antipsychotic medication. J Psychiatr Res 1998;32:215-228
5. McEvoy JP, Scheifler PL, Frances A, eds. The Expert Consensus Guidelines Series: Treatment of Schizophrenia 1999. J Clin Psychiatry 1999;60 (suppl 11):1-80
6. Schammell TE, Eastbrook IV, McCarthy MT, et al. Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J Neurosci 2000;20:8620-8628
7. Tandon R, Shipley JE, Taylor S, et al. Electroencephalographic abnormalities in schizophrenia: relationship to positive/negative symptoms an superior neuroleptic treatment. Arch Gen Psychiatry 1992;49:185-194
8. Yanishita H, Morinobu S, Yamawaki S, et al. Effect of risperidone on sleep and schizophrenia: a comparison with haloperidol. Psychiatry Res 2002;109:137-142
Del Miller, Pharm. D., M.D.
METABOLIC CHANGES ASSOCIATED WITH ANTIPSYCHOTIC USE
Among patients treated with antipyschotics, physical changes such as weight gain may be indication of metabolic side effects. Physicians treating patients with psychiatric disorders need to be attuned to physical changes that may be a sign of serious medical conditions such as diabetes or syndrome X.
In the United States, the risk of type II diabetes is growing to epidemic proportions. Today, physicians are more attuned to the risk of diabetes among patients, but many physicians are unaware that disorders such as bipolar disorder and schizophrenia are associated with increased risk of diabetes.
A recent analysis of prescription claims for patients receiving diabetes-related medications and antipsychotic medications and antipsychotic medications suggests that patients with schizophrenia suffer from increased rates of type II diabetes mellitus when compared with the general population. This increase was largely independent of which antipsychotic medication patients were prescribed.
While untreated patients with schizophrenia have a higher risk for abnormalities in glucose regulation and insulin resistance than the general population, conventional and atypical antipsychotics and anticonvulsants are also associated with factors in the development of diabetes such as increased weight gain, hyperglycemia, and diabetic ketoacidosis.
Sernyak et al. observed the development of type 1 and 2 diabetes among patients treated with atypical and typical antipsychotics. Outpatients with schizophrenia who had been prescribed either atypical or typical antipsychotics within a 4-month period were divided into 5 groups according to age: under 40, 40 to 49, 50 to 59, 60 to 69, and over 70 years old. Patients treated with atypical antipsychotics (N=22,648) had significantly higher rate of diagnosis of diabetes among the 3 younger age groups during treatment. For example, the under 40 age group had an 8.7% rate of diabetes when prescribed atypicals, compared with a 6.43% rate with typical antipsychotics (p=.007) (Figure1).
The use of antipsychotics not only increases the risk of diabetes but also increases the risk of metabolic syndrome, which is sometimes referred to as syndrome X and can include weight gain and hypertriglyceridemia along with increased insulin, glucose, and cholesterol levels. A patient's genetic makeup and environment directly contribute to syndrome X, and patients who develop syndrome X are at an increased risk for heart disease.
Treatment Strategies
When treating a patient with or at-risk for syndrome X, physicians need to be especially vigilant in monitoring antipsychotic medication. With the increased emergence of diabetes and syndrome X, clinicians should consider screening hyperlipidemia or hyperglycemia annually and prior to starting or changing an antipsychotic treatment. Physicians should consider treatment for lipid dysfunction or weight gain if they emerge during treatment.
Although a dose-response relationship for weight gain has not been established, the development of hyperglycemia after the initiation of or increase in antipsychotic dose could signal a problem. Likewise, physicians who have been worried about metabolic issues with a patient on antipsychotic treatment should increase the level of monitoring when raising the dose.
Dramatic weight gain, such as 30 to 40 lb, in a patient also signals a problem. Weight gain poses serious health risks and can be distressing issue for the patient. Physicians should educate patients and their families that weight gain is possible and to be on the lookout for it. Patients can monitor weight by watching how their clothes fit, especially around the waist. Most patients are at risk to gain 5 to 7 lbs. This weight, while perhaps cosmetically undesirable, is much easier to manage and less of a health risk than 30 or 40 lbs.
Physicians should not only weigh patients on regular visits, but pay attention to an increase in weight and be proactive in advising patients. Physicians might remind patients to try leaving food on their plate or walking stairs instead of taking the elevator. With extremely impaired patients or those who already have substantial weight gain, suggesting a nutritional consultation may help.
Despite the risk of a serious medical condition that weight gain and metabolic changes present, clinicians need to treat the mental disorder. The treatment of bipolar disorder and schizophrenia involves the right balance for the patient in terms of adverse effects versus benefit. Failing to treat a patient because of the risk or complications of diabetes places the patient at a higher risk for more serious problems.
References
1. Kwong K, Cavazzoni P, Hornbuckle K, et al. Higher incidences of diabetes mellitus during exposure to antipsychotics: findings from a retrospective cohort study in the U.S. Presented at the 41st annual meeting of the New Clinical Drug Evaluation Unit; May 28-31, 2001; Phoenix, Ariz
2. Braceland FJ, Meduna LJ, Vaichulis JA. Delayed action of insulin in schizophrenia. Am J Psychiatry 1945;102:108-110
3. Allison DB, Mentore JL, Heo M, et al. Antipsychotic induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999;156:1686-1696
4. Jallon P, Picard F.Body weight gain and anticonvulsants: a comparative review. Drug Saf 2001;24:969-978
5. Sernyak MJ, Leslie DL, Alarcon RD, et al. Association of diabetes mellitus with the use of atypical neuroleptics in the treatment of schizophrenia. Am J psychiatry 2002;159:561-566
6. Liese, AD, Mayer-Davis EJ, Haffner SM. Development of the multiple metabolic syndrome: an epidemiologic perspective. Epidemiologic Rev 1998; 20:157-172
7. American Heart Association. Syndrome X or metabolic syndrome. Available at: http://ww.americanheart.org/presenter.jhtml?identifier=534. Accessed April 8, 2003
Stephen M. Stahl, M.D., Ph. D.
DRUG-INDUCED MOVEMENT DISORDERS
In the elderly population, antipsychotic drugs are often underutilized, and many mental illnesses are misdiagnosed, unrecognized, or under-treated. Studies of the availability of mental health services in nursing homes, revealed that 65% of nearly 2000 nursing home residents were found to have some type of mental disorder. However, the 1-month rate of contact with mental health professionals for this group was only 4.5%.
Although many elderly patients suffer from the underutilization of antipsychotics, patients who do receive conventional antipsychotic treatment are at risk for developing serious side effects. The risk is much lower in patients who receive atypical antipsychotics. Drug-induced movement disorders are more common and more persistent in the elderly than in the younger population. The prevalence of extrapyramidal dysfunction-tardive dyskinesias and dystonia, drug-induced parkinsonism, and akathisia-is 3 to 6 times more prevalent in institutionalized elderly patients who take conventional antipsychotic medication than in elderly patients who do not.
Movement disorders can be detrimental to an elderly patient's quality of life, creating difficulties in moving, eating, sleeping. Physicians need to be able to recognize the difference the difference between movement disorders in order to adequately provide treatments for their patients.
Tardive Dyskinesia
Tardive dyskinesia is a chronic drug-induced movement disorder. Patients with tardive dyskinesia most often suffer from involuntary movements of the muscles of the face but can also have involuntary movement of the arms, fingers legs, and toes (Table 3). It tends to be persistent in older adults, typically after several months of treatment with conventional antipsychotics. In younger patients, the incidence of tardive dyskinesia after 1 year of exposure to an antipsychotic drug is approximately 5% per year. In contract, the incidence of tardive dyskinesia development in older adults was reported as 25%. After 3 years of conventional treatment, the incidence of tardive dyskinesia in the older population increased to 53%.
Currently, a uniformly effective treatment for tardive dyskinesia or chronic tardive-type dystonias does not exist. Low-potency and high-potency conventional antipsychotics are both likely to cause movement side effects. However, newer antipsychotics such as olanzapine and risperidone are less likely than haloperidol to cause tardive dyskinesia and dystonia.
When treating tardive dyskinesia, physicians should try lowering the antipsychotic dose or discontinuing the antipsychotic altogether. However, if symptoms persist, a dose increase may actually cause suppression of these movements in the most severe version of choreiform dyskinesia and dystonia.
Drug-Induced Parkinsonism
Drug-induced parkinsonism is a common side effect of treatment with conventional antipsychotic medications. Approximately 40%of older patients treated with conventional antipsychotics, even at very low doses, develop drug-induced parkinsonism. Once parkinsonism develops, it may continue unabated for as long as the patient is treated with the offending agent. Drug-induced parkinsonism can cause discomfort and can contribute to falls in older adults. The added difficulty in moving may also contribute to social isolation and create an additional burden on caregivers.
Tremors are one of the cardinal features of drug-induced parkinsonism and may occur at rest or upon moving. They can disappear with sleep and worsen with stress and anxiety. Parkinsonian tremor is sometimes difficult distinguish from lithium-induced tremor or tremor associated with thyroid, liver, or cerebellar diseases. However, these other tremors usually oscillate at a slightly faster frequency, and cerebellar disease tremor is often a more coarse form (Table 4).
One way physicians can determine drug-induced parkinsonism is to observe the patient. Watching the patient enter the examination room, perform incidental activities such as removing shoes and socks, and exit the examination room may reveal clinically important findings not seen at other times. The treatment of drug-induced parkinsonism includes lowering the dose of the antipsychotic, changing to a low-potency or atypical antipsychotic, and adding an anticholinergic agent if necessary.
Akathisia
Akathisia is a type of restlessness that many clinicians confuse with tremor. It usually involves the lower extremities but can also involve the upper body (Table 5). Debates are ongoing among researchers about whether rocking behavior is primarily an akathisia or choreiform-type of dyskinesia. Akathisia usually worsens when the dose of a drug is raised. Lowering the dosage is likely to reduce symptoms of akathisia. Also, adding a benzodiazepine, a B-blocker, or an a-adrenergic agent may help.
Conclusion
As a greater number of older adults are switching to managed care programs for medical and mental health care, it's becoming increasingly common for non-psychiatric physicians to prescribe antipsychotics. With this increase in non-psychiatric prescribing, educational programs are needed to train specialists, nurses, psychologists, social workers, and primary care physicians in the use of these agents and recognition of drug-induced motor side effects.
References
1. Lair T, Lefkowitz D. National Medical Expenditure Survey Research Findings and Mental Health: Mental Health and Functional Status of Results of Nursing and Personal Homes. Rockville, MD: US Dept Health Human Services Care, Agency for Health Care Policy and Research; 1990. DHHS Publication 90-30470
2. Rovner BW, Kafonek S, Filipp L, et al. Prevalence of mental illness in community nursing homes. Am J Psychiatry 1986;143:1446-1449
3. Avorn J, Monane E, Everitt DE, et al. Clinical assessment of extrapyramidal signs in nursing home patients given antipsychotic medication. Arch Intern Med 1994;154:1113-1117
4. Talbott JA, Hales RE, Yudofsky SC, et al. The American Psychiatric Press Textbook of Psychiatry. Washington, D.C.: American Psychiatric Press, Inc; 1988:781-782
5. Kane JM, Woerner M, Lieberman JA. Tardive dyskinesia: prevalence, incidence, and risk factors. J Clin Psychopharmacol 1988;8 (suppl 4):259-262
6. Saltz BL, Woerner MG, Lieberman JA, et al. Development of drug-induced parkinsonism in elderly individuals receiving neuroleptics for the first time. Presented at the International Congress on Schizophrenia Research. Tucson, AZ; April 1990
7. Woerner MG, Alvir JM, Saltz BL, et al. Prospective study of tardive dyskinesia in the elderly: rates and risk factors. Am J Psychiatry 1998;155:1521-1528
8. Glazer WM. Expected incidence of tardive dyskinesia associated with atypical antipsychotics. J Clin Psychiatry 2000;61 (suppl 4):21-26
9. Talbott JA, Hales RE, Yudofsky SC, et al. The American Psychiatric Press Textbook of Psychiatry. Washington, D.C.: American Psychiatric Press, Inc; 1988:779-780
10. Saltz BL, Woerner MG, Robinson DG, et al. Side effects of antipsychotic drugs: avoiding and minimizing their impact in elderly patients. Postgrad Med 2000;107:169-178
Bruce L. Saltz, M.D.
Side Effects Associated With Increased Prolactin
Galactorrhea
One upsetting side effect of hyperprolactinemia is galactorrhea, a discharge from one or both breasts. Galactorrhea does not pose a risk to women's overall health, but most women consider this side effect to be unacceptable. Although women choose to continue with the antipsychotic treatment and cope with galactorrhea, many women are unhappy with this side effect and choose to discontinue treatment.
Amenorrhea
Increased prolactin levels can also cause amenorrhea or irregular menstruation. For some women, the lack of menstruation can be extremely distressing. Physicians should be supportive and remind patients that amenorrhea is not always bad. Amenorrhea may reduce the risk of unplanned pregnancies among patients with schizophrenia. Menstrual irregularities are common in women who have participated in clinical schizophrenia trials.
Gynecomastia
Another consequence is gynecomastia, an increase in breast tissue associated with pain, which can be cosmetically troubling to men, especially young men. Generally, gynecomastia is not reported in women.
Sexual Side Effects
Hyperprolactinemia has also been associated with sexual side effects, such as erectile dysfunction, reduced libido, or anorgasmia. One double-blind, randomized trial compared risperidone and olanzapine in patients with schizophrenia or schizoaffective disorder. Participants were asked a series of questions to determine a relationship between specific side effects and prolactin levels. At the end of 8 weeks, no correlation between prolactin levels and sexual dysfunction was found.
Children
Children have been safely treated with conventional and atypical antipsychotics for decades. It may be difficult to distinguish a side effect possibly related to increased prolactin from normal sexual maturation in youngsters. For example, it is not uncommon for children during the peripubertal years to develop gynecomastia.
A definitive study has yet to be conducted on the effect of prolactin changes in children. With limited data, physicians need to be aware that children are at risk for prolactin irregularities and balance potential risks and benefits of antipsychotic treatment.
Management of Increased Prolactin Levels
Antipsychotic treatment does not require routine tests of a patient's prolactin levels. Physicians can assume that a patient treated with a conventional antipsychotic or risperidone is likely to experience some degree of hyperprolactinemia. Physicians should focus on patients' complaints of troublesome overt symptoms related to hyperprolactinemia. For example, since fertility problems and irregular menstrual cycles are associated with hyperprolactinemia, women complaining about these symptoms should have their prolactin levels checked. Steps to reduce hyperprolactinemia include reducing the dosage, switching to an antipsychotic not associated with hyperprolactinemia, and adding a dopamine agonist (Table 6).
References
1. Maguire GA. Prolactin elevation with antipsychotic medications: mechanisms of action and clinical consequences. J Clin Psychiatry 2002;62 (suppl 4):56-62
2. SeemanP. Atypical antipsychotics: mechanisms of action. Can J Psychiatry 2002;47:27-38
3. Kleinberg DL, Davis JM, DeCoster R, et al. Prolactin levels and adverse events in patients treated with risperidone. J Clin Psychopharmacol 1999;19:57-61
4. Berry SA, Martinez RA, Gudelsky GA, et al. Serum prolactin in schizophrenia. Presented at the 39th annual meeting of the American College of Neuropsychopharmacology; Dec 10-14, 2000; San Juan, Puerto Rico
5. Mather R, Braunstein GD. Gynecomastia: pathophysiologic mechanisms and treatment strategies. Horm Res 1997;48:95-102
Sally Berry, M.D.
MANAGING ANTICHOLINERGIC SIDE EFFECTS
The potential medical complications of anticholinergic side effects are appreciable, and in susceptible patients-particularly older patients or patients with preexisting conditions-these side effects can be debilitating. Physicians need to be able to identify anticholinergic side effects and to effectively treat patients before these side effects result in serious medical conditions.
Anticholinergic side effects occur in medications with high anticholinergic properties. Atypical antipsychotics tend to have higher anticholinergic properties than conventional antipsychotics, although the anticholinergic level varies between drugs. For example, Chengappa and colleagues observed the differences between the atypical antipsychotics olanzapine and clozapine. Twenty-four participants with a DSM-IV diagnosis of chronic schizophrenia, schizoaffective disorder, or bipolar I disorder and who had been prescribed either clozapine or olanzapine for a minimum of 8 weeks were recruited. Participants were required to have been on a stable dose of either medication for at least 4 weeks, the average daily doses being 15 mg/day for olanzapine and 444 mg/day for clozapine. When blood samples were obtained, the olanzapine group had lower serum anticholinergic levels than the clozapine group. Olanzapine-treated patients also had significantly lower scores on anticholinergic items such as constipation, micturition disturbances, palpitations, and tachycardia, while a few clozapine-treated patients scored in the markedly impaired range on items pertaining to constipation, palpitations, and excessive salivation.
Anticholinergic side effects can be broken down into 2 categories: peripheral and central. Peripheral side effects carry a higher risk for multiple health problems (Table 7). Central side effects are often misdiagnosed or not recognized because they resemble the patient's psychosis (Table 8). Physicians must thoroughly interview patients with possible anticholinergic side effects and pay attention to their responses in order to adequately treat these symptoms.
General Approaches to Anticholinergic Side Effects
As in most cases, the first step to relieve anticholinergic side effects is to decrease the dose of the antipsychotic while attempting to maintain the therapeutic effect. Another option is to change to an antipsychotic with a lower anticholinergic profile. The clinician should review other medications a patient may be taking and eliminate or lessen the dose of the agents known to produce anticholinergic side effects. Reviewing a patient's medications can be particularly beneficial in elderly patients who are often prescribed several different medications at one time. It is important for physicians to determine how many of these medications are really necessary to the patient's health.
Although most problems with antipsychotics, for instance sleep disturbances or metabolic changes, can be resolved by reducing the dosage or switching the medication, specific situations arise that physicians should know how to handle. Problems such as narrow angle glaucoma, prostatic hypertrophy, and anticholinergic delirium are not only serious to a patient's health, they also have the potential to nullify the efficacy of antipsychotic treatment.
Contraindications to Antipsychotic Treatment
Narrow angle glaucoma is an absolute contraindication to the use of antipsychotics. Antipsychotic treatment while a patient is suffering from glaucoma is inadvisable. Glaucoma must be treated before a patient can continue with an antipsychotic treatment.
Prostatic hypertrophy is a relative contraindication to the use of antipsychotics. Bethanechol at 25 to 50 mg/day can be used throughout treatment to offset the obstruction, but patients must be carefully monitored.
Anticholinergic Delirium and Crisis
Anticholinergic delirium constitutes a medical emergency. Symptoms and anticholinergic delirium consists of hot dry skin, dry mucous membranes, dilated pupils, absent bowel sounds and tachycardia. Physostigmine can be used to establish a diagnosis of anticholinergic delirium. However, physostigmine cannot be used to sustain a reversal of symptoms. Patients who are not treated for anticholinergic delirium are at risk for developing a cholinergic crisis. Symptoms of cholinergic crisis are nausea, vomiting, bradycardia, and seizures. Atropine can adequately treat a cholinergic crisis.
References
1. Chengappa KN, Pollock BG, Parepally H, et al. Anticholinergic differences among patients receiving standard clinical doses of olanzapine or clozapine. J Clin Psychopharmacol 2000;20:311-316
Joseph A. Lieberman III, M.D., M.P.H.
Drug Names: atropine (Atropine and others), bethanechol (Urecholine), bupropion (Wellbutrin and others), clozapine (Clozaril and others), haloperidol (Haldol and others), lithium (Lithobid, Eskalith CR, and others), modafinil (Provigil), olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ziprasidone (Geodon).
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