Maintenance and Long-Term Treatment Issues in Special Populations: BD and Dementia

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Psychiatric Times

January 2005

Vol. XXII

Issue 1

Sponsored by CME LLC for 1.5

Category 1 credits.

Original release date 1/05. Approved for CME credit through 12/31/05.

Educational Objectives:

After reading this article, you will be familiar with:

• The needs of special populations with bipolar disorder with regard to long-term compliance with pharmacotherapy.
• Gender and ethnic differences in the treatment of various forms of dementia.

Who will benefit from reading this article?

Psychiatrists, primary care physicians, neurologists, nurse practitioners, psychiatric nurses and other mental health care professionals.

Continuing education credit is available for most specialties. To determine if this article meets the CE requirements for your specialty, please contact your state licensing board.

Dr. Pies is clinical professor of psychiatry at Tufts University. His most recent books include Creeping Thyme, a collection of poetry (Brandylane Publishing); Zimmerman's Tefillin, a short story collection (Publish America); and Handbook of Essential Psychopharmacology, 2nd ed., forthcoming from American Psychiatric Publishing.

(This is the second of a two-part series on long-term treatment issues in special populations. The first one focused on issues in schizophrenia and ran in Psychiatric Times December 2004, p66--Ed.)

"Ms. P" is a 32-year-old married female with a diagnosis of bipolar I disorder. The patient has a history of three previous manic episodes with psychotic features and four episodes of severe major depression, accompanied by suicidal ideation. The patient has been poorly tolerant of several anticonvulsant mood stabilizers, including divalproex (Depakote), carbamazepine (Epital, Tegretol) and lamotrigine (Lamictal). She has been maintained on lithium (Eskalith, Lithobid) 900 mg/day for the past two years, with reasonably good control of her mood swings. However, she has developed mild hypothyroidism within the past two months (thyroid stimulating hormone [TSH]=7, normal >5) attributed to the lithium and now expresses the wish to become pregnant. What are the most feasible treatment options at this point?

Issues in Bipolar Disorder

Women. Whereas the prevalence of bipolar disorder (BD) is roughly equal in males and females, some evidence suggests higher rates of rapid cycling among women (Bauer and Whybrow, 1991; Burt and Hendrick, 1997; Leibenluft, 1996). Notably, thyroid abnormalities--which may predispose to rapid cycling--are several times more common among women than men (Bauer and Whybrow, 1991). Furthermore, women with BD may experience premenstrual relapse or exacerbation of symptoms (Hendrick et al., 1996).

Special long-term challenges arise in treating women with BD of child-bearing age (Chaudron and Pies, 2003). Women with BD have a 100-fold higher risk to develop a puerperal (postpartum) psychosis than women without BD (Pariser, 1993). Most postpartum psychotic episodes are manic or depressive and occur within the first 30 days following delivery (Kendell et al., 1987). Stewart et al. (1991) suggested that lithium prophylaxis during the acute postpartum period may reduce the rate of relapse from 50% to 10%.

The issues of long-term treatment with a mood stabilizer during pregnancy, however, are more complex. The teratogenic effects of mood stabilizers, together with their effects on the nursing infant, are serious concerns (Chaudron and Pies, 2003). Maternal exposure in the first trimester to carbamazepine or divalproex is associated with a markedly increased risk of neural tube defects, with a risk of 1% and between 3% and 8%, respectively. For divalproex, this risk is estimated to be a 15-fold increase compared with the general population (Burt and Hendrick, 1997). Although polycystic ovarian syndrome (PCOS) has been associated with divalproex use in women with epilepsy, this association has not been clearly seen in women with BD (Rasgon et al., 2000).

Altshuler et al. (1996) concluded that the prevalence of Ebstein's anomaly (a malformation of the tricuspid valve) is roughly 10 to 20 times the rate in the general population following first-trimester exposure to lithium. However, the absolute risk appears to be less than once believed. Furthermore, the risk of untreated bipolar illness must also be considered; abrupt discontinuation of lithium will typically lead to relapse of mania or major depression and occasionally to lithium "resistance" upon re-starting treatment. Therefore, compared with divalproex or carbamazepine, lithium may be the safest mood stabilizer to use during pregnancy--at least after the first trimester. There are as yet too few well-designed studies of lamotrigine or oxcarbazepine (Trileptal) in pregnancy to provide confident advice to patients (Newport et al., 2004).

The use of psychotropic medications during the postpartum period can be complicated by a mother's wish to breast-feed. For women with BD, this may pose complex risk-benefit decisions, as reviewed by Chaudron and Pies (2003). In general, the trend has been toward relaxing restrictions on breast-feeding while taking mood stabilizers, albeit with very careful monitoring of the neonate.

There are conflicting data regarding gender differences in rates of long-term medication adherence in BD (Colom and Vieta, 2002). However, one early study of nonadherence found that women more than men were prone to missing their high periods and to feel bothered by the idea of their moods being "controlled" by medication (Jamison et al., 1979). These concerns--in addition to the not unrealistic fear of weight gain--may pose significant challenges in the long-term treatment of women with BD.

The take-home message regarding women with BD. Thyroid disease, premenstrual exacerbation of bipolar symptoms, teratogenic effects of medications used during pregnancy, postpartum psychosis and neonatal toxicity from the use of medications while breast-feeding are all potential complications in females with BD. Long-term treatment in this population entails a careful risk-benefit assessment of these issues, as well as close cooperation between psychiatrists, obstetricians and other physicians. Compared with divalproex or carbamazepine, lithium may be the safest mood stabilizer to use during pregnancy, notwithstanding some risk of cardiac malformations with first-trimester lithium use. Asking about missing their high periods or feeling "controlled" by medication may help improve medication adherence among female patients with BD. Helping the patient reduce medication-related weight gain may also improve compliance.

Children and adolescents. The prevalence of BD in younger populations remains a matter of some controversy; however, prevalence rates may be as high as 5% when including subsyndromal forms of the illness (Wolf and Wagner, 2003). Bipolar disorder in younger cohorts may be difficult to diagnose, owing to the presence of comorbid conditions (e.g., attention-deficit/hyperactivity disorder) and mixed features of mania and depression. Bipolar disorder beginning in the younger years is associated with chronicity, high severity and disruption of normal psychosocial development (Wolf and Wagner, 2003).

Long-term, controlled studies of treatment in younger populations are generally lacking; hence, treatment decisions are often based on small cases studies and extrapolations from the adult literature. This problem is especially vexing, because many children and adolescents with BD require more than one medication for long-term management (Wagner, 2004; Wolf and Wagner, 2003). A comprehensive review of BD treatment in younger populations is beyond the scope of this paper. Although most information is derived from experience with lithium and divalproex, several reviews cite evidence favoring use of lithium, divalproex, carbamazepine and several atypical antipsychotics, including olanzapine (Zyprexa), risperidone (Risperdal) and quetiapine (Seroquel) (Wagner, 2004; Wolf and Wagner, 2003). Unfortunately, few of the studies cited used long-term, randomized, placebo-controlled designs. Most were small, uncontrolled or involved more than one medication. Indeed, Wolf and Wagner (2003) concluded:

Controlled research is needed to identify efficacious treatment for bipolar disorder in children and adolescents and to establish optimal treatment duration. It is important to determine whether early treatment intervention affects the course of the illness and reduces the likelihood of its occurrence in adulthood.

Current American Psychiatric Association guidelines recommend that treatment with a maintenance agent should continue for at least 18 months after stabilization of a manic episode in adolescents and children with BD (Hirschfeld et al., 2002). Full stabilization may require several years of treatment. Unfortunately, currently available treatments are associated with numerous side effects in younger patients with BD, including gastrointestinal symptoms, weight gain, neurotoxicity, hyperprolactinemia, sedation, acne and alopecia. Furthermore, Colom and Vieta (2002) suggested that younger patients with BD may be at particularly high risk for noncompliance with maintenance treatment. Thus, long-term treatment of younger patients with BD must constantly monitor for both adverse effects of and adherence to pharmacotherapy. Psychosocial support, including involvement with support groups for adolescent BD, is often critical in maintaining the younger patient in treatment.

The take-home message regarding children and BD. Diagnosis and treatment of younger patients with BD requires careful evaluation for the presence of mixed features as well as comorbid disorders such as ADHD. Lithium, divalproex, carbamazepine and atypical antipsychotics appear to be useful in younger patients with BD, but long-term, controlled data are lacking. Nevertheless, expert guidelines indicate that maintenance agents should be continued for at least 18 months after stabilization of a manic episode in adolescents and children with BD. Clinicians need to monitor these children and adolescents carefully for such side effects as weight gain, endocrine abnormalities and neurotoxicity. Because younger patients with BD are at high risk for noncompliance with maintenance treatment, careful assessment, education and support are required to enhance adherence to treatment. Disruption of normal adolescent psychosocial development as a result of BD may require counseling and peer group support.

Elderly patients with BD. Some data indicate that about 10% of all patients with BD are age 50 or older and that BD accounts for 5% to 19% of mood disorders in the elderly (Manisses Communications Group, Inc., 2002; Sajatovic, 2002). However, a clear picture of the prevalence of BD among the elderly is lacking, owing to under-use of the mental health system by this population. Furthermore, new manic episodes in the elderly may not represent true BD as defined by DSM-IV, but rather, secondary manifestations of thalamic infarction, white matter changes, general medical conditions, prescribed medications or substance use (Ghaemi, 2003; Hirschfeld et al., 2002).

Regardless of the cause of bipolar-like symptoms in the elderly, special concerns arise with respect to pharmacotherapy. For example, many elderly patients may show increased brain sensitivity to lithium, sometimes developing neuropsychiatric side effects at apparently therapeutic blood levels; hence, some older patients with BD may require lower serum lithium levels to achieve comparable brain lithium levels, compared with younger patients (Ghaemi, 2003; Hirschfeld et al., 2002). Indeed, in long-term maintenance treatment, some elderly patients with BD may be stabilized at serum lithium levels in the range of only 0.2 mEq/L to 0.6 mEq/L (Jacobson et al., 2002). Decreased renal function--commonly seen in old age--may warrant further decreases in lithium dosing in the elderly. Although we lack systematic investigations of divalproex blood levels in elderly patients with BD, clinical experience suggests that therapeutic levels for acute mania are similar in older and younger adults (Ghaemi, 2003; Jacobson et al., 2002). With respect to the use of atypical antipsychotics in the elderly, we have few randomized, controlled studies in cohorts with BD. However, olanzapine and risperidone are increasingly being used as first-line treatments for mania in geriatric populations (Jacobson et al., 2002). Monitoring for postural hypotension secondary to antipsychotics is especially important in older patients with BD, owing to the risk of falls and cerebrovascular adverse events. Older patients may be more likely to develop extrapyramidal symptoms (EPS) and tardive dyskinesia (TD) than are younger patients (Hirschfeld et al., 2002). Benzodiazepines--often used as adjunctive treatment in BD--are associated with greater risk of falls and hip fractures in geriatric patients (Cumming and Le Couteur, 2003; Jacobson et al., 2002).

Treatment response, unfortunately, is often partial or inadequate in a substantial subgroup of elderly patients with BD; in some cases, this requires either switching or augmentation strategies. As Jacobson et al. (2002) pointed out, it is not logical to try to augment a nonresponse. Failure to discontinue totally ineffective agents may lead to unnecessary and potentially harmful polypharmacy in the elderly. Hence, long-term treatment should always include periodic reassessment of a medication's efficacy and side-effect burden. Finally, psychosocial support should be part of the treatment approach in elderly, as well as in other age groups. Although a preferred form of therapy has not been determined, interpersonal and cognitive-behavioral approaches have garnered some research support in cohorts with BD (Scott and Todd, 2002).

The take-home message regarding the elderly and BD. Many elderly patients may show increased brain sensitivity to lithium and other mood stabilizers and may develop neuropsychiatric side effects at apparently therapeutic blood levels. Reduced hepatic and renal function in the elderly may also predispose to adverse drug reactions. Thus, conservative dosing is prudent in older patients with BD, especially with respect to lithium. Olanzapine and risperidone are increasingly being used as first-line treatments for mania in the geriatric population, and other atypical antipsychotics are also finding increased use. However, monitoring for postural hypotension, EPS and TD is especially important when antipsychotics are used in the elderly. Unnecessary and potentially harmful polypharmacy should also be avoided. Psychosocial support is no less important in treating the elderly bipolar patient than in younger patients.

Table 1 contains a summary of treatment recommendations for special population patients with BD.

Dementia: Gender and Minority Issues

"Mr. G" is a 68-year-old former construction worker diagnosed with frontotemporal dementia who now lives in a nursing home. Mr. G's behavior has been marked by periods of shouting, throwing objects and occasionally, by assaults on nursing home staff. Over the past four years, Mr. G has been managed with high doses of antipsychotic medication (haloperidol [Haldol] 15 mg/day to 20 mg/day) and more recently with a combination of two atypical antipsychotics. Mr. G has not shown evidence of a psychotic disorder such as delusions or hallucinations. On physical exam, the patient is a large, muscular, well-developed man who shows marked akathisia, cogwheeling and evidence of orofacial dyskinesia. Another nursing home resident--an 81-year-old female--also carries a diagnosis of frontotemporal dementia and also exhibits bouts of aggression and disinhibited behavior. However, she has been treated with a combination of a selective serotonin reuptake inhibitor and valproic acid (Depakene), with generally good control of symptoms.

This vignette makes two major points: 1) Antipsychotics--especially older "neuroleptic" agents--are often over-utilized or inappropriately prescribed in non-psychotic patients with dementia (Jacobson et al., 2002; Kasckow et al., 2004); and 2) gender differences may subtly influence the management of behavioral problems associated with dementia.

Excessive use of antipsychotics in non-psychotic elderly patients with dementia may result in significant side effects. In general, atypical antipsychotics are regarded as more useful than first-generation antipsychotics in managing dementia-related behavioral disturbances (Figure). (Due to copyright concerns, this Figure cannot be reproduced online. Please see p68 of the print edition--Ed.) For example, one double-blind study found that low-dose, once-a-day olanzapine and risperidone are equally safe and effective in the treatment of dementia-related behavioral disturbances in residents of extended care facilities (Fontaine et al., 2003). Some uncontrolled data also support the use of quetiapine, ziprasidone (Geodon) and aripiprazole (Abilify) in patients with dementia, but these results must be considered preliminary (Kasckow et al., 2004). Atypical antipsychotics should be used in low dosage and titrated slowly, with careful monitoring for side effects such as orthostasis. Moreover, recent concerns about cerebrovascular adverse events associated with risperidone and other atypical antipsychotics in populations with dementia warrant caution (Wooltorton, 2002). In some instances, alternate medications--such as divalproex or other anticonvulsants--may be useful in managing aggressive behaviors in patients with dementia (Porsteinsson et al., 1997). Adjunctive medications should be added with caution in this population, owing to the risk of pharmacokinetic and/or pharmacodynamic drug interactions.

With respect to the gender differences, a study of patients with Alzheimer's disease cared for in nursing homes found that men were more likely than women to show behavioral problems such as wandering or socially inappropriate behavior (Ott et al., 2000). Although psychotic symptoms were equally prevalent in men and women, men were more likely to receive antipsychotic drugs and less likely to receive antidepressants. Similar disparities have been documented in patients with Parkinson's disease (PD) and associated cognitive impairment. Thus, Fernandez et al. (2000) studied the management of behavioral problems of patients with PD living in nursing homes. Once again, psychotic symptoms (e.g., hallucinations, delusions) were equally prevalent in men and women; nevertheless, men were more likely to receive antipsychotic drugs and less likely to receive antidepressants compared to women. The gender disparity was greatest in the patients with more severe dementia.

Gender issues. Gender differences may inappropriately affect the management of behavioral problems associated with dementia. Thus, clinicians treating patients with dementia should scrutinize their prescribing practices with respect to gender. Because gender disparities in treatment may be greatest in patients with more severe dementia, prescribing patterns in this subgroup should be evaluated very carefully.

Age, race and ethnicity. Age, race and ethnicity may also influence prescribing patterns in the long-term care of the elderly. Quilliam and Lapane (2001) studied the use of drug prevention strategies among nursing home residents with a history of stroke. Those residents over the age of 85, as well as African-American residents, were less likely to be prescribed secondary drug prevention than were younger white residents. African-American residents were 20% less likely to have been treated with anti-platelet or anticoagulant therapy, despite an elevated risk of stroke in African-Americans.

The take-home message regarding elderly care and race. Long-term care of the elderly may be inappropriately influenced by ethnicity or race. Clinicians should be especially vigilant in evaluating prescribing practices for African-American patients with dementia because this group may be under-treated.

Finally, medication should not be considered a remedy of first resort in managing the behavioral disturbances of dementia (Kasckow et al., 2004). After medical causes (Table 2) have been ruled out, psychosocial treatment is considered the first-line intervention. For an agitated patient, for example, ensuring a quiet, consistent environment with good orienting cues may be helpful (Jacobson et al., 2002).

Conclusions

Whether considering schizophrenia, BD or dementia, special populations often present special challenges. Women, children and adolescents, elderly people, and various ethnic and racial minorities may receive suboptimal treatment unless the clinician is attuned to their particular needs. This means attending to pharmacodynamic, pharmacokinetic and psychosocial issues that may affect these groups in unique ways.

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