Challenges in the Management of Psychosis and Alzheimer’s Disease

At an industry-supported symposium held at the American Association for Geriatric Psychiatry’s 2003 Annual Meeting, a panel of experts discussed the importance of psychosocial intervention in the treatment of Alzheimer’s disease and dementia and debated the effective management of behavioral disturbances and psychosis in Alzheimer’s disease. Other topics included the identification of barriers to optimizing the pharmacotherapeutic management of Alzheimer’s disease, and the latest clinical trials examining the safety and tolerability of antipsychotic agents in Alzheimer’s disease.

This program was supported by an unrestricted educational grant from Bristol-Myers Squibb Company and Otsuka America Pharmaceutical Co., Inc.

The Role of Psychosocial Intervention in the Treatment of Dementia

Mary S. Mittelman, DrPH, Director of the Psychosocial Research and Support Program of the William and Sylvia Silberstein Institute for Aging and Dementia, and Research Associate Professor in the Department of Psychiatry at New York University School of Medicine in New York, reviewed the impact of psychosocial intervention programs for caregivers of patients with dementia.

How Can Psychosocial Interventions Help the Caregiver?
Psychosocial intervention can improve social support for caregivers and thereby help them manage the patient’s behavior and daily activities. This can reduce family conflict and hence have a major impact on caregiver depression and the placement of patients in nursing homes.

Dr. Mittelman pointed out that a single intervention strategy cannot work uniformly for all caregivers. Many
factors, such as the relationship with the patient, income, existing living arrangements, and cultural backgrounds of
the caregivers can affect the care they provide.

The NYU Caregiver Intervention Study
In a randomized, controlled trial to test the efficacy of counseling and support for spouse caregivers, the caregivers were randomly assigned to a treatment or a control group after comprehensive baseline interviews. (Mittelman, et al.
In: Heston LL, ed. Progress in Alzheimer’s Disease and Similar Conditions. Washington, DC:American Psychiatric Publishing; 1997:259). At baseline, all of the caregivers were living with the patients and were required to have at least one close relative in the area because the intervention included family counseling. All caregivers, including those in the control group, received the services routinely available at the New York University Alzheimer’s Disease Center. Regular follow-up evaluations were scheduled and are still continuing for some caregivers.

Caregivers in the treatment group received individual and family counseling within 4 months of baseline. This counseling included telephone access for caregivers and their families to counselors, plus caregivers in the treatment group were required to join support groups.

What Is the Importance of Individual, Family, and Ad Hoc Counseling for Caregivers?
Individual counseling tailors the treatment to the needs of the caregivers, while family counseling improves communication among family members. In this study, two individual and four family counseling sessions were scheduled within the first 4 months of enrollment.

The symptoms of Alzheimer’s disease change over time, as do the needs of caregivers. Ad hoc counseling provided caregivers and their family members the opportunity for unlimited consultation on request over the course of the illness. This allowed caregivers to cope with the changing demands of caregiving.

Effects of Long-Term Programs on Caregivers and Patient Survival at Home
Psychosocial intervention did not affect the patient’s behavior, but markedly improved the caregiver’s reaction to this behavior (F3.43, 1369 = 4.04, P = 0.005) (Mittelman. Presentation. 8th Intl Conf Alzheimer’s Disease and Related Disorders, 2002) (Figure 1). Caregivers in the treatment group reported fewer symptoms of depression (b = -2.91, t = -3.72, P < 0.001) over the first year compared with the control group after controlling for baseline level of depression, gender, and severity of patient dementia (Mittelman, et al. Gerontologist. 1995;35:792). Importantly, this difference remained even after 3 years (Mittelman. Presentation. 8th Intl Conf Alzheimer’s Disease and Related Disorders, 2002).

The long-term effect of the intervention might be attributed to the participation of most of the caregivers in support groups and by the availability of ad hoc counseling, Dr. Mittelman suggested. Over the first 7 years of the study, caregivers in the treatment group were able to keep patients at home for a significantly longer period (median 329 days) than the control group (Mittelman, et al. JAMA. 1996;276:1725).

Similar effects on caregiver depression were obtained in an international study, in which patients received donepezil for treatment of mild dementia, and half of the caregivers were randomly assigned to counseling and support intervention similar to the one developed at NYU (Mittelman. Presentation. 8th Intl Conf Alzheimer’s Disease and Related Disorders, 2002).

Thus, long-term programs of family counseling and support, in combination with pharmacologic intervention for the AD patient, can prevent increased caregiver depression, reduce the severity of the caregiver’s reaction to the patient’s behavior, and can help the caregiver keep the patient at home.

Mechanism of Action of Antipsychotic Drugs andTheir Role in the Management of
Psychotic Disorders

Jacobo E. Mintzer, MD, Professor of Psychiatry & Neurology, Director of the Geriatric Psychiatry Program and Fellowship, and Director of the Institute for Research Minority Training on Mental Health and Aging at the Medical University of South Carolina in Charleston, observed that the mechanism of action of early antipsychotic agents, such as haloperidol, involves antagonism of dopamine receptors. While these agents are effective in reducing psychotic symptoms, higher doses are associated with extrapyramidal symptoms (EPS). Kapur et al. showed that this dose-related phenomenon correlated with excessive dopamine antagonism (Kapur, et al. Am J Psychiatry. 2000;157:514).

Role of Occupancy of D2 Receptors in Causing EPS
Higher doses of haloperidol result in occupancy of dopamine (D2) receptors in other areas of the brain, thereby causing adverse effects such as EPS, explained Dr. Mintzer. The risk of EPS was believed to be reduced with the use of atypical antipsychotics. These agents exhibit transient D2 occupancy, whereby blocking of the receptor decreases over time. As a result, the atypical antipsychotic quetiapine is associated with placebo-level EPS across the full dose range (Kapur, et al. Arch Gen Psychiatry. 2000;57:553). Thus, to achieve an antipsychotic effect, a drug need not block the receptors for extended periods but merely occupy them long enough to generate a physiologic response. Prolonged or excessive occupation of the D2 receptors can lead to EPS, possibly because D2 receptors in areas of dopamine deficiency also are blocked.

Thus, Dr. Mintzer observed, antipsychotic agents ideally should be able to balance D2 occupancy in areas of dopamine excess and areas of dopamine deficiency. Dr. Mintzer described the in vivo pharmacology of aripiprazole, a dopamine partial agonist that is reported to block dopamine receptors in some areas of the brain but not in others.

What Are the Effects of Dopamine Partial Agonists on Positive Symptoms and EPS?
In animal models of hyperactivity, aripiprazole inhibits the action of dopamine agonists, whereas in animal models of dopamine hypoactivity, aripiprazole mimics the action of dopamine.

When administered to a dopamine-rich environment, aripiprazole reduces dopamine activity at the receptor but only to the extent that it increases the activity in a dopamine-deficient environment. In other words, aripiprazole appears to maintain a “thermostat” or uniform level of dopamine activity in the brain. When the activity drops or increases beyond this level, aripiprazole adjusts the level of receptor activity accordingly to reach the uniform level. Whether this partial antagonism is clinically relevant needs to be further explored, Dr. Mintzer stated.

Effective Management of Geriatric Patients with
Dementia and Psychotic Symptoms: Unanswered Questions

With their modified receptor binding kinetics, the atypical antipsychotics exhibit a substantially different mechanism of action compared with conventional antipsychotic agents, believes Joel E. Streim, MD, Associate Professor of Psychiatry and Director of the Geriatric Psychiatry Fellowship at the Hospital of the University of Pennsylvania in Philadelphia. Dr. Streim reviewed the efficacy of various atypical antipsychotics in the treatment of geriatric patients with psychosis and dementia-related behavioral disturbances, and discussed some of the issues that remain unresolved
regarding treatment of such patients.

Clinical Trials of Atypical Antipsychotic Agents in Older Nursing Home Patients with Dementia
In geriatric patients with severe dementia, risperidone 1 mg/d or 2 mg/d significantly (P < 0.01) improved symptoms of psychosis and aggression (Katz, et al. J Clin Psychiatry. 1999;60:107), and doses of 0.75 mg/d–1.5 mg/d resulted in significant improvements in psychosis and aggression (P<0.05, P<0.005) with minimal incidence of tardive dyskinesia (Jeste, et al. Am J Psychiatry. 2000; 157:1150). However, ambulatory patients with dementia who received
doses outside this optimal range—e.g., 0.5 mg/d or 2 mg/d—had increased incidences of falls (Katz, et al. 2nd Annual Meeting, Intl Coll Geriatric Psychoneuropharmacol, 2002). This suggests that untreated agitation or psychosis may
increase the risk of falls, hypothesized Dr. Streim.

Functional ability is another important consideration, particularly in patients who already are quite disabled. In older AD patients with moderate to severe dementia, quetiapine flexible dosing and placebo had similar effects on functional abilities, whereas haloperidol flexible dosing was associated with significant worsening of functional abilities (Tariot, et al. 15th Annual Meeting, Am Assoc Geriatr Psychiatry, 2002). Thus, an additional advantage of the atypical antipsychotics might be their lack of detrimental effects on functional abilities, Dr. Streim remarked. The study results showed an increased, albeit statistically nonsignificant, incidence of falls and fractures among patients receiving haloperidol or placebo. Whether this trend could be attributed to adverse drug effects, untreated agitation, or both, needs to be explored further.

Use of Aripiprazole in Psychosis of AD
With flexible dosing of aripiprazole for the treatment of psychosis in geriatric outpatients with AD, the discontinuation rates, including discontinuation due to adverse events, were low and comparable in the aripiprazole and placebo groups (8% and 7%, respectively). Few patients in the aripiprazole group discontinued treatment because of lack of efficacy (3%, versus 6% in placebo) (data on file, Bristol-Myers Squibb Company, Otsuka America Pharmaceutical, Inc).

On the NeuroPsychiatric Inventory subscale for hallucinations and delusions, as rated by caregivers, the placebo
response rates were high, and a trend toward more improvement with aripiprazole was not statistically significant. However, with the Brief Psychiatric Rating Scale (BPRS), a clinician-rated instrument, aripiprazole-treated patients at week 10 showed significant (P < 0.05) improvement compared to baseline in mean scores for conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thoughts. Additionally, aripiprazole was associated with statistically significantimprovement compared to placebo (P < 0.05) at week 10 in the BPRS psychosis subscale for hallucinatory behavior and unusual thought content (Figure 1). Dose-response relationships remain unclear, but will be examined in upcoming studies, Dr. Streim reported.

Unanswered Questions in the Effective Management of Patients with Dementia and Psychosis
Many questions exist regarding the efficacy and safety of antipsychotics in patients with dementia and psychosis, Dr. Streim noted. For example, what is the appropriate threshold for starting drug treatment for psychosis and agitation in dementia, and when is agitation in the absence of psychosis an appropriate target for treatment? What are the optimal doses of the newer antipsychotics? Guidelines are lacking also on a reasonable titration schedule for newer agents. Furthermore, how durable are the remissions of psychosis in AD and what is the optimal duration of treatment? This is particularly relevant in patients with dementia who have a degenerative disease involving brain changes and a declining course, and whose symptoms of psychosis vary over time as the illness progresses.

Questions remain unanswered over which drug combinations are appropriate and how the newer antipsychotic agents affect patients’ functional status and quality of life. Finally, what are the relative benefits of pharmacologic treatment and nonpharmacologic interventions, such as caregiver support programs? “How caregivers perceive their support programs may be very important in answering questions on efficacy,” Dr. Streim concluded.

Sleep, Fatigue, and Anxiety in Patients with Parkinson’s Disease

Patients with Parkinson’s disease (PD) often experience sleep disorders, fatigue, and anxiety, reported Matthew A. Menza, MD, Vice Chairman of the Department of Psychiatry, Chief of the Division of Clinical Psychopharmacology, and Associate Professor of Psychiatry and Neurology at Robert Wood Johnson Medical School in Piscataway, New Jersey. Sleep disorders are characterized by frequent nighttime wakening and daytime naps, and excessive daytime sleepiness (Menza, et al. Psychosomatics. 1995;36:262), whereas fatigue implies a lack of energy. In PD patients, anxiety is closely interlinked with depression: most individuals exhibiting anxiety also have a comorbid depressive disorder (92%) and vice versa (67%) (Menza, et al. Biol Psychiatry. 1993;34:465).

Common Sleep Disorders in PD
Restless legs syndrome in PD patients and, contradictorily, nocturnal muscular rigidity contribute to the difficulty in falling asleep or staying asleep. In addition, the incidence of sleep apnea increases. Excessive daytime sleepiness (EDS), experienced by up to 51% of PD patients, worsens as the disease progresses. Furthermore, dopaminergic agents can induce both sedation and arousal (Hobson, et al. JAMA. 2002; 287:455).

Among PD patients, 3.8% report experiencing sleep attacks (sudden onset of sleep) while driving, with 0.7% stating that they had no warning (Hobson, et al.) Whether sleep attacks may be attributed to dopaminergic drugs or to EDS is not clear, but Dr. Menza advises clinicians to question their patients about these dangerous situations.

Patients also should be questioned about rapid eye movement (REM) behavior disorder, in which skeletal muscles remain active during REM sleep. Thus, patients “act out their dreams.” PD accounts for 27% of REM behavior disorder, with 32% of patients injuring themselves and 64% assaulting their spouses (Stacy. Drugs Aging. 2002; 19:733).

Understanding and Treating Insomnia in PD Patients
Sleep is regulated by a complex interaction of neurotransmitters, many of which are variably affected by PD. Comorbid depression or anxiety, in addition to the normal changes of aging, also contribute to sleep disturbances (Larsen, et al. CNS Drugs. 2001;15:267). Likewise, dopaminergic drugs, which may relieve nighttime rigidity, may disturb the patient’s sleep by acting as stimulators. In early PD, doses of levodopa are stronger predictors of sleep disturbances than is disease severity. In the later stages of the disease, however, movement disorder plays a greater role (Van Hilten, et al. Arch Neurol. 1994; 51:922).

Effective strategies for treating insomnia include the intermittent use of non-benzodiazepine hypnotics; sleep hygiene (e.g., regular sleep hours, physical activity); cognitive behavioral therapy; and stimulus control interventions. Stimulants, such as modafinil or methylphenidate, may be of use but have not been studied in PD.

Fatigue in PD
Up to 40% of PD patients experience significant fatigue, which develops early and is not correlated with disease severity (Shulman, et al. Mov Disord. 2001; 16:507). Fatigue is clearly related to depression and probably to the use of medications, such as dopaminergics and antidepressants. Treatment of fatigue requires a multimodal approach, including cognitive behavioral therapy, the use of stimulants, and mild exercise to combat deconditioning.

Anxiety in PD
Anxiety, which often is present before the onset of PD (Shiba, et al. Mov Disorder. 2000;15:669), has been diagnosed in 65% of PD patients (Menza, et al. Biol Psychiatry. 1993;34:465). Importantly, in the subset of patients who have fluctuations in motor symptoms (“on/off” syndrome), symptoms of anxiety and depression are significantly
(P < 0.001, P < 0.005, respectively) worse when the movement disorder is not well controlled (Figure 1) (Menza, et al. Mov Disorder. 1990;5:148).

Because the management of anxiety in PD has not been studied, anxiety generally is treated as an aspect of depression. Effective treatment of depression has been associated with a significant (P < 0.001) decrease in anxiety (Menza, et al. Neuropsychiatry Clin Neurosci. In press). Other treatment options that may be effective in select patients include deep brain stimulation (Martinez-Martin, et al. Mov Disorder. 2002;17:372) and surgical intervention (Higginson, et al. Neuropsychiatry Neuropsychol Behav Neurol. 2001;14:117).

Overcoming Barriers in the Management of Neuropsychiatric Symptoms of Dementia

To provide the most benefit to older patients with dementia, clinicians must first clearly identify and effectively control the neuropsychiatric symptoms with minimal safety risks, stated J. Michael Ryan, MD, Assistant Professor of Psychiatry at the University of Rochester Medical Center and Director of Psychiatric Consultation Services at Monroe Community Hospital in Rochester, New York. Dr. Ryan reviewed the safety and tolerability of antipsychotic agents in older patients with psychosis associated with Alzheimer’s disease (AD).

Special Considerations for Antipsychotic Use in Older Patients
A growing body of evidence indicates that older patients are at higher risk for developing extrapyramidal symptoms (EPS) and tardive dyskinesia (TD) and frequently have serious comorbid illnesses. Furthermore, patients with AD and other dementias are more sensitive to anticholinergic effects. Additional considerations when treating older patients include age-related differences in drug metabolism and the increasing risk of drug-drug interactions.

The potential adverse effects of antipsychotic medications in geriatric patients include EPS, TD, sedation or somnolence, and postural hypotension. These effects may lead to feeding problems, worsening of cognition, falls and fractures, and may interfere with activities of daily living. Moreover, these adverse effects often hinder effective treatment.

Incidence of Adverse Events in Older Patients Treated With Atypical Antipsychotics
The atypical antipsychotics are associated with lower incidences of EPS and TD than are conventional antipsychotics and most are prolactin-sparing (Kapur, et al. Ann Rev Med. 2001;52:503). However, some of these agents (e.g., risperidone, olanzapine) induce EPS and somnolence at higher doses (Katz, et al. J Clin Psychiatry. 1999;60:107; Street, et al. Arch Gen Psychiatry. 2000; 57:968), and an inadequate response has been observed in many patients (Kapur, et al. Ann Rev Med. 2001;52:503). Long-term use of atypical antipsychotics in some patients may be limited by their metabolic side effects, such as weight gain, diabetes, and dyslipidemias.

Effects of Atypical Antipsychotics on Diabetes and Hyperlipidemia
Olanzapine has been associated with the development of diabetes in patients with schizophrenia compared to patients not receiving antipsychotic medications or those receiving conventional antipsychotics (P < 0.008 and P < 0.001, respectively) (Koro, et al. BMJ. 2002; 325:243). A similar but lesser effect was seen with risperidone. However, Dr. Ryan cautioned that these data, based on retrospective pharmacoepidemiologic records, apply to a study population of which only 30% was > 65 years.

The same investigators found that olanzapine raised the risk of hyperlipidemia compared with conventional antipsychotics or no antipsychotic therapy (P < 0.001) (Koro, et al. Arch Gen Psychiatry. 2002;59:1021). Other studies also have shown that clozapine, olanzapine, and quetiapine can cause extreme elevations in triglyceride levels without associated elevations in total cholesterol levels (Meyer. J Clin Psychopharmacol. 2001;21:369).

Aripiprazole in the Treatment of Psychosis of AD
Aripiprazole was comparable to placebo in terms of the incidence of EPS adverse events and mean change from baseline on EPS scales (Simpson-Angus, Barnes Akathisia, and Abnormal Involuntary Movement Scale). Other common adverse events related to the use of aripiprazole in treating psychosis of AD included somnolence, accidental injury, urinary tract infection, and hypertension, but none of these occurred in > 10% of patients (data on file, Bristol-Myers Squibb Company,
Otsuka America Pharmaceutical, Inc.). Aripiprazole also was associated with a weight gain of < 1 kg, compared with a slight weight loss among patients receiving placebo.

The Clinical Antipsychotic Trials of Intervention Effectiveness
Efficacy information obtained in clinical trials may not always pertain to patients in “real-world” settings, observed Dr. Ryan. To this effect, the National Institutes for Mental Health is sponsoring the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE; www.catie.unc.edu). CATIE aims to evaluate the efficacy and tolerability of antipsychotic medications for schizophrenia and AD in broad patient populations and “real-world” settings.