Return to American Society of Consultant Pharmacists                                    Print This
Challenges in the Management of Psychotic Symptoms Associated with Dementia

Psychosis in Long-Term Care: The Scope of the Challenge

Michael W. Jann, PharmD, FCCP, FCP, BCPPP, Director of the Center for Clinical Research and Professor of Pharmacy Practice, Mercer University Southern School of Pharmacy, Atlanta, Georgia, reviewed the prevalence and etiology of psychotic symptoms in long-term care, as well as mechanisms of action of antipsychotic medications. Psychotic symptoms affect about 34% of residents in long-term care facilities. These could be associated with Alzheimer’s disease (AD), may be secondary to other general medical conditions or could be caused by primary psychoses (e.g., schizophrenia, bipolar disorder) (Bullock and Saharan. Int J Clin Pract. 2002;56:515).

Psychosis of AD
About 30% to 50% of AD patients exhibit psychosis (Jeste and Finkel. Am J Geriatr Psychiatry. 200;8:29); cumulative incidence of psychosis reaches 51% within 4 years of AD diagnosis (Paulsen et al. Neurology. 2000;54:1965). Other causes of dementia include vascular dementia and Lewy body disease.
Diagnostic criteria for psychosis of AD include (Jeste and Finkel. Am J Geriatr Psychiatry. 2000;8:29):


• Diagnosis of Alzheimer’s dementia
• Exclusion of other causes of psychotic symptoms (e.g., schizophrenia)
• Hallucinations and/or delusions of late-onset present intermittently for at least 1 month, and disruptive to patient functioning
• Associated agitation, depression, and negative symptoms
• Disturbances that do not correlate exclusively with delirium


Dr. Jann then contrasted symptoms of psychosis of AD with those of schizophrenia in the elderly (Jeste and Finkel. Am J Geriatr Psychiatry. 2000;8:29). Psychosis of AD is far more common than schizophrenia; the latter affects less than 1% of the general population. Hallucinations are auditory in schizophrenia, but visual in psychosis of AD. Remission of psychosis, and caregiver misidentification, are frequent in psychosis of AD but uncommon or rare with schizophrenia. Past history of psychosis is rare with AD but very common in those with schizophrenia.

Many antipsychotic medications have side effects that are associated with increased risk of falls in the elderly. Elderly patients are at increased risk for antipsychotic-related adverse events (AEs) like extrapyramidal symptoms (EPS), tardive dyskinesia (TD), orthostatic hypotension, sedation, anticholinergic effects, cardiac conduction abnormalities, and cognitive impair-ment. Cumulative incidence of TD in older adults receiving first-generation antipsychotics is roughly 63% at 3 years of therapy (Jeste et al. Arch Gen Psychiatry. 1995;52:756; Kane et al. J Clin Psychopharmacol. 1988;8(suppl):52S). “That’s what really led to the…development of the atypical antipsychotics,” he said.

Chlorpromazine was the initial first-generation antipsychotic agent. Clozapine led the wave of second-generation antipsychotics. Aripiprazole represents the next generation of antipsychotic medications.

Antipsychotic agents – Mechanism of action
The dopamine hypothesis of schizophrenia states that there are 4 main dopaminergic pathways in the brain. The mesolimbic pathway is involved in the control of the positive symptoms of schizophrenia (e.g., hallucinations, delusions). The mesocortical pathway has been implicated in the aspects of cognition and negative symptoms (e.g., anhedonia). The nigrostriatal pathway is part of the extrapyramidal system, and the the tuberoinfundibular pathway regulates prolactin secretion (Inoue and Nakata. Jpn J Pharmacol. 2001;86:376).

First-generation antipsychotics are specific D2 antagonists, he said, and all cause EPS (Goff et al. Med Clin North Am. 2001;85:663). These agents reduce positive symptoms but have little effect on negative symptoms.

Second-generation agents reduce both positive and negative symptoms, and benefit patients considered refractory to treatment. Risk of EPS and TD is lower than with first-generation medications. Risperidone, olanzapine, quetiapine, and ziprasidone offer D2 and 5HT2A antagonism. “You can see now we’re teasing out better receptor pharmacology,” he said. These agents show a broad range of efficacy in dementia and mania. However, side effects include agranulocytosis (clozapine), lipid abnormalities, glucose intolerance, moderate to high weight gain, increased risk of seizures, QTc prolongation (ziprasidone), and hyperprolactinemia (risperidone). “So, it’s not quite yet the perfect drug,” Dr. Jann said.

Aripiprazole – the “next generation”
Aripiprazole functions as a partial D2 receptor agonist, he explained (Tamminga. J Neural Transm. 2002;109:411). Older agents such as haloperidol are complete D2 antagonists, blocking all receptor activity. This alleviates positive symptoms but causes adverse effects (e.g., EPS, hyperprolactinemia). Partial agonist activity improves positive symptoms without causing hyperprolactinemia and with minimal EPS (Burris et al. J Pharmacol Exp Ther. 2002;302:381; Kane et al. J Clin Psychiatry. 2002;63:763).

Aripiprazole offers high-binding affinity for the D2, 5-HT1A and 5-HT2A receptors, but it functions as a partial agonist at the D2 and 5-HT1A receptors. It is a functional antagonist under conditions of dopamine hyperactivity, which leads to control of positive symptoms. It acts as a functional agonist under conditions of dopamine hypoactivity, which results in cognitive improvement, control of negative symptoms, and minimal motor effects.

Aripiprazole is a dopamine-serotonin system stabilizer. It has no affinity for muscarinic receptors, and low to moderate affinity for a-1 and H1 receptors. Therefore, it has low potential for cognitive impairment, orthostatic hypotention, weight gain, and somnolence (Richelson. J Clin Psychiatry. 1999;60 (suppl 10):5; Abilify™ prescribing information). “It’s a very favorable profile,” he summarized.

Barriers to the Effective Management of Psychosis in Geriatric Patients

Stephen R. Saklad, PharmD, BCPP, Clinical Associate Professor, The University of Texas College of Pharmacy and Clinical Pharmacologist, San Antonio State Hospital, reviewed risk factors, adverse drug reactions (ADRs), drug interactions, and comorbidities that may complicate antipsychotic drug therapy in the elderly.

Older patients displaying agitated or psychotic behavior should receive a complete workup prior to administration of any drug therapy for these symptoms, Dr. Saklad said. This includes a history and physical examination to rule out delirium. Effects of poor or unusual diet, medications, and comorbid medical conditions also should be evaluated. Consider whether unreported or improperly treated pain may cause agitated behavior. “Merely putting people on routine, not PRN, analgesics, has dramatically decreased the… incidence of agitation,” he said.

Side effects of antipsychotics
Medical comorbidities and drug-specific side effect profile should influence choice of antipsychotic therapy in the elderly, he said (Table 1). Dr. Saklad urged attendees to avoid antipsychotic agents that cause adverse reactions such as sedation, rigidity, EPS, or orthostasis because they could lead to falls and
fractures.

Anticholinergic effects that occur with many antipsychotic medications “are clearly toxic to any cognitive process the person has,” he stated. A retrospective cohort study has reported a 16% increase in the long-term risk of breast cancer with antipsychotic dopamine antagonists, he said (Wang et al. Arch Gen Psychiatry. 2002;59:1147-54).

Risperidone, one of the atypical antipsychotics to be studied in detail in dementia, is associated with dose-related increases in the incidence of somnolence, EPS, and TD (Katz et al. J Clin Psychiatry. 1999;60:107; Jeste et al. Am J Psychiatry. 2000;157:1150). “We want to keep the dose of a drug like risperidone down,” Dr. Saklad asserted. A study of olanzapine in elderly dementia patients revealed a statistically significant elevation in the incidence of somnolence with all doses (5 to 15 mg/d) evaluated (P <.05 to P <.001 vs placebo; Street et al. Arch Gen Psychiatry. 2000;57:968). “(This) leads me to believe that they tried too much (of the drug),” he said.

Quetiapine has been associated with a low incidence of EPS (less than 5%) when used in nursing home residents (Tariot et al. AAGP Annual Meeting. 2002). Incidence of somnolence with this agent was about 25%, and risk of falls was roughly 28%, however. Weight gain liability of each of the individual antipsychotic is very important to consider. Clozapine causes the most weight gain of all antipsychotics in which this effect has been studied, he said.

Drug interactions
Drug interactions are of special concern in the elderly. Medications that can interact with antipsychotics include anticholinergics (e.g., some agents used to treat urinary incontinence); a1 adrenergic antagonists (e.g., antihypertensives, afterload reducers), which are frequently associated with orthostatic hypotension; CNS depressants (e.g., H1 blocking antihistamines such as diphenhydramine, sedatives, hypnotics, analgesics and anxiolytics).


Dr. Saklad then reviewed drug interactions for 5 antipsychotic agents:
• Risperidone: 275% increase in area under the curve (AUC) when fluoxetine is coadministered.
• Olanzapine: 108% increase in AUC when fluvoxamine is coadministered to men; the comparable figure in women is 52%.
   Fluvoxamine impairs olanzapine’s primary metabolic pathway.
• Quetiapine: The AUC of quetiapine falls by 500% in the presence of phenytoin, but rises by 84% in the presence of ketoconazole.
• Ziprasidone: The AUC of ziprasidone falls by 35% in the presence of carbamazepine, and rises by 38% in the presence of ketoconazole. Dr.    Saklad characterized these as “small changes that are probably not clinically significant.”
• Aripiprazole: AUC of aripiprazole rises by 63% in the presence of ketoconazole, and by 112% in the presence of quinidine. It falls by 70% in the    presence of carbamazepine. The package insert for aripiprazole recommends dosage adjustments when these agents are coadministered, he    said, “but clinically I’ve never seen a reason…to do that.”

 

Recent Developments in the Management of Psychosis Associated with Dementia

Anton P. Porsteinsson, MD, Asso-ciate Director, Program in Neuro-behavioral Therapeutics at the University of Rochester Medical Center, and Assistant Professor of Psychiatry at the University of Rochester School of Medicine in Rochester, New York, reviewed the efficacy and side effects profiles of first- and second-generation antipsychotics, and of aripiprazole.

In addition to the advantages and disadvantages of second-generation agents discussed by other presenters, Dr. Porsteinsson said that these medications can cause cerebrovascular events in the elderly with psychosis, and produce an inadequate response in many patients (Kapur and Remington. Annu Rev Med. 2001;52:503).

Efficacy of Atypical Agents
He then reviewed data regarding the use of certain agents in the elderly population. Clozapine is not a first-line agent because of its side effect profile, Dr. Porsteinsson said. Still, it has a small role as therapy for patients with Parkinson’s disease, psychosis associated with Parkinson’s disease; and Lewy body dementia, he said. Starting dose should be 6.25 to 12.5 mg qhs, with target dose of 25 to 75 mg.

“Risperidone is currently the best studied of the atypical antipsychotics in individuals with dementia and psychosis, or dementia and behavioral disturbances,” he said. The target dose should be .75 to 1.5 mg daily, he said. Higher doses do not result in greater improved outcome, but do lead to higher incidence of TD and EPS (Jeste et al. Am J Psychiatry. 2000;157:1150; Katz et al. J Clin Psychiatry. 1999;60:107).

A 6-week, double-blind, placebo-controlled trial of olanzapine in nursing home residents (N= 206) with AD found that 5 mg daily was associated with better treatment outcome than 10 or 15 mg daily (Street et al. Arch Gen Psychiatry. 2000;57:968). There was a dose-dependent increase in somnolence but the highest incidence of gait disturbance occurred with the 5-mg dose. “Hard to explain why,” he said.

A 10-week prospective double-blind placebo-controlled study compared quetiapine to haloperidol (N = 284). Active therapies did not differ from placebo on measures of psychosis but each improved agitation compared to placebo (P = .03 for quietiapine vs placebo; P = .001 for haloperidol vs placebo). Fewer EPS events occurred with quetiapine than with haloperidol, but rates of somnolence were higher with quetiapine than with placebo (P < .001) (Tariot et al. AAGP 15th Annual Meeting Poster. 2002).

Some atypical antipsychotic agents are associated with increased rates of falls and fractures “when you go over the mark with dosing,” he said. “That’s why it’s…important to understand where… the therapeutic window (is).”

Aripiprazole – New data
Data from the first phase of a multinational trial of aripiprazole in outpatients with psychosis of AD (N = 208; mean age, 81.5 years; Mini-Mental Status Examination (MMSE) mean score 13.4 to 13.9) was presented recently (De Deyn et al. AAGP 16th Annual Meeting 2003. Poster). A 10-week, double-blind, placebo-controlled phase was followed by an open-label extension phase of an additional 130 weeks. Efficacy measures were the Neuropsychiatric Inventory (NPI) psychosis subscale, and the Brief Psychiatric Rating Scale (BPRS) psychosis subscale.

This was a flexible-dose study (2 to 15 mg qd). Mean dose at endpoint was 10 mg daily, “which in my experience is the target dose for aripiprazole in this population,” he said. Due to the “very slow titration,” the mean dose did not reach 10 mg until about week 5 or 6, he noted. Mean change from baseline in BPRS total score reached statistical significance (P <.05 vs placebo) at week 6, and showed a clear trend favoring aripiprazole thereafter. Mean changes in the BPRS core subscale (conceptual disorganization, suspiciousness, hallucinations, unusual thought) and in the BPRS psychosis subscale (hallucinations, unusual thought content) reached statistical significance (P <.05 vs placebo) at weeks 8 and 10. “At the time we start to get more adequate dosing, we start to see clear and numerical separation,” he said.

The BPRS scale is a clinician-rated measure. The NPI psychosis subscale, which reflects a nonprofessional caregiver’s assessment, showed a nonsig-
nificant but numerically greater improvement favoring aripiprazole at weeks 6 and 10. “This comes back to how hard it is even for professionals to define what are true delusions and hallucinations in this population,” he said.

Mild to moderate somnolence occurred more commonly with aripiprazole than placebo (8% vs 1%). This effect was associated with doses of 10 to 15 mg daily, resolved with dose reduction, was not related to falls or accidental injuries, and did not cause discontinuation of the drug. Incidence of EPS-related AEs, orthostatic events, ECG abnormalities, and clinically significant weight gain was comparable to placebo. More information will be forthcoming, as 2 United States studies in nursing home patients with psychosis of AD are ongoing.

 

Return to American Society of Consultant Pharmacists                                    Print This

All contents Copyright © 1999 - 2003 Medical Association Communications