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Drugs, Death, and Disconcerting Dilemmas: Page 2 of 3

Drugs, Death, and Disconcerting Dilemmas: Page 2 of 3

What clinicians, patients, and caregivers are left with is an unenviable quandary. While there are some alternative medications that have been tried off-label to target psychosis or agitation in patients with dementia, their overall evidence base is weak and their safety profiles in dementia (while they do not yield the legally ominous black box) are unknown. Although psychosocial/behavioral treatments are likely to be underused because they are time-intensive and not well reimbursed, they are also generally more difficult to study than medications. This leaves many unanswered questions about the empirical efficacy of many proposed psychosocial/behavioral therapies. A 2005 review of RCTs reported the best empirical evidence for caregiver psychoeducation/support, music therapy, cognitive stimulation therapy, Snoezelen therapy, behavioral management–based techniques, and staff training/education.7

Table 1 outlines the medications that have shown at least some promise in efficacy for psychosis or agitation in patients with dementia. However, these studies in the aggregate still pale in comparison to the number of trials and overall strength of evidence (albeit modest) for at least efficacy (if not effectiveness) of antipsychotics for such symptoms.2

Clinicians must digest this dizzying accumulation of data and act. What should occur, if possible, is a process of informed consent and shared decision making about the options for intervention. These include nonpharmacological management strategies, no intervention, using off-label medications with their available risk-benefit information, or institutionalizing the patient.

In a previous publication, my colleague and I2 proposed a potential algorithm for decision making regarding the off-label use of antipsychotics for patients with dementia-related psychosis or agitation (Figure). It may provide some guidance in admittedly murky waters. Table 2 outlines suggested starting and target doses of atypical antipsychotics if used in patients with dementia. One important point to consider in discussions of informed consent is the means in which one communicates numbers related to risks and benefits. Numerical literacy is notably lacking in many persons and often clouded by emotion. A helpful hint is to recall that citing absolute risks (versus relative risks) usually conveys more realistic and accessible information.


The illness for which the most evidence exists for the efficacy of antipsychotics in older adults is schizophrenia. While industry-sponsored trials make a nominal nod for the need of clinical trial data in older adults, trials for FDA approval for schizophrenia may exclude the old-old (85 years or older) or include a small nonrepresentative subsample of older adults. This is why trials designed specifically to assess the efficacy of antipsychotics in older adults were major milestones in recent years.

In 1 such trial, among older adults aged 60 to 86 years with schizophrenia, haloperidol (mean dose, 9.4 mg/d) was compared with olanzapine (mean dose, 11.9 mg/d).8 Olanzapine proved superior to haloperidol on global positive and negative symptoms and also caused fewer extrapyramidal symptoms. Although olanzapine has more inherent anticho-linergic potency than haloperidol, this was offset by the use of anticholinergics to treat haloperidol-related extrapyramidal symptoms. Olanzapine caused more weight gain than haloperidol and tended to increase glucose levels, whereas haloperidol increased prolactin levels to a greater extent.

Another RCT of antipsychotics among older adults compared olanzapine (median dose, 10 mg/d) with risperidone (median dose, 2 mg/d).9 The 2 medications showed equal efficacy in reducing positive and negative symptoms associated with schizophrenia or schizoaffective disorder. Weight gain, observed in both treatment groups, was significantly greater in the olanzapine-treated group. Extrapolating from these studies and others that have examined real-world prescribing patterns, suggests that antipsychotic doses in older adults be one-third to one-half those used in comparable younger patients.

With reasonably established efficacy in treating older adults with schizophrenia, the question of possible adverse effects arises. The risk of tardive dyskinesia (TD) is 4 to 5 times higher in older patients with schizophrenia than in their younger cohorts.10 This risk is diminished with the use of atypical versus typical antipsychotics (eg, 4 times higher relative risk of TD with the use of haloperidol 1 mg/d vs risperidone 1 mg/d for 9 months).11 Thus, the American Psychiatric Association (APA) treatment guidelines for schizophrenia suggest more frequent monitoring for TD in older patients (ie, every 3 months for older adults receiving typical antipsychotics and every 6 months for those receiving atypical antipsychotics). Older adults are also particularly susceptible to antipsychotic-induced parkinsonism, especially from typical agents and, relative to other atypicals, risperidone.

However, atypical agents come with their own problem—namely, the metabolic syndrome. Atypical antipsychotics may cause substantial abdominal weight gain, hyperglycemia, and dyslipidemia, which increase the risk of cardiovascular disease. The metabolic effects of atyp-ical antipsychotics, which were first observed in younger adults, also apply to older adults, although some evidence suggests that these adverse effects decrease with increasing age. The APA and the American Diabetes Association (ADA) published a joint consensus on monitoring metabolic adverse effects of antipsychotics (Table 3), and for now, this extrapolates to older adults as well.11

Warnings regarding adverse metabolic effects extend across the spectrum of atypical antipsychotics, although evidence suggests the risk is somewhat drug-specific. Clinical experience along with published data (eg, from the APA/ADA guidelines) suggest that metabolic risks are highest with clozapine and olanzapine, intermediate with quetiapine and risperidone, and lowest with aripipra-zole and ziprasidone. All atypicals (except clozapine) have shown the same efficacy in RCTs, but they are not created equal. Their different adverse-effect profiles can help guide treatment choices (eg, use of quetiapine in persons with parkinsonism because of low risk of extrapyrami-dal symptoms, use of olanzapine in someone with anorexia and weight loss, or avoidance of higher doses of olanzapine in those susceptible to anticholinergic effects).


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