Hallucinations Predict Relapse After Discontinuation of Risperidone in Patients With Alzheimer's Disease and Psychosis or Agitation

EDITORIALS Hallucinations Predict Relapse After Discontinuation of Risperidone in Patients With Alzheimer’s Disease and Psychosis or Agitation Helen Lavretsky, M.D., M.S. An article in this issue by Patel and colleagues (1) provides new evidence of the predictors of relapse after discontinuing anti- psychotic medications in older adults with Alzheimer’s disease and psychosis or agitation. This is a post hoc analysis following the initial publication of the multicenter Antipsychotic Dis- continuation in Alzheimer’s Disease trial results, which indi- cated that patients who responded to risperidone over 16 weeks of open-label treatment showed a twofold to fourfold higher risk of relapse 16–32 weeks after discontinuation of risperidone compared with continuation on risperidone (2). In the present study, the researchers examined the associa- tions between neuropsychiatric symptoms, both at study base- line and immediately after open risperidone treatment, and the likelihood of relapse after subsequent randomization to con- tinued risperidone treatment or discontinuation to placebo. Of 180 patients with Alzheimer’s disease and symptoms of agita- tion or psychosis who received treatment with risperidone for 16 weeks, 110 responded and were randomly assigned to 1) continue risperidone for 32 weeks, 2) continue risperidone for 16 weeks followed by a switch to placebo for 16 weeks, or 3) switch to placebo for 32 weeks. Compared with patients who had mild hallucinations or no hallucinations at baseline, patients with severe hallucinations showed a higher likelihood of relapse (hazard ratio52.96, 95% CI51.52, 5.76; p50.001). This effect was present for the subsample of patients with auditory hallucina- tions but not those with visual hallucinations. Among patients with baseline hallucinations, 13 of 17 (76.5%) who discontinued risperidone relapsed, compared with 10 of 26 (38.5%) who continued risperidone (p,0.02). This group difference remained for severe (77.8%) compared with mild (36%) hallucinations (p50.02). Neuropsychiatric Inventory domain scores after the initial open-treatment phase prior to randomization were not as- sociated with relapse. The authors conclude with a caution that physicians must be mindful of the potential for relapse in patients with Alzheimer’s disease who present with severe hallucinations at baseline, particularly auditory hallucinations. The study results provide important information that could contribute to guidelines for discontinuation of antipsychotics in patients with Alzheimer’s disease and related dementing illnesses (3). With the global aging trend, our society is deal- ing with rising rates of Alzheimer’s disease and other forms of dementia that currently afﬂict an estimated 5.4 million Am J Psychiatry 174:4, April 2017 individuals in the United States, 96% of whom are over 65 years of age (Alzheimer’s Facts and Figures, 2016; http://m.alz.org/ facts-and-ﬁgures.asp). As of 2016, the aggregated cost of care for all individuals with Alzheimer’s disease and other dementias is estimated at $236 billion, with 68% of the cost covered by Medicare and Medicaid (Alzheimer’s Facts and Figures, 2016). Besides cognitive decline, noncognitive behavioral symptoms or neuropsychiatric symptoms (4) accompany dementia in 80%290% of patients and are associated with excess morbidity and mortality as well as more suffering on the part of both patients and caregivers (5, 6). Nonetheless, compared with in- vestments made to develop pharmacotherapy for cognitive symptoms, systematic efforts to improve the use of medications to treat noncognitive behavioral symptoms have been modest. While numerous stud- ies have provided vari- The study results provide ous degrees of efﬁcacy for important information noncognitive behavioral that could contribute symptoms for a wide va- to guidelines for riety of medications, in- discontinuation of cluding antipsychotics, there is still limited evi- antipsychotics in patients dence to provide guid- with Alzheimer’s disease and ance on their continuous related dementing illnesses. use (7, 8). For individuals who have a good response to antipsychotics, withdrawal from them has been associated with signiﬁcant relapse (2). At the same time, the efﬁcacy of antipsychotics has been called into question by reports suggesting that the existing evidence is based on trials of short duration that use small samples and varying assessment instruments and often show a high placebo response (9). The use of antipsychotics in dementia is com- plicated by a variety of concerning side effects, including ex- trapyramidal symptoms (particularly tardive dyskinesia [10]), hyperglycemia, diabetes mellitus, weight gain, increases in serum lipid levels, and cardiovascular effects (11, 12). A review of the literature found a 1.3- to 2-fold increased risk of cere- brovascular accidents in case-control studies of elderly pa- tients on antipsychotics, which was highest in the ﬁrst weeks of treatment and among those who had certain risk factors, such as higher age, cognitive impairment, and vascular disease (11). A review of 17 studies on antipsychotics in individuals with ajp.psychiatryonline.org