Do cholinesterase inhibitors enhance cognition in schizophrenia? Disorder’s heterogeneity may help explain why the answer is unclear ® Dowden Healthome schizophrenia Media patients have shown sig- nifi cant improvements in positive and negative Ssymptoms when my colleagues and I added CopyrightFor personalacetylcholinesterase use only inhibitors (AChEIs) to their anti- psychotic regimens. We cannot rule out these benefi ts as placebo effects, but nevertheless they have been sustained over time. When patients appear to have benefi ted from AChEIs but stopped them, the ben- efi ts rapidly disappeared. Then, when these patients restarted the medications, the benefi ts recurred. Unfortunately, recent well-controlled clinical stud- ies have not supported these anecdotal fi ndings or the IMAGES results of approximately 20 preliminary trials. Thus, JUPITER this article explains: 2008 • why we don’t recommend using off-label AChEIs © as a “fi rst choice” augmentation strategy in schizo- Samuel C. Risch, MD phrenia patients at this time Professor of psychiatry • under what circumstances the adjunctive use of University of California, San Francisco these agents might be reasonable. Why Alzheimer’s medications? Schizophrenia and Alzheimer’s disease (AD) have dramatically different onset, symptoms, course, and pathophysiology. As reviewed below, schizophrenia patients are no more likely to develop AD than the general population, and AChEIs—even when effec- tive—have a short-term, limited benefi t in AD. So why are psychiatrists trying AD medications in patients with schizophrenia? The answer has to do with Current Psychiatry 96 March 2008 the intriguing effects of cholinergic agents on cognition. For mass reproduction, content licensing and permissions contact Dowden Health Media. Table 1 Toward cognitive enhancement Cholinesterase inhibitors Schizophrenia’s cognitive impairments have shown benefi t in many may occur at a very early age, often before neuropsychiatric conditions* other overt symptoms,1 then may wors- en—sometimes to dementia levels—when Alcoholism with Wernicke’s encephalopathy obvious psychotic symptoms emerge.2 Attention-defi cit/hyperactivity disorder Positive symptoms (hallucinations, delu- Autism sions, thought disorder, etc.) and—to a less- er extent—negative symptoms (anhedonia, Bipolar disorder asociality, blunted affect, etc.) often improve Creutzfeldt-Jakob disease when patients are treated with antipsychot- Dementia pugilistica ics. Antipsychotics do not signifi cantly im- Dementia with Lewy bodies prove cognitive symptoms (attention, reac- Olivopontocerebellar atrophy tion time, working memory, verbal fl uency, etc.), however, and cognitive symptoms are Parkinson’s disease with dementia the strongest predictors of poor functional Parkinsonism dementia complex of Guam Clinical Point outcomes in our patients. Pick’s disease Neurologic studies Progressive supranuclear palsy suggest cholinergic Heterogeneous disorder. In 2000, Cum- Schizophrenia mings3 summarized evidence from case re- neurotransmission ports and small studies that AChEIs were Sleep disorders defi cits found in useful in treating neuropsychiatric condi- Subacute sclerosing panencephalitis schizophrenia might tions other than AD (Table 1). Cholinergic Traumatic brain injury be amenable to agents, Cummings noted, “affect many as- Vascular dementia pects of cognition, which suggests that the supplementation * Data from case reports and small studies. Cholinesterase primary effect may be on an attentional or inhibitors are FDA-approved only for Alzheimer’s dementia. executive system with a secondary, pan- Source: Reference 3 intellectual modulating infl uence on mem- ory, language, and visuospatial skills.”4 cholinergic neurotransmission alterations In schizophrenia, different patients have in schizophrenia patients, including: different types of cognitive impairment.5 • a defi cit in regulation of the low-affi n- Thus, broad-based cognitive enhancers ity alpha-7 nicotinic receptor in those such as AChEIs may be necessary for gen- with impaired sensory gating7 eral use in this illness. • altered high-affi nity nicotinic receptor binding8 Acetyltransferase activity. Schizophrenia • decreased hippocampal muscarinic patients—even those meeting criteria for receptor binding compared with dementia—do not usually have typical AD matched normal controls9 neuropathology, and the incidence of AD • reduced density of cholinergic inter- is no different in elderly patients with or neurons in the ventral striatum.10 without comorbid schizophrenia.6 At au- These fi ndings—plus the presumably topsy, schizophrenia patients and normal “nonspecifi c” benefi ts of AChEIs in many controls have similar brain cortical choline illnesses3—suggest that some patients with acetyltransferase levels. schizophrenia may have defi cits in nico- Nevertheless, persons with AD and tinic and/or muscarinic cholinergic neuro- those with schizophrenia show a similar, physiology, which might be amenable to statistically signifi cant negative correla- pharmacologic supplementation. tion between premorbid Clinical Dementia Rating scale scores and brain cortical cho- line acetyltransferase activity (r = – 0.36, AChEI augmentation P <0.0003 vs r = – 0.29, P <0.005, respec- Mixed results. A number of investiga- Current Psychiatry tively).6 Furthermore, studies have found tors—including myself—have published Vol. 7, No. 3 97 Box Early studies: Modest benefit from AChEIs in schizophrenia pproximately 20 published studies inhibitor augmentation in schizophrenia A have reported clinically signifi cant (Table 2). Some included larger sample benefi ts (positive symptom, negative sizes than earlier investigations and a symptom, and/or cognitive improvement) placebo-active drug parallel design. Cognition in when schizophrenia patients received schizophrenia cholinesterase inhibitors with their fMRI fi ndings. A few crossover design antipsychotic regimens. These include studies of schizophrenia patients taking case reports, case series, and double- antipsychotics included functional blind, placebo-controlled, crossover magnetic resonance imaging (fMRI) at or parallel-design studies, most with baseline and after cholinesterase inhibitor relatively small numbers of subjects.a-o and placebo augmentation. Of interest, the Recent studies, however, have failed basal “abnormal” pattern of the baseline to show a clinically or statistically fMR image became more “normal” when signifi cant benefi t from cholinesterase subjects were treated with donepezil. Clinical Point Source: For reference citations, see this article at CurrentPsychiatry.com In a large 12-week controlled trial, data indicating that adding AChEIs—most The last word? Within weeks, however, donepezil was no often donepezil, but also rivastigmine or results of a large multicenter trial by Keefe more eff ective than galantamine—to antipsychotic regimens et al21 showed that donepezil augmenta- placebo in improving may improve some schizophrenia patients’ tion was no more effective than placebo cognition in patients symptoms and general functioning. These in improving cognition in patients with benefi ts were modest, however, when they schizophrenia or schizoaffective disorder. with schizophrenia were seen in these relatively small case re- In this 38-center, randomized, double- ports and studies (Box). blind, placebo-controlled, parallel design Other studies of AChEI augmentation study, 250 patients with mild to moderate of typical or atypical antipsychotics have cognitive impairment received adjunc- been: tive donepezil—5 mg/d for 6 weeks, then • equivocal, reporting benefi ts in some 10 mg/d for 6 weeks—or placebo for 12 but not all patients (with no clear statistical weeks. or clinical conclusions) or in schizophrenia Both the treatment and placebo groups patients with comorbid dementia11-14 experienced statistically and clinically sig- • decisively negative, showing no ben- nifi cant benefi ts from baseline in measures efi ts, particularly in comparatively larger, of cognition, positive symptoms, and neg- randomized, placebo-controlled trials ative symptoms. For all measures, placebo (Table 2).15-19 augmentation was equal to or superior to donepezil augmentation. Meta-analysis power. In an attempt to understand these wide-ranging results, Chouinard et al20 performed an elegant Analyzing trial results meta-analysis of oral AChEI augmenta- The large, well-designed clinical trial by tion therapies for cognitive enhancement Keefe et al21 suggests conclusively that in schizophrenia. This review emphasized donepezil augmentation is not more ef- the available studies’ complexity, small fective than placebo in most stable schizo- number and sample sizes, and small ben- phrenia or schizoaffective disorder pa- efi t effect sizes. tients with mild to moderate cognitive The authors concluded that—based impairment. on preliminary data—adjunctive AChEIs Even so, it is arguably diffi cult to “prove seemed to have “some benefi cial effects” a negative.” For example: on attention and memory for schizophre- • Different dosages might have been Current Psychiatry 98 March 2008 nia patients. more effective. Table 2 Controlled trials: No benefi t from AChEIs in schizophrenia Study design Subjects Drug (dosage) Results Friedman et al (2002),15 36 patients with Donepezil, 5 or 10 mg/d Neither dose produced double-blind, schizophrenia for 12 weeks signifi cant improvement placebo-controlled in any cognitive measure Tugal et al (2004),16 12 patients with stable Donepezil,