Do Cholinesterase Inhibitors Enhance Cognition in Schizophrenia?

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 signifi cant improvements in positive and negative Ssymptoms when my colleagues and I added CopyrightFor personalacetylcholinesterase use only inhibitors (AChEIs) to their antipsychotic 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 benefi ts rapidly disappeared. Then, when these patients restarted the medications, the benefi ts recurred. Unfortunately, recent well-controlled clinical studies 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 effective—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 worsen—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 memory, 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 choline 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, 5 mg/d for Treatment effect was double-blind, placebo- schizophrenia 6 weeks, with crossover not signifi cant in any controlled, crossover to placebo for 6 weeks cognitive measure

Freudenreich et al 36 stable outpatients Donepezil, ≤10 mg/d No improvement (2005),17 double-blind, with schizophrenia for 8 weeks in cognition or placebo-controlled psychopathology measures

Sharma et al (2006),18 21 patients with stable Rivastigmine, 12 mg/d No signifi cant randomized, double- schizophrenia for 24 weeks improvement in any blind, placebo-controlled cognitive measure Clinical Point Fagerlund et al (2007),19 21 patients enrolled, Donepezil, 5 or 10 mg/d No differences in double-blind, 11 completed for 4 months added to changes on PANSS Many augmentation placebo-controlled ziprasidone scores or a global agents have eﬃ cacy cognitive score in schizophrenia, Keefe et al (2007),21 250 stable outpatients Donepezil, 5 mg for 6 Donepezil was but only in a randomized, with schizophrenia or weeks then 10 mg for 6 well-tolerated but did double-blind, schizoaffective disorder weeks not improve cognition minority of patients placebo-controlled any more than placebo

PANSS: Positive and Negative Syndrome Scale

• Longer treatment (>3 months) might Recommendations have been necessary for donepezil to “sur- Clinical experience, case reports, and small pass” the large placebo effect. case series indicate that occasional patients • Other AChEIs—such as galantamine, may benefi t from AChEI augmentation. which stimulates nicotinic receptors—might On the other hand, the only large, multi- be more effective than donepezil, which is center, placebo-controlled, parallel-design predominantly muscarinic. study found no difference between donepezil and placebo augmentation of atypi- ‘Subgroup’ hypothesis. Finally, if schizo- cal antipsychotics.21 phrenia’s pathophysiology is extremely Thus this review of available evidence heterogeneous, AChEI augmentation might does not support the routine use of AChEI benefi t only the small subgroup of patients augmentation of typical or atypical anti- with decreased cholinergic activity. Most psychotics as a viable psychopharmacolog- other patients—without decreased cholin- ic strategy. Until more supportive evidence ergic activity—would not benefi t or might has been reported, this reviewer cannot even worsen. In support of the “subgroup” recommend AChEIs as a “fi rst line” aug- hypothesis, Miller22 has reported that many mentation strategy. Furthermore, because augmentation agents have effi cacy in schizo- these medications do not have an FDA- phrenia—but only in a minority of patients. approved indication in schizophrenia and If this hypothesis is true, clinicians are expensive, a cost-benefi t appraisal also would need to differentiate patients be- would not support their routine use. fore giving them trials of AChEIs or other Nevertheless, AChEIs are relatively safe augmentation therapies. Genetic testing and occasionally have been dramatically ef- might identify different pathophysiologies fective in a small subgroup of schizophrenia among patients, but these technologies are patients when used as augmentation. They Current Psychiatry not yet clinically available. may represent a reasonable approach: Vol. 7, No. 3 99 • when other adjuncts have failed • as a supplement to other augmenta- Related Resources tion strategies, such as cognitive-behavioral • Mohamed S, Paulsen JS, O’Leary D, et al. Generalized cognitive deﬁ cits in schizophrenia. Arch Gen Psychiatry therapy or family therapy. 1999;56:749-54. • Risch SC, Horner MD, McGurk S, et al. Double-blind References donepezil-placebo crossover augmentation study of atypical 1. Hans SL, Marcus J, Nuechterlein KH, et al. Neurobehavioral antipsychotics in chronic, stable schizophrenia: a pilot study. defi cits at adolescence in children at risk for schizophrenia. Schizophr Res 2007;93:131-5. The Jerusalem Infant Development Study. Arch Gen Psychiatry Cognition in 1999;56:741-8. Drug Brand Names schizophrenia 2. Heaton R, Paulsen JS, McAdams LA, et al. Neuropsychological defi cits in schizophrenia: relationship to age, chronicity and Donepezil • Aricept Rivastigmine • Exelon dementia. Arch Gen Psychiatry 1994;51(6):469-76. Galantamine • Reminyl, Razadyne Ziprasidone • Geodon 3. Cummings JL. Cholinesterase inhibitors: a new class of Disclosure psychotropic compounds. Am J Psychiatry 2000;157(1):4-15. 4. Lawrence AD, Sahakian BJ. Alzheimer disease, attention, Dr. Risch receives research support from the National Institute and the cholinergic system. Alzheimer Dis Assoc Disord 1995; of Mental Health, Abbott Laboratories, GlaxoSmithKline, 9(suppl 2):43-9. Bristol-Myers Squibb, and Forest Pharmaceuticals. He is a 5. Green MF, Kern RS, Broff DL, et al. Neurocognitive defi cits consultant to and speaker for AstraZeneca and Pﬁ zer Inc. and functional outcome in schizophrenia: are we measuring the “right stuff”? Schizophr Bull 2000;26:119-36. 6. Powchick P, Davidson M, Haroutunian V, et al. Postmortem Clinical Point studies in schizophrenia. Schizophr Bull 1998;24(3):325-41. 15. Tugal O, Yazici KM, Anil Y, Gögüs A. A double-blind placebo 7. Breese CR, Lee MJ, Adams CE, et al. Abnormal regulation of controlled, cross-over trial of adjunctive donepezil for cognitive impairment in schizophrenia. Int J Neuropsychopharmacol high affi nity nicotinic receptors in subjects with schizophrenia. AChEIs may be a 2004;7:117-23. Neuropsychopharmacol 2000;23(4):351-64. 16. Freudenreich O, Herz L, Deckersbach T, et al. Added donepezil 8. Crook JM, Tomaskovic-Crook E, Copolov DL, Dean B. reasonable approach for stable schizophrenia: a double-blind, placebo-controlled Decreased muscarinic receptor binding in subjects with trial. Psychopharmacology (Berl) 2005;181:358-63. when other adjuncts schizophrenia: a study of the human hippocampal formation. Biol Psychiatry 2000;48(5):381-8. 17. Sharma T, Reed C, Aasen I, Kumari V. Cognitive effects of adjunctive 24-weeks rivastigmine treatment to antipsychotics have failed and as 9. Holt DJ, Bachus SE, Hyde TM, et al. Reduced density in schizophrenia: a randomized, placebo-controlled, double- of cholinergic interneurons in the ventral striatum in blind investigation. Schizophr Res 2006;85:73-83. a supplement to schizophrenia: an in situ hybridization study. Biol Psychiatry 2005;58:408-16. 18. Fagerlund B, Soholm B, Fink-Jensen A, et al. Effects of donepezil adjunctive treatment ziprasidone on cognitive cognitive-behavioral 10. MacEwan GW, Ehmann TS, Khanbhai I, Wrixon C. Donepezil defi cits in schizophrenia: a double-blind, placebo-controlled in schizophrenia—is it helpful? An experimental design case study. Clin Neuropharmacol 2007;30:3-12. or family therapy study. Acta Psychiatr Scand 2001;104(6):469-72. 19. Chouinard S, Sepehry, A, Amir A, et al. Oral cholinesterase 11. Stryjer R, Strous RD, Bar F, et al. Benefi cial effect of donepezil inhibitor add-on therapy for cognitive enhancement in augmentation for the management of comorbid schizophrenia schizophrenia: a quantitative systematic review, part I. Clin and dementia. Clin Neuropharmacol 2003;26:12-7. Neuropharmacol 2007;30:169-82. 12. Aasen I, Kumari V, Sharma T. Effects of rivastigmine on 20. Keefe RS, Malhotra AK, Meltzer HY, et al. Effi cacy and safety sustained attention in schizophrenia: an fMRI study. J Clin of donepezil in patients with schizophrenia or schizoaffective Psychopharmacol 2005;25:311-7. disorder: signifi cant placebo/practice effects in a 12- 13. Arnold DS, Rosse RB, Dickinson D, et al. Adjuvant therapeutic week, randomized, double-blind, placebo-controlled trial. effects of galantamine on apathy in a schizophrenia patient. J Neuropharmacol 2007; July 11 [Epub ahead of print]. Clin Psychiatry 2004;65:1723-4. 21. Maelicke A, Albuquerque EX. Allosteric modulation of 14. Friedman JI, Adler DN, Howanitz E, et al. A double blind nicotinic acetylcholine receptors as a treatment strategy for placebo controlled trial of donepezil adjunctive treatment to Alzheimer’s disease. Eur J Pharmacol 2000;393:165-70. risperidone for the cognitive impairment of schizophrenia. 22. Miller AL. Combination treatments for schizophrenia. CNS Biol Psychiatry 2002;51:349-57. Spectr 2004;9(9):19-23.

Bottom Line Available evidence and cost-beneﬁ t analysis suggest that acetylcholinesterase inhibitors (AChEIs) should not be high on your list as potential augmentation strategies for schizophrenia. Yet because schizophrenia is a heterogeneous brain disease, oﬀ -label AChEI augmentation might be a reasonable option for some patients when other add-on strategies fail to improve cognitive symptoms.

Current Psychiatry 100 March 2008