An open-labeled trial of adjunctive donepezil for cognitive impairments in patients with schizophrenia

doi:10.1016/S0920-9964(01)00387-5

Schizophrenia Research

Volume 59, Issue 1, 1 January 2003, Pages 29-33

https://doi.org/10.1016/S0920-9964(01)00387-5 Get rights and content

Abstract

A pilot study was conducted to examine if donepezil could enhance cognitive function in patients with schizophrenia. Fifteen subjects who were on stable olanzapine treatment were entered into a 6-week open-labeled trial of donepezil. Subjects received baseline and end-of-study P50 and neuropsychological assessments. Donepezil treatment resulted in significant improvement in manual dexterity. There were moderate improvements in verbal recall memory and visual memory and processing speed, with smaller changes in P50 and verbal recognition memory. There was no effect on an attention measure. There were no changes in either positive or negative symptoms. These results suggest that cholinergic tone modulation may enhance selective behavioral functions in patients with schizophrenia, but further study is required to delineate the full extent of the potential benefit of this approach.

Introduction

Patients with schizophrenia are characterized by a broad range of cognitive impairments (Goldberg and Gold, 1995). These include impairments in attention; visual and verbal memory; working memory; processing speed; abnormalities in sensory gating, as measured by P50; and eye-tracking. Cognitive impairments are hypothesized to be a major determinant of the poor social and occupational functioning observed in schizophrenia (Green, 1996). Conventional antipsychotics have limited beneficial or deleterious effects on cognition in patients with schizophrenia (Blyler and Gold, 2000). New generation antipsychotics may have modest benefits for cognitive function (Keefe et al., 1999), but whether these benefits represent a direct cognitive enhancing effect or an indirect effect through decreased adverse side effects has not been established (Blyler and Gold, 2000). Regardless, patients with schizophrenia continue to exhibit pronounced cognitive impairments despite adequate new generation antipsychotic treatment (Purdon et al., 2000).

Adjunctive pharmacotherapy may offer a viable alternative approach for the treatment of cognitive impairments. Adjunctive agents can be used to modulate specific neurotransmitter systems that are hypothesized to be involved in the pharmacology of specific cognitive functions.

Acetylcholine acts at muscarinic and nicotinic cholinergic receptors. These receptors are broadly distributed through the brain, including the neocortex, hippocampus, and basal ganglia (Cummings, 2000). Cholinergic mechanisms have been implicated in the regulation of attention, memory, processing speed, and sensory gating processes Vitiello et al., 1997, Broocks et al., 1998, Furey et al., 2000; processes which are impaired in patients with schizophrenia. Further, acute nicotine administration has previously been shown to improve sensory gating, as measured by P50, in patients with schizophrenia (Adler et al., 1998).

Donepezil is a selective acetylcholinesterase inhibitor that has been demonstrated to produce improvement on general measures of cognitive impairment in patients with Alzheimer's disease (Rogers et al., 1998). However, its efficacy for specific cognitive functions has not been evaluated. In the current study, we examined the feasibility of using adjunctive donepezil for the treatment of cognitive abnormalities in patients with schizophrenia.

Section snippets

Methods

Fifteen patients were selected for entry into a 6-week, open-labeled study. Patients were diagnosed using a best estimate diagnostic approach and met DSM-IV diagnostic criteria for schizophrenia or schizoaffective disorder. All patients had been treated with olanzapine for a minimum of 6 months. Patients with concurrent substance abuse; organic brain disorder; mental retardation; or medical conditions that could be exacerbated by donepezil were excluded from the study. All patients provided

Results

Fifteen patients entered and 14 patients completed the study. One patient withdrew with a complaint of sedation. The demographic characteristics of the patients who completed the study were: mean (±S.D.) age: 43.1±6.6; 71% male; 78% Caucasian; and mean (±S.D.) duration of illness: 24.7±7.2. The mean (±S.D.) olanzapine dose was 25.7±11.9 mg/day. Two patients were receiving benzodiazepines, two patients were receiving antidepressants, and one patient was receiving valproic acid.

Patients

Conclusions

The study results suggest that adjunctive donepezil treatment may be associated with enhanced performance on selected behaviors and cognitive functions in patients with schizophrenia. Donepezil was well tolerated; only one patient dropped out of the study and nine of the remaining subjects chose to continue on the drug beyond the protocol.

The most pronounced effect was observed for the Grooved Pegboard manual dexterity measure. This is an unanticipated, but potentially important result.

Acknowledgments

The study was funded in part by Grants MH40279 and MH45074, and the UMB-Novartis collaboration. We would also like to acknowledge Pfizer Pharmaceutical for their provision of the study medications, and Royce W. Waltrip, II, M.D. for his scientific contributions.

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The ability of the brain to reduce the amount of trivial or redundant sensory inputs is called gating function. Dysfunction of sensory gating may lead to cognitive fragmentation and poor real-world functioning. The auditory dual-click paradigm is a pertinent neurophysiological measure of sensory gating function. This meta-analysis aimed to examine the subcomponents of abnormal P50 waveforms in bipolar disorder and schizophrenia to assess P50 sensory gating deficits and examine effects of diagnoses, illness states (first-episode psychosis vs. schizophrenia, remission vs. episodes in bipolar disorder), and treatment status (medication-free vs. medicated). Literature search of PubMed between Jan 1st 1980 and March 31st 2019 identified 2091 records for schizophrenia, 362 for bipolar disorder. 115 studies in schizophrenia (4932 patients), 16 in bipolar disorder (975 patients) and 10 in first-degree relatives (848 subjects) met the inclusion criteria. P50 sensory gating ratio (S2/S1) and S1–S2 difference were significantly altered in schizophrenia, bipolar disorder and their first-degree relatives. First-episode psychosis did not differ from schizophrenia, however episodes altered P50 sensory gating in bipolar disorder. Medications improve P50 sensory gating alterations in schizophrenia significantly and at trend level in bipolar disorder. Future studies should examine longitudinal course of P50 sensory gating in schizophrenia and bipolar disorder.
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Cholinesterase inhibitors act by blocking the acetylcholinesterase enzymes, which metabolize acetylcholine. The first randomized placebo-controlled add-on trials (Sharma et al., 2006; Chouinard et al., 2007; Freudenreich et al., 2005; Friedman et al., 2002; Tugal et al., 2004; Fagerlund et al., 2007) and an open-label add-on trial (Buchanan et al., 2003) conducted to examine the cognitive effect of cholinesterase inhibitors included relatively small samples (n≤40) and reported negative findings (see Table 1). Also, the largest randomized double-blind placebo-controlled add-on trial in 245 chronic patients with schizophrenia or schizoaffective disorder showed no cognitive enhancing effect for donepezil, measured by an extensive cognitive battery (see Table 1) (Keefe et al., 2008).
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Most neuropsychiatric disorders produce cognitive deficits, sometimes representing core features of the illness. Thus, memory is the main cognitive domain disturbed in Alzheimer's disease, whereas attention is principally affected in patients with attention deficit hyperactivity disorder (ADHD). In other neuropsychiatric diseases such as schizophrenia, a more general cognitive impairment is evident. In recent decades, advances in neuroscience and the appearance of new pharmacological tools has strengthened the belief that we are close to developing nootropic drugs that can enhance cognition in healthy individuals and restore cognitive function in patients suffering from neuropsychiatric disorders. While research in animals has identified different drugs that positively modulate some aspects of cognition, such as attention, executive function, memory consolidation, and retrieval, not all of them exert therapeutic effects in clinical trials. In this chapter we focus on pharmacological treatments that might improve cognition in certain neuropsychological disorders, including ADHD, schizophrenia, bipolar disorder, major depression, and posttraumatic stress disorder. Although the neurobiological heterogeneity underlying each neuropsychiatric disorder requires the use of different pharmacological strategies to restore cognitive function, here we review the recent clinical evidence supporting the efficacy and adequacy of several medications in ameliorating such cognitive deficits without worsening the other symptoms of these illnesses.
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Acetylcholinesterase inhibitors (AChEIs) constitute another class of drugs that have mixed degrees of efficacy for improving cognition in schizophrenia. Several small-scale, open-label studies reported positive effects of AChEIs on cognition in schizophrenia (Bora et al., 2005; Buchanan et al., 2003; Mendelsohn et al., 2004; Stryjer et al., 2003), supported by some randomized double-blind trials (Buchanan et al., 2008; Schubert et al., 2006). The majority of larger double-blind randomized placebo designs (Chouinard et al., 2007; Fagerlund et al., 2007; Ferreri et al., 2006; Keefe et al., 2008; Lee et al., 2007; Mazeh et al., 2006; Risch et al., 2007; Sacco et al., 2008; Sharma et al., 2006) reported no improvement of cognition in patients with schizophrenia.
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This article is part of a Special Issue entitled ‘Schizophrenia’.

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An open-labeled trial of adjunctive donepezil for cognitive impairments in patients with schizophrenia

Abstract

Introduction

Section snippets

Methods

Results

Conclusions

Acknowledgments

Biol. Psychiatry

Neuropsychopharmacology

Lancet

Neuropharmacology

Schizophrenia, sensory gating, and nicotinic receptors

Schizophr. Bull.

Cognitive effects of typical antipsychotic treatment: another look

Statistical Power Analysis for the Behavioral Sciences, Revised Edition

Cholinesterase inhibitors: a new class of psychotropic compounds

Am. J. Psychiatry

Cholinergic enhancement and increased selectivity of perceptual processing during working memory

Science

Inhibitory gating of an evoked response to repeated auditory stimuli in schizophrenic and normal subjects

Arch. Gen. Psychiatry