Priority communicationA double blind placebo controlled trial of donepezil adjunctive treatment to risperidone for the cognitive impairment of schizophrenia
Introduction
On average, schizophrenic patients perform poorly in most domains of cognition (Saykin et al 1994). Therefore, the introduction of several new atypical antipsychotic medications over the last decade represents an advance in the treatment of schizophrenia given their reported superior effects on cognitive functioning compared .with typical antipsychotics. To date, 24 published reports of 20 different studies indicate that clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole have greater effects on cognitive functioning compared with treatment with typical antipsychotics (Harvey and Keefe 2001). While many of these studies report statistically significant effects, a statistically significant effect does not necessarily translate into a clinically meaningful effect. The weighted average of the improvement effects of atypical antipsychotics on cognitive functions determined byHarvey and Keefe (2001) demonstrate modest effects by atypicals (range = .13 – .39). When considering the severity of neuropsychological impairment in schizophrenic patients, these improvements will not return most patients to normative standards of cognitive functioning. For example, the weighted average improvement effect of atypical antipsychotics on secondary memory of .39(Harvey and Keefe 2001) would, on average, only restore secondary memory to within one to two standard deviations of normative standards according to the severity of impairment observed bySaykin et al (1994). Therefore, other treatments need to be considered to address the continued problem of cognitive impairment in the face of atypical antipsychotic treatment.
While dopamine (DA) has been regarded as the key neurotransmitter involved in the pathogenesis of schizophrenic symptoms (Davis et al 1991), there are a number of studies implicating a role of cholinergic neurons in schizophrenia. Although the obvious pathology of the cholinergic system as seen in Alzheimer’s disease (e.g., decreased cell density in the nucleus basalis of Meynert) is absent from the brains of schizophrenic patients (el-Mallack et al 1991), a correlation has been found at post mortem examination between decreases in brain choline acetyltransferase levels and the severity of ante mortem cognitive impairments Haroutunian et al in press, Karson et al 1996. Therefore, subtle changes in cholinergic function may contribute to the cognitive impairment associated with schizophrenia.
Patients with schizophrenia have deficits in episodic memory, a cognitive ability dependent upon normal hippocampal function. Moreover, significant reductions in hippocampal volume and function of schizophrenic patients have been identified by structural(Nelson et al 1998) and functional imaging. At the receptor level, muscarinic receptors, important to hippocampal functions such as learning and memory Levey et al 1995, McAlonan et al 1995, are reduced in the brains of schizophrenic patients (Crook et al 2000). Therefore, these changes may contribute to the memory impairments associated with schizophrenia. Indeed, the administration of the muscarinic antagonists scopolamine or atropine induces memory impairments in animal models and healthy humans Blozovski et al 1977, Aigner and Mishkin 1986, Drachman 1977 similar to the memory impairments of schizophrenia. This drug-induced impairment is subsequently reversed by the administration of acetylcholinesterase inhibitors Nielsen et al 1989, Wanibuchi et al 1994, Rupniak et al 1997.
A role for muscarinic receptors in the processes of attention has also been demonstrated. For example, impaired performance of rats on the five-choice serial reaction task is observed following basal forebrain lesions (Robbins et al 1989). Furthermore, both the systemic administration of physostigmine and the transplant of cholinergic embryonic cells into the brains of rats with basal forebrain lesions improve the visual attentional impairments(Muir et al 1992). In addition, continuous intraventricular injections of scopolamine during a continuous performance task impair the performance of monkeys (Callahan et al 1993).
Alterations in nicotinic cholinergic receptor function may also contribute to the cognitive impairment of schizophrenia. Nicotinic receptor stimulation can increase arousal, improve attention, and influence a number of cognitive functions. In addition, nicotinic receptor stimulation transiently normalizes sensory gating deficits(Adler et al 1993) and dysfunctional smooth eye pursuit movements (Klein and Anderson 1991) in schizophrenic patients. Sensory motor gating is a hippocampal phenomenon which manifests itself in the schizophrenic symptomatology as an inability to attend appropriately to sensory stimuli and, therefore, may impact greatly on cognitive performance.
Schizophrenic patients have been shown to have a reduced number of nicotinic receptors, especially in the hippocampus Freedman et al 1995, Leonard et al 1996. Furthermore, pharmacological studies show that treatment with high affinity nicotinic receptor antagonists blocks habituation of auditory-evoked responses(Luntz-Leybman et al 1992). Moreover, nicotine self administration through cigarette smoking has been shown to diminish this impairment in schizophrenic patients (Adler et al 1993).
Given these data, it is reasonable to speculate that increasing cholinergic activity at muscarinic and nicotinic receptors may alleviate some of the cognitive impairment associated with schizophrenia. Treatment with a cholinesterase inhibitor is an effective means of stimulating nicotinic and muscarinic receptor activity, since inhibition of acetylcholinesterase increases the synaptic level of the natural agonist acetylcholine (ACh). Newer generation drugs such as donepezil have pharmacological and pharmacokinetic advantages over drugs such as tacrine that permit easier administration and reduce the adverse effect profile. Donepezil is a mixed inhibitor of acetylcholinesterase exhibiting primarily noncompetitive, but also some competitive, inhibition of this enzyme(Nochi et al 1995). Donepezil selectively inhibits acetylcholinesterase rather than butylcholinesterase, producing a more favorable side effect profile than Tacrine (Sugimoto et al 1992). Its long half life (70 hours) supports once-daily administration (Rogers et al 1998a). Given this, donepezil appeared to be the optimal choice of acetylcholinesterase inhibitor to use as an adjunct to antipsychotic treatment to target the cognitive impairment of schizophrenia. Donepezil has proven effective in treating the cognitive symptoms of patients with mild to moderate Alzheimer’s disease (AD) Rogers et al 1998b, Rogers et al 1998c, but to date has not been studied as a treatment of cognitive symptoms of schizophrenia. Therefore, we aimed to determine if donepezil added to the atypical antipsychotic risperidone in schizophrenic patients would improve secondary memory and attention compared with placebo.
Section snippets
Subjects
Subjects were recruited from both inpatient and outpatient departments at Mount Sinai Hospital, New York, NY; Pilgrim Psychiatric Center, Brentwood, NY; Bronx Veterans Hospital, Bronx, NY; and Montrose Veterans Hospital, Montrose, NY. All participants met DSM-IV diagnostic criteria for schizophrenia utilizing the Comprehensive Assessment of Symptoms and History (CASH) structured interview (Andreasen et al 1992). A structured diagnostic procedure, including chart reviews, preceded a census
Results
Thirty-six subjects entered the study and 36 were randomized to study drug (18 placebo, 18 donepezil). Ten subjects were randomized to receive 5 mg/day of donepezil for the entire 12 weeks, while 8 patients had their dose of donepezil increased to 10 mg per day for the last 8 weeks of the study. Thirty-four subjects completed the entire protocol. Two subjects in the donepezil 10 mg group terminated early from the study shortly after the dose increase due to increased agitation and
Discussion
The primary efficacy hypothesis for donepezil as adjunctive treatment to risperidone for cognitive impairment in schizophrenia was not supported by the data from this study. Indeed, the change in performance on measures of serial verbal learning, delayed recall, and vigilance associated with donepezil treatment was not significantly different from placebo. Nonetheless, there appeared to be an increasing effect on vigilance (measured by the CPT) with an increasing dose of donepezil (Table 2).
Acknowledgements
Funding was provided by the Janssen Research Foundation and the Clinical Trials Unit, VA VISN 3 MIRECC.
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