Some schizophrenia patients have shown significant improvements in positive and negative symptoms when my colleagues and I added acetylcholinesterase inhibitors (AChEIs) to their anti-psychotic regimens. We cannot rule out these benefits as placebo effects, but nevertheless they have been sustained over time. When patients appear to have benefited from AChEIs but stopped them, the benefits rapidly disappeared. Then, when these patients restarted the medications, the benefits recurred.
Unfortunately, recent well-controlled clinical studies have not supported these anecdotal findings or the results of approximately 20 preliminary trials. Thus, this article explains:
- why we don’t recommend using off-label AChEIs as a “first choice” augmentation strategy in schizophrenia patients at this time
- under what circumstances the adjunctive use of 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 benefit in AD.
So why are psychiatrists trying AD medications in patients with schizophrenia? The answer has to do with the intriguing effects of cholinergic agents on cognition.
Toward cognitive enhancement
Schizophrenia’s cognitive impairments may occur at a very early age, often before other overt symptoms,1 then may worsen—sometimes to dementia levels—when obvious psychotic symptoms emerge.2
Positive symptoms (hallucinations, delusions, thought disorder, etc.) and—to a lesser extent—negative symptoms (anhedonia, asociality, blunted affect, etc.) often improve when patients are treated with antipsychotics. Antipsychotics do not significantly improve cognitive symptoms (attention, reaction time, working memory, verbal fluency, etc.), however, and cognitive symptoms are the strongest predictors of poor functional outcomes in our patients.
Heterogeneous disorder. In 2000, Cummings3 summarized evidence from case re-ports and small studies that AChEIs were useful in treating neuropsychiatric conditions other than AD (Table 1). Cholinergic agents, Cummings noted, “affect many aspects of cognition, which suggests that the primary effect may be on an attentional or executive system with a secondary, pan-intellectual modulating influence on memory, language, and visuospatial skills.”4
In schizophrenia, different patients have different types of cognitive impairment.5 Thus, broad-based cognitive enhancers such as AChEIs may be necessary for general use in this illness.
Acetyltransferase activity. Schizophrenia patients—even those meeting criteria for dementia—do not usually have typical AD neuropathology, and the incidence of AD is no different in elderly patients with or without comorbid schizophrenia.6 At autopsy, schizophrenia patients and normal controls have similar brain cortical choline acetyltransferase levels.
Nevertheless, persons with AD and those with schizophrenia show a similar, statistically significant negative correlation between premorbid Clinical Dementia Rating scale scores and brain cortical choline acetyltransferase activity (r=– 0.36, P 6 Furthermore, studies have found cholinergic neurotransmission alterations in schizophrenia patients, including:
- a deficit in regulation of the low-affinity alpha-7 nicotinic receptor in those with impaired sensory gating7
- altered high-affinity nicotinic receptor binding8
- decreased hippocampal muscarinic receptor binding compared with matched normal controls9
- reduced density of cholinergic inter-neurons in the ventral striatum.10
Table 1
Cholinesterase inhibitors have shown benefit in many neuropsychiatric conditions*
| Alcoholism with Wernicke’s encephalopathy |
| Attention-deficit/hyperactivity disorder |
| Autism |
| Bipolar disorder |
| Creutzfeldt-Jakob disease |
| Dementia pugilistica |
| Dementia with Lewy bodies |
| Olivopontocerebellar atrophy |
| Parkinson’s disease with dementia |
| Parkinsonism dementia complex of Guam |
| Pick’s disease |
| Progressive supranuclear palsy |
| Schizophrenia |
| Sleep disorders |
| Subacute sclerosing panencephalitis |
| Traumatic brain injury |
| Vascular dementia |
| * Data from case reports and small studies. Cholinesterase inhibitors are FDA-approved only for Alzheimer’s dementia. |
| Source: Reference 3 |
AChEI augmentation
Mixed results. A number of investigators—including myself—have published data indicating that adding AChEIs—most often donepezil, but also rivastigmine or galantamine—to antipsychotic regimens may improve some schizophrenia patients’ symptoms and general functioning. These benefits were modest, however, when they were seen in these relatively small case reports and studies (Box).
Early studies: Modest benefit from AChEIs in schizophrenia
Approximately 20 published studies have reported clinically significant benefits (positive symptom, negative symptom, and/or cognitive improvement) when schizophrenia patients received cholinesterase inhibitors with their antipsychotic regimens. These include case reports, case series, and double-blind, placebo-controlled, crossover or parallel-design studies, most with relatively small numbers of subjects.a-o
Recent studies, however, have failed to show a clinically or statistically significant benefit from cholinesterase inhibitor augmentation in schizophrenia (Table 2). Some included larger sample sizes than earlier investigations and a placebo-active drug parallel design.
fMRI findings. A few crossover design studies of schizophrenia patients taking antipsychotics included functional magnetic resonance imaging (fMRI) at baseline and after cholinesterase inhibitor and placebo augmentation. Of interest, the basal “abnormal” pattern of the baseline fMR image became more “normal” when subjects were treated with donepezil.
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