Three acetylcholinesterase inhibitors are on the market for the treatment of Alzheimer’s disease: Japan&Japan/Shire/Janssen’s galantamine (Reminyl), Eisai/Pfizer’s donepezil (Aricept), and Novartis’s rivastigmine (Exelon/Prometax). Clinical studies evaluating these agents in the treatment of the cognitive dysfunction and negative symptoms associated with schizophrenia have been performed, but only galantamine appears to be in commercial development for schizophrenia (donepezil and rivastigmine are being evaluated in exploratory studies). Experience with donepezil suggests that in addition to inhibiting acetylcholinesterase, acetylcholinesterase inhibitors may need to allosterically modulate the a7 nicotinic receptor because, without this action, these agents do not appear to have efficacy in the treatment of schizophrenia. Because galantamine is the only acetylcholinesterase inhibitor to possess both mechanisms of action and the only one in clinical development for this indication, this compound is discussed in detail here.
Mechanism Of Action
Acetylcholine acts at muscarinic and nicotinic cholinergic receptors. Cholinergic mechanisms have been implicated in the regulation of attention, memory, processing speed, and sensory-gating processes — processes that are impaired in patients with schizophrenia. Some researchers theorize that reduced cholinergic activity may contribute to the cognitive impairment in patients with schizophrenia and that the impairment may be alleviated by using acetylcholinesterase inhibitors to increase cholinergic activity at muscarinic and nicotinic receptors. This theory is based on evidence indicating a correlation between (1) reductions in postmortem brain choline acetyltransferase (ChAT) levels and ante mortem cognitive dysfunction and (2) receptor studies indicating decreased muscarinic and nicotinic receptors, critical to hippocampal cognitive functions (especially attention), in brains of schizophrenic patients. Furthermore, the a1 nicotinic receptor is prominently involved in sensory gating and smooth pursuit eye movement, two psychophysiological functions that are disturbed in patients with schizophrenia. Ultimately, acetylcholinesterase inhibitors are expected to reduce cognitive and negative symptoms of schizophrenia when used as adjuvant medication to antipsychotics.
Japan&Japan has undertaken a Phase II exploratory study that will evaluate galantamine (Japan&Japan/Shire/Janssen’s Reminyl) in the treatment of cognitive deficits (specifically, learning) in patients with schizophrenia. The compound is currently marketed for the treatment of mild to moderate Alzheimer’s disease in the United States and Europe.
Three case reports suggest that, when dosed concomitantly with an antipsychotic, galantamine shows therapeutic benefit in the treatment of schizophrenia. In one case, galantamine was added to a multiantipsychotic regimen for a man manifesting severe and persistent positive and negative symptoms as well as mood disturbance and cognitive dysfunction. His multiantipsychotic regimen included clozapine (500 mg), fluphenazine (30 mg), olanzapine (15 mg), and ziprasidone (20 mg). Galantamine was administered for a period of eight weeks, with a final dose of 12 mg twice daily. Over the treatment period, the patient experienced a clinically significant improvement in negative symptoms, as reflected by the Scale for the Assessment of Negative Symptoms (Scale for the Assessment of Negative Symptoms). Furthermore, galantamine treatment was associated with an improvement in activities of daily living (especially self care) within one week of initiation. Upon galantamine’s withdrawal at study end, Scale for the Assessment of Negative Symptoms scores worsened and returned to baseline values within a few days. Galantamine was well tolerated. The patient did experience a mild tremor, but it was most likely not galantamine-induced because it persisted after he stopped taking the drug.
Despite these exciting results, the future of acetylcholinesterase inhibitors in the treatment of schizophrenia is unclear. Studies with other acetylcholinesterase inhibitors (rivastigmine and donepezil) have produced uncertain as well as conflicting results. In a small open-design study (n = 16), rivastigmine statistically improved quality of life (as assessed by the Satisfaction with Life Domains Scale [SLDS]), cognition (as assessed by the Mini Mental State Examination [MMSE]), and memory (as assessed by the Wechsler Memory Scale [WMS]). However, these results should be interpreted with caution because the trial was small and did not have a control group.
Donepezil has been evaluated more extensively than its two acetylcholinesterase inhibitor competitors in the treatment of schizophrenia, and data from these trials are conflicting. Some trials (on average less stringently designed) suggest that donepezil may improve neuropsychological functioning in schizophrenic patients while two trials (both well-designed but small) failed to demonstrate significant improvements. For example, in a recent 12-week, double-blind, placebo-controlled, crossover study, 12 schizophrenic patients were randomly assigned to receive donepezil (5 mg) or placebo for six weeks and then were crossed over to the alternate therapy for six additional weeks. At the study end, donepezil’s effect on cognition measures, Positive and Negative Syndrome Scale, and depression scores was not significant.
The authors suggest that the lack of response to donepezil may be due to a desensitization of the nicotinic receptor to acetylcholine caused by chronic tobacco use and that other neurotransmitter defects may be implicated in the cognitive dysfunction seen in schizophrenia. They theorize that compounds that (1) interact with the nicotinic receptor at binding sites separate from that for acetylcholine and nicotinic agonists and (2) act specifically to enhance the activity of nicotinic receptors in the presence of acetylcholine may prove more efficacious. Galantamine is such a compound: it acts as both a cholinesterase inhibitor and a nicotinic-receptor modulator. Despite this intriguing theory, previous experience with a compound similar to galantamine (physostigmine) did not improve schizophrenia symptoms.