To treat patients with difficult clinical dilemmas, physicians often must think "out of the box"—that is, consider treatment pathways that they would not have thought possible in the past. Indeed, the treatment of a patient with both dementia and psychosis—a long-standing clinical conundrum—has challenged geriatric psychiatrists to broaden their understanding of both cause and effect.
The topic garnered intense discussion and debate at the annual meeting of the American Association for Geriatric Psychiatry last month in Honolulu. Numerous seminars, symposia, and lectures attempted to shed light on this difficult but increasingly common combination.
Borson challenged several hundred attendees to compare rather than to contrast the two disorders in late life. Cholinergic systems in the neurodegenerative dementias and schizophrenia both entail "a change in expression or availability of brain cholinergic receptors—although this is not straightforward," she noted. Stimulation of nicotinic receptors improves the core symptoms of both, while the blockade of muscarinic receptors worsens the core symptoms of both. Both disorders involve at some level, she continued, the dopaminergic systems, differentiated by region-specific pathological effects on behavior or cognition. Dopamine systems are partly regulated by nicotinic cholinergic mechanisms, and she noted that dopamine receptor blockade is common to antipsychotic drugs—which can benefit patients with both disorders.
"Cognitive dysfunction is the principal source of disability at the disease onset," she said, regardless of whether it is Alzheimer’s or late-life schizophrenia. "And cognitive function in both is a powerful predictor of functional disability," she said. She noted that recent work has shown that the long-term outcomes in schizophrenia are not necessarily what psychiatrists were told in the past. It is not a foregone conclusion that schizophrenia is a lifelong debilitating and progressive disorder, she said.
"In fact, those patients with schizophrenia who do deteriorate often have an underlying cognitive disorder that leads to their later functional disability. Progression is the rule in Alzheimer’s, yet the exception in schizophrenia. Nevertheless, treatment must be effective without further impairing cognition," she emphasized. If cognition is impaired, patients with either disorder undoubtedly worsen.
Borson noted that new research in the last year or two has broadened the field’s thinking on what traditional "antipsychotic" and "antidementia" medications actually do. That expanding knowledge has led to the prescription of more antipsychotic medications to dementia patients as well as to more antidementia medications to patients with schizophrenia.
For some time, Borson noted, atypical antipsychotics have been used to alleviate deteriorating behavioral symptoms in dementia patients, such as agitation and aggression. New research that she cited shows some atypical antipsychotics can actually improve cognition through activating the release of acetylcholine in the cortex. Clozapine, olanzapine, and risperidone, she reported, robustly increased acetylcholine release in the cortex, while ziprasidone only moderately increased levels, compared with haloperidol and thioridazine, which did not elevate acetylcholine levels at all.
"This is really a new finding and an encouraging one," noted Borson. She added that the blockade of high levels of dopaminergic activity in the limbic system, known to be a property of most atypical antipsychotics, "allows inhibitory responses in the frontal lobes that could also lead to better cognitive function."
The cholinesterase inhibitors, long used in an attempt to stave off the progression of dementia, have been shown as a drug class to have broad-spectrum effects in outpatients and nursing home patients, improving both cognition and behavior.
Several single-case reports and one small open-label trial have in the last few years shown some benefits of using cholinesterase inhibitors on cognition and psychosis in patients with schizophrenia; however, more research must be done, Borson noted.
"But with several diseases [the dementias as well as schizophrenia], you can postulate a common mechanism—stimulation of nicotinic cholinergic activity," Borson said. Presynaptic nicotinic receptors control the release of several neurotransmitters—glutamate, acetylcholine, dopamine, norepinephrine, and serotonin—all important for memory and mood.
"Blocking of nicotinic receptors impairs cognition, while stimulating those nicotinic receptors improves cognition and memory," she said. "So you can start to see a sort of therapeutic synergy where atypical antipsychotics increase cortical dopamine and cholinesterase inhibitors at the very least increase cortical acetylcholine action, leading to an improvement in memory and thinking, as well as improvement in psychosis and behavior.
"What we have here," Borson concluded, "is a potential for higher therapeutic synergy that greatly benefits our patients." ▪