Dementia praecox redux: a systematic review of the nicotinic receptor as a target for cognitive symptoms of schizophrenia

Most individuals with schizophrenia suffer some cognitive dysfunction: such deficits are predictive of longer-term functioning; and current dopamine-blocking antipsychotics have made little impact on this domain. There is a pressing need to develop novel pharmacological agents to tackle this insidious but most disabling of problems. The acetylcholinergic system is involved in cognitive and attentional processing, and its metabotropic and nicotinic receptors are widespread throughout the brain. Deficits in acetylcholinergic functioning occur in schizophrenia, and high rates of tobacco smoking have been posited to represent a form of self-medication. The nicotinic acetylcholine receptor (nAChR) has emerged as a putative target to improve cognitive deficits in schizophrenia, and this study systematically reviewed the emerging data. Nineteen studies were identified, covering three compound classes: agonists at the α7 and α 4β2 nAChRs, and positive allosteric modulators. Overall data are underwhelming: some studies showed significant improvements in cognition but as many studies had negative findings. It remains unclear if this represents drug limitations or nascent study methodology problems. The literature is particularly hindered by variability in inclusion of smokers, generally small sample sizes, and a lack of consensus on cognitive test batteries. Future work should evaluate longer-term outcomes, and, particularly, the effects of concomitant cognitive training.