Dr. Shekhar Replies

To the Editor: We are grateful to Drs. Janowsky and Davis for presenting findings from some very important early psychopharmacologic literature that further supports the role of cholinergic neurotransmission in the pathophysiology of psychosis. Many of these findings were from studies that utilized acetylcholinesterase inhibitors such as physostigmine, although more recent studies have used relatively centrally selective novel cholinesterase inhibitors (1) . A number of these recent studies have demonstrated some benefit from the use of cholinesterase inhibitors in the treatment of schizophrenia, including improvement in several cognitive (2) and neuroimaging measures (3), although an equal number of studies have reported negative findings (4) . Unfortunately, the strategy of utilizing cholinesterase inhibitors is limited by the fact that these drugs increase acetylcholine levels at all cholinergic synapses and thus possess nonselective agonistic effects on all subtypes of muscarinic and nicotinergic receptors. Therefore, many of the beneficial effects of stimulating a particular cholinergic receptor subtype are likely to be opposed or canceled by stimulation at another subtype of cholinergic receptor. For example, loss of the muscarinic type 4 receptor is shown to increase limbic dopamine release (5), whereas loss of the muscarinic type 5 receptor decreases dopamine release in the same pathways (6) . This is perhaps why several larger studies and meta-analyses have been unable to demonstrate any robust beneficial effects of cholinesterase inhibitors in schizophrenia (4) .

Nevertheless, the early studies cited by Drs. Janowsky and Davis demonstrate the long-standing recognition of the therapeutic potential within the cholinergic strategy to develop novel antipsychotics. With recently emerging receptor selective agonists such as xanomeline, on which we reported (7), and newer positive allosteric modulators of muscarinic receptor (8), there is finally a real possibility of a cholinergic drug emerging for ameliorating symptoms of schizophrenia.