The Muscarinic Hypothesis of Schizophrenia

April 16, 2008
Thomas J. Raedler, MD

Volume 25, Issue 5

Since the discovery of dopamine as a neurotransmitter in the late 1950s, schizophrenia has been associated with changes in the dopaminergic system. However, the dopamine hypothesis of schizophrenia cannot explain all the symptoms associated with this disorder. Therefore, research has also focused on the role of other neurotransmitter systems, including glutamate, g-aminobutyric acid, serotonin, and acetylcholine (ACh) in schizophrenia.

Since the discovery of dopamine as a neurotransmitter in the late 1950s, schizophrenia has been associated with changes in the dopaminergic system. However, the dopamine hypothesis of schizophrenia cannot explain all the symptoms associated with this disorder. Therefore, research has also focused on the role of other neurotransmitter systems, including glutamate, g-aminobutyric acid, serotonin, and acetylcholine (ACh) in schizophrenia.

Recently, schizophrenia has been linked to changes in the muscarinic ACh system.1,2 This review focuses on the muscarinic hypothesis of schizophrenia and the potential implications of ACh for the treatment of schizophrenia.

Acetylcholine as a neurotransmitter
For almost a century, ACh has been recognized as a neurotransmitter both in the CNS and in the peripheral nervous system (PNS). ACh plays a crucial role in a variety of CNS and PNS functions, including sensory perception, motor function, cognitive processing, memory, arousal, attention, sleep, nociception, motivation, reward, mood, psychosis, and neuroplasticity.

ACh is synthesized in neurons from acetyl-CoA and choline in a reaction catalyzed by the enzyme choline acetyltransferase (Figure restricted. Please see print version for content). In the synaptic cleft, ACh binds to presynaptic and postsynaptic receptors and is inactivated through hydrolysis by the enzyme cholinesterase. Choline is transported back into the presynaptic neuron through a specific choline transporter and is recycled into the synthesis of ACh.

Cholinergic neurons in the brain
Most cholinergic projection neurons are located in the basal forebrain and the brain stem. Basal forebrain cholinergic neurons (eg, nucleus basalis of Meynert) innervate the cerebral cortex and hippocampus. Brain stem cholinergic neurons project to the midbrain and brain stem, including dopaminergic cells in the substantia nigra and ventral tegmental area. Cholinergic interneurons are mainly located in the striatum and nucleus accumbens.

Muscarinic and nicotinic ACh receptors
The muscarinic and the nicotinic system are 2 distinct families of the ACh system. Muscarinic and nicotinic ACh receptors differ in function and structure. Nicotinic ACh receptors are ligand-gated ion channel receptors. The binding of ACh to the nicotinic receptor leads to an activation of the ion channel, resulting in a rapid inflow of sodium ions. In contrast, muscarinic ACh receptors are G-protein-coupled receptors. The activation of muscarinic receptors results in a slow- er but potentially more sustained response. Although nicotinic ACh receptors also play a role in the pathophysiology and treatment of schizophrenia, this review will focus on the role of the muscarinic system in schizophrenia.

Muscarinic ACh receptors
Muscarinic ACh receptors belong to the superfamily of G-protein-coupled receptors that either activate or inhibit message transduction systems, thus having an effect on the intracellular second messengers, such as cyclic adenosine monophosphate or inositol triphosphate. Muscarinic ACh receptors can be found on cholinergic and noncholinergic cells in presynaptic and postsynaptic locations. There are 5 known muscarinic ACh receptors (M1 through M5). All 5 subtypes of the muscarinic ACh receptor are present in the human CNS, albeit in regionally varying concentrations. M1, M2, and M4 are the predominant muscarinic ACh receptor subtypes in the CNS. Animal studies-genetically modified animals studies, in particular-have helped clarify the physiological role of the different mus-carinic receptor subtypes.3The muscarinic hypothesis of schizophrenia
The muscarinic hypothesis of schizophrenia postulates that the muscarinic ACh system plays a crucial role in the pathology and treatment of schizophrenia. Data from clinical, postmortem, neuroimaging, and preclinical and clinical pharmacology studies support this hypothesis.

Postmortem and neuroimaging studies Postmortem studies have shown a decreased number of M1 and M4 muscarinic ACh receptors in persons with schizophrenia in several key areas, including caudate and putamen, hippocampus, anterior and posterior cingulate cortex, and prefrontal cortex. (For more information, see the work by Raedler and colleagues.1) Similar changes were not found in persons with bipolar disorder or major depression.4 The levels of M2 and M4 muscarinic ACh receptors were unchanged in schizophrenia. These findings are supported by a single-photon emission CT (SPECT) study that found a significant decrease in vivo in the availability of muscarinic receptors in the cortex and basal ganglia in patients with schizophrenia compared with healthy controls.5Pharmacological studies of the muscarinic system
Different pharmacological approaches (eg, increase of intrasynaptic ACh concentration; agonistic and antagonistic effects on muscarinic receptors) can be used to target the muscarinic system. Some of these approaches have been applied to schizophrenia and represent promising novel targets for its pharmacological treatment.

Cholinesterase inhibitors
Cholinesterase inhibitors (donepezil, galantamine, and rivastigmine) increase the intrasynaptic concentration of ACh through inhibition of the enzyme acetylcholinesterase. These inhibitors are used to improve cognitive function in dementia.

A series of studies in schizophrenia failed to show convincing improvement in cognitive function after the addition of cholinesterase inhibitors to antipsychotic medication.1,6 More recently, a study of cotreatment with donepezil in 250 patients with schizophrenia showed no advantage for donepezil over placebo.7

Galantamine differs from the other cholinesterase inhibitors. In addition to being a cholinesterase inhibitor, galantamine is an allosteric modulator at nicotinic receptors. This combined mechanism of action may be more beneficial in schizophrenia, and first add-on studies of galantamine have shown significant improvement in some aspects of cognitive function.8Muscarinic antagonists
For several decades, anticholinergics such as benztropine, biperiden, and trihexyphenidyl have been beneficial for the prophylaxis and treatment of antipsychotic-induced motor adverse effects. At the same time, anticholinergics have been found to cause cognitive dysfunction in healthy controls as well as in patients with schizophrenia.9,10 Anticholinergics have been associated with a worsening of positive symptoms and an improvement in negative symptoms of schizophrenia.11 Patients with schizophrenia report activating effects of anticholinergics, which occasionally results in the misuse of these medications.12 Because of these effects as well as potential adverse effects (eg, urinary retention, dry mouth, constipation), the use of anticholinergics has recently been viewed with a more critical eye. Because the muscarinic receptor antagonist scopolamine was recently associated with robust antidepressant effects, the spectrum of action of anticholinergics may need to be reevaluated.13Antimuscarinic effects of antipsychotics
Several antipsychotics have antimuscarinic properties in vitro and can cause antimuscarinic adverse effects (eg, dry mouth, urinary hesitancy, constipation) in vivo. Looking at atypical antipsychotics, in vitrostudies show that clozapine and olanzapine have strong binding affinity for muscarinic ACh receptors, while quetiapine shows a moderately strong binding affinity.14,15

SPECT-imaging can be used to assess the in vivobinding properties of antipsychotic medications to muscarinic receptors. Treatment with clozapine and olanzapine results in a significantly decreased availability of muscarinic receptors.16,17 In a direct comparison, the reduction of muscarinic receptor availability was shown to be significantly stronger after treatment with clozapine than with olanzapine.18

The anticholinergic properties of atypical antipsychotics may contribute to their reduced rate of treatment-induced motor adverse effects. However, recent studies have shown that muscarinic receptors, in particular M3 muscarinic receptors, play a major role in blood sugar regulation.19 Thus, the binding profile of antipsychotics to muscarinic receptors may contribute to their risk of inducing diabetes mellitus.20Muscarinic agonists
Muscarinic agonists may be a beneficial new treatment approach in schizophrenia. Betel nut chewing is a widespread practice in some Asian and Pacific cultures. In schizophrenia, betel nut chewing has been associated with fewer positive and negative symptoms.21 These findings are of special interest in this context, as some psychoactive components of betel nut, in particular arecoline, are muscarinic agonists.

Xanomeline, a synthetic arecoline derivative, is an M1/M4 muscarinic ACh receptor agonist. Xanomeline was initially evaluated as a therapeutic agent for Alzheimer disease. It showed dose-dependent efficacy against psychotic symptoms (eg, agitation, delusions, hallucinations) in Alzheimer disease.22 In a small pilot study of schizophrenia, monotherapy with xanomeline resulted in an improvement in positive symptoms as well as in cognitive function.23 In animal studies, xanomeline and other muscarinic agents (eg, BuTAC, PTAC) showed antipsychotic-like properties without any affinity to dopamine receptors.

Several M1 muscarinic agonists were developed for potential treatment of patients with dementia. Alvameline, milameline, sabcomeline, SDZ 210-086, and xanomeline were all discontinued for lack of effectiveness or because of their adverse-effect profiles.3 Some of these agents lacked true specificity for the M1 receptor subtype, which resulted in limitations in dosage. With the exception of xanomeline, no M1 muscarinic agonist has been assessed in schizophrenia. Several novel M1 muscarinic agonists are currently under development, which should overcome the shortcomings of these older agents.24 In addition, M4 muscarinic agonists are in the early stages of development for use in schizophrenia.

N-desmethylclozapine as the first partial M1 muscarinic agonist
Clozapine remains the antipsychotic of choice in patients with treatment-refractory schizophrenia. Recent studies have confirmed the superiority of clozapine for this patient group.25,26 The mechanism of clozapine remains poorly understood. Clozapine has strong in vivoeffects on muscarinic receptors.16 While it is traditionally associated with muscarinic antagonism, some of its adverse effects (eg, hypersalivation) actually improve under treatment with anticholinergics, suggesting possible muscarinic agonist effects.

Because of its unique pharmacological properties, N-desmethylclozapine (norclozapine; NDMC), the main active metabolite of clozapine, has been the focus of attention. In addition to being a partial agonist at dopamine D2 and D3 receptors, NDMC is also a partial agonist at M1 muscarinic receptors.27 NDMC (ACP-104) is currently undergoing a phase 2 study in patients with schizophrenia. The results of this study will help further assess the usefulness of M1 muscarinic agonists in schizophrenia.

Summary
The muscarinic hypothesis of schizophrenia postulates an alteration of the muscarinic cholinergic system as part of the underlying pathophysiology of this disorder and is supported by data from neuropathology, brain imaging, preclinical and clinical pharmacology, and clinical studies. The muscarinic hypothesis should be seen as an addition to existing theories on schizophrenia and offers a potential new approach for the pharmacological treatment of schizophrenia.

All currently available antipsychotics focus on the dopaminergic system. The interactions between the muscarinic and the dopaminergic systems are complex and occur at different levels in the brain. It remains unclear if beneficial effects of muscarinic agonists in schizophrenia are primarily caused by direct muscarinic effects or are secondary to a modulatory effect on the dopaminergic system. These 2 mechanisms are not mutually exclusive and can combine for additional efficacy.

Some currently available pharmacological agents affect the muscarinic cholinergic system. Several older and newer antipsychotics interact with muscarinic receptors in vitro and in vivo. While muscarinic antagonism may help lower the risk of treatment-emergent motor adverse effects, muscarinic antagonism also carries the potential of worsening cognitive function. The effects of the adjunctive use of cholinesterase inhibitors on cognitive function in schizophrenia have been modest at best.

Positive and negative symptoms as well as cognitive symptoms are potential target symptoms for muscarinic agonists in schizophrenia. Different muscarinic agonists were developed primarily for the treatment of dementia. These agents were abandoned because of problems with dosing and tolerability. New muscarinic agonists are under development with the potential for better specificity and tolerability. For the treatment of schizophrenia, M1 muscarinic agonists seem the most promising new approach.

Experimental data and first clinical data suggest that M1 muscarinic agonists are effective against psychotic and cognitive symptoms. However, there are limited clinical data. NDMC, the active metabolite of clozapine, is a partial M1 muscarinic agonist. The results of first clinical trials with NDMC will shed additional light on the effects of M1 muscarinic agonists in schizophrenia.

The muscarinic cholinergic system is a promising new target for the pharmacological treatment of schizophrenia. However, large studies with newly developed agents are needed to determine the clinical usefulness of this approach. Tables 1 and 2 present brief summaries of muscarinic treatment strategies for schizophrenia and the effects of psychotropic medications on muscarinic receptors, respectively.

 

   
   
 • Muscarinic antagonists (anticholinergics) are beneficial against antipsychoticinduced motor adverse effects
 • Anticholinergics impair cognition
 • Different antipsychotics (eg, clozapine and olanzapine) as well as tricyclic antidepressants antagonize muscarinic receptors in vitro and in vivo
 • The effects of cholinesterase inhibitors on cognition in schizophrenia are modest at best
 • N-desmethylclozapine, the active metabolite of clozapine, is a partial agonist at M



 

   
   
 • Preclinical and small clinical studies suggest that muscarinic agonists may be beneficial for the treatment of positive and cognitive symptoms of schizophrenia
 • All previously developed M1 muscarinic agonists had to be abandoned because of their lack of specificity and adverse-effect profiles
 • Several M
 • Future clinical studies will show whether muscarinic agonism emerges as a new treatment option in schizophrenia

References:

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