Cholinergic mechanisms in schizophrenia: Current concepts

Although the neurotransmitter dopamine plays a prominent role in the treatment of schizophrenia, the dopamine hypothesis fails to explain several aspects of the disorder. It is evident that the pathophysiology of schizophrenia involves other neurotransmitter systems as well. In this review, we discuss the increasing data implicating the cholinergic system in its pathogenesis. Cholinergic neurotransmission plays a crucial role in various central nervous system functions. The cholinergic system consists of two families of receptors, the muscarinic cholinergic and the nicotinic cholinergic, that use acetylcholine as a neurotransmitter. Data from clinical pharmacology, neuroimaging, and postmortem studies suggest an alteration of the muscarinic cholinergic system in schizophrenia. Muscarinic agonists are being evaluated as new treatment options with putative antipsychotic and cognition enhancing properties. Smoking is highly prevalent among schizophrenic subjects. Nicotine improves attention in schizophrenia. Nicotinic receptors, in particular the α7 nicotinic receptor, are candidates for the development of new medications to treat cognitive and perceptual deficits in schizophrenia. This review summarizes the evidence in support of a role for the muscarinic cholinergic system and the nicotinic cholinergic system in the pathophysiology of schizophrenia. As current treatments fail to sufficiently address all aspects of schizophrenia, promising new pharmacologic approaches that focus on the cholinergic system are currently under development.     

Serotonergic mechanisms in schizophrenia: Evolution and current concepts

Serotonin (5-HT) was once thought to have a role in visual hallucinations based on the findings that lysergic acid diethylamide was found to be a serotonin agonist. This led to a search for endogenous indole hallucinogens in schizophrenia, which ultimately proved unsuccessful. Studies of 5-HT receptor subtypes opened up the issue in several ways, with the 5-HT2A, 5-HT2C, and 5-HT1A receptors seeming to be of greatest importance, and 5-HT6 and 5-HT7 receptors of secondary importance. Linkages between 5-HT, dopamine (DA), glutamate, acetylcholine, and brain-derived neurotrophic factor, have provided some important leads as to how 5-HT may be involved in schizophrenia. It has been found that 5-HT2A rather than 5-HT2C receptor stimulation is the most likely basis for the hallucinogenic effects of lysergic acid diethylamide, but recent neurochemical and genetic studies have raised the possibility that the 5-HT2C receptor may also be important in psychosis based on its ability to regulate tonic dopaminergic function. The discovery that 5-HT2A receptor blockade was an important component of the action of clozapine and other atypical antipsychotic drugs also restored interest in a primary role of 5-HT2A receptors in the etiology of psychosis. 5-HT1A receptors also have been found to enhance DA release in the cortex and hippocampus and are primary factor in the regulation of DA release in both of these regions. Postmortem studies have found some evidence of non-drug-induced increased density of 5-HT1A receptors. Genetic studies are ongoing to link single nucleotide polymorphisms of the 5-HT2A, 5-HT2C, and 5-HT1A receptors to some schizophrenia phenotypes. It is likely that serotonergic function will become even more important in developing genetic and other markers for schizophrenia novel therapies, particularly for psychosis and cognition.     

Current concepts of pharmacological treatment in schizophrenia

The modern concepts of pharmacotherapy of schizophrenia, with the special emphasis put on new antipsychotic drugs were presented. The attention was put on the need for careful evaluation of the patient's state: the diagnosis, treatment which the patient receives and compliance with the treatment. It was stated that modern concepts of treatment of schizophrenia do not solely rely on the use of modern drugs, but include the multidirectional therapeutic actions with an active participation of the patient and his/her relatives.     

Glutamatergic mechanisms in addiction

Traditionally, addiction research in neuroscience has focused on mechanisms involving dopamine and endogenous opioids. More recently, it has been realized that glutamate also plays a central role in processes underlying the development and maintenance of addiction. These processes include reinforcement, sensitization, habit learning and reinforcement learning, context conditioning, craving and relapse. In the past few years, some major advances have been made in the understanding of how glutamate acts and interacts with other transmitters (in particular, dopamine) in the context of processes underlying addiction. It appears that while many actions of glutamate derive their importance from a stimulatory interaction with the dopaminergic system, there are some glutamatergic mechanisms that contribute to addiction independent of dopaminergic systems. Among those, context-specific aspects of behavioral determinants (ie control over behavior by conditioned stimuli) appear to depend heavily on glutamatergic transmission. A better understanding of the underlying mechanisms might open new avenues to the treatment of addiction, in particular regarding relapse prevention.     

Glutamatergic hypothesis of schizophrenia

Schizophrenia is a devastating psychiatric disorder whose pathophysiology has not been fully clarified yet. Although dopamine dysfunction in schizophrenia is unequivocal, there are many evidences suggesting the involvement of the glutamatergic system. This paper briefly describes some basic knowledge regarding the functioning of the glutamatergic receptors with emphasis on the N-methyl-D-aspartate (NMDA) receptors. Presents evidence for glutamatergic dysfunction in schizophrenia, more specifically NMDA receptor hypofunction. Finaly the paper discusses the interaction between the dopaminergic and the glutamatergic systems; in special how hyperdopaminergic state found in schizophrenia can be associated to glutamatergic dysfunctions.     

Glutamatergic aspects of schizophrenia

Almost all the neurons in the brain are influenced by the excitatory amino acid glutamate. Glutamatergic neurotransmission has been associated functionally with a number of physiological processes and with certain pathophysiological processes, including schizophrenia. Imaging studies provide indirect evidence that glutamate may be involved in schizophrenia. Positron emission tomography scanning has shown a correlation between positive symptoms of schizophrenia and abnormalities of glucose metabolism in components of the limbic system with the highest concentration of glutamate receptors. Studies with ketamine, an anaesthetic that antagonises the N-methyl-D-aspartate (NMDA) glutamate receptor, show an exacerbation or worsening of positive symptoms when this drug is administered to patients with schizophrenia. Regional cerebral blood flow studies with ketamine show that the drug produces increased blood flow in the anterior cingulate cortex, the area where high concentrations of NMDA receptors exist and where alterations in glucose metabolism seem to occur in people with schizophrenia. Diminished glutamatergic neurotransmission in the hippocampal glutamate-mediated efferent pathways and cerebral dysfunction in the hippocampus and its target areas, particularly the anterior cingulate cortex, may underlie some of the clinical manifestations of schizophrenia.     

Polyamines and polyamine-metabolizing enzymes in schizophrenia: Current knowledge and concepts of therapy

Polyamines play preeminent roles in a variety of cellular functions in the central nervous system and other organs. A large body of evidence suggests that the polyamine pathway is prominently involved in the etiology and pathology of schizophrenia. Alterations in the expression and activity of polyamine metabolizing enzymes, as well as changes in the levels of the individual polyamines, their precursors and derivatives, have been measured in schizophrenia and animal models of the disease. Additionally, neuroleptic treatment has been shown to influence polyamine concentrations in brain and blood of individuals with schizophrenia. Thus, the polyamine system may appear to be a promising target for neuropharmacological treatment of schizophrenia. However, for a number of practical reasons there is currently only limited hope for a polyamine-based schizophrenia therapy.     

Glutamatergic agents in Autism Spectrum Disorders: Current trends

Glutamate transmission dysfunction has been found in various preclinical models of Autism Spectrum Disorders (ASD), thus the glutamate system is a target for therapeutics. This report reviews current treatments for glutamate dysfunction in ASD models and clinical trials. Antagonists of metabotropic glutamate receptor subtype 5 (mGluR5) have been tested in preclinical models of autism. Black and Tan Bachyuric (BTBR) mice model behavioral phenotypes of the three core diagnostic domains of autism, e.g. social deficits, impaired language and communication, and repetitive behaviors. A significant reduction in repetitive self-grooming was observed after mGluR5 antagonist administration in BTBR mice. SHANK 3 deficient mice which have altered synaptic transmission and plasticity, were administered IGF-1 treatment to reverse these deficits based on the hypothesis that reduced AMPA receptor levels reflect less mature synapses. Clinical trials have been carried out in ASD with glutamate NMDA receptors, but current findings are not sufficient for conclusions on safety and efficacy. Memantine is an NMDA antagonist under investigation in controlled trials that hopefully will provide new insight on its use in autism. Studies using novel treatments with other glutamatergic agents are also underway and encouraging results have been observed with N-acetylcysteine in treating irritability in ASD.     

Glutamatergic abnormalities of the thalamus in schizophrenia: a systematic review

Summary. The thalamus, a key information processing centre in facilitating sensory discrimination and cognitive processes, has been implicated in schizophrenia due to the increasing evidence showing structural and functional thalamic abnormalities. Glutamatergic abnormalities, in particular, have been examined since glutamate is one of the main neurotransmitters found in the thalamus. We aimed to review the existing literature (1978 till 2007) on post-mortem and in vivo studies of the various components of glutamatergic neurotransmission as well as studies of the glutamate receptor genes within the thalamus in schizophrenia. The literature search was done using multiple databases including Scopus, Web of Science, EBSCO host, Pubmed and ScienceDirect. Keywords used were “glutamate”, “thalamus”, “schizophrenia”, “abnormalities”, and “glutamatergic”. Further searches were made using the bibliographies in the main journals and related papers were obtained. The extant data suggest that abnormalities of the glutamate receptors as well as other molecules involved in glutamatergic neurotransmission (including glutamate transporters and associated proteins, N-methyl D-aspartate (NMDA) receptor-associated intracellular signaling proteins, and glutamatergic enzymes) are found within the thalamus in schizophrenia. There is a pressing need for more rapid replication of findings from post mortem and genetic studies as well as the promotion of multi-component or multi-modality assessments of glutamatergic anomalies within the thalamus in order to allow a better appreciation of disruptions in these molecular networks in schizophrenia. These and future findings may represent potential novel targets for antipsychotic drugs to ameliorate the symptoms of schizophrenia. Correspondence: Kang Sim, Institute of Mental Health/Woodbridge Hospital, 10 Buangkok View, Singapore 539747, Singapore     

Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis

OBJECTIVE: To evaluate the efficacy of glutamatergic drugs, acting agonistically on the N-methyl-D-aspartate (NMDA) or the non-NMDA receptors, in schizophrenia. METHOD: All relevant randomized controlled trials of glutamatergic drugs for schizophrenia were obtained from the Cochrane Schizophrenia Group's Register of Trials without any language or year limitations. Trials were classified according to their methodological quality. For binary and continuous data, relative risks and weighted (WMD) or standardized mean differences (SMD) were calculated, respectively. RESULTS: Eighteen short-term trials with 343 randomized patients were included in the meta-analysis. In all of these trials, glycine, D-serine, D-cycloserine or ampakine CX516 was used to augment antipsychotics. NMDA receptor co-agonists glycine and D-serine are effective in reducing negative symptoms (N = 132, fixed effect model SMD = -0.66, 95% CI -1.02 to -0.29, p = 0.0004) of schizophrenia, the magnitude of the effect is moderate. D-Cycloserine, a partial agonist of NMDA receptors, is less effective towards negative symptoms (N = 119, fixed effect model SMD = -0.11, 95% CI -0.48 to 0.25, p = 0.6). Positive symptoms fail to respond to glutamatergic medication. Available derived data on cognitive functioning do not indicate a significant effect of glycine or D-serine (N = 80, random effect model WMD = -2.79, 95% CI -6.17 to 0.60, p = 0.11). CONCLUSIONS: In the current limited data set, a moderate amelioration of negative symptoms of schizophrenia was found, but no other statistically significant beneficial effects on symptoms of schizophrenia.     

Modern treatment concepts in schizophrenia

On the basis of available practice guidelines for schizophrenia, contemporary treatment principles for schizophrenia leading to phase- or stage-oriented, multidimensional treatment approaches are described. Additionally, based on current research programmes, future treatment developments are presented.     

Echopraxia in schizophrenia: possible mechanisms

The aim of the current study was to present a possible mechanism underpinning echopraxia in schizophrenia. It is proposed that echopraxia occurs in schizophrenia when the mirror neuron system provides a representation to the inferior frontal gyrus (IFG) and the motor cortex (and via the IFG, to the anterior cingulate cortex) and that this potential becomes executed movement, when the disorder is associated with decreased inhibition and increased arousal.     

Glutamatergic mechanisms in alcohol dependence--genetic,molecular-biological and neuropharmacological findings

A number of preclinical and clinical findings suggest that the glutamate system, especially NMDA-receptors has a major function in neuropsychiatric disorders related to chronic alcoholism. Other findings suggest, that glutamatergic mechanisms may also play a role for the addictive process itself including craving and addiction memory. A number of genetic and molecular-biological findings and more recent neuropharmacological studies point in this direction. NMDA-modulators and antagonists have been found to be possible or even clinically effective so called anti-craving-drugs. A better understanding of the glutamatergic mechanisms in alcohol dependence may therefore also be of relevance for the development of new anti-craving-drugs and therapy-research.     

Etiological concepts of chronification in schizophrenia

Kraepelin and Eugen Bleuler understood the chronicity of schizophrenia as a typical expression of its natural course. Although they erred in this pessimistic assessment, some 30-35 % of all schizophrenia patients do suffer from chronic residual symptoms after years of having the disease, despite sociopsychiatric reform efforts that led to open hospitals and greater patient autonomy. According to the vulnerability conception, schizophrenia is regarded as a vulnerability that causes decompensation leading to psychotic episodes under the influence of internal and/or external stressors. The vulnerability threshold can be increased or lowered by influencing variables. In addition to factors immanent to the disease, some of these variables are related directly or indirectly to chronicity of the disease.     

Glutamatergic deficits and parvalbumin-containing inhibitory neurons in the prefrontal cortex in schizophrenia

Background

Clinician training deficits and a low and declining autopsy rate adversely impact the quality of death certificates in the United States. Self-report and records data for the general population indicate that proximate mental and physical health of minority suicides was at least as poor as that of white suicides.

Methods

This cross-sectional mortality study uses data from Multiple Cause-of-Death (MCOD) public use files for 1999–2003 to describe and evaluate comorbidity among black, Hispanic, and white suicides. Unintentional injury decedents are the referent for multivariate analyses.

Results

One or more mentions of comorbid psychopathology are documented on the death certificates of 8% of white male suicides compared to 4% and 3% of black and Hispanic counterparts, respectively. Corresponding female figures are 10%, 8%, and 6%. Racial-ethnic discrepancies in the prevalence of comorbid physical disease are more attenuated. Cross-validation with National Violent Death Reporting System data reveals high relative underenumeration of comorbid depression/mood disorders and high relative overenumeration of schizophrenia on the death certificates of both minorities. In all three racial-ethnic groups, suicide is positively associated with depression/mood disorders [whites: adjusted odds ratio (AOR) = 31.9, 95% CI = 29.80–34.13; blacks: AOR = 60.9, 95% CI = 42.80–86.63; Hispanics: AOR = 34.7, 95% CI = 23.36–51.62] and schizophrenia [whites: AOR = 2.4, 95% CI = 2.07–2.86; blacks: AOR = 4.2, 95% CI = 2.73–6.37; Hispanics: AOR = 4.1, 95% CI = 2.01–8.22]. Suicide is positively associated with cancer in whites [AOR = 1.8, 95% CI = 1.69–1.93] and blacks [AOR = 1.8, 95% CI = 1.36–2.48], but not with HIV or alcohol and other substance use disorders in any group under review.

Conclusion

The multivariate analyses indicate high consistency in predicting suicide-associated comorbidities across racial-ethnic groups using MCOD data. However, low prevalence of documented comorbid psychopathology in suicides, and concomitant racial-ethnic discrepancies underscore the need for training in death certification, and routinization and standardization of timely psychological autopsies in all cases of suicide, suspected suicide, and other traumatic deaths of equivocal cause.