Over the last 20 years, glutamatergic models of schizophrenia have become increasingly accepted as etiopathological models of schizophrenia, based on the observation that phencyclidine (PCP) induces a schizophrenia-like psychosis by blocking neurotransmission at N-methyl-D-aspartate (NMDA)-type glutamate receptors. This article reviews developments in two key predictions of the model: first, that neurocognitive deficits in schizophrenia should follow the pattern of deficit predicted based on underlying NMDAR dysfunction and, second, that agents that stimulate NMDAR function should be therapeutically beneficial. As opposed to dopamine receptors, NMDAR are widely distributed throughout the brain, including subcortical as well as cortical brain regions, and sensory as well as association cortex. Studies over the past 20 years have documented severe sensory dysfunction in schizophrenia using behavioral, neurophysiological, and functional brain imaging approaches, including impaired generation of key sensory-related potentials such as mismatch negativity and visual P1 potentials. Similar deficits are observed in humans following administration of NMDAR antagonists such as ketamine in either humans or animal models. Sensory dysfunction, in turn, predicts impairments in higher order cognitive functions such as auditory or visual emotion recognition. Treatment studies have been performed with compounds acting directly at the NMDAR glycine site, such as glycine, D-serine, or D-cycloserine, and, more recently, with high-affinity glycine transport inhibitors such as RG1678 (Roche). More limited studies have been performed with compounds targeting the redox site. Overall, these compounds have been found to induce significant beneficial effects on persistent symptoms, suggesting novel approaches for treatment and prevention of schizophrenia.

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Has an Angel Shown the Way? Etiological and Therapeutic Implications of the PCP/NMDA Model of Schizophrenia

The observation that antagonists of the N-methyl-D-aspartate glutamate receptor (NMDAR), such as phencyclidine (PCP) and ketamine, transiently induce symptoms of acute schizophrenia had led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. The glutamate hypothesis can explain negative and cognitive symptoms of schizophrenia better than the dopamine hypothesis, and has the potential to explain dopamine dysfunction itself. The pharmacological and psychomimetic effects of ketamine, which is safer for human subjects than phencyclidine, are herein reviewed. Ketamine binds to a variety of receptors, but principally acts at the NMDAR, and convergent genetic and molecular evidence point to NMDAR hypofunction in schizophrenia. Furthermore, NMDAR hypofunction can explain connectional and oscillatory abnormalities in schizophrenia in terms of both weakened excitation of inhibitory -aminobutyric acidergic (GABAergic) interneurons that synchronize cortical networks and disinhibition of principal cells. Individuals with prenatal aberrations of NMDAR might experience the onset of schizophrenia towards the completion of synaptic pruning in adolescence, when network connectivity drops below a critical value. We conclude that ketamine challenge is useful for studying the positive, negative, and cognitive symptoms, dopaminergic and GABAergic dysfunction, age of onset, functional dysconnectivity, and abnormal cortical oscillations observed in acute schizophrenia.

/pdf/reviewing-the-ketamine-model-for-schizophrenia-3cu7h8w8rn.pdf

Reviewing the ketamine model for schizophrenia.

Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the „dorsal nexus “(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.

/pdf/ketamine-decreases-resting-state-functional-network-22rnzqtox7.pdf

Ketamine decreases resting state functional network connectivity in healthy subjects: implications for antidepressant drug action.

Purpose of review The past 20 years have seen the glutamatergic hypothesis go from theory to phase III trials of novel mechanism antipsychotics. Recent findings We review the recent literature on glutamatergic theory, covering assessment and genetic studies, as well as drug development in animals and humans. Summary Although evidence continues to accumulate in support of glutamate hypotheses, further research continues to be required and interactions with other key systems need to be explored.

Glutamatergic transmission in schizophrenia: from basic research to clinical practice.

BACKGROUND The influence of psychoactive drugs on the central nervous system has been investigated with positron emission tomography and task-related functional magnetic resonance imaging. However, it is not known how these drugs affect the intrinsic large-scale interactions of the brain (resting-state functional magnetic resonance imaging connectivity). In this study, the effect of low-dose S(+)-ketamine on intrinsic brain connectivity was investigated. METHODS Twelve healthy, male volunteers received a 2-h intravenous S(+)-ketamine infusion (first hour 20 mg/70 kg, second hour 40 mg/70 kg). Before, during, and after S(+)-ketamine administration, resting-state brain connectivity was measured. In addition, heat pain tests were performed between imaging sessions to determine ketamine-induced analgesia. A mixed-effects general linear model was used to determine drug and pain effects on resting-state brain connectivity. RESULTS Ketamine increased the connectivity most importantly in the cerebellum and visual cortex in relation to the medial visual network. A decrease in connectivity was observed in the auditory and somatosensory network in relation to regions responsible for pain sensing and the affective processing of pain, which included the amygdala, insula, and anterior cingulate cortex. Connectivity variations related to fluctuations in pain scores were observed in the anterior cingulate cortex, insula, orbitofrontal cortex, and the brainstem, regions involved in descending inhibition of pain. CONCLUSIONS Changes in connectivity were observed in the areas that explain ketamine's pharmacodynamic profile with respect to analgesia and psychedelic and other side effects. In addition, pain and ketamine changed brain connectivity in areas involved in endogenous pain modulation.

Effect of subanesthetic ketamine on intrinsic functional brain connectivity: a placebo-controlled functional magnetic resonance imaging study in healthy male volunteers.

Ketamine effects on brain function--simultaneous fMRI/EEG during a visual oddball task.

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Ketamine effects on brain function--simultaneous fMRI/EEG during a visual oddball task.