Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia

Schizophr Bull. 2012 Sep;38(5):958-66. doi: 10.1093/schbul/sbs069.

Has an angel shown the way? Etiological and therapeutic implications of the PCP/NMDA model of schizophrenia.

Source

Department of Psychiatry, Nathan Kline Institute for Psychiatric Research/Columbia University College of Physicians and Surgeons, Orangeburg, NY 10962, USA. javitt@nki.rfmh.org

Abstract

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.

PMID:
22987851
[PubMed – in process]
PMCID:
PMC3446214
[Available on 2013/9/1]

 

[Anti-NMDA-receptor encephalitis. An interdisciplinary clinical picture].

Nervenarzt. 2010 Apr;81(4):396, 398, 400, passim.

[Article in German]

Source

Experimentelle Neurologie und Klinik und Poliklinik für Neurologie, Charité – Universitätsmedizin Berlin, Berlin.

Abstract

Anti-NMDA-receptor encephalitis is a severe and considerably underdiagnosed form of encephalitis with characteristic clinical features including psychiatric symptoms, decreased levels of consciousness, hypoventilation, epileptic seizures, autonomic dysfunction and dyskinesias. Most patients are primarily seen by psychiatrists, often on the assumption of a drug-induced psychosis. Anti-NMDA-receptor encephalitis had initially been described in young women with ovarian teratoma, but is also common in women without tumour, in men and in children. The diagnosis is based on the characteristic clinical picture, supporting findings of brain MRI, electroencephalogram and cerebrospinal fluid (CSF), and the presence of highly specific autoantibodies directed against the NR1 subunit of NMDA-type glutamate receptors in the serum or CSF. In particular, anti-NMDA-receptor encephalitis must be excluded in patients with ‘encephalitis of unknown cause’. In principle, the prognosis is favourable and recovery from symptoms can be expected even after prolonged intensive care treatment and mechanical ventilation. However, improvement correlates with prompt identification of the disorder, early immunotherapy and – in the case of a malignancy – with complete tumour removal. Patient care requires an interdisciplinary approach including neurologists, psychiatrists, paediatricians, oncologists and gynaecologists.

PMID:
20119656
[PubMed – indexed for MEDLINE]

Anti-NMDA-receptor encephalitis presenting as postpartum psychosis in a young woman

Click here to open

Anti-NMDA-receptor encephalitis presenting as postpartum psychosis in a young woman, treated with rituximab

A severe paraneoplastic form of acute encephalitis associated with antibodies against the N-methyl D-aspartate (NMDA) receptor typically occurs in young individuals and is associated, but not always, with an underlying tumor. If diagnosed early, initiation of immunotherapy and tumor removal (if present) may result in recovery. We report a case in a 25-year-old young woman who presented to ourmedical center with postpartum psychosis. Treatment with rituximab (a chimeric monoclonal antibody against the protein CD20) resulted in gradual improvement in mental status and resolution of seizure activity episodes. A year after diagnosis and treatment, the patient was doing well without recurrences, and no tumors appeared. This is the first described case of anti–NMDA-receptor antibodies encephalitis that presented initially as a postpartum psychosis disorder and was successfully treated with rituximab.

Click here to download

Up ↑