Mismatch negativity (MMN) is an auditory event-related potential that provides an index of automatic context-dependent information processing and auditory sensory memory. Many studies have reported ...abnormalities in the generation of MMN in schizophrenia. The objective of this study was to assess the magnitude of this deficit and associated factors.
Studies of MMN in schizophrenia were identified and included in a meta-analysis to estimate the mean effect size. Effects of duration of illness, gender ratio, age of patients, type of MMN (duration versus frequency MMN) and characteristics of the test paradigms (deviant probability, magnitude of standard-deviant difference) on effect size were assessed.
Of 62 identified studies 32 met our inclusion criteria. The mean effect size was 0.99 (95% confidence intervals: 0.79, 1.29). Overall, no specific factor was significantly associated with MMN deficits, although MMN to stimuli differing in duration appeared more impaired in schizophrenia than MMN to frequency deviants. In addition, effect sizes of frequency MMN were significantly correlated with duration of illness.
MMN deficits are a robust feature in chronic schizophrenia and indicate abnormalities in automatic context-dependent auditory information processing and auditory sensory memory in these patients. Reports of normal MMN in first-episode schizophrenia and the association of deficits in frequency MMN with illness duration suggest that MMN may index ongoing neuropathological changes in the auditory cortex in schizophrenia.
Deficits in amplitudes of auditory event-related potentials (ERP) indexing preattentive, automatic (mismatch negativity, MMN) and controlled, attention-dependent (N2, P3) auditory information ...processing have been well described in chronic schizophrenia. Normal MMN, but deficient N2 and P3 have been reported in first-episode patients. No study has investigated these ERPs concurrently in first-episode patients; thus, reported differences in MMN, N2 and P3 generation may reflect differences in patient samples rather than genuine differences in abnormal generation of these ERPs.
We recorded MMN, N2 and P3 in 26 first-episode patients, 25 recent-onset patients within 1.5 to 5 years after first admission, 25 chronic patients and 39 healthy controls.
Recent-onset and chronic, but not first-episode patients showed reduced MMN. However, among first-episode patients those with low premorbid educational achievement demonstrated significantly reduced MMN. All patient groups showed pronounced N2 deficits and, to a variable extent, abnormalities in P3 generation.
Abnormalities in N2 and P3 generation appear to reflect premorbid neuropathology, whereas MMN deficits may index both ongoing disease processes associated with illness progression as well as premorbid neurocognitive impairment. ERPs may provide tools to assess static and progressive neuropathology in schizophrenia. These findings need confirmation in longitudinal studies.
Abstract Background Most effort in ultra high-risk (UHR) research has been directed at defining the clinical and neurobiological characteristics of those UHR subjects who go on to develop psychosis. ...The characteristics and outcome of the remaining UHR subjects have remained relatively unexplored. Method We performed a systematic review of clinical UHR studies to investigate whether information was available on the characteristics and outcome of UHR subjects who did not convert to psychosis. Results Of 2462 potentially relevant papers, 31 met inclusion criteria, i.e. 20 naturalistic and 11 intervention studies. On average 76% (range 46–92.6%) of the UHR patients made no transition to psychosis during follow-up (range 6 to 40 months). Nearly half of the studies provided no characteristics of those UHR subjects who did not develop psychosis. Six studies reported remission rates from initial UHR status (range 15.4% to 54.3%). Linear regression showed that more recent studies reported significantly lower transition rates as compared to earlier publications. An older mean age at baseline was associated with significant lower transition rates in publications with follow-ups exceeding 1 year. Conclusions Our review illustrates that the long-term outcome of UHR subjects that do not develop psychosis is to date under-investigated. The studies reporting remission rates suggest that UHR criteria capture a non-negligible proportion of subjects that do not convert to psychosis.
Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific ...neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.
Glycine transporter-1 (GlyT1) inhibition has been extensively studied both in pharmaceutical companies and academic institutions primarily as a potential new approach to treat schizophrenia, a severe ...and chronic mental illness. More recently, preclinical results have suggested that this approach could also have therapeutic potential for CNS disorders beyond schizophrenia as well as for non-CNS indications. Over the past 17 years, Roche has been a key player in the GlyT1 field with the discovery and development of bitopertin, the most advanced GlyT1 inhibitor to date and the only one which completed Phase III clinical studies for schizophrenia. In this article, we relate the eventful journey of the discovery and development of bitopertin, from project initiation in 2001 to its evaluation today in patients suffering from beta-thalassemia, a monogenic hereditary haematological disorder.
The neurotransmitter glutamate is the primary excitatory neurotransmitter in mammalian brain and is responsible for most corticocortical and corticofugal neurotransmission. Disturbances in ...glutamatergic function have been implicated in the pathophysiology of several neuropsychiatric disorders-including schizophrenia, drug abuse and addiction, autism, and depression-that were until recently poorly understood. Nevertheless, improvements in basic information regarding these disorders have yet to translate into Food and Drug Administration-approved treatments. Barriers to translation include the need not only for improved compounds but also for improved biomarkers sensitive to both structural and functional target engagement and for improved translational models. Overcoming these barriers will require unique collaborative arrangements between pharma, government, and academia. Here, we review a recent Institute of Medicine-sponsored meeting, highlighting advances in glutamatergic theories of neuropsychiatric illness as well as remaining barriers to treatment development.
Cognitive impairment, in particular of attention and memory, is often reported by patients suffering from major depressive disorder (MDD) and deficits in attention are part of the current diagnostic ...criteria of MDD. Objectively measured cognitive deficits associated with MDD have been described in many studies. They have been conceptualized as an integral facet and epiphenomenon of MDD. However, evidence accumulated in recent years has challenged this notion and demonstrated that in a subset of patients the degree of cognitive deficits cannot be accounted for by the severity of depression. In addition, in some patients cognitive deficits persist despite resolution of depressive symptomatology. It is plausible to assume that cognitive deficits contribute to functional impairment even though supportive data for such a relationship are lacking. However, the exact association between cognitive deficits and major depression and the clinical and neurobiological characteristics of patients with MDD in whom cognitive deficits seem partially or fully independent of the clinical manifestation of depressive symptoms remain poorly understood.
This review focuses on objective measures of non-emotional cognitive deficits in MDD and discusses the presence of a subgroup of patients in whom these symptoms can be defined independently and in dissociation from the rest of the depressive symptomatology. The current understanding of brain circuits and molecular events implicated in cognitive impairment in MDD are discussed with an emphasis on the missing elements that could further define the specificity of cognitive impairment in MDD and lead to new therapeutics. Furthermore, this article presents in detail observations made in behavioral studies in rodents with potential novel therapeutic agents, such as negative allosteric modulators at the metabotropic glutamate receptor type 2/3 (mGlu2/3 NAM) which exhibit both cognitive enhancing and antidepressant properties. Such a compound, RO4432717, was tested in tests of short term memory (delayed match to position), cognitive flexibility (Morris water maze, reversal protocol), impulsivity and compulsivity (5-choice serial reaction time) and spontaneous object recognition in rodents, providing first evidence of a profile potentially relevant to address cognitive impairment in MDD.
This article is part of a Special Issue entitled ‘Cognitive Enhancers’.
► Substantial cognitive deficits are present in some patients with Major Depressive Disorder (MDD) ► Cognitive deficits cannot be accounted for as a simple epiphenomenon of the depressive state. ► Abnormal connectivity, cellular and synaptic abnormalities likely involved in cognitive deficits in MDD ► Metabotropic glutamate receptor type 2 exert precognitive and antidepressant effects in preclinical assays. ► They may offer a novel therapeutic approach addressing not only the mood symptoms, but also the cognitive deficits associated with MDD.
Nicotine addiction is a major public health problem, resulting in primary glutamatergic dysfunction. We measured the glutamate receptor binding in the human brain and provided direct evidence for the ...abnormal glutamate system in smokers. Because antagonism of the metabotropic glutamate receptor 5 (mGluR5) reduced nicotine self-administration in rats and mice, mGluR5 is suggested to be involved in nicotine addiction. mGluR5 receptor binding specifically to an allosteric site was observed by using positron emission tomography with ¹¹CABP688. We found a marked global reduction (20.6%; P < 0.0001) in the mGluR5 distribution volume ratio (DVR) in the gray matter of 14 smokers. The most prominent reductions were found in the bilateral medial orbitofrontal cortex. Compared with 14 nonsmokers, 14 ex-smokers had global reductions in the average gray matter mGluR5 DVR (11.5%; P < 0.005), and there was a significant difference in average gray matter mGluR5 DVR between smokers and ex-smokers (9.2%; P < 0.01). Clinical variables reflecting current nicotine consumption, dependence and abstinence were not correlated with mGluR5 DVR. This decrease in mGluR5 receptor binding may be an adaptation to chronic increases in glutamate induced by chronic nicotine administration, and the decreased down-regulation seen in the ex-smokers could be due to incomplete recovery of the receptors, especially because the ex-smokers were abstinent for only 25 wk on average. These results encourage the development and testing of drugs against addiction that directly target the glutamatergic system.
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