Variability and magnitude of brain glutamate levels in schizophrenia: a meta and mega-analysis.

Glutamatergic dysfunction is implicated in schizophrenia pathoaetiology, but this may vary in extent between patients. It is unclear whether inter-individual variability in glutamate is greater in schizophrenia than the general population. We conducted meta-analyses to assess (1) variability of glutamate measures in patients relative to controls (log coefficient of variation ratio: CVR); (2) standardised mean differences (SMD) using Hedges g; (3) modal distribution of individual-level glutamate data (Hartigan's unimodality dip test). MEDLINE and EMBASE databases were searched from inception to September 2022 for proton magnetic resonance spectroscopy (1H-MRS) studies reporting glutamate, glutamine or Glx in schizophrenia. 123 studies reporting on 8256 patients and 7532 controls were included. Compared with controls, patients demonstrated greater variability in glutamatergic metabolites in the medial frontal cortex (MFC, glutamate: CVR = 0.15, p < 0.001; glutamine: CVR = 0.15, p = 0.003; Glx: CVR = 0.11, p = 0.002), dorsolateral prefrontal cortex (glutamine: CVR = 0.14, p = 0.05; Glx: CVR = 0.25, p < 0.001) and thalamus (glutamate: CVR = 0.16, p = 0.008; Glx: CVR = 0.19, p = 0.008). Studies in younger, more symptomatic patients were associated with greater variability in the basal ganglia (BG glutamate with age: z = -0.03, p = 0.003, symptoms: z = 0.007, p = 0.02) and temporal lobe (glutamate with age: z = -0.03, p = 0.02), while studies with older, more symptomatic patients associated with greater variability in MFC (glutamate with age: z = 0.01, p = 0.02, glutamine with symptoms: z = 0.01, p = 0.02). For individual patient data, most studies showed a unimodal distribution of glutamatergic metabolites. Meta-analysis of mean differences found lower MFC glutamate (g = -0.15, p = 0.03), higher thalamic glutamine (g = 0.53, p < 0.001) and higher BG Glx in patients relative to controls (g = 0.28, p < 0.001). Proportion of males was negatively associated with MFC glutamate (z = -0.02, p < 0.001) and frontal white matter Glx (z = -0.03, p = 0.02) in patients relative to controls. Patient PANSS total score was positively associated with glutamate SMD in BG (z = 0.01, p = 0.01) and temporal lobe (z = 0.05, p = 0.008). Further research into the mechanisms underlying greater glutamatergic metabolite variability in schizophrenia and their clinical consequences may inform the identification of patient subgroups for future treatment strategies.

1H-MRS at 4 tesla in minimally treated early schizophrenia.

We investigated glutamate-related neuronal dysfunction in the anterior cingulate (AC) early in schizophrenia before and after antipsychotic treatment. A total of 14 minimally treated schizophrenia patients and 10 healthy subjects were studied with single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) of the AC, frontal white matter and thalamus at 4 T. Concentrations of N-acetylaspartate (NAA), glutamate (Glu), glutamine (Gln) and Gln/Glu ratios were determined and corrected for the partial tissue volume. Patients were treated with antipsychotic medication following a specific algorithm and (1)H-MRS was repeated after 1, 6 and 12 months. There were group x region interactions for baseline NAA (P=0.074) and Gln/Glu (P=0.028): schizophrenia subjects had lower NAA (P=0.045) and higher Gln/Glu (P=0.006) in the AC before treatment. In addition, AC Gln/Glu was inversely related to AC NAA in the schizophrenia (P=0.0009) but not in the control group (P=0.92). Following antipsychotic treatment, there were no further changes in NAA, Gln/Glu or any of the other metabolites in any of the regions studied. We conclude that early in the illness, schizophrenia patients already show abnormalities in glutamatergic metabolism and reductions in NAA consistent with glutamate-related excitotoxicity.

Auditory oddball deficits in schizophrenia: an independent component analysis of the fMRI multisite function BIRN study.

Deficits in the connectivity between brain regions have been suggested to play a major role in the pathophysiology of schizophrenia. A functional magnetic resonance imaging (fMRI) analysis of schizophrenia was implemented using independent component analysis (ICA) to identify multiple temporally cohesive, spatially distributed regions of brain activity that represent functionally connected networks. We hypothesized that functional connectivity differences would be seen in auditory networks comprised of regions such as superior temporal gyrus as well as executive networks that consisted of frontal-parietal areas. Eight networks were found to be implicated in schizophrenia during the auditory oddball paradigm. These included a bilateral temporal network containing the superior and middle temporal gyrus; a default-mode network comprised of the posterior cingulate, precuneus, and middle frontal gyrus; and multiple dorsal lateral prefrontal cortex networks that constituted various levels of between-group differences. Highly task-related sensory networks were also found. These results indicate that patients with schizophrenia show functional connectivity differences in networks related to auditory processing, executive control, and baseline functional activity. Overall, these findings support the idea that the cognitive deficits associated with schizophrenia are widespread and that a functional connectivity approach can help elucidate the neural correlates of this disorder.

fMRI activity correlated with auditory hallucinations during performance of a working memory task: data from the FBIRN consortium study.

INTRODUCTION: Auditory hallucinations are a hallmark symptom of schizophrenia. The neural basis of auditory hallucinations was examined using data from a working memory task. Data were acquired within a multisite consortium and this unique dataset provided the opportunity to analyze data from a large number of subjects who had been tested on the same procedures across sites. We hypothesized that regions involved in verbal working memory and language processing would show activity that was associated with levels of hallucinations during a condition where subjects were rehearsing the stimuli. METHODS: Data from the Sternberg Item Recognition Paradigm, a working memory task, were acquired during functional magnetic resonance imaging procedures. The data were collected and preprocessed by the functional imaging biomedical informatics research network consortium. Schizophrenic subjects were split into nonhallucinating and hallucinating subgroups and activity during the probe condition (in which subjects rehearsed stimuli) was examined. Levels of activation from contrast images for the probe phase (collapsed over levels of memory load) of the working memory task were also correlated with levels of auditory hallucinations from the Scale for the Assessment of Positive Symptoms scores. RESULTS: Patients with auditory hallucinations (relative to nonhallucinating subjects) showed decreased activity during the probe condition in verbal working memory/language processing regions, including the superior temporal and inferior parietal regions. These regions also showed associations between activity and levels of hallucinations in a correlation analysis. DISCUSSION: The association between activation and hallucinations scores in the left hemisphere language/working memory regions replicates the findings of previous studies and provides converging evidence for the association between superior temporal abnormalities and auditory hallucinations.

Working memory and DLPFC inefficiency in schizophrenia: the FBIRN study.

BACKGROUND: The Functional Imaging Biomedical Informatics Network is a consortium developing methods for multisite functional imaging studies. Both prefrontal hyper- or hypoactivity in chronic schizophrenia have been found in previous studies of working memory. METHODS: In this functional magnetic resonance imaging (fMRI) study of working memory, 128 subjects with chronic schizophrenia and 128 age- and gender-matched controls were recruited from 10 universities around the United States. Subjects performed the Sternberg Item Recognition Paradigm1,2 with memory loads of 1, 3, or 5 items. A region of interest analysis examined the mean BOLD signal change in an atlas-based demarcation of the dorsolateral prefrontal cortex (DLPFC), in both groups, during both the encoding and retrieval phases of the experiment over the various memory loads. RESULTS: Subjects with schizophrenia performed slightly but significantly worse than the healthy volunteers and showed a greater decrease in accuracy and increase in reaction time with increasing memory load. The mean BOLD signal in the DLPFC was significantly greater in the schizophrenic group than the healthy group, particularly in the intermediate load condition. A secondary analysis matched subjects for mean accuracy and found the same BOLD signal hyperresponse in schizophrenics. CONCLUSIONS: The increase in BOLD signal change from minimal to moderate memory loads was greater in the schizophrenic subjects than in controls. This effect remained when age, gender, run, hemisphere, and performance were considered, consistent with inefficient DLPFC function during working memory. These findings from a large multisite sample support the concept not of hyper- or hypofrontality in schizophrenia, but rather DLPFC inefficiency that may be manifested in either direction depending on task demands. This redirects the focus of research from direction of difference to neural mechanisms of inefficiency.

Multimodal Neuroimaging in Schizophrenia: Description and Dissemination.

In this paper we describe an open-access collection of multimodal neuroimaging data in schizophrenia for release to the community. Data were acquired from approximately 100 patients with schizophrenia and 100 age-matched controls during rest as well as several task activation paradigms targeting a hierarchy of cognitive constructs. Neuroimaging data include structural MRI, functional MRI, diffusion MRI, MR spectroscopic imaging, and magnetoencephalography. For three of the hypothesis-driven projects, task activation paradigms were acquired on subsets of ~200 volunteers which examined a range of sensory and cognitive processes (e.g., auditory sensory gating, auditory/visual multisensory integration, visual transverse patterning). Neuropsychological data were also acquired and genetic material via saliva samples were collected from most of the participants and have been typed for both genome-wide polymorphism data as well as genome-wide methylation data. Some results are also presented from the individual studies as well as from our data-driven multimodal analyses (e.g., multimodal examinations of network structure and network dynamics and multitask fMRI data analysis across projects). All data will be released through the Mind Research Network's collaborative informatics and neuroimaging suite (COINS).

A critical review of research on psychosocial treatment of schizophrenia.

In the following review, the evidence for the effectiveness of the psychosocial treatments of schizophrenia are evaluated. Although most studies focus on relapse and hospitalization, when available, we present information on other domains of outcome (e.g., social adjustment and employment). We begin with family treatments for schizophrenia, then intensive case management, followed by social skills training, supported employment programs, and finally, individual psychotherapy. The topics have been chosen in descending order of available critical supportive studies. Recommendations for specific psychosocial interventions (including target populations) are discussed. Overall psychosocial treatments have been shown to reduce schizophrenic relapses but have not convincingly generalized to improving other facets of the illness. Despite this, psychosocial treatments should be supported and further research to improve them is necessary.

Placebos and paradoxes in psychiatric research: an ethics perspective.

The use of placebos in clinical trials, particularly in research with mentally ill people, has emerged as a subject of considerable controversy. We first outline ethical aspects of the primary scientific arguments for and against placebo use in research. Three examples of paradoxical aspects of the ethical use of placebos are discussed: involvement of relatively more vulnerable populations, use of apparently "less than standard" therapy, and the omission of information in placebo comparisons. In the current scientific and regulatory context, placebo use in psychiatric research may be necessary for scientific reasons, and when certain conditions are present, it may be justified on ethical grounds. Four key recommendations to facilitate the ethical use of placebos in research trials are presented. We conclude that placebo trials should be undertaken only after careful evaluation of alternative scientific strategies and, as with all human research, with great respect and genuine consideration for the individuals who choose to participate in these protocols.

The cholinergic REM sleep induction test with pilocarpine in mildly depressed patients and normal controls.

Previous studies suggested that depressed patients enter rapid-eye movement (REM) sleep more quickly than normal controls following the administration of muscarinic agonists such as arecoline or RS 86. We recently reported that pilocarpine, an orally active muscarinic agonist, induced REM sleep and reduced Stage 3 & 4 (Delta) sleep in young normal volunteers. In this study we present preliminary evidence that pilocarpine had similar effects on REM latency, REM percentage, and Delta (Stages 3 & 4) sleep percentage in depressed patients and controls. Pilocarpine, however, decreased stage-4 sleep in controls more than in depressed patients. Because this group of patients were only mildly depressed at the time of the study, had a high frequency of comorbid substance abuse diagnoses, and had normal electroencephalogram (EEG) sleep patterns under placebo conditions, further studies are necessary to test the hypothesis that depressed patients show hypersensitive cholinergic REM sleep induction.

Association between regional brain volumes and clozapine response in schizophrenia.

BACKGROUND: Clozapine has shown considerable therapeutic promise in the treatment of schizophrenia; however, the clinical risks and initial high treatment costs associated with its administration motivate the search to identify patients who will best respond. Neuroimaging studies have suggested that prefrontal sulcal prominence may be a predictor of nonresponsiveness. METHODS: We used magnetic resonance imaging (MRI) to test whether volumes in any cortical regions of the brain were associated with symptom improvement with clozapine treatment. The 21 schizophrenic men studied were clinically evaluated during treatment with typical neuroleptics (baseline) and after a mean of 6.2 months treatment with clozapine (final dose 300-900, median = 562 mg/day). At least a 20% improvement on total Brief Psychiatric Rating Scale (BPRS) was seen in 47.6% of the schizophrenics. Clinical improvement was regressed on baseline differences in clinical severity, and the residual scores were related to MRI values. RESULTS: Patients with larger anterior superior temporal lobe cerebrospinal fluid volumes (primarily sylvian fissure) showed greater improvement on total BPRS and withdrawal/retardation symptoms. CONCLUSIONS: Even schizophrenics with significant brain dysmorphology can have a positive clinical response to clozapine.

The psychosocial treatment of schizophrenia: an update.

OBJECTIVE: The authors sought to update the randomized controlled trial literature of psychosocial treatments for schizophrenia. METHOD: Computerized literature searches were conducted to identify randomized controlled trials of various psychosocial interventions, with emphasis on studies published since a previous review of psychosocial treatments for schizophrenia in 1996. RESULTS: Family therapy and assertive community treatment have clear effects on the prevention of psychotic relapse and rehospitalization. However, these treatments have no consistent effects on other outcome measures (e.g., pervasive positive and negative symptoms, overall social functioning, and ability to obtain competitive employment). Social skills training improves social skills but has no clear effects on relapse prevention, psychopathology, or employment status. Supportive employment programs that use the place-and-train vocational model have important effects on obtaining competitive employment. Some studies have shown improvements in delusions and hallucinations following cognitive behavior therapy. Preliminary research indicates that personal therapy may improve social functioning. CONCLUSIONS: Relatively simple, long-term psychoeducational family therapy should be available to the majority of persons suffering from schizophrenia. Assertive community training programs ought to be offered to patients with frequent relapses and hospitalizations, especially if they have limited family support. Patients with schizophrenia can clearly improve their social competence with social skills training, which may translate into a more adaptive functioning in the community. For patients interested in working, rapid placement with ongoing support offers the best opportunity for maintaining a regular job in the community. Cognitive behavior therapy may benefit the large number of patients who continue to experience disabling psychotic symptoms despite optimal pharmacological treatment.

Similar extent of brain dysmorphology in severely ill women and men with schizophrenia.

OBJECTIVE: The purpose of this study was to determine whether women with chronic, severe schizophrenia manifest a widespread deficit in cortical gray matter and ventricular enlargement similar to that seen in men with schizophrenia and whether this deficit is related to age at onset of illness, length of illness, or current illness severity. METHOD: Volumetric measures of head size, cortical gray matter, white matter and sulci, and lateral and third ventricles were obtained from magnetic resonance images of chronic inpatient schizophrenic women (N = 19) and men (N = 18) and healthy comparison women (N = 19) and men (N = 18). Sex and group differences were assessed by using a two-factor analysis of variance of brain measures. Age was entered as a covariate in assessments of associations between brain measures and age at onset and length of illness. RESULTS: The schizophrenic patients as a group had less cortical gray matter but comparable white matter and significantly more lateral and third ventricular CSF than the comparison group. Compared to the combined groups of men, women, regardless of diagnosis, had smaller heads, less cortical gray and white matter, and less sulcal, lateral, and third ventricular CSF. There were no group-by-sex interactions, suggesting that in schizophrenia these aspects of gross volumetric morphology in male and female brains are affected equally. There was no relationship between cortical gray matter deficit or ventricular enlargements and age at symptom onset or length of illness in either men or women with schizophrenia, when variance due to age was accounted for statistically. CONCLUSIONS: The process that contributes to cortical gray matter deficit in schizophrenia appears to affect men and women to a similar extent.

Association of estrogen levels with neuropsychological performance in women with schizophrenia.

OBJECTIVE: This study sought to determine the relationship of estrogen levels with psychiatric symptoms and neuropsychological function in female patients with schizophrenia. METHOD: Psychiatric symptoms were assessed and average estrogen and progesterone levels from four consecutive weekly blood samples were measured in 22 female inpatients with schizophrenia who were also administered a neuropsychological battery. RESULTS: There were strong positive correlations between average estrogen level and cognitive function, especially measures of global cognitive function, verbal and spatial declarative memory, and perceptual-motor speed. Correlations of hormone levels with psychiatric symptoms were nonsignificant. CONCLUSIONS: Higher estrogen levels in female patients with schizophrenia are associated with better cognitive ability. These results may have implications for potential treatment of cognitive dysfunction with adjunctive estrogen in female patients with schizophrenia.

Sildenafil for iatrogenic serotonergic antidepressant medication-induced sexual dysfunction in 4 patients.

OBJECTIVE: To evaluate the effect of sildenafil on iatrogenic serotonergic antidepressant-induced sexual dysfunction. METHOD: Four outpatients (2 men, 2 women) who developed sexual dysfunction (erectile impotence, anorgasmia) during treatment with a serotonin reuptake inhibitor antidepressant for psychiatric disorder were selected. Each subject was initially prescribed sildenafil 50 mg to be taken approximately 1 hour before sexual activity. The dose was increased to 100 mg for a partial or failed response. RESULTS: Four cases are detailed in case report fashion. All 4 had rapid reversal of their sexual dysfunction, usually with the first dose. Reversal equates to 1 successful use of sildenafil in each of 2 patients and 3 uses in 2 patients. CONCLUSION: Sildenafil may be an effective treatment for serotonergic antidepressant-induced sexual dysfunction and deserves further evaluation in randomized placebo-controlled studies.

Slow wave sleep and computed tomographic measures of brain morphology in schizophrenia.

To test the hypothesis that slow wave sleep in schizophrenia is inversely correlated with ventricular system volume, polysomnography and computed tomographic (CT) brain imaging were carried out in 14 psychiatric patients who met Research Diagnostic Criteria for schizophrenia (h = 11) or schizoaffective disorder (n = 3). Three measures of ventricular system volume were analyzed: (1) raw ventricular volume expressed in cm3; (2) ventricle-to-brain ratio; and (3) ventricular volume corrected for normal variation in age and head size expressed as a standardized (z) score. All three quantifications of ventricular volume were significantly and inversely correlated with visually scored measures of stage 3 and stage 4 sleep. This finding suggests that the etiology of slow wave sleep deficits in schizophrenia is related either directly or indirectly to underlying brain dysmorphology.

No antidepressant effect of biperiden compared with placebo in depression: a double-blind 6-week clinical trial.

Depression may result from an increased ratio of cholinergic to aminergic central neurotransmission. The effect of centrally active anticholinergic agents on depressive ratings in depressed patients, however, has not been well studied. In a previous open label 4-week clinical trial, Kasper et al. (1981) reported that biperiden (Akineton) had antidepressant effects in depressed patients. We compared the effects of placebo and biperiden in a randomized, double-blind, parallel-design 6-week study. All patients received placebo for the first week and then received either biperiden (< or = 12 mg/day) or a peripherally acting anticholinergic agent, glycopyrrolate (Robinul, 1 mg/day) for 4 weeks. All patients received placebo during week 6. Both groups significantly improved, but biperiden did not demonstrate any significant benefit compared with glycopyrrolate. In a subgroup of patients receiving biperiden, the percentage of rapid eye movement sleep was significantly decreased only in the first week of biperiden compared with the initial placebo week, suggesting that tolerance to the central effects of biperiden developed. Further studies would be needed to determine whether anticholinergic agents possess antidepressant properties.

Effects of chronic haloperidol and clozapine treatments on frontal and caudate neurochemistry in schizophrenia.

N-Acetyl-aspartate (NAA), a marker of neuronal integrity, has been found to be reduced in frontal regions in schizophrenia. However, the impact of antipsychotic drug type on NAA has not been carefully evaluated. We studied outpatients with schizophrenia/schizoaffective disorders chronically treated with haloperidol or clozapine and normal controls with single-voxel 1H-MRS of the caudate nuclei and the left frontal lobe. Concentrations of NAA, choline containing compounds (Cho) and creatine plus phosphocreatine (Cre) were determined and corrected for the proportion of cerebrospinal fluid (CSF) in each voxel. The haloperidol-treated group had significantly lower CSF-uncorrected and CSF-corrected left frontal NAA than the normal controls, with the clozapine group having intermediate concentrations. The haloperidol-treated group had significantly lower CSF-uncorrected caudate NAA than the normal controls, but the three groups did not differ after correcting for CSF fraction. Performance times in the Grooved Pegboard, a measure of motor dexterity and proxy for parkinsonism, were correlated with CSF-uncorrected and CSF-corrected left frontal NAA. Demographic and illness-related variables were not related to NAA. Exposure to haloperidol-like drugs may in part account for the frontal NAA reductions previously reported in schizophrenia. Adjustment for proportion of voxel CSF should be considered in 1H-MRS studies.

Schizophrenia: improving outcome.

Therapeutic advances over the last four decades have enabled most persons with schizophrenia to live in the community. Nevertheless, the majority will continue to experience various symptoms and to have social and cognitive disabilities. With the development of new medications and psychosocial interventions, outpatient status can no longer be viewed as a satisfactory final outcome. This article presents the current state of schizophrenia therapeutics in a variety of clinically relevant situations: first-episode psychosis, treatment-resistant psychosis, chronic, relapsing psychosis, continuous poor functioning, and chronic psychosis not responsive to pharmacotherapy. The first-line atypical antipsychotics should generally be used, mainly because of their comparatively benign side-effect profiles, and they should be given as early as possible in the illness. The clinician should not be quick to accept persistent psychosis; the second-line atypical clozapine should be tried early in the course of the disease in patients showing treatment resistance. For patients residing with their families, educational and supportive family interventions have an important effect on relapse prevention; for those who live on their own and suffer frequent relapses, Assertive Community Treatment may be helpful. Patients with psychosis that is not responsive to pharmacotherapy may benefit from specific modalities of cognitive-behavioral therapy currently being developed, while persons with persistent negative symptoms and limited social competence may find social-skills training useful. In addition, new programs of supported employment may enable some patients to maintain competitive employment.

Sildenafil for women patients with antidepressant-induced sexual dysfunction.

In an open study, sildenafil (Viagra) was prescribed for nine women outpatients who reported sexual dysfunction induced by antidepressant medication, primarily selective serotonin reuptake inhibitors. A 50 mg dose of sildenafil was prescribed, and patients were instructed to take it approximately one hour before sexual activity. They were told to increase the dose to 100 mg on the next occasion if they experienced a partial response or a lack of response to sildenafil. The nine patients, all of whom had experienced either anorgasmia or delayed orgasm with or without associated disturbances, reported significant reversal of sexual dysfunction, usually with the first dose of 50 mg of sildenafil.

Medication treatments for schizophrenia: translating research findings into better outcomes.

The atypical or novel antipsychotics have advanced the treatment of schizophrenia, especially given their reduced extrapyramidal side effect liability. In this article, the authors examine a number of recently published or presented studies of the atypical antipsychotics, many of them post approval studies, that shed additional light on this class of medications. Clozapine stands alone as a medication for treatment-resistant schizophrenia, but the other first-line atypical agents appear to reduce relapse rates during maintenance treatment and to have less of a long-term risk for tardive dyskinesia. However, additional research is needed to distinguish the atypical antipsychotics from each other and to better understand their non-neurological side effects.