Associations Between Cognitive Function and Levels of Glutamatergic Metabolites and Gamma-Aminobutyric Acid in Antipsychotic-Naïve Patients With Schizophrenia or Psychosis.

BACKGROUND: Abnormal glutamate and GABA (gamma-aminobutyric acid) levels have been found in the early phase of schizophrenia and may underlie cognitive deficits. However, the association between cognitive function and levels of glutamatergic metabolites and GABA has not been investigated in a large group of antipsychotic-naïve patients. METHODS: In total, 56 antipsychotic-naïve patients with schizophrenia or psychotic disorder and 51 healthy control subjects underwent magnetic resonance spectroscopy to measure glutamate, glutamate+glutamine (Glx), and GABA levels in dorsal anterior cingulate cortex (ACC) and glutamate and Glx levels in left thalamus. The cognitive domains of attention, working memory, and IQ were assessed. RESULTS: The whole group of antipsychotic-naïve patients had lower levels of GABA in dorsal ACC (p = .03), and the subgroup of patients with a schizophrenia diagnosis had higher glutamate levels in thalamus (p = .01), but Glx levels in dorsal ACC and thalamus did not differ between groups. Glx levels in dorsal ACC were positively associated with working memory (logarithmically transformed: b = -.016 [higher score indicates worse performance], p = .005) and attention (b = .056, p = .035) in both patients and healthy control subjects, although the association with attention did not survive adjustment for multiple comparisons. CONCLUSIONS: The findings suggest a positive association between glutamatergic metabolites and cognitive function that do not differ between patients and healthy control subjects. Moreover, our data indicate that decreased GABAergic levels in dorsal ACC are involved in schizophrenia and psychotic disorder, whereas increased glutamate levels in thalamus seem to be implicated in schizophrenia pathophysiology. The findings imply that first-episode patients with cognitive deficits may gain from glutamate-modulating compounds.

Cerebral Glutamate and Gamma-Aminobutyric Acid Levels in Individuals at Ultra-high Risk for Psychosis and the Association With Clinical Symptoms and Cognition.

BACKGROUND: Studies examining glutamate or gamma-aminobutyric acid (GABA) in ultra-high risk for psychosis (UHR) and the association with pathophysiology and cognition have shown conflicting results. We aimed to determine whether perturbed glutamate and GABA levels in the anterior cingulate cortex and glutamate levels in the left thalamus were present in UHR individuals and to investigate associations between metabolite levels and clinical symptoms and cognition. METHODS: We included 122 UHR individuals and 60 healthy control subjects. Participants underwent proton magnetic resonance spectroscopy to estimate glutamate and GABA levels and undertook clinical and cognitive assessments. RESULTS: We found no differences in metabolite levels between UHR individuals and healthy control subjects. In UHR individuals, we found negative correlations in the anterior cingulate cortex between the composite of glutamate and glutamine (Glx) and the Comprehensive Assessment of At-Risk Mental States composite score (p = .04) and between GABA and alogia (p = .01); positive associations in the anterior cingulate cortex between glutamate (p = .01) and Glx (p = .01) and spatial working memory and between glutamate (p = .04), Glx (p = .04), and GABA (p = .02) and set-shifting; and a positive association in the thalamus between glutamate and attention (p = .04). No associations between metabolites and clinical or cognitive scores were found in the healthy control subjects. CONCLUSIONS: An association between glutamate and GABA levels and clinical symptoms and cognition found only in UHR individuals suggests a loss of the normal relationship between metabolite levels and cognitive function. Longitudinal studies with investigation of clinical and cognitive outcome and the association with baseline levels of glutamate and GABA could illuminate whether glutamatergic and GABAergic dysfunction predicts clinical outcome.

Cerebral glutamate and GABA levels in high-risk of psychosis states: A focused review and meta-analysis of 1H-MRS studies.

Disturbances in the brain glutamate and GABA (γ-aminobutyric acid) homeostasis may be markers of transition to psychosis in individuals at high-risk (HR). Knowledge of GABA and glutamate levels in HR stages could give an insight into changes in the neurochemistry underlying psychosis. Studies on glutamate in HR have provided conflicting data, and GABA studies have only recently been initialized. In this meta-analysis, we compared cerebral levels of glutamate and GABA in HR individuals with healthy controls (HC). We searched Medline and Embase for articles published on 1H-MRS studies on glutamate and GABA in HR states until April 9th, 2019. We identified a total of 28 eligible studies, of which eight reported GABA (243 HR, 356 HC) and 26 reported glutamate (299 HR, 279 HC) or Glx (glutamate + glutamine) (584 HR, 632 HC) levels. Sample sizes varied from 6 to 75 for HR and 10 to 184 for HC. Our meta-analysis of 1H-MRS studies on glutamate and GABA in HR states displayed significantly lower (P = 0.0003) levels of thalamic glutamate in HR individuals than in HC and significantly higher (P = 0.001) Glx in the frontal lobe of genetic HR individuals (1st-degree relatives) than in HC. No other significant differences in glutamate and GABA levels were found. Subject numbers in the studies on glutamate as well as GABA levels were generally small and the data conflicting. Our meta-analytical findings highlight the need for larger and more homogeneous studies of glutamate and GABA in high-risk states.

Supplementary data for a focused review and meta-analysis of 1H-MRS studies on cerebral glutamate and GABA levels in high-risk of psychosis states.

Data (attached) for a focused review and meta-analysis of cerebral levels of glutamate, Glx, and GABA levels assessed with 1H-MRS in high-risk of psychosis states was collected and stored at covidence.org and extracted to The Cochrane Collaboration Review Manager software package (RevMan Version 5.3) for meta-analytical purposes. Meta-analyses were performed with a random-effects, inverse-variance weighted model to calculate the pooled effect size. Heterogeneity was measured using the I2 value. Significance was assessed using two-sided 95% confidence intervals. Potential publication bias was assessed by visual inspection of funnel plots. Supplementary to the co-submitted article are comprehensive meta-analyses of glutamate, Glx, and GABA, as well as the PRISMA flow diagram of included studies and a list of studies included in the review along with available measures and methodological variables. The attached data offers an insight into the included studies and the specified metabolite values for each study and offers possible further investigation for other researchers, as well as an insight into the review and meta-analyses performed. The supplementary material also serves to support findings and interpretations in the main article.

Heritability of cerebral glutamate levels and their association with schizophrenia spectrum disorders: a 1[H]-spectroscopy twin study.

Research findings implicate cerebral glutamate in the pathophysiology of schizophrenia, including genetic studies reporting associations with glutamatergic neurotransmission. The extent to which aberrant glutamate levels can be explained by genetic factors is unknown, and if glutamate can serve as a marker of genetic susceptibility for schizophrenia remains to be established. We investigated the heritability of cerebral glutamate levels and whether a potential association with schizophrenia spectrum disorders could be explained by genetic factors. Twenty-three monozygotic (MZ) and 20 dizygotic (DZ) proband pairs con- or discordant for schizophrenia spectrum disorders, along with healthy control pairs (MZ = 28, DZ = 18) were recruited via the National Danish Twin Register and the Psychiatric Central Register (17 additional twins were scanned without their siblings). Glutamate levels in the left thalamus and the anterior cingulate cortex (ACC) were measured using 1[H]-magnetic resonance spectroscopy at 3 Tesla and analyzed by structural equation modeling. Glutamate levels in the left thalamus were heritable and positively correlated with liability for schizophrenia spectrum disorders (phenotypic correlation, 0.16, [0.02-0.29]; p = 0.010). The correlation was explained by common genes influencing both the levels of glutamate and liability for schizophrenia spectrum disorders. In the ACC, glutamate and glx levels were heritable, but not correlated to disease liability. Increases in thalamic glutamate levels found in schizophrenia spectrum disorders are explained by genetic influences related to the disease, and as such the measure could be a potential marker of genetic susceptibility, useful in early detection and stratification of patients with psychosis.

Glucocorticoids and the risk of schizophrenia spectrum disorder in childhood and adolescence - A Danish nationwide study.

Glucocorticoids can have psychosis as a potential side effect, but have also been suggested to yield protective effects due to anti-inflammatory properties. Nonetheless, knowledge is sparse on the association between glucocorticoid treatment and development of psychosis, which we aimed to study in this first large-scale longitudinal study. Among all individuals born in Denmark 1995-2003 (n=597,257), we compared individuals who had redeemed ≥1 prescription for glucocorticoids to an active comparator group and a non-exposed group concerning subsequent development of schizophrenia spectrum disorders until 2013. Hazard rate ratios (HRR) were estimated using Cox regression adjusted for calendar year, age, gender, urbanization, somatic diseases, parental educational level and psychiatric history. The risk for a subsequent diagnosis of early-onset schizophrenia spectrum disorder (N=1141) was increased after exposure to both non-systemic (HRR=1.47; 95%-CI=1.25-1.73; N=371) and systemic glucocorticoids (HRR=1.66; 95%-CI=1.13-2.43; N=34), when compared to non-exposed individuals. Similar elevated risks were observed when comparing to the active comparator group, for schizophrenia and acute psychosis, and within an older cohort. The risk of psychosis was elevated the most within the first year after exposure to glucocorticoids (P<0.001) without any indication for a dose-response association. However, in individuals with asthma, exposure to glucocorticoids did not further increase the risk of psychosis. Glucocorticoid exposure was associated with an increased risk for psychotic disorders, which may be explained by an effect of the underlying somatic disease, such as asthma. A potential beneficial effect of glucocorticoids on psychotic symptoms should be investigated in clinical trials.

Glutamate Levels and Resting Cerebral Blood Flow in Anterior Cingulate Cortex Are Associated at Rest and Immediately Following Infusion of S-Ketamine in Healthy Volunteers.

Progressive loss of brain tissue is seen in some patients with schizophrenia and might be caused by increased levels of glutamate and resting cerebral blood flow (rCBF) alterations. Animal studies suggest that the normalisation of glutamate levels decreases rCBF and prevents structural changes in hippocampus. However, the relationship between glutamate and rCBF in anterior cingulate cortex (ACC) of humans has not been studied in the absence of antipsychotics and illness chronicity. Ketamine is a noncompetitive N-methyl-D-aspartate receptor antagonist that transiently induces schizophrenia-like symptoms and neurobiological disturbances in healthy volunteers (HVs). Here, we used S-ketamine challenge to assess if glutamate levels were associated with rCBF in ACC in 25 male HVs. Second, we explored if S-ketamine changed the neural activity as reflected by rCBF alterations in thalamus (Thal) and accumbens that are connected with ACC. Glutamatergic metabolites were measured in ACC with magnetic resonance (MR) spectroscopy and whole-brain rCBF with pseudo-continuous arterial spin labelling on a 3-T MR scanner before, during, and after infusion of S-ketamine (total dose 0.375 mg/kg). In ACC, glutamate levels were associated with rCBF before (p < 0.05) and immediately following S-ketamine infusion (p = 0.03), but not during and after. S-Ketamine increased rCBF in ACC (p < 0.001) but not the levels of glutamate (p = 0.96). In subcortical regions, S-ketamine altered rCBF in left Thal (p = 0.03). Our results suggest that glutamate levels in ACC are associated with rCBF at rest and in the initial phase of an increase. Furthermore, S-ketamine challenge transiently induces abnormal activation of ACC and left Thal that both are implicated in the pathophysiology of schizophrenia. Future longitudinal studies should investigate if increased glutamate and rCBF are related to the progressive loss of brain tissue in initially first-episode patients.

Negative Symptoms and Reward Disturbances in Schizophrenia Before and After Antipsychotic Monotherapy.

BACKGROUND: Negative symptoms (NS) are a central part of the symptomatology of schizophrenia, which is highly correlated to the functional outcome. Disturbances of the brain reward system are suggested to be central in the pathogenesis of NS by decreasing motivation and hedonic experiences. In this study, we compared reward-related brain activity in patients improving and not improving in NS after treatment with amisulpride. METHODS: Thirty-nine antipsychotic-naive patients and 49 healthy controls completed functional magnetic resonance imaging with a modified monetary incentive delay task. Psychopathology of the patients was characterised with Positive and Negative Syndrome Scale (PANSS), and they were treated with individual doses of amisulpride (mean 271 mg) for 6 weeks, after which the examinations were repeated. RESULTS: Patients improved on positive, general, and total PANSS score after treatment ( P < .001). Fourteen patients had ≥20% improvement of NS, whereas 25 patients improved <20%. At baseline, one-way analysis of variance showed group difference bilaterally in the caudate nucleus and in the right nucleus accumbens (all P < .002), which was caused by decreased reward anticipation activity in the nonimproving patients compared to healthy controls. There was a significant group × time interaction, with the healthy controls and the improvers decreasing and the nonimprovers increasing in reward anticipation activity after treatment, most pronounced in the left caudate nucleus ( P = .001). DISCUSSION: Patients improving in NS score had a less aberrant reward system at baseline, but reward related activity was reduced over time. Patients not improving in NS showed decreased striatal reward-activity at baseline, which improved over time. Whether this is associated with alteration in working memory and reward learning or with pronounced symptoms within specific domains of NS may be addressed in future studies.

Improvement of brain reward abnormalities by antipsychotic monotherapy in schizophrenia.

CONTEXT Schizophrenic symptoms are linked to a dysfunction of dopamine neurotransmission and the brain reward system. However, it remains unclear whether antipsychotic treatment, which blocks dopamine transmission, improves, alters, or even worsens the reward-related abnormalities. OBJECTIVE To investigate changes in reward-related brain activations in schizophrenia before and after antipsychotic monotherapy with a dopamine D2/D3 antagonist. DESIGN Longitudinal cohort study. SETTING Psychiatric inpatients and outpatients in the Capital Region of Denmark. PARTICIPANTS Twenty-three antipsychotic-naive patients with first-episode schizophrenia and 24 healthy controls initially matched on age, sex, and parental socioeconomic status were examined with functional magnetic resonance imaging while playing a variant of the monetary incentive delay task. INTERVENTIONS Patients were treated for 6 weeks with the antipsychotic compound amisulpride. Controls were followed up without treatment. MAIN OUTCOME MEASURES Task-related blood oxygen level-dependent activations as measured by functional magnetic resonance imaging before and after antipsychotic treatment. RESULTS At baseline, patients, as compared with controls, demonstrated an attenuation of brain activation during reward anticipation in the ventral striatum, bilaterally. After 6 weeks of treatment, patients showed an increase in the anticipation-related functional magnetic resonance imaging signal and were no longer statistically distinguishable from healthy controls. Among the patients, there was a correlation between the improvement of positive symptoms and normalization of reward-related activation. Those who showed the greatest clinical improvement in positive symptoms also showed the greatest increase in reward-related activation after treatment. CONCLUSIONS To our knowledge, this is the first controlled, longitudinal study of reward disturbances in schizophrenic patients before and after their first antipsychotic treatment. Our results demonstrate that alterations in reward processing are fundamental to the illness and are seen prior to any treatment. Antipsychotic treatment tends to normalize the response of the reward system; this was especially seen in the patients with the most pronounced treatment effect on the positive symptoms. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01154829.

Assessment of auditory sensory processing in a neurodevelopmental animal model of schizophrenia--gating of auditory-evoked potentials and prepulse inhibition.

The use of translational approaches to validate animal models is needed for the development of treatments that can effectively alleviate cognitive impairments associated with schizophrenia, which are unsuccessfully treated by the current available therapies. Deficits in pre-attentive stages of sensory information processing seen in schizophrenia patients, can be assessed by highly homologues methods in both humans and rodents, evident by the prepulse inhibition (PPI) of the auditory startle response and the P50 (termed P1 here) suppression paradigms. Treatment with the NMDA receptor antagonist PCP on postnatal days 7, 9, and 11 reliably induce cognitive impairments resembling those presented by schizophrenia patients. Here we evaluate the potential of early postnatal PCP (20mg/kg) treatment in Lister Hooded rats to induce post-pubertal deficits in PPI and changes, such as reduced gating, in the P1 suppression paradigm in the EEG. The results indicate that early postnatal PCP treatment to rats leads to a reduction in PPI of the acoustic startle response. Furthermore, treated animals were assessed in the P1 suppression paradigm and produced significant changes in auditory-evoked potentials (AEP), specifically by an increased P1 amplitude and reduced P2 (P200 in humans) gating. However, the treatment neither disrupted normal P1 gating nor reduced N1 (N100 in humans) amplitude, representing two phenomena that are usually found to be disturbed in schizophrenia. In conclusion, the current findings confirm measures of early information processing to show high resemblance between rodents and humans, and indicate that early postnatal PCP-treated rats show deficits in pre-attentional processing, which are distinct from those observed in schizophrenia patients.

Reversal of cognitive deficits by an ampakine (CX516) and sertindole in two animal models of schizophrenia--sub-chronic and early postnatal PCP treatment in attentional set-shifting.

RATIONALE: Therapies treating cognitive impairments in schizophrenia especially deficits in executive functioning are not available at present. OBJECTIVE: The current study evaluated the effect of ampakine CX516 in reversing deficits in executive functioning as represented in two animal models of schizophrenia and assessed by a rodent analog of the intradimensional-extradimensional (ID-ED) attentional set-shifting task. The second generation antipsychotic, sertindole, provided further validation of the schizophrenia-like disease models. METHODS: Animals were subjected to (a) sub-chronic or (b) early postnatal phencyclidine (PCP) treatment regimes: (a) Administration of either saline or PCP (5 mg/kg, intraperitonally b.i.d. for 7 days) followed by a 7-day washout period and testing on day 8. (b) On postnatal days (PNDs) 7, 9, and 11, rats were subjected to administration of either saline or PCP (20 mg/kg, subcutaneously (s.c.)) and tested on PNDs 56-95, after reaching adulthood. The single test session required rats to dig for food rewards in a series of discriminations following acute administration of either vehicle, or CX516 (5-40 mg/kg, s.c.), or sertindole (1.25 mg/kg, perorally). RESULTS: The specific extradimensional deficits produced by sub-chronic or early postnatal PCP treatment were significantly attenuated by sertindole and dose-dependently by CX516. CONCLUSION: Findings here further establish PCP treatment as model of executive functioning deficits related to schizophrenia and provide evidence that direct glutamatergic interventions could improve these, when assessed in the ID-ED attentional set-shifting task.

Evaluation of a neurodevelopmental model of schizophrenia--early postnatal PCP treatment in attentional set-shifting.

Phencyclidine (PCP) was administered to male and female Lister hooded rats on postnatal days (PND) 7, 9 and 11. All PCP animals tested in adulthood (PND 53-93) showed deficits in cognitive flexibility, specifically in their ability to shift attentional set, compared to controls. This novel finding is reminiscent of the impairment observed in schizophrenia patients, and supports the validity of the early postnatal PCP regimen as a disease-like model.