Treatment-resistant Schizophrenia Group Research Articles

Association of SLC6A3 variants with treatment-resistant schizophrenia: a genetic association study of dopamine-related genes in schizophrenia.

Most genetic analyses that have attempted to identify a locus or loci that can distinguish patients with treatment-resistant schizophrenia (TRS) from those who respond to treatment (non-TRS) have failed. However, evidence from multiple studies suggests that patients with schizophrenia who respond well to antipsychotic medication have a higher dopamine (DA) state in brain synaptic clefts whereas patients with TRS do not show enhanced DA synthesis/release pathways. To examine the contribution (if any) of genetics to TRS, we conducted a genetic association analysis of DA-related genes in schizophrenia patients (TRS, n = 435; non-TRS, n = 539) and healthy controls (HC: n = 489). The distributions of the genotypes of rs3756450 and the 40-bp variable number tandem repeat on SLC6A3 differed between the TRS and non-TRS groups. Regarding rs3756450, the TRS group showed a significantly higher ratio of the A allele, whereas the non-TRS group predominantly had the G allele. The analysis of the combination of COMT and SLC6A3 yielded a significantly higher ratio of the putative low-DA type (i.e., high COMT activity + high SLC6A3 activity) in the TRS group compared to the two other groups. Patients with the low-DA type accounted for the minority of the non-TRS group and exhibited milder psychopathology. The overall results suggest that (i) SLC6A3 could be involved in responsiveness to antipsychotic medication and (ii) genetic variants modulating brain DA levels may be related to the classification of TRS and non-TRS.

Associations Between Structural Covariance Network and Antipsychotic Treatment Response in Schizophrenia.

Schizophrenia is associated with widespread cortical thinning and abnormality in the structural covariance network, which may reflect connectome alterations due to treatment effect or disease progression. Notably, patients with treatment-resistant schizophrenia (TRS) have stronger and more widespread cortical thinning, but it remains unclear whether structural covariance is associated with treatment response in schizophrenia. We organized a multicenter magnetic resonance imaging study to assess structural covariance in a large population of TRS and non-TRS, who had been resistant and responsive to non-clozapine antipsychotics, respectively. Whole-brain structural covariance for cortical thickness was assessed in 102 patients with TRS, 77 patients with non-TRS, and 79 healthy controls (HC). Network-based statistics were used to examine the difference in structural covariance networks among the 3 groups. Moreover, the relationship between altered individual differentiated structural covariance and clinico-demographics was also explored. Patients with non-TRS exhibited greater structural covariance compared with HC, mainly in the fronto-temporal and fronto-occipital regions, while there were no significant differences in structural covariance between TRS and non-TRS or HC. Higher individual differentiated structural covariance was associated with lower general scores of the Positive and Negative Syndrome Scale in the non-TRS group, but not in the TRS group. These findings suggest that reconfiguration of brain networks via coordinated cortical thinning is related to treatment response in schizophrenia. Further longitudinal studies are warranted to confirm if greater structural covariance could serve as a marker for treatment response in this disease.

Greater Choline-Containing Compounds and Myo-inositol in Treatment-Resistant Versus Responsive Schizophrenia: A 1H-Magnetic Resonance Spectroscopy Meta-analysis

BackgroundThe neurobiology of treatment-resistant schizophrenia (TRS) is poorly understood, and meta-analytic consensus regarding magnetic resonance spectroscopic profiles of glutamate, choline-containing compounds, myo-inositol, and other metabolites in the condition is lacking. MethodsIn this meta-analysis, we examined published findings for N-acetylaspartate, choline-containing compounds (phosphocholine+glycerophosphocholine), myo-inositol, creatine+phosphocreatine, glutamate, and glutamate+glutamine in the anterior cingulate cortex and dorsal striatum in people with TRS versus non-TRS as well as TRS versus healthy control participants (HCs) and TRS versus ultra TRS (i.e., TRS with clozapine resistance). A MEDLINE search revealed 9 articles including 239 people with pooled TRS and ultra TRS, 59 with ultra TRS, 175 with non-TRS, and 153 (HCs) that met meta-analytic criteria. ResultsSignificant effects included higher anterior cingulate cortex phosphocholine+glycerophosphocholine and myo-inositol in the pooled TRS and ultra TRS group than in both the non-TRS group and HCs as well as higher dorsal striatal phosphocholine+glycerophosphocholine in ultra TRS versus HCs, but no differences in other regional metabolites. ConclusionsThe observed metabolite profile in TRS (higher phosphocholine+glycerophosphocholine and myo-inositol signal) is consistent with the hypothesis that TRS has a neuroinflammatory component, although this meta-analysis is not a critical test of that hypothesis. A similar profile is seen in healthy aging, which is known to involve increased neuroinflammation and glial activation. Because the overall number of datasets was low, however, results should be considered preliminary and highlight the need for additional studies of brain metabolites in TRS and their possible association with inflammatory processes.

Altered functional connectivity in anterior cingulate cortex subregions in treatment-resistant schizophrenia patients

BackgroundThe anterior cingulate cortex (ACC) plays a key role in motor control, attention, and cognitive control. It is well established that schizophrenia is associated with impaired functional connectivity (FC) of the ACC pathway. So far, however, there has been little discussion about the ACC subregions function in patients with treatment-resistant schizophrenia (TRS). AimThis study aims to characterize resting-state functional connectivity (rs-FC) profiles of ACC subregions in patients with TRS. The association between these FC and clinical symptoms, neurocognitive function, and grey matter volume (GMV) was studied as well. MethodsA total of 81 patients with schizophrenia (40 patients with TRS = 40, 41 patients with non-treatment-resistant schizophrenia (NTRS)) and 39 age- and gender-matched healthy controls (HC) were enrolled, and underwent structural magnetic resonance imaging (MRI), resting-state functional MRI (rs-fMRI), clinical evaluation. The ACC subregions, including subgenual ACC (sgACC), pregenual ACC (pgACC), and dorsal ACC (dACC), were selected as seed regions from the automated anatomical labelling atlas 3 (AAL3). The GMV of the ACC subregions were calculated and seed-based FC maps for all ACC subregions were generated and compared between the TRS and NTRS, HC group. Additionally, correlations between altered FC and clinical symptoms, GMV, and neurocognitive functions in the TRS patients were explored. ResultCompared with HC, increased FC was observed in TRS and NTRS groups between bilateral sgACC and left cuneus, right cuneus, and left lingual gyrus, while decreased FC was found between bilateral dACC and thalamic. Additionally, compared with NTRS, the TRS group showed increased FC between bilateral dACC and right cuneus and decreased FC between bilateral dACC and thalamic. The TRS group showed decreased GMV in all ACC subregions than the HC group, and there is no significant difference between the TRS group and the NTRS group. ConclusionThe findings in this study suggest that disrupted FC of subregional ACC has the potential as a marker for TRS. The dysconnectivity of bilateral dACC- right cuneus and bilateral dACC-thalamus, are likely to be the unique FC profiles of TRS. These findings further our understanding of the neurobiological impairments in TRS.

Sex differences in the association of treatment-resistant schizophrenia and serum interleukin-6 levels

BackgroundLow-grade inflammation and altered inflammatory markers have been observed in treatment-resistant schizophrenia (TRS). Interleukin-6 (IL-6) is one of the pro-inflammatory cytokines linked with TRS and receives increasing attention. Previous studies showed that patients with TRS might have higher IL-6 levels compared with healthy individuals and treatment-responsive patients. Besides, emerging evidence has suggested that there are sex differences in the associations between IL-6 levels and various illnesses, including chronic hepatitis C, metabolic syndrome, etc.; however, there is limited study on TRS. In this present study, we aimed to compare the serum IL-6 levels of TRS and partially responsive schizophrenia (PRS) and explore potential sex differences in the association of TRS and IL-6 levels.MethodsThe study population consisted of a total of 90 patients with schizophrenia: 64 TRS patients (45.3% males and 54.7% females) and 26 PRS patients (46.2% males and 53.8% females). We measured serum IL-6 levels using enzyme-linked immunosorbent assay (ELISA) and analyzed them separately by gender, controlling for confounders (age, education, medication, body mass index, and PANSS scores) rigorously.ResultThe results showed that patients with TRS had higher serum IL-6 levels than patients with PRS (p = 0.002). In females, IL-6 levels increased significantly in the TRS group compared with the PRS group (p = 0.005). And a positive correlation tendency was observed between IL-6 levels and PANSS general sub-scores (r = 0.31, p = 0.039), although this correlation was not significant after correcting for multiple comparisons. Whereas, there were no differences in IL-6 levels between the TRS and PRS (p = 0.124) in males.ConclusionOur findings provided evidence supporting the hypothesis that the inflammatory response system (IRS) may play a role in the pathogenesis of TRS in a sex-dependent manner. In addition, sex differences in the immune dysfunction of individuals with schizophrenia cannot be neglected, and inflammation in male and female TRS should be discussed separately.

Evaluation of Serum Complement Levels and Factors Affecting Treatment Resistance in Patients with Schizophrenia.

There are increasing investigations about the potential role of the complement system in disorders affecting the central nervous system, including schizophrenia. Therefore, we aim to evaluate the levels of complement 3 and complement 4 and the factors affecting treatment resistance in schizophrenia patients. This cross-sectional study was conducted between January 2020 and January 2021 and included schizophrenia patients resistant to treatment or in remission and healthy controls. The Structured Clinical Interview for Diagnostic and Statistical Manual-5 was used to confirm the diagnosis according to Diagnostic and Statistical Manual -5 criteria. We evaluated the patients with some scales and forms. The complement 3 and complement 4 levels were measured from blood samples. In the treatment-resistant schizophrenia group, complement 3 (P = .001) and complement 4 (P = .001) levels were significantly higher compared to schizophrenia patients in remission and healthy controls. While the Brief Psychiatric Rating Scale (P < .001), the Positive and Negative Syndrome Scale-positive (P < .001), the Positive and Negative Syndrome Scale-negative (P < .001), the Positive and Negative Syndrome Scale-psychopathology (P < .001), the Positive and Negative Syndrome Scale-total (P < .001), and the Clinical Global Impression Scale-Severity (P < .001) scores were significantly higher in treatment-resistant schizophrenia patients, the General Assessment of Functioning (P < .001), and Beck Cognitive Insight Scale (P < .001) scores were significantly lower compared to the other groups. In schizophrenia patients, complement 3 levels were positively correlated with the Positive and Negative Syndrome Scale-negative (P = .046), the Positive and Negative Syndrome Scale-psychopathology (P = .001), the Positive and Negative Syndrome Scale -total (P = .025), and Clinical Global Impression Scale-Severity of Disease (P = .004). Also, complement 4 levels were positively correlated with Brief Psychiatric Rating Scale (P = .004), the Positive and Negative Syndrome Scale-positive (P = .003), the Positive and Negative Syndrome Scale -negative (P = .014), the Positive and Negative Syndrome Scale-psychopathology (P < .001), the Positive and Negative Syndrome Scale-total (P = .002), and Clinical Global Impression Scale-Severity of Disease (P = .001) in patients with schizophrenia. It was determined that a higher C4 level increased the risk of treatment resistance (odds ratio: 1.133, 95% CI: 1.012-1.268; P = .030), while a higher Beck Cognitive Insight Scale score decreased the risk of treatment resistance (odds ratio: 0.317, 95% CI: 0.191-0.526; P < .001). In light of the analyses, it can be said that complement concentration increases in certain stages of schizophrenia, and its imbalance may be associated with symptom severity and treatment resistance.

Music rhythm perception and production relate to treatment response in schizophrenia

Accumulating evidence indicates that pathophysiology of schizophrenia involves abnormalities in the dopamine and glutamatergic neuronal systems. Antipsychotic medications are currently used to normalize dopaminergic function for schizophrenia. However, approximately 30 % of the patients have no response to antipsychotic medications, which is classified as treatment-resistant schizophrenia (TRS). Furthermore, dopamine and glutamate levels in the neural basis have been reported to differ between TRS and non-TRS. In this study, we assumed that these differences may affect music rhythm perception and production abilities between the two groups. We examined fifty-seven schizophrenia (26 TRS, 31 non-TRS) and thirty-one healthy controls (HCs) by using the Harvard Beat Assessment Test (H-BAT). As a result, we found that rhythm production was worse in patients with TRS compared to patients with non-TRS and HCs, while no difference was observed between patients with non-TRS and HCs. In addition, rhythm perception and production abilities were impaired in the whole patient group compared with HCs. Furthermore, in the patient group, the deficits were correlated with cognitive impairments. Collectively, these results suggest that patients with schizophrenia may have rhythm processing deficits, with particular a rhythm production problem in the TRS group.

Mind over what matters: How training in emotional self-regulation can strengthen the immune response in lonely elders

Patients with treatment-resistant schizophrenia (TRS) suffer severe, long-term psychotic symptoms and chronic stress. Salivary kynurenic acid (KYNA) and choroid plexus were evidenced to relate to psychological stress. We hypothesized that TRS patients would have higher salivary KYNA levels than patients who respond to antipsychotics (NTRS) and healthy controls (HC), and increased salivary KYNA levels are associated with clinical phenotypes and choroid plexus volume. A total of 66 HC participants, 53 patients with TRS and 46 with NTRS were enrolled. Salivary KYNA levels were measured by liquid chromatography-tandem mass spectrometry, choroid plexus volume by magnetic resonance imaging, and cognitive functions with the MATRICS Consensus Cognitive Battery. The TRS group had significantly higher salivary KYNA levels than the NTRS group (p = 0.003), who in turn had higher salivary KYNA than HC (p = 0.02). Higher salivary KYNA levels were associated with larger choroid plexus volume (r = 0.48, p = 0.004); lower attention/vigilance (r = -0.44, p = 0.004), verbal learning (r = -0.44, p = 0.004), total MCCB score (r = -0.42, p = 0.005); and a higher total PANSS score (r = 0.48, p = 0.004) in TRS patients. An enlarged choroid plexus also related to worse attention/vigilance (r = -0.39, p = 0.03), verbal learning (r = -0.55, p = 0.001), total MCCB score (r = -0.41, p = 0.02) and clinical symptoms (r = 0.48, p = 0.004) in TRS patients only. We conclude that elevated salivary KYNA levels and associated choroid plexus enlargement are clinically relevant indicators of TRS, with salivary KYNA being particularly valuable as a peripheral marker. Our findings should benefit TRS research and benefit the improvement of personalized treatment.

Elevated salivary kynurenic acid levels related to enlarged choroid plexus and severity of clinical phenotypes in treatment-resistant schizophrenia

Patients with treatment-resistant schizophrenia (TRS) suffer severe, long-term psychotic symptoms and chronic stress. Salivary kynurenic acid (KYNA) and choroid plexus were evidenced to relate to psychological stress. We hypothesized that TRS patients would have higher salivary KYNA levels than patients who respond to antipsychotics (NTRS) and healthy controls (HC), and increased salivary KYNA levels are associated with clinical phenotypes and choroid plexus volume. A total of 66 HC participants, 53 patients with TRS and 46 with NTRS were enrolled. Salivary KYNA levels were measured by liquid chromatography-tandem mass spectrometry, choroid plexus volume by magnetic resonance imaging, and cognitive functions with the MATRICS Consensus Cognitive Battery. The TRS group had significantly higher salivary KYNA levels than the NTRS group (p = 0.003), who in turn had higher salivary KYNA than HC (p = 0.02). Higher salivary KYNA levels were associated with larger choroid plexus volume (r = 0.48, p = 0.004); lower attention/vigilance (r = -0.44, p = 0.004), verbal learning (r = -0.44, p = 0.004), total MCCB score (r = -0.42, p = 0.005); and a higher total PANSS score (r = 0.48, p = 0.004) in TRS patients. An enlarged choroid plexus also related to worse attention/vigilance (r = -0.39, p = 0.03), verbal learning (r = -0.55, p = 0.001), total MCCB score (r = -0.41, p = 0.02) and clinical symptoms (r = 0.48, p = 0.004) in TRS patients only. We conclude that elevated salivary KYNA levels and associated choroid plexus enlargement are clinically relevant indicators of TRS, with salivary KYNA being particularly valuable as a peripheral marker. Our findings should benefit TRS research and benefit the improvement of personalized treatment.

A preliminary genetic association study of GAD1 and GABAB receptor genes in patients with treatment-resistant schizophrenia.

GABAergic system dysfunction has been implicated in the etiology of schizophrenia and of cognitive impairments in particular. Patients with treatment-resistant schizophrenia (TRS) generally suffer from profound cognitive impairments in addition to severe positive symptoms, suggesting that GABA system dysfunction could be involved more closely in patients with TRS. In the present study, exome sequencing was conducted on fourteen TRS patients, whereby four SNPs were identified on GAD1, GABBR1 and GABBR2 genes. An association study for five SNPs including these 4 SNPs and rs3749034 on GAD1 as then performed among 357 patients with TRS, 682 non-TRS patients and 508 healthy controls (HC). The results revealed no significant differences in allelic and/or genetic distributions for any of the five SNPs. However, several subanalyses in comparisons between schizophrenia and HC groups, as well as between the three groups, showed nominal-level significance for rs3749034 on GAD1 and rs10985765/rs3750344 on GABBR2. In particular, in comparisons of female subjects, rigorous analysis for rs3749034 showed a statistical difference between the schizophrenia and HC groups and between the TRS and HC groups. Several positive results in subanalyses suggested that genetic vulnerability in the GABA system to schizophrenia or TRS could be affected by sex or sampling area, and overall, that rs3749034 on GAD1 and rs10985765 on GABBR2 could be related to TRS. In the present study, only a few SNPs were examined; it is possible that other important genetic variants in other regions of GABA-related genes were not captured in this preliminary study.

Interacting Roles of COMT and GAD1 Genes in Patients with Treatment-Resistant Schizophrenia: a Genetic Association Study of Schizophrenia Patients and Healthy Controls.

The projection from dopaminergic neurons to gamma-aminobutyric acid (GABA) interneurons in the prefrontal cortex is involved in the etiology of schizophrenia. The impact of interacting effects between dopamine signals and the expression of GABA on the clinical phenotypes of schizophrenia has not been studied. Since these interactions could be closely involved in prefrontal cortex functions, patients with specific alleles of these relevant molecules (which lead to lower or vulnerable genetic functions) may develop treatment-refractory symptoms. We conducted a genetic association study focusing on COMT and GAD1 genes for a treatment-resistant schizophrenia (TRS) group (n=171), a non-TRS group (n=592), and healthy controls (HC: n=447), and we examined allelic combinations specific to TRS. The results revealed that the percentage of subjects with Met allele of rs4680 on the COMT gene and C/C homozygote of rs3470934 on the GAD1 gene was significantly higher in the TRS group than the other two groups. There was no significant difference between the non-TRS group and HC groups. Considering the direction of functions of these single-nucleotide polymorphisms revealed by previous studies, we speculate that subjects with the Met/CC allelic combination could have a higher dopamine level and a lower expression of GABA in the prefrontal cortex. Our results suggest that an interaction between the dopaminergic signal and GABA signal intensities could differ between TRS patients and patients with other types of schizophrenia and healthy subjects.

Investigating aberrantly expressed microRNAs in peripheral blood mononuclear cells from patients with treatment‑resistant schizophrenia using miRNA sequencing and integrated bioinformatics.

Treatment-resistant schizophrenia (TRS) is a common phenotype of schizophrenia that places a considerable burden on patients as well as on society. TRS is known for its tendency to relapse and uncontrollable nature, with a poor response to antipsychotics other than clozapine. Therefore, it is urgent to identify objective biological markers, so as to guide its treatment and associated clinical work. In the present study, the peripheral blood mononuclear cells (PBMCs) of patients with TRS and a healthy control group, which were gender-, age- and ethnicity-matched, were subjected to microRNA (miRNA/miR) sequencing to screen out the top three miRNAs with the highest fold change values. These were then validated in the TRS (n=34) and healthy control (n=31) groups by reverse transcription-quantitative PCR. For two of the top three miRNAs, the PCR results were in accordance with the sequencing result (P<0.01), while the third miRNA exhibited the opposite trend (P<0.01). To elucidate the functions of these two miRNAs, Homo sapiens (hsa)-miR-218-5p and hsa-miR-1262 and their regulatory network, target gene prediction was first performed using online TargetScan and Diana-micro T software. Bioinformatics analysis was then performed using functional enrichment analysis to determine the Gene Ontology terms in the category biological process and the Kyoto Encyclopedia of Genes and Genomes pathways. It was revealed that these target genes were markedly associated with the nervous system and brain function, and it was obvious that the differentially expressed miRNAs most likely participated in the pathogenesis of TRS. A receiver operating characteristic curve was generated to confirm the distinct diagnostic value of these two miRNAs. It was concluded that aberrantly expressed miRNAs in PMBCs may be implicated in the pathogenesis of TRS and may serve as specific peripheral blood-based biomarkers for the early diagnosis of TRS.

Autistic traits and cognitive profiles of treatment-resistant schizophrenia

The complex pathophysiology of treatment-resistant schizophrenia (TRS) includes severe positive symptoms but also other symptom domains. The overlapping psychological profiles of schizophrenia and autistic spectrum disorder (ASD) are not established. We compared TRS patients (n = 30) with schizophrenia patients in remission (RemSZ, n = 28) and ASD patients (n = 28), focusing on both neurodevelopmental aspects and general and social cognitive impairments. The TRS group performed the worst on general neurocognition (measured by the MATRICS Consensus Cognitive Battery) and social cognition (measured by the theory of mind and emotional expression). The RemSZ group performed the best among the three groups. Regarding autistic traits, all measurements by the Autism-Spectrum Quotient/Autism Screening Questionnaire/Pervasive Developmental Disorder Assessment Rating Scale showed that (1) the ASD patients had the highest autistic traits (2) the TRS patients' scores were less severe than the ASD group's, but (3) the overall trends placed the TRS group between the ASD and the RemSZ group. These findings indicate that TRS patients and remitted patients could have distinctive neurodevelopmental and cognitive profiles. Further, the degrees of social cognitive dysfunction and autistic traits in TRS patients could be close to those of ASD patients, suggesting similarities between TRS and ASD.

M16. PROFILING GLUTAMATE AND D-SERINE PATHWAYS IN TREATMENT RESISTANT EARLY PSYCHOSIS PATIENTS

BackgroundPharmacological, neurochemical and electrophysiological studies provide compelling evidence that N-methyl-D-aspartate-receptor (NMDAR) hypofunction is a pathologic feature of schizophrenia (SZ). GWAS studies highlighted risk genes such as Serine Racemase (SRR), which synthesizes D-Serine (D-Ser), the co-agonist of glycine site at NMDARs, and Serine Hydroxymethyltransferase (SHMT1) which synthesizes L-Serine (L-Ser), the substrate of SRR. Around 30% of patients do not respond to dopamine modulation and are considered to suffer from treatment resistant SZ (TRS). While the exact cause of TRS remains unclear, multiple lines of evidence suggest the involvement of a dysregulation of the Glutamate (Glu) neurotransmission. To test the hypothesis whether Glu system dysregulation mediated by NMDAR hypofunction is an underlying mechanism of TRS, we investigate the Glu and D-Ser pathways in TRS and treatment responder (RESP) early psychosis patients (EPP).MethodsFrom a total of 621 EPP aged 18 to 35, included in the TIPP (early Intervention Program in Lausanne, Baumann & al., 2013), 225 EPP were classified as TRS (n=33) or RESP (n=192) according to the strict Treatment Response and Resistance in Psychosis (TRRIP) criteria (Howes & al., 2017), with compliance ascertained by antipsychotic plasma levels. A matched healthy control (HC) group (N=114) was also recruited (DIGS criteria). No patient was taking clozapine at baseline. Clinical data was collected over a 3-year period. At baseline, following systems were assessed: 1) D-Ser pathway: plasmatic D-Ser, L-Ser and Glycine by HPLC (Hashimoto & al., 2016), protein levels of SRR and SHMT1 by ELISA; 2) Glu pathway: Glu and glutamine in plasma (HPLC) and prefrontal cortex (magnetic resonance spectroscopy, Xin & al., 2016).ResultsD-Ser pathway: in TRS, SRR levels were decreased by 56% as compared to RESP. Interestingly, we observed a positive correlation between plasma levels of D-Ser (SRR metabolite) and L-Ser (SRR substrate) in the TRS (r= 0.58; p =0.0015) but not in the RESP group, suggesting that SRR dysregulation might be a limiting factor in TRS patients. Moreover, in TRS patients, SHMT1 levels were decreased by 15% as compared to RESP, with a positive correlation between the substrate and metabolite of SHMT1, glycine and L-Ser (r =0.48; p =0.011). Dysregulation of SHMT1 might thus be a limiting factor in the TRS group. As compared to HC, L-Ser and D-Ser were significantly increased in patients (p <0.001 for L-Ser, p =0.0001 for D-Ser). However, no difference was observed in D-Ser, L-Ser and glycine in TRS as compared to RESP, although L-Ser tended to be higher in male TRS patients (p =0.06).Glu pathway: comparing TRS with RESP patients, plasma Glu levels were increased in the TRS group (p <0.0001), whereas they were higher in both patient groups compared to HC (p <0.0001). Interestingly, plasma and brain Glu levels showed a negative correlation in EPP, mostly driven by RESP (r = -0.42; p =0.035), a correlation which was absent in HC.Global Assessment of Functioning (GAF): at baseline, TRS and RESP displayed the same range of GAF. After a 3-year follow-up, TRS patients had poorer functioning as compared to RESP group (p <0.0001).DiscussionTaken together, our results suggest that the TRS group, in which the levels of SRR and SHMT1 were lower and Glu plasma levels were higher, display a different regulation of the synthesis, degradation and/or accumulation of D-Ser and Glu as compared to the RESP group. However, replication in larger groups is needed. Moreover, our findings highlighted a dysregulation of D-Ser and Glu pathways in TRS patients in their early phase of psychosis. On the clinical side, our results confirm the significantly poorer functioning outcome in TRS patients.

M139. DIFFERENTIAL PATTERNS OF BRAIN METABOLISM IN STABILIZED, ACTIVELY SYMPTOMATIC TREATMENT RESISTANT VS. TREATMENT RESPONDER SCHIZOPHRENIA PATIENTS: A STUDY BY 18F-FDG-POSITRON EMISSION TOMOGRAPHY AND STRUCTURAL 3T MRI

BackgroundSchizophrenia is a disabling psychiatric disease with a lifetime prevalence of 1%, which usually starts in late adolescence or initial adulthood and has a rare possibility of recovery. According to the extent of antipsychotic response, schizophrenia individuals can be divided into treatment resistant schizophrenia (TRS) and Treatment responders (non-TRS). Currently, it is unclear whether these categories belong to different biological and prognostic groups. Therefore, in order to deepen the knowledge of these conditions, we analyzed the cerebral metabolism of a sample of stabilized but still actively symptomatic TRS and non-TRS patients with substantial cognitive deficits.MethodsWe recruited 35 schizophrenia patients (18 TRS and 17 non-TRS) among approximately 80 consecutive non-affective psychotic patients, that were referred to our academic outpatient unit for supposed resistance to antipsychotics. The diagnosis of TRS was made by a structured diagnostic flowchart, according to published guidelines. Patients underwent a wide set of clinical and cognitive evaluations by trained raters. All patients who exhibited substantial cognitive deficits (at least two BACS/MATRICS items < than 1 - adjusted scores) and met inclusion/not met exclusion criteria were included in the neuroimaging study by 18F-fluorodeoxyglucose PET scans and structural 3T Magnetic Resonance Imaging. There were no statistically significant differences in age, chlorpromazine equivalents, and duration of illness between the TRS/non-TRS groups. Patients groups were matched with a control group. PET images were normalized on SPM template and then examined in visual and voxel-based analyses.ResultsGlobally, the visual analysis of the images showed a diffuse relative metabolic reduction in the cerebral cortex with prevalent frontal involvement in the majority of the patients of the TRS group and to a lesser extent in the non-TRS group. The voxel-per-voxel analysis revealed an extensive cluster of significant relative metabolic reduction in TRS patients compared to controls and to non-TRS patients (13653 voxels) localized bilaterally in the frontal cortex with a mild left prevalence. In particular, the metabolic reduction peaks involved the upper right and left medial frontal girder (BA6 and BA8, respectively), left opercular frontal (BA44), middle frontal girth (BA10) bilaterally, left lower frontal girth (BA47). Notably, at least three patients from the TRS group were excluded from the initial pool due to the observation of previously unrecognized structural brain anomalies.DiscussionIn this study, we observed that TRS patients had a relative hypometabolic state in dorsal and medial prefrontal cortex, including frontobasal areas, compared to controls and to non-TRS patients, while the striatum and the occipital cortex appeared relatively preserved. In non-TRS patients, brain distribution of 18F-FDG was more homogeneous and only slightly reduced in the cerebral cortex, as compared to controls.These patterns of brain metabolism cannot be associated with more severe cognitive dysfunctions in TRS patients since all patients included in the study had substantial cognitive impairments, irrespective of being TRS or non-TRS. Although it cannot be excluded that these differential patterns may stem from the lack of response to antipsychotics, our findings suggest distinct neurobiological alterations in TRS vs. non-TRS patients, which may include more relevant brain disconnections in non-responder ones.

M23. ALTERATION OF REGIONAL CEREBRAL BLOOD FLOW MEASURED BY ARTERIAL SPIN LABELING IN PATIENTS WITH TREATMENT-RESISTANT SCHIZOPHRENIA

BackgroundApproximately 30% of patients with schizophrenia do not respond to antipsychotics, which is called treatment-resistant schizophrenia (TRS). A recent systematic review showed decreased regional cerebral blood flow (rCBF) in the cerebral cortex and increased rCBF in the putamen in patients with schizophrenia. However, to date, no study has examined rCBF using arterial spin labeling (ASL) in patients with TRS. Thus, we compared rCBF between patients with TRS and those with non-TRS to investigate neural basis of this condition.MethodsWe acquired whole-brain rCBF measurements using 1.5T magnetic resonance imaging (MRI) with pseudo-continuous ASL in those with TRS and non-TRS. TRS was defined as 1) a Clinical Global Impression Severity (CGI-S) score of ≧ 4 (moderate) and 2) a score of ≧ 4 (moderate) on two Positive and Negative Syndrome Scale (PANSS) positive symptom items after optimal antipsychotic treatment. Non-TRS was defined as 1) a CGI-S score of ≦3, 2) scores of ≦ 3 on all positive symptom items of the PANSS, and 3) no symptomatic relapse during the previous 3 months. Optimal antipsychotic treatment was defined as ≧ 6 consecutive weeks with ≧ 400 mg of chlorpromazine (CPZ) equivalent daily dose antipsychotic treatment. The rCBF maps were subsequently derived from the proton-density-weighted reference images. Group differences in rCBF between the two groups (non-TRS vs. TRS) were tested using two sample t-test with age, gender, and PANSS positive scores as covariates. Multiple comparisons were corrected using familywise error (FWE) method with a significance threshold of P <.05.ResultsA total of 32 participants were included (13 TRS [6 females, age= 41.2±9.8, PANSS=80.3±9.7] and 19 non-TRS [6 females, age= 40.6±11.9, PANSS=58.9±10.0]). rCBF in the cerebellum was increased in the TRS group compared with the non-TRS group. In addition, there are inverse correlation between rCBF in the cerebellum and PANSS positive score in the non-TRS group.DiscussionThese preliminary results suggest that perfusion in the cerebellum may be implicated in the pathophysiology of TRS. This study will continue to enroll participants (our target sample is 30/each group). To identify the abnormal rCBF in patients with TRS will facilitate elucidating the pathophysiology of TRS and pave a way of developing novel treatment of this difficult-to-treat population.

T212. LEVELS OF GLUTAMATERGIC NEUROMETABOLITES IN PATIENTS WITH SEVERE TREATMENT-RESISTANT SCHIZOPHRENIA: A PROTON MAGNETIC RESONANCE SPECTROSCOPY STUDY

BackgroundApproximately 30% of patients with schizophrenia do not respond to antipsychotics and are thus considered to have treatment-resistant schizophrenia (TRS). To date, only four studies have examined glutamatergic neurometabolite levels using proton magnetic resonance spectroscopy (1H-MRS) in patients with TRS, collectively suggesting that glutamatergic dysfunction may be implicated in the pathophysiology of TRS. Notably, the TRS patient population in these studies had mild to moderate illness severity, which is not entirely reflective of what is observed in clinical practice.MethodsIn this present work, we compared glutamate+glutamine (Glx) levels in the dorsal anterior cingulate cortex (dACC) and caudate among patients with TRS, patients with non-TRS, and healthy controls (HCs), using 3T 1H-MRS (PRESS, TE=35ms). TRS criteria were defined by severe positive symptoms (i.e. ≥5 on 2 Positive and Negative Syndrome Scale (PANSS) positive symptom items or ≥4 on 3 PANSS positive symptom items) despite standard antipsychotic treatment.ResultsA total of 95 participants were included (29 TRS patients [PANSS=111.2±20.4], 33 non-TRS patients [PANSS=49.8±13.7], and 33 HCs). dACC Glx levels were higher in the TRS group versus HCs (group effect: F[2,75]=4.74, p=0.011; TRS vs. HCs: p=0.012). No group differences were identified in the caudate. There were no associations between Glx levels in these regions and clinical severity in either patient group.DiscussionOur results confirm that higher dACC Glx might be related to the pathophysiology underlying TRS, by demonstrating this phenomenon in a TRS patient population reflective of clinical practice.

White matter microstructural organizations in patients with severe treatment-resistant schizophrenia: A diffusion tensor imaging study

Previous diffusion tensor imaging (DTI) studies have reported white matter alterations in patients with schizophrenia. Notably, one third of this population does not respond to first-line antipsychotics and is thus referred to as treatment-resistant schizophrenia (TRS). Despite potentially distinct neural bases between TRS and non-TRS, few studies have compared white matter integrity between these groups. In order to reflect clinical picture of TRS, we enrolled TRS patients who had severe symptoms. According to the consensus criteria for TRS. TRS was defined by severe positive symptomatology despite optimal antipsychotic treatment. Fractional anisotropy (FA), an index of white matter integrity, was examined by DTI and analyzed with tract-based spatial statistics in 24 TRS patients (mean PANSS = 108.9), 28 non-TRS patients (mean PANSS = 50.0), and 27 healthy controls (HCs) for group comparison. Additionally, correlation analyses were conducted between FA values and symptomatology. The TRS group had lower FA values in multiple tracts (cerebral peduncle, corona radiata, corpus callosum, external and internal capsules, posterior thalamic radiation, sagittal stratum, superior longitudinal fasciculus, tapetum, and uncinate fasciculus) compared to the HC group as well as the non-TRS group (p < .05; family-wise error-corrected), while no differences were found between the non-TRS and HC groups. In the TRS group, FA values in most of the tracts (other than the left anterior limb of internal capsule, left cerebral peduncle, and right uncinate fasciculus) were negatively correlated with the Positive and Negative Syndrome Scale total scores, and negative and general symptom scores. No such relationships were found in the non-TRS group. The identified white matter integrity deficits may reflect the pathophysiology of TRS.

Frontostriatal Structural Connectivity and Striatal Glutamatergic Levels in Treatment-Resistant Schizophrenia: An Integrative Analysis of DTI and 1H-MRS

Abstract Given that approximately one-third of patients with schizophrenia do not respond to antipsychotics, different neurobiological bases may underlie treatment resistance in schizophrenia. Previous studies showed that treatment response is associated with both frontostriatal connectivity and glutamatergic neurometabolite levels in the caudate in patients with schizophrenia, which leads to the hypothesis that the relationship between them may be altered, specifically in patients with treatment-resistant schizophrenia (TRS). Employing analyses of covariance and subsequent partial correlation analyses, we compared the relationship between glutamate+glutamine (Glx) levels in the caudate and fractional anisotropy (FA) values in the tract between the dorsolateral prefrontal cortex and caudate in 19 patients with TRS, 20 patients responsive to first-line antipsychotics (FL-Resp), and 19 healthy controls (HCs). TRS was defined by severe positive symptomatology despite first-line antipsychotic treatment. Patients with TRS had lower FA values in the bilateral frontostriatal tracts than patients with FL-Resp and HCs (P &amp;lt; .001), while no group differences were found in caudate Glx levels. There was a significant frontostriatal FA value-by-group interaction on caudate Glx levels (F = 7.37, P = .009). Frontostriatal FA values positively correlated with caudate Glx levels in HCs (r = −.55, P = .028), while they were negatively associated with caudate Glx levels in the TRS group (r = .53, P = .043). Furthermore, in the FL-Resp group, frontostriatal FA values did not significantly correlated with caudate Glx levels. The altered relationship between white matter integrity and the glutamate system in the frontostriatal circuit in the TRS group may reflect the pathophysiology underlying treatment response/resistance in schizophrenia.

Levels of glutamatergic neurometabolites in patients with severe treatment-resistant schizophrenia: a proton magnetic resonance spectroscopy study.

Approximately 30% of patients with schizophrenia do not respond to antipsychotics and are thus considered to have treatment-resistant schizophrenia (TRS). To date, only four studies have examined glutamatergic neurometabolite levels using proton magnetic resonance spectroscopy (1H-MRS) in patients with TRS, collectively suggesting that glutamatergic dysfunction may be implicated in the pathophysiology of TRS. Notably, the TRS patient population in these studies had mild-to-moderate illness severity, which is not entirely reflective of what is observed in clinical practice. In this present work, we compared glutamate + glutamine (Glx) levels in the dorsal anterior cingulate cortex (dACC) and caudate among patients with TRS, patients with non-TRS, and healthy controls (HCs), using 3T 1H-MRS (PRESS, TE = 35 ms). TRS criteria were defined by severe positive symptoms (i.e., ≥5 on 2 Positive and Negative Syndrome Scale (PANSS)-positive symptom items or ≥4 on 3 PANSS-positive symptom items), despite standard antipsychotic treatment. A total of 95 participants were included (29 TRS patients [PANSS = 111.2 ± 20.4], 33 non-TRS patients [PANSS = 49.8 ± 13.7], and 33 HCs). dACC Glx levels were higher in the TRS group vs. HCs (group effect: F[2,75] = 4.74, p = 0.011; TRS vs. HCs: p = 0.012). No group differences were identified in the caudate. There were no associations between Glx levels and clinical severity in either patient group. Our results are suggestive of greater heterogeneity in TRS relative to non-TRS with respect to dACC Glx levels, necessitating further research to determine biological subtypes of TRS.