A comparison of neuropsychological dysfunction in first-episode psychosis patients with unipolar depression, bipolar disorder, and schizophrenia

The severity and profile of cognitive dysfunction in first episode schizophrenia and psychotic affective disorders were compared before and after antipsychotic treatment. Parallel recruitment of consecutively admitted study-eligible first-episode psychotic patients (30 schizophrenia, 22 bipolar with psychosis, and 21 psychotic depression) reduced confounds of acute and chronic disease/medication effects as well as differential treatment and course. Patient groups completed a neuropsychological battery and were demographically similar to healthy controls (n = 41) studied in parallel. Prior to treatment, schizophrenia patients displayed significant deficits in all cognitive domains. The two psychotic affective groups were also impaired overall, generally performing intermediate between the schizophrenia and healthy comparison groups. No profile differences in neuropsychological deficits were observed across patient groups. Following 6 weeks of treatment, no patient group improved more than practice effects seen in healthy individuals, and level of performance improvement was similar for affective psychosis and schizophrenia groups. Although less severe in psychotic affective disorders, similar profiles of generalized neuropsychological deficits were observed across patient groups. Recovery of cognitive function after clinical stabilization was similar in mood disorders and schizophrenia. To the extent that these findings are generalizable, neuropsychological deficits in psychotic affective disorders, like schizophrenia, may be trait-like deficits with persistent functional implications.     

Metacognition in psychosis: Comparison of schizophrenia with bipolar disorder

While deficits in metacognition have been observed in schizophrenia (SZ), it is less clear whether these are specific to the disorder. Accordingly, this study compared metacognitive abilities of patients with schizophrenia and bipolar disorder (BD) and examined the degree to which neurocognition contributed to metacognitive deficits in both groups. Participants were 30 patients with SZ and 30 with BD. Metacognitive capacity was measured using the Metacognition Assessment Scale Abbreviated (MAS-A). This scale comprises four domains: self-reflectivity, understanding others? minds, decentration and mastery. Verbal memory, executive functioning and symptoms were concurrently assessed. Group comparisons revealed that SZ patients had greater deficits in metacognitive self-reflectivity, which correctly classified 85.2% of patients with SZ in a logistic regression. Self-reflectivity and understanding others? minds were related to verbal memory and executive functioning in the SZ group, but not in the BD group. Furthermore, greater positive and general psychotic symptoms were associated with poorer metacognition in SZ. Results suggest SZ involves unique deficits in the ability to self-reflect and that these deficits may be uniquely linked with neurocognition.     

Pituitary volume in unaffected relatives of patients with schizophrenia and bipolar disorder

BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) axis hyperactivity has been demonstrated in both schizophrenia and bipolar disorder, but the mechanisms underlying this abnormality are still unclear. Enlarged pituitary volume has been recently reported in patients with first episode psychosis and been interpreted as a consequence of an increased activation of the HPA axis. The aim of this study was to assess the contribution of familial liability to pituitary volume in schizophrenia and bipolar disorder. Pituitary volume may be an indirect measure of HPA axis activity. METHODS: MRI brain scans and measurements of pituitary volumes were obtained for 183 subjects: 26 patients with established schizophrenia or schizoaffective disorder, 44 of their unaffected first-degree relatives (22 familial schizophrenia, 22 non-familial schizophrenia), 29 patients with established bipolar disorder, 38 of their unaffected first-degree relatives, and 46 healthy comparison subjects. RESULTS: We found a significantly larger pituitary volume (effect size=0.7) in unaffected relatives of patients with schizophrenia compared with controls (p=0.002); the pituitary was even larger in relatives of patients with familial schizophrenia (effect size=0.8, p=0.005). We did not find a significant difference in pituitary volume when comparing the relatives of bipolar patients with controls. Among patients, those with schizophrenia who were receiving prolactin-elevating antipsychotics had an increased pituitary volume compared with controls (effect size=1.0, p=0.006). CONCLUSIONS: These results suggest that the larger pituitary volume previously reported in first episode schizophrenia could be partly due to a genetic susceptibility to over-activate the HPA axis.     

Insights into myelin dysfunction in schizophrenia and bipolar disorder

Schizophrenia and bipolar disorder are disabling psychiatric disorders with a worldwide prevalence of approximately 1%. Both disorders present chronic and deteriorating prognoses that impose a large burden, not only on patients but also on society and health systems. These mental illnesses share several clinical and neurobiological traits; of these traits, oligodendroglial dysfunction and alterations to white matter (WM) tracts could underlie the disconnection between brain regions related to their symptomatic domains. WM is mainly composed of heavily myelinated axons and glial cells. Myelin internodes are discrete axon-wrapping membrane sheaths formed by oligodendrocyte processes. Myelin ensheathment allows fast and efficient conduction of nerve impulses through the nodes of Ranvier, improving the overall function of neuronal circuits. Rapid and precisely synchronized nerve impulse conduction through fibers that connect distant brain structures is crucial for higher-level functions, such as cognition, memory, mood, and language. Several cellular and subcellular anomalies related to myelin and oligodendrocytes have been found in postmortem samples from patients with schizophrenia or bipolar disorder, and neuroimaging techniques have revealed consistent alterations at the macroscale connectomic level in both disorders. In this work, evidence regarding these multilevel alterations in oligodendrocytes and myelinated tracts is discussed, and the involvement of proteins in key functions of the oligodendroglial lineage, such as oligodendrogenesis and myelination, is highlighted. The molecular components of the axo-myelin unit could be important targets for novel therapeutic approaches to schizophrenia and bipolar disorder.     

Prevalence of liver disease in veterans with bipolar disorder or schizophrenia

Objective

To assess the prevalence of three liver diseases [hepatitis C virus (HCV), nonalcoholic fatty liver disease and alcohol-induced cirrhosis] in patients (veterans) with/without schizophrenia/schizoaffective disorder and bipolar disorder.

Methods

A retrospective electronic chart review of Veterans Integrated Services Network 20 facilities from January 1, 2001 to December 21, 2006 selected patients to one of two groups: schizophrenia/schizoaffective disorder or bipolar disorder. Patients in both groups were compared with veterans in an equal-sized random sample from the same data set of veterans without psychiatric diagnoses. Logistic regression models evaluated risk for overall liver diseases as well as HCV, nonalcoholic fatty liver disease and alcoholic-induced cirrhosis.

Results

Patients with schizophrenia (n=6521) had a higher prevalence of liver disease [22.4% versus 3.2%; odds ratio (OR)=8.73]; HCV (16.5% versus 1.9%; OR=10.21); and alcohol-related cirrhosis (1.6% versus 0.4%; OR=4.09) than matched controls. Patients with bipolar disorder (n=5319) had a higher prevalence of liver disease (21.5% versus 3.5%; OR=7.58); HCV (15.5% versus 2.1%; OR=8.60); and alcohol-related cirrhosis (1.6% versus 0.4%; OR=3.82) than matched controls. Risk factors for liver disease in patients with schizophrenia (versus matched controls) included diabetes (OR=1.29), hypertension (OR=1.27), HIV (OR=3.54), substance use disorder (SUD) (OR=2.28), alcohol use disorder (OR=3.05) and schizophrenia (OR=2.74). Risk factors for development of liver disease for patients with bipolar disorder: diabetes (OR=1.40), HIV (OR=3.66), SUD (OR=2.68), alcohol use disorder (OR=3.22) and bipolar disorder (OR=2.27).

Conclusions

This study in veterans shows that the presence of mental illness and its comorbidities represents a significant risk factor for the diagnosis of liver disease, including HCV and alcohol-related cirrhosis.     

Plasma cortisol-dehydroepiandrosterone (DHEA) ratios in schizophrenia and bipolar disorder

Hypercortisolaemia is a feature of many severe psychiatric illnesses and has been suggested to be both a causal and exacerbating factor of clinical symptoms and neurocognitive impairment. The adrenal steroid dehydroepiandrosterone (DHEA) has antiglucocorticoid properties that may have regulatory effects on glucocorticoid action in the brain. However, there is a paucity of data on these steroids and their ratio in schizophrenia and bipolar disorder. We therefore sought to assess cortisol and DHEA levels and the cortisol-DHEA ratio in patients with schizophrenia (n = 20) and bipolar disorder (n = 20), on stable medication for a minimum of 6 weeks, and healthy age- and sex-matched control subjects (n = 20). Steroid levels were measured from plasma samples collected at 30 min intervals from 1:00 p.m. to 4:00 p.m. Cortisol levels were found to be significantly elevated in both patient groups compared with controls. DHEA levels were elevated in schizophrenic patients compared with bipolar patients and controls, but there was no evidence of a difference in the cortisol-DHEA ratio of the groups. These data suggest that afternoon hypercortisolaemia is evident in symptomatic bipolar and schizophrenic patients compared to controls. However, an elevation in DHEA levels may represent a specific endocrine marker in schizophrenia.     

Temperament and character dimensions in bipolar I disorder: a comparison to healthy controls

Research on phenotypic markers of vulnerability to bipolar disorder has focused on the identification of personality traits uniquely associated with the illness. To expand knowledge in this area, we compared Cloninger's seven temperament and character dimensions in 85 euthymic/subsyndromal bipolar I inpatients and outpatients and 85 age and sex matched community controls. We also examined associations between Cloninger's personality traits and mood state in the patient group. Bipolar subjects were administered the Structured Clinical Interview for DSM-IV (SCID), Hamilton Rating Scale for Depression, and Clinician-Administered Rating Scale for Mania. Controls received the SCID, a family psychiatric history questionnaire, and urine toxicology screen to confirm healthy status. Both groups competed the 240-item Temperament and Character Inventory (TCI). A multivariate analysis of covariance, accounting for demographic factors, was conducted to compare the groups on the TCI. Bipolar I patients scored higher on harm avoidance, lower on self-directedness, and higher on self-transcendence compared to controls. Harm avoidance and self-directedness were correlated with residual depressive symptoms positively and negatively, respectively; persistence was correlated with residual manic symptoms; and selftranscendence was correlated with residual psychotic symptoms in patients. The results indicate that bipolar I subjects do possess personality traits that are significantly different from non-ill individuals. However, only a prospective, longitudinal study may determine whether these traits mark a vulnerability to the disorder, or represent the scarring effect of affective episodes and chronic subsyndromal symptoms.     

住院双相障碍与精神分裂症患者自知力水平的保护性因素

目的 探讨住院双相障碍与精神分裂症患者自知力水平及其保护性因素。方法 在广州市4家精神科住院部连续入组符合《国际疾病分类（第10版）》（ICD-10）双相障碍或精神分裂症诊断标准的患者465例。采用自编人口学及临床特征问卷、自知力与治疗态度问卷（ITAQ）进行调查,比较不同自知力水平患者的人口学和临床特征,采用两分类Logistic回归分析探讨自知力的保护因素。结果 年龄小（OR=0.977）、男性（OR=1.705）、曾经结婚或同居（OR=1.677）、诊断为双相障碍（OR=2.185）、最近一个月有悲观厌世（OR=2.663）、每天睡眠时间≥7小时（OR=1.620）、每周运动1~2次（OR=1.770）是住院双相障碍和精神分裂症患者自知力的保护因素。结论 住院双相障碍和精神分裂症患者自知力水平与多种人口学特征及临床特征相关。     

Cross-diagnostic comparison of visual processing in bipolar disorder and schizophrenia

Patients with Schizophrenia (SZ) show deficits across various stages of visual information processing. Whether patients with Bipolar Disorder (BD) exhibit these deficits is unclear. In this study, we conducted a detailed comparison of specific stages of early visual perception in BD and SZ. Forty-three BD patients, 43 SZ patients, and 51 matched healthy control subjects (HC) were administered three visual processing paradigms emphasizing: 1) an early stage of object formation (location backward masking), 2) a middle stage of object substitution (four-dot backward masking), and 3) a later stage at the perception–attention interface (rapid serial visual processing (RSVP) task eliciting the attentional blink). SZ performed significantly worse than BD and HC on location and four-dot masking. BD did not significantly differ from HC on either masking task. Both patient groups performed significantly worse than HC on the RSVP task; unlike SZ, BD did not show a significant attentional blink effect compared to HC. Our results indicate that BD patients were intact at the early and middle stages of visual processing (object formation and substitution) but intermediate between the SZ and HC groups at a later processing stage involving perceptual and attentional processes (RSVP task). These findings suggest that SZ is characterized by a diffuse pathophysiology affecting all stages of visual processing whereas in BD disruption is only at the latest stage involving higher order attentional functions.     

Heart disease treatment and mortality in schizophrenia and bipolar disorder - Changes in the danish population between 1994 and 2006

Persons with schizophrenia and bipolar disorder have much higher heart disease mortality rates than the general population. The objective was to compare the general population with persons with schizophrenia, bipolar disorder or other psychiatric disorders in terms of rates of somatic hospitalization and invasive heart disease procedures, and in terms of heart disease mortality during the period 1994 to 2006. Survival analysis was used to analyze heart disease mortality and somatic care trends in a cohort of all persons residing in Denmark. During the study period, heart disease mortality rose significantly among persons with schizophrenia: compared with the general population, the rise in the mortality rate ratio equalled 1.12 (95% confidence interval (CI) 1.08-1.15) every second year. This was not the case for persons with bipolar disorder [1.02 (0.98-1.05), not significant] or other psychiatric disorders [1.00 (0.99-1.01), not significant]. The entire period saw a lower hospitalization rate and fewer invasive cardiac procedures among persons with schizophrenia than among the general population. The higher mortality (with increasing trends) from heart disease in persons with schizophrenia compared to the rest of the cohort members can be explained partly by low rates of invasive cardiac procedures. However, other reasons, such as antipsychotic-induced weight gain, primary prevention, and difficulty following smoking cessation advice could also be part of the explanation. The results call for a greater focus on improvement in somatic care and lifestyle factors for this group of patients.     

Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia

Bipolar disorder (BPD) and schizophrenia (SZ) are severe psychiatric illnesses with a combined prevalence of 4%. A disturbance of energy metabolism is frequently observed in these disorders. Several pieces of evidence point to an underlying dysfunction of mitochondria: (i) decreased mitochondrial respiration; (ii) changes in mitochondrial morphology; (iii) increases in mitochondrial DNA (mtDNA) polymorphisms and in levels of mtDNA mutations; (iv) downregulation of nuclear mRNA molecules and proteins involved in mitochondrial respiration; (v) decreased high-energy phosphates and decreased pH in the brain; and (vi) psychotic and affective symptoms, and cognitive decline in mitochondrial disorders. Furthermore, transgenic mice with mutated mitochondrial DNA polymerase show mood disorder-like phenotypes. In this review, we will discuss the genetic and physiological components of mitochondria and the evidence for mitochondrial abnormalities in BPD and SZ. We will furthermore describe the role of mitochondria during brain development and the effect of current drugs for mental illness on mitochondrial function. Understanding the role of mitochondria, both developmentally as well as in the ailing brain, is of critical importance to elucidate pathophysiological mechanisms in psychiatric disorders.     

Improvements in metabolic abnormalities among overweight schizophrenia and bipolar disorder patients

PurposeAs weight-gain and metabolic abnormalities during treatment with psychotropic drugs are of great concern, we evaluated effects of psycho-education and medical monitoring on metabolic changes among severely mentally ill patients.Materials and methodsDuring repeated, systematic psycho-education about general health among 66 consecutive patients diagnosed with DSM-IV-TR schizophrenia (n = 33) or type-I bipolar disorder (n = 33), we evaluated (at intake 1, 2, 3, and 6 months) clinical psychiatric status, treatments and doses, recorded physiological parameters, and assessed attitudes about medication.ResultsAt intake, patients with schizophrenia vs bipolar disorder were receiving 3–7 times more psychotropic medication, with 14% higher initial body-mass index (BMI: 29.1 vs 25.6 kg/m2), 12 times more obesity, and significantly higher serum lipid concentrations. During 6-months follow-up, among bipolar disorder patients, polytherapy and serum lipid concentrations declined more than among schizophrenia patients (e.g., total cholesterol + triglycerides, by 3.21 vs 1.75%/month). BMI remained stable. Declining lipid levels were associated with older age, bipolar disorder, being unemployed, higher antipsychotic doses, and lower initial BPRS scores (all P ≤ 0.001).ConclusionsPsychotropic treatments were more complex, and metabolic measures more abnormal among bipolar disorder than schizophrenia patients. Intensive psycho-education, clinical monitoring, and encouragement of weight-control for six months were associated with improvements in metabolic measures (but not to BMI), and more realistic attitudes about medication.     

Personality in relation to genetic liability for schizophrenia and bipolar disorder: Differential associations with the COMT ValMet polymorphism

Schizophrenia and bipolar disorder may share aspects of genetic etiology. Evidence supports the Val^108/158Met polymorphism of the Catechol-o-Methyltransferase (COMT) gene as potentially contributing to the etiology of both disorders. To determine whether the COMT gene is associated with personality traits related to genetic risk for either schizophrenia or bipolar disorder, we examined dimensions of personality psychopathology in biological relatives of individuals with the disorders. Specifically, we contrasted personality characteristics of first-degree relatives of people with schizophrenia, first-degree relatives of people with bipolar-I disorder, and nonpsychiatric control participants using scores from the Dimensional Assessment of Personality Pathology-Brief Questionnaire (DAPP-BQ). We also characterized the COMT Val^108/158Met polymorphism of subjects. Compared to controls, relatives of schizophrenia patients scored lower on stimulus seeking and higher on restrictive expression and social avoidance. Compared to relatives of bipolar patients, relatives of schizophrenia patients had lower scores on narcissism, rejectionality (i.e., rejection of ideas of others), stimulus seeking, passive-aggressive oppositionality, and self-harm. The subset of relatives of schizophrenia patients who were COMT val homozygotes exhibited lower scores on narcissism, rejectionality, and stimulus seeking than met homozygote relatives of schizophrenia patients and control participants. Although relatives of bipolar patients showed scale elevations consistent with emotional dysregulation, the scores failed to be associated with the Val^108/158Met polymorphism. Abnormally low narcissism and rejectionality in val homozygote relatives of schizophrenia patients suggests that the val allele of the COMT polymorphism may be associated with an underdeveloped self-concept phenomenologically similar to made volition and passivity experiences comprising first-rank symptoms of schizophrenia.     

Resting state EEG power and coherence abnormalities in bipolar disorder and schizophrenia

Resting state electroencephalogram (EEG) abnormalities in schizophrenia and bipolar disorder patients suggest alterations in neural oscillatory activity. However, few studies directly compare these anomalies between patient groups, and none have examined EEG coherence. Therefore, this study investigated whether these electrophysiological characteristics differentiate clinical populations from one another, and from non-psychiatric controls. To address this question, resting EEG power and coherence were assessed in 76 bipolar patients (BP), 132 schizophrenia patients (SZ), and 136 non-psychiatric controls (NC). We conducted separate repeated-measures ANOVAs to examine group differences within seven frequency bands across several brain regions. BP showed significantly greater power relative to SZ at higher frequencies including Beta and Gamma across all regions. In terms of intra-hemispheric coherence, while SZ generally exhibited higher coherence at Delta compared to NC and BP, both SZ and BP showed higher coherence at Alpha1 and Alpha2. In contrast, BP and HC showed higher coherence within hemispheres compared to SZ at Beta 1. In terms of inter-hemispheric coherence, SZ displayed higher coherence compared to NC at temporal sites at both Alpha1 and Alpha2. Taken together, BP exhibited increased high frequency power with few disruptions in neural synchronization. In contrast, SZ generally exhibited enhanced synchronization within and across hemispheres. These findings suggest that resting EEG can be a sensitive measure for differentiating between clinical disorders.     

Mitochondrial activity and oxidative stress markers in peripheral blood mononuclear cells of patients with bipolar disorder,schizophrenia, and healthy subjects

Evidence suggests that mitochondrial dysfunction is involved in the pathophysiology of psychiatric disorders such as schizophrenia (SZ) and bipolar disorder (BD). However, the exact mechanisms underlying this dysfunction are not well understood. Impaired activity of electron transport chain (ETC) complexes has been described in these disorders and may reflect changes in mitochondrial metabolism and oxidative stress markers. The objective of this study was to compare ETC complex activity and protein and lipid oxidation markers in 12 euthymic patients with BD type I, in 18 patients with stable chronic SZ, and in 30 matched healthy volunteers. Activity of complexes I, II, and III was determined by enzyme kinetics of mitochondria isolated from peripheral blood mononuclear cells (PBMCs). Protein oxidation was evaluated using the protein carbonyl content (PCC) method, and lipid peroxidation, the thiobarbituric acid reactive substances (TBARS) assay kit. A significant decrease in complex I activity was observed (p = 0.02), as well as an increase in plasma levels of TBARS (p = 0.00617) in patients with SZ when compared to matched controls. Conversely, no significant differences were found in complex I activity (p = 0.17) or in plasma TBARS levels (p = 0.26) in patients with BD vs. matched controls. Our results suggest that mitochondrial complex I dysfunction and oxidative stress play important roles in the pathophysiology of SZ and may be used in potential novel adjunctive therapy for SZ, focusing primarily on cognitive impairment and disorder progression.     

The effects of DISC1 risk variants on brain activation in controls, patients with bipolar disorder and patients with schizophrenia

Three risk variants (rs1538979, rs821577, and rs821633) in the Disrupted-in-Schizophrenia-1 (DISC1) gene have previously been associated with both schizophrenia and bipolar disorder in a recent collaborative analysis of European cohorts. In this study we examined the effects of these risk variants on brain activation during functional magnetic resonance imaging (fMRI) of the Hayling Sentence Completion Task (HSCT) in healthy volunteers (n = 33), patients with schizophrenia (n = 20) and patients with bipolar disorder (n = 36). In the healthy controls the risk associated allele carriers of SNPs rs1538979 and rs821633 demonstrated decreased activation of the cuneus. Moreover, there was an effect of SNP rs1538979 in the pre/postcentral gyrus with decreased activation in healthy controls and increased activation in patients with schizophrenia. In the bipolar group there was decreased activation in the risk carriers of SNP rs821633 in the inferior parietal lobule and left cingulate cortex. Clusters in the precentral gyrus, left middle temporal gyrus and left cerebellum were found to be significant on examining the group × genotype interactions. These findings may provide a better understanding of the neural effects of DISC1 variants and on the pathophysiology of schizophrenia and bipolar disorder.     

Systematic review of appropriate cognitive assessment instruments used in clinical trials of schizophrenia,major depressive disorder and bipolar disorder

Cognitive dysfunction is increasingly recognized as a symptom in mental conditions including schizophrenia, major depressive disorder (MDD), and bipolar disorder (BPD). Despite the many available cognitive assessment instruments, consensus is lacking on their appropriate use in clinical trials. We conducted a systematic literature review in Embase, PubMed/Medline and PsychINFO to identify appropriate cognitive function instruments for use in clinical trials of schizophrenia, MDD, and BPD. Instruments were identified from the articles. Instruments and articles were excluded if they did not address schizophrenia, MDD, or BPD. Instrument appropriateness was further assessed by the criteria of the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative: test–retest reliability, utility, relationship to functional status, potential changeability to pharmacological agents, and tolerability and practicality for clinical trials. The database search yielded 173 articles describing 150 instruments used to assess cognitive function. Seventeen additional instruments were identified through Google and clinicaltrials.gov. Among all these, only 30 (18%) were deemed appropriate for use in the diseases of interest. Of these, 27 were studied in schizophrenia, one in MDD and two in BPD. These findings suggest the need for careful selection of appropriate cognitive assessment instruments, as not all may be valid in these disorders.     

Influence of TPH2 variants on diagnosis and response to treatment in patients with major depression, bipolar disorder and schizophrenia

The present study is aimed at exploring whether some single nucleotide polymorphisms (SNPs) within the tryptophan hydroxylase 2 gene (TPH2) could be associated with major depression (MD), bipolar disorder (BD) and schizophrenia and whether they could predict clinical outcomes in Korean in-patients treated with antidepressants, mood stabilizers and antipsychotics, respectively. One hundred forty-five patients with MD, 132 patients with BD, 221 patients with schizophrenia and 170 psychiatrically healthy controls were genotyped for six TPH2 SNPs (rs4570625, rs10748185, rs11179027, rs1386498, rs4469933, and rs17110747). Baseline and final clinical measures, including the Montgomery-Åsberg Depression Rating Scale (MADRS), Young Mania Rating Scale and Positive and Negative Syndrome Scale, for patients with MD, BD and schizophrenia, respectively were recorded. None of the SNPs under investigation were associated with MD, BD and schizophrenia. However, in patients with MD, the rs4570625-rs10748185 G-A haplotype was significantly associated with higher endpoint MADRS severity, though not with response. Our results suggest that TPH2 variants neither have a major role in MD, BD and schizophrenia nor in response to treatments.