[Historical Development of Symptomatology in Psychosis with Reference to Pathogenesis].

The role of mental symptomatology is to describe various clinical symptoms without refer- ring to their pathogenesis. This may be because of the influence of K. Jasper's General Psycho- pathology. However, from the mid-19th to early 20th century, when modern psychiatry was estab- lished, some excellent hypotheses concerning the pathogenesis of mental symptoms were pro- posed, although it was difficult to verify these hypotheses because of technical limitations. The purpose of this article was to review the historical development of symptomatology in psycho- sis with reference to the pathogenesis. W. Griesinger (1845, 1861) distinguished between the etiology and pathogenesis of a disease, and stated that every mental disease is a manifestation of brain disease. Subsequent investigators elaborated on this view : C. Wernicke (1894, 1906) proposed the disconnection of the association tracts, and P. Flechsig (1894, 1920) regarded the late myelinating "association areas"' (this term was from Flechsig) as the field of the mind. J. H. Jackson (1895) proposed the evolutionary and hierarchical organization of the nervous system. E. Kraepelin (1913) speculated on the hypoactivity of the frontal cortex-the highest cerebral centers according to Jackson's terminology-and hyperactivity of the temporal speech cortex as the pathogenesis of psychotic symptoms in dementia praecox, which were found to be the case based on neuroimaging methods over sixty years later. Currently, the pathogenesis of mental symptoms is being investigated from the viewpoint of the dysfunctions of neural cir- cuits, such as cortico-limbic, cortico-thalamic, or cortico-striatal circuitry.

Neonatal exposure to MK-801 reduces mRNA expression of mGlu3 receptors in the medial prefrontal cortex of adolescent rats.

Schizophrenia is considered as a "neurodegenerative" and "neurodevelopmental" disorder, the pathophysiology of which may include hypofunction of the N-methyl-D-aspartate receptor (NMDA-R) or subsequent pathways. Accordingly, administration of NMDA-R antagonists to rodents during the perinatal period may emulate some core pathophysiological aspects of schizophrenia. The effect of 4-day (postnatal day; PD 7-10) administration of MK-801, a selective NMDA-R antagonist, on gene expression in the medial prefrontal cortex (mPFC), hippocampus, and amygdala was evaluated using quantitative polymerase chain reaction methods. Specifically, we sought to determine whether genes related to Glu transmissions, for example those encoding for NMDA-Rs, metabotropic Glu receptors (mGluRs), or Glu transporters, were altered by neonatal treatment with MK-801. Model rats showed downregulation of the mGluR3 subtype in the mPFC around puberty, especially at PD 35 in response to MK-801 or during ontogenesis without pharmacological manipulations. Genes encoding for other mGluRs subtypes, that is NMDA-Rs and Glu transporters, were not affected by the neonatal insult. These results suggest that NMDA-R antagonism in the early course of development modulates the expression of mGluR3 in mPFC around puberty. Thus, mGluR3 may serve as a potential target to prevent the onset and progression of schizophrenia.

[Early intervention practice in Toyama Prefecture: efforts to improve the clinical service].

We report our activity in the Consultation and Support Service in Toyama (CAST), a clinical service provided by the collaboration of Toyama Prefectural Mental Health Center and University Hospital of Toyama(UHT). About 23% of users diagnosed with at-risk mental state (ARMS), during October 2006 until March 2012, transitioned to overt schizophrenia. More than half of the subjects who continued to visit the specialized clinic in UHT were treated with antipsychotic drugs. We encountered a case of schizophrenia in which early treatment with an atypical psychotic drug was effective in normalizing cognitive function and achieving a good social consequence. The ability of mismatch negativity, an event-related potential, to predict progression to psychosis in subjects with ARMS is discussed. Further efforts should be directed towards improving long-term outcomes, such as social function, for users of the CAST.

Longitudinal MRI study of the pituitary volume in chronic schizophrenia: a preliminary report.

This longitudinal MRI study investigated the pituitary volume in 17 patients with chronic schizophrenia and 17 matched controls. In contrast to previous findings of pituitary expansion during the first episode of schizophrenia, the chronic patients showed non-significant mild pituitary atrophy, suggesting that the pituitary volume changes differently at different illness stages.

Relationships between exploratory eye movement dysfunction and clinical symptoms in schizophrenia.

AIM: Many psychophysiological tests have been widely researched in the search for a biological marker of schizophrenia. The exploratory eye movement (EEM) test involves the monitoring of eye movements while subjects freely view geometric figures. Suzuki et al. (2009) performed discriminant analysis between schizophrenia and non-schizophrenia subjects using EEM test data; consequently, clinically diagnosed schizophrenia patients were identified as having schizophrenia with high probability (73.3%). The aim of the present study was to investigate the characteristics of schizophrenia patients who were identified as having schizophrenia on EEM discriminant analysis (SPDSE) or schizophrenia patients who were identified as not having schizophrenia on EEM discriminant analysis (SPDNSE). METHODS: The data for the 251 schizophrenia subjects used in the previous discriminant-analytic study were analyzed, and the demographic or symptomatic characteristics of SPDSE and SPDNSE were investigated. As for the symptomatic features, a factor analysis of the Brief Psychiatric Rating Scale (BPRS) rating from the schizophrenia subjects was carried out. RESULTS: Five factors were found for schizophrenia symptoms: excitement/hostility; negative symptoms; depression/anxiety; positive symptoms; and disorganization. SPDSE had significantly higher factor scores for excitement/hostility, negative symptoms and disorganization than SPDNSE. Furthermore, the BPRS total score for the SPDSE was significantly higher than that for the SPDNSE. CONCLUSION: SPDSE may be a disease subtype of schizophrenia with severe symptoms related to excitement/hostility, negative symptoms and disorganization, and EEM parameters may detect this subtype. Therefore, the EEM test may be one of the contributors to the simplification of the heterogeneity of schizophrenia.

Development and validation of a scale of self-alienation-related attributes for the early diagnosis of schizophrenia.

BACKGROUND: The onset of schizophrenia is often preceded by a prodromal phase. However, it is difficult to predict the future transition to schizophrenia from the prodromal symptoms. Based on the diagnostic significance of Schneider's first rank symptoms (FRS), especially those representing "ego disorders (Ichstörungen)", we developed a scale of self-alienation-related attributes (Self-A) to assess the psychological characteristics associated with ego disorders for the early diagnosis of schizophrenia. METHODS: In total, 153 schizophrenia (Sz) patients, 83 at-risk mental state (ARMS) subjects, and 154 healthy control (HC) subjects participated in this study. The Self-A scale was constructed by items from the Minnesota Multiphasic Personality Inventory (MMPI) based on the differences between schizophrenia patients with and without FRS representing ego-disorders designated as "self-alienation symptoms". The Self-A scale was tested for its reliability and validity in a different sample of schizophrenia patients, and was then applied to different cohorts including first-episode schizophrenia (FES) patients, ARMS individuals, and HC subjects. RESULTS: The Self-A consisting of 27 items exhibited good internal consistency reliability. The validity was well demonstrated by the high correlation of the Self-A scores with the self-alienation symptom scores. The ARMS and FES groups had higher Self-A scores than the HC group. The Self-A score in the ARMS individuals who later developed schizophrenia was higher than that in the ARMS subjects who did not, and was comparable with that in the FES group. CONCLUSIONS: This study suggests that the newly developed Self-A scale assessing the self-alienation-related attributes can improve the early diagnosis of schizophrenia.

Apocynin-Tandospirone Derivatives Suppress Methamphetamine-Induced Hyperlocomotion in Rats with Neonatal Exposure to Dizocilpine.

Accumulating evidence implicates oxidative stress as a potential pathophysiological mechanism of schizophrenia. Accordingly, we synthesized new chemicals using apocynin and tandospirone as lead compounds (A-2, A-3 and A-4). These novel compounds decreased reactive oxygen species (ROS) concentrations in vitro and reversed decreases in glutathione levels in the medial prefrontal cortex of rats transiently exposed to MK-801, an N-methyl-d-aspartate receptor antagonist, in the neonatal period. To determine whether A-2, A-3 and A-4 show behavioral effects associated with antipsychotic properties, the effects of these compounds on methamphetamine (MAP)-induced locomotor and vertical activity were examined in the model rats. A-2 and A-3, administered for 14 days around the puberty period, ameliorated MAP-induced hyperlocomotion in MK-801-treated rats in the post-puberty period, while A-4 suppressed MAP-induced vertical activity. These findings indicate that apocynin-tandospirone derivatives present anti-dopaminergic effects and may alleviate psychotic symptoms of schizophrenia.

Membrane fatty acid levels as a predictor of treatment response in chronic schizophrenia.

Abnormal fatty acid composition in neural membranes, that is, the balance between essential polyunsaturated fatty acids (EPUFAs) and saturated fatty acids, has been suggested to be related to the psychotic symptoms and cognitive impairment of schizophrenia. This study was conducted to test the hypothesis that the ability of atypical antipsychotic drugs to ameliorate positive symptoms and cognitive function relevant to daily living would be predicted by baseline EPUFAs concentrations in the erythrocyte membrane in subjects with schizophrenia. A total of 24 actively psychotic patients with schizophrenia participated in the study. After blood drawing, they were treated with olanzapine or perospirone. The Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for Assessment of Negative symptoms (SANS), as well as the script tasks, a measure of event schema recognition, were administered at baseline and 3months after the start of treatment. Erythrocyte membrane fatty acid levels were analysed using a gas chromatography system. Scores of SAPS and SANS, as well as script task performance, were improved during treatment with either antipsychotic drug. Regression analysis indicates baseline EPUFAs concentrations were positively and negatively related with percent improvement of positive symptoms and script task performance, respectively. The results of this study suggest composition of phospholipids in the erythrocyte membrane provide a feasible marker to predict treatment response in patients with schizophrenia.

Useful visual field in patients with schizophrenia: a choice reaction time study.

This study examined the size of the useful visual field in patients (9 men, 6 women) with schizophrenia. A choice reaction task was conducted, and performances at 2.5, 5, 7, 10, and 25 degrees in both visual fields were measured. Three key findings were shown. First, patients had slower choice reaction times (choice RTs) than normal controls. Second, patients had slower choice RTs in the right visual field than in the left visual field. Third, patients and normal controls showed the same U-shaped choice RT pattern. The first and second findings were consistent with those of other studies. The third finding was a clear indication of the patients' performance in peripheral vision, and a comparison with normal controls suggested that there was no difference in the size of the useful visual field, at least within

Change in the expression of myelination/oligodendrocyte-related genes during puberty in the rat brain.

Age-dependent changes of gene expression in the prefrontal cortex (PFC) of rats around the time of puberty were investigated by means of microarray and quantitative polymerase chain reaction (qPCR). About 127 and 138 genes were increased and decreased, respectively, in the PFC of rats at post-puberty (PD56) compared with those at pre-puberty (PD35). Functional analysis showed significant associations of these genes with aging, cellular development, and neuropsychological disorders. qPCR analysis confirmed down-regulation of seven genes related to myelination. As these genes have been reported to be diminished in the brain of patients with schizophrenia, the results of this study suggest an exaggerated maturation process may contribute to the pathogenesis of psychotic disorders.

Increased pituitary volume in schizophrenia spectrum disorders.

While hypothalamic-pituitary-adrenal (HPA) axis hyperactivity has been implicated in psychotic disorders, previous magnetic resonance imaging (MRI) studies of the pituitary gland volume in schizophrenia have yielded controversial results. It is also unknown whether patients with schizophrenia spectrum such as schizotypal disorder exhibit pituitary volume changes. In this study, we investigated the pituitary volume using MRI in 47 schizotypal disorder patients (29 males, mean age=25.0 years), 72 schizophrenia patients (38 males, mean age=26.2 years), and 81 age and gender matched healthy controls (46 males, mean age=24.5 years). Both patient groups had a larger pituitary volume compared with controls, but no difference was found between the schizophrenia and schizotypal patients. The pituitary volume was larger in females than in males for all diagnostic groups. There was no association between the pituitary volume and type (typical versus atypical), daily dosage, or duration of antipsychotic medication in either patient group. These findings are consistent with a stress-diathesis model of schizophrenia and further suggest that the schizotypal patients share HPA axis hyperactivity with young established schizophrenia patients reflecting a common vulnerability to stress within the schizophrenia spectrum.

Effect of perospirone on P300 electrophysiological activity and social cognition in schizophrenia: a three-dimensional analysis with sloreta.

The purpose of this study was to determine if perospirone, a second generation antipsychotic drug and partial agonist at serotonin-5-HT(1A) receptors, enhances electrophysiological activity, such as event-related potentials (ERPs), in frontal brain regions, as well as cognitive function in subjects with schizophrenia. P300 current source images were obtained by means of standardized low resolution brain electromagnetic tomography (sLORETA) before and after treatment with perospirone for 6 months. Perospirone significantly increased P300 current source density in the left superior frontal gyrus, and improved positive symptoms and performance on the script tasks, a measure of verbal social cognition, while verbal learning memory tended to be improved. There was a significant correlation between the changes in P300 amplitude on the left frontal lead and those in social cognition. These results suggest the changes in three-dimensional distribution of cortical activity, as demonstrated by sLORETA, may mediate some of the actions of antipsychotic drugs. The distinct cognition-enhancing profile of perospirone in patients with schizophrenia may be related to its actions on 5-HT(1A) receptors.

The Disrupted-in-Schizophrenia-1 Ser704Cys polymorphism and brain morphology in schizophrenia.

The Disrupted-in-Schizophrenia-1 (DISC1) polymorphism is a strong candidate for a schizophrenia-susceptibility gene as it is widely expressed in cortical and limbic regions, but the effect of its genotype variation on brain morphology in schizophrenia is not well known. This study examined the association between the DISC1 Ser704Cys polymorphism and volumetric measurements for a broad range of fronto-parietal, temporal, and limbic-paralimbic regions using magnetic resonance imaging in a Japanese sample of 33 schizophrenia patients and 29 healthy comparison subjects. The Cys carriers had significantly larger volumes of the medial superior frontal gyrus and short insular cortex than the Ser homozygotes only for healthy comparison subjects. The Cys carriers tended to have a smaller supramarginal gyrus than the Ser homozygotes in schizophrenia patients, but not in healthy comparison subjects. The right medial superior frontal gyrus volume was significantly correlated with daily dosage of antipsychotic medication in Ser homozygote schizophrenia patients. These different genotype effects of the DISC1 Ser704Cys polymorphism on the brain morphology in schizophrenia patients and healthy comparison subjects suggest that variation in the DISC1 gene might be, at least partly, involved in the neurobiology of schizophrenia. Our findings also suggest that the DISC1 genotype variation might have some relevance to the medication effect on brain morphology in schizophrenia.

Exploratory eye movement dysfunction as a discriminator for schizophrenia : a large sample study using a newly developed digital computerized system.

In our previous studies, we identified that exploratory eye movement (EEM) dysfunction appears to be specific to schizophrenia. The availability of a biological marker specific to schizophrenia would be useful for clinical diagnosis of schizophrenia. Consequently, we performed the discriminant analysis between schizophrenics and non-schizophrenics on a large sample using the EEM test data and examined an application of the EEM for clinical diagnosis of schizophrenia. EEM performances were recorded in 251 schizophrenics and 389 non-schizophrenics (111 patients with mood disorders, 28 patients with neurotic disorders and 250 normal controls). The patients were recruited from eight university hospitals and three affiliated hospitals. For this study with a large sample, we developed a new digital computerized version of the EEM test, which automatically handled large amounts of data. We measured four parameters: number of eye fixations (NEF), total eye scanning length (TESL), mean eye scanning length (MESL) and responsive search score (RSS). These parameters of schizophrenics differed significantly from those of the other three groups. The stepwise regression analysis selected the TESL and the RSS as the valid parameters for discriminating between schizophrenics and non-schizophrenics. In the discriminant analysis using the RSS and TESL as prediction parameters, 184 of the 251 clinically diagnosed schizophrenics were discriminated as having schizophrenia (sensitivity 73.3%); and 308 of the 389 clinically diagnosed non-schizophrenic subjects were discriminated as non-schizophrenics (specificity 79.2%). Based on our findings we believe that the EEM measures may be useful for the clinical diagnosis of schizophrenia.

The effects of cognitive rehabilitation on social knowledge in patients with schizophrenia.

This study examined the extent to which cognitive rehabilitation alleviates cognitive deficits in schizophrenia compared to treatment as usual, and explored the mediating and moderating effects on cognitive improvement. Two groups who received cognitive rehabilitation and treatment as usual were assessed at baseline, three months (immediately post-intervention) and at follow-up (three months post-intervention). Cognitive rehabilitation focused on deficits in social knowledge and was conducted once a week for three months. The principles of errorless leaning and scaffolding informed the intervention. Outcomes were assessed using Script Test measures of social cognition. Other cognitive functions (executive functions and memory) and clinical symptoms were also assessed. Script Test for social knowledge and Rule Shift Test for cognitive flexibility scores were significantly better post-intervention in the cognitive rehabilitation group, while in the control group only free recall Script Test scores improved. Cognitive rehabilitation focused on social knowledge deficits can contribute to improvements in the social cognitive abilities of schizophrenic patients. Improvements in social cognitive functioning were durable at three-month follow-up. Cognitive rehabilitation can clearly benefit schizophrenic patients, at least when combined with atypical antipsychotic medication.

Altered neural basis of self-reflective processing in schizophrenia: An fMRI study.

BACKGROUND: Impaired self-awareness has often been described in schizophrenia. Recent neuroimaging studies examining the self-reflection processes in schizophrenia have produced inconsistent results. METHOD: We examined the self-reflective neural network using self- and other-evaluation tasks in schizophrenia. Fifteen schizophrenia patients and fifteen age- and sex-matched healthy subjects underwent functional magnetic resonance imaging. Subjects were required to decide whether the sentence described their own personal trait (self-evaluation) and that of their close friends (other-evaluation). RESULTS: Unlike normal control subjects, the schizophrenia patients did not have greater activation of the left posterior cingulate gyrus and hippocampus during self-evaluation than during other-evaluation. On the other hand, the schizophrenia patients had higher activation of the right superior frontal and right supramarginal gyri during self-evaluation than control subjects. Only the patient group exhibited hyperactivation in the left hippocampus and right external capsule associated with the other-evaluation task. CONCLUSIONS: These findings provide evidence for an altered neural basis of self-reflective processing, which may underlie the self-awareness deficits in schizophrenia.

Antipsychotic drugs scavenge radiation-induced hydroxyl radicals and intracellular ROS formation, and protect apoptosis in human lymphoma U937 cells.

Antioxidant activity has been reported for some atypical antipsychotic drugs; however, the detailed mechanism is not well known. Here, we investigated the effects of atypical antipsychotic drugs on •OH radical formation, intracellular reactive oxygen species (ROS), and apoptosis induced by ionising radiation. The reaction rate constants with •OH radicals were determined for five antipsychotic drugs as follows, in descending order: olanzapine, aripiprazole, clozapine, haloperidol, and risperidone. Experiments with aminophenyl fluorescein, a fluorescent dye, showed that olanzapine and clozapine could scavenge intracellular ROS. However, experiments with hydroxyphenyl fluorescein showed that only olanzapine inhibited ROS generation. X-irradiation-induced apoptosis in human lymphoma U937 cells was inhibited by clozapine at relatively low concentrations and by olanzapine at higher concentrations. Clozapine inhibited caspase-8 and caspase-3 activation and prevented loss of mitochondrial membrane potential. In contrast, olanzapine inhibited X-irradiation-induced p-JNK activation. Although the atypical antipsychotic drugs used here have relatively high reaction rate constants with •OH radicals in aqueous solutions, inhibition of intracellular ROS was not due to •OH radical scavenging. In addition, suppression of X-irradiation-induced apoptosis was not directly linked with intracellular ROS scavenging. When apoptosis signalling pathways were studied, clozapine-mediated inhibition of apoptosis was dependent on caspase-3 and caspase-8. In contrast, olanzapine inhibited apoptosis via down regulation of X-irradiation-induced p-JNK. These results suggested that both olanzapine and clozapine have antioxidative and antiapoptotic activities via distinct pathways, and provide useful information for better understanding of drug characteristics.

T-817MA, a novel neurotrophic compound, ameliorates phencyclidine-induced disruption of sensorimotor gating.

RATIONALE: Neurodegenerative changes have been suggested to provide a basis for the pathophysiology of schizophrenia. T-817MA (1-{3-[2-(1-benzothiophen-5-yl) ethoxy] propyl} azetidin-3-ol maleate) is a novel compound with neuroprotective and neurite-outgrowth effects, as elicited in rat primary cultured neurons. OBJECTIVES: We examined the effect of T-817MA on phencyclidine (PCP)-induced disruption of prepulse inhibition (PPI), a measure of sensorimotor gating, in male Wistar rats. MATERIALS AND METHODS: In chronic experiments, male Wistar rats were injected intermittently with PCP (2.0 mg/kg, i.p., three times per week) or vehicle (saline, 2.0 ml/kg) for 1 month. T-817MA (0.21 or 0.07 mg/ml, p.o.) or distilled water was administered throughout the study period. In an acute experiment, T-817MA (8.4 mg/kg, p.o.) or distilled water was administered, followed by treatment with PCP (2.0 mg/kg, i.p.) or vehicle (saline, 2.0 ml/kg), before PPI measurements. RESULTS: Intermittent administration of PCP for 1 month induced persistent disruption of PPI. Coadministration of T-817MA at 0.21 mg/ml but not 0.07 mg/ml completely blocked PCP-induced disruption of PPI, whereas T-817MA (0.21 mg/ml) by itself did not show a significant effect on PPI in control rats. On the other hand, single administration of T-817MA did not affect PPI disruption by acute treatment with PCP. CONCLUSIONS: These results suggest that T-817MA is effective in ameliorating sensorimotor gating deficits caused by chronic PCP treatment, possibly via neuroprotective actions. Our findings provide a novel therapeutic approach for patients with schizophrenia.

Electrophysiological basis for the ability of olanzapine to improve verbal memory and functional outcome in patients with schizophrenia: a LORETA analysis of P300.

Abnormality of P300 waveforms of event-related potentials (ERPs) has been suggested to represent an aspect of the pathophysiology of schizophrenia. Previous work points to the contribution of altered neural function in discrete brain regions in the left hemisphere to psychotic symptoms and cognitive deficits of schizophrenia. In this study, we sought to determine: 1) if patients with schizophrenia elicit a decreased P300 current source density in brain areas, such as the superior temporal gyrus (STG); 2) if decreased P300 generator density in the left STG is recovered by treatment with the most widely-used antipsychotic drug olanzapine; and 3) if the recovery of P300 source density is associated with improvements of cognitive and functional status. P300 in response to an auditory oddball task, as well as verbal learning memory, psychopathology, and quality of life were evaluated in 16 right-handed patients with schizophrenia before and after treatment with olanzapine for 6 months. ERP data were also obtained from 16 right-handed age and gender-matched normal volunteers. Low resolution electromagnetic tomography (LORETA) analysis was used to obtain current density images of P300. Patients with schizophrenia showed significantly smaller LORETA values in several brain regions in the left side, particularly STG, middle frontal gyrus, and precentral gyrus, compared with control subjects. Six-month treatment with olanzapine significantly increased P300 source density only in the left STG. Positive symptoms, negative symptoms, verbal learning memory, and quality of life were also improved during treatment. Significant correlations were found between the increase in LORETA values of left STG vs. improvements of negative symptoms, as measured by Scale for the Assessment of the Negative Symptoms, and verbal learning memory, as measured by the Japanese Verbal Learning Test. Improvement of quality of life, as evaluated by the Quality of Life Scale, were significantly associated with an increase in LORETA values of middle frontal gyrus, and tended to correlate with that of precentral gyrus. The results of this study suggest that changes in cortical activity, as measured by ERPs, are responsible for the ability of some antipsychotic drugs to improve cognition and functional outcome in patients with schizophrenia.

Association between the brain-derived neurotrophic factor Val66Met polymorphism and brain morphology in a Japanese sample of schizophrenia and healthy comparisons.

Magnetic resonance imaging was used to investigate the relation between the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and volumetric measurements for the medial temporal lobe structures (amygdala, hippocampus, and parahippocampal gyrus) and prefrontal sub-regions (the superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, ventral medial prefrontal cortex, orbitofrontal cortex, and straight gyrus) in a Japanese sample of 33 schizophrenia patients and 29 healthy subjects. For the controls, the Met carriers had significantly smaller parahippocampal and left superior frontal gyri than the Val homozygotes. The schizophrenia patients carrying the Met allele had a significantly smaller right parahippocampal gyrus than those with the Val/Val genotype, but the genotype did not affect the prefrontal regions in schizophrenia patients. These findings might reflect different genotypic effects of BDNF on brain morphology in schizophrenia patients and healthy controls, implicating the possible role of the brain morphology as an endophenotype for future genetic studies in schizophrenia.