Cortical morphology and early adverse birth events in men with first-episode psychosis.

BACKGROUND: Reduced cortical gray-matter volume is commonly observed in patients with psychosis. Cortical volume is a composite measure that includes surface area, thickness and gyrification. These three indices show distinct maturational patterns and may be differentially affected by early adverse events. The study goal was to determine the impact of two distinct obstetrical complications (OCs) on cortical morphology. METHOD: A detailed birth history and MRI scans were obtained for 36 patients with first-episode psychosis and 16 healthy volunteers. RESULTS: Perinatal hypoxia and slow fetal growth were associated with cortical volume (Cohen's d = 0.76 and d = 0.89, respectively) in patients. However, the pattern of associations differed across the three components of cortical volume. Both hypoxia and fetal growth were associated with cortical surface area (d = 0.88 and d = 0.72, respectively), neither of these two OCs was related to cortical thickness, and hypoxia but not fetal growth was associated with gyrification (d = 0.85). No significant associations were found within the control sample. CONCLUSIONS: Cortical dysmorphology was associated with OCs. The use of a global measure of cortical morphology or a global measure of OCs obscured important relationships between these measures. Gyrification is complete before 2 years and its strong relationship with hypoxia suggests an early disruption to brain development. Cortical thickness matures later and, consistent with previous research, we found no association between thickness and OCs. Finally, cortical surface area is largely complete by puberty and the present results suggest that events during childhood do not fully compensate for the effects of early disruptive events.

White matter tract abnormalities in first-episode psychosis.

Fibers connecting fronto-temporal and fronto-medial structures that pass through the anterior limb of the internal capsule (ALIC) subserve executive and psychomotor functioning. Both of these functions are adversely affected in schizophrenia, and may be abnormal at illness onset. In a study of first-episode psychosis, we used diffusion tensor imaging (DTI) and cognitive testing to examine ALIC integrity. Fourteen early psychosis patients and 29 healthy volunteers were included. Symptoms were assessed with the Positive and Negative Syndromes Scale (PANSS). All structural and diffusion scans were acquired on a GE Signa 1.5T scanner. A T1-weighted 3D FSPGR Inversion Recovery imaging series was acquired for manual seeding in structural space. Diffusion tensor imaging (DTI) was performed, and all DTI images were co-registered to structural space. Seeds were manually drawn bilaterally on the coronal plane at a specified location. Diffusion images were post-processed for subsequent Tract-based Spatial Statistics (TBSS) analysis. First-episode psychosis patients had significantly smaller fronto-medial and fronto-temporal AIC tract volumes compared to healthy volunteers on the left and the right (p-values<0.04). No differences in mean fractional anisotropy (FA) were seen within either left or right tracts (p-values>0.05), nor did TBSS reveal any other differences in FA values between groups in other regions. Relationships between tract volumes and symptom severity were not observed in this study.

Anterior internal capsule volumes increase in patients with schizophrenia switched from typical antipsychotics to olanzapine.

Abnormalities in connectivity are thought to contribute to the symptoms of schizophrenia. Accumulating evidence suggests that antipsychotic medication affects both subcortical and cortical grey and white matter volumes. The goal of this study was to investigate the effects of antipsychotic medication on two white matter tracts: a subcortical-cortical tract, the anterior and posterior limbs of the internal capsule; and a cortical-cortical tract, the corpus callosum. Magnetic resonance imaging was conducted on 10 chronic schizophrenia patients treated with typical antipsychotics and 20 healthy controls at baseline. Patients were switched to olanzapine and both groups were rescanned after 1 year. At baseline, the volume of the anterior limb of the internal capsule was 24% smaller in typical-treated patients than controls (p = 0.009). Patients treated with greater amounts of chlorpromazine-equivalent daily dosage had smaller anterior internal capsule volumes at baseline (r = -0.65, p = 0.04). At follow-up, after being switched to olanzapine, there were no significant differences between patients and controls. Patients with schizophrenia had a significant 25% increase in anterior internal capsule volume from baseline to follow-up compared with controls (p = 0.04). These effects were most prominent in the anterior limb of the internal capsule, which consists of fronto-thalamic pathways, and were not statistically significant in the posterior limb of the internal capsule or corpus callosum. Olanzapine may be effective in normalizing fronto-thalamic structural connectivity in schizophrenia.

Reduced anterior internal capsule and thalamic volumes in first-episode psychosis.

BACKGROUND: The thalamus is the gateway for sensory and motor information en route to the cortex. Information is processed via thalamocortical and corticothalamic pathways coursing through the internal capsules. In this study, we investigated the relationship between the anterior limb of the internal capsule, posterior limb of the internal capsule, and thalamus in first-episode psychosis (FEP). METHODS: Twenty-nine FEP subjects (26 DSM-IV schizophrenia, 2 schizoaffective disorder, 1 psychosis not otherwise specified) and 22 healthy volunteers participated in this study. Anterior limb of the internal capsule (AIC), posterior limb of the internal capsule (PIC), and the thalamus volumes were manually determined from MRI scans. RESULTS: FEP subjects had reduced AIC volumes (F(1,45)=6.18, p=0.017) and thalamic volumes (F(1,45)=8.00, p=0.007) compared to healthy volunteers. PIC volumes did not differ. Significant correlations between AIC volumes and thalamic volumes were observed in subjects with FEP, but not in healthy volunteers. Negative relationships between thalamic volumes and symptom severity were also observed. CONCLUSIONS: The AIC and thalamic volumes were reduced in subjects with FEP compared to healthy volunteers. Abnormalities in thalamocortical and orticothalamic pathways may contribute to functional disruption of neural circuits in psychosis.

The Canadian National Outcomes Measurement Study in Schizophrenia: overview of the patient sample and methodology.

OBJECTIVE: The Canadian National Outcomes Measurement Study in Schizophrenia (CNOMSS) is a prospective survey of routine clinical practice. METHOD: Patients with schizophrenia or a related disorder were consecutively enrolled from all regions of Canada. Both academic and community psychiatric clinics were included and patients were followed up for 2 years. Clinical and functional status, quality of life, medication and economic costs were assessed at enrollment and monitored throughout the follow-up period. RESULTS: Patients attending an academic clinic tended to be younger and more severely ill than those from community clinics. Both types of sites prescribed atypical neuroleptics to more than three-quarters of the patients. The majority of those enrolled were unemployed and living in poverty. Poor clinical status was associated with poverty. CONCLUSION: The CNOMSS provides demographic, clinical and treatment-related information about a large Canada-wide sample of psychiatric patients. The following three articles in this issue of Acta Psychiatrica Scandinavica explore issues related to medication, quality of life and resource utilization.

Outcome on quality of life in a Canadian national sample of patients with schizophrenia and related psychotic disorders.

OBJECTIVE: To examine changes in subjective and objective dimensions of quality of life (QoL) in a large Canadian sample of patients with diagnosis of schizophrenia or schizoaffective disorder treated in academic and non-academic settings over a 2-year period. METHOD: Patients recruited in the study across the country were assessed for QoL and functioning using the Client and Provider versions of the Wisconsin Quality of Life Questionnaire (WQoL) and the Short Form-36 (SF-36) at baseline (n = 448), 1 year (n = 308-353) and 2 years (188-297). Data were analyzed to examine change across time using multivariate analyses controlling for potential influence of variables such as age, regional variation, gender, duration of illness, type of treatment taken and baseline measures of symptoms and QoL. RESULTS: The weighted quality of life index (W-QoL-I) showed a significant change on both the client and the provider versions of the WQoL while the physical and mental composites of the SF-36 showed change only at 2 years. These changes were influenced significantly by baseline scores on W-QoL-I and in the case of provider version of the WQoL by baseline Brief Psychiatric Rating Scale (BPRS) scores. Regional variation or type of medication had no impact on improvement in QoL. CONCLUSION: Within a naturalistic sample of schizophrenia patients treated and followed in routine care the overall QoL showed an improvement over time but this improvement was not influenced by the type of medication prescribed.

Medication decisions and clinical outcomes in the Canadian National Outcomes Measurement Study in Schizophrenia.

OBJECTIVE: To evaluate over a 2-year period, patients from academic/non-academic centres, from each region of Canada, to determine whether location or other variables such as medication type, gender or income was associated with outcome as defined by non-hospitalization and persistence on original treatment. METHOD: A total of 448 patients were recruited from academic and non-academic centres across all provinces of Canada and followed up for 2 years. RESULTS: Patients from British Columbia had significantly lower rates of hospitalization than patients from other provinces. Male patients showed greater symptomatic improvement at 2 years from initial assessment compared to females. Patients on clozapine, risperidone and olanzapine were least likely to be hospitalized. CONCLUSION: There were some regional differences noted in both utilization of types of antipsychotic medications and hospitalization rates. In this sample of stable out-patients over 70% who started on monotherapy with clozapine, risperidone, olanzapine and quetiapine remained on the same medication over the 2-year study period.

Resource utilization in a Canadian national study of people with schizophrenia and related psychotic disorders.

OBJECTIVE: To determine how the use of the newer, so called atypical antipsychotic medications, effects the pharmacoeconomic treatment burden of schizophrenia and related conditions and to provide a clear comparison of the costs and risks associated with these atypical drugs. METHOD: In this 2-year, open-label, prospective study, resource utilization (RU) data were collected on 160 patients with these conditions. A comparison between risks and costs was performed by combining the generalized CNOMSS data on both economic factors and risk assessments. RESULTS: The main findings of the study were that the total adjusted 1- and 2-year costs were lowest for quetiapine. Drug acquisition costs were lowest for risperidone for both the 1- and 2-year cohorts. Clozapine use was predictably associated with the highest overall and medication costs at both 1 and 2 years. CONCLUSION: Treatment with risperidone or quetiapine was associated with the lowest overall costs when compared with olanzapine or clozapine.

First episode psychosis: early intervention strategies with second-generation antipsychotic medications.

Schizophrenia is a debilitating chronic illness that has its onset in adolescence or the early years of adulthood. The benefit of early diagnosis and treatment has been acknowledged for decades, although facilitating the early identification of patients with schizophrenia remains a challenge. Research has demonstrated that many individuals are living with the symptoms of psychosis for prolonged periods in the community, and family physicians are well positioned to identify such patients. Community education is an important strategy, in that it increases the general awareness of psychotic illness and lessens the stigma of mental illness, eventually encouraging individuals to seek help. We review here some of the evidence indicating the benefit of early treatment, and describe the strategies to assist in the identification of patients with a first episode of schizophrenia and key treatment modalities available. Ultimately, there is a need for comprehensive, accessible healthcare including medications that have minimal side-effects and are effective.

Improvement in cognitive functioning in patients with first-episode psychosis during treatment with quetiapine: an interim analysis.

BACKGROUND: The efficacies of second-generation antipsychotic medications in reducing symptoms are reasonably well-documented, but their effects on cognition are less clearly understood. AIMS: To under take an interim analysis of an open label, 2-year study examining the effects of quetiapine on cognition in patients with a first episode of schizophrenia and related disorders. METHOD: Cognitive testing was performed before quetiapine was initiated and repeated after 3, 6 and 12 months of treatment. To date, 13 patients have been fully assessed (mean dose 517.9 mg/day; s.d. = 225.8). RESULTS: Statistically significant improvement was noted on measures of attention (Continuous Performance Test; CPT), verbal productivity (Verbal Fluency Test) and executive function (Object Alternation Test) after 6 and 12 months of treatment. For the CPT, improvement was also noted after 3 months of treatment. CONCLUSIONS: During treatment for 1 year with quetiapine, cognitive performance was improved in young patients with psychosis. Continued controlled investigations of the effects of quetiapine on cognition are desirable.

Impaired olfactory identification in relatives of patients with familial schizophrenia.

OBJECTIVE: Impaired olfactory identification ability has previously been demonstrated in patients with schizophrenia. This study assessed olfactory function in psychotic and nonpsychotic members of multigenerational families with familial schizophrenia to determine whether deficits were present in both groups. METHOD: The University of Pennsylvania Smell Identification Test was administered birhinally to three groups of subjects aged less than 65 years: 19 psychotic and 27 nonpsychotic members of families with familial schizophrenia and 43 age- and sex-matched healthy volunteers. RESULTS: Nonpsychotic family members had significantly higher mean University of Pennsylvania Smell Identification Test scores than psychotic family members but were impaired relative to the healthy volunteer group. These group differences could not be accounted for by age, sex, or smoking habit. Fifty-eight percent of the psychotic and 34% of the nonpsychotic family members performed in the microsmic (impaired) range, compared to 9% of the healthy volunteers. CONCLUSIONS: Impaired olfactory deficits may aggregate in families with schizophrenia and may be indicative of a genetic predisposition to psychosis.

Regional cerebral glucose metabolism in never-medicated patients with schizophrenia.

OBJECTIVE: The purpose of this study was to assess regional cerebral glucose metabolism in patients with schizophrenia who had never received antipsychotic medication and whose olfactory identification ability had been assessed. Two hypotheses were examined. First, the patients were compared with normal controls to determine whether differences in regional cerebral metabolism were apparent. Second, regional rates of metabolism were correlated with olfactory ability and the relation between them determined. METHODS: The patient (n = 26) and control (n = 32) subjects were scanned at rest using positron emission tomography (PET) after administration of 18F-fluorodeoxyglucose (FDG). In addition, the University of Pennsylvania Smell Identification Test was administered to each patient. RESULTS: Patients with schizophrenia had reduced rates of glucose metabolism in the right and left thalamus that reached significance if not corrected for multiple comparisons. However, if a Bonferroni correction was applied over the 27 regions of interest, the differences were not significant. Scores on the Smell Identification Test were negatively correlated with 8 regions of interest. When scores were analyzed using multiple regression, the left frontal cortex and the medial parietal cortex were significant predictors. CONCLUSIONS: The finding of reduced metabolism in the thalami is consistent with some of the previous literature, whereas the negative correlations between specific regions and olfactory function are not consistent with studies using activation paradigms.

An MRI study of basal ganglia volumes in first-episode schizophrenia patients treated with risperidone.

OBJECTIVE: The basal ganglia may contribute to extrapyramidal movement disorders, affective disturbances, and cognitive deficits in schizophrenia. Basal ganglia volumes are putatively affected by antipsychotic medications. The purpose of this study was to determine the long-term effects of risperidone treatment in a cohort of first-episode patients with schizophrenia. METHOD: The subjects were 30 patients with first-episode schizophrenia, 12 patients chronically treated with typical antipsychotics, and 23 healthy comparison subjects. They were scanned by magnetic resonance imaging at baseline. The first-episode patients received 1 year of continuous risperidone treatment, after which they and the comparison subjects were rescanned. Caudate, putamen, and globus pallidus volumes were determined from coronal images. RESULTS: The baseline caudate, putamen, and globus pallidus volumes were significantly larger in the chronically treated patients than in the untreated first-episode subjects and comparison subjects. These volumes did not differ between the first-episode patients and healthy comparison subjects. Basal ganglia volumes were unchanged after 1 year of exposure to risperidone in the first-episode subjects. Extrapyramidal movement disorders were present in the majority of chronically treated patients and more than one-third of the never-medicated first-episode patients at baseline. CONCLUSIONS: This group of first-episode patients did not exhibit abnormalities of basal ganglia volumes, nor were basal ganglia volumes affected by exposure to risperidone. Movement disorders were observed in both first-episode and chronically treated patients, suggesting effects of both illness and medications.

Low birthweight in schizophrenia: prematurity or poor fetal growth?

In the general population, low birthweight (LBW) is associated with neurological and psychological problems during childhood and adolescence. LBW may result from premature birth or poor fetal growth, and the independent effects of these two events on childhood development are not fully understood. The rate of low weight births is increased in schizophrenia and is associated with social withdrawal during childhood and an early onset of illness. However, it is unclear whether this LBW reflects poor fetal growth or premature birth, or whether these two risk factors have distinct implications for childhood functioning and age at onset of schizophrenia. Subjects included 270 patients with schizophrenia for whom a detailed history of obstetric events could be obtained. The rate of low weight births was high and was associated with poorer premorbid functioning and an earlier age at illness onset. The rate of both premature births and poor fetal growth was high relative to the normal population. Prematurity, but not poor fetal growth, was associated with premorbid social withdrawal and an early age at illness onset. Poor fetal growth, but not prematurity, was associated with low educational achievement. These results suggest that poor fetal growth and prematurity are associated with distinct patterns of childhood maladjustment in individuals who develop schizophrenia.

Duration of untreated psychosis predicts treatment outcome in an early psychosis program.

For patients first presenting with a non-affective psychotic disorder, the duration of untreated psychosis (DUP; the time between the onset of positive psychotic symptoms and the initiation of appropriate treatment) varies widely, from a few weeks to several years. A number of studies report that a longer DUP is associated with poorer clinical outcomes. We studied DUP and its association with clinical outcomes in a group of patients with schizophrenia and related psychotic disorders treated in the naturalistic clinical setting of an early psychosis program. DUP was determined for 19 patients with a non-affective psychotic disorder (schizophrenia, schizoaffective disorder or schizophreniform disorder) and no previous treatment for psychosis, by use of the IRAOS, a retrospective structured interview carried out with patients and their families. Positive and Negative Syndrome Scale (PANSS) and Global Assessment of Function (GAF) ratings were available at baseline and 6month follow-up. For analysis, patients were categorized into a short DUP (n=9) or long DUP (n=10) group. The median DUP (57weeks) was used as the dividing point. At baseline, the two groups did not differ significantly on positive symptoms or total PANSS ratings. However, negative symptoms were more severe in the long DUP group at baseline (P=0.029), and the long DUP group had a significantly higher mean rating for the passive/apathetic social withdrawal item of the PANSS (P=0.024). At 6month follow-up, the long DUP group had significantly higher ratings for positive symptoms (P=0.028) and had lower GAF scores (P=0.044). Significantly more (P=0.033) long DUP patients had enduring positive psychotic symptoms. The results confirm both the wide range of DUP among patients first presenting with schizophrenia and related psychotic disorders and the association of long DUP, defined as greater than approximately 1year, with a poorer clinical outcome. This study highlights the importance of collecting data regarding DUP and supports the view that patients with a long DUP are likely to be less responsive to treatment in general and will require greater resources and more intensive interventions.

An innovative approach to clinical communication in schizophrenia: the approaches to schizophrenia communication checklists.

Side effects from antipsychotic medications can have a profound effect on patients' lives and may adversely affect their willingness to comply with treatment. Identification of side effects through improved communication between psychiatrists, other members of the healthcare team, and their patients might increase treatment compliance. The Approaches to Schizophrenia Communication (ASC) Steering Group developed two simple, practical checklists for use in the busy clinical setting. The ASC-Self-Report (ASC-SR) checklist is completed by the patient and comprises a list of the more common or clinically important side effects of antipsychotic treatment. The ASC-Clinic (ASC-C) checklist is completed by both clinician and patient together, being used as the basis for a semi-structured interview. In a multicenter pilot study set up to evaluate the utility of checklists, 86% of patients responding considered the ASC-SR to be useful in communicating their problems to psychiatrists and other members of the healthcare team. All healthcare team respondents found both checklists to be helpful when discussing side effect problems with their patients. Moreover, 41% and 47% of healthcare team respondents reported that the ASC-SR and ASC-C, respectively, had assisted them in identifying side-effect problems not previously acknowledged. Preliminary evaluation of the ASC-SR and ASC-C in this multicenter pilot study suggests that both tools were user-friendly, encouraged communication between patients and healthcare professionals about antipsychotic drug side effects, and could readily integrated into everyday clinical practice.

Earlier puberty as a predictor of later onset of schizophrenia in women.

OBJECTIVE: The aim of this study was to determine whether puberty plays a mediating role in onset of schizophrenia. The hypothesis was that there is an inverse relation between age at puberty (menarche) and age at onset in women. METHOD: Competent and consenting individuals with DSM-IV-defined schizophrenia or schizoaffective disorder and their mothers underwent a 45-minute interview to ascertain age at first odd behavior, age at first psychotic symptoms, age at first hospitalization, and ages at various indices of puberty. Information about substance use, head injury, perinatal trauma, and first-degree family history of schizophrenia was also obtained. RESULTS: In the women (N = 35), the earlier the age at menarche, the later the ages at both the first psychotic symptoms and the first hospitalization. There was no significant association between puberty and onset in the men (N = 45). Other than gender, none of the examined variables played a role in the interaction of puberty and onset of illness. CONCLUSIONS: In women, early puberty (whether through hormonal or social influence) was associated with later onset of schizophrenia. This effect was not found in men; in fact, the trend was in the opposite direction.

Olfactory identification and psychosis.

BACKGROUND: Olfactory identification performance has been investigated in several psychiatric populations, with deficits most commonly reported in patients with schizophrenia. In this study, olfactory identification performance was investigated in a more homogenous group of treatment-refractory patients with schizophrenia (T-RS) and in two additional psychiatric groups who demonstrate some similarities to the patients with schizophrenia in terms of symptomotology and medication regime. METHODS: The olfactory identification performance of 16 T-RS patients was assessed using the University of Pennsylvania Smell Identification Test (UPSIT) and compared to that of 16 normal control subjects and two other psychiatric patient groups: 19 affective disorder patients requiring maintenance antipsychotic medication and 20 affective disorder patients not receiving antipsychotic medication. RESULTS: The olfactory identification performance of T-RS patients was significantly lower than that of normal controls but not significantly different from either affective disorder group. The olfactory identification performance of affective disorder patients receiving antipsychotic medication was significantly lower than that of affective disorder patients not receiving antipsychotic medication. DISCUSSION: Results are discussed in the context of a possible link between psychotic symptomotology and olfactory identification performance.