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.

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.

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.

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.

Overcoming challenges in the management of schizophrenia.

The authors discuss the impact of the recently available 'atypical' antipsychotic drugs on the management of people with schizophrenia. The better tolerability of the atypical agents, compared with conventional antipsychotics, should encourage their use as first-line therapy and therefore increase the acceptability of early intervention strategies. Tailoring treatment to the individual by appropriate selection of an atypical agent should facilitate the establishment of a productive, long-term therapeutic alliance and could achieve greater concordance between doctors and patients. Atypical antipsychotic drugs enable an improvement in management strategies which should contribute to a better outcome for patients with schizophrenia.

A case of risperidone overdose in early schizophrenia: a review of potential complications.

Deliberate drug overdose is a frequent occurrence in patients with schizophrenia. Typical antipsychotic medications can be lethal at doses 5 times the recommended therapeutic range. Clozapine, an atypical antipsychotic, can be toxic at doses 4 times a moderate dose. Little is known about the lethal effects of the novel antipsychotic risperidone, despite the fact that it is now one of the most widely prescribed antipsychotics in North America. To date, only 1 death attributable to risperidone overdose has been reported. The case presented here documents adverse cardiac effects in a 28-year-old man who intentionally ingested 24 mg of risperidone--4 times the recommended dose. A potential drug interaction with fluvoxamine and the role of active metabolites are discussed.

Left nostril olfactory identification impairment in a subgroup of male patients with schizophrenia.

Abnormal structural brain asymmetries have been reported in schizophrenia in brain areas which overlap with olfactory processing regions, with abnormalities more often described within the left hemisphere. We attempted to determine whether the olfactory agnosia observed in some male patients with schizophrenia was more likely left-hemisphere based. We assessed unirhinal (single nostril) olfactory identification and detection threshold in 65 male patients who met DSM-IV criteria for the diagnosis of schizophrenia and 59 healthy male control subjects. A two-way, mixed-design ANCOVA with diagnosis as the between-group factor, nostril as the within-subject factor and age as covariate was used to compare olfactory identification ability. This analysis demonstrated that patients with schizophrenia performed more poorly than the healthy controls across nostrils, but no differences were observed in either group between nostrils. However, when patients were classified according to unirhinal olfactory status (impaired left < right, impaired right < left, normosmic left < right, normosmic right < left), impaired patients were more than twice as likely to be classified as having a left nostril disadvantage than right nostril disadvantage. In contrast, within the normosmic group of patients, this pattern was reversed. Moreover, when those patients whose unirhinal olfactory scores differed by less than two points were removed from the analysis, a 2:1 ratio of left < right versus right < left was observed in the impaired patients. These results suggest that for impaired male patients with schizophrenia, olfactory identification deficits are more likely found for the left nostril, perhaps indicative of abnormalities in olfactory processing within the left hemisphere.

Obstetric complications, treatment response and brain morphology in adult-onset and early-onset males with schizophrenia.

BACKGROUND: Substantial variability in age at onset of illness and course of illness exists between patients with schizophrenia. Recent studies suggest that age at illness onset may be useful in defining biologically and clinically distinct subgroups of patients. METHODS: Two hundred and ten males with schizophrenia were classified as early-onset or adult-onset according to their age at first hospitalization. Birth history, clinical functioning and treatment response was assessed in a subgroup of patients. Brain anatomy was assessed from CT scans in all patients and in 32 non-psychiatric control subjects. RESULTS: Patients with an early-onset were likely to have a history of obstetric complications, a poor response to neuroleptic treatment, and showed no relationship between ventricle size and duration of illness. Adult-onset patients were less likely to have obstetric complications, more likely to respond to treatment in the first years of illness, and showed an association between brain structure and duration of illness. CONCLUSIONS: The distinction between early- and adult-onset patients may have important aetiological and treatment implications.

Olfactory deficits in patients with schizophrenia and severe polydipsia.

BACKGROUND: The present study was designed to assess olfactory function in severely polydipsic/hyponatremic patients with schizophrenia who also had intermittent water intoxication. METHODS: The University of Pennsylvania Smell Identification Test and an olfactory acuity battery were administered to three groups of male subjects: 9 patients with schizophrenia and severe polydipsia/hyponatremia, 9 control nonpolydipsic/normonatremic patients with schizophrenia, and 9 normal controls. RESULTS: Male patients with severe polydipsia/hyponatremia and intermittent water intoxication had marked olfactory acuity and identification deficits when compared to the patient control group of similar age and age at illness onset, and to normal controls. CONCLUSIONS: The finding of deficient acuity (detection threshold) in the polydipsic/hyponatremic group but not the nonpolydipsic, normonatremic group suggests that for this subgroup, abnormalities of olfactory sensory function may occur in a pattern previously reported for other brain disorders such as Alzheimer's disease.

An open comparison of clozapine and risperidone in treatment-resistant schizophrenia.

BACKGROUND: Clozapine and risperidone are used in treatment-resistant schizophrenia. At present, there are few reported comparisons of these drugs in this population. We report on a consecutive series of treatment-resistant schizophrenics given either clozapine or risperidone in open clinical trials. METHOD: Subjects were treated with clozapine (n = 57) or risperidone (n = 29). Pretreatment GAF, CGI, and PANSS scores did not differ between the groups, nor did demographic variables including age, age at first hospitalization, years ill, number of previous hospitalizations, or gender. The mean treatment trial was 12.1 weeks, with mean doses of clozapine 420 mg, and risperidone 7.75 mg. The length of the trial did not differ significantly between the groups. Response was taken to be a 20% decrease in the PANSS score. RESULTS: Using repeated measures ANOVA, PANSS total scores (F = 5.3, p = 0.02) and positive subscore (F = 7.4, p = 0.008) showed greater improvement in the clozapine group than the risperidone group, while other PANSS subscores showed a trend toward greater improvement with clozapine. The PANSS-derived factors of excitement (F = 6.7, p = 0.01), psychosocial withdrawal (F = 3.8, p = 0.05), and psychomotor retardation (F = 3.9, p = 0.05) improved more in the group treated with clozapine. The GAF (F = 10.9, p = 0.0014), CGI (F = 11.5, p = 0.0011), and CGI improvement (p = 0.0001) scores also improved more in the clozapine group. Of the clozapine group, 25 (44%) responded, while 8 (28%) of the risperidone group responded to treatment. DISCUSSION: Clozapine had better efficacy in subjects with treatment-resistant schizophrenia compared to risperidone, although risperidone appears to yield better response rates than those previously reported for typical antipsychotics. Double-blind, controlled trials of risperidone are needed to establish its efficacy in treatment-resistant schizophrenia.

Olfactory function in monozygotic twins discordant for schizophrenia.

OBJECTIVE: Abnormalities of olfactory identification ability have been proposed as a marker of cerebral dysfunction in schizophrenia. The authors studied the potential role of genetic factors in olfactory dysfunction by assessing monozygotic twins discordant for schizophrenia and matched comparison subjects. METHOD: The subjects were 12 pairs of monozygotic twins discordant for schizophrenia and 12 healthy subjects matched for sex and age. Each subject completed the University of Pennsylvania Smell Identification Test. RESULTS: The combined twin group scored significantly lower on smell identification than did the comparison group. The affected and unaffected twin groups did not differ from each other. CONCLUSIONS: Genetic factors may contribute to cerebral dysfunction as assessed by olfactory identification ability.