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.

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.

Olfactory identification ability in pre- and postmenopausal women with schizophrenia.

Previously we reported olfactory deficits in young male but not female patients with schizophrenia. In the present report, olfactory identification ability in pre- and postmenopausal women with schizophrenia and normal control subjects was assessed using the University of Pennsylvania Smell Identification Test (UPSIT). Additionally, serum estradiol levels were measured on the same 2 days as smell testing was completed. Olfactory deficits were observed in pre- and postmenopausal women with schizophrenia but were more pronounced in the postmenopausal patients. Regarding estradiol levels, women with schizophrenia had lower estradiol levels than did normal control subjects. The findings of this study indicate that olfactory deficits do exist in women with schizophrenia and may be accentuated by estrogen depletion.

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.

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.

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.

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.

Olfactory deficits in neuroleptic naive patients with schizophrenia.

Because previous studies have shown deficits in olfactory identification for male patients with schizophrenia, either withdrawn from or receiving neuroleptic medication, the purpose of the current study was to determine if such deficits occurred in male patients who had never received neuroleptics. A sample of male (n = 30) and female (n = 10) patients as well as age appropriate controls (males, n = 28, females, n = 30) was assessed in terms of olfactory acuity and identification ability. No differences were found in olfactory acuity, but an olfactory identification deficit was present in 31% of the male patients with schizophrenia. As the olfactory pathways project through the limbic system and to the orbitofrontal cortex, odour identification may be a measure of the functional integrity of these structures. Therefore, these results suggest that for a sub-sample of male patients, the functional integrity of these structures is compromised.

Olfactory hallucinations and olfactory identification ability in patients with schizophrenia and other psychiatric disorders.

Olfactory identification ability and the prevalence of olfactory hallucinations were examined in 183 hospitalized patients from three diagnostic groups. One hundred and thirty-one patients with schizophrenia, 21 patients with major depression, 31 women with eating disorders along with 77 normal control subjects were examined using the University of Pennsylvania Smell Identification Test (UPSIT) and were questioned regarding the presence of olfactory hallucinations. Olfactory identification deficits were observed only in patients with schizophrenia. In contrast, olfactory hallucinations were reported by members of all psychiatric diagnostic categories (34.6% of patients with schizophrenia; 19% of depressed patients and 29% of eating disorders patients). For patients with schizophrenia, women were more likely to report olfactory hallucinations and had higher UPSIT scores than men.

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.

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.

Left cerebral hemiatrophy and schizophrenia-like psychosis in an adolescent.

A previous report of cerebral hemiatrophy and schizophrenia added to the list of neurodevelopmental abnormalities associated with schizophrenia. In a new case, the birth history indicated perinatal hemorrhage and prematurity (30-31 weeks of gestation). CT and MR imaging showed reduction in left hemisphere size with ventricular enlargement and mild skull thickening. Loss of periventricular white matter was detected. Changes in skull thickness, size of air cells and volume of the cranial vault may be measurable correlates of putative developmental abnormalities in schizophrenia.

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.

Acute and longer-term effects of risperidone in a case of first-episode catatonic schizophrenia.

This case report documents the response of a young, first-episode, neuroleptic naive male with severe catatonic schizophrenia to the novel antipsychotic, risperidone. Initial assessments included the Positive and Negative Syndrome Scales, Global Assessment of Function and the Extrapyramidal Symptom Rating Scale. These were repeated at discharge from hospital and during a 3.5 year outpatient follow-up. Neuroimaging (computed tomography, magnetic resonance imaging and single photon emission tomography) along with electroencephalogram and laboratory examinations were completed. Response to risperidone was prompt, dramatic and sustained over the follow-up period. Possible neurochemical brain mechanisms resulting in catatonia and the role of serotonin/dopamine antagonists such as risperidone are discussed. No other literature on the effect of risperidone in the treatment of severe catatonic schizophrenia in a first-episode patient has been reported.

Clinical experience in developing treatment regimens with the novel antipsychotic risperidone.

Early intervention with antipsychotic treatment has been shown to reduce the risk of relapse and to improve long-term morbidity in patients with schizophrenia. However, treatment with conventional neuroleptics carries with it a significant risk of developing extrapyramidal side effects. Conventional neuroleptics exert their antipsychotic effects at doses similar to those that cause extrapyramidal side effects. Although anticholinergic medication (e.g. benztropine) may reduce the severity of these side effects, anticholinergics are themselves associated with significant side effects, such as dry mouth, constipation, blurred vision, urinary retention and sexual dysfunction. Anticholinergic drugs are also associated with impaired cognition and worsening of the patient's psychosis. Newer antipsychotic drugs, such as risperidone, which have a dual mechanism of action (serotonin-dopamine antagonism) are reported to have a lower risk of extrapyramidal side effects than conventional agents. In particular, risperidone produces significant antipsychotic effects at doses lower than those that cause extrapyramidal side effects. Patients presenting with a first episode of psychosis and who are antipsychotic drug-naïve may exhibit abnormal movements before treatment is initiated. Unless these patients are carefully assessed at baseline these movements could be mistaken for drug-induced extrapyramidal side effects. It is important to develop treatment strategies for these patients that improve positive and negative psychotic symptoms as quickly as possible, with a minimal risk of extrapyramidal side effects developing. Prompt and appropriate antipsychotic treatment can substantially reduce the risk of relapse. Whereas approximately 60% of unmedicated patients will relapse in the first year following resolution of the acute psychotic episode, prophylactic antipsychotic medication can reduce this rate to less than 20%. Recent clinical experience in Canada has shown that risperidone is effective in the treatment of patients with first-episode psychosis. Moreover, lower doses of risperidone were required than those previously used to treat chronically ill patients with a history of multiple psychotic episodes and prolonged exposure to conventional neuroleptics. As further data are accumulated, the mean daily dose of risperidone required by first-episode patients has been shown to be close to 4 mg. The low incidence of extrapyramidal side effects in these patients (< 10% required anticholinergic medication) supports the use of risperidone and offers the prospect of improved compliance and a better long-term outcome.

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.