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.

Obstetric complications and age-related changes in brain morphology in schizophrenia.

Birth problems can lead to changes in brain morphology in the general population and an increased prevalence of both birth problems and altered brain morphology are found in patients with schizophrenia. The purpose of this study was to test the hypothesis that these two findings are related. Birth history and the size of ventricular and sulcal spaces from nine regions of the brain were assessed in 80 male subjects with schizophrenia. No differences were found between patients with and those without a history of birth problems for the size of any brain space; however, ventricular size increased significantly with age in patients who had no birth complications but not in patients with a history of birth problems. The size of cortical sulci increased with age in patients with and those without a history of birth problems. These results suggest that region-specific rates of change in size may identify clinically meaningful patients subgroups.

Regional cortical anatomy and clozapine response in refractory schizophrenia.

Regional measures of cortical sulcal and ventricular enlargement on computed tomography scan were studied in a clinical sample of patients treated with clozapine. Cortical sulci were significantly enlarged in clozapine nonresponders compared to responders. The Clinical Global Impressions score at discharge was related to the size of the posterior frontal and lateral temporal sulci, with large sulci predicting a poorer response to clozapine treatment.

Diagnostic confusion in treatment-refractory psychotic patients.

BACKGROUND: Two surveys of diagnostic practices in the United States suggest that many clinicians base their diagnoses on presenting symptoms and pay little attention to course and exclusionary criteria. Failure to correctly diagnose patients may result in inappropriate therapy and poor treatment response. The purpose of the present study was to investigate diagnostic practices. METHODS: We made detailed assessments of 50 consecutively admitted treatment-refractory psychotic patients and carefully applied DSM-III-R criteria. RESULTS: Referral diagnoses were changed in 23 of the 50 patients. Diagnoses of schizophrenia and schizoaffective disorder were made far less frequently and mood disorders (bipolar disorder and major depression) were diagnosed far more frequently by our group than by referring psychiatrists. Patients whose diagnosis was changed were more likely to be given mood-stabilizing medication and tended to show more improvement than patients whose diagnosis was not changed. CONCLUSIONS: These findings raise the possibility that patients may not respond to treatment because incorrect diagnoses result in inappropriate treatment.

Diagnostic reassessment and treatment response in schizophrenia.

BACKGROUND: The reasons for poor treatment response in some patients with schizophrenia remain unclear. It is possible that misdiagnosis of nonschizophrenic disorders as schizophrenia could result in suboptimal pharmacotherapy in some patients. METHOD: To assess this possibility, 110 severely ill, chronic patients with a referral diagnosis of schizophrenia were comprehensively assessed and rediagnosed according to DSM-III-R criteria. Global Assessment of Function (GAF) and Clinical Global Impressions (CGI) ratings were made at admission and at discharge from the ward, after the implementation of individualized treatment plans. RESULTS: The diagnosis of schizophrenia was confirmed in 80 patients (73%) and revised to another type of psychotic illness in 30 patients (27%). The GAF and CGI ratings were similar at admission in patients with confirmed and revised diagnoses. All patients improved by the time of discharge (p = .0001); however, patients with a revised diagnosis improved more than those with confirmed schizophrenia (p = .02). Patients with a revised diagnosis were less likely to require continued hospitalization on chronic care wards (p = .004). At admission, medication regimens were similar in the two groups of patients. At discharge, patients with a revised diagnosis were less likely to have received neuroleptics (p = .007) and more likely to have received antimanic drugs (p = .0002) or electroconvulsive therapy (p = .0004). CONCLUSION: These findings from a clinical sample suggest that diagnostic reassessment is an important first step in the management of apparently refractory schizophrenia.

Obstetric complications and severity of illness in schizophrenia.

A history of obstetric complications (OCs) is common in schizophrenia and may lead to a severe form of the disorder. In order to test this possibility, three questions were identified: (1) Is a history of OCs in schizophrenia common in patients with a severe form of illness? (2) Do patients with OCs have more impaired function, greater severity of illness, and poorer treatment outcome than those with no identified OCs? (3) Are OCs associated with an early age at onset of illness? Obstetric history, clinical indices of functioning, and illness severity were obtained for 83 severely ill patients with schizophrenia. The proportion of patients with a history of OCs was greater in this study than has been reported previously. Subjects with a history of OCs had better functioning than those with no OCs at the time of admission but no group differences were found at discharge. No difference in age at onset of illness was found between patients with and without an OC history.

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.

Lorazepam in the elderly--a retrospective study of the side-effects in 20 patients.

In a retrospective study of 20 elderly patients who were prescribed lorazepam prior to their admission to a geriatric psychiatry inpatient unit, the average length of prescription of the drug was 18 weeks with inadequate follow-up. Side-effects were common and consisted of oversedation, amnestic disorders, confusion, depression and ataxia. The majority of such events resolved on withdrawal of lorazepam in hospital. Particular note is made of the pro duction of a drug-induced pseudodementia misdiagnosed as a 'true' dementia which again resolved on cessation of the drug. It is concluded that there are insufficient data to recommend lorazepam over any other agent in the elderly and care should always be exercised when prescribing in older patients.

Outcome measurement in pharmacological trials: validity of the Routine Assessment of Patient Progress (RAPP).

The assessment of outcomes after treatment with antipsychotic medication is fundamental to clinical care and research. The Routine Assessment of Patient Progress (RAPP) is a reliable multidimensional scale that employs nurses' ratings of symptoms and functioning in psychiatric inpatients. The present study sought to extend validity evidence for the RAPP by examining its ability to reflect changes associated with treatment by antipsychotic medications. The use of a different sample in this study also provided the opportunity to replicate earlier validity data collected on the original set of patients. Ninety-seven separate trials were conducted, involving 65 consecutive admissions to a unit that specializes in the assessment and treatment of patients with long standing severe psychiatric disorders. The RAPP, along with the Positive and Negative Syndrome Scale and global measures of severity, were administered at baseline and at the end of each trial. Both factor scores and clinically-derived subscales were analysed for sensitivity to change. Patients were globally rated as improved, unchanged or worsened at the end of the medication trial. Results indicated that the RAPP factor, clinical scale and total scores compared favourably to other outcome measures in patients rated as improved or worse. In patients rated as unchanged, RAPP scores displayed significantly less change than did the PANSS scores. These findings support the validity of the RAPP as an outcome measure in treatment trials.

Treatment delay and pathways to care in early psychosis.

OBJECTIVE: To examine the treatment delay associated with community and inpatient pathways into care for persons experiencing a first episode of psychosis. METHODS: A total of 104 clients entering a specialized early psychosis intervention (EPI) program and their family members were assessed for help-seeking behaviours, psychiatric symptoms, level of functioning and duration of untreated psychosis (DUP). RESULTS: DUP (median = 30.5 weeks) was associated with younger age of onset, poorer engagement with the EPI program and more severe symptoms. Almost one-third of clients had four or more contacts before receiving antipsychotic medication or entering the EPI program and one in five received interventions not specifically indicated for psychosis. Referrals directly involving family members accounted for about 81% of hospital-initiated treatment (39% of all referrals) and 46% of community-initiated treatment (61% of all referrals). Community entry was associated with longer DUP, more time-seeking treatment, younger age of onset, younger age at referral, greater likelihood of receiving other medication or counselling before receiving antipsychotic medication, schizophrenia, less severe symptoms and less substance use in the previous year. Those with schizophrenia showed no differences across pathway type for time-seeking treatment, being provided interventions not specifically indicated for psychosis after onset or rates of substance use. CONCLUSIONS: Treatment delay and the provision of interventions not specifically indicated for psychosis may be increased in first-episode populations who are younger and have less severe symptoms. Improving literacy about early psychosis in both professionals and families merits greater attention.

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.

Self-reported cognitive and everyday functioning in persons with psychosis: the Patient Perception of Functioning Scale.

UNLABELLED: This study examined the reliability and validity of a brief, face-valid self-report measure designed to assess subjective judgments of functioning. The Patient Perception of Functioning Scale (PPFS) is a 6-item scale with ratings for both community functioning and cognition. METHOD: Sixty-eight subjects with psychotic disorders were recruited to complete the PPFS on 2 occasions and to complete a battery of neurocognitive tests. Objective ratings of overall illness severity (Clinical Global Impression), illness severity (Global Assessment of Functioning), and functioning (Social and Occupational Functioning Assessment Scale and Role Functioning Scale) were also obtained. RESULTS: The internal consistency and test-retest correlation coefficients revealed that the PPFS possesses good reliability characteristics. The PPFS did not show relationships to demographic, historical, or illness-related variables such as diagnosis or length of illness. The PPFS did show significant associations with several dimensions of community functioning. However, no significant associations were found with neurocognitive measures or clinical status. CONCLUSIONS: In populations with psychotic disorders, self-reported ratings of community function and cognition may converge less with objective cognitive measures than with objective ratings of everyday functioning. Several factors inherent to self-report methodology may have contributed to the poor convergent validity results. Theoretical underpinnings and operationalization of the underlying constructs of some neuropsychological instruments may not closely match how patients conceptualize those constructs.

New antipsychotic medications: do research results relate to clinical practice?

A number of new agents to treat schizophrenia have been, or will soon be, introduced that address the limitations of traditional neuroleptics. The new class of atypical neuroleptics promises better efficacy and/or side-effects profiles, leading to improved overall clinical outcomes. However, in order to assess the potential clinical value of these new therapies, it is important not only to study the results of various clinical trials, but also to analyze the methodology and design of the trials themselves. An understanding of the relevant patient-related issues, outcome measures, pharmacological and non-pharmacological factors is necessary to apply the findings of clinical trials to daily clinical practice.

Treatment resistant depression: a clinical perspective.

One hundred and fourteen patients with a diagnosis of "treatment resistant depression" (TRD) were assessed and treated at a Mood Disorders Clinic. Diagnostically, 52 (45.6%) subjects met criteria for bipolar disorder, 49 (42.9%) for recurrent depression, and 13 (11.4%) patients did not fulfill diagnostic criteria for affective disorder which explained their treatment resistance. With appropriate, individualized treatment, 59 of 98 (60.2%) patients had complete symptom remission based on clinical and psychometric ratings (initial Ham-D 26.7, final Ham-D 5.9). Eighteen of 98 patients had partial remission (final Ham-D 15.9) with vigorous pharmacological interventions, and 8 subjects exhibited "absolute" TRD (final Ham-D 23.4). The results suggest the value of specialized mood disorder services. The partial and absolute TRD's were more likely to be older, received more Axis II diagnoses, and had previous histories of drug or alcohol abuse.

The use and misuse of psychotropic prescribing for elderly psychiatric patients.

The presenting problems and pre-admission diagnoses of 100 consecutive admissions to a geriatric psychiatry inpatient assessment unit were assessed in a retrospective survey and the use of psychotropic medication examined. Although post-admission diagnoses showed a high proportion of depressive illness amongst the patients, depression was infrequently diagnosed prior to admission and antidepressants infrequently used. The majority of these elderly patients were referred with a diagnosis of dementia and 'behaviour problems'. These were treated prior to admission with neuroleptics or benzodiazepines in line with prescribing habits in this population reported elsewhere in North America. Attention is drawn to the significant incidence of major depression in these patients and the excellent response to treatment, both with chemotherapy or with electrotherapy. Attention is also drawn to the pre-admission prescribing of psychotropic drugs which are likely to lead to problems when used in the elderly and likely to result in significant iatrogenic disorders.

Multidimensional assessment of psychosis: a factor-analytic validation study of the Routine Assessment of Patient Progress.

The areas of function affected by major mental disorders are more diverse than the list of core symptoms assessed by many psychiatric rating scales, and the cross-sectional picture obtained in mental status interviews often fails to capture important data. Information on patient function can be obtained from measures that are based on extended observation and complement symptom-focused assessments. The Routine Assessment of Patient Progress (RAPP) is a 21-item rating scale that assesses both functional and psychiatric symptoms. It is usually completed by nursing staff who have observed patients over a 1-week period. Previous research has shown it to be reliable, valid, simple to complete, and of substantial value for patient care and diagnosis. The present study sought to examine the psychometric structure of the RAPP to define what domains of symptoms and behavior it measures. RAPP scores obtained from 165 psychotic inpatients were submitted to a factor analysis. A five-factor solution was derived in which 18 of 21 RAPP items were assigned to factors. The factors were labeled aggression, positive symptoms, negative symptoms, somatization/anxiety, and organic/ disorganization. The RAPP factors were moderately correlated with conceptually similar factor scores derived from the Positive and Negative Syndrome Scale (PANSS). RAPP aggression scores were validated with an independent clinical measure of aggression. Patients who were independently rated as improved over their hospital stay showed significant improvement on all RAPP factors, and unimproved patients showed stability or deterioration on RAPP measures. The data indicate that RAPP factors assess domains of psychopathology that are moderately correlated with both global ratings and symptom-focused scales. The RAPP's sensitivity to change suggests it is a valid measure of treatment outcome that could be used in controlled trials, as well as standard care outcome evaluation.

Donepezil in schizophrenia--is it helpful? An experimental design case study.

OBJECTIVE: To assess the clinical and cognitive effects of adding donepezil, a reversible acetylcholinesterase inhibitor, to the risperidone treatment of a high functioning stable out-patient with schizophrenia. METHOD: Case study using an experimental ABAB design. Assessments were completed objectively by standardized neuropsychological tests and clinical rating scales and subjectively with visual analogue scales. RESULTS: Strong improvements attributable to donepezil were found for verbal fluency and the patient's subjective response. No adverse changes were noted in psychiatric symptoms or side effects. CONCLUSION: Cholinergic enhancement as an adjunctive treatment in schizophrenia should be explored in larger controlled trials.

Neuropsychological correlates of the PANSS Cognitive Factor.

OBJECTIVE: Factor analytic studies of the Positive and Negative Syndrome Scale (PANSS) have consistently isolated a factor that is frequently labeled as 'cognitive'. The present study sought to further explore the factor by examining the relationships between 4 versions of the cognitive factor and a set of neuropsychological tests. METHOD: Thirty-seven inpatients diagnosed with schizophrenia or schizoaffective disorder were assessed with the PANSS and neuropsychological measures. RESULTS: Verbal intelligence and verbal memory were found to be most closely associated with cognitive factor scores. A global rating of illness severity showed greater relationships to cognitive variables than any cognitive factor. CONCLUSIONS: The PANSS cognitive factor may reflect verbal ability and memory, but is not sufficiently comprehensive to be considered as a replacement for direct assessment of cognitive functioning.

Structural brain imaging abnormalities associated with schizophrenia and partial trisomy of chromosome 5.

Chromosomal abnormalities occurring in association with mental illness provide a unique opportunity to study the interaction of genetic abnormalities and the brain in mental illness. Four individuals from a family in which schizophrenia was found to cosegregate with a partial trisomy of chromosome 5 were studied with computed tomography and magnetic resonance imaging. Temporal lobe atrophy was found in the two trisomic males and in the asymptomatic balanced translocation female. In addition, a large cavum septum pellucidum and a cavum vergae were found in the older trisomic individual. Scans from the normal male were free of abnormalities. These results suggest that molecular studies of the translocation breakpoints in this chromosomal abnormality may be of interest, and encourage further studies of brain structure in other chromosomal abnormalities associated with psychosis.