Assessing and addressing cognitive impairment in bipolar disorder: the International Society for Bipolar Disorders Targeting Cognition Task Force recommendations for clinicians.

OBJECTIVES: Cognition is a new treatment target to aid functional recovery and enhance quality of life for patients with bipolar disorder. The International Society for Bipolar Disorders (ISBD) Targeting Cognition Task Force aimed to develop consensus-based clinical recommendations on whether, when and how to assess and address cognitive impairment. METHODS: The task force, consisting of 19 international experts from nine countries, discussed the challenges and recommendations in a face-to-face meeting, telephone conference call and email exchanges. Consensus-based recommendations were achieved through these exchanges with no need for formal consensus methods. RESULTS: The identified questions were: (I) Should cognitive screening assessments be routinely conducted in clinical settings? (II) What are the most feasible screening tools? (III) What are the implications if cognitive impairment is detected? (IV) What are the treatment perspectives? Key recommendations are that clinicians: (I) formally screen cognition in partially or fully remitted patients whenever possible, (II) use brief, easy-to-administer tools such as the Screen for Cognitive Impairment in Psychiatry and Cognitive Complaints in Bipolar Disorder Rating Assessment, and (III) evaluate the impact of medication and comorbidity, refer patients for comprehensive neuropsychological evaluation when clinically indicated, and encourage patients to build cognitive reserve. Regarding question (IV), there is limited evidence for current evidence-based treatments but intense research efforts are underway to identify new pharmacological and/or psychological cognition treatments. CONCLUSIONS: This task force paper provides the first consensus-based recommendations for clinicians on whether, when, and how to assess and address cognition, which may aid patients' functional recovery and improve their quality of life.

Validating two survey methods for identifying cases of autism spectrum disorder among adults in the community.

BACKGROUND: There are no tested methods for conducting epidemiological studies of autism spectrum disorders (ASDs) in adult general population samples. We tested the validity of the Autism Diagnostic Observation Schedule module-4 (ADOS-4) and the 20-item Autism-Spectrum Quotient (AQ-20). METHOD: Randomly sampled adults aged ≥16 years were interviewed throughout England in a general population multi-phase survey. The AQ-20 was self-completed by 7353 adults in phase 1. A random subset completed phase 2, ADOS-4 assessments (n=618); the probability of selection increased with AQ-20 score. In phase 3, informant-based Diagnostic Interview Schedule for Social and Communication Disorders (DISCO) and Autism Diagnostic Interview-Revised (ADI-R) developmental assessments were completed (n=56). Phase 1 and 2 data were presented as vignettes to six experienced clinicians (working in pairs). The probability of respondents having an ASD was compared across the three survey phases. RESULTS: There was moderate agreement between clinical consensus diagnoses and ADOS-4. A range of ADOS-4 caseness thresholds was identified by clinicians: 5+ to 13+ with greatest area under the curve (AUC) at 5+ (0.88). Modelling of the presence of ASD using 56 DISCO assessments suggested an ADOS-4 threshold in the range of 10+ to 13+ with the highest AUC at ADOS 10+ to 11+ (0.93-0.94). At ADOS 10+, the sensitivity was 1 [95% confidence interval (CI) 0.59-1.0] and the specificity 0.86 (95% CI 0.72-0.94). The AQ-20 was only a weak predictor of ADOS-4 cases. CONCLUSIONS: Clinically recommended ADOS-4 thresholds are also recommended for community cases: 7+ for subthreshold and 10+ for definite cases. Further work on adult population screening methods is needed.

Neuropsychological change in early phase schizophrenia during 12 months of treatment with olanzapine, risperidone, or haloperidol. The Canadian Collaborative Group for research in schizophrenia.

BACKGROUND: The purpose of this investigation was to test the efficacy of novel antipsychotic medications in the treatment of cognitive impairment in early phase schizophrenia. METHODS: Sixty-five patients in this multicenter double-blind study were randomly assigned to olanzapine (5-20 mg), risperidone (4-10 mg), or haloperidol (5-20 mg). Standard measures of clinical and motor syndromes were administered, as well as a comprehensive battery of tests to assess (1) motor skills, (2) attention span, (3) verbal fluency and reasoning, (4) nonverbal fluency and construction, (5) executive skills, and (6) immediate recall at baseline and after 6, 30, and 54 weeks of treatment. RESULTS: The general cognitive index derived from the 6 domain scores revealed a significantly greater benefit from treatment with olanzapine relative to haloperidol and olanzapine relative to risperidone, but no significant difference was shown between risperidone and haloperidol. The improvement related to olanzapine was apparent after 6 weeks and enhanced after 30 and 54 weeks of treatment. Exploratory within-group analyses of the 6 cognitive domains after a conservative Bonferroni adjustment revealed a significant improvement with olanzapine only on the immediate recall domain, and similar analyses of the 17 individual tests revealed a significant improvement with olanzapine only on the Hooper Visual Organization Test. CONCLUSIONS: These data suggest that olanzapine has some superior cognitive benefits relative to haloperidol and risperidone. A larger sample replication study is necessary to confirm and generalize the observations of this study and begin evaluation of the implications of this change to cerebral function and quality of life for people with schizophrenia.

The role of abacavir (ABC, 1592) in antiretroviral therapy-experienced patients: results from a randomized, double-blind, trial. CNA3002 European Study Team.

OBJECTIVE: To compare the antiviral activity of abacavir (ABC) with stable background therapy (SBG) and SBG alone in antiretroviral therapy-experienced subjects as demonstrated by the proportion of subjects with plasma HIV-1 RNA < or = 400 copies/ml, plasma HIV-1 RNA and CD4 cell count profiles, and safety and tolerance of the two regimens over 16 weeks. DESIGN: One-hundred and eighty-five HIV-1 infected adults, with CD4 cell counts > or = 100 x 10(6)/l and plasma HIV-1 RNA of 400-50,000 copies/ml and who had received SBG therapy for at least 12 weeks, were randomized to receive ABC (300 mg twice daily) or placebo in a double blind, multi-centre study. METHODS: Antiretroviral activity was assessed by measuring changes in plasma HIV-1 RNA levels and CD4 cell counts. Genotypic and phenotypic resistance was determined at baseline and week 16. Evaluation of safety and tolerance was based on clinical adverse events and laboratory analyses. RESULTS: At week 16 significantly more subjects receiving ABC + SBG had plasma HIV-1 RNA < or = 400 copies/ml (36/92, 39%) than subjects receiving SBG alone (7/93, 8%; P < 0.001). A similar response was observed in both the lamivudine naive and lamivudine-experienced subjects. The presence of the M184V mutation did not preclude an antiviral response to ABC; 73% of subjects with the M184V mutation alone experienced a > or = 1.0 log10 copies/ml reduction in plasma HIV-1 RNA or had a value of < or = 400 copies/ml by week 16. CONCLUSIONS: ABC was generally well tolerated and exerted significant antiviral effect when added to combination antiretroviral therapy over 16 weeks.

Effects on behavior of modulation of gonadal function in men with gonadotropin-releasing hormone antagonists.

The effects of acute gonadal suppression on sexual function and behavior were studied in eight normal men. Administration of a newly developed, potent gonadotropin-releasing hormone antagonist induced azoospermia and reduced levels of serum testosterone, luteinizing hormone, and follicle-stimulating hormone. These effects coincided with a reduction in outward-directed aggression in all men. Self-reported measures of anxiety and sexual desire revealed less consistent change over time. Measures of anger control, inward-directed anger, and affective state were unaffected.

Cognitive improvement in schizophrenia with novel antipsychotic medications.

The syndrome of schizophrenia often includes negative symptoms and severe cognitive deficits that are resistant to change with conventional pharmacotherapy. The efficacy of clozapine in the reduction of the negative syndrome has prompted a series of studies implicating circumscribed cognitive improvements. Restrictions on the use of clozapine have encouraged the development and introduction of novel compounds with a clinical efficacy profile similar to clozapine that are hoped also to have beneficial cognitive effects. The present review summarizes studies of the cognitive efficacy of novel antipsychotic medications, particularly in regard to issues in experiment design and study implementation that might facilitate additional research. Although preliminary support exists for relatively circumscribed improvement of cognitive status with the use of clozapine and risperidone--and more general improvement with the use of olanzapine--specific inferences relating cognitive change to particular treatments will remain speculative until more sophisticated investigations are completed. The present review emphasises the most relevant design limitations in past studies to provide practical suggestions for the implementation of subsequent investigations Previous results have established the possibility of a medication-based change in cognitive status in schizophrenia Future research will determine the validity of these changes, the cerebral mechanism involved, and their significance to improved prognosis.

Asymmetrical olfactory acuity and neuroleptic treatment in schizophrenia.

Uni-rhinal olfactory acuity in schizophrenia was investigated in two experiments. The first assessed the presence of a predicted atypical asymmetry of nostril laterality and the second assessed the effect of antipsychotic treatment on the asymmetry. Although olfactory identification impairment has been well documented in schizophrenia, olfactory acuity has been neglected. This may be an oversight as cerebral structures of the mesial temporal lobe important to olfactory perception have often been implicated in the pathophysiology of schizophrenia and it is thus reasonable to postulate a primary impairment of olfactory acuity in schizophrenia. In addition, unmedicated patients with schizophrenia have exhibited asymmetrical laterality favouring the right over the left hemisphere in studies of visual, haptic, and auditory perception, and the few published prospective treatment studies have suggested a reversal of this asymmetry with first generation neuroleptic treatments. In experiment 1 a generalization of the perceptual asymmetry to olfactory acuity was examined by measurement of n-butanol olfactory thresholds with the Connecticut Chemosensory Perception Exam (CCPE) in an unmedicated sample of 17 patients with schizophrenia and 17 age, gender, and handedness matched normal controls. The patient sample showed an asymmetrical impairment of the left nostril that was not apparent in the normal control sample. In experiment 2, the CCPE was administered to a new sample of 10 patients with schizophrenia before and after neuroleptic treatment. The asymmetry observed in experiment 1 was replicated, and the relative advantage of the right nostril shifted to a relative advantage of the left nostril over the course of 8weeks of treatment. Results are discussed in relation to cerebral aspects of schizophrenia and potential implications to cognitive change from treatment.

Neuropsychological change in schizophrenia after 6 weeks of clozapine.

Neuropsychological change after 6weeks of clozapine treatment was examined in 18 treatment-refractory patients to test anticipated domain-specific cognitive improvements. The first aim of this study was to test the assumption that increased homogeneity of sample and treatment would yield an experimental design with sufficient sensitivity to detect general intellectual changes with clozapine that were not apparent in one previous investigation. The second aim was to test predictions derived from a domain-specific review of all other investigations with clozapine suggesting salient gains on tests sensitive to motor and mental speed, visual spatial manipulation, and new learning of verbal material. The results showed that the comprehensive neuropsychological test battery was sensitive to general cognitive changes with clozapine, and supported the hypothesized domain-specific gains on tests of motor and mental speed, visual spatial manipulation and new verbal learning. Novel gains were also apparent on tests of new learning with nonverbal material. The results are discussed in relation to aspects of experimental design necessary for the evaluation of prospective medication-induced changes in cognitive skill, particularly in future investigations designed to differentiate between second-generation antipsychotic medications.

Molecular mechanisms of cardiac hypertrophy induced by toxicants.

Cardiac hypertrophy is an end point of chronic cardiac toxicity from a number of toxicants. Doxorubicin, cocaine, acetaldehyde, monocrotaline, and azide are examples of these toxicants, which may induce hypertrophy by increasing oxidants, circulating levels of catecholamines, and hemodynamic load or by inducing hypoxia. We summarize here the major signal transduction pathways and common changes in gene expression found with the classical hypertrophy inducers angiotensin II, endothelin 1, and catecholamines. Activation of G-proteins, calcium signaling, phosphoinositide 3-kinase (PI3K), certain family members of protein kinase Cs (PKCs), and three branches of mitogenactivated protein kinases (MAPKs), i.e. extracellular signal-regulated kinases (ERKs), p38, and c-Jun N-terminal kinases (JNKs), are important for developing a hypertrophic phenotype in cardiomyocytes. Characteristic changes of gene expression in hypertrophy include the elevated transcription of atrial natriuretic factor (ANF), beta-myosin heavy chain (beta MHC), skeletal alpha-actin (SkA), certain variants of integrins and perhaps tubulin genes, and reduced expression of the sarcoplasmic reticulum proteins phospholamban and sarco(endo)plasmic reticulum Ca2+-ATPase 2 alpha (SERCA2 alpha), and of the ryanodine receptors. Although which toxicants induce these molecular changes remains to be tested, increasing lines of evidence support that oxidants play a central role in cardiac hypertrophy. Oxidants activate small G-proteins, calcium signaling, PI3K, PKCs, and MAPKs. Oxidants cause cardiomyocytes to enlarge in vitro. Recent developments in transgenic, genomic, and proteomic technologies will provide needed tools to reveal the mechanism of chronic cardiac toxicity at the cellular and molecular levels.

Differential classification of dementia.

In the absence of biological markers, dementia classification remains complex both in terms of characterization as well as early detection of the presence or absence of dementing symptoms, particularly in diseases with possible secondary dementia. An empirical, statistical approach using neuropsychological measures was therefore developed to distinguish demented from non-demented patients and to identify differential patterns of cognitive dysfunction in neurodegenerative disease. Age-scaled neurobehavioral test results (Wechsler Adult Intelligence Scale-Revised and Wechsler Memory Scale) from Alzheimer's (AD) and Huntington's (HD) patients, matched for intellectual disability, as well as normal controls were used to derive a classification formula. Stepwise discriminant analysis accurately (99% correct) distinguished controls from demented patients, and separated the two patient groups (79% correct). Variables discriminating between HD and AD patient groups consisted of complex psychomotor tasks, visuospatial function, attention and memory. The reliability of the classification formula was demonstrated with a new, independent sample of AD and HD patients which yielded virtually identical results (classification accuracy for dementia: 96%; AD versus HD: 78%). To validate the formula, the discriminant function was applied to Parkinson's (PD) patients, 38% of whom were classified as demented. The validity of the classification was demonstrated by significant PD subgroup differences on measures of dementia not included in the discriminant function. Moreover, a majority of demented PD patients (65%) were classified as having an HD-like pattern of cognitive deficits, in line with previous reports of the subcortical nature of PD dementia. This approach may thus be useful in classifying presence or absence of dementia and in discriminating between dementia subtypes in cases of secondary or coincidental dementia.

Guarding confidentiality in clinical groups: the therapist's dilemma.

This study examines the confidentiality practices of highly experienced, well-trained group psychotherapists. A provocative finding was that practitioners rarely inform prospective clients of confidentiality limitations. Their reluctance to do so appears to be based upon the belief that it might discourage persons from entering treatment, as well as having negative ramifications for the therapeutic process (e.g., members may be less likely to talk about unprotected topics). The prevalence and content of breaches in confidentiality are explored. Ethical, legal, clinical, and educational implications of these and other findings are addressed. Research recommendations are offered.

Olfactory identification and Stroop interference converge in schizophrenia.

OBJECTIVE: To test the discriminant validity of a model predicting a dissociation between measures of right and left frontal lobe function in people with schizophrenia. PARTICIPANTS: Twenty-one clinically stable outpatients with schizophrenia. INTERVENTIONS: Patients were administered the University of Pennsylvania Smell Identification Test (UPSIT), the Stroop Color-Word Test (Stroop), and the Positive and Negative Syndrome Scale (PANSS). OUTCOME MEASURES: Scores on these tests and relation among scores. RESULTS: There was a convergence of UPSII and Stroop interference scores consistent with a common cerebral basis for limitations in olfactory identification and inhibition of distraction. There was also a divergence of UPSIT and Stroop reading scores suggesting that the olfactory identification limitation is distinct from a general limitation of attention or a dysfunction of the left dorsolateral prefrontal cortex. Most notable was the 81% classification convergence between the UPSIT and Stroop incongruous colour naming scores compared with the near-random 57% classification convergence of the UPSIT and Stroop reading scores. CONCLUSIONS: These data are consistent with a right orbitofrontal dysfunction in a subgroup of patients with schizophrenia, although the involvement of mesial temporal structures in both tasks must be ruled out with further study. A multifactorial model depicting contributions from diverse cerebral structures is required to describe the pathophysiology of schizophrenia. Valid behavioural methods for classifying suspected subgroups of patients with particular cerebral dysfunction would be of value in the construction of this model.

Neuropsychological change in patients with schizophrenia after treatment with quetiapine or haloperidol.

OBJECTIVE: To assess the efficacy of quetiapine, a recently introduced second generation antipsychotic medication, in reducing cognitive impairment in patients with schizophrenia. DESIGN: Prospective, randomized, double-blind clinical trial. PATIENTS: 25 patients who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, (DSM-IV) criteria for schizophrenia were recruited from 3 Canadian hospitals. INTERVENTION AND OUTCOME MEASURES: After a 48-hour washout period, 25 patients with schizophrenia were randomly assigned to double-blind treatment with quetiapine or haloperidol for 6 months and evaluated with rating scales for psychotic symptoms, mood and extrapyramidal side effects, as well as standardized neuropsychological measures sensitive to 6 cognitive domains: fine motor skill, attention span, verbal reasoning and fluency, visuospatial construction and fluency, executive skills and visuomotor tracking, and immediate recall of verbal and nonverbal materials. The measures were repeated 8 weeks and 6 months after treatment was initiated. RESULTS: Quetiapine improved psychosis and mood without inducing extrapyramidal symptoms. Quetiapine also had beneficial effects on cognitive skills, particularly verbal reasoning and fluency skills and immediate recall, with additional improvements on executive skills and visuomotor tracking and on the average of the 6 cognitive domains with sustained treatment. Patients taking haloperidol showed improvements in general clinical status, but no specific improvements on the positive syndrome, the negative syndrome, depression ratings or cognitive skills. CONCLUSIONS: These preliminary results support the potential value of quetiapine for improving cognitive impairment in patients with schizophrenia and emphasize the importance of further research with this promising atypical antipsychotic.

Effects of professional affiliation on group therapists' confidentiality attitudes and behaviors.

This study examines the influence of group therapists' professional characteristics on their attitudes and practices regarding confidentiality. Eighty-three highly experienced and well-trained group therapy providers representing the fields of psychiatry, psychology, and social work completed a survey questionnaire inquiring into their confidentiality practices. Although there is considerable consensus between medical and nonmedical practitioners on the issues addressed, there are also interesting differences and trends. Implications of the findings for clinical practice, ethics training, and confidentiality legislation are addressed.

Asymmetrical hand force persistence and neuroleptic treatment in schizophrenia.

The recent development of an isometric instrument for the precise quantification of hand force persistence has created a novel opportunity for the evaluation of potential motor asymmetries in schizophrenia and their response to treatment. A study of asymmetries in the unmedicated state may provide insight into the pathogenesis of schizophrenia, whereas alterations of asymmetries in response to antipsychotic medication could assist the delineation of a cerebral mechanism for the effects of pharmacotherapy. The hand force persistence of 21 unmedicated patients with schizophrenia was compared to 21 age, gender, and handedness matched normal controls. The effect of neuroleptic treatment on hand force persistence was then evaluated on a subset of 10 patients after at least 30 days of treatment. The anticipated asymmetry was evident in the unmedicated sample that showed impaired right hand force persistence compared to the normal control sample. The prospective comparison showed an alleviation of the asymmetry resulting from an improvement of right hand force persistence with treatment. In addition to providing further support to a primary left hemisphere cerebral involvement in schizophrenia, the present results suggest that prior investigations of motor asymmetry may have been compromised by the study of medicated patients. The apparently paradoxical improvement of motor skill may relate to the substantial number of patients treated with 2nd generation neuroleptic medications which may implicate an improvement in left hemisphere physiology in the cognitive advantages of the novel treatments.

Menstrual effects on asymmetrical olfactory acuity.

Gender specific discrepancies on psychometric examination are often interpreted to reflect static differences in cerebral hemisphere specialization, but dynamic alterations relating to circulating gonadal hormones may also be relevant after puberty. The often cited inference of a right hemisphere advantage in males and left hemisphere advantage in females derived from small but reliable differences on spatial tasks and verbal tasks, for example, may to some extent relate to gender-specific differences in circulating gonadal hormones. Performance fluctuations on other higher order cognitive tasks through the menstrual cycle tend to support a temporal association between alterations in cerebral laterality and hormone fluctuations. A potential left hemisphere advantage after menstruation when estrogen and progesterone levels are high in contrast to a right hemisphere advantage at menstruation when estrogen and progesterone levels are low has also received support from shifts in visual field perception. The present investigation continues this line of work by measurement of prospective changes in unirhinal olfactory acuity in the menstrual, ovulatory, and midluteal phases of the menstrual cycle in 11 healthy women who agreed to blood assays of estradiol and progesterone prior to completing a modified version of the Connecticut Chemosensory Perception Exam (CCPE). The CCPE detection of n-butanol showed a clear pattern of changes over the menstrual cycle marked by an asymmetry favoring the right nostril during menstruation when estradiol and progesterone levels were low, an asymmetry favoring the left nostril during ovulation when estradiol levels were high and progresterone levels were low, and an absence of asymmetry during the midluteal phase when estradiol levels decreased and progesterone levels increased. Preliminary correlation analyses revealed a potential competitive influence of estradiol and progesterone on this apparent shift in cerebral laterality. There is thus sufficient evidence to conclude that dynamic changes in relative cerebral hemisphere advantages have a temporal relation to fluctuations in circulating gonadal hormones and to suggest the value of additional investigation of more specific causal relations.

Prediction equations for normal and low lung function from the Health Survey for England.

The aim of this study was to derive new spirometric reference equations for the English population, using the 1995/1996 Health Survey for England, a large nationally representative cross-sectional study. The measurements used were the forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) of a sample of 6,053 "healthy" (nonsmokers with no reported diagnosis of asthma or respiratory symptoms) White people aged > or = 16 yrs. Multiple regression analysis, with age and height as predictors, was carried out to estimate prediction equations for mean FEV1, FVC and FEV1/FVC, separately for males and females. A method based on smoothing multiple estimates of the fifth percentiles of residuals was used to derive prediction equations for the lower limit of normal lung function. The new equations fit the current English adult population considerably better than the European Coal and Steel Community equations, and the proportions of people with "low" (below the fifth percentile) lung function are closer to those expected throughout the whole adult age range (16 to > 75 yrs). For the age ranges the studies share in common, the new equations give estimates close to those derived from other nonlinear equations in recent studies. It is, therefore, suggested that these newly developed prediction equations be used for the White English population in both epidemiological studies and clinical practice.

Risperidone in the treatment of pervasive developmental disorder.

Elevated concentrations of blood serotonin have been documented in autistic children and mentally retarded adults. Antiserotonergic pharmacotherapy has been partially effective in treating a subgroup of children with autistic disorder. Therefore, the possibility is raised that an antiserotonergic treatment may be of value to adult psychiatric patients with a history of pervasive developmental disorder. Two such cases are described where the patients underwent psychiatric and neuropsychological examination before and after treatment with risperidone, a potent 5-HT2 antagonist with additional D2 antagonistic properties. Particular improvements were documented in both patients, despite long histories of cognitive compromise and high likelihood of damage to the central nervous system.

Huntington's disease: pathogenesis, diagnosis and treatment.

This review of the clinical features of Huntington's disease incorporates recent developments in pathophysiology, preclinical diagnosis and treatment. Although the mechanism initiating and guiding the cell destruction in this illness is currently unknown, the excitatory neurotoxin and the energy metabolism models may provide a valuable direction for future research. Similarly, although the precise relation between the neuroanatomical damage in Huntington's disease and the functional disability is not clear, applications of recently developed neural connection models have implicated a number of important brain-behavior associations. Preclinical diagnostic procedures have evolved through successive iterations that have each contributed to increased reliability. New functional brain imaging techniques are sure to add to this promising domain in the future. Preclinical diagnosis has been stimulated by the recent isolation of the Huntington's gene which has also rekindled awareness of the importance of informed genetic counselling and the inherent ethical dilemmas in genetic testing. Treatment approaches to Huntington's disease have been confined to palliative care with secondary symptom management and psychotherapeutic support. Experimental therapeutic strategies for the illness itself have had a rather disappointing record to date. Further developments in NMDA antagonism and neural cell grafting may provide some hope for the future.