Conceptual and methodological issues in designing a randomized, controlled treatment trial for geriatric bipolar disorder: GERI-BD.

AIM: This report considers the conceptual and methodological concerns confronting clinical investigators seeking to generate knowledge regarding the tolerability and benefits of pharmacotherapy in geriatric bipolar disorder (BD) patients. METHOD: There is continuing need for evidence-based guidelines derived from randomized controlled trials that will enhance drug treatment of geriatric BD patients. Therefore, we present the complex conceptual and methodological choices encountered in designing a multisite clinical trial and the decisions reached by the investigators with the intention that study findings be pertinent to, and can facilitate, routine treatment decisions. RESULTS: Guided by a literature review and input from peers, the tolerability and antimanic effects of lithium and valproate were judged to be the key mood stabilizers to investigate with regard to treating bipolar I disorder manic, mixed, and hypomanic states. The patient selection criteria are intended to generate a sample that not only experiences common treatment needs but also represents the variety of older patients seen in university-based clinical settings. The clinical protocol guides titration of lithium and valproate to target serum concentrations, with lower levels allowed when necessitated by limited tolerability. The protocol emphasizes initial monotherapy. However, augmentation with risperidone is permitted after three weeks when indicated by operational criteria. CONCLUSIONS: A randomized, controlled trial that both investigates commonly prescribed mood stabilizers and maximizes patient participation can meaningfully address high-priority clinical concerns directly relevant to the routine pharmacologic treatment of geriatric BD patients.

Translational research in late-life mood disorders: implications for future intervention and prevention research.

Clinical and epidemiological studies have consistently observed the heterogeneous symptomatology and course of geriatric depression. Given the importance of genetic and environmental risk factors, aging processes, neurodegenerative and cerebrovascular disease processes, and medical comorbidity, the integration of basic and clinical neuroscience research approaches is critical for the understanding of the variability in illness course, as well as the development of prevention and intervention strategies that are more effective. These considerations were the impetus for a workshop, sponsored by the Geriatrics Research Branch in the Division of Adult Translational Research and Treatment Development of the National Institute of Mental Health that was held on September 7-8, 2005. The primary goal of the workshop was to bring together investigators in geriatric psychiatry research with researchers in specific topic areas outside of geriatric mental health to identify priority areas to advance translational research in geriatric depression. As described in this report, the workshop focused on a discussion of the development and application of integrative approaches combining genetics and neuroimaging methods to understand such complex issues as treatment response variability, the role of medical comorbidity in depression, and the potential overlap between depression and dementia. Future directions for integrative research were identified. Understanding the nature of geriatric depression requires the application of translational research and interdisciplinary research approaches. Geriatric depression could serve as a model for translational research integrating basic and clinical neuroscience approaches that would have implications for the study of other neuropsychiatric disorders.

Contributions of subtype and spectral frequency analyses to the study of P50 ERP amplitude and suppression in schizophrenia.

BACKGROUND: Poor suppression of P50 event-related potential (ERP) amplitudes to paired-click stimuli may indicate genetic liability for schizophrenia and weak "sensory gating." Evidence suggests, however, that P50 amplitude is selectively impaired in nonparanoid, but not paranoid, schizophrenia subtypes. Furthermore, paired-click suppression can appear deficient in schizophrenia due to smaller evoked responses to the first stimulus (S1), rather than larger, less effectively "gated" responses to the second (S2). Finally, the P50 ERP is comprised of activity from at least two frequency components that may be distinctly impaired: the gamma band, associated with sensory registration, and the low frequency response, associated with attention/encoding processes. P50 and related frequency subcomponents were examined as a function of illness subtype to further integrate these concepts. METHOD: The standard paired-click paradigm was administered to 38 schizophrenia (27 paranoid, 11 nonparanoid) and 38 age-matched healthy control participants. P50 amplitudes and spectral power of gamma band (GBR; 20-50 Hz) and low frequency (LFR; 1-20 Hz) responses were analyzed. RESULTS: P50 analyses revealed smaller S1 amplitude and normal S2 in schizophrenia participants collectively, but no differentiation of schizophrenia subtypes. Spectral analyses revealed smaller magnitude S1 and normal S2 responses in schizophrenia across both the GBR and LFR. The LFR, but not GBR, was found to distinguish nonparanoid from control groups, while paranoid participants evidenced no impairment in either frequency domain. LFR amplitude values correlated with clinical ratings of cognitive symptomatology. CONCLUSIONS: ERP deficits in the dual-click paradigm were specific to S1 amplitudes and most prominent in the low frequency response. These results replicate previous findings and extend their relevance to schizophrenia subtype distinctions. Implications for the recurrent inhibition model of sensory gating are discussed.

The relationship of neuropsychological abilities to specific domains of functional capacity in older schizophrenia patients.

BACKGROUND: This study sought to determine the relative importance of cognitive measures in predicting various domains of everyday functional capacity in older outpatients with schizophrenia. METHODS: Ninety-three psychiatry outpatients with diagnoses of schizophrenia and schizoaffective disorders underwent a comprehensive neuropsychiatric evaluation, including neuropsychological testing and clinical ratings of psychopathology. Functional capacity was assessed with the Direct Assessment of Functional Status, a performance measure of basic and instrumental activities of daily living (ADLs/IADLs). RESULTS: Neuropsychological performance significantly predicted most ADLs/IADLs measured, except simple eating behaviors, time orientation, and grooming. Lower educational level and negative symptoms also were associated with worse functional capacity, whereas positive symptoms and depressed mood were not. Measures of cognitive functioning accounted for more variance in functional capacity than did psychiatric ratings of symptoms, and multiple regression analyses demonstrated that neuropsychological performance was predictive of functional capacity, over and above clinical symptoms. No specific cognitive domains were differentially predictive of specific domains of functional capacity. CONCLUSIONS: Neurocognitive abilities were more predictive of functional capacity than level of clinical symptoms; however, these abilities were not specific predictors of functioning. This is consistent with findings of relatively generalized, intercorrelated cognitive impairment in schizophrenia and multiply determined domains of everyday functioning.

Comparative neuropsychological function in obsessive-compulsive disorder and schizophrenia with and without obsessive-compulsive symptoms.

Executive function deficits are seen in both schizophrenia and obsessive-compulsive disorder (OCD), but research suggests that dorsolateral prefrontal (DLPF) dysfunction is associated with schizophrenia and orbitofrontal (OBF) dysfunction is associated with OCD. As part of a comprehensive neuropsychological assessment, the Bechara Gambling Task (BGT) was used to assess OBF function and the Wisconsin Card Sorting Test (WCST) was used to assess DLPF function among three groups: 26 individuals with schizophrenia/schizoaffective disorder with obsessive-compulsive symptoms (SCZ+), 28 individuals with schizophrenia/schizoaffective disorder without obsessive-compulsive symptoms (SCZ-), and, 11 individuals with OCD. It was predicted that the SCZ+ group and the OCD group would show impairments in OBF function, as compared to the SCZ- group, and that the SCZ+ and SCZ- groups would show impairments in DLPF function, as compared to the OCD group. It was also predicted that the SCZ+ group would perform more poorly than the SCZ- and OCD groups in a number of other cognitive domains. Contrary to expectation, no divergence between groups was seen on tests of executive function. Instead, there was a statistical trend for the SCZ+ and SCZ- groups, when combined, to perform worse than individuals with OCD on the measure of OBF. Although not significant at the designated alpha level, the profile results showed that the SCZ+ group performed slightly below the OCD and SCZ- groups across nearly all neuropsychological domains.

Insight in schizophrenia: associations with executive function and coping style.

It has been suggested that lack of awareness of illness in schizophrenia may result from deficits in executive function and/or an avoidant style of coping. To examine this question, 132 persons with schizophrenia spectrum disorders were rated as either "aware," "partially unaware" or "unaware" of: (a) their illness, (b) need for treatment and (c) consequences of disorder on the abbreviated Scale to Assess Unawareness of Mental Disorder. We next compared the performance of the aware, partially unaware and unaware groups on the "escape-avoidance" and "positive reappraisal" subtests of the Ways of Coping Questionnaire and on two tests of executive function: the Letter Number Sequencing Subtest of the WAIS III and Wisconsin Card Sorting Test. MANCOVA followed by ANCOVA and planned comparisons, controlling for age indicated that the participants who were unaware of symptoms, treatment need and consequences generally performed more poorly than the aware groups on tests of executive function. Participants unaware of symptoms also had a greater preference for positive reappraisal than aware or partially unaware participants. The participants unaware of the consequences of disorder endorsed a greater preference for escape-avoidance than the partially unaware participants. Implications for understanding the etiology of lack of awareness in schizophrenia are discussed.

Heterogeneity in functional status among older outpatients with schizophrenia: employment history, living situation, and driving.

Schizophrenia and aging are both risk factors for deficits in independent functioning, yet relatively few studies have examined the level and predictors of functional status of older outpatients with schizophrenia. We compared employment history, current living situation, and driving status of 83 middle-aged and elderly outpatients with schizophrenia (mean age 59 years), and 46 demographically equivalent normal comparison subjects. We also examined the relationships of neuropsychological functioning and psychiatric symptoms to these aspects of everyday functioning. The schizophrenia patient group had consistently worse functional status than the normal comparison group, but 30% of the patients were employed at least 50% of the time during their post-schizophrenia-onset adult lives, 73% were living in a house or apartment and responsible for meeting most of their own daily needs, and 43% were current drivers. Severity of negative symptoms (but not that of positive symptoms) was inversely correlated with functional status. Worse performance on a neuropsychological battery was generally associated with worse functional status. These findings counter notions that functional impairment is inevitable in older schizophrenia patients, and highlight the importance of assessment of functional skills and possibly targeting them as a treatment focus.

Cognitive and clinical predictors of success in vocational rehabilitation in schizophrenia.

Cognitive impairments in schizophrenia appear to be associated with social problem solving, social and vocational functioning, and psychosocial skill acquisition. The present study examined the relationship of cognitive functioning, as well as clinical symptoms, to vocational outcomes among individuals with schizophrenia. One hundred and twelve participants with DSM-IV schizophrenia spectrum diagnoses underwent a comprehensive neuropsychiatric evaluation after enrolling in one of several employment programs. The neuropsychological evaluation examined verbal learning and memory, attention, speed of information processing, and executive functioning. Clinical symptoms were evaluated with the Positive and Negative Syndrome Scale (PANSS). Vocational outcomes were assessed 4 months after baseline assessment and included both measures of employment outcome (e.g., earnings) and of work performance as assessed by the Work Behavior Inventory (WBI). Negative symptoms, learning and memory performance, processing speed, and executive functioning were related to hours, weeks, and wages earned on the job. Stepwise multiple regression analyses found that among baseline clinical and cognitive predictors, only verbal learning and memory and cognitive disorganization symptoms were significant predictors of work behaviors 4 months later. Learning and memory were the only significant predictors of integrated employment at 4 months. These results suggest specific aspects of cognition may be modestly predictive of vocational outcomes.

Response to vocational rehabilitation during treatment with first- or second-generation antipsychotics.

OBJECTIVE: Second-generation antipsychotics may enhance the rehabilitation of individuals with schizophrenia. The authors hypothesized that clients receiving second-generation antipsychotics would use vocational rehabilitation services more effectively and would have better employment outcomes than those receiving first-generation antipsychotics. METHODS: Ninety unemployed clients with schizophrenia and related disorders who were beginning a vocational rehabilitation program were followed for nine months. Three groups were defined according to the medication in use at study entry: olanzapine (N=39), risperidone (N=27), or first-generation antipsychotics only (N=24). Participants were interviewed monthly. RESULTS: The olanzapine and risperidone groups did not differ on any employment outcomes. On most vocational indicators, clients receiving second-generation agents did not differ from those receiving first-generation agents. However, at nine months the second-generation group had a significantly higher rate of participation in vocational training; a trend was found toward a higher rate of paid employment. All groups showed substantial improvement in employment outcomes after entering a vocational program. CONCLUSIONS: The hypothesis that second-generation antipsychotics promote better employment outcomes than first-generation antipsychotics was not upheld. However, second-generation agents appear to be associated with increased participation in vocational rehabilitation.

Differences in perceptions by stage of fluid adherence.

OBJECTIVE: The purpose of this study was to determine in a group of hemodialysis patients whether perceptions of barriers to and benefits of adherence to fluid limitations, perceived seriousness of and susceptibility to the consequences of nonadherence, self-efficacy, and thirst differed by stage of fluid adherence. DESIGN: Cross-sectional descriptive design. SETTING: There were 147 participants from rural, suburban, and urban outpatient hemodialysis units. RESULTS: Significant differences were found in perceived benefits, barriers, seriousness, susceptibility, and thirst intensity by stage of fluid adherence. There were no significant differences in self-efficacy by stage of fluid adherence. CONCLUSION: Stage of fluid adherence may be important to consider when designing interventions to reduce fluid intake.

Cognitive status in hemodialysis as a function of fluid adherence.

Previous work has shown that dialysis improves cognitive functioning in hemodialysis patients, perhaps due to improvements in anemia among these patients. Such improvements in cognitive performance may lead to better levels of self-care and adherence with treatment. This study examined the relationship between fluid adherence and cognitive functioning in patients receiving hemodialysis. One hundred forty-seven patients were assessed with a brief screening instrument, the Cognistat, to determine their current level of functioning during the first hour of hemodialysis. Fluid nonadherence was operationalized as interdialytic weight gain above 1 kg/day. Rates of impairment on the Cognistat subscale ranged from 2.7% (orientation) to 54% (memory) in this sample. Roughly 68% of the sample was nonadherent during the course of treatment. Results found no differences in mean levels of cognitive performance between those who were adherent and those who were not and only modest relationships of measures of anemia to certain aspects of cognitive performance. For the hemodialysis patient to benefit from self-care education, the patient must be able to understand, remember, reason, and use cognitive processes to modify behavior. These results suggest that more in-depth assessment of cognitive performance may be needed. In addition, this assessment may need to be conducted on a day when treatment is not received.

Racial and ethnic diversity among trainees and professionals in psychology and neuropsychology: needs, trends, and challenges.

The United States is rapidly becoming a more racially and ethnically diverse nation, bringing the challenge of ensuring that health care specialties, including neuropsychology, are representative of and competent to serve the needs of this population. Initiatives have been undertaken to increase minority representation in training for psychology and neuropsychology. However, tracking progress requires reliable race/ethnicity data collection and reporting. On the 2002 American Psychological Association (APA) Directory Survey (APA Research Office, 2002), up to 42% of the APA membership and up to 25% of the Division 40 membership did not specify race/ethnicity status. Within Division 40, data for members who did report race/ethnicity suggest that representation of Hispanic, Asian, Black/African American, and Native American members lags substantially behind that of White members. Improved methods for collecting information on race/ethnicity are needed to meet diversity objectives.

Psychiatric disorder and unmet service needs among welfare clients in a representative payee program.

This study assessed psychiatric problems, needs for psychiatric and social services, and service utilization among clients of a public assistance program. Sixty-five clients were assessed using a structured clinical interview to determine the presence of a psychiatric disorder (using the CIDI-A), extent of social service need, and health-related quality of life (RAND SF-36). Seventy-seven percent of the sample met criteria for at least one current or lifetime psychiatric disorder. Health-related quality of life was substantially below published norms. Most clients reported needing financial, housing, and vocational assistance. Many had contact with mental health services, but few were actually receiving psychiatric treatment. Although many clients were assessed as having serious psychiatric, physical, or social needs, very few were receiving appropriate services for these problems. Findings suggest problems or barriers to the provision of services that need to be investigated among this vulnerable community population.

Social cognition and neurocognitive deficits in schizophrenia.

While research equivocally supports a relationship between social cognition and neurocognition, it is less clear whether social cognition is related to general cognitive functioning or whether specific aspects of social cognition are linked with specific forms of neurocognition. Thus, this study sought to investigate the relationships between various domains of neurocognition and two forms of social cognition, social cue recognition and social problem solving, for 40 people with schizophrenia spectrum disorders. Step-wise multiple regressions found that performance on neurocognitive tests was able to predict 47% and 38% of the variance on measures of the ability to recognize actual and suggested social cues, respectively, and 13% of participants' ability to problem solve in ambiguous social situations. Once estimated intelligence and hospitalization history were controlled, however, neurocognition no longer significantly predicted social problem solving. Executive functioning was uniquely related to each type of social cue recognition, while memory predicted only the recognition of concrete social cues.

Hemodynamic response patterns: responder type differences in reactivity and recovery.

We examined whether responder type groups reflecting patterns of hemodynamic reactivity might also differ in recovery responses. Cardiac output (CO), total peripheral resistance (TPR), systolic and diastolic blood pressure, heart rate, and Heather index were assessed at rest and during speech and cold pressor tasks in young adults. Participants (n = 152) were classified as myocardial, vascular, or mixed-mild responders based on CO and TPR responses to speech presentation. Vascular responders exhibited slower CO and TPR speech recovery than the myocardial and/or mixed-mild groups. Responder type differences in reactivity showed limited task-generalizability. The sustained vascular response pattern of the vascular group is consistent with that seen in hypertension. In light of associations of heightened TPR with markers of disease risk, this suggests potentially negative health implications for vascular responders.