Absence of evidence for bornavirus infection in schizophrenia, bipolar disorder and major depressive disorder.

In 1983, reports of antibodies in subjects with major depressive disorder (MDD) to an as-yet uncharacterized infectious agent associated with meningoencephalitis in horses and sheep led to molecular cloning of the genome of a novel, negative-stranded neurotropic virus, Borna disease virus (BDV). This advance has enabled the development of new diagnostic assays, including in situ hybridization, PCR and serology based on recombinant proteins. Since these assays were first implemented in 1990, more than 80 studies have reported an association between BDV and a wide range of human illnesses that include MDD, bipolar disorder (BD), schizophrenia (SZ), anxiety disorder, chronic fatigue syndrome, multiple sclerosis, amyotrophic lateral sclerosis, dementia and glioblastoma multiforme. However, to date there has been no blinded case-control study of the epidemiology of BDV infection. Here, in a United States-based, multi-center, yoked case-control study with standardized methods for clinical assessment and blinded serological and molecular analysis, we report the absence of association of psychiatric illness with antibodies to BDV or with BDV nucleic acids in serially collected serum and white blood cell samples from 396 subjects, a study population comprised of 198 matched pairs of patients and healthy controls (52 SZ/control pairs, 66 BD/control pairs and 80 MDD/control pairs). Our results argue strongly against a role for BDV in the pathogenesis of these psychiatric disorders.

Simultaneous evaluation of the harms and benefits of treatments in randomized clinical trials: demonstration of a new approach.

BACKGROUND: One aim of personalized medicine is to determine which treatment is to be preferred for an individual patient, given all patient information available. Particularly in mental health, however, there is a lack of a single objective, reliable measure of outcome that is sensitive to crucial individual differences among patients. METHOD: We examined the feasibility of quantifying the total clinical value provided by a treatment (measured by both harms and benefits) in a single metric. An expert panel was asked to compare 100 pairs of patients, one from each treatment group, who had participated in a randomized clinical trial (RCT) involving interpersonal psychotherapy (IPT) and escitalopram, selecting the patient with the preferred outcome considering both benefits and harms. RESULTS: From these results, an integrated preference score (IPS) was derived, such that the differences between any two patients' IPSs would predict the clinicians' preferences. This IPS was then computed for all patients in the RCT. A second set of 100 pairs was rated by the panel. Their preferences were highly correlated with the IPS differences (r=0.84). Finally, the IPS was used as the outcome measure comparing IPT and escitalopram. The 95% confidence interval (CI) for the effect size comparing treatments indicated clinical equivalence of the treatments. CONCLUSIONS: A metric that combines benefits and harms of treatments could increase the value of RCTs by making clearer which treatments are preferable and, ultimately, for whom. Such methods result in more precise estimation of effect sizes, without increasing the required sample size.

Who is really at risk? Identifying risk factors for subthreshold and full syndrome eating disorders in a high-risk sample.

BACKGROUND: Numerous longitudinal studies have identified risk factors for the onset of most eating disorders (EDs). Identifying women at highest risk within a high-risk sample would allow for focusing of preventive resources and also suggests different etiologies. METHOD: A longitudinal cohort study over 3 years in a high-risk sample of 236 college-age women randomized to the control group of a prevention trial for EDs. Potential risk factors and interactions between risk factors were assessed using the methods developed previously. Main outcome measures were time to onset of a subthreshold or full ED. RESULTS: At the 3-year follow-up, 11.2% of participants had developed a full or partial ED. Seven of 88 potential risk factors could be classified as independent risk factors, seven as proxies, and two as overlapping factors. Critical comments about eating from teacher/coach/siblings and a history of depression were the most potent risk factors. The incidence for participants with either or both of these risk factors was 34.8% (16/46) compared to 4.2% (6/144) for participants without these risk factors, with a sensitivity of 0.75 and a specificity of 0.82. CONCLUSIONS: Targeting preventive interventions at women with high weight and shape concerns, a history of critical comments about eating weight and shape, and a history of depression may reduce the risk for EDs.

Predictors and moderators of time to remission of major depression with interpersonal psychotherapy and SSRI pharmacotherapy.

BACKGROUND: Although many studies suggest that, on average, depression-specific psychotherapy and antidepressant pharmacotherapy are efficacious, we know relatively little about which patients are more likely to respond to one versus the other. We sought to determine whether measures of spectrum psychopathology are useful in deciding which patients with unipolar depression should receive pharmacotherapy versus depression-specific psychotherapy. METHOD: A total of 318 adult out-patients with major depression were randomly assigned to escitalopram pharmacotherapy or interpersonal psychotherapy (IPT) at academic medical centers at Pittsburgh, Pennsylvania and Pisa, Italy. Our main focus was on predictors and moderators of time to remission on monotherapy at 12 weeks. RESULTS: Participants with higher scores on the need for medical reassurance factor of the Panic-Agoraphobic Spectrum Self-Report (PAS-SR) had more rapid remission with IPT and those with lower scores on the psychomotor activation factor of the Mood Spectrum Self-Report (MOODS-SR) experienced more rapid remission with selective serotonin reuptake inhibitor (SSRI) pharmacotherapy. Non-specific predictors of longer time to remission with monotherapy included several panic spectrum and mood spectrum factors and the Social Phobia Spectrum (SHY) total score. Higher baseline scores on the 17- and 25-item Hamilton Depression Rating Scales (HAMD-17 and HAMD-25) and the Work and Social Adjustment Scale (WSAS) also predicted a longer time to remission, whereas being married predicted a shorter time to remission. CONCLUSIONS: This exploratory study identified several non-specific predictors but few moderators of psychotherapy versus pharmacotherapy outcome. It offers useful indicators of the characteristics of patients that are generally difficult to treat, but only limited guidance as to who benefits from IPT versus SSRI pharmacotherapy.

Is late-onset schizophrenia a subtype of schizophrenia?

OBJECTIVE: To determine whether late-onset schizophrenia (LOS, onset after age 40) should be considered a distinct subtype of schizophrenia. METHOD: Participants included 359 normal comparison subjects (NCs) and 854 schizophrenia out-patients age >40 (110 LOS, 744 early-onset schizophrenia or EOS). Assessments included standardized measures of psychopathology, neurocognition, and functioning. RESULTS: Early-onset schizophrenia and LOS groups differed from NCs on all measures of psychopathology and functioning, and most cognitive tests. Early-onset schizophrenia and LOS groups had similar education, severity of depressive, negative, and deficit symptoms, crystallized knowledge, and auditory working memory, but LOS patients included more women and married individuals, had less severe positive symptoms and general psychopathology, and better processing speed, abstraction, verbal memory, and everyday functioning, and were on lower antipsychotic doses. Most EOS-LOS differences remained significant after adjusting for age, gender, severity of negative or deficit symptoms, and duration of illness. CONCLUSION: Late-onset schizophrenia should be considered a subtype of schizophrenia.

Spatial test for agricultural pesticide "blow-in" effect on prevalence of Parkinson's disease.

The current study used Department of Veteran's Affairs (VA) clinical records, State of California pesticide application records, spatial maps of distribution of Parkinson's disease patients, and pesticide applications to determine if there was evidence for "blow-in" of pesticides as a factor in explaining the prevalence of Central Valley Parkinson's disease. The results did not support the hypothesis of increasing prevalence of Parkinsonism attributable to wind drift.

Diurnal cortisol rhythm as a predictor of breast cancer survival.

BACKGROUND: : Abnormal circadian rhythms have been observed in patients with cancer, but the prognostic value of such alterations has not been confirmed. We examined the association between diurnal variation of salivary cortisol in patients with metastatic breast cancer and subsequent survival. We explored relationships between cortisol rhythms, circulating natural killer (NK) cell counts and activity, prognostic indicators, medical treatment, and psychosocial variables. METHODS: Salivary cortisol levels of 104 patients with metastatic breast cancer were assessed at study entry at 0800, 1200, 1700, and 2100 hours on each of 3 consecutive days, and the slope of diurnal cortisol variation was calculated using a regression of log-transformed cortisol concentrations on sample collection time. NK cell numbers were measured by flow cytometry, and NK cell activity was measured by the chromium release assay. The survival analysis was conducted by the Cox proportional hazards regression model with two-sided statistical testing. RESULTS: Cortisol slope predicted subsequent survival up to 7 years later. Earlier mortality occurred among patients with relatively "flat" rhythms, indicating a lack of normal diurnal variation (Cox proportional hazards, P =. 0036). Patients with chest metastases, as opposed to those with visceral or bone metastases, had more rhythmic cortisol profiles. Flattened profiles were linked with low counts and suppressed activity of NK cells. After adjustment for each of these and other factors, the cortisol slope remained a statistically significant, independent predictor of survival time. NK cell count emerged as a secondary predictor of survival. CONCLUSIONS: Patients with metastatic breast cancer whose diurnal cortisol rhythms were flattened or abnormal had earlier mortality. Suppression of NK cell count and NK function may be a mediator or a marker of more rapid disease progression.

The evaluation of different approaches to randomized clinical trials. Report on the 1987 MacArthur Foundation Network I Methodology Workshop.

The second annual MacArthur Foundation Network I Methodology Workshop focused on the different approaches to implementing randomized controlled clinical trials (RCTs) and the situations in which each approach seems to be most appropriate. We reviewed the advantages and disadvantages of various approaches (single-site RCTs, multisite collaborative RCTs, multiple single-site RCTs, and meta-analysis of existing RCTs), and we make recommendations based on these considerations proposed.

Relaxation therapy in the treatment of hypertension. A review.

The literature on the use of relaxation or relaxation-like procedures (relaxation therapy) in the treatment of hypertension was critically reviewed. Relaxation therapy resulted in greater reduction of blood pressure than placebo or other control procedures. A positive relationship was found between the average blood pressure decrease and the average pretreatment pressure. Relaxation-like therapies shared the features of muscular relaxation, regular practice, mental focusing, and task awareness. Research on the relative contributions of these components indicated that task awareness adds to the treatment effect in the laboratory setting, and that regular practice is necessary for optimal results in the clinical setting. The role of muscular relaxation and mental focusing is unclear. We concluded that relaxation therapy may become a useful adjunct to medication in the clinical management of hypertension, especially for individuals whose blood pressures remain high despite pharmacological treatment.

A multicenter comparison of cognitive-behavioral therapy and interpersonal psychotherapy for bulimia nervosa.

BACKGROUND: Research suggests that cognitive-behavioral therapy (CBT) is the most effective psychotherapeutic treatment for bulimia nervosa. One exception was a study that suggested that interpersonal psychotherapy (IPT) might be as effective as CBT, although slower to achieve its effects. The present study is designed to repeat this important comparison. METHOD: Two hundred twenty patients meeting DSM-III-R criteria for bulimia nervosa were allocated at random to 19 sessions of either CBT or IPT conducted over a 20-week period and evaluated for 1 year after treatment in a multisite study. RESULTS: Cognitive-behavioral therapy was significantly superior to IPT at the end of treatment in the percentage of participants recovered (29% [n=32] vs 6% [n=71), the percentage remitted (48% [n=53] vs 28% [n = 31]), and the percentage meeting community norms for eating attitudes and behaviors (41% [n=45] vs 27% [n=30]). For treatment completers, the percentage recovered was 45% (n= 29) for CBT and 8% (n= 5) for IPT. However, at follow-up, there were no significant differences between the 2 treatments: 26 (40%) CBT completers had recovered at follow-up compared with 17 (27%) IPT completers. CONCLUSIONS: Cognitive-behavioral therapy was significantly more rapid in engendering improvement in patients with bulimia nervosa than IPT. This suggests that CBT should be considered the preferred psychotherapeutic treatment for bulimia nervosa.

Relaxation training, twenty-four-hour blood pressure reductions.

If the demonstrated effects of relaxation training on blood pressure (BP) occur only during relaxation practice, then little effect on the morbidity and mortality of exssential hypertensives would be expected. This question was addressed by inpatient monitoring of five hypertensive patients' BP for 24 hours during six experimental days, including a no-treatment baseline, three days of relaxation training, and one day of recovery. Lowering of both systolic and diastolic pressures persisted beyond the end of the training sessions. Moreover, systolic BP was significantly lower during relaxation training days than during either baseline or recovery days, a difference particularly noticeable at night when patients were sleeping. The BPs of the three patients showing the largest initial effects of training averaged 12.5/7.3 mm Hg less during nights following relaxation sessions than during nights following no treatment.

Relaxation training. Blood pressure lowering during the working day.

Controlled studies have demonstrated that relaxation training can lead to significant in-clinic blood pressure (BP) reductions in patients with essential hypertension. We examined the BP-lowering effect of relaxation training during the working day. Forty-two patients being treated for essential hypertension with diastolic BPs greater than 90 mm Hg were randomized into either a relaxation training program or no treatment. Multiple BP measurements were made during the working hours, using an ambulatory monitoring device, before and after training. Significant work-site differences between groups were evident after treatment both for systolic and diastolic pressures. These results suggest that relaxation therapy leads to a reduction in BP that is evident in the natural environment, providing new evidence that the procedure is a useful adjunct to the treatment of hypertensive patients.

Methodology in psychiatric research. Report on the 1986 MacArthur Foundation Network I Methodology Institute.

This report discusses many of the issues raised during a two-day institute that focused on methodological problems encountered in psychiatric research. The topics range from the problems with psychiatric diagnosis and measurement to sampling issues and biases to specific statistical concerns. Attention is given to the need for improved communication and collaboration between psychiatric researchers and biostatisticians.

Coming to terms with the terms of risk.

Terms such as risk, risk factors, and especially the term cause are inconsistently and imprecisely used, fostering scientific miscommunication and misleading research and policy. Clarifying such terms is the essential first step. We define risk and a risk factor (protective factor) and their potency, set out the conceptual basis of the methods by which risk factors are identified and potency demonstrated, and propose criteria for establishing the status of a risk factor as a fixed or variable marker or a causal risk factor. All definitions are based on the state of scientific knowledge (empirical documentation), rather than on hypotheses, speculations, or beliefs. We discuss common approaches and pitfalls and give a psychiatric research example. Imprecise reports can impede the search for understanding the cause and course of any disease and also may be a basis of inadequate clinical or policy decision-making. The issues in risk research are much too important to tolerate less than precise terminology or the less than rigorous research reporting that results from imprecise and inconsistent terminology.

Supportive-expressive group therapy and distress in patients with metastatic breast cancer: a randomized clinical intervention trial.

BACKGROUND: Metastatic breast cancer carries with it considerable psychosocial morbidity. Studies have shown that some patients with metastatic breast cancer experience clinically significant anxiety and depression and traumatic stress symptoms. Supportive-expressive group psychotherapy was developed to help patients with cancer face and adjust to their existential concerns, express and manage disease-related emotions, increase social support, enhance relationships with family and physicians, and improve symptom control. METHODS: Of 125 women with metastatic breast cancer recruited into the study, 64 were randomized to the intervention and 61 to the control condition. Intervention women were offered 1 year of weekly supportive-expressive group therapy and educational materials. Control women received educational materials only. Participants were assessed at baseline and every 4 months during the first year. Data at baseline and from at least 1 assessment were collected from 102 participants during this 12-month period, and these participants compose the study population. RESULTS: Primary analyses based on all available data indicated that participants in the treatment condition showed a significantly greater decline in traumatic stress symptoms on the Impact of Event Scale (effect size, 0.25) compared with the control condition, but there was no difference in Profile of Mood States total mood disturbance. However, when the final assessment occurring within a year of death was removed, a secondary analysis showed a significantly greater decline in total mood disturbance (effect size, 0.25) and traumatic stress symptoms (effect size, 0.33) for the treatment condition compared with the control condition. CONCLUSION: Supportive-expressive therapy, with its emphasis on providing support and helping patients face and deal with their disease-related stress, can help reduce distress in patients with metastatic breast cancer.

Some conceptual and statistical issues in analysis of longitudinal psychiatric data. Application to the NIMH treatment of Depression Collaborative Research Program dataset.

Longitudinal studies have a prominent role in psychiatric research; however, statistical methods for analyzing these data are rarely commensurate with the effort involved in their acquisition. Frequently the majority of data are discarded and a simple end-point analysis is performed. In other cases, so called repeated-measures analysis of variance procedures are used with little regard to their restrictive and often unrealistic assumptions and the effect of missing data on the statistical properties of their estimates. We explored the unique features of longitudinal psychiatric data from both statistical and conceptual perspectives. We used a family of statistical models termed random regression models that provide a more realistic approach to analysis of longitudinal psychiatric data. Random regression models provide solutions to commonly observed problems of missing data, serial correlation, time-varying covariates, and irregular measurement occasions, and they accommodate systematic person-specific deviations from the average time trend. Properties of these models were compared with traditional approaches at a conceptual level. The approach was then illustrated in a new analysis of the National Institute of Mental Health Treatment of Depression Collaborative Research Program dataset, which investigated two forms of psychotherapy, pharmacotherapy with clinical management, and a placebo with clinical management control. Results indicated that both person-specific effects and serial correlation play major roles in the longitudinal psychiatric response process. Ignoring either of these effects produces misleading estimates of uncertainty that form the basis of statistical tests of hypotheses.

Medical evaluation of psychiatric patients. I. Results in a state mental health system.

Thorough medical evaluation of 529 patients drawn from eight program categories in California's public mental health system revealed active, important physical disease in 200 patients who had 291 diseases. Fourteen percent of the patients had diseases known to themselves but not to the mental health system, and 12% of the patients had diseases newly detected by the study team. We estimate that of the more than 300,000 patients treated in the California public mental health system in fiscal year 1983 to 1984, 45% had an active, important physical disease. The mental health system had recognized only 47% of study patients' physical diseases, including 32 of 38 diseases causing a mental disorder and 23 of 51 diseases exacerbating a mental disorder. Patients treated in public sector mental health facilities should receive careful medical evaluations.

National Institute of Mental Health Collaborative Multimodal Treatment Study of Children with ADHD (the MTA). Design challenges and choices.

The Collaborative Multimodal Treatment Study of Children with Attention Deficit Hyperactivity Disorder (ADHD), the MTA, is the first child multisite cooperative agreement treatment study of children conducted by the National Institute of Mental Health, Rockville, Md. It examines the long-term effectiveness of medication vs behavioral treatment vs both for treatment of ADHD and compares state-of-the-art treatment with routine community care. In a parallel-groups design, 576 children (age, 7-9 years) with ADHD (96 at each site) are thoroughly assessed and randomized to 4 conditions: (1) medication alone, (2) psychosocial treatment alone, (3) the combination of both, (4) or community comparison. The first 3 groups are treated for 14 months and all are reassessed periodically for 24 months. Designers met the following challenges: framing clinically relevant primary questions; defining the target population; choice, intensity, and integration and combination of treatments for fair comparisons; combining scientific controls and standardization with clinical flexibility; and implementing a controlled clinical trial in a nonclinical setting (school) controlled by others. Innovative solutions included extensive decision algorithms and manualized adaptations of treatments to specific needs.

A cycle of plasma testosterone in the human male.

The object of the study was to assess the lability of testosterone levels in plasma of normal human males over a long period of time and to search for periodicities in changing levels. Blood samples obtained from 20 healthy young men every second day for 2 months were assayed for total testosterone concentration by radioligand saturation analysis with late-pregnancy plasma. The flucturations of plasma testosterone levels over the total time span were substantial for most individuals; the coefficients of variation ranged from 14 to 42% (median 21%). The presence of periodic functions in these fluctuations was tested by 4 different, relatively independent methods. Close agreement among at least 3 analytic methods was found for 12 out of the 20 subjects. These 12 subjects had cycles of plasma testosterone levels with periods ranging between 8-30 days, with a cluster of periods around 20-22 days. The majority of such cycles were significant at least at the 5% level. The mean amplitudes of these cycles ranged from 9 to 28% of the subjects' mean testosterone levels (average 17%).

Use of placebo control groups in evaluating efficacy of treatment of unipolar major depression.

Double-blind, random-assignment placebo-controlled trials are routinely used in evaluating efficacy of potential antidepressant agents. In recent years concern has risen that placebo response rates in unipolar depression are too high, and this has eroded confidence in both old and new agents. At the same time, the use of placebos has been questioned by patients and their advocates. We review factors that have been commonly explored as associated with placebo response (e.g., length of episode, severity, subtype), as well as issues in methodology (e.g., interrater reliability, statistical artifacts). We discuss possible methods of dealing with the problem of placebo response, emphasizing reconceptualizing effect sizes to design more powerful single trials and a systematic sequence of trials to achieve the right answers.