Obesity, but not metabolic syndrome, negatively affects outcome in bipolar disorder.

OBJECTIVE: Examine the effects of obesity and metabolic syndrome on outcome in bipolar disorder. METHOD: The Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer and a Classic Mood Stabilizer for Bipolar Disorder (Bipolar CHOICE) study randomized 482 participants with bipolar disorder in a 6-month trial comparing lithium- and quetiapine-based treatment. Baseline variables were compared between groups with and without obesity, with and without abdominal obesity, and with and without metabolic syndrome respectively. The effects of baseline obesity, abdominal obesity, and metabolic syndrome on outcomes were examined using mixed effects linear regression models. RESULTS: At baseline, 44.4% of participants had obesity, 48.0% had abdominal obesity, and 27.3% had metabolic syndrome; neither obesity, nor abdominal obesity, nor metabolic syndrome were associated with increased global severity, mood symptoms, or suicidality, or with poorer functioning or life satisfaction. Treatment groups did not differ on prevalence of obesity, abdominal obesity, or metabolic syndrome. By contrast, among the entire cohort, obesity was associated with less global improvement and less improvement in total mood and depressive symptoms, suicidality, functioning, and life satisfaction after 6 months of treatment. Abdominal obesity was associated with similar findings. Metabolic syndrome had no effect on outcome. CONCLUSION: Obesity and abdominal obesity, but not metabolic syndrome, were associated with less improvement after 6 months of lithium- or quetiapine-based treatment.

Medication adherence in a comparative effectiveness trial for bipolar disorder.

OBJECTIVE: Psychopharmacology remains the foundation of treatment for bipolar disorder, but medication adherence in this population is low (range 20-64%). We examined medication adherence in a multisite, comparative effectiveness study of lithium. METHOD: The Lithium Moderate Dose Use Study (LiTMUS) was a 6-month, six-site, randomized effectiveness trial of adjunctive moderate dose lithium therapy compared with optimized treatment in adult out-patients with bipolar I or II disorder (N=283). Medication adherence was measured at each study visit with the Tablet Routine Questionnaire. RESULTS: We found that 4.50% of participants reported missing at least 30% of their medications in the past week at baseline and non-adherence remained low throughout the trial (<7%). Poor medication adherence was associated with more manic symptoms and side-effects as well as lower lithium serum levels at mid- and post-treatment, but not with poor quality of life, overall severity of illness, or depressive symptoms. CONCLUSION: Participants in LiTMUS were highly adherent with taking their medications. The lack of association with possible predictors of adherence, such as depression and quality of life, could be explained by the limited variance or other factors as well as by not using an objective measure of adherence.

General medical burden in bipolar disorder: findings from the LiTMUS comparative effectiveness trial.

OBJECTIVE: This study examined general medical illnesses and their association with clinical features of bipolar disorder. METHOD: Data were cross-sectional and derived from the Lithium Treatment - Moderate Dose Use Study (LiTMUS), which randomized symptomatic adults (n = 264 with available medical comorbidity scores) with bipolar disorder to moderate doses of lithium plus optimized treatment (OPT) or to OPT alone. Clinically significant high and low medical comorbidity burden were defined as a Cumulative Illness Rating Scale (CIRS) score ≥4 and <4 respectively. RESULTS: The baseline prevalence of significant medical comorbidity was 53% (n = 139). Patients with high medical burden were more likely to present in a major depressive episode (P = .04), meet criteria for obsessive-compulsive disorder (P = .02), and experience a greater number of lifetime mood episodes (P = 0.02). They were also more likely to be prescribed a greater number of psychotropic medications (P = .002). Sixty-nine per cent of the sample was overweight or obese as defined by body mass index (BMI), with African Americans representing the racial group with the highest proportion of stage II obesity (BMI ≥35; 31%, n = 14). CONCLUSION: The burden of comorbid medical illnesses was high in this generalizable sample of treatment-seeking patients and appears associated with worsened course of illness and psychotropic medication patterns.

The association between course of illness and subsequent morbidity in bipolar I disorder.

OBJECTIVE: We examined the relationship between certain bipolar I disorder clinical course variables over 5 years with outcome over the subsequent 5-year period. METHODS: Prospective observational follow-up data of 123 bipolar I subjects were analyzed. Predictive clinical variables included the frequency and direction of switches, and the quantity, polarity and length of affective periods. Outcome variables were an affective burden index (ABI) accounting for week-by-week severity and weeks hospitalized. Bivariate analyses guided the selection of predictors for multivariable analyses against the outcome variables. RESULTS: Affective burden index: while the number and direction of switches, the number of polyphasic episodes, weeks in hypomania/mania/mixed state, weeks in minor/major depression, weeks in at least marked affective syndrome, and weeks in any affective syndrome all had bivariate correlation (p<0.01) with the ABI, only weeks in hypomania/mania/mixed state and weeks in minor/major depression made significant contributions in the multivariable analysis (p<0.01) with the ABI. Weeks hospitalized: weeks in at least marked affective syndrome were significantly correlated with weeks hospitalized in bivariate analysis (p<0.01), and maintained a contribution to weeks hospitalized in the multivariable analysis (p<0.01). CONCLUSIONS: The quantity and severity of weeks in symptomatic affective states are possibly greater predictors of affective burden in bipolar I patients than the quantity and direction of affective switches.

More reliable outcome measures can reduce sample size requirements.

In the design of a clinical trial, considerations of statistical power primarily involve the evaluation of prospective sample sizes. Another strategy for increasing statistical power that is rarely used focuses on the selection of the outcome measure. When an outcome measure is selected, its reliability and validity must be carefully evaluated. Here the relationship between reliability and statistical power is explored empirically. We show that as the number of related items in an outcome scale increases, the internal consistency reliability of the scale also increases. As a consequence, the within-group variability decreases and, in turn, the between-group effect size increases and sample size requirements decrease. As a result, sample size requirements can be reduced and research costs decreased. We recommend careful consideration of the psychometric properties of outcome measures prior to sample size determination in any statistical power analyses.

Cognitive behavioral treatment compared with nonprescriptive treatment of panic disorder.

BACKGROUND: The efficacy of cognitive behavioral treatment for panic disorder has been established in controlled studies. However, little is known about the efficacy of other psychological treatments. We report the results of a study comparing cognitive behavioral treatment with a focused nonprescriptive treatment for panic. METHODS: Three sessions of panic-related information were provided in each treatment, followed by 12 sessions of either nonprescriptive, reflective listening (non-prescriptive treatment) or a treatment package that included breathing retraining, muscle relaxation, cognitive reframing, and exposure to interoceptive and agoraphobic stimuli (cognitive behavioral treatment). RESULTS: Posttreatment and 6-month follow-up assessments revealed a good response to both treatments. We observed a high rate of panic remission and significant improvement in associated symptoms in subjects in each treatment group. CONCLUSION: These findings raise questions about the specificity of cognitive behavioral treatment.

The effect of access to lethal methods of injury on suicide rates.

The relationship between the availability of lethal methods of injury and suicide rates is an important, but unresolved question. We investigated this relationship by prospectively classifying lethal methods according to their accessibility in the five counties of New York City. These counties have both similarities and differences in the proportion of their populations with access to specific lethal means. We then compared the age- and gender-adjusted method-specific suicide rates of these counties. There were marked differences in overall crude suicide rates among the five counties. The counties had similar suicide rates involving methods that were equally accessible to all persons in each county (eg, hanging, laceration, suffocation, and burns) as well as methods that were accessible to a smaller, but similar proportion of the population in each county (eg, firearms and drowning in waterways). Virtually all of the differences in overall suicide risk among counties were explained by differences in rates involving methods that were differentially available in the counties, principally fall from height, overdose of prescription medications, and carbon monoxide poisoning. We conclude that differences in suicide rates between communities are, in large part, due to differences in accessibility to lethal methods of injury. Therefore, systematic studies should evaluate the effect of reducing accessibility to specific lethal means on suicide rates.

Subthreshold psychiatric symptoms in a primary care group practice.

BACKGROUND: The authors define 6 groups of subthreshold psychiatric symptoms that do not meet the full criteria for a DSM-IV Axis I disorder and examine the clinical significance of these symptoms in an outpatient primary care sample. METHODS: The subjects were 1001 adult primary care patients in a large health maintenance organization. Data on sociodemographic characteristics and functional impairment, including scores on the Sheehan Disability Scale, were collected at the time of the medical visit, and a structured diagnostic interview for DSM-IV disorders was completed by telephone within 4 days of the visit. Subthreshold symptoms were defined for depressive, anxiety, panic, obsessive-compulsive, drug, and alcohol symptoms. RESULTS: Subthreshold symptoms were as or more common than their respective Axis I disorders: panic (10.5% vs 4.8%), depression (9.1% vs 7.3%), anxiety (6.6% vs 3.7%), obsessive-compulsive (5.8% vs 1.4%), and alcohol (5.3% vs 5.2%) and other drug (3.7% vs 2.4%) cases. Patients with each of the subthreshold symptoms had significantly higher Sheehan Disability Scale scores (greater impairment) than did patients with no psychiatric symptoms. Many patients (22.6%-53.4%) with subthreshold symptoms also met the full criteria for other Axis I disorders. After adjusting for the confounding effects of other Axis I disorders, other subthreshold symptoms, age, sex, race, marital status, and perceived physical health status, only depressive symptoms, major depressive disorder, and, to a lesser extent, panic symptoms were significantly correlated with the impairment measures. CONCLUSIONS: In these primary care patients, the morbidity of subthreshold symptoms was often explained by confounding mental, physical, or demographic factors. However, depressive symptoms and, to a lesser extent, panic symptoms were disabling even after controlling for these factors. Primary care clinicians who detect subthreshold psychiatric symptoms should consider a broad psychiatric assessment.

The time course of nonchronic major depressive disorder. Uniformity across episodes and samples. National Institute of Mental Health Collaborative Program on the Psychobiology of Depression--Clinical Studies.

BACKGROUND: Most natural history studies of affective disorders have emphasized the prediction of eventual recovery. Little is known of changes over time in the immediate probability of recovery. METHODS: To identify regularities in the timing of recovery from nonbipolar major depressive disorders, we considered only episodes that began during follow-up to increase the accuracy with which onsets were timed and to limit the study sample to individuals who had a demonstrably episodic course. Five participating centers conducted baseline assessments and followed probands (N = 605) and nonclinical subjects (relatives, controls, and spouses, N = 826) up for 6 years. During that time, 359 probands had at least one prospectively observed episode, and 181 had two episodes; corresponding numbers for the nonclinical subjects were 216 and 78, respectively. Our analyses considered the distribution of episode lengths across ascertainment source (probands vs nonclinical subjects), center, and episode number (first vs second prospectively observed episode). RESULTS: Distribution was remarkably uniform. Regardless of ascertainment source, center, or episode number, recovery occurred within 3 months in 40% of episodes, within 6 months in 60%, and within 1 year in 80%; 20% had more protracted courses. CONCLUSIONS: Once triggered, the immediate likelihood of recovery changes over time in a predictable fashion. This has practical implications for the study of antidepressant efficacy and theoretical implications for factors involved in affective dysregulation.

Relationship between central and peripheral serotonin indexes in depressed and suicidal psychiatric inpatients.

Serious suicidal behavior, affective disorders, and a variety of other psychopathologic behaviors and syndromes have been found to correlate with measures of the serotonin system. Clinical studies have employed a range of serotonin indexes, including the cerebrospinal fluid level of 5-hydroxyindoleacetic acid, the prolactin response to serotonin agonists, such as fenfluramine hydrochloride, and platelet serotonin-related proteins or serotonin content. Many of these indexes are correlated with suicidal behavior, but the interrelationship of these biologic measures has been uncertain. We studied the relationship of a series of serotonin indexes in patients in whom these measures were correlated with suicidal behavior. A positive correlation was found between cerebrospinal fluid 5-hydroxyindoleacetic acid and the maximal prolactin response to fenfluramine but not with platelet serotonin2 receptor indexes. The fenfluramine-stimulated maximal prolactin response correlated with platelet serotonin2 receptor number, particularly in older patients. We conclude that cerebrospinal fluid 5-hydroxyindoleacetic acid measurements cannot be replaced but can be complemented by less invasive procedures, such as a fenfluramine challenge test or platelet serotonin2 measures, in the study of the relationship of the serotonin system to psychiatric disorders.

Maintenance therapy for chronic depression. A controlled clinical trial of desipramine.

BACKGROUND: Previous studies have shown the efficacy of antidepressants in the treatment of chronic depression. We report the results of a long-term study comparing desipramine hydrochloride and placebo for maintenance therapy of remitted patients with chronic depression. METHODS: Outpatients who met DSM-III-R diagnostic criteria for "pure" dysthymia (n = 51), dysthymia with current major depression ("double depression") (n = 64), or chronic major depression (n = 14) were treated on an open basis with desipramine. Full and partial remitters after 10 weeks entered a continuation phase of open treatment with desipramine for 16 weeks. Remitted patients then were randomized to continue desipramine treatment or tapered to placebo treatment for a maintenance phase of up to 2 years. Relapse rates and time to relapse during maintenance therapy were compared between the two treatment groups. RESULTS: Acute-phase treatment results did not differ significantly according to chronic depression subtype. Remission persisted with a high degree of stability during the continuation phase. Relapse rates during the maintenance phase were 52% for the placebo group and 11% for the active desipramine group (chi 2 = 8.1, P = .004). Most placebo relapses occurred during the first 6 months of maintenance therapy. Active medication was significantly more effective than placebo in that subgroup entering the maintenance phase in full remission and in those patients who fulfilled criteria for a diagnosis of pure dysthymia or double depression on entry to the study. CONCLUSION: Long-term maintenance treatment with desipramine appeared to be effective in the prevention or postponement of relapse of depression in patients who responded to desipramine during the acute and continuation phases.

Recovery after 5 years of unremitting major depressive disorder.

BACKGROUND: The long-term course of depression in patients who present for treatment carries prognostic and therapeutic implications. This study presents prospective data on the time to recovery from an episode of major depressive disorder of 5 years' duration among patients followed up since 1978 in the National Institutes of Mental Health Collaborative Program on the Psychobiology of Depression. METHODS: Survival analysis was used to examine the 10-year course of the 431 probands with major depressive disorder with a specific focus on the 35 probands who were observed to be continuously ill for the first 5 years. Univariate analytic techniques were used to describe the demographic and clinical variables in the group that recovered and the group that did not. By study design, somatic treatment was assessed but not controlled by the investigators. RESULTS: By year 10, 93% (Kaplan-Meier estimate) of probands had recovered from their intake episode of major depressive disorder. In those ill for the first 5 years, 38% had recovered within the next 5 years. Shorter duration of illness prior to intake and being married were associated with the group that recovered. Pharmacological treatment dosages averaged 100 mg of imipramine hydrochloride equivalent in the chronically ill group. CONCLUSIONS: Despite lengthy periods of illness, people continued to recover from major depressive disorder for up to 10 years of prospective follow-up. Few demographic and clinical variables distinguished those who recovered from those who did not. Treatment, as observed in this naturalistic study, was at a low level despite lengthy illness.

Recovery from major depression. A 10-year prospective follow-up across multiple episodes.

BACKGROUND: Major depressive disorder is often marked by repeated episodes of depression. We describe recovery from major depression across multiple mood episodes in patients with unipolar major depression at intake and examine the association of sociodemographic and clinical variables with duration of illness. METHODS: A cohort of 258 subjects treated for unipolar major depressive disorder was followed up prospectively for 10 years as part of the Collaborative Depression Study, a multicenter naturalistic study of the mood disorders. Diagnoses were made according to the Research Diagnostic Criteria, and the course of illness was assessed with the Longitudinal Interval Follow-up Evaluation. Survival analyses were used to calculate the duration of illness for the first 5 recurrent mood episodes after recovery from the index episode. RESULTS: Diagnosis remained unipolar major depressive disorder for 235 subjects (91%). The median duration of illness was 22 weeks for the first recurrent mood episode, 20 weeks for the second, 21 weeks for the third, and 19 weeks for the fourth and fifth recurrent mood episodes; the 95% confidence intervals were highly consistent. From one episode to the next, the proportion of subjects who recovered by any one time point was similar. For subjects with 2 or more recoveries, the consistency of duration of illness from one recovery to the next was low to moderate. None of the sociodemographic or clinical variables consistently predicted duration of illness. CONCLUSION: In this sample of patients treated at tertiary care centers for major depressive disorder, the duration of recurrent mood episodes was relatively uniform and averaged approximately 20 weeks.

Psychosocial disability during the long-term course of unipolar major depressive disorder.

BACKGROUND: The goal of this study was to investigate psychosocial disability in relation to depressive symptom severity during the long-term course of unipolar major depressive disorder (MDD). METHODS: Monthly ratings of impairment in major life functions and social relationships were obtained during an average of 10 years' systematic follow-up of 371 patients with unipolar MDD in the National Institute of Mental Health Collaborative Depression Study. Random regression models were used to examine variations in psychosocial functioning associated with 3 levels of depressive symptom severity and the asymptomatic status. RESULTS: A progressive gradient of psychosocial impairment was associated with a parallel gradient in the level of depressive symptom severity, which ranges from asymptomatic to subthreshold depressive symptoms to symptoms at the minor depression/dysthymia level to symptoms at the MDD level. Significant increases in disability occurred with each stepwise increment in depressive symptom severity. CONCLUSIONS: During the long-term course, disability is pervasive and chronic but disappears when patients become asymptomatic. Depressive symptoms at levels of subthreshold depressive symptoms, minor depression/ dysthymia, and MDD represent a continuum of depressive symptom severity in unipolar MDD, each level of which is associated with a significant stepwise increment in psychosocial disability.

A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders.

BACKGROUND: Investigations of unipolar major depressive disorder (MDD) have focused primarily on major depressive episode remission/recovery and relapse/recurrence. This is the first prospective, naturalistic, long-term study of the weekly symptomatic course of MDD. METHODS: The weekly depressive symptoms of 431 patients with MDD seeking treatment at 5 academic centers were divided into 4 levels of severity: (1) depressive symptoms at the threshold for MDD; (2) depressive symptoms at the threshold for minor depressive or dysthymic disorder (MinD); (3) subsyndromal or subthreshold depressive symptoms (SSDs), below the thresholds for MinD and MDD; and (4) no depressive symptoms. The percentage of weeks at each level, number of changes in symptom level, and medication status were analyzed overall and for 3 subgroups defined by mood disorder history. RESULTS: Patients were symptomatically ill in 59% of weeks. Symptom levels changed frequently (1.8/y), and 9 of 10 patients spent weeks at 3 or 4 different levels during follow-up. The MinD (27%) and SSD (17%) symptom levels were more common than the MDD (15%) symptom level. Patients with double depression and recurrent depression had more chronic symptoms than patients with their first lifetime major depressive episode (72% and 65%, respectively, vs 46% of follow-up weeks). CONCLUSION: The long-term weekly course of unipolar MDD is dominated by prolonged symptomatic chronicity. Combined MinD and SSD level symptoms were about 3 times more common (43%) than MDD level symptoms (15%). The symptomatic course is dynamic and changeable, and MDD, MinD, and SSD symptom levels commonly alternate over time in the same patients as a symptomatic continuum of illness activity of a single clinical disease.

Impact of screening for mental health concerns on health service utilization and functional status in primary care patients.

BACKGROUND: Mental health concerns are common in primary care patients and are often inadequately addressed by primary care physicians. OBJECTIVE: To assess the impact of screening for mental disorders in internal medicine patients. METHODS: Randomly selected patients (n = 358) visiting physicians in 2 firms of an urban academic internal medicine clinic were screened for mental disorders using the 16-item Symptom-Driven Diagnostic System for Primary Care (Upjohn Co, Kalamazoo, Mich) first-stage screening questionnaire. In the experimental firm, physicians received the screening results and then administered second-stage diagnostic modules. In the control firm, physicians were not notified of the results of the screening questionnaire. Baseline and 3-month function were assessed using the SF-36 Health Survey, the Zung Self-Rating Depression Scale, and the Sheehan Patient-Rated Anxiety Scale. Patient satisfaction and health care utilization were also assessed by questionnaire at baseline and after 3 months. RESULTS: Patients screening positively for any mental disorder (n = 238, 66.5%) had markedly lower baseline functional status than those screening negatively (P < .05 on all 8 SF-36 Health Survey subscales) and more total (+/- SD) outpatient visits over 3 months (4.5 +/- 5.5 vs 2.5 +/- 2.6 visits, P = .001). Among patients who screened positively, functional outcomes and patient satisfaction were similar in experimental and control groups; mean utilization (+/- SD) was lower in the experimental group (3.7 +/- 3.9 vs 5.3 +/- 6.7 total outpatient visits at 3 months, P = .06; 0.9 +/- 1.5 vs 2.1 +/- 3.7 visits to non-mental health specialists, P = .003; 0.2 +/- 0.5 vs 0.4 +/- 0.9 x-ray films per patient, P = .01). The follow-up response rate was 286 (79.9%) of 358 patients. CONCLUSIONS: The 16-item first-stage Symptom-Driven Diagnostic System for Primary Care screening questionnaire for mental disorders can identify primary care patients who are at risk for lower functional status and higher utilization. Use of the Symptom-Driven Diagnostic System for Primary Care second-stage diagnostic modules in patients who screened positively for mental disorders was associated with lower utilization rates but had no impact on functional outcome or patient satisfaction after 3 months.

Electrochemical fabrication of graphene nanomesh via colloidal templating.

A simple electrochemical fabrication of graphene nanomesh (GNM) via colloidal templating is reported for the first time. The process involves the arraying of polystyrene (PS) spheres onto a CVD-deposited graphene, electro-deposition of carbazole units, removal of the PS template and electrochemical oxidative etching. The GNM was characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM) and Raman spectroscopy.

On the antibacterial mechanism of graphene oxide (GO) Langmuir-Blodgett films.

The Langmuir-Blodgett (LB) technique was used to immobilize flat graphene oxide (GO) sheets on a PET substrate to ascertain as to whether the edges of GO play an integral part in its antimicrobial mechanism. The observed antibacterial activity suggests that contact with the edges is not a fundamental part of the mechanism.

Family history and symptom levels during treatment for bipolar I affective disorder.

BACKGROUND: Studies of family history and lithium response in patients with bipolar affective disorder have produced mixed results, but the majority have shown relationships between the presence of affective disorder among relatives and positive responses to lithium in probands. The analysis presented here sought to confirm and to further characterize such relationships. METHODS: Subjects described here participated in a long-term, prospective follow-up; had a history of Research Diagnostic Criteria manic disorder or schizoaffective disorder, manic type; and took lithium for periods of 26 weeks or longer. The majority participated in a family study in which first-degree relatives were directly interviewed. Morbidity during lithium and during anticonvulsant trials was quantified in alternative ways, as were the risks among first-degree relatives for bipolar I and nonbipolar affective disorders. RESULTS: Familial loading for bipolar affective disorder was not associated with better outcomes during lithium treatment. Rather, the presence of major depressive disorder (MDD) among relatives was associated with slower improvement during acute treatment and with higher symptom levels during continuing treatment. Findings for morbidity during anticonvulsant treatment were similar. The patients who experienced symptom persistence with lithium did so as well during periods of anticonvulsant treatment and during periods without thymoleptics. CONCLUSIONS: A family history of MDD may have an enduring and negative prognostic significance that manifests across treatment conditions. Though difficult to reconcile with several earlier studies, these findings invite replication and further exploration.

Increase in fatal suicidal poisonings and suffocations in the year Final Exit was published: a national study.

Final Exit was a best-selling book that recommended poisoning and suffocation by plastic bag as lethal means of suicide for those with terminal medical illnesses. The authors sought to determine whether the number of suicides involving these methods increased in the United States in 1991, the year the book was published, compared with 1990. Suicidal asphyxiations involving a plastic bag increased 30.8%, from 334 to 437, and poisonings increased 5.4%, from 3,143 to 3,314. There was no change in the number of suicides involving each of the other methods or in the total number of suicides between 1990 and 1991. These ecological data support, but cannot conclusively prove, the hypothesis that Final Exit influenced the choice of lethal means of suicidal individuals.