Mixed state and suicide: Is the effect of mixed state on suicidal behavior more than the sum of its parts?

OBJECTIVE: To assess whether suicidal behavior during mixed states exceeds that expected from the manic or depressive components alone. METHODS: This study included 429 participants with bipolar disorder from the National Institute of Mental Health Collaborative Depression Study (CDS). Mood and suicidal behavior were captured using the Longitudinal Interval Follow-up Evaluation and the Schedule of Affective Disorders and Schizophrenia. Suicidal behavior during each mood state, relative to euthymia, was analyzed using Cox regression to allow for repeated events, with a frailty term to account for intra-participant correlation. Mixed states were modeled as a depression-by-mania interaction. RESULTS: Individuals with a history of mixed states were at higher risk of suicidal behavior and spent more time depressed, compared to subjects with no such history. In bipolar I disorder, risk increased during episodes of mania (hazard ratio [HR]: 1.96, 95% confidence interval [CI]: 1.28-2.99, P = .0019) and depression (HR: 5.49, 95% CI: 4.01-7.51, P < .0001) and there was a less than additive effect of mixed states. In bipolar II disorder, risk was increased during episodes of depression (HR: 3.66, 95% CI: 2.51-5.35, P < .0001) and there was no excess risk during mixed states beyond that attributable to the depressed component. Most of the excess risk (71%) among those with a history of mixed states was attributable to a depression predominant course of illness. CONCLUSIONS: Individuals with mixed states are at high risk of suicidal behavior, largely due to more time spent depressed. Clinicians should aggressively treat depression to mitigate suicide risk for patients with or without mixed states.

Fourth consensus of the International Society for Premenstrual Disorders (ISPMD): auditable standards for diagnosis and management of premenstrual disorder.

Whilst professional bodies such as the Royal College and the American College of Obstetricians and Gynecologists have well-established standards for audit of management for most gynaecology disorders, such standards for premenstrual disorders (PMDs) have yet to be developed. The International Society of Premenstrual Disorders (ISPMD) has already published three consensus papers on PMDs covering areas that include definition, classification/quantification, clinical trial design and management (American College Obstetricians and Gynecologists 2011; Brown et al. in Cochrane Database Syst Rev 2:CD001396, 2009; Dickerson et al. in Am Fam Physician 67(8):1743-1752, 2003). In this fourth consensus of ISPMD, we aim to create a set of auditable standards for the clinical management of PMDs. All members of the original ISPMD consensus group were invited to submit one or more auditable standards to be eligible in the inclusion of the consensus. Ninety-five percent of members (18/19) responded with at least one auditable standard. A total of 66 auditable standards were received, which were returned to all group members who then ranked the standards in order of priority, before the results were collated. Proposed standards related to the diagnosis of PMDs identified the importance of obtaining an accurate history, that a symptom diary should be kept for 2 months prior to diagnosis and that symptom reporting demonstrates symptoms in the premenstrual phase of the menstrual cycle and relieved by menstruation. Regarding treatment, the most important standards were the use of selective serotonin reuptake inhibitors (SSRIs) as a first line treatment, an evidence-based approach to treatment and that SSRI side effects are properly explained to patients. A set of comprehensive standards to be used in the diagnosis and treatment of PMD has been established, for which PMD management can be audited against for standardised and improved care.

Predictors of functional response and remission with desvenlafaxine 50 mg/d in patients with major depressive disorder.

BACKGROUND: The predictive value of early functional improvement for treatment success at week 8 was assessed in a pooled analysis in patients with major depressive disorder (MDD). METHODS: Data were pooled from 7 double-blind studies in adult patients with MDD randomly assigned to desvenlafaxine 50 mg/d or placebo. Four levels of treatment success were determined at week 8 for patients with baseline Sheehan Disability Scale (SDS) score > 12 (N = 2156): functional response (SDS ≤12 and ≥50% improvement in SDS), functional/depression response (SDS ≤12 and ≥50% improvement in both SDS and 17-item Hamilton Rating Scale for Depression [HAM-D17] score), functional remission (SDS < 7), and functional/depression remission (SDS < 7 and HAM-D17 ≤7). Week 2 improvement in SDS was evaluated as a predictor of later functional response/remission using receiver operating characteristic analysis. Odds ratios (ORs) of the predictability of improvement thresholds were computed from a logistic regression model. RESULTS: The proportion of patients achieving each level of treatment success was significantly greater for patients treated with desvenlafaxine (40%, 32%, 23%, 15%, respectively) vs placebo (31%, 22%, 17%, 10%; all P ≤ 0.002). Early change in SDS was a highly significant predictor of functional response/remission (ORs, 0.958-0.970; all P < 0.0001). Discussion Patients' early functional response to desvenlafaxine 50 mg/d is predictive of treatment success.

Seasonal variation of depressive symptoms in unipolar major depressive disorder.

OBJECTIVES: Retrospective and cross-sectional studies of seasonal variation of depressive symptoms in unipolar major depression have yielded conflicting results. We examined seasonal variation of mood symptoms in a long-term prospective cohort - the Collaborative Depression Study (CDS). METHODS: The sample included 298 CDS participants from five academic centers with a prospectively derived diagnosis of unipolar major depression who were followed for at least ten years of annual or semi-annual assessments. Generalized linear mixed models were utilized to investigate the presence of seasonal patterns. In a subset of 271 participants followed for at least 20 years, the stability of a winter depressive pattern was assessed across the first two decades of follow-up. RESULTS: A small increase in proportion of time depressed was found in the months surrounding the winter solstice, although the greatest symptom burden was seen in December through April with a peak in March. The relative burden of winter depressive symptoms in the first decade demonstrated no relationship to that of the second decade. The onset of new episodes was highest October through January, peaking in January. CONCLUSIONS: There exists a small but statistically significant peak in depressive symptoms from the month of the winter solstice to the month of the spring equinox. However, the predominance of winter depressive symptoms did not appear stable over the long-term course of illness.

ISPMD consensus on the management of premenstrual disorders.

The second consensus meeting of the International Society for Premenstrual Disorders (ISPMD) took place in London during March 2011. The primary goal was to evaluate the published evidence and consider the expert opinions of the ISPMD members to reach a consensus on advice for the management of premenstrual disorders. Gynaecologists, psychiatrists, psychologists and pharmacologists each formally presented the evidence within their area of expertise; this was followed by an in-depth discussion leading to consensus recommendations. This article provides a comprehensive review of the outcomes from the meeting. The group discussed and agreed that careful diagnosis based on the recommendations and classification derived from the first ISPMD consensus conference is essential and should underlie the appropriate management strategy. Options for the management of premenstrual disorders fall under two broad categories, (a) those influencing central nervous activity, particularly the modulation of the neurotransmitter serotonin and (b) those that suppress ovulation. Psychotropic medication, such as selective serotonin reuptake inhibitors, probably acts by dampening the influence of sex steroids on the brain. Oral contraceptives, gonadotropin-releasing hormone agonists, danazol and estradiol all most likely function by ovulation suppression. The role of oophorectomy was also considered in this respect. Alternative therapies are also addressed, with, e.g. cognitive behavioural therapy, calcium supplements and Vitex agnus castus warranting further exploration.

Course of illness following prospectively observed mania or hypomania in individuals presenting with unipolar depression.

OBJECTIVES: In a well-defined sample, we sought to determine which clinical variables, some of potential nosological relevance, influence subsequent course following prospectively observed initial episodes of hypomania or mania (H/M). METHODS: We identified 108 individuals in the National Institute of Mental Health Collaborative Depression Study diagnosed with unipolar major depression at intake who subsequently developed H/M. We assessed time to repeat H/M based on whether one had been started on an antidepressant or electroconvulsive therapy within eight weeks of developing H/M, had longer episodes, or had a family history of bipolar disorder. RESULTS: Modeling age of onset, treatment-associated H/M, family history of bipolar disorder, duration of index H/M episode, and psychosis in Cox regression analysis, family history of bipolar disorder (n=21) was strongly associated with repeat episodes of H/M [hazard ratio (HR)=2.01, 95% confidence interval (CI): 1.06-3.83, p=0.03]. Those with treatment-associated episodes (n=12) were less likely to experience subsequent episodes of H/M, although this was not significant in the multivariate model (HR=0.25, 95% CI: 0.06-1.05, p=0.06). These individuals also had a later age of onset for affective illness and were more likely to be depressed. Duration of illness with a temporal resolution of one week, psychosis, and age of onset were not associated with time to repeat H/M episode. CONCLUSIONS: A family history of bipolar disorder influences the course of illness, even after an initial H/M episode. In this select sample, treatment-associated H/M did not appear to convey the same risk for a course of illness characterized by recurrent H/M episodes.

Development and content validity of a patient reported outcomes measure to assess symptoms of major depressive disorder.

BACKGROUND: Although many symptoms of Major Depressive Disorder (MDD) are assessed through patient-report, there are currently no patient-reported outcome (PRO) instruments that incorporate documented evidence of patient input in PRO instrument development. A review of existing PROs used in MDD suggested the need to conduct qualitative research with patients with MDD to better understand their experience of MDD and develop an evaluative instrument with content validity. The aim of this study was to develop a disease-specific questionnaire to assess symptoms important and relevant to adult MDD patients. METHODS: The questionnaire development involved qualitative interviews for concept elicitation, instrument development, and cognitive interviews to support content validity. For concept elicitation, ten MDD severity-specific focus group interviews with thirty-eight patients having clinician-confirmed diagnoses of MDD were conducted in January 2009. A semi-structured discussion guide was used to elicit patients' spontaneous descriptions of MDD symptoms. Verbatim transcripts of focus groups were coded and analyzed to develop a conceptual framework to describe MDD. A PRO instrument was developed by operationalizing concepts elicited in the conceptual framework. Cognitive interviews were carried out in patients (n = 20) to refine and test the content validity of the instrument in terms of item relevance and comprehension, instructions, recall period, and response categories. RESULTS: Concept elicitation focus groups identified thirty-five unique concepts falling into several domains: i) emotional, ii) cognitive, iii) motivation, iv) work, v) sleep, vi) appetite, vii) social, viii) activities of daily living, ix) tired/fatigue, x) body pain, and xi) suicidality. Concept saturation, the point at which no new relevant information emerges in later interviews, was achieved for each of the concepts. Based on the qualitative findings, the PRO instrument developed had 15 daily and 20 weekly items. The cognitive interviews confirmed that the instructions, item content, and response scales were understood by the patients. CONCLUSIONS: Rigorous qualitative research resulted in the development of a PRO measure for MDD with supported content validity. The MDD PRO can assist in understanding and assessing MDD symptoms from patients' perspectives as well as evaluating treatment benefit of new targeted therapies.

Assessing quality of life in patients with schizophrenia in an acute psychiatric setting: reliability, validity and feasibility of the EQ-5D and the Q-LES-Q.

BACKGROUND: Quality of life (QoL) is considered an important outcome of treatment in psychiatry. Two QoL instruments, the EuroQoL-5D (EQ-5D) and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), have been increasingly used among patients with schizophrenia. AIMS: The aim of this study was to investigate the reliability, validity and feasibility of the EQ-5D and the Q-LES-Q among patients with schizophrenia and related disorders (n = 311) in the most acute stage of their illness. METHODS: The study was carried out in nine acute psychiatric wards of two psychiatric hospitals in Finland. The instruments' internal consistency, construct validity and missing values were evaluated. RESULTS: Our findings show high internal consistency for the Q-LES-Q (Cronbach's alpha 0,89). For the EQ-5D, the Cronbach's alpha value was minimally acceptable (0.63) taking in to consideration the low number of items. Lower overall functioning indicated poorer QoL measured by the EQ-5D (U = 3098, P < 0.001) or the Q-LES-Q (U = 3357, P < 0.001). Missing values in the EQ-5D ranged from 6% to 7% and in the Q-LES-Q from 6% to 31%. CONCLUSION: Our results suggest that both QoL scales are reasonably reliable, valid and feasible in this patient group. The decision regarding which instrument to use would depend on clinical or research questions. When more detailed information for patients' satisfaction with QoL is needed then the Q-LES-Q would be a better choice, whereas if the primary interest is to briefly assess patients' QoL problems related to health status the EQ-5D would be a better choice.

The burden of moderate/severe premenstrual syndrome and premenstrual dysphoric disorder in a cohort of Latin American women.

OBJECTIVES: The aim of this study was to investigate the relationship between symptom severity, cost, and impairment in women with moderate/severe premenstrual syndrome (PMS) or premenstrual dysphoric disorder (PMDD) in a Latin American setting. METHODS: A model was constructed based on analysis of an observational dataset. Data were included from four Latin American countries. Responder-level data were analysed according to four categories of symptom severity: Category 1 comprised Daily Record of Severity of Problems score 21 to 41.9, Category 2 score was 42 to 62.9, Category 3 score was 63 to 83.9, and Category 4 was a score of 84 or higher. Burden was estimated in terms of impact on job and activities using the modified work productivity and impairment questionnaire and affect on quality of life using the SF-12 questionnaire. Costs were estimated in Brazilian reals from a Brazilian private health care and societal perspective. The outputs of the analysis were estimates of burden, mean annual cost and affect on quality of life (as measured by quality adjusted life years) by symptom severity. Confidence intervals around key outcomes were generated through nonparametric bootstrapping. RESULTS: Analysis suggests a significant cost burden associated with moderate/severe PMS and PMDD with mean per patient annual costs estimated at 1618 BRL (95% confidence interval 957-2,481). Although the relationship between cost, quality of life, and severity was not clear, analysis showed a consistent relationship between disease severity and measures of disease burden (job and daily activity). Burden on activities increased with disease severity. CONCLUSIONS: Our analysis, conducted from a Latin American perspective, suggests a significant burden and an increasing impairment associated with moderate/severe PMS and PMDD.

Towards a consensus on diagnostic criteria, measurement and trial design of the premenstrual disorders: the ISPMD Montreal consensus.

Premenstrual disorders (PMD) are characterised by a cluster of somatic and psychological symptoms of varying severity that occur during the luteal phase of the menstrual cycle and resolve during menses (Freeman and Sondheimer, Prim Care Companion J Clin Psychiatry 5:30-39, 2003; Halbreich, Gynecol Endocrinol 19:320-334, 2004). Although PMD have been widely recognised for many decades, their precise cause is still unknown and there are no definitive, universally accepted diagnostic criteria. To consider this issue, an international multidisciplinary group of experts met at a face-to-face consensus meeting to review current definitions and diagnostic criteria for PMD. This was followed by extensive correspondence. The consensus group formally became established as the International Society for Premenstrual Disorders (ISPMD). The inaugural meeting of the ISPMD was held in Montreal in September 2008. The primary aim was to provide a unified approach for the diagnostic criteria of PMD, their quantification and guidelines on clinical trial design. This report summarises their recommendations. It is hoped that the criteria proposed here will inform discussions of the next edition of the World Health Organisation's International Classification of Diseases (ICD-11), and the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-V) criteria that are currently under consideration. It is also hoped that the proposed definitions and guidelines could be used by all clinicians and investigators to provide a consistent approach to the diagnosis and treatment of PMD and to aid scientific and clinical research in this field.

Fine mapping of candidate regions for bipolar disorder provides strong evidence for susceptibility loci on chromosomes 7q.

Genomewide scans of bipolar disorder (BP) have not produced consistent linkage findings. Follow-up studies using enlarged samples and enhanced marker density can bolster or refute claims of linkage and pave the way to gene discovery. We conducted linkage and association analyses, using a ~3-cM density map of 10 candidate regions, in a large BP pedigree sample (865 individuals from 56 pedigrees). The candidate regions were identified in a previous 10-cM genome-wide scan using a subset of this sample (373 individuals from 40 pedigrees). The present sample consists of the expanded original pedigrees ("core" pedigrees) and 16 additional pedigrees. We obtained experiment-wide significant linkage on chromosome 7q34 (LOD score 3.53, P < 0.001), substantially stronger than that observed in the genome-wide scan. Support for linkage was sustained on chromosomes 2p13, 4q31, 8q13, 13q32, 14q21, and 17q11, though at a more modest level. Family-based association analysis was consistent with the linkage results at all regions with linkage evidence, except 4q an 8q, but the results fell short of statistical significance. Three of the previously implicated regions-9q31, 10q21 and 10q24-showed substantial reduction in evidence of linkage. Our results strongly support 7q34 as a region harboring susceptibility locus for BP. Somewhat lesser, yet notable support was obtained for 2p13, 4q31, 8q13, 13q32, 14q21, and 17q11. These regions could be considered prime candidates for future gene finding efforts.

Manic/hypomanic symptom burden and cardiovascular mortality in bipolar disorder.

OBJECTIVES: To compare the risk for cardiovascular mortality between bipolar I and bipolar II subtypes and determine correlates of cardiovascular mortality. Bipolar disorder conveys an increased risk of cardiovascular mortality. METHODS: Participants with major affective disorders were recruited for the National Institute of Mental Health Collaborative Depression Study and followed prospectively for up to 25 years. A total of 435 participants met the diagnostic criteria for bipolar I (n = 288) or bipolar II (n = 147) disorder based on Research Diagnostic Criteria at intake and measures of psychiatric symptoms during follow-up. Diagnostic subtypes were contrasted by cardiovascular mortality risk using Cox proportional hazards regression. Affective symptom burden (the proportion of time with clinically significant manic/hypomanic or depressive symptoms) and treatment exposure were additionally included in the models. RESULTS: Thirty-three participants died from cardiovascular causes. Participants with bipolar I disorder had more than double the cardiovascular mortality risk of those with bipolar II disorder, after controlling for age and gender (hazard ratio = 2.35, 95% Confidence Interval = 1.04-5.33; p = .04). The observed difference in cardiovascular mortality between these subtypes was at least partially confounded by the burden of clinically significant manic/hypomanic symptoms which predicted cardiovascular mortality independent of diagnosis, treatment exposure, age, gender, and cardiovascular risk factors at intake. Selective serotonin uptake inhibitors seemed protective although they were introduced late in follow-up. Depressive symptom burden was not related to cardiovascular mortality. CONCLUSIONS: Participants with bipolar I disorder may face a greater risk of cardiovascular mortality than those with bipolar II disorder. This difference in cardiovascular mortality risk may reflect manic/hypomanic symptom burden.

Empirical typology of bipolar I mood episodes.

BACKGROUND: Much remains unknown about the phenomenology of bipolar I disorder. AIMS: To determine the type of bipolar I mood episodes that occur over time, and their relative frequency. METHOD: A total of 219 individuals with Research Diagnostic Criteria bipolar I disorder were prospectively followed for up to 25 years (median 20 years). Psychopathology was assessed with the Longitudinal Interval Follow-up Evaluation. RESULTS: Overall, 1208 mood episodes were prospectively observed. The episodes were empirically classified as follows: major depression, 30.9% (n = 373); minor depression, 13.0% (n = 157); mania, 20.4% (n = 246); hypomania, 10.4% (n = 126); cycling, 17.3% (n = 210); cycling plus mixed state, 7.8% (n = 94); and mixed, 0.2% (n = 2). CONCLUSIONS: Cycling episodes constituted 25% of all episodes. Work groups revising ICD-10 and DSM-IV should add a category for bipolar I cycling episode.

A multidimensional spectrum approach to post-traumatic stress disorder: comparison between the Structured Clinical Interview for Trauma and Loss Spectrum (SCI-TALS) and the Self-Report instrument (TALS-SR).

Dimensional approaches to psychiatric disorders have shown an increased relevance in the ongoing debate for the forthcoming Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. In line with previously validated instruments for the assessment of different mood, anxiety, eating and psychotic spectra, we tested the validity and reliability of a newly developed Structured Clinical Interview for Trauma and Loss Spectrum (SCI-TALS). The instrument is based on a multidimensional approach to post-traumatic stress spectrum that includes a range of threatening or frightening experiences, as well as a variety of potentially significant losses, to which an individual can be exposed. Furthermore, it explores the spectrum of the peritraumatic reactions and post-traumatic symptoms that may ensue from either type of life events, targeting soft signs and subthreshold conditions, as well as temperamental and personality traits that may constitute risk factors for the development of the disorder. The aim of the present study is to describe the reliability of the self-report version of the SCI-TALS: the TALS-SR. Thirty patients with PTSD and thirty healthy control subjects were assessed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Half of the patients and controls received the TALS-SR first and the SCI-TALS after 15 days; for the other half of the sample, the order of administration was reversed. Agreement between the self-report and the interview formats was substantial. Intraclass correlation coefficients ranged from 0.934 to 0.994, always exceeding the threshold of 0.90. Our findings provide substantial support for the reliability of the TALS-SR questionnaire.

Anxiety Symptom Severity and Long-term Risk for Suicidal Behavior in Depressive Disorders.

OBJECTIVE: We have previously shown that the severity of anxiety symptoms during major depressive episodes is associated in a linear fashion with the proportion of weeks in depressive episodes during a subsequent 25 years of follow-up. Here, we test whether the negative prognostic implications of anxiety comorbidity extend to higher likelihoods of suicidal behavior. METHODS: We used the NIMH Collaborative Depression Study (CDS) cohort to test both the severity of eight anxiety symptoms and the presence or absence of four anxiety disorders as risk factors for suicide attempts or completions over a mean (SD) follow-up of 16.6 (8.5) years. Separate analyses tested potential predictors of events that occurred within 2 years and those that occurred later. RESULTS: None of the baseline anxiety manifestations were significantly associated with overall risks for past or future suicide attempts. Only the diagnosis of phobic disorder was overrepresented in the 36 who committed suicide. Psychic anxiety was a risk factor for suicide attempts beyond 2 years of follow-up, and phobic anxiety was protective of suicides within this period. CONCLUSIONS: These results did not show anxiety comorbidity to be an important risk factor for suicide attempts or completions.

Examining quality of life in patients with generalized anxiety disorder: clinical relevance and response to duloxetine treatment.

BACKGROUND: Duloxetine, a serotonergic noradrenergic reuptake inhibitor, improved functional outcomes in each of three clinical studies for the treatment of adults with generalized anxiety disorder (GAD). Using comparison norms, the current work describes the clinical relevance of these functional improvements in terms of return to normative functioning and symptom remission. METHODS: Data were pooled at the individual patient level from three double-blind, placebo-controlled trials of duloxetine treatment (9-10 weeks acute therapy, dose ranges 60-120mg). Inclusion/exclusion criteria were consistent across studies, and outcome measures included the Sheehan Disability Scale (SDS), Quality of Life Enjoyment and Satisfaction Questionnaire Short Form (Q-LES-Q-SF), and European Quality of Life 5 Dimensions (EQ-5D). RESULTS: Adult patients (mean age=42.4 years; 65% women) were randomly assigned to duloxetine (N=668) or placebo (N=495). At baseline, the majority of patients were impaired on the SDS global functioning (89%), Q-LES-Q-SF maximum percent (95%), and EQ-5D (76%) scores. On each measure, a greater percentage of duloxetine-treated patients converted from an impaired baseline to a normative endpoint score than did placebo-treated patients (p0.001, all comparisons). Remission defined as a HAMA total score at endpoint of 10, compared with 7, captured a greater proportion of patients who were functionally in remission. CONCLUSIONS: GAD is associated with substantial impairment in functioning and subjective well-being, and patients treated with duloxetine 60-120mg/day, compared with placebo, experienced a greater return to normative functioning. Attention to role functioning and quality of life may refine our definition of remission when using standard symptom measures of anxiety.

Development and evaluation of the Daily Assessment of Symptoms - Anxiety (DAS-A) scale to evaluate onset of symptom relief in patients with generalized anxiety disorder.

BACKGROUND: Fast-acting anxiolytics are important to patients and society. Measuring early onset, however, requires a sensitive and clinically responsive measure. This study develops and evaluates the psychometric properties of a new patient-reported instrument, the Daily Assessment of Symptoms - Anxiety (DAS-A), designed to detect reduction of anxiety symptoms in patients with Generalized Anxiety Disorder (GAD) during the first week of treatment. METHODS: Clinician interviews and patient focus groups were conducted to identify relevant constructs; discussions focused on early symptom improvement and meaningful changes in GAD symptoms. The draft questionnaire underwent iterative sets of cognitive interviews to inform item reduction and revision. A double-blind, randomized, placebo-controlled study of paroxetine and lorazepam assessed the performance of the new instrument in GAD patients. Analyses evaluated the structure, reliability, validity, and utility of the instrument. RESULTS: There was consistency across focus groups and clinicians in the description of symptoms that improve first. The final item set was easily understood by interview participants. Factor analyses indicated that a unidimensional structure best described the data. Item-level descriptive statistics, Cronbach's alphas, effect sizes, and validity correlations with other scales were favorable. Most importantly, the DAS-A demonstrated separation of lorazepam from placebo within 24h of first dose and correlated with other anxiety measures. CONCLUSIONS: This study resulted in the development of a reliable and valid instrument addressing the DSM-IV dimensions of GAD. The DAS-A is capable of detecting reduction in anxiety symptoms within 24h, making it a desirable measure to include in future trials of fast-acting anxiety medications.

The factor structure of clinical symptoms in mixed and manic episodes prior to and after antipsychotic treatment.

BACKGROUND: While the factor structure of clinical symptoms in schizophrenia has been examined and provided crucial information about the illness, there is much less information available in bipolar disorder. This study examined the structure of symptoms of bipolar disorder at an unmedicated baseline assessment and after double-blind treatment with ziprasidone, haloperidol, or placebo. We hypothesized, consistent with recent studies of schizophrenia, that the factor structure after treatment would be similar to the structure of untreated symptoms at study baseline. METHODS: Hospitalized patients with manic (n = 363) or mixed (n = 71) bipolar episodes were rated with the Hamilton Depression Rating Scale (HAM-D) and the Mania Rating Scale [(MRS); derived from the Schedule for Affective Disorders and Schizophrenia - Change Bipolar Scale]. After 21 days of double-blind treatment, all patients were again rated with the MRS and HAM-D. RESULTS: Exploratory orthogonal factor analysis (varimax rotation) including both HAM-D total scores and the MRS items found different five-factor solutions for mixed and manic patients at the unmedicated baseline assessment. Confirmatory modeling indicated that these models, with some modifications, fit the data well. At the endpoint, however, a single-factor solution was found for mixed and manic groups. IMPLICATIONS: Symptomatology in bipolar disorder is multifactorial in an acute and unmedicated state, with slightly different factor structures for mixed and manic episodes. Following treatment, a single severity dimension is detected. These results suggest that symptom dimensions in mania may be different from those seen in schizophrenia, where different elements of symptoms have been proven to have different functional correlates and treatment response.

Quetiapine monotherapy in the treatment of depressive episodes of bipolar I and II disorder: Improvements in quality of life and quality of sleep.

INTRODUCTION: The depressive symptoms of bipolar disorder impact health-related quality of life, quality of sleep and functioning. The BOLDER I and II trials demonstrated that quetiapine significantly improves depressive symptoms in patients with acute bipolar depression. Post-hoc analysis of the BOLDER I and II data permits a detailed investigation of the effects of quetiapine on these other measures in this patient population. METHODS: Secondary analysis was performed on data from BOLDER I and II, which were two 8-week, double-blind, randomized, placebo-controlled studies of quetiapine at fixed doses (300 or 600 mg/day) in a total of 1051 patients with acute depressive episodes of bipolar I or II disorder. Measures included the Short-Form Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q SF) in BOLDER I and II, the Pittsburgh Sleep Quality Index (PSQI) in BOLDER I, and the Sheehan Disability Scale (SDS) in BOLDER II. Analyses of Q-LES-Q SF score changes were based on data from the combined BOLDER I and II populations, and analyses of PSQI and SDS score changes were based on BOLDER I and BOLDER II populations, respectively. RESULTS: Assessments at day 57 by mixed-model repeated measures analysis demonstrated that quetiapine relative to placebo provided significant or numerical improvements in rating scale score on the Q-LES-Q SF (10.89 with 300 mg/day and 12.14 with 600 mg/day vs. 7.79 with placebo; p<0.001 for each quetiapine dose), PSQI (-5.34 and -6.00 vs. -3.35; p<0.001, each dose), and SDS (-7.78 and -8.25 vs. -6.49; p=0.156 and 0.054, respectively). Effect sizes at day 57 with quetiapine 300 and 600 mg/day, respectively, were 0.34 and 0.46 for Q-LES-Q SF, 0.59 and 0.79 for PSQI, and 0.17 and 0.23 for SDS. Improvements were evident at first post-baseline assessment on day 29 and were consistent over the majority of rating scale domains. Quetiapine was generally well tolerated and most adverse events were of mild to moderate intensity. CONCLUSIONS: Quetiapine monotherapy is effective in improving impairment in important aspects of life that accompany improvements in depressive symptoms in patients with acute bipolar depression.

Predicting recovery from episodes of major depression.

BACKGROUND: This study examined psychosocial functioning as a predictor of recovery from episodes of unipolar major depression. METHODS: 231 subjects diagnosed with major depressive disorder according to Research Diagnostic Criteria were prospectively followed for up to 20 years as part of the NIMH Collaborative Depression Study. The association between psychosocial functioning and recovery from episodes of unipolar major depression was analyzed with a mixed-effects logistic regression model which controlled for cumulative morbidity, defined as the amount of time ill with major depression during prospective follow-up. Recovery was defined as at least eight consecutive weeks with either no symptoms of major depression, or only one or two symptoms at a mild level of severity. RESULTS: In the mixed-effects model, a one standard deviation increase in psychosocial impairment was significantly associated with a 22% decrease in the likelihood of subsequent recovery from an episode of major depression (OR=0.78, 95% CI: 0.74-0.82, Z=-3.17, p<0.002). Also, a one standard deviation increase in cumulative morbidity was significantly associated with a 61% decrease in the probability of recovery (OR=0.3899, 95% CI: 0.3894-0.3903, Z=-7.21, p<0.001). LIMITATIONS: The generalizability of the study is limited in so far as subjects were recruited as they sought treatment at academic medical centers. The analyses examined the relationship between psychosocial functioning and recovery from major depression, and did not include episodes of minor depression. Furthermore, this was an observational study and the investigators did not control treatment. CONCLUSIONS: Assessment of psychosocial impairment may help identify patients less likely to recover from an episode of major depression.