Showing papers in "The Journal of Clinical Psychiatry in 2009"

The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness.

Abstract: Objectives Poor adherence to medication treatment can have devastating consequences for patients with mental illness. The goal of this project was to develop recommendations for addressing adherence problems to improve patient outcomes. Methods The editors identified important topics and questions concerning medication adherence problems in serious mental illness that are not fully addressed in the literature. A survey was developed containing 39 questions (521 options) asking about defining nonadherence, extent of adherence problems in schizophrenia and bipolar disorder, risk factors for nonadherence, assessment methods, and interventions for specific types of adherence problems. The survey was completed by 41 (85%) of the 48 experts to whom it was sent. Results of the literature review and survey were used to develop recommendations for assessing and improving adherence in patients with serious mental illness. Results ASSESSING ADHERENCE: The experts endorsed percentage of medication not taken as the preferred method of defining adherence, with 80% or more of medication taken endorsed as an appropriate cut-off for adherence in bipolar disorder and schizophrenia. Although self- and physician report are the most common methods used to assess adherence in clinical settings, they are often inaccurate and may underestimate nonadherence. The experts recommend that, if possible, clinicians also use more objective measures (e.g., pill counts, pharmacy records, and, when appropriate, serum levels such as are used for lithium). Use of a validated self-report scale may help improve accuracy. Scope of the problem The majority of the experts believed the average patient with schizophrenia or bipolar disorder in their practices takes only 51%-70% of prescribed medication. FACTORS ASSOCIATED WITH NONADHERENCE: The experts endorsed poor insight and lack of illness awareness, distress associated with specific side effects or a general fear of side effects, inadequate efficacy with persistent symptoms, and believing medications are no longer needed as the most important factors leading to adherence problems in schizophrenia and bipolar disorder. The experts considered weight gain a side effect that is very likely to lead to adherence problems in patients with schizophrenia and bipolar disorder; sedation was considered a more important contributor to adherence problems in bipolar disorder than schizophrenia. The experts rated persistent positive or negative symptoms in schizophrenia and persistent grandiosity and manic symptoms in bipolar disorder as the most important symptomatic contributors to adherence problems in these illnesses. Interventions It is important to identify the specific factors that may be contributing to a patient's adherence problems in order to customize interventions to target those problems. Multiple problems may be involved, requiring a combination of interventions. Conclusions Adherence problems are complex and multidetermined. The experts recommended customized interventions focused on the underlying causes.

Inflammation and the Phenomenology, Pathophysiology, Comorbidity, and Treatment of Bipolar Disorder: A Systematic Review of the Literature

Abstract: Objective To review extant literature implicating inflammation in the pathophysiology of bipolar disorder. Furthermore, we review evidence regarding the anti-inflammatory actions of mood-stabilizing medication, the putative reciprocal association of inflammation with behavioral parameters and medical burden in bipolar disorder, and the potential role of anti-inflammatory agents in the treatment of bipolar disorder. Data sources MEDLINE and PubMed searches were conducted of English-language articles published from 1950 to April 2008 using the search terms bipolar disorder, manic, or mania, cross-referenced with inflammation, inflammatory, interleukin, cytokine, C-reactive protein, or tumor necrosis factor. The search, which was conducted most recently on August 20, 2008, was supplemented by manually reviewing reference lists from the identified publications. Study selection Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality. Data extraction Studies were reviewed for statistical comparisons of cytokines among persons with and without bipolar disorder, during symptomatic and non-symptomatic intervals and before and after pharmacologic treatment. Significant and nonsignificant findings were tabulated. Data synthesis Available evidence indicates that bipolar disorder and inflammation are linked through shared genetic polymorphisms and gene expression as well as altered cytokine levels during symptomatic (i.e., mania and depression) and asymptomatic intervals. However, results are inconsistent. Several conventional mood stabilizers have anti-inflammatory properties. The cyclooxygenase-2-selective anti-inflammatory celecoxib may offer antidepressant effects. Inflammation is closely linked with behavioral parameters such as exercise, sleep, alcohol abuse, and smoking, as well as with medical comorbidities including coronary artery disease, obesity and insulin resistance, osteoporosis, and pain. Methodological limitations precluding definitive conclusions are heterogeneity in sample composition, cytokine assessment procedures, and treatment regimens. The inclusion of multiple ethnic groups introduces another source of variability but also increases the generalizability of study findings. Conclusion Inflammation appears relevant to bipolar disorder across several important domains. Further research is warranted to parse the reciprocal associations between inflammation and symptoms, comorbidities, and treatments in bipolar disorder. Studies of this topic among youth are needed and may best serve this purpose.

Family problems among recently returned military veterans referred for a mental health evaluation.

Abstract: CONTEXT: Existing evidence suggests that military veterans with mental health disorders have poorer family functioning, although little research has focused on this topic. OBJECTIVE: To test whether psychiatric symptoms are associated with family reintegration problems in recently returned military veterans. DESIGN: Cross-sectional survey of a clinical population. Respondents who were referred to behavioral health evaluation from April 2006 through August 2007 were considered for the survey. SETTING: Philadelphia Veterans Affairs Medical Center, Pa. PARTICIPANTS: 199 military veterans who served in Iraq or Afghanistan after 2001 and were referred for behavioral health evaluation from primary care (mean age = 32.7 years, SD = 9.1). MAIN OUTCOME MEASURES: Measures included the Mini-International Neuropsychiatric Interview for psychiatric diagnoses, the 9-item Patient Health Questionnaire for depression diagnosis and severity, and screening measures of alcohol abuse and illicit substance use. A measure of military family readjustment problems and a screening measure of domestic abuse were developed for this study. RESULTS: Three fourths of the married/cohabiting veterans reported some type of family problem in the past week, such as feeling like a guest in their household (40.7%), reporting their children acting afraid or not being warm toward them (25.0%), or being unsure about their family role (37.2%). Among veterans with current or recently separated partners, 53.7% reported conflicts involving "shouting, pushing, or shoving," and 27.6% reported that this partner was "afraid of them." Depression and posttraumatic stress disorder symptoms were both associated with higher rates of family reintegration problems. CONCLUSIONS: Mental health problems may complicate veterans' readjustment and reintegration into family life. The findings suggest an opportunity to improve the treatment of psychiatric disorders by addressing family problems. Language: en

Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression, 2nd ed

Abstract: Iin this magnificent second edition, Drs. Frederick Goodwin and Kay Redfield Jamison bring their unique contribution to mental health science into the 21st century. In collaboration with a team of other leading scientists, a collaboration designed to preserve the unified voice of the two authors, they exhaustively review the biological and genetic literature that has dominated the field in recent years and incorporate cutting-edge research conducted since publication of the first edition. They also update their surveys of psychological and epidemiological evidence, as well as that pertaining to diagnostic issues, course, and outcome, and they offer practical guidelines for differential diagnosis and clinical management. The medical treatment of manic and depressive episodes is described, strategies for preventing future episodes are given in detail, and psychotherapeutic issues common in this illness are considered. Special emphasis is given to fostering compliance with medication regimens and treating patients who abuse drugs and alcohol or who pose a risk of suicide. This book, unique in the way that it retains the distinct perspective of its authors while assuring the maximum in-depth coverage of a vastly expanded base of scientific knowledge, will be a valuable and necessary addition to the libraries of psychiatrists and other physicians, psychologists, clinical social workers, neuroscientists, pharmacologists, and the patients and families who live with manic-depressive illness.

Lithium trial in Alzheimer's disease: a randomized, single-blind, placebo-controlled, multicenter 10-week study.

Abstract: Objective: Lithium, a first-line drug for the treatment of bipolar depression, has recently been shown to regulate glycogen synthase kinase-3 (GSK-3), a kinase that is involved in the phosphorylation of the tau protein. Since hyperphosphorylation of tau is a core pathological feature in Alzheimer’s disease, lithium-induced inhibition of GSK-3 activity may have therapeutic effects in Alzheimer’s disease. In the current study, we tested the effect of short-term lithium treatment in patients with Alzheimer’s disease. Method: A total of 71 patients with mild Alzheimer’s disease (Mini-Mental State Examination score ≥ 21 and ≤ 26) were successfully randomly assigned to placebo (N = 38) or lithium treatment (N = 33) at 6 academic expert memory clinics. The 10-week treatment included a 6-week titration phase to reach the target serum level of lithium (0.5‐0.8 mmol/L). The primary outcome measures were cerebrospinal fluid (CSF) levels of phosphorylated tau (p-tau) and GSK-3 activity in lymphocytes. Secondary outcome measures were CSF concentration of total tau and β-amyloid1‐42 (Aβ1‐42), plasma levels of Aβ1‐42, Alzheimer’s Disease Assessment Scale (ADAS)-Cognitive summary scores, MMSE, and Neuropsychiatric Inventory (NPI). Patients were enrolled in the study from November 2004 to July 2005. Results: No treatment effect on GSK-3 activity or CSF-based biomarker concentrations (P > .05) was observed. Lithium treatment did not lead to change in global cognitive performance as measured by the ADAS-Cog subscale (P =. 11) or in depressive symptoms. Conclusions: The current results do not support the notion that lithium treatment may lead to reduced hyperphosphorylation of tau protein after a short 10-week treatment in the Alzheimer’s disease target population. Trial Registration: controlled-trials.com

The importance of childhood trauma and childhood life events for chronicity of depression in adults

Abstract: Background: Childhood trauma is linked to adult depression and might be a risk factor for a more chronic course of depression. However, the link between childhood trauma and chronicity of depression has not been investigated using a large and representative sample in which other depression characteristics, such as severity; age at onset, and comorbid psychopathology, were taken into account. Method: Baseline data, collected during 2004 through 2007, were drawn from the Netherlands Study of Depression and Anxiety (NESDA). Participants had a current DSM-IV-TR diagnosis of major depressive disorder (MDD) and were recruited from the community, primary care settings, and specialized mental health care facilities (N = 1230). Relationships between both childhood trauma and childhood life events and chronicity of depression were examined using multiple logistic regression models. Chronicity of depression was defined as being depressed for 24 months or more in the past 4 years. Results: Chronicity of depression was associated with a significantly higher prevalence of childhood trauma but was not associated with childhood life events. We found the strongest association for those with the highest score on a cumulative index summarizing frequency of childhood trauma (OR = 3.26; 95% CI = 1.86 to 5.72, p <.001). After controlling for comorbid anxiety disorders, severity of depressive symptoms, and age at onset of depression, we found that the association between childhood trauma index and chronicity of depression remained significant (OR = 2.06; 95% CI = 1.13 to 3.73, p = .02). Conclusions. These results suggest that multiple childhood traumas can be seen as an independent determinant of chronicity of depression. For treatment of depressed patients, it is therefore important to detect the presence of childhood trauma. J Clin Psychiatry 2009;70(7):983-989 (c) Copyright 2009 Physicians Postgraduate Press, Inc.

Intervention in individuals at ultra-high risk for psychosis: a review and future directions.

Abstract: OBJECTIVE: Over the last 15 years, a focus on early intervention in psychotic disorders has emerged. Initially, the early psychosis movement focused on timely recognition and phase-specific treatment of first-episode psychosis. However, early psychosis researchers suspected that pushing the point of intervention even further back to the prodromal phase of psychotic disorders may result in even better outcomes. This article reviews intervention research in the ultra-high-risk phase of psychotic disorders. DATA SOURCES: A literature search of intervention trials with ultra-high-risk cohorts published after 1980 was conducted on PubMed with the search terms prodrome and intervention. STUDY SELECTION: All published intervention trials with ultra-high-risk cohorts. DATA SYNTHESIS: The first generation of intervention trials indicated that both pharmacologic and psychological intervention strategies may be of value in terms of symptom reduction and delay or prevention of onset of threshold psychotic disorder. CONCLUSIONS: Further controlled intervention trials with larger sample sizes are required in order to confirm and extend these findings. We argue that the clinical staging model provides a framework for the rationale and design of such studies, with simpler, safer, and more benign interventions being better candidates for first-line treatment, while more complex and potentially harmful treatments should be reserved for those cases in which response has failed to occur. Recent evidence indicates that neuroprotective agents, such as essential fatty acids, may be a suitable form of intervention for the ultra-high-risk phase of psychotic disorders, with a positive risk-benefit balance. Ethical aspects have become more salient given the recently observed declining transition rate in ultra-high-risk samples. We outline the key questions for the next generation of ultra-high-risk intervention trials.

Early improvement in the first 2 weeks as a predictor of treatment outcome in patients with major depressive disorder: a meta-analysis including 6562 patients.

Abstract: OBJECTIVE New evidence indicates that treatment response can be predicted with high sensitivity after 2 weeks of treatment. Here, we assess whether early improvement with antidepressant treatment predicts treatment outcome in patients with major depressive disorder (MDD). DATA SOURCES Forty-one clinical trials comparing mirtazapine with active comparators or placebo in inpatients and outpatients (all-treated population, N = 6907; intent-to-treat population, N = 6562) with MDD (DSM-III-R or DSM-IV Criteria) were examined for early improvement (>or= 20% score reduction from baseline on the 17-item Hamilton Rating Scale for Depression [HAM-D-17] within 2 weeks of treatment) and its relationship to treatment outcome. STUDY SELECTION Data were obtained from a systematic search of single- or double-blind clinical trials (clinical trials database, Organon, a part of Schering-Plough Corporation, Oss, The Netherlands). All included trials (a total of 41) employed antidepressant treatment for more than 4 weeks and a maximum of 8 weeks. The studies ranged from March 1982 to December 2003. Trials were excluded if there were no HAM-D-17 ratings available, no diagnosis of MDD, or if the study was not blinded. Trials were also excluded if HAM-D-17 assessments were not available at week 2, week 4, and at least once beyond week 4. DATA SYNTHESIS Early improvement predicted stable response and stable remission with high sensitivity (>or= 81% and >or= 87%, respectively). Studies utilizing rapid titration vs. slow titration of mirtazapine demonstrated improved sensitivity for stable responders (98%, [95% CI = 93% to 100%] vs. 91% [95% CI = 89% to 93%]) and stable remitters (100%, [95% CI = 92% to 100%] vs. 93% [95% CI = 91% to 95%]). Negative predictive values for stable responders and stable remitters were much higher (range = 82%-100%) than positive predictive values (range = 19%-60%). CONCLUSIONS These results indicate that early improvement with antidepressant medication can predict subsequent treatment outcome with high sensitivity in patients with major depressive disorder. The high negative predictive values indicate little chance of stable response or stable remission in the absence of improvement within 2 weeks. A lack of improvement during the first 2 weeks of therapy may indicate that changes in depression management should be considered earlier than conventionally thought.

The duration of the suicidal process: how much time is left for intervention between consideration and accomplishment of a suicide attempt?

Abstract: OBJECTIVE: A history of suicide attempts is a major predictive factor for completed suicide with repeated self-harm constituting a particularly high risk. This study was undertaken to investigate suicide attempters' reports on the length of the period between consideration and accomplishment of a suicide attempt. METHOD: Eighty-two patients referred to a psychiatric university hospital after a suicide attempt were approached within 3 days after the act. A semistructured interview focusing on the duration and related aspects of the suicidal process, the Barratt Impulsiveness Scale, the Beck Suicide Intent Scale, and the Montgomery-Asberg Depression Rating Scale were administered. Data were collected from July 2004 to December 2005. RESULTS: Nearly half of the patients (47.6%; N = 39) reported that the period between the first current thought of suicide and the actual attempt had lasted 10 minutes or less. Those patients in which this process had taken longer showed a higher suicidal intent (p < .001). Impulsivity was not associated with the duration of the suicidal process. Although the majority of the patients were alone during the suicidal process, 76.8% (N = 63) reported having had any kind of interpersonal contact. CONCLUSION: The process from the emergence of suicidal thoughts to the accomplishment of a suicide attempt, and thus the time for intervention, generally is short. However, in a considerable number of suicide attempters, there is at least some readiness for interpersonal contact with partner, family, or friends. Professional helpers appear to have limited potential for intervention during this phase. Thus, spreading information on signs of suicidality and interventional measures among the general population should be incorporated into suicide prevention strategies. Language: en

Are weight gain and metabolic side effects of atypical antipsychotics dose dependent? A literature review.

Abstract: Background Numerous publications have provided evidence for clinically important metabolic adverse effects of antipsychotics, but there is no systematic evaluation as to whether weight gain and other metabolic changes are dose dependent. Objective This review of the available literature aimed to explore a possible relationship between dosage of second-generation antipsychotics (SGAs) and the degree of metabolic side effects. Data sources A literature review was conducted in 3 steps: (1) Articles published between 1975 and 2004 were identified on the basis of the bibliography of an extensive review of the metabolic effects of SGAs. (2) Articles published between 2004 and 2008 were identified by a PubMed search with the keywords weight gain, metabolic, glucose, insulin, and lipid AND dose combined with amisulpride, aripiprazole, clozapine, quetiapine, risperidone, sertindole, and ziprasidone. (3) A hand search was conducted based on the bibliography of the identified articles. Study selection and data extraction All studies that provided information on metabolic side-effects in different dose ranges were selected. Data extraction was carried out independently by 2 observers. Data synthesis Preliminary evidence suggests a dose-response relationship between clozapine and olanzapine serum concentrations and metabolic outcomes, although the association between administered daily dose and metabolic outcomes is not clear. Data are controversial with regard to risperidone, and no study has as yet assessed risperidone serum concentrations in association with metabolic outcomes. For the other SGAs, there was little evidence to suggest a dose-response relationship, although, in these agents also, no assessment of serum concentrations was conducted. Conclusions The finding that metabolic complications may be associated with clozapine and olanzapine plasma concentrations provides further evidence for a causal contribution to the metabolic disturbances observed with these agents. Further well-designed, prospective studies investigating a possible association between SGA serum concentrations and metabolic outcomes are needed.

Presenting ADHD Symptoms, Subtypes, and Comorbid Disorders in Clinically Referred Adults with ADHD

Abstract: Objective Despite the increasing presentation of ADHD in adults, many practitioners remain reluctant to assess individuals for ADHD, in part related to the relative lack of data on the presenting symptoms of ADHD in adulthood. Comorbidity among adults with ADHD is also of great interest due to the high rates of psychiatric comorbidity, which can lead to a more persistent ADHD among adults.

Adding psychotherapy to pharmacotherapy in the treatment of depressive disorders in adults: a meta-analysis

Abstract: Objective: A considerable number of studies has examined whether adding psychotherapy to pharmacotherapy results in stronger effects than pharmacotherapy alone. However, earlier meta-analyses in this field have included only a limited number of available studies and did not conduct extended subgroup analyses to examine possible sources of heterogeneity. Data Sources: We used a database derived from a comprehensive literature search in PubMed, PsycINFO, EMBASE, and the Cochrane Central Register of Controlled Trials for studies published from 1966 to January 2008 that examined the psychological treatment of depression. The abstracts of these studies were identified by combining terms indicative of psychological treatment and depression. Study Selection: We included randomized trials in which the effects of a pharmacologic treatment were compared to the effects of a combined pharmacologic and psychological treatment in adults with a depressive disorder. Data Extraction: For each of the studies, we calculated a standardized mean effect size indicating the difference between pharmacotherapy and the combined treatment at posttest. We also coded major characteristics of the population, the interventions, and the quality and design of the study. Data Synthesis: Twenty-five randomized trials, with a total of 2,036 patients, were included. A mean effect size of d = 0.31 (95% CI, 0.20 ~ 0.43) was found for the 25 included studies, indicating a small effect in favor of the combined treatment over pharmacotherapy alone. Studies aimed at patients with dysthymia resulted in significantly lower effect sizes compared to studies aimed at patients with major depression, a finding that suggests that the added value of psychotherapy is less in patients with dysthymia. The dropout rate was significantly lower in the combined treatment group compared to the pharmacotherapy only group (OR = 0.65; 95% CI, 0.50 ~ 0.83). Conclusions: Psychotherapy seems to have an additional value compared to pharmacotherapy alone for depression.

A multidimensional tool to quantify treatment resistance in depression: the Maudsley staging method.

Abstract: Objective Treatment resistance is a common clinical phenomenon in depression. However, current unitary models of staging fail to represent its complexity. We aimed to devise a model to stage treatment-resistant depression, taking into account the core factors contributing to treatment failure. Method We reviewed the literature to identify factors consistently associated with treatment resistance. We also analyzed data from a subgroup of patients discharged from a specialist inpatient unit for whom adequate data were obtainable. Results We present a points-based staging model incorporating 3 factors: treatment, severity of illness, and duration of presenting episode. In this model, the rating of symptom severity ranges from subsyndromal depression (score 1) to severe syndromal depression with psychosis (score 5). Antidepressant treatment is rated on a 5-point subscale based on number of medications used, while duration of the presenting episode is rated on a 3-point subscale. The overall level of resistance estimated using this model varies from minimal resistance (score of 3) to severe resistance (score of 15). The rating system allows the overall severity of treatment resistance to be summarized either as a single numeric score or under a single descriptive category. It may also be possible to specify categories (mild, moderate, and severe) based on severity of resistance. Analysis of inpatient data indicates that the factors incorporated in the model and the model itself have some predictive validity. Conclusion This staging model has reasonable face and predictive validity and may have better utility in staging treatment resistance than currently available methods.

A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients.

Abstract: Objective Recent molecular, preclinical, and preliminary clinical studies suggest that the therapeutic effects of mood stabilizers may be mediated by modulating expression of potent neurotrophic and neuroprotective factors having the potential to reverse impairments of cellular resilience, reductions in brain volume, and cell death or atrophy. Our main goal was to investigate the potential clinical significance of these findings in relation to bipolar disorder. Method The longitudinal effect of lithium on brain gray matter volume was investigated in well-characterized (DSM-IV criteria) bipolar depressed subjects (N = 28) at baseline (medication-free) and after lithium administration (4 weeks). Total brain gray matter, prefrontal gray matter, and left subgenual prefrontal gray matter volumes were determined using validated semiautomated segmentation and region of interest methodology. The study was conducted from November 1997 until April 2004 at Wayne State University School of Medicine, Detroit, Mich. Results Significant increases in total brain gray matter volume in bipolar subjects were observed after 4 weeks of lithium administration (p = .0043). Moreover, regional analyses in the bipolar subjects revealed significant differences between responders (>50% decrease in Hamilton Depression Rating Scale total score) and nonresponders; only responders showed a significant increase in gray matter volume in the prefrontal cortex (p = .003) and an increase at trend level in the left subgenual prefrontal cortex volume (p = .0786). Conclusion The increase in gray matter volume in these areas, which various neuroimaging and postmortem neuropathology studies have implicated in the neuropathophysiology of bipolar disorder, suggests that the observed effects may be linked to clinical response. The findings also support the notion that future treatments that more directly target molecules in critical central nervous system pathways that regulate cellular plasticity hold promise as novel, improved, long-term treatments for mood disorders as well as some neurodegenerative conditions, such as Alzheimer's disease. Trial registration clinicaltrials.gov Identifier: NCT00870311.

Extended-Release Quetiapine as Adjunct to an Antidepressant in Patients With Major Depressive Disorder: Results of a Randomized, Placebo-Controlled, Double-Blind Study

Abstract: Objective: This 6-week, randomized, double-blind study evaluated efficacy and safety of adjunctive extended-re lease (XR) quetiapine in patients with major depressive disorder (MDD) and an inadequate response to >= 1 antidepressant. Method: Male or female patients aged 18 to 65 years with DSM-IV-TR MDD were randomly assigned to receive quetiapine XR (150 or 300 mg/day) or placebo adjunctive to continuing antidepressant. Primary endpoint was change from randomization to week 6 in Montgomery-Asberg Depression Rating Scale (MADRS) total score. Secondary variables included MADRS response (>= 50% reduction in score from randomization) at weeks 1 and 6, MADRS remission (<= 8 total score) at week 6, and week 6 change in Hamilton Rating Scale for Depression and Hamilton Rating Scale for Anxiety total scores. Safety was assessed throughout the study. The study was conducted between May 8, 2006, and April 7, 2007. Results: Four hundred ninety-three patients were randomly assigned. Mean change from randomization to week 6 in MADRS score was -15.26 and -14.94 for quetiapine XR 150 mg/day and 300 mg/day, respectively (both p <.01 vs. placebo [-12.21]). Quetiapine XR showed separation from placebo in MADRS score from week 1 (p < .001) onward. The MADRS response rates were 55.4%, 57.8%, and 46.3% for quetiapine XR 150 mg/day (p = .107 vs. placebo), 300 mg/day (p < .05), and placebo, respectively; MADRS remission rates were 36.1% (p < .05 vs. placebo), 31.1% (p = .126), and 23.8% for quetiapine XR 150 mg/day, 300 mg/day, and placebo, respectively. Withdrawal rates due to adverse events were 6.6%, 11.7%, and 3.7% with quetiapine XR 150 mg/day, 300 mg/day, and placebo, respectively. The most common adverse events were dry mouth (20.4%, 35.6%, and 6.8%) and somnolence (16.8%, 23.3%, and 3.1%). Conclusions: Adjunctive quetiapine XR (150 mg/day and 300 mg/day) was effective in patients with MDD who had shown an inadequate response to antidepressant treatment. Significant reduction of depressive symptoms occurred as early as week 1. Findings were consistent with the known safety and tolerability profile of quetiapine.

Time Trends in Age at Onset of Anorexia Nervosa and Bulimia Nervosa

Abstract: Objective This study aims to explore the time trends in age at onset of anorexia nervosa and bulimia nervosa. Method The sample was composed of 1,666 anorexia nervosa subjects and 793 bulimia nervosa subjects (according to DSM-IV criteria) without previous anorexia nervosa consecutively referred to our outpatient unit in the period between 1985 and 2008. Time trends in illness onset were analyzed according to the year of birth of subjects. Results In both anorexia nervosa and bulimia nervosa, age at onset showed a significant decrease according to year of birth. A regression model showed a significant independent effect of socioeconomic status, age at menarche, and number of siblings in predicting age at onset lower than 16 years. Conclusion Age at onset of anorexia nervosa and bulimia nervosa is decreasing in younger generations. The implications of our findings in terms of long-term outcome remain to be understood. Biologic and sociocultural factors explaining this phenomenon need to be explored in future studies.

Efficacy and Safety of Lamotrigine as Add-On Treatment to Lithium in Bipolar Depression: A Multicenter, Double-Blind, Placebo-Controlled Trial

Abstract: Objective: Lamotrigine is one of the pharmacologic options for the treatment of bipolar depression but has only been studied as monotherapy. This study compared the acute effects of lamotrigine and placebo as add-on therapy to ongoing treatment with lithium in patients with bipolar depression. Method: Outpatients (N = 124) aged 18 years and older with a DSM-lV bipolar I or 11 disorder and a major depressive episode (Montgomery-Asberg Depression Rating Scale [MADRS] score ! 18 and Clinical Global Impressions-Bipolar Version [CGI-BP] severity of depression score ! 4) while receiving lithium treatment (0.6-1.2 mmol/L) were randomly assigned to 8 weeks of double-blind treatment with lamotrigine (titrated to 200 mg/d) or placebo. The primary outcome measure was mean change from baseline in total score on the MADRS at week 8. Secondary outcome measures were response (defined as a reduction of >= 50% on the MADRS and/or change of depression score on the CGI-BP of "much improved" or "very Much improved" compared to baseline) and switch to mania or hypomania (defined as a CGI-BP? severity of mania score of at least mildly ill at any visit). Patients were included in the study between August 2002 (Spain started in October 2003) and May 2005. Results: Endpoint mean change from baseline MADRS total score was -15.38 (SE = 1.32) points for lamotrigine and -11.03 (SE = 1.36) points for placebo (t = -2.29, df = 104, p =.024). Significantly more patients responded to lamotrigine than to placebo on the MADRS (51.6% vs. 31.7%, p = .030), but not on the CGI-BP change of depression (64.1% vs. 49.2%, p = .105). Switch to mania or hypomania occurred in 5 patients (7.8%) receiving lamotrigine and 2 patients (3.3%) receiving placebo (p = .441). Conclusion: Lamotrigine was found effective and safe as add-on treatment to lithium in the acute treatment of bipolar depression. Trial Registration: clinicaltrials.gov Identifier: NCT00224510

Effects of lithium on cognitive performance: a meta-analysis.

Abstract: Background Cognitive impairment is underrecognized among patients with bipolar disorder and may represent not only effects of the illness but also adverse effects of its treatments Among these, lithium is the best-studied mood stabilizer As its cognitive effects are mixed and not well-known, we assessed reported effects of lithium on cognitive performance Data sources MEDLINE, PsycINFO, and EMBASE databases (1950 to December 2008) were queried with the keywords lithium, cognit*, neurocognit*, neuropsych*, psycholog*, attention, concentration, processing speed, memory, executive, and learning Database searches were supplemented with bibliographic cross-referencing by hand The literature search was conducted independently by 2 authors (APW and TSW) during August and September 2008, and questions about appropriate inclusion or exclusion were resolved between them by consensus Study selection Of 586 reports initially identified as being of potential interest, 12, involving 539 subjects, met our inclusion criteria: (1) cognitive performance compared between subjects taking lithium and comparable subjects not taking lithium; comparability was assured by: (2) patients with the same affective disorder diagnoses in euthymic or remitted status or healthy volunteers; (3) groups of similar age and sex; (4) similar intelligence, education, or occupation; (5) similar distribution of other concurrent psychotropic drugs; and (6) cognitive abilities (outcomes) assessed with performance-based measures Data extraction Standardized mean-difference effect size (ES), corrected for small-sample bias (Hedges' g), was computed for cognitive tasks in each study ES estimates were transformed so that positive values indicate poorer performance by lithium-treated subjects Infrequently, when means and standard deviations were not provided, ES was estimated from reported values of t, F, or z tests For analysis, similar neurocognitive tests were grouped a priori based on the cognitive domains they aimed to assess Data synthesis We identified 12 studies involving 276 lithium-treated and 263 similar or the same subjects, lithium-free Lithium was taken for a mean duration of 39 years by affective disorder patients and 25 weeks by healthy volunteers, yielding a mean daily trough serum concentration of 080 mEq/L Overall, lithium treatment was associated with small but significant impairment in immediate verbal learning and memory (ES = 024; 95% CI, 005-043) and creativity (ES = 033; 95% CI, 002-064), whereas delayed verbal memory, visual memory, attention, executive function, processing speed, and psychomotor performance were not significantly affected Selectively, among the 326 affective-disorder patients, in addition to these overall impairments, long-term lithium treatment also was associated with even greater impairment in psychomotor performance (ES = 062; 95% CI, 027-097), with no evidence of cognitive improvements Conclusions Lithium treatment appears to have only few and minor negative effects on cognition

Lurasidone in the treatment of acute schizophrenia: a double-blind, placebo-controlled trial.

Abstract: Objective Lurasidone is a novel psychotropic agent with high affinity for D(2) and 5-HT(2A) receptors, as well as for receptors implicated in the enhancement of cognition and mood and the reduction of negative symptoms (5-HT(7), 5-HT(1A), and alpha(2c)). The objective of the study was to evaluate the safety and efficacy of lurasidone in patients hospitalized for an acute exacerbation of DSM-IV-defined schizophrenia. Method Patients were randomly assigned to 6 weeks of double-blind treatment with a fixed dose of lurasidone 80 mg (N = 90, 75.6% male, mean age = 39.7 years, mean baseline score on the Brief Psychiatric Rating Scale derived from the Positive and Negative Syndrome Scale [BPRSd] = 55.1) or placebo (N = 90, 77.8% male, mean age = 41.9 years, mean BPRSd score = 56.1). The primary efficacy measure was the BPRSd. The study was conducted from May to December 2004. Results At day 42, last-observation-carried-forward endpoint, treatment with lurasidone was associated with significant improvement compared to placebo on the BPRSd (least squares mean +/- SE = -8.9 +/- 1.3 vs. -4.2 +/- 1.4; p = .012), as well as on all secondary efficacy measures, including the PANSS total score (-14.1 +/- 2.1 vs. -5.5 +/- 2.2; p = .004) and the PANSS positive (-4.3 +/- 0.7 vs. -1.7 +/- 0.7; p = .006), negative (-2.9 +/- 0.5 vs. -1.3 +/- 0.5; p = .025), and general psychopathology (-7.0 +/- 1.1 vs. -2.7 +/- 1.2; p = .0061) subscales. Significant improvement was seen as early as day 3, based on BPRSd, PANSS, and Clinical Global Impressions-Severity of Illness assessments. Treatment with lurasidone was generally well tolerated and was not associated with adverse changes in metabolic or electrocardiogram parameters. There were no clinically significant differences between lurasidone and placebo in objective measures of extrapyramidal symptoms. Conclusions The results of this study suggest that the novel psychotropic agent lurasidone is a safe and effective treatment for patients with an acute exacerbation of schizophrenia. Trial registration (ClinicalTrials.gov) Identifier: NCT00088634.

The effects of undertreated chronic medical illnesses in patients with severe mental disorders.

Abstract: Severe mental disorders such as bipolar disorder and schizophrenia often co-occur with chronic medical illnesses, especially cardiovascular disease and diabetes. These comorbidities are associated with a more severe course of mental illness, reduced quality of life, and premature mortality. Although the association between mental disorders and physical health complications has long been recognized, medical conditions remain undertreated in clinical psychiatric practice, and the life expectancy for individuals with serious psychiatric disorders is approximately 30% shorter than that of the general US population. Factors that are related to the mental illness (eg, cognitive impairment, reduced ability to function, and a lack of communication skills) as well as factors such as the high cost of medical care may make accessing general health care a difficult task for patients. Even when medical care is received by patients, the quality is often poor, and dangerous illnesses may be undiagnosed and untreated. In addition, harmful side effects of medications used to treat psychiatric disorders, unhealthy habits and lifestyles, and a possible genetic susceptibility to medical conditions increase the likelihood of comorbid physical conditions in patients with severe mental illness. Implementing behavioral interventions into clinical practice may help patients improve their overall health and prevent chronic medical conditions.

Agomelatine prevents relapse in patients with major depressive disorder without evidence of a discontinuation syndrome: a 24-week randomized, double-blind, placebo-controlled trial.

Abstract: Objective This study evaluates the efficacy of agomelatine, the first antidepressant that is an agonist at MT(1)/MT(2) receptors and an antagonist at 5-HT(2C) receptor, in the prevention of relapse of depression following successful response. Method Patients with DSM-IV-TR major depressive disorder who responded to an 8- or 10-week course of agomelatine 25- or 50-mg daily treatment were randomly assigned to receive continuation treatment with agomelatine (n=165) or placebo (n=174) during a 24-week, randomized, double-blind treatment period. The main outcome measure was time to relapse during the double-blind treatment period. The cumulative probability of relapse was calculated using the Kaplan-Meier method of survival analysis. The study was conducted from February 2005 to February 2007. Results During the 6-month evaluation period, the incidence of relapse was significantly lower in patients who continued treatment than in those switched to placebo (P=.0001). The cumulative relapse rate at 6 months for agomelatine-treated patients was 21.7%; that for placebo-treated patients was 46.6%. Agomelatine was also superior to placebo in preventing relapse in the subset of patients with baseline 17-item Hamilton Depression Rating Scale total score > or = 25. Measures of tolerability and safety of both doses of agomelatine were similar to placebo. No pattern of early relapse or adverse events suggestive of withdrawal symptoms was obtained after abrupt cessation of agomelatine. Conclusions The findings are important in 2 respects. First, agomelatine is an effective and safe antidepressant continuation therapy, which confirms efficacy seen in short-term studies. Second, few early relapses were observed in the patient group switched to placebo: the survival curve for placebo separated gradually from that of patients taking agomelatine. We suggest this reflects solely the underlying properties of the illness, which is only possible due to the lack of discontinuation syndrome after agomelatine withdrawal. It underlines the novel clinical profile of agomelatine, which quite likely reflects its innovative pharmacology. Trial registration isrctn.org Identifier: ISRCTN53193024.

Delayed Posttraumatic Stress Disorder: Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Prospective Studies

Abstract: Objective: Prevalence estimates of delayed posttraumatic stress disorder (PTSD) have varied widely in the literature. This study is the first to establish the prevalence of delayed PTSD in prospective studies and to evaluate associated factors through meta-analytic techniques. Data sources; Studies were located by an electronic search using the databases EMBASE, MEDLINE, and PsycINFO. Search terms were posttraumatic stress disorder [include all subheadings] AND (delayed OR prospective OR longitudinal OR follow-up). Results were limited to journal articles published between 1980 and April 4, 2008. Study selection: We included longitudinal, prospective studies of humans exposed to a potentially traumatic event that assessed participants at I to 6 months after the event, that included a follow-up of at least 12 months after the event, and that specified rates of new onset and remission between assessments in study completers. Data extraction: Data were extracted concerning the study design, demographic features, and event-related characteristics and the number of PTSD cases at first assessment, the number of PTSD cases among study dropouts, and the number of new event-related PTSD cases at each subsequent assessment among study completers. Data from 24 studies were included. Four of these provided additional data on initial subthreshold PTSD and subsequent risk of delayed PTSD. Data synthesis: The proportion of PTSD cases with delayed PTSD was 24.8% (95% CI = 22.6% to 27.2%) after adjusting for differences in study methodology, demographic features, and event-related characteristics. Military combat exposure, Western cultural background, and lower cumulative PTSD incidence were associated with delayed PTSD. Participants with initial subthreshold PTSD were at increased risk of developing delayed PTSD. Conclusions: Delayed PTSD was found among about a quarter of PTSD cases and represents exacerbations of prior symptoms. J Clin Psychiatry 2009,70(11):1572-1582 (C) Copyright 2009 Physicians Postgraduate Press, Inc

Acute treatment of pediatric bipolar I disorder, manic or mixed episode, with aripiprazole: a randomized, double-blind, placebo-controlled study.

Abstract: OBJECTIVES To determine the efficacy and safety of aripiprazole for the treatment of pediatric bipolar I disorder, manic or mixed episode, with or without psychotic features. METHOD Subjects were enrolled between March 2005 and February 2007 in a randomized, multicenter, double-blind 4-week study of aripiprazole 10 mg/d, aripiprazole 30 mg/d, and placebo. Subjects (n = 296) were 10 to 17 years old with a DSM-IV diagnosis of bipolar I disorder with current manic or mixed episodes, with or without psychotic features, and a Young Mania Rating Scale (YMRS) score > or = 20. The primary efficacy variable was change from baseline in the YMRS total score. RESULTS Both doses of aripiprazole were superior to placebo on the YMRS total score beginning at week 1 and continuing through week 4. Aripiprazole 10 mg and 30 mg were more effective than placebo on global improvement, mania, and overall bipolar illness outcome measures. Response ( > or = 50% reduction in YMRS total score) at week 4 was achieved by 44.8%, 63.6%, and 26.1% of subjects in the aripiprazole 10 mg, aripiprazole 30 mg, and placebo groups, respectively (P < .01 both doses vs placebo). Both doses were generally well tolerated. The most common adverse events were extrapyramidal disorder and somnolence; rates were higher for aripiprazole 30 mg compared with aripiprazole 10 mg. Average weight gain was not significantly different between the aripiprazole 10 mg (+0.82 kg) or 30 mg (+1.08 kg) groups compared with the placebo group (+0.56 kg) (P = .35 and P = .13, respectively). CONCLUSIONS Aripiprazole in daily doses of 10 mg or 30 mg is an effective and generally well-tolerated acute treatment for pediatric subjects with bipolar I mania or mixed episodes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00110461.

A review of fragile X premutation disorders: expanding the psychiatric perspective.

Abstract: Objective: Fragile X premutation conditions are associated with a significant degree of psychopathology and thus are of interest to the psychiatrist. Remarkable advances at the molecular level have enhanced our understanding of fragile X premutation disorders.

Mild behavioral impairment and risk of dementia: a prospective cohort study of 358 patients.

Abstract: Background Mild cognitive impairment (MCI) is a transitional state between normal ageing and dementia, at least for some patients. Behavioral symptoms in MCI are associated with a higher risk of dementia, but their association with dementia risk in patients without MCI is unknown. Mild Behavioral Impairment (MBI) refers to a late life syndrome with prominent psychiatric and related behavioral symptoms in the absence of prominent cognitive symptoms, which may also be a dementia prodrome.

Medication nonadherence and treatment outcome in patients with schizophrenia or schizoaffective disorder with suboptimal prior response.

Abstract: OBJECTIVE To examine the impact of medication nonadherence on treatment outcome in schizophrenia and potential risk factors for nonadherence. METHOD A post hoc analysis of a randomized, double-blind, 8-week, fixed-dose study comparing olanzapine 10, 20, and 40 mg/day for patients with schizophrenia or schizoaffective disorder (DSM-IV criteria) with suboptimal response to current treatment (N = 599) was conducted between September 12, 2003, and November 3, 2005, at 55 study centers in the United States. Nonadherence was defined as not taking medication as prescribed based on daily pill counts. Because there was no significant difference in nonadherence between dose groups, effects of nonadherence on efficacy and safety outcomes were examined using all 3 groups combined. Baseline demographics and symptom severity were investigated as potential risk factors for nonadherence. RESULTS During the 8-week study, 34.5% of patients were nonadherent at least once. Nonadherent patients had significantly less improvement compared to adherent patients as measured by change in Positive and Negative Syndrome Scale total score (-22.57 vs. -26.84, p = .002). Longer duration of nonadherence was associated with reduced likelihood of treatment response (odds ratio = 0.94, 95% CI = 0.90 to 0.99, p = .008). The early treatment discontinuation rate was higher in nonadherent compared to adherent patients (40.8% vs. 24.5%, p < .001). Adherent and nonadherent patients had comparable outcomes in most safety measures, except for weight change, for which adherent patients had greater weight gain than nonadherent patients (2.63 kg vs. 1.96 kg, p = .02). Greater depression severity at baseline (p = .01) and greater hostility level during the study were significant risk factors for nonadherence (p = .02). CONCLUSIONS Medication nonadherence had a significantly negative impact on treatment response, highlighting the importance of adherence to achieve satisfactory treatment outcome. Findings may also help clinicians identify patients at risk for nonadherence and utilize interventions to improve adherence. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00100776.

Relationships between obsessive-compulsive symptomatology and severity of psychosis in schizophrenia: a systematic review and meta-analysis.

Abstract: Objective The presence of obsessive-compulsive symptoms (OCS) or obsessive-compulsive disorder (OCD) is common in patients with schizophrenia. The impact of OCS and OCD on severity of psychotic symptoms has been assessed in several past studies yielding inconclusive results. In this report, we aim to integrate the findings of prior studies by means of a systematic review followed by a meta-analysis. Data sources A search of studies in PubMed (from 1950 to September 2006) and PsycINFO (from 1966 to September 2006) databases was performed to assess the influence of OCS and OCD on severity of psychotic symptoms in patients with schizophrenia using as syntax ("schizophrenia" OR "psychosis" OR "psychotic") AND ("obsessive-compulsive disorder" OR "OCD" OR "obsession*" OR "compulsion*" OR "obsessiv*" OR "compulsiv*"). Reference lists of all retrieved articles were also hand-searched. Study selection Twenty-three studies were included in the systematic review, and 18 articles provided usable data for the meta-analysis. Data extraction All relevant data were extracted using a standardized report form by 2 investigators. Effect sizes and pooled estimates were calculated. Data were analyzed separately for studies using an OCS or OCD definition. Data synthesis The presence of OCS was significantly associated with greater severity of global psychotic symptoms (standardized mean difference [95% CI], 0.39 [0.14 to 0.64]), positive psychotic symptoms (0.28 [0.00 to 0.56]), and negative psychotic symptoms (0.36 [0.11 to 0.62]). In contrast, no differences in the severity of global psychotic symptoms (0.19 [-0.14 to 0.51]), positive psychotic symptoms (-0.01 [-0.20 to 0.19]), or negative psychotic symptoms (-0.11 [-0.30 to 0.08]) were found for the OCD versus non-OCD subgroups. Conclusion This first meta-analysis revealed that the presence of obsessive-compulsive symptoms in schizophrenia is associated with higher global, positive, and negative psychotic symptoms. This association was not found when a categorical definition of obsessive-compulsive disorder was used.

McLean-Harvard International First-Episode Project: two-year stability of DSM-IV diagnoses in 500 first-episode psychotic disorder patients.

Abstract: Objective Since stability of DSM-IV diagnoses of disorders with psychotic features requires validation, we evaluated psychotic patients followed systematically in the McLean-Harvard First Episode Project.

Patient preference as a moderator of outcome for chronic forms of major depressive disorder treated with nefazodone, cognitive behavioral analysis system of psychotherapy, or their combination.

Abstract: Background Little is known about moderators of response to psychotherapy, medication, and combined treatment for chronic forms of major depressive disorder (MDD). We hypothesized that patient preference at baseline would interact with treatment group to differentially affect treatment outcome. Method We report outcomes for 429 patients who participated in a randomized multicenter trial of nefazodone, Cognitive Behavioral Analysis System of Psychotherapy (CBASP), or combination therapy for chronic forms of MDD (DSM-IV criteria) and who indicated their preference for type of treatment at study entry. The primary outcome measures were total scores on the 24-item Hamilton Rating Scale for Depression (HAM-D-24) and categorical definitions of remission or partial response. The patients were recruited between June 1996 and December 1997. Results There was an interactive effect of preference and treatment group on outcome. The treatment effect varied as a function of preference, and was particularly apparent for patients who initially expressed preference for one of the monotherapies. Patients who preferred medication had a higher remission rate (45.5%) and lower mean HAM-D-24 score (11.6) at study exit if they received medication than if they received psychotherapy (remission rate, 22.2%; mean HAM-D-24 score, 21.0). Patients who preferred psychotherapy had a higher remission rate (50.0%) and lower mean HAM-D-24 score (12.1) if they received psychotherapy than if they received medication (remission rate 7.7%, mean HAM-D-24 score 18.3). Nevertheless, treatment preference was not associated with risk of dropout from the study. Conclusions These results suggest that patient preference is a potent moderator of treatment response for patients with chronic forms of MDD; however, relatively low proportions of the patient sample preferred one of the monotherapies, participants were not blinded to treatment assignment, and there was no placebo group.