Advancing research: a commentary on the untapped potential of acceptance and commitment therapy in alcohol use disorder treatment.

Alcohol use disorder poses a significant global health threat, with profound consequences for individuals, families, and communities, necessitating continued exploration of novel treatment approaches. Acceptance and Commitment Therapy, an evidence-based approach for various mental health disorders, offers promise in addressing alcohol use disorder as well, but controlled trials are lacking, highlighting a crucial gap in research.

Lithium plus antipsychotics or anticonvulsants for bipolar disorder: Comparing clinical response and metabolic changes.

OBJECTIVE: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied. METHODS: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4-0.6 mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24 weeks of treatment. RESULTS: Among 379 outpatients (57% female, mean age 38 years, mean Clinical Global Impression 4.4), users of Li+AP (N = 50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement = 1.6, standard deviation = 1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N = 149, mean Clinical Global Impression improvement = 1.7, standard deviation = 1.4) (p = 0.59). Users of Li+AC (N = 107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement = 1.2, standard deviation = 1.3) and users of Li+AP+AC (N = 73, mean Clinical Global Impression improvement = 1.1, standard deviation = 1.3) showed worse response compared to lithium-only users (all p < 0.01). When comparing Li+AP to Li+AC, users of Li+AP improved slightly better on general (p = 0.05) and manic symptoms (p = 0.01), but showed a worse development of glucose, triglycerides, and metabolic syndrome. CONCLUSION: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.

Childhood trauma and treatment outcomes during mood-stabilising treatment with lithium or quetiapine among outpatients with bipolar disorder.

BACKGROUND: Childhood trauma affects the course of mood disorders. Researchers are now considering childhood trauma as an influential factor in the treatment of mood disorders. However, the role of childhood trauma in the treatment of bipolar disorder remains understudied. METHODS: The effect of childhood trauma on treatment outcomes was evaluated among participants randomised to treatment with lithium or quetiapine in the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study by clinician assessment. Mixed effects linear regression models were used to analyse rates of improvement in symptom severity (assessed with the Bipolar Inventory of Symptoms Scale and the Clinical Global Impression Scale for Bipolar Disorder) and functional impairment (assessed with the Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool). RESULTS: A history of any childhood trauma was reported by 52.7% of the sample (N = 476). Although participants with a history of any childhood trauma presented with greater symptom severity and functional impairment at most study visits, participants with and without a history of any childhood trauma showed similar rates of improvement in symptom severity and functional impairment over the 24 weeks of treatment. CONCLUSION: This is the first study to explore the association between childhood trauma and treatment outcomes during treatment with lithium or quetiapine in the context of a randomised trial. In Bipolar CHOICE, a history of childhood trauma did not inhibit improvement in symptom severity or functional impairment. Nevertheless, these findings need replication across different settings.

COVID-19 and substance use disorders: a review of international guidelines for frontline healthcare workers of addiction services.

BACKGROUND: People with substance use disorders may be at a greater risk of contracting COVID-19 infection and developing medical complications. Several institutional and governmental health agencies across the world developed ad hoc guidance for substance use disorder services and care of individuals misusing substances. We aimed to synthesise the best available recommendations on management and care of people with or at risk of substance use disorders during the COVID-19 pandemic from existing guidelines published in UK, USA, Australia, Canada, New Zealand, and Singapore. METHODS: We systematically searched existing guidelines and websites from 28 international institutions and governmental bodies in the context of the COVID-19 pandemic (May 4th 2021). We summarized the extracted data as answers to specific clinical questions. RESULTS: We organised the available recommendations from 19 sources in three sections. First, we focused on general advice and recommendations for people who misuse alcohol or drugs during the COVID-19 pandemic, the design of contingency plans, safeguarding issues for children and families of service users and advice to the public, patients, and carers. Then, we summarised specific guidelines for people who use illicit drugs and related services, such as opioid substitution treatment and needle and syringe programmes. Finally, we provided a synthesis on specific recommendations for services supporting people who misuse alcohol and key topics in the field, such as management of alcohol detoxification and safe transition between supervised and unsupervised consumption. CONCLUSIONS: Available guidance reflected different approaches, ranging from being extremely cautious in providing recommendations other than generic statements to proposing adaptation of previously available guidelines to confront the challenges of the COVID-19 pandemic. After the early phase, guidance focused on reduction of infection transmission and service delivery. Guidance did not provide advice on infection prevention via vaccination programmes and service access strategies tailored to individuals with substance use disorders.

Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial.

Importance: Selecting effective antidepressants for the treatment of major depressive disorder (MDD) is an imprecise practice, with remission rates of about 30% at the initial treatment. Objective: To determine whether pharmacogenomic testing affects antidepressant medication selection and whether such testing leads to better clinical outcomes. Design, Setting, and Participants: A pragmatic, randomized clinical trial that compared treatment guided by pharmacogenomic testing vs usual care. Participants included 676 clinicians and 1944 patients. Participants were enrolled from 22 Department of Veterans Affairs medical centers from July 2017 through February 2021, with follow-up ending November 2021. Eligible patients were those with MDD who were initiating or switching treatment with a single antidepressant. Exclusion criteria included an active substance use disorder, mania, psychosis, or concurrent treatment with a specified list of medications. Interventions: Results from a commercial pharmacogenomic test were given to clinicians in the pharmacogenomic-guided group (n = 966). The comparison group received usual care and access to pharmacogenomic results after 24 weeks (n = 978). Main Outcomes and Measures: The co-primary outcomes were the proportion of prescriptions with a predicted drug-gene interaction written in the 30 days after randomization and remission of depressive symptoms as measured by the Patient Health Questionnaire-9 (PHQ-9) (remission was defined as PHQ-9 ≤ 5). Remission was analyzed as a repeated measure across 24 weeks by blinded raters. Results: Among 1944 patients who were randomized (mean age, 48 years; 491 women [25%]), 1541 (79%) completed the 24-week assessment. The estimated risks for receiving an antidepressant with none, moderate, and substantial drug-gene interactions for the pharmacogenomic-guided group were 59.3%, 30.0%, and 10.7% compared with 25.7%, 54.6%, and 19.7% in the usual care group. The pharmacogenomic-guided group was more likely to receive a medication with a lower potential drug-gene interaction for no drug-gene vs moderate/substantial interaction (odds ratio [OR], 4.32 [95% CI, 3.47 to 5.39]; P < .001) and no/moderate vs substantial interaction (OR, 2.08 [95% CI, 1.52 to 2.84]; P = .005) (P < .001 for overall comparison). Remission rates over 24 weeks were higher among patients whose care was guided by pharmacogenomic testing than those in usual care (OR, 1.28 [95% CI, 1.05 to 1.57]; P = .02; risk difference, 2.8% [95% CI, 0.6% to 5.1%]) but were not significantly higher at week 24 when 130 patients in the pharmacogenomic-guided group and 126 patients in the usual care group were in remission (estimated risk difference, 1.5% [95% CI, -2.4% to 5.3%]; P = .45). Conclusions and Relevance: Among patients with MDD, provision of pharmacogenomic testing for drug-gene interactions reduced prescription of medications with predicted drug-gene interactions compared with usual care. Provision of test results had small nonpersistent effects on symptom remission. Trial Registration: ClinicalTrials.gov Identifier: NCT03170362.

Adjunctive antidepressant treatment among 763 outpatients with bipolar disorder: Findings from the Bipolar CHOICE and LiTMUS trials.

BACKGROUND: Adjunctive antidepressants are frequently used for bipolar depression but their clinical efficacy has been studied in few trials and little is known about how co-occurring manic symptoms affect treatment response. METHODS: Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (N = 482) and Lithium Treatment Moderate-Dose Use Study (N = 281) were similar comparative effectiveness trials on outpatients with bipolar disorder comparing four different randomized treatment arms with adjunctive personalized guideline-based treatment for 24 weeks. Adjunctive antidepressant treatment could be used if clinically indicated and was assessed at every study visit. Adjusted mixed effects linear regression analyses compared users of antidepressants to nonusers overall and in different subcohorts. RESULTS: Of the 763 patients, 282 (37.0%) used antidepressant drugs during the study. Antidepressant users had less improvement compared to nonusers on the Clinical Global Impression Scale for Bipolar Disorder and on measures of depression. This was particularly true among patients with co-occurring manic symptoms. Exclusion of individuals begun on antidepressants late in the study (potentially due to overall worse response) resulted in no differences between users and nonusers. We found no differences in treatment effects on mania scales. CONCLUSIONS: In this large cohort of outpatients with bipolar disorder, clinically indicated and guideline-based adjunctive antidepressant treatment was not associated with lower depressive symptoms or higher mania symptoms. The treatment-by-indication confounding due to the nonrandomized design of the trials complicates causal interpretations, but no analyses indicated better treatment effects of adjunctive antidepressants.

Investigation of a Capnometry Guided Respiratory Intervention in the Treatment of Posttraumatic Stress Disorder.

Evidence-based treatments for posttraumatic stress disorder (PTSD), including psychotherapies and medications, have high dropout and nonresponse rates, suggesting that more acceptable and effective treatments for PTSD are needed. Capnometry Guided Respiratory Intervention (CGRI) is a digital therapeutic effective in panic disorder that measures and displays end-tidal carbon dioxide (EtCO2) and respiratory rate (RR) in real-time within a structured breathing protocol and may have benefit in PTSD by moderating breathing and EtCO2 levels. We conducted a single-arm study of a CGRI system, Freespira®, to treat symptoms of PTSD. Participants with PTSD (n = 55) were treated for four weeks with twice-daily, 17-min at-home CGRI sessions using a sensor and tablet with pre-loaded software. PTSD and associated symptoms were assessed at baseline, end-of treatment, 2-months and 6-months post-treatment. Primary efficacy outcome was 50% of participants having ≥ 6-point decrease in Clinician Administered PTSD Scale (CAPS-5) score at 2-month follow up. Tolerability, usability, safety, adherence and patient satisfaction were assessed. CGRI was well tolerated, with 88% [95% CI 74-96%] having ≥ 6-point decrease in CAPS-5 scores at 2-months post-treatment follow up. Mean CAPS-5 scores decreased from 49.5 [s.d. = 9.2] at baseline to 27.1 [s.d. = 17.8] at 2-months post-treatment follow up. Respiratory rate decreased and EtCO2 levels increased. Associated mental and physical health symptoms also improved. This CGRI intervention was safe, acceptable, and well-tolerated in improving symptoms in this study in PTSD. Further study against an appropriate comparator is warranted.Trial registration Clinicaltrials.gov NCT#03039231.

Pilot Randomized Controlled Trial of Web-Delivered Acceptance and Commitment Therapy Versus Smokefree.gov for Smokers With Bipolar Disorder.

INTRODUCTION: Smokers with bipolar disorder (BD) are less successful at quitting than the general population. In this study, we evaluated in a pilot randomized controlled trial a novel, targeted, web-based intervention for smokers with BD based on acceptance and commitment therapy (ACT) and designed for reach and disseminability. AIMS AND METHODS: Daily smokers (n = 51) with bipolar I or II disorder were recruited from four US sites and randomly assigned to one of two web-based smoking cessation interventions-ACT-based WebQuit Plus (n = 25) or Smokefree.gov (n = 26) over a 10-week treatment period. All participants received nicotine patch for 8 weeks. Key outcomes were trial design feasibility, intervention acceptability, and cessation at end of treatment and 1-month follow-up. RESULTS: We screened 119 to enroll 51 participants (target sample size = 60) over 24 months. The most common reason for ineligibility was the inability to attend study appointments. Retention was 73% at end of treatment and 80% at follow-up, with no differences by arm. The mean number of logins was twice as high for WebQuit Plus (10.3 vs. 5.3). The usefulness of program skills was rated higher for WebQuit Plus (75% vs. 29%). Biochemically confirmed, 7-day abstinence at end of treatment was 12% in WebQuit Plus versus 8% in Smokefree.gov (odds ratio = 1.46, 95% confidence interval = 0.21 to 9.97). At follow-up, abstinence rates were 8% in both arms. CONCLUSIONS: Trial design produced favorable retention rates, although alternative recruitment methods will be needed for a larger trial. At end of treatment, acceptability and estimated effect size of WebQuit Plus relative to Smokefree.gov were promising and support continued program refinement and evaluation. IMPLICATIONS: In this first randomized controlled trial of a targeted intervention for smokers with BD, we found that the ACT-based WebQuit Plus intervention, delivered in combination with the nicotine patch, had promising acceptability and cessation outcomes relative to Smokefree.gov. The observed signals for acceptability and cessation suggest that the WebQuit Plus program should be refined based on participant feedback and evaluated in a larger trial. Feasibility findings from this study also provide direction for refining trial procedures to enhance the recruitment of smokers with BD.

A Novel Study Design to Systematically Explore the Impact of Trial Methodology on Psychopharmacological Treatment Outcome in Patients with Depression.

INTRODUCTION: Randomized, double-blind, placebo-controlled trials were developed to draw rather unbiased conclusions regarding the efficacy of antidepressants in the treatment of a major depressive episode (internal validity), mostly with the purpose of formal approval of new compounds in this indication. However, at the same time, data suggest that the very process of randomization and blinded administrations of placebo will have a significant impact on the efficacy of the antidepressant tested and therefore may limit the external validity of results obtained from this type of studies. Therefore, there is an urgent need to systematically study the impact of randomization/placebo control/blinding on patient population, efficacy, tolerability, and external validity in the psychopharmacological treatment of patients with a major depressive episode. METHODS: To develop a study design that allows the systematic exploration of the impact of trial design on characteristics of included patient population and outcome. RESULTS: We propose a study design including sample size calculation and statistical analysis in which patients with a major depressive episode are randomized to 3 distinct study designs that differ with regard to control, randomization, and blindness. DISCUSSION: The results of the proposed study design may have substantial consequences when it comes to how to best interpret the results of traditional randomized, double-blind, placebo-controlled trials in the acute treatment of major depressive disorder. Furthermore, they may lead to the implementation of new study designs that may be more suitable for assessing the effectiveness of new antidepressant compounds in everyday clinical practice.

Correlation between white blood cell count and mood-stabilising treatment response in two bipolar disorder trials.

BACKGROUND: Immune system markers may predict affective disorder treatment response, but whether an overall immune system marker predicts bipolar disorder treatment effect is unclear. METHODS: Bipolar CHOICE (N = 482) and LiTMUS (N = 283) were similar comparative effectiveness trials treating patients with bipolar disorder for 24 weeks with four different treatment arms (standard-dose lithium, quetiapine, moderate-dose lithium plus optimised personalised treatment (OPT) and OPT without lithium). We performed secondary mixed effects linear regression analyses adjusted for age, gender, smoking and body mass index to investigate relationships between pre-treatment white blood cell (WBC) levels and clinical global impression scale (CGI) response. RESULTS: Compared to participants with WBC counts of 4.5-10 × 109/l, participants with WBC < 4.5 or WBC ≥ 10 showed similar improvement within each specific treatment arm and in gender-stratified analyses. CONCLUSIONS: An overall immune system marker did not predict differential treatment response to four different treatment approaches for bipolar disorder all lasting 24 weeks.

Comparative efficacy and acceptability of psychosocial interventions for individuals with cocaine and amphetamine addiction: A systematic review and network meta-analysis.

BACKGROUND: Clinical guidelines recommend psychosocial interventions for cocaine and/or amphetamine addiction as first-line treatment, but it is still unclear which intervention, if any, should be offered first. We aimed to estimate the comparative effectiveness of all available psychosocial interventions (alone or in combination) for the short- and long-term treatment of people with cocaine and/or amphetamine addiction. METHODS AND FINDINGS: We searched published and unpublished randomised controlled trials (RCTs) comparing any structured psychosocial intervention against an active control or treatment as usual (TAU) for the treatment of cocaine and/or amphetamine addiction in adults. Primary outcome measures were efficacy (proportion of patients in abstinence, assessed by urinalysis) and acceptability (proportion of patients who dropped out due to any cause) at the end of treatment, but we also measured the acute (12 weeks) and long-term (longest duration of study follow-up) effects of the interventions and the longest duration of abstinence. Odds ratios (ORs) and standardised mean differences were estimated using pairwise and network meta-analysis with random effects. The risk of bias of the included studies was assessed with the Cochrane tool, and the strength of evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We followed the PRISMA for Network Meta-Analyses (PRISMA-NMA) guidelines, and the protocol was registered in PROSPERO (CRD 42017042900). We included 50 RCTs evaluating 12 psychosocial interventions or TAU in 6,942 participants. The strength of evidence ranged from high to very low. Compared to TAU, contingency management (CM) plus community reinforcement approach was the only intervention that increased the number of abstinent patients at the end of treatment (OR 2.84, 95% CI 1.24-6.51, P = 0.013), and also at 12 weeks (OR 7.60, 95% CI 2.03-28.37, P = 0.002) and at longest follow-up (OR 3.08, 95% CI 1.33-7.17, P = 0.008). At the end of treatment, CM plus community reinforcement approach had the highest number of statistically significant results in head-to-head comparisons, being more efficacious than cognitive behavioural therapy (CBT) (OR 2.44, 95% CI 1.02-5.88, P = 0.045), non-contingent rewards (OR 3.31, 95% CI 1.32-8.28, P = 0.010), and 12-step programme plus non-contingent rewards (OR 4.07, 95% CI 1.13-14.69, P = 0.031). CM plus community reinforcement approach was also associated with fewer dropouts than TAU, both at 12 weeks and the end of treatment (OR 3.92, P < 0.001, and 3.63, P < 0.001, respectively). At the longest follow-up, community reinforcement approach was more effective than non-contingent rewards, supportive-expressive psychodynamic therapy, TAU, and 12-step programme (OR ranging between 2.71, P = 0.026, and 4.58, P = 0.001), but the combination of community reinforcement approach with CM was superior also to CBT alone, CM alone, CM plus CBT, and 12-step programme plus non-contingent rewards (ORs between 2.50, P = 0.039, and 5.22, P < 0.001). The main limitations of our study were the quality of included studies and the lack of blinding, which may have increased the risk of performance bias. However, our analyses were based on objective outcomes, which are less likely to be biased. CONCLUSIONS: To our knowledge, this network meta-analysis is the most comprehensive synthesis of data for psychosocial interventions in individuals with cocaine and/or amphetamine addiction. Our findings provide the best evidence base currently available to guide decision-making about psychosocial interventions for individuals with cocaine and/or amphetamine addiction and should inform patients, clinicians, and policy-makers.

Revising Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for the bipolar disorders: Phase I of the AREDOC project.

OBJECTIVE: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations. METHOD: The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified. RESULTS: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge 'impairment' (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders. CONCLUSION: This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically.

Clinically relevant and simple immune system measure is related to symptom burden in bipolar disorder.

OBJECTIVE: Immunological theories, particularly the sickness syndrome theory, may explain psychopathology in mood disorders. However, no clinical trials have investigated the association between overall immune system markers with a wide range of specific symptoms including potential gender differences. METHODS: We included two similar clinical trials, the lithium treatment moderate-dose use study and clinical and health outcomes initiatives in comparative effectiveness for bipolar disorder study, enrolling 765 participants with bipolar disorder. At study entry, white blood cell (WBC) count was measured and psychopathology assessed with the Montgomery and Aasberg depression rating scale (MADRS). We performed analysis of variance and linear regression analyses to investigate the relationship between the deviation from the median WBC, and multinomial regression analysis between different WBC levels. All analyses were performed gender-specific and adjusted for age, body mass index, smoking, race, and somatic diseases. RESULTS: The overall MADRS score increased significantly for each 1.0×109/l deviation from the median WBC among 322 men (coefficient=1.10; 95% CI=0.32-1.89; p=0.006), but not among 443 women (coefficient=0.56; 95% CI=-0.19-1.31; p=0.14). Among men, WBC deviations were associated with increased severity of sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, inability to feel, and suicidal thoughts. Among women, WBC deviations were associated with increased severity of reduced appetite, concentration difficulties, lassitude, inability to feel, and pessimistic thoughts. Both higher and lower WBC levels were associated with increased severity of several specific symptoms. CONCLUSION: Immune system alterations were associated with increased severity of specific mood symptoms, particularly among men. Our results support the sickness syndrome theory, but furthermore emphasise the relevance to study immune suppression in bipolar disorder. Due to the explorative nature and cross-sectional design, future studies need to confirm these findings.

Mixed features in major depressive disorder: diagnoses and treatments.

For the first time in 20 years, the American Psychiatric Association (APA) updated the psychiatric diagnostic system for mood disorders in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Perhaps one of the most notable changes in the DSM-5 was the recognition of the possibility of mixed symptoms in major depression and related disorders (MDD). While MDD and bipolar and related disorders are now represented by 2 distinct chapters, the addition of a mixed features specifier to MDD represents a structural bridge between bipolar and major depression disorders, and formally recognizes the possibility of a mix of hypomania and depressive symptoms in someone who has never experienced discrete episodes of hypomania or mania. This article reviews historical perspectives on "mixed states" and the recent literature, which proposes a range of approaches to understanding "mixity." We discuss which symptoms were considered for inclusion in the mixed features specifier and which symptoms were excluded. The assumption that mixed symptoms in MDD necessarily predict a future bipolar course in patients with MDD is reviewed. Treatment for patients in a MDD episode with mixed features is critically considered, as are suggestions for future study. Finally, the premise that mood disorders are necessarily a spectrum or a gradient of severity progressing in a linear manner is argued.

Guidelines for the recognition and management of mixed depression.

A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM-5 codified a new nosological entity, the "mixed features specifier," referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM-IV definition of "mixed states" wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

White blood cell count correlates with mood symptom severity and specific mood symptoms in bipolar disorder.

OBJECTIVE: Immune alterations may play a role in bipolar disorder etiology; however, the relationship between overall immune system functioning and mood symptom severity is unknown. METHODS: The two comparative effectiveness trials, the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder Study (Bipolar CHOICE) and the Lithium Treatment Moderate-Dose Use Study (LiTMUS), were similar trials among patients with bipolar disorder. At study entry, white blood cell count and bipolar mood symptom severity (via Montgomery-Aasberg Depression Rating Scale and Bipolar Inventory of Symptoms Scale) were assessed. We performed analysis of variance and linear regression analyses to investigate relationships between deviations from median white blood cell and multinomial regression analysis between higher and lower white blood cell levels. All analyses were adjusted for age, gender, body mass index, smoking, diabetes, hypertension and hyperlipidemia. RESULTS: Among 482 Bipolar CHOICE participants, for each 1.0 × 109/L white blood cell deviation, the overall Bipolar Inventory of Symptoms Scale severity increased significantly among men (coefficient = 2.13; 95% confidence interval = [0.46, -3.79]; p = 0.013), but not among women (coefficient = 0.87; 95% confidence interval = [-0.87, -2.61]; p = 0.33). Interaction analyses showed a trend toward greater Bipolar Inventory of Symptoms Scale symptom severity among men (coefficient = 1.51; 95% confidence interval = [-0.81, -3.82]; p = 0.2). Among 283 LiTMUS participants, higher deviation from the median white blood cell showed a trend toward higher Montgomery-Aasberg Depression Rating Scale scores among men (coefficient = 1.33; 95% confidence interval = [-0.22, -2.89]; p = 0.09), but not among women (coefficient = 0.34; 95% confidence interval = [-0.64, -1.32]; p = 0.50). When combining LiTMUS and Bipolar CHOICE, Montgomery-Aasberg Depression Rating Scale scores increased significantly among men (coefficient = 1.09; 95% confidence interval = [0.31, -1.87]; p = 0.006) for each 1.0 × 109/L white blood cell deviation, whereas we found a weak association among women (coefficient = 0.55; 95% confidence interval = [-0.20, -1.29]; p = 0.14). Lower and higher white blood cell levels correlated with greater symptom severity and specific symptoms, varying according to gender. CONCLUSION: Deviations in an overall immune system marker, even within the normal white blood cell range, correlated with mood symptom severity in bipolar disorder, mostly among males. Studies are warranted investigating whether white blood cell count may predict response to mood-stabilizing treatment.

A randomized, placebo-controlled proof-of-concept trial of adjunctive topiramate for alcohol use disorders in bipolar disorder.

BACKGROUND AND OBJECTIVES: Topiramate is effective for alcohol use disorders (AUDs) among non-psychiatric patients. We examined topiramate for treating comorbid AUDs in bipolar disorder (BD). METHODS: Twelve participants were randomized to topiramate or placebo for 12 weeks. RESULTS: The topiramate group, with two out of five participants (40%) completing treatment, experienced less improvement in drinking patterns than the placebo group, with five out of seven participants (71%) completing treatment. DISCUSSION AND CONCLUSIONS: Topiramate did not improve drinking behavior and was not well-tolerated. This study failed to recruit adequately. Problems surrounding high attrition, a small study sample, and missing data preclude interpretation of study findings. SCIENTIFIC SIGNIFICANCE: This is the first randomized, placebo-controlled trial of topiramate for AUDs in BD.

Antidepressants in Type II Versus Type I Bipolar Depression: A Randomized Discontinuation Trial.

BACKGROUND: We sought to test the hypothesis that antidepressants (ADs) may show preferential efficacy and safety among patients with type II bipolar disorder (BD, BD-II) more than patients with type I BD (BD-I). METHODS: Patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, BD-I (n = 21) and BD-II (n = 49) in acute major depressive episodes were treated with ADs plus mood stabilizers to euthymia sustained for 2 months and then randomized openly to continue or discontinue ADs for up to 3 years. Outcomes were episode recurrences and changes in standardized symptom ratings. RESULTS: In follow-up averaging 1.64 years, both subgroups showed improvement in depressive episode frequency with AD continuation, but contrary to the hypothesis, more improvement was seen in BD-I than in BD-II (for type II, mean [standard deviation] decrease in depressive episodes per year, 0.21 [0.26]; for type I, mean (SD) decrease, 0.35 [0.15]). Subjects with BD-II who continued on ADs had slightly more depressive, but fewer manic/hypomanic, episodes than subjects with BD-I. No notable differences were seen in either group in time to a recurrence of mood episodes or total time-in-remission. CONCLUSIONS: The findings do not confirm the hypothesis that long-term AD treatment in patients with BP-II has better outcomes than in patients with BD-I, except somewhat lower risk of manic/hypomanic episodes.