Impact of Nicotine Replacement Therapy Sampling on Cessation-Related Processes.

OBJECTIVES: Smoking prevalence remains high among low-income smokers. Understanding processes (eg, withdrawal, craving, motivation) in early smoking cessation is crucially important for designing effective interventions for this population. METHODS: This is a secondary analysis of a novel, in-session sampling intervention (ie, In Vivo) as compared with standard care behavioral smoking cessation counseling (SC) among community-dwelling low-income smokers (n = 83). This analysis examined the effect of 5 in-session sampling interventions on cessation-related processes and perceived advantages or disadvantages of nicotine replacement therapy (NRT) products over time using daily diaries. RESULTS: The In Vivo treatment had an early positive impact in terms of decreasing withdrawal symptoms and cravings, and increasing perceived advantages to NRT, with moderate to large effect sizes. Results also showed that the treatment effectively reduced withdrawal symptoms and cravings in-session, with small-to-medium and medium-to-large effect sizes, respectively. In-session reduction of withdrawal symptoms and cravings did not occur for the SC group, with the exception of decreased withdrawal symptoms occurring during week 4. The In Vivo treatment did not impact quit goal, desire to quit, abstinence self-efficacy, perceived difficulty in quitting, motivational engagement, or perceived disadvantages to NRT. The In Vivo group reported less daily cigarette use relative to the SC group, in addition to reporting less cigarette use on days they reported greater combination NRT use. CONCLUSIONS: There is preliminary support for this In Vivo treatment over SC in reducing withdrawal, craving, and the number of cigarettes smoked per day, as well as promoting perceived advantages of NRT among low-income smokers.

Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial.

Further research is needed to help improve both the standard of care and the outcome for patients with treatment-resistant depression. A particularly critical evidence gap exists with respect to whether pharmacological or non-pharmacological augmentation is superior to antidepressant switch, or vice-versa. The objective of this study was to compare the effectiveness of augmentation with aripiprazole or repetitive transcranial magnetic stimulation versus switching to the antidepressant venlafaxine XR (or duloxetine for those not eligible to receive venlafaxine) for treatment-resistant depression. In this multi-site, 8-week, randomized, open-label study, 278 subjects (196 females and 82 males, mean age 45.6 years (SD 15.3)) with treatment-resistant depression were assigned in a 1:1:1 fashion to treatment with either of these three interventions; 235 subjects completed the study. 260 randomized subjects with at least one post-baseline Montgomery-Asberg Depression Rating (MADRS) assessment were included in the analysis. Repetitive transcranial magnetic stimulation (score change (standard error (se)) = -17.39 (1.3) (p = 0.015) but not aripiprazole augmentation (score change (se) = -14.9 (1.1) (p = 0.069) was superior to switch (score change (se) = -13.22 (1.1)) on the MADRS. Aripiprazole (mean change (se) = -37.79 (2.9) (p = 0.003) but not repetitive transcranial magnetic stimulation augmentation (mean change (se) = -42.96 (3.6) (p = 0.031) was superior to switch (mean change (se) = -34.45 (3.0)) on the symptoms of depression questionnaire. Repetitive transcranial magnetic stimulation augmentation was shown to be more effective than switching antidepressants in treatment-resistant depression on the study primary measure. In light of these findings, clinicians should consider repetitive transcranial magnetic stimulation augmentation early-on for treatment-resistant depression.Trial registration: ClinicalTrials.gov, NCT02977299.

Cognitive behavioral therapy following esketamine for major depression and suicidal ideation for relapse prevention: The CBT-ENDURE randomized clinical trial study protocol.

In 2020, esketamine received a supplemental indication as a therapy for major depression with suicidal ideation (MDSI), based on protocols enrolling hospitalized patients. Given the high risk of suicide following hospital discharge and the high relapse rates following discontinuation of esketamine, the optimal long-term treatment approach remains unclear. Cognitive behavioral therapy (CBT) is highly effective in relapse prevention and has been shown to prevent suicide attempts in high-risk populations. Here we describe the study protocol for the CBT-ENDURE trial: Cognitive Behavioral Therapy Following Esketamine for Major Depression and SUicidal Ideation for RElapse Prevention. Patients with depression (N = 100) who are admitted to hospital or are outpatients with clinically significant suicidal ideation will be enrolled in the study. All patients will receive esketamine (twice weekly for four weeks) and will be randomly assigned (1:1 ratio) to receive a 16-week course of CBT plus treatment as usual (CBT group) or treatment as usual only (TAU only group). Patients are followed for a total of 6 months. Supported under a funding announcement from NIMH to conduct safety and feasibility trials for patients at high risk for suicide, the primary outcome of the CBT-ENDURE study is feasibility (as measured by recruitment and retention), with a key secondary outcome being relapse among those who experience substantial benefit following two weeks of esketamine.

Strong associations of telomere length and mitochondrial copy number with suicidality and abuse history in adolescent depressed individuals.

Major depressive disorder (MDD) is highly prevalent in adolescents and is a major risk factor for suicidality. Recent evidence shows that accelerated cellular senescence/aging is associated with psychiatric illness, including depression, in adults. The present study examined if the relationships of telomere length (TL) and mitochondrial DNA copy number (mtDNAcn), two critical indicators of cellular senescence/aging, are altered in depressed adolescents and whether these alterations are associated with suicidality, early-life adversities, and other co-occuring factors. In genomic DNA isolated from 53 adolescents (ages 16-19, 19 MDD with suicide attempt/suicidal ideation [MDD + SI/SA], 14 MDD without SA/SI [MDD-SI/SA], and 20 healthy controls [HC]), TL and mtDNAcn were measured as the ratio between the number of telomere repeats and that of a single-copy nuclear-hemoglobin [HBG] gene or the amount of mtDNA (NADH dehydrogenase, subunit 1) relative to HBG. Our data show that TL was significantly lower, and mtDNAcn was significantly higher in the total MDD group than HC. TL was significantly lower and mtDNAcn was significantly higher in the MDD + SA/SI group than in the HC, whereas there were no differences in the MDD-SI/SA group. TL was positively correlated with mtDNAcn in both HC and MDD-SA/SI groups; however, TL was negatively correlated with mtDNAcn in MDD + SA/SI. Furthermore, TL was negatively correlated with the severity of both depression and anxiety, while mtDNAcn was positively correlated with the severity of prior emotional abuse. Our study indicates that cellular senescence is more advanced in depressed adolescents with suicidal ideation and that childhood emotional abuse may participate in such a process.

Preliminary effectiveness of online opioid overdose and naloxone administration training and impact of naloxone possession on opioid use.

BACKGROUND: Despite the demonstrated value of opioid overdose education and naloxone distribution (OEND) programs, uptake and utilization remains low. Accessibility to OEND is limited and traditional programs may not reach many high-risk individuals. This study evaluated the effectiveness of online opioid overdose and naloxone administration education and the impact of naloxone possession. METHODS: Individuals with self-reported illicit use of opioids were recruited via Craigslist advertisements and completed all assessments and education online via REDCap. Participants watched a 20-minute video outlining signs of opioid overdose and how to administer naloxone. They were then randomized to either receive a naloxone kit or be given instructions on where to obtain a kit. Effectiveness of training was measured with pre- and post-training knowledge questionnaires. Naloxone kit possession, overdoses, opioid use frequency, and treatment interest were self-reported on monthly follow-up assessments. RESULTS: Mean knowledge scores significantly increased from 6.82/9.00 to 8.22 after training (t(194)=6.85, p <0.001, 95% CI[1.00, 1.81], Cohen's d=0.85). Difference in naloxone possession between randomized groups was significant with a large effect size (p <0.001, diff=0.60, 95% CI[0.47, 0.73]). A bidirectional relationship was found between naloxone possession and frequency of opioid use. Overdoses and treatment interest were similar across possession status. CONCLUSIONS: Overdose education is effective in online video format. Disparity in naloxone possession across groups indicates barriers to obtaining naloxone from pharmacies. Naloxone possession did not influence risky opioid use or treatment interest and its impact on frequency of use warrants further investigation. TRIAL REGISTRATION: Clinitaltrials.gov-NCT04303000.

Feasibility and acceptability of online opioid overdose education and naloxone distribution: Study protocol and preliminary results from a randomized pilot clinical trial.

Drug overdose is the leading cause of accidental death in the United States, with over 70% of drug related fatalities resulting from the use of opioids. Federal agencies have responded to this crisis with various recommendations including enhancing harm reduction approaches such as training laypersons to administer naloxone through Opioid Overdose Education and Naloxone Distribution (OEND) programs. Several studies have demonstrated that OEND programs effectively reduce opioid overdose mortality and are both safe and cost-effective, however, they are typically implemented in urban areas as part of large medical center research programs, needle exchanges, or drug treatment programs. Individuals living in areas without these programs or services lack access to critical and life-saving OEND. The current study examined the acceptability and feasibility of online recruitment, online opioid overdose education, and remote distribution of naloxone kits. Persons who illicitly use opioids and are at risk for overdose were recruited through online media and completed an opioid use questionnaire. If interested in receiving opioid overdose and naloxone administration training, participants completed pre- and post-intervention knowledge questionnaires, engaged in audiovisual training, and were randomized to either receive a naloxone kit or be given information on where they could obtain one. Preliminary results indicate feasibility and acceptability as evidenced by strong recruitment and retention, as well as high participant satisfaction ratings. Successful implementation of remote OEND through this project supports future employment of similar remote programs to expand this critical harm reduction strategy to high-risk individuals in areas lacking traditional OEND programs. Trial Registration #: Clinitaltrials.gov- NCT04303000.

Genomics in Treatment Development.

The Human Genome Project mapped the 3 billion base pairs in the human genome, which ushered in a new generation of genomically focused treatment development. While this has been very successful in other areas, neuroscience has been largely devoid of such developments. This is in large part because there are very few neurological or mental health conditions that are related to single-gene variants. While developments in pharmacogenomics have been somewhat successful, the use of genetic information in practice has to do with drug metabolism and adverse reactions. Studies of drug metabolism related to genetic variations are an important part of drug development. However, outside of cancer biology, the actual translation of genomic information into novel therapies has been limited. Epigenetics, which relates in part to the effects of the environment on DNA, is a promising newer area of relevance to CNS disorders. The environment can induce chemical modifications of DNA (e.g., cytosine methylation), which can be induced by the environment and may represent either shorter- or longer-term changes. Given the importance of environmental influences on CNS disorders, epigenetics may identify important treatment targets in the future.

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.

SIBAT-A Computerized Assessment Tool for Suicide Ideation and Behavior: Development and Psychometric Properties.

Objective: Most assessments of suicidal ideation and behavior (SIB) are limited by reliance on a single assessor, typically a clinician or patient, with scant detail on patient-related drivers of SIB and inability to detect rapid change in SIB. Furthermore, many techniques do not include a semistructured interview, increasing rater variability. The Suicide Ideation and Behavior Assessment Tool (SIBAT) addresses these limitations. Design: More than 30 experts in scale development, statistics, and clinical management of suicidal patients collaborated over a greater than four-year period to develop the SIBAT. Input for content and validity was received from patients, clinicians, and regulatory authorities in the United States (US) and Europe. Psychometric properties of the SIBAT were evaluated in validation studies. Results: The SIBAT is organized into eight independent patient- or clinician-rated modules with branching logic and scoring algorithms, which necessitates computerization. Patient-reported information is first captured in Modules 1 to 5. Thereafter, an experienced clinician reviews the patient's report, conducts a semistructured interview (Module 6), and assesses the patient's suicide risk (Module 7) and optimal antisuicide management (Module 8). Input from cognitive interviews of diverse adult, adolescent, and clinician participants was incorporated into the final version of the SIBAT. Psychometric testing demonstrated good inter-rater reliability (intraclass coefficient range: 0.68-0.82), intra-rater reliability (weighted-kappa range: 0.64-0.76), and concurrent validity with other instruments for assessing SIB. Conclusion: Patient- and clinician-based assessments and the psychometric studies summarized in this report support the validity and reliability of the SIBAT for capturing critical information related to assessment of SIB in adolescents and adults at risk for suicide.

The effect of IV ketamine in patients with major depressive disorder and elevated features of borderline personality disorder.

BACKGROUND: Comorbid borderline personality disorder and major depressive disorder is common and often not adequately responsive to standard antidepressant therapies. Ketamine is a potentially life-saving option. METHODS: 153 adult patients with MDD were assessed with the Personality Assessment Inventory (PAI) Borderline Subscale. Data was normally distributed with a mean + SD of 38.95 + 11.54. Patients >1 SD above the mean were assigned to the MDD + BF group. All others were assigned to the MDD-BF group. Patients were administered IV ketamine 0.5 mg/kg of ketamine over 40 min. Mood was assessed using the Beck Depression Inventory-II at baseline, 3 and 24 h post-ketamine. Scores between the MDD + BF and MDD-BF group at each time point were compared using t-test or analysis of covariance (ANCOVA) model. The primary outcome was response at 24 h. RESULTS: The LS mean change in BDI at 24 h was -23.8 (15.3) for MDD + BF and -21.0 (13.5) for MDD-BF (F [1151] = 0.043, p = 0.51). The LS mean change in BDI at 3 h was -21.3 (13.2) for MDD + BF and -19.6 (13.2) for MDD-BF (F[1151] = 0.045, p = 0.83). The LS mean change in BDI at 14 days was -23.2 (15.3) for MDD + BF and -15.3 (15.2) for MDD-BF (F[1130] = 4.24, p = 0.04). LIMITATIONS: People in the MDD + BF group were not necessarily diagnosable with borderline personality disorder. CONCLUSIONS: These data indicate that IV ketamine is effective in MDD patients with and without elevated borderline features. This can provide clinicians some reassurance about using ketamine in this population.

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.

Combinatorial pharmacogenomic algorithm is predictive of sertraline metabolism in patients with major depressive disorder.

Pharmacogenomic testing can be used to guide medication selection in patients with major depressive disorder (MDD). Currently, there is no consensus on which gene or genes to consider in medication management. Here, we assessed the clinical validity of the combinatorial pharmacogenomic algorithm to predict sertraline blood levels in a subset of patients enrolled in the Genomics Used to Improve DEpression Decisions (GUIDED) trial. Patients who reported taking sertraline within ≤2 weeks of the screening blood draw were included. All patients received combinatorial pharmacogenomic testing, which included a weighted assessment of individual phenotypes for multiple pharmacokinetic genes relevant for sertraline (CYP2C19, CYP2B6, and CYP3A4). Sertraline blood levels were compared between phenotypes based on: 1) the pharmacokinetic portion of the combinatorial pharmacogenomic algorithm, and 2) individual genes. When evaluated separately, individual genes (for CYP2C19 and CYP2B6) and the combinatorial algorithm were significant predictors of sertraline blood levels. However, in multivariate analyses that included individual genes and the combinatorial pharmacogenomic algorithm, only the combinatorial pharmacogenomic algorithm remained a significant predictor of sertraline blood levels. These findings support the clinical validity of the combinatorial pharmacogenomic algorithm, in that it is a superior predictor of sertraline blood levels compared to individual genes.

A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials.

Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD.

Cardiometabolic risk markers during mood-stabilizing treatment: Correlation with drug-specific effects, depressive symptoms and treatment response.

BACKGROUND: Patients with bipolar disorder have higher rates of cardiometabolic comorbidities and mortality. Although guidelines emphasize the importance of cardiovascular monitoring, few studies characterized the cardiometabolic risk profile during treatment and their relation to symptomatology and treatment response. METHODS: We analyzed data from two similar 24-weeks comparative effectiveness trials, with a combined sample of 770 participants randomized to two different lithium doses, quetiapine (300 mg/day), or standard treatment without lithium. Glucose, lipids and vital signs were measured before and after 24 weeks of treatment. We calculated several cardiovascular risk scores, assessed baseline correlations and compared the four treatment arms via multiple linear regression models. RESULTS: Higher cholesterol and LDL levels were associated with greater depression severity, showing differential correlations to specific symptoms, particularly agitation, low energy and suicidality. Those randomized to quetiapine showed a significant worsening of cardiometabolic markers during the 24-week trial. Neither baseline nor change in lipid levels correlated with differential treatment response. LIMITATIONS: Study duration was short from the perspective of cardiometabolic risk markers, and all treatment arms included patients taking adjunct antipsychotics. The trials compared quetiapine to lithium, but not to other medications known to affect similar risk factors. CONCLUSIONS: Treatment with 300 mg/day quetiapine for 24 weeks, representing a short and common dose course, resulted in increased cardiometabolic risk markers, emphasizing the importance of monitoring during mood-stabilizing treatment. The symptom-specific associations are in line with previous studies in unipolar depression, suggesting a cardiometabolic-depression link that needs to be further studied in bipolar depression.

Obesogenic Medications and Weight Gain Over 24 Weeks in Patients with Depression: Results from the GUIDED Study.

Weight gain is a common side-effect of medications used to treat major depressive disorder (MDD). We sought to estimate the frequency of weight gain for obesogenic medications prescribed for MDD and to evaluate if bupropion mitigated risk for weight gain. We analyzed a prospective cohort of patients with weight available at baseline and 12 weeks (n = 1,032) or 24 weeks (n = 871) in a post hoc analysis of the Genomics Used to Improve DEpression Decisions (GUIDED) study of patients with MDD who failed at least one medication trial. We compared weight gain between those on versus not on medications with high risk for weight gain, including a subgroup receiving combination treatment with bupropion. A second analysis evaluated weight gain across traditional medication classes, adjusting for potential confounding variables. Those on medications identified as high risk for weight gain were significantly more likely to experience clinically significant weight gain (≥3%) at 12 weeks (29.3% vs. 16.3%, p < .001) and 24 weeks (33.5% vs. 23.5%, p = .015). No protection from clinically significant weight gain was observed among patients treated with a high-risk medication concomitantly with bupropion (N = 31, 35% and 52% with clinically significant weight gain at 12 and 24 weeks). Antipsychotic medications and tricyclic antidepressants were most often associated with clinically significant weight gain. This study helps quantify the real-world risk of weight gain for patients with MDD on medications with high risk for weight gain, especially for patients taking antipsychotics. Concurrent treatment with bupropion does not appear to mitigate the weight gain risk.

Combinatorial Pharmacogenomic Testing Improves Outcomes for Older Adults With Depression.

(Reprinted with permission from Am J Geriatr Psychiatry 2020; 28:933-945).

Response and remission rates during 24 weeks of mood-stabilizing treatment for bipolar depression depending on early non-response.

BACKGROUND: We aimed to study the probability of bipolar depression response at 24 weeks given initial non-response. METHODS: We combined two multi-site, 24-week trials including similar populations following the same evidence-based guidelines randomizing patients to lithium or quetiapine. Additional mood-stabilizing treatment was possible if clinically indicated. We report cumulative proportions of response (>50% improvement in MADRS) and remission (MADRS<10). RESULTS: We included 592 participants with bipolar depression (mean 39 years, 59% female, mean MADRS 25). Among 393 (66%) participants without response after 2 weeks, 46% responded by 24 weeks; for 291 (49%) without response at 4 weeks, 40% responded and 33% remitted by 24 weeks; for 222 (38%) without a response at 6 weeks, 36% responded and 29% remitted by 24 weeks; for 185 (31%) without a response at 8 weeks, 29% responded and 24% remitted by 24 weeks. Rates were similar for participants who had started an additional mood-stabilizing drug during the first 6 or 8 weeks. CONCLUSIONS: Among patients with bipolar depression and non-response after 6 weeks treatment, representing an adequate bipolar depression trial, only one-third responded by 24 weeks. These results highlight the need for better treatment alternatives for non-responders to evidence-based treatments for bipolar depression.

Illness stage and predominant polarity in bipolar disorder: Correlation with burden of illness and moderation of treatment outcome.

Bipolar disorder often follows a set progression best described in stages where advanced stages are associated with poorer outcomes. Bipolar disorder is also often characterized by a predominance of episode polarity, where some individuals experience more depressive episodes (termed predominant depressive polarity) while others experience more hypo/manic episodes (termed predominant hypo/manic polarity). We examined the associations between staging and predominant polarity with measures of illness burden and treatment outcome utilizing data from a six-month comparative effectiveness trial of lithium and quetiapine in bipolar disorder (Bipolar CHOICE). We used number of self-reported lifetime mood (depressive and hypo/manic) episodes as a proxy for staging and ratio of depressive to manic episodes to define predominant polarity. Polarity and staging were correlated with several measures of burden of illness. Childhood abuse was correlated with more lifetime mood episodes, while more depressive episodes and depressive polarity were correlated with more anxiety disorder comorbidity. Depressive polarity was also correlated with more past trials of psychotropics, particularly antidepressants. However, neither staging nor predominant polarity moderated the randomized treatment effect of lithium vs. quetiapine. Number of depressive episodes in the past year was identified as a potential predictor of overall worse treatment outcome, regardless of medication condition. In conclusion, though staging and predominant episode polarity correlated with several measures of illness burden, they were not associated with differential treatment outcomes. This could be because many of our patients presented for treatment at advanced stages of illness and further highlights the need for early intervention in bipolar disorder.

A Pilot Study of Nicotine Replacement Therapy Sampling and Selection to Increase Medication Adherence in Low-Income Smokers.

INTRODUCTION: Adherence to smoking cessation medications remains suboptimal, particularly among low-income smokers. Guided, experiential sampling of nicotine replacement therapies (NRTs) may increase NRT adherence and smoking cessation over gold standard counseling plus NRT. The present pilot study aimed to examine feasibility, acceptability, and preliminary efficacy of a novel experiential intervention. AIMS AND METHODS: This pilot randomized controlled trial (N = 83) compared gold standard smoking cessation treatment (four weekly sessions of behavioral counseling followed by self-selected combination NRT in week 5) to a novel experiential approach (ie, In Vivo; four weekly sessions of sampling each short form of NRT-gum, lozenge, inhaler, nasal spray-in-session while wearing the nicotine patch followed by NRT selection in week 5). Both groups received 8 weeks of nicotine patch plus their selected additional short form NRT for smoking cessation followed by a 1-month assessment. RESULTS: Screening and enrollment rates supported feasibility. In Vivo was comparable in acceptability with the gold standard of care intervention; however, there was greater attrition in the In Vivo group compared with the gold standard of care group. Results suggested higher medication adherence and improvements in smoking behavior in the In Vivo intervention; with generally small-to-medium effect sizes. CONCLUSIONS: This experiential approach to sampling NRT is feasible and acceptable to low-income people who smoke. This intervention may increase adherence and reduce harmful smoking behavior but needs to be tested on a larger scale. IMPLICATIONS: Medication adherence remains a significant impediment to the successful smoking cessation. The results of this study suggest that guided sampling of NRT products improves adherence among low-income smokers. Additionally, this approach yielded greater improvements in smoking behavior compared with gold standard smoking cessation treatment. This intervention shows promise as a feasible smoking cessation treatment for low-income smokers.

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.