Psychotherapies for Panic Disorder: A Tale of Two Sites.

OBJECTIVE: To compare cognitive-behavioral therapy (CBT), panic-focused psychodynamic psychotherapy (PFPP), and applied relaxation training (ART) for primary DSM-IV panic disorder with and without agoraphobia in a 2-site randomized controlled trial. METHOD: 201 patients were stratified for site and DSM-IV agoraphobia and depression and were randomized to CBT, PFPP, or ART (19-24 sessions) over 12 weeks in a 2:2:1 ratio at Weill Cornell Medical College (New York, New York) and University of Pennsylvania ("Penn"; Philadelphia, Pennsylvania). Any medication was held constant. RESULTS: Attrition rates were ART, 41%; CBT, 25%; and PFPP, 22%. The most symptomatic patients were more likely to drop out of ART than CBT or PFPP (P = .013). Outcome analyses revealed site-by-treatment interactions in speed of Panic Disorder Severity Scale (PDSS) change over time (P = .013). At Cornell, no differences emerged on improvement on the primary outcome, estimated speed of change over time on the PDSS; at Penn, ART (P = .025) and CBT (P = .009) showed greater improvement at treatment termination than PFPP. A site-by-treatment interaction (P = .016) for a priori-defined response (40% PDSS reduction) showed significant differences at Cornell: ART 30%, CBT 65%, PFPP 71% (P = .007), but not at Penn: ART 63%, CBT 60%, PFPP 48% (P = .37). Penn patients were more symptomatic, differed demographically from Cornell patients, had a 7.2-fold greater likelihood of taking medication, and had a 28-fold greater likelihood of taking benzodiazepines. However, these differences did not explain site-by-treatment interactions. CONCLUSIONS: All treatments substantially improved panic disorder with or without agoraphobia, but patients, particularly the most severely ill, found ART less acceptable. CBT showed the most consistent performance across sites; however, the results for PFPP showed the promise of psychodynamic psychotherapy for this disorder. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00353470.

Bipolar CHOICE (Clinical Health Outcomes Initiative in Comparative Effectiveness): a pragmatic 6-month trial of lithium versus quetiapine for bipolar disorder.

BACKGROUND: Bipolar disorder is among the 10 most disabling medical conditions worldwide. While lithium has been used extensively for bipolar disorder since the 1970s, second-generation antipsychotics (SGAs) have supplanted lithium since 1998. To date, no randomized comparative-effectiveness study has compared lithium and any SGA. METHOD: Within the duration of the study (September 2010-September 2013), participants with bipolar I or II disorder (DSM-IV-TR) were randomized for 6 months to receive lithium (n = 240) or quetiapine (n = 242). Lithium and quetiapine were combined with other medications for bipolar disorder consistent with typical clinical practice (adjunctive personalized treatment [APT], excluding any SGA for the lithium + APT group and excluding lithium or any other SGA for the quetiapine + APT group). Coprimary outcome measures included Clinical Global Impressions-Efficacy Index (CGI-EI) and necessary clinical adjustments, which measured number of changes in adjunctive personalized treatment. Secondary measures included a full range of symptoms, cardiovascular risk, functioning, quality of life, suicidal ideation and behavior, and adverse events. RESULTS: Participants improved across all measures, and over 20% had a sustained response. Primary (CGI-EI, P = .59; necessary clinical adjustments, P = .15) and secondary outcome changes were not statistically significantly different between the 2 groups. For participants with greater manic/hypomanic symptoms, CGI-EI changes were significantly more favorable with quetiapine + APT (P = .02). Among those with anxiety, the lithium + APT group had fewer necessary clinical adjustments per month (P = .02). Lithium was better tolerated than quetiapine in terms of the burden of side effects frequency (P = .05), intensity (P = .01), and impairment (P = .01). CONCLUSIONS: Despite adequate power to detect clinically meaningful differences, we found outcomes with lithium + APT and quetiapine + APT were not significantly different across 6 months of treatment for bipolar disorder. TRIAL REGISTRATION: ClinicalTrials.gov identifier for the Bipolar CHOICE study: NCT01331304.

A clinical measure of suicidal ideation, suicidal behavior, and associated symptoms in bipolar disorder: Psychometric properties of the Concise Health Risk Tracking Self-Report (CHRT-SR).

OBJECTIVE: People with bipolar disorder are at high risk of suicide, but no clinically useful scale has been validated in this population. The aim of this study was to evaluate the psychometric properties in bipolar disorder of the 7- and 12-item versions of the Concise Health Risk Tracking Self-Report (CHRT-SR), a scale measuring suicidal ideation, suicidal behavior, and associated symptoms. METHODS: The CHRT was administered to 283 symptomatic outpatients with bipolar I or II disorder who were randomized to receive lithium plus optimized personalized treatment (OPT), or OPT without lithium in a six month longitudinal comparative effectiveness trial. Participants were assessed using structured diagnostic interviews, clinician-rated assessments, and self-report questionnaires. RESULTS: The internal consistency (Cronbach α) was 0.80 for the 7-item CHRT-SR and 0.90 for the 12-item CHRT-SR with a consistent factor structure, and three independent factors (current suicidal thoughts and plans, hopelessness, and perceived lack of social support) for the 7-item version. CHRT-SR scores are correlated with measures of depression, functioning, and quality of life, but not with mania scores. CONCLUSIONS: The 7- and 12-item CHRT-SR both had excellent psychometric properties in a sample of symptomatic subjects with bipolar disorder. The scale is highly correlated with depression, functioning, and quality of life, but not with mania. Future research is needed to determine whether the CHRT-SR will be able to predict suicide attempts in clinical practice.

An exploratory study of responses to low-dose lithium in African Americans and Hispanics.

OBJECTIVES: Few prospective studies examine the impact of ethnicity or race on outcomes with lithium for bipolar disorder. This exploratory study examines differences in lithium response and treatment outcomes in Hispanics, African Americans, and non-Hispanic whites with bipolar disorder in the Lithium Treatment Moderate Dose Use Study (LiTMUS). METHODS: LiTMUS was a six-site randomized controlled trial of low-dose lithium added to optimized treatment (OPT; personalized, evidence-based pharmacotherapy) vs. OPT alone in outpatients with bipolar disorder. Of 283 participants, 47 African Americans, 39 Hispanics, and 175 non-Hispanic whites were examined. We predicted minority groups would have more negative medication attitudes and higher attrition rates, but better clinical outcomes. RESULTS: African Americans in the lithium group improved more on depression and life functioning compared to whites over the 6 month study. African Americans in the OPT only group had marginal improvement on depression symptoms. For Hispanics, satisfaction with life did not significantly improve in the OPT only group, in contrast to whites and African Americans who improved over time on all measures. Attitudes toward medications did not differ across ethnic/racial groups. CONCLUSIONS: African Americans show some greater improvements with lithium than non-Hispanic whites, and Hispanics showed more consistent improvements in the lithium group. The impact of low-dose lithium should be studied in a larger sample as there may be particular benefit for African Americans and Hispanics. Given that the control group (regardless of ethnicity/race) had significant improvements, optimized treatment may be beneficial for any ethnic group.

Clinical effectiveness of integrating depression care management into medicare home health: the Depression CAREPATH Randomized trial.

IMPORTANCE: Among older home health care patients, depression is highly prevalent, is often inadequately treated, and contributes to hospitalization and other poor outcomes. Feasible and effective interventions are needed to reduce this burden of depression. OBJECTIVE: To determine whether, among older Medicare Home Health recipients who screen positive for depression, patients of nurses receiving randomization to an intervention have greater improvement in depressive symptoms during 1 year than patients receiving enhanced usual care. DESIGN, SETTING, AND PARTICIPANTS: This cluster randomized effectiveness trial conducted at 6 home health care agencies nationwide assigned nurse teams to an intervention (12 teams) or to enhanced usual care (9 teams). Between January 13, 2009, and December 6, 2012, Medicare Home Health patients 65 years and older who screened positive for depression on routine nursing assessments were recruited, underwent assessment, and were followed up at 3, 6, and 12 months by research staff blinded to intervention status. Patients were interviewed at home and by telephone. Of 502 eligible patients, 306 enrolled in the study. INTERVENTIONS: The Depression Care for Patients at Home (Depression CAREPATH) trial requires nurses to manage depression at routine home visits by weekly symptom assessment, medication management, care coordination, education, and goal setting. Nurses' training totaled 7 hours (4 onsite and 3 via the web). Researchers telephoned intervention team supervisors every other week. MAIN OUTCOMES AND MEASURES: Depression severity, assessed by the 24-item Hamilton Scale for Depression (HAM-D). RESULTS: The 306 participants were predominantly female (69.6%), were racially/ethnically diverse (18.0% black and 16.0% Hispanic), and had a mean (SD) age of 76.5 (8.0) years. In the full sample, the intervention had no effect (P = .13 for intervention × time interaction). Adjusted HAM-D scores (Depression CAREPATH vs control) did not differ at 3 months (10.5 vs 11.4, P = .26) or at 6 months (9.3 vs 10.5, P = .12) but reached significance at 12 months (8.7 vs 10.6, P = .05). In the subsample with mild depression (HAM-D score, <10), the intervention had no effect (P = .90), and HAM-D scores did not differ at any follow-up points. Among 208 participants with a HAM-D score of 10 or higher, the Depression CAREPATH demonstrated effectiveness (P = .02), with lower HAM-D scores at 3 months (14.1 vs 16.1, P = .04), at 6 months (12.0 vs 14.7, P = .02), and at 12 months (11.8 vs 15.7, P = .005). CONCLUSION AND RELEVANCE: Home health care nurses can effectively integrate depression care management into routine practice. However, the clinical benefit seems to be limited to patients with moderate to severe depression. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01979302.

The effect of personalized guideline-concordant treatment on quality of life and functional impairment in bipolar disorder.

OBJECTIVES: The aims of this study were to evaluate correlates and predictors of life functioning and quality of life in bipolar disorder during a comparative effectiveness trial of moderate doses of lithium. METHODS: In the Lithium treatment moderate-dose use study (LiTMUS), 283 symptomatic outpatients with bipolar disorder type I or II were randomized to receive lithium plus "optimal personalized treatment (OPT)", or OPT alone. Participants were assessed using structured diagnostic interviews, clinician-rated blinded assessments, and questionnaires. We employ linear mixed effects models to test the effect of treatment overall and adjunct lithium specifically on quality of life or functioning. Similar models are used to examine the association of baseline demographics and clinical features with quality of life and life functioning. RESULTS: Quality of life and impaired functioning at baseline were associated with lower income, higher depressive severity, and more psychiatric comorbid conditions. Over 6 months, patients in both treatment groups improved in quality of life and life functioning (p-Values<0.0001); without a statistically significant difference between the two treatment groups (p-Values>0.05). Within the lithium group, improvement in quality of life and functioning was not associated with concurrent lithium levels at week 12 or week 24 (p-Values>0.05). Lower baseline depressive severity and younger age of onset predicted less improvement in functioning over 6 months. CONCLUSIONS: Optimized care for bipolar disorder improves overall quality of life and life functioning, with no additional benefit from adjunct moderate doses of lithium. Illness burden and psychosocial stressors were associated with worse quality of life and lower functioning in individuals with bipolar disorder.

Risk of suicidal behavior with antidepressants in bipolar and unipolar disorders.

OBJECTIVE: To examine the risk of suicidal behavior (suicide attempts and deaths) associated with antidepressants in participants with bipolar I, bipolar II, and unipolar major depressive disorders. DESIGN: A 27-year longitudinal (1981-2008) observational study of mood disorders (Research Diagnostic Criteria diagnoses based on Schedule for Affective Disorders and Schizophrenia and review of medical records) was used to evaluate antidepressants and risk for suicidal behavior. Mixed-effects logistic regression models examined propensity for antidepressant exposure. Mixed-effects survival models that were matched on the propensity score examined exposure status as a risk factor for time until suicidal behavior. SETTING: Five US academic medical centers. RESULTS: Analyses of 206 participants with bipolar I disorder revealed 2,010 exposure intervals (980 exposed to antidepressants; 1,030 unexposed); 139 participants with bipolar II disorder had 1,407 exposure intervals (694 exposed; 713 unexposed); and 361 participants with unipolar depressive disorder had 2,745 exposure intervals (1,328 exposed; 1,417 unexposed). Propensity score analyses confirmed that more severely ill participants were more likely to initiate antidepressant treatment. In mixed-effects survival analyses, those with bipolar I disorder had a significant reduction in risk of suicidal behavior by 54% (HR = 0.46; 95% CI, 0.31-0.69; t = -3.74; P < .001) during periods of antidepressant exposure compared to propensity-matched unexposed intervals. Similarly, the risk was reduced by 35% (HR = 0.65; 95% CI, 0.43-0.99; t = -2.01; P = .045) in bipolar II disorder. By contrast, there was no evidence of an increased or decreased risk with antidepressant exposure in unipolar disorder. CONCLUSIONS: Based on observational data adjusted for propensity to receive antidepressants, antidepressants may protect patients with bipolar disorders but not unipolar depressive disorder from suicidal behavior.

A novel application of the Intent to Attend assessment to reduce bias due to missing data in a randomized controlled clinical trial.

BACKGROUND: Missing data are unavoidable in most randomized controlled clinical trials, especially when measurements are taken repeatedly. If strong assumptions about the missing data are not accurate, crude statistical analyses are biased and can lead to false inferences. Furthermore, if we fail to measure all predictors of missing data, we may not be able to model the missing data process sufficiently. In longitudinal randomized trials, measuring a patient's intent to attend future study visits may help to address both of these problems. Leon et al. developed and included the Intent to Attend assessment in the Lithium Treatment - Moderate dose Use Study (LiTMUS), aiming to remove bias due to missing data from the primary study hypothesis. PURPOSE: The purpose of this study is to assess the performance of the Intent to Attend assessment with regard to its use in a sensitivity analysis of missing data. METHODS: We fit marginal models to assess whether a patient's self-rated intent predicted actual study adherence. We applied inverse probability of attrition weighting (IPAW) coupled with patient intent to assess whether there existed treatment group differences in response over time. We compared the IPAW results to those obtained using other methods. RESULTS: Patient-rated intent predicted missed study visits, even when adjusting for other predictors of missing data. On average, the hazard of retention increased by 19% for every one-point increase in intent. We also found that more severe mania, male gender, and a previously missed visit predicted subsequent absence. Although we found no difference in response between the randomized treatment groups, IPAW increased the estimated group difference over time. LIMITATIONS: LiTMUS was designed to limit missed study visits, which may have attenuated the effects of adjusting for missing data. Additionally, IPAW can be less efficient and less powerful than maximum likelihood or Bayesian estimators, given that the parametric model is well specified. CONCLUSIONS: In LiTMUS, the Intent to Attend assessment predicted missed study visits. This item was incorporated into our IPAW models and helped reduce bias due to informative missing data. This analysis should both encourage and facilitate future use of the Intent to Attend assessment along with IPAW to address missing data in a randomized trial.

Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE): a pragmatic trial of complex treatment for a complex disorder.

BACKGROUND: Classic and second-generation antipsychotic mood stabilizers are recommended for treatment of bipolar disorder, yet there are no randomized comparative effectiveness studies that have examined the 'real-world' advantages and disadvantages of these medications. PURPOSE: We describe the strategic decisions in the design of the Clinical and Health Outcomes Initiative in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE). This article outlines the key issues and solutions the investigators faced in designing a clinical trial that would maximize generalizability and inform real-world clinical treatment of bipolar disorder. METHODS: Bipolar CHOICE was a 6-month, multi-site, prospective, randomized clinical trial of outpatients with bipolar disorder. This study compares the effectiveness of quetiapine versus lithium, each with adjunctive personalized treatments (APTs). The co-primary outcomes selected are the overall benefits and harms of the study medications (as measured by the Clinical Global Impression-Efficacy Index) and the Necessary Clinical Adjustments (a measure of the number of medication changes). Secondary outcomes are continuous measures of mood, the Framingham General Cardiovascular Risk Score, and the Longitudinal Interval Follow up Evaluation Range of Impaired Functioning Tool (LIFE-RIFT). RESULTS: The final study design consisted of a single-blind, randomized comparative effectiveness trial of quetiapine versus lithium, plus APT, across 10 sites. Other important study considerations included limited exclusion criteria to maximize generalizability, flexible dosing of APT medications to mimic real-world treatment, and an intent-to-treat analysis plan. In all, 482 participants were randomized to the study, and 364 completed the study. LIMITATIONS: The potential limitations of the study include the heterogeneity of APT, selection of study medications, lack of a placebo-control group, and participants' ability to pay for study medications. CONCLUSION: We expect that this study will inform our understanding of the benefits and harms of lithium, a classic mood stabilizer, compared to quetiapine, a second-generation antipsychotic with broad-spectrum activity in bipolar disorder, and will provide an example of a well-designed and well-conducted randomized comparative effectiveness clinical trial.

The Medication Recommendation Tracking Form: a novel tool for tracking changes in prescribed medication, clinical decision making, and use in comparative effectiveness research.

This paper describes the development and use of the Medication Recommendation Tracking Form (MRTF), a novel method for capturing physician prescribing behavior and clinical decision making. The Bipolar Trials Network developed and implemented the MRTF in a comparative effectiveness study for bipolar disorder (LiTMUS). The MRTF was used to assess the frequency, types, and reasons for medication adjustments. Changes in treatment were operationalized by the metric Necessary Clinical Adjustments (NCA), defined as medication adjustments to reduce symptoms, optimize treatment response and functioning, or to address intolerable side effects. Randomized treatment groups did not differ in rates of NCAs, however, responders had significantly fewer NCAs than non-responders. Patients who had more NCAs during their previous visit had significantly lower odds of responding at the current visit. For each one-unit increase in previous CGI-BP depression score and CGI-BP overall severity score, patients had an increased NCA rate of 13% and 15%, respectively at the present visit. Ten-unit increases in previous Montgomery Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) scores resulted in an 18% and 14% increase in rates of NCAs, respectively. Patients with fewer NCAs had increased quality of life and decreased functional impairment. The MRTF standardizes the reporting and rationale for medication adjustments and provides an innovative metric for clinical effectiveness. As the first tool in psychiatry to track the types and reasons for medication changes, it has important implications for training new clinicians and examining clinical decision making. (ClinicalTrials.gov number NCT00667745).

Use of treatment services in a comparative effectiveness study of bipolar disorder.

OBJECTIVE Bipolar disorder is a severe, chronic mental illness with a high incidence of medical and psychological comorbidities that make treatment and prevention of future episodes challenging. This study investigated the use of services among outpatients with bipolar disorder to further understanding of how to maximize and optimize personalization and accessibility of services for this difficult-to-treat population. METHODS The Lithium Treatment-Moderate Dose Use Study (LiTMUS) was a six-month multisite, comparative effectiveness trial that randomly assigned 283 individuals to receive lithium plus optimized care-defined as personalized, guideline-informed care-or optimized care without lithium. Relationships between treatment service utilization, captured by the Cornell Service Index, and demographic and illness characteristics were examined with generalized linear marginal models. RESULTS Analyses with complete data (week 12, N=246; week 24, N=236) showed that increased service utilization was related to more severe bipolar disorder symptoms, physical side effects, and psychiatric and general medical comorbidities. Middle-aged individuals and those living in the United States longer tended to use more services than younger individuals or recent immigrants, respectively. CONCLUSIONS These data suggest that not all individuals with bipolar disorder seek treatment services at the same rate. Instead, specific clinical or demographic features may affect the degree to which one seeks treatment, conveying clinical and public health implications and highlighting the need for specific approaches to correct such discrepancies. Future research is needed to elucidate potential moderators of service utilization in bipolar disorder to ensure that those most in need of additional services utilize them.

Defining a clinically meaningful effect for the design and interpretation of randomized controlled trials.

OBJECTIVE: This article captures the proceedings of a meeting aimed at defining clinically meaningful effects for use in randomized controlled trials for psychopharmacological agents. DESIGN: Experts from a variety of disciplines defined clinically meaningful effects from their perspectives along with viewpoints about how to design and interpret randomized controlled trials. SETTING: The article offers relevant, practical, and sometimes anecdotal information about clinically meaningful effects and how to interpret them. PARTICIPANTS: The concept for this session was the work of co-chairs Richard Keefe and the late Andy Leon. Faculty included Richard Keefe, PhD; James McNulty, AbScB; Robert S. Epstein, MD, MS; Shelby D. Reed, PhD; Juan Sanchez, MD; Ginger Haynes, PhD; Andrew C. Leon, PhD; Helena Chmura Kraemer, PhD; Ellen Frank, PhD, and Kenneth L. Davis, MD. RESULTS: The term clinically meaningful effect is an important aspect of designing and interpreting randomized controlled trials but can be particularly difficult in the setting of psychopharmacology where effect size may be modest, particularly over the short term, because of a strong response to placebo. Payers, regulators, patients, and clinicians have different concerns about clinically meaningful effects and may describe these terms differently. The use of moderators in success rate differences may help better delineate clinically meaningful effects. CONCLUSION: There is no clear consensus on a single definition for clinically meaningful differences in randomized controlled trials, and investigators must be sensitive to specific concerns of stakeholders in psychopharmacology in order to design and execute appropriate clinical trials.

Subject-level matching for imbalance in cluster randomized trials with a small number of clusters.

In a cluster randomized controlled trial (RCT), the number of randomized units is typically considerably smaller than in trials where the unit of randomization is the patient. If the number of randomized clusters is small, there is a reasonable chance of baseline imbalance between the experimental and control groups. This imbalance threatens the validity of inferences regarding post-treatment intervention effects unless an appropriate statistical adjustment is used. Here, we consider application of the propensity score adjustment for cluster RCTs. For the purpose of illustration, we apply the propensity adjustment to a cluster RCT that evaluated an intervention to reduce suicidal ideation and depression. This approach to adjusting imbalance had considerable bearing on the interpretation of results. A simulation study demonstrates that the propensity adjustment reduced well over 90% of the bias seen in unadjusted models for the specifications examined.

A controlled clinical treatment trial of interpersonal psychotherapy for depressed pregnant women at 3 New York City sites.

OBJECTIVE: While treatment decisions for antepartum depression must be personalized to each woman and her illness, guidelines from the American Psychiatric Association and the American College of Obstetrics and Gynecology include the recommendation of psychotherapy for mild-to-moderate depression in pregnant women. Although we previously demonstrated the efficacy of interpersonal psychotherapy for antepartum depression in a sample of Hispanic women, this study provides a larger, more diverse sample of African American, Hispanic, and white pregnant women from 3 New York City sites in order to provide greater generalizability. METHOD: A 12-week bilingual, parallel-design, controlled clinical treatment trial compared interpersonal psychotherapy for antepartum depression to a parenting education program control group. An outpatient sample of 142 women who met DSM-IV criteria for major depressive disorder was randomly assigned to interpersonal psychotherapy or the parenting education program from September 2005 to May 2011. The 17-item Hamilton Depression Rating Scale (HDRS-17) was the primary outcome measure of mood. Other outcome scales included the Edinburgh Postnatal Depression Scale (EPDS) and the Clinical Global Impressions scale (CGI). The Maternal Fetal Attachment Scale (MFAS) assessed mother's interaction with the fetus. RESULTS: Although this study replicated previous findings that interpersonal psychotherapy is a beneficial treatment for antepartum depression, the parenting education program control condition showed equal benefit as measured by the HDRS-17, EPDS, CGI, and MFAS. CONCLUSIONS: This study supports the recommendation for the use of interpersonal psychotherapy for mild-to-moderate major depressive disorder in pregnancy. The parenting education program may be an alternative treatment that requires further study. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00251043

Recovery from multiple episodes of bipolar I depression.

OBJECTIVE: To describe the duration of bipolar I major and minor depressive episodes and factors associated with time to recovery. METHOD: As part of the National Institute of Mental Health Collaborative Depression Study, 219 participants with bipolar I disorder based on Research Diagnostic Criteria analogs to DSM-IV-TR criteria were recruited at 5 academic medical centers from 1978 to 1981 and followed for up to 25 years with the Longitudinal Interval Follow-Up Evaluation. The probability of recovery over time from depressive episodes, the primary outcome measure, was examined with mixed-effects grouped-time survival models. RESULTS: The median duration of major depressive episodes was 14 weeks, and over 70% of participants recovered within 12 months of episode onset. The median duration of minor depressive episodes was 8 weeks, and approximately 90% of participants recovered within 6 months of onset of the episode. Aggregated data demonstrated similar durations of the first 3 major depressive episodes. However, for each participant with multiple episodes of major depression or minor depression, the duration of each episode was not consistent (intraclass correlation coefficient = 0.07 and 0.25 for major and minor depression, respectively). The total number of years in episode over follow-up with major plus minor depression prior to onset of a major depressive episode was significantly associated with a decreased probability of recovery from that episode; with each additional year, the likelihood of recovery was reduced by 7% (hazard ratio = 0.93; 95% CI, 0.89-0.98; P = .002). CONCLUSIONS: Bipolar I major depression generally lasts longer than minor depression, and the duration of multiple episodes within an individual varies. However, the probability of recovery over time from an episode of major depression appears to decline with each successive episode.

Lithium treatment moderate-dose use study (LiTMUS) for bipolar disorder: a randomized comparative effectiveness trial of optimized personalized treatment with and without lithium.

OBJECTIVE: Lithium salts, once the mainstay of therapy for bipolar disorder, have tolerability issues at a higher dosage that often limit adherence. The authors investigated the comparative effectiveness of more tolerable dosages of lithium as part of optimized personalized treatment (OPT). METHOD: The authors randomly assigned 283 bipolar disorder outpatients to 6 months of open, flexible, moderate dosages of lithium plus OPT or to 6 months of OPT alone. The primary outcome measures were the Clinical Global Impression Scale for Bipolar Disorder-Severity (CGI-BP-S) and "necessary clinical adjustments" (medication adjustments per month). Secondary outcome measures included mood symptoms and functioning. The authors also assessed sustained remission (defined as a CGI-BP-S score ≤2 for 2 months) and treatment with second-generation antipsychotics. The authors hypothesized that lithium plus OPT would result in greater clinical improvement and fewer necessary clinical adjustments. RESULTS: The authors observed no statistically significant advantage of lithium plus OPT on CGI-BP-S scores, necessary clinical adjustments, or proportion with sustained remission. Both groups had similar outcomes across secondary clinical and functional measures. Fewer patients in the lithium-plus-OPT group received second-generation antipsychotics compared with the OPT-only group (48.3% and 62.5%, respectively). CONCLUSIONS: In this pragmatic comparative effectiveness study, a moderate but tolerated dosage of lithium plus OPT conferred no symptomatic advantage when compared with OPT alone, but the lithium-plus-OPT group had less exposure to second-generation antipsychotics. Only about one-quarter of patients in both groups achieved sustained remission of symptoms. These findings highlight the persistent and chronic nature of bipolar disorder as well as the magnitude of unmet needs in its treatment.

Dysfunctional attitudes as a moderator of pharmacotherapy and psychotherapy for chronic depression.

OBJECTIVE: Individuals with chronic depression exhibit heterogeneous responses to treatment. Important individual differences may therefore exist within this particularly difficult to treat population that act as moderators of treatment response. METHOD: The present study examined whether pretreatment levels of dysfunctional attitudes (DA) moderated treatment response in a large sample of chronically depressed individuals. Data were taken from the Research Evaluating the Value of Augmenting Medication with Psychotherapy (REVAMP) treatment study--a multi-site treatment and augmentation study of 808 chronically depressed individuals. REVAMP comprised two phases: 1) a 12-week open-label antidepressant trial and 2), a subsequent phase, in which phase 1 non-remitters (N = 491) were randomized to either receive an ongoing medication algorithm alone, medication plus cognitive behavioral analysis system of psychotherapy, or medication plus brief supportive psychotherapy. RESULT: In phase 1, compared to the pharmacotherapy response of patients with lower DA scores, the response for patients with higher DA scores was steeper, but leveled off toward the end of the phase. In phase 2, DA predicted a differential response in the medication only arm, but not in the two psychotherapy + medication conditions. Specifically, in the phase 2 medication only condition, patients with higher DA improved while those with lower DA scores did not. CONCLUSION: These results indicate that the relation between DA and treatment response in chronic depression is complex, but suggest that greater DA may be associated with a steeper reduction and/or better response to pharmacotherapy.

Age of onset and the prospectively observed course of illness in bipolar disorder.

BACKGROUND: To test the validity of age-of-onset grouping in bipolar disorder through the use of prospectively observed time in mood episodes. METHODS: Age-of-onset ranges from prior admixture analyses were used to divide 427 individuals with bipolar I or bipolar II disorders into early-, middle- and late- onset groups. These were compared by the proportions of weeks depressed and manic or hypomanic during a mean (SD) prospective follow-up of 17.4 (8.4) years. RESULTS: As predicted, the group with the earliest onsets reported at intake more previous episodes, suicide attempts and panic attacks. An early age of onset, but not current age, was predictive of significantly more time in depressive episodes during follow-up but was not predictive of time in manic or hypomanic episodes. LIMITATIONS: This was a naturalistic study with no control of treatment so variability in treatment may have obscured relationships between predictors and outcomes. Age of onset was retrospectively determined and subject to inaccuracies in recall. CONCLUSIONS: An early age of onset conveys, to a modest degree, a poorer prognosis as expressed in more depressive morbidity.

Two propensity score-based strategies for a three-decade observational study: investigating psychotropic medications and suicide risk.

The US Food and Drug Administration issued separate warnings for suicidality with antidepressants and antiepileptic drugs in the past 5 years. This study describes methods for examining the association of these agents with suicide attempts and suicide deaths in more broadly generalizable samples than examined by the US Food and Drug Administration. An observational study of mood disorders was examined that includes three decades of prospective assessments. Because of sample size differences, two distinct longitudinal implementations of the propensity adjustment are used in separate analyses of antidepressants and antiepileptic drugs. Propensity score quintile-stratified safety analyses were used with the large antidepressant data set; whereas, propensity score matched safety analyses were used with the smaller antiepileptic drug data because stratification was not feasible. In each case, mixed-effects survival models compared the safety of participants when receiving the respective class of medication to periods when they did not receive that medication. When participants were more severely ill, they were significantly more likely to receive either class of psychotropics. Propensity quintile-stratified safety analyses found that risk of suicide attempts or suicides was significantly reduced when participants received antidepressants. In contrast, propensity score matched safety analyses found neither significant risk nor protection from suicidality among participants receiving antiepileptics.

Performance of a propensity score adjustment in longitudinal studies with covariate-dependent representation.

Longitudinal observational studies provide rich opportunities to examine treatment effectiveness during the course of a chronic illness. However, there are threats to the validity of observational inferences. For instance, clinician judgment and self-selection play key roles in treatment assignment. To account for this, an adjustment such as the propensity score can be used if certain assumptions are fulfilled. Here, we consider a problem that could surface in a longitudinal observational study and has been largely overlooked. It can occur when subjects have a varying number of distinct periods of therapeutic intervention. We evaluate the implications of baseline variables in the propensity model being associated with the number of post baseline observations per subject and refer to it as 'covariate-dependent representation'. An observational study of antidepressant treatment effectiveness serves as a motivating example. The analyses examine the first 20 years of follow-up data from the National Institute of Mental Health Collaborative Depression Study, a longitudinal, observational study. A simulation study evaluates the consequences of covariate-dependent representation in longitudinal observational studies of treatment effectiveness under a range of data specifications.The simulations found that estimates were adversely affected by underrepresentation when there was lower ICC among repeated doses and among repeated outcomes.