Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions.

Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

Coverage Parity And Racial And Ethnic Disparities In Mental Health And Substance Use Care Among Medicare Beneficiaries.

Many older Americans do not receive needed care for mental health and substance use disorders (MHSUD), and there are substantial racial and ethnic disparities in receipt of this care across the lifespan. Medicare introduced cost-sharing parity for outpatient MHSUD care during the period 2010-14, reducing beneficiaries' out-of-pocket share of MHSUD spending from 50 percent to 20 percent. Among traditional Medicare beneficiaries ages sixty-five and older, we examined changes in MHSUD use and spending during the period 2008-18 for low-income beneficiaries with the cost-sharing reduction versus a control group of beneficiaries with free care throughout the study period among Black, Hispanic, Asian, and American Indian/Alaska Native versus White beneficiaries. Among older Medicare beneficiaries, overall use of MHSUD services increased during this period. For White beneficiaries, MHSUD cost-sharing parity was associated with an increased likelihood of having specialty MHSUD visits and medication use and a reduced likelihood of having unmonitored MHSUD medication use and MHSUD emergency department visits and hospitalizations. However, cost-sharing parity was associated with smaller or no gains in MHSUD services use for racial and ethnic minority beneficiaries compared with White beneficiaries, thus widening racial and ethnic disparities in MHSUD care.

The United States index of socioeconomic deprivation for individuals (USiDep).

Background: Individuals experiencing socioeconomic deprivation consistently demonstrate poorer physical and mental health. Income alone is inadequate as a measure of socioeconomic status (SES); a better measure for assessing the deprivation status of individuals is needed. Methods: The New Zealand Index of Socioeconomic Deprivation for Individuals, a validated, eight-item measure of deprivation, was modified to create the United States Index of Socioeconomic Deprivation for Individuals (USiDep). The questionnaire was administered to patients with major depressive disorder participating in two clinical trials. Spearman's correlation coefficients evaluated associations between USiDep scores with income and other measures associated with deprivation. Results: The USiDep was completed by 118 participants, demonstrating adequate internal consistency (Crohnbach's alpha = 0.766) and strong item-total correlations. USiDep scores were moderately correlated with past-year personal income (Spearman's rho = -0.362, p < .001) and several other measures related to deprivation, including body mass index, level of education, quality of life, severity of childhood traumatic events, self-reported physical health, and negative life events. Patients scoring 5 on the USiDep (the highest possible score, indicating greater deprivation) had significantly lower rates of remission after 12 weeks of treatment than those scoring ≤ 4 (1/12, 8.3% vs 40/98, 40.8%, respectively, p = .03), whereas the lowest income group showed no significant associations with outcomes. Conclusion: The USiDep is a valid, brief questionnaire for assessing SES that has utility for clinical research and may serve as a predictor of treatment outcomes in clinical trials. Validation of the USiDep in healthy controls and other medically and psychiatrically ill populations is warranted.

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.

Association Between Care Utilization and Anxiety Outcomes in an On-Demand Mental Health System: Retrospective Observational Study.

BACKGROUND: Anxiety is an extremely prevalent condition, and yet, it has received notably less attention than depression and other mental health conditions from a research, clinical, and public health perspective. The COVID-19 pandemic has only exacerbated growing concerns about the burden of anxiety due to the confluence of physical health risks, economic stressors, social isolation, and general disruption of daily activities. OBJECTIVE: This study examines differences in anxiety outcomes by care modality (coaching, teletherapy and telepsychiatry, and combined care) within an on-demand mental health system. We also explore the association between levels of engagement within each care modality and odds of improvement in symptoms of anxiety. METHODS: We conducted a retrospective observational study of individuals who accessed Ginger, an on-demand mental health system. Data were collected from 1611 Ginger members between January 1, 2018, and December 31, 2019. We used logistic regression to assess the association between care modality and improvement in anxiety symptoms. Within each modality, we assessed the association between level of engagement and improvement. RESULTS: Of 1611 Ginger members, 761 (47.0%) experienced a decrease in anxiety symptoms, as measured by a change from a positive to a negative 2-item Generalized Anxiety Disorder (GAD-2) screen. Among members who still screened positive at follow-up (865/1611, 53%), a total of 192 members (11.9%) experienced a clinically significant score reduction in the full GAD-7 (ie, a score reduction of >5 points), even though their GAD-2 scores were still positive. All modalities showed increased odds of improvement compared to those who were not engaged with coaching or clinical services ("app-only"). Higher GAD-7 intake scores were also associated with decreased odds of improvement. CONCLUSIONS: This study found increased odds of anxiety improvement for all care modalities compared to those who did not engage in care, with larger effect sizes for higher utilization within all care modalities. Additionally, there is a promising observation that those engaged in combined care (teletherapy and text-based coaching) had the greatest odds of anxiety improvement. Future directions include more detailed classifications of utilization patterns and an exploration of explanations and solutions for lower-utilization members.

Assessment of Behavioral Health Services Use Among Low-Income Medicare Beneficiaries After Reductions in Coinsurance Fees.

Importance: Medicare has historically imposed higher beneficiary coinsurance for behavioral health services than for medical and surgical care but gradually introduced parity between 2009 and 2014. Although Medicare insures many people with serious mental illness (SMI), there is limited information on the impact of coinsurance parity in this population. Objective: To examine the association between coinsurance parity and outpatient behavioral health care use among low-income beneficiaries with SMI. Design, Setting, and Participants: This cohort study used Medicare claims data for a 50% national sample of lower-income Medicare beneficiaries from January 1, 2007, to December 31, 2016. The study sample included patients with SMI (schizophrenia, bipolar disorder, or major depressive disorder). Data analysis was performed from August 1, 2018, to July 15, 2020. Exposures: Reduction in behavioral health care coinsurance from 50% to 20% between January 1, 2009, and January 1, 2014. Main Outcomes and Measures: Total annual spending for outpatient behavioral health care visits and the percentage of beneficiaries with an annual outpatient behavioral health care visit overall, with a prescriber, and with a psychiatrist. A difference-in-difference approach was used to compare outcomes before and after the reduction in coinsurance for beneficiaries with and without cost-sharing decreases. Linear regression models with beneficiary fixed effects that adjusted for time-changing beneficiary- and area-level covariates were used to examine changes in outcomes. Results: The study included 793 275 beneficiaries with SMI in 2008; 518 893 (65.4%) were younger than 65 years (mean [SD] age, 57.6 [16.1] years), 511 265 (64.4%) were female, and 552 056 (69.6%) were White. In 2008, the adjusted percentage of beneficiaries with an outpatient behavioral health care visit was 40.7% (95% CI, 40.4%-41.0%) among those eligible for the cost-sharing reduction and 44.9% (95% CI, 44.9%-45.0%) among those with free care. The mean adjusted out-of-pocket costs for outpatient behavioral health care visits decreased from $132 (95% CI, $129-$136) in 2008 to $64 (95% CI, $61-$66) in 2016 among those with reductions in cost-sharing. The adjusted percentage of beneficiaries with behavioral health care visits increased to 42.2% (95% CI, 41.9%-42.5%) in the group with a reduction in coinsurance and to 47.2% (95% CI, 47.0%-47.3%) in the group with free care. The cost-sharing reduction was not positively associated with visits (eg, relative change of -0.76 percentage points [95% CI, -1.12 to -0.40 percentage points] in the percentage of beneficiaries with outpatient behavioral health care visits in 2016 vs 2008). Conclusions and Relevance: This cohort study found that beneficiary costs for outpatient behavioral health care decreased between 2009 and 2014. There was no association between cost-sharing reductions and changes in behavioral health care visits. Low levels of use in this high-need population suggest the need for other policy efforts to address additional barriers to behavioral health care.

Revisiting the Abnormal Involuntary Movement Scale: Proceedings From the Tardive Dyskinesia Assessment Workshop.

OBJECTIVE: To provide an historic overview of the Abnormal Involuntary Movement Scale (AIMS) in clinical trials of tardive dyskinesia (TD), with current recommendations for analyzing and interpreting AIMS data. PARTICIPANTS: Seven psychiatrists and 1 neurologist were selected by the workshop sponsor based on each individual's clinical expertise and research experience. EVIDENCE: Using PubMed entries from January 1970 to August 2017, participants selected studies that used the AIMS to evaluate TD treatments. The selections were intended to be representative rather than prescriptive or exhaustive, and no specific recommendations for TD treatment are implied. CONSENSUS PROCESS: The Working Group met in October 2016 to discuss the AIMS as an assessment tool, outline the challenges of translating clinical trial results into everyday clinical practice, and propose different methods for reporting AIMS data in clinically relevant terms. Recommendations for selecting TD studies for review, analyzing and interpreting AIMS data, and synthesizing discussions among the participants were initiated during the onsite workshop and continued remotely throughout development of this report. Disagreements were resolved via group e-mails and teleconferences. Consensus was based on final approval of this report by all workshop participants. CONCLUSIONS: For both research and clinical practice, the AIMS is a valid measure for assessing TD and the effects of treatment, but alternative analyses of AIMS data (eg, effect size, minimal clinically important difference, response analyses, category shifts) may provide broader evidence of clinical effectiveness. No single analysis of AIMS data can be considered the standard of clinical efficacy; multiple analytic approaches are recommended.

The introduction of generic risperidone in Medicare Part D.

OBJECTIVES: The introduction of generic second-generation antipsychotics (SGAs), starting with risperidone in July 2008, could reduce antipsychotic spending and cost-related use barriers. This study examines associations between generic risperidone use and spending and adherence after introduction among Medicare Advantage (MA) beneficiaries. STUDY DESIGN: Historic cohort study. METHODS: The study included MA beneficiaries receiving SGA treatment prior to July 2008. We examined antipsychotic spending using linear models, adherence (proportion of days covered ≥ 80%) using logistic models, and nonpersistence (time to first gap in antipsychotic use > 30 days) in 2009 using Cox proportional hazard models, comparing beneficiaries with versus without generic use, adjusting for individual and plan characteristics. RESULTS: Between July 2008 and December 2009, 22.8% of beneficiaries had ≥ 1 fill of generic risperidone: 73% of those previously using branded risperidone and 6.7% of those previously using other SGAs. Beneficiaries in private fee-for-service (FFS) versus health maintenance organization (HMO) plans had lower rates of generic use (hazard ratio [HR], 0.73 [95% CI, 0.56-0.96]); however, cost-sharing levels were not associated with generic use. Compared with beneficiaries who continued using other SGAs, those who switched from other SGAs to generic risperidone in 2008 had lower out-of-pocket spending (-$214; 95% CI, -$314 to -$115), higher adherence (odds ratio, 2.34; 95% CI, 1.62-3.40) and lower rates of nonpersistence (HR, 0.56; 95% CI, 0.46-0.69) in 2009. CONCLUSIONS: Generic use was concentrated among patients previously using branded risperidone. HMO plans appeared to be more effective at encouraging generic use than unmanaged private FFS plans; however, patient financial incentives had limited influence on switching. Additional opportunity remains to encourage greater generic SGA use, reduce spending, and potentially improve treatment adherence and outcomes.

Patient perceptions of physical health and bipolar symptoms: The intersection of mental and physical health.

BACKGROUND: Affective symptoms and medical comorbidities have a negative impact on the course of bipolar disorder. The aim of this analysis was to examine how the perceptions of physical health and functioning in individuals with bipolar disorder relate to their mood symptoms. METHODS: We analyzed longitudinal data from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) on the physical subscales of the Short Form Health Survey (SF-36) (physical functioning, role limitations due to physical problems, bodily pain, and general health). RESULTS: Participants' perception of their overall physical health predicted severity of mania/hypomania, depression, and life satisfaction at concurrent and future visits. Perceptions of role limitations due to physical health problems predicted depressive symptoms and poor life satisfaction. Worse bodily pain predicted symptoms of mania/hypomania. Reports of specific or concrete physical limitations in daily life showed no associations with psychiatric symptoms at concurrent assessments, but did predict worse course of illness one year later. SF-36 scores showed significant, but small associations with the presence of medical comorbidities. LIMITATIONS: Perceptions of physical health and quality of life were self-report, potentially lending themselves to transient negative biases, particularly among depressed participants. Additionally, the SF-36 was selected as a generic, widely used measure; as a result, it was not specific to the illness burden of bipolar disorder. CONCLUSION: Overall, broad perceptions of poor physical health were associated with worse course of illness over the 24 months of the study. Though further research is warranted, changes in subjective physical health related quality of life, even independent of objective health changes, may offer important insight into global wellbeing and be targets of psychotherapy treatment.

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.

Adverse clinical events among medicare beneficiaries using antipsychotic drugs: linking health insurance benefits and clinical needs.

OBJECTIVE: Medicare Part D provides formulary protections for antipsychotics but does not exempt these drugs from cost-sharing. We investigated the impact of Part D coverage on antipsychotic drug spending, adherence, and clinical outcomes among beneficiaries with varying indications for use. METHODS: We conducted a historical cohort study of Medicare Advantage beneficiaries who received antipsychotic drugs, with diagnoses of schizophrenia or bipolar disorder or with no mental health diagnoses (N=10,190). Half had a coverage gap; half had no gap because of low-income subsidies. Using fixed effects regression models, we examined changes in spending and adherence as beneficiaries experienced cost-sharing increases after reaching the gap. We examined changes in hospitalizations and emergency department visits using proportional hazard models. RESULTS: Across all diagnostic groups, total monthly expenditure on antipsychotic drugs decreased with cost-sharing increases in the gap compared with those with no gap (eg, schizophrenia: -$123 95% confidence interval [-$138, -$108]), and out-of-pocket spending increased (eg, schizophrenia: $104 [$98, $110]). Adherence similarly decreased, with the largest declines among those with schizophrenia (-20.6 percentage points [-22.3, -18.9] in proportion of days covered). Among beneficiaries with schizophrenia and bipolar disorder, hospitalizations and emergency department visit rates increased with cost-sharing increases (eg, schizophrenia: hazard ratio=1.32 [1.06, 1.65] for all hospitalizations), but did not among subjects without mental health diagnoses. Clinical event rates did not change among beneficiaries with low-income subsidies without gaps. CONCLUSIONS: There is evidence of interruptions in antipsychotic use attributable to Part D cost-sharing. Adverse events increased among beneficiaries with approved indications for use, but not among beneficiaries without such indications.

Association between therapeutic alliance, care satisfaction, and pharmacological adherence in bipolar disorder.

OBJECTIVES: We sought to understand the association of specific aspects of care satisfaction, such as patients' perceived relationship with their psychiatrist and access to their psychiatrist and staff, and therapeutic alliance with participants' likelihood to adhere to their medication regimens among patients with bipolar disorder. METHODS: We examined data from the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder, an effectiveness study investigating the course and treatment of bipolar disorder. We expected that participants (n = 3037) with positive perceptions of their relationship with their psychiatrist and quality of psychopharmacologic care, as assessed by the Helping Alliance Questionnaire and Care Satisfaction Questionnaire, would be associated with better medication adherence. We utilized logistic regression models controlling for already established factors associated with poor adherence. RESULTS: Patients' perceptions of collaboration, empathy, and accessibility were significantly associated with adherence to treatment in individuals with bipolar disorder completing at least 1 assessment. Patients' perceptions of their psychiatrists' experience, as well as of their degree of discussing medication risks and benefits, were not associated with medication adherence. CONCLUSIONS: Patients' perceived therapeutic alliance and treatment environment impact their adherence to pharmacotherapy recommendations. This study may enable psychopharmacologists' practices to be structured to maximize features associated with greater medication adherence.

Effect of antidepressant medication treatment on suicidal ideation and behavior in a randomized trial: an exploratory report from the Combining Medications to Enhance Depression Outcomes Study.

OBJECTIVE: To explore relationships between baseline sociodemographic and clinical features and baseline suicidal ideation, and treatment effects on suicidal ideation and behavior, in depressed outpatients. METHOD: From March 2008 to September 2009, the Combining Medications to Enhance Depression Outcomes study, a single-blind, 7-month randomized trial, enrolled outpatients with nonpsychotic chronic and/or recurrent major depressive disorder (DSM-IV-TR criteria) in primary and psychiatric care (N = 665). Participants received escitalopram plus placebo, bupropion sustained release (SR) plus escitalopram, or venlafaxine extended release (XR) plus mirtazapine. The primary outcome measure for this report is presence of suicidal ideation assessed by the Concise Health Risk Tracking Self-Report, which measures suicidal ideation and behaviors over the last 24 hours. Sociodemographic and clinical features were compared in those with versus without baseline ideation. At 4, 12, and 28 weeks, treatment effects on suicidality were assessed, and unadjusted and adjusted outcomes were compared among those with and without baseline ideation using linear, logistic, ordinal logistic, and negative binomial regression models. RESULTS: Baseline suicidal ideation was associated with greater depressive severity, childhood neglect, childhood abuse, early major depressive disorder onset, greater psychiatric comorbidity, and worse functioning and quality of life. After adjustment for treatment, gender, age at first depressive episode, obsessive-compulsive symptoms, and depressive severity, depressive symptom outcomes did not differ between ideation groups at 12 or 28 weeks or between treatments. Overall, 79% of participants with baseline suicidal ideation had none at week 4, 83% had none at week 12, and 86% had none at week 28. All treatments reduced ideation, with bupropion-SR plus escitalopram the most effective at week 12 (P < .01). In participants without baseline ideation, emergent ideation did not differ between treatments: 2.5% had ideation at 4 weeks, 1.3% had ideation at 12 weeks, and only 1.7% had ideation at 28 weeks. Four patients (all receiving venlafaxine-XR plus mirtazapine) attempted suicide (P = .0162). CONCLUSION: Baseline ideation did not affect depressive symptom outcome. Bupropion-SR plus escitalopram most effectively reduced ideation. Ideation emergence was uncommon. Venlafaxine-XR plus mirtazapine may pose a higher risk of suicide attempts. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00590863.

Development of an integrated psychosocial treatment to address the medical burden associated with bipolar disorder.

We developed an integrated psychosocial treatment for bipolar disorder to decrease the disproportionate medical burden associated with this illness. Three treatment modules, Nutrition/weight loss, Exercise, and Wellness Treatment (NEW Tx) were administered in twelve 60-minute group sessions over 14 weeks. After the first group (N=4) had completed the treatment, it was revised, and then a second group (N=6) completed the revised treatment. Participants completed all of the study assessments and attended 82% of the sessions. Both groups added over 100 minutes of weekly exercise to their baseline duration. Participants in the second group showed improvements in their quality of life, depressive symptoms, and weight. It appears that NEW Tx may be a feasible intervention with promising pilot data for reducing the medical burden in bipolar disorder, but future research is needed to further evaluate the efficacy of NEW Tx.

A critical review of pharmacotherapy for major depressive disorder.

Newer generation antidepressant drugs, with improvements in safety and tolerability, have replaced tricyclic antidepressants as first-line treatment of depressive illness. However, no single antidepressant drug from any class has distinguished itself as the obvious first-line treatment of major depression. The choice of therapy is driven primarily by patient choice, with informed consent for the risks of adverse effects. Cost has become an additional factor in this decision as several of the newer antidepressant drugs are now available in generic form. Several augmentation and drug-switching strategies have demonstrated benefit in refractory illness. While no single strategy distinguished itself as superior to the others, some have been more rigorously tested. Ongoing efforts at improving effectiveness, time to response, and tolerability have led to novel drug therapies. Efforts at characterizing predictors of treatment outcomes now include pharmacogenetic studies.

Health-related quality of life in depression: a STAR*D report.

BACKGROUND: Although major depressive disorder (MDD) is associated with significant impairments in health-related quality of life (HRQOL), few studies have evaluated HRQOL dysfunction in multiple domains. This report examined the psychological, physical, and social domains in a large sample of outpatients who entered the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHODS: The relationship of HRQOL and baseline sociodemographic and clinical features, including depressive severity, was evaluated. We assessed HRQOL with the 12-item Short Form Health Survey, the 5-item Work and Social Adjustment Scale, and the 16-item Quality of Life Enjoyment and Satisfaction Questionnaire. RESULTS: Among 2307 participants, greater depressive symptom severity was associated with poorer HRQOL. After controlling for age and depression severity, lower HRQOL was related independently to being African American or Hispanic, less educated, unemployed, divorced or separated, having public medical insurance, and to having more general medical disorders. We found impairments across all 3 domains, with low correlations between the 3 measures of HRQOL chosen, suggesting that they evaluate different and nonoverlapping aspects of function. CONCLUSION: Sociodemographically disadvantaged patients with greater general medical and depressive illness burden are at greatest risk for poorer quality of life. Distinct impairments are seen in the 3 domains of HRQOL.

Integrating statistical and clinical research elements in intervention-related grant applications: summary from an NIMH workshop.

OBJECTIVE: The authors summarize points for consideration generated in a National Institute of Mental Health (NIMH) workshop convened to provide an opportunity for reviewers from different disciplines-specifically clinical researchers and statisticians-to discuss how their differing and complementary expertise can be well integrated in the review of intervention-related grant applications. METHODS: A 1-day workshop was convened in October, 2004. The workshop featured panel presentations on key topics followed by interactive discussion. This article summarizes the workshop and subsequent discussions, which centered on topics including weighting the statistics/data analysis elements of an application in the assessment of the application's overall merit; the level of statistical sophistication appropriate to different stages of research and for different funding mechanisms; some key considerations in the design and analysis portions of applications; appropriate statistical methods for addressing essential questions posed by an application; and the role of the statistician in the application's development, study conduct, and interpretation and dissemination of results. RESULTS: A number of key elements crucial to the construction and review of grant applications were identified. It was acknowledged that intervention-related studies unavoidably involve trade-offs. Reviewers are helped when applications acknowledge such trade-offs and provide good rationale for their choices. Clear linkage among the design, aims, hypotheses, and data analysis plan and avoidance of disconnections among these elements also strengthens applications. CONCLUSION: The authors identify multiple points to consider when constructing intervention-related grant applications. The points are presented here as questions and do not reflect institute policy or comprise a list of best practices, but rather represent points for consideration.