Psychometric Evaluation of the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire in a General Youth Population.

Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire is a brief 15-item self-report measure of quality of life and life satisfaction originally developed for clinical populations (6 to 17 years old). The current paper examines the initial factor structure proposed by the developers and underlying psychometric properties of the measure in a non-clinical population of teens. A cross-sectional adolescent sample (N = 3222) completed self-report measures as part of mental health promotion program. A confirmatory factor analysis was conducted with construct validity analyses. The original factor structure was replicated with strong internal consistency (Cronbach α = .912). Strong construct validity (e.g. resilience, well-being, depression, and anxiety) was found. Minimal differences were found based on gender, race, and ethnicity. PQ-LES-Q has strong, replicable psychometric properties, which makes it a generally reliable and valid assessment tool to evaluate the quality of life and life satisfaction in adolescents.

Drug repurposing for opioid use disorders: integration of computational prediction, clinical corroboration, and mechanism of action analyses.

Morbidity and mortality from opioid use disorders (OUD) and other substance use disorders (SUD) is a major public health crisis, yet there are few medications to treat them. There is an urgency to accelerate SUD medication development. We present an integrated drug repurposing strategy that combines computational prediction, clinical corroboration using electronic health records (EHRs) of over 72.9 million patients and mechanisms of action analysis. Among top-ranked repurposed candidate drugs, tramadol, olanzapine, mirtazapine, bupropion, and atomoxetine were associated with increased odds of OUD remission (adjusted odds ratio: 1.51 [1.38-1.66], 1.90 [1.66-2.18], 1.38 [1.31-1.46], 1.37 [1.29-1.46], 1.48 [1.25-1.76], p value < 0.001, respectively). Genetic and functional analyses showed these five candidate drugs directly target multiple OUD-associated genes including BDNF, CYP2D6, OPRD1, OPRK1, OPRM1, HTR1B, POMC, SLC6A4 and OUD-associated pathways, including opioid signaling, G-protein activation, serotonin receptors, and GPCR signaling. In summary, we developed an integrated drug repurposing approach and identified five repurposed candidate drugs that might be of value for treating OUD patients, including those suffering from comorbid conditions.

Prediction of short-term antidepressant response using probabilistic graphical models with replication across multiple drugs and treatment settings.

Heterogeneity in the clinical presentation of major depressive disorder and response to antidepressants limits clinicians' ability to accurately predict a specific patient's eventual response to therapy. Validated depressive symptom profiles may be an important tool for identifying poor outcomes early in the course of treatment. To derive these symptom profiles, we first examined data from 947 depressed subjects treated with selective serotonin reuptake inhibitors (SSRIs) to delineate the heterogeneity of antidepressant response using probabilistic graphical models (PGMs). We then used unsupervised machine learning to identify specific depressive symptoms and thresholds of improvement that were predictive of antidepressant response by 4 weeks for a patient to achieve remission, response, or nonresponse by 8 weeks. Four depressive symptoms (depressed mood, guilt feelings and delusion, work and activities and psychic anxiety) and specific thresholds of change in each at 4 weeks predicted eventual outcome at 8 weeks to SSRI therapy with an average accuracy of 77% (p = 5.5E-08). The same four symptoms and prognostic thresholds derived from patients treated with SSRIs correctly predicted outcomes in 72% (p = 1.25E-05) of 1996 patients treated with other antidepressants in both inpatient and outpatient settings in independent publicly-available datasets. These predictive accuracies were higher than the accuracy of 53% for predicting SSRI response achieved using approaches that (i) incorporated only baseline clinical and sociodemographic factors, or (ii) used 4-week nonresponse status to predict likely outcomes at 8 weeks. The present findings suggest that PGMs providing interpretable predictions have the potential to enhance clinical treatment of depression and reduce the time burden associated with trials of ineffective antidepressants. Prospective trials examining this approach are forthcoming.

The symptom-specific efficacy of antidepressant medication vs. cognitive behavioral therapy in the treatment of depression: results from an individual patient data meta-analysis.

A recent individual patient data meta-analysis showed that antidepressant medication is slightly more efficacious than cognitive behavioral therapy (CBT) in reducing overall depression severity in patients with a DSM-defined depressive disorder. We used an update of that dataset, based on seventeen randomized clinical trials, to examine the comparative efficacy of antidepressant medication vs. CBT in more detail by focusing on individual depressive symptoms as assessed with the 17-item Hamilton Rating Scale for Depression. Five symptoms (i.e., "depressed mood" , "feelings of guilt" , "suicidal thoughts" , "psychic anxiety" and "general somatic symptoms") showed larger improvements in the medication compared to the CBT condition (effect sizes ranging from .13 to .16), whereas no differences were found for the twelve other symptoms. In addition, network estimation techniques revealed that all effects, except that on "depressed mood" , were direct and could not be explained by any of the other direct or indirect treatment effects. Exploratory analyses showed that information about the symptom-specific efficacy could help in identifying those patients who, based on their pre-treatment symptomatology, are likely to benefit more from antidepressant medication than from CBT (effect size of .30) versus those for whom both treatments are likely to be equally efficacious. Overall, our symptom-oriented approach results in a more thorough evaluation of the efficacy of antidepressant medication over CBT and shows potential in "precision psychiatry" .

Clinical Implications of the STAR*D Trial.

This chapter provides a synopsis of the clinically relevant findings derived from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and selected ancillary studies appended to the primary trial. The chapter describes the participants, their recruitment and treatment, and the study design, primary outcomes, and clinically informative results. In particular, the chapter describes acute phase response and remission rates from each of the five treatment steps which entail antidepressant monotherapies and combinations, and psychotherapy alone or in combination with an antidepressant. In addition, longer-term outcomes beyond the 12 week acute trial are described for each treatment step. The treatment challenges described include patient retention and relapse, and longer-term follow-up. The chapter discusses the use of measurement-based care for delivering high-quality care, describes "treatment-resistant" depression and discusses its implications for clinical practice, and discusses the contributions of STAR*D to patient-oriented research and patient care.

Toward a very brief self-report to assess the core symptoms of depression (VQIDS-SR5 ).

OBJECTIVE: To develop a short, 5-item measure of the core symptoms of depression based on the 16-item Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR16 ) and to evaluate psychometric properties of this new measure (Very Quick Inventory of Depressive Symptomatology - Self-Report: VQIDS-SR5 ). METHOD: Using data from a convenience sample of the Combining Medications to Enhance Depression Outcomes (CO-MED) trial, we evaluated the psychometric properties of the VQIDS-SR5 , its sensitivity to change, and its comparability to the QIDS-SR16 and clinician-rated scales (QIDS-C16 and VQIDS-C5 ). RESULTS: The VQIDS-SR5 has a single-factor structure with an acceptable internal consistency (Cronbach's alpha: 0.67-0.81). The VQIDS-SR5 was as sensitive to change as its parent scale, then QIDS-SR16 and, detected change at an earlier time frame. Additionally, the VQIDS-SR5 was comparable to the QIDS-SR16 , QIDS-C16 , and VQIDS-C5 . CONCLUSION: The VQIDS-SR5 can effectively evaluate the core symptoms of depression during the course of treatment.

Impairment and distress patterns distinguishing the melancholic depression subtype: an iSPOT-D report.

BACKGROUND: This study seeks to provide a comprehensive and systematic evaluation of baseline clinical and psychological features and treatment response characteristics that differentiate Major Depressive Disorder (MDD) outpatients with and without melancholic features. Reflecting the emphasis in DSM-5, we also include impairment and distress. METHODS: Participants were assessed pre-treatment on clinical features (severity, risk factors, comorbid conditions, illness course), psychological profile (personality, emotion regulation), functional capacity (social and occupational function, quality of life) and distress/coping (negativity bias, emotional resilience, social skills, satisfaction with life). Participants were randomized to sertraline, escitalopram or venlafaxine extended-release and re-assessed post-treatment at 8 weeks regarding remission, response, and change in impairment and distress. RESULTS: Patients with melancholic features (n=339; 33.7%) were distinguished clinically from non-melancholics by more severe depressive symptoms and greater exposure to abuse in childhood. Psychologically, melancholic patients were defined by introversion, and a greater use of suppression to regulate negative emotion. Melancholics also had poorer capacity for social and occupational function, and physical and psychological quality of life, along with poorer coping, reflected in less emotional resilience and capacity for social skills. Post-treatment, melancholic patients had lower remission and response, but some of this effect was due to the more severe symptoms pre-treatment. The distress/coping outcome measure of capacity for social skills remained significantly lower for melancholic participants. LIMITATIONS: Due to the cross-sectional nature of this study, causal pathways cannot be concluded. CONCLUSIONS: Findings provide new insights into a melancholic profile of reduced ability to function interpersonally or effectively deal with one׳s emotions. This distinctly poorer capacity for social skills remained post-treatment. The pre-treatment profile may account for some of the difficulty in achieving remission or response with treatment.

Do atypical features affect outcome in depressed outpatients treated with citalopram?

Depressed patients with atypical features have an earlier onset of depression, a more chronic course of illness, several distinctive biological and familial features, and a different treatment response than those without atypical features. The efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) have not been fully evaluated in depression with atypical features. This report evaluates data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study to determine whether depressed outpatients with and without atypical features respond differently to the SSRI citalopram. Treatment-seeking participants with non-psychotic major depressive disorder were recruited from primary- and psychiatric-care settings. The presence/absence of atypical features was approximated using baseline ratings on the 30-item Inventory of Depressive Symptomatology - Clinician-rated. Following baseline assessments, participants received citalopram up to 60 mg/d for up to 14 wk. Baseline sociodemographic and clinical characteristics, and treatment outcomes, were compared between participants with and without atypical features. Of the 2876 evaluable STAR*D participants, 541 (19%) had atypical features. Participants with atypical features were significantly more likely to be female, younger, unemployed, have greater physical impairment, a younger age of depression onset, a longer index episode, greater depressive severity, and more concurrent anxiety diagnoses. Those with atypical features had significantly lower remission rates, although this difference was no longer present after adjustment for baseline differences. Depressed patients with atypical features are less likely to remit with citalopram than those without atypical features. This finding is probably due to differences in baseline characteristics other than atypical symptom features.

Genome-wide association study of suicidal ideation emerging during citalopram treatment of depressed outpatients.

OBJECTIVES: Suicidal ideation is an uncommon but worrisome symptom than can emerge during antidepressant treatment. We have described earlier the association between treatment-emergent suicidal ideation (TESI) and markers in genes encoding glutamate receptor subunits GRIK2 and GRIA3. The present genome-wide association study was conducted to identify additional genetic markers associated with TESI that may help identify individuals at high risk who may benefit from closer monitoring, alternative treatments, and/or specialty care. METHODS: A clinically representative cohort of outpatients with nonpsychotic major depressive disorder enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were treated with citalopram under a standard protocol for up to 14 weeks. DNA samples from 90 White participants who developed TESI and a sex-matched and race-matched equal number of treated participants who denied any suicidal ideas were genotyped with 109 365 single nucleotide polymorphisms on the Illumina's Human-1 BeadChip. RESULTS: One marker was found to be associated with TESI in this sample at the experiment-wide adjusted P less than 0.05 level (marker rs11628713, allelic P = 6.2x10, odds ratio = 4.7, permutation P = 0.01). A second marker was associated at the experiment-wide adjusted P = 0.06 level (rs10903034, allelic P = 3.02x10, odds ratio = 2.7, permutation P = 0.06). These markers reside within the genes PAPLN and IL28RA, respectively. PAPLN encodes papilin, a protoglycan-like sulfated glycoprotein. IL28RA encodes an interleukin receptor. CONCLUSION: Together with our earlier report, these findings may shed light on the biological basis of TESI and may help identify patients at increased risk of this potentially serious adverse event.

A randomized, double-blind, placebo-controlled pilot study of naltrexone in outpatients with bipolar disorder and alcohol dependence.

BACKGROUND: Alcohol dependence is extremely common in patients with bipolar disorder and is associated with unfavorable outcomes including treatment nonadherence, violence, increased hospitalization, and decreased quality of life. While naltrexone is a standard treatment for alcohol dependence, no controlled trials have examined its use in patients with co-morbid bipolar disorder and alcohol dependence. In this pilot study, the efficacy of naltrexone in reducing alcohol use and on mood symptoms was assessed in bipolar disorder and alcohol dependence. METHODS: Fifty adult outpatients with bipolar I or II disorders and current alcohol dependence with active alcohol use were randomized to 12 weeks of naltrexone (50 mg/d) add-on therapy or placebo. Both groups received manual-driven cognitive behavioral therapy designed for patients with bipolar disorder and substance-use disorders. Drinking days and heavy drinking days, alcohol craving, liver enzymes, and manic and depressed mood symptoms were assessed. RESULTS: The 2 groups were similar in baseline and demographic characteristics. Naltrexone showed trends (p < 0.10) toward a greater decrease in drinking days (binary outcome), alcohol craving, and some liver enzyme levels than placebo. Side effects were similar in the 2 groups. Response to naltrexone was significantly related to medication adherence. CONCLUSIONS: Results suggest the potential value and acceptable tolerability of naltrexone for alcohol dependence in bipolar disorder patients. A larger trial is needed to establish efficacy.

Sex differences in response to citalopram: a STAR*D report.

OBJECTIVE: Controversy exists as to whether women with depression respond better to selective serotonin reuptake inhibitors (SSRIs) than men. The purpose of this report was to determine whether men and women differ in their responses to treatment with the SSRI citalopram using a large sample of real world patients from primary and psychiatric specialty care settings. METHOD: As part of the sequenced treatment alternatives to relieve depression (STAR *D) study, 2876 participants were treated with citalopram for up to 12-14 weeks. Baseline demographic and clinical characteristics and outcomes were gathered and compared between men and women. RESULTS: At baseline, women were younger, had more severe depressive symptoms and were more likely to have: early onset; previous suicide attempt(s); a family history of depression, alcohol abuse or drug abuse; atypical symptom features; and one or more of several concurrent psychiatric disorders. Despite greater baseline severity and more Axis I comorbidities, women were more likely to reach remission and response with citalopram than men. CONCLUSIONS: Women have a better response to the SSRI citalopram than men, which may be due to sex-specific biological differences particularly in serotonergic systems.

Clinical features of depression in outpatients with and without co-occurring general medical conditions in STAR*D: confirmatory analysis.

BACKGROUND: Concurrent medical comorbidity influences the accurate diagnosis and treatment of major depressive disorder (MDD). OBJECTIVE: The objective of this study was to validate previous findings from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study using a confirmation analysis in a previously unanalyzed cohort. DESIGN: Baseline cross-sectional case-control study of patients enrolling in a prospective randomized multistage treatment study of nonpsychotic MDD. SETTING: Fourteen regional U.S. centers representing 18 primary care and 23 psychiatric practices. PARTICIPANTS: 2541 outpatients with DSM-IV nonpsychotic MDD. MEASUREMENTS: Sociodemographic status, medical illness ratings, psychiatric status, quality of life, and DSM-IV depression symptom ratings. RESULTS: The prevalence of significant general medical comorbidity in this population was 50.0% (95% CI = 48.1% to 52.0%), consistent with findings reported for the first cohort. Concurrent significant medical comorbidity was associated with older age, lower income, unemployment, limited education, and longer duration of index depressive episode. The group with significant medical comorbidity reported higher rates of somatic symptoms, gastrointestinal symptoms, sympathetic arousal, and leaden paralysis. These results were generally consistent between the 2 cohorts from STAR*D. CONCLUSIONS: Major depressive disorder with concurrent general medical conditions is associated with a specific sociodemographic profile and pattern of depressive symptoms. This association has implications for diagnosis and clinical care.

Clinical and demographic factors associated with DSM-IV melancholic depression.

BACKGROUND: The purpose of this paper is to use demographic and clinical data from a large diverse group of outpatients diagnosed with non-psychotic major depression to investigate the validity of the DSM-IV concept of melancholic depression. METHODS: Baseline clinical and demographic data were collected on 1500 outpatients (1456 of whom melancholia could be determined) with non-psychotic major depressive disorder (MDD) participating in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Depressive symptom severity was assessed by clinical telephone interview using the 17-item Hamilton Rating Scale for Depression (HRS-D17) and the 30-item Inventory of Depressive Symptomatology (IDS-C30). The types and degrees of concurrent psychiatric symptoms were measured using a self report, the Psychiatric Diagnostic Screening Questionnaire (PDSQ), by recording the number of items relevant to each diagnostic category endorsed by study participants. RESULTS: Adjusting for severity of depression (as measured by the total HRS-D17 scores), no differences were found in the rate of melancholic depression by race, marital status, education, employment status, family history of depression, primary care versus specialty care, monthly income, and degree of psychiatric and medical co-morbidity. Melancholic depression was significantly more likely in men than women. Melancholic depression after adjustment for severity was associated with a slightly younger age at study entry, as well as with greater illness severity, and slightly shorter duration of current episode. Hispanic ethnicity was associated with lower melancholic depression rates at the .06 level of significance. CONCLUSIONS: Among outpatients with MDD, melancholic features were less likely in Hispanic patients, but more likely in slightly younger patients and in men. Melancholic features were also related to a slightly shorter current episode. These findings are consistent with the notion that external socio-demographic factors do not play an important role in the pathophysiology of melancholic depression.

Psychiatric emergency service use after implementation of managed care in a public mental health system.

OBJECTIVE: This study examined whether implementation of managed care in a public mental health system affected return visits to psychiatric emergency services within 180 days of an index visit. METHODS: Data were taken from an administrative database of 75,815 patient visits made to a hospital-based psychiatric emergency service for mental health care between January 1, 1995, and December 31, 2002. Rates of return visits for patients whose index visit occurred at least 26 weeks before a system of managed care was implemented in 1999 were compared with rates for patients whose index visit occurred after the implementation but at least 26 weeks before the data collection period ended. Declining-effects modeling was used to adjust for patients' gender, ethnicity, age, and admission status. RESULTS: A total of 37,371 patients met study criteria for inclusion: 21,135 before managed care was implemented and 16,236 after managed care was implemented. In the pre-managed care group, 3,687 patients (17 percent) made a repeat visit within 26 weeks of their index visit; 2,369 patients (15 percent) in the post-managed care group made such a repeat visit. For any given index visit to the psychiatric emergency department, patients who presented for treatment after managed care were only 90 percent as likely as patients who presented before managed care to have a return visit within the first five weeks after the index visit. However, there was essentially no difference between groups in the likelihood of a return visit by week 26 after the index visit, suggesting that managed care delayed, but did not eliminate, return visits. In addition, the number of police-accompanied index visits continued to rise after managed care was implemented (from 32.0 to 52.6 percent of all index visits), suggesting that increasing numbers of patients with mental illness in need of treatment were coming to the attention of law enforcement officials after managed care was implemented. CONCLUSIONS: Managed care strategies are often used to reduce reliance on emergency services. In this study, managed care delayed, rather than prevented, return visits to the psychiatric emergency service.

What moderator characteristics are associated with better prognosis for depression?

A retrospective data analysis was conducted to evaluate the usefulness of baseline characteristics in predicting treatment response to antidepressant medication in 97 outpatients with nonpsychotic major depression treated for up to sixteen weeks with nefazodone. Baseline demographics (gender), illness features (symptom severity, length of illness, length of current episode, number of episodes, age of onset, longitudinal subtype, endogenicity, melancholia, family history of mood disorders), and social features (living status) were evaluated. Response to treatment was defined as a >/= 50% reduction in the 17-item Hamilton Rating Scale for Depression (HRSD(17)) score. The results of a survival analysis indicated that patients with shorter histories of illness (< 4 years), a negative family history of depression, and those who were either married or were living with someone were more likely to have a positive outcome during the acute phase treatment of depression. The main findings are consistent with extensive previous literature indicating a better short-term outcome of depression where illness is shorter, where there is no family history, and where there is better social support.

Development of a computerized assessment of clinician adherence to a treatment guideline for patients with bipolar disorder.

The adoption of treatment guidelines for complex psychiatric illness is increasing. Treatment decisions in psychiatry depend on a number of variables, including severity of symptoms, past treatment history, patient preferences, medication tolerability, and clinical response. While patient outcomes may be improved by the use of treatment guidelines, there is no agreed upon standard by which to assess the degree to which clinician behavior corresponds to those recommendations. This report presents a method to assess clinician adherence to the complex multidimensional treatment guideline for bipolar disorder utilized in the Texas Medication Algorithm Project. The steps involved in the development of this system are presented, including the reliance on standardized documentation, defining core variables of interest, selecting criteria for operationalization of those variables, and computerization of the assessment of adherence. The computerized assessment represents an improvement over other assessment methods, which have relied on laborious and costly chart reviews to extract clinical information and to analyze provider behavior. However, it is limited by the specificity of decisions that guided the adherence scoring process. Preliminary findings using this system with 2035 clinical visits conducted for the bipolar disorder module of TMAP Phase 3 are presented. These data indicate that this system of guideline adherence monitoring is feasible.