Doctors have a variety of drug options for treatment of depression. But there is currently no way to determine which antidepressant will work best for a given patient, which means that many people continue to suffer while their doctors try a series of medications. As Marisa Toups and Madhukar H. Trivedi write, however, many researchers have focused their efforts on developing biomarkers for depression—tests for aspects of a patient’s physiology that can predict a clinical outcome. In the future, doctors may be able to screen patients to determine which treatment options will work for them, reducing the time a patient must continue to live with the effects of depression.
Despite years of antidepressant drug development and patient and provider education, suboptimal medication dosing and duration of exposure resulting in incomplete remission of symptoms remains the norm in the treatment of depression. Additionally, since no one treatment is effective for all patients, optimal implementation focusing on the measurement of symptoms, side effects, and function is essential to determine effective sequential treatment approaches. There is a need for a paradigm shift in how clinical decision making is incorporated into clinical practice and for a move away from the trial-and-error approach that currently determines the “next best” treatment. This paper describes how our experience with the Texas Medication Algorithm Project (TMAP) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial has confirmed the need for easy-to-use clinical support systems to ensure fidelity to guidelines. To further enhance guideline fidelity, we have developed an electronic decision support system that provides critical feedback and guidance at the point of patient care. We believe that a measurement-based care (MBC) approach is essential to any decision support system, allowing physicians to individualize and adapt decisions about patient care based on symptom progress, tolerability of medication, and dose optimization. We also believe that successful integration of sequential algorithms with MBC into real-world clinics will facilitate change that will endure and improve patient outcomes. Although we use major depression to illustrate our approach, the issues addressed are applicable to other chronic psychiatric conditions including comorbid depression and substance use disorder as well as other medical illnesses.
Measurement-Based Care; Decision Support Systems; Adaptive Treatment Strategies; Depression
The objective of this manuscript is to report associations between baseline depressive severity and (1) baseline sociodemographic and clinical characteristics, (2) treatment outcomes, and (3) differential outcomes for three treatment groups. Six hundred and sixty-five outpatients with nonpsychotic, major depressive disorder were prospectively randomized to treatment with either a selective serotonin reuptake inhibitor (SSRI) monotherapy (escitalopram plus placebo) or one of two antidepressant medication combinations (bupropion-sustained release plus escitalopram, or venlafaxine-extended release plus mirtazapine). For purposes of these analyses, participants were divided into four groups based on baseline severity by the 16-item Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR16) total score: mild (0–10) [N=81], moderate (11–15) [N=238], severe (16–20) [N=260] and very severe (21–27) [N=67]. Treatment outcomes at 12 and 28 weeks were compared among the four severity groups. A history of childhood neglect and/or abuse was strongly associated with the severity of adult depression (1/2 of participants in the very severy group versus 1/5–1/4 of those in the mild group reported abuse and/or neglect). The degree of suicidality (e.g., 15/.4% of the very severe group ever attempted suicide versus none in the mild group), the number of suicide attempts (e.g., mean of .41 +/− 1.99 suicide attempts in the severe group versus o.o +/−0.0 in the mild group) and severity of suicidality (e.g., 9.2% of participants in very severe group had a plan or made a gesture versus 5.6% in moderate group and none in the mild group) were increased in more severe groups. Participants with a greater baseline depressive severity reported significantly more psychiatric comorbitities (e..g. [at p < 0.05] increased rates of agoraphobia, bulimia, generalized anxiety, hypocondriasis, panic disorder, post-traumatic stress disorder, social phobia and somatoform disorder, with 23.9 % of participants in the very severe group having reported four or more psychiatric disorders versus 1.2% of the mild group). Combination medication treatments were no more effective in treating severe depressions than was SSRI monotherapy. Remission (61.7% of participants in the mild group achieved remission versus 28.4% in the very severe group) is more difficult to achieve in more severe groups than is response (48.8% of participants in the mild group achieved response versus 58.2% in the very severe group) (p < 0.03) . These data may help us to understand the impact of baseline features on antidepressant medication effectiveness and to inform the personalization of depression treatment across the spectrum of depressive severity.
Depression; abuse; suicide; combination treatment severity; response; remission
The co-occurrence of substance use disorder (SUD) and major depressive disorder (MDD) is common and is often thought to impair response to antidepressant therapy. These patients are often excluded from clinical trials, resulting in a significant knowledge gap regarding optimal pharmacotherapy for the treatment of MDD with concurrent SUD.
In the Combining Medications to Enhance Depression Outcomes study, 665 adult outpatients with chronic and/or recurrent MDD were prospectively treated with either escitalopram monotherapy (escitalopram and placebo) or an antidepressant combination (venalfaxine-XR and mirtazapine or escitalopram and bupropion-SR). Participants with MDD and concurrent SUD (13.1%) were compared to those without SUD (86.9%) on sociodemographic and clinical characteristics at baseline and treatment response at 12-week and 28-week endpoints.
The participants with MDD and SUD were more likely to be male and have current suicidal thoughts/plans, and had a greater lifetime severity and number of suicide attempts, and a higher number of concurrent Axis I disorders, particularly concurrent anxiety disorders. There were no significant differences between the MDD with or without SUD groups in terms of dose, time in treatment, response or remission at week 12 and 28. Furthermore, no significant differences in response or remission rates were noted between groups on the basis of the presence or absence of SUD and treatment assignment.
Although significant baseline sociodemographic and clinical differences exist, patients with MDD and concurrent SUD are as likely to respond and remit to a single or combination antidepressant treatment as those presenting without SUD.
major depressive disorder; substance use disorder; dual diagnosis; combination antidepressants; treatment outcome
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 (HRSD17) 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.
antidepressant; treatment predictor; social support; major depression
Although the selection of appropriate clinical sites has a significant impact on the successful conduct of clinical trials, no generally accepted model is available for site selection. Use of an appropriate site selection process is even more pertinent when conducting large scale, practical clinical trials in practice settings.
This report provides a rationale for selecting sites by identifying both a set of basic site selection criteria important to most trials as well as criteria specific to the features of a particular study’s design. In this two-tier system, although all these criteria must be met, some criteria are firm and viewed as essential for a site to conduct the trial. Other criteria, such as those that support study recruitment or participant retention, are flexible. These flexible criteria may be addressed through several alternative solutions that meet the original intent of the criterion.
We illustrate how the study specific features and requirements of Stimulant Reduction Intervention using Dosed Exercise (STRIDE), a multisite clinical trial evaluating the efficacy of exercise or health education, added to treatment as usual for stimulant abuse are linked to firm and flexible site selection criteria. We also present an iterative, multi-step approach to site selection including building awareness about the study and screening and evaluating sites using these criteria.
This simple model could maximize the chance that selected sites will implement a study successfully and achieve trial aims. It may be helpful to researchers who are developing criteria and methods for site selection for specific clinical trials.
Site selection; clinical trials; effectiveness; efficacy; substance use; exercise
There is growing evidence suggesting that early adversity may be a marker for a distinct pathway to major depressive disorder (MDD). We examined associations between childhood adversity and a broad variety of clinical characteristics and response to pharmacotherapy in a large sample of patients with chronic forms of MDD.
Subjects included 808 patients with chronic forms of MDD (chronic MDD, double depression, or recurrent MDD with incomplete recovery between episodes and a total continuous duration of >2 years) who were enrolled in a 12-week open-label trial of algorithm-guided pharmacotherapy. Baseline assessments included a semi-structured diagnostic interview, and clinician- and self-rated measures of depressive symptoms, social functioning, depressotypic cognitions, and personality traits, and childhood adversity. Patients were re-evaluated every 2 weeks.
A longer duration of illness; earlier onset; greater number of episodes, symptom severity, self-rated functional impairment, suicidality, and comorbid anxiety disorder; and higher levels of dysfunctional attitudes and self-criticism were each associated with multiple forms of childhood adversity. A history of maternal overcontrol, paternal abuse, paternal indifference, sexual abuse, and an index of clinically significant abuse each predicted a lower probability of remission. Among patients completing the 12-week trial, 32% with a history of clinically significant abuse, compared to 44% without such a history, achieved remission.
These findings indicate that a history of childhood adversity is associated with an especially chronic form of MDD that is less responsive to antidepressant pharmacotherapy.
major depression; mood disorders; childhood maltreatment; clinical features; treatment response
During a multisite, NIMH-sponsored clinical trial entitled, “Research Evaluating the Value of Augmentation of Medication by Psychotherapy” (REVAMP), we assessed the adequacy of prior antidepressant treatment in patients with chronic forms of major depressive disorder using the Antidepressant Treatment History Form (ATHF). We hypothesized that when compared to earlier studies treatment adequacy would not have increased over the past decade.
We found that only 33% of the 801 subjects enrolled had ever had a prior adequate trial of antidepressant medication. Patients significantly more likely to have received prior adequate antidepressant trials were older, married, white, had a longer duration of illness, had more melancholic features or met criteria for the melancholic subtype or met lifetime criteria for panic disorder.
The hypothesis that rates of treatment adequacy have not significantly increased over the past decade was supported. These results and the consistency of similar results over time point to the dire need for patient and provider education regarding the signs and symptoms of depression and its treatment.
Depression; Chronic; Treatment; Pharmacotherapy
Previous studies have found that few chronically depressed patients remit with antidepressant medications alone.
To determine the role of adjunctive psychotherapy in the treatment of chronically depressed patients with less than complete response to an initial medication trial.
This trial compared 12 weeks of (1) continued pharmacotherapy and augmentation with cognitive behavioral analysis system of psychotherapy (CBASP), (2) continued pharmacotherapy and augmentation with brief supportive psychotherapy (BSP), and (3) continued optimized pharmacotherapy (MEDS) alone. We hypothesized that adding CBASP would produce higher rates of response and remission than adding BSP or continuing MEDS alone.
Eight academic sites.
Chronically depressed patients with a current DSM-IV–defined major depressive episode and persistent depressive symptoms for more than 2 years.
Phase 1 consisted of open-label, algorithm-guided treatment for 12 weeks based on a history of antidepressant response. Patients not achieving remission received next-step pharmacotherapy options with or without adjunctive psychotherapy (phase 2). Individuals undergoing psychotherapy were randomized to receive either CBASP or BSP stratified by phase 1 response, ie, as nonresponders (NRs) or partial responders (PRs).
Main Outcome Measures
Proportions of remitters, PRs, and NRs and change on Hamilton Scale for Depression (HAM-D) scores.
In all, 808 participants entered phase 1, of which 491 were classified as NRs or PRs and entered phase 2 (200 received CBASP and MEDS, 195 received BSP and MEDS, and 96 received MEDS only). Mean HAM-D scores dropped from 25.9 to 17.7 in NRs and from 15.2 to 9.9 in PRs. No statistically significant differences emerged among the 3 treatment groups in the proportions of phase 2 remission (15.0%), partial response (22.5%), and non-response (62.5%) or in changes on HAM-D scores.
Although 37.5% of the participants experienced partial response or remitted in phase 2, neither form of adjunctive psychotherapy significantly improved outcomes over that of a flexible, individualized pharmacotherapy regimen alone. A longitudinal assessment of later-emerging benefits is ongoing.
clinicaltrials.gov Identifier: NCT00057551
No consensus is available for identifying the best primary outcome for substance abuse trials. While abstinence is the most desirable outcome for substance use interventions, a wide variety of other endpoints have been used to evaluate efficacy trials.
This report provides a framework for determining an optimal primary endpoint and the relevant measurement approach for substance use disorder treatment trials. The framework was developed based on a trial for stimulant abuse using exercise as an augmentation treatment, delivered within the NIDA Clinical Trials Network. The use of a common primary endpoint across trials will facilitate comparisons of treatment efficacy.
Primary endpoint options in existing substance abuse studies were evaluated. This evaluation included surveys of the literature for endpoints and measurement approaches, followed by assessment of endpoint choices against study design issues, population characteristics, tests of sensitivity and tests of clinical meaningfulness.
We concluded that the best current choice for a primary endpoint is percent days abstinent, as measured by the Time Line Follow Back (TLFB) interview conducted three times a week with recall aided by a take-home Substance Use Diary. To further improve the accuracy of the self-reported drug use, an algorithm will be applied to reconcile the results from the TLFB with the results of qualitative urine drug screens.
There is a need for a standardized endpoint in this field to allow for comparison across treatment studies, and we suggest that the recommended endpoint be considered for use in this field.
cocaine abuse; methamphetamine abuse; measurement; abstinence endpoint; exercise
Irritability is common during major depressive episodes, but its clinical significance and overlap with symptoms of anxiety or bipolar disorder remains unclear. We examined clinical correlates of irritability in a confirmatory cohort of Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study participants with major depressive disorder (MDD).
Logistic regression was used to identify features associated with presence of irritability on the clinician-rated Inventory of Depressive Symptomatology.
Of 2,307 study participants, 1067(46%) reported irritability at least half the time during the preceding week; they were more likely to be female, to be younger, to experience greater depression severity and anxiety, and to report poorer quality of life, prior suicide attempts, and suicidal ideation. Bipolar spectrum features were not more common among those with irritability.
Irritable depression is not a distinct subtype of MDD, but irritability is associated with greater overall severity, anxiety comorbidity, and suicidality.
major depressive disorder; bipolar disorder; diagnosis; irritability; anger; suicide
Major Depressive Disorder (MDD) in pregnancy, or antenatal depression poses unique treatment challenges and has serious consequences for mothers, unborn babies, and families when untreated. This review presents current knowledge on exercise during pregnancy, antidepressant effects of exercise, and the rationale for the specific study of exercise for antenatal depression.
A systematic literature review was performed using English language articles published in Medline, PsycINFO, CINAHL, and the Cochrane Library from 1985 to January 2010.
There is a broad literature supporting the antidepressant effects of exercise, but a paucity of studies specifically for antenatal depression. A small number of observational studies have reported that regular physical activities improve self-esteem and reduce symptoms of anxiety and depression during pregnancy. To date, there have not been randomized controlled studies of exercise for the treatment of MDD in pregnant women.
Systematic studies are needed to assess exercise as a treatment alternative for MDD during pregnancy. In consideration of the benefits of exercise for the mother and baby, and the burden of depression, studies are needed to determine the role of exercise for pregnant women with depression.
Exercise; Physical Activity; Pregnancy; Postpartum; Mood; Depression; Gestational Diabetes; Preeclampsia
Missing data in clinical efficacy and effectiveness trials continue to be a major threat to the validity of study findings. The purpose of this report is to describe methods developed to ensure completion of outcome assessments with public mental health sector subjects participating in a longitudinal, repeated measures study for the treatment of major depressive disorder. We developed longitudinal assessment procedures that included telephone-based clinician interviews in order to minimize missing data commonly encountered with face-to-face assessment procedures.
A pre-planned, multi-step strategy was developed to ensure completeness of data collection. The procedure included obtaining multiple pieces of patient contact information at baseline, careful education of both staff and patients concerning the purpose of assessments, establishing good patient rapport, and finally being flexible and persistent with phone appointments to ensure the completion of telephone-based follow-up assessments. A well-developed administrative and organizational structure was also put in place prior to study implementation.
The assessment completion rate for the primary outcome for 310 of 504 subjects who enrolled and completed 52 weeks (at the time of manuscript) of telephone-based follow-up assessments was 96.8%.
By utilizing telephone-based follow-up procedures and adapting our easy-to-use pre-defined multi-step approach, researchers can maximize patient data retention in longitudinal studies.
telephone assessments; follow-up strategies; rapport; longitudinal study; retention; patient contact; appointment adherence; compliance
The clinician-rated (QIDS-C16) and self-report (QIDS-SR16) versions of the 16-item Quick Inventory of Depressive Symptomatology have been extensively examined in adult populations. This study evaluated both versions of the QIDS and the 17-item Children’s Depressive Rating Scale-Revised (CDRS-R) in an adolescent outpatient sample.
Both the QIDS-C16 and QIDS-SR16 were completed for the adolescents. Three different methods were used to complete the QIDS-C16: (a) adolescents’ responses to clinician interviews; (b) parents’ responses to clinician interview; and (c) a composite score using the most pathological response from the two interviews. Both classical and item response theory methods were used. Factor analyses evaluated the dimensionality of each scale.
The sample included 140 adolescent outpatients. All versions of the QIDS, save the parent interview, and the CDRS-R were very reliable (α ≥ 0.8). All four versions of the QIDS are reasonably effective and unidimensional. The CDRS-R was clearly at least two-dimensional. The CDRS-R was the most discriminating among low and extremely high levels of depression. The QIDS-SR16 was the most discriminating at moderate levels of depression. There was no relation between the QIDS scores and concurrent Axis III comorbidities.
The QIDS-C16 and the QIDS-SR16 are suitable for use in adolescents.
Adolescent; depression; depressive symptom ratings; psychometrics; Quick Inventory of Depressive Symptomatology–Clinician-rated; Quick Inventory of Depressive Symptomatology–Self-report
Patients with chronic kidney disease (CKD) experience increased rates of hospitalization and death. Depressive disorders are associated with morbidity and mortality. Whether depression contributes to poor outcomes in patients with CKD not receiving dialysis is unknown.
To determine whether the presence of a current major depressive episode (MDE) is associated with poorer outcomes in patients with CKD.
Design, Setting, and Patients
Prospective cohort study of 267 consecutively recruited outpatients with CKD (stages 2–5 and who were not receiving dialysis) at a VA medical center between May 2005 and November 2006 and followed up for 1 year. An MDE was diagnosed by blinded personnel using the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria.
Main Outcome Measures
The primary outcome was event-free survival defined as the composite of death, dialysis initiation, or hospitalization. Secondary outcomes included each of these events assessed separately.
Among 267 patients, 56 had a current MDE (21%) and 211 did not (79%). There were 127 composite events, 116 hospitalizations, 38 dialysis initiations, and 18 deaths. Events occurred more often in patients with an MDE compared with those without an MDE (61% vs 44%, respectively, P=.03). Four patients with missing dates of hospitalization were excluded from survival analyses. The mean (SD) time to the composite event was 206.5 (19.8) days (95% CI, 167.7–245.3 days) for those with an MDE compared with 273.3 (8.5) days (95% CI, 256.6–290.0 days) for those without an MDE (P=.003). The adjusted hazard ratio (HR) for the composite event for patients with an MDE was 1.86 (95% CI, 1.23–2.84). An MDE at baseline independently predicted progression to dialysis (HR, 3.51; 95% CI, 1.77–6.97) and hospitalization (HR, 1.90; 95% CI, 1.23–2.95).
The presence of an MDE was associated with an increased risk of poor outcomes in CKD patients who were not receiving dialysis, independent of comorbidities and kidney disease severity.
The inability to experience pleasure, anhedonia, is recognized as a hallmark symptom of depression. An instrument developed for the assessment of hedonic capacity is the 14-item, self-report, Snaith–Hamilton Pleasure Scale, but its psychometric properties have not been adequately evaluated. The current study examined the reliability and validity of the SHAPS using a large sample of adult outpatients with major depressive disorder (MDD). Data for the current study were obtained from 461 adult outpatients with a diagnosis of MDD who participated in Project IMPACTS. Internal consistency of the SHAPS was assessed using Cronbach’s coefficient alpha. A Principal Factor Analysis was used to define the dimensionality of the SHAPS. Convergent and discriminant validity was assessed by evaluating the Pearson correlations between the SHAPS total score and the pleasure/enjoyment item of the IDS-C30, QLES-Q, HRSD17, IDS-C30, QIDS-C16, and MADRS10, respectively. The internal consistency of the SHAPS was .91. A one-factor solution emerged for the SHAPS (eigenvalues of the first two initial factors were 5.95 and 0.43, respectively). Pearson correlations revealed a positive linear relationship between the SHAPS total score and the total scores on the HRSD17 (r = .49, p<.0001), IDS-C30 (r = .56, p<.0001), QIDS-C16 (r = .55, p<.0001), and MADRS10 (r = .53, p<.0001). The SHAPS total score was negatively correlated with the QLES-Q (r = -0.65, p<.0001). The current study shows that the SHAPS is a reliable, valid, and unidimensional instrument to assess hedonic capacity in adult outpatients with MDD.
Major depression; hedonic capacity; Snaith-Hamilton pleasure scale; reliability and validity
There is a need for novel approaches to the treatment of stimulant abuse and dependence. Clinical data examining the use of exercise as a treatment for the abuse of nicotine, alcohol, and other substances suggest that exercise may be a beneficial treatment for stimulant abuse, with direct effects on decreased use and craving. In addition, exercise has the potential to improve other health domains that may be adversely affected by stimulant use or its treatment, such as sleep disturbance, cognitive function, mood, weight gain, quality of life, and anhedonia, since it has been shown to improve many of these domains in a number of other clinical disorders. Furthermore, neurobiological evidence provides plausible mechanisms by which exercise could positively affect treatment outcomes. The current manuscript presents the rationale, design considerations, and study design of the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) CTN-0037 Stimulant Reduction Intervention using Dosed Exercise (STRIDE) study.
STRIDE is a multisite randomized clinical trial that compares exercise to health education as potential treatments for stimulant abuse or dependence. This study will evaluate individuals diagnosed with stimulant abuse or dependence who are receiving treatment in a residential setting. Three hundred and thirty eligible and interested participants who provide informed consent will be randomized to one of two treatment arms: Vigorous Intensity High Dose Exercise Augmentation (DEI) or Health Education Intervention Augmentation (HEI). Both groups will receive TAU (i.e., usual care). The treatment arms are structured such that the quantity of visits is similar to allow for equivalent contact between groups. In both arms, participants will begin with supervised sessions 3 times per week during the 12-week acute phase of the study. Supervised sessions will be conducted as one-on-one (i.e., individual) sessions, although other participants may be exercising at the same time. Following the 12-week acute phase, participants will begin a 6-month continuation phase during which time they will attend one weekly supervised DEI or HEI session.
Clinical Trials Registry
stimulant abuse; stimulant dependence; exercise; health education; behavioral intervention
Adverse events during selective serotonin reuptake inhibitor (SSRI) treatment are frequent and may lead to premature treatment discontinuation. If attrition is associated with early worsening of side effects or the frequency, intensity, or burden of side effects, interventions to maximize retention could be focused on patients with these events. Outpatient participants (n=265) with nonpsychotic major depressive disorder entered an 8-week trial with an SSRI. At baseline and week 2, specific side effects were evaluated with the Systematic Assessment for Treatment Emergent Events – Systematic Inquiry, and at week 2 the Frequency, Intensity, and Burden of Side Effects Rating globally assessed side effects. Attrition was defined by those participants who left treatment after week 2 but before week 8. No specific week 2 side effect, either treatment emergent or with worsening intensity, was independently associated with attrition. Global ratings of side effect frequency, intensity, or burden at week 2 were also not associated with subsequent attrition. Neither global ratings nor specific side effects at week 2 were related to patient attrition during SSRI treatment. Other factors appear to contribute to patient decisions about continuing with treatment.
attrition; adherence; adverse events; antidepressant; depression
Effective management of major depressive disorder often includes the long-term use of multiple medications, and the longer-term utility and safety of adjunctive aripiprazole has not been evaluated in a controlled setting.
Patients and methods:
Patients (n = 706) completing one of two 14-week double-blind studies of aripiprazole augmentation, as well as de novo patients (n = 296) nonresponsive to current antidepressant therapy, were enrolled in this open-label study. Patients received open-label aripiprazole for up to 52 weeks.
Open-label treatment was completed by 323 patients (32.2%). At endpoint (n = 987), the mean dose of aripiprazole was 10.1 mg/day. Common (>15% of patients) spontaneously reported adverse events were akathisia (26.2%), fatigue (18.0%), and weight gain (17.1%). The incidence of serious adverse events was 4.0%. Four spontaneous reports of possible tardive dyskinesia were submitted (0.4%); all resolved within 45 days of drug discontinuation. Mean weight change was 4.4 kg; 36.6% experienced ≥7% increase in weight from baseline (observed case analysis, n = 303). No clinically relevant changes in other metabolic parameters were seen. At the end of open-label treatment, 221 patients (69.7%) had a Clinical Global Impression-Severity of Illness score of 1 (not at all ill) or 2 (borderline ill).
Long-term adjunctive aripiprazole therapy was well tolerated with an acceptable long-term safety and tolerability profile in patients with major depressive disorder who had not responded to treatment with one or more antidepressant therapies. Clinically significant weight gain was observed in about one-third of patients. Overall, the adverse event profile was consistent with that reported in the short-term trials and readily managed clinically.
adjunctive aripiprazole; antidepressant therapy; major depressive disorder; long-term safety and tolerability
Identifying biosignatures to assess the probability of response to an antidepressant for patients with major depressive disorder (MDD) is critically needed. Functional connectivity MRI (fcMRI) offers the promise to provide such a measure. Previous work with fcMRI demonstrated that the correlation in signal from one region to another is a measure of functional connectivity. In this pilot work, a baseline non-task fcMRI was acquired in 14 adults with MDD who were free of all medications. Participants were then treated for 8 weeks with an antidepressant and then clinically re-evaluated. Probabilistic anatomic regions of interest (ROI) were defined for 16 brain regions (eight for each hemisphere) previously identified as being important in mood disorders. These ROIs were used to determine mean time courses for each individual's baseline non-task fcMRI. The correlations in time courses between 16 brain regions were calculated. These calculated correlations were considered to signify measures of functional connectivity. The degree of connectivity for each participant was correlated with treatment outcome. Among 13 participants with 8 weeks follow-up data, connectivity measures in several regions, especially the subcallosal cortex, were highly correlated with treatment outcome. These connectivity measures could provide a means to evaluate how likely a patient is to respond to an antidepressant treatment. Further work using larger samples is required to confirm these findings and to assess if measures of functional connectivity can be used to predict differential outcomes between antidepressant treatments.
major depressive disorder; antidepressant; functional MRI; treatment prediction; connectivity; non-task fcMRI
There is an important need for non-medication interventions for depressed youth. The aim of this study is to evaluate the feasibility of using a standardized aerobic exercise regime to treat non-medicated clinically depressed adolescents based on adherence and completion rates, including 1) establishing effect sizes for the primary outcomes including the Chidren’s Depression Rating Scale – Revised (CDRS-R) and Actical (energy expenditure data) as well as selected secondary outcomes; (e.g., Clinical Global Improvement, depression rating scales, exercise logs, attitudes), and 2) determining whether moderate to strenuous exercise (12 kcal/kg/week [KKW]) versus a control stretching activity (<4 KKW) for 12 weeks leads to a clinically meaningful reduction in depressive symptoms and/or improved psychosocial functioning. The challenge is to develop an exercise intervention that can motivate a typically sedentary depressed adolescent to exercise on a regular basis. The goal is to demonstrate that exercise alone can provide an important and effective non-medication intervention for adolescent depression. This paper reports on the rationale and design of a pilot study which aims to inform the design of a larger trial to evaluate the efficacy of aerobic exercise to treat adolescent depression. After describing the case for exercise within the broader context of the prevalence of adolescent depression and other treatments, the paper describes the intervention and procedures for data collection.
Childhood depression; Exercise; Exercise and depression; Pediatric depression; Adolescent depression; MDD
Understanding patients’ ambivalence about treatment persistence may be useful in tailoring retention interventions for individual patients with major depressive disorder.
Participants (n = 265) with major depressive disorder were enrolled into an 8-week trial with a selective serotonin reuptake inhibitor. At baseline and week 2, the participants were asked about their intent to return for the next visit, complete the study and continue in the study should they experience side effects or no improvement. Dropouts were defined as participants who discontinued attending clinic visits before completing the trial.
Participants who at baseline reported an uncertain/negative intent to continue if they experienced side effects or no improvement dropped out at a significantly higher rate by weeks 6 and 8. Uncertain/negative intent at week 2 predicted attrition at all following visits. Dropouts without side effects were more likely to have reported an uncertain/negative intent to attend at both baseline and week 2, while dropouts who experienced side effects were more likely to have reported an uncertain/negative intent to attend only at baseline. Positive intent to continue was associated with greater symptom improvement in both dropouts and completers despite the possibility of lack of efficacy.
Participants’ pretreatment concerns about continuing antidepressant treatment in the presence of side effects signals challenges to the completion of a full 8-week acute phase treatment, even if the participant does not develop side effects. Individualized review of concerns and tailoring appropriate interventions may be necessary to reduce attrition.
Attrition; Adherence; Depression; Antidepressant; Attitudes
Nine DSM-IV-TR criterion symptom domains are evaluated to diagnose major depressive disorder (MDD). The Quick Inventory of Depressive Symptomatology (QIDS) provides an efficient assessment of these domains and is available as a clinician rating (QIDS-C16), a self-report (QIDS-SR16), and in an automated, interactive voice response (IVR) (QIDS-IVR16) telephone system. This report compares the performance of these three versions of the QIDS and the 17-item Hamilton Rating Scale for Depression (HRSD17).
Data were acquired at baseline and exit from the first treatment step (citalopram) in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. Outpatients with nonpsychotic MDD who completed all four ratings within ±2 days were identified from the first 1500 STAR*D subjects. Both item response theory and classical test theory analyses were conducted.
The three methods for obtaining QIDS data produced consistent findings regarding relationships between the nine symptom domains and overall depression, demonstrating interchangeability among the three methods. The HRSD17, while generally satisfactory, rarely utilized the full range of item scores, and evidence suggested multidimensional measurement properties.
In nonpsychotic MDD outpatients without overt cognitive impairment, clinician assessment of depression severity using either the QIDS-C16 or HRSD17 may be successfully replaced by either the self-report or IVR version of the QIDS.
Quick Inventory of Depressive Symptomatology; Inventory of Depressive Symptomatology; item response theory; Samejima graded response model; depressive symptoms
Attrition from treatment in the short and long term for major depressive disorder (MDD) is clearly an adverse outcome. To assist in tailoring the delivery of interventions to specific patients to reduce attrition, this study reports the incidence, timing, and predictors of attrition from outpatient treatment in public mental health clinics.
Outpatients with psychotic and nonpsychotic MDD receiving measurement-based care in the Texas Medication Algorithm Project (N = 179) were evaluated to determine timing and rates of attrition as well as baseline sociodemographic, clinical, and attitudinal predictors of attrition.
Overall, 23% (42/179) of the patients left treatment by 6 months, and 47% (84/179) left by 12 months. Specific beliefs about the impact of medication, such as its perceived harmfulness, predicted attrition at both 6 and 12 months. Younger age (p = 0.0004) and fewer side effects at baseline (p = 0.0376) were associated with attrition at 6 months. Younger age (p = 0.0013), better perceived physical functioning (p = 0.0007), and more negative attitudes about psychiatric medications at baseline (p = 0.0075) were associated with attrition at 12 months.
Efforts to elicit attitudes about medications and tailoring educational and other retention interventions for patients with negative beliefs about antidepressants both when initiating a new medication and throughout treatment may reduce attrition. Particular focus on younger patients and those requiring frequent visits may be helpful.
adherence; compliance; major depressive disorder; antidepressant medication; beliefs; attitudes; attrition
Major depressive disorder (MDD) is an illness of great morbidity that affects many people across the world. The current goal for treatment of MDD is to achieve remission (i.e., no depressive symptoms). However, despite scientific advances in the treatment for MDD, antidepressants as first-line agents yield only modest remission rates. In fact, a recent study indicated that only one out of three subjects who received a standard, first-line antidepressant attained remission. Not achieving remission from depressive symptoms increases the risk of a more chronic and debilitating course of illness with frequent recurrences. Although a number of reasons contribute to these modest outcomes, the presence of residual symptoms is a major problem. Residual symptoms are defined as symptoms that linger despite an adequate dose and duration of an antidepressant medication. This article reviews the prevalence and clinical impact of common residual symptoms and discusses the utility of aggressively addressing residual symptoms to enhance the efficacy of antidepressant medications.
antidepressant medication; augmentation strategy; depressive subtype; major depressive disorder; remission; residual symptom