Objective:
This report describes the participants and compares the acute and longer-term treatment outcomes associated with each of four successive steps in the Sequenced Treatment Alternatives to ...Relieve Depression (STAR*D) trial.
Method:
A broadly representative adult outpatient sample with nonpsychotic major depressive disorder received one (N=3,671) to four (N=123) successive acute treatment steps. Those not achieving remission with or unable to tolerate a treatment step were encouraged to move to the next step. Those with an acceptable benefit, preferably symptom remission, from any particular step could enter a 12-month naturalistic follow-up phase. A score of ≤5 on the Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR
16
) (equivalent to ≤7 on the 17-item Hamilton Rating Scale for Depression HRSD
17
) defined remission; a QIDS-SR
16
total score of ≥11 (HRSD
17
≥14) defined relapse.
Results:
The QIDS-SR
16
remission rates were 36.8%, 30.6%, 13.7%, and 13.0% for the first, second, third, and fourth acute treatment steps, respectively. The overall cumulative remission rate was 67%. Overall, those who required more treatment steps had higher relapse rates during the naturalistic follow-up phase. In addition, lower relapse rates were found among participants who were in remission at follow-up entry than for those who were not after the first three treatment steps.
Conclusions:
When more treatment steps are required, lower acute remission rates (especially in the third and fourth treatment steps) and higher relapse rates during the follow-up phase are to be expected. Studies to identify the best multistep treatment sequences for individual patients and the development of more broadly effective treatments are needed.
Objective:
In controlled treatment trials, 40%-60% of unmedicated depressed individuals respond to cognitive behavior therapy (CBT). The authors examined whether pretreatment neural reactivity to ...emotional stimuli accounted for this variation.
Method:
Unmedicated depressed individuals (N=14) and never depressed comparison subjects (N=21) underwent fMRI during performance of a task sensitive to sustained emotional information processing. Afterward, depressed participants completed 16 sessions of CBT.
Results:
Participants whose sustained reactivity to emotional stimuli was low in the subgenual cingulate cortex (Brodmann's area 25) and high in the amygdala displayed the strongest improvement with CBT.
Conclusions:
The presence of emotion regulation disruptions, which are targeted in CBT, may be the key to recovery with this intervention.
To characterize the safety and tolerability of adjunctive cariprazine in patients with major depressive disorder (MDD) and inadequate response to monotherapy antidepressant treatment (ADT). Post hoc ...analyses evaluated pooled data from 2 fixed-dose phase 3 cariprazine studies (1.5 and 3 mg/d approved doses for MDD). In a separate safety analysis, cariprazine 0.1-4.5 mg/d was evaluated using data from the 2 fixed-dose trials plus 3 flexible-dose studies grouped by modal-daily dose. In the pooled phase 3 studies (placebo = 503, 1.5 mg/d = 502, 3 mg/d = 503), overall cariprazine-treated patients had high rates of study completion (90%). Patients had mostly mild/moderate treatment-emergent adverse events that caused premature discontinuation of 4.3%. Only akathisia, nausea, and insomnia occurred in ≥5% of cariprazine patients (any group) and at twice the rate of placebo; potential dose-dependent responses were observed for akathisia and insomnia. Cariprazine had a neutral metabolic profile, with mean weight increase of <1 kg. Modal-dose results were similar, and both analyses were consistent with the known safety profile of cariprazine across its approved indications. Adjunctive cariprazine therapy was safe and generally well tolerated in patients with MDD who had not obtained an adequate response to ADT monotherapy; no new safety signals were identified.
Residual symptoms of major depressive disorder (MDD) following treatment are increasingly recognized as having a negative impact on the patient because of their association with lack of remission, ...poorer psychosocial functioning, and a more chronic course of depression. Although the effects of specific residual symptoms have not been as systematically studied, several symptoms, including fatigue, sleep disturbance, anxiety, and concentration difficulties, commonly occur as part of the residual state in MDD. In particular, the relatively high prevalence of residual fatigue suggests that this symptom is not being adequately addressed by standard antidepressant therapies. A review of the clinical relevance of residual fatigue was undertaken, using the published literature with respect to its assessment, neurobiology, and treatment implications. The findings of this review suggest that fatigue is highly prevalent as a residual symptom; its response to treatment is relatively poor or delayed; and the presence of residual fatigue is highly predictive of inability to achieve remission with treatment as well as impaired psychosocial functioning. Recognition of the significant consequences of residual fatigue should reinforce the need for further therapeutic interventions to help reduce the impact of this symptom of MDD.
Acute-phase cognitive therapy (CT) is an efficacious treatment for major depressive disorder (MDD), but how CT helps patients is incompletely understood. As a potential means to clarify CT ...mechanisms, we defined “symptom linkage density” (SLD) as a patient’s mean time-lagged correlation among nine depressive symptoms across 13 weekly assessments. We hypothesized that patients with higher SLD during CT have better outcomes (treatment response, and fewer symptoms after response), and we explored whether SLD correlated with other possible CT processes (growth in social adjustment and CT skills).
Data were drawn from two clinical trials of CT for adult outpatients with recurrent MDD (primary sample
n
= 475, replication sample
n
= 146). In both samples, patients and clinicians completed measures of depressive symptoms and social adjustment repeatedly during CT. In the primary sample, patients and cognitive therapists rated patients’ CT skills. After CT, responders were assessed for 32 (primary sample) or 24 (replication sample) additional months to measure long-term depression outcomes.
Higher SLD predicted increases in social adjustment (both samples) and CT skills (primary sample) during CT, CT response (both samples), and lower MDD severity for at least 2 years after CT response (both samples). Analyses controlled patient-level symptom means and variability to estimate SLD’s incremental predictive validity.
These novel findings from two independent samples with longitudinal follow-up require further replication and extension. SLD may reflect or facilitate generalization of CT skills, improvement in social functioning, or other processes responsible for CT’s shorter and longer term benefits.
This study assessed prevention of relapse in patients with treatment-resistant depression (TRD) taking olanzapine/fluoxetine combination (OFC). Patients with major depressive disorder (MDD) who ...failed to satisfactorily respond to ≥ 2 different antidepressants for ≥ 6 weeks within the current MDD episode were acutely treated for 6-8 weeks, followed by stabilization (12 weeks) on OFC. Those who remained stable were randomized to OFC or fluoxetine for up to 27 weeks. Time-to-relapse was the primary efficacy outcome defined as 50% increase in Montgomery-Åsberg Depression Rating Scale score with Clinical Global Impressions-Severity of Depression score of ≥ 4; hospitalization for depression or suicidality; or discontinuation for lack of efficacy or worsening of depression or suicidality. A total of 444 patients were randomized 1:1 to OFC (N=221) or fluoxetine (N=223). Time-to-relapse was significantly longer in OFC-treated patients compared with fluoxetine-treated patients (p<0.001). Treatment-emergent weight gain and some mean and categorical fasting metabolic changes were significantly greater in OFC-treated patients. Clinically significant weight gain (≥ 7%) was observed in 55.7% of patients who remained on OFC throughout the study, including the relapse-prevention phase (up to 47 weeks). There were no significant differences between patients treated with OFC and fluoxetine in extrapyramidal symptoms or serious adverse events. We believe this is the first controlled relapse-prevention study in subjects with TRD that supports continued use of a second-generation antipsychotic beyond stabilization. A thorough assessment of benefits and risks (in particular metabolic changes) associated with continuing treatment with OFC or fluoxetine must be done based on individual patient needs.
Stewart et al (2009) have outlined the evidence in support of the validity of the DSM-IV definition of the 'With Atypical Features' episode specifier. Although recognizing the historical significance ...and clinical utility of the concept of atypical depression, this article takes issue with the DSM-IV criteria. It is concluded that mood reactivity, the A or obligative criterion, is neither significantly associated with the other symptomatic criteria nor useful to diagnose atypical depression, and thus should be eliminated. Problems with operationalization, specification, and reliability of ratings of the diagnostic criteria further limit validity. Despite these limitations in classification, many of the features associated with atypical depression are linked to an early onset of affective illness, including trait-like interpersonal sensitivity, comorbid social anxiety and agoraphobia, a history of childhood physical or sexual trauma, and indicators of the 'soft' side of the bipolar spectrum. Neurophysiologic studies also suggest that chronic, early-onset atypical depressions differ from both melancholia and normality. Re-analyses of the Columbia group's seminal studies suggest that preferential response to phenelzine vs imipramine--arguably the strongest validator of atypical depression--similarly appears to be limited to patients with chronic, early-onset syndromes. The criteria for atypical depression need to be revised in DSM-V, including sharpening the operational definitions for the specific symptoms. The importance of age of onset and comorbid anxiety warrant further study. Research examining the validity of a subform of atypical depression characterized by trait-like interpersonal sensitivity and a chronic, early-onset course may further enhance the clinical utility of the DSM-V classification.
Abstract
Study Objectives
The primary aim of the present study was to estimate the incidence per annum of acute insomnia and to what extent those that develop acute insomnia recover good sleep or ...develop chronic insomnia. Unlike prior studies, a dense-sampling approach was used here (i.e. daily diaries) and this allowed for a more precise detection of acute insomnia and the follow-on states (the transitions to either recovery or chronic insomnia).
Methods
Good sleeper subjects (n = 1,248; 67% female) that were at least 35 years old participated in this prospective study on the natural history of insomnia. Subjects were recruited nationwide and completed online assessments for 1 year. The online measures consisted primarily of daily sleep diaries, as well as weekly/bi-weekly and monthly measures of sleep, stress, and psychological and physical health.
Results
The 1-year incidence rate of acute insomnia was 27.0% (n = 337). The incidence rate of chronic insomnia was 1.8% (n = 23). Of those that developed acute insomnia, 72.4% (n = 244) went on to recover good sleep. 19.3% (n = 65) of the acute insomnia sample continued to experience persistent poor sleep, but did not meet criteria for chronic insomnia.
Conclusions
The incidence rate of acute insomnia (3 or more nights a week for between 2 and 12 weeks) is remarkably high. This said, most incident cases resolve within a few days to weeks. Incident chronic insomnia only occurs in about 2 in 100 individuals.
To evaluate feasibility, efficacy, and tolerability of Sudarshan Kriya yoga (SKY) as an adjunctive intervention in patients with major depressive disorder (MDD) with inadequate response to ...antidepressant treatment.
Patients with MDD (defined by DSM-IV-TR) who were depressed despite ≥ 8 weeks of antidepressant treatment were randomized to SKY or a waitlist control (delayed yoga) arm for 8 weeks. The primary efficacy end point was change in 17-item Hamilton Depression Rating Scale (HDRS-17) total score from baseline to 2 months. The key secondary efficacy end points were change in Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) total scores. Analyses of the intent-to-treat (ITT) and completer sample were performed. The study was conducted at the University of Pennsylvania between October 2014 and December 2015.
In the ITT sample (n = 25), the SKY arm (n = 13) showed a greater improvement in HDRS-17 total score compared to waitlist control (n = 12) (-9.77 vs 0.50, P = .0032). SKY also showed greater reduction in BDI total score versus waitlist control (-17.23 vs -1.75, P = .0101). Mean changes in BAI total score from baseline were significantly greater for SKY than waitlist (ITT mean difference: -5.19; 95% CI, -0.93 to -9.34; P = .0097; completer mean difference: -6.23; 95% CI, -1.39 to -11.07; P = .0005). No adverse events were reported.
Results of this randomized, waitlist-controlled pilot study suggest the feasibility and promise of an adjunctive SKY-based intervention for patients with MDD who have not responded to antidepressants.
ClinicalTrials.gov identifier: NCT02616549.
This 24-week double-blind placebo-controlled multicenter randomized phase 2 trial evaluated efficacy and safety of onabotulinumtoxinA (onabotA; BOTOX) vs. placebo for major depressive disorder (MDD) ...NCT02116361. Primary endpoint was the change in Montgomery-Åsberg Depression Rating Scale (MADRS); secondary endpoints were Clinical Global Impressions-Severity and 17-item Hamilton Depression Rating Scale at week 6. A total of 255 adult females were treated. OnabotA 30 U approached significance compared to placebo on MADRS (mixed-effect model repeated measures least-squares mean difference−3.7; P = 0.053) and reached significance least-squares mean differences−3.6 to −4.2; P < 0.05 (two-sided) at weeks 3 and 9. Secondary endpoints were also significant at several time points. At week 6, onabotA 50 U did not separate from placebo in any parameters. OnabotA was generally well-toleratedthe only treatment-emergent adverse events reported in ≥5% in either onabotA group, and more than matching placebo were headache, upper respiratory infection, and eyelid ptosis. OnabotA 30 U, administered in a standardized injection pattern in a single session, had a consistent efficacy signal across multiple depression symptom scales for 12 or more weeks. OnabotA 30 U/placebo MADRS differences of (observed ANCOVA) ≥4.0 points (up to week 15) and ≥2.0 points (weeks 18–24) agree with the 2-point change threshold considered clinically relevant in MDD. OnabotA is a local therapy and is not commonly associated with systemic effects of conventional antidepressants and may represent a novel treatment option for MDD.
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