Not all types of depressed patients who persist with their antidepressant treatment improve in side effect complaints: A comparison of treatment completers and dropouts in the STAR*D trial.

INTRODUCTION: There is a "traditional belief" that antidepressant side effect complaints improve with medication persistence; however, support for this theory has remained inconclusive. We aimed to examine if side effect complaints improved over time by modeling the relationship between side effect complaints and time at dropout for patients receiving citalopram during the first level of acute treatment in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial. METHODS: We categorized the 2833 patients into five patterns by week of dropout. We used pattern-mixture modeling to model change in side effect complaints (frequency, intensity, and burden) over the 12-week course of treatment, while accounting for attrition and depressive severity. Using post-hoc linear contrasts, we compared the attrition patterns with the completers' pattern for severity of side effect complaints at each respective last visit prior to dropout as well as averaged side effect complaints across the duration of treatment. We also reported frequencies and tolerability of side effects for nine organ/function systems over the course of treatment. RESULTS: Patients who dropped out early exhibited worsening side effect burden and patients who dropped out later showed improvements in side effect frequency and intensity. Treatment completers improved in all side effect complaints over the course of treatment. Early attrition patterns had more severe side effect complaints for both tests of post-hoc linear contrasts than later attrition patterns and completers. CONCLUSIONS: Side effect complaints from antidepressant treatment improve over time, but only for some types of patients. As a precaution for early dropout, clinicians should monitor patients who exhibit worsening and more severe side effect complaints-especially in the first 6 weeks of antidepressant treatment. In addition, clinicians may want to consider changing the type of treatment early on for these patients, rather than encouraging them to persist with their current medication.

Multi-trial, aggregated, individual participant data mega-analysis of short-term antidepressant versus mood stabilizer monotherapy of bipolar type II major depressive episode.

BACKGROUND: Few studies have systematically examined the safety and effectiveness of antidepressant versus mood stabilizer monotherapy of bipolar II depression. To date, there are no aggregated or mega-analyses of prospective trials of individual participant-level data (IPD) to inform future treatment guidelines on the relative safety and effectiveness of antidepressant or lithium monotherapy. METHODS: Data from a series of four independent, similarly designed trials of antidepressant or lithium monotherapy (where longitudinal IPD were available) (n = 393) were aggregated into an IPD dataset (i.e., mega-analysis). Hierarchical log-linear growth models were used to analyze primary outcome of change over time in Hamilton Rating Scale for Depression (HRSD) scores; while secondary outcomes examined Clinical Global Impressions severity (CGI/S) and change (CGI/C) scores, and change over time in Young Mania Rating (YMR) scores. RESULTS: Relative to lithium monotherapy, antidepressant monotherapy demonstrated significantly greater symptom reduction on HRSD scores across time (b = -2.33, t = -6.68, p < 0.0001), significantly greater symptom reduction on the CGI/S across time (b = -0.414, t = -6.32, p < 0.001), and a significant improvement in CGI/C across time (b = -0.47, t = -7.43, p < 0.0001). No differences were observed in change over time for YMR scores between antidepressant and lithium monotherapy (b = 0.06, t = 0.49, p = 0.62). CONCLUSION: Findings from this IPD mega-analysis of bipolar II depression trials suggest a divergence from current evidence-based guidelines recommending combined mood stabilizer plus antidepressant therapy. The current mega-analysis suggests that antidepressant monotherapy may provide superior short-term effectiveness without clinically meaningful increase in treatment-emergent hypomanic symptoms compared to lithium monotherapy.

Patients' judgments of the importance of treatment-induced reductions in symptoms of depression: The role of specific symptoms, magnitudes of change, and post-treatment levels.

Objective: An implicit assumption in the use of depressive severity measures to assess change during treatment, such as the Hamilton Rating Scale for Depression (HRSD), is that reductions from pre- to post-treatment that are equal to each other are of equal value. However, stakeholders' valuations of changes might depart substantially from this assumption. Method: Vignettes were constructed that reflected the six possible 1, 2, and 3-point reductions on five cognitive and four somatic symptoms derived from the HRSD. Former or currently depressed patients provided judgments of the importance of the symptom reductions. Mean importance ratings were modeled using symptom category and the pre/post-treatment combination. Differences were explored using the Tukey method. Results: Results indicated that mean ratings, from most to least important, were: Anxiety, Suicide, Depressed Mood, Work, and Guilt (the cognitive symptoms) followed by Somatic, Sleep, Appetite & Weight, and Retardation (the somatic symptoms). Participants valued reductions that resulted in posttreatment scores of zero more than expected, given the magnitude of the reductions. Conclusions: The value of reductions in symptoms captured by the HRSD, as judged by patients, appears to differ as a function of symptom category and the post-treatment score. Similar patterns might characterize other measures of depression severity.

Predictive modeling for response to lithium and quetiapine in bipolar disorder.

OBJECTIVES: Lithium and quetiapine are known to be effective treatments for bipolar disorder. However, little information is available to inform prediction of response to these medications. Machine-learning methods can identify predictors of response by examining variables simultaneously. Further evaluation of models on a test sample can estimate how well these models would generalize to other samples. METHODS: Data (N = 482) were drawn from a randomized clinical trial of outpatients with bipolar I or II disorder who received adjunctive personalized treatment plus either lithium or quetiapine. Elastic net regularization (ENR) was used to generate models for lithium and quetiapine; these models were evaluated on a test set. RESULTS: Predictions from the lithium model explained 17.4% of the variance in actual observed scores of patients who received lithium in the test set, while predictions from the quetiapine model explained 32.1% of the variance of patients that received quetiapine. Of the baseline variables selected, those with the largest parameter estimates were: severity of mania; attention-deficit/hyperactivity disorder (ADHD) comorbidity; nonsuicidal self-injurious behavior; employment; and comorbidity with each of two anxiety disorders (social phobia/society anxiety and agoraphobia). Predictive accuracy of the ENR model outperformed the simple and basic theoretical models. CONCLUSION: ENR is an effective approach for building optimal and generalizable models. Variables identified through this methodology can inform future research on predictors of response to lithium and quetiapine, as well as future modeling efforts of treatment choice in bipolar disorder.

Starling forces drive intracranial water exchange during normal and pathological states.

AIM: To quantify the exchange of water between cerebral compartments, specifically blood, tissue, perivascular pathways, and cerebrospinal fluid-filled spaces, on the basis of experimental data and to propose a dynamic global model of water flux through the entire brain to elucidate functionally relevant fluid exchange phenomena. METHODS: The mechanistic computer model to predict brain water shifts is discretized by cerebral compartments into nodes. Water and species flux is calculated between these nodes across a network of arcs driven by Hagen-Poiseuille flow (blood), Darcy flow (interstitial fluid transport), and Starling's Law (transmembrane fluid exchange). Compartment compliance is accounted for using a pressure-volume relationship to enforce the Monro-Kellie doctrine. This nonlinear system of differential equations is solved implicitly using MATLAB software. RESULTS: The model predictions of intraventricular osmotic injection caused a pressure rise from 10 to 22 mmHg, followed by a taper to 14 mmHg over 100 minutes. The computational results are compared to experimental data with R2=0.929. Moreover, simulated osmotic therapy of systemic (blood) injection reduced intracranial pressure from 25 to 10 mmHg. The modeled volume and intracranial pressure changes following cerebral edema agree with experimental trends observed in animal models with R2=0.997. CONCLUSION: The model successfully predicted time course and the efficacy of osmotic therapy for clearing cerebral edema. Furthermore, the mathematical model implicated the perivascular pathways as a possible conduit for water and solute exchange. This was a first step to quantify fluid exchange throughout the brain.

Urbanicity and depression: A global meta-analysis.

BACKGROUND: Previous meta-analyses have revealed that in adult and older adult populations of developed countries, depression is more prevalent in urban than rural areas. No meta-analyses have identified the effects of urbanicity on the general age demographic for developing countries. We conducted a meta-analysis of urban-rural differences in depression across all age demographics for developed and developing countries. METHODS: PubMed and PsycINFO databases were searched for studies published between 1980 and 2020. Studies were included if they reported prevalences of urban and rural depression, or odds ratios comparing urban-rural depression prevalence. Studies were excluded for: nonrepresentative samples, non-standard measures of depression, and reporting continuous outcomes only. Meta-analytic models of urban-rural differences in the odds of depression were conducted across country development levels and age demographics. RESULTS: From 1597 records screened and 302 full texts assessed for eligibility, 80 studies (N = 539,557) were included for meta-analysis. Urban residence was significantly associated with a higher prevalence of depression in developed countries (OR = 1.30, 95 % CI [1.17, 1.46], z = 4.75, p < .001), which was primarily driven by urban-rural differences in the general population age demographic (OR = 1.37, 95 % CI [1.22, 1.54], z = 5.38, p < .001). LIMITATIONS: Studies reporting urban-rural differences in depression in terms of continuous symptom severity scores were not included. CONCLUSIONS: Urbanicity appears to uniquely be associated with a higher prevalence of depression in developed countries, but not in developing countries.

What are the treatment remission, response and extent of improvement rates after up to four trials of antidepressant therapies in real-world depressed patients? A reanalysis of the STAR*D study's patient-level data with fidelity to the original research protocol.

OBJECTIVE: Reanalyse the patient-level data set of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study with fidelity to the original research protocol and related publications. DESIGN: The study was open label and semirandomised examining the effectiveness of up to four optimised and increasingly aggressive, antidepressant therapies in depressed adults. Patients who failed to gain adequate relief from their level 1 trial on the SSRI citalopram could receive up to three additional treatment trials in levels 2-4. SETTING: 41 North American psychiatry and primary care treatment centres. PARTICIPANTS: 4041 adults screened positive for major depressive disorder. In contrast to most clinical trials, STAR*D enrolled patients seeking care (vs recruited) and included patients with a wide range of common comorbid medical and psychiatric conditions to enhance the generalisability of findings to real-world clinical practice. INTERVENTIONS: STAR*D evaluated the relative effectiveness of 13 antidepressants therapies in treatment levels 2-4 for depressed patients who failed to gain adequate benefit from their level 1 medication trial. MAIN OUTCOME MEASURES: According to the STAR*D protocol, the primary outcome was remission, defined as a score <8 on the blinded Hamilton Rating Scale for Depression (HRSD). Response was a secondary outcome defined as ≥50% reduction in HRSD scores. STAR*D's protocol specifically excluded all non-blinded clinic-administered assessments from use as research outcome measures. RESULTS: STAR*D investigators did not use the protocol-stipulated HRSD to report cumulative remission and response rates in their summary article and instead used a non-blinded clinic-administered assessment. This inflated their report of outcomes, as did their inclusion of 99 patients who scored as remitted on the HRSD at study outset as well as 125 who scored as remitted when initiating their next-level treatment. These patients should have been excluded from data analysis. In contrast to the STAR*D-reported 67% cumulative remission rate after up to four antidepressant treatment trials, the rate was 35.0% when using the protocol-stipulated HRSD and inclusion in data analysis criteria. CONCLUSION: STAR*D's cumulative remission rate was approximately half of that reported.

Time to fellow eye involvement in patients with unilateral diabetic macular oedema.

OBJECTIVE: To examine the time to onset of disease in the fellow eye of patients with unilateral DMO in routine clinical practice and to identify risk factors for development of bilateral DMO. DESIGN: Retrospective cohort study. PARTICIPANTS: One hundred forty treatment-naive patients 18 years or older with unilateral DMO presenting to Cole Eye Institute between January 2012 and July 2021. METHODS: Records of patients with unilateral DMO were reviewed for development of DMO in the fellow eye. Demographic, diabetic, ocular, and systemic characteristics were collected at initial DMO diagnosis date. Bivariate and multivariate analyses were performed and significant factors were modelled using Kaplan-Meier curves. RESULTS: Fifty patients with conversion to bilateral DMO and 90 patients without conversion were identified. Average time to bilateral DMO was 15.0 ± 15.7 months. 64% of patients converted within 1 year and 90% converted within 3 years. HbA1c (p = 0.003), diabetic retinopathy duration (p = 0.029), and diabetic foot disease (DFD) (p = 0.002) were identified as significant risk factors for conversion. Patients with better visual acuity at time of initial diagnosis and history of panretinal photocoagulation (PRP) (p = 0.044) or focal laser (p = 0.035) in the primary eye were also more likely to convert. CONCLUSIONS: Participants were most likely to develop fellow eye DMO within the first year after initial DMO diagnosis. In routine clinical practice, poor glycaemic control and DFD were risk factors associated with bilateral eye involvement. Clinicians may consider screening the fellow eye of high-risk individuals at each appointment within the first year of diagnosis.

Mapping Female Patients' Judgments of Satisfaction to Hypothetical Changes in Depression Symptom Severity.

Within mental health, approaches to determine whether a patient experienced "meaningful" change from treatment have predominantly involved imposing thresholds on three types of metrics derived from assessments of symptom severity: end score (posttreatment score), absolute change (pre- minus posttreatment score), and proportion of change. However, none of these approaches have considered input from the consumer. This study examined correspondences between various reductions from pre- to posttreatment symptom severity levels and patients' judgments of satisfaction with change. Former or currently depressed patients were asked to provide judgments of their satisfaction reflected in vignettes that used descriptions from the Hamilton Rating Scale for Depression. Judgments from 108 female participants were fit using four metrics: end score, absolute change, proportion of change, and the combination of end score and absolute change. Akaike information criteria (AICs) and Akaike weights were used to determine the best-fitting model. Cutoffs were calculated for the five levels of satisfaction with change. Proportion of change best accounted for variation in the patients' ratings. For "slightly … ," "somewhat … ," "moderately … ," and "very … ," the proportions of reduction that corresponded with each of these ratings of satisfaction were, respectively: 17%, 39%, 62%, and 84%. Our a priori level of satisfaction (between "somewhat" and "moderately") corresponded to a 50% reduction in pretreatment severity. This study may provide services some insight into their female patients' satisfaction with change from treatment for depression using only the proportion of reduction from pretreatment severity. A similar procedure could be applied to other diagnostic groups, as well as other constructs that attend to the patient's perspective.

Emotion regulation strategy correlates with discrete state emotion in major depression.

BACKGROUND AND OBJECTIVES: Research has shown that state emotion can affect emotion regulation strategies in healthy samples. Emotion regulation plays an important role in depression. We hypothesized that for depressed individuals, experiencing anxiety or anger affects emotion regulation strategy use differently than experiencing sadness. DESIGN AND METHODS: Individuals diagnosed with chronic or recurrent depression (N = 386) responded to vignettes of hypothetical stressors and reported their state emotions and emotion regulation strategies in a thought-listing procedure. We modeled the effect of reporting anger or anxiety compared to sadness on the use of seven emotion regulation strategies: avoidance, distraction, other-blame, problem-solving, rumination, self-blame, and social support. RESULTS: Compared to sadness, anger was associated with a greater likelihood of using other-blame, and a lower likelihood of using avoidance, rumination, or self-blame. Compared to sadness, anxiety was associated with a greater likelihood of using self-blame. Responses with anger or anxiety did not significantly differ from sadness in coder-rated adaptiveness. CONCLUSIONS: Differences in observed emotion regulation strategy use were correlated with the discrete emotions experienced, and not overall adaptiveness of a response. These results highlight the importance of assessing for emotion type when studying emotion regulation strategy use in depression.

Benchmarking the Effectiveness and Accuracy of Multiple Mitochondrial DNA Variant Callers: Practical Implications for Clinical Application.

Mitochondrial DNA (mtDNA) mutations contribute to human disease across a range of severity, from rare, highly penetrant mutations causal for monogenic disorders to mutations with milder contributions to phenotypes. mtDNA variation can exist in all copies of mtDNA or in a percentage of mtDNA copies and can be detected with levels as low as 1%. The large number of copies of mtDNA and the possibility of multiple alternative alleles at the same DNA nucleotide position make the task of identifying allelic variation in mtDNA very challenging. In recent years, specialized variant calling algorithms have been developed that are tailored to identify mtDNA variation from whole-genome sequencing (WGS) data. However, very few studies have systematically evaluated and compared these methods for the detection of both homoplasmy and heteroplasmy. A publicly available synthetic gold standard dataset was used to assess four mtDNA variant callers (Mutserve, mitoCaller, MitoSeek, and MToolBox), and the commonly used Genome Analysis Toolkit "best practices" pipeline, which is included in most current WGS pipelines. We also used WGS data from 126 trios and calculated the percentage of maternally inherited variants as a metric of calling accuracy, especially for homoplasmic variants. We additionally compared multiple pathogenicity prediction resources for mtDNA variants. Although the accuracy of homoplasmic variant detection was high for the majority of the callers with high concordance across callers, we found a very low concordance rate between mtDNA variant callers for heteroplasmic variants ranging from 2.8% to 3.6%, for heteroplasmy thresholds of 5% and 1%. Overall, Mutserve showed the best performance using the synthetic benchmark dataset. The analysis of mtDNA pathogenicity resources also showed low concordance in prediction results. We have shown that while homoplasmic variant calling is consistent between callers, there remains a significant discrepancy in heteroplasmic variant calling. We found that resources like population frequency databases and pathogenicity predictors are now available for variant annotation but still need refinement and improvement. With its peculiarities, the mitochondria require special considerations, and we advocate that caution needs to be taken when analyzing mtDNA data from WGS data.

Anti-Vascular Endothelial Growth Factor Treatment Patterns and Outcomes in Retinal Vein Occlusion in Routine Clinical Practice.

BACKGROUND AND OBJECTIVE: To characterize treatment patterns for retinal vein occlusion (RVO)-related macular edema (ME) in routine clinical practice and its impact on long-term best-corrected visual acuity (BCVA) and central subfield thickness (CST). PATIENTS AND METHODS: Retrospective study of 365 eyes with branch RVO (BRVO) or central/hemi-RVO (CRVO/HRVO)-related ME between 2003 and 2020. Regression analysis identified factors associated with maintenance injection interval (MII). Subgroup analysis compared outcomes between different MIIs. RESULTS: 51.3% of BRVO patients received injections ≤q8 weeks, 26.4% received injections q8-12 weeks, and 22.3% received injections >q12 weeks. 45.2% of CRVO/HRVO patients received injections ≤q8 weeks, 32.1% received injections q8-12 weeks, and 22.6% received injections >q12 weeks. Age, diabetes, and baseline CST were found to predict MII. There was no significant difference in BCVA and CST at baseline, 12, or 24 months in all MII groups in BRVO and CRVO/HRVO. CONCLUSION: There exists a significant heterogeneity in anti-VEGF treatment frequency for RVO-associated ME in routine clinical practice. [Ophthalmic Surg Lasers Imaging Retina 2022;53:626-633.].

Influence of Race, Ethnicity, and Socioeconomic Factors in Idiopathic Macular Hole Presentation and Surgical Outcomes.

BACKGROUND AND OBJECTIVE: To characterize the influence of race, ethnicity, and socioeconomic factors on idiopathic macular hole (IMH) presentation and surgical outcomes. PATIENTS AND METHODS: This retrospective cohort study of patients diagnosed with IMH who underwent surgical repair collected IMH data from optical coherence tomography scans as well as demographic information. Univariate and multivariate regression models interrogated relevant relationships. RESULTS: Of 292 eyes analyzed, 223 (76.4%) patients were White and 53 (18.2%) were Black. Mean income was $57,076.9 ± 17,794.7. Black patients presented with 0.05 mm2 larger IMH area (95% CI, 0.01 to 0.09; P = .01) and 69.07 µm wider minimum linear diameter (95% CI, 15.05 to 123.10; P = .01). Patients with higher income presented with 3.76 µm narrower base diameter (95% CI, -6.42 to -1.09; P = .006). CONCLUSIONS: Black patients were associated with larger IMH at presentation, and higher income patients were associated with smaller IMH. [Ophthalmic Surg Lasers Imaging Retina 2022;53(6): 333-344.].

Progression to Vision-Threatening Retinopathy Complications Following Panretinal Laser for Proliferative Diabetic Retinopathy.

BACKGROUND AND OBJECTIVE: To report the time in which patients with panretinal photocoagulation (PDR) progress to vision-threatening retinopathy (VTR) complications after receiving PRP, and risk factors in routine clinical practice. PATIENTS AND METHODS: Records of patients with complete PRP for PDR were retrospectively reviewed for up to 3.5 years after PRP. Two hundred twenty eyes were selected. RESULTS: Time from PRP to VTR was 1.25 ± 0.82 years. Age, Black race, neovascularization of the disc on examination, diabetic foot disease (DFD), and high-risk PDR characteristics on fluorescein angiography were identified as significant risk factors. Half of patients with DFD on examination developed a VTR within 1.5 years after PRP (P < .001). CONCLUSION: In clinical practice, providers may consider DFD and Black race as predictors of time to VTR event within 4 years after PRP in patients with PDR. [Ophthalmic Surg Lasers Imaging Retina. 2022;53(4):186-193.].

A comparison of prolonged exposure therapy, pharmacotherapy, and their combination for PTSD: What works best and for whom; study protocol for a randomized trial.

BACKGROUND: Several efficacious psychological and pharmacological treatments for posttraumatic stress disorder (PTSD) are available; however, the comparative effectiveness of these treatments represents a major gap in the literature. The proposed study will compare the effectiveness of two leading PTSD treatments - Prolonged Exposure (PE) therapy and pharmacotherapy with paroxetine or venlafaxine extended release - as well as the combination of PE and medication. METHODS: In a randomized clinical trial, veterans with PTSD (N = 450) recruited across six Veterans Affairs Medical Centers will complete assessments at baseline, mid-treatment (Week 7), post-treatment (Week 14), and follow-up (Weeks 27 and 40). The primary outcome will be change in (both clinician-rated and self-reported) PTSD severity. Depression symptoms, quality of life, and functioning will also be measured and examined as secondary outcomes. Baseline demographic and clinical data will be used to develop "personalized advantage indices" (PAIs), with the goal of identifying who is most likely to benefit from which treatment. CONCLUSIONS: This planned trial will yield findings to directly inform clinical practice guidelines for PTSD, by providing comparative effectiveness data to support recommendations about what can be considered the "first-line" treatment option(s) for PTSD. Further, findings from this trial have the potential to guide treatment planning for individual patients, through implementation of PAIs developed from study data, in service of "personalized medicine." TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT04961190.

Adding cognitive therapy to antidepressant medications decreases suicidal ideation.

BACKGROUND: Psychotherapy for depression and antidepressant medications have both been associated with decreases in suicidal ideation. Studies have not examined whether adding psychotherapy to antidepressant medications further reduces suicidal ideation relative to medications alone in adults. METHODS: Participants (N = 452) were randomized to 7 months of treatment with antidepressant medications or combined treatment with both medications and cognitive therapy for depression. We examined change in the suicide items from the Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS) across treatment using Bayesian generalized linear mixed models for non-continuous outcomes. RESULTS: Suicidal ideation decreased across treatment. When measured with the BDI, participants receiving both cognitive therapy and antidepressant medications showed 17% greater reductions in suicidal ideation relative to those receiving medications alone; this effect remained significant when controlling for depression severity. While the same pattern was observed when suicidal ideation was measured with the HDRS, the effect was smaller (7%) and not statistically significant. When BDI and HDRS scores were combined, participants receiving both therapy and medications showed 9% greater reductions in suicidal ideation relative to those receiving medications alone; this effect was marginally significant when controlling for depression severity. LIMITATIONS: This is a secondary analysis of a randomized clinical trial designed to treat depression, in which suicidal ideation was assessed using single-item measures. CONCLUSIONS: Adding cognitive therapy to antidepressant medications may reduce suicidal ideation to a greater extent than medications alone. Pending replication, combination treatment may be preferred for individuals with suicidal ideation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00057577.

Distress and anhedonia as predictors of depression treatment outcome: A secondary analysis of a randomized clinical trial.

Two core features of depression include depressed mood (heightened distress) and anhedonia (reduced pleasure). Despite their centrality to depression, studies have not examined their contribution to treatment outcomes in a randomized clinical trial providing mainstream treatments like antidepressant medications (ADM) and cognitive therapy (CT). We used baseline distress and anhedonia derived from a factor analysis of the Mood and Anxiety Symptom Questionnaire to predict remission and recovery in 433 individuals with recurrent/chronic major depressive disorder. Patients were provided with only ADM or both ADM and CT. Overall, higher baseline distress and anhedonia predicted longer times to remission within one year and recovery within three years. When controlling for treatment condition, distress improved prediction of outcomes over and above anhedonia, while anhedonia did not improve prediction of outcomes over and above distress. Interactions with treatment condition demonstrated that individuals with higher distress and anhedonia benefited from receiving CT in addition to ADM, whereas there was no added benefit of CT for individuals with lower distress and anhedonia. Assessing distress and anhedonia prior to treatment may help select patients who will benefit most from CT in addition to ADM. For the treatments and outcome measures tested, utilizing distress to guide treatment planning may yield the greatest benefit. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00057577.

Prevention of Recurrence After Recovery From a Major Depressive Episode With Antidepressant Medication Alone or in Combination With Cognitive Behavioral Therapy: Phase 2 of a 2-Phase Randomized Clinical Trial.

Importance: Antidepressant medication (ADM) maintenance treatment is associated with the prevention of depressive recurrence in patients with major depressive disorder (MDD), but whether cognitive behavioral therapy (CBT) treatment is associated with recurrence prevention remains unclear. Objective: To determine the effects of combining CBT with ADM on the prevention of depressive recurrence when ADMs are withdrawn or maintained after recovery in patients with MDD. Design, Setting, and Participants: A total of 292 adult outpatients with chronic or recurrent MDD who participated in the second phase of a 2-phase trial. Participants had recovered in the first phase of the trial receiving ADM, either alone or in combination with CBT. The trial was conducted in research clinics in 3 university medical centers in the United States. Patients in phase 2 were randomized to receive maintenance of or withdrawal from ADM and were followed up for 3 years. The first and last patients entered phase 2 in August 2003 and October 2009, respectively. The last patient completed phase 2 in August 2012. Data were analyzed from December 2013 to December 2018. Interventions: Maintenance of or withdrawal from treatment with ADM. Main Outcomes and Measures: Recurrence of an MDD episode using longitudinal interval follow-up evaluations; sustained recovery across both phases. Results: A total of 292 participants (171 women, 121 men; mean [SD] age 45.1 [12.9] years) were included in analyses of depressive recurrence. Maintenance ADM yielded lower rates of recurrence compared with ADM withdrawal regardless of whether patients had achieved recovery in phase 1 with ADM alone (48.5% vs 74.8%; z = -3.16; P = .002; number needed to treat [NNT], 2.8; 95% CI, 1.8-7.0) or ADM plus CBT (48.5% vs 76.7%; z = -3.49; P < .001; NNT, 2.7; 95% CI, 1.9-5.9). Sustained recovery rates differed as a function of phase 2 condition, with maintenance ADM superior to ADM withdrawal (z = 2.90; P = .004; OR, 2.54; 95% CI, 1.37-4.84; NNT, 2.3; 95% CI, 1.5-6.4). Phase 1 condition was not associated with differential rates of sustained recovery (ADM alone vs ADM plus CBT; z = 0.22; P = .83; OR, 1.08; 95% CI, 0.52-2.11; NNT, 26.0; 95% CI, number needed to harm 3.2 to NNT 2.8), nor was there a significant interaction of phase 1 condition and phase 2 condition (z = 0.30; P = .77; OR, 1.14; 95% CI, 0.49-2.88). Conclusions and Relevance: Maintenance ADM treatment, but not previous exposure to CBT, was associated with reduced rates of depressive recurrence. In previous studies, when CBT has been provided without ADM, CBT has shown a preventive effect on depressive relapse. Whether CBT also has a preventive effect on depressive recurrence, or if adding ADM interferes with any such preventive effect, remains unclear. Trial Registration: ClinicalTrial.gov identifier: NCT00057577.

Relative effectiveness of tricyclic antidepressant versus monoamine oxidase inhibitor monotherapy for treatment-resistant depression.

OBJECTIVES: Antidepressants may be less effective in treatment-resistant depression (TRD). In this exploratory study, we examined the widely held hypothesis that monoamine oxidase inhibitor (MAOI) therapy may be superior to tricyclic antidepressant (TCA) therapy for TRD. We also examined the influence of the number of prior treatment trials on TCA versus MAOI effectiveness in TRD. METHODS: Data were retrospectively extracted from approximately 2,500 treatment charts of patients with TRD who were attending a university mood disorder clinic between 1983 and 2015. Hierarchical linear modeling was used to examine the efficacy of drug class on outcome as well as the interaction between drug class and the number of prior antidepressant trials. RESULTS: 147 treatment outcome observations were made from 94 unipolar, depressed patients who either received TCA (N = 47) or MAOI (N = 100) monotherapy for TRD. For patients unresponsive to at least one prior trial, drug class significantly predicted end-of-treatment CGI/S scores, with TCAs showing worse (i.e., higher) end-of-treatment CGI/S scores relative to MAOI therapy (b = 1.04, t = 4.98, p < 0.0001). When examining the interaction between drug class and the number of prior antidepressant trials, the interaction effect was significant (b = -0.50, t = -2.43, p = 0.02); however, the advantage for MAOI versus TCA therapy decreases with more prior, failed, antidepressant trials. CONCLUSION: Results suggest that MAOIs may be more effective than TCAs for early stage TRD. This difference in effectiveness between MAOIs and TCAs diminished as the number of prior treatment trials increased. However, the TCA sample size was limited and the analysis was retrospective with non-randomized conditions.