Medication For Major Depressive Disorder Research Articles

Brain Scans May Offer Clues About Depression Remission

Brain Scans May Offer Clues About Depression Remission

Carbazole derivatives as promising competitive and allosteric inhibitors of human serotonin transporter: computational pharmacology

The human serotonin transporters (hSERTs) are neurotransmitter sodium symporters of the aminergic G protein-coupled receptors, regulating the synaptic serotonin and neuropharmacological processes related to neuropsychiatric disorders, notably, depression. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and (S)-citalopram are competitive inhibitors of hSERTs and are commonly the first-line medications for major depressive disorder (MDD). However, treatment-resistance and unpleasant aftereffects constitute their clinical drawbacks. Interestingly, vilazodone emerged with polypharmacological (competitive and allosteric) inhibitions on hSERTs, amenable to improved efficacy. However, its application usually warrants adjuvant/combination therapy, another subject of critical adverse events. Thus, the discovery of alternatives with polypharmacological potentials (one-drug-multiple-target) and improved safety remains essential. In this study, carbazole analogues from chemical libraries were explored using docking and molecular dynamics (MD) simulation. Selectively, two IBScreen ligands, STOCK3S-30866 and STOCK1N-37454 predictively bound to the active pockets and expanded boundaries (extracellular vestibules) of the hSERTs more potently than vilazodone and (S)-citalopram. For instance, the two ligands showed docking scores of −9.52 and −9.59 kcal/mol and MM-GBSA scores of −92.96 and −65.66 kcal/mol respectively compared to vilazodone’s respective scores of −7.828 and −59.27 against the central active site of the hSERT (PDB 7LWD). Similarly, the two ligands also docked to the allosteric pocket (PDB 5I73) with scores of −8.15 and −8.40 kcal/mol and MM-GBSA of −96.14 and −68.46 kcal/mol whereas (S)-citalopram has −6.90 and −69.39 kcal/mol respectively. The ligands also conferred conformational stability on the receptors during 100 ns MD simulations and displayed interesting ADMET profiles, representing promising hSERT modulators for MDD upon experimental validation. Communicated by Ramaswamy H. Sarma

Dynamic Feedback Between Antidepressant Placebo Expectancies and Mood

Despite high antidepressant placebo response rates, the mechanisms underlying the persistence of antidepressant placebo effects are still poorly understood. To investigate the neurobehavioral mechanisms underlying the evolution of antidepressant placebo effects using a reinforcement learning (RL) framework. In this acute within-patient cross-sectional study of antidepressant placebos, patients aged 18 to 55 years not receiving medication for major depressive disorder (MDD) were recruited at the University of Pittsburgh between February 21, 2017, to March 1, 2021. The antidepressant placebo functional magnetic resonance imaging task manipulates placebo-associated expectancies using visually cued fast-acting antidepressant infusions and controls their reinforcement with sham visual neurofeedback while assessing expected and experienced mood improvement. The trial-by-trial evolution of expectancies and mood was examined using multilevel modeling and RL, relating model-predicted signals to spatiotemporal dynamics of blood oxygenation level-dependent (BOLD) response. A bayesian RL model comparison in 60 individuals (mean [SE] age, 24.5 [0.8] years; 51 females [85%]) with MDD revealed that antidepressant placebo trial-wise expectancies were updated by composite learning signals multiplexing sensory evidence (neurofeedback) and trial-wise mood (bayesian omnibus risk <0.001; exceedance probability = 97%). Placebo expectancy, neurofeedback manipulations, and composite learning signals modulated the visual cortex and dorsal attention network (threshold-free cluster enhancement [TFCE] = 1 - P >.95). As participants anticipated antidepressant infusions, learned placebo expectancies modulated the salience network (SN, TFCE = 1 - P >.95), positively scaling with depression severity. Results of this cross-sectional study suggest that on a timescale of minutes, antidepressant placebo effects were maintained by positive feedback loops between expectancies and mood improvement. During learning, representations of placebos and their perceived effects were enhanced in primary and secondary sensory cortices. Latent learned placebo expectancies were encoded in the SN.

The effects of varenicline, bupropion, nicotine patch, and placebo on smoking cessation among smokers with major depression: A randomized clinical trial.

Improving treatment outcomes for smokers with major depressive disorder (MDD) can have significant public health implications. To evaluate the safety and efficacy of smoking cessation pharmacotherapy among smokers with MDD. Secondary analysis of a randomized, double-blind, active- (nicotine patch) and placebo-controlled trial of 12 weeks of either varenicline or bupropion with a 12-week follow-up. Community volunteers 18-75 years of age; smoke 10+ cigarettes/day; with clinically stable MDD (N = 2635) or no psychiatric disorder (N = 4028), from 140 sites in 16 countries. Twelve weeks of pharmacotherapy (placebo[PLA], nicotine replacement therapy[NRT], bupropion[BUP], varenicline[VAR]) plus brief cessation counseling. Primary safety outcome: the occurrence of ≥1 treatment-emergent, moderate to severe neuropsychiatric adverse event (NPSAE). Primary efficacy outcome: biochemically confirmed continuous abstinence(CA) during the final 4 weeks of treatment (Weeks 9-12). A total of 6653 participants (56% female; 39% MDD) ~47 years old. Risk of NPSAEs did not differ by medication for MDD. MDD had higher risk (p < .0001) for NPSAEs than the NPC. Efficacy (6653; intent-to-treat): CA rates for MDD versus NPC respectively were 31.2% versus 38.0% VAR; 23.0% versus 26.1% BUP; 22.6% versus 26.4% NRT; and 13.4% versus 13.7% PLA but no differential treatment effect was noted within the cohorts. All active treatments differed from PLA but VAR showed the largest effect. Results suggest that for MDD smokers, inclusive of those with recurrent episode, varenicline plus counseling may be the best pharmacological option for the treatment of smoking given its greater efficacy effect size and similar risk of NPSAEs. ClinicalTrials.gov Identifier: NCT01456936. https://clinicaltrials.gov/ct2/show/NCT01456936.

Gut Microbiota Changes in Patients With Major Depressive Disorder Treated With Vortioxetine.

Vortioxetine hydrobromide is a common clinical medication for major depressive disorder (MDD). However, it remains unclear whether vortioxetine hydrobromide acts by affecting the structure and composition of gut microbiota. Here, we analyzed fecal samples from 28 healthy controls (HCs) and 26 patients with MDD before treatment with vortioxetine hydrobromide, at 4 weeks after treatment, and at 8 weeks after treatment. High-throughput pyrosequencing showed that, according to the Chao1 and Shannon indices, fecal bacterial α-diversity was higher in the patients with MDD than in the HCs (p < 0.05), but no significant differences were observed after vortioxetine hydrobromide treatment (p > 0.05). PCoA results revealed that the gut microbiota composition was significantly different between the MDD groups and HCs. Proteobacteria and Actinobacteria were strongly increased, whereas Firmicutes were significantly reduced in the MDD group compared with the HCs. After treatment with vortioxetine hydrobromide, Firmicutes were significantly increased, and the proportion of Bacteroidetes decreased. Most notably, Lachnospira, Roseburia, and Faecalibacterium were negatively correlated with the severity of depressive symptoms. Taken together, our data indicate changes in the fecal microbiota composition in MDD patients compared with HCs, and vortioxetine hydrobromide may treat MDD through regulation of the gut microflora.

Treatment of Major Depressive Disorder in Japanese Patients with Cancer: A Matched Cohort Study Using Employer-Based Health Insurance Claims Data.

Background and ObjectivePatients with cancer are at high risk of major depressive disorder (MDD), but little is known about their MDD treatment. We investigated the use of antidepressants and other drugs for MDD after cancer diagnosis, and patient characteristics associated with their use.MethodsAdults with a new cancer diagnosis were matched to cancer-free patients using a Japanese employee health insurance database (JMDC); this exploratory analysis included only cohort patients diagnosed with MDD between 6 months before and 12 months after the cancer diagnosis index month. Initial prescription frequencies of antidepressants and other MDD medications were compared between cancer and cancer-free groups and analyzed according to age, sex, and hospital characteristics.ResultsCompared with the cancer-free group (n = 4097), significantly fewer patients in the cancer group (n = 1199) were prescribed antidepressants {622 (51.9%) [95% CI 49.0–54.7] vs 2385 (58.2%) [95% CI 56.7–59.7]}, particularly selective serotonin reuptake inhibitors. In contrast, prescription of other medications, especially antipsychotics and anxiolytics (tandospirone, hydroxyzine), was more frequent in the cancer group than in the cancer-free group. In the cancer group, women were prescribed antidepressants (mostly selective serotonin reuptake inhibitors) and other medications (mostly benzodiazepines) more than men. Antidepressant prescription decreased with age; patients aged < 40 years had the highest selective serotonin reuptake inhibitor and the lowest conventional antidepressant prescription rate compared with patients aged 40–64 years and ≥ 65 years. Lower selective serotonin reuptake inhibitor and benzodiazepine prescription rates were seen in large (≥ 100 beds) hospitals and in hospitals where patients received their cancer diagnosis.ConclusionsThese results suggest Japanese patients with cancer may be undertreated for MDD compared with cancer-free patients. However, when prescribed, medications may be chosen according to patient needs, including avoiding adverse effects and drug–drug interactions.Electronic supplementary materialThe online version of this article (10.1007/s40261-020-00976-6) contains supplementary material, which is available to authorized users.

Implementation research for public sector mental health care scale-up (SMART-DAPPER): a sequential multiple, assignment randomized trial (SMART) of non-specialist-delivered psychotherapy and/or medication for major depressive disorder and posttraumatic stress disorder (DAPPER) integrated with outpatient care clinics at a county hospital in Kenya

BackgroundMental disorders are a leading cause of global disability, driven primarily by depression and anxiety. Most of the disease burden is in Low and Middle Income Countries (LMICs), where 75% of adults with mental disorders have no service access. Our research team has worked in western Kenya for nearly ten years. Primary care populations in Kenya have high prevalence of Major Depressive Disorder (MDD) and Posttraumatic Stress Disorder (PTSD). To address these treatment needs with a sustainable, scalable mental health care strategy, we are partnering with local and national mental health stakeholders in Kenya and Uganda to identify 1) evidence-based strategies for first-line and second-line treatment delivered by non-specialists integrated with primary care, 2) investigate presumed mediators of treatment outcome and 3) determine patient-level moderators of treatment effect to inform personalized, resource-efficient, non-specialist treatments and sequencing, with costing analyses. Our implementation approach is guided by the Exploration, Preparation, Implementation, Sustainment (EPIS) framework.Methods/designWe will use a Sequential, Multiple Assignment Randomized Trial (SMART) to randomize 2710 patients from the outpatient clinics at Kisumu County Hospital (KCH) who have MDD, PTSD or both to either 12 weekly sessions of non-specialist-delivered Interpersonal Psychotherapy (IPT) or to 6 months of fluoxetine prescribed by a nurse or clinical officer. Participants who are not in remission at the conclusion of treatment will be re-randomized to receive the other treatment (IPT receives fluoxetine and vice versa) or to combination treatment (IPT and fluoxetine). The SMART-DAPPER Implementation Resource Team, (IRT) will drive the application of the EPIS model and adaptations during the course of the study to optimize the relevance of the data for generalizability and scale –up.DiscussionThe results of this research will be significant in three ways: 1) they will determine the effectiveness of non-specialist delivered first- and second-line treatment for MDD and/or PTSD, 2) they will investigate key mechanisms of action for each treatment and 3) they will produce tailored adaptive treatment strategies essential for optimal sequencing of treatment for MDD and/or PTSD in low resource settings with associated cost information – a critical gap for addressing a leading global cause of disability.Trial registrationClinicalTrials.govNCT03466346, registered March 15, 2018.

Optimizing patient expectancy in the pharmacologic treatment of major depressive disorder.

Patient expectancy is an important source of placebo effects in antidepressant clinical trials, but all prior studies measured expectancy prior to the initiation of medication treatment. Little is known about how expectancy changes during the course of treatment and how such changes influence clinical outcome. Consequently, we undertook the first analysis to date of in-treatment expectancy during antidepressant treatment to identify its clinical and demographic correlates, typical trajectories, and associations with treatment outcome. Data were combined from two randomized controlled trials of antidepressant medication for major depressive disorder in which baseline and in-treatment expectancy assessments were available. Machine learning methods were used to identify pre-treatment clinical and demographic predictors of expectancy. Multilevel models were implemented to test the effects of expectancy on subsequent treatment outcome, disentangling within- and between-patient effects. Random forest analyses demonstrated that whereas more severe depressive symptoms predicted lower pre-treatment expectancy, in-treatment expectancy was unrelated to symptom severity. At each measurement point, increased in-treatment patient expectancy significantly predicted decreased depressive symptoms at the following measurement (B = -0.45, t = -3.04, p = 0.003). The greater the gap between expected treatment outcomes and actual depressive severity, the greater the subsequent symptom reductions were (B = 0.49, t = 2.33, p = 0.02). Greater in-treatment patient expectancy is associated with greater subsequent depressive symptom reduction. These findings suggest that clinicians may benefit from monitoring and optimizing patient expectancy during antidepressant treatment. Expectancy may represent another treatment parameter, similar to medication compliance and side effects, to be regularly monitored during antidepressant clinical management.

Heart rate variability as a biomarker of anxious depression response to antidepressant medication.

There is a need to identify biomarkers of treatment outcomes for major depressive disorder (MDD) that can be disseminated. We investigated the predictive utility of pretreatment heart rate variability (HRV) for outcomes of antidepressant medication in MDD, with pretreatment anxious depression as a hypothesized moderator of HRV effects. A large, randomized, multicenter practical trial (International Study to Predict Optimized Treatment in Depression) in patients with current nonpsychotic MDD (N=1,008; 722 completers) had three arms: escitalopram, sertraline, and venlafaxine-extended release. At pretreatment, patients were defined as having anxious (N=309) versus nonanxious (N=413) depression and their resting high-frequency HRV (root mean square of successive differences) was assessed. Patients' usual treating clinicians managed medication. At 8weeks, primary outcomes were clinician-rated depressive symptom response and remission; secondary outcomes were self-reported response and remission. Pretreatment HRV predicted antidepressant outcomes as a function of anxious versus nonanxious depression. In anxious depression, patients with higher HRV had better outcomes, whereas patients with lower HRV had poorer outcomes. In nonanxious depression, patients with lower HRV had better outcomes, whereas patients with higher HRV had poorer outcomes. Some simple effects were not significant. Results did not differ by treatment arm and remained significant when controlling for important covariates. These findings inform a precision medicine approach in which clinical and biological assessments may be integrated to facilitate treatment outcome prediction. Knowing about HRV may help determine which patients with anxious depression could benefit from antidepressants and which patients may require a different treatment approach.

Optimizing Patient Expectancy in the Pharmacologic Treatment of Major Depressive Disorder

Objective: Patient expectancy is an important source of placebo effects in antidepressant clinical trials, but all prior studies measured expectancy prior to the initiation of medication treatment. Little is known about how expectancy changes during the course of treatment and how such changes influence clinical outcome. Consequently, we undertook the first analysis to date of in-treatment expectancy during antidepressant treatment to identify its clinical and demographic correlates, typical trajectories, and associations with treatment outcome. Method: Data were combined from two randomized controlled trials of antidepressant medication for Major Depressive Disorder in which baseline and in-treatment expectancy assessments were available. Machine learning methods were used to identify pre-treatment clinical and demographic predictors of expectancy. Multilevel models were implemented to test the effects of expectancy on subsequent treatment outcome, disentangling within- and between-patient effects. Results: Random forest analyses demonstrated that whereas more severe depressive symptoms predicted lower pre-treatment expectancy, in-treatment expectancy was unrelated to symptom severity. At each measurement point, increased in-treatment patient expectancy significantly predicted decreased depressive symptoms at the following measurement (p=.003). The greater the gap between expected treatment outcomes and actual depressive severity, the greater the subsequent symptom reductions were (p=.02). Conclusions: Greater in-treatment patient expectancy is associated with greater subsequent depressive symptom reduction. These findings suggest that clinicians may benefit from monitoring and optimizing patient expectancy during antidepressant treatment. Expectancy may represent another treatment parameter, perhaps similar to medication compliance and side effects, to be regularly monitored during antidepressant clinical management. Funding Statement: Work on this paper was supported by NIMH grant K23 MH085236 and R01 MH102293 (Dr. Rutherford). Declaration of Interests: Drs. Zilcha-Mano, Brown, Roose, Cappetta and Rutherford have no disclosures to report.

Healthcare professionals\u2019 perceptions on the emotional impact of having an inadequate response to antidepressant medications: survey and prospective patient audit

BackgroundDespite the availability of effective antidepressants, about half of patients with major depressive disorder (MDD) display an inadequate response to their initial treatment. A large patient survey recently reported that 29.8% of MDD patients experiencing an inadequate treatment response felt frustrated about their medication and 19.2% were frustrated with their healthcare provider. This survey and chart audit evaluated healthcare professionals’ (HCP) views on the emotional impact of having an inadequate response to antidepressant medication.MethodsHCPs who frequently treat patients with MDD completed a survey and chart audit of their MDD patients currently experiencing an inadequate response to antidepressant treatment.Results287 HCPs completed 1336 chart audits. HCPs reported that 38% of their patients were trusting/accepting of their MDD medications and 41% of their patients trusted/felt confident with their healthcare provision. Conversely, HCPs reported that 11% of their patients were frustrated with their medication and 5% with their healthcare benefits. HCPs cited impact on daily life (53%) and treatment issues (lack of efficacy and side effects; 50%) as the main drivers for their patients’ feelings of frustration. When HCPs recognized patients’ feelings of frustration, the top concerns of the HCPs were worsening of symptoms (43%) and non-compliance (41%).ConclusionsThis survey and chart audit highlights the emotional burden associated with inadequate responses to MDD treatment in addition to persistent symptoms. Differences between the views of the HCPs and patients are highlighted and suggest that HCPs may underestimate the full impact that having to try numerous medications has on their patients.

Efficacy of negative allosteric modulators of mGlu2 and mGlu3 in a rodent model of Major depressive disorder

IntroductionCurrent first‐line medications for Major depressive disorder (MDD) exhibit an undesirable delay in onset and poor efficacy in the general population, and there remains a great unmet need for novel fast‐acting antidepressant medications that retain efficacy in treatment‐resistant populations. The rapid reversal of depressive‐like symptoms by ketamine and related antidepressants is thought to be mediated by acutely enhancing glutamate signaling within the prefrontal cortex (PFC). Likewise, non‐selective antagonists that inhibit metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3), exemplified by LY341495, modulate PFC glutamate transmission and have shown efficacy in preclinical models of MDD. Previous research has relied heavily on molecules that display similar potency for inhibiting mGlu2 and mGlu3, thus the specific contributions of each individual mGlu subtype remain unclear. Recently, our lab has developed highly selective and centrally penetrant negative allosteric modulators (NAMs) for both mGlu2 and mGlu3. These exciting new tools have allowed us to test the hypothesis that selectively inhibiting mGlu2 or mGlu3 will confer rapid antidepressant efficacy in rodent models of depressive‐like behavior.MethodsWe modeled MDD symptomology in adult C57Bl/6J mice through chronic (4‐week) treatment with the stress hormone corticosterone (CORT). Anxiogenic, anhedonic, and depressive outcomes were assessed using a battery of behavioral assays. To interrogate the effects of CORT treatment on PFC function, we evaluated basal membrane and synaptic properties of layer 5 pyramidal neurons and we assessed mGlu function through a variety of pharmacological approaches.ResultsChronic CORT treatment induced anhedonic‐ and depressive‐like behaviors in adult mice while no effects on anxiety‐like behavior were observed. Acute treatment with either the mGlu2 NAM VU6001966 or the mGlu3 NAM VU0650786 reversed CORT‐induced anhedonia as assessed with the sucrose preference test. In contrast, VU6001966 and VU0650786 exhibited differential effects on despair‐like behavior in the tail suspension and forced swim tests. In slices prepared from the PFC, we found that acute application of LY341495 or VU6001966 enhanced glutamate transmission, while VU0650786 was without effect.ConclusionsWe have validated that chronic CORT treatment induces several behavioral and synaptic changes consistent with a depressive‐like phenotype. Together, our data suggest that NAMs of both mGlu2 or mGlu3 reverse stress‐induced anhedonia and should continue to be explored as potential treatments for MDD. However, the mechanisms of action of these two drug classes is distinct and warrants further study. We are continuing to explore these mechanistic differences as well as the specific neurocircuits affected by CORT exposure and mGlu2 and mGlu3 NAM treatment.Support or Funding InformationThis work was supported by National Institutes of Health (NIH) grants R01MH062646 and R37NS031373 (P.J.C.). M.E.J. was supported by NIH grant T32MH093366 and a postdoctoral fellowship through the Pharmaceutical Research and Manufacturers of America Foundation.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Novel Glutamatergic Treatments for Severe Mood Disorders.

All currently approved antidepressant medications for major depressive disorder (MDD) and bipolar disorder act primarily on the monoaminergic system and have varying affinities for serotonergic, norepinephrine-ergic, and/or dopaminergic receptors. Unfortunately, these drugs are only effective in approximately two-thirds of patients. Glutamate is the major excitatory neurotransmitter in the central nervous system, and the glutamatergic system has been implicated in the pathophysiology of MDD. Here, we review the putative involvement of the glutamate receptor subtypes-N-methyl-D-aspartate (NMDA), α-amino-3-hydroxyl-5-methyl-4-isoxazoleproprionic acid (AMPA), kainate, and the group I, II, and III metabotropic glutamate receptors (mGluRs)-in the development of novel and more effective treatments for MDD as well as preclinical and clinical trials of drugs targeting these receptors. The rapid and robust antidepressant effects of ketamine-an NMDA receptor antagonist-have been consistently replicated in multiple trials. Other glutamatergic drugs have been investigated with varying success. Here, we highlight some of the most interesting results, including: 1) repeated oral, intramuscular, and sublingual ketamine appears to be less robustly effective than intravenous ketamine, but also causes fewer significant adverse effects; 2) the glycine partial agonist GLYX-13 appears to be effective both as monotherapy and adjunctive treatment in the treatment of MDD. An oral analogue, NRX-1074, is currently under investigation; and 3) mGluR modulators targeting mGluR5 have demonstrated convincing preclinical results.

Brexpiprazole: another multipurpose antipsychotic drug?

Brexpiprazole (also known as OPC-34712 or Lu-AF41156) is a novel molecular compound chemically and structurally similar to aripiprazole. This drug is currently under review by the U.S. Food and Drug Administration as a monotherapy for schizophrenia and an adjunct to antidepressant medication for major depressive disorder. Additional clinical trials include studies of brexpiprazole in attention-deficit/hyperactivity disorder and posttraumatic stress disorder, and for agitation associated with dementia of the Alzheimer's type. Brexpiprazole is an example that illustrates how pharmacological drug diversity may be translated to multipurpose uses.

Copy number variants and therapeutic response to antidepressant medication in major depressive disorder

It would be beneficial to find genetic predictors of antidepressant response to help personalise treatment of major depressive disorder (MDD). Rare copy number variants (CNVs) have been implicated in several psychiatric disorders, including MDD, but their role in antidepressant response has yet to be investigated. CNV data were available for 1565 individuals with MDD from the NEWMEDS (Novel Methods leading to New Medications in Depression and Schizophrenia) consortium with prospective data on treatment outcome with either a serotonergic or noradrenergic antidepressant. No association was seen between the presence of CNV (rare or common), the overall number of CNVs or genomic CNV 'burden' and antidepressant response. Specific CNVs were nominally associated with antidepressant response, including 15q13.3 duplications and exonic NRXN1 deletions. These were associated with poor response to antidepressants. Overall burden of CNVs is unlikely to contribute to personalising antidepressant treatment. Specific CNVs associated with antidepressant treatment require replication and further study to confirm their role in the therapeutic action of antidepressant.

PMH48 - Factors Associated with Poor Adherence in Patients Initiating Medication for Major Depressive Disorder: Interim Results from a Prospective, Longitudinal Study

PMH48 - Factors Associated with Poor Adherence in Patients Initiating Medication for Major Depressive Disorder: Interim Results from a Prospective, Longitudinal Study

The influence of comorbid personality disorder on the effects of behavioural activation vs. antidepressant medication for major depressive disorder: Results from a randomized trial in Iran

There is a disagreement about the impact of personality disorder (PD) on treatment outcome for patients with major depressive disorder (MDD). 100 out-patients with MDD were randomized to 16 sessions of behavioural activation (BA) (n = 50) or antidepressant medication (ADM) (n = 50) in Iran. Main outcome was depression severity, measured with the Beck Depression Inventory (BDI-II) and the Hamilton Rating Scale for Depression (HRSD), and assessed at 0, 4, 13 and 49 weeks. Participants with comorbid PDs had higher scores on BDI and HRSD at baseline and throughout the study than participants without comorbid PD. Patients with and without comorbid personality pathology responded equally to treatment on the short-and the long-term. Overall, BA was better in reducing symptoms in patients but this effect was not influenced by comorbid PD. Similar effects were found for a dimensional PD-measure. Only cluster-C PD-traits turned out to be associated with overall depression severity. Cluster-A PD-traits predicted poorer long-term treatment response to ADM and BA, but only on the BDI, not on the HRSD. No effects of cluster-B PD-traits were found. However, PD was associated with higher dropout. The general conclusion is that comorbid PD pathology, especially from cluster-C, is associated with higher depression severity, but not with less response to treatment. Comorbid PD did predict increased chance of dropout.

Selecting Among Second-Step Antidepressant Medication Monotherapies

Little is known about selecting among second-step medications for major depressive disorder after intolerance or lack of remission with an initial selective serotonin reuptake inhibitor. To determine whether sociodemographic, clinical, or first-step treatment features predict remission with or intolerance overall or differentially to any 1 of 3 second-step medications after an unsatisfactory outcome with citalopram hydrobromide. An equipoise stratified randomized study. Participants were recruited from July 17, 2001, through April 20, 2004. Public or private sector primary care (n = 18) and psychiatric care (n = 23) settings across the United States. Representative outpatients aged 18 to 75 years with nonpsychotic major depressive disorder (N = 727). Sustained-release bupropion hydrochloride was started at 150 mg/d and incrementally increased to 400 mg/d. Sertraline hydrochloride was started at 50 mg/d and incrementally increased to 200 mg/d. Extended-release venlafaxine hydrochloride was started at 37.5 mg/d and incrementally increased to 375 mg/d. The 16-item Quick Inventory of Depressive Symptomatology, Self-Rated and the Frequency, Intensity, and Burden of Side Effects Rating. Remission was more likely among participants who were white, employed, cohabiting or married, or privately insured or who had prior intolerance to citalopram or at least a response to citalopram, and no prior suicide attempts. Remission was less likely among participants with concurrent generalized anxiety, obsessive-compulsive, panic, or posttraumatic stress disorders; social phobia; anxious or melancholic features; or more severe depression. Intolerance was less likely for Hispanic participants, but more likely for participants with previous suicide attempts or intolerance to citalopram. Participants with concurrent substance use were less likely to remit (odds ratio, 0.37) and more likely not to tolerate extended-release venlafaxine. Intolerance to citalopram was associated with intolerance to sertraline (P = .04). Clinical, demographic, and treatment history were of little value in recommending 1 medication vs another as a second-step treatment for major depressive disorder. Participants most likely to remit in the second step had less Axis I psychiatric disorder comorbidity, less social disadvantage, and at least a response to citalopram in the first step. clinicaltrials.gov Identifier: NCT00021528.

Placebo Control Groups in Trials of Major Depressive Disorder Among Older Patients

Ethical concerns have been raised regarding the continued use of placebo control groups in randomized controlled trials of antidepressant medications for major depressive disorder. These concerns may be especially relevant for geriatric patients who may experience significant morbidity related to major depressive disorder. Sixty-eight randomized placebo-controlled trials of antidepressant medication for major depressive disorder were examined, 6 of which measured response to medication and placebo in elderly patients. Although this review is limited by the small number of studies focusing on older individuals, there are a number of similarities and some differences in geriatric studies in comparison to other studies of adults with major depressive disorder. In comparison to studies of younger adults, the proportion of patients responding to placebo in studies of older individuals was slightly higher, and the proportion of patients responding to active medication was lower, leading to a significantly reduced effect size. The scientific importance of using control groups in studies of major depression poses ethical challenges. However, the substantial and variable response to placebo and the inability to predict accurately the response to placebo or medication raise serious doubts about the scientific value of trials of new medications in which there is no placebo group.

Placebo response in studies of major depression: variable, substantial, and growing.

Intense debate persists about the need for placebo-controlled groups in clinical trials of medications for major depressive disorder (MDD). There is continuing interest in the development of new medications, but because effective antidepressants are already available, ethical concerns have been raised about the need for placebo groups in new trials. To determine whether the characteristics of placebo control groups in antidepressant trials have changed over time. We searched MEDLINE and PsychLit for all controlled trials published in English between January 1981 and December 2000 in which adult outpatients with MDD were randomly assigned to receive medication or placebo. Seventy-five trials met our criteria for inclusion. Data were extracted from the articles by 2 of the authors and discrepancies were resolved via discussion and additional review by a third author. The mean (SD) proportion of patients in the placebo group who responded was 29.7% (8.3%) (range, 12.5%-51.8%). Most studies examined more than a single active medication, and, in the active medication group with the greatest response, the mean (SD) proportion of patients responding was 50.1% (9.0%) (range, 31.6%-70.4%). Both the proportion of patients responding to placebo and the proportion responding to medication were significantly positively correlated with the year of publication (for placebo: n = 75; r = 0.45; 95% confidence interval [CI], 0.25-0.61; P<.001; for medication: n = 75; r = 0.26; 95% CI, 0.03-0.46; P =.02). The association between year of publication and response rate was more statistically robust for placebo than medication. The response to placebo in published trials of antidepressant medication for MDD is highly variable and often substantial and has increased significantly in recent years, as has the response to medication. These observations support the view that the inclusion of a placebo group has major scientific importance in trials of new antidepressant medications and indicate that efforts should continue to minimize the risks of such studies so that they may be conducted in an ethically acceptable manner.