Antidepressant Trials Research Articles

Cause-specific life years lost in individuals with treatment-resistant depression: A Danish nationwide register-based cohort study

BackgroundDepression is associated with excess mortality, but it is not known how treatment-resistance influences life expectancy. We estimated cause-specific excess mortality and Life Years Lost (LYL) in patients with treatment-resistant depression (TRD). MethodsThe population included all individuals born and living in Denmark who redeemed their first prescription for an antidepressant at age 18–69 years between 2005 and 2012, identified in the Danish National Prescription Registry. TRD was defined as at least two additional and different antidepressant trials within two years. Mortality rate ratios (MRRs) were estimated with Cox regression adjusted for age at first prescription, calendar year and comorbidity. Differences in life expectancy were estimated by the Life Years Lost (LYL) method. ResultsThe cohort included 154,513 first-time pharmacologically treated patients with depression, of whom 8,294 (5.4%) were identified as having TRD. Patients were followed for 1,032,245 person-years during which 9,795 deaths occurred. Men and women with TRD had significantly higher mortality than non-TRD (aMRR: 1.34, 95% CI 1.18–1.52 and aMRR: 1.39, 95% CI 1.19–1.63, respectively). Life expectancy for men and women with TRD was 1.21 (95% CI 0.36–2.44) and 1.24 (95% CI 0.35–2.34) years shorter than in all patients with depression. Suicide accounted for the majority of excess LYL, with 1.10 (95% CI 0.46–1.61) years in men and 0.82 (95% CI 0.44–1.27) years in women with TRD. LimitationsUsing redeemed prescriptions to define TRD may increase the risk of misclassification. ConclusionsPatients not responding adequately to several treatment trials are at increased risk for premature death, particularly suicide.

Slowed Processing Speed Disrupts Patient Expectancy in Late Life Depression

ObjectiveSlowed processing speed and executive dysfunction are associated with poor outcomes in Late Life Depression (LLD), though it is unclear why. We investigated whether these variables interfere with the development of positive treatment expectancies in an antidepressant trial. MethodsDepressed older subjects were randomized to Open (intended to increase patient expectancy) or Placebo-controlled (termed ‘Hidden,’ intended to decrease expectancy) administration of antidepressant medication for 8 weeks. Analysis of covariance analyzed the between-group difference on expectancy (Credibility and Expectancy Scale [CES]) and depression (Hamilton Rating Scale for Depression [HRSD], Clinical Global Impressions [CGI] Severity). Moderator analyses examined whether these Open versus Hidden differences varied based on higher versus lower processing speed and executive function. ResultsAmong the 108 participants, a significant between-group difference was observed on expectancy (effect size [ES, Cohen's d] = 0.51 on CES Item 2; ES = 0.64 on Item 4), indicating the manipulation was effective. Processing speed as measured by the Stroop Color-Word Test (number color-words named in congruent condition) was a significant moderator of the Open versus Hidden effect on expectancy. Depressive symptom improvement was greater on average for Open versus Hidden participants who received active drug (CGI-severity ES = 1.25, HRSD ES = 0.41), but no neurocognitive moderators of the between-group difference reached statistical significance. ConclusionsSlowed processing speed impairs the development of expectancies in antidepressant trials for LLD, which may help explain lower antidepressant response among older adults. Future studies may address whether interventions to optimize treatment expectancies are capable of improving treatment outcomes.

The association between placebo arm inclusion and adverse event rates in antidepressant randomized controlled trials: An examination of the Nocebo Effect

BackgroundAntidepressant efficacy is influenced by patient expectations and, in randomized controlled trials (RCTs), the probability of receiving a placebo. It is unclear whether tolerability demonstrates a similar pattern. This study aimed to determine whether study design influences adverse event (AE) rates in antidepressant trials for subjects receiving active treatment or placebo. MethodsRCTs comparing one antidepressant to another antidepressant, placebo, or both in major depressive disorder (MDD) (1996-2018) were retrieved from Medline and PsycINFO. Clinicaltrials.gov was searched for unpublished trials. Of 1,997 studies screened, 77 trials were included. Studies were classified as drug-drug, drug-drug-placebo, or drug-placebo based on design and overall number of subjects experiencing any AE was recorded. Subgroup meta-analysis of proportions and meta-regression techniques were used to compare AE rates across study designs in patients receiving active antidepressant treatment and placebo. ResultsAmong the actively treated, AE rates were lower in drug-drug trials (58.5%) compared to drug-drug-placebo (75.7%) and drug-placebo (76.4%) (the model reported coefficients for percent differences between AE rates of different study designs were B=17.0, p<0.001 and B=17.8, p<0.001, respectively). AE rates in patients receiving placebo were not different between study designs. LimitationsThe present study is limited by the diverse range of study populations, variability in reporting of AEs, and specific antidepressants employed in the included trials. ConclusionsThe inclusion of a placebo arm in the study design was unexpectedly associated with higher rates of AEs among patients receiving active medication in antidepressant trials. This observation has important implications for interpretation of trial tolerability findings.

Post Marketing Rate of Seizures During Transcranial Magnetic Stimulation (TMS) Treatment with NeuroStar Advanced Therapy Is Lower Than Previously Estimated

Background: Published reviews and surveys of incident rate of seizures with any TMS device (Wasserman et al. 1998, Rossi et al. 2009, and Lerner 2019) revealed that the rate ranges from 0.003-0.043%. Many subjects that developed seizures during TMS were treated with parameters outside those recommended in TMS guidelines or were predisposed due to seizure threshold-lowering factors, e.g., concurrent use of certain medications or alcohol, sleep deprivation. Additionally, some non-epileptic events may have been misreported. The objective of this research is to determine the rate of seizures reported to Neuronetics, Inc. relative to treatment sessions and review the number of seizures reported in literature naming this device as the means of TMS delivery. Design/Methods: 1. We conducted a review of TMS literature published after Wasserman (1998) and Rossi (2009) that mentioned seizures and that named this system as the device used for TMS treatment through June 30, 2019. These are captured as part of Neuronetics’ post marketing surveillance procedure. We also reviewed articles that identified this device as that used to deliver TMS treatment. Articles that referenced single-pulse TMS and those that reported seizures during TMS treatment delivered to subjects with epilepsy were excluded. 2. We reviewed all seizure events reported to Neuronetics, Inc., directly or through FDA MedWatch, from time of FDA clearance through June 30, 2019. 3. Seizure incidences reported from antidepressant medication trials were reviewed for comparison. Results: The post marketing surveillance seizure rate with this system is 0.001%, or approximately 1 in 89,000 TMS treatments. Our literature review revealed that no seizures have been reported in articles that identified this system as the TMS system used. Additionally, this system was not named in any articles that reported seizures and identified the TMS system used. Conclusions: The rate of seizures reported for individuals receiving TMS with this system (0.001%) is generally lower than the rates reported in clinical trials for widely used antidepressant medications (0.1% to 0.4%).

Presence of PTSD does not affect outcomes from antidepressant treatment

The presence of concurrent post‐traumatic stress disorder (PTSD) did not affect the comparative effectiveness of medication strategies for a group of veterans with major depressive disorder and a prior failed antidepressant trial. Concurrent PTSD was associated with lower response and remission rates for all of the treatments, the researchers reported.

109 - Novel Treatments for Resistant Depression: Comparison of Older and Younger Patients

Treatment resistant depression (TRD) is defined as the failure to respond to two adequate antidepressant trials. TRD patients have high levels of psychosocial distress, poor levels of functioning and are at increased risk for suicide. Novel treatment approaches are being developed to address TRD involving both pharmacological and neuromodulation interventions. In this symposium, leaders in the field will outline three strategies for treating depression which has not responded to conventional therapy and contrast the efficacy of these strategies in younger vs. older patients. William McDonald MD (JB Fuqua Professor of Late -Life Depression, Emory University, Atlanta, GA) will provide a brief overview of TRD and moderate the discussion. George Petrides MD (Director of Clinical Trials Operation and Division of ECT, Zucker Hillside Hospital, New York, NY) will discuss recent data from the National Institute of Mental Health sponsored Consortium on ECT Research (CORE) outlining the response of older patients to ultrabrief right unilateral ECT in TRD. He will contrast the response to ECT in older vs, younger patients from the CORE database accumulated over the last 15 years. Collin Reiff MD (Addiction Psychiatrist, New York University Langone Health Center, NY, NY) will discuss his recent review in the American Journal of Psychiatry on Psychedelic and Psychedelic Assisted Psychotherapy and the implications on the treatment of medication resistant depression, including late life mood disorders. The FDA’s breakthrough designation of MDMA for the treatment of PTSD and psilocybin for the treatment of depression reflects the drugs’ potential to treat resistant psychiatric disorders. Psychedelic assisted therapy may play a unique role in late life mood disorders. Finally, Patricio Riva Posse MD (Director of the TRD and Ketamine Clinic, Emory University, Atlanta, GA) will discuss ketamine treatment in resistant depression including a comparison of response rates and safety data on ketamine treatment in older vs. younger patients. He has recently published the largest compilation of safety data for ketamine infusions and he will review a new tool to monitor safety in clinical practice. Dr. Riva Posse is medical director of the Emory TRD program and has enrolled over 1000 patients (100 in his IV ketamine clinic and about half over the age of 60 years) and followed patients through several novel treatments including transcranial magnetic stimulation, ketamine infusion therapy and ECT to start to look at differential response rates.

Preliminary Evidence That Cortical Amyloid Burden Predicts Poor Response to Antidepressant Medication Treatment in Cognitively Intact Individuals With Late-Life Depression

Amyloid accumulation, the pathological hallmark of Alzheimer's disease, may predispose some older adults to depression and cognitive decline. Deposition of amyloid also occurs prior to the development of cognitive decline. It is unclear whether amyloid influences antidepressant outcomes in cognitively intact depressed elders. A pharmacoimaging trial utilizing florbetapir (18F) PET scanning followed by 2 sequential 8-week antidepressant medication trials. Twenty-seven depressed elders who were cognitively intact on screening. After screening, diagnostic testing, assessment of depression severity and neuropsychological assessment, participants completed florbetapir (18F) PET scanning. They were then randomized to receive escitalopram or placebo for 8 weeks in a double-blinded two-to-one allocation rate. Individuals who did not respond to initial treatment transitioned to a second open-label trial of bupropion for another 8 weeks. Compared with 22 amyloid-negative participants, 5 amyloid-positive participants exhibited significantly less change in depression severity and a lower likelihood of remission. In the initial blinded trial, 4 of 5 amyloid-positive participants were nonremitters (80%), while only 18% (4 of 22) of amyloid-negative participants did not remit (p = 0.017; Fisher's Exact test). In separate models adjusting for key covariates, both positive amyloid status (t = 3.07, 21 df, p = 0.003) and higher cortical amyloid binding by standard uptake value ratio (t = 2.62, 21 df, p = 0.010) were associated with less improvement in depression severity. Similar findings were observed when examining change in depression status across both antidepressant trials. In this preliminary study, amyloid status predicted poor antidepressant response to sequential antidepressant treatment. Alternative treatment approaches may be needed for amyloid-positive depressed elders.

Comparative efficacy of placebos in short-term antidepressant trials for major depression: a secondary meta-analysis of placebo-controlled trials

BackgroundThe issue of unblinded outcome-assessors and patients has repeatedly been stressed as a flaw in allegedly double-blind antidepressant trials. Unblinding bias can for example result from a drug‘s marked side effects. If such unblinding bias is present for a given drug, then it might be expected that the placebos of that drug are rated significantly less effective than that of other antidepressants.MethodsTo test this hypothesis, the present exploratory analysis conducted a Bayesian network meta-analysis (NMA) comparing the efficacy of 19 different placebos in placebo-controlled trials provided in the dataset by Cipriani et al. (Lancet 2018; 391: 1357–66). Primary outcome was efficacy (continuous) estimated on the standardized mean difference (SMD) scale and defined as the pre-post change on the Hamilton Depression scale (HAMD-17), on which information was available in N = 258 trials.ResultsComparative placebo ranking suggested mirtazapine-placebo (SMD -2.0 [− 5.0–1.0 95% CrI]) to be the most, and amitriptyline- (SMD 1.2 [− 1.6–3.9 95% CrI]) and trazodone- (SMD 2.1 [− 0.9–5.2 95% CrI]) placebos to be the least effective placebos. Other placebos suggested to be more effective than amitriptyline- and trazodone-placebos (based on 95% CrIs excluding zero) were citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, sertraline, and venlafaxine placebos. These NMA results were corroborated by the observation that the relative efficacy between drug and placebo was considerably larger for amitriptyline and trazodone than for instance mirtazapine, duloxetine, and venlafaxine, supported by a small and insignificant correlation between drug-efficacy and placebo-efficacy (r = − 0.202, p = 0.408).DiscussionThe present exploratory NMA indicates that distinguishable side effects of older drugs may unblind outcome-assessors thus resulting in overestimation of the average drug-placebo difference and underrating bias in placebo-arms, particularly for the older antidepressant drugs amitriptyline and trazodone. If confirmed in prospective studies, these findings suggest that efficacy rankings for antidepressants are susceptible to bias and should be considered unreliable or misleading. The analysis is limited by the focus on the single-comparison placebos (76%, i.e., placebos assessed in two-arm trials), since double-comparison placebos (25%, i.e., placebos assessed in three-arm trials) are hard to interpret and therefore not included in the present interpretation. Another limitation is the problem of multiplicity, which was only approximately accounted for in the Bayesian NMA by modelling treatment effects as exchangeable.

Pharmacological Management of Neuropsychiatric Symptoms of Dementia.

Neuropsychiatric symptoms are universal across all stages and types of dementia and can cause significant challenges for patients and caregivers. While there are currently no approved medications for treatment of neuropsychiatric symptoms of dementia, a variety of psychotropic medications such as antipsychotics, benzodiazepines, anticonvulsants, and antidepressants are used off-label to treat these symptoms. This systematic review evaluated the available evidence for effectiveness and tolerability of pharmacologic treatments in addressing behavioral disturbances in dementia. Inclusion criteria were placebo-controlled, randomized controlled clinical trials (RCTs) or meta-analyses; a total of 38 studies and 3 meta-analyses representing an additional 27 RCTs met the inclusion criteria. Of the medication classes evaluated, atypical antipsychotics had the greatest available evidence for use, however, the treatment effect size was modest. Nine trials of antidepressants were included; 3 trials supported use in dementia. Eight trials of anticonvulsants were included; only one showed benefit. For benzodiazepines, 2 RCTs were included; only one trial of lorazepam showed improvement. Six trials of melatonin agonists were included; none showed efficacy outside of improved sleep measures. Evidence for effectiveness of pimavanserin and dextromethorphan-quinidine was limited to one study each, both of which showed benefit. Despite the widespread off-label use of psychotropic medications for treatment of neuropsychiatric symptoms in dementia, there are relatively few RCTs to evaluate their use with treatment effect sizes absent or modest for most medication classes. Of the medication classes reviewed, atypical antipsychotics have the best evidence for effectiveness, however, the overall magnitude of treatment effect is modest and must be balanced with risk of serious adverse events including death.

Bilateral sequential theta burst stimulation for multiple-therapy-resistant depression: A naturalistic observation study

Depression is a significant health issue with treatment resistance reported in about one third of patients. Treatment resistance results in significant disability, impaired quality of life, and increased healthcare costs. Repetitive transcranial magnetic stimulation (rTMS) is a treatment option for treatment resistant depression (TRD) with response and remission rates in open-label studies being as high as 58% and 37% respectively. Theta-burst is a faster and novel rTMS paradigm that has shown promise as a treatment for TRD in some preliminary studies. In a naturalistic design, we evaluated the response, remission and tolerability of bilateral sequential (right then left) prefrontal theta-burst rTMS (bsTBS) in 50 patients with TRD (600 pulses/session, 20 sessions, 100% of resting motor threshold (80% if intolerant to 100%, n = 2), F4/F3 of 10-20-20 EEG localization). Data was collected over 36 months from a specialized academic TMS clinic. Patients had multiple-treatment resistance with at least two failed trials of different antidepressants with 20% also having failed electroconvulsive therapy and 66% having received professional therapy. We found a 28% remission rate (HAMD-17 score of ≤7) and a 52% response rate (≥50% reduction in HAMD-17) with a 42% reduction in average HAMD-17 score. The treatment was well tolerated, with muscle contractions, mild pain or discomfort, headache, scalp irritation, and changes to vitals being captured as occasional adverse events with two instances of syncope (0.22% of treatments). This naturalistic study shows that bsTBS is a promising paradigm for a multiple-TRD patient population with approximately one-third of treatments achieving remission and over half achieving significant response.

What have antidepressants been tested for? A systematic review.

Antidepressants are much used and have been tested for many conditions. To investigate the type of diagnoses in placebo-controlled trials apart from depression and anxiety. This was a systematic review. We downloaded 5471 records from PubMed and excluded 3017 that contained depression or anxiety. After exclusion of non-eligible studies, meta-analyses and reviews, and records that were unclear, 1273 records remained. We counted 214 unique diagnoses, of which the most common were abuse of drugs or substances (227 records), pain or neuropathy (170), obesity (125), other eating disorders (45), obsessive compulsive disorder (66), sexual dysfunction (41), gastrointestinal disorders (40), menopausal symptoms/hot flashes (36), premenstrual dysphoric disorder (27), urinary incontinence (21), post-traumatic stress disorder (38), schizophrenia (31), dementia or cognition problems (25), insomnia (19), ADHD (17), autism spectrum disorders (14), and stroke or traumatic brain injury (15). Trials of antidepressants may be driven mainly by commercial interests, focusing on prevalent diseases and everyday problems. No one can live a full life without experiencing several of the problems for which these drugs were tested. Antidepressants, sometimes called happy pills, could be seen as the modern version of Aldous Huxley's soma pill intended to keep everyone happy in the "Brave New World".

Pharmacologic and psychological interventions for depression treatment in patients with kidney disease.

It remains controversial whether existing therapies, including pharmacologic and psychological interventions, are effective for treatment of depression in patients with chronic kidney disease (CKD) and end-stage kidney disease. Most studies of depression treatment were underpowered or uncontrolled. The CKD Antidepressant Sertraline Trial showed no benefit of a serotonin-selective reuptake inhibitor (SSRI), sertraline, over double-blind matched placebo for the treatment of depressive symptoms in patients with nondialysis CKD. A Trial of Sertraline vs. Cognitive Behavioral Therapy (CBT) for End-stage Renal Disease Patients with Depression showed improvement in depressive symptoms from baseline in both groups and a marginal benefit of sertraline over CBT that was of unclear clinical significance, given the lack of an active control group. SSRIs are associated with poor tolerability in clinical trials and serious adverse outcomes in large retrospective studies. Although the data do not support unlimited use of SSRIs in patients with CKD or end-stage kidney disease, it is reasonable to initiate a cautious trial of sertraline while closely monitoring for depressive symptom improvement and adverse effects. CBT is a low-risk, possibly effective intervention to treat major depressive disorder in patients with kidney disease who have access to such treatments.

Procognitive Effects of Antidepressants and Other Therapeutic Agents in Major Depressive Disorder: A Systematic Review.

To review the efficacy of antidepressants and other therapeutic agents for the treatment of cognitive impairment in adults with major depressive disorder (MDD). We conducted a database search of MEDLINE, PsycINFO, and Embase through Ovid on May 7, 2019. The year of publication was not restricted. The search terms "Major Depressive Disorder," "depress*," "cognit*," and "therapeutics" were used. The studies included in this review were clinical trials of antidepressants and other therapeutic agents in MDD populations. Participants were aged between 18 and 65 years and had a DSM-III, -IV, or -5 diagnosis of MDD. In total, 2,045 research papers were screened, 53 full-text articles were assessed, and 26 articles were eligible to be included in this systematic review. The data and quality of research papers were assessed and screened by 2 independent reviewers. Discrepancies were resolved through a third reviewer. Overall, studies demonstrated that tricyclic antidepressants do not have procognitive effects, while vortioxetine and bupropion have demonstrated procognitive effects in MDD populations relative to selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. Several non-antidepressant agents, such as modafinil, amphetamines, and erythropoietin, have also demonstrated significant positive effects on cognition in depression. Present-day antidepressants and other agents have demonstrated procognitive effects in MDD, but the findings between various agents are mixed. Further research looking at objective measures of cognitive performance would be helpful to obtain more definitive results regarding the efficacy of therapeutics for cognitive impairment in MDD.

An old but still burning problem: Inter-rater reliability in clinical trials with antidepressant medication

BackgroundAntidepressant trials are criticized due to potential methodological flaws. Root causes of failing methodology can be found in insufficient inter-rater reliability (IRR) and training practices, leading to higher placebo response and reduced study-power. However, it is unknown to what extent reliability estimates or training procedures are currently included in antidepressant reports. Therefore, we aimed to determine the proportion of publications concerning double-blind randomized controlled antidepressant trials that report on IRR coefficients and training procedures. MethodsWe extracted all double-blind randomized clinical trials (RCTs) from the meta-analysis of Cipriani et al. (2018) concerning the period from 2000 until January 2016. Further, we conducted a Medline-search for double-blind RCTs from January 2016 until January 2020 for additional reports. We identified IRR coefficients and training procedures in these publications. ResultsIn total we identified 179 double-blind RCTs. Only 4.5% reported an IRR coefficient whereas 27.9% reported training procedures. LimitationsWe did not contact individual authors for additional information regarding implementation of training procedures or inter-rater reliability assessment. ConclusionsThere is a substantial lack of reporting IRR coefficients and training procedures in RCTs with antidepressant medication. Considering the large implications of insufficient reliability, we urge researchers to conduct and report training procedures and reliability estimations.

The effects of childhood trauma on the onset, severity and improvement of depression: The role of dysfunctional attitudes and cortisol levels

Background: Childhood trauma is an important early social risk factor for the development of the major depressive disorder (MDD). Both childhood trauma and depression are associated with dysfunctional attitudes and dysregulation in stress hormones. We aimed to clarify the path from childhood trauma to depression and identify potential predictors of antidepressant treatment outcomes.Objectives: One hundred and thirty-nine MDD patients and 112 healthy controls were included at baseline. Depressive symptoms were assessed with both self-reported and expert-rated scales. Childhood trauma and dysfunctional attitudes were evaluated and blood cortisol levels were assayed. Patients received an open-label antidepressant trial with paroxetine and their depressive symptoms were monitored by the Hamilton Depression Rating Scale (HAMD) during 6 months of treatment. After 6 months, 94 patients received the same assessments as the baseline.Results: At baseline, the influence of childhood trauma on depression diagnosis was mediated by dysfunctional attitudes. In patients with MDD, the influence of childhood trauma on depression severity was mediated by both dysfunctional attitudes and cortisol levels. Baseline childhood trauma predicted the antidepressant treatment outcome during early treatment phase and baseline cortisol levels predicted the antidepressant treatment outcome at later treatment phase. After 6-month antidepressant treatment, a significant remission by time effect was found on dysfunctional attitudes and depression severity but not on cortisol levels.Conclusion: Effect of childhood trauma on depression onset was mediated by dysfunctional attitudes. The relationship between childhood trauma and depressive symptoms was mediated by dysfunctional attitudes and cortisol levels in MDD patients. Baseline childhood trauma and cortisol levels may be moderators for antidepressant treatment response at different treatment phase.

Impacts of rTMS on Refractory Depression and Comorbid PTSD Symptoms at a Military Treatment Facility.

Repetitive transcranial magnetic stimulation (rTMS) as a treatment for depression has been studied for over two decades. Repetitive TMS was approved by the Food and Drug Administration in 2008 for the treatment of depression after at least one failed trial of an antidepressant medication of adequate dose and duration. This study evaluated whether rTMS treatments may be associated with measurable improvements in depression and post-traumatic stress disorder (PTSD) symptoms for treated military beneficiaries in Hawaii suffering from depression. It also examined the number of failed medication trials that patients underwent before rTMS treatment. A retrospective chart review of 77 rTMS patients who received and completed treatment between January 1, 2010 and October 31, 2016 was performed. Under a typical treatment regimen, patients receive rTMS for 6 weeks as well as weekly psychiatric assessments, which included completion of Beck's Depression Inventory (BDI) and PTSD Checklist (PCL). A mixed model repeated measures analysis was done assuming an autoregressive order one covariance structure to evaluate changes over time. Adjusted analyses were done to assess whether changes over time differed by age, prior diagnosis of PTSD, active duty status, and gender. The majority of patients were from the army (74%) and 56% were on active duty. Just over half (53%) were male. Most patients (52%) had completed trials of three or more different antidepressant medications before initiation of treatment with rTMS. The mean number of antidepressant trials was 2.7. BDI and PCL scores were significantly lower at end of treatment on average compared to the pretreatment baseline scores. Mean differences for BDI and PCL were significant with P<0.001 15, 30, and 45days after TMS treatment was initiated. Overall, 44% of patients experienced a reduction ≥10 points on BDI, and 38% experienced a reduction ≥10 points on PCL. Additionally, scores fell similarly regardless of whether or not patients had a comorbid diagnosis of PTSD. Our research suggests that rTMS treatments may produce a reduction in symptoms of both depression and PTSD in patients with refractory depression and comorbid PTSD. It may be a useful alternative to antidepressants in the treatment of depression in the military population, including those with comorbid PTSD. Broader implementation of this treatment modality may prove beneficial for the purposes of military readiness, given current policies and restrictions on service members who are initiated on antidepressant medications.

Treatment-Resistant depression enhances risks of dementia and alzheimer's disease: A nationwide longitudinal study

BackgroundPrevious evidence indicates late-onset depression or depression with greater severity are associated with subsequent risk of dementia or Alzheimer's disease (AD). However, whether treatment-resistant depression is associated with such risks remain elusive. MethodsUsing the Taiwan Nationwide Health Insurance Research Database, 3,345 patients with newly-diagnosed major depressive disorder (MDD) and 13,380 well-matched controls were enrolled between 2002 and 2004. MDD patients were stratified according to their treatment response to adequate antidepressant trials, and all participants were followed up until the end of 2013. Those who developed dementia and AD were identified. ResultsMDD patients were more likely to develop dementia and AD than controls. Difficult-to-treat patients (i.e., DTT; those who failed to respond to at least two adequate antidepressant trials) had the highest risk of developing dementia (hazard ratio [HR] = 5.19) and AD (HR 4.44), whereas easy-to-treat patients (i.e., ETT-1; those who had no prescription of antidepressants) had the lowest risk of developing dementia (HR 2.37) and AD (HR 2.59) compared with controls. Subsequent analysis demonstrated that only among patients with late-onset depression (age > 65 years), DTT patients consistently showed higher risks and faster development of dementia (HR 6.64, mean: 1.45 yr) and AD (HR 4.97, mean: 1.67 yr) than did ETT-1 patients and controls. LimitationsSubjects who have not received medical examination were not included as diagnosis were determined by ICD codes. Also, longer follow-up period might be needed for the younger group. ConclusionsLate-onset treatment-resistant depression is associated with an elevated risk of dementia and AD.

Depression and the Effect of Sertraline on Inflammatory Biomarkers in Patients with Nondialysis CKD.

Inflammatory biomarkers are elevated in patients with CKD and associated with poor outcomes. Major depressive disorder (MDD) is prevalent in CKD and associated with inflammation. No studies investigated the effect of MDD treatment on plasma inflammatory biomarkers in patients with nondialysis CKD. In a prespecified analysis of the randomized, double-blind CKD Antidepressant Sertraline Trial, we investigated whether treatment with sertraline versus placebo or response to treatment would affect plasma levels of albumin, prealbumin, IL-6, and high-sensitivity C-reactive protein (hsCRP), measured at baseline and after 12 weeks of treatment. We also explored whether somatic versus nonsomatic depressive symptoms, measured using the Quick Inventory of Depressive Symptomatology, and quality-of-life subscales, measured using the Kidney Disease Quality of Life Short Form, were associated with baseline levels of these inflammatory biomarkers. Of the 193 participants, mean age was 58.4 (SD 13) years and 58% were black, 42% were white, and 18% were Hispanic. Higher baseline hsCRP correlated with somatic depressive symptoms (r=0.21; P=0.01), fatigue (r=0.22; P=0.005), and poorer physical functioning (r=-0.26; P=0.001). There was no change in hsCRP in the sertraline group. hsCRP increased in placebo nonresponders from baseline (median, 3.7 mg/L; interquartile range [IQR], 1.7-10.0 mg/L) to exit (median, 4.9 mg/L; IQR, 1.8-8.8 mg/L; P=0.01). The change from baseline to exit differed between placebo responders (median, -0.4 mg/L; IQR, -9.3 to 0.2 mg/L) and nonresponders (median, 0.8 mg/L; IQR, -0.1 to 3.9 mg/L; P=0.008). There were no differences in changes in albumin, prealbumin, or IL-6 from baseline in any group. Among patients with CKD and MDD, hsCRP correlated with somatic symptoms of depression and fatigue, but not with nonsomatic symptoms. Sertraline treatment was not associated with a longitudinal change in hsCRP from baseline regardless of treatment effect on depressive symptoms, but those who failed to respond to placebo had an increase in hsCRP over time. This area deserves further investigation. CKD Antidepressant Sertraline Trial (CAST), NCT00946998.

Electroconvulsive Therapy in Veterans Health Administration Hospitals: Prevalence, Patterns of Use, and Patient Characteristics.

The body of large-scale, epidemiological research on electroconvulsive therapy (ECT) in the United States is limited. To address this gap, we assessed demographic, clinical, pharmacological, and mental health treatment history as well as 2-year mortality outcomes associated with ECT use in the largest U.S. health care system. Among all patients who sought mental health care at Veterans Health Administration (VHA) hospitals in 2012, we used bivariate analyses to compare patients who did and not receive ECT during 2 years of follow-up. Among the population who received ECT, descriptive statistics were calculated to characterize prior mental health treatment patterns and ECT receipt. 0.11% (N = 1616) of all VHA mental health patients in 2012 (N = 1,457,053) received ECT in 2 years of follow-up. There was significant regional variation in provision of ECT. Those who received ECT were more likely to have diagnoses of major depressive, bipolar, and personality disorders and were significantly more likely to have had a recent mental health inpatient stay (risk ratio, 6.94). Receipt of ECT was not associated with a difference in all-cause mortality (risk ratio, 0.88). Thirty-two percent of those who received ECT had no substantial antidepressant or therapy trial in the year before index mental health encounter. Use of ECT in the VHA is rare. Patients who receive ECT have a complex and high-risk profile, not necessarily consistent with the most common indications for ECT.

Understanding the effects of chronic benzodiazepine use in depression: a focus on neuropharmacology.

Benzodiazepines are frequently prescribed on an ongoing basis to individuals with depression, mainly to alleviate anxiety or insomnia, despite current guideline recommendations that continuous use should not exceed 4 weeks. Currently, there are no efficacy trials published beyond 8 weeks. Several antidepressant trials demonstrate that the concomitant use of a benzodiazepine is associated with poorer depressive outcomes and functional status; however, it is unclear why this is the case. Patients with depression receiving a benzodiazepine may reflect a more ill or high anxiety group, although even within anxiety disorders, the use of a benzodiazepine is associated with poorer outcomes. The neuroadaptive consequences of long-term benzodiazepine use may be a factor underlying these findings. Chronic benzodiazepine use results in decreased gamma-aminobutyric acid and monoaminergic function, as well as interference with neurogenesis, which are all purported to play a role in antidepressant efficacy. This review will discuss the oppositional neuropharmacological interactions between chronic benzodiazepine use and antidepressant mechanism of action, which could result in reduced antidepressant efficacy and function in depression.