Antidepressant Trials Research Articles

Outlier-response pattern checks to improve measurement with the Montgomery-Asberg depression rating scale (MADRS)

Symptom manifestations in affective disorders can be subtle. Small imprecisions in measurement can lead to incorrect estimation of change. Previously, expert-derived scoring inconsistency flags were developed for MADRS. Currently, we derive empirically based outlier-pattern flags, to further detect imprecisions in ratings. NEWMEDS data repository of almost 25,000 MADRS administrations from 11 registration trials of antidepressants was used to identify outlier response patterns reflecting potentially careless responses. Coverage of these flags was compared to previously published expert derived flags. Both sets of flags were also further tested in Monte Carlo simulated data as a proxy to applying flags under conditions of known inconsistency. The outlier flags derived provide cutting points to identify: (1) under and overuse of values (e.g., Scoring “1″ on 6 or more items), (2) disproportionate use of even or odd response choices (e.g., 8 or more odd values), (3) longest consecutive use of value (e.g., more than 5 items in a row scored with same value), (4) high variability within administration (standard deviation greater than 1.8), (5) outlier responses on multiple items (i.e., multivariate outliers), and (6) outlier scoring (e.g., scoring 4,5 or 6 on item 1). Outlier response flags were raised in 26% of the MADRS administration and in 97% of the Monte Carlo data. Of administrations with no expert flag, 21.7% had an outlier flag and of administrations with at least one expert flag, 27.7% also had an outlier flag. Outlier-pattern flags appear to be a useful adjunct to expert derived flags in the quest to improve measurement in clinical trials.

Electroconvulsive therapy in treatment resistant depression

Electroconvulsive therapy (ECT) is a treatment modality for patients with treatment resistant depression (TRD), defined as failure of two adequate antidepressant medication trials. We provide a qualitative review of ECT's effectiveness for TRD, methods to optimize ECT parameters to improve remission rates and side effect profiles, and ECT's proposed neurobiological mechanisms. Right unilateral (RUL) electrode placement has been shown to be as effective for major depression as bilateral ECT, and RUL is associated with fewer cognitive side effects. There is mixed evidence on how to utilize ECT to sustain remission (i.e., continuation ECT, psychotropic medications alone, or a combination of ECT and psychotropic medications). Related to neurobiological mechanisms, an increase in gray matter volume in the hippocampus-amygdala complex is reported post-ECT. High connectivity between the subgenual anterior cingulate and the middle temporal gyrus before ECT is associated with better treatment response. Rodent models have implicated changes in neurotransmitters including glutamate, GABA, serotonin, and dopamine in ECT's efficacy; however, findings in humans are limited. Altogether, while ECT remains a highly effective therapy, the neurobiological underpinnings associated with improvement of depression remain uncertain.

P.0089 The placebo effect in clinical trials of modern antidepressants: a meta-analysis

P.0089 The placebo effect in clinical trials of modern antidepressants: a meta-analysis

P.0884 Routinely accessible parameters of mineralocorticoid receptor function, depression subtypes and response prediction: a post-hoc analysis from an antidepressant treatment trial

P.0884 Routinely accessible parameters of mineralocorticoid receptor function, depression subtypes and response prediction: a post-hoc analysis from an antidepressant treatment trial

Structural MRI-Based Measures of Accelerated Brain Aging do not Moderate the Acute Antidepressant Response in Late-Life Depression

ObjectiveLate-life depression (LLD) is characterized by accelerated biological aging. Accelerated brain aging, estimated from structural magnetic resonance imaging (sMRI) data by a machine learning algorithm, is associated with LLD diagnosis, poorer cognitive performance, and disability. We hypothesized that accelerated brain aging moderates the antidepressant response. Design and InterventionsFollowing MRI, participants entered an 8-week randomized, controlled trial of escitalopram. Nonremitting participants then entered an open-label 8-week trial of bupropion. ParticipantsNinety-five individuals with LLD. MeasurementsA machine learning algorithm estimated each participant's brain age from sMRI data. This was used to calculate the brain-age gap (BAG), or how estimated age differed from chronological age. Secondary sMRI measures of aging pathology included white matter hyperintensity (WMH) volumes and hippocampal volumes. Mixed models examined the relationship between sMRI measures and change in depression severity. Initial analyses tested for a moderating effect of MRI measures on change in depression severity with escitalopram. Subsequent analyses tested for the effect of MRI measures on change in depression severity over time across trials. ResultsIn the blinded initial phase, BAG was not significantly associated with a differential response to escitalopram over time. BAG was also not associated with a change in depression severity over time across both arms in the blinded phase or in the subsequent open-label bupropion phase. We similarly did not observe effects of WMH volume or hippocampal volume on change in depression severity over time. ConclusionsMRI markers of accelerated brain aging were not associated with treatment response in this sequential antidepressant trial.

Association of Single-blind Placebo Run-in Periods With the Placebo Response in Randomized Clinical Trials of Antidepressants

Single-blind placebo run-in (PRI) periods are common in randomized clinical trials (RCTs) of treatment for depression. They aim to increase sensitivity to detect drug effects; however, the association of PRI periods with study outcomes remains unclear. This is concerning given the costs of PRI periods to patients and investigators. To examine the association of the use of PRI periods with the placebo response, drug response, and drug-placebo difference among RCTs of antidepressants. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and PsycINFO, as well as repositories of unpublished studies, were systematically searched up to July 2021. Included studies were double-blind, placebo-controlled RCTs of antidepressant medication among adults with depressive disorders. Data were extracted into a coding sheet, including the characteristics of studies, the characteristics of PRI periods, and the outcomes of studies. Study outcomes were the primary depression symptom measure reported by the RCT. These outcomes were used to calculate effect sizes (Hedges g) of the within-group drug response and placebo response as well as the drug-placebo difference. Random-effects meta-analysis was used to calculate effect sizes, and subgroup analyses were used to compare outcomes depending on use of PRI periods. A total of 347 trials (representing 89 183 participants) were included; 174 studies (50%) reported using a single-blind PRI period. Response outcome data were available for 189 studies. Studies using PRI periods reported a smaller placebo response (g = 1.05 [95% CI, 0.98-1.11]; I2 = 82%) than studies that did not use a PRI period (g = 1.15 [95% CI, 1.09-1.21]; I2 = 81%; P = .02). Subgroup analysis showed a larger drug response size among studies that did not use a PRI period (g = 1.55 [95% CI, 1.49-1.61]; I2 = 85%) than those that did use a PRI period (g = 1.42 [95% CI, 1.36-1.48]; I2 = 81%; P = .001). The drug-placebo difference did not differ by use of PRI periods (g = 0.33 [95% CI, 0.29-0.38]; I2 = 47% for use of a PRI period vs g = 0.34 [95% CI, 0.30-0.38]; I2 = 54% for no use of PRI periods; P = .92). The likelihood of response to drug vs placebo also did not differ between studies that used a PRI period (odds ratio, 1.89 [95% CI, 1.76-2.03]) and those that did not use a PRI period (odds ratio, 1.77 [95% CI, 1.65-1.89]; P = .18). This study suggests that RCTs using PRI periods yield smaller within-group changes across both placebo and drug groups compared with RCTs without PRI periods. The reduction in effect size across groups was equivalent in magnitude. Consequently, PRI studies do not observe larger drug-placebo differences, suggesting that they do not increase trial sensitivity. As such, given the resources and probable deception required and risk to external validity, the practice of using PRI periods in RCTs of antidepressants should be ended.

Antidepressant efficacy of Agomelatine: Meta-analysis of placebo controlled and active comparator studies.

Agomelatine is a novel antidepressant that was developed to counter the adverse effects associated with the standard SSRIs and SNRIs that limited their usage. Publication bias was identified in antidepressant trials which can potentially overestimate the treatment efficacy. This meta-analysis was designed to assess the overall antidepressant effect of Agomelatine by pooling all the published and unpublished studies available till date. Studies conducted on adult patients who met with the criteria for MDD that evaluated efficacy of Agomelatine at acute phase (6-12weeks) and at long term phase (24weeks) were included. The primary efficacy measured with SMD of final mean scores of HAM-D and MADRS. Secondary efficacy measures of Response, remission and safety parameters were evaluated with relative risks. RevMan version 5.4 was used for analysis of both continuous (Standardized mean difference) and dichotomous outcomes (response, remission and all cause of discontinuation). Efficacy parameters were presented with 99% confidence intervals while safety parameters were presented with 95% CI. A total of 9233 patients were included from 27 studies. In acute phase placebo controlled studies, Agomelatine had a statistically significant SMD of -0.24 (-0.39 to -0.09) and response rate of (1.25, 1.07-1.47). In comparison (RR 0.99, 0.92-1.07) Agomelatine is an effective antidepressant having similar efficacy with the currently used antidepressants.

Antidepressants Effects on Pain in Parkinson Disease: A Systematic Review.

Pain in Parkinson disease (PD) is complex as this symptom can be multifactorial in origin because deficits in dopaminergic but also other neurotransmitters are involved. Pain and depression are increasingly recognized to have clinical importance for the quality of life of people living with PD. This systematic review aims to summarize the existing evidence on the potential benefit of using prescribed antidepressants for decreasing or controlling pain associated with PD. PubMed databases were searched for relevant studies using keywords and our exclusion/inclusion criteria and targeting only randomized placebo-controlled trials for antidepressants in PD. After screening 108 articles, only 3 focused articles were analyzed. Two of the included studies reported were on nortriptyline and paroxetine antidepressants. Unfortunately, included studies did not align in their outcome measures and did not directly compare the drug groups against each other or the placebo. Therefore, the complex nature of the unaligned outcome measures is inadequate for interpreting the efficacy of antidepressants in treating pain symptoms in PD. The third study focused solely on observing the effects of duloxetine but showed no favorable effects of this drug on pain. Prospective studies with a direct comparison of antidepressants and placebo should be conducted, focusing on pain-related scales and questions to understand further the role of antidepressants in treating pain in PD.

Guidance on Navigating Insurance Plans for TMS-Eligible Patients

Guidance on Navigating Insurance Plans for TMS-Eligible Patients

59.3 MDD IN AUTISM SPECTRUM DISORDER

Depression is a common comorbid disorder in youth with autism spectrum disorder (ASD), with reported prevalence of up to 10% in adolescents. It is important to identify and treat comorbid depression in youth with ASD. Diagnostic assessment methods for depression in youth with ASD will be discussed. Evidence-based treatments for depression will be reviewed. Although there are no controlled trials of antidepressants for depression in youth with ASD, medication treatment is often needed. CBT has shown some benefit. Increased awareness of the comorbidity of depression in youth with ASD may improve early identification of depression. Controlled trials of antidepressant medications and psychosocial interventions are needed to identify effective treatments for youth with comorbid depression and ASD.

Meta-Analysis: Pediatric Placebo Response in Depression Trials Does Not Replicate in Anxiety and Obsessive-Compulsive Disorder Trials.

Background: Placebo response has been identified as an important factor influencing the success of adult antidepressant trials, yet little research of placebo response has been conducted in pediatric populations. Understanding disorder-specific and transdiagnostic predictors of pediatric placebo response is important in designing successful child psychopharmacological trials. Methods: A PubMed search was conducted for all pediatric antidepressant randomized controlled trials treating depression, anxiety, or obsessive-compulsive disorder (OCD). A random-effects model was utilized to examine the magnitude of placebo symptom improvement using standardized mean difference (SMD) and placebo response rates. Stratified subgroup analysis was performed by diagnostic indication. Meta-regression was utilized to search possible correlates of placebo symptom improvement and placebo response rate. Results: Thirty antidepressant trials involving 2911 participants receiving placebo were included in this meta-analysis. Magnitude of placebo improvement and placebo response rates varied significantly across disorders; being greater in depression (SMD = 1.44, 95% confidence interval [CI]: 1.18 to 1.71) than anxiety disorders (SMD = 1.09, 95% CI: 0.77 to 1.41) and the lowest in OCD (SMD = 0.71, 95% CI: 0.32 to 1.12). Different predictors were associated with placebo response in different indications. Conclusions: Both the magnitude and predictors of placebo response in pediatric depression trials do not replicate across anxiety and OCD. Based on our results, across disorders, minimizing the number of sites might significantly reduce placebo improvement. In addition to these, we could potentially decrease the placebo response in depression trials by increasing the number of subjects enrolled per study site, minimizing the number of study visits and conducting the studies in the United States. Further research is needed into the predictors of placebo response in pediatric anxiety and OCD.

Who benefits most from expectancy effects? A combined neuroimaging and antidepressant trial in depressed older adults

Depressed patients’ expectations of improvement drive placebo effects in antidepressant clinical trials, yet there is considerable heterogeneity in the magnitude of expectancy effects. The present study seeks to identify those individuals who benefit most from expectancy effects using baseline neuroimaging and cognitive measures. Older adult outpatients diagnosed with major depressive disorder (MDD) participated in a prospective, 8-week clinical trial in which expectancy was experimentally manipulated and its effects on depression outcome measured. Based on the literature, we selected a priori 12 cognitive and brain-based variables linked to depression and expectancy, together with demographic variables, and incorporated them into a combined moderator. The combined moderator was developed as a weighted combination of the individual moderators, and was used to identify individuals who benefited most from expectancy effects. The combined moderator was found to predict differential change in depression severity scores between the high- vs. low-expectancy groups with a medium-size effect (Spearman effect size: 0.28). While at the sample level no expectancy effect was found, the combined moderator divided older adults with MDD into those who did and those who did not improve as the result of expectancy manipulation, with those benefiting from the manipulation showing greater processing speed, executive function, and frontostriatal white matter tract integrity. The findings suggest that it is possible to identify a subgroup of older adult individuals with MDD for whom expectancy manipulation results in greater antidepressant treatment response, supporting a precision medicine approach. This subgroup is characterized by distinct cognitive dysfunction and neuroimaging impairments profiles.

Treatment-Resistant Depression: Approaches to Treatment.

Approximately 30% of people treated for a major depressive episode will not achieve remission after two or more treatment trials of first-line antidepressants and are considered to have treatment-resistant depression (TRD). Because the odds of remission decrease with every subsequent medication trial, it is important for clinicians to understand the characteristics and risk factors for TRD, subtypes of major depressive disorder that are more likely to be less responsive to first-line anti-depressants, and the available treatment options. In the current article, we review the approved treatments for TRD, including esketamine, and the evidence for psilocybin and pramipexole. Although limited in specificity, guidelines to help prescribers identify person-centered treatments for TRD are available. [Journal of Psychosocial Nursing and Mental Health Services, 59(9), 7-11.].

Evaluating pimavanserin as a treatment for psychiatric disorders: A pharmacological property in search of an indication

ABSTRACT Introduction: Pimavanserin is FDA-approved to treat hallucinations and delusions associated with Parkinson’s disease psychosis. As a potent 5-HT2A inverse agonist/antagonist, it could be efficacious in other psychiatric disorders. Recently, several studies have investigated this potential. Areas covered: The authors review the efficacy and adverse effects of pimavanserin for hallucinations in dementia, major depression, and schizophrenia. Expert opinion: Two controlled studies suggest pimavanserin has potential as a treatment for hallucinations in dementia. In patients with depression who did not respond to antidepressant treatment, pimavanserin augmentation was efficacious in a phase 2 study. Pimavanserin augmentation also alleviated sexual side effects of SSRI and SSNI. However, Acadia Pharmaceuticals stated in a press release that it does not plan further antidepressant trials based on its phase 3 trial, which showed a nonsignificant trend toward an antidepressant effect. Since almost all existing antipsychotics fail to substantially benefit negative symptoms, better treatments are needed. Pimavanserin augmentation of antipsychotics did benefit negative symptoms (effect size≈0.2) but failed to reduce the total PANSS score significantly in two large, well-controlled double-blind studies. Pimavanserin has a good safety profile.

Combination of Tranylcypromine and Mirtazapine in Difficult-to-Treat Depression.

About one third of depression patients do not respond to the first antidepressant trial. Difficult-to-treat depression was suggested to characterize the often chronic and severe course of disease. Previous data indicate that tranylcypromine is effective in case of treatment-refractory depression. Many antidepressants are contraindicated in combination with tranylcypromine and other monoamine-oxidase inhibitors because of the risk of serotonin syndrome. The combination of tranylcypromine and amitriptyline was reported to be efficacious and safe in patients with electroconvulsive therapy-resistant major depression. In this retrospective chart review, we report a series of 3 cases, in which patients with electroconvulsive therapy-resistant depression were treated with the combination of tranylcypromine and mirtazapine. There are no published clinical data on this combination yet. Disease severity and treatment response were retrospectively assessed with the Clinical Global Impression-Severity and Improvement Scales. All 3 patients had severe difficult-to-treat depression with chronic course of disease and several times of inpatient treatment without achieving remission. The combination treatment was tolerated well, although the patients had somatic comorbidities. One patient developed mild and self-limiting neuroleptic malignant syndrome in the long-term course after dose increase of concomitant aripiprazole. All 3 patients showed either much or very much improvement. Under tight clinical controls in inpatient setting and after exhausting of alternatives, the combination of tranylcypromine and mirtazapine could be considered in patients, who do not achieve adequate improvement through common treatment options recommended in the guidelines. The combination has to be ceased, if symptoms of possible serotonin syndrome occur.

The Right to Choose

The Right to Choose

Placebo nasal spray protects female participants from experimentally induced sadness and concomitant changes in autonomic arousal

BackgroundTo investigate the powerful placebo effects in antidepressant drug trials and their mechanisms, recent pioneering experimental studies showed that expectation manipulation combined with an active placebo attenuated induced sadness. In the present study, we aimed at extending these findings by assessing the psychophysiological response in addition to mere self-report. MethodsOne hundred and thirteen healthy female students were randomly assigned to a drug expectation group (active placebo, positive treatment expectation), placebo expectation group (active placebo, no treatment expectation), or a no-treatment group (no placebo, no treatment expectation). After placebo intake, sadness was induced by self-deprecating statements using the Velten method combined with sad music, including a rumination phase. Sadness was measured using the Positive and Negative Affect Schedule Expanded Form (PANAS-X). Heart rate and skin conductance were assessed continuously. ResultsAfter mood induction and after rumination, self-reported sadness was significantly lower, and skin conductance level was significantly higher, in the drug expectation group than in the no-treatment group. The mood induction was further accompanied by a heart rate deceleration within all groups. LimitationsGeneralizability is limited by sample selectivity and focusing on sadness as a symptom of depression, exclusively. ConclusionExpectation-induced placebo effects significantly influenced sadness-correlated changes in autonomic arousal, and not only subjectively reported sadness, indicating that placebo effects in the context of affect are not merely due to subjective response bias. The systematic modification of treatment expectation could be utilized in clinical practice to optimize current therapeutic approaches to improve mood regulation.

Cortical Thickness and Hippocampal Volume in Vascular and Non-vascular Depressed Patients.

Background: Reduced cortical thickness and hippocampal volume are prevalent markers of late life depression as well as mild cognitive impairment (MCI) but are conspicuously absent in the vascular depression (VD) literature. The present study aimed to determine differences in cortical thickness and hippocampal volume between VD and non-VD patients.Methods: Participants were enrolled in an 8-week open treatment antidepressant trial. Forty-one depressed individuals aged 50 and older underwent brain magnetic resonance imaging at baseline and were classified as VD or non-VD. Cortical thickness values for the left and right entorhinal, parahippocampal, and precuneal cortices, as well as left and right hippocampal volume, were linearly regressed on VD status to determine mean differences between VD and non-VD. Covariates included site, age, sex, and mean thickness or intracranial volume.Results: No statistical differences were found between VD and non-VD patients in cortical thickness of the bilateral precuneal, entorhinal, or parahippocampal cortices, or hippocampal volume (p > 0.001).Conclusions: The absence of statistical differences in gray matter between VD and non-VD patients raises several diagnostic, etiological, and developmental possibilities, namely that VD may not be connected with other late-life psychiatric illnesses such as MCI or dementia and that vascular disease may not be a common etiological risk factor for depression and dementia. Larger datasets, prospective longitudinal studies, and cognitively intact controls are needed to further address these types of questions.

Determining maximal achievable effect sizes of antidepressant therapies in placebo-controlled trials.

Antidepressants outperform placebo with an effect size of around 0.30. It has been suggested that effect sizes as high as 0.875 are necessary for a minimal clinically important difference. Whether such effect sizes are achievable in placebo-controlled trials is unknown. Therefore, we aimed to assess what effect sizes are theoretically achievable in placebo-controlled trials of antidepressants. Patient-level analyses comparing Hamilton Depression Rating Scale (HDRS-17) outcomes for simulated antidepressant therapies to placebo-treated participants (n=2201) from clinical trials of selective serotonin reuptake inhibitors. An optimally effective antidepressant, where all treated participants achieve HDRS-17scores comparable to those displayed by healthy volunteers (remission-type model), had a maximum effect size of 1.75, with a mean difference of 11.6 points on the HDRS-17. In simulations where patients received an additional 50% symptom reduction over that obtained with placebo (improvement-type model), the maximum effect size was 1.08 with a mean HDRS-17 difference of 7.2. When adjusting for normal rates of treatment discontinuation, maximum effect sizes were 1.10 (remission-type model) and 0.76 (improvement-type model) with HDRS-17mean differences of 8.8 and 5.6, respectively. Three methodological issues (i) a large and variable placebo response, (ii) a high rate of dropout and (iii) HDRS-17-ratings significantly larger than zero in healthy volunteers, reduce the degree of treatment-placebo separation achievable in depression trials. Assuming that those who discontinue treatment have only partial response, even a highly effective antidepressant would have difficulties surpassing such effect size cut-offs as have been suggested to signify a minimal clinically important difference.

Antidepressant treatment effects and country income: meta-regression analysis of individual participant data from duloxetine trials.

In recent decades, significant numbers of pharmaceutical trials have gradually been relocated to low- and middle-income countries. However, there is little evidence regarding the transferability of trial outcomes across countries. Analysing duloxetine randomised controlled trials (RCTs) conducted in different countries, we investigated whether per capita gross national income (GNI) and healthcare expenditure (HE) are associated with pre-post mean changes of depression severity and differences in duloxetine-placebo effect sizes. Meta-analyses included RCTs investigating duloxetine efficacy in patients with depression. Individual participant data (IPD) from multi-centre duloxetine trials were provided by the manufacturer. Data extracted from published reports also entered analyses in case of trials conducted in only one country. A meta-regression approach was applied to analyse associations of GNI and HE with standardised pre-post mean change using raw score standardisation (SMCR) and comparative effect size, that is, the mean differences (MD) in pre-post effect size between duloxetine and placebo treatment. 23 trials with 8417 randomised participants entered analyses. Regression coefficients indicated a negative linear relationship of SMCR with GNI (z-standardised β=-3.61, R2 =14.8%, p < 0.001) and HE (β=-4.72, R2 =24.8%, p < 0.001) for participants treated with duloxetine. Similar associations were found for placebo treatment (GNI: β=-3.52, R2 =23.8%, p < 0.001; β=-3.34, R2 =21.0% p < 0.001). Neither GNI nor HE was associated with the MD between duloxetine and placebo pre-post differences. Findings challenge the idea of the universal transferability of antidepressant trial outcomes across countries. Understanding the results of antidepressant RCTs demands more sophisticated clarification of context factors involved in determining effectiveness of antidepressant medication and should be discussed with a view to socio-economic context in their countries of origin.