Strawn, Jeffrey R.

Introduction: Transcranial magnetic stimulation (TMS) is a promising intervention for adolescents with treatment-resistant depression (TRD). However, the durability of TMS-related improvement in adolescents is unclear. This 6-month study followed adolescents with TRD who had responded to TMS and provided TMS retreatment for adolescents with a partial relapse. Methods: The study enrolled adolescents (12–21 years) with TRD who had at least a partial response to sham or active TMS in a randomized controlled trial. Partial response was defined as ≥25% reduction of Hamilton Depression Rating Scale-24 (HAMD24). Participants with a partial relapse (≥1 point increase in Clinical Global Impression–Severity) received retreatment with daily 10 Hz TMS sessions until depressive symptom severity returned to the baseline score or after 30 TMS treatments. Results: There were 84 eligible participants, 66 were enrolled, and 41 completed the 6-month study. Twenty-eight participants (42%) were retreated with TMS. TMS retreatment courses had a mean of 22 sessions. At the 6-month follow-up, the complete sample exhibited reduced depressive symptoms (mean HAMD24 of 5.24) compared with baseline at entry into follow-up (mean HAMD24 of 8.21). Baseline depressive symptom severity was positively correlated with the risk of partial relapse, while the number of previous TMS interventions showed no correlation with the risk of partial relapse. TMS was well tolerated. Conclusions: This is the largest, long-term follow-up study with TMS retreatment for adolescents with TRD. These findings demonstrate the feasibility and clinical effects of a TMS retreatment protocol for adolescents with TRD, following a standard course of acute TMS.

Abstract Introduction Selective serotonin reuptake inhibitors (SSRIs) and, to a lesser extent, serotonin‐norepinephrine reuptake inhibitors (SNRIs) are the cornerstone of pharmacotherapy for children and adolescents with anxiety and depressive disorders. These medications alleviate symptoms and restore function for many youths; however, they are associated with a distinct adverse effect profile, and their tolerability may complicate treatment or lead to discontinuation. Yet, SSRI/SNRI tolerability has received limited attention in the pediatric literature. Methods This review examines the early‐ (e.g., activation, gastrointestinal symptoms, sedation) and late‐emerging (e.g., weight gain) adverse effects of SSRIs and some SNRIs in pediatric patients. Results We provide a framework for discussing SSRI/SNRI tolerability with patients and their families and describe the pharmacologic basis, course, and predictors of adverse events in youth. Strategies to address specific tolerability concerns are presented. For selected adverse events, using posterior simulation of mean differences over time, we describe their course based on Physical Symptom Checklist measures in a prospective, randomized trial of anxious youth aged 7–17 years who were treated with sertraline ( n = 139) or placebo ( n = 76) for 12 weeks in the Child/Adolescent Anxiety Multimodal Study (CAMS). Main Results In CAMS, the relative severity/burden of total physical symptoms ( p < 0.001), insomnia ( p = 0.001), restlessness ( p < 0.001), nausea ( p = 0.002), abdominal pain ( p < 0.001), and dry mouth ( p = 0.024) decreased from baseline over 12 weeks of sertraline treatment, raising the possibility that these symptoms are transient. No significant changes were observed for sweating ( p = 0.103), constipation ( p = 0.241), or diarrhea ( p = 0.489). Finally, we review the antidepressant withdrawal syndrome in children and adolescents and provide guidance for SSRI discontinuation, using pediatric pharmacokinetic models of escitalopram and sertraline—two of the most used SSRIs in youth. Conclusion SSRI/SNRIs are associated with both early‐emerging (often transient) and late‐emerging adverse effects in youth. Pharmacokinetically‐informed appraoches may address some adverse effects and inform SSRI/SNRI discontinuation strategies.

Introduction: The Clinical Global Impressions-Improvement (CGI-I) scale is widely used in clinical research to assess symptoms and functioning in the context of treatment. The correlates of the CGI-I with efficacy scales for adolescent major depressive disorder are poorly understood. This study focused on benchmarking CGI-I scores with changes in the Children's Depression Rating Scale-Revised (CDRS-R) and the Quick Inventory of Depressive Symptomatology-Adolescent (17-item) Self-Report (QIDS-A17-SR). Methods: We examined three datasets with the clinician-rated CDRS-R to ascertain equivalent percent changes in total scores and CGI-I ratings. Exploratory analyses examined corresponding percentage changes in the QIDS-A17-SR and the CGI-I ratings. The CGI-I was the reference scale for nonparametric equipercentile linking with the Equate package in R. Results: CGI-I scores of 1 mapped to ≥78%–95% change in CDRS-R scores at 4–6 weeks across three datasets. CGI-I scores of 2 mapped to 56%–94% change in CDRS-R scores at 4–6 weeks across three studies. CGI-I scores of 3 mapped to 30%–68% changes in CDRS-R scores at 4–6 weeks across three studies. CGI-I scores of 4 mapped to a range of 29%–44% at 4–6 weeks across three studies. There was no significant difference ( p ≥ 0.6) between treatment groups in both the Treatment of Adolescents with Depression and Treatment of Resistant Depression in Adolescents studies, for each CGI-I score ( = 1, or = 2 or = 3, or ≥4), associated mapping of total depression severity score, or associated percent change from baseline for corresponding follow-up visits. There was no significant sex difference ( p > 0.2) in CGI-I linkages to CDRS-R total or percentage changes. Conclusions: These findings establish clear relationships among CGI-I scores and the CDRS-R and the QIDS-A17-SR. These benchmarks have utility for clinical trial study design, inter-rater reliability training, and clinical implementation.

Abstract Background Despite its morbidity and mortality, the neurobiology of treatment-resistant depression (TRD) in adolescents and the impact of treatment on this neurobiology is poorly understood. Methods Using automatic segmentation in FreeSurfer, we examined brain magnetic resonance imaging baseline volumetric differences among healthy adolescents (n = 30), adolescents with major depressive disorder (MDD) (n = 19), and adolescents with TRD (n = 34) based on objective antidepressant treatment rating criteria. A pooled subsample of adolescents with TRD were treated with 6 weeks of active (n = 18) or sham (n = 7) 10-Hz transcranial magnetic stimulation (TMS) applied to the left dorsolateral prefrontal cortex. Ten of the adolescents treated with active TMS were part of an open-label trial. The other adolescents treated with active (n = 8) or sham (n = 7) were participants from a randomized controlled trial. Results Adolescents with TRD and adolescents with MDD had decreased total amygdala (TRD and MDD: −5%, P = .032) and caudal anterior cingulate cortex volumes (TRD: −3%, P = .030; MDD: −.03%, P = .041) compared with healthy adolescents. Six weeks of active TMS increased total amygdala volumes (+4%, P &lt; .001) and the volume of the stimulated left dorsolateral prefrontal cortex (+.4%, P = .026) in adolescents with TRD. Conclusions Amygdala volumes were reduced in this sample of adolescents with MDD and TRD. TMS may normalize this volumetric finding, raising the possibility that TMS has neurostructural frontolimbic effects in adolescents with TRD. TMS also appears to have positive effects proximal to the site of stimulation.

Abstract Background Anxiety disorders such as generalized anxiety disorder (GAD) impact 10% of the US population, and many patients do not completely respond to first-line treatments (e.g., selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and psychotherapy). Given the dearth of evidence for non-pharmacologic, non-psychotherapeutic interventions, we performed a systematic review and meta-analysis of repetitive transcranial magnetic stimulation (rTMS) in adults with GAD. Methods A systematic literature review using the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines was conducted. Pre- and post-treatment anxiety scores were extracted, and a random-effects meta-analysis was conducted to determine the magnitude of improvement (standardized mean difference). Standard assessments of heterogeneity (e.g., Q-statistic, I2, and τ 2) and publication bias were performed. Results The initial search resulted in 3194 citations, of which 6 studies were included in the meta-analysis. In total, 152 patients were studied, including 97 patients who received active treatment and 55 who received sham treatment, and heterogeneity was modest (I2 13.32, Q = 5.77). In patients with GAD, rTMS produced a standardized mean difference of −1.857 (confidence interval: −2.219 to −1.494; P &lt; .001) with a prediction interval of −2.55 to −1.16. Conclusions The results suggest a robust effect of rTMS in GAD in the context of limited, heterogenous studies. Rigorously designed, randomized controlled trials of rTMS for GAD and related anxiety disorders are urgently needed. These studies will provide opportunities for biomarker development and integration of concurrent evidence-based psychotherapy to maximize results.

Objective: To describe the clinical characteristics of adolescents with antidepressant treatment-resistant major depressive disorder (MDD) and to examine the utility of the Antidepressant Treatment Record (ATR) in categorizing treatment resistance in this population. Methods: Adolescents with treatment-resistant MDD enrolled in an interventional study underwent a baseline evaluation with the ATR, Children's Depression Rating Scale-Revised (CDRS-R), and Clinical Global Impressions-Severity (CGI-S) scales. Demographic and clinical characteristics were examined with regard to ATR-defined level of resistance (level 1 to ≥3) using analysis of variance and χ 2 tests. Results: In adolescents with treatment-resistant MDD ( N = 97), aged 12–21 years, most were female (65%), white (89%), and had recurrent illness (78%). Patients were severely ill (median CGI-S score of 5), had a mean CDRS-R score of 63 ± 10, and 17.5% had been hospitalized for depression-related symptoms. Fifty-two patients were classified as ATR 1, whereas 32 were classified as ATR level 2 and 13 patients as ≥3, respectively. For increasing ATR-defined levels, illness duration increased from 12.0 (range: 1.5–31.9) to 14.8 (range: 1.8–31.7) to 19.5 (range: 2.5–36.2) months and the likelihood of treatment with serotonin norepinephrine reuptake inhibitors (SNRIs) and dopamine norepinephrine reuptake inhibitors (DNRIs) similarly increased ( p = 0.006 for both SNRIs and DNRIs) as did the likelihood of treatment with mixed dopamine serotonin receptor antagonists (χ 2 = 17, p < 0.001). Conclusions: This study underscores the morbidity and chronicity of treatment-resistant MDD in adolescents. The present characterization of related clinical features describes the use of nonselective serotonin reuptake inhibitors in adolescents with treatment-resistant depression and raises the possibility that those with the greatest medication treatment resistance are less likely to have had recurrent episodes. The study also demonstrates the utility of the ATR in categorizing treatment resistance in adolescents with MDD.

Nearly two in five youth with major depressive disorder fail to respond to first‐line interventions. As such, treatment‐resistant depression represents a formidable challenge for clinicians and researchers. In fact, even considering the diagnosis of treatment‐resistant depression in children and adolescents requires (a) defining treatment‐resistant depression and, by extension, treatment failure; (b) defining recovery; (c) understanding its developmental trajectory; and in addition to (d) understanding the evidence for treatment interventions in this population. Accumulating data suggest that treatment‐resistant depression is heterogeneous and that this heterogeneity may inform interventions. Additionally, these data suggest that substantially more nuance is needed in evaluating the ‘adequacy’ of prior treatments whether they are psychotherapeutic or psychopharmacologic. Last, adjunctive interventions that focus on neuromodulation, glutamatergic, GABAergic, and inflammatory pathways remain poorly understood in youth with treatment‐resistant depression despite very significant advances in adults with treatment‐resistant depression.

Objective: To guide clinicians in selecting the “next line” selective serotonin reuptake inhibitor (SSRI) for adolescents with treatment-resistant major depressive disorder, we sought to compare response rates among SSRIs in the Treatment of SSRI-Resistant Depression in Adolescents (TORDIA) study and to jointly model tolerability and efficacy for the specific SSRI comparisons. Methods: Efficacy and tolerability data for paroxetine, citalopram, and fluoxetine were extracted from the TORDIA study. Using a joint bivariate normal likelihood for response and tolerability (based on the maximum implied variance from the 95% credible intervals previously reported for the three SSRIs), a Monte Carlo pseudorandom sample (100,000 draws) was obtained, from which credible intervals, means, posterior tail probabilities, etc. were determined. Joint null hypotheses of no difference in efficacy and tolerability were then evaluated with regard to superiority of each SSRI over the others. Results: No significant differences in response were observed for citalopram compared with fluoxetine ( p = 0.247) or for fluoxetine compared with paroxetine ( p = 0.110), although citalopram trended toward being superior to paroxetine (mean difference: 0.2, p = 0.055). For efficacy–tolerability models, citalopram and fluoxetine were superior to paroxetine ( p = 0.029 and p = 0.022, respectively) but did not differ between each other ( p = 0.146). Conclusions: Joint efficacy–tolerability models suggest that citalopram and fluoxetine were statistically significantly superior to paroxetine while citalopram trended toward superiority over paroxetine in the efficacy model. These findings provide a more granular and practical evidence base for clinicians faced with treatment sequencing decisions in adolescents with SSRI-resistant depression.