An open label pilot trial of sequential bifrontal low frequency r-TMS in the treatment of primary insomnia.

This pilot study examines the therapeutic effects of bifrontal low frequency (LF) TMS on primary insomnia. In this prospective, open-label study 20 patients with primary insomnia and without major depressive disorder received 15 sequential bifrontal LF rTMS stimulation sessions. By week 3, PSQI scores declined from baseline score of 12.57(sd 2.74) to 9.50 (sd 4.27), a large effects size (0.80 (CI 0.29, 1.36)), and CGI-I scores improved for 52.6% of participants. Results of this pilot indicate that the novel bifrontal LF rTMS benefitted this group of patients suffering from primary insomnia, with absence of sham control a significant study limitation.

Case report: Rapid symptom resolution of a mixed affective state with high-frequency repetitive transcranial magnetic stimulation.

Introduction: Bipolar major depressive episodes with mixed features are diagnosed in patients who meet the full criteria for a major depressive episode exhibiting three additional concurrent symptoms of hypomania or mania. Up to half of patients with bipolar disorder experience mixed episodes, which are more likely to be treatment-refractory than pure depression or mania/hypomania alone. Case: We present a 68-year-old female with Bipolar Type II Disorder with a four-month medication-refractory major depressive episode with mixed features referred for neuromodulation consultation. Previous failed medication trials over several years included lithium, valproate, lamotrigine, topiramate, and quetiapine. She had no history of treatment with neuromodulation. At the initial consultation, her baseline Montgomery-Asberg Depression Rating Scale (MADRS) was moderate in severity at 32. Her Young Mania Rating Scale (YMRS) was 22, with dysphoric hypomanic symptoms consisting of heightened irritability, verbosity and increased rate of speech, and decreased sleep. She declined electroconvulsive therapy but elected to receive repetitive transcranial magnetic stimulation (rTMS). Interventions: The patient underwent repetitive transcranial magnetic stimulation (rTMS) with a Neuronetics NeuroStar system, receiving nine daily sessions over the left dorsolateral prefrontal cortex (DLPFC). Standard settings of 120% MT, 10 Hz (4 sec on, 26 sec off), and 3,000 pulses/session were used. Her acute symptoms showed a brisk response, and at the final treatment, her repeat MADRS was 2, and YMRS was 0. The patient reported feeling "great," which she defined as feeling stable with minimal depression and hypomania for the first time in years. Conclusion: Mixed episodes present a treatment challenge given their limited treatment options and diminished responses. Previous research has shown decreased efficacy of lithium and antipsychotics in mixed episodes with dysphoric mood such as the episode our patient experienced. One open-label study of low-frequency right-sided rTMS showed promising results in patients with treatment-refractory depression with mixed features, but the role of rTMS in the management of these episodes is largely unexplored. Given the concern for potential manic mood switches, further investigation into the laterality, frequency, anatomical target, and efficacy of rTMS for bipolar major depressive episodes with mixed features is warranted.

Depression phenotype identified by using single nucleotide exact amplicon sequence variants of the human gut microbiome.

Single nucleotide exact amplicon sequence variants (ASV) of the human gut microbiome were used to evaluate if individuals with a depression phenotype (DEPR) could be identified from healthy reference subjects (NODEP). Microbial DNA in stool samples obtained from 40 subjects were characterized using high throughput microbiome sequence data processed via DADA2 error correction combined with PIME machine-learning de-noising and taxa binning/parsing of prevalent ASVs at the single nucleotide level of resolution. Application of ALDEx2 differential abundance analysis with assessed effect sizes and stringent PICRUSt2 predicted metabolic pathways. This multivariate machine-learning approach significantly differentiated DEPR (n = 20) vs. NODEP (n = 20) (PERMANOVA P < 0.001) based on microbiome taxa clustering and neurocircuit-relevant metabolic pathway network analysis for GABA, butyrate, glutamate, monoamines, monosaturated fatty acids, and inflammasome components. Gut microbiome dysbiosis using ASV prevalence data may offer the diagnostic potential of using human metaorganism biomarkers to identify individuals with a depression phenotype.

Left prefrontal transcranial magnetic stimulation for treatment-resistant depression in adolescents: a double-blind, randomized, sham-controlled trial.

Treatment-resistant depression (TRD) is prevalent and associated with a substantial psychosocial burden and mortality. There are few prior studies of interventions for TRD in adolescents. This was the largest study to date examining the feasibility, safety, and efficacy of 10-Hz transcranial magnetic stimulation (TMS) for adolescents with TRD. Adolescents with TRD (aged 12-21 years) were enrolled in a randomized, sham-controlled trial of TMS across 13 sites. Treatment resistance was defined as an antidepressant treatment record level of 1 to 4 in a current episode of depression. Intention-to-treat patients (n = 103) included those randomly assigned to active NeuroStar TMS monotherapy (n = 48) or sham TMS (n = 55) for 30 daily treatments over 6 weeks. The primary outcome measure was change in the Hamilton Depression Rating Scale (HAM-D-24) score. After 6 weeks of blinded treatment, improvement in the least-squares mean (SE) HAM-D-24 scores were similar between the active (-11.1 [2.03]) and sham groups (-10.6 [2.00]; P = 0.8; difference [95% CI], - 0.5 [-4.2 to 3.3]). Response rates were 41.7% in the active group and 36.4% in the sham group (P = 0.6). Remission rates were 29.2% in the active group and 29.0% in the sham group (P = 0.95). There were no new tolerability or safety signals in adolescents. Although TMS treatment produced a clinically meaningful change in depressive symptom severity, this did not differ from sham treatment. Future studies should focus on strategies to reduce the placebo response and examine the optimal dosing of TMS for adolescents with TRD.

Treatment-Resistant Depression in Adolescents: Clinical Features and Measurement of Treatment Resistance.

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 χ2 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 (χ2 = 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.

Pharmacotherapy for the treatment of tardive dyskinesia in schizophrenia patients.

INTRODUCTION: Tardive dyskinesia (TD) is an iatrogenic movement disorder most commonly observed in patients with psychotic disorders who are treated with dopamine blocking antipsychotic medications. Treatment options are limited, and recommendations for treatment are based on a relative scarcity of evidence. Areas covered: After briefly highlighting current mechanistic theories of TD, this review will discuss the evidence for a number of medications of several different classes that have been studied for the treatment of TD since the 1970s with an emphasis on placebo controlled trials when possible. We used a Pubmed search of primary studies, reviews, and metaanalyses on the topic of TD treatment in order to cover this topic. Expert opinion: Treatment of TD is difficult given limited data and incomplete understanding of the mechanism. Treatment of TD must be evaluated on an individual basis with careful weight given to severity of symptoms. We suggest the use of atypical versus conventional antipsychotics whenever possible and would recommend trials with one or more of a number of additional agents starting with valbenazine.