The effect of older age on outcomes of rTMS treatment for treatment-resistant depression.

Clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) for treatment of treatment-resistant depression (TRD) vary widely and there is no mood rating scale that is standard for assessing rTMS outcome. It remains unclear whether TMS is as efficacious in older adults with late-life depression (LLD) compared to younger adults with major depressive disorder (MDD). This study examined the effect of age on outcomes of rTMS treatment of adults with TRD. Self-report and observer mood ratings were measured weekly in 687 subjects ages 16-100 years undergoing rTMS treatment using the Inventory of Depressive Symptomatology 30-item Self-Report (IDS-SR), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item, and Hamilton Depression Rating Scale 17-item (HDRS). All rating scales detected significant improvement with treatment; response and remission rates varied by scale but not by age (response/remission ≥ 60: 38%-57%/25%-33%; <60: 32%-49%/18%-25%). Proportional hazards models showed early improvement predicted later improvement across ages, though early improvements in PHQ and HDRS were more predictive of remission in those < 60 years (relative to those ≥ 60) and greater baseline IDS burden was more predictive of non-remission in those ≥ 60 years (relative to those < 60). These results indicate there is no significant effect of age on treatment outcomes in rTMS for TRD, though rating instruments may differ in assessment of symptom burden between younger and older adults during treatment.

Safety and efficacy of targeting the supplementary motor area with double-cone deep transcranial magnetic stimulation vs figure-eight coil in treatment of obsessive-compulsive disorder with comorbid major depressive disorder.

BACKGROUND AND OBJECTIVE: The Supplementary Motor Area (SMA), a relatively large brain structure predominantly located along the interhemispheric fissure, is an established target for repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Obsessive-Compulsive Disorder (OCD). We investigated the feasibility, safety, and efficacy of targeting SMA using a double-cone "deep" TMS coil compared to conventional figure-eight coil for treatment of OCD with comorbid Major Depressive Disorder (MDD). METHODS: Sixty-two patients with treatment-resistant OCD and comorbid MDD participated in the study. All patients received high-frequency rTMS over the left dorsolateral prefrontal cortex (DLPFC) with a figure-eight coil (MagVenture B70), followed by 1 Hz rTMS over the bilateral SMA using either the B70 (N = 25) or double-cone deep coil (MagVenture DB80) (n = 23) for 36 treatment sessions. Weekly clinical assessments were conducted. RESULTS: Subjects overall had significant reductions in OCD and depressive symptom severity at the primary endpoint. Subjects stimulated at SMA with the double-cone deep coil had statistically significantly lesser reductions in overall OCD and depression symptom severity compared to the figure-eight group. The intensity of stimulation at SMA was significantly greater with the double-cone deep than figure-eight coil and e-field modeling showed that it affected broader regions beyond SMA (off-target stimulation). There was no significant difference in reported tolerability between groups. CONCLUSIONS: SMA stimulation using either a double-cone deep or conventional figure-of-eight coil was safe and was associated with a significant reduction in comorbid OCD and depression symptoms, but the higher intensities of stimulation with the double-cone deep coil used in this study were significantly less clinically beneficial than figure-eight coil stimulation.

The Correlation of Pain, Psychological Aspects, and Sleep in Fibromyalgia: A Cross-Sectional Analysis.

Background: This pilot study measures pain perception, somatosensory amplification and its relationship to health anxiety in patients with fibromyalgia (FM) and patients with FM and obstructive sleep apnea (OSA); this study also examines the effects of OSA on pain perception in patients with FM. Methods: In this pilot study, patients diagnosed with FM or FM and OSA, completed three self-reported questionnaires: Short-Form McGill Pain Questionnaire (SF-MPQ), Somatosensory Amplification Scale (SSAS), and Illness Behavior Questionnaire (IBQ). Sleep study results were analyzed. Scores were summarized using medians and interquartile ranges and are compared using Wilcoxon rank sum tests. Results: Overall FM (n = 25), female n=23 male n=3 mean age, 57.48 years. OSA n=17 (68%) and 8 (32%) were not. The SF-MPQ Sensory sub-scale scores and the SF-MPQ overall scores differed significantly between patients with and without OSA. The SF-MPQ Sensory sub-scale scores were significantly lower for patients with OSA (p=0.03), as were SF-MPQ overall scores (p=0.04). SSAS overall scores and IBQ overall scores did not differ significantly by OSA diagnosis. Correlations of the different dimensions of IBQ with SSAS and mean number of diagnoses in FM and FM+OSA, mean number of diagnoses in problem list of SSAS ≤30 was 29.5, mean number of diagnoses in SSAS ≥30 was 34.9. Discussion: Developing a better understanding of the effects of OSA on pain perception in patients with FM is needed for improved health status. More research is needed to see if higher pain perception and SSAS score lead to increased health care utilization and to evaluate the relationship between untreated disordered sleeping and pain perception in patients with FM. Conclusion: Our findings highlight the need for more research to evaluate the relationship between treated and untreated disordered sleeping, pain perception, somatization and illness behavior in the health status of individuals with FM.

A comparison of self- and observer-rated scales for detecting clinical improvement during repetitive transcranial stimulation (rTMS) treatment of depression.

Clinical outcomes of repetitive Transcranial Magnetic Stimulation (rTMS) for treatment of Major Depressive Disorder (MDD) vary widely, and no single mood rating scale is standard for assessing rTMS outcomes. This study of 708 subjects undergoing clinical rTMS compared the performance of four scales in measuring symptom change during rTMS treatment. Self-report and observer ratings were examined weekly with the Inventory of Depressive Symptomatology 30-item (IDS), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item (POMS), and Hamilton Depression Rating Scale 17-item (HDRS). While all scales were correlated and detected significant improvement, the degree of improvement over time as well as response (33-50%) and remission (20-24%) rates varied significantly. Higher baseline severity was associated with lower likelihood of remission, and greater improvement by sessions 5 and 10 predicted response across all scales. Use of only a single scale to assess outcome conferred 14-36% risk of failing to detect response/remission indicated by another scale. The PHQ was most likely to indicate improvement and least likely to miss response or remission. These findings indicate that assessment of symptom burden during rTMS treatment may be most accurately assessed through use of multiple instruments.

Response to intravenous racemic ketamine after switch from intranasal (S)-ketamine on symptoms of treatment-resistant depression and post-traumatic stress disorder in Veterans: A retrospective case series.

BACKGROUND: Racemic (R,S)-ketamine is a glutamatergic drug with potent and rapid acting antidepressant effects. An intranasal formulation of (S)-ketamine was recently approved by the US Food and Drug Administration (FDA) to be used in individuals with treatment-resistant depression (TRD). There are no data directly comparing outcomes on depression or other comorbidities between these two formulations of ketamine. However, recent meta-analyses have suggested that IV racemic ketamine may be more potent than IN-(S)-ketamine. METHODS: We retrospectively analyzed clinical outcomes in 15 Veterans with comorbid TRD and post-traumatic stress disorder (PTSD) who underwent ketamine treatment at the VA San Diego Neuromodulation Clinic. All Veterans included in this analysis were given at least 6 intranasal (IN)-(S)-ketamine treatments prior to switching to treatment with IV racemic ketamine. RESULTS: Veterans receiving ketamine treatment ( across both IN-(S)-ketamine and IV-(R,S)-ketamine) showed significant reductions in both the Patient Health Questionnaire-9 (PHQ-9), a self-report scale measuring depression symptoms (rm ANOVA F(14,42) = 12.6, p < 0.0001), and in the PTSD checklist for DSM-5 (PCL-5), a self-report scale measuring PSTD symptoms (rm ANOVA F(13,39) = 5.9, p = 0.006). Post hoc testing revealed that PHQ-9 scores were reduced by an average of 2.4 ± 1.2 compared to baseline after (S)-ketamine treatments (p = 0.1) and by an average of 5.6 ± 1 after IV-ketamine treatments (p = 0.0003) compared to pretreatment baseline scores. PCL-5 scores were reduced by an average of 4.3 ± 3.3 after IN (S)-ketamine treatments (p = 0.6) and 11.8 ± 3.5 after IV-ketamine treatments (p = 0.03) compared to pretreatment baseline scores. CONCLUSIONS: This work suggests that off-label IV-(R,S)-ketamine could be considered a reasonable next step in patients who do not respond adequately to the FDA-approved IN-(S)-ketamine. Further double-blinded, randomized controlled trials are warranted to assess whether IV racemic ketamine is more effective than IN-(S)-ketamine.

Effects of intranasal (S)-ketamine on Veterans with co-morbid treatment-resistant depression and PTSD: A retrospective case series.

Background: (S)-ketamine is a glutamatergic drug with potent and rapid acting effects for the treatment of depression. Little is known about the effectiveness of intranasal (S)-ketamine for treating patients with comorbid depression and post-traumatic stress disorder (PTSD). Methods: We performed a retrospective case series analysis of clinical outcomes in 35 Veterans with co-morbid depression and PTSD who were treated with intranasal (S)-ketamine treatments at the VA San Diego Neuromodulation Clinic between Jan 2020 and March 2021. Veterans were not randomized or blinded to treatment. The primary outcome measured was a change in patient health questionnaire-9 (PHQ-9) and PTSD Checklist for DSM-5 (PCL-5) scores across the first 8 treatments (induction period) using a repeated measures analysis of variance (ANOVA). In a smaller sub-group (n = 19) of Veterans who received at least 8 additional treatments, we analyzed whether intranasal (S)-ketamine continued to show treatment effects. Finally, we performed a sub-group and correlation analyses to understand how changes in PHQ-9 and PCL-5 scores were related across treatments. Findings: During the induction phase of treatment there was an absolute reduction of 5.1 (SEM 0.7) on the patient health questionnaire-9 (PHQ-9) rating scale for depression, from 19.8 (SEM 0.7) at treatment 1 to 14.7 (SEM 0.8) at treatment 8 (week 4) (F(7238) = 8.3, p = 1e-6, partial η2 = 0.2). Five Veterans (14%) showed a clinically meaningful response (50% reduction in PHQ-9 score) at treatment 8. There was an absolute reduction of 15.5 +/- 2.4 on the patient checklist 5 (PCL-5) rating scale for PTSD, from 54.8 (SEM 2) at treatment 1 down to 39.3 (SEM 2.5) at treatment 8 (F(7238) = 15.5, p = 2e-7, partial η2 = 0.31). Sixteen Veterans (46%) showed a clinically meaningful response (reduction in PCL-5 of > 30%) in PTSD. Change in PHQ-9 correlated with change in PCL-5 at treatment 8 (r = 0.47, p = 0.005), but a decrease in PTSD symptoms were observable in some individuals with minimal anti-depressant response. Interpretations: While this is an open-label retrospective analysis, our results indicate that both depression and PTSD symptoms in Veterans with dual-diagnoses may improve with repeated intranasal (S)-ketamine treatment. The effects of (S)-ketamine on PTSD symptoms were temporally and individually distinct from those on depression, suggesting potentially different modes of action on the two disorders. This work may warrant formal randomized controlled studies on the effects of intranasal (S)-ketamine for individuals with co-morbid MDD and PTSD. Funding: VA Center of Excellence in Stress and Mental Health, VA ORD (Career Development Award to DSR), Burroughs-Wellcome Fund Award (DSR), NIMH (EL).

How do serotonergic psychedelics treat depression: The potential role of neuroplasticity.

Depression is a common mental disorder and one of the leading causes of disability around the world. Monoaminergic antidepressants often take weeks to months to work and are not effective for all patients. This has led to a search for a better understanding of the pathogenesis of depression as well as to the development of novel antidepressants. One such novel antidepressant is ketamine, which has demonstrated both clinically promising results and contributed to new explanatory models of depression, including the potential role of neuroplasticity in depression. Early clinical trials are now showing promising results of serotonergic psychedelics for depression; however, their mechanism of action remains poorly understood. This paper seeks to review the effect of depression, classic antidepressants, ketamine, and serotonergic psychedelics on markers of neuroplasticity at a cellular, molecular, electrophysiological, functional, structural, and psychological level to explore the potential role that neuroplasticity plays in the treatment response of serotonergic psychedelics.

Obstructive sleep apnea co-morbidity in patients with fibromyalgia: a single-center retrospective analysis and literature review.

Background: Fibromyalgia (FM) is a chronic medical condition characterized by widespread pain, sleep disturbance, and cognitive dysfunction. Sleep disorders are thought to play a prominent role in the etiology and symptomatic management of FM, specifically obstructive sleep apnea (OSA). In order to provide collaborative care, we need a better understanding of any overlapping presentation of FM and OSA. We conducted a site-wide review of patients from 2012-2016 to identify FM patients diagnosed with OSA. Methods: Charts were reviewed in patients aged 18 and above from 2012-2016 using ICD codes from a clinical data repository. Intersection of patients with a diagnosis of FM and OSA in clinics of psychiatry, sleep, rheumatology, and other outpatient clinics was compared. Polysomnography order patterns for FM patients were investigated. Results: Co-morbidity was highest in the sleep clinic (85.8%) compared to psychiatry (42.0%), rheumatology (18.7%), and other outpatient clinics (3.6%) (p<0.001). In the rheumatology and other outpatient clinics, 93.5% and 96% of patients respectively, had no polysomnography ordered. Pairwise comparison of co-morbidity in clinics: sleep vs psychiatry, sleep vs rheumatology, sleep vs other clinics, psychiatry vs rheumatology, psychiatry vs other clinics, and rheumatology vs other clinics were statistically significant after applying a Sidak adjustment to the p-values (all p<0.001). Conclusion: Our analysis suggests that there could be a correlation between FM and OSA, and referral to sleep studies is recommended in the management of patients with FM. The varying prevalence of FM patients with co-morbid OSA in sleep clinics when compared to other outpatient clinics suggests a discrepancy in the identification of FM patients with OSA. When properly screened, OSA co-morbidity has the potential to be higher in other outpatient clinics.