Psychomotor retardation: What about the partial responders to magnetic transcranial stimulation in treatment resistant depression ?

OBJECTIVE: Psychomotor retardation is a core clinical component of Major Depressive Disorder responsible for disability and is known as a treatment response marker of biological treatments for depression. Our objective was to describe cognitive and motoric measures changes during a treatment by repetitive Transcranial Magnetic Stimulation (rTMS) within the THETAD-DEP trial for treatment-resistant depression (TRD), and compare those performances at the end of treatment and one month after between responders (>50% improvement on MADRS score), partial responders (25-50%) and non-reponders (no clinically relevant improvement). Our secondary aim was to investigate baseline psychomotor performances associated with non-response and response even partial. METHODS: Fifty-four patients with treatment-resistant unipolar depression and treated by either high frequency 10 Hz rTMS or iTBS for 4 weeks (20 sessions) underwent assessment including French Retardation Rating Scale for Depression (ERD), Verbal Fluency test, and Trail Making Test A. before, just after treatment and one month later. RESULTS: 20 patients were responders (R, 21 partial responders (PR) and 13 non-responders (NR). rTMS treatment improved psychomotor performances in the R and PR groups unlike NR patients whose psychomotor performance was not enhanced by treatment. At baseline, participants, later identified as partial responders, showed significantly higher performances than non-responders. CONCLUSION: Higher cognitivo-motor performances at baseline may be associated with clinical improvement after rTMS treatment. This work highlights the value of objective psychomotor testing for the identification of rTMS responders and partial responders, and thus may be useful for patient selection and protocol individualization such as treatment continuation for early partial responders.

Impact of deep transcranial magnetic stimulation on insomnia outcomes in patients with treatment-resistant depression: a retrospective study.

Deep transcranial magnetic stimulation (dTMS) is an Food and Drug Administration-approved treatment for treatment-resistant depression (TRD). Our study aims to examine the impact of baseline insomnia severity on mood outcomes of dTMS and the impact of dTMS on comorbid insomnia in patients with treatment-resistant depression using a retrospective analysis. Twenty-five patients with treatment-resistant depression who underwent dTMS were divided into two groups: "low insomnia" and "high insomnia," depending on Insomnia Severity Index scores at baseline. Significant improvements in depression and anxiety from baseline to final dTMS session were noted in both groups. Baseline insomnia severity was not associated with poorer treatment outcomes after dTMS. Final insomnia scores of the two groups were not significantly different, suggesting dTMS alleviated insomnia symptoms in patients with treatment-resistant depression. Further research incorporating a prospective study design in a multicenter setting is warranted to replicate these findings and elucidate the mechanistic action of dTMS on insomnia outcomes. CITATION: Chopra A, Singal P, Kodya S. Impact of deep transcranial magnetic stimulation on insomnia outcomes in patients with treatment-resistant depression: a retrospective study. J Clin Sleep Med. 2024;20(5):813-815.

Sleep Quality After Quetiapine Augmentation in Patients With Treatment-Resistant Depression and Personality Disorders.

PURPOSE/BACKGROUND: Quetiapine is a first-line augmenting agent for treatment-resistant depression (TRD) and is used off-label in insomnia. Quetiapine and its active metabolite norquetiapine act mostly on 5-HT2A, 5-HT2C, H1, and D2 as antagonists and on 5-HT1A as partial agonists. Patients with TRD often have comorbid personality disorder (PD), and evidence suggests an association between sleep disturbance and recovery among patients with PD. Here, we aimed to evaluate the effects of quetiapine on sleep in TRD patients with and without PD (PD+/PD-). METHODS/PROCEDURES: We reviewed health records of 38 patients with TRD (20 TRD/PD+) who had been treated with a pharmacotherapy regimen including quetiapine. Clinical outcomes were determined by comparing changes in sleep items of the Hamilton Depression Rating Scale at the beginning (T0) and after 3 months of an unchanged treatment (T3). FINDINGS/RESULTS: Patients with TRD/PD+ and TRD/PD- taking quetiapine showed significant improvement in sleep items from T0 to T3 (P < 0.001, ηp2 ≥ 0.19). There was a significant personality × time interaction for sleep-maintenance insomnia (P = 0.006, ηp2 = 0.23), with TRD/PD+ showing a greater improvement at T3 compared with TRD/PD- (P = 0.01). While exploring other sleep items, no personality × time interaction was found. In the TRD/PD- group, improvement in sleep items was associated with an overall improvement in depressive symptoms (r = 0.55, P = 0.02). IMPLICATIONS/CONCLUSIONS: Quetiapine induced greater improvements in sleep-maintenance insomnia among TRD/PD+ patients than TRD/PD-. These findings suggest quetiapine could have a therapeutic role for insomnia in PD underscoring a distinct underlying neurobiological mechanism of sleep disturbance in people living with PD.

Tinnitus and treatment-resistant depression.

Tinnitus, a frequent disorder, is the conscious perception of a sound in the absence of a corresponding external acoustic sound source in the sense of a phantom sound. Although the majority of people who perceive a tinnitus sound can cope with it and are only minimaly impaired in their quality of lfe, 2-3% of the population perceive tinnitus as a major problem. Recently it has been proposed that the two groups should be differentiated by distict terms: "Tinnitus" describes the auditory or sensory component, whereas "Tinnitus Disorder" reflects the auditory component and the associated suffering. There is overwhelming evidence that a high tinnitus burden is associated with the increased occurrence of comorbidities, including depression. Since no causal therapeutic options are available for patients with tinnitus at the present time, the identification and adequate treatment of relevant comorbidities is of great importance for the reduction of tinnitus distress. This chapter deals with the relationship between tinnitus and depression. The neuronal mechanisms underlying tinnitus will first be discussed. There will also be an overview about depression and treatment resistant depression (TRD). A comprehensive review about the state-of-the-art evidences of the relationship between tinnitus and TRD will then be provided.

Role of klotho on antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression and suicidal ideation.

OBJECTIVE: Previous studies have found an association between klotho, an anti-aging hormone, and major depressive disorder. However, whether low-dose ketamine infusion alters klotho levels among patients with treatment-resistant depression (TRD) remains unknown. METHODS: In total, 48 patients with TRD and strong suicidal ideation were randomly assigned to a single 0.5 mg/kg ketamine or 0.045 mg/kg midazolam regimen and were subjected to a 2-week follow-up. Depressive and suicidal symptoms were assessed before the infusion and during the follow-up. The serum levels of klotho were assessed at baseline and 3 days postinfusion. RESULTS: A generalized linear model with adjustment of baseline klotho levels showed that, despite the fact that ketamine did not significantly increase levels of klotho, patients in the ketamine group had higher levels of klotho at Day 3 postinfusion than patients in the midazolam group (p = 0.043). However, we found no association between changes in klotho levels and changes in depressive and suicidal symptoms (all p > 0.05). Higher klotho levels at baseline were associated with poorer antidepressant effect of low-dose ketamine during postinfusion follow-up. DISCUSSION: Klotho may play a role in the antidepressant effect of low-dose ketamine. Additional molecular studies are necessary to elucidate the neuromechanisms of TRD, ketamine, and klotho.

Esketamine in treatment-resistant depression patients comorbid with substance-use disorder: A viewpoint on its safety and effectiveness in a subsample of patients from the REAL-ESK study.

Esketamine, the S-enantiomer of ketamine, has recently emerged as a therapy for treatment-resistant depression (TRD), showing both rapid antidepressant action and good efficacy and high safety. It is also indicated for the acute short-term treatment of psychiatric emergency due to major depressive disorder (MDD) and for depressive symptoms in adults with MDD with acute suicidal thoughts/behavior. We here provide preliminary insights on esketamine nasal spray (ESK-NS) effectiveness and safety among patients with a substance use disorder (SUD) within the sample of patients with TRD collected for the observational, retrospective, multicentre REAL-ESK study. Twenty-six subjects were retrospectively selected according to the presence of a SUD in comorbidity. Subjects enrolled completed the three different follow-up phases (T0/baseline, T1/after one month, and T2/after three months) and there were no dropouts. A decrease in Montgomery-Asberg depression rating scale (MADRS) scores was recorded, thus highlighting the antidepressant efficacy of ESK-NS (MADRS decreased from T0 to T1, t = 6.533, df=23, p<0.001, and from T1 to T2, t = 2.029, df=20, p = 0.056). Considering tolerability and safety issues, one or more side effects were reported by 19/26 subjects (73%) after treatment administration. All reported side effects were time-dependent and did not cause significant sequelae; among them, dissociative symptoms (38%) and sedation (26%) were the most frequently reported. Finally, no cases of abuse or misuse of ESK-NS were reported. Despite study limitations related to the inherent nature of the study, a limited number of patients, and a short follow-up period, ESK-NS showed to be effective and safe in patients diagnosed with TRD comorbid with a SUD.

Treatment-Resistant Late-Life Depression: A Review of Clinical Features, Neuropsychology, Neurobiology, and Treatment.

Major depression is common in older adults (≥ 60 years of age), termed late-life depression (LLD). Up to 30% of these patients will have treatment-resistant late-life depression (TRLLD), defined as depression that persists despite two adequate antidepressant trials. TRLLD is challenging for clinicians, given several etiological factors (eg, neurocognitive conditions, medical comorbidities, anxiety, and sleep disruption). Proper assessment and management is critical, as individuals with TRLLD often present in medical settings and suffer from cognitive decline and other marks of accelerated aging. This article serves as an evidence-based guide for medical practitioners who encounter TRLLD in their practice.

Real world effectiveness of repeated ketamine infusions for treatment-resistant depression with comorbid borderline personality disorder.

Borderline personality disorder (BPD) has high rates of comorbidity with mood disorders, including treatment-resistant depression (TRD). Comorbidity of BPD with depression is associated with poorer response to antidepressants. Intravenous ketamine is a novel treatment for TRD that has not been specifically evaluated in patients with comorbid BPD. In this retrospective analysis of data collected from participants who received care at the Canadian Rapid Treatment Centre of Excellence (CRTCE; Braxia Health; ClinicalTrials.gov: NCT04209296), we evaluated the effectiveness of intravenous ketamine in a TRD population with comorbid BPD (N=100; n=50 BPD-positive compared with n=50 BPD-negative). Participants were administered four doses of intravenous ketamine (0.5-0.75mg/kg over 40 minutes) over two weeks. The primary outcome measures were changes in depressive symptom severity (as measured by Quick Inventory of Depressive Symptomatology-Self Report 16-item (QIDS-SR16)) and borderline symptom severity (as measured by Borderline Symptom List 23-item (BSL-23)). Both BPD-positive and BPD-negative groups improved significantly on the QIDS-SR16, QIDS-SR16 suicide ideation item, anxiety, and functionality scales with large effect sizes. There was no significant difference between groups. The BPD-positive group exhibited significant reduction of 0.64 on BSL-23 scores and a significant reduction of 5.95 on QIDS-SR16 scores. Patients with TRD and comorbid BPD receiving ketamine exhibited a significant reduction in symptoms of depression, borderline personality, suicidality, and anxiety.

A case of treatment-resistant bipolar depression and comorbid OCD treated with deep brain stimulation of the medial forebrain bundle: 5 years follow-up results.

Limited though promising evidence exists on the efficacy of Deep Brain Stimulation (DBS) of the Medial Forebrain Bundle (MFB) in otherwise intractable patients with Major Depression and Obsessive-Compulsive Disorder (OCD). Herein, we present acute and follow-up results (up to 5 years) of a 42 year old man with a diagnosis of treatment-resistant Bipolar Depression (BD) and comorbid OCD, successfully treated with DBS of the MFB. Regular follow-up visits with psychometric evaluations highlighted a considerable improvement of patient's depressive and OC symptoms at 5 years from implant. According to the limited, reported experience, we support the efficacy and tolerability of DBS of the MFB as a promising intervention in patients with treatment-resistant BD and comorbid OCD, with specific emphasis on the long-term outcome.

Oral S-ketamine effective after deep brain stimulation in severe treatment-resistant depression and extensive comorbidities.

This case report describes successful maintenance treatment with oral S-ketamine in a patient with severe depression, who previously was resistant to electroconvulsive therapy and deep brain stimulation, and who also had comorbid psychotic and obsessive compulsive symptoms.

Efficacy of low-dose ketamine infusion in anxious vs nonanxious depression: revisiting the Adjunctive Ketamine Study of Taiwanese Patients with Treatment-Resistant Depression.

BACKGROUND: The antidepressant effect of low-dose ketamine infusion on Taiwanese patients with anxious vs nonanxious treatment-resistant depression (ANX-TRD vs NANX-TRD) has remained unknown. METHODS: In total, 71 patients with TRD were randomized to three groups. Each group had participants who received saline infusions mixed with 0 (a normal saline infusion), 0.2, and 0.5 mg/kg of ketamine. Participants were followed up for 2 weeks. Anxious depression was defined as major depressive disorder with a total score of 7 or more on the 17-item Hamilton Depression Rating Scale Anxiety-Somatization factor. Generalized estimating equation models were used to investigate the effects of treatment (ketamine vs placebo) and depression type (ANX-TRD vs NANX-TRD) in the reduction of depressive symptoms during the follow-up period. RESULTS: Patients with ANX-TRD were less likely to respond to a single low-dose ketamine infusion than those with NANX-TRD. Among patients with NANX-TRD, low-dose ketamine infusion was significantly superior to placebo for reducing depressive symptoms. However, among patients with ANX-TRD, ketamine was not superior to placebo; nonetheless, approximately 30% of the patients responded to ketamine infusion compared to 13% who responded to the placebo. CONCLUSIONS: Low-dose ketamine infusion was effective for Taiwanese patients with NANX-TRD but not so effective for those with ANX-TRD. A higher level of anxiety severity accompanying depression was related to greater depression severity. This may confound and reduce the antidepressant effect of ketamine infusion.

Economic burden of treatment-resistant depression in privately insured US patients with co-occurring anxiety disorder and/or substance use disorder.

OBJECTIVE: To assess the burden of treatment-resistant depression (TRD) among privately insured patients with anxiety disorder and/or substance use disorders (SUD). METHODS: Adults <65 years old were identified in the Optum Health Care Solutions Inc. database (July 2009-March 2017). Among those with major depressive disorder (MDD) and antidepressant use, patients who initiated a third antidepressant (index date) after two regimens at adequate dose and duration were classified in the TRD cohort and patients without evidence of TRD were classified in the non-TRD MDD control cohort. The non-MDD control cohort comprised patients without MDD. In the non-TRD MDD and non-MDD cohorts, the index date was imputed to mimic the distribution of time in the TRD cohort from the first antidepressant to the index date or from the start of eligibility to the index date, respectively. Patients with <6 months of continuous insurance eligibility pre-/post-index, psychosis, schizophrenia, bipolar disorder and related conditions, dementia, and development disorders, and/or no baseline anxiety disorder and/or SUD were excluded. Patients with TRD were matched 1:1 to patients with non-TRD MDD and patients without MDD, based on exact matching factors (i.e. availability of work loss data) and propensity scores computed based on characteristics measured pre-index. Outcomes, including healthcare resource use (HRU) and costs, work productivity loss and related costs measured per patient per year ≤24 months post-index were compared between matched TRD, non-TRD MDD and non-MDD cohorts. RESULTS: A total of 3166 patients were identified in the TRD cohort and matched to non-TRD MDD and non-MDD cohorts. Among patients with TRD (mean age 39 years, 60.5% female), 87.3% had an anxiety disorder, 24.1% had SUD. The TRD cohort had higher HRU vs non-TRD MDD and non-MDD cohorts: 0.32 vs 0.20 and 0.14 inpatient admissions, 0.91 vs 0.73 and 0.58 emergency department visits, and 23.8 vs 16.8 and 11.6 outpatient visits, respectively (all p < .01). The TRD cohort had higher healthcare costs ($16,674) vs non-TRD MDD ($10,945) and non-MDD ($6493) cohorts (all p < .01). Among patients with work loss data (N = 310/cohort), patients with TRD had more work loss days (54) and higher work loss-related costs ($13,674) vs patients with non-TRD MDD (32 days; $7131) and without MDD (17 days; $4798; all p < .01). CONCLUSIONS: In patients with an anxiety disorder and/or SUD, TRD was associated with higher HRU, healthcare costs, work loss days and work loss-related costs.

Body Mass Index as a Moderator of Treatment Response to Ketamine for Major Depressive Disorder.

PURPOSE/BACKGROUND: Major depressive disorder (MDD) and obesity commonly co-occur. We sought to assess the impact of body mass index (BMI) on the acute antidepressant effects of ketamine in patients with treatment-resistant depression. METHODS/PROCEDURES: Post hoc analyses were conducted from a multisite, randomized, double-blind, placebo-controlled trial designed to assess the rapid-onset effects of intravenous ketamine. Patients (n = 99) were randomized to a single dose administration of ketamine 0.1 mg/kg (n = 18), ketamine 0.2 mg/kg (n = 20), ketamine 0.5 mg/kg (n = 22), ketamine 1.0 mg/kg (n = 20), or active placebo, midazolam 0.045 mg/kg (n = 19). Patients were stratified for BMI. For patients randomized to ketamine (n = 80), BMI was assessed as a continuous variable and also categorically (obese, overweight, not obese/overweight [reference]). The primary outcome measure was the change on the 6-item Hamilton Depression Rating Scale 24 hours after treatment. Outcomes at day 3 were also assessed. FINDINGS/RESULTS: The 6-item Hamilton Depression Rating Scale change scores at 24 hours were inversely associated with BMI (-0.28 ± 0.12, P = 0.02). With BMI operationalized categorically, both obese (-4.15 ± 1.41, P = 0.004) and overweight (-1.99 ± 1.14, P = 0.08) categories were inversely related to the 6-item Hamilton Depression Rating Scale change score at 24 hours, statistically significant for the obese category, as compared with the reference group. Similar but weaker findings were observed at 72 hours after infusion. IMPLICATIONS/CONCLUSIONS: Higher BMI and obesity were associated with a more robust acute antidepressant response to ketamine. This may have clinical relevance for a great number of patients who have both MDD and obesity. CLINICAL TRIAL REGISTRATION: NCT01920555.

Improvement in hypersomnia with high frequency repetitive transcranial magnetic stimulation in depressed adolescents: Preliminary evidence from an open-label study.

STUDY OBJECTIVES: Sleep disruption is a significant symptom of major depressive disorder (MDD). To our knowledge, no prior work has examined the impact of repetitive transcranial magnetic stimulation (rTMS) on sleep disturbances in adolescents with MDD. METHODS: Seventeen adolescents with treatment-resistant depression received 30 daily sessions of 10-Hz rTMS applied to the left dorsolateral prefrontal cortex (L-DLPFC). Clinical symptoms were assessed at baseline; after 10, 20, and 30 treatments; and at a 6-month follow-up visit. Insomnia was measured with a 3-item subscale of the Quick Inventory of Depressive Symptomatology-Adolescent (17 Item)-Self Report (QIDS-A17-SR). Hypersomnia was measured with a single QIDS-A17-SR item. Depression severity was rated with the Children's Depression Rating Scale, Revised (CDRS-R). The effect of rTMS on sleep was examined via linear mixed model analyses, with fixed effects of time (as a proxy of treatment), depression severity, age, and hypnotic medication use. RESULTS: No significant main effect of time was observed on the insomnia subscale (F4,43.442 = 1.078, p = 0 .379). However, there was a significant main effect of time on the QIDS-A17-SR hypersomnia score (F4,46.124 = 2.733, p = 0 .040), with significant improvement from baseline to treatment 10 (padj = 0.019) and from baseline to 6-month follow-up (padj = 0.044). In exploratory sensitivity analyses, response/nonresponse to rTMS for overall depressive symptoms had no significant effect on sleep outcomes. CONCLUSIONS: rTMS may have intrinsic effects on hypersomnia apart from its antidepressant effects in depressed adolescents. Future work should utilize sham controls and objective, quantitative measurements of sleep architecture to assess effects of rTMS in depressed adolescents. CLINICAL TRIAL REGISTRY: Clinicaltrials.gov identifiers are NCT00587639, NCT01502033, NCT01804270.

Metabolic Syndrome Rather Than Body Mass Index Is Associated With Treatment Response to Ketamine Infusions.

PURPOSE: There is a practical need for the identification of pretreatment clinical and epidemiological response predictors to repeat ketamine infusions. Response predictors can serve to guide clinical inclusion of patients and weigh risks versus benefits for those receiving maintenance ketamine. Previous studies indicate a link between obesity, depression, and treatment response. We sought to investigate if body mass index (BMI) or metabolic syndrome could predict treatment response to ketamine. METHODS: Patients aged 18 to 72 years who were electroconvulsive therapy nonresponders were given a subanesthetic ketamine hydrochloride dose of 0.5 mg/kg delivered intravenously for 40 minutes for an acute series of 3 to 6 infusions every other day. If patients reported at least a 50% decrease in depression symptoms after the acute series, they were moved to a maintenance series of infusions, on an individualized basis. To assess if BMI or metabolic syndrome could predict response, logistic regression models were run to analyze initial responders, sustained responders, and nonresponders. Models were adjusted for age, sex, and baseline depression severity. RESULTS: Of the 150 patients analyzed, 56 did not respond to the acute phase, 38 initially responded to the acute phase but relapsed during the maintenance phase, and 56 sustained their response for 1 year. In unadjusted models, BMI was not shown to be a predictor of initial or sustained response. Alternatively, metabolic syndrome defined by a diagnosis of hypertension, hyperglycemia, or hyperlipidemia was determined to be significantly associated with diminished initial response but not sustained response. CONCLUSIONS: In our patient group, results support the literature that outcome in antidepressant therapy is affected by the presence of metabolic syndrome rather than obesity itself. Although BMI did not predict initial response to ketamine, the presence of metabolic syndrome was significantly negatively associated with the initial response to an acute series of ketamine infusions.

Repeated intravenous infusions of ketamine: Neurocognition in patients with anxious and nonanxious treatment-resistant depression.

BACKGROUND: Recent studies have suggested that neurocognition is changed after repeated infusions of ketamine in patients with treatment-resistant depression (TRD). The objective of this study was to investigate whether differences existed in the neurocognitive effect of six ketamine infusions in patients with anxious and nonanxious TRD and to determine the association between baseline neurocognition and changes in symptoms after the infusions. METHOD: Patients with anxious (n = 30) and nonanxious TRD (n = 20) received six intravenous infusions of ketamine (0.5 mg/kg over 40 min) over 12 days. Speed of processing (SOP), working memory (WM), verbal learning and memory (VBM), visual learning and memory (VSM) and the severity of depressive and anxious symptoms were assessed at baseline, one day after the last infusion (day 13) and two weeks after the completion of the serial infusions (day 26). A linear mixed model was used to determine whether the neurocognitive changes differed between the two groups. Pearson correlation analysis was used to determine the relationship between baseline neurocognition and the changes in the symptomatic scores. RESULTS: Patients with anxious TRD had significant increases in SOP on day 13 and day 26 (both p < 0.001), and in VBM on day 13 (p = 0.028). However, no significant increase in any neurocognitive domain was found in patients with nonanxious TRD. Faster SOP at baseline was associated with greater improvement of anxious symptoms in patients with anxious TRD, and better VSM at baseline was associated with greater improvement of depressive symptoms in patients with nonanxious TRD. LIMITATION: The major limitation of this study is the open-label design. CONCLUSION: After six ketamine infusions, neurocognitive improvement was observed in patients with anxious TRD but not in patients with nonanxious TRD.