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.

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.

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.

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.

Efficacy of intravenous ketamine treatment in anxious versus nonanxious unipolar treatment-resistant depression.

OBJECTIVE: To examine the effect of high baseline anxiety on response to ketamine versus midazolam (active placebo) in treatment-resistant depression (TRD). METHODS: In a multisite, double-blind, placebo-controlled trial, 99 subjects with TRD were randomized to one of five arms: a single dose of intravenous ketamine 0.1, 0.2, 0.5, 1.0 mg/kg, or midazolam 0.045 mg/kg. The primary outcome measure was change in the six-item Hamilton Rating Scale for Depression (HAMD6). A linear mixed effects model was used to examine the effect of anxious depression baseline status (defined by a Hamilton Depression Rating Scale Anxiety-Somatization score ≥7) on response to ketamine versus midazolam at 1 and 3 days postinfusion. RESULTS: N = 45 subjects had anxious TRD, compared to N = 54 subjects without high anxiety at baseline. No statistically significant interaction effect was found between treatment group assignment (combined ketamine treatment groups versus midazolam) and anxious/nonanxious status on HAMD6 score at either days 1 or 3 postinfusion (Day 1: F(1, 84) = 0.02, P = 0.88; Day 3: F(1, 82) = 0.12, P = 0.73). CONCLUSION: In contrast with what is observed with traditional antidepressants, response to ketamine may be similar in both anxious and nonanxious TRD subjects. These pilot results suggest the potential utility of ketamine in the treatment of anxious TRD.

[CBASP as an Inpatient Concept for Treatment-Resistant Chronic Depression: A Pilot Study of the Relationship between Adverse Effects and Treatment Outcome]. / CBASP als stationäres Behandlungskonzept der therapieresistenten chronischen Depression: Eine Pilotstudie zum Zusammenhang von Nebenwirkungen und Therapieerfolg.

BACKGROUND: Inpatient psychotherapy might trigger adverse effects among others due to short but intensive treatment. Thus, in this pilot study, certain adverse effects of the multidisciplinary inpatient Cognitive Behavioral Analysis System of Psychotherapy (CBASP) for treatment-resistant chronically depressed patients as well as their relationship to treatment outcome (response-, remission-, and relapse-rates) are examined. MATERIAL AND METHODS: 50 patients with treatment-resistant and chronic depression completed the structured 12-weeks inpatient treatment program. Adverse effects were assessed by 1) deterioration of depressive symptoms (measured by the Hamilton Depression Rating Scale, HDRS) at discharge and 2) a self-report questionnaire measuring Adverse Effects of Inpatient Psychotherapy (ADEFIP), which were filled out 6 to 12 months after discharge by the patients. RESULTS: After 12 weeks of treatment, 84% could be classified as responder, of whom 44% fulfilled the remission criterion. 16% were Non-Responder. According to HDRS, none of the patients showed objective deterioration of the depressive symptoms. Six months after discharge, 40% of the responders suffered from relapse. Concerning the ADEFIP, 66% of the patients reported transient deterioration of symptoms. These patients were less likely to achieve remission. Over 50% reported interpersonal conflicts with treatment team members or other patients without any relation to outcome. Finally, more than half of the patients reported significant changes in social relationships after discharge. These patients were less likely to relapse. Overall, 94% of the patients reported at least one of the in this study assessed adverse effects. CONCLUSIONS: Despite some limitations, this pilot study suggests that the CBASP inpatient program could indeed cause adverse effects. However, only subjective transient deterioration appeared to have a negative impact on the individual treatment outcome in the short-term. Results encourage further research concerning adverse treatment effects in the context of short- and long-term treatment outcome investigating how relevant adverse effects are.

Impact of deep brain stimulation of the ventral anterior limb of the internal capsule on cognition in depression.

BACKGROUND: Preliminary studies report no negative and a possible positive impact of deep brain stimulation (DBS) on cognition of patients with treatment-resistant depression (TRD). However, these studies neither controlled for practice effects nor compared active with sham stimulation. METHOD: To address these limitations, we compared 25 TRD patients, who underwent DBS of the ventral anterior limb of the internal capsule (vALIC), with 21 healthy controls (HCs) matched on gender, age and education level. Both groups did subtests of the Cambridge Neuropsychological Test Automated Battery assessing verbal and visuospatial memory, attention, cognitive flexibility, psychomotor functioning, planning and object naming. TRD patients were tested 3 weeks prior to DBS surgery (baseline), 3 weeks following surgery (T1) and following 52 weeks of DBS optimization (T2). HCs were tested at baseline, 6 weeks following baseline (T1) and 20-24 weeks following baseline (T2). Subsequently, TRD patients entered a randomized, double-blind crossover phase, in which they were tested in an active and a sham stimulation phase. RESULTS: TRD patients did not improve on a test of immediate verbal recognition from baseline to T1, whereas HCs did (group x time: p = 0.001). Both TRD patients and HCs improved over sessions on tests measuring delayed verbal recall, visuospatial memory, planning and object naming (all p < 0.01). Active and sham stimulation did not have an impact on any of the tests differentially. CONCLUSIONS: vALIC DBS neither has a lasting positive nor negative impact on cognition in TRD patients. DBS surgery might have a temporary negative effect on verbal memory.

Self-reported obstructive sleep apnea is associated with nonresponse to antidepressant pharmacotherapy in late-life depression.

BACKGROUND: Obstructive sleep apnea (OSA) is frequently comorbid with late-life depression. The purpose of this project was to determine, using a sample of older adults with major depressive disorder, whether patient-reported diagnosis of OSA was associated with rate of response to venlafaxine. METHODS: Participants from this multisite study were adults ≥60 years old (n = 468) with major depressive disorder and a Montgomery Asberg Depression Rating Scale (MADRS) score of ≥15. Depression response was the outcome variable, defined as a MADRS score of ≤10 for two consecutive assessments at the end of 12 weeks of open-label treatment with venlafaxine 300 mg/day. To assess OSA, participants were asked if they had been diagnosed with OSA using polysomnography. RESULTS: Eighty participants (17.1%) reported a diagnosis of OSA prior to baseline. Participants with OSA were more likely to be male, report greater impairment on measures of health, experience a longer duration of the index episode, and receive an adequate antidepressant trial prior to entering the study. During the 12 weeks of treatment, 40.8% responded to treatment with venlafaxine (43.6%, n = 169/388 of the no OSA group, and 27.5%, n = 22/80 of the OSA group). Participants without OSA were 1.79 times more likely to respond to treatment (HR: 1.79 [95%CI: 1.13-2.86], P < .05) compared to those with OSA. CONCLUSIONS: OSA may impair response to antidepressant pharmacotherapy in depressed older adults. Future studies of antidepressant response rates among depressed older adults with OSA should both prospectively diagnose OSA and monitor adherence to treatments such as continuous positive airway pressure.

Automatic implantable cardioverter defibrillator in electroconvulsive therapy.

As the number of patients with implantable cardiac devices increases so too does the frequency with which these individuals present for electroconvulsive therapy (ECT). The rationale for deactivating an automatic implantable cardioverter defibrillator before ECT has been made based on the concern that artifacts generated during treatment could be interpreted as a treatable rhythm by the internal device, resulting in a discharge. We believe that the risk of inappropriate discharge during ECT is very low and outweighed by the considerable benefit of an active device being able to more quickly treat a malignant dysrhythmia.

Case report of a 24-year-old man with resolution of treatment-resistant major depressive disorder and comorbid PTSD using rTMS.

Although there is a large amount of literature indicating the effectiveness of repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant major depressive disorder (trMDD), the authors did not find any literature supporting rTMS for MDD with the comorbid condition of posttraumatic stress disorder (PTSD). Here, we report an original case of a patient whose trMDD and PTSD remitted using rTMS at the left dorsolateral prefrontal cortex.

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.