Functional changes in sleep-related arousal after ketamine administration in individuals with treatment-resistant depression.

The glutamatergic modulator ketamine is associated with changes in sleep, depression, and suicidal ideation (SI). This study sought to evaluate differences in arousal-related sleep metrics between 36 individuals with treatment-resistant major depression (TRD) and 25 healthy volunteers (HVs). It also sought to determine whether ketamine normalizes arousal in individuals with TRD and whether ketamine's effects on arousal mediate its antidepressant and anti-SI effects. This was a secondary analysis of a biomarker-focused, randomized, double-blind, crossover trial of ketamine (0.5 mg/kg) compared to saline placebo. Polysomnography (PSG) studies were conducted one day before and one day after ketamine/placebo infusions. Sleep arousal was measured using spectral power functions over time including alpha (quiet wakefulness), beta (alert wakefulness), and delta (deep sleep) power, as well as macroarchitecture variables, including wakefulness after sleep onset (WASO), total sleep time (TST), rapid eye movement (REM) latency, and Post-Sleep Onset Sleep Efficiency (PSOSE). At baseline, diagnostic differences in sleep macroarchitecture included lower TST (p = 0.006) and shorter REM latency (p = 0.04) in the TRD versus HV group. Ketamine's temporal dynamic effects (relative to placebo) in TRD included increased delta power earlier in the night and increased alpha and delta power later in the night. However, there were no significant diagnostic differences in temporal patterns of alpha, beta, or delta power, no ketamine effects on sleep macroarchitecture arousal metrics, and no mediation effects of sleep variables on ketamine's antidepressant or anti-SI effects. These results highlight the role of sleep-related variables as part of the systemic neurobiological changes initiated after ketamine administration. Clinical Trials Identifier: NCT00088699.

Sleep Delta power, age, and sex effects in treatment-resistant depression.

Electroencephalographic (EEG) deficits in slow wave activity or Delta power (0.5-4 Hz) indicate disturbed sleep homeostasis and are hallmarks of depression. Sleep homeostasis is linked to restorative sleep and potential antidepressant response via non-rapid eye movement (NREM) slow wave sleep (SWS) during which neurons undergo essential repair and rejuvenation. Decreased Low Delta power (0.5-2 Hz) was previously reported in individuals with depression. This study investigated power levels in the Low Delta (0.5-<2 Hz), High Delta (2-4 Hz), and Total Delta (0.5-4 Hz) bands and their association with age, sex, and disrupted sleep in treatment-resistant depression (TRD). Mann-Whitney U tests were used to compare the nightly progressions of Total Delta, Low Delta, and High Delta in 100 individuals with TRD and 24 healthy volunteers (HVs). Polysomnographic parameters were also examined, including Total Sleep Time (TST), Sleep Efficiency (SE), and Wake after Sleep Onset (WASO). Individuals with TRD had lower Delta power during the first NREM episode (NREM1) than HVs. The deficiency was observed in the Low Delta band versus High Delta. Females with TRD had higher Delta power than males during the first NREM1 episode, with the most noticeable sex difference observed in Low Delta. In individuals with TRD, Low Delta power correlated with WASO and SE, and High Delta correlated with WASO. Low Delta power deficits in NREM1 were observed in older males with TRD, but not females. These results provide compelling evidence for a link between age, sex, Low Delta power, sleep homeostasis, and non-restorative sleep in TRD.

Hypothalamic-pituitary-adrenal axis hyperactivity is normalized after successful intermittent theta-burst stimulation in resistant depressed patients.

The present pilot study assessed the effects of multi-session intermittent theta-burst stimulation (iTBS) applied to the left dorsolateral prefrontal cortex in 17 treatment resistant depressed inpatients (TRDs) showing cortisol non-suppression to the overnight dexamethasone suppression test (DST) at baseline (i.e., maximum post-DST cortisol [CORmax] level > 130 nmol/L). After 20 iTBS sessions, the DST was repeated in all TRDs. At baseline, post-DST CORmax levels were higher in TRDs compared to healthy control subjects (HCs; n = 17) (p < 0.0001). After 20 iTBS sessions, post-DST CORmax levels decreased from baseline (p < 0.03) and were comparable to HCs. Decreases in post-DST CORmax levels were related to decreases in 17-item Hamilton Depression Rating Scale (HAMD-17) scores (ρ = 0.53; p < 0.03). At endpoint, 10 TRDs showed DST normalization (among them 7 were responders [i.e., HAMD-17 total score > 50% decrease from baseline]), and 7 did not normalize their DST (among them 6 were non-responders) (p < 0.05). Our results suggest that successful iTBS treatment may restore normal glucocorticoid receptor feedback inhibition at the pituitary level.

Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits.

Cortical processing depends on finely tuned excitatory and inhibitory connections in neuronal microcircuits. Reduced inhibition by somatostatin-expressing interneurons is a key component of altered inhibition associated with treatment-resistant major depressive disorder (depression), which is implicated in cognitive deficits and rumination, but the link remains to be better established mechanistically in humans. Here we test the effect of reduced somatostatin interneuron-mediated inhibition on cortical processing in human neuronal microcircuits using a data-driven computational approach. We integrate human cellular, circuit, and gene expression data to generate detailed models of human cortical microcircuits in health and depression. We simulate microcircuit baseline and response activity and find a reduced signal-to-noise ratio and increased false/failed detection of stimuli due to a higher baseline activity in depression. We thus apply models of human cortical microcircuits to demonstrate mechanistically how reduced inhibition impairs cortical processing in depression, providing quantitative links between altered inhibition and cognitive deficits.

High-resolution virtual brain modeling personalizes deep brain stimulation for treatment-resistant depression: Spatiotemporal response characteristics following stimulation of neural fiber pathways.

Over the past 15 years, deep brain stimulation (DBS) has been actively investigated as a groundbreaking therapy for patients with treatment-resistant depression (TRD); nevertheless, outcomes have varied from patient to patient, with an average response rate of ∼50%. The engagement of specific fiber tracts at the stimulation site has been hypothesized to be an important factor in determining outcomes, however, the resulting individual network effects at the whole-brain scale remain largely unknown. Here we provide a computational framework that can explore each individual's brain response characteristics elicited by selective stimulation of fiber tracts. We use a novel personalized in-silico approach, the Virtual Big Brain, which makes use of high-resolution virtual brain models at a mm-scale and explicitly reconstructs more than 100,000 fiber tracts for each individual. Each fiber tract is active and can be selectively stimulated. Simulation results demonstrate distinct stimulus-induced event-related potentials as a function of stimulation location, parametrized by the contact positions of the electrodes implanted in each patient, even though validation against empirical patient data reveals some limitations (i.e., the need for individual parameter adjustment, and differential accuracy across stimulation locations). This study provides evidence for the capacity of personalized high-resolution virtual brain models to investigate individual network effects in DBS for patients with TRD and opens up novel avenues in the personalized optimization of brain stimulation.

Efficacy and Tolerability of Combination Treatments for Major Depression: Antidepressants plus Second-Generation Antipsychotics vs. Esketamine vs. Lithium.

BACKGROUND: Successful treatment of major depressive disorder (MDD) can be challenging, and failures ("treatment-resistant depression" [TRD]) are frequent. Steps to address TRD include increasing antidepressant dose, combining antidepressants, adding adjunctive agents, or using nonpharmacological treatments. Their relative efficacy and tolerability remain inadequately tested. In particular, the value and safety of increasingly employed second-generation antipsychotics (SGAs) and new esketamine, compared to lithium as antidepressant adjuncts remain unclear. METHODS: We reviewed randomized, placebo-controlled trials and used random-effects meta-analysis to compare odds ratio (OR) versus placebo, as well as numbers-needed-to-treat (NNT) and to-harm (NNH), for adding SGAs, esketamine, or lithium to antidepressants for major depressive episodes. RESULTS: Analyses involved 49 drug-placebo pairs. By NNT, SGAs were more effective than placebo (NNT = 11 [CI: 9-15]); esketamine (7 [5-10]) and lithium (5 [4-10]) were even more effective. Individually, aripiprazole, olanzapine+fluoxetine, risperidone, and ziprasidone all were more effective (all NNT < 10) than quetiapine (NNT = 13), brexpiprazole (16), or cariprazine (16), with overlapping NNT CIs. Risk of adverse effects, as NNH for most-frequently reported effects, among SGAs versus placebo was 5 [4-6] overall, and highest with quetiapine (NNH = 3), lowest with brexpiprazole (19), 5 (4-6) for esketamine, and 9 (5-106) with lithium. The risk/benefit ratio (NNH/NNT) was 1.80 (1.25-10.60) for lithium and much less favorable for esketamine (0.71 [0.60-0.80]) or SGAs (0.45 [0.17-0.77]). CONCLUSIONS: Several modern antipsychotics and esketamine appeared to be useful adjuncts to antidepressants for acute major depressive episodes, but lithium was somewhat more effective and better tolerated. LIMITATIONS: Most trials of adding lithium involved older, mainly tricyclic, antidepressants, and the dosing of adjunctive treatments were not optimized.

Characterization of brain functional connectivity in treatment-resistant depression.

OBJECTIVE: To characterize the functional connectivity (FC) of target brain regions for deep brain stimulation (DBS) in patients with treatment-resistant depression (TRD), and to evaluate its gender and brain lateralization dependence. METHODS: Thirty-one TRD patients and twenty-nine healthy control (HC) subjects participated. FC of subcallosal cingulate gyrus (SCG), ventral caudate (VCa), nucleus accumbens (NAc), lateral habenula (LHb), and inferior thalamic peduncle (ITP) were evaluated using resting-state fMRI. FC was characterized by calculating the nodal 'degree', a major feature of the graph theory. RESULTS: The degree measures of the left and right VCa, the left LHb, and the left ITP were significantly greater in the TRD than in the HC group. The degree was greater in females with TRD in all these regions except the right LHb. Finally, the left hemisphere was generally more affected by depression and presented significant degrees in LHb and ITP regions of the patients. CONCLUSION: Our findings demonstrate the ability of degree to characterize brain FC and identify the regions with abnormal activities in TRD patients. This implies that the degree may have the potential to be used as an important graph-theoretical feature to further investigate the mechanisms underlying TRD, and consequently along with other diagnostic markers, to assist in the determination of the appropriate target region for DBS treatment in TRD patients.

Postictal generalized electroencephalographic suppression following electroconvulsive therapy: Temporal characteristics and impact of anesthetic regimen.

OBJECTIVE: Postictal generalized electroencephalographic suppression (PGES) has been defined as electroencephalographic (EEG) activity of less than 10 microvolts following a generalized seizure. PGES is associated with an increased risk of sudden unexplained death in epilepsy, as well as treatment efficacy of electroconvulsive therapy (ECT). We investigated the impact of anesthetic on PGES expression and temporal characteristics. METHODS: We recorded postictal EEG in 50 ECT sessions in 11 patients with treatment resistant depression (ClinicalTrials.gov NCT02761330). For each participant, repeated sessions included either ketamine or etomidate general anesthesia during ECT. An automated algorithm was employed to detect PGES within 5 minutes after seizure termination. RESULTS: PGES was detected in 31/50 recordings, with intermittent epochs recurring up to five minutes after seizure termination. PGES total duration was greater following ketamine than etomidate anesthesia (p = 0.04). PGES expression declined loglinearly as a function of time (r = -0.89, p < 10-4). EEG amplitude during PGES did not vary linearly with time. CONCLUSIONS: PGES can occur intermittently for several minutes following seizure termination. Anesthetic effects should be considered when correlating PGES duration to clinical outcomes. SIGNIFICANCE: Prolonged EEG monitoring several minutes following seizure termination may be necessary to fully evaluate the presence and total duration of PGES.

Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression.

BACKGROUND: Ketamine's potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor-dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states. METHODS: Resting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined. RESULTS: A reduction in Montgomery-Åsberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t = 5.18, P < .0001, FDR-corrected), right temporal pole (t = 4.97, P < .0001, FDR-corrected), right parahippocampal gyrus (t = 5.80, P = .001, FDR-corrected), and left lateral occipital cortex (t = 4.73, P = .03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results. CONCLUSIONS: These preliminary results suggest that the Hb might be involved in ketamine's antidepressant action in patients with MDD, although these findings are limited by the lack of a control group.

Longitudinal effects of rTMS on neuroplasticity in chronic treatment-resistant depression.

Major depressive disorder (MDD) is amongst the most prevalent of psychiatric disorders. Unfortunately, a third of patients will not respond to conventional treatments and suffer from treatment-resistant depression (TRD). Repetitive transcranial magnetic stimulation (rTMS) has been proven effective in treating TRD. The research suggests that rTMS acts via neuroplastic effects on the brain, which can be measured by changes in hippocampal and amygdala volume as well as cortical thickness. This sham-controlled study investigates longitudinal effects of rTMS on the volumes of the hippocampus and amygdala and cortical thickness in patients with chronic TRD. 31 patients received 20 sessions of high-frequency rTMS (N = 15) or sham treatment (N = 16) over the left dorsolateral prefrontal cortex during 4 consecutive weeks. Using structural magnetic resonance imaging, we investigated longitudinal treatment effects on hippocampus and amygdala volume as well as thickness of the paralimbic cortex. We found no clinical differences between the active and sham rTMS group. Longitudinal changes in hippocampal and amygdala volume did not differ significantly, although males showed a significant decrease in left amygdala volume, irrespective of treatment group. Changes in cortical thickness of the paralimbic cortex differed significantly between the active and sham groups. Most notably, the increase in cortical thickness of the isthmus of the left cingulate gyrus was greater in the active as compared to the sham rTMS group. Our data suggest that rTMS can induce neuroplastic changes, particularly in cortical thickness, independent of treatment response. We also found longitudinal changes in amygdala volume in males. For clinical effects to follow these neuroplastic effects, more intensive rTMS treatment might be needed in chronically depressed patients.Trial registration number: ISRCTN 15535800, registered on 29-06-2017.

Mechanism of Intermittent Theta-Burst Stimulation in Synaptic Pathology in the Prefrontal Cortex in an Antidepressant-Resistant Depression Rat Model.

Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation, is considered a potential therapy for treatment-resistant depression. The synaptic mechanism of iTBS has long been known to be an effective method to induce long-term potentiation (LTP)-like plasticity in humans. However, there is limited evidence as to whether the antidepressant effect of iTBS is associated with change in synaptic function in the prefrontal cortex (PFC) in preclinical study. Hence, we applied an antidepressant (i.e., fluoxetine)-resistant depression rat model induced by severe foot-shocks to investigate the antidepressant efficacy of iTBS in the synaptic pathology. The results showed that iTBS treatment improved not only the impaired LTP, but also the aberrant long-term depression in the PFC of antidepressant-resistant depression model rats. Moreover, the mechanism of LTP improvement by iTBS involved downstream molecules of brain-derived neurotrophic factor, while the mechanism of long-term depression improvement by iTBS involved downstream molecules of proBDNF. The aberrant spine morphology was also improved by iTBS treatment. This study demonstrated that the mechanism of the iTBS paradigm is complex and may regulate not only excitatory but also inhibitory synaptic effects in the PFC.

Happiness During Low-Dose Ketamine Infusion Predicts Treatment Response: Reexploring the Adjunctive Ketamine Study of Taiwanese Patients With Treatment-Resistant Depression.

BACKGROUND: Studies have reported that ketamine potentially increases subjective happiness in healthy volunteers. However, whether ketamine-induced happiness can predict the treatment response of ketamine infusion among patients with treatment-resistant depression (TRD) remains unknown. METHODS: Between 2012 and 2015, 71 adult patients with TRD (based on DSM-IV-TR criteria) were enrolled and randomly assigned to receive a 40-minute ketamine (0.5 mg/kg or 0.2 mg/kg) or normal saline placebo infusion. Depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale. Measurements were conducted prior to infusion, at 40 and 240 minutes postinfusion, and, sequentially, on days 2 to 7 and 14 postinfusion. The visual analog scale for happiness (VASH) was used to assess happiness during infusion. The positive symptoms subscale of the Brief Psychiatric Rating Scale (BPRS-P) was used to measure the potential psychotomimetic effects of ketamine. RESULTS: For both the 2-factor (ketamine vs placebo) and 3-factor (ketamine 0.5 mg/kg vs 0.2 mg/kg vs placebo) models, a generalized estimating equation model indicated that infusion response type (happiness vs nonhappiness) significantly (P = .008 vs P = .002) predicted the trajectory of depressive symptoms after infusion. Changes in VASH and BPRS-P measures were not associated with each other. CONCLUSIONS: Subjective happiness during ketamine infusion predicted the antidepressant effect of both 0.5 mg/kg and 0.2 mg/kg ketamine infusion over time. Happiness during ketamine infusion, which was not related to the psychotomimetic effect of ketamine, may be associated with the reduction of depressive symptoms during the follow-up. TRIAL REGISTRATION: UMIN Clinical Trials Registry registration number: UMIN000016985.

Clinical Correlates and Outcome of Major Depressive Disorder and Comorbid Migraine: A Report of the European Group for the Study of Resistant Depression.

BACKGROUND: The present multicenter study aimed at defining the clinical profile of patients with major depressive disorder (MDD) and comorbid migraine. METHODS: Demographic and clinical information for 1410 MDD patients with vs without concurrent migraine were compared by descriptive statistics, analyses of covariance, and binary logistic regression analyses. RESULTS: The point prevalence rate for comorbid migraine was 13.5% for female and 6.2% for male patients. MDD + migraine patients were significantly younger, heavier, more likely female, of non-Caucasian origin, outpatient, and suffering from asthma. The presence of MDD + migraine resulted in a significantly higher functional disability. First-line antidepressant treatment strategy revealed a trend towards agomelatine. Second-generation antipsychotics were significantly less often administered for augmentation treatment in migraineurs. Overall, MDD + migraine patients tended to respond worse to their pharmacotherapy. CONCLUSION: Treatment guidelines for comorbid depression and migraine are warranted to ensure optimal efficacy and avoid possible pitfalls in psychopharmacotherapy, including serotonin syndrome.

The effectiveness of mindfulness-based cognitive therapy for reducing rumination and improving mindfulness and self-compassion in patients with treatment-resistant depression.

Introduction Depression is one of the most important psychiatric disorders, and the rate of recurrence is high. The heavy cost burden of depression is probably due to treatment-resistant depression. The purpose of this study was to determine the effectiveness of mindfulness-based cognitive therapy (MBCT) in patients with treatment-resistant depression (TRD). Method The present study was a quasi-experimental study conducted with twenty-four patients with treatment-resistant depression. Participants were selected by purposive sampling and randomly assigned to two groups, an experimental group and a control group. The experimental group received MBCT and antidepressants, while the control group received antidepressants only. The Hamilton and Beck Depression Inventory, Self-Compassion Scale, Thought Rumination Scale, and Mindfulness Scale were administered. The treatment program was conducted in eight sessions; with a follow-up period of one month subsequent to treatment termination. Data were analyzed using descriptive statistics (mean and standard deviation) and inferential statistics (analysis of variance for repeated measures and Bonferroni's post-hoc test). Results The results showed that MBCT significantly reduced depression and ruminative thinking in the experimental group and also improved mediators such as mindfulness and self-compassion. Patients maintained gains over the one month follow-up period (p < 0.01). Conclusion The present study provides additional evidence for the effectiveness of MBCT for TRD.

Intranasal esketamine: A novel drug for treatment-resistant depression.

PURPOSE: To review the efficacy, safety, and place in therapy of intranasal esketamine, a treatment modality for treatment-resistant depression. SUMMARY: An electronic literature search of PubMed, MEDLINE, and the ClinicalTrials.gov and Food and Drug Administration (FDA) websites covering the period April 2015 through June 2020 was performed using the following search terms: esketamine, intranasal esketamine, depression, and treatment-resistant depression. Other resources included review articles and the manufacturer's product labeling. All relevant English-language articles and reports on clinical trials conducted in humans were included. Esketamine (Spravato, Janssen Pharmaceuticals) is an intranasal antidepressant approved by FDA for management of treatment-resistant depression (TRD) in patients with inadequate response to traditional antidepressant therapy. Esketamine is self-administered under the supervision of a healthcare provider and is used as an adjunct to oral antidepressant therapy. Patients are supervised for 2 hours after self-administering the medication to monitor for sedation, dizziness, dissociation reactions, and increased blood pressure. Esketamine has a favorable risk-to-benefit profile, with demonstrated efficacy in reducing depressive symptoms more rapidly than monotherapy with traditional oral antidepressants. Reported adverse effects include sedation, dizziness, dissociation reactions, and blood pressure elevations, but these effects are primarily confined to the 2-hour postdose monitoring window. CONCLUSION: Patients with moderate to severe depression who are not sufficiently responsive to traditional strategies for managing TRD may benefit from adjunctive esketamine therapy.