Treatment-resistant Depression Patients Research Articles

Long-Term Cognitive Outcomes of Esketamine Nasal Spray in Treatment-Resistant Depression: A Preliminary Report

Background/Objectives: Ketamine/esketamine has a rapid/robust antidepressant effect on treatment-resistant depression (TRD). However, its long-term cognitive effects remain unclear. In this study, we investigated the potential cognitive effects of an esketamine spray on a series of TRD patients. Methods: We evaluated the cognitive performance of eight TRD patients subjected to an esketamine nasal spray as an adjunct treatment for six months. Cognitive assessments were performed before treatment initiation (T0) and at three (T3) and six (T6) months by an experienced neuropsychologist using a comprehensive neuropsychological battery. Depression severity was assessed by the Montgomery–Åsberg Depression Rating Scale. Changes in cognitive performance were analyzed by determining the bias between time points. To investigate the association between the severity of depression and performance on cognitive tests, we used correlation with correction for repeated measures and regression analysis with a general linear mixed model. We used the Tukey method to compare three estimates and the Dunnett method to compare two estimates. Results: Improvements in at least one test from T0 to T6 were found for attention, memory, and the executive functions of working memory, set-shifting, and inhibitory control. Most of the improvements had occurred by T3, but working memory and set-shifting improvements were significant only at T6. The severity of depression decreased significantly from T0 to T6, and most cognitive improvements were correlated with an improvement in depression severity. No test indicated a worsening of cognitive performance from T0 to T6. Conclusions: Our results suggest that the cognitive performance of TRD patients improved with long-term adjunct treatment with an esketamine nasal spray. Confirmatory studies are necessary.

A Retrospective Analysis of the Impact of Electroconvulsive Therapy on Anxiety Symptoms in Patients With Treatment-Resistant Depression.

Electroconvulsive therapy (ECT) is an effective treatment for treatment-resistant depression (TRD). There are limited data on the improvement of anxiety symptoms in patients receiving ECT for TRD. The aim of the study was to examine the extent to which anxiety symptom severity improves, relative to improvements in depressive symptoms, in TRD patients receiving an acute course of ECT. A retrospective chart review of 117 TRD patients who received an acute ECT course in a naturalistic outpatient setting was conducted. Symptomatic response was measured using the Beck Depression Inventory II and Generalized Anxiety Disorder 7 Scale. Two generalized estimating equation models assessed the degree of change in anxious symptoms relative to the change in depressive symptoms. Both depression (-0.09, P < 0.001) and anxiety (-0.08, P < 0.001) improved after ECT treatment, with a greater standardized decrease for symptoms of depression. Higher levels of anxiety over the treatment (-0.42, P < 0.001) were associated with smaller antidepressant improvements. ECT may improve symptoms of anxiety in patients with TRD. Anxiety symptoms show a favorable trajectory of improvement, though to a lesser extent, relative to changes in symptoms of depression. Higher symptoms of anxiety throughout the treatment course may be a negative predictor of antidepressant response in ECT.

Plasma microRNA Levels After Electroconvulsive Therapy in Treatment-Resistant Depressed Patients.

Electroconvulsive therapy (ECT) is one of the most effective treatments for treatment-resistant depression (TRD), even though the molecular mechanisms underlying its efficacy remain largely unclear. This study aimed, for the first time, to analyze plasma levels of miRNAs, key regulators of gene expression, in TRD patients undergoing ECT to investigate potential changes during treatment and their associations with symptom improvement. The study involved 27 TRD patients who underwent ECT. Plasma samples were collected at baseline (T0) and 1 month after the last ECT session (T1), and miRNA analysis was conducted by qRT-PCR. We also performed gene prediction of miRNAs differentially expressed and KEGG pathway analysis. miR-95-3p, miR-194-5p, miR-324-3p, miR-195-5p, miR-19b-3p, miR-30c-5p, let-7i-5p, and miR-497-5p were nominally downregulated at T1. Changes in miR-324-3p and miR-30c-5p levels between T0 and T1 significantly correlated with symptom improvement. Among the predicted miRNA target genes of these 2 miRNAs, we noticed the presence of VEGF and SIRT1, whose expression regulation has been associated with the ECT mechanism of action in previous studies. The study's most relevant results are related to the correlation between reductions in miR-30c-5p and miR-324-3p and the improvement of symptoms in response to ECT, positioning these miRNAs as promising candidates for further studies. These findings support and extend previous clinical and preclinical research indicating a role of miRNAs in ECT mechanism of action. However, no significant effects in ECT miRNA modulation were observed, highlighting the need for future replications in broader samples to confirm these results.

Effects of repeated intravenous esketamine administration on affective biases

Objectives While neuropsychological effects of conventional antidepressants are well-documented, more research is needed for rapid-acting antidepressants. This study examines the effects of esketamine on emotion processing and cognitive functioning, both acutely and sub-chronically. Methods Eighteen treatment-resistant depression (TRD) patients received repeated intravenous esketamine infusions. Mood state was reported daily, and the Facial Expression Recognition Task was administered 1h before and 4h after each infusion. Other assessments included the Digit Symbol Substitution Task. Results 66.7% participants who received at least five infusions (n = 12) showed significant improvement. Emotion recognition improved for all emotions except sadness, where accuracy decreased, particularly for low-intensity expressions (p = .007, d = −1.09). Misclassifications of other emotions as sad also decreased (p = .035, d = −0.79), indicating a reduced response bias towards sadness. This shift in bias emerged after the first infusion and then consolidated over time. In parallel, participants showed significant reductions in feelings of sadness (p = .015, d = −0.89) and irritability (p = .001, d = −1.35). Symptomatic improvement negatively correlated with accuracy for and misclassifications of sadness, and cognitive functioning also improved (p = .001, d = 1.62). Conclusions Improvement of TRD by esketamine may involve shifts in emotion processing and cognition, with the acute mood-lifting effects of esketamine being discernible from longer-lasting antidepressant response, which consolidates after repeated administration.

EEG alpha activity as predictor for TBS-rTMS treatment outcome in depression.

Repetitive transcranial magnetic stimulation (rTMS) is an established psychiatric procedure for patients suffering from treatment-resistant depression (TRD). Biomarker identification to predict rTMS outcomes may assist the clinician in optimizing treatment selection. In recent years, different electrophysiological markers, in particular electroencephalographic (EEG) markers, were shown to yield discriminative power between responders and non-responders to various TRD treatments. However, so far, predictive markers for the Theta Burst Stimulation (TBS) protocol have remained scarce. The present study, therefore, aimed to identify such markers. Resting state EEGs of 10-15min were done in a group of 46 TRD patients prior to rTMS TBS treatment (600 stimuli over the left dorsolateral prefrontal cortex). Each patient underwent 19-21 sessions with 4-5 sessions per week. Depression was assessed using the Hamilton Depression Rating Scale and the Beck Depression Inventory II. Our study demonstrated that responders exhibited significantly lower FAA values in a baseline EEG indicating that left frontal alpha dominance was associated with a positive response to TBS-rTMS in TRD patients. FAA was independent of both gender and age. No other biomarker, including alpha peak frequency, or alpha power, showed a significant difference between responders and non-responders. Taken together, FAA observed in EEG readings is emerging as a promising indicator of treatment outcomes in patients with TRD. Given these findings, we suggest considering FAA as a predictive factor when assessing the effectiveness of therapeutic interventions. Further studies replicating these results in larger, diverse populations are needed to confirm FAA as a reliable biomarker of clinical outcome.

Chronic invivo sequelae of repetitive acute mfb-DBS on accumbal dopamine and midbrain neuronal activity.

Medial Forebrain Bundle Deep Brain Stimulation (MFB-DBS) can have rapid and long lasting antidepressant effects in Treatment Resistant Depression (TRD) patients. The mechanisms are not well understood, but one hypothesis stipulates that modulation of the dopaminergic (DAergic) fibers contribute to the therapeutic outcome. Acute DBS effects on DA release have been studied; however, longitudinal studies with acute-repetitive DBS are lacking. Long-Evans accumbal DA release and Ventral Tegmental Area (VTA) calcium tonic and phasic signaling to different mfb-DBS parameters were measured using fiber photometry over 8 weeks, following acute and repetitive stimulation in behaving and non-behaving animals. DBS-induced release was observed in both targets, with increased frequency and DBS duration. 130 Hz stimulation increased phasic and tonic DA response over time, with the latter being a potential mechanism for its long-term clinical effectiveness. VTA calcium transients decreased, while phasic activity increased with frequency. Pulse width (PW)-mediated differential peak release timing also suggests potential parallel activation of diverse fiber types. Additionally, decreased DA transients rate during Elevated Plus Maze (EPM) suggests context and stimulation duration-dependent DA release. The data confirm chronic antidromic/orthodromic DAergic responses with stimulation parameter dependent variability, providing novel insights into temporal adaptations, connectivity and fiber recruitment on mfb DBS.

Esketamine Treatment Trajectory of Patients with Treatment-Resistant Depression in the Mid and Long-Term Run: Data from REAL-ESK Study Group.

Data on long-term treatment with Esketamine Nasal Spray (ESKNS) in real-world patients with treatment resistant depression (TRD) is scarce. The primary aim of the study is to evaluate the effectiveness and tolerability of ESK-NS treatment at 6 and 12-month follow-ups. This is part of an observational, retrospective, multicentric Italian study (REAL-ESK study). Subjects for the present study underwent psychiatric assessments after 6 and 12 months from the start of ESK-NS treatment. Repeated measures analysis of variance (ANOVA) was used to assess changes in continuous variables, such as scores on psychometric scales from baseline to follow-up time points. Of 63 patients who maintained ESK-NS treatment for at least 6 months, 48 were responders or remitters (76.2%). Among 15 non-responders at 6 months, 4 significantly improved at 12-month follow-up. At least one side effect was reported by 71.8% of subjects with a 6-month follow-up assessment. An overall reduction of side effects was noticed as treatment progressed (42% of patients who continued the treatment reported side effects at 12 months). The most common side effects were sedation (31.7%) and dissociation (28.6%) during ESK-NS sessions. Only 2 patients discontinued ESK-NS for tolerability reasons. The results support the effectiveness and safety of esketamine in the mid and long-term treatment of TRD patients. The late clinical response of a subgroup of patients represents a novel finding. Data needs to be confirmed in larger samples and longer observation periods.

TMS-induced modulation of brain networks and its associations to rTMS treatment for depression: a concurrent fMRI-EEG-TMS study.

Transcranial magnetic stimulation (TMS) over the left dorsolateral prefrontal cortex (L-DLPFC) is an established intervention for treatment-resistant depression (TRD), yet the underlying therapeutic mechanisms remain not fully understood. This study employs an integrative approach that combines TMS with concurrent functional magnetic resonance imaging (fMRI) and electroencephalography (EEG), aimed at assessing the acute/immediate effects of TMS on brain network dynamics and their correlation with clinical outcomes. Our study demonstrates that TMS acutely modulates connectivity within vital brain circuits, particularly the cognitive control and default mode networks. We found that the baseline TMS-evoked responses in the cognitive control and limbic networks significantly predicted clinical improvement in patients receiving a novel EEG-synchronized repetitive TMS treatment. Furthermore, this study explored the brain-state dependent effects of TMS, as the brain-state indexed by the phase of EEG prefrontal alpha oscillation. We found that clinical outcomes in this novel treatment are linked to state-specific TMS-modulated functional connectivity within a pivotal brain circuit of the L-DLPFC and the posterior subgenual anterior cingulate cortex within the limbic system. These findings contribute to our understanding of the therapeutic effects underlying TMS treatment in depression and support the potential of assessing state-dependent TMS effects in TMS timing target selection. This study emphasizes the importance of personalized timing of TMS for optimizing target engagement of specific clinically relevant brain circuits. Our results are crucial for future research into the development of personalized neuromodulation therapies for TRD patients.

Ketamine and Esketamine in Treatment of Resistant Depression

Aims: This review aims to explore the efficacy, mechanisms, administration routes, and safety profiles of ketamine and esketamine in the treatment of treatment-resistant depression (TRD). Methods: A comprehensive review of recent studies on ketamine and esketamine’s therapeutic applications in TRD was conducted. Sources included randomized controlled trials, systematic reviews, and meta-analyses from PubMed and Google Scholar. Results: Ketamine demonstrated rapid antidepressant effects within hours of administration, with symptom relief lasting several days to weeks. Esketamine, developed as an intranasal spray, provided an alternative route, improving accessibility while delivering therapeutic benefits. Additionally, ketamine has shown rapid effects on suicidal ideation, making it a viable option for crisis management in TRD patients. Both ketamine and esketamine enhance neuroplasticityby antagonizing NMDA receptors, leading to increased glutamate release, which activates AMPA receptors and promotes synaptogenesis. Clinical studies have shown that ketamine induces an immediate surge in brain-derived neurotrophic factor (BDNF) and upregulates the mTOR pathway, essential for the formation and strengthening of synaptic connections in mood-regulating brain regions. Although treatment is effective in the short-term, the data on long-term safety is scarce. Conclusions: Ketamine and esketamine represent significant advancements in the treatment of TRD, offering rapid symptom relief and neuroplastic benefits not achieved with traditional antidepressants. Future studies are required to establish long-term safety profiles and optimize dosing regimens. Overall, ketamine-based therapies provide a promising alternative for patients unresponsive to conventional treatments.

Effects of Ketamine and Esketamine on Cognitive Functions in Treatment-Resistant Depression

Major depressive disorder is a public health issue that negatively impacts quality of life and leads to cognitive impairments, causing significant disruptions in work, education, and social life. Treatment-resistant depression is defined as the failure to achieve improvement in depressive symptoms despite the use of at least two different antidepressant medications at adequate doses and durations. Current pharmacological approaches are inadequate for about half of treatment-resistant depression patients, and the effects of these medications on cognitive impairments are limited. Therefore, there is a need for new and effective treatment methods. This review aims to evaluate the effects of ketamine and esketamine on cognitive functions in the treatment of treatment-resistant depression patients. Relevant literature has been reviewed and recent studies have been evaluated. The results of randomized controlled trials indicate that ketamine is effective in treating treatment-resistant depression and can improve specific cognitive domains. Significant improvements in cognitive functions such as visual memory, processing speed, working memory, and attention have been recorded in patients responding to 0.5 mg/kg ketamine infusion. However, long-term use of ketamine may have negative effects on spatial working memory. Esketamine, an NMDA receptor antagonist, has shown rapid and effective antidepressant outcomes, providing stability or improvement in cognitive functions. Additionally, its intranasal administration offers practical advantages. However, findings suggest that high doses of esketamine may have neurotoxic effects and negatively impact cognitive functions. The effects of both drugs on depressive symptoms and cognitive functions vary depending on dose, duration of use, and frequency of administration. In conclusion, while ketamine and esketamine show significant potential in the treatment of treatment-resistant depression and improvement of cognitive symptoms, further research is needed regarding their long-term effects and safety.

A APLICAÇÃO DA ESTIMULAÇÃO MAGNÉTICA TRANSCRANIANA REPETITIVA NO TRATAMENTO DA DEPRESSÃO RESISTENTE

Treatment-resistant depression (TRD) affects about one-third of patients with major depressive disorder (MDD) and is characterized by the failure to respond to at least two antidepressants. Repetitive transcranial magnetic stimulation (rTMS) has been studied as an effective alternative for TRD, with potential benefits in reducing depressive symptoms. This study aimed to evaluate the effectiveness of rTMS as an adjunctive treatment for TRD through a literature review that analyzed articles published in the last five years, using the PubMed and LILACS databases. rTMS showed effectiveness in reducing depressive symptoms and suicidal ideation in TRD patients, despite variations in stimulation protocols, such as different frequencies and durations. Although rTMS demonstrated neuroplastic effects, there was no clear evidence that these structural changes resulted in significant short-term clinical improvements. It is concluded that rTMS is a promising approach for TRD treatment, but further studies are needed to optimize protocols and understand its long-term effects.

Cortical hypometabolism as a predictor of intermittent theta burst stimulation response in treatment-resistant depression patients: An open-label study.

Intermittent theta burst stimulation (iTBS) is an accepted and approved brain stimulation technique to treat patients with treatment-resistant depression. Using neuroimaging, this open-label study aimed to predict the response by observing glucose metabolism with the help of 18-FDG PET scan. A total of 25 treatment-resistant depression patients received 15 sessions of iTBS on the left dorsolateral prefrontal cortex. Two FDG-PET scans were done for all the patients. Fifty-six percent of patients responded to treatment with iTBS. We found that there was hypometabolism in left and right prefrontal lateral regions, left and right inferior parietal regions, and left prefrontal medial regions at baseline but no statistically significant difference in the metabolism between responders and nonresponders. We did not find any statistically significant difference in the metabolism between responders and nonresponders in any brain regions at T0 as well as T1. Further large-scale studies are required.

Ketamine and chronic treatment-resistant depression: real-world practice and after relapse

BackgroundChronic treatment-resistant depression (TRD) poses a major challenge for clinicians. Ketamine has shown a rapid but short-lived antidepressant effect in several studies involving TRD patients with different demographic and clinical profiles. Our study aimed to assess the antidepressant effect of serial infusion sessions of ketamine in patients with chronic TRD and evaluate the severity of symptoms after relapse and the general psychiatric health of the responding patients.MethodsIn this single arm open-label study, six infusions of ketamine at 0.5 mg/kg were administered to chronic TRD patients for approximately two weeks. Response and remission rates, side effects, adverse events and after-relapse symptoms were evaluated, and patients were followed for three months.Results23 patients underwent at least one infusion session, and 18 patients completed the six sessions. Twelve (66.67%) patients responded to the treatment at some point, and 11 (61.11%) patients maintained response after the end of the treatment protocol. One infusion was not sufficient to achieve a response (P > 0.9999, z = 1.81), and more than half of the responders met the response criteria after the third infusion. Only one patient (5.56%) achieved remission at the end of the infusion phase. All but one ketamine responders relapsed within one month after the end of the treatment. There was no statistical difference between baseline and after-relapse MADRS scores (P = 0.7886, 95% CI=-5.512-4.312, R2 = 0,008411). However, a high incidence of serious adverse events related to suicidality was evident; one of the non-responding patients attempted suicide and several attempts to sedate this patient with benzodiazepines failed. Two responding patients ended up with a suicidal attempt or severe suicidal thoughts.ConclusionsIntroducing rapid-acting antidepressant to manage TRD patients in clinical practice demands further investigation, and the benefit-to-harm ratio should be assessed in the light of the increased risk of suicidality.

Does depression with current suicidal ideation lead to treatment-resistant depression? Two large naturalistic cohorts of outpatients with depression and current suicidal ideation

As treatment-resistant depression (TRD) is linked to suicidal behaviors and suicidal risk is a predictor of TRD, depression with current suicidal ideation (SI) may lead to TRD. Early identification of TRD risk factors in patients with depression and current SI is crucial. The aims of our study were: i) to identify risk factors for depression non-remission and TRD in patients with depression and current SI; ii) to assess if SI at baseline mediated the relationship between depression severity at baseline and depression remission at week 6. We analyzed data from two large, prospective, naturalistic French cohorts of adult outpatients with depression (DSM-IV criteria) followed for 6 weeks after starting or changing antidepressants (LUEUR and GENESE). Sociodemographic and clinical characteristics, along with early symptom improvement, were compared between patients with and without current SI using logistic regression models (univariate and multivariate). Patients with antidepressant change or initiation were analyzed separately. Those without depression remission at week 6 after an antidepressant change were considered TRD cases. In patients with antidepressant change, the major predictor of non-remission was poorer early improvement (at week 2) of anxiety. For patients with treatment initiation, SI at baseline mediated the relation between depression severity at baseline and depression remission. Depression severity at baseline alone did not explain depression remission. Clinicians should systematically target with specific pharmacological and non-pharmacological treatments anxiety and SI and assess their changes in the short term to increase the chance of depression remission in depressed patients with current SI.

Telomere length and mitochondrial DNA copy number in association with trauma-focused psychotherapy efficacy

Early life adversities (ELA) have been linked to a greater risk for major depressive disorder (MDD) and treatment-resistant depression (TRD). The molecular mechanisms underlying the link between ELA and MDD and/or TRD are yet unknown. It has been suggested that ELA induces an allostatic burden, which in turn promotes oxidative stress and an inflammatory response that are further intensified by the influence of maladaptive coping behaviour. In this study we explored the role of two markers of cellular aging and oxidative stress (leukocyte telomere length (LTL) and mitochondrial DNA copy number (mtDNAcn)) in TRD and in response to trauma-focused psychotherapies. The study comprised 30 TRD patients receiving trauma-focused psychotherapies and 65 healthy controls. LTL and mtDNAcn were measured at baseline and four weeks after the end of the psychotherapy sessions. Response was defined based on reduction in the Montgomery-Åsberg Depression Rating Scale (MADRS). In the case control analysis, the logistic regression model showed that mtDNAcn but not LTL was a significant predictor of diagnosis (chi-square 92.108, p = 7.72e-20; contribution of mtDNAcn, B = −9-297, p = 0.00009). In the TRD sample, LTL and mtDNAcn were inversely correlated with MADRS score at baseline (LTL, Pearson's r = −0.478, p = 0.008; mtDNAcn, Pearson's r = −0.656, p = 0.00008), but there was no difference in either LTL or mtDNAcn between responders and non-responders. In conclusion, our findings support an involvement of cellular aging in TRD, and suggest that LTL and mtDNAcn are not predictors or mediators of response to trauma-focused psychotherapies.

Group Interpersonal Psychotherapy in Patients with Treatment Resistant Depression: A Qualitative Analysis

Depressive disorders are a worldwide leading cause of health-related burden, and a subgroup of depression patients fail to respond to available psychopharmacological treatments, a condition called Treatment Resistant Depression (TRD). While evidence suggests that both traditional and group (IPT-G) Interpersonal Psychotherapy interventions are efficient treatments for depression, few studies have evaluated the effect of IPT on TRD. Qualitatively analyze an IPT-G intervention conducted with TRD patients using a deductive, theory informed approach, to explore how TDR patients understand, contextualize and apply IPT’s problem-areas throughout the course of the treatment. 10 IPT-G sessions were analyzed using Framework Analysis. Sessions were video recorded and transcribed verbatim, and participants’ accounts were coded with predetermined, conceptually derived codes that were based on the three main problem areas identified in IPT. Following IPT’s main problem areas, three themes were generated: “Mechanisms of change—Improving communication”; “Acceptance of loss”; and “Finding new roles—depression, role transition, and reclaiming life conditions.” Our analysis suggests that patients with TRD can benefit from IPT-G. Depression is seen as a chronic condition that deeply affects the lives of patients, and IPT-G was seen as a way of promoting change and regaining control. However, we identified that patients to whom IPT-G did not achieve the same effect in terms of symptom reduction have greater difficulty in acquiring and generalizing new interpersonal skills, and often were immersed in severe family or marital interpersonal disputes.

Inflammatory cytokines, cortisol, and anhedonia in patients with treatment-resistant depression after consecutive infusions of low-dose esketamine.

Anhedonia, defined as a significant loss of interest or pleasure, is one of the core symptoms of treatment- resistant depression (TRD) and is often associated with poor prognosis. This article primarily investigates the changes in anhedonia symptoms, inflammatory markers, and cortisol levels in TRD patients after low-dose esketamine treatments. A total of sixty patients with TRD were enrolled in the clinical study of esketamine. We primarily assessed the severity of depressive symptoms and anhedonia using the Hamilton Rating Scale for Depression (HAMD) and the Snaith-Hamilton Pleasure Scal(SHAPS), respectively, before esketamine treatment and within 24h after each treatment. Blood specimens were collected before the first treatment and within 1h after the sixth treatment, measuring the levels of cortisol, interleukin-6(IL-6), interleukin-4(IL-4), and tumor necrosis factor-alpha(TNF-α) in plasma. We found that after six consecutive infusions of low-dose esketamine, patients' depressive symptoms and anhedonia showed improvement. After six treatments, plasma levels of cortisol, IL-6, and TNF-α decreased in patients with TRD, while the anti-inflammatory cytokine IL-4 increased. Multiple linear regression analysis revealed that baseline cortisol levels were correlated with anhedonia, while inflammatory factors showed no significant correlation. Add-on esketamine appears to be a good choice for the treament of the anhedonia in TRD. It has also shown promising effects on altering inflammatory markers in patients with TRD. Moreover, elevated plasma cortisol levels may serve as a potential biomarker for anhedonia in patients with TRD.

Altered brain function in treatment-resistant depression patients: A resting-state functional magnetic resonance imaging study

BackgroundIt has been established that there are functional changes in the brain of treatment-resistant depression (TRD) patients, but previous studies of functional connectivity (FC) usually involved selection of regions of interest based on accumulated a priori knowledge of the disorder. In this study, we combine amplitude of low-frequency fluctuation (ALFF) and FC; this approach, based on the abnormal ALFF, may provide some insights into the neural basis of the disease in terms of fMRI signals of low-frequency fluctuations. MethodsA total of 16 TRD patients, who visited the Qingdao Mental Health Center, Shandong Province, China between March 2023 and January 2024, along with 16 normal subjects, were enrolled into this study for functional imaging. In this study, we first explored the ALFF changes of TRD patients at a baseline resting state. Second, we selected the regions that were significantly changed in the ALFF as seeds and calculated the regional activity and functional connectivity (FC) of these regions using a seed-based approach. We also calculated correlations between the percent change in the PDQ-5D scores and ALFF values in brain regions with differing activity for TRD patients. ResultsDuring the baseline resting state, by using the ALFF, we found a significantly decreased or increased ALFF in the TRD patients relative to the controls. These regions were located in the left/right postcentral gyrus (PoCG.L/PoCG.R), right cuneus(CUN.R). We found that the ALFF values of the right hippocampus (HIP.R) in the TRD group were negatively correlated with the PDQ-5D score. Then, we selected these brain regions as seeds to investigate the FC changes in brains of TRD patients. We found abnormal functional connectivity in left/right middle frontal gyrus(MFG.L/MFG.R), the right Inferior frontal gyrus, opercular part (IFGoperc.R), the left/right Anterior cingulate and paracingulate gyri (ACC.L/ACC.R), the right supramarginal gyrus (SMG.R), and the right Calcarine fissure and surrounding cortex (CAL.R). ConclusionWe found a larger range of altered brain regions in TRD patients compared to healthy controls, especially in the central executive network (CEN), salience network (SN) and default mode network (DMN).

Repeated subcutaneous esketamine on treatment-resistant depression: An open-label dose titration study

BackgroundKetamine has gained prominence as one of the most effective therapeutic options in unipolar treatment-resistant depression (TRD). However, most studies related to the antidepressant action of ketamine used intravenous (IV) or intranasal (IN) administration. The subcutaneous (SC) route of administration is a promising alternative, as it results in plasma levels comparable to IV, causes fewer side effects, and is easier and cheaper to administer than both IV and/or IN routes. MethodsIn this context, we conducted an open-label clinical trial for investigating the efficacy and safety of 8 weekly sessions of SC esketamine in TRD patients (n = 30). ResultsAt the end of the treatment, a partial response rate of 26.09 %, a response rate of 52.17 % and remission rate of 34.78 % were observed, assessed by Montgomery-Åsberg Depression Rating Scale. Moreover, the self-reported depressive symptoms, as measured by the Beck Depression Inventory II (BDI-II), significantly decreased from the baseline to the final session, and the improvements were sustained throughout the week. Follow-up evaluations (BDI-II) up to the sixth month consistently showed scores lower than the baseline. LimitationsThe small sample size and the drop-out during the follow-up phase may limit the generalizability of the findings. Additionally, the absence of a control group necessitates cautious interpretation of causality. ConclusionsThis groundbreaking study, which addresses SC esketamine treatment for TRD, reported promising response and remission rates, as well as sustained antidepressant effects. It highlights the need for further research to improve and expand our knowledge of this innovative, more accessible, and cost-effective therapeutic approach.

Brain structural changes underlying clinical symptom improvement following fast-acting treatments in treatment resistant depression

BackgroundElectroconvulsive therapy (ECT), ketamine infusion (KI), and total sleep deprivation (TSD) are effective and fast in treating patients with treatment-resistant depression (TRD). However, it remains unclear whether the three treatments have the same effect on clinical symptom improvement and have common brain structural mechanisms. MethodsThe current study included 127 TRD patients and 37 healthy controls, which were obtained from the Perturbation of the Treatment Resistant Depression Connectome Project. We aimed to investigate the shared and distinct brain structural changes underlying clinical symptom improvement among ECT, KI, and TSD treatments. ResultsAll of the three treatments significantly reduced the depressive symptoms in TRD patients, but they differently affected other clinical measurements. Neuroimaging results also revealed that all of ECT, KI, and TSD treatments significantly increased gray matter volume of left caudate after treatment in TRD patients. However, the gray matter volume of other brain regions including hippocampus, parahippocampus, amygdala, insula, fusiform gyrus, several occipital and temporal areas was increased only after ECT treatment. Still, the baseline or the change of gray matter volume did not correlate with the depressive symptom improvement for all of the three treatments. LimitationsA higher sample size would be required to further validate our findings. ConclusionsThe results observed in the current study suggested that the ECT, KI, and TSD treatments differently affected clinical measurements and brain structures in TRD patients, though all of them were effective in depressive symptom improvement, which might facilitate the development of personalized treatment protocol for this disease.