Resistant Depression Research Articles

Cariprazine augmentation in patients with treatment resistant unipolar depression who failed to respond to previous atypical antipsychotic add-on. A case-series.

Among individuals receiving an adequate pharmacological treatment for Major Depressive Disorder (MDD), only 30% reach a full symptom recovery; the remaining 70% will experience either a pharmacological response without remission or no response at all thus configuring treatment resistant depression (TRD). After an inadequate response to an antidepressant, possible next step options include optimizing the dose of the current antidepressant, switching to a different antidepressant, combining antidepressants, or augmenting with a non-antidepressant medication. Augmentation strategies with the most evidence-based support include atypical antipsychotics (AAs). Few data are available in literature about switching to another antipsychotic when a first augmentation trial has failed. We present a case-series of patients with unipolar treatment resistant depression who were treated with a combination of antidepressant and low dose of cariprazine after failing to respond to a first augmentation with another AA. We report data about ten patients affected by unipolar depression, visited at the outpatients unit of Mental Health Department of ASL CN2 of Bra and NA1 of Napoli (Italy). All patients failed to respond to conventional antidepressant therapy. A low dose of AA (aripiprazole, risperidone or brexpiprazole) was added for one month to the ongoing antidepressant treatment without clinical improvement. A second augmentation trial was then made with cariprazine. Seven out of ten patients were responders at the end of period, of them 1 patient reached responder status by week 2. HAM-D mean scores decreased from 23.9 ± 3.9 (baseline) to 14.8 ± 5.3 (4 weeks). Cariprazine was well tolerated, no severe side effect was observed during the trial. Our sample of treatment resistant unipolar patients showed good response to augmentation with cariprazine. Failure to a first AA-augmentation trial does not preclude response to a second one. This preliminary result requires confirmation through more rigorous studies conducted over greater samples.

71 Treatment with TMS Improves Aspects of Attention in Depression: A Pilot Study

Objective:Repetitive transcranial magnetic stimulation (TMS) is an evidenced based treatment for adults with treatment resistant depression (TRD). The standard clinical protocol for TMS is to stimulate the left dorsolateral prefrontal cortex (DLPFC). Although the DLPFC is a defining region in the cognitive control network of the brain and implicated in executive functions such as attention and working memory, we lack knowledge about whether TMS improves cognitive function independent of depression symptoms. This exploratory analysis sought to address this gap in knowledge by assessing changes in attention before and after completion of a standard treatment with TMS in Veterans with TRD.Participants and Methods:Participants consisted of 7 Veterans (14.3% female; age M = 46.14, SD = 7.15; years education M = 16.86, SD = 3.02) who completed a full 30-session course of TMS treatment and had significant depressive symptoms at baseline (Patient Health Questionnaire-9; PHQ-9 score >5). Participants were given neurocognitive assessments measuring aspects of attention [Wechsler Adult Intelligence Scale 4th Edition (WAIS-IV) subtests: Digits Forward, Digits Backward, and Number Sequencing) at baseline and again after completion of TMS treatment. The relationship between pre and post scores were examined using paired-samples t-test for continuous variables and a linear regression to covary for depression and posttraumatic stress disorder (PTSD), which is often comorbid with depression in Veteran populations.Results:There was a significant improvement in Digit Span Forward (p=.01, d=-.53), but not Digit Span Backward (p=.06) and Number Sequencing (p=.54) post-TMS treatment. Depression severity was not a significant predictor of performance on Digit Span Forward (f(1,5)=.29, p=.61) after TMS treatment. PTSD severity was also not a significant predictor of performance on Digit Span Forward (f(1,5)=1.31, p=.32).Conclusions:Findings suggested that a standard course of TMS improves less demanding measures of working memory after a full course of TMS, but possibly not the more demanding aspects of working memory. This improvement in cognitive function was independent of improvements in depression and PTSD symptoms. Further investigation in a larger sample and with direct neuroimaging measures of cognitive function is warranted.

49 A Preliminary Neurocognitive Profile Characterization of Treatment Resistant Depression

Objective:Major Depressive Disorder (MDD) subtypes have been shown to differentially impact psychiatric symptom presentation, clinical features, and functional abilities. While there is extensive research regarding MDD subtypes and clinical characteristics, there has been limited information regarding the relationship between MDD subtypes and neurocognitive functioning. In particular, the neurocognitive impact of the subtype of treatment resistant depression (TRD), defined as MDD that is unresponsive to treatment, is unknown. The aim of this preliminary study was to address this gap by characterizing the neurocognitive profile of TRD. We characterized the performance of older adults with TRD on measures across multiple neurocognitive domains, and explored whether performance varied based on age and education.Participants and Methods:Data utilized were drawn from a broader NIMH-funded, randomized, controlled study conducted at the University of New Mexico that investigated the clinical and cognitive outcomes of varying pulse amplitudes during acute electroconvulsive therapy (ECT) in adults with MDD. Participants in the study were age 50+ with a diagnosis of MDD, and further delineated by subtype as TRD. For this analysis, we utilized demographic and baseline neurocognitive data collected prior to start of treatment for those diagnosed with MDD, recurrent, severe (TRD). Neurocognitive measures included the Delis Kaplan Executive Function System (D-KEFS) Verbal Fluency and Color-Word Interference Subtests, Hopkins Verbal Learning Test-Revised (HVLT-R), and the Wechsler Adult Intelligence Scale 4th Edition (WAIS-IV) Digit Spans. Demographic-adjusted scaled scores were computed, and descriptive statistics were used to characterize the demographic and neurocognitive features of the sample. Multiple Analysis of Variance (MANOVA) was used to investigate difference in performance across neurocognitive measures based on level of education, with age as a covariate.Results:The sample (n = 42) had a mean age of 65 (SD=8), education level between12 and 14 years, 66.6% were female and 93% were Caucasian. DKEFS Verbal Fluency Category Switching Total Switching Accuracy fell in the Average range (Mean SS=9.5, SD=3.1), and Color Word Inhibition Total Completion Time fell in the Average range (Mean SS=8.5, SD=3.3). HVLT-R Total Recall Correct fell in the Mildly Impaired range (Mean T=35.5, SD=9.9) and Delayed Recall Correct fell in the Mildly to Moderately Impaired range (Mean T=32.9, SD=11.0). WAIS-IV Digit Span fell in the Average range (Mean SS=9.5, SD=2.2). Results indicated that age did not adjust outcomes on the neurocognitive variables, Wilks's λ=0.63, F(6, 23)=2.13, p=0.08. We found no evidence for significant effect of level of education on neurocognitive functioning when controlling for the covariate of age, Wilks's λ=-0.16, F(36, 103.7)=1.47, p=0.07.Conclusions:To our knowledge, this is one of two studies to examine neurocognitive functioning in patients with TRD. The analysis indicated generally intact performance in the neurocognitive domains of executive function (inclusive of verbal fluency, cognitive flexibility, and inhibition), auditory attention and working memory, and Impaired performance on indices of verbal learning and memory. Age did not impact performance on neurocognitive measures, and there was no significant effect for level of education. Further research is warranted to confirm these findings and further explicate the neurocognitive profile of TRD.

EEG synchronized left prefrontal transcranial magnetic stimulation (TMS) for treatment resistant depression is feasible and produces an entrainment dependent clinical response: A randomized controlled double blind clinical trial

BackgroundSynchronizing a TMS pulse with a person's underlying EEG rhythm can modify the brain's response. It is unclear if synchronizing rTMS trains might boost the antidepressant effect of TMS. In this first-in-human trial, we demonstrated that a single TMS pulse over the prefrontal cortex produces larger effects in the anterior cingulate depending on when it is fired relative to the individual's EEG alpha phase. Objective/hypothesesWe had three hypotheses. 1) It is feasible to synchronize repetitive TMS (rTMS) delivery to a person's preferred prefrontal alpha phase in each train of every session during a 30-visit TMS depression treatment course. 2) EEG-synchronized rTMS would produce progressive entrainment greater than unsynchronized (UNSYNC) rTMS. And 3) SYNC TMS would have better antidepressant effects than UNSYNC (remission, final Hamilton Depression Rating <10). MethodsWe enrolled (n = 34) and treated (n = 28) adults with treatment resistant depression (TRD) and randomized them to receive six weeks (30 treatments) of left prefrontal rTMS at their individual alpha frequency (IAF) (range 6–13 Hz). Prior to starting the clinical trial, all patients had an interleaved fMRI-EEG-TMS (fET) scan to determine which phase of their alpha rhythm would produce the largest BOLD response in their dorsal anterior cingulate. Our clinical EEG-rTMS system then delivered the first TMS pulse in each train time-locked to this patient-specific ‘preferred phase’ of each patient's left prefrontal alpha oscillation. We randomized patients (1:1) to SYNC or UNSYNC, and all were treated at their IAF. Only the SYNC patients had the first pulse of each train for all sessions synchronized to their individualized preferred alpha phase (75 trains/session ×30 sessions, 2250 synchronizations per patient over six weeks). The UNSYNC group used a random firing with respect to the alpha wave. All other TMS parameters were balanced between the two groups.The system interfaced with a MagStim Horizon air-cooled Fig. 8 TMS coil. All patients were treated at their IAF, coil in the F3 position, 120 % MT, frequency 6–13 Hz, 40 pulses per train, average 15-s inter-train interval, 3000 pulses per session. All patients, raters, and treaters were blinded. ResultsIn the intent to treat (ITT) sample, both groups had significant clinical improvement from baseline with no significant between-group differences, with the USYNC group having mathematically more remitters but fewer responders. (ITT -15 SYNC; 13 UNSYNC, response 5 (33 %), 1 (7 %), remission 2 (13 %), 6 (46 %). The same was true with the completer sample - 12 SYNC; 12 UNSYNC, response 4, 4 (both 30 %), remission 2 (17 %), 3 (25 %)). The clinical EEG phase synchronization system performed well with no failures. The average treatment session was approximately 90 min, with 30 min for placing the EEG cap and the actual TMS treatment for 45 min (which included gathering 10 min of resting EEG). Four subjects (1 SYNC) withdrew before six weeks of treatment. All 24 completer patients were treated for six weeks despite the trial occurring during the COVID pandemic. SYNC patients exhibited increased post-stimulation EEG entrainment over the six weeks. A detailed secondary analysis of entrainment data in the SYNC group showed that responders and non-responders in this group could be cleanly separated based on the total number of sessions with entrainment and the session-to-session precision of the entrained phase. For the SYNC group only, depression improvement was greater when more sessions were entrained at similar phases. ConclusionsSynchronizing prefrontal TMS with a patient's prefrontal alpha frequency in a blinded clinical trial is possible and produces progressive EEG entrainment in synchronized patients only. There was no difference in overall clinical response in this small clinical trial. A secondary analysis showed that the consistency of the entrained phase across sessions was significantly associated with response outcome only in the SYNC group. These effects may not simply be due to how the stimulation is delivered but also whether the patient's brain can reliably entrain to a precise phase. EEG-synchronized clinical delivery of TMS is feasible and requires further study to determine the best method for determining the phase for synchronization.

Indirect adjusted comparison of 6-month clinical outcomes between esketamine nasal spray and other real-world polypharmacy treatment strategies for treatment resistant depression: results from the ICEBERG study.

The efficacy of esketamine nasal spray (NS) as a rapid-acting agent for treatment resistant depression (TRD) was demonstrated in comparisons with placebo, when both were given in addition to a newly initiated selective serotonin reuptake inhibitor (SSRI)/serotonin norepinephrine reuptake inhibitor (SNRI). How esketamine NS compares with commonly used real-world (RW) polypharmacy treatment strategies is not known. ICEBERG was an adjusted indirect treatment comparison that analysed data from SUSTAIN-2 (NCT02497287; clinicaltrials.gov), a long-term, open-label study of esketamine NS plus SSRI/SNRI, and the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov), an observational study of routine clinical practice. Data were compared between patients receiving esketamine NS (SUSTAIN-2) and those from the EOTC treated with polypharmacy treatment strategies, either combination or augmentation. Analyses were adjusted for potential confounders, using rescaled average treatment effect among treated estimates. Threshold analyses were conducted to assess potential impact of unmeasured confounders on the robustness of analyses where esketamine NS was found to be significantly superior. Sensitivity analyses were used to understand the impact of analysis method selection and data handling. Esketamine NS treatment resulted in a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6-53.9]) and remission (33.6% [95% CI 29.7-37.6]) versus RW polypharmacy (26.8% [95% CI 21.0-32.5] and 19.4%, [95% CI 14.2-24.6], respectively). Relative risk calculations showed esketamine NS was 1.859 (95% CI 1.474-2.345; p < 0.0001) times as likely to result in response and 1.735 (1.297-2.322; p = 0.0002) times as likely to result in remission versus RW polypharmacy at 6 months. Threshold and extensive sensitivity analyses supported that analyses of esketamine NS superiority were robust. ICEBERG supports esketamine NS being superior to current RW individualized polypharmacy strategies, including augmentation, with benefits extending beyond acute use, to improved chance of 6-month response and remission. While unobserved confounding factors may certainly impact results of an indirect comparison, threshold analysis supported a low likelihood of this affecting the conclusions.To view an animated summary of this publication, please click on the Supplementary video.

ICEBERG study: an indirect adjusted comparison estimating the long-term benefit of esketamine nasal spray when compared with routine treatment of treatment resistant depression in general psychiatry.

Treatment resistant depression (TRD) affects 10-30% of patients with major depressive disorder. In 4-week trials, esketamine nasal spray (NS) was efficacious vs. placebo when both were initiated in addition to a new selective serotonin or serotonin norepinephrine reuptake inhibitor. However, comparison with an extended range of real-world treatments (RWT) is lacking. ICEBERG was an adjusted indirect treatment comparison using propensity score-based inverse probability weighting, performed on 6-month response and remission data from patients receiving esketamine NS plus oral antidepressant from the SUSTAIN-2 (NCT02497287; clinicaltrials.gov) study, compared with patients receiving other RWT from the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov) study. SUSTAIN-2 was a long-term open-label study of esketamine NS, while the EOTC was conducted at a time when esketamine NS was not available as RWT. Threshold and sensitivity analyses were conducted to assess how robust the primary analyses were. Patients receiving esketamine NS had a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6-53.9]) and remission (33.6% [95% CI 29.7-37.6]) vs. patients receiving RWT (26.4% [95% CI 21.5-31.4] and 18.2% [95% CI 13.9-22.5], respectively), according to rescaled average treatment effect among treated estimates. Resulting adjusted odds ratios (OR) and relative risk (RR) favoured esketamine NS over RWT for 6-month response (OR 2.756 [95% CI 2.034-3.733], p < 0.0001; RR 1.882 [95% CI 1.534-2.310], p < 0.0001) and remission (OR 2.276 [95% CI 1.621-3.196], p < 0.0001; RR 1.847 [95% CI 1.418-2.406], p < 0.0001). Threshold analyses suggested that differences between the two studies were robust, and results were consistent across extensive sensitivity analyses. ICEBERG supports that, at 6 months, esketamine NS has a substantial and significant benefit over RWT for patients with TRD. While results may be affected by unobserved confounding factors, threshold analyses suggested these were unlikely to impact the study conclusions.To view an animated summary of this publication, please click on the Supplementary video.

Treatment-Resistant Depression in America Latina study: one-year follow-up of treatment resistant depression patients under standard of care reveals insights on quality of life, disability, work impairment, and depressive symptoms.

Depressive Disorders are on the rise worldwide. This is also the case in Latin America (LatAm). Treatment-Resistant Depressive Disorder (TRD) poses additional burden to patients with depression. Impacts quality of life (QoL) and other dimensions, and standard of care (SOC) is insufficient to achieve the desired clinical outcomes. Evidence from LatAm is, however, lacking. The present study was devised as a 1-year follow-up of the SOC in TRD patients in LatAm to explore the burden of TRD. This was an observational, multinational, longitudinal study. Patients with clinical diagnosis of TRD in LatAm were included in a 1-year follow-up with SOC. Beyond the Sociodemographic characterization, outcome measures were QoL (EQ-5D-5L), disability (Sheehan Disability Scale - SDS), work productivity (Work Productivity and Activity Incapacity Questionnaire: depression - WPAI:D) and depression severity (Patient Health Questionnaire-PHQ9). Patients were assessed every 3-months and comparison was performed based on change from baseline to each visit and end of study (EOS - 12 months). Patients averaged 48 (± 13.12) years, mostly female (80.9%) and married/consensual union (42.5%) or single patients (34.4%). Despite the SOC treatment, three-quarters of the patients remained symptomatic at EOS, regardless of the significant longitudinal decrease (p ≤ 0.001). Similar trends were found for disability (p ≤ 0.001) -82.2% of the patients reporting work/school disruption at EOS-, percentage of work (34%) and activity impairment (40%) at EOS (p ≤ 0.001) and only 29.2% of patients with depressive severity "none" at EOS (p ≤ 0.001). The results portray the need to improve clinical outcomes in this complex and burdensome disease in LatAm. Here we show that the burden of TRD remains significant in essential dimensions of everyday life at EOS underlining the need for better therapeutic solutions. The improvements in most patients do not provide the desired outcome of return to the state before the condition. Further research should focus on identifying which treatments provide better outcomes in a real-world context.

Biological correlates of treatment resistant depression: a review of peripheral biomarkers.

Many patients fail to respond to multiple antidepressant interventions, being defined as "treatment-resistant depression" (TRD) patients. TRD is usually associated with increased severity and chronicity of symptoms, increased risk of comorbidity, and higher suicide rates, which make the clinical management challenging. Efforts to distinguish between TRD patients and those who will respond to treatment have been unfruitful so far. Several studies have tried to identify the biological, psychopathological, and psychosocial correlates of depression, with particular attention to the inflammatory system. In this paper we aim to review available studies assessing the full range of biomarkers in TRD patients in order to reshape TRD definition and improve its diagnosis, treatment, and prognosis. We searched the most relevant medical databases and included studies reporting original data on possible biomarkers of TRD. The keywords "treatment resistant depression" or "TRD" matched with "biomarker," "inflammation," "hormone," "cytokine" or "biological marker" were entered in PubMed, ISI Web of Knowledge and SCOPUS databases. Articles were included if they included a comparison with healthy controls (HC). Of the 1878 papers identified, 35 were included in the present study. Higher plasma levels of IL-6 and TNF-α were detected in TRD patients compared to HC. While only a few studies on cortisol have been found, four papers showed elevated levels of C-reactive protein among these patients and four articles focused on immunological cells. Altered kynurenine metabolism in TRD patients was reported in two studies, while contrasting results were found with regard to BDNF. Only a few biological alterations correlate with TRD. TNF-α seems to be the most relevant biomarker to discriminate TRD patients from both HC and treatment-responsive MDD patients. Moreover, several discrepancies among studies have been found, due to methodological differences and the lack of a standardized diagnostic definition of TRD.

Aromatase inhibition and ketamine in rats: sex-differences in antidepressant-like efficacy

BackgroundKetamine has been recently approved to treat resistant depression; however preclinical studies showed sex differences in its efficacy. Sex steroids, such as estrogens and testosterone, both in the periphery and locally in the brain, are regarded as important modulators of these sex differences. Therefore, the present study evaluated how inhibiting the biosynthesis of estrogens with letrozole (an aromatase inhibitor) could affect the observed sex differences in ketamine's antidepressant-like-response.MethodsWe performed several consecutive studies in adult Sprague–Dawley rats to evaluate potential sex differences in the antidepressant-like effects of ketamine (5 mg/kg, 7 days, i.p.), letrozole (1 mg/kg, 8 days, i.p.) and their combination (letrozole pre-treatment 3 h before ketamine). Acute and repeated antidepressant-like responses were ascertained in a series of behavioral tests (forced-swim, novelty-suppressed feeding, two-bottle choice for sucrose preference).ResultsThe main results proved clear sex differences in the antidepressant-like response induced by ketamine, which was observed following a repeated paradigm in adult male rats, but rendered inefficacious in female rats. Moreover, decreasing estrogens production with letrozole induced on itself an antidepressant-like response in female rats, while also increased ketamine's response in male rats (i.e., quicker response observed after only a single dose). Interestingly, both the antidepressant-like effects induced by ketamine in male rats or letrozole in female rats persisted over time up to 65 days post-treatment, suggesting long-term sex-directed benefits for these drugs.ConclusionsThe present results demonstrated a sex-specific role for aromatase inhibition with letrozole in the antidepressant-like response induced by ketamine in male rats. Moreover, letrozole itself presented as a potential antidepressant for females with persistent effects over time. Clearly, the production of estrogens is key in modulating, in a sex-specific manner, affective-like responses and thus deserve further studies.

Repetitive transcranial magnetic stimulation implementation within residential substance use disorder treatment centers for patients with comorbid depression

PurposeRepetitive transcranial magnetic stimulation (rTMS) is a well-established treatment with efficacy for several psychiatric disorders and has yielded promising yet mixed data showing reductions in craving for substance use. Patients with substance use disorders and comorbid depression may encounter obstacles to receiving rTMS in outpatient settings for treatment of depression. In turn, implementation of rTMS in residential substance use programs would greatly benefit those with comorbid treatment resistant depression. This paper aims to provide recommendations for implementing rTMS within residential substance use treatment centers.Design/methodology/approachUsing PubMed, the authors conducted a narrative review of manuscripts using various combinations of the following search terms: rTMS, depression, substance use and substance use disorder. The authors read manuscripts for their methodology, outcomes and adverse events to synthesize their results, which correspond to their recommendations for patient selection, safely implementing rTMS in residential substance use facilities and optimal rTMS protocols to start with.FindingsAdvantages of this approach include increased compliance, monitoring and access to care. Recommendations to safely incorporate rTMS in residential substance use disorder treatment centers revolve around selection of patients eligible for rTMS, allowing for sufficient time to elapse prior to commencing rTMS, monitoring for signs of recent substance use or withdrawal and using rTMS protocols compatible with the therapeutic programming of a treatment center.Originality/valueThis paper details the challenges and benefits of implementing rTMS for patients with dual diagnosis and provides recommendations to safely do so. To the best of the authors’ knowledge, this is a novel and unpublished endeavor.

Hippocampal subfield volumes in treatment resistant depression and serial ketamine treatment.

Subanesthetic ketamine is a rapidly acting antidepressant that has also been found to improve neurocognitive performance in adult patients with treatment resistant depression (TRD). Provisional evidence suggests that ketamine may induce change in hippocampal volume and that larger pre-treatment volumes might be related to positive clinical outcomes. Here, we examine the effects of serial ketamine treatment on hippocampal subfield volumes and relationships between pre-treatment subfield volumes and changes in depressive symptoms and neurocognitive performance. Patients with TRD (N = 66; 31M/35F; age = 39.5 ± 11.1 years) received four ketamine infusions (0.5 mg/kg) over 2 weeks. Structural MRI scans, the National Institutes of Health Toolbox (NIHT) Cognition Battery, and Hamilton Depression Rating Scale (HDRS) were collected at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks post-treatment. The same data was collected for 32 age and sex matched healthy controls (HC; 17M/15F; age = 35.03 ± 12.2 years) at one timepoint. Subfield (CA1/CA3/CA4/subiculum/molecular layer/GC-ML-DG) volumes corrected for whole hippocampal volume were compared across time, between treatment remitters/non-remitters, and patients and HCs using linear regression models. Relationships between pre-treatment subfield volumes and clinical and cognitive outcomes were also tested. All analyses included Bonferroni correction. Patients had smaller pre-treatment left CA4 (p = 0.004) and GC.ML.DG (p = 0.004) volumes compared to HC, but subfield volumes remained stable following ketamine treatment (all p > 0.05). Pre-treatment or change in hippocampal subfield volumes over time showed no variation by remission status nor correlated with depressive symptoms (p > 0.05). Pre-treatment left CA4 was negatively correlated with improved processing speed after single (p = 0.0003) and serial ketamine infusion (p = 0.005). Left GC.ML.DG also negatively correlated with improved processing speed after single infusion (p = 0.001). Right pre-treatment CA3 positively correlated with changes in list sorting working memory at follow-up (p = 0.0007). These results provide new evidence to suggest that hippocampal subfield volumes at baseline may present a biomarker for neurocognitive improvement following ketamine treatment in TRD. In contrast, pre-treatment subfield volumes and changes in subfield volumes showed negligible relationships with ketamine-related improvements in depressive symptoms.

Changes in neurotrophic signaling pathways in brain areas of the chronic mild stress rat model of depression as a signature of ketamine fast antidepressant response/non-response

Major Depressive Disorder (MDD) is a highly debilitating disorder characterized by a persistent feeling of sadness and anhedonia. Traditional antidepressants have a delayed onset of action and lack of efficacy in up to one third of patients, leading to treatment resistant depression (TRD). Recent years have witnessed a revolutionary treatment of TRD with the introduction of the fast-acting antidepressant ketamine. However, ketamine's mechanisms of action are still poorly understood. Here, we used the chronic mild stress animal model of depression on male rats to investigate the involvement of neurotrophic signaling pathways in stress vulnerability/resilience and fast antidepressant response/non-response to acute subanesthetic ketamine. We performed our analysis on both the hippocampus and the prefrontal cortex, two brain areas implicated in stress-related disorders, considering different subcellular fractions. We measured the activation by phosphorylation of protein kinase B (AKT), extracellular signal-regulated kinases (ERKs), glycogen synthase kinase-3 beta (GSK3 β), mammalian target of rapamycin (mTOR), and eukaryotic elongation factor 2 (eEF2), key effectors in the regulation of neuroplasticity and glutamatergic transmission which were previously associated to ketamine's fast antidepressant effect. We showed here for the first time that both stress and ketamine induced brain area and subcellular fraction specific changes in these pathways. Our study represents the first attempt to identify molecular mechanisms underlying the response/non-response to ketamine in an animal model of depression. This approach could give a crucial contribution to the study of etiopathogenetic mechanisms as well as to the identification of novel targets for the development of innovative therapeutic strategies.

Use of thyroid hormones in hypothyroid and euthyroid patients: a 2022 THESIS questionnaire survey of members of the Latin American Thyroid Society (LATS)

PurposeInconsistencies in the medical management of hypothyroidism have been reported between endocrinologists in different countries. This study aimed to identify the attitudes of Latin America thyroid specialists towards the use of thyroid hormones.MethodsOnline survey of members of the Latin America Thyroid Society.Results81/446 (18.2%) completed the questionnaire. Levothyroxine (LT4) was the initial treatment of choice for all respondents. 56.8% would consider LT4 use in biochemically euthyroid patients: infertile women with elevated anti-thyroid antibodies (46.9%), resistant depression (17.3%) and growing goiter (12%). Most respondents preferred tablets (39.5%) over liquid formulations (21.0%) or soft gel capsules (22.2%) and would not consider switching formulations in patients with persistent symptoms. 39.5% would never use LT4 + liothyronine (LT3) combination therapy in symptomatic euthyroid patients, due to low quality evidence for benefit. 60.5% reported that persistence of symptoms despite normal TSH is rare (below 5% of patients) and its prevalence has been stable over the last five years. Psychosocial factors (84.0%), comorbidities (86.4%) and the patient unrealistic expectation (72.8%) were considered the top three explanations for this phenomenon.ConclusionLT4 tablets is the treatment of choice for hypothyroidism. A significant proportion of respondents would use LT4 in some groups of euthyroid individuals, contrasting the recommendations of the major clinical practice guideline indications. LT4 + LT3 combination treatment in euthyroid symptomatic patients was considered by nearly 50%. Practices based on weak or absent evidence included use of thyroid hormones for euthyroid subjects by 56.8% of respondents and use of LT4 + LT3 treatment by 60.5% of respondents for patients with persistent symptoms. In contrast to many European countries, LATS respondents report a low and unchanged proportion of dissatisfied patients over the last five years.

Potential efficacy of dopaminergic antidepressants in treatment resistant anergic-anhedonic depression results of the chronic anergic-anhedonic depression open trial - CADOT.

Among treatment-resistant depression (TRD), we identified anergic-anhedonic clinical presentations (TRAD) as putatively responsive to pro-dopaminergic strategies. Based on the literature, non-selective monoamine oxidase inhibitors (MAOI) and dopamine D2 receptor agonists (D2RAG) were sequentially introduced, frequently under the coverage of a mood stabilizer. This two-step therapeutic strategy will be referred to as the Dopaminergic Antidepressant Therapy Algorithm (DATA). We describe the short and long-term outcomes of TRAD managed according to DATA guidelines. Out of 52 outpatients with TRAD treated with DATA in a single expert center, 48 were included in the analysis [severity - QIDS (Quick Inventory of Depressive Symptomatology) = 16 ± 3; episode duration = 4.1 ± 2.7 years; Thase and Rush resistance stage = 2.9 ± 0.6; functioning - GAF (Global Assessment of Functioning) = 41 ± 8]. These were followed-up for a median (1st - 3rd quartile) of 4 (1-9) months before being prescribed the first dopaminergic treatment and remitters were followed up 21 (11-33) months after remission. At the end of DATA step 1, 25 patients were in remission (QIDS <6; 52% [38-66%]). After DATA step 2, 37 patients were in remission (77% [65-89%]) to whom 5 patients with a QIDS score = 6 could be added (88% [78-97%]). Many of these patients felt subjectively remitted (GAF = 74 ± 10). There was a significant benefit to combining MAOI with D2RAG which was maintained for at least 18 months in 30 patients (79% [62-95%]). These results support TRAD sensitivity to pro-dopaminergic interventions. However, some clinical heterogeneities remain in our sample and suggest some improvement in the description of dopamine-sensitive form(s).

O.1.1-8 Impact on health-related quality of life after a concurrent exercise program in adults with treatment resistant depression: TRACE-RMD study

Abstract Purpose Treatment-resistant depression (TRD) is defined as those who do not remit to major depressive disorder with pharmacological treatment. TRD is associated with a worse health-related quality of life (QoL). Thus, people with TRD have reported greater disability than those healthy control (HC) in QoL, assessed by the 36-Item Short-Form Health Survey questionnaire (SF-36). Concurrent exercise training (i.e., a combination of aerobic and resistance exercise in the same session) could be an efficient non-pharmacological treatment strategy for improving QoL. Exercise is recommended as a non-pharmacological adjuvant program for patients with TRD. Therefore, this study aimed to determine the effectiveness of a concurrent exercise program on QoL in a TRD population. Methods Participants (n = 15, 73.3% women, 57.7±13.7 yr old) with TRD carried out a concurrent exercise program (2 days/week and 12 weeks of intervention). The SF-36 questionnaire was used to assess health-related QoL. At baseline, the TRD population showed lower scores (P ≤ 0.001) in physical function, role-physical, bodily pain, general health, vitality, social functioning, emotional role, mental health, and physical and mental component summaries compared to HC. Results After 12-week of intervention, general health (↑50.5%), vitality (↑41.2%), social functioning (↑76.4%), and mental component summary (↑24.9%) were increased (P &amp;lt; 0.05). However, there was not a significant (P &amp;gt; 0.05) change increase in physical functioning, role physical, bodily pain, emotional role, mental health, and physical component summary. Conclusion In conclusion, beneficial effects on QoL variables in patients with TRD after concurrent exercise should lead to considering exercise as an adjuvant program in their treatment.

Treating Treatment-resistant Depression with Esketamine Nasal Spray When All Therapeutic Options Have Been Exhausted: Clinical Experience from a Spanish Cohort of Expanded Use.

: Treatment Resistant Depression (TRD) is commonly defined as the lack of response to two or more anti-depressants with different mechanisms of action. Up to 30% of patients diagnosed with major depressive disorder might be considered to present TRD. The objective of this study was to assess the effectiveness and tolerability of esketamine in patients diagnosed with TRD, who were referred to our program after exhausting all available treatments. A secondary objective consisted in researching the relationship between response and previous use of electroconvulsive therapy. : A prospective, observational study was carried out in patients enrolled in the expanded use of esketamine in our center. They received esketamine prior to its marketing authorisation, for therapeutic purposes. Sixteen subjects were analyzed. Effectiveness was assessed with the Montgomery-Asberg depression rating scale (MADRS). Patients were followed up to 4 months after the administration. : Esketamine showed a rapid, robust effect in improving depressive symptoms, with no specific correlation between outcome and any demographic or clinical traits evaluated. No differences were found between patients that previously received Electroconvulsive Therapy, and those that didn't. 10 out of 16 patients responded (＞ 50% change in baseline MADRS scores), but only five achieved remission (＜ 12 points in the global MADRS score). We provide some recommendations, based on clinical experience, to improve tolerability and adherence, and to manage adverse effects. : Results suggest that esketamine is a safe, effective and rapid-acting option for TRD. More studies are needed to properly assess predictors of response outcome.

Reduced reward responsiveness in treatment resistant depression of middle-aged adults: Association with carotid artery stiffness and tetrahydrobiopterin.

Nearly one third of the population diagnosed with major depressive disorder (MDD) fail to respond to two or more antidepressant drugs of adequate dose and duration. This necessitates identification of confounding psychological and physiological factors that could contribute to treatment resistant depression (TRD). The present longitudinal study investigated the influence of behavioural inhibition system (BIS) and behavioural approach system (BAS) in treatment resistance. Further, the association of depression severity with physiological factors contributing to arterial stiffness was also investigated. Baseline data was acquired from 101 middle-aged (36-56 years) patients on immediate diagnosis with MDD using DSM-V criteria. Follow ups were conducted at 06 months and 12 months during treatment. Psychological assessment battery at baseline and follow ups comprised of Hamilton depression rating (HAM-D) for depression severity, WHODAS-2 and BIS-BAS score. Atherosclerosis and central arterial stiffness were measured by intima-media thickness of internal carotid artery and brachial-ankle pulse wave velocity. Physiological factors influencing central vascular function viz., body-mass index, estimated glomerular filtration rate, HbA1c, central systolic and diastolic blood pressure, heart rate and tetrahydrobiopterin were also investigated. Our results show lower reward responsiveness (BAS-RR) and higher BIS scores in TRD patients along with differentially higher intima-media thickness of left internal carotid artery. Higher depression severity at all stages of the study was correlated with lower tetrahydrobiopterin and BAS-RR scores. We, therefore, suggest that vascular depression resulting due to increased intima-media thickness of left carotid artery and lower tetrahydrobiopterin could be contributing factors for treatment resistance in middle-aged MDD patients.

Psilocybin therapy for treatment resistant depression: prediction of clinical outcome by natural language processing.

Therapeutic administration of psychedelics has shown significant potential in historical accounts and recent clinical trials in the treatment of depression and other mood disorders. A recent randomized double-blind phase-IIb study demonstrated the safety and efficacy of COMP360, COMPASS Pathways' proprietary synthetic formulation of psilocybin, in participants with treatment-resistant depression. While the phase-IIb results are promising, the treatment works for a portion of the population and early prediction of outcome is a key objective as it would allow early identification of those likely to require alternative treatment. Transcripts were made from audio recordings of the psychological support session between participant and therapist 1 day post COMP360 administration. A zero-shot machine learning classifier based on the BART large language model was used to compute two-dimensional sentiment (valence and arousal) for the participant and therapist from the transcript. These scores, combined with the Emotional Breakthrough Index (EBI) and treatment arm were used to predict treatment outcome as measured by MADRS scores. (Code and data are available at https://github.com/compasspathways/Sentiment2D .) RESULTS: Two multinomial logistic regression models were fit to predict responder status at week 3 and through week 12. Cross-validation of these models resulted in 85% and 88% accuracy and AUC values of 88% and 85%. A machine learning algorithm using NLP and EBI accurately predicts long-term patient response, allowing rapid prognostication of personalized response to psilocybin treatment and insight into therapeutic model optimization. Further research is required to understand if language data from earlier stages in the therapeutic process hold similar predictive power.

Anti-neuroinflammatory microRNA-146a-5p as a potential biomarker for neuronavigation-guided rTMS therapy success in medication resistant depression disorder

Treatment-resistant depression (TRD) is a challenging issue to address. Repetitive transcranial magnetic stimulation (rTMS) is commonly used but shows varying efficacy, necessitating a deeper understanding of depression physiology and rTMS mechanisms. Notably, an increasing amount of recent data has displayed the connection of TRD and its clinical outcome with chronic inflammatory processes. The current study included 19 TRD patients undergoing rTMS and 11 depressed patients responding to medication as a comparison group. We assessed therapeutic efficacy using MADRS, HAM-D-17, GAD-7, and PHQ-9 tests. Inflammatory markers, neurotrophins, and associated miRNAs were measured in patients blood serum before and during treatment. A control group of 18 healthy individuals provided baseline data. The results of our study showed significantly higher levels of pro-inflammatory interleukins-6 and − 8 in TRD patients compared to drug-responders, which also related to more severe symptoms before treatment. In addition, TRD patients, both before and during treatment, exhibited higher average blood serum concentrations of pro-inflammatory interleukin-18 and lower levels of anti-neuroinflammatory miR-146a-5p compared to healthy controls. We also observed that the expression of miR-16-5p, miR-93-5p, and especially miR-146a-5p correlated with clinical changes following rTMS. Our study confirmed that TRD patients possess a higher inflammatory status, while the anti-neuroinflammatory miR-146a-5p was demonstrated to have a considerable potential for predicting their rTMS treatment success.

Long Term Antidepressant Effects of Deep Brain Stimulation for Treatment Resistant Depression – A Research Protocol

Introduction: Individuals with treatment resistant depression (TRD) are those with severe major depressive disorder who fail to respond to conventional pharmacological treatment. As a result, novel technologies in the field of neuromodulation have been investigated to alleviate depressive symptoms in this population. One such neuromodulation therapy is deep brain stimulation (DBS), in which electrodes are neurosurgically implanted into target regions of the brain associated with depression, such as the subgenual anterior cingulate cortex (sgACC). While previous studies have explored the use of DBS as a therapy for TRD, few studies with adequate statistical power have explored the sustained antidepressant effects of DBS when targeting the sgACC of the brain. Methods: This study aims to explore the long-term effects in DBS patients for TRD by measuring changes in cerebral blood flow and cerebral metabolic rate in the sgACC, and its correlation to changes in self-reported depressive symptoms. Forty-five participants will be enlisted into this study. Psychometric evaluation and positron-emission topography imaging will be conducted prior to neurosurgery. Electrodes will be implanted into the sgACC, with extension wires attaching the electrodes to the internal pulse generator. In the six-week blinded phase, progressive increases in stimulation will be administered within the blinded group and sham stimulation in controls. The three-month open label phase will administer the same degree of high-frequency biphasic stimulation to the control and blinded groups and assess depression scores, neuroimaging, and adverse events. After cessation of active stimulation, a one-year, three-year, seven-year, and ten-year follow-up will monitor changes in antidepressant effects of DBS using simple linear contrasts and paired-sample t-tests. Expected Results: This study expects to find a sustained antidepressant response marked by decreases in sgACC metabolism and cerebral blood flow, and a reduction in self-report depression scores. Discussion: The use of DBS shows promise as a successful treatment intervention with sustained long-term effects for individuals with TRD. Additional secondary outcomes to be expected are improved quality of life and health behaviours. Conclusion: Though minor fluctuations are expected due to the presence of comorbidities, this study expects to showcase the long-term efficacy of deep brain stimulation for treatment resistant depression.