Treatment-resistant Depression Group Research Articles

How different definition criteria may predict clinical outcome in treatment resistant depression: Results from a prospective real-world study

Management of treatment-resistant depression (TRD) remains a major public health challenge, also due to the lack of a consensus around TRD definition. We investigated the impact of different definitions of TRD on identifying patients with distinct features in terms of baseline characteristics, treatment strategies, and clinical outcome. We conducted a prospective naturalistic study on 538 depressed inpatients. Patients were screened for treatment resistance by two TRD definitions: looser criteria (lTRD) and stricter criteria (sTRD). We compared baseline characteristics, treatment and clinical outcome between the TRD groups and their non-TRD counterparts. 52.97 % of patients were identified as lTRD, only 28.81 % met the criteria for sTRD. sTRD patients showed lower rates of remission and slower symptom reduction compared to non-TRD patients and received more challenging treatments. Surprisingly, patients identified as sTRD also exhibited lower rates of psychiatric comorbidities, including personality disorders, substance abuse, or alcohol misuse. Stricter TRD criteria identify patients with worse clinical outcomes. Looser criteria may lead to overdiagnosis and over treatment. Clinical features known to be possible risk factors for TRD, as psychiatric comorbidities, showed to be more suggestive of a “difficult to manage” depression rather than a proper TRD.

Neuroplasticity of the left dorsolateral prefrontal cortex in patients with treatment-resistant depression as indexed with paired associative stimulation: a TMS-EEG study.

Major depressive disorder affects over 300 million people globally, with approximately 30% experiencing treatment-resistant depression (TRD). Given that impaired neuroplasticity underlies depression, the present study focused on neuroplasticity in the dorsolateral prefrontal cortex (DLPFC). Here, we aimed to investigate the differences in neuroplasticity between 60 individuals with TRD and 30 age- and sex-matched healthy controls (HCs). To induce neuroplasticity, participants underwent a paired associative stimulation (PAS) paradigm involving peripheral median nerve stimulation and transcranial magnetic stimulation (TMS) targeting the left DLPFC. Neuroplasticity was assessed by using measurements combining TMS with EEG before and after PAS. Both groups exhibited significant increases in the early component of TMS-evoked potentials (TEP) after PAS (P < 0.05, paired t-tests with the bootstrapping method). However, the HC group demonstrated a greater increase in TEPs than the TRD group (P = 0.045, paired t-tests). Additionally, event-related spectral perturbation analysis highlighted that the gamma power significantly increased after PAS in the HC group, whereas it was decreased in the TRD group (P < 0.05, paired t-tests with the bootstrapping method). This gamma power modulation revealed a significant group difference (P = 0.006, paired t-tests), indicating an inverse relationship for gamma power modulation. Our findings underscore the impaired neuroplasticity of the DLPFC in individuals with TRD.

Care pathways, prescribing practices and treatment outcomes in major depressive disorder and treatment-resistant depression: retrospective, population-based cohort study.

Despite the availability of effective therapies, many patients with major depressive disorder (MDD) develop treatment-resistant depression (TRD). To evaluate and compare prescribing patterns, contact with specialist services and treatment outcomes in patients with MDD and TRD. This was a retrospective analysis of linked primary and secondary care National Health Service data in the north-west London Discover-NOW data-set. Eligible patients were adults who had diagnostic codes for depression and had been prescribed at least one antidepressant between 2015 and 2020. A total of 110 406 patients were included, comprising 101 333 (92%) with MDD and 9073 (8%) with TRD. Patients with TRD had significantly higher risks of suicidal behaviour and comorbidities such as anxiety, asthma, and alcohol or substance misuse (all P < 0.0001). Citalopram, sertraline, fluoxetine and mirtazapine accounted for 83% of MDD and 71% of TRD prescriptions. Use of antidepressant switching (1% MDD, 7% TRD) and combination therapy (1%, 5%) was rare, whereas augmentation occurred more frequently in the TRD group (4%, 35%). Remission was recorded in 42 348 (42%) patients with MDD and 1188 (13%) with TRD (P < 0.0001), whereas relapse was seen in 20 970 (21%) and 4923 (54%), respectively (P < 0.0001). Mean times from diagnosis to first contact with mental health services were 38.9 (s.d. 33.6) months for MDD and 41.5 (s.d. 32.0) months for TRD (P < 0.0001). There appears to be a considerable difference between treatment guidelines for depression and TRD and the reality of clinical practice. Long-term treatment with single antidepressants, poor remission, and high relapse rates among patients in primary care highlight the need to optimise treatment pathways and access to newer therapies.

Preliminary evidence that ketamine alters anterior cingulate resting-state functional connectivity in depressed individuals

Activity changes within the anterior cingulate cortex (ACC) are implicated in the antidepressant effects of ketamine, but the ACC is cytoarchitectonically and functionally heterogeneous and ketamine’s effects may be subregion specific. In the context of a double-blind randomized placebo-controlled crossover trial investigating the clinical and resting-state fMRI effects of intravenous ketamine vs. placebo in patients with treatment resistant depression (TRD) vs. healthy volunteers (HV), we used seed-based resting-state functional connectivity (rsFC) analyses to determine differential changes in subgenual ACC (sgACC), perigenual ACC (pgACC) and dorsal ACC (dACC) rsFC two days post-infusion. Across cingulate subregions, ketamine differentially modulated rsFC to the right insula and anterior ventromedial prefrontal cortex, compared to placebo, in TRD vs. HV; changes to pgACC-insula connectivity correlated with improvements in depression scores. Post-hoc analysis of each cingulate subregion separately revealed differential modulation of sgACC-hippocampal, sgACC-vmPFC, pgACC-posterior cingulate, and dACC-supramarginal gyrus connectivity. By comparing rsFC changes following ketamine vs. placebo in the TRD group alone, we found that sgACC rsFC was most substantially modulated by ketamine vs. placebo. Changes to sgACC-pgACC, sgACC-ventral striatal, and sgACC-dACC connectivity correlated with improvements in anhedonia symptoms. This preliminary evidence suggests that accurate segmentation of the ACC is needed to understand the precise effects of ketamine’s antidepressant and anti-anhedonic action.

Human in vivo evidence of reduced astrocyte activation and neuroinflammation in patients with treatment-resistant depression following electroconvulsive therapy.

This study aimed to investigate the neuroinflammatory hypothesis of depression and the potential anti-inflammatory effect of electroconvulsive therapy (ECT) in vivo, utilizing astrocyte-derived extracellular vesicles (ADEVs) isolated from plasma. A total of 40 patients with treatment-resistant depression (TRD) and 35 matched healthy controls (HCs) were recruited at baseline, and 34 TRD patients completed the post-ECT visits. Blood samples were collected at baseline and post-ECT. Plasma ADEVs were isolated and confirmed, and the concentrations of two astrocyte markers (glial fibrillary acidic protein (GFAP) and S100β), an EV marker cluster of differentiation (CD) 81, and nine inflammatory markers in ADEVs were measured as main analyses. Additionally, correlation analysis was conducted between clinical features and ADEV protein levels as exploratory analysis. At baseline, the TRD group exhibited significantly higher levels of two astrocyte markers GFAP and S100β, as well as CD81 compared to the HCs. Inflammatory markers interferon (IFN)-γ, interleukin (IL)-1β, IL-4, IL-6, tumor necrosis factor (TNF)-α, IL-10, and IL-17A were also significantly higher in the TRD group. After ECTs, there was a significant reduction in the levels of GFAP, S100β, and CD81, along with a significant decrease in the levels of IFN-γ and IL-4. Furthermore, higher levels of GFAP, S100β, CD81 and inflammatory cytokines were associated with more severe depressive symptoms and poorer cognitive function. This study provides direct insight supporting the astrocyte activation and neuroinflammatory hypothesis of depression using ADEVs. ECT may exert anti-inflammatory effect through inhibition of such activation of astrocytes. This article is protected by copyright. All rights reserved.

The prevalence and economic burden of treatment-resistant depression in Thailand

BackgroundThe objectives of this study were to investigate the proportion of treatment-resistant depression (TRD) among patients with diagnosed major depressive disorder (MDD) and undergoing antidepressant treatment, to estimate the economic cost of MDD, TRD, and non-treatment-resistant depression (non-TRD), and to examine the differences between TRD and non-TRD MDD in a Thai public tertiary hospital.MethodsThis was a combined study between retrospective review of medical records and a cross-sectional survey. The sample size was 500 dyads of antidepressant-treated MDD patients and their unpaid caregivers. MDD patients’ medical records, the concept of healthcare resource utilization, the Work Productivity and Activity Impairment Questionnaire: depression and mood & mental state versions (WPAI: D, MM), the Class Impairment Questionnaire (CIQ), and the Family Experiences Interview Schedule (FEIS) were applied as the tools of the study. Pearson Chi’s square, Fisher’s Exact test, and independent T-test were employed for statistical analysis.ResultsThe proportion of TRD was 19.6% among antidepressant-treated MDD patients in a Thai tertiary public hospital. The results of the study indicated that several factors showed a statistically significant association with TRD criteria. These factors included younger age of MDD patients, a younger age of onset of MDD, lower body mass index (BMI), a history of suicide attempts and self-harm, as well as frequent smoking behavior. The annualized economic cost of TRD was 276,059.97 baht per person ($7,668.33), which was significantly higher than that of cost of non-TRD (173,487.04 baht or $4,819.08). The aggregated economic costs of MDD were 96.8 million baht annually ($2.69 M) if calculated from 500 MDD patients and unpaid caregivers. This contributed to the economic cost of TRD 27.05 million baht (98 respondents) and the economic cost of non-TRD 69.74 million baht (402 respondents).ConclusionsThe economic burden associated with TRD was significantly higher compared to non-TRD among antidepressant-treated MDD patients. Specifically, both direct medical costs and indirect costs were notably elevated in the TRD group.

Abnormal Prefrontal Brain Activation During a Verbal Fluency Task in Treatment-Resistant Depression Using Near-Infrared Spectroscopy.

The study investigated cognitive performance and brain function between treatment-resistant depression (TRD) and non- TRD patients to find potential neurobiological markers associated with refractoriness in depression patients. Fourteen TRD patients, 26 non-TRD patients and 23 healthy controls (HC) were included in the present study. The neural function of prefrontal cortex (PFC) and cognitive performance among the three group were examined using near-infrared spectroscopy (NIRS) during verbal fluency task (VFT). Both TRD and non-TRD groups exhibited significantly worse VFT performance and lower activation of oxygenated hemoglobin (oxy-Hb) changes in the bilateral dorsolateral PFC (DLPFC) compared to the HC group. Within the TRD and non-TRD groups, VFT performance was no significant difference, but activation of oxy-Hb changes in dorsomedial PFC (DMPFC) in TRD patients was significantly lower than non-TRD patients. In addition, activation of oxy-Hb changes in right DLPFC were negatively correlated with the severity of depressive symptoms in depression patients. Both TRD patients and non-TRD patients exhibited lower oxy-Hb activation in DLPFC. TRD patients exhibit lower oxy- Hb activation in DMPFC than non-TRD patients. fNIRS maybe a useful tool for predict depressive patients with or without treatment resistant.

Response to electroconvulsive therapy in treatment-resistant depression: nationwide observational follow-up study.

Previous studies have not investigated response rates after electroconvulsive therapy (ECT) in patients with non-psychotic treatment-resistant depression (TRD). To assess and compare the response rate of ECT for patients with TRD and non-TRD, in a large and clinically representative patient sample. Patients aged ≥18 years, who were treated for a unipolar, non-psychotic depressive episode with at least one ECT session as part of a first-time, index ECT series between 1 January 2011 and 31 December 2017 were included from the Swedish National Quality Register for ECT. Patients who had initiated a third consecutive trial of antidepressants or add-on medications before start of ECT were classified as having TRD. Patients not meeting criteria for TRD were classified as non-TRD. The main outcome was response to ECT according to the Clinical Global Impressions - Improvement Scale (CGI-I), scored as 1 or 2 ('very much' or 'much improved' after ECT, respectively). Logistic regression was used to compare outcome measures between TRD and non-TRD, adjusting for potential confounders. A total of 4244 patients were included. Of these, 1121 patients had TRD and 3123 patients had non-TRD. The CGI-I response rate was 65.9% in the TRD group compared with 75.9% in the non-TRD group (adjusted odds ratio 0.64, 95% CI 0.54-0.75). Older age and more severe depression were predictors of response in patients with TRD. A clear majority of patients with TRD, as well as patients with non-TRD, responded to ECT, although the response rate was somewhat lower for TRD.

Sex Differences of the Functional Brain Activity in Treatment-Resistant Depression: A Resting-State Functional Magnetic Resonance Study.

The presence of different clinical symptoms in patients with treatment-resistant depression (TRD) of different sexes may be related to different neuropathological mechanisms. A total of 16 male patients with TRD, 18 female patients with TRD, 18 male healthy controls (HCs) and 19 female HCs completed this study. We used the amplitude of low frequency fluctuations (ALFF) method to analyze the results. Moreover, the correlation between abnormal brain areas and clinical symptoms in different sexes of the TRD groups was also analyzed. The effects of the sex-by-group interaction difference in ALFF among the four groups was located in the left middle frontal gyrus, left precentral gyrus and left precuneus. Post hoc comparisons revealed that the male TRD group had lower ALFF in the left middle frontal gyrus and left precentral gyrus compared with the female TRD group. There was a positive correlation between the left middle frontal gyrus, the left precuneus and the 17-item Hamilton Rating Scale for Depression scale (HAMD-17) scores, and a negative correlation between the left precentral gyrus and the HAMD-17 scores in the female TRD group. This study will provide some clinical reference value for the sex differences in neuropathological mechanisms of TRD.

Different characteristics of striatal resting-state functional conectivity in treatment-resistant and non-treatment-resistant depression

Major depressive disorder is associated with a reward deficit manifested by abnormal striatal function. However, differences between treatment-resistant depression (TRD) and non TRD (nTRD) in striatal whole-brain functional connectivity (FC) have not been elucidated. Thirty-eight patients with TRD, 42 patients with nTRD, and 39 healthy controls (HCs) were recruited for this study. A seed-based FC approach was used to analyze abnormalities in six predefined striatal subregion circuits in the three groups of subjects, and further explore the correlation between abnormal FC and clinical symptoms. Results revealed that compared with the nTRD group, the TRD group showed increased FC of the inferior ventral striatum with the bilateral orbital area of the middle frontal gyrus, right cerebellum posterior lobe, left parahippocampal gyrus, left middle occipital gyrus and left lingual gyrus. Compared with the HC group, the TRD group showed a wider range of altered striatal function than the nTRD group. In the TRD group, the HAMD-17 scores were positively correlated with the FC between the right VRP and the left caudate. This study provides new insights into understanding the specificity of TRD striatal circuits.

Distinct patterns of functional brain network integration between treatment-resistant depression and non treatment-resistant depression: A resting-state functional magnetic resonance imaging study

BackgroundPrevious neuroimaging has paid little attention to the differences in brain network integration between patients with treatment-resistant depression(TRD) and non-TRD (nTRD), and the relationship between their impaired brain network integration and clinical symptoms has not been elucidated. MethodEighty one major depressive disorder (MDD) patients (40 in TRD, 41 in nTRD) and 40 healthy controls (HCs) were enrolled for the functional magnetic resonance imaging (fMRI) scans. A seed-based functional connectivity (FC) method was used to investigate the brain network abnormalities of default mode network (DMN), affective network (AN), salience network (SN) and cognitive control network (CCN) for the MDD. Finally, the correlation was analyzed between the abnormal FCs and 17-item Hamilton Rating Scale for Depression scale (HAMD-17) scores. ResultsCompared with the HC group, the FCs in DMN, AN, SN, CCN were altered in both the TRD and nTRD groups. Compared with the nTRD group, FC alterations in the AN and CCN were more abnormal in the TRD group, and the FC alterations were generally decreased at the SN in the TRD group. In addition, the FC values of right dorsolateral prefrontal cortices and left caudate nucleus in the TRD group and the FC values of right subgenual anterior cingulate cortex and left middle temporal gyrus in the nTRD group were positively correlated with HAMD-17 scale scores. ConclusionsAbnormal FCs are present in four brain networks (DMN, AN, SN, CCN) in both the TRD and nTRD groups. Except of DMN, FCs in AN, SN and CCN maybe underlay the neurobiological mechanism in differentiating TRD from nTRD.

Altered Brain Function in Treatment-Resistant and Non-treatment-resistant Depression Patients: A Resting-State Functional Magnetic Resonance Imaging Study.

ObjectiveIn this study, we used amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) to observe differences in local brain functional activity and its characteristics in patients with treatment-resistant depression (TRD) and non-treatment-resistant depression (nTRD), and to explore the correlation between areas of abnormal brain functional activity and clinical symptoms.MethodThirty-seven patients with TRD, 36 patients with nTRD, and 35 healthy controls (HCs) were included in resting-state fMRI scans. ALFF and ReHo were used for image analysis and further correlation between abnormal brain regions and clinical symptoms were analyzed.ResultsANOVA revealed that the significantly different brain regions of ALFF and ReHo among the three groups were mainly concentrated in the frontal and temporal lobes. Compared with the nTRD group, the TRD group had decreased ALFF in the left/right inferior frontal triangular gyrus, left middle temporal gyrus, left cuneus and bilateral posterior lobes of the cerebellum, and increased ALFF in the left middle frontal gyrus and right superior temporal gyrus, and the TRD group had decreased ReHo in the left/right inferior frontal triangular gyrus, left middle temporal gyrus, and increased ReHo in the right superior frontal gyrus. Compared with the HC group, the TRD group had decreased ALFF/ReHo in both the right inferior frontal triangular gyrus and the left middle temporal gyrus. Pearson correlation analysis showed that both ALFF and ReHo values in these abnormal brain regions were positively correlated with HAMD-17 scores (P < 0.05).ConclusionAlthough the clinical symptoms were similar in the TRD and nTRD groups, abnormal neurological functional activity were present in some of the same brain regions. Compared with the nTRD group, ALFF and ReHo showed a wider range of brain area alterations and more complex neuropathological mechanisms in the TRD group, especially in the inferior frontal triangular gyrus of the frontal lobe and the middle temporal gyrus of the temporal lobe.

Immediate Modulation of Transcutaneous Auricular Vagus Nerve Stimulation in Patients With Treatment-Resistant Depression: A Resting-State Functional Magnetic Resonance Imaging Study.

BackgroundPrevious studies found that transcutaneous auricular vagus nerve stimulation (taVNS) was clinically effective in treating a case of treatment-resistant depression (TRD). However, the brain neural mechanisms underlying the immediate effects of taVNS treatment for TRD have not been elucidated.Materials and MethodsDifferences in the amplitude of low-frequency fluctuations (ALFF) between TRD and healthy control (HC) groups were observed. The TRD group was treated with taVNS for 30 min, and changes in ALFF in the TRD group before and after immediate treatment were observed. The ALFF brain regions altered by taVNS induction were used as regions of interest to analyze whole-brain functional connectivity (FC) changes in the TRD group.ResultsA total of 44 TRD patients and 44 HCs completed the study and were included in the data analysis. Compared with the HC group, the TRD group had increased ALFF in the left orbital area of the middle frontal gyrus. After taVNS treatment, ALFF in the left orbital area of the middle frontal gyrus and right middle frontal gyrus decreased in the TRD group, while ALFF in the right orbital area of the superior frontal gyrus increased. The FC in the left orbital area of the middle frontal gyrus with left middle frontal gyrus and the right inferior occipital gyrus was significantly increased.ConclusionTranscutaneous auricular vagus nerve stimulation demonstrates immediate modulation of functional activity in the emotional network, cognitive control network, and visual processing cortex, and may be a potential brain imaging biomarker for the treatment of TRD.

Serum Cortisol, Nesfatin-1, and IL-1β: Potential Diagnostic Biomarkers in Elderly Patients with Treatment-Resistant Depression.

AimTreatment-resistant depression (TRD) affects approximately 30% of patients with major depressive disorder (MDD), especially elderly patients. As individuals with TRD are at an increased risk of committing suicide and pose a higher risk of relapse, early diagnostic biomarkers of TRD and a better understanding of the resistance mechanism are highly needed. This study aimed to determine whether serum cortisol, nesfatin-1, and pro-inflammatory cytokines can be used as biomarkers for the diagnosis of elderly patients with TRD.MethodsThirty elderly patients with TRD were selected as the TRD group. Thirty elderly patients with MDD who were effectively treated with conventional antidepressants were selected as the non-TRD group. The baseline levels of serum cortisol, nesfatin-1, and pro-inflammatory cytokines were measured and compared, and their diagnostic values were evaluated using the receiver operating characteristic (ROC) curve method for discriminating patients with TRD from those without TRD.ResultsSerum cortisol, C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were significantly higher in the non-TRD and TRD groups than in the control group. Moreover, serum cortisol, CRP, TNF-α, and IL-6 levels in the TRD group were significantly lower than those in the non-TRD group. Furthermore, serum nesfatin-1 levels in the non-TRD group were significantly lower than those in the control and TRD groups, while the serum IL-1β levels in the non-TRD group were significantly higher than those in the control and TRD groups. Additionally, an ROC analysis revealed an area under the curve (AUC) of 0.929 for the combination of nesfatin-1 and IL-1β and an AUC of 0.956 for the combination of cortisol, nesfatin-1, and IL-1β in discriminating elderly patients with TRD from those without non-TRD.ConclusionSerum cortisol, nesfatin-1, and IL-1β may be potential diagnostic biomarkers for discriminating elderly patients with TRD from those without TRD.

Clinical and Biological Factors Are Associated with Treatment-Resistant Depression.

Background: Treatment-resistant depression (TRD) is a debilitating condition associated with unmet clinical needs. Few studies have explored clinical characteristics and serum biomarkers associated with TRD. Aims: We investigated whether there were differences in clinical and biochemical variables between patients affected by TRD than those without. Methods: We recruited 343 patients (165 males and 178 females) consecutively hospitalized for MDD to the inpatient clinics affiliated to the Fondazione IRCCS Policlinico, Milan, Italy (n = 234), and ASST Monza, Italy (n = 109). Data were obtained through a screening of the clinical charts and blood analyses conducted during the hospitalization. Results: TRD versus non-TRD patients resulted to be older (p = 0.001), to have a longer duration of illness (p < 0.001), to be more currently treated with a psychiatric poly-therapy (p < 0.001), to have currently more severe depressive symptoms as showed by the Hamilton Depression Rating Scale (HAM-D) scores (p = 0.016), to have lower bilirubin plasma levels (p < 0.001). In addition, more lifetime suicide attempts (p = 0.035), more antidepressant treatments before the current episode (p < 0.001), and a lower neutrophil to lymphocyte ratio at borderline statistically significant level (p = 0.060) were all associated with the TRD group. Conclusion: We identified candidate biomarkers associated with TRD such as bilirubin plasma levels and NLR, to be confirmed by further studies. Moreover, TRD seems to be associated with unfavorable clinical factors such as a predisposition to suicidal behaviors. Future research should replicate these results to provide robust data in support of the identification of new targets of treatment and implementation of prevention strategies for TRD.

Understanding the Relationship Between Depression Symptom Severity and Health Care Costs for Patients With Treatment-Resistant Depression.

Objective: To examine whether measures of depression symptom severity could improve understanding of health care costs for patients with major depressive disorder (MDD) or treatment-resistant depression (TRD) from the health plan perspective.Methods: In this retrospective cohort study within an integrated health system, cohorts consisted of 2 mutually exclusive groups: (1) adults with TRD based on a standard treatment algorithm and (2) adults with MDD, but no TRD, identified through ICD-9/10-CM codes. Depression severity was measured using the Patient Health Questionnaire-9 (PHQ-9). Patterns of health care resource utilization (HRU) and costs were compared between the TRD and MDD groups overall and within the groups at different symptom levels. A general linear model with a γ distribution and log link for cost outcomes, logistic regression for binary outcomes, and negative binomial regression for count outcomes were used.Results: Patients with TRD (n = 24,534) had greater comorbidity than those in the MDD group (n = 17,628). Mean age in the TRD group was 52.8 years versus 48.2 for MDD (P < .001). Both groups were predominantly female (TRD: 72.8% vs MDD: 66.9%; P < .001). Overall, the TRD group had greater costs than the MDD group, with 1.23 times (95% CI, 1.21-1.26; P < .001) greater total cost on average over 1 year following index date. Within both groups, those with severe symptoms had greater total mean (SD) costs (TRD: moderate: $12,429 [$23,900] vs severe: $13,344 [$22,895], P < .001; low: $12,220 [$31,864] vs severe: $13,344 [$22,895], P < .001; MDD: moderate: $8,899 [$20,755] vs severe: $10,098 [$22,853]; P < .001; low: $8,752 [$25,800] vs severe: $10,098 [$22,853], P < .001).Conclusions: MDD and TRD impose high costs for health systems, with increasing costs as PHQ-9 symptom severity rises. Better understanding of subgroups with different symptom levels could improve clinical care by helping target interventions.

Abnormal habenula functional connectivity characterizes treatment-resistant depression

BackgroundA significant proportion of patients with major depressive disorder are resistant to antidepressant medication and psychological treatments. A core symptom of treatment-resistant depression (TRD) is anhedonia, or the inability to feel pleasure, which has been attributed to disrupted habenula function – a component of the reward network. This study aimed to map detailed neural circuitry architecture related to the habenula to identify neural mechanisms of TRD. Methods35 TRD patients, 35 patients with treatment-sensitive depression (TSD), and 38 healthy controls (HC) underwent resting-state functional magnetic resonance imaging. Functional connectivity analyses were performed using the left and right habenula as seed regions of interest, and the three groups were compared using whole-brain voxel-wise comparisons. ResultsThe TRD group demonstrated hyperconnectivity of the left habenula to the left precuneus cortex and the right precentral gyrus, compared to the TSD group, and to the right precuneus cortex, compared to the TSD and HC groups. In contrast, TSD demonstrated hypoconnectivity than HC for both connectivity measures. These connectivity values were significantly higher in patients with a history of suicidal ideation. ConclusionsThis study provides evidence that, unlike TSD, TRD is characterized by hyperconnectivity of the left habenula particularly with regions of the default mode network. An increased interplay between reward and default mode networks is linked to suicidality and could be a possible mechanism for anhedonia in hard to treat depression.

Polymorphisms of COMT and CREB1 are associated with treatment-resistant depression in a Chinese Han population.

Genetic factors play a crucial role for the pathophysiology of treatment-resistant depression (TRD). It has been established that Catechol-O-methyltransferase (COMT) and cyclic amp-response element-binding protein (CREB) are associated with antidepressant response. The aim of this study was to explore the association between single nucleotide polymorphisms (SNPs) in COMT and CREB1 genes and TRD in a Chinese population. We recruited 181 patients with major depressive disorder (MDD) and 80 healthy controls, including 81 TRD patients. Depressive symptoms were assessed with the Hamilton Depression Rating Scale-17 (HDRS). Genotyping was performed using mass spectrometry. Genetic analyses were conducted by PLINK Software. The distribution of COMT SNP rs4818 allele and genotypes were significantly different between TRD and controls. Statistical differences in allele frequencies were observed between TRD and non-TRD groups, including rs11904814 and rs6740584 in CREB1 gene, rs4680 and rs4818 in COMT gene. There were differences in the distribution of HDRS total scores among different phenotypes of CREB1 rs11904814, CREB1 rs6740584, COMT rs4680 and rs4818. Gene-gene interaction effect of COMT-CREB1 (rs4680 × rs6740584) revealed significant epistasis in TRD. There findings indicate that COMT and CREB1 polymorphisms influence the risk of TRD and affect the severity of depressive symptoms of MDD.

Higher rates of allergies, autoimmune diseases and low-grade inflammation markers in treatment-resistant major depression

Only 30% of patients with major depressive disorder (MDD) reach full recovery or remission. Treatment-resistant depression (TRD) is MDD that does not respond to adequate treatment attempts with at least two antidepressants. TRD is associated more with immune activation than with treatment responsive depression. The current retrospective population-based cross-sectional study, utilizing data from a large nation-wide health maintenance organization in Israel which provides services to estimated 725,000 members, aimed to assess the clinical signs and laboratory markers of autoimmune comorbidity and low-grade inflammation, in patients with TRD. Included were participants aged 18–70 years, diagnosed twice within one year with ICD-9-CM MDD and two control groups, MDD responders (MDD-r) consisting of people with MDD and no TRD and a non-MDD group that included people with no MDD or TRD. The case (570 subjects in TRD group) to control ratio in both control groups (2850 subjects in MDD-r and 2850 subjects in non-MDD control group) was 1:5. Compared to MDD-r, the overall proportion of allergic diseases was higher among the TRD than among the MDD-r [OR 1.52 (1.19–1.94); p ​< ​0.001]. Any systemic autoimmune disease was associated with increased likelihood of MDD-r [OR 1.52 (1.04–2.24); p ​= ​0.03] or TRD [OR 2.22 (1.30–3.78); p ​= ​0.003]. Higher rates of positive (>1:80) antinuclear antibodies [33 (5.79%)] were found among the TRD than among the MDD-r [98 (3.44%); p ​= ​0.011). More allergy and autoimmune comorbidities and presence of low-grade inflammation biomarkers, were found mainly in TRD.

Blood transcriptional response to treatment-resistant depression during electroconvulsive therapy

Selective serotonin reuptake inhibitors (SSRIs) are currently the first-line antidepressant drug treatment for major depressive disorder (MDD). Treatment-resistant depression (TRD), defined as failure to achieve remission despite adequate treatment, affects ~30% of persons with MDD. The current recommended treatment for TRD is electroconvulsive therapy (ECT), while ketamine is an experimentally suggested treatment. This study aimed to elucidate the transcriptional differences in peripheral blood mononuclear cells (PBMC) between individuals with TRD and a control group without a psychiatric illness; and between patients with TRD, treated with either standard antidepressant drugs alone, or in combination with ECT or ketamine. Additionally, PBMC transcriptomics were compared between treatment responders, following completion of their treatment protocols. Total RNA was extracted from PBMC of the TRD group at two time points, and RNA and miRNA expression were profiled. Multiple mRNAs and miRNAs were found to be modified, with two protein coding genes, FKBP5 and ITGA2B, which are up- and downregulated, respectively; and several miRNAs have shown changes following successful ECT treatment. Further analysis demonstrated the direct functional regulation of ITGA2B by miR-24–3p. Our findings suggest that PBMC expression levels of FKBP5, ITGA2B, and miR-24–3p should be further explored as tentative ECT response biomarkers.