Deep Learning-Based Artificial Intelligence Can Differentiate Treatment-Resistant and Responsive Depression Cases with High Accuracy.

Elevated tumor necrosis factor-alpha receptor subtype 1 and the association with abnormal brain function in treatment-resistant depression

Background Treatment-resistant depression (TRD) is associated with gray matter volume reduction compared to healthy controls (HC). Since depression has increasingly been recognized as a disorder of dysregulated neural networks, it is important to evaluate these structural changes in terms of brain networks. Structural covariance is a measurement that gauges the association strength of structural measures between two regions, which is used to examine network-level alteration of brain structure. Although several studies reported abnormal structural covariance in depression, few studies have thus far investigated structural covariance alteration in relation to TRD. Aims and Objectives In this study, we aimed to examine structural covariance alteration in TRD compared to HC. Methods T1 images were obtained from 116 patients with TRD and 54 HC who were recruited at Keio University. Brain volume was calculated for each of 85 regions of the DK atlas using FreeSurfer 6.0. Group differences in brain volumes were examined by analysis of covariance controlling for age and sex. Structural covariances of brain volumes across 3570 pairs of brain regions were obtained by partial correlation analysis using age, sex, and total intracranial volume as covariates. Network-based statistics were used to extract networks with group differences in structural covariances. This study was conducted after obtaining approval from the respective ethics review committees. Results There were no significant differences in brain volumes between the TRD and HC groups. The null hypothesis of equality in structural covariance between them was rejected using network-based statistics. We found a single network comprising connections with elevated structural covariance in patients with TRD compared with HC. The left nucleus accumbens, bilateral pericalcarine, and supramarginal gyrus had high degree centrality in the structural covariance network. Discussion and Conclusion Patients with TRD showed coordinated brain volume alterations in comparison with HC, even though there was no difference in brain volumes between them. Nucleus accumbens, an integral hub in the reward circuit, was one of the hubs of extracted network with elevated structural covariance in TRD, which is in line with a previous study that reported higher structural covariance of nucleus accumbens in depression. Further studies are warranted to examine structural covariance differences among TRD, non-TRD, and HC in order to confirm the link between structural alteration and pathophysiology of treatment resistance in depression.

Objective. In this study, we determined the prevalence of bipolarity in patients with treatment-resistant depression (TRD) by investigating demographic and clinical characteristics, diagnostic subtypes and illness outcome of patients with resistant depression. Methods. A medical record review of patients who were admitted to a university hospital with the diagnosis of major depressive disorder (MDD) was conducted. DSM-IV diagnoses at the index hospitalization and 6 months after discharge and detailed clinical information were obtained. We categorized subjects into a TRD group or a non-TRD group and re-evaluated the patients using the criteria for bipolar spectrum disorders. Results. There were 281 patients diagnosed with MDD. At discharge, the number of patients who fulfilled the criteria for BSD was higher in the TRD group (47.1%) than in the non-TRD group (3.8%) (P<0.001). At the end of the 6-month follow-up period, the diagnoses of 38 patients were changed; 18 (26.5%) of the TRD group were subsequently classified as having a bipolar disorder, as were seven (3.3%) in the non-TRD group (P<0.001). There was no difference between these two groups for other clinical and demographic variables. Conclusion. The findings of this study suggest that many patients with TRD have a bipolar diathesis.

This study compared health care use and costs among patients with treatment-resistant versus treatment-responsive depression across Medicaid, Medicare, and commercial payers. A retrospective cohort study was conducted by using Truven Health Analytics' commercial (2006-2017; N=111,544), Medicaid (2007-2017; N=24,036), and Medicare supplemental (2006-2017; N=8,889) claims databases. Participants were adults with major depressive disorder who had received one or more antidepressant treatments. Treatment resistance was defined as failure of two or more antidepressant treatments of adequate dose and duration. Annual use (hospitalizations and outpatient and emergency department [ED] visits) and costs were compared across patients by treatment-resistant status in each payer population. Incremental burden of treatment-resistant depression was estimated with regression analyses. Monthly changes in costs during 1-year follow-up were assessed to understand differential cost trends by treatment-resistant status. In the three payer populations, patients with treatment-resistant depression incurred higher health care utilization than those with treatment-responsive depression (hospitalization, odds ratios [ORs]=1.32-1.76; ED visits, ORs=1.38-1.45; outpatient visits, incident rate ratio=1.29-1.54; p<0.001 for all). Compared with those with treatment-responsive depression, those with treatment resistance incurred higher annual costs (from $4,093 to $8,054 higher; p<0.001). Patients with treatment-resistant depression had higher costs at baseline compared with patients with treatment-responsive depression and incurred higher costs each month throughout follow-up. Treatment-resistant depression imposes a significant health care burden on insurers. Treatment-resistant depression may exist and affect health care burden before a patient is identified as having treatment-resistant depression. Findings underscore the need for effective and timely treatment of treatment-resistant depression.

Aim: In this study, incidental findings of brain magnetic resonance imaging (MRI) of patients diagnosed with treatment-resistant depression (TRD) were compared with healthy controls (HC). Materials and Methods: The study included 68 patients with TRD (42 females, 26 males) and 72 HC (35 females, 37 males). Global assessment scale (GAS) was administered. Results: In the TRD group, those with general cerebral atrophy were found to have significantly lower global assessment scale (GAS) scores (p&amp;lt;0.001). In the TRD group, those with cavum veli interpositi (CVI) were found to have significantly lower GAS scores (p=0.001). In the TRD group, when the effect of age was controlled, a significant correlation was found between the GAS score and the duration of the disorder (r=-0.400; p=0.001). Conclusion: CVI, a neurodevelopmental abnormality, has been shown to be more common in patients diagnosed with TRD.

BackgroundDespite the availability of effective therapies, many patients with major depressive disorder (MDD) develop treatment-resistant depression (TRD).AimsTo evaluate and compare prescribing patterns, contact with specialist services and treatment outcomes in patients with MDD and TRD.MethodThis 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.ResultsA 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).ConclusionsThere 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.

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.

This literature review assessed the burden of treatment-resistant depression in the United States by compiling published data about the clinical, societal, and economic outcomes associated with failure to respond to one or more adequate trials of drug therapy. PubMed and the Tufts Cost-Effectiveness Analyses Registry were searched for English-language articles published between January 1996 and August 2013 that collected primary data about treatment-resistant depression. Two researchers independently assessed study quality and extracted data. Sixty-two articles were included (N=59,462 patients). Patients with treatment-resistant depression had 3.8±2.1 prior depressive episodes and illness duration of 4.4±3.3 years and had completed 4.7±2.7 unsuccessful drug trials involving 2.1±.3 drug classes. Response rates for treatment-resistant depression were 36%±1%. A total of 17%±6% of patients had prior suicide attempts (1.1±.2 attempts per patient). Quality-of-life scores (scale of 0-1, with 0 indicating death and 1 indicating perfect health) for patients with treatment-resistant depression were .41±.8 and .26±.8 points lower, respectively, than for patients who experienced remission or response. Annual costs for health care and lost productivity were $5,481 and $4,048 higher, respectively, for patients with treatment-resistant versus treatment-responsive depression. Treatment-resistant depression exacts a substantial toll on patients' quality of life. At current rates of 12%-20% among all depressed patients, treatment-resistant depression may present an annual added societal cost of $29-$48 billion, pushing up the total societal costs of major depression by as much as $106-$118 billion. These findings underscore the need for research on the mechanisms of depression, new therapeutic targets, existing and new treatment combinations, and tests to improve the efficacy of and adherence to treatments for treatment-resistant depression.

Back to table of contents Previous article Next article Letters to the EditorFull AccessThe Effects of Treatment-Resistant Depression and First-Ever Depression on Mortality Following Acute Coronary Syndrome: Interactive or Independent?MARIJ ZUIDERSMA M.Sc.,PETER de JONGE Ph.D.,MARIJ ZUIDERSMA M.Sc.Search for more papers by this author,PETER de JONGE Ph.D.Search for more papers by this author,Published Online:1 Jul 2009https://doi.org/10.1176/appi.ajp.2009.09040482AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Drs. Carney and Freedland (1) presented a fascinating review on treatment-resistant depression and mortality following acute coronary syndrome. As a possible mechanism explaining the association between treatment-resistant depression and mortality in acute coronary syndrome patients, the authors suggested the presence of first-ever depressive episodes, which are associated with both treatment resistance and increased risk of cardiac events. We therefore explored the association between treatment-resistant depression, first-ever depression, and cardiovascular prognosis using data from the Myocardial INfarction and Depression Intervention Trial (MIND-IT), a multi-center randomized controlled trial on the treatment of post-acute coronary syndrome depression. We previously reported (2) , using Cox regression analysis, that patients who did not respond to treatment had an unadjusted hazard ratio of 4.89 (95% confidence interval [CI]=1.08–22.10) for new cardiovascular events relative to patients who responded to treatment. Testing the hypothesis of Drs. Carney and Freedland, we adjusted for the presence of first episodes. However, adjusting hardly affected the association (hazard ratio=4.42; 95% CI=0.97–20.10), which is indicative of no support for the hypothesis. An explanation may be that in our sample first episodes were not associated with new cardiovascular events or treatment resistance. However, they are associated with both new cardiovascular events (hazard ratio=4.12 [95% CI=0.53–31.77]) and with treatment resistance (odds ratio=2.57 [95% CI=0.82–8.03]). The number of patients in each subgroup and their associated risk of cardiac events are shown in Table 1 . Enlarge tableOur tentative conclusion is that first depressive episodes and treatment resistance are two independent risk factors for worse outcomes that do not interact but add up independently. Our results do not support the hypothesis that first depressive episodes would underlie the association between treatment-resistant depression and negative cardiac outcomes. Since cell numbers in our study were very low, however, we feel that caution is warranted and no firm conclusions can yet be determined.We agree with Drs. Carney and Freedland that treatment-resistant depression is likely a marker of an underlying cardiac risk factor associated with treatment resistance in patients with coronary heart disease and that researchers should investigate this factor. One possible risk factor that is often overlooked is treatment nonadherence, which is associated with both depression and cardiac prognosis. Treatment nonadherence is one of the reasons for treatment resistance in depressed patients, and it is likely that a patient who is nonadherent to antidepressant treatment is also nonadherent to cardiac aftercare.Groningen, the NetherlandsGroningen and Tilburg, the NetherlandsPresented in part at the annual meeting of the European Association for Consultation-Liaison Psychiatry and Psychosomatics (EACLPP), Zaragoza, Spain, June 27, 2008. Drs. Zuidersma and de Jonge receive VIDI grant support from the Dutch Medical Research Council (grant # 016.086.397).This letter (doi: 10.1176/appi.ajp.2009.09040482) was accepted for publication in May 2009.

Magnetization transfer imaging reveals the brain deficit in patients with treatment-refractory depression

Major depressive disorder (MDD) and chronic non-cancer pain conditions (CNPC) often co-occur and exacerbate one another. Treatment-resistant depression (TRD) in adults with CNPC can amplify the economic burden. This study examined the impact of TRD on direct total and MDD-related healthcare resource utilization (HRU) and costs among commercially insured patients with CNPC and MDD in the US. The retrospective longitudinal cohort study employed a claims-based algorithm to identify adults with TRD from a US claims database (January 2007 to June 2017). Costs (2018 US$) and HRU were compared between patients with and without TRD over a 12-month period after TRD/non-TRD index date. Counterfactual recycled predictions from generalized linear models were used to examine associations between TRD and annual HRU and costs. Post-regression linear decomposition identified differences in patient-level factors between TRD and non-TRD groups that contributed to the excess economic burden of TRD. Of the 21,180 adults with CNPC and MDD, 10.1% were identified as having TRD. TRD patients had significantly higher HRU, translating into higher average total costs (US$21,015TRD vs US$14,712No TRD) and MDD-related costs (US$1201TRD vs US$471No TRD) compared with non-TRD patients (all p< 0.001). Prescription drug costs accounted for 37.6% and inpatient services for 30.7% of the excess total healthcare costs among TRD patients. TRD patients had a significantly higher number of inpatient (incidence rate ratio [IRR] 1.30, 95% CI 1.14-1.47) and emergency room visits (IRR 1.21, 95% CI 1.10-1.34) than non-TRD patients. Overall, 46% of the excess total costs were explained by differences in patient-level characteristics such as polypharmacy, number of CNPC, anxiety, sleep, and substance use disorders between the TRD and non-TRD groups. TRD poses a substantial direct economic burden for adults with CNPC and MDD. Excess healthcare costs may potentially be reduced by providing timely interventions for several modifiable risk factors.

Treatment-resistant depression (TRD) poses a serious challenge to psychopharmacology, as many patients do not achieve remission despite available therapies. The persistence and recurrence of the disease in the absence of response to antidepressant treatment highlight the complex and multifactorial nature of the disease, including the dysregulation of biological processes such as oxidative stress (OS). Although the role of OS in the pathogenesis of depressive disorders has been well documented, a growing body of evidence also points to its potential significance as a biomarker of persistence and symptom severity in TRD. Furthermore, growing evidence suggests that the severity of OS may be a measure of treatment resistance in depressive disorders, shedding light on OS as a potential biomarker of symptom persistence and a therapeutic target in TRD. This article presents the current state of knowledge on the importance of OS as a modifiable risk factor for the severity, chronicity, and persistence of TRD symptoms. Integrating the latest scientific evidence, this review describes the mechanisms linking OS to the development of TRD and discusses fast-acting antidepressants extended by a non-pharmacological nutraceutical approach, which appears to fill a therapeutic gap and increase the chances of recovery for chronically ill individuals. An integrated approach aimed at reducing OS may be a key point of leverage in overcoming treatment resistance in the most severe forms of TRD, thereby contributing to modifying the course of the disease and improving prognosis, which makes this approach the most clinically useful.

Treatment resistant depression can be very disabling and has a significant negative impact on a patient, their family or caregivers, and the society. There is a growing evidence on the efficacy and safety of ketamine for treatment resistant depression. Ketamine is a racemate consisting of esketamine and arketamine, is an N-methyl D-aspartate receptor antagonist and comes in different formulations and in fact intranasal ketamine is FDA-approved in the US. Despite the existing evidence and FDA approval for treatment resistant depression, data on older individuals remains limited. Late life depression especially those that are treatment resistant can be very disabling, with significant functional and cognitive impairments, increased morbidity and mortality, and the psychosocial burdens.This presentation describes outcomes for 2 cases of older individuals with treatment resistant depression who were treated with intranasal ketamine. One improved, and one did not. The scarce available literature of the use of ketamine in the geriatric population shows ketamine is well tolerated and effective. Remission rates in 3 separate show remission rates of 46.5%, 57% and 69.5% respectively. The discussion will include a review of the mechanism of action of ketamine as a novel antidepressant, the mixed evidence for its role in treatment resistant late life depression, and the practical and operational aspects relevant to running a ketamine clinic.

Cognitive Profiles in Treatment-Resistant Late-Life Depression and Their Impact on Treatment Outcomes

Strategically timed trauma- and attachment-informed psychotherapy to address underlying emotional wounds, paired with ketamine administered in precision-calibrated doses to ensure high-entropy brain states, may be key to improving the quality and duration of ketamine’s therapeutic efficacy for treatment-resistant depression. This approach optimizes the opportunities for change created by ketamine’s known effects as a rapid antidepressant that stimulates synaptogenesis, normalizes neural connectivity and coherence, enhances neuroplasticity, reduces inflammation, and induces high-entropy brain states with associated subjective psychedelic experiences. Ketamine, a non-selective N-methyl-D-aspartate (NMDA) receptor antagonist is a safe, effective, fast-acting dissociative anesthetic that, as a standalone treatment, also exhibits rapid sustained antidepressant effects, even in many patients with treatment-resistant depression. A prior history of developmental trauma and attachment injuries are known primary factors in the etiology of treatment resistance in depression and other mental disorders. Thus, the adjunct of targeted psychotherapy attuned to trauma and attachment injuries may enhance and prolong ketamine efficacy and provide an opportunity for lasting therapeutic change. Psychotherapy engagement during repeated ketamine sessions for patient safety and integration of altered states, paired with separate individualized psychotherapy-only sessions timed 24–48 h post ketamine induction, takes advantage of peak ketamine-induced dendritic spine growth in the prefrontal cortex and limbic system, and normalized network connectivity across brain structures. This strategically timed paired-session approach also exploits the therapeutic potential created by precision-calibrated ketamine-linked high-entropy brain states and associated psychedelic experiences that are posited to disrupt overly rigid maladaptive thoughts, behaviors, and disturbing memories associated with treatment-resistant depression; paired sessions also support integration of the felt sense of happiness and connectivity associated with psychedelic experiences.