PMH2 Treatment Outcomes for Patients with Treatment Resistant Depression in European Standard Clinical Practice

Long-Term Vagus Nerve Stimulation for Severe Refractory Depression: A Case Study With a Six-Year Follow-Up

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.

Oral ketamine for treatment resistant major depression – A double blind randomized controlled trial

Objectives: Depression is the second most prevalent mental illness among the elderly. Nonetheless, treatment- resistant depression (TRD) is prevalent among the elderly; one-third of elderly patients with major depressive disorder (MDD) who received antidepressant treatment failed to achieve remission. Although there have been several studies regarding the associations between MDD and increased mortality and suicidal risk, studies between TRD and mortality/suicidal risk in the elderly still remains limited. In this national cohort study, we examined the association between TRD, non-TRD MDD, and non-depression with all-cause mortality, accident mortality, and suicide mortality.Methods: For this retrospective longitudinal analysis on the entire population, the National Health Insurance Research Database of Taiwan, which comprises claims data from a lifetime insurance program and provided comprehensive medical inpatient and outpatient information categorized by ICD-9-CM and ICD-10. The National Mortality Registry offered information regarding mortality resulting from all causes, natural causes, suicide, and accidents. A cohort of ≥60-year-old patients, including both those with and without MDD, was observed between January 2003 and December 2017. Individuals were classified as TRD if they had undergone aminimum of two distinct antidepressant trials within the current episode’s two-year duration and dose, as documented in the prescribing records. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) were calculated for mortality risk utilizing Cox regression models.Results: Among those &gt;60 years old, after adjusting with sex and comorbidities, TRD was associated with increased risk of suicide (aHR 7.4, 95% CI [5.6-9.8]; MDD without TRD 4.4 [4.1- 4.6], compared with non-MDD group). Simliar risk of accident mortality was observed among three groups (TRD aHR 1.3 [0.9-1.9]; MDD without TRD 0.9 [0.9-1.0], compared with non-MDD group). Surprisely, TRD might presented lower mortality risk of natural mortality than the non- MDD group (TRD aHR 0.8 [0.7-0.8]; MDD without TRD 0.9 [0.8-0.9], compared with non- MDD group).Conclusions: The suicide mortality among elderly patients with TRD is higher in comparison to non-MDD patients; nevertheless, accident mortality does not appear to have increased and the natural mortality rate is reduced. The lower mortality may reflect patient selection, and the contributing factors need further evaluation.

Background: Although there are many treatment options available for depression, a large portion of patients with depression are diagnosed with treatment-resistant depression (TRD), which is characterized by an inadequate response to antidepressant treatment. Identifying the TRD population is crucial in terms of saving time and resources in depression treatment. Recently several studies employed various methods on EEG datasets for automatic depression detection or treatment outcome prediction. However, no previous study has used the deep learning (DL) approach and EEG signals for detecting treatment resistance. Method: 77 patients with TRD, 43 patients with non-TRD, and 40 healthy controls were compared using GoogleNet convolutional neural network and DL on EEG data. Additionally, Class Activation Maps (CAMs) acquired from the TRD and non-TRD groups were used to obtain distinctive regions for classification. Results: GoogleNet classified the healthy controls and non-TRD group with 88.43%, the healthy controls and TRD subjects with 89.73%, and the TRD and non-TRD group with 90.05% accuracy. The external validation accuracy for the TRD-non-TRD classification was 73.33%. Finally, the CAM analysis revealed that the TRD group contained dominant features in class detection of deep learning architecture in almost all electrodes. Limitations: Our study is limited by the moderate sample size of clinical groups and the retrospective nature of the study. Conclusion: These findings suggest that EEG-based deep learning can be used to classify treatment resistance in depression and may in the future prove to be a useful tool in psychiatry practice to identify patients who need more vigorous intervention.

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.

Objective To explore cognitive function impairment and clinical effect of patients with treatment-resistant depression. Methods 576 patients with depression who were treated in hospital from January 2010 to January 2012 were selected for prospective study, including 115 cases of treatment-resistant depression and 461 cases of non- treatment-resistant depression by assessment after therapy. Clinical characteristics and effect of patients with treatment-resistant depression were discussed with case-control study.Correlation was analyzed between cognitive function and clinical characteristics. Cognitive function impairment and clinical effect of patients with treatment-resistant depression were evaluated with the brain evoked potentials P300 and the appropriate and sensitive neuropsychological tests. Results Difference between total scores of HAMD in patients of two groups before treatment was statistically significant(t=5.383, P<0.05). There was a correlation between disease severity and RBANS test, Stroop color word test, WCST card test score. Amplitudes of N1, N2 and P3 were significantly increased in patient with treatment resistant depression after treatment, while latency and reaction time of P3 were significantly shortened and total score of HAMD decreased significantly. The differences were statistically significant (t=8.337, P<0.05). There were significant differences between RBANS test scores, Stroop color word test and WCST card test continuity errors in patient with treatment resistant depression before and after treatment (t=8.372, 4.852, 6.142, P<0.05). Conclusion The cognitive function may be impaired in patients with treatment-resistant depression. Improving cognitive function should be paid more attention during treating treatment-resistant depression, which can help patients return to society. Key words: Treatment-resistant depression; Cognitive function impairment; Event-related potentials

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

Based on the fact that antagonists at the glutamatergic N-methyl-D-aspartate (NMDA) receptor cause psychosis, a dysfunction of the glutamate system has been proposed to play a role in schizophrenia and major depression. In a detailed review, Hashimoto et al. [1] compared schizophrenia add-on treatments with glycine, D-serine, D-alanine, D-cycloserine, D-amino acid oxidase inhibitors and recently glycine transporter inhibitors as well as modulators of group II metabotropic glutamate receptors, which have shown to improve function of the NMDA receptor and exert effects on negative symptoms and cognition. In depression, an overactive glutamate system has been suggested due to magnetic resonance spectroscopy (MRS) studies reporting increased levels of glutamine/glutamate in the frontal and occipital cortex. Concordantly, NMDA receptor antagonists, partial antagonists at the glycine site of the receptor, metabotropic glutamate receptor (mGluR) 2/3 and mGluR5 allosteric modulators have been proven to be effective in animal models and first clinical trials. In the need of innovative treatment approaches in major psychiatric disorders, such investigations should be encouraged and may lead to new add-on therapeutic strategies. A dysregulation of the glutamate system has been implicated in autism as well. In a MRS study at 4 Tesla measuring glutamate levels more accurately, Joshi et al. [2] compared patients suffering from autistic disorder to healthy controls. They found higher glutamate levels in the anterior cingulate cortex and a similar trend in the right medial temporal lobe in autism, indicating higher glutamate activity in these patients. Since many risk genes are targeting the glutamate system, in larger study effects of polymorphisms should be investigated. The cytochrome P450 oxidase group is involved in the metabolism of antidepressants. In treatment-resistant depression, suicidality has been associated with the cytochrome P450 metabolizer status. Hofer et al. [3] investigated the impact of cytochrome P450 genes on suicide attempts and suicide risk in treatment-resistant major depression. No association has been found after corrections for multiple testing, but results should be verified in a larger sample. In contrast, Antypa et al. [4] found variations in three monoamine oxidase A (MAOA) genes to be associated with higher levels of outwardly expressed anger in male suicidal patients. They suggest MAOA genes to be related to impulsivity, anger and aggression, which are risk factors for suicidality. Recent studies reported a potential association of polymorphisms in brain-derived neurotrophic factor (BDNF) genes with worse treatment outcome in patients with melancholic depression. Musil et al. [5] genotyped three BDNF polymorphisms in 324 patients with major depression and 470 healthy controls. No associations with diagnosis have been detected, but in tendency, rs6265 was associated with treatment response. However, this investigation is a pilot study and needs replication in larger patient samples to receive more reliable results. Since inpatients with depression tend to high relapse rates and chronicity, in a prospective study, Kuehner and Huffziger [6] identified predictors for outcome such as psychosocial functioning, depression levels at discharge and unsatisfactory relationships within the support network. The authors assume a need of treatment until full remission plus individual psychological interventions. Furthermore, affective disorders are associated with an A. Schmitt (&) P. Falkai Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nusbaumstr. 7, 80336 Munich, Germany e-mail: Andrea.Schmitt@med.uni-muenchen.de

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.

Up to 15% of depression patients eventually present with treatment-resistant or refractory depression (TRD), a condition that causes significant social and economic burdens. Our paper aims to summarize the current medical literature on the conceptual and methodologic issues involved in the definition, assessment, and staging of TRD. We reviewed the recently published medical literature to identify papers that specifically discuss TRD. For this, we searched MEDLINE, EMBASE, and PsycINFO for potentially relevant English-language articles published between January 1996 and June 2006. Recent methodologic and conceptual advances have contributed to the achievement of an acceptable level of theoretical consensus on the general meaning of TRD. Accordingly, depression is usually considered resistant or refractory when at least 2 trials with antidepressants from different pharmacologic classes (adequate in terms of dosage, duration, and compliance) fail to produce a significant clinical improvement. Regarding diagnostic assessments, an accurate and systematic evaluation should be made to elicit the potential role of several contributing factors, such as medical and psychiatric comorbidity. Recently, 3 staging methods for TRD have been described, but they currently require extensive empirical support. Future research on TRD should include prospective studies addressing the validity of the proposed criteria, the impact of depression comorbid with other psychiatric disorders and (or) physical conditions, and the possible predictors o treatment outcome. There is an important and clear need for studies that empirically test current definitions, assessment strategies, and staging methods of TRD.

Major Depressive Disorder is a common and disabling psychiatric illness whose pharmacological treatment options have historically been characterized by relatively low response rates. "Treatment-resistant depression" has emerged to describe patients whose depressive symptoms fail to respond to multiple courses of oral antidepressant medications. In 2019, the FDA approved intranasal esketamine as augmentation to an oral antidepressant in patients with treatment-resistant depression (TRD). While intranasal esketamine's efficacy was demonstrated in Janssen pharmaceutical's drug development program, publications on its real-world use have shown varying degrees of effectiveness. We aim to assess intranasal esketamine's effectiveness in a real-world clinical setting in Hartford, Connecticut, and are among the first to do so in an American sample using the Montgomery-Asberg Depression Rating Scale (MADRS), the same outcome measure used in the clinical trials where efficacy was established. In this analysis, a sample of 50 patients were enrolled in an intranasal esketamine treatment program at the Institute of Living (IOL) in Hartford, Connecticut. Information for these patients was obtained through retrospective analysis of the electronic health record. Descriptive statistics were used to analyze symptom severity and outcomes, using the Montgomery-Asberg Depression Rating Scale (MADRS) score at baseline and over 16 weeks of treatment. Assessment showed that moderate to severe baseline symptoms of depression were reduced to the mild range after 4 weeks and this effect was sustained over 16 weeks of treatment. Adverse effects were transient and generally mild (dissociation and sedation being the most common), with no safety events, and very few discontinuations related to tolerability. Results of this analysis demonstrate real-world effectiveness of intranasal esketamine as augmentation therapy in treatment resistant depression. The medication was well tolerated, with no safety events, misuse or dependence. While results demonstrating the efficacy of intranasal esketamine in patients with TRD were observed in the clinical trial studies, this analysis shows intranasal esketamine treatment to be safe and effective in a real-world clinical setting.

P281 Augmentative repetitive transcranial magnetic stimulation (RTMS) in highly treatment-resistant unipolar and bipolar depression – First Polish experiences

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.

A closer look at treatment resistant depression: is it due to a bipolar diathesis?