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Gałecki, Piotr, Jerzy Samochowiec, Magdalena Mikułowska, and Agata Szulc. "Treatment-Resistant Depression in Poland—Epidemiology and Treatment." Journal of Clinical Medicine 11, no. 3 (January 18, 2022): 480. http://dx.doi.org/10.3390/jcm11030480.
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(1) Background: Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders worldwide. Although several antidepressant drugs have been developed, up to 30% of patients fail to achieve remission, and acute remission rates decrease with the number of treatment steps required. The aim of the current project was to estimate and describe the population of treatment-resistant depression (TRD) patients in outpatient clinics in Poland. (2) Methods: The project involved a representative sample of psychiatrists working in outpatient clinics, chosen through a process of quota random sampling. The doctors completed two questionnaires on a consecutive series of patients with MDD, which captured the patients’ demographics, comorbidities, and medical histories. TRD was defined as no improvement seen after a minimum of two different antidepressant drug therapies applied in sufficient doses for a minimum of 4 weeks each. The data were weighted and extrapolated to the population of TRD outpatients in Poland. (3) Results: A total of 76 psychiatrists described 1781 MDD patients, out of which 396 fulfilled the criteria of TRD. The TRD patients constituted 25.2% of all MDD patients, which led to the number of TRD outpatients in Poland being estimated at 34,800. The demographics, comorbidities, medical histories, and histories of treatment of Polish TRD patients were described. In our sample of the TRD population (mean age: 45.6 ± 13.1 years; female: 64%), the patients had experienced 2.1 ± 1.6 depressive episodes (including the current one), and the mean duration of the current episode was 4.8 ± 4.4 months. In terms of treatment strategies, most patients (around 70%) received monotherapy during the first three therapies, while combination antidepressant drugs (ADs) were applied more often from the fourth line of treatment. The use of additional medications and augmentation was reported in only up to one third of the TRD patients. During all of the treatment steps, patients most often received a selective serotonin reuptake inhibitor (SSRI) and a serotonin norepinephrine reuptake inhibitor (SNRI). (4) Conclusions: TRD is a serious problem, affecting approximately one fourth of all depressive patients and nearly 35,000 Poles.
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Brenner, Philip, Johan Reutfors, Michel Nijs, and Therese M.-L. Andersson. "Excess deaths in treatment-resistant depression." Therapeutic Advances in Psychopharmacology 11 (January 2021): 204512532110065. http://dx.doi.org/10.1177/20451253211006508.
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Background: Patients with treatment-resistant depression (TRD) have an increased mortality risk compared with other patients with depression, but it is not known how this translates into absolute numbers of excess deaths. Methods: Swedish national registers were used to identify a cohort of 118,774 antidepressant initiators 18–69 years old with a depression diagnosis. Patients who initiated a third consecutive treatment trial were classified as having TRD. Flexible parametric survival models were used to estimate the mortality risk due to all causes and external causes (suicides and accidents), comparing TRD patients with patients with other depression while adjusting for clinical and sociodemographic covariates and including interactions with TRD, age, and Charlson comorbidity index (CCI) for a number of somatic comorbidities. Standardized survival was estimated, as were numbers of excess deaths among TRD patients within each age and comorbidity category. Results: Compared with the mortality risk of other depressed patients, patients with TRD experienced excess deaths in most age and comorbidity categories in the range of 7–16 deaths per 1000 patients during 5 years. Highest numbers for all-cause excess deaths were found among patients 18–29 years old with CCI 1, where 16 [95% confidence interval 5–28] of the expected 37 [25–48] deaths per 1000 patients were excess deaths. The majority of the excess deaths were due to external causes. Conclusion: Patients with TRD experience significant numbers of excess deaths compared with other patients with depression.
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Kasper, Siegfried, and Alan Frazer. "Editorial for Treatment-Resistant Depression (TRD)." International Journal of Neuropsychopharmacology 22, no. 2 (February 1, 2019): 83–84. http://dx.doi.org/10.1093/ijnp/pyz006.
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Bonner, Deirdre, and Robert Howard. "Treatment-Resistant Depression in the Elderly." International Psychogeriatrics 7, S1 (October 1995): 83–94. http://dx.doi.org/10.1017/s1041610295002377.
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Apparent treatment-resistant depression (TRD) is frequently encountered by and poses particular challenges for the old-age psychiatrist. The prevalence of true nonresponse to treatment is not known with accuracy but reports put it at 18% to 40% for the elderly. This article reviews the concept of TRD in the elderly, discussing the factors involved in apparent resistance and the treatment of this group. We suggest that absolute TRD may be a rarer entity than the estimated 18% to 40% if depressed patients are treated carefully and vigorously.
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PETERSEN, T., J. A. GORDON, A. KANT, M. FAVA, J. F. ROSENBAUM, and A. A. NIERENBERG. "Treatment resistant depression and Axis I co-morbidity." Psychological Medicine 31, no. 7 (October 2001): 1223–29. http://dx.doi.org/10.1017/s0033291701004305.
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Background. Treatment resistant depression (TRD) continues to present a formidable challenge to clinicians, accounts for over half of the annual costs associated with treatment for depression and causes great frustration to patients. Although there have been studies attempting to define TRD, little information is available as to the cause of TRD. One suggestion is that patients with TRD have a greater frequency of co-morbid psychiatric disorders, which explains their resistance to standard antidepressant treatments. The objective of this study was to compare the co-morbidity of Axis I disorders between a sample of TRD patients and a sample of non-TRD patients.Methods. TRD and non-TRD patients, recruited from two separate antidepressant treatment studies, were assessed for Axis I co-morbidity using the SCID-P for the DSM-III-R. Patients for the two samples were then matched for baseline HAM-D-17 total score and gender.Results. Results reveal that non-TRD patients had a higher rate of both lifetime and current generalized anxiety disorder co-morbidity than did the TRD patients. No other statistically significant differences in Axis I co-morbidity were found.Conclusions. These findings do not support the idea that current or lifetime Axis I co-morbidity is more common in TRD than non-TRD patients. In fact, the only statistical difference showed non-TRD patients with higher co-morbidity rates.
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Petersen, Timothy, George I. Papakostas, Yasmin Mahal, Wendy M. Guyker, Erin C. Beaumont, Jonathan E. Alpert, Maurizio Fava, and Andrew A. Nierenberg. "Psychosocial functioning in patients with treatment resistant depression." European Psychiatry 19, no. 4 (June 2004): 196–201. http://dx.doi.org/10.1016/j.eurpsy.2003.11.006.
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AbstractBackgroundDepression is a disorder that causes disability, with a profound adverse impact on all areas of psychosocial functioning. This is particularly true for those with treatment resistant depression (TRD). However, to date, no systematic assessments of psychosocial functioning for patients with TRD have been conducted.MethodsIn the present study, we used the Longitudinal Interval Follow-up Evaluation (LIFE) scale to measure psychosocial functioning in 92 patients with TRD. These patients met formal criteria for TRD and were part of a clinical trial examining the efficacy of lithium augmentation of nortriptyline.ResultsClinicians rated this sample of patients as experiencing mild to moderate impairment in work-related activities, good to fair interpersonal relations, poor level of involvement in recreational activities, and mild impairment of ability to enjoy sexual activity. Patients and clinicians rated global social adjustment as poor.ConclusionsPatients with formally defined TRD experience significant impairment in psychosocial functioning. In this sample a tendency existed for both clinicians and patients to assign more severely impaired global ratings when compared with ratings for specific functional areas.
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Kolar, D. "Treatment-Resistant Depression – What is the Effective Maintenance Treatment." European Psychiatry 65, S1 (June 2022): S555—S556. http://dx.doi.org/10.1192/j.eurpsy.2022.1422.
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Introduction Treatment-resistant depression (TRD) presents a significant challenge in clinical practice. Besides antidepressant medications, neurostimulation methods (ECT, rTMS) and ketamine are viable treatment options. Objectives To objectively evaluate the real effectiveness of treatments within interventional psychiatry in the maintenance treatment. Methods The extensive literature review of the efficacy of ECT, rTMS, and ketamine treatment in the maintenance treatment of TRD and the author’s clinical and research experience will be included in this presentation. Results Neurostimulation, particularly ECT and ketamine treatment are usually effective treatments for patients with TRD. However, both of these treatment modalities do not have sustained benefits and after discontinuing treatment the majority of patients relapse. Ketamine has rapid therapeutic effects in depression, but these effects are short-lived. Continuation treatment with ketamine in the form of intranasal ketamine is an option, but concerns over cognitive impairment, interstitial cystitis and significant addictive potential related to longer use of ketamine are significant limiting factors. rTMS is a first-line treatment option for patients with TRD according to the Canadian CANMAT guidelines. However, the majority of patients may relapse following the course of rTMS. The maintenance rTMS over an extended period of time is usually not feasible as it may significantly affect the waiting time for newly referred patients. Portable TMS machine for home use would be an alternative option for a limited number of patients. Conclusions Maintenance treatment has been always a big clinical challenge in mood disorder psychiatry. Only well-established multimodal treatment is a realistic option for getting long-term benefits in treating patients with TRD. Disclosure No significant relationships.
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Millet, E., R. Icick, and J. P. Lépine. "Treatment-resistant depression: From pseudo-resistance to full resistance." European Psychiatry 26, S2 (March 2011): 638. http://dx.doi.org/10.1016/s0924-9338(11)72344-6.
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IntroductionTreatment-resistant depression (TRD) has been a controversial issue for more than 35 years. Despite a large number of publications, clinicians and researchers still know few about the prevalence of TRD since no staging method has been validated.ObjectivesWe sought to assess similarities and differences between the 4 TRD-staging methods published to date and assess TRD prevalence in a clinical sample. We also wanted to look for clinical factors associated with TRD.MethodsWe conducted a clinical study in a psychiatric unit of a university hospital. We designed a hetero-questionnaire to stage TRD according to the 4 methods. Psychiatric diagnosis, depression severity and cognitive status were assessed using standardized tools. Patients were not included in the study if they suffer from schizophrenia, bipolar disorder, current substance dependence or major cognitive impairment.ResultsWe recruited 37 inpatients. Twenty-four had received an inadequate treatment, four had not responded after one adequate antidepressant trial and 9 after two trials. Only 7 were resistant according to the 4 staging methods, which showed several differences. The Massachussetts General Hospital (MGH) method appeared as the most specific and easy-to-use. Complete TRD seemed much less frequent than pseudo-resistance and relative resistance with untreated comorbidity. Chronic depression and comorbidity were frequent in the TRD subgroup.ConclusionThe concept of “difficult-to-treat” depression might be more appropriate for clinical practice than TRD. The MGH tool seems to fit best to clinical practice. Further research is needed to confirm these descriptive findings in a larger sample.
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Rannanpää, S., H. Taipale, A. Tanskanen, M. Lähteenvuo, S. Huoponen, and J. Tiihonen. "Healthcare costs and productivity losses in treatment-resistant depression in Finland." European Psychiatry 65, S1 (June 2022): S268. http://dx.doi.org/10.1192/j.eurpsy.2022.686.
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Introduction Due to its relatively high prevalence and recurrent nature, depression causes a major burden on healthcare systems and societies. Objectives To investigate healthcare resource utilization and costs associated with treatment-resistant depression (TRD) compared with non-TRD depression in Finland. Methods Of all patients aged 16-65 years and diagnosed with depression in Finland during 2004-2016, persons with TRD (N=15 405) were identified from nationwide registers and matched 1:1 with comparison persons with depression but no TRD. TRD was defined as initiation of a third treatment trial after having failed two pharmacological treatment trials. Follow-up period covered five years after TRD or corresponding matching data (until end of 2018). Healthcare resource utilization was studied with negative binomial regression and average excess costs of TRD with generalized estimating equations, by adjusting for baseline costs, comorbidity and baseline severity of depression. Results Persons with TRD (mean age 38.7, SD 13.1, 60.0% women) had more healthcare utilization and work disability (sick leaves and disability pensions), adjusted incidence rate ratio for work disability days was 1.72 (95% CI 1.64-1.80). This resulted in higher total costs for persons with TRD, adjusted mean difference 7572 (95% CI 7215-7929) EUR per patient per year, higher productivity losses (due to sick leaves and disability pensions, mean difference 5296, 95% CI 5042-5550) and direct healthcare costs (2002, 95% CI 1853-2151) compared with non-TRD patients. Mean difference was highest during the first year after TRD (total costs difference 11760, 95% CI 11314-12206). Conclusions Treatment-resistant depression is associated with a significant cost burden. Disclosure This study was funded by Janssen-Cilag Finland and the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. ML was partly funded by personal grants from the Finnish Medical Foundation and Emil Aaltonen fou
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Macewan, G. William, and Ronald A. Remick. "Treatment Resistant Depression: A Clinical Perspective*." Canadian Journal of Psychiatry 33, no. 9 (December 1988): 788–92. http://dx.doi.org/10.1177/070674378803300902.
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One hundred and fourteen patients with a diagnosis of “treatment resistant depression” (TRD) were assessed and treated at a Mood Disorders Clinic. Diagnostically, 52 (45.6%) subjects met criteria for bipolar disorder, 49 (42.9%) for recurrent depression, and 13 (11.4%) patients did not fulfill diagnostic criteria for affective disorder which explained their treatment resistance. With appropriate, individualized treatment, 59 of 98 (60.2%) patients had complete symptom remission based on clinical and psychometric ratings (initial Ham-D 26.7, final Ham-D 5.9). Eighteen of 98 patients had partial remission (final Ham-D 15.9) with vigorous pharmacological interventions, and 8 subjects exhibited “absolute” TRD (final Ham-D 23.4). The results suggest the value of specialized mood disorder services. The partial and absolute TRD's were more likely to be older, received more Axis II diagnoses, and had previous histories of drug or alcohol abuse.
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Halaris, Angelos, Emilie Sohl, and Elizabeth A. Whitham. "Treatment-Resistant Depression Revisited: A Glimmer of Hope." Journal of Personalized Medicine 11, no. 2 (February 23, 2021): 155. http://dx.doi.org/10.3390/jpm11020155.
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Major Depressive Disorder (MDD) is a highly prevalent psychiatric disorder worldwide. It causes individual suffering, loss of productivity, increased health care costs and high suicide risk. Current pharmacologic interventions fail to produce at least partial response to approximately one third of these patients, and remission is obtained in approximately 30% of patients. This is known as Treatment-Resistant Depression (TRD). The burden of TRD exponentially increases the longer it persists, with a higher risk of impaired functional and social functioning, vast losses in quality of life and significant risk of somatic morbidity and suicidality. Different approaches have been suggested and utilized, but the results have not been encouraging. In this review article, we present new approaches to identify and correct potential causes of TRD, thereby reducing its prevalence and with it the overall burden of this disease entity. We will address potential contributory factors to TRD, most of which can be investigated in many laboratories as routine tests. We discuss endocrinological aberrations, notably, hypothalamic-pituitary-adrenal (HPA) axis dysregulation and thyroid and gonadal dysfunction. We address the role of Vitamin D in contributing to depression. Pharmacogenomic testing is being increasingly used to determine Single Nucleotide Polymorphisms in Cytochrome P450, Serotonin Transporter, COMT, folic acid conversion (MTHFR). As the role of immune system dysregulation is being recognized as potentially a major contributory factor to TRD, the measurement of C-reactive protein (CRP) and select immune biomarkers, where testing is available, can guide combination treatments with anti-inflammatory agents (e.g., selective COX-2 inhibitors) reversing treatment resistance. We focus on established and emerging test procedures, potential biomarkers and non-biologic assessments and interventions to apply personalized medicine to effectively manage treatment resistance in general and TRD specifically.
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Bozymski, Kevin M., Ericka L. Crouse, Erika N. Titus-Lay, Carol A. Ott, Jill L. Nofziger, and Cynthia K. Kirkwood. "Esketamine: A Novel Option for Treatment-Resistant Depression." Annals of Pharmacotherapy 54, no. 6 (December 4, 2019): 567–76. http://dx.doi.org/10.1177/1060028019892644.
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Objective:To review the pharmacology, pharmacokinetics, efficacy, safety, use requirements, and place in therapy of esketamine for treatment-resistant depression (TRD). Data Sources: A comprehensive PubMed search (1966 to October 2019) was conducted using the search terms depression, treatment-resistant, suicide, intranasal, esketamine, and JNJ-54135419. Additional data were obtained from references of identified articles, governmental sources, manufacturer product labeling, and Clinicaltrials.gov . Study Selection and Data Extraction: All English-language trials evaluating intranasal esketamine for TRD were included and discussed. Data Synthesis: Intranasal esketamine was approved by the US Food and Drug Administration, in conjunction with an oral antidepressant, for treating TRD in adults. Two short-term trials (TRANSFORM-1 and -2) found statistically significant reduction in the Montgomery-Asberg Depression Rating Scale score at day 28 for the fixed 56-mg dose (−4.1; 95% CI = −7.69 to −0.49; P = 0.027 [exploratory]) and flexible-dosed arms (−4.0; 95% CI = −7.31 to −0.64; P = 0.02), though the fixed-dose 84-mg arm (−3.2; 95% CI = −6.88 to 0.45; P = 0.088) of TRANSFORM-1 and TRANSFORM-3 did not (−3.6; 95% CI = −7.2 to 0.07; P = 0.059). Two long-term trials (SUSTAIN-1 and -2) suggested maintenance of response with continued use. Esketamine’s adverse effects include dizziness, dysgeusia, somnolence, dissociation, suicidal thoughts and behaviors, and increased heart rate and blood pressure. Relevance to Patient Care and Clinical Practice: Although providing a novel antidepressant mechanism and formulation for TRD, esketamine’s role in treatment will likely be limited by cost, administration, and diversion concerns. Conclusion: Intranasal esketamine significantly reduced depression symptoms in TRD, though with tolerability issues.
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Ruberto, Valerie L., Manish K. Jha, and James W. Murrough. "Pharmacological Treatments for Patients with Treatment-Resistant Depression." Pharmaceuticals 13, no. 6 (June 4, 2020): 116. http://dx.doi.org/10.3390/ph13060116.
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Over a third of patients with major depressive disorder (MDD) do not have an adequate response to first-line antidepressant treatments, i.e., they have treatment-resistant depression (TRD). These patients tend to have a more severe course of illness and are at an increased risk of suicide. Next step treatment options for patients with TRD, include switching to a different antidepressant, combining more than one antidepressant, or augmenting an antidepressant with another (non-antidepressant) medication. It is unclear which of these treatment approaches should be applied to a given patient, and in what order. Due to this ambiguity, comparing antidepressants and augmentation agents on the basis of their efficacy, tolerability, and speed of symptom relief would be beneficial for clinicians. To accomplish this, a systematic search was conducted following PRISMA guidelines. Only randomized controlled trials were included in this qualitative synthesis, resulting in 66 articles. This review identified several effective pharmaco-therapeutic strategies that are currently available for patients with TRD. Ketamine and esketamine appear to be effective for the treatment of TRD. Augmentation with certain second generation antipsychotics, such as quetiapine or aripiprazole is likewise effective, and may be preferred over switching to antidepressant monotherapy. While the combination of olanzapine and fluoxetine was one of the first pharmacotherapy approved for TRD, and its use may be limited by metabolic side-effects. Other effective strategies include augmentation with lithium, liothyronine (T3), lamotrigine, or combination of antidepressants including bupropion, tricyclics, or mirtazapine. There is insufficient research to demonstrate the efficacy of ziprasidone or levothyroxine (T4). A shared decision-making approach is recommended to guide treatment selection to address each patient’s individual needs.
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Buoli, Massimiliano, Enrico Capuzzi, Alice Caldiroli, Alessandro Ceresa, Cecilia Maria Esposito, Cristina Posio, Anna Maria Auxilia, et al. "Clinical and Biological Factors Are Associated with Treatment-Resistant Depression." Behavioral Sciences 12, no. 2 (February 3, 2022): 34. http://dx.doi.org/10.3390/bs12020034.
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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.
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Kennedy, Noel, and Michael McDonough. "Pharmacological management of treatment resistant depression: a clinical review." Irish Journal of Psychological Medicine 20, no. 1 (March 2003): 18–23. http://dx.doi.org/10.1017/s0790966700007473.
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AbstractObjectives: Treatment resistant depression (TRD), commonly encountered in clinical practice, leads to socioeconomic disability and therapeutic pessimism. This paper reviews evidence for pharmacological approaches used in TRD.Method: Electronic literature searches were performed using Medline and Psychlit using broad search terms relating to TRD.Results: Agents that potentiate both serotonin and noradrenaline may allow more patients to achieve full remission. Attention must be paid to dose titration and length of treatment courses in TRD. Augmentation with lithium and switching within antidepressant class or between classes can often improve symptoms but efficacy of other augmentation approaches remains uncertain. Antidepressant combinations and addition of atypical antipsychotics can be useful but combinations of predominantly serotonergic antidepressants should be avoided. Electroconvulsive therapy retains an important role in TRD but pharmacological treatments need to be continued concomitantly.Conclusions: Good improvement is seen in TRD after vigorous antidepressant treatment but most patients continue to have lower grade symptomatology.
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Jannini, T., L. Longo, Y. Barone, C. Niolu, S. Bernardini, A. Siracusano, P. Bertucci, and G. Di Lorenzo. "Polyunsaturated fatty acid in treatment resistant depression: A pilot study." European Psychiatry 64, S1 (April 2021): S323—S324. http://dx.doi.org/10.1192/j.eurpsy.2021.868.
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IntroductionThe deficiency of polyunsaturated fatty acids (PUFAs) and an alteration between the ratio of omega-6 and omega-3 PUFAs may contribute to the pathogenesis of depressive disorders.ObjectivesTo investigate the levels of omega-3 and omega-6 in red cell membranes (mPUFAs) and plasma (pPUFAs) of patients with treatment-resistant (TRD) and non-treatment resistant depression (non-TRD).MethodsTRD and non-TRD consisted of 75 patients enrolled at the Psychiatric and Clinic Psychology Unit of the University of Rome Tor Vergata, Rome, Italy, and met the DSM-IV criteria for major depressive disorder (MDD). A group of healthy controls (HC) matched for agender and age was enrolled. All blood samples were performed in conditions of an empty stomach between 07:00 am and 09:00 am. For each subject were obtained 5 ml of whole blood with the use of tubes for plasma with EDTA as an anticoagulant. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) for omega-3 and arachidonic acid (AA) for omega-6 were measured.ResultsLevels of pPUFAs did not differ between the three groups. The mPUFAs were altered in the MDD. TRD and non-TRD had lower EPA and AA values respect to the HC. DHA in red cell membranes was lower in TRD than non-TRD and HC.ConclusionsChanges in levels of PUFAs in red cell membranes, but not in plasma, may be an important factor to evaluate the resistance to the pharmacological treatment.
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Ming, Timothy, Tom Denee, Gemma Scott, Joachim Morrens, and Christopher Weatherburn. "Epidemiology and current treatment patterns of treatment-resistant depression in Scotland: a CPRD study." BJPsych Open 7, S1 (June 2021): S334. http://dx.doi.org/10.1192/bjo.2021.876.
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AimsTo assess the incidence and treatments currently used in clinical practice for the treatment of treatment-resistant depression (TRD) in Scotland.BackgroundPatients with major depressive disorder (MDD) who have not responded to at least two successive antidepressant (AD) treatments in a single episode are described as having Treatment-Resistant Depression (TRD). Epidemiological data on TRD in Scotland is lacking. Furthermore, there is no data to our knowledge on therapies prescribed in Scottish clinical practice to treat TRD.MethodA retrospective, longitudinal cohort study was conducted using Clinical Practice Research Datalink (CPRD) medical records. Adult patients were indexed on AD prescription, requiring MDD diagnosis within 90 days, from Jan 2011-May 2018 with 360-day baseline and 180-day minimum follow-up periods. Failure of ≥2 adequate oral AD regimens following indexing constituted TRD classification. Incidence rates of MDD and TRD (within the MDD cohort) and treatment lines following TRD classification were derived.ResultThe analysis included 20,059 patients with MDD (mean age 44 years, 63% female, median follow-up 59 months); 1,374 (6.8%) were classified as TRD. Median time-to-TRD classification was 25 months. The incidence rate of MDD was 15.9 per 1,000 patient-years and for TRD was 14.7 per 1,000 MDD-patient-years. For all first four post-TRD treatment lines, SSRI monotherapy was the most commonly prescribed therapy, followed by combination (dual/triple) therapy and augmentation therapy (at least one oral AD supplemented with lithium, an antipsychotic or an anticonvulsant therapy). At first-line of TRD treatment, 1,050 (76.4%) patients received monotherapy AD, 212 (15.4%) received combination AD therapy and 112 (8.2%) received augmentation therapy. The most common monotherapy treatments at first-line TRD were sertraline (15.6%), mirtazapine (13.8%), fluoxetine (12.2%) and venlafaxine (11.6%). Among combination therapies, mirtazapine, venlafaxine, sertraline and amitriptyline were frequently used. Among the TRD and MDD cohort, no somatic treatments were coded in CPRD, although the use of these treatments was likely underestimated.ConclusionMonotherapy AD treatment was the most common therapy type for all four post-TRD treatment lines. These data support the need for new treatments that can achieve and maintain therapeutic response, and avoid continuous cycling through similar AD therapies.This study was sponsored by Janssen Cilag Ltd.
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Xue, Song, Shanshan Wang, Xia Kong, and Jiang Qiu. "Abnormal Neural Basis of Emotional Conflict Control in Treatment-Resistant Depression." Clinical EEG and Neuroscience 48, no. 2 (July 10, 2016): 103–10. http://dx.doi.org/10.1177/1550059416631658.
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Emotional conflict has received increased attention as a research topic. The objective of this study is to confirm that the processing of emotional conflict is impaired in treatment-resistant depression (TRD). We compared the event-related potentials of 17 patients with TRD and 17 healthy controls during the face-word Stroop task, which is an effective way of assessing the effects of emotional conflict directly. Compared with healthy controls, the accuracy scores of the TRD patients were lower in both “congruent stimuli” and “incongruent stimuli” conditions, and their response times were longer. The TRD patients also had larger N2 amplitudes over the frontal region, regardless of stimulus condition, which might reflect that TRD patients pay more attention to emotional information. A larger P3 amplitude over the frontal region for “incongruent stimuli minus congruent stimuli” was also found among patients with TRD, which indicates interference effects in the Stroop task. The results of this study provide novel behavioral and neurophysiological evidence of anomalies in cognitive inhibition among patients with TRD using the word-face task. These findings not only improve our understanding of deficient inhibition in TRD, but also pave the way for a cognitive neuropsychiatric model of depression.
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Jensen, Kristoffer Jarlov, Frederikke Hørdam Gronemann, Mikkel Zöllner Ankarfeldt, Espen Jimenez-Solem, Sarah Alulis, Jesper Riise, Nikolaj Bødker, Merete Osler, and Janne Petersen. "Healthcare resource utilization in patients with treatment-resistant depression—A Danish national registry study." PLOS ONE 17, no. 9 (September 27, 2022): e0275299. http://dx.doi.org/10.1371/journal.pone.0275299.
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Objectives To investigate healthcare resource utilization (HRU) and associated costs by depression severity and year of diagnosis among patients with treatment-resistant depression (TRD) in Denmark. Methods Including all adult patients with a first-time hospital contact for major depressive disorder (MDD) in 1996–2015, TRD patients were defined at the second shift in depression treatment (antidepressant medicine or electroconvulsive therapy) and matched 1:2 with non-TRD patients. The risk of utilization and amount of HRU and associated costs including medicine expenses 12 months after the TRD-defining date were reported, comparing TRD patients with non-TRD MDD patients. Results Identifying 25,321 TRD-patients matched with 50,638 non-TRD patients, the risk of psychiatric hospitalization following TRD diagnosis was 138.4% (95%-confidence interval: 128.3–149.0) higher for TRD patients than for non-TRD MDD patients. The number of hospital bed days and emergency department (ED) visits were also higher among TRD patients, with no significant difference for somatic HRU. Among patients who incurred healthcare costs, the associated HRU costs for TRD patients were 101.9% (97.5–106.4) higher overall, and 55.2% (50.9–59.6) higher for psychiatric services than those of non-TRD patients. The relative differences in costs for TRD-patients vs non-TRD patients were greater for patients with mild depression and tended to increase over the study period (1996–2015), particularly for acute hospitalizations and ED visits. Limitations TRD was defined by prescription patterns besides ECT treatments. Conclusion TRD was associated with increased psychiatric-related HRU. Particularly the difference in acute hospitalizations and ED visits between TRD and non-TRD patients increased over the study period.
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Shah, P. J., M. F. Glabus, G. M. Goodwin, and K. P. Ebmeier. "Chronic, treatment-resistant depression and right fronto-striatal atrophy." British Journal of Psychiatry 180, no. 5 (May 2002): 434–40. http://dx.doi.org/10.1192/bjp.180.5.434.
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BackgroundTreatment-resistant depression (TRD) is relatively common but its neurobiological basis is poorly understood. Fronto-striatal structural brain changes have been reported in patients with depression but their association with treatment resistance and chronicity has not been established.MethodMagnetic resonance images of 20 patients with TRD were compared with images of 20recovered patients and 20 healthy controls. Images were compared using a voxel-based analysis (VBA) method; the results were validated by conventional volumetric analysis. The clinical associations of magnetic resonance imaging (MRI) changes with illness duration and severity were examined by VBA.ResultsOnly the TRD group exhibited right fronto-striatal atrophy, and subtle MRI changes in the left hippocampus on VBA. Atrophy was confirmed on volumetric analysis, the degree correlating with the cumulative number of electroconvulsive therapy (ECT) treatments received, suggesting an acquired deficit.ConclusionsThis is the first study to demonstrate fronto-striatal atrophy in patients with depression with poor outcome; the atrophy is more marked in those with more severe illness.
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Roet, Milaine, Jackson Boonstra, Erdi Sahin, Anne E. P. Mulders, Albert F. G. Leentjens, and Ali Jahanshahi. "Deep Brain Stimulation for Treatment-Resistant Depression: Towards a More Personalized Treatment Approach." Journal of Clinical Medicine 9, no. 9 (August 24, 2020): 2729. http://dx.doi.org/10.3390/jcm9092729.
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Major depressive disorder (MDD) affects approximately 4.4% of the world’s population. One third of MDD patients do not respond to routine psychotherapeutic and pharmacotherapeutic treatment and are said to suffer from treatment-resistant depression (TRD). Deep brain stimulation (DBS) is increasingly being investigated as a treatment modality for TRD. Although early case studies showed promising results of DBS, open-label trials and placebo-controlled studies have reported inconsistent outcomes. This has raised discussion about the correct interpretation of trial results as well as the criteria for patient selection, the choice of stimulation target, and the optimal stimulation parameters. In this narrative review, we summarize recent studies of the effectiveness of DBS in TRD and address the relation between the targeted brain structures and clinical outcomes. Elaborating upon that, we hypothesize that the effectiveness of DBS in TRD can be increased by a more personalized and symptom-based approach. This may be achieved by using resting-state connectivity mapping for neurophysiological subtyping of TRD, by using individualized tractography to help decisions about stimulation target and electrode placement, and by using a more detailed registration of symptomatic improvements during DBS, for instance by using ‘experience sampling’ methods.
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Hickie, Ian, Barbara Bennett, Philip Mitchell, Kay Wilhelm, and Wendy Orlay. "Clinical and Subclinical Hypothyroidism in Patients with Chronic and Treatment-Resistant Depression." Australian & New Zealand Journal of Psychiatry 30, no. 2 (April 1996): 246–52. http://dx.doi.org/10.3109/00048679609076101.
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Objective: To investigate the relationship between hypothyroidism and treatment-resistant depression (TRD). Method: A retrospective case audit of 93 inpatients of a specialist Mood Disorders Unit. Patients referred with TRD were sub-classified into ‘adequate’ or ‘inadequate’ prior treatment groups on the basis of pre-established criteria, and compared with a ‘non-TRD’ control sample. Grades I (clinical) and II (subclinical) hypothyroidism were determined by review of relevant thyroid indices. Results: Patients had chronic depressive disorders (sub-group means of 57.5-82.2 weeks of illness). Of those patients referred with TRD, 22% (10/46) had evidence of clinical or subclinical hypothyroidism compared with 2% (1/47) of the non-TRD patients (p < 0.01). A gradient in the rates of grade I hypothyroidism was observed with the adequately-treated TRD patients having the highest rate (13%), the inadequately-treated TRD patients having an intermediate rate (7%), and the non-TRD patients having the lowest rate (2%). Consistent with this view, the inadequately-treated TRD group had the highest rate of grade II hypothyroidism (p = 0.01) and tended to have higher thyroid stimulating hormone (TSH) values (p = 0.06). Differences in the rates of hypothyroidism could not be accounted for by differences in age or prior exposure to lithium and/or carbamazepine. Duration of the depressive episode was negatively correlated with both the free thyroxine indices (r = −0.25, P < 0.05) and TSH levels (r = −0.32, p < 0.01). Conclusions: This study suggests that relative hypothyroidism may play a role in the development of some treatment-resistant depressive disorders.
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Salahudeen, Mohammed S., Cameron M. Wright, and Gregory M. Peterson. "Esketamine: new hope for the treatment of treatment-resistant depression? A narrative review." Therapeutic Advances in Drug Safety 11 (January 2020): 204209862093789. http://dx.doi.org/10.1177/2042098620937899.
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This narrative review aims to provide an overview of the current literature on the pharmacology, safety, efficacy and tolerability of intranasal esketamine, the S-enantiomer of ketamine, for the treatment of treatment-resistant depression (TRD). A literature search using Medline, Embase, PsycINFO and Cochrane Central was conducted (January 2000 to July 2019). Product information and www.clinicaltrials.gov were also reviewed. The literature search was limited to human studies published in English. Phase I, II, and III studies of intranasal esketamine for TRD were reviewed. About a third of patients with major depressive disorder fail to achieve remission despite treatment with multiple antidepressants. This article examines the trials that led to the approval of esketamine in the United States, as well as other recent studies of esketamine for TRD. The findings from limited phase III trials illustrate that intranasal esketamine is effective and safe in reducing depressive symptoms and achieving clinical response in patients with TRD. The optimum duration and frequency of use are not fully understood. Although the nasal spray is a convenient dosage form, its use in practice may be limited by cost and administrative regulation. While it may prove beneficial to many patients who suffer from TRD, further long-term data are required, along with comparative trials with the R-isomer (arketamine). In the interim, care and monitoring should be exercised in its use in clinical practice.
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Zydb, Tatiana, and MIchael Hart. "Efficacy of Oral Ketamine Combined with Psychotherapy for Treatment Resistant Depression." European Journal of Medical and Health Sciences 3, no. 4 (August 5, 2021): 106–8. http://dx.doi.org/10.24018/ejmed.2021.3.4.979.
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Background: Treatment resistant depression (TRD) is defined as a major depressive episode that does not improve in response to at least two trials, each of a different class, of antidepressant medication. Pharmacotherapy of TRD with low dose ketamines has been shown as relatively successful in recent studies. Effects of such pharmacotherapy can be augmented by combining ketamine with psychotherapeutic interventions such as Zdyb’s Therapeutic Reset of Internal Processes (TRIP) protocol.
Method: 10 adult TRD patients (4 men, 6 women) were treated with low dose ketamines and were also receiving psychotherapeutic intervention as per TRIP protocol. All patients were administered the Patient Health Questionnaire, module 9 (PHQ9) which is a measure of a major depressive episode. The PHQ9 was administered twice: on baseline (i.e., prior to treatment) and after the treatment.
Results: On average, our patients fell in the moderate range of severity with respect to symptoms of TRD at baseline (pre-TRIP) as by their mean PHQ9 score of 17.9, (SD = 5.1). Their mean PHQ9 score decreased post TRIP treatment to 9.5 (SD = 6.6): the difference is significant in a t-test, t(10) = 4.3172, p = 0002 (two-tailed). The magnitude of the decrease amounts to 46.9% of the average baseline score.
Discussion and Conclusions: Our patients experienced significant reductions in symptoms of TRD in this pilot study. Research studies are now needed with control groups of TRD patients on a waiting list or also of those receiving only the ketamine pharmacotherapy.
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Murphy, Jenifer A., Jerome Sarris, and Gerard J. Byrne. "A Review of the Conceptualisation and Risk Factors Associated with Treatment-Resistant Depression." Depression Research and Treatment 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/4176825.
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Major depression does not always remit. Difficult-to-treat depression is thought to contribute to the large disease burden posed by depression. Treatment-resistant depression (TRD) is the conventional term for nonresponse to treatment in individuals with major depression. Indicators of the phenomenon are the poor response rates to antidepressants in clinical practice and the overestimation of the efficacy of antidepressants in medical scientific literature. Current TRD staging models are based on anecdotal evidence without an empirical rationale to rank one treatment strategy above another. Many factors have been associated with TRD such as inflammatory system activation, abnormal neural activity, neurotransmitter dysfunction, melancholic clinical features, bipolarity, and a higher traumatic load. This narrative review provides an overview of this complex clinical problem and discusses the reconceptualization of depression using an illness staging model in line with other medical fields such as oncology.
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Nunez, N., M. Ghabrash, J. Tabaka, M. Saint-Laurent, S. Vida, E. Zikos, T. Kolivakis, et al. "Treatment resistant depression (TRD): psychopathological profiles and pharmacological outcomes." European Neuropsychopharmacology 26 (October 2016): S415—S416. http://dx.doi.org/10.1016/s0924-977x(16)31383-9.
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Kasper, S. "CS02-01 - European program for treatment resistant depression (TRD)." European Psychiatry 27 (January 2012): 1. http://dx.doi.org/10.1016/s0924-9338(12)74062-2.
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Burrage, Alex, Samantha Green, Katrina Turner, Willem Kuyken, Chris Williams, Nicola Wiles, and Glyn Lewis. "Conditional Beliefs of Primary-Care Patients with Treatment-Resistant Depression." Behavioural and Cognitive Psychotherapy 44, no. 5 (November 4, 2015): 513–26. http://dx.doi.org/10.1017/s1352465815000624.
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Background:Cognitive behaviour therapy (CBT) for patients with treatment-resistant depression (TRD) aims to reframe underlying conditional beliefs that are thought to maintain depression.Aim:To systematically explore conditional beliefs expressed by primary-care based patients with TRD, defined as non-response to at least 6 weeks of antidepressants.Method:Conditional beliefs (stated in an “If. . .then. . .” format) were extracted from a random sample of 50 sets of therapist notes from the CoBalT trial, a large randomized controlled trial of CBT for TRD in primary care. The beliefs were separated into their two constituent parts; the demands (Ifs) and consequences (thens). An approach based on framework analysis provided a systematic way of organizing the data, and identifying key themes.Results:Four main themes emerged from the demand part of the conditional beliefs (Ifs): 1. High standards; 2. Putting others first/needing approval; 3. Coping; and 4. Hiding “true” self. Three main themes emerged from the consequence part of the conditional beliefs (thens): 1. Defectiveness; 2. Responses of others; 3. Control of emotions.Conclusions: Identifying common themes in the conditional beliefs of patients with TRD adds to our clinical understanding of this client group, providing useful information to facilitate the complex process of collaborative case conceptualization and working with conditional beliefs within CBT interventions.
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Goh, Kah K., Shen-Chieh Chang, Chun-Hsin Chen, and Mong-Liang Lu. "Therapeutic Strategies for Treatment-resistant Depression: State of the Art and Future Perspectives." Current Pharmaceutical Design 26, no. 2 (March 4, 2020): 244–52. http://dx.doi.org/10.2174/1381612826666200110101604.
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In this narrative review, we intended to summarize the evidence of pharmacological and somatic treatment choices for treatment-resistant depression (TRD). There are several types of therapeutic strategies to improve inadequate response to antidepressant treatment. The first step for patients with TRD is to optimize the dosage and duration of antidepressants as well as to ensure their drug compliance. The shift to antidepressant and antidepressant combination therapy for patients with TRD cannot be regarded as an evidence-based strategy. Only the combination of a monoamine reuptake inhibitor with a presynaptic α2-autoreceptor antagonist might have better efficacy than other antidepressant combinations. Currently, the most evidence-based treatment options for TRD are augmentation strategies. Among augmentative agents, second-generation antipsychotics and lithium have the strongest evidence for the management of TRD. Further studies are needed to evaluate the augmentative efficacy of anticonvulsants, thyroid hormone, glutamatergic agents, anti-inflammatory agents, and nutraceuticals for TRD. Among somatic therapies, electroconvulsive therapy and repetitive transcranial magnetic stimulation are effective for TRD. Further studies are warranted to provide clinicians with a better recommendation in making treatment choices in patients with TRD.
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Sun, Jing-Jing, Chen-Yu Shen, Xiao-Min Liu, and Po-Zi Liu. "Abnormal Prefrontal Brain Activation During a Verbal Fluency Task in Treatment-Resistant Depression Using Near-Infrared Spectroscopy." Psychiatry Investigation 20, no. 2 (February 25, 2023): 84–92. http://dx.doi.org/10.30773/pi.2021.0372.
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Objective 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.Methods 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).Results 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.Conclusion 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.
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Adu, Medard Kofi, Reham Shalaby, Pierre Chue, and Vincent I. O. Agyapong. "Repetitive Transcranial Magnetic Stimulation for the Treatment of Resistant Depression: A Scoping Review." Behavioral Sciences 12, no. 6 (June 17, 2022): 195. http://dx.doi.org/10.3390/bs12060195.
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Treatment-resistant depression (TRD) is associated with significant disability, and due to its high prevalence, it results in a substantive socio-economic burden at a global level. TRD is the inability to accomplish and/or achieve remission after an adequate trial of antidepressant treatments. Studies comparing repetitive transcranial magnetic stimulation (rTMS) with electroconvulsive therapy (ECT) and pharmacotherapy have revealed evidence of the therapeutic efficacy of rTMS in TRD. These findings suggest a crucial role for rTMS in the management of TRD. This article aims to conduct a comprehensive scoping review of the current literature concerning the use of rTMS and its therapeutic efficacy as a treatment modality for TRD. PubMed, PsycINFO, Medline, Embase, and Cinahl were used to identify important articles on rTMS for TRD. The search strategy was limited to English articles within the last five years of data publication. Articles were included if they reported on a completed randomized controlled trial (RCT) of rTMS intervention for TRD. The exclusion criteria involved studies with rTMS for the treatment of conditions other than TRD, and study and experimental protocols of rTMS on TRD. In total, 17 studies were eligible for inclusion in this review. The search strategy spanned studies published in the last five years, to the date of the data search (14 February 2022). The regional breakdown of the extracted studies was North American (n = 9), European (n = 5), Asian (n = 2) and Australian (n = 1). The applied frequencies of rTMS ranged from 5 Hz to 50 Hz, with stimulation intensities ranging from 80% MT to 120% MT. Overall, 16 out of the 17 studies suggested that rTMS treatment was effective, safe and tolerated in TRD. For patients with TRD, rTMS appears to provide significant benefits through the reduction of depressive symptoms, and while there is progressive evidence in support of the same, more research is needed in order to define standardized protocols of rTMS application in terms of localization, frequency, intensity, and pulse parameters.
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Subramanian, L., T. Bracht, P. Jenkins, S. Choppin, D. E. J. Linden, G. Phillips, and B. A. Simpson. "Clinical improvements following bilateral anterior capsulotomy in treatment-resistant depression." Psychological Medicine 47, no. 6 (December 15, 2016): 1097–106. http://dx.doi.org/10.1017/s0033291716003159.
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BackgroundThe purpose of this study was to evaluate a programme of lesion surgery carried out on patients with treatment-resistant depression (TRD).MethodThis was a retrospective study looking at clinical and psychometric data from 45 patients with TRD who had undergone bilateral stereotactic anterior capsulotomy surgery over a period of 15 years, with the approval of the Mental Health Act Commission (37 with unipolar depression and eight with bipolar disorder). The Beck Depression Inventory (BDI) before and after surgery was used as the primary outcome measure. The Montgomery–Asberg Depression Rating Scale was administered and cognitive aspects of executive and memory functions were also examined. We carried out a paired-samples t test on the outcome measures to determine any statistically significant change in the group as a consequence of surgery.ResultsPatients improved on the clinical measure of depression after surgery by −21.20 points on the BDI with a 52% change. There were no significant cognitive changes post-surgery. Six patients were followed up in 2013 by phone interview and reported a generally positive experience. No major surgical complications occurred.ConclusionsWith the limitations of an uncontrolled, observational study, our data suggest that capsulotomy can be an effective treatment for otherwise TRD. Performance on neuropsychological tests did not deteriorate.
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Caldiroli, Alice, Enrico Capuzzi, Ilaria Tagliabue, Martina Capellazzi, Matteo Marcatili, Francesco Mucci, Fabrizia Colmegna, Massimo Clerici, Massimiliano Buoli, and Antonios Dakanalis. "Augmentative Pharmacological Strategies in Treatment-Resistant Major Depression: A Comprehensive Review." International Journal of Molecular Sciences 22, no. 23 (December 2, 2021): 13070. http://dx.doi.org/10.3390/ijms222313070.
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Treatment resistant depression (TRD) is associated with poor outcomes, but a consensus is lacking in the literature regarding which compound represents the best pharmacological augmentation strategy to antidepressants (AD). In the present review, we identify the available literature regarding the pharmacological augmentation to AD in TRD. Research in the main psychiatric databases was performed (PubMed, ISI Web of Knowledge, PsychInfo). Only original articles in English with the main topic being pharmacological augmentation in TRD and presenting a precise definition of TRD were included. Aripiprazole and lithium were the most investigated molecules, and aripiprazole presented the strongest evidence of efficacy. Moreover, olanzapine, quetiapine, cariprazine, risperidone, and ziprasidone showed positive results but to a lesser extent. Brexpiprazole and intranasal esketamine need further study in real-world practice. Intravenous ketamine presented an evincible AD effect in the short-term. The efficacy of adjunctive ADs, antiepileptic drugs, psychostimulants, pramipexole, ropinirole, acetyl-salicylic acid, metyrapone, reserpine, testosterone, T3/T4, naltrexone, SAMe, and zinc cannot be precisely estimated in light of the limited available data. Studies on lamotrigine and pindolol reported negative results. According to our results, aripiprazole and lithium may be considered by clinicians as potential effective augmentative strategies in TRD, although the data regarding lithium are somewhat controversial. Reliable conclusions about the other molecules cannot be drawn. Further controlled comparative studies, standardized in terms of design, doses, and duration of the augmentative treatments, are needed to formulate definitive conclusions.
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Veluri, N., and Z. Mansuri. "How effective are ketamine or esketamine in treatment-resistant depression?" European Psychiatry 64, S1 (April 2021): S330. http://dx.doi.org/10.1192/j.eurpsy.2021.886.
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IntroductionGlobally, depression affects millions of individuals. A third of depression patients meet the criteria for treatment-resistant depression (TRD). The N-methyl-D-aspartate receptor antagonist, ketamine, improved depressive symptoms in a span of 24-hours. Recently, the FDA approved esketamine, an enantiomer of ketamine for TRD.ObjectivesTo determine the effectiveness of ketamine and esketamine in TRD, and observe their role in suicidality.MethodsIndividual systematic searches were conducted on the PubMed database following the PRISMA protocol (Figure 1). Inclusion criteria included randomized clinical trials (RCT). Search strings were (i) “ketamine” OR “esketamine” AND “treatment-resistant depression” (ii) “ketamine” OR “esketamine” AND “suicide.” Eleven studies were included for depression and five studies for suicidality (Table 1). Comparison analysis for suicide appeared trivial because of only one inclusion eligible esketamine RCT. This review was submitted for registration at PROSPERO. Randomized odds ratios, 95% confidence interval (CI), and heterogeneity were obtained.ResultsThe comprehensive meta-analysis, version 3.0, was used for analysis. Ketamine improved TRD symptoms and reduced suicidality by a nine-fold and three-fold odds, respectively (OR 9.01, CI 4.89–16.6, p<0.001 and OR 2.9, CI 1.67–5.06, p<0.001). Esketamine also improved TRS symptoms (OR= 2.61, 95% CI= 1.56–4.37, p<0.001). The heterogeneity ranged from 11% to 60% between the three groups. Sensitivity analysis did not alter the results.ConclusionsFindings must be cautiously interpreted as the primary endpoint differed. The primary endpoint was set at 24-hours and 28-days for ketamine and esketamine, respectively. Esketamine’s effectiveness over 28 days appears promising for TRD. Current aim should consist of structured guidance for clinicians in esketamine administration.
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Bariyeva, Gulzada, Andrey Avdeyev, Valeriy Benberin, Nasrulla Shanazarov, Ruslan Akhmedullin, Makpal Akhmetova, Makhabbat Okesh, and Tansolpan Aimanova. "PP79 Use Of Vagus Nerve Stimulation Therapy In Treatment-Resistant Depression." International Journal of Technology Assessment in Health Care 38, S1 (December 2022): S66. http://dx.doi.org/10.1017/s0266462322002094.
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IntroductionMajor depressive disorder (MDD) severely limits a person’s psychosocial functioning and reduces quality of life. According to world statistics, about 3.8 percent of the population, or about 280 million people, suffer from depression. Approximately one-third of patients with MDD have treatment-resistant depression (TRD). Meanwhile, Vagus Nerve Stimulation (VNS) therapy was approved by the US Food and Drug Administration and received CE marking in Europe for the treatment of chronic or recurrent depression in the early 2000s. The aim of this analysis is to determine the impact of VNS use in the treatment of TRD.MethodsA comprehensive literature search was performed in MEDLINE/PubMed and Google Scholar databases in order to estimate the clinical effectiveness of neurostimulator implantation for treatment of TRD. The main assessment methods were the Hamilton Rating Scale for Depression, the Montgomery-Asberg Depression Rating Scale and the Beck Depression Inventory.ResultsIn total, 6 systematic reviews with meta-analyses on the effectiveness of VNS in TRD were studied. The identified meta-analyses did not report any statistically significant differences in treatment outcomes favoring VNS compared to placebo and treatment as usual (TAU). However, the results of two studies demonstrate its positive clinical effect in the form of additional treatment to the TAU with longer follow-up period. An improvement in the clinical response is observed on average after 12 months as a decrease of about 50 percent in the initial estimates of depression.ConclusionsDespite the lack of clinical evidence of the benefits of treating depression, VNS therapy should be used as a standard adjunct treatment to antidepressants or other treatments for people with TRD. Many studies tend to suggest that the efficacy and safety of VNC in depression is still unclear, and additional further research is still needed to establish clinically significant effects.
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Wilhelm, Kay, Philip Mitchell, Ian Hickie, Henry Brodaty, Marie-Paule Austin, Gordon Parker, and Philip Boyce. "Treatment Resistant Depression in an Australian Context I: The Utility of the Term and Approaches to Management." Australian & New Zealand Journal of Psychiatry 28, no. 1 (March 1994): 14–22. http://dx.doi.org/10.3109/00048679409075841.
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The concept of “treatment resistant depression” (TRD) has generally been defined in terms of failure to respond to a standard course of somatic therapy with little reference to diagnostic sub-types or relevant psychosocial factors. In this paper we examine problems with the use of the term “treatment resistant depression” and then outline an approach to TRD employed in an Australian mood disorders unit. After discussing the need for a biopsychosocial assessment, multimodal management strategies for melancholic and non-melancholic TRD patients are described.
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Jeng, Jia-Shyun, Cheng-Ta Li, Hui-Ching Lin, Shih-Jen Tsai, Ya-Mei Bai, Tung-Ping Su, Yu-Wen Chang, and Chih-Ming Cheng. "Antidepressant-resistant depression is characterized by reduced short- and long-interval cortical inhibition." Psychological Medicine 50, no. 8 (June 3, 2019): 1285–91. http://dx.doi.org/10.1017/s0033291719001223.
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AbstractBackgroundMajor depressive disorder (MDD) is highly heterogeneous and can be classified as treatment-resistant depression (TRD) or antidepressant-responsive depression (non-TRD) based on patients' responses to antidepressant treatment. Methods for distinguishing between TRD and non-TRD are critical clinical concerns. Deficits of cortical inhibition (CI) have been reported to play an influential role in the pathophysiology of MDD. Whether TRD patients' CI is more impaired than that of non-TRD patients remains unclear.MethodsPaired-pulse transcranial magnetic stimulation (ppTMS) was used to measure cortical inhibitory function including GABAA- and GABAB-receptor-related CI and cortical excitatory function including glutamate-receptor-related intracortical facilitation (ICF). We recruited 36 healthy controls (HC) and 36 patients with MDD (non-TRD, n = 16; TRD, n = 20). All participants received evaluations for depression severity and ppTMS examinations. Non-TRD patients received an additional ppTMS examination after 3 months of treatment with the SSRI escitalopram.ResultsPatients with TRD exhibited reduced short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI), as shown by abnormally higher estimates, than those with non-TRD or HC (F = 11.030, p < 0.001; F = 10.309, p < 0.001, respectively). After an adequate trial of escitalopram treatment, the LICI of non-TRD reduced significantly (t = − 3.628, p < 0.001), whereas the ICF remained lower than that of HC and showed no difference from pretreatment non-TRD.ConclusionsTRD was characterized by relatively reduced CI, including both GABAA- and GABAB-receptor-mediated neurons while non-TRD preserved partial CI. In non-TRD, SSRIs may mainly modulate GABAB-receptor-related LICI. Our findings revealed distinguishable features of CI in antidepressant-resistant and responsive major depression.
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Wang, Shikai, Shanfei Cheng, Min Feng, Ping Guo, Mincai Qian, Xinhua Shen, Runsen Chen, and Gang Wang. "Sevoflurane augmentation in treatment-resistant depression: a clinical case study." Therapeutic Advances in Psychopharmacology 10 (January 2020): 204512532095712. http://dx.doi.org/10.1177/2045125320957126.
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Compared with other inhaled anaesthetics, sevoflurane has a faster onset and offset, causes less irritation to the mucous membranes, and has a better safety profile. These characteristics warrant investigating the effect of sevoflurane in depression. In this Case Report, we describe that sevoflurane treatment was feasible and well tolerated by a patient with treatment-resistant depression (TRD). Sevoflurane had rapid and durable antidepressant effects, with few adverse effects. Moreover, the patient showed significant improvements in neurocognitive measurements. Our preliminary results suggest that further clinical trials are needed to determine the independent efficacy and safety of sevoflurane in patients with TRD.
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Serafini, G., G. Adavastro, G. Canepa, C. Conigliaro, M. Pompili, P. Girardi, and M. Amore. "Clinical and neurocognitive characteristics associated with treatment-resistant depression." European Psychiatry 41, S1 (April 2017): S542. http://dx.doi.org/10.1016/j.eurpsy.2017.01.753.
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IntroductionTreatment resistant depression (TRD) is a disabling condition associated with a relevant psychosocial impairment worldwide.ObjectivesThis exploratory study is aimed to evaluate the main clinical and neurocognitive characteristics in a sample of 21 subjects admitted to the Psychiatric Clinic of University of Genoa as inpatients between 2015 and 2016 and diagnosed with TRD according to Thase and Rush staging method.MethodsPatients have been assessed using the Hamilton Depression Rating Scale (HDRS), Hamilton Anxiety Rating Scale, and Clinical Global Impression (CGI). The Continuous Performance Test (CPT), Trial Making Test (TMT-A/B), Stroop Color Word Interference Test, Verbal Fluency Test, and Rey auditory-verbal learning test (RAVLT) have been administered as well.ResultsSubjects with early-onset (< 50 years) depression had a longer illness duration, higher depressive episodes and more impaired performance at RAVLT while individuals with late-onset (> 50 years) depression showed a higher severity of depressive symptoms and more anxiety symptoms. Depressive symptoms were positively associated with anxiety (r = 0.82; P = 0.00) and negatively with TMT-A/B (r = −0.56, P = 0.01), Stroop Color Word Interference Test (r = −0.72, P = 0.005 and r = −0.616, P = 0.008), and RAVLT (r = −0.60; P = 0.02) performances. According to regression analyses, anxiety symptoms were the only significant predictor of depression severity (P = 0.02).ConclusionsEarly-onset depression is associated with more disability and worse neurocognitive performance whereas late-onset depression is linked to more anxiety symptoms and more depressive symptoms severity. Clinicians should closely monitor patients with TRD for the presence of anxiety symptoms that may represent a significant risk factor of poorer long-term outcome.Disclosure of interestThe authors have not supplied their declaration of competing interest.
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Mechlińska, Agnieszka, Adam Włodarczyk, Marta Gruchała-Niedoszytko, Sylwia Małgorzewicz, and Wiesław Jerzy Cubała. "Dietary Patterns of Treatment–Resistant Depression Patients." Nutrients 14, no. 18 (September 13, 2022): 3766. http://dx.doi.org/10.3390/nu14183766.
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Depression is a common mental disorder that occurs all over the world with treatment resistance commonly seen in clinical practice. Ketamine exhibits an antidepressant that is more often used in the case of treatment-resistant depression (TRD) in MDD and BP. Research emphasizes that a healthy diet and the nutrients it contains can lower the risk of developing depression and form a strategy that supports conventional treatment. The aim of the study was to evaluate the patients’ diet and to analyze the effect of ketamine on food intake among patients with TRD. The study involved 15 patients suffering from treatment-resistant depression and 15 healthy volunteers. The data required for the analysis were collected using the food frequency questionnaire (FFQ) and 4-day food diaries. The study group was statistically significantly less likely to consume milk and plain milk beverages, plain white cheese, wholemeal bread, various vegetables, wine, and drinks. Our results show several disorders in the eating habits of patients with treatment–resistant depression. After the administration of ketamine, the patients consumed significantly less protein, fats, monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA), fiber, tryptophan, vitamins, and minerals compared to the control group. There is a lack of research describing the effects of ketamine on nutrition. In order to confirm the results of the study, more participants are required, and the assessment of food diaries filled in at the patient’s home with a longer interval after the last dose of ketamine as well.
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Hauptman, Jason S., Antonio A. F. DeSalles, Randall Espinoza, Mark Sedrak, and Warren Ishida. "Potential surgical targets for deep brain stimulation in treatment-resistant depression." Neurosurgical Focus 25, no. 1 (July 2008): E3. http://dx.doi.org/10.3171/foc/2008/25/7/e3.
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Object The goal of this study was to evaluate the definition of treatment-resistant depression (TRD), review the literature regarding deep brain stimulation (DBS) for TRD, and identify potential anatomical and functional targets for future widespread clinical application. Methods A comprehensive literature review was performed to determine the current status of DBS for TRD, with an emphasis on the scientific support for various implantation sites. Results The definition of TRD is presented, as is its management scheme. The rationale behind using DBS for depression is reviewed. Five potential targets have been identified in the literature: ventral striatum/nucleus accumbens, subgenual cingulate cortex (area 25), inferior thalamic peduncle, rostral cingulate cortex (area 24a), and lateral habenula. Deep brain stimulation electrodes thus far have been implanted and activated in only the first 3 of these structures in humans. These targets have proven to be safe and effective, albeit in a small number of cases. Conclusions Surgical intervention for TRD in the form of DBS is emerging as a viable treatment alternative to existing modalities. Although the studies reported thus far have small sample sizes, the results appear to be promising. Various surgical targets, such as the subgenual cingulate cortex, inferior thalamic peduncle, and nucleus accumbens, have been shown to be safe and to lead to beneficial effects with various stimulation parameters. Further studies with larger patient groups are required to adequately assess the safety and efficacy of these targets, as well as the optimal stimulation parameters and long-term effects.
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Taipale, H., M. Lähteenvuo, A. Tanskanen, S. Rannanpää, and J. Tiihonen. "Use of pharmacotherapies for treatment resistant depression in finland: A nationwide cohort study." European Psychiatry 64, S1 (April 2021): S108. http://dx.doi.org/10.1192/j.eurpsy.2021.311.
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IntroductionThere is a lack of knowledge on utilized pharmacotherapies for treatment resistant depression (TRD).ObjectivesTo investigate the courses of treatment of TRD.MethodsAll patients aged 16-65 years and diagnosed with depression in Finland during 2004-2016 were included (identified from nationwide registers for inpatient and specialized outpatient care, sick leaves and disability pensions). New antidepressant users were identified with six-month washout period and followed up for two years to observe the possible emergence of TRD, which was defined as initiation of a third treatment after having two failed pharmacological treatments with adequate duration. Pharmacological treatments were analyzed using PRE2DUP-method.ResultsDuring follow-up, 177,144 persons had their first registered depression (mean age:39.5, 62.5% women). Of them, 10.9% (N=19,322) met TRD criteria. Among the TRD patients, most common first and second lines antidepressants were as follows: SSRIs (44.6%), mirtazapine (19.0%) and SNRIs (16.5%). As the third line of treatment, 44.2% of TRD patients had antidepressant monotherapy, 32.1% a combination of ≥2 antidepressants, 15.8% antipsychotic or mood stabilizer augmentation and an antidepressant, 4.9% both combination of antidepressants and an augmentation with a mood stabilizer or antipsychotic, 2.7% antipsychotic or mood stabilizer monotherapy and 0.3% ECT monotherapy. Of TRD patients, 36.2% (N=6985) progressed to the fourth line of treatment and most common treatments were antidepressant monotherapy (37.5%), antidepressant combinations (30.8%) and augmentation (20.3%).ConclusionsAlthough antidepressant combination and augmentation strategies became more frequent, antidepressant monotherapies were still the most common third and fourth lines of depression treatment.DisclosureThe study was funded by Janssen and SR is an employee of Janssen.
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Chopra, Amit, and Suzanne Kodya. "748 Impact of Deep Transcranial Magnetic Stimulation on Insomnia Comorbid with Treatment Resistant Depression." Sleep 44, Supplement_2 (May 1, 2021): A292. http://dx.doi.org/10.1093/sleep/zsab072.745.
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Abstract Introduction Deep Transcranial Magnetic Stimulation (dTMS) is an FDA-approved non-invasive brain stimulation treatment for management of treatment-resistant depression (TRD). However, the efficacy of dTMS on Insomnia, a commonly prevalent and one of the most refractory symptoms of depression, is not clearly established. Our study aims to assess the impact of dTMS on outcomes of insomnia comorbid with TRD. Methods Single center retrospective study examining mood and insomnia outcomes in TRD patients (n=25), with greater than 3 failed psychotropic medication trials, undergoing dTMS for unipolar major depression.. Questionnaires including Patient Health Questionnaire (PHQ-9), Insomnia Severity Index (ISS),Generalized Anxiety Disorder-7 (GAD-7) were compared at baseline and at the end of dTMS treatment course. Results TRD patients with ‘low insomnia’ (n=12; ISS=7.9) and ‘high insomnia’ (n=13; ISS=20) were examined in terms of mood and insomnia ouctomes. No significant differences at baseline were noted between two groups in terms of demographic, mood, and anxiety variables. Depression and anxiety symptoms for patients in ‘Low Insomnia’ group significantly improved from baseline to final dTMS session- PHQ-9 [t(11) = 6.021, p < .0001]], GAD-7 [t(11) = 2.389, p = .036]. TRD patients in ‘High Insomnia’ group also reported significant improvements in depression [t(12) = 5.596, p < .0001], anxiety [t(12) = 2.743, p = .018], and insomnia [t(12) = 6.057, p < .0001]] at final dTMS session as compared to baseline. Non-responders in ‘High Insomnia’ group did not achieve statistically significant improvements in either depression or insomnia outcomes. Conclusion Insomnia comorbid with TRD responds to treatment with dTMS irrespective of the insomnia severity at baseline. Prospective research with the use of objective assessment measures for insomnia is warranted to confirm these findings. Non-response to insomnia was associated with poor mood outcomes as well in TRD patients. The probable mechanistic action of insomnia improvement in patients with TRD undergoing dTMS is unclear and further systematic research to understand the clinical and neural correlates of insomnia response with dTMS is needed. Support (if any) N/A
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Klein, Nikolas, Julia Sacher, Helene Wallner, Johannes Tauscher, and Siegfried Kasper. "Therapy of Treatment Resistant Depression: Focus on the Management of TRD with Atypical Antipsychotics." CNS Spectrums 9, no. 11 (November 2004): 823–32. http://dx.doi.org/10.1017/s1092852900002248.
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ABSTRACTTreatment-resistant depression (TRD) represents a significant challenge for physicians. About one third of patients with major depressive disorder fail to experience sufficient symptom improvement despite adequate treatment. Despite this high occurrence of TRD there was no general consensus on diagnosis criteria for TRD until 1997 when researchers proposed a model of defining and staging TRD. In 1999, others defined operational criteria for the definition of TRD. Treatment of TRD is commonly separated into pharmacologic and nonpharmacologic methods. This review gives a short overview of these two methods. The nonpharmacologic methods include psychotherapy, electroconvulsive therapy, and vagus nerve stimulation. Pharmacologic methods include switching to another antidepressant monotherapy, and augmentation or combination with two or more antidepressants or other agents. This review especially focuses on the augmentation of the antidepressant therapy with atypical antipsychotics.
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Del Sant, L. C., E. Magalhães, A. C. Lucchese, H. N. Palhares Alves, L. M. Sarin, J. A. Del Porto, and A. L. Tavares de Lacerda. "Clinical predictors of antidepressant response to ketamine in unipolar treatment-resistant depression." European Psychiatry 41, S1 (April 2017): S525—S526. http://dx.doi.org/10.1016/j.eurpsy.2017.01.704.
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IntroductionThe non-competitive N-methyl-d-aspartate glutamate receptor antagonist ketamine has been shown to have rapid antidepressant effects in treatment-resistant depression (TRD). However, only a few studies have investigated which clinical characteristics predict a response to ketamine.ObjectivesTo assess sociodemographic variables and clinical markers that predict response to ketamine in unipolar TRD patients.MethodsSearches of Pubmed, NCBI and Google Scholar were conducted for clinical trials and systematic reviews, through October 2016, using the keywords:ketamine, N-methyl-d-aspartate receptor antagonist, rapid-acting antidepressant, depression, treatment-resistant depression, clinical predictors.ResultsFindings support the following clinical predictors:– sociodemographic variables: positive family history of alcohol abuse disorder in first-degree relative (increased antidepressant response and fewer depressive symptoms for up to 4 weeks post-infusions), higher BMI (improvement in depression severity at 230 minutes and one day post-infusion), negative history of suicide attempt (greater improvement at day 7);– infusion-associated events: greater dissociation during infusion (better antidepressant response at 230 minutes and one week post-infusion); rapid response to first infusion (sustained response to subsequent infusions in one-third responders for up to 83 days);– symptomatology: anxious depression (fewer depression symptoms at day one up to 25 associated with longer time to relapse); neurocognitive performance (lower attention) predicts change in severity of depressive symptoms over six infusions.ConclusionsFindings suggest that specific clinical characteristics are predictors of ketamine response in TRD. Future studies confirming reliable predictors will assist clinicians to implement efficacious and individualized treatment for TRD patients.Disclosure of interestThe authors have not supplied their declaration of competing interest.
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Fraga, A., D. Esteves-Sousa, J. Facucho-Oliveira, M. Albuquerque, M. Costa, P. Espada Dos Santos, N. Moura, and A. Moutinho. "Effects of psilocybin-assisted therapy on treatment-resistant depression." European Psychiatry 64, S1 (April 2021): S693—S694. http://dx.doi.org/10.1192/j.eurpsy.2021.1836.
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Introduction Major depressive disorder is a highly prevalent clinical condition, affecting more than 300 million individuals worldwide. About 1/3 of patients with MDD fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression (TRD). Novel antidepressants with rapid and sustained effects on mood and cognition could represent a breakthrough in the TRD and may potentially improve or save lives. Psilocybin, a classic hallucinogen, more commonly found in the Psilocybe mushrooms has a combined serotonergic and glutamatergic action. The preliminary evidence of antidepressant effects of psilocybin-assisted therapy indicates the potential of psilocybin-assisted therapy as a novel antidepressant intervention.ObjectivesThe authors elaborate a narrative literature review about the effects of Psilocybin-based therapy on patients diagnosed with treatment-resistant depression.MethodsPubMed database searched using the terms “Treatment-Resistant Depression AND Psilocybin” and targeting clinical trials. References of selected articles and review articles were also assessed.Results2 articles evaluate psilocybin effects in 32 patients with TRD and showed that two doses of psilocybin alongside psychological support significantly reduces depressive symptoms. All patients presented some reduction in symptoms from baseline to one week after the second dose and reproduced immediate and substantial improvements in depression that ultimately could sustain up to 6 months.ConclusionsPsilocybin-assisted therapy is a very appealing new possibility in the treatment of depression. However, due to the small populations of the existing trials, future studies are needed to prove this positive association and to fully understand Psilocybin’s mechanisms of actions and effects.DisclosureNo significant relationships.
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Fraga, A., D. Esteves-Sousa, J. Facucho-Oliveira, M. Albuquerque, M. Costa, P. Espada-Santos, and A. Moutinho. "The role of intranasal esketamine in treatment-resistant depression." European Psychiatry 64, S1 (April 2021): S478—S479. http://dx.doi.org/10.1192/j.eurpsy.2021.1278.
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IntroductionMajor depressive disorder (MDD) is a highly prevalent clinical condition with a leading cause of disability worldwide. Unfortunately, about 1/3 of patients with MDD fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression (TRD). Research showed abnormalities in glutamatergic transmission in neural circuits and antidepressant efficacy with the N-methyl-D-aspartate (NMDA) receptor antagonist, ketamine.ObjectivesThe authors elaborate a narrative literature review on the intranasal esketamine as a new-class antidepressant.MethodsPubMed database searched using the terms “treatment-resistant depression” and “esketamine”.ResultsKetamine, synthetized from PCP, acts as an antagonist of NMDA receptor, reducing Central Nervous System excitability. One limitation of ketamine for treating depression is that requires intravenous administration, reducing its applicability in outpatient settings. Esketamine, the S-enantiomer of ketamine, developed as an intranasal formulation has a higher affinity for the NMDA receptor. The evidence of the rapid antidepressant effect of intranasal esketamine was first made by Lapidus et al, that demonstrated intranasal esketamine ability to reduce depressive symptomatology. However, some recent studies reported significant acute cardiovascular, psychotomimetic and neurological side-effects. Thus, drug formulation, delivery device, insufflation technique, and individual factors seem to contribute importantly to the tolerability and efficacy of the intranasal administration rote.ConclusionsThere is the need to develop novel treatments providing effective, more rapid-acting, and sustained relief of depressive symptoms, especially in patients with TRD. Intranasal esketamine has shown antidepressant effects in patients with TRD but further investigation is required to strongly reinforce this potential and safety.
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Jóhannesdóttir, Árný, and Engilbert Sigurðsson. "The use of psilocybin for treatment-resistant depression." Læknablaðið 108, no. 09 (September 8, 2022): 403–10. http://dx.doi.org/10.17992/lbl.2022.09.706.
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The hallucinogen psilocybin is a potential novel treatment for treatment-resistant depression (TRD). Our goal is to review current knowledge on psilocybin and its efficacy in TRD. Literature searches were done on PubMed, Web of Science and Google Scholar, references reviewed in identified articles and other articles found on the website of COMPASS Pathways. Psilocybin treatment consists usually of a single oral administration of 25 mg of psilocybin along with psychological support for 5-8 hours during the ensuing hallucinogenic trip. Common side-effects include headache, nausea, fatigue and insomnia. A systematic review has demonstrated significant antidepressant efficacy in certain groups and a double-blind randomized study found antidepressant efficacy of psilocybin comparable to the SSRI escitalopram. In the phase 2 study of COMPASS Pathways, the psilocybin-COMP360 treatment led to a rapid response and remission as early as three weeks following the treatment for around one third of participants. Recent studies have shown that psilocybin significantly decreases the severity of depressive symptoms and is generally well tolerated. Further research will reveal whether it will be granted a license to treat treatment-resistant depression in the near future. There remains an urgent need for novel treatments for those who do not respond to current antidepressant therapies.
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Cassano, Paolo, Lorenzo Lattanzi, Maurizio Fava, Serena Navari, Giulia Battistini, Marianna Abelli, and Giovanni B. Cassano. "Ropinirole in Treatment-Resistant Depression: A 16-Week Pilot Study." Canadian Journal of Psychiatry 50, no. 6 (May 2005): 357–60. http://dx.doi.org/10.1177/070674370505000612.
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Objective: The study aimed to assess the antidepressant efficacy and tolerability of adjunctive ropinirole in outpatients with treatment-resistant depression (TRD). Method: The study sample consisted of patients with a major depressive episode (diagnosed according to DSM-IV criteria) and TRD. Ropinirole 0.25 to 1.5 mg daily was added to tricyclic antidepressants or selective serotonin reuptake inhibitors. We conducted assessments at baseline and at weeks 2, 4, 8, 12, and 16. We defined response as a 50% or greater reduction of the Montgomery–Asberg Depression Rating Scale (MADRS) total score plus a score of 1 (“very much improved”) or 2 (“much improved”) on the Clinical Global Impression of Improvement scale at endpoint. Tolerability was monitored with the Dosage Record Treatment Emergent Symptom Scale. Results: Seven patients had major depressive disorder, and 3 had bipolar II disorder. The mean maximum dose of ropinirole was 1.33 mg daily. Mean (SD) scores on the MADRS decreased from 29.6 (7.6) at baseline to 16.9 (12.1) at endpoint ( P < 0.02). At endpoint, 4 of 10 (40%) patients were responders. Two patients discontinued ropinirole because of dizziness. Conclusions: These pilot data suggest that, in selected cases of TRD, ropinirole augmentation of antidepressants is effective and relatively well tolerated.
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Ramli, Fitri Fareez, Philip J. Cowen, and Beata R. Godlewska. "The Potential Use of Ebselen in Treatment-Resistant Depression." Pharmaceuticals 15, no. 4 (April 16, 2022): 485. http://dx.doi.org/10.3390/ph15040485.
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Ebselen is an organoselenium compound developed as an antioxidant and subsequently shown to be a glutathione peroxidase (GPx) mimetic. Ebselen shows some efficacy in post-stroke neuroprotection and is currently in trial for the treatment and prevention of hearing loss, Meniere’s Disease and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In vitro screening studies show that ebselen is also an effective inhibitor of the enzyme inositol monophosphatase (IMPase), which is a key target of the mood-stabilising drug lithium. Further, in animal experimental studies, ebselen produces effects on the serotonin system very similar to those of lithium and also decreases behavioural impulsivity. The antidepressant effects of lithium in treatment-resistant depression (TRD) have been attributed to its ability to facilitate presynaptic serotonin activity; this suggests that ebselen might also have a therapeutic role in this condition. Human studies utilising magnetic resonance spectroscopy support the notion that ebselen, at therapeutic doses, inhibits IMPase in the human brain. Moreover, neuropsychological studies support an antidepressant profile for ebselen based on positive effects on emotional processing and reward seeking. Ebselen also lowers a human laboratory measure of impulsivity, a property that has been associated with lithium’s anti-suicidal effects in patients with mood disorders. Current clinical studies are directed towards assessment of the neuropsychological effects of ebselen in TRD patients. It will also be important to ascertain whether ebselen is able to lower impulsivity and suicidal behaviour in clinical populations. The objective of this review is to summarise the developmental history, pre-clinical and clinical psychopharmacological properties of ebselen in psychiatric disorders and its potential application as a treatment for TRD.