Special Populations: Treatment-Resistant Depression in Children and Adolescents.

Major depressive disorder is a substantial public health challenge impacting at least 3 million adolescents annually in the United States. Depressive symptoms do not improve in approximately 30% of adolescents who receive evidence-based treatments. Treatment-resistant depression in adolescents is broadly defined as a depressive disorder that does not respond to a 2-month course of an antidepressant medication at a dose equivalent of 40 mg of fluoxetine daily or 8 to 16 sessions of a cognitive behavioral or interpersonal therapy. This article reviews historical work, recent literature on classification, current evidence-based approaches, and emerging interventional research.

Quantifying the level of difficulty to treat major depressive disorder with antidepressants: Treatment Resistance to Antidepressants Evaluation Scale.

BACKGROUND: The present study aimed to develop a new scale to evaluate the level of difficulty in treating major depressive disorder with antidepressants based on the lifetime treatment profile. METHODS: In addition to evaluating the difficulty of treatment with antidepressants (A subscale), the Treatment Resistance to Antidepressants Evaluation Scale (TRADES) is comprised of a subscale to account for the attributes that compromise the efficacy of treatment (B subscale). One hundred and six participants aged 18 to 65 years with remitted major depressive disorder were enrolled. Eligible cases were those with at least 2 years from disease onset until the scoring date of the TRADES (the index date), with a complete treatment record. Various psychosocial and clinical features, such as neuroticism, harm avoidance, and utilization of psychiatric services, were used to validate the TRADES. RESULTS: The mean duration of the course before and after the index date were 5.5 ± 3.5 and 3.1 ± 1.7 years, respectively. In a multiple regression analysis, the final total scores of the TRADES independently correlated with higher levels of neuroticism and harm avoidance. Total scores were also associated with a higher utilization of psychiatric outpatient and admission services before the index date. Furthermore, it is thought that total scores could predict a higher number of visits to psychiatric outpatient, emergency, and admission services following the index date. CONCLUSIONS: The TRADES has acceptable validity and could help to quantify the level of treatment difficulty with antidepressants in major depressive disorder.

Defining treatment-resistant depression.

BACKGROUND: Varying conceptualizations of treatment-resistant depression (TRD) have made translating research findings or systematic reviews into clinical practice guidelines challenging and inconsistent. METHODS: We conducted a review for the Centers for Medicare & Medicaid Services and the Agency for Healthcare Research and Quality to clarify how experts and investigators have defined TRD and to review systematically how well this definition comports with TRD definitions in clinical trials through July 5, 2019. RESULTS: We found that no consensus definition existed for TRD. The most common TRD definition for major depressive disorder required a minimum of two prior treatment failures and confirmation of prior adequate dose and duration. The most common TRD definition for bipolar disorder required one prior treatment failure. No clear consensus emerged on defining adequacy of either dose or duration. Our systematic review found that only 17% of intervention studies enrolled samples meeting the most frequently specified criteria for TRD. Depressive outcomes and clinical global impressions were commonly measured; functional impairment and quality-of-life tools were rarely used. CONCLUSIONS: Two key steps are critical to advancing TRD research: (a) Developing a consensus definition of TRD that addresses how best to specify the number of prior treatment failures and the adequacy of dose and duration; and (b) identifying a core package of outcome measures that can be applied in a standardized manner. Our recommendations about stronger approaches to designing and conducting TRD research will foster better evidence to translate into clearer guidelines for treating patients with this serious condition.

Association between depression subtypes and response to repeated-dose intravenous ketamine.

OBJECTIVE: About half or more of treatment-resistant depressed patients do not respond to ketamine, and few clinical predictors to gauge the most likely antidepressant response have been proposed. We explored whether depression subtypes are associated with response to ketamine. METHOD: Ninety-seven participants with depression were administered six repeated-dose intravenous ketamine and assessed for depression (Montgomery-Åsberg Depression Rating Scale, MADRS), anxiety (Hamilton Anxiety Rating Scale, HAMA), and suicidal ideation (Beck Scale for Suicidal Ideation, SSI) at baseline, 24 h after each infusion, and 2 weeks after the whole treatment. Participants were classified by melancholic/anxious subtype. Individuals who met criteria for neither or both subtypes were classified separately, resulting in four mutually exclusive groups. RESULTS: Patients with melancholic or melancholic-anxious features were less likely to respond (e.g., day 13, melancholic-anxious vs. anxious, OR 0.138, 95% CI 0.032-0.584, P = 0.007) or remit (e.g., day 26, melancholic vs. no subtype, OR 0.182, 95% CI 0.035-0.960, P = 0.045) and took longer to achieve response/remission than those with anxious or no subtype features. Faster HAMA score reductions were observed in patients with anxious or melancholic-anxious features, and faster SSI score reductions were observed among those with melancholic-anxious features. CONCLUSION: Our study shows promising results for ketamine as a novel antidepressant preferentially for the treatment of non-melancholic or anxious depression.

Subtypes of treatment-resistant depression determined by a latent class analysis in a Chinese clinical population.

BACKGROUND: This study aimed to explore subtypes of treatment-resistant depression (TRD). METHODS: Latent class analysis (LCA) was performed on clinical and demographic data collected from 375 patients with TRD. Clinical variables were compared across subtypes. Treatment outcomes across subtypes of TRD were compared separately for those within each subtype with anxiety (those with a HRSD-17 anxiety/somatization factor score ≥ 7) and those without anxiety. LCA subtypes were compared using Cochran's and Mantel-Haenszel χ2 test, respectively. Unordered multinomial logistic regression was used to assess clinical correlates of TRD subtypes. RESULTS: Three categories were detected: severe depression (66%), moderate depression with anxiety (9%) and mild depression with anxiety/somatization (25%). Gender, age, age at first onset, family monthly income, number of hospitalizations, HRSD-17 and clinical global impression-severity (CGI) scores were significantly different across the three groups. Remission rates were significantly different among anxious cases with severe (43.75%), moderate (22.73%) and mild (26.25%) depression subtypes. Compared to cases in the mild depression group, those in the severe depression group had a greater likelihood of being male, having a later age of first onset, higher numbers of hospitalization, higher HRSD-17 and CGI total scores, and lower family income. Those in the moderate depression group were more likely to be male and have lower family income than those in the mild depression group. LIMITATIONS: Representative bias, relatively small sample size, unbalanced group size and incomplete indicator variables might have a negative effect on the validity and generalization of the findings. CONCLUSIONS: Depression severity could be a basis for subtype classification of patients with TRD. The classification of latent class of TRD observed in our study was similar to the structure found in MDD. Longitudinal research into the stability of the latent structure of TRD across illness course is merited as is research into treatment outcomes for TRD subtypes.

The Impact of (the Concept of) Treatment-Resistant Depression: An Opinion Review.

Treatment-resistant depression refers to major depressive disorder, treatment of the disorder, and failure to obtain an "acceptable" outcome. Regarding the disorder, the heterogeneous concept of major depressive disorder and the multiple definitions of treatment-resistant depression, hesitating between a categorical and a more dimensional approach, as well as the divergence between diagnostic criteria and the items in the assessment scales are a source of confusion. Classifications do not take into account the dramatic influence of patient characteristics strongly impacting outcome, although these can be the cause of so-called pseudo-resistance. Outcome is the result of spontaneous evolution, nonspecific factors (including placebo), and active treatment factors. These should be differentiated to have a reliable estimation of the impact of different treatment modalities before we can asses treatment-resistant depression or before we can ascertain the (non)efficacy of treatments for treatment-resistant depression.The impact and burden of major depressive disorder and treatment-resistant depression are immense and go far beyond their economic cost. It is often forgotten that both are not only associated with increased suicidality but also with nonsuicidal mortality and that both can even result in requests for assisted dying. The caregiver burden and associated stigma are also too often overlooked despite that it has been suggested that they do influence (treatment) outcome.

Incidence of, Risk Factors for, and Changes Over Time in Treatment-Resistant Depression in Denmark: A Register-Based Cohort Study.

OBJECTIVE: Varying definitions of treatment-resistant depression (TRD) across studies make it difficult to estimate the size of the problem and to identify patients at increased risk. The aim of this cohort study was to examine the incidence of TRD, disease-related risk factors, and changes over time using different definitions of TRD. METHODS: From 1996 through 2014, all patients with a first-time hospital contact for depression (ICD-10 codes F32 and F33) were identified in Danish National Patient Registries. A total of 211,689 patients were followed for shifts in antidepressant treatment in the Danish Patient and Prescription Registries. TRD was defined at the second shift in treatment during the first 12 months after diagnosis. The associations of year and type of hospital contact, depression subtype, and severity of TRD were analyzed using Cox proportional hazard regression. RESULTS: A total of 14.0% of patients experienced a second shift in antidepressant treatment during the first year after admission. When applying 3 other common TRD definitions, the proportion varied from 13% to 31%. Psychiatric inpatients and patients with recurrent or severe depression had the highest incidence of TRD. The incidence of TRD was also slightly higher in patients diagnosed after 2001. All associations were replicated when data were reanalyzed using the alternative definitions of TRD. CONCLUSIONS: About 14% of patients with depression developed TRD during the first year after first hospital contact. The incidence was highest in patients with severe depression and was relatively stable over time. Various definitions of TRD provided different estimates of the frequency of TRD but were all associated with disease severity.

[French Society for Biological Psychiatry and Neuropsychopharmacology and Fondation FondaMental task force: Formal Consensus for the management of treatment-resistant depression]. / Prise en charge des troubles dépressifs résistants : recommandations françaises formalisées par des experts de l'AFPBN et de la fondation FondaMental.

Major depression represents among the most frequent psychiatric disorders in the general population with an estimated lifetime prevalence of 16-17%. It is characterized by high levels of comorbidities with other psychiatric conditions or somatic diseases as well as a recurrent or chronic course in 50 to 80% of the cases leading to negative repercussions on the daily functioning, with an impaired quality of life, and to severe direct/indirect costs. Large cohort studies have supported that failure of a first-line antidepressant treatment is observed in more than 60% of patients. In this case, several treatment strategies have been proposed by classical evidence-based guidelines from internationally recognized scientific societies, referring primarily on: I) the switch to another antidepressant of the same or different class; II) the combination with another antidepressant of complementary pharmacological profile; III) the addition of a wide range of pharmacological agents intending to potentiate the therapeutic effects of the ongoing antidepressant medication; IV) the association with appropriate psychological therapies; and, V) the use of non-invasive brain stimulation techniques. However, although based on the most recently available data and rigorous methodology, standard guidelines have the significant disadvantage of not covering a large variety of clinical conditions, while currently observed in everyday clinical practice. From these considerations, formalized recommendations by a large panel of French experts in the management of depressed patients have been developed under the shared sponsorship of the French Association of Biological Psychiatry and Neuropsychopharmacology (AFPBN) and the Fondation FondaMental. These French recommendations are presented in this special issue in order to provide relevant information about the treatment choices to make, depending particularly on the clinical response to previous treatment lines or the complexity of clinical situations (clinical features, specific populations, psychiatric comorbidities, etc.). Thus, the present approach will be especially helpful for the clinicians enabling to substantially facilitate and guide their clinical decision when confronted to difficult-to-treat forms of major depression in the daily clinical practice. This will be expected to significantly improve the poor prognosis of the treatment-resistant depression thereby lowering the clinical, functional and costly impact owing directly to the disease.

Nocturnal motor activity and light exposure: Objective actigraphy-based marks of melancholic and non-melancholic depressive disorder. Brief report.

Differentiation of melancholic (MEL) and non-melancholic (N-MEL) depression results from subjective assessment of psychomotor disturbance, which obscures their accurate diagnosis. CORE instrument assigned participants with severe or refractory depression to MEL or N-MEL group. Participants underwent 7 days of actigraphy. Data was fitted to a cosinusoidal curve corresponding to a 24-h rhythm. Nocturnal activity was significantly higher in N-MEL. ROC curve shows that average night activity discriminate participants with 71% sensitivity and 100% specificity (area under the curve = 0.84). Actigraphy contribute to the objective differentiation of depression subtypes, and have implications for research on their neurobiology and clinical management.

Guidelines for the recognition and management of mixed depression.

A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM-5 codified a new nosological entity, the "mixed features specifier," referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM-IV definition of "mixed states" wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

[Antidepressant-resistant depression and the bipolar spectrum -- diagnostic and therapeutic considerations]. / Antidepresszívum-rezisztens depresszióés a bipoláris spektrum kapcsolata -- diagnosztikaiés terápiás szempontok.

According to the results of epidemiological studies mood disorders with unipolar (major and minor depressive disorder; dysthymia) or bipolar features are among the most prevalent psychiatric disorders. These disorders with their frequent comorbidities (alcohol and/or drug use disorders, smoking, suicide, cardiovascular disorders) pose great public health challenge and cause substantial individual and familar burdens as well. Since SSRIs and other new antidepressant agents entered the market the possibilities to treat depression improved substantially but 25-35 percent of major depressives do not respond even to the second antidepressant trial but the rate of patients who are resistant after the third and fourth adequate antidepressant trial are around only 15-25 and 10 percent, respectively. Pharmacotherapy-resistant depression is a multicausal phenomenon. Along with its well-known risk-factors investigations of the past decade have revealed that unrecognised or hidden (subsyndromal or subthreshold) bipolarity is one of the most frequent causes of treatment resistance. In the case of bipolar depression (either as a part of syndromal bipolar I or II disorder or a subsyndromal manifestation) antidepressant monotherapy should be avoided and, instead of it, the administration of a mood stabilizer (primarily lithium and lamotrigine) or some atypical antipsychotics (preferably quetiapine) are recommended. If antidepressant is inevitably necessary in bipolar depression, we should use it always in combination with mood stabilizers or atypical antipsychotics.

[Treatment-resistant depression: state of the art. Part I. Nosography and clinic]. / Depressione resistente al trattamento: stato dell'arte. Parte I. Nosografia e clinica.

AIMS: This work would give an overall vision of the actual knowledge about nosography and clinic of treatment-resistant depression. METHOD: A PubMed, PsychInfo, Google Scolar search was done using the key words "resistant depression", "STAR*D", "bipolar depression", "staging". Have been selected exclusively works in English, French and Italian languages. RESULTS: Treatment-resistant depression is one of the most important problem in public health. Nevertheless a general consensus about its definition and staging does not exist at now. Principal risk factors and associated comorbidities are well known including the association with bipolar spectrum; anyway the disease particularly common among depressed outpatients is still very disabling, responsible of an often chronic course, with numerous relapses and high risk of suicide. DISCUSSION AND CONCLUSION: The future investigations, once improved procedures for differential diagnosis and subtyping of clinical depression, should be directed to the search of a shared definition of treatment resistance and the development of specific therapeutic protocols.

Defining treatment-resistant depression: a comprehensive review of the literature.

BACKGROUND: Despite the common occurrence and debilitating nature of treatment-resistant depression (TRD), currently there is no universally accepted definition for TRD. This review summarizes the different methods used to define TRD, and provides an overview of the TRD literature. METHODS: PsycInfo, Medline, and Ovid were searched to identify relevant articles published in peer-reviewed journals. A combination and/or variation of the following keywords were searched: treatment resistant, treatment refractory, depression, defining, staging, and modeling. Identified articles provided a description of the methods utilized for defining and/or measuring TRD, prevalence and impact of TRD, risk factors for TRD, and/or factors that contribute to the misclassification of non-TRD patients. RESULTS: Multiple methods for defining/measuring TRD have been proposed; however, variability in these methods has limited the comparability between TRD studies. Although various risk factors for TRD have been suggested, few have been consistently supported. The misclassification of non-TRD patients as having TRD is related to various clinical and treatment-related factors. CONCLUSIONS: Adopting a universal standard definition for TRD is necessary to reduce the variability in how TRD is defined, and the misclassification of non-TRD patients. A universal definition would benefit clinical and research settings by allowing data to be easily compared across these settings.

The mistreatment of major depressive disorder.

OBJECTIVE: To examine the effects of classification on treatment in major depressive disorder (MDD). METHOD: This is a narrative review. RESULTS: MDD is a highly heterogeneous category, leading to problems in classification and in specificity of treatment. Current models classify all depressions within a single category. However, the construct of MDD obscures important differences between severe disorders that require pharmacotherapy, and mild-to-moderate disorders that can respond to psychotherapy or remit spontaneously. Patients with mild-to-moderate MDD are being treated with routine or overly aggressive pharmacotherapy. CONCLUSIONS: The current classification fails to address the heterogeneity of depression, leading to mistreatment.

[Staging of unipolar affective illness]. / Etapy przebiegu choroby afektywnej jednobiegunowej.

In this article, a concept of staging of unipolar affective illness (recurrent depression) is presented. In respective subchapters, three most important aspects of this issue have been discussed: 1) staging of unipolar affective illness; 2) staging of treatment-resistant depression; and 3) conversion of unipolar into bipolar affective illness. The evidence for so called neuroprogression of the illness, accumulated in recent years, has allowed for a classification of staging based on a concept of allostasis and allostatic load. In the course of illness, changes in neuroendocrine system (mainly hypothalamic pituitary-adrenal (HPA) axis), immunological system, mechanisms of oxidative stress, neurotransmitters, neurotrophic factors as well as structural and functional changes of the brain occur. In their paper of 2007, Fava and Tossani elaborated a concept of staging of unipolar affective illness presenting a continuum model of five consecutive stages with specific clinical features. In the present paper, a concept of treatment-resistant depression and staging of treatment resistance is presented in the context of several models. An important determinant of treatment-resistant depression is so called subthreshold bipolarity which is connected with worse efficacy of antidepressant drugs. In the course of illness, there is a possibility of changing diagnosis from recurrent depression into bipolar affective illness. The studies on this issue show that frequency of such diagnostic conversion is 1,5% of depressed patients per year.

Treatment resistance in severe unipolar depression: no association with psychotic or melancholic features.

BACKGROUND: Depressive subtypes generally have been neglected in research on treatment efficacy. We studied a sample of 699 severe unipolar depressed patients to detect any association between depressive features and treatment resistance. METHODS: Participants were divided into psychotic (PSY, n = 90), melancholic (MEL, n = 430) and non-melancholic (n = 179) subjects according to clinical features. Formal diagnostic criteria (Mini International Neuropsychiatric Interview items), and items from 17-item Hamilton Rating Scale for Depression (HRSD17) were compared across groups. Non-responders were defined by a HRSD17 cut-off score of ≥17 after the last adequate antidepressant treatment. Treatment-resistant depression (TRD) was defined as the failure to respond to ≥2 adequate antidepressant trials. Non-linear regression models were designed to detect associations between depressive subtypes and TRD. RESULTS: PSY and MEL patients appeared to be more severely affected and to share some "core" melancholic symptoms. Both PSY and MEL patients reported a higher rate of seasonality. However, we found no clinical or illness course variable associated with TRD. CONCLUSIONS: Our results indicate that psychotic and melancholic depression share some "core" melancholia symptoms, while no distinguishing psychopathological feature appears to be associated with TRD in severely depressed patients.

Bipolar disorder: the shift to overdiagnosis.

Sometimes dramatically changing vogues in diagnostic practice in psychiatry resemble the volatility of international share markets. One such quickly shifting diagnostic area has been that of bipolar disorder (BD). Historically regarded as a relatively uncommon condition until recent decades, the construct of BD underwent a major expansion in the 1990s and 2000s with promulgation of the concept of the soft bipolar spectrum disorder, from which the recent research focus on subthreshold BD presentations was derived. Related to this has been renewed interest in treatments for BD from the pharmaceutical industry. The increasing rates of diagnosis have largely related to BD II, for which there has been a dramatic broadening of diagnostic criteria. This article critically reviews research data, both for broadening the diagnostic criteria for BD and, conversely, for the growing evidence of overdiagnosis in clinical practice. Why does this debate matter? I would suggest that there are many valid reasons to be concerned about overdiagnosis: first, the potential for overtreatment or inappropriate treatment of such patients with mood stabilizing treatments, including antipsychotics; second, the potential for diagnostic oversimplification, with consequent diagnostic deskilling and loss of credibility for the psychiatric profession; and third, the potential major impact on etiologic research for this condition. Psychiatry should not uncritically accept the shift to overdiagnosis, which has developed a rapid momentum in recent decades, in both clinical and academic circles. We must ensure, as a profession, that any change in diagnostic practice is underpinned by rigorous and critical research inquiry.