Antidepressant-resistant Depression Research Articles

Disease progression to bipolar disorder among adolescents and young adults with antidepressant-resistant and antidepressant-responsive depression: Does antidepressant class matter?

Studies have demonstrated a positive relationship between antidepressant resistance and the progression of bipolar disorder. However, the influence of antidepressant classes such as selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) in this context has yet to be investigated. A total of 5,285 adolescents and young adults with antidepressant-resistant depression and 21,140 with antidepressant-responsive depression were recruited in the present study. The antidepressant-resistant depression group was divided into two subgroups: only resistant to SSRIs (n = 2,242, 42.4%) and additionally resistant to non-SSRIs (n = 3,043, 57.6%) groups. The status of bipolar disorder progression was monitored from the date of depression diagnosis to the end of 2011. Patients with antidepressant-resistant depression were more likely to develop bipolar disorder during the follow-up (hazard ratio [HR]: 2.88, 95% confidence interval [CI]: 2.67–3.09) than those with antidepressant-responsive depression. Furthermore, the group that was additionally resistant to non-SSRIs were at the highest risk of bipolar disorder (HR: 3.02, 95% CI: 2.76–3.29), followed by the group that was only resistant to SSRIs (2.70, 2.44–2.98). Adolescents and young adults with antidepressant-resistant depression, especially those who responded poorly to both SSRIs and SNRIs, were at increased risk of subsequent bipolar disorder compared with those with antidepressant-responsive depression. Further studies are warranted to elucidate the molecular pathomechanisms underlying the resistance to SSRIs and SNRIs and subsequent bipolar disorder.

Risk of type 2 diabetes mellitus between adolescents with antidepressant-resistant and antidepressant-responsive depression: A cohort study of 15,651 adolescents

BackgroundWhether response to antidepressants is related to the risk of developing type 2 diabetes mellitus (T2DM) in adolescents with depression remains unknown. MethodsThis study used the Taiwan National Health Insurance Research Database to enroll 1739 adolescents with antidepressant-resistant depression, 6956 with antidepressant-responsive depression, and 6956 controls between 2001 and 2010, with an end-of-2011 follow-up. Physician-diagnosed T2DM was identified at follow-up. T2DM-related risk factors, namely hypertension, dyslipidemia, and obesity, were assessed and controlled for as confounding factors. ResultsAdolescents with antidepressant-resistant depression (hazard ratio [HR], 95 % confidence interval [CI]: 4.62, 2.75–7.75) and those with antidepressant-responsive depression (HR, 95 % CI: 3.06, 1.98–4.72) had a higher risk of developing T2DM at follow-up than did the control group. Those with antidepressant-resistant depression were more likely to receive a diagnosis of T2DM (HR, 95 % CI: 1.51, 1.04–2.19) later in life than were those with antidepressant-responsive depression. DiscussionClinicians should closely monitor factors related to T2DM, such as fasting blood sugar, in high-risk populations, especially in adolescents with antidepressant-resistant depression.

Risk of parental psychiatric disorders among adolescents with major depressive disorder according to response to antidepressant treatment: does the type of antidepressant matter?

The genetic load for major depressive disorder (MDD) may be higher in people who develop MDD earlier in life. This study aimed to investigate whether the parents of adolescents with MDD were more likely to have MDD, bipolar disorder (BD), schizophrenic disorder (SZ), alcohol use disorder, or substance use disorder than the parents of adolescents without MDD. We also examined whether the response to antidepressant treatment predicted the likelihood of parental psychiatric disorders. In all, 1,758 adolescents aged 12-19 years with antidepressant-resistant depression, 7,032 (1:4) age-/sex-matched adolescents with antidepressant-responsive depression and 7,032 (1:4) age-/sex-matched controls were included. Parental psychiatric disorders of individuals enrolled were assessed. The parents of the adolescents with MDD were more likely to be diagnosed with MDD, BD, SZ, alcohol use disorder, or substance use disorder than the parents of the control group. The parents of adolescents who were antidepressant resistant and the mothers of adolescents who were either treatment resistant or treatment responsive were more likely to be diagnosed with a psychiatric disorder. Our study demonstrated that parents of adolescents with MDD may be more likely to be diagnosed with MDD, BD, SZ, alcohol use disorder, or substance use disorder than parents of adolescents without MDD, suggesting the within-disorder transmission and cross-disorder transmission of these psychiatric disorders. Furthermore, the parent's sex and the response to antidepressant treatment may affect the within-disorder transmission of MDD.

Is psilocybin an effective antidepressant and what is its Mechanism of action?

Goodwin etal.1 report a single 25mg dose of psilocybin has an antidepressant effect short-term in medication-resistant depression. Unanswered questions include drug blood level as a guide to dose, psychedelic effects relationship to antidepressant benefit, and potential suicide risk of psilocybin.

The use of esketamine in the treatment of patients with oral antidepressant-resistant depression: systematic review and meta-analysis.

The Guidelines Project, an initiative of the Brazilian Medical Association, aims to combine information from the medical field to standardize how to conduct, and to assist in the reasoning and decision-making of doctors. The information provided by this project must be critically evaluated by the physician responsible for the conduct that will be adopted, depending on the conditions and the clinical condition of each patient. Guideline conclusion: April 2023. Societies: Brazilian Medical Association.

Factors associated with antidepressant responses to repetitive transcranial magnetic stimulation in antidepressant-resistant depression.

A significant proportion of patients with major depressive disorder (MDD) failed to respond to antidepressant medications. Repetitive transcranial magnetic stimulation (rTMS) is an effective option for treating such treatment-resistant patients with MDD (TRD). Reliable clinical predictors for antidepressant responses to rTMS remain elusive. In total, 212 patients with MDD who failed to respond to at least one adequate antidepressant trial and had a detailed evaluation before rTMS were recruited for chart review. Demographic data, clinical characteristics, psychiatric comorbidities, symptom ratings [e.g., objective and subjective depression, life stress, depression refractoriness by Maudsley Staging Method (MSM)], and antidepressant treatment responses were analyzed. MSM-subitem1 (duration of current depressive episode; Beta = 0.209, p = 0.004), MSM-subitem5 (a history of ECT treatment; Beta = -0.210, p = 0.004), and psychiatric admissions (Beta = 0.241, p = 0.001) predicted antidepressant response of rTMS treatment. ECT was underutilized (only 3.3%). Psychiatric admissions [Exp(B) = 1.382, p = 0.021], a comorbidity of OCD [0.047, 0.005], and life stress level [0.984, 0.029] predicted the history of ECT treatment. Several clinical variables (e.g., number of psychiatric admissions, OCD as a comorbidity, and life stress level) were reliable clinical factors associated with antidepressant responses of rTMS treatment and may be utilized in combination with MSM subitems to evaluate levels of TRD.

Worse Outcomes in Patients With Depression Linked to Low Thyroid Hormones

Worse Outcomes in Patients With Depression Linked to Low Thyroid Hormones

Panorama general de la terapia electroconvulsiva: indicaciones y funcionamiento

"The electroconvulsive therapy (ECT) constitutes one of the many treatment modalities available for management of psychiatric illnesses like depression, mania, schizophrenia, and catatonic states. It is even considered the single most effective and fastest treatment modality for patients with conditions like antidepressant-resistant depression, recurring suicidal ideations, acute psychoses, and potentially fatal conditions like malignant neuroleptic syndrome. ECT is a brain-stimulation therapy in which the therapeutic goal can be achieved through generating an electrical stimulus with enough intensity to produce a controlled seizure, achieving a positive and favorable neurobiological and neurochemical response.This article focuses on the use of ECT in treating the various neuropsychiatric conditions, its athophysiological principles, the employed technique, its main complications and overall a description of its use, its efficiency and safety, as to the experience of its employment in our institution. This comprises one of the few articles in Mexico with this kind of content that we deem fundamental as part of the general knowledge for healthcare professionals. Keywords: Electroconvulsive therapy, neuropsychiatry, mental health.

Candidate Strategies for Development of a Rapid-Acting Antidepressant Class That Does Not Result in Neuropsychiatric Adverse Effects: Prevention of Ketamine-Induced Neuropsychiatric Adverse Reactions.

Non-competitive N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonism has been considered to play important roles in the pathophysiology of schizophrenia. In spite of severe neuropsychiatric adverse effects, esketamine (racemic enantiomer of ketamine) has been approved for the treatment of conventional monoaminergic antidepressant-resistant depression. Furthermore, ketamine improves anhedonia, suicidal ideation and bipolar depression, for which conventional monoaminergic antidepressants are not fully effective. Therefore, ketamine has been accepted, with rigorous restrictions, in psychiatry as a new class of antidepressant. Notably, the dosage of ketamine for antidepressive action is comparable to the dose that can generate schizophrenia-like psychotic symptoms. Furthermore, the psychotropic effects of ketamine precede the antidepressant effects. The maintenance of the antidepressive efficacy of ketamine often requires repeated administration; however, repeated ketamine intake leads to abuse and is consistently associated with long-lasting memory-associated deficits. According to the dissociative anaesthetic feature of ketamine, it exerts broad acute influences on cognition/perception. To evaluate the therapeutic validation of ketamine across clinical contexts, including its advantages and disadvantages, psychiatry should systematically assess the safety and efficacy of either short- and long-term ketamine treatments, in terms of both acute and chronic outcomes. Here, we describe the clinical evidence of NMDAR antagonists, and then the temporal mechanisms of schizophrenia-like and antidepressant-like effects of the NMDAR antagonist, ketamine. The underlying pharmacological rodent studies will also be discussed.

Mechanism of Intermittent Theta-Burst Stimulation in Synaptic Pathology in the Prefrontal Cortex in an Antidepressant-Resistant Depression Rat Model.

Intermittent theta-burst stimulation (iTBS), a form of repetitive transcranial magnetic stimulation, is considered a potential therapy for treatment-resistant depression. The synaptic mechanism of iTBS has long been known to be an effective method to induce long-term potentiation (LTP)-like plasticity in humans. However, there is limited evidence as to whether the antidepressant effect of iTBS is associated with change in synaptic function in the prefrontal cortex (PFC) in preclinical study. Hence, we applied an antidepressant (i.e., fluoxetine)-resistant depression rat model induced by severe foot-shocks to investigate the antidepressant efficacy of iTBS in the synaptic pathology. The results showed that iTBS treatment improved not only the impaired LTP, but also the aberrant long-term depression in the PFC of antidepressant-resistant depression model rats. Moreover, the mechanism of LTP improvement by iTBS involved downstream molecules of brain-derived neurotrophic factor, while the mechanism of long-term depression improvement by iTBS involved downstream molecules of proBDNF. The aberrant spine morphology was also improved by iTBS treatment. This study demonstrated that the mechanism of the iTBS paradigm is complex and may regulate not only excitatory but also inhibitory synaptic effects in the PFC.

Brexpiprazole for treatment-resistant major depressive disorder

ABSTRACTIntroduction:Treatment-resistant depression (TRD), seldom interchangeably referred to as ‘depression inadequately responding to the standard antidepressant drug,’ carries a significant burden. The atypical antipsychotics represent a popular augmentation strategy for antidepressant-resistant depression, although their efficacy/safety profiles vary across different agents and presentations of depression.Areas covered: This review appraises the evidence supporting the use of brexpiprazole augmentation for major depressive disorder (MDD) adults showing an inadequate response to standard antidepressants, covering the related regulatory affairs, and essential pharmacology.Expert opinion: Brexpiprazole is a ‘third-generation’ antipsychotic featuring dopaminergic D2 and serotonergic 5-HT1A partial agonism approved by the U.S. Food and Drug Administration for the treatment of MDD, besides schizophrenia in adults. The clinical trials leading to the extended approval of brexpiprazole rely on the definition of ‘inadequate response’ to antidepressants, which seems to poorly represent the most severe cases of TRD seen in clinical practice. TRD definitions appraised in the literature are likewise inconsistent and questionable from a clinical-standpoint. Compared to aripiprazole, brexpiprazole has lower D2 intrinsic activity, although the latter features a more potent serotonergic 5-HT2A antagonism. The actual propensity of brexpiprazole to induce akathisia and tardive dyskinesia warrants assessment by ad-hoc designed long-term, controlled trials.

Antidepressant-resistant depression is characterized by reduced short- and long-interval cortical inhibition.

Major 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. Paired-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. Patients 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. TRD 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.

Ketamine ameliorates severe traumatic event-induced antidepressant-resistant depression in a rat model through ERK activation

Treatment-resistant depression (TRD) is a major public health issue, as it is common for patients with depression to fail to respond to adequate trials of antidepressants. However, a well-established animal model of TRD is still warranted. The present study focused on selective serotonin reuptake inhibitor (SSRI) resistance, and aimed to investigate whether higher levels of traumatic stress caused by greater numbers of foot-shocks may lead to severe depression and to examine the feasibility of this as an animal model of SSRI-resistant depression. To reveal the correlation between traumatic stress and severe depression, rats received 3, 6 and 10 tone (conditioned stimulus, CS)–shock (unconditioned stimulus, US) pairings to mimic mild, moderate, and severe traumatic events, and subsequent depressive-like behaviors and protein immunocontents were analyzed. The antidepressant efficacy was assessed for ketamine and SSRI (i.e., fluoxetine) treatment. We found that only the severe stress group presented depressive-like behaviors. Phosphorylation of extracellular signal-regulated kinases (ERKs) was decreased in the amygdala and prefrontal cortex (PFC). The immunocontents of GluA1 and PSD 95 were increased in the amygdala and decreased in the PFC. Moreover, the glutamate-related abnormalities in the amygdala and PFC were normalized by single-dose (10 mg/kg, i.p.) ketamine treatment. In contrast, the depressive-like behaviors were not reversed by 28 days of fluoxetine treatment (10 mg/kg, i.p.) in the severe stress group. Our data demonstrated that high levels of traumatic stress could lead to SSRI-resistant depressive symptoms through impacts on the glutamatergic system, and that this rat model has the potential to be a feasible animal model of SSRI-resistant depression.

Correction: Smartphone Cognitive Behavioral Therapy as an Adjunct to Pharmacotherapy for Refractory Depression: Randomized Controlled Trial.

[This corrects the article DOI: 10.2196/jmir.8602.].

Repeated Low-Grade Infections Predict Antidepressant-Resistant Depression: A Nationwide Population-Based Cohort Study.

The relationship between severe inflammation and clinical depression in the context of major medical illnesses has been addressed, but the relationship between inflammation caused by mild infections and clinical depression is unclear. We aimed to examine whether a history of repeated low-grade infections (RLGI) in medically healthy subjects (MHS) could increase their vulnerability to major depressive disorder (MDD) (ICD-9-CM) and whether RLGI could be associated with higher resistance to antidepressants in those developing MDD. A nationwide, population-based cohort study (January 1996 to December 2011) was conducted for MHS with and without a history of RLGI. The rates of MDD during an up to 8-year follow-up period were compared between the 2 groups in 2 independent cohorts. The stratified responses to adequate antidepressant trials, including easy-to-treat (ETT) and difficult-to-treat (DTT) responses, were also compared in the MDD patients. During the follow-up, the 2 cohorts consistently revealed that the RLGI(+) (ie, high-inflammation; n = 727) group had a significantly higher chance of developing MDD over time than the RLGI(-) (ie, low-inflammation; n = 443) group: Cox proportional hazards regression models showed that the hazard ratio associated with a history of RLGI was 1.369 to 1.911 (P < .001), after adjusting for confounding factors. The RLGI(+) group was consistently associated with a higher likelihood of DTT responses than was the RLGI(-) group (Cohort-2002: 11.5% vs 7.6%; Cohort-2004: 11.8% vs 4.3%; P < .05 by Wald χ² tests in both cohorts). This is the first large-scale retrospective cohort study to report a reliable temporal association between a history of RLGI and subsequent diagnosis of MDD and poor responses to antidepressants in 2 independent cohorts. Our data support the view that repeated mild infections play a role in the pathophysiology of MDD and antidepressant-resistant depression.

Smartphone Cognitive Behavioral Therapy as an Adjunct to Pharmacotherapy for Refractory Depression: Randomized Controlled Trial.

BackgroundIn the treatment of major depression, antidepressants are effective but not curative. Cognitive behavioral therapy (CBT) is also effective, alone or in combination with pharmacotherapy, but accessibility is a problem.ObjectiveThe aim is to evaluate the effectiveness of a smartphone CBT app as adjunctive therapy among patients with antidepressant-resistant major depression.MethodsA multisite, assessor-masked, parallel-group randomized controlled trial was conducted in 20 psychiatric clinics and hospitals in Japan. Participants were eligible if they had a primary diagnosis of major depression and were antidepressant-refractory after taking one or more antidepressants at an adequate dosage for four or more weeks. After a 1-week run-in in which participants started the medication switch and had access to the welcome session of the app, patients were randomized to medication switch alone or to medication switch plus smartphone CBT app via the centralized Web system. The smartphone app, called Kokoro-app (“kokoro” means “mind” in Japanese), included sessions on self-monitoring, behavioral activation, and cognitive restructuring presented by cartoon characters. The primary outcome was depression severity as assessed by masked telephone assessors with the Patient Health Questionnaire-9 (PHQ-9) at week 9. The secondary outcomes included the Beck Depression Inventory-II (BDI-II) and Frequency, Intensity, and Burden of Side Effects Ratings (FIBSER).ResultsIn the total sample (N=164), 81 participants were allocated to the smartphone CBT in addition to medication change and 83 to medication change alone. In the former group, all but one participant (80/81, 99%) completed at least half, and 71 (88%) completed at least six of eight sessions. In the intention-to-treat analysis, patients allocated the CBT app scored 2.48 points (95% CI 1.23-3.72, P<.001; standardized mean difference 0.40) lower on PHQ-9 than the control at week 9. The former group also scored 4.1 points (95% CI 1.5-6.6, P=.002) lower on BDI-II and 0.76 points (95% CI –0.05 to 1.58, P=.07) lower on FIBSER. In the per-protocol sample (comfortable with the smartphone app, still symptomatic, and adherent to medication with mild or less side effects after run-in), the intervention group (n=60) scored 1.72 points (95% CI 0.25-3.18, P=.02) lower on PHQ-9, 3.2 points (95% CI –0.01 to 6.3, P=.05) lower on BDI-II, and 0.75 points (95% CI 0.03-1.47, P=.04) lower on FIBSER than the control (n=57). The treatment benefits were maintained up to week 17.ConclusionsThis is the first study to demonstrate the effectiveness of a smartphone CBT in the treatment of clinically diagnosed depression. Given the merits of the mobile mental health intervention, including accessibility, affordability, quality control, and effectiveness, it is clinically worthwhile to consider adjunctive use of a smartphone CBT app when treating patients with antidepressant-resistant depression. Research into its effectiveness in wider clinical contexts is warranted.Trial RegistrationJapanese Clinical Trials Registry UMIN CTR 000013693; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ ctr_view.cgi?recptno=R000015984 (Archived by WebCite at http://www.webcitation.org/6u6pxVwik)

PS93. Repeated Low-Grade Inflammation Increases the Risk of Antidepressant-Resistant Depression: A Nationwide Population-Based Cohort Study

PS93. Repeated Low-Grade Inflammation Increases the Risk of Antidepressant-Resistant Depression: A Nationwide Population-Based Cohort Study

Personality traits as predictors for the outcome of lithium augmentation in treatment-resistant depression

The NEO Personality Inventory-Revised (NEO) and the Temperament and Character Inventory (TCI) were administered to patients with treatment-resistant depression (n=21) before lithium augmentation. Analysis showed that the poor outcome group (n=11) had lower openness scores on the NEO, and lower cooperativeness scores on the TCI compared with the good outcome group (n=10). These findings may be predictors of poor responsiveness to lithium augmentation in the treatment of antidepressant-resistant depression.

Antidepressant augmentation with anti-inflammatory agents.

Antidepressant augmentation strategies are commonly employed to treat depressed patients who do not respond to antidepressant monotherapy. Neuroinflammatory mechanisms have been implicated in depression, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been found effective in animal models of depression both in monotherapy and when used to augment antidepressant drugs. However, results with NSAIDs have been mixed in human observational studies, with both better and worse depression outcomes reported. Four small (pooled N = 160) randomized controlled trials suggest that celecoxib (200-400 mg/d) augmentation of antidepressant medication improves 4-6 week outcomes in major depressive disorder. There are no data, however, to support the use of celecoxib or other NSAIDs in antidepressant-resistant depression. There are also concerns about adverse events associated with NSAID treatment, and about pharmacodynamic drug interactions between these drugs and serotonin reuptake inhibitors. A reasonable conclusion for the present is that NSAID augmentation of antidepressants is, at best, a tentative approach in nonrefractory major depression.

Combined treatment with atypical antipsychotics and antidepressants in treatment-resistant depression: preclinical and clinical efficacy

Several clinical reports have documented a beneficial effect of adding atypical antipsychotic drugs to ongoing treatments with antidepressants, particularly selective serotonin reuptake inhibitors, in ameliorating drug-resistant depression. The aim of this paper was to summarize some preclinical evidence describing the mechanism responsible for the therapeutic action of combined treatment with antidepressants and atypical antipsychotics and also some clinical data supporting the efficacy and safety of the augmentation strategy for improving antidepressant-resistant depression using atypical antipsychotics. This analysis is based on five microdialysis studies and nine behavioral studies assessing the impact of combined atypical antipsychotic and antidepressant treatments on extracellular levels of dopamine, serotonin and noradrenaline in the prefrontal cortex of freely moving rats and on antidepressant-induced effects, respectively. In addition, clinical data demonstrating the efficacy and safety of augmentation strategies for treatmentresistant depression using atypical antipsychotics were included. Combined treatment of rats with all studied atypical antipsychotics (olanzapine, risperidone, clozapine and quetiapine) and antidepressants (citalopram, fluoxetine and fluvoxamine) increased the extracellular level of dopamine in the prefrontal cortex compared to a respective drug given alone; in addition, a combination of olanzapine or quetiapine plus fluoxetine or fluvoxamine increased the levels of dopamine and noradrenaline. Moreover, atypical antipsychotics administered in a low dose enhanced the antidepressant-like activity of antidepressants, with (among other mechanisms) the serotonin 5-HT1A, 5-HT2A and adrenergic a2 receptors likely playing an important role in their action. The results support the conclusion that atypical antipsychotics may be effective as adjunctive therapy in treatment-resistant depression; however, their adverse effect profile may be unfavorable in some patients.