Adequate Antidepressant Trials Research Articles

A genetic risk score to predict treatment nonresponse in psychotic depression

Psychotic depression is a severe and difficult-to-treat subtype of major depressive disorder for which higher rates of treatment-resistant depression were found. Studies have been performed aiming to predict treatment-resistant depression or treatment nonresponse. However, most of these studies excluded patients with psychotic depression. We created a genetic risk score (GRS) based on a large treatment-resistant depression genome-wide association study. We tested whether this GRS was associated with nonresponse, nonremission and the number of prior adequate antidepressant trials in patients with a psychotic depression. Using data from a randomized clinical trial with patients with a psychotic depression (n = 122), we created GRS deciles and calculated positive prediction values (PPV), negative predictive values (NPV) and odds ratios (OR). Nonresponse and nonremission were assessed after 7 weeks of treatment with venlafaxine, imipramine or venlafaxine plus quetiapine. The GRS was negatively correlated with treatment response (r = −0.32, p = 0.0023, n = 88) and remission (r = −0.31, p = 0.0037, n = 88), but was not correlated with the number of prior adequate antidepressant trials. For patients with a GRS in the top 10%, we observed a PPV of 100%, a NPV of 73.7% and an OR of 52.4 (p = 0.00072, n = 88) for nonresponse. For nonremission, a PPV of 100%, a NPV of 51.9% and an OR of 21.3 (p = 0.036, n = 88) was observed for patients with a GRS in the top 10%. Overall, an increased risk for nonresponse and nonremission was seen in patients with GRSs in the top 40%. Our results suggest that a treatment-resistant depression GRS is predictive of treatment nonresponse and nonremission in psychotic depression.

The longer, the better ? Longer left-sided prolonged intermittent theta burst stimulation in patients with major depressive disorder: A randomized sham-controlled study.

Prolonged intermittent theta-burst stimulation (iTBS) is effective for major depressive disorder (MDD). However, whether longer piTBS treatment in a single session could have antidepressant efficacy remains elusive. Therefore, this double-blind, randomized, sham-controlled study aimed to investigate the antidepressant efficacy of 2 daily piTBS sessions for treating MDD patients with a history of poor responses to at least 1 adequate antidepressant trial in the current episode. All patients received 2 uninterrupted sessions per day for 10 weekdays (i.e., 2 weeks; a total of 20 sessions). Seventy-two patients were recruited and 1:1:1 randomly assigned to one of three groups: piTBS (piTBSx2), 10-Hz rTMS (rTMSx2), or sham treatment (shamx2, randomly assigned to piTBS or rTMS). 10-Hz rTMS group was included as an active comparison group to enhance assay sensitivity. piTBSx2 group had significantly more responders at week 2 than shamx2 group, but it did not yield better antidepressant effects regarding the %depression changes. The changes of antidepressant scores were not different among the three groups at week 1 (-26.2% vs. -23.3% vs. -22.%) or at week 2 (-34.1% vs. -37.1% vs. -30.1%). Longer treatment duration did not result in stronger placebo effects [sham(piTBS)x2: -31.7% vs. sham(rTMS)x2: -26.7%]. The present sham-controlled study confirmed that piTBS is an effective antidepressant option, but found no evidence to support that longer piTBS treatment duration resulted in more rapid or better antidepressant effects. A high placebo effect was observed, but longer treatment duration of brain stimulation was not linearly associated with stronger placebo effects.

Effect of Adjunctive Simvastatin on Depressive Symptoms Among Adults With Treatment-Resistant Depression

Immune-metabolic disturbances have been implicated in the pathophysiology of major depressive disorder and may be more prominent in individuals with treatment-resistant depression (TRD). Preliminary trials suggest that lipid-lowering agents, including statins, may be useful adjunctive treatments for major depressive disorder. However, no adequately powered clinical trials have assessed the antidepressant efficacy of these agents in TRD. To assess the efficacy and tolerability of adjunctive simvastatin compared with placebo for reduction of depressive symptoms in TRD. This 12-week, double-blind, placebo-controlled randomized clinical trial was conducted in 5 centers in Pakistan. The study involved adults (aged 18-75 years) with a Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) major depressive episode that had failed to respond to at least 2 adequate trials of antidepressants. Participants were enrolled between March 1, 2019, and February 28, 2021; statistical analysis was performed from February 1 to June 15, 2022, using mixed models. Participants were randomized to receive standard care plus 20 mg/d of simvastatin or placebo. The primary outcome was the difference between the 2 groups in change in Montgomery-Åsberg Depression Rating Scale total scores at week 12. Secondary outcomes included changes in scores on the 24-item Hamilton Rating Scale for Depression, the Clinical Global Impression scale, and the 7-item Generalized Anxiety Disorder scale and change in body mass index from baseline to week 12. C-reactive protein and plasma lipids were measured at baseline and week 12. A total of 150 participants were randomized to simvastatin (n = 77; median [IQR] age, 40 [30-45] years; 43 [56%] female) or placebo (n = 73; median [IQR] age, 35 [31-41] years; 40 [55%] female). A significant baseline to end point reduction in Montgomery-Åsberg Depression Rating Scale total score was observed in both groups and did not differ significantly between groups (estimated mean difference for simvastatin vs placebo, -0.61; 95% CI, -3.69 to 2.46; P = .70). Similarly, there were no significant group differences in any of the secondary outcomes or evidence for differences in adverse effects between groups. A planned secondary analysis indicated that changes in plasma C-reactive protein and lipids from baseline to end point did not mediate response to simvastatin. In this randomized clinical trial, simvastatin provided no additional therapeutic benefit for depressive symptoms in TRD compared with standard care. ClinicalTrials.gov Identifier: NCT03435744.

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.

Effect of priming on adjunctive repetitive transcranial magnetic stimulation in treatment of late life depression: Protocol of a prospective randomized sham-controlled study.

AbstractObjectivePriming stimulation, which involves high-frequency repetitive transcranial magnetic stimulation (rTMS) followed by low-frequency, has been shown to enhance neural response and is one of the novel paradigms found beneficial in adult patients with depression and has not been studied in late-life depression (LLD). This study aims to compare the effect of adjunctive priming vis-a-vis no priming rTMS over right dorso-lateral prefrontal cortex (DLPFC), on treatment of LLD.MethodsThis trial is registered in Clinical Trial Registry-India (CTRI) on www.ctri.nic.in. CTRI registration number: CTRI/2020/08/027230. Forty patients of LLD who are symptomatic after an adequate antidepressant trial will be randomized into 2 groups (active priming and sham priming rTMS); each receiving 10 sessions of rTMS over 2 weeks. Patients will remain blind to treatment allocation. Assessments will be done using Hamilton rating scale for depression, Geriatric Depression Scale, Hamilton rating scale for Anxiety, Somatic Symptom Severity Scale 8, Hindi Mental Status Examination, and Clinical Global Impression scale at baseline, week 1, 2, and 4. Side effect checklist will be applied after each session in both groups and at the end of 4 weeks.ResultData will be analyzed using statistical software Statistical Package for Social Sciences. Both the groups (active and sham groups) will be compared at the four given timepoints. Also, the baseline characteristics will be compared with the 3 follow-up points for any change.ConclusionThe findings of the study will give an insight to the possible role of priming to augment the effect of low-frequency rTMS in LLD.

Tolerability and Safety of Transcranial Photobiomodulation for Mood and Anxiety Disorders

Introduction: Mood and anxiety disorders are a prevalent and significant leading cause of years lived with a disability worldwide. Existing antidepressants drugs are only partially effective, having burdensome side effects. One-third of patients do not achieve remission after several adequate antidepressant trials, and relapses of depression are frequent. Psychotherapies for depression are limited by the lack of trained professionals, and further by out-of-pocket prohibitive costs. Existing FDA-approved, device-based interventions are either invasive or only administered in the office. Transcranial photobiomodulation (t-PBM) with near-infrared (NIR) light may be a promising treatment option for mood and anxiety disorders. Due to its low cost, and ease of self-administration, t-PBM has the potential to become widely accessible. The safety profile of t-PBM is a relevant factor for widespread use and administration. Aim: To further investigate the t-PBM safety profile, this study aims to evaluate the tolerability and safety of t-PBM for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD). Method: We completed a systematic analysis of the side effects from repeated sessions of t-PBM in three studies: an open-label study for GAD (LIGHTEN GAD) and two randomized control studies for MDD (ELATED-2; ELATED-3). Overall, 80 subjects were studied. Result: Our results show that a low dose of NIR per t-PBM session can be administered with increasing frequency (up to daily sessions) and for several weeks (up to 12 weeks) without a corresponding increase in the occurrence or severity of adverse events. Additionally, there were no significant predictors for the variance in the number of reported adverse events (such as age, sex or diagnosis). Conclusion: The literature indicates that higher dosages of transcranial NIR could lead to greater antidepressant and anxiolytic effects; this study did not find any correlation between the increasing number of t-PBM sessions and the occurrence of adverse events.

Efficacy and acceptability of next step treatment strategies in adults with treatment-resistant major depressive disorder: protocol for systematic review and network meta-analysis

IntroductionFor major depression, a one-size-fits-all treatment does not exist. Patients enter a ‘trial-and-change’ algorithm in which effective therapies are subsequently applied. Unfortunately, an empirically based order of treatments has not...

The Neglected Role of Psychotherapy for Treatment-Resistant Depression.

The Neglected Role of Psychotherapy for Treatment-Resistant Depression.

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BACKGROUNDThe association between testosterone and depression is extensively debated1. Testosterone being a neuro-active steroid hormone, is responsible for growth and development of male primary sexual organs2, musculoskeletal system and influencing mood and appetitive behaviour1. Several lines of research have examined the potential role of testosterone therapy in alleviating depressive symptoms1. Thus, considering hypo-testosteronism as a differential diagnosis of depressive disorders in males or testosterone supplementation in such cases as treatment for depression is important but not commonly practiced.CASE SERIESIn this case series, we describe two male patients with young onset depression, who did not respond to adequate trials of multiple antidepressants, were evaluated independently elsewhere by endocrinologist,and detected to have low levels of testosterone. The depressive symptoms improved with initiation of testosterone supplementation in both the cases.DISCUSSION & CONCLUSIONThis case series provides insight into this clinical phenomenon where low testosterone may be associated with depressive mood symptoms, thus testosterone supplementation being imperative in such cases. Testosterone causes increased serotonin release in the dorsal raphe nuclei and facilitates general and antidepressant-induced neuroplasticity in the hippocampal formation, which can be considered as central mechanisms of action against depression1. The beneficial role of testosterone use may thus be independent of hypogonal state as well.However, further studies are needed to ascertain the utility of initiating testosterone use in certain patient groups and develop guidelines to assess for hypo-testosteronism in young males with treatment resistant depression.Reference1. Walther A, Breidenstein J, Miller R. Association of testosterone treatment with alleviation of depressive symptoms in men: a systematic review and meta-analysis. JAMA psychiatry. 2019 Jan 1;76(1):31-40.2. Ravan JP, Pattnaik JI, Nath S, Kumar S. Intervention Strategy for Amennorhoea, Galactorrhoea, osteopenia and Sexual dysfunction caused by Antipsychotic induced Hyperprolactinemia. In indian journal of psychiatry 2019 jan 1 (vol. 61, no. 9, pp. S443-s443). Wolters kluwer india pvt ltd, a-202, 2nd flr, qube, cts no 1498a-2 village marol, andheri east, mumbai, 400059, india: wolters kluwer medknow publications.

Electroconvulsive therapy in treatment resistant depression

Electroconvulsive therapy (ECT) is a treatment modality for patients with treatment resistant depression (TRD), defined as failure of two adequate antidepressant medication trials. We provide a qualitative review of ECT's effectiveness for TRD, methods to optimize ECT parameters to improve remission rates and side effect profiles, and ECT's proposed neurobiological mechanisms. Right unilateral (RUL) electrode placement has been shown to be as effective for major depression as bilateral ECT, and RUL is associated with fewer cognitive side effects. There is mixed evidence on how to utilize ECT to sustain remission (i.e., continuation ECT, psychotropic medications alone, or a combination of ECT and psychotropic medications). Related to neurobiological mechanisms, an increase in gray matter volume in the hippocampus-amygdala complex is reported post-ECT. High connectivity between the subgenual anterior cingulate and the middle temporal gyrus before ECT is associated with better treatment response. Rodent models have implicated changes in neurotransmitters including glutamate, GABA, serotonin, and dopamine in ECT's efficacy; however, findings in humans are limited. Altogether, while ECT remains a highly effective therapy, the neurobiological underpinnings associated with improvement of depression remain uncertain.

Current Updates on Newer Forms of Transcranial Magnetic Stimulation in Major Depression.

Repetitive transcranial magnetic stimulation (rTMS) is an FDA-approved technique for treating medication-resistant depression. Conventional rTMS includes high frequency (HF) to left dorsolateral prefrontal cortex (DLPFC) and low frequency to right DLPFC. However, not all depressed patients could benefit from standard rTMS protocols. Meta-analytical evidence indicated that there was an average response rate of 29.3% for patients receiving the most commonly adopted HF rTMS to the left DLPFC. Hence, newer forms of rTMS paradigms are warranted to improve antidepressant response and remission rate in patients with depression, especially those who are refractory to adequate antidepressant trials. In the current chapter, we review newer forms of rTMS paradigms and the content will cover standard theta burst stimulation (TBS), prolonged iTBS (piTBS), accelerated rTMS (aTMS), deep TMS (dTMS), priming TMS (pTMS), synchronized TMS (sTMS), and magnetic seizure therapy (MST).

Management of Treatment-Resistant Depression in Real-World Clinical Practice Settings Across Asia.

PurposeConsensus is lacking on the management of treatment-resistant depression (TRD), resulting in significant variations on how TRD patients are being managed in real-world practice. A survey explored how clinicians managed TRD across Asia, followed by an expert panel that interpreted the survey results and provided recommendations on how TRD could be managed in real-world clinical settings.MethodsBetween March and July 2018, 246 clinicians from Hong Kong, Japan, Mainland China, South Korea, and Taiwan completed a survey related to their treatment approaches for TRD.ResultsThe survey showed physicians using more polytherapy (71%) compared to maintaining patients on monotherapy (29%). The most commonly (23%) administered polytherapy involved antidepressant augmentation with antipsychotics that 19% of physicians also indicated as their most important approach for managing TRD. The highest number of physicians (34%) ranked switching to another class of antidepressants as their most important approach, while 16% and 9% chose antidepressant combinations and electroconvulsive therapy (ECT), respectively.ConclusionTaking into account the survey results, the expert panel made general recommendations on the management of TRD. TRD partial-responders to antidepressants should be considered for augmentation with second-generation antipsychotics. For non-responders, switching to another class of antidepressants ought to be considered. TRD patients achieving remission with acute treatment should consider continuing their antidepressants for at least another 6 months to prevent relapse. ECT is a treatment consideration for patients with severe depression or persistent symptoms despite multiple adequate trials of antidepressants. Physicians should also consider the response, tolerability and adherence to the current and previous antidepressants, the severity of symptoms, comorbidities, concomitant medications, preferences, and cost when choosing a TRD treatment approach for each individual patient.

109 - Novel Treatments for Resistant Depression: Comparison of Older and Younger Patients

Treatment resistant depression (TRD) is defined as the failure to respond to two adequate antidepressant trials. TRD patients have high levels of psychosocial distress, poor levels of functioning and are at increased risk for suicide. Novel treatment approaches are being developed to address TRD involving both pharmacological and neuromodulation interventions. In this symposium, leaders in the field will outline three strategies for treating depression which has not responded to conventional therapy and contrast the efficacy of these strategies in younger vs. older patients. William McDonald MD (JB Fuqua Professor of Late -Life Depression, Emory University, Atlanta, GA) will provide a brief overview of TRD and moderate the discussion. George Petrides MD (Director of Clinical Trials Operation and Division of ECT, Zucker Hillside Hospital, New York, NY) will discuss recent data from the National Institute of Mental Health sponsored Consortium on ECT Research (CORE) outlining the response of older patients to ultrabrief right unilateral ECT in TRD. He will contrast the response to ECT in older vs, younger patients from the CORE database accumulated over the last 15 years. Collin Reiff MD (Addiction Psychiatrist, New York University Langone Health Center, NY, NY) will discuss his recent review in the American Journal of Psychiatry on Psychedelic and Psychedelic Assisted Psychotherapy and the implications on the treatment of medication resistant depression, including late life mood disorders. The FDA’s breakthrough designation of MDMA for the treatment of PTSD and psilocybin for the treatment of depression reflects the drugs’ potential to treat resistant psychiatric disorders. Psychedelic assisted therapy may play a unique role in late life mood disorders. Finally, Patricio Riva Posse MD (Director of the TRD and Ketamine Clinic, Emory University, Atlanta, GA) will discuss ketamine treatment in resistant depression including a comparison of response rates and safety data on ketamine treatment in older vs. younger patients. He has recently published the largest compilation of safety data for ketamine infusions and he will review a new tool to monitor safety in clinical practice. Dr. Riva Posse is medical director of the Emory TRD program and has enrolled over 1000 patients (100 in his IV ketamine clinic and about half over the age of 60 years) and followed patients through several novel treatments including transcranial magnetic stimulation, ketamine infusion therapy and ECT to start to look at differential response rates.

Treatment-Resistant depression enhances risks of dementia and alzheimer's disease: A nationwide longitudinal study

BackgroundPrevious evidence indicates late-onset depression or depression with greater severity are associated with subsequent risk of dementia or Alzheimer's disease (AD). However, whether treatment-resistant depression is associated with such risks remain elusive. MethodsUsing the Taiwan Nationwide Health Insurance Research Database, 3,345 patients with newly-diagnosed major depressive disorder (MDD) and 13,380 well-matched controls were enrolled between 2002 and 2004. MDD patients were stratified according to their treatment response to adequate antidepressant trials, and all participants were followed up until the end of 2013. Those who developed dementia and AD were identified. ResultsMDD patients were more likely to develop dementia and AD than controls. Difficult-to-treat patients (i.e., DTT; those who failed to respond to at least two adequate antidepressant trials) had the highest risk of developing dementia (hazard ratio [HR] = 5.19) and AD (HR 4.44), whereas easy-to-treat patients (i.e., ETT-1; those who had no prescription of antidepressants) had the lowest risk of developing dementia (HR 2.37) and AD (HR 2.59) compared with controls. Subsequent analysis demonstrated that only among patients with late-onset depression (age > 65 years), DTT patients consistently showed higher risks and faster development of dementia (HR 6.64, mean: 1.45 yr) and AD (HR 4.97, mean: 1.67 yr) than did ETT-1 patients and controls. LimitationsSubjects who have not received medical examination were not included as diagnosis were determined by ICD codes. Also, longer follow-up period might be needed for the younger group. ConclusionsLate-onset treatment-resistant depression is associated with an elevated risk of dementia and AD.

Predicting Remission in Late-Life Major Depression: A Clinical Algorithm Based Upon Past Treatment History.

To determine the likelihood of antidepressant response in older adults with major depression as a function of their prior antidepressant trials. 500 older adults with major depression as diagnosed by DSM-IV criteria for major depressive episode were treated with venlafaxine extended release for 12 weeks. Participants were recruited from July 2009 to January 2014. For each participant, we collected detailed data on prior antidepressant trials for the current episode of depression. We examined the prospective remission rates as a function of number and class of prior antidepressant trials in a post hoc analysis of pooled data from 2 prior trials. Remission rates with venlafaxine were inversely correlated with the number of prior adequate medication trials (66% for no prior adequate trials, 45% for 1 prior adequate trial, 23% for 2 or more prior adequate trials; P < .0001). Additionally, if prior treatment trials included a serotonin-norepinephrine reuptake inhibitor, participants were even less likely to achieve remission with venlafaxine (32% for 1 prior adequate trial, 18% for 2 or more prior adequate trials; P < .0001). Those with prior adequate trials were also more likely to require a higher dosage of venlafaxine to achieve remission. Information on an individual patient's number and class of prior adequate antidepressant trials can be used to predict the likelihood of a successful treatment outcome with a given antidepressant in older adults with major depression. Further work is needed to refine this approach to provide personalized antidepressant treatment. ClinicalTrials.gov identifiers: NCT00892047 and NCT02263248.

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.

Trajectories of Response to Dorsolateral Prefrontal rTMS in Major Depression: A THREE-D Study.

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for refractory major depressive disorder, yet no studies have characterized trajectories of rTMS response. The aim of this study was to characterize response trajectories for patients with major depression undergoing left dorsolateral prefrontal cortex rTMS and to determine associated baseline clinical characteristics. This was a secondary analysis of a randomized noninferiority trial (N=388) comparing conventional 10-Hz rTMS and intermittent theta burst stimulation (iTBS) rTMS. Participants were adult outpatients who had a primary diagnosis of major depressive disorder, had a score ≥18 on the 17-item Hamilton Depression Rating Scale (HAM-D), and did not respond to one to three adequate antidepressant trials. Treatment was either conventional 10-Hz rTMS or iTBS rTMS applied to the dorsolateral prefrontal cortex, 5 days/week over 4-6 weeks (20-30 sessions). Group-based trajectory modeling was applied to identify HAM-D response trajectories, and regression techniques were used to identify associated characteristics. Four trajectories were identified: nonresponse (N=43, 11%); rapid response (N=73, 19%); higher baseline symptoms, linear response (N=118, 30%); and lower baseline symptoms, linear response (N=154, 40%). Significant differences in response and remission rates between trajectories were detectable by week 1. There was no association between treatment protocol and response trajectory. Higher baseline scores on the HAM-D and the Quick Inventory of Depression Symptomatology-Self-Report (QIDS-SR) were associated with the nonresponse trajectory, and older age, lower QIDS-SR score, and lack of benzodiazepine use were associated with the rapid response trajectory. Major depression shows distinct response trajectories to rTMS, which are associated with baseline clinical characteristics but not treatment protocol. These response trajectories with differential response to rTMS raise the possibility of developing individualized treatment protocols.

A review of ketamine's role in ECT and non-ECT settings.

Up to 20% of depressed patients demonstrate treatment resistance to one or more adequate antidepressant trials, resulting in a disproportionately high burden of illness. Ketamine is a non-barbiturate, rapid-acting general anesthetic that has been increasingly studied in treatment resistant depression (TRD), typically at sub-anesthetic doses (0.5 mg/kg over 40 min by intravenous infusion). More recent data suggest that ketamine may improve response rates to electroconvulsive therapy (ECT) when used as an adjunct, but also as a sole agent. In the ECT setting, a dose of 0.8 mg/kg or greater of ketamine demonstrates improved reduction in depressive symptoms than lower doses; however, inconsistency and significant heterogeneity among studies exists. Clinical predictors of responses to ketamine have been suggested in terms of non-ECT settings. Ketamine does increase seizure duration in ECT, which is attenuated when concomitant barbiturate anesthetics are used. However, most studies are small, with considerable heterogeneity of the sample population and variance in dosing strategies of ketamine, ECT, and concomitant medications, and lack a placebo control, which limits interpretation. Psychotomimetic and cardiovascular adverse effects are reported with ketamine. Cardiovascular adverse effects are particularly relevant when ketamine is used in an ECT setting. Adverse effects may be mitigated with concurrent propofol; however, this adds complexity and cost compared to standard anesthesia. Long-term adverse effects are still unknown, but relevant, given recent class concerns for anesthetic and sedative agents.

Antidepressant treatment resistance is associated with increased inflammatory markers in patients with major depressive disorder

BackgroundOne third of patients with major depressive disorder (MDD) fail to respond to currently available antidepressant medications. Inflammation may contribute to treatment non-response through effects on neurotransmitter systems relevant to antidepressant efficacy. In post-hoc analyses, increased concentrations of inflammatory markers prior to treatment predict poor antidepressant response. However, limited data exists on whether depressed patients with multiple failed treatment trials in their current episode of depression exhibit increased inflammation. MethodsPlasma concentrations of inflammatory markers were measured in unmedicated, medically stable patients with MDD (n = 98) and varying numbers of adequate antidepressant treatment trials in the current depressive episode as measured by the Massachusetts General Hospital Antidepressant Treatment Response Questionnaire. Covariates including age, sex, race, education, body mass index (BMI) and severity of depression were included in statistical models where indicated. ResultsA significant relationship was found between number of failed treatment trials and tumor necrosis factor (TNF), soluble TNF receptor 2 (sTNF-R2) and interleukin (IL)-6 (all p < 0.05 in multivariate analyses). Post hoc pairwise comparisons with correction for multiple testing revealed that patients with 3 or more failed trials in the current episode had significantly higher plasma TNF, sTNF-R2 and IL-6 compared to individuals with 0 or 1 trial (all p < 0.05). High sensitivity c-reactive protein was also associated with a greater number of treatment failures, but only in models with BMI excluded. ConclusionsMeasuring inflammatory markers and targeting inflammation or its downstream mediators may be relevant for depressed patients with multiple failed antidepressant treatment trials in their current depressive episode.

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.