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Despite promising results from several randomized controlled trials (RCTs) and meta-analyses, the efficacy of r-TMS as a treatment for OCD remains controversial, at least in part owing to inconsistency in the trial methodologies and heterogeneity in the trial outcomes. This meta-analysis attempts to explain some of this heterogeneity by comparing the efficacy of r-TMS in patients with or without resistance to treatment with selective serotonin reuptake inhibitors (SSRI), defined using standardized criteria. We conducted a pre-registered (PROSPERO ID: 241381) systematic review and meta-analysis. English language articles reporting blinded RCTs were retrieved from searches using MEDLINE, PsycINFO, and Cochrane Library databases. Studies were subjected to subgroup analysis based on four stages of treatment resistance, defined using an adaptation of published criteria (1 = not treatment resistant, 2 = one SSRI trial failed, 3 = two SSRI trials failed, 4 = two SSRI trials failed plus one or more CBT trial failed). Meta-regression analyses investigated patient and methodological factors (age, duration of OCD, illness severity, stage of treatment-resistance, or researcher allegiance) as possible moderators of effect size. Twenty-five independent comparisons (23 studies) were included. Overall, r-TMS showed a medium-sized reduction of Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) scores (Hedge's g: -0.47; 95%CI: - 0.67 to −0.27) with moderate heterogeneity (I2 = 39.8%). Assessment of publication bias using Trim and Fill analysis suggested a reduced effect size that remained significant (g: -0.29; 95%CI: −0.51 to −0.07). Subgroup analysis found that those studies including patients non-resistant to SSRI (stage 1) (g: -0.65; 95%CI: −1.05 to −0.25, k = 7) or with low SSRI-resistance (stage 2) (g:-0.47; 95%CI: −0.86 to −0.09, k = 6) produced statistically significant results with low heterogeneity, while studies including more highly resistant patients at stage 3 (g: −0.39; 95%CI: −0.90 to 0.11, k = 4) and stage 4 (g: -0.36; 95%CI: −0.75 to 0.03, k = 8) did not. Intriguingly, the only significant moderator of the effect size found by meta-regression was the severity of baseline depressive symptoms. All trials showed evidence of researcher allegiance in favour of the intervention and therefore caution is required in interpreting the reported effect sizes. This meta-analysis shows that r-TMS is an effective treatment for OCD, but largely for those not resistant to SSRI or failing to respond to only one SSRI trial. As a consequence, r-TMS may be best implemented earlier in the care pathway. These findings would have major implications for clinical service development, but further well-powered RCTs, which eliminate bias from researcher allegiance, are needed before definitive conclusions can be drawn. •r-TMS is an effective treatment for OCD.•The effect is larger for those not resistant to SSRI or failing to respond to only one SSRI trial.•Severity of baseline depressive symptoms could be a significant moderator of the effect size.•r-TMS may be best implemented earlier in the care pathway and this could have major implications for clinical service development.•Further well-powered RCTs, which eliminate biases such as researcher allegiance, are needed.

IntroductionNovel, evidence-based treatments are required for treatment-resistant post-traumatic stress disorder (PTSD). 3,4-Methylenedioxymethamphetamine (MDMA) has beneficially augmented psychotherapy in several small clinical trials.ObjectivesTo review the use of MDMA-assisted psychotherapy in treatment-resistant PTSD.MethodsSystematic searches of four databases were conducted from inception to February 2020. A meta-analysis was performed on trials which were double-blinded, randomised, and compared MDMA-assisted psychotherapy to psychotherapy and placebo. The primary outcomes were the differences in Clinician Administered PTSD Scale (CAPS-IV) score and Beck’s Depression Inventory (BDI). Secondary outcome measures included neurocognitive and physical adverse effects, at the time, and within seven days of intervention.ResultsFour randomised controlled trials (RCTs) met inclusion criteria. When compared to active placebo, intervention groups taking 75mg (MD -46.90; 95% CI -58.78, -35.02), 125mg (MD -20.98; 95% CI -34.35, -7.61) but not 100mg (MD -12.90; 95% CI -36.09, 10.29) of MDMA with psychotherapy, had significant decreases in CAPS-IV scores, as did the inactive placebo arm (MD -33.20; 95% CI -40.53, -25.87). A significant decrease in BDI when compared to active placebo (MD -10.80; 95% CI -20.39, -1.21) was only observed at 75mg. Compared to placebo, participants reported significantly more episodes of low mood, nausea and jaw-clenching during sessions and lack of appetite after seven days.ConclusionsThese results demonstrate potential therapeutic benefit with minimal physical and neurocognitive risk for the use of MDMA-assisted psychotherapy in TR-PTSD, despite little effect on Beck’s Depression Inventory. Better powered RCTs are required to investigate further.DisclosureJames Rucker has attended trial related meetings paid for by Compass Pathways Ltd.

Prostate cancer (PCa) is the leading cause of cancer-related death among men worldwide. PCa often develops resistance to standard androgen deprivation therapy and androgen receptor (AR) pathway inhibitors, such as enzalutamide (ENZ). Therefore, there is an urgent need to develop novel therapeutic strategies for this disease. The efficacy of ADA-308 was evaluated through in vitro assessments of AR activity and cell proliferation, alongside in vivo studies. ADA-308 has emerged as a promising candidate, demonstrating potent inhibition of AR-sensitive adenocarcinoma as well as ENZ-resistant PCa cell lines. The results of the study revealed that ADA-308 effectively blocked AR activity, including its nuclear localization, and inhibited cell proliferation in vitro. Furthermore, ADA-308 demonstrated notable efficacy in vivo, with a robust antitumor response in ENZ-resistant models. These findings establish the role of ADA-308 as a potent AR inhibitor that overcomes resistance to AR-targeted therapies and highlights its potential as a novel therapeutic approach in advanced PCa management.

Restoration of weight and nutritional status are key elements in the treatment of anorexia nervosa (AN). This review aims to describe issues related to the caloric requirements needed to gain and maintain weight for short and long-term recovery for AN inpatients and outpatients. We reviewed the literature in PubMed pertaining to nutritional restoration in AN between 1960–2012. Based on this search, several themes emerged: 1. AN eating behavior; 2. Weight restoration in AN; 3. Role of exercise and metabolism in resistance to weight gain; 3. Medical consequences of weight restoration; 4. Rate of weight gain; 5. Weight maintenance; and 6. Nutrient intake. A fair amount is known about overall caloric requirements for weight restoration and maintenance for AN. For example, starting at 30–40 kilocalories per kilogram per day (kcal/kg/day) with increases up to 70–100 kcal/kg/day can achieve a weight gain of 1–1.5 kg/week for inpatients. However, little is known about the effects of nutritional deficits on weight gain, or how to meet nutrient requirements for restoration of nutritional status. This review seeks to draw attention to the need for the development of a foundation of basic nutritional knowledge about AN so that future treatment can be evidenced-based.

Background Treatment resistance is an omnipresent frustration in eating disorders. Attempts to identify the features of this resistance and subsequently develop novel treatments have had modest effects. This selective review examines treatment resistant features expressed in core eating disorder psychopathology, comorbidities and biological features. Novel treatments addressing resistance are discussed. Description The core eating disorder psychopathology of anorexia nervosa becomes a coping mechanism likely via vulnerable neurobiological features and conditioned learning to deal with life events. Thus it is reinforcing and ego syntonic resulting in resistance to treatment. The severity of core features such as preoccupations with body image, weight, eating and exercising predicts greater resistance to treatment. Bulimia nervosa patients are less resistant to treatment with treatment failure related to greater body image concerns, impulsivity, depression, severe diet restriction and poor social adjustment. For those with binge eating disorder overweight in childhood and high emotional eating predicts treatment resistance. There is suggestive data that a diagnosis of an anxiety disorder and severe perfectionism may confer treatment resistance in anorexia nervosa and substance use disorders or personality disorders with impulse control problems may produce resistance to treatment in bulimia nervosa. Traits such as perfectionism, cognitive inflexibility and negative affect with likely genetic influences may also affect treatment resistance. Pharmacotherapy and novel therapies have been developed to address treatment resistance. Atypical antipsychotic drugs have shown some effect in treatment resistant anorexia nervosa and topiramate and high doses of SSRIs are helpful for treatment of resistant binge eating disorder patients. There are insufficient randomized controlled trials to evaluate the novel psychotherapies which are primarily based on the core psychopathological features of the eating disorders. Conclusion Treatment resistance in eating disorders is usually predicted by the severity of the core eating disorder psychopathology which develops from an interaction between environmental risk factors with genetic traits and a vulnerable neurobiology. Future investigations of the biological features and neurocircuitry of the core eating disorders psychopathology and behaviors may provide information for more successful treatment interventions.

Introduction Electroconvulsive therapy (ECT) is an effective treatment for patients with mood disorders and is most often used for treatment‐resistant cases. This study aimed to examine the effectiveness of ECT in a real‐world treatment sample in a Chinese psychiatric hospital which included both treatment‐resistant and nontreatment‐resistant patients. Methods An observational study of symptom outcomes from admission to the time of discharge was conducted with 37 inpatients diagnosed with unipolar or bipolar depression treated with ECT. Symptom severity was assessed with the 17‐item Hamilton Rating Scales for Depression (HRSD‐17) and treatment‐resistance with the Maudsley Staging Model (MSM). Stratifying at the MSM median admission characteristics and symptom change was compared between patients who were treatment‐resistant (n = 18) and who were not (n = 19). The outcome difference between groups was compared using analyses of covariance adjusted for baseline characteristics including symptom severity, followed by linear regression to identify factors associated symptom improvement in the entire sample. Results The sample (n = 37) showed moderate treatment‐resistance (MSM = 7.30 ± 1.13) at admission and both groups received 8.3 ± 2 ECT sessions. The treatment‐resistant group had a smaller proportion of bipolar patients and more severe symptoms, but showed no significant difference from the nontreatment‐resistant group in HDRS‐17 scores at the time of discharge (adjusted means = 6.23 ± 1.00 vs. 5.94 ± 0.97, Partial η2 = 0.001, p = .845). Baseline symptom severity was the strongest correlate of reduction in HDRS‐17 scores (β = 0.891, p < .001). Conclusions Symptom change with ECT in depression did not differ by level of treatment‐resistance but was greatest among those with more severe baseline symptoms. Correlates of ECT effectiveness should be further evaluated in stratified randomized trials. The reduction of depressive symptoms with ECT does not appear to be affected by overall “treatment‐resistance” but is greatest for those with the most severe symptoms at baseline.

Anhedonia, defined as the state of reduced ability to experience feelings of pleasure, is one of the hallmarks of depression. Hedonic tone is the trait underlying one's characteristic ability to feel pleasure. Low hedonic tone represents a reduced capacity to experience pleasure, thus increasing the likelihood of experiencing anhedonia. Low hedonic tone has been associated with several psychopathologies, including major depressive disorder (MDD), substance use, and attention-deficit hyperactivity disorder (ADHD). The main neural pathway that modulates emotional affect comprises the limbic-cortical-striatal-pallidal-thalamic circuits. The activity of various components of the limbic-cortical-striatal-pallidal-thalamic pathway is correlated with hedonic tone in healthy individuals and is altered in MDD. Dysfunction of these circuits has also been implicated in the relative ineffectiveness of selective serotonin reuptake inhibitors used to treat anxiety and depression in patients with low hedonic tone. Mood disorders such as MDD, ADHD, and substance abuse share low hedonic tone as well as altered activation of brain regions involved in reward processing and monoamine signaling as their features. Given the common features of these disorders, it is not surprising that they have high levels of comorbidities. The purpose of this article is to review the neurobiology of hedonic tone as it pertains to depression, ADHD, and the potential for substance abuse. We propose that, since low hedonic tone is a shared feature of MDD, ADHD, and substance abuse, evaluation of hedonic tone may become a diagnostic feature used to predict subtypes of MDD, such as treatment-resistant depression, as well as comorbidities of these disorders.

Background: Optimising treatments for patients with treatment-resistant depression (TRD) is key to reducing the burden of this severe illness. The anti-glucocorticoid medication metyrapone has mixed evidence supporting a role as a possible augmentation treatment in TRD. The degree of treatment resistance in depression has been associated prospectively and retrospectively with elevated inflammation, and inflammatory activity may influence responses to antidepressant treatments. Aims: To investigate whether levels of pro-inflammatory cytokines are associated with clinical outcomes to metyrapone or placebo. Methods: A double-blind RCT randomised patients with TRD to 3 weeks of placebo or metyrapone augmentation to ongoing serotonergic antidepressants. No benefit of metyrapone was reported in the primary analysis. The current study assessed levels of pro-inflammatory proteins interleukin-6 (IL-6), tumour necrosis factor (TNFα), c-reactive protein (CRP) and interleukin-10 (IL-10) before randomisation and after treatment as potential moderators and/or mediators of clinical outcomes. Results: The three pro-inflammatory proteins (but not IL-10) were elevated in this sample of patients with TRD compared to a non-affected control group. High pre-treatment IL-6 levels predicted a poorer response in the trial overall but did not moderate response to metyrapone versus placebo. Changes in IL-6 indirectly mediated depression outcome, with metyrapone increasing IL-6 levels and IL-6 increase associated with a poorer outcome on depression. Other inflammatory proteins did not mediate or moderate treatment outcomes. Interpretation: Metyrapone is hypothesised to have a therapeutic effect in depression on the basis of inhibiting the synthesis of cortisol. In this study, metyrapone did not reduce cortisol, possibly due to glucocorticoid system overcompensation). The mediation effect of IL-6 may support this and perhaps help to indicate why the treatment was not effective.

IntroductionIn ESCAPE-TRD (NCT04338321), a randomized, open-label, rater-blinded, long-term, phase 3b trial, augmentation with esketamine nasal spray (ESK) demonstrated increased probability of achieving meaningful clinical benefit versus quetiapine extended release (QUE XR) in patients (pts) with treatment-resistant depression (TRD). This subgroup analysis of ESCAPE-TRD evaluated the incidence, duration, and impact of treatment-emergent adverse events (TEAEs) on treatment discontinuation in adults with TRD treated with ESK or QUE XR according to US prescribing information.MethodsPts aged 18-64 years were randomly assigned to receive flexibly dosed ESK (56 or 84 mg) or QUE XR (150-300 mg), both consistent with US label dosing and in combination with an ongoing oral antidepressant. The incidence and duration of the most commonly occurring TEAEs, as well as the most common TEAEs leading to treatment discontinuation, were summarized descriptively. All randomly assigned participants receiving ≥1 dose of study drug were included in the safety analyses.ResultsAmong the 636 pts included in the subgroup analysis, 316 and 320 were randomly assigned to ESK and QUE XR, respectively; 314 and 316 were included in the safety population. In the combined acute and maintenance phases, TEAEs occurred in 92.0% of pts in the ESK group and 78.5% of pts in the QUE XR group. The most commonly reported TEAEs with ESK or QUE XR in the combined acute and maintenance phases were dizziness (47.1% and 7.9%, respectively), headache (25.5% and 13.0%, respectively), somnolence (15.0% and 23.4%, respectively), and nausea (29.9% and 3.2%, respectively). Across all TEAE events reported in >5% of pts in either arm, 91.8% (5831 of 6351) resolved within 1 day in the ESK arm compared to 11.6% (90 of 776) with QUE XR. For specific TEAE events of clinical interest for ESK, same-day resolution rates for increased blood pressure, sedation, and dissociation in the ESK group were 93.5% (116 of 124), 96.2% (127 of 132), and 99.6% (740 of 743), respectively. The majority of TEAEs of clinical interest in the ESK group that occurred on the same day of dosing resolved within the first 2 hours after dosing. For the most frequently reported TEAEs with QUE XR, same-day resolution rates for somnolence, headache, and fatigue were 7.8% (8 of 103), 49.2% (29 of 59), and 9.5% (4 of 42), respectively. Fewer pts treated with ESK discontinued treatment due to TEAEs compared to QUE XR (4.4% versus 10.6%).ConclusionsSafety data from this subgroup analysis were consistent with the overall study population as well as the known tolerability profile of each treatment. TEAEs were reported at higher incidence with ESK than with QUE XR; however, the majority of TEAEs occurring with ESK were transient in nature and did not result in a higher rate of treatment discontinuation compared to QUE XR.FundingJanssen Scientific Affairs, LLC

Background An increasing body of research points to a significant association of obesity to Attention-Deficit/Hyperactivity Disorder (ADHD) and deficits in executive functions. There is also preliminary evidence suggesting that children with ADHD may be at risk of obesity in adulthood. Discussion In this article, we discuss the evidence showing that ADHD and/or deficits in executive functions are a barrier to a successful weight control in individuals enrolled in weight loss programs. Impairing symptoms of ADHD or deficits in executive functions may foster dysregulated eating behaviors, such as binge eating, emotionally-induced eating or eating in the absence of hunger, which, in turn, may contribute to unsuccessful weight loss. ADHD-related behaviors or neurocognitive impairment may also hamper a regular and structured physical activity. There is initial research showing that treatment of comorbid ADHD and executive functions training significantly improve the outcome of obesity in individuals with comorbid ADHD or impairment in executive functions. Summary Preliminary evidence suggests that comorbid ADHD and deficits in executive functions are a barrier to a successful weight loss in individuals involved in obesity treatment programs. If further methodologically sound evidence confirms this relationship, screening and effectively managing comorbid ADHD and/or executive functions deficits in individuals with obesity might have the potential to reduce not only the burden of ADHD but also the obesity epidemics.