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Major depressive disorder (MDD) is highly prevalent in youth. Conventional treatment paradigms primarily involve selective serotonin reuptake inhibitors (SSRIs) and psychotherapy, yet a significant proportion of this population exhibits treatment-resistant depression (TRD). In adults, interventional therapies like Electroconvulsive Therapy (ECT), repetitive Transcranial Magnetic Stimulation (rTMS), and ketamine have shown promise for TRD, but their comparative efficacy remains underexplored in Adolescent and pediatric population. This systematic review and meta-analysis aims to assess the relative effectiveness of ECT, rTMS, and ketamine in treating TRD among adolescents. Following PRISMA guidelines, we systematically searched databases for studies of ECT, rTMS, or ketamine for treatment-resistant depression in youth ages 10–24. Three reviewers independently screened for inclusion based on predefined criteria. Included observational and randomized controlled trials reported depression symptoms with measures like HDRS and MADRS in youth treated with ECT, rTMS, or ketamine. Two reviewers extracted data on interventions, patients, and depression symptom outcomes. Chance-adjusted inter-reviewer agreement was calculated. For meta-analysis, we pooled standardized mean differences (SMDs) in depression scores using random effects models and assessed heterogeneity with I2 statistics. Meta-analysis of 10 observational studies examined SMD in depression scores for treatment resistant depression patients treated with ECT, ketamine, or rTMS. Patients treated with ECT had a significantly lower SMD of 1.99 (95 % CI 0.92–3.05, p < 0.001) compared to baseline. Patients treated with ketamine also had a significantly lower SMD of 1.58 (95 % CI 1.04–2.12, p < 0.001). Patients treated with rTMS had the lowest SMD of 2.79 (95 % CI 0.79–4.80, p = 0.006). There was no significant difference between the three groups overall (p > 0.05). Comparative analysis between ECT and ketamine found no significant difference in SMD (p = 0.387). Comparison of ECT versus rTMS found a significant difference in SMD favoring rTMS (p = 0.004). Comparison of ketamine versus rTMS suggested a potential difference in SMD favoring rTMS (p = 0.058). In summary, rTMS resulted in significantly larger reductions in depression scores than ECT, and potentially larger reductions than ketamine. This meta-analysis illustrates the ability of rTMS, ECT, and ketamine to improve depression in youth. rTMS resulted in the largest improvements, highlighting its potential as a first-line treatment for pediatric treatment-resistant depression given its favorable side effect profile compared to ECT. Further research directly comparing these modalities is needed. • This systematic review assesses ECT, rTMS, and Ketamine for treating treatment-resistant depression in youth. • Standardized mean differences (SMDs) in depression scores for patients treated with ECT, ketamine, or rTMS were compared. • All 3 interventions significantly reduced depression symptoms with rTMS resulting in the largest SMD reduction of 2.79. • rTMS should be strongly considered for treatment-resistant depression in youth given its side effect profile and efficacy. [ABSTRACT FROM AUTHOR]

Objective: To compare the efficacy and discontinuation of augmentation agents in adult patients with treatment-resistant depression (TRD). We conducted a systematic review and network meta-analyses (NMA) to combine direct and indirect comparisons of augmentation agents.Methods: We included randomized controlled trials comparing one active drug with another or with placebo following a treatment course up to 24 weeks. Nineteen agents were included: stimulants, atypical antipsychotics, thyroid hormones, antidepressants, and mood stabilizers. Data for response/remission and all-cause discontinuation rates were analyzed. We estimated effect-size by relative risk using pairwise and NMA with random-effects model.Results: A total of 65 studies (N = 12,415) with 19 augmentation agents were included in the NMA. Our findings from the NMA for response rates, compared to placebo, were significant for: liothyronine, nortriptyline, aripiprazole, brexpiprazole, quetiapine, lithium, modafinil, olanzapine (fluoxetine), cariprazine, and lisdexamfetamine. For remission rates, compared to placebo, were significant for: thyroid hormone(T4), aripiprazole, brexpiprazole, risperidone, quetiapine, and olanzapine (fluoxetine). Compared to placebo, ziprasidone, mirtazapine, and cariprazine had statistically significant higher discontinuation rates. Overall, 24% studies were rated as having low risk of bias (RoB), 63% had moderate RoB and 13% had high RoB.Limitations: Heterogeneity in TRD definitions, variable trial duration and methodological clinical design of older studies and small number of trials per comparisons.Conclusions: This NMA suggests a superiority of the regulatory approved adjunctive atypical antipsychotics, thyroid hormones, dopamine compounds (modafinil and lisdexamfetamine) and lithium. Acceptability was lower with ziprasidone, mirtazapine, and cariprazine. Further research and head-to-head studies should be considered to strengthen the best available options for TRD. [ABSTRACT FROM AUTHOR]

Non-Invasive Brain Stimulation (NIBS) techniques and in particular, repetitive Transcranial Magnetic Stimulation (rTMS), are developing beyond mere clinical application. Although originally purposed for the treatment of resistant neuropsychiatric disorders, NIBS is also contributing to a deeper understanding of psychiatric disorders. rTMS is also changing the model of the disorder itself, from "mental" to one of neural connectivity. TMS allows the assessment of brain circuit excitability and eventually, of plastic changes affecting these circuits. While a clinical translational approach is, at the present time, the most adequate to meet the dimensional-circuit base model of the disorder, it refines the standard categorical classification of psychiatric disorders. The discovery of the fundamental importance of the balance between neuroplasticity and inflammation is also now explored through neuro-modulation findings consistently with the evidence of anti-inflammatory actions of the magnetic pulses. rTMS may activate, inhibit, or otherwise interfere with the activity of neuronal cortical networks, depending on stimulus frequency and intensity of brain-induced electric field. Of particular interest, yet still unclear, is how the relatively unspecific nature of TMS stimulation may lead to specific neuronal reorganization, as well as a definition of the TMS-triggered reorganization of functional brain modules, raising attention on the importance of the active participation of the patient to the treatment.. Configuration and state of consciousness of the subject have made subjective experience under treatment regain importance in the neuro-scientific Psychiatry based on the requirement of United States National Institute of Health (NIH) and the substantial importance of the consciousness state in the efficacy of the TMS treatment. By focusing on the subjective experience, a renaissance of the phenomenology offers Psychiatry an opportunity to become proficient and to distinguish itself from other disciplines. For all these reasons, TMS should be included in the cluster of the sub-specialties as a new "Super-Specialty" and an appropriate training course has to be inaugurated. Psychiatrists are nowadays multi-specialists, moving from a specialty to another, vs super-specialist. The cultivation of a properly trained cohort of TMS psychiatrists will better meet the challenges of treatment-resistant psychiatric conditions (disorders of connectivity), through appropriate and ethical practice, meanwhile facilitating an informed development and integration of additional emerging neuro-modulation techniques. The aim of this consensus paper is to underline the interdisciplinary nature of NIBS, that also encompasses the subjective experience and to point out the necessity of a neuroscience-applied approach to NIBS in the context of the European College of Neuro-psychopharmacology (ECNP). [ABSTRACT FROM AUTHOR]

• The left corpus callosum (CC) was statistically significantly thicker in the TRS patient group as compared to the non-TRS group. • Significant difference was not determined in the other brain regions. • Correlation analyses revealed positive correlation between the left CC thickness and PANSS scores, disease duration and age at disease onset in overall schizophrenia patients. • It was found to be left CC thickness positively correlated only with PANSS scores in the TRS patient group. Recent developments in neuroimaging have improved our understanding of the biological mechanisms underlying schizophrenia. However, neuroimaging findings in treatment-resistant schizophrenia (TRS) remain unclear. In the present study, we aimed to explore potential neuroanatomical regions that may be associated with treatment resistance in schizophrenia patients by comparing neuroanatomical regions of TRS and non-TRS patients using the MRICloud method. A total of 33 schizophrenia patients (meeting DSM 5 diagnostic criteria for schizophrenia) were included in the study. Patients were dichotomized into TRS (n = 18) and non-TRS (n = 15) groups, and all patients underwent MRI. Neuroanatomical regions of TRS and non-TRS patients were compared using the MRICloud method. Disease severity was measured using the Positive and Negative Syndrome Scale (PANSS). Interestingly, a statistically significant greater left Corpus Collosum (CC) thickness was found in TRS patients compared to non-TRS patients. It is clear that further studies comparing TRS patients with non-TRS patients are needed, and these studies should focus on the circuits in the corpus callosum that are thought to play a role in treatment resistance. Further longitudinal studies are also needed to complement the cross-sectional studies, using a multimodal imaging approach in the patients with clearly defined TRS criteria. [ABSTRACT FROM AUTHOR]

Background: Depressed patients with chronic and complex health issues commonly relapse; therefore, examining longer-term outcomes is an important consideration. For treatment resistant depression (TRD), the post-treatment efficacy of time-limited Intensive Short-Term Dynamic Psychotherapy (ISTDP) has been demonstrated but longer-term outcomes and cost-effectiveness are unclear.Method: In this superiority trial, 60 patients referred to Community Mental Health Teams (CMHT) were randomised to 2 groups (ISTDP=30 and CMHT=30). The primary outcome was Hamilton Depression Rating scale (HAM-D) scores at 18 months. Secondary outcomes included Patient Health Questionnaire (PHQ-9) depression scores and dichotomous measure remission. A health economic evaluation examined mental health costs with quality-adjusted life years (QALYs).Results: Statistically significant treatment differences in depression previously found at 6 months favouring ISTDP were maintained at 18-month follow-up. Group differences in depression were in the moderate to large range on both the observer rated (Cohen's d = .64) and self-report measures (Cohen's d = .70). At 18 months follow-up the remission rate in ISTDP patients was 40.0%, and 23.4% had discontinued antidepressants. Health economic analysis suggests that ISTDP was more cost-effective than CMHT at 18 months. Probabilistic analysis suggests that there is a 64.5% probability of ISTDP being cost-effective at a willingness to pay for a QALY of $25,000 compared to CMHT at 18 months.Limitations: Replication of these findings is necessary in larger samples and future cost analyses should also consider indirect costs.Conclusions: ISTDP demonstrates long-term efficacy and cost-effectiveness in TRD. [ABSTRACT FROM AUTHOR]

Posttraumatic stress disorder (PTSD) is a debilitating disorder with limited medication treatment options. Recent reports have described the dearth of research on new drug development as a crisis in the pharmacotherapy of PTSD. There are only two PTSD medications approved by the U.S. Food and Drug Administration, and both are serotonergic antidepressants. Therefore, there is a tremendous need to identify more effective and more rapidly acting pharmacotherapies for PTSD that work through novel neural mechanisms. Pilot evidence and case reports provided preliminary evidence supporting the safety and utility of investigating the therapeutic effects of ketamine in PTSD. However, the efficacy of this drug for PTSD has not yet been tested in active duty military or veteran populations. Here, we report the design and methods of a study funded under the Consortium to Alleviate PTSD. The study is a multisite, placebo-controlled, double–blind, randomized clinical trial to examine the dose-related efficacy of ketamine, as compared to placebo, in producing a rapid and sustained reduction in PTSD symptomatology in veterans and active duty military populations with antidepressant-resistant PTSD. Approximately 198 eligible participants who meet criteria for PTSD will be randomized to the study drug (i.e., ketamine 0.5 mg/kg, ketamine 0.2 mg/kg, or placebo). The study drug will be administered intravenously twice per week for 4 weeks, followed by a 4-week follow-up period. This ongoing study is the only trial of therapeutic effects of ketamine for PTSD and the first placebo-controlled trial to determine the dose-related effects of repeated ketamine on PTSD. [ABSTRACT FROM AUTHOR]

Highlights • Reductions in cortical volume, thickness and surface area observed in schizophrenia. • Reductions in temporal, parietal and medial regions in treatment-resistance. • Cortical thickness reductions left-lateralised: implicated in auditory hallucinations. • Increased surface area in parietal lobe could reflect over-activation. • Regional changes may index mechanisms specific to treatment-resistant schizophrenia. Abstract Decreases in cortical volume (CV), thickness (CT) and surface area (SA) have been reported in individuals with schizophrenia by in vivo MRI studies. However, there are few studies that examine these cortical measures as potential biomarkers of treatment resistance (TR) and treatment response (NTR) in schizophrenia. This study used structural MRI to examine differences in CV, CT, and SA in 42 adults with schizophrenia (TR = 21, NTR = 21) and 23 healthy controls (HC) to test the hypothesis that individuals with TR schizophrenia have significantly greater reductions in these cortical measures compared to individuals with NTR schizophrenia. We found that individuals with TR schizophrenia showed significant reductions in CV and CT compared to individuals with NTR schizophrenia in right frontal and precentral regions, right parietal and occipital cortex, left temporal cortex and bilateral cingulate cortex. In line with previous literature, the temporal lobe and cingulate gyrus in both patient groups showed significant reductions of all three measures when compared to healthy controls. Taken together these results suggest that regional changes in CV and CT may index mechanisms specific to TR schizophrenia and potentially identify patients with TR schizophrenia for earlier treatment. [ABSTRACT FROM AUTHOR]

Abstract Background While ketamine has been increasingly studied for treatment resistant depression (TRD), the impact of sex differences on treatment outcomes has not been well studied. The objective was to ascertain whether there were differences in response to a single administration of ketamine for TRD between men and women, and between pre- and post-menopausal women. Methods A randomized, double-blind, placebo-controlled trial (N = 99; N = 50 male; N = 49 female) was conducted to investigate the efficacy of intravenous ketamine versus active placebo as augmentation of antidepressant therapy for TRD. Patients were assigned to one of five arms; one-time administration of ketamine of varying doses (i.e., 0.1, 0.2, 0.5, and 1.0 mg/kg), and one group receiving active placebo (intravenous midazolam). A priori -planned analyses were conducted to compare responses between women and men, as well pre-vs. postmenopausal women. Results Analyses demonstrated no significant differences between women and men in terms of treatment response (F(1,80) = 0.06, p = 0.80). There were no significant differences in the frequency of adverse effects (AEs) reported by those assigned to ketamine treatment groups (p > 0.21 for all AEs reported more than once), although women reported more headaches (12% vs. 6%, p = 0.30) and nausea (10% vs. 6%, p = 0.47). In comparing pre-vs. postmenopausal women, no differences in efficacy were observed (F(1,76) = 0.36, p = 0.55). Conclusions Results do not support differential efficacy or tolerability of ketamine for the treatment of TRD between women and men, nor based on menopause status among women. However, larger trials with these a priori aims are needed to confirm these results. [ABSTRACT FROM AUTHOR]

Treatment resistant major depressive disorder (TR-MDD) is a severe disease, with very low remission rates. The resistance to pharmacotherapy leads to the search of non-pharmacological alternative approaches. Animal therapy has been used in patients with psychiatric conditions and the results have been promising. However, there have been no studies in TR-MDD patients with pet adoption. This study assessed the impact of TR-MDD patients adopting a pet. Eighty patients were suggested to adopt a pet, and 33 accepted the challenge. Other 33 patients constituted the control group (did not accept the suggestion of pet adoption and did not already have a pet). All patients maintained their usual pharmacotherapy. All participants were evaluated at baseline, 4, 8 and 12 weeks for depressive symptoms using HAMD17 and GAF. Results show that the pet group had an improvement in HAMD17 and GAF scores as well as higher response and remission rates compared to the control group, where no patient responded or remitted. Therefore, pets can be used as an effective adjuvant to pharmacotherapy with regular medical appointments. [ABSTRACT FROM AUTHOR]

Background: The use of clozapine is limited due to the occurrence of neutropenia, and the rare but life threatening adverse event of agranulocytosis. There is little epidemiological research into clinical factors that may impact on this risk. We conducted a case control study examining the clinical risk factors for neutropenia patients treated with clozapine.Method: A case-control study was conducted within a database of anonymised electronic clinical records. All patients who discontinued clozapine due to a neutropenic event were included as cases. Matched controls were selected from patients with a documented clozapine exposure at the time of the clozapine neutropenic event of the case patient, matched by duration of clozapine treatment.Results: 136 cases and 136 controls were included. In multivariable analysis, the concurrent use of sodium valproate was associated with neutropenia (Odds Raito (OR) 2.28, 95%CI: 1.27-4.11, p=0.006). There was a dose-response effect, with greater associations for higher doses. Patients who discontinued clozapine due to neutropenia were more likely to be of black ethnicity (OR 2.99, p<0.001), were younger (t=5.86, df=267, p<0.001), and received lower doses of clozapine (t=-2.587, p=0.01) than those who did not develop neutropenia.Conclusion: We identified an association between the concurrent use of sodium valproate and an increased risk of clozapine associated neutropenia. These results, taken in combination with the results from previous case series, suggest that the risk of clozapine associated neutropenia could be reduced by avoiding concurrent valproate treatment. [ABSTRACT FROM AUTHOR]

The efficacy of ketamine to alleviate depressive symptoms has promoted a wealth of research exploring alternate therapeutic targets for depression. Given the caveats of ketamine treatment taken together with the increasingly greater emphasis on combinatorial therapeutic approaches to depression, we sought to asses whether the hypothalamic “hunger hormone”, ghrelin, would augment the effects of ketamine. Indeed, ghrelin has recently been found to possess antidepressant potential and may be especially effective against the metabolic and feeding deficits observed with depression. Two studies were performed: 1. mice were given an intraperitoneal injection of ghrelin (80 μg/kg) or saline, followed by a saline or a low or high dose of ketamine (5 or 10 mg/kg) and 2. mice received 10 mg/kg of ketamine together with saline or the ghrelin receptor antagonist JMV2959 (3 or 6 mg/kg) and Forced Swim Test (FST) performance was assessed. In both studies, ketamine alone reduced FST immobility. Similarly, ghrelin alone reduced swim immobility suggesting an antidepressant-like response. However, ghrelin did not augment the impact of ketamine when co-administered and in fact, it appeared to antagonize its actions at the lower dose. As well, JMV2959 did not significantly influence FST performance. These data confirm the antidepressant-like effects of ketamine and further suggest that ghrelin might have similar properties. Yet, our results caution against combinatorial treatment with these agents, probably owing to unexpected allosteric or other antagonist actions. [ABSTRACT FROM AUTHOR]

Background: At least one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD), defined as lack of response to two or more adequate antidepressant trials. For these patients, novel antidepressant treatments are urgently needed.Methods: The current study is a phase IIa open label clinical trial examining the efficacy and tolerability of a combination of dextromethorphan (DM) and the CYP2D6 enzyme inhibitor quinidine (Q) in patients with TRD. Dextromethorphan acts as an antagonist at the glutamate N-methyl-d-aspartate (NMDA) receptor, in addition to other pharmacodynamics properties that include activity at sigma-1 receptors. Twenty patients with unipolar TRD who completed informed consent and met all eligibility criteria we enrolled in an open-label study of DM/Q up to 45/10mg by mouth administered every 12h over the course of a 10-week period, and constitute the intention to treat (ITT) sample. Six patients discontinued prior to study completion.Results: There was no treatment-emergent suicidal ideation, psychotomimetic or dissociative symptoms. Montgomery-Asberg Depression Rating Scale (MADRS) score was reduced from baseline to the 10-week primary outcome (mean change: -13.0±11.5, t19=5.0, p<0.001), as was QIDS-SR score (mean change: -5.9±6.6, t19=4.0, p<0.001). The response and remission rates in the ITT sample were 45% and 35%, respectively.Limitations: Open-label, proof-of-concept design.Conclusions: Herein we report acceptable tolerability and preliminary efficacy of DM/Q up to 45/10mg administered every 12h in patients with TRD. Future larger placebo controlled randomized trials in this population are warranted. [ABSTRACT FROM AUTHOR]

Background: Little is known about the antidepressive effects of repeated intravenous ketamine infusions beyond the acute phase of treatment in patients with refractory depression.Methods: Twelve subjects with treatment-resistant non-psychotic unipolar or bipolar major depression and suicidal ideation were given repeated (up to 6) thrice-weekly acute-phase intravenous infusions of ketamine (0.5mg/kg, administered over 100min). Those who remitted during acute-phase treatment received continuation-phase treatment that consisted of 4 weekly ketamine infusions, followed by 4 weeks of post-continuation phase follow-up (during which no further ketamine infusions were administered). Clinical measures were assessed at baseline, at 24h following each infusion, at the last acute-phase observation, and during continuation and post-continuation follow-up (acute phase remitters only).Results: Of the 12 enrollees, 5 (41.7%) remitted and 7 (58.3%) responded to ketamine treatment during the acute-phase. All five subjects who remitted during the acute-phase experienced further depressive symptom improvement during continuation-phase treatment. Four subjects lost remission status during the post-continuation phase, but all were still classified as positive treatment responders at the end of the post-continuation phase. Adverse effects were generally mild and transient during acute- and continuation-phase treatment; however, one subject developed behavioral outbursts and suicide threats during follow-up while hospitalized, and one subject died by suicide several weeks after the end of follow-up.Limitations: This was an uncontrolled feasibility study with a small sample size.Conclusions: The continuation-phase administration of ketamine at weekly intervals to patients with treatment-resistant depression who remitted during acute-phase ketamine treatment can extend the duration of depressive symptom remission. The antidepressive effect of ketamine persisted for several weeks after the end of continuation-phase treatment. Our results highlight the need for close monitoring of subjects who are at high baseline risk for suicide but do not respond clinically to ketamine. CLINICALTRIALS.Gov Identifier: NCT02094898. [ABSTRACT FROM AUTHOR]

Objectives: Executive dysfunction (ED) is a predictor of poor treatment response of late-life depression to pharmacotherapy. In response to the consistency of these findings, we designed neuroplasticity-based computerized cognitive remediation (nCCR-GD) intervention to target and improve ED in patients who failed to remit with antidepressant treatment. This study tests the hypothesis that ED at baseline will predict favorable treatment response to nCCR-GD.Methods: 11 elderly patients with treatment-resistant major depression were treated with a 30-hour, 4-week, unblinded, nCCR-GD treatment trial. Neuropsychological performance was assessed at baseline and after treatment ceased.Results: ED at baseline was associated with greater reduction in Montgomery-Asberg Depression Rating Scale score over the 4-week treatment β = -0.74, F(2,8) = 10.85, p = 0.009, R(2) = 0.55.Conclusions: ED predicts favorable treatment response to nCCR-GD in older adults suffering from major depression resistant to antidepressants. This finding is opposed to studies testing pharmacotherapy where ED predicts poorer treatment response. [ABSTRACT FROM AUTHOR]

Previous studies suggest that insulin-sensitizing agents could play a significant role in the treatment of major depression, particularly depression in patients with documented insulin resistance or those who are resistant to standard psychopharmacological approaches. This study aimed to assess the effects on depressive symptoms with adjuvant treatment with the PPARγ-agonist pioglitazone. Patients ( N =37) with non-psychotic, non-remitting depression receiving standard psychiatric regimens for depression were randomized across an insulin sensitivity spectrum in a 12-week double blind, randomized controlled trial of pioglitazone or placebo. Improvement in depression was associated with improvement in glucose metabolism but only in patients with insulin resistance. An age effect was also shown in that response to pioglitazone was more beneficial in younger aged patients. Study findings suggest differential improvement in depression severity according to both glucose metabolic status and level of depression at baseline. A greater understanding of the reciprocal links between depression and IR may lead to a dramatic shift in the way in which depression is conceptualized and treated, with a greater focus on treating and/or preventing metabolic dysfunction. [ABSTRACT FROM AUTHOR]

Background The N -methyl-D-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant depression. The current study was designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. Methods In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. Results Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo ( t = 4.39, p < .001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95% confidence interval, 3.9–11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo ( p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. Conclusions This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression. [ABSTRACT FROM AUTHOR]

Approximately 30% of patients with schizophrenia are treatment resistant (TRS), i.e. have persistent psychotic symptoms despite adequate trials of at least two antipsychotic drugs (APDs). Most TRS patients are candidates for clozapine treatment which is underutilized because of its side effects and difficulty in identifying TRS. We conducted a genome-wide association study (GWAS) of 79 TRS and 95 non-treatment resistant (NTRS) Caucasian schizophrenia patients to identify possible biomarkers for TRS, which might also provide insight into the pathobiology of TRS. The single nucleotide polymorphism, rs2237457, located in 7p12.2, a region reported to have imprinted inheritance, was found to have the lowest p value in an allelic association test (unadjusted p = 5.53 × 10 − 6 ). Haploview disclosed a 30 kb block flanking this SNP within GRB10, 70 kb upstream of l -dopa decarboxylase (DDC), an enzyme which is rate-limiting in the synthesis of trace amines and neurotransmitters implicated in schizophrenia and the action of APDs. This SNP or haplotype was identified as an exclusive cis -acting eQTL for DDC in human dorsolateral prefrontal cortex by BrainCloud®. A replication sample genotyped for this SNP produced a weaker result, but in the same direction. After combining the two samples, rs2237457 remained significantly associated with TRS (unadjusted p = 5.66 × 10 − 7 in recessive mode; 9.42 × 10 − 5 in allelic association). If replicated in an independent sample, rs2237457 may provide a biomarker to identify a significant proportion of Caucasian TRS. The results implicate trace amines and their synthesis in the pathophysiology of TRS. [ABSTRACT FROM AUTHOR]

Background: The intravenous administration of scopolamine produces rapid antidepressant effects. Generally, failing multiple previous antidepressant trials is associated with a poor prognosis for response to future medications. This study evaluated whether treatment history predicts antidepressant response to scopolamine. Methods: Treatment resistant patients (2 failed medication trials) (n=31) and treatment naïve patients (no exposure to psychotropic medication) (n=31) with recurrent major depressive or bipolar disorder participated in a double-blind, placebo-controlled, crossover clinical trial. Following a placebo lead-in, participants randomly received P/S or S/P (P=3 placebo; S=3 scopolamine (4ug/kg) sessions 3 to 5 days apart). The Montgomery–Asberg Depression Rating Scale (MADRS) was the primary outcome measure. A linear mixed model was used to examine the interaction between clinical response and treatment history, adjusting for baseline MADRS. Results: Treatment resistant and treatment naïve subjects combined responded significantly to scopolamine compared to placebo (F=15.06, p<0.001). Reduction in depressive symptoms was significant by the first post-scopolamine session (F=42.75, p<0.001). A treatment history by scopolamine session interaction (F=3.37, p=0.04) indicated treatment naïve subjects had lower MADRS scores than treatment resistant patients; this was significant after the second scopolamine infusion (t=2.15, p=0.03). Limitations: Post-hoc analysis: Also, we used a single regimen to administer scopolamine, and smokers were excluded from the sample, limiting generalizability. Conclusions: Treatment naïve and treatment resistant patients showed improved clinical symptoms following scopolamine, while those who were treatment naïve showed greater improvement. Scopolamine rapidly reduces symptoms in both treatment history groups, and demonstrates sustained improvement even in treatment resistant patients. [ABSTRACT FROM AUTHOR]

Abstract: It has been suggested that atypical antipsychotic drugs (A-APDs) other than clozapine may be effective to improve positive symptoms in some patients with treatment resistant schizophrenia (TRS), if both the dose is higher, and the duration of the trial longer, than those which have been ineffective in non-TRS (NTRS) patients. This hypothesis was tested with long acting injectable risperidone (Risperdal Consta®, RLAI). One hundred sixty TRS patients selected for persistent moderate–severe delusions or hallucinations, or both, were randomized to RLAI, 50 or 100mg biweekly, in a six month, outpatient, double-blind, multicenter trial. We hypothesized that RLAI, 100mg, would be more effective than RLAI, 50mg. However, both doses produced clinically significant and equivalent improvement in PANSS Total, Positive, and Negative subscale scores, as well as key cognitive, global and functional measures, with increasing response during the course of the study, confirming the value of longer clinical trial duration for patients with TRS, but not superiority of the higher dose. The overall response rate was comparable to that previously reported for clozapine and high dose olanzapine, another A-APD, in TRS. Both doses of RLAI were equally well tolerated, producing minimal extrapyramidal side effects and few drop outs. Plasma levels of the active moiety, risperidone+9-hydroxyrisperidone, during treatment with RLAI 100mg, were comparable to those for 6–8mg/day oral risperidone, which have not been effective in TRS. Further study of RLAI, ≥50–100mg biweekly, should compare it with clozapine and oral risperidone in TRS, with duration of treatment ≥six months. [Copyright &y& Elsevier]

Abstract: Background: Treatment resistance affects up to one third of patients with schizophrenia (SCZ). A better understanding of its biological underlying processes could improve treatment. The aim of this study was to compare cortical thickness between non-resistant SCZ (NR-SCZ), treatment-resistant SCZ (TR-SCZ) patients and healthy controls (HC). Methodology: Structural MRI scans were obtained from 3 groups of individuals: 61 treatment resistant SCZ individuals, 67 non-resistant SCZ and 80 healthy controls. Images were analyzed using cortical surface modelling (implemented in freesurfer package) to identify group differences in cortical thickness. Statistical significant differences were identified using Monte-Carlo simulation method with a corrected p-cluster<0.01. Results: Patients in the TR-SCZ group showed a widespread reduction in cortical thickness in frontal, parietal, temporal and occipital regions bilaterally. NR-SCZ group had reduced cortex in two regions (left superior frontal cortex and left caudal middle frontal cortex). TR-SCZ group also showed decreased thickness in the left dorsolateral prefrontal cortex (DLPFC) when compared with patients from NR-SCZ group. Conclusions: The reduction in cortical thickness in DLPFC indicates a more severe form of the disease or a specific finding for this group. Alterations in this region should be explored as a putative marker for treatment resistance. Prospective studies, with individuals being followed from first episode psychosis until refractoriness is diagnosed, are needed to clarify these hypotheses. [Copyright &y& Elsevier]

Abstract: Background: Pregabalin is a structural analog of GABA, similar to gabapentin. It does not have a FDA indication for any psychiatric disorder in the USA. There has been one case report of the successful use of pregabalin as an augmenting agent in a patient with Bipolar Disorder (BD). In the present open label study, not subsidized by the manufacturer, the investigators prospectively evaluated the acute and maintenance efficacy of pregabalin as an adjunctive medication for a group of treatment refractory outpatients with BD. Methods: Older adolescent and adult outpatients with any type of DSM-IV diagnosed BD, who were considered treatment nonresponders to multiple standard medications for BD, were treated with adjunctive pregabalin. The baseline mood state before initiation of pregabalin was compared to the mood state after an acute trial of pregabalin using the Clinical Global Impression-Bipolar Version Scale (CGI-BP). All acute responders were treated for a minimum of two months. Follow-up maintenance treatment data was obtained for the acute pregabalin responders for three years after the 18 month acute phase of the study. Results: Fifty-eight total patients were treated adjunctively with pregabalin. Twenty-four (41%) were rated as acute responders. For the acute responders, pregabalin produced either a mood stabilizing effect, antidepressant effect or antimanic effect. Intolerable side-effects were the most common reason (79%) for a failed acute trial of pregabalin. None of the side effects resulted in serious medical complications. No patient abused pregabalin, and there were no adverse drug-drug interactions despite an average of 3.3 concurrent other psychiatric medications. The maintenance data revealed that 10 (42%) of the original 24 acute pregabalin responders were still taking pregabalin as an add-on medicine for an average of 45.2 months (range 42–48, SD: 2.35). Limitations: This study has an open label observation design. Conclusions: The results of this preliminary open study suggest that pregabalin is a safe and effective acute and maintenance adjunctive treatment for a significant number of treatment-resistant outpatients with any type of BPD. It appears to have mood stabilizing and antidepressant properties in addition to antimanic effects. Similar studies using a double-blind, randomly controlled design would be useful to confirm the reliability and validity of the results of this study. [Copyright &y& Elsevier]

Abstract: Background: Antidepressants are often the first-line treatment for depression but only one third of patients respond fully to pharmacotherapy. This paper describes the protocol for a randomised controlled trial (RCT) designed to evaluate the clinical and cost effectiveness of cognitive behavioural therapy (CBT) as an adjunct to pharmacotherapy for patients with treatment resistant depression in primary care. Methods/design: CoBalT is a two parallel group multi-centre pragmatic RCT. Eligible participants were those who: (i) were aged 18–75years; (ii) were currently taking antidepressant medication (for at least 6weeks at an adequate dose); (iii) scored ≥14 on the Beck Depression Inventory (BDI-II); (iv) had adhered to their medication; and (v) met ICD-10 criteria for depression (assessed using the Clinical Interview Schedule — revised version). Those who gave written informed consent were randomised to one of two treatment groups: usual care or usual care plus CBT. The primary outcome is depressive symptoms assessed using the BDI-II at 6months post-randomisation. Secondary outcomes measured at 6 and 12months include quality of life, antidepressant use and health care utilisation. Outcomes will be analysed on an intention-to-treat basis. Discussion: The CoBalT trial will provide evidence on the clinical and cost effectiveness of CBT as an adjunct to antidepressant medication in the treatment of depression that has not responded to pharmacotherapy. Given the move to widen access to ‘talking therapies’, the results of this study will be timely. [Copyright &y& Elsevier]

Abstract: Background: Patients with schizophrenia requiring long-term institutionalization represent those with the worst outcome, leading to personal costs for patients and relatives and constituting a large economical burden for society. Aim: To identify characteristics and predictors of outcome of institutionalized patients with schizophrenia. Method: One-year follow-up cohort study, utilizing the Danish national registers, of all institutionalized and non-institutionalized patients with schizophrenia in Denmark with an ICD-10 lifetime diagnosis of schizophrenia (F20.0–F20.9) since 1969 and alive at the index date of January 1st 2006 (total number 22,395). Results: Compared with non-institutionalized patients, institutionalized patients (n=2188; 9.8%) had earlier onset of schizophrenia and lower scholastic achievements, were more often diagnosed with a hebephrenic subtype (odds ratio (OR), 2.34; 95% confidence interval (CI), 1.95–2.80; p<0.001), received higher dosages of antipsychotics, more antipsychotic polypharmacy and more concomitant medications, and had more substance misuse and early retirement pension. In a logistic regression model adjusted for sex and age, institutionalized patients with schizophrenia had an increased risk of type II diabetes (AOR, 1.22; CI, 1.01–1.42; p<0.001), but the mean age of onset of type II diabetes did not differ. The mean patient age was higher in the institutionalized group (62.7 vs. 58.7years; p=0.027), which was mainly driven by absence of death from suicide in the institutionalized group. Multivariate predictors of institutionalization included hebephrenic subtype, a diagnosis of epilepsy, early retirement pension, male sex, a greater proportion of prior hospitalization, and substance misuse. Conclusions: Institutionalized patients with schizophrenia had a more complex and worse outcome of the disorder, except for less suicide, illustrated by lower scholastic achievement, receiving higher dosages of antipsychotic medications, more concomitant medications and more prior bed-days. [Copyright &y& Elsevier]

Background: The efficacy of transcranial magnetic stimulation (TMS) in the treatment of major depression has already been shown. Novel TMS coils allowing stimulation of deeper brain regions have recently been developed and studied. Objective: Our study is aimed at exploring the possible efficacy of deep TMS in patients with resistant depression, who previously underwent electroconvalsive therapy (ECT). Methods: Using Brainsway''s deep TMS H1 coil, six patients who previously underwent ECT, were treated with 120% power of the motor threshold at a frequency of 20 Hz. Patients underwent five sessions per week, up to 4 weeks. Before the study, patients were evaluated using the Hamilton depression rating scale (HDRS, 24 items), the Hamilton anxiety scale, and the Beck depression inventory and were again evaluated after 5, 10, 15, and 20 daily treatments. Response to treatment was considered a reduction in the HDRS of at least 50%, and remission was considered a reduction of the HDRS-24 below 10 points. Results: Two of six patients responded to the treatment with deep TMS, including one who achieved full remission. Conclusions: Our results suggest the possibility of a subpopulation of depressed patients who may benefit from deep TMS treatment, including patients who did not respond to ECT previously. However, the power of the study is small and similar larger samples are needed. [Copyright &y& Elsevier]

Treatment resistant schizophrenia (TRS), affecting approximately one-third of patients with schizophrenia, is associated with a serious impairment in global psychosocial functioning. Clozapine is the only licensed drug for TRS. However its prescription remains limited by its side effects requiring mandatory monitoring. The need to identify clinical factors associated with good response to clozapine in TRS has been established. The presence of ethnic differences in these factors and the scarcity of data on the Tunisian or more generally the North-African population warrants the conduct of a clinical study on the subject. The aim of this study was to investigate demographic, clinical, and biochemical patient characteristics as potential predictors of response to clozapine. This is a cross-sectional and retrospective study, at the "F and A psychiatry departments" of Razi Hospital in Manouba, Tunisia. All patients, with DSM 5 diagnosis of schizophrenia in its resistant form, on clozapine for at least 12 months and who consulted from June 1, 2018 to November 30, 2018 were included. We investigated premorbid functioning by the premorbid adjusment scale, demographic and clinical characteristics, and clozapine plasma level as potential clozapine response predictors. The response to clozapine was defined by a total BPRS score of 35 or less. Sixty-three patients were included in the study. The mean age at clozapine introduction was 30,84 ±9,25 years. The mean duration of clozapine treatment was 7,22 ± 4,02 years. There were 16 clozapine responders (25%) who had BPRS total scores below or equal to 35 and 47 non-responders (75%). A higher premorbid social functioning in childhood (p = 0,018) and early adolescence (p = 0,024) was associated with better response to clozapine. A delay clozapine initiation shorter than 7 years(p = 0,036), one atypical antipsychotic trial (p = 0,029) and schizophrenia paranoid subtype (p < 0.01) were found to be significantly predictive of good clozapine response. None of the demographic factors or biochemical characteristics were associated with clozapine response. Our work is consistent with previous studies suggesting the need for clinicians to be aware of the clinical predictors of a good response to clozapine to overcome their reluctance to prescribe it. It also highlighted the major prognostic role of premorbid adjustment in the clinical response to treatment. However, prospective studies including therapeutic drug monitoring would be very useful to better delineate the sub-group of patients to whom clozapine would benefit the most and to improve prescription modalities. • Investigation of factors predicting response to clozapine in a Tunisian or more generally the North-African population where data are scarce. • This study highlithed the major prognostic role of premorbid adjustment in the clinical response to treatment • Responders to clozapine had plasma clozapine levels similar to Caucasians population [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Aripiprazole may be an effective adjunctive treatment in outpatients with unipolar depression that has been refractory to treatment with SSRI or SNRI medication. Methods: Fifteen subjects with a current DSM-IV diagnosis of MDD which had not responded to SSRI or SNRI treatment were enrolled in a 12 week open-label study of aripiprazole with a maximum dose of 30 mg/day. Patients'' current episode averaged 10.4±16.6 years, with a range of 3 months to 54 years. Baseline severity averaged 30.1±7.1 on HDRS-24, and 19.7±8.4 on BDI. Patients had been treated with a mean dose of 79.2±28.2 mg/day of fluoxetine equivalents for an average of 1 year prior to starting the study. Five subjects were on SNRI medications and 10 on SSRIs. Results: Seven of 14 (50.0%) subjects were classified as treatment responders, as defined by at least 50% reduction in the HDRS-24 at week 12. Four subjects (28.6%) achieved remission, based on STAR⁎D criteria (HDRS-17 score≤7). 26.7% (4/15) of subjects discontinued participation due to side effects. Two (40%) of 5 SNRI-treated subjects responded to aripiprazole augmentation. Conclusions: These findings support previous studies for the effectiveness of aripiprazole in augmenting SSRIs or SNRIs in treatment-resistant major depression. [Copyright &y& Elsevier]

Background: Excessive glutamatergic neurotransmission may contribute to the pathophysiology of major depressive disorder (MDD). Recent evidence suggests that riluzole and other agents that target glutamate neurotransmission may show antidepressant activity. Methods: Ten patients with treatment-resistant depression had riluzole added to their ongoing medication regimen for 6 weeks, followed by an optional 6-week continuation phase. Depression and anxiety severity were assessed using the Hamilton Depression Rating Scale (HDRS) and the Hamilton Anxiety Rating Scale (HARS). Linear mixed models were used to test for a linear trend in HDRS and HARS scores across time with treatment. Results: Subjects’ HDRS and HARS scores declined significantly following the initiation of riluzole augmentation therapy. The effect of riluzole was significant at the end of the first week of treatment and persisted for the 12-week duration of the study. Conclusions: These data suggest that riluzole augmentation produces antidepressant and anxiolytic effects in patients with treatment-resistant depression. [Copyright &y& Elsevier]

Previously, we observed that the presence of a court-mandate doubled adherence to supervised disulfiram treatment over voluntary supervised disulfiram treatment during the initial twelve weeks. To assess persistence, we conducted a naturalistic followup study of adherence at 15 months in 19 voluntary and 17 court-ordered patients from the original groups. Treatment adherence, measured by the percentage of completed disulfiram clinic visits during the study period, was significantly higher in court-ordered subjects: 61.0% vs. 18.2% in the voluntary group (p< .0001). The data suggest that court assistance can exert a significant effect in maintaining adherence. Factors mediating adherence, as well as the effects of adherence on behavior change and abstinence, must be determined through prospective, controlled study. [Copyright &y& Elsevier]

Objective: To determine the effects of ECT combined with antipsychotic medication therapy on psychopathology, quality of life, and social functioning in patients with refractory schizophrenia.Method: An open acute (Phase I) and maintenance (Phase II) study of the combination of ECT and flupenthixol in the treatment of 46 schizophrenic patients who were nonresponsive to antipsychotic medication from at least two different classes. Scales used: the Brief Psychiatric Rating Scale (BPRS), the Quality of Life Scale (QLS), Social and Occupational Functioning Assessment Scale (SOFAS), Global Assessment of Functioning (GAF), and Mini-Mental State Exam (MMSE). The duration of Phase II was 1 year.Results: In Phase I, there were marked reductions in the BPRS scores, and substantial increases in the QLS, SOFAS, GAF, and MMSE scores. During Phase II, the BPRS negative symptoms worsened but remained improved from baseline. Changes in other outcome measures were negligible.Conclusion: ECT and MECT combined with flupenthixol were effective in improving psychopathology in patients refractory to antipsychotic medication alone. Ratings of psychopathology, quality of life, and social functioning all improved in Phase I and were generally sustained during Phase II in patients who had remitted. [ABSTRACT FROM AUTHOR]

In this review, we examine several special psychosocial contexts, including pregnancy and motherhood, that may seriously interfere with depressed patients’ ability or willingness to engage and remain in treatment for their depression. We also explore the kinds of often-unrecognized subsyndromal comorbidities, such as panic–agoraphobic spectrum, that may complicate conventional treatments for depression or prevent depressed patients from remaining engaged long enough to fully benefit from treatment. We argue that psychotherapy can play a crucial role in addressing the special psychosocial contexts and the kinds of comorbidities experienced by the patient with difficult-to-treat depression. For difficult-to-treat depression during pregnancy and motherhood, preliminary data from several studies suggest that 8–24 sessions of weekly interpersonal psychotherapy (IPT), often followed by monthly maintenance IPT, is a promising long-term treatment for both middle- and low-income women. For difficult-to-treat depression with panic–agoraphobic subsyndromal features, preliminary results suggest that an integrated treatment approach, combining IPT for depression and cognitive–behavioral treatment for coexisting symptoms of panic, leads to higher depression response rates. These data imply that tailoring treatments to patients’ specific needs and circumstances may be the real key to making depression less difficult to treat. [Copyright &y& Elsevier]

Treatment-resistant depression (TRD) continues to represent a major challenge for treating clinicians. This report reviews the relevant literature to evaluate whether TRD can be considered a specific subtype of depression based on 1) clinical characteristics and course (behavioral phenotype), 2) neurobiological profile, and 3) context and environment in which TRD develops. Although patients with TRD share a number of clinical, neurobiological, and context and environment characteristics, the lack of available data and the clinical heterogeneity of this condition do not currently permit the classification of TRD as a unique subtype of depression; however, this topic is worthy of further evaluation and research. Performing genetics and neuroimaging studies on patients enrolled in large, prospective and controlled studies may provide enough data for classifying TRD (or at least a part of what is currently described as TRD) as a specific subtype of depression. This in turn may facilitate the identification of more effective treatment strategies. [Copyright &y& Elsevier]

Background: Approximately half of patients who are prescribed selective serotonin reuptake inhibitors (SSRIs) either do not respond to treatment or do not experience a sustained response.Objective: The purpose of this study was to assess the efficacy of venlafaxine immediate-release (IR) and extended-release (XR) in outpatients who either did not respond to SSRI treatment or did not maintain a sustained response.Methods: Outpatients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for major depressive disorder who were previously treated with an SSRI (fluoxetine ≥20 mg/d; sertraline ≥50 mg/d; paroxetine ≥20 mg/d) for ≥6 weeks, but demonstrated an inadequate or unsustained response, were switched to venlafaxine (IR or XR formulation, 50–400 mg/d, titrated from 37.5 mg/d) for ≥6 weeks. Response at 6 to 8 weeks was defined as total score ≤10 on the modified 25-item Hamilton Depression (HAM-D25) rating scale or total score ≥5 on the 21-item Patient Global Improvement (PGI-21) scale. Remission was defined as a HAM-D25 total score ≤8 or PGI-21 score ≥7. Tests were administered by an unblinded, board-certified psychiatrist.Results: A total of 73 patients (54 women, 19 men; mean age, 38.6 years) were enrolled and treated with venlafaxine IR (n = 63) or venlafaxine XR (n = 10); 33 were SSRI nonresponders and 36 had an unsustained response to SSRI treatment. Four patients receiving venlafaxine IR discontinued due to drug-related adverse events (agitation, sedation, or nausea). Data from these patients were excluded from the analysis. After 6 to 8 weeks of treatment, 94.2% (65/69) of patients were considered responders (HAM-D25 or PGI-21 criteria); 91.3% (63/69) of patients responded to treatment as assessed by both measures. Eighty-seven percent (60/69) and 85.5% (59/69) of patients achieved remission based on HAM-D25 and PGI-21 criteria, respectively. Response/remission rates were comparable among patients treated with SSRIs, regardless of whether patients had failed to respond to treatment with 1 or 2 SSRIs.Conclusion: Venlafaxine IR/venlafaxine XR may be effective in outpatients with major depressive disorder who do not respond or have an unsustained response to SSRIs. However, randomized, controlled trials are needed before any conclusions can be drawn about the efficacy of this agent in this population. [Copyright &y& Elsevier]

• It is reported 10-year results of a clinic that applies TMS to treatment-resistant psychiatric disorders. • TMS responses of all patients were evaluated 26.1% as response, 29.2% as partial response, and 44.7% as inadequate response. • It has been determined that MDD responds to treatment better than other disorders. • Regardless of the diagnosis, a significant relationship was found between response and age. • Age and diagnosis were found to have an effect on the response to TMS. Transcranial Magnetic Stimulation (TMS) is used reliably as an alternative method in the treatment of a number of treatment-resistant psychiatric disorders. However, information about the daily practice is limited. In this article, we aim to report and discuss the 10-years results of a clinic that applies TMS to treatment-resistant psychiatric disorders. This naturalistic study is a retrospective review of data routinely collected from patients undergoing TMS between 2010 and 2020. A total of 284 patients with diagnoses of major depressive disorder (MDD), obsessive-compulsive disorder, generalized anxiety disorder, and post-traumatic stress disorder (PTSD) were included in the study. The mean age of the participants was 40.49±12.64 years. In general, when the responses of all patients were examined, 26.1% were evaluated as response, 29.2% as partial response, and 44.7% as inadequate response. It has been determined that MDD responds to treatment better than other disorders. Regardless of the diagnosis, a significant relationship was found between response and age. The multivariate logistic regression analysis suggested that patients with improvement from TMS were less likely to have advanced age and not to have been diagnosed with PTSD. The idea that TMS may be useful for some patients, but not every patient, is supported. [ABSTRACT FROM AUTHOR]

Treatment-resistant schizophrenia (TRS) is one of the subgroups of schizophrenia of which little is known with regard to its optimal mechanism. Treatment response, either as full remission of symptoms or prediction by biomarker, is important in psychiatry. We have proposed a model that integrates dopaminergic and glutamatergic systems with the biological interactions of TRS patients. We hypothesize that the subgroups of schizophrenia may be determined by glutamatergic and dopaminergic concentrations prior to medical treatment. This hypothesis implies that higher glutamatergic concentration in the brain with normalized or decreased dopamine synthesis capacity may explain aspects of TRS as observed in clinical medical practice, neuroimaging measurements, and brain stimulations. According to this hypothesis, the ability to prescribe a proper medication combination, to predict the outcome in first-episode psychosis, and personalized medicine for chronic schizophrenia patients can be applied into practice. This represents an initial step in explaining psychosis due to the valence of two neurotransmitters. Future studies are needed to examine the validity of this mechanism. [ABSTRACT FROM AUTHOR]

A growing body of evidence has demonstrated that extraintestinal pathogenic E. coli (ExPEC), such as the urinary pathogenic E. coli (UPEC), are common constituents of treated wastewater, and therefore represent a potential public health risk. However, no single virulence gene, or set of virulence genes, can be used to conclusively identify this genetically diverse pathotype. As such we sought to identify and characterize the public health relevance of potential UPEC found in treated sewage/wastewater using a comparative genomics approach. Presumptive wastewater UPEC (W-UPEC) were initially identified by virulence gene screening against 5 virulence genes, and for which isolates containing ≥3 virulence genes were whole genome sequenced (n = 24). Single nucleotide polymorphic (SNP) spanning tree analysis demonstrated that many of these wastewater UPEC (WUPEC) were virtually identical at the core genome (0.4 Mbp) when compared to clinical UPEC (C-UPEC) sequences obtained from NCBI, varying by as little as 1 SNP. Remarkably, at the whole genome level, W-UPEC isolates displayed >96% whole genome similarity to C-UPEC counterparts in NCBI, with one strain demonstrating 99.5% genome similarity to a particular C-UPEC strain. The W-UPEC populations were represented by sequence types (ST) known to be clinically important, including ST131, ST95, ST127 and ST640. Many of the W-UPEC carried the exact same complement of virulence genes as their most closely related C-UPEC strains. For example, O25b-ST131 W-UPEC strains possessed the same 80 virulence genes as their most closely related C-UPEC counterparts. Concerningly, W-UPEC strains also carried a plethora of antibiotic resistance genes, and O25b-ST131strains were designated as extended spectrum beta-lactamase (ESBL) producing E. coli by both genome profiling and phenotypic resistance testing. W-UPEC ST131 strains were found in the effluents of a single treatment plant at different times, as well as different wastewater treatment plants, suggesting a differentially ability to survive wastewater treatment. Indeed, in sewage samples treated with chlorine doses sufficient for inducing a ∼99.99% reduction in total E. coli levels, UPEC represented a significant proportion of the chlorine-resistant population. By contrast, no Shiga toxin-producing E. coli were observed in these chlorinated sewage libraries. Our results suggest that clinically-relevant UPEC exist in treated wastewater effluents and that they appear to be specifically adapted to survive wastewater treatment processes. Image 1 • Urinary pathogenic E. coli (UPEC) appear to be resistant to wastewater treatment. • Based on comparative genomics, the UPEC found in treated wastewater are clinically important. • Pathogenic UPEC strains, such as ST-131 ESBL, can be frequently found in effluents. • UPEC comprise a major portion of the E. coli discharged from wastewater treatment plants. • Unlike shigatoxin producing E. coli, UPEC appear adapted to survive wastewater treatment. [ABSTRACT FROM AUTHOR]

The opioid overdose epidemic kills about 130 people a day in the United States and it is estimated that there are about 2.1 million people who suffer from an opioid use disorder (OUD). Academic neuroscientists, psychiatrists and the National Institute of Drug Abuse have spent the last forty-years establishing the foundation of addiction as a brain disorder. It is now clear that extended opioid use causes multiple important and at times, irreversible changes to the brain, especially to its dopamine and opioid systems. With our recognized criteria for diagnosis and the accepted multifaceted treatment approach of both professional psychotherapy and medications that assist treatments, treatment failures should be limited. Unfortunately, this is not the case. Slips, relapses, overdose and multiple failures are all too common. Similar to treatment resistant depression there is a subpopulation who do not respond to standard OUD treatments. However, the field has suggested that if a treatment does not work, it is either the patients fault, they have not hit bottom or simply we need to try the same treatment again. There is a rational to consider this a new category of OUD, treatment resistant opioid use disorder (TROUD). This paper explores past treatment attempts data from OUD patients entering traditional outpatient treatment and makes recommendations how TROUD can be defined. It challenges the addiction research and treatment providers to change its focus from individuals being resistant to the unique conditions associated with this brain disorder as being resistant to treatment as usual. • We are in the midst of an OUD epidemic, characterized by overdose and relapses. • Opioid use disorder can result in irreversible changes to the brain. • The best treatments consists of professional psychotherapy interventions and medications. • There is a subpopulation who do not respond to existing best treatments. • The condition of treatment resistant opioid use disorder (TROUD) may exist. [ABSTRACT FROM AUTHOR]

Background Deep brain stimulation (DBS) has been introduced as a treatment option for treatment-resistant obsessive-compulsive disorder (OCD). However, the optimal stimulation target and the corresponding stimulation settings remain unclear. Furthermore, there is limited knowledge about the acute effects of DBS. Methods In 3 patients with treatment-resistant OCD, DBS electrodes were implanted in the bed nucleus of the stria terminalis (BNST)/internal capsule (IC). On the next day, different electrode pairs (BNST only, IC only, and BNST/IC) were stimulated at different voltages (1, 2, and 3.5 V) for 5 minutes each. Afterwards, patients rated their perceived OCD symptoms and various emotional states on corresponding visual analog scales. Results Across locations, low voltage stimulation (1 and 2 V) was associated with reduction of OCD symptoms (i.e., anxiety and tension), in particular when the IC was stimulated. High voltage stimulation (3.5 V), in particular when BNST was involved, led to less reduction of OCD symptoms. Moreover, 3.5-V stimulation of the BNST (BNST only and BNST/IC) induced higher levels of anxiety, tension, and discomfort. Subjects also reported an increase in vegetative sensations. Conclusions In summary, we demonstrate that both stimulation site and voltage settings show sweet spots (2 V at IC or BNST/IC) at which OCD symptom severity decreased while negative effects were minimal. Stimulation of IC fibers might be relevant both for acute and chronic effects. Whether acute effects are useful for outcome prediction remains to be shown in future studies. [ABSTRACT FROM AUTHOR]