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Major depressive disorder (MDD) is prevalent. Although standards antidepressants are more effective than placebo, up to 35% of patients do not respond to 4 or more conventional treatments and are considered to have treatment-resistant depression (TRD). Considerable effort has been devoted to trying to find effective treatments for TRD. This review focuses on vagus nerve stimulation (VNS), approved for TRD in 2005 by the Food and Drugs Administration. Stimulation is carried by bipolar electrodes on the left cervical vagus nerve, which are attached to an implanted stimulator generator. The vagus bundle contains about 80% of afferent fibers terminating in the medulla, from which there are projections to many areas of brain, including the limbic forebrain. Various types of brain imaging studies reveal widespread functional effects in brain after either acute or chronic VNS. Although more randomized control trials of VNS need to be carried out before a definitive conclusion can be reached about its efficacy, the results of open studies, carried out over period of 1 to 2 years, show much more efficacy when compared with results from treatment as usual studies. There is an increase in clinical response to VNS between 3 and 12 months, which is quite different from that seen with standard antidepressant treatment of MDD. Preclinically, VNS affects many of the same brain areas, neurotransmitters (serotonin, norepinephrine) and signal transduction mechanisms (brain-derived neurotrophic factor–tropomyosin receptor kinase B) as those found with traditional antidepressants. Nevertheless, the mechanisms by which VNS benefits patients nonresponsive to conventional antidepressants is unclear, with further research needed to clarify this.

IntroductionRepetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulatory treatment option, which is used in a variety of neurological and psychiatric diseases. It is approved for depression treatment and recommended in international guidelines. A significant reduction in treatment duration was achieved by using theta burst stimulation (TBS) protocols, which are practicable and non-inferior to conventional TMS.ObjectivesTo analyse the efficacy and safety of intermittent theta burst stimulation (iTBS) of left DLPFC in inpatients with treatment-resistant depression.MethodsWe evaluated n=44 inpatients with treatment resistant major depressive disorder (n=37) and bipolar depression (n=7), who were treated with the 5 Hz intermittent TBS once daily for 3-6 weeks according to clinical decision. A total of 600 pulses and 200 bursts were applied in each treatment session. Clinical and response data were obtained by chart review.ResultsMean age at time of first stimulation was 54 years. 61,3 % of patients were female. On average, the current episode started 21 months before the first stimulation. In total, 924 treatment sessions were performed. On average, patients received 21 sessions. The mean MADRS Score pre-treatment was 27.2. Post-treatment, there was a clear reduction in depression severity (MADRS 18.3). No severe adverse events and no seizures occurred in this clinical observational analysis.ConclusionsIntermittent TBS is efficacious and safe in patients with chronic and refractory depression.DisclosureNo significant relationships.

IntroductionThe lack of a standardised definition for the concept of TRD and an adequate criteria for therapeutic response make difficult the management of patients with MDD who do not achieve remission with one or more courses of treatment. All classifications suggested to define TRD are arbitrary, partially evidence-based, subordinated to the pharmacological findings of the time in which they are written and with serious inconsistencies, making it difficult to construct a universal and enduring diagnostic system.ObjectivesConsidering that the most important goal in treating a patient with Major Depressive Disorder (MDD) should be remission and return to previous functionality, the search for a standardised, evidence-based classification system will allow timely and effective interventions leading to the reduction of this devastating condition.MethodsBibliographic reviewResultsThe proposed therapeutic algorithm arises from the combination of several fundamental principles for the management of treatment-resistant depression: the different classification systems of the concept, as well as the concepts of response, relapse, recurrence and remission; the scientific evidence found in the current literature, routine clinical practice, knowledge of switching and augmentation strategies, the new pharmacological targets and neurobiological hypothesis discovered, without forgetting finally the different clinical profiles of depressive symptomatology and the specific indications of each antidepressant.ConclusionsResistant depression is difficult to treat successfully and is not a uniform entity. Recently there has been a move to characterise treatment-resistant depression as ‘difficult-to-treat’ depression on the basis that the former description implies that depression treatments are normally effective and that non-response is therefore somehow abnormal.DisclosureNo significant relationships.

Background Several meta-analyses demonstrated the efficacy of unilateral High-Frequency Left-sided (HFL) repetitive Transcranial Magnetic Stimulation (rTMS) for individuals with Major Depressive Disorder (MDD); however, results are contradictory due to heterogeneity of the included studies. Methods A systematic literature review (SLR) of English language articles published since 2000 was performed in March 2022 on PubMed and Scopus databases. Empirical evidence on the relative efficacy of rTMS treatment compared with standard pharmacotherapy in Treatment-Resistant Depression (TRD) were extracted. Random effects models were used to assess the effects of rTMS on response and remission rates. Results 19 randomized double-blinded sham-controlled studies were included for quantitative analysis for response (n = 854 patients) and 9 studies for remission (n = 551 patients). The risk ratio (RR) for response and remission are 2.25 and 2.78, respectively for patients after two treatment failures using rTMS as add-on treatment compared to standard pharmacotherapy. Cochrane’s Q test showed no significant heterogeneity. No publication bias was detected. Conclusions rTMS is significantly more effective than sham rTMS in TRD in response and remission outcomes and may be beneficial as an adjunctive treatment in patients with MDD after two treatment failures. This finding is consistent with previous meta-analyses; however, the effect size was smaller than in the formerly published literature.

[This corrects the article DOI: 10.3389/fimmu.2022.960920.].[This corrects the article DOI: 10.3389/fimmu.2022.960920.].

Starting at birth, the immune system of newborns and children encounters and is influenced by environmental challenges. It is still not completely understood how γδ T cells emerge and adapt during early life. Studying the composition of T cell receptors (TCRs) using next-generation sequencing (NGS) in neonates, infants, and children can provide valuable insights into the adaptation of T cell subsets. To investigate how neonatal γδ T cell repertoires are shaped by microbial exposure after birth, we monitored the γ-chain (TRG) and δ-chain (TRD) repertoires of peripheral blood T cells in newborns, infants, and young children from Europe and sub-Saharan Africa. We identified a set of TRG and TRD sequences that were shared by all children from Europe and Africa. Thesewere primarily public clones, characterized by simple rearrangements of Vγ9 and Vδ2 chains with low junctional diversity and usage of non-TRDJ1 gene segments, reminiscent of early ontogenetic subsets of γδ T cells. Further profiling revealed that these innate, public Vγ9Vδ2⁺ T cells underwent an immediate TCR-driven polyclonal proliferation within the first 4 wk of life. In contrast, γδ T cells using Vδ1⁺ and Vδ3⁺ TRD rearrangements did not significantly expand after birth. However, different environmental cues may lead to the observed increase of Vδ1⁺ and Vδ3⁺ TRD sequences in the majority of African children. In summary, we show how dynamic γδ TCR repertoires develop directly after birth and present important differences among γδ T cell subsets.

Objectives NLX-101 and NLX-204 are highly selective serotonin 5-HT 1A ‘biased’ agonists, displaying potent and efficacious antidepressant-like activity upon acute administration in models such as the forced swim test. Methods we compared the effects of repeated administration of NLX-101, NLX-204 and ketamine in the chronic mild stress (CMS) model of depression, considered to have high translational potential, on sucrose consumption (anhedonia measure), novel object recognition (NOR; working memory measure) and elevated plus maze (EPM; anxiety measure) in male Wistar and Wistar-Kyoto rats (the latter being resistant to classical antidepressants). Results in Wistar rats, NLX-204 and NLX-101 (0.08–0.16 mg/kg i.p.), like ketamine (10 mg/kg i.p.) dose-dependently reversed CMS-induced sucrose intake deficit from treatment Day 1, with nearly full reversal observed at the higher dose at Days 8 and 15. These effects persisted for 3 weeks following treatment cessation. In the NOR test, both doses of NLX-101/NLX-204, and ketamine, rescued the deficit in discrimination index caused by CMS on Days 3 and 17; all three compounds increased time spent in open arms (EPM) but only NLX-204 achieved statistical significance on Days 2 and 16. In Wistar-Kyoto rats, all 3 compounds were also active in the sucrose test and, to a lesser extent, in the NOR and EPM. In non-stressed rats (both strains), the three compounds produced no significant effects in all tests. Conclusions these observations further strengthen the hypothesis that biased agonism at 5-HT 1A receptors constitutes a promising strategy to achieve rapid-acting/sustained antidepressant effects combined with activity against TRD, in addition to providing beneficial effects against memory deficit and anxiety in depressed patients.

There is growing evidence to support the use of the psychedelic drug psilocybin for difficult-to-treat depression. This paper compares the cost-effectiveness of psilocybin-assisted psychotherapy (PAP) with conventional medication, cognitive behavioural therapy (CBT), and the combination of conventional medication and CBT. A decision model simulated patient events (response, remission, and relapse) following treatment. Data on probabilities, costs and quality-adjusted life years (QALYs) were derived from previous studies or from best estimates. Expected healthcare and societal costs and QALYs over a 6-month time period were calculated. Sensitivity analyses were used to address uncertainty in parameter estimates. The expected healthcare cost of PAP varied from £6132 to £7652 depending on the price of psilocybin. This compares to £3528 for conventional medication alone, £4250 for CBT alone, and £4197 for their combination. QALYs were highest for psilocybin (0.310), followed by CBT alone (0.283), conventional medication alone (0.278), and their combination (0.287). Psilocybin was shown to be cost-effective compared to the other therapies when the cost of therapist support was reduced by 50% and the psilocybin price was reduced from its initial value to £400 to £800 per person. From a societal perspective, psilocybin had improved cost-effectiveness compared to a healthcare perspective. Psilocybin has the potential to be a cost-effective therapy for severe depression. This depends on the level of psychological support that is given to patients receiving psilocybin and the price of the drug itself. Further data on long-term outcomes are required to improve the evidence base.

Abstract Background Anhedonic features within major depressive disorder (MDD) have been associated with worse course and outcome and may predict nonresponse to treatment. However, a detailed clinical profile of anhedonia in MDD is still lacking. Materials and Methods One thousand two hundred ninety-four patients with MDD were selected from the cross-sectional European multicenter Group for the Study of Resistant Depression study. Anhedonia was assessed through the Montgomery–Åsberg Depression Rating Scale anhedonia item “inability to feel.” Clinical and demographic features were then analyzed. Results The presence of anhedonia related to a distinct demographical (living alone) and clinical profile (thyroid diseases, diabetes, suicide risk, high number of previous depressive episodes, more severe MDD, and more frequent inpatient status). Furthermore, anhedonia was associated with nonresponse to treatment and treatment resistance, even after adjusting for confounding variables. Conclusions Our findings support the role of anhedonia as a modulating feature of MDD, being associated with a more severe depression profile. Moreover, anhedonic features are independent predictors of poor treatment response.