Amygdala real-time fMRI neurofeedback upregulation in treatment resistant depression: Proof of concept and dose determination.

Previous work has shown that adults suffering from major depressive disorder (MDD) can increase their amygdala reactivity while recalling positive memories via real-time neurofeedback (rt-fMRI-nf) training, which is associated with reduction in depressive symptoms. This study investigated if this intervention could also be considered for patients suffering from MDD who do not respond to standard psychological and pharmacological interventions, i.e., treatment resistant (TR-MDD). 15 participants received 5 neurofeedback sessions. Outcome measures were depressive symptoms assessed by BDI scores up to 12 weeks following acute intervention, and amygdala activity changes from initial baseline to final transfer run during neurofeedback sessions (neurofeedback success). Participants succeeded in increasing their amygdala activity. A main effect of visit on BDI scores indicated a significant reduction in depressive symptomatology. Percent signal change in the amygdala showed a learning curve during the first session only. Neurofeedback success computed by session was significantly positive only during the second session. When examining the baseline amygdala response, baseline activity stabilized/asymptoted by session 3. This proof-of-concept study suggests that only two neurofeedback sessions are necessary to enable those patients to upregulate their amygdala activity, warranting a future RCT. Over the course of the rtfMRI-nf intervention, participants also reported reduced depressive symptomatology. Clinical trial registration number: NCT03428828 on ClinicalTrials.gov.

THE EFFECT OF REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION AND PHARMACOTHERAPY ON SERUM PROTEIN S100B IN TREATMENT-RESISTANT DEPRESSION.

BACKGROUND: Transcranial magnetic stimulation (TMS) is considered an effective and fast option for treating patients with major depressive disorder. With the increase in treatment options, the determination of biomarkers that predict which treatment will benefit patients the most has been a matter of curiosity for researchers. SUBJECTS AND METHODS: In this study, we aimed to determine the changes in serum concentrations of S100B, a neurotrophic factor thought to play a role in psychiatric disorders after repetitive TMS (rTMS) and anti-depressant drugs (AD) therapy in patients with major depressive disorder(MDD).In this cohort study, rTMS was applied to the left dorsolateral prefrontal cortex(DLPFC) of drug-resistant MDD patients, while another group of MDD patients was treated with AD for three weeks. Patients were evaluated by psychometric tests and serum S100B concentration at baseline and following intervention. There was also a healthy control group in which patients' S100B values were compared at baseline. RESULTS: There is a population with a total of 48 participants.(16 healthy controls,16 anti-depressant treatment groups, 16 individuals who received rTMS in addition to anti-depressant ) A total of 48 participants completed the study, and the S100B levels of the rTMS group and the anti-depressant drug group were found to be significantly higher than the healthy control group. S100B values, which were higher in the anti-depressant and rTMS groups compared to healthy controls, showed a significant reduction in group time interaction (start and end of treatment). CONCLUSION: rTMS of DLPFC demonstrated an effective complementary treatment for treatment-resistant patients with MDD, especially for patients with relatively high serum S100B concentrations.

Cost-effectiveness analysis comparing repetitive transcranial magnetic stimulation therapy with antidepressant treatment in patients with treatment-resistant depression in Japan.

Repetitive transcranial magnetic stimulation (rTMS) for patients with treatment-resistant depression (TRD) became covered by the National Health Insurance (NHI) in Japan since 2019. Although the evidence of rTMS for TRD is well established, the cost-effectiveness of rTMS versus antidepressants has not been thoroughly analyzed in Japan. Thus, we aimed to evaluate the cost-effectiveness of rTMS for TRD under the NHI system using a microsimulation model to compare the direct costs and quality-adjusted life years (QALYs). Model inputs of clinical parameters and the utility were derived from published literature. Cost parameters were estimated from the Japanese Claim Database. The robustness of the analyses was evaluated with sensitivity analysis and scenario analysis. The analysis estimated that rTMS increased effectiveness by 0.101QALYs and total cost by ¥94,370 ($689) compared with antidepressant medications. As a result, the incremental cost-effectiveness ratio (ICER) of rTMS was estimated to be ¥935,984 ($6,832)/QALY. In the sensitivity and scenario analyses, ICER did not exceed ¥5 million ($36,496)/QALY as the reference value of the Japanese public cost-effectiveness evaluation system. rTMS therapy for TRD can be a cost-effective treatment strategy compared to antidepressant medication under the NHI system in Japan.

Tinnitus and treatment-resistant depression.

Tinnitus, a frequent disorder, is the conscious perception of a sound in the absence of a corresponding external acoustic sound source in the sense of a phantom sound. Although the majority of people who perceive a tinnitus sound can cope with it and are only minimaly impaired in their quality of lfe, 2-3% of the population perceive tinnitus as a major problem. Recently it has been proposed that the two groups should be differentiated by distict terms: "Tinnitus" describes the auditory or sensory component, whereas "Tinnitus Disorder" reflects the auditory component and the associated suffering. There is overwhelming evidence that a high tinnitus burden is associated with the increased occurrence of comorbidities, including depression. Since no causal therapeutic options are available for patients with tinnitus at the present time, the identification and adequate treatment of relevant comorbidities is of great importance for the reduction of tinnitus distress. This chapter deals with the relationship between tinnitus and depression. The neuronal mechanisms underlying tinnitus will first be discussed. There will also be an overview about depression and treatment resistant depression (TRD). A comprehensive review about the state-of-the-art evidences of the relationship between tinnitus and TRD will then be provided.

Have Effective Antidepressants Finally Arrived? Developments in Major Depressive Disorder Therapy.

Among the greatest unmet needs in major depressive disorder (MDD) is a lack of effective pharmacotherapies for patients who do not respond to first- and second-line antidepressant medications. After decades of muted progress, optimism regarding the future of MDD therapy rose after scientists serendipitously uncovered the antidepressant effects of ketamine. The discovery of ketamine's antidepressant effects inspired the search for related newer medications, such as S-ketamine. Orally administered NMDA antagonists have also demonstrated considerable promise in recently concluded, late-stage clinical trials. Researchers evaluating an extended-release combination of bupropion (105 mg) and dextromethorphan (45 mg) found that recipients experienced a decline in MADRS total score. Neurosteroids, such as brexanolone and zuranolone, appear to represent another class of antidepressants. These drugs appear to modulate GABA neurotransmission, which has long been known to be a pathway for drugs that are used to treat insomnia and anxiety. After nearly 50 years of legal injunctions against their use, psychedelic drugs have attracted interest among researchers seeking alternative antidepressants. Psilocybin, derived from mushrooms, remains under investigation for its benefits in treatment-resistant depression.

Medicare Benefits Schedule item numbers for transcranial magnetic stimulation (TMS): Questions arising.

OBJECTIVE: Four Medicare Benefits Schedule item numbers for Transcranial Magnetic Stimulation (TMS) treatment of unresponsive MDD were declared in Australia in 2021. They are accompanied by rules/conditions. The aim is to consider these rules/conditions in light of recent research and real-world experience. CONCLUSIONS: While evidence supports some listed rules/conditions, others lack clinical justification and deserve to be reconsidered. These include (a) ineligibility of patients who have previously received TMS, (b) a lifetime total limit of 50 treatments, (c) a second/final course being unavailable for 4 months following the completion of the first course, and (d) the second/final course being limited to 15 treatments.

Personal recovery associated with deep brain stimulation for treatment-resistant depression: A constructivist grounded theory study.

WHAT IS KNOWN ON THE SUBJECT?: Major depressive disorder is the most prevalent of all mental illnesses. 10%-20% of patients with depression and 1% of the population overall have treatment-resistant depression (TRD). DBS is an emerging investigational treatment for TRD with documented clinical efficacy and safety. The framework of the recovery model includes both clinical and personal recovery. Personal recovery is a self-process in which hope, empowerment and optimism are embraced to overcome the impact of mental illness on one's sense of self. Although clinical and functional outcomes of DBS for TRD have been well documented in the previous studies, personal recovery as an outcome has been explored only in a handful of studies. WHAT THIS PAPER ADDS TO EXISTING KNOWLEDGE?: This is the first qualitative study exploring personal recovery from DBS treatment specific to the target of subcallosal cingulate cortex in patients with TRD. Since the existing literature on personal recovery in DBS studies is limited, the contribution of this paper is crucial to this field. For individuals who responded to deep brain stimulation clinically, neither participants nor family believed it cured their depression, but rather there was a significant decrease in the severity of symptoms of depression. A holistic-oriented framework (that includes personal recovery) is significant for those individuals with TRD undergoing DBS. Personal and clinical recovery are two different constructs, and individuals may experience one or the other or both. The experience of participants who responded to deep brain stimulation recognized that the recovery from depression is a process of reconstructing self. This process involved a period of adjustment that evoked a deeper self-awareness, re-engagement with daily living and newfound gratitude in living. Individuals transitioned from an emotionally driven life to one where future goals were considered. Supportive relationships were instrumental in this process. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: A deep brain stimulation intervention for treatment-resistant depression offered individuals an opportunity for personal recovery where a reconstruction of self occurred. Personal recovery can be considered as an outcome in conjunction with clinical and functional outcomes in future DBS trials for TRD. The relevance of personal recovery in the prevention of relapses needs further investigation. To advocate for care and services that facilitate the process of recovery from depression, it is important to understand the personal dimensions and experience of recovery that may influence the process. To develop recovery-oriented interventions to help patients and families in recovery post-deep brain stimulation, further understanding of support and negotiating relationships during this life-altering experience is needed. ABSTRACT: Introduction Multiple trials of antidepressant treatments in patients with depression pose a major challenge to the mental health system. Deep brain stimulation (DBS) is an emerging and promising investigational treatment to reduce depressive symptoms in individuals with treatment-resistant depression (TRD). The clinical and functional outcomes of DBS for TRD have been well documented in previous studies; however, studies of personal recovery as an outcome of DBS specific to the target of subcallosal cingulate cortex in patients with TRD are limited. Aim To explore the processes of personal recovery in patients with treatment-resistant depression following subcallosal cingulate-deep brain stimulation. Method Participants were 18 patients with TRD who participated in the subcallosal cingulate (SCC)-DBS trial and 11 family members. They also participated in add-on individual cognitive behavioural therapy during the trial. A qualitative constructivist grounded theory approach was used to conceptualize the personal recovery process of patients and families. Results While every participant and their families' journey were unique following the deep brain stimulation intervention, a theoretical model of Balancing to Establish a Reconstructed Self emerged from the data. The themes underlying the model were (1) Balancing to Establish a Reconstructed Self: A Whole-Body Experience, (2) The Liminal Space in-between: Balancing with Cautious Optimism, (3) Hope: Transitioning from Emotion-Focussed Living to Goal-Oriented Planning and (4) Support: Negotiating Relationships. Discussion This is the first study examining recovery from patients' perspectives as an outcome of SCC-DBS intervention for TRD. The study shows that personal recovery is a gradual and continual process of reconstruction of the self, developing through supportive relationships. Clinical and personal recovery are two distinct constructs, and individuals may experience one or the other or both. Most patients who do respond clinically experience improvement in terms of having optimism and hope. Some patients, however, respond with significant symptom reduction but are not able to achieve personal recovery to experience joy or hope for improved quality of living. Implications for Practice Strategies for personal recovery for both patients and family need to be considered during and post deep brain stimulation intervention. Nurses working with these patients and families may benefit from education, training and support to assess and engage in conversations about their recovery process.

Brain metabolic changes and clinical response to superolateral medial forebrain bundle deep brain stimulation for treatment-resistant depression.

Deep brain stimulation (DBS) to the superolateral branch of the medial forebrain bundle is an efficacious therapy for treatment-resistant depression, providing rapid antidepressant effects. In this study, we use 18F-fluorodeoxyglucose-positron emission tomography (PET) to identify brain metabolic changes over 12 months post-DBS implantation in ten of our patients, compared to baseline. The primary outcome measure was a 50% reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) score, which was interpreted as a response. Deterministic fiber tracking was used to individually map the target area; probabilistic tractography was used to identify modulated fiber tracts modeled using the cathodal contacts. Eight of the ten patients included in this study were responders. PET imaging revealed significant decreases in bilateral caudate, mediodorsal thalamus, and dorsal anterior cingulate cortex metabolism that was evident at 6 months and continued to 12 months post surgery. At 12 months post-surgery, significant left ventral prefrontal cortical metabolic decreases were also observed. Right caudate metabolic decrease at 12 months was significantly correlated with mean MADRS reduction. Probabilistic tractography modeling revealed that such metabolic changes lay along cortico-limbic nodes structurally connected to the DBS target site. Such observed metabolic changes following DBS correlated with clinical response provide insights into how future studies can elaborate such data to create biomarkers to predict response, the development of which likely will require multimodal imaging analysis.

Understanding the Relationship Between Depression Symptom Severity and Health Care Costs for Patients With Treatment-Resistant Depression.

Objective: To examine whether measures of depression symptom severity could improve understanding of health care costs for patients with major depressive disorder (MDD) or treatment-resistant depression (TRD) from the health plan perspective.Methods: In this retrospective cohort study within an integrated health system, cohorts consisted of 2 mutually exclusive groups: (1) adults with TRD based on a standard treatment algorithm and (2) adults with MDD, but no TRD, identified through ICD-9/10-CM codes. Depression severity was measured using the Patient Health Questionnaire-9 (PHQ-9). Patterns of health care resource utilization (HRU) and costs were compared between the TRD and MDD groups overall and within the groups at different symptom levels. A general linear model with a γ distribution and log link for cost outcomes, logistic regression for binary outcomes, and negative binomial regression for count outcomes were used.Results: Patients with TRD (n = 24,534) had greater comorbidity than those in the MDD group (n = 17,628). Mean age in the TRD group was 52.8 years versus 48.2 for MDD (P < .001). Both groups were predominantly female (TRD: 72.8% vs MDD: 66.9%; P < .001). Overall, the TRD group had greater costs than the MDD group, with 1.23 times (95% CI, 1.21-1.26; P < .001) greater total cost on average over 1 year following index date. Within both groups, those with severe symptoms had greater total mean (SD) costs (TRD: moderate: $12,429 [$23,900] vs severe: $13,344 [$22,895], P < .001; low: $12,220 [$31,864] vs severe: $13,344 [$22,895], P < .001; MDD: moderate: $8,899 [$20,755] vs severe: $10,098 [$22,853]; P < .001; low: $8,752 [$25,800] vs severe: $10,098 [$22,853], P < .001).Conclusions: MDD and TRD impose high costs for health systems, with increasing costs as PHQ-9 symptom severity rises. Better understanding of subgroups with different symptom levels could improve clinical care by helping target interventions.

Racemic Ketamine as an Alternative to Electroconvulsive Therapy for Unipolar Depression: A Randomized, Open-Label, Non-Inferiority Trial (KetECT).

BACKGROUND: Ketamine has emerged as a fast-acting and powerful antidepressant, but no head to head trial has been performed, Here, ketamine is compared with electroconvulsive therapy (ECT), the most effective therapy for depression. METHODS: Hospitalized patients with unipolar depression were randomized (1:1) to thrice-weekly racemic ketamine (0.5 mg/kg) infusions or ECT in a parallel, open-label, non-inferiority study. The primary outcome was remission (Montgomery Åsberg Depression Rating Scale score ≤10). Secondary outcomes included adverse events (AEs), time to remission, and relapse. Treatment sessions (maximum of 12) were administered until remission or maximal effect was achieved. Remitters were followed for 12 months after the final treatment session. RESULTS: In total 186 inpatients were included and received treatment. Among patients receiving ECT, 63% remitted compared with 46% receiving ketamine infusions (P = .026; difference 95% CI 2%, 30%). Both ketamine and ECT required a median of 6 treatment sessions to induce remission. Distinct AEs were associated with each treatment. Serious and long-lasting AEs, including cases of persisting amnesia, were more common with ECT, while treatment-emergent AEs led to more dropouts in the ketamine group. Among remitters, 70% and 63%, with 57 and 61 median days in remission, relapsed within 12 months in the ketamine and ECT groups, respectively (P = .52). CONCLUSION: Remission and cumulative symptom reduction following multiple racemic ketamine infusions in severely ill patients (age 18-85 years) in an authentic clinical setting suggest that ketamine, despite being inferior to ECT, can be a safe and valuable tool in treating unipolar depression.

Molecular Mechanisms of Psilocybin and Implications for the Treatment of Depression.

Therapeutic deficiencies with monoaminergic antidepressants invites the need to identify and develop novel rapid-acting antidepressants. Hitherto, ketamine and esketamine are identified as safe, well-tolerated rapid-acting antidepressants in adults with treatment-resistant depression, and also mitigate measures of suicidality. Psilocybin is a naturally occurring psychoactive alkaloid and non-selective agonist at many serotonin receptors, especially at serotonin 5-HT2A receptors, and is found in the Psilocybe genus of mushrooms. Preliminary studies with psilocybin have shown therapeutic promise across diverse populations including major depressive disorder. The pharmacodynamic mechanisms mediating the antidepressant and psychedelic effects of psilocybin are currently unknown but are thought to involve the modulation of the serotonergic system, primarily through agonism at the 5-HT2A receptors and downstream changes in gene expression. It is also established that indirect effects on dopaminergic and glutamatergic systems are contributory, as well as effects at other lower affinity targets. Along with the direct effects on neurochemical systems, psilocybin alters neural circuitry and key brain regions previously implicated in depression, including the default mode network and amygdala. The aim of this review is to synthesize the current understanding of the receptor pharmacology and neuronal mechanisms underlying the psychedelic and putative antidepressant properties of psilocybin.

A Patient With Electroconvulsive Therapy-resistant Major Depressive Disorder With a Full Response to Heated Yoga: A Case Report.

Depression remains difficult to treat as a result of less than optimal efficacy and troublesome side effects of antidepressants. The authors present the case of a patient with treatment-resistant depression with melancholic features who had previously been unresponsive to electroconvulsive therapy (ECT) plus an antidepressant regimen but whose condition fully remitted with the addition of a standardized form of heated hatha yoga (HY; Bikram yoga) practiced in a room heated to 105°F. The patient was a 28-year-old woman who underwent 8 weeks of HY as part of a randomized controlled trial of HY for depression while continuing her antidepressant treatment. The patient was asked to attend a minimum of 2 weekly, 90-minute HY classes. After 8 weeks (12 classes in total), the patient no longer met the criteria for a major depressive episode with melancholic features, per Mini-International Neuropsychiatric Interview (MINI) criteria. Her depressive symptoms had improved dramatically, with Inventory of Depressive Symptomatology, Clinician-Rated (IDS-C30), and Hamilton Depression Rating Scale (HAM-D28) scores decreasing from 28 at baseline to 3, and from 28 at baseline to 4, respectively, indicating remission. This patient's ECT-resistant depression remitted with the addition of HY to her antidepressant regimen. Because of her youth and athleticism, this patient was likely well suited to this rigorous form of yoga. Further research is needed to explore HY as a potential intervention for treatment-resistant depression.

The forced swim test has poor accuracy for identifying novel antidepressants.

Despite the prevalence of treatment-resistant depression, many pharmaceutical companies have abandoned the development of new antidepressants. Experts have attributed this, in part, to the low quality of preclinical tests available in this field, often citing over-reliance on animal behavioral screens, such as the forced swim test (FST). This retrospective review assessed whether compounds tested in the FST by major pharmaceutical companies were shown to have antidepressant effects in humans. Of 109 compounds identified, only 28% had been explored for antidepressant effects in humans. Of these, there were only three for which the FST appeared to positively predict antidepressant efficacy, but none are currently approved to treat any type of depression. With such poor accuracy for identifying novel antidepressants, the FST might not be a useful screening tool for this purpose.

Ketamine: Safe and Effective Treatment for Severe Depression.

OBJECTIVE: Depression resistant to standard treatment is devastating to an individual's quality of life. Ketamine offers a safe and effective alternative to standard depression treatment, but many patients and providers are often unaware of this option. The American Association of Nurse Anesthetists and the American Psychiatric Nurses Association partnered in developing a collaborative approach to providing ketamine infusion therapy for psychiatric disorders. The purpose of this project was to disseminate information through an educational video about the safety and efficacy of outpatient low-dose ketamine infusions as an alternative therapy for treatment-resistant depression. METHODS: A thorough literature review was conducted in PubMed, PsychINFO, CINAHL, and Google Scholar for articles describing the safety and efficacy of ketamine use in treatment-resistant depression. Based on the current research, an educational video reporting the benefits and safety of ketamine was developed and launched on two social media platforms-YouTube and Facebook-for individuals to view. The effectiveness of the video was evaluated through the number of views, likes, shares, and comments recorded. RESULTS: At 9 months, 156 views, 60 likes, 8 shares, and 4 comments were recorded in both platforms. Comments indicated that viewers found the video informative and encouraging. CONCLUSIONS: A short evidence-based educational video provides individuals with information regarding the safety and efficacy of low-dose ketamine infusions as an option for depression treatment. Ketamine outpatient clinics support and treat depressed patients who do not benefit from conventional pharmacologic medications.

Theta burst stimulation for the acute treatment of major depressive disorder: A systematic review and meta-analysis.

Patients with major depressive disorder (MDD) may be refractory to or have contraindications that preclude treatment with antidepressant pharmacotherapies. Alternative therapies such as repetitive transcranial magnetic stimulation (rTMS) continue to evolve, and include theta burst stimulation (TBS), which has advantages over conventional rTMS. The aim of this study was to identify and meta-analyze efficacy data from all randomized controlled trials (RCTs) investigating TBS as a treatment for MDD. Published reports of RCTs (January 1, 2010 to October 23, 2020) were identified via systematic searches in computerized databases, followed by review of individual reports for inclusion. Inclusion criteria included primary diagnosis of MDD ≥ 1 week duration of therapy with ≥10 sessions, and treatment with any form of TBS. The Cochrane GRADE methodology and PRISMA criteria were used for evaluation of individual trials. Data from ten RCTs were included, representing 667 patients. Of these, 8 RCTs compared TBS to sham treatment and one compared TBS to standard rTMS (i.e., high frequency stimulation over left dorsolateral prefrontal cortex [HFL]). Quality of evidence assessment yielded high confidence in the finding of TBS being superior to sham on response measured by the Hamilton Depression Rating Scale (HRSD) (RR = 2.4; 95% CI: 1.27 to 4.55; P = 0.007; I2 = 40%). Comparison of HRSD response rates for TBS versus rTMS produced no statistically significant difference (RR = 1.02; 95% CI: 0.85 to 1.23; P = 0.80; I2 = 0%). The incidence of adverse events between TBS and rTMS was not statistically different. The findings of a positive effect of TBS vs. sham, and noninferiority of TBS vs. standard HFL rTMS support the continued development of TBS to treat depression.

Characterization of brain functional connectivity in treatment-resistant depression.

OBJECTIVE: To characterize the functional connectivity (FC) of target brain regions for deep brain stimulation (DBS) in patients with treatment-resistant depression (TRD), and to evaluate its gender and brain lateralization dependence. METHODS: Thirty-one TRD patients and twenty-nine healthy control (HC) subjects participated. FC of subcallosal cingulate gyrus (SCG), ventral caudate (VCa), nucleus accumbens (NAc), lateral habenula (LHb), and inferior thalamic peduncle (ITP) were evaluated using resting-state fMRI. FC was characterized by calculating the nodal 'degree', a major feature of the graph theory. RESULTS: The degree measures of the left and right VCa, the left LHb, and the left ITP were significantly greater in the TRD than in the HC group. The degree was greater in females with TRD in all these regions except the right LHb. Finally, the left hemisphere was generally more affected by depression and presented significant degrees in LHb and ITP regions of the patients. CONCLUSION: Our findings demonstrate the ability of degree to characterize brain FC and identify the regions with abnormal activities in TRD patients. This implies that the degree may have the potential to be used as an important graph-theoretical feature to further investigate the mechanisms underlying TRD, and consequently along with other diagnostic markers, to assist in the determination of the appropriate target region for DBS treatment in TRD patients.

Bright light therapy accelerates the antidepressant effect of repetitive transcranial magnetic stimulation in treatment resistant depression: a pilot study.

Objectives: We performed a randomized single-blinded study to assess the superiority of the combination strategy of repetitive Transcranial Magnetic Stimulation (rTMS) and Bright Light Therapy (BLT) over rTMS treatment alone in reducing depressive symptoms in treatment-resistant depression (TRD).Methods: We enrolled 80 inpatients with a diagnosis of TRD. All patients were randomly assigned into two groups: group A was treated with rTMS, compared to group B treated with a combination of rTMS and BLT. Depressive symptoms were weekly assessed (T0, T1, T2, T3) through the 17-item Hamilton depression rating scale (HDRS-17).Results: rANOVA (F=2.766, p=0.043) and post-hoc in HDRS-17 showed significant better scores in favour of group B every week (p<0.025, T1: 22.075 vs 17.200; T2: 16.100 vs 12.775; T3: 12.225 vs 8.900).Conclusions: The antidepressant effect of rTMS was enhanced and accelerated by its combination with BLT in treating resistant depression.KEYPOINTSAlmost one third of depressed patients does not respond to antidepressants; emerging neuromodulation and chronobiological techniques are effective antidepressant augmentation treatments.The aim of this study was to assess the superiority of the combination strategy of Light Therapy and TMS over TMS treatment alone in a group of treatment resistant depressed patients.The implication of this study in clinical practice is that a safe, low risk and cost-effective treatment, as Light Therapy, improves and accelerates the antidepressant effect of TMS.

[Psychiatry]. / Psychiatrie.

The Covid-19 pandemic has a major impact on psychiatry by its social consequences and possible direct effect of certain forms of Covid-19 on mental health. During this crisis, the accessibility of technology meets a state of necessity, which has propelled telepsychiatry from the shadows into the light. The contribution of several technologies (i.e. virtual reality, actigraphy, computational psychiatry) combining clinical data and neuroscience underlines the great neurobehavioural variability even within the same diagnostic category, calling for greater precision in therapeutic offers as suggested e.g. by developments in neurofeedback. The place of intranasal esketamin in the panoply of antidepressent drug treatments for resistant depression has not yet been defined.

La pandémie de Covid-19 bouleverse la psychiatrie par ses conséquences sociales et par de possibles séquelles psychiatriques. La crise actuelle révèle l'accessibilité de technologies digitales telles que la télépsychiatrie. Des technologies comme la réalité virtuelle, l'actigraphie, la psychiatrie computationnelle combinées aux données cliniques et aux neurosciences révèlent une importante variabilité neurocomportementale même au sein d'une catégorie diagnostique donnée, invitant à une plus grande précision des traitements comme suggéré par les recherches en neurofeedback. La place de l'eskétamine intranasale dans la panoplie thérapeutique médicamenteuse de la dépression résistante doit encore être définie.

The burden and the challenge of treatment-resistant depression.

Treatment resistant depression (TRD) is a serious public health problem. It is estimated that around 20- 40% of patients with a major depressive episode (whether monopolar or bipolar) do not exhibit clinical response to the current treatment with antidepressants, that is at least 50% decline in the symptoms scale. Furthermore, about half of the patients with symptom amelioration present residual symptoms which continue to negatively affect their functioning and increase the chance of relapse. Therefore, only 20-40% of patients (36.8% in STAR*D)1 who receive therapy for a major depressive episode for the first time exhibit remission (i.e., at least 70% decrease in symptom severity or HAMD score ≤7/MADRS score ≤10)2 - which is the goal of current treatments. Even when remission is achieved, though, there is often a long way to recovery and to the patient's return to the prior state of occupational and social functioning. Moreover, long-term medical treatment is needed in order to achieve and maintain the above.3 TRD is characterized by high rates of comorbidity (hypertension, diabetes mellitus, heart failure), doubles the rates of hospitalizations and lengthens the time of hospitalization by 36%, while the percentage of suicidal incidents is seven times higher in TRD compared to cases of treatment-responsive depression.4 TRD exhibits higher rates of mortality than treatment-responsive depression, with all-cause mortality rate being higher5 by 29-35% and similar to that of older by 13 years, non-depressed individuals. Despite its common occurrence and the fact that TRD constitutes an important issue in the treatment of major depression disorder (MDD), experts still disagree on the exact meaning of the term. The most widely accepted and used term of TRD refers to treatment resistance as treatment with at least two different antidepressants (of the same or different classes), administered in the right doses and for an adequate amount of time, with verified patient compliance to treatment which, however, fails to produce significant clinical results.6 Other terms have also been used as an alternative, for example Difficult to Treat Depression in order to avoid nihilism - something often seen in these cases;7 Drug Resistant Depression so as to determine the exact kind of resistance and also to underline the need for combination therapy with intervention such as psychotherapy and ECT; Multiple Therapy Resistant MDD; Pernicious Depression8 etc. Treatment of TRD is a challenge for every clinician. After excluding the possibility of pseudo-resistance due to misdiagnosis, insufficient therapeutic regimen, comorbid disorders, such as anxiety disorders, eating disorders, personality disorders, substance abuse/addiction, PTSD, non-compliance to treatment, non-identified organicity and chronic stressors, the therapeutic methods used include: optimization, watchful waiting, past response, combination treatment, add-on treatments, ECT, TMS, vagus nerve stimulation, phototherapy, psychotherapy, neurosurgery. All the above are thoroughly discussed in this Supplement issue of Psychiatriki.9.

[Clinical characteristics and treatment of treatment-resistant bipolar depression].

Depression represents the predominant mood pole in bipolar disorder. Bipolar depression typically has a poor response to antidepressant medication, and also involves the risk of polarity shifts, induction of mixed states, and / or rapid cycle induction. The diagnosis of bipolar depression can be delayed by 8 to 10 years. The reason for this delay is mainly the fact that both manic and hypomanic episodes appear lately in the course of the disorder. It is therefore necessary to diagnose this clinical entity as early as possible versus monopolar depression in order to treat it more effectively. This differential diagnosis is based on certain clinical features of bipolar depression, which are often difficult to be distinguished from those of monopolar depression and therefore it is necessary to know specific criteria that differentiate them to some extent qualitatively and / or quantitatively. Such characteristics are daily mood swings, multiple physical complaints, psychomotor retardation, psychotic elements (delusions and perceptual disorders mood congruent or noncongruent), the disturbance of certain bodily functions, including circadian rhythms, sexual desire, appetite, and disorders of sleep architecture. The treatment of bipolar depression is based on the options known from monopolar depression (such as the use of antidepressants, antipsychotics, and certain antiepileptic agents) and their combinations, while in recent years it has been enriched with new pharmaceutical agents and non-pharmacological approaches. New glutaminergic regulators dominate the new pharmacological agents' research, and among them the antidepressant effect of ketamine and esketamine at sub-anesthetic doses is being extensively investigated during recent years. Non-pharmacological approaches include methods such as electroconvulsive therapy, repetitive transcranial magnetic stimulation (rTMS), sleep deprivation, and phototherapy.