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.

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.

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.

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.

Lithium treatment in the era of personalized medicine.

In 1949, an Australian psychiatrist, John Cade, reported on the antimanic efficacy of lithium carbonate, which is regarded as an introduction of lithium into contemporary psychiatry. Since the 1960s, lithium has been a precursor of mood stabilizers and has become first-choice drug for the prevention of affective episodes in mood disorders. For nearly four decades, lithium has also been used for the augmentation of antidepressant drugs in treatment-resistant depression. The knowledge of clinical and biological factors connected with the capability of long-term lithium treatment to prevent manic and depressive recurrences makes an important element of the personalized medicine of mood disorders. Excellent prophylactic lithium responders can be characterized by distinct mood episodes, with full remissions between them, the absence of other psychiatric morbidity, and the family history of bipolar illness. In recent years, many other clinical and biological factors connected with such a response have been identified, helping to select the best candidates for lithium prophylaxis. The antisuicidal effect of lithium during its long-term administration has been demonstrated and should also be taken into account as the element of personalized medicine for the pharmacological prophylaxis of patients with mood disorders. Several studies pertaining to personalized medicine were also dedicated to lithium treatment of acute mood episodes. Lithium still has a value in the treatment of mania and bipolar depression. However, it seems that the more important indication would be the augmentation of antidepressant drugs in treatment-resistant depression. The factors connected with the efficacy of lithium in these conditions are reviewed.

Changes in inflammatory biomarkers are related to the antidepressant effects of Ayahuasca.

BACKGROUND: Ayahuasca is a traditional Amazon brew and its potential antidepressant properties have recently been explored in scientific settings. We conducted a double-blind placebo-controlled trial of ayahuasca with treatment-resistant depression patients (n = 28) and healthy controls (n = 45). AIMS: We are evaluating the blood inflammatory biomarkers: C-reactive protein and interleukin 6, as a potential consequence of ayahuasca intake and their correlation with serum cortisol and brain-derived neurotrophic factor levels. Blood samples were collected at pre-treatment and 48 hours after substance ingestion to assess the concentration of inflammatory biomarkers, together with administration of the Montgomery-Åsberg Depression Rating Scale. RESULTS: At pre-treatment, patients showed higher C-reactive protein levels than healthy controls and a significant negative correlation between C-reactive protein and serum cortisol levels was revealed (rho = -0.40, n = 14). C-reactive protein in those patients was not correlated with Montgomery-Åsberg Depression Rating Scale scores. We observed a significant reduction of C-reactive protein levels across time in both patients and controls treated with ayahuasca, but not with placebo. Patients treated with ayahuasca showed a significant correlation (rho = + 0.57) between larger reductions of C-reactive protein and lower depressive symptoms at 48 hours after substance ingestion (Montgomery-Åsberg Depression Rating Scale). No significant result with respect to interleukin 6 and brain-derived neurotrophic factor was found. Furthermore, these biomarkers did not predict the antidepressant response or remission rates observed. CONCLUSIONS: These findings enhance the understanding of the biological mechanisms behind the observed antidepressant effects of ayahuasca and encourage further clinical trials in adults with depression.

Effects of ketamine on circadian rhythm and synaptic homeostasis in patients with treatment-resistant depression: A protocol for mechanistic studies of its rapid and sustained antidepressant actions in humans.

BACKGROUND: The breakthrough discovery has been made that a single dose of ketamine, an N-methyl-D-aspartate receptor antagonist, achieves rapid and sustained (~7 days) antidepressant activity in patients with major depressive disorder (MDD). This discovery has ushered in an exciting era of research and brought new hope for patients with MDD. However, the mechanisms underlying the specific antidepressant actions of ketamine in humans remain to be elucidated. OBJECTIVES: This study protocol was designed to test the main hypothesis that ketamine could rapidly reverse depression- and stress-associated synaptic loss and deficits in resting-state functional connectivity and that this action could be affected by circadian rhythm, in patients with treatment-resistant depression. METHODS/STUDY DESIGN: In this clinical study, adults (aged 18-65 years) with treatment-resistant depression will be randomized to intravenous administration of placebo (control group) or ketamine (0.5 mg/kg body weight) at 11 a.m. (daytime group), or 6 p.m. (nighttime group) for 24 weeks. The primary outcome will be the change from baseline to 24 weeks in the total Montgomery-Asberg Depression Rating Scale score. Brain imaging, sleep, and genetic studies, including functional magnetic resonance imaging, positron emission tomography, polysomnography, and genetic analyses, will be performed to examine whether and how ketamine can rapidly reverse deficits in synaptic function and to identify objective markers for the assessment of ketamine infusion therapy for treatment-resistant depression. CONCLUSIONS: This clinical study protocol is the first, to our knowledge, to describe the prospective testing of the hypothesis that daytime and nighttime administrations of ketamine would have different antidepressant effects. The brain imaging, sleep, and genetic findings from patients with treatment-resistant depression are expected to shed new light on the mechanisms of ketamine and its interaction with target sites in the brain, which can be used for objective evaluation of the efficacy of ketamine.

Keeping up with the clinical advances: depression.

Major depressive disorder (MDD) is a prevalent and heterogeneous disorder. Although there are many treatment options for MDD, patients with treatment-resistant depression (TRD) remain prevalent, wherein delayed time to response results in inferior chances of achieving remission. Recently, therapeutics have been developed that depart from the traditional monoamine hypothesis of depression and focus instead on the glutamatergic, GABAergic, opioidergic, and inflammatory systems. The literature suggests that the foregoing systems are implicated in the pathophysiology of MDD and preclinical trials have informed the development of pharmaceuticals using these systems as therapeutic targets. Pharmaceuticals that target the glutamatergic system include ketamine, esketamine, and rapastinel; brexanolone and SAGE-217 target the GABAergic system; minocycline targets the inflammatory system; and the combinatory agent buprenorphine + samidorphan targets the opioidergic system. The aforementioned agents have shown efficacy in treating MDD in clinical trials. Of particular clinical relevance are those agents targeting the glutamatergic and GABAergic systems as they exhibit rapid response relative to conventional antidepressants. Rapid response pharmaceuticals have the potential to transform the treatment of MDD, demonstrating reduction in depressive symptoms within 24 hours, as opposed to weeks noted with conventional antidepressants. Novel therapeutics have the potential to improve both patient mood symptomatology and economical productivity, reducing the debased human capital costs associated with MDD. Furthermore, a selection of therapeutic targets provides diverse treatment options which may be beneficial to the patient considering the heterogeneity of MDD.

Treatment-resistant depression as risk factor for substance use disorders-a nation-wide register-based cohort study.

BACKGROUND AND AIMS: Treatment-resistant depression (TRD) is common among patients with major depressive disorder (MDD). MDD may increase the risk for developing substance use disorders (SUD). The aim of this study was to investigate the risk for developing SUD among patients with TRD compared with other depressed patients. DESIGN: Observational cohort study. SETTING: Nation-wide governmental health registers in Sweden. PARTICIPANTS: All patients aged 18-69 years with an MDD diagnosis in specialized health care who had received at least one antidepressant prescription during 2006-14 were identified. Patients with at least three treatment trials within a single depressive episode were classified with TRD. MEASUREMENTS: Patients with TRD were compared with the whole MDD cohort regarding risk for obtaining a SUD diagnosis or medication using survival analyses adjusted for socio-demographics and comorbidities. FINDINGS: Of 121 669 MDD patients, 13% were classified with TRD. Among the patients without any history of SUD, patients with TRD had a risk increase for any SUD both ≤ 1 and > 1 year after antidepressant initiation [> 1 year hazard ratio (HR) = 1.4; 95% confidence interval (CI) = 1.3-1.5]. Risks were elevated for the subcategories of opioid (HR = 1.9, 95% CI = 1.4-2.5) and sedative SUD (HR = 2.7, 95% CI = 2.2-3.2). Patients with a history of SUD had a risk increase for any SUD ≤ 1 year after start of treatment (HR = 1.2, 95% CI = 1.1-1.4), and both ≤ 1 year and > 1 year for sedative (> 1 year HR = 2.0, 95% CI = 1.3-3.0) and multiple substance SUD (HR = 1.9, 95% CI = 1.4-2.5). CONCLUSIONS: Patients with treatment-resistant depression may be at greater risk for substance use disorders compared with other patients with major depressive disorder. Patterns may differ for patients with and without a history of substance use disorders, and for different categories of substance use disorder.

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial.

BACKGROUND: Recent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression. METHODS: To test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing. RESULTS: We observed significant antidepressant effects of ayahuasca when compared with placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared with placebo at D1 and D2 (p = 0.04), and at D7 (p < 0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen's d = 0.84; D2: Cohen's d = 0.84; D7: Cohen's d = 1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64% v. 27%; p = 0.04). Remission rate showed a trend toward significance at D7 (36% v. 7%, p = 0.054). CONCLUSIONS: To our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression. This study is registered at http://clinicaltrials.gov (NCT02914769).

Augmentation of Pharmacotherapy by Sleep Deprivation with Sleep Phase Advance in Treatment-Resistant Depression.

INTRODUCTION: The aim was to assess the efficacy of total sleep deprivation (TSD) with sleep phase advance (SPA) in treatment-resistant depression (TRD) and associated biochemical factors. METHODS: We studied nine males and 12 females, aged 49±14 years, with treatment-resistant unipolar or bipolar depression, receiving antidepressant and mood-stabilizing drugs. The four-day schedule included single TSD and three consecutive nights with SPA. Biochemical markers were measured on the day before and on 1st, 7th and 14th day after the TSD. RESULTS: Ten subjects met criteria for response, defined as a reduction of ≥50% in the Hamilton Depression Rating Scale, on the 14th day. Concentrations of cortisol at baseline were lower in responders, and they decreased during therapy in both groups. In responders, there was an increase of interleukin-10 (IL-10) and IL-1ß on the 14th day. DISCUSSION: Our preliminary study demonstrated the efficacy of pharmacotherapy augmentation by TSD and SPA in half of the patients with TRD. The main biochemical factors related to clinical response included status of cortisol and increase in IL-10 and IL-1ß levels.