Cytokines changes associated with electroconvulsive therapy in patients with treatment-resistant depression: a Meta-analysis.

One third of depressive patients do not achieve remission after several steps of treatment and are considered as treatment resistant. Electroconvulsive therapy (ECT) improves symptoms in 70 to 90% of such cases. Resistant depression is associated with a dysregulation of the immune system with a dysbalance between the pro- and the anti-inflammatory cytokines. Therefore, we aimed to measure the kinetic of cytokines levels before, during and at the end of ECT. To test this hypothesis, we performed a meta-analysis assessing cytokines plasma levels before, during and after ECT in patients with major depressive disorders. After a systematic database search, means and standard deviations were extracted to calculate standardized mean differences. We found that IL-6 levels increased after 1 or 2 ECT session (p = 0.01) then decrease after 4 ECT sessions (p < 0.01) with no difference at the end of ECT (p = 0.94). A small number of studies were included and there was heterogeneity across them. The present meta-analysis reveals that ECT induces an initial increase of IL-6 levels and a potential decrease of TNF-α levels. No changes on IL-4 and IL-10 levels were found. Further work is necessary to clarify the impact of ECT on peripheral cytokines.

Inflammation-related microRNAs are involved in stressful life events exposure and in trauma-focused psychotherapy in treatment-resistant depressed patients.

Background: About 30% of major depressive disorder (MDD) patients are classified as resistant to treatment (treatment-resistant depression, TRD). Among the factors associated with unfavourable treatment outcomes, stressful life events play a relevant role, and trauma-focused psychotherapy has been successfully proposed for the treatment of patients with a history of such events. Stressful experiences are related to enhanced inflammation and, recently, microRNAs (miRNAs) have emerged as potential mediators of the association between these experiences and psychiatric disorders. To date, no study has explored the effects of stressful life events on miRNAs in MDD patients. Objective: The objective of the present study was to assess possible miRNA blood expression alterations in TRD patients induced by the exposure to stressful life events and to investigate the effects of trauma-focused psychotherapy on the expression profiles of the same miRNAs, as well as their possible predictivity in relation to therapy outcome. Method: The basal levels (T0) of seven candidate miRNAs (miR-15a/miR-29a/miR-125b/miR-126/miR-146a/miR-195/let-7f) were measured in the whole blood of 41 TRD patients. A subgroup of patients (n = 21) underwent trauma-focused psychotherapy; for all of them, miRNA levels were also longitudinally assessed (T4: after 4 weeks of treatment; T8: end of treatment; T12: follow-up visit), contextually to clinical evaluations. Results: miR-146a levels negatively correlated with recent stressful life event scores (p = .001), whereas the levels of miR-15a, miR-29a, miR-126, miR-195, and let-7f changed during the psychotherapy (best p = 1.98*10-9). miR-29a was also identified as a response predictor, with lower baseline levels predicting non-response (p = .019) or worse improvement in mood symptoms (p = .032). Conclusions: The study results could contribute to clarify the underlying molecular mechanisms and to identify novel biomarkers of stressful experiences and response to targeted treatments.

Antecedentes: Alrededor del 30% de los pacientes con un Trastorno Depresivo Mayor (TDM) son clasificados como resistentes a tratamiento (Depresión Resistente a Tratamiento, TRD por su sigla en inglés). Entre los factores asociados a resultados de tratamiento desfavorables, los eventos vitales estresantes juegan un rol relevante, y la psicoterapia con foco en el trauma ha sido propuesta con éxito para el tratamiento de los pacientes con historia de tales eventos. Las experiencias estresantes están relacionadas a un aumento de la inflamación y, recientemente, microARNs (miARNs), han surgido como potenciales mediadores de la asociación entre estas experiencias y trastornos psiquiátricos. A la fecha, ningún estudio ha explorado los efectos de los eventos vitales estresantes sobre los miARNs en pacientes con TDM.Objetivo: El objetivo del presente estudio fue evaluar posibles alteraciones en la expresión de miARN en sangre en pacientes con TRD inducidas por la exposición a eventos vitales estresantes e investigar los efectos de la psicoterapia con foco en el trauma sobre los perfiles de expresión de los mismos miARNs, así como su posible predictividad en relación al resultado de la terapia.Método: Los niveles basales (T0) de 7 miARN candidatos (miR-15a/miR-29a/miR-125b/miR-126/miR-146a/miR-195/let-7f) fueron medidos en la sangre completa de 41 pacientes con TRD. Un subgrupo de pacientes (n = 21) se sometió a psicoterapia con foco en el trauma; para todos ellos, los niveles de miARN fueron también evaluados longitudinalmente (T4: después de 4 semanas de tratamiento; T8: fin del tratamiento; T12: visita de seguimiento), contextualmente a evaluaciones clínicas.Resultados: Los niveles de miR-146a se correlacionaron negativamente con los puntajes de eventos vitales estresantes recientes (p = .001), mientras que los niveles de miR-15a, miR-29a, miR-126, miR-195, y let-7f cambiaron durante la psicoterapia (mejor p = p = 1.98*10−9). miR-29a también fue identificado como un predictor de respuesta, con menores niveles basales prediciendo falta de respuesta (p = .019) o menor mejoría en los síntomas anímicos (p = .032).Conclusiones: Los resultados del estudio contribuyen a clarificar los mecanismos moleculares subyacentes y a identificar nuevos biomarcadores de experiencias estresantes y respuesta a tratamientos dirigidos.

Peripheral vascular endothelial growth factor changes after transcranial magnetic stimulation in treatment-resistant depression.

OBJECTIVES: To determine if vascular endothelial growth factor (VEGF) changes with transcranial magnetic stimulation (TMS) in treatment-resistant major depressive disorder (MDD). METHODS: Serum from a naturalistic population of 15 patients with MDD was collected at baseline and after standard TMS treatment. VEGF concentration was determined via ELISA. Inventory of Depressive Symptomatology Self Report and Patient Health Questionnaire were used as a measure of depression symptom severity, clinical response and remission. Mann-Whitney U and Kendall's Tau Correlation were used for continuous variables. RESULTS: VEGF increased from pre- to post-TMS (+30.3%) in remitters whereas VEGF decreased in non-remitters (-9.87%) (P < 0.05). This same pattern was observed when comparing mean %change in VEGF between responders (+14.7%) and non-responders (-14.9%) (P = 0.054). Correlation was present between change in VEGF concentration (baseline to post) and change in Inventory of Depressive Symptomatology-Self Report at Tx30 (r = -0.371, P < 0.054), reflecting greater increases in VEGF linked to greater improvement in depressive symptoms following the standard 6-week course of TMS. CONCLUSION: Patients with a successful treatment with TMS had significantly greater increase in VEGF from baseline to after treatment compared to non-responders/non-remitters and a larger increase in VEGF was associated with greater improvement in depressive symptoms after TMS. This is the first report examining VEGF levels in depressed patients receiving TMS. This study provides correlative data supporting further investigation into VEGF's role as an important mediator in the processes underpinning TMS' antidepressant effects and as a potential biomarker of clinical outcomes.

Changes in interleukin-1 beta induced by rTMS are significantly correlated with partial improvement of cognitive dysfunction in treatment-resistant depression: a pilot study.

The impairment experienced by many individuals with depression is closely related to the cognitive symptoms of the disorder. Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation method that provides a promising technique for improving cognitive symptoms in treatment-resistant depression (TRD). It has recently been demonstrated that TRD is associated with increased inflammatory process. In the present study, we investigated whether a relationship exists between changes in cognitive function and those in inflammatory cytokines before and after rTMS treatment. Eleven patients with TRD were enrolled in a high-frequency (10 Hz) rTMS study. Cognitive function, depressive symptoms and serum concentration of inflammatory cytokines (interleukin (IL)-1ß, IL-6 and tumor necrosis factor-α) were measured at baseline and at the endpoint of rTMS treatment. rTMS treatment significantly improved depressive symptom scores and some subscales of cognitive dysfunction. The present study has demonstrated that partial changes in cognitive function and changes in IL-1ß were significantly correlated. The partial improvement of cognitive dysfunction by rTMS in the present study might be attributable to the reduction of peripheral IL-1ß levels. The present results should be replicated for verification in future studies.

Rare variants and biological pathways identified in treatment-refractory depression.

Individuals diagnosed with major depressive disorder not responding to at least two adequate treatments are defined as treatment-refractory major depressive disorder (TR-MDD). Some TR-MDD patients have altered metabolic phenotypes that may be pharmacologically reversed. The characterization of these phenotypes and their underlying etiologies is paramount, particularly their genetic components. In this study, TR-MDD patients (n = 124) were recruited and metabolites were quantified in their cerebrospinal fluid (CSF) and peripheral blood. Three sub-categories of deficiencies were examined, namely 5-methyltetrahydrofolte (in CSF; n = 13), tetrahydrobiopterin (in CSF; n = 11), and abnormal acylcarnitine profiles (in peripheral blood; n = 8). Whole exome sequencing was performed on genomic DNA from the entire TR-MDD cohort and exonic variant allele frequencies for cases were compared to a control cohort (1:5 matching on ancestry). Low frequency, damaging alleles were identified and used for in silico pathway analyses. Three association signals for TR-MDD approached genome-wide significance on chromosomes 22, 7, and 3. Three risk-associated variants from a prior depression study were replicated. Relevant biological pathways were identified that contained an enrichment of rare, damaging variants in central nervous system (CNS)-specific pathways, including neurotransmitter receptors, potassium channels, and synapse transmission. Some TR-MDD patients had rare variants in genes that were previously associated with other psychiatric disorders, psychiatric endophenotypes, CNS structural defects, and CNS-related cellular and molecular functions. Exome analysis of metabolically phenotyped TR-MDD patients has identified potentially functional gene pathways and low frequency, deleterious gene variants for further investigation. Further studies in larger cohorts of biochemically phenotyped TR-MDD patients are desirable to extend and confirm these findings.

Serum level of soluble interleukin 6 receptor is a useful biomarker for identification of treatment-resistant major depressive disorder.

AIM: A substantial proportion of major depressive disorder patients are treatment-resistant to antidepressant therapy, who require augmentation drugs, or other treatments including electroconvulsive therapy or transcranial magnetic stimulation. Identifying treatment-resistant major depressive disorder patients before the actual administration of antidepressant is, however, often difficult. Accordingly, the serum biomarker to identify treatment-resistant patients will be helpful in clinical settings. This study aims to clarify the appropriate biomarkers for identification of treatment-resistant major depressive disorder. METHOD: Given that immune-inflammatory processes are involved in the pathogenesis of major depressive disorder, it is possible that certain cytokine-related molecules could serve as clinically useful biomarkers of treatment-resistant major depressive disorder patients. In this study, we measured serum levels of tumor necrosis factor-α, interleukin 6, and soluble interleukin 6 receptor after major depressive disorder patients underwent antidepressant therapy. RESULTS: The serum level of soluble interleukin 6 receptor, but not interleukin 6 or tumor necrosis factor-α, was significantly higher in treatment-resistant major depressive disorder patients than in remitted patients, suggesting that serum soluble interleukin 6 receptor could be a good biomarker of treatment-resistant major depressive disorder. Receiver operating characteristic analysis confirmed that serum soluble interleukin-6 receptor level measurement was useful for identification of treatment-resistant major depressive disorder patients. Multiple regression analysis using the serum levels of the aforementioned cytokines as explanatory variables and the Quick Inventory of Depressive Symptomatology-Self Report score (QIDS-SR16 ) as a target variable showed that only serum soluble interleukin-6 receptor level could explain the severity of major depressive disorder. CONCLUSION: Based on these results, we recommend measurement of serum soluble interleukin-6 receptor level to discriminate treatment-resistant major depressive disorder patients. High serum soluble interleukin-6 receptor level is associated with the pathogenesis of treatment-resistant major depressive disorder, suggesting the involvement of the interleukin 6 trans-signaling system in onset of treatment-resistant major depressive disorder.

A High Plasma Lamotrigine Concentration at Week 2 as a Risk Factor for Lamotrigine-Related Rash.

BACKGROUND: Reportedly, a high plasma concentration of lamotrigine plays a role in the development of lamotrigine-related rash. The relationship between plasma concentrations of lamotrigine at week 2 and the lamotrigine-related rash was prospectively studied in 84 patients (22 males and 62 females) with treatment-resistant depressive disorder during an 8-week treatment of lamotrigine augmentation. METHODS: Eighty-four depressed patients with an insufficient response to at least 3 psychotropics, including antidepressants, mood stabilizers, and atypical antipsychotics, were included. The diagnoses were major depressive disorder (n = 39), bipolar I disorder (n = 10), and bipolar II disorder (n = 35). The final doses of lamotrigine were 100 mg/d for 57 subjects who were not taking valproate and 75 mg/d for 27 subjects taking valproate. Blood sampling was performed at week 2. Lamotrigine plasma concentrations were measured using high-performance liquid chromatography. The development of lamotrigine-related rash was assessed during the 8-week treatment. RESULTS: Six females developed lamotrigine-related rash. The mean plasma lamotrigine concentrations at week 2 were significantly (P = 0.009) higher in the rash group (4.81 ± 1.23 µmol/L) than in the nonrash group (3.35 ± 1.39 µmol/L). Receiver-operating characteristic analysis indicated that a plasma lamotrigine concentration of 4.38 µmol/L or greater at week 2 was significantly (P < 0.0001) predictive of lamotrigine-related rash. The proportion of patients with a lamotrigine concentration of 4.38 µmol/L or greater was significantly divided by the cutoff point into the rash group and the nonrash group (5/1 versus 13/65, P = 0.001). CONCLUSIONS: This study suggests that a high plasma lamotrigine concentration during week 2 is a risk factor for lamotrigine-related rash and a plasma lamotrigine concentration of 4.38 µmol/L may be a considered a threshold for rash in treatment-resistant depressive disorder.

Inflammatory markers and treatment outcome in treatment resistant depression: A systematic review.

BACKGROUND: A substantial percentage of depressed patients do not respond satisfactorily to conventional antidepressant treatment. This treatment resistant depression (TRD) may be partly related to inflammatory processes in the central nervous system. Accordingly, peripheral inflammatory markers might serve to predict treatment response with novel but still experimental forms of antidepressant treatment. METHODS: A literature search on treatment of TRD and inflammatory markers was performed using the PubMed/Medline database on November 8th 2018, and 95 articles were retrieved initially, which were subsequently screened and selected only when the inclusion and exclusion criteria were met. RESULTS: Ten studies were recruited. In five studies higher baseline interleukin-6 (IL-6) or C-reactive protein (CRP)/high-sensitivity-CRP (hsCRP) in blood predicted better response to medication with anti-inflammatory characteristics, such as ketamine and infliximab. One study found that higher IL-6 predicted worse response to antidepressant treatment in patients with TRD. No evidence was found for the predictive value of other inflammatory markers (e.g., Tumor Necrosis Factor-α, Interferon-γ). LIMITATIONS: The number of available studies was limited; included studies showed considerable methodological variation and used different definitions for TRD. CONCLUSION: The inflammatory markers IL-6 and CRP/hsCRP could hold promise as markers for the prediction of treatment response in TRD. Clearly, this field of research is still far from mature but it could pave the way for novel and efficacious treatments for at least the inflammatory type of TRD with more well-designed studies and more convincing results.

Treatment of patients with geriatric depression with repetitive transcranial magnetic stimulation.

Repetitive transcranial magnetic stimulation (rTMS) has become a useful tool to treat different neuropsychiatric conditions such as depression, dementia and extrapyramidal syndromes insufficiently responding to conventional treatment. In this SHAM-controlled exploratory study safety, symptom improvement as well as changes in inflammation markers and neurotransmitter precursor amino acids availability were studied after a prefrontal cortex (PFC) stimulation using rTMS as add-on treatment in 29 patients with geriatric depression. Out of these, ten patients received SHAM treatment. Treatment was well tolerated, no serious adverse effects were observed. A clear improvement in symptoms of depression with a significant decrease in the HAMD-7 (U = 3.306, p = 0.001) was found by rTMS treatment. In parallel, serum phenylalanine dropped significantly (U = 2.340, p < 0.02), and there was a decline of tryptophan and of Phe/Tyr concentrations, both the effects, however, failed to reach the levels of statistical significance. In the patients who underwent SHAM treatment, no significant changes of HAMD-7 or the concentrations of any biomarker in the study could be found. In addition to the significant effect of rTMS on depression scores, these results point to a possible influence of rTMS on the enzyme phenylalanine hydroxylase (PAH), which plays a crucial role in the biosynthesis of neurotransmitter precursors related to geriatric depression.

Esketamine and rapastinel, but not imipramine, have antidepressant-like effect in a treatment-resistant animal model of depression.

OBJECTIVES: Treatment-resistance to antidepressants is a major problem in the pharmacotherapy of major depressive disorder (MDD). Unfortunately, only a few animal models are suitable for studying treatment-resistant depression, among them repeated treatment with Adrenocorticotropic hormone (ACTH) appears to be useful to mimic treatment-resistance to monoaminergic antidepressants. Therefore, the present work aimed to investigate the effectiveness of s-ketamine and rapastinel (formerly GLYX13), modulators of the glutamatergic N-methyl-D-aspartate receptor in ACTH-treated animals. METHODS: Naïve male Sprague Dawley rats were subjected to repeated subcutaneous injections with ACTH (100 µg/0.1 ml/rat/day) for 14 days and drug treatment on the test day (open field and forced swim test) with imipramine, s-ketamine or rapastinel. In addition, assessment of plasma levels of corticosterone and ACTH was carried out. RESULTS: We found that rats repeatedly treated with ACTH for 14 days responded to single injections with s-ketamine (15 mg/kg) and rapastinel (10 mg/kg), but failed to respond to imipramine (15 mg/kg). In the plasma, the levels of corticosterone and ACTH were increased after 14 days of daily treatment with ACTH, independently of the treatment. CONCLUSION: The present data confirm development of a resistance to treatment following chronic ACTH administration. In addition, the study confirms the possible effectiveness of s-ketamine and rapastinel as treatment options in treatment-resistant depression. Moreover, it highlights the importance of the glutamatergic system in the neurobiology of depression. Further studies are necessary to evaluate how repeated treatment with ACTH leads to a depressed condition resistant to monoaminergic antidepressants.

BDNF Genotype and Baseline Serum Levels in Relation to Electroconvulsive Therapy Effectiveness in Treatment-Resistant Depressed Patients.

OBJECTIVES: Electroconvulsive therapy (ECT) represents one of the most effective therapies for treatment-resistant depression (TRD). The brain-derived neurotrophic factor (BDNF) is a neurotrophin implicated in major depressive disorder and in the effects of different therapeutic approaches, including ECT. Both BDNF peripheral levels and Val66Met polymorphism have been suggested as biomarkers of treatment effectiveness. The objective of this study was to test the potential of serum BDNF levels and Val66Met polymorphism in predicting ECT outcome in TRD patients. METHODS: Seventy-four TRD patients scheduled to undergo ECT were included in the study. Illness severity was assessed through the Montgomery and Asberg Depression Rating Scale before beginning ECT (T0), the day after the end of ECT (T1), and 1 month after the end of ECT (T2). At T1, patients were classified as responders/nonresponders and remitters/nonremitters, whereas at T2, they were classified as sustained responders/nonresponders and sustained remitters/nonremitters. Serum concentrations of BDNF were measured at T0, and the BDNF Val66Met polymorphism was genotyped. RESULTS: No difference in BDNF concentrations was observed in responders versus nonresponders, in remitters versus nonremitters, in sustained responders versus sustained nonresponders, and in sustained remitters versus sustained nonremitters. No association of Val66Met polymorphism was detected with both the response and the remission status. CONCLUSIONS: Baseline serum BDNF levels and the BDNF Val66Met polymorphism showed no clinical utility in predicting ECT outcome in TRD patients.

Increased levels of plasma IL-1b and BDNF can predict resistant depression patients.

BACKGROUND: There is no strong evidence on the link between inflammatory profile and pattern of drug treatment response in depressive patients that could result in Coronary Artery Disease occurrence. OBJECTIVE: This study aimed to compare the subclinical atherosclerosis markers, inflammatory profile, and BDNF production in Resistant Depression (RD) or Bipolar Affective Disorder (BAD) patients under conventional treatment. METHODS: The population evaluated was comprised of 34 RD, 43 BAD, and 41 controls. Subclinical atherosclerosis markers were evaluated using ultrasonography, tomography, and exercise stress test. Plasma concentrations of TNFα, IL-1ß, IL-6, and BDNF were measured using Luminex100™. The usCRP concentration was measured using turbidimetric immunoassay. IL1B, IL6, and TNFA expression were determined using TaqMan®. For the statistical analysis, the significance level was established at p<0.05. RESULTS: Concerning subclinical atherosclerosis markers, only O2 consumption was reduced in the BAD group (p = 0.001). Although no differences were found in gene expression, BDNF and IL-1ß plasma concentration was increased in the RD group (p = 0.002 and p = 0.005, respectively) even with an antidepressant treatment, which suggests that these drugs have no effect in IL-1ß secretion and that the inflammasome may play a role in therapy response. CONCLUSION: Taken together, both BDNF and IL-1ß plasma concentrations could be used to the early identification of RD patients.

Increased levels of plasma IL-1b and BDNF can predict resistant depression patients

SUMMARY BACKGROUND: There is no strong evidence on the link between inflammatory profile and pattern of drug treatment response in depressive patients that could result in Coronary Artery Disease occurrence. OBJECTIVE: This study aimed to compare the subclinical atherosclerosis markers, inflammatory profile, and BDNF production in Resistant Depression (RD) or Bipolar Affective Disorder (BAD) patients under conventional treatment. METHODS: The population evaluated was comprised of 34 RD, 43 BAD, and 41 controls. Subclinical atherosclerosis markers were evaluated using ultrasonography, tomography, and exercise stress test. Plasma concentrations of TNFα, IL-1β, IL-6, and BDNF were measured using Luminex100™. The usCRP concentration was measured using turbidimetric immunoassay. IL1B, IL6, and TNFA expression were determined using TaqMan®. For the statistical analysis, the significance level was established at p<0.05. RESULTS: Concerning subclinical atherosclerosis markers, only O2 consumption was reduced in the BAD group (p = 0.001). Although no differences were found in gene expression, BDNF and IL-1β plasma concentration was increased in the RD group (p = 0.002 and p = 0.005, respectively) even with an antidepressant treatment, which suggests that these drugs have no effect in IL-1β secretion and that the inflammasome may play a role in therapy response. CONCLUSION: Taken together, both BDNF and IL-1β plasma concentrations could be used to the early identification of RD patients.

RESUMO FUNDAMENTAÇÃO: Não há fortes evidências sobre a associação entre o perfil inflamatório e o padrão de resposta ao tratamento medicamentoso em pacientes depressivos que podem resultar em ocorrência de doença coronariana. OBJETIVO: O objetivo deste estudo foi comparar os marcadores de aterosclerose subclínica, o perfil inflamatório e a produção de BDNF em pacientes com Depressão Resistente (DR) ou Transtorno Afetivo Bipolar (BAD) sob tratamento convencional. MÉTODOS: A população avaliada incluiu 34 RD, 43 BAD e 41 controles. Os marcadores de aterosclerose subclínica foram avaliados por ultrassonografia, tomografia e teste de esforço. As concentrações plasmáticas de TNFα, IL-1β, IL-6 e BDNF foram medidas utilizando Luminex100TM. A concentração de usCRP foi medida por imunoensaio turbidimétrico. A expressão de IL1B, IL6 e TNFA foi determinada usando TaqMan®. Para as análises estatísticas, foi estabelecido o nível de significância de p < 0,05. RESULTADOS: Quanto aos marcadores de aterosclerose subclínica, apenas o consumo de O2 foi reduzido no grupo BAD (p = 0,001). Embora não tenham sido encontradas diferenças na expressão gênica, a concentração plasmática de BDNF e IL-1β foi aumentada no grupo RD (p = 0,002 e p = 0,005, respectivamente) mesmo sob tratamento antidepressivo, o que sugere que esses medicamentos não têm efeito na secreção de IL-1β e que o inflamassomo pode desempenhar um papel na resposta terapêutica. CONCLUSÃO: Juntas, as concentrações BDNF e IL-1β poderiam ser usadas para a identificação precoce de pacientes com DR.

Repetitive transcranial magnetic stimulation increases serum brain-derived neurotrophic factor and decreases interleukin-1ß and tumor necrosis factor-α in elderly patients with refractory depression.

OBJECTIVE: To investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on serum levels of brain-derived neurotrophic factor (BDNF), interleukin (IL)-1ß, and tumor necrosis factor (TNF)-α in elderly patients with refractory depression. METHODS: A total of 58 elderly patients diagnosed with refractory depression between January 2015 and December 2016 were divided randomly into two groups: 29 patients who received rTMS and 29 controls without rTMS. Thirty healthy individuals were also enrolled and all received rTMS. Serum levels of BDNF, IL-1ß, and TNF-α were measured before the study (0 days), and at 48 hours and 1, 2, 3, and 4 weeks after the first TMS treatment. RESULTS: BDNF levels gradually increased with treatment duration in the rTMS group and were significantly higher compared with the control group. In contrast, IL-1ß and TNF-α levels gradually decreased and were significantly lower than in the control group. None of the serum factors were affected by rTMS in the healthy individuals. BDNF levels were negatively correlated and IL-1ß and TNF-α levels were positively correlated with Hamilton Depression Rating Scale-24 scores. CONCLUSION: These results suggest that rTMS may increase BDNF and decrease IL-1ß and TNF-α serum levels in elderly patients with refractory depression.

Relationship Between UGT1A4 and UGT2B7 Polymorphisms and the Steady-State Plasma Concentrations of Lamotrigine in Patients With Treatment-Resistant Depressive Disorder Receiving Lamotrigine as Augmentation Therapy.

BACKGROUND: In a previous study, the authors had shown that in treatment-resistant depressive disorder, an early therapeutic response to lamotrigine augmentation therapy is dependent on its plasma concentrations. Lamotrigine is mainly metabolized by UGT1A4 and UGT2B7, and polymorphisms of said UGTs that affect enzyme activities have been reported. This study investigated the effect of these polymorphisms on the steady-state plasma concentrations (Css) of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy. METHODS: The subjects were 103 depressed patients who had already shown insufficient response to at least 3 psychotropics including antidepressants, mood stabilizers, and atypical antipsychotics. The diagnoses were major depressive disorder (n = 46), bipolar II disorder (n = 44), and bipolar I disorder (n = 13). They received augmentation therapy with lamotrigine for 8 weeks. The final doses of lamotrigine were 100 mg/d for 67 subjects who were not taking valproate and 75 mg/d for 36 subjects taking valproate, respectively. Blood sampling was performed at the 8th week. Plasma concentrations of lamotrigine were measured by high-performance liquid chromatography. The genotypes of UGT1A4 142T>G, UGT2B7 -161C>T, and UGT2B7 372A>G were identified by polymerase chain reaction analyses. RESULTS: There were no significant relationships between these polymorphisms and the Css of lamotrigine in the subjects regardless of valproate comedication. CONCLUSIONS: This study suggests that these genetic polymorphisms do not affect the Css of lamotrigine in patients with treatment-resistant depressive disorder receiving lamotrigine as augmentation therapy.

Inflammatory profiles of severe treatment-resistant depression.

BACKGROUND: Treatment-resistant depression (TRD) contributes substantially to the burden of mood disorders and is undoubtedly an important subpopulation in whom there are clear unmet treatment needs. Despite a paucity of research focusing specifically on TRD, recent studies indicate that inflammatory activity may be particularly elevated in these patients. METHODS: 36 patients with TRD were investigated longitudinally before and after undertaking a specialist inpatient treatment program. 27 inflammatory proteins were compared between patients and a matched sample of non-depressed controls, as well as between treatment responders and non-responders. Treatment outcomes were calculated from depression severity scores before and after admission, and at a long-term follow-up 3-12 months after discharge. RESULTS: TRD patients had higher levels of numerous inflammatory proteins than controls, and elevated interleukins 6 and 8, tumour necrosis factor, c-reactive protein and macrophage inflammatory protein-1 were associated with poorer treatment outcomes. A separate set of proteins (either anti-inflammatory in nature or attenuated at baseline) showed increases during treatment, regardless of clinical response. Participants with the greatest elevations in inflammation tended to be older, more cognitively impaired and more treatment-resistant at baseline. LIMITATIONS: The small sample and large number of comparisons examined in this study must be taken into account when interpreting these results. CONCLUSIONS: However, this study provides empirical support for theories that more severe, chronic or treatment-resistant depressive disorders are associated with dysregulated inflammatory activity. If a predictor or predictors of response in TRD are established, improved and targeted care might be more reliably provided to this vulnerable population.

Treatment-resistant depression and peripheral C-reactive protein.

BACKGROUND: C-reactive protein (CRP) is a candidate biomarker for major depressive disorder (MDD), but it is unclear how peripheral CRP levels relate to the heterogeneous clinical phenotypes of the disorder.AimTo explore CRP in MDD and its phenotypic associations. METHOD: We recruited 102 treatment-resistant patients with MDD currently experiencing depression, 48 treatment-responsive patients with MDD not currently experiencing depression, 48 patients with depression who were not receiving medication and 54 healthy volunteers. High-sensitivity CRP in peripheral venous blood, body mass index (BMI) and questionnaire assessments of depression, anxiety and childhood trauma were measured. Group differences in CRP were estimated, and partial least squares (PLS) analysis explored the relationships between CRP and specific clinical phenotypes. RESULTS: Compared with healthy volunteers, BMI-corrected CRP was significantly elevated in the treatment-resistant group (P = 0.007; Cohen's d = 0.47); but not significantly so in the treatment-responsive (d = 0.29) and untreated (d = 0.18) groups. PLS yielded an optimal two-factor solution that accounted for 34.7% of variation in clinical measures and for 36.0% of variation in CRP. Clinical phenotypes most strongly associated with CRP and heavily weighted on the first PLS component were vegetative depressive symptoms, BMI, state anxiety and feeling unloved as a child or wishing for a different childhood. CONCLUSIONS: CRP was elevated in patients with MDD, and more so in treatment-resistant patients. Other phenotypes associated with elevated CRP included childhood adversity and specific depressive and anxious symptoms. We suggest that patients with MDD stratified for proinflammatory biomarkers, like CRP, have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs.Declaration of interestS.R.C. consults for Cambridge Cognition and Shire; and his input in this project was funded by a Wellcome Trust Clinical Fellowship (110049/Z/15/Z). E.T.B. is employed half time by the University of Cambridge and half time by GlaxoSmithKline; he holds stock in GlaxoSmithKline. In the past 3 years, P.J.C. has served on an advisory board for Lundbeck. N.A.H. consults for GlaxoSmithKline. P.d.B., D.N.C.J. and W.C.D. are employees of Janssen Research & Development, LLC., of Johnson & Johnson, and hold stock in Johnson & Johnson. The other authors report no financial disclosures or potential conflicts of interest.

Rapid inflammation modulation and antidepressant efficacy of a low-dose ketamine infusion in treatment-resistant depression: A randomized, double-blind control study.

Increasing evidence supports the rapid antidepressant effect of a low-dose ketamine infusion in treatment-resistant depression (TRD). Proinflammatory cytokines play a crucial role in the pathophysiology of TRD. However, it is unknown whether the rapid antidepressant effect of ketamine is related to the rapid suppression of proinflammatory cytokines. Seventy-one patients with TRD were randomized into three groups according to the treatment received: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, and normal saline infusion. Proinflammatory markers, including C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α were examined at baseline and at 40 min, 240 min, Day 3, and Day 7 postinfusion. Montgomery-Åsberg Depression Rating Scale (MADRS) was assessed for depressive symptoms across time. Log-transformed IL-6 and TNF-α levels differed significantly over time. The decrease in TNF-α between baseline and 40 min postinfusion was positively correlated with a decrease in MADRS scores across time in the 0.5 mg/kg ketamine group. This is the first clinical study to support a positive correlation between changes in cytokine levels after ketamine infusion and improvements in depressive symptoms with TRD. The rapid suppression of proinflammatory cytokines may contribute to the rapid antidepressant effect of the ketamine infusion.

Does Physical Exercise Increase Brain-Derived Neurotrophic Factor in Major Depressive Disorder? A Meta-Analysis.

BACKGROUND: Major depressive disorder (MDD) is one of the most common disorders in the world, but is generally refractory to antidepressant treatment. However, physical exercise has been demonstrated to improve MDD symptoms, though the mechanism through which this is achieved is not clear. This systematic review and meta-analysis aimed to clarify whether physical exercise increased brain-derived neurotrophic factor (BDNF) in patients with MDD to either establish or rule out this effect as a possible mechanism. SUBJECTS AND METHODS: We searched five electronic databases (PubMed, PsycINFO, CHINAL, Cochran Library, and Japanese Central Review of Medicine) for interventional studies released prior to 24 October 2017, examining the effects of physical exercise on BDNF in patients with MDD that compared the experimental group with an MDD control group. Those studies meeting the inclusion criteria were subjected to a meta-analysis in which changes of BDNF from baseline to post-exercise were quantified, with a standard mean difference and random effect model. RESULTS: Five studies were eligible and included 199 participants. All articles included subjects with severe symptoms; three articles studied inpatient populations. All articles introduced aerobic exercise. We found no significant effect of physical exercise on BDNF levels (Z=0.32, p=0.75), and no heterogeneity (I2=0%). The risk of bias was moderate. CONCLUSIONS: We conclude that physical exercise does not significantly increase BDNF in patients with MDD. Thus, while increased BDNF has been shown to be beneficial in patients with MDD, physical exercise likely produces its benefits through a different mechanism. However, the small number of included articles and lack of multiple reviewers increase the risk of the result being a false negative.