-
1.
Add-on Treatment with Curcumin Has Antidepressive Effects in Thai Patients with Major Depression: Results of a Randomized Double-Blind Placebo-Controlled Study.
Kanchanatawan, B, Tangwongchai, S, Sughondhabhirom, A, Suppapitiporn, S, Hemrunrojn, S, Carvalho, AF, Maes, M
Neurotoxicity research. 2018;(3):621-633
Abstract
Activation of immune-inflammatory and oxidative-nitrosative (IO&NS) stress pathways plays a role in major depression (MDD). Evidence suggests that curcumin (500-1000 mg/day), a polyphenol with strong anti-IO&NS properties, may have efficacy either as monotherapy or as an adjunctive treatment for depression. Further controlled trials with extended treatment periods (> 8 weeks) and higher curcumin doses are warranted. This 12-week study was carried out to examine the effects of adjunctive curcumin for the treatment of MDD. In this double-blind, placebo-controlled trial, 65 participants with MDD were randomized to receive either adjunctive curcumin (increasing dose from 500 to 1500 mg/day) or placebo for 12 weeks. Four weeks after the active treatment phase, a follow-up visit was conducted at week 16. Assessments of the primary, i.e., the Montgomery-Asberg Depression Rating Scale (MADRS), and secondary, i.e., the Hamilton Anxiety Rating Scale (HAM-A), outcome measures were rated at baseline and 2, 4, 8, 12, and 16 weeks later. Curcumin was more efficacious than placebo in improving MADRS scores with significant differences between curcumin and placebo emerging at weeks 12 and 16. The effects of curcumin were more pronounced in males compared to females. There were no statistically significant treatment-emerging adverse effects and no significant effects of curcumin on blood chemistry and ECG measurements. Adjunctive curcumin has significant antidepressant effects in participants with MDD as evidenced by significant benefits occurring 12 and 16 weeks after treatment initiation. Curcumin administration was safe and well-tolerated even when combined with antidepressants. Future trials should include treatment-by-sex interactions to examine putative antidepressant effects of immune-modifying compounds.
-
2.
Acetyl-l-carnitine deficiency in patients with major depressive disorder.
Nasca, C, Bigio, B, Lee, FS, Young, SP, Kautz, MM, Albright, A, Beasley, J, Millington, DS, Mathé, AA, Kocsis, JH, et al
Proceedings of the National Academy of Sciences of the United States of America. 2018;(34):8627-8632
-
-
Free full text
-
Abstract
The lack of biomarkers to identify target populations greatly limits the promise of precision medicine for major depressive disorder (MDD), a primary cause of ill health and disability. The endogenously produced molecule acetyl-l-carnitine (LAC) is critical for hippocampal function and several behavioral domains. In rodents with depressive-like traits, LAC levels are markedly decreased and signal abnormal hippocampal glutamatergic function and dendritic plasticity. LAC supplementation induces rapid and lasting antidepressant-like effects via epigenetic mechanisms of histone acetylation. This mechanistic model led us to evaluate LAC levels in humans. We found that LAC levels, and not those of free carnitine, were decreased in patients with MDD compared with age- and sex-matched healthy controls in two independent study centers. Secondary exploratory analyses showed that the degree of LAC deficiency reflected both the severity and age of onset of MDD. Moreover, these analyses showed that the decrease in LAC was larger in patients with a history of treatment-resistant depression (TRD), among whom childhood trauma and, specifically, a history of emotional neglect and being female, predicted the decreased LAC. These findings suggest that LAC may serve as a candidate biomarker to help diagnose a clinical endophenotype of MDD characterized by decreased LAC, greater severity, and earlier onset as well as a history of childhood trauma in patients with TRD. Together with studies in rodents, these translational findings support further exploration of LAC as a therapeutic target that may help to define individualized treatments in biologically based depression subtype consistent with the spirit of precision medicine.
-
3.
Predictors of Response to Ketamine in Treatment Resistant Major Depressive Disorder and Bipolar Disorder.
Rong, C, Park, C, Rosenblat, JD, Subramaniapillai, M, Zuckerman, H, Fus, D, Lee, YL, Pan, Z, Brietzke, E, Mansur, RB, et al
International journal of environmental research and public health. 2018;(4)
Abstract
OBJECTIVES Extant evidence indicates that ketamine exerts rapid antidepressant effects in treatment-resistant depressive (TRD) symptoms as a part of major depressive disorder (MDD) and bipolar disorder (BD). The identification of depressed sub-populations that are more likely to benefit from ketamine treatment remains a priority. In keeping with this view, the present narrative review aims to identify the pretreatment predictors of response to ketamine in TRD as part of MDD and BD. METHOD Electronic search engines PubMed/MEDLINE, ClinicalTrials.gov, and Scopus were searched for relevant articles from inception to January 2018. The search term ketamine was cross-referenced with the terms depression, major depressive disorder, bipolar disorder, predictors, and response and/or remission. RESULTS Multiple baseline pretreatment predictors of response were identified, including clinical (i.e., Body Mass Index (BMI), history of suicide, family history of alcohol use disorder), peripheral biochemistry (i.e., adiponectin levels, vitamin B12 levels), polysomnography (abnormalities in delta sleep ratio), neurochemistry (i.e., glutamine/glutamate ratio), neuroimaging (i.e., anterior cingulate cortex activity), genetic variation (i.e., Val66Met BDNF allele), and cognitive functioning (i.e., processing speed). High BMI and a positive family history of alcohol use disorder were the most replicated predictors. CONCLUSIONS A pheno-biotype of depression more, or less likely, to benefit with ketamine treatment is far from complete. Notwithstanding, metabolic-inflammatory alterations are emerging as possible pretreatment response predictors of depressive symptom improvement, most notably being cognitive impairment. Sophisticated data-driven computational methods that are iterative and agnostic are more likely to provide actionable baseline pretreatment predictive information.
-
4.
Glutamatergic Modulators in Depression.
Henter, ID, de Sousa, RT, Zarate, CA
Harvard review of psychiatry. 2018;(6):307-319
-
-
Free full text
-
Abstract
After participating in this activity, learners should be better able to evaluate the evidence supporting the antidepressant effects of glutamatergic modulators.Both preclinical and clinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders such as bipolar depression and major depressive disorder. In particular, rapid reductions in depressive symptoms have been noted in response to subanesthetic doses of the glutamatergic modulator ketamine in subjects with major depressive disorder or bipolar depression. These results have prompted the repurposing or development of other glutamatergic modulators, both as monotherapy or adjunctive to other therapies. Here, we highlight the evidence supporting the antidepressant effects of various glutamatergic modulators, including (1) broad glutamatergic modulators (ketamine, esketamine, dextromethorphan, dextromethorphan-quinidine [Nuedexta], AVP-786, nitrous oxide [N2O], AZD6765), (2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (CP-101,606/traxoprodil, MK-0657 [CERC-301]), (3) glycine-site partial agonists (D-cycloserine, GLYX-13, sarcosine, AV-101), and (4) metabotropic glutamate receptor modulators (AZD2066, RO4917523/basimglurant, JNJ40411813/ADX71149, R04995819 [RG1578]).
-
5.
Efficacy of Crocus sativus (saffron) in treatment of major depressive disorder associated with post-menopausal hot flashes: a double-blind, randomized, placebo-controlled trial.
Kashani, L, Esalatmanesh, S, Eftekhari, F, Salimi, S, Foroughifar, T, Etesam, F, Safiaghdam, H, Moazen-Zadeh, E, Akhondzadeh, S
Archives of gynecology and obstetrics. 2018;(3):717-724
Abstract
PURPOSE Due to concerns regarding the side effects of hormone therapy, many studies have focused on the development of non-hormonal agents for treatment of hot flashes. The aim of this study was to evaluate the efficacy and safety of saffron (stigma of Crocus sativus) in treatment of major depressive disorder associated with post-menopausal hot flashes. METHODS Sixty women with post-menopausal hot flashes participated in this study. The patients randomly received either saffron (30 mg/day, 15 mg twice per day) or placebo for 6 weeks. The patients were assessed using the Hot Flash-Related Daily Interference Scale (HFRDIS), Hamilton Depression Rating Scale (HDRS) and the adverse event checklist at baseline and also at the second, fourth, and sixth weeks of the study. RESULTS Fifty-six patients completed the trial. Baseline characteristics of the participants did not differ significantly between the two groups. General linear model repeated measures demonstrated significant effect for time × treatment interaction on the HFRDIS score [F (3, 162) = 10.41, p = 0.0001] and HDRS score [F (3, 162) = 5.48, p = 0.001]. Frequency of adverse events was not significantly different between the two groups. CONCLUSIONS Results from this study revealed that saffron is a safe and effective treatment in improving hot flashes and depressive symptoms in post-menopausal healthy women. On the other hand, saffron, with fewer side effects, may provide a non-hormonal and alternative herbal medicine option in treatment of women with hot flashes.
-
6.
Metabotropic Glutamatergic Receptor 5 and Stress Disorders: Knowledge Gained From Receptor Imaging Studies.
Esterlis, I, Holmes, SE, Sharma, P, Krystal, JH, DeLorenzo, C
Biological psychiatry. 2018;(2):95-105
-
-
Free full text
-
Abstract
The metabotropic glutamatergic receptor subtype 5 (mGluR5) may represent a promising therapeutic target for stress-related psychiatric disorders. Here, we describe mGluR5 findings in stress disorders, particularly major depressive disorder (MDD), highlighting insights from positron emission tomography studies. Positron emission tomography studies report either no differences or lower mGluR5 in MDD, potentially reflecting MDD heterogeneity. Unlike the rapidly acting glutamatergic agent ketamine, mGluR5-specific modulation has not yet shown antidepressant efficacy in MDD and bipolar disorder. Although we recently showed that ketamine may work, in part, through significant mGluR5 modulation, the specific role of mGluR5 downregulation in ketamine's antidepressant response is unclear. In contrast to MDD, there has been much less investigation of mGluR5 in bipolar disorder, yet initial studies indicate that mGluR5-specific treatments may aid in both depressed and manic mood states. The direction of modulation needed may be state dependent, however, limiting clinical feasibility. There has been relatively little study of posttraumatic stress disorder or obsessive-compulsive disorder to date, although there is evidence for the upregulation of mGluR5 in these disorders. However, while antagonism of mGluR5 may reduce fear conditioning, it may also reduce fear extinction. Therefore, studies are needed to determine the role mGluR5 modulation might play in the treatment of these conditions. Further challenges in modulating this prevalent neurotransmitter system include potential induction of significant side effects. As such, more research is needed to identify level and type (positive/negative allosteric modulation or full antagonism) of mGluR5 modulation required to translate existing knowledge into improved therapies.
-
7.
Facilitators and barriers to modifying dietary and hygiene behaviours as adjuvant treatment in patients with depression in primary care: a qualitative study.
Olivan-Blázquez, B, Montero-Marin, J, García-Toro, M, Vicens-Pons, E, Serrano-Ripoll, MJ, Castro-Gracia, A, Sarasa-Bosque, MC, Mendive-Arbeloa, JM, López-Del-Hoyo, Y, Garcia-Campayo, J
BMC psychiatry. 2018;(1):205
Abstract
BACKGROUND Major depression is a highly prevalent condition. Its pathogenesis is related to a wide variety of biological and psychosocial factors and among these is factors related to lifestyle. Lifestyle-based interventions seem to be appropriate strategies as coadjutant treatment. The objective of this study is to explore and identify expectations and experiences of both patients and healthcare professionals that can point to the main barriers and facilitators with regard to the promotion of healthy dietary and hygiene behaviours in patients suffering from major depression. METHODS A qualitative design was used to collect information from a wide range of purposefully and theoretically guided samples of depressed patients and health professionals from Primary Care (PC). Both in-depth interviews and discussion groups were used. A standardized protocol was designed to guide the interviews and groups, including the preparation of a topic list to be addressed, with previously tested, open suggestions that could be of interest. A thematic analysis was performed from grounded theory in order to explore, develop and define until saturation the emergent categories of analysis derived from the individual interview and group data. RESULTS Both patients as well as PC professionals noted a series of central aspects with respect to the implementation of a programme for the acquisition of healthy dietary and hygiene habits for depressive patients, which may be organized around 'personal', 'programmatic', and 'transversal' aspects. As for the personal aspects, categories regarding 'patient history', and 'disposition' were found; the programmatic aspects included categories such as 'presentation and monitoring', and modification of 'cognitive' and 'behavioural' habits; whereas the transversal aspects comprised the possibilities of 'social support' and defining categories of 'objectives'. CONCLUSION The implementation of intervention programmes that combine dietary and hygiene-related factors in patients with depression is complex, given the nature of the disorder itself, and its symptoms such as apathy and feelings of guilt or incompetence. Key issues exist for the success of the intervention, such as the simplicity of guidelines, tailoring through motivational interviewing, prolonged and intense monitoring throughout the different stages of the disorder, and the provision of adequate feedback and social support. PC could be an appropriate level in which to implement these interventions.
-
8.
Does oral administration of ketamine accelerate response to treatment in major depressive disorder? Results of a double-blind controlled trial.
Arabzadeh, S, Hakkikazazi, E, Shahmansouri, N, Tafakhori, A, Ghajar, A, Jafarinia, M, Akhondzadeh, S
Journal of affective disorders. 2018;:236-241
Abstract
BACKGROUND Major depressive disorder (MDD) exerts a high health and financial burden on society. The conventional pharmacotherapies for MDD are partially effective and the response to medication often starts with some delay. There are recent reports of antidepressant effects for oral ketamine. METHODS We employed a double-blind controlled trial to examine the time course of the therapeutic effect of ketamine when combined with the conventional administration of sertraline. A total of 81 patients participated in the study and were scored with the Hamilton Depression Rating Scale (HDRS) at baseline and at 2, 4 and 6 weeks after the start of the trial RESULTS General linear model repeated measures demonstrated significant effect for time × treatment interaction on the HDRS scores, with significant difference at all time points post treatment. Early improvement was significantly greater in the ketamine group (85.4%) compared to the placebo group (42.5%). We did not observe any side effects for ketamine administration. LIMITATIONS Our follow up was limited to 6 weeks post initiation of treatment and cannot reveal the potential long-term adverse effects of oral ketamine and the sustainability of its benefit. CONCLUSION Altogether, our results suggest that oral ketamine may be considered as suitable adjuvant to sertraline in relieving depressive symptoms.
-
9.
Peripheral Alterations in Cytokine and Chemokine Levels After Antidepressant Drug Treatment for Major Depressive Disorder: Systematic Review and Meta-Analysis.
Köhler, CA, Freitas, TH, Stubbs, B, Maes, M, Solmi, M, Veronese, N, de Andrade, NQ, Morris, G, Fernandes, BS, Brunoni, AR, et al
Molecular neurobiology. 2018;(5):4195-4206
Abstract
Mounting evidence suggests that aberrations in immune-inflammatory pathways contribute to the pathophysiology of major depressive disorder (MDD), and individuals with MDD may have elevated levels of predominantly pro-inflammatory cytokines and C-reactive protein. In addition, previous meta-analyses suggest that antidepressant drug treatment may decrease peripheral levels of interleukin-1 beta (IL-1β) and IL-6. Recently, several new studies examining the effect of antidepressants on these cytokines have been published, and so we performed an updated meta-analysis of studies that measured peripheral levels of cytokines and chemokines during antidepressant treatment in patients with MDD. The PubMed/MEDLINE, EMBASE, and PsycInfo databases were searched from inception through March 9, 2017. Forty-five studies met inclusion criteria (N = 1517). Peripheral levels of IL-6, tumor necrosis factor-alpha (TNF-α), IL-1β, IL-10, IL-2, IL-4, interferon-γ, IL-8, the C-C motif ligand 2 chemokine (CCL-2), CCL-3, IL-1 receptor antagonist, IL-13, IL-17, IL-5, IL-7, and the soluble IL-2 receptor were measured in at least three datasets and thus were meta-analyzed. Antidepressant treatment significantly decreased peripheral levels of IL-6 (Hedges g = -0.454, P <0.001), TNF-α (g = -0.202, P = 0.015), IL-10 (g = -0.566, P = 0.012), and CCL-2 (g = -1.502, P = 0.006). These findings indicate that antidepressants decrease several markers of peripheral inflammation. However, this meta-analysis did not provide evidence that reductions in peripheral inflammation are associated with antidepressant treatment response although few studies provided separate data for treatment responders and non-responders.
-
10.
Toward Prevention of Mild Cognitive Impairment in Older Adults With Depression: An Observational Study of Potentially Modifiable Risk Factors.
Gallagher, D, Kiss, A, Lanctot, KL, Herrmann, N
The Journal of clinical psychiatry. 2018;(1)
-
-
Free full text
-
Abstract
OBJECTIVE Late-life depression has been associated with increased risk of mild cognitive impairment (MCI) and dementia. Predictors of increased risk are incompletely understood. Identification of potentially modifiable risk factors could facilitate prevention of MCI and dementia. This study aimed to determine which clinical characteristics are associated with increased risk of MCI among older adults with depression and normal cognition at baseline. METHODS Data from the National Alzheimer's Coordinating Center dataset were used. Study participants who attended a participating Alzheimer's Disease Center from September 2005 through September 2017 with normal cognition and a history of clinically defined depression (broadly based on DSM criteria) were followed until first diagnosis of MCI (or dementia when MCI was not diagnosed). RESULTS A total of 2,655 study participants were followed for a median duration of 41.8 months. Of these, 586 (22.1%) developed either MCI (n = 509, 19.2%) or dementia (n = 77, 2.9%). In survival analyses, cognitive decline was associated with age, sex, education, baseline cognition, and several potentially modifiable risk factors including vascular risk factors, hearing impairment, vitamin B₁₂ deficiency, active depression within the last 2 years, and increased severity of depression. In an adjusted survival analysis, the only variables that remained significantly associated with development of MCI or dementia were female sex (HR = 0.72; 95% CI, 0.59-0.88), higher education (HR = 0.96; 95% CI, 0.93-0.99), and higher baseline cognition (HR = 0.87; 95% CI, 0.82-0.93), which were associated with reduced risk, and older age (HR = 1.07; 95% CI, 1.05-1.08), active depression within the last 2 years (HR = 1.41; 95% CI, 1.15-1.74), and increased severity of depression (HR = 1.05; 95% CI, 1.02-1.09), which were associated with increased risk. CONCLUSIONS Development of MCI is associated with several potentially modifiable risk factors in older adults with depression. Future studies should determine whether active management of risk factors could reduce incidence of MCI in this vulnerable population.