Mood disorders have been recognized by the World Health Organization (WHO) as the leading cause of disability worldwide. Notwithstanding the established efficacy of conventional mood agents, many ...treated individuals continue to remain treatment refractory and/or exhibit clinically significant residual symptoms, cognitive dysfunction, and psychosocial impairment. Therefore, a priority research and clinical agenda is to identify pathophysiological mechanisms subserving mood disorders to improve therapeutic efficacy.
During the past decade, inflammation has been revisited as an important etiologic factor of mood disorders. Therefore, the purpose of this synthetic review is threefold: 1) to review the evidence for an association between inflammation and mood disorders, 2) to discuss potential pathophysiologic mechanisms that may explain this association and 3) to present novel therapeutic options currently being investigated that target the inflammatory–mood pathway.
Accumulating evidence implicates inflammation as a critical mediator in the pathophysiology of mood disorders. Indeed, elevated levels of pro-inflammatory cytokines have been repeatedly demonstrated in both major depressive disorder (MDD) and bipolar disorder (BD) patients. Further, the induction of a pro-inflammatory state in healthy or medically ill subjects induces ‘sickness behavior’ resembling depressive symptomatology.
Potential mechanisms involved include, but are not limited to, direct effects of pro-inflammatory cytokines on monoamine levels, dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, pathologic microglial cell activation, impaired neuroplasticity and structural and functional brain changes.
Anti-inflammatory agents, such as acetyl-salicylic acid (ASA), celecoxib, anti-TNF-α agents, minocycline, curcumin and omega-3 fatty acids, are being investigated for use in mood disorders. Current evidence shows improved outcomes in mood disorder patients when anti-inflammatory agents are used as an adjunct to conventional therapy; however, further research is needed to establish the therapeutic benefit and appropriate dosage.
•Inflammation and mood disorders have a bidirectional interaction.•Cytokines, monoamines, the HPA axis and microglial cells are key players involved.•Anti-inflammatory agents show promise for use in the treatment of mood disorders.
Abstract Background Most adults with major depressive disorder (MDD) fail to achieve remission with index pharmacological treatment. Moreover, at least half will not achieve and sustain remission ...following multiple pharmacological approaches. Herein, we succinctly review treatment modalities proven effective in treatment-resistant depression (TRD). Methods We conducted a review of computerized databases (PubMed, Google Scholar) from 1980 to April 2013. Articles selected for review were based on author consensus, adequacy of sample size, the use of a standardized experimental procedure, validated assessment measures and overall manuscript quality. Results The evidence base supporting augmentation of conventional antidepressants with atypical antipsychotics (i.e., aripiprazole, quetiapine, and olanzapine) is the most extensive and rigorous of all pharmacological approaches in TRD. Emerging evidence supports the use of some psychostimulants (i.e., lisdexamfetamine) as well as aerobic exercise. In addition, treatments informed by pathogenetic disease models provide preliminary evidence for the efficacy of immune-inflammatory based therapies and metabolic interventions. Manual based psychotherapies remain a treatment option, with the most compelling evidence for cognitive behavioral therapy. Disparate neurostimulation strategies are also available for individuals insufficiently responsive to pharmacotherapy and/or psychosocial interventions. Limitations Compared to non-treatment-resistant depression, TRD has been less studied. Most clinical studies on TRD have focused on pharmacotherapy-resistant depression, with relatively fewer studies evaluating “next choice” treatments in individuals who do not initially respond to psychosocial and/or neurostimulatory treatments. Conclusion The pathoetiological heterogeneity of MDD/TRD invites the need for mechanistically dissimilar, and empirically validated, treatment approaches for TRD.
Abstract Background While women with breast cancer often face varying levels of psychological distress, there is a subgroup whose symptomatology reaches a threshold for diagnosis of major depressive ...disorder (MDD). Major depressive disorder is known to influence patient outcomes, such as health-related quality of life and treatment adherence. There are no systematic reviews that evaluate pharmacological and psychotherapeutic treatment trials for MDD among individuals with breast cancer. Methods Two authors independently searched MEDLINE, EMBASE, Cochrane and Clinical Trials.gov databases through February 20, 2013 without language restrictions. Core journals, reference lists and citation tracking were also searched. Articles on breast cancer patients were included if they (1) included participants with a diagnosis of MDD; (2) investigated pharmacological or psychotherapeutic treatments for MDD compared to placebo or usual care in a randomized controlled trial (RCT). Results Two RCTs on antidepressant treatment met inclusion criteria. However, no RCTs investigating the effects of psychological treatments for MDD in breast cancer were identified. Notwithstanding the paucity of data investigating the effects of psychological treatments for MDD in breast cancer, numerous psychotherapeutic strategies targeting depressive symptoms were identified. Mianserin had significant antidepressant effects when compared to placebo in a 6-week, parallel-group, RCT of Stage I–II breast cancer in women with MDD. Desipramine and paroxetine were reported to be no more efficacious than placebo in a 6-week, RCT of Stage I–IV breast cancer in women with MDD. Conclusions The evidence reviewed herein underscores the paucity of data available to guide clinicians in treatment decisions for MDD in individuals with breast cancer. Therefore, the treatment of MDD in breast cancer is primarily based on clinical experience. Some antidepressants (for example, paroxetine) should be avoided in women concurrently taking tamoxifen due to relevant interactions involving the cytochrome CYP2D6.
Background
Few reports have aimed to describe the mediational effect of cognitive deficits on functional outcomes in major depressive disorder (MDD), and relatively few interventions are demonstrated ...to mitigate cognitive deficits in MDD.
Methods
Studies enrolling subjects between the ages of 18–65 were selected for review. Bibliographies from identified articles were reviewed to identify additional original reports aligned with our objectives.
Results
Cognitive deficits in MDD are consistent, replicable, nonspecific, and clinically significant. The aggregated estimated effect size of cognitive deficits in MDD is small to medium. Pronounced deficits in executive function (≥1 SD below the normative mean) are evident in ∼20–30% of individuals with MDD). Other replicated abnormalities are in the domains of working memory, attention, and psychomotor processing speed. Mediational studies indicate that cognitive deficits may account for the largest percentage of variance with respect to the link between psychosocial dysfunction (notably workforce performance) and MDD. No conventional antidepressant has been sufficiently studied and/or demonstrated robust procognitive effects in MDD.
Conclusions
Cognitive deficits in MDD are a principal mediator of psychosocial impairment, notably workforce performance. The hazards posed by cognitive deficits in MDD underscore the need to identify a consensus‐based neurocognitive battery for research and clinical purposes. Interventions (pharmacological, behavioral, neuromodulatory) that engage multiple physiological systems implicated in cognitive deficits hold promise to reduce, reverse, and prevent cognitive deficits.
Machine learning capability holds promise to inform disease models, the discovery and development of novel disease modifying therapeutics and prevention strategies in psychiatry. Herein, we provide ...an introduction on how machine learning/Artificial Intelligence (AI) may instantiate such capabilities, as well as provide rationale for its application to psychiatry in both research and clinical ecosystems.
Databases PubMed and PsycINFO were searched from 1966 to June 2016 for keywords:Big Data, Machine Learning, Precision Medicine, Artificial Intelligence, Mental Health, Mental Disease, Psychiatry, Data Mining, RDoC, and Research Domain Criteria. Articles selected for review were those that were determined to be aligned with the objective of this particular paper.
Results indicate that AI is a viable option to build useful predictors of outcome while offering objective and comparable accuracy metrics, a unique opportunity, particularly in mental health research. The approach has also consistently brought notable insight into disease models through processing the vast amount of already available multi-domain, semi-structured medical data. The opportunity for AI in psychiatry, in addition to disease-model refinement, is in characterizing those at risk, and it is likely also relevant to personalizing and discovering therapeutics.
Machine learning currently provides an opportunity to parse disease models in complex, multi-factorial disease states (e.g. mental disorders) and could possibly inform treatment selection with existing therapies and provide bases for domain-based therapeutic discovery.
Abstract Background Previous studies showed that the insulin resistance (IR) could be related to depression. However, this association is still equivocal in the general population. Herein, we aimed ...to investigate the association between IR and depressive symptoms in a large sample in South Korea. Methods A cross-sectional study was carried out for 165,443 Korean men and women who received a health checkup including various clinical parameters and the Center for Epidemiologic Studies Depression scales (CES-D). Subjects were stratified into subgroups by CES-D score, sex, age, and presence of diabetes. The odd ratios (ORs) for homeostasis model assessment of insulin resistance (HOMA-IR) were compared between groups using multivariable logistic regression analyses. Results After adjusting covariates (e.g. smoking, family income, marriage state, unemployment status, average alcohol use, BMI, physical activity, systolic blood pressure, diabetes), increased IR was weakly associated with greater depressive symptoms (adjusted OR = 1.01 95% CI 1.0001 - 1.03). Subgroup analysis revealed this association was statistically significant in females (adjusted OR = 1.03, 95% CI 1.001 – 1.06), non-diabetic group (adjusted OR = 1.04, 95% CI 1.02 – 1.06), and young participants under the age of thirty (adjusted OR =1.17, 95% CI 1.07 – 1.27). But we couldn’t find significant association in diabetic and middle to elderly participants. Conclusions This study demonstrates that there is a relationship between IR and depressive symptoms in the Korean general population. Results from this epidemiological study revealed that young adults and non-diabetic individuals with increased IR may be related with depressive symptoms.
Incomplete response to monoaminergic antidepressants in major depressive disorder (MDD), and the phenomenon of neuroprogression, suggests a need for additional pathophysiological markers and ...pharmacological targets. Neuronal zinc is concentrated exclusively within glutamatergic neurons, acting as an allosteric modulator of the N-methyl D-aspartate and other receptors that regulate excitatory neurotransmission and neuroplasticity. Zinc-containing neurons form extensive associational circuitry throughout the cortex, amygdala and hippocampus, which subserve mood regulation and cognitive functions. In animal models of depression, zinc is reduced in these circuits, zinc treatment has antidepressant-like effects and dietary zinc insufficiency induces depressive behaviors. Clinically, serum zinc is lower in MDD, which may constitute a state-marker of illness and a risk factor for treatment-resistance. Marginal zinc deficiency in MDD may relate to multiple putative mechanisms underlying core symptomatology and neuroprogression (e.g. immune dysfunction, monoamine metabolism, stress response dysregulation, oxidative/nitrosative stress, neurotrophic deficits, transcriptional/epigenetic regulation of neural networks). Initial randomized trials suggest a benefit of zinc supplementation. In summary, molecular and animal behavioral data support the clinical significance of zinc in the setting of MDD.
There is a paucity of treatments that are capable of reliably and robustly improving cognitive function in adults with mood disorders. Glucagon-like peptide-1 is synthesized centrally and its ...receptors are abundantly expressed in neural circuits subserving cognitive function. We aimed to determine the effects of liraglutide, a GLP-1 receptor (GLP-1R) agonist, on objective measures of cognition in adults with a depressive or bipolar disorder.
In this 4-week, pilot, open-label, domain-based study (e.g. cognition), we recruited 19 individuals with major depressive disorder (MDD) or bipolar disorder (BD) and an impairment in executive function, defined as a below-average performance in the Trail Making Test-B (TMTB). Liraglutide 1.8mg/day was added as an adjunct to existing pharmacotherapy.
Participants had significant increases from baseline to week 4 in the TMTB standard score (age and education corrected) (Cohen's d=0.64, p=0.009) and in a composite Z-score comprising multiple cognitive tests (i.e. Digit Symbol Substitution Test, Rey Auditory Verbal Learning Test, Stroop test) (Cohen's d=0.77, p<0.001). Neither changes in mood rating scales nor metabolic parameters were associated with changes in cognitive performance (all p>0.05); however baseline insulin resistance (IR) and body mass index (BMI) moderated the changes in the composite Z-score (p=0.021 and p=0.046, respectively), indicating larger responses in individuals with higher IR and BMI at baseline. There was a significant increase in lipase (p<0.001), but individual values were above the upper limit of normality.
Small sample size, open-label design, lack of a placebo group.
Liraglutide was safe and well tolerated by a sample of non-diabetic individuals with mood disorders and had beneficial effects on objective measures of cognitive function. Larger studies with controlled trial designs are necessary to confirm and expand the results described herein.
•Cognitive deficits in mood disorders are highly prevalent and impactful.•Few interventions have evidence of pro-cognitive effects in mood disorders.•In this pilot study we explored the cognitive effect of a GLP-1R agonist.•4-week treatment with liraglutide was associated with cognitive improvements.•Liraglutide was also safe and well tolerated by individuals with mood disorders.
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.
Electronic search engines PubMed/MEDLINE, ClinicalTrials.gov, and Scopus were searched for relevant articles from inception to January 2018. The search term
was cross-referenced with the terms
, and
and/or
.
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.
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.
To validate the THINC-integrated tool (THINC-it)-a freely available, patient-administered, computerized screening tool integrating subjective and objective measures of cognitive function in adults ...with major depressive disorder (MDD).
Subjects aged 18 to 65 years (n = 100) with recurrent MDD experiencing a major depressive episode of at least moderate severity were evaluated and compared to age-, sex-, and education-matched healthy controls (n = 100). Between January and June 2016, subjects completed the THINC-it, which includes variants of the Choice Reaction Time Identification Task (IDN), One-Back Test, Digit Symbol Substitution Test, Trail Making Test-Part B, and the Perceived Deficits Questionnaire for Depression-5-item (PDQ-5-D).
The THINC-it required approximately 10 to 15 minutes for administration and was capable of detecting cognitive deficits in adults with MDD. A total of 44.4% of adults with MDD exhibited cognitive performance at ≥ 1.0 SD below that of healthy controls on standardized mean scores of the THINC-it. Concurrent validity of the overall tool, based on a calculated composite score, was acceptable (r = 0.539, P < .001). Concurrent validity of the component tests ranged from -0.083 (IDN) to 0.929 (PDQ-5-D). Qualitative survey results indicated that there was a high level of satisfaction and perceived value in administering the THINC-it regarding its impact on the appropriateness and quality of care being received.
The THINC-it is a valid and sensitive tool for detecting cognitive dysfunction in adults with MDD that is free, easy to use, and rapidly administered. The THINC-it should be incorporated into the assessment and measurement of all patients with MDD, particularly among those with enduring functional impairment.
ClinicalTrials.gov identifier: NCT02508493.
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