Current Antidepressant Therapies Research Articles

Repurposing of dextromethorphan as an adjunct therapy in patients with major depressive disorder: a randomised, group sequential adaptive design, controlled clinical trial protocol

BackgroundTherapeutic latency, lack of efficacy and adverse drug reactions are the major concerns in current antidepressant therapies. To overcome these treatment hurdles, add-on therapy to conventional antidepressant medications may lead...

Diagnosis & Treatment Options in Depression with comorbid Dementia

AbstractDepression and Dementia Professor Allan H Young, Head of Academic Psychiatry, Maudsley Hospital and King’s College London UK. allan.young@kcl.ac.uk Mood Disorders are common, encompass cognitive impairments and occur in later life including first onset after the age of 50 years of age. There is a considerable overlap between depression and dementia. The relationship between depression and dementia will be reviewed and the implications for diagnosis and treatment will be discussed. Novel agents targeting alternative neurotransmitter pathways and inflammatory processes are promising potential treatment options. Neurostimulation treatments play a role with ECT at present having the best utility for late onset depression. Key words: depression, dementia, antidepressants; pharmacotherapyDisclosure of Interest A. Young Grant / Research support from: Principal Investigator in the Restore-Life VNS registry study funded by LivaNova. Principal Investigator on ESKETINTRD3004: “An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression.” Principal Investigator on “The Effects of Psilocybin on Cognitive Function in Healthy Participants” Principal Investigator on “The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD)” Principal Investigator on “A Double-Blind, Randomized, Parallel-Group Study with Quetiapine Extended Release as Comparator to Evaluate the Efficacy and Safety of Seltorexant 20 mg as Adjunctive Therapy to Antidepressants in Adult and Elderly Patients with Major Depressive Disorder with Insomnia Symptoms Who Have Responded Inadequately to Antidepressant Therapy.” (Janssen) Principal Investigator on “ An Open-label, Long-term, Safety and Efficacy Study of Aticaprant as Adjunctive Therapy in Adult and Elderly Participants with Major Depressive Disorder (MDD).” (Janssen) Principal Investigator on “A Randomized, Double-blind, Multicentre, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants with Major Depressive Disorder (MDD) with Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy.” Principal Investigator on “ A Study of Disease Characteristics and Real-life Standard of Care Effectiveness in Patients with Major Depressive Disorder (MDD) With Anhedonia and Inadequate Response to Current Antidepressant Therapy Including an SSRI or SNR.” (Janssen) UK Chief Investigator for Compass; COMP006 & COMP007 studies UK Chief Investigator for Novartis MDD study MIJ821A12201, Consultant of: Paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Flow Neuroscience, Novartis, Roche, Janssen, Takeda, Noema pharma, Compass, Astrazenaca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Livanova, Janssen, Allegan, Bionomics, Sumitomo Dainippon Pharma, Sage, Neurocentrx

ASSOCIATION BETWEEN CARDIOVASCULAR DISEASE AND COGNITIVE IMPAIRMENT: IS DEPRESSION A MEDIATOR?

Abstract By 2040, over 9 million US adults will live with dementia. Understanding the relationship between risk factors and cognitive decline is critical to prevent disease and slow progression. Depression and cardiovascular disease (CVD) are independent risk factors for cognitive impairment (CI) which may interact, suggesting depression may play a mediating role in the relationship between CVD and CI, an hypothesis explored in this study. Data from the Systolic Blood Pressure Intervention Trial (SPRINT), a multi-center, randomized, controlled trial were used in this multivariate logistic regression analysis. CI was defined as adjudicated cases of mild CI and probable dementia. Depression was defined as a Patient Health Questionnaire-9 score ≥10 or current antidepressant therapy. We developed a CVD risk score using data from SPRINT participants and discretized the scores into tertiles. Of 9259 SPRINT participants, our analytic sample included 8456 who had adjudicated mild CI or dementia and had baseline depression scores. They were on average 68 years and 36% were female. After adjusting for age, sex, education, race, prior CVD, chronic kidney disease and treatment assignment, participants with high cardiovascular risk were more likely to have CI (OR: 1.55, 95% CI: 1.17-2.05). Participants with depression were more likely to have CI (OR: 1.29, 95% CI: 1.05-1.58) however, the interaction between cardiovascular risk and cognition was not significant. Findings from this study suggest that while depression and CVD are associated with CI, depression may not explain the CVD-CI relationship. More research is needed to understand the relationship between depression, CVD and CI.

Lipids in major depressive disorder: new kids on the block or old friends revisited?

Major depressive disorder (MDD) is a psychiatric mood disorder that results in substantial functional impairment and is characterized by symptoms such as depressed mood, diminished interest, impaired cognitive function, and vegetative symptoms such as disturbed sleep. Although the exact etiology of MDD is unclear, several underlying mechanisms (disturbances in immune response and/or stress response) have been associated with its development, with no single mechanism able to account for all aspects of the disorder. Currently, about 1 in 3 patients are resistant to current antidepressant therapies. Providing an alternative perspective on MDD could therefore pave the way for new, unexplored diagnostic and therapeutic solutions. The central nervous system harbors an enormous pool of lipids and lipid intermediates that have been linked to a plethora of its physiological functions. The aim of this review is therefore to provide an overview of the implications of lipids in MDD and highlight certain MDD-related underlying mechanisms that involve lipids and/or their intermediates. Furthermore, we will also focus on the bidirectional relationship between MDD and the lipid-related disorders obesity and type 2 diabetes.

Use of verapamil as a P-glycoprotein inhibitor in patients with drug-resistant depression

Drug-resistant depression is a common occurrence in clinical practice. Current antidepressant therapies have a high failure rate. A P-glycoprotein as a blood-brain barrier component could limit the distribution of these drugs into the brain. Verapamil is the most extensively characterized P-gp inhibitor and probably verapamil prevents up-regulation of P-gp expression. Co-administration of P-gp inhibitors with P-gp-substarate drugs (antidepressants) represents a potential strategy to overcome drug resistance.

The use of psilocybin for treatment-resistant depression

The hallucinogen psilocybin is a potential novel treatment for treatment-resistant depression (TRD). Our goal is to review current knowledge on psilocybin and its efficacy in TRD. Literature searches were done on PubMed, Web of Science and Google Scholar, references reviewed in identified articles and other articles found on the website of COMPASS Pathways. Psilocybin treatment consists usually of a single oral administration of 25 mg of psilocybin along with psychological support for 5-8 hours during the ensuing hallucinogenic trip. Common side-effects include headache, nausea, fatigue and insomnia. A systematic review has demonstrated significant antidepressant efficacy in certain groups and a double-blind randomized study found antidepressant efficacy of psilocybin comparable to the SSRI escitalopram. In the phase 2 study of COMPASS Pathways, the psilocybin-COMP360 treatment led to a rapid response and remission as early as three weeks following the treatment for around one third of participants. Recent studies have shown that psilocybin significantly decreases the severity of depressive symptoms and is generally well tolerated. Further research will reveal whether it will be granted a license to treat treatment-resistant depression in the near future. There remains an urgent need for novel treatments for those who do not respond to current antidepressant therapies.

Maintenance or Discontinuation of Antidepressants in Primary Care

BackgroundPatients with depression who are treated in primary care practices may receive antidepressants for prolonged periods. Data are limited on the effects of maintaining or discontinuing antidepressant therapy in this setting.MethodsWe conducted a randomized, double-blind trial involving adults who were being treated in 150 general practices in the United Kingdom. All the patients had a history of at least two depressive episodes or had been taking antidepressants for 2 years or longer and felt well enough to consider stopping antidepressants. Patients who had received citalopram, fluoxetine, sertraline, or mirtazapine were randomly assigned in a 1:1 ratio to maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group). The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to-event analysis. Secondary outcomes were depressive and anxiety symptoms, physical and withdrawal symptoms, quality of life, time to stopping an antidepressant or placebo, and global mood ratings.ResultsA total of 1466 patients underwent screening. Of these patients, 478 were enrolled in the trial (238 in the maintenance group and 240 in the discontinuation group). The average age of the patients was 54 years; 73% were women. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group. By 52 weeks, relapse occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group (hazard ratio, 2.06; 95% confidence interval, 1.56 to 2.70; P<0.001). Secondary outcomes were generally in the same direction as the primary outcome. Patients in the discontinuation group had more symptoms of depression, anxiety, and withdrawal than those in the maintenance group.ConclusionsAmong patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy. (Funded by the National Institute for Health Research; ANTLER ISRCTN number, ISRCTN15969819.)

Social cognition and major depressive disorder: impact on psychosocial function and therapeutic opportunities

AimsThis poster aims to examine the impact of social cognitive deficits on psychosocial functioning in depressed patients, as well as summarise the utility of various evidence-based therapeutic interventions employed to target these deficits. The stated hypotheses were twofold: (1) that social cognitive impairment in major depressive disorder will correlate with poorer psychosocial functioning; and (2) that these deficits will respond to existing anti-depressant therapies.BackgroundSocial cognition is an important adaptive trait that incorporates the identification, perception and interpretation of socially relevant information from the external world. It is frequently affected in major depressive disorder such that depressed patienMethodA review of the existing literature was performed in order to test the stated hypotheses. Pertinent sources were identified via the MEDLINE, EMBASE, PsycINFO, PubMed, Scopus and Google Scholar databases. A total of 107 studies met inclusion criteria for review.ResultImpaired social cognitive performance in depressed patients correlated with poorer psychosocial functioning across the key domains of general cognitive functioning and quality of life. Many current anti-depressant therapies were found to have a normalising effect on the social cognitive abilities of depressed subjects, both at a neural and functional level. Anti-depressant medications, in particular citalopram and reboxetine, appeared to correct facial affect recognition deficits, while a psychotherapeutic approach demonstrated improvements in theory of mind and negative interpretive bias. Data relating to other common treatments, such as electroconvulsive therapy, are limited.ConclusionThe impact and treatment of social cognitive deficits in major depressive disorder is an important emerging field. The social cognitive deficits evident in depressed patients are sometimes subtle, but afford a significant functional impact. Additionally, it appears these impairments are at least partially reversible using anti-depressants or psychotherapy.

The impact of hospital-diagnosed depression or use of antidepressants on treatment initiation, adherence and HbA1c/LDL target achievement in newly diagnosed type 2 diabetes.

We aimed to assess whether current antidepressant therapy or a history of hospital-diagnosed depression affects diabetes treatment initiation, adherence, and HbA1c and LDL-cholesterol target achievement. In this register-based study, we included all individuals from Central and Northern Denmark with newly diagnosed type 2 diabetes, defined as a first-ever HbA1c measurement of ≥48mmol/mol (6.5%), between 2000 and 2016. Individuals either diagnosed with depression at a psychiatric hospital in the 2years prior to their diabetes diagnosis or currently receiving treatment with an antidepressant were compared with individuals with type 2 diabetes, but without depression treatment or previous history of depression. Outcome measures included initiation of glucose-lowering drugs and lipid-modifying agents, adherence to these medications (medication possession ratio >80%), and HbA1c (<53mmol/mol [7%]) and LDL-cholesterol (<2.6mmol/l) target achievement. The assessment of association between depression or antidepressant treatment and these outcomes was conducted using regression analyses with adjustment for potential confounders. We included a total of 87,650 individuals with first-ever HbA1c-diagnosed type 2 diabetes, of whom 0.9% (n = 784) had hospital-diagnosed depression and 11.4% (n = 9963) currently received antidepressant treatment. Compared with those without depression treatment, treatment with an antidepressant was associated with increased likelihood of glucose-lowering drug initiation (HR 1.39 [95% CI 1.34, 1.44]) and adherence (OR 1.27 [95% CI 1.18, 1.36]), lipid-modifying agent initiation (HR 1.17 [95% CI 1.11, 1.23]) and adherence (OR 1.25 [95% CI 1.09, 1.43]), and achievement of LDL (OR 1.08 [95% CI 1.03, 1.14]) but not HbA1c target (OR 0.99 [95% CI 0.93, 1.06]). The findings were similar for individuals who had hospital-diagnosed depression. In individuals with newly diagnosed type 2 diabetes, antidepressant treatment and depression were associated with improved diabetes treatment quality. Graphical abstract.

Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT1A receptor partial agonists

Current antidepressant therapy has several disadvantages related to the properties of antidepressants. Considering their unfavourable features, the process of searching for new antidepressant drugs with better safety and tolerability requires consistent efforts and many complementary studies. Serotonin 5-HT1A receptor is considered as an interesting target of antidepressant therapy. In the present study, the intrinsic activity at different signaling pathways coupled to serotonin 5-HT1A receptor, antidepressant-like and pharmacokinetic properties, and the safety profile of two novel imidazopurine-2,4-dione derivatives, namely compounds AZ-853 (8-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-1,3-dimethyl-1H- imidazo[2,1-f]purine-2,4(3H,8H)-dione) and AZ-861 (1,3-dimethyl-8-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), were studied in animal models through in vitro and in vivo experiments. We demonstrated that AZ-853 and AZ-861, which structurally differ by one substituent and its placement in the phenyl ring, showed varied functional, pharmacological, and pharmacokinetic properties as well as side effect profiles. AZ-861 exhibited stronger agonistic action in all functional assays. After acute and repeated administration in mice, both compounds showed antidepressant-like activity in the forced swim test, which was partially mediated by 5-HT1A receptor activation. AZ-853 showed a more potent antidepressant-like effect, presumably due to its better penetration into brain structures. Both compounds did not show anticholinergic properties, but after repeated administration, they induced weak sedation and lipid metabolism disturbances without affecting serum glucose level. The stronger α1-adrenolytic effect of AZ-853 is responsible for decreased systolic blood pressure, and in contrast to AZ-861, AZ-853 induced weight gain in mice. The interesting comparative pharmacological profiles of AZ-853 and AZ-861 encourage to conduct further experiments to fully understand their mechanisms and differences in action.

Efficacy and safety of TS-121, a novel vasopressin V1B receptor antagonist, as adjunctive treatment for patients with major depressive disorder: A randomized, double-blind, placebo-controlled study

Vasopressin 1B (V1B) receptor has a pivotal role in the regulation of the hypothalamus-adrenal-pituitary axis, and V1B receptor antagonists have shown efficacy in a number of preclinical models of depression. The efficacy and safety of, TS-121 (active ingredient: THY1773), a novel V1B receptor antagonist, was investigated in patients with major depressive disorder (MDD) who had an inadequate response to current antidepressant therapy. In a randomized, double-blind, placebo-controlled phase 2 study, 51 MDD patients (43 of whom completed the study) were randomly assigned to either TS-121 10 mg, 50 mg or placebo for 6 weeks treatment period. The primary endpoint was change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) score at week 6. The study was conducted from Jul 2017 to Dec 2018.The changes from baseline in MADRS score at week 6 (Least Square Mean [95% Confidence interval] were: TS-121 10 mg (-9.0 [-13.9, -4.1]), TS-121 50 mg (-9.0 [-13.4, -4.5]), and placebo (-6.4 [-10.7, -2.2]). TS-121 groups showed greater numerical reductions in MADRS score change from baseline compared to placebo, though these reductions did not achieve statistical significance. Similar trends of numerically greater improvements in TS-121 groups were observed across secondary endpoints. Higher baseline urinary and hair cortisol levels were associated with a greater separation between TS-121 groups and the placebo group in the primary endpoint. These findings, combined with favorable safety and tolerability, warrant further investigation of TS-121 in an adequately powered study in patients with MDD.

Pharmacological interventions for treatment-resistant depression in adults.

Pharmacological interventions for treatment-resistant depression in adults.

Systemic Inhibition of Soluble Tumor Necrosis Factor with XPro1595 Exacerbates a Post-Spinal Cord Injury Depressive Phenotype in Female Rats.

Spinal cord injury (SCI) is associated with a three-fold risk of major depressive disorder compared with the general population. Current antidepressant therapy is often not as effective in this patient population, suggesting the need for a more efficacious therapeutic target. The goal of this study was to elucidate the role of inflammatory cytokine tumor necrosis factor (TNF) in the dorsal raphe nucleus (DRN, the principle source of serotonin to the brain) in the development and possible treatment of depression after SCI. A depressive phenotype following moderate T9 contusion was identified in adult female rats using a battery of behavioral tests (forced swim test, sucrose preference test, novel object recognition test, open field locomotion, and social exploration). Data revealed two clusters of injured rats (58%) that exhibit increased immobility in the forced swim test, indicating depressive phenotype or a melancholic-depressive phenotype with concomitant decrease in sucrose preference. ElevatedTNF levels in the DRN of these two clusters correlated with increased immobility in the forced swim test. We then tested the efficacy of soluble TNF inhibition with XPro1595 treatment to prevent the depressive phenotype after SCI. Subcutaneous (s.c.) delivery of XPro1595 caused an exacerbation of depressive phenotype, with all treated clusters exhibiting increased forced swim immobility compared with saline-treated non-depressed rats. Intracerebroventricular (i.c.v.) administration of the drug did not prevent or enhance the development of depression after injury. These results suggest a complex role for TNF-based neuroinflammation in SCI-induced depression that needs to be further explored, perhaps in conjunction with a broader targeting of additional post-SCI inflammatory cytokines.

Systems Approach to Identify Common Genes and Pathways Associated with Response to Selective Serotonin Reuptake Inhibitors and Major Depression Risk.

Despite numerous studies on major depressive disorder (MDD) susceptibility, the precise underlying molecular mechanism has not been elucidated which restricts the development of etiology-based disease-modifying drug. Major depressive disorder treatment is still symptomatic and is the leading cause of (~30%) failure of the current antidepressant therapy. Here we comprehended the probable genes and pathways commonly associated with antidepressant response and MDD. A systematic review was conducted, and candidate genes/pathways associated with antidepressant response and MDD were identified using an integrative genetics approach. Initially, single nucleotide polymorphisms (SNPs)/genes found to be significantly associated with antidepressant response were systematically reviewed and retrieved from the candidate studies and genome-wide association studies (GWAS). Also, significant variations concerning MDD susceptibility were extracted from GWAS only. We found 245 (Set A) and 800 (Set B) significantly associated genes with antidepressant response and MDD, respectively. Further, gene set enrichment analysis revealed the top five co-occurring molecular pathways (p ≤ 0.05) among the two sets of genes: Cushing syndrome, Axon guidance, cAMP signaling pathway, Insulin secretion, and Glutamatergic synapse, wherein all show a very close relation to synaptic plasticity. Integrative analyses of candidate gene and genome-wide association studies would enable us to investigate the putative targets for the development of disease etiology-based antidepressant that might be more promising than current ones.

P.1.018 - The impact of selective CREB deletion in serotonergic neurons on the effects of fluoxetine administration and antidepressive behaviour

The majority of current antidepressant therapies is based on the enhancement of monoaminergic transmission observed directly after drug administration, yet alleviation of depressive symptoms occurs weeks later. Therefore, the mechanism of molecular changes arising during chronic antidepressant treatment is intensively researched. Many studies have pointed to an important role of cAMP response element binding (CREB) protein in the mechanism of antidepressant drug action, however the data are inconclusive. Generally, an increase of CREB level or activity after chronic antidepressant treatment was postulated, but in other studies opposite effects were observed [1]. Moreover, CREB-deficient animals show antidepressant-like phenotype. However, the feedback from knock-out studies could have been disturbed by cAMP response element modulator (CREM) upregulation occurring upon CREB loss [2], which was not taken into consideration. In our studies we investigated the role of CREB in the mechanism of antidepressant treatment using novel, inducible transgenic mouse model lacking CREB selectively in serotonergic neurons [3], maintained in CREM-deficient background (Creb1TPH2CreERT2Crem-/- mice). The animals have been phenotypically characterized showing no impairments in their basal behavior. However, single Creb1TPH2CreERT2 mutants of both sexes presented drug-resistant phenotype in tail suspension test after fluoxetine treatment, whereas male but not female double mutants (Creb1TPH2CreERT2Crem-/-) reacted to the drug similar to control animals [4]. The aim of current studies was to assess the molecular changes induced by chronic fluoxetine (10 mg/kg i.p., 21 days, 1x daily) treatment in hippocampus and prefrontal cortex (PFC). Animals were sacrificed 24h after last injection and the brain structures were collected. Assessment of mRNA expression for Creb1 and Bdnf genes was measured by RT-PCR using TaqMan probes. The levels of phosphorylated CREB, total CREB and BDNF proteins were studied using Western Blot. The results were analyzed using two-way ANOVA, followed by Fisher’s LSD test. We observed no effect in mRNA expression of Creb1 and Bdnf genes in control animals after fluoxetine treatment, nor in any of studied mutants. Moreover, no changes in phosphorylation of CREB or total CREB protein were visible in any of studied group. On the other hand, BDNF protein was strongly increased in response to drug in hippocampus of control males and females (by 212% and 120%, respectively), and in PFC of control females only (by 47%). Both treated and non-treated Creb1TPH2CreERT2 single mutant mice did not show any changes in BDNF in both studied brain structures; the result was significantly different from the effect observed in control animals after fluoxetine administration. Creb1TPH2CreERT2Crem-/- double mutants presented only non-significant tendency of increased BDNF protein level in hippocampus (both males and females) and PFC (females only). Despite the absence of any effect in CREB mRNA or protein levels observed in both mutant lines, the BDNF upregulation in fluoxetine-treated control mice suggests increased activity of CREB in hippocampus after antidepressant treatment as observed by other investigators [5]. Lack of molecular or behavioral changes after fluoxetine treatment in Creb1TPH2CreERT2 single mutant animals suggests that compensatory role of CREM upregulation in the inducible line may have different effects from that observed previously in constitutive CREB knockouts.

Disruption of lipid-raft localized Gαs/tubulin complexes by antidepressants: a unique feature of HDAC6 inhibitors, SSRI and tricyclic compounds.

Current antidepressant therapies meet with variable therapeutic success and there is increasing interest in therapeutic approaches not based on monoamine signaling. Histone deacetylase 6 (HDAC6), which also deacetylates α-tubulin shows altered expression in mood disorders and HDAC6 knockout mice mimic traditional antidepressant treatments. Nonetheless, a mechanistic understanding for HDAC6 inhibitors in the treatment of depression remains elusive. Previously, we have shown that sustained treatment of rats or glioma cells with several antidepressants translocates Gαs from lipid rafts toward increased association with adenylyl cyclase (AC). Concomitant with this is a sustained increase in cAMP production. While Gαs modifies microtubule dynamics, tubulin also acts as an anchor for Gαs in lipid-rafts. Since HDAC-6 inhibitors potentiate α-tubulin acetylation, we hypothesize that acetylation of α-tubulin disrupts tubulin-Gαs raft-anchoring, rendering Gαs free to activate AC. To test this, C6 Glioma (C6) cells were treated with the HDAC-6 inhibitor, tubastatin-A. Chronic treatment with tubastatin-A not only increased α-tubulin acetylation but also translocated Gαs from lipid-rafts, without changing total Gαs. Reciprocally, depletion of α-tubulin acetyl-transferase-1 ablated this phenomenon. While escitalopram and imipramine also disrupt Gαs/tubulin complexes and translocate Gαs from rafts, they evoke no change in tubulin acetylation. Finally, two indicators of downstream cAMP signaling, cAMP response element binding protein phosphorylation (pCREB) and expression of brain-derived-neurotrophic-factor (BDNF) were both elevated by tubastatin-A. These findings suggest HDAC6 inhibitors show a cellular profile resembling traditional antidepressants, but have a distinct mode of action. They also reinforce the validity of antidepressant-induced Gαs translocation from lipid-rafts as a biosignature for antidepressant response that may be useful in the development of new antidepressant compounds.

Therapeutic Strategies for Treatment of Inflammation-related Depression.

Background:Mounting evidence demonstrates enhanced systemic levels of inflammatory mediators in depression, indicating that inflammation may play a role in the etiology and course of mood disorders. Indeed, proinflammatory cytokines induce a behavioral state of conservation-withdrawal resembling human depression, characterized by negative mood, fatigue, anhedonia, psychomotor retardation, loss of appetite, and cognitive deficits. Neuroinflammation also contributes to non-responsiveness to current antidepressant (AD) therapies. Namely, response to conventional AD medications is associated with a decrease in inflammatory biomarkers, whereas resistance to treatment is accompanied by increased inflammation.Methods:In this review, we will discuss the utility and shortcomings of pharmacologic AD treatment strategies focused on inflammatory pathways, applied alone or as an adjuvant component to current AD therapies.Results:Mechanisms of cytokine actions on behavior involve activation of inflammatory pathways in the brain, resulting in changes of neurotransmitter metabolism, neuroendocrine function, and neuronal plasticity. Selective serotonin reuptake inhibitors exhibit the most beneficial effects in restraining the inflammation markers in depression. Different anti-inflammatory agents exhibit AD effects via modulating neurotransmitter systems, neuroplasticity markers and glucocorticoid receptor signaling. Anti-inflammatory add-on therapy in depression highlights such treatment as a candidate for enhancement strategy in patients with moderate-to-severe depression.Conclusion:The interactions between the immune system and CNS are not only involved in shaping behavior, but also in responding to therapeutics. Even though, substantial evidence from animal and human research support a beneficial effect of anti-inflammatory add-on therapy in depression, further research with special attention on safety, particularly during prolonged periods of anti-inflammatory co-treatments, is required.

Serum Concentrations of 25-Hydroxyvitamin D and Depression in a General Middle-Aged to Elderly Population in Finland.

Low concentrations of serum 25-hydroxyvitamin D [25(OH)D] have been postulated to associate with an increased prevalence of depression. As there are a limited number of publications on this issue, we examined the association between serum 25(OH)D and depression in a general middle-aged or older population. A population-based cross-sectional study. A total of 1602 men and women from the population-based Kuopio Ischaemic Heart Disease Risk Factor Study (KIHD) in Eastern Finland, aged 53-73 y in 1998-2001, were analysed. Depressive symptoms were assessed with the DSM-III depression scale, and those individuals who had scores over 4 (range 0-12) or had reported undergoing current antidepressant therapy, were considered as suffering from depression. Associations were estimated in serum 25(OH)D tertiles using logistic regression. Among the participants, 183 subjects (11.4%) were considered to have depression. The mean age of the subjects was 62.6 years (SD 6.4, range 53.4-73.8 years). The mean serum 25(OH)D concentration was 43.8 nmol/L (SD 17.7, range 8.5-112.8 nmol/L), concentrations <50 nmol/L were observed in 65.0% of the subjects, and only 5.0% displayed concentrations ≥75 nmol/L. After multivariable adjustments, the odds ratios for having depression in the tertiles (from highest to the lowest) of serum 25(OH)D were 1, 1.35 (95 % CI: 0.87, 2.09) and 1.64 (95 % CI: 1.03, 2.59), P for trend=0.036. These findings indicate that a lower concentration of serum 25(OH)D is associated with a higher prevalence of depression in an elderly general population.

Patients Treated with Antidepressants and the Relative Risk of Suicide Attempt

Tricyclic antidepressants (TCAs) have been approved by the Food and Drug Administration (FDA) specifically to treat depression, with their generic or chemical names. The aim of this study was to characterize patients on antidepressants after self-poisoning with suicidal intent regarding age, sex, type of current antidepressant therapy, and type of substances ingested in order to commit suicide. This study was conducted on patients (n=1283) of different ages, 924 males and 359 female. These patients were attended to poison unit at emergency hospital, Mansoura University during the period from January 2002 to December 2009. During the study period, 175-Para suicide patients were found with current antidepressants therapy and presented with self-poisoning using their antidepressant therapy or other medications. A substantial difference between different types of antidepressants was found. Para suicide risks for selective serotonin reuptake inhibitor were significantly low than those of tricyclic antidepressants, so in suicide prevention, risks and benefits of antidepressant should be taken into account when choosing treatment for depressive patients. At the same time, depressed patients should be under close psychiatric assessment in order to prevent such possible suicidal attempts.

The role of inflammation in depression: from evolutionary imperative to modern treatment target.

Crosstalk between inflammatory pathways and neurocircuits in the brain can lead to behavioural responses, such as avoidance and alarm, that are likely to have provided early humans with an evolutionary advantage in their interactions with pathogens and predators. However, in modern times, such interactions between inflammation and the brain appear to drive the development of depression and may contribute to non-responsiveness to current antidepressant therapies. Recent data have elucidated the mechanisms by which the innate and adaptive immune systems interact with neurotransmitters and neurocircuits to influence the risk for depression. Here, we detail our current understanding of these pathways and discuss the therapeutic potential of targeting the immune system to treat depression.