In patients with major depressive disorder (MDD), antidepressant response and remission rates are low, highlighting the need for new treatment approaches. Recently, the abundant literature linking ...inflammatory processes and depressive symptoms have led to the hypothesis that selecting treatment for MDD based on the patient's inflammatory status could be a promising strategy to improve outcomes in patients suffering from MDD. The aim of the randomised control trial we propose is to investigate the antidepressant efficacy of the combined treatment of MDD with antidepressant medication plus anti-inflammatory medication in individuals with raised inflammation levels. For the first time, this study will prospectively test the efficacy of an antidepressant plus anti-inflammatory augmentation based on baseline inflammatory maker levels in MDD using a randomised controlled trial design.
This study proposes to measure blood C-reactive protein (CRP) levels before the initiation of treatment in 200 participants with MDD. Study participants are then assigned into one of two study strata: either into the 'Depression with inflammation' stratum (CRP levels > 3 mg/L); or into the 'Depression without inflammation' stratum (CRP levels ≤ 3 mg/L). Within each of the two study strata, participants randomly receive either antidepressant medication alone (vortioxetine) plus anti-inflammatory medication (celecoxib) or vortioxetine plus placebo for six weeks. At the end of the treatment period, participants have the opportunity to continue vortioxetine alone for a six-month post-trial period. Clinical outcomes are measured at baseline, fortnightly during the treatment period and at the three-month and six-month post-trial visits. The primary outcome is change in MADRS score, with a primary endpoint of a score reduction by 50% from baseline to six weeks (end of augmentation treatment with celecoxib). Secondary clinical outcomes are changes in the cognitive dimensions of depression (cognitive function, emotion processing and social cognition). Biological outcome measures (levels of CRP and other inflammatory markers) are measured at baseline, after six weeks of treatment and at the six-month post-trial visit.
The current study will generate novel evidence for biomarker-based personalised antidepressant treatment selection based on patient inflammatory status before treatment.
Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p . Registered on 11 April 2017.
Patients with depression often report pain. Evidence regarding altered pain sensitivity in depressed patients remains, however, inconclusive. In a large cross-sectional study we investigated the ...association between depression and pain sensitivity with regard to 2 different dimensions of pain sensitivity, as well as the effect of somatic cofactors, symptom severity, and subtype of depression. In 735 patients with a current episode of major depression and 456 never-depressed control participants pain thresholds (pressure pain thresholds, PPTs) were measured at the index finger pad and self-rated suprathreshold pain intensity ratings were obtained using the Pain Sensitivity Questionnaire (PSQ)-minor subscore, an instrument that assesses pain intensity in daily life situations. Additionally, lifestyle factors, medical, and psychiatric conditions were assessed. Unadjusted, patients with depression had lower PPTs and higher PSQ-minor scores indicating increased pain sensitivity. After adjusting for potential mediators, such as poor sleep quality and physical inactivity, patients did not differ from control participants regarding PPTs, but still had significantly higher PSQ-minor ratings. Among patients with depression, severity of anxiety symptoms predicted higher PSQ-minor scores. In conclusion, we found a differential effect of depression on the 2 pain sensitivity dimensions: Decreased experimentally obtained pain thresholds were explained by depression-associated somatic factors whereas increased self-rated suprathreshold pain intensity ratings were associated with increased anxiety symptoms.
Because increased pain intensity perception is hypothesized to be a risk factor for the development of chronic pain, our findings may contribute to understanding the high incidence of chronic pain in depressed patients. They also encourage clinicians to consider the role of anxiety in treatment programs for pain in patients with depression.
To systematic review and meta-analyse the association and mechanistic links between atrial fibrillation (AF) and cognitive impairment.
PubMed, EMBASE, and Cochrane Library were searched up to 27 ...March 2021 and yielded 4534 citations. After exclusions, 61 were analysed; 15 and 6 studies reported on the association of AF and cognitive impairment in the general population and post-stroke cohorts, respectively. Thirty-six studies reported on the neuro-pathological changes in patients with AF; of those, 13 reported on silent cerebral infarction (SCI) and 11 reported on cerebral microbleeds (CMB). Atrial fibrillation was associated with 39% increased risk of cognitive impairment in the general population n = 15: 2 822 974 patients; hazard ratio = 1.39; 95% confidence interval (CI) 1.25-1.53, I2 = 90.3%; follow-up 3.8-25 years. In the post-stroke cohort, AF was associated with a 2.70-fold increased risk of cognitive impairment adjusted odds ratio (OR) 2.70; 95% CI 1.66-3.74, I2 = 0.0%; follow-up 0.25-3.78 years. Atrial fibrillation was associated with cerebral small vessel disease, such as white matter hyperintensities and CMB (n = 8: 3698 patients; OR = 1.38; 95% CI 1.11-1.73, I2 = 0.0%), SCI (n = 13: 6188 patients; OR = 2.11; 95% CI 1.58-2.64, I2 = 0%), and decreased cerebral perfusion and cerebral volume even in the absence of clinical stroke.
Atrial fibrillation is associated with increased risk of cognitive impairment. The association with cerebral small vessel disease and cerebral atrophy secondary to cardioembolism and cerebral hypoperfusion may suggest a plausible link in the absence of clinical stroke. PROSPERO CRD42018109185.
Abstract Alzheimer’s disease (AD) is a devastating neurodegenerative condition associated with severe cognitive and behavioral impairments. Circadian rhythms are recurring cycles that display periods ...of approximately 24 hours and are driven by an endogenous circadian timekeeping system centered on the suprachiasmatic nucleus of the hypothalamus. We review the compelling evidence that circadian rhythms are significantly disturbed in AD and that such disturbance is of significant clinical importance in terms of behavioral symptoms. We also detail findings from neuropathological studies of brain areas associated with the circadian system in postmortem studies, the use of animal models of AD in the investigation of circadian processes, and the evidence that chronotherapeutic approaches aimed at bolstering weakened circadian rhythms in AD produce beneficial outcomes. We argue that further investigation in such areas is warranted and highlight areas for future research that might prove fruitful in ultimately providing new treatment options for this most serious and intractable of conditions.
Major Depressive Disorder (MDD) is a complex disease characterized by emotional, physical and cognitive symptoms. We explored the efficacy of vortioxetine versus placebo on outcomes of cognition, ...functioning and mood symptoms in working patients with depression, using paroxetine as an active reference.
Gainfully employed patients (18–65 years, N = 152) with MDD were randomized 1:1:1 to 8 weeks’ double-blind, parallel treatment either with vortioxetine (10mg/day) or paroxetine (20mg/day), or with placebo. The primary efficacy measure was the Digit Symbol Substitution Test (DSST), analyzed using a mixed model for repeated measurements, and the key secondary efficacy measure was the University of San Diego Performance-based Skills Assessment – Brief (UPSA-B), analyzed using analysis of covariance (last observation carried forward).
At week 8, DSST and UPSA-B performance had improved relative to baseline in all treatment groups, with no statistically significant differences between treatment groups. While improvements in mood were comparable for vortioxetine and paroxetine, numerical improvements in cognitive performance (DSST) were larger with vortioxetine. Vortioxetine significantly improved overall cognitive performance and clinician-rated functioning relative to placebo. The majority of adverse events were mild or moderate, with nausea being the most common adverse event for vortioxetine.
Small sample sizes implied limited statistical power.
This explorative study showed no significant differences versus placebo in DSST or UPSA-B performance at week 8. However, secondary results support vortioxetine as an effective and well-tolerated antidepressant, supporting an added benefit for cognition and functioning, which could have particular therapeutic relevance for the working patient population.
•The efficacy of vortioxetine on cognition in working depressed patients is explored.•Primary study endpoints of cognitive and functional test performance were not met.•Secondary endpoints support vortioxetine-specific cognitive and functional effects.•Improvement in cognitive function was associated with improvement in functioning.
Altered adaptive immunity involving T lymphocytes has been found in depressed patients and in stress-induced depression-like behavior in animal models. Peripheral T cells play important roles in ...homeostasis and function of the central nervous system and thus modulate behavior. However, the T cell phenotype and function associated with susceptibility and resilience to depression remain largely unknown. Here, we characterized splenic T cells in susceptible and resilient mice after 10 days of social defeat stress (SDS). We found equally decreased T cell frequencies and comparably altered expression levels of genes associated with T helper (Th) cell function in resilient and susceptible mice. Interleukin (IL)-17 producing CD4
and CD8
T cell numbers in the spleen were significantly increased in susceptible mice. These animals further exhibited significantly reduced numbers of regulatory T cells (T
) and decreased gene expression levels of TGF-β. Mice with enhanced Th17 differentiation induced by conditional deletion of PPARγ in CD4
cells (CD4-PPARγ
), an inhibitor of Th17 development, were equally susceptible to SDS when compared to CD4-PPARγ
controls. These data indicate that enhanced Th17 differentiation alone does not alter stress vulnerability. Thus, SDS promotes Th17 cell and suppresses T
cell differentiation predominantly in susceptible mice with yet unknown effects in immune responses after stress exposure.
Abstract Clozapine is the most effective anti-psychotic medication for treatment refractory schizophrenia. A growing number of case reports have linked infection to high clozapine levels and ...associated adverse outcomes. We present a systematic review of published cases to clarify the relationship between infection and elevated clozapine levels. The case reports were located through PubMed and Embase. In addition, 8 new cases from two Australian states were included. Demographics, psychiatric diagnoses and medical morbidities, medications, clinical symptoms, clozapine levels, inflammatory markers and final clinical outcome were extracted. 40 cases were identified in 23 publications that demonstrated elevated clozapine levels associated with infection. Infections were commonly respiratory in origin. Adverse events, typically sedation, were associated with raised clozapine levels during infection. In many cases the signs of infection such as fever and white blood cell count were reduced. Severe adverse effects were uncommon, with one case each of seizure, myocarditis and neutropenia. The relationship between infection, clozapine levels and adverse events is complex and multi-factorial. Monitoring of clozapine levels is essential during hospitalisation for infection and consideration should be given to gradual dose reduction to minimise dose related side effects.
Personalized medicine (personalized psychiatry in a specific setting) is a new model towards individualized care, in which knowledge from genomics and other omic pillars (microbiome, epigenomes, ...proteome, and metabolome) will be combined with clinical data to guide efforts to new drug development and targeted prescription of the existing treatment options. In this review, we summarize pharmacogenomic studies in mood disorders that may lay the foundation towards personalized psychiatry. In addition, we have discussed the possible strategies to integrate data from omic pillars as a future path to personalized psychiatry. So far, the progress of uncovering single nucleotide polymorphisms (SNPs) underpinning treatment efficacy in mood disorders (e.g., SNPs associated with selective serotonin re-uptake inhibitors or lithium treatment response in patients with bipolar disorder and major depressive disorder) are encouraging, but not adequate. Genetic studies have pointed to a number of SNPs located at candidate genes that possibly influence response to; (a) antidepressants
COMT
,
HTR2A
,
HTR1A
,
CNR1
,
SLC6A4, NPY
,
MAOA
,
IL1B
,
GRIK4
,
BDNF
,
GNB3
,
FKBP5
,
CYP2D6
,
CYP2C19
, and
ABCB1
and (b) mood stabilizers (lithium)
5
-
HTT
,
TPH
,
DRD1
,
FYN
,
INPP1
,
CREB1
,
BDNF
,
GSK3β
,
ARNTL
,
TIM
,
DPB
,
NR3C1
,
BCR
,
XBP1
, and
CACNG2
. We suggest three alternative and complementary strategies to implement knowledge gained from pharmacogenomic studies. The first strategy can be to implement diagnostic, therapeutic, or prognostic genetic testing based on candidate genes or gene products. The second alternative is an integrative analysis (systems genomics approach) to combine omics data obtained from the different pillars of omics investigation, including genomics, epigenomes, proteomics, metabolomics and microbiomes. The main goal of system genomics is an identification and understanding of biological pathways, networks, and modules underlying drug-response. The third strategy aims to the development of multivariable diagnostic or prognostic algorithms (tools) combining individual’s genomic information (polygenic score) with other predictors (e.g., omics pillars, neuroimaging, and clinical characteristics) to finally predict therapeutic outcomes. An integration of molecular science with that of traditional clinical practice is the way forward to drug discoveries and novel therapeutic approaches and to characterize psychiatric disorders leading to a better predictive, preventive, and personalized medicine (PPPM) in psychiatry. With future advances in the omics technology and methodological developments for data integration, the goal of PPPM in psychiatry is promising.
Psychosocial dysfunction is associated with poor longitudinal course of depression and is not sufficiently addressed by existing pharmaceutical or psychological treatments. The aim of the current ...study is to evaluate the efficacy of a novel intervention designed to improve psychosocial function in depressed individuals. Impaired cognition, emotion processing, and social cognition appear to underlie (i.e., cause) psychosocial dysfunction in depression. The current treatment will target functioning in these domains (i.e., cognition, emotion, social cognition) with repeated training tasks, following the rationale that therapeutic benefits will arise in psychosocial functioning. It is expected that personalizing treatment by participants' baseline functioning will enhance clinical efficacy, by comparison with standard treatment in which baseline functioning is not considered.
The study is a randomized, controlled treatment (RCT), in which the efficacy of a personalized and standard intervention will be compared. Sixteen treatment sessions will be administered over an 8-week period. These treatments are designed to improve cognition, emotion processing and social cognition. Assessments of psychosocial functioning, as well as a number of secondary outcomes, will occur at baseline, 4 weeks (mid-RCT), 8 weeks (end of RCT), and in the observational period at baseline (week 9) and 3 and 6 months post-RCT. Recruitment will commence in July 2017, including subjects diagnosed with major depressive disorder according to DSM-IV-TR criteria.
This research will provide new insight into the roles of cognition, emotion processing, and social cognition in psychosocial dysfunction in depression. In addition, the relative clinical efficacy of personalized versus standard treatment approaches will be assessed.
This study has been approved by the human research ethics committees of the Royal Adelaide Hospital and the University of Adelaide (ethics code: R20170611). The study has been registered with the Australia and New Zealand Clinical Trials Registry Registration number: ACTRN12617000899347, web link: http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000899347p. The results of the current study will be published in academic journals following completion of recruitment in 2019. Data will be owned and retained by the University of Adelaide, with access restricted to the research team responsible for the study.
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