Use of a gene expression signature to identify trimetazidine for repurposing to treat bipolar depression.

OBJECTIVES: The aim of this study was to repurpose a drug for the treatment of bipolar depression. METHODS: A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal-like (NT2-N) cells. A compound library of 960 approved, off-patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co-cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive-like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats). RESULTS: The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal-like cells. Transcriptomic analysis in induced pluripotent stem cell-derived neuron/astrocyte co-cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive-like behaviours, trimetazidine exhibited antidepressant-like activity with reduced anhedonia and reduced immobility in the forced swim test. CONCLUSION: Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression.

Mapping Cancer incidence across Western Victoria: the association with age, accessibility, and socioeconomic status among men and women.

BACKGROUND: Cancer is a leading burden of disease in Australia and worldwide, with incidence rates varying with age, sex and geographic location. As part of the Ageing, Chronic Disease and Injury study, we aimed to map the incidence rates of primary cancer diagnoses across western Victoria and investigate the association of age, accessibility/remoteness index of Australia (ARIA) and area-level socioeconomic status (SES) with cancer incidence. METHODS: Data on cancer incidence in the study region were extracted from the Victorian Cancer Registry (VCR) for men and women aged 40+ years during 2010-2013, inclusive. The age-adjusted incidence rates (per 10,000 population/year), as well as specific incidence for breast, prostate, lung, bowel and melanoma cancers, were calculated for the entire region and for the 21 Local Government Areas (LGA) that make up the whole region. The association of aggregated age, ARIA and SES with cancer incidence rates across LGAs was determined using Poisson regression. RESULTS: Overall, 15,120 cancer cases were identified; 8218 (54%) men and 6902 women. For men, the age-standardised rate of cancer incidence for the whole region was 182.1 per 10,000 population/year (95% CI 177.7-186.5) and for women, 162.2 (95% CI: 157.9-166.5). The incidence of cancer (overall) increased with increasing age for men and women. Geographical variations in cancer incidence were also observed across the LGAs, with differences identified between men and women. Residents of socioeconomically disadvantaged and less accessible areas had higher cancer incidence (p < 0.001). CONCLUSION: Cancer incidence rates varied by age, sex, across LGAs and with ARIA. These findings not only provide an evidence base for identifying gaps and assessing the need for services and resource allocation across this region, but also informs policy and assists health service planning and implementation of preventative intervention strategies to reduce the incidence of cancer across western Victoria. This study also provides a model for further research across other geographical locations with policy and clinical practice implications, both nationally and internationally.

Recalibrating the risks and benefits of lithium therapy.

Recent data might subtly recalibrate the risk/benefit ratio of lithium, the prototypical mood stabiliser for bipolar disorder. There are hints that lithium might be associated with a reduction in dementia risk and as noted in this Journal, a surprising reduction in the risk of cancer.

Depressive symptomology and cancer incidence in men and women: Longitudinal evidence from the HUNT study.

BACKGROUND: Depressive symptoms and mood disorders are associated with a host of physical conditions. However, it is inconclusive whether depressive symptoms are also associated with cancer onset. The aim of this study was to investigate whether depressive symptoms are associated with cancer incidence in a large population-based sample of men and women. METHODS: This study examined data from waves two (HUNT 2, 1995-97) and three (HUNT 3, 2006-08) of the Trøndelag Health Study (HUNT). Depressive symptoms were ascertained using the Hospital Anxiety and Depression Scale (HADS-D ≥ 8), cancer onset was identified via linkage with the Cancer Registry of Norway, death records by the national Cause of Death Register (CDR), and information on lifestyle and demographic factors was self-reported. Cox-proportional hazard regression models were used to test associations. Unadjusted, age-adjusted and multivariable best models accounting for smoking, education, marital status and current employment are presented. RESULTS: Men and women (n = 61,985; 46.0 % men) were followed from baseline over a period of 778,802 person-years. During the 20-year study period, there were 6856 (11.1 %) individuals with incident cancers and 12,480 (20.1 %) deaths (n = 2498 attributed to cancer). For men with depressive symptoms, 505 (15.3 %) developed incident cancer during the follow-up period, whereas among those without depressive symptoms, 3164 (12.5 %) developed incident cancer. Following adjustment for age, depressive symptomology was not significantly associated with risk of overall cancer onset, nor among prostate, colon or melanoma subtypes. Depressive symptoms were associated with an increased risk of bronchus and lung cancer both before (HR 1.90, 95 % CI 1.43-2.50, p ≤0.001) and after adjustment for age (HR 1.38, 95 % CI 1.04-1.80, p = 0.025). However, further adjustment for additional possible confounders explained this association. For women with depressive symptoms, 384 (11.2 %) developed incident cancer during the follow-up period, whereas among those with no depressive symptomology, 2803 (9.3 %) developed incident cancer. After accounting for age, depressive symptomology was not associated with risk of overall cancer onset, nor among breast, colon, lung and bronchus, or melanoma subtypes. Additional analyses evaluating relationship of depression symptom severity and cancer onset did not alter findings for men or women. LIMITATIONS: This report is limited by the post-hoc study design and subsequent non-randomised nature. Future prospective studies are required. CONCLUSION: These results suggest that depressive symptoms are not associated with an increased risk of overall or site-specific cancer onset in these men and women. Given the increased co-occurrence of other medical conditions such as cardiovascular disease, diabetes, stroke and musculoskeletal disorders in people with depression, the role of clinically diagnosed depression and other psychiatric disorders in association with cancer onset necessitates further consideration.

Mood disorder and cancer onset: evidence from a population-based sample of Australian women.

OBJECTIVE: The role of mood disorders in cancer onset is unclear. The aim of this study was to investigate the association between mood disorder and incident cancer in a population-based sample of women. METHODS: Data were derived from women aged 28-94 years participating in the Geelong Osteoporosis Study. Mood disorder was identified via Clinical Interview (SCID-I/NP). Cancer data was obtained following linkage with the Victorian Cancer Registry. Demographic and lifestyle factors were self-reported. Nested case-control and retrospective study designs were utilized. RESULTS: In the case-control study (n=807), mood disorder was documented for 18 of the 75 (9.3%) cancer cases and among 288 controls (24.0% vs. 39.3%, p = 0.009). Prior exposure to mood disorder was associated with reduced cancer incidence (OR 0.49, 95%CI 0.28-0.84); this was sustained following adjustment for confounders (ORadj 0.52, 95%CI 0.30-0.90). In the retrospective cohort study (n=655), among 154 women with a history of mood disorder at baseline, 13 (8.5%) developed incident cancer during follow-up, whereas among 501 women with no history of mood disorder, 54 (10.8%) developed incident cancer. Exposure to mood disorder was not associated with incident cancer over the follow-up period (HR 0.58, 95%CI 0.31-1.08, p = 0.09). CONCLUSION: Mood disorder was associated with reduced odds of cancer onset. However, this finding was not supported in the retrospective cohort study. Larger studies able to investigate specific cancers and mood disorders as well as underlying mechanisms in both men and women are warranted.

Systematic review and meta-analysis of the role of personality disorder in randomised controlled trials of pharmacological interventions for adults with mood disorders.

BACKGROUND: Personality disorder (PD) may affect the efficacy of pharmacological interventions for mood disorders, but the extent to which this occurs is uncertain. We aimed to examine the available published evidence concerning the role of PD in pharmacological treatment outcomes of randomised controlled trials (RCTs) for adults with mood disorders (i.e. depressive and bipolar spectrum disorders). METHODS: A systematic search of Cochrane Central Register of Controlled Clinical Trials, PubMed, EMBASE, PsycINFO, CINAHL Complete, and Google Scholar databases was undertaken to identify studies of interest. Data were independently extracted by two reviewers. The Cochrane Risk of Bias tool was used to assess methodological quality and risk of bias. A random effects model was utilised and statistical heterogeneity was assessed using the I2 statistic. This systematic review was registered with PROSPERO (CRD42018089279) and the protocol is published. RESULTS: The search yielded 11,640 studies. Subsequent to removing duplicates, 9657 studies were screened at title and abstract stage and 1456 were assessed at full-text stage. Eighteen studies met criteria for inclusion in this review. Meta-analysis did not reveal a significant difference between groups for treatment outcome (standardised mean difference 0.22 [-0.09, 0.54]; I2: 69%, p=0.17) and remission (risk ratio 0.84 [0.64, 1.11]; I2: 51%, p=0.22). LIMITATIONS: This review was limited by lack of studies on bipolar disorder. CONCLUSION: PD comorbidity does not appear to affect treatment efficacy of pharmacological interventions for adults with mood disorders.

Risk of cancer in bipolar disorder and the potential role of lithium: International collaborative systematic review and meta-analyses.

We examined bipolar disorder (BD) as a risk factor for developing cancer and the role of lithium on cancer incidence. We conducted two systematic review and meta-analyses of population-based studies providing data on these associations. We screened articles indexed in MEDLINE, Scopus, Embase, and PsycINFO up to August 2020. The first random-effects meta-analysis, based on 4,910,661 individuals from nine studies estimated an increased risk of cancer of any kind [RR = 1.24 (1.05-1.46); p < 0.01], especially breast cancer [RR = 1.33 (1.15-1.55); p < 0.01] in BD. The second random-effects meta-analysis, based on 2,606,187 individuals from five studies did not show increased risk of cancer in people with BD using lithium, and even suggested a small protective effect both in overall [RR = 0.94 (0.72-1.22); p = 0.66] and urinary cancer [RR = 0.93 (0.75-1.14); p = 0.48] although these findings did not reach statistical significance. The current evidence highlights that cancer risk is increased in individuals with BD, particularly breast cancer in women. Lithium may have a potential protective effect on cancer, including urinary cancer. The role of lithium as a mainstay of treatment for BD is reinforced by this study.

Validity of self-reported cancer: Comparison between self-report versus cancer registry records in the Geelong Osteoporosis Study.

BACKGROUND: Determining the validity of self-reported data is important. The aim of this study was to assess the validity of self-reported cancer and investigate factors associated with accurate reporting in men and women. METHODS: Study participants (n = 1727) from the Geelong Osteoporosis Study, located in south-eastern Australia, were utilised. Self-reported cancer data were compared to Victorian Cancer Registry records. Age, socioeconomic status (SES), education and time between cancer diagnosis and study appointment were investigated as factors associated with accuracy of self-report. RESULTS: There were 142 participants who self-reported a cancer and 135 with a VCR record. Comparing self-report to any registry record, sensitivity was 63.7 %, specificity 96.5 %, PPV 60.6 %, NPV 96.9 %, and overall agreement ĸ0.588. Comparing exact-match records, sensitivity was 58.8 %, specificity 95.5 %, PPV 49.3 %, NPV 96.9 % and overall agreement ĸ0.499. In logistic regression models, post-secondary education was independently associated with accuracy of any (OR 1.72, 95 % CI 1.10-2.70) and exact-match (OR 1.59, 95 % CI 1.05-2.42) self-report, compared to cancer registry record. For any cancer, being aged >70 years was inversely associated with accuracy (OR 0.24, 95 % CI 0.15-0.38). Likewise, for matched cancer reporting, those aged 60-70 years (OR 0.51, 95 %CI 0.30-0.88) and >70 years (OR 0.23, 95 % CI 0.15-0.35) were less accurate. No other significant associations were detected. CONCLUSION: Results suggest moderate agreement between self-report and registry data for any cancer among men and women. However, when comparing self-report to registry data for exact-match cancer type, level of overall agreement deteriorated. Self-report cancer data may be acceptable for determining a history of cancer, although, is less accurate in identifying history of specific cancer types documented in registry-based data.

Bone health in bipolar disorder: a study protocol for a case-control study in Australia.

INTRODUCTION: Little is known about the bone health of adults with bipolar disorder, aside from evidence purporting bone deficits among individuals with other mental illnesses, or those taking medications commonly used in bipolar disorder. In this paper, we present the methodology of a case-control study which aims to examine the role of bipolar disorder as a risk factor for bone fragility. METHODS AND ANALYSIS: Men and women with bipolar disorder (~200 cases) will be recruited and compared with participants with no history of bipolar disorder (~1500 controls) from the Geelong Osteoporosis Study. Both cases and controls will be drawn from the Barwon Statistical Division, south-eastern Australia. The Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition is the primary diagnostic instrument, and psychiatric symptomatology will be assessed using validated rating scales. Demographic information and detailed lifestyle data and medical history will be collected via comprehensive questionnaires. Participants will undergo dual energy X-ray absorptiometry scans and other clinical measures to determine bone and body composition. Blood samples will be provided after an overnight fast and stored for batch analysis. ETHICS AND DISSEMINATION: Ethics approval has been granted from Barwon Health Research Ethics Committee. Participation in the study is voluntary. The study findings will be disseminated via peer-reviewed publications, conference presentations and reports to the funding body.