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Concept: Bipolar disorder

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Suicides are a leading cause of death in psychiatric patients, and in society at large. Developing more quantitative and objective ways (biomarkers) for predicting and tracking suicidal states would have immediate practical applications and positive societal implications. We undertook such an endeavor. First, building on our previous blood biomarker work in mood disorders and psychosis, we decided to identify blood gene expression biomarkers for suicidality, looking at differential expression of genes in the blood of subjects with a major mood disorder (bipolar disorder), a high-risk population prone to suicidality. We compared no suicidal ideation (SI) states and high SI states using a powerful intrasubject design, as well as an intersubject case-case design, to generate a list of differentially expressed genes. Second, we used a comprehensive Convergent Functional Genomics (CFG) approach to identify and prioritize from the list of differentially expressed gene biomarkers of relevance to suicidality. CFG integrates multiple independent lines of evidence-genetic and functional genomic data-as a Bayesian strategy for identifying and prioritizing findings, reducing the false-positives and false-negatives inherent in each individual approach. Third, we examined whether expression levels of the blood biomarkers identified by us in the live bipolar subject cohort are actually altered in the blood in an age-matched cohort of suicide completers collected from the coroner’s office, and report that 13 out of the 41 top CFG scoring biomarkers (32%) show step-wise significant change from no SI to high SI states, and then to the suicide completers group. Six out of them (15%) remained significant after strict Bonferroni correction for multiple comparisons. Fourth, we show that the blood levels of SAT1 (spermidine/spermine N1-acetyltransferase 1), the top biomarker identified by us, at the time of testing for this study, differentiated future as well as past hospitalizations with suicidality, in a live cohort of bipolar disorder subjects, and exhibited a similar but weaker pattern in a live cohort of psychosis (schizophrenia/schizoaffective disorder) subjects. Three other (phosphatase and tensin homolog (PTEN), myristoylated alanine-rich protein kinase C substrate (MARCKS), and mitogen-activated protein kinase kinase kinase 3 (MAP3K3)) of the six biomarkers that survived Bonferroni correction showed similar but weaker effects. Taken together, the prospective and retrospective hospitalization data suggests SAT1, PTEN, MARCKS and MAP3K3 might be not only state biomarkers but trait biomarkers as well. Fifth, we show how a multi-dimensional approach using SAT1 blood expression levels and two simple visual-analog scales for anxiety and mood enhances predictions of future hospitalizations for suicidality in the bipolar cohort (receiver-operating characteristic curve with area under the curve of 0.813). Of note, this simple approach does not directly ask about SI, which some individuals may deny or choose not to share with clinicians. Lastly, we conducted bioinformatic analyses to identify biological pathways, mechanisms and medication targets. Overall, suicidality may be underlined, at least in part, by biological mechanisms related to stress, inflammation and apoptosis.Molecular Psychiatry advance online publication, 20 August 2013; doi:10.1038/mp.2013.95.

Concepts: DNA, Gene, Genetics, Gene expression, Organism, Schizophrenia, Bipolar disorder, Suicide

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Individuals with a history of recurrent depression have a high risk of repeated depressive relapse or recurrence. Maintenance antidepressants for at least 2 years is the current recommended treatment, but many individuals are interested in alternatives to medication. Mindfulness-based cognitive therapy (MBCT) has been shown to reduce risk of relapse or recurrence compared with usual care, but has not yet been compared with maintenance antidepressant treatment in a definitive trial. We aimed to see whether MBCT with support to taper or discontinue antidepressant treatment (MBCT-TS) was superior to maintenance antidepressants for prevention of depressive relapse or recurrence over 24 months.

Concepts: Selective serotonin reuptake inhibitor, Bipolar disorder, Major depressive disorder, Bupropion, Sertraline, Mindfulness-based cognitive therapy

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BACKGROUND:Ecological studies support the hypothesis that suicide may be “contagious” (i.e., exposure to suicide may increase the risk of suicide and related outcomes). However, this association has not been adequately assessed in prospective studies. We sought to determine the association between exposure to suicide and suicidality outcomes in Canadian youth. METHODS:We used baseline information from the Canadian National Longitudinal Survey of Children and Youth between 1998/99 and 2006/07 with follow-up assessments 2 years later. We included all respondents aged 12-17 years in cycles 3-7 with reported measures of exposure to suicide. RESULTS:We included 8766 youth aged 12-13 years, 7802 aged 14-15 years and 5496 aged 16-17 years. Exposure to a schoolmate’s suicide was associated with ideation at baseline among respondents aged 12-13 years (odds ratio [OR] 5.06, 95% confidence interval [CI] 3.04-8.40), 14-15 years (OR 2.93, 95% CI 2.02-4.24) and 16-17 years (OR 2.23, 95% CI 1.43-3.48). Such exposure was associated with attempts among respondents aged 12-13 years (OR 4.57, 95% CI 2.39-8.71), 14-15 years (OR 3.99, 95% CI 2.46-6.45) and 16-17 years (OR 3.22, 95% CI 1.62-6.41). Personally knowing someone who died by suicide was associated with suicidality outcomes for all age groups. We also assessed 2-year outcomes among respondents aged 12-15 years: a schoolmate’s suicide predicted suicide attempts among participants aged 12-13 years (OR 3.07, 95% CI 1.05-8.96) and 14-15 years (OR 2.72, 95% CI 1.47-5.04). Among those who reported a schoolmate’s suicide, personally knowing the decedent did not alter the risk of suicidality. INTERPRETATION:We found that exposure to suicide predicts suicide ideation and attempts. Our results support school-wide interventions over current targeted interventions, particularly over strategies that target interventions toward children closest to the decedent.

Concepts: Death, Bipolar disorder, Suicide, The Complete Manual of Suicide, Parasuicide

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Evidence suggests that pathological eating behaviours in bulimia nervosa (BN) are underpinned by alterations in reward processing and self-regulatory control, and by functional changes in neurocircuitry encompassing the dorsolateral prefrontal cortex (DLPFC). Manipulation of this region with transcranial direct current stimulation (tDCS) may therefore alleviate symptoms of the disorder.

Concepts: Randomized controlled trial, Cerebrum, Attention versus memory in prefrontal cortex, Bipolar disorder, Dorsolateral prefrontal cortex, Brodmann area, Working memory, Transcranial direct current stimulation

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We wanted to examine tolerability and efficacy of NSI-189, a benzylpiperizine-aminiopyridine neurogenic compound for treating major depressive disorder (MDD). This was a Phase 1B, double blind, randomized, placebo controlled, multiple-dose study with three cohorts. The first cohort received 40 mg q.d. (n=6) or placebo (n=2), the second cohort 40 mg b.i.d. (n=6) or placebo (n=2), and the third cohort 40 mg t.i.d. (n=6) or placebo (n=2). Twenty-four patients with MDD were recruited, with the diagnosis and severity confirmed through remote interviews. Eligible patients received NSI-189 or placebo for 28 days in an inpatient setting with assessments for safety, pharmacokinetics (PK) and efficacy. Outpatient follow-up visits were conducted until day 84 (±3). NSI-189 was relatively well tolerated at all doses, with no serious adverse effects. NSI-189 area under the curve increased in a dose-related and nearly proportional manner across the three cohorts, with a half-life of 17.4-20.5 h. The exploratory efficacy measurements, including Symptoms Of Depression Questionnaire (SDQ), Montgomery-Asberg Depression Scale (MADRS), Clinical Global Impressions-Improvement (CGI-I), and The Massachusetts General Hospital (MGH) Cognitive and Physical Functioning Questionnaire (CPFQ) showed a promising reduction in depressive and cognitive symptoms across all measures for NSI-189, with significant improvement in the SDQ and CPFQ, and a medium to large effect size for all measures. These improvements persisted during the follow-up phase. In summary, NSI-189 shows potential as a treatment for MDD in an early phase study. The main limitation of this preliminary study was the small sample size of each cohort.Molecular Psychiatry advance online publication, 8 December 2015; doi:10.1038/mp.2015.178.

Concepts: Sample size, Cognitive behavioral therapy, Bipolar disorder, Major depressive disorder, Seasonal affective disorder, Dysthymia, Depression, Types of psychological depression

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BACKGROUND: Cola is an extremely popular caffeinated soft drink. The media have recently cited a poll in which 16% of the respondents considered themselves to be addicted to cola soft drinks. We find the contrast between the apparent prevalence of cola addiction and the lack of scientific literature on the subject remarkable. To our knowledge, this is the first case of cola dependency described in the scientific literature. CASE PRESENTATION: The patient is a 40-year-old woman, who when feeling down used cola to give her an energy boost and feel better about herself. During the past seven years her symptoms increased, and she was prescribed antidepressant medication by her family doctor. Due to worsening of symptoms she was hospitalised and later referred to a specialised outpatient clinic for affective disorders. At entry to the clinic she suffered from constant tiredness, lack of energy, failing concentration, problems falling asleep as well as interrupted sleep. She drank about three litres of cola daily, and she had developed a metabolic syndrome.The patient fulfilled the ICD-10 criteria for dependency, and on the Yale Food Addiction Scale (YFAS) she scored 40 points. Her clinical mental status was at baseline assessed by the Major Depression Inventory (MDI) = 41, Hamilton Depression - 17 item Scale (HAMD-17) = 14, Young Mania Rating Scale (YMRS) = 2 and the Global Assessment of Functioning (GAF) Scale = 45.During cognitive therapy sessions she was guided to stop drinking cola and was able to moderate her use to an average daily consumption of 200 ml of cola Her concentration improved and she felt mentally and physically better. At discharge one year after entry her YFAS was zero. She was mentally stable (MDI =1, HAMD-17 = 0, YMRS = 0 and GAF = 85) and without antidepressant medication. She had lost 7.2 kg, her waistline was reduced by 13 cm and the metabolic syndrome disappeared. CONCLUSION: This case serves as an example of how the overconsumption of a caffeinated soft drink likely was causing or accentuating the patient’s symptoms of mental disorder. When diagnosing and treating depression, health professionals should pay attention to potential overuse of cola or other caffeinated beverages.

Concepts: Coffee, Addiction, Caffeine, Bipolar disorder, Major depressive disorder, Soft drink, Energy drink, Coca-Cola

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There is compelling evidence to support an aetiological role for inflammation, oxidative and nitrosative stress (O&NS), and mitochondrial dysfunction in the pathophysiology of major neuropsychiatric disorders, including depression, schizophrenia, bipolar disorder, and Alzheimer’s disease (AD). These may represent new pathways for therapy. Aspirin is a non-steroidal anti-inflammatory drug that is an irreversible inhibitor of both cyclooxygenase (COX)-1 and COX-2, It stimulates endogenous production of anti-inflammatory regulatory ‘braking signals’, including lipoxins, which dampen the inflammatory response and reduce levels of inflammatory biomarkers, including C-reactive protein, tumor necrosis factor- and interleukin (IL)–6 , but not negative immunoregulatory cytokines, such as IL-4 and IL-10. Aspirin can reduce oxidative stress and protect against oxidative damage. Early evidence suggests there are beneficial effects of aspirin in preclinical and clinical studies in mood disorders and schizophrenia, and epidemiological data suggests that high-dose aspirin is associated with a reduced risk of AD. Aspirin, one of the oldest agents in medicine, is a potential new therapy for a range of neuropsychiatric disorders, and may provide proof-of-principle support for the role of inflammation and O&NS in the pathophysiology of this diverse group of disorders.

Concepts: Inflammation, Cyclooxygenase, Anti-inflammatory, Paracetamol, Mental disorder, Schizophrenia, Bipolar disorder, Tumor necrosis factor-alpha

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Several classic studies have concluded that the accuracy of identifying uncontrollable situations depends heavily on depressive mood. Nondepressed participants tend to exhibit an optimistic illusion of control, whereas depressed participants tend to better detect a lack of control. Recently, we suggested that the different activity levels (measured as the probability of responding during a contingency learning task) exhibited by depressed and nondepressed individuals is partly responsible for this effect. The two studies presented in this paper provide further support for this mediational hypothesis, in which mood is the distal cause of the illusion of control operating through activity level, the proximal cause. In Study 1, the probability of responding, P®, was found to be a mediator variable between the depressive symptoms and the judgments of control. In Study 2, we intervened directly on the mediator variable: The P® for both depressed and nondepressed participants was manipulated through instructions. Our results confirm that P® manipulation produced differences in the participants' perceptions of uncontrollability. Importantly, the intervention on the mediator variable cancelled the effect of the distal cause; the participants' judgments of control were no longer mood dependent when the P® was manipulated. This result supports the hypothesis that the so-called depressive realism effect is actually mediated by the probability of responding.

Concepts: Intervention, Bipolar disorder, Mediation, The Mediator

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BACKGROUND: There is a significant treatment gap for patients with depression. A third of sufferers never seek help, and the vast majority of those who do only do so after considerable delay. Little is understood regarding poor help-seeking rates amongst people with depression, with existing research mainly focussed on the impact of barriers to treatment. The current study explored psychological factors affecting help-seeking behaviour in clinically depressed individuals. METHODS: Semi-structured interviews were conducted with 20 current or previously clinically depressed participants who either had or had not sought professional help. Thematic analysis was used to analyse results. RESULTS: The onset of depressive symptoms created conflict with participants' identity and personal goals. Delays in seeking help were primarily attributed to the desire to protect identity and goals from the threat of depressive symptoms. Participants used avoidance strategies to reduce the perceived threat of depressive symptoms on identity. These strategies interfered with help-seeking. Help-seeking was only undertaken once participants reached a point of acceptance and began to make concessions in their identity and goals, at which time they reduced their use of avoidance. CONCLUSIONS: Difficulties resolving conflict between identity and depressive symptoms may account for significant delays in seeking help for depression. The results have implications for predicting health behaviour and improving treatment uptake for depression, and may inform existing help-seeking models.

Concepts: Cognitive behavioral therapy, Bipolar disorder, Major depressive disorder, Seasonal affective disorder, Dysthymia, Types of psychological depression, Suicide, Leonard Cohen