New use for old drugs: The protective effect of atypical antipsychotics on hepatocellular carcinoma.

It has been encouraged to use large existing data like insurance claims data to investigate the new indications of old drugs. New strategies of research are warranted to identify feasible drugs. We conducted a dual research model with a population-based case-control study using Taiwan's National Health Insurance Research Database and an in vitro study to investigate the association between atypical antipsychotic and Hepatocellular carcinoma (HCC) risk. The study herein consists of two components. The first is a population-based case-control study using existing data from the Taiwan National Health Insurance Research Database. The second component was an in vitro study in which HCC cell lines (Huh7 and Hep G2) were treated with risperidone, quetiapine and clozapine. after treatment of the foregoing antipsychotics, the HCC cell lines were assessed for cell proliferation, invasion and apoptosis. Multivariate conditional logistic regression analysis revealed that antipsychotic use was independently and inversely associated with HCC risk (adjusted odds-ratio [aOR]:0.85, 95% CI: 0.81-0.89). The protective effect was dose-dependent: compared to the low cumulative defined daily dose (cDDD) group (0-29 cDDD), the 30-89 cDDD and ≥90 cDDD groups were associated with significantly reduced risk for HCC (aOR: 0.56, 95% CI: 0.41-0.76; aOR: 0.37, 95% CI: 0.27-0.50, respectively). In vitro study results indicated that risperidone, quetiapine and clozapine significantly inhibited cell proliferation, invasion and induced apoptosis in human HCC cell lines. Our results herein suggested that antipsychotic use might reduce the risk of HCC and may provide evidence for new uses of old drugs.

Perceived sleep quality predicts cognitive function in adults with major depressive disorder independent of depression severity.

BACKGROUND: The aim of this study was to examine the role of perceived sleep quality in predicting subjective as well as objective cognitive function in adults with major depressive disorder (MDD). METHODS: Adults with recurrent MDD (n = 100) experiencing a major depressive episode of at least moderate severity and age-, sex-, and education-matched healthy controls (HC) (n = 100) were recruited to participate in a clinical trial validating the THINC-integrated tool (THINC-it; NCT02508493) for cognitive function. The THINC-it includes subjective and objective measures of cognitive function. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI). RESULTS: Compared with HC, individuals with MDD reported significantly poorer sleep quality, as assessed by domain and global PSQI scores (all P values <.05). Both perceived sleep quality (P < .001) and depression severity (P = .002) were found to independently predict impairments in subjective cognitive performance. Only perceived sleep quality predicted objective cognitive impairments (P = .017). Exploratory mediation analysis revealed depression severity to be a partial mediator of the relationship between perceived sleep quality and subjective cognitive performance (95% confidence interval [CI]: -0.56, -0.33). CONCLUSIONS: The results indicate that the subjective and objective cognitive impairments are differentially related to perceived sleep quality and depression severity and emphasize the importance of treating sleep disturbances in MDD.

Is binge eating a cognitive disorder? Results from the International Mood Disorders Collaborative Project.

BACKGROUND: Individuals with binge eating disorder (BED) are differentially affected by attention-deficit/hyperactivity disorder (ADHD), obesity, and substance use disorder. We have investigated to what extent cognitive deficits are relevant to binge eating behavior (BEB). METHODS: Data from the International Mood Disorders Collaborative Project were retrospectively and cross-sectionally analyzed to compare individuals with and without BEB on measures of anhedonia and general cognitive functions (n = 566). BEB was assessed using items from the Mini International Neuropsychiatric Interview Plus 5.0.0 for DSM-IV-TR that correspond with DSM-5-defined diagnostic criteria for BED. Individuals currently prescribed benzodiazepines were excluded from analyses. RESULTS: Individuals with BEB were more likely to exhibit anhedonia (P = .044) and general cognitive (P = .005) symptoms, when compared to those without BEB. We also observed that individuals with BEB were more likely to have specific psychiatric (eg, ADHD) and medical (eg, obesity) disorders (P < .05). CONCLUSIONS: Our results suggest that a central disturbance in cognitive processes may be mechanistically relevant to the cause and treatment of BEB in adults.

Determinants of cognitive function in individuals with type 2 diabetes mellitus: A meta-analysis.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is associated with deficits across multiple cognitive domains; however, the determinants of cognitive impairment in T2DM are not well characterized. We aimed to evaluate body mass index (BMI), glycemic control, and T2DM duration as moderators of cognitive dysfunction in T2DM. METHODS: We conducted a meta-analytic review of the literature reporting data on BMI, hemoglobin A1c (HbA1c), T2DM duration, and validated measures of processing speed (ie, Digit Symbol Substitution Test, Trail Making Test [TMT]-A), verbal learning and memory (ie, Rey Auditory Verbal Learning Test), and working memory/executive function (ie, TMT-B) among individuals with vs without T2DM. RESULTS: Individuals with T2DM demonstrated deficits across multiple cognitive domains (k = 40; n = 4,252 T2DM; n = 22,322 non-T2DM; effect sizes 0.21 to 0.35). Illness duration and BMI did not significantly moderate measures of cognition; however, higher HbA1c levels were significantly associated with deficits in measures of processing speed (R2 values 0.41 to 0.73, P < .01) and working memory/executive function (R2 = 0.62, P < .001). CONCLUSIONS: Adults with T2DM exhibited significant deficits across multiple domains of cognitive function. Additionally, we identified an association between poorer glycemic control and cognitive dysfunction. A clinical translation of our findings relates to the reduction in morbidity by improving glycemic control.

The Efficacy of Psychostimulants in Major Depressive Episodes: A Systematic Review and Meta-Analysis.

BACKGROUND: Psychostimulants are frequently prescribed off-label for adults with major depressive disorder or bipolar disorder. The frequent and increasing usage of stimulants in mood disorders warrants a careful appraisal of the efficacy of this class of agents. Herein, we aim to estimate the efficacy of psychostimulants in adults with unipolar or bipolar depression. METHODS: The PubMed/Medline database was searched from inception to January 16, 2016 for randomized, placebo-controlled clinical trials investigating the antidepressant efficacy of psychostimulants in the treatment of adults with unipolar or bipolar depression. RESULTS: Psychostimulants were associated with statistically significant improvement in depressive symptoms in major depressive disorder (odds ratio [OR], 1.41; 95% confidence interval [CI], 1.13-1.78; P = 0.003) and bipolar disorder (OR, 1.42; 95% CI, 1.13-1.78; P = 0.003). Efficacy outcomes differed across the psychostimulants evaluated as a function of response rates: ar/modafinil (OR, 1.47; 95% CI, 1.20-1.81; P = 0.0002); dextroamphetamine (OR, 7.11; 95% CI, 1.09-46.44; P = 0.04); lisdexamfetamine dimesylate (OR, 1.21; 95% CI, 0.94-1.56; P = ns); methylphenidate (OR, 1.49; 95% CI, 0.88-2.54; P = ns). Efficacy outcomes also differed between agents used as adjunctive therapy (OR, 1.39; 95% CI, 1.19-1.64) or monotherapy (OR, 2.25; 95% CI, 0.67-7.52). CONCLUSIONS: Psychostimulants are insufficiently studied as adjunctive or monotherapy in adults with mood disorders. Most published studies have significant methodological limitations (eg, heterogeneous samples, dependent measures, type/dose of agent). In addition to improvements in methodological factors, a testable hypothesis is that psychostimulants may be more appropriately tested in select domains of psychopathology (eg, cognitive emotional processing), rather than as "broad-spectrum" antidepressants.

Mutation of a cleavage site adjacent to the mature domain leads to increase in secreted mature BMP-2 with reduced activity.

Proteolytic cleavage of precursor bone morphogenetic protein (proBMP) is an important step in generating the active mature BMP. ProBMP-2 contains two proprotein convertase (PC) recognition sites (S1 and S2) and is postulated to be cleaved by PCs at those sites. Cell lines expressing proBMP-2, with a silenced S1 site (mS1) that inhibited PC cleavage, secreted the 20-kDa form BMP-2, while cells expressing wild type (wt) BMP-2 secreted 18- and 20-kDa mature BMP-2 N-terminal isoforms. The mS1 cells secreted 15-fold more mature BMP-2 than the wt, despite their similar mRNA levels. Mutant-secreted BMP-2 demonstrated biological activity in vitro; however, its activity was reduced compared with wt. These data demonstrate that proBMP-2 can be cleaved at an alternative cleavage site without prior S1 site cleavage in cell lines overexpressing BMP-2 and more importantly suggest that the presence of the 2-kDa linker peptide can affect activity and secretion of the mature protein.

Polyarginine peptide IND-1 enhances recombinant human bone morphogenetic protein-2 yield in mammalian cells.

To improve recombinant human bone morphogenetic protein-2 (rhBMP-2) yield, cell lines stably expressing hBMP2 were cultured in the presence of polyarginine peptide IND-1 and showed up to 6-fold increase in the yield of mature BMP-2. Repeated addition of IND-1 to cell cultures consistently improved BMP-2 yields over 53 days without affecting cell growth and viability. Investigation of its mechanism of action showed that IND-1 inhibited pro-protein convertase (PC) activity when incubated with cell lysates. However, when intact cells were cultured with IND-1, no change in cellular PC activity was observed. Furthermore, knockdown of furin (a prototypical member of the PCs) in cells did not affect their BMP-2 yields, suggesting furin/PC inhibition is unlikely the mechanism by which IND-1 enhances BMP-2 yields. IND-1 as a medium additive thus enhances BMP-2 production in mammalian cell expression systems.

Sirukumab: A Potential Treatment for Mood Disorders?

Convergent evidence indicates that abnormalities in the innate immune system may be pertinent to the pathogenesis, phenomenology, and possible treatment of several mental disorders. In keeping with this view, the targeting of interleukin-6 with the human monoclonal antibody sirukumab may represent a possible treatment and disease modification approach, for adults with brain-based disorders (e.g., major depressive disorder). A PubMed/Medline database search was performed using the following search terms: sirukumab; anti-IL-6; IL-6; major depressive disorder; inflammation. A systematic review was conducted of both preclinical and clinical trials reporting on the pharmacology of sirukumab or investigating the efficacy of targeting IL-6 signaling. Overall, sirukumab has been reported to be a safe and well-tolerated agent, capable of modulating the immune response in healthy populations as well as in subjects with inflammatory disorders (e.g., rheumatoid arthritis). Sirukumab's effects on cytokine networks as part of the innate immune system provide a coherent rationale for possible application in neuropsychiatric disorders with possible benefits across several domains of the biobehavioral Research Domain Criteria matrix (e.g., general cognitive processes, positive valence systems). Amongst individuals with complex brain-based disorders (e.g., mood disorders), the dimensions/domains most likely to benefit with sirukumab are negative valence disturbances (e.g., anxiety, depression, rumination), positive valence disturbances (e.g., anhedonia) as well as general cognitive processes. We suggest that sirukumab represents a prototype and possibly a proof-of-concept that agents that engage IL-6 targets have salutary effects in psychiatry.

Pain and major depressive disorder: Associations with cognitive impairment as measured by the THINC-integrated tool (THINC-it).

OBJECTIVES: To examine the role of pain on cognitive function in adults with major depressive disorder (MDD). METHODS: Adults (18-65) with a Diagnostic and Statistical Manual - Fifth Edition (DSM-5)-defined diagnosis of MDD experiencing a current major depressive episode (MDE) were enrolled (nMDD=100). All subjects with MDD were matched in age, sex, and years of education to healthy controls (HC) (nHC=100) for comparison. Cognitive function was assessed using the recently validated THINC-integrated tool (THINC-it), which comprises variants of the choice reaction time (i.e., THINC-it: Spotter), One-Back (i.e., THINC-it: Symbol Check), Digit Symbol Substitution Test (i.e., THINC-it: Codebreaker), Trail Making Test - Part B (i.e., THINC-it: Trails), as well as the Perceived Deficits Questionnaire for Depression - 5-item (i.e., THINC-it: PDQ-5-D). A global index of objective cognitive function was computed using objective measures from the THINC-it, while self-rated cognitive deficits were measured using the PDQ-5-D. Pain was measured using a Visual Analogue Scale (VAS). Regression analyses evaluated the role of pain in predicting objective and subjective cognitive function. RESULTS: A significant between-group differences on the VAS was observed (p<0.001), with individuals with MDD reporting higher pain severity as evidenced by higher scores on the VAS than HC. Significant interaction effects were observed between self -rated cognitive deficits and pain ratings (p<0.001) on objective cognitive performance (after adjusting for MADRS total score), suggesting that pain moderates the association between self-rated and objective cognitive function. CONCLUSIONS: Results indicated that pain is associated with increased self-rated and objective cognitive deficits in adults with MDD. IMPLICATIONS: The study herein provides preliminary evidence demonstrating that adults with MDD reporting pain symptomatology and poorer subjective cognitive function is predictive of poorer objective cognitive performance. THINC-it is capable of detecting cognitive dysfunction amongst adults with MDD and pain.

An evaluation of hydroxyapatite and biphasic calcium phosphate in combination with Pluronic F127 and BMP on bone repair.

Calcium phosphates like hydroxyapatite (HA), beta-tricalcium phosphate (beta-TCP), and their mixtures (biphasic calcium phosphates; BCP) are used clinically to repair bone defects. These materials can be difficult to handle and have no inherent biological activity. Handling properties of other bone substitute materials have been improved by combining them with an inert carrier such as Pluronic F-127 (Pluronic, BASF, Mt. Olive, NJ), while the addition of bone morphogenetic proteins (BMP) with such implants has also been shown to enhance bone repair. This study assessed the impact of adding Pluronic and BMPs to an HA (C-Graft) or a BCP (80/20 HA/beta-TCP ratio; Algisorb) implant's ability of promote bony repair in the rabbit calvarial defect model.Twenty-five New Zealand white rabbits were divided into 5 groups of 5 animals each. Bilateral calvarial defects were made in the parietal bones of each animal. HA or BCP alone or combined with Pluronic and/or BMP were implanted into the defect sites. Animals were euthanized at 6 weeks, postoperatively. Bone regeneration was evaluated quantitatively by histomorphometry. The amount of bone regeneration, which occurred in defects containing HA and BCP, was similar over the time period studied. Incorporating Pluronic increased handling and moldability without compromising osteoconductivity of either calcium phosphate. The addition of BMP significantly increased the amount of new bone formed with all calcium phosphates studied (P < 0.05). These results suggest that Pluronic can be added to calcium phosphates to enhance handling and moldability without any negative effects on their biocompatibility and that healing can be enhanced with the incorporation of BMPs.