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Co-shared genetics and possible risk gene pathway partially explain the comorbidity of schizophrenia, major depressive disorder, type 2 diabetes, and metabolic syndrome.
Postolache, TT, Del Bosque-Plata, L, Jabbour, S, Vergare, M, Wu, R, Gragnoli, C
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics. 2019;(3):186-203
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Abstract
Schizophrenia (SCZ) and major depressive disorder (MDD) in treatment-naive patients are associated with increased risk for type 2 diabetes (T2D) and metabolic syndrome (MetS). SCZ, MDD, T2D, and MetS are often comorbid and their comorbidity increases cardiovascular risk: Some risk genes are likely co-shared by them. For instance, transcription factor 7-like 2 (TCF7L2) and proteasome 26S subunit, non-ATPase 9 (PSMD9) are two genes independently reported as contributing to T2D and SCZ, and PSMD9 to MDD as well. However, there are scarce data on the shared genetic risk among SCZ, MDD, T2D, and/or MetS. Here, we briefly describe T2D, MetS, SCZ, and MDD and their genetic architecture. Next, we report separately about the comorbidity of SCZ and MDD with T2D and MetS, and their respective genetic overlap. We propose a novel hypothesis that genes of the prolactin (PRL)-pathway may be implicated in the comorbidity of these disorders. The inherited predisposition of patients with SCZ and MDD to psychoneuroendocrine dysfunction may confer increased risk of T2D and MetS. We illustrate a strategy to identify risk variants in each disorder and in their comorbid psychoneuroendocrine and mental-metabolic dysfunctions, advocating for studies of genetically homogeneous and phenotype-rich families. The results will guide future studies of the shared predisposition and molecular genetics of new homogeneous endophenotypes of SCZ, MDD, and metabolic impairment.
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Effect of metabolic syndrome and thyroid hormone on efficacy of desvenlafaxine 50 and 100 mg/d in major depressive disorder.
McIntyre, RS, Fayyad, R, Mackell, JA, Boucher, M
Current medical research and opinion. 2016;(3):587-99
Abstract
OBJECTIVE This pooled, post hoc analysis evaluated the efficacy of desvenlafaxine vs placebo in adults with major depressive disorder (MDD) with and without metabolic syndrome, and above or at or below median baseline thyroid-stimulating hormone (TSH) levels. RESEARCH DESIGN AND METHODS Patients were randomly assigned to receive desvenlafaxine 50 or 100 mg/d or placebo in nine short-term, double-blind studies. Metabolic syndrome was defined as meeting at least three of five criteria based on body mass index, triglycerides, high-density lipoprotein, fasting glucose, blood pressure, current medication, and medical history. CLINICAL TRIAL REGISTRATION NCT00072774; NCT00277823; NCT00300378; NCT00384033; NCT00798707; NCT00863798; NCT01121484; NCT00824291; NCT01432457. MAIN OUTCOME MEASURES Treatment effects on change from baseline in 17-item Hamilton Rating Scale for Depression (HAM-D17) total score at week 8 (last observation carried forward [LOCF]) were analyzed in four subgroups-metabolic syndrome and no metabolic syndrome, baseline TSH levels above median or at or below median-using analysis of covariance with treatment, study, and baseline in the model. Metabolic syndrome and TSH were examined as predictors of change in HAM-D17 total score using regression analysis. RESULTS The pooled analysis included 4279 patients; 971 (22.7%) patients had metabolic syndrome. In all subgroups, HAM-D17 total scores improved significantly from baseline to week 8 (LOCF) with desvenlafaxine 50 or 100 mg/d compared with placebo (all p ≤ 0.006). There was no significant treatment by metabolic syndrome or by TSH interaction. Neither metabolic syndrome nor TSH above median predicted change in HAM-D17 total scores, response (≥50% reduction in HAM-D17 total score), or remission (HAM-D17 total score ≤7; all p > 0.05). LIMITATIONS Individual studies included in this analysis were not designed to examine the relationship between metabolic syndrome or TSH and response to desvenlafaxine treatment. Metabolic syndrome status was determined post hoc based on available baseline measures and not diagnosed at study entry. Exclusion criteria were selected to enroll medically healthy patients with a primary diagnosis of MDD (i.e., patients healthier than the general MDD population). CONCLUSIONS Desvenlafaxine 50 and 100 mg/d significantly improved depression compared with placebo in patients with and without metabolic syndrome, and in patients with baseline TSH above median and at or below median levels.
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Drug interactions with vortioxetine, a new multimodal antidepressant.
Spina, E, Santoro, V
Rivista di psichiatria. 2015;(5):210-5
Abstract
This article summarized the available knowledge on clinically relevant drug interactions of vortioxetine, a new antidepressant with a “multimodal” serotonergic mechanism of action, recently approved for the treatment of major depressive disorder. Although information is still limited and mainly based on studies performed in healthy volunteers, vortioxetine appears to have a favorable drug interaction profile. Concerning the potential for pharmacokinetic drug interactions, vortioxetine has little to no effect on various cytochrome P450 (CYP) isoforms and therefore is not expected to markedly affect plasma concentrations of other medications metabolized by these enzymes. This is a major advantage when compared to other antidepressants which are known to inhibit the activity of one or more CYP isoforms. On the other hand, dosage adjustments may be required when vortioxetine is coadministered with strong CYP2D6 inhibitors or broad-spectrum CYP inducers. Vortioxetine carries a relatively low risk for pharmacodynamic drug interactions, at least as compared to first-generation antidepressants. Like other antidepressants enhancing serotonergic activity, vortioxetine is associated with a potential risk of serotonin syndrome when used in combination with other serotonergic agents. Based on all available clinical data, vortioxetine has no increased risk of serotonin syndrome when used without other serotoninergic agents and at therapeutic doses.