Evaluation of the Potential for a Pharmacokinetic Drug-Drug Interaction Between Armodafinil and Ziprasidone in Healthy Adults.
Clin Drug Investig. 2014 Jul 22;
Authors: Darwish M, Bond M, Yang R, Hellriegel ET, Robertson P
BACKGROUND: Armodafinil has been studied as adjunctive therapy for major depressive episodes associated with bipolar I disorder. This open-label, single-centre, 2-period study evaluated the effect of armodafinil, a moderate inducer of cytochrome-P450 (CYP) isoenzyme CYP3A4, on the pharmacokinetics and safety of ziprasidone, an atypical antipsychotic used to treat bipolar I disorder and metabolized in part by CYP3A4.
METHODS: Thirty-five healthy subjects received ziprasidone (20 mg) alone and after armodafinil pretreatment (titrated to 250 mg/day); of those, 25 were evaluable for pharmacokinetics. Pharmacokinetic parameters were derived from plasma concentrations of ziprasidone collected prior to and over the 48 h after each ziprasidone administration. Plasma concentrations of armodafinil and its circulating metabolites, R-modafinil acid and modafinil sulfone, were also obtained after repeated daily dosing of armodafinil alone. Safety and tolerability were assessed.
RESULTS: Systemic exposure to ziprasidone was similar following administration alone or after pretreatment with armodafinil, as assessed by mean peak plasma concentration (C max, 52.1 vs 50.4 ng/mL) and area under the plasma concentration-time curve from time 0 to infinity (AUC0-?, 544.6 vs 469.1 ng·h/mL). Geometric mean ratios of systemic exposure (ziprasidone alone: ziprasidone after pretreatment with armodafinil) were close to unity, with associated 90 % confidence intervals (CIs) within the range of 0.80-1.25 (C max, 0.97; 90 % CI, 0.87-1.08; AUC0-?, 0.86; 90 % CI, 0.82-0.91). Adverse events were consistent with the known safety profiles of each agent.
CONCLUSION: Systemic exposure to ziprasidone was not affected by pretreatment with armodafinil. Both drugs were generally safe and well tolerated under the conditions studied.
PMID: 25047407 [PubMed - as supplied by publisher]
All the world's a (clinical) stage: rethinking bipolar disorder from a longitudinal perspective.
Mol Psychiatry. 2014 Jul 22;
Authors: Frank E, Nimgaonkar VL, Phillips ML, Kupfer DJ
Psychiatric disorders have traditionally been classified using a static, categorical approach. However, this approach falls short in facilitating understanding of the development, common comorbid diagnoses, prognosis and treatment of these disorders. We propose a 'staging' model of bipolar disorder that integrates genetic and neural information with mood and activity symptoms to describe how the disease progresses over time. From an early, asymptomatic, but 'at-risk' stage to severe, chronic illness, each stage is described with associated neuroimaging findings as well as strategies for mapping genetic risk factors. Integrating more biologic information relating to cardiovascular and endocrine systems, refining methodology for modeling dimensional approaches to disease and developing outcome measures will all be crucial in examining the validity of this model. Ultimately, this approach should aid in developing targeted interventions for each group that will reduce the significant morbidity and mortality associated with bipolar disorder.Molecular Psychiatry advance online publication, 22 July 2014; doi:10.1038/mp.2014.71.
PMID: 25048003 [PubMed - as supplied by publisher]
Neuropsychological performance of patients with soft bipolar spectrum disorders.
Bipolar Disord. 2014 Jul 22;
Authors: Lin K, Xu G, Lu W, Ouyang H, Dang Y, Guo Y, So KF, Lee TM
OBJECTIVES: There is much evidence that shows that a substantial number of individuals with DSM-IV-defined unipolar depression (UP) manifest hypomanic sub-syndrome and bipolar diathesis. Other definitions have conceptualized the term soft bipolar spectrum (SBP) for these individuals. Little is known about the cognitive profiles of individuals with SBP. We hypothesized that they are representative of individuals with bipolar II disorder and are different from that of 'strict' UP.
METHODS: Consecutive referrals suffering major depressive episodes were categorically assigned to groups of either bipolar I disorder (n = 98), bipolar II disorder (n = 138), or UP (n = 300). Based on the SBP criteria by Akiskal and Pinto (17), patients with UP were subdivided into 81 SBP and 219 strict UP. We administered self- and clinician-administered scales to evaluate affective temperaments, and neuropsychological tests to assess seven cognitive domains.
RESULTS: Patients with SBP performed significantly better than strict UP patients in the domains of processing speed (p = 0.002), visual-spatial memory (p = 0.017), and verbal working memory (p = 0.017). Compared to patients with bipolar I disorder, patients with SBP were significantly better in set shifting (p < 0.001) and visual-spatial memory (p = 0.042). Patients with SBP performed similarly to patients with bipolar II disorder in all of the cognitive domains tested (p > 0.05). There was a group × cognitive domain interaction effect between bipolar I disorder, bipolar II disorder, SBP, and strict UP groups [Pillai's F = 2.231, df = (18,1437), p = 0.002].
CONCLUSIONS: Our data suggest that patients with SBP differ from patients with UP not only in external validators (e.g., family history of bipolar disorder) and hypomanic symptoms, but also in neuropsychological performance and that the profiles of cognitive functioning were different across bipolar I disorder and 'bipolar II spectrum' that subsumes bipolar II disorder and SBP.
PMID: 25048414 [PubMed - as supplied by publisher]
Are 'buy-polar' forces and 'try-polar' thinking expanding bipolarity?
Aust N Z J Psychiatry. 2014 Jul 21;48(8):697-700
Authors: Malhi GS, Porter RJ
PMID: 25048651 [PubMed - as supplied by publisher]
Comorbidity between attention deficit hyperactivity disorder (ADHD) and bipolar disorder in a specialized mood disorders outpatient clinic.
J Affect Disord. 2014 Jul 9;168C:161-166
Authors: Perroud N, Cordera P, Zimmermann J, Michalopoulos G, Bancila V, Prada P, Dayer A, Aubry JM
BACKGROUND: Comorbidity between ADHD and Bipolar Disorder (BD) is associated with greater severity of BD. The current study aims at investigating, in a specialized mood disorders clinic, the percentage of comorbid ADHD-BD subjects and assessing the impact of ADHD on the severity of BD.
METHODS: Out of 539 mood disorders subjects, the medical records of 138 BD subjects were scrutinized in terms of their clinical and demographic characteristics, and their scores at the Adult ADHD Self-Report Scale (ASRS-v1.1) Symptom Checklist were logged. Those positively scoring at the ASRS-v1.1 underwent clinical assessment by a senior psychiatrist specialized in ADHD. Comorbid ADHD-BD subjects were then compared with BD sufferers without ADHD.
RESULTS: Sixty-three (45.65%) of the participants were screened positive at the ASRS-v1.1. 49 were clinically assessed for the presence of ADHD. Only 27 (55%) received a diagnosis of ADHD. Comorbid ADHD-BD subjects were found to be younger at the onset of BD, showed higher numbers of depressive episodes, more anxiety and substance use disorders, more borderline personality traits and greater cyclothymic temperament. Comorbid BD-ADHD subjects reported more childhood emotional abuse.
LIMITATIONS: Some subjects were unreachable and thus not clinically assessed for ADHD.
CONCLUSIONS: More than 20% of BD subjects were suffering from ADHD. The comorbidity of the two disorders was associated with worse outcomes, possibly resulting from stressful early-life events. More than 40% of the subjects who scored positively at the ASRS-v1.1 did not suffer from ADHD, which suggests that this scale should be used with caution in BD subjects.
PMID: 25051093 [PubMed - as supplied by publisher]
Illness-course modulates suicidality-related prefrontal gray matter reduction in women with bipolar disorder.
Acta Psychiatr Scand. 2014 Jul 9;
Authors: Lijffijt M, Rourke ED, Swann AC, Zunta-Soares GB, Soares JC
OBJECTIVE: Explore interrelationships between suicide attempt history (Objective 1) or suicide attempt severity (Objective 2) with prefrontal cortex gray matter (PFCGM ) volume and illness-course in patients with bipolar disorder (BD).
METHOD: Ninety-three women with BD-I or -II diagnosis (51 with and 42 without suicide attempt history) underwent structural MRI and filled out questionnaires. Measured were GM volumes of 11 PFC regions, BD illness-course, and attempt history and severity. Effects were examined with repeated measures GLM or logit analyses.
RESULTS: Objective 1: Attempt history was associated with increased trait impulsivity and aggression, and higher prevalence of BD-I, past drug use disorder, and past psychiatric hospitalization. PFCGM volume was lower in patients with than without attempt history in those with past psychiatric hospitalization. PFCGM volume was higher in patients with than without attempt history in those without hospitalization. Higher trait aggression predicted attempt history. Objective 2: Increased frontal pole volume and younger age at first hospitalization predicted many suicide attempts.
CONCLUSION: Attempt history in patients with BD related to PFCGM volume reduction or increase. Volume modulation by psychiatric hospitalization could reflect effects of illness-course or care. Attempt severity was not related to volume reduction. Research on suicidality-brain relationships should include illness-course and attempt severity measures.
PMID: 25039251 [PubMed - as supplied by publisher]
Monocyte activation, brain-derived neurotrophic factor (BDNF), and S100B in bipolar offspring: a follow-up study from adolescence into adulthood.
Bipolar Disord. 2014 Jul 17;
Authors: Mesman E, Hillegers MH, Ambree O, Arolt V, Nolen WA, Drexhage HA
OBJECTIVES: There is increasing evidence that both immune and neurochemical alterations are involved in the pathogenesis of bipolar disorder; however, their precise role remains unclear. In this study, we aimed to evaluate neuro-immune changes in a prospective study on children of patients with bipolar disorder.
METHODS: Bipolar offspring, from the prospective Dutch bipolar offspring study (n = 140), were evaluated cross-sectionally within a longitudinal context at adolescence, young adulthood, and adulthood. We examined the expression of 44 inflammation-related genes in monocytes, the cytokines pentraxin 3 (PTX3), chemokine ligand 2 (CCL2), and interleukin-1? (IL-1?), and brain-derived neurotrophic factor (BDNF) and S100 calcium binding protein B (S100B) in the serum of bipolar offspring and healthy controls.
RESULTS: During adolescence, bipolar offspring showed increased inflammatory gene expression in monocytes, high serum PTX3 levels, but normal CCL2 levels. BDNF levels were decreased, while S100B levels were normal. During young adulthood, monocyte activation remained, although to a lesser degree. Serum PTX3 levels remained high, and signs of monocyte migration became apparent through increased CCL2 levels. BDNF and S100B levels were not measured. At adulthood, circulating monocytes had lost their activation state, but CCL2 levels remained increased. Both BDNF and S100B were now increased. Abnormalities were independent of psychopathology state at all stages.
CONCLUSIONS: This study suggests an aberrant neuro-immune state in bipolar offspring, which followed a dynamic course from adolescence into adulthood and was present irrespective of lifetime or future mood disorders. We therefore assumed that the aberrant neuro-immune state reflects a general state of vulnerability for mood disorders rather than being of direct predictive value.
PMID: 25039314 [PubMed - as supplied by publisher]
Impulsivity predicts time to reach euthymia in adults with bipolar disorder.
Bipolar Disord. 2014 Jul 16;
Authors: Dawson EL, Shear PK, Howe SR, Adler CM, DelBello MP, Fleck DE, Strakowski SM
OBJECTIVES: Specific demographic and illness characteristics have been identified as predictors of overall morbidity and treatment course among individuals with bipolar disorder. However, the role of specific cognitive limitations on disease severity and treatment response is unclear. The present study evaluated whether impulsiveness during acute mania was a significant predictor of achieving euthymia within one year following psychiatric hospitalization.
METHODS: Participants were 94 adult inpatients (60 manic) with bipolar I disorder. Baseline symptom severity was assessed using the Young Mania Rating Scale and the Montgomery-Åsberg Depression Rating Scale. Impulsivity was measured with the Stop Signal Task, Degraded Stimulus Continuous Performance Task, Delayed Response Task, and Barratt Impulsiveness Scale-11.
RESULTS: Individual predictors of time to reach euthymia included fewer depressive symptoms and better impulse control at baseline, later age at illness onset, shorter illness duration, and the absence of comorbid attention-deficit hyperactivity disorder. Self-reported impulsivity was a significant independent predictor of time to euthymia, even after accounting for relevant clinical variables.
CONCLUSIONS: Better trait impulse control may be associated with better treatment responsiveness among adults with bipolar disorder.
PMID: 25039396 [PubMed - as supplied by publisher]
Personal view: hormones and depression in women.
Climacteric. 2014 Jul 21;:1-3
Authors: Studd J
Depression is more common in women, occurring at times of hormonal fluctuations as premenstrual depression, postnatal depression and perimenopausal depression. These are all related to changes in hormone levels and constitute the diagnosis of reproductive depression. There is a risk that severe premenstrual depression can be misdiagnosed as bipolar disorder and that women will be started on inappropriate antidepressants or mood-stabilizing therapy. The most effective treatment for severe premenstrual syndrome is by suppression of ovulation and suppression of the cyclical hormonal changes by transdermal estrogens or by GnRH analogs. Postnatal depression is more common in women with a history of premenstrual depression and also responds to transdermal estrogens. Transdermal testosterone gel can be also used in women who suffer loss of energy and loss of libido which may be due to the inappropriate prescription of antidepressants. There is also a role for the Mirena IUS and laparoscopic hysterectomy and oophorectomy in women who are progestogen-intolerant. The hormonal causation of certain common types of depression in women and the successful treatment by estrogens should be understood by psychiatrists and gynecologists.
PMID: 25040604 [PubMed - as supplied by publisher]
Valnoctamide, a non-teratogenic amide derivative of valproic acid, inhibits arachidonic acid activation in vitro by recombinant acyl-CoA synthetase-4.
Bipolar Disord. 2014 Jul 8;
Authors: Modi HR, Basselin M, Rapoport SI
OBJECTIVE: Valproic acid (VPA), a mood stabilizer used for treating bipolar disorder (BD), uncompetitively inhibits acylation of arachidonic acid (AA) by recombinant AA-selective acyl-CoA synthetase 4 (Acsl4) at an enzyme inhibition constant (Ki ) of 25 mM. Inhibition may account for VPA's ability to reduce AA turnover in brain phospholipids of unanesthetized rats and to be therapeutic in BD. However, VPA is teratogenic. We tested whether valnoctamide (VCD), a non-teratogenic amide derivative of a VPA chiral isomer, which had antimanic potency in a phase III BD trial, also inhibits recombinant Acsl4.
METHODS: Rat Acsl4-flag protein was expressed in Escherichia coli. We used Michaelis-Menten kinetics to characterize and quantify the ability of VCD to inhibit conversion of AA to AA-CoA by recombinant Acsl4 in vitro.
RESULTS: Acsl4-mediated activation of AA to AA-CoA by Acsl4 was inhibited uncompetitively by VCD, with a Ki of 6.38 mM.
CONCLUSIONS: VCD's ability to uncompetitively inhibit AA activation to AA-CoA by Acsl4, at a lower Ki than VPA, suggests that, like VPA, VCD may reduce AA turnover in rat brain phospholipids. If so, VCD and other non-teratogenic Acsl4 inhibitors might be considered further for treating BD.
PMID: 25041123 [PubMed - as supplied by publisher]
The role of brain-derived neurotrophic factor (BDNF) Val66Met genetic polymorphism in bipolar disorder: a case-control study, comorbidities, and meta-analysis of 16,786 subjects.
Bipolar Disord. 2014 Jul 8;
Authors: González-Castro TB, Nicolini H, Lanzagorta N, López-Narváez L, Genis A, Pool García S, Tovilla-Zárate CA
OBJECTIVES: The aim of this study was to evaluate the association of Val66Met brain-derived neurotrophic factor (BDNF) polymorphism with bipolar disorder in (i) a meta-analysis and (ii) a case-control study in a Mexican population. We also investigated the possible association of this polymorphism with clinical features.
METHODS: We performed a keyword search of the PubMed and Web of Science databases. A total of 22 studies that have investigated the association of Val66Met (rs6265) with bipolar disorder were selected for inclusion and combined with random effects meta-analysis, using allelic, additive, dominant, and recessive models. Finally, the single nucleotide polymorphism (rs6265) Val66Met in the BDNF gene was genotyped and compared between 139 patients with bipolar disorder and 141 healthy volunteers in a Mexican population.
RESULTS: The pooled results from the meta-analysis (9,349 cases and 7,437 controls) did not show a significant association in any of the models. The same results were obtained in our case-control study when analyzing the distribution of the genotypic frequencies of the Val66Met polymorphism in patients with bipolar disorder. However, when we analyzed the association between rs6265 and lifetime history of suicidal behavior, we found an association between genotype Val-Val and suicide attempt (p = 0.02).
CONCLUSIONS: Although the present study has some limitations, the results indicate a lack of association between the Val66Met polymorphism and bipolar disorder. However, in our case-control study in a Mexican population, the Val66Met polymorphism was associated with suicidal behavior in patients with bipolar disorder. Nevertheless, it is important to consider potential interactions of the BDNF gene, the environment, and different inheritance patterns, when carrying out future genetic studies with larger samples.
PMID: 25041243 [PubMed - as supplied by publisher]
Region-specific dysregulation of glycogen synthase kinase-3? and ?-catenin in the postmortem brains of subjects with bipolar disorder and schizophrenia.
Bipolar Disord. 2014 Jul 8;
Authors: Pandey GN, Rizavi HS, Tripathi M, Ren X
OBJECTIVES: There is both direct and indirect evidence suggesting abnormalities of glycogen synthase kinase (GSK)-3? and ?-catenin, two important components of the Wingless-type (Wnt) signaling pathway, in the pathophysiology of bipolar illness and possibly schizophrenia (SZ). In order to further clarify the role of the Wnt signaling pathway in the pathophysiology of bipolar disorder (BP) and SZ, we studied GSK-3? and ?-catenin in the postmortem brains of subjects with these disorders.
METHODS: We determined the protein expression of GSK-3?, phosphorylated form at serine 9 position (pGSK-3-ser-9), and ?-catenin using the western blot technique, and mRNA using the quantitative polymerase chain reaction (qPCR) method, in the dorsolateral prefrontal cortex (DLPFC), cingulate gyrus (CG), and temporal cortex (TEMP) obtained from 19 subjects with BP, 20 subjects with SZ, and 20 normal control (NC) subjects.
RESULTS: We found that the protein expression of GSK-3?, pGSK-3?-ser-9, and ?-catenin was significantly decreased in the DLPFC and TEMP, but not in the CG, of subjects with BP compared with NC subjects. The mRNA expression of GSK-3? and ?-catenin was significantly decreased in the DLPFC and TEMP, but not in the CG, of subjects with BP compared with NC subjects. There were no significant differences in the protein or mRNA expression of GSK-3?, pGSK-3?-ser-9, or ?-catenin between subjects with SZ and NC subjects in any of the brain areas studied.
CONCLUSIONS: These studies show region-specific abnormalities of both protein and mRNA expression of GSK-3? and ?-catenin in postmortem brains of subjects with BP but not subjects with SZ. Thus, abnormalities of the Wnt signaling pathway may be associated with the pathophysiology of bipolar illness.
PMID: 25041379 [PubMed - as supplied by publisher]
Reduced activities of phospholipases A2 in platelets of drug-naïve bipolar disorder patients.
Bipolar Disord. 2014 Jul 8;
Authors: Ikenaga EH, Talib LL, Ferreira AS, Machado-Vieira R, Forlenza OV, Gattaz WF
OBJECTIVE: Phospholipases A2 (PLA2 ) comprise a family of hydrolytic enzymes that cleave membrane phospholipids and play a key role in cellular homeostasis. Alterations in enzymatic activity have been hypothesized in bipolar disorder (BD). Recent studies suggest that PLA2 activity in platelets may reflect PLA2 activity in the brain. The aim of this study was to determine PLA2 activity in platelets of BD patients.
METHODS: We determined the activity of PLA2 subtypes [extracellular, calcium-dependent PLA2 (sPLA2 ), intracellular, calcium-dependent PLA2 (cPLA2 ), and intracellular, calcium-independent PLA2 (iPLA2 )] by a radioenzymatic method in platelets from 20 patients with BD (15 drug-naïve and five drug-free) and from 16 age- and gender-matched healthy controls.
RESULTS: We found that iPLA2 , cPLA2 , and sPLA2 activities were lower in drug-naïve patients with BD when compared to the control group (p = 0.017, p < 0.001, and p < 0.001, respectively).
CONCLUSIONS: Reduced PLA2 activity at the early stage of BD may disrupt brain function and increase the risk for the disease. Moreover, epidemiological studies show that patients with BD have a fivefold increased risk for developing Alzheimer's disease. Because patients with Alzheimer's disease also have reduced PLA2 activity, the present finding of reduced PLA2 in the BD group may be related to the risk factor for these individuals developing Alzheimer's disease in advanced age.
PMID: 25041493 [PubMed - as supplied by publisher]
DNA methylation and expression of KCNQ3 in bipolar disorder.
Bipolar Disord. 2014 Jul 11;
Authors: Kaminsky Z, Jones I, Verma R, Saleh L, Trivedi H, Guintivano J, Akman R, Zandi P, Lee RS, Potash JB
OBJECTIVES: Accumulating evidence implicates the potassium voltage-gated channel, KQT-like subfamily, member 2 and 3 (KCNQ2 and KCNQ3) genes in the etiology of bipolar disorder (BPD). Reduced KCNQ2 or KCNQ3 gene expression might lead to a loss of inhibitory M-current and an increase in neuronal hyperexcitability in disease. The goal of the present study was to evaluate epigenetic and gene expression associations of the KCNQ2 and KCNQ3 genes with BPD.
METHODS: DNA methylation and gene expression levels of alternative transcripts of KCNQ2 and KCNQ3 capable of binding the ankyrin G (ANK3) gene were evaluated using bisulfite pyrosequencing and the quantitative real-time polymerase chain reaction in the postmortem prefrontal cortex of subjects with BPD and matched controls from the McLean Hospital. Replication analyses of DNA methylation findings were performed using prefrontal cortical DNA obtained from the Stanley Medical Research Institute.
RESULTS: Significantly lower expression was observed in KCNQ3, but not KCNQ2. DNA methylation analysis of CpGs within an alternative exonic region of KCNQ3 exon 11 demonstrated significantly lower methylation in BPD, and correlated significantly with KCNQ3 mRNA levels. Lower KCNQ3 exon 11 DNA methylation was observed in the Stanley Medical Research Institute replication cohort, although only after correcting for mood stabilizer status. Mood stabilizer treatment in rats resulted in a slight DNA methylation increase at the syntenic KCNQ3 exon 11 region, which subsequent analyses suggested could be the result of alterations in neuronal proportion.
CONCLUSION: The results of the present study suggest that epigenetic alterations in the KCNQ3 gene may be important in the etiopathogenesis of BPD and highlight the importance of controlling for medication and cellular composition-induced heterogeneity in psychiatric studies of the brain.
PMID: 25041603 [PubMed - as supplied by publisher]
Increased intrasubject variability in response time in unaffected preschoolers at familial risk for bipolar disorder.
Psychiatry Res. 2014 Jul 1;
Authors: Adleman NE, Yi JY, Deveney CM, Guyer AE, Leibenluft E, Brotman MA
Increased intrasubject variability in response time (ISVRT) is evident in healthy preschoolers at familial risk for bipolar disorder, suggesting it may be an endophenotype.
PMID: 25041984 [PubMed - as supplied by publisher]
Cardiovascular risk factors among bipolar disorder patients admitted to an inpatient unit of a tertiary care hospital in India.
Asian J Psychiatr. 2014 Aug;10:51-5
Authors: Grover S, Nebhinani N, Chakrabarti S, Avasthi A, Basu D, Kulhara P, Mattoo SK, Malhotra S
OBJECTIVE: The study aimed to examine the prevalence of cardiovascular risk factors in patients with bipolar disorder.
METHODS: By consecutive sampling, 93 inpatients (aged ?20 years) diagnosed with bipolar disorder were evaluated for 10 year coronary heart disease (CHD) risk and 10-year cardiovascular mortality risk (CMR) on the Framingham (10-year all CHD events) function/risk equation and Systematic Coronary Risk Evaluation (SCORE) respectively.
RESULTS: Ten-year CHD risk was 3.36% and 10-year CMR was estimated to be 1.73%. One tenth (10.7%) of the sample was found to have very high/high CHD risk (?10) and 6.45% of the sample had high CMR risk (?5). More than half (54.88%) of patients had metabolic syndrome. Compared to females, males had higher Framingham function score (4.09±5.75 vs 1.59±1.05, U value - 634.5*, p<0.05) and had higher very high/high CHD risk (?10) (15.1% vs 0, ?(2) 4.58, p<0.05).
CONCLUSIONS: Findings of the present study suggest the presence of cardiovascular risk factors and higher rate of metabolic syndrome in patients with bipolar disorder. Considering this fact, there is an urgent need for routine screening for cardiovascular risk factors in these patients. Mental health professionals should be aware of these risks; there is need to develop preventive strategies to reduce the cardiovascular risk in this population.
PMID: 25042952 [PubMed - in process]
Effective connectivity of the posterior cingulate and medial prefrontal cortices relates to working memory impairment in schizophrenic and bipolar patients.
Schizophr Res. 2014 Jul 16;
Authors: Wu G, Wang Y, Mwansisya TE, Pu W, Zhang H, Liu C, Yang Q, Chen EY, Xue Z, Liu Z, Shan B
BACKGROUND: Schizophrenia (SZ) and bipolar I disorder (BD) share many overlapping clinical features, confounding the current diagnostic systems. Recent studies suggest the posterior cingulate (PCC) and medial prefrontal (MPFC) cortices that are involved in SZ and BD pathophysiology. However, the roles of PCC and MPFC in providing specific distinctive and shared neural substrates between these two disorders remain largely unknown. Examining the neurophysiologic mechanism of these diseases may help explain the clinical observations and differentiate the two disorders.
METHODS: We used the Dynamic Casual Modeling (DCM), which is capable of eliciting hidden neuronal dynamics and reveal cross-regulation of multiple neuronal systems, to characterize the pattern of disrupted effective connectivity in the left PCC-MPFC circuit during working memory tasks in 36 SZ and 20 BD patients as well as 29 healthy controls.
RESULTS: Compared to the healthy controls, both SZ and BD patient groups exhibited significant negative effective connectivity from the left MPFC to PCC. The negative effective connectivity was more remarkable in schizophrenic patients. Only patients with BD differed from healthy controls with positive effective connectivity from the left PCC to MPFC.
CONCLUSIONS: Whole brain analysis revealed deactivation of the left PCC and MPFC across all patient groups. This study provides new insight that changes in effective connectivity of the left MPFC to left PCC circuit during working memory processing may be a core pathophysiological feature distinguishing SZ from BD.
PMID: 25043264 [PubMed - as supplied by publisher]
Cognitive performance and quality of life early in the course of bipolar disorder.
J Affect Disord. 2014 Jul 2;168C:119-124
Authors: Mackala SA, Torres IJ, Kozicky J, Michalak EE, Yatham LN
BACKGROUND: Several studies have reported cognitive functioning as a significant predictor of quality of life (QoL) in patients with established bipolar disorder (BD), in addition to mood symptoms. However, it is unclear whether cognitive functioning predicts QoL early in the course of illness. The purpose of this study was therefore to evaluate the relationship between mood and neuropsychological variables and self-reported QoL early in the course of BD.
METHODS: Patients with BD-I (n=54) completed a neuropsychological battery and clinical assessment within 3 months of resolution of their first manic episode. QoL was assessed 6 months later using the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Cognitive predictors of QoL were assessed through Pearson correlations and hierarchical multiple regression.
RESULTS: After accounting for mood rating scores at the time of cognitive testing (?R²=.27, p<.001), measures of sustained attention (?R²=.08, p<.05), verbal memory (?R²=.09, p<.01), working memory (?R²=.06, p<.05), and executive functioning (?R²=.08, p<.05) each predicted QoL when entered independently in separate regression models. When entered simultaneously, the cognitive domains explained 15% (R(2)=.42, p<.05) of the variance in QoL beyond mood.
LIMITATIONS: Some aspects of QoL that are particularly important in BD may be missing as a result of using the Q-LES-Q, because the measure was not specifically developed to assess QoL in BD.
CONCLUSIONS: In addition to mood symptoms, poorer cognitive functioning is a significant predictor of reduced QoL early in the course of BD. Recently diagnosed patients with BD may benefit from early cognitive-enhancing interventions to maintain or restore their QoL.
PMID: 25043323 [PubMed - as supplied by publisher]
Time-dependent tree-structured survival analysis with unbiased variable selection through permutation tests.
Stat Med. 2014 Jul 14;
Authors: Wallace ML
Incorporating time-dependent covariates into tree-structured survival analysis (TSSA) may result in more accurate prognostic models than if only baseline values are used. Available time-dependent TSSA methods exhaustively test every binary split on every covariate; however, this approach may result in selection bias toward covariates with more observed values. We present a method that uses unbiased significance levels from newly proposed permutation tests to select the time-dependent or baseline covariate with the strongest relationship with the survival outcome. The specific splitting value is identified using only the selected covariate. Simulation results show that the proposed time-dependent TSSA method produces tree models of equal or greater accuracy as compared to baseline TSSA models, even with high censoring rates and large within-subject variability in the time-dependent covariate. To illustrate, the proposed method is applied to data from a cohort of bipolar youths to identify subgroups at risk for self-injurious behavior. Copyright © 2014 John Wiley & Sons, Ltd.
PMID: 25043382 [PubMed - as supplied by publisher]
The Developmental Basis of Epigenetic Regulation of HTR2A and Psychiatric Outcomes.
J Cell Biochem. 2014 Jul 15;
Authors: Paquette AG, Marsit CJ
The serotonin receptor 5-HT2A (encoded by HTR2A) is an important regulator of fetal brain development and adult cognitive function. Environmental signals that induce epigenetic changes of serotonin response genes, including HTR2A, have been implicated in adverse mental health outcomes. The objective of this perspective article is to address the medical implications of HTR2A epigenetic regulation, which has been associated with both infant neurobehavioral outcomes and adult mental health. Ongoing research has identified a region of the HTR2A promoter that has been associated with a number of medical outcomes in adults and infants, including bipolar disorder, schizophrenia, chronic fatigue syndrome, borderline personality disorder, suicidality, and neurobehavioral outcomes. Epigenetic regulation of HTR2A has been studied in several different types of tissues, including the placenta. The placenta is an important source of serotonin during fetal neurodevelopment, and placental epigenetic variation of HTR2A has been associated with infant neurobehavioral outcomes, which may represent the basis of adult mental health disorders. Further analysis is needed to identify intrinsic and extrinsic factors modulate HTR2A methylation, and the mechanism by which this epigenetic variation influences fetal growth and leads to altered brain development, manifesting in psychiatric disorders. © 2014 Wiley Periodicals, Inc.
PMID: 25043477 [PubMed - as supplied by publisher]
A genome-wide linkage scan of bipolar disorder in Latino families identifies susceptibility loci at 8q24 and 14q32.
Am J Med Genet B Neuropsychiatr Genet. 2014 Jul 18;
Authors: Gonzalez S, Camarillo C, Rodriguez M, Ramirez M, Zavala J, Armas R, Contreras SA, Contreras J, Dassori A, Almasy L, Flores D, Jerez A, Raventós H, Ontiveros A, Nicolini H, Escamilla M
A genome-wide nonparametric linkage screen was performed to localize Bipolar Disorder (BP) susceptibility loci in a sample of 3757 individuals of Latino ancestry. The sample included 963 individuals with BP phenotype (704 relative pairs) from 686 families recruited from the US, Mexico, Costa Rica, and Guatemala. Non-parametric analyses were performed over a 5?cM grid with an average genetic coverage of 0.67?cM. Multipoint analyses were conducted across the genome using non-parametric Kong & Cox LOD scores along with Sall statistics for all relative pairs. Suggestive and significant genome-wide thresholds were calculated based on 1000 simulations. Single-marker association tests in the presence of linkage were performed assuming a multiplicative model with a population prevalence of 2%. We identified two genome-wide significant susceptibly loci for BP at 8q24 and 14q32, and a third suggestive locus at 2q13-q14. Within these three linkage regions, the top associated single marker (rs1847694, P?=?2.40?×?10(-5) ) is located 195 Kb upstream of DPP10 in Chromosome 2. DPP10 is prominently expressed in brain neuronal populations, where it has been shown to bind and regulate Kv4-mediated A-type potassium channels. Taken together, these results provide additional evidence that 8q24, 14q32, and 2q13-q14 are susceptibly loci for BP and these regions may be involved in the pathogenesis of BP in the Latino population. © 2014 Wiley Periodicals, Inc.
PMID: 25044503 [PubMed - as supplied by publisher]
Transcription factor Sp4 regulates expression of nervous wreck 2 to control NMDAR1 levels and dendrite patterning.
Dev Neurobiol. 2014 Jul 16;
Authors: Sun X, Pinacho R, Saia G, Punko D, Meana JJ, Ramos B, Gill G
Glutamatergic signaling through N-methyl-D-aspartate receptors (NMDARs) is important for neuronal development and plasticity and is often dysregulated in psychiatric disorders. Mice mutant for the transcription factor Sp4 have reduced levels of NMDAR subunit 1 (NR1) protein, but not mRNA, and exhibit behavioral and memory deficits (Zhou et al., 2010). In developing cerebellar granule neurons (CGNs), Sp4 controls dendrite patterning (Ramos et al., 2007). Sp4 target genes that regulate dendrite pruning or NR1 levels are not known. Here we report that Sp4 activates transcription of Nervous Wreck 2 (Nwk2; also known as Fchsd1) and, further, that Nwk2, an F-BAR-domain containing protein, mediates Sp4-dependent regulation of dendrite patterning and cell surface expression of NR1. Knockdown of Nwk2 in CGNs increased primary dendrite number, phenocopying Sp4 knockdown, and exogenous expression of Nwk2 in Sp4-depleted neurons rescued dendrite number. We observed that acute Sp4 depletion reduced levels of surface, but not total, NR1, and this was rescued by Nwk2 expression. Furthermore, expression of Nr1 suppressed the increase in dendrite number in Sp4- or Nwk2- depleted neurons. We previously reported that Sp4 protein levels were reduced in cerebellum of subjects with bipolar disorder (BD) (Pinacho et al., 2011). Here we report that Nwk2 mRNA and NR1 protein levels were also reduced in postmortem cerebellum of BD subjects. Our data suggest a role for Sp4-regulated Nwk2 in NMDAR trafficking and identify an Sp4-Nwk2-NMDAR1 pathway that regulates neuronal morphogenesis during development and may be disrupted in bipolar disorder. © 2014 Wiley Periodicals, Inc. Develop Neurobiol, 2014.
PMID: 25045015 [PubMed - as supplied by publisher]
The functional GRM3 Kozak sequence variant rs148754219 affects the risk of schizophrenia and alcohol dependence as well as bipolar disorder.
Psychiatr Genet. 2014 Jul 18;
Authors: O'Brien NL, Way MJ, Kandaswamy R, Fiorentino A, Sharp SI, Quadri G, Alex J, Anjorin A, Ball D, Cherian R, Dar K, Gormez A, Guerrini I, Heydtmann M, Hillman A, Lankappa S, Lydall G, O'Kane A, Patel S, Quested D, Smith I, Thomson AD, Bass NJ, Morgan MY, Curtis D, McQuillin A
PMID: 25046171 [PubMed - as supplied by publisher]
Combined treatment: impact of optimal psychotherapy and medication in bipolar disorder.
Bipolar Disord. 2014 Jul 21;
Authors: Parikh SV, Hawke LD, Velyvis V, Zaretsky A, Beaulieu S, Patelis-Siotis I, MacQueen G, Young LT, Yatham LN, Cervantes P
OBJECTIVES: The current study investigated the longitudinal course of symptoms in bipolar disorder among individuals receiving optimal treatment combining pharmacotherapy and psychotherapy, as well as predictors of the course of illness.
METHODS: A total of 160 participants with bipolar disorder (bipolar I disorder: n = 115; bipolar II disorder: n = 45) received regular pharmacological treatment, complemented by a manualized, evidence-based psychosocial treatment - that is, cognitive behavioral therapy or psychoeducation. Participants were assessed at baseline and prospectively for 72 weeks using the Longitudinal Interval Follow-up Evaluation (LIFE) scale scores for mania/hypomania and depression, as well as comparison measures (clinicaltrials.gov identifier: NCT00188838).
RESULTS: Over a 72-week period, patients spent a clear majority (about 65%) of time euthymic. Symptoms were experienced more than 50% of the time by only a quarter of the sample. Depressive symptoms strongly dominated over (hypo)manic symptoms, while subsyndromal symptoms were more common than full diagnosable episodes for both polarities. Mixed symptoms were rare, but present for a minority of participants. Individuals experienced approximately six significant mood changes per year, with a full relapse on average every 7.5 months. Participants who had fewer depressive symptoms at intake, a later age at onset, and no history of psychotic symptoms spent more weeks well over the course of the study.
CONCLUSIONS: Combined pharmacological and adjunctive psychosocial treatments appeared to provide an improved course of illness compared to the results of previous studies. Efforts to further improve the course of illness beyond that provided by current optimal treatment regimens will require a substantial focus on both subsyndromal and syndromal depressive symptoms.
PMID: 25046246 [PubMed - as supplied by publisher]
Efficacy of olanzapine in the treatment of bipolar mania with mixed features defined by DSM-5.
J Affect Disord. 2014 Jul 3;168C:136-141
Authors: Tohen M, McIntyre RS, Kanba S, Fujikoshi S, Katagiri H
BACKGROUND: These analyses compared efficacy of olanzapine in patients with bipolar mania with or without mixed features, as defined in the DSM-5.
METHODS: Pooled data from 3 placebo-controlled olanzapine studies in patients having bipolar I disorder with manic/mixed episode were analyzed (N=228 olanzapine; N=219 placebo). Patients were categorized for mixed features by number of concurrent depressive symptoms at baseline (0, 1, and 2 [category A; without mixed features], and ?3 [category B; with mixed features]), as determined by HAM-D17 item score ?1. Depressive symptoms corresponded to 6 HAM-D17 items in the DSM-5 definition of manic episode with mixed features. Primary efficacy was evaluated by changes in the baseline-to-3-week YMRS total score.
RESULTS: Patients were categorized into A (N=322; 72.0%) or B (N=125; 28.0%). Mean baseline YMRS total scores were 28.1 in category A and 27.8 in category B. Least-squares mean change of YMRS total scores in categories A and B (olanzapine versus placebo) were -11.78 versus -6.86 and -13.21 versus -4.72, respectively. Patients in the olanzapine- compared with placebo-group experienced a greater decrease in YMRS total score for both categories (p<0.001). An interaction between mixed features and treatment was seen in YMRS change at a 0.3 significance level (p=0.175).
LIMITATIONS: The results are from post-hoc analyses.
CONCLUSIONS: Olanzapine was efficacious in the treatment of bipolar I mania, in patients both with and without mixed features, defined by DSM-5; however, greater efficacy was observed in patients with mixed features having more severe depressive symptoms.
PMID: 25046739 [PubMed - as supplied by publisher]
J Affect Disord. 2014 Jul 7;168C:142-150
Authors: Wittman D
BACKGROUND: The standard evolutionary explanation for depression is that being in an emotionally depressed state is adaptive.
METHOD: The article first undertakes a critical review of the extant literature. It then provides an alternative evolutionary explanation for event-based depression and elation. It argues that being in a depressed state is not adaptive (indeed, quite the opposite), but that the threat of depression for bad outcomes and the promise of pleasure for good outcomes are adaptive because they motivate the individual toward undertaking effort that increases fitness. The article then explains reasons for failure in the motivation system and the mood disorders that arise as a consequence.
RESULTS: The article explains why motivation depends on both elation and depression and why individual happiness is not permanently improved by winning the lottery (or permanently reduced by becoming wheelchair bound). It explains the comorbidity of bipolar disorder and panic disorder, why mood stabilizers tend to reduce motivation, and when anti-depressants are unlikely to cure "laziness."
LIMITATIONS: The evolutionary explanation for depression does not directly provide clinical criteria for determining when major depressive disorder is present nor has it yet provided new treatment strategies for mood disorders.
CONCLUSIONS: The theory presented here provides a coherent explanation for depression and elation and leads research in a different direction from previous evolutionary explanations.
PMID: 25046740 [PubMed - as supplied by publisher]
Bipolar disorder in adults with Asperger?s Syndrome: A systematic review.
J Affect Disord. 2014 Jul 8;168C:151-160
Authors: Vannucchi G, Masi G, Toni C, Dell?Osso L, Erfurth A, Perugi G
BACKGROUND: Asperger?s Syndrome (AS) is a neurodevelopmental disorder included in the Autism Spectrum (ASD). The current literature shows growing evidence of a high rate of comorbidity between AS and other psychiatric disorders, particularly Bipolar Disorder (BD). We reviewed available epidemiological and clinical data on BD-AS comorbidity and its diagnostic and therapeutic implications METHODS: A systematic review of the literature was conducted through PubMed, Scopus and Psych-Info using combinations of the following search terms: Asperger?s Syndrome, Bipolar Disorder, depression, mood disorder, psychiatric comorbidity, treatment, mood stabilizers, anticonvulsants, antipsychotics, and antidepressants.
RESULTS: BD prevalence in adults with AS ranges from 6% to 21.4% of the cases. Relatives of patients with AS showed a doubled risk of being affected by BD and a BD prevalence near to 10%. When comorbid with AS, BD assumes peculiar features which might shape its under-recognition or misdiagnosis (especially schizophrenia when psychotic symptoms are prominent). Although controlled data on pharmacological treatments in BD-AS comorbidity are substantially lacking, information is derived by open observations, case series and chart reviews. Mood stabilizers should be considered the first choice, and antipsychotics, especially second generation drugs (SGA) with 5-HT2a antagonism, have been shown useful in controlling psychotic and behavioral symptoms and improving social withdrawal. Some evidence of efficacy for the treatment of anxiety, obsessive-compulsive symptoms and depression is reported for SSRI antidepressants. The use of these drugs should be carefully monitored, because activation with hypomanic or manic switches is reported up to 54% of the treated subjects.
CONCLUSION: BD in AS patients is frequent, usually it onsets during adolescence and is often characterized by atypical presentation, making its correct identification particularly difficult. A correct diagnosis of BD in AS individuals has relevant implications on the choice of adequate psychopharmacological, psycho-social and rehabilitative treatments.
PMID: 25046741 [PubMed - as supplied by publisher]
Ketamine administration in depressive disorders: a systematic review and meta-analysis.
Psychopharmacology (Berl). 2014 Jul 20;
Authors: Fond G, Loundou A, Rabu C, Macgregor A, Lançon C, Brittner M, Micoulaud-Franchi JA, Richieri R, Courtet P, Abbar M, Roger M, Leboyer M, Boyer L
INTRODUCTION: Ketamine's efficacy in depressive disorders has been established in several controlled trials. The aim of the present study was to determine whether or not ketamine administration significantly improves depressive symptomatology in depression and more specifically in major depressive disorder (MDD), bipolar depression, resistant depression (non-ECT studies), and as an anesthetic agent in electroconvulsive therapy (ECT) for resistant depression (ECT studies). Secondary outcomes were the duration of ketamine's effect, the efficacy on suicidal ideations, the existence of a dose effect, and the safety/tolerance of the treatment.
METHODS: Studies were included if they met the following criteria (without any language or date restriction): design: randomized controlled trials, intervention: ketamine administration, participants: diagnosis of depression, and evaluation of severity based on a validated scale. We calculated standardized mean differences (SMDs) with 95 % confidence intervals (CIs) for each study. We used fixed and random effects models. Heterogeneity was assessed using the I2 statistic.
RESULTS: We included nine non-ECT studies in our quantitative analysis (192 patients with major depressive disorder and 34 patients with bipolar depression). Overall, depression scores were significantly decreased in the ketamine groups compared to those in the control groups (SMD?=?-0.99; 95 % CI -1.23, -0.75; p?<?0.01). Ketamine's efficacy was confirmed in MDD (resistant to previous pharmacological treatments or not) (SMD?=?-0.91; 95 % CI -1.19,-0.64; p?<?0.01), in bipolar depression (SMD?=?-1.34; 95 % CI -1.94, -0.75), and in drug-free patients as well as patients under medication. Four ECT trials (118 patients) were included in our quantitative analysis. One hundred and three patients were diagnosed with major depressive disorder and 15 with bipolar depression. Overall, depression scores were significantly improved in the 58 patients receiving ketamine in ECT anesthesia induction compared to the 60 patients (SMD?=?-0.56; 95 % CI -1.10, -0.02; p?=?0.04; I2?=?52.4 %). The duration of ketamine's effects was assessed in only two non-ECT studies and seemed to persist for 2-3 days; this result needs to be confirmed. Three of four studies found significant decrease of suicidal thoughts and one found no difference between groups, but suicidal ideations were only studied by the suicide item of the depressive scales. It was not possible to determine a dose effect; 0.5 mg/kg was used in the majority of the studies. Some cardiovascular events were described (mostly transient blood pressure elevation that may require treatment), and ketamine's use should remain cautious in patients with a cardiovascular history.
CONCLUSION: The present meta-analysis confirms ketamine's efficacy in depressive disorders in non-ECT studies, as well as in ECT studies. The results of this first meta-analysis are encouraging, and further studies are warranted to detail efficacy in bipolar disorders and other specific depressed populations. Middle- and long-term efficacy and safety have yet to be explored. Extrapolation should be cautious: Patients included had no history of psychotic episodes and no history of alcohol or substance use disorders, which is not representative of all the depressed patients that may benefit from this therapy.
PMID: 25038867 [PubMed - as supplied by publisher]
Paraoxonase (PON)1 Q192R functional genotypes and PON1 Q192R genotype by smoking interactions are risk factors for the metabolic syndrome, but not overweight or obesity.
Redox Rep. 2014 Jul 18;
Authors: Bortolasci CC, Vargas HO, Souza-Nogueira A, Gastaldello Moreira E, Vargas Nunes SO, Berk M, Dodd S, Barbosa DS, Maes M
Background The metabolic syndrome (MetS) is a complex of multiple risk factors that contribute to the onset of cardiovascular disorder, including lowered levels of high-density lipoprotein (HDL) and abdominal obesity. Smoking, mood disorders, and oxidative stress are associated with the MetS. Paraoxonase (PON)1 is an antioxidant bound to HDL, that is under genetic control by functional polymorphisms in the PON1 Q192R coding sequence. Aims and methods This study aimed to delineate the associations of the MetS with plasma PON1 activity, PON1 Q192R genotypes, smoking, and mood disorders (major depression and bipolar disorder), while adjusting for HDL cholesterol, body mass index, age, gender, and sociodemographic data. We measured plasma PON1 activity and serum HDL cholesterol and determined PON1 Q192R genotypes through functional analysis in 335 subjects, consisting of 97 with and 238 without MetS. The severity of nicotine dependence was measured using the Fagerström Nicotine Dependence Scale. Results PON1 Q192R functional genotypes and PON1 Q192R genotypes by smoking interactions were associated with the MetS. The QQ and QR genotypes were protective against MetS while smoking increased metabolic risk in QQ carriers only. There were no significant associations between PON1 Q192R genotypes and smoking by genotype interactions and obesity or overweight, while body mass index significantly increased MetS risk. Smoking and especially severe nicotine dependence are significantly associated with the MetS although these effects were no longer significant after considering the effects of the smoking by PON1 Q192R genotype interaction. The MetS was not associated with mood disorders, major depression or bipolar disorder. Discussion PON1 Q192R genotypes and genotypes by smoking interactions are risk factors for the MetS that together with lowered HDL and increased body mass and age contribute to the MetS.
PMID: 25037113 [PubMed - as supplied by publisher]
Applying polygenic risk scores to postpartum depression.
Arch Womens Ment Health. 2014 Jul 19;
Authors: Byrne EM, Carrillo-Roa T, Penninx BW, Sallis HM, Viktorin A, Chapman B, Henders AK, Psychiatric Genomic Consortium Major Depressive Disorder Working Group, Pergadia ML, Heath AC, Madden PA, Sullivan PF, Boschloo L, van Grootheest G, McMahon G, Lawlor DA, Landén M, Lichtenstein P, Magnusson PK, Evans DM, Montgomery GW, Boomsma DI, Martin NG, Meltzer-Brody S, Wray NR
The etiology of major depressive disorder (MDD) is likely to be heterogeneous, but postpartum depression (PPD) is hypothesized to represent a more homogenous subset of MDD. We use genome-wide SNP data to explore this hypothesis. We assembled a total cohort of 1,420 self-report cases of PPD and 9,473 controls with genome-wide genotypes from Australia, The Netherlands, Sweden and the UK. We estimated the total variance attributable to genotyped variants. We used association results from the Psychiatric Genomics Consortia (PGC) of bipolar disorder (BPD) and MDD to create polygenic scores in PPD and related MDD data sets to estimate the genetic overlap between the disorders. We estimated that the percentage of variance on the liability scale explained by common genetic variants to be 0.22 with a standard error of 0.12, p?=?0.02. The proportion of variance (R (2)) from a logistic regression of PPD case/control status in all four cohorts on a SNP profile score weighted by PGC-BPD association results was small (0.1 %) but significant (p?=?0.004) indicating a genetic overlap between BPD and PPD. The results were highly significant in the Australian and Dutch cohorts (R (2)?>?1.1 %, p?<?0.008), where the majority of cases met criteria for MDD. The genetic overlap between BPD and MDD was not significant in larger Australian and Dutch MDD case/control cohorts after excluding PPD cases (R (2)?=?0.06 %, p?=?0.08), despite the larger MDD group affording more power. Our results suggest an empirical genetic evidence for a more important shared genetic etiology between BPD and PPD than between BPD and MDD.
PMID: 25037970 [PubMed - as supplied by publisher]