A positive correlation between serum amyloid β levels and depressive symptoms among community-dwelling elderly individuals in Japan

Koji Tsuruga,1 Norio Sugawara,1 Norio Yasui-Furukori,1 Ippei Takahashi,2 Shoko Tsuchimine,1 Ayako Kaneda,1 Shigeyuki Nakaji,2 Kazuhiko Nakamura1 1Department of Neuropsychiatry, 2Department of Social Medicine, Hirosaki University School of Medicine, Hirosaki, Japan Background: Amyloid beta (Aβ) levels have been associated with an increased risk of Alzheimer’s disease (AD). As depression is common before the onset of AD, serum Aß levels could be associated with depressive symptoms. The aim of this study was to investigate whether serum Aβ levels are associated with depressive symptoms and/or cognitive function in community-dwelling elderly individuals. Methods: We examined the association between serum Aβ levels and depression among 419 Japanese community-dwelling elderly individuals aged 60 years and over. Subjects were divided into two subgroups: younger elderly between 60 and 69 years old and older elderly over 69 years old. The Mini-Mental State Examination (MMSE) was used to assess cognitive function, and symptoms of depression were assessed using the Center for Epidemiologic Studies Depression Scale (CES-D). The ability to perform activities of daily living was evaluated using the Tokyo Metropolitan Institute of Gerontology Index of Competence. Serum Aβ levels were measured with a human amyloid beta enzyme-linked immunosorbent assay kit. Results: After controlling for potential confounding variables, a multiple linear regression analysis showed that increased levels of serum Aβ40 and Aβ42 were associated with higher CES-D scores in the older elderly subgroup. Under the same condition, multiple regression showed that serum Aβ levels were not associated with MMSE scores among the total subjects, younger elderly, or older elderly. Conclusion: Serum Aβ levels were associated with depressive symptoms in community-dwelling elderly individuals. The present study indicates the possibility that serum Aβ may be involved in the development of late-onset depression. Keywords: Alzheimer’s disease, depression, dementia, Japanes

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis

Association of the MAOA promoter uVNTR polymorphism with suicide attempts in patients with major depressive disorder

<p>Abstract</p> <p>Background</p> <p>The MAOA uVNTR polymorphism has been documented to affect the MAOA gene at the transcriptional level and is associated with aggressive impulsive behaviors, depression associated with suicide (depressed suicide), and major depressive disorder (MDD). We hypothesized that the uVNTR polymorphism confers vulnerability to MDD, suicide or both. The aim of this study was to explore the association between the MAOA uVNTR and depressed suicide, using multiple controls.</p> <p>Methods</p> <p>Four different groups were included: 432 community controls, 385 patients with MDD who had not attempted suicide, 96 community subjects without mental disorders who had attempted suicide, and 109 patients with MDD who had attempted suicide. The MAOA uVNTR polymorphism was genotyped by a PCR technique. The symptom profiles and personal characteristics in each group were also compared.</p> <p>Results</p> <p>The MAOA 4R allele was more frequent in males with MDD than in male community controls (χ²= 4.182, p = 0.041). Logistic regression analysis showed that, among the depressed subjects, those younger in age, more neurotic or who smoked had an increased risk of suicide (β = -0.04, p = 0.002; β = 0.15, p = 0.017; β = 0.79, p = 0.031, respectively). Moreover, among those who had attempted suicide, those younger in age, with more paternal overprotection, and more somatic symptoms were more likely to be in the MDD group than in the community group (β = -0.11, p < 0.001; β = 0.15, p = 0.026; β = 1.11, p < 0.001). Structural equation modeling (SEM) showed that nongenetic factors, such as age, paternal overprotection, and somatic symptoms, were associated with MDD, whereas depressed suicide were associated with severity of depression, personality traits, age, marital status, and inversely associated with anxiety symptoms. However, depression did not affect suicidal behavior in the community group.</p> <p>Conclusion</p> <p>The MAOA 4R allele is associated with enhanced vulnerability to suicide in depressed males, but not in community subjects. The MAOA 4R allele affects vulnerability to suicide through the mediating factor of depressive symptoms. Further large-scale studies are needed to verify the psychopathology of the relationships among MAOA uVNTR polymorphism, symptom profiles, and suicidal behavior.</p

Sex differences in the prediction of the effectiveness of paroxetine for patients with major depressive disorder identified using a receiver operating characteristic curve analysis for early response [Corrigendum]

Tomita T, Norio YF, Sato Y, et al. Neuropsychiatr Dis Treat. 2014;10:599&ndash;606.On page 599, there is an error in the author list &quot;Yasui-Furukori Norio&quot; should read &quot;Norio Yasui-Furukori&quot;.Read the original articl

Possible impact of the CYP2D6*10 polymorphism on the nonlinear pharmacokinetic parameter estimates of paroxetine in Japanese patients with major depressive disorders

Junji Saruwatari,1 Hiroo Nakashima,1 Shoko Tsuchimine,2 Miki Nishimura,1 Naoki Ogusu,1 Norio Yasui-Furukori21Division of Pharmacology and Therapeutics, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; 2Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, JapanAbstract: It has been suggested that the reduced function allele with reduced cytochrome P450 (CYP) 2D6 activity, CYP2D6*10, is associated with the interindividual differences in the plasma paroxetine concentrations, but there is no data presently available regarding the influence of the CYP2D6*10 polymorphism on the pharmacokinetic parameters, eg, Michaelis&ndash;Menten constant (Km) and maximum velocity (Vmax), in Asian populations. The present study investigated the effects of the CYP2D6 polymorphisms, including CYP2D6*10, on the pharmacokinetic parameters of paroxetine in Japanese patients with major depressive disorders. This retrospective study included 15 Japanese patients with major depressive disorders (four males and eleven females) who were treated with paroxetine. The CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, CYP2D6*18, CYP2D6*39, and CYP2D6*41 polymorphisms were evaluated. A total of 56 blood samples were collected from the patients. The Km and Vmax values of paroxetine were estimated for each patient. The allele frequencies of CYP2D6*2, CYP2D6*4, CYP2D6*5, CYP2D6*10, CYP2D6*18, CYP2D6*39, and CYP2D6*41 were 6.7%, 0%, 10.0%, 56.7%, 0%, 26.7%, and 0%, respectively. The mean values of Km and Vmax were 50.5&plusmn;68.4 ng/mL and 50.6&plusmn;18.8 mg/day, respectively. Both the Km and Vmax values were significantly smaller in CYP2D6*10 allele carriers than in the noncarriers (24.2&plusmn;18.3 ng/mL versus 122.5&plusmn;106.3 ng/mL, P=0.008; 44.2&plusmn;16.1 mg/day versus 68.3&plusmn;15.0 mg/day, P=0.022, respectively). This is the first study to demonstrate that the CYP2D6*10 polymorphism could affect the nonlinear pharmacokinetic parameter estimates of paroxetine in Asian populations. The findings of this study suggest that the CYP2D6*10 polymorphism may be associated with the smaller values of both the Km and Vmax in Japanese patients with major depressive disorders, and these results need to be confirmed in further investigations with a larger number of patients.Keywords: pharmacokinetics, dose requirement, Michaelis&ndash;Menten constant, maximum velocit

Effects of personality on the association between paroxetine plasma concentration and response

Tetsu Tomita,1 Norio Yasui-Furukori,1 Taku Nakagami,2 Shoko Tsuchimine,3 Masamichi Ishioka,4 Ayako Kaneda,1 Kazuhiko Nakamura1 1Department of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan; 2Department of Psychiatry, Nakagami Mental Clinic, Odate, Japan; 3Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan; 4Department of Psychiatry, Minato Hospital, Hachinohe, Japan Background: We studied the differences between groups that were divided according to personality characteristics with respect to the relationship between drug concentration and symptom improvement.Methods: A total of 120 patients with major depressive disorder were treated with paroxetine for 6 weeks, and 89 patients completed the protocol. The Montgomery&ndash;&Aring;sberg Depression Rating Scale (MADRS) was used to evaluate the patients. Patients&rsquo; paroxetine plasma concentrations at week 6 were measured. Their personalities were evaluated by the Temperament and Character Inventory (TCI) at the first visit. We divided the patients into two groups according to the median of each TCI dimension. We compared the responder rate between &ldquo;high&rdquo; and &ldquo;low&rdquo; groups in each TCI dimension and analyzed Pearson&rsquo;s correlation coefficients of paroxetine plasma concentration and MADRS-improvement rate.Results: A total of 62 patients completed the TCI. Low-novelty-seeking, high-harm-avoidance, low-reward-dependence, and low-self-directedness groups exhibited significant negative correlations between paroxetine plasma concentration and MADRS improvement. Among the groups with combined personality traits, the high-harm-avoidance and low-self-directedness groups showed a markedly significant negative correlation.Conclusion: Patients with depression exhibiting specific personality traits, especially those with high harm-avoidance and low self-directedness scores, exhibited a significant negative association between paroxetine plasma concentration and MADRS-improvement rate. Therefore, a lower dose might be suitable for patients with specific personality traits. Keywords: depression, paroxetine, concentration, personality, Temperament and Character Inventory, TCI&nbsp