Associations of the A118G OPRM1 polymorphism with sociotropy and interpersonal sensitivity.

BACKGROUND: The µ-opioid receptor (MOR) plays an important role in social bonding behaviors, while it is implicated in the pathophysiology of depression. It is shown that the A118G polymorphism (rs1799971) of the MOR gene (OPRM1) causes amino-acid exchange from Asn to Asp, and that this polymorphism is associated with altered mu-opioid receptor function. Meanwhile, sociotropy/autonomy and interpersonal sensitivity are personality vulnerabilities to depression characterized by distinctive interpersonal styles. The present study tested the hypothesis that the functional A118G OPRM1 polymorphism influences these personality traits. METHODS: The subjects were 402 physically and mentally healthy Japanese volunteers. Sociotropy and autonomy were measured by the Sociotropy-Autonomy Scale, and interpersonal sensitivity was evaluated by the Interpersonal Sensitivity Measure. The A118G polymorphism of the OPRM1 was determined by the PCR method. RESULTS: In one factor analysis of covariance, there were differences in scores of sociotropy (uncorrected p < .001, corrected p < .003) and interpersonal sensitivity (uncorrected p = .015, corrected p = .045), but not autonomy, among the A/A, A/G, and G/G genotypes. Post hoc LSD tests showed that sociotropy scores were higher in the A/A group than in the A/G (p = .029) and G/G (p < .001) groups, and higher in the A/G group than in the G/G group (p = .004). Interpersonal sensitivity scores were higher in the A/A group than in the A/G (p = .023) and G/G (p = .009) groups. CONCLUSION: This study suggests that the A118G OPRM1 polymorphism is associated with sociotropy and interpersonal sensitivity, interpersonal vulnerabilities to depression.

Oxytocin receptor polymorphism influences characterization of harm avoidance by moderating susceptibility to affectionless control parenting.

INTRODUCTION: Oxytocin receptor (OXTR) gene polymorphism reportedly moderates effects of negative environments during childhood on mental function and behavior such as depressive symptoms and externalizing problems. This study examined OXTR gene polymorphism effects on personality traits in healthy participants, considering interaction effects of polymorphism with affectionless control (AC) parenting which is one of the dysfunctional and pathogenic parenting styles. METHODS: For 496 Japanese volunteers, personality was evaluated using the Temperament and Character Inventory. The Parental Bonding Instrument, which has subscales of care and protection, was used to assess perceived parental rearing. AC parenting was defined as low care and high protection. A/G polymorphism of the OXTR gene (rs53576) was detected using TaqMan SNP Genotyping Assay. RESULTS: Two-way analysis of covariance revealed significant interaction effects between the genotype and the number of AC parents on scores of harm avoidance, with no significant main effect of genotype on any personality. Post-hoc analysis revealed that the harm avoidance scores were increased in a stepwise manner with respect to the increase of the number of AC parents in the A allele carriers. No similar association was observed in the A allele noncarriers. CONCLUSION: The results of this study suggest that OXTR polymorphism influences characterization of harm avoidance by moderating susceptibility to AC parenting.

Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial.

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is an enveloped, single-stranded RNA virus. Favipiravir is an orally administrable antiviral drug whose mechanism of action is to selectively inhibit RNA-dependent RNA polymerase. A preliminary trial in COVID-19 patients reported significant improvements across a multitude of clinical parameters, but these findings have not been confirmed in an adequate well-controlled trial. We conducted a randomized, single-blind, placebo-controlled Phase III trial assessing the efficacy and safety of favipiravir in patients with moderate pneumonia not requiring oxygen therapy. METHODS: COVID-19 patients with moderate pneumonia (SpO2 ≥ 94%) within 10 days of onset of fever (temperature ≥ 37.5 °C) were assigned to receive either placebo or favipiravir (1800 mg twice a day on Day 1, followed by 800 mg twice a day for up to 13 days) in a ratio of 1:2. An adaptive design was used to re-estimate the sample size. The primary endpoint was a composite outcome defined as the time to improvement in temperature, oxygen saturation levels (SpO2), and findings on chest imaging, and recovery to SARS-CoV-2-negative. This endpoint was re-examined by the Central Committee under blinded conditions. RESULTS: A total of 156 patients were randomized. The median time of the primary endpoint was 11.9 days in the favipiravir group and 14.7 days in the placebo group, with a significant difference (p = 0.0136). Favipiravir-treated patients with known risk factors such as obesity or coexisting conditions provided better effects. Furthermore, patients with early-onset in the favipiravir group showed higher odds ratio. No deaths were documented. Although adverse events in the favipiravir group were predominantly transient, the incidence was significantly higher. CONCLUSIONS: The results suggested favipiravir may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia, should be carefully considered. TRIAL REGISTRATION: Clinicaltrials.jp number: JapicCTI-205238.

Mu-Opioid Receptor Polymorphism Moderates Sensitivity to Parental Behaviors During Characterization of Personality Traits.

PURPOSE: Attachment research shows that attachment experiences with parents in childhood influence the characterization of personality traits. Meanwhile, it is known that mu-opioid receptor function is involved in human attachment. Furthermore, a few studies suggest that the A118G polymorphism of the mu-opioid receptor gene (OPRM1) is associated with altered mu-opioid receptor function. Thus, we examined if the OPRM1 polymorphism moderates the sensitivity to parental behaviors and thereby contributes to the characterization of personality traits. MATERIALS AND METHODS: Participants were 725 healthy Japanese. Parenting practices of their parents were evaluated by the Parental Bonding Instrument (PBI) with the care and protection subscales. Personality was evaluated using the Temperament and Character Inventory (TCI). The OPRM1 A118G polymorphism was detected by a PCR method. RESULTS: Multiple regression analyses revealed significant effects of the interaction between the OPRM1 genotype and maternal protection on scores of the self-directedness and cooperativeness dimensions, while significant main effects of the OPRM1 genotype on scores of the TCI were not found. Further analyses showed that there were significant negative correlations between maternal protection scores and the two dimensional scores in the A/A and A/G genotypes with higher correlation coefficients in the former, but not in the G/G genotype. CONCLUSION: The present study suggests that the OPRM1 polymorphism contributes to the characterization of personality traits by moderating the sensitivity to parental behaviors, especially maternal protection.

Interrelation Between Increased BDNF Gene Methylation and High Sociotropy, a Personality Vulnerability Factor in Cognitive Model of Depression.

PURPOSE: It is suggested that increased methylation of the brain-derived neurotrophic factor (BDNF) gene is involved in the pathogenesis of depression, while sociotropy and autonomy are proposed as personality vulnerability factors in cognitive model of depression. We examined the interrelation between BDNF gene methylation and sociotropy or autonomy, with taking into account the previously reported deleterious effect of parental overprotection on sociotropy. MATERIALS AND METHODS: The participants consisted of 90 healthy Japanese volunteers. Methylation levels of the BDNF gene in peripheral blood were quantified by bisulfite pyrosequencing. Sociotropy and autonomy were assessed by the Sociotropy-Autonomy Scale, and perceived parental protection was evaluated by the Parental Bonding Instrument. RESULTS: In Pearson's correlation analysis, there was a positive correlation between methylation levels of the BDNF gene and sociotropy scores (p<0.05) but not autonomy scores, and a positive correlation between maternal protection scores and sociotropy scores (p<0.05). In structural equation modeling, two models were proposed; the first one is that hypermethylation of the BDNF gene and maternal overprotection independently contribute to high sociotropy, and the second one is that maternal overprotection contributes to high sociotropy which then leads to hypermethylation of the BDNF gene. CONCLUSION: The present study suggests an interrelation between increased BDNF gene methylation and high sociotropy.

Implication of core beliefs about negative-self in neuroticism.

Objective: Core beliefs about negative-self are beliefs about self-deficiencies in basic aspects of human adaptation. Meanwhile, neuroticism is a personality trait characterised by negative emotionality, i.e., a tendency to react to stress with negative emotions. The present study tested the hypothesis that core beliefs about negative-self are implicated in neuroticism.Methods: The subjects were 309 Japanese healthy volunteers. Core beliefs about negative-self were evaluated by the Brief Core Schema Scales, and neuroticism was evaluated by the NEO Personality Inventory-Revised.Results: In both multiple regression analysis and structural equation modelling, higher neuroticism was strongly predicted by higher levels of core beliefs about negative-self.Limitations: The present study cannot determine the causal relationship between core beliefs about negative-self and neuroticism, because of its cross sectional design.Conclusions: The present study suggests that core beliefs about negative-self are deeply implicated in neuroticism.Key PointsImplication of core beliefs about negative-self in neuroticism was examined.Neuroticism was predicted by higher levels of these core beliefs.These core beliefs may be involved in negative emotionality of neuroticism.

Link of negative core beliefs about the self with perceived dysfunctional parenting.

Cognitive theory posits the central role of negative core beliefs about the self in cognitive vulnerabilities to depression, and this position is supported by empirical studies. It is also hypothesized that these core beliefs develop as a result of negative interactions with significant others in early life. To test the hypothesis that negative core beliefs about the self are formed by dysfunctional parenting, we examined their relations with perceived parental rearing. The subjects were 355 Japanese healthy volunteers. Core beliefs of negative-self were assessed by the corresponding subscale of the Brief Core Schema Scales. Perceived parental care and protection were evaluated by the corresponding subscales of the Parental Bonding Instrument. In both multiple regression analysis and structural equation modeling, core beliefs of negative-self were predicted by perceptions of high maternal protection and low paternal care. The present study shows that negative core beliefs about the self are linked with perceived dysfunctional parenting, suggesting that the formation mechanism of these core beliefs is at least partly ascribable to dysfunctional parenting.

Interrelations among negative core beliefs, attachment anxiety and low self-directedness, putative central constructs of depression vulnerabilities in cognitive, attachment and psychobiological personality theories.

The present study examined the interrelations among negative core beliefs, attachment anxiety and low self-directedness, to test if the central constructs of depression vulnerabilities in cognitive, attachment and psychobiological personality theories are integrated into negative self-image. The subjects were 410 healthy Japanese medical students and staff. Negative core beliefs, attachment anxiety and self-directedness were evaluated by the Brief Core Schema Scales, Experiences in Close Relationships and Temperament and Character Inventory, respectively. There were strong interrelations among the three factors. The present study suggests that the central constructs of depression vulnerabilities in the three theories are integrated into negative self-image.

Relation of high neuroticism with increased methylation of the BDNF gene.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that has an important function in neuroplasticity and neuronal development. It is suggested that increased methylation of the BDNF gene resulting in decreased BDNF activity is associated with depression. Meanwhile, neuroticism is a well-known risk factor for developing depression. In the present study, the relationship between methylation of the BDNF gene and personality traits including neuroticism was examined. SUBJECTS AND METHODS: The subjects were 98 healthy Japanese. Methylation levels of the BDNF gene were determined by the bisulfite-pyrosequencing method. Personality traits including neuroticism were assessed by the NEO Personality Inventory-Revised. RESULTS: There was a positive correlation between neuroticism scores and methylation levels of the BDNF gene. The subjects with higher neuroticism scores had higher levels of BDNF gene methylation compared with those with lower neuroticism scores. Meanwhile, other personality traits were not associated with BDNF gene methylation. CONCLUSION: The present study suggests that high neuroticism is related to increased methylation of the BDNF gene.

Implication of the DGKH genotype in openness to experience, a premorbid personality trait of bipolar disorder.

AIMS: The diacylglycerol kinase η gene (DGKH) is one of the few replicated risk genes for bipolar disorder. Meanwhile, specific personality traits, especially openness to experience, have been suggested as premorbid personality traits of the disorder. The aim of the present study was to examine the relation of the DGKH genotype with broad dimensions of personality, to obtain further evidence for its implication in the etiology of bipolar disorder. METHODS: The subjects were 319 Japanese healthy volunteers. Personality was assessed by the NEO Personality Inventory-Revised, which has the neuroticism, extraversion, openness to experience, agreeableness and conscientiousness dimensions. The A/G polymorphism of DGKH (rs9525580) was detected by a PCR-RFLP method. The subjects were divided into two groups with respect to the presence or absence of the A allele, which is a putative risk allele for bipolar disorder. RESULTS: The group with the A allele had significantly (p < 0.05) higher scores of openness to experience compared to that without this allele. Scores of other dimensions were not different between the two groups. LIMITATIONS: The subjects had a homogeneous but rather specific background, and we did not employ a longitudinal design. CONCLUSIONS: The present study shows that a bipolar-risk allele of DGKH is associated with higher openness to experience, providing further evidence for the implication of this gene in the etiology of bipolar disorder.

Marked differences in core beliefs about self and others, between sociotropy and autonomy: personality vulnerabilities in the cognitive model of depression.

OBJECTIVE: The cognitive model of depression posits two distinctive personality vulnerabilities termed sociotropy and autonomy, each of which is composed of a cluster of maladaptive self-schemas. It is postulated that negative core beliefs about self underlie maladaptive self-schemas as a whole, whereas those about others may be implicated in the autonomous self-schemas. Therefore, the present study examined the relations of sociotropy and autonomy with core beliefs about self and others. METHODS: The sample of this study consisted of 321 healthy Japanese volunteers. Sociotropy and autonomy were evaluated by the corresponding subscales of the Sociotropy-Autonomy Scale. Core beliefs about self and others were assessed by the negative-self, positive-self, negative-other and positive-other subscales of the Brief Core Schema Scales. RESULTS: In the forced multiple regression analysis, sociotropy scores were correlated with negative-self scores (ß = 0.389, P < 0.001). Meanwhile, autonomy scores were correlated with positive-self scores (ß = 0.199, P < 0.01) and negative-other scores (ß = 0.191, P < 0.01). CONCLUSION: The present study suggests marked differences in core beliefs about self and others between sociotropy and autonomy, further contrasting the two personality vulnerabilities to depression.

Close relation of interpersonal sensitivity with negative core beliefs about the self, the central construct of cognitive vulnerability to depression.

Interpersonal sensitivity is a personality trait linked with anxious attachment conceptualized in attachment theory. This personality trait is comprised of four components, i.e., interpersonal awareness, separation anxiety, timidity and fragile inner-self, which are measured by the corresponding subscales of the Interpersonal Sensitivity Measure (IPSM). Meanwhile, one study showed that six items of the IPSM tentatively used as negative self-schemas predicted the onset of depression. To clarify if interpersonal sensitivity reflects cognitive vulnerability, we examined the relation of this personality trait with negative core beliefs about the self. The study population consisted of 335 Japanese volunteers. Interpersonal sensitivity was measured by the IPSM, and negative core beliefs about the self were assessed by the negative-self subscale of the Brief Core Schema Scales (BCSS). Multiple regression analysis showed that scores of the four subscales of the IPSM were strongly correlated with those of the negative-self subscale of the BCSS (P < 0.001). Similarly, sequential equation modeling demonstrated that the four components of interpersonal sensitivity were strongly predicted by core beliefs of negative-self (P < 0.001). The present study shows that interpersonal sensitivity is closely related to negative core beliefs about the self, suggesting that this personality trait can be regarded as a cognitive vulnerability to depression.

Relationship of negative and positive core beliefs about the self with dysfunctional attitudes in three aspects of life.

OBJECTIVE: Cognitive theory assumes a pivotal role of negative core beliefs about the self in dysfunctional attitudes predisposing to depression. Meanwhile, the role of positive core beliefs about the self in cognitive vulnerability to depression is unknown. Therefore, we examined the relationship of negative and positive core beliefs about the self with dysfunctional attitudes in three aspects of life. METHODS: The subjects were 311 Japanese volunteers. Core beliefs of negative-self and positive-self were evaluated by the corresponding subscales of the Brief Core Schema Scales. Dysfunctional attitudes in the areas of achievement, dependency and self-control were measured by the corresponding subscales of the 24-item Dysfunctional Attitude Scale. RESULTS: The negative-self subscale was correlated with the achievement, dependency and self-control subscales. The positive-self subscale was correlated with the achievement and self-control subscales. CONCLUSION: The present study suggests that negative core beliefs about the self underlie all types of dysfunctional attitudes, while positive core beliefs about the self have some connections with dysfunctional attitudes related to achievement and self-control.

Relationship between interpersonal sensitivity and leukocyte telomere length.

BACKGROUND: Telomeres are repetitive DNA sequences located at the ends of chromosomes, and telomere length represents a biological marker for cellular aging. Interpersonal sensitivity, excessive sensitivity to the behavior and feelings of others, is one of the vulnerable factors to depression. In the present study, we examined the effect of interpersonal sensitivity on telomere length in healthy subjects. METHODS: The subjects were 159 unrelated healthy Japanese volunteers. Mean age ± SD (range) of the subjects was 42.3 ± 7.8 (30-61) years. Interpersonal sensitivity was assessed by the Japanese version of the Interpersonal Sensitivity Measure (IPSM). Leukocyte telomere length was determined by a quantitative real-time PCR method. RESULTS: Higher scores of the total IPSM were significantly (ß = -0.163, p = 0.038) related to shorter telomere length. In the sub-scale analysis, higher scores of timidity were significantly (ß = -0.220, p = 0.044) associated with shorter telomere length. CONCLUSIONS: The present study suggests that subjects with higher interpersonal sensitivity have shorter leukocyte telomere length, implying that interpersonal sensitivity has an impact on cellular aging.

Perceived parental affectionless control is associated with high neuroticism.

OBJECTIVE: Depressed patients are prone to perceive that they were exposed to affectionless control by parents. Meanwhile, high neuroticism is a well-established risk factor for developing depression. Therefore, this study examined whether perceived parental affectionless control is associated with high neuroticism. METHODS: The subjects were 664 healthy Japanese volunteers. Perceived parental care and protection were assessed by the Parental Bonding Instrument. Parental rearing was categorized into either optimal parenting (high care/low protection) or three dysfunctional parenting styles including affectionless control (low care/high protection). Neuroticism was evaluated by the NEO Personality Inventory-Revised. RESULTS: The subjects with paternal affectionless control had higher neuroticism scores than those with paternal optimal parenting. Similar tendency was observed in maternal rearing. Neuroticism scores increased in a stepwise manner with respect to the increase in the number of parents with affectionless control. CONCLUSION: The present study shows that perceived parental affectionless control is associated with high neuroticism, suggesting that this parental style increases neuroticism in recipients.

Effects of perceived affectionless control parenting on working models of the self and other.

Attachment theory contends that insecure working models of the self and other built through negative attachment experiences are predisposing factors for depression and anxiety disorders. Meanwhile, patients with these psychiatric disorders tend to perceive that they received the affectionless control parenting, which is a combination of lack of care and overprotection. To test the hypothesis that the affectionless control parenting impairs the formation of positive working models, we examined the effects of perceived parenting styles on qualities of working models. The subjects were 691 healthy Japanese volunteers. Working models of the self and other were assessed by the Relationship Scales Questionnaire. Perceived parental rearing was evaluated by the Parental Bonding Instrument, which has the care and protection subscales. Parental rearing was classified into one of the four types defined by combinations of levels of care and protection. In all combinations of recipient sexes and parental sexes, the subjects with the affectionless control parenting (low care/high protection) had lower scores of the self-model and other-model than those with the optimal parenting (high care/low protection). The present study suggests that the affectionless control parenting impairs the formation of positive working models of the self and other.

Link of dysfunctional attitudes with the negative self-model.

BACKGROUND: Beck's cognitive theory postulates that dysfunctional attitudes predisposing to depression are formed by early negative experiences. Meanwhile, Bowlby's attachment theory contends that distorted working models built through insecure attachment relationships lead to various psychopathologies such as depression. The present study examined the correlations of dysfunctional attitudes about achievement, dependency, and self-control with working models of the self and other, and tried to promote understanding of those dysfunctional attitudes from an attachment perspective. METHODS: The subjects were 591 Japanese healthy volunteers. Dysfunctional attitudes about achievement, dependency, and self-control were evaluated by the corresponding subscales of the 24-item Dysfunctional Attitude Scale, and working models of the self and other were assessed by the relationship scales questionnaire. RESULTS: The scores of the achievement (ß = -0.26, P < 0.001), dependency (ß = -0.41, P < 0.001), and self-control (ß = -0.14, P < 0.01) subscales had negative correlations with the self-model score, suggesting the connections of all clusters of dysfunctional attitudes with the negative self-model. The score of the dependency subscale (ß = 0.21, P < 0.001) had a positive correlation with the other-model score, suggesting the connection of this cluster of dysfunctional attitudes with the positive other-model. Meanwhile, the scores of the achievement (ß = -0.17, P < 0.001) and self-control (ß = -0.13, P < 0.01) subscales had negative correlations with the other-model score, suggesting the connections of these clusters of dysfunctional attitudes with the negative other-model. CONCLUSION: The present study suggests that dysfunctional attitudes as a whole are linked with the negative self-model built through negative attachment experiences, while the content specificity of each cluster is related to the differential correlations with the other-model.