Nerve growth factor gene polymorphisms may be associated with heroin dependence in women but do not mediate specific personality traits.

Heroin dependence (HD) is a complex disease with a substantial genetic contribution and is associated with traits of impulsivity and specific personality traits. The neurotrophic factor nerve growth factor (NGF) may mediate the reward processes in HD. This study aims to investigate whether NGF gene polymorphisms are associated with the co-occurrence of HD and impulsivity/specific personality traits in HD patients. To minimize the potential confounding effects of population stratification, we selected a homogeneous Han Chinese population and recruited 1364 participants (831 HD patients and 533 healthy controls). In addition, 163 female HD patients completed the Chinese version of the Barratt Impulsiveness Scale Version 11 (BIS-11), and 440 HD patients completed the Chinese version of the Tridimensional Personality Questionnaire (TPQ) for subsequent analysis. We identified three polymorphisms with altered allele and genotype frequency in HD patients versus controls (p = 0.035 for rs2254527; p = 0.005 for rs6678788; p = 0.006 for rs7523654), especially in the female subgroup. Four associations identified via haplotype analysis were significant in the female subgroup (p = 0.003 for T-T-A haplotype and p = 0.002 for C-C-A haplotype in block 1; p = 0.011 for T-T haplotype and p = 0.009 for C-T haplotypes in block 2), but not in the male subgroup. Male HD patients had higher novelty-seeking (NS) scores, and female HD patients had higher harm avoidance (HA) scores. However, there was no significant association between the selected NGF polymorphisms and BIS or TPQ scores in HD patients. NGF variants may contribute to the risk of HD development in females but do not mediate the relationship between impulsivity and specific personality traits in the female population.

Increased incidence of alcohol use disorder and alcohol-related psychiatric disorders in patients with obstructive sleep apnea: A nationwide population-based cohort study.

BACKGROUND: Obstructive sleep apnea (OSA) and alcohol-related diseases (ARDs), including alcohol use disorder, alcohol-related psychiatric disorders, alcoholic liver disease, alcoholic polyneuropathy alcoholic cardiomyopathy, and alcoholic gastritis, are both highly prevalent conditions. Alcohol consumption is associated with a higher risk of sleep apnea. However, whether OSA increases the risk of ARD has not, as yet, been studied comprehensively. Our study aimed to determine whether OSA increases the subsequent risk of ARD. METHODS: This study utilized the data from Taiwan's National Health Insurance Database between 2000 and 2015. We identified 7722 individuals newly diagnosed with OSA and randomly selected sex-, age-, and index date-matched (1:3) 22,166 controls without OSA, with a total of 29,888 subjects. We used the Fine and Gray's survival analysis to estimate the effects of OSA on ARD. RESULTS: The OSA cohort had an adjusted hazard ratio of subsequent ARDs as 1.486 (95% Confidence Interval: 1.301-1.698), when comparing the cohort without OSA. The Kaplan-Meier analysis showed that the cumulative incidence of ARDs was significantly higher in the OSA cohort than in the controls in the first year of follow-up, till the end of the follow-up. A post-hoc analysis showed that OSA was associated with alcohol use disorder, alcohol-related psychiatric disorders, and alcoholic liver disease, but not alcoholic polyneuropathy, alcoholic cardiomyopathy, and alcoholic gastritis. The use of psychoactive medication, including the sedative-hypnotics, antidepressants or antipsychotics were associated with a lower risk of ARDs. CONCLUSIONS: Our study demonstrates that the OSA patients are at a higher risk of developing ARDs.

DRD2 and ANKK1 genes associate with late-onset heroin dependence in men.

Objectives: Dopamine plays an important role in reward system of heroin dependence (HD), and dopaminergic D2 receptor (DRD2) gene is a candidate for the aetiology of HD. Ankyrin repeat and kinase domain containing 1 (ANKK1) gene is proximal to DRD2 and may influence its expression. We explored whether DRD2 and ANKK1 associate with occurrence of HD, and whether the genetic variants influence personality traits in male patients with HD.Methods:DRD2/ANKK1 polymorphisms were analysed in 950 unrelated Han Chinese male participants (601 HD patients and 349 healthy controls). All participants were screened using the same assessment tools and all patients met the diagnostic criteria of HD. Personality traits were assessed in 274 patients and 142 controls using the Tridimensional Personality Questionnaire.Results: According to the allele, genotype and haplotype frequency analysis, we observed an association between HD and several DRD2/ANKK1 polymorphisms (rs1800497, rs1800498, rs1079597 and rs4648319); this was most notable in the late-onset HD subgroup. However, these DRD2/ANKK1 polymorphisms did not associate with specific personality traits in HD patients and controls.Conclusions:DRD2/ANKK1 may play an important role in occurrence of late-onset HD, but does not mediate the relationship between personality traits and HD in Han Chinese male population.

OPRD1 gene affects disease vulnerability and environmental stress in patients with heroin dependence in Han Chinese.

Exposure to stress not only increases the vulnerability to heroin dependence (HD) but also provokes relapse. The etiology of HD and the role of life stress remain unclear, but prior studies suggested that both genetic and environmental factors are important. Opioid related genes, including OPRM1, OPRD1, OPRK1, and POMC, are obvious candidates for HD. Therefore, this study was conducted to explore whether the genetic polymorphisms of the candidates could affect vulnerability to HD and response to life stress in patients with HD. Ten polymorphisms of the opioid related genes were analyzed in 801 patients and 530 controls. The Life Event Questionnaire was used to assess the perspective and response to life stress in the past year. The genotype distribution and allelic frequency analyses showed that the minor C allele of rs2234918 in OPRD1 is over-represented in the HD group (P = .006 and P = .002, respectively). This finding was further confirmed by logistic regression analysis, showing that C allele carriers have a 1.42 times greater risk for HD compared to T/T homozygotes. A subgroup of 421 patients and 135 controls were eligible for life stress assessment. Patients with HD have a higher occurrence of negative events (No), negative events score (Ns), and average negative event score (Na) than those of controls (all P < .001), but there was no difference regarding positive recent events between the two groups. Gene-stress assessment in the HD group showed that T/T homozygotes of OPRD1 rs2236857 have more severe stress than C allele carriers (Ns, P = .004 and Na, P = .047). Our results indicate that the OPRD1 gene may not only play a role in the pathogenesis of HD but also affect the response to life stress among patients with HD in our Han Chinese population. Patients with the risk genotype may need additional psychosocial intervention for relapse prevention.

NGF gene polymorphisms are not associated with heroin dependence in a Taiwanese male population.

BACKGROUND AND OBJECTIVES: Heroin dependence (HD) is a chronic relapsing brain illness with substantial heritability. Nerve growth factor (NGF) is a crucial modulator in the neurodevelopment, and may be a key mediator of reward processes in HD. The purpose of this genetic study was to investigate whether NGF gene polymorphisms associate with the occurrence of HD and the specific personality traits of patients with HD. METHODS: We selected a homogeneous Han Chinese male population to overcome possible confounding effects of population and gender. For the study, 272 HD patients and 141 controls completed the Tridimensional Personality Questionnaire to evaluate their personality traits. In addition, a further sample 303 HD patients and 204 controls was added (with totally 920 participants) for the gene association and genotype-phenotype interaction studies. RESULTS: Patients with HD had higher novelty seeking (NS) and harm avoidance (HA) scores than healthy subjects. Nonetheless, NGF gene polymorphisms did not associate with specific personality traits in HD patients and controls. There is no significant difference in NGF gene polymorphisms between patients with HD and controls. DISCUSSION AND CONCLUSIONS: The NGF gene may neither contribute to the risk of development of HD, nor mediate the relationship between specific personality traits and HD in Han Chinese male population. SCIENTIFIC SIGNIFICANCE: Patients with HD had higher novelty seeking (NS) and harm avoidance (HA) scores than healthy subjects. However, none of the polymorphisms in the NGF gene affected the NS and HA scores in both patients and healthy subjects. (Am J Addict 2018;27:516-523).

Differential effect of the DRD3 genotype on inflammatory cytokine responses during abstinence in amphetamine-dependent women.

Amphetamine exposure impacts on innate and adaptive immunity and DRD3 may modulate the effect of amphetamine on the immune response. We assessed the immune-cytokine markers in 72 female patients with amphetamine dependence (AD) at baseline and after 4-week drug abstinence and in 51 healthy women. Multiplex magnetic bead assay was used to measure the plasma cytokine expression level simultaneously in all participants and DRD3 rs6280 polymorphism was genotyped in patients. We demonstrated an increase of the T helper 1 (Th1) cytokines (IL-2), Th2 cytokines (IL-4, IL-5, IL-6 and IL-10) and other cytokines (IL-1ß) in the entire AD cohort. A similar cytokine pattern, along with a significantly decreased IL-8 and IL-10 levels was observed after 4-week abstinence. Among AD patients with DRD3 rs6280 TT genotype, the cytokine expression profile was consistent with total AD cohort at baseline and revealed a significant down-regulated plasma level of the Th1, Th2, and other cytokines except for IL-6 after 4-week abstinence. In AD group with DRD3 rs6280 C allele carrier, we found IL-2 level was significantly higher than healthy controls at baseline and remained higher, accompanied with a borderline increase in IL-4, IL-6 and IL-1ß levels after 4-week abstinence. Our results suggest that chronic use of amphetamine increased both pro- and anti-inflammatory cytokines in AD patients, indicating the immune imbalance that may persist for 4 weeks or more. Besides, DRD3 rs6280 TT genotype may be associated with favorable recovery in general inflammatory cytokines during period of abstinence.

Differences in immunomodulatory properties between venlafaxine and paroxetine in patients with major depressive disorder.

Inflammatory processes play a crucial role in the pathophysiology of depression, and identifying the specific cytokines targeted by different antidepressants is important for personalized treatment. The aims of this study were to examine whether venlafaxine and paroxetine cause different immunomodulatory effects when used to treat patients with major depression and to clarify the relationships between plasma cytokine levels and the therapeutic effectiveness of these drugs. A total of 91 Han Chinese patients with major depression completed the 8-week paroxetine or venlafaxine treatment and 90 healthy controls were recruited. A multiplex assay was used to measure cytokines levels in patients with major depression before and after an 8-week venlafaxine and paroxetine treatment. Cytokine levels were measured in healthy controls at the baseline. The 21-item Hamilton Depression Rating Scale was used to assess the changes in psychopathological symptoms from the baseline to the end point in each patient. Venlafaxine treatment caused greater decreases in the levels of interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin 4 (IL-4), IL-5, IL-1ß, and IL-8 than did paroxetine. Paroxetine treatment increased the levels of proinflammatory cytokines IFN-γ, TNF-α, and IL-6 and decreased Th2 cytokine levels. After paroxetine treatment, IL-6 levels increased more in the non-remitter group than in the remitter group. In the remitter group, IL-4 and IL-5 levels decreased to values seen in the healthy controls. After venlafaxine treatment in both the remitter and non-remitter groups, IL-1ß levels decreased to values seen in the healthy controls. Our results suggest that venlafaxine and paroxetine have different immunomodulatory properties and that venlafaxine has greater anti-inflammatory effects than paroxetine.

Novelty seeking mediates the effect of DRD3 variation on onset age of amphetamine dependence in Han Chinese population.

The dopamine receptor D3 (DRD3) gene, one of the candidate genes for amphetamine dependence (AD), is involved in the mesolimbic dopaminergic system, implicated as the underlying mechanism of addiction. Our case-control study aimed to investigate whether the DRD3 gene is associated with the susceptibility to AD and specific personality traits in AD patients. A total of 1060 unrelated Han Chinese subjects (559 AD patients and 501 controls) were screened using the same assessment tool and genotyped for eight DRD3 polymorphisms. All patients met the DSM-IV-TR criteria for AD, and personality traits of 539 were assessed using a Tridimensional Personality Questionnaire. Furthermore, AD individuals were divided into four clinical subgroups based on gender and psychosis status, to reduce the clinical heterogeneity. We found that the ATA haplotype combination for SNPs rs324029, rs6280, and rs9825563, respectively, was significantly associated with total AD patients (p = 0.0003 after 10,000 permutations). Similar results were observed in the both male and non-psychosis subgroup but not in other subgroups. In addition, DRD3 rs9825563 may influence onset age of drug use, partially mediated by novelty seeking in the non-psychosis AD group. In conclusion, DRD3 is a potential genetic factor in the susceptibility to AD and is associated with onset age of drug use through interaction with novelty seeking in a specific patient group in the Han Chinese population.

The SLC6A3 gene possibly affects susceptibility to late-onset alcohol dependence but not specific personality traits in a Han Chinese population.

Dopaminergic dysfunction has an important role in the pathoetiology of alcohol dependence (AD). The purpose of this study was to determine whether the solute carrier family 6 member 3 (SLC6A3) gene (also known as the dopamine transporter DAT gene) was associated with AD, and whether variants in the SLC6A3 locus were associated with specific personality traits in patients with AD. Sixteen polymorphisms in SLC6A3 were analyzed using 637 patients with AD and 523 healthy controls. To reduce clinical heterogeneity, patients were classified into two subgroups: early-onset AD (EOAD) and late-onset AD (LOAD). The Tridimensional Personality Questionnaire was used to assess the personality traits novelty seeking (NS) and harm avoidance (HA) in the patients with AD. Using allele frequency and genotype distribution comparisons and logistic regression analysis, we found evidence of association between rs6350 and AD (P < 0.05). Following subgroup analysis, we confirmed evidence of an association in patients with LOAD (P = 0.003), but not in patients with EOAD. Heterozygous carriers of the A allele have a nearly 3 times greater risk to develop LOAD compared to individuals who do not have an A allele. Although we found that patients with AD had higher NS and HA scores compared to controls (P < 0.001), we did not find evidence of association between SLC6A3 polymorphisms and either NS or HA in patients with AD using linear regression analysis. The findings from our study indicate that the SLC6A3 gene may have a role in susceptibility to late-onset AD in the Han Chinese population.

The relationship between the striatal dopamine transporter and novelty seeking and cognitive flexibility in opioid dependence.

Novelty seeking (NS) is a core personality trait that primes the susceptibility to drug addiction. Striatal dopamine activity contributes to cognitive flexibility, an important cognitive strategy to inhibit impulsivity and compulsive drug-seeking behavior. Evidence supports the association between dopamine and NS. Opioid-dependent patients show higher levels of NS, and repeated opioid exposure can cause cognitive deficits including poor cognitive flexibility and impaired impulse control. However, in opioid-dependent patients, the link between NS, striatal dopamine activity, and cognitive flexibility is still unclear. We recruited 22 opioid-dependent individuals and 30 age- and sex-matched healthy controls. Single-photon emission computed tomography with [99mTc]TRODAT-1 as a ligand was used to measure the striatal dopamine transporter (DAT) availability. The Trail Making Test (TMT) was performed to assess cognitive flexibility. Cloninger's Tridimensional Personality Questionnaire (TPQ) was used to measure NS. We found that in opioid-dependent patients, the striatal DAT availability was lower and negatively associated with TMT Part B÷Part A. Moreover, an inverted-U shape significantly matched the scores of NS as a function of the striatal DAT availability, with maximum NS potential in the midrange of the DAT availability. An extra sum-of-squares F test was conducted, indicating that a quadratic model fitted the association between the DAT and NS better than a linear model did. In brief, in opioid-dependent patients, the striatal DAT availability is nonlinearly linked to NS and linearly linked to cognitive flexibility. The role of the striatal DAT in the transition from controlled to compulsive opioid use warrants further research.

Differential cytokine levels between early withdrawal and remission states in patients with alcohol dependence.

Alcohol dependence (AD) leads to altered innate and adaptive immune responses, and frequently co-occurs with inflammation. Therefore, inflammatory cytokines potentially play a crucial role in the development of alcohol-related illnesses. This study evaluated changes in plasma cytokine concentrations, liver function, cravings, depression severity, and cognitive function in male patients with AD, during the course of an alcohol-detoxification program. A total of 78 male patients with AD were recruited for a conservative detoxification program; and cytokine levels, depressive score, and cognitive impairment applying the Trail Making Test (TMT) were evaluated during early withdrawal (baseline) and after 4 weeks of abstinence from alcohol. Healthy volunteers (86 males) were also recruited as controls. Inflammatory cytokine expression in all participants was assessed by multiplex magnetic bead assay. AD patients during early withdrawal demonstrated higher cytokine levels than the healthy controls (P≤0.001 for all cytokines). However, the levels of cytokine expression were significantly lower after 4 weeks of abstinence from alcohol (P≤0.001, except for IL-1ß and IL-5). Higher liver function marker levels, depressive severity, and TMT times were observed in patients at the beginning of the detoxification program than in healthy controls. Fortunately, these functions significantly ameliorated after 4 weeks of abstinence. (P≤0.001). Levels of circulating cytokines, liver function, and cognitive function may markers of alcohol use disorder.

Catechol-O-methyltransferase gene variants may associate with negative symptom response and plasma concentrations of prolactin in schizophrenia after amisulpride treatment.

Catechol-O-methyltransferase (COMT) enzyme is involved in the pathogenesis of psychotic symptoms and may be associated with a therapeutic response to antipsychotic drugs. The aim of this study was to examine the relationship between COMT variants, plasma prolactin level, and the therapeutic effectiveness of amisulpride treatment in patients with schizophrenia. A 12-week naturalistic study of amisulpride treatment was carried out in 185 Han Chinese patients with schizophrenia. The patients were screened for 14 single-nucleotide polymorphisms of the COMT gene. The Positive and Negative Syndrome Scale (PANSS) was used to assess the improvement of psychopathological symptoms from the baseline to the end point in each subject. For better presentation of time-course changes in response status, a mixed model for repeated-measures (MMRM) analysis of symptom improvement during the 12-week treatment period was conducted. The change in plasma prolactin level after amisulpride treatment was also examined (n=51). No significant differences in the genotype frequencies of the COMT variants investigated were observed between responders and non-responders. Moreover, an MMRM analysis of psychopathological symptom improvement during the 12-week treatment course showed that it depended significantly on COMT variants (rs4680, rs4633, and rs6267), particularly regarding changes in negative symptoms. The increase in plasma prolactin levels observed was influenced by the COMT rs4680 variant and was positively correlated with a reduction in PANSS negative scores. Our results suggest that variation of the COMT gene is associated with treatment response regarding negative symptoms and prolactin changes after amisulpride treatment in patients with schizophrenia.

Reduced striatal dopamine transporter density associated with working memory deficits in opioid-dependent male subjects: a SPECT study.

Research on the effects of repeated opioid use on striatal dopamine transporters has yielded inconsistent results, possibly confounded by a history of methamphetamine or methadone exposure in opioid-dependent individuals. Previous studies have shown that striatal dopamine transporter density is positively correlated with the cognitive performance of healthy volunteers. This study aimed to investigate changes in striatal dopamine transporter density and their functional significance in opioid-dependent individuals. Single-photon emission computed tomography with [(99m) Tc]TRODAT-1 as a ligand was used to measure striatal dopamine transporter levels in 20 opioid-dependent individuals and 20 age- and sex-matched healthy controls. Opioid-dependent individuals had no history of methamphetamine or methadone use. The Wisconsin Card Sorting Test (WCST) was performed to assess neurocognitive function. We found that compared with healthy controls, opioid-dependent individuals showed a significant reduction in striatal dopamine transporter density. They also showed poorer performance on the WCST in terms of the trials administered, total errors, perseverative responses, perseverative errors, and non-perseverative errors. Striatal dopamine transporter levels negatively correlated with non-perseverative errors not only in opioid-dependent individuals but also in healthy controls. These findings suggest that in human, repeated opioid exposure reduces striatal dopamine transporter density, which can be associated with non-perseverative errors. Non-perseverative errors may be one of the more sensitive parameters in WCST to identify working memory deficits associated with striatal dopamine transporter reduction. Moreover, we suggest that whether opioid-associated neurotoxicity is reversible depends on the brain region.

Reduced Dopamine Transporter Availability and Neurocognitive Deficits in Male Patients with Alcohol Dependence.

Dopamine plays an important role in the development of alcohol dependence, cognitive dysfunction, and is regulated via dopamine transporter activity. Although dopamine transporter activity is critically involved in alcohol dependence, studies observing this relationship are limited. Thus the current study examined whether dopamine transporter availability is associated with developing of alcohol dependence and cognitive dysfunction. Brain imaging with 99mTc-TRODAT-1 as a ligand was used to measure dopamine transporter availability among 26 male patients with pure alcohol dependence and 22 age- and sex- matched healthy volunteers. The Wisconsin Card Sorting Test (WCST) and Tridimensional Personality Questionnaire (TPQ) were administered to assess neurocognitive functioning and personality traits, respectively. Compared to healthy controls, patients with alcohol dependence showed a significant reduction in dopamine transporter availability (p < 0.001), as well as diminished performance on the WCST (p < 0.001). Dopamine transporter availability was negatively correlated with both total and perseverative WCST errors among healthy controls, but only patients with alcohol dependence showed a positive correlation between dopamine transporter availability and a harm avoidance personality profile. Thus, reductions in dopamine transporter availability may play a pathophysiological role in the development of pure alcohol dependence, given its association with neurocognitive deficits. Moreover, personality may influence the development of pure alcohol dependence; however, additional clinical subgroups should be examined to confirm this possibility.

Suicidal ideation modulates the reduction in serotonin transporter availability in male military conscripts with major depression: A 4-[18F]-ADAM PET study.

OBJECTIVES: Suicide is an important issue in the military service, since it can influence military morale and create dangerous situations for other personnel. The serotonin transporter (SERT) has been suggested to be involved in the pathophysiology of depression and suicidal behaviours. The aims of this study were to examine whether the brain SERT availability differs between military conscripts with depression and control subjects, and whether suicidal ideation is correlated with SERT availability. METHODS: We used N,N-dimethyl-2-(2-amino-4-[(18)F]-fluorophenylthio)benzylamine (4-[(18)F]-ADAM) as a radioligand for positron emission tomography (PET) imaging. All participants completed the Hamilton Depression Rating Scale and Beck Scale for Suicide Ideation (BSS) prior to PET imaging. RESULTS: The effect of major depression and BSS scores had an interaction on SERT availability. After adjusting for the BSS score, subjects with depression had lower SERT availability than control subjects (F1,17 = 23.85, P < 0.001). A positive correlation between SERT availability and BSS scores was observed in the depression group (F1,8 = 30.67, P = 0.001). The status of depression and intensity of suicidal ideation exert opposite effects on SERT availability. CONCLUSIONS: The extent of suicidal ideation may moderate the reduction effect in SERT binding observed in major depression in male military conscripts.

Harm avoidance involved in mediating the association between nerve growth factor (NGF) gene polymorphisms and antidepressant efficacy in patients with major depressive disorder.

BACKGROUND: Antidepressants have variable efficacies in subjects with major depressive disorder (MDD). Nerve growth factor (NGF) has been suggested to play an important role in the pathogenesis of depressive symptoms and the response to antidepressant therapy. The aim of this study was to examine whether NGF gene polymorphisms are associated with the antidepressant therapeutic efficacy in subjects with MDD. METHODS: A naturalistic follow-up study was carried out on 557 subjects with MDD. Of the enrolled patients, 304 completed the 8-week open-label antidepressant treatment. Seven single-nucleotide polymorphisms (SNPs) of the NGF gene were genotyped. The 21-item Hamilton Depression Rating Scale was used to assess depressive severity from baseline to endpoint. Tridimensional Personality Questionnaire was used to assess baseline personality traits. Single marker and haplotype analyses were conducted. Binary logistic regression was used to calculate odds ratios of remission. Structural equation modeling was used to analyze the predicted mediation effect. RESULTS: A significant difference in genotype frequencies between remitters and non-remitters was observed in three NGF SNPs (rs12760036, rs7523654, and rs17033692). The haplotype analysis revealed that the CCC haplotype (rs2254527-rs6678788-rs12760036) was associated with a higher remission rate, while the CCA haplotype was associated with a lower remission rate. The harm avoidance psychological factor partially mediated the effect of NGF variants on antidepressant efficacy. LIMITATIONS: The selected SNPs may not cover whole NGF gene. CONCLUSIONS: NGF variants are associated with remission rates after 8-week antidepressant treatment, and harm avoidance partially mediated the effect of NGF variants on treatment outcomes.