Chih-Sung Liang

DRD3 variation associates with early-onset heroin dependence, but not specific personality traits

Dopamine D3 receptor-mediated pathways are involved in the mechanism of addiction, and genetic factors play a role in the vulnerability to heroin dependence. The aim of this study was to examine whether the corresponding gene, DRD3, is associated with the development of heroin dependence and specific personality traits in HD patients. Eight polymorphisms in DRD3 were analyzed in 1067 unrelated Han Chinese subjects (566 heroin dependence patients and 501 controls). All participants were screened using the same assessment tool and all patients met the criteria for heroin dependence. A Tridimensional Personality Questionnaire was used to assess personality traits in 276 heroin dependence patients. In addition, heroin dependence patients were divided into 4 clinical subgroups based on age-of-onset and family history of substance abuse, to reduce the clinical heterogeneity. The rs6280 and rs9825563 variants showed association with the development of early-onset heroin dependence. The GTA haplotype frequency in the block (rs324029, rs6280, rs9825563) was significantly associated with early-onset heroin dependence (p=0.003). However, these significant associations were weaker after Bonferronis correction. In addition, these DRD3 polymorphisms did not influence novelty seeking and harm avoidance scores in HD patients. DRD3 is possibly a genetic factor in the development of early-onset heroin dependence, but is not associated with specific personality traits in these patients among the Han Chinese population.

A shift toward T helper 2 responses and an increase in modulators of innate immunity in depressed patients treated with escitalopram

Depression is hypothesized to involve inflammatory processes, and identifying the key cytokines targeted by antidepressant drugs is critical for tailoring treatment to specific cases. However, investigating a limited number of cytokines at one time cannot provide a broad picture of antidepressant-associated immunomodulation. Cytokines act in a network where one could demonstrate pleiotropism, redundancy, synergy, and antagonism with other cytokine functions. This study was aimed at determining whether escitalopram functions as an anti-inflammatory agent and, if so, how it influences cytokine networks. A total of 24 healthy controls and 26 patients with clinical depression requiring inpatient treatment were recruited. A multiplex assay, an efficient tool to simultaneously measure 27 cytokines, was applied in patients with depression before and after 4-week escitalopram treatment. Healthy controls did not take escitalopram and completed cytokine analyses once. We demonstrated that escitalopram increased the levels of interleukin (IL)-1 receptor antagonist and IL-2. Moreover, escitalopram contributed to a shift toward T helper 2 responses and an increase in modulators of innate immunity, leading to a decrease of immune system activation, both innate and adaptive. We suggest that escitalopram modulates the balance of IL-1 and IL-1 receptor antagonist and improves the function and number of T regulatory cells. However, diverse conclusions could be drawn if only a few cytokines were assessed or different significance levels were used. Further studies should investigate a wide range of cytokines in a reliable and valid way, which is key to disentangling the effects of different antidepressants on inflammatory processes.

Reactive heart rate variability in male patients with first-episode major depressive disorder

OBJECTIVEnThe association between cardiovascular reactivity and major depressive disorder (MDD) remains unclear. This study aimed to examine this association via reactive heart rate variability (HRV) in a well-diagnosed first-episode MDD group and a control group.nnnMETHODSnA total of 160 physically healthy, drug-naive patients presenting with their first-episode MDD and 50 healthy controls were recruited. All participants underwent a 5-min electrocardiography at rest and during a mental arithmetic task. Depression severity was assessed using the Beck Depression Inventory II (BDI).nnnRESULTSnHRV measures that showed between-group differences at rest did not reached significance during mental stress. In contrast, HRV measures that revealed between-group differences during stress did not reach significance at rest. In response to mental stress, HRV measures did not significantly change in both group. However, LF and HF in response to stress were different between groups. Patients with MDD revealed an increasing trend in HF and a decreasing trend in LF; conversely, healthy controls had a decreasing trend in HF and an increasing trend in LF. BDI scores correlated with changes in heart rate in the control group.nnnCONCLUSIONSnThe fundamental change to reactive HRV in patients with first-episode MDD appears qualitative, not quantitative. A distinctly reverse trend in reactive HRV measures were evident between these two groups. Moreover, patients with MDD showed entirely distinct changes in reactive HRV from those in resting HRV. We suggest that in patients with MDD, autonomic system shifts to sympathetic dominance at rest but toward parasympathetic dominance in response to stress.

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 [99mTc]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.

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-[18F]-fluorophenylthio)benzylamine (4-[18F]-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.

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.

SLC6A2 variants may predict remission from major depression after venlafaxine treatment in Han Chinese population

OBJECTIVEnVenlafaxine, an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNRI) type, is used to treat patients with major depressive disorder (MDD). Much evidence suggests that genetic polymorphisms may modulate serotonergic and noradrenergic function, thereby affecting the treatment efficacy of venlafaxine. The aim of this study was to examine whether polymorphisms in the norepinephrine transporter gene (SLC6A2) associate with remission after venlafaxine treatment for MDD.nnnMETHODnAn 8-week naturalistic treatment study with venlafaxine was carried out in 243 Han Chinese patients with MDD. The patients were screened for seven single-nucleotide polymorphisms of the SLC6A2 gene. Of the enrolled patients, 161 completed the 8-week treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was used to assess the improvement of depressive symptoms in each subject from baseline to the endpoint. For better presentation of time-course change of remission status, a Cox regression analysis for remission incidence during the 8-week treatment was conducted.nnnRESULTSnBetween remitters and non-remitters, significant differences in genotype frequencies were observed in five of the investigated SLC6A2 variants (rs28386840, rs1532701, rs40434, rs13333066, rs187714). GCG haplotype (rs40434 - rs13333066 - rs187714) in the SLC6A2 gene showed a association with non-remission. A Cox regression analysis for remission incidence during the 8-week treatment course significantly depends on SLC6A2 variants (rs28386840, rs40434, and rs187714).nnnCONCLUSIONnOur results suggest that the variation of the SLC6A2 gene is associated with treatment remission after venlafaxine in patients with MDD.

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

ABSTRACT 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. Cloningers 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. Graphical abstract Figure. No caption available. HighlightsHeroin users show high novelty seeking, reduced striatal DAT, and poor cognitive flexibility.In heroin users, the striatal DAT availability is linearly linked to cognitive flexibility.In heroin users, the striatal DAT availability is nonlinearly linked to novelty seeking.An inverted‐U‐shaped relationship exists between novelty seeking and DAT in heroin users.

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

ABSTRACT 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. HIGHLIGHTSThe minor C allele of rs2234918 in OPRD1 is considered a risk allele for heroin dependence in Han Chinese.Patients with heroin dependence sustained more negative recent events and more severe life stress than controls.The polymorphism of OPRD1 rs2236857 may affect the response to life stress in patients with heroin dependence.

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-1β) 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-1β 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.