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.

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.

Disproportionate Reduction of Serotonin Transporter May Predict the Response and Adherence to Antidepressants in Patients with Major Depressive Disorder: A Positron Emission Tomography Study with 4-[18F]-ADAM.

BACKGROUND: Many lines of evidence suggest the role of serotonin transporter (SERT)-mediated reuptake of serotonin in the pathophysiology and treatment of major depressive disorder (MDD). This study aimed to examine whether the pretreatment of SERT binding potential or SERT binding ratio between terminal projection regions relative to the midbrain raphe nuclei was associated with treatment outcomes to SERT-targeted antidepressants. METHODS: We recruited 39 antidepressant-naïve patients with MDD and 39 heathy controls. Positron emission tomography with N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) was used to measure in vivo SERT availability prior to antidepressant treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was use to assess the severity of depression from baseline to week 6. All the patients with MDD had HDRS scores of 18 or more. RESULTS: Pretreatment SERT binding in the thalamus and striatum positively correlated with an early reduction in HDRS scores at week 3. Nonresponders and dropout patients showed a proportionate reduction in SERT binding in the terminal projection regions and midbrain compared to healthy controls. In contrast, a disproportionate reduction in SERT binding in the terminal projection regions relative to midbrain was observed in responders. CONCLUSIONS: The results of this study suggested that a disproportionate reduction in SERT binding between terminal projection regions and midbrain may predict better treatment outcomes in patients with MDD.

Dopamine transporter gene may be associated with bipolar disorder and its personality traits.

Dopamine transporter and its genetic factors have been suggested to play a critical role in the development of bipolar disorder (BPD). However, the importance of the dopamine transporter gene (DAT1) in the pathogenesis of BPD remains unclear. The aims of this study were to assess 18 polymorphisms of the DAT1 gene to determine whether this gene is associated with BPD and whether it influences personality traits of patients with BPD. DAT1 polymorphisms were analyzed in 492 BPD (374 BPDI and 118 BPDII) patients and 436 controls. All participants were screened using the same assessment tool, and all met the criteria for BPD. The Tridimensional Personality Questionnaire was used to assess personality traits in both patients and controls. Several polymorphisms had a weak association with BPD, including rs2550948, rs2652511, and rs2975226 in allele distribution analysis (P < 0.05). Furthermore, the promoter G-A-C-G haplotype (rs6350-rs2975226-rs2652511-rs6413429) was over-represented in the BPD patients compared to the controls (P = 0.007). In personality assessment, the BPDII patients had the highest harm avoidance score, followed by the BPDI patients and controls (P = 3.7 × 10(-32)). In addition, a significant association between rs40184 and harm avoidance was found in the patients with BPD. The DAT1 promoter may be associated with vulnerabilities in BPD. The BPD patients had a higher rate of harm avoidance personality traits than the controls, and DAT1 variants may influence personality traits in patients with BPD.

Incongruent reduction of serotonin transporter associated with suicide attempts in patients with major depressive disorder: a positron emission tomography study with 4-[18F]-ADAM.

BACKGROUND: Much evidence supports the role of the serotonin transporter (SERT) in the pathophysiology and pharmacotherapy of major depressive disorder (MDD) and suicidal behaviors. METHODS: In this study, we recruited 17 antidepressant-naïve patients with MDD and 17 age- and gender-matched healthy controls. SERT availability was measured in vivo with N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) positron emission tomography (PET) imaging. The 21-item Hamilton Depression Rating Scale (HDRS) and Beck Scale for Suicide Ideation were used to assess the severity of depression and the intent of suicide ideation prior to PET imaging. All subjects with MDD were in a current state of depression with HDRS scores ≧18. Subjects who attempted suicide within two weeks of the study onset were recruited in the depressed suicidal group (n = 8). Subjects with MDD who denied any prior suicide attempt were recruited into the depressed non-suicidal group (n = 9). RESULTS: A significant reduction of SERT availability in the midbrain, thalamus, and striatum was noted in the MDD group relative to the control group (Bonferroni-adjusted p-value < 0.05). Moreover, this effect was more pronounced in the depressed suicidal group compared to the control group (Bonferroni-adjusted p-value < 0.01). Relative to both the depressed non-suicidal and control groups, the depressed suicidal group showed an increased prefrontal cortex (PFC)/midbrain SERT binding ratio (Bonferroni-adjusted p-value < 0.01). CONCLUSIONS: This study suggests an incongruent reduction of PFC SERT binding relative to the midbrain might discriminate between depressed suicide attempters and non-attempters in patients with MDD and may be involved in the pathophysiology of suicide behaviors.

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.

A possible association of the norepinephrine transporter gene in the development of heroin dependence in Han Chinese.

OBJECTIVE: Noradrenergic pathways have been suggested to play a crucial role in the motivation-reward system of heroin dependence (HD), but so far, the role of the human norepinephrine transporter (NET; SLC6A2) gene in the pathogenesis of HD has never been investigated. The purpose of this study was to examine whether the NET gene is associated with the development of HD, and whether the NET gene influences specific personality traits. METHODS: Twelve single-nucleotide polymorphisms of the NET gene were analyzed in a case-control study of 965 Han Chinese participants (603 patients and 362 controls). All participants were screened using a Chinese version of the modified Schedule of Affective Disorder and Schizophrenia-Lifetime and all patients met the criteria for HD. A Chinese version of the Tridimensional Personality Questionnaire was used to assess personality traits and examine the association between specific personality traits and NET polymorphisms. RESULTS: No statistically significant differences in allele or genotype frequencies were observed in any of the investigated NET variants between HD patients and controls. After logistic regression analyses, no statistically significant effect of NET variants in the development of HD was found. In haplotype analysis, the frequency of AATA haplotype in rs1532701-rs40434-rs13333066-rs187714 was significantly different between HD patients and controls. These NET polymorphisms did not influence novelty seeking and harm avoidance scores. CONCLUSION: This study suggests that the NET gene may be associated with the development of HD, but not associated with specific personality traits among Han Chinese.

Low-Dose Lurasidone-Induced Polydipsia Complicated by Hyponatremia in a Patient With Bipolar Disorder.

OBJECTIVE: Atypical antipsychotic-induced hyponatremia has been reported in patients with psychiatric disorders. To date, hyponatremia due to lurasidone, an atypical antipsychotic approved for the treatment of schizophrenia and bipolar depression, has never been reported. CASE REPORT: A female patient with bipolar depression and a history of subdural hematoma experienced a rapid onset of hyponatremia after the initiation of low-dose lurasidone. The hyponatremia worsened after the dose of lurasidone was increased and resolved only after lurasidone was ceased. According to the Naranjo Adverse Drug Reaction Probability Scale, this case report scores 6 as a possible drug reaction between lurasidone and hyponatremia. RESULTS: Based on laboratory results, the syndrome of inappropriate antidiuretic hormone secretion and thyroid or adrenal dysfunction as differential diagnoses were excluded. Lurasidone-induced polydipsia complicated by hyponatremia was confirmed. Lurasidone was subsequently discontinued. The sodium level returned to normal within 1 week without any sodium supplementation. CONCLUSIONS: This case report highlighted that low-dose lurasidone may induce polydipsia complicated by hyponatremia. Physicians should be aware of the adverse reactions of hyponatremia associated with lurasidone, particularly in patients with a history of intracranial hemorrhage.

Dose-Dependent Effects of Lithium Treatment on the Aggravation of Antipsychotic-Induced Pisa Syndrome.

Pisa syndrome (PS) is a rare lateral truncal dystonia that is related to dopamine-acetylcholine imbalances, and most cases develop during antipsychotic treatment. Here, we report a case of PS that developed during switching to new antipsychotics and titrating lithium, and PS was aggravated when the lithium dose was increased. Truncal deviation was not relieved with switching back to prior antipsychotics or by discontinuation of all antipsychotics. Pisa syndrome resolved only after discontinuing the lithium treatment. This is the first report of dose-dependent effects of lithium treatment on the aggravation of PS, which may be related to dose-related effects on dopaminergic and cholinergic transmission.

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.

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.

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.