The Journal of neuropsychiatry and clinical neurosciences
... Ahmad R. Hariri, Terry E. Goldberg, * Venkata S. Mattay, * Bhaskar S. Kolachana, Joseph H. Ca... more ... Ahmad R. Hariri, Terry E. Goldberg, * Venkata S. Mattay, * Bhaskar S. Kolachana, Joseph H. Callicott, Michael F. Egan, and Daniel R ... Furthermore, all subjects underwent genotyping of the apolipoprotein (APO) E gene alleles, because the 4 allele has a dose-dependent effect ...
Milnacipran is a dual-action antidepressant which inhibits both serotonin and norepinephrine reup... more Milnacipran is a dual-action antidepressant which inhibits both serotonin and norepinephrine reuptake. To our knowledge, it has limited affinity for most monoamine neurotransmitter receptors. With limited pharmacokinetic interaction with the cytochrome 450 system, milnacipran may have a low risk in drug interaction. The present study compares milnacipran with paroxetine, a selective serotonin reuptake inhibitor (SSRI) and which has been used
Dopamine plays an important role in the development of alcohol dependence, cognitive dysfunction,... more 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.
Objective: The purpose of this study was to explore the effects of a smoking cessation program in... more Objective: The purpose of this study was to explore the effects of a smoking cessation program in the change of schizophrenic patients' health beliefs(perception of susceptibility of smoking-induced diseases, sever- ity of smoking-induced diseases, benefits of quit-smoking, and perception of disturbance of quit-smoking). Methods: This study was an interrupted time series with non-equivalent control group design. Subjects were divided into
Low-dose memantine might have anti-inflammatory and neurotrophic effects mechanistically remote f... more Low-dose memantine might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. We investigated whether add-on memantine reduced cytokine levels and benefitted patients with opioid dependence undergoing methadone maintenance therapy (MMT) in a randomized, double-blind, controlled 12-week study. Patients were randomly assigned to a group: Memantine (5 mg/day) (n = 53) or Placebo (n = 75). The methadone dose required and retention in treatment were monitored. Plasma tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-6, IL-8, transforming growth factor (TGF)-β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. General linear mixed models were used to examine therapeutic effect. After 12 weeks, Memantine-group required a somewhat lower methadone dose than did Placebo-group (P = 0.039). They also had significantly lower plasma TNF-α and significantly higher TGF-β1 levels. We pr...
A high prevalence rate of bipolar disorder (BP) comorbid with alcohol dependence (AD) (BP+AD) in ... more A high prevalence rate of bipolar disorder (BP) comorbid with alcohol dependence (AD) (BP+AD) in Western patients with BP has been reported, but whether this is true for Han Chinese with BP is uncertain. We explored the prevalence of BP+AD in a Han Chinese population with BP, and investigated the effect of alcohol-metabolizing genotypes on bipolar I disorder (BP-I) + AD and bipolar II disorder (BP-II) + AD. Healthy controls (HCs) (n = 672) and 18- to 65-year-old patients with BP (BP-I: n = 530; BP-II: n = 788) were recruited. Patients with any other major or minor mental illnesses, neurological disorders, or organic mental disorders were excluded. A polymerase chain reaction and restriction fragment length polymorphism analysis was used to determine genotypes for alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2), two alcohol-metabolizing enzymes. AD comorbidity rates were 11.7% with BP-I and 17.1% with BP-II. Significantly fewer patients with BP not comorbid with...
Background: Antidepressants have variable efficacies in subjects with major depressive disorder (... more 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.
An important interaction between opioid and dopamine systems has been indicated, and using opioid... more An important interaction between opioid and dopamine systems has been indicated, and using opioids may negatively affect cognitive functioning. Memantine, a medication for Alzheimer's disease, increasingly is being used for several disorders and maybe important for cognitive improvement. Opioid-dependent patients undergoing methadone-maintenance-therapy (MMT) and healthy controls (HCs) were recruited. Patients randomly assigned to the experimental (5 mg/day memantine (MMT1M) or placebo (MMT1P) group: 57 in MMT1M, 77 in MMT1P. Those completed the cognitive tasks at the baseline and after the 12-week treatment were analyzed. Thirty-seven age-and gender-matched HCs, and 42 MMT1P and 39 MMT1M patients were compared. The dropout rates were 49.4% in the MMT1P and 26.3% in the MMT1M. Both patient groups' cognitive performances were significantly worse than that of the HCs. After the treatment, both patient groups showed improved cognitive performance. We also found an interaction between the patient groups and time which indicated that the MMT1M group's post-treatment improvement was better than that of the MMT1P group. Memantine, previously reported as neuroprotective may attenuate chronic opioid-dependence-induced cognitive decline. Using such low dose of memantine as adjuvant treatment for improving cognitive performance in opioid dependents; the dose of memantine might be a worthy topic in future studies. C hronic psychoactive substance users are associated with a wide variety of neuropsychological impairments, although there is no consensus on whether the impairment are permanent or temporary 1,2 . The chronic opioid users are associated with dysfunctional frontal networks 3 , which lead to impaired executive function and attention 4 . In addition, Baldacchnio et al. (2012) 5 reviewed 52 articles relative to studying on how opioid affects neuropsychological function in adult patients with chronic opioid use/dependence using metaanalysis. Their analyses suggested that chronic opioid exposure is associated with impairment across variety of neuropsychological domains, including cognitive flexibility.
The purpose of this study was to determine the effectiveness of nicotine-patch therapy for smokin... more The purpose of this study was to determine the effectiveness of nicotine-patch therapy for smoking cessation in patients with schizophrenia. This was a longitudinal study and sixty-eight schizophrenic patients were assigned to 8 weeks of a nicotine-patch therapy program or a control group. The generalized estimating equation analysis revealed that there were significant reductions in the subjects' nicotine dependence (Fagerstrom Tolerance Questionnaire), the number of cigarettes per day, and CO levels over an 8-week period of nicotine-patch therapy and 3-month follow-up. The point-prevalence rates of abstinence from smoking were an abstinence of 26.9% at 8 weeks and 26.9% at a 3-month follow-up. At the 3-month follow-up, the rate of continuous smoking abstinence in the nicotine-patch group was 23.1%.
Although the physiological mechanisms contributing to the development of major depression remain ... more Although the physiological mechanisms contributing to the development of major depression remain unclear, several lines of evidence suggest that the catecholaminergic system involving the norepinephrine transporter (NET) is implicated in the etiology of major depression. This study aims to determine whether major depression is associated with the NET gene in a Han Chinese population. We analyzed the NET promoter T-182C polymorphism and another silent polymorphism G1287A in exon 9 of the NET gene with a polymerase chain reaction (PCR)-based method in 216 patients with major depression and 210 unrelated, age-and sex-matched healthy control subjects. We interviewed all subjects with the Chinese Version of the Modified Schedule of Affective Disorders and Schizophrenia-Lifetime; major depressive disorder was diagnosed according to DSM-IV criteria. In addition, to reduce the clinical heterogeneity, we performed a subtype analysis with clinically important variables, such as family history...
Decreased heart rate variability (HRV) has been reported in generalized anxiety disorder (GAD), b... more Decreased heart rate variability (HRV) has been reported in generalized anxiety disorder (GAD), but the results are mixed. Little is known about the impact of comorbid major depression (MD) on HRV in GAD patients. Both issues necessitate further investigation. Twenty unmedicated, physically healthy GAD patients, 20 GAD patients with a secondary diagnosis of MD, 40 MD patients and 60 matched controls were recruited. We used the Hamilton Anxiety Rating Scale and the Hamilton Depression Rating Scale to assess anxiety and depression severity, respectively. Cardiac autonomic function was evaluated by measuring HRV parameters. Frequency-domain indices of HRV were obtained. Three patient groups had more anxiety and depression symptoms than control subjects, but heart rates (HRs) were significantly elevated only in GAD patients with comorbid depression. Relative to controls, GAD patients had reduced HRV while GAD patients with comorbid depression displayed the greatest reductions in HRV amo...
Several genes that are involved in the regulation of circadian rhythms are implicated in the susc... more Several genes that are involved in the regulation of circadian rhythms are implicated in the susceptibility to bipolar disorder (BD). The current study aimed to investigate the relationships between genetic variants in NR1D1 RORA, and RORB genes and BD in the Han Chinese population. We conducted a case-control genetic association study with two samples of BD patients and healthy controls. Sample I consisted of 280 BD patients and 200 controls. Sample II consisted of 448 BD patients and 1770 healthy controls. 27 single nucleotide polymorphisms in the NR1D1, RORA, and RORB genes were genotyped using GoldenGate VeraCode assays in sample I, and 492 markers in the three genes were genotyped using Affymetrix Genome-Wide CHB Array in sample II. Single marker and genebased association analyses were performed using PLINK. A combined p-value for the joining effects of all markers within a gene was calculated using the rank truncated product method. Multifactor dimensionality reduction (MDR) method was also applied to test genegene interactions in sample I. All markers were in Hardy-Weinberg equilibrium (P>0.001). In sample I, the associations with BD were observed for rs4774388 in RORA (OR = 1.53, empirical p-value, P = 0.024), and rs1327836 in RORB (OR = 1.75, P = 0.003). In Sample II, there were 45 SNPs showed associations with BD, and the most significant marker in RORA was rs11639084 (OR = 0.69, P = 0.002), and in RORB was rs17611535 (OR = 3.15, P = 0.027). A combined p-value of 1.6×10−6, 0.7, and 1.0 was obtained for RORA, RORB and NR1D1, respectively, indicting a strong association for RORA with the risk of developing BD. A four way interaction was found among markers in NR1D1, RORA, and RORB with the testing accuracy 53.25% and a cross-validation consistency of 8 out of 10. In sample II, 45 markers had empirical p-values less than 0.05. The most significant markers in RORA and RORB genes were rs11639084 (OR = 0.69, P = 0.002), and rs17611535 (OR = 3.15, P = 0.027), respectively. Gene-based association was significant for RORA gene (P = 0.0007).
The deduced memory consolidation and reconsolidation phases are sensitive to similar amnesic and ... more The deduced memory consolidation and reconsolidation phases are sensitive to similar amnesic and memory-enhancing treatment. Electroconvulsive stimulus has been well known to impair memory consolidation. Therefore, we hypothesized that electroconvulsive stimulus might disrupt reconsolidation for conditioning-established memories. Delivery of a 200-msec electroconvulsive stimulus (500 V, 25 mA) between mouse pinnas immediately after recall of the cocaine-induced conditioned place preference (CPP) impaired the reconsolidation and subsequent expression of this memory. In contrast, the electroconvulsive stimulus (500 V, 25 mA, lasting for 200 ms) did not affect subsequent cocaine-induced CPP performance when the recall procedure was omitted. Systemic pentobarbital injection immediately after the CPP test did not affect subsequent cocaine-induced CPP. Interestingly, several regimens of electroconvulsive stimulus given immediately after the recall of cocaine-induced CPP did not affect sub...
Bipolar II disorder (BP-II), characterized by recurrent dysregulation of mood, is a serious and c... more Bipolar II disorder (BP-II), characterized by recurrent dysregulation of mood, is a serious and chronic psychiatric illness. However, BP-II is commonly under-recognized, even in psychiatric settings. Because dopaminergic disturbance is thought to be involved in the development of bipolar disorder (BPD), it seems essential to investigate dopamine-related genes like the catechol-O-methyltransferase (COMT) gene, which are involved in dopamine metabolism, and the methylenetetrahydrofolate reductase (MTHFR) gene, which may affect COMT methylation and COMT function. The current study examined the association and interaction of the COMT Val158Met and MTHFR C677T variants with BP-II. Nine hundred seventy-eight participants were recruited: 531 with BP-II and 447 healthy controls. The genotypes of the COMT and MTHFR polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism analysis. Logistic regression analysis showed a significant interaction ef...
One of the consequences of heroin dependency is a huge expenditure on drugs. This underlying econ... more One of the consequences of heroin dependency is a huge expenditure on drugs. This underlying economic expense may be a grave burden for heroin users and may lead to criminal behavior, which is a huge cost to society. The neuropsychological mechanism related to heroin purchase remains unclear. Based on recent findings and the established dopamine hypothesis of addiction, we speculated that expenditure on heroin and central dopamine activity may be associated. A total of 21 heroin users were enrolled in this study. The annual expenditure on heroin was assessed, and the availability of the dopamine transporter (DAT) was assessed by single-photon emission computed tomography (SPECT) using [(99m)TC]TRODAT-1. Parametric and nonparametric correlation analyses indicated that annual expenditure on heroin was significantly and negatively correlated with the availability of striatal DAT. After adjustment for potential confounders, the predictive power of DAT availability was significant. Striatal dopamine function may be associated with opioid purchasing behavior among heroin users, and the cycle of spiraling dysfunction in the dopamine reward system could play a role in this association.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2011
Studies exploring neuropsychological functions of bipolar disorder (BP) specifically include pati... more Studies exploring neuropsychological functions of bipolar disorder (BP) specifically include patients comorbid with alcohol abuse (AB), alcohol dependence (AD), or both (AB/AD). Contradictory assessments of neuropsychological impairment may be caused by not excluding the confounding effects of comorbid AB/AD. Most of the literature discusses BP without subtyping, which overlooks that BP-II may be a valid diagnosis different from BP-I. Because neuropsychological functions are involved in overall BP-II outcomes, we hypothesized that the neuropsychological functions of patients with BP-II comorbid with AD (BP(+AD)) are significantly different from and more impaired than those of patients with BP-II not comorbid with AD (BP(-AD)). Using DSM-IV criteria, the study included 69 patients with BP-II (19 with BP(+AD); 28 with BP(-AD)) and 22 healthy controls compared using a battery of neuropsychological tests that assessed memory, psychomotor speed, and certain aspects of frontal executive function. All BP-II patients were in an inter-episode period (a period of remission between states of mania, hypomania, and depression). BP(+AD) patients had lower scores than did BP(-AD) patients and controls in verbal memory, visual memory, attention, psychomotor speed, and executive function. Working memory was poorer for BP(+AD) than BP(-AD) patients and for both BP groups than for controls. BP(+AD) patients manifested wide neuropsychological dysfunctions, and BP(-AD) patients showed a reduction in working memory, which suggested that working memory might be related to a history of BP-II. Neuropsychological dysfunctions seemed more strongly associated with AB/AD than with BP-II in inter-episode periods.
BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and m... more BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency.
A substantial amount of evidence suggests that dysfunction of the dopamine transporter may be inv... more A substantial amount of evidence suggests that dysfunction of the dopamine transporter may be involved in the pathophysiology of amphetamine dependence (AD). The aim of this study was to examine whether the dopamine transporter gene (DAT1, SLC6A3) is associated with development of AD and whether this gene influences personality traits in patients with AD. Eighteen polymorphisms of the DAT1 gene were analyzed in a case-control study that included 909 Han Chinese men (568 patients with AD and 341 control subjects). The patients fulfilled the DSM-IV-TR criteria for AD. The Tridimensional Personality Questionnaire (TPQ) was used to assess personality traits and to examine the association between these traits and DAT1 gene variants. A weak association was found between the rs27072 polymorphism and development of AD, but these borderline associations were unconfirmed by logistic regression and haplotype analysis. Although harm avoidance and novelty seeking scores were significantly higher in patients than in controls, DAT1 polymorphisms did not influence these scores. This study suggests that high harm avoidance and novelty seeking personality traits may be a risk factor for the development of AD. However, the DAT1 gene may not contribute to AD susceptibility and specific personality traits observed in AD among Han Chinese men.
Objective: Venlafaxine, an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNR... more Objective: Venlafaxine, 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. Method: An 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. Results: Between 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). Conclusion: Our results suggest that the variation of the SLC6A2 gene is associated with treatment remission after venlafaxine in patients with MDD.
The Journal of neuropsychiatry and clinical neurosciences
... Ahmad R. Hariri, Terry E. Goldberg, * Venkata S. Mattay, * Bhaskar S. Kolachana, Joseph H. Ca... more ... Ahmad R. Hariri, Terry E. Goldberg, * Venkata S. Mattay, * Bhaskar S. Kolachana, Joseph H. Callicott, Michael F. Egan, and Daniel R ... Furthermore, all subjects underwent genotyping of the apolipoprotein (APO) E gene alleles, because the 4 allele has a dose-dependent effect ...
Milnacipran is a dual-action antidepressant which inhibits both serotonin and norepinephrine reup... more Milnacipran is a dual-action antidepressant which inhibits both serotonin and norepinephrine reuptake. To our knowledge, it has limited affinity for most monoamine neurotransmitter receptors. With limited pharmacokinetic interaction with the cytochrome 450 system, milnacipran may have a low risk in drug interaction. The present study compares milnacipran with paroxetine, a selective serotonin reuptake inhibitor (SSRI) and which has been used
Dopamine plays an important role in the development of alcohol dependence, cognitive dysfunction,... more 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.
Objective: The purpose of this study was to explore the effects of a smoking cessation program in... more Objective: The purpose of this study was to explore the effects of a smoking cessation program in the change of schizophrenic patients' health beliefs(perception of susceptibility of smoking-induced diseases, sever- ity of smoking-induced diseases, benefits of quit-smoking, and perception of disturbance of quit-smoking). Methods: This study was an interrupted time series with non-equivalent control group design. Subjects were divided into
Low-dose memantine might have anti-inflammatory and neurotrophic effects mechanistically remote f... more Low-dose memantine might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. We investigated whether add-on memantine reduced cytokine levels and benefitted patients with opioid dependence undergoing methadone maintenance therapy (MMT) in a randomized, double-blind, controlled 12-week study. Patients were randomly assigned to a group: Memantine (5 mg/day) (n = 53) or Placebo (n = 75). The methadone dose required and retention in treatment were monitored. Plasma tumor necrosis factor (TNF)-α, C-reactive protein (CRP), interleukin (IL)-6, IL-8, transforming growth factor (TGF)-β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. General linear mixed models were used to examine therapeutic effect. After 12 weeks, Memantine-group required a somewhat lower methadone dose than did Placebo-group (P = 0.039). They also had significantly lower plasma TNF-α and significantly higher TGF-β1 levels. We pr...
A high prevalence rate of bipolar disorder (BP) comorbid with alcohol dependence (AD) (BP+AD) in ... more A high prevalence rate of bipolar disorder (BP) comorbid with alcohol dependence (AD) (BP+AD) in Western patients with BP has been reported, but whether this is true for Han Chinese with BP is uncertain. We explored the prevalence of BP+AD in a Han Chinese population with BP, and investigated the effect of alcohol-metabolizing genotypes on bipolar I disorder (BP-I) + AD and bipolar II disorder (BP-II) + AD. Healthy controls (HCs) (n = 672) and 18- to 65-year-old patients with BP (BP-I: n = 530; BP-II: n = 788) were recruited. Patients with any other major or minor mental illnesses, neurological disorders, or organic mental disorders were excluded. A polymerase chain reaction and restriction fragment length polymorphism analysis was used to determine genotypes for alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2), two alcohol-metabolizing enzymes. AD comorbidity rates were 11.7% with BP-I and 17.1% with BP-II. Significantly fewer patients with BP not comorbid with...
Background: Antidepressants have variable efficacies in subjects with major depressive disorder (... more 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.
An important interaction between opioid and dopamine systems has been indicated, and using opioid... more An important interaction between opioid and dopamine systems has been indicated, and using opioids may negatively affect cognitive functioning. Memantine, a medication for Alzheimer's disease, increasingly is being used for several disorders and maybe important for cognitive improvement. Opioid-dependent patients undergoing methadone-maintenance-therapy (MMT) and healthy controls (HCs) were recruited. Patients randomly assigned to the experimental (5 mg/day memantine (MMT1M) or placebo (MMT1P) group: 57 in MMT1M, 77 in MMT1P. Those completed the cognitive tasks at the baseline and after the 12-week treatment were analyzed. Thirty-seven age-and gender-matched HCs, and 42 MMT1P and 39 MMT1M patients were compared. The dropout rates were 49.4% in the MMT1P and 26.3% in the MMT1M. Both patient groups' cognitive performances were significantly worse than that of the HCs. After the treatment, both patient groups showed improved cognitive performance. We also found an interaction between the patient groups and time which indicated that the MMT1M group's post-treatment improvement was better than that of the MMT1P group. Memantine, previously reported as neuroprotective may attenuate chronic opioid-dependence-induced cognitive decline. Using such low dose of memantine as adjuvant treatment for improving cognitive performance in opioid dependents; the dose of memantine might be a worthy topic in future studies. C hronic psychoactive substance users are associated with a wide variety of neuropsychological impairments, although there is no consensus on whether the impairment are permanent or temporary 1,2 . The chronic opioid users are associated with dysfunctional frontal networks 3 , which lead to impaired executive function and attention 4 . In addition, Baldacchnio et al. (2012) 5 reviewed 52 articles relative to studying on how opioid affects neuropsychological function in adult patients with chronic opioid use/dependence using metaanalysis. Their analyses suggested that chronic opioid exposure is associated with impairment across variety of neuropsychological domains, including cognitive flexibility.
The purpose of this study was to determine the effectiveness of nicotine-patch therapy for smokin... more The purpose of this study was to determine the effectiveness of nicotine-patch therapy for smoking cessation in patients with schizophrenia. This was a longitudinal study and sixty-eight schizophrenic patients were assigned to 8 weeks of a nicotine-patch therapy program or a control group. The generalized estimating equation analysis revealed that there were significant reductions in the subjects' nicotine dependence (Fagerstrom Tolerance Questionnaire), the number of cigarettes per day, and CO levels over an 8-week period of nicotine-patch therapy and 3-month follow-up. The point-prevalence rates of abstinence from smoking were an abstinence of 26.9% at 8 weeks and 26.9% at a 3-month follow-up. At the 3-month follow-up, the rate of continuous smoking abstinence in the nicotine-patch group was 23.1%.
Although the physiological mechanisms contributing to the development of major depression remain ... more Although the physiological mechanisms contributing to the development of major depression remain unclear, several lines of evidence suggest that the catecholaminergic system involving the norepinephrine transporter (NET) is implicated in the etiology of major depression. This study aims to determine whether major depression is associated with the NET gene in a Han Chinese population. We analyzed the NET promoter T-182C polymorphism and another silent polymorphism G1287A in exon 9 of the NET gene with a polymerase chain reaction (PCR)-based method in 216 patients with major depression and 210 unrelated, age-and sex-matched healthy control subjects. We interviewed all subjects with the Chinese Version of the Modified Schedule of Affective Disorders and Schizophrenia-Lifetime; major depressive disorder was diagnosed according to DSM-IV criteria. In addition, to reduce the clinical heterogeneity, we performed a subtype analysis with clinically important variables, such as family history...
Decreased heart rate variability (HRV) has been reported in generalized anxiety disorder (GAD), b... more Decreased heart rate variability (HRV) has been reported in generalized anxiety disorder (GAD), but the results are mixed. Little is known about the impact of comorbid major depression (MD) on HRV in GAD patients. Both issues necessitate further investigation. Twenty unmedicated, physically healthy GAD patients, 20 GAD patients with a secondary diagnosis of MD, 40 MD patients and 60 matched controls were recruited. We used the Hamilton Anxiety Rating Scale and the Hamilton Depression Rating Scale to assess anxiety and depression severity, respectively. Cardiac autonomic function was evaluated by measuring HRV parameters. Frequency-domain indices of HRV were obtained. Three patient groups had more anxiety and depression symptoms than control subjects, but heart rates (HRs) were significantly elevated only in GAD patients with comorbid depression. Relative to controls, GAD patients had reduced HRV while GAD patients with comorbid depression displayed the greatest reductions in HRV amo...
Several genes that are involved in the regulation of circadian rhythms are implicated in the susc... more Several genes that are involved in the regulation of circadian rhythms are implicated in the susceptibility to bipolar disorder (BD). The current study aimed to investigate the relationships between genetic variants in NR1D1 RORA, and RORB genes and BD in the Han Chinese population. We conducted a case-control genetic association study with two samples of BD patients and healthy controls. Sample I consisted of 280 BD patients and 200 controls. Sample II consisted of 448 BD patients and 1770 healthy controls. 27 single nucleotide polymorphisms in the NR1D1, RORA, and RORB genes were genotyped using GoldenGate VeraCode assays in sample I, and 492 markers in the three genes were genotyped using Affymetrix Genome-Wide CHB Array in sample II. Single marker and genebased association analyses were performed using PLINK. A combined p-value for the joining effects of all markers within a gene was calculated using the rank truncated product method. Multifactor dimensionality reduction (MDR) method was also applied to test genegene interactions in sample I. All markers were in Hardy-Weinberg equilibrium (P>0.001). In sample I, the associations with BD were observed for rs4774388 in RORA (OR = 1.53, empirical p-value, P = 0.024), and rs1327836 in RORB (OR = 1.75, P = 0.003). In Sample II, there were 45 SNPs showed associations with BD, and the most significant marker in RORA was rs11639084 (OR = 0.69, P = 0.002), and in RORB was rs17611535 (OR = 3.15, P = 0.027). A combined p-value of 1.6×10−6, 0.7, and 1.0 was obtained for RORA, RORB and NR1D1, respectively, indicting a strong association for RORA with the risk of developing BD. A four way interaction was found among markers in NR1D1, RORA, and RORB with the testing accuracy 53.25% and a cross-validation consistency of 8 out of 10. In sample II, 45 markers had empirical p-values less than 0.05. The most significant markers in RORA and RORB genes were rs11639084 (OR = 0.69, P = 0.002), and rs17611535 (OR = 3.15, P = 0.027), respectively. Gene-based association was significant for RORA gene (P = 0.0007).
The deduced memory consolidation and reconsolidation phases are sensitive to similar amnesic and ... more The deduced memory consolidation and reconsolidation phases are sensitive to similar amnesic and memory-enhancing treatment. Electroconvulsive stimulus has been well known to impair memory consolidation. Therefore, we hypothesized that electroconvulsive stimulus might disrupt reconsolidation for conditioning-established memories. Delivery of a 200-msec electroconvulsive stimulus (500 V, 25 mA) between mouse pinnas immediately after recall of the cocaine-induced conditioned place preference (CPP) impaired the reconsolidation and subsequent expression of this memory. In contrast, the electroconvulsive stimulus (500 V, 25 mA, lasting for 200 ms) did not affect subsequent cocaine-induced CPP performance when the recall procedure was omitted. Systemic pentobarbital injection immediately after the CPP test did not affect subsequent cocaine-induced CPP. Interestingly, several regimens of electroconvulsive stimulus given immediately after the recall of cocaine-induced CPP did not affect sub...
Bipolar II disorder (BP-II), characterized by recurrent dysregulation of mood, is a serious and c... more Bipolar II disorder (BP-II), characterized by recurrent dysregulation of mood, is a serious and chronic psychiatric illness. However, BP-II is commonly under-recognized, even in psychiatric settings. Because dopaminergic disturbance is thought to be involved in the development of bipolar disorder (BPD), it seems essential to investigate dopamine-related genes like the catechol-O-methyltransferase (COMT) gene, which are involved in dopamine metabolism, and the methylenetetrahydrofolate reductase (MTHFR) gene, which may affect COMT methylation and COMT function. The current study examined the association and interaction of the COMT Val158Met and MTHFR C677T variants with BP-II. Nine hundred seventy-eight participants were recruited: 531 with BP-II and 447 healthy controls. The genotypes of the COMT and MTHFR polymorphisms were determined using a polymerase chain reaction-restriction fragment length polymorphism analysis. Logistic regression analysis showed a significant interaction ef...
One of the consequences of heroin dependency is a huge expenditure on drugs. This underlying econ... more One of the consequences of heroin dependency is a huge expenditure on drugs. This underlying economic expense may be a grave burden for heroin users and may lead to criminal behavior, which is a huge cost to society. The neuropsychological mechanism related to heroin purchase remains unclear. Based on recent findings and the established dopamine hypothesis of addiction, we speculated that expenditure on heroin and central dopamine activity may be associated. A total of 21 heroin users were enrolled in this study. The annual expenditure on heroin was assessed, and the availability of the dopamine transporter (DAT) was assessed by single-photon emission computed tomography (SPECT) using [(99m)TC]TRODAT-1. Parametric and nonparametric correlation analyses indicated that annual expenditure on heroin was significantly and negatively correlated with the availability of striatal DAT. After adjustment for potential confounders, the predictive power of DAT availability was significant. Striatal dopamine function may be associated with opioid purchasing behavior among heroin users, and the cycle of spiraling dysfunction in the dopamine reward system could play a role in this association.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2011
Studies exploring neuropsychological functions of bipolar disorder (BP) specifically include pati... more Studies exploring neuropsychological functions of bipolar disorder (BP) specifically include patients comorbid with alcohol abuse (AB), alcohol dependence (AD), or both (AB/AD). Contradictory assessments of neuropsychological impairment may be caused by not excluding the confounding effects of comorbid AB/AD. Most of the literature discusses BP without subtyping, which overlooks that BP-II may be a valid diagnosis different from BP-I. Because neuropsychological functions are involved in overall BP-II outcomes, we hypothesized that the neuropsychological functions of patients with BP-II comorbid with AD (BP(+AD)) are significantly different from and more impaired than those of patients with BP-II not comorbid with AD (BP(-AD)). Using DSM-IV criteria, the study included 69 patients with BP-II (19 with BP(+AD); 28 with BP(-AD)) and 22 healthy controls compared using a battery of neuropsychological tests that assessed memory, psychomotor speed, and certain aspects of frontal executive function. All BP-II patients were in an inter-episode period (a period of remission between states of mania, hypomania, and depression). BP(+AD) patients had lower scores than did BP(-AD) patients and controls in verbal memory, visual memory, attention, psychomotor speed, and executive function. Working memory was poorer for BP(+AD) than BP(-AD) patients and for both BP groups than for controls. BP(+AD) patients manifested wide neuropsychological dysfunctions, and BP(-AD) patients showed a reduction in working memory, which suggested that working memory might be related to a history of BP-II. Neuropsychological dysfunctions seemed more strongly associated with AB/AD than with BP-II in inter-episode periods.
BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and m... more BDNF and its gene polymorphism may be important in synaptic plasticity and neuron survival, and may become a key target in the physiopathology of long-term heroin use. Thus, we investigated the relationships between brain-derived neurotrophic factor (BDNF) plasma concentrations and the BDNF Val66Met nucleotide polymorphism (SNP) in heroin-dependent patients. The pretreatment expression levels of plasma BDNF and the BDNF Val66Met SNP in 172 heroin-dependent patients and 102 healthy controls were checked. BDNF levels were significantly lower in patients (F = 52.28, p < 0.0001), but the distribution of the SNP was not significantly different. Nor were plasma BDNF levels significantly different between Met/Met, Met/Val, and Val/Val carriers in each group, which indicated that the BDNF Val66Met SNP did not affect plasma BDNF levels in our participants. In heroin-dependent patients, plasma BDNF levels were negatively correlated with the length of heroin dependency. Long-term (>15 years) users had significantly lower plasma BDNF levels than did short-term (<5 years) users. We conclude that plasma BDNF concentration in habitual heroin users are not affected by BDNF Val66Met gene variants, but by the length of the heroin dependency.
A substantial amount of evidence suggests that dysfunction of the dopamine transporter may be inv... more A substantial amount of evidence suggests that dysfunction of the dopamine transporter may be involved in the pathophysiology of amphetamine dependence (AD). The aim of this study was to examine whether the dopamine transporter gene (DAT1, SLC6A3) is associated with development of AD and whether this gene influences personality traits in patients with AD. Eighteen polymorphisms of the DAT1 gene were analyzed in a case-control study that included 909 Han Chinese men (568 patients with AD and 341 control subjects). The patients fulfilled the DSM-IV-TR criteria for AD. The Tridimensional Personality Questionnaire (TPQ) was used to assess personality traits and to examine the association between these traits and DAT1 gene variants. A weak association was found between the rs27072 polymorphism and development of AD, but these borderline associations were unconfirmed by logistic regression and haplotype analysis. Although harm avoidance and novelty seeking scores were significantly higher in patients than in controls, DAT1 polymorphisms did not influence these scores. This study suggests that high harm avoidance and novelty seeking personality traits may be a risk factor for the development of AD. However, the DAT1 gene may not contribute to AD susceptibility and specific personality traits observed in AD among Han Chinese men.
Objective: Venlafaxine, an antidepressant of the serotonin-norepinephrine reuptake inhibitor (SNR... more Objective: Venlafaxine, 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. Method: An 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. Results: Between 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). Conclusion: Our results suggest that the variation of the SLC6A2 gene is associated with treatment remission after venlafaxine in patients with MDD.
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