Shih-Ku Lin

Pre-morbid characteristics and co-morbidity of methamphetamine users with and without psychosis.

BACKGROUNDnThe long-term use of methamphetamine (MAMP) can result in psychosis but it is not clear why some individuals develop psychotic symptoms, while others use MAMP regularly over long periods and remain unscathed. We set out to characterize MAMP users and to examine the relationship of pre-morbid personality, pre-morbid social function and other psychiatric disorders to MAMP psychosis.nnnMETHODnFour hundred and forty-five amphetamine users were recruited from a psychiatric hospital and a detention centre in Taipei, and were assessed with the Diagnostic Interview for Genetic Studies (DIGS). Their parents were interviewed with the Premorbid Schizoid and Schizotypal Traits (PSST) and the Premorbid Social Adjustment (PSA) schedules. Pre-morbid characteristics and psychiatric co-morbidity were compared between the MAMP users with a lifetime diagnosis of MAMP psychosis and those without.nnnRESULTSnThe MAMP users with psychosis presented a clinical picture which mimicked the positive symptoms of schizophrenia: 85% had auditory hallucinations; 71% persecutory delusions; 63% delusions of reference. Compared with their non-psychotic counterparts, these MAMP users were younger at first MAMP use, used larger amounts of MAMP, had a significantly higher mean PSST score, and higher rates of major depressive disorder, alcohol dependence and antisocial personality disorder.nnnCONCLUSIONSnEarlier and larger use of MAMP was associated with increased risk of psychosis. Our data are also compatible with the view that pre-morbid schizoid/schizotypal personality predisposes MAMP users to develop psychosis, and that the greater the personality vulnerability, the longer the psychosis will persist.

Genome-Wide Association for Methamphetamine Dependence : Convergent Results From 2 Samples

CONTEXTnWe can improve understanding of human methamphetamine dependence, and possibly our abilities to prevent and treat this devastating disorder, by identifying genes whose allelic variants predispose to methamphetamine dependence.nnnOBJECTIVEnTo find methamphetamine dependence genes identified by each of 2 genome-wide association (GWA) studies of independent samples of methamphetamine-dependent individuals and matched controls.nnnDESIGNnReplicated GWA results in each of 2 case-control studies.nnnSETTINGnJapan and Taiwan.nnnPARTICIPANTSnIndividuals with methamphetamine dependence and matched control subjects free from psychiatric, substance abuse, or substance dependence diagnoses (N = 580).nnnMAIN OUTCOME MEASURESnMethamphetamine dependence genes that were reproducibly identified by clusters of nominally positive single-nucleotide polymorphisms (SNPs) in both samples in ways that were unlikely to represent chance observations, based on Monte Carlo simulations that corrected for multiple comparisons, and subsets of methamphetamine dependence genes that were also identified by GWA studies of dependence on other addictive substances, success in quitting smoking, and memory.nnnRESULTSnGenes identified by clustered nominally positive SNPs from both samples were unlikely to represent chance observations (Monte Carlo P < .00001). Variants in these methamphetamine dependence genes are likely to alter cell adhesion, enzymatic functions, transcription, cell structure, and DNA, RNA, and/or protein handling or modification. Cell adhesion genes CSMD1 and CDH13 displayed the largest numbers of clustered nominally positive SNPs. Methamphetamine dependence genes overlapped, to extents much greater than chance, with genes identified in GWA studies of dependence on other addictive substances, success in quitting smoking, and memory (Monte Carlo P range < .04 to < .00001).nnnCONCLUSIONnThese data support polygenic contributions to methamphetamine dependence from genes that include those whose variants contribute to dependence on several addictive substances, success in quitting smoking, and mnemonic processes.

Morbid Risk for Psychiatric Disorder Among the Relatives of Methamphetamine Users With and Without Psychosis

It is not clear why some methamphetamine (MAMP) abusers develop psychotic symptoms, while others use MAMP regularly over long periods and remain unscathed. We tested the hypotheses that those users who develop MAMP‐induced psychosis (MIP) have greater familial loading for psychotic disorders than users with no psychosis. Four hundred forty‐five MAMP users were recruited from a psychiatric hospital and a detention center in Taipei, and were assessed with the Diagnostic Interview for genetic studies (DIGS‐C) and the Family Interview for genetic study (FIGS‐C). Morbid risk (MR) for psychiatric disorders in first‐degree relatives was compared between those MAMP users with a lifetime diagnosis of MAMP psychosis and those without. The relatives of MAMP users with a lifetime diagnosis of MAMP psychosis had a significantly higher MR for schizophrenia (ORu2009=u20095.4, 95% CI: 2.0–14.7, Pu2009<u20090.001) than the relatives of those probands who never became psychotic. Furthermore, the MR for schizophrenia in the relatives of the subjects with a prolonged MAMP psychosis (MIP‐P) was higher than in the relatives of those users with a brief MAMP psychosis (MIP‐B) (ORu2009=u20092.8, 95% CI: 1.0–8.0, Pu2009=u20090.042). The greater his or her familial loading for schizophrenia, the more likely a MAMP user is to develop psychosis, and the longer that psychosis is likely to last.

The dopamine transporter gene is associated with attention deficit hyperactivity disorder in a Taiwanese sample

Genetic variation of the dopamine transporter gene (DAT1) is of particular interest in the study of attention-deficit hyperactivity disorder (ADHD), since stimulant drugs interact directly with the transporter protein. Association between ADHD and the 10-repeat allele of a 40-bp VNTR polymorphism that lies within the 3′-UTR of DAT1 was first reported in 1995, a finding that has been replicated in at least six independent samples from Caucasian populations. We analysed the DAT1 polymorphism in a sample of 110 Taiwanese probands with a DSM-IV diagnosis of ADHD and found evidence of increased transmission of the 10-repeat allele using TRANSMIT (χ2=10.8, 1 d.f., p=0.001, OR=2.9, 95% CI 1.4–6.3). These data give rise to a similar odds ratio to that observed in Caucasian poplulations despite a far higher frequency of the risk allele in this Taiwanese population; 82.3% in the un-transmitted parental alleles and 94.5% in the ADHD probands. These data support the role of DAT1 in ADHD susceptibility among Asian populations.

Association analysis of the DRD4 and COMT genes in methamphetamine abuse

We analyzed two polymorphisms in genes encoding proteins of the dopamine system, the Val158Met polymorphism in the catechol‐O‐methyltransferase gene and the 120‐bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene for association with methamphetamine abuse. We used a case/control design with 416 methamphetamine abusing subjects and 435 normal controls. All subjects were Han Chinese from Taiwan. We found an excess of the high activity Val158 allele in the methamphetamine abuser group, consistent with several previous reports of association of this allele with drug abuse. The 120‐bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene itself did not show significant association with methamphetamine abuse. However, analysis of the 120‐bp VNTR polymorphism and the exon 3 VNTR in the dopamine D4 receptor as a haplotype showed significant association with methamphetamine abuse, which gave an empirical P value 0.0034 for a heterogeneity model. Moreover, there were significant interactive effects between polymorphisms in the catechol‐O‐methyltransferase and dopamine D4 genes. The evidence of interaction between COMT 158 Val/Met and DRD4 48‐bp VNTR polymorphisms (Pu2009=u20090.0003, ORu2009=u20091.45, 95% CI: 1.148–1.77), and between COMT 158 Val/Met and DRD4 120 bp promoter polymorphisms (Pu2009=u20090.01, ORu2009=u20091.10, 95% CI: 1.10–1.18) were significant but the latter was weak. We conclude that genetic variation in the dopamine system may encode an additive effect on risk of becoming a methamphetamine abuser.

Double-blind randomised controlled trial of lofexidine versus clonidine in the treatment of heroin withdrawal.

Lofexidine is an analogue of clonidine, an agonist at the alpha 2 noradrenergic receptor. Reports from preliminary open studies have suggested that it may be at least as effective as clonidine in the management of opiate withdrawal, and without the same limitation of postural hypotension. We report on a randomised double-blind comparison of lofexidine versus clonidine in the treatment of heroin withdrawal. A total of 80 hospitalized heroin addicts were randomly assigned to treatment with lofexidine or clonidine during in-patient opiate withdrawal. Maximum daily doses were 1.6 mg for lofexidine and 0.6 mg for clonidine. There was marked diurnal variation of withdrawal symptoms with severity being greatest at the daytime reading at 16.00 h and being markedly less at the night-time reading (recorded at 08.00 h). Lofexidine and clonidine were equally effective in treating the withdrawal syndrome. However, significantly more problems relating to hypotension were encountered with subjects on clonidine, with twice as many instances of withholding medication due to hypotension in the clonidine group. Better treatment retention rates were seen in the lofexidine group, although no difference was found in the proportion who had reached minimal symptom severity by the time of their discharge. We conclude that lofexidine and clonidine are equally effective, but with significantly fewer hypotensive problems with lofexidine. Further benefit from lofexidine may be possible with revised dosing regimens. Outpatient studies of lofexidine are now indicated.

Psychiatric comorbidity and gender differences of persons incarcerated for methamphetamine abuse in Taiwan

Abstractu2002 Methamphetamine (MAP) abuse has been common in Taiwan for the past decade. The purpose of the present study was to investigate MAP abuse in Taiwan, with specific attention to psychiatric comorbidity and gender differences. A total of 325 MAP abuse subjects (180 male, 145 female) from a detention center in Taipei were assessed with the Diagnostic Interview for Genetic Studies. The following were studied: drug use behavior, treatment‐seeking behavior, lifetime prevalence of mood disorders, MAP psychosis, alcohol use disorders, pathological gambling and antisocial personality. The MAP‐abuse subjects in Taiwan had high psychiatric morbidity and low access to mental health services. There also exist certain differences in the prevalence of psychiatric illnesses and treatment‐seeking behavior between male and female subjects. Compared with their male counterparts, more female subjects reported experience of mental disturbance and experience of psychiatric treatment. The female subjects more commonly reported suicidal behaviors than the male subjects.

Association analysis of dopamine D2-like receptor genes and methamphetamine abuse.

Objectives Substance use disorders are familial, and genetic factors explain a substantial degree of their familial aggregation. This study employs an association approach to examine the genetic underpinning of methamphetamine (MAMP) use and MAMP-induced psychosis. Methods A total of 416 MAMP abusers from a hospital and a detention center in Taipei were interviewed with the Diagnostic Interview for Genetic Study and the Family Interview for Genetic Study. Genetic polymorphisms of D2-like dopamine receptor genes, DRD2 TaqI A, DRD3 Ser-9-Gly, and DRD4 exon III variable number of tandem repeats, were compared between: (a) MAMP users as a whole and 435 normal controls, and (b) those 154 individuals with MAMP-induced psychosis and the 252 MAMP users with no psychosis. Results None of the three markers we studied were associated with predisposition to psychosis among the MAMP abusers. The MAMP abusers had a higher (P=0.011) prevalence of the seven-repeat allele of DRD4 than normal controls. Conclusions Chance fluctuations in the frequency of rare alleles and ascertainment differences in the case and control samples cannot be ruled out. Therefore, further studies of the seven-repeat allele in MAMP abusers and controls should be performed before an association can be established.

Gender-specific contribution of the GABA A subunit genes on 5q33 in methamphetamine use disorder

ABSTRACTFamily and twins studies have suggested that genetic factors are involved in the development of substance use disorders. Several unrelated case/control association studies have reported associations of the GABAA subunit genes on 5q33 with the development of alcohol dependence. We hypothesized that these particular GABAA subunit genes also contribute to the development of methamphetamine use disorder. To test our hypothesis, we recruited cases using a series of questionnaires. Among the polymorphic SNPs, significant differences between cases and controls were identified in the female sample in the rs2279020 of the GABAAα1 subunit gene, and the novel SNP rs4480617 in the GABAAγ2 subunit gene. No associations were found in the male sample. Further haplotype analysis identified several marker blocks significantly associated with methamphetamine use disorder in females; each block consists of the rs4480617. Our study provides preliminary evidence that the GABAA subunit genes on 5q33 may preferentially contribute to methamphetamine use disorder in females.

Persistence of psychotic symptoms as an indicator of cognitive impairment in methamphetamine users

BACKGROUNDnProlonged exposure to methamphetamine (meth) has neurotoxic effects and impairs neurocognitive functions. This study aims to ascertain whether meth users who experience persistent psychosis suffer more severe cognitive impairment than those not experiencing persistent psychosis.nnnMETHODSnThis cross-sectional study includes 252 participants: 25 meth users without psychosis (METH-P), 50 with brief psychosis (METH+BP), and 56 with persistent psychosis (METH+PP), as well as 54 patients with schizophrenia and 67 healthy controls. The neurocognitive function and clinical psychopathology of each patient were evaluated with the Brief Assessment of Cognition in Schizophrenia (BACS) and the Brief Psychiatric Rating Scale (BPRS), respectively.nnnRESULTSnAll cognitive domains evaluated with BACS (verbal memory, working memory, motor speed, verbal fluency, attention and processing speed, executive function, and composite scores) in METH+PP patients were similar to those in the schizophrenia patients and were worse than those in METH-P, METH+BP, and the healthy control subjects. Furthermore, cognitive functioning in meth users that did not experience persistent psychosis showed no statistically significant difference compared with the healthy control subjects. Among the meth users in this study, the negative symptom scores in the BPRS correlated to cognitive performance on the BACS, with the exception of motor speed.nnnCONCLUSIONSnMeth users display heterogeneity in their psychotic symptoms and cognitive profiles. Therefore, persistent psychotic symptoms may denote a risk for cognitive decline among meth users. Further longitudinal studies should be performed in the future to clarify the causal relationship between cognitive deficits and the development of persistent psychosis.