Association study between the PIK4CA gene and methamphetamine use disorder in a Japanese population.

Accumulating evidence suggests that phosphatidylinositol (PI) pathways have been involved in the secretion of dopamine (DA) and the regulation of DA transporter, which is a target of methamphetamine (METH). A recent large-scale gene-association study in a Dutch population demonstrated that the PIK4CA gene was closely linked to schizophrenia [Jungerius et al. (2007); Mol Psychiatry]. Here, we conducted a case (N = 232)-control (N = 233) study of the PIK4CA gene on Japanese METH abusers, which can manifest severe psychosis similar to schizophrenia. The genotype and allelic distributions of all four single nucleotide polymorphisms (SNPs) did not differ significantly between the METH abusers and the controls. The comparisons based on the classification of the psychosis as transient or prolonged and on the presence or absence of spontaneous relapse revealed no significant distribution of the four SNPs compared to the controls. Furthermore, haplotype analyses showed almost the same frequencies between the METH abusers and the controls. The present study suggests that the PIK4CA gene does not play a significant role in the vulnerability to METH use disorder in the Japanese population.

Reduced CYP2D6 activity is a negative risk factor for methamphetamine dependence.

Because methamphetamine (METH) is metabolized by CYP2D6 at the first step of hydroxylation and demethylation, it is possible that functional variants of CYP2D6 alter susceptibility to methamphetamine-induced dependence. We genotyped CYP2D6*1, *4, *5, *10, and *14 for 202 patients with METH dependence and 337 controls in a Japanese population and found a significant association of the CYP2D6 gene with METH dependence (p=0.0299). The patients had fewer *10 and *14 alleles, which are hypofunction alleles, than the controls. CYP2D6 genotypes were divided into three phenotypes: extensive metabolizers, intermediate metabolizers, and poor metabolizers. There was no poor metabolizer among our Japanese subjects, and intermediate metabolizers of CYP2D6 were significantly fewer in methamphetamine-dependent subjects than in controls (p=0.0212), with an odds ratio of 0.62 (95% confidence interval: 0.51-0.76). The present study demonstrated that reduced CYP2D6 activity was a negative risk factor for methamphetamine dependence.

Association study between polymorphisms in glutathione-related genes and methamphetamine use disorder in a Japanese population.

Accumulating evidence suggests that oxidative stress plays a role in the mechanisms of action of methamphetamine (METH) in the brain. In the present study, we investigated the association between the genetic polymorphisms among glutathione (GSH)-related enzymes; glutathione S-transferases (GSTs) such as GSTT1 (Non-deletion/Null), GSTT2 (Met139Ile), GSTA1 (-69C/T), and GSTO1 (Ala140Asp); glutathione peroxidase 1 (GPX1) (Pro198Leu); and glutamate-cysteine ligase modifier (GCLM) subunit and METH use disorder in a Japanese population. Two hundred eighteen METH abusers and 233 healthy controls were enrolled in the study. There was a significant difference in GSTT1 genotype frequency between patients with METH psychosis and controls (P = 0.039, odds ratio: 1.52, 95% CI 1.03-2.24). Furthermore, the frequency (66.0%) of the GSTT1 null genotype among prolonged-type METH psychotic patients with spontaneous relapse was significantly higher (P = 0.025, odds ratio: 2.43, 95% CI 1.13-5.23) than that (44.4%) of transient-type METH psychotic patients without spontaneous relapse. However, there were no associations between the polymorphisms of other genes and METH abuse. The present study suggests that the polymorphism of the GSTT1 gene might be a genetic risk factor of the development of METH psychosis in a Japanese population.

The glycine transporter 1 gene (GLYT1) is associated with methamphetamine-use disorder.

Glycine transporter (GlyT)-1 plays a pivotal role in maintaining the glycine level at the glutamatergic synapse. Glycine is an allosteric agonist of N-methyl-D-aspartate (NMDA) receptors. Because activation of NMDA receptors is an essential step for induction of methamphetamine dependence and psychosis, differences in the functioning of GlyT-1 due to genetic variants of the GlyT-1 gene (GLYT1) may influence susceptibility. A case-control genetic association study of the GLYT1 gene examined 204 patients with methamphetamine-use disorder and 210 healthy controls. We examined three single nucleotide polymorphisms (SNPs), SNP1, IVS3 + 411C > T, rs2486001; SNP2, 1056G > A, rs2248829; and SNP3, IVS11 + 22G > A, rs2248632, of the GLYT1 gene and found that SNP1 showed a significant association in both genotype (P = 0.0086) and allele (P = 0.0019) with methamphetamine-use disorder. The T-G haplotype at SNP1 and SNP2 was a significant risk factor for the disorder (P = 0.000039, odds ratio: 2.04). The present findings indicate that genetic variation of the GLYT1 gene may contribute to individual vulnerability to methamphetamine dependence and psychosis.

Identification of functional polymorphisms in the promoter region of the human PICK1 gene and their association with methamphetamine psychosis.

OBJECTIVE: Protein interacting with C-kinase-1 (PICK1) plays a role in the targeting and clustering of dopamine transporter, which is the primary target site for the abused drug methamphetamine. Based on the interaction of PICK1 with dopamine transporter, it is of particular interest to investigate the association between the PICK1 gene and methamphetamine abusers. METHOD: The authors studied the association between PICK1 gene polymorphisms and methamphetamine abusers in a Japanese group. Two hundred and eight methamphetamine abusers and 218 healthy comparison subjects were enrolled in the study. Furthermore, the authors also examined the effects of single nucleotide polymorphisms (SNPs) in the promoter and 5'-untranslated region on transcription levels of PICK1. RESULTS: The authors identified four highly frequent SNPs, rs737622 (-332 C/G) and rs3026682 (-205 G/A) in the promoter region and rs713729 (T/A) in intron3 and rs2076369 (T/G) in intron4. Of these SNPs, rs713729 was significantly associated with methamphetamine abusers in general, and rs713729 and rs2076369 were significantly associated with those with spontaneous relapse of psychosis. Furthermore, haplotype analysis revealed that specific haplotypes of these SNPs were associated with methamphetamine abusers. A gene reporter assay revealed that the two SNPs in the promoter region significantly altered transcriptional activity. CONCLUSIONS: Our findings suggest that the PICK1 gene may be implicated in the susceptibility to spontaneous relapse of methamphetamine psychosis and that, as an intracellular adapter protein, PICK1 may play a role in the pathophysiology of methamphetamine psychosis.

Development and validation of the Stimulant Relapse Risk Scale for drug abusers in Japan.

OBJECTIVE: To develop and validate a multidimensional measure of relapse risk for stimulants in Japanese drug abusers. METHODS: A Stimulant Relapse Risk Scale (SRRS) was developed based on the Marijuana Craving Questionnaire and a discussion among three psychiatrists. We created 48 items after confirming the items including a variety of relapse risk, such as craving (expectancy, compulsivity, etc.) and emotionality problems. One hundred inpatients and outpatients with a history of stimulant abuse (71 males and 29 females) were recruited with informed consent, and were administered the SRRS. The Visual Analogue Scale for drug craving (VAS), Addiction Severity Index for Japanese (ASI-J), and data on relapse within 3 and 6 months after the rating were used for the validation. RESULTS: Exploratory factor analysis highlighted five factors: anxiety and intention to use drug (AI), emotionality problems (EP), compulsivity for drug use (CD), positive expectancies and lack of control over drug (PL), and lack of negative expectancy for drug use (NE). These accounted for 48.3% of the total variance. Thirty of the 43 items were classified into the five subscales. Cronbach's alpha coefficient for each subscale ranged from .55 to .82, and was .86 for the total SRRS, indicating their adequate internal consistency. AI, CD, PL, and total SRRS were significantly correlated with the drug-use composite score of the ASI-J, supporting their concurrent validity. AI, PL, NE, and total SRRS were significantly correlated with relapse, implying their predictive validity. CONCLUSIONS: The SRRS has multidimensional psychometric properties useful for assessing the various aspects of stimulant relapse risk.

An association study between catechol-O-methyl transferase gene polymorphism and methamphetamine psychotic disorder.

OBJECTIVE: A series of methamphetamine psychosis reveals two kinds of clinical courses of methamphetamine psychosis: transient type and prolonged type. Furthermore, paranoid psychosis sometimes recurs without methamphetamine reuse, referred to as spontaneous relapse. Dysfunction of central dopaminergic neurotransmission has been implicated in the pathogenesis of these psychiatric states. Catechol-O-methyl transferase appears to play a unique role in regulating synaptic dopaminergic activity. This study aimed to investigate whether a functional polymorphism of the catechol-O-methyl transferase gene would be involved in the development of these psychiatric states. BASIC METHODS: We examined the functional polymorphism of val 158 met (catechol-O-methyl transferase) in 143 patients with methamphetamine psychosis and 200 healthy controls in Japan. The patients were divided into subgroups by several characteristic clinical features. MAIN RESULTS: We found a significant difference in the catechol-O-methyl transferase allele frequency between patients with spontaneous relapse and the controls (P=0.018, odds ratio=1.67). Odds ratio implied that the patients with spontaneous relapse had a nearly 1.7-fold higher rate of the low activity alleles (met) than the controls. CONCLUSIONS: Our results indicate that the met allele frequency of the catechol-O-methyl transferase is associated with patients who experienced methamphetamine psychosis and spontaneous relapse, suggesting that patients with a met allele appear to be at increased risk of an adverse response to methamphetamine.

Genetic variant of prodynorphin gene is risk factor for methamphetamine dependence.

Previous studies have indicated that genetic factors substantially affect development of substance use disorders, including methamphetamine dependence. Prodynorphin (PDYN) is an opioid peptide precursor that yields dynorphins, endogenous kappa opioid-receptor agonists that play important roles in substance abuse. A physiologically active polymorphism of 1-4 repeats of a 68-bp element in the promoter region of the PDYN gene has been identified. We analyzed this polymorphism of the PDYN gene by a case-control association study in 143 patients with methamphetamine dependence and 209 healthy controls in the Japanese population. A 3- or 4-repeat allele in the PDYN gene promoter was found significantly more frequently in patients with methamphetamine dependence than in controls (chi(2)=9.45, p=0.0021). A 3- or 4-repeat allele in the PDYN gene promoter, which was shown to produce significantly higher transcription activity of the PDYN gene than a 1- or 2-repeat allele, is a genetic risk factor for development of methamphetamine dependence (odds ratio: 1.83, 95% CI=1.24-2.68).

Reliability and validity of the Japanese version of the Addiction Severity Index (ASI-J).

The Addiction Severity Index (ASI) is a frequently used clinical and research instrument that collects data from substance abusers in seven problem areas: medical, employment, alcohol, drug use, legal, family-social functioning, and psychiatric status. In each area, the ASI provides a composite score and severity rating that estimate the seriousness of the problem and the client's need for treatment. In the present study, we investigated the reliability and validity of the Japanese version of the ASI (ASI-J). One hundred and eleven subjects with a history of drug abuse were interviewed with a test battery including the ASI with informed consent. This revealed that: (a) the problem areas were independent of each other, underscoring the need for multidimensional assessment, (b) the inter-rater correlation of severity ratings in each area ranged from 0.68 to 0.99, and Cronbach's alpha coefficient for the items used for the composite score in each area ranged from 0.57 to 0.86, indicating their reliability with the exception of the drug and employment areas, and (c) several composite scores were significantly correlated with the drug craving levels assessed by a visual analogue scale, the abstinence period, mental health, and/or relapse, supporting their concurrent and predictive validity. These results suggest that the ASI-J has acceptable reliability and validity.

The X-box binding protein 1 (XBP1) gene is not associated with methamphetamine dependence.

Bipolar disorder has known as a high risk factor for substance abuse and dependence such as alcohol and illegal drugs. Recently, Kakiuchi et al. reported that the -116C/G polymorphism in the promoter region of the X-box binding protein 1 (XBP-1) gene, which translates a transcription factor specific for endoplasmic reticulum stress caused by misfolded proteins, was associated with bipolar disorders and schizophrenia in a Japanese population. Abuse of methamphetamine often produces affective disorders such as manic state, depressive state, and psychosis resembling paranoid-type schizophrenia. To clarify a possible involvement of XBP-1 in the etiology of methamphetamine dependence, we examined the genetic association of the -116C/G polymorphism of the XBP-1 gene by a case-control study. We found no significant association in allele and genotype frequencies of the polymorphism either with methamphetamine dependence or any clinical phenotype of dependence. Because the polymorphism is located in the promoter region of the XBP-1 gene and affects transcription activity of the gene, it is unlikely that dysfunction of XBP-1 may induces susceptibility to methamphetamine dependence.

A nonsynonymous polymorphism in the human fatty acid amide hydrolase gene did not associate with either methamphetamine dependence or schizophrenia.

Genetic contributions to the etiology of substance abuse and dependence are topics of major interest. Acute and chronic cannabis use can produce drug-induced psychosis resembling schizophrenia and worsen positive symptoms of schizophrenia. The endocannabinoid system is one of the most important neural signaling pathways implicated in substance abuse and dependence. The fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme of endocannabinoids. To clarify a possible involvement of FAAH in the etiology of methamphetamine dependence/psychosis or schizophrenia, we examined the genetic association of a nonsynonymous polymorphism of the FAAH gene (Pro129Thr) by a case-control study. We found no significant association in allele and genotype frequencies of the polymorphism with either disorder. Because the Pro129Thr polymorphism reduces enzyme instability, it is unlikely that dysfunction of FAAH and enhanced endocannabinoid system induce susceptibility to either methamphetamine dependence/psychosis or schizophrenia.

[Treatment of substance dependence by a bio-cognitive model based on behavioral pharmacology].

We have introduced cognitive behavior therapy (CBT) into the treatment of substance dependence patients, which involves disease education and focused group therapy to obtain insight into the taking behavior and to establish concrete countermeasures to prevent relapse. We have created a bio-cognitive model based on biological aspects to explain the pathology of substance dependence. 'Dependence' is a term in behavioral pharmacology defined as reinforced drug seeking and taking behavior. Changes in taking behavior are thought to occur due to the repetition of the reinforcement action of psychoactive substances in the reward system of the brain. Therefore, when intake desire is strong, it is hard for patients to control themselves, and there is a feature of difficulties considering the process of thinking in CBT. In other words, when craving becomes strong, a chain of behavior happens spontaneously, without schema, involving automatic thoughts. We think that the improvement of protracted withdrawal syndrome (PWS) and entire frontal lobe function are important in learning to discern distortion of cognition. When PWS is improved, a conflict is easy to bring about in the process of drug seeking and taking behavior. And, it is easy to execute avoidance plans (coping skills) which are established to cope with craving in advance. We think that a goal for treatment is to discern drug seeking and taking behavior with natural emotion. The recovery of PWS and frontal lobe dysfunction takes a long time with a serious dependence, so we must perform repetition of CBT. As the treatment introduction of involuntary admission cases is adequate or cases of 1 to 3 months of admission treatment based on voluntary admission are hard to treat, treatment to obtain insights into patients while carrying out repeated CBT using a bio-cognitive model and to improve PWS could be a possibility as one treatment for the pathology of diversified substance dependence.

Gene polymorphisms of the mu opioid receptor in methamphetamine abusers.

In drug addiction, the opioid system is thought to mediate motivational effects through dopamine-independent mechanisms. We have investigated associations of the mu-opioid receptor gene (OPRM) variations with methamphetamine (MAP) dependence/psychosis. The allelic frequency of A118G (Asn40Asp) in exon 1 of ORPM was 45.3% in our control subjects, but only 7.5-25.8% in the Caucasian or African-American population of previous studies. We have identified several novel polymorphisms in intron 1 and the 5' untranslated region (5'UTR) of OPRM. Polymorphisms in the functionally relevant 5' regulatory region of OPRM were different in our Japanese population from Caucasian or African-American populations. No significant differences between controls and MAP abusers were found in either genotype or allele frequency at any single nucleotide polymorphism (SNP) or (AC)n dinucleotide repeat in intron 1. A subdivision of our MAP group revealed that A118G of OPRM shows a significant association with MAP psychosis having latency less than three years. Further analysis should be capable of identifying associations between the OPRM variations and MAP dependence/psychosis.

Study of association between alpha-synuclein gene polymorphism and methamphetamine psychosis/dependence.

Methamphetamine (MAP) dissipates proton gradients across the membranes of synaptic vesicles, enhances cytoplasmic dopamine (DA) concentrations, and causes calcium-independent, nonvesicular DA release into synapses. MAP is taken into the cytosol by the dopamine transporter (DAT) on the synaptic terminals of DA neurons, and endogenous DA is concurrently released through the transporter by carrier exchange mechanisms, resulting in a robust increase in DA concentration in the synaptic clefts. The enhanced DA release through DAT by MAP is the main mechanism for the reinforcing effects of MAP. The complexes of alpha-synuclein and DAT facilitate membrane clustering of the DAT, thereby accelerating DA uptake in vitro. alpha-Synuclein has been shown to be overexpressed in the midbrain DA neurons of chronic cocaine abusers. The present study was performed to study the association between the alpha-synuclein gene polymorphisms and MAP psychosis/dependence in Japanese population. Since the T10A7 polymorphic site at the 5' end of the noncoding exon 1' in the alpha-synuclein gene is highly polymorphic, we analyzed the noncoding exon 1' and intron 1, including this polymorphic site by sequencing. We confirmed four single nucleotide polymorphisms (SNPs) within 1.38 kbp of the T10A7 polymorphic site. No significant difference was found in genotype or allele frequencies in the T10A7 polymorphic site between MAP psychotic/dependent and control subjects. We found significant association between three SNPs in the vicinity of this polymorphic site in intron 1 and MAP psychosis/dependence in female subjects, but not in males. These results suggest an association of the alpha-synuclein gene polymorphisms with MAP psychosis/dependence in our female subjects. Further analyses are necessary to clarify the gender difference, by using a larger sample size and/or different ethnic groups, as well as functional variations in the alpha-synuclein gene.

Impaired sleep during the post-alcohol withdrawal period in alcoholic patients.

Twenty-seven patients who suffered from alcohol dependence syndrome and who were admitted to the Department of Psychiatry at NCNP were investigated for impaired sleep. The incidence of "insomnia night", when a patient has trouble getting sufficient sleep even after taking additional drugs for insomnia, was used as the index for impaired sleep. "Insomnia night" was observed among 51.9% (14 of 27) of the patients during administration; 18.5% (nine of 27) experienced "insomnia night" only during the withdrawal period. The mean incidence was 3.5 nights of 10 nights for 0-9th day after abstinence and 2.0 nights of 10 nights for 10-19th day after abstinence; 33.3% (nine of 27) claimed "insomnia night" even after the withdrawal period and the highest incidence was the 160-169th day after abstinence, average frequency being 4.4 nights of 10 nights. Impaired sleep emerging after the withdrawal period neared the clinical course of Komiyama's protracted withdrawal symptoms, thus suggesting that it might be one of the protracted withdrawal symptoms.

Effectiveness of Information Technology Aided Relapse Prevention Programme in Schizophrenia excluding the effect of user adherence: a randomized controlled trial.

BACKGROUND: A relapse prevention program called the Information Technology Aided Relapse Prevention Programme in Schizophrenia (ITAREPS) has been developed and is reported to be highly effective. However the effectiveness was influenced by user adherence to the protocol of the program, the exact effectiveness and the role of the ITAREPS have been partially uncertain. OBJECTIVE: The purpose of this study is to evaluate the effectiveness of the ITAREPS excluding the effect of user adherence to the protocol of the program. METHOD: We attempted to perform a randomized controlled trial by the devised method with visiting nurse service. Outpatients with schizophrenia were randomized to the ITAREPS (n=22) or control group (n=23) and were observed for 12 months. RESULTS: The risk of rehospitalization was reduced in the ITAREPS group (2 [9.1%]) compared with the control group (8 [34.8%]) (hazard ratio=0.21, 95% CI 0.04-0.99, p=0.049; number needed to treat (NNT)=4, 95% CI 2.1-35.5). The mean number of inpatient days was significantly lower in the ITAREPS group (18.5 days) compared with the control group (88.8 days) (p=0.036). The ratio of the number of rehospitalizations to that of relapses was significantly lower (p=0.035) and the mean change in total BPRS scores at relapse from baseline was significantly less in the ITAREPS group (p=0.019). CONCLUSIONS: The relapse prevention effectiveness of the ITAREPS was high, and we confirmed that the ITAREPS, i.e., detecting signs of relapse and increasing medication during the warning state, is an effective intervention during the early stages of relapse.

An association study of monoamine oxidase A (MAOA) gene polymorphism in methamphetamine psychosis.

Methamphetamine continues to be the most widely abused drug in Japan. Chronic methamphetamine users show psychiatric signs, including methamphetamine psychosis. Monoamine oxidase A (MAOA) is one of the major enzymes responsible for the degradation of neurotransmitters. Abnormalities in MAO levels have been related to a wide range of psychiatric disorders. We examined whether or not the MAOA-u variable-number tandem repeat (VNTR) has a functional polymorphism in methamphetamine psychosis and whether or not such a polymorphism is related to the prolongation of psychosis. As expected, there was a significant difference in the MAOA-u VNTR between males with persistent versus transient methamphetamine psychosis (p=0.018, odds ratio (OR)=2.76, 95% CI: 1.18-6.46). Our results suggest that the high-activity allele class of MAOA-u VNTR in males may be involved in susceptibility to a persistent course of methamphetamine psychosis. We found no differences among females. The sample size of females with methamphetamine psychosis was too small to have significant analysis.

The dysbindin gene (DTNBP1) is associated with methamphetamine psychosis.

BACKGROUND: The dysbindin (DTNBP1 [dystrobrevin-binding protein 1]) gene has repeatedly been shown to be associated with schizophrenia across diverse populations. One study also showed that risk haplotypes were shared with a bipolar disorder subgroup with psychotic episodes, but not with all cases. DTNBP1 may confer susceptibility to psychotic symptoms in various psychiatric disorders besides schizophrenia. METHODS: Methamphetamine psychosis, the psychotic symptoms of which are close to those observed in schizophrenia, was investigated through a case (n = 197)-control (n = 243) association analyses of DTNBP1. RESULTS: DTNBP1 showed significant associations with methamphetamine psychosis at polymorphisms of P1635 (rs3213207, p = .00003) and SNPA (rs2619538, p = .049) and the three-locus haplotype of P1655 (rs2619539)-P1635-SNPA (permutation p = .0005). The C-A-A haplotype, which was identical to the protective haplotype previously reported for schizophrenia and psychotic bipolar disorders, was a protective factor (p = .0013, odds ratio [OR] = .62, 95% confidence interval [CI] .51-.77) for methamphetamine psychosis. The C-G-T haplotype was a risk for methamphetamine psychosis (p = .0012, OR = 14.9, 95% CI 3.5-64.2). CONCLUSIONS: Our genetic evidence suggests that DTNBP1 is involved in psychotic liability not only for schizophrenia but also for other psychotic disorders, including substance-induced psychosis.