Risk factors for the onset of dependence and chronic psychosis due to cannabis use: Survey of patients with cannabis-related psychiatric disorders.

AIM: The objective of the current study was to identify risk factors that affect the onset of dependence and chronic psychosis due to cannabis use. METHODS: We examined clinical genetic factors, psychiatric disorders prior to cannabis use, starting age of cannabis use, duration and frequency of cannabis use, types of cannabis products used, combined use of other psychoactive substances, and the psychiatric diagnosis of 71 patients with cannabis-related psychiatric disorders who underwent treatment at nine mental health hospitals in Japan. Information was collected from cross-sectional interview surveys conducted by each patient's attending psychiatrist. RESULTS: For the diagnosis of dependence syndrome due to the use of cannabis, we found associations with the number of years of cannabis use and the use of cannabis products with a high Δ9-tetrahydrocannabinol (THC) content. However, we found no association between diagnosis of residual and late-onset psychotic disorders and clinical genetic factors, presence of preceding psychiatric disorders, duration and frequency of cannabis use, starting age of cannabis use, or combined use of other psychoactive substances; an association was found only for the absence of use of cannabis products other than dried cannabis. CONCLUSION: The onset of cannabis dependence was related to long-term cannabis use and the use of cannabis products with a high THC content. However, chronic psychosis was not associated with total THC intake or psychiatric vulnerability. Thus, unknown factors appear to be involved in the onset of chronic psychosis.

A Single Medical Marker for Diagnosis of Methamphetamine Addiction - DNA Methylation of SHATI/NAT8L Promoter Sites from Patient Blood.

BACKGROUND: Methamphetamine (METH) is one of the most widely distributed psychostimulants worldwide. Despite active counter measures taken by different countries, neither overall usage of METH nor the frequency of repeat users has reduced over the past decade. METH induces abuse and dependence as it acts on the central nervous system and temporarily stimulates the brain. The recidivism rate for abuse of stimulants in Japan is very high and therefore prevention of repeated usage is paramount. However, we lack information about the relationship between METH users and genomic changes in humans in Japan, which would provide important information to aid such efforts. OBJECTIVE: Shati/Nat8l is a METH-inducible molecule and its overexpression has protective effects on the brain upon METH usage. Here we investigated the effect of METH usage on DNA methylation rates at the promoter site of SHATI/NAT8L. We used DNA samples from human METH users, who are usually difficult to recruit in Japan. METHODS: We measured DNA methylation at SHATI/NAT8L promoter sites by pyrosequencing method using 193 samples of METH users and 60 samples of healthy subjects. In this method, DNA methylation is measured by utilizing the property that only non-methylated cytosine changes to urasil after bisulfite conversion. RESULTS: We found that the rate of DNA methylation at six CpG islands of SHATI/NAT8L promoter sites is significantly higher in METH users when compared to healthy subjects. CONCLUSION: These results suggest that the DNA methylation rate of SHATI/NAT8L promotor regions offers a new diagnostic method for METH usage.

Changes of clinical symptoms in patients with new psychoactive substance (NPS)-related disorders from fiscal year 2012 to 2014: A study in hospitals specializing in the treatment of addiction.

AIMS: The use of new psychoactive substances (NPS) has become increasingly widespread over the last decade, in Japan and internationally. NPS are associated with a range of increasingly serious clinical, public, and social issues. Political measures to ameliorate the effects of NPS in Japan have focused on tightening regulation rather than establishing treatment methods. The current study sought to compare the neuropsychiatric symptoms of patients with NPS-related disorders across several years. We examined patients who attended specialized hospitals for treating addiction, to elucidate the impacts of legal measures to control NPS. METHODS: Subjects (n = 864) were patients with NPS-related disorders who received medical treatment at eight specialized hospitals for treating addiction in Japan between April 2012 and March 2015. Clinical information was collected retrospectively from medical records. RESULTS: Among psychiatric symptoms, the ratio of hallucinations/delusions decreased over time across 3 years of study (first year vs second year vs third year: 40.1% vs 30.9% vs 31.7%, P = 0.037). Among neurological symptoms, the ratio of coma/syncope increased over the 3-year period (7.8% vs 11.0% vs 17.0%, P = 0.002), as did the ratio of convulsions (2.8% vs 4.3% vs 9.7%, P = 0.001). CONCLUSION: The symptoms associated with NPS were primarily psychiatric in the first year, while the prevalence of neurological symptoms increased each year. The risk of death and the severity of symptoms were greater in the third year compared with the first year, as regulation of NPS increased.

[Methamphetamine, cannabis].

The persons with marijuana abuse tend to be increasing in Japan, although illegal drugs use in lifetime is remarkably lower than other advanced countries, Europe and USA. In addition, there have been many methamphetamine users in Japan. As use of methamphetamine induces psychotic states, we recognize them as one of the key illegal drugs for clinical psychiatrists. Regarding to diagnosis of methamphetamine psychosis, there is a large difference between Japanese psychiatrists and other advanced countries' ones. The former considers that they have persistent symptoms. In contrast, the latter embraces it as the model of acute toxicosis. The Japanese government has been based on a full commitment to the crackdown on drug problems. However, they will execute the new law in 2016, in which some persons charged with violating the methamphetamine control law will be adapted to partially probation on drug charges. Then, we have to improve our therapeutic and recovery supports to charged illegal drug users as rapidly as possible.

Associations between the orexin (hypocretin) receptor 2 gene polymorphism Val308Ile and nicotine dependence in genome-wide and subsequent association studies.

BACKGROUND: Many genetic and environmental factors are involved in the etiology of nicotine dependence. Although several candidate gene variations have been reported by candidate gene studies or genome-wide association studies (GWASs) to be associated with smoking behavior and the vulnerability to nicotine dependence, such studies have been mostly conducted with subjects with European ancestry. However, genetic factors have rarely been investigated for the Japanese population as GWASs. To elucidate genetic factors involved in nicotine dependence in Japanese, the present study comprehensively explored genetic contributors to nicotine dependence by using whole-genome genotyping arrays with more than 200,000 markers in Japanese subjects. RESULTS: The subjects for the GWAS and replication study were 148 and 374 patients, respectively. A two-stage GWAS was conducted using the Fagerström Test for Nicotine Dependence (FTND), Tobacco Dependence Screener (TDS), and number of cigarettes smoked per day (CPD) as indices of nicotine dependence. For the additional association analyses, patients who underwent major abdominal surgery, patients with methamphetamine dependence/psychosis, and healthy subjects with schizotypal personality trait data were recruited. Autopsy specimens with various diseases were also evaluated. After the study of associations between more than 200,000 marker single-nucleotide polymorphisms (SNPs) and the FTND, TDS, and CPD, the nonsynonymous rs2653349 SNP (located on the gene that encodes orexin [hypocretin] receptor 2) was selected as the most notable SNP associated with FTND, with a p value of 0.0005921 in the two-stage GWAS. This possible association was replicated for the remaining 374 samples. This SNP was also associated with postoperative pain, the initiation of methamphetamine use, schizotypal personality traits, and susceptibility to goiter. CONCLUSIONS: Although the p value did not reach a conventional genome-wide level of significance in our two-stage GWAS, we obtained significant results in the subsequent analyses that suggest that the rs2653349 SNP (Val308Ile) could be a genetic factor that is related to nicotine dependence and possibly pain, schizotypal personality traits, and goiter in the Japanese population.

Evidence for shared genetic risk between methamphetamine-induced psychosis and schizophrenia.

Methamphetamine (METH) use can provoke psychotic reactions requiring immediate treatment, namely METH-induced psychosis. Although the distinction between METH-induced and primary psychosis is important for understanding their clinical courses, we do not have clear diagnostic procedure by their symptoms. Not only are there similarities between the clinical features of METH-induced psychosis and schizophrenia (SCZ), but there is also epidemiological evidence of a shared genetic risk between 'METH-related' disorders and SCZ, which makes the differentiation of these two conditions difficult. In this study, we conducted a genome-wide association study (GWAS) targeting METH-dependent patients. The METH sample group, used in the METH-dependence GWAS, included 236 METH-dependent patients and 864 healthy controls. We also included a 'within-case' comparison between 194 METH-induced psychosis patients and 42 METH-dependent patients without psychosis in a METH-induced psychosis GWAS. To investigate the shared genetic components between METH dependence, METH-induced psychosis, and SCZ, data from our previous SCZ GWAS (total N=1108) were re-analyzed. In the SNP-based analysis, none of the SNPs showed genome-wide significance in either data set. By performing a polygenic component analysis, however, we found that a large number of 'risk' alleles for METH-induced psychosis are over-represented in individuals with SCZ (Pbest=0.0090). Conversely, we did not detect enrichment either between METH dependence and METH-induced psychosis or between METH dependence and SCZ. The results support previous epidemiological and neurobiological evidence for a relationship between METH-induced psychosis and SCZ. These also suggest that the overlap between genes scored as positive in these data sets can have higher probability as susceptibility genes for psychosis.

Sex differences in risk factors for suicidality among Japanese substance use disorder patients: association with age, types of abused substances, and depression.

AIM: The aim of this study was to identify risk factors for suicide in Japanese substance use disorder (SUD) patients, adjusting for age and sex, and to examine sex differences in suicide risk among these patients. METHODS: A self-reporting questionnaire on age, sex, types of abused substances, current depression, and suicidality was administered to 1420 SUD patients who consecutively visited seven hospitals specializing in SUD treatment during the month of December 2009. Unadjusted/adjusted odds ratios of factors associated with suicidality were calculated for each sex. RESULTS: The multivariate analysis using the total sample identified younger age, female sex, and current depression as risk factors for severe suicidality in SUD patients. The multivariate analysis by each sex demonstrated that younger age and current depression were associated with severe suicidality in male SUD patients. Only current depression was associated with severe suicidality in female patients. CONCLUSION: Current depression is a risk factor for suicide in SUD patients common in both Western countries and Japan, although in Japanese SUD patients both younger age and female sex were more closely associated with severe suicidality than aspects of SUD. Additionally, young male SUD patients are speculated to have psychosocial features associated with suicidality in common with female SUD patients.

[A study on clinical features of patients with benzodiazepines use disorder (BZsUD), and characteristics of psychiatric treatments which may cause BZsUD].

BACKGROUND AND AIMS: The aims of present study are to clarify the clinical features of patients with benzodiazepine use disorder (BZsUD), and to examine the characteristics of psychiatric treatments which may cause BZsUD. METHODS: We conducted a medical chart and interview survey to 87 outpatients with benzodiazepine use disorder, who had consecutively visited the four hospitals, specialized in addiction problems, located in metropolitan area, during a month of December, 2011. RESULTS: Consequently, 88.5% of the patients with BZsUD reported to obtain BZs to be abused from general psychiatric clinics, and 83.9% contracted BZsUD in process of general psychiatric treatment. Among the patients who contracted BZsUD in process of psychiatric treatment, 43.8% were speculated to have the other substance-related disorders such as methamphetamine or alcohol-related disorder at start of the psychiatric treatment. Further, approximately 70% of them reported that surplus BZs were prescribed without consideration of storing drugs, and over 40% also reported that BZs were prescribed without a medical examination. CONCLUSIONS: The findings of the present study may let us to propose the following four measures to be taken for prevention of BZsUD: First, latent substance-related disorders should not be overlooked, second, short-acting and high-potency BZs should not be prescribed if possible, third, storing and abusing BZs should always be considered, and finally, BZs should be prescribed with a medical examination.

Mental health and emotional relationships of family members whose relatives have drug problems.

The presence of a drug abuser in a family can seriously affect the family's mental health and relationships. This study focuses on the stress of families of drug abusers, relationships, and their relevant factors, as well as examines ways to support them. The subjects of this study were family members of drug abusers treated at drug abuser family support groups, medical institutions, or municipal mental health and welfare centers. To these institutions, 1,298 questionnaires were sent, and 543 responses with sufficient data were used for analysis. The survey consisted of the 12-item General Health Questionnaire (GHQ-12), and questionnaire items regarding disruptions to family life, relationship with drug users, and the use of family support services. The survey results showed that the mean GHQ score was 4.5, and those whose score are cut-off 3 and more, indicating poor mental health accounted for 54.7%. More than half of the subjects responded that drug problems have affected family members in terms of the health condition, daily living, and financial problems. Regarding emotional relationships with the addicts, most of the families answered that they have had negative feelings toward them, such as "being dragged into drug problems" and "being over-protective". A significant correlation was observed between the GHQ score and family members' relationship with the addict, and these variables were closely correlated with participation in the family group, the status of drug abstinence, living environment, and participation in a self-support group by the addict. As the results, most of the family members of drug users have problems with mental health and the recovery of relationships even though they have accessed support centers, and it was verified that the family support group works effectively to help solve their problems.

Depression and suicide risk of outpatients at specialized hospitals for substance use disorder: comparison with depressive disorder patients at general psychiatric clinics.

The present study used a self-reporting questionnaire to compare suicide risk in outpatients being treated for substance use disorder at specialized hospitals to suicide risk in outpatients being treated for depressive disorder at general psychiatric clinics. Although patients in both groups exhibited an equal severity of depression, the patients with drug use disorder had a higher suicide risk than those with depressive disorder. These findings indicate that drug-abusing patients at specialized hospitals may have a severe risk of committing suicide, suggesting that carefully assessing the comorbidity of depression with drug abuse may be required for preventing suicide in drug-abusing patients.

[A study on differences of suicide risk in substance use disorder patients by types of an abused substance: a comparison among alcohol, amphetamine, and sedative, hypnotic or anxiolytic use disorder patients].

BACKGROUND AND PURPOSE: Substance use disorder is one of the important mental health problems related to suicide, nearly equal with depressive disorder. However, it is unclear how differences of abused substances influence the suicide risk of individuals with substance use disorder in Japan. The purpose of the present study is to compare an estimated suicide risk among patients with alcohol, amphetamine, and sedative, hypnotic or anxiolytic use disorders. METHODS: Subjects were 1082 outpatients with alcohol use disorder (AUD), 191 with amphetamine-like use disorder (AMUD), and 63 with sedative, hypnotic or anxiolytic use disorder (SUD), all of whom consecutively had consulted seven medical facilities specialized for treatment of substance use disorder during a month of December 2009. A self-reporting questionnaire including the items of Kessler 10 (K10) and the Mini International Neuropsychiatric Interview (M.I.N.I.) was administered, and scores of the K10 and M.I.N.I., and the other clinical information were compared among the patients with AUD, AMUD, and SUD. RESULTS: Patients with AMUD and SUD showed significantly higher score on the M.I.N.I. than those with AUD, while those with SUD showed highest score on the K10, followed by those with AMUD. In either of patients with AUD, AMUD, or SUD, approximately 60% of the subjects who attempted suicide within a month reported to take any psychoactive substance in the attempted suicide. Additionally, a remarkable difference was found in histories of general psychiatric treatment before consulting medical facilities specialized for treatment of substance use disorder between these three groups. Most of outpatients with SUD reported such histories. CONCLUSIONS: Outpatients with SUD appeared to involve the highest risk for suicide of all patients with substance use disorder, probably because of the comorbid-severe depression. In our speculation, SUD which our subjects suffered from might be induced or accelerated by pharmacotherapy performed in general psychiatric facilities. Education on dependency of prescribed psychotropic drugs to general psychiatrists is required.

[Patients with drug dependence can be treated in a ward for alcohol dependence on certain conditions].

The treatment for drug dependence in Japan only focuses on detoxification and psychotic disorders, treatment facilities for this study are limited. My proposal for this problem is to improve this situation by having the alcohol treatment ward accept the drug dependency patients. However, drug dependency in-patient treatment has the following concerns, 1. Most patients have tendencies of violence. 2. Motivation and continuation of treatment by the patient is difficult. 3. Breaking rules and deviational conduct. 4. Disintegration of conduct. 5. Disorder of uniformity of group treatment. 6. Lack of specialized resources. In a response to these problems, I am presenting some techniques now on practice at Saitama Prefecture Psychiatric Hospital. Some of these important points are, 1. Building a treatment relationship before admission. 2. Establishing motivation before admission. 3. Stabilization of mental condition before admission. 4. Establishing an explanation and consensus about admission treatment. 5. Knowledge of the craving phase stage and its effects. 6. Devise the program to focus on recovery.7. Create an atmosphere to encourage participation in alcohol and drug dependency groups. 8. Preserve the balance of the program which respects the originality of both groups. I sincerely hope that the above devises will allow the opportunity for the alcohol treatment facilities to open up to the drug dependent patients in the future.

Determining vulnerability to schizophrenia in methamphetamine psychosis using exploratory eye movements.

Patients with methamphetamine (MAP) psychosis whose psychotic symptoms continued after MAP withdrawal were observed at Saitama Prefecture Government Psychiatric Hospital. The purpose of the present study was to ascertain whether some of these MAP psychosis subjects have a vulnerability to schizophrenia. Forty-eight patients with MAP psychosis were divided into three groups based on clinical course: transient type, prolonged type and persistent type. Furthermore, the patients with the persistent type were divided into two groups: one group were moderately disturbed in social adaptive functioning and had Global Assessment Functioning scale (GAF) points >50, and the other group consisted of those who were severely disturbed in social adaptive functioning and who had GAF points of < or =50. These MAP patients were tested for exploratory eye movements, which are the vulnerability marker of schizophrenia, and were compared with 30 patients with schizophrenia and 30 healthy control subjects. The responsive search score of the severely disturbed group of patients of the persistent type was lowest, significantly lower than those of the transient type and the healthy controls. It did not differ from that of the schizophrenic subjects. These results suggest that the severely disturbed group of patients with the persistent type of MAP psychosis have a vulnerability to schizophrenia.