Long-term safety and efficacy of nalmefene in Japanese patients with alcohol dependence.

AIM: The safety and efficacy of nalmefene in Japanese patients with high or very high World Health Organization drinking risk level of alcohol dependence were assessed in a multicenter, randomized, double-blind, placebo-controlled, phase 3 (lead-in) study. Here, the long-term safety and efficacy of nalmefene in an open-label extension of the lead-in study are presented. METHODS: Patients who completed the 24-week lead-in study were eligible for the extension study, where they were treated with nalmefene 20 mg as needed for 24 weeks. The long-term safety and efficacy of nalmefene 20 mg during the total 48-week period were evaluated. Treatment-emergent adverse events during the study period were recorded and change from baseline in the number of heavy drinking days and total alcohol consumption were calculated. RESULTS: Overall, long-term nalmefene 20 mg was well tolerated; the main treatment-emergent adverse events reported in ≥5% of patients included nasopharyngitis (37.2%), nausea (36.5%), somnolence (21.2%), dizziness (16.8%), malaise (14.6%), and vomiting (12.4%). The number of heavy drinking days and total alcohol consumption decreased from baseline to 48 weeks (mixed model for repeated measures, least squares mean ± standard error, -15.09 ± 0.77 days/month and -53.20 ± 2.29 g/day, respectively) during the study. CONCLUSION: This long-term evaluation in Japanese patients with high or very high drinking risk levels of alcohol dependence indicated that nalmefene was safe, well tolerated, and efficacious.

Nalmefene in alcohol-dependent patients with a high drinking risk: Randomized controlled trial.

AIMS: Reducing alcohol consumption is one treatment approach for alcohol-dependent patients. This study compared nalmefene 20 mg and 10 mg with placebo, combined with psychosocial support, in alcohol-dependent Japanese patients with a high or very high drinking risk level (DRL). METHODS: This was a multicenter, randomized, double-blind, phase 3 study conducted in alcohol-dependent patients with a high or very high DRL. Patients were randomized to 24 weeks of treatment with as-needed nalmefene 20 mg, 10 mg, or placebo with psychosocial support. The primary endpoint was change in heavy drinking days (HDD) from baseline to week 12. A key secondary endpoint was the change in total alcohol consumption (TAC) from baseline to week 12. RESULTS: At week 12, 234, 206, and 154 patients who received placebo, nalmefene 20 mg, and 10 mg were included in the primary endpoint analysis. Compared with placebo, nalmefene was associated with significant reductions in HDD at week 12 (difference in 20 mg group, -4.34 days/month; 95% confidence interval [CI]: -6.05 to -2.62; P < 0.0001; difference in 10 mg group, -4.18 days/month; 95%CI: -6.05 to -2.32; P < 0.0001), as well as a significant reduction in TAC at week 12 (P < 0.0001). The incidence of treatment-emergent adverse events was 87.9%, 84.8%, and 79.2% in the groups receiving nalmefene 20 mg, 10 mg, and placebo, respectively. These events were mostly of mild or moderate severity. CONCLUSIONS: Nalmefene 20 mg or 10 mg effectively reduced alcohol consumption and was well tolerated in alcohol-dependent patients with a high or very high DRL.

Current viewpoints on DSM-5 in Japan.

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was published in 2013, and its official Japanese version was published in 2014. The Japanese Government uses classifications from the 10th revision of the I nternational C lassification of D iseases (ICD-10) to categorize disorders and determine treatment fees. However, since the publication of the DSM-III, the use of the DSM system has become prevalent in research and educational settings in Japan. In addition to traditional psychiatry, both the ICD and the DSM are taught by many Japanese medical schools, and virtually all clinical research and trials refer to the DSM to define targeted disorders. Amid the current backdrop in which the reputation of the DSM-5 is being established, the editorial board of P sychiatry and C linical N eurosciences has asked Japanese experts across 12 specialties to examine the structure of the DSM-5, including the following categories: Neurodevelopmental Disorders, Schizophrenia Spectrum Disorders, Major Depression, Bipolar Disorders, Obsessive-Compulsive Disorders, Somatic Symptom Disorder, Eating Disorders, Substance-Related and Addictive Disorders, Gender Dysphoria, and Neurocognitive Disorders. Although opinions were only obtained from these selected experts, we believe that we have succeeded, to a certain extent, in presenting views that are representative of each specialty.

[Behavioral characteristics of nicotine seeking: a role of the nicotine-conditioned effects and other mechanisms].

Nicotine dependence and its neural mechanisms have been well documented by pharmacological, behavioral and neuroscience studies. In this review, we introduce recent new findings in this theme, particularly on the role of nicotine -associated stimuli as non-pharmacological factors affecting maintaining/reinstating nicotine seeking. By using the techniques of drug self-administration and conditioned place preference, nicotine's specific property of forming seeking/taking behavior is well characterized, and the mechanisms of seeking/taking could be partly explained by discrete and/or contextual conditioned stimuli (dCS and cCS). After having the repeated Pavlovian conditioning in the training/conditioning sessions, CSs begin to play a key role for eliciting nicotine seeking behavior, with the activation of mesolimbic dopaminergic systems. In our study, intracranial self- stimulation (ICSS) was used to assess the mesolimbic dopamine activity. The nicotine-associated cCS also activated this neural system, which resulted in decreasing the ICSS threshold approximately 20% in the testing session under the cCS presentation. This finding would support the evidence of CS-induced incentive motivation for nicotine. According to the incentive salience hypothesis, the mesolimbic dopamine reflects the motivation elicited by incentives (CSs), and induces the drug seeking behavior, which is activated through amygdala--nucleus accumbens--medial prefrontal cortex circuit. Additionally, human brain imaging studies have revealed that tobacco- associated stimuli activate not only these regions, but also right temporo-parietal junction of human cortex, which is relevant to the visual attention. In summary, the above evidence shows that nicotine-conditioned stimuli might have powerful incentive salience and regulate nicotine seeking/taking behavior in animals and humans, though stress and nicotine-withdrawal could also enhance nicotine taking in the same way as other dependence -producing mechanisms.

Characteristics of patients with anxiety disorder without selective serotonin reuptake inhibitor prescription over a two-year period of pharmacotherapy.

INTRODUCTION: Pharmacotherapy such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-noradrenaline reuptake inhibitors is recommended for the treatment of anxiety disorders. Although there are patients with persisted symptoms of anxiety disorders who are treated with monotherapy of benzodiazepine anxiolytics without SSRIs, the characteristics of these patients are unclear. In the present study, we investigated the characteristics of patients with persisted symptoms of anxiety disorder without SSRI prescription. METHODS: From a prescription dataset covering 2018 and 2020, the prescriptions of 243 patients with anxiety disorder were analyzed. Patients were classified into two groups: SSRI non-prescription and prescription groups. RESULTS: The SSRI non-prescription group had a higher ratio of females than did the SSRI prescription group (60.1% vs. 44.6%, respectively, p = 3.12 × 10-2 ), but statistically not significant after the Bonferroni correction. No significant differences in age, body mass index, or duration of outpatient visits were found between groups. Among the independent variables, sex (female) was the only variable identified that predicted SSRI non-prescription. CONCLUSION: The present study showed that among patients with anxiety disorders, sex (female) was the only variable that predicted SSRI non-prescription.

[Reconsideration of nicotine and other substance dependence: a clue from dependence-related mentation including reward, motivation, learning, delusion and hallucination toward understanding the concept of non-substance-related addiction].

Nicotine produces core symptoms of substance dependence (craving and withdrawal) without any psychotic symptoms. The psychopharmacological structure of craving is hypothesized to be constituted by three components: the primary reinforcing property of a substance, the secondary reinforcing property of that substance (conditioned aspects of the environment, such as contextual or specific cues associated with substance taking), and the negative affective motivational property during withdrawal (i.e. the desire to avoid the dysphoric withdrawal symptoms elicits craving). Among the three components, the primary reinforcing property of a substance forms the most fundamental factor for establishing substance dependence. Sensitization or reverse tolerance observed in locomotor activity of animals, which had been believed to be a methamphetamine psychosis model, is demonstrated to reflect the establishment of conditioned reinforcement. Finally, non-substance-related addiction such as gambling, internet, and sex is discussed. From the aspect of the above hypothetical psychopharmacological structure of craving, the most significant difference between substance dependence and non-substance-related addiction is that the primary reinforcing property of non-substance reward is relatively intangible in comparison with that of a substance of abuse.

Prevalence and Clinical Significance of Psychiatric Comorbidities With Gambling Disorder in 12 Clinical Settings in Japan.

OBJECTIVES: This study investigated the occurrence rate of psychiatric disorders comorbid with gambling disorder, and their clinical significance in the severity of gambling disorder using a retrospective cross-sectional design. METHODS: The medical records of 359 patients (men/women, 326/33; median age, 37.0 years) with gambling disorder as the primary disorder from 12 treatment facilities specializing in addiction (9 clinics and 3 hospitals) in Japan were studied. We investigated patients' comorbid psychiatric disorders, demographic and clinical characteristics, and the severity of gambling disorder based on criteria from the Diagnostic and Statistical Manual of Mental Disorders, fifth edition. RESULTS: Of all patients, 58.3% had comorbidities (tobacco use disorder, 20.9%; alcohol use disorder, 13.9%; major depressive disorder, 13.1%; behavioral addictions, 13.1%; attention-deficit hyperactivity disorder, 6.1%; etc.). Statistical analysis indicated that as the number of comorbid psychiatric disorders increased, psychosocial problems also increased (e.g., proportion of adverse childhood experiences [ P < 0.001], and history of suicide attempts [ P = 0.009]). In the multivariable analysis, behavioral addictions ( ß = 0.666; t = 3.151) were significantly associated with gambling disorder severity. Specifically, individuals with gambling disorder comorbid with behavioral addictions including kleptomania, excessive buying, and excessive sex-related behavior may present more severe gambling problems than those without behavioral addictions. CONCLUSIONS: Patients with gambling disorder should be carefully assessed for psychiatric comorbidities and interventions should reflect the individual diagnosis.

Association between functional recovery and medication adherence in schizophrenia.

AIM: Medication adherence is important for achieving functional recovery from schizophrenia and is commonly assessed using the Drug Attitude Inventory-30 (DAI-30). Subscales of the DAI-30, including "awareness of the need for medication," "awareness of the effects of psychiatric drugs," and "impression of medication," have been used to assess medication adherence. To determine which of these subscales are associated with the prognosis of schizophrenia, this study followed patients with schizophrenia to identify the prognosis and examine the subscales related to "recovery." METHODS: In total, 89 patients were recruited, 78 of whom were registered in the study. After assessing adherence using the DAI-30, Positive and Negative Syndrome Scale and Global Assessment of Functioning scores were assessed at 0 and 24 week to define the functional prognosis. RESULTS: At the end of the 24-week follow-up period, 36% of patients showed recovery from schizophrenia. A comparison of subscales revealed that the score for "impression of medication" was significantly higher in the recovery than in the non-recovery group. Logistic regression analysis identified only the "impression of medication" score as being predictive of recovery. CONCLUSION: The results indicated that among the three DAI-30 subscales, "impression of medication" was the most closely associated with recovery in patients with schizophrenia.

Future direction of addiction research-An expert questionnaire survey in Japan.

Addiction has become a major worldwide medical, public health, and social problem. Because the prevalence of addiction varies widely geographically, due to differences in ethnicity, culture, education, social environment, and regulation, each country or region needs to understand its current state of addiction and to take appropriate measures, in multidisciplinary collaboration. In order to understand the direction of addiction research in Japan, we analyzed 50 research and development topics and their characteristics, based on an expert questionnaire survey. The topics were placed in five categories, as follows. Category 1: Basic science; all 10 topics were of the Long-term project and International cooperation types. Category 2: Translational and clinical research; 6 out of 10 topics were of the Long-term project. Category 3: Fact-finding surveys; 8 out of 10 topics were of the Japan-specific type. Category 4: Health system and service; 8 out of 10 topics were of the Japan-specific type and Short-term project. Category 5: Study on society, culture, environment, education, and regulation; 7 out of 10 topics were of the Short-term project (similar to Category 4). As far as we know, this is the first systematic questionnaire survey on the direction of addiction research. The results of this study might support developing a strategy for addiction research, not only in Japan, but also in other countries.

[Current trends of nicotine dependence].

This article reviews clinical features and neural mechanisms of nicotine dependence as well as medications for it. The ICD-10 and DSM-IV-TR classifications define nicotine dependence and nicotine withdrawal. The rewarding effects of nicotine have been reported to include a sense of well-being, increased vigilance, relaxation, anxiolytic effects, increased capacity to cope with stressors, and increased ability of learning and memory. These psychopharmacological effects of nicotine may be produced by the ability of nicotine to promote the release of catecholamines, acetylcholine, beta-endorphin, glucocorticoid, and other hormones. As for medications used to treat nicotine dependence, nicotine gum and nicotine patches are used to alleviate nicotine withdrawal, whereas bupropion, varenicline, and rimonabant are used to decrease rewarding effects of nicotine.

Associations between parental bonding during childhood and functional recovery in patients with schizophrenia.

INTRODUCTION: Schizophrenia is believed to be etiologically associated with environmental factors. Poor parental bonding, especially arising from "low care" and "overprotection," may contribute to the prognosis in patients with psychosis. In the present study, we investigated the associations between the aforementioned two different parental bonding types and the prognosis, in terms of the functional recovery, of patients with schizophrenia. METHODS: A total of 89 patients with schizophrenia were recruited, and 79 patients were registered for the study. After the parental bonding types and representative childhood adverse events were assessed, specific items on the PANSS were assessed at 0 and 24 weeks of the study period to define the functional prognosis. RESULTS: At the end of the 24-week follow-up period, 36% of the patients were judged as showing recovery from schizophrenia. The score for "overprotective attitude," but not that for "low care," was found to be significantly higher in the non-recovery (defined below) group. Exploratory logistic regression analysis identified only "overprotective attitude" of the parents as being predictive of non-recovery. Moreover, a significant negative correlation was found between "low care" and "overprotective attitude" only in the non-recovery group. CONCLUSION: In the present study, we showed that an overprotective attitude of the parents was associated with non-recovery in patients with schizophrenia.

[Role of smoking and nicotine in neuropsychiatric disorders: evidence for therapeutic role of nicotinic acetylcholine receptors].

The role of smoking and nicotine in various neuropsychiatric disorders has been attracting increasing attention. Recently, investigations into the neurobiological properties of brain nicotinic acetylcholine receptors (nAChRs) have led to an improved understanding of their role in the above disorders, alpha4beta2 and alpha7 subunit containing nAChRs are predominantly identified in the brain among all types of nAChRs composed of nine alpha (alpha2 to alpha10) and three beta (beta2 to beta4) subunits. These receptors play important roles in attention, memory, and cognition and participate in the pathogenesis of several neuropsychiatric disorders (schizophrenia, depression, anxiety disorders, Parkinson's and Alzheimer's diseases, attention-deficit hyperactivity disorders, Tourette's syndrome, and autosomal dominant nocturnal frontal lobe epilepsy). For the majority of these disorders, the use of nAChRs agonists may represent either a prophylactic (especially for Parkinson's and Alzheimer's diseases) or a symptomatic treatment. The possible mechanisms underlying these beneficial effects as well as the characteristics and potential therapeutic use of new, subtype-selective nAChRs agonists are presented.

[Clinical features of nicotine dependence].

Nicotine dependence is characterized by weak dependence potential and less ability to produce psychotoxicity and social disturbance. A two-compartment model consisting of "dependence" and "dependence syndrome" was used to clarify clinical features of nicotine dependence. "Dependence" was defined by drug liking. "Dependence syndrome" was defined by a compulsion to take a drug, and drug-induced pathological symptoms (withdrawal syndrome and acute disorders) and social disturbance. Nicotine produced a mild or the least degree of drug liking and withdrawal syndrome, without any significant social disturbance, or acute disorders. Thus, nicotine dependence differed from other forms of drug dependence in that nicotine was not associated with "dependence syndrome". This review also introduced other current topics of nicotine dependence. First, adolescence is regarded as a risk factor for the development of nicotine dependence, whereas the involvement of gender difference (female) in this respect is controversial. Secondly, many smokers feel difficulties in quitting smoking in spite of the weak dependence potential of nicotine, which is known as the "nicotine paradox". Several working hypotheses have been presented to explain this phenomenon. For example, nicotine has relatively strong conditioning effects and/or dependence liability compared with other drugs of abuse. However, further studies should be carried out to clarify clinical characteristics of the "nicotine paradox".

Brain regions mediating the discriminative stimulus effects of nicotine in rats.

The involvement of cerebral regions in the discriminative stimulus (DS) effects of nicotine was studied using rats. Substitution tests with nicotine administered into the medial prefrontal cortex, nucleus accumbens, and ventral tegmental area, all of which are located on the mesolimbocortical dopaminergic neurons, and into the dorsal hippocampus and medial habenular nucleus, which possess high densities of nicotinic cholinergic receptors, were conducted in rats trained to discriminate nicotine (0.5 mg/kg s.c.) from saline solution in a two-lever, food-reinforced, operant task. Nicotine administered into the medial prefrontal cortex substituted for nicotine (0.5 mg/kg s.c.), whereas nicotine administered into the nucleus accumbens and ventral tegmental area partially substituted for sc injected nicotine. However, nicotine administered into the dorsal hippocampus and medial habenular nucleus did not substitute for sc injected nicotine. These results suggest that the medial prefrontal cortex is primarily involved in the DS effects of nicotine, whereas the nucleus accumbens and ventral tegmental area are partially involved.

Clinical features of nicotine dependence compared with those of alcohol, methamphetamine, and inhalant dependence.

A new clinical evaluation form was developed to compare the clinical features of nicotine dependence with those associated with other abused drugs. A new scoring system for clinical evaluation was developed. The form consisted of five scoring items: subjective effects, liking (of drug), withdrawal syndrome, acute psychic and physical disorders, and social disturbance. A preliminary clinical investigation was performed to test the validity of the evaluation form. Study subjects were those showing dependence on nicotine (cigarette smoking, n = 40), alcohol (n = 39), methamphetamine (n = 31), and inhalants (n = 30), who fulfilled the DSM-IV-TR criteria for drug dependence disregarding the state of "a maladaptive pattern of substance use, leading to clinically significant impairment or distress," and gave written informed consent for participation in the study. Nicotine caused a mild or the least degree of subjective effects, liking, and psychic and physical withdrawal symptoms, without any significant social disturbance or acute disorders. With alcohol, liking, withdrawal syndrome, and acute physical disorders were prominent. Methamphetamine produced the most serious acute psychic disorders, with intensive acute physical disorders and psychic withdrawal symptoms. Inhalants were characterized by an intensive degree of acute psychic disorders. As for social disturbance, alcohol, methamphetamine, and inhalants showed more significant influence than nicotine. Our study findings revealed that the clinical features of drug dependence could be evaluated by using the new clinical evaluation form. Further study is required to clarify the clinical features of nicotine dependence compared with those of other drugs of dependence.

[Studies on clinical features of nicotine dependence in comparison with those of alcohol and methamphetamine dependence using a two compartment model of drug dependence].

The purpose of the present study was to develop a new clinical evaluation form to compare the clinical features of nicotine dependence with those associated with alcohol and methamphetamine dependence, using a two compartment model consisting of "drug dependence" and "dependence syndrome". The evaluation form consisted of six scoring items: subjective effects, tolerance, drug liking, social disturbance, withdrawal syndrome, and acute psychic and acute physical disorders. "Drug dependence" was defined by positive scores on the "drug liking" item. "Dependence syndrome" was defined by positive scores on drug-induced pathological symptoms (withdrawal syndrome, and acute psychic and physical disorders) and social disturbance. The subjects were dependent on nicotine (n = 68), alcohol (n = 62), or methamphetamine (n = 55). All subjects met DSM-IV diagnostic criteria for drug dependence. Nicotine produced a mild degree of drug liking and psychic withdrawal symptoms, but did not cause significant physical withdrawal symptoms, acute psychic or physical disorders or social disturbance. Alcohol and methamphetamine produced a moderate degree of drug liking and significant levels of withdrawal syndrome, acute disorders and social disturbance. Thus, in the present study, nicotine dependence differed from other forms of drug dependence in that nicotine was not associated with "dependence syndrome".

[Studies on clinical characteristics of nicotine dependence using a two compartment model of drug dependence].

The purpose of the present study was to develop a new clinical evaluation form to compare the clinical characteristics of nicotine dependence with those associated with other drugs of abuse, using a two-compartment model consisting of "drug dependence" and "dependence syndrome". The evaluation form consisted of five scoring items: subjective effects, drug liking, withdrawal syndrome, acute psychic and acute physical disorders, and social disturbance. "Drug dependence" was defined by positive scores on the "drug liking" item. "Dependence syndrome" was defined by positive scores on drug-induced pathological symptoms (withdrawal syndrome, and acute psychic and physical disorders) and social disturbance. The subjects were dependent on nicotine (cigarette smoking) (n = 114), alcohol (n = 101), methamphetamine (n = 90), inhalants (n = 63), and benzodiazepines (n = 39). All subjects met the DSM-IV-TR criteria for drug dependence. Nicotine produced a mild or the least degree of drug liking and withdrawal syndrome, without any significant social disturbance, or acute disorders. The other four drugs produced more intensive degrees of withdrawal syndrome and acute psychic and physical symptoms, with more significant social disturbance than nicotine. The present study indicated that nicotine dependence differed from other forms of drug dependence in that nicotine was not associated with "dependence syndrome".

Facilitation of intracranial self-stimulation behavior in rats by environmental stimuli associated with nicotine.

Environmental stimuli associated with nicotine act as a trigger for nicotine-seeking behavior and make it difficult to quit smoking. The trigger action might be related to the activity of the mesolimbic dopamine "reward" system. Thus, in the present study, we investigated the effects of nicotine-associated stimuli on reward seeking, assessed by current intensity thresholds of intracranial self-stimulation (ICSS) in rats. Rats were unilaterally implanted with an electrode into the lateral hypothalamus and trained to press a lever to obtain electrical brain stimulation. After stable responses had been established, the rats underwent six conditioning sessions with subcutaneous nicotine at 0.4 mg/kg in particular visual and tactile contexts. The threshold for electrical stimulation was then tested in either the nicotine-conditioned environment or novel environment under saline or nicotine treatment. Nicotine enhanced the responding for ICSS and significantly lowered the threshold in both environments. Under saline treatment, the responding for ICSS was facilitated and the threshold was significantly lower in the nicotine-conditioned environment than in the novel environment. The present results demonstrate that nicotine-conditioned contextual stimuli may affect the mesolimbic dopamine system through ICSS threshold lowering effect.