Strengths of the pilotstudy include the randomized, placebo-controlled design and examination of a complicated clinical population that has not been extensively studied in clinical trials. Small sample size is a limitation since this study may have been
underpowered to detect significant differences despite large numerical differences and effect sizes. Use of concomitant psychotropic medications is a potential confound. However, these medications were similar in the two groups and were controlled for in the data analysis. The use of CBT as a psychosocial platform in both groups could have resulted in a reduction in alcohol use that limited our ability to detect medication effects. However, prior research suggests that the specific CBT used in this study increases retention in treatment without significantly reducing substance use (Schmitz et al., 2002). The COMBINE study found that either naltrexone or a combined behavioral intervention that integrated aspects of CBT was superior to medication management alone on drinking outcomes (Anton et al., 2006). However, the combination of combined behavioral intervention and naltrexone was not superior to either intervention alone. In addition, some data suggest that CBT may even increase naltrexone vs. placebo differences in clinical trials (Anton et al., 2005; Oslin et al., 2008). Naltrexone dose was fixed at 50 mg/day. We might have observed a greater reduction in alcohol use with a higher dose or a flexible dosing schedule (McCaul et al., 2000). It would have been useful to have genotyped the participants given emerging data on genotype as a predictor of response to naltrexone (Anton et al., 2008; Ray and Hutchison, 2007). Although participants in each group were similar at baseline, the modest sample size and relatively high attrition rate could have introduced bias in the study sample. A small study is also vulnerable to effects from outliers. However, the data analysis did not identify any outliers in the study. The participants were primarily Caucasian and recruited from a single geographic area, and many were not taking common bipolar disorders medications such as valproate or lithium at baseline potentially limiting the generalizability of the findings. In summary, this study suggests that naltrexone was associated with improvement in some, but not all, alcohol-related outcome measures in patients with bipolardisorder and alcoholdependence. Reduction in alcohol use with naltrexone was related to medication adherence. Larger naltrexone trials in patients with bipolardisorder and alcoholdependence seem warranted.
The study participants were recruited in the psychiatric clinics mentioned previously and by public announcement. The study par- ticipants were not paid for their participation. To be included, the participants had to fulfill the criteria for alcohol and nicotine depen- dence listed in the Diagnostic and Statistical Manual for Mental Disorders (Fourth Edition). We included man and women between 18 and 65 years of age who had completed alcohol withdrawal therapy successfully. Each participant had last consumed alcohol between 7 and 21 days before the baseline study visit. Participants' motivations for joining the study were assessed by study investi- gators who had been trained to perform short motivational inter- ventions. Only participants who clearly stated a motive to abstain from alcohol were included. The motivation to quit smoking was not an inclusion criterion. At the time of study inclusion, participants could be either inpatients or outpatients. All inpa- tients were discharged from inpatient care between 2 to 7 days after randomization.
Patients with comorbid DSM-IV-defined bipolar dis- order, cluster A personality disorder, schizophrenia or other psychotic disorders were excluded, as were those with alcohol/drug dependency, convulsive disorders, glaucoma, suicidal tendencies or serious organic brain disorders. Additional exclusion criteria included seri- ous somatic symptoms, drug hypersensitivity, treat- ment with monoamine oxidase inhibitors (MAOI) within 1 week of the start of the observation period, and electroconvulsive therapy or treatment with other investigational drugs within 12 weeks of study initia- tion. Pregnant or lactating women were also excluded from the study.
tory of seizure disorder, gastrointestinal disease, or neo- plastic disorder; or major acute illness within 90 days prior to screening. Patients with current psychoactive substance abuse or dependence (including alcohol), manic episode, posttraumatic stress disorder, obsessive-compulsive dis- order, or a lifetime diagnosis of bipolar or psychotic dis- order; current generalized anxiety disorder, panic disorder, or social anxiety disorder considered by the investigator to be primary (causing a higher degree of distress or impair- ment than MDD); or a clinically important personality dis- order were also excluded, as were patients with any unstable hepatic, renal, pulmonary, cardiovascular (includ- ing uncontrolled hypertension or myocardial infarction within 180 days of the screening visit), ophthalmologic, neurologic, or other medical condition. Prohibited con- comitant treatments included electroconvulsive therapy or formal psychotherapy (exclusive of supportive therapy) within 180 days of study day 1; venlafaxine within 90 days; investigational drugs or procedures, antipsychotics, or flu- oxetine with 30 days; other antidepressants, monoamine oxidase inhibitors, anxiolytics, sumatriptan, naratriptan, zolmitriptan, and drugs with a similar mechanism of ac- tion, or tryptophan supplements within 14 days; and seda- tive hypnotics (other than zolpidem or zaleplon, allowed only during the first 14 days after randomization), herbal products intended to treat anxiety, insomnia, and de- pression, other psychotropic drugs or substances, or initiation of treatment with nonpsychopharmacologic drugs with psychotropic effects within 7 days of study day 1. Nonpsychopharmacologic drugs with psycho- tropic effects were permitted if the patient has been re- ceiving a stable dose of the drug for at least 90 days before study day 1 and is expected to continue taking the drug without dose changes throughout the study.
Inconsistent with this research, in the study of Akkasheh et al on 40 patients with MDD taking daily probiotics (Bifidobacterium bifidum, Lactobacillus casei, Lactobacillus acidophilus) for 8 weeks, significant reduction was found in depression symptoms (18). The Reininghaus et al study in 2018 titled " The Impact of Probiotic Supplements on Cognitive Parameters in Euthymic Individuals With BipolarDisorder: A PilotStudy " was conducted in Australia on 20 patients with bipolardisorder, Bifidobacterium bifidum, and lactobacillus. Using the Young Mania Scale, it was found that psychomotor processing speed and attention significantly improved and significant reductions in mania symptoms were achieved 1 and 3 months after the commencement of the study (19). Likewise, in the present study, there was a decrease in the Young Mania Rating Scale over time.
pyruvate kinase, and lactate dehydrogenase, as well as fu- marate hydratase, aconitase, and the malic enzymes ME1 and ME2, have shown increased expression in cerebellar samples. Nevertheless, several metabolites related to energy metabolism (e.g., creatine, succinic acid, and glucose-1- phosphate) have been shown to be decreased both in the cerebellum and the prefrontal cortex (PFC), suggesting that energy deficiency with depression leads to compensatory upregulation of the enzymes associated with energy metab- olism [10 – 12]. Positron emission tomography of patients with MDD, reflecting the blood flow and glucose metabolic rate in the brain, suggests reduced blood flow or glucose metabolism in the PFC, anterior cingulate cortex, and caud- ate nucleus. Conversely, in patients with bipolar disease, the reduced metabolic rate increases when transitioning from depression to the manic state . The studies have dem- onstrated that altered metabolism in the PFC-limbic-striatal region could be normalized after alleviating clinical symp- toms by both ADs treatment and non-pharmaceutical ther- apy [14, 15]. Bremner et al. found that when patients with MDD were in a remission state after SSRI treatment and underwent tryptophan-depletion procedures, 7 of 21 pa- tients experienced a depressive relapse, accompanied by decreased or unchanged cerebral metabolism in the thal- amus and middle frontal gyrus, whereas those without re- lapse displayed unaltered cerebral metabolism. Moreover, there is a significant inverse correlation between the meta- bolic state and the Hamilton Depression Rating Scale (HAMD) score .
This study is a randomized, double-blind, placebo-con- trolled procedure. Seventy-four healthy subjects with both males and females were recruited by local advertisement aged between 18 and 34 years (mean age: 25.7±4.7years) in the study from March to November 2012. The study was approved by the Institutional Review Board of Shandong University (No. 1031). Before enrolment, participants underwent thorough screening, including a medical history interview, physical examination, typical tea consumption patterns, and clinical laboratory tests (including ECG and blood chemistry). The exclusion criteria were current or past history of psychotic disorders, a history of substance abuse or dependence, a history of neurological illness (sleeping disorder, epilepsy) or history of severe heart failure, abnormal ECG or other laboratory findings, and daily intake of tea more than three cups. Montgomery-Asberg depression rating scale (MADRS) and 17-item Hamilton Rating Scale for Depression (HRSD-17) were used to assess the depressive symptoms [15,16]. The scores of MADRS and HRSD-17 were measured before consumption of green tea and placebo as the baseline level and were measured again on the end of the experiment 5weeks later. Subjects in different treatment groups were similar in age, education as well as behavioral phenotype demonstrated by baseline MADRS total, HRSD-17 total scores (Table 1).Written informed consent was obtained before the experiment as approved by the Human Ethics Committee of Shandong University (No. 1031).
Male and female patients aged 18 and 65 years who met diagnostic criteria for a major depressive episode and for bipolar I disorder, depressed, according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR), were eligible for randomization and double-blind treatment. In terms of key inclusion criteria, patients must have had a current Hamilton Depression Rating Scale-17 (HAMD-17) score 18 at Visits 1 and 2, and have experienced at least one previous manic or mixed episode, as defined in the DSM-IV-TR, before Visit 1 and within the past 6 years without currently being in a manic episode (Young Mania Rating Scale [YMRS] total score 8 at Visit 2). Patients were excluded principally if they had a history of serious unstable medical illness, diabetes, hemoglobin A1c 6.5% (or blood glucose level indicative of diabetes), serious psychiatric illness other than bipolar depression, or current rapid-cycling mood disturbance. Patients were also excluded for recent substance dependence or use of clozapine, depot antipsychotics, or central nervous system medications other than mood stabilizers. However, certain agents were allowed as concomitant medications in the acute phase of the trial. Investigators were instructed to maintain benzodiazepine use at a minimum level throughout the study. Lorazepam was permitted, if necessary, as a first-line treat- ment to alleviate anxiety.
An intriguing possibility for enhancing alcohol use reduc- tions and smoking cessation in heavy-drinking smokers is combining eﬀective smoking cessation pharmacotherapies with pharmacotherapies that impact alcohol use (Yardley et al., 2015). In this study, we focused on naltrexone, an opi- ate antagonist that is Food and Drug Administration (FDA)- approved for alcohol use disorder treatment and has been shown to reduce heavy drinking in non-abstinence-oriented alcohol treatments (Kranzler et al., 2003; Morgenstern et al., 2012; O’Malley et al., 2015). Although some laboratory stud- ies (Epstein and King, 2004; King and Meyer, 2000; Rohse- now et al., 2007; Rukstalis et al., 2005) but not others (Epstein and King, 2004; Rohsenow et al., 2007; Sutherland et al., 1995) have suggested that naltrexone may reduce crav- ing and the reinforcing value of cigarettes, its eﬃcacy as a smoking cessation pharmacotherapy has not been supported (Hartmann-Boyce et al., 2014). One recent exception demon- strated short-term eﬃcacy for smoking cessation when nal- trexone was combined with bupropion (Mooney et al., 2016). There is some evidence from a human laboratory study that naltrexone may reduce the eﬀect of alcohol use on cigar- ette craving in nontreatment seeking heavy-drinking light smokers (Ray et al., 2007), which suggests that naltrexone could protect against lapses to smoking that occur when recently quit smokers are drinking. This hypothesis has not been evaluated in a treatment-oriented clinical trial. How- ever, 2 randomized clinical trials that evaluated naltrexone versus placebo combined with nicotine patch for smoking cessation have conducted post hoc analyses to determine whether naltrexone had beneﬁcial eﬀects on alcohol use and smoking outcomes in participants who were heavy drinkers. One study found that 12 weeks of naltrexone 50 mg/d com- pared to placebo increased smoking abstinence and reduced
Patients from the parent study were men and women in- patients and outpatients, age 18 to 64 years. They were recruited in Japan, China, Taiwan, Korea, and the United States and met diagnostic criteria for a major depressive episode and for bipolar I disorder (Diagnostic and Statis- tical Manual of Mental Disorders, fourth edition, text revision). Only patients who were recruited in Japan were included in this subanalysis. At the time of randomization, all patients were in a depressive episode that had lasted 90 days or less, and was defined by a 17-item Hamilton Depression Rating Scale (HAMD-17)  total score ≥18. None were actively in a manic epi- sode, defined as having a Young Mania Rating Scale (YMRS)  total score ≤8. All patients had a history of at least 1 manic or mixed episode in the previous 6 years. Exclusion criteria included unstable medical illness; his- tory of diabetes, hemoglobin A 1c ≥6.5% or blood glucose
All patients will be administered the Structured Clinical Interviews for DSM-IV Axis I and Axis II (SCID-I and SCID-II, respectively) by a trained psychiatrist [31,32]. Patients will be eligible if they meet the inclusion criteria: 1) DSM-IV criteria for a diagnosis of PTSD , 2) both gender, aged between 18 to 60 years of age. 3) Women of childbearing potential have to be practicing reliable con- traception and cannot be pregnant or breast-feeding dur- ing the course of the study. The exclusion criteria will be: 1) lifetime history of bipolar, psychotic, borderline per- sonality disorder; substance dependence or abuse (exclud- ing nicotine and caffeine) in the previous 6 months; 2) serious or unstable concurrent illness; history of nephro- lithiasis, 3) use of psychotropic medications for the previ- ous 2 weeks (6 weeks for fluoxetine); 4) body mass index below 20; 5) current suicidal ideation or psychotic symp- toms will be excluded from the study.
Twelve male subjects (six smokers, mean age 25.8¡ 2.6 yr, and six non-smokers, 23.7¡2.7 yr) participated in a double-blind, randomized, placebo-controlled, cross-over pilotstudy. Smokers had a smoking history of at least 4 yr, with current use of o15 cigarettes per day. The Fagerstrom test for nicotine dependence (FTND) was applied (Heatherton et al., 1991). The FTND, consisting of six questions (e.g. How soon after you wake up do you smoke your ﬁrst cigarette ? How many cigarettes per day do you smoke?), yields a score ranging from 0 to 10 (0–2, very low depen- dence ; 8–10 very high dependence). The non-smokers had no history of recreational use of cigarettes. None of the subjects were taking alcohol at the time, nor did they have a history of psychiatric disorder, signiﬁcant physical illness, head injury, neurological disorder, or alcohol or drug (other than nicotine) dependence. MRI demonstrated intact cerebral structures in all subjects. All subjects were right-handed according to the Edinburgh Handedness Inventory. Smokers were in- structed not to smoke for 24 h before scanning, and abstinence was veriﬁed by plasma nicotine measure- ment. Both before and after the administration of nicotine, the strength of cigarette craving was assessed using a 6-point scale (0=no urge, 5=extremely strong urge). After description of the study to the subjects, written informed consent was obtained, and the study was approved by the Ethics and Radiation Safety Committee of the National Institute of Radiological Sciences, Japan.
Agonist therapies aim to replace harmful modes of drug use in terms of dose, route of administration and adverse effects while engaging and retaining cocaine users in treatment. Substitution or agonist therapies are recognized as highly effective for drugs such as nicotine (Jarvik & Henningfield 1993) and heroin (Ward et al . 1998) and more recently have been explored for amphet- amine users (Shearer et al . 2002). Agonist therapies assessed for management of cocaine dependence have included methylphenidate and dexamphetamine. Levin et al . (1998) reported significantly reduced cocaine use and cravings in a group of 12 patients dually diagnosed for adult attention deficit hyperactivity disorder (ADHD) and cocaine dependence receiving 40 mg/day sustained release methylphenidate. However, a placebo-controlled trial of 48 cocaine-dependent ADHD adult patients found improvements in reported ADHD symptoms in subjects receiving active methylphenidate, but no between-group differences in cocaine use or cravings (Schubiner et al . 2002). Further, in a randomizedplacebocontrolled trial of methylphenidate (20 mg twice daily slow release) in 49 patients without adult ADHD, methylphenidate was inef- fective in reducing cocaine intake (Grabowski et al . 1998). They suggested consideration of other stimulants that may be more adequate reinforcers. In a three-arm trial ( n = 128) including placebo, 15–30 mg d- amphetamine and 30–60 mg d-amphetamine groups, Grabowski et al . (2001) found dose-related changes in retention and cocaine use in favour of dexamphetamine treatment with no serious adverse events or cardiovascu- lar complications.
This research study was a two-group, randomized, doubleblind, placebo-controlled design, comparing a 50 mg dose of naltrexone to placebo over a 12-week treatment period on 116 alcohol-dependent males. The present study was conducted in the Iranian city of Shiraz. Patients were re- cruited from alcohol-dependent, self-referred individuals. Informed consent was obtained from all subjects. The in- clusion criteria were: males aged 23-56 years; a current diagnosis of alcoholdependence; and maintenance of at least 3 days, and at most 30 days, sobriety before study entry. The exclusion criteria were: other current drug abuse or dependence (excluding tobacco); current use of opioids (including opioids contained in analgesics) or disulfiram; bilirubin level and alanine aminotransferase higher than five times normal and intake of neuroleptic drugs.
Although LBP is prevalent and has a high risk of chro- nicity and recurrence, evidence on effective treatment of acute phase patients is generally lacking. The requirement for optimum treatment is emphasized by the fact that effective treatment of the acute phase reduces chronicity. 26,27 A broad spectrum of therapy approaches is being used in clinical practice today, ranging from pharmacological and physical agents to exercise and manipulative practice. Various types of physical agents are not sufficiently supported, which is re- flected in the clinical practice guidelines for treatment of acute lumbar pain. The general recommendation is that further studies are required or that physical agents as a form of therapy could be potentially useful in patients for whom no improvement has been achieved by previous treatments. 28–30 This study included patients with severe pain and moderate disability and discomfort during daily activities on baseline
Baseline assessment will be of 40 minutes’ duration and will be conducted upon consent to enter the trial. Data will be gathered on demographics, long-term alcohol con- sumption, medical history of alcohol- and nonalcohol- related illness, drug abuse, age of onset, and family history of alcohol problems. Recent (past 30-day) alcohol consumption will also be assessed by the timeline follow- back (TLFB) method . Severity of dependence will be assessed by the Obsessive-Compulsive Drinking Scale (OCDS)  and by the AlcoholDependence Scale (ADS) . Functional disability will be assessed by the Short- Form Health Survey (SF-12) . Depression, anxiety, and stress levels will be measured by the Depression Anxiety Stress Scales (DASS) . Motivation to change and per- ceived self-efficacy are likely to vary between individuals and be a determinant of treatment outcome; therefore, these will be assessed by the Stages of Change Readiness and Treatment Eagerness (SOCRATES) Scale  and the Alcohol Abstinence Self-Efficacy (AASE) Scale . Sleep disturbance will be assessed by the Insomnia Severity Index (ISI) , and the psychological basis of insomnia will be assessed by the Glasgow Sleep Effort (GSES) Scale. History of other drug use will be determined by the Opi- ate Treatment Index (OTI) interviewer-conducted ques- tionnaire. Blood samples will be taken for full blood count and liver function tests.
each medical institution for eligibility for the current study, and baseline characteristics such as time of initial COPD diagnosis, clinical phenotype, the presence or absence of concurrent bronchial asthma, and smoking history were recorded. The investigators were experts with a lot of experi- ence in the diagnosis and treatment of COPD. In daily clinical practice in Japan, a definitive diagnosis of COPD is made using computed tomography (CT) in most cases, in addition to spirometry. The investigators classified COPD as airway- or emphysema-dominant phenotype on the basis of clinical symptoms (eg, cough and sputum) as well as findings on CT images of the patients (if available).
, 5, normal laboratory values, stable medications for 4 months, and stable use of cholinesterase inhibitors or memantine. Exclusion criteria included non-AD dementia, Down syndrome, sensory impairments precluding participation, pregnancy, contraindication to lumbar puncture or MRI, .4 microhemorrhages on a recent MRI, treated diabetes mellitus, use of resveratrol-containing supplements, and unsuitable disorder or laboratory finding. Participants were assigned to resveratrol or placebo using a stratified permuted block method with an allocation ratio of 1:1. Assignment to groups was stratified by site. After participants signed informed consent and eligibility was confirmed, study sites received randomization numbers from the Informatics Core. A subgroup (n 5 15) was randomized 4:1 (12 treated, 3 placebo) for 24-hour pharmacokinetics. Sample sizes (60 per group) were determined from power analyses utilizing published data on CSF biomarkers in AD trials, and a predicted 20% dropout rate.
first to our knowledge in which montelukast was admin- istered from the first day of admission, during the acute phase of the disease. This report is also the first to our knowledge to include details of the Th2 and Th1 cyto- kines and their ratio in an intervention study of bron- chiolitis. No difference was observed between the 2 groups at baseline and during the time scale of our study. There are a number of possible reasons why monte- lukast was ineffective, including administration failure, different pharmacokinetics in infants, too short a time period of therapy, insufficient power to detect differ- ences, or that montelukast treatment is indeed not ef- fective. Administration failure is unlikely, because there were no failures in administering the granules. Compli- ance with therapy was 90%, on the basis of the final sachet count, and all the infants swallowed the granules without significant difficulty or vomiting. Pharmacoki- netics in infants may differ, particularly in bronchiolitis. It is possible that the plasma level of the drug did not reach therapeutic levels because of reduced absorption, increased metabolism, or interference with other metab- olites. A recent study reported similar pharmacokinetic behavior of montelukast in young (median age: 4 months) versus older infants. 29 Because of the different
Data analyses were conducted on the enrolled subjects who met eligibility criteria for participation in the trial (intention-to-treat analysis). Patients were compared for socio-demographic variables by means of the chi-square for categorical variables, and the t-test for continuous var- iables. Associations between these variables and the pri- mary outcome measure (retention in treatment) were analyzed with the Cox's regression model. Retention rates were assessed by the Kaplan-Meier method . Kaplan- Meier curves were compared using the log-rank test [31,32]. Patients who completed the 12-week trial were regarded as censored observation. Data on the SOWS, HAM-D, opioid craving, and self-reports of opioids and alcohol use were analyzed with repeated measures analy- sis of variance (ANOVA), using treatment group as the between-subjects factor and time as the within-subjects variable. Missing data were replaced using a last-observa- tion-carried-forward approach. Other outcome measures were assessed by the chi-square and t-tests, and Mann- Whitney U-tests. The chi-square test was used to verify dif-