Betaine prevents and reverses the behavioral deficits and synaptic dysfunction induced by repeated ketamine exposure in mice.

As an N-methyl-D-aspartate (NMDA) receptor inhibitor, ketamine has become a popular recreational substance and currently is used to address treatment-resistant depression. Since heavy ketamine use is associated with persisting psychosis, cognitive impairments, and neuronal damage, the safety of ketamine treatment for depression should be concerned. The nutrient supplement betaine has been shown to counteract the acute ketamine-induced psychotomimetic effects and cognitive dysfunction through modulating NMDA receptors. This study aimed to determine whether the adjunctive or subsequent betaine treatment would improve the enduring behavioral disturbances and hippocampal synaptic abnormality induced by repeated ketamine exposure. Mice received ketamine twice daily for 14 days, either combined with betaine co-treatment or subsequent betaine post-treatment for 7 days. Thereafter, three-chamber social approach test, reciprocal social interaction, novel location/object recognition test, forced swimming test, and head-twitch response induced by serotonergic hallucinogen were monitored. Data showed that the enduring behavioral abnormalities after repeated ketamine exposure, including disrupted social behaviors, recognition memory impairments, and increased depression-like and hallucinogen-induced head-twitch responses, were remarkably improved by betaine co-treatment or post-treatment. Consistently, betaine protected and reversed the reduced hippocampal synaptic activity, such as decreases in field excitatory post-synaptic potentiation (fEPSP), long-term potentiation (LTP), and PSD-95 levels, after repeated ketamine treatment. These results demonstrated that both co-treatment and post-treatment with betaine could effectively prevent and reverse the adverse behavioral manifestations and hippocampal synaptic plasticity after repeated ketamine use, suggesting that betaine can be used as a novel adjunct therapy with ketamine for treatment-resistant depression and provide benefits for ketamine use disorders.

N, N-dimethylglycine Protects Behavioral Disturbances and Synaptic Deficits Induced by Repeated Ketamine Exposure in Mice.

Ketamine, an N-methyl-d-aspartate receptor (NMDAR) blocker, is gaining ground as a treatment option for depression. The occurrence of persistent psychosis and cognitive impairment after repeated use of ketamine remains a concern. N, N-dimethylglycine (DMG) is a nutrient supplement and acts as an NMDAR glycine site partial agonist. The objective of this study was to assess whether DMG could potentially prevent the behavioral and synaptic deficits in mice after repeated ketamine exposure. Male ICR mice received ketamine (20 mg/kg) from postnatal day (PN) 33-46, twice daily, for 14 days. The locomotor activity, novel location recognition test (NLRT), novel object recognition test (NORT), social interaction test, head twitch response induced by serotonergic hallucinogen, and the basal synaptic transmission and long-term potentiation (LTP) in the hippocampal slices were monitored after repeated ketamine treatment. Furthermore, the protective effects of repeated combined administration of DMG (30 and 100 mg/kg) with ketamine on behavioral abnormalities and synaptic dysfunction were assessed. The results showed that mice exhibited memory impairments, social withdrawal, increased head twitch response, reduced excitatory synaptic transmission, and lower LTP after repeated ketamine exposure. The ketamine-induced behavioral and synaptic deficits were prevented by co-treatment with DMG. In conclusion, these findings may pave a new path forward to developing a combination formula with ketamine and DMG for the treatment of depression and other mood disorders.

The Changes of qEEG Approximate Entropy during Test of Variables of Attention as a Predictor of Major Depressive Disorder.

Evaluating brain function through biosignals remains challenging. Quantitative electroencephalography (qEEG) outcomes have emerged as a potential intermediate biomarker for diagnostic clarification in psychological disorders. The Test of Variables of Attention (TOVA) was combined with qEEG to evaluate biomarkers such as absolute power, relative power, cordance, and approximate entropy from covariance matrix images to predict major depressive disorder (MDD). EEG data from 18 healthy control and 18 MDD patients were monitored during the resting state and TOVA. TOVA was found to provide aspects for the evaluation of MDD beyond resting electroencephalography. The results showed that the prefrontal qEEG theta cordance of the control and MDD groups were significantly different. For comparison, the changes in qEEG approximate entropy (ApEn) patterns observed during TOVA provided features to distinguish between participants with or without MDD. Moreover, ApEn scores during TOVA were a strong predictor of MDD, and the ApEn scores correlated with the Beck Depression Inventory (BDI) scores. Between-group differences in ApEn were more significant for the testing state than for the resting state. Our results provide further understanding for MDD treatment selection and response prediction during TOVA.

Regulating anger in different relationship contexts: A comparison between psychiatric outpatients and community controls.

BACKGROUND: The capacity to regulate emotion is important for individuals' ability to adapt to society, the long-term lack of which can lead to related emotional disorders. However, evaluating whether an emotion-regulation strategy is appropriate requires consideration of the individual's distinct culture and situation. In this study, we compared the anger regulation strategies employed in various interpersonal situations by psychiatric outpatients and a community control group in Taiwan. METHODS: We surveyed 150 psychiatric outpatients (mean age = 45.30, SD = 12.48, 73.3% female) and 150 community controls (mean age = 45.05, SD = 12.24, 73.3% female) congruent in age and sex. Participants evaluated their emotion regulation in two interpersonal contexts by completing a set of questionnaires related to a recent incident of anger they experienced with family and friends, respectively. RESULTS: Outpatients used the emotion-regulation strategies of cognitive reappraisal and expressive suppression equally in various relationships; while the community control group made more use of cognitive reappraisal to regulate anger, which arose in their relationships with both family and friends. Relationship intimacy influenced the strategy adopted, and the community control group was more likely to use suppression to regulate anger towards friends than family members, which reflected a cultural belief-maintaining harmony in social relationships. LIMITATIONS: Context-specific emotion regulation was assessed via a retrospective self-report measure, which is subject to recall bias. CONCLUSIONS: Our findings highlight the importance of considering interpersonal contexts when studying emotion regulation and developing psychological interventions that target anger or other negative emotion regulation.

Prevalence and clinical correlates of flunitrazepam-related complex sleep behaviors.

AIM: Complex sleep behaviors (CSB) are often associated with the use of hypnotic drugs. This study investigated the prevalence and correlates of CSB among psychiatric patients who were given flunitrazepam. METHODS: From June 2011 to May 2012, a total of 268 psychiatric outpatients who had received flunitrazepam for at least 3 months were enrolled. Data on occurrence of CSB, demographic characteristics, flunitrazepam dosage and duration of use, psychiatric diagnoses, physical illnesses, and alcohol use were collected. Logistic regression analysis was used to examine the clinical correlates of CSB. RESULTS: Sixty-six participants (24.6%) reported experiencing CSB. Logistic regression analysis showed that a high dosage (>2 mg/day) of flunitrazepam (odds ratio [OR] = 1.941, 95% confidence interval [CI] = 1.090-3.455, P = 0.024) and alcohol use (OR = 1.948, 95%CI = 1.023-3.709, P = 0.042) were significantly associated with the occurrence of CSB. Sex, age, duration of flunitrazepam use, psychiatric diagnoses, and physical illnesses were not significantly associated with the occurrence of CSB. CONCLUSION: CSB among flunitrazepam users should be monitored routinely, especially among those receiving a high dosage who also consume alcohol.

Delayed extinction and stronger drug-primed reinstatement of methamphetamine seeking in rats prenatally exposed to morphine.

Prenatal morphine (PM) affects the development of brain reward system and cognitive function. The present study aimed to determine whether PM exposure increases the vulnerability to MA addiction. Pregnant Sprague-Dawley rats were administered saline or morphine during embryonic days 3-20. The acquisition, extinction and reinstatement of methamphetamine (MA) conditioned place preference (CPP) and intravenous self-administration (SA) paradigms were assessed in the male adult offspring. There was no difference in the acquisition and expression of MA CPP between saline- and PM-exposed rats, whereas PM-exposed rats exhibited slower extinction and greater MA priming-induced reinstatement of drug-seeking behavior than controls. Similarly, MA SA under progressive ratio and fixed ratio schedules was not affected by PM exposure, but PM-exposed rats required more extinction sessions to reach the extinction criteria and displayed more severe MA priming-, but not cue-induced, reinstatement. Such alterations in extinction and reinstatement were not present when PM-exposed rats were tested in an equivalent paradigm assessing operant responding for food pellets. Our results demonstrate that PM exposure did not affect the association memory formation during acquisition of MA CPP or SA, but impaired extinction learning and increased MA-primed reinstatement in both tasks. These findings suggest that the offspring of women using morphine or heroin during pregnancy might predict persistent MA seeking during extinction and enhanced propensity to MA relapse although they might not be more susceptible to the reinforcing effect of MA during initiation of drug use.

Buprenorphine, methadone, and morphine treatment during pregnancy: behavioral effects on the offspring in rats.

Methadone and buprenorphine are widely used for treating people with opioid dependence, including pregnant women. Prenatal exposure to opioids has devastating effects on the development of human fetuses and may induce long-term physical and neurobehavioral changes during postnatal maturation. This study aimed at comparing the behavioral outcomes of young rats prenatally exposed to buprenorphine, methadone, and morphine. Pregnant Sprague-Dawley rats were administered saline, morphine, methadone, and buprenorphine during embryonic days 3-20. The cognitive function, social interaction, anxiety-like behaviors, and locomotor activity of offsprings were examined by novel object recognition test, social interaction test, light-dark transition test, elevated plus-maze, and open-field test between 6 weeks and 10 weeks of age. Prenatal exposure to methadone and buprenorphine did not affect locomotor activity, but significantly impaired novel object recognition and social interaction in both male and female offsprings in the same manner as morphine. Although prenatal exposure to methadone or buprenorphine increased anxiety-like behaviors in the light-dark transition in both male and female offsprings, the effects were less pronounced as compared to that of morphine. Methadone affected elevated plus-maze in both sex, but buprenorphine only affected the female offsprings. These findings suggest that buprenorphine and methadone maintenance therapy for pregnant women, like morphine, produced detrimental effects on cognitive function and social behaviors, whereas the offsprings of such women might have a lower risk of developing anxiety disorders.

Correlates of dependence and beliefs about the use of hypnotics among zolpidem and zopiclone users.

BACKGROUND: Zolpidem and zopiclone are the two most commonly prescribed Z-drugs approved to treat insomnia. OBJECTIVES: To examine the demographic and clinical correlates of dependence and beliefs about hypnotic use among long-term zolpidem and zopiclone users in psychiatric treatment for insomnia. METHODS: A total of 392 psychiatric outpatients who received zolpidem or zopiclone treatment for at least 3 months for insomnia were studied. Participants' severity of hypnotic dependence and beliefs about the use of hypnotics to treat sleep problems were assessed. The correlation of dependence and beliefs about zolpidem and zopiclone treatment with demographic characteristics, hypnotic-using behaviors, co-use of addictive substances, and depressive symptoms were analyzed using multiple regression analysis models. RESULTS: Zolpidem users reported more severe dependence and a lower level of necessity regarding the use of hypnotics than zopiclone users did. High equivalent doses of hypnotics and long duration of use were significantly associated with severe dependence and a low level of necessity. Severe depressive symptoms were signiciantly associated with severe dependence, a low level of necessity, and a low level of concern. Educational level was also associated with the levels of concern and necessity. Conclusions/Importance: There were differences in the level of dependence and belief about hypnotic use between zolpidem and zopiclone users. The correlates of dependence and belief identified in this study can serve as the basis for prevention and intervention programs.

Severity of alprazolam dependence and associated features among long-term alprazolam users from psychiatric outpatient clinics in Taiwan.

BACKGROUND/PURPOSE: The aim of this study was to examine the correlations between the severity of alprazolam dependence and socio-demographic characteristics, the characteristics of alprazolam use, psychiatric comorbidity, and beliefs toward alprazolam use among long-term alprazolam users in Taiwan. METHODS: A total of 148 long-term alprazolam users participated in this study. The Chinese version of the Severity of Dependence Scale was used to assess participants' severity of alprazolam dependence in the preceding month. Their socio-demographic characteristics, family function characteristics, dosage of prescribed alprazolam, duration of alprazolam use, alcohol use pattern, pain reliever and cigarette use pattern, severity of depressive symptoms, psychiatric diagnosis, and belief toward alprazolam use were investigated. RESULTS: The results of multiple regression analysis indicated that a longer duration of alprazolam use, severe depressive symptoms, a high level of belief in the necessity of alprazolam treatment, and a high level of concern about the potential adverse consequences of alprazolam use were significantly associated with more severe alprazolam dependence. CONCLUSION: Doctors should closely monitor the severity of alprazolam dependence among long-term users, especially patients' levels of depression, beliefs in the necessity of alprazolam treatment, and their concerns over the adverse consequences of continued treatment with alprazolam.

Clinical correlates of zolpidem-associated complex sleep-related behaviors: age effect.

OBJECTIVE: Complex sleep-related behaviors (CSBs) are often associated with hypnotic use, especially zolpidem. The age effect on the occurrence of CSBs has not been adequately investigated. This study aimed to investigate and compare the clinical correlates of CSBs between adult and elderly subjects who were taking zolpidem. METHOD: A total of 253 adults (aged 20-55 years) and 64 elderly subjects (aged ≥ 65 years) who were administered zolpidem for at least 3 months were enrolled from psychiatric outpatient clinics from June 2011 to May 2012. The sociodemographic characteristics of the participants, the dose of zolpidem, and the occurrence of CSBs were collected. Logistic regression analysis was used to examine the clinical correlates of CSBs. RESULTS: In total, there were 62 members of the adult group (24.5%) and 11 elderly subjects (17.2%) with CSBs; however, the difference did not reach statistical significance. Logistic regression analysis showed that there was a main effect of zolpidem dose (≥ 10 mg; OR = 2.82, P = .038) and alcohol use (OR = 2.05, P = .026), but not sex or age group. There were interactive effects between age group and zolpidem dose (P = .043), indicating that a higher dose of zolpidem was associated with CSBs only in the adult group and not in the elderly group. Adults with CSBs used a higher dose of zolpidem than adults without (mean ± SD: 15.4 ± 6.8 mg vs 11.3 ± 5.7 mg), whereas elderly patients with CSBs did not use a higher dose of zolpidem than those without (12.2 ± 5.4 mg vs 11.9 ± 7.0 mg). CONCLUSIONS: A higher dose of zolpidem was correlated with CSBs only in the adult group and not in the elderly group. Future studies investigating the factors, other than dose, related to CSBs in the elderly will be performed.

Long-lasting alterations in 5-HT2A receptor after a binge regimen of methamphetamine in mice.

The repeated administration of methamphetamine (MA) to animals in a single-day 'binge' dosing regimen produces damage to dopamine and serotonin terminals and psychosis-like behaviours similar to those observed in MA abusers. The present study aimed to examine the effects of MA binge exposure on 5-HT2A receptors, the subtype of serotonin receptors putatively involved in psychosis. ICR male mice were treated with MA (4 × 5 mg/kg) or saline at 2 h intervals. Recognition memory and social behaviours were sequentially evaluated by a novel location recognition test, a novel object recognition test, a social interaction and a nest-building test to confirm the persistent cognitive and behavioural impairments after this dosing regimen. Subsequently, a hallucinogenic 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head-twitch, molecular and electrophysiological responses were monitored. Finally, the levels of 5-HT2C, 5-HT1A, 5-HT2A and mGlu2 receptors in the medial prefrontal cortex were determined. MA binge exposure produced recognition memory impairment, reduced social behaviours, and increased DOI-induced head-twitch response, c-Fos and Egr-2 expression and field potentials in the medial prefrontal cortex. Furthermore, MA binge exposure increased 5-HT2A and decreased mGlu2 receptor expression in the medial frontal cortex, whereas 5-HT2C and 5-HT1A receptors were unaffected. These data reveal that the increased behavioural, molecular and electrophysiological responses to DOI might be associated with an up-regulation of 5-HT2A receptors in the medial prefrontal cortex after MA binge exposure. Identifying the biochemical alterations that parallel the behavioural changes in a mouse model of MA binge exposure may facilitate targeting therapies for treatment of MA-related psychiatric disorders.

Superior antidepressant effect occurring 1 month after rTMS: add-on rTMS for subjects with medication-resistant depression.

Depression is a major psychiatric disorder. The standard treatment for depression is antidepressant medication, but the responses to antidepressant treatment are only partial, even poor, among 30%-45% of patients. Refractory depression is defined as depression that does not respond to antidepressant therapy after 4 weeks of use. There is evidence that repetitive transcranial magnetic stimulation (rTMS) may exert effects in treating psychiatric disorder through moderating focal neuronal functions. High-frequency rTMS on the left prefrontal area and low-frequency rTMS on the right prefrontal area were shown to be effective in alleviating depressive symptoms. Given the statistically significant antidepressant effectiveness noted, the clinical application of rTMS as a depression treatment warrants further studies. Application of rTMS as an add-on therapy would be a practical research model. High-frequency (5-20 Hz) rTMS over the left dorsolateral prefrontal cortex was found to have a significant effect on medication-resistant depression. In the present study, we not only measured the acute antidepressant effect of rTMS during treatment and immediately after its completion but also evaluated participants 1 month after completion of the treatment protocol. Study participants were divided into two groups: an active rTMS group (n = 10) and a sham group (n = 10). The active rTMS group was defined as participants who received the rTMS protocol, and the sham group was defined as participants who received a sham rTMS procedure. A significant Hamilton Depression Rating Scale score reduction was observed in both groups after the fifth and tenth treatments. However, those in the active rTMS group maintained their improvement as measured one month after completion of the rTMS protocol. Participants who received active rTMS were more likely to have persistent improvement in depression scores than participants who received sham rTMS.

Simultaneous determination of opiates, methadone, buprenorphine and metabolites in human urine by superficially porous liquid chromatography tandem mass spectrometry.

For monitoring compliance of methadone or buprenorphine maintenance patient, a method for the simultaneous determination of methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), buprenorphine, norbuprenorphine, opiates (morphine, codeine, 6-monoacetylmorphine) in urine by superficially porous liquid chromatography tandem mass spectrometry was developed and validated. After enzyme digestion and liquid-liquid extraction, reverse-phase separation was achieved in 5.2 min and quantification was performed by multiple reaction monitoring. Chromatographic separation was performed at 40 °C on a reversed phase Poroshell column with gradient elution. The mobile phase consisted of water and methanol, each containing 0.1% formic acid, at a flow rate of 0.32 mL/min. Intra-day and inter-day precision were less than 12.1% and accuracy was between -9.8% and 13.7%. Extraction efficiencies were more than 68%. Although ion suppression was detected, deuterated internal standards compensated for these effects. Carryover was minimal, less than 0.20%. All analytes were stable at room temperature for 16 h, 4 °C for 72 h, and after three freeze-thaw cycles. The assay also fulfilled compound identification criteria in accordance with the European Commission Decision 2002/657/EC. We analyzed 62 urine samples from patients received maintenance therapy and found that 54.8% of the patient samples tested were detected for morphine, codeine, or 6-monoacetylmorphine. This method provides a reliable and simultaneous quantification of opiates, maintenance drugs, and their metabolites in urine samples. It facilitates the routine monitoring in individuals prescribed the drug to ensure compliance and help therapeutic process.

Changes in heart rate variability during TOVA testing in patients with major depressive disorder.

AIM: The aim of this study was to identify major depressive disorder (MDD) based on heart rate variability (HRV) during tests of variables of attention (TOVA). METHOD: Forty-five MDD patients without cardiovascular disease and 45 controls matched by age and gender participated in this study. RESULTS: Compared to the controls, the MDD group had lower resting HRV parameters, more omissions and variability and longer response times on TOVA, and failure of attention employment to decrease HRV. CONCLUSIONS: The resting HRV parameters may provide easily measured, clinically useful ways to identify patients with MDD and to monitor their progress in treatment.

The effectiveness and safety of adjunctive aripiprazole in Taiwanese patients with antidepressant-refractory major depressive disorder: a prospective, open-label trial.

There is currently no published clinical trial on the safety and effectiveness of aripiprazole in Taiwanese patients with treatment-refractory major depressive disorder. We were interested in determining the applicability of current recommended doses of aripiprazole as an adjunct to antidepressant therapy in this population. We conducted a prospective, open-label nonrandomized, 4-week flexibly dosed (2.5-5 mg/d) trial with aripiprazole augmentation in 9 Taiwanese patients who had a history of nonresponse to at least 2 adequate courses of antidepressant therapy with different types of antidepressants. The primary end point for clinical effectiveness was mean change in the 17-item Hamilton Rating Scale for Depression at the end of the 4-week trial. Secondary end points for clinical effectiveness included mean change in Beck Depression Inventory and Beck Anxiety Inventory scores. The Systematic Assessment of Treatment Emergent Events-General Inquiry was used to assess adverse effects. All patients completed the trial and responded to treatment; the remission rate was 77.8%. The mean daily dose of adjunctive aripiprazole was 4.2 mg. Common treatment-emergent adverse events included insomnia and sedation (33.3%) and akathisia (22.2%). We found high effectiveness despite a lower mean daily dose of adjunctive aripiprazole (4.2 mg) when compared with previously reported findings; however, we also observed a higher frequency of treatment-emergent adverse effects. Additional studies are required to ascertain whether there are ethnic differences in the pharmacokinetics and/or pharmacodynamics of aripiprazole in treatment-refractory depression.

A 64-week, multicenter, open-label study of aripiprazole effectiveness in the management of patients with schizophrenia or schizoaffective disorder in a general psychiatric outpatient setting.

OBJECTIVE: To evaluate the overall long-term effectiveness of aripiprazole in patients with schizophrenia in a general psychiatric practice setting in Taiwan. METHODS: This was a prospective, open-label, multicenter, post-market surveillance study in Taiwanese patients with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) diagnosis of schizophrenia or schizoaffective disorder requiring a switch in antipsychotic medication because current medication was not well tolerated and/or clinical symptoms were not well controlled. Eligible patients were titrated to aripiprazole (5-30 mg/day) over a 12-week switching phase, during which their previous medication was discontinued. Patients could then enter a 52-week, long-term treatment phase. Aripiprazole was flexibly dosed (5-30 mg/day) at the discretion of the treating physicians. Efficacy was assessed using the Clinical Global Impression scale Improvement (CGI-I) score, the Clinical Global Impression scale Severity (CGI-S) score, The Brief Psychiatry Rating Scale (BPRS), and the Quality of Life (QOL) scale, as well as Preference of Medicine (POM) ratings by patients and caregivers. Safety and tolerability were also assessed. RESULTS: A total of 245 patients were enrolled and switched from their prior antipsychotic medications, and 153 patients entered the 52-week extension phase. In all, 79 patients (32.2%) completed the study. At week 64, the mean CGI-I score was 3.10 and 64.6% of patients who showed response. Compared to baseline, scores of CGI-S, QOL, and BPRS after 64 weeks of treatment also showed significant improvements. At week 12, 65.4% of subjects and 58.9% of caregivers rated aripiprazole as better than the prestudy medication on the POM. The most frequently reported adverse events (AEs) were headache, auditory hallucinations and insomnia. A total of 13 patients (5.3%) discontinued treatment due to AEs. No statistically significant changes were noted with respect to fasting plasma glucose, lipid profile, body weight, and body mass index after long-term treatment with aripiprazole. CONCLUSIONS: Although the discontinuation rate was high, aripiprazole was found to be effective, safe and well tolerated in the long-term treatment of Taiwanese patients with schizophrenia who continued to receive treatment for 64 weeks.