Neural oscillations while remembering traumatic memories in post-traumatic stress disorder.

OBJECTIVE: The current study investigated the oscillatory brain activity of PTSD patients during directed and imaginal exposure to the traumatic memory using magnetoencephalography (MEG), in a paradigm resembling exposure therapy. METHODS: Brain activity of healthy trauma-exposed controls and PTSD participants was measured with MEG as they listened to individualized trauma narratives as well as to a neutral narrative and as they imagined the narrative in detail. Source localization analysis by frequency bands was conducted in order to map neural generators of oscillatory activity. RESULTS: Elicitation of traumatic memories resulted in a distinct neural pattern in PTSD patients compared to healthy trauma-exposed individuals. In response to trauma scripts PTSD patients showed increases in high-gamma band power in visual areas, increased frontal and temporal theta as well as prefrontal alpha and medial temporal beta power relative to neutral scripts. CONCLUSIONS: Results suggest that when recollecting and imagining traumatic memories PTSD patients attempt to engage control or inhibition mechanisms. However, these are either not successfully recruited or inefficient leading to heightened responses and recollection. SIGNIFICANCE: Investigating the oscillatory neural dynamics of PTSD patients can help us better understand the processes underlying trauma re-experiencing.

Cannabis use is associated with lower retention in methadone maintenance treatment, but not among schizophrenic- and other chronically psychotic patients.

The findings of studies on cannabis use and retention in methadone maintenance treatment (MMT) are inconsistent.To study cannabis use and its relationship to patients' outcomes in MMT with/without lifetime DSM-IV-TR schizophrenia/chronic-psychosis diagnosis.Since June 1993, 877 patients with available lifetime DSM-IV-TR psychiatric diagnosis were followed-up until December 2017. Urine drug screens on admission and after one year were analyzed.Lifetime schizophrenia/psychosis was diagnosed in 50 (5.7%) patients. They did not differ from the other 827 by admission cannabis use (18.0% vs. 12.3%) and had similar 1-year retention rates (76.0% vs.77.0%, respectively). Cumulative retention of the cohort excluding schizophrenia/chronic-psychosis was longer for the 667 patients who did not use cannabis after 1-year (9.1 years, 95%CI 8.4-9.9) compared with the 118 cannabis-users after 1-year (6.0 years, 95% CI 4.8-7.2, p<.001). Among the schizophrenia/chronic-psychosis group, cannabis was not related to retention (38 non-users, 7.9 years 95%CI 5.2-10.5 vs. 9 cannabis-users, 9.9 years, 95% CI 3.8-16.0, p=.5). Survival was shorter for the 41 schizophrenia/chronic-psychosis non-users (15.2 years, 95% CI 12.8-17.7) than for the 719 non-schizophrenia/chronic-psychosis non-users (18.5, 95%CI 17.9-19.2, p = 0.009). However, survival was comparable among the 9 cannabis-users with schizophrenia/chronic-psychosis (20.1, 95% CI 16.2-24.1) and 101 other cohort users (18.6, 95% CI 16.9-20.4).Cannabis use is associated with decreased retention among MMT patients, however the effects of cannabis on schizophrenia/psychosis patients on retention and survival cannot be verified due to the small sample size and the limited data regarding chronicity of cannabis use. Future larger, prospective studies are needed.

Pregabalin misuse in methadone maintenance treatment patients in Israel: Prevalence and risk factors.

BACKGROUND: Drug users reportedly abuse pregabalin, and its combination with opiates was related to fatalities. We aimed to estimate the prevalence of pregabalin misuse and risk factors among patients in methadone maintenance treatment (MMT). METHODS: A cross-sectional study included all current MMT patients (n = 300) after excluding 9 with prescriptions, from a large tertiary medical center university-affiliated MMT clinic in Israel. Pregabalin was tested in one of the routine urine tests for other substances in December 2017. Data on urine results and patients' characteristics were retrieved from the patients' records. RESULTS: Pregabalin was detected among 53 (17.7%) patients. The group had higher depressive symptoms severity score (21-HAM-D) (11.1 ±â€¯8.4 vs. 8.3 ±â€¯7.8, p = 0.03), a higher prevalence of sero-positive HIV (13.7% vs. 4.2%, p = 0.02), sero-positive hepatitis C (66.7% vs. 50.4%, p = 0.04), DSM-IV-TR Axis I psychiatric diagnosis (54.0% vs. 41.7%, p = 0.03), and positive urine for opiates (22.6% vs. 8.9%, p = 0.008), cannabis (39.6% vs. 4.0 p < 0.0005) benzodiazepine (BDZ) (77.4% vs. 18.2%, p < 0.0005) and oxycodone (11.3% vs. 0.4%, p < 0.0005). Logistic regression found pregabalin group as more likely to be urine positive to BDZ (OR = 12.8 95%CI 5.0-32.5) cannabis (OR = 22.7, 95%CI 6.3-81.6) and oxycodone (OR = 43.9, 95%CI 3.6-541.4), with higher 21-HAM-D scores (OR = 1.1, 95%CI 1.04-1.2) and hepatitis C sera-positive (OR = 4.1, 95% CI 1.5-11.4). Unexpectedly, 13.2% of the pregabalin group had take-home dose privileges, which are rewards to non-drug abusers. CONCLUSIONS: High prevalence of pregabalin misuse among both BDZ abusers and non-abusers and patients with depressive symptoms supports both the inclusion of routine monitoring for pregabalin and intervention in MMT population.

Newborn birth-weight of pregnant women on methadone or buprenorphine maintenance treatment: A national contingency management approach trial.

BACKGROUND AND OBJECTIVES: Methadone maintenance treatment (MMT) is the gold standard for pregnant women with opioid use disorders. Still, low birth-weights were reported, in particular of mothers who became pregnant before admission to MMT. We studied whether an escalating incentive contingency-management approach may contribute to better newborn birth-weights. METHODS: A nationwide controlled randomized trial among all Israeli methadone/buprenorphine maintenance treatment (MBMT), newly or already in treatment pregnant women was performed. A modified contingency-management protocol with coupons of escalating value depending upon reduction of drug use, cigarette smoking, and alcohol consumption was compared to standard care arm. Drugs in urine, smoking (Fagerstrom score), alcohol use, and depression were monitored. RESULTS: Thirty-five women had 46 pregnancies. In their first pregnancy, 19 from the contingency-management and 16 from the standard care arms were studied. Contingency-management group as compared to the standard care arm included more newly admitted women (36.8% vs. 6.3%, p = .05), with benzodiazepine and cannabis onset at a younger age, and higher proportion of any drug abuse while pregnant (100% vs. 68.8%, p = .01). Fifteen of the contingency-management and 14 of the control arm gave birth (78.9% vs. 87.5%, p = .3) with similar proportions of normal (>2,500 g) birth-weight (71.4% vs. 61.5%, p = .8). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Newborns' birth-weight was comparable among the two study arms indicating no contribution of the contingency-management approach. Small sample and baseline differences between arms might have influenced results. Intensive intervention should be evaluated on a larger scale of participants. (Am J Addict 2017;26:167-175).

Differences in methylphenidate abuse rates among methadone maintenance treatment patients in two clinics.

Methylphenidate, an amphetamine-like prescription medication for attention deficit hyperactivity disorder (ADHD) was suspected as being abused among methadone maintenance treatment (MMT) patients. We tested its presence in the routine urine monitoring of all patients in both Tel Aviv and Las Vegas MMT clinics. Data on demographic and addiction history, ADHD (Wender Utah Rating Scale), cognitive impairment (Mini Mental State Exam), and lifetime DSM-IV-TR psychiatric diagnosis from admission were retrieved, and retention following 6 months. None of the 190 patients in Las Vegas tested positive for methylphenidate, while 14.7% (45/306) did in Tel Aviv. Abusers were less educated (p = 0.01), had higher ADHD scores (p = 0.02), lower cognitive scores (p = 0.05), and a higher benzodiazepine (BDZ) abuse rate (p < 0.0005), with no difference in age, gender, duration in MMT, cannabis, opiates, and cocaine abuse and infectious disease. Of the methylphenidate abuse 42.2% have take-home methadone dose privileges. Not like opiate use, being methylphenidate positive did not relate to 6-months retention. Compared to Tel Aviv, Las Vegas patients were more educated, with lower BDZ, and cocaine abuse. The greater abuse of methylphenidate among ADHD subjects might indicate their using it as self-medication, raising a possible indication for its prescription for that subgroup of MMT patients. The high rate of methylphenidate abuse in Israel needs future study.

Duration of methadone maintenance treatment during pregnancy and pregnancy outcome parameters in women with opiate addiction.

OBJECTIVES: Methadone maintenance treatment (MMT) is the standard treatment of choice for pregnant opiate addicts; however, data on newborn outcomes are contradictory. We studied the effect of the timing of starting MMT and of MMT related drug abstinence on the outcome of newborns of former and current opiate-addicted pregnant women. METHODS: All babies (excluding repeated deliveries) of all pregnant women who were admitted to 1 MMT clinic between 1993 and 2008 were studied. Former opiate-addicted women who became pregnant while already on MMT (full-pregnancy MMT, FP-MMT) and opiate-addicted women who only started MMT during pregnancy (partial-pregnancy MMT, PP-MMT) were retrospectively compared for birth weight and gestational age of newborns. Abstinence was defined as negative urine sample results for opiates, cocaine, amphetamines, benzodiazepine and cannabis during the month before delivery. RESULTS: We examined 59 newborn babies: 14 in the FP-MMT group and 45 in the PP-MMT group. The mean birth weight was 2733.2 ± 392.0 g versus 2240.0 ± 680.4 g respectively (F[1] = 6.6, P = 0.01). Abstinence was determined among 73.3% of the FP-MMT and 28.6% of the PP-MMT (P = 0.004). Gestational age was higher in the abstinence (37.9 ± 2.8 weeks) versus no-abstinence group (35.8 ± 4.6 weeks; F[1] = 4.4, P = 0.04). CONCLUSIONS: The best pregnancy outcome, characterized by a higher gestational and birth weight, was associated with a longer duration on MMT and substance abstinence, emphasizing the importance of MMT stabilization before and during pregnancy.

Sense of coherence as a stable predictor for methadone maintenance treatment (MMT) outcome.

We studied stability of sense of coherence (SOC) over time and in relation to the outcomes of former heroin addicts in MMT. Between September of 2003 and April of 2006, all 90 newly admitted patients to a MMT clinic in Tel Aviv were studied and followed up for one year. A SOC (inner resources) questionnaire was done at baseline and after one year. Use of opiates, cocaine, benzodiazepines, cannabis and amphetamines in the 13 months after admission was recorded, and defined as positive if at least one urine test for any drug was positive. After one year, 77 (85.6%) stayed in treatment. SOC scores were similar at baseline and after one year, but were lower among 42 patients who still abused any drugs (118.8 + 27.4), compared with the 35 patients who did not (128.5 + 26.5, Repeated measures, Groups p = 0.003, Time effect p = 0.5, Time*Group p = 0.003). Cumulative retention revealed that 30 patients with SOC scores greater than 130 had longer retention (3.5 years, 95% CI 3.2-3.9) as compared with 60 patients with SOC scores of 130 or less (2.9 years, 95% CI 2.5-3.3). SOC is a stable parameter that can serve as a predictor for success in MMT, both as retention in treatment and drug abstinence.

Depression in methadone maintenance treatment patients: rate and risk factors.

BACKGROUND: Depression is widely prevalent among former heroin addicts in methadone maintenance treatment (MMT). The risk factors for depression among MMT patients that have not been well characterized, was studied. METHODS: In a cross-sectional study (January, 2004-August, 2005), 90 MMT patients were evaluated for depression by the 21-item Hamilton Rating Scale for Depression (21-HAM-D) and the Brief Psychiatric Rating scale (BPRS). To study possible induction of depression by drug abuse, urine samples tested for opiates, cocaine metabolite (benzoylecgonine), benzodiazepines (BDZ), cannabis (THC), amphetamines and methadone metabolite during 1 month preceding study entry: a drug was defined as being positive if at least one sample was positive. RESULTS: The 21-HAM-D and BPRS scores were significantly correlated (Pearson R=0.76, p<0.0005). Fifty percent were found to be suffering from depression (21-HAM-D, scored > or = 18). Fifteen new patients in MMT had better scores (5.1+/-5.7) than continuous patients (17.7+/-6.2, p<0.0005), independent of treatment duration. Higher scores were in 51 patients with any Axis I psychiatric diagnosis (18.9+/-5.7 vs. 11.4+/-7.9, p<0.0005), 74 abusing and or using prescribed BDZ (16.3+/-7.4 vs. 11.7+/-8, p=0.03), and 36 prescribed more than one type of medication (17.5+/-7.3 vs. 14.2+/-7.7, p=0.05). Females (N=40) had poorer scores than males (17.6+/-7 vs. 14.1+/-7.9, p=0.03), especially 12 admitted into treatment while pregnant (20.2+/-4.1). LIMITATION: Patient drug abuse and withdrawal could distort evaluation and lead to misclassification of depression. CONCLUSION: The major risk factors for depression were already being in MMT, female gender, any DSM-IV Axis I psychiatric diagnosis, taking any psychotropic medication, abuse or using prescribed BDZ, and methadone dose > 120 mg/day.

Variables associated with perceived sleep disorders in methadone maintenance treatment (MMT) patients.

To characterize sleep disorders in methadone maintenance treatment (MMT) patients, we evaluated sleep quality of 101 non-selective patients from our MMT clinic in Israel between July, 2003 and July, 2004 by using the self-report questionnaire Pittsburgh Sleep Quality Index (PSQI). Patients' urine tests were analyzed for methadone metabolite, opiates, benzodiazepine, cocaine, cannabis and amphetamines. Their urine results for drug abuse throughout the months prior to filling in the questionnaire and their maintenance methadone doses were recorded. Drug abuse was defined by at least one positive urine test. Methadone serum levels were available in 55 patients, assessed by Gas Chromatography Mass Spectroscopy. The patients' self-reported chronic pain questionnaires and their diagnosed psychiatric disorders were analyzed. Out of the 101 study patients, 78.2% were male, 52.5% had psychiatric disorders, 46.5% reported having chronic pain and 46.5% had positive urine for benzodiazepine. The mean daily methadone dose was 157+/-52.9 mg. The mean PSQI score was 9+/-4.8 (75.2% had scores >5 indicating "poor sleepers"). PSQI scores were higher in patients with positive urine for benzodiazepine, chronic pain and psychiatric disorders and they correlated with years of opiate abuse before admission to MMT, and with the methadone dose (r=0.48, p<0.0005). The latter two also correlated with each other. The PSQI was not correlated with duration in MMT, gender, age, abuse of opiates, cannabis or cocaine. We concluded that sleep disorders should be evaluated and treated among MMT patients, particularly in those with psychiatric disorders, benzodiazepine abuse, chronic pain and high methadone dose.

Right prefrontal rTMS treatment for refractory auditory command hallucinations - a neuroSPECT assisted case study.

Auditory command hallucinations probably arise from the patient's failure to monitor his/her own 'inner speech', which is connected to activation of speech perception areas of the left cerebral cortex and to various degrees of dysfunction of cortical circuits involved in schizophrenia as supported by functional brain imaging. We hypothesized that rapid transcranial magnetic stimulation (rTMS), by increasing cortical activation of the right prefrontal brain region, would bring about a reduction of the hallucinations. We report our first schizophrenic patient affected with refractory command hallucinations treated with 10 Hz rTMS. Treatment was performed over the right dorsolateral prefrontal cortex, with 1200 magnetic stimulations administered daily for 20 days at 90% motor threshold. Regional cerebral blood flow changes were monitored with neuroSPECT. Clinical evaluation and scores on the Positive and Negative Symptoms Scale and the Brief Psychiatric Rating Scale demonstrated a global improvement in the patient's condition, with no change in the intensity and frequency of the hallucinations. NeuroSPECT performed at intervals during and after treatment indicated a general improvement in cerebral perfusion. We conclude that right prefrontal rTMS may induce a general clinical improvement of schizophrenic brain function, without directly influencing the mechanism involved in auditory command hallucinations.

The antinociceptive effect of mirtazapine in mice is mediated through serotonergic, noradrenergic and opioid mechanisms.

The antinociceptive effects of the noradrenergic and specific serotonergic antidepressant (NaSSA) drug mirtazapine and its interaction with various opioid receptor subtypes were evaluated in mice with a hotplate analgesicmeter. Mirtazapine elicited an antinociceptive effect in a dose-dependent manner following doses from 1 to 7.5mg/kg. As the mirtazapine dose increased beyond 10mg/kg latencies returned to baseline, yielding a biphasic dose-response curve. The effect of opioid, adrenergic, and serotonergic receptor antagonists was examined as to their ability to block mirtazapine antinociception. Mirtazapine (at 10mg/kg)-induced antinociception was significantly inhibited by naloxone, nor-BNI, and naltrindole, but neither by beta-FNA nor by naloxonazine, implying the involvement of kappa(1)- and delta-opioid mechanisms. When adrenergic and serotonergic antagonists were used, both metergoline and yohimbine, decreased antinociception elicited by mirtazapine, implying a combined serotonergic and noradrenergic mechanism of antinociception. When mirtazapine was administered together with various agonists of the opioid receptor subtypes, it significantly potentiated antinociception mediated only by kappa(3)-opioid receptor subtypes. Summing up these results we conclude that the antinociceptive effect of mirtazapine is mainly influenced by the kappa(3)-opioid receptor subtype combined with both serotonergic and noradrenergic receptors. These results suggest a potential use of mirtazapine in the management of some pain syndromes, and raise questions regarding a possible indirect opioid-dependence induced by mirtazapine. However, further research is needed in order to establish both the exact clinical indications and the effective doses of mirtazapine when prescribed for pain.