- [Show abstract] [Hide abstract] ABSTRACT: Obsessive compulsive disorder (OCD) is a brain disorder with a lifetime prevalence of 2.3%, causing severe functional impairment as a result of anxiety and distress, persistent and repetitive, unwanted, intrusive thoughts (obsessions), and repetitive ritualized behavior (compulsions). Approximately 40-60% of patients with OCD fail to satisfactorily respond to standard treatments. Intractable OCD has been treated by anterior capsulotomy and cingulotomy, but more recently neurostimulation approaches have become more popular due to their reversibility.
- [Show abstract] [Hide abstract] ABSTRACT: Aims: Use of synthetic cannabinoids is associated with significant physical and psychological harms. This research quantified reported toxicities from published reports and assessed the influence of size of the reported study population on rates of symptom reporting.
- [Show abstract] [Hide abstract] ABSTRACT: Objective: This pilot study assessed the feasibility, efficacy and safety of an individual dose-titration approach, and of the intravenous (IV), intramuscular (IM) and subcutaneous (SC) routes for treating depression with ketamine. Method: Fifteen treatment-refractory depressed participants received ketamine or midazolam (control treatment) in a multiple crossover, double-blind study. Ketamine was administered by IV (n = 4), IM (n = 5) or SC (n = 6) injection. Dose titration commenced at 0.1 mg/kg, increasing by 0.1 mg/kg up to 0.5 mg/kg, given in separate treatment sessions separated by ≥1 week, with one placebo control treatment randomly inserted. Mood, psychotomimetic and hemodynamic effects were assessed and plasma ketamine concentrations assayed. Results: Twelve participants achieved response and remission criteria, achieved at doses as low as 0.1 mg/kg. All three routes of administration resulted in comparable antidepressant effects. Fewest adverse effects were noted with the SC route. Antidepressant response, adverse effects and ketamine concentrations were dose-related. Conclusion: Antidepressant response occurred at a range of doses and at <0.5 mg/kg. The dose-titration approach is a practical method for optimizing the efficacy - side-effects trade-off on an individual patient basis. This pilot study provides preliminary evidence for SC injection as a practical, feasible and efficacious treatment approach.
- [Show abstract] [Hide abstract] ABSTRACT: Ethnopharmacological relevance Root bark from Tabernanthe iboga has been used traditionally in West Africa as a psychoactive substance in religious rituals. In smaller doses it is reported anecdotally to have stimulant properties. Aim of the study To evaluate the influence of a single 20 mg ibogaine dose on psychological variables reflecting subjective mood state and a range of cognitive functions. Materials and methods 21 healthy male volunteers received single 20 mg doses of ibogaine after 6 days pretreatment with double-blind paroxetine or placebo. We compared responses to a battery of psychometric tests and subjective mood ratings performed before and 2 h after ibogaine dosing, and assessed relationships between changes in test scores and concentrations of active moiety (the sum of molar noribogaine and ibogaine concentrations). Psychological tests were chosen based on responsiveness to opioid and serotonergic ligands. Results Ibogaine had minimal influence on psychological tests and mood ratings. The ability to selectively ignore distracting spatial information showed some evidence of modulation; however because this effect was limited to the less challenging condition calls into question the reliability of this result. Conclusion We were unable to identify stimulant effects after single 20 mg doses of ibogaine. Future research is needed to confirm whether active moiety concentrations impact selective attention abilities while leaving other cognitive functions and mood state unaffected.
- [Show abstract] [Hide abstract] ABSTRACT: BACKGROUND AND IMPORTANCE: Alcohol dependence is related to dysfunctional brain processes, in which a genetic background and environmental factors shape brain mechanisms involved with alcohol consumption. Craving, a major component determining relapses in alcohol abuse, has been linked to abnormal brain activity. CLINICAL PRESENTATION: We report the results of a treatment-intractable, alcohol-addicted patient with associated agoraphobia and anxiety. Functional imaging studies consisting of functional magnetic resonance imaging and resting-state electroencephalogram were performed as a means to localize craving-related brain activation and for identification of a target for repetitive transcranial magnetic stimulation and implant insertion. Repetitive transcranial magnetic stimulation of the dorsal anterior cingulate cortex with a double-cone coil transiently suppressed his very severe alcohol craving for up to 6 weeks. For ongoing stimulation, 2 "back-to-back" paddle electrodes were implanted with functional magnetic resonance imaging neuronavigation guidance for bilateral dorsal anterior cingulate cortex stimulation. Using a recently developed novel stimulation design, burst stimulation, a quick improvement was obtained on craving, agoraphobia, and associated anxiety without the expected withdrawal symptoms. The patient has remained free of alcohol intake and relieved of agoraphobia and anxiety for over 18 months, associated with normalization of his alpha and beta activity on electroencephalogram in the stimulated area. He perceives a mental freedom by not being constantly focused on alcohol. CONCLUSION: This case report proposes a new pathophysiology-based target for the surgical treatment of alcohol dependence and suggests that larger studies are warranted to explore this potentially promising avenue for the treatment of intractable alcohol dependence with or without anxiety and agoraphobia.
- [Show abstract] [Hide abstract] ABSTRACT: Background: Several recent trials indicate low-dose ketamine produces rapid antidepressant effects. However, uncertainty remains in several areas: dose response, consistency across patient groups, effects on suicidality, and possible biases arising from crossover trials. Methods: A systematic search was conducted for relevant randomized trials in Medline, Embase, and PsycINFO databases up to August 2014. The primary endpoints were change in depression scale scores at days 1, 3 and 7, remission, response, suicidality, safety, and tolerability. Data were independently abstracted by 2 reviewers. Where possible, unpublished data were obtained on treatment effects in the first period of crossover trials. Results: Nine trials were identified, including 201 patients (52% female, mean age 46 years). Six trials assessed low-dose ketamine (0.5mg/kg i.v.) and 3 tested very low-dose ketamine (one trial assessed 50mg intra-nasal spray, another assessed 0.1–0.4mg/kg i.v., and another assessed 0.1–0.5mg/kg i.v., intramuscular, or s.c.). At day 3, the reduction in depression severity score was less marked in the very low-dose trials (P homogeneity <.05) and among bipolar patients. In analyses excluding the second period of crossover trials, response rates at day 7 were increased with ketamine (relative risk 3.4, 95% CI 1.6–7.1, P=.001), as were remission rates (relative risk 2.6, CI 1.2–5.7, P=.02). The absolute benefits were large, with day 7 remission rates of 24% vs 6% (P=.02). Seven trials provided unpublished data on suicidality item scores, which were reduced on days 1 and 3 (both P<.01) but not day 7. Conclusion: Low-dose ketamine appears more effective than very low dose. There is substantial heterogeneity in clinical response, with remission among one-fifth of patients at 1 week but most others having benefits that are less durable. Larger, longer term parallel group trials are needed to determine if efficacy can be extended and to further assess safety.
- [Show abstract] [Hide abstract] ABSTRACT: Treatments for addiction are of limited effectivity and characterized by high relapse rates, requiring the development of novel pathophysiology-based treatment approaches. One such option is to use neuromodulation. Neuromodulation can be defined as the use of techniques to focally induce directed neuroplasticity. Both nonsurgical and surgical neuromodulation have been experimentally used for the suppression of craving. Noninvasive techniques used include transcranial magnetic stimulation, transcranial electrical stimulation, and neurofeedback. Surgical neuromodulation techniques involve lesioning and electrical stimulation via implanted electrodes. Most studies using noninvasive stimulation have investigated the dorsolateral prefrontal cortex as the target. The two brain areas most commonly used as targets for lesioning are the anterior cingulate and nucleus accumbens. For implanted electrodes the nucleus accumbens and subthalamic nucleus have been investigated. The targets used can be linked to brain circuits involved in craving or withdrawal. For noninvasive neuromodulation no long-term studies have been performed and for implanted electrodes only small case series have been reported. Thus even if results seem to be promising, they still have to be considered preliminary.
- [Show abstract] [Hide abstract] ABSTRACT: We have previously reported an anxiolytic-sensitive human EEG biomarker, goal conflict specific rhythmicity (GCSR), using an auditory stop signal task (SST). Here we test if a visual SST could allow testing of GCSR in people with hearing impairments. The visual SST produced GCSR within the 4–12 Hz band at the expected right frontal site, F8, but to a lesser extent than in previous auditory SSTs, possibly due to response instability. Positive GCSR appeared to be reduced by both buspirone (10 mg), and triazolam (0.25 mg), as previously; negative GCSR was increased. However, neuroticism, trait anxiety and Behavioural Inhibition System scores failed to show consistent positive correlations with GCSR, contrary to prediction. The visual SST generates anxiolytic-sensitive GCSR; but its limited extent and unexpected personality correlations suggest it needs further development to obtain quantitative equivalence with the auditory SST.
- [Show abstract] [Hide abstract] ABSTRACT: Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled, single ascending dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST, who had been switched to morphine during the previous week. Noribogaine doses were 60, 120 or 180mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were non-euphoric changes in light perception at ∼1h post dose, headache and nausea. Noribogaine had dose-linear increases for AUC and Cmax, and was slowly eliminated (mean t1/2 range 24–30h). There was a concentration-dependent increase in QTcI (0.17msec/ng/mL) with largest observed mean effect of ∼16msec, 28msec, and 42msec in the 60mg, 120mg, and 180mg groups, respectively. Noribogaine showed a non-statistically significant trend to decrease total scores in opioid withdrawal ratings, most notably at the 120mg dose, however the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues. This article is protected by copyright. All rights reserved
- [Show abstract] [Hide abstract] ABSTRACT: Objective: A definition of free will is the ability to select for or against a course of action to fulfill a desire, without extrinsic or intrinsic constraints that compel the choice. Free will has been linked to the evolutionary development of flexible decision making. In order to develop flexibility in thoughts and behavioral responses, learning mechanisms have evolved as a modification of reflexive behavioral strategies. The ultimate goal of the brain is to reduce uncertainty inherently present in a changing environment. A way to reduce the uncertainty, which is encoded by the rostral anterior cingulate, is to make multiple predictions about the environment which are updated in parallel by sensory inputs. The prediction/behavioral strategy that fits the sensory input best is then selected, becomes the next percept/behavioral strategy, and is stored as a basis for future predictions. Acceptance of predictions (positive feedback) is mediated via the accumbens, and switching to other predictions by the dorsal anterior cingulate cortex (ACC) (negative feedback). Maintenance of a prediction is encoded by the pregenual ACC. Different cingulate territories are involved in rejection, acceptance and maintenance of predictions. Free will is known to be decreased in multiple psychopathologies, including obsessive compulsive disorder and addictions. Methodology: In modern psychosurgery three target structures exist for obsessive compulsive disorder and addiction: the dorsal ACC, the nucleus accumbens, and/or the anterior limb of the internal capsula. Research in all three areas reports favorable results with acceptable side effects. Psychosurgical interventions seem to exert their effect by a common final common pathway mediated via the pregenual ACC. Conclusion: Successful neuromodulation increases the capacity to choose from different options for the affected individual, as well as inhibiting unwanted options, therefore increasing free will and free won't.
- [Show abstract] [Hide abstract] ABSTRACT: The aim of this study was to switch patients established on methadone opioid substitution therapy (OST) to morphine over 1 week. Subjects established on daily methadone OST (mean dose 60mg/day) were switched to morphine slow release capsules, dosed at 4x the previous total daily methadone dose, for 6 days, then given morphine syrup dosed q3h. All 27 subjects enrolled in this study completed the switch from methadone to morphine. Opioid withdrawal symptoms (OWS) peaked within 12-24h of starting morphine, and 24/27 subjects required higher daily morphine doses (mean 5.2x multiple). Pharmacokinetic evaluation showed that 91% of methadone was cleared during this time, with a mean elimination half-life of 59h. The most frequent treatment-emergent non-OWS adverse events were headache, nausea, constipation and neck pain. The method described here appears to be a safe and acceptable approach to switch subjects from methadone to morphine. This article is protected by copyright. All rights reserved.
- [Show abstract] [Hide abstract] ABSTRACT: Anxiety disorders are among the most common mental illness in the western world with a major impact on disability. But their diagnosis has lacked objective biomarkers. We previously demonstrated a human anxiety process biomarker, goal-conflict-specific electroencephalography (EEG) rhythmicity (GCSR) in the stop-signal task (SST). Here we have developed and characterized an improved test appropriate for clinical group testing. We modified the SST to produce balanced numbers of trials in clearly separated stop-signal delay groups. As previously, right frontal (F8) GCSR was extracted as the difference in EEG log Fourier power between matching stop and go trials (that is, stop-signal-specific power) of a quadratic contrast of the three delay values (that is, power when stopping and going are in balanced conflict compared with the average of when stopping or going is greater). Separate experiments assessed drug sensitivity (n = 34) and personality relations (n = 59). GCSR in this new SST was reduced by three chemically distinct anxiolytic drugs (administered double-blind): buspirone (10 mg), triazolam (0.25 mg) and pregabalin (75 mg); had a frequency range (4–12 Hz) consistent with rodent model data; and positively correlated significantly with neuroticism and nonsignificantly with trait anxiety scores. GCSR, measured in our new form of the SST, should be suitable as a biomarker for one specific anxiety process in the testing of clinical groups and novel drugs and in the development of measures suitable for individual diagnosis. Translational Psychiatry (2015) 5, e699; doi:10.1038/tp.2015.188; published online 15 December 2015
- [Show abstract] [Hide abstract] ABSTRACT: Objectives: Recent network meta-analyses of drug treatments for acute mania have only evaluated the efficacy and acceptability of individual drug treatments. The relative efficacy and acceptability of combined drug treatment has not been assessed. Methods: Double-blind drug trials in acute mania were identified using a systematic search strategy. We recorded numbers of patients enrolled, endpoints for efficacy (changes in mania rating scales, numbers of responders) and acceptability (numbers of dropouts) and treatment administered (categorized as antipsychotic, mood stabilizer, combined antipsychotic/mood stabilizer or placebo). Data were analyzed using a random effects frequentist network meta-analysis. Results: All three drug categories were more effective than placebo. Antipsychotics and combined antipsychotic/mood stabilizer were significantly more effective than mood stabilizers for changes in mania rating scales. Combined antipsychotic/mood stabilizer was significantly more effective than mood stabilizers and antipsychotics for responder rate. Dropout rates were significantly lower for antipsychotics compared with placebo and mood stabilizers. Combined antipsychotic/mood stabilizer had the highest probability of being the best treatment based on change in mania rating scales (96.1% for all mania scales; 85.5% for Young Mania Rating Scale), and 99.3% for being the best treatment for responders. Antipsychotics had 82.0% probability as the best treatment to minimize dropouts. Conclusion: Combined antipsychotic/mood stabilizer appears to have efficacy advantages over antipsychotic or mood stabilizer monotherapy in acute mania, and should be considered as first line therapy.
- [Show abstract] [Hide abstract] ABSTRACT: Use of synthetic cannabinoids is associated with a range of mental health harms. The 2013 Psychoactive Substances Act (PSA) was intended to limit retail availability of synthetic cannabinoids which had acceptable safety profiles. We evaluated numbers and clinical characteristics of patients presenting with mental health harms associated with use of synthetic cannabinoids for three months before and after implementation of the PSA on 18July 2013. Retrospective audit of case notes of patients presenting to an emergency psychiatric service (EPS) in Dunedin. In the three months post-PSA, there was a 42% reduction in EPS contacts and 52% reduction in patient presentations, compared with the three months pre-PSA. Patient demographics (predominantly young males with prior contact with mental health services), presenting symptoms (mood and psychotic symptoms and suicidality), and management and disposition were identical in both periods. The decrease in mental health harms, as measured by frequency of EPS contacts, appeared to be due to reduced retail availability of synthetic cannabinoids rather that reduced toxicity of available products.
- [Show abstract] [Hide abstract] ABSTRACT: Evaluation of noribogaine safety, pharmacokinetics and effects on opioid withdrawal in methadone-dependent patients Paul Gluea, Michelle Lockhartb, Fred Lamc, Noelyn Hungc, C Tak Hungc, Donna Tunnicliffed, Gavin Caped, Jane Devanee, Holger Weise, John Howese and Lawrence Friedhofff aUniversity of Otago, Dunedin, New Zealand; bUniversity of Auckland, NZ; cZenith Technology Ltd, Dunedin, NZ; dCommunity Alcohol and Drug Service, Dunedin, NZ; eDemeRx, Inc., Fort Lauderdale, Florida, USA; fPharmaceutical Special Projects Group, LLC Introduction: The iboga alkaloids appear to have striking efficacy for treatment of substance dependence in individual and case series reports, but no blinded, controlled clinical trials have been performed. This study tested single doses of noribogaine hydrochloride (NI), an analog of ibogaine, in opioid-dependent patients. Objectives: To evaluate the safety, tolerability, pharmacokinetics (PK) and changes in withdrawal ratings after single doses of NI or placebo (PLA) administered to opioid-dependent patients. Methods: This was a phase 1B, randomized, double-blind, placebo-controlled, single ascending dose study in 27 patients seeking to discontinue methadone opioid substitution treatment (OST). The study was conducted in 3 cohorts each with 6 active and 3 placebo patients. NI doses were 60mg, 120mg or 180mg. 1 week prior to NI administration, methadone was replaced by oral, controlled-release morphine (6 days) followed by 1 day of oral immediate-release (IR) morphine. On the NI treatment day, a single dose of IR morphine was administered followed 2 hours later by a single blinded oral dose of NI or PLA. Patients resuming OST received morphine within 24h of blinded NI/PLA dosing, and methadone post-24h. PK blood samples were collected for 7 days following NI/PLA. Safety assessments were conducted to Day 21 (±3) following NI/PLA. Safety monitoring included: physical examinations, vital signs, serum chemistry, hematology, urinalysis, 12 lead ECGs, Holter monitoring, telemetry, oximetry, capnography, pupillometry, opioid withdrawal rating scales and mood VAS. Results: NI was well tolerated. In addition to signs and symptoms of opioid withdrawal, the most frequent treatment-emergent adverse events were headache and nausea. Non-euphoric changes in light perception occurred at ~1h post dosing and decreased/disappeared by 2.5-3h post-dose. NI peak concentrations occurred 2-4 hours post-dose, with dose-linear increases for AUC and Cmax. The drug was slowly eliminated with t1/2 estimates of 24-30 hours across dose groups. There was a concentration-dependent increase in QTcI (0.17msec/ng/mL) and dose-dependent peak increases in QTcI of ~16msec, 28msec, and 42msec in the 60mg, 120mg, and 180mg groups, respectively. There were no changes in vital signs or safety laboratory tests. There were no statistical differences between the mean time to OST in the NI cohorts vs PLA. The 120mg cohort had the longest time to OST resumption with trend significance vs PLA. NI showed a trend to decrease total scores in the opioid withdrawal rating scales, most notably at the 120mg dose, but the study was not powered for this endpoint. Conclusions: NI pharmacokinetic parameters in opioid-dependent patients were similar to those from a prior healthy volunteer study. NI was well tolerated. The main safety finding was a concentration-dependent increase in QTcI. QTc increases from NI continued to decline after restarting methadone. The lack of statistically significant dose-related changes in time to OST resumption could be due to the small number of patients, and possible contamination effects from co-localization of patients during the in-patient portion of the study. Future multiple-dose NI studies are planned, using dosing regimens to limit changes in QTc.
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