The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson9s and Huntington9s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB 1 receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB 1 receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB 2 receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients9 need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.

http://www.phytecs.com/wp-content/uploads/2015/02/Pharmacol-Rev-2006-Pacher-389-462.pdf

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

ContextAlcohol dependence treatment may include medications, behavioral therapies, or both. It is unknown how combining these treatments may impact their effectiveness, especially in the context of primary care and other nonspecialty settings.ObjectivesTo evaluate the efficacy of medication, behavioral therapies, and their combinations for treatment of alcohol dependence and to evaluate placebo effect on overall outcome.Design, Setting, and ParticipantsRandomized controlled trial conducted January 2001-January 2004 among 1383 recently alcohol-abstinent volunteers (median age, 44 years) from 11 US academic sites with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnoses of primary alcohol dependence.InterventionsEight groups of patients received medical management with 16 weeks of naltrexone (100 mg/d) or acamprosate (3 g/d), both, and/or both placebos, with or without a combined behavioral intervention (CBI). A ninth group received CBI only (no pills). Patients were also evaluated for up to 1 year after treatment.Main Outcome MeasuresPercent days abstinent from alcohol and time to first heavy drinking day.ResultsAll groups showed substantial reduction in drinking. During treatment, patients receiving naltrexone plus medical management (n = 302), CBI plus medical management and placebos (n = 305), or both naltrexone and CBI plus medical management (n = 309) had higher percent days abstinent (80.6, 79.2, and 77.1, respectively) than the 75.1 in those receiving placebos and medical management only (n = 305), a significant naltrexone × behavioral intervention interaction (P = .009). Naltrexone also reduced risk of a heavy drinking day (hazard ratio, 0.72; 97.5% CI, 0.53-0.98; P = .02) over time, most evident in those receiving medical management but not CBI. Acamprosate showed no significant effect on drinking vs placebo, either by itself or with any combination of naltrexone, CBI, or both. During treatment, those receiving CBI without pills or medical management (n = 157) had lower percent days abstinent (66.6) than those receiving placebo plus medical management alone (n = 153) or placebo plus medical management and CBI (n = 156) (73.8 and 79.8, respectively; P<.001). One year after treatment, these between-group effects were similar but no longer significant.ConclusionsPatients receiving medical management with naltrexone, CBI, or both fared better on drinking outcomes, whereas acamprosate showed no evidence of efficacy, with or without CBI. No combination produced better efficacy than naltrexone or CBI alone in the presence of medical management. Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment. Naltrexone with medical management could be delivered in health care settings, thus serving alcohol-dependent patients who might otherwise not receive treatment.Trial Registrationclinicaltrials.gov Identifier: NCT00006206

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Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence: The COMBINE Study: A Randomized Controlled Trial

Inhibition and impulsivity: Behavioral and neural basis of response control

http://homepages.se.edu/cvonbergen/files/2013/01/Fifty-Years-of-the-Barratt-Impulsivenss-Scale_An-Update-and-Review.pdf

Fifty years of the Barratt Impulsiveness Scale: An update and review

The discovery of cannabinoid receptors and subsequent identification of their endogenous ligands (endocannabinoids) in early 1990s have greatly accelerated research on cannabinoid actions in the br...

Endocannabinoid-Mediated Control of Synaptic Transmission

Objectives: Treatment-resistant depression is a common occurrence in clinical practice as well as combination treatment with 2 different antidepressants. In the present case series, we study the effectiveness of the addition of reboxetine, during 12 weeks, to 14 outpatients diagnosed with major depressive disorder, according to Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) criteria, who had previously failed to respond or who had only responded partially, over a period of 6 weeks, to conventional treatment with mirtazapine. Methods: Evaluation of antidepressant efficacy was carried out through the application of the 21-item Hamilton Depression Rating Scale (HDRS) and the Clinical Global Impressions-Global Improvement Scale (CGI-I). Results: The percentages of responders (HDRS ≥50%), patients in remission (HDRS ≤10), and improving patients (CGI-I absolute value <4) were 35.7%, 28.6%, and 64.3%, respectively. No serious side effects were observed during combination therapy, being more frequent dry mouth (2 cases). Conclusions: The initial findings of our study show that reboxetine and mirtazapine may constitute an effective and low side effects combination.

Reboxetine addition in patients with mirtazapine-resistant depression : A case series

Background : We carried out a bibliometric study on the scientific publications on atypical antipsychotic drugs (AADs) from India. Methods : Using the EMBASE and MEDLINE databases, we performed the selection of documents produced in India. We applied bibliometric indicators of production and dispersion, namely Price’s law on the increase of scientific literature and Bradford’s law, respectively. We also calculated the participation index (PI) of different countries. The bibliometric data have also been correlated with relevant social and health data from India (including total per capita expenditure on health and gross domestic expenditure on research and development). Results : In this study, we identified 639 original documents published between 1998 and 2013 from India. Our results indicated fulfilment of Price’s law (correlation coefficient r = 0.9619 after exponential adjustment vs. r = 0.9382 after linear adjustment). The most widely studied AADs were olanzapine (173 documents), clozapine (117), risperidone (100) and quetiapine (65). Publications appeared in 221 different journals, with only 4 of the top 10 journals having an impact factor greater than 2. Division into Bradford zones yielded a nucleus occupied by the Indian Journal of Psychiatry (53 articles). It is remarkable that the 27.38% of the production is devoted to “medical/pharmaceutical chemistry” field. India has the largest ratio PI AAD / PI Psychiatry and Neurology in the world’s 12 most productive countries in biomedicine and health sciences. Conclusions : The publications on AADs in India have undergone exponential growth over the studied period, without evidence of reaching a saturation point. Financial disclosure : The authors have no proprietary or commercial interest in any materials discussed in this article.

A Bibliometric Analysis of Scientific Research on Atypical Antipsychotic Drugs in India during 1998-2013

Objective: The purpose of present study was to evaluate the efficacy of the addition of reboxetine in patients that had not previously responded, or had done so only partially, over 6 weeks of conventional pharmacological treatment with venlafaxine.



Methods:  This open-label, prospective and multicentric study included 40 outpatients diagnosed with major depressive disorder according to the DSM-IV criteria. Efficacy was assessed using the 21-item Hamilton Depression Rating Scale (HAMD) and the Clinical Global Impression-Improvement (CGI-I). Safety was evaluated by recording spontaneously reported adverse events. Data were analysed on an intent-to-treat basis, using the last-observation-carried-forward method.



Results:  Mean HAMD reduction was 34.9% (P < 0.0001). The percentages of responders (≥50% reduction in HAMD) and patients considered as benefiting from complete remission (HAMD ≤ 10 points) at week 6 were 27.5 and 12.5%, respectively. By the end of the treatment, the score of CGI-I decreased 24.8% (P < 0.0001). Percentage of patient improving (CGI < 4 points) was 47.5%. The most common non-serious adverse events were constipation, nervousness, anxiety and insomnia.



Conclusion:  These findings suggest that the combined treatment of reboxetine and venlafaxine, in venlafaxine-resistant patients, may be an effective and well-tolerated strategy.

Combined treatment with reboxetine in depressed patients with no response to venlafaxine: a 6-week follow-up study.

Aims: Prepulse inhibition (PPI) of the startle reflex, which refers to the ability of innocuous sensory events to reduce the startle reflex, has been described as an operational measure of sensorimotor gating that is reduced in several neuropsychiatric disorders, such as schizophrenia, but experience is lacking in addictions and alcoholism. The aim of this study was to examine the existence of impairments in the startle response and PPI in abstinent alcoholic men. Methods: Testing for PPI was conducted on 60 abstinent alcoholic men aged 18–65 years (mean 46.37) who met DSM-IV criteria for alcohol dependence and had been abstinent for more than a month at the time of testing. The comparison group were compared with 37 sex- age- and education-matched controls without alcohol dependence. Results: Magnitudes of the startle reflex were lower in patients than in controls. The differences were statistically significant ( P <  0.05) in trials with prepulses presented 30 and 120 ms before the onset of the startle stimulus. There was also a statistically significant ( P <  0.05) reduced percentage of PPI when the prepulse was presented 30 ms before the startle stimulus. Conclusions: These data suggest that sensory information processing mechanisms could be damaged in abstinent alcoholic patients. The fact that these findings are common to other psychiatric disorders could indicate the existence of a common vulnerability marker and explain the high degree of comorbidity between alcoholism and other mental illnesses.

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Gabriel Rubio

Papers

Reboxetine addition in patients with mirtazapine-resistant depression : A case series

A Bibliometric Analysis of Scientific Research on Atypical Antipsychotic Drugs in India during 1998-2013

Combined treatment with reboxetine in depressed patients with no response to venlafaxine: a 6-week follow-up study.

Impairments of prepulse inhibition of the startle response in abstinent alcoholic male patients.

Instrumentos de evaluación en el alcoholismo