Cannabinoid levels description in a cohort of patients with chronic and neuropathic pain treated with Cannabis decoction: A possible role of TDM.

The phytocomplex of Cannabis is made up of approximately 500 substances: terpeno-phenols metabolites, including Δ-9-tetrahydrocannabinol and cannabidiol, exhibit pharmacological activity. Medical Cannabis has several pharmacological potential applications, in particular in the management of chronic and neuropathic pain. In the literature, a few data are available concerning cannabis pharmacokinetics, efficacy and safety. Thus, aim of the present study was the evaluation of cannabinoid pharmacokinetics in a cohort of patients, with chronic and neuropathic pain, treated with inhaled medical cannabis and decoction, as a galenic preparation. In this study, 67 patients were enrolled. Dried flower tops with different THC and CBD concentrations were used: Bedrocan® medical cannabis with THC level standardized at 19% and with a CBD level below 1%, Bediol® medical cannabis with THC and CBD level standardized at similar concentration of 6.5% and 8%, respectively. Cannabis was administered as a decoction in 47 patients and inhaled in 11 patients. The blood withdrawn was obtained before the new dose administration at the steady state and metabolites plasma concentrations were measured with an UHPLC-MS/MS method. Statistically significant differences were found in cannabinoids plasma exposure between inhaled and oral administration of medical cannabis, between male and female and cigarette smokers. For the first time, differences in cannabinoid metabolites exposures between different galenic formulations were suggested in patients. Therapeutic drug monitoring could be useful to allow for dose adjustment, but further studies in larger cohorts of patients are required in order to confirm these data.

A new UHPLC-MS/MS method for cannabinoids determination in human plasma: A clinical tool for therapeutic drug monitoring.

Cannabinoid derivates have been largely used for different medical purpose. In the literature, several methods capable of separating THC and its principles metabolites are described, although Δ8- and Δ9-THC separation has not been completely achieved. THC metabolism has not been fully understood and metabolites plasma distribution in healthy and pathological patients remains to further deepen. The aim of this study was the validation of UHPLC-MS/MS method for the quantification of 10 cannabinoids in human plasma, as important tool for improving clinical efficacy of cannabis administration. Obtained results were in accordance with recommendations of ICH Harmonised Guideline for bioanalytical method validation, showing a good linearity, optimal accuracy as well as satisfactory results in terms of intra-day and inter-day precision and matrix effect. Furthermore, blood sampling study was performed to investigate the better collection method. Optimal separation of Δ-9-tetrahydrocannabinol (Δ9-THC), Δ8-tetrahydrocannabinol (Δ8-THC) was obtained. The present method showed optimal linearity and satisfactory results in terms of specificity and selectivity. Recovery was between 92.0% and 96.5% for all analytes. The matrix-effect showed good performance; no carry over was observed. Cannabinoid metabolites present in higher plasma concentrations were: 11-Hydroxy-Δ9-tetrahydrocannabinol, 11-Nor-9carboxy-Δ9-tetrahydrocannabinol and THC-COOH-glucuronide. Method performance makes it suitable for routine purposes and a potential tool for therapeutic ranges definition. The present work will be used to test several samples in a long-term clinical study, paving the way for further future works.

Role and clinical implications of atypical antipsychotics in anxiety disorders, obsessive-compulsive disorder, trauma-related, and somatic symptom disorders: a systematized review.

Atypical antipsychotics (AAs) may play a role in the treatment of anxiety disorders, obsessive-compulsive disorder (OCD), and trauma-related disorders. No reviews on their differential use in these different disorders have been performed recently. The aim of this systematized review was to obtain data on efficacy and comparative effectiveness of AAs as a treatment of anxiety disorders, OCD, and trauma-related disorders to provide guidance for clinicians on when and which AA to use. We searched on PubMed, Psychnet, and Cochrane Libraries from inception to July 2015. Search results were limited to randomized, placebo-controlled trials of adult patients. Evidence of efficacy was considered the presence of positive results in two or more double-blind placebo-controlled studies. Our systematized search identified 1298 papers, of which 191 were subjected to a full-text review and 56 were included. Quetiapine extended-release showed a role in both acute and maintenance treatment of uncomplicated generalized anxiety disorder, whereas more studies are needed before drawing practical recommendations on the use of olanzapine and risperidone; aripiprazole and risperidone are effective in resistant OCD as augmentation treatments. Risperidone and olanzapine add-on may have a role in resistant or chronic post-traumatic stress disorder patients, although only risperidone addition can be recommended on the basis of the criterion of two or more positive placebo-controlled trials. This systematized review supports the evidence that only a few AAs are effective in only a minority of the off-label conditions in which they are currently used and confirms that AAs are not all the same. Their use should be on the basis of a balance between efficacy and side effects, and the characteristics as well as the preference of the patient.

Effects of maintenance lithium treatment on serum parathyroid hormone and calcium levels: a retrospective longitudinal naturalistic study.

OBJECTIVE: The aim of this retrospective longitudinal naturalistic study was to evaluate the effects of maintenance lithium treatment on parathyroid hormone (PTH) and calcium levels. METHODS: A retrospective longitudinal naturalistic study design was used. Data were collected from the database of a tertiary psychiatric center covering the years 2010-2014. Included were bipolar patients who had never been exposed to lithium and had lithium started, and who had PTH, and total and ionized calcium levels available before and during lithium treatment. Paired t-tests were used to analyze changes in PTH and calcium levels. Linear regressions were performed, with mean lithium level and duration of lithium exposure as independent variables and change in PTH levels as dependent variable. RESULTS: A total 31 patients were included. The mean duration of lithium treatment was 18.6±11.4 months. PTH levels significantly increased during lithium treatment (+13.55±14.20 pg/mL); the rate of hyperparathyroidism was 12.9%. Neither total nor ionized calcium increased from baseline to follow-up; none of our patients developed hypercalcemia. Linear regressions analyses did not show an effect of duration of lithium exposure or mean lithium level on PTH levels. CONCLUSION: Lithium-associated stimulation of parathyroid function is more common than assumed to date. Among parameters to be evaluated prior to lithium implementation, calcium and PTH should be added.

Increased uric acid levels in bipolar disorder subjects during different phases of illness.

BACKGROUND: Recent evidence indicates the possible involvement of adenosine and the purinergic system in the pathophysiology of bipolar disorder (BD). The aim of this study is to compare serum uric acid (UA) levels in a large group of BD patients (in mania, depression and euthymia) vs. a control group of patients with different psychiatric disorders. METHODS: 150 BD (SCID-I; DSM-IV) patients were compared to 150 age- and gender-matched subjects with MDD, OCD, or Schizophrenia. Mean serum UA values were compared with the ANOVA, with Bonferroni's post-hoc tests. RESULTS: Mean serum UA levels (5.06 ± 1.45 vs. 4.17 ± 1.05 mg/dL) and rates of hyperuricaemia (30.7% vs. 6.7%) were significantly higher in the bipolar than in the control group. No differences were detected between bipolars in different phases of illness, with all three groups (manic, depressive and euthymic bipolars) showing significantly higher UA levels as compared to controls. No correlations were found between UA levels and YMRS or HAM-D scores. Mean UA levels were also higher in bipolars never exposed to mood stabilizers vs. controls (5.08 ± 1.43 vs. 4.17 ± 1.05 mg/dL), with no differences compared to other bipolars. LIMITATIONS: Our study suffers from the lack of a healthy comparison group; moreover, longitudinal data are missing. CONCLUSIONS: Our study provides further evidence of a purinergic dysfunction associated with BD, in all phases of the illness. It is possible that increased UA levels are a trait marker of higher vulnerability to bipolar disorder, and are even more increased during mania (mostly in the first manic episode of drug-naïve patients).

[Lithium treatment and potential long-term side effects: a systematic review of the literature]. / Trattamento con litio e potenziali effetti collaterali a lungo termine: una revisione sistematica della letteratura.

INTRODUCTION AND AIM: Lithium is recommended by all treatment guidelines for bipolar disorder (BD) as a first-line maintenance treatment. However, the potential side effects and risks associated with long-term lithium use may at times make the implementation of these recommendations in daily practice challenging. The aim of the study is to review available literature on potential long-term side effects of lithium. MATERIALS AND METHODS: A PubMed/Medline search was performed on papers dealing with long-term treatment with lithium and side effects. Articles published from January 1980 to February 2013 were selected. RESULTS: Long-term lithium treatment is associated with a reduced urinary concentrating ability, with subsequent polyuria and polidypsia and nephrogenic diabetes insipidus (in 10-40% of patients). Lithium also reduces glomerular filtration rate, and increases risk of renal failure, although the absolute risk is small (0.5% of patients). Lithium treatment is associated with significant higher TSH levels, with a 6-fold greater risk of hypothyroidism in lithium-treated than in control subjects. Less known is the increase of PTH and calcium levels induced by lithium. An exacerbation of psoriasis is also frequently associated with lithium treatment. CONCLUSIONS: Lithium remains a fundamental tool for the treatment of BD. Clinicians should know potential side effects (renal, endocrine and dermatological) associated with long-term treatment with lithium, for a correct management of the patient. A specialist referral is often necessary; the question is how to deal with long-term side effects more than whether or not withdrawing lithium. This decision should remain a psychiatrist's competence.

Lithium-associated hyperparathyroidism and hypercalcaemia: a case-control cross-sectional study.

BACKGROUND: Lithium is recommended as a first-line treatment for Bipolar Disorder (BD). Thyroid and renal alterations are well known lithium side-effects, while effects on parathyroids are less studied. The aim of this case-control cross-sectional study is to compare parathyroid hormone (PTH) and calcium levels in lithium-exposed bipolar patients and in subjects who had never been exposed to lithium. METHODS: 112 BD patients were enrolled, 58 on lithium since at least 1 month (mean exposure 60.8 ± 74.8 months) and 54 in the control group. Blood exams included complete blood count, PTH, total and ionized calcium, TSH, T3 and T4, creatinine, urea, sodium and potassium, and lithium serum levels. The Student's t-test and the Pearson's Chi-square test were used for bivariate analyses. A linear regression model was used to analyze the relationship between the duration of exposure to lithium and PTH and calcium levels. RESULTS: PTH and ionized calcium levels were significantly higher in lithium-exposed patients; the proportions of subjects with hyperparathyroidism (8.6%) and hypercalcaemia (24.1%) were significantly greater in lithium-exposed patients. The linear regression analyses showed a significant effect of exposure to lithium in months on ionized calcium levels but not on PTH levels. LIMITATIONS: Given the cross-sectional design of the study we could not identify the exact time of occurrence of hyperparathyroidism. CONCLUSIONS: Our results indicate that lithium-associated stimulation of parathyroid function is more common than assumed to date. Among parameters to be evaluated prior to lithium implementation and during long-term lithium maintenance, calcium (and eventually PTH) should be added.