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Purpose To describe the extent to which patients with mental health problems after admission to an Intensive Care Unit (ICU) initiate and use psychotropic medication. Methods All adult patients who stayed in the ICU of the University Medical Center Utrecht for 48 h or more between 2013 and 2017, alive after 1 year and not admitted to the ICU with brain injury, were eligible. Questionnaires were used to identify mental health problems, depression, anxiety and posttraumatic stress disorder (PTSD) and psychotropic medication use. Results Of the 1328 former ICU patients, 24.3% (n = 323) had developed any of the mental health problems. Of this group, 29.7% (n = 96) used psychotropic medication one year after discharge versus the 10.6% (n = 107) of patients without these problems (OR 3.17, 95% CI 2.29–4.38). They were further 4.33 (95% CI 2.62–7.16) times more likely to initiate psychotropic medication (18.7% vs 4.8%) after ICU admission. Similar patterns were observed for individual groups of psychotropics: antidepressants, antipsychotics and benzodiazepines. Discussion Former ICU patients with mental health problems were almost four times more likely to use psychotropic medication than former ICU patients without these problems. Future research should investigate whether mental health problems are properly diagnosed and treated in former ICU patients.

Noscapine is a phthalide isoquinoline alkaloid with antitussive activity. Noscapine protects oligodendroglia from ischemic and chemical injury, binds to bitter taste receptors, antagonizes the bradykinin and histaminergic systems, which may be of benefit in treatment of multiple sclerosis. Noscapine normalizes axonal transport and exerts significant therapeutic efficacy in animal models of Parkinson's Disease and Amyotrophic Lateral Sclerosis. Noscapine exerts neuroprotective effects on oxygen- and glucose-deprived fetal cortical neuronal cells and reduces ischemic brain damage in neonatal rat pups. Pilot clinical studies indicated some beneficial effects of noscapine in stroke. Noscapine harbours anxiolytic activity and methyl-noscapine blocks small conductance SK channels, which is beneficial in alleviating anxiety and depression. Noscapine exerts anticholinesterase activity and acts inhibitory on the inflammatory transcription factor NF-κB, which may be harnessed in treatment of Alzheimer's Disease. With its blood-brain barrier traversing features and versatile actions, noscapine may be a promising agent in the armamentarium against neurodegenerative and psychiatric diseases.

PURPOSE: Breast cancer and psychiatric disorders negatively impact work life, both positively associated with unemployment and early retirement. Our purpose was to assess whether being prescribed psychiatric medication, 2-4 yrs prior to a diagnosis of breast cancer, could impact the likelihood of returning to work after cancer therapy.METHODS: 16,868 self-supporting women, diagnosed with breast cancer in Denmark from 2000 to 2012, were identified from a population-based clinical database, then cross-referenced to data held for psychiatric medication usage, sociodemographics, and labour-market participation. The association between historic psychiatric medication and return to work was estimated using a modified Poisson regression model. 'Return to work' was defined as being self-supporting one year after diagnosis of breast cancer.RESULTS: 16% of our cohort had used psychiatric medical treatment 2-4 years before their diagnosis. Sixty-three per cent of these individuals had returned to work one year later, compared to 69% of the patient group with no prior history of using psychiatric medication treatments. In the fully adjusted model, prior use of psychiatric medication diminished the likelihood of returning to work one year after cancer diagnosis (RR = 0.91 (0.87-0.94)). High income and older age were positively associated with returning to work; negative correlates included those related to disease severity.CONCLUSIONS: Historic use of psychiatric medication provoked a minor, although statistically significant reduction in the resumption of working life one year after a diagnosis of breast cancer.IMPLICATIONS FOR CANCER SURVIVORS: Although historic use of psychiatric medication may incur a minor effect on working life, further research is needed on the long-term social consequences for sub-groups.

Lipid disturbances following treatment with second-generation antipsychotics (SGAs) represent a major health concern. A previous study determined that early changes of plasma lipid levels ≥ 5% during the first month of treatment with SGAs predicts further lipid worsening and development of dyslipidemia. This current study aimed to determine the proportion of adolescents with early lipid changes ≥ 5% and who develop dyslipidemia during SGA treatment. Data were obtained from a 1-year longitudinal study ongoing since 2007 including 53 adolescent psychiatric (ICD-10) patients (median age 16.5 years; interquartile range [IQR], 14.8-17.5 years) whose metabolic parameters were monitored prospectively during treatment. Plasma lipid levels (total, low-density lipoprotein, high-density lipoprotein [HDL-C], and non-high-density lipoprotein cholesterol and fasting triglycerides ) were measured at baseline and after 1, 3, and/or 12 months of SGA treatment. Half (n = 26; 49%) the adolescents had an early increase of total cholesterol levels by 5% or more during the first month of treatment, and one-third (n = 8/24; 33%) developed new-onset hypercholesterolemia during the first year of treatment. Hypercholesterolemia developed more frequently in female patients (P = .01) and in patients with an early increase of total cholesterol ≥ 5% (P = .02). Finally, patients whose HDL-C levels decreased by ≥ 5% during the first month of treatment had a larger HDL-C worsening after 3 months of treatment as compared with patients with early decrease of HDL-C by < 5% (P = .02). This study underlines the importance of prospectively monitoring metabolic parameters in adolescents after the introduction of SGAs.

Psychiatric patients are known to be at high risk of developing cardiovascular diseases (CVDs), leading to an increased mortality rate. To assess the CVD risk (presence of metabolic syndrome [MetS] and calculated 10-year CVD risk) in a Swiss psychiatric cohort taking weight gain-inducing psychotropic drugs, compare the findings to a Swiss population-based cohort, and evaluate the prevalence of participants treated for metabolic disruptions in both cohorts. Data for 1,216 psychiatric patients (of whom 634 were aged 35-75 years) were obtained between 2007 and 2017 from a study with metabolic parameters monitored during psychotropic treatment and between 2003 and 2006 for 6,733 participants from the population-based CoLaus|PsyCoLaus study. MetS as defined by the International Diabetes Federation (IDF) was identified in 33% of the psychiatric participants and 24.7% of the population-based subjects. Specifically, prevalence per the IDF definition was more than 3 times higher in the psychiatric cohort among women aged 35 to 49 years (25.6% vs 8.0%; P < 10-4). The psychiatric and population-based cohorts, respectively, had comparable predicted CVD risk (10-year risk of CVD event > 20%: 0% vs 0.1% in women and 0.3% vs 1.8% [P = .01] in men; 10-year risk of CVD death > 5%: 8.5% vs 8.4% [P = .58] in women and 13.4% vs 16.6% [P = .42] in men). No difference was observed among the proportion of participants with MetS treated for metabolic disturbances in the two cohorts, with the exception of women aged 35-49 years, for whom those in the psychiatric cohort were half as likely to receive treatment compared to participants in CoLaus|PsyCoLaus (17.8% vs 38.8% per the IDF definition; P = .0004). These findings emphasize the concern that psychiatric patients present an altered metabolic profile and that they do not receive adequate treatment for metabolic disruptions. Presence of metabolic disturbances should be routinely assessed, and adequate follow-up is needed to intervene early after illness onset.

This retrospective study aims to evaluate off-label prescriptions and administrations of psychotropic medications in adolescents in a university psychiatric hospital in Switzerland. Data were collected during the entire stays from the electronic database for 76 inpatients in 2008 and 76 inpatients in 2014. Data collected included gender, age, psychiatric diagnosis, duration of hospitalization, and psychotropic drug prescriptions and administrations. A total of 224 psychotropic drugs (mean 2.9 drugs/patient) were prescribed in 2008 and 268 (mean 3.5 drugs/patient) in 2014. Due to the prescriptions of some drugs as required, only 76% of the prescriptions were actually administered in 2008 (mean 2.3 drugs/patient) and 55% in 2014 (mean 1.9 drugs/patient). Antipsychotics were the most frequently prescribed drugs in 2008 (74% of patients) and 2014 (86% of patients). Anxiolytics were also highly prescribed in 2008 (54% of patients) and 2014 (66% of patients), as well as antidepressants in 2008 (30% of patients), but less in 2014 (13% of patients). Overall, 69% of prescriptions were found to be off label in 2008 and 68% in 2014, according to age, diagnosis, dose, or formulation as approved by Swissmedic. The medication classes with the highest rate of off-label prescriptions were antidepressants (100% for both years), antipsychotics (94% in 2008 and 92% in 2014), and hypnotics (67% in 2008 and 100% in 2014). For both study periods, at least one off-label psychotropic drug prescription and administration was recorded in 96% and 79% of the patients, respectively. The high rate of off-label psychotropic drug use strengthens the need for clinical trials to better evaluate the efficacy and safety of these treatments in adolescents.

Background:In randomized controlled trials, Ginkgo biloba extract EGb 761® has been found to be effective in the treatment of behavioral and psychological symptoms of dementia (BPSD).Methods:To assess the effects of EGb 761® on specific BPSD, we analyzed data from all randomized, placebo-controlled, at least 20-week, trials of EGb 761® enrolling patients with dementia (probable Alzheimer's disease (AD), probable vascular dementia or probable AD with cerebrovascular disease) who had clinically significant BPSD (Neuropsychiatric Inventory (NPI) total score at least 6). Data were pooled and joint analyses of NPI single item composite and caregiver distress scores were performed by meta-analysis with a fixed effects model.Results:Four trials involving 1628 patients (EGb 761®, 814; placebo, 814) were identified; treatment duration was 22 or 24 weeks; the daily dose of EGb 761® was 240 mg in all trials. Pooled analyses including data from the full analysis sets of all trials (EGb 761®, 796 patients; placebo, 802 patients) revealed significant superiority of EGb 761® over placebo in total scores and 10 single symptom scores. Regarding caregiver distress scores, EGb 761®-treated patients improved significantly more than those receiving placebo in all symptoms except delusions, hallucinations, and elation/euphoria. The benefit of EGb 761® mainly consists of improvement in symptoms present at baseline, but the incidence of some symptoms was also decreased.Conclusions:Twenty two- to twenty four-week treatment with Ginkgo biloba extract EGb 761® improved BPSD (except psychotic-like features) and caregiver distress caused by such symptoms.

Genetic factors associated with Body Mass Index (BMI) have been widely studied over the last decade. We examined whether genetic variants previously associated with BMI in the general population are associated with cardiometabolic parameter worsening in the psychiatric population receiving psychotropic drugs, a high-risk group for metabolic disturbances. Classification And Regression Trees (CARTs) were used as a tool capable of describing hierarchical associations, to pinpoint genetic variants best predicting worsening of cardiometabolic parameters (i.e total, HDL and LDL-cholesterol, triglycerides, body mass index, waist circumference, fasting glucose, and blood pressure) following prescription of psychotropic drugs inducing weight gain in a discovery sample of 357 Caucasian patients. Significant findings were tested for replication in a second Caucasian psychiatric sample (n=140). SH2B1 rs3888190C>A was significantly associated with LDL levels in the discovery and in the replication sample, with A-allele carriers having 0.2mmol/l (p=0.005) and 0.36mmol/l (p=0.007) higher LDL levels compared to others, respectively. G-allele carriers of RABEP1 rs1000940A>G had lower fasting glucose levels compared to others in both samples (-0.16mmol/l; p

Background Cardiovascular diseases and dyslipidemia represent a major health issue in psychiatry. Many psychotropic drugs can induce a rapid and substantial increase of blood lipid levels. Objective This study aimed to determine the potential predictive power of an early change of blood lipid levels during psychotropic treatment on long-term change and on dyslipidemia development. Methods Data were obtained from a prospective study including 181 psychiatric patients with metabolic parameters monitored during the first year of treatment and with adherence ascertained. Blood lipid levels (ie, total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], non–high-density lipoprotein cholesterol [non-HDL-C], and fasting triglycerides [TGs]) were measured at baseline and after 1, 3, and/or 12 months of treatment. Results Receiver-operating characteristic analyses indicated that early (ie, after 1 month of psychotropic treatment) increases (≥5%) for TC, LDL-C, TG, and non-HDL-C and decrease (≥5%) for HDL-C were the best predictors for clinically relevant modifications of blood lipid levels after 3 months of treatment (≥30% TC, ≥40% LDL-C, ≥45% TG, ≥55% non-HDL-C increase, and ≥20% HDL-C decrease; sensitivity 70%–100%, specificity 53%–72%). Predictive powers of these models were confirmed by fitting longitudinal multivariate models in the same cohort ( P ≤ .03) as well as in a replication cohort (n = 79; P ≤ .003). Survival models showed significantly higher incidences of new onset dyslipidemia (TC, LDL-C, and non-HDL-C hypercholesterolemia, HDL-C hypocholesterolemia, and hypertriglyceridemia) for patients with early changes of blood lipid levels compared to others ( P ≤ .01). Conclusion Early modifications of blood lipid levels following prescription of psychotropic drugs inducing dyslipidemia should therefore raise questions on clinical strategies to control long-term dyslipidemia.

Decisions about the use of psychotropic medication in pregnancy are an ongoing challenge for clinicians and women with mental health problems, owing to the uncertainties around risks of the illness itself to mother and fetus/infant, effectiveness of medications in pregnancy and risks to the fetus/infant from in utero exposure or via breast milk. These consensus guidelines aim to provide pragmatic advice regarding these issues. They are divided into sections on risks of untreated illness in pregnancy; general principles of using drugs in the perinatal period; benefits and harms associated with individual drugs; and recommendations for the management of specific disorders.

Background: Many patients with psychiatric illnesses have difficulty maintaining medication over time. Many take their medicine irregularly and studies show that it is the most vulnerable patients who have the greatest problems adhering to treatment. Often only 50% are still under medical treatment after 6 months. Aim: In this study we investigated whether text message reminders could improve medicine compliance amongst vulnerable young people with psychiatric disorders who were being treated in the outpatient department for child and adolescent psychiatry and who either are under or were to commence medicinal treatment. Methods: This study was conducted as a randomized controlled trial including all non-acute referrals to an outpatient department for adolescent psychiatry within a group aged 15-20 years starting medical treatment. The patients were followed until the end of their treatment, for a minimum of 3 months. To enhance medicine compliance, text messages were sent daily to one group. No message was sent to the other group. Results: Compliance was not associated with text message intervention in any of the drug interventions. The effect size was calculated to 0.3013, which is low and therefore indicates a weak association between text message and compliance. The power in this study was calculated to 0.3539, which is also low and therefore the likelihood of finding significant association is low. Conclusion: This study does not show increased medicine compliance from the text message intervention group. The conclusion of this study is that it is essential that significant resources are spent preparing and testing a text message strategy. © 2015 Taylor & Francis.

Weight gain is a major health problem among psychiatric populations. It implicates several receptors and hormones involved in energy balance and metabolism. Phosphoenolpyruvate carboxykinase 1 is a rate-controlling enzyme involved in gluconeogenesis, glyceroneogenesis and cataplerosis and has been related to obesity and diabetes phenotypes in animals and humans. The aim of this study was to investigate the association of phosphoenolpyruvate carboxykinase 1 polymorphisms with metabolic traits in psychiatric patients treated with psychotropic drugs inducing weight gain and in general population samples. One polymorphism (rs11552145G > A) significantly associated with body mass index in the psychiatric discovery sample (n = 478) was replicated in 2 other psychiatric samples (n(1) = 168, n(2) = 188), with AA-genotype carriers having lower body mass index as compared to G-allele carriers. Stronger associations were found among women younger than 45 years carrying AA-genotype as compared to G-allele carriers (-2.25 kg/m(2), n = 151, P = 0.009) and in the discovery sample (-2.20 kg/m(2), n = 423, P = 0.0004). In the discovery sample for which metabolic parameters were available, AA-genotype showed lower waist circumference (-6.86 cm, P = 0.008) and triglycerides levels (-5.58 mg/100 mL, P < 0.002) when compared to G-allele carriers. Finally, waist-to-hip ratio was associated with rs6070157 (proxy of rs11552145, r(2) = 0.99) in a population-based sample (N = 123,865, P = 0.022). Our results suggest an association of rs11552145G > A polymorphism with metabolic-related traits, especially in psychiatric populations and in women younger than 45 years.

Background: SSRIs are widely used in the treatment of mental illness for both children and adults. Studies have found a slightly increased risk of suicidal thoughts and suicide attempts in young people using SSRIs but SSRIs’ impact on risk for suicides in youth is not well-established. Aim: Is there indication that SSRIs might raise risk for suicide attempts in young people? Methods: We used an observational register-based historical cohort design, a large cohort of all Danish individuals born in 1983–1989 (n = 392,458) and a propensity score approach to analyse the impact from SSRIs on risk for suicide attempts. Every suicide attempt and redeemed prescription of SSRIs was analysed by Cox regression. Results: We found a significant overlap between redeeming a prescription on SSRIs and subsequent suicide attempt. The risk for suicide attempt was highest in the first 3 months after redeeming the first prescription. The hazard ratio for suicide attempts after redeeming a prescription was estimated to 5.23, 95% CI 4.82–5.68. Conclusion: We conclude that the risk of suicide attempt is higher for young people in the first months after redeeming their first prescription for SSRIs, compared to non-users. For SSRI users with lower propensity score (fewer risk factors for SSRIs) the risk of suicide attempt is estimated to be highest. Although the design may miss some explicit reason for prescription of SSRIs and SSRIs might be a marker for those in high risk rather than a causal risk factor, we would recommend systematic risk assessment in the period after redeeming the first prescription.

© 2014 Elsevier Inc. Niemann-Pick disease type A (NPDA) is a fatal disease due to mutations in the acid sphingomyelinase (ASM) gene, which triggers the abnormal accumulation of sphingomyelin (SM) in lysosomes and the plasma membrane of mutant cells. Although the disease affects multiple organs, the impact on the brain is the most invalidating feature. The mechanisms responsible for the cognitive deficit characteristic of this condition are only partially understood. Using mice lacking the ASM gene (ASMko), a model system in NPDA research, we report here that high sphingomyelin levels in mutant neurons lead to low synaptic levels of phosphoinositide PI(4,5)P2 and reduced activity of its hydrolyzing phosphatase PLCγ, which are key players in synaptic plasticity events. In addition, mutant neurons have reduced levels of membrane-bound MARCKS, a protein required for PI(4,5)P2 membrane clustering and hydrolysis. Intracerebroventricular infusion of a peptide that mimics the effector domain of MARCKS increases the content of PI(4,5)P2 in the synaptic membrane and ameliorates behavioral abnormalities in ASMko mice., Fund for Scientific Research Flanders (FWO) G0.666.10N (CGD) and G0D7614N (RD'H), Interuniversity Attraction Poles Program IUAP P6P7/1658 (RD'H) and Neurobrainnet IAP 7/16 (CGD) of the Belgian Federal Science Policy Office and Methusalem grant of the Flemish Government, Spanish Ministry of Science and Innovation Ingenio-Consolider CSD2010-00064 and SAF2010-14906 and Spanish Ministry of Economy and Competitiveness SAF2013-45392 to CGD

Background: Thyroid hormones are necessary for fetal brain development, while hypothyroidism in adults has been associated with mood symptoms and reduced quality of life. Nevertheless, our knowledge regarding the association and temporal relation between hypothyroidism and mental disorders is ambiguous. Our objective was to investigate, at a nationwide level, whether a diagnosis of hypothyroidism is associated with psychiatric morbidity. Methods: Observational cohort study. Based on record-linkage between different Danish health registers, 2822 hypothyroid singletons each matched with 4 non-hypothyroid controls were identified and followed over a mean period of 6 years (range 1-13). Additionally, we included 385 same sex twin pairs discordant for hypothyroidism. Diagnoses of psychiatric disorders as well as treatment with antidepressants, antipsychotics and anxiolytics were recorded. Logistic and cox regression models were used to assess the risk of psychiatric morbidity before and after the diagnosis of hypothyroidism, respectively. Results: Prior to the diagnosis of hypothyroidism, such individuals had an increased prevalence of diagnoses with psychiatric disorders (Odds ratio, OR, 1.51; 95% confidence interval (CI): 1.12-2.04) and increased prevalence of treatment with antipsychotics (OR 1.49; 95% CI: 1.29-1.73), antidepressants (OR 1.50; 95% CI: 1.35-1.67), and anxiolytics (OR 1.28; 95% CI: 1.16-1.41). After the diagnosis of hypothyroidism, patients had a higher risk of being diagnosed with a psychiatric disorder (Hazard ratio, HR, 2.40; 95% CI: 1.81-3.18), and an increased risk of being treated with antidepressants (HR 1.30; 95% CI: 1.15-1.47) and anxiolytics (HR 1.27; 95% CI: 1.10-1.47), but not antipsychotics (HR 1.13; 95% CI: 0.91-1.41). Based on the twin data, we could not demonstrate genetic confounding. Conclusions: Subjects with hypothyroidism have an increased risk of being diagnosed with a psychiatric disorder as well as being treated with antidepressants, antipsychotics and anxiolytics both before and after the diagnosis of hypothyroidism. Background: Thyroid hormones are necessary for fetal brain development, and hypothyroidism in adults has been associated with mood symptoms and reduced quality of life. Nevertheless, our knowledge regarding the association and temporal relation between hypothyroidism and mental disorders is ambiguous. Our objective was to investigate, at a nationwide level, whether a diagnosis of hypothyroidism is associated with psychiatric morbidity. Methods: This is an observational cohort study. On the basis of record linkage between different Danish health registers, 2822 hypothyroid singletons each matched with 4 nonhypothyroid controls were identified and followed over a mean period of 6 years (range 1-13). Additionally, we included 385 same-sex twin pairs discordant for hypothyroidism. Diagnoses of psychiatric disorders as well as treatment with antidepressants, antipsychotics, and anxiolytics were recorded. Logistic and cox regression models were used to assess the risk of psychiatric morbidity before and after the diagnosis of hypothyroidism, respectively. Results: Before the diagnosis of hypothyroidism, such individuals had an increased prevalence of diagnoses with psychiatric disorders (odds ratio, OR, 1.51; 95% confidence interval [CI 1.12-2.04]) and increased prevalence of treatment with antipsychotics (OR 1.49 [CI 1.29-1.73]), antidepressants (OR 1.50 [CI 1.35-1.67]), and anxiolytics (OR 1.28 [CI 1.16-1.41]). After the diagnosis of hypothyroidism, patients had a higher risk of being diagnosed with a psychiatric disorder (hazard ratio, HR, 2.40 [CI 1.81-3.18]), and an increased risk of being treated with antidepressants (HR 1.30 [CI 1.15-1.47]) and anxiolytics (HR 1.27 [CI 1.10-1.47]), but not antipsychotics (HR 1.13 [CI 0.91-1.41]). On the basis of the twin data, we could not demonstrate genetic confounding. Conclusions: Subjects with hypothyroidism have an increased risk of being diagnosed with a psychiatric disorder as well as being treated with antidepressants, antipsychotics, and anxiolytics both before and after the diagnosis of hypothyroidism.

ObjectiveThyroid hormones are essential for the normal development of the fetal brain, while hyperthyroidism in adults is associated with mood symptoms and reduced quality of life. In this study, we aimed to investigate the association and temporal relationship between hyperthyroidism and psychiatric morbidity.DesignRegister-based nationwide cohort study.MethodData on hyperthyroidism and psychiatric morbidity were obtained by record linkage of the Danish National Patient Registry and the Danish National Prescription Registry. A total of 2631 hyperthyroid individuals were identified and matched 1:4 with non-hyperthyroid controls and followed for a mean duration of 6 years (range 0–13). Logistic and Cox regression models were used to assess the risk of psychiatric morbidity before and after the diagnosis of hyperthyroidism respectively.ResultsBefore the diagnosis of hyperthyroidism, such individuals had an increased risk of being hospitalized with psychiatric diagnoses (odds ratio (OR): 1.33; 95% CI: 0.98–1.80) and an increased risk of being treated with antipsychotics (OR: 1.17; 95% CI: 1.00–1.38), antidepressants (OR: 1.13; 95% CI: 1.01–1.27), or anxiolytics (OR: 1.28; 95% CI: 1.16–1.42). After the diagnosis of hyperthyroidism, there was a higher risk of being hospitalized with psychiatric diagnoses (hazard ratio (HR): 1.51; 95% CI: 1.11–2.05) and an increased risk of being treated with antipsychotics (HR: 1.46; 95% CI: 1.20–1.79), antidepressants (HR: 1.54; 95% CI: 1.36–1.74), or anxiolytics (HR: 1.47; 95% CI: 1.27–1.69).ConclusionsHyperthyroid individuals have an increased risk of being hospitalized with psychiatric diagnoses and being treated with antipsychotics, antidepressants, and anxiolytics, both before and after the diagnosis of hyperthyroidism.

Journal article Although the pharmacological and medicinal properties of the plant Cannabis sativa have long been known and appreciated, the discovery of the endocannabinoid system began with the isolation of [delta]9-tetrahydrocannabinol (THC), the major psychoactive component of the plant, in the mid-1960s (Gaoni and Mechoulam, 1964). Extensive pharmacological studies followed, and, by the end of the last century, the endogenous cannabinoid (endocannabinoid) system was known to comprise at least two metabotropic receptors, cannabinoid receptor types 1 and 2 (CB1 and CB2); two endogenous ligands, the ethanolamine of arachidonic acid, also known as anandamide (AEA), and 2-arachidonoyl-glycerol (2-AG); and the enzymes responsible for their synthesis and catabolism. However, in the last decade (2000-2010), our understanding of the endocannabinoid system has experienced a true revolution. Novel lipid molecules with endocannabinoid activity have been identified; endocannabinoids have been reported to activate additional targets, including the Transient Receptor Potential Vanilloid 1 (TRPV1) channel, nuclear peroxisome proliferator activated receptors (PPARs) and the G protein-coupled receptor GPR55. Moreover, novel pathways for endocannabinoid synthesis and degradation have been discovered. In this special issue, Pamplona and Takahashi (2012) review the discovery of the endocannabinoid system and present the most recent advances in our understanding of the physiology of this system. peer-reviewed

BACKGROUND: High interindividual variability in plasma concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, may lead to suboptimal drug concentration. OBJECTIVE: Using a population pharmacokinetic approach, we aimed to characterize the genetic and non-genetic sources of variability affecting risperidone and 9-hydroxyrisperidone pharmacokinetics, and relate them to common side effects. METHODS: Overall, 150 psychiatric patients (178 observations) treated with risperidone were genotyped for common polymorphisms in NR1/2, POR, PPARα, ABCB1, CYP2D6 and CYP3A genes. Plasma risperidone and 9-hydroxyrisperidone were measured, and clinical data and common clinical chemistry parameters were collected. Drug and metabolite concentrations were analyzed using non-linear mixed effect modeling (NONMEM(®)). Correlations between trough concentrations of the active moiety (risperidone plus 9-hydroxyrisperidone) and common side effects were assessed using logistic regression and linear mixed modeling. RESULTS: The cytochrome P450 (CYP) 2D6 phenotype explained 52% of interindividual variability in risperidone pharmacokinetics. The area under the concentration-time curve (AUC) of the active moiety was found to be 28% higher in CYP2D6 poor metabolizers compared with intermediate, extensive and ultrarapid metabolizers. No other genetic markers were found to significantly affect risperidone concentrations. 9-hydroxyrisperidone elimination was decreased by 26% with doubling of age. A correlation between trough predicted concentration of the active moiety and neurologic symptoms was found (p = 0.03), suggesting that a concentration >40 ng/mL should be targeted only in cases of insufficient, or absence of, response. CONCLUSIONS: Genetic polymorphisms of CYP2D6 play an important role in risperidone, 9-hydroxyrisperidone and active moiety plasma concentration variability, which were associated with common side effects. These results highlight the importance of a personalized dosage adjustment during risperidone treatment.