A rating scale for drug-induced akathisia has been derived that incorporates diagnostic criteria for pseudoakathisia, and mild, moderate, and severe akathisia. It comprises items for rating the observable, restless movements which characterise the condition, the subjective awareness of restlessness, and any distress associated with the akathisia. In addition, there is an item for rating global severity. A standard examination procedure is recommended. The inter-rater reliability for the scale items (Cohen's kappa) ranged from 0.738 to 0.955. Akathisia was found in eight of 42 schizophrenic in-patients, and nine had pseudoakathisia, where the typical sense of inner restlessness was not reported.

A rating scale for drug-induced akathisia

Evaluating Model Fit

Background
Clinical research affecting how doctors practice medicine is increasingly sponsored by companies that make drugs and medical devices. Previous systematic reviews have found that pharmaceutical industry sponsored studies are more often favorable to the sponsor’s product compared with studies with other sources of sponsorship. This review is an update using more stringent methodology and also investigating sponsorship of device studies.

Objectives
To investigate whether industry sponsored drug and device studies have more favorable outcomes and differ in risk of bias, compared with studies having other sources of sponsorship.

Search methods
We searched MEDLINE (1948 to September 2010), EMBASE (1980 to September 2010), the Cochrane Methodology Register (Issue 4, 2010) and Web of Science (August 2011). In addition, we searched reference lists of included papers, previous systematic reviews and author files.

Selection criteria
Cross-sectional studies, cohort studies, systematic reviews and meta-analyses that quantitatively compared primary research studies of drugs or medical devices sponsored by industry with studies with other sources of sponsorship. We had no language restrictions.

Data collection and analysis
Two assessors identified potentially relevant papers, and a decision about final inclusion was made by all authors. Two assessors extracted data, and we contacted authors of included papers for additional unpublished data. Outcomes included favorable results, favorable conclusions, effect size, risk of bias and whether the conclusions agreed with the study results. Two assessors assessed risk of bias of included papers. We calculated pooled risk ratios (RR) for dichotomous data (with 95% confidence intervals).

Main results
Forty-eight papers were included. Industry sponsored studies more often had favorable efficacy results, risk ratio (RR): 1.32 (95% confidence interval (CI): 1.21 to 1.44), harms results RR: 1.87 (95% CI: 1.54 to 2.27) and conclusions RR: 1.31 (95% CI: 1.20 to 1.44) compared with non-industry sponsored studies. Ten papers reported on sponsorship and effect size, but could not be pooled due to differences in their reporting of data. The results were heterogeneous; five papers found larger effect sizes in industry sponsored studies compared with non-industry sponsored studies and five papers did not find a difference in effect size. Only two papers (including 120 device studies) reported separate data for devices and we did not find a difference between drug and device studies on the association between sponsorship and conclusions (test for interaction, P = 0.23). Comparing industry and non-industry sponsored studies, we did not find a difference in risk of bias from sequence generation, allocation concealment and follow-up. However, industry sponsored studies more often had low risk of bias from blinding, RR: 1.32 (95% CI: 1.05 to 1.65), compared with non-industry sponsored studies. In industry sponsored studies, there was less agreement between the results and the conclusions than in non-industry sponsored studies, RR: 0.84 (95% CI: 0.70 to 1.01).

Authors' conclusions
Sponsorship of drug and device studies by the manufacturing company leads to more favorable results and conclusions than sponsorship by other sources. Our analyses suggest the existence of an industry bias that cannot be explained by standard 'Risk of bias' assessments.

/pdf/industry-sponsorship-and-research-outcome-1zaeyoxoy7.pdf

Industry sponsorship and research outcome

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.

/pdf/evidence-based-guidelines-for-treating-bipolar-disorder-4spyuaidig.pdf

Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology

Atlas of the Human Brain.

Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, is attracting growing attention in medicine for its anxiolytic, antipsychotic, antiemetic and anti-inflammatory properties. However, up to this point, a comprehensive literature review of the effects of CBD in humans is lacking. The aim of the present systematic review is to examine the randomized and crossover studies that administered CBD to healthy controls and to clinical patients. A systematic search was performed in the electronic databases PubMed and EMBASE using the key word "cannabidiol". Both monotherapy and combination studies (e.g., CBD + ∆9-THC) were included. A total of 34 studies were identified: 16 of these were experimental studies, conducted in healthy subjects, and 18 were conducted in clinical populations, including multiple sclerosis (six studies), schizophrenia and bipolar mania (four studies), social anxiety disorder (two studies), neuropathic and cancer pain (two studies), cancer anorexia (one study), Huntington's disease (one study), insomnia (one study), and epilepsy (one study). Experimental studies indicate that a high-dose of inhaled/intravenous CBD is required to inhibit the effects of a lower dose of ∆9-THC. Moreover, some experimental and clinical studies suggest that oral/oromucosal CBD may prolong and/or intensify ∆9-THC-induced effects, whereas others suggest that it may inhibit ∆9-THC-induced effects. Finally, preliminary clinical trials suggest that high-dose oral CBD (150-600 mg/d) may exert a therapeutic effect for social anxiety disorder, insomnia and epilepsy, but also that it may cause mental sedation. Potential pharmacokinetic and pharmacodynamic explanations for these results are discussed.

https://halcyonorganics.com/wp-content/uploads/2014/01/Cannabidiol-in-Humans-as-Therapeutic-Targets.pdf

Cannabidiol in Humans—The Quest for Therapeutic Targets

Long-acting injectable antipsychotics (LAIs) should offer better efficacy and tolerability, compared to oral antipsychotics due to improved adherence and more stable pharmacokinetics. However, data on LAIs has been mixed, with some studies finding that they are more effective and tolerable than oral antipsychotics, and others finding the contrary. One possibility for the disparate results may be that some studies administered different antipsychotics in the oral and injectable form. The present systematic review examined the efficacy and tolerability of LAIs versus their oral equivalents in randomized and naturalistic studies. In addition, it examined the impact of LAIs on special populations such as patients with first-episode psychosis, substance use disorders, and a history of violence or on involuntary outpatient commitment. Randomized studies suggest that not all LAIs are the same; for example, long-acting risperidone may be associated with equal or less side effects than oral risperidone, whereas fluphenazine decanoate and enanthate may be associated with equal or more side effects than oral fluphenazine. They also suggest that LAIs reduce risk of relapse versus oral antipsychotics in schizophrenia outpatients when combined with quality psychosocial interventions. For their part, naturalistic studies point to a larger magnitude of benefit for LAIs, relative to their oral equivalents particularly among first-episode patients.

/pdf/oral-versus-long-acting-injectable-antipsychotics-in-the-4zo220pj2i.pdf

Oral versus Long-Acting Injectable Antipsychotics in the Treatment of Schizophrenia and Special Populations at Risk for Treatment Nonadherence: A Systematic Review.

Multiple sclerosis (MS) is a chronic central nervous system disease that is associated with progressive loss of myelin and subsequent axonal degeneration. Cholesterol is an essential component of mammalian cellular and myelin membranes. In this systematic review, we examined the relationship between levels of cholesterol and markers of cholesterol turnover in circulation and/or cerebrospinal fluid (CSF) and disease outcomes in adults with clinically isolated syndrome (CIS) or confirmed MS. Studies suggest that elevated levels of circulating low density lipoprotein cholesterol (LDL), total cholesterol, and particularly, apolipoprotein B and oxidized LDL are associated with adverse clinical and MRI outcomes in MS. These relationships were observed as early as CIS. The studies also suggest that oxysterols, cholesterol precursors, and apolipoprotein E may be markers of specific disease processes in MS, but more research is required to elucidate these processes and relationships. Taken together, the data indicate that cholesterol and markers of cholesterol turnover have potential to be used clinically as biomarkers of disease activity and may even be implicated in the pathogenesis of MS.

Cholesterol and markers of cholesterol turnover in multiple sclerosis : Relationship with disease outcomes

Background:Depression is a common comorbidity in multiple sclerosis (MS), but little is known about its long-term prognosis. Depression in the general population is usually episodic with relatively short-lasting depressive episodes. In this study we investigate the long-term prognosis of depression in MS.Methods:Using data from a large longitudinal observational study and from the Calgary MS clinic database, we investigated changes in Center for Epidemiological Studies Depression Scale (CESD) scores in MS patients over four years of follow-up. We used logistic regression to investigate the association of the factors sex, age, disease duration, Expanded Disability Status Scale (EDSS), depression at baseline, and antidepressant use with depression at each year of follow-up.Results:CESD scores remained largely stable, or decreased slightly over four years of follow-up, whereas EDSS scores steadily increased. Depression at baseline was the strongest predictor of depression at follow-up; the other factors were...

Depression in multiple sclerosis: a long-term longitudinal study.

Second-generation APs have become increasingly popular for the treatment of schizophrenia owing to their low potential to induce extrapyramidal symptoms, relative to FGAs.1 However, some SGAs such as olanzapine, clozapine, and quetiapine (less so) are associated with significant metabolic side effects, including weight gain, and elevations in insulin, triglyceride, glucose, and LDL cholesterol levels.2–5 Metabolic side effects are associated with poor treatment adherence and high rates of diabetes mellitus type 2, cardiovascular disease, and morbidity among schizophrenia patients.6–9

The mechanisms responsible for metabolic side effects associated with SGAs are not completely understood. Leptin—a cytokinelike peptide that is synthesized in adipose tissue—acts to reduce appetite and increase metabolic rate after it reaches the brain through regions outside the blood–brain barrier, including parts of the hypothalamus. Leptin is considered one of the best markers of total body fat in animals and humans.10,11 In mice, there is evidence that ob (obese) and db (diabetes) genes encode leptin and the leptin receptor, respectively—recessive mutations in these genes result in obesity and diabetes.12–15 Subcutaneous leptin infusion to lean mice results in a dose-dependent loss of body weight, whereas chronic infusions of intracerebroventricular leptin results in complete depletion of visible adipose tissue. When subcutaneous leptin is infused into diet-induced obese mice it results in loss of adipose tissue, but less so than in lean mice, suggesting the development of leptin resistance.16


Clinical Implications

Only high-to-moderate risk APs (olanzapine, clozapine, and quetiapine) produced significant leptin elevations.


Hyperleptinemia in schizophrenia is likely to represent a secondary effect related to AP-induced weight gain.


The overall increase in leptin levels suggests that leptin acts as a negative feedback signal in the event of fat increase.




Limitations

We were unable to include some prospective studies that did not report absolute changes in leptin levels and this may have biased our results.


Our analysis contained a low number of studies that treated patients with APs that are known to induce little or no weight gain, and most studies were comprised of a small sample of patients.


We were not able to calculate an effect size for changes in ghrelin.





In obese humans, a paradoxical hyperleptinemic state has been observed, which appears to indicate a loss of leptin’s ability to stop overeating behaviour (that is, leptin resistance).17–20 In patients with schizophrenia, hyperleptinemia has also been observed and it is associated with AP-induced weight gain and metabolic side effects.21–25 Numerous studies examined AP-induced changes in leptin among patients with schizophrenia. Thus far, results have been mixed such that some studies report increased leptin levels,26–29 while others report no change.30–32 Taking into account AP-type (high-to-moderate risk, compared with low risk of metabolic side effects) should resolve these issues, but this is not necessarily the case. For example, some studies reveal that only high-to-moderate risk APs (olanzapine, clozapine, and quetiapine) significantly increase leptin levels,33–35 while others show that all APs produce equal changes in leptin (or no changes), independent of their propensity to induce metabolic side effects.36–41 Other confounding factors that may lead to the differential results include age and sex of patients, as well as baseline AP, study duration, and type of blood sample (plasma, compared with serum).

Our meta-analysis of prospective studies aims to resolve some of the discrepant findings by examining the effects of APs on blood leptin levels in patients with schizophrenia. Sufficient data were available for 4 SGAs (olanzapine, clozapine, quetiapine, and risperidone) and 1 FGA (haloperidol). Further, we performed meta-regressions to analyze the relation between changes in leptin, demographic variables, metabolic markers, and other confounding factors.

Simon Zhornitsky

Papers

Cannabidiol in Humans—The Quest for Therapeutic Targets

Oral versus Long-Acting Injectable Antipsychotics in the Treatment of Schizophrenia and Special Populations at Risk for Treatment Nonadherence: A Systematic Review.

Cholesterol and markers of cholesterol turnover in multiple sclerosis : Relationship with disease outcomes

Depression in multiple sclerosis: a long-term longitudinal study.

Antipsychotic-induced changes in blood levels of leptin in schizophrenia: a meta-analysis.