The Pharmacogenetics of Symptom Response to Antipsychotic Drugs

Antipsychotic drugs are limited in their efficacy by the relatively poor response of negative and cognitive symptoms of schizophrenia as well as by the substantial variability in response between patients. Pharmacogenetic studies have sought to identify the genetic factors that underlie the individual variability in response to treatment, with a past emphasis on dopamine and serotonin receptors as candidate genes. Few studies have separated effects on positive and negative symptoms, despite the established differences in response to drug treatment between these syndromes. Where this has been done most findings are consistent with the conclusion that dopamine receptor polymorphisms relate to positive symptom response, while negative symptom improvement is influenced by polymorphisms of genes involved in 5-HT neurotransmission. A wide range of polymorphisms in other candidate genes have been investigated, with some positive findings in those genes associated with glutamatergic transmission and/or risk factors for schizophrenia. However, there remains a lack of good replicated findings; furthermore there is little evidence to support drug-specific genetic associations with treatment response. While most past studies focused on single candidate genes, technology now permits genome-wide association studies with response to antipsychotics. Although not without major limitations, these "hypothesis-free" approaches are beginning to identify further important risk factors for treatment response. Again there is little consistency between various studies, although some of the polymorphisms identified are in genes involved in neurodevelopment, which is increasingly being recognized as important in the pathophysiology of schizophrenia

Gain and loss of function of P2X7 receptors: Mechanisms, pharmacology and relevance to diabetic neuropathic pain

Background: Genetic causes of exaggerated or reduced pain sensitivity in humans are well known. Recently, single nucleotide polymorphisms (SNPs) in the gene P2RX7, coding for the ATP-gated ion channel P2X7, have been described that cause gain-of-function (GOF) and loss-of-function (LOF), respectively of this channel. Importantly, P2RX7 SNPs have been associated with more or less severe pain scores in patient suffering of post-mastectomy pain and osteoarthritis. Results: The functional consequences of some P2RX7 SNPs (rs208294 (His155Tyr), rs1718119 (Ala348Thr) and rs3751143 (Glu496Ala)) were studied in recombinant cells in vitro. Our findings suggest a correlation between GOF and LOF of P2X7 and actual channel protein expression. Both channel and pore function for these mutant P2X7 receptors changed in parallel to protein levels. On the other hand, the mutant receptors did not differ in their sensitivity to known P2X7 agonists and antagonists. We further demonstrated that in patients with diabetic peripheral neuropathic pain (DPNP), the presence of the GOF SNPs rs208294 (His155Tyr) and rs1718119 (Ala348Thr) is associated, in females, with higher pain intensity scores. Conclusions: Our present results confirm the physiological relevance of some of the SNPs in the P2RX7 gene and show that the presence of these genetic variants correlates with pain sensitivity also in a diabetic neuropathic pain patient population

Association between type-three metabotropic glutamate receptor gene ( GRM3 ) variants and symptom presentation in treatment refractory schizophrenia

Objective Positive associations between polymorphisms in the type-three metabotropic glutamate receptor gene ( GRM3 ) and the pathogenesis of schizophrenia as well as response to antipsychotic treatment have been reported. The objective of this study was to determine whether refractory psychiatric symptoms in antipsychotic non-responders are related to polymorphisms in GRM3 . Methods Ninety-five treatment refractory schizophrenia participants were enrolled. Prior to a medication switch, global psychopathology and negative symptoms were rated. These participants were genotyped for seven markers in GRM3 . Genotype associations with symptoms were assessed. Results Two markers in GRM3 (rs1989796 and rs1476455), were associated with the presence of refractory global symptoms as measured by the Brief Psychiatric Rating Scale (BPRS) Total scores. Participants with an rs1476455_CC genotype had significantly higher BPRS scores than A-carriers (55.1 ± 10.4 vs. 48.3 ± 9.2; F  = 7.6, p  = 0.0071). Additionally, participants with the rs1989796_CC genotype had significantly higher BPRS scores than T-carriers (50.1 ± 5.7 vs. 55.8 ± 10.5, F  = 7.1, p  = 0.0091). No evidence for significant associations with negative symptoms was observed. Conclusions Polymorphisms in the GRM3 gene may be associated with refractory global psychosis symptoms but not negative symptoms in persons with schizophrenia. Copyright © 2011 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83458/1/1163_ftp.pd

Preclinical and Clinical Assessment of Cannabinoids as Anti-Cancer Agents

Cancer is the second leading cause of death in the United States with 1.7 million new cases estimated to be diagnosed in 2016. This disease remains a formidable clinical challenge and represents a substantial financial burden to the US health care system. Therefore, research and development of novel therapeutics for the treatment of cancer is of high priority. Cannabinoids and their derivatives have been utilized for their medicinal and therapeutic properties throughout history. Cannabinoid activity is regulated by the endocannabinoid system (ECS), which is comprised of cannabinoid receptors, transporters, and enzymes involved in cannabinoid synthesis and breakdown. More recently, cannabinoids have gained special attention for their role in cancer cell proliferation and death. However, many studies investigated these effects using in vitro models which may not adequately mimic tumor growth and metastasis. As such, this article aims to review study results which evaluated effects of cannabinoids from plant, synthetic and endogenous origins on cancer development in preclinical animal models and to examine the current standing of cannabinoids that are being tested in human cancer patients

Barriers to participation in mental health research: are there specific gender, ethnicity and age related barriers?

<p>Abstract</p> <p>Background</p> <p>It is well established that the incidence, prevalence and presentation of mental disorders differ by gender, ethnicity and age, and there is evidence that there is also differential representation in mental health research by these characteristics. The aim of this paper is to a) review the current literature on the nature of barriers to participation in mental health research, with particular reference to gender, age and ethnicity; b) review the evidence on the effectiveness of strategies used to overcome these barriers.</p> <p>Method</p> <p>Studies published up to December 2008 were identified using MEDLINE, PsycINFO and EMBASE using relevant mesh headings and keywords.</p> <p>Results</p> <p>Forty-nine papers were identified. There was evidence of a wide range of barriers including transportation difficulties, distrust and suspicion of researchers, and the stigma attached to mental illness. Strategies to overcome these barriers included the use of bilingual staff, assistance with travel, avoiding the use of stigmatising language in marketing material and a focus on education about the disorder under investigation. There were very few evaluations of such strategies, but there was evidence that ethnically matching recruiters to potential participants did not improve recruitment rates. Educational strategies were helpful and increased recruitment.</p> <p>Conclusion</p> <p>Mental health researchers should consider including caregivers in recruitment procedures where possible, provide clear descriptions of study aims and describe the representativeness of their sample when reporting study results. Studies that systematically investigate strategies to overcome barriers to recruitment are needed.</p

Perceived emotions in music : if musical experience effects perception of emotion in music

We know little about the mechanics behind emotions perceived in music because of the subjective nature of emotional experience. This makes it difficult to measure responses and make comparisons across individuals, since we have a factor that we can’t fully control: the individual’s perception and earlier experiences. But how big is the effect of earlier experiences in perception of music? In this essay the focus is on musical experience and whether musical experience makes a difference in how we perceive emotions in music. Listening tests were done by three groups of subjects with differing experience of music to see if there was any detectable difference. The groups where audio engineers, musicians and people with very little experience in music. The results from the listening test showed indications of that the musicians perceive more emotions in the music. Any reasons for and against these signs are discussed.Validerat; 20101217 (root