No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide, and bortezomib in patients with Multiple Myeloma

BACKGROUND: The response to treatment varies among patients with multiple myeloma and markers for prediction of treatment outcome are highly needed. Bioactivation of cyclophosphamide and thalidomide, and biodegradation of bortezomib, is dependent on cytochrome P450 metabolism. We explored the potential influence of different polymorphisms in the CYP enzymes on the outcome of treatment. METHODS: Data was analyzed from 348 patients undergoing high-dose treatment and stem cell support in Denmark in 1994 to 2004. Clinical information on relapse treatment in 243 individual patients was collected. The patients were genotyped for the non-functional alleles CYP2C19*2 and CYP2D6*3, *4, *5 (gene deletion), *6, and CYP2D6 gene duplication. RESULTS: In patients who were treated with bortezomib and were carriers of one or two defective CYP2D6 alleles there was a trend towards a better time-to-next treatment. We found no association between the number of functional CYP2C19 and CYP2D6 alleles and outcome of treatment with cyclophosphamide or thalidomide. Neither was the number of functional CYP2C19 and CYP2D6 alleles associated with neurological adverse reactions to thalidomide and bortezomib. CONCLUSION: There was no association between functional CYP2C19 and CYP2D6 alleles and treatment outcome in multiple myeloma patients treated with cyclophosphamide, thalidomide or bortezomib. A larger number of patients treated with bortezomib are needed to determine the role of CYP2D6 alleles in treatment outcome

A mouse model of the schizophrenia-associated 1q21.1 microdeletion syndrome exhibits altered mesolimbic dopamine transmission

Abstract 1q21.1 hemizygous microdeletion is a copy number variant leading to eightfold increased risk of schizophrenia. In order to investigate biological alterations induced by this microdeletion, we generated a novel mouse model (Df(h1q21)/+) and characterized it in a broad test battery focusing on schizophrenia-related assays. Df(h1q21)/+ mice displayed increased hyperactivity in response to amphetamine challenge and increased sensitivity to the disruptive effects of amphetamine and phencyclidine hydrochloride (PCP) on prepulse inhibition. Probing of the direct dopamine (DA) pathway using the DA D1 receptor agonist SKF-81297 revealed no differences in induced locomotor activity compared to wild-type mice, but Df(h1q21)/+ mice showed increased sensitivity to the DA D2 receptor agonist quinpirole and the D1/D2 agonist apomorphine. Electrophysiological characterization of DA neuron firing in the ventral tegmental area revealed more spontaneously active DA neurons and increased firing variability in Df(h1q21)/+ mice, and decreased feedback reduction of DA neuron firing in response to amphetamine. In a range of other assays, Df(h1q21)/+ mice showed no difference from wild-type mice: gross brain morphology and basic functions such as reflexes, ASR, thermal pain sensitivity, and motor performance were unaltered. Similarly, anxiety related measures, baseline prepulse inhibition, and seizure threshold were unaltered. In addition to the central nervous system-related phenotypes, Df(h1q21)/+ mice exhibited reduced head-to tail length, which is reminiscent of the short stature reported in humans with 1q21.1 deletion. With aspects of both construct and face validity, the Df(h1q21)/+ model may be used to gain insight into schizophrenia-relevant alterations in dopaminergic transmission

Diagnostic stability among chronic patients with functional psychoses: an epidemiological and clinical study

<p>Abstract</p> <p>Background</p> <p>Diagnostic stability and illness course of chronic non-organic psychoses are complex phenomena and only few risk factors or predictors are known that can be used reliably. This study investigates the diagnostic stability during the entire course of illness in patients with non-organic psychoses and attempts to identify non-psychopathological risk factors or predictors.</p> <p>Method</p> <p>100 patients with functional psychosis were initially characterised using the Operational Criteria Checklist for Psychotic Illness and Affective Illness (OPCRIT), medical records and health registers. To study the stability of diagnoses (i.e. shifts per time), we used registry data to define four measures of diagnostic variation that were subsequently examined in relation to four possible measures of time (i.e. observation periods or hospitalisation events). Afterwards, we identified putative co-variables and predictors of the best measures of diagnostic stability.</p> <p>Results</p> <p>All four measures of diagnostic variation are very strongly associated with numbers-of-hospitalisations and less so with duration-of-illness, duration-of-hospitalisation and with year-of-first-admission. The four measures of diagnostic variation corrected for numbers-of-hospitalisations were therefore used to study the diagnostic stability. Conventional predictors of illness course – e.g. age-of-onset and premorbid-functioning – are not significantly associated with stability. Only somatic-comorbidity is significantly associated with two measures of stability, while family-history-of-psychiatric-illness and global-assessment-of-functioning (GAF) scale score show a trend. However, the traditional variables age-of-first-admission, civil-status, first-diagnosis-being-schizophrenia and somatic-comorbidity are able to explain two-fifth of the variation in numbers-of-hospitalisations.</p> <p>Conclusion</p> <p>Diagnostic stability is closely linked with the contact between patient and the healthcare system. This could very likely be due to fluctuation of disease manifestation over time or presence of co-morbid psychiatric illness in combination with rigid diagnostic criteria that are unable to capture the multiple psychopathologies of the functional psychoses that results in differential diagnoses and therefore diagnostic instability. Not surprisingly, somatic-comorbidity was found to be a predictor of diagnostic variation thereby being a non-psychiatric confounder.</p

Restless legs syndrome is associated with major comorbidities in a population of Danish blood donors.

BACKGROUND: Restless Legs Syndrome (RLS) is characterized by uncomfortable nocturnal sensations in the legs making sedentary activities and sleep difficult, and is thus linked with psychosocial distress. Due to the symptomatology and neurobiology of RLS (disrupting brain iron and dopamine) it is likely that RLS associates with poorer health-related quality of life (HRQL) and depressive disorder. The objective of this study was to investigate the RLS-HRQL and the RLS-depressive disorder links in a generally healthy population that is not biased by medications. METHODS: Complete data, including the Cambridge-Hopkins RLS questionnaire, the 12-item short-form standardized health survey (SF-12), the Major Depression Inventory (MDI), body mass index, smoking status, alcohol consumption, and education were available for 24,707 participants enrolled in the Danish Blood Donor Study from May 1, 2015 to February 1, 2017. Information on quality of sleep was available for all RLS cases. T-tests and multivariable logistic regression models were applied to examine the associations of RLS and MDI scores, and the physical and mental component scores (PCS and MCS) of SF-12, respectively. Analyses were conducted separately for men and women. RESULTS: RLS associated with poorer MCS and poorer PCS. Moreover, Participants with RLS were more likely to classify with depressive disorder. Poor quality of sleep was associated with depressive disorder and poorer MCS among RLS cases, and with poorer PCS in female RLS cases. CONCLUSION: Thus, we demonstrated that RLS is associated with a significantly lower HRQL and a higher prevalence of depressive disorder among otherwise healthy individuals

Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 micro-deletion syndrome – a study in male mice

Background: The hemizygous 22q11.2 micro-deletion is a common copy number variant in humans. The deletion confers high risk of neurodevelopmental disorders including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms. Methods: We present a new mouse model (Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report on the most comprehensive study undertaken in 22q11.2DS models. The study was conducted in male mice. Results: We found elevated post-pubertal NMDA receptor antagonist induced hyper-locomotion, age-independent prepulse inhibition (PPI) deficits and increased acoustic startle response (ASR). The PPI deficit and increased ASR was resistant to antipsychotic treatment. The PPI deficit was not a consequence of impaired hearing measured by auditory brain stem responses. The Df(h22q11)/+ mice also displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal (DStr) elevations of the dopamine metabolite DOPAC and increased DStr expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice in a wide range of other behavioural and biochemical assays. Limitations: The 22q11.2 micro-deletion has incomplete penetrance in humans and the severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more marked phenotypes reflecting the severe conditions related to 22q11.2DS it is suggested to expose the Df(h22q11)/+ mice to environmental stressors which may unmask latent psychopathology. Conclusion: The Df(h22q11)/+ model will be a valuable tool for increasing our understanding of the aetiology of schizophrenia and other psychiatric disorders associated with the 22q11DS.The research leading to these results was conducted as part of NEWMEDS and received support from the Innovative Medicine Initiative Joint Undertaking under grant agreement n° 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). This work was further supported by grants from the Danish Advanced Technology Foundation (File no. 001-2009-2) and by the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)

Differences in the genetic architecture of common and rare variants in childhood, persistent and late-diagnosed attention-deficit hyperactivity disorder

Analyses of the polygenic architecture of childhood, persistent and late-diagnosed attention-deficit hyperactivity disorder (ADHD) in a Danish population-based case-cohort sample identify differences among ADHD subgroups with respect to common and rare variants. Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with onset in childhood (childhood ADHD); two-thirds of affected individuals continue to have ADHD in adulthood (persistent ADHD), and sometimes ADHD is diagnosed in adulthood (late-diagnosed ADHD). We evaluated genetic differences among childhood (n = 14,878), persistent (n = 1,473) and late-diagnosed (n = 6,961) ADHD cases alongside 38,303 controls, and rare variant differences in 7,650 ADHD cases and 8,649 controls. We identified four genome-wide significant loci for childhood ADHD and one for late-diagnosed ADHD. We found increased polygenic scores for ADHD in persistent ADHD compared with the other two groups. Childhood ADHD had higher genetic overlap with hyperactivity and autism compared with late-diagnosed ADHD and the highest burden of rare protein-truncating variants in evolutionarily constrained genes. Late-diagnosed ADHD had a larger genetic overlap with depression than childhood ADHD and no increased burden in rare protein-truncating variants. Overall, these results suggest a genetic influence on age at first ADHD diagnosis, persistence of ADHD and the different comorbidity patterns among the groups.Peer reviewe