Genetic variants associated with syncope implicate neural and autonomic processes.

AIMS: Syncope is a common and clinically challenging condition. In this study, the genetics of syncope were investigated to seek knowledge about its pathophysiology and prognostic implications. METHODS AND RESULTS: This genome-wide association meta-analysis included 56 071 syncope cases and 890 790 controls from deCODE genetics (Iceland), UK Biobank (United Kingdom), and Copenhagen Hospital Biobank Cardiovascular Study/Danish Blood Donor Study (Denmark), with a follow-up assessment of variants in 22 412 cases and 286 003 controls from Intermountain (Utah, USA) and FinnGen (Finland). The study yielded 18 independent syncope variants, 17 of which were novel. One of the variants, p.Ser140Thr in PTPRN2, affected syncope only when maternally inherited. Another variant associated with a vasovagal reaction during blood donation and five others with heart rate and/or blood pressure regulation, with variable directions of effects. None of the 18 associations could be attributed to cardiovascular or other disorders. Annotation with regard to regulatory elements indicated that the syncope variants were preferentially located in neural-specific regulatory regions. Mendelian randomization analysis supported a causal effect of coronary artery disease on syncope. A polygenic score (PGS) for syncope captured genetic correlation with cardiovascular disorders, diabetes, depression, and shortened lifespan. However, a score based solely on the 18 syncope variants performed similarly to the PGS in detecting syncope risk but did not associate with other disorders. CONCLUSION: The results demonstrate that syncope has a distinct genetic architecture that implicates neural regulatory processes and a complex relationship with heart rate and blood pressure regulation. A shared genetic background with poor cardiovascular health was observed, supporting the importance of a thorough assessment of individuals presenting with syncope.

[Intravenous drug users in Iceland: Use of emergency departments, hospital admissions and mortality].

INTRODUCTION: Drug abuse is a significant contributor to premature disease and mortality. Drug users are less likely to attend traditional Primary Health Care and more likely to present to Emergency Departments with their problems. Drug users often present late for treatment and find difficult ot engage and follow through treatment in standard models of health services. MATERIALS AND METHODS: The study is retrospective. 108 intravenous drug users were identified upon admission to one of three intpatient addiction treatment centres in Iceland in the years 2012-2013. Case notes for the two years leading to admission were examined. RESULTS: The study group had significantyl more contacts with Emergency Departments than a matched sample from the community (p<0.001). Mean number of visits for the study group per year was 4.8 (median 3.5) and 43% had four or more visits in a year. Majority of visits were for pshychiatric symptoms with a third considered serious. The two main medical reasons were infections from injecting and accidents/violence. There was no significant difference in study parameters between those who mainly use methylphenidate vs other substances. Mortality rate for the study group compared to the general population of same age was 26.4 (CI 16.7-41.5, (p<0.01)). CONCLUSION: Intravenous drug users are a vulnerable group with high level of psychiatric and medical problems and high mortality. It is important that this group has good access to evicence based addiction treatment, but also to medical and psychiatric services that are adapted to their needs.

P300 Analysis Using High-Density EEG to Decipher Neural Response to rTMS in Patients With Schizophrenia and Auditory Verbal Hallucinations.

Schizophrenia is a complex disorder about which much is still unknown. Potential treatments, such as transcranial magnetic stimulation (TMS), have not been exploited, in part because of the variability in behavioral response. This can be overcome with the use of response biomarkers. It has been however shown that repetitive transcranial magnetic stimulation (rTMS) can the relieve positive and negative symptoms of schizophrenia, particularly auditory verbal hallucinations (AVH). This exploratory work aims to establish a quantitative methodological tool, based on high-density electroencephalogram (HD-EEG) data analysis, to assess the effect of rTMS on patients with schizophrenia and AVH. Ten schizophrenia patients with drug-resistant AVH were divided into two groups: the treatment group (TG) received 1 Hz rTMS treatment during 10 daily sessions (900 pulses/session) over the left T3-P3 International 10-20 location. The control group (CG) received rTMS treatment over the Cz (vertex) EEG location. We used the P300 oddball auditory paradigm, known for its reduced amplitude in schizophrenia with AVH, and recorded high-density electroencephalography (HD-EEG, 256 channels), twice for each patient: pre-rTMS and 1 week post-rTMS treatment. The use of HD-EEG enabled the analysis of the data in the time domain, but also in the frequency and source-space connectivity domains. The HD-EEG data were linked with the clinical outcome derived from the auditory hallucinations subscale (AHS) of the Psychotic Symptom Rating Scale (PSYRATS), the Quality of Life Scale (QoLS), and the Depression, Anxiety and Stress Scale (DASS). The general results show a variability between subjects, independent of the group they belong to. The time domain showed a higher N1-P3 amplitude post-rTMS, the frequency domain a higher power spectral density (PSD) in the alpha and beta bands, and the connectivity analysis revealed a higher brain network integration (quantified using the participation coefficient) in the beta band. Despite the small number of subjects and the high variability of the results, this work shows a robust data analysis and an interplay between morphology, spectral, and connectivity data. The identification of a trend post-rTMS for each domain in our results is a first step toward the definition of quantitative neurophysiological parameters to assess rTMS treatment.

[Effectiveness of medical treatment in the adult ADHD unit of Landspitali 2015-2017].

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder among children but symptoms may persist into adulthood. At Landspitali - the National University Hospital an interdisciplinary unit is responsible for ADHD-diagnosis and for commencing treatment of adult ADHD. The aim of this study is to evaluate the effectiveness of pharmaceu-tical treatment provided by the unit and the effects of psychiatric comorbidities. METHODS: The study is retrospective and includes all individuals ≥18 years of age who received pharmaceutical treatment in the adult ADHD unit at Landspitali 2015-2017. Individuals who had previously received treatment by the unit or were already on medication for ADHD were excluded. Information on symptoms and wellbeing before and after treatment were obtained from three questionnaires, an ADHD rating scale, DASS and QOLS. RESULTS: Of 211 patients who met inclusion criteria 144 (68%) completed the treatment provided by the unit on average 143 days. Impulsivity/hyperactivity predicted treatment failure with OR=0.96 (p=0.015). There was a statistically significant difference in all key response variables before and after pharmaceutical treatment (p<0.001). The Cohen's d effect size for ADHD variables were 3.18 for attention-deficit and 1.40 for impulsivity/hyperactivity. The effect size for quality of life was 1.00 and among the DASS subscales the maximum effect size was 1.43 for stress. Increased quality of life correlated with decreased symptoms as rated by DASS and the ADHD rating scale. Treatment success rates were significantly -higher for DASS but not for attention-deficit, impulsivity/hyperactivity and quality of life among individuals with psychiatric comorbidities alongside ADHD. Gender did not affect treatment effectiveness. CONCLUSIONS: Those who complete treatment within the ADHD unit achieve good results with decreased psychiatric symptoms and improved quality of life. Treatment discontinuation is a challenge.

Schizophrenia, cognition, and aging: cognitive deficits and the relationship between test performance and aging.

Most measures of cognitive function decline with age during adulthood. Research indicates that people with schizophrenia experience considerable cognitive deficits. These deficits appear to become more troublesome with increasing age, but this has been debated. The aim of this research was to better understand the age related cognitive deficits of Icelandic subjects with schizophrenia in comparison to healthy individuals. Cognition of individuals 18 to 64 years of age was evaluated with 10 neuropsychological tests. People with schizophrenia performed significantly worse on all tests, as expected, indicating widespread cognitive deficits compared to healthy individuals, independent of age. Furthermore, the results suggest that people with schizophrenia follow a similar age-related trajectory of cognitive decline as healthy individuals. Overall, we conclude that the cognitive difficulties often experienced by older people with schizophrenia are better explained by lower cognitive function at the time of diagnosis than by faster cognitive decline with increasing age.

[Loperamide abuse - constipation or heart attack?]

Loperamide is a µ-opioid receptor agonist with antidiarrhoeal effects. It is considered to have a low abuse potential because of substantial first-pass metabolism and P-glycoprotein-mediated efflux at the level of the blood-brain barrier. Previous case reports have described that high dosage of loperamide can induce an opioid-like effect on the central nervous system. The most common presentation of loperamide intoxication is syncope which is caused by serious cardiac dysrhythmia and can lead to death. Therefore, it was decided to analyze whether drug prescriptions in the prescription drug database from The Directorate of Health would indicate loperamide misuse in Iceland from 2006-2017. In total 94 individuals used more than one DDD (10 mg) and 17 individuals used more than two DDD (20 mg), if taken daily over one year. These results indicate that loperamide is being used excessively but the reason for each prescription and the total amount sold over the counter is unknown. Increased surveillance and decreased availability of prescription opioids might possibly boost the usage of drugs with similar function such as loperamide. Loperamide overdose can result in serious adverse effects and thus, it is important to inform healthcare employees about such severe consequences.

Truncating mutations in RBM12 are associated with psychosis.

Thus far, a handful of highly penetrant mutations conferring risk of psychosis have been discovered. Here we used whole-genome sequencing and long-range phasing to investigate an Icelandic kindred containing ten individuals with psychosis (schizophrenia, schizoaffective disorder or psychotic bipolar disorder). We found that all affected individuals carry RBM12 (RNA-binding-motif protein 12) c.2377G>T (P = 2.2 × 10-4), a nonsense mutation that results in the production of a truncated protein lacking a predicted RNA-recognition motif. We replicated the association in a Finnish family in which a second RBM12 truncating mutation (c.2532delT) segregates with psychosis (P = 0.020). c.2377G>T is not fully penetrant for psychosis; however, we found that carriers unaffected by psychosis resemble patients with schizophrenia in their non-psychotic psychiatric disorder and neuropsychological test profile (P = 0.0043) as well as in their life outcomes (including an increased chance of receiving disability benefits, P = 0.011). As RBM12 has not previously been linked to psychosis, this work provides new insight into psychiatric disease.

Risk of diabetes and dyslipidemia during clozapine and other antipsychotic drug treatment of schizophrenia in Iceland.

BACKGROUND: Type 2 diabetes (T2D) and raised blood lipids are associated with the use of antipsychotics, not least clozapine. AIMS: To describe the prevalence of high blood glucose levels, T2D, and dyslipidemia, in association with the use of clozapine or other antipsychotics in patients with schizophrenia in Iceland. METHOD: This study identified 188 patients treated with clozapine and 395 patients never treated with clozapine by searching the electronic health records of Landspitali, the National University Hospital. The comparison group consisted of Icelandic population controls. Data were obtained on blood glucose, HbA1c, and blood lipid levels from these health records. RESULTS: The prevalence of T2D was 14.3% in the clozapine group, where the mean age was 51.2 years, and 13.7% in the never-on-clozapine group, where the mean age was 58.6 years. Males on clozapine were 2.3-times more likely and females 4.4-times more likely to have developed T2D than controls from an age-adjusted Icelandic cohort, while males on other antipsychotics were 1.5-times more likely and females 2.3-times as likely to have T2D than controls. Only one case of ketoacidosis was identified. Triglyceride levels were significantly higher in both treatment groups compared to controls in the age-adjusted Icelandic cohort. CONCLUSIONS: Clinicians must take active steps to reduce the risk of T2D and raised triglycerides in patients with schizophrenia. Antipsychotics were associated with a greater risk of T2D developing in females compared to males.

Neutropenia and agranulocytosis during treatment of schizophrenia with clozapine versus other antipsychotics: an observational study in Iceland.

BACKGROUND: Data on the haematological outcomes of patients who continue clozapine treatment following neutropenia are very rare as even mild neutropenia results in mandatory discontinuation of clozapine in most countries. However, in Iceland where clozapine monitoring is less stringent allows an observational study to be done on the risk of agranulocytosis and neutropenia during treatment with clozapine compared with other antipsychotics among patients with schizophrenia. METHODS: The present study is a part of a wider ongoing longitudinal study of schizophrenia in Iceland. We identified 201 patients with schizophrenia treated with clozapine and 410 patients with schizophrenia who had never been on clozapine by searching the electronic health records of Landspitali, the National University Hospital. Neutrophil counts were searched in electronic databases to identify patients who developed neutropenia/agranulocytosis and the frequency of neutrophil measurements was examined as well. RESULTS: The median number of days between neutrophil measurements during the first 18 weeks of clozapine treatment was 25 days but after the first 18 weeks on the drug the median became 124 days. Thirty four cases of neutropenia were identified during clozapine treatment with an average follow up time of 9.2 years. The majority, 24 individuals developed mild neutropenia (1500-1900 neutrophils/mm3). None of these progressed to agranulocytosis. The remaining 10 patients developed neutropenia in the range 500-1400 /mm3 of whom one developed agranulocytosis, three stopped clozapine use and 6 patients continued on clozapine for at least a year without developing agranulocytosis. Unexpectedly, schizophrenia patients on other antipsychotics had an equal risk of developing neutropenia as those on clozapine. CONCLUSIONS: Neutropenia is common both in patients with schizophrenia on clozapine treatment and in those never on clozapine. Therefore a large part of neutropenia during clozapine treatment is probably not caused by clozapine. These findings have implications in assessing the balance between the risk of progression from neutropenia to agranulocytosis against the morbidity resulting from the premature discontinuation of clozapine under the current monitoring regulations in the US and in most of Europe.

Clozapine treatment and discontinuation in Iceland: A national longitudinal study using electronic patient records.

BACKGROUND: Clozapine is the only drug approved for treatment-resistant schizophrenia. There is evidence that clozapine is underutilized. AIMS: To evaluate the initiation and discontinuation of clozapine at Landspitali University Hospital in Iceland and the prevalence of antipsychotic polypharmacy in clozapine-treated patients. METHODS: The study is a part of an ongoing longitudinal study of schizophrenia in Iceland. We identified 201 patients on clozapine or who have been on clozapine by using a keyword search in the electronic health records and by reviewing their medical records. RESULTS: Mean age at first treatment with clozapine was 37.8 years. Mean follow-up period on clozapine was 11 years. After 20 years of treatment 71.2% of patients were still on clozapine. After one year of treatment 84.4% of patients were still receiving clozapine treatment. We estimate that 11.4% of patients with schizophrenia in Iceland are taking clozapine and that 16% have been treated with clozapine at some point. Polypharmacy is common, since nearly 2/3, 65.6%, of patients taking clozapine use at least one other antipsychotic and 16.9% are also receiving depot injections. CONCLUSIONS: We need to increase the awareness of psychiatrists in Iceland with regard to treatment with clozapine, since only about half of the estimated population of patients with treatment-resistant schizophrenia in Iceland have ever been treated with clozapine. Nearly two thirds of patients who are prescribed clozapine in Iceland remain on it long-term.

[Obsessive-compulsive disorder. A hidden disorder]. / Thráhyggjuárátturöskun--falinn sjúkdómur.

Obsessive-compulsive disorder is a common and often chronic psychiatric illness that significantly interferes with the patient´s functioning and quality of life. The disorder is characterized by excessive intrusive and inappropriate anxiety evoking thoughts as well as time consuming compulsions that cause significant impairment and distress. The symptoms are often accompanied by shame and guilt and the knowledge of the general public and professional community about the disorder is limited. Hence it is frequently misdiagnosed or diagnosed late. There are indications that the disorder is hereditary and that neurobiological processes are involved in its pathophysiology. Several psychological theories about the causes of obsessive-compulsive disorder are supported by empirical evidence. Evidence based treatment is either with serotoninergic medications or cognitive behavioral therapy, particularly a form of behavioral therapy called exposure response prevention. Better treatment options are needed because almost a third of people with obsessive-compulsive disorder respond inadequatly to treatment. In this review article two cases of obsessive-compulsive disorder are presented. The former case is a young man with typical symptoms that respond well to treatment and the latter is a middle aged lady with severe treatment resistant symptoms. She underwent stereotactic implantation of electrodes and received deep brain stimulation, which is an experimental treatment for severe obsessive-compulsive disorder that does not respond to any conventional treatment. Landspitali University Hospital, Division of Psychiatry. Faculty of Medicine, University of Iceland.

CNVs conferring risk of autism or schizophrenia affect cognition in controls.

In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.

Discovery of leukotriene A4 hydrolase inhibitors using metabolomics biased fragment crystallography.

We describe a novel fragment library termed fragments of life (FOL) for structure-based drug discovery. The FOL library includes natural small molecules of life, derivatives thereof, and biaryl protein architecture mimetics. The choice of fragments facilitates the interrogation of protein active sites, allosteric binding sites, and protein-protein interaction surfaces for fragment binding. We screened the FOL library against leukotriene A4 hydrolase (LTA4H) by X-ray crystallography. A diverse set of fragments including derivatives of resveratrol, nicotinamide, and indole were identified as efficient ligands for LTA4H. These fragments were elaborated in a small number of synthetic cycles into potent inhibitors of LTA4H representing multiple novel chemotypes for modulating leukotriene biosynthesis. Analysis of the fragment-bound structures also showed that the fragments comprehensively recapitulated key chemical features and binding modes of several reported LTA4H inhibitors.

Common variants conferring risk of schizophrenia.

Schizophrenia is a complex disorder, caused by both genetic and environmental factors and their interactions. Research on pathogenesis has traditionally focused on neurotransmitter systems in the brain, particularly those involving dopamine. Schizophrenia has been considered a separate disease for over a century, but in the absence of clear biological markers, diagnosis has historically been based on signs and symptoms. A fundamental message emerging from genome-wide association studies of copy number variations (CNVs) associated with the disease is that its genetic basis does not necessarily conform to classical nosological disease boundaries. Certain CNVs confer not only high relative risk of schizophrenia but also of other psychiatric disorders. The structural variations associated with schizophrenia can involve several genes and the phenotypic syndromes, or the 'genomic disorders', have not yet been characterized. Single nucleotide polymorphism (SNP)-based genome-wide association studies with the potential to implicate individual genes in complex diseases may reveal underlying biological pathways. Here we combined SNP data from several large genome-wide scans and followed up the most significant association signals. We found significant association with several markers spanning the major histocompatibility complex (MHC) region on chromosome 6p21.3-22.1, a marker located upstream of the neurogranin gene (NRGN) on 11q24.2 and a marker in intron four of transcription factor 4 (TCF4) on 18q21.2. Our findings implicating the MHC region are consistent with an immune component to schizophrenia risk, whereas the association with NRGN and TCF4 points to perturbation of pathways involved in brain development, memory and cognition.

Large recurrent microdeletions associated with schizophrenia.

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

Synthesis and biological evaluation of novel 2,4-diaminoquinazoline derivatives as SMN2 promoter activators for the potential treatment of spinal muscular atrophy.

Proximal spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by death of motor neurons in the spinal cord that is caused by deletion and/or mutation of the survival motor neuron gene ( SMN1). Adjacent to SMN1 are a variable number of copies of the SMN2 gene. The two genes essentially differ by a single nucleotide, which causes the majority of the RNA transcripts from SMN2 to lack exon 7. Although both SMN1 and SMN2 encode the same Smn protein amino acid sequence, the loss of SMN1 and incorrect splicing of SMN2 have the consequence that Smn protein levels are insufficient for the survival of motor neurons. The therapeutic goal of our medicinal chemistry effort was to identify small-molecule activators of the SMN2 promoter that, by up-regulating gene transcription, would produce greater quantities of full-length Smn protein. Our initial medicinal chemistry effort explored a series of C5 substituted benzyl ether based 2,4-diaminoquinazoline derivatives that were found to be potent activators of the SMN2 promoter; however, inhibition of DHFR was shown to be an off-target activity that was linked to ATP depletion. We used a structure-guided approach to overcome DHFR inhibition while retaining SMN2 promoter activation. A lead compound 11a was identified as having high potency (EC50 = 4 nM) and 2.3-fold induction of the SMN2 promoter. Compound 11a possessed desirable pharmaceutical properties, including excellent brain exposure and long brain half-life following oral dosing to mice. The piperidine compound 11a up-regulated expression of the mouse SMN gene in NSC-34 cells, a mouse motor neuron hybrid cell line. In type 1 SMA patient fibroblasts, compound 11a induced Smn in a dose-dependent manner when analyzed by immunoblotting and increased the number of intranuclear particles called gems. The compound restored gems numbers in type I SMA patient fibroblasts to levels near unaffected genetic carriers of SMA.