Validation of dried blood spot sampling for detecting SARS-CoV-2 antibodies and total immunoglobulins in a large cohort of asymptomatic young adults.

BACKGROUND: Detecting antibody responses following infection with SARS-CoV-2 is necessary for sero-epidemiological studies and assessing the role of specific antibodies in disease, but serum or plasma sampling is not always viable due to logistical challenges. Dried blood spot sampling (DBS) is a cheaper, simpler alternative and samples can be self-collected and returned by post, reducing risk for SARS-CoV-2 exposure from direct patient contact. The value of large-scale DBS sampling for the assessment of serological responses to SARS-CoV-2 has not been assessed in depth and provides a model for examining the logistics of using this approach to other infectious diseases. The ability to measure specific antigens is attractive for remote outbreak situations where testing may be limited or for patients who require sampling after remote consultation. METHODS: We compared the performance of SARS-CoV-2 anti-spike and anti-nucleocapsid antibody detection from DBS samples with matched serum collected by venepuncture in a large population of asymptomatic young adults (N = 1070) living and working in congregate settings (military recruits, N = 625); university students, N = 445). We also compared the effect of self-sampling (ssDBS) with investigator-collected samples (labDBS) on assay performance, and the quantitative measurement of total IgA, IgG and IgM between DBS eluates and serum. RESULTS: Baseline seropositivity for anti-spike IgGAM antibody was significantly higher among university students than military recruits. Strong correlations were observed between matched DBS and serum samples in both university students and recruits for the anti-spike IgGAM assay. Minimal differences were found in results by ssDBS and labDBS and serum by Bland Altman and Cohen kappa analyses. LabDBS achieved 82.0% sensitivity and 98.2% specificity and ssDBS samples 86.1% sensitivity and 96.7% specificity for detecting anti-spike IgGAM antibodies relative to serum samples. For anti-SARS-CoV-2 nucleocapsid IgG there was qualitatively 100% agreement between serum and DBS samples and weak correlation in ratio measurements. Strong correlations were observed between serum and DBS-derived total IgG, IgA, and IgM. CONCLUSIONS: This is the largest validation of DBS against paired serum for SARS-CoV-2 specific antibody measurement and we have shown that DBS retains performance from prior smaller studies. There were no significant differences regarding DBS collection methods, suggesting that self-collected samples are a viable sampling collection method. These data offer confidence that DBS can be employed more widely as an alternative to classical serology.

Clinical implementation of preemptive pharmacogenomics in psychiatry: Τhe "PREPARE" study.

PREemptive Pharmacogenomic testing for Preventing Adverse drug REactions (PREPARE) is the first prospective, pre-emptive pharmacogenomic study conducted in Europe, within the frame of the Horizon 2020 program. It aims to determine whether implementing pre-emptive pharmacogenomics (PGx) testing of clinically relevant biomarkers, so as the dose and drug selection to be guided, will result in an overall reduction of both the occurrence and the severity of drug-genotype-associated adverse drug reactions (ADRs). To achieve that, two groups of patients will be recruited; one that will receive treatment according to standard clinical practice and one other that will receive pharmacogenomic-guided treatment. The Laboratory of Pharmacogenomics and Individualized Treatment of the University of Patras, which coordinates and represents Greece in this study, in collaboration with the Department of Psychiatry of the General University Hospital of Patras, the Department of Psychiatry of the Hospital "Attikon" and the Departments of Psychiatry of the Psychiatric Hospital of Athens "Dafni" is going to recruit 1500 psychiatric patients that are going to receive antidepressant or antipsychotic treatment. Our scientific hypothesis is that patients who receive pharmacogenomic guided drug and dose selection will experience 30% less ADRs than patients following standard care. Eligible drugs for inclusion in the PREPARE study, are those for which the clinical decision regarding drug and dose choice can be guided according to the Dutch Pharmacogenomics Working Group Guidelines (DPWG). Overall, 7 antidepressants (citalopram, escitalopram, sertraline, paroxetine, venlafaxine, clomipramine, amitriptyline) and 3 antipsychotics (haloperidol, zuclopenthixol, aripiprazole) related to 17 genetic variations in 2 genes (CYP2D6, CYP2C19) will be examined. Occurrence, severity and causality of adverse drug events (ADEs) will be assessed during monitoring, at month 1 and 3 after starting the index-drug, and at the end of each arm, by using the Common Toxicity Criteria for Adverse Events Scale (CTCAE) and the Liverpool Causality Assessment Tool (LCAT), respectively. The results of our study are expected to significantly contribute to the improvement of psychiatric patients' quality of life, by helping to provide the right drug, to the right dose in terms of efficacy, safety and cost-effectiveness.

Hypothalamus-pituitary-adrenal (HPA) axis parameters and neurocognitive evaluation in patients with bipolar disorder.

Bipolar disorder is associated with neurocognitive impairment but the etiology of such impairment remains largely unknown. The present study aimed at investigating the performance of bipolar patients in various neuropsychological tasks within the framework of HPA axis hyperactivity model and also the impact of disease characteristics on neuropsychological functioning. Cognitive performance of 60 bipolar-I patients and 30 healthy controls was evaluated by using tasks from the CANTAB battery targeting visual memory, executive function and inhibitory control. Current symptoms were evaluated via administration of the Hamilton Depression Rating Scale (HAMD) and Young Mania Rating Scale (YMRS) whereas assessment of functioning was performed with the Global Assessment of Functioning (GAF). Basal cortisol levels were determined and all patients were administered the Dexamethasone Suppression Test (DST). Statistically significant differences between patients and controls were found in visuo-spatial associative learning and memory, planning, attentional set shifting and inhibitory control. Worse performance in visuospatial associative memory correlated with longer duration of illness and higher levels of basal cortisol. Poorer attentional set shifting was related to higher number of manic episodes. We found no relationship of neurocognitive measures with DST suppression status, current symptom severity or history of psychosis. The results of our study confirm the presence of cognitive deficits in bipolar disorder and provide evidence on the relation of cortisol with neuropsychological functioning, especially visuo-spatial associative memory. Moreover, we have found that number of previous manic episodes and duration of illness is associated with worse cognitive performance. It is known that neurocognitive deficits are evident in many patients with bipolar disorder. These deficits are often a cause of considerable distress and can lead to impairment of psychosocial and occupational functioning. The role of HPA axis needs to be further examined in bipolar disorder. Nevertheless, the identification of factors affecting neurocognitive functioning, like basal cortisol and number of manic episodes, may contribute to the implementation of more appropriate prevention strategies.

Familial aggregation of schizotypy in schizophrenia-spectrum disorders and its relation to clinical and neurodevelopmental characteristics.

INTRODUCTION: This study explored schizotypy as a familial liability marker for schizophrenia-spectrum disorders (SSD) by examining: 1) the aggregation of schizotypy in families with a SSD patient, 2) whether familial resemblance of schizotypy is associated with ridge dissociations (RD), another SSD liability marker, 3) whether schizotypy aggregation patterns influence patients' psychopathology. METHODS: The sample comprised 30 SSD patients and 82 healthy first-degree relatives. Schizotypy was assessed using the Structured Interview for Schizotypy-Revised (SIS-R). Patients' psychopathology was evaluated using the Comprehensive Assessment of Symptoms and History (CASH). RD were identified as anomalies of the dermal ridge junction. Familiality of SIS-R was investigated using a linear mixed model (LMM) and its strength was assessed using an intraclass correlation coefficient (ICC). Another LMM using the absolute differences in SIS-R scores between all possible pairs of relatives as the dependent variable was fitted to obtain an intra-family resemblance score, a family-specific indicator of resemblance of SIS-R scores within each family. RESULTS: 1) Schizotypy was familial (ICC = 0.30); families with high resemblance displayed low schizotypy, whereas families with low resemblance included at least one healthy relative with high schizotypy (p < 0.001). 2) Relatives with RD had higher SIS-R scores (p = 0.018) and belonged to families with discordant schizotypy scores among members (p < 0.001). 3) Patients from high schizotypy families showed more severe disorganized symptoms at the psychotic episode (p = 0.035) and 1 year later (p = 0.011). CONCLUSIONS: Schizotypy is a marker of vulnerability for SSD that runs within a subgroup of families. The schizotypy familial aggregation pattern correlates with RD in relatives and with patients' psychopathology.

Familiality and SNP heritability of age at onset and episodicity in major depressive disorder.

BACKGROUND: Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability). METHOD: For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software. RESULTS: Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity. CONCLUSIONS: AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.

Alexithymia, depression and serum lipids in suicide attempters.

Over the last decade several studies have discussed the association between serum cholesterol, depressive disorders and suicide. A specific psychological variable related to affect is alexithymia. Alexithymia has been linked to depression and suicidal behaviour. Concerning lipid levels there are several studies that suggest changes in serum lipid composition maybe related to depression and suicidal behaviour. In this study we examined the possible relationship between alexithymia, depression and serum lipids in suicide attempters. We studied 50 non-violent suicide attempters (drug overdosers) with a mean age of 35.0 (±12.2) years. Alexithymia was measured using the Shalling-Sifneos Personality Scale Revised (SSPS-R) and depression using the Montgomery-Asberg Depression Rating Scale (MADRS). Serum lipids concentrations were determined by enzymatic method within 24h of hospital admission. For the statistical evaluation Spearman's rank correlation coefficients were used. The mean serum lipid levels were: total serum cholesterol (TC) 175.2 (±29.6) mg/dL, highdensity lipoprotein cholesterol (H-DLC) 47.08 (±13.1) mg/dL, low density lipoprotein cholesterol (L-DLC) 109.5 (±23.5) mg/dL and the mean serum triglycerides (TR) level was 89.4 (±39.1) mg/dL. The mean scores on the questionnaires were: SSPS-R 10.3 (±3.7), MADRS 33.5 (±5.9). There were significant correlations between: (a) SSPS-R score and MADRS score (r=0.439, p<0.001), (b) SSPS-R score and TR level (r=0.323, p<0.05). There were no significant correlations between MADRS score and any of the lipid fractions measured. To our knowledge, only few studies have examined the association between alexithymia and clinical-psychopathological parameters in suicide attempters. There are no previous studies comparing serum lipid profile with alexithymia in suicide attempters. This is the first study to compare at the same time serum lipids, alexithymia and depression in suicide attempters. The results suggest that although there was a strong relationship between alexithymia and depression in suicide attempters only alexithymia was correlated to Serum triglyceride levels.

Glandular cystitis and lithium intoxication in a patient with bipolar disorder.

A 42-year-old woman, with a 12-year history of bipolar disorder was referred to our department due to tremor, sedation, dysarthria, polyuria and polydipsia. She had been on lithium monotherapy during the last 3 years. On admission, her cognitive status was intact, and neither depression nor euphoria was reported. Lithium plasma levels were 1.6 mEq/L, whereas creatinine and urea levels were 2.8 IU/L and 110 IU/L, respectively. The patient did not take other medications or misused lithium. Lithium was immediately discontinued. Ultrasound scans of the urinary tract were suggestive of bilateral hydronephrosis secondary to bladder contraction and cystoscopy-guided bladder biopsy revealed glandular cystitis a benign tumour into the bladder's wall, which impeded the bladder's contraction leading to hydronephrosis and subsequent toxic lithium plasma levels. The patient was switched to valproate and was referred for surgical excision of the lesion. One year later, she was in good physical and mental health under treatment with valproate (1000 mg/day). This is the first case report of glandular cystitis leading to lithium intoxication by impairing renal function. Acute renal failure leading to lithium intoxication would be possible. However, a thorough imaging, endoscopical and histological study revealed glandular cystitis as the cause of renal impairment. Although physicians are alert about lithium's toxicity and a monitoring of renal function is routinely prescribed, little focus has been made on the integrity of the urinary tract. We suggest that urinary tract imaging should be part of the routine work-up in patients presenting with symptoms and signs of lithium intoxication, since concomitant urinary tract lesions might occasionally be the cause of renal impairment leading to reduced lithium excretion.

Fatigue in female patients with major depression: the effect of comorbid anxiety disorders.

Several studies have investigated fatigue in the general population, in primary care facilities as well as in patients with fatigue-related physical diseases, but only marginally in patients with Major Depressive Disorder (MDD). Therefore, the investigation of correlates of depression-related fatigue is highly warranted and expected to facilitate the implementation of effective fatigue-specific treatment strategies. Depressed patients often suffer from comorbid anxiety disorders (CADs) or subthreshold anxiety symptoms. This study aimed to investigate the independent correlation of the severity of fatigue in female patients with MDD with the presence, number and type of CADs. We studied 70 consecutive female MDD patients (48.6% inpatients), aged 23-65 years (mean 48.2±10.6 years), currently in a Major Depressive Episode [17-item Hamilton Depression Rating Scale (HDRS) score≥17] and free of other fatigue-associated conditions. Diagnostic assessments were made with the short structured DSM-IV-based MINI version 5.0.0. Reported fatigue was assessed with the 14-item Chalder Fatigue Questionnaire (FQ). Correlations between the FQ score and age, inpatient status, HDRS score, presence and number of CADs were calculated. Then, stepwise multiple regression analyses were performed, with the FQ score as the dependent variable,so as to isolate independent predictors of the severity of fatigue. 92.9% of patients had clinically significant fatigue. 62.9% were suffering from at least one CAD (38.6% met criteria for one CAD,21.4% for two and 2.9% for three). 51.4% were diagnosed with generalized anxiety disorder (GAD),25.7% with panic disorder and/or agoraphobia (PD/AP), 17.1% with social anxiety disorder and 7.1%with obsessive-compulsive disorder. The FQ score was significantly correlated with the HDRS score(r=0.406, p<0.001), the presence of any CAD(s) (rho=0.4, p=0.001), the number of CADs (rho=0.393,p=0.001), the presence of GAD (rho=0.421, p<0.001) and the presence of PD/AP (rho=0.252, p=0.035).In multiple regression analyses, the presence and number of CADs and the presence of comorbid GAD turned out as significant independent predictors of the FQ score along with the HDRS score.The severity of fatigue in female MDD patients is independently correlated with the presence and number of CADs and, in specific, comorbid GAD. Our findings imply that: (1) this effect might in part account for greater impairment/disability and adverse prognosis for MDD with CADs; (2) high levels of fatigue, putatively clustering with anxiety symptoms, may be a marker of severity and anxiety disorders comorbidity for MDD and may define an "anxious-fatigued" subtype/phenotype in this population; (3) medications and psychotherapies for the management of severe depression-related fatigue should also target CADs.

Attitudes on euthanasia and physician-assisted suicide among medical students in Athens.

Attitudes towards assisted death activities among medical students, the future health gatekeepers, are scarce and controversial. The aims of this study were to explore attitudes on euthanasia and physician-assisted suicide among final year medical students in Athens, to investigate potential differences in attitudes between male and female medical students and to review worldwide attitudes of medical students regarding assisted death activities. A 20- item questionnaire was used. The total number of participants was 251 (mean age 24.7±1.8 years). 52.0% and 69.7% of the respondents were for the acceptance of euthanasia and physician-assisted suicide, respectively. Women's attitudes were more often influenced by religious convictions as well as by the fact that there is a risk that physician-assisted suicide might be misused with certain disadvantaged groups. On the other hand, men more often believed that a request for physician-assisted suicide from a terminally ill patient is prima-facie evidence of a mental disorder, usually depression. Concerning attitudes towards euthanasia among medical students in various countries there are contradictory results. In USA, the Netherlands, Hungary and Switzerland most of the students supported euthanasia and physician-assisted suicide. However, in many other countries such as Norway, Sweden, Yugoslavia, Italy, Germany, Sudan, Malaysia and Puerto Rico most students expressed negative positions regarding euthanasia and physician assisted suicide.

Fatigue and somatic anxiety in patients with major depression.

The objective this study aimed to investigate the independent contribution of somatic anxiety to the severity of depression-related fatigue. Seventy-six patients (85.5% female), aged 23-65 years (mean 48.7±10.6), diagnosed with major depressive disorder and currently in a major depressive episode (ΜΙΝΙ 5.0.0.) with a 17-item Hamilton Depression Rating Scale (HDRS) score ≥17, were studied. Forty-nine patients (64.5%) were concurrently suf fering from anxiety disorder(s). Patients with physical diseases or other fatigue-related conditions were excluded. Reported fatigue was measured with the 14-item Fatigue Questionnaire (FQ). Based on HDRS item 11 (somatic anxiety) scores, patients were divided into those with somatic anxiety (HDRS-11≥2) and those without (HDRS-11≤1). Pearson's (r) and Spearman's (rho) correlations between FQ score, age, gender, inpatient status, HDRS score and somatic anxiety status were calculated. A multiple regression analysis was then performed, with FQ as the dependent variable. Fifty-seven patients (75%) were rated as suffering from somatic anxiety (HDRS-11≥2). Patients with somatic anxiety had significantly higher HDRS and FQ scores. The FQ score significantly correlated with the HDRS score (r=0.36, p=0.001) and somatic anxiety status (rho=0.35, p=0.002). The FQ score was independently predicted by HDRS score and somatic anxiety status, with standardised beta coefficients of 0.259 (p=0.028) and 0.255 (p=0.031), respectively. R2 was 0.185. Both the severity of depression and the presence of somatic anxiety independently correlate with the severity of reported fatigue in patients with major depression. This finding has potential implications for the management of depression-related fatigue.

Switching to amisulpride monotherapy for treatment-resistant schizophrenia.

The objective of this study was to assess switching to amisulpride (AMS) in treatment-resistant schizophrenia. Seven male subjects were switched to AMS and followed for 8 weeks. PANSS scores improved from 123 to 66 over this period. We conclude that AMS is of interest in the treatment of refractory schizophrenia.