A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study.

BACKGROUND: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. METHODS: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants. FINDINGS: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54-0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61-0·79]; p <0·0001). INTERPRETATION: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe. FUNDING: European Union Horizon 2020.

Integrating Clinical Neuropsychology and Psychotic Spectrum Disorders: A Systematic Analysis of Cognitive Dynamics, Interventions, and Underlying Mechanisms.

Background and Objectives: The study aims to provide a comprehensive neuropsychological analysis of psychotic spectrum disorders, including schizophrenia, bipolar disorder, and depression. It focuses on the critical aspects of cognitive impairments, diagnostic tools, intervention efficacy, and the roles of genetic and environmental factors in these disorders. The paper emphasizes the diagnostic significance of neuropsychological tests in identifying cognitive deficiencies and their predictive value in the early management of psychosis. Materials and Methods: The study involved a systematic literature review following the PRISMA guidelines. The search was conducted in significant databases like Scopus, PsycINFO, PubMed, and Web of Science using keywords relevant to clinical neuropsychology and psychotic spectrum disorders. The inclusion criteria required articles to be in English, published between 2018 and 2023, and pertinent to clinical neuropsychology's application in these disorders. A total of 153 articles were identified, with 44 ultimately included for detailed analysis based on relevance and publication status after screening. Results: The review highlights several key findings, including the diagnostic and prognostic significance of mismatch negativity, neuroprogressive trajectories, cortical thinning in familial high-risk individuals, and distinct illness trajectories within psychosis subgroups. The studies evaluated underline the role of neuropsychological tests in diagnosing psychiatric disorders and emphasize early detection and the effectiveness of intervention strategies based on cognitive and neurobiological markers. Conclusions: The systematic review underscores the importance of investigating the neuropsychological components of psychotic spectrum disorders. It identifies significant cognitive impairments in attention, memory, and executive function, correlating with structural and functional brain abnormalities. The paper stresses the need for precise diagnoses and personalized treatment modalities, highlighting the complex interplay between genetic, environmental, and psychosocial factors. It calls for a deeper understanding of these neuropsychological processes to enhance diagnostic accuracy and therapeutic outcomes.

Cognitive Rehabilitation for Patients with Schizophrenia: A Narrative Review of Moderating Factors, Strategies, and Outcomes.

OBJECTIVE: Antipsychotic drugs constitute the basis of schizophrenia therapy; however, available pharmaceutical agents lack efficacy for treating the cognitive deficits caused by the illness. The aim of the present work is to present current data regarding cognitive rehabilitation of schizophrenia, providing information and guidance to health professionals. METHOD: A literature search was conducted in the PubMed and Google Scholar Databases from inception up to 1/9/2022. Relevant articles were explored for factors affecting cognitive function, including genetics, psychopathology, time in the course of the illness, and drug therapy. Characteristics and outcome of cognitive rehabilitation programs are briefly presented. RESULTS: A total of 562 relevant articles were retrieved, 39 of which were selected for the review. Factors contributing to a favorable outcome are young age, early phase of disease, symptomatic control of hostility and conceptual disorganization, lack of negative symptoms, management of drug side effects, and cognitive and cortical reserve. Some evidence for a procognitive effect seems to exist for atypical antipsychotics, clozapine, aripiprazole, memantine, modafinil, d-serine, and cycloserine. The Val/Val polymorphism of the COMT gene seems to be associated with worse outcome. Specific remediation strategies include programs such as Cognitive Enhancement Therapy (CET), Cognitive Adaptation Training (CAT), and RehaCom Cognitive Therapy Software, among others, all employing a range of techniques, from paper-and-pencil to computer-assisted, bottom-up, or top-down approaches, and varying neurocognitive targets. CONCLUSION: Cognitive symptoms, closely related to functional impairment, still remain a therapeutic challenge. Cognitive rehabilitation strategies are as yet the only treatment modality offering cognitive improvement to patients who struggle to recover.

Economic evaluation in psychiatric pharmacogenomics: a systematic review.

Nowadays, many relevant drug-gene associations have been discovered, but pharmacogenomics (PGx)-guided treatment needs to be cost-effective as well as clinically beneficial to be incorporated into standard health care. To address current challenges, this systematic review provides an update regarding previously published studies, which assessed the cost-effectiveness of PGx testing for the prescription of antidepressants and antipsychotics. From a total of 1159 studies initially identified by literature database querying, and after manual assessment and curation of all of them, a mere 18 studies met our inclusion criteria. Of the 18 studies evaluations, 16 studies (88.89%) drew conclusions in favor of PGx testing, of which 9 (50%) genome-guided interventions were cost-effective and 7 (38.9%) were less costly compared to standard treatment based on cost analysis. More precisely, supportive evidence exists for CYP2D6 and CYP2C19 drug-gene associations and for combinatorial PGx panels, but evidence is limited for many other drug-gene combinations. Amongst the limitations of the field are the unclear explanation of perspective and cost inputs, as well as the underreporting of study design elements, which can influence though the economic evaluation. Overall, the findings of this article demonstrate that although there is growing evidence on the cost-effectiveness of genome-guided interventions in psychiatric diseases, there is still a need for performing additional research on economic evaluations of PGx implementation with an emphasis on psychiatric disorders.

Discrepancies and similarities in the genome-informed guidance for psychiatric disorders amongst different regulatory bodies and research consortia using next generation sequencing-based clinical pharmacogenomics data.

Undoubtedly, pharmacogenomics (PGx) aims in optimizing drug treatment responses whilst also improving the patients' quality of life, either via a reduction of adverse drug reactions and/or an enhancement of drug treatment efficacy. To achieve this, PGx guidance is provided by the two major regulatory bodies in a worldwide level, specifically the U.S. Food and Drug Administration (FDA) and the European Medicine Agency (EMA), and occasionally some research consortia, such as the Clinical Pharmacogenetics Implementation Consortium (CPIC) or the Dutch Pharmacogenomics Working Group (DPWG). However, so far, there is a limited number of studies focusing on the delineation of the similarities and more importantly, the discrepancies in the PGx guidance by the different regulatory bodies and consortia. Herein, we use real-life clinical PGx data to highlight such discrepancies and similarities for genome-guided interventions in psychiatric disorders, thus demonstrating the need for harmonization of the guidelines and recommendations. More precisely, we used the PharmCAT genome-informed drug treatment reports from 304 Greek individuals with psychiatric disorders in order to emphasize on the discrepancies in the PGx guidance/guidelines between FDA vs EMA and CPIC vs DPWG, respectively. For example, CYP2D6-pimozide pair is characterized as 'Testing Required' according to FDA and is accompanied by a DPWG PGx guideline, whilst no EMA or CPIC PGx guidance is found for this drug-gene pair. Moreover, discrepancies are observed regarding the type of PGx guidance for CYP2C19-doxepin pair, with 89 individuals from our study cohort requiring a dose prescribing change based on FDA, whilst only 5 individuals have to receive genome-guided treatment adjustment according to CPIC. To our knowledge, this is the first study, in which discrepancies regarding the type of PGx guidance and the number of actionable drug-gene pairs amongst FDA and EMA, as well as CPIC and DPWG, are brought to light with an emphasis on psychiatric disorders.

Reliability, validity and psychometric properties of the Greek version of the Altman self rating mania scale.

BACKGROUND: Although self-rating mania scales have been developed, a lack of such instruments validated for the Greek population is noted. This study aims to examine the validity, reliability and psychometric properties of the Altman Self Rating Mania Scale (ASRM) adapted in Greek (G-ASRM). METHODS: A sample of 86 consecutive inpatient and outpatient bipolar patients diagnosed by the DSM-5 criteria and 37 healthy controls were assessed by using the Young Mania Rating Scale (YMRS) and the Montgomery Asberg Depression Rating Scale (MADRS), and self-administered the G-ASRM. Factor analysis, test-retest analysis, measurement invariance tests, mean differences, Pearson's Correlation analysis and ROC analysis were used to confirm the validity of G-ASRM as a scale, test its reliability, study its psychometric properties in different subgroups and establish a cut-off value for indicating the presence of (hypo)mania in BD patients. Also, regression models were built to expose dependencies between YMRS and G-ASRM items. RESULTS: Monofactoriality of the scale was verified, based on Exploratory Factor Analysis (EFA). Cronbach's alpha was 0.895. G-ASRM is highly correlated with YMRS (r = 0.856, p < 0.0005) and uncorrelated with MADRS (r = -0.051, p = 0.623). Test- retest r-coefficient was calculated at 0.85. The optimal cut-off score, set at ≥6 for (hypo)mania assessment, is in agreement with the results reported for the original version. Limitations of the study are that the scale was not normed on diagnostic groups other than bipolar, nor was it administered longitudinally, so as to assess its sensitivity to symptom changes overtime. CONCLUSION: The G-ASRM can be validly and reliably used in the Greek population for the assessment of (hypo)mania in bipolar patients.

Leukocyte telomere length is reduced in patients with major depressive disorder.

Major depressive disorder (MDD) is a chronic, severe psychiatric illness with an incidence of 3% worldwide. MDD patients have a significantly impaired quality of life and reduced life expectancy compared to unaffected individuals, the latter being largely accounted for by an increased incidence of suicide and cardiovascular disorders. The premature mortality observed in MDD has been considered a signature of accelerated aging, a hypothesis supported by data showing altered functioning and morphology of several brain regions that are typically present in the aging population. Telomere shortening is a hallmark of cellular aging, and as such several studies explored the involvement of disrupted telomere dynamics in MDD, reporting contrasting findings. In the current study, we measured leukocyte telomere length (LTL) in a sample of 54 MDD patients and 47 non-psychiatric controls characterized for response to antidepressant treatment. After correcting for age, sex, and body mass index, we showed significantly reduced LTL in affected individuals compared to controls (beta = -.22, p = .02). There was no difference in LTL between treatment resistant or responsive MDD patients. Moreover, we observed no correlation between lifetime exposure to antidepressants and LTL. Our study showed that MDD patients have shorter telomeres compared to controls, supporting the hypothesis of accelerated aging in this disorder. However, LTL seemed not to be influenced by antidepressant treatment or to correlate with clinical response to these antidepressants. Further investigations in larger samples and possibly with longitudinal design are warranted to elucidate the role of altered telomere dynamics in MDD.

Clinical implementation of preemptive pharmacogenomics in psychiatry.

BACKGROUND: Pharmacogenomics (PGx) holds promise to revolutionize modern healthcare. Although there are several prospective clinical studies in oncology and cardiology, demonstrating a beneficial effect of PGx-guided treatment in reducing adverse drug reactions, there are very few such studies in psychiatry, none of which spans across all main psychiatric indications, namely schizophrenia, major depressive disorder and bipolar disorder. In this study we aim to investigate the clinical effectiveness of PGx-guided treatment (occurrence of adverse drug reactions, hospitalisations and re-admissions, polypharmacy) and perform a cost analysis of the intervention. METHODS: We report our findings from a multicenter, large-scale, prospective study of pre-emptive genome-guided treatment named as PREemptive Pharmacogenomic testing for preventing Adverse drug REactions (PREPARE) in a large cohort of psychiatric patients (n = 1076) suffering from schizophrenia, major depressive disorder and bipolar disorder. FINDINGS: We show that patients with an actionable phenotype belonging to the PGx-guided arm (n = 25) present with 34.1% less adverse drug reactions compared to patients belonging to the control arm (n = 36), 41.2% less hospitalisations (n = 110 in the PGx-guided arm versus n = 187 in the control arm) and 40.5% less re-admissions (n = 19 in the PGx-guided arm versus n = 32 in the control arm), less duration of initial hospitalisations (n = 3305 total days of hospitalisation in the PGx-guided arm from 110 patients, versus n = 6517 in the control arm from 187 patients) and duration of hospitalisation upon readmission (n = 579 total days of hospitalisation upon readmission in the PGx-guided arm, derived from 19 patients, versus n = 928 in the control arm, from 32 patients respectively). It was also shown that in the vast majority of the cases, there was less drug dose administrated per drug in the PGx-guided arm compared to the control arm and less polypharmacy (n = 124 patients prescribed with at least 4 psychiatric drugs in the PGx-guided arm versus n = 143 in the control arm) and smaller average number of co-administered psychiatric drugs (2.19 in the PGx-guided arm versus 2.48 in the control arm. Furthermore, less deaths were reported in the PGx-guided arm (n = 1) compared with the control arm (n = 9). Most importantly, we observed a 48.5% reduction of treatment costs in the PGx-guided arm with a reciprocal slight increase of the quality of life of patients suffering from major depressive disorder (0.935 versus 0.925 QALYs in the PGx-guided and control arm, respectively). INTERPRETATION: While only a small proportion (∼25%) of the entire study sample had an actionable genotype, PGx-guided treatment can have a beneficial effect in psychiatric patients with a reciprocal reduction of treatment costs. Although some of these findings did not remain significant when all patients were considered, our data indicate that genome-guided psychiatric treatment may be successfully integrated in mainstream healthcare. FUNDING: European Union Horizon 2020.

Perfusion abnormalities in mild cognitive impairment and mild dementia in Alzheimer's disease measured by pulsed arterial spin labeling MRI.

Alzheimer's disease (AD) and mild cognitive impairment (MCI), the transitional clinical stage between cognition in normal aging and dementia, have been linked to abnormalities in brain perfusion. Pulsed arterial spin labeling (PASL) is a magnetic resonance imaging (MRI) technique for evaluating brain perfusion. The present study aimed to determine regional perfusion abnormalities in 19 patients with mild dementia in AD and 24 patients with MCI as compared to 24 cognitively healthy elderly controls using PASL. In line with nuclear imaging methods, lower perfusion in patients with MCI and AD was found mainly in the parietal lobe, but also in angular and middle temporal areas as well as in the left middle occipital lobe and precuneus. Our data imply that PASL may be a valuable instrument for investigating perfusion changes in the transition from normal aging to dementia and indicate that it might become an alternative to nuclear imaging techniques in AD diagnostics.

Comment on Keeler et al. Ketamine as a Treatment for Anorexia Nervosa: A Narrative Review. Nutrients 2021, 13, 4158.

Anorexia Nervosa (AN) represents a difficult therapeutic challenge, with up to 4% prevalence among females and increasing incidence among youth [...].

Adverse Drug Reactions in Relation to Clozapine Plasma Levels: A Systematic Review.

Clozapine is the gold standard for treatment-resistant schizophrenia. Serious and even life-threatening adverse effects, mostly granulocytopenia, myocarditis, and constipation, are of great clinical concern and constitute a barrier to prescribing clozapine, thus depriving many eligible patients of a lifesaving treatment option. Interestingly, clozapine presents variable pharmacokinetics affected by numerous parameters, leading to significant inter- and intra-individual variation. Therefore, therapeutic drug monitoring of plasma clozapine levels confers a significant benefit in everyday clinical practice by increasing the confidence of the prescribing doctor to the drug and the adherence of the patient to the treatment, mainly by ensuring effective treatment and limited dose-related side effects. In the present systematic review, we aimed at identifying how a full range of adverse effects relates to plasma clozapine levels, using the Jadad grading system for assessing the quality of the available clinical evidence. Our findings indicate that EEG slowing, obsessive-compulsive symptoms, heart rate variability, hyperinsulinemia, metabolic syndrome, and constipation correlate to plasma clozapine levels, whereas QTc, myocarditis, sudden death, leucopenia, neutropenia, sialorrhea, are rather unrelated. Rapid dose escalation at the initiation of treatment might contribute to the emergence of myocarditis, or leucopenia. Strategies for managing adverse effects are different in these conditions and are discussed accordingly.

Suicidality in the "prodromal" phase of schizophrenia.

OBJECTIVES: Patients with schizophrenia are at high risk for suicide ideation, attempts, and completed suicide. However, suicidal behavior during the prodromal phase of schizophrenia and a possible association between prodromal suicidal behavior and suicidality after the onset of overt psychosis are not studied. METHODS: One hundred six consecutively admitted schizophrenia patients with recent onset were evaluated retrospectively for prodromal symptoms and suicidality during the prodromal phase and after the onset of frank psychosis. In addition, 106 matched control subjects from the general population were evaluated for suicidality during the same age period of the prodromal phase of the corresponding patient. RESULTS: Suicide ideation and attempt during the prodromal period were reported in 25.5% and 7.5% of the patients, which are 3.8- and 8-fold greater than in the controls, respectively. Patients with suicidal behavior experienced a greater number of prodromal symptoms than those without. Prodromal depressive mood, marked impairment in role functioning, and tobacco smoking exerted an independent effect on suicide ideation, whereas depressive mood was the symptom significantly more frequent in patients with suicide attempt. Suicide attempts were associated with an earlier onset of prodromal symptoms and frank psychosis. All patients with prodromal suicide attempts were cigarette smokers. Suicide ideation during the prodromal phase was strongly associated with lifetime suicidality after the onset of frank psychosis. CONCLUSIONS: Suicidal behavior is quite common during the prodromal period. The association of smoking, depressive mood, impaired functioning, and a large number of prodromal symptoms, particularly in patients with an early onset of symptomatology, carries a substantially increased risk for suicide ideation. Particular care is needed in patients with prodromal suicide ideation after the onset of frank psychosis because the risk to attempt suicide is high.

Nicotine consumption during the prodromal phase of schizophrenia - a review of the literature.

Recent research has fueled a debate concerning the role of nicotine in the emergence of schizophrenia. The three main hypotheses are: (a) the self-medication effect, (b) the causal relationship hypothesis, or (c) the shared diathesis hypothesis. To explore this role, the study of nicotine consumption during the initial prodromal phase of schizophrenia offers important opportunities. In the present work, 10 relevant studies are reviewed, out of 727 retrieved citations, in order to address questions regarding the prevalence of smoking in the prodromal period, the time of smoking initiation, existing patterns of tobacco use in relation with the escalation of prodromal symptoms into first psychotic episode, and potential differences in symptomatology between smokers and nonsmokers. Even though there was considerable heterogeneity among studies, relevant findings are discussed. Prevalence of nicotine use during the prodromal period was reported to be 16.6-46%. Tobacco use was found to be taken up most often before or during the prodromal period of schizophrenia. Even though a protective role of smoking has been reported by one study, other studies report an increased risk for psychosis, with hazard ratios 2.77 (95% CI: 2.34-3.43) and 2.21 (95% CI: 1.11-4.42) for female and male heavy smokers (11-20 and >20 cigarettes/day), respectively. In a different study, the risk of onset was associated with the progressive use of cannabis and tobacco prior to onset, particularly with rapid escalation to the highest levels of use. Also, nicotine use in ultra high risk (UHR) for developing psychosis subjects is associated with elevated cognitive performance, namely better processing speed, visual learning, and spatial working memory. As a conclusion, it appears that evidence accumulates supporting a possible etiologic role of smoking, in the emergence of schizophrenia along with diverse effects on patients' symptomatology, already demonstrable at the prodromal phase. Future research employing better-defined criteria should further explore the patterns of use and effects of nicotine during the schizophrenia prodrome.

Physiological Basis of the Couvade Syndrome and Peripartum Onset of Bipolar Disorder in a Man: A Case Report and a Brief Review of the Literature.

Rapid hormonal changes during pregnancy as well as psycho-social stressors accompanying parenthood have often been associated with peripartum mood episodes in women with bipolar disorder or with not yet clinically expressed bipolar diathesis. Yet, little is known about the correlation of peripartum onset of bipolar disorder in men. We present the case of a man with bipolar disorder with peripartum onset and subsequent episodes following the peripartum initiation of the disease, as well as the association of the couvade syndrome, as a pathological response to a man due to hormonal shifts observed in males cohabiting with a pregnant female. The patient had his first depressive episode during the peripartum period of his spouse, followed by two mixed episodes with psychotic features that leaded to his compulsory psychiatric evaluation and subsequent hospitalization and the diagnosis of Bipolar Disorder I. There is a well-known correlation between the peripartum period and mood disturbances to the point of inducing full blown episodes, suggesting of a bipolar disorder initiation or mood episodes relapsing in female patients already diagnosed with bipolar disorder. Due to the patient's psychological disturbances and the phenomenology of his symptoms, mainly concerning the psychotic features accompanying his episodes, we discuss the possible underlying biological correlates as a triggering mechanism, that might overlap the manifestation of the Couvade Syndrome as well as the initiation or relapse of Bipolar Disorder in males. It seems that males are not less influenced by hormonal and psycho-social factors posed upon them during the peripartum period of their cohabiting female spouse.

Complex posttraumatic stress disorder: The need to consolidate a distinct clinical syndrome or to reevaluate features of psychiatric disorders following interpersonal trauma?

Complex posttraumatic stress disorder (Complex PTSD) has been recently proposed as a distinct clinical entity in the WHO International Classification of Diseases, 11th version, due to be published, two decades after its first initiation. It is described as an enhanced version of the current definition of PTSD, with clinical features of PTSD plus three additional clusters of symptoms namely emotional dysregulation, negative self-cognitions and interpersonal hardship, thus resembling the clinical features commonly encountered in borderline personality disorder (BPD). Complex PTSD is related to complex trauma which is defined by its threatening and entrapping context, generally interpersonal in nature. In this manuscript, we review the current findings related to traumatic events predisposing the above-mentioned disorders as well as the biological correlates surrounding them, along with their clinical features. Furthermore, we suggest that besides the present distinct clinical diagnoses (PTSD; Complex PTSD; BPD), there is a cluster of these comorbid disorders, that follow a continuum of trauma and biological severity on a spectrum of common or similar clinical features and should be treated as such. More studies are needed to confirm or reject this hypothesis, particularly in clinical terms and how they correlate to clinical entities' biological background, endorsing a shift from the phenomenologically only classification of psychiatric disorders towards a more biologically validated classification.

Genetic Variations Associated with Sleep Disorders in Patients with Schizophrenia: A Systematic Review.

Background: Schizophrenic patients commonly suffer from sleep disorders which are associated with acute disease severity, worsening prognoses and a poorer quality of life. Research is attempting to disentangle the complex interplay between schizophrenia and sleep disturbances by focusing not only on demographic and clinical characteristics, but also on the identification of genetic factors. Methods: Here, we performed a systematic literature review on the topic of genetic variations in sleep-disordered schizophrenic patients in an attempt to identify high quality investigations reporting scientifically sound and clinically useful data. For this purpose, we conducted a thorough search of PubMed, ScienceDirect and GoogleScholar databases, according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol. Results: Our search yielded 11 eligible studies. Certain genetic variations were reported to be associated with schizophrenia-related sleep disorders. Antipsychotic-induced restless legs syndrome was linked to polymorphisms located on CLOCK, BTBD9, GNB3, and TH genes, clozapine-induced somnolence was correlated with polymorphisms of HNMT gene, while insomnia was associated with variants of the MTNR1 gene. Conclusions: There are significant genetic associations between schizophrenia and co-morbid sleep disorders, implicating the circadian system, dopamine and histamine metabolism and signal transduction pathways.

Treatment of Tardive Dystonia Induced by Antipsychotics, Old and New.

OBJECTIVES: Tardive dystonia is a serious extrapyramidal side effect emerging after long-term treatment with antipsychotics, frequently with a deteriorating course, and unsatisfactory treatment. Presently, clozapine is used for the cotreatment of tardive dystonia and psychosis, at the cost of serious side effects. Apart from clozapine, there have been case reports describing positive effects of quetiapine on dystonic symptoms. Aim of the present study was to demonstrate the ameliorating effects of quetiapine on dystonic symptoms, in a sample of patients suffering from antipsychotic-induced tardive dystonia. METHODS: Quetiapine was administered to 16 consecutively enrolled stabilized patients with psychotic or mood disorders and tardive dystonia, replacing the "offending drugs," over a 3-month cross-tapering period. Target dose of quetiapine was set according to the defined daily dose of the received antipsychotic(s) at baseline, as reviewed by the World Health Organization Center of Drug Statistics Methodology, aiming at both maintenance of psychosis control and reduction of dystonic symptoms. RESULTS: Patients were found to have significant positive results in amelioration of dystonia (P < 0.001) over a 1-year period, without loss of antipsychotic efficacy. Reduction of dystonic symptoms with the use of quetiapine could be considered comparable with the positive effects of clozapine, with the additional advantage of relatively lacking serious side effects. CONCLUSIONS: Quetiapine may represent a valuable therapeutic choice for the treatment of tardive dystonia.

Demographic features and premorbid personality disorder traits in relation to age of onset and sex in paranoid schizophrenia.

Personality disorders in the premorbid period of schizophrenia and particularly in relation to age of onset and sex, seem to be a rather under-researched area. In the present study, 88 patients with paranoid schizophrenia were examined, regarding demographic characteristics and premorbid personality disorder traits, in order to investigate for differences in the premorbid period of the disease, in relation to age of onset and sex. Age cutoff points were set at <30 years and ≥35 years of age for young and late onset groups, respectively. The Structured Clinical Interview for DSM-IV-Patient Edition for Axis I disorders (SCID-P) was used prospectively for diagnoses. Premorbid personality disorder traits were retrospectively assessed by using the Structured Clinical Interview for DSM-IV-Patient Edition for Axis II disorders (SCID-II). Comparisons were performed by applying the two-tailed Wilcoxon rank-sum and the χ(2) statistical tests. Young onset patients were characterized by significantly higher proportion of urban birth, single status, more avoidant premorbid personality disorder traits, and less passive-aggressive premorbid personality disorder traits, than late onset counterparts. Differences were more prominently shown in men. Earlier age of onset seems to be associated to increased social inhibition and worse psychosocial adaptation in the premorbid period of paranoid schizophrenia.

Pulmonary embolism related to amisulpride treatment: a case report.

Venous thromboembolism has been associated with antipsychotic drugs, but the underlying mechanisms are largely unknown. Hypotheses that have been made include body weight gain, sedation, enhanced platelet aggregation, increased levels of antiphospholipid antibodies, hyperhomocysteinemia, whereas hyperprolactinemia has recently attracted attention as a potential contributing factor. The highest risk has been demonstrated for clozapine, olanzapine, and low-potency first-generation antipsychotics; however, presently there is no data for amisulpride. In the present paper we describe a case of pulmonary embolism in a female bipolar patient, receiving treatment with amisulpride, aripiprazole, and paroxetine. Although a contribution of aripiprazole and paroxetine cannot completely be ruled out, the most probable factor underlying the thromboembolic event seems to be hyperprolactinemia, which was caused by amisulpride treatment. Increased plasma levels of prolactin should probably be taken into account during the monitoring of antipsychotic treatment as well as in future research concerning venous thromboembolism in psychiatric settings.

Depression in multiple sclerosis: a review of assessment and treatment approaches in adult and pediatric populations.

Multiple sclerosis is a chronic demyelinating disease affecting one million people worldwide, with a significant burden of psychiatric comorbidity. Depression is the commonest psychiatric manifestation but still remains largely underdiagnosed and undertreated. The present work reviews current knowledge on diagnosis, assessment, and somatic and psychotherapeutic treatment interventions for depression in adult and pediatric populations of patients with multiple sclerosis.