A small number of rare, recurrent genomic copy number variants (CNVs) are known to substantially increase susceptibility to schizophrenia. As a consequence of the low fecundity in people with ...schizophrenia and other neurodevelopmental phenotypes to which these CNVs contribute, CNVs with large effects on risk are likely to be rapidly removed from the population by natural selection. Accordingly, such CNVs must frequently occur as recurrent de novo mutations. In a sample of 662 schizophrenia proband-parent trios, we found that rare de novo CNV mutations were significantly more frequent in cases (5.1% all cases, 5.5% family history negative) compared with 2.2% among 2623 controls, confirming the involvement of de novo CNVs in the pathogenesis of schizophrenia. Eight de novo CNVs occurred at four known schizophrenia loci (3q29, 15q11.2, 15q13.3 and 16p11.2). De novo CNVs of known pathogenic significance in other genomic disorders were also observed, including deletion at the TAR (thrombocytopenia absent radius) region on 1q21.1 and duplication at the WBS (Williams-Beuren syndrome) region at 7q11.23. Multiple de novos spanned genes encoding members of the DLG (discs large) family of membrane-associated guanylate kinases (MAGUKs) that are components of the postsynaptic density (PSD). Two de novos also affected EHMT1, a histone methyl transferase known to directly regulate DLG family members. Using a systems biology approach and merging novel CNV and proteomics data sets, systematic analysis of synaptic protein complexes showed that, compared with control CNVs, case de novos were significantly enriched for the PSD proteome (P=1.72 × 10⁻⁶. This was largely explained by enrichment for members of the N-methyl-D-aspartate receptor (NMDAR) (P=4.24 × 10⁻⁶) and neuronal activity-regulated cytoskeleton-associated protein (ARC) (P=3.78 × 10⁻⁸) postsynaptic signalling complexes. In an analysis of 18 492 subjects (7907 cases and 10 585 controls), case CNVs were enriched for members of the NMDAR complex (P=0.0015) but not ARC (P=0.14). Our data indicate that defects in NMDAR postsynaptic signalling and, possibly, ARC complexes, which are known to be important in synaptic plasticity and cognition, play a significant role in the pathogenesis of schizophrenia.
Objective
To determine the level of agreement across a set of evidence‐based guidelines for management of the unipolar depressive disorders and with a focus on physical treatments.
Method
A ...literature search was undertaken using the terms ‘depression’, ‘depressive’ and ‘guidelines’, using PubMed, Cochrane Database of Systematic Reviews and the National Guideline Clearinghouse. Twelve national psychiatric or professional guideline‐producing organizations were identified from the period 2007–2017, with guidelines qualitatively reviewed by two assessors.
Results
For major depressive disorder (MDD), there was general consensus to use an antidepressant (AD) in cases of greater severity, although disagreement on AD use in mild to moderate depression. There was some agreement on choice of AD class in first‐line treatment recommendations, though great variability in second‐ and third‐line management particularly in recommended augmentation and combined AD strategies. Electroconvulsive therapy was considered in all but one guideline, with other neurostimulation treatments being less consistently covered and with variable recommendations. Finally, there was low consistency in the management of dysthymia, persistent depressive disorder and treatment resistant depression.
Conclusion
Our review identifies varying levels of consistency in guideline recommendations. Strategies to improve reliability in guideline formulation should also improve their validity.
How to choose an antidepressant medication Bayes, A.; Parker, G.
Acta psychiatrica Scandinavica,
March 2019, 2019-03-00, 20190301, Letnik:
139, Številka:
3
Journal Article
Recenzirano
Objective
We consider how to choose an antidepressant (AD) medication for the treatment of clinical depression.
Method
A narrative review was undertaken addressing antidepressant ‘choice’ considering ...a range of parameters either weighted by patients and clinicians or suggested in the scientific literature. Findings were synthesised and incorporated with clinical experience into a model to assist AD choice.
Results
Efficacy studies comparing ADs offer indicative guidance, while precision psychiatry prediction based on genetics, developmental trauma, neuroimaging, behavioural and cognitive biomarkers, currently has limited clinical utility. Our model offers guidance for AD choice by assessing first for the presence of a depressive subtype or symptom cluster and matching choice of AD class accordingly. Failing this, an AD can be chosen based on depression severity. Within‐class choice can be determined by reference to personality style, patient preference, medical or psychiatric comorbidities and side‐effect profile.
Conclusion
Clarification of AD choice would occur if medications are trialled in specific depressive subtypes rather than using the generic diagnosis of major depressive disorder (MDD). Such ‘top‐down’ methods could be enhanced by ‘bottom‐up’ studies to classify individuals according to symptom clusters and biomarkers with AD efficacy tested in these categories. Both methods could be utilised for personalised AD choice.
Objective
We sought to determine the differential diagnostic efficiency of all DSM‐IV borderline personality disorder (BPD) criteria by studying a sample of those with BPD and a contrast group with a ...bipolar disorder (BP).
Method
Participants were clinically assessed and assigned diagnoses based on DSM criteria – with prevalence rates and diagnostic efficiency values calculated.
Results
Fifty‐three participants were assigned a BPD diagnosis, 83 a BP diagnosis, with comorbid participants excluded. The mean number of DSM BPD criteria assigned was 6.6 (SD = 1.0) in the BPD group and 1.9 (SD = 1.3) in the BP group. The most prevalent criterion in the BPD group was ‘affective instability’ (AI) (92.5%), with ‘inappropriate anger’ least endorsed (49%). The highest specificity criterion was ‘abandonment fears’, which displayed the greatest positive predictive value (PPV) = 0.9, and with AI offering the lowest specificity. ‘Unstable relationships’ had the highest overall negative predictive value (NPV) = 0.91. The highest percentage accuracy of classification was provided by ‘identity disturbance’ and ‘abandonment fears’ criteria, both 85%.
Conclusion
The transdiagnostic nature of ‘affective instability’ means it is less useful for diagnostic decisions, whereas ‘abandonment fears’ and ‘identity disturbance’ offer superior diagnostic efficiency in distinguishing BPD from BP.
Abstract
Aims
Advanced interatrial block (IAB), is an unrecognized surrogate of atrial dysfunction and a trigger of atrial dysrhythmias, mainly atrial fibrillation (AF). Our aim was to prospectively ...assess whether advanced IAB in sinus rhythm is associated with AF and stroke in elderly outpatients with structural heart disease, a group not previously studied.
Methods and results
Prospective observational registry that included outpatients aged ≥70 years with structural heart disease and no previous diagnosis of AF. Patients were divided into three groups: normal P-wave duration (<120 ms), partial IAB (P-wave duration ≥120 ms, positive in the inferior leads), and advanced IAB P-wave duration ≥120 ms, biphasic (plus/minus) morphology in the inferior leads. Among 556 individuals, 223 had normal P-wave (40.1%), 196 partial IAB (35.3%), and 137 advanced IAB (24.6%). After a median follow-up of 694 days, 93 patients (16.7%) developed AF, 30 stroke (5.4%), and 34 died (6.1%). Advanced IAB was independently associated with AF –hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.7–5.1; P < 0.001, stroke HR 3.8, 95% CI 1.4–10.7; P = 0.010), and AF/stroke (HR 2.6, 95% CI 1.5–4.4; P = 0.001). P-wave duration (ms) was independently associated with AF (HR 1.05, 95% CI 1.03–1.07; P < 0.001), AF/stroke (HR 1.04, 95% CI 1.02–1.06; P < 0.001), and mortality (HR 1.04, 95% CI 1.00–1.08; P = 0.021).
Conclusions
The presence of advanced IAB in sinus rhythm is independently associated with AF and stroke in an elderly population with structural heart disease and no previous diagnosis of AF. P-wave duration was also associated with all-cause mortality.
Objective
To investigate the extent and reasons contributing to discrepancies between those receiving a DSM as against a clinical diagnosis of a bipolar disorder (BP) and/or a borderline personality ...disorder (BPD).
Method
We interviewed participants previously receiving a BP or BPD diagnosis, studying those who met DSM or clinical criteria for one or both conditions. We compared the numbers of participants allocated to the three diagnostic categories according to rater strategy to calculate concordance rates and determine reasons for discordance.
Results
Rates of assignment to BP, BPD and comorbid BP/BPD varied according to the diagnostic strategy. Concordance rates were reduced as BP disorder duration criteria were relaxed, with discordance mainly arising from clinical allocation of a BP disorder for those DSM assigned as unipolar depression. Rates of BPD allocation varied marginally, with discordance mostly arising from so clinically diagnosed receiving a comorbid BP/BPD DSM diagnosis. Finally, DSM overestimated comorbidity compared with clinician diagnoses. Of central importance, not imposing the DSM duration criteria for BP did not increase the prevalence of misdiagnosing BPD, a finding at variance with the literature.
Conclusion
Rates and reasons for discordance between clinical and DSM diagnosis are detailed, which should assist clinical decision‐making.
Evidence regarding any association of HDL-particle (HDL-P) derangements and HDL-cholesterol content with cardiovascular (CV) death in chronic heart failure (HF) is lacking. To investigate the ...prognostic value of HDL-P size (HDL-Sz) and the number of cholesterol molecules per HDL-P for CV death in HF patients. Outpatient chronic HF patients were enrolled. Baseline HDL-P number, subfractions and HDL-Sz were measured using 1H-NMR spectroscopy. The HDL-C/P ratio was calculated as HDL-cholesterol over HDL-P. Endpoint was CV death, with non-CV death as the competing event. 422 patients were included and followed-up during a median of 4.1 (0-8) years. CV death occurred in 120 (30.5%) patients. Mean HDL-Sz was higher in CV dead as compared with survivors (8.39 nm vs. 8.31 nm, p < 0.001). This change in size was due to a reduction in the percentage of small HDL-P (54.6% vs. 60% for CV-death vs. alive; p < 0.001). HDL-C/P ratio was higher in the CV-death group (51.0 vs. 48.3, p < 0.001). HDL-Sz and HDL-C/P ratio were significantly associated with CV death after multivariable regression analysis (HR 1.22 95% CI 1.01-1.47, p = 0.041 and HR 1.04 95% CI 1.01-1.07, p = 0.008 respectively). HDL-Sz and HDL-C/P ratio are independent predictors of CV death in chronic HF patients.
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Cannabis is the most consumed illicit drug worldwide. Its principal psychoactive component, Δ9-tetrahydrocannabinol (THC), affects multiple brain functions, including cognitive ...performance, by modulating cannabinoid type-1 (CB1) receptors. These receptors are strongly enriched in presynaptic terminals, where they modulate neurotransmitter release. We analyzed, through a proteomic screening of hippocampal synaptosomal fractions, those proteins and pathways modulated 3 h after a single administration of an amnesic dose of THC (10 mg/kg, i.p.). Using an isobaric labeling approach, we identified 2040 proteins, 1911 of them previously reported in synaptic proteomes, confirming the synaptic content enrichment of the samples. Initial analysis revealed a significant alteration of 122 proteins, where 42 increased and 80 decreased their expression. Gene set enrichment analysis indicated an over-representation of mitochondrial associated functions and cellular metabolic processes. A second analysis focusing on extreme changes revealed 28 proteins with altered expression after THC treatment, 15 of them up-regulated and 13 down-regulated. Using a network topology-based scoring algorithm we identified those proteins in the mouse proteome with the greatest association to the 28 modulated proteins. This analysis pinpointed a significant alteration of the proteasome function, since top scoring proteins were related to the proteasome system (PS), a protein complex involved in ATP-dependent protein degradation. In this regard, we observed that THC decreases 20S proteasome chymotrypsin-like protease activity in the hippocampus. Our data describe for the first time the modulation of the PS in the hippocampus following THC administration under amnesic conditions that may contribute to an aberrant plasticity at synapses.
Objective
As limitations exist across DSM criteria sets for defining and differentiating the bipolar disorders generally and their component bipolar I (BP‐1) and bipolar II (BP‐II) sub‐types, we ...sought to generate empirically based criteria.
Method
We formed an international Task Force (TF) comprising members with bipolar disorder expertise, and who recruited 74 patients with a TF‐diagnosed bipolar I and 104 with a bipolar II condition (with patients responding to definitional queries and symptom questionnaires), while 33 unipolar depressed patients recruited by the first author also completed the symptom questionnaire. A factor analysis sought to determine granular hypo/manic constructs.
Results
The bipolar disorder subjects strongly affirmed a new general definition of a bipolar disorder (capturing both manic and hypomanic episodes). While DSM‐5 requires impaired functioning, we established that a high percentage of individuals with a BP‐I or a BP‐II disorder reported improved functioning and therefore modified this criterion. Analyses identified syptoms with differential high rates in individuals with bipolar disorder and its sub‐types (and thus not simply capturing happiness), while a factor analysis generated seven symptom constructs both linked with and differing from DSM‐5 bipolar symptom criteria.
Conclusion
This second‐stage report details a new set of criteria for differentiating the bipolar disorders from unipolar depressive conditions, while arguing for BP‐I and BP‐II disorders being differentiated principally by the respective presence or absence of psychotic features. Future studies will evaluate whether further modifications are required and examine for differential treatment benefits for those with a BP‐I versus a BP‐II condition.
Objective
To identify features differentiating bipolar disorder (BP) from borderline personality disorder (BPD) and with each condition variably defined.
Method
Participants were assigned a BP or BPD ...diagnosis on the basis of DSM criteria and, separately, by clinical judgment, and undertook a diagnostic interview and completed self‐report measures.
Results
Predictors of BPD status varied according to diagnostic decisions, but with the most consistent items being childhood sexual abuse, childhood depersonalization, personality variables relating to relationship difficulties and sensitivity to criticism, and the absence of any BP family history. Across diagnostic groups, personality measure items alone predicted diagnostic allocation with an accuracy of 81–84%, the refined study variables other than hypo/manic features improved the classification rates to 88%, and when the presence or absence of hypo/manic features was added, classification rates increased to 92–95%.
Conclusion
Study findings indicate that BPD can be differentiated from BP with a high degree of accuracy.
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