Refined diagnostic criteria for the bipolar disorders: phase two of the AREDOC project.

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.

Differentiating borderline personality disorder (BPD) from bipolar disorder: diagnostic efficiency of DSM BPD criteria.

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.

How to choose an antidepressant medication.

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.

Δ9-tetrahydrocannabinol modulates the proteasome system in the brain.

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.

Comparison of guidelines for the treatment of unipolar depression: a focus on pharmacotherapy and neurostimulation.

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.

Clinical vs. DSM diagnosis of bipolar disorder, borderline personality disorder and their co-occurrence.

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.

Differentiating the bipolar disorders from borderline personality disorder.

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.

Diseases of the Synaptic Vesicle: A Potential New Group of Neurometabolic Disorders Affecting Neurotransmission.

The general concept of inborn error of metabolism is currently evolving into the interface between classical biochemistry and cellular biology. Basic neuroscience is providing increasing knowledge about the mechanisms of neurotransmission and novel related disorders are being described. There is a necessity of updating the classic concept of "inborn error of neurotransmitters (NT)" that considers mainly defects of synthesis and catabolism and transport of low weight NT molecules. Monogenic defects of the synaptic vesicle (SV), and especially those affecting the SV cycle are a potential new group of NT disorders since they end up in abnormal NT turnover and release. The most common clinical manifestations include epilepsy, intellectual disability, autism and movement disorders, and are in the continuum symptoms of synaptopathies. Interestingly, brain malformations and neurodegenerative conditions are also present within SV diseases. Metabolomics, proteomics, and other -omic techniques probably will provide biomarkers and contribute to therapeutic targets in the future.

De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia.

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.

Crystal structure of a novel mid-gut procarboxypeptidase from the cotton pest Helicoverpa armigera.

The cotton bollworm Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae) is one of the most serious insect pests in Australia, India and China. The larva causes substantial economical losses to legume, fibre, cereal oilseed and vegetable crops. This pest has proven to be difficult to control by conventional means, mainly due to the development of pesticide resistance. We present here the 2.5 A crystal structure from the novel procarboxypeptidase (PCPAHa) found in the gut extracts from H. armigera larvae, the first one reported for an insect. This metalloprotease is synthesized as a zymogen of 46.6 kDa which, upon in vitro activation with Lys-C endoproteinase, yields a pro-segment of 91 residues and an active carboxypeptidase moiety of 318 residues. Both regions show a three-dimensional structure quite similar to the corresponding structures in mammalian digestive carboxypeptidases, the most relevant structural differences being located in the loops between conserved secondary structure elements, including the primary activation site. This activation site contains the motif (Ala)(5)Lys at the C terminus of the helix connecting the pro- and the carboxypeptidase domains. A remarkable feature of PCPAHa is the occurrence of the same (Ala)(6)Lys near the C terminus of the active enzyme. The presence of Ser255 in PCPAHa instead of Ile and Asp found in the pancreatic A and B forms, respectively, enlarges the S1' specificity pocket and influences the substrate preferences of the enzyme. The C-terminal tail of the leech carboxypeptidase inhibitor has been modelled into the PCPAHa active site to explore the substrate preferences and the enzymatic mechanism of this enzyme.

Preconditioning prevents myocardial stunning after cardiac transplantation.

BACKGROUND: Preconditioning has been shown to reduce myocardial stunning after reversible global ischemia. To determine whether preconditioning improves functional recovery after cardiac transplantation, 16 sheep were randomly assigned to a preconditioning protocol or to a control group. METHODS: Preconditioning was achieved with 5 minutes of global ischemia followed by 10 minutes of reperfusion. The heart was then arrested with 1 L of crystalloid cardioplegia, explanted, stored in a transport cooler, and then transplanted into recipient sheep. The total ischemia time was 2 hours. Pressure-volume loops were used to calculate preload recruitable stroke work, the maximum elastance, and diastolic compliance. Linear regression analysis was used to determine the preload recruitable stroke work, maximum elastance, and diastolic compliance-and end-diastolic volume relationship. The area under the regression curve for preload recruitable stroke work was defined as the preload recruitable stroke work area. Biopsies were taken for high-energy phosphates. RESULTS: Systolic function, represented by preload recruitable stroke work area, was preserved after cardiac transplantation in preconditioned animals. Maximum elastance and diastolic compliance were unaffected by preconditioning or ischemia. High-energy phosphates were better preserved in preconditioned animals. CONCLUSION: Preconditioning prevented myocardial stunning and preserved high-energy phosphates after experimental cardiac transplantation.

NGO-promoted microcredit programs and women's empowerment in rural Bangladesh: quantitative and qualitative evidence.

PIP: Nongovernmental organizations (NGOs) in rural Bangladesh are reaching out to poor women with collateral-free credit programs aimed at both alleviating poverty and increasing women's status. The present study investigated the hypothesis that participation in credit-related activities by NGO credit members leads to greater empowerment of credit members compared to nonmembers. The sample was comprised of 1164 loanees and 1200 nonloanees from the five NGO areas in Bangladesh and of 1200 nonloanees from non-program areas of rural Bangladesh with no significant NGO presence. NGO credit members had significantly higher scores on all three indices of female empowerment: inter-spouse consultation, autonomy, and authority. Moreover, nonmembers within NGO program areas had higher autonomy and authority scores than nonmembers within the comparison areas. Even after background variables were controlled in the multivariate analysis, NGO credit membership and residence in an NGO program area remained significantly and positively associated with both the autonomy and authority indices. Other variables that exerted a significant positive effect on women's empowerment were concrete or corrugated buildings, area of residence outside the southern or eastern regions, nonagricultural occupation, respondent's education, and age. In focus group discussions, NGO credit loanees reported that the program made them more confident, assertive, intelligent, self-reliant, and aware of their rights. NGO credit programs that target poor women are likely to produce substantial improvements in women's social and economic status, without the long delays associated with education or employment opportunities in the formal sector.^ieng

Government, university, and community collaboration to develop a cardiac surgery database and report of morbidity and mortality while waiting for open heart surgery.

The Provincial Advisory Committee on Cardiovascular Services was established in January of 1990 to advise concerning these services. One of the first tasks assigned was to monitor waiting times for cardiac surgery. Referring cardiologists categorized their patients into four priorities: emergency, urgent-inpatient, urgent-outpatient, and planned. Data of the southern Alberta centers for the past three years were analyzed for events while waiting for surgery. (Median time to event in days) M1=Myocardial Infarction EM=Emergency D=Day A hierarchy was used to assign the single most serious event for patients having more than one event: death>MI>readmission or change from urgent-inpatient to emergency. Events were frequent and unpredictable, particularly in outpatients. Categorization of patient suitable to wait at home for cardiac surgery is imperfect. The risk of having an event while on the waiting list is much greater for out-patients than in-patients: 12.8% (169/1323) versus 1.9% (19/1002). All adverse events for the in-patients occurred at four days--one day less than the proposed maximum waiting time. In the out-patient population, the median waiting time to experiencing adverse events ranged between 32 and 54 days. Target waiting times set by PACCS for these two categories is 14 and 56 days respectively. Total adverse events occurred to 8% of the patients on the waiting list. Median waiting time to experiencing an adverse event while on the list occurs much earlier than suspected: four days in urgent in-patients and 36 days for out-patients; well below the intended maximum of 56 days. This database proved invaluable for this important critical data collection. It is hoped it will serve as a model for similar future projects.

Magnetic resonance imaging in patients with concurrent Tourette's disorder and Asperger's syndrome.

OBJECTIVE: The purpose of the study was to examine behavioral/cognitive and neuroradiological features of patients with concurrent Tourette's disorder (TD) and Asperger's syndrome (AS). METHODS: The authors studied the occurrence of structural brain abnormalities using magnetic resonance imaging (MRI) in seven males with concurrent TD and AS, and in nine age-matched males, who had TD but did not have AS. Both groups were tested with an extensive battery of neurological and psychiatric rating scales and cognitive tests. RESULTS: Five of the seven patients with TD and AS had developmental brain anomalies. In contrast, normal MRI scans were found in all but one TD patient without AS. Both groups were not significantly different in the severity of motor and phonic tics, obsessionality, depression and anxiety, or in measures of general intelligence, memory, and language function; but patients with TD and AS had a history of more psychiatric hospitalizations, poor academic achievement, more neurological soft signs and appeared more impaired on complex problem-solving and spatial tests than did TD patients without AS. CONCLUSION: These findings suggest that structural cortical and subcortical abnormalities are more common among individuals with concurrent TD and AS than among sex- and age-matched TD patients without AS. Dysfunction of frontal-subcortical systems may play a role in the pathophysiology of concurrent TD and AS.

Chronic intestinal pseudoobstruction and ophthalmoplegia in a patient with mitochondrial myopathy.

A 38 year old woman having chronic intestinal pseudoobstruction associated with mitochondrial myopathy is reported. The clinical and radiographic features suggested the diagnosis of chronic intestinal pseudoobstruction. Muscular atrophy and ophthalmoplegia led to muscle biopsy, which disclosed accumulation of normal and abnormal mitochondria ('ragged red fibres'), characteristic of mitochondrial myopathy.