Neuropathological substrates and structural changes in late-life depression: the impact of vascular burden.

A first episode of depression after 65 years of age has long been associated with both severe macrovascular and small microvascular pathology. Among the three more frequent forms of depression in old age, post-stroke depression has been associated with an abrupt damage of cortical circuits involved in monoamine production and mood regulation. Late-onset depression (LOD) in the absence of stroke has been related to lacunes and white matter lesions that invade both the neocortex and subcortical nuclei. Recurrent late-life depression is thought to induce neuronal loss in the hippocampal formation and white matter lesions that affect limbic pathways. Despite an impressive number of magnetic resonance imaging (MRI) studies in this field, the presence of a causal relationship between structural changes in the human brain and LOD is still controversial. The present article provides a critical overview of the contribution of neuropathology in post-stroke, late-onset, and late-life recurrent depression. Recent autopsy findings challenge the role of stroke location in the occurrence of post-stroke depression by pointing to the deleterious effect of subcortical lacunes. Despite the lines of evidences supporting the association between MRI-assessed white matter changes and mood dysregulation, lacunes, periventricular and deep white matter demyelination are all unrelated to the occurrence of LOD. In the same line, neuropathological data show that early-onset depression is not associated with an acceleration of aging-related neurodegenerative changes in the human brain. However, they also provide data in favor of the neurotoxic theory of depression by showing that neuronal loss occurs in the hippocampus of chronically depressed patients. These three paradigms are discussed in the light of the complex relationships between psychosocial determinants and biological vulnerability in affective disorders.

Abnormal sensitivity to negative feedback in late-life depression.

AIMS: The purpose of the present study was to probe sensitivity to potentially misleading negative feedback on cognitive tasks as a possible mechanism of cognitive impairment in elderly patients with mild depression. METHODS: A total of 22 mildly depressed elderly subjects were compared to 22 healthy controls, using a computerized Tower-of-London task. RESULTS: Failure and magnitude of failure were significantly worse after negative but not positive feedback. Depression predicted failure after negative feedback but not the magnitude of failure. Neither failure nor magnitude of failure increased as a consequence of repeated negative feedback. CONCLUSIONS: Altered sensitivity to negative feedback occurs in mild late-life unipolar depression and may represent a subtle context-specific phenomenon.

Naltrexone-assisted rapid methadone discontinuation : a pilot study

Rapport de Synthèse : Un sevrage lent comme méthode élective pour l'interruption de la méthadone est coûteux en termes de temps, le plus souvent associé à un taux élevé d'abandon. Bien que les méthodes ultrarapides de désintoxication des opiacés aient gagné en popularité récemment, elles sont chères et posent les problèmes spécifiques liés aux patients traités par la méthadone. Méthodologie: ont été inclus dans l'étude dix patients en traitement de substitution avec de la méthadone. La dernière dose de méthadone a été administrée le matin même du jour de l'admission, en préalable à l'hospitalisation. Les médicaments suivants ont été administrés le jour suivant l'admission: ondansetron 36mg, ranitidine 40mg, loperamide 8m., clonazepam 4m., promazine 1OOmg, metoclopramide 70mg, naltrexone 5Omg. L'échelle objective de sevrage des opiacés (Objective Opiate Withdrawal Scale) a été appliquée au deuxième, troisième et quatrième jour d'hospitalisation, deux fois par jour, à 8h00 et 18h00. Un suivi a été réalisé sous la forme d'entretiens téléphoniques pendant une semaine, respectivement six mois après la date de sortie de l'hôpital, faisant suite à la désintoxication. Un autre entretient téléphonique a été réalisé dans les six mois suivant le "post-sevrage", avec pour objectif d'investiguer la continuité du traitément, une éventuelle rechute dans l'abus de drogues et une possible réintroduction de la méthadone. Résultats: nous avons pu déterminer quatre groupes de symptômes, sur la base d'une observation de trois jours d'évolution: 1) Les signes typiques du syndrome de sevrage de retrait des opiacés, symptôme de froid et chaud, pilo-érection, anxiété caractérisée par une intensité initiale élevée et une disparition relativement continue. 2) Hyperactivité neurovégétative caractérisée par une intensité initiale élevée et une rapide disparition. 3) Phénomènes neurovégétatifs dont l'intensité s'est maintenue durant toute la période d'observation. 4) Contractions musculaires, insomnies et anorexie, manque d'appétit, réapparaissant chez certains patients au 2ème et au début du 3ème jour. Conclusions: une procédure courte de désintoxication utilisant une dose unique de naltrexone s'avère être une méthode alternative valable pour un sevrage de la méthadone. Cette méthode semble accélérer et écourter la symptomatologie associée au sevrage. Le cours des symptômes peut être interprété comme biphasique. Une première phase de retrait est éminemment caractérisée par tous les symptômes typiques eux-mêmes et probablement induits par la naltrexone. La seconde phase, pour un plus petit nombre de patients, peut être interprétée comme en corrélation avec une concentration de méthadone en diminution significative ultérieurement.

Periprocedural Hemodynamic Depression Is Associated With a Higher Number of New Ischemic Brain Lesions After Stenting in the International Carotid Stenting Study-MRI Substudy.

BACKGROUND AND PURPOSE: Carotid artery stenting (CAS) is associated with a higher risk of both hemodynamic depression and new ischemic brain lesions on diffusion-weighted imaging than carotid endarterectomy (CEA). We assessed whether the occurrence of hemodynamic depression is associated with these lesions in patients with symptomatic carotid stenosis treated by CAS or CEA in the randomized International Carotid Stenting Study (ICSS)-MRI substudy. METHODS: The number and total volume of new ischemic lesions on diffusion-weighted imaging 1 to 3 days after CAS or CEA was measured in the ICSS-MRI substudy. Hemodynamic depression was defined as periprocedural bradycardia, asystole, or hypotension requiring treatment. The number of new ischemic lesions was the primary outcome measure. We calculated risk ratios and 95% confidence intervals per treatment with Poisson regression comparing the number of lesions in patients with or without hemodynamic depression. RESULTS: A total of 229 patients were included (122 allocated CAS; 107 CEA). After CAS, patients with hemodynamic depression had a mean of 13 new diffusion-weighted imaging lesions, compared with a mean of 4 in those without hemodynamic depression (risk ratio, 3.36; 95% confidence interval, 1.73-6.50). The number of lesions after CEA was too small for reliable analysis. Lesion volumes did not differ between patients with or without hemodynamic depression. CONCLUSIONS: In patients treated by CAS, periprocedural hemodynamic depression is associated with an excess of new ischemic lesions on diffusion-weighted imaging. The findings support the hypothesis that hypoperfusion increases the susceptibility of the brain to embolism. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN25337470.

Assessing depression outcome in patients with moderate dementia: sensitivity of the HoNOS65+ scale.

To date, there is no widely accepted clinical scale to monitor the evolution of depressive symptoms in demented patients. We assessed the sensitivity to treatment of a validated French version of the Health of the Nation Outcome Scale (HoNOS) 65+ compared to five routinely used scales. Thirty elderly inpatients with ICD-10 diagnosis of dementia and depression were evaluated at admission and discharge using paired t-test. Using the Brief Psychiatric Rating Scale (BPRS) "depressive mood" item as gold standard, a receiver operating characteristic curve (ROC) analysis assessed the validity of HoNOS65+F "depressive symptoms" item score changes. Unlike Geriatric Depression Scale, Mini Mental State Examination and Activities of Daily Living scores, BPRS scores decreased and Global Assessment Functioning Scale score increased significantly from admission to discharge. Amongst HoNOS65+F items, "behavioural disturbance", "depressive symptoms", "activities of daily life" and "drug management" items showed highly significant changes between the first and last day of hospitalization. The ROC analysis revealed that changes in the HoNOS65+F "depressive symptoms" item correctly classified 93% of the cases with good sensitivity (0.95) and specificity (0.88) values. These data suggest that the HoNOS65+F "depressive symptoms" item may provide a valid assessment of the evolution of depressive symptoms in demented patients.

5-HT2A and alpha1b-adrenergic receptors entirely mediate dopamine release, locomotor response and behavioural sensitization to opiates and psychostimulants.

Addictive properties of drugs of misuse are generally considered to be mediated by an increased release of dopamine (DA) in the ventral striatum. However, recent experiments indicated an implication of alpha1b-adrenergic receptors in behavioural responses to psychostimulants and opiates. We show now that DA release induced in the ventral striatum by morphine (20 mg/kg) is completely blocked by prazosin (1 mg/kg), an alpha1-adrenergic antagonist. However, morphine-induced increases in DA release in the ventral striatum were found to be similar in mice deleted for the alpha1b-adrenergic receptor (alpha1b-AR KO) and in wild-type (WT) mice, suggesting the presence of a compensatory mechanism. This acute morphine-evoked DA release was completely blocked in alpha1b-AR KO mice by SR46349B (1 mg/kg), a 5-HT2A antagonist. SR46349B also completely blocked, in alpha1b-AR KO mice, the locomotor response and the development of behavioural sensitization to morphine (20 mg/kg) and D-amphetamine (2 mg/kg). Accordingly, the concomitant blockade of 5-HT2A and alpha1b-adrenergic receptors in WT mice entirely blocked acute locomotor responses but also the development of behavioural sensitization to morphine, D-amphetamine or cocaine (10 mg/kg). We observed, nevertheless, that inhibitory effects of each antagonist on locomotor responses to morphine or D-amphetamine were more than additive (160%) in naïve WT mice but not in those sensitized to either drug. Because of these latter data and the possible compensation by 5-HT2A receptors for the genetic deletion of alpha1b-adrenergic receptors, we postulate the existence of a functional link between these receptors, which vanishes during the development of behavioural sensitization.

A Survey of NHS Services for Opiate Dependents in Scotland

The aim of this study was to investigate the range of opiates available within the Scottish NHS for patients with opiate dependancy and to assess the process underlying clinical decision-making. Clinicians, representitives of drug action teams and NHS personnel were apporached and semi-structured phone conversations were the primary means to elicit information. Whilst methadone is almost universally prescribed in Scotland, buprenorphine, dihydrocodeine (not currently licensed for opiate dependance management), lofexidine and naltrexone are also used. Alternative therapies are variably used.This resource was contributed by The National Documentation Centre on Drug Use.

Guidelines for the management of depression and anxiety disorders in primary care.

High risk groups for depression and anxiety disorders include those with co-occuring alcohol or other drug misuse.This resource was contributed by The National Documentation Centre on Drug Use.

The impact of vascular burden on late-life depression.

Small vessel pathology and microvascular lesions are no longer considered as minor players in the fields of cognitive impairment and mood regulation. Although frequently found in cognitively intact elders, both neuroimaging and neuropathological data revealed the negative impact on cognitive performances of their presence within neocortical association areas, thalamus and basal ganglia. Unlike cognition, the relationship between these lesions and mood dysregulation is still a matter of intense debate. Early studies focusing on the role of macroinfarct location in the occurrence of post-stroke depression (PSD) led to conflicting data. Later on, the concept of vascular depression proposed a deleterious effect of subcortical lacunes and deep white matter demyelination on mood regulation in elders who experienced the first depressive episode. More recently, the chronic accumulation of lacunes in thalamus, basal ganglia and deep white matter has been considered as a strong correlate of PSD. We provide here a critical overview of neuroimaging and neuropathological sets of evidence regarding the affective repercussions of vascular burden in the aging brain and discuss their conceptual and methodological limitations. Based on these observations, we propose that the accumulation of small vascular and microvascular lesions constitutes a common neuropathological platform for both cognitive decline and depressive episodes in old age.

Assessing attachment cognitions and their associations with depression in youth with eating or drug misuse disorders.

The study investigates associations between attachment cognitions and depression symptoms in 71 15-25-year-olds, 26 of whom have eating disorders, and 20 of whom are drug misusers. Attachment cognitions were measured with the CaMir Q-sort, which provides indexes for secure, avoidant, and preoccupied attachment, as well as scores on 13 dimensions. The BDI-13 was used to measure depressive symptomatology. Consistent with the literature, BDI scores were associated with cognitions of preoccupied attachment. They were also related to cognitions of avoidant attachment, confirming Bowlby's theory on defensive exclusion. For participants with eating disorders, depressive symptomatology was related to preoccupation and parental interference, whereas for drug misusers, it was negatively related to security, preoccupation, parental support, and lack of parental concern. These findings help understand how attachment cognitions may participate in depressive symptomatology, namely in youth whose behavior problems may be associated with specific attachment experiences.

The "help" question doesn't help when screening for major depression: external validation of the three-question screening test for primary care patients managed for physical complaints.

BACKGROUND: Major depression, although frequent in primary care, is commonly hidden behind multiple physical complaints that are often the first and only reason for patient consultation. Major depression can be screened by two validated questions that are easier to use in primary care than the full DSM-IV criteria. A third question, called the "help" question, improves the specificity without apparently decreasing the sensitivity of this screening procedure. We validated the abbreviated screening procedure for major depression with and without the "help" question in primary care patients managed for a physical complaint. METHODS: This diagnostic accuracy study used data from a cohort study called SODA (for SOmatisation Depression Anxiety ) conducted by 24 general practitioners (GPs) in western Switzerland that included patients over 18 years of age with at least one physical complaint at index consultation. Major depression was identified with the full Patient Health Questionnaire. GPs were asked to screen patients for major depression with the three screening questions one year after inclusion. RESULTS: Out of 937 patients with at least one physical complaint, 751 were eligible one year after index consultation. Major depression was diagnosed in 69/724 (9.5%) patients. The sensitivity and specificity of the two-question method alone were 91.3% (95% confidence interval 81.4-96.4%) and 65.0% (95% confidence interval 61.2-68.6%), respectively. Adding the "help" question decreased the sensitivity (59.4% ; 95% confidence interval 47.0-70.9%) but improved the specificity (88.2% ; 95% confidence interval 85.4-90.5%) of the three-question method. CONCLUSIONS: The use of two screening questions for major depression was associated with high sensitivity and low specificity in primary care patients presenting a physical complaint. Adding the "help" question improved the specificity but clearly decreased the sensitivity; when using the "help" question; four out of ten patients with depression will be missed, compared to only one out of ten with the two-question method. Therefore, the "help" question is not useful as a screening question, but may help discussing management strategies.

Correlated evolution of mating strategy and inbreeding depression within and among populations of the hermaphroditic snail Physa acuta

Inbreeding depression is one of the main forces opposing the evolution of self-fertilization. Of central importance is the hypothesis that inbreeding depression and selfing coevolve antagonistically, generating either low selfing rate and high inbreeding depression or vice versa. However, there is limited evidence for this coevolution within species. We investigated this topic in the hermaphroditic snail Physa acuta. In this species, isolated individuals delay the onset of egg laying compared to individuals having access to mates. Longer delays (''waiting times'') indicate more intense selfing avoidance. We measured inbreeding depression and waiting time in a large quantitative-genetic experiment (281 outbred families derived from 26 natural populations). We observed large genetic variance for both traits and a strong positive genetic covariance between them, most of which resided within rather than among populations. It means that, within populations, individuals with higher mutation load avoided selfing more strongly on average. This genetic covariance may result from pleiotropy and/or linkage disequilibrium. Whatever its genetic architecture, the fact it emerges specifically when individuals are deprived of mates suggests it is not fortuitous and rather reflects the action of natural selection. We conclude that a diversity of mating strategies can arise within populations subjected to variation in inbreeding depression.