The 5-year longitudinal diagnostic profile and health services utilization of patients treated with electroconvulsive therapy in Quebec: a population-based study.

PURPOSE: Electroconvulsive therapy (ECT) is effective for treating several psychiatric disorders. However, only a minority of patients are treated with ECT. It is of primary importance to characterize their profile for epidemiological purposes and to inform clinical practice. We aimed to characterize the longitudinal profile of psychopathology and services utilization of patients first treated with ECT. METHODS: We conducted a population-based comparative study using data from a national administrative database in Quebec. Patients who received a first ECT between 2002 and 2016 were compared to controls who were hospitalized in psychiatry but did not receive ECT. We performed descriptive analyses to compare psychiatric diagnoses, domains of psychopathology (internalizing, externalizing and thought/psychotic disorders), medical services and medication use in the 5 years prior to the ECT or hospitalization. RESULTS: 5 080 ECT patients were compared with 179 594 controls. Depressive, anxiety, bipolar and psychotic disorders were more frequent in the ECT group. 96.2% of ECT patients had been diagnosed with depression and 53.8% with a primary psychotic disorder. In the ECT group, 1.0% had been diagnosed exclusively with depression and 47.0% had disorders from that belong to all three domains of psychopathology. Having both internalizing and thought/psychotic disorders was associated with an increased likelihood of receiving ECT vs having internalizing disorders alone (unadjusted OR = 2.93; 95% CI = 2.63, 3.26). All indicators of mental health services utilization showed higher use among ECT patients. CONCLUSION: Our results provide robust evidence of complex longitudinal psychopathology and extensive services utilization among ECT patients.

The Pattern of Change in Depressive Symptoms and Inflammatory Markers After Electroconvulsive Therapy: A Systematic Review.

ABSTRACT: Depression is a major mental health disorder, and its pathophysiology is still largely unknown, as is the action mechanism of electroconvulsive therapy (ECT). Some evidence suggests that inflammation might play a role in depression, and several studies have attempted to demonstrate a link between ECT and cytokines. This systematic review used a qualitative analysis to assess the effect of ECT on inflammatory markers as it relates to the clinical response of depressive symptoms in major depressive disorders. The bibliographic search engines CINAHL, Embase, PsychInfo, and PubMed were used to identify articles published up to July 2020. Search terms related to depression, ECT, and inflammation were used. Descriptive statistical analyses were performed to relate changes in inflammatory markers to clinical response to ECT. Twenty-five studies were included in the analysis. No systematic increases or decreases were found in a given inflammatory marker over the ECT; however, we observed that tumor necrosis factor α and interleukin-6 (IL-6) were more often found to be decreased after ECT, whereas IL-8 and IL-10 were more often found to be increased after treatment. No trend in correlation was found between the degree of clinical improvement of depressive symptoms and the variation of any inflammatory markers, despite positive clinical response to ECT. Great heterogeneity with regard to methodology used and lack of power of the studies included in this review could explain the lack of systematic change and correlation found in this study. Future research conducted on this subject should take into account these methodological limitations to allow subsequent meta-analysis.

Current Practices of Electroconvulsive Therapy in Mental Disorders: A Systematic Review and Meta-Analysis of Short and Long-Term Cognitive Effects.

ABSTRACT: Electroconvulsive therapy (ECT) remains one of the most effective treatments for major depressive disorder, but uncertainties persist regarding the cognitive tests to include in ECT follow-up. The current study is a systematic review and meta-analysis of the most frequent cognitive side effects after ECT. We also discuss the most common cognitive tests in ECT follow-up. We searched studies published from 2000 to 2017 in English and French language in Pubmed, EBM Reviews, EMBASE, and PsycINFO. Standardized cognitive tests were separated into 11 cognitive domains. Comparisons between cognitive measures included pre-ECT baseline with post-ECT measures at 3 times: PO1, immediately post-ECT (within 24 hours after last ECT); PO2, short term (1-28 days); and PO3, long term (more than 1 month). A total of 91 studies were included, with an aggregated sample of 3762 individuals. We found no significant changes in global cognition with Mini-Mental State Examination at PO1. Hedges g revealed small to medium effect sizes at PO2, with individuals presenting a decrease in autobiographical memory, verbal fluency, and verbal memory. Verbal fluency problems showed an inverse correlation with age, with younger adults showing greater deficits. At PO3, there is an improvement on almost all cognitive domains, including verbal fluency and verbal memory. There is a lack of standardization in the choice of cognitive tests and optimal cognitive timing. The Mini-Mental State Examination is the most common screening test used in ECT, but its clinical utility is extremely limited to track post-ECT cognitive changes. Cognitive assessment for ECT purposes should include autobiographical memory, verbal fluency, and verbal memory.

The clinical relevance of dose titration in electroconvulsive therapy: A systematic review of the literature.

Electroconvulsive therapy is a highly effective treatment of several psychiatric disorders. The debate regarding which charge dosing method offers the most favorable risk-benefit ratio remains. Our objective was to review the comparative evidence regarding efficacy and tolerability of dose titration (DT) vs other charge dosing methods, such as the age-based method (ABM) and the fixed dose method. Our secondary objective was to examine which populations would most benefit from DT. We conducted a systematic review of the literature in March 2020. Studies comparing DT to another charge dosing method were included. Fourteen articles depicting hypothetical comparisons between DT and another dosing method were found and seven articles made hypothetical comparisons without measurement of clinical outcomes. Although there is a trend in favor of DT in these articles, no clear recommendations could be drawn regarding the clinical superiority of one method. Older patients could be at higher risk of overstimulation with ABM, especially older women. The lack of high-quality prospective trials was a limitation as well as the fact that many studies used suprathreshold stimulus intensity deemed insufficient according to recent guidelines. This review emphasizes that more studies are needed to establish the differential clinical relevance of each method.

A Descriptive Study of Data Collection Systems Used in Electroconvulsive Therapy Units in the Province of Quebec, Canada.

OBJECTIVES: This study aimed to describe the data collection systems routinely used by electroconvulsive therapy (ECT) units across the province of Quebec, Canada. METHODS: We conducted a descriptive, cross-sectional study. Using an online survey, 31 ECT units delivering inpatient or outpatient ECT treatments in the province of Quebec provided information on the data collection systems used, data recorded, data collection strategies, indicators of satisfaction, limitations of the current data collection systems, and expectations toward the improvement of ECT data collection. RESULTS: Most units routinely collected information on individuals receiving ECT treatments, mainly on the medical chart (80%) and in paper format (71%). Most units (88.9%) collected ECT data manually. Electroconvulsive therapy parameters are collected by 66% to 80% of units, but only 16% of them have computerized records. The main limitations of the current systems are as follows: (a) the low frequency of computerization, (b) the underutilization of data, and (c) difficulties in the integration of information from different ECT units. Although 83.3% were satisfied with the current data collection strategies, 80% had a very positive opinion about the development and implementation of an innovative ECT provincial data collection registry. CONCLUSIONS: An integrated ECT provincial data collection system could overcome the variability documented in existing strategies and respond to the current provincial needs and expectations. Also, an integrated ECT provincial data collection system could support both clinical research and quality assurance necessary to inform standards of ECT practice in Quebec.

Pertinence of Titration and Age-Based Dosing Methods for Electroconvulsive Therapy: An International Retrospective Multicenter Study.

BACKGROUND: Although the dosage of electroconvulsive therapy (ECT) stimulus has a major impact on the efficacy and safety of this treatment, the method used to determine an optimal dosage remains a matter of debate. OBJECTIVE: We investigated factors influencing the seizure threshold (ST) in a large-sample study and compared age-based and titration dosing methods in terms of charge. METHODS: A retrospective study examined data from 503 patients across France and Canada. The patients underwent right unilateral (RUL) or bitemporal (BT) ECT during a titration session before undergoing ECT. Seizure threshold and charge differences between age-based and titration-predicted methods were derived for each RUL and BT patient and compared according to sex, age, and anesthetic agents. RESULTS: Based on our results, ST is a function of electrode placement, sex, age, and anesthetic agents. Titration and age-based methods led to completely different patterns of charges for the same electrode placement, especially in elderly and in women in the RUL group. Regression models showed that differences between the age-based and titration methods varied with respect to age, sex, and anesthetic agent. Specifically, significant effects of sex and age were observed for RUL ECT and of sex and anesthetics for BT ECT. CONCLUSIONS: This study revealed that several factors significantly influence the prediction of ECT dose, depending on individuals and treatment modalities. Caution should be exercised when using nonindividualized methods to calculate ST.

Electroconvulsive Therapy Practice in the Province of Quebec: Linked Health Administrative Data Study from 1996 to 2013.

OBJECTIVE: As part of a quality improvement process, we propose a model of routinely monitoring electroconvulsive therapy (ECT) in Canadian provinces using linked health administrative databases to generate provincial periodic reports, influence policy, and standardise ECT practices. METHODS: ECT practice in Quebec was studied from 1996 to 2013, using longitudinal data from the Quebec Integrated Chronic Disease Surveillance System of the Institut National de Santé Publique du Québec, which links 5 health administrative databases. The population included all persons, aged 18 y and over, eligible for the health insurance registry, who received an ECT treatment at least once during the year. RESULTS: Among recorded cases, 75% were identified by physician claims and hospitalisation files, 19% exclusively by physician claims, and 6% by hospitalisation files. From 1996 to 2013, 8,149 persons in Quebec received ECT with an annual prevalence rate of 13 per 100,000. A decline was observed, which was more pronounced in women and in older persons. On average, each patient received 9.7 treatments of ECT annually. The proportion of acute ECT decreased whereas maintenance treatment proportions increased. A wide variation in the use of ECT was observed among regions and psychiatrists. CONCLUSION: This study demonstrates the profitable use of administrative data to monitor ECT use in Quebec, and provides a reliable method that could be replicated in other Canadian provinces. Although Quebec has one of the lowest utilisation rates reported in industrialized countries, regional disparities highlighted the need for a deeper examination of the quality and monitoring of ECT care and services.

The Prevalence of Electroconvulsive Therapy Use Since 1973: A Meta-analysis.

OBJECTIVES: A formal meta-analysis of the use of electroconvulsive therapy (ECT) has never been conducted before in literature reviews or syntheses. Such a study would be hampered by heterogeneity and potential reporting biases. However, it would provide a single comparable measure to allow an analysis of statistical key dimensions such as trends across time and psychiatric resources available. It would also help planners and decision makers to set standards and benchmarks for national and regional guidelines for quality assurance and research in health services. METHODS: We surveyed different databases for relevant studies, limited from 1973 to October 2013. Data were extracted independently by 4 reviewers. The articles retrieved were peerreviewed studies (data-based studies or surveys) presenting ECT population rates (annual patient rates calculated from the general population) or number of patients receiving ECT during or after 1973 and attending a psychiatric establishment (either hospitals or approved ECT delivery centers for inpatients and outpatients in well-defined geographic areas). RESULTS: This meta-analysis includes a total of 18 studies from 12 countries. A composite event rate of 16.9/100,000 inhabitants emerged, characterized by high heterogeneity. Across the countries assessed, the prevalence of ECT was higher in older studies. CONCLUSIONS: By its prevalence, ECT remains rare to exceptional as a specialist treatment for mental disorders. Heterogeneity across regions or countries could best be explained by insufficient standardization of ECT procedures and practices. Linked health databases and audits could help strengthen the effectiveness of ECT in relation to primary outcomes such as suicide and help determine the gap in ECT provision, if any.

FXR1P is a GSK3ß substrate regulating mood and emotion processing.

Inhibition of glycogen synthase kinase 3ß (GSK3ß) is a shared action believed to be involved in the regulation of behavior by psychoactive drugs such as antipsychotics and mood stabilizers. However, little is known about the identity of the substrates through which GSK3ß affects behavior. We identified fragile X mental retardation-related protein 1 (FXR1P), a RNA binding protein associated to genetic risk for schizophrenia, as a substrate for GSK3ß. Phosphorylation of FXR1P by GSK3ß is facilitated by prior phosphorylation by ERK2 and leads to its down-regulation. In contrast, behaviorally effective chronic mood stabilizer treatments in mice inhibit GSK3ß and increase FXR1P levels. In line with this, overexpression of FXR1P in the mouse prefrontal cortex also leads to comparable mood-related responses. Furthermore, functional genetic polymorphisms affecting either FXR1P or GSK3ß gene expression interact to regulate emotional brain responsiveness and stability in humans. These observations uncovered a GSK3ß/FXR1P signaling pathway that contributes to regulating mood and emotion processing. Regulation of FXR1P by GSK3ß also provides a mechanistic framework that may explain how inhibition of GSK3ß can contribute to the regulation of mood by psychoactive drugs in mental illnesses such as bipolar disorder. Moreover, this pathway could potentially be implicated in other biological functions, such as inflammation and cell proliferation, in which FXR1P and GSK3 are known to play a role.

Stimulation of 5-HT2C receptors improves cognitive deficits induced by human tryptophan hydroxylase 2 loss of function mutation.

Polymorphisms in the gene encoding the serotonin synthesis enzyme Tph2 have been identified in mental illnesses, including bipolar disorder, major depression, autism, schizophrenia, and ADHD. Deficits in cognitive flexibility and perseverative behaviors are shared common symptoms in these disorders. However, little is known about the impact of Tph2 gene variants on cognition. Mice expressing a human TPH2 variant (Tph2-KI) were used to investigate cognitive consequences of TPH2 loss of function and pharmacological treatments. We applied a recently developed behavioral assay, the automated H-maze, to study cognitive functions in Tph2-KI mice. This assay involves the consecutive discovery of three different rules: a delayed alternation task, a non-alternation task, and a delayed reversal task. Possible contribution of locomotion, reward, and sensory perception were also investigated. The expression of loss-of-function mutant Tph2 in mice was associated with impairments in reversal learning and cognitive flexibility, accompanied by perseverative behaviors similar to those observed in human clinical studies. Pharmacological restoration of 5-HT synthesis with 5-hydroxytryptophan or treatment with the 5-HT(2C) receptor agonist CP809.101 reduced cognitive deficits in Tph2-KI mice and abolished perseveration. In contrast, treatment with the psychostimulant methylphenidate exacerbated cognitive deficits in mutant mice. Results from this study suggest a contribution of TPH2 in the regulation of cognition. Furthermore, identification of a role for a 5-HT(2) receptor agonist as a cognition-enhancing agent in mutant mice suggests a potential avenue to explore for the personalized treatment of cognitive symptoms in humans with reduced 5-HT synthesis and TPH2 polymorphisms.

Dissociations between cognitive and motor effects of psychostimulants and atomoxetine in hyperactive DAT-KO mice.

RATIONALE: Psychostimulants such as amphetamine and methylphenidate, which target the dopamine transporter (DAT), are the most frequently used drugs for the treatment of hyperactivity and cognitive deficits in humans with attention deficit hyperactivity disorder (ADHD). While psychostimulants can increase activity in healthy subjects, they exert a "paradoxical" calming effect in humans with ADHD as well as in hyperactive mice lacking the dopamine transporter (DAT-KO mice). However, the mechanism of action of these drugs and their impact on cognition in the absence of DAT remain poorly understood. OBJECTIVES: This study was conducted to investigate the effects of psychostimulants and noradrenergic and serotonergic drugs on cognition in DAT-KO mice and normal (WT) littermates. METHODS: We used a recently developed behavioral apparatus, the automated H-maze. The H-maze involves the consecutive learning of three different rules: delayed alternation, nonalternation, and reversal tasks. RESULTS: Treatment of WT animals with the psychostimulants replicated the behavior observed in untreated DAT-KO mice while "paradoxically" restoring cognitive performances in DAT-KO mice. Further investigation of the potential involvement of other monoamine systems in the regulation of cognitive functions showed that the norepinephrine transporter blocker atomoxetine restored cognitive performances in DAT-KO mice without affecting hyperactivity. In contrast, the nonselective serotonin receptor agonist 5CT, which antagonizes hyperactivity in DAT-KO mice, had no effect on cognitive functions. CONCLUSIONS: Taken together, these data allow dissociation of the locomotor and cognitive effects of ADHD drugs and suggest that the combination of DAT-KO mice with the automated H-maze can constitute a powerful experimental paradigm for the preclinical development of therapeutic approaches for ADHD.

Beyond cAMP: The Regulation of Akt and GSK3 by Dopamine Receptors.

Brain dopamine receptors have been preferred targets for numerous pharmacological compounds developed for the treatment of various neuropsychiatric disorders. Recent discovery that D2 dopamine receptors, in addition to cAMP pathways, can engage also in Akt/GSK3 signaling cascade provided a new framework to understand intracellular signaling mechanisms involved in dopamine-related behaviors and pathologies. Here we review a recent progress in understanding the role of Akt, GSK3, and related signaling molecules in dopamine receptor signaling and functions. Particularly, we focus on the molecular mechanisms involved, interacting partners, role of these signaling events in the action of antipsychotics, psychostimulants, and antidepressants as well as involvement in pathophysiology of schizophrenia, bipolar disorder, and Parkinson's disease. Further understanding of the role of Akt/GSK3 signaling in dopamine receptor functions could provide novel targets for pharmacological interventions in dopamine-related disorders.

Role of Beta-arrestin 2 downstream of dopamine receptors in the Basal Ganglia.

Multifunctional scaffolding protein beta-arrestins (ßArr) and the G protein-receptor kinases are involved in the desensitization of several G protein-coupled receptors (GPCR). However, arrestins can also contribute to GPCR signaling independently from G proteins. In this review, we focus on the role of ßArr in the regulation of dopamine receptor functions in the striatum. First, we present in vivo evidence supporting a role for these proteins in the regulation of dopamine receptor desensitization. Second, we provide an overview of the roles of ßArr2 in the regulation of extracellular-signal-regulated kinases/MAP kinases and Akt/GSK3 signaling pathways downstream of the D1 and D2 dopamine receptors. Thereafter, we examine the possible involvement of ßArr-mediated signaling in the action of dopaminergic drugs used for the treatment of mental disorders. Finally, we focus on different potential cellular proteins regulated by ßArr-mediated signaling which could contribute to the regulation of behavioral responses to dopamine. Overall, the identification of a cell signaling function for ßArr downstream of dopamine receptors underscores the intricate complexity of the intertwined mechanisms regulating and mediating cell signaling in the basal ganglia. Understanding these mechanisms may lead to a better comprehension of the several roles played by these structures in the regulation of mood and to the development of new psychoactive drugs having better therapeutic efficacy.

Interneurons produced in adulthood are required for the normal functioning of the olfactory bulb network and for the execution of selected olfactory behaviors.

Olfactory bulb (OB) interneurons are continuously renewed throughout an animal's lifespan. Despite extensive investigation of this phenomenon, little is known about bulbar circuitry functioning and olfactory performances under conditions of ablated arrival of new neurons into the adult OB. To address this issue we performed morphological, electrophysiological, and behavioral analysis in mice with suppressed bulbar neurogenesis. Infusion of the antimitotic drug AraC to the lateral ventricle via 28 d osmotic minipumps abolished the arrival of newly born neurons into the adult OB without affecting the total number of granule cells. The number, dendritic arborization, and spine density of interneurons generated in adulthood, before pump installation, were also not affected by AraC treatment. As a result of ablated neurogenesis, mitral cells--the principal output neurons in the OB--receive fewer inhibitory synapses, display reduced frequency of spontaneous IPSCs, experience smaller dendrodendritic inhibition, and exhibit decreased synchronized activity. Consequently, short-term olfactory memory was drastically reduced in AraC-treated mice. In contrast, olfactory performances of AraC-treated animals were undistinguishable from those of control mice in other odor-associated tests, such as spontaneous odor discrimination and long-term odor-associative memory tasks. Altogether, our data highlight the importance of adult neurogenesis for the proper functioning of the OB network and imply that new bulbar interneurons are involved in some, but not all, odor-associated tasks.

Vasculature guides migrating neuronal precursors in the adult mammalian forebrain via brain-derived neurotrophic factor signaling.

Adult neuronal precursors retain the remarkable capacity to migrate long distances from the posterior (subventricular zone) to the most anterior [olfactory bulb (OB)] parts of the brain. The knowledge about the mechanisms that keep neuronal precursors in the migratory stream and organize this long-distance migration is incomplete. Here we show that blood vessels precisely outline the migratory stream for new neurons in the adult mammalian forebrain. Real-time video imaging of cell migration in the acute slices demonstrate that neuronal precursors are retained in the migratory stream and guided into the OB by blood vessels that serve as a physical substrate for migrating neuroblasts. Our data suggest that endothelial cells of blood vessels synthesize brain-derived neurotrophic factor (BDNF) that fosters neuronal migration via p75NTR expressed on neuroblasts. Interestingly, GABA released from neuroblasts induces Ca(2+)-dependent insertion of high-affinity TrkB receptors on the plasma membrane of astrocytes that trap extracellular BDNF. We hypothesize that this renders BDNF unavailable for p75NTR-expressing migrating cells and leads to their entrance into the stationary period. Our findings provide new insights into the functional organization of substrates that facilitate the long-distance journey of adult neuronal precursors.

Delayed onset of odor detection in neonatal mice lacking tenascin-C.

The olfactory bulb is one of the few regions in the adult mammalian forebrain in which neurons are constitutively replaced throughout life. New neurons generated in the subventricular zone migrate long distances along the rostral migratory stream to the olfactory bulb where they differentiate into interneurons. Neuronal precursor generation, migration and incorporation into the bulbar network occur in an environment rich in extracellular matrix molecules. We investigated the potential role of one of the constituents of the extracellular matrix, tenascin-C (TNC), in bulbar neurogenesis and olfactory performance using TNC-deficient mice. We found that TNC deficiency resulted in a delayed onset of olfactory responses in neonatal animals. This delay normalized at around postnatal day 10. Interestingly, this delay in early olfactory performance was not due to impaired bulbar neurogenesis as proliferation, migration, incorporation and fate determination of newborn bulbar interneurons were normal in TNC-deficient animals. Thus, we conclude that a constitutive lack of TNC does not affect bulbar neurogenesis, but instead leads to ontogenetically early impairments in olfactory detection.

Neonatal and adult neurogenesis provide two distinct populations of newborn neurons to the mouse olfactory bulb.

In mammals, the olfactory bulb (OB) constitutes one of two regions of the postnatal brain with continuous neurogenesis throughout life. Despite intense explorations of neuronal replacement in the adult OB, little is known about the mechanisms that operate at earlier postnatal stages. This question is particularly pertinent, because the majority of local interneurons are born in the neonate, when olfaction controls vital functions. Here, we analyzed the recruitment of newborn cells to the granule cell (GC) layer (GCL) and found that the postnatal mouse OB is supplied with two spatiotemporally distinct populations of newborn interneurons. Early born [postnatal day 3 (P3) to P7] GCs constitute a threefold larger population compared with those generated later (P14-P60), and some of them are produced locally within the OB itself. Newborn interneurons generated at P3-P7 were predominantly targeted to the external edge of the GCL, whereas newly generated cells were positioned deeper in older mice. Additionally, although approximately 50% of adult newborn cells were eliminated within a few weeks of reaching the OB, almost the entire population of early born GCs survived until adulthood. Importantly, early olfactory experience specifically modifies the number of newborn GCs in neonates but leaves unaltered the amount of neurons generated during adulthood. Together, these results demonstrate that early postnatal neurogenesis endows the neonate bulbar circuit with newborn GCs that differ morphologically and functionally from those produced in the adult.

Inhibitory interneurons in the olfactory bulb: from development to function.

Identifying and defining the characteristic features of the inhibitory neurons in the nervous system has become essential for achieving a cellular understanding of complex brain activities. For this, the olfactory bulb is ideally suited because it is readily accessible, it is a laminated structure where local interneurons can be easily distinguished from projecting neurons, and, more important, GABAergic interneurons are continuously replaced. How the newly generated neurons integrate into a preexisting neural network and how basic network functions are maintained when a large percentage of neurons are subjected to continuous renewal are important questions that have recently received new insights. Here, it is seen that the production of bulbar interneurons is specifically adapted to experience-dependent regulation of adult neural networks. In particular, the authors report the degree of sensitivity of the bulbar neurogenesis to the activity level of sensory inputs and, in turn, how the adult neurogenesis adjusts the neural network functioning to optimize information processing. By maintaining a constitutive neurogenesis sensitive to environmental cues, this neuronal recruitment leads to improving sensory abilities. This review brings together recently described properties and emerging principles of interneuron functions that may convey, into bulbar neuronal networks, a degree of circuit adaptation unmatched by synaptic plasticity alone.