Publications by authors named "Pierre Blier"

246 Publications

Long-Lived Species of Bivalves Exhibit Low MT-DNA Substitution Rates.

Front Mol Biosci 2021 15;8:626042. Epub 2021 Mar 15.

Laboratoire De Physiologie Intégrative Et Evolutive, Département De Biologie, Université Du Québec à Rimouski, Rimouski, QC, Canada.

Bivalves represent valuable taxonomic group for aging studies given their wide variation in longevity (from 1-2 to >500 years). It is well known that aging is associated to the maintenance of Reactive Oxygen Species homeostasis and that mitochondria phenotype and genotype dysfunctions accumulation is a hallmark of these processes. Previous studies have shown that mitochondrial DNA mutation rates are linked to lifespan in vertebrate species, but no study has explored this in invertebrates. To this end, we performed a Bayesian Phylogenetic Covariance model of evolution analysis using 12 mitochondrial protein-coding genes of 76 bivalve species. Three life history traits (maximum longevity, generation time and mean temperature tolerance) were tested against 1) synonymous substitution rates (dS), 2) conservative amino acid replacement rates (Kc) and 3) ratios of radical over conservative amino acid replacement rates (Kr/Kc). Our results confirm the already known correlation between longevity and generation time and show, for the first time in an invertebrate class, a significant negative correlation between dS and longevity. This correlation was not as strong when generation time and mean temperature tolerance variations were also considered in our model (marginal correlation), suggesting a confounding effect of these traits on the relationship between longevity and mtDNA substitution rate. By confirming the negative correlation between dS and longevity previously documented in birds and mammals, our results provide support for a general pattern in substitution rates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fmolb.2021.626042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005583PMC
March 2021

Repeated but not single administration of ketamine prolongs increases of the firing activity of norepinephrine and dopamine neurons.

Int J Neuropsychopharmacol 2021 Mar 1. Epub 2021 Mar 1.

Mood Disorders Research Unit, University of Ottawa Institute of Mental Health Research, Ottawa, Ontario, Canada.

Background: Clinical studies have shown that the rapid antidepressant effect of the glutamate N-Methyl-D-Aspartate receptor antagonist ketamine generally disappears within one week but can be maintained by repeated administration. Preclinical studies showed that a single ketamine injection immediately increases the firing and burst activity of norepinephrine (NE) neurons, but not that of serotonin (5-HT) neurons. It also enhances the population activity of dopamine (DA) neurons. In the present study, we investigated whether such alterations of monoamine neuronal firing are still present one day after a single injection, and whether they can be maintained by repeated injections.

Methods: Rats received a single ketamine injection or 6 over 2 weeks and the firing activity of dorsal raphe nucleus 5-HT, locus coeruleus NE, and ventral tegmental area DA neurons was assessed.

Results: One-day following a single injection of ketamine, there was no change in the firing activity of 5-HT, NE, or DA neurons. One day after repeated ketamine administration, however, there was a robust increase of the firing activity of NE neurons, an enhancement of burst and population activities of DA neurons, but still no change in firing parameters of 5-HT neurons. The increased activity of NE neurons was no longer present 3 days after the last injection, whereas that of DA neurons was still present. DA neurons were firing normally 7 days after repeated injections.

Conclusion: These results imply that the enhanced activity of NE and DA neurons may play a significant role in the maintenance of the antidepressant action of ketamine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ijnp/pyab010DOI Listing
March 2021

THE DEPRESSION INVENTORY DEVELOPMENT SCALE: Assessment of Psychometric Properties Using Classical and Modern Measurement Theory in a CAN-BIND Trial.

Innov Clin Neurosci 2020 Jul;17(7-9):30-40

Drs. Vaccarino, Evans and Gilbert Evans are with Indoc Research in Toronto, Ontario, Canada.

The goal of the Depression Inventory Development (DID) project is to develop a comprehensive and psychometrically sound rating scale for major depressive disorder (MDD) that reflects current diagnostic criteria and conceptualizations of depression. We report here the evaluation of the current DID item bank using Classical Test Theory (CTT), Item Response Theory (IRT) and Rasch Measurement Theory (RMT). The present study was part of a larger multisite, open-label study conducted by the Canadian Biomarker Integration Network in Depression (ClinicalTrials.gov: NCT01655706). Trained raters administered the 32 DID items at each of two visits (MDD: baseline, n=211 and Week 8, n=177; healthy participants: baseline, n=112 and Week 8, n=104). The DID's "grid" structure operationalizes intensity and frequency of each item, with clear symptom definitions and a structured interview guide, with the current iteration assessing symptoms related to and . Participants were also administered the Montgomery- Åsberg Depression Rating Scale (MADRS) and Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR) that allowed DID items to be evaluated against existing "benchmark" items. CTT was used to assess data quality/reliability (i.e., missing data, skewness, scoring frequency, internal consistency), IRT to assess individual item performance by modelling an item's ability to discriminate levels of depressive severity (as assessed by the MADRS), and RMT to assess how the items perform together as a scale to capture a range of depressive severity (item targeting). These analyses together provided empirical evidence to base decisions on which DID items to remove, modify, or advance. Of the 32 DID items evaluated, eight items were identified by CTT as problematic, displaying low variability in the range of responses, floor effects, and/or skewness; and four items were identified by IRT to show poor discriminative properties that would limit their clinical utility. Five additional items were deemed to be redundant. The remaining 15 DID items all fit the Rasch model, with person and item difficulty estimates indicating satisfactory item targeting, with lower precision in participants with mild levels of depression. These 15 DID items also showed good internal consistency (alpha=0.95 and inter-item correlations ranging from r=0.49 to r=0.84) and all items were sensitive to change following antidepressant treatment (baseline vs. Week 8). RMT revealed problematic item targeting for the MADRS and QIDSSR, including an absence of MADRS items targeting participants with mild/moderate depression and an absence of QIDS-SR items targeting participants with mild or severe depression. The present study applied CTT, IRT, and RMT to assess the measurement properties of the DID items and identify those that should be advanced, modified, or removed. Of the 32 items evaluated, 15 items showed good measurement properties. These items (along with previously evaluated items) will provide the basis for validation of a penultimate DID scale assessing and . The strategies adopted by the DID process provide a framework for rating scale development and validation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839654PMC
July 2020

[A review of the antidepressant properties of ketamine].

Med Sci (Paris) 2021 Jan 25;37(1):27-34. Epub 2021 Jan 25.

The Royal's Institute of Mental Health Research, 1145 Carling Avenue, Ottawa, ON, K1Z 7K4, Canada - Department of Psychiatry, University of Ottawa, 1145 Carling Avenue, Ottawa, ON, K1Z 7K4, Canada - Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada.

Major depression is a frequent and disabling disorder. Despite great developments in the field of psychopharmacology since the 1950's, delayed onset of action and treatment resistance to current pharmacological options, such as serotonin reuptake inhibitors, remain a therapeutic challenge. The recent discovery of the rapid antidepressant action of ketamine, an NMDA (N-methyl-D-aspartate) receptor antagonist, has brought a revolution to this field. This paper presents a comprehensive review of the clinical research on the antidepressant properties of ketamine as well as its presumed mechanisms of action.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1051/medsci/2020256DOI Listing
January 2021

Thermal tolerance and fish heart integrity: fatty acids profiles as predictors of species resilience.

Conserv Physiol 2020 26;8(1):coaa108. Epub 2020 Dec 26.

Département de Biologie, Université du Québec à Rimouski, Rimouski, Québec, G5L3A1, Canada.

The cardiovascular system is a major limiting system in thermal adaptation, but the exact physiological mechanisms underlying responses to thermal stress are still not completely understood. Recent studies have uncovered the possible role of reactive oxygen species production rates of heart mitochondria in determining species' upper thermal limits. The present study examines the relationship between individual response to a thermal challenge test (CT), susceptibility to peroxidation of membrane lipids, heart fatty acid profiles and cardiac antioxidant enzyme activities in two salmonid species from different thermal habitats (, ) and their hybrids. The susceptibility to peroxidation of membranes in the heart was negatively correlated with individual thermal tolerance. The same relationship was found for arachidonic and eicosapentaenoic acid. Total HO buffering activity of the heart muscle was higher for the group with high thermal resistance. These findings underline a potential general causative relationship between sensitivity to oxidative stress, specific fatty acids, antioxidant activity in the cardiac muscle and thermal tolerance in fish and likely other ectotherms. Heart fatty acid profile could be indicative of species resilience to global change, and more importantly the plasticity of this trait could predict the adaptability of fish species or populations to changes in environmental temperature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/conphys/coaa108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771578PMC
December 2020

Single, Repeated, and Maintenance Ketamine Infusions for Treatment-Resistant Depression: A Randomized Controlled Trial.

Focus (Am Psychiatr Publ) 2020 Apr 23;18(2):236-243. Epub 2020 Apr 23.

Mood Disorders Research Unit, The Royal's Institute of Mental Health Research, Ottawa (Phillips, Norris, Talbot, Birmingham, Hatchard, Ortiz, Owoeye, Batten, Blier); the Department of Psychiatry, University of Ottawa (Phillips, Norris, Talbot, Owoeye, Blier); and the Department of Cellular and Molecular Medicine, University of Ottawa (Blier).

(Reprinted with permission from 2019; 176:401-409).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1176/appi.focus.18206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587876PMC
April 2020

Reconceptualising treatment-resistant depression as difficult-to-treat depression.

Lancet Psychiatry 2021 01;8(1):14-15

Duke University School of Medicine, Durham, NC, USA; Texas Tech University Health Sciences Center, Midland, TX, USA; Duke-National University of Singapore Medical School, Singapore.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S2215-0366(20)30516-2DOI Listing
January 2021

Divergences in the Control of Mitochondrial Respiration Are Associated With Life-Span Variation in Marine Bivalves.

J Gerontol A Biol Sci Med Sci 2021 Apr;76(5):796-804

Département de Biologie, Université du Québec, Rimouski, Québec, Canada.

The role played by mitochondrial function in the aging process has been a subject of intense debate in the past few decades, as part of the efforts to understand the mechanistic basis of longevity. The mitochondrial oxidative stress theory of aging suggests that a progressive decay of this organelle's function leads to an exacerbation of oxidative stress, with a deleterious impact on mitochondrial structure and DNA, ultimately promoting aging. Among the traits suspected to be associated with longevity is the variation in the regulation of oxidative phosphorylation, potentially affecting the management of oxidative stress. Longitudinal studies using the framework of metabolic control analysis have shown age-related differences in the flux control of respiration, but this approach has seldom been taken on a comparative scale. Using 4 species of marine bivalves exhibiting a large range of maximum life span (from 28 years to 507 years), we report life-span-related differences in flux control at different steps of the electron transfer system. Increased longevity was characterized by a lower control by NADH (complex I-linked) and Succinate (complex II-linked) pathways, while respiration was strongly controlled by complex IV when compared to shorter-lived species. Complex III exerted strong control over respiration in all species. Furthermore, high longevity was associated with higher citrate synthase activity and lower ATP synthase activity. Relieving the control exerted by the electron entry pathways could be advantageous for reaching higher longevity, leading to increased control by complex IV, the final electron acceptor in the electron transfer system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/gerona/glaa301DOI Listing
April 2021

The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Recommendations for the Use of Racemic Ketamine in Adults with Major Depressive Disorder: Recommandations Du Groupe De Travail Du Réseau Canadien Pour Les Traitements De L'humeur Et De L'anxiété (Canmat) Concernant L'utilisation De La Kétamine Racémique Chez Les Adultes Souffrant De Trouble Dépressif Majeur.

Can J Psychiatry 2021 Feb 11;66(2):113-125. Epub 2020 Nov 11.

Department of Psychiatry, 8166University of British Columbia, Vancouver, British Columbia, Canada.

Objective: Patients with major depressive disorder often have limited response to first-line and second-line medications; hence, novel pharmacological treatments are needed for treatment-resistant depression (TRD). Ketamine, an -methyl-d-aspartate (NMDA) receptor antagonist, has demonstrated rapid antidepressant effects in patients with TRD. The Canadian Network for Mood and Anxiety Treatments (CANMAT) convened a task force to review the evidence for efficacy and safety of racemic ketamine and to provide recommendations for its use in clinical practice.

Methods: A systematic review was conducted with computerized search of electronic databases up to January 31, 2020 using combinations of search terms, inspection of bibliographies, and review of other ketamine guidelines and consensus statements. The level of evidence and lines of treatment were assigned according to CANMAT criteria. Recommendations were given in question-answer format.

Results: Intravenous (IV) racemic ketamine given as a single infusion has Level 1 evidence for efficacy in adults with TRD. The evidence for multiple infusions, given as an acute series or as ongoing maintenance treatment, is limited to Level 3. Adverse events associated with ketamine infusions include behavioral (e.g., dissociative symptoms) and physiological (e.g., hypertension) events. There is only Level 3 or 4 evidence for non-IV formulations of racemic ketamine. Consensus recommendations are given for clinical administration of IV ketamine including patient selection, facility and personnel issues, monitoring, and maintaining response.

Conclusions: Single-dose IV racemic ketamine is a third-line recommendation for adults with TRD. The need for repeated and maintenance ketamine infusions should be carefully assessed on a case-by-case basis with consideration of potential risks and benefits. Because of limited evidence for efficacy and risk for misuse and diversion, the use of oral and other formulations of racemic ketamine should be limited to specialists with ketamine-prescribing expertise and affiliations with tertiary or specialized centers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0706743720970860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918868PMC
February 2021

Adjustments of cardiac mitochondrial phenotype in a warmer thermal habitat is associated with oxidative stress in European perch, Perca fluviatilis.

Sci Rep 2020 10 19;10(1):17697. Epub 2020 Oct 19.

Department of Biological and Environmental Sciences, University of Gothenburg, 405 30, Gothenburg, Sweden.

Mitochondria are playing key roles in setting the thermal limits of fish, but how these organelles participate in selection mechanisms during extreme thermal events associated with climate warming in natural populations is unclear. Here, we investigated the thermal effects on mitochondrial metabolism, oxidative stress, and mitochondrial gene expression in cardiac tissues of European perch (Perca fluviatilis) collected from an artificially heated ecosystem, the "Biotest enclosure", and an adjacent reference area in the Baltic sea with normal temperatures (~ 23 °C and ~ 16 °C, respectively, at the time of capture in summer). Fish were sampled one month after a heat wave that caused the Biotest temperatures to peak at ~ 31.5 °C, causing significant mortality. When assayed at 23 °C, Biotest perch maintained high mitochondrial capacities, while reference perch displayed depressed mitochondrial functions relative to measurements at 16 °C. Moreover, mitochondrial gene expression of nd4 (mitochondrial subunit of complex I) was higher in Biotest fish, likely explaining the increased respiration rates observed in this population. Nonetheless, cardiac tissue from Biotest perch displayed higher levels of oxidative damage, which may have resulted from their chronically warm habitat, as well as the extreme temperatures encountered during the preceding summer heat wave. We conclude that eurythermal fish such as perch are able to adjust and maintain mitochondrial capacities of highly aerobic organs such as the heart when exposed to a warming environment as predicted with climate change. However, this might come at the expense of exacerbated oxidative stress, potentially threatening performance in nature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-74788-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572411PMC
October 2020

Editorial: Evolutionary and Integrative Approaches for Revealing Adaptive Mechanisms in Marine Animals Along Environmental Gradients.

Front Physiol 2020 14;11:764. Epub 2020 Jul 14.

Unidad Multidisciplinaria de Docencia e Investigación, Facultad de Ciencias, Universidad Nacional Autónoma de México, Sisal, Mexico.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2020.00764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372082PMC
July 2020

Long-term administration of cariprazine increases locus coeruleus noradrenergic neurons activity and serotonin receptor neurotransmission in the hippocampus.

J Psychopharmacol 2020 10 20;34(10):1143-1154. Epub 2020 Jul 20.

Mood Disorders Research Unit, University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada.

Background: Cariprazine, the novel dopamine (DA) D-preferring D/D and serotonin (5-HT) receptor partial agonist, has activity as an adjunctive therapy in major depressive disorder (MDD).

Aims: This study aims to investigate the effects of chronic cariprazine administration in combination with the selective serotonin reuptake inhibitor escitalopram on the activity of monoaminergic systems.

Methods: Rats received cariprazine alone and in adjunct to escitalopram for 2 and 14 days and the firing activity of dorsal raphe nucleus 5-HT, locus coeruleus norepinephrine (NE) and ventral tegmental area DA neurons was assessed. 5-HT and NE neurotransmission in hippocampus pyramidal neurons was evaluated by assessing tonic activation of their 5-HT, and α- and α-adrenergic receptors, using their selective antagonists.

Results: Two and 14-day cariprazine regimens increased the firing rate of NE, but not 5-HT and DA neurons. Addition of cariprazine to escitalopram reversed the inhibitory effect of escitalopram on NE but not 5-HT and DA neurons. In the hippocampus, there was an increase in neurotransmission at 5-HT receptors in cariprazine-treated rats, but no change in overall NE transmission by either regimen.

Conclusion: Cariprazine increased NE neuronal firing and reversed the escitalopram-induced inhibition of these neurons. Despite a lack of effect on 5-HT neuronal firing activity, there was an increase in tonic activation of hippocampus 5-HT receptors by cariprazine alone but not with the combination. These effects provide a possible rationale for the clinical efficacy of cariprazine as an adjunctive strategy in patients with MDD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0269881120936891DOI Listing
October 2020

Symptom Dimension of Interest-Activity Indicates Need for Aripiprazole Augmentation of Escitalopram in Major Depressive Disorder: A CAN-BIND-1 Report.

J Clin Psychiatry 2020 06 16;81(4). Epub 2020 Jun 16.

Members of the CAN-BIND Investigator Team are listed at www.canbind.ca/about-can-bind/our-team/.

Objective: Differential predictors of response to alternative treatment options are needed to improve the outcomes in major depressive disorder. The symptom dimension comprising loss of interest and reduced activity has been reported as a predictor of poor outcome of treatment with antidepressants. We hypothesized that augmentation with partial dopamine agonist aripiprazole will be effective for individuals with pronounced interest-activity symptoms.

Methods: We tested the hypothesis in the 2-phase Canadian Biomarker Integration Network in Depression trial 1 (CAN-BIND-1). All participants had a primary diagnosis of major depressive disorder confirmed with the Mini-International Neuropsychiatric Interview. In phase 1, 188 individuals received escitalopram monotherapy 10-20 mg daily for 8 weeks. In phase 2, nonresponders received augmentation with aripiprazole 2-10 mg daily while responders continued escitalopram monotherapy for another 8 weeks. Outcomes were measured with the Montgomery-Åsberg Depression Rating Scale (MADRS) every 2 weeks. Effects of baseline interest-activity symptoms on outcomes were tested in repeated-measures mixed-effects models.

Results: Higher baseline interest-activity score (indicative of more severe loss of interest and reduction in activity) predicted worse outcome of escitalopram monotherapy in phase 1 (b = 1.75; 95% CI, 0.45 to 3.05; P = .009), but the association disappeared with the augmentation option in phase 2 (b = -0.19; 95% CI, -1.30 to 0.92; P = .739). A significant interaction between the baseline interest-activity score and aripiprazole reflected the opposite direction of the relationship between baseline interest-activity score and degree of improvement with escitalopram monotherapy versus aripiprazole augmentation (b = -1.60; 95% CI, -2.35 to -0.84; P < .001).

Conclusions: Individuals with prominent loss of interest and reduction in activity benefit less from escitalopram monotherapy and more from aripiprazole augmentation. Future trials may test the benefits of early prodopaminergic augmentation guided by interest-activity symptoms.

Trial Registration: ClinicalTrials.gov identifier: NCT01655706.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4088/JCP.20m13229DOI Listing
June 2020

A randomized, crossover comparison of ketamine and electroconvulsive therapy for treatment of major depressive episodes: a Canadian biomarker integration network in depression (CAN-BIND) study protocol.

BMC Psychiatry 2020 06 2;20(1):268. Epub 2020 Jun 2.

The Royal's Institute of Mental Health Research, 1145 Carling Avenue, Ottawa, ON, K1Z 7K4, Canada.

Background: Recent evidence underscores the utility of rapid-acting antidepressant interventions, such as ketamine, in alleviating symptoms of major depressive episodes (MDE). However, to date, there have been limited head-to-head comparisons of intravenous (IV) ketamine infusions with other antidepressant treatment strategies in large randomized trials. This study protocol describes an ongoing multi-centre, prospective, randomized, crossover, non-inferiority trial comparing acute treatment of individuals meeting diagnostic criteria for a major depressive episode (MDE) with ketamine and electroconvulsive therapy (ECT) on efficacy, speed of therapeutic effects, side effects, and health care resource utilization. A secondary aim is to compare a 6-month maintenance strategy for ketamine responders to standard of care ECT maintenance. Finally, through the measurement of clinical, cognitive, neuroimaging, and molecular markers we aim to establish predictors and moderators of treatment response as well as treatment-elicited effects on these outcomes.

Methods: Across four participating Canadian institutions, 240 patients with major depressive disorder or bipolar disorder experiencing a MDE are randomized (1:1) to a course of ECT or racemic IV ketamine (0.5 mg/kg) administered 3 times/week for 3 or 4 weeks. Non-responders (< 50% improvement in Montgomery-Åsberg Depression Rating Scale [MADRS] scores) crossover to receive the alternate treatment. Responders during the randomization or crossover phases then enter the 6-month maintenance phase during which time they receive clinical assessments at identical intervals regardless of treatment arm. ECT maintenance follows standard of care while ketamine maintenance involves: weekly infusions for 1 month, then bi-weekly infusions for 2 months, and finally monthly infusions for 3 months (returning to bi-weekly in case of relapse). The primary outcome measure is change in MADRS scores after randomized treatment as assessed by raters blind to treatment modality.

Discussion: This multi-centre study will help identify molecular, imaging, and clinical characteristics of patients with treatment-resistant and/or severe MDEs who would benefit most from either type of therapeutic strategy. In addition to informing clinical practice and influencing health care delivery, this trial will add to the robust platform and database of CAN-BIND studies for future research and biomarker discovery.

Trial Registration: ClinicalTrials.gov identifier NCT03674671. Registered September 17, 2018.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12888-020-02672-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265624PMC
June 2020

Using prefrontal and midline right frontal EEG-derived theta cordance and depressive symptoms to predict the differential response or remission to antidepressant treatment in major depressive disorder.

Psychiatry Res Neuroimaging 2020 08 22;302:111109. Epub 2020 May 22.

University of Ottawa Institute of Mental Health Research, 1145 Carling Avenue, Ottawa K1Z 7K4, ON, Canada; School of Psychology, University of Ottawa, Ottawa, ON, Canada.

There is a growing need for optimizing treatment selection and response prediction in individuals with major depressive disorder (MDD). Prior investigations have shown that changes in electroencephalographic (EEG)-based measures precede symptom improvement and could serve as biomarkers of treatment outcome. One such method is cordance, a computation of regional brain activity based on a combination of absolute and relative resting EEG activity. Specifically, early reduction in prefrontal (PF) and midline right frontal (MRF) theta (4-8Hz) cordance has been shown to predict response to various antidepressants, though replication is required. Thus, this study examined early changes (baseline to week 1) in PF and MRF cordance in 47 MDD patients undergoing antidepressant treatment. Early changes in cordance and in Montgomery Åsberg Depression Rating Scale (MADRS) scores were assessed alone, and in combination, to predict eventual (by week 12) treatment response and remission. Models combining early changes in theta cordance (PF and MRF) and depressive symptoms were most predictive of response to treatment at week 12; remission models (cordance, MADRS, and their combination) were weaker, though provided modest prediction values. These results suggest that antidepressant response may be optimally predicted by combining both EEG and symptom-based measures after one week of treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pscychresns.2020.111109DOI Listing
August 2020

Triple reuptake inhibition of serotonin, norepinephrine, and dopamine increases the tonic activation of α-adrenoceptors in the rat hippocampus and dopamine levels in the nucleus accumbens.

Prog Neuropsychopharmacol Biol Psychiatry 2020 12 29;103:109987. Epub 2020 May 29.

University of Ottawa Institute of Mental Health Research, 1145 Carling Avenue, Ottawa, Ontario K1Z 7K4, Canada.

Clinical studies have shown the therapeutic efficacy of an increase in dopamine (DA) transmission in treatment of major depressive disorder (MDD). In the present study, we investigated whether blockade of DA transporters in addition to serotonin (5-HT) and norepinephrine (NE) produced additional adaptations of monoaminergic systems. In vivo electrophysiological recordings were carried out in male anesthetized rats. Vehicle, the 5-HT reuptake inhibitor escitalopram, the NE/DA reuptake blocker nomifensine and their combination (triple reuptake inhibition; TRI) were delivered for 2 or 14 days. Firing activity of NE, 5-HT and DA neurons was assessed. Tonic activation of 5-HT receptors and α- and α-adrenoceptors was determined in the hippocampus and extracellular DA levels in the nucleus accumbens (NAc). Unlike escitalopram, nomifensine and TRI administration increased the tonic activation of α-adrenoceptors in the hippocampus despite decreasing NE neuronal firing activity after 2 and 14 days of administration. The firing activity of 5-HT neurons was increased after prolonged nomifensine and TRI regimens, while addition of nomifensine to escitalopram prevented the early 2-day suppression of firing by 5-HT reuptake inhibition. The tonic activation of 5-HT receptors was enhanced only with escitalopram. Whereas escitalopram and nomifensine decreased firing activity of DA neurons after a 2-day administration, their combination normalized it to baseline level after 14 days; this was accompanied by a robust increase in extracellular DA levels in the NAc. In summary, these results indicate that TRI increases NE and DA but not 5-HT transmission, suggesting a differential efficacy profile in MDD patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pnpbp.2020.109987DOI Listing
December 2020

Serotonin-2B receptor antagonism increases the activity of dopamine and glutamate neurons in the presence of selective serotonin reuptake inhibition.

Neuropsychopharmacology 2020 11 30;45(12):2098-2105. Epub 2020 May 30.

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.

Previous research has implicated the serotonin-2B (5-HT) receptor as a possible contributor to the antidepressant-like response. Aripiprazole has been successfully used in combination with selective serotonin reuptake inhibitors (SSRIs) in treatment-resistant depression and it, among all receptors, exhibits the highest affinity for the 5-HT receptor. However, the potential contribution of such an antagonistic action on 5-HT receptors in the context of adjunct therapy is not known. In vivo electrophysiological recordings of ventral tegmental area (VTA) dopamine (DA) neurons, dorsal raphe nucleus (DRN) 5-HT neurons and pyramidal neurons in the medial prefrontal cortex (mPFC), and the hippocampus were conducted in anaesthetized Sprague-Dawley rats after the administration of 5-HT receptor ligands alone or in combination with the SSRI escitalopram. An escitalopram-induced decrease in DA, but not 5-HT firing activity, was rescued by 2-day co-administration of the selective 5-HT receptor antagonist LY266097. In the mPFC, 14-day escitalopram administration alone had no effect on pyramidal neuron firing and burst activity, whereas, aripiprazole administered alone or in combination with escitalopram for 14 days increased pyramidal neuron firing and burst activity. Likewise, the administration of LY266097 alone or its addition on the last 3 days of a 14-day escitalopram regimen increased pyramidal neuron firing and burst activity. These results indicated that 5-HT receptors play, at least in part, a role in this enhancement. In the hippocampus, 5-HT receptor activation by BW723c86 decreased escitalopram-induced inhibition of 5-HT reuptake, which was reversed by a 5-HT receptor antagonist. Altogether, these results put into evidence the possibility that 5-HT receptor blockade contributes to the therapeutic effect of aripiprazole addition to SSRIs in depression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41386-020-0723-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547697PMC
November 2020

Reverse translation of major depressive disorder symptoms: A framework for the behavioural phenotyping of putative biomarkers.

J Affect Disord 2020 02 23;263:353-366. Epub 2019 Nov 23.

Department of Psychology and Neuroscience, University of Guelph, Guelph N1G 2W1, Ontario, Canada. Electronic address:

Background: Reverse translating putative biomarkers of depression from patients to animals is complex because Major Depressive Disorder (MDD) is a highly heterogenous condition. This review proposes an approach to reverse translation based on relating relevant bio-behavioural functions in laboratory rodents to MDD symptoms.

Methods: This systematic review outlines symptom clusters assessed by psychometric tests of MDD and antidepressant treatment response including the Montgomery-Åsberg Depression Rating Scale, the Hamilton Depression Rating Scale, and the Beck Depression Inventory. Symptoms were related to relevant behavioural assays in laboratory rodents.

Results: The resulting battery of tests includes passive coping, anxiety-like behaviours, sleep, caloric intake, cognition, psychomotor functions, hedonic reactivity and aversive learning. These assays are discussed alongside relevant clinical symptoms of MDD, providing a framework through which reverse translation of a biomarker can be interpreted.

Limitations: Certain aspects of MDD may not be quantified by tests in laboratory rodents, and their biological significance may not always be of clinical relevance.

Conclusions: Using this reverse translation approach, it is possible to clarify the functional significance of a putative biomarker in rodents and hence translate its contribution to specific clinical symptoms, or clusters of symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jad.2019.11.108DOI Listing
February 2020

The CINP Guidelines on the Definition and Evidence-Based Interventions for Treatment-Resistant Bipolar Disorder.

Int J Neuropsychopharmacol 2020 04;23(4):230-256

Psychiatric Department, Ludwig Maximilians University, Munich, Germany.

Background: Resistant bipolar disorder is a major mental health problem related to significant disability and overall cost. The aim of the current study was to perform a systematic review of the literature concerning (1) the definition of treatment resistance in bipolar disorder, (2) its clinical and (3) neurobiological correlates, and (4) the evidence-based treatment options for treatment-resistant bipolar disorder and for eventually developing guidelines for the treatment of this condition.

Materials And Methods: The PRISMA method was used to identify all published papers relevant to the definition of treatment resistance in bipolar disorder and the associated evidence-based treatment options. The MEDLINE was searched to April 22, 2018.

Results: Criteria were developed for the identification of resistance in bipolar disorder concerning all phases. The search of the literature identified all published studies concerning treatment options. The data were classified according to strength, and separate guidelines regarding resistant acute mania, acute bipolar depression, and the maintenance phase were developed.

Discussion: The definition of resistance in bipolar disorder is by itself difficult due to the complexity of the clinical picture, course, and treatment options. The current guidelines are the first, to our knowledge, developed specifically for the treatment of resistant bipolar disorder patients, and they also include an operationalized definition of treatment resistance. They were based on a thorough and deep search of the literature and utilize as much as possible an evidence-based approach.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ijnp/pyz064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177170PMC
April 2020

Linking paternally inherited mtDNA variants and sperm performance.

Philos Trans R Soc Lond B Biol Sci 2020 01 2;375(1790):20190177. Epub 2019 Dec 2.

Département des Sciences Biologiques, Université de Montréal, Montréal, Québec, Canada H2V 2S9.

Providing robust links between mitochondrial genotype and phenotype is of major importance given that mitochondrial DNA (mtDNA) variants can affect reproductive success. Because of the strict maternal inheritance (SMI) of mitochondria in animals, haplotypes that negatively affect male fertility can become fixed in populations. This phenomenon is known as 'mother's curse'. Doubly uniparental inheritance (DUI) of mitochondria is a stable exception in bivalves, which entails two mtDNA lineages that evolve independently and are transmitted separately through oocytes and sperm. This makes the DUI mitochondrial lineages subject to different sex-specific selective sieves during mtDNA evolution, thus DUI is a unique model to evaluate how direct selection on sperm mitochondria could contribute to male reproductive fitness. In this study, we tested the impact of mtDNA variants on sperm performance and bioenergetics in DUI and SMI species. Analyses also involved measures of sperm performance following inhibition of main energy pathways and sperm response to oocyte presence. Compared to SMI, DUI sperm exhibited (i) low speed and linearity, (ii) a strict OXPHOS-dependent strategy of energy production, and (iii) a partial metabolic shift towards fermentation following egg detection. Discussion embraces the adaptive value of mtDNA variation and suggests a link between male-energetic adaptation, fertilization success and paternal mitochondria preservation. This article is part of the theme issue 'Linking the mitochondrial genotype to phenotype: a complex endeavour'.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1098/rstb.2019.0177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6939365PMC
January 2020

Cardiac mitochondrial plasticity and thermal sensitivity in a fish inhabiting an artificially heated ecosystem.

Sci Rep 2019 11 28;9(1):17832. Epub 2019 Nov 28.

Department of Biological and Environmental Sciences, University of Gothenburg, Gothenburg, 405 30, Sweden.

Some evidence suggests that cardiac mitochondrial functions might be involved in the resilience of ectotherms such as fish to environmental warming. Here, we investigated the effects of acute and chronic changes in thermal regimes on cardiac mitochondrial plasticity and thermal sensitivity in perch (Perca fluviatilis) from an artificially heated ecosystem; the "Biotest enclosure" (~25 °C), and from an adjacent area in the Baltic Sea with normal temperatures (reference, ~16 °C). We evaluated cardiac mitochondrial respiration at assay temperatures of 16 and 25 °C, as well as activities of lactate dehydrogenase (LDH) and citrate synthase (CS) in Biotest and reference perch following 8 months laboratory-acclimation to either 16 or 25 °C. While both populations exhibited higher acute mitochondrial thermal sensitivity when acclimated to their natural habitat temperatures, this sensitivity was lost when Biotest and reference fish were acclimated to 16 and 25 °C, respectively. Moreover, reference fish displayed patterns of metabolic thermal compensation when acclimated to 25 °C, whereas no changes were observed in Biotest perch acclimated to 16 °C, suggesting that cardiac mitochondrial metabolism of Biotest fish expresses local adaptation. This study highlights the adaptive responses of cardiac mitochondria to environmental warming, which can impact on fish survival and distribution in a warming climate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-54165-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883045PMC
November 2019

Cardiac mitochondrial plasticity and thermal sensitivity in a fish inhabiting an artificially heated ecosystem.

Sci Rep 2019 11 28;9(1):17832. Epub 2019 Nov 28.

Department of Biological and Environmental Sciences, University of Gothenburg, Gothenburg, 405 30, Sweden.

Some evidence suggests that cardiac mitochondrial functions might be involved in the resilience of ectotherms such as fish to environmental warming. Here, we investigated the effects of acute and chronic changes in thermal regimes on cardiac mitochondrial plasticity and thermal sensitivity in perch (Perca fluviatilis) from an artificially heated ecosystem; the "Biotest enclosure" (~25 °C), and from an adjacent area in the Baltic Sea with normal temperatures (reference, ~16 °C). We evaluated cardiac mitochondrial respiration at assay temperatures of 16 and 25 °C, as well as activities of lactate dehydrogenase (LDH) and citrate synthase (CS) in Biotest and reference perch following 8 months laboratory-acclimation to either 16 or 25 °C. While both populations exhibited higher acute mitochondrial thermal sensitivity when acclimated to their natural habitat temperatures, this sensitivity was lost when Biotest and reference fish were acclimated to 16 and 25 °C, respectively. Moreover, reference fish displayed patterns of metabolic thermal compensation when acclimated to 25 °C, whereas no changes were observed in Biotest perch acclimated to 16 °C, suggesting that cardiac mitochondrial metabolism of Biotest fish expresses local adaptation. This study highlights the adaptive responses of cardiac mitochondria to environmental warming, which can impact on fish survival and distribution in a warming climate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-019-54165-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883045PMC
November 2019

Atypical Temporal Dynamics of Resting State Shapes Stimulus-Evoked Activity in Depression-An EEG Study on Rest-Stimulus Interaction.

Front Psychiatry 2019 15;10:719. Epub 2019 Oct 15.

University of Ottawa Institute of Mental Health Research, Ottawa, ON, Canada.

Major depressive disorder (MDD) is a complex psychiatric disorder characterized by changes in both resting state and stimulus-evoked activity. Whether resting state changes are carried over to stimulus-evoked activity, however, is unclear. We conducted a combined rest (3 min) and task (three-stimulus auditory oddball paradigm) EEG study in =28 acute depressed MDD patients, comparing them with =25 healthy participants. Our focus was on the temporal dynamics of both resting state and stimulus-evoked activity for which reason we measured peak frequency (PF), coefficient of variation (CV), Lempel-Ziv complexity (LZC), and trial-to-trial variability (TTV). Our main findings are: i) atypical temporal dynamics in resting state, specifically in the alpha and theta bands as measured by peak frequency (PF), coefficient of variation (CV) and power; ii) decreased reactivity to external deviant stimuli as measured by decreased changes in stimulus-evoked variance and complexity-TTV, LZC, and power and frequency sliding (FS and PS); iii) correlation of stimulus related measures (TTV, LZC, PS, and FS) with resting state measures. Together, our findings show that resting state dynamics alone are atypical in MDD and, even more important, strongly shapes the dynamics of subsequent stimulus-evoked activity. We thus conclude that MDD can be characterized by an atypical temporal dynamic of its rest-stimulus interaction; that, in turn, makes it difficult for depressed patients to react to relevant stimuli such as the deviant tone in our paradigm.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fpsyt.2019.00719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6803442PMC
October 2019

From Africa to Antarctica: Exploring the Metabolism of Fish Heart Mitochondria Across a Wide Thermal Range.

Front Physiol 2019 4;10:1220. Epub 2019 Oct 4.

Département de Biologie, Université du Québec à Rimouski, Rimouski, QC, Canada.

The thermal sensitivity of ectotherms is largely dictated by the impact of temperature on cellular bioenergetics, particularly on mitochondrial functions. As the thermal sensitivity of bioenergetic pathways depends on the structural and kinetic properties of its component enzymes, optimization of their function to different thermal niches is expected to have occurred through selection. In the present study, we sought to characterize mitochondrial phenotypic adjustments to thermal niches in eight ray-finned fish species occupying a wide range of thermal habitats by comparing the activities of key mitochondrial enzymes in their hearts. We measured the activity of four enzymes that control substrate entrance into the tricarboxylic acid (TCA) cycle: pyruvate kinase (PK), pyruvate dehydrogenase complex (PDHc), carnitine palmitoyltransferase (CPT), and hydroxyacyl-CoA dehydrogenase (HOAD). We also assayed enzymes of the electron transport system (ETS): complexes I, II, I + III, and IV. Enzymes were assayed at five temperatures (5, 10, 15, 20, and 25°C). Our results showed that the activity of CPT, a gatekeeper of the fatty acid pathway, was higher in the cold-water fish than in the warmer-adapted fish relative to the ETS (complexes I and III) when measured close to the species optimal temperatures. The activity of HOAD showed a similar pattern relative to CI + III and thermal environment. By contrast, PDHc and PK did not show the similar patterns with respect to CI + III and temperature. Cold-adapted species had high CIV activities compared to those of upstream complexes (I, II, I + III) whereas the converse was true for warm-adapted species. Our findings reveal a significant variability of heart mitochondrial organization among species that can be linked to temperature adaptation. Cold-adapted fish do not appear to compensate for PDHc activity but likely adjust fatty acids oxidation through higher activities of CPT and HOAD relative to complexes I + III.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2019.01220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6788138PMC
October 2019

Integrated genome-wide methylation and expression analyses reveal functional predictors of response to antidepressants.

Transl Psychiatry 2019 10 8;9(1):254. Epub 2019 Oct 8.

Department of Psychiatry, McGill Group for Suicide Studies, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.

Major depressive disorder (MDD) is primarily treated with antidepressants, yet many patients fail to respond adequately, and identifying antidepressant response biomarkers is thus of clinical significance. Some hypothesis-driven investigations of epigenetic markers for treatment response have been previously made, but genome-wide approaches remain unexplored. Healthy participants (n = 112) and MDD patients (n = 211) between 18-60 years old were recruited for an 8-week trial of escitalopram treatment. Responders and non-responders were identified using differential Montgomery-Åsberg Depression Rating Scale scores before and after treatment. Genome-wide DNA methylation and gene expression analyses were assessed using the Infinium MethylationEPIC Beadchip and HumanHT-12 v4 Expression Beadchip, respectively, on pre-treatment peripheral blood DNA and RNA samples. Differentially methylated positions (DMPs) located in regions of differentially expressed genes between responders (n = 82) and non-responders (n = 95) were identified, and technically validated using a targeted sequencing approach. Three DMPs located in the genes CHN2 (cg23687322, p = 0.00043 and cg06926818, p = 0.0014) and JAK2 (cg08339825, p = 0.00021) were the most significantly associated with mRNA expression changes and subsequently validated. Replication was then conducted with non-responders (n = 76) and responders (n = 71) in an external cohort that underwent a similar antidepressant trial. One CHN2 site (cg06926818; p = 0.03) was successfully replicated. Our findings indicate that differential methylation at CpG sites upstream of the CHN2 and JAK2 TSS regions are possible peripheral predictors of antidepressant treatment response. Future studies can provide further insight on robustness of our candidate biomarkers, and greater characterization of functional components.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41398-019-0589-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6783543PMC
October 2019

Ketamine for chronic depression: two cautionary tales

J Psychiatry Neurosci 2019 Nov;44(6):384-385

From the The Royal’s Institute of Mental Health Research, Mood Disorders Research Unit, Ottawa, Ont. (Talbot, Phillips, Blier); and the Department of Psychiatry, University of Ottawa, Ottawa, Ont. (Talbot, Phillips, Blier).

A growing body of literature has shown the effectiveness of ketamine for treating chronic depression. How long the beneficial effects of repeated ketamine last once infusions are stopped, however, remains largely unknown. Understanding the challenges that ensue after ketamine cessation can help clinicians optimally guide patients who opt for ketamine treatment and minimize the associated risks. In this commentary, we discuss some unexpected data gathered from participants of a pilot study on the effects of adjunctive ketamine infusion for resistant depression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1503/jpn.190073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821514PMC
November 2019

Mitochondrial Traits Previously Associated With Species Maximum Lifespan Do Not Correlate With Longevity Across Populations of the Bivalve .

Front Physiol 2019 26;10:946. Epub 2019 Jul 26.

Département de Biologie, Université du Québec, Rimouski, QC, Canada.

The mitochondrial oxidative stress theory of aging posits that membrane susceptibility to peroxidation and the organization of the electron transport system (ETS) linked with reactive oxygen species (ROS) generation are two main drivers of lifespan. While a clear correlation has been established from species comparative studies, the significance of these characteristics as potential modulators of lifespan divergences among populations of individual species is still to be tested. The bivalve , the longest-lived non-colonial animal with a record lifespan of 507 years, possesses a lower mitochondrial peroxidation index (PI) and reduced HO efflux linked to complexes I and III activities than related species. Taking advantage of the wide variation in maximum reported longevities (MRL) among 6 European populations (36-507 years), we examined whether these two mitochondrial properties could explain differences in longevity. We report no relationship between membrane PI and MRL in populations of , as well as a lack of intraspecific relationship between ETS complex activities and MRL. Individuals from brackish sites characterized by wide temperature and salinity windows had, however, markedly lower ETS enzyme activities relative to citrate synthase activity. Our results highlight environment-dependent remodeling of mitochondrial phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphys.2019.00946DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676799PMC
July 2019

Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1).

Int J Neuropsychopharmacol 2019 10;22(10):616-630

Janssen Research and Development, Department of Neuroscience, San Diego, California.

Background: About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression.

Methods: This Phase 3, double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (esketamine [56 or 84 mg] or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, esketamine 84 mg/antidepressant had to be significant for esketamine 56 mg/antidepressant to be formally tested.

Results: Statistical significance was not achieved with esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares [LS] means difference [95% CI]: -3.2 [-6.88, 0.45]; 2-sided P value = .088). Although esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was -4.1 [-7.67, -0.49] (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache.

Conclusions: Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression.

Trial Registration: ClinicalTrials.gov identifier: NCT02417064.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ijnp/pyz039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822141PMC
October 2019

Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.

JAMA Psychiatry 2019 09;76(9):893-903

Department of Neuroscience, Janssen Research and Development LLC, San Diego, California.

Importance: Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established.

Objective: To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant.

Design, Setting, And Participants: In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase.

Interventions: Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group.

Main Outcomes And Measures: Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test.

Results: Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo.

Conclusions And Relevance: For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo.

Trial Registration: ClinicalTrials.gov identifier: NCT02493868.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamapsychiatry.2019.1189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551577PMC
September 2019

Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.

JAMA Psychiatry 2019 09;76(9):893-903

Department of Neuroscience, Janssen Research and Development LLC, San Diego, California.

Importance: Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established.

Objective: To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant.

Design, Setting, And Participants: In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase.

Interventions: Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group.

Main Outcomes And Measures: Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test.

Results: Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo.

Conclusions And Relevance: For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo.

Trial Registration: ClinicalTrials.gov identifier: NCT02493868.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamapsychiatry.2019.1189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551577PMC
September 2019