52 results on '"Lacerda ALT"'
Search Results
2. Fronto-limbic brain structures in suicidal and nonsuicidal patients with unipolar depression
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Monkul, Es, Fawthrop, Sc, paolo brambilla, Nicoletti, Ma, Sassi, Rb, Lacerda, Alt, Mallinger, Ag, Kupfer, Dj, Keshavan, Ms, Frank, E., and Soares, Jc
3. Anatomical MRI study of corpus callosum in unipolar depression
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Lacerda, Alt, Nicoletti, Ma, paolo brambilla, Sassi, Rb, Mallinger, Ag, Frank, E., Kupfer, Dj, Keshavan, Ms, and Soares, Jc
4. Ketamine for catatonia: A novel treatment for an old clinical challenge? A systematic review of the evidence.
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Caliman-Fontes AT, Vieira F, Leal GC, Carneiro BA, Quarantini-Alvim Y, Andrade TV, Mello RP, Gadelha A, Lacerda ALT, and Quarantini LC
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Introduction: Catatonia, documented since the 19th century, remains a significant challenge in terms of recognition and treatment. Over the last two decades, ketamine has brought new perspectives to psychiatry, sparking widespread interest. Concurrently, catatonia has attracted heightened scientific attention. Preliminary evidence suggests the therapeutic potential of ketamine for catatonia., Methods: We systematically searched Medline/PubMed, Embase, PsycINFO, Lilacs, and Cochrane Library databases, as well as Google Scholar, for studies with ketamine or its enantiomers as intervention for catatonia, with no restrictions to underlying diagnosis, date, language, or study design., Results: Twenty articles were included, encompassing a total of 25 catatonic patients receiving ketamine or esketamine. Predominantly female (61.9 %), with a mean age of 44.4 years, patients mostly exhibited manifestations compatible with the retarded subtype of catatonia. Mood disorders were the most prevalent underlying diagnoses. Ketamine was primarily administered intravenously over a 40-minute period and in multiple-dosing schemes. Mean response and remission rates of catatonic manifestations for the whole sample were 80 % and 44 %, respectively, with no reports of worsening catatonic features or psychotic symptoms. Only one patient discontinued treatment due to intolerable dissociative effects., Conclusion: Challenging the conventional contraindication of ketamine in psychotic disorders, current evidence highlights its potential efficacy, particularly in treating catatonia. Pending further research, we advocate reevaluating this contraindication, as it may offer a promising therapeutic option, especially for challenging cases. Preliminary evidence suggests potentially greater benefits for catatonic patients with underlying mood disorders compared to primary psychotic disorders., Competing Interests: Declaration of competing interest LCQ reports consulting fees from Allergan, Abbot, Janssen Pharmaceutical and Lundbeck, and research fees from Janssen Pharmaceutical. ALTL has received consulting fees from Hoffmann–La Roche, Genentech, Janssen Pharmaceutical, Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Pfizer, Mantecorp Indústria Química e Farmacêutica, Libbs Farmacêutica, FQM Farma, and Sanofi-Aventis over the last 24 months and has received research fees from Janssen Pharmaceutical, Eli Lilly, Novartis, Biophytis, Celltrion, Azidus, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, FQM Farma, and Forum Pharmaceuticals. AG has been a consultant and/or advisor to or has received honoraria from Aché, Daiichi Sankyo, Torrent, Bayer, Cristália, and Janssen. We declare no other conflicts of interest concerning the publication of this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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5. How far have we advanced in early intervention for bipolar disorder?
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Cerqueira R, Surjan J, Lacerda ALT, and Noto C
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- Humans, Early Medical Intervention methods, Bipolar Disorder therapy, Bipolar Disorder drug therapy
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- 2024
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6. Efficacy of sodium nitroprusside in the treatment of drug-naive subjects in first episode psychosis - An open label study.
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Adelino MPM, Nunes MV, Nunes MFQ, Quarantini LC, Hallak JEC, and Lacerda ALT
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- Humans, Female, Male, Adult, Young Adult, Treatment Outcome, Adolescent, Psychiatric Status Rating Scales, Psychotic Disorders drug therapy, Nitroprusside administration & dosage, Nitroprusside therapeutic use, Nitroprusside pharmacology
- Abstract
Competing Interests: Declaration of competing interest Marcelo P. M. Adelino reports grants and personal fees from Janssen Pharmaceutical, Boehringer-Ingelheim, Novo Nordisk, Acadia Pharmaceutical, NeuromaTherapeutics, Cellavita, LiraNova, Parexel, IQVIA, Azidus, Synova, PPD, ICON. Marcel V. Nunes reports grants and personal fees from Janssen Pharmaceutical, Boehringer-Ingelheim, Novo Nordisk, Acadia Pharmaceutical, NeuromaTherapeutics, Cellavita, LiraNova, Parexel, IQVIA, Azidus, Synova, PPD, ICON. Marielle F. Q. Nunes reports grants and personal fees from Janssen Pharmaceutical, Eli Lilly, Novartis, Boehringer-Ingelheim, Novo Nordisk, Acadia Pharmaceutical, NeuromaTherapeutics, Cellavita, LiraNova, Parexel, IQVIA, Azidus, Synova, PPD, ICON. Lucas C. Quarantini reports consulting fees from Allergan, Abbot, Janssen Pharmaceutical, Libbs, Cristalia and Lundbeck and research fees from Janssen Pharmaceutical, CNPq. No others conflicts of interest declared concerning the publication of this article. Jaime C. E. Hallak is recipient of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil) productivity fellowship (1A). Acioly L. T. Lacerda reports grants and personal fees from Janssen Pharmaceutical, Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Libbs, Apsen, Aché Laboratórios, Sanofi-Aventis, Novartis, Eli Lilly, H. Lundbeck A/S, Boehringer-Ingelheim, Novo Nordisk, Acadia Pharmaceutical, Neumora Therapeutics, Cellavita, LivaNova, EMS, Parexel, IQVIA, Azidus, Synova, PPD, Eurofarma, Abbott.
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- 2024
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7. Editorial: Perspectives on new fast-acting antidepressants.
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Delfino RS, Singh B, and Lacerda ALT
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Competing Interests: RD has received, in the past 24 months, consulting fees from Boehringer-Ingelheim and Janssen, speaker fees from Lundbeck, Janssen, Teva, bibliographic production fees from Pfizer, Abbott, Daiichi-Sankyo, Moksha8 and Libbs. BS has received research grant support from Mayo Clinic, the National Network of Depression Centers NNDC Momentum grant, and Breakthrough Discoveries for thriving with bipolar disorder BD2. AL has received consulting fees from Libbs Farmacêutica, LivaNova, EMS, Cristalia Produtos Químicos e Farmacêuticos, Biogen, Eurofarma, Sanofi-Aventis, Abbott over the last 24 months, has received speaker fees from Cristalia Produtos Químicos e Farmacêuticos, Janssen Pharmaceutical, Boehringer-Ingelheim, Lundbeck, Daiichi Sankyo, Apsen, EMS, Libbs Farmacêutica and has received research fees from Eli Lilly, Janssen Pharmaceutical, Novo Nordisk, Acadia Pharmaceuticals, Novartis, Icon, Parexel, Neumora Therapeutics, IQVIA, PPD, Azidus, Synova.
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- 2024
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8. Does the intensity of dissociation predict antidepressant effects 24 hours after infusion of racemic ketamine and esketamine in treatment-resistant depression? A secondary analysis from a randomized controlled trial.
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Echegaray MVF, Mello RP, Magnavita GM, Leal GC, Correia-Melo FS, Jesus-Nunes AP, Vieira F, Bandeira ID, Caliman-Fontes AT, Telles M, Guerreiro-Costa LNF, Marback RF, Souza-Marques B, Lins-Silva DH, Santos-Lima C, Cardoso TA, Kapczinski F, Lacerda ALT, and Quarantini LC
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Background: Ketamine and esketamine have both shown significant antidepressant effects in treatment-resistant depression (TRD), and conflicting evidence suggests that induced dissociation by these drugs can be a clinical predictor of esketamine/ketamine's efficacy., Methods: This study is a secondary analysis from a bi-center, randomized, controlled trial. Participants were randomly assigned 1:1 to receive an IV infusion of esketamine (.25 mg/kg) or racemic ketamine (.50 mg/kg) over 40 minutes. Dissociative symptoms were assessed using the Clinician-Administered Dissociative State Scale (CADSS) 40 minutes following the beginning of the infusion. The variation in depression scores was measured with the Montgomery-Asberg Depression Rating Scale (MADRS), which was administered before the intervention as a baseline measure and 24 hrs, 72 hrs, and 7 days following infusion., Results: Sixty-one patients were included in the analysis. Examining CADSS scores of 15 or below, for every 1-point increment in the CADSS score, there was a mean change of -0.5 (SD = 0.25; p-value 0.04) of predicted MADRS score from baseline to 24 hrs. The results for 72 hrs and 7 days following infusion were not significant. Limitations: This study was not designed to assess the relationship between ketamine or esketamine-induced dissociation and antidepressant effects as the main outcome, therefore confounding variables for this relationship were not controlled., Conclusion: We suggest a positive relationship between dissociation intensity, measured by CADSS, and antidepressant effect 24 hours after ketamine and esketamine infusion for a CADSS score of up to 15 points., Competing Interests: ALTL reports grants and personal fees from Janssen Pharmaceutical, personal fees from Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Libbs, Pfizer, Myralis Farma, Aché Laboratórios, Hypera Pharma, and Sanofi-Aventis, grants from Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, Forum Pharmaceuticals and from the following public funding programs CNPq and FAPESP. LCQ reports consulting fees from Allergan, Abbott, Cristalia, Janssen Pharmaceutical, and Lundbeck and research fees from Janssen Pharmaceutica and Fundação Baiana de Infectologia. No other conflicts of interest declared concerning the publication of this article.
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- 2023
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9. Arketamine for bipolar depression: Open-label, dose-escalation, pilot study.
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Bandeira ID, Leal GC, Correia-Melo FS, Souza-Marques B, Silva SS, Lins-Silva DH, Mello RP, Vieira F, Dorea-Bandeira I, Faria-Guimarães D, Carneiro B, Caliman-Fontes AT, Kapczinski F, Miranda-Scippa Â, Lacerda ALT, and Quarantini LC
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- Female, Humans, Male, Antidepressive Agents therapeutic use, Depression, Double-Blind Method, Pilot Projects, Treatment Outcome, Bipolar Disorder drug therapy, Bipolar Disorder diagnosis, Depressive Disorder, Major drug therapy, Ketamine
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There are significantly fewer options for the treatment of bipolar depression than major depressive disorder, with an urgent need for alternative therapies. In this pilot study, we treated six subjects with bipolar disorder types I and II (according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria) who had been in a current depressive episode for at least four weeks. Four subjects were female (66.66%), and the mean age was 45.33 (±12.32). Subjects received adjunct treatment with two arketamine intravenous infusions one week apart-0.5 mg/kg first and then 1 mg/kg. The mean baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score was 36.66, which decreased to 27.83 24h after the first infusion of 0.5 mg/kg of arketamine (p = 0.036). In respect of the 1 mg/kg dose, the mean MADRS total score before the second infusion was 32.0, which dropped to 17.66 after 24h (p < 0.001). Arketamine appears to have rapid-acting antidepressant properties, consistent with previous animal studies on major depression. All individuals tolerated both doses, exhibiting nearly absent dissociation, and no manic symptoms. To the best of our knowledge, this pilot trial is the first to test the feasibility and safety of the (R)-enantiomer of ketamine (arketamine) for bipolar depression., Competing Interests: Declaration of competing interest Dr. Quarantini reports consulting fees from Allergan, Abbott, Janssen Pharmaceuticals and Lundbeck and research fees from Janssen Pharmaceuticals. Dr. Lacerda reports grants and personal fees from Janssen Pharmaceuticals, personal fees from Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Libbs, Pfizer, Myralis Farma, Aché Laboratórios, Hypera Pharmaand Sanofi-Aventis, grants from Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, Forum Pharmaceuticals and from public programs: CNPq and FAPESP., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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10. Arketamine as adjunctive therapy for treatment-resistant depression: A placebo-controlled pilot study.
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Leal GC, Souza-Marques B, Mello RP, Bandeira ID, Caliman-Fontes AT, Carneiro BA, Faria-Guimarães D, Guerreiro-Costa LNF, Jesus-Nunes AP, Silva SS, Lins-Silva DH, Fontes MA, Alves-Pereira R, Cordeiro V, Rugieri-Pacheco S, Santos-Lima C, Correia-Melo FS, Vieira F, Sanacora G, Lacerda ALT, and Quarantini LC
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- Humans, Pilot Projects, Antidepressive Agents adverse effects, Drug Therapy, Combination, Double-Blind Method, Treatment Outcome, Depression drug therapy, Depressive Disorder, Treatment-Resistant drug therapy
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Background: Racemic ketamine is a mixture of (R)-ketamine (arketamine) and (S)-ketamine (esketamine), with the latter regarded as the main isomer for antidepressant effects. However, preclinical data and one open-label human trial suggest arketamine might exert a more potent and longer-lasting antidepressant effect with fewer side effects. We aimed to explore the feasibility of a randomized controlled trial of arketamine for treatment-resistant depression (TRD) and to assess its efficacy and safety compared to placebo., Methods: This is a, randomized, double-blind, crossover, pilot trial (n = 10). All participants received saline and arketamine (0.5 mg/kg) with a one-week interval. Treatment effects were analyzed with a linear mixed effects (LME) model., Results: Our analysis suggested the presence of a carryover effect, so the main efficacy analysis was limited to the first week, which demonstrated a main effect of time (p = 0.038) but not for treatment (p = 0.40) or their interaction (p = 0.95). This indicates that depression improved over time, but without significant difference between arketamine and placebo. Analyzing the two weeks together, findings were the same. Dissociation and other adverse events were minimal., Limitations: This was a pilot study with a small sample and underpowered., Conclusions: Arketamine was not superior to placebo for TRD but demonstrated to be extremely safe. Our findings reinforce the importance of continuing studies with this drug, with better powered clinical trials, perhaps considering a parallel design with higher or flexible doses and repeated administrations., Competing Interests: Conflict of interest Dr. Lacerda reports grants and personal fees from Janssen Pharmaceutical, Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Libbs, Pfizer, Myralis Farma, Aché Laboratórios, Hypera Pharma, Sanofi-Aventis, Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, and Forum Pharmaceuticals. Dr. Sanacora, in the last 12 months, has provided consulting services to Ancora, Aptinyx, Axsome Therapeutics, Biohaven Pharmaceuticals, Bristol-Myers Squibb, Clexio Biosciences, Denovo Biopharma, EMA Wellness, Engrail, Gilgamesh, Freedom Biosciences, Intra-Cellular Therapies, Janssen, miCure Therapeutics, Merck, Navitor Pharmaceuticals, Neurocrine, Novartis, Noven Pharmaceuticals, Perception Neuroscience, Praxis, Sage Pharmaceuticals, Seelos Pharmaceuticals, and XW Labs. He has received funds for contracted research from Janssen Pharmaceuticals, Merck, and Usona Institute. He holds equity in Biohaven Pharmaceuticals and has received royalties paid from patent licenses with Biohaven Pharmaceuticals. His employer, Yale University, has a financial relationship with Janssen Pharmaceuticals and may receive financial benefits from this relationship. Other authors have no conflicts of interest to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)
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- 2023
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11. Brain-derived neurotrophic factor serum levels following ketamine and esketamine intervention for treatment-resistant depression: secondary analysis from a randomized trial.
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Caliman-Fontes AT, Leal GC, Correia-Melo FS, Paixão CS, Carvalho MS, Jesus-Nunes AP, Vieira F, Magnavita G, Bandeira ID, Mello RP, Beanes G, Silva SS, Echegaray M, Carvalho LP, Machado P, Sampaio AS, Cardoso TA, Kapczinski F, Lacerda ALT, and Quarantini LC
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- Humans, Brain-Derived Neurotrophic Factor, Depression, Ketamine therapeutic use, Depressive Disorder, Treatment-Resistant drug therapy
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Objectives: Evidence suggests that ketamine's influence on brain-derived neurotrophic factor (BDNF) might be involved in its mechanism of rapid antidepressant action. We aimed to evaluate the differential impact of ketamine and esketamine on serum BDNF levels and its association with response patterns in treatment-resistant depression (TRD)., Methods: Participants (n = 53) are from a randomized, double-blind clinical trial comparing the efficacy of single-dose ketamine (0.5mg/kg, n = 27) and esketamine (0.25mg/kg, n = 26) in TRD. Depression severity was assessed before and 24 hours, 72 hours, and 7 days after the intervention, using the Montgomery-Åsberg Depression Rating Scale (MADRS). Blood samples were collected before infusion, 24 hours, and 7 days afterwards., Results: There were no significant changes in BDNF levels at post-infusion evaluation points, and no difference in BDNF levels comparing ketamine and esketamine. Both drugs exhibited similar therapeutic effect. There was no association between BDNF levels and response to treatment or severity of depressive symptoms., Conclusion: There was no significant treatment impact on BDNF serum levels - neither with ketamine nor esketamine - despite therapeutic response. These results suggest that ketamine or esketamine intervention for TRD has no impact on BDNF levels measured at 24 hours and 7 days after the infusion., Competing Interests: Acioly L. T. Lacerda reports grants and personal fees from Janssen Pharmaceutical; personal fees from DaiichiSankyo, Cristália, Libbs, Pfizer, Myralis-Farma, Aché Laboratórios, Hypera-Pharma, and Sanofi-Aventis; grants from Eli-Lilly, Lundbeck, Servier-Laboratories, Hoffman-La-Roche, and Forum-Pharmaceuticals. Lucas C. Quarantini reports consulting fees from Allergan, Abbot, Janssen-Pharmaceutical and Lundbeck, and research fees from Janssen-Pharmaceutical. No other conflicts of interest declared concerning the publication of this article.
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- 2023
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12. Authors' Response to Comment on "Efficacy and Safety of Subcutaneous Esketamine in the Treatment of Suicidality in Major Depressive Disorder and Bipolar Depression".
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Grossi JD, Surjan J, Delfino RS, Del Porto JA, and Lacerda ALT
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- Humans, Depressive Disorder, Major drug therapy, Bipolar Disorder drug therapy, Suicide, Ketamine adverse effects
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- 2023
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13. Impact of Repeated Doses of Subcutaneous Esketamine on Acute Dissociative Symptoms in Treatment-Resistant Depression.
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Del Sant LC, Sarin LM, Lucchese AC, Magalhães EJM, Tuena MA, Nakahira C, Del Porto JA, De Lacerda ALT, and Mari JJ
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Background: Esketamine has been approved by the US Food and Drug Administration (FDA) as an adjunctive treatment for use in conjunction with an oral antidepressant for patients with treatment-resistant depression (TRD), but dissociative symptoms are common adverse effects., Methods: A retrospective analysis of 394 subcutaneous esketamine injections given to 70 patients with TRD that were administered once a week during a six-week trial in conjunction with oral antidepressant therapy. Doses between 0.5 to 1.0 mg/kg were administered according to the patient's response. Dissociative symptoms were assessed using the Clinician-Administered Dissociative States Scale (CADSS) 30 and 60 min after every weekly treatment (day 1, 8, 15, 22, 29 and 36)., Results: Seventy patients received a total of 394 subcutaneous esketamine injections over six weeks. Over time, the evolution of CADSS scores demonstrated a significant mean difference of CADSS at 60 min post-injection ( p = 0.010) throughout the six infusions. The mean CADSS scores at 60 min on day 22, 29 and 36 were similar. There were no differences between mean CADSS scores 30 min after the injections, no clinical correlation between response and dissociative symptoms, no correlation between time and demographic and clinical characteristics and no interactions between time and combined medication., Conclusions: Our results suggest that repeated subcutaneous esketamine doses are safe and well-tolerated regarding their acute dissociative and psychotomimetic symptoms. Symptoms usually peak at 30 min and decrease at 60 min post-injection, returning to their pretreatment levels at 120 min. Dissociative symptoms do not correlate with antidepressant response.
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- 2022
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14. Effects of GRIN2B , GRIA1 , and BDNF Polymorphisms on the Therapeutic Action of Ketamine and Esketamine in Treatment-Resistant Depression Patients: Secondary Analysis From a Randomized Clinical Trial.
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Beanes G, Caliman-Fontes AT, Souza-Marques B, Silva HDS, Leal GC, Carneiro BA, Guerreiro-Costa LNF, Figueiredo AV, Figueiredo CAV, Lacerda ALT, Costa RDS, and Quarantini LC
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- Humans, Brain-Derived Neurotrophic Factor genetics, Depression drug therapy, Double-Blind Method, Polymorphism, Single Nucleotide, Treatment Outcome, Receptors, AMPA genetics, Receptors, N-Methyl-D-Aspartate genetics, Antidepressive Agents therapeutic use, Depressive Disorder, Treatment-Resistant drug therapy, Depressive Disorder, Treatment-Resistant genetics, Ketamine therapeutic use
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Objective: This study aimed to evaluate the effect of genetic variants in glutamate ionotropic receptor N-methyl- d -aspartate type subunit 2B ( GRIN2B ), glutamate ionotropic receptor α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid type subunit 1 ( GRIA1 ), and brain-derived neurotrophic factor ( BDNF ) genes on therapeutic response, remission, and total Montgomery-Åsberg Depression Rating Scale scores after treatment with ketamine or esketamine in treatment-resistant depression (TRD) patients., Methods: Participants (N = 60) are from a double-blind, randomized, noninferiority clinical trial comparing single-dose intravenous ketamine (0.5 mg/kg) to esketamine (0.25 mg/kg) for TRD. Montgomery-Åsberg Depression Rating Scale was applied at baseline, 24 hours, 72 hours, and 7 days postinfusion to assess depressive symptoms. Blood samples were collected to evaluate single nucleotide polymorphisms rs1805502 ( GRIN2B ), rs1994862 ( GRIA1 ), and rs6265 ( BDNF )., Results: There was no association between rs1805502, rs1994862, or rs6265 polymorphisms and antidepressant response ( P = 0.909, P = 0.776, and P = 0.482, respectively), remission P = 0.790, P = 0.086, and P = 0.669), or Montgomery-Åsberg Depression Rating Scale scores at each time point ( P = 0.907, P = 0.552, and P = 0.778)., Conclusions: We found no association between the studied single nucleotide polymorphisms (rs6265, rs1805502, and rs1994862) and ketamine's therapeutic action in TRD patients. Further studies with larger samples are needed to clarify the utility of these genes of interest as predictors for antidepressant treatment., Competing Interests: Conflicts of Interest and Source of Funding: The research leading to these results was supported by the Programa de Pesquisa para o SUS (PPSUS/BA) (grant number 003/2017), Fundação de Amparo à Pesquisa do Estado da Bahia (FAPESB). Sponsors did not have any role in study design, writing of the manuscript, or the decision to submit it for publication., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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15. Efficacy and Safety of Subcutaneous Esketamine in the Treatment of Suicidality in Major Depressive Disorder and Bipolar Depression.
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Surjan J, Grossi JD, Del Porto JA, Delfino RS, de Oliveira Cerqueira R, Lucchese AC, Magalhães E, Del Sant LC, Tuena MA, Nakahira C, Fava VAR, Steglich MS, Abdo GL, Barbosa MG, Sarin LM, and Lacerda ALT
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- Administration, Intranasal, Antidepressive Agents adverse effects, Double-Blind Method, Humans, Bipolar Disorder diagnosis, Bipolar Disorder drug therapy, Depressive Disorder, Major diagnosis, Depressive Disorder, Major drug therapy, Depressive Disorder, Treatment-Resistant chemically induced, Depressive Disorder, Treatment-Resistant diagnosis, Depressive Disorder, Treatment-Resistant drug therapy, Ketamine adverse effects
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Background and Objective: Affective disorders account for most cases of suicide. The pharmacological arsenal to treat suicidality is limited and available agents take too long to take effect. A large body of evidence shows optimal results of ketamine for treating depression, but the evidence concerning suicidality has not been fully described. We report the first real-world study of severely depressed patients presenting with suicide ideation who were treated with repeated administration of subcutaneous esketamine., Methods: We analyzed data from 70 acutely depressed subjects diagnosed with resistant major depressive disorder or bipolar depression. Subjects were administered subcutaneous esketamine once a week for 6 weeks. The primary efficacy endpoint, the change from baseline to 24-h post-administration 6 in the item 10 Montgomery-Åsberg Depression Rating Scale score, was analyzed using a mixed-effects repeated-measures model., Results: There were significant effects for time on item 10 Montgomery-Åsberg Depression Rating Scale scores (p < 0.0001) but not for a time × diagnosis interaction (p = 0.164) from baseline to the end of the study. Efficacy of esketamine did not differ between groups (major depressive disorder vs bipolar depression) at any timepoint. Statistical significance on suicidality scores was observed from 24 h after the first administration (p < 0.001), and a further reduction was observed with repeated administrations. Esketamine was safe and well tolerated. Mean heart rate remained stable during the administrations and the blood pressure increase was self-limited., Conclusions: Repeated subcutaneous esketamine administration had significant anti-suicidality effects in both major depressive disorder and bipolar groups, with a rapid onset of action and a good tolerability profile. Large randomized controlled trials are warranted to confirm these preliminary findings., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
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- 2022
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16. Letter to the Editor: Antidepressant and Antisuicidal Effects of Esketamine in Adolescents with Major Depressive Disorder and Suicidal Ideation: A Case Series.
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Faria-Guimarães D, Vieira F, Souza-Marques B, Silva SS, Bandeira ID, Souza LS, Alves-Pereira R, Fontes M, Mello RP, Leal GC, Cardoso TA, Kapczinski F, Lacerda ALT, Sampaio AS, and Quarantini LC
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- Adolescent, Antidepressive Agents pharmacology, Antidepressive Agents therapeutic use, Humans, Suicidal Ideation, Depressive Disorder, Major drug therapy, Ketamine therapeutic use
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- 2022
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17. Esketamine for Unipolar Major Depression With Psychotic Features: A Retrospective Chart Review and Comparison With Nonpsychotic Depression.
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Souza-Marques B, Telles M, Leal GC, Faria-Guimarães D, Correia-Melo FS, Jesus-Nunes AP, Vieira F, Souza L, Lins-Silva D, Mello RP, Guerreiro-Costa L, Bandeira ID, Lacerda ALT, Sampaio AS, and Quarantini LC
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- Administration, Intranasal, Antidepressive Agents therapeutic use, Depression, Humans, Ketamine, Retrospective Studies, Depressive Disorder, Major drug therapy, Depressive Disorder, Treatment-Resistant drug therapy
- Abstract
Purposes/background: The aims of the study were to assess subanesthetic esketamine as an antidepressant for major depressive disorder with psychotic features (PMDD) and to compare posttreatment symptoms among those with PMDD to a sample of nonpsychotic depression (major depressive disorder [MDD])., Methods/procedures: This study is a retrospective chart review of patients with major depression and current psychotic symptoms, treated with a single parenteral 0.5-mg/kg dose of esketamine. Depression symptoms were assessed at baseline and 24-hour posttreatment with the Montgomery-Åsberg Depression Rating Scale. Individuals with PMDD were matched in a 1:2 ratio to nonpsychotic MDD patients from a randomized, noninferiority clinical trial of esketamine., Findings/results: A total of 15 individuals with PMDD were included, which had higher baseline depression scores (PMDD = 40.9, MDD = 33.6, P = 0.004). A statistically significant change in depressive symptoms was found for the PMDD sample (β = -16.20 [95% confidence interval, -23.30 to -9.10], P < 0.001), and no difference between PMDD and MDD groups was observed in the matched-sample analysis (β = -2.2 [95% confidence interval, -9.32 to 4.58], P = 0.537). Treatment-induced dissociative symptoms were present for both groups, self-contained to within 2 hours after treatment, and no exacerbation of psychotic symptoms was found in clinical assessments., Implications/conclusions: Results suggest a single 0.5-mg/kg dose of esketamine may benefit individuals with PMDD, and the symptom reduction may be comparable with esketamine's effects for MDD. Furthermore, esketamine may induce an antidepressant response in those with PMDD without complication of psychotic symptoms. Future research with controlled designs is warranted., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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18. Clinical predictors of depressive symptom remission and response after racemic ketamine and esketamine infusion in treatment-resistant depression.
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Jesus-Nunes AP, Leal GC, Correia-Melo FS, Vieira F, Mello RP, Caliman-Fontes AT, Echegaray MVF, Marback RF, Guerreiro-Costa LNF, Souza-Marques B, Santos-Lima C, Souza LS, Bandeira ID, Kapczinski F, Lacerda ALT, and Quarantini LC
- Subjects
- Adult, Depression, Double-Blind Method, Female, Humans, Male, Middle Aged, Treatment Outcome, Depressive Disorder, Major drug therapy, Depressive Disorder, Treatment-Resistant diagnosis, Depressive Disorder, Treatment-Resistant drug therapy, Ketamine therapeutic use
- Abstract
Background: Major depressive disorder (MDD) is a leading cause of disability worldwide and most people do not achieve symptom remission. Treatment-resistant depression (TRD) is characterized by the failure of at least one adequate trial of a major class of antidepressant, with adequate time and dosage. We aimed to identify clinical predictors of depressive symptom remission and response 24 h and 7 days after racemic ketamine and esketamine infusions., Methods: A randomized, double-blind, active-controlled, non-inferiority trial using ketamine and esketamine in TRD. Individuals diagnosed with MDD according to Diagnostic and Statistical Manual of Mental Disorders version IV and fulfilling TRD criteria were recruited from March 2017 to June 2018. Participants received a single subanesthetic dose of ketamine (0.5 mg/kg) or esketamine (0.25 mg/kg) for 40 min. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) and symptom remission was defined as a MADRS score ≤7 and response defined as ≥50% reduction in depressive symptom severity, 24 h and 7 days after the infusion. Clinical variables were selected based on previous clinical trials. Stepwise backward logistic regression was used, considering a confidence level of 95%., Results: 61 subjects were included: 39 (63.9%) were females with a mean age of 47.2 ± 14.9. Higher number of therapeutic failures (Odds Ratio (OR) = 0.677; 95% confidence interval (CI): 0.47-0.97) and higher severity of illness (OR = 0.912; 95% CI: 0.83-0.99) were associated with fewer remissions of depressive symptoms 7 days after intervention, and with fewer response in 24 h (OR = 0.583; 95% CI: 0,40; 0,84 and OR = 0.909; 95% CI: 0,83; 0,99, respectively)., Conclusion: Number of treatment failures and severity of illness were predictors of fewer remissions and responses of depressive symptoms in this TRD population. Study of predictors of remission may contribute to better selection patients that may benefit from receiving ketamine., (© 2022 John Wiley & Sons Ltd.)
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- 2022
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19. Suicide attempt, impulsivity, and exposure to trauma in college students.
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Lira SB, Vieira F, Cavalcanti DE, Souza-Marques B, Netto LR, Correia-Melo FS, Leal GC, Pereira JL, Santos LL, Guedes GM, Teles CA, Cardoso TA, Miranda-Scippa Â, Kapczinski F, Lacerda ALT, Koenen KC, Turecki G, and Quarantini LC
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- Brazil epidemiology, Humans, Impulsive Behavior, Students, Suicidal Ideation, Stress Disorders, Post-Traumatic epidemiology, Suicide, Attempted
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Objectives: Past suicide attempt (SA) is one of the most important risk factors for suicide death. An ideation-to-action framework posits that impulsivity, potentially traumatic events, and mental disorders also play a role in increasing suicide risk. This study aimed to assess the association between trait impulsivity, lifetime exposure to trauma, and post-traumatic stress disorder (PTSD) with SA in a sample of Brazilian college students., Methods: A total of 2,137 participants filled self-reported questionnaires consisting of a sociodemographic and clinical questionnaire, Trauma History Questionnaire, Post-Traumatic Stress Disorder Checklist - Civilian version, and Barratt Impulsiveness Scale., Results: Our findings suggest that trait impulsivity may be interpreted as exerting a distal effect on SA, even in the presence of other variables - such as trauma history, psychological neglect, and PTSD - which also increase the odds of SA. High and medium levels of impulsivity, history of trauma, and PTSD increased the likelihood of SA., Conclusions: Intervention strategies to prevent SA may target trait impulsivity and exposure to traumatic experiences.
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- 2022
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20. Intranasal esketamine and the dawn of precision psychiatry.
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Watts D, Garcia FD, Lacerda ALT, Mari JJ, Quarantini LC, and Kapczinski F
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- Administration, Intranasal, Humans, Depressive Disorder, Treatment-Resistant drug therapy, Ketamine therapeutic use, Psychiatry
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- 2022
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21. Prevalence and Impact of Treatment-Resistant Depression in Latin America: a Prospective, Observational Study.
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Soares B, Kanevsky G, Teng CT, Pérez-Esparza R, Bonetto GG, Lacerda ALT, Uribe ES, Cordoba R, Lupo C, Samora AM, and Cabrera P
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- Depression, Female, Health Care Costs, Humans, Latin America epidemiology, Male, Middle Aged, Prevalence, Prospective Studies, Retrospective Studies, Depressive Disorder, Major drug therapy, Depressive Disorder, Major epidemiology
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Approximately one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD). The TRAL study will evaluate the prevalence and impact of TRD among patients with MDD in four Latin American countries. In this multicenter, prospective, observational study, patients with MDD were recruited from 33 reference sites in Mexico, Colombia, Brazil, and Argentina. Patients were assessed for TRD, defined as failure to respond to ≥ 2 antidepressant medications of adequate dose and duration. Demographics, previous/current treatments, depressive symptoms, functioning, healthcare resource utilization, and work impairment were also collected and evaluated using descriptive statistics, chi-square test, Fisher exact test, t-test for independent samples, or the Mann-Whitney nonparametric test, as appropriate. 1475 patients with MDD were included in the analysis (mean age, 45.6 years; 78% women); 89% were receiving relevant psychiatric treatment. 429 patients met criteria for TRD, and a numerically higher proportion of patients with TRD was present in public versus private sites of care (31% vs 27%). The mean Montgomery-Asberg Depression Rating Scale score was 25.0 among all MDD patients and was significantly higher for patients with TRD versus non-TRD (29.4 vs 23.3; P < 0.0001). Patients with TRD, versus those with non-TRD, were significantly more likely to be older, have a longer disease duration, have more comorbidities, be symptomatic, have a higher median number of psychiatric consultations, and report greater work impairment. Patients with TRD have a disproportionate burden of disease compared to those with non-TRD. Appropriate treatment for TRD is a substantial unmet need in Latin America. https://www.ClinicalTrials.gov identifier NCT03207282, 07/02/2017., (© 2021. The Author(s).)
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- 2021
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22. The probability of response after each subcutaneous injection of esketamine in treatment-resistant depression.
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Fava VAR, Sarin LM, Lucchese AC, Del Sant L, Magalhães E, Delfino RS, Tuena MA, Nakahira C, Jackowski AP, Abdo G, Surjan J, Steiglich M, Barbosa MG, Porto JAD, Lacerda ALT, and Cogo-Moreira H
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- Humans, Injections, Subcutaneous, Ketamine, Probability, Retrospective Studies, Antidepressive Agents therapeutic use, Depression drug therapy
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Introduction: The administration of multiple esketamine doses has shown efficacy for unipolar and bipolar treatment-resistant depression (TRD). Nevertheless, the probability of responding or not after each dose in the real-world remains unknown. This study aimed to estimate it throughout four doses of esketamine, administrated via subcutaneous (SC)., Material and Methods: We conducted a retrospective analysis of a case series of 70 patients with TRD who received treatment from the esketamine assistance program at Federal University of Sao Paulo, between April 2017 and December 2018. The SC injections were administrated weekly at a dose of 0.5-1.0mg/kg, in conjunction with patients' psychotropic drugs. Response was defined as a decrease of at least 50% in the Montgomery-Åsberg Depression Rating Scale between baseline and 24h after dose. We used hidden Markov modeling in order to estimate de probability of response after each esketamine injection., Results: The probability of a patient that was a "non-responder" to become a "responder" following a SC injection of esketamine was 17.30% and the probability that this patient remains a "non-responder" was 82.70%. The probability of a patient that was a "responder" to remain as a "responder" was 95%., Conclusions: Patients with TRD who had not responded after the first dose of esketamine, still had a chance of responding after the subsequent dose administrated via SC., (Copyright © 2021. Published by Elsevier España, S.L.U.)
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- 2021
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23. Neurocognitive aspects of ketamine and esketamine on subjects with treatment-resistant depression: A comparative, randomized and double-blind study.
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Araújo-de-Freitas L, Santos-Lima C, Mendonça-Filho E, Vieira F, França RJAF, Magnavita G, Cardoso TL, Correia-Melo FS, Leal GC, Jesus-Nunes AP, Souza-Marques B, Marback R, Teles M, Echegaray MV, Beanes G, Guerreiro-Costa LNF, Mello RP, Rabanea T, Lucchese AC, Abreu N, Lacerda ALT, and Quarantini LC
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- Depression, Double-Blind Method, Humans, Depressive Disorder, Treatment-Resistant drug therapy, Ketamine
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The objective of this study is to evaluate cognition in patients using either ketamine or esketamine to treat TRD. We also evaluate if both ketamine and esketamine as one group influence cognition in patients with TRD. Fifty-four patients with TRD were infused with either ketamine or esketamine and were assessed at three time points: baseline, 24 h, and 7 days after infusion. We applied neuropsychological tests to evaluate executive functions, processing speed, short term memory, and auditory-verbal episodic memory. There is no cognitive difference between ketamine and esketamine, with the exception of one variable. When considered as one group, ketamine and esketamine do not impair cognition; on the contrary, they improve some neuropsychological functions such as visuospatial short-term memory, executive functions, processing speed, and several measures related to episodic verbal memory. Ketamine and esketamine do not present differing cognitive effects when used in antidepressant doses to treat TRD. Furthermore, they rapidly improve many cognitive aspects of patients with TRD at 24 h after the infusion and maintain these effects for at least 7 days., (Copyright © 2021 Elsevier B.V. All rights reserved.)
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- 2021
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24. A Clinical Rationale for Assessing the Impact of Childhood Sexual Abuse on Adjunctive Subcutaneous Esketamine for Treatment-Resistant Depression.
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Magalhães EJM, Sarin LM, Del Sant LC, Lucchese AC, Nakahira C, Tuena MA, Puertas CB, Rodovalho Fava VA, Delfino RS, Surjan J, Steglich MS, Barbosa MG, Abdo G, Del Porto JA, Nemeroff CB, Cogo-Moreira H, Lacerda ALT, and Mello AF
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Background: A history of child sexual abuse (CSA) is related to higher suicide rates and poor treatment outcomes in depressed adult patients. Twenty years after the first study investigating the effects of ketamine/esketamine on depression and suicide, there is a lack of data on the CSA effects on this emerging treatment. Here, we assess the impact of CSA on adjunctive subcutaneous (SC) esketamine for treatment-resistant depression (TRD). Methods: A directed acyclic graphic (DAG) was designed to identify clinical confounders between CSA and esketamine predictors of response. The confounders were applied in a statistical model to predict depression symptom trajectory in a sample of 67 TRD outpatients. Results: The patient sample had a relatively high prevalence rate of CSA (35.82%). Positive family history of first-degree relatives with alcohol use disorder and sex were clinical mediators of the effects of esketamine in a CSA adult population. Overall, the presence of at least one CSA event was unrelated to esketamine symptom reduction. Conclusions: Unlike responses to conventional antidepressants and psychotherapy, CSA does not appear to predict poor response to esketamine., Competing Interests: EM reports non-financial support from Torrent Pharma and non-financial support from Hypera Pharma, outside of the submitted work. LS reports personal fees from Daiichi Sankyo Brasil, Lundbeck Brasil, Pfizer, and Janssen, and non-financial support from Takeda Brasil, Moksha8 Brasil, Torrent Pharma, outside of the submitted work. CN reports non-financial support from Eurofarma, Cristália, and Sanofi, outside of the submitted work. Dr. Oliveira reports personal fees from Janssen outside of the submitted work. CBN research is supported by the NIMH grant MH-117293 and the National Institute on Alcohol Abuse and Alcoholism grant AA-024933. CBN has served as a consultant for Acadia Pharmaceuticals, Axsome, Compass Pathways, EMA Wellness, Epiodyne, Gerson Lehrman Group, Intra-Cellular Therapies, Janssen Research and Development, Magnolia CNS, Magstim, Navitor Pharmaceuticals, Signant Health, Sophos, Sunovion Pharmaceuticals, Taisho Pharmaceutical, Takeda, TC MSO, and Xhale, he is a stockholder in AbbVie, Antares, BI Gen Holdings, Celgene, Corcept Therapeutics Pharmaceuticals Company, EMA Wellness, OPKO Health, Seattle Genetics, TC MSO, Trends in Pharma Development, and Xhale, he has served on scientific advisory boards for the American Foundation for Suicide Prevention, the Anxiety Disorders Association of America (ADAA), the Brain and Behavior Research Foundation, the Laureate Institute for Brain Research, Magnolia CNS, Signant Health, Skyland Trail, and Xhale, he has served on boards of directors for ADAA, Gratitude America, and Xhale Smart, he has income sources or equity of $10,000 or more from American Psychiatric Association Publishing, CME Outfitters, EMA Wellness, Intra-Cellular Therapies, Magstim, Signant Health, and Xhale, and he has patents on a method and devices for transdermal delivery of lithium (US 6,375,990B1), on a method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2), and on compounds, compositions, methods of synthesis, and methods of treatment (CRF receptor-binding ligand) (US 8,551,996B2). ALTL has received consulting fees from Janssen Pharmaceutical, Daiichi Sankyo Brasil, Cristalia Produtos Químicos e Farmacêuticos, Pfizer, Mantecorp Indústria Química e Farmacêutica, Libbs Farmacêutica, and Sanofi-Aventis over the last 24 months, and has received research fees from Janssen Pharmaceutical, Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, and Forum Pharmaceuticals, not related to the submitted manuscript. AM has received non-financial support from Lundbeck not related to the present research. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Magalhães, Sarin, Del Sant, Lucchese, Nakahira, Tuena, Puertas, Rodovalho Fava, Delfino, Surjan, Steglich, Barbosa, Abdo, Del Porto, Nemeroff, Cogo-Moreira, Lacerda and Mello.)
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- 2021
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25. Trait dissociation as a predictor of induced dissociation by ketamine or esketamine in treatment-resistant depression: Secondary analysis from a randomized controlled trial.
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Mello RP, Echegaray MVF, Jesus-Nunes AP, Leal GC, Magnavita GM, Vieira F, Caliman-Fontes AT, Telles M, Guerreiro-Costa LNF, Souza-Marques B, Bandeira ID, Santos-Lima C, Marback RF, Correia-Melo FS, Lacerda ALT, and Quarantini LC
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- Adult, Antidepressive Agents adverse effects, Depression, Humans, Depressive Disorder, Treatment-Resistant drug therapy, Ketamine adverse effects
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Dissociative symptoms are common, possibly severe, side effects associated with the use of ketamine and esketamine in depression. We investigated the relationship between trait dissociation and dissociation induced by ketamine and esketamine used as augmentation therapy in treatment-resistant depression (TRD). Adults with TRD were randomly assigned to receive a single intravenous infusion, with a duration of 40 min, of either esketamine 0.25 mg/kg or ketamine 0.5 mg/kg. We assessed trait dissociation with the Dissociative Experience Scale (DES) and, to evaluate induced dissociation, the Clinician-Administered Dissociative States Scale (CADSS) was used. Thirty-two subjects received esketamine and 29 received ketamine. The groups had similar median DES scores (p = 0.26). More than 30% of the patients in both groups had DES scores ≥30 points. The median CADSS score in the esketamine group was equivalent to that in the ketamine group (p = 0.40). Every 5 points increment in the DES was associated with a 10.9% (95% CI 4.5-17.8%) increase in the CADSS, in an exponential fashion when the two groups were pooled together. Subjects with high trait dissociation had a higher risk of induced dissociation state (relative risk [RR] 1.41, 95% CI 1.11-1.78) and very high induced dissociation (RR 3.05, 95% CI 1.14-8.15). Induced dissociation was not a serious adverse effect. The findings suggest that trait dissociation is a predictor of induced dissociation by Ketamine or Esketamine in TRD subjects. Screening for trait dissociation and counseling patients with high trait dissociation on the risks of dissociation by these drugs are recommended., (Copyright © 2021. Published by Elsevier Ltd.)
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- 2021
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26. Subcutaneous Ketamine in Depression: A Systematic Review.
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Cavenaghi VB, da Costa LP, Lacerda ALT, Hirata ES, Miguel EC, and Fraguas R
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Background: Ketamine has been shown to produce a rapid and robust antidepressant effect. Though numerous routes of administration have been studied, subcutaneous (SC) has proven to be a convenient and cost-effective route making its use particularly relevant in developing countries. Here we provide a systematic review covering the use of SC racemic ketamine and esketamine in depression, including its efficacy, safety and tolerability. Methods: A systematic literature search was carried out, from inception through March, 2021, using PubMed/MEDLINE, EMBASE and Web of Science, with no limits of language. After identifying 159 potentially relevant articles, 12 articles were selected after applying our inclusion/exclusion criteria. These comprised two randomized clinical trials, five case-reports and five retrospective studies. Given the small number of studies found and their heterogeneous nature, a meta-analysis was not considered appropriate. Here we provide a synthesis of these data including participant characteristics, dose range, efficacy, safety/ tolerability. Risk of bias was accessed using the Cochrane risk of bias tool. Results: SC Ketamine was administered to unipolar and bipolar patients a single or multiple doses, weekly or twice-weekly, a dose-titration approach was made in major studies, dose ranged from 0.1 to 0.5 mg/Kg of racemic ketamine and 0.5-1 mg/Kg of esketamine. Across all studies, SC ketamine showed a rapid and robust antidepressant effect, with response/ remission rates from 50 to 100% following both single or multiple doses, with transitory side effects. Conclusion: SC racemic ketamine and esketamine in depression is a promising strategy showing beneficial efficacy and tolerability. Future studies exploring the SC route, its cost-effectiveness, and a direct comparison with IV and intranasal (IN) protocols are warranted. Systematic Review Registration: CRD42019137434., Competing Interests: AL has received consulting fees from Hoffmann–La Roche, Genentech, Janssen Pharmaceutical, Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Pfizer, Mantecorp Indústria Química e Farmacêutica, Libbs Farmacêutica, FQM Farma, and Sanofi-Aventis over the last 24 months and has received research fees from Janssen Pharmaceutical, Eli Lilly, Novartis, Biophytis, Celltrion, Azidus, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, FQM Farma, and Forum Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Cavenaghi, da Costa, Lacerda, Hirata, Miguel and Fraguas.)
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- 2021
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27. Treatment-resistant schizophrenia - A RCT on the effectiveness of repeated-dose sodium nitroprusside.
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Adelino MPM, Nunes MV, Nunes MFQ, Costa ER Jr, Ajub E, Mitrovitch MPB, Ushirohira JM, Quarantini LC, Hallak JCE, and Lacerda ALT
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- Adolescent, Adult, Double-Blind Method, Humans, Middle Aged, Nitroprusside, Psychiatric Status Rating Scales, Schizophrenic Psychology, Treatment Outcome, Young Adult, Antipsychotic Agents therapeutic use, Schizophrenia drug therapy
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Objectives: Sodium nitroprusside (SNP) has shown efficacy in schizophrenia in early stages of the disease in a previous study, but in more recent studies it has not shown efficacy in patients with longer disease duration. In present study, we evaluated the efficacy of repeated-dose SNP in treatment-resistant schizophrenia., Methods: This was a double-blind, randomized, placebo-controlled trial. Twenty DSM-IV schizophrenia subjects, aged 18-60 years, with a history of nonresponse to ≥2 trials of antipsychotics of adequate dose and duration (≥6 weeks) were enrolled. Participants received SNP or placebo 4-hour infusions at 0.5 μg/kg/min. A total of 4 infusions and 4 follow-up evaluations, with an interval of 2 weeks, were performed. Severity of symptoms were assessed by using Positive and Negative Syndrome Scale (PANSS), Brief Psychiatric Rating Scale (BPRS-18) and Clinical Global Impression (CGI) scales., Results: SNP and placebo groups did not differ at baseline or in change from baseline for PANSS-total (F = 0.525; p = 0.841), PANSS-positive (F = 0.32; p = 0.958), PANSS-negative (F = 1.05; p = 0.483), BPRS (F = 0.615; p = 0.734), or CGI-S (F = 1.11; p = 0.416) scores. SNP was well tolerated and showed a good safety profile., Conclusion: Although preliminary, the present findings suggest that SNP is not efficacious in TRS, reinforcing previous studies that have not demonstrated symptom improvement in chronic schizophrenia subjects. At this time, it is conceivable to speculate that efficacy of SNP might be restricted to early stages of disease., (Copyright © 2021. Published by Elsevier B.V.)
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- 2021
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28. Mononitrate Isosorbide as an Adjunctive Therapy in Schizophrenia: A Randomized Controlled Crossover Trial.
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Guimarães TM, Guimarães MRC, Oliveira ÍAF, Leoni RF, Santos AC, Dursun SM, Crippa JAS, Bressan RA, Machado-de-Sousa JP, Lacerda ALT, and Hallak JEC
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- Adult, Cross-Over Studies, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Isosorbide Dinitrate administration & dosage, Male, Psychiatric Status Rating Scales, Schizophrenia physiopathology, Treatment Outcome, Vasodilator Agents administration & dosage, Antipsychotic Agents administration & dosage, Isosorbide Dinitrate analogs & derivatives, Schizophrenia drug therapy
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Background: Schizophrenia is a complex disabling mental disorder, and many patients present poor response to available treatments. Accumulating evidence about the role of the glutamate/nitric oxide pathway in mediating the positive and negative symptoms of schizophrenia suggests potential benefits of drugs that modulate this system. The aim of this study was to test the efficacy of isosorbide mononitrate (ISMN) as an adjunctive therapy for symptomatic outpatients with schizophrenia., Methods: This was a 2-month randomized, double-blind, placebo-controlled trial with 24 schizophrenia patients. Participants were treated with ISMN 50 mg for 1 month and placebo for another month in a crossover design. The Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Scale, Global Assessment of Functioning, and MATRICS Cognitive Consensual Battery were used for symptom assessment and arterial spin labeling was used to assess brain activation patterns., Results: We found significant differences in the total, general, and positive subscales of the PANSS, Global Assessment of Functioning scores, and Clinical Global Impression scores during treatment with ISMN relative to placebo. No treatment effects were found comparing scores in the MATRICS Cognitive Consensual Battery and the negative subscale of the PANSS between the active and placebo conditions. A post hoc analysis of neuroimaging data showed reduced activity in the thalamus in subgroup of patients with severe psychopathology., Conclusions: Schizophrenia patients with persistent symptoms showed significant improvement after 4 weeks of treatment with ISMN 50 mg/d compared with placebo. Isosorbide mononitrate added beneficial effects to antipsychotic treatment in terms of positive symptoms and functioning., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2021
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29. Intravenous arketamine for treatment-resistant depression: open-label pilot study.
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Leal GC, Bandeira ID, Correia-Melo FS, Telles M, Mello RP, Vieira F, Lima CS, Jesus-Nunes AP, Guerreiro-Costa LNF, Marback RF, Caliman-Fontes AT, Marques BLS, Bezerra MLO, Dias-Neto AL, Silva SS, Sampaio AS, Sanacora G, Turecki G, Loo C, Lacerda ALT, and Quarantini LC
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- Adult, Aged, Antidepressive Agents administration & dosage, Antidepressive Agents adverse effects, Female, Humans, Infusions, Intravenous, Ketamine administration & dosage, Ketamine adverse effects, Middle Aged, Pilot Projects, Psychiatric Status Rating Scales, Remission Induction, Severity of Illness Index, Antidepressive Agents pharmacology, Depressive Disorder, Major drug therapy, Depressive Disorder, Treatment-Resistant drug therapy, Ketamine pharmacology, Outcome Assessment, Health Care
- Abstract
We aimed to analyze the efficacy and safety of arketamine, the R(-)-enantiomer of ketamine, for treatment-resistant depression (TRD) in humans. Open-label pilot trial, seven subjects with TRD received a single intravenous infusion of arketamine (0.5 mg/kg); primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) 24 h after. Mean MADRS dropped from 30.7 before infusion to 10.4 after one day, a mean difference of 20.3 points [CI 95% 13.6-27.0; p < 0.001]; dissociation was nearly absent. Arketamine might produce fast-onset and sustained antidepressant effects in humans with favorable safety profile, like previously reported with animals; further controlled-trials are needed.
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- 2021
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30. Esketamine for Postpartum Suicidality.
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Machado C, Lacerda ALT, Bressan RA, and Noto C
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- Female, Humans, Postpartum Period, Depressive Disorder, Treatment-Resistant, Ketamine, Suicide
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- 2021
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31. Psychometric properties the of Brazilian Portuguese version of Snaith-Hamilton Pleasure Scale (SHAPS).
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Jesus-Nunes AP, Coroa JPBB, Argolo FC, Moreira TM, Morais-de-Jesus M, Marback RF, Correia-Melo FS, Lacerda ALT, and Quarantini LC
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- Brazil, Humans, Psychiatric Status Rating Scales, Psychometrics, Reproducibility of Results, Depressive Disorder, Major, Pleasure
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Introduction: Anhedonia is defined as the reduced ability to feel pleasure and is a core symptom of various psychiatric disorders such as depression and schizophrenia. The Snaith-Hamilton Pleasure Scale (SHAPS) was developed to assess the presence of anhedonia. The objective of this study was to assess the psychometric properties of the Brazilian Portuguese version of the SHAPS., Methods: In this study, the SHAPS (14 items) was translated into Brazilian Portuguese and validated using data obtained from 228 subjects within a clinical sample. Psychometric properties were assessed using item response theory (logistic models) and classical test theory (Cronbach's alpha). We checked for external validity using a non-parametric correlation with an independent scale: Hospital Anxiety and Depression Scale - Depression subscale (HAD-D)., Results: The SHAPS presented good internal consistency, with a Cronbach's α coefficient of 0.759 and adequacy to an IRT 1 parameter logistic (Rasch) model. The SHAPS presented significant correlation with the external measure HAD-D, with Spearman's ρ = 0.249 (S = 1368914; p < 0.001)., Conclusion: These results suggest that the Brazilian Portuguese version of the SHAPS is a reliable and valid instrument to assess hedonic tone.
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- 2021
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32. Comparative effectiveness of esketamine in the treatment of anhedonia in bipolar and unipolar depression.
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Delfino RS, Del-Porto JA, Surjan J, Magalhães E, Sant LCD, Lucchese AC, Tuena MA, Nakahira C, Fava VAR, Steglich MS, Barbosa MG, Sarin LM, and Lacerda ALT
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- Anhedonia, Antidepressive Agents therapeutic use, Humans, Bipolar Disorder drug therapy, Ketamine therapeutic use
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Background: Anhedonia is a symptom associated with poorer outcomes in depression treatment, including resistance to treatment, higher functional impact and suicidality. Few drugs are known to adequately treat anhedonia in both unipolar and bipolar depression. The NMDA antagonist ketamine has been demonstrated to be effective in rapidly ameliorating anhedonia in depressive episodes. The main aim of present study is to evaluate the anti-anhedonic effect of esketamine, the S-enantiomer of ketamine recently approved for treatment-resistant depression, in unipolar and bipolar depression., Methods: 70 patients with unipolar or bipolar depression were treated with 6 weekly subcutaneous esketamine infusions (0.5-1mg/kg). Anhedonia was measured through MADRS item 8 before and 24h after each infusion., Results: A significant reduction in anhedonia severity was observed (p<0.0001) after 6 infusions. The effect was statistically significant 24h after the first infusion (p<0.001) in both unipolar and bipolar groups and increased with repeated infusions. Anti-anhedonic effect of esketamine did not differ between groups., Limitations: This is an open-label, real-world study. Lack of blinding and of a placebo arm may limit the interpretation of findings., Conclusion: Although preliminary, present findings suggest that repeated subcutaneous esketamine infusions are effective for the treatment of anhedonia in both unipolar and bipolar depressed patients. These results need to be confirmed through replication in larger double-blinded controlled trials., (Copyright © 2020. Published by Elsevier B.V.)
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- 2021
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33. Ketamine and Esketamine augmentation for suicidal ideation: A randomized, double-blinded clinical trial.
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Vieira F, Correia-Melo FS, Santos-Lima C, Souza-Marques B, Leal GC, Jesus-Nunes AP, Mello RP, Caliman-Fontes AT, Bandeira ID, Marback RF, Telles M, Argolo FC, Lins-Silva DH, Echegaray MVF, Beanes G, Araújo-de-Freitas L, Silva SS, Cardoso TA, Kapczinski F, Turecki G, Lacerda ALT, and Quarantini LC
- Subjects
- Antidepressive Agents therapeutic use, Humans, Suicidal Ideation, Depressive Disorder, Treatment-Resistant, Ketamine
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- 2021
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34. Esketamine/ketamine for treatment-resistant depression.
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Lacerda ALT
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- Antidepressive Agents therapeutic use, Depression, Humans, Depressive Disorder, Treatment-Resistant drug therapy, Ketamine
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- 2020
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35. The probability of response after each subcutaneous injection of esketamine in treatment-resistant depression.
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Fava VAR, Sarin LM, Lucchese AC, Del Sant L, Magalhães E, Delfino RS, Tuena MA, Nakahira C, Jackowski AP, Abdo G, Surjan J, Steiglich M, Barbosa MG, Porto JAD, Lacerda ALT, and Cogo-Moreira H
- Abstract
Introduction: The administration of multiple esketamine doses has shown efficacy for unipolar and bipolar treatment-resistant depression (TRD). Nevertheless, the probability of responding or not after each dose in the real-world remains unknown. This study aimed to estimate it throughout four doses of esketamine, administrated via subcutaneous (SC)., Material and Methods: We conducted a retrospective analysis of a case series of 70 patients with TRD who received treatment from the esketamine assistance program at Federal University of Sao Paulo, between April 2017 and December 2018. The SC injections were administrated weekly at a dose of 0.5-1.0mg/kg, in conjunction with patients' psychotropic drugs. Response was defined as a decrease of at least 50% in the Montgomery-Åsberg Depression Rating Scale between baseline and 24h after dose. We used hidden Markov modeling in order to estimate de probability of response after each esketamine injection., Results: The probability of a patient that was a "non-responder" to become a "responder" following a SC injection of esketamine was 17.30% and the probability that this patient remains a "non-responder" was 82.70%. The probability of a patient that was a "responder" to remain as a "responder" was 95%., Conclusions: Patients with TRD who had not responded after the first dose of esketamine, still had a chance of responding after the subsequent dose administrated via SC., (Copyright © 2020. Publicado por Elsevier España, S.L.U.)
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- 2020
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36. Effects of subcutaneous esketamine on blood pressure and heart rate in treatment-resistant depression.
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Del Sant LC, Sarin LM, Magalhães EJM, Lucchese AC, Tuena MA, Nakahira C, Fava VAR, Delfino R, Surjan J, Steiglich MS, Barbosa M, Abdo G, Cohrs FM, Liberatori A, Del Porto JA, Lacerda ALT, and de Jesus Mari J
- Subjects
- Adult, Antidepressive Agents adverse effects, Cohort Studies, Depressive Disorder, Treatment-Resistant drug therapy, Dose-Response Relationship, Drug, Drug Monitoring methods, Female, Heart Rate drug effects, Humans, Hypertension chemically induced, Hypertension epidemiology, Injections, Subcutaneous, Ketamine adverse effects, Male, Middle Aged, Retrospective Studies, Antidepressive Agents administration & dosage, Blood Pressure drug effects, Depressive Disorder, Treatment-Resistant diet therapy, Ketamine administration & dosage
- Abstract
Introduction and Objectives: The impact of multiple subcutaneous (s.c.) esketamine injections on the blood pressure (BP) and heart rate (HR) of patients with unipolar and bipolar treatment-resistant depression (TRD) is poorly understood. This study aimed to assess the cardiovascular safety of multiple s.c. doses of esketamine in patients with TRD., Methods: Seventy TRD patients received 394 weekly s.c. esketamine injections in conjunction with oral antidepressant therapy for up to six weeks. Weekly esketamine doses were 0.5, 0.75 or 1.0 mg/kg according to each patient's response to treatment. Participants were monitored before each treatment and every 15 minutes thereafter for 120 minutes. We assessed systolic blood pressure (SBP), diastolic blood pressure (DBP), and HR measurements for the entire treatment course., Results: BP increased after the first s.c. esketamine injection, reaching maximum mean SBP/DBP levels of 4.87/5.54 mmHg within 30-45 minutes. At the end of monitoring, 120 minutes post dose, vital signs returned to pretreatment levels. We did not detect significant differences in BP between doses of 0.5, 0.75, and 1 mg/kg esketamine. Mean HR did not differ significantly between doses or before and after s.c. esketamine injection., Conclusions: The BP changes observed with repeated s.c. esketamine injections were mild and well tolerated for doses up to 1 mg/kg. The s.c. route is a simple and safe method of esketamine administration, even for patients with clinical comorbidities, including obesity, hypertension, diabetes, and dyslipidemia. However, 14/70 patients experienced treatment-emergent transient hypertension (SBP >180 mmHg and/or a DBP >110 mmHg). Therefore, we strongly recommend monitoring BP for 90 minutes after esketamine dosing. Since s.c. esketamine is cheap, requires less frequent dosing (once a week), and is a simpler procedure compared to intravenous infusions, it might have an impact on public health.
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- 2020
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37. Efficacy and safety of adjunctive therapy using esketamine or racemic ketamine for adult treatment-resistant depression: A randomized, double-blind, non-inferiority study.
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Correia-Melo FS, Leal GC, Vieira F, Jesus-Nunes AP, Mello RP, Magnavita G, Caliman-Fontes AT, Echegaray MVF, Bandeira ID, Silva SS, Cavalcanti DE, Araújo-de-Freitas L, Sarin LM, Tuena MA, Nakahira C, Sampaio AS, Del-Porto JA, Turecki G, Loo C, Lacerda ALT, and Quarantini LC
- Subjects
- Adult, Antidepressive Agents adverse effects, Depression, Double-Blind Method, Humans, Japan, Treatment Outcome, Depressive Disorder, Treatment-Resistant drug therapy, Ketamine adverse effects
- Abstract
Background: Ketamine and its enantiomers have recently been highlighted as one of the most effective therapeutic options in refractory depression. However, racemic ketamine and esketamine have not been directly compared. The aim of this study is to assess the efficacy and safety of esketamine compared to ketamine in patients with treatment-resistant depression (TRD)., Methods: This is a randomized, double-blind, active-controlled, bicentre, non-inferiority clinical trial, with two parallel groups. Participants were randomly assigned to a 40-min single intravenous infusion of ketamine 0.5 mg/kg or esketamine 0.25 mg/kg. The primary outcome was the difference in remission rates for depression 24 h following intervention using the Montgomery-Åsberg Depression Rating Scale (MADRS), with a non-inferiority margin of 20%., Results: 63 subjects were included and randomly assigned (29 to receive ketamine and 34 to receive esketamine). At 24 h, 24.1% of participants in the ketamine group and 29.4% of participants in the esketamine group showed remission, with a difference of 5.3% (95% CILB -13.6%), confirming non-inferiority. MADRS scores improved from 33 (SD 9.3) to 16.2 (SD 10.7) in the ketamine group and from 33 (SD 5.3) to 17.5 (SD 12.2) in the esketamine one, with a difference of -5.27% (95% CILB, -13.6). Both groups presented similar mild side effects., Conclusions: Esketamine was non-inferior to ketamine for TRD 24 h following infusion. Both treatments were effective, safe, and well tolerated., Trial Registration: Registered in Japan Primary Registries Network: UMIN000032355., Competing Interests: Declaration of Competing Interest LCQ reports consulting fees from Allergan, Abbot, Janssen Pharmaceutical and Lundbeck and research fees from Janssen Pharmaceutical. ALTL reports grants and personal fees from Janssen Pharmaceutical, personal fees from Daiichi Sankyo, Cristalia Produtos Químicos e Farmacêuticos, Libbs, Pfizer, Myralis Farma, Aché Laboratórios, Hypera Pharmaand Sanofi-Aventis, grants from Eli Lilly, H. Lundbeck A/S, Servier Laboratories, Hoffman-La Roche, Forum Pharmaceuticalsand from public programs: CNPq and FAPESP; LMS received personal fees from Daiichi Sankyo Brasil, Lundbeck Brasil, Moksha8 Brasil, Takeda Brasil, Pfizer, Sanofi Aventis, and Torrent Pharma. The other authors report no conflicts of interest., (Copyright © 2019 Elsevier B.V. All rights reserved.)
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- 2020
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38. Efficacy and Safety of Transcranial Direct Current Stimulation for Treating Negative Symptoms in Schizophrenia: A Randomized Clinical Trial.
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Valiengo LDCL, Goerigk S, Gordon PC, Padberg F, Serpa MH, Koebe S, Santos LAD, Lovera RAM, Carvalho JB, van de Bilt M, Lacerda ALT, Elkis H, Gattaz WF, and Brunoni AR
- Subjects
- Adult, Antipsychotic Agents therapeutic use, Combined Modality Therapy, Double-Blind Method, Humans, Male, Psychiatric Status Rating Scales, Schizophrenic Psychology, Treatment Outcome, Schizophrenia therapy, Transcranial Direct Current Stimulation adverse effects, Transcranial Direct Current Stimulation methods
- Abstract
Importance: Negative symptoms represent a substantial burden in schizophrenia. Although preliminary studies have suggested that transcranial direct current stimulation (tDCS) is effective for some clusters of symptoms, the clinical benefits for negative symptoms are unclear., Objective: To determine the efficacy and safety of tDCS vs sham as an add-on treatment for patients with schizophrenia and predominant negative symptoms., Design, Setting, and Participants: The double-blind Schizophrenia Treatment With Electric Transcranial Stimulation (STARTS) randomized clinical trial was conducted from September 2014 to March 2018 in 2 outpatient clinics in the state of São Paulo, Brazil. Patients with schizophrenia with stable negative and positive symptoms and a minimum score of 20 points in the negative symptoms subscale of the Positive and Negative Syndrome Scale (PANSS) were included., Interventions: Ten sessions of tDCS performed twice a day for 5 days or a sham procedure. The anode and the cathode were positioned over the left prefrontal cortex and the left temporoparietal junction, respectively., Main Outcomes and Measures: Change in the PANSS negative symptoms subscale score at week 6 was the primary outcome. Patients were followed-up for an additional 6 weeks., Results: Of the 100 included patients, 20 (20.0%) were female, and the mean (SD) age was 35.3 (9.3) years. A total of 95 patients (95.0%) finished the trial. In the intention-to-treat analysis, patients receiving active tDCS showed a significantly greater improvement in PANSS score compared with those receiving the sham procedure (difference, 2.65; 95% CI, 1.51-3.79; number needed to treat, 3.18; 95% CI, 2.12-6.99; P < .001). Response rates for negative symptoms (20% improvement or greater) were also higher in the active group (20 of 50 [40%]) vs the sham group (2 of 50 [4%]) (P < .001). These effects persisted at follow-up. Transcranial direct current stimulation was well tolerated, and adverse effects did not differ between groups, except for burning sensation over the scalp in the active group (43.8%) vs the sham group (14.3%) (P = .003)., Conclusions and Relevance: Transcranial direct current stimulation was effective and safe in ameliorating negative symptoms in patients with schizophrenia., Trial Registration: ClinicalTrials.gov identifier: NCT02535676.
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- 2020
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39. Evaluation of the efficacy of transcranial direct current stimulation in the treatment of cognitive symptomatology in the early stages of psychosis: study protocol for a double-blind randomized controlled trial.
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Rabanea-Souza T, Cirigola SMC, Noto C, Gomes JS, Azevedo CC, Gadelha A, Cordeiro Q, Dias ÁM, and Lacerda ALT
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- Adolescent, Adult, Brazil, Cognition Disorders diagnosis, Cognition Disorders physiopathology, Cognition Disorders psychology, Double-Blind Method, Female, Humans, Male, Middle Aged, Parietal Lobe physiopathology, Prefrontal Cortex physiopathology, Randomized Controlled Trials as Topic, Schizophrenia diagnosis, Schizophrenia physiopathology, Temporal Lobe physiopathology, Time Factors, Treatment Outcome, Young Adult, Cerebral Cortex physiopathology, Cognition, Cognition Disorders therapy, Schizophrenia therapy, Schizophrenic Psychology, Transcranial Direct Current Stimulation adverse effects
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Background: Cognitive deficits are core symptoms of schizophrenia that occur from the early stages of the disorder. There is reliable evidence that cognitive deficits are associated with outcomes in schizophrenia; thus, early treatment could be particularly important. Studies with different neuromodulation techniques involving subjects with schizophrenia suggest that application of transcranial direct current stimulation (tDCS) with inhibitory stimulation over the left temporo-parietal cortex and excitatory stimulation over the left dorsolateral prefrontal cortex could ameliorate positive, negative, and cognitive symptoms. The aim of the present study protocol is to evaluate the efficacy of tDCS in the treatment of cognitive symptomatology in the early stages of psychosis., Methods/design: Seventy patients in the early stages of psychosis will be randomly allocated to receive 20 min of active 2-mA tDCS or sham stimulation once a day for 10 consecutive weekdays. The anode will be placed over the left dorsolateral prefrontal cortex and the cathode over the left temporo-parietal cortex. Neuropsychological and psychiatric assessments will be performed at baseline and at 1 and 3 months following the end of the intervention (sustained effect)., Discussion: The development and utilization of potentially effective neuroenhancement tools such as the non-invasive brain stimulation technique tDCS for the treatment and rehabilitation of cognitive impairment in the early stages of schizophrenia may contribute to improving outcomes of the disorder and eventually provide a further understanding of the nature of the complex and dynamic neural processes underlying those abnormalities., Trial Registration: ClinicalTrials.gov, NCT03071484 . Registered on 7 March 2017.
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- 2019
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40. Transcranial direct current stimulation (tDCS) in elderly with mild cognitive impairment: A pilot study.
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Gomes MA, Akiba HT, Gomes JS, Trevizol AP, de Lacerda ALT, and Dias ÁM
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Transcranial direct current stimulation (tDCS) is a non-invasive, painless and easy-to use-technology. It can be used in depression, schizophrenia and other neurological disorders. There are no studies about longer usage protocols regarding the ideal duration and weekly frequency of tDCS., Objective: to study the use of tDCS twice a week for longer periods to improve memory in elderly with MCI., Methods: a randomized double-blind controlled trial of anodal tDCS on cognition of 58 elderly aged over 60 years was conducted. A current of 2.0 mA was applied for 30 minutes for 10 sessions, twice a week. The anode was placed over the left dorsolateral prefrontal cortex (LDLFC). Subjects were evaluated before and after 10 sessions by the following tests: CAMCOG, Mini-Mental State Examination (MMSE), Trail Making, Semantic Verbal Fluency (Animals), Boston naming, Clock Drawing Test, Word list memory (WLMT), Direct and Indirect Digit Order (WAIS-III and WMS-III) and N-back., Results: After 10 sessions of tDCS, significant group-time interactions were found for the CAMCOG - executive functioning (χ
2 = 3.961, p = 0.047), CAMCOG - verbal fluency (χ2 = 3.869, p = 0.049), CAMCOG - Memory recall (χ2 = 9.749, p = 0.004), and WMLT - recall (χ2 = 7.254, p = 0.007). A decline in performance on the CAMCOG - constructional praxis (χ2 = 4.371, p = 0.037) was found in the tDCS group after intervention. No significant differences were observed between the tDCS and Sham groups for any other tasks., Conclusion: tDCS at 2 mA for 30 min twice a week over 5 consecutive weeks proved superior to placebo (Sham) for improving memory recall, verbal fluency and executive functioning in elderly with MCI., Competing Interests: Disclosure: The authors report no conflicts of interest.- Published
- 2019
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41. Insights into the Effects of Crack Abuse on the Human Metabolome Using a NMR Approach.
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Costa TBBC, Lacerda ALT, Mas CD, Brietzke E, Pontes JGM, Marins LAN, Martins LG, Nunes MV, Pedrini M, Carvalho MSC, Mitrovitch MP, Hayashi MAF, Saldanha NL, Poppi RJ, and Tasic L
- Subjects
- Blood Specimen Collection, Carnitine blood, Case-Control Studies, Histidine blood, Humans, Lactic Acid blood, Tyrosine blood, Cocaine-Related Disorders, Crack Cocaine pharmacology, Magnetic Resonance Spectroscopy methods, Metabolome drug effects
- Abstract
Approximately 255 million people consume illicit drugs every year, among which 18 million use cocaine. A portion of this drug is represented by crack, but it is difficult to estimate the number of users since most are marginalized. However, there are no recognized efficacious pharmacotherapies for crack-cocaine dependence. Inflammation and infection in cocaine users may be due to behavior adopted in conjunction with drug-related changes in the brain. To understand the metabolic changes associated with the drug abuse disorder and identify biomarkers, we performed a
1 H NMR-based metabonomic analysis of 44 crack users' and 44 healthy volunteers' blood serum. The LDA model achieved 98% of accuracy. From the water suppressed1 H NMR spectra analyses, it was observed that the relative concentration of lactate was higher in the crack group, while long chain fatty acid acylated carnitines were decreased, which was associated with their nutritional behavior. Analyses of the aromatic region of CPMG1 H NMR spectra demonstrated histidine and tyrosine levels increased in the blood serum of crack users. The reduction of carnitine and acylcarnitines and the accumulation of histidine in the serum of the crack users suggest that histamine biosynthesis is compromised. The tyrosine level points to altered dopamine concentration.- Published
- 2019
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42. Efficacy of esketamine in the treatment of negative symptoms in schizophrenia - A case series.
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Nunes MV, Adelino MPM, Ajub E, Quarantini LC, and Lacerda ALT
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- Adult, Excitatory Amino Acid Antagonists administration & dosage, Female, Humans, Ketamine administration & dosage, Male, Middle Aged, Treatment Outcome, Young Adult, Excitatory Amino Acid Antagonists pharmacology, Ketamine pharmacology, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Schizophrenia drug therapy, Schizophrenia physiopathology
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- 2018
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43. Comparative study of esketamine and racemic ketamine in treatment-resistant depression: Protocol for a non-inferiority clinical trial.
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Correia-Melo FS, Leal GC, Carvalho MS, Jesus-Nunes AP, Ferreira CBN, Vieira F, Magnavita G, Vale LAS, Mello RP, Nakahira C, Argolo FC, Cardoso T, Souza CDS, Fontes ATC, Ferreira MB, Araújo-de-Freitas L, Tuena MA, Echegaray MVF, Cavalcanti DE, Lucchese AC, Bandeira ID, Telles M, Lima CS, Sampaio AS, Silva SS, Marback RF, Del-Porto JA, Abreu JN, Sarin LM, Paixão CS, Carvalho LP, Machado PRL, Turecki G, Lacerda ALT, and Quarantini LC
- Subjects
- Anesthetics, Dissociative pharmacology, Anesthetics, Dissociative therapeutic use, Brazil epidemiology, Depression epidemiology, Depression psychology, Depressive Disorder, Treatment-Resistant epidemiology, Depressive Disorder, Treatment-Resistant psychology, Female, Humans, Infusions, Intravenous, Ketamine administration & dosage, Ketamine therapeutic use, Male, Prospective Studies, Treatment Outcome, Depression drug therapy, Depressive Disorder, Treatment-Resistant drug therapy, Ketamine pharmacology
- Abstract
Introduction: The use of ketamine as an option in the treatment of depressive disorder is growing rapidly, supported by numerous clinical trials attesting its efficacy and safety. Esketamine, the S (+) enantiomer of ketamine, is the most widely used form in the anesthetic environment in some countries, and new studies have shown that it may also be effective in depression and with better tolerability. However, no study so far has directly compared esketamine with racemic ketamine. Here we propose a protocol of a clinical trial to evaluate esketamine as a noninferior medication when compared to ketamine in the treatment of patients with treatment-resistant depression., Methods/design: This study protocol is for a randomized, controlled, double-blind noninferiority clinical trial. Subjects will be 18 years or older, with major depression characterized as treatment-resistant. Participants will receive a single infusion of either esketamine (0.25 mg/kg) or ketamine (0.5 mg/kg) over 40 minutes. The primary outcome will be the difference in remission rates between the 2 treatment arms at 24 and 72 hours after drug infusion. Secondary outcomes will include other timepoints, measurements of cognition, dissociation, and blood biomarkers., Discussion: A head-to-head study is the best way to evaluate whether the esketamine is in fact comparable to the racemic ketamine in terms of both efficacy and safety, and, if positive, it would be an initial step to increase the access to that type of treatment worldwide., Ethics and Dissemination: The study was approved by the local Institutional Review Board (University Hospital Professor Edgard Santos-Federal University of Bahia-Number: 46657415.0.0000.0049). Subjects will only participate after voluntarily agreeing and signing the Informed Consent Form. The study findings will be published in peer-reviewed journals and presented at national and international conferences., Trial Registration: This trial has been registered in the Japan Primary Registries Network (JPRN): UMIN000032355, which is affiliated with the World Health Organization.
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- 2018
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44. Sodium nitroprusside is effective in preventing and/or reversing the development of schizophrenia-related behaviors in an animal model: The SHR strain.
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Diana MC, Peres FF, Justi V, Bressan RA, Lacerda ALT, Crippa JA, Hallak JEC, and Abilio VC
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- Age Factors, Animals, Body Weight drug effects, Conditioning, Psychological drug effects, Disease Models, Animal, Dose-Response Relationship, Drug, Fear drug effects, Interpersonal Relations, Locomotion drug effects, Male, Rats, Rats, Inbred SHR, Rats, Wistar, Mental Disorders etiology, Mental Disorders prevention & control, Nitric Oxide Donors therapeutic use, Nitroprusside therapeutic use, Schizophrenia complications, Schizophrenic Psychology
- Abstract
Aims: The treatment of schizophrenia with antipsychotics is still unsatisfactory. Therefore, the search for new treatments and prevention is crucial, and animal models are fundamental tools for this objective. Preclinical and clinical data evidence the antipsychotic profile of sodium nitroprusside (SNP), a nitric oxide (NO) donor. We aimed to investigate SNP in treating and/or preventing the schizophrenia-related behaviors presented by the spontaneously hypertensive rats (SHR) strain., Methods: Wistar rats (WR) and SHRs were submitted to two schemes of treatment: (i) a single injection of SNP or vehicle in adulthood; (ii) a long-term early treatment from 30 to 60 postnatal day with SNP or vehicle. The following behaviors were evaluated 24 hours after the acute treatment or 30 days after the long-term treatment: locomotion, social interaction, and contextual fear conditioning., Results: Spontaneously hypertensive rats presented hyperlocomotion, decreased social interaction, and impaired contextual fear conditioning. Single injection of SNP decreased social interaction in both strains and induced a deficit in contextual fear conditioning in WR. Oppositely, early treatment with SNP prevented the behavioral abnormalities in adult SHRs without promoting any effects in WR., Conclusion: Our preclinical data point to SNP as a preventive and safe strategy with a broad range of effectiveness to the positive, negative, and cognitive symptoms of schizophrenia., (© 2018 John Wiley & Sons Ltd.)
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- 2018
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45. Non-invasive brain stimulation for negative symptoms in schizophrenia: An updated systematic review and meta-analysis.
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Osoegawa C, Gomes JS, Grigolon RB, Brietzke E, Gadelha A, Lacerda ALT, Dias ÁM, Cordeiro Q, Laranjeira R, de Jesus D, Daskalakis ZJ, Brunelin J, Cordes J, and Trevizol AP
- Subjects
- Humans, Outcome Assessment, Health Care statistics & numerical data, Schizophrenia therapy, Transcranial Direct Current Stimulation statistics & numerical data, Transcranial Magnetic Stimulation statistics & numerical data
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Background: Schizophrenia is a mental disorder with significant socioeconomic burden. Although current pharmacological treatments are effective for treating positive symptoms, medications have little-to-no effect in the treatment of negative symptoms., Objective: To assess the efficacy of non-invasive brain stimulation (NIBS) for negative symptoms in schizophrenia in randomized clinical trials (RCTs)., Methods: A systematic review in Medline and Cochrane Library databases was performed up to May 31, 2017. The primary outcome was Hedges' g for continuous scores in a random-effects model. Heterogeneity was evaluated with the I
2 and χ2 tests. Publication bias was assessed using Begg's funnel plot., Results: 31 RCTs (n = 1272) were included, most with small-to-modest sample sizes. Both repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) were superior to sham (Hedges' g = 0.19; 95% CI 0.07-0.32; and 0.5; 0.02-0.97, respectively). Only one study evaluated the use of transcutaneous auricular vagus nerve stimulation (taVNS). The funnel plot and Eggers test showed that the risk of publication bias was low. In relation to heterogeneity, we found an I2 of 0% (p = 0.749) and 51.3% (0.055) for rTMS and tDCS, respectively., Conclusion: Both rTMS and tDCS were superior to sham stimulation for ameliorating negative symptoms in schizophrenia. We found no considerable heterogeneity or publication bias in our analysis, corroborating the strength of our findings. Not enough studies on other NIBS techniques, such as taVNS, were found for an isolated analysis. Further RCTs with larger sample sizes are needed to clarify the specific impact of NIBS on negative symptoms in schizophrenia., (Copyright © 2018 Elsevier B.V. All rights reserved.)- Published
- 2018
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46. Efficacy of Esketamine in the Treatment of Depression With Psychotic Features: A Case Series.
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Ajub E and Lacerda ALT
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- Adult, Bipolar Disorder complications, Bipolar Disorder drug therapy, Female, Humans, Male, Middle Aged, Depressive Disorder, Major complications, Depressive Disorder, Major drug therapy, Ketamine therapeutic use, Psychotic Disorders complications, Psychotic Disorders drug therapy
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- 2018
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47. Attention and memory deficits in crack-cocaine users persist over four weeks of abstinence.
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Almeida PP, de Araujo Filho GM, Malta SM, Laranjeira RR, Marques ACRP, Bressan RA, and Lacerda ALT
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- Adult, Cognitive Dysfunction chemically induced, Humans, Male, Memory Disorders chemically induced, Middle Aged, Time Factors, Young Adult, Attention physiology, Cocaine-Related Disorders complications, Cognitive Dysfunction etiology, Cognitive Dysfunction physiopathology, Crack Cocaine adverse effects, Memory Disorders etiology, Memory Disorders physiopathology
- Abstract
Background: Crack-cocaine addiction is an important public health problem worldwide. Although there is not a consensus, preliminary evidence has suggested that cognitive impairments in patients with crack-cocaine dependence persist during abstinence, affecting different neuropsychological domains. However, few studies have prospectively evaluated those deficits in different phases of abstinence., Objectives: The main aim of present study was to examine neuropsychological performance of patients with crack-cocaine dependence during early abstinence and after four weeks, comparing with matched controls., Methods: Thirty-five males with crack-cocaine dependence, aged 18 to 50years, who met DSM-IV criteria for cocaine dependence and a control group of 33 healthy men were enrolled. They were assessed through Block Design, Digit Span and Vocabulary of Wechsler Adult Intelligence Scale (WAIS-III), the Rey Auditory Learning Test (RAVLT) and the Verbal Fluency (FAS) between 3 and 10days (mean of 6.1±2.0days) and after 4weeks of abstinence., Results: Compared to controls, the crack-cocaine dependent group exhibited deficits in cognitive performance affecting attention, verbal memory and learning tasks in early withdrawal. Most of the cognitive deficits persisted after four weeks of abstinence., Conclusion: Present results observed that the group of patients with crack-cocaine dependence presented persistent deficits affecting memory and attention even after four weeks of abstinence, confirming previous studies that had disclosed such cognitive impairments., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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48. The Brazilian standardization of the MATRICS consensus cognitive battery (MCCB): Psychometric study.
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Fonseca AO, Berberian AA, de Meneses-Gaya C, Gadelha A, Vicente MO, Nuechterlein KH, Bressan RA, and Lacerda ALT
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- Adult, Brazil, Consensus, Female, Humans, Male, Middle Aged, Neuropsychological Tests statistics & numerical data, Psychiatric Status Rating Scales, Psychometrics methods, Schizophrenic Psychology, Cognition Disorders diagnosis, Cognition Disorders etiology, Neuropsychological Tests standards, Psychometrics standards, Schizophrenia complications, Translating
- Abstract
Objective: Translate, adapt, and validate the MATRICS Consensus Cognitive Battery (MCCB) in Brazil., Method: The present study followed three steps: 1) translation to Portuguese, cultural adaptation, and back translation to English; 2) completion of a pilot study (N=30) conducted with the purpose of assessing whether the general comprehension of the items was clear and all participants adequately responded to the battery; 3) completion of a Reliability and Validation Study of the Brazilian version of the MCCB with 99 individuals with schizophrenia and 99 healthy subjects. All participants were administered the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) and patients were also rated on the Global Assessment of Functioning (GAF) Scale and the Positive and Negative Symptoms Scale (PANSS)., Results: The results showed adequate to high levels of baseline and 4-week retest reliability, except the MSCEIT-ME; adequate internal consistency for the MSCEIT-ME for the total sample and patients group, and moderate Alpha for the health control sample; as well as evidence of convergent validity and sensitivity to differentiate performance between the groups. All the 10 MCCB measures showed the lowest learning effects., Conclusion: Overall the Brazilian version of the MCCB showed similar results to the original North American version. Our findings provides reassurance that the MCCB is a reliable and valid measure of cognition across different countries and cultures, which is especially important to the ongoing work in attempting to discover cognition-enhancing drugs and the effects of cognitive interventions for the treatment of schizophrenia., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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49. Metabolomics and lipidomics analyses by 1 H nuclear magnetic resonance of schizophrenia patient serum reveal potential peripheral biomarkers for diagnosis.
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Tasic L, Pontes JGM, Carvalho MS, Cruz G, Dal Mas C, Sethi S, Pedrini M, Rizzo LB, Zeni-Graiff M, Asevedo E, Lacerda ALT, Bressan RA, Poppi RJ, Brietzke E, and Hayashi MAF
- Subjects
- Adult, Female, Humans, Male, Middle Aged, Principal Component Analysis, Psychiatric Status Rating Scales, Young Adult, Biomarkers blood, Lipid Metabolism physiology, Metabolomics methods, Proton Magnetic Resonance Spectroscopy, Schizophrenia blood, Schizophrenia diagnostic imaging
- Abstract
Using
1 H NMR-based metabolomics in association to chemometrics analysis, we analyzed here the metabolic differences between schizophrenia patients (SCZ) compared to healthy controls (HCs). HCs and SCZ patients underwent clinical interview using the Structured Clinical Interview for DSM Disorders (SCID). SCZ patients were further assessed by Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, Global Assessment of Functioning Scale (GAF), and Clinical Global Impressions Scale (CGI). Using the principal component analysis (PCA) and supervised partial least-squares discriminate analysis (PLS-DA) in obtained NMR data, a clear group separation between HCs and SCZ patients was achieved. Interestingly, all metabolite compounds identified as exclusively present in the SCZ group, except for the gamma-aminobutyric acid (GABA), were never previously associated with mental disorders. Although the initial perception of an absence of obvious biological link among the different key molecules exclusively observed in each group, and no identification of any specific pathway yet, the present work represents an important contribution for the identification of potential biomarkers to inform diagnosis, as it was possible to completely separate the affected SCZ patients from HCs, with no outliers or exceptions. In addition, the data presented here reinforced the role of the modulation of glycolysis pathway and the loss of GABA interneuron/hyperglutamate hypothesis in SCZ., (Copyright © 2016 Elsevier B.V. All rights reserved.)- Published
- 2017
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50. Neuropsychological correlates of remission in chronic schizophrenia subjects: The role of general and task-specific executive processes.
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Rabanea-Souza T, Akiba HT, Berberian AA, Bressan RA, Dias ÁM, and Lacerda ALT
- Abstract
Background: Although cognitive deficits have consistently been characterized as core features of schizophrenia, they have not been incorporated into definitions of remission. Furthermore, just a few studies have examined the relationship between cognitive deficits and symptomatic remission. The main aim of the present study is to evaluate the executive functioning of nonremitted schizophrenia patients., Methods: 72 remitted and 42 nonremitted schizophrenia patients, and 119 healthy controls were examined. Subjects were tested with a comprehensive battery of cognitive tests, including a measure to assess the general components of executive functioning and individual tasks to tap the three specific executive dimensions assessed in the present study, namely updating, shifting and inhibition., Results: Schizophrenia subjects performed poorly on general executive functioning and shifting tasks in comparison to healthy controls. Remitted subjects performed better than nonremitted on inhibition and updating tasks. Whereas being a male and showing decreases in updating increase the chances of being in the nonremitted schizophrenia subjects group, increases in shifting and updating enhance the odds of being in the healthy control group., Conclusion: The present findings suggest that executive function deficits are present in chronic schizophrenic patients. In addition, specific executive processes might be associated to symptom remission. Future studies examining prospectively first-episode, drug naive patients diagnosed with schizophrenia may be especially elucidative.
- Published
- 2016
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