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1.
Rev Med Suisse ; 17(720-1): 85-89, 2021 Jan 13.
Artigo em Francês | MEDLINE | ID: mdl-33443837

RESUMO

The Covid-19 pandemic has a major impact on psychiatry by its social consequences and possible direct effect of certain forms of Covid-19 on mental health. During this crisis, the accessibility of technology meets a state of necessity, which has propelled telepsychiatry from the shadows into the light. The contribution of several technologies (i.e. virtual reality, actigraphy, computational psychiatry) combining clinical data and neuroscience underlines the great neurobehavioural variability even within the same diagnostic category, calling for greater precision in therapeutic offers as suggested e.g. by developments in neurofeedback. The place of intranasal esketamin in the panoply of antidepressent drug treatments for resistant depression has not yet been defined.


Assuntos
Psiquiatria/tendências , Telemedicina , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Humanos , Ketamina/administração & dosagem , Neurorretroalimentação , Pandemias
2.
Psychopharmacology (Berl) ; 238(4): 1157-1169, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33483802

RESUMO

Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. ClinicalTrials.gov : Treatment Resistant Depression (Pilot), NCT01179009.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ketamina/uso terapêutico , Sistema Límbico/efeitos dos fármacos , Adolescente , Adulto , Idoso , Antidepressivos/administração & dosagem , Clonidina/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/diagnóstico por imagem , Transtorno Depressivo Resistente a Tratamento/psicologia , Feminino , Giro do Cíngulo/efeitos dos fármacos , Alucinógenos/efeitos adversos , Humanos , Infusões Intravenosas , Ketamina/administração & dosagem , Ketamina/antagonistas & inibidores , Sistema Límbico/diagnóstico por imagem , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/efeitos dos fármacos , Escalas de Graduação Psiquiátrica , Simpatolíticos/uso terapêutico , Resultado do Tratamento , Adulto Jovem
4.
Psychopharmacology (Berl) ; 238(3): 857-865, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33471146

RESUMO

BACKGROUND: Interest and activity are part of the positive mood domain. Evidence suggests the symptom domain of interest-activity at baseline as a clinical predictor for treatment response to traditional antidepressants. However, whether this domain is related to the response to a single low-dose ketamine infusion remains unclear. METHODS: Seventy-one patients with treatment-resistant depression were randomized to 3 treatment groups: a single 0.5 or 0.2 mg/kg ketamine or normal saline placebo infusion. Depressive symptoms were measured using the 17-item Hamilton Depression Rating Scale before infusions and at postinfusion period (at 40 min and up to 2 weeks). Low (mild) versus medium versus high (severe) interest-activity symptom domain groups were classified on the basis of the cutoff point of ± 0.4 standard deviation. The effect of baseline interest-activity symptoms on outcomes was tested using generalized estimating equation models. RESULTS: The interest-activity symptom domain as a continuous variable (ß = 8.413, p = .016) was related to the trajectory of depressive symptoms. Stratified by levels of the interest-activity symptom domain, in the low interest-activity, 0.2 mg/kg ketamine infusion (ß = 0.013) demonstrated the greatest antidepressant effect (p < .01) compared with 0.5 mg/kg ketamine (ß = 0.739) and placebo infusions; however, in the high interest-activity, 0.5 mg/kg ketamine infusion (ß = 0.001) demonstrated the best antidepressant effect (p < .01) compared with 0.2 mg/kg ketamine (ß = 1.372) and placebo infusions. DISCUSSION: The symptom domain of interest-activity was an independent predictor for the treatment response to a single low-dose ketamine infusion.


Assuntos
Anedonia/efeitos dos fármacos , Antidepressivos/administração & dosagem , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ketamina/administração & dosagem , Escalas de Graduação Psiquiátrica , Adulto , Transtorno Depressivo Resistente a Tratamento/psicologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
7.
PLoS One ; 15(9): e0238843, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32915863

RESUMO

OBJECTIVE: The economic burden of commercially insured patients in the United States with treatment-resistant depression and patients with non-treatment-resistant major depressive disorder was compared using data from the Optum Clinformatics™ claims database. METHODS: Patients 18-63 years on antidepressant treatment between 1/1/13 and 9/30/13, who had no treatment claims for depression 6 months before the index date (first antidepressant dispensing), and who had a major depressive disorder or depression diagnosis within 30 days of the index date, were included. Treatment-resistant depression was defined as receiving 3 antidepressant regimens during 1 major depressive disorder episode. Patients with treatment-resistant depression were matched with patients with non-treatment-resistant major depressive disorder at a 1:4 ratio using propensity score matching. The study consisted of 1-year baseline (pre-index) and 2-year follow-up (post index) periods. Cost outcomes were compared using a generalized linear model. RESULTS: 2,370 treatment-resistant depression and 9,289 non-treatment-resistant major depressive disorder patients were included. In year 1 of the follow-up period, compared with non-treatment-resistant major depressive disorder, patients with treatment-resistant depression had: more emergency department visits (odds ratio = 1.39, 95% confidence interval = 1.24-1.56); more inpatient hospitalizations (odds ratio = 1.73, 95% confidence interval = 1.46-2.05); longer hospital stays (mean difference vs non-treatment-resistant major depressive disorder = 2.86, 95% confidence interval = 0.86-4.86 days); and more total healthcare costs (mean difference vs non-treatment-resistant major depressive disorder = US$3,846, 95% confidence interval = $2,855-$4,928). These patterns remained consistent in year 2 of the follow-up period. CONCLUSION: Treatment-resistant depression was associated with higher healthcare resource utilization and costs versus non-treatment-resistant major depressive disorder in this commercially insured cohort of patients in the United States.


Assuntos
Antidepressivos/economia , Assistência à Saúde/estatística & dados numéricos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Custos de Cuidados de Saúde , Recursos em Saúde/estatística & dados numéricos , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Adolescente , Adulto , Antidepressivos/uso terapêutico , Bases de Dados Factuais , Assistência à Saúde/economia , Transtorno Depressivo Maior/economia , Transtorno Depressivo Maior/epidemiologia , Transtorno Depressivo Resistente a Tratamento/economia , Transtorno Depressivo Resistente a Tratamento/epidemiologia , Feminino , Humanos , Revisão da Utilização de Seguros , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Estados Unidos/epidemiologia , Adulto Jovem
8.
J Clin Psychiatry ; 81(4)2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32663909

RESUMO

OBJECTIVE: To assess putative antidepressant and procognitive effects of decoglurant, a selective metabotropic glutamate receptor type 2/3 (mGlu2/3) negative allosteric modulator, as adjunctive treatment to selective serotonin reuptake inhibitors and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) in patients with partially refractory major depressive disorder (MDD), diagnosed using DSM-IV-TR criteria. METHODS: This randomized, placebo-controlled, double-blind, multicenter phase 2 trial consisted of 4 weeks' screening, 6 weeks' treatment, and 8 weeks' follow-up between September 2011 and June 2014. Individuals with Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 25 and Clinical Global Impressions-Severity of Illness scale score ≥ 4, despite up to 2 adequate trials of an SSRI/SNRI and compliance confirmed by positive SSRI/SNRI blood levels, were randomized to decoglurant 5 mg (n = 101), 15 mg (n = 102), or 30 mg (n = 55) daily or placebo (n = 99) as adjunct to ongoing treatment with 1 SSRI/SNRI. An adaptive design was used with an interim analysis after 30 patients in each group had received 6 weeks' treatment. The primary outcome variable was change in MADRS total score from baseline to end of treatment. Primary assessments were performed by fully blinded centralized raters. RESULTS: Of 357 participants, 310 completed 6 weeks' treatment. At 6 weeks, no significant differences between any active treatment arm and placebo in reducing MADRS total score or response or remission rates were observed. Decoglurant exerted no significant effects on Cambridge Neuropsychological Test Automated Battery cognitive accuracy and cognitive speed composite scores or on secondary measures of mood and functioning. A relatively high placebo response was observed, which may have constrained the ability to detect treatment effects. No deaths occurred; few patients reported serious adverse events. CONCLUSIONS: Decoglurant was well tolerated overall but did not exert any antidepressant or procognitive effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01457677.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Adulto , Regulação Alostérica/efeitos dos fármacos , Antidepressivos/uso terapêutico , Método Duplo-Cego , Quimioterapia Combinada , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
9.
J Clin Psychiatry ; 81(4)2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32603560

RESUMO

OBJECTIVE: To determine whether concurrent posttraumatic stress disorder (PTSD) should affect whether to augment or switch medications when major depressive disorder (MDD) has not responded to a prior antidepressant trial. METHODS: Patients at 35 Veterans Health Administration medical centers from December 2012 to May 2015 with nonpsychotic MDD (N = 1,522) and a suboptimal response to adequate antidepressant treatment were randomly assigned to 3 "next step" treatments: switching to bupropion, augmenting the current antidepressant with bupropion, and augmenting with the antipsychotic aripiprazole. Blinded ratings with the 16-item Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) determined remission and response by 12 weeks and relapse after remission. Survival analyses compared treatment effects in patients with concurrent PTSD diagnosed with the Mini-International Neuropsychiatric Interview (n = 717, 47.1%) and those without PTSD (n = 805, 52.9%). RESULTS: Patients diagnosed with PTSD showed more severe depressive symptoms at baseline and were less likely to achieve either remission or response by 12 weeks. Augmentation with aripiprazole was associated with greater likelihood of achieving response (68.4%) than switching to bupropion (57.7%) in patients with PTSD (relative risk [RR] = 1.26; 95% CI, 1.01-1.59) as well as in patients without PTSD (RR = 1.29; 95% CI, 1.05-1.97) (78.9% response with aripiprazole augmentation vs 66.9% with switching to bupropion). Treatment comparisons with the group receiving augmentation with bupropion were not significant. There was no significant interaction between treatment group and PTSD on remission (P = .70), response (P = .98), or relapse (P = .15). CONCLUSIONS: Although PTSD was associated with poorer overall outcomes, the presence of concurrent PTSD among Veterans in this trial did not affect the comparative effectiveness of medications on response, remission, or relapse after initial remission. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01421342.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Adolescente , Adulto , Antidepressivos/uso terapêutico , Aripiprazol/uso terapêutico , Bupropiona/uso terapêutico , Transtorno Depressivo Maior/complicações , Resistência a Medicamentos/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Transtornos de Estresse Pós-Traumáticos/complicações , Adulto Jovem
10.
Adv Pharmacol ; 89: 237-259, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32616208

RESUMO

Major depressive disorder (MDD) is the leading cause of disability worldwide and reduces life expectancy. Achieving and sustaining remission from depression is challenging after initial improvement of an acute episode with an antidepressant, especially for patients whose depressive episodes have proven treatment-resistant in response to conventional antidepressant pharmacotherapy. While standard antidepressants are at least partly effective for the short-term treatment of acute depressive episodes of MDD, many patients relapse within 6 months of apparent clinical remission, with faster and higher rates observed in those with treatment-resistant depression (TRD). Efficacy of IV ketamine, a rapid-acting N-methyl d-aspartate (NMDA) receptor antagonist, in maintaining antidepressant effect was suggested in a few small, single center, open-label studies and case series. More recently, maintenance of antidepressant effects beyond the initial acute (induction) treatment period has been shown with esketamine nasal spray, an enantiomer of ketamine, in conjunction with an oral antidepressant in three phase 2/3 registration studies (SYNAPSE, SUSTAIN-1, SUSTAIN-2) of adult patients with TRD. In these studies the maintenance of efficacy of an intermittently-dosed esketamine treatment regimen was established in which twice-weekly dose administration during a 4-week induction period was followed initially by weekly administration and later by either weekly or every-other-week administration. During long-term maintenance therapy the antidepressant effect persisted in most patients with this regimen, despite their history of being resistant to conventional antidepressants prior to entering esketamine studies. These data suggest that the neurobiological changes induced by initial esketamine treatment, which putatively underlie its antidepressant effect, can be maintained using repeated administration.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Prevenção Secundária , Antidepressivos/farmacologia , Ensaios Clínicos como Assunto , Humanos , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Ketamina/uso terapêutico
11.
Am J Psychiatry ; 177(10): 965-973, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32660299

RESUMO

OBJECTIVE: Low-dose testosterone has been shown to improve depression symptom severity, fatigue, and sexual function in small studies in women not formally diagnosed with major depressive disorder. The authors sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with antidepressant-resistant major depression. A functional MRI (fMRI) substudy examined effects on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation. METHODS: The authors conducted an 8-week randomized double-blind placebo-controlled trial of adjunctive testosterone cream in 101 women, ages 21-70, with antidepressant-resistant major depression. The primary outcome measure was depression symptom severity as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. The primary outcome of the fMRI substudy (N=20) was change in ACC activity. RESULTS: The participants' mean age was 47 years (SD=14) and their mean baseline MADRS score was 26.6 (SD=5.9). Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS scores decreased in both study arms from baseline to week 8 (testosterone arm: from 26.8 [SD=6.3] to 15.3 [SD=9.6]; placebo arm: from 26.3 [SD=5.4] to 14.4 [SD=9.3]), with no significant difference between groups. Improvement in fatigue and sexual function did not differ between groups, nor did side effects. fMRI results showed a relationship between ACC activation and androgen levels before treatment but no difference in ACC activation with testosterone compared with placebo. CONCLUSIONS: Adjunctive transdermal testosterone, although well tolerated, was not more effective than placebo in improving symptoms of depression, fatigue, or sexual dysfunction. Imaging in a subset of participants demonstrated that testosterone did not result in greater activation of the ACC.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Testosterona/uso terapêutico , Adulto , Idoso , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Resistente a Tratamento/diagnóstico por imagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Neuroimagem Funcional , Giro do Cíngulo/diagnóstico por imagem , Humanos , Hidrocortisona/sangue , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Creme para a Pele , Testosterona/administração & dosagem , Testosterona/sangue , Adulto Jovem
12.
J Clin Psychiatry ; 81(4)2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32558402

RESUMO

OBJECTIVE: The neuroactive steroid metabolite of progesterone, allopregnanolone, is a positive allosteric modulator of γ-aminobutyric acid-A (GABAA) receptors and a putative treatment for mood disorders. This pilot study was performed to determine whether an oral allopregnanolone analog (ganaxolone) may be effective adjunctive therapy for persistent depression despite adequate antidepressant treatment in postmenopausal women. METHOD: Ten postmenopausal women (mean ± SD age: 62.8 ± 6.3 years; range, 53-69 years) with persistent depression despite adequate antidepressant treatment (current DSM-IV-TR major depressive episode per the Structured Clinical Interview for DSM-IV-TR, Montgomery-Asberg Depression Rating Scale [MADRS] score ≥ 16, and treated with an adequately dosed antidepressant for ≥ 6 weeks) were studied from December 2016 to April 2018. Open-label ganaxolone (225 mg twice daily, increased to 450 mg twice daily if tolerated) was administered for 8 weeks, followed by a 2-week taper. RESULTS: Mean ± SEM total MADRS score (primary endpoint) decreased by 8 weeks (24.4 ± 1.6 to 12.8 ± 2.9, P = .015), and the decrease persisted over the 2-week taper (P = .019); of the 9 subjects who completed the full 8-week treatment period, 44% (4/9) experienced response (MADRS score decrease ≥ 50%) and remission (final MADRS score < 10), which persisted in 100% and 50% of subjects at 10 weeks, respectively. Secondary endpoints showed significant improvement, including Inventory of Depressive Symptomatology-Self-Report score (P = .003), MADRS reduced sleep subscale score (P < .001), total Symptoms of Depression Questionnaire (SDQ) score (P = .012), and scores on SDQ subscales for disruptions in sleep quality (P = .003) and changes in appetite and weight (P = .009) over 8 weeks. No significant effects were observed on quality of life or sexual function. All subjects experienced sleepiness and fatigue; 60% experienced dizziness. CONCLUSIONS: In this open-label, uncontrolled pilot study, adjunctive ganaxolone appears to exert antidepressant effects but produces sedation with twice-daily dosing. Ganaxolone may also improve sleep, which may be useful in patients with depression and insomnia. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02900092.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Pregnanolona/análogos & derivados , Idoso , Quimioterapia Combinada , Feminino , Moduladores GABAérgicos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Projetos Piloto , Pós-Menopausa , Pregnanolona/uso terapêutico , Resultado do Tratamento
13.
Neuron ; 106(5): 715-726, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32497508

RESUMO

Ketamine exerts rapid antidepressant action in depressed and treatment-resistant depressed patients within hours. At the same time, ketamine elicits a unique form of functional synaptic plasticity that shares several attributes and molecular mechanisms with well-characterized forms of homeostatic synaptic scaling. Lithium is a widely used mood stabilizer also proposed to act via synaptic scaling for its antimanic effects. Several studies to date have identified specific forms of homeostatic synaptic plasticity that are elicited by these drugs used to treat neuropsychiatric disorders. In the last two decades, extensive work on homeostatic synaptic plasticity mechanisms have shown that they diverge from classical synaptic plasticity mechanisms that process and store information and thus present a novel avenue for synaptic regulation with limited direct interference with cognitive processes. In this review, we discuss the intersection of the findings from neuropsychiatric treatments and homeostatic plasticity studies to highlight a potentially wider paradigm for treatment advance.


Assuntos
Antimaníacos/farmacologia , Transtorno Bipolar/tratamento farmacológico , Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/farmacologia , Homeostase/efeitos dos fármacos , Ketamina/farmacologia , Compostos de Lítio/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Animais , Antimaníacos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Ketamina/uso terapêutico , Compostos de Lítio/uso terapêutico , Transtornos do Humor/tratamento farmacológico , Sinapses/efeitos dos fármacos
15.
J Clin Psychiatry ; 81(4)2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32459407

RESUMO

OBJECTIVE: Esketamine, the S-enantiomer of ketamine, was recently approved as a rapid-acting intranasal therapy for depression and is currently under development for suicidality. The authors sought to determine the efficacy of adjunctive intranasal esketamine in major depressive disorder (MDD). DATA SOURCES: A systematic search of PubMed/MEDLINE was conducted up to January 2019, in addition to abstracts of major psychiatric meetings held since 2010. Searches were conducted by cross-referencing the term intranasal with the term esketamine. Where necessary, authors and/or study sponsors were contacted in order to obtain a copy of the presentation as well as any pertinent study details. STUDY SELECTION: 241 study abstracts were initially identified and reviewed. Selected studies were randomized, double-blind clinical trials comparing adjunctive intranasal esketamine to adjunctive placebo for MDD. DATA EXTRACTION: Data were extracted independently by two of the authors. A random effects model was used to calculate the standardized mean difference (SMD) between esketamine and placebo (intranasal saline) in the Montgomery-Asberg Depression Rating Scale (MADRS) score change from baseline to endpoint, serving as the primary outcome of the study. RESULTS: Five trials with 774 patients were pooled. Adjunctive esketamine was significantly more effective than placebo for MADRS score change, response, and remission (N = 774, SMD = 0.36, 95% CI = 0.24-0.49, P < .0001; response: risk ratio [RR] = 1.40, 95% CI = 1.22-1.61, P < .0001; remission: RR = 1.45, 95% CI = 1.20-1.75, P < .0001). Results remained statistically significant regardless of differences in the study sample, fixed vs new/optimized baseline antidepressants. CONCLUSIONS: Adjunctive intranasal esketamine for patients with MDD who are either treatment-resistant or acutely suicidal appears to be an effective treatment strategy.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Ketamina/uso terapêutico , Administração Intranasal , Antidepressivos/administração & dosagem , Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Quimioterapia Combinada/métodos , Humanos , Ketamina/administração & dosagem , Resultado do Tratamento
16.
J Clin Psychiatry ; 81(3)2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32316080

RESUMO

OBJECTIVE: To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD). METHODS: This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase. RESULTS: Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]). CONCLUSIONS: Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02497287.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ketamina/uso terapêutico , Administração Intranasal , Administração Oral , Adolescente , Adulto , Idoso , Antidepressivos/administração & dosagem , Cognição/efeitos dos fármacos , Quimioterapia Combinada , Feminino , Humanos , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Sprays Nasais , Adulto Jovem
17.
Epidemiol Psychiatr Sci ; 29: e122, 2020 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-32345395

RESUMO

Maju et al. provided clarifications on important and controversial issues related to esketamine clinical trial data, in response to a vivid debate triggered by the marketing authorisation recently granted by this new medicine. In this commentary, we reply to their comments attempting to critically discuss the evidence base needed to obtain regulatory approval.


Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ketamina/uso terapêutico , Aprovação de Drogas , Controle de Medicamentos e Entorpecentes , Medicina Baseada em Evidências , Humanos , Estados Unidos , United States Food and Drug Administration
18.
Cell ; 181(1): 7, 2020 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-32243798

RESUMO

The discovery of the strikingly rapid and robust antidepressant effects of r/s-ketamine for the treatment of antidepressant-resistant symptoms of depression has led to new insights into the biology of antidepressants and the FDA approval of its s-isomer, Esketamine (Spravato), the first mechanistically new treatment for depression in over 60 years. To view this Bench to Bedside, open or download the PDF.


Assuntos
Antidepressivos , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Aprovação de Drogas , Ketamina , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Neurônios GABAérgicos/efeitos dos fármacos , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico , Receptores de AMPA/metabolismo
19.
Braz J Psychiatry ; 42(3): 317-321, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32159712

RESUMO

OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) are the cornerstone of treatment of major depressive disorder (MDD). However, non-response is common, often necessitating combination strategies. The present study assessed the efficacy of vortioxetine as an add-on therapy in patients with SSRI-resistant MDD. METHODS: The charts of 36 adult outpatients with DSM-IV-TR MDD who had not achieved a response after at least 8 weeks of treatment with an SSRI were reviewed retrospectively. Subjects were treated with vortioxetine (5-20 mg/day) for 8 weeks added to the current SSRI. The main outcome measures were change from baseline in total Hamilton Scale for Depression (HAM-D) score and the rate of response (a 50% or greater reduction in HAM-D score and a Clinical Global Impression - Improvement module [CGI-I] score of 1 or 2 at endpoint). HAM-D scores ≤ 7 were considered as remission. Additional outcome measures included the Snaith-Hamilton Pleasure Scale (SHAPS) and the Scale for Suicide Ideation (SSI). RESULTS: 32 patients completed the 8 weeks of treatment. At 8 weeks, a significant reduction in HAM-D score was observed (p ≤ 0.001), with response obtained by 41.7% and remission by 33.3% of patients. Significant reductions in SHAPS and SSI were also observed (p ≤ 0.001 for both scales). CONCLUSIONS: Adjunctive vortioxetine may be useful and well-tolerated in stage I treatment-resistant depression. However, the limitations of this study (such as small sample size, absence of randomization and control group, retrospective design, etc.) must be considered.


Assuntos
Antidepressivos/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem , Vortioxetina/administração & dosagem , Adulto , Análise de Variância , Quimioterapia Combinada , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Reprodutibilidade dos Testes , Estudos Retrospectivos , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do Tratamento
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