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Suicide is a worldwide health crisis. We aimed to identify genetic risk variants associated with suicide death and suicidal behavior. Meta-analysis for suicide death was performed using 3765 cases from Utah and matching 6572 controls of European ancestry. Meta-analysis for suicidal behavior using data across five cohorts (n = 8315 cases and 256,478 psychiatric or populational controls of European ancestry) was also performed. One locus in neuroligin 1 (NLGN1) passing the genome-wide significance threshold for suicide death was identified (top SNP rs73182688, with p = 5.48 × 10-8 before and p = 4.55 × 10-8 after mtCOJO analysis conditioning on MDD to remove genetic effects on suicide mediated by MDD). Conditioning on suicidal attempts did not significantly change the association strength (p = 6.02 × 10-8), suggesting suicide death specificity. NLGN1 encodes a member of a family of neuronal cell surface proteins. Members of this family act as splice site-specific ligands for beta-neurexins and may be involved in synaptogenesis. The NRXN-NLGN pathway was previously implicated in suicide, autism, and schizophrenia. We additionally identified ROBO2 and ZNF28 associations with suicidal behavior in the meta-analysis across five cohorts in gene-based association analysis using MAGMA. Lastly, we replicated two loci including variants near SOX5 and LOC101928519 associated with suicidal attempts identified in the ISGC and MVP meta-analysis using the independent FinnGen samples. Suicide death and suicidal behavior showed positive genetic correlations with depression, schizophrenia, pain, and suicidal attempt, and negative genetic correlation with educational attainment. These correlations remained significant after conditioning on depression, suggesting pleiotropic effects among these traits. Bidirectional generalized summary-data-based Mendelian randomization analysis suggests that genetic risk for the suicidal attempt and suicide death are both bi-directionally causal for MDD.
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Ideação Suicida , Suicídio , Humanos , Estudo de Associação Genômica Ampla , Suicídio/psicologia , Tentativa de Suicídio/psicologia , Fatores de RiscoRESUMO
PURPOSE: To assess the effect of esketamine nasal spray on patient-reported outcomes (PROs) in patients with major depressive disorder having active suicidal ideation with intent (MDSI). METHODS: Patient-level data from two phase 3 studies (ASPIRE I; ASPIRE II) of esketamine + standard of care (SOC) in patients (aged 18-64 years) with MDSI, were pooled. PROs were evaluated from baseline through end of the double-blind treatment phase (day 25). Outcome assessments included: Beck Hopelessness Scale (BHS), Quality of Life (QoL) in Depression Scale (QLDS), European QoL Group-5-Dimension-5-Level (EQ-5D-5L), and 9-item Treatment Satisfaction Questionnaire for Medication (TSQM-9). Changes in BHS and QLDS scores (baseline to day 25) were analyzed using a mixed-effects model for repeated measures (MMRM). RESULTS: Pooled data for esketamine + SOC (n = 226; mean age: 40.5 years, 59.3% females) and placebo + SOC (n = 225; mean age: 39.6 years, 62.2% females) were analyzed. Mean ± SD change from baseline to day 25, esketamine + SOC vs placebo + SOC (least-square mean difference [95% CI] based on MMRM): BHS total score, - 7.4 ± 6.7 vs - 6.8 ± 6.5 [- 1.0 (- 2.23, 0.21)]; QLDS score, - 14.4 ± 11.5 vs - 12.2 ± 10.8 [- 3.1 (- 5.21, - 1.02)]. Relative risk (95% CI) of reporting perceived problems (slight to extreme) in EQ-5D-5L dimensions (day 25) in esketamine + SOC vs placebo + SOC: mobility [0.78 (0.50, 1.20)], self-care [0.83 (0.55, 1.27)], usual activities [0.87 (0.72, 1.05)], pain/discomfort [0.85 (0.69, 1.04)], and anxiety/depression [0.90 (0.80, 1.00)]. Mean ± SD changes from baseline in esketamine + SOC vs placebo + SOC for health status index: 0.23 ± 0.21 vs 0.19 ± 0.22; and for EQ-Visual Analogue Scale: 24.0 ± 27.2 vs 19.3 ± 24.4. At day 25, mean ± SD in domains of TSQM-9 scores in esketamine + SOC vs placebo + SOC were: effectiveness, 67.2 ± 25.3 vs 56.2 ± 26.8; global satisfaction, 69.9 ± 25.2 vs 56.3 ± 27.8; and convenience, 74.0 ± 19.4 vs 75.4 ± 18.7. CONCLUSION: These PRO data support the patient perspective of the effect associated with esketamine + SOC in improving health-related QoL in patients with MDSI. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: ASPIRE I, NCT03039192 (Registration date: February 1, 2017); ASPIRE II, NCT03097133 (Registration date: March 31, 2017).
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Transtorno Depressivo Maior , Feminino , Humanos , Adulto , Masculino , Transtorno Depressivo Maior/tratamento farmacológico , Antidepressivos/uso terapêutico , Antidepressivos/efeitos adversos , Ideação Suicida , Qualidade de Vida/psicologia , Método Duplo-Cego , Medidas de Resultados Relatados pelo Paciente , Ensaios Clínicos Fase III como Assunto , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: Esketamine (ESK) nasal spray, taken with oral antidepressant therapy, is approved for the treatment of depressive symptoms in adults with major depressive disorder (MDD) with acute suicidal ideation or behavior. In pooled analyses of two pivotal phase 3 studies, ASPIRE I and II, remission rates were consistently higher among patients with MDD with active suicidality who were treated with ESK + standard of care (SOC) versus placebo (PBO) + SOC at all time points in the double-blind and most time points in the follow-up phases. The current analysis of the ASPIRE data sets assessed the effect of ESK + SOC versus PBO + SOC on additional remission-related endpoints: time to achieving remission and consistent remission, proportion of patients in remission and consistent remission, and days in remission. METHODS: Post hoc analysis of pooled data from ASPIRE I and II (N = 451). Remission and consistent remission were defined as Montgomery-Åsberg Depression Rating Scale (MADRS) total score ≤ 12 at any given visit or two consecutive visits, respectively. Combined endpoints utilizing Clinical Global Impression-Severity of Suicidality-revised version [CGI-SS-r] ≤ 1 (i.e., not suicidal/questionably suicidal) along with the remission and consistent remission definitions (i.e., MADRS total score ≤ 12) were also examined. RESULTS: The median times to remission and consistent remission of MDD were significantly shorter in ESK + SOC versus PBO + SOC (15 versus 23 [p = 0.005] and 23 versus 50 days [p = 0.007], respectively) and a greater proportion of patients in ESK + SOC achieved remission and consistent remission by Day 25 (65.2% versus 55.5% and 54.2% versus 39.8%, respectively). Similar results were obtained using the combined endpoint for both remission definitions. The median percent of days in remission during the double-blind treatment phase was significantly greater in ESK + SOC (27.1% or 5 days) versus PBO + SOC (8.3% or 2 days; p = 0.006), and the significant difference was maintained during follow-up. CONCLUSION: Treatment with ESK + SOC versus PBO + SOC resulted in significantly shorter time to remission, greater proportion of patients in remission, and greater percent of days in remission using increasingly rigorous definitions of remission. These findings underscore the clinical benefits of ESK for adults with MDD with suicidality. TRIAL REGISTRATION: ClinicalTrials.gov registry NCT03039192 (registered February 1, 2017) and NCT03097133 (registered March 31, 2017).
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Transtorno Depressivo Maior , Suicídio , Adulto , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Antidepressivos/uso terapêutico , Ideação Suicida , Método Duplo-Cego , Resultado do TratamentoRESUMO
The objective of this analysis was to determine if there are sex differences with esketamine for treatment-resistant depression (TRD). Post hoc analyses of three randomized, controlled studies of esketamine in patients with TRD (TRANSFORM-1, TRANSFORM-2 [18-64 years], TRANSFORM-3 [≥ 65 years]) were performed. In each 4-week study, adults with TRD were randomized to esketamine or placebo nasal spray, each with a newly initiated oral antidepressant. Change from baseline to day 28 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score was assessed by sex in pooled data from TRANSFORM-1/TRANSFORM-2 and separately in data from TRANSFORM-3 using a mixed-effects model for repeated measures. Use of hormonal therapy was assessed in all women, and menopausal status was assessed in women in TRANSFORM-1/TRANSFORM-2. Altogether, 702 adults (464 women) received ≥ 1 dose of intranasal study drug and antidepressant. Mean MADRS total score (SD) decreased from baseline to day 28, more so among patients treated with esketamine/antidepressant vs. antidepressant/placebo in both women and men: TRANSFORM-1/TRANSFORM-2 women-esketamine/antidepressant -20.3 (13.19) vs. antidepressant/placebo -15.8 (14.67), men-esketamine/antidepressant -18.3 (14.08) vs. antidepressant/placebo -16.0 (14.30); TRANSFORM-3 women-esketamine/antidepressant -9.9 (13.34) vs. antidepressant/placebo -6.9 (9.65), men-esketamine/antidepressant -10.3 (11.96) vs. antidepressant/placebo -5.5 (7.64). There was no significant sex effect or treatment-by-sex interaction (p > 0.35). The most common adverse events in esketamine-treated patients were nausea, dissociation, dizziness, and vertigo, each reported at a rate higher in women than men. The analyses support antidepressant efficacy and overall safety of esketamine nasal spray are similar between women and men with TRD. The TRANSFORM studies are registered at clinicaltrials.gov (identifiers: NCT02417064 (first posted 15 April 2015; last updated 4 May 2020), NCT02418585 (first posted 16 April 2015; last updated 2 June 2020), and NCT02422186 (first posted 21 April 2015; last updated 29 September 2021)).
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Transtorno Depressivo Resistente a Tratamento , Sprays Nasais , Adulto , Depressão , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Ketamina , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment. METHODS: This double-blind study (ASPIRE II) randomized adults (aged 18-64 years) with MDD having active suicidal ideation with intent to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression-Severity of Suicidality-revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change. RESULTS: Of 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with esketamine (mean [SD]: -15.7 [11.56]) vs placebo (-12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: -3.9 [1.39], 95% CI: -6.60, -1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference -4.2, 95% CI: -6.38, -1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression-Severity of Suicidality-revised score; the between-group difference was not statistically significant. The most common adverse events among esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia. CONCLUSION: This study confirmed rapid and robust reduction of depressive symptoms with esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent. Trial Registration: Clinical Trials.gov identifier: NCT03097133.
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Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Ketamina/farmacologia , Ideação Suicida , Administração Intranasal , Adolescente , Adulto , Antidepressivos/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Ketamina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Sprays Nasais , Avaliação de Resultados em Cuidados de Saúde , Gravidade do Paciente , Adulto JovemRESUMO
PURPOSE/BACKGROUND: Numerous health authority approvals of esketamine nasal spray, combined with oral antidepressant, to treat depressive symptoms in adults with major depressive disorder and acute suicidal ideation or behavior were based on 2 identically designed, double-blind, phase 3 studies. METHODS/PROCEDURES: Across both ASPIRE studies (NCT03039192, NCT03097133), patients (N = 456) were randomized to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks plus comprehensive standard of care, including hospitalization and newly initiated or optimized antidepressant(s). In post hoc analyses of pooled data, changes from baseline at 24 hours after the first dose in Montgomery-Åsberg Depression Rating Scale total score and Clinical Global Impression-Severity of Suicidality-Revised, in the full cohort and in subgroups, were analyzed using analysis of covariance. FINDINGS/RESULTS: Esketamine plus standard of care demonstrated significantly greater improvement in Montgomery-Åsberg Depression Rating Scale total score versus placebo plus standard of care at 24 hours (least square mean difference [95% confidence interval], -3.8 [-5.75 to -1.89]) and at earlier (4 hours: -3.4 [-5.05 to -1.71]) and later time points (day 25: -3.4 [-5.36 to -1.36]). The between-group difference (95% confidence interval) for change in Clinical Global Impression-Severity of Suicidality-Revised at 24 hours was -0.20 (-0.43 to 0.04) for all patients and -0.31 (-0.61 to -0.01) for those with a history of suicide attempt. Common adverse events (≥20%) during esketamine treatment were dizziness, dissociation, nausea, somnolence, and headache. IMPLICATIONS/CONCLUSIONS: Esketamine plus comprehensive standard of care rapidly reduces depressive symptoms in patients with major depressive disorder who have acute suicidal ideation or behavior, especially in those with a history of suicide attempt, providing a new treatment option for this particularly ill and vulnerable population.
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Antidepressivos/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/psicologia , Ketamina/administração & dosagem , Administração Intranasal , Adulto , Depressão/prevenção & controle , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sprays Nasais , Ideação Suicida , Fatores de Tempo , Resultado do TratamentoRESUMO
INTRODUCTION: It is critical to assess who is being treated with a new marketed drug like esketamine to understand how it is used in the real-world setting and the effects of the medication. METHODS: Retrospective analysis using two large U.S. health care databases that included commercially insured and Medicaid patients. Patients treated with esketamine were identified and their baseline characteristics described and compared with the baseline characteristics of patients with treatment resistant depression (TRD) and with patients undergoing transcranial magnetic stimulation (TMS). To quantify the differences, standardized mean differences were calculated. RESULTS: In the commercially insured database, 418 patients were treated with esketamine and 830,047 patients were in the TRD group. Large differences in baseline characteristics were observed. Patients in the esketamine group were more likely to have severe depression, suicidal thoughts, and prior treatments with TMS or electroconvulsive therapy than the TRD control group. Patients in the esketamine group had more comorbid psychiatric conditions (anxiety disorder, posttraumatic stress disorders, substance use disorders) and higher exposure to antipsychotics, antiepileptics, hypnotics and sedatives. In terms of general health, patients in the esketamine group had many more outpatient visits, were more likely to have chronic pain and higher Charlson comorbidity scores, a predicator of mortality. Results were similar for both the Medicaid and TMS populations. CONCLUSION: Patients treated with esketamine have a higher burden of disease than other patients with TRD. In any real-world comparative effectiveness or safety study these differences need to be understood and accounted for to produce valid results.
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Transtorno Depressivo Resistente a Tratamento , Antidepressivos/uso terapêutico , Efeitos Psicossociais da Doença , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/epidemiologia , Humanos , Ketamina , Estudos RetrospectivosRESUMO
This was a double-blind, randomized, phase 2 study of adults (18-64 years) with DSM-5 diagnosis of major depressive disorder (MDD), with moderate-to-severe episode severity (Montgomery-Åsberg Depression Rating Scale [MADRS] ≥25) despite an adequate course with ongoing antidepressant for ≥6 weeks to ≤12 months. Following a double-blind placebo lead-in period (up to 3 weeks), participants were randomized to receive once daily aticaprant 10 mg or continue placebo, added to their ongoing treatment, for 6 weeks. Of 184 participants enrolled, 169 were included in safety analyses (aticaprant n = 85, placebo n = 84) and 166 in full intent-to-treat (fITT) efficacy analyses; 121 placebo lead-in non-responders (<30% reduction in MADRS total score) in fITT were included in enriched ITT (eITT) analyses. Improvement (least squares mean difference [upper limit 1-sided 80% CI] versus placebo) in MADRS total score at week 6 for aticaprant was significant versus placebo (eITT: -2.1 [-1.09], 1-sided p = 0.044; effect size (ES) 0.23; fITT -3.1 [2.21], 1-sided p = 0.002; ES 0.36). The between-group difference was larger among participants with Snaith-Hamilton Pleasure Scale (SHAPS) score greater/equal to versus less than baseline median SHAPS. The most common treatment-emergent adverse events reported for aticaprant (versus placebo) were headache (11.8% versus 7.1%), diarrhea (8.2% versus 2.4%), nasopharyngitis (5.9% versus 2.4%), and pruritus (5.9% versus 0%). One participant (1.2%) in each arm discontinued treatment due to an adverse event. In this study of participants with MDD and inadequate response to SSRI/SNRI, adjunctive treatment with aticaprant significantly reduced depressive symptoms versus placebo, without resulting in significant safety signals, supporting further investigation in larger trials.
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Transtorno Depressivo Maior , Quimioterapia Combinada , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Resultado do Tratamento , Adolescente , Receptores Opioides kappa/antagonistas & inibidores , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem , Inibidores da Recaptação de Serotonina e Norepinefrina/efeitos adversos , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Administração OralRESUMO
BACKGROUND: Cochrane recently published a review of esketamine and other glutamate receptor modulators in depression. AIM: To address the limitations of the review, analyses of esketamine data were conducted to provide additional perspective to the reviewers' interpretation of their findings. METHODS: Response rate, remission rate, and change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score were determined using data from all esketamine phase 2/3 registration studies of treatment-resistant depression (TRD) and, separately, all esketamine phase 2/3 registration studies of major depressive disorder (MDD) and active suicidal ideation with intent. Outcomes were assessed at all timepoints (i.e., 24 h, 72 h (MDD with active suicidal intent only), and 1, 2, and 4 weeks). Enrollment criteria of the TRD studies were different than those of the studies of MDD and active suicidal ideation with intent, resulting in differences in patients' clinical characteristics and depression severity between the cohorts. Thus, we did not compare results between these cohorts (as was done in the Cochrane review). RESULTS/OUTCOMES: In the combined TRD studies, a statistically significant between-group difference favored esketamine plus antidepressant over antidepressant plus placebo at 24 h (based on response, remission, and change in MADRS score), 1 week (change in MADRS score), 2 weeks (response and change in MADRS score), and 4 weeks (response, remission, and change in MADRS score). In the combined studies of MDD and active suicidal ideation with intent, the between-group difference was statistically different, favoring esketamine plus standard-of-care over placebo plus standard-of-care, at 24 h (response, remission, and change in MADRS score), 72 h and 1 week (change in MADRS score), 2 weeks (response), and 4 weeks (response, remission, and change in MADRS score). For both study types, the between-group difference in outcomes was not statistically significant at the other timepoints. CONCLUSIONS/INTERPRETATION: Esketamine improves response, remission, and depressive symptoms as early as 24 h post-first dose among patients with TRD and among patients with MDD and active suicidal ideation with intent.
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Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Ketamina , Adulto , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Ketamina/farmacologia , Ketamina/uso terapêutico , Depressão , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológicoRESUMO
BACKGROUND: The impact of treatment-resistant depression (TRD) or prior suicidal ideation/suicide attempt (SI/SA) on mortality by suicide among patients with major depressive disorder (MDD) is not well known. This retrospective, observational, descriptive cohort study characterized real-world rates of suicide-specific mortality among patients with MDD with or without TRD or SI/SA. METHODS: Adult patients with MDD among commercially insured and Medicare enrollees in Optum Research Database were included and assigned to three cohorts: those with treatment-resistant MDD (TRD), those with MDD and SI/SA (MDD+SI/SA), and those with MDD without TRD or SI/SA (MDD alone). Suicide-specific mortality was obtained from the National Death Index. The effects of demographic characteristics and SI/SA in the year prior to the end of observation on suicide-specific mortality were assessed. RESULTS: For the 139,753 TRD, 85,602 MDD+SI/SA, and 572,098 MDD alone cohort patients, mean age ranged from 55 to 59 years and the majority were female. At baseline, anxiety disorders were present in 53.92%, 44.11%, and 21.72% of patients with TRD, MDD+SI/SA, and MDD alone, respectively. Suicide-mortality rates in the three cohorts were 0.14/100 person-years for TRD, 0.27/100 person-years for MDD+SI/SA, and 0.04/100 person-years for MDD alone. SI/SA during the year prior to the end of observation, younger age, and male sex were associated with increased suicide risk. CONCLUSIONS: Patients with TRD and MDD+SI/SA have a heightened risk of mortality by suicide compared with patients with MDD alone. Suicide rates were higher in patients with recent history versus older or no history of SI/SA, men versus women, and those of young age versus older age.
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Transtorno Depressivo Maior , Adulto , Humanos , Masculino , Feminino , Idoso , Estados Unidos/epidemiologia , Pessoa de Meia-Idade , Ideação Suicida , Tentativa de Suicídio , Estudos Retrospectivos , Estudos de Coortes , MedicareRESUMO
Purpose: This meta-analysis assessed whether atypical antipsychotics (AAPs) and esketamine nasal spray (ESK-NS), which are mechanistically distinct, differ in antidepressant outcomes. Patients and Methods: Data were extracted from 12 trials of ESK-NS or AAPs in depressed patients (4276) with inadequate response or resistance to conventional antidepressants. Montgomery-Åsberg Depression Rating Scale (MADRS) score reductions from baseline and response rates (≥50% reduction) were analyzed. Results: At endpoint, the estimated MADRS score reduction of pooled ESK-NS arms was greater than pooled AAP arms (+9.16 points, p < 0.0001). The reduction also was greater in the pooled control arms of the ESK-NS trials than the pooled control arms of the AAP trials (+7.57 points, p < 0.0001). The mean difference in the reductions between pooled ESK-NS and control arms was 1.87 points greater than that between pooled AAP and control arms, but this difference was not significant (95% CI: -4.49, 0.74, p = 0.16). Relative to their respective control arms, the mean difference in response rates was 25% for the pooled ESK-NS and 9% for the pooled AAP arms; the mean response rate was 16% greater in the pooled ESK-NS studies than the pooled AAP studies (p = 0.0004). Comparisons against specific AAPs showed mean differences in the MADRS score reductions at 1 week between the experimental and control arms that were numerically larger in the ESK-NS trials than in the aripiprazole trials (mean difference of 1.71 points, p = 0.06) and the brexpiprazole trials (mean difference of 2.05 points, p = 0.02). Conclusion: The ESK-NS arms showed numerically larger MADRS score reductions at week-1 and endpoint, and a significantly larger response rate compared with AAP arms. Prospective studies involving direct comparisons are warranted to compare the relative efficacy between these treatment regimens.
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Atypical antipsychotics have an important role in the acute and maintenance treatment of bipolar disorder. While robust evidence supports the efficacy of these agents in the treatment of mania and in the prevention of manic relapse, few atypical antipsychotics have shown efficacy in the treatment or prevention of depressive episodes. These agents pose a lower risk of extrapyramidal side effects compared to typical neuroleptics, but carry a significant liability for weight gain and other metabolic side effects such as hyperglycemia and hyperlipidemia. More comparative effectiveness studies are needed to assess the optimal treatment regimens, including the relative benefits and risks of antipsychotics versus mood stabilizers. The exploration of the molecular mechanisms of antipsychotics has helped to shed further light on the underlying neurobiology of bipolar disorder, since these compounds target systems thought to be key to the pathophysiology of bipolar disorder. In addition to modulating monoaminergic neurotransmission, atypical antipsychotics appear to share properties with mood-stabilizing agents known to alter intracellular signal transduction leading to changes in neuronal activity and gene expression. Atypical antipsychotic drugs have been shown to exhibit neuroprotective properties that are mediated by upregulation of trophic and cellular resilience factors. Building on our understanding of existing therapeutics, especially as it relates to underlying disease pathology, newer "plasticity enhancing" strategies hold promise for future treatments of bipolar disorder.
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Antipsicóticos/uso terapêutico , Transtorno Bipolar/tratamento farmacológico , Antipsicóticos/efeitos adversos , Antipsicóticos/farmacologia , Dopamina/fisiologia , Quinase 3 da Glicogênio Sintase/fisiologia , Humanos , Fármacos Neuroprotetores/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , Serotonina/fisiologia , Transdução de Sinais , Via de Sinalização WntRESUMO
Objective: Most assessments of suicidal ideation and behavior (SIB) are limited by reliance on a single assessor, typically a clinician or patient, with scant detail on patient-related drivers of SIB and inability to detect rapid change in SIB. Furthermore, many techniques do not include a semistructured interview, increasing rater variability. The Suicide Ideation and Behavior Assessment Tool (SIBAT) addresses these limitations. Design: More than 30 experts in scale development, statistics, and clinical management of suicidal patients collaborated over a greater than four-year period to develop the SIBAT. Input for content and validity was received from patients, clinicians, and regulatory authorities in the United States (US) and Europe. Psychometric properties of the SIBAT were evaluated in validation studies. Results: The SIBAT is organized into eight independent patient- or clinician-rated modules with branching logic and scoring algorithms, which necessitates computerization. Patient-reported information is first captured in Modules 1 to 5. Thereafter, an experienced clinician reviews the patient's report, conducts a semistructured interview (Module 6), and assesses the patient's suicide risk (Module 7) and optimal antisuicide management (Module 8). Input from cognitive interviews of diverse adult, adolescent, and clinician participants was incorporated into the final version of the SIBAT. Psychometric testing demonstrated good inter-rater reliability (intraclass coefficient range: 0.68-0.82), intra-rater reliability (weighted-kappa range: 0.64-0.76), and concurrent validity with other instruments for assessing SIB. Conclusion: Patient- and clinician-based assessments and the psychometric studies summarized in this report support the validity and reliability of the SIBAT for capturing critical information related to assessment of SIB in adolescents and adults at risk for suicide.
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BACKGROUND: To compare the efficacy and tolerability of paliperidone extended-release (ER) with risperidone immediate-release using propensity score methodology. METHODS: Six double-blind, randomized, placebo-controlled, short-term clinical trials for acute schizophrenia with availability of individual patient-level data were identified (3 per compound). Propensity score pairwise matching was used to balance observed covariates between the paliperidone ER and risperidone patient populations. Scores were generated using logistic regression models, with age, body mass index, race, sex, baseline Positive and Negative Syndrome Scale (PANSS) total score and baseline Clinical Global Impressions-Severity (CGI-S) score as factors. The dosage range of paliperidone ER (6-12 mg/day) was compared with 2 risperidone dosage ranges: 2-4 and 4-6 mg/day. The primary efficacy measure was change in PANSS total score at week 6 end point. Tolerability end points included adverse event (AE) reports and weight. AEs with rates ≥ 5% and with a ≥ 2% difference between paliperidone ER and risperidone were identified. RESULTS: Completion rates for placebo-treated subjects in paliperidone ER trials (n = 95) and risperidone trials (n = 122) groups were 36.8% and 51.6%, respectively; end point changes on PANSS total scores were similar (p = 0.768). Completion rates for subjects receiving paliperidone ER 6-12 mg/day (n = 179), risperidone 2-4 mg/day (n = 113) or risperidone 4-6 mg/day (n = 129) were 64.8%, 54.0% and 66.7%, respectively (placebo-adjusted rates: paliperidone ER vs risperidone 2-4 mg/day, p = 0.005; paliperidone ER vs risperidone 4-6 mg/day, p = 0.159). PANSS total score improvement with paliperidone ER was greater than with risperidone 2-4 mg/day (difference in mean change score, -6.7; p < 0.05) and similar to risperidone 4-6 mg/day (0.2; p = 0.927). Placebo-adjusted AEs more common with paliperidone ER were insomnia, sinus tachycardia and tachycardia; more common with risperidone were somnolence, restlessness, nausea, anxiety, salivary hypersecretion, akathisia, dizziness and nasal congestion. Weight changes with paliperidone ER and risperidone were similar (paliperidone ER vs risperidone 2-4 mg/day, p = 0.489; paliperidone ER vs risperidone 4-6 mg/day, p = 0.236). CONCLUSIONS: This indirect database analysis suggested that paliperidone ER 6-12 mg/day may be more efficacious than risperidone 2-4 mg/day and as efficacious as risperidone 4-6 mg/day. The AE-adjusted incidence rates suggest differences between treatments that may be relevant for individual patients. Additional randomized, direct, head-to-head clinical trials are needed to confirm these findings.
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Antipsicóticos/uso terapêutico , Isoxazóis/uso terapêutico , Pirimidinas/uso terapêutico , Risperidona/uso terapêutico , Esquizofrenia/tratamento farmacológico , Administração Oral , Adulto , Antipsicóticos/administração & dosagem , Bases de Dados como Assunto/estatística & dados numéricos , Preparações de Ação Retardada , Esquema de Medicação , Feminino , Humanos , Isoxazóis/administração & dosagem , Masculino , Palmitato de Paliperidona , Pontuação de Propensão , Escalas de Graduação Psiquiátrica/estatística & dados numéricos , Pirimidinas/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricos , Risperidona/administração & dosagem , Esquizofrenia/diagnóstico , Resultado do TratamentoRESUMO
In the absence of head-to-head studies directly comparing the efficacy of intranasal esketamine to that of intravenous ketamine, valid conclusions regarding comparative efficacy cannot be made based on the existing data from trials using markedly differing study designs and patient populations.
Assuntos
Transtorno Depressivo Maior , Transtorno Depressivo Resistente a Tratamento , Ketamina , Antidepressivos/uso terapêutico , Depressão , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Humanos , Ketamina/uso terapêuticoRESUMO
This 6-week, double-blind, placebo-controlled study evaluated paliperidone extended-release (ER) as both monotherapy and adjunctive therapy to mood stabilizers and/or antidepressants (MS/ADs) for schizoaffective disorder. Included subjects had a schizoaffective disorder diagnosis; a Positive and Negative Syndrome Scale (PANSS) total score of 60 or higher; a score of 4 or higher on 2 or more of the PANSS items for hostility, excitement, tension, uncooperativeness, or poor impulse control; and prominent mood symptoms (≥16 on the Young Mania Rating Scale and/or the 21-item Hamilton Rating Scale for Depression). Subjects were randomized to 6 mg/d paliperidone ER or placebo with flexible dosing (3-12 mg/d) until day 15. Randomization was stratified by use of MS/AD and study site. The primary analysis outcome was change in PANSS total score at week 6 last observation carried forward end point. A total of 311 subjects received paliperidone ER (n = 216) or placebo (n = 95); 52.0% received MS/AD. The mean (SD) modal dose of paliperidone ER was 8.6 (2.5) mg/d. Greater improvement was observed with paliperidone ER than placebo on mean (SE) PANSS total scores: -20.0 (1.3) and -10.8 (1.9), respectively. Subjects with prominent manic or depressive symptoms showed greater improvement with paliperidone ER versus placebo: mean (SE) Young Mania Rating Scale (-10.6 [0.9] vs -5.7 [1.2], respectively) and 21-item Hamilton Rating Scale for Depression (-10.2 [0.7] vs -6.2 [1.1], respectively). The most common adverse events with paliperidone ER were headache, akathisia, dizziness, insomnia, and dyspepsia. Paliperidone ER improved psychotic and affective symptoms both as monotherapy and as an adjunct to MS/AD. No new safety findings were observed in this population.
Assuntos
Afeto/efeitos dos fármacos , Antidepressivos/administração & dosagem , Isoxazóis/administração & dosagem , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/psicologia , Pirimidinas/administração & dosagem , Adulto , Preparações de Ação Retardada/administração & dosagem , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Palmitato de Paliperidona , Resultado do TratamentoRESUMO
BACKGROUND: The purpose of this analysis was to evaluate relationships between hospital admission or discharge and scores for symptom or functioning in patients with schizophrenia. METHODS: Data were from three 52-week open-label extensions of the double-blind pivotal trials of paliperidone extended-release (ER). Symptoms and patient function were measured every 4 weeks using the Personal and Social Performance (PSP) scale and the Positive and Negative Syndrome Scale (PANSS). The intent-to-treat analysis set was defined as open-label patients who had at least one post-baseline PSP and PANSS measurement. Time until first hospitalization was evaluated using the Cox proportional hazard model with categorical time-dependent measures for the PSP (1 to 30, 31 to 70, 71 to 100) or PANSS (< 75, >/= 75 to < 95, >/= 95), as well as age, gender, schizophrenia duration, and country. Similar analyses were performed for time to discharge. RESULTS: Of the 1,077 enrolled patients, 1,028 (95.5%) met study criteria; of these, 382 (37.2%) were hospitalized at open-label baseline. Compared with patients with PSP >/= 71 group, the hazard for new hospitalization was 8.351 times greater (P = 0.0001) for patients with the poorest functioning (PSP 1 to 30) and 1.977 times greater (P = 0.0295) for patients with PSP of 31-70 compared to the >/= 71 group. The hazard for new hospitalization was 5.457 times greater (P < 0.0001) for patients PANSS >/= 95 and 2.316 times greater (P = 0.0027) for the >/= 75 to < 95 group compared with the < 75 group. For patients hospitalized at baseline, the PANSS >/= 95 patients had a discharge hazard that was 0.456 times lower than for the < 75 patients (P < 0.0001). The hazard for discharge was 0.646 times lower (P = 0.0012) for the PANSS >/= 75 to < 95 group compared with the < 75 group. A patient's country was a significant predictor variable, with US patients being admitted and discharged faster. CONCLUSIONS: Better functioning or being less symptomatic is associated with reduced risk for hospitalization and greater chance for early discharge. Treatments or programs that reduce symptoms or improve function decrease the risk of hospitalization in community patients or increase the chance of discharge for hospitalized patients.