OBJECTIVE: Evaluate the efficacy and safety of lisdexamfetamine dimesylate augmentation for major depressive disorder (MDD) in escitalopram nonremitters.
METHOD: In this proof-of-concept study (conducted from July 2009-August 2010) with a prespecified critical α = .10, adults with nonpsychotic MDD (DSM-IV-TR criteria) and residual depressive symptoms (17-item Hamilton Depression Rating Scale score ≥ 4) after 8 weeks of open-label escitalopram were randomized to 6 weeks of lisdexamfetamine dimesylate (20-50 mg/d) or placebo augmentation. The primary endpoint, Montgomery-Asberg Depression Rating Scale (MADRS) total score change in escitalopram nonremitters (MADRS total score > 10) from week 8 (augmentation baseline) to week 14/end of study, was assessed using analysis of covariance, with last observation carried forward.
RESULTS: For nonremitters (placebo, n = 64; lisdexamfetamine dimesylate, n = 65), the least squares (LS) mean (90% CI) treatment difference for MADRS total score reduction at week 14/end of study (-2.3 [-4.5 to -0.1]; P = .0902) met the prespecified criterion for lisdexamfetamine dimesylate superiority (adjusted effect size, -0.3); the number needed to treat for MADRS remission (MADRS total score ≤ 10) was 6.7. The LS mean treatment difference in remitters was not statistically significant (1.2 [-1.6 to 4.0]; P = .4726). Among randomized participants, 49.4% (42/85) receiving placebo and 60.2% (53/88) receiving lisdexamfetamine dimesylate had ≥ 1 treatment-emergent adverse event, the most frequent with lisdexamfetamine dimesylate being dry mouth and headache (both 11.4%). Mean (SD) vital sign and electrocardiogram changes (placebo vs lisdexamfetamine dimesylate) were 0.5 (8.98) versus 2.3 (9.04) mm Hg (systolic blood pressure), -1.0 (7.19) versus 0.9 (6.61) mm Hg (diastolic blood pressure), -0.4 (7.39) versus 4.8 (8.64) beats per minute (heart rate), and -1.6 (11.23) versus -4.9 (11.84) milliseconds (Fridericia-adjusted QTc).
CONCLUSIONS: Lisdexamfetamine dimesylate augmentation reduced depressive symptoms in participants with inadequate escitalopram response.
TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00905424.
BACKGROUND: There is growing interest in the identification of novel therapeutic agents for the treatment of affective disorders, with modafinil being one promising substance. The purpose of the present investigation was to compare the efficacy of a combination of fluoxetine plus modafinil with that of fluoxetine plus placebo in the treatment of major depression in a 6-week double blind and placebo-controlled trial.
METHODS: Forty-six adult outpatients who met the DSM-IV-TR criteria for major depression participated in the trial. Patients had a baseline Hamilton Rating Scale for depression score of at least 18. Patients were allocated in a random fashion, 23 to fluoxetine 40 mg/day plus modafinil 400 mg/day (200 mg bid) (morning and evening) and 23 to fluoxetine 40 mg/day plus placebo. Patients were assessed at baseline and after 1, 2, 4, and 6 weeks after start of medication.
RESULTS: Forty-four patients completed the trial. Fluoxetine+modafinil and fluoxetine+placebo significantly decreased the Hamilton Rating Scale score for Depression over the trial period. However, the combination of fluoxetine and modafinil was significantly superior over fluoxetine alone in the treatment of symptoms of major depression. The difference between the two treatments was significant as indicated by the effect of group, the between-subjects factor (df = 1, F = 4.42, P = 0.046). There were no significant differences in the two groups in terms of observed side-effects.
CONCLUSION: These findings suggest modafinil as a well-tolerated and potentially effective agent in combination with fluoxetine in the management of patients with major depression.
OBJECTIVE: As the authors have observed clinical benefit from the psychostimulants methylphenidate and dexamphetamine for treating resistant melancholic and bipolar depression, those drugs were evaluated in a consecutively recruited sample of 50 such patients.
METHOD: Patients (27 bipolar, 23 unipolar) received either methylphenidate (n = 44) or dexamphetamine (n = 6), with 30 having it prescribed as an augmenting drug and 20 as monotherapy. At the final review, ranging from 6 weeks to 62 months (mean 57 weeks), 52% were still receiving their psychostimulant.
RESULTS: Thirty-four per cent reported the psychostimulant as distinctly improving their depression, 30% reported some level of improvement and 36% reported no improvement and/or side-effects. For improvers, the modal dose of methylphenidate was 20 mg. Significant side-effects were reported by 18% (including one manic response), switching was rare and limited to the bipolar subjects, and most side-effects were minor. Any positive response occurred rapidly and loss of efficacy was rare. Testing of tricyclic levels in some patients suggested that stimulant drugs may raise tricyclic levels in those who are rapid metabolizers.
CONCLUSION: Although this study was not controlled, the high success rate in a diagnostically refined sample implies that the psychostimulants may be efficacious for patients with melancholic and bipolar depression who have failed to respond to orthodox antidepressant drugs.
OBJECTIVE: To evaluate the efficacy, safety, and tolerability of adjunctive osmotic-release oral system (OROS) methylphenidate in outpatients with major depressive disorder (MDD) receiving a stable oral antidepressant regimen.
METHOD: This multicenter, double-blind, randomized, placebo-controlled, parallel-group, 5-week trial enrolled 145 subjects who met DSM-IV-TR criteria for MDD and who had failed 1 to 3 previous antidepressant monotherapies (including current antidepressant) of adequate dose and duration. Augmentation therapy was initiated with 18 mg of OROS methylphenidate and increased to a maximum dose of 54 mg of OROS methylphenidate until an optimal dose was achieved. Efficacy scales included the Montgomery-Asberg Depression Rating Scale (MADRS), 7 atypical items from the 31-item Hamilton Rating Scale for Depression, the Clinical Global Impressions-Severity of Illness (CGI-S) scale, the CGI-Improvement scale (CGI-I), the Sex Effects scale, the Multidimensional Assessment of Fatigue (MAF) scale, and the Apathy Evaluation Scale (AES). Subjects were recruited at 17 community and academic centers across Canada. The study was conducted from June 8, 2005, to April 18, 2006.
RESULTS: There was no statistically significant difference between the groups at endpoint on the MADRS. OROS methylphenidate was superior to placebo in improving apathy and fatigue as measured by the AES and the MAF. Statistically significant differences using mixed-model analysis were observed on the AES at all visits and at endpoint (p = .01) and on the MAF (p < .01). No differences were observed on other secondary measures, including the CGI-I and CGI-S. There were no clinically significant findings on electrocardiogram.
CONCLUSIONS: OROS methylphenidate did not demonstrate statistical significance on the MADRS at endpoint. Apathy and fatigue were significantly improved with OROS methylphenidate treatment, which was well tolerated with minimal side effects.
CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT00246233.
BACKGROUND: Partial response, no response, or residual symptoms following antidepressant therapy is common in clinical psychiatry. This study evaluated modafinil in patients with major depressive disorder (MDD) who were partial responders to adequate selective serotonin reuptake inhibitor (SSRI) therapy and excessive sleepiness and fatigue.
METHODS: This retrospective analysis pooled the data of patients (18-65 yrs) who participated in two randomized, double-blind, placebo-controlled studies of modafinil (6-week, flexible-dose study of 100-400 mg/day or 8-week, fixed-dose study of 200 mg/day) plus SSRI therapy. Patients (n=348) met criteria for several residual symptoms (Epworth Sleepiness Scale [ESS] score>or=10; 17-item Hamilton Depression Scale [HAM-D] score between 4 and 25; and Fatigue Severity Scale [FSS] score>or=4).
RESULTS: Compared to placebo, modafinil augmentation rapidly (within 1 week) and significantly improved overall clinical condition (Clinical Global Impression-Improvement), wakefulness (ESS), depressive symptoms (17-item HAM-D), and fatigue (FSS) (p<.01 for all). At final visit, patients receiving modafinil augmentation experienced statistically significant improvements in overall clinical condition, wakefulness, and depressive symptoms. Modafinil was well tolerated in combination with SSRI.
CONCLUSIONS: Results of this pooled analysis provide further evidence suggesting that modafinil is an effective and well-tolerated augmentation therapy for partial responders to SSRI therapy, particularly when patients continue to experience fatigue and excessive sleepiness.
OBJETIVO: El modafinilo es aprobado por la Food and Drug Administration de los Estados Unidos para mejorar la vigilia en pacientes con somnolencia excesiva asociada con la narcolepsia, la apnea obstructiva del sueño, y el trabajo por turnos trastorno del sueño. Este estudio se realizó para evaluar la eficacia y seguridad de modafinilo en la depresión bipolar, que a menudo se caracteriza por somnolencia excesiva y la fatiga.
MÉTODO: Ochenta y cinco pacientes con depresión bipolar que era inadecuada respuesta a un estabilizador del ánimo con o sin terapia antidepresiva concomitante fueron asignados al azar para recibir modafinilo adyuvante (N = 41) o placebo (N = 44) durante 6 semanas. La medida de resultado primario fue la línea base al punto final del cambio en la puntuación en el Inventario de síntomas depresivos - Clínico Calificación (IDS).
RESULTADOS: El cambio de línea base hasta el punto final en la puntuación IDS fue significativamente mayor en el grupo modafinilo (dosis, 177 mg / día promedio) en comparación con el grupo placebo. Mejora en los síntomas depresivos fue significativamente mayor en el grupo de modafinilo por semana 2, y esta mayor mejora se mantuvo en las semanas 4, 5 y 6. Tanto las tasas de respuesta y remisión fueron significativamente mayores en el grupo de modafinilo (44% y 39%) en comparación con el grupo placebo (23% y 18%). Durante el período de estudio de 6 semanas, no hubo diferencia entre los grupos en la hipomanía tratamiento emergente o manía (seis pacientes en el grupo modafinilo y cinco en el grupo placebo) u hospitalización por manía (uno en cada grupo).
CONCLUSIONES: Estos datos sugieren que el modafinilo adyuvante en dosis de 100 a 200 mg al día puede mejorar los síntomas depresivos en los pacientes con trastorno bipolar.
BACKGROUND: Previous studies suggest that adjunctive modafinil treatment provides benefit for patients with depression with significant sleepiness and fatigue.
METHODS: We conducted a multisite, double-blind, placebo-controlled study of the treatment of major depression characterized by excessive sleepiness and fatigue, adding adjunctive modafinil or placebo to a selective serotonin reuptake inhibitor from the beginning of treatment. Seventy-three of 90 consenting patients met all screening criteria to begin treatment with open-label selective serotonin reuptake inhibitor therapy and double-blind addition of either modafinil (100 mg/d for 1 week then 200 mg/d) or matching placebo for 6 weeks.
RESULTS: Mixed-model analysis of the change in the Epworth Sleepiness Scale, the primary outcome measure, showed no difference between modafinil- and placebo-treated patients. However, the hypersomnia items on the 31-item Hamilton Depression Scale were significantly more improved with modafinil than placebo. The total 31-item Hamilton Depression Scale score was significantly better with modafinil than placebo at Weeks 4 and 5, but not at the final study visit. There was no difference in dropout rates caused by adverse events, but 2 patients in the modafinil-treated group developed new onset or worsening of suicidal ideation, leading to the trial being discontinued prematurely.
CONCLUSIONS: Power to detect differences between modafinil and placebo was limited because of the premature discontinuation of the trial. Although modafinil did not show evidence of benefit over placebo on the Epworth Sleepiness Scale, secondary measures suggested modafinil may have provided benefit for symptoms of excessive sleepiness in patients with depression.
OBJETIVO: A pesar de un tratamiento adecuado con inhibidores selectivos de la recaptación de serotonina (ISRS), muchos pacientes deprimidos no alcanzan la remisión. Además de una intervención noradrenérgica en pacientes mal o parcialmente sensible a los ISRS puede mejorar los resultados, pero pocas pruebas de estudios bien controlados se ha informado de esta hipótesis.
Método: Los pacientes con trastorno depresivo mayor (confirmado por la Entrevista Clínica Estructurada para el DSM-IV) fueron tratados con sertralina a dosis de hasta 200 mg / día en este estudio, llevado a cabo a partir del 18 de junio de 2003 al 28 de enero del 2005. Los pacientes que siguieron a experimentar signos y síntomas depresivos después de 8 semanas fueron asignados al azar a tener atomoxetina 40 a 120 mg / día o placebo añadido a la sertralina durante otras 8 semanas.
Resultados: De 276 pacientes que iniciaron el estudio, 146 con síntomas depresivos persistentes después de 8 semanas de tratamiento con sertralina (media [DE] La dosis de sertralina definitiva: 161,1 [43,4] mg / día) fueron asignados al azar a la adición de la atomoxetina o placebo. Después de 8 semanas adicionales, no hubo diferencias entre los grupos de tratamiento en el cambio medio en la severidad de los síntomas o en la proporción de pacientes cuyos síntomas remitido (sertralina / atomoxetina 29/72 [40,3%], sertralina / placebo 28/74 [37,8%], p = 0,865). Los análisis secundarios que separaban los subgrupos con las mejoras en los síntomas que no alcanzaron la remisión (respuesta parcial) y los que tienen poca o ninguna mejora (no respondedores) también mostraron ningún efecto de la atomoxetina. El número de pacientes que interrumpieron debido a eventos adversos no difirió entre los grupos.
En conclusión, en pacientes deprimidos con síntomas persistentes después de un ensayo inicial de sertralina, además de la atomoxetina no mejoró la respuesta más que el placebo.
OBJECTIVE: To assess the effectiveness and safety of atomoxetine as an adjunctive medication for residual fatigue in a naturalistic treatment setting.
METHODS: A retrospective chart review was conducted to identify major depressive disorder (MDD) patients who had experienced significant symptom improvement (either partial response or remission) following treatment with conventional antidepressants but who were continuing to complain of fatigue. Fourteen such patients (42.2+/-13.4 years of age, five women, baseline HDRS 6.2+/-2.4) with a 17-item Hamilton Depression Rating Scale (HDRS17)<11 who received adjunctive atomoxetine for fatigue were included in the report. Antidepressants augmented were the selective serotonin reuptake inhibitors (SSRIs) (n=11; 78.6%), mirtazapine (n=2, 14.3%), and amitriptyline (n=1, 7.1%).
RESULTS: Twelve (85.7%) patients (nine remitters, three partial responders) received at least 4 weeks of atomoxetine treatment. The remaining two (partial responders) discontinued atomoxetine within 1-3 days due to increased anxiety. The brief fatigue inventory (BFI) and Clinical Global Impressions Scale (CGI) were administered when atomoxetine was first prescribed, and following 4-10 weeks of treatment (mean of 5.4+/-1.8 weeks). There was a significant decrease in BFI scores (41.9+/-14.9 versus 24.3+/-13.4, p=0.0015), and HDRS-17 scores (6.2+/-2.4 versus 3.5+/-2.8, p=0.0466), but not CGI-S scores (1.3+/-1.4-1.0+/-0.0, p=0.08) following treatment with atomoxetine. 5/12 (41.6%) patients had a 50% or greater decrease in BFI scores. All 12 patients were remitters at follow-up. The mean atomoxetine dose was 42.8+/-10.6 mg. Side effects included insomnia (n=6), increased anxiety (n=3), nausea (n=1) and dry mouth (n=1).
CONCLUSIONS: Although preliminary, these results suggest a possible augmentation role for atomoxetine when used in conjunction with conventional antidepressants for residual fatigue in MDD. Prospective as well as controlled studies are necessary to further explore the role of atomoxetine augmentation in MDD.
Evaluate the efficacy and safety of lisdexamfetamine dimesylate augmentation for major depressive disorder (MDD) in escitalopram nonremitters.
METHOD:
In this proof-of-concept study (conducted from July 2009-August 2010) with a prespecified critical α = .10, adults with nonpsychotic MDD (DSM-IV-TR criteria) and residual depressive symptoms (17-item Hamilton Depression Rating Scale score ≥ 4) after 8 weeks of open-label escitalopram were randomized to 6 weeks of lisdexamfetamine dimesylate (20-50 mg/d) or placebo augmentation. The primary endpoint, Montgomery-Asberg Depression Rating Scale (MADRS) total score change in escitalopram nonremitters (MADRS total score > 10) from week 8 (augmentation baseline) to week 14/end of study, was assessed using analysis of covariance, with last observation carried forward.
RESULTS:
For nonremitters (placebo, n = 64; lisdexamfetamine dimesylate, n = 65), the least squares (LS) mean (90% CI) treatment difference for MADRS total score reduction at week 14/end of study (-2.3 [-4.5 to -0.1]; P = .0902) met the prespecified criterion for lisdexamfetamine dimesylate superiority (adjusted effect size, -0.3); the number needed to treat for MADRS remission (MADRS total score ≤ 10) was 6.7. The LS mean treatment difference in remitters was not statistically significant (1.2 [-1.6 to 4.0]; P = .4726). Among randomized participants, 49.4% (42/85) receiving placebo and 60.2% (53/88) receiving lisdexamfetamine dimesylate had ≥ 1 treatment-emergent adverse event, the most frequent with lisdexamfetamine dimesylate being dry mouth and headache (both 11.4%). Mean (SD) vital sign and electrocardiogram changes (placebo vs lisdexamfetamine dimesylate) were 0.5 (8.98) versus 2.3 (9.04) mm Hg (systolic blood pressure), -1.0 (7.19) versus 0.9 (6.61) mm Hg (diastolic blood pressure), -0.4 (7.39) versus 4.8 (8.64) beats per minute (heart rate), and -1.6 (11.23) versus -4.9 (11.84) milliseconds (Fridericia-adjusted QTc).
CONCLUSIONS:
Lisdexamfetamine dimesylate augmentation reduced depressive symptoms in participants with inadequate escitalopram response.
