Morbidity in Depressive Disorders

Baldessarini, Ross J.; Forte, Alberto; Selle, Valerio; Sim, Kang; Tondo, Leonardo; Undurraga, Juan; Vázquez, Gustavo

doi:10.1159/000448661

Cited by 54 publications

(33 citation statements)

References 84 publications

(150 reference statements)

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“…Major depressive disorder (MDD) is a highly prevalent medical illness [1], often associated with significant morbidity, mortality, and functional impairment [2,3]. For many patients suffering from MDD, treatments delivered do not always have the desired effect [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder

et al. 2019

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NSI-189 is a novel neurogenic compound independent of monoamine reuptake pathways. This trial evaluated oral NSI-189 as monotherapy in major depressive disorder. To improve signal detection, the sequential-parallel comparison design (SPCD) was chosen. Two hundred and twenty subjects were randomized to NSI-189 40 mg daily, 80 mg daily, or placebo for 12 weeks. The primary outcome measure was the Montogmery Asberg Depression Rating Scale (MADRS). Secondary subject-rated measures included the Symptoms of Depression Questionnaire (SDQ), the Cognitive and Physical Functioning Scale (CPFQ), the patient-rated version of the Quick Inventory of Depressive Symptomatology Scale (QIDS-SR), and subtests from the CogScreen and Cogstate cognitive tests. MADRS score reduction versus placebo did not reach significance for either dose (40 mg pooled mean difference −1.8, p = 0.22, 80 mg pooled mean difference −1.4, p = 0.34, respectively). However, the 40 mg dose showed greater overall reduction in SDQ (pooled mean difference −8.2; Cohen's d for Stages 1 and 2 = −0.11 and −0.64, p = 0.04), and CPFQ scores (pooled mean difference −1.9; Cohen's d for Stages 1 and 2 = −0.28 and −0.47, p = 0.03) versus placebo, as well as QIDS-SR scores in Stage 2 of SPCD (−2.5; Cohen's d Stages 1 and 2 = −0.03 and −0.68, p = 0.04). The 40 mg dose also showed advantages on some objective cognitive measures of the CogScreen (absolute Cohen's d ranged between 0.12 and 1.12 in favor of NSI-189, p values between 0.002 and 0.048 for those with overall significance), but not the Cogstate test. Both doses were well tolerated. These findings replicate those of phase 1b study, and warrant further exploration of the antidepressant and pro-cognitive effects of NSI-189.

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Section: Introductionmentioning

confidence: 99%

A phase 2, double-blind, placebo-controlled study of NSI-189 phosphate, a neurogenic compound, among outpatients with major depressive disorder

et al. 2019

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“…Major depressive disorder (MDD) is associated with significant morbidity [1], and is a leading cause of global disability, affecting some 300 million people worldwide [2]. Predominant pharmacotherapies approved for treatment of MDD include selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (SNRIs), and bupropion [3], all of which target various aspects of monoaminergic neurotransmission, such as serotonin, norepinephrine, or dopamine transporters [4].…”

Section: Introductionmentioning

confidence: 99%

Opioid system modulation with buprenorphine/samidorphan combination for major depressive disorder: two randomized controlled studies

et al. 2018

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The endogenous opioid system is thought to play an important role in the regulation of mood. Buprenorphine/samidorphan (BUP/SAM) combination is an investigational opioid system modulator for adjunctive treatment of major depressive disorder (MDD). To confirm results from early studies, we report the efficacy and safety of BUP/SAM as adjunctive treatment in patients with MDD and an inadequate response to antidepressant therapy (ADT) in FORWARD-4 and FORWARD-5: two phase 3, randomized, double-blind, placebo-controlled studies that utilized the same sequential parallelcomparison design. Efficacy was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS). FORWARD-5 achieved the primary endpoint and demonstrated that adjunctive BUP/SAM 2 mg/2 mg was superior to placebo (average difference change from baseline to week 3 through end of treatment [EOT] in MADRS-6 and −10 versus placebo: −1.5, P = 0.018; −1.9, P = 0.026, respectively). FORWARD-4 did not achieve the primary endpoint (change from baseline in MADRS-10 at week 5 versus placebo: -1.8, P = 0.109), although separate analyses showed significant treatment differences at other timepoints using traditional, regulatory-accepted endpoints such as reduction in MADRS-10 at EOT. The pooled analysis of the two studies demonstrated consistently greater reduction in MADRS-10 scores from baseline for BUP/ SAM 2 mg/2 mg versus placebo at multiple timepoints including EOT and average change from baseline to week 3 through EOT (-1.8, P = 0.010; -1.8, P = 0.004, respectively). The overall effect size (Hedges' g) in the pooled analyses for MADRS-10 change from baseline to EOT was 0.22. Overall, BUP/SAM was generally well tolerated, with most adverse events (AEs) being mild or moderate in severity. The most common AEs, occurring in ≥5% of patients in the BUP/SAM 2 mg/2 mg treatment group, which was more frequently than the placebo group, included nausea, constipation, dizziness, vomiting, somnolence, fatigue, and sedation. There was minimal evidence of abuse, and no evidence of dependence or opioid withdrawal by AEs or objective measures. This report describes adjunctive BUP/SAM 2 mg/2 mg combination, a therapy with a novel opioidergic mechanism of action, as a potential new treatment option for patients with MDD who have an inadequate response to currently available ADT.

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“…Major depressive disorder (MDD) is a chronic disease with a lifetime prevalence of 16.2% for adults in the USA ( Kessler et al , 2003 ). MDD is associated with significant morbidity ( Baldessarini et al , 2017 ), can lead to substantial disability, and has larger effects on disability and days out of role than most other medical conditions ( Merikangas et al , 2007 ). Despite the availability of a wide range of antidepressant treatment (ADT) options with diverse molecular targets, insufficient treatment response remains a significant problem in MDD, and patients frequently experience inadequate response to one or more ADTs of adequate dose and duration ( Fava, 2003 ).…”

Section: Introductionmentioning

confidence: 99%