Adverse Effects of Second-Generation Antipsychotics as Adjuncts to Antidepressants

Thase, Michael E.

doi:10.1016/j.psc.2016.04.008

Cited by 12 publications

(5 citation statements)

References 22 publications

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“…In clinical practice, augmentation with partial agonists should be considered after failed trials antidepressant agents across at least 2 classes of antidepressants, particularly when symptoms severity or the urgency for rapid benefit is sufficient to justify the potential risks (Thase, 2016). Clinicians must consider the main side-effects reported in RCT, explaining relevant dropout rate (weight gain, akathisia, metabolic parameters) (for review, see Citrome, 2015).…”

Section: Resultsmentioning

confidence: 99%

“…There are several mechanisms that might, at least in part, explain antidepressive efficacy of antipsychotics: blockade of neurotransmitter receptors other than dopamine, blockade of monoamine transporters, effects on sleep, decrease in cortisol levels, and increase in neurotrophic growth factors (Sagud et al, 2011). However, many side effects reported with SGAs could lead to diminished treatment adhesion and also inhibit the clinician from prescribing such adjunct treatment (Thase, 2016). D2 partial agonism became a new approach, stabilizing dopamine function while mitigating side effects.…”

Section: Introductionmentioning

confidence: 99%

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Major Depressive Disorder (MDD) and Schizophrenia– Addressing Unmet Needs With Partial Agonists at the D2 Receptor: A Review

Mallet

Gorwood

Strat

et al. 2019

International Journal of Neuropsychopharmacology

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Second-generation antipsychotics are common candidates for the adjunctive treatment of major depressive disorder and for the treatment of schizophrenia. However, unmet needs remain in the treatment of both disorders. Considering schizophrenia, antipsychotics are the most common treatment and have demonstrated good efficacy. Still, side effects of these treatments are commonly reported and may impact adherence to the medication and functioning in patients with schizophrenia. Regarding major depressive disorder, despite the availability of several classes of antidepressants, many patients do not achieve remission. Adjunctive treatment with antipsychotics may improve clinical and functional outcomes. Compared with dopamine D2 receptor antagonism that is exhibited by most antipsychotics, partial agonism may result in improved outcomes in major depressive disorder and in schizophrenia. Aripiprazole, cariprazine, and brexpiprazole have partial agonism at the dopamine D2 receptor and could potentially overcome limitations associated with D2 antagonism. The objectives of this review were (1) to discuss the goal of treatment with second-generation antipsychotics in major depressive disorder and schizophrenia, and the clinical factors that should be considered, and (2) to examine the short- and long-term existing data on the efficacy and safety of D2 receptor partial agonists (aripiprazole, cariprazine, and brexpiprazole) in the adjunctive treatment of major depressive disorder and in the treatment of schizophrenia.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Major Depressive Disorder (MDD) and Schizophrenia– Addressing Unmet Needs With Partial Agonists at the D2 Receptor: A Review

Mallet

Gorwood

Strat

et al. 2019

International Journal of Neuropsychopharmacology

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“…The faster onset and improved effects of adjunctive APs may be related to why these more severe patients initiated these medications earlier. AP medications are known for their relatively rapid onset, showing clinical benefits within 1–2 weeks [ 15 ], and these effects are at doses as low as a quarter to half of those used to treat acute schizophrenia or mania [ 16 ]. A recent study found that augmentation with an atypical AP medication demonstrated added benefit in patients with a higher degree of treatment-resistant depression (TRD) [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Earlier Versus Later Augmentation with an Antipsychotic Medication in Patients with Major Depressive Disorder Demonstrating Inadequate Efficacy in Response to Antidepressants: A Retrospective Analysis of US Claims Data

et al. 2018

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IntroductionThere is little evidence regarding the most effective timing of augmentation of antidepressants (AD) with antipsychotics (AP) in patients with major depressive disorder (MDD) who inadequately respond to first-line AD (inadequate responders). The study’s objective was to understand the association between timing of augmentation of AD with AP and overall healthcare costs in inadequate responders.MethodsUsing the Truven Health MarketScan® Medicaid, Commercial, and Medicare Supplemental databases (7/1/09–12/31/16), we identified adult inadequate responders if they had one of the following indicating incomplete response to initial AD: psychiatric hospitalization or emergency department (ED) visit, initiating psychotherapy, or switching to or adding on a different AD. Two mutually exclusive cohorts were identified on the basis of time from first qualifying event date to first date of augmentation with an AP (index date): 0–6 months (early add-on) and 7–12 months (late add-on). Patients were further required to be continuously enrolled 1 year before (baseline) and 1 year after (follow-up) index date. Patients with schizophrenia or bipolar disorder diagnoses were excluded. General linear regression was used to estimate adjusted healthcare costs in the early versus late add-on cohort, controlling for baseline demographic and clinical characteristics, insurance type, medications, and ED visits or hospitalizations.ResultsOf the 6935 identified inadequate responders, 68.7% started an AP early and 31.3% late. At baseline, before AP augmentation, patients in the early add-on cohort had higher psychiatric comorbid disease burden (47.3% vs. 42.5%; p < 0.001) and higher inpatient utilization [mean (SD) 0.41 (0.72) vs. 0.27 (0.67); p < 0.001] than in late add-on cohort. During follow-up, the adjusted total all-cause healthcare cost was significantly lower in the early vs. late add-on cohort ($18,864 vs. $20,452; p = 0.046).ConclusionFindings of this real-world study suggest that, in patients with MDD who inadequately responded to first-line AD treatment, adding an AP earlier reduces overall healthcare costs.FundingOtsuka Pharmaceutical Development and Commercialization, Inc. and Lundbeck.Electronic supplementary materialThe online version of this article (10.1007/s12325-018-0838-2) contains supplementary material, which is available to authorized users.

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“…Among the many strategies evaluated for antidepressant non-responders, switching to antidepressants from a different class, combining antidepressants, or adding atypical antipsychotics as adjunctive treatments to the ineffective antidepressant are the widely used strategies after nonresponse to 1 or 2 trials of conventional antidepressant pharmacotherapy ( Al-Harbi, 2012 ; de Sousa et al, 2015 ). Among these strategies, adjunctive therapy with atypical antipsychotics (e.g., aripiprazole, brexpiprazole, or quetiapine XR) are approved by health authorities for this indication, although adverse effects and long-term side effects limit or complicate their use ( Fleurence et al, 2009 ; Wright et al, 2013 ; Thase, 2016 ). Thus, there remains an unmet need for new treatments with different mechanisms of action that are effective and better tolerated to improve treatment strategies for MDD ( Thase, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major Depressive Disorder: A Phase 2b, Randomized, Placebo-Controlled, Adaptive Dose-Finding Study

Savitz

Wajs

Zhang

et al. 2021

International Journal of Neuropsychopharmacology

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Background Seltorexant, a selective antagonist of human orexin-2 receptors, demonstrated antidepressant effects in a previous exploratory study in patients with major depressive disorder (MDD). Methods To replicate and extend this observation, a double-blind, adaptive dose-finding study was performed in patients with MDD who had an inadequate response to 1-3 selective serotonin/serotonin-norepinephrine reuptake inhibitors in the current episode. Patients were randomized (2:1:1) to placebo or seltorexant (20 mg or 40 mg) once-daily, administered adjunctively to the antidepressant which the patient had been receiving at screening. After an interim analysis (6 weeks post-randomization of 160 th patient), newly recruited patients randomly received (3:3:1) placebo or seltorexant 10 mg or 20 mg; the 40 mg dose was no longer assigned. Patients were stratified by baseline Insomnia Severity Index scores (ISI ≥15 vs ISI <15). Primary endpoint was change from baseline Montgomery-Åsberg Depression Rating Scale (MADRS) total score at week 6. Results Mixed-Model for Repeated Measures (MMRM) analysis showed a greater improvement in MADRS total score in the seltorexant 20 mg group vs placebo at weeks 3 and 6; least-square means (LSM) difference (90% CI): -4.5 (-6.96;-2.07), p=0.003 and -3.1 (-6.13; -0.16), p=0.083, respectively. The improvement in MADRS score at week 6 for seltorexant 20 mg was greater in patients with baseline ISI ≥15 vs those with ISI <15; LSM difference (90% CI) vs placebo: -4.9 (-8.98;-0.80) and -0.7 (-5.16;3.76), respectively. The most common (≥5%) adverse events with seltorexant were somnolence, headache, and nausea. Conclusions A clinically meaningful reduction of depressive symptoms was observed for seltorexant 20 mg. In the subset of patients with sleep disturbance (ISI ≥15), a larger treatment difference between seltorexant 20 mg and placebo was observed, warranting further investigation. No new safety signal was identified.

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Adverse Effects of Second-Generation Antipsychotics as Adjuncts to Antidepressants

Cited by 12 publications

References 22 publications

Major Depressive Disorder (MDD) and Schizophrenia– Addressing Unmet Needs With Partial Agonists at the D2 Receptor: A Review

Major Depressive Disorder (MDD) and Schizophrenia– Addressing Unmet Needs With Partial Agonists at the D2 Receptor: A Review

Earlier Versus Later Augmentation with an Antipsychotic Medication in Patients with Major Depressive Disorder Demonstrating Inadequate Efficacy in Response to Antidepressants: A Retrospective Analysis of US Claims Data

Efficacy and Safety of Seltorexant as Adjunctive Therapy in Major Depressive Disorder: A Phase 2b, Randomized, Placebo-Controlled, Adaptive Dose-Finding Study

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