Samidorphan/olanzapine combination therapy for schizophrenia: Efficacy, tolerance and adverse outcomes of regimen, evidence-based review of clinical trials

Rehan, Syeda Tayyaba; Siddiqui, Abdul Hannan; Khan, Zayeema; Imran, Laiba; Ahad, Syed Abdul; Tahir, Muhammad Junaid; Jassani, Zahra; Singh, Manjeet; Asghar, Muhammad Sohaib; Ahmed, Aziza

doi:10.1016/j.amsu.2022.104115

Cited by 7 publications

(8 citation statements)

References 39 publications

(189 reference statements)

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“… 181 – 184 , 352 Recently, samidorphan – an opioid receptor antagonist – was introduced as an adjunctive treatment for olanzapine-associated weight gain. 353 , 354 This might be also a promising approach for clozapine.…”

Section: Side Effects Of Clozapinementioning

confidence: 99%

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Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia

Qubad

Bittner

2023

Therapeutic Advances in Psychopharmacology

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Despite its enduring relevance as the single most effective and important evidence-based treatment for schizophrenia, underutilization of clozapine remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to offer clozapine due to its relatively large side-effect burden and the complexity of its use. This underscores the necessity for continued education regarding both the vital nature and the intricacies of clozapine treatment. This narrative review summarizes all clinically relevant areas of evidence, which support clozapine’s wide-ranging superior efficacy – for treatment-resistant schizophrenia (TRS) and beyond – and make its safe use eminently feasible. Converging evidence indicates that TRS constitutes a distinct albeit heterogeneous subgroup of schizophrenias primarily responsive to clozapine. Most importantly, the predominantly early onset of treatment resistance and the considerable decline in response rates associated with its delayed initiation make clozapine an essential treatment option throughout the course of illness, beginning with the first psychotic episode. To maximize patients’ benefits, systematic early recognition efforts based on stringent use of TRS criteria, a timely offer of clozapine, thorough side-effect screening and management as well as consistent use of therapeutic drug monitoring and established augmentation strategies for suboptimal responders are crucial. To minimize permanent all-cause discontinuation, re-challenges after neutropenia or myocarditis should be considered. Owing to clozapine’s unique efficacy, comorbid conditions including substance use and most somatic disorders should not dissuade but rather encourage clinicians to consider clozapine. Moreover, treatment decisions need to be informed by the late onset of clozapine’s full effects, which for reduced suicidality and mortality rates may not even be readily apparent. Overall, the singular extent of its efficacy combined with the high level of patient satisfaction continues to distinguish clozapine from all other available antipsychotics.

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Section: Side Effects Of Clozapinementioning

confidence: 99%

“…Topiramate can also be considered as its efficacy appears to be comparable to metformin [242][243][244][245][246] . Recently, samidorphanan opioid receptor antagonistwas introduced as an adjunctive treatment for olanzapine-associated weight gain 247,248 .…”

Section: Metabolic Side Effectsmentioning

confidence: 99%

Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia

Qubad

Bittner

2023

Therapeutic Advances in Psychopharmacology

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“…At the same time, according to Rehan et al, the combination can be helpful in the long-term treatment as it demonstrated a significant decline in PANSS score. 9,20 The plausible reason behind their equivalent efficacy could be Systematic Review and Meta-Analysis that olanzapine alone demonstrates an antipsychotic effect (via antagonism at D2 and 5HT2A receptors), while the effect of the addition of samidorphan (which acts on opioid receptors) is to blunt the weight gain associated with the use of olanzapine. This effect culminates from the antagonism of the µ-opioid receptor, inhibiting the mesolimbic reward system responsible for inducing food cravings.…”

Section: Events (Especially Weight Gain) the Outcomes Are Based On We...mentioning

confidence: 99%

“…7,8 However, there are significant drawbacks concerning OLZ's long-term use, such as weight Systematic Review and Meta-Analysis gain, dyslipidemia, cardio-metabolic syndrome, and diabetes mellitus. [9][10][11] To reduce its adverse effects, a novel opioid receptor modulator, samidorphan (SAM), was introduced to be administered in combination with OLZ. Structurally related to naltrexone, SAM is also an antagonist at the mu-opioid receptor and a partial agonist at the kappa and delta opioid receptors.…”

mentioning

confidence: 99%

Olanzapine-Samidorphan for Schizophrenia: A Systematic Review and Meta-Analysis

Gupta,

Singh

2023

Indian Journal of Psychological Medicine

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Background and Objective: United States Food and Drug Administration (USFDA) recently approved a novel combination of olanzapine-samidorphan (OLZSAM) for managing olanzapine-associated adverse events (weight gain) in adult patients with schizophrenia and bipolar disorder. To opine about the safety and efficacy of OLZSAM, authors performed a systematic review and meta-analysis to convene justifiable evidence. Methods: A thorough literature search was performed through the databases Embase, Cochrane Library, PubMed, and clinicaltrials.gov, from inception to September 2022, with the keywords: ‘olanzapine and samidorphan’ and schizophrenia; and “ALKS3831” and “lybalvi.” Clinical trials published in English that analyzed the efficacy and safety of OLZSAM were included. The significant outcomes included in this study were change from baseline (CFB) in Positive and Negative Syndrome Scale (PANSS) at the end of the study, the proportion of patients with weight gain at the end of the study, the proportion of patients with at least one adverse event, and the incidence of drug discontinuation due to adverse events. Results: The change in PANSS score at the end of the study was comparable among groups receiving OLZSAM and olanzapine alone: standardized mean difference (SMD) = 0.04; 95% CI = -0.09 to 0.17; p = 0.57. The OLZSAM group reported less incidence of weight gain: risk ratio (RR) = 0.91; 95% CI = 0.62–1.34; p = 0.63, and any adverse event: RR = 0.99; 95% CI = 0.90–1.09; p = 0.81. Drug discontinuation incidence was higher in the OLZSAM group: RR = 1.22; 95% CI = 0.84–1.79; p = 0.30. Conclusions: The combination OLZSAM showed comparable efficacy to olanzapine alone in schizophrenia patients, with relatively less incidence of weight gain and adverse events; however, the drug discontinuation due to adverse events was more in the OLZSAM group.

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Section: Metabolic Side Effectsmentioning

confidence: 99%

Second to None – Rationale, Timing, and Clinical Management of Clozapine Use in Schizophrenia

Qubad¹,

Bittner²

2022

Preprint

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Despite its continued relevance as the single most effective and important evidence-based treatment for schizophrenia, the degree of underutilization of clozapine across health systems remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to use clozapine due to its relatively large side-effect burden and its comparatively complex dosing and monitoring requirements. This underscores the necessity for continued education of clinicians in the intricacies of clozapine use and in the still growing case in favor of this vital treatment option. Consequently, this narrative review provides a comprehensive outline of all lines of evidence, which support clozapine’s wide-ranging superior efficacy, and of the current knowledge regarding the prevalence and diagnosis of treatment resistance. The distinct neurobiological and clinical characteristics of this condition makes the swift initiation of clozapine indispensable. Moreover, we review the extensive literature regarding clozapine’s side effect profile and current recommendations for optimal treatment and monitoring algorithms including for particularly vulnerable populations such as elderly patients and pregnant women and for potential re-challenges after myocarditis and neutropenia. We also discuss established approaches to increase treatment response as well as augmentation strategies for patients with partial or full clozapine resistance. We argue for a clear focus on early and consistent detection and management of side effects, which can ensure patient safety and reduce permanent all-cause discontinuation. This strategy needs to be combined with a long-term approach acknowledging the late onset of clozapine’s full advantageous effects, which – in cases like reduced mortality rates – even then may not be easily discernible. Our aim is to encourage a safer, more frequent, and timely use of clozapine to maximize patients’ short- and long-term benefits. Even now, the extent of these benefits as well as patient’s satisfaction with treatment still clearly set clozapine apart from all other available treatment options.

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Samidorphan/olanzapine combination therapy for schizophrenia: Efficacy, tolerance and adverse outcomes of regimen, evidence-based review of clinical trials

Cited by 7 publications

References 39 publications

Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia

Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia

Olanzapine-Samidorphan for Schizophrenia: A Systematic Review and Meta-Analysis

Second to None – Rationale, Timing, and Clinical Management of Clozapine Use in Schizophrenia

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