New discoveries for an old drug: a review of recent olanzapine research

Meftah, Amir Mohammad; Deckler, Elizabeth; Citrome, Leslie; Kantrowitz, Joshua T.

doi:10.1080/00325481.2019.1701823

Cited by 49 publications

(36 citation statements)

References 88 publications

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“…Moving beyond the brain and the kidney, D -Serine may play a physiologic role in both appetite and insulin regulation in the pancreas, which is of potential clinical relevance since many antipsychotics are associated with clinically significant weight gain and metabolic disturbances ( 110 , 111 ). D -Serine appears to be elevated in pre-clinical mice models of diabetes, but this seems to be an effect, and not a contributing cause of diabetes in vivo ( 112 , 113 ).…”

Section: -Serine and The Pancreas And Metabolismmentioning

confidence: 99%

D-Serine: A Cross Species Review of Safety

2021

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Background:D-Serine, a direct, full agonist at the D-serine/glycine modulatory site of the N-methyl-D-aspartate-type glutamate receptors (NMDAR), has been assessed as a treatment for multiple psychiatric and neurological conditions. Based on studies in rats, concerns of nephrotoxicity have limited D-serine research in humans, particularly using high doses. A review of D-serine's safety is timely and pertinent, as D-serine remains under active study for schizophrenia, both directly (R61 MH116093) and indirectly through D-amino acid oxidase (DAAO) inhibitors. The principal focus is on nephrotoxicity, but safety in other physiologic and pathophysiologic systems are also reviewed.Methods: Using the search terms “D-serine,” “D-serine and schizophrenia,” “D-serine and safety,” “D-serine and nephrotoxicity” in PubMed, we conducted a systematic review on D-serine safety. D-serine physiology, dose-response and efficacy in clinical studies and dAAO inhibitor safety is also discussed.Results: When D-serine doses >500 mg/kg are used in rats, nephrotoxicity, manifesting as an acute tubular necrosis syndrome, seen within hours of administration is highly common, if not universal. In other species, however, D-serine induced nephrotoxicity has not been reported, even in other rodent species such as mice and rabbits. Even in rats, D--serine related toxicity is dose dependent and reversible; and does not appear to be present in rats at doses producing an acute Cmax of <2,000 nmol/mL. For comparison, the Cmax of D-serine 120 mg/kg, the highest dose tested in humans, is ~500 nmol/mL in acute dosing. Across all published human studies, only one subject has been reported to have abnormal renal values related to D-serine treatment. This abnormality did not clearly map on to the acute tubular necrosis syndrome seen in rats, and fully resolved within a few days of stopping treatment. DAAO inhibitors may be nephroprotective. D-Serine may have a physiologic role in metabolic, extra-pyramidal, cardiac and other systems, but no other clinically significant safety concerns are revealed in the literature.Conclusions: Even before considering human to rat differences in renal physiology, using current FDA guided monitoring paradigms, D-serine appears safe at currently studied maximal doses, with potential safety in combination with DAAO inhibitors.

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Section: -Serine and The Pancreas And Metabolismmentioning

confidence: 99%

D-Serine: A Cross Species Review of Safety

2021

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“…[15][16][17] Based on data from clinical trials, 18,19 real-world settings, [20][21][22] meta-analyses, 23,24 and pooled analyses, 25 olanzapine is one of the most effective antipsychotics for the treatment of schizophrenia. 26,27 Olanzapine also effectively treats manic or mixed episodes associated with BD-I and reduces relapse risk during maintenance treatment. [28][29][30] While olanzapine's efficacy is well established, 18,23,28,29,31 the clinical utility of olanzapine has been hampered by the risk of substantial weight gain and metabolic effects, [32][33][34][35][36][37][38] such as elevations in blood glucose and lipid concentrations, waist circumference increases, and development of metabolic syndrome.…”

Section: Introductionmentioning

confidence: 99%

An Evidence-Based Review of OLZ/SAM for Treatment of Adults with Schizophrenia or Bipolar I Disorder

Citrome¹,

Graham²,

Simmons³

et al. 2021

NDT

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Olanzapine effectively treats schizophrenia and bipolar I disorder (BD-I); however, its use is limited by the risk of significant weight gain and metabolic effects. OLZ/SAM, a combination of olanzapine and samidorphan, was recently approved in the United States for the treatment of adults with schizophrenia or BD-I. OLZ/SAM provides the efficacy of olanzapine while mitigating olanzapine-associated weight gain through opioid-receptor blockade. Here, we summarize OLZ/SAM clinical data characterizing pharmacokinetics, antipsychotic efficacy, weight mitigation efficacy, safety, and long-term treatment effects. In an acute exacerbation of schizophrenia, OLZ/SAM and olanzapine provided similar symptom improvements versus placebo at week 4. In stable outpatients with schizophrenia, OLZ/SAM treatment resulted in significantly less weight gain, reducing the risk for clinically significant weight gain and waist circumference increases of ≥5 cm by half, compared with olanzapine at week 24. Based on openlabel extension studies, OLZ/SAM is safe and well tolerated for up to 3.5 years of treatment, while maintaining schizophrenia symptom control and stabilizing weight. The olanzapine component of OLZ/SAM was bioequivalent to branded olanzapine (Zyprexa); adjunctive OLZ/SAM had no clinically significant effects on lithium or valproate pharmacokinetics. Additionally, OLZ/SAM had no clinically relevant effect on electrocardiogram parameters in a dedicated thorough QT study. Overall, safety and tolerability findings from clinical studies with OLZ/SAM indicate a similar safety profile to that of olanzapine, with the exception of less weight gain. As OLZ/SAM contains the opioid antagonist samidorphan, it is contraindicated in patients using opioids and in those undergoing acute opioid withdrawal. Clinical trial results from more than 1600 subjects support the use of OLZ/SAM as a new treatment option for patients with schizophrenia or BD-I.

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“…11 There seems to be no significant difference in the efficacy of these two classes. 13 These antipsychotic medications also show limited efficacy for negative symptoms and cognitive deficits. 14 the development of drugs that treat positive symptoms was a significant step towards improving patients' quality of life.…”

Section: Introductionmentioning

confidence: 99%

Lumateperone tosylate, A Selective and Concurrent Modulator of Serotonin, Dopamine, and Glutamate, in the Treatment of Schizophrenia

Maini

Hollier

Gould

et al. 2021

Health Psychology Research

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This is a comprehensive review of the literature regarding the use of Lumateperone tosylate for schizophrenia. This review presents the background, evidence, and indications for the use of lumateperone tosylate in the treatment of schizophrenia. Recent FindingsSchizophrenia is a chronic mental health disorder that affects approximately 3.3 million people in the United States. Its symptoms, which must be present more than six months, are comprised of disorganized behavior and speech, a diminished capacity to comprehend reality, hearing voices unheard by others, seeing things unseen by others, delusions, decreased social commitment, and decreased motivation. The majority of these symptoms can be managed with antipsychotic medication. Lumateperone is a selective and concurrent modulator of serotonin, dopamine, and glutamate, which all mediate or modulate serious mental illness.

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New discoveries for an old drug: a review of recent olanzapine research

Cited by 49 publications

References 88 publications

D-Serine: A Cross Species Review of Safety

D-Serine: A Cross Species Review of Safety

An Evidence-Based Review of OLZ/SAM for Treatment of Adults with Schizophrenia or Bipolar I Disorder

Lumateperone tosylate, A Selective and Concurrent Modulator of Serotonin, Dopamine, and Glutamate, in the Treatment of Schizophrenia

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