Relationship of Brain Glutamate Response to D-Cycloserine and Lurasidone to Antidepressant Response in Bipolar Depression: A Pilot Study

Dong, Zhengchao; Grunebaum, Michael F.; Lan, Martin; Wagner, Vashti; Choo, Tse‐Hwei; Milak, Matthew S.; Sobeih, Tarek; Mann, J. John; Kantrowitz, Joshua T.

doi:10.3389/fpsyt.2021.653026

Cited by 9 publications

(7 citation statements)

References 55 publications

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“…Our preclinical studies with mice (71), suggest a comparable mice dose of approximately 100 mg/kg for the 60 mg/kg clinical dose. In this study, D-cycloserine, which acts as an agonist at the Dserine/glycine site of the NMDAR, but a ketamine like antagonist at higher doses (130)(131)(132), also attenuated haloperidol induced bradykinesia at doses up to 30 mg/kg, which likely is in the NMDAR agonist range.…”

Section: D-serine and Extrapyramidal Effectssupporting

confidence: 48%

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: D-serine and Extrapyramidal Effectssupporting

confidence: 48%

D-Serine: A Cross Species Review of Safety

2021

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“…For instance, in animals, D-cycloserine has been combined with pioglitazone as a possible treatment for a mouse model of chronic orofacial neuropathic pain ( 104 ). In humans, D-cycloserine has been used as part of a combination treatment regimen with lurasidone for bipolar depression or acute suicidal ideation and behavior in bipolar depression ( 105 , 106 ).…”

Section: Hypothesismentioning

confidence: 99%

Substrate Reduction Therapy for Krabbe Disease: Exploring the Repurposing of the Antibiotic D-Cycloserine

Levine

Tsau

2022

Front. Pediatr.

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Krabbe disease is a lysosomal storage disease that is caused by a deficiency in galactosylceramidase. Infantile onset disease is the most common presentation, which includes progressive neurological deterioration with corresponding demyelination, development of globoid cells, astrocyte gliosis, etc. Hemopoietic stem cell transplantation (HSCT) is a disease modifying therapy, but this intervention is insufficient with many patients still experiencing developmental delays and progressive deterioration. Preclinical studies have used animal models, e.g., twitcher mice, to test different experimental therapies resulting in developments that have led to progressive improvements in the therapeutic impact. Some recent advances have been in the areas of gene therapy and substrate reduction therapy (SRT), as well as using these in combination with HSCT. Unfortunately, new experimental approaches have encountered obstacles which have impeded the translation of novel therapies to human patients. In an effort to identify a safe adjunct therapy, D-cycloserine was tested in preliminary studies in twitcher mice. When administered as a standalone therapy, D-cycloserine was shown to lengthen the lifespan of twitcher mice in a small but significant manner. D-Cycloserine is an FDA approved antibiotic used for drug resistant tuberculosis. It also acts as a partial agonist of the NMDA receptor, which has led to numerous human studies for a range of neuropsychiatric and neurological conditions. In addition, D-cycloserine may inhibit serine palmitoyltransferase (SPT), which catalyzes the rate-limiting step in sphingolipid production. The enantiomer, L-cycloserine, is a much more potent inhibitor of SPT than D-cycloserine. Previously, L-cycloserine was found to act as an effective SRT agent in twitcher mice as both a standalone therapy and as part of combination therapies. L-Cycloserine is not approved for human use, and its potent inhibitory properties may limit its ability to maintain a level of partial inactivation of SPT that is also safe. In theory, D-cycloserine would encompass a much broader dosage range to achieve a safe degree of partial inhibition of SPT, which increases the likelihood it could advance to human studies in patients with Krabbe disease. Furthermore, additional properties of D-cycloserine raise the possibility of other therapeutic mechanisms that could be exploited for the treatment of this disease.

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“…Data preprocessing We combined the data from coil elements using unsuppressed water signal as a reference 19,20 . We removed the residual water signal using an SVD-based method [21][22][23] and performed spectral alignment among the 30 water suppressed FIDs by aligning the 2 nd to the 30 th FIDs to the 1 st one, using a fitting procedure like that of Near et al, using the Lorentzian lineshape function. 24 Evaluation of the temperature averaging -by repeated measurements We used two methods to evaluate the performance of temperature averaging.…”

Section: H Mrs Data Acquisition and Processing 221 Phantom Datamentioning

confidence: 99%

Improving reproducibility of proton MRS brain thermometry: theoretical and empirical approaches

Dong

Kantrowitz

Mann

2021

Preprint

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Purpose: In 1H MRS-based thermometry of brain, averaging temperatures measured from more than one reference peak offers several advantages including improving the reproducibility, i.e. precision, of the measurement. This paper proposes theoretically and empirically optimal weighting factors to improve the weighted average of temperatures measured from three references. Methods: We first proposed concepts of equivalent noise and equivalent signal-to-noise ratio in terms of frequency measurement and a concept of relative frequency that allows the combination of different peaks in a spectrum for improving the accuracy of frequency measurement. Based on these, we then developed a theoretically optimal weighting factor and suggested an empirical weighting factor for weighted average of temperatures measured from three references in 1H MRS-based thermometry. We assessed the two new weighting factors, together with other two previously proposed weighting factors, by comparing the errors of temperatures measured from individual references and the errors of averaged temperatures using these differing weighting factors. These errors were defined as the standard deviations in repeated measurements and in Monte Carlo studies. We also performed computer simulations to aid error analyses in temperature averaging. Results: Both the proposed theoretical and empirical weighting factors outperformed the other two previously proposed weighting factors as well as the three individual references in all phantom and in vivo experiments. In phantom experiments with 4 Hz or 10 Hz line broadening, the theoretical weighting outperformed the empirical one, but the latter was superior in all other repeated and Monte Carlo tests performed on phantom and in vivo data. Computer simulations offered explanations for the performances of the two new proposed weightings. Conclusion: The proposed two new weighting factors are superior to the two previously proposed weighting factors and can improve the measurement of temperature using 1H MRS-based thermometry.

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Relationship of Brain Glutamate Response to D-Cycloserine and Lurasidone to Antidepressant Response in Bipolar Depression: A Pilot Study

Cited by 9 publications

References 55 publications

D-Serine: A Cross Species Review of Safety

D-Serine: A Cross Species Review of Safety

Substrate Reduction Therapy for Krabbe Disease: Exploring the Repurposing of the Antibiotic D-Cycloserine

Improving reproducibility of proton MRS brain thermometry: theoretical and empirical approaches

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