{"doi":"10.3389/fpsyt.2021.653026","title":"Relationship of Brain Glutamate Response to D-Cycloserine and Lurasidone to Antidepressant Response in Bipolar Depression: A Pilot Study","abstract":"<jats:p>N-methyl-D-aspartate glutamate-receptor (NMDAR) antagonists such as ketamine have demonstrated efficacy in both major depressive disorder (MDD) and bipolar disorder depression (BP-D). We have previously reported that reduction in Glx (glutamate + glutamine) in the ventromedial prefrontal cortex/anterior cingulate cortex (vmPFC/ACC), measured by proton magnetic resonance spectroscopy (<jats:sup>1</jats:sup>H MRS) at 3T during a ketamine infusion, mediates the relationship of ketamine dose and blood level to improvement in depression. In the present study, we assessed the impact of <jats:sc>D</jats:sc>-cycloserine (DCS), an oral NMDAR antagonist combined with lurasidone in BP-D on both glutamate and Glx. Subjects with DSM-V BP-D-I/II and a Montgomery-Asberg Depression Rating Scale (MADRS) score&amp;gt;17, underwent up to three <jats:sup>1</jats:sup>H MRS scans. During Scan 1, subjects were randomized to receive double-blind lurasidone 66 mg or placebo. During Scan 2, all subjects received single-blind DCS 950 mg + lurasidone 66 mg, followed by 4 weeks of open label phase of DCS+lurasidone and an optional Scan 3. Five subjects received lurasidone alone and three subjects received placebo for Scan 1. Six subjects received DCS+lurasidone during Scan 2. There was no significant baseline or between treatment-group differences in acute depression improvement or glutamate response. In Scan 2, after a dose of DCS+lurasidone, peak change in glutamate correlated negatively with improvement from baseline MADRS (r = −0.83, <jats:italic>p</jats:italic> = 0.04). There were no unexpected adverse events. These preliminary pilot results require replication but provide further support for a link between antidepressant effect and a decrease in glutamate by the NMDAR antagonist class of antidepressants.</jats:p>","journal":"Frontiers in Psychiatry","year":2021,"id":646310,"datarank":0.3958585994422889,"base_score":2.639057329615259,"endowment":2.639057329615259,"self_citation_contribution":0.3958585994422889,"citation_network_contribution":0.0,"self_endowment_contribution":0.3958585994422889,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":13,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":345570,"name":"Michael F. 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In the present study, we assessed the impact of <jats:sc>D</jats:sc>-cycloserine (DCS), an oral NMDAR antagonist combined with lurasidone in BP-D on both glutamate and Glx. Subjects with DSM-V BP-D-I/II and a Montgomery-Asberg Depression Rating Scale (MADRS) score&amp;gt;17, underwent up to three <jats:sup>1</jats:sup>H MRS scans. During Scan 1, subjects were randomized to receive double-blind lurasidone 66 mg or placebo. During Scan 2, all subjects received single-blind DCS 950 mg + lurasidone 66 mg, followed by 4 weeks of open label phase of DCS+lurasidone and an optional Scan 3. Five subjects received lurasidone alone and three subjects received placebo for Scan 1. Six subjects received DCS+lurasidone during Scan 2. There was no significant baseline or between treatment-group differences in acute depression improvement or glutamate response. In Scan 2, after a dose of DCS+lurasidone, peak change in glutamate correlated negatively with improvement from baseline MADRS (r = −0.83, <jats:italic>p</jats:italic> = 0.04). There were no unexpected adverse events. These preliminary pilot results require replication but provide further support for a link between antidepressant effect and a decrease in glutamate by the NMDAR antagonist class of antidepressants.</jats:p>","is_dataset_classified":null,"base_score":2.639057329615259,"endowment":2.639057329615259,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"34149476","pmcid":"PMC8208505","openalex_id":"https://openalex.org/W3168202391","authors":[],"funders":[],"total_grants":0,"fwci":1.5122,"citation_percentile":0.80919553,"influential_citations":0,"citation_trend":[{"year":2021,"count":4},{"year":2022,"count":4},{"year":2023,"count":1},{"year":2024,"count":1},{"year":2025,"count":3}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.frontiersin.org/articles/10.3389/fpsyt.2021.653026/pdf","host_type":"journal"},{"url":"https://www.frontiersin.org/articles/10.3389/fpsyt.2021.653026/pdf","host_type":"publisher"},{"url":"https://www.frontiersin.org/articles/10.3389/fpsyt.2021.653026/full","host_type":"publisher"},{"url":"https://doi.org/10.3389/fpsyt.2021.653026","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/34149476","host_type":"repository"},{"url":"https://doaj.org/article/90870e5f05f849b0aa4d2ed27c3f7f09","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/8208505","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC8208505","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC8208505?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["Treatment of Major Depression","Tryptophan and brain disorders","Bipolar Disorder and Treatment"],"mesh_terms":[],"keywords":["Lurasidone","Antidepressant","Anterior cingulate cortex","Major depressive disorder","Escitalopram","Psychology","Glutamate receptor","Placebo","Internal medicine","Partial agonist","Bipolar disorder","Ventromedial prefrontal cortex","Aripiprazole","Medicine","Anesthesia","Pharmacology","Prefrontal cortex","Psychiatry","Schizophrenia (object-oriented programming)","Agonist","Mood","Antipsychotic","Amygdala","Hippocampus","Receptor","Glutamate","Biomarker","N-methyl-D-aspartate","Bipolar Depression","D-cycloserine","Mrs—1h Nuclear Magnetic Resonance Spectra"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[{"name":"nct"}],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-09T12:34:11.239452Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}