2022
Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial
Abdallah CG, Roache JD, Gueorguieva R, Averill LA, Young-McCaughan S, Shiroma PR, Purohit P, Brundige A, Murff W, Ahn KH, Sherif MA, Baltutis EJ, Ranganathan M, D’Souza D, Martini B, Southwick SM, Petrakis IL, Burson RR, Guthmiller KB, López-Roca AL, Lautenschlager KA, McCallin JP, Hoch MB, Timchenko A, Souza SE, Bryant CE, Mintz J, Litz BT, Williamson DE, Keane TM, Peterson AL, Krystal JH. Dose-related effects of ketamine for antidepressant-resistant symptoms of posttraumatic stress disorder in veterans and active duty military: a double-blind, randomized, placebo-controlled multi-center clinical trial. Neuropsychopharmacology 2022, 47: 1574-1581. PMID: 35046508, PMCID: PMC8767037, DOI: 10.1038/s41386-022-01266-9.Peer-Reviewed Original ResearchConceptsPosttraumatic stress disorderClinical trialsOutcome measuresMontgomery-Åsberg Depression Rating ScaleSelf-report PTSD ChecklistÅsberg Depression Rating ScaleStress disorderPTSD symptomsAntidepressant-resistant symptomsPrevious antidepressant treatmentClinician-Administered PTSD ScaleMulti-center clinical trialRapid antidepressant effectsSecondary outcome measuresPrimary outcome measureSignificant dose-related effectsRole of ketamineDepression Rating ScaleDose-related effectsEffects of ketamineDSM-5Intravenous placeboDose ketamineTreatment discontinuationActive duty military
2020
A robust and reproducible connectome fingerprint of ketamine is highly associated with the connectomic signature of antidepressants
Abdallah CG, Ahn KH, Averill LA, Nemati S, Averill CL, Fouda S, Ranganathan M, Morgan PT, D’Souza D, Mathalon DH, Krystal JH, Driesen NR. A robust and reproducible connectome fingerprint of ketamine is highly associated with the connectomic signature of antidepressants. Neuropsychopharmacology 2020, 46: 478-485. PMID: 32967000, PMCID: PMC7852889, DOI: 10.1038/s41386-020-00864-9.Peer-Reviewed Original ResearchConceptsConnectome fingerprintN-methyl-d-aspartate modulatorsNovel rapid-acting antidepressantsMajor depressive disorder patientsMechanism of antidepressantsWeeks of sertralineRapid-acting antidepressantsMagnetic resonance imaging studyDepressive disorder patientsExecutive networkEffects of ketamineLongitudinal functional magnetic resonance imaging studyResonance imaging studyFunctional magnetic resonance imaging studyBrain functional connectivityCohort AIntravenous infusionSubanesthetic doseClinical trialsNormal salineDisorder patientsConnectomics signaturesBrain circuitryKetamineImaging studiesAssociation of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia
Beck K, Hindley G, Borgan F, Ginestet C, McCutcheon R, Brugger S, Driesen N, Ranganathan M, D’Souza D, Taylor M, Krystal JH, Howes OD. Association of Ketamine With Psychiatric Symptoms and Implications for Its Therapeutic Use and for Understanding Schizophrenia. JAMA Network Open 2020, 3: e204693. PMID: 32437573, PMCID: PMC7243091, DOI: 10.1001/jamanetworkopen.2020.4693.Peer-Reviewed Original ResearchConceptsBrief Psychiatric Rating ScalePlacebo conditionPositive symptomsNegative symptomsHealthy participantsMean differenceKetamine administrationPANSS scoresHealthy volunteersPsychotomimetic symptomsTherapeutic useAcute ketamine administrationAcute ketamine challengePlacebo-controlled studyEffect sizeMagnitude of symptomsStudy-level dataPsychiatric Rating ScaleMeta-Analyses (PRISMA) guidelinesPreferred Reporting ItemsAssociation of ketamineNegative Syndrome ScaleSignificant increaseAcute administrationBolus dosesModulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin
Abdallah CG, Averill LA, Gueorguieva R, Goktas S, Purohit P, Ranganathan M, Sherif M, Ahn KH, D’Souza D, Formica R, Southwick SM, Duman RS, Sanacora G, Krystal JH. Modulation of the antidepressant effects of ketamine by the mTORC1 inhibitor rapamycin. Neuropsychopharmacology 2020, 45: 990-997. PMID: 32092760, PMCID: PMC7162891, DOI: 10.1038/s41386-020-0644-9.Peer-Reviewed Original ResearchConceptsAntidepressant effectsKetamine administrationRapamycin pretreatmentMontgomery-Åsberg Depression Rating ScaleDouble-blind cross-over designBenefits of ketamineRobust antidepressant effectsKetamine's antidepressant effectsMajor depressive episodeDepression Rating ScaleCross-over designKetamine exertsOral rapamycinRemission rateDepressive episodePlacebo 2Ketamine 0.5Local blockadeDepressed patientsIntravenous administrationTreatment daysDepression relapseDepression severityKetamineRating Scale
2018
Dose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects
D’Souza D, Carson RE, Driesen N, Johannesen J, Ranganathan M, Krystal JH, Ahn K, Bielen K, Carbuto M, Deaso E, D’Souza D, Ranganathan M, Naganawa M, Ranganathan M, D’Souza D, Nabulsi N, Zheng M, Lin S, Huang Y, Carson R, Driesen N, Ahn K, Morgan P, Suckow R, He G, McCarthy G, Krystal J, Johannesen J, Kenney J, Gelernter J, Gueorguieva R, Pittman B. Dose-Related Target Occupancy and Effects on Circuitry, Behavior, and Neuroplasticity of the Glycine Transporter-1 Inhibitor PF-03463275 in Healthy and Schizophrenia Subjects. Biological Psychiatry 2018, 84: 413-421. PMID: 29499855, PMCID: PMC6068006, DOI: 10.1016/j.biopsych.2017.12.019.Peer-Reviewed Original ResearchMeSH KeywordsAdultAzabicyclo CompoundsBrainCognitive DysfunctionDose-Response Relationship, DrugDouble-Blind MethodFemaleGlycine Plasma Membrane Transport ProteinsHumansImidazolesKetamineLong-Term PotentiationMagnetic Resonance ImagingMaleMemory, Short-TermMiddle AgedPositron-Emission TomographySchizophreniaYoung AdultConceptsHealthy control subjectsLong-term potentiationSchizophrenia patientsControl subjectsCognitive impairmentClinical trialsGlyT1 occupancyN-methyl-D-aspartate receptor functionGlycine transporter-1 inhibitorKetamine-induced disruptionKetamine-induced effectsFunctional magnetic resonance imagingMagnetic resonance imagingPositron emission tomographyMemory-related activationF-MKSubstudy 1Schizophrenia subjectsResonance imagingReceptor functionCortical regionsEmission tomographyTarget engagementPotentiationSchizophrenia
2017
Interactive effects of an N-methyl-d-aspartate receptor antagonist and a nicotinic acetylcholine receptor agonist on mismatch negativity: Implications for schizophrenia
Hamilton HK, D'Souza DC, Ford JM, Roach BJ, Kort NS, Ahn KH, Bhakta S, Ranganathan M, Mathalon DH. Interactive effects of an N-methyl-d-aspartate receptor antagonist and a nicotinic acetylcholine receptor agonist on mismatch negativity: Implications for schizophrenia. Schizophrenia Research 2017, 191: 87-94. PMID: 28711472, PMCID: PMC5745273, DOI: 10.1016/j.schres.2017.06.040.Peer-Reviewed Original ResearchConceptsNicotinic acetylcholine receptor agonistAcetylcholine receptor agonistReceptor agonistHealthy volunteersN-methyl-D-aspartate receptor antagonistPathophysiology of schizophreniaAuditory processing abnormalitiesProfile of effectsMMN amplitudeNicotine preventsNicotine administrationReceptor hypofunctionNMDAR hypofunctionNMDAR antagonistsReceptor antagonistMismatch negativity (MMN) event-related potential (ERP) componentPresent doseNicotinic agonistsSchizophrenia patientsCigarette useKetamineDeviant typesNeurophysiological effectsSecondary analysisMMN abnormalitiesAttenuation of ketamine-induced impairment in verbal learning and memory in healthy volunteers by the AMPA receptor potentiator PF-04958242
Ranganathan M, DeMartinis N, Huguenel B, Gaudreault F, Bednar MM, Shaffer CL, Gupta S, Cahill J, Sherif MA, Mancuso J, Zumpano L, D’Souza D. Attenuation of ketamine-induced impairment in verbal learning and memory in healthy volunteers by the AMPA receptor potentiator PF-04958242. Molecular Psychiatry 2017, 22: 1633-1640. PMID: 28242871, DOI: 10.1038/mp.2017.6.Peer-Reviewed Original ResearchConceptsKetamine-induced impairmentVerbal learningAMPAR potentiatorsHopkins Verbal Learning TestN-methyl-D-aspartate receptorsVerbal Learning TestDissociative Symptoms ScaleKetamine-induced deficitsPsychotomimetic effectsMemory taskImmediate recallLearning TestCogState batteryMemory deficitsNegative Syndrome ScaleTreatment periodCognitive symptomsNMDAR functioningNMDAR antagonist ketamineNonhuman primatesNegative symptomsCognitive impairmentMemoryIsoxazolepropionic acid (AMPA) receptorsPathophysiology of schizophrenia
2013
The Impact of NMDA Receptor Blockade on Human Working Memory-Related Prefrontal Function and Connectivity
Driesen NR, McCarthy G, Bhagwagar Z, Bloch MH, Calhoun VD, D'Souza DC, Gueorguieva R, He G, Leung HC, Ramani R, Anticevic A, Suckow RF, Morgan PT, Krystal JH. The Impact of NMDA Receptor Blockade on Human Working Memory-Related Prefrontal Function and Connectivity. Neuropsychopharmacology 2013, 38: 2613-2622. PMID: 23856634, PMCID: PMC3828532, DOI: 10.1038/npp.2013.170.Peer-Reviewed Original ResearchConceptsNMDA-RsRelationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans
Driesen NR, McCarthy G, Bhagwagar Z, Bloch M, Calhoun V, D'Souza DC, Gueorguieva R, He G, Ramachandran R, Suckow RF, Anticevic A, Morgan PT, Krystal JH. Relationship of resting brain hyperconnectivity and schizophrenia-like symptoms produced by the NMDA receptor antagonist ketamine in humans. Molecular Psychiatry 2013, 18: 1199-1204. PMID: 23337947, PMCID: PMC3646075, DOI: 10.1038/mp.2012.194.Peer-Reviewed Original ResearchConceptsFunctional connectivityNegative symptomsGamma-aminobutyric acid (GABA) neuronsNMDA receptor antagonist ketamineAspartate glutamate receptor antagonistContinuous ketamine infusionGlutamate receptor antagonistsNMDA-R antagonistsCortical functional connectivityNMDA-R antagonist ketamineSchizophrenia-like symptomsHealthy human subjectsNegative Syndrome ScaleBrain functional connectivityPrimary samplesRegion-specific mannerFunctional magnetic resonanceKetamine infusionReceptor antagonistPathological increaseSyndrome ScaleSymptomsPreclinical researchKetamineBrain oscillations
2012
Nicotine Fails to Attenuate Ketamine-Induced Cognitive Deficits and Negative and Positive Symptoms in Humans: Implications for Schizophrenia
D'Souza DC, Ahn K, Bhakta S, Elander J, Singh N, Nadim H, Jatlow P, Suckow RF, Pittman B, Ranganathan M. Nicotine Fails to Attenuate Ketamine-Induced Cognitive Deficits and Negative and Positive Symptoms in Humans: Implications for Schizophrenia. Biological Psychiatry 2012, 72: 785-794. PMID: 22717030, DOI: 10.1016/j.biopsych.2012.05.009.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAttentionCognitionCognition DisordersCross-Over StudiesDouble-Blind MethodDrug InteractionsExecutive FunctionHumansInhibition, PsychologicalKetamineMemoryMiddle AgedMotor SkillsNicotinePsychiatric Status Rating ScalesPsychomotor PerformanceReaction TimeRecognition, PsychologySchizophreniaConceptsCognitive deficitsPositive symptomsExecutive functionResponse inhibitionKetamine-induced cognitive deficitsChoice reaction time taskSpeed of processingReaction time taskReaction timeVisual memoryEmotion recognitionImmediate recallSustained attentionTime taskFeeling statesPerceptual alterationsSerial processingEffects of nicotineNegative symptomsMemoryBehavioral effectsDeficitsInteractive effectsNicotine infusionTest day
2011
Glycine Transporter Inhibitor Attenuates the Psychotomimetic Effects of Ketamine in Healthy Males: Preliminary Evidence
D'Souza DC, Singh N, Elander J, Carbuto M, Pittman B, de Haes J, Sjogren M, Peeters P, Ranganathan M, Schipper J. Glycine Transporter Inhibitor Attenuates the Psychotomimetic Effects of Ketamine in Healthy Males: Preliminary Evidence. Neuropsychopharmacology 2011, 37: 1036-1046. PMID: 22113087, PMCID: PMC3280648, DOI: 10.1038/npp.2011.295.Peer-Reviewed Original ResearchGlutamatergic Modulation of Auditory Information Processing in the Human Brain
Gunduz-Bruce H, Reinhart RM, Roach BJ, Gueorguieva R, Oliver S, D'Souza DC, Ford JM, Krystal JH, Mathalon DH. Glutamatergic Modulation of Auditory Information Processing in the Human Brain. Biological Psychiatry 2011, 71: 969-977. PMID: 22036036, PMCID: PMC3290754, DOI: 10.1016/j.biopsych.2011.09.031.Peer-Reviewed Original ResearchConceptsN-acetylcysteineAuditory mismatch negativityReceptor antagonistN-methyl-D-aspartate receptor antagonistAspartate glutamate receptor antagonistOral N-acetylcysteinePlacebo-controlled studyGlutamate receptor antagonistsEffects of ketamineInfusion of salineMismatch negativityTest dayMMN amplitudeCystine-glutamate exchangerAuditory information processingP300 event-related potentialGlutamatergic modulationCognitive enhancing agentsEvent-related potentialsKetamine effectsHealthy volunteersHealthy humansSchizophrenia patientsPositive symptomsKetamine
2010
Capgras Syndrome Induced by Ketamine in a Healthy Subject
Corlett PR, D'Souza DC, Krystal JH. Capgras Syndrome Induced by Ketamine in a Healthy Subject. Biological Psychiatry 2010, 68: e1-e2. PMID: 20385373, PMCID: PMC3721067, DOI: 10.1016/j.biopsych.2010.02.015.Peer-Reviewed Original Research
2007
Psychiatric safety of ketamine in psychopharmacology research
Perry EB, Cramer JA, Cho HS, Petrakis IL, Karper LP, Genovese A, O’Donnell E, Krystal JH, D’Souza D. Psychiatric safety of ketamine in psychopharmacology research. Psychopharmacology 2007, 192: 253-260. PMID: 17458544, DOI: 10.1007/s00213-007-0706-2.Peer-Reviewed Original ResearchConceptsSubanesthetic dosesHealthy human subjectsKetamine administrationClinical research programHuman subjectsTest sessionsPsychotic spectrum disordersPsychiatric safetyResidual sequelaePlacebo infusionIntravenous infusionKetamine effectsPsychopharmacology studiesResultsFour hundredAdverse reactionsObjectiveTo reportHealthy subjectsStudy participationClinical investigationHealthy humansSide effectsKetamineInfusionDosesAdministration
2006
Greater vulnerability to the amnestic effects of ketamine in males
Morgan CJ, Perry EB, Cho HS, Krystal JH, D’Souza D. Greater vulnerability to the amnestic effects of ketamine in males. Psychopharmacology 2006, 187: 405-414. PMID: 16896964, DOI: 10.1007/s00213-006-0409-0.Peer-Reviewed Original ResearchConceptsAmnestic effectsProcessing of wordsGeneral cognitive functioningGreater performance decrementsGreater subjective senseGender differencesObjectivesThe current studyGreater vulnerabilityCognitive measuresCognitive differencesCognitive functioningPerceptual alterationsPerformance decrementsNMDA-R functionAttention dataMemory impairmentSubjective senseNegative symptomsCurrent studyFunctioningHVLTKetamine studiesAnxietyMemoryKetamine administrationPotentiation of Low Dose Ketamine Effects by Naltrexone: Potential Implications for the Pharmacotherapy of Alcoholism
Krystal JH, Madonick S, Perry E, Gueorguieva R, Brush L, Wray Y, Belger A, D'Souza DC. Potentiation of Low Dose Ketamine Effects by Naltrexone: Potential Implications for the Pharmacotherapy of Alcoholism. Neuropsychopharmacology 2006, 31: 1793-1800. PMID: 16395307, DOI: 10.1038/sj.npp.1300994.Peer-Reviewed Original ResearchConceptsNMDA glutamate receptorsNMDA receptor antagonismKetamine doseReceptor antagonismGlutamate receptorsKetamine effectsProtective effectPlacebo-controlled human laboratory studyOpiate receptor antagonismEfficacy of naltrexoneDose-related fashionNMDA receptor antagonist effectsReceptor antagonist effectsTotal PANSS scoreHuman laboratory studiesPharmacotherapy of alcoholismTreatment of alcoholismHealthy human subjectsHigher ketamine doseNegative Syndrome ScaleLower ketamine doseSignificant behavioral effectsSubanesthetic dosePANSS scoresEthanol drink
2005
Comparative and Interactive Human Psychopharmacologic Effects of Ketamine and Amphetamine: Implications for Glutamatergic and Dopaminergic Model Psychoses and Cognitive Function
Krystal JH, Perry EB, Gueorguieva R, Belger A, Madonick SH, Abi-Dargham A, Cooper TB, MacDougall L, Abi-Saab W, D’Souza D. Comparative and Interactive Human Psychopharmacologic Effects of Ketamine and Amphetamine: Implications for Glutamatergic and Dopaminergic Model Psychoses and Cognitive Function. JAMA Psychiatry 2005, 62: 985-995. PMID: 16143730, DOI: 10.1001/archpsyc.62.9.985.Peer-Reviewed Original ResearchAbsence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine
Cho HS, D’Souza D, Gueorguieva R, Perry EB, Madonick S, Karper LP, Abi-Dargham A, Belger A, Abi-Saab W, Lipschitz D, Bennet A, Seibyl JP, Krystal JH. Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine. Psychopharmacology 2005, 179: 136-143. PMID: 15682309, DOI: 10.1007/s00213-004-2066-5.Peer-Reviewed Original ResearchConceptsHealthy human subjectsBehavioral sensitizationReceptor antagonistN-methyl-D-aspartate (NMDA) glutamate receptor antagonistBehavioral effectsHuman subjectsGlutamate receptor antagonistsNMDA receptor antagonistConclusionsThe current dataEvidence of sensitizationRetrospective studyKetamine administrationOutcome measuresNegative symptomsObjectivesThe purposePrevious exposureFirst exposureKetamineSensitizationAntagonistExposurePerceptual alterationsCurrent dataSeparate studiesSubjects
2004
Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects
Krystal JH, Abi-Saab W, Perry E, D’Souza D, Liu N, Gueorguieva R, McDougall L, Hunsberger T, Belger A, Levine L, Breier A. Preliminary evidence of attenuation of the disruptive effects of the NMDA glutamate receptor antagonist, ketamine, on working memory by pretreatment with the group II metabotropic glutamate receptor agonist, LY354740, in healthy human subjects. Psychopharmacology 2004, 179: 303-309. PMID: 15309376, DOI: 10.1007/s00213-004-1982-8.Peer-Reviewed Original ResearchConceptsGroup II metabotropic glutamate receptor agonistMetabotropic glutamate receptor agonistHealthy human subjectsNMDA glutamate receptor antagonistGlutamate receptor agonistsGlutamate receptor antagonistsTest dayCognitive effectsPerceptual changesKetamine infusionReceptor antagonistReceptor agonistDysphoric moodMemory impairmentBehavioral consequencesSignificant dose-related improvementGroup II mGluR agonistReceptor functionHuman subjectsMemoryNegative symptomsDose-related improvementNMDA receptor functionPreliminary evidenceDisruptive effects
2003
NMDA Receptor Antagonism and the Ethanol Intoxication Signal
KRYSTAL JH, PETRAKIS IL, KRUPITSKY E, SCHÜTZ C, TREVISAN L, D'SOUZA DC. NMDA Receptor Antagonism and the Ethanol Intoxication Signal. Annals Of The New York Academy Of Sciences 2003, 1003: 176-184. PMID: 14684445, DOI: 10.1196/annals.1300.010.Peer-Reviewed Original Research