Steven Madonick

Publications (5)32.42 Total impact

• Article: Enhanced sensitivity to the euphoric effects of alcohol in schizophrenia.

  Deepak C D'Souza, Roberto B Gil, Steven Madonick, Edward B Perry, Kimberlee Forselius-Bielen, Gabriel Braley, Lia Donahue, Tahir Tellioglu, Zoran Zimolo, Ralitza Gueorguieva, John H Krystal
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  ABSTRACT: The purpose of this study was to determine whether schizophrenia was associated with alterations in alcohol response that might explain the elevated risk for AUDs in this population. In a randomized, double-blind, placebo-controlled, counter-balanced 3 test day laboratory study, the effects of alcohol were compared in 23 subjects with schizophrenia (without any previous alcohol use disorder (AUD) but with some alcohol exposure) and in 14 healthy subjects matched for age, gender, education, and lifetime exposure to alcohol. Standard alcohol drinks in a scheduled design were administered to produce blood alcohol levels of 0, 0.02-0.04 mg%, or 0.06-0.08 mg%. Schizophrenia symptoms, perceptual alterations, stimulant and depressant subjective effects of alcohol, and 'high' were measured before alcohol administration and at several post-drug time points. Verbal learning and recall, vigilance and distractibility, and motor function were assessed once per test day. Relative to healthy subjects, subjects with schizophrenia reported greater euphoria and stimulatory effects in response to alcohol. Alcohol produced small transient increases in positive psychotic symptoms and perceptual alterations without affecting negative symptoms. Alcohol also impaired several aspects of immediate and delayed recall, and vigilance, and distractibility. Schizophrenia patients showed increased euphoric and stimulatory responses to alcohol. These exaggerated positive responses to alcohol doses may contribute to the increased risk for AUDs associated with schizophrenia. The absence of 'beneficial' effects of alcohol does not support a self-medication hypothesis of alcohol use in schizophrenia.
  Neuropsychopharmacology 01/2007; 31(12):2767-75. · 7.99 Impact Factor
• Article: Potentiation of low dose ketamine effects by naltrexone: potential implications for the pharmacotherapy of alcoholism.

  John H Krystal, Steven Madonick, Edward Perry, Ralitza Gueorguieva, Laura Brush, Yola Wray, Aysenil Belger, Deepak Cyril D'Souza
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  ABSTRACT: The interplay of opiate and NMDA glutamate receptors may contribute to psychosis, cognitive function, alcoholism, and substance dependence. Ketamine and ethanol block the NMDA glutamate receptor. The purpose of this randomized double-blind, placebo-controlled human laboratory study was to evaluate whether the interactive effects of drugs acting at opiate and NMDA glutamate receptors might partially explain the efficacy of naltrexone for the treatment of alcoholism, that is, whether naltrexone 25 mg pretreatment would modulate ketamine effects in healthy human subjects. Two groups of healthy subjects were studied. An initial group (n=31) received a perception-altering subanesthetic dose of ketamine (bolus of 0.23 mg/kg over 1 min followed by a 60-min infusion of 0.58 mg/kg or saline bolus and infusion). A second group (n=24) completed the same testing procedures, but received a subperceptual ketamine dose (bolus 0.081 mg/kg over 10 min followed by an infusion of 0.4 mg/kg/h). Ketamine produced positive symptoms, negative symptoms, emotional discomfort, and cognitive effects as measured by the Positive and Negative Syndrome Scale (PANSS) in a dose-related fashion. The lower ketamine dose produced subjective effects similar to two standard ethanol drinks, whereas the higher ketamine dose produced effects similar to five standard drinks. Although naltrexone produced no significant behavioral effects, it significantly magnified the increase in the total PANSS score produced by the lower subperceptual dose of ketamine, but not the higher perception-altering dose of ketamine. These data suggest that the interplay of opiate receptor antagonism and NMDA receptor antagonism may be relevant to the protective effects of naltrexone on alcohol consumption via potentiation of dysphoric effects associated with the NMDA receptor antagonist effects of ethanol. However, these data suggest that at levels of NMDA receptor antagonism associated with heavy drinking, this protective effect of naltrexone on drinking is no longer present.
  Neuropsychopharmacology 09/2006; 31(8):1793-800. · 7.99 Impact Factor
• Article: Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine.

  Hyun-Sang Cho, Deepak C D'Souza, Ralitza Gueorguieva, Edward B Perry, Steven Madonick, Laurence P Karper, Anissa Abi-Dargham, Aysenil Belger, Walid Abi-Saab, Deborah Lipschitz, Alexandre Bennet, John P Seibyl, John H Krystal
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  ABSTRACT: Sensitization to the effects of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists is robust in animals. However, the applicability of this model to humans is unclear because it currently rests on highly confounded retrospective studies of individuals who experienced protracted psychoses following repeated binges with NMDA receptor antagonists. The purpose of the current study was to determine whether there was evidence of sensitization to the behavioral effects of ketamine in healthy human subjects with repeated exposure to this drug. Data were studied from 295 healthy human subjects who participated in one or more of 11 separate studies that involved ketamine administration over 14 years. Positive and negative symptoms (Brief Psychiatric Rating Scale: BPRS), perceptual alterations (Clinician-Administered Dissociative States Scale: CADSS), and "high" and "anxiety" states (Visual Analog Scale: VAS) that were measured in all studies were included as outcome measures. After including the number of previous exposures, number of previous studies, and time since first exposure as variables, repeated exposure to ketamine did not result in increased behavioral responses, suggestive of behavioral sensitization. The current data do not provide evidence that repeated exposure to ketamine, albeit limited, is associated with sensitization to the behavioral effects of ketamine.
  Psychopharmacologia 05/2005; 179(1):136-43. · 4.08 Impact Factor
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  Available from: ukcia.org

  Article: Delta-9-tetrahydrocannabinol effects in schizophrenia: implications for cognition, psychosis, and addiction.

  Deepak Cyril D'Souza, Walid Michel Abi-Saab, Steven Madonick, Kimberlee Forselius-Bielen, Anne Doersch, Gabriel Braley, Ralitza Gueorguieva, Thomas B Cooper, John Harrison Krystal
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  ABSTRACT: Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and psychotic disorders. In a 3-day, double-blind, randomized, placebo-controlled study, the behavioral, cognitive, motor, and endocrine effects of 0 mg, 2.5 mg, and 5 mg intravenous Delta-9-tetrahydrocannabinol (Delta-9-THC) were characterized in 13 stable, antipsychotic-treated schizophrenia patients. These data were compared with effects in healthy subjects reported elsewhere. Delta-9-tetrahydrocannabinol transiently increased 1) learning and recall deficits; 2) positive, negative, and general schizophrenia symptoms; 3) perceptual alterations; 4) akathisia, rigidity, and dyskinesia; 5) deficits in vigilance; and 6) plasma prolactin and cortisol. Schizophrenia patients were more vulnerable to Delta-9-THC effects on recall relative to control subjects. There were no serious short- or long-term adverse events associated with study participation. Delta-9-tetrahydrocannabinol is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia. These data do not provide a reason to explain why schizophrenia patients use or misuse cannabis. Furthermore, Delta-9-THC might differentially affect schizophrenia patients relative to control subjects. Finally, the enhanced sensitivity to the cognitive effects of Delta-9-THC warrants further study into whether brain cannabinoid receptor dysfunction contributes to the pathophysiology of the cognitive deficits associated with schizophrenia.
  Biological Psychiatry 04/2005; 57(6):594-608. · 8.28 Impact Factor
• Article: Absence of behavioral sensitization in healthy human subjects following repeated exposure to ketamine

  Hyun-Sang Cho, Deepak C. D’Souza, Ralitza Gueorguieva, Edward B. Perry, Steven Madonick, Laurence P. Karper, Anissa Abi-Dargham, Aysenil Belger, Walid Abi-Saab, Deborah Lipschitz, Alexandre Bennet, John P. Seibyl, John H. Krystal
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  ABSTRACT: RationaleSensitization to the effects of N-methyl-d-aspartate (NMDA) glutamate receptor antagonists is robust in animals. However, the applicability of this model to humans is unclear because it currently rests on highly confounded retrospective studies of individuals who experienced protracted psychoses following repeated binges with NMDA receptor antagonists.ObjectivesThe purpose of the current study was to determine whether there was evidence of sensitization to the behavioral effects of ketamine in healthy human subjects with repeated exposure to this drug.MethodsData were studied from 295 healthy human subjects who participated in one or more of 11 separate studies that involved ketamine administration over 14years. Positive and negative symptoms (Brief Psychiatric Rating Scale: BPRS), perceptual alterations (Clinician-Administered Dissociative States Scale: CADSS), and high and anxiety states (Visual Analog Scale: VAS) that were measured in all studies were included as outcome measures.ResultsAfter including the number of previous exposures, number of previous studies, and time since first exposure as variables, repeated exposure to ketamine did not result in increased behavioral responses, suggestive of behavioral sensitization.ConclusionsThe current data do not provide evidence that repeated exposure to ketamine, albeit limited, is associated with sensitization to the behavioral effects of ketamine.
  Psychopharmacologia 03/2005; 179(1):136-143. · 4.08 Impact Factor