- Email: [email protected]
Pharmacologic properties and antipsychotic effect of (-)-3PPP in schizophrenic patients
241
METHODS: Healthy subjects (n=17) completed 3 test days in a randomized order in which a medication (placebo, ketamine 0.1 m&g, or ketamine 0.5 mg/kg i.v. over 40 min.). RESULTS: Ketamine did not affect total Mini-mental Status Examination scores. Ketamine dose-dependently produced the positive symptoms of schizophrenia assessed by the BPRS Thought Disorder Factor (p=O.OOOl), negative symptoms assessed by the BPRS Withdrawal-Retardation Factor (p=O.OOOl), and dissociative symptoms assessed by the Clinician-Administered Dissociation Scale (p=O.OOOl). There was a small but significant dose-related impairment in indices related to frontal lobe function including attention (Gordon Box Vigilence CPT, p=O.O02), verbal fluency (p=O.O5), and Wisconsin Card Sort Perseverative Errors (p=O.O3). Ketamine dose-dependently interfered with delayed recall, but had little effect on immediate recall or postinterference recall (Dose x Delay x Time: p=O.O002). There were dose-dependent increases in plasma prolactin (p=O.OOl) and cortisol (p=O.Ol), while ketamine appeared to dose-dependently suppress plasma HVA (p=O.O02). IMPLICATIONS: These data provide evidence of contributions of NMDA receptors to attention, frontal lobe function, and tempero-hippocampal function in humans. They also provide further evidence that NMDA antagonists elicit positive and negative symptoms of schizophrenia in healthy humans.
KETAMINE EFFECTS REDUCED BY LORAZEPAM IN HEALTHY HUMANS John H. Krystal*, Laurence P. Karper, Anissa Abi-Dargham, Ricnard Delaney, J. Douglas Bremner, Malcolm B. Bowers, Dennis S. Chamey Department
of Psychiatry,
West Haven VA Medical
Yale University Center,
School of Medicine,
West Haven,
CT 06516,
USA
In healthy subjects, the NMDA antagonist, ketamine, did not effect the Mini-Mental Status Examination, but dose-dependently produced positive and negative symptoms of schizophrenia, dissociative symptoms, impairments in vigilance, performance impairments on tests of frontal lobe function, and selective tmpairments in delayed recall that spared immediate and postdistraction recall. This study evaluated the capacity of lorazepam, an agent used to treat PCP intoxication, to reverse ketamine effects. METHODS: In an ongoing study (n=5), healthy subjects completed 4 test days in a randomized order: 1) ketamine + placebo lorazepam, 2) placebo ketamine + placebo lorazepam, 3) ketamine + lorazepam (3 mg, p.o.), or 4) placebo ketamine + lorazepam. Ketamine was administered as a bolus of 0.26 m&g over 2 min. followed by a one-hour infusion of 0.65 mg/kg. RESULTS: In 5/5 subjects, lorazepam reduced ketamine effects: BPRS positive and negative symptoms, dissociative symptoms on the WHDES, vigilence impairments on the CPI, perseverative errors on the Wisconsin Card Sort, decrements in verbal fluency, and impairments in delayed recall. IMPLICATIONS: These data suggest that lorazepam reduces the behavioural effects produced by NMDA antagonists beyond
providing anxiolysis. Interactions of GABA-excitatory amino acid systems that might underly the findings observed in this study will be reviewed.
PHARMACOLOGIC PROPERTIES AND ANTIPSYCHOTIC EFFECT OF (-)-3PPP IN SCHIZOPHRENIC PATIENTS A.C. Lahti*, N.G. Cascella, R. Conley, R.A. Lahti, A. Carlsson, CA. Tamminga Maryland
Psychiatric
Baltimore,
MD 21228,
Research
Center,
University
of Maryland,
USA
(-)-3PPP (preclamol) is a partial dopamine (DA) agonist with potent autoreceptor agonist properties and partial limbic selectivity. The drug decreases DA synthesis and release, thereby reducing DA-mediated neurotransmission. Thus, it is an interesting candidate as an antipsychotic agent. A phase I safety study in 8 male schizophrenic patients showed the drug to be safe at doses up to 40 mg given intramuscularly. A linear dose-plasma level relationship was found across the doses tested. Peak plasma levels occurred at 15-30 minutes after a single dose. Peak plasma level in the range of 200 and 500 nanomolar were achieved at 40 mg in all subjects. Plasma GH levels increased linearly be tween 1 and 30 mg. At 40 mg, however, the levels were not elevated. Overall, subjects reported feeling more “relaxed.” Among the 4 subjects who received doses up to 40 mg, one subject showed a moderate drop in psychosis and one a more dramatic reduction in symptoms. An oral bioavailability in the range of 4% was calculated from a subject who received both IM and PO drug. The next phase of the study was to establish an oral dose range; 3 different oral doses of (-)-3PPP (20&400 and 500 mg tid) and a placebo, were given blindly for a week and in random order. Again, a linear dose-plasma level relationship was found and mean plasma levels were between 100 and 300 pmol/ ml at the highest dose. No side effects were apparent. At a dose of 200 mg/tid, but not 400 mg or 500 mg, one of the patients presented a clinical improvement with a decrease in psychosis scores. There were no carried over effects of the drug over time. In view of these results, we have now begun a 6 week doubleblind placebo-controlled cross-over study to determine the antipsychotic efficacy of the drug. These preliminary data suggest that (-)-3PPP is a safe drug, and in some patients, but not all, it may reduce psychotic symptoms.
CAN NMDA ANTAGONISTS HELP US UNDERSTAND THE PSYCHOSIS MECHANISM IN SCHIZOPHRENIA? A.C. Lahti*, X.M. Gao, N.G. Cascella, B. Mokriski, D. LaPorte, R.A. Lahti, C.A. Tamminga Maryland Baltimore,
Psychiatric MD 21228,
Research USA
Center,
University
of Maryland.
METHODS: Healthy subjects (n=17) completed 3 test days in a randomized order in which a medication (placebo, ketamine 0.1 m&g, or ketamine 0.5 mg/kg i.v. over 40 min.). RESULTS: Ketamine did not affect total Mini-mental Status Examination scores. Ketamine dose-dependently produced the positive symptoms of schizophrenia assessed by the BPRS Thought Disorder Factor (p=O.OOOl), negative symptoms assessed by the BPRS Withdrawal-Retardation Factor (p=O.OOOl), and dissociative symptoms assessed by the Clinician-Administered Dissociation Scale (p=O.OOOl). There was a small but significant dose-related impairment in indices related to frontal lobe function including attention (Gordon Box Vigilence CPT, p=O.O02), verbal fluency (p=O.O5), and Wisconsin Card Sort Perseverative Errors (p=O.O3). Ketamine dose-dependently interfered with delayed recall, but had little effect on immediate recall or postinterference recall (Dose x Delay x Time: p=O.O002). There were dose-dependent increases in plasma prolactin (p=O.OOl) and cortisol (p=O.Ol), while ketamine appeared to dose-dependently suppress plasma HVA (p=O.O02). IMPLICATIONS: These data provide evidence of contributions of NMDA receptors to attention, frontal lobe function, and tempero-hippocampal function in humans. They also provide further evidence that NMDA antagonists elicit positive and negative symptoms of schizophrenia in healthy humans.
KETAMINE EFFECTS REDUCED BY LORAZEPAM IN HEALTHY HUMANS John H. Krystal*, Laurence P. Karper, Anissa Abi-Dargham, Ricnard Delaney, J. Douglas Bremner, Malcolm B. Bowers, Dennis S. Chamey Department
of Psychiatry,
West Haven VA Medical
Yale University Center,
School of Medicine,
West Haven,
CT 06516,
USA
In healthy subjects, the NMDA antagonist, ketamine, did not effect the Mini-Mental Status Examination, but dose-dependently produced positive and negative symptoms of schizophrenia, dissociative symptoms, impairments in vigilance, performance impairments on tests of frontal lobe function, and selective tmpairments in delayed recall that spared immediate and postdistraction recall. This study evaluated the capacity of lorazepam, an agent used to treat PCP intoxication, to reverse ketamine effects. METHODS: In an ongoing study (n=5), healthy subjects completed 4 test days in a randomized order: 1) ketamine + placebo lorazepam, 2) placebo ketamine + placebo lorazepam, 3) ketamine + lorazepam (3 mg, p.o.), or 4) placebo ketamine + lorazepam. Ketamine was administered as a bolus of 0.26 m&g over 2 min. followed by a one-hour infusion of 0.65 mg/kg. RESULTS: In 5/5 subjects, lorazepam reduced ketamine effects: BPRS positive and negative symptoms, dissociative symptoms on the WHDES, vigilence impairments on the CPI, perseverative errors on the Wisconsin Card Sort, decrements in verbal fluency, and impairments in delayed recall. IMPLICATIONS: These data suggest that lorazepam reduces the behavioural effects produced by NMDA antagonists beyond
providing anxiolysis. Interactions of GABA-excitatory amino acid systems that might underly the findings observed in this study will be reviewed.
PHARMACOLOGIC PROPERTIES AND ANTIPSYCHOTIC EFFECT OF (-)-3PPP IN SCHIZOPHRENIC PATIENTS A.C. Lahti*, N.G. Cascella, R. Conley, R.A. Lahti, A. Carlsson, CA. Tamminga Maryland
Psychiatric
Baltimore,
MD 21228,
Research
Center,
University
of Maryland,
USA
(-)-3PPP (preclamol) is a partial dopamine (DA) agonist with potent autoreceptor agonist properties and partial limbic selectivity. The drug decreases DA synthesis and release, thereby reducing DA-mediated neurotransmission. Thus, it is an interesting candidate as an antipsychotic agent. A phase I safety study in 8 male schizophrenic patients showed the drug to be safe at doses up to 40 mg given intramuscularly. A linear dose-plasma level relationship was found across the doses tested. Peak plasma levels occurred at 15-30 minutes after a single dose. Peak plasma level in the range of 200 and 500 nanomolar were achieved at 40 mg in all subjects. Plasma GH levels increased linearly be tween 1 and 30 mg. At 40 mg, however, the levels were not elevated. Overall, subjects reported feeling more “relaxed.” Among the 4 subjects who received doses up to 40 mg, one subject showed a moderate drop in psychosis and one a more dramatic reduction in symptoms. An oral bioavailability in the range of 4% was calculated from a subject who received both IM and PO drug. The next phase of the study was to establish an oral dose range; 3 different oral doses of (-)-3PPP (20&400 and 500 mg tid) and a placebo, were given blindly for a week and in random order. Again, a linear dose-plasma level relationship was found and mean plasma levels were between 100 and 300 pmol/ ml at the highest dose. No side effects were apparent. At a dose of 200 mg/tid, but not 400 mg or 500 mg, one of the patients presented a clinical improvement with a decrease in psychosis scores. There were no carried over effects of the drug over time. In view of these results, we have now begun a 6 week doubleblind placebo-controlled cross-over study to determine the antipsychotic efficacy of the drug. These preliminary data suggest that (-)-3PPP is a safe drug, and in some patients, but not all, it may reduce psychotic symptoms.
CAN NMDA ANTAGONISTS HELP US UNDERSTAND THE PSYCHOSIS MECHANISM IN SCHIZOPHRENIA? A.C. Lahti*, X.M. Gao, N.G. Cascella, B. Mokriski, D. LaPorte, R.A. Lahti, C.A. Tamminga Maryland Baltimore,
Psychiatric MD 21228,
Research USA
Center,
University
of Maryland.