Psychopharmacology (1992) 106: S 68-S 70
Psychopharmacology © Springer-Verlag 1992
Mini-Paper Comparative investigation of the effect of moclobemide and toloxatone on monoamine oxidase activity and psychometric performance in healthy subjects J. Dingemanse 1, I. Berlin 2, C. Payan 2, H.M. Thiede 3, and A.J. Pueeh 2 Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, CH-4002 Basel, Switzerland 2 Department of Clinical Pharmacology, H6pital de la Salp6tri6re, 47 BD. de L'H6pital, F-75013 Paris, France 3 I. medizinische Klinik, Klinikum Steglitz, W-1000 Berlin 45, Federal Republic of Germany
Abstract. The effects o f m o c l o b e m i d e and toloxatone, two reversible m o n o a m i n e oxidase-A inhibitors, on biochemical parameters that reflect m o n o a m i n e m e t a b o lism and on p s y c h o m o t o r p e r f o r m a n c e parameters were investigated in a study in 12 healthy volunteers. Treatments were given double-blind in a randomised, placebocontrolled cross-over design, with 1 week w a s h - o u t between the treatments. D r u g s were given thrice daily in the following doses: m o c l o b e m i d e 150-150-150 m g and tolo x a t o n e 400-200-400 rag. All assessments were performed on d a y 8 u n d e r standardized conditions. There was no difference with regard to adverse events between m o clobemide and toloxatone: b o t h drugs induced a slight decrease in b o t h supine and standing heart rate. J u d g e d on the basis o f the area under the curve, the two M A O inhibitors reduced the plasma levels o f D H P G and H V A , with m o r e p r o n o u n c e d effects for m o c l o b e m i d e than for toloxatone. After m o c l o b e m i d e M A O - A inhibition was almost c o n s t a n t over 24 h, whereas the effect o f toloxatone was short lasting after each dose. The same differences were reflected in plasma 5 - H I A A concentrations and urinary excretion o f 3 - m e t h o x y t y r a m i n e and normetanephine. Neither o f the c o m p o u n d s tested had any influence on the m e m o r y , vigilance, m o o d , or sleeping habits o f the subjects.
Key words: M o c l o b e m i d e
Toloxatone - Monoamine oxidase-A - Psychometric p e r f o r m a n c e
The therapeutic value o f m o n o a m i n e oxidase inhibitors ( M A O I s ) in the treatment o f depression is undeniable, but in order to reduce the risk o f hypertensive crises, selective and reversible M A O I s which only inhibit the Offprint requests to : J. Dingemanse
type A isoenzyme have been developed. Currently, toloxatone and m o c l o b e m i d e are the only reversible and selective M A O A inhibitors available for clinical use. The objectives o f this study in healthy subjects were to: 1. Assess and c o m p a r e the effects o f 1 week's administration o f placebo, moclobemide, and toloxatone on biochemical parameters that reflect m o n o a m i n e metabolism 2. Investigate the effects o f these three substances on vigilance, m e m o r y functions, subjective feelings, and subjective sleep characteristics
Materials and methods Subjects. Twelve healthy male volunteers, age 20-29 years and weighing 58-77 kg, participated in this study. All had normal results on three different psychological examinations. Design. Treatments were administered double-blind, according to a balanced Latin square design. Each treatment period was separated by 1 week of wash-out. Treatments were given for a period of 8 days: moclobemide 150mg t.i.d., toloxatone 40~20OM00 nag per day, and placebo t.i.d. Assessments. All assessments were performed on day 8. Norepinephrine, DHPG, 5-HIAA and HVA were determined in plasma every 2 h from T o to T16 and at T24 , with the morning dose as reference point. At the same time-points, normetanephrine and 3-methoxytyramine were determined in urine fractions. The metabolic pathways for the catecholamines are presented in Fig. 1. Heart rate and blood pressure were measured in supine and standing position every 2 h from T o to T12 and at T24. The following psychometric tests were performed just before intake of each medication: Vigilance: critical flicker fusion frequency choice reaction time digit symbol substitution test Memory: coupled words test picture test Subjective feelings: visual analogue rating scales Sleep characteristics: sleep questionnaire
S69 PNMT
DBH >
Dopamine
Norepinephrine
>
Epinephrine
OOMT
Fig. 1. Metabolic pathways of catecholamines. The underlined compounds were determined in this study, (DBH) dopamine-[3-hydroxylase; (PNMT) phenylethanol-N-methyltransferase; ( COMT) catechol-O-methyltransferase; (MA O) monoamine oxidase; (MHPG) 3-methoxy-4-hydroxyphenylglycol; ( VMA) vanillomandelic acid; (DOPAC) 3,4-dihydroxyphenylacetic acid; (MHPE) 3methoxy-4-hydroxyphenylethanol; (HVA) homovanillic acid; (DOMA) 3,4-dihydroxymandelic acid aldehyde; (DHPG) 3,4-dihydroxyphenylglycol
v COMT DOMA
3- Methoxy_tyramine
Normetanephrine
Metanephrine
DOPAC
Homovanillic aldehyde
/
MHPE
\
Vanillomandelic aldehyde
DHPG COMT ~ . ~
HVA
/ \
MHPG
Statistical analysis. For each variable, the area under the plasma concentration-time curve (AUC) was determined by the trapezoidal rule. The analysis was performed using an A N O V A for repeated measurements with the factors subject, time, period and treatment. If a significant treatment effect occurred, treatments were compared by the Tukey test. Psychometric test results were also analysed by ANOVA.
VMA
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50
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Results
;
8
1'2 24
90
Adverse events There was no difference with regard to adverse events between moclobemide and toloxatone. M o r e subjects reported one or more symptoms during active than during placebo treatment.
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2
4
6
8
10
12
24
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Heart rate and blood pressure N o modification of either systolic or diastolic blood pressure was found. A significant treatment effect occurred for supine and standing heart rate, but without any difference between the two active treatments (Fig. 2).
Plasma concentrations of DHPG, HVA, 5-HIAA and norepinephrine (Fig. 3) DHPG:
Both M A O I s decreased plasma D H P G as judged on AUC. The decrease was 44% on moclobemide and 12% on toloxatone (P
Psychopharmacology © Springer-Verlag 1992
Mini-Paper Comparative investigation of the effect of moclobemide and toloxatone on monoamine oxidase activity and psychometric performance in healthy subjects J. Dingemanse 1, I. Berlin 2, C. Payan 2, H.M. Thiede 3, and A.J. Pueeh 2 Department of Clinical Pharmacology, F. Hoffmann-La Roche Ltd, CH-4002 Basel, Switzerland 2 Department of Clinical Pharmacology, H6pital de la Salp6tri6re, 47 BD. de L'H6pital, F-75013 Paris, France 3 I. medizinische Klinik, Klinikum Steglitz, W-1000 Berlin 45, Federal Republic of Germany
Abstract. The effects o f m o c l o b e m i d e and toloxatone, two reversible m o n o a m i n e oxidase-A inhibitors, on biochemical parameters that reflect m o n o a m i n e m e t a b o lism and on p s y c h o m o t o r p e r f o r m a n c e parameters were investigated in a study in 12 healthy volunteers. Treatments were given double-blind in a randomised, placebocontrolled cross-over design, with 1 week w a s h - o u t between the treatments. D r u g s were given thrice daily in the following doses: m o c l o b e m i d e 150-150-150 m g and tolo x a t o n e 400-200-400 rag. All assessments were performed on d a y 8 u n d e r standardized conditions. There was no difference with regard to adverse events between m o clobemide and toloxatone: b o t h drugs induced a slight decrease in b o t h supine and standing heart rate. J u d g e d on the basis o f the area under the curve, the two M A O inhibitors reduced the plasma levels o f D H P G and H V A , with m o r e p r o n o u n c e d effects for m o c l o b e m i d e than for toloxatone. After m o c l o b e m i d e M A O - A inhibition was almost c o n s t a n t over 24 h, whereas the effect o f toloxatone was short lasting after each dose. The same differences were reflected in plasma 5 - H I A A concentrations and urinary excretion o f 3 - m e t h o x y t y r a m i n e and normetanephine. Neither o f the c o m p o u n d s tested had any influence on the m e m o r y , vigilance, m o o d , or sleeping habits o f the subjects.
Key words: M o c l o b e m i d e
Toloxatone - Monoamine oxidase-A - Psychometric p e r f o r m a n c e
The therapeutic value o f m o n o a m i n e oxidase inhibitors ( M A O I s ) in the treatment o f depression is undeniable, but in order to reduce the risk o f hypertensive crises, selective and reversible M A O I s which only inhibit the Offprint requests to : J. Dingemanse
type A isoenzyme have been developed. Currently, toloxatone and m o c l o b e m i d e are the only reversible and selective M A O A inhibitors available for clinical use. The objectives o f this study in healthy subjects were to: 1. Assess and c o m p a r e the effects o f 1 week's administration o f placebo, moclobemide, and toloxatone on biochemical parameters that reflect m o n o a m i n e metabolism 2. Investigate the effects o f these three substances on vigilance, m e m o r y functions, subjective feelings, and subjective sleep characteristics
Materials and methods Subjects. Twelve healthy male volunteers, age 20-29 years and weighing 58-77 kg, participated in this study. All had normal results on three different psychological examinations. Design. Treatments were administered double-blind, according to a balanced Latin square design. Each treatment period was separated by 1 week of wash-out. Treatments were given for a period of 8 days: moclobemide 150mg t.i.d., toloxatone 40~20OM00 nag per day, and placebo t.i.d. Assessments. All assessments were performed on day 8. Norepinephrine, DHPG, 5-HIAA and HVA were determined in plasma every 2 h from T o to T16 and at T24 , with the morning dose as reference point. At the same time-points, normetanephrine and 3-methoxytyramine were determined in urine fractions. The metabolic pathways for the catecholamines are presented in Fig. 1. Heart rate and blood pressure were measured in supine and standing position every 2 h from T o to T12 and at T24. The following psychometric tests were performed just before intake of each medication: Vigilance: critical flicker fusion frequency choice reaction time digit symbol substitution test Memory: coupled words test picture test Subjective feelings: visual analogue rating scales Sleep characteristics: sleep questionnaire
S69 PNMT
DBH >
Dopamine
Norepinephrine
>
Epinephrine
OOMT
Fig. 1. Metabolic pathways of catecholamines. The underlined compounds were determined in this study, (DBH) dopamine-[3-hydroxylase; (PNMT) phenylethanol-N-methyltransferase; ( COMT) catechol-O-methyltransferase; (MA O) monoamine oxidase; (MHPG) 3-methoxy-4-hydroxyphenylglycol; ( VMA) vanillomandelic acid; (DOPAC) 3,4-dihydroxyphenylacetic acid; (MHPE) 3methoxy-4-hydroxyphenylethanol; (HVA) homovanillic acid; (DOMA) 3,4-dihydroxymandelic acid aldehyde; (DHPG) 3,4-dihydroxyphenylglycol
v COMT DOMA
3- Methoxy_tyramine
Normetanephrine
Metanephrine
DOPAC
Homovanillic aldehyde
/
MHPE
\
Vanillomandelic aldehyde
DHPG COMT ~ . ~
HVA
/ \
MHPG
Statistical analysis. For each variable, the area under the plasma concentration-time curve (AUC) was determined by the trapezoidal rule. The analysis was performed using an A N O V A for repeated measurements with the factors subject, time, period and treatment. If a significant treatment effect occurred, treatments were compared by the Tukey test. Psychometric test results were also analysed by ANOVA.
VMA
80 -
Supine
75-
65
•
z~
60 55 co
50
,
i
®
Results
;
8
1'2 24
90
Adverse events There was no difference with regard to adverse events between moclobemide and toloxatone. M o r e subjects reported one or more symptoms during active than during placebo treatment.
¢~
85
Standing •
a
"-.Y 65 60
i
t
t
t
i
i
t
i
2
4
6
8
10
12
24
h
Heart rate and blood pressure N o modification of either systolic or diastolic blood pressure was found. A significant treatment effect occurred for supine and standing heart rate, but without any difference between the two active treatments (Fig. 2).
Plasma concentrations of DHPG, HVA, 5-HIAA and norepinephrine (Fig. 3) DHPG:
Both M A O I s decreased plasma D H P G as judged on AUC. The decrease was 44% on moclobemide and 12% on toloxatone (P
