Effects of Methyldopa on Psychometric Performance Brian
Johnson,
MD,
FCP,
Kathy
Hoch,
BS, Ann
Errichetti,
MD,
and
Johanna
Johnson,
MSN
Double-blind, crossover comparisons of methyldopa with placebo were performed in 16 patients with mild to moderate hypertension. Methyldopa (250 mg tid) for 14 days significantly reduced blood pressure, impaired card-sorting time and digital symbol substitution score, and caused trends for impairment of other psychometric tests. Effects of practice were greater than those of treatment on all tests other than card sorting, although no interaction impairs psychometric crossover studies are performance.
between performance, inadequate
treatment and but practice for detecting
H
ypertension is frequently symptomless until medications are prescribed, and adverse effects of antihypertensive agents are common causes for discontinuing treatment. Antihypertensive agents differ in risk of causing adverse effects and therefore in their impact on overall quality of life.1 Fatigue, depression, lethargy, and other symptoms indicating central nervous system (CNS) impairment are the most important adverse effects associated with antihypertensive agents.2 It is well recognized that methyldopa is an agent with a relatively high frequency of CNS adverse effects.34 As reviewed by Hindmarch,5 psychometric tests may represent a more sensitive method of detecting adverse drug effects on the CNS. It was decided to determine whether a battery of psychometric tests could be used to detect CNS impairment with moderate doses of methyldopa. A second objective was to evaluate
drug
effects
a crossover
design
on psychometric
as a basis
for
studying
tests.
METHODS Five men and 11 women with uncomplicated hypertension were weaned off previous antihypertensive drug treatment. All stopped previous therapy for at least 4 weeks before entering the study. All had untreated supine diastolic blood pressure read-
From the Division of Clinical Pharmacology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655. Address for reprints: Brian F. Johnson, MD. Division of Clinical Pharmacology, University of Massachusetts Medical Center, Worcester, MA 01655.
1102
#{149} J CIIn Pharmacol
1990;30:1102-1105
practice effect moderate
was seen. Continued dosage is a major confounder. Simple drug effects on intellectual
ings of 90 to 105 mm Hg. Age ranged from 26 to 67 (mean: 51.9 years) and weight ranged from 51 to 100 kg. None were taking other drugs, and all agreed to abstain from caffeine, smoking, or alcohol for 48 hours before psychometric testing sessions. One training session was given to each patient before randomization to treatment. In a crossover design study, patients were randomly assigned to receive either methyldopa (250 mg) every 8 hours for 3 weeks followed by matching placebo tablets for 3 more weeks, or the reverse sequence of treatments. Psychometric testing was performed at 3 hours after the first daily medication dose at 5 and 14 days of each period of treatment. Psychometric
Tests
Life Sciences (LS) Choice Reaction Time (Model RT400, Life Science Associates, Bayport, NY 11705). Speed of reaction time to a light signal in one of four possible radial positions was tested repeatedly over 5 minutes. The average time taken to extinguish the light by pressing the switch next to the light was measured over 40 trials. Short-Term Memory. Immediate recall of eight-digit sequences relayed to the subject from a tape recording was tested. A series of 90 sequences were administered over 13 minutes. The subject was allowed 5 seconds between each sequence to write down the eight digits from memory. The total number of errors and the total number of lines containing errors were counted.
METHYLDOPA
ON
PSYCHOMETRIC
Mental Arithmetic. The numbers of sums of three four-digit numbers completed in 10 minutes and of three-digit times two-digit multiplication problems completed in 15 minutes were determined. Visual letters minutes
Vigilance. The number EE detected in a page was determined.
TABLE
From shuffled packs of 32 cards conone or two dots, one to four dots, or one to eight dots, the time taken to sort the cards into separate piles was determined. Digit Symbol Substitution. The average number of correct symbol substitutions for coded numbers on five pages, each with a separate code, was determined, with 90 seconds allowed per page.6 Wilkinson (W) Four-Choice Reaction Time. The mean reaction time to press the appropriate key below a group of four lights arranged in a square was determined. Each response initiated a new light signal, the cycle being repeated for a period of 5 minutes.7
II
Mean (±SD) Psychometric Receiving Continuing or Methyldopa
of sequences of the of random letters in 3
Card Sorting. taining either
PERFORMANCE
Scores in Patients Doses of Placebo at 5 Days Placebo
LS choice reaction time (sec) Memory (number of errors) Visual vigilance (number correct) Digit substitution (number correct) Card sort 1-2 time (sec) 1-4 time (sec) 1-8 time (sec) W. choice reaction
16;’
=
P
Johnson,
MD,
FCP,
Kathy
Hoch,
BS, Ann
Errichetti,
MD,
and
Johanna
Johnson,
MSN
Double-blind, crossover comparisons of methyldopa with placebo were performed in 16 patients with mild to moderate hypertension. Methyldopa (250 mg tid) for 14 days significantly reduced blood pressure, impaired card-sorting time and digital symbol substitution score, and caused trends for impairment of other psychometric tests. Effects of practice were greater than those of treatment on all tests other than card sorting, although no interaction impairs psychometric crossover studies are performance.
between performance, inadequate
treatment and but practice for detecting
H
ypertension is frequently symptomless until medications are prescribed, and adverse effects of antihypertensive agents are common causes for discontinuing treatment. Antihypertensive agents differ in risk of causing adverse effects and therefore in their impact on overall quality of life.1 Fatigue, depression, lethargy, and other symptoms indicating central nervous system (CNS) impairment are the most important adverse effects associated with antihypertensive agents.2 It is well recognized that methyldopa is an agent with a relatively high frequency of CNS adverse effects.34 As reviewed by Hindmarch,5 psychometric tests may represent a more sensitive method of detecting adverse drug effects on the CNS. It was decided to determine whether a battery of psychometric tests could be used to detect CNS impairment with moderate doses of methyldopa. A second objective was to evaluate
drug
effects
a crossover
design
on psychometric
as a basis
for
studying
tests.
METHODS Five men and 11 women with uncomplicated hypertension were weaned off previous antihypertensive drug treatment. All stopped previous therapy for at least 4 weeks before entering the study. All had untreated supine diastolic blood pressure read-
From the Division of Clinical Pharmacology, University of Massachusetts Medical Center, Worcester, Massachusetts 01655. Address for reprints: Brian F. Johnson, MD. Division of Clinical Pharmacology, University of Massachusetts Medical Center, Worcester, MA 01655.
1102
#{149} J CIIn Pharmacol
1990;30:1102-1105
practice effect moderate
was seen. Continued dosage is a major confounder. Simple drug effects on intellectual
ings of 90 to 105 mm Hg. Age ranged from 26 to 67 (mean: 51.9 years) and weight ranged from 51 to 100 kg. None were taking other drugs, and all agreed to abstain from caffeine, smoking, or alcohol for 48 hours before psychometric testing sessions. One training session was given to each patient before randomization to treatment. In a crossover design study, patients were randomly assigned to receive either methyldopa (250 mg) every 8 hours for 3 weeks followed by matching placebo tablets for 3 more weeks, or the reverse sequence of treatments. Psychometric testing was performed at 3 hours after the first daily medication dose at 5 and 14 days of each period of treatment. Psychometric
Tests
Life Sciences (LS) Choice Reaction Time (Model RT400, Life Science Associates, Bayport, NY 11705). Speed of reaction time to a light signal in one of four possible radial positions was tested repeatedly over 5 minutes. The average time taken to extinguish the light by pressing the switch next to the light was measured over 40 trials. Short-Term Memory. Immediate recall of eight-digit sequences relayed to the subject from a tape recording was tested. A series of 90 sequences were administered over 13 minutes. The subject was allowed 5 seconds between each sequence to write down the eight digits from memory. The total number of errors and the total number of lines containing errors were counted.
METHYLDOPA
ON
PSYCHOMETRIC
Mental Arithmetic. The numbers of sums of three four-digit numbers completed in 10 minutes and of three-digit times two-digit multiplication problems completed in 15 minutes were determined. Visual letters minutes
Vigilance. The number EE detected in a page was determined.
TABLE
From shuffled packs of 32 cards conone or two dots, one to four dots, or one to eight dots, the time taken to sort the cards into separate piles was determined. Digit Symbol Substitution. The average number of correct symbol substitutions for coded numbers on five pages, each with a separate code, was determined, with 90 seconds allowed per page.6 Wilkinson (W) Four-Choice Reaction Time. The mean reaction time to press the appropriate key below a group of four lights arranged in a square was determined. Each response initiated a new light signal, the cycle being repeated for a period of 5 minutes.7
II
Mean (±SD) Psychometric Receiving Continuing or Methyldopa
of sequences of the of random letters in 3
Card Sorting. taining either
PERFORMANCE
Scores in Patients Doses of Placebo at 5 Days Placebo
LS choice reaction time (sec) Memory (number of errors) Visual vigilance (number correct) Digit substitution (number correct) Card sort 1-2 time (sec) 1-4 time (sec) 1-8 time (sec) W. choice reaction
16;’
=
P
