Biological Psychiatry ° 1990-91 S. Karger AG, Basel 0302-282X/90-9 1/0244-0 165S2.75/0
N europsychobiology 1990-91:24:165—168
Absence of Nimodipine Premedication Effect on Memory after Electroconvulsive Therapy Marlin R. Cohen, Conrad M. Swartz North Chicago Veterans Affairs Medical Center and Department of Psychiatry, University of Health Sciences/Chicago Medical School, North Chicago, 111., USA
Keywords. Electroconvulsive therapy • Nimodipine • Calcium channels • Memory • Cognition
Following electroconvulsive therapy (ECT), patients typically experience disorientation that lasts for about 15 min but anterograde amnesia and a shrinking retro grade amnesia to experiences just prior to ECT can last for hours [1]. Performance decrements can be attributed directly to ECT, rather than anesthesia or premedications, because changes in the ECT seizure stimulus location and waveform markedly alter the memory effect. Specifically, brief-pulse square-wave stimuli are as effective as sinewave stimuli, with remission in over 90% of depressives, yet cognitive side effects are less [2, 3]. Similarly, there is a large difference in cognitive side effects but a small dif ference in efficacy between bilateral bifrontotemporal electrode placement and unilateral temporal-vertex non dominant electrode placement, given stimuli not forced to be at seizure threshold [4], Together with these observa tions, the absence of close correspondence between mem ory deficits and therapeutic benefits in individual cases suggests that the cognitive side effects of ECT can be dis
sociated from its efficacy. Our aim was to enlarge this dissociation by administering nimodipine, a calcium channel blocker that crosses the blood-brain barrier. In animal studies, Nimodipine inhibited seizure-in duced loss of behavioral memory. Using a one-trial pas sive-avoidance paradigm, nimodipine prevented electro shock-induced retrograde amnesia [5]. In a model less specific to ECT, nimodipine reversed learning deficits in the acquisition of eye-blink classical conditioning in the aging rabbit [6], As with other nootropics, these effects of nimodipine on abnormal cognition were apparent at doses well below those required to affect normal patterns of behavior. Attenuation of cognitive defects by nimodi pine might be attributed to reduction in vasospasm or intraneuronal (particularly hippocampal) calcium con centration [7, 8], Both mechanisms might be active in mediating ECT-induced memory deficits. In this study, we assessed the ability of nimodipine premedication to attenuate ECT-induced acute memory impairment.
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 2:31:45 PM
Abstract. While highly efficacious for affective disorders, electroconvulsive therapy (ECT) is sometimes accom panied by troublesome although temporary cognitive dysfunction. We speculated that the efficacy of ECT can be separated from its cognitive dysfunction by administration of nimodipine, a calcium channel blocker that crosses the blood-brain barrier and has prevented electroshock-induced amnesia in animal studies. However, in our single-blind repeated-measures trial on 8 patients, nimodipine 30-60 mg orally 2 h prior to ECT was indistinguishable from placebo in effects on verbal learning and retrograde and anterograde memory during the 2 h after ECT.
166
Participation was limited to patients of ages 18-65 who had been clinically selected to receive a series o f bilateral ECT and were able to cooperate with cognitive testing. Exclusion criteria included pre-ECT diagnosis of organic brain syndrome, mental retardation or schizophrenia: cardiovascular or hepatic disease significant enough to alter nimodipine metabolism or increase risk of hypotension [9] or concurrent medications that could affect memory (including ben zodiazepines given at ECT for any reason). All patients gave informed consent. The study sample consisted of 8 men (mean age. SEM: 48.3, 9.4) suffering from major depressive disorder. Cognitive functioning was measured as follows. Orientation to person, place and time was assessed every 5 min for 30 min and then 1 and 2 h after ECT or until full orientation was regained. Retro grade amnesia was assessed by recall at I and 2 h after ECT for two category groups of 3 words learned at 10 and 5 min prior to anes thesia and 3 numbers learned at 60, 15, and 5 s prior to anesthesia. Anterograde learning and memory were assessed at I and 2 h after ECT using a test procedure modeled after Cohen et al. [10]. Improvements between the 1- and 2-hour measurements were ex pected because recognition performance is not better than chance within the 1st hour, but improves to significantly better than chance during the 2nd hour [11], In biref, the experimenter read aloud a list of 18 nouns from a single category (e.g., carpenter's tools), 6 appearing once and 6 twice; the lists were balanced for drug. The subject was instructed to interrupt the tester whenever a word was presented a second time during the reading. Scores for the number of correct and incorrect interruptions were calculated as an assessment of attention and ‘vi gilance-. i.e., working memory. After a 5-min delay, the subject was asked to recall all words he had heard. His report was scored for numbers correctly identified (recall) and incorrectly asserted (intru sion). The subject was then read a list of 24 items, only 12 of which had been previously presented. The subject was asked to identify each word as to whether it had been read to him (word recognition), and if so. to identify whether it had been read once or twice (fre quency recognition). Word and frequency recognition were inde pendently scored for discrimination (d'H and bias (C l ) after Snod grass and Corwin [12]. During the 5-min delay, the patient's ability to generate words in a given category (scored for number of correct responses) or beginning with a given letter (verbal fluency) was assessed, and working memory was further assessed by having the patient subtract 3 serially from 200; ‘calculation' was scored as the number of correct responses. The study utilized a within-subjects repeated-measures design, comparing nimodipine and placebo for each subject. The dependent variables were the post-ECT cognitive scores and motor seizure duration by the cuffed-arm method [13], which was the only physi ological measure made. These were compared for the day the patient received nimodipine premedication to the day he received placebo (independent variable). The significance of each drug effect on a cognitive measure was assessed with the paired t test. Because this was a preliminary study to assess the potential utility of nimodipine. we planned to regard a p < 0.05 two-tail result without correction for multiple measures as significant. Patients were always studied on the 4th, 5th or 6th ECT in a series administered on a 3-per-week schedule. Nimodipine or pla cebo was taken orally with a sip of water, 2-2.5 h prior to ECT. This permitted the subjects to experience the maximum blood level and
cardiovascular response to nimodipine about 1 h before the ECT procedure [14], The ECT anesthesia consisted of intravenous glycopyrrolate 0.0044 mg/kg, mcthohexital 0.5-1.0 mg/kg and succinylcholine 0.4-0.8 mg/kg in sequence, accompanied by hyperoxygena tion by mask. Doses were the same for both placebo and nimodipine trials on each subject. After muscle paralysis was well developed, a brief-pulse square-wave stimulus was applied bifrontotemporally, with a Thymatron instrument (70 pulse pairs/s. I ms pulse width, constant 0.9 A. 378 mC charge; Somatics Inc.. Lake Bluff. 111.. USA). In every case, resultant motor seizure duration was at least 25 s. The study utilized a single-blind design, and, in the interests of caution, a dose of 30 mg was given to the first 4 subjects. Because no adverse effects occurred, the next 4 subjects received 60 mg. The first 3 sub jects were studied in a double-blind manner; because no differences were seen between nimodipine and placebo, the double-blind sys tem was not continued.
Results No adverse consequences of nimodipine were ob served, and nimodipine had no effect on motor seizure duration (mean = 49.8 s with and without nimodipine). However, nimodipine produced no trend for benefit on the cognitive measures with each dose separately or with data from both doses combined. Therefore, results for both doses were combined in listing the high p values in table 1, reflecting that none of the measures approached statistical significance. All subjects were overtly markedly impaired; as ta ble 1 illustrates, they typically remained disoriented for 1 h or more. Variations among patients and between trials were small, as reflected in the observation that the range of times for the return of orientation X2 and X3 were the same with and without nimodipine.
Discussion In this pilot study, we did not observe any trend for an effect of nimodipine on the verbal memory functions that are substantially impaired during the first hours after ECT. Although the conclusions are limited to the dose range studied, it is well above the threshold for attenuation of cognitive impairment in animals and is the usual range in the clinical treatment of cerebral vaso spasm after subarachnoid hemorrhage [5, 15]. Further, both 30 and 60 mg of nimodipine have observable ef fects on EEG, significantly more than a 15-mg dose [ 16]. Although it is possible that nimodipine has a small ben
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 2:31:45 PM
Methods
Cohen/Swartz
167
Nimodipine and Memory after ECT
Acknowledgment Funds for this project were provided by the UHS/The Chicago Medical School Department of Psychiatry.
Table 1.Nimodipine and memory testing after ECT
A. Orientation“ (min)
Person Place Time
Nimodipine
Placebo
Significance, p (D F -7 )
16.6 (2.3) 49.1 (31.9) 72.5 (30.1)
19.6(7.1) 60.6 (39.0) 86.3 (37.4)
0.29 0.29 0.45
B Cognitive function (mean score) Nimodipine 1h Verbal fluency Calculation
2.3 (1.7)
2h 5.3 (4.3)
18.1 12.8 (14.4) (22.5)
Placebo 1h
Significance
Pt*
Pü*
4.9 (4.9)
0.91
0.88
10.5 20.1 (13.4) (17.6)
0.69
0.69
2.1 (2.1)
2h
Vigilance
1.4 (2.1)
3.8 (2.3)
2.0 (2.6)
3.0 (2.2)
0.57
0.22
d'L
0.7 (1.6)
1.4 (1.1)
0.8 (1.4)
1.5 (1.2)
0.88
0.60
c,.
0.2 (2.5)
-0.2 (2.0)
0.0 (1.9)
0.2 (1.8)
0.82
0.95
Results are means (SD). d'i_ = discrimination: C l = bias [12]. a See Methods section for scoring details. * Probabilities for chance occurrence of the differences reported between nimodipine and placebo at 1 and 2 h respectively.
References 1 Abrams R: Electroconvulsive Therapy. New York. Oxford Uni versity Press, 1988. 2 Daniel WF. Crovitz HF: Recovery of orientation after electro convulsive therapy. Acta Psychiatr Scand 1982:66:421-428. 3 Daniel WF, Crovitz HF: Acute memory impairment following electroconvulsive therapy. 1. Effects of electrical stimulus wave form and number of treatments. Acta Psychiatr Scand 1983a;67: 1-7. 4 Daniel WF. Crovitz HF: Acute memory impairment following electroconvulsive therapy. 2. Effects of electrode placement. Acta Psychiatr Scand 1983b:67:57—68. 5 Hoffmeister F. Benz U, Hcise A, Krause HP, Neuser V: Behav ioral effects of nimodipine in animals. Arzneimittelforschung 1982;32:347-360. 6 Deyo A, Staube KT, Disterhoft JF: Nimodipine facilitates trace conditioning of the eye-blink response in aging rabbits. Science 1989:243:809-811.
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 2:31:45 PM
eficial effect we could not detect, because we did not see any distinct benefit of nimodipine on our 8 subjects, it is highly unlikely (p < 0.008) that nimodipine provides substantial clinical benefits that we did not see. These results are not surprising, even though disap pointing. Although nootropics decrease cognitive defi cits in animals at doses well below those needed to affect normal behavior, investigators have been frustrated by failure of nootropics in clinical trials. The results of the present investigation suggest that nimodipine is not an exception, although its cognitive effects have been attrib uted to actions on hippocampal neurons [6. 8], Mesial temporal lobe impairment has been used to rationalize memory difficulties in some amnestic patients and in the early stages of dementia [17.18]. Resemblances between cognitive dysfunction after ECT and amnestic syn dromes have led to speculation that learning and mem ory dysfunction after ECT may also be attributed to mesial temporal lobe impairment [17]. If so. the present results suggest that nimodipine will not succeed in miti gating learning deficits in amnestic or demented pa tients. The difference in results between animal and clinical studies can be attributed to differences between behav ioral and direct measures of memory. Of necessity, ani mal studies use implicit or indirect measures of memory function. In clinical disorders in which explicit or direct memory measures such as recall and recognition are markedly impaired implicit measures such as condition ing, priming, and procedural memory can be essentially intact [17], Thus, the beneficial effects of pharmacologic agents on memory seen in animal studies (i.e., improve ment in implicit measures) may have limited-applicabil ity to the treatment of human disorders (i.e., improve ment in explicit measures). Specifically, ECT-induced cognitive dysfunction is characterized by aberrant ex plicit memory measures but normal memory for condi tioning [ 17]; however, nimodipine improves memory for conditioning, according to animal studies [5, 6], The dis crepancy in the effects of nootropics on animal and human memory impairment can be regarded as further support for the existence of more than one physiological system for learning and memory in man.
Cohen/Swartz
168
15 Weintraub M. Standish R: Nimodipine: A calcium antagonist for use in subarachnoid hemorrhage. Hosp Formul 1989;24: 310-321. 16 Itil TM, Michael ST, Hoffmeistcr F, Kuntz A, Eralp E: Nimo dipine, a calcium antagonist vasodilator with psychotropic prop erties (a controlled quantitative pharmaco-EEG study). Curr Ther Res 1984;35:1-18. I 7 Squire LR: The neuropsychology of human memory. Annu Rev Neurosci 1982;5:241-273. 18 Van Hoesen GW, Damasio AR: Neural correlates of cognitive impairment in Alzheimtcr’s disease: in Plum F (ed): Handbook of Physiology: the Nervous System. Bethesda, American Physio logical Society, 1987, pp 871-898.
Martin R. Cohen. MD Department of Psychiatry UHS/The Chicago School 3533 Green Bay Road North Chicago, IL 60064-3095 (USA)
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 2:31:45 PM
7 Docherty RJ, Brown DA: Interaction of 1.4-dihydropyridines with somatic Ca currents in hippocampal CAi neurons of the guinea pig in vitro. Neurosci Lett I986;70:l 10-115. 8 Scriabine A, Schuurman T. Traber J: Pharmacological basis for the use of nimodipine in central nervous system disorders. FASEB 1989:3:1799-1806. 9 Gcngo FM, Fagan SC, Krol G, Bernhard H: Nimodipine dispo sition and haemodynamic effects in patients with cirrhosis and age-matched controls. Br J Clin Pharmacol 1987;23:47-53. 10 Cohen MR; Cohen RM, Pickar D, Weingartner H, Murphy DL: High-dose naloxone infusions in normals. Arch Gen Psychiatry 1983;40:613-619. 11 Squire LR. Shimamura AP, Graf P: Independence of recognition memory and priming effects: A neuropsychological analysis. J Exp Psychol [Learn Mem Cogn] 1985:11:37-44. 12 Snodgrass JG, Corwin J: Pragmatics of measuring recognition memory: Applications to dementia and amnesia. J Exp Psychol [Gen] 1988;117:34-50. 13 Fink M, Johnson L: Monitoring the duration of electroconvul sive therapy seizure. Arch Gen Psychiatry 1982:39:1189-1191. 14 Raemsch KD, Graefe KH, Sommer J: Pharmacokinetics and metabolism of nimodipine; in Betz E, Deck K, Hoffmeister F (eds): Nimodipine: Pharmacological and Clinical Properties. New York, Schattauer, 1985, pp 147-159.
N europsychobiology 1990-91:24:165—168
Absence of Nimodipine Premedication Effect on Memory after Electroconvulsive Therapy Marlin R. Cohen, Conrad M. Swartz North Chicago Veterans Affairs Medical Center and Department of Psychiatry, University of Health Sciences/Chicago Medical School, North Chicago, 111., USA
Keywords. Electroconvulsive therapy • Nimodipine • Calcium channels • Memory • Cognition
Following electroconvulsive therapy (ECT), patients typically experience disorientation that lasts for about 15 min but anterograde amnesia and a shrinking retro grade amnesia to experiences just prior to ECT can last for hours [1]. Performance decrements can be attributed directly to ECT, rather than anesthesia or premedications, because changes in the ECT seizure stimulus location and waveform markedly alter the memory effect. Specifically, brief-pulse square-wave stimuli are as effective as sinewave stimuli, with remission in over 90% of depressives, yet cognitive side effects are less [2, 3]. Similarly, there is a large difference in cognitive side effects but a small dif ference in efficacy between bilateral bifrontotemporal electrode placement and unilateral temporal-vertex non dominant electrode placement, given stimuli not forced to be at seizure threshold [4], Together with these observa tions, the absence of close correspondence between mem ory deficits and therapeutic benefits in individual cases suggests that the cognitive side effects of ECT can be dis
sociated from its efficacy. Our aim was to enlarge this dissociation by administering nimodipine, a calcium channel blocker that crosses the blood-brain barrier. In animal studies, Nimodipine inhibited seizure-in duced loss of behavioral memory. Using a one-trial pas sive-avoidance paradigm, nimodipine prevented electro shock-induced retrograde amnesia [5]. In a model less specific to ECT, nimodipine reversed learning deficits in the acquisition of eye-blink classical conditioning in the aging rabbit [6], As with other nootropics, these effects of nimodipine on abnormal cognition were apparent at doses well below those required to affect normal patterns of behavior. Attenuation of cognitive defects by nimodi pine might be attributed to reduction in vasospasm or intraneuronal (particularly hippocampal) calcium con centration [7, 8], Both mechanisms might be active in mediating ECT-induced memory deficits. In this study, we assessed the ability of nimodipine premedication to attenuate ECT-induced acute memory impairment.
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 2:31:45 PM
Abstract. While highly efficacious for affective disorders, electroconvulsive therapy (ECT) is sometimes accom panied by troublesome although temporary cognitive dysfunction. We speculated that the efficacy of ECT can be separated from its cognitive dysfunction by administration of nimodipine, a calcium channel blocker that crosses the blood-brain barrier and has prevented electroshock-induced amnesia in animal studies. However, in our single-blind repeated-measures trial on 8 patients, nimodipine 30-60 mg orally 2 h prior to ECT was indistinguishable from placebo in effects on verbal learning and retrograde and anterograde memory during the 2 h after ECT.
166
Participation was limited to patients of ages 18-65 who had been clinically selected to receive a series o f bilateral ECT and were able to cooperate with cognitive testing. Exclusion criteria included pre-ECT diagnosis of organic brain syndrome, mental retardation or schizophrenia: cardiovascular or hepatic disease significant enough to alter nimodipine metabolism or increase risk of hypotension [9] or concurrent medications that could affect memory (including ben zodiazepines given at ECT for any reason). All patients gave informed consent. The study sample consisted of 8 men (mean age. SEM: 48.3, 9.4) suffering from major depressive disorder. Cognitive functioning was measured as follows. Orientation to person, place and time was assessed every 5 min for 30 min and then 1 and 2 h after ECT or until full orientation was regained. Retro grade amnesia was assessed by recall at I and 2 h after ECT for two category groups of 3 words learned at 10 and 5 min prior to anes thesia and 3 numbers learned at 60, 15, and 5 s prior to anesthesia. Anterograde learning and memory were assessed at I and 2 h after ECT using a test procedure modeled after Cohen et al. [10]. Improvements between the 1- and 2-hour measurements were ex pected because recognition performance is not better than chance within the 1st hour, but improves to significantly better than chance during the 2nd hour [11], In biref, the experimenter read aloud a list of 18 nouns from a single category (e.g., carpenter's tools), 6 appearing once and 6 twice; the lists were balanced for drug. The subject was instructed to interrupt the tester whenever a word was presented a second time during the reading. Scores for the number of correct and incorrect interruptions were calculated as an assessment of attention and ‘vi gilance-. i.e., working memory. After a 5-min delay, the subject was asked to recall all words he had heard. His report was scored for numbers correctly identified (recall) and incorrectly asserted (intru sion). The subject was then read a list of 24 items, only 12 of which had been previously presented. The subject was asked to identify each word as to whether it had been read to him (word recognition), and if so. to identify whether it had been read once or twice (fre quency recognition). Word and frequency recognition were inde pendently scored for discrimination (d'H and bias (C l ) after Snod grass and Corwin [12]. During the 5-min delay, the patient's ability to generate words in a given category (scored for number of correct responses) or beginning with a given letter (verbal fluency) was assessed, and working memory was further assessed by having the patient subtract 3 serially from 200; ‘calculation' was scored as the number of correct responses. The study utilized a within-subjects repeated-measures design, comparing nimodipine and placebo for each subject. The dependent variables were the post-ECT cognitive scores and motor seizure duration by the cuffed-arm method [13], which was the only physi ological measure made. These were compared for the day the patient received nimodipine premedication to the day he received placebo (independent variable). The significance of each drug effect on a cognitive measure was assessed with the paired t test. Because this was a preliminary study to assess the potential utility of nimodipine. we planned to regard a p < 0.05 two-tail result without correction for multiple measures as significant. Patients were always studied on the 4th, 5th or 6th ECT in a series administered on a 3-per-week schedule. Nimodipine or pla cebo was taken orally with a sip of water, 2-2.5 h prior to ECT. This permitted the subjects to experience the maximum blood level and
cardiovascular response to nimodipine about 1 h before the ECT procedure [14], The ECT anesthesia consisted of intravenous glycopyrrolate 0.0044 mg/kg, mcthohexital 0.5-1.0 mg/kg and succinylcholine 0.4-0.8 mg/kg in sequence, accompanied by hyperoxygena tion by mask. Doses were the same for both placebo and nimodipine trials on each subject. After muscle paralysis was well developed, a brief-pulse square-wave stimulus was applied bifrontotemporally, with a Thymatron instrument (70 pulse pairs/s. I ms pulse width, constant 0.9 A. 378 mC charge; Somatics Inc.. Lake Bluff. 111.. USA). In every case, resultant motor seizure duration was at least 25 s. The study utilized a single-blind design, and, in the interests of caution, a dose of 30 mg was given to the first 4 subjects. Because no adverse effects occurred, the next 4 subjects received 60 mg. The first 3 sub jects were studied in a double-blind manner; because no differences were seen between nimodipine and placebo, the double-blind sys tem was not continued.
Results No adverse consequences of nimodipine were ob served, and nimodipine had no effect on motor seizure duration (mean = 49.8 s with and without nimodipine). However, nimodipine produced no trend for benefit on the cognitive measures with each dose separately or with data from both doses combined. Therefore, results for both doses were combined in listing the high p values in table 1, reflecting that none of the measures approached statistical significance. All subjects were overtly markedly impaired; as ta ble 1 illustrates, they typically remained disoriented for 1 h or more. Variations among patients and between trials were small, as reflected in the observation that the range of times for the return of orientation X2 and X3 were the same with and without nimodipine.
Discussion In this pilot study, we did not observe any trend for an effect of nimodipine on the verbal memory functions that are substantially impaired during the first hours after ECT. Although the conclusions are limited to the dose range studied, it is well above the threshold for attenuation of cognitive impairment in animals and is the usual range in the clinical treatment of cerebral vaso spasm after subarachnoid hemorrhage [5, 15]. Further, both 30 and 60 mg of nimodipine have observable ef fects on EEG, significantly more than a 15-mg dose [ 16]. Although it is possible that nimodipine has a small ben
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 2:31:45 PM
Methods
Cohen/Swartz
167
Nimodipine and Memory after ECT
Acknowledgment Funds for this project were provided by the UHS/The Chicago Medical School Department of Psychiatry.
Table 1.Nimodipine and memory testing after ECT
A. Orientation“ (min)
Person Place Time
Nimodipine
Placebo
Significance, p (D F -7 )
16.6 (2.3) 49.1 (31.9) 72.5 (30.1)
19.6(7.1) 60.6 (39.0) 86.3 (37.4)
0.29 0.29 0.45
B Cognitive function (mean score) Nimodipine 1h Verbal fluency Calculation
2.3 (1.7)
2h 5.3 (4.3)
18.1 12.8 (14.4) (22.5)
Placebo 1h
Significance
Pt*
Pü*
4.9 (4.9)
0.91
0.88
10.5 20.1 (13.4) (17.6)
0.69
0.69
2.1 (2.1)
2h
Vigilance
1.4 (2.1)
3.8 (2.3)
2.0 (2.6)
3.0 (2.2)
0.57
0.22
d'L
0.7 (1.6)
1.4 (1.1)
0.8 (1.4)
1.5 (1.2)
0.88
0.60
c,.
0.2 (2.5)
-0.2 (2.0)
0.0 (1.9)
0.2 (1.8)
0.82
0.95
Results are means (SD). d'i_ = discrimination: C l = bias [12]. a See Methods section for scoring details. * Probabilities for chance occurrence of the differences reported between nimodipine and placebo at 1 and 2 h respectively.
References 1 Abrams R: Electroconvulsive Therapy. New York. Oxford Uni versity Press, 1988. 2 Daniel WF. Crovitz HF: Recovery of orientation after electro convulsive therapy. Acta Psychiatr Scand 1982:66:421-428. 3 Daniel WF, Crovitz HF: Acute memory impairment following electroconvulsive therapy. 1. Effects of electrical stimulus wave form and number of treatments. Acta Psychiatr Scand 1983a;67: 1-7. 4 Daniel WF. Crovitz HF: Acute memory impairment following electroconvulsive therapy. 2. Effects of electrode placement. Acta Psychiatr Scand 1983b:67:57—68. 5 Hoffmeister F. Benz U, Hcise A, Krause HP, Neuser V: Behav ioral effects of nimodipine in animals. Arzneimittelforschung 1982;32:347-360. 6 Deyo A, Staube KT, Disterhoft JF: Nimodipine facilitates trace conditioning of the eye-blink response in aging rabbits. Science 1989:243:809-811.
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 2:31:45 PM
eficial effect we could not detect, because we did not see any distinct benefit of nimodipine on our 8 subjects, it is highly unlikely (p < 0.008) that nimodipine provides substantial clinical benefits that we did not see. These results are not surprising, even though disap pointing. Although nootropics decrease cognitive defi cits in animals at doses well below those needed to affect normal behavior, investigators have been frustrated by failure of nootropics in clinical trials. The results of the present investigation suggest that nimodipine is not an exception, although its cognitive effects have been attrib uted to actions on hippocampal neurons [6. 8], Mesial temporal lobe impairment has been used to rationalize memory difficulties in some amnestic patients and in the early stages of dementia [17.18]. Resemblances between cognitive dysfunction after ECT and amnestic syn dromes have led to speculation that learning and mem ory dysfunction after ECT may also be attributed to mesial temporal lobe impairment [17]. If so. the present results suggest that nimodipine will not succeed in miti gating learning deficits in amnestic or demented pa tients. The difference in results between animal and clinical studies can be attributed to differences between behav ioral and direct measures of memory. Of necessity, ani mal studies use implicit or indirect measures of memory function. In clinical disorders in which explicit or direct memory measures such as recall and recognition are markedly impaired implicit measures such as condition ing, priming, and procedural memory can be essentially intact [17], Thus, the beneficial effects of pharmacologic agents on memory seen in animal studies (i.e., improve ment in implicit measures) may have limited-applicabil ity to the treatment of human disorders (i.e., improve ment in explicit measures). Specifically, ECT-induced cognitive dysfunction is characterized by aberrant ex plicit memory measures but normal memory for condi tioning [ 17]; however, nimodipine improves memory for conditioning, according to animal studies [5, 6], The dis crepancy in the effects of nootropics on animal and human memory impairment can be regarded as further support for the existence of more than one physiological system for learning and memory in man.
Cohen/Swartz
168
15 Weintraub M. Standish R: Nimodipine: A calcium antagonist for use in subarachnoid hemorrhage. Hosp Formul 1989;24: 310-321. 16 Itil TM, Michael ST, Hoffmeistcr F, Kuntz A, Eralp E: Nimo dipine, a calcium antagonist vasodilator with psychotropic prop erties (a controlled quantitative pharmaco-EEG study). Curr Ther Res 1984;35:1-18. I 7 Squire LR: The neuropsychology of human memory. Annu Rev Neurosci 1982;5:241-273. 18 Van Hoesen GW, Damasio AR: Neural correlates of cognitive impairment in Alzheimtcr’s disease: in Plum F (ed): Handbook of Physiology: the Nervous System. Bethesda, American Physio logical Society, 1987, pp 871-898.
Martin R. Cohen. MD Department of Psychiatry UHS/The Chicago School 3533 Green Bay Road North Chicago, IL 60064-3095 (USA)
Downloaded by: Kings's College London 137.73.144.138 - 11/17/2017 2:31:45 PM
7 Docherty RJ, Brown DA: Interaction of 1.4-dihydropyridines with somatic Ca currents in hippocampal CAi neurons of the guinea pig in vitro. Neurosci Lett I986;70:l 10-115. 8 Scriabine A, Schuurman T. Traber J: Pharmacological basis for the use of nimodipine in central nervous system disorders. FASEB 1989:3:1799-1806. 9 Gcngo FM, Fagan SC, Krol G, Bernhard H: Nimodipine dispo sition and haemodynamic effects in patients with cirrhosis and age-matched controls. Br J Clin Pharmacol 1987;23:47-53. 10 Cohen MR; Cohen RM, Pickar D, Weingartner H, Murphy DL: High-dose naloxone infusions in normals. Arch Gen Psychiatry 1983;40:613-619. 11 Squire LR. Shimamura AP, Graf P: Independence of recognition memory and priming effects: A neuropsychological analysis. J Exp Psychol [Learn Mem Cogn] 1985:11:37-44. 12 Snodgrass JG, Corwin J: Pragmatics of measuring recognition memory: Applications to dementia and amnesia. J Exp Psychol [Gen] 1988;117:34-50. 13 Fink M, Johnson L: Monitoring the duration of electroconvul sive therapy seizure. Arch Gen Psychiatry 1982:39:1189-1191. 14 Raemsch KD, Graefe KH, Sommer J: Pharmacokinetics and metabolism of nimodipine; in Betz E, Deck K, Hoffmeister F (eds): Nimodipine: Pharmacological and Clinical Properties. New York, Schattauer, 1985, pp 147-159.
