Effects of Antidepressants on Skilled Performance

Br. J. clin. Pharmac. (1984), 18, 109S-120S

Effects of antidepressants on skilled performance

M. LINNOILA1, JEANNETTE JOHNSON1, KRISTINE DUBYOSKI1, M. S. BUCHSBAUM2, MIKA SCHNEININ2 & C. KILTS3 Laboratory of Clinical Studies, National Institute of Alcohol Abuse and Alcoholism', National Institute of Mental Health2, Bethesda, Maryland, and Department of Psychiatry3, Duke University Medical Centre, Durham, North Carolina, USA

1 Effects of amitriptyline 50 mg, desipramine 100 mg, and zimelidine 200 mg alone and in combination with ethanol 0.8 g/kg were investigated in healthy, male volunteers. 2 Amitriptyline increased body sway and impaired tracking as well as information processing. It had an additive deleterious pharmacodynamic interaction with ethanol. 3 Desipramine and zimelidine were free of adverse effects on performance and did not have significant interactions with ethanol. 4 The dose of ethanol used in the present study did not inhibit biotransformation of the antidepressants. Keywords antidepressants performance amitriptyline desipramine zimelidine

Introduction Two recent reviews have examined effects of an antidepressant for traffic safety is the quality antidepressants on skilled performance (Linnoila of its interaction with ethanol. This is because a & Seppala, 1984; Seppala & Linnoila, 1984). significant proportion of psychiatric out-patients There are four main messages in the published are at a risk of drinking and driving during their reports: (1) sedative antidepressants impair treatment (Milner, 1969). performance of healthy volunteers and de- With these considerations in mind, we inves- pressed patients during the first week of treat- tigated effects of amitriptyline, desipramine ment at a steady dose; (2) depressed patients and zimelidine both alone and in combination have impaired performance compared with with ethanol on skilled performance. healthy volunteers. Their information processing is slowed down, and they have difficulties in concentrating; (3) during prolonged treat- Methods ment the adverse effects of even sedative antidepressants on performance are diminished Preparations and become nonsignificant; (4) successful treatment of depression corrects the infor- Identical appearing capsules containing ami- mation processing and performance deficits triptyline (50 mg), desipramine (100 mg), zime- observed in untreated depressed patients. lidine (200 mg) or placebo were given in Because the adverse effects of antidepres- combination with ethanol (0.8 g/kg of body sants are worse at the very beginning of weight) or placebo drinks. treatment, there is a rationale to investigate such effects after a single dose. Furthermore, Subjects the sedative antidepressant-induced impairment is qualitatively similar in depressed Twelve Caucasian male volunteers between the patients and healthy volunteers. Thus, it is ages of 21 and 27 years (mean + s.d. = 24 + reasonable to use healthy volunteers rather 1.7) were recruited for the study and paid for than depressed patients as subjects in an their time. The subjects qualified as social experiment designed to rank order antidepres- drinkers (they drank, on the average, about sants according to their impairment producing twice a week 1 to 6, 355 ml cans of beer at a potencies. Another important characteristic of time) and were healthy as determined by blood 109S 1 los M. Linnoila et al. pressure, pulse, respiratory and cardiovascular Depending on the stimulus, subjects responded assessment and a psychiatric interview. They by switching two levers either up (HAY and were within + 15% of their ideal weight. None WAX, or largest and second smallest angle) or was taking medications, had had any operations down (HAM and TAX, or smallest and second within the previous year, nor had family his- largest angle). The total number of words and tories of alcoholism or mental illness, including angles presented in a session was 48 each. The schizophrenia, or a major affective disorder. faster reaction time from either the left or right All were right-handed and had only right- lever was recorded, as well as the number of handed first degree relatives except for two correct and incorrect responses. Because in a subjects who had left-handed sisters. majority of responses the right-hand reaction time was shorter than the left-hand reaction Tests time only the former were used. Four tasks were used to assess psychomotor Study design functions. Subjects participated in training sessions prior (a) Body sway The amount of body sway was to actual drug administration and experimental measured with a platform, which transformed testing. At the beginning of these sessions they subject's sway along the fore to aft and side to were fully informed about the protocol, re- side axes into voltage readings. Amount of ceived the physical and psychiatric interview sway was determined for three conditions and spent 1-2 h practising each of the three lasting 30 s each: (1) eyes open looking at a psychomotor tests (Tracking, Words, and fixation point at eye level about 1.5 m away, (2) Angles). The purpose of the training sessions eyes closed, and (3) eyes closed with the was to ensure proficiency at less than a 10% platform vibrating. Total amount of sway and a error rate in each of the information processing power spectrum across frequencies from 0 to 14 tasks, and to improve tracking skills to a level Hz were recorded separately for each condition. where major learning effects were excluded. The four drug treatments were administered (b) Tracking test Tracking ability was in random order, crossover, in combination measured with a continuous subcritical tracking with ethanol or ethanol placebo on eight separ- task (Linnoila et al., 1978). The target (a 25 cm ate days approximately 1 week apart. Sub- high and 2 cm wide, illuminated bar) was jects were blind to the medication; however, located in the middle of a 36 cm diagonal the experimenter was not. cathode ray tube (CRT). The movement of the On each testing day, subjects were first bar across the screen horizontally was con- administered a breath test for ethanol and acet- trolled by both the computer and the subject aldehyde levels. They ate a light breakfast with a car steering wheel. Two levels of task between 07.00 h and 08.00 h, received their difficulty were administered, the first being medication at 08.00 h and ingested the drinks (a established by previous work to be relatively total volume of 400 ml) 2 h after the medications. easy (X = 2) and the second relatively difficult They were allowed 30 min to consume the (A = 3). The task was to maintain the position drinks. Psychomotor testing started 30 min of the bar as close to the target as possible. The after drinking and was repeated three times root mean square (RMS) error score and a during a test day. power spectrum of the frequency of the steering wheel movements were analyzed. Pharmacokinetics (c) Words and (d) Angles Verbal and spatial information processing were measured by pro- Venous 5 ml blood samples were drawn into viding the subject with a midscreen fixation heparinized clean glass tubes 2, 3, 4, 6, 8 and 24 point and after a pseudo random 2 to 6 s h after drug administration. Plasma amitripty- interval flashing a three letter word or an angle line, nortriptyline, desipramine and their hyd- 50 to either side of this fixation point. A roxy metabolite concentrations were quantified computer monitoring the electro aculogram with a modified liquid chromatographic method delivered the stimuli only when the subjects according to Sutfin & Jusko (1979). Zimelidine were actually staring at the fixation point and norzimelidine concentrations were measured without blinking their eyes. The stimulus lasted according to the method of Westerlund et al. 100 ms. Thus, the information was assumed to (1979). Breath ethanol concentrations were be transmitted preferentially into only one of measured with a gas chromatographic analyzer the cerebral hemispheres because this stimulus (Intoximeter Mark IV) immediately prior to duration is too brief to initiate a saccade. and after each test session. Antidepressants and skilled performance ills Statistical analysis Effects of testing over time Significant differences were not found between the three daily Each of the 12 subjects was tested on the testing sessions while the eyes were open (F = psychomotor tasks during three separate ses- 0.18; d.f. = 1,3; 10,43; P = 0.67) or closed (F sions (1 h, 2 h, and 4 h after starting to drink) = 2.05; d.f. = 1,37; 10,97; P = 0.18) or while with four drugs (amitriptyline, desipramine, the platform was vibrating (F = 1.69; d.f. = zimelidine, and placebo) in combination with 1,7; 13.57; P < 0.22). ethanol (ethanol and ethanol-placebo). The statistical analysis thus consisted of a 2 x 3 x 4 (b) Tracking (ethanol by session by drug treatment) repeated measures analysis of variance. For the Words Easy The easy tracking task revealed an and Angles testing, an additional factor for left interesting pattern of significant effects. Both and right visual field presentation was included the drug by ethanol interaction (F = 4,98; d.f. to result in a 2 x 2 x 3 x 4 repeated measures = 1,23; 13,54; P = 0.04) and the drug by analysis of variance. Greenhouse-Geisser session interaction (F = 5,2; d.f. = 1,68;18,52; adjusted degrees of freedom were used to P < 0.02) suggested two patterns of response adjust for the liberal application of the uni- confirmed by Duncan's test of multiple com- variate repeated measures ANOVA. Duncan's parisons. Administration of placebo, amitripty- multiple range test was used to assess differ- line, and zimelidine in combination with ethanol ences between individual means. Nonpara- showed an increase of the RMS score from metric analysis of variance using ranked scores session 1 to session 2, while in session 3 the was computed as well. Because the parametric score decreased (Table 2). and nonparametric tests were found to yield The RMS score remained relatively stable similar levels of statistical significance, only the across time after desipramine in combination results of the parametric analyses are reported. with ethanol. Amitriptyline in combination with ethanol produced significantly larger values than placebo in combination with ethanol. Results Difficult The difficult tracking task was differ- entially affected by ethanol administration dur- (a) Body sway ing placebo, desipramine, and zimelidine (F = 21,8; d.f. = 1, 11; P = 0.007) but not during Effects of ethanol Body sway with eyes open amitriptyline administration (Table 2). Repeated was significantly increased by ethanol adminis- daily testing showed a pattern similar to the tration (F = 12,05; d.f. = 1, 8; P < 0.008), but easy tracking task, as confirmed by the drug by not while the eyes were closed (F = 3,71; d.f. session interaction (F = 4,17; d.f. 2,9; 31,92; P = 1, 8; P = 0.09) or while the platform was c 0.01). Overall ethanol administration also vibrating (F = 2,45; d.f. = 1, 8; P = 0.15). For produced higher values, as confirmed by its eyes open, when placebo with ethanol was main effect (F = 21,8; d.f. = 1, 11; P c compared to each drug in combination with 0.0007). ethanol, amitriptyline administration during sessions 1 and 2 resulted in more body sway (c) Words while desipramine administration during session 3 resulted in less body sway. Zimelidine ad- Correct responses Ethanol significantly im- ministration did not significantly alter body paired responses in either the left or right visual sway (Table 1) either alone or in combination field of presentation (F = 6,21; d.f. = 1, 11; P with ethanol. = 0.03; Table 3). Amitriptyline reduced the number of correct responses more than any Effect of drugs Body sway was significantly other drug treatment (main effects = F = affected by drug treatment with the eyes open 11,95; d.f. = 1,49; 16,37; P = 0.001) either (F = 6,78; d.f. = 1,6; 12,79; P < 0.008), with alone or in combination with ethanol (drug by the eyes closed (F = 19,68; d.f. = 1,29; 10,34; ethanol interaction: F = 4,84; d.f. = 1,23; P = P < 0.007), and while the platform was 0.04). Overall significant differences between vibrating (F .157 11,91; d.f. = 1,64; 13,10; P = left or right side presentation were also revealed 0.002). More body sway was observed with (main effect: F = 4,71; d.f. = 1, 11; P c 0.05) amitriptyline administration than with any of with the right side being more adversely affected. the other experimental drugs. Zimelidine and placebo produced very similar body sway Reaction time While ethanol did not signifi- (Table 1). cantly impair performance (F = 2,39; d.f. = 1, 112S M. Linnoila et al.

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11; P = 0.15), drug administration did (F = formance of most subjects, in all tasks, but 4,99; d.f. 2,33; 25,63; P < 0.01), with amitrip- striking individual variability in sensitivity to- tyline producing longer reaction times both wards amitriptyline-induced impairment was alone and in combination with ethanol. Interes- evident; (2) amitriptyline 50 mg had an additive tingly, repeated testing interacted significantly deleterious interaction with ethanol 0.8 g/kg with drug treatment as confirmed by the session body weight; (3) desipramine 100 mg and by drug interaction (F = 2,74; d.f. = 3,54; zimelidine 200 mg were remarkably free of 38,98; P s 0.05; Table 4). adverse effects on skilled performance and interactions with ethanol; (4) no significant (d) Angles pharmacokinetic interactions were detected between the antidepressants and ethanol. Correct responses While main effects and The present findings concerning effects of higher order interactions did not reveal signifi- antidepressants on performance are in full cance, Duncan's multiple range test showed agreement with previous research (for review; that in most sessions, amitriptyline in combina- Linnoila & Seppala, 1984; Seppala & Linnoila, tion with ethanol resulted in impaired perfor- 1984): Drugs with relatively specific pharmaco- mance (Table 5). logical effects such as desipramine and zimelidine are free of adverse psychomotor effects. Reaction time Similar to correct responses, Whereas nonspecific drugs which block recep- significant main effects for each factor were not tors of several neurotransmitters at similar revealed with the exception of the drug of daily plasma levels to those inhibiting transmitter testing (F = 3,75; d.f. = 1,7; 18,66; P = 0.05). reuptake, such as amitriptyline, have strong The right and left side presentation by daily adverse effects on skilled performance. Further- testing session interaction was also significant more, these drugs have an additive interaction (F = 7,43; d.f. 1,53, 16,82; P < 0.007; Table 6) with ethanol. with the right visual field being more adversely Recently, Dorian et al. (1983) demonstrated affected. a large increment in plasma amitriptyline concentrations during administration of ethanol. Pharmacokinetics Their design was to administer 25 mg of amitriptyline during continuous drinking. The Plasma amitriptyline, nortriptyline and desip- dose of ethanol was computed to yield a blood ramine concentrations were increased transi- concentration of 800 mg/l maintained for several ently but nonsignificantly after ingestion of hours and was much higher than used in the ethanol. The hydroxymetabolite concentrations present study. Assuming that Dorian et al.'s were slightly decreased after ethanol. Zimeli- (1983) and the present results are correct, the dine and norzimelidine concentrations were practical conclusion is that depressed out- unaffected by ethanol (Table 7). patients taking tricylic antidepressants can Breath ethanol concentrations were not drink small amounts without increasing their affected by the antidepressants at any test time. plasma antidepressant levels but alcoholics The maximum blood ethanol concentration treated with these drugs should stay sober to (extrapolated from breath) of 560 mg/l was avoid inhibition of drug metabolism by large reached between 2 and 3 h (during the first hour doses of ethanol. However, there is a significant after drinking). pharmacodynamic interaction between low doses of amitriptyline and ethanol which can become a safety hazard in traffic. In conclusion, desipramine and zimelidine Discussion are preferred over amitriptyline in the treatment of depressed outpatients because they The main findings of the present study were: (1) produce less impairment of skilled performance amitriptyline 50 mg significantly impaired per- both alone and in combination with ethanol. 120S M. Linnoila et al. References

Dorian, P., Sellers, E. M., Reed, K. L., Warsh, J. J., Seppala, T. & Linnoila, M. (1984). Effects of zimeli- Hamilton, C., Kaplan, H. L. & Fan, T. (1983). dine and other antidepressants on skilled perfor- Amitriptyline and ethanol: pharmacokinetic and mance: A comprehensive review. Acta Psychiat. pharmacodynamic interaction. Eur. J. clin. Scand. (in press). Pharmac., 25, 325-331. Sutfin, T. A. & Jusko, W. J. (1979). High perfor- Linnoila, M. & Seppala, T. (1984). Antidepressants mance liquid chromatographic assay for imipra- and driving. Acc. Anal. Prev. (in press). mine, desipramine, and their 2-hydroxylated Linnoila, M., Erwin, C. W., Cleveland, W. P., metabolites. J. pharm. Sci., 68, 703-705. Logue, P. & Gentry, D. (1978). Effects of alcohol Westerlund, D., Nilsson, L. B. & Zaks, Y. (1979). on psychomotor performance of men and women. Straight-phase ion-pair chromatography of zimeli- J. Alc., 39, 745-758. dine and similar divalent amines: I. Bioanalysis. J. Milner, G. (1969). Drinking and driving in 753 liq. Chromatogr., 2, 373-405. general practice and psychiatric patients. Br. J. Psychiat., 115, 99-100.