Dexamphetamine on Performance, Subjective Feelings, Autonomic Variables and Electro- Encephalogram in Healthy Volunteers

Br. J. clin. Phanmac. (1983), 15, 367-374

EFFECTS OF BUPROPION, NOMIFENSINE AND DEXAMPHETAMINE ON PERFORMANCE, SUBJECTIVE FEELINGS, AUTONOMIC VARIABLES AND ELECTRO- ENCEPHALOGRAM IN HEALTHY VOLUNTEERS. MARGARET J. HAMILTON, P.R. SMITH AND A.W. PECK Department of Clinical Pharmacology, Wellcome Research Laboratories, Beckenham, Kent

1 Bupropion, a novel antidepressant, has been compared with nomifensine and dexamphetamine in a controlled double blind trial in 12 healthy volunteers. 2 Signals detected in an auditory vigilance test were increased by dexamphetamine 5 and 10 mg when compared with lactose dummy, but unaffected by bupropion 100 and 200 mg and nomifensine 100 mg. Auditory reaction time was decreased by dexamphetamine but unaffected by bupropion and nomifensine. 3 Heart rate was increased after all active treatments but the largest rise followed dexamphetamine 10 mg which differed from both lactose dummy and all other active treatments. Systolic blood pressure was higher after dexamphetamine 10 mg than all other treatments, none of which differed from lactose. No changes occurred in diastolic blood pressure. Pupil size increased after dexamphetamine 10 mg but no changes followed other treatments. 4 Visual analogue scales showed that subjects were more alert, attentive, proficient, excited, interested and elated after dexamphetamine but no changes followed bupropion or nomifensine. Subjects were able to recognise that they had received an active drug only after dexamphetamine 10 mg. 5 Increased activity was seen in the 7.5-13.5 Hz and 13.5-26 Hz frequency bands of the electro- encephalogram after dexamphetamine 10 mg but not after bupropion or nomifensine. 6 These findings in man suggest that neither of these two, non-sedative antidepressants possess amphetamine-like stimulant activity, and are discussed in relation to the animal pharmacology of the drugs.

Introduction Cl Bupropion (+-2-t-butylamino-3'-chloropropiophenone HCI) (Figure 1) is a novel antidepressant (Fabre & McLendon, 1978). Structurally it resembles amphetamine, but a previous study failed to detect CO any amphetamine-like activity in healthy subjects CH-CH3 using doses up to 100 mg (Peck et al., 1979). Nomifensine (8 amino-2 methyl4 phenyl-1,2,3,4 NH tetrahydroisoquinoline) is an antidepressant lacking CH3- C-CH3 the anticholinergic and sedative properties which result in many of the side effects of the older tricyclic CH3 compounds (Hanks, 1977). Both nomifensine and bupropion may act by potentiating dopaminergic Figure 1 The structural formula of bupropion. systems (Soroko et al., 1977). While nomifensine lacks sedative properties it has not been shown to While bupropion lacks stimulant activity using doses possess any stimulant effects using tests of critical up to 100 mg it is possible that such activity might flicker fusion and simple and complex reaction time appear with higher doses. The present investigation (Hindmarch & Parrott, 1977; Taeuber et al., 1979). was designed to see if stimulant effects could be 0306-5251/83/0300-0367 $02.00 ©) 1983 Blackwell Scientific Publications 368 MARGARET J. HAMILTON, P.R. SMITH & A.W. PECK detected after higher doses of bupropion, and also one another but capable of being observed by the nomifensine, using principally an auditory vigilance experimentor through one-way glass mirrors and TV test which has proved particularly sensitive to monitors. The sequence of tests through the experi- dexamphetamine (Bye et al., 1973). mental day beginning at 08.15 h was as follows: Baseline recording of visual analogue scales (Lader & Norris, 1969) and side effects. Methods 09.30 Recording of EEG (for 5 min with eyes closed); heart rate (from ECG); blood pres- Subjects sure (supine - measured using sphyg- momanometer); pupil size (recorded using a Twelve healthy subjects were recruited from the staff fixed focus camera). of the Wellcome Research Laboratories, six women 10.00 Administration of treatment with 100 ml aged 20-41 years (weight 50-64 kg) and six men aged water. 22-32 years (weight 63-102 kg. They were allowed a 11.00 Auditory vigilance test. The Wilkinson (1968) light standard breakfast before 07.30 h but no caffeine test was used in which the subject listens via containing drinks, alcohol or cigarettes on the test headphones to a tape recording lasting 1 h day until completion of the measurements. Contact and consisting of tones occurring every 2 s. lenses which interfere with photographic recording of The majority oftones are 0.5 s in duration and pupil size were prohibited. Subjects were transported these constitute the 'noise' tones. Shorter between home and laboratory. tones 0.4 s in duration occur randomly, constitute the signals. Treatments 12.00 Visual analogue scales. 12.05 Auditory reaction time test. This test, lasting The following 6 treatments were all administered to 15 min, consists of randomly occurring short all subjects: tones (Hart etal., 1976). Lactose dummy capsules and lactose dummy tablets 12.20 Tapping test. Subjects tap a microswitch as Bupropion hydrochloride 100 mg (tabs) plus lactose rapidly as possible for 1 min. dummy capsules 12.35 After 10 min resting in reclining chairs repeat Bupropion hydrochloride 200 mg (tabs) plus lactose measures of EEG, BP, heart rate and pupil dummy capsules diameter were made. Nomifensine 100 mg (caps) plus lactose dummy 12.50 Side effects. tablets 13.00 Lunch. Dexamphetamine sulphate 5 mg (caps) plus lactose 14.15 Complete repeat of the test schedule. dummy tablets Dexamphetamine sulphate 10 mg (caps) plus lactose dummy tablets. EEG Bupropion tablets were identical in appearance to the dummy tablets, and nomifensine capsules were This was recorded from bipolar surface recordings identical in appearance to the dexamphetamine sited at positions Fz and Pz and referred to the left capsules and lactose dummy capsules. Use of this mastoid process according to the method of Jasper 'double dummy' type design enabled double-blind (1958). Leads were attached at the beginning of the conditions to be maintained. Treatments were day and remained in position until 16.30 h. Record- administered at intervals of not less than 1 week ings were made using a Grass model 78D, solid state according to a balanced design based on two 6 x 6 polygraph with 50 Hz filters in use and amplifier band Latin squares enabling complete balance for treat- width set at 0.1-60 Hz. The EEG was simultaneously ments and occasions and also the immediate preced- recorded on a 7-channel FM tape recorder for sub- ing treatment. sequent playback. Analysis of the EEG was made by measuring voltage levels in the following frequency The experimental day ranges using tuned filters: 2.3-4, 4-7.5, 7.5-13.5 and 13.5-26 Hz. Voltages for 5 s epochs of each 10 s of Subjects were studied in groups of 4 on Tuesdays, recording were generated and the mean ± s.e. mean Wednesdays and Thursdays. Rarely a subject failed of these values for each subject were computed for to attend on an occasion. In this event treatment the epochs through the 5 min of eyes closed EEG. order was maintained and additional testing con- tinued into the week after completion of the main Analysis ofresults part of the study. Tests were conducted in a soundproof room main- All measured variables were analysed as raw scores tained at 21°C, with the subjects visually isolated from by analysis of variance. Differences ascribable to BUPROPION, NOMIFENSINE AND DEXAMPHETAMINE IN MAN 369

Table 1 Behavioural tests. Mean values for 12 subjects after the 6 treatments are shown. Time post-drug Treatments Vigilance - signals detected (per 15 min) L BJOO B200 N D5 DJO s.e. mean Overall analysis 5.47 5.49 5.91 5.85 6.32* 6.70* 0.43 I h - 2 h 5.63 5.92 6.10 5.56 6.42 6.50 0.37 4 h 1l min - 5 h 15 min 5.31 5.06 5.71 6.15 6.23 6.90* 0.47 Reaction time (ms) 2h5min 244 248 241 238 232* 226* 3.79 S h 20 min 252 260 241 238 235* 231* 5.25 Tapping test (taps/min) 2 h 20 min 367 358 361 370 374 369 6.71 5 h 35 min 361 360 362 364 368 365 8.64 Abbreviations for treatments are: Lactose dummy, L; bupropion 100 and 200 mg respectively, BI00 and B200; nomifensine hydrogen maleate 100 mg, N; dexamphetamine sulphate 5 and 10 mg, D5 and D10. In the case of auditory vigilance, values for the 2 test sessions are shown and also combined in the overall analysis. Where analysis of variance revealed a mean value significantly different (P < 0.05) from lactose, this is shown by an asterisk,*. treatments were regarded as significant when P < ascribable to treatments were seen 1-2 h after admini- 0.05. stration of treatments, but at 4 h 15 min - 5 h 15 min dexamphetamine 10 mg produced an increase in correct detections compared with lactose. Analysis of the Results ratios d' and 18 (Swets et al., 1961), which reflect the ability of subjects to discriminate between the short The performance tests results are summarised in (signal) tones and the longer (noise) tones, from Table 1. changes in their willingness to report, respectively, are shown in Table 2. No significant changes ascrib- Auditory vigilance able to treatments occurred during the first test, but during the second dexamphetamine 10 mg increased Analysis of the combined data from the two test the ability of subjects to discriminate between the sessions revealed an increase in correct detections after shorter signal and the longer tones, compared with dexamphetamine 5 and 10 mg compared with lactose. their performance after lactose dummy. Neither None of the other three active treatments differed bupropion nor nomifensine affected d', and no treat- from the lactose dummy. No significant differences ment affected the willingness of subjects to report.

Table 2 Analysis of d' and f3 values. Mean values ford' and f calculated for the second vigilance test for the 12 subjects after each treatment are shown. The values were calculated by adding a value of 1 to each subjects' false report score, because in occasional tests, occasional subjects made no false reports (Peck & Fowle, 1980). Time post-drug Treatment means d' BJOO L B200 N D5 DJO 4h 15min-Sh 15min 3.04 3.11 3.16 3.32 3.36 3.58 DJO B200 D5 N L BJOO 4h 15 min-5h 15 min 85.5 99.2 104 105 110 124 Abbreviations for treatments as for Table 1. Values have been ranked in ascending order and those underlined by a common bar are not significantly different (P < 0.05). Values not underlined by a common bar are significantly different (P < 0.05). No significant differences occurred in the first test. 370 MARGARET J. HAMILTON, P.R. SMITH & A.W. PECK

Reaction time Subjective effects

Reaction times were significantly decreased by both The significance of differences on the visual analogue doses of dexamphetamine at both times oftesting, 2 h scales are shown in Table 4. After both doses of 5 min and 5 h 20 min after treatment. None ofthe other dexamphetamine subjects obviously felt more alert, active treatments produced any changes differing excited, interested and elated than after treatment from lactose. with lactose or the other active treatments at 2 h. Significant effects persisted on some dimensions for 5 Tapping test h 15 min. No evidence of stimulant or euphoriant activity followed treatment with bupropion or No significant differences ascribable to any treatment nomifensine, never after either of these drugs did were observed when compared with performance ratings on any dimension differ from those after after lactose, at either time of testing. lactose.

Autonomic variables Electroencephalographic changes These are shown in Table 3. Significant differences were only seen in the a (7.5-13.5 Hz) and (13.5-26 Hz) frequency bands Heart rate This was significantly higher after all and values are shown in Table 5. Dexamphetamine 10 active treatments when compared with lactose, at mg significantly elevated the activity in both both 2 h 40 min and 5 h 50 min after treatment. these frequency bands 2 h 35 min after treatment, Dexamphetamine 10 mg however produced the compared biggest increase at both times, with values which dif- with values obtained after lactose. No other treatments produced values differing from fered significantly from the other 4 active treatments lactose. as well as lactose.

Bloodpressure Dexamphetamine 10 mg produced a Recognition ofactive drug rise in systolic blood pressure differing from both lactose and all other treatments at both times of Table 6 records the responses ofsubjects on all occasions measurement. No other treatment produced any to the question 'Do you think you received an active changes significantly different from values after drug?' The manner of comparison was arranged to be lactose. No treatment produced any change in as conservative as possible. After each treatment diastolic blood pressure. subjects were divided into those correctly identifying an active drug or lack of it (after dummy), and those Pupil diameter Dexamphetamine 10 mg produced who were incorrect or uncertain. Proportions after significant dilatation of the pupil 5 h 45 min post- each treatment were then compared with proportions treatment, when left and right pupils were combined. after lactose using Fisher's exact test. It can be seen No other active treatment produced values differing that only after dexamphetamine 10 mg was there a from those after lactose. significant effect in the subject group as a whole.

Table 3 Autonomic variables. Mean values for 12 subjects after 6 treatments are shown. Treatments Variable Time post-drug L B100 B200 N D5 DJO s.e. mean Heart rate 2h40min 56.3 60.4* 63.8* 64.6* 63.3* 69.5* + 1.47 (beats/min) h50hmin 64.8 69.7* 70.6* 72.8* 71.3* 77.2* --+ 1.35

Systolic blood 2h45min 113 116 115 115 118 122* + 1.61 pressure (mm Hg) 5h55min 112 116 113 115 117 122* 1.63 Diastolic blood 2h45min 69.7 70.7 73.7 65.5 70.8 71.3 + 1.58 pressure (mm Hg) Sh55min 61.8 62.0 65.0 62.5 62.0 64.0 1.79 Combined pupil 2 h 45 min 4.61 4.61 4.59 4.48 4.74 4.83* - 0.09 diameter (mm) S h 55 min 4.69 4.60 4.63 4.90 4.77 5.02* 0.08

Abbreviations for treatments as in Table 1. Where values after active drug are significantly different from lactose these are shown by an asterisk. BUPROPION, NOMIFENSINE AND DEXAMPHETAMINE IN MAN 371

Table 4 Significance of differences of visual analogue scales. Mean values for 12 subjects after treatments in the visual analogue scales were ranked in ascending order. Scale Treatments 2 h post-drug Alert/drowsy DIO D5 N L B200 B100 Excited/calm D1O D5 B2200 N BIOO L Clear headed/muzzy DIO D5 L N B200 B100 Quick witted/mentally slow D1O D5 N B100 L B200 Attentive/dreamy D1O D5 N B200 B100 L Proficient/incompetent D1O D5 N L B100 B200 Interested/bored DIO D5 B200 N L B100 Elated/depressed DIO D5 N B200 L B100 Mental sedation DIO D5 N L B100 B200 Physical sedation DIO D5 N L B100 B200

5 h 15 min post-drug Alert/drowsy D1O D5 N 8100 B200 L Strong/feeble DIO D5 B100 N B200 L Attentive/dreamy D1O D5 B200 N L B100 Interested/bored D1O D5 N B100 B200 L Mental sedation DIO D5 N B200 B100 L Physical sedation D5 DIO B200 B100 N L

Abbreviations for treatments as in Table 1. Values not significantly different are underlined by a common bar. Values not underlined by a common bar are significantly different, (P < 0.05). Absolute values for some have been omitted for clarity. Pretreatment scales and post-treatment scales which also revealed no significant differences have been omitted. Mental sedation and physical sedation scores were each acquired from grouping 4 scales as in Lader & Norris (1969).

Discussion remained a possibility that bupropion might have amphetamine-like effects in man. In their description of the behavioural pharmacology A more complicated animal model was used by of bupropion, Soroko et al. (1977) observed signific- Jones et al. (1980). They trained rats to operate a 2 ant increase in locomotor activity using a photocell, at lever system with either saline or different doses of doses of 25 mg/kg i.p. No stereotyped gnawing and bupropion as cues. Selection of the correct lever in licking, so typical of amphetamine occurred following response to a cue resulted in a food reward. A high bupropion even with doses as high as 100 mg/kg i.p. level of discrimination was possible between the In addition the increase of locomotor activity at low saline and 20 mg/kg bupropion stimulus, but not at doses was much less evident than the anti- the 5 and 10 mg/kg bupropion stimulus. The follow- tetrabenazene effect suggesting that the stimulant ing list of drugs produced dose-related responding on action was not the cause of the anti-tetrabenazene the bupropion lever: viloxazine, nomifensine, effect. Despite these interesting differences it caffeine, dexamphetamine, cocaine, methylphenidate 372 MARGARET J. HAMILTON, P.R. SMITH & A.W. PECK

Table 5 EEG analysis. Mean values for EEG energy in the 2 frequency bands where significant differences occurred for 12 subjects at different times after treatments are shown. L BJOO B200 N D5 D1O s.e. mean 7.5-13.5 Hz Pre-drug 67.5 58.7 60.5 67.1 64.4 66.4 + 3.81 2 h 35 min post-drug 52.4 58.6 57.6 55.5 58.6 75.4* + 4.74 5 h 45 min post-drug 50.4 50.9 50.1 48.8 56.0 64.9 + 5.62 13.5 - 26.0 Hz Pre-drug 31.1 29.6 30.7 29.8 31.2 30.7 + 0.80 2 h 35 min post-drug 27.9 30.1 29.8 29.8 31.7* 34.1* -+ 1.16 5 h 45 min post-drug 28.9 29.3 27.7 29.1 30.4 32.4 ± 1.29 Abbreviations for treatments as in Table 1. The energy is expressed on an arbitrary scale ranging from 0 to 255 and represents means of 5s epochs of each 10s of the 5 min period under the eyes closed condition. Asterisks show where analysis of variance revealed a significant difference between an active treatment and lactose. and benzylpiperazine. The last compound has been 1977) which could complicate interpretation of self shown to possess amphetamine-like properties in administration studies. healthy subjects (Bye et al., 1973) and also in former Using self-stimulation behaviour in rats, with a addicts (Campbell et al., 1973). By contrast phen- stimulating electrode in the medial forebrain bundle, ylethylamine, thyrotropin releasing hormone, bupropion, like amphetamine, increased the re- imipramine, nortriptyline, amitriptyline, desipram- sponding, though the latter was 10-15 times more ine, mianserin, chlordiazepoxide, diazepam, potent than the former (Howard, 1980, personal scopolamine, phenobarbitone and morphine failed to communication). Blockade of the effects of produce responses on the bupropion lever. In amphetamine could be achieved with a-methyl- general, therefore, this animal model suggested that tyrosine but this inhibitor of catecholamine synthesis bupropion and nomifensive might have more in was ineffective in blocking the effects of bupropion common with the locomotor stimulant drugs than on self-stimulation. Using a-methyltyrosine and also with antidepressants and tranquillisers. Recently, reserpine to block changes in locomotor activity in however, the predictive value of some self adminis- rats produced by amphetamine and also methyl- tration experiments must be questioned by the work phenidate Howard observed that bupropion of Woolverton & Balster (1982) who showed that resembled methylphenidate more closely than several local anaesthetics reinforced self adminis- amphetamine. Obviously experiments of this sort tration of monkeys trained on cocaine. In similar raised the possibility that bupropion might possess experiments in rats dexamphetamine produced re- stimulant properties. sponses in animals trained on procaine. Bupropion Stimulant effects had not been observed in clinical possews local anaesthetic properties (Soroko et al., trials of bupropion, however, and the negative study

T-be 6 Recognition of an active drug. All 12 subjects were asked whether they thought they had received an active drug that day at 2 h and 5 h 15 ain post-tr,eatment. They could respond with a Yes, or No or oncertain(?). The numbers in each category after different treatments are shown.

Time 2 h post-drug S h 15 min post-drug Yes No ? P Yes No ? P

Placebo 2 7 3 0 9 3 BIOO 4 4 4 0.30 4 7 1 0.31 B200 3 3 6 0.24 3 6 3 0.36 N 2 7 3 0.15 2 9 1 0.34 D5 6 2 4 0.29 3 6 3 0.36 DIO 8 0 4 0.16 8 3 1 0.04 BUPROPION, NOMIFENSINE AND DEXAMPHETAMINE IN MAN 373

by Peck et al. (1979) using healthy volunteer subjects failed to produce any significant differences from supported these findings. In that study dexam- values obtained after lactose. The one exception was phetamine and amitriptyline clearly changed the heart rate, which increased after all active treat- performance in auditory vigilance and in subjective ments. The increase while significant was always feelings measured using visual analogue scales. small, between 3 and 8 beats/min. After bupropion Autonomic measures were clearly influenced by and nomifensine it was significantly less than after dexamphetamine 10 mg and amitriptyline 25 mg dexamphetamine 10 mg. It is possible that this treatment and typical EEG changes followed apparent elevation after bupropion and nomifensine amitriptyline. Bupropion up to 100 mg by contrast is spurious and really due to a fortuitously low value produced no significant differences in comparison obtained after lactose. This increase in heart rate was with lactose. There remained, however, the possibil- not seen in the previous study after bupropion 100 mg ity that an increased dose of bupropion might show (Peck et al., 1979) but in that study supine systolic stimulant or autonomic effects analogous to the blood pressure was increased compared with lactose effects on operant behaviour in the study by Jones et after all treatments except bupropion 50 mg. This al. (1980). finding was ascribed to a spuriously low value after Clinical studies of nomifensine in depressed lactose and this explanation was probably correct, the patients, reviewed by Hanks (1977) have shown the finding not being replicated for bupropion in the lack of sedation and 'possibly a mild central stimulat- present study despite the increased dose. It is inevit- ing effect'. Experiments in rats have shown self able in studies of this type with repeated measures, administration of nomifensine i.v. both in animals where many comparisons are made that some type 1 trained to administer cocaine and naive animals errors occur when a relatively liberal P < 0.05 is (Spyraki & Fibiger, 1981). However, abuse potential regarded as significant. of the amphetamine-type has not been observed with Further support for failure of bupropion to produce nomifensine in patients (Stonier, 1980, personal any stimulant effects of the amphetamine type in man communication) and the studies in healthy volunteers was seen in the recent study of male volunteers with a of Hindmarch & Parrott (1977) and Taeuber et al. history of psycho stimulant abuse by Griffith et al. (1979) failed to show amphetamine-like effects in (1983). Doses of bupropion up to 400 mg were healthy subjects using doses of 75 and 100 mg and compared with placebo and dexamphetamine up to observing critical flicker fusion and reaction time. 30mg. These tests, however, are of brief duration, and the In conclusion, no evidence was found in this in- most sensitive tests for the detection of amphetamine- vestigation to suggest that bupropion in doses up to like activity are prolonged and monotonous. The 200 mg and nomifensine 100 mg possessed either auditory vigilance test ofWilkinson (1968) has proved central nervous stimulant activity of an amphetamine ideal in this regard (Bye et al., 1973) and it seemed type on objective performance tests or on ratings of reasonable to use it to examine the effects of feelings. Neither was there any evidence ofassociated nomifensine. electroencephalographic effects or effects on In the present study the effects of dexamphetamine autonomic variables such as heart rate, systolic blood on vigilance reaction time, feelings of alertness and pressure or pupil diameter. elation, autonomic measures such as heart rate, systolic blood pressure and pupil diameter and finally the faster components of the EEG, were all quite The authors wish to thank Dr Peter Stonier of Hoechst clearly seen. The effects were frequently significant (UK) Ltd and Miss Massey Stewart of Smith, Kline and even after the 5 mg dose, and a dose-response rela- French Laboratories Ltd for arranging supplies of tionship was usually seen. By contrast, with one nomifensine (Merital) and dexamphetamine (Dexedrine) exception, both doses of bupropion and nomifensine respectively.

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