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'-chloropropio- phenone 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, con- stitute 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.