Comparison of clozapine and haloperidol on some autonomic and psychomotor functions, and on serum prolactin concentration, in healthy subjects

Abstract

Aims

To compare the autonomic, neuroendocrine and psychomotor effects of single doses of the ‘atypical’ antipsychotic clozapine and the ‘classical’ antipsychotic haloperidol, in healthy male volunteers.

Methods

Clozapine (50 mg), haloperidol (3 mg) and placebo were administered to 12 healthy male volunteers at weekly intervals, according to a balanced double-blind design. Resting pupil diameter, salivary output, heart rate, blood pressure, plasma prolactin concentration, critical flicker fusion frequency and subjective ‘alertness’, ‘contentedness’ and ‘anxiety’ were measured at baseline and 2, 3, 4 and 5 h after drug ingestion. Data were analysed by analysis of variance with individual comparisons (Dunnett's test) with a significance criterion of P < 0.05.

Results

Significant treatment effects (difference from placebo [mean, 95% CI] 5 h after drug ingestion) were as follows: clozapine reduced pupil diameter (mm; −3.02 [−3.56, −2.47]), salivary output (g; −0.34 [−0.60, −0.08]), mean arterial blood pressure (mm Hg; −8.7 [−14.3, −3.1]), critical flicker fusion frequency (Hz; −3.26 [−3.94, −2.58]), and subjectively-rated ‘alertness’ (mm; −20.94 [−29.21, −12.67]) and ‘contentedness’ (mm; −12.98 [−17.90, −8.06]), whereas haloperidol increased prolactin concentration (mU l⁻¹; 301.3 [196.7, 405.8]) and caused small reductions in pupil diameter (mm; −0.68 [−1.23, −0.14]), mean arterial blood pressure (mm Hg; −7.0 [−12.6, −1.4]) and critical flicker fusion frequency (Hz; −1.15 [−1.83, −0.47]).

Conclusions

The effects of the antipsychotics are in agreement with their receptor binding profiles: α₁-adrenoceptor blockade by clozapine may contribute to reductions in pupil diameter, salivation, mean arterial blood pressure and sedation, and muscarinic cholinoceptor blockade by the drug may underlie the reduction in salivation. Conversely, D₂ dopamine receptor blockade by haloperidol is likely to be responsible for the increase in prolactin secretion evoked by the drug.

Introduction

The ‘atypical’ antipsychotic drug clozapine, in contrast to ‘classical’ antipsychotics, does not cause extrapyramidal side-effects and hyperprolactinæmia; however, it is more effective than ‘classical’ drugs for the treatment of some schizophrenic patients [1]. The drug is licensed in the U.K. for the treatment of patients suffering from ‘treatment-resistant’ schizophrenia [1]. The atypical pharmacological profile of clozapine is usually attributed to its receptor binding profile: although the drug has a somewhat lower affinity for D₂ dopamine receptors than ‘classical’ antipsychotics, it has high affinities for a number of 5-HT receptors (5-HT_2A, 5-HT_2C, 5-HT₃, 5-HT₆, 5-HT₇), muscarinic and H₁ histamine receptors and for α₁-and α₂-adrenoceptors [2]. The drug also has appreciable affinity for D₁ dopamine receptors [2]. On the other hand, the ‘classical’ antipsychotic haloperidol is generally regarded as a relatively selective D₂ dopamine receptor antagonist, although it also has relatively high affinities for α₁-adrenoceptors [2] and σ receptors [3]. In contrast to clozapine, haloperidol is rather ineffective at most 5-HT receptor subtypes (with the exception of 5-HT_2A), α₂-adrenoceptors, all muscarinic receptor subtypes, and H₁ histamine receptors [2]. On the basis of their different receptor binding profiles, it can be predicted that clozapine and haloperidol will have different effects on autonomic, neuroendocrine and psychomotor functions. In the present study, we compared single doses of the two drugs in healthy male volunteers on these functions. Some of these results have been presented to the British Association for Psychopharmacology, and have been published in abstract form [4].

Methods

Subjects

Twelve healthy drug-free male volunteers, aged 20–54 years, participated. Each subject completed a brief medical history, and underwent a complete physical and psychiatric examination before inclusion in the study. All subjects had a blood sample for a full blood count before entering the study and upon its completion, to check the subjects' hæmatological status, as clozapine may reduce white cell count [1]. All volunteers gave their written informed consent following a verbal explanation of the study and after reading a detailed information sheet. The study protocol complied with the Declaration of Helsinki and its revisions, and was approved by the University of Nottingham Medical School Ethics Committee.

Drugs

Clozapine (50 mg), haloperidol (3 mg) and placebo were prepared in identical capsules for oral administration. The single dosages of haloperidol (3 mg) and clozapine (50 mg) were selected on the basis of the approximate dose equivalence of the two drugs: 3 mg haloperidol corresponds to 100 mg chlorpromazine [5], and clozapine is somewhat less potent than chlorpromazine [6].

Design

Subjects were allocated to treatment conditions and sessions double-blind, according to a balanced crossover design. Tests were carried out prior to drug ingestion and 2, 3, 4 and 5 h afterwards. The times of postdrug testing were chosen on the basis of the single dose pharmacokinetics of clozapine (peak plasma concentration 1 h, peak pharmacodynamic effect 4 h) and of haloperidol (peak plasma concentration 2–6 h) [1].

Tests

Resting pupil diameter was measured in the dark by infra-red television pupillometry [7]. Heart rate was measured by palpating the radial artery and blood pressure, in the sitting position, by sphygmomanometry. Salivary output was measured by placing three dental rolls in the mouth, one sublingually and two buccally, for a period of 1 min; the test was repeated three times at 5 min intervals, and the mean of the increases in weight of the dental rolls in the three tests was taken as an index of salivary output [8]. For the assessment of plasma prolactin concentration, plasma was obtained from a 10 ml blood sample taken from an antecubital vein at the end of each testing time. Prolactin concentrations were measured by the Department of Clinical Chemistry at University Hospital, Queen's Medical Centre, Nottingham, U.K., using a radioimmunoassay method. Critical flicker fusion frequency, a measure of CNS arousal [9], and subjective ratings of ‘alertness’, ‘contentedness’ and ‘anxiety’, using a battery of visual analogue scales [10], were assessed as described previously [11, 12].

Data analysis

For each measure, the difference between the pretreatment baseline and the post-treatment values was calculated for each subject and for each time point, and the mean (± s.e. mean) of these values was calculated for the whole group. Two-factor (treatment × time) analysis of variance, with repeated measures on both factors, was used. In the case of significant treatment and/or interaction effects, individual comparisons between active drugs and placebo were made using Dunnett's test (significance criterion P < 0.05). In addition, the mean differences between the effects of active treatments were calculated for the last (5 h) post-treatment assessment, together with their 95% confidence intervals, corrected for multiple comparisons.

Results

Autonomic and neuroendocrine functions

There were significant treatment effects on resting pupil diameter (F_2,22 = 12.99; P < 0.001), salivary output (F_2,22 = 6.18; P < 0.01) and on plasma prolactin concentration (F_2,22 = 7.43; P < 0.001). There were significant main effects of time for salivation (F_3,33 = 3.50; P < 0.05) and plasma prolactin concentration (F_3,33 = 8.78; P < 0.01). Individual comparisons showed that clozapine significantly reduced resting pupil diameter and salivary output, and haloperidol significantly increased plasma prolactin concentration and reduced resting pupil diameter (Figure 1). Of the cardiovascular measures, heart rate (F_2,22 = 3.82; P < 0.05) and mean arterial pressure (F_2,22 = 5.21; P < 0.01) were significantly affected by the treatments: these treatment effects were due to a significant increase in heart rate and a significant decrease in mean arterial pressure after clozapine and haloperidol. The differences between the effects of the treatments 5 h after drug ingestion are shown in Table 1.

Figure 1.

Effects of the treatments on autonomic and neuroendocrine functions. Ordinate: change in measure from pretreatment. Abscissa: time following drug ingestion, h. Each point corresponds to the group mean (n = 12). ○ placebo; • haloperidol; ▪ clozapine. Asterisks denote treatments whose effects are significantly different from those of placebo (Dunnett's test; P < 0.05).

Table 1.

Differences between the treatments (mean, 95% CI) 5 h after their administration.

Test	Placebo vs Haloperidol	Placebo vs Clozapine	Haloperidol vs Clozapine
Pupil diameter (mm)	−0.68 (−1.23, −0.14)*	−3.02 (−3.56, −2.47)*	−2.34 (−1.79, −2.88)*
Salivation (g)	0.01 (0.28, −0.25)	−0.34 (−0.60, −0.08)*	−0.33 (−0.06, −0.59)*
Serum prolactin (mU l−1)	301.3 (196.7, 405.8)*	−67.4 (−172.0, 37.1)	−368.7 (−264.1, −473.2)*
Heart rate (beats min−1)	0.8 (−7.1, 8.6)	14.3 (6.5, 22.2)*	13.6 (21.4, 5.7)*
Systolic BP (mmHg)	−8.7 (−17.0, −0.4)	−10.3 (−18.6, −2.1)	−1.7 (6.6, −9.9)
Diastolic BP (mmHg)	−6.2 (0.0, 12.4)	−7.9 (−14.1, −1.7)	−1.8 (4.4, −7.9)
MAP (mmHg)	−7.0 (−12.6, −1.4)*	−8.7 (−14.3, −3.1)*	−1.7 (3.9, −7.3)
CFFF (Hz)	−1.15 (−1.83, −0.47)*	−3.26 (−3.94, −2.58)*	−2.10 (−1.42, −2.79)*
‘Alertness’ (mm)	−4.91 (−13.19, 3.35)	−20.94 (−29.21, −12.67)*	−16.03 (−7.76, −24.29)*
‘Contentedness’ (mm)	−1.17 (−6.09, 3.75)	−12.98 (−17.90, −8.06)*	−11.81 (−6.90, −16.73)*
‘Anxiety’ (mm)	−5.78 (−11.75, 0.19)	−3.28 (−9.25, 2.69)	2.50 (8.50, −3.47)

Note that the basis of reference is placebo for columns 1 and 2, and haloperidol for column 3. MAP=mean arterial pressure, CFFF=critical flicker fusion frequency.

^*Significant difference (anova, followed by LSD test), P < 0.05.

Psychomotor functions

There were significant treatment effects on critical flicker fusion frequency (F_2,22 = 12.87; P < 0.001) and on the ‘alertness’ (F_2,22 = 11.56; P < 0.001) and ‘contentedness’ (F_2,22 = 10.29; P < 0.001) factors. There was also a significant main effect of time (F_3,33 = 5.65; P < 0.01) and a significant treatment–time interaction (F_6,66 = 5.54; P < 0.01) for critical flicker fusion frequency. Individual comparisons showed that these treatment effects reflected decrements in critical flicker fusion frequency after clozapine and haloperidol and in ‘alertness’ and ‘contentedness’ after clozapine (Figure 2). The differences between the effects of the treatments 5 h after drug ingestion are shown in Table 1.

Figure 2.

Effects of the treatments on psychomotor functions. CFFF=critical flicker fusion frequency, ‘alertness’, ‘contentedness’ and ‘anxiety’ are factors obtained from the visual analogue scales (see text for details). Ordinate: change in measure from pretreatment. Abscissa: time following drug ingestion, h. Each point corresponds to the group mean (n = 12). ○ placebo; • haloperidol; ▪ clozapine. Asterisks denote treatments whose effects are significantly different from those of placebo (Dunnett's test; P < 0.05).

Discussion

Both clozapine and haloperidol exerted effects which are consistent with their well–documented interactions with central and peripheral neuroreceptors.

Clozapine caused considerable miosis, which could be related both to central sedation and the antagonism of α₁-adrenoceptors in the dilator muscle of the iris. The miotic effect of clozapine seemed to have superseded a predictable mydriatic effect resulting from the blockade of muscarinic cholinoceptors on the constrictor muscle of the iris. The high affinity of clozapine for muscarinic cholinoceptors, however, could be revealed unimpeded in the case of salivary output, which was considerably reduced by the drug. Although this was a pharmacologically predictable effect, it was rather unexpected since it is well known that clozapine causes an increase in salivation in patients treated with the drug [1, 13]. The mechanism of the hypersalivation observed in patients is not clear, and it has been related to the blockade of central α₂-adrenoceptors, D₂ dopamine receptors, or an agonistic effect at M₄ muscarinic receptors [13]. It should also be noted that the results of our acute experiment may not be directly applicable to patients who are treated with clozapine chronically over periods of weeks and months when the development of adaptive changes in receptors and neuroeffector systems can be anticipated. However, it is unlikely that this explains the discrepancy between the laboratory finding of decreased salivation in the present study and the hypersalivation reported by patients since no increase in salivary output could be detected in a group of schizophrenic patients treated with clozapine, who complained of noctural sialorrhœa, and it has been suggested that the clozapine-induced sialorrhœa may be due to swallowing difficulties rather than to a true increase in salivary secretion [13]. Clozapine also appeared to be strongly sedative in the present study: all the subjects complained of drowsiness, and some of them fell asleep during the session. This sedative effect is reflected in the reductions in critical flicker fusion frequency and subjectively rated ‘alertness’. The reduction in subjectively rated ‘contentedness’ is likely to reflect the malaise or dysphoria associated with the drowsiness and dry mouth. The single dose of clozapine used in the present study had only minor cardiovascular effects: only a reduction in mean arterial pressure reached statistical significance. In agreeement with previous reports [1], clozapine failed to cause any increase in plasma prolactin concentration, consistent with its relatively low affinity for D₂ dopamine receptors.

Haloperidol had a completely different profile of action from clozapine: its most prominent effect was a marked increase in plasma prolactin concentration. Again, this finding is in agreement with previous reports [1, 2, 14], and it can be related to the blockade of hypothalamic D₂ dopamine receptors by the drug. As in previous studies [14], the small dose of haloperidol used in this study had no major autonomic or psychomotor & effects.

In conclusion, while clozapine has advantages due to its lack of effects on the motor and endocrine systems, its profound autonomic and sedative effects can be the cause of considerable distress for patients. As clozapine reduces rather than increases salivary secretion, the mechanism underlying the nocturnal sialorrhœa observed in patients treated with the drug requires further investigation.