Prolactin and psychophysiologic measures after single doses of thioridazine Six normal men ingested thioridazine, high and low doses, and placebo on three occasions. Their plasma and urinary thioridazine and mesoridazine plus sulJoridazine were measured over 5 hr, together with their plasma prolactin, and a battery oi psychophysiologic variables. Drowsiness and EEG changes correlated highly with rise in prolactin, but not with drug plasma concentrations. Finger tremor increased, and some psychologic tests were impaired by thioridazine; other psychologic tests, the auditory-evoked response, and palmar skin conductance were unaffected and showed no relationship to drug or prolactin levels. This suggests that plasma prolactin may be a useful indicator oi some aspects of the individual' s response to a psychotropic drug, and possibly a better guide to the selection oi a suitable drug and its appropriate dose in clinical practice than the measurement oi plasma concentrations oi the drug itse(f.
Georgia Nikitopoulou, M.D.,* Michael Thorner, M.D.,** John Crammer, F.R.C.Psych., and Malcolm Lader, M.D. London, England Institute oi Psychiatry, De Crespigny Park
Phenothiazines are a family of drugs with a variety of short- and long-term actions on the central nervous system. Thus chlorpromazine ("Thorazine") and thioridazine ("Mellaril") have almost immediate sedative and hypnotic effects, in both normal people and agitated patients. They have delayed antipsychotic effects in schizophrenies, and chlorpromazine but not thioridazine frequently induces extrapyramidal effects. The size of an effective dose varies greatly among individuals and sometimes one patient res ponds to one partieular phenothiazine but not to another. It is not clear wh ether all this Received for publication Sept. 30, 1976. Accepted for publication Oct. 20, 1976. Reprint requests to: Dr. J. L. Crammer, Institute of Psychiatry, De Crespigny Park, London S.E.5, England. *British Council Scholar. "St. Bartholomew's Hospital, London E.C.I.
422
varIatIOn is due to differences in pharmacokineties or whether some of it reftects individual differences in brain pathology, at present unexplored. 3 If drug plasma concentrations, or under certain circumstances urinary excretion rates, are monitored, much individual pharmacokinetic variation can be taken into account when studying the effects of a psychotropic drug. Prolactin release from the anterior pituitary is inhibited by a hypothalamic factor, probably dopamine, which itself is blocked by chlorpromazine or thioridazine. 7 , 11 Monitoring the plasma prolactin concentration in an individual, therefore, offers another measure of drug action on the central nervous system. In particular, it is of interest to correlate drug and prolactin concentrations with degrees of change in both physiologie and psychologic indices of central
Volum e 2 1 Number 4
Prolactin and phenothiazines
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63 ng/ml rather than exactly. If, instead of doses, plasma concentrations were compared, some individuals showed a proportional prolactin response but with large differences between them: the subject with prolactin levels >63 ng/ml had some unmeasurably low thioridazine concentrations. Mood scales. The following sc ales yielded significant drug effects in the direction of the second adjective of the pair: alert-drowsy, attentive-dreamy, interested-bored, strong-feeble, gregarious-withdrawn. With the exception of the first scale, drug effects reached significant levels after the higher dose only.
Physiologie measures. EEG. Both the 7.5 to 13.5 Hz and the 13.5 to 26 Hz wavebands were significantly increased after the administration of thioridazine (Fig. 3). This was a dose-related effect, maximal about 3 hr after the drug. As would be expected, total EEG amplitude was increased by the drug. The average evoked response was not consistently altered by thioridazine. Tremor power was increased by the phenothiazine to a highly significant degree. However, neither dose effects nor time effects were clearly apparent (Fig. 4). No effects on the skin conductance were seen but the systolic blood pressure was reduced by the drug and the pulse rate elevated. Psychologie tests. Neither reaction time nor key tapping were significantly affected by thioridazine but performance on both the DSST and SeT were impaired, fewer items being completed (Fig. 4). Similarly, cancellation time was prolonged (Fig. 4). In all three tests, significant drug effects were observed only after the higher dose. Correlations between measures. The with-
Prolactin and phenothiazines
427
in-subject within-occasion correlations estimate how closely two variables covary during one day's recordings. The correlations between the drug variables, plasma prolactin concentration, and some of the drug-sensitive variables are set out in Table I. These correlations were computed excluding the data on the placebo occasion. There are significant interrelationships among the drug variables but prolactin concentrations are mostly unrelated to the thioridazine levels. Of the physiologic variables, significant correlations are found only with the urinary thioridazine concentrations, whereas the psychologic variables (alert-drowsy and DSST) correlate with all the drug measures. Plasma prolactin concentrations correlate strongly with the physiologic variables and the mood rating. Discussion
Preliminary trial of all subjects with a 50 mg dose allowed for some individual dose adjustment in the experiments themselves and may have reduced the scatter of drug plasma concentrations found in the group. Thioridazine values were mostly below 100 ng/ml (the highest was 162 mg/mi), the peak being reached in less than 3 hr after taking the dose, and the value then declining. The values were lower than expected in the light of earlier work, which showed plasma values of 200 to 300 ng/ml in patients undergoing therapy9 and indeed on several occasions were too low to be measured. The chief clinical effect to be expected after a single dose was sedative, and the self-rating of fall in alertness and the increase in EEG alpha-frequency activity were not unexpected and followed a similar time curve to that of plasma thioridazine and plasma prolactin. Plasma metabolites, mesoridazine and sulforidazine, of wh ich the former at least also has clinical activity, increased with time. One explanation of changes in those tests, such as tremor power or symbol-copying time, which also increased with time or failed to decline at 5 hr, could be that they were metabolite activated, and it is noteworthy that the highest correlation (p < 0.001) for the DSST in Table I was with plasma metabolite level. Table I also shows that urinary thioridazine, rather than plasma thioridazine, correlated weil
Nikitopoulou et al.
428
Clini63 ng/ml.
In 14 chronic schizophrenics studied by Kolakowska and associates, 4 the mean plasma prolactin measured once a week for at least 4 wk correlated (r = 0.67) with the mean plasma chlorpromazine over the same period, but not with the drug dose, but the levels of both drug and hormone fluctuated erratically from sampie to sampie and there was sometimes no prolactin rise after a chlorpromazine dose. Wilson and associates l l successfully correlated thioridazine dose and me an prolactin value in 49 chronic patients. Their results show, however, an enormous scatter of values for each dose of drug. Gur resuIts showed prolactin rises every time after the single dose of thioridazine in our normal subjects, with a fall at 5 hr, but the relationship between plasma concentration and prolactin release was different for each individual, which is why the statistics fail to show a correlation. In fact, this is another focus of biologic variability, quite separate from that of drug metabolism: the ease of disinhibition of prolactin secretion. It is quite possible that this variable is modified by chronic phenothiazine treatment, and indeed different also in the psychotic as opposed to the normal. Because of this and because of the firm corre-
Prolactin and phenothiazines
Valume 2/ Number 4
timations, and to B. H. Aschkenasy, B.Sc., for formulating the thioridazine and placebo liquid preparations.
EEG
7.5-
I
429
/3.5-
Tremor
B.P.
DSST
References I. Curry, S. H., and Mould, G. P.: Gas chro-
2.
3. 0.91* 0.10
0.34t
-OA2t
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lations found between plasma prolactin, drowsiness, and change in EEG, the monitoring of plasma prolactin du ring the course of antipsychotic drug therapy may prove a much more useful guide to management than the measurement of drug plasma levels. Meltzer and Fang6 have indeed in a first study of 27 schizophrenie patients shown raised prolactin levels throughout thioridazine treatment over 1 to 3 mo, with some suggestion of a correlation between cIinical response and level of prolactin. In our results plasma concentrations of thioridazine did not correlate weH with central effects, as Sakalis and associates found also for chlorpromazine. The explanation of this is to be seen in the prolactin values: individual differences between different nervous systems in their responses to the same plasma concentrations of drug. We are indebted to D. Dobson, B.Sc., and G. Crane, B.Sc., for assistance with the thioridazine es-
6.
7.
8.
9. 10.
11.
matographic identification of thioridazine in plasma and a method for routine assay of the drug, J. Pharm. Pharmaco\. 21:674-677, 1969. Greenwood, M. H., Friedel, J., Bond, A. J., Curzon, c., and Lader, M.: The acute effects of intravenous infusion of L-tryptophan in normal subjects, CUN. PHARMACOL. THER. 16:455464, 1974. Hollister, L.: Clinical differences among phenothiazines in schizophrenics, in Forrest, \. S., Carr, C. J., and Usdin, E. editors: The phenothiazines and structurally-related drugs, New York, 1974, Raven Press, pp. 667-673. Kolakowska, T, Wiles, D. H., McNeilly, A. S., and Gelder, M. G.: Correlation between plasma levels of prolactin and chlorpromazine in psychiatric patients, Psycho\. Med. 5:214-216, 1975. McNeilly, A. S.: Radioimmunoassay of human prolactin, Proc. R. Soc. Med. 66:863, 1973. Meltzer, H. Y., and Fang, V. S.: The effect of neuroleptics on serum prolactin in schizophrenie patients, Areh. Gen. Psyehiat. 33:279-286, 1976. Meltzer, H. Y., Sachar, E. J., and Frantz, A. G.: Dopamine antagonism by thioridazine in schizophrenia, Biol. Psychiat. 10:53-57, 1975. Nakra, B. R. S, Bond, A. J., and Lader, M.: Comparative psychotropic effects of metoclopramide and prochlorperazine in normal subjects, J. Clin.Pharmacol. 15:449-454, 1975. Ng, T. H., and Crammer, J. L.: The measurement of thioridazine in plasma and urine, Br. J. Clin. Pharmacol., 1977. (In press.) Sakalis, G., Curry, S. H., Mould, G. P., and Lader, M.: Physiologic and c1inical effects of chlorpromazine and their relationship to plasma level, CUN. PHARMACOL. THER. 13:931-946, 1972. Wilson, R. G., Hamilton, J. R., Boyd, W. D., Forrest, A. P. M., eole, E. N., Boyns, A. R., and Griffiths, K.: The effect of long-term phenothiazine therapy on plasma prolactin, Br. J. Psychiat. 127:71-74, 1975.
Georgia Nikitopoulou, M.D.,* Michael Thorner, M.D.,** John Crammer, F.R.C.Psych., and Malcolm Lader, M.D. London, England Institute oi Psychiatry, De Crespigny Park
Phenothiazines are a family of drugs with a variety of short- and long-term actions on the central nervous system. Thus chlorpromazine ("Thorazine") and thioridazine ("Mellaril") have almost immediate sedative and hypnotic effects, in both normal people and agitated patients. They have delayed antipsychotic effects in schizophrenies, and chlorpromazine but not thioridazine frequently induces extrapyramidal effects. The size of an effective dose varies greatly among individuals and sometimes one patient res ponds to one partieular phenothiazine but not to another. It is not clear wh ether all this Received for publication Sept. 30, 1976. Accepted for publication Oct. 20, 1976. Reprint requests to: Dr. J. L. Crammer, Institute of Psychiatry, De Crespigny Park, London S.E.5, England. *British Council Scholar. "St. Bartholomew's Hospital, London E.C.I.
422
varIatIOn is due to differences in pharmacokineties or whether some of it reftects individual differences in brain pathology, at present unexplored. 3 If drug plasma concentrations, or under certain circumstances urinary excretion rates, are monitored, much individual pharmacokinetic variation can be taken into account when studying the effects of a psychotropic drug. Prolactin release from the anterior pituitary is inhibited by a hypothalamic factor, probably dopamine, which itself is blocked by chlorpromazine or thioridazine. 7 , 11 Monitoring the plasma prolactin concentration in an individual, therefore, offers another measure of drug action on the central nervous system. In particular, it is of interest to correlate drug and prolactin concentrations with degrees of change in both physiologie and psychologic indices of central
Volum e 2 1 Number 4
Prolactin and phenothiazines
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63 ng/ml rather than exactly. If, instead of doses, plasma concentrations were compared, some individuals showed a proportional prolactin response but with large differences between them: the subject with prolactin levels >63 ng/ml had some unmeasurably low thioridazine concentrations. Mood scales. The following sc ales yielded significant drug effects in the direction of the second adjective of the pair: alert-drowsy, attentive-dreamy, interested-bored, strong-feeble, gregarious-withdrawn. With the exception of the first scale, drug effects reached significant levels after the higher dose only.
Physiologie measures. EEG. Both the 7.5 to 13.5 Hz and the 13.5 to 26 Hz wavebands were significantly increased after the administration of thioridazine (Fig. 3). This was a dose-related effect, maximal about 3 hr after the drug. As would be expected, total EEG amplitude was increased by the drug. The average evoked response was not consistently altered by thioridazine. Tremor power was increased by the phenothiazine to a highly significant degree. However, neither dose effects nor time effects were clearly apparent (Fig. 4). No effects on the skin conductance were seen but the systolic blood pressure was reduced by the drug and the pulse rate elevated. Psychologie tests. Neither reaction time nor key tapping were significantly affected by thioridazine but performance on both the DSST and SeT were impaired, fewer items being completed (Fig. 4). Similarly, cancellation time was prolonged (Fig. 4). In all three tests, significant drug effects were observed only after the higher dose. Correlations between measures. The with-
Prolactin and phenothiazines
427
in-subject within-occasion correlations estimate how closely two variables covary during one day's recordings. The correlations between the drug variables, plasma prolactin concentration, and some of the drug-sensitive variables are set out in Table I. These correlations were computed excluding the data on the placebo occasion. There are significant interrelationships among the drug variables but prolactin concentrations are mostly unrelated to the thioridazine levels. Of the physiologic variables, significant correlations are found only with the urinary thioridazine concentrations, whereas the psychologic variables (alert-drowsy and DSST) correlate with all the drug measures. Plasma prolactin concentrations correlate strongly with the physiologic variables and the mood rating. Discussion
Preliminary trial of all subjects with a 50 mg dose allowed for some individual dose adjustment in the experiments themselves and may have reduced the scatter of drug plasma concentrations found in the group. Thioridazine values were mostly below 100 ng/ml (the highest was 162 mg/mi), the peak being reached in less than 3 hr after taking the dose, and the value then declining. The values were lower than expected in the light of earlier work, which showed plasma values of 200 to 300 ng/ml in patients undergoing therapy9 and indeed on several occasions were too low to be measured. The chief clinical effect to be expected after a single dose was sedative, and the self-rating of fall in alertness and the increase in EEG alpha-frequency activity were not unexpected and followed a similar time curve to that of plasma thioridazine and plasma prolactin. Plasma metabolites, mesoridazine and sulforidazine, of wh ich the former at least also has clinical activity, increased with time. One explanation of changes in those tests, such as tremor power or symbol-copying time, which also increased with time or failed to decline at 5 hr, could be that they were metabolite activated, and it is noteworthy that the highest correlation (p < 0.001) for the DSST in Table I was with plasma metabolite level. Table I also shows that urinary thioridazine, rather than plasma thioridazine, correlated weil
Nikitopoulou et al.
428
Clini63 ng/ml.
In 14 chronic schizophrenics studied by Kolakowska and associates, 4 the mean plasma prolactin measured once a week for at least 4 wk correlated (r = 0.67) with the mean plasma chlorpromazine over the same period, but not with the drug dose, but the levels of both drug and hormone fluctuated erratically from sampie to sampie and there was sometimes no prolactin rise after a chlorpromazine dose. Wilson and associates l l successfully correlated thioridazine dose and me an prolactin value in 49 chronic patients. Their results show, however, an enormous scatter of values for each dose of drug. Gur resuIts showed prolactin rises every time after the single dose of thioridazine in our normal subjects, with a fall at 5 hr, but the relationship between plasma concentration and prolactin release was different for each individual, which is why the statistics fail to show a correlation. In fact, this is another focus of biologic variability, quite separate from that of drug metabolism: the ease of disinhibition of prolactin secretion. It is quite possible that this variable is modified by chronic phenothiazine treatment, and indeed different also in the psychotic as opposed to the normal. Because of this and because of the firm corre-
Prolactin and phenothiazines
Valume 2/ Number 4
timations, and to B. H. Aschkenasy, B.Sc., for formulating the thioridazine and placebo liquid preparations.
EEG
7.5-
I
429
/3.5-
Tremor
B.P.
DSST
References I. Curry, S. H., and Mould, G. P.: Gas chro-
2.
3. 0.91* 0.10
0.34t
-OA2t
-0.53:j:
-0.50+
-0.19
-0.19
-0.19
4. 0.13
5.
lations found between plasma prolactin, drowsiness, and change in EEG, the monitoring of plasma prolactin du ring the course of antipsychotic drug therapy may prove a much more useful guide to management than the measurement of drug plasma levels. Meltzer and Fang6 have indeed in a first study of 27 schizophrenie patients shown raised prolactin levels throughout thioridazine treatment over 1 to 3 mo, with some suggestion of a correlation between cIinical response and level of prolactin. In our results plasma concentrations of thioridazine did not correlate weH with central effects, as Sakalis and associates found also for chlorpromazine. The explanation of this is to be seen in the prolactin values: individual differences between different nervous systems in their responses to the same plasma concentrations of drug. We are indebted to D. Dobson, B.Sc., and G. Crane, B.Sc., for assistance with the thioridazine es-
6.
7.
8.
9. 10.
11.
matographic identification of thioridazine in plasma and a method for routine assay of the drug, J. Pharm. Pharmaco\. 21:674-677, 1969. Greenwood, M. H., Friedel, J., Bond, A. J., Curzon, c., and Lader, M.: The acute effects of intravenous infusion of L-tryptophan in normal subjects, CUN. PHARMACOL. THER. 16:455464, 1974. Hollister, L.: Clinical differences among phenothiazines in schizophrenics, in Forrest, \. S., Carr, C. J., and Usdin, E. editors: The phenothiazines and structurally-related drugs, New York, 1974, Raven Press, pp. 667-673. Kolakowska, T, Wiles, D. H., McNeilly, A. S., and Gelder, M. G.: Correlation between plasma levels of prolactin and chlorpromazine in psychiatric patients, Psycho\. Med. 5:214-216, 1975. McNeilly, A. S.: Radioimmunoassay of human prolactin, Proc. R. Soc. Med. 66:863, 1973. Meltzer, H. Y., and Fang, V. S.: The effect of neuroleptics on serum prolactin in schizophrenie patients, Areh. Gen. Psyehiat. 33:279-286, 1976. Meltzer, H. Y., Sachar, E. J., and Frantz, A. G.: Dopamine antagonism by thioridazine in schizophrenia, Biol. Psychiat. 10:53-57, 1975. Nakra, B. R. S, Bond, A. J., and Lader, M.: Comparative psychotropic effects of metoclopramide and prochlorperazine in normal subjects, J. Clin.Pharmacol. 15:449-454, 1975. Ng, T. H., and Crammer, J. L.: The measurement of thioridazine in plasma and urine, Br. J. Clin. Pharmacol., 1977. (In press.) Sakalis, G., Curry, S. H., Mould, G. P., and Lader, M.: Physiologic and c1inical effects of chlorpromazine and their relationship to plasma level, CUN. PHARMACOL. THER. 13:931-946, 1972. Wilson, R. G., Hamilton, J. R., Boyd, W. D., Forrest, A. P. M., eole, E. N., Boyns, A. R., and Griffiths, K.: The effect of long-term phenothiazine therapy on plasma prolactin, Br. J. Psychiat. 127:71-74, 1975.
