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Prolactin response to submaximal stimulation by TRH in nonaffective psychoses
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Prolactin Response to Submaximal Stimulation by TRH in Nonaffective Psychoses Joban Spaov, Per-Erik Bredbacka, Bj6m Appelberg, Heikki Katila, Sirkka-Liisa Karonen, Ranan Rim6n, and Seppo San,a
Nonaffective psychotic symptoms are heterogeneous and probably caused by mixed biopathology. A preliminary investigative tool to snaty pituitary dopamine activity, the prolactin response to submaximal stimulation by tilyrotropin-releasing hormone (TRlt) (mini-TRH tesO was correlated in 20 subjects with nonaffective psychoses to positive psychotic symptoms as assessed by the Comprehensive Psychiatric Rating Scale psychosis subscale. A significam positive correlation was observed between the response and ratings of nonparanoid symptoms, especially nonparanoid delusions and disrupted thoughts. Because, in addition to pituitary dopamine activity, there is evidence to suggest that the response reflects extrapituitary dopamine activity as well, the results extend the evidence that nonparanoid acute productive psychotic symptoms may be associated with hypoactivity rather than with hyperactivity of brain dopcminergic systems.
Introduction The dopamine hypothesis of schizophrenia (Ran&up and Munkvad 1972) evolved from observations of the ressemblence of amphetamine psychosis to paranoid schizophrenia (Connell 1958), as well as from observations hat neuroleptic drags block dopamine receptors (Carlsson and Lindqvist 1963). Amphe~mine action is mediated presynaptically and increases levels of catecholamines at receptor sites (Snyder 1972). In nonschizophrenic subjects, the administration of small repetitive do:~es of amphetamine has been reported I " +" to induce a paranoid state with no sehizoplh-enic thought disorder or hallucinations (f~_--~gg6L u..,u, et al 1972). The administration of large doses frequently provokes visual and auditory hallucinations as well (Angrist et al 1969). The intramuscular (IM) administration of haloperidol, the relatively specific dopamine receptor blocking drug, has been reported to immediately ameliorate symptoms of amphetamine psychosis, especially suspiciousness (Angrist et al 1974). Using neuroendocrinologic methods, the generality of the dopamine hypothesis of schizophrenia has been extensively studied. In drug-free schizophrenic subjects, serum prolactin response to 25 mg IM chl,3rpromazine has been reported to negatively correlate
From the Departments of Psychiatry US, P-EB, BA, I-IK, F,R), Clinical Chemistry (JS, S-LK), and Public Heal.',h (SS), University of Helsinki, Helsinki, Fmlm~d. Address reprint requests to Johan Spoor, MD, Department of Psychiatry, University of Helsinki, Lapinlahdentie, SF-O0180 Helsinki, Finland. Received October 3, 1989; revised April 16, 1990. © 1991 Society of Biological Psychiatry
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with ratings of severity of delusions (Meltzer and Busch 1983). In chronically schizophrenic subjects, prolactin response to neurolepfic activity has ~een reported to negatively correlate with paranoid symptoms (Csernansky et al 1986). However, in drugfree schizophrenic subjects, prolactin response to 0.5-mg intravenous (IV) haloperidol has been reported to positively correlate with total Brief Psychiatric Rating Scale (BPRS) score (Keks et al 1987). The seemingly contradictory findings may be explained by a different relation to hypothalamic-pimitary dopamine activity of p ~ o i d versus nonparanoid psychotic sy~ptoms. In humans, a mutatai antagonism has been observed between thyrotropin-releasing hormone (TRH) and dopamine with regard io prolactin secretion (Burrow et ai 1977). In smaller doses than those needed to directly stimulate prolactin release, TRH can L o s t completely block the ~ibitory effect of dcpamine on pituitary prolactin release in vitro (Hill-Samli and Mac Leod 1974). We have reported that prolactin response to 12.5 ~g IV TRH is submaximal and that 24-hr urinary excretion of homovanillic acid (HVA) as well as prolactin response to 0.5 mg IM haloperidol significantly correlates with it, but not with basal prolactin level or with maximal prolactm response to "IRH (Slx.,ov 1985; Spoov and Karonen 1987). Our studies thus suggest that submaximal prolactin response to stimulation by TRH may reflect endogenous dopamine activity. As opposed to the effects of neuroleptic dopamine antagonists, there is no evidence to suggest that TRH induces prolactin secretion by hypothalamic mechanisms. Therefore, in the present study, in an attempt to study the relation of pituitary dopamine activity and psychosis, plasma prolactin responses to stimulation by 12.5 lag IV TRH were correlated with scores of the Comprehensive Psychosis Rating Scale (CPRS) psychosis subscale (Bartfai et al 1984).
Materials and Methods The subjects were 20 patients (9 female, 1 male, 32 +__3.1 years [mean +__SD]) treated for a nonaffective psychotic episode at the University Psychiatric Hospital in HelsJnki. Using different sources, a reliable drug ~istory of all the subjects was obtained. Nine of the subjects had never been given neuroleptic medication and three subjects had not taken neuroleptic drugs for at least 4 months before the study. One additional subject had not taken neuroleptic drugs for 38 days. These 13 subjects were classified as the drug-free group. Si~ of the subjects were receiving neuro!eptic drugs upon admission and one additional subject had discontinued her neuroleptic drug treatment a few days before admission. These seven subjects were classified as the drug-withdrawal group. The diagnoses were made by clinical ~nterview according to DSM-III-R (American Psychiatric Association 1987). In eight subjects, a diagnosis of schizophrenia was made. In four subjects, a delusional disorder and in tl-~ee an atypical psychosis was diagnosed. In three subjects, a personality disorder with psychotic breakdown was diagnosed and in one subject each, a diagnosis of schizophreniform psychosis and of brief reactive psychosis was made. Six of the subjects had been suffering from psychotic episodes for more than 3 years, seven of the subjects for 1-3 years, and seven for less than 1 year. After admission, a washout period of at least 4 days was executed in all the subjects before assessment of the CPRS psychosis subscale (Bartfai et al 1984) and before the prolactin test. The subscale is a measure of positive psychotic symptoms. The item "disrupted thoughts" represents the experience of thought blocking, insertion, or withdrawal or listened to or broadcast thoughts. The subscale contains the item "ideas of
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persecution" and the item "other delusions." The latter represents any delusion other than pessimistic thought, hypochondriasis, feeling controlled, ideas of persecution, ideas of grandeur, delusional mood, or morbid jealousy. There are four items in the psychosis subscale representing various auditory, visual, and other hallucinations. The total of the hallucination items scores is used in the present study as the score of various hallucinations. The prolactin test was, in 16 of the subjects, done within 1 day of the assessment ot ~the psychosis subscale. In none of the subjects was a change observed in the clinical condition between rating of psychosis and prolactin test. None of the subjects had received longacting parenteral neuroleptic agents within 6 months. The number of drug free days was 8.6 +_. 1.6 (mean - SEM) among subjects in the withdrawal group. The subjects were permitted small doses of be~zodiazepines on an as-needed basis for sedation, but no patient received psychotropic medication during the 12 hr preceding the prolactin test. On the morning of the prolactin test, Emla cream (containing lidocain and prilocain) was applied on an antebrachial vein for local anesthesia, although it is by no means certain that pain associated with venipuncture is responsible for the "spuriously" high basal prolactin levels in some schizophrenic subjects (Kleinman et al 1982). After 1.52 hr, at 10:00-11:30 AM, blood was drawn for the basal prolactin level and an IV bolus of 12.5 Ixg TRH was administered. Utilizing a small insulin needle by one of the authors (P-EB), a standard preparation of TRH, 100 ixg/ml, could be injected in reproducible doses. Fifteen minutes thereafter, a second blood specimen was obtained for the stimulated prolactin level. In normal male subjects, peak prolactin levels have been reported to occur 15 min (Bowers et al 1971; Jacobs et al 1973; Noel et al 1973) or 10 rain (l'Hermite et al 1972) after the IV administration of TRH. Because the present study is the first to utilize submaximal prolactin response to stimulation by TRH in psychiatric patients, there is no information as yet regarding the possibility that in some psychiatric patients, the peak prolactin level might occur erratically or even systematically at some other time. During the procedure the patients were in the supine position and no interruptions were allowed. Plasma samples were frozen at -20°C until assayed in duplicate for prolactin by a radioimmunoassay method (Pharmacia, Sweden, 1983). The intraassay and interassay coefficients of variation ([SD/meanl × 100) were 5.0 and 12.0, respectively. The associations between prolactin response and psychosis subscale and its items were studied by partial correlation and multivariate regression methods. Age, sex, and drug use were considered as covariates, whose linear effect was removed from the correlation results. Because the distribution of prolactin response and basal prolactin were skewed, a logarithmic transformation was performed before the multiple regression. The distribution of psychosis subscale score was symmetric and fairly normal. For comparison of group means, an independent-sample, two-tailed t-test was used. Results The individual results are given in Figure 1. As a response measure we used post-TRH minus baseline prolactin level. There seemed to be no association between prolactin response and diagnosis, although the number of patients in each diagnostic group is too small for definite conclusions. No association was found between prolactin response and duration of psychotic illness. Prolactin response to stimulation by 12.5 Ixg IV TRH was significantly higher in female (22.0 ___ 3.4 txg/L [mean 4-_ SEM]) than in male (10.7 ___
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Figure 1. The residuals of CPRS psychosis subscale score and log of prolactin response after adjusting for sex, age, and drug use in 20 psychotic su~ects (r = 0.7!, df = 15, p < 0.01).
2.0 p,g/L [mean _+ SEM]) subjects (t = 2.9, df = 18, p < 0.01). The age of female patients did not differ significantly from the age of male patients (t = !.. 1, df = 18, p > 0.05). Removing the linear effects of :+ge, sex, and drug use revealed a significant partial con'elation between CPRS psychosis subsca!e score and plasma pro!actin response to stimulation by 12.5 lxg IV TRH (rp - +0.71, df = 15, p < 0.01). The partial correlation remained the same even when patients in the drug-withdrawal group were excluded (rp = +0.69) er when the patients were examined by gender group (rp = + 0 . 8 4 and rp = + 0 . 6 6 for female and male patients, respectively). Of the individual items in the CPRS psychosis subscale, only ratings of other delusions significantly correlated with prolactin response (rp = 0.73, df = 15, p < 0.001). Ratings of disrdpted thoughts marginally correlated with prolactin response (rp = 0.5 i, df = 15, 0.01 < p < 0.05). On the other hand, no significant correlations were found between ratings of various hallucinations or ideas of persecution and prolactin response (rp = 0.36 and rp = 0.05, respectively). In all the psychotic subjects, basal plasma prolactin level was within the normal range. It was 3.6 _+ 0.5 ixg/L (mean +_ SEM) in female subjects and 2.9 +_ 0.3 Ixg/L in male subjects, a difference that was not statistically significant (t = 1.3, df = 18, p > 0.05).
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Removing the linear effects of age, sex, and drug use did not reveal a significant partial correlation between ratings of psychosis subscale and basal prolacfin level ( r v = - 0.20, df = 15, p > 0.05). Removing the linear effects of age, sex, and drug use did not reveal a significant partial correlation between basal prolactin level and prolactin response to stimulation by 12.5 pLg IV TRH (rp = +0.17, df = 15, p > 0.05).
Discussion One of the major findings in the present study was the positive correlation between ratings of the CPRS psychosis subscale and prol~cti,! response to TRH. Because a similar finding has been reported between positive symptoms and prolactin response to stimulation by parenteral haloperidol (Keks et al 1987), and because the latter probably is not affected by sensitivity of TRH receptors and correlates positively with prolactin response to stimulation by 12.5 I~g IV TRH (Spoov 1985), it is probable that endogenous dopamine rather than sensitivity to TRH receptors was responsible for the correlation. Moreover, in humans, submaximal prolactin response to stimulation by TRH has been reported not to correlate with maximal prolactin response to TRH (Spoov 1988), wtdch has been found to closely correlate with the number of TRH receptors in vitro (DeLean et al 1977). Because extrahypothalamic brain TRH has been rel~orted to be independent of the hypothalamic secretion (Jackson and Reichlin 1977) it is difficult to see why sensitivity of pituitary TRH receptors would correlate with psychotic symptoms, which are produced in extrapituitary brain areas. Tuberoinfundibular dopamine (TIDA) may, however, both decrease sensitivity of prolactin responses to TRH and be associated with psychotic symptoms (see Spoov and Karonen 1987). Of ti~" items in the CPRS psychosis subscale only ratings of other delusions and dismpte0 thoughts contributed to the positive correlation between ratings of the subscale and prolactin response to stimulation by 12.5 ttg IV TRH. On the other hand, with regard to prolaetin response, ratings of persecutory delusions and various hallucinations seemed to behave independently. The absent correlation did not support our hypothesis of an increased pituitary dopamine activity among psychotic subjects in association with paranoid delusions. Interestingly, the relation of delusions to dopamine activity seemed to depend on the t~pe of delusions. in schizophrenic subjects, the basal proiactin level has been reported to negatively correlate with positive symptoms in some (Johnstone et al 1977; Kleinman et al 1982) but not in other (Meltzer et al 1974, 1984) studies. In one of these studies, an intraindividual but not interindividual negative correlation was reported between basal prolactin level and positive symptoms (Johnstone et al 1977), suggesting the possibility that fluctuations in neurotransmitters involved in prolactin release may be reflected in both positive symptoms and basal prol~ctin levels. Because it has been reported that pro!actin responses to maximal stimulation by TRH but not to submaximal stimulation by TRH reflect fluctuations in the basal prolactin level (Spoov 1987) it can be argued that such fluctuations may not be mediated by dopamine. In the present study, no significant correlation was observed between basal prolactin level and CPRS psychosis subscale. In the present population of psychotic male subjects, basal prolactin level tended to be lower and prolactin response to stimulation by 12.5 ttg IV TRH ter~ded to be higher as compared to our previous results in 28 nonpsychiatric subjects (Spoo~, 1985). Because our previous method for measuring plasma prolactin was different from the present one,
Prolactin Response to TRH in Psychoses
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accurate comparisons were not pessible. Nondopmnine hypothalamic PIFs may be stimulated by dopamine and the possibility ex'ht~ that their sensitivity to d o p ~ e antagonism may be blunted in acute schizophrenia (Keks et al 1987). Such a mechanism is not tikely to contribute to the prolactin response to stimulation by 12.5 ~g IV TRH, which is modest as compared to the increase of prolactin provoked by parenteral 0.5 mg halopefidol (Spoor 1985). R is concluded that sensitivity of the hypothalamic-pituitary TRI-I system is related to psychotic symptoms. We believe that this association is mediated ~ o u g h dopamine. Because TIDA turnover represents a very small fraction of total brain dopamine turnover, our previous finding of a significantly negative correlation between prolactin response to submaximal stimulation by TRH and 24-hr urinary excretio, of HVA ,;uggests that the response reflects dopamine turnover at extrapituitary sites in humans (Spoor and Karonen 1987) :rod that TIDA activity may be related to activity in other dopamine systems. In unmasking postsynaptic dopamine effects, the prolactin response to TRH or to o~er dopamine antagonists probably also reflects dopamine receptor sensitivity on lactotrops. Our results do not support the theory of increased dopamine activity in acute productive schizophrenic illness (Mackay 1980). An association between central dopamine hypoactivity and nonparanoid psychotic symptoms has been suggested by studies utilizing cerebrospinal fluid and urine HVA (Bowers 1974; Karoum et al 1987). Utilizing a totally different methodology, the present results extend such findings. For more definite conclusions, dose-response studies describing the time-response curve after submaximal prolactin stimulation by TRH and reproducibility in larger numbers of drug-naive psychotic subjects are needed. The advice of Prof. H.Y. Mcitzerin preparing this manuscriT:"~~ f : l l y acknowledged.
References American Psychiatric Association (1987): Diagnostic and Statistic Manual of Mental Disorders, 3rd ed rev. Washington, DC: American Psychiatric Press. Angrist BM, Schweitzer J, Friedhoff AJ, Gershon S, Hekimian LI, lloyd A (1969): The c ~ c a l symptomatology of amphetamine psychosis and its relationship to amphetamine levels in urine. Int Pharmacopsychiatry 2:125-139. Angrist B, Lee HK, Gershon S (1974): The antzgonism of amphetamine-induced symptomztoiogy by a neuroeptic. Am J Psychiatry 131:817-819. Bartfai A, Edman G, Levander SE, Schalling D, Sedvall G (1984): Bilateral skin conductance activity, clinical symptoms and CSF monoamine metabolite levels in unmedicated schizophrenics, differing in rate of habituation. Biol Psychology 18:201-218. Bowers CY, Friesen HG, Hwang P, Guyda HI, Folkers K (1971): Prolactin and thyrotropin release in man by synthetic pyroglutamy-histidyl-prolinamide.Biophys Biochem Res Commun 45:10331041. Bowers MB Jr (1974): Centa'aldopamine turnover in schizophrenic syndromes. Arch Gen Psychiatry 31:50-54. Burrow GN, May PB, Spaulding SW, Donabedian RK (1977): TRH and dopamine interactions affecting pituitary hormone secretion. J Clin Endocrinol Metab 45:65-72. Carlsson A, Lindqvist M (1963): Effect of chlorpromazine or haloperidol on formation of 3methoxy-tyramine and normetanephrine in mouse brain.Acta Pharmacol Toxicol 20:!40-144. Connell PH (1958): Amphetamine Psychosis. Maudsley Monographs No 5. London: Chapman & Hall, for the Instituteof Psychiatry.
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Csemansky JG, Prosser E, Kaplan J, Mahler E, Berger PA, Hollister LE (1986): Possible associations among plasma prolactin levels, tardive dysklnesia and paranoia in treated male schizophrenics. Biol Psychiatry 21:632-642. DeLean A, Ferland L, Drouin J, Kelly PA, Labrie F (1977): Modulation of pituitary thyrotropin releasing hormone receptor levels by estrogens and thyroid hormones. Endocrinology 100:14961504.
Griffith JD, Cavanaugh J, Held J, Oates AJ (1972): Dcxtroamphetamine. Evaluation of psychomimetic properties in man. Arch Gen Psychiatry 26:97-100. l'Hermite M, Vanhaelst L, Copinschi G, Leclerc R, Goldstein J, Bruno OD, Robyn C (1972): Prolactin release after injection of thyrotropin-releasing hormone in man. Lancet 1:763-765. Hill-Samli M, MacI.~od RM (1974): Interaction of thyrotropin-releasing hormone and dopamine on the release of prolactin from the rat anterior pituitary in vitro. Endocrinology 95:1189-1192. Jackson I, Reichlin S (1977): Brain thyrotropin-releasing hormone is independent of the hypothalamus. Nature 267:853-854. Jacobs LS, Snyder PJ, Ii:.~c,: ? ~ , Daughaday WH (1973): Protactin response to thyrotropinreleasing hormone in nonn ~l subjects. J Clin Endocrinol Metab 36:1069-1073. Johnstone EC, Crow TJ, Mashiter K (1977): Anterior pituitary hormone secretion in chronic schizophrenia - - An approach to neurohumoral mechanisms. Psychol Med 7:223-228. Karoum F, Karson CN, Bigelow LB, Lawson WB, Wyatt RJ (!987): Preliminary evidence of reduced combined output of dopamine and its metabolites in chronic schizophrenia. Arch Gen Psychiatry 44:604-607. Kcks NA, Copolov DL, Singh BS (1987): Abnormal prolactin response to haloperidol challenge in men with schizophrenia. Am J Psychiatry 144:1335-1337. Klcinman JE, Weinberger DR, Rogol AD, et al (1982): Plasma prolactin concentrations and psychopathology in chronic schizophrenia. Arch Gen Psychiatry 39:655-657. Mackay AVP (1980): Positive and negative schizophrenic symptoms and the role of dopaminc. Br J Psychiatry 137:379-383. Meltzer HY, Busch D (1983): Serum prolactin response to chlorpromazine and psychopathology in schizophrenics: Implications for the dopamine hypothesis. Psychiatry Res 9:285-299. Meltzer HY, Sachar F_J, Frantz AG (1974): Serum prolactin levels in unmedicated schizophrenic patients. Arch Gen Psychiatry 31:564-569. Meltzer HY, Kolakowska T, Fang VS, et al (1984): Growth hormone and prolactin response to apomorphine in schizophrenia and the major affectivc disorders. Relation to duration of illness and depressive symptoms. Arch Gen Psychiatry 41:512-519. Noel GL, Suh HK, Frantz AG (1973): L-Dopa suppression of TRH stimulated prolactin release in man. j Clin Endocrinoi Metab 36:1255-i258. Ranch-up A, Munkvad I (1972): Evidence indicating an association between schizophrenia and dopaminergic hyperactivity in the brain. Orthomol Psychiatry 1:2-7. Snyder SH (1972): Catecholamines in the brain as mediators of amphetamine psychosis. Arch Gen Psychiatry 27:169-179. Spoov J (1985): Submaximal plasma prolactin response to TRH and dopamine activity in man. Pharmacopsychiatry 18:330-332. Spoov J (1987): Plasma prolactin response to submaximal stimulation by TRH and endogenous corticosteroids in man. Pharmacopsychiatry 20:96-98. Spoov J (1988): The TSH response to TRH and endogenous dopamine activity. Psychiatry Res 24:117-118. Spoov J, Karonen S-L (1987): Urinary HVA reflects central dopamine activity in man. New Trends Exp Clin Psychiatry 3:93-99.
BIOL PSYCHIATRY 1991;29:204-210
Prolactin Response to Submaximal Stimulation by TRH in Nonaffective Psychoses Joban Spaov, Per-Erik Bredbacka, Bj6m Appelberg, Heikki Katila, Sirkka-Liisa Karonen, Ranan Rim6n, and Seppo San,a
Nonaffective psychotic symptoms are heterogeneous and probably caused by mixed biopathology. A preliminary investigative tool to snaty pituitary dopamine activity, the prolactin response to submaximal stimulation by tilyrotropin-releasing hormone (TRlt) (mini-TRH tesO was correlated in 20 subjects with nonaffective psychoses to positive psychotic symptoms as assessed by the Comprehensive Psychiatric Rating Scale psychosis subscale. A significam positive correlation was observed between the response and ratings of nonparanoid symptoms, especially nonparanoid delusions and disrupted thoughts. Because, in addition to pituitary dopamine activity, there is evidence to suggest that the response reflects extrapituitary dopamine activity as well, the results extend the evidence that nonparanoid acute productive psychotic symptoms may be associated with hypoactivity rather than with hyperactivity of brain dopcminergic systems.
Introduction The dopamine hypothesis of schizophrenia (Ran&up and Munkvad 1972) evolved from observations of the ressemblence of amphetamine psychosis to paranoid schizophrenia (Connell 1958), as well as from observations hat neuroleptic drags block dopamine receptors (Carlsson and Lindqvist 1963). Amphe~mine action is mediated presynaptically and increases levels of catecholamines at receptor sites (Snyder 1972). In nonschizophrenic subjects, the administration of small repetitive do:~es of amphetamine has been reported I " +" to induce a paranoid state with no sehizoplh-enic thought disorder or hallucinations (f~_--~gg6L u..,u, et al 1972). The administration of large doses frequently provokes visual and auditory hallucinations as well (Angrist et al 1969). The intramuscular (IM) administration of haloperidol, the relatively specific dopamine receptor blocking drug, has been reported to immediately ameliorate symptoms of amphetamine psychosis, especially suspiciousness (Angrist et al 1974). Using neuroendocrinologic methods, the generality of the dopamine hypothesis of schizophrenia has been extensively studied. In drug-free schizophrenic subjects, serum prolactin response to 25 mg IM chl,3rpromazine has been reported to negatively correlate
From the Departments of Psychiatry US, P-EB, BA, I-IK, F,R), Clinical Chemistry (JS, S-LK), and Public Heal.',h (SS), University of Helsinki, Helsinki, Fmlm~d. Address reprint requests to Johan Spoor, MD, Department of Psychiatry, University of Helsinki, Lapinlahdentie, SF-O0180 Helsinki, Finland. Received October 3, 1989; revised April 16, 1990. © 1991 Society of Biological Psychiatry
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with ratings of severity of delusions (Meltzer and Busch 1983). In chronically schizophrenic subjects, prolactin response to neurolepfic activity has ~een reported to negatively correlate with paranoid symptoms (Csernansky et al 1986). However, in drugfree schizophrenic subjects, prolactin response to 0.5-mg intravenous (IV) haloperidol has been reported to positively correlate with total Brief Psychiatric Rating Scale (BPRS) score (Keks et al 1987). The seemingly contradictory findings may be explained by a different relation to hypothalamic-pimitary dopamine activity of p ~ o i d versus nonparanoid psychotic sy~ptoms. In humans, a mutatai antagonism has been observed between thyrotropin-releasing hormone (TRH) and dopamine with regard io prolactin secretion (Burrow et ai 1977). In smaller doses than those needed to directly stimulate prolactin release, TRH can L o s t completely block the ~ibitory effect of dcpamine on pituitary prolactin release in vitro (Hill-Samli and Mac Leod 1974). We have reported that prolactin response to 12.5 ~g IV TRH is submaximal and that 24-hr urinary excretion of homovanillic acid (HVA) as well as prolactin response to 0.5 mg IM haloperidol significantly correlates with it, but not with basal prolactin level or with maximal prolactm response to "IRH (Slx.,ov 1985; Spoov and Karonen 1987). Our studies thus suggest that submaximal prolactin response to stimulation by TRH may reflect endogenous dopamine activity. As opposed to the effects of neuroleptic dopamine antagonists, there is no evidence to suggest that TRH induces prolactin secretion by hypothalamic mechanisms. Therefore, in the present study, in an attempt to study the relation of pituitary dopamine activity and psychosis, plasma prolactin responses to stimulation by 12.5 lag IV TRH were correlated with scores of the Comprehensive Psychosis Rating Scale (CPRS) psychosis subscale (Bartfai et al 1984).
Materials and Methods The subjects were 20 patients (9 female, 1 male, 32 +__3.1 years [mean +__SD]) treated for a nonaffective psychotic episode at the University Psychiatric Hospital in HelsJnki. Using different sources, a reliable drug ~istory of all the subjects was obtained. Nine of the subjects had never been given neuroleptic medication and three subjects had not taken neuroleptic drugs for at least 4 months before the study. One additional subject had not taken neuroleptic drugs for 38 days. These 13 subjects were classified as the drug-free group. Si~ of the subjects were receiving neuro!eptic drugs upon admission and one additional subject had discontinued her neuroleptic drug treatment a few days before admission. These seven subjects were classified as the drug-withdrawal group. The diagnoses were made by clinical ~nterview according to DSM-III-R (American Psychiatric Association 1987). In eight subjects, a diagnosis of schizophrenia was made. In four subjects, a delusional disorder and in tl-~ee an atypical psychosis was diagnosed. In three subjects, a personality disorder with psychotic breakdown was diagnosed and in one subject each, a diagnosis of schizophreniform psychosis and of brief reactive psychosis was made. Six of the subjects had been suffering from psychotic episodes for more than 3 years, seven of the subjects for 1-3 years, and seven for less than 1 year. After admission, a washout period of at least 4 days was executed in all the subjects before assessment of the CPRS psychosis subscale (Bartfai et al 1984) and before the prolactin test. The subscale is a measure of positive psychotic symptoms. The item "disrupted thoughts" represents the experience of thought blocking, insertion, or withdrawal or listened to or broadcast thoughts. The subscale contains the item "ideas of
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persecution" and the item "other delusions." The latter represents any delusion other than pessimistic thought, hypochondriasis, feeling controlled, ideas of persecution, ideas of grandeur, delusional mood, or morbid jealousy. There are four items in the psychosis subscale representing various auditory, visual, and other hallucinations. The total of the hallucination items scores is used in the present study as the score of various hallucinations. The prolactin test was, in 16 of the subjects, done within 1 day of the assessment ot ~the psychosis subscale. In none of the subjects was a change observed in the clinical condition between rating of psychosis and prolactin test. None of the subjects had received longacting parenteral neuroleptic agents within 6 months. The number of drug free days was 8.6 +_. 1.6 (mean - SEM) among subjects in the withdrawal group. The subjects were permitted small doses of be~zodiazepines on an as-needed basis for sedation, but no patient received psychotropic medication during the 12 hr preceding the prolactin test. On the morning of the prolactin test, Emla cream (containing lidocain and prilocain) was applied on an antebrachial vein for local anesthesia, although it is by no means certain that pain associated with venipuncture is responsible for the "spuriously" high basal prolactin levels in some schizophrenic subjects (Kleinman et al 1982). After 1.52 hr, at 10:00-11:30 AM, blood was drawn for the basal prolactin level and an IV bolus of 12.5 Ixg TRH was administered. Utilizing a small insulin needle by one of the authors (P-EB), a standard preparation of TRH, 100 ixg/ml, could be injected in reproducible doses. Fifteen minutes thereafter, a second blood specimen was obtained for the stimulated prolactin level. In normal male subjects, peak prolactin levels have been reported to occur 15 min (Bowers et al 1971; Jacobs et al 1973; Noel et al 1973) or 10 rain (l'Hermite et al 1972) after the IV administration of TRH. Because the present study is the first to utilize submaximal prolactin response to stimulation by TRH in psychiatric patients, there is no information as yet regarding the possibility that in some psychiatric patients, the peak prolactin level might occur erratically or even systematically at some other time. During the procedure the patients were in the supine position and no interruptions were allowed. Plasma samples were frozen at -20°C until assayed in duplicate for prolactin by a radioimmunoassay method (Pharmacia, Sweden, 1983). The intraassay and interassay coefficients of variation ([SD/meanl × 100) were 5.0 and 12.0, respectively. The associations between prolactin response and psychosis subscale and its items were studied by partial correlation and multivariate regression methods. Age, sex, and drug use were considered as covariates, whose linear effect was removed from the correlation results. Because the distribution of prolactin response and basal prolactin were skewed, a logarithmic transformation was performed before the multiple regression. The distribution of psychosis subscale score was symmetric and fairly normal. For comparison of group means, an independent-sample, two-tailed t-test was used. Results The individual results are given in Figure 1. As a response measure we used post-TRH minus baseline prolactin level. There seemed to be no association between prolactin response and diagnosis, although the number of patients in each diagnostic group is too small for definite conclusions. No association was found between prolactin response and duration of psychotic illness. Prolactin response to stimulation by 12.5 Ixg IV TRH was significantly higher in female (22.0 ___ 3.4 txg/L [mean 4-_ SEM]) than in male (10.7 ___
Prolactin Response to TRH in Psychoses
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'.3.2 --v
RE,SIDLAL OF PSYCHOSIS $1_BS(ALE
Figure 1. The residuals of CPRS psychosis subscale score and log of prolactin response after adjusting for sex, age, and drug use in 20 psychotic su~ects (r = 0.7!, df = 15, p < 0.01).
2.0 p,g/L [mean _+ SEM]) subjects (t = 2.9, df = 18, p < 0.01). The age of female patients did not differ significantly from the age of male patients (t = !.. 1, df = 18, p > 0.05). Removing the linear effects of :+ge, sex, and drug use revealed a significant partial con'elation between CPRS psychosis subsca!e score and plasma pro!actin response to stimulation by 12.5 lxg IV TRH (rp - +0.71, df = 15, p < 0.01). The partial correlation remained the same even when patients in the drug-withdrawal group were excluded (rp = +0.69) er when the patients were examined by gender group (rp = + 0 . 8 4 and rp = + 0 . 6 6 for female and male patients, respectively). Of the individual items in the CPRS psychosis subscale, only ratings of other delusions significantly correlated with prolactin response (rp = 0.73, df = 15, p < 0.001). Ratings of disrdpted thoughts marginally correlated with prolactin response (rp = 0.5 i, df = 15, 0.01 < p < 0.05). On the other hand, no significant correlations were found between ratings of various hallucinations or ideas of persecution and prolactin response (rp = 0.36 and rp = 0.05, respectively). In all the psychotic subjects, basal plasma prolactin level was within the normal range. It was 3.6 _+ 0.5 ixg/L (mean +_ SEM) in female subjects and 2.9 +_ 0.3 Ixg/L in male subjects, a difference that was not statistically significant (t = 1.3, df = 18, p > 0.05).
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Removing the linear effects of age, sex, and drug use did not reveal a significant partial correlation between ratings of psychosis subscale and basal prolacfin level ( r v = - 0.20, df = 15, p > 0.05). Removing the linear effects of age, sex, and drug use did not reveal a significant partial correlation between basal prolactin level and prolactin response to stimulation by 12.5 pLg IV TRH (rp = +0.17, df = 15, p > 0.05).
Discussion One of the major findings in the present study was the positive correlation between ratings of the CPRS psychosis subscale and prol~cti,! response to TRH. Because a similar finding has been reported between positive symptoms and prolactin response to stimulation by parenteral haloperidol (Keks et al 1987), and because the latter probably is not affected by sensitivity of TRH receptors and correlates positively with prolactin response to stimulation by 12.5 I~g IV TRH (Spoov 1985), it is probable that endogenous dopamine rather than sensitivity to TRH receptors was responsible for the correlation. Moreover, in humans, submaximal prolactin response to stimulation by TRH has been reported not to correlate with maximal prolactin response to TRH (Spoov 1988), wtdch has been found to closely correlate with the number of TRH receptors in vitro (DeLean et al 1977). Because extrahypothalamic brain TRH has been rel~orted to be independent of the hypothalamic secretion (Jackson and Reichlin 1977) it is difficult to see why sensitivity of pituitary TRH receptors would correlate with psychotic symptoms, which are produced in extrapituitary brain areas. Tuberoinfundibular dopamine (TIDA) may, however, both decrease sensitivity of prolactin responses to TRH and be associated with psychotic symptoms (see Spoov and Karonen 1987). Of ti~" items in the CPRS psychosis subscale only ratings of other delusions and dismpte0 thoughts contributed to the positive correlation between ratings of the subscale and prolactin response to stimulation by 12.5 ttg IV TRH. On the other hand, with regard to prolaetin response, ratings of persecutory delusions and various hallucinations seemed to behave independently. The absent correlation did not support our hypothesis of an increased pituitary dopamine activity among psychotic subjects in association with paranoid delusions. Interestingly, the relation of delusions to dopamine activity seemed to depend on the t~pe of delusions. in schizophrenic subjects, the basal proiactin level has been reported to negatively correlate with positive symptoms in some (Johnstone et al 1977; Kleinman et al 1982) but not in other (Meltzer et al 1974, 1984) studies. In one of these studies, an intraindividual but not interindividual negative correlation was reported between basal prolactin level and positive symptoms (Johnstone et al 1977), suggesting the possibility that fluctuations in neurotransmitters involved in prolactin release may be reflected in both positive symptoms and basal prol~ctin levels. Because it has been reported that pro!actin responses to maximal stimulation by TRH but not to submaximal stimulation by TRH reflect fluctuations in the basal prolactin level (Spoov 1987) it can be argued that such fluctuations may not be mediated by dopamine. In the present study, no significant correlation was observed between basal prolactin level and CPRS psychosis subscale. In the present population of psychotic male subjects, basal prolactin level tended to be lower and prolactin response to stimulation by 12.5 ttg IV TRH ter~ded to be higher as compared to our previous results in 28 nonpsychiatric subjects (Spoo~, 1985). Because our previous method for measuring plasma prolactin was different from the present one,
Prolactin Response to TRH in Psychoses
BIOl. PSYCHIATRY 1991;29:204-210
accurate comparisons were not pessible. Nondopmnine hypothalamic PIFs may be stimulated by dopamine and the possibility ex'ht~ that their sensitivity to d o p ~ e antagonism may be blunted in acute schizophrenia (Keks et al 1987). Such a mechanism is not tikely to contribute to the prolactin response to stimulation by 12.5 ~g IV TRH, which is modest as compared to the increase of prolactin provoked by parenteral 0.5 mg halopefidol (Spoor 1985). R is concluded that sensitivity of the hypothalamic-pituitary TRI-I system is related to psychotic symptoms. We believe that this association is mediated ~ o u g h dopamine. Because TIDA turnover represents a very small fraction of total brain dopamine turnover, our previous finding of a significantly negative correlation between prolactin response to submaximal stimulation by TRH and 24-hr urinary excretio, of HVA ,;uggests that the response reflects dopamine turnover at extrapituitary sites in humans (Spoor and Karonen 1987) :rod that TIDA activity may be related to activity in other dopamine systems. In unmasking postsynaptic dopamine effects, the prolactin response to TRH or to o~er dopamine antagonists probably also reflects dopamine receptor sensitivity on lactotrops. Our results do not support the theory of increased dopamine activity in acute productive schizophrenic illness (Mackay 1980). An association between central dopamine hypoactivity and nonparanoid psychotic symptoms has been suggested by studies utilizing cerebrospinal fluid and urine HVA (Bowers 1974; Karoum et al 1987). Utilizing a totally different methodology, the present results extend such findings. For more definite conclusions, dose-response studies describing the time-response curve after submaximal prolactin stimulation by TRH and reproducibility in larger numbers of drug-naive psychotic subjects are needed. The advice of Prof. H.Y. Mcitzerin preparing this manuscriT:"~~ f : l l y acknowledged.
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