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Serum prolactin levels in manic patients
BIOL PSYCHIATRY 1991;30:421-423
421
Serum Prolactin Levels in Manic Patients Alice Kuruvilla, Geetha Srikrishna, Jacob Peedicayil, K. Kuruvilla, and A. S. Kanagasabapathy
Introduction
Methods
According to the monoamine hypothesis of affective disorders, mania is due to an excess of monoaminergic neurotransmission in the brain (Schildkraut 1969; Ashcroft et al 1972). Although noradrenaline and serotonin have been the monoamines most implicated in the pathophysiology of mania, there is evidence indicating that mania is due to dopaminergic overactMty (Gerner et al 1976; Post et al 1980; Cookson et al 1981; Silverstone 1984; Silverstone and Romans-Clarkson 1989). If there is overactivity of cerebral dopaminergic neurotransmission in mania involving the tuberoinfundibular dopaminergic tract, one could expect serum prolactin levels in manic patients to be less than normal because of the inhibitory effect of dopamine on the release of prolactin from the pituitary. When compared to schizophrenia, very few studies have been conducted on serum prolactin levels in manic patients. The few studies that have been conducted used small numbers of patients and obtained conflicting results (Maeda et al 1979; Cookson et a~ i982; Cookson et al 1983; Hitzemann et ~d 1984; Whalley et al 1985). This study was conducted to detenrfine serum prolactin levels in a cohort of 121 manic patients to see if the levels are influenced by factors such as age, sex, type of clinical presentation, and duration of illness.
The criteria used for the diagnosis of mania were those of Feighner et al (1972). Outpatients or new admissions who had not received any psychotropic drugs for the preceding eight weeks were selected. Pregnant or nursing patients were excluded. One hundred twenty-one patients (68 men and 53 women) were selected. The mean age --- SD of the men was 31 _ 13 years and that of the women was 3 ! +__ 11 years. Ninetyone patients presented with i~itability and 30 with elation. To serve as controls, 120 hospital staff, student volunteers, and relatives of nonpsychotic patients (78 men and 42 women) were selected. They were matched for age and sex with the patients. The mean age __+ SD of the male controls was 33 - 11 years and that of the female controls was 31 __+ 11 years. None of the controls had a history of mental illness and none were on any psychotropic drugs. Pregnant or nursing females were excluded from the control group. Blood samples for prolactin estimation from all patients and controls were drawn between 9 AM and 12 PM. Serum was prepared and stored at - 20°C until the time of analysis. Serum prolactin levels were estimated by radioimmunoassay using a kit from Diagnostic Products Corporation, Los Angeles, California. After the initial testing of serum prolactin levels, all patients were started on neuroleptic medication. The neuroleptics used were phenothiazines (chlorpromazine, trifluoperazine, fluphenazine decanoate) and haloperidol. Serum prolactin levels were again estimated three weeks
From the Departments of Pharmacology (AK. JP), Psychiatry (KK), and Clinical BiochemistD, (GS, ASK), Christian Medical College, Vellore, South India. Received July 12, 1990; revised January 22, 1991.
© 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
422
BIOLPSYCHIATRY
Brief Reports
1991 ;30:421-423
Table 1. Serum Prolactin Levels in Unmedicated Manic Patients and Controls Group
n
Control (male) Mania (male) Control (female) Mania (female)
78 68 42 53
after three weeks of neuroleptic medication. Women had higher and more variable prolactin levels even though they received neuroleptics at a lower dosage (Table 2).
Mean serum prolactin level - SEM (ng/ml) 9.81 9.29 11.82 9.93
--- 0.73 - 1,12 - 1.28 -+ 0.82
Discussion In this study, the mean serum prolactin level of the female controls was found to be higher than that of the male controls although the difference was not significant (Table 1). It is a known fact that females have slightly higher serum prolactin levels than males although there is considerable overlap (Frantz 1978). The mean serum prolactin levels of unmedicated manic patients were also not significantly different from those of ageand sex-matched controls, even though they were slightly lower (Table 1). This suggests that if mania is associated with cerebral dopami~ergic overactivity this does not include the tuberoinfundibular dopaminergic tract and probably involves other dopaminergic pathways. It is possible that overactivity of mesolimbic dopaminergic pathways may contribute to the pathogenesis of mania (Cookson et al 1983). After the commencement of neuroleptic medication, the greater rise in serum prolactin levels in women as compared to men (Table 2) was probably a result of hormonal influences. It is known that estrogens enhance responsiveness of the pituitary to prolactin-releasing stimuli (Frantz 1978). In conclusion, the results of this study indicate that serum prolactin is not a specific index of the underlying disease process in mania. However, it may be usethl as an indicator of neuroleptic medication.
T~- differenceswerenot statisticallysignificant.
after the commencement of neuroleptic medication, in those patients who returned for follow-up. Neuroleptic dosage in patients was expressed as chlorpromazine equivalents (Loudon 1983). The intraassay and interassay coefficients of variation of the radioimmunoassay at normal serum prolactin levels were 4.1% and 7.1% and at high levels were 3.6% to 3.8% and 6.8% to 7.3%, respectively. The Z test and Student's t-test were used to compare serum prolactin levels cf unmedicated patients and controls according to age and sex. The Z test was used to compare serum prolactin levels in unmedicated patients according to type of clinical presentation. The Kruskal Wallis test was used likewise for duration of illness.
Results Table 1 compares serum prolactin levels of unmedicated manic patients and controls. There were no significant differences between the serum prolactin levels of any of the four groups. Serum prolactin levels were also not influenced significantly by ages of patients, type of clinical presentation (elation or irritability), and duration of illness. 3emm prolactin levels were significantly raised
This study was supported by the Indian council of Medical Research. The authors thank Drs. G. Ganga Raju, Ajanta Phookan, and T. Manoj Kumar for data collection.
Table 2. Serum Prolactin Levels in Either Sex after 3 Weeks of Neuroleptic Medication Group
n
Mean daily neuroleptic dosage (mg)a
Mean serum prolactin level +__SEM (ng/ml)
Male Female
23 17
1176 560
37.51 -+ ao28 141.90 + 35.07
ODosagein chlorpromazineequivalentsduringprecedingweek
Brief Reports
References Ashcroft GW, Eccleston D, Murray LG, et at (1972): Modified amine hypothesis for the aetiology of affective illness. Lancet 2:573-577. Cookson J, Silverstone T, Wells B (1981): Double-blind comparative clinical trial of pimozide and chtorpromazine in mania: a test of the dopamine hypothesis. Acta Psychiatr Scand 64:381-397. Cookson JC, Silverstone T, Rees L (1982): Plasma prolactin and growth hormone levels in manic patients treated with pimozide. Br J Psychiatry 140:274-279. Cookson JC, Moult PJA, Wiles D, Besser GM (1983): The relationship between prolactin levels and clinical ratings in manic patients treated with oral and intravenou~ test doses of haloperidol. Psychol Med 13:279-285. Feighner JP, Robins E, Guze SB, Woodruff RA, Winokur G, Munoz R (1972): Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 26:57-63. Frantz AG (197~D: Prolactin. N Engl J Med 298:201-207. Gerner RH, Post RM, Bunney WE (1976): A dopaminergic mechanism in mania. Am J Psychiatry 133:1177-1180. Hitzemann, R, l~a-~chowitzJ, Hitzemarm B, Garver D O984):
BIOL PSYCHIATRY t 991 ;30:421-423
423
The prolactin response in schizophrenic, schizophreniform, and manic disorders. BiolPsychiat,'3, 19:913-918. Loudon JB (1983): Drug treatments. In Kendell RE, Zealley AK (eds), Compc.nion to Psychiatric Sttdies. New York: Churchill Livingstone, p 607. Maeda K, Tanimoto K, Yamaguchi N, lwasaki Y, Chihara K, Fujita T (1979): Increased prolactin response to TRH in mania. N Engl J Med 301:1400. Post RM, Jimerson DC, Bunney WE Jr, Goodwin FK (1980): Dopamine and mania: behaviourat and biochemical effects of the dopamine receptor blocker pimozide. Psychopharmacology 67:297-305. Schildkraut JJ (1969): Neuropsychopharmacology and the affective disorders. N Engl J Med 281:302-308. Silverstone T (1984): Response to bromocriptine distinguishes bipolar from unipolar depression. Lancet 1:903904. Silverstone T, Romans-Clarkson S (1989): Bipolar affective disorder: causes and prevention of relapse. Br J Psychiatry I54:321-335. Whalley LJ, Christie JE, Bennie J, et al (t985): Selective increase in plasma luteinising hormone concentrations in drug free young men with mania. Br M e d J 290:99102.
421
Serum Prolactin Levels in Manic Patients Alice Kuruvilla, Geetha Srikrishna, Jacob Peedicayil, K. Kuruvilla, and A. S. Kanagasabapathy
Introduction
Methods
According to the monoamine hypothesis of affective disorders, mania is due to an excess of monoaminergic neurotransmission in the brain (Schildkraut 1969; Ashcroft et al 1972). Although noradrenaline and serotonin have been the monoamines most implicated in the pathophysiology of mania, there is evidence indicating that mania is due to dopaminergic overactMty (Gerner et al 1976; Post et al 1980; Cookson et al 1981; Silverstone 1984; Silverstone and Romans-Clarkson 1989). If there is overactivity of cerebral dopaminergic neurotransmission in mania involving the tuberoinfundibular dopaminergic tract, one could expect serum prolactin levels in manic patients to be less than normal because of the inhibitory effect of dopamine on the release of prolactin from the pituitary. When compared to schizophrenia, very few studies have been conducted on serum prolactin levels in manic patients. The few studies that have been conducted used small numbers of patients and obtained conflicting results (Maeda et al 1979; Cookson et a~ i982; Cookson et al 1983; Hitzemann et ~d 1984; Whalley et al 1985). This study was conducted to detenrfine serum prolactin levels in a cohort of 121 manic patients to see if the levels are influenced by factors such as age, sex, type of clinical presentation, and duration of illness.
The criteria used for the diagnosis of mania were those of Feighner et al (1972). Outpatients or new admissions who had not received any psychotropic drugs for the preceding eight weeks were selected. Pregnant or nursing patients were excluded. One hundred twenty-one patients (68 men and 53 women) were selected. The mean age --- SD of the men was 31 _ 13 years and that of the women was 3 ! +__ 11 years. Ninetyone patients presented with i~itability and 30 with elation. To serve as controls, 120 hospital staff, student volunteers, and relatives of nonpsychotic patients (78 men and 42 women) were selected. They were matched for age and sex with the patients. The mean age __+ SD of the male controls was 33 - 11 years and that of the female controls was 31 __+ 11 years. None of the controls had a history of mental illness and none were on any psychotropic drugs. Pregnant or nursing females were excluded from the control group. Blood samples for prolactin estimation from all patients and controls were drawn between 9 AM and 12 PM. Serum was prepared and stored at - 20°C until the time of analysis. Serum prolactin levels were estimated by radioimmunoassay using a kit from Diagnostic Products Corporation, Los Angeles, California. After the initial testing of serum prolactin levels, all patients were started on neuroleptic medication. The neuroleptics used were phenothiazines (chlorpromazine, trifluoperazine, fluphenazine decanoate) and haloperidol. Serum prolactin levels were again estimated three weeks
From the Departments of Pharmacology (AK. JP), Psychiatry (KK), and Clinical BiochemistD, (GS, ASK), Christian Medical College, Vellore, South India. Received July 12, 1990; revised January 22, 1991.
© 1991 Society of Biological Psychiatry
0006-3223/91/$03.50
422
BIOLPSYCHIATRY
Brief Reports
1991 ;30:421-423
Table 1. Serum Prolactin Levels in Unmedicated Manic Patients and Controls Group
n
Control (male) Mania (male) Control (female) Mania (female)
78 68 42 53
after three weeks of neuroleptic medication. Women had higher and more variable prolactin levels even though they received neuroleptics at a lower dosage (Table 2).
Mean serum prolactin level - SEM (ng/ml) 9.81 9.29 11.82 9.93
--- 0.73 - 1,12 - 1.28 -+ 0.82
Discussion In this study, the mean serum prolactin level of the female controls was found to be higher than that of the male controls although the difference was not significant (Table 1). It is a known fact that females have slightly higher serum prolactin levels than males although there is considerable overlap (Frantz 1978). The mean serum prolactin levels of unmedicated manic patients were also not significantly different from those of ageand sex-matched controls, even though they were slightly lower (Table 1). This suggests that if mania is associated with cerebral dopami~ergic overactivity this does not include the tuberoinfundibular dopaminergic tract and probably involves other dopaminergic pathways. It is possible that overactivity of mesolimbic dopaminergic pathways may contribute to the pathogenesis of mania (Cookson et al 1983). After the commencement of neuroleptic medication, the greater rise in serum prolactin levels in women as compared to men (Table 2) was probably a result of hormonal influences. It is known that estrogens enhance responsiveness of the pituitary to prolactin-releasing stimuli (Frantz 1978). In conclusion, the results of this study indicate that serum prolactin is not a specific index of the underlying disease process in mania. However, it may be usethl as an indicator of neuroleptic medication.
T~- differenceswerenot statisticallysignificant.
after the commencement of neuroleptic medication, in those patients who returned for follow-up. Neuroleptic dosage in patients was expressed as chlorpromazine equivalents (Loudon 1983). The intraassay and interassay coefficients of variation of the radioimmunoassay at normal serum prolactin levels were 4.1% and 7.1% and at high levels were 3.6% to 3.8% and 6.8% to 7.3%, respectively. The Z test and Student's t-test were used to compare serum prolactin levels cf unmedicated patients and controls according to age and sex. The Z test was used to compare serum prolactin levels in unmedicated patients according to type of clinical presentation. The Kruskal Wallis test was used likewise for duration of illness.
Results Table 1 compares serum prolactin levels of unmedicated manic patients and controls. There were no significant differences between the serum prolactin levels of any of the four groups. Serum prolactin levels were also not influenced significantly by ages of patients, type of clinical presentation (elation or irritability), and duration of illness. 3emm prolactin levels were significantly raised
This study was supported by the Indian council of Medical Research. The authors thank Drs. G. Ganga Raju, Ajanta Phookan, and T. Manoj Kumar for data collection.
Table 2. Serum Prolactin Levels in Either Sex after 3 Weeks of Neuroleptic Medication Group
n
Mean daily neuroleptic dosage (mg)a
Mean serum prolactin level +__SEM (ng/ml)
Male Female
23 17
1176 560
37.51 -+ ao28 141.90 + 35.07
ODosagein chlorpromazineequivalentsduringprecedingweek
Brief Reports
References Ashcroft GW, Eccleston D, Murray LG, et at (1972): Modified amine hypothesis for the aetiology of affective illness. Lancet 2:573-577. Cookson J, Silverstone T, Wells B (1981): Double-blind comparative clinical trial of pimozide and chtorpromazine in mania: a test of the dopamine hypothesis. Acta Psychiatr Scand 64:381-397. Cookson JC, Silverstone T, Rees L (1982): Plasma prolactin and growth hormone levels in manic patients treated with pimozide. Br J Psychiatry 140:274-279. Cookson JC, Moult PJA, Wiles D, Besser GM (1983): The relationship between prolactin levels and clinical ratings in manic patients treated with oral and intravenou~ test doses of haloperidol. Psychol Med 13:279-285. Feighner JP, Robins E, Guze SB, Woodruff RA, Winokur G, Munoz R (1972): Diagnostic criteria for use in psychiatric research. Arch Gen Psychiatry 26:57-63. Frantz AG (197~D: Prolactin. N Engl J Med 298:201-207. Gerner RH, Post RM, Bunney WE (1976): A dopaminergic mechanism in mania. Am J Psychiatry 133:1177-1180. Hitzemann, R, l~a-~chowitzJ, Hitzemarm B, Garver D O984):
BIOL PSYCHIATRY t 991 ;30:421-423
423
The prolactin response in schizophrenic, schizophreniform, and manic disorders. BiolPsychiat,'3, 19:913-918. Loudon JB (1983): Drug treatments. In Kendell RE, Zealley AK (eds), Compc.nion to Psychiatric Sttdies. New York: Churchill Livingstone, p 607. Maeda K, Tanimoto K, Yamaguchi N, lwasaki Y, Chihara K, Fujita T (1979): Increased prolactin response to TRH in mania. N Engl J Med 301:1400. Post RM, Jimerson DC, Bunney WE Jr, Goodwin FK (1980): Dopamine and mania: behaviourat and biochemical effects of the dopamine receptor blocker pimozide. Psychopharmacology 67:297-305. Schildkraut JJ (1969): Neuropsychopharmacology and the affective disorders. N Engl J Med 281:302-308. Silverstone T (1984): Response to bromocriptine distinguishes bipolar from unipolar depression. Lancet 1:903904. Silverstone T, Romans-Clarkson S (1989): Bipolar affective disorder: causes and prevention of relapse. Br J Psychiatry I54:321-335. Whalley LJ, Christie JE, Bennie J, et al (t985): Selective increase in plasma luteinising hormone concentrations in drug free young men with mania. Br M e d J 290:99102.