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The hypothalamic–pituitary–adrenal axis in chronic schizophrenic patients long-term treated with neuroleptics
Progress in Neuro-Psychopharmacology & Biological Psychiatry 26 (2002) 935 – 938
Article
The hypothalamic–pituitary–adrenal axis in chronic schizophrenic patients long-term treated with neuroleptics Yasuhiro Kanedaa,b,*, Akira Fujiib, Tetsuro Ohmoria a
Department of Neuropsychiatry, The University of Tokushima School of Medicine, 3-18-15 Kuramoto-Cho, Tokushima 770-8503, Japan b Department of Neuropsychiatry, Fujii Hospital, 1-1 Tsukudame, Minobayashi-Cho, Anan 774-0017, Japan
Abstract Purpose: The authors investigated the hypothalamic – pituitary – adrenal (HPA) axis of regularly medicated schizophrenic patients. Methods: The subjects were 53 patients who were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders — Fourth Edition (DSM-IV) criteria for schizophrenia. Each patient gave informed consent for the research. Psychiatric symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). Based on the dosages of neuroleptics (NLPs), the subjects were classified into two groups: those with lower dosages (LD) and those with higher dosages (HD). Findings: (a) The medicated schizophrenic patients had significantly higher plasma corticotropin (ACTH) levels than the normals. (b) There was no significant difference in plasma cortisol levels between the schizophrenic patients and normals. (c) There was a significant difference in plasma ACTH levels between the HD and normal groups, but not between the LD and normal groups. (d) There was no significant difference in administration periods of NLPs, positive (POS) or negative symptoms (NES) between the HD and LD groups. (e) There was a positive correlation between the plasma ACTH and plasma cortisol levels in patients. Conclusions: Our results showed that, in chronic schizophrenic patients long-term treated with NLPs, ACTH secretion was elevated. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Corticotropin, ACTH; Cortisol; Neuroleptic; Schizophrenia
1. Introduction A hypothalamic – pituitary– adrenal (HPA) axis function is involved in emotion, and the functional impairment of this axis causes psychiatric illness. Some abnormal findings of the HPA axis in schizophrenic patients have been observed (Brambilla et al., 1975; Elman et al., 1998; Saffer et al., 1985). Regarding the effects of acute administration of neuroleptics (NLPs) on HPA activity, previous reports revealed contradictory and conflicting point of views (De Wied, 1967; Debreceni et al., 1971a,b; Roy et al., 1986). Many patients with schizophrenia have been taking NLPs chronically for preventing exacerbation, but the date obtained from these previous reports make it hard for us to presume Abbreviations: BPRS, Brief Psychiatric Rating Scale; ACTH, corticotropin; HD, higher dosages; HPA, hypothalamic – pituitary – adrenal; LD, lower dosages; NES, negative symptoms; NLPs, neuroleptics; POS, positive symptoms; STAI, Spielberger’s State – Trait Anxiety Inventory * Corresponding author. Department of Neuropsychiatry, The University of Tokushima School of Medicine, 3-18-15 Kuramoto-Cho, Tokushima 770-8503, Japan. Tel.: +81-88-633-7130; fax: +81-88-633-7131. E-mail address: [email protected] (Y. Kaneda).
chronic effects of NLPs on HPA activity. Therefore, the present study was conducted to investigate the HPA function in schizophrenic patients with long-term NLP administration.
2. Methods 2.1. Subjects The subjects in this study were 23 normal (10 females and 13 males) and 53 chronically medicated schizophrenic patients (20 females and 33 males) that met the Diagnostic and Statistical Manual of Mental Disorders — Fourth Edition’s (DSM-IV) (American Psychiatric Association, 1994) diagnostic criteria for schizophrenia. The study was approved by the relevant ethics committees and was performed in accordance with the Declaration of Helsinki II. Informed consent was obtained from all subjects for the research in this study. Subjects were excluded if they presented with any organic central nervous system disorder, significant substance abuse, and mental retardation. Table 1 shows the demographic characteristics of the subjects.
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Table 1 Demographic characteristics of subjects Patients with schizophrenia Normals Mean (S.D.)
Low-dose High-dose Total mean group mean group mean (S.D.) (S.D.) (S.D.)
n 23 53 27 Schizophrenia subtype Catatonic – 0 0 Disorganized – 10 3 Paranoid – 11 6 Undifferentiated – 13 8 Residual – 19 10 Age (years) 50.7 (15.8) 51.9 (10.3) 53.8 (11.2) Age at onset (years) – 29.2 (9.2) 30.1 (9.3) Administration – 22.6 (10.2) 23.6 (11.3) period (years) Length of – 19.4 (9.1) 20.4 (9.1) hospitalization (years) Body weight (kg) 57.0 (13.2) 60.9 (11.4) 59.7 (9.2) Dosea (mg/day) – 12.2 (9.6) 5.8 (2.9) POS – 4.8 (2.8) 4.1 (2.5) NES – 6.3 (2.8) 5.6 (2.2) STAI (state anxiety) 42.0 (7.3) 43.5 (9.6) 43.5 (8.2)
26 0 7 5 5 9 49.9 (9.2) 28.3 (9.3) 21.6 (9.0) 18.5 (9.4)
62.2 18.7 5.5 7.0 43.5
(13.4) (9.8)*** (2.9) (3.2) (11.0)
a
Haloperidol equivalent. *** P < .001 versus LD group by the t test.
2.2. Procedure Since the patients had been prescribed NLPs with various chemical structures, each NLP was converted to its haloperidol equivalent using the dosage comparability table (Inagaki et al., 1998a); for depot NLPs, the procedure adopted was based on the equivalence table for long-term therapy (Inagaki et al., 1998b). The mean converted dosage of the patients is shown in Table 1. All of the 53 patients were first considered as one group and then, based on their dosages of NLPs, divided into two groups: those with lower dosages (< 0.16 mg/day/kg: LD, n = 27) and those with higher dosages (> 0.16 mg/day/kg: HD, n = 26).
patients are also shown in Table 1. The levels of anxiety were assessed using the Japanese version (Nakazato and Mizuguchi, 1982) of the Spielberger’s State – Trait Anxiety Inventory (STAI) (Spielberger et al., 1970). The STAI is composed of two separate 20-item scales constructed to measure ‘‘state’’ and ‘‘trait’’ anxiety, using four-point scales. The STAI scores were calculated for 20-item measure for ‘‘state’’ anxiety. 2.4. Hormonal assessments Blood samples for hormone estimation were once drawn from all subjects between 0600 and 0700 h. They were off food, beverages, smoking, and drinking for at least 9 h. As corticotropin (ACTH) is secreted episodically and the level of ACTH in plasma changes every moment, several points sampling and the use of the mean of the data may be preferable for the assessment of ACTH. We, however, took just one sampling, since one assessment is practical in the clinical setting. The plasma was prepared and stored at 20 C until the time of analysis. ACTH and cortisol were assayed by an immunoradiometric assay (Fukuchi et al., 1990) and fluorescence polarization immunoassay (TDx) (Suzuki et al., 1987), respectively. According to the results of the laboratory, we considered a normal range of 5– 50 pg/ml and 5.0– 25.0 mg/dl for ACTH and cortisol, respectively. 2.5. Data analysis Statistical analyses were carried out using parametric tests (e.g., Student’s t test, Scheffe’s test, Pearson’s Product – Moment Correlations), if the data were normally distributed. Otherwise, the nonparametric tests (e.g., Mann – Whitney’s U test, Kruskal – Wallis’s test, Spearman’s rank correlations) were used.
3. Results
2.3. Psychiatric assessments
3.1. Concentrations of each hormone
Psychiatric ratings were done using the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962). The BPRS provided a standardized method of assessing 18 psychiatric symptoms using operationally defined sevenpoint scales. Two symptoms, namely hallucinatory behavior and unusual thought content, were derived from this scale as positive symptoms (POS) based on previous groupings of BPRS symptoms (Crow, 1985; Guy, 1976; Kitamura et al., 1989; Nicholson et al., 1995). The POS scores were formed using the sum of the ratings of the POS. Three symptoms, emotional withdrawal, motor retardation, and blunted affect, were derived from this scale as negative symptoms (NES) (Crow, 1985; Guy, 1976; Nicholson et al., 1995). The NES scores were formed using the sum of the ratings of the NES. The mean POS and NES scores in the
In the normals and in the medicated schizophrenic patients, the plasma ACTH concentrations were 36.7 (S.D. = 18.5, range 14 – 78) and 60.1 pg/ml (S.D. = 36.5, range 14 –211), respectively. The medicated schizophrenic patients showed significantly higher plasma ACTH levels than normals (t test, P = .0015). In the LD and HD groups, the plasma ACTH concentrations were 56.4 (S.D. = 32.9, range 14 – 133) and 63.8 pg/ml (S.D. = 40.2, range 18 – 211), respectively (Fig. 1). Scheffe’s test showed that the mean level of the plasma ACTH in the HD schizophrenics was significantly higher than that in the normal group ( P = .0058) (Fig. 1). There was no significant difference in the mean levels of the plasma ACTH between the LD schizophrenics and normal group, or between the HD schizophrenics and LD schizophrenics.
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cortisol levels in the group of normal subjects (Pearson’s r = .28, P = .2077). 3.5. Anxiety scores There was no significant difference in the mean state anxiety scores between the patient and normal groups (Table 1). Also, there was no significant difference in the mean state anxiety scores between the HD and LD groups (Table 1).
4. Discussion
Fig. 1. Concentrations of each hormone. Results are means with S.D. The mean level of the plasma ACTH in the HD schizophrenics was significantly higher than that in the normals. However, there was no significant difference in the mean levels of the plasma cortisol between the normal and LD or HD group. ** P < .01 versus normals by Scheffe’s test.
In the normals and medicated schizophrenic patients, the plasma cortisol concentrations were 14.89 (S.D. = 5.72, range 6.0 –26.9) and 16.43 mg/dl (S.D. = 4.83, range 6.4 –29.2), respectively. Although there was no significant difference in the mean levels of the plasma cortisol between the groups, patient group tended to have higher levels of it than the other group. In the LD and HD groups, the plasma cortisol concentrations were 15.78 (S.D. = 5.10, range 6.4 –29.2) and 17.11 mg/dl (S.D. = 4.53, range 9.2 –26.4), respectively (Fig. 1). There was no significant difference in the mean levels of the plasma cortisol between the normal and LD or HD group as shown by Scheffe’s test. 3.2. Differences in variables between LD and HD groups Although the HD group had been taking significantly higher dose of NLPs than the LD group, there was no significant difference in administration periods of NLPs, POS, or NES between the groups (Table 1). 3.3. Relationship between NLP treatment and ACTH and psychotic symptoms We did not find a significant correlation between the plasma ACTH and dose of NLPs. Dose of NLPs was significantly correlated with POS in the group of patients (Pearson’s r = .313, P = .0238), but not with NES. We did not find a significant correlation between the administration period of NLPs and plasma ACTH. 3.4. Relationship between ACTH and cortisol A positive and significant correlation was found between the plasma ACTH and cortisol levels in the group of patients (Pearson’s r = .52, P < .0001), and a positive but nonsignificant correlation was found between the plasma ACTH and
NLPs are basically competitive antagonists of several neurotransmitters, being effective in blocking catecholamine receptors. Catecholamines are indicated to be involved in the ACTH release, although the data on effects of catecholamines on ACTH release are contradicted. It has been reported that dopamine (DA) exerts a tonic inhibition on the release of ACTH (Hirata et al., 1984), and thus DA antagonists stimulate ACTH secretion (Seki et al., 1995). DA agonists, however, have been reported to have stimulatory role in the regulation of HPA activity (Borowsky and Kuhn, 1992). Considering these findings, it is not at all surprising that previous reports of effects of NLPs on HPA activity reveals contradictory and conflicting point of views (De Wied, 1967; Debreceni et al., 1971a,b; Roy et al., 1986). Contradictory findings may be due to types and/or dosages being used. In general, baseline plasma ACTH levels were not elevated in drug-free schizophrenic patients (Elman et al., 1998; Roy et al., 1986). Although we did not find a significant correlation between the plasma ACTH and dose of NLPs, we found that the mean level of the plasma ACTH in the HD, but not LD schizophrenics was significantly higher than that in the normal group. Our results, therefore, seem to indicate that ACTH secretion might be still increased in chronic schizophrenic patients by long-term treatment with NLPs. Although ACTH levels have been elevated during acute stress in humans (Jeˆzova´ et al., 1994) and patients with schizophrenia (Elman et al., 1998), we have found that patients in our sample were not necessarily more anxious than healthy persons. In drug-free schizophrenic patients, plasma cortisol levels have been reported to be elevated (Lerer et al., 1988) or not different compared to controls (Jansen et al., 1998; Roy et al., 1986). Considering our findings that, in patients, (1) plasma ACTH levels were elevated and (2) plasma ACTH levels were correlated with plasma cortisol level, plasma cortisol levels may not be elevated, at least in our sample with schizophrenia medicated chronically. Franze´n (1971) also showed that the serum cortisol did not vary after withdrawal of NLPs in chronic schizophrenic patients. Previous studies using dexamethasone suppression test have suggested central dysfunction of the HPA axis (Kaneko et al., 1992) and its association with psychotic
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symptoms (Tandon et al., 1991). However, since our results showed that ACTH but not cortisol secretion was elevated in our schizophrenic sample, cortisol secretion might be still somewhat impaired in the response to ACTH stimuli under the NLP treatment, which has been suggested to improve adrenal function (Brambilla et al., 1975). It might be that tolerance could explain the findings. Meanwhile, our finding of a correlation between the plasma ACTH and cortisol level indicated that cortisol secretion might not be severely impaired. Anyway, to clarify the effects of chronic NLP administration on the HPA axis, long-term prospective studies will be required.
5. Conclusions Our results showed that, in chronic schizophrenic patients long-term treated with NLPs, ACTH secretion was elevated.
Acknowledgments The authors appreciate the cooperation of the staff in our department. Some of these results were presented at the 6th World Congress on Innovations in Psychiatry, London, UK, April 2000 and at the 97th Annual Meeting of the Japanese Society of Psychiatry and Neurology, Osaka, Japan, May 2001.
References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). American Psychiatric Association, Washington, DC. Borowsky, B., Kuhn, C.M., 1992. D1 and D2 dopamine receptors stimulate hypothalamo-pituitary – adrenal activity in rats. Neuropharmacology 31, 671 – 678. Brambilla, F., Guerrini, A., Guastalla, A., Rovere, C., Riggi, F., 1975. Neuroendocrine effects of haloperidol therapy in chronic schizophrenia. Psychopharmacologia 44, 17 – 22. Crow, T.J., 1985. The two-syndrome concept: origins and current status. Schizophr. Bull. 11, 471 – 486. Debreceni, L., Csonka-Taka´cs, L., Horva´th, P., Csete, B., 1971a. The effect of chronic droperidol treatment on pituitary – adrenocortical function in the rat. Acta Physiol. Acad. Sci. Hung. 40, 235 – 238. Debreceni, L., Te´nyi, I., Csete, B., Csonka-Taka´cs, L., 1971b. The effect of dehydrobenzperidol, chlorpromazine and reserpine on the pituitary – adrenal system in human. Endokrinologie 58, 410 – 413. De Wied, D., 1967. Chlorpromazine and endocrine function. Pharmacol. Rev. 19, 251 – 288. Elman, I., Adler, C.M., Malhotra, A.K., Bir, C., Pickar, D., Breier, A., 1998. Effect of acute metabolic stress on pituitary – adrenal axis activation in patients with schizophrenia. Am. J. Psychiatry 155, 979 – 981. Franze´n, G., 1971. Serum cortisol in chronic schizophrenia. Changes in the diurnal rhythm and psychiatric mental status on withdrawal of drugs. Psychiatr. Clin. (Basel) 4, 237 – 246.
Fukuchi, M., Matsuo, Y., Murakami, M., Omote, M., Kawanaka, M., Matsushima, H., 1990. Fundamental and clinical evaluation of IRMA for plasma ACTH (1 – 39). Kaku Igaku (Jpn. J. Nucl. Med.). 27, 155 – 163 (in Japanese). Guy, W., 1976. ECDU Assessment Manual. U.S. Department of Health Education and Welfare, Rockville, MD. Hirata, Y., Nakashima, H., Uchihashi, M., Tomita, M., Fujita, T., Ikeda, M., 1984. Effects of bromocriptine and cyproheptadine on basal and corticotropin-releasing factor (CRF) induced ACTH release in a patient with Nelson’s syndrome. Endocrinol. Jpn. 31, 619 – 626. Inagaki, A., Inada, T., Fujii, Y., Yagi, K., 1998a. Dose equivalence of psychotropic drugs: Part 4. Dose equivalence of orally administered neuroleptics (4). Rinsyo Seisin Yakuri (Jpn. J. Clin. Psychopharmacol.). 1, 443 – 448 (in Japanese). Inagaki, A., Inada, T., Fujii, Y., Yagi, K., 1998b. Dose equivalence of psychotropic drugs: Part 6. Dose equivalence of depot administered neuroleptics (2). Rinsyo Seisin Yakuri (Jpn. J. Clin. Psychopharmacol.). 1, 557 – 561 (in Japanese). Jansen, L.M., Gispen-de Wied, C.C., Gademan, P.J., De Jonge, R.C., van der Linden, J.A., Kahn, R.S., 1998. Blunted cortisol response to a psychosocial stressor in schizophrenia. Schizophr. Res. 33, 87 – 94. Jeˆzova´, D., Kvetnansky, R., Vigas, M., 1994. Sex differences in endocrine response to hyperthermia in sauna. Acta Physiol. Scand. 150, 293 – 298. Kaneko, M., Yokoyama, F., Hoshino, Y., Takahagi, K., Murata, S., Watanabe, M., Kumashiro, H., 1992. Hypothalamic – pituitary – adrenal axis function in chronic schizophrenia: association with clinical features. Neuropsychobiology 25, 1 – 7. Kitamura, T., Shima, S., Kato, M., Iwashita, S., Kanba, S., Shiratsuchi, T., Fujihara, S., Ikuta, Y., Kato, M., Kanba, K., Iino, T., Ikuta, N., Miyaoka, H., Takei, S., Hiyama, M., Koshikawa, H., Tsugeno, M., Chiba, C., 1989. Positive and negative symptoms of chronic schizophrenia. Seishin Igaku (Clin. Psychiatry). 31, 131 – 136 (in Japanese). Lerer, B., Ran, A., Blacker, M., Silver, H., Weller, M.P., Drummer, D., Ebstein, B., Calev, A., 1988. Neuroendocrine responses in chronic schizophrenia. Evidence for serotonergic dysfunction. Schizophr. Res. 1, 405 – 410. Nakazato, K., Mizuguchi, T., 1982. Development and validation of Japanese version of State – Trait Anxiety Inventory: a study with female subjects. Shinshin Igaku (Jpn. J. Psychosom. Med.). 22, 107 – 112 (in Japanese). Nicholson, I.R., Chapman, J.E., Neufeld, R.W., 1995. Variability in BPRS definitions of positive and negative symptoms. Schizophr. Res. 17, 177 – 185. Overall, J.E., Gorham, D.R., 1962. The Brief Psychiatric Rating Scale. Psychol. Rep. 10, 799 – 812. Roy, A., Pickar, D., Doran, A., Wolkowitz, O., Gallucci, W., Chrousos, G., Gold, P., 1986. The corticotropin-releasing hormone stimulation test in chronic schizophrenia. Am. J. Psychiatry 143, 1393 – 1397. Saffer, D., Metcalfe, M., Coppen, A., 1985. Abnormal dexamethasone suppression test in type II schizophrenia. Br. J. Psychiatry 147, 721 – 723. Seki, K., Mitsui, C., Nagata, I., 1995. Effects of a dopamine antagonist (metoclopramide) on the release of beta-endorphin, ACTH and cortisol in hyperprolactinemic – amenorrheic women. Gynecol. Obstet. Invest. 40, 42 – 45. Spielberger, C.D., Gorsuch, R.L., Lushene, R.E., 1970. STAI Manual. Consulting Psychologists Press, Palo Alto, CA. Suzuki, S., Nakagawa, S., Toyosaki, I., 1987. Fundamental evaluation and clinical application of plasma and urinary cortisol by fluorescence polarization immunoassay (TDx). Igaku To Yakugaku (J. Med.). 17, 659 – 668 (in Japanese). Tandon, R., Mazzara, C., DeQuardo, J., Craig, K.A., Meador-Woodruff, J.H., Goldman, R., Greden, J.F., 1991. Dexamethasone suppression test in schizophrenia: relationship to symptomatology, ventricular enlargement, and outcome. Biol. Psychiatry 29, 953 – 964.
Article
The hypothalamic–pituitary–adrenal axis in chronic schizophrenic patients long-term treated with neuroleptics Yasuhiro Kanedaa,b,*, Akira Fujiib, Tetsuro Ohmoria a
Department of Neuropsychiatry, The University of Tokushima School of Medicine, 3-18-15 Kuramoto-Cho, Tokushima 770-8503, Japan b Department of Neuropsychiatry, Fujii Hospital, 1-1 Tsukudame, Minobayashi-Cho, Anan 774-0017, Japan
Abstract Purpose: The authors investigated the hypothalamic – pituitary – adrenal (HPA) axis of regularly medicated schizophrenic patients. Methods: The subjects were 53 patients who were diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders — Fourth Edition (DSM-IV) criteria for schizophrenia. Each patient gave informed consent for the research. Psychiatric symptoms were assessed using the Brief Psychiatric Rating Scale (BPRS). Based on the dosages of neuroleptics (NLPs), the subjects were classified into two groups: those with lower dosages (LD) and those with higher dosages (HD). Findings: (a) The medicated schizophrenic patients had significantly higher plasma corticotropin (ACTH) levels than the normals. (b) There was no significant difference in plasma cortisol levels between the schizophrenic patients and normals. (c) There was a significant difference in plasma ACTH levels between the HD and normal groups, but not between the LD and normal groups. (d) There was no significant difference in administration periods of NLPs, positive (POS) or negative symptoms (NES) between the HD and LD groups. (e) There was a positive correlation between the plasma ACTH and plasma cortisol levels in patients. Conclusions: Our results showed that, in chronic schizophrenic patients long-term treated with NLPs, ACTH secretion was elevated. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Corticotropin, ACTH; Cortisol; Neuroleptic; Schizophrenia
1. Introduction A hypothalamic – pituitary– adrenal (HPA) axis function is involved in emotion, and the functional impairment of this axis causes psychiatric illness. Some abnormal findings of the HPA axis in schizophrenic patients have been observed (Brambilla et al., 1975; Elman et al., 1998; Saffer et al., 1985). Regarding the effects of acute administration of neuroleptics (NLPs) on HPA activity, previous reports revealed contradictory and conflicting point of views (De Wied, 1967; Debreceni et al., 1971a,b; Roy et al., 1986). Many patients with schizophrenia have been taking NLPs chronically for preventing exacerbation, but the date obtained from these previous reports make it hard for us to presume Abbreviations: BPRS, Brief Psychiatric Rating Scale; ACTH, corticotropin; HD, higher dosages; HPA, hypothalamic – pituitary – adrenal; LD, lower dosages; NES, negative symptoms; NLPs, neuroleptics; POS, positive symptoms; STAI, Spielberger’s State – Trait Anxiety Inventory * Corresponding author. Department of Neuropsychiatry, The University of Tokushima School of Medicine, 3-18-15 Kuramoto-Cho, Tokushima 770-8503, Japan. Tel.: +81-88-633-7130; fax: +81-88-633-7131. E-mail address: [email protected] (Y. Kaneda).
chronic effects of NLPs on HPA activity. Therefore, the present study was conducted to investigate the HPA function in schizophrenic patients with long-term NLP administration.
2. Methods 2.1. Subjects The subjects in this study were 23 normal (10 females and 13 males) and 53 chronically medicated schizophrenic patients (20 females and 33 males) that met the Diagnostic and Statistical Manual of Mental Disorders — Fourth Edition’s (DSM-IV) (American Psychiatric Association, 1994) diagnostic criteria for schizophrenia. The study was approved by the relevant ethics committees and was performed in accordance with the Declaration of Helsinki II. Informed consent was obtained from all subjects for the research in this study. Subjects were excluded if they presented with any organic central nervous system disorder, significant substance abuse, and mental retardation. Table 1 shows the demographic characteristics of the subjects.
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Table 1 Demographic characteristics of subjects Patients with schizophrenia Normals Mean (S.D.)
Low-dose High-dose Total mean group mean group mean (S.D.) (S.D.) (S.D.)
n 23 53 27 Schizophrenia subtype Catatonic – 0 0 Disorganized – 10 3 Paranoid – 11 6 Undifferentiated – 13 8 Residual – 19 10 Age (years) 50.7 (15.8) 51.9 (10.3) 53.8 (11.2) Age at onset (years) – 29.2 (9.2) 30.1 (9.3) Administration – 22.6 (10.2) 23.6 (11.3) period (years) Length of – 19.4 (9.1) 20.4 (9.1) hospitalization (years) Body weight (kg) 57.0 (13.2) 60.9 (11.4) 59.7 (9.2) Dosea (mg/day) – 12.2 (9.6) 5.8 (2.9) POS – 4.8 (2.8) 4.1 (2.5) NES – 6.3 (2.8) 5.6 (2.2) STAI (state anxiety) 42.0 (7.3) 43.5 (9.6) 43.5 (8.2)
26 0 7 5 5 9 49.9 (9.2) 28.3 (9.3) 21.6 (9.0) 18.5 (9.4)
62.2 18.7 5.5 7.0 43.5
(13.4) (9.8)*** (2.9) (3.2) (11.0)
a
Haloperidol equivalent. *** P < .001 versus LD group by the t test.
2.2. Procedure Since the patients had been prescribed NLPs with various chemical structures, each NLP was converted to its haloperidol equivalent using the dosage comparability table (Inagaki et al., 1998a); for depot NLPs, the procedure adopted was based on the equivalence table for long-term therapy (Inagaki et al., 1998b). The mean converted dosage of the patients is shown in Table 1. All of the 53 patients were first considered as one group and then, based on their dosages of NLPs, divided into two groups: those with lower dosages (< 0.16 mg/day/kg: LD, n = 27) and those with higher dosages (> 0.16 mg/day/kg: HD, n = 26).
patients are also shown in Table 1. The levels of anxiety were assessed using the Japanese version (Nakazato and Mizuguchi, 1982) of the Spielberger’s State – Trait Anxiety Inventory (STAI) (Spielberger et al., 1970). The STAI is composed of two separate 20-item scales constructed to measure ‘‘state’’ and ‘‘trait’’ anxiety, using four-point scales. The STAI scores were calculated for 20-item measure for ‘‘state’’ anxiety. 2.4. Hormonal assessments Blood samples for hormone estimation were once drawn from all subjects between 0600 and 0700 h. They were off food, beverages, smoking, and drinking for at least 9 h. As corticotropin (ACTH) is secreted episodically and the level of ACTH in plasma changes every moment, several points sampling and the use of the mean of the data may be preferable for the assessment of ACTH. We, however, took just one sampling, since one assessment is practical in the clinical setting. The plasma was prepared and stored at 20 C until the time of analysis. ACTH and cortisol were assayed by an immunoradiometric assay (Fukuchi et al., 1990) and fluorescence polarization immunoassay (TDx) (Suzuki et al., 1987), respectively. According to the results of the laboratory, we considered a normal range of 5– 50 pg/ml and 5.0– 25.0 mg/dl for ACTH and cortisol, respectively. 2.5. Data analysis Statistical analyses were carried out using parametric tests (e.g., Student’s t test, Scheffe’s test, Pearson’s Product – Moment Correlations), if the data were normally distributed. Otherwise, the nonparametric tests (e.g., Mann – Whitney’s U test, Kruskal – Wallis’s test, Spearman’s rank correlations) were used.
3. Results
2.3. Psychiatric assessments
3.1. Concentrations of each hormone
Psychiatric ratings were done using the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962). The BPRS provided a standardized method of assessing 18 psychiatric symptoms using operationally defined sevenpoint scales. Two symptoms, namely hallucinatory behavior and unusual thought content, were derived from this scale as positive symptoms (POS) based on previous groupings of BPRS symptoms (Crow, 1985; Guy, 1976; Kitamura et al., 1989; Nicholson et al., 1995). The POS scores were formed using the sum of the ratings of the POS. Three symptoms, emotional withdrawal, motor retardation, and blunted affect, were derived from this scale as negative symptoms (NES) (Crow, 1985; Guy, 1976; Nicholson et al., 1995). The NES scores were formed using the sum of the ratings of the NES. The mean POS and NES scores in the
In the normals and in the medicated schizophrenic patients, the plasma ACTH concentrations were 36.7 (S.D. = 18.5, range 14 – 78) and 60.1 pg/ml (S.D. = 36.5, range 14 –211), respectively. The medicated schizophrenic patients showed significantly higher plasma ACTH levels than normals (t test, P = .0015). In the LD and HD groups, the plasma ACTH concentrations were 56.4 (S.D. = 32.9, range 14 – 133) and 63.8 pg/ml (S.D. = 40.2, range 18 – 211), respectively (Fig. 1). Scheffe’s test showed that the mean level of the plasma ACTH in the HD schizophrenics was significantly higher than that in the normal group ( P = .0058) (Fig. 1). There was no significant difference in the mean levels of the plasma ACTH between the LD schizophrenics and normal group, or between the HD schizophrenics and LD schizophrenics.
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cortisol levels in the group of normal subjects (Pearson’s r = .28, P = .2077). 3.5. Anxiety scores There was no significant difference in the mean state anxiety scores between the patient and normal groups (Table 1). Also, there was no significant difference in the mean state anxiety scores between the HD and LD groups (Table 1).
4. Discussion
Fig. 1. Concentrations of each hormone. Results are means with S.D. The mean level of the plasma ACTH in the HD schizophrenics was significantly higher than that in the normals. However, there was no significant difference in the mean levels of the plasma cortisol between the normal and LD or HD group. ** P < .01 versus normals by Scheffe’s test.
In the normals and medicated schizophrenic patients, the plasma cortisol concentrations were 14.89 (S.D. = 5.72, range 6.0 –26.9) and 16.43 mg/dl (S.D. = 4.83, range 6.4 –29.2), respectively. Although there was no significant difference in the mean levels of the plasma cortisol between the groups, patient group tended to have higher levels of it than the other group. In the LD and HD groups, the plasma cortisol concentrations were 15.78 (S.D. = 5.10, range 6.4 –29.2) and 17.11 mg/dl (S.D. = 4.53, range 9.2 –26.4), respectively (Fig. 1). There was no significant difference in the mean levels of the plasma cortisol between the normal and LD or HD group as shown by Scheffe’s test. 3.2. Differences in variables between LD and HD groups Although the HD group had been taking significantly higher dose of NLPs than the LD group, there was no significant difference in administration periods of NLPs, POS, or NES between the groups (Table 1). 3.3. Relationship between NLP treatment and ACTH and psychotic symptoms We did not find a significant correlation between the plasma ACTH and dose of NLPs. Dose of NLPs was significantly correlated with POS in the group of patients (Pearson’s r = .313, P = .0238), but not with NES. We did not find a significant correlation between the administration period of NLPs and plasma ACTH. 3.4. Relationship between ACTH and cortisol A positive and significant correlation was found between the plasma ACTH and cortisol levels in the group of patients (Pearson’s r = .52, P < .0001), and a positive but nonsignificant correlation was found between the plasma ACTH and
NLPs are basically competitive antagonists of several neurotransmitters, being effective in blocking catecholamine receptors. Catecholamines are indicated to be involved in the ACTH release, although the data on effects of catecholamines on ACTH release are contradicted. It has been reported that dopamine (DA) exerts a tonic inhibition on the release of ACTH (Hirata et al., 1984), and thus DA antagonists stimulate ACTH secretion (Seki et al., 1995). DA agonists, however, have been reported to have stimulatory role in the regulation of HPA activity (Borowsky and Kuhn, 1992). Considering these findings, it is not at all surprising that previous reports of effects of NLPs on HPA activity reveals contradictory and conflicting point of views (De Wied, 1967; Debreceni et al., 1971a,b; Roy et al., 1986). Contradictory findings may be due to types and/or dosages being used. In general, baseline plasma ACTH levels were not elevated in drug-free schizophrenic patients (Elman et al., 1998; Roy et al., 1986). Although we did not find a significant correlation between the plasma ACTH and dose of NLPs, we found that the mean level of the plasma ACTH in the HD, but not LD schizophrenics was significantly higher than that in the normal group. Our results, therefore, seem to indicate that ACTH secretion might be still increased in chronic schizophrenic patients by long-term treatment with NLPs. Although ACTH levels have been elevated during acute stress in humans (Jeˆzova´ et al., 1994) and patients with schizophrenia (Elman et al., 1998), we have found that patients in our sample were not necessarily more anxious than healthy persons. In drug-free schizophrenic patients, plasma cortisol levels have been reported to be elevated (Lerer et al., 1988) or not different compared to controls (Jansen et al., 1998; Roy et al., 1986). Considering our findings that, in patients, (1) plasma ACTH levels were elevated and (2) plasma ACTH levels were correlated with plasma cortisol level, plasma cortisol levels may not be elevated, at least in our sample with schizophrenia medicated chronically. Franze´n (1971) also showed that the serum cortisol did not vary after withdrawal of NLPs in chronic schizophrenic patients. Previous studies using dexamethasone suppression test have suggested central dysfunction of the HPA axis (Kaneko et al., 1992) and its association with psychotic
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symptoms (Tandon et al., 1991). However, since our results showed that ACTH but not cortisol secretion was elevated in our schizophrenic sample, cortisol secretion might be still somewhat impaired in the response to ACTH stimuli under the NLP treatment, which has been suggested to improve adrenal function (Brambilla et al., 1975). It might be that tolerance could explain the findings. Meanwhile, our finding of a correlation between the plasma ACTH and cortisol level indicated that cortisol secretion might not be severely impaired. Anyway, to clarify the effects of chronic NLP administration on the HPA axis, long-term prospective studies will be required.
5. Conclusions Our results showed that, in chronic schizophrenic patients long-term treated with NLPs, ACTH secretion was elevated.
Acknowledgments The authors appreciate the cooperation of the staff in our department. Some of these results were presented at the 6th World Congress on Innovations in Psychiatry, London, UK, April 2000 and at the 97th Annual Meeting of the Japanese Society of Psychiatry and Neurology, Osaka, Japan, May 2001.
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