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Relationship between anxiety and thyroid function in patients with panic disorder
Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 77 – 81 www.elsevier.com/locate/pnpbp
Relationship between anxiety and thyroid function in patients with panic disorder Mitsuru Kikuchia,*, Ryutarou Komurob, Hiroshi Okac, Tomokazu Kidania, Akira Hanaokaa, Yoshifumi Koshinoa a
Department of Psychiatry and Neurobiology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan b Department of Psychiatry, National Kanazawa Hospital, Kanazawa 920-8650, Japan c Department of Psychiatry, Jyuzen Hospital, Kanazawa 920-1185, Japan Accepted 15 October 2004
Abstract The aim of this study was to investigate correlations between thyroid function and severity of anxiety or panic attacks in patients with panic disorder. The authors examined 66 out-patients with panic disorder (medicated, n=41; non-medicated, n=25), and measured their free thriiodothyronine (T3), free thyroxine (T4) and thyroid-stimulating hormone (TSH) levels. Significant correlations between the thyroid hormone levels and clinical features were observed in the non-medicated patients. The more severe current panic attacks were, the higher the TSH levels were. In addition, severity of anxiety correlated negatively with free T4 levels. In this study, we discuss relationship between thyroid function and the clinical severity or features of panic disorder. D 2004 Elsevier Inc. All rights reserved. Keywords: Anxiety; Panic disorder; Severity; STAI; Thyroid hormone
1. Introduction Panic disorder is a chronic and recurring condition (Davidson, 1998), so that patients are chronically exposed to recurrent stress, and some patients require long-term therapy. Numerous studies have demonstrated that the endocrine system reacts to various stressful stimuli. Many investigators have explored changes in hormones of the hypothalamic–pituitary–thyroid (HPT) axis in response to stress. Bauer et al. (1994) reported that marked abnormalities of the HPT axis observed in refugees from the former East Germany would seem to reflect prolonged severe
Abbreviations: HPT, hypothalamic–pituitary–thyroid; STAI, State-Trait Anxiety Inventory; T3, thriiodothyronine; T4, thyroxine; TRH, thyrotropine-releasing hormone; TSH, thyroid-stimulating hormone. * Corresponding author. Tel.: +81 76 2652301; fax: +81 76 2344254. E-mail address: [email protected] (M. Kikuchi). 0278-5846/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2004.10.008
psychological stress situations rather than any specific psychiatric disorder. Studies of panic disorder have found evidence of a blunted thyroid-stimulating hormone (TSH) response to thyrotropine-releasing hormone (TRH) stimulation (Roy-Byrne et al., 1986; Tukel et al., 1999). In addition, Yeragani et al. (1987) reported greater variability in thriiodothyronine (T3) and thyroxine (T4) values of patients than in those of controls, although there were no significant differences in the mean values. However, no published study has dealt with a possible association between anxiety and thyroid function in patients with panic disorder. The objective of this study was therefore to investigate any association between thyroid function and subjective anxiety (based on a self-rating scale) or severity of panic attacks in patients with panic disorder. Because various antidepressants are known to influence plasma thyroid hormone concentrations (Brady and Anton, 1989; Balon et al., 1991; Sagud et al., 2002), we investigated non-medicated and medicated patients separately.
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M. Kikuchi et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 77–81 Table 2 Medication and mean hormone concentrations
2. Materials and methods 2.1. Subjects The subjects were 66 patients with panic disorder (29 men and 37 women) diagnosed according to DSM-IV criteria (American Psychiatric Association, 1994) (Table 1). Twenty of the patients met criteria for panic disorder without agoraphobia and 46 patients with agoraphobia. Twenty-eight patients met DSM-III-R criteria for current severity of panic attacks as mild, 18 as moderate and 20 as severe. Twenty-five of the patients had never been medicated and 41 had been treated with medication at the time blood samples were obtained. Their mean age (Fstandard deviation) was 34.4 years (range=16–75 years) and the mean duration of disease was 15.8 months (range=0.1–180 months). All patients assessed themselves by using the State-Trait Anxiety Inventory (STAI) (Spielberger et al., 1970) at the time blood samples were obtained. Their mean STAI state score was 53.5F10.9 (range=28–78). Subjects with a history of known thyroid dysfunction or other endocrinological diseases, of cardiovascular, respiratory, hepatic or renal disease and of psychiatric disorders other than panic disorder were excluded from this study. Patients whose TSH values were outside the normal range were also excluded. Informed consent was obtained from each participant prior to the study. 2.2. Procedures Blood samples were drawn on the same day clinical assessments were made. The subjects were seated and blood samples were drawn between 10 a.m. and 2 p.m. from a single venipuncture. Free T3 and free T4 were measured
Medication Medicated (n=48) Non-medicated (n=29)
Free T3
Free T4
TSH
3.03F0.65 3.12F0.71
1.20F0.18* 1.30F0.24
1.54F0.84 1.59F0.94
Significance was determined by unpaired t-test. * p=0.0393, medicated patients vs. non-medicated patients.
with a competitive enzyme immunoassay (Tosoh, Tokyo, Japan), and TSH with a two-site immunoenzymetric assay (Tosoh). Normal values were 2.2–4.3 pg/ml for free T3, 0.80–1.8 ng/dl for free T4 and 0.27–5.00 AIU/ml for TSH. 2.3. Data analysis Differences in hormone levels between medicated and non-medicated patients were analyzed with the unpaired ttest. Then, differences between male and female patients or between patients with and without agoraphobia were analyzed by unpaired t-test separately for the medicated and non-medicated groups. The differences in hormone levels among the three groups differentiated by current severity of panic attacks were assessed separately for the medicated and non-medicated groups by means of oneway ANOVA. Relationships between hormone levels and STAI state scores were analyzed by using Pearson’s correlation coefficient. A value of pb0.05 was considered significant.
3. Results 3.1. Hormone levels of medicated and non-medicated patients
Table 1 Demographics Sex Male Female Age—mean (years) Range Duration of illness—mean (month) Range Current severity of attacks Mild Moderate Severe STAI state score—mean (FS.D.) Agoraphobia With agoraphobia Without agoraphobia
Total
Medicated
Non-medicated
29 37 34.4 16–75 15.8
17 24 35.7 16–75 8.6
12 13 32.2 19–51 27.5*
0.1–180
0.1–60
0.1–180
28 18 20 53.5F10.9
14 13 14 54.1F11.6
14 5 6 52.6F9.9
46 20
31 10
15 10
Significance was determined by unpaired t-test. * p=0.0093, medicated vs. non-medicated patients.
Table 2 shows the mean (FS.D.) thyroid hormone concentrations in medicated and non-medicated patients. The unpaired t-test demonstrated that free T4 levels of the medicated patients were significantly lower than those of the medicated patients ( p=0.0393). 3.2. Hormone levels of medicated patients The unpaired t-test demonstrated that free T3 levels of the patients with agoraphobia were significantly higher than those of the patients without agoraphobia ( p=0.0345). No significant differences in these thyroid hormone concentrations were found between male and female patients. Oneway ANOVA did not detect any significant differences in hormone levels among the three groups differentiated by current severity of panic attacks. Table 4 shows Pearson’s correlation coefficient between the hormone levels and STAI state scores, indicating that there were no significant relationships between them.
M. Kikuchi et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 77–81
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Table 3 Severity of panic attacks and mean hormone concentrations in non-medicated patients Hormone
Mild
Moderate
Severe
F-value
p-value
Post-hoc (Bonferroni/Dun)
Free T3 FreeT4 TSH
3.12 1.37 1.38
2.94 1.29 0.95
3.27 1.17 2.61
0.28 1.62 7.88
n.s. n.s 0.0026
Mild, moderatebsevere
Significance was determined by one-way ANOVA.
3.3. Hormone levels in non-medicated patients No significant differences in thyroid hormone concentrations were found between male and female patients, or patients with and without agoraphobia. Table 3 shows the mean thyroid hormone concentrations for the three groups differentiated by current severity of panic attacks. One-way ANOVA detected significant differences in TSH levels among the three groups. Post-hoc analyses showed that TSH levels of the high severity group were higher than those of either the mild ( p=0.0028) or moderate ( p=0.0015) severity group. No differences in free T3 and free T4 levels were found. Table 4 shows Pearson’s correlation coefficient between hormone levels and STAI state scores. Free T4 levels correlated negatively with the STAI state scores ( p=0.0195) in non-medicated patients (Fig. 1).
4. Discussion 4.1. Panic disorder and thyroid dysfunction Some previous studies found that panic disorder disturbed the HPT axis. Yeragani et al. (1987) detected no significant differences in thyroid hormone levels of T3 or T4 between normal controls and panic disorder patients; however, there was a significantly greater variability in T3 and T4 values among the patients. In addition, there is evidence of a blunted TSH response to TRH stimulation in patients with panic disorder (Roy-Byrne et al., 1986; Tukel et al., 1999). Therefore, suffering from panic disorder is likely to have an effect on the HPT axis. In addition, Simon et al. (2002) suggested a increased risk for lifetime prevalence of thyroid dysfunction in patients with panic disorder. Some clinical studies have found association between panic disorder and thyroid problems (Orenstein et al., 1988; Placidi et al., 1998), and recent study suggested that there were genes on chromosome 13q that influence the
susceptibility toward a pleiotropic syndrome that includes panic disorder, bladder problems, mitral valve prolapse and thyroid conditions (Hamilton et al., 2003). In the present study, however, we could not evaluate the differences in rates of thyroid dysfunction between normal control and the patients with panic disorder because of the experimental design. 4.2. Interrelations between thyroid hormones and other hormones The pathogenesis of endogenous panic disorder is not yet known, but is most probably multifactorial. The currently favored hypothesis is that a lack of serotonin in the brain plays a central role (Gorman et al., 2000; Bell and Nutt, 1998; Klein, 1996). This dysfunction of serotonergic neural system may contribute to higher TSH levels observed in the patients with high severity of panic attacks in our study. Previous studies reported that reduced intracerebral serotonin concentration led to increased TRH concentrations in brain tissue (Morley, 1981). As a consequence of this mechanism, peripheral TSH level may be disturbed by frequent panic attacks. Many studies have been reported the changes in hormones of the hypothalamo–pituitary–adrenocortical (HPA) axis or the HPT axis in response to stress (Bauer et al., 1994; Kudielka et al., 2004). In patients with panic disorder, much more studies have reported the endocrine
Table 4 Correlation coefficients between mean thyroid hormone and clinical features Medicated STAI score Non-medicated STAI score
Free T3
Free T4
0.27
0.29
0.087
0.32
0.46*
0.09
Significance was determined by Pearson’s correlation coefficient. * p=0.0195.
TSH
Fig. 1. Correlation between STAI state score and free thyroxine (T4) concentration in non-medicated patients (n=25, ). Pearson’s correlation coefficient showed significant correlation ( p=0.0195). Free T4, free thyroxin.
.
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disturbances in the HPA axis compared with the HPT axis (Abelson and Curtis, 1996; Bandelow et al., 1997; Wedekind et al., 2000). Recent study concluded that, in patients with severe panic disorder, plasma free and salivary cortisol levels were significantly elevated (Wedekind et al., 2000). From the point of view of the interrelation between HPA and HPT axes, Re et al. (1976) reported that physiologic levels of circulating cortisol had a suppressive effect on serum TSH. Then, we expected that suppressed serum TSH would be caused by higher cortisol levels in severe patients. However, in the present study, we found the higher TSH levels in severe patients. Further studies should include assessment of both the HPA and the HPT axes to investigate these interrelations in patients with panic disorder.
Balon et al., 1991). Balon et al. (1991) reported that treatment with imipramine or diazepam was associated with a decrease of T4 in patients with panic disorder. In fact, in this study, free T4 levels of the medicated patients were significantly lower than those of the non-medicated patients. As for clinical features, no significant differences were found between medicated and non-medicated patients in distribution of current severity of panic attacks, sex and occurrence of agoraphobia. There was also no significant difference in STAI state score between these groups. Thus, these clinical feature did not seem to influence on this discrepancy between medicated and non-medicated patients. The only significant difference was found in duration of disease. Further studies should include longitudinal (preand post-treatment) assessment to investigate relationships between the HPT axis and response to treatment.
4.3. The central and the autonomic nerve system It has been reported that thyroid hormones play an important role in the central nerve system (Baldini et al., 1997; Dratman and Gordon, 1996; Bauer et al., 2002; Strawn et al., 2004). A decrease in T4 synthesis in the thyroid gland leads to a reduced T3 content in brain tissues, because intracerebral T3 seems to be mainly the result of local production by deiodination of T4 (Kohrle et al., 1991). A reduction in the T3 content of brain tissues may lead to a serotonin deficiency in brain tissues, as has been hypothesized from experiments on animals (Singhal et al., 1975; Rastogi and Singhal, 1976; Atterwill, 1981). In addition to central nerve system, thyroid hormones may influence the autonomic nerve system. Some previous studies have been published with regard to the effect of thyroid function on sympathetic nerve activity (Matsukawa et al., 1993; SafaTisseront et al., 1998; Cacciatori et al., 2000; Foley et al., 2001). Although the exact role of the HPT axis on the both central and autonomic nerve systems remains controversial, peripheral thyroid hormone levels may affect clinical symptom in patients with panic disorder through the both nerve systems. Few studies, however, have dealt with the effect of treatment with thyroid supplements on panic disorder, and Stein et al. (1991) reported that patients with panic disorder have normal tissue-level responsivity to normal levels of peripherally circulating thyroid hormones. Therefore, it is still difficult to conclude that T4 has a direct effect on anxiety level in patients with panic disorder. 4.4. Medication effect on the HPT axis In contrast to non-medicated patient, significant correlations between the thyroid hormone levels and clinical features were not observed in medicated patient. Almost all the medicated patients were treated with an antidepressant or a benzodiazepine derivative or a combination of the two. These drugs may have obscured correlations between thyroid hormone levels and clinical features, because both drugs may affect the HPT axis (Brady and Anton, 1989;
5. Conclusions In this study, we have shown the relationship between clinical features and thyroid hormone levels in patients with panic disorder. Although caution must be exercised when drawing any definitive conclusions from the cross sectional findings, our results suggest that clinical severity of panic disorder may affect hormonal secretion in the HPT axis.
References Abelson, J.L., Curtis, G.C., 1996. Hypothalamic–pituitary–adrenal axis activity in panic disorder. 24-hour secretion of corticotropin and cortisol. Arch. Gen. Psychiatry 53, 323 – 331. American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. American Psychiatric Press, Washington, DC. Atterwill, C.K., 1981. Effect of acute and chronic tri-iodothyronine (T3) administration to rats on central 5-HT and dopamine-mediated behavioural responses and related brain biochemistry. Neuropharmacology 20, 131 – 144. Baldini, I.M., Vita, A., Mauri, M.C., Amodei, V., Carrisi, M., Bravin, S., Cantalamessa, L., 1997. Psychopathological and cognitive features in subclinical hypothyroidism. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 21, 925 – 935. Balon, R., Pohl, R., Yeragani, V.K., Ramesh, C., Glitz, D.A., 1991. The changes of thyroid hormone during pharmacological treatment of panic disorder patients. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 15, 595 – 600. Bandelow, B., Sengos, G., Wedekind, D., Huether, G., Pilz, J., Broocks, A., Hajak, G., Ruther, E., 1997. Urinary excretion of cortisol, norepinephrine, testosterone, and melatonin in panic disorder. Pharmacopsychiatry 30, 113 – 117. Bauer, M., Priebe, S., Kurten, I., Graf, K.J., Baumgartner, A., 1994. Psychological and endocrine abnormalities in refugees from East Germany: Part I. Prolonged stress, psychopathology, and hypothalamic–pituitary–thyroid axis activity. Psychiatry Res. 51, 61 – 73. Bauer, M., Heinz, A., Whybrow, P.C., 2002. Thyroid hormones, serotonin and mood: of synergy and significance in the adult brain. Mol. Psychiatry 7, 140 – 156. Bell, CJ., Nutt, D.J., 1998. Serotonin and panic. Br. J. Psychiatry 172, 465 – 471.
M. Kikuchi et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 77–81 Brady, K.T., Anton, R.F., 1989. The thyroid axis and desipramine treatment in depression. Biol. Psychiatry 15, 703 – 709. Cacciatori, V., Gemma, M.L., Bellavere, F., Castello, R., De Gregori, M.E., Zoppini, G., Thomaseth, K., Moghetti, P., Muggeo, M., 2000. Power spectral analysis of heart rate in hypothyroidism. Eur. J. Endocrinol. 143, 327 – 333. Davidson, J.R., 1998. The long-term treatment of panic disorder. J. Clin. Psychiatry 59, 17 – 21. Dratman, M.B., Gordon, J.T., 1996. Thyroid hormones as neurotransmitters. Thyroid 6, 639 – 647. Foley, C.M., McAllister, R.M., Hasser, E.M., 2001. Thyroid status influences baroreflex function and autonomic contributions to arterial pressure and heart rate. Am. J. Physiol, Heart Circ. Physiol. 280, 2061 – 2068. Gorman, J.M., Kent, J.M., Sullivan, G.M., Coplan, J.D., 2000. Neuroanatomical hypothesis of panic disorder, revised. Am. J. Psychiatry 157, 493 – 505. Hamilton, S.P., Fyer, A.J., Durner, M., Heiman, G.A., de Leon, A., Hodge, S.E., Knowles, J.A., Weissman, M.M., 2003. Further genetic evidence for a panic disorder syndrome mapping to chromosome 13q. Proc. Natl. Acad. Sci. U. S. A. 100, 2550 – 2555. Klein, D.F., 1996. Panic disorder and agoraphobia: hypothesis hothouse. J. Clin. Psychiatry 57 (Suppl. 6), S21 – S27. Kohrle, J., Hesch, R.D., Leonard, J.L., 1991. Intracellular pathways of iodothyronines metabolism. In: Braverman, L.E., Utiger, R.D. (Eds.), Werner and Ingbar’s The Thyroid: A Fundamental and Clinical Text, 6th ed. Lippincott, Philadelphia, pp. 144 – 189. Kudielka, B.M., Buske-Kirschbaum, A., Hellhammer, D.H., Kirschbaum, C., 2004. HPA axis responses to laboratory psychosocial stress in healthy elderly adults, younger adults, and children: impact of age and gender. Psychoneuroendocrinology 29, 83 – 98. Matsukawa, T., Mano, T., Gotoh, E., Minamisawa, K., Ishii, M., 1993. Altered muscle sympathetic nerve activity in hyperthyroidism and hypothyroidism. J. Auton. Nerv. Syst. 42, 171 – 175. Morley, J.E., 1981. Neuroendocrine control of thyrotropin secretion. Endocr. Rev. 2, 396 – 436. Orenstein, H., Peskind, A., Raskind, M.A., 1988. Thyroid disorders in female psychiatric patients with panic disorder or agoraphobia. Am. J. Psychiatry 145, 1428 – 1430. Placidi, G.P., Boldrini, M., Patronelli, A., Fiore, E., Chiovato, L., Perugi, G., Marazziti, D., 1998. Prevalence of psychiatric disorders in thyroid diseased patients. Neuropsychobiology 38, 222 – 225.
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Rastogi, R.B., Singhal, R.L., 1976. Influence of neonatal and adult hyperthyroidism on behavior and biosynthetic capacity for norepinephrine, dopamine and 5-hydroxytryptamine in rat brain. J. Pharmacol. Exp. Ther. 198, 609 – 618. Re, R.N., Kourides, I.A., Ridgway, E.C., Weintraub, B.D., Maloof, F., 1976. The effect of glucocorticoid administration on human pituitary secretion of thyrotropin and prolactin. J. Clin. Endocrinol. Metab. 43, 338 – 346. Roy-Byrne, P.P., Uhde, T.W., Rubinow, D.R., Post, R.M., 1986. Reduced TSH and prolactin responses to TRH in patients with panic disorder. Am. J. Psychiatry 143, 503 – 507. Safa-Tisseront, V., Ponchon, P., Laude, D., Elghozi, J.L., 1998. Autonomic contribution to the blood pressure and heart rate variability changes in early experimental hyperthyroidism. J. Hypertens. 16, 1989 – 1992. Sagud, M., Pivac, N., Muck-Seler, D., Jakovljevic, M., Mihaljevic-Peles, A., Korsic, M., 2002. Effects of sertraline treatment on plasma cortisol, prolactin and thyroid hormones in female depressed patients. Neuropsychobiology 45, 139 – 143. Simon, N.M., Blacker, D., Korbly, N.B., Sharma, S.G., Worthington, J.J., Otto, M.W., Pollack, M.H., 2002. Hypothyroidism and hyperthyroidism in anxiety disorders revisited: new data and literature review. J. Affect. Disord. 69, 209 – 217. Singhal, R.L., Rastogi, R.B., Hrdina, P.D., 1975. Brain biogenic amines and altered thyroid function. Life Sci. 17, 1617 – 1626. Spielberger, C.P., Gorsuch, R.L., Luschen, R.D., 1970. STAI Manual. Consulting Psychologists Press, Palo Alto, CA. Stein, M.B., Muir-Nash, J., Uhde, T.W., 1991. The QKd interval in panic disorder: an assessment of end-organ thyroid hormone responsivity. Biol. Psychiatry 29, 1209 – 1214. Strawn, J.R., Ekhator, N.N., D’Souza, B.B., Geracioti Jr., T.D., 2004. Pituitary-thyroid state correlates with central dopaminergic and serotonergic activity in healthy humans. Neuropsychobiology 49, 84 – 87. Tukel, R., Kora, K., Hekim, N., Oguz, H., Alagol, F., 1999. Thyrotropin stimulating hormone response to thyrotropin releasing hormone in patients with panic disorder. Psychoneuroendocrinology 24, 155 – 160. Wedekind, D., Bandelow, B., Broocks, A., Hajak, G., Ruther, E., 2000. Salivary, total plasma and plasma free cortisol in panic disorder. J. Neural Transm. 107, 831 – 837. Yeragani, V.K., Rainey, J.M., Pohl, R., Ortiz, A., Weinberg, P., Gershon, S., 1987. Thyroid hormone levels in panic disorder. Can. J. Psychiatry 32, 467 – 469.
Relationship between anxiety and thyroid function in patients with panic disorder Mitsuru Kikuchia,*, Ryutarou Komurob, Hiroshi Okac, Tomokazu Kidania, Akira Hanaokaa, Yoshifumi Koshinoa a
Department of Psychiatry and Neurobiology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8641, Japan b Department of Psychiatry, National Kanazawa Hospital, Kanazawa 920-8650, Japan c Department of Psychiatry, Jyuzen Hospital, Kanazawa 920-1185, Japan Accepted 15 October 2004
Abstract The aim of this study was to investigate correlations between thyroid function and severity of anxiety or panic attacks in patients with panic disorder. The authors examined 66 out-patients with panic disorder (medicated, n=41; non-medicated, n=25), and measured their free thriiodothyronine (T3), free thyroxine (T4) and thyroid-stimulating hormone (TSH) levels. Significant correlations between the thyroid hormone levels and clinical features were observed in the non-medicated patients. The more severe current panic attacks were, the higher the TSH levels were. In addition, severity of anxiety correlated negatively with free T4 levels. In this study, we discuss relationship between thyroid function and the clinical severity or features of panic disorder. D 2004 Elsevier Inc. All rights reserved. Keywords: Anxiety; Panic disorder; Severity; STAI; Thyroid hormone
1. Introduction Panic disorder is a chronic and recurring condition (Davidson, 1998), so that patients are chronically exposed to recurrent stress, and some patients require long-term therapy. Numerous studies have demonstrated that the endocrine system reacts to various stressful stimuli. Many investigators have explored changes in hormones of the hypothalamic–pituitary–thyroid (HPT) axis in response to stress. Bauer et al. (1994) reported that marked abnormalities of the HPT axis observed in refugees from the former East Germany would seem to reflect prolonged severe
Abbreviations: HPT, hypothalamic–pituitary–thyroid; STAI, State-Trait Anxiety Inventory; T3, thriiodothyronine; T4, thyroxine; TRH, thyrotropine-releasing hormone; TSH, thyroid-stimulating hormone. * Corresponding author. Tel.: +81 76 2652301; fax: +81 76 2344254. E-mail address: [email protected] (M. Kikuchi). 0278-5846/$ - see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2004.10.008
psychological stress situations rather than any specific psychiatric disorder. Studies of panic disorder have found evidence of a blunted thyroid-stimulating hormone (TSH) response to thyrotropine-releasing hormone (TRH) stimulation (Roy-Byrne et al., 1986; Tukel et al., 1999). In addition, Yeragani et al. (1987) reported greater variability in thriiodothyronine (T3) and thyroxine (T4) values of patients than in those of controls, although there were no significant differences in the mean values. However, no published study has dealt with a possible association between anxiety and thyroid function in patients with panic disorder. The objective of this study was therefore to investigate any association between thyroid function and subjective anxiety (based on a self-rating scale) or severity of panic attacks in patients with panic disorder. Because various antidepressants are known to influence plasma thyroid hormone concentrations (Brady and Anton, 1989; Balon et al., 1991; Sagud et al., 2002), we investigated non-medicated and medicated patients separately.
78
M. Kikuchi et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 77–81 Table 2 Medication and mean hormone concentrations
2. Materials and methods 2.1. Subjects The subjects were 66 patients with panic disorder (29 men and 37 women) diagnosed according to DSM-IV criteria (American Psychiatric Association, 1994) (Table 1). Twenty of the patients met criteria for panic disorder without agoraphobia and 46 patients with agoraphobia. Twenty-eight patients met DSM-III-R criteria for current severity of panic attacks as mild, 18 as moderate and 20 as severe. Twenty-five of the patients had never been medicated and 41 had been treated with medication at the time blood samples were obtained. Their mean age (Fstandard deviation) was 34.4 years (range=16–75 years) and the mean duration of disease was 15.8 months (range=0.1–180 months). All patients assessed themselves by using the State-Trait Anxiety Inventory (STAI) (Spielberger et al., 1970) at the time blood samples were obtained. Their mean STAI state score was 53.5F10.9 (range=28–78). Subjects with a history of known thyroid dysfunction or other endocrinological diseases, of cardiovascular, respiratory, hepatic or renal disease and of psychiatric disorders other than panic disorder were excluded from this study. Patients whose TSH values were outside the normal range were also excluded. Informed consent was obtained from each participant prior to the study. 2.2. Procedures Blood samples were drawn on the same day clinical assessments were made. The subjects were seated and blood samples were drawn between 10 a.m. and 2 p.m. from a single venipuncture. Free T3 and free T4 were measured
Medication Medicated (n=48) Non-medicated (n=29)
Free T3
Free T4
TSH
3.03F0.65 3.12F0.71
1.20F0.18* 1.30F0.24
1.54F0.84 1.59F0.94
Significance was determined by unpaired t-test. * p=0.0393, medicated patients vs. non-medicated patients.
with a competitive enzyme immunoassay (Tosoh, Tokyo, Japan), and TSH with a two-site immunoenzymetric assay (Tosoh). Normal values were 2.2–4.3 pg/ml for free T3, 0.80–1.8 ng/dl for free T4 and 0.27–5.00 AIU/ml for TSH. 2.3. Data analysis Differences in hormone levels between medicated and non-medicated patients were analyzed with the unpaired ttest. Then, differences between male and female patients or between patients with and without agoraphobia were analyzed by unpaired t-test separately for the medicated and non-medicated groups. The differences in hormone levels among the three groups differentiated by current severity of panic attacks were assessed separately for the medicated and non-medicated groups by means of oneway ANOVA. Relationships between hormone levels and STAI state scores were analyzed by using Pearson’s correlation coefficient. A value of pb0.05 was considered significant.
3. Results 3.1. Hormone levels of medicated and non-medicated patients
Table 1 Demographics Sex Male Female Age—mean (years) Range Duration of illness—mean (month) Range Current severity of attacks Mild Moderate Severe STAI state score—mean (FS.D.) Agoraphobia With agoraphobia Without agoraphobia
Total
Medicated
Non-medicated
29 37 34.4 16–75 15.8
17 24 35.7 16–75 8.6
12 13 32.2 19–51 27.5*
0.1–180
0.1–60
0.1–180
28 18 20 53.5F10.9
14 13 14 54.1F11.6
14 5 6 52.6F9.9
46 20
31 10
15 10
Significance was determined by unpaired t-test. * p=0.0093, medicated vs. non-medicated patients.
Table 2 shows the mean (FS.D.) thyroid hormone concentrations in medicated and non-medicated patients. The unpaired t-test demonstrated that free T4 levels of the medicated patients were significantly lower than those of the medicated patients ( p=0.0393). 3.2. Hormone levels of medicated patients The unpaired t-test demonstrated that free T3 levels of the patients with agoraphobia were significantly higher than those of the patients without agoraphobia ( p=0.0345). No significant differences in these thyroid hormone concentrations were found between male and female patients. Oneway ANOVA did not detect any significant differences in hormone levels among the three groups differentiated by current severity of panic attacks. Table 4 shows Pearson’s correlation coefficient between the hormone levels and STAI state scores, indicating that there were no significant relationships between them.
M. Kikuchi et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 77–81
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Table 3 Severity of panic attacks and mean hormone concentrations in non-medicated patients Hormone
Mild
Moderate
Severe
F-value
p-value
Post-hoc (Bonferroni/Dun)
Free T3 FreeT4 TSH
3.12 1.37 1.38
2.94 1.29 0.95
3.27 1.17 2.61
0.28 1.62 7.88
n.s. n.s 0.0026
Mild, moderatebsevere
Significance was determined by one-way ANOVA.
3.3. Hormone levels in non-medicated patients No significant differences in thyroid hormone concentrations were found between male and female patients, or patients with and without agoraphobia. Table 3 shows the mean thyroid hormone concentrations for the three groups differentiated by current severity of panic attacks. One-way ANOVA detected significant differences in TSH levels among the three groups. Post-hoc analyses showed that TSH levels of the high severity group were higher than those of either the mild ( p=0.0028) or moderate ( p=0.0015) severity group. No differences in free T3 and free T4 levels were found. Table 4 shows Pearson’s correlation coefficient between hormone levels and STAI state scores. Free T4 levels correlated negatively with the STAI state scores ( p=0.0195) in non-medicated patients (Fig. 1).
4. Discussion 4.1. Panic disorder and thyroid dysfunction Some previous studies found that panic disorder disturbed the HPT axis. Yeragani et al. (1987) detected no significant differences in thyroid hormone levels of T3 or T4 between normal controls and panic disorder patients; however, there was a significantly greater variability in T3 and T4 values among the patients. In addition, there is evidence of a blunted TSH response to TRH stimulation in patients with panic disorder (Roy-Byrne et al., 1986; Tukel et al., 1999). Therefore, suffering from panic disorder is likely to have an effect on the HPT axis. In addition, Simon et al. (2002) suggested a increased risk for lifetime prevalence of thyroid dysfunction in patients with panic disorder. Some clinical studies have found association between panic disorder and thyroid problems (Orenstein et al., 1988; Placidi et al., 1998), and recent study suggested that there were genes on chromosome 13q that influence the
susceptibility toward a pleiotropic syndrome that includes panic disorder, bladder problems, mitral valve prolapse and thyroid conditions (Hamilton et al., 2003). In the present study, however, we could not evaluate the differences in rates of thyroid dysfunction between normal control and the patients with panic disorder because of the experimental design. 4.2. Interrelations between thyroid hormones and other hormones The pathogenesis of endogenous panic disorder is not yet known, but is most probably multifactorial. The currently favored hypothesis is that a lack of serotonin in the brain plays a central role (Gorman et al., 2000; Bell and Nutt, 1998; Klein, 1996). This dysfunction of serotonergic neural system may contribute to higher TSH levels observed in the patients with high severity of panic attacks in our study. Previous studies reported that reduced intracerebral serotonin concentration led to increased TRH concentrations in brain tissue (Morley, 1981). As a consequence of this mechanism, peripheral TSH level may be disturbed by frequent panic attacks. Many studies have been reported the changes in hormones of the hypothalamo–pituitary–adrenocortical (HPA) axis or the HPT axis in response to stress (Bauer et al., 1994; Kudielka et al., 2004). In patients with panic disorder, much more studies have reported the endocrine
Table 4 Correlation coefficients between mean thyroid hormone and clinical features Medicated STAI score Non-medicated STAI score
Free T3
Free T4
0.27
0.29
0.087
0.32
0.46*
0.09
Significance was determined by Pearson’s correlation coefficient. * p=0.0195.
TSH
Fig. 1. Correlation between STAI state score and free thyroxine (T4) concentration in non-medicated patients (n=25, ). Pearson’s correlation coefficient showed significant correlation ( p=0.0195). Free T4, free thyroxin.
.
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disturbances in the HPA axis compared with the HPT axis (Abelson and Curtis, 1996; Bandelow et al., 1997; Wedekind et al., 2000). Recent study concluded that, in patients with severe panic disorder, plasma free and salivary cortisol levels were significantly elevated (Wedekind et al., 2000). From the point of view of the interrelation between HPA and HPT axes, Re et al. (1976) reported that physiologic levels of circulating cortisol had a suppressive effect on serum TSH. Then, we expected that suppressed serum TSH would be caused by higher cortisol levels in severe patients. However, in the present study, we found the higher TSH levels in severe patients. Further studies should include assessment of both the HPA and the HPT axes to investigate these interrelations in patients with panic disorder.
Balon et al., 1991). Balon et al. (1991) reported that treatment with imipramine or diazepam was associated with a decrease of T4 in patients with panic disorder. In fact, in this study, free T4 levels of the medicated patients were significantly lower than those of the non-medicated patients. As for clinical features, no significant differences were found between medicated and non-medicated patients in distribution of current severity of panic attacks, sex and occurrence of agoraphobia. There was also no significant difference in STAI state score between these groups. Thus, these clinical feature did not seem to influence on this discrepancy between medicated and non-medicated patients. The only significant difference was found in duration of disease. Further studies should include longitudinal (preand post-treatment) assessment to investigate relationships between the HPT axis and response to treatment.
4.3. The central and the autonomic nerve system It has been reported that thyroid hormones play an important role in the central nerve system (Baldini et al., 1997; Dratman and Gordon, 1996; Bauer et al., 2002; Strawn et al., 2004). A decrease in T4 synthesis in the thyroid gland leads to a reduced T3 content in brain tissues, because intracerebral T3 seems to be mainly the result of local production by deiodination of T4 (Kohrle et al., 1991). A reduction in the T3 content of brain tissues may lead to a serotonin deficiency in brain tissues, as has been hypothesized from experiments on animals (Singhal et al., 1975; Rastogi and Singhal, 1976; Atterwill, 1981). In addition to central nerve system, thyroid hormones may influence the autonomic nerve system. Some previous studies have been published with regard to the effect of thyroid function on sympathetic nerve activity (Matsukawa et al., 1993; SafaTisseront et al., 1998; Cacciatori et al., 2000; Foley et al., 2001). Although the exact role of the HPT axis on the both central and autonomic nerve systems remains controversial, peripheral thyroid hormone levels may affect clinical symptom in patients with panic disorder through the both nerve systems. Few studies, however, have dealt with the effect of treatment with thyroid supplements on panic disorder, and Stein et al. (1991) reported that patients with panic disorder have normal tissue-level responsivity to normal levels of peripherally circulating thyroid hormones. Therefore, it is still difficult to conclude that T4 has a direct effect on anxiety level in patients with panic disorder. 4.4. Medication effect on the HPT axis In contrast to non-medicated patient, significant correlations between the thyroid hormone levels and clinical features were not observed in medicated patient. Almost all the medicated patients were treated with an antidepressant or a benzodiazepine derivative or a combination of the two. These drugs may have obscured correlations between thyroid hormone levels and clinical features, because both drugs may affect the HPT axis (Brady and Anton, 1989;
5. Conclusions In this study, we have shown the relationship between clinical features and thyroid hormone levels in patients with panic disorder. Although caution must be exercised when drawing any definitive conclusions from the cross sectional findings, our results suggest that clinical severity of panic disorder may affect hormonal secretion in the HPT axis.
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