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β-adrenoceptor affinity as a biological predictor of treatment response to paroxetine in patients with acute panic disorder
Journal of Affective Disorders 110 (2008) 156 – 160 www.elsevier.com/locate/jad
Brief report
β-adrenoceptor affinity as a biological predictor of treatment response to paroxetine in patients with acute panic disorder ☆ In-Soo Lee a , Kyung-Jeong Kim b , Eun-Ho Kang c , Bum-Hee Yu c,⁎ a
c
Department of Psychiatry, Semin Mental Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea b Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea Received 14 September 2007; received in revised form 11 December 2007; accepted 11 December 2007 Available online 15 January 2008
Abstract Background: Few studies have reported on the functional differences of the β-adrenoceptor between treatment responders and nonresponders in panic disorder (PD). The aim of this study was to compare the nature of the β-adrenoceptor function and clinical variables between treatment responders and non-responders to paroxetine treatment in acute PD patients. Method: Paroxetine was administered to all of the panic patients for 12 weeks. The lymphocyte β-adrenoceptor density (Bmax), affinity (1/Kd), and sensitivity (cAMP ratio) were measured in 22 untreated outpatients with acute PD and 22 age, sex and BMI matched control subjects. Psychological assessments were conducted using the HAM-A, and HAM-D, STAI-S and STAI-T, Anxiety sensitivity index (ASI), and Acute panic inventory (API). Results: A significantly higher Kd was observed in the panic patients before treatment as compared with the control subjects, but there was no significant difference in Kd between the panic patients and control subjects after the treatment. Among the 22 patients, the 11 treatment responders (50%) showed a significantly higher Kd and lower mean scores of HAM-D, STAI-S, STAI-T, and ASI at baseline, compared with the non-responders. Logistic regression revealed that the pretreatment Kd and HAM-D were significantly reliable predictors for treatment response (p b 0.05). Conclusion: The β-adrenoceptor affinity (1/Kd) was decreased and adaptively normalized after treatment with paroxetine in the acute panic patients. In addition, a low pretreatment β-adrenoceptor affinity (1/Kd) was found to predict the treatment response and can be suggested as a biological predictor of treatment response in acute PD. © 2007 Elsevier B.V. All rights reserved. Keywords: β-adrenoceptor affinity; Panic disorder; Paroxetine; Treatment response
1. Introduction ☆
Part of this article was presented at the Annual Meeting of the Korean Neuropsychiatric Association, which was held on October 20th, 2006 at the 63rd building, Seoul, South Korea. ⁎ Corresponding author. Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Ilwon-Dong 50, Gangnam-Gu, Seoul, South Korea 135-710. Tel.: +82 2 3410 3583; fax: +82 2 3410 0050. E-mail address: [email protected] (B.-H. Yu). 0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.12.007
Recent studies have found evidence of abnormal functioning of peripheral β-adrenoceptor system in panic disorder(PD) ( Aronson et al., 1989; Brown et al., 1988; Maddock et al., 1993a; Nesse et al., 1984). Moreover, Maddock et al. (1993a) found a relationship between a lower β-adrenoceptor density and better treatment
I.-S. Lee et al. / Journal of Affective Disorders 110 (2008) 156–160
response to adinazolam, and proposed the pretreatment β-adrenoceptor density as a possible predictor of treatment response (Maddock et al., 1993a). Park and Yu (2005) also reported that the pretreatment β-adrenoceptor affinity (1/Kd) and density could be useful biological markers that predict the treatment response to paroxetine (Park and Yu, 2005). However, these results were inconsistent and few studies directly compared the functional differences of β-adrenoceptor between treatment responders and treatment non-responders in PD. This study was designed to compare the nature of the peripheral β-adrenoceptor function and clinical variables between treatment responders and non-responders in acute PD patients before and after 12 weeks of paroxetine treatment. The lymphocyte β2-adrenoceptor is a useful model for measuring peripheral β-adrenoceptor function in man ( Mills et al., 1990), so the authors hypothesized that the lymphocyte β-adrenoceptor density (Bmax), affinity (1/Kd), and sensitivity (cAMP ratio) of patients with PD are lower than those of normal control subjects and that they are different between treatment responders and non-responders before and after paroxetine treatment.
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tion in the study. The BMI (kg/m2) was required to be between 18 and 30 in all subjects. All of the women participants were required not to be pregnant and not to take oral contraceptives during the study period. 2.2. Treatment Paroxetine was administered to all of the panic patients for 12 weeks. The starting dosage was 10–20 mg/day and the maximum dosage during the 12 weeks was 40 mg/day. No other psychotropic medications were allowed except for alprazolam. 2.3. Biochemical measure
2. Materials and methods
All of the subjects were instructed to refrain from drinking caffeinated beverages or alcohol and from smoking for the 24-h period prior to the study. The study began at 8 a.m., whereupon the subjects were seated and a 20gauge catheter was inserted into a forearm vein permitting blood collection. After instrumentation, the subjects rested quietly for 30 min. Then, the physiological conditions of the subjects were examined and blood samples were collected. The same procedure was followed in all of the subjects after the 12-week treatment with paroxetine.
2.1. Subjects
2.4. Beta-adrenergic receptor binding data analysis
Forty-six patients with acute PD, ranging in age from 20 to 50 years, were recruited from the outpatient clinic of the Department of Psychiatry in Samsung Medical Center. The diagnosis was made using the Anxiety Disorder Interview Schedule for DSM-IV (ADIS-IV) (First et al., 1997). Only those patients whose duration of PD did not exceed 1 year were enrolled in this study. Patients with medical illnesses or with other psychiatric illnesses were excluded from the study, because such illnesses might affect the adrenergic receptor responsiveness (Dao et al., 1998; Johnson, 1998; Johnson and Lydiard, 1995; Joyce et al., 1992; Mills et al., 1995a; Pandey et al., 1987). Thirty-nine patients were assigned to 12 weeks of paroxetine treatment. However, 17 of these patients did not complete the 12-week treatment. Thus, the final study population comprised 22 patients (male: 16, female: 6). Twenty two control subjects who were matched for age, sex, and BMI and had no major psychiatric or medical disorders were recruited (male: 17, female: 5). The Institutional Review Board of Samsung Medical Center approved the study and written informed consent was obtained from all participants. All of the participants were required to be free of any medication for at least 2 weeks prior to their participa-
The lymphocyte isolation and receptor assay was conducted to determine the level of the β2-adrenoceptor according to previously published methods (Yu et al., 1999). The binding data were transformed mathematically and analyzed using the Inplot program (GraphPad, Sandiego, CA). The lymphocyte β-adrenoceptor density (Bmax) and affinity (1/Kd) were determined by using a gamma counter to measure the radioactivity from the lymphocyte binding after incubation with radioligand [125I]-iodopindolol at six concentrations ranging from 10 to 320 pM for 1 h at 37 °C. The specific binding was determined using 10− 6 M 1-propranolol. The lymphocyte β-adrenoceptor sensitivity was determined in whole cells by quantifying the cyclic AMP (cAMP) accumulation following incubation with 10 μM isoproterenol. The basal non-stimulated, intracellular cAMP was determined and the βAR sensitivity defined as the ratio of the stimulated to basal cAMP (the cAMP ratio). 2.5. Psychological assessment Clinical variables were assessed with the Hamilton rating scale for anxiety (HAM-A) (Hamilton, 1959), the Hamilton rating scale for depression (HAM-D)
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Table 1 Comparison of pretreatment demographic data, psychological states and β-adrenoceptor function between panic patients and normal control subjects
Gender
Male Female
Age BMI Exercise HAMA⁎⁎ HAMD⁎⁎ STAI-S⁎⁎ STAI-T⁎⁎ ASI⁎⁎ Bmax Kd⁎ cAMP ratio
Panic (Mean ± SD) (N = 22)
Control (Mean ± SD) (N = 22)
16 (73%) 6 (27%) 37.32 ± 6.60 22.34 ± 2.65 2.55 ± 1.34 17.36 ± 8.08 13.32 ± 6.07 44.91 ± 9.59 48.73 ± 8.50 22.64 ± 14.07 8.69 ± 6.22 76.38 ± 28.17 6.72 ± 3.48
17 (77%) 5 (23%) 35.36 ± 7.10 23.42 ± 2.35 2.68 ± 1.29 3.75 ± 3.02 2.67 ± 2.50 5.10 ± 5.44 34.57 ± 10.53 37.41 ± 10.36 9.54 ± 5.01 56.12 ± 24.97 5.48 ± 2.52
2.6. Statistics To analyze the differences at baseline between the panic patients and the normal control subjects and between the responders and non-responders to paroxetine treatment, the χ2-test and one-way ANOVA or Kruskal– Wallis analysis of variance were performed using three receptor variables (Bmax, Kd, cAMP ratio) and various clinical variables. To analyze the difference at the endpoint between the responders and non-responders to paroxetine treatment, the t-test or Mann–Whitney U test was performed. For the prediction of treatment response, a stepwise logistic regression analysis was carried out for all significant baseline variables. All of the statistical tests were two-tailed and were performed at a level of significance of 5%. All of the statistical analyses were performed using the SPSS 13.0 statistical software.
p
0.731 0.350 0.161 0.818 b0.001 b0.001 b0.001 b0.001 b0.001 0.467 0.015 0.185
BMI: body mass index, Exercise: score 1–6 (number of exercise per week), HAM-A: Hamilton rating scale for anxiety, HAM-D: Hamilton rating scale for depression, STAI-S: Spielberger state-trait anxiety inventory-state, STAI-T: Spielberger state-trait anxiety inventory-trait. ASI: Anxiety sensitivity index, API: Acute panic inventory, Bmax: maximum binding capacity, cAMP ratio: isoproterenol stimulated cAMP to basal cAMP, Kd: dissociation constant. One-way ANOVA or Kruskal–Wallis analysis of variance for all comparisons, except chi square test for gender. ⁎: p b 0.05,⁎⁎: p b 0.01.
3. Results In the comparison of the demographic data and psychological states between the panic patients and control subjects, there were no statistically significant differences in sex, age, BMI, or exercise level. However, all of the psychological variables were significantly higher in the panic patients at baseline (Table 1). One-way ANOVA revealed a significantly higher Kd (p = 0.015) in the patients compared with the control subjects before treatment. However, there were no significant differences in the means of Bmax and the cAMP ratio between the patients and control subjects before treatment (Table 1). Among the 22 patients, 11 (50%) were treatment responders. There were no significant differences in the means of age, sex, duration of illness, or fitness level between the responder group and non-responder group before treatment. However, the mean scores of the HAMD (p = 0.011), STAI-S (p = 0.047), STAI-T (p = 0.020) and ASI (p = 0.020) were significantly higher and the mean BMI (p = 0.014) was significantly lower in the non-responder group. After 12 weeks of treatment, the mean
(Hamilton, 1960), the Spielberger state-trait anxiety inventory-State and Trait (STAIS and STAIT) (Spielberger et al., 1983), Anxiety sensitivity index (ASI) (Reiss et al., 1986), and Acute panic inventory (API) (Liebowitz et al., 1984). The psychological evaluation of the control subjects was also done by means of the HAM-A, HAM-D, STAIS, STAIT, and ASI assessment. Treatment responders were defined as patients who showed a greater than 50% increase on their API scores after 12 weeks of paroxetine treatment. The API inquires into 23 symptoms that the subjects rate as absent (0), mild (1), moderate (2), or severe (3) and generates a total score (possible range, 0–69).
Table 2 Comparison of β-adrenoceptor density, affinity and sensitivity between treatment responders and non-responders before and after 12 weeks of paroxetine treatment Baseline
Bmax Kd cAMP ratio
p
Responder (N = 11)
Non-responder (N = 11)
8.46 ± 5.89 88.50 ± 29.64 5.65 ± 3.33
8.915 ± 6.81 64.27 ± 21.53 7.79 ± 3.44
0.922 0.040⁎ 0.155
Endpoint
p
Responder (N = 11)
Non-responder (N = 11)
8.63 ± 4.61 70.84 ± 21.20 9.80 ± 6.86
11.28 ± 8.46 59.91 ± 32.00 8.98 ± 6.31
0.373 0.356 0.773
Bmax: maximum binding capacity, cAMP ratio: isoproterenol stimulated cAMP to basal cAMP, Kd: dissociation constant. One-way ANOVA or Kruskal–Wallis analysis of variance for all comparisons. ⁎: p b 0.05.
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paroxetine dosage was not significantly different between the responder group (23.98 ± 5.86 mg/day) and non-responder group (26.70 ± 6.50 mg/day) (p = 0.316), but the mean scores of the HAM-A (p = 0.008), API (p = 0.001), STAI-S (p = 0.031), and STAI-T (p = 0.014) and the mean dosage of alprazolam during the study were significantly lower in the responder group. In addition, the β-adrenoceptor Kd was significantly higher (p = 0.040) in the treatment responders (Kd = 88.50 ±29.67) compared with the non-responders (Kd = 64.27 ± 21.53) at baseline. However, after 12 weeks of treatment, there were no statistically significant differences in any of the β-adrenoceptor measures between the responders and non-responders (Table 2). For the prediction of treatment response to 12 weeks of paroxetine treatment, a logistic regression analysis was performed. Pretreatment Kd (p = 0.050) and HAMD (p = 0.021) were found to predict treatment response. 4. Discussion In this study, the pretreatment Kd was significantly higher in the panic patients and was normalized after paroxetine treatment. These results demonstrated that the β-adrenoceptor affinity (1/Kd) was decreased in the acute panic patients, which is consistent with previous studies which reported a decreased lymphocyte β-adrenoceptor binding in PD (Brown et al., 1988; Maddock et al., 1993a; Park and Yu, 2005). The alteration of Kd may represent a difference in the ratio of the high and low affinity receptor binding components rather than a change in the affinity for the radioligand (Perry and U'Prichard, 1984). Therefore these results suggest the existence of an association of PD with the conformational change of the postsynaptic lymphocyte β-adrenoceptor, due to the increase in the presynaptic noradrenergic activity in response to the panic anxiety state. This assumption can be tested by displacing 125I-iodopindolol with an agonist (e.g. isoproterenol) in the future study. After 12 weeks of successful treatment, the Kd tended to be normalized and there was no significant difference between the panic patients and normal control subjects. Paroxetine has a secondary effect of decreasing the noradrenergic activity (Gorman et al., 2000). By this mechanism of action, after successful treatment with paroxetine, the presynaptic noradrenergic activity decreased and resulted in an increase of the β-adrenoceptor affinity (1/Kd). Although small doses of alprazolam were allowed in some panic patients, a previous study reported that benzodiazepine had little effect on the β-adrenoceptor receptors (Lafaille et al., 1991). Thus, it seems reasonable to suppose that the
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change of the β-adrenoceptor function observed in this study was caused by the paroxetine treatment. Contrary to our initial hypothesis, the pretreatment β-adrenergic receptor density (Bmax) and sensitivity (cAMP ratio) in the panic patients showed no significant difference compared with those of the control subjects and changes in Kd did not reflect changes in cAMP ratio. The decrease in the β-adrenoceptor affinity (1/Kd) may affect the efficiency with which agonist binding translates into cAMP production. This process determines the decreased sensitivity (desensitization) (Mills and Dimsdale, 1988). In a previous study, the β-adrenoceptor responsiveness decreased in the female patients, but not in the male patients, in comparison with the normal controls ( Kim et al., 2004). Consequently, the uneven gender ratio in this study might have affected this result. Additionally, the existence of a racial difference in the β-adrenoceptor sensitivity and density was demonstrated in a previous study ( Mills et al., 1995b), which might also affect the result of this study. The true loss of receptor numbers (down-regulation) can occur after more chronic exposure to high concentrations of an agonist (De Blasi et al., 1985; Motulsky et al., 1986), and a time-dependent sequential decrease of the central β-adrenoceptor affinity (1/Kd) was demonstrated in a previous study (Flugge et al., 1997). In this study, the mean duration of illness in the panic patients (17.19 ± 18.20 weeks) was much shorter than that of a previous study (110 ± 90 months) (Maddock et al., 1993b). In this regard, decreased β-adrenoceptor affinity (1/Kd) could be a time-dependent characteristic in acute PD patients. Our study is the first report on the functional differences in the β-adrenoceptor measures between treatment responders and non-responders to short-term pharmacotherapy with paroxetine in acute PD. The responders to pharmacotherapy with paroxetine in the acute panic patients had a lower β-adrenoceptor affinity (1/Kd) before treatment compared with the non-responders. Furthermore, decreased pretreatment β-adrenoceptor affinity (1/Kd) reliably predicted treatment response. This result is consistent with previous studies which reported that decreased β-adrenoceptor function predicted good treatment response (Maddock et al., 1993b; Park and Yu, 2005) and support the hypothesis that the more adaptive the response of the β-adrenoceptors to panic anxiety, the better the treatment response that could be obtained (Maddock et al., 1993b). Our study has some limitations. First, the uneven gender ratio of the panic patients might have affected our results. Second, the size of our study population was too small to generalize the results concerning panic disorder. Third, we did not consider the severity of agoraphobia
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for the analysis, although the presence of agoraphobia did not differ between the treatment responders and nonresponders at baseline. In conclusion, only the β-adrenoceptor affinity (1/kd) was decreased in the acute panic patients and was adaptively normalized after treatment. We suggest that low pretreatment β-adrenoceptor affinity (1/kd) could be a biological marker to predict the treatment response in acute PD. Role of funding source Funding for this study was provided by SBRI Grants CA00141 and C-A6-418-2 from the Samsung Biomedical Research Institute. The Samsung Biomedical Research Institute had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Conflict of interest None.
References Aronson, T.A., Carasiti, I., McBane, D., Whitaker-Azmitia, P., 1989. Biological correlates of lactate sensitivity in panic disorder. Biol. Psychiatry 26, 463–477. Brown, S.L., Charney, D.S., Woods, S.W., Heninger, G.R., Tallman, J., 1988. Lymphocyte beta-adrenergic receptor binding in panic disorder. Psychopharmacology (Berl.) 94, 24–28. Dao, T.T., Kailasam, M.T., Parmer, R.J., Le, H.V., Le Verge, R., Kennedy, B.P., Ziegler, G., Insel, P.A., Wright, F.A., O'Connor, D.T., 1998. Expression of altered alpha2-adrenergic phenotypic traits in normotensive humans at genetic risk of hereditary (essential) hypertension. J. Hypertens. 16, 779–792. De Blasi, A., Lipartiti, M., Motulsky, H.J., Insel, P.A., Fratelli, M., 1985. Agonist-induced redistribution of beta-adrenergic receptors on intact human mononuclear leukocytes: redistributed receptors are nonfunctional. J. Clin. Endocrinol. Metab. 61, 1081–1088. First, M.B., Spitzer, R.L., Gibbon, M., Williams, J.B.W., 1997. Structured Clinical Interview for DSM IV Axis I Disorders—Clinician version(SCID-CV). American Psychiatric Press, Washington, D.C. Flugge, G., Ahrens, O., Fuchs, E., 1997. Beta-adrenoceptors in the tree shrew brain. II. Time-dependent effects of chronic psychosocial stress on [125I]iodocyanopindolol bindings sites. Cell. Mol. Neurobiol. 17, 417–432. 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, M., 1959. The assessment of anxiety states by rating. Br. J. Med. Psychol. 32, 50–55. Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23, 56–62. Johnson, M., 1998. The beta-adrenoceptor. Am. J. Respir. Crit. Care Med. 158, S146–S153. Johnson, M.R., Lydiard, R.B., 1995. The neurobiology of anxiety disorders. Psychiatr. Clin. North Am. 18, 681–725. Joyce, J.N., Lexow, N., Kim, S.J., Artymyshyn, R., Senzon, S., Lawrence, D., Cassanova, M.F., Kleinman, J.E., Bird, E.D.,
Winokur, A., 1992. Distribution of beta-adrenergic receptor subtypes in human post-mortem brain: alterations in limbic regions of schizophrenics. Synapse 10, 228–246. Kim, Y.R., Min, S.K., Yu, B.H., 2004. Differences in beta-adrenergic receptor sensitivity between women and men with panic disorder. Eur. Neuropsychopharmacol. 14, 515–520. Lafaille, F., Welner, S.A., Suranyi-Cadotte, B.E., 1991. Regulation of serotonin type 2 (5-HT2) and beta-adrenergic receptors in rat cerebral cortex following novel and classical antidepressant treatment. J. Psychiatry Neurosci. 16, 209–214. Liebowitz, M.R., Fyer, A.J., Gorman, J.M., Dillon, D., Appleby, I.L., Levy, G., Anderson, S., Levitt, M., Palij, M., Davies, S.O., et al., 1984. Lactate provocation of panic attacks. I. Clinical and behavioral findings. Arch. Gen. Psychiatry 41, 764–770. Maddock, R.J., Carter, C.S., Magliozzi, J.R., Gietzen, D.W., 1993a. Evidence that decreased function of lymphocyte beta adrenoreceptors reflects regulatory and adaptive processes in panic disorder with agoraphobia. Am. J. Psychiatry 150, 1219–1225. Maddock, R.J., Gietzen, D.W., Goodman, T.A., 1993b. Decreased lymphocyte beta-adrenoreceptor function correlates with less agoraphobia and better outcome in panic disorder. J. Affect. Disord. 29, 27–32. Mills, P.J., Dimsdale, J.E., 1988. The promise of receptor studies in psychophysiologic research. Psychosom. Med. 50, 555–566. Mills, P.J., Dimsdale, J.E., Ziegler, M.G., Berry, C.C., Bain, R.D., 1990. Beta-adrenergic receptors predict heart rate reactivity to a psychosocial stressor. Psychosom. Med. 52, 621–623. Mills, P.J., Dimsdale, J.E., Coy, T.V., Ancoli-Israel, S., Clausen, J.L., Nelesen, R.A., 1995a. Beta 2-adrenergic receptor characteristics in sleep apnea patients. Sleep 18, 39–42. Mills, P.J., Dimsdale, J.E., Ziegler, M.G., Nelesen, R.A., 1995b. Racial differences in epinephrine and beta 2-adrenergic receptors. Hypertension 25, 88–91. Motulsky, H., Cunningham, E.M.S., Deblasi, A., Insel, P.A., 1986. Agonists promote rapid desensitization and redistribution of beta adrenergic receptors on intact human molecular leukocytes. Am. J. Physiol. 250, 583–590. Nesse, R.M., Cameron, O.G., Curtis, G.C., McCann, D.S., HuberSmith, M.J., 1984. Adrenergic function in patients with panic anxiety. Arch. Gen. Psychiatry 41, 771–776. Pandey, G.N., Janicak, P.G., Davis, J.M., 1987. Decreased betaadrenergic receptors in the leukocytes of depressed patients. Psychiatry Res. 22, 265–273. Park, J.E., Yu, B.H., 2005. Biological markers that predict the treatment response of paroxetine in panic disorder. J. Korean Neuropsychiatr. Assoc. 44, 238–246. Perry, B., U'Prichard, D.C., 1984. Alpha adrenergic receptors in neural tissues: methods and applications of radioligand binding assays. In: Marangos, P.J., Campbell, I.C., Cohen, R.M. (Eds.), Brain Receptor Methodologies. Academic press, Florida, pp. 255–283. Reiss, S., Peterson, R.A., Gursky, D.M., McNally, R.J., 1986. Anxiety sensitivity, anxiety frequency and the prediction of fearfulness. Behav. Res. Ther. 24, 1–8. Spielberger, C., Gorsuch, R., Lushene, R., Vagg, P.R., Jacobs, G.A., 1983. Manual for the State–Trait Anxiety Inventory, STAI (Form Y). Consulting Psychologists Press, palo Alto, CA. Yu, B.H., Dimsdale, J.E., Mills, P.J., 1999. Psychological states and lymphocyte beta-adrenergic receptor responsiveness. Neuropsychopharmacology 21, 147–152.
Brief report
β-adrenoceptor affinity as a biological predictor of treatment response to paroxetine in patients with acute panic disorder ☆ In-Soo Lee a , Kyung-Jeong Kim b , Eun-Ho Kang c , Bum-Hee Yu c,⁎ a
c
Department of Psychiatry, Semin Mental Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea b Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea Received 14 September 2007; received in revised form 11 December 2007; accepted 11 December 2007 Available online 15 January 2008
Abstract Background: Few studies have reported on the functional differences of the β-adrenoceptor between treatment responders and nonresponders in panic disorder (PD). The aim of this study was to compare the nature of the β-adrenoceptor function and clinical variables between treatment responders and non-responders to paroxetine treatment in acute PD patients. Method: Paroxetine was administered to all of the panic patients for 12 weeks. The lymphocyte β-adrenoceptor density (Bmax), affinity (1/Kd), and sensitivity (cAMP ratio) were measured in 22 untreated outpatients with acute PD and 22 age, sex and BMI matched control subjects. Psychological assessments were conducted using the HAM-A, and HAM-D, STAI-S and STAI-T, Anxiety sensitivity index (ASI), and Acute panic inventory (API). Results: A significantly higher Kd was observed in the panic patients before treatment as compared with the control subjects, but there was no significant difference in Kd between the panic patients and control subjects after the treatment. Among the 22 patients, the 11 treatment responders (50%) showed a significantly higher Kd and lower mean scores of HAM-D, STAI-S, STAI-T, and ASI at baseline, compared with the non-responders. Logistic regression revealed that the pretreatment Kd and HAM-D were significantly reliable predictors for treatment response (p b 0.05). Conclusion: The β-adrenoceptor affinity (1/Kd) was decreased and adaptively normalized after treatment with paroxetine in the acute panic patients. In addition, a low pretreatment β-adrenoceptor affinity (1/Kd) was found to predict the treatment response and can be suggested as a biological predictor of treatment response in acute PD. © 2007 Elsevier B.V. All rights reserved. Keywords: β-adrenoceptor affinity; Panic disorder; Paroxetine; Treatment response
1. Introduction ☆
Part of this article was presented at the Annual Meeting of the Korean Neuropsychiatric Association, which was held on October 20th, 2006 at the 63rd building, Seoul, South Korea. ⁎ Corresponding author. Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Ilwon-Dong 50, Gangnam-Gu, Seoul, South Korea 135-710. Tel.: +82 2 3410 3583; fax: +82 2 3410 0050. E-mail address: [email protected] (B.-H. Yu). 0165-0327/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.jad.2007.12.007
Recent studies have found evidence of abnormal functioning of peripheral β-adrenoceptor system in panic disorder(PD) ( Aronson et al., 1989; Brown et al., 1988; Maddock et al., 1993a; Nesse et al., 1984). Moreover, Maddock et al. (1993a) found a relationship between a lower β-adrenoceptor density and better treatment
I.-S. Lee et al. / Journal of Affective Disorders 110 (2008) 156–160
response to adinazolam, and proposed the pretreatment β-adrenoceptor density as a possible predictor of treatment response (Maddock et al., 1993a). Park and Yu (2005) also reported that the pretreatment β-adrenoceptor affinity (1/Kd) and density could be useful biological markers that predict the treatment response to paroxetine (Park and Yu, 2005). However, these results were inconsistent and few studies directly compared the functional differences of β-adrenoceptor between treatment responders and treatment non-responders in PD. This study was designed to compare the nature of the peripheral β-adrenoceptor function and clinical variables between treatment responders and non-responders in acute PD patients before and after 12 weeks of paroxetine treatment. The lymphocyte β2-adrenoceptor is a useful model for measuring peripheral β-adrenoceptor function in man ( Mills et al., 1990), so the authors hypothesized that the lymphocyte β-adrenoceptor density (Bmax), affinity (1/Kd), and sensitivity (cAMP ratio) of patients with PD are lower than those of normal control subjects and that they are different between treatment responders and non-responders before and after paroxetine treatment.
157
tion in the study. The BMI (kg/m2) was required to be between 18 and 30 in all subjects. All of the women participants were required not to be pregnant and not to take oral contraceptives during the study period. 2.2. Treatment Paroxetine was administered to all of the panic patients for 12 weeks. The starting dosage was 10–20 mg/day and the maximum dosage during the 12 weeks was 40 mg/day. No other psychotropic medications were allowed except for alprazolam. 2.3. Biochemical measure
2. Materials and methods
All of the subjects were instructed to refrain from drinking caffeinated beverages or alcohol and from smoking for the 24-h period prior to the study. The study began at 8 a.m., whereupon the subjects were seated and a 20gauge catheter was inserted into a forearm vein permitting blood collection. After instrumentation, the subjects rested quietly for 30 min. Then, the physiological conditions of the subjects were examined and blood samples were collected. The same procedure was followed in all of the subjects after the 12-week treatment with paroxetine.
2.1. Subjects
2.4. Beta-adrenergic receptor binding data analysis
Forty-six patients with acute PD, ranging in age from 20 to 50 years, were recruited from the outpatient clinic of the Department of Psychiatry in Samsung Medical Center. The diagnosis was made using the Anxiety Disorder Interview Schedule for DSM-IV (ADIS-IV) (First et al., 1997). Only those patients whose duration of PD did not exceed 1 year were enrolled in this study. Patients with medical illnesses or with other psychiatric illnesses were excluded from the study, because such illnesses might affect the adrenergic receptor responsiveness (Dao et al., 1998; Johnson, 1998; Johnson and Lydiard, 1995; Joyce et al., 1992; Mills et al., 1995a; Pandey et al., 1987). Thirty-nine patients were assigned to 12 weeks of paroxetine treatment. However, 17 of these patients did not complete the 12-week treatment. Thus, the final study population comprised 22 patients (male: 16, female: 6). Twenty two control subjects who were matched for age, sex, and BMI and had no major psychiatric or medical disorders were recruited (male: 17, female: 5). The Institutional Review Board of Samsung Medical Center approved the study and written informed consent was obtained from all participants. All of the participants were required to be free of any medication for at least 2 weeks prior to their participa-
The lymphocyte isolation and receptor assay was conducted to determine the level of the β2-adrenoceptor according to previously published methods (Yu et al., 1999). The binding data were transformed mathematically and analyzed using the Inplot program (GraphPad, Sandiego, CA). The lymphocyte β-adrenoceptor density (Bmax) and affinity (1/Kd) were determined by using a gamma counter to measure the radioactivity from the lymphocyte binding after incubation with radioligand [125I]-iodopindolol at six concentrations ranging from 10 to 320 pM for 1 h at 37 °C. The specific binding was determined using 10− 6 M 1-propranolol. The lymphocyte β-adrenoceptor sensitivity was determined in whole cells by quantifying the cyclic AMP (cAMP) accumulation following incubation with 10 μM isoproterenol. The basal non-stimulated, intracellular cAMP was determined and the βAR sensitivity defined as the ratio of the stimulated to basal cAMP (the cAMP ratio). 2.5. Psychological assessment Clinical variables were assessed with the Hamilton rating scale for anxiety (HAM-A) (Hamilton, 1959), the Hamilton rating scale for depression (HAM-D)
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Table 1 Comparison of pretreatment demographic data, psychological states and β-adrenoceptor function between panic patients and normal control subjects
Gender
Male Female
Age BMI Exercise HAMA⁎⁎ HAMD⁎⁎ STAI-S⁎⁎ STAI-T⁎⁎ ASI⁎⁎ Bmax Kd⁎ cAMP ratio
Panic (Mean ± SD) (N = 22)
Control (Mean ± SD) (N = 22)
16 (73%) 6 (27%) 37.32 ± 6.60 22.34 ± 2.65 2.55 ± 1.34 17.36 ± 8.08 13.32 ± 6.07 44.91 ± 9.59 48.73 ± 8.50 22.64 ± 14.07 8.69 ± 6.22 76.38 ± 28.17 6.72 ± 3.48
17 (77%) 5 (23%) 35.36 ± 7.10 23.42 ± 2.35 2.68 ± 1.29 3.75 ± 3.02 2.67 ± 2.50 5.10 ± 5.44 34.57 ± 10.53 37.41 ± 10.36 9.54 ± 5.01 56.12 ± 24.97 5.48 ± 2.52
2.6. Statistics To analyze the differences at baseline between the panic patients and the normal control subjects and between the responders and non-responders to paroxetine treatment, the χ2-test and one-way ANOVA or Kruskal– Wallis analysis of variance were performed using three receptor variables (Bmax, Kd, cAMP ratio) and various clinical variables. To analyze the difference at the endpoint between the responders and non-responders to paroxetine treatment, the t-test or Mann–Whitney U test was performed. For the prediction of treatment response, a stepwise logistic regression analysis was carried out for all significant baseline variables. All of the statistical tests were two-tailed and were performed at a level of significance of 5%. All of the statistical analyses were performed using the SPSS 13.0 statistical software.
p
0.731 0.350 0.161 0.818 b0.001 b0.001 b0.001 b0.001 b0.001 0.467 0.015 0.185
BMI: body mass index, Exercise: score 1–6 (number of exercise per week), HAM-A: Hamilton rating scale for anxiety, HAM-D: Hamilton rating scale for depression, STAI-S: Spielberger state-trait anxiety inventory-state, STAI-T: Spielberger state-trait anxiety inventory-trait. ASI: Anxiety sensitivity index, API: Acute panic inventory, Bmax: maximum binding capacity, cAMP ratio: isoproterenol stimulated cAMP to basal cAMP, Kd: dissociation constant. One-way ANOVA or Kruskal–Wallis analysis of variance for all comparisons, except chi square test for gender. ⁎: p b 0.05,⁎⁎: p b 0.01.
3. Results In the comparison of the demographic data and psychological states between the panic patients and control subjects, there were no statistically significant differences in sex, age, BMI, or exercise level. However, all of the psychological variables were significantly higher in the panic patients at baseline (Table 1). One-way ANOVA revealed a significantly higher Kd (p = 0.015) in the patients compared with the control subjects before treatment. However, there were no significant differences in the means of Bmax and the cAMP ratio between the patients and control subjects before treatment (Table 1). Among the 22 patients, 11 (50%) were treatment responders. There were no significant differences in the means of age, sex, duration of illness, or fitness level between the responder group and non-responder group before treatment. However, the mean scores of the HAMD (p = 0.011), STAI-S (p = 0.047), STAI-T (p = 0.020) and ASI (p = 0.020) were significantly higher and the mean BMI (p = 0.014) was significantly lower in the non-responder group. After 12 weeks of treatment, the mean
(Hamilton, 1960), the Spielberger state-trait anxiety inventory-State and Trait (STAIS and STAIT) (Spielberger et al., 1983), Anxiety sensitivity index (ASI) (Reiss et al., 1986), and Acute panic inventory (API) (Liebowitz et al., 1984). The psychological evaluation of the control subjects was also done by means of the HAM-A, HAM-D, STAIS, STAIT, and ASI assessment. Treatment responders were defined as patients who showed a greater than 50% increase on their API scores after 12 weeks of paroxetine treatment. The API inquires into 23 symptoms that the subjects rate as absent (0), mild (1), moderate (2), or severe (3) and generates a total score (possible range, 0–69).
Table 2 Comparison of β-adrenoceptor density, affinity and sensitivity between treatment responders and non-responders before and after 12 weeks of paroxetine treatment Baseline
Bmax Kd cAMP ratio
p
Responder (N = 11)
Non-responder (N = 11)
8.46 ± 5.89 88.50 ± 29.64 5.65 ± 3.33
8.915 ± 6.81 64.27 ± 21.53 7.79 ± 3.44
0.922 0.040⁎ 0.155
Endpoint
p
Responder (N = 11)
Non-responder (N = 11)
8.63 ± 4.61 70.84 ± 21.20 9.80 ± 6.86
11.28 ± 8.46 59.91 ± 32.00 8.98 ± 6.31
0.373 0.356 0.773
Bmax: maximum binding capacity, cAMP ratio: isoproterenol stimulated cAMP to basal cAMP, Kd: dissociation constant. One-way ANOVA or Kruskal–Wallis analysis of variance for all comparisons. ⁎: p b 0.05.
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paroxetine dosage was not significantly different between the responder group (23.98 ± 5.86 mg/day) and non-responder group (26.70 ± 6.50 mg/day) (p = 0.316), but the mean scores of the HAM-A (p = 0.008), API (p = 0.001), STAI-S (p = 0.031), and STAI-T (p = 0.014) and the mean dosage of alprazolam during the study were significantly lower in the responder group. In addition, the β-adrenoceptor Kd was significantly higher (p = 0.040) in the treatment responders (Kd = 88.50 ±29.67) compared with the non-responders (Kd = 64.27 ± 21.53) at baseline. However, after 12 weeks of treatment, there were no statistically significant differences in any of the β-adrenoceptor measures between the responders and non-responders (Table 2). For the prediction of treatment response to 12 weeks of paroxetine treatment, a logistic regression analysis was performed. Pretreatment Kd (p = 0.050) and HAMD (p = 0.021) were found to predict treatment response. 4. Discussion In this study, the pretreatment Kd was significantly higher in the panic patients and was normalized after paroxetine treatment. These results demonstrated that the β-adrenoceptor affinity (1/Kd) was decreased in the acute panic patients, which is consistent with previous studies which reported a decreased lymphocyte β-adrenoceptor binding in PD (Brown et al., 1988; Maddock et al., 1993a; Park and Yu, 2005). The alteration of Kd may represent a difference in the ratio of the high and low affinity receptor binding components rather than a change in the affinity for the radioligand (Perry and U'Prichard, 1984). Therefore these results suggest the existence of an association of PD with the conformational change of the postsynaptic lymphocyte β-adrenoceptor, due to the increase in the presynaptic noradrenergic activity in response to the panic anxiety state. This assumption can be tested by displacing 125I-iodopindolol with an agonist (e.g. isoproterenol) in the future study. After 12 weeks of successful treatment, the Kd tended to be normalized and there was no significant difference between the panic patients and normal control subjects. Paroxetine has a secondary effect of decreasing the noradrenergic activity (Gorman et al., 2000). By this mechanism of action, after successful treatment with paroxetine, the presynaptic noradrenergic activity decreased and resulted in an increase of the β-adrenoceptor affinity (1/Kd). Although small doses of alprazolam were allowed in some panic patients, a previous study reported that benzodiazepine had little effect on the β-adrenoceptor receptors (Lafaille et al., 1991). Thus, it seems reasonable to suppose that the
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change of the β-adrenoceptor function observed in this study was caused by the paroxetine treatment. Contrary to our initial hypothesis, the pretreatment β-adrenergic receptor density (Bmax) and sensitivity (cAMP ratio) in the panic patients showed no significant difference compared with those of the control subjects and changes in Kd did not reflect changes in cAMP ratio. The decrease in the β-adrenoceptor affinity (1/Kd) may affect the efficiency with which agonist binding translates into cAMP production. This process determines the decreased sensitivity (desensitization) (Mills and Dimsdale, 1988). In a previous study, the β-adrenoceptor responsiveness decreased in the female patients, but not in the male patients, in comparison with the normal controls ( Kim et al., 2004). Consequently, the uneven gender ratio in this study might have affected this result. Additionally, the existence of a racial difference in the β-adrenoceptor sensitivity and density was demonstrated in a previous study ( Mills et al., 1995b), which might also affect the result of this study. The true loss of receptor numbers (down-regulation) can occur after more chronic exposure to high concentrations of an agonist (De Blasi et al., 1985; Motulsky et al., 1986), and a time-dependent sequential decrease of the central β-adrenoceptor affinity (1/Kd) was demonstrated in a previous study (Flugge et al., 1997). In this study, the mean duration of illness in the panic patients (17.19 ± 18.20 weeks) was much shorter than that of a previous study (110 ± 90 months) (Maddock et al., 1993b). In this regard, decreased β-adrenoceptor affinity (1/Kd) could be a time-dependent characteristic in acute PD patients. Our study is the first report on the functional differences in the β-adrenoceptor measures between treatment responders and non-responders to short-term pharmacotherapy with paroxetine in acute PD. The responders to pharmacotherapy with paroxetine in the acute panic patients had a lower β-adrenoceptor affinity (1/Kd) before treatment compared with the non-responders. Furthermore, decreased pretreatment β-adrenoceptor affinity (1/Kd) reliably predicted treatment response. This result is consistent with previous studies which reported that decreased β-adrenoceptor function predicted good treatment response (Maddock et al., 1993b; Park and Yu, 2005) and support the hypothesis that the more adaptive the response of the β-adrenoceptors to panic anxiety, the better the treatment response that could be obtained (Maddock et al., 1993b). Our study has some limitations. First, the uneven gender ratio of the panic patients might have affected our results. Second, the size of our study population was too small to generalize the results concerning panic disorder. Third, we did not consider the severity of agoraphobia
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for the analysis, although the presence of agoraphobia did not differ between the treatment responders and nonresponders at baseline. In conclusion, only the β-adrenoceptor affinity (1/kd) was decreased in the acute panic patients and was adaptively normalized after treatment. We suggest that low pretreatment β-adrenoceptor affinity (1/kd) could be a biological marker to predict the treatment response in acute PD. Role of funding source Funding for this study was provided by SBRI Grants CA00141 and C-A6-418-2 from the Samsung Biomedical Research Institute. The Samsung Biomedical Research Institute had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Conflict of interest None.
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