Citalopram challenge in social anxiety disorder

Transcription

1 International Journal of Neuropsychopharmacology (2004), 7, Copyright f 2004 CINP DOI: /S X Citalopram challenge in social anxiety disorder Jakov Shlik, Eduard Maron, Innar Tõru, Anu Aluoja and Veiko Vasar Department of Psychiatry, University of Tartu, Tartu, Estonia BRIEF REPORT Abstract The aim of the present study was to evaluate neuroendocrine and behavioural responses to a challenge with the selective serotonin (5-HT) reuptake inhibitor citalopram (Cit) in patients with social anxiety disorder (SAD). Cit was given intravenously (20 mg over 30 min) to 18 patients with SAD and 18 matched healthy subjects in a double-blind, placebo-controlled cross-over design. Cit challenge resulted in the increased plasma concentrations of cortisol and prolactin relatively to placebo without significant differences between the patients and controls. The patients had higher ratings of anxiety that were not affected by Cit, and more headaches than controls after Cit. Thus, the neuroendocrine sensitivity to 5-HT stimulation with Cit in patients with SAD was not different from the response in controls indicating lack of major alterations in the function of 5-HT receptors. The increased headache in patients may suggest hypersensitivity of some subtypes of 5-HT receptors in SAD. Received 5 May 2003; Reviewed 1 July 2003; Revised 23 July 2003; Accepted 30 July 2003 Key words: Citalopram, cortisol, prolactin, serotonin, social anxiety disorder. Introduction Social anxiety disorder (SAD) is a prevalent and disabling anxiety disorder characterized by unreasonable fear of social and performance situations and resulting phobic avoidance. There is an increasing interest in the brain mechanisms of social anxiety. Studies show that changes in dopamine, serotonin (5-HT) and GABA functions may be involved (Bell et al., 1999). Efficacy of the selective serotonin reuptake inhibitors (SSRIs) in the treatment of SAD (Blanco et al., 2002) indicates involvement of brain 5-HT function in the neurobiology of this disorder. One of the directions of research on the 5-HT system is use of neuroendocrine challenges with serotonergic substances based on an assumption that the extent of release of pituitary hormones and cortisol in response to a 5-HT agonist may serve as an index of brain 5-HT activity (Murphy et al., 1986). Previous neuroendocrine challenges with 5-HT agonists in SAD have shown augmented cortisol responses to fenfluramine (Tancer et al., ) and to m-chlorophenylpiperazine (m-cpp; Hollander et al., 1998). These findings suggest a hypersensitivity of 5-HT receptors in SAD. In the current study we intended to elaborate this line of investigations using a challenge with the SSRI citalopram (Cit). Intravenous Cit Address for correspondence: Dr J. Shlik, Department of Psychiatry, University of Tartu, Raja 31, Tartu 50417, Estonia. Tel.: Fax: jakov.shlik@kliinikum.ee infusion has been previously shown to be suitable for probing the 5-HT function in healthy subjects (Seifritz et al., 1996), depressed patients (Attenburrow et al., 2001; Bhagwagar et al., 2002; Kapitany et al., 1999) and abstinent patients with alcohol dependence (Gotjen et al., 2002). The specific aim of this study was to evaluate the neuroendocrine and behavioural responses to 5-HT stimulation with Cit in patients with SAD in comparison to healthy controls. Methods Subjects The patients were recruited by newspaper advertisement and from the outpatients at the Clinic of Psychiatry of Tartu University Clinics. The inclusion criteria were: age between 18 and 55 yr, diagnosis of generalized SAD according to the DSM-IV criteria, good physical health, and body mass index (BMI) between 21 and 24. The exclusion criteria were: presence of any mood disorder or other significant psychiatric comorbidity, smoking more than 10 cigarettes per day, alcohol use of more than 4 drinks per week, and use of psychotropic medications in the last month. The healthy volunteers were matched by age, sex and BMI and did not have a personal or family history of psychiatric disorders. Female subjects were excluded if they had a positive pregnancy test, irregular menstrual cycle, used hormonal contraceptives or had a delivery or abortion in the last 6 months. All subjects gave

2 178 J. Shlik et al. µg/dl Figure 1. Cortisol response in patients (PT) and healthy subjects (HS) to citalopram (Cit) and placebo (Pla). &, PT Cit; --%- -, PT Pla; m, HS Cit; --¾- -, HS Pla. written informed consent after explanations of study procedures and substances, and healthy volunteers were paid E20 for their participation. The Human Studies Ethics Committee at the University of Tartu approved the study protocol and the informed consent form. The psychiatric diagnosis or its absence was confirmed and comorbidity was ruled out using the Mini International Neuropsychiatry Interview, version (Sheehan et al., 1998). Additionally, the subjects were assessed at inclusion in the study with the Liebowitz Social Anxiety Scale (LSAS) and Hamilton Depression Rating Scale (HDRS). In total 20 subjects diagnosed with SAD entered the study and two of them failed to complete the study procedures. Thus, the study sample consisted of 18 patients (9 males, 9 females) with a mean age 29.5 yr (S.D.=10.1, range yr) and 18 healthy volunteers (9 males, 9 females) with mean age 29.1 yr (S.D.=9.5, range yr). At inclusion, the mean LSAS score was 67.4 (S.D.=18.7, range 36 99) in patients and 16.2 (S.D.=10.9, range 1 37) in controls; HDRS mean scores were respectively 6.6 (4) and 1.4 (2). Cit challenge Cit was provided by H. Lundbeck A/S (Copenhagen, Denmark) as a solution for injections in ampoules of 0.5 ml (40 mg/ml). Cit challenge was given as intravenous infusion of 20 mg (0.5 ml) in 100 ml of 0.9% NaCl solution over 30 min using infusion pump Infusomat 1 (B. Braun Melsungen AG, Germany). Placebo (Pla) infusions were performed with 100 ml of NaCl solution. The Cit and Pla infusions were performed under double-blind conditions in a randomized cross-over order separated by an interval of 3 5 wk. In females the challenges were performed between the first week of their menstrual cycle. The challenges started at 09:00 or 11:00 hours. Blood samples for detection of cortisol and prolactin were taken at baseline and 4 times during 120 min after starting infusion in 30-min intervals. Prior to each blood drawing the subjects rated their level of anxiety and physical symptoms on a Visual Analogue Scale (VAS). The VAS included the most common acute side-effects of SSRIs (nausea, dizziness, tremor, fatigue, headache, and sweating). At the same time-points arterial blood pressure and heart rate were recorded using automatic monitor Lohmeier B606 (B. Braun Melsungen AG, Germany). The measurements of the concentrations of cortisol and prolactin were done by HTI Laboratory Services (Tallinn, Estonia) by chemilumenescenceimmunoassay IMMULITE 1 (DPC, Los Angeles, CA, USA) with the analytical sensitivity of 5 pg/ml for cortisol and 0.5 ng/ml for prolactin. The statistical analysis was performed using the software system STATISTICA 6 (StatSoft, Inc., Tulsa, OK, USA). The baseline values were compared by one-way analysis of variance (ANOVA) and the effects of categorical predictors were estimated by main factor ANOVA. The factors included in the analyses were group (patients and controls), drug (Cit and Pla), sex and order of infusions (Cit first vs. Pla first). The changes in hormone concentrations, behavioural and cardiovascular outcome measures were examined with the ANOVA for repeated measures (ANOVA-R) including the time of assessment as the repeatedmeasure factor with a follow-up of significant effects by Tukey honest significance tests. The data are presented as means and standard deviations (S.D.). Results The effects of Cit on the plasma concentrations of cortisol are presented in Figure 1. The baseline values

3 Citalopram challenge in social anxiety disorder ng/ml 4 0 Infusion Baseline 30 min 60 min 90 min 120 min Figure 2. Prolactin response in patients (PT) and healthy subjects (HS) to citalopram (Cit) and placebo (Pla). &, PT Cit; --%- -, PT Pla; m, HS Cit; - -¾--, HS Pla. were not different between patients and controls prior to Cit [10.7 (3.5) vs. 9.4 (4.2); F 1,34 =1.0, p=0.3], but were higher in patients prior to Pla [12.3 (3.4) vs. 8.3 (4.9); F 1,34 =8.2, p=0.007]. The main-factor ANOVA for the cortisol values indicated significant effects of group (F 5,52 =4.1, p=0.003) and drug (F 5,52 =4.3, p= 0.003), but not for sex or order of infusions. The latter two factors were therefore not included in the further analysis. The ANOVA-R in patients indicated no significant effect of drug (F 1,34 =1.7, p=0.2) or time (F 4,136 =0.8, p=0.5), but a significant effect of drugr time interaction (F 4,136 =9.6, p<0.0001). The follow-up analysis showed that Cit increased cortisol release at significantly higher concentrations than after Pla, detected at 60 and 90 min (p<0.0005) after the start of infusion. Similarly to the patients in the control group there were no significant effects of drug (F 1,34 =3.1, p=0.1) or time (F 4,136 =1.5, p=0.2) and a significant effect of drugrtime interaction (F 4,136 =2.6, p=0.04) with the concentration of cortisol significantly higher at 90 min after Cit (p<0.0001). A between-group comparison of the effect of Cit on cortisol demonstrated a significant effect of time (F 4,136 =3.9, p=0.005) but not of group (F 1,34 =2.4, p=0.1) or grouprtime interaction (F 4,136 =0.4, p=0.8). Thus, the stimulating effect of Cit on cortisol release was evident in both patients and controls without significant differences in its magnitude. The effects of Cit on the plasma concentrations of prolactin are presented in Figure 2. There were no differences in the baseline values of prolactin before either Cit or Pla infusion. The main-factor ANOVA indicated a significant effect of drug (F 5,52 =3.1, p= 0.02), but not for group, sex or order. In both patients and controls the ANOVA-R showed a significant effect of drugrtime interaction (F 4,136 =2.6, p=0.04), but no separate effects of drug or time. In patients the prolactin levels were significantly higher at 60 min and in controls at 90 min after Cit than after Pla (p< and p=0.05 respectively). A between-group comparison of the effect of Cit on prolactin demonstrated a significant effect of time (F 4,136 =2.5, p=0.04), but not of group or grouprtime interaction. Hence, the stimulating effect of Cit on prolactin release was observed in both patients and controls without significant differences between the groups. An additional analysis was made for the subgroups of patients with more and less severe social anxiety symptoms according to the LSAS cut-off score of 70, and more and less severe symptoms of depression according to HDRS cut-off score of 7. The effect of Cit on cortisol release was not different between the high (n=10) and low (n=8) LSAS score or high (n=8) and low (n=10) HDRS score subgroups of patients. Similarly there were no differences in the effect of Cit on prolactin between the more and less symptomatic groups. The data and statistics on the behavioural response to Cit and Pla are presented in Table 1. A betweengroup analysis of the VAS-rated anxiety response to Cit demonstrated a significant effect of group (F 1,34 =4.8, p=0.04) but no significant effects of time or groupr time interaction. This indicates higher VAS ratings of anxiety in patients that were not differently affected by Cit than by Pla. For headache after Cit the effect of group was not significant, however, there were significant effects of time (F 1,34 =3.4, p=0.01) and group rtime interaction (F 4,136 =3.6, p=0.008). A follow-up analysis indicated that patients receiving Cit had significantly higher ratings of headache than at baseline and than controls at 60 min (Table 1). No significant differences between patients and controls were

4 180 J. Shlik et al. Table 1. VAS ratings of anxiety and headache Scale 100 mm (none to extreme) Patients Controls Cit Pla Cit Pla ANOVA-R results (see text for between-group analyses) Anxiety Baseline 19 (18) 32 (26) 12 (17) 11 (13) Group: F 1,68 =11.9, p= min 22 (30) 17 (17) 11 (17) 8 (10) Drug: F 1,68 =0.1, p= min 20 (29) 12 (14) 7 (13) 6 (5) Time: F 4,272 =4.7, p= min 20 (24) 16 (18) 8 (12) 6 (10) Interaction: F 4,272 =1.8, p= min 15 (21) 14 (18) 3 (2) 6 (6) Headache Baseline 5 (6) 12 (15) 5 (4) 5 (3) Group: F 1,68 =4.2, p= min 11 (15) 12 (18) 5 (3) 5 (3) Drug: F 1,68 =0.4, p= min 21 (23)* 7 (5) 6 (11) 6 (9) Time: F 4,272 =1.5, p= min 11 (17) 8 (7) 10 (14) 6 (10) Interaction: F 4,272 =3.9, p= min 11 (17) 13 (15) 9 (13) 7 (9) * Higher than at baseline and than in control group after Cit at the same time-point, p< observed in the changes of other VAS-rated symptoms and, therefore, these data are omitted from the Table. The heart rate and arterial blood pressure were not significantly influenced by Cit in either group. Discussion The results of this study show that cortisol and prolactin responses to Cit challenge in patients with SAD were not substantially different from the response in healthy controls. This may indicate a normal responsiveness of 5-HT mechanisms that mediate the neuroendocrine activation resulting from the enhancement of 5-HT transmission by acute and selective blockade of the 5-HT reuptake. Previously, an augmented cortisol release was observed in patients with SAD in two 5-HT challenge studies. Tancer et al. ( ) first described an increased release of cortisol after challenge with 5-HT releaser/reuptake inhibitor fenfluramine. Subsequently, Hollander et al. (1998) demonstrated an enhanced cortisol response to a partial 5-HT receptor agonist m-cpp in female patients with SAD. Similarly to our results with Cit, the prolactin response in these studies was normal while a recent study has demonstrated a stimulation of prolactin release with the 5-HT 1A partial agonist buspirone (Condren et al., 2002). Several explanations for the discrepancies between the results with Cit and other challenge agents could be considered. As reviewed by Raap and Van de Kar (1999), SSRIs produce a weaker neuroendocrine response than 5-HT releasers such as fenfluramine or direct post-synaptic agonists, such as m-cpp. This may be due to the activating effects of 5-HT reuptake blockade on the somatodendritic 5-HT 1A autoreceptors in the raphe resulting in the inhibition of the 5-HT firing rate and the consequent offset of the release of 5-HT and its post-synaptic effects in the hypothalamus. Therefore, the extent of Citinduced neuroendocrine activation in our study may have not been sufficient to reveal the alterations in the sensitivity of post-synaptic 5-HT receptors. It should also be taken into account that the effect of an SSRI depends on the synaptic availability of 5-HT that may be decreased in anxiety disorders. For instance, a recent positron emission tomography study in patients with SAD demonstrated a suppressed 5-HT synthesis rate in the anxiety-related brain regions indexed by a lowered uptake derived from the labelled 5-HT precursor 5-hydroxytryptophan (Marteinsdottir et al., 2001). Thus, acute administration of a SSRI may have a weaker 5-HT-enhancing effect under the conditions of a low synaptic supply of 5-HT and, therefore, less robust neuroendocrine effects. It would be of interest to investigate the Cit-induced neuroendocrine activation in panic disorder, where the post-synaptic hypersensitivity of 5-HT receptors has been more consistently demonstrated in neuroendocrine challenge studies (Kahn et al., 1988; Targum, 1990) as well as in other anxiety disorders. The behavioural data of our study show that patients were more anxious during the challenge procedures without apparent augmentation of the anxiety response with Cit. Interestingly, among the somatic symptoms after Cit only headache was reported more in patients than in controls peaking simultaneously with the increased levels of hormones. Headache is

5 a well-known side-effect of serotonergic medications. The specific mechanism responsible for SSRI-induced headache is not clear and it is usually attributed to the agonistic effects on the post-synaptic 5-HT receptors. The increased headache response in patients with SAD may, therefore, indicate hypersensitivity of the serotonergic pathways related to some subtypes of 5-HT 2 or 5-HT 3 receptors. Recent studies in depression have proved that Cit has a sufficient sensitivity to detect a decrease in the sensitivity of post-synaptic 5-HT receptors. Kapitany et al. (1999) have demonstrated that in comparison to healthy controls patients with major depression displayed a blunted prolactin response after the intravenous infusion of 20 mg Cit. Further, Bhagwagar et al. (2002) using a dose of 10 mg Cit demonstrated that both cortisol and prolactin response to Cit were blunted in acutely depressed patients, but only prolactin in recovered subjects. Absence of blunted neuroendocrine responses in our study underscores the dissimilarities in the 5-HT function in depression and SAD. The dose and route of administration are obviously important in the use of Cit challenge. Recently use of oral challenge with 20 mg Cit has been evaluated in healthy volunteers (Henning and Netter, 2002). The results demonstrated less robust neuroendocrine activation in comparison to the intravenous challenge. The oral challenge with Cit may, however, be practical and the possible usefulness of escitalopram instead of Cit should be evaluated in further studies. Several limitations of this study must be addressed. First, a relatively small sample size may have prevented detection of more subtle differences in the responses to Cit. Further, the neuroendocrine variables are susceptible to various confounding factors, such as season, time of the day, preceding diet and anticipatory anxiety that could not be fully controlled in this study. In addition, most of the patients in our study were in the low-to-moderate range of the severity of symptoms according to the LSAS total scores at inclusion. Therefore, we cannot exclude the possibility of different results in more severely ill patients. According to the recent study of Attenburrow et al. (2001) Cit in the dose range of 5 10 mg may be sufficient to elicit neuroendocrine activation. Thus, use of a lowdose Cit test or establishing a dose response curve might have been more appropriate to reveal an increased serotonergic sensitivity. Finally, we did not use additional exposure methods to specifically increase social anxiety during the challenge that could have enhanced the sensitivity of this study. In conclusion, the results of this study suggest that patients with SAD have a comparable extent of neuroendocrine activation after Cit challenge compared to healthy controls. This may indicate lack of major alternations in the sensitivity of the 5-HT receptors in SAD; however, the mechanism of 5-HT reuptake blockade may be not sufficient to reveal more subtle alterations in the function of 5-HT receptors. An increased headache response to Cit in patients may indicate that at least some subtypes of post-synaptic 5-HT receptors may still be hypersensitive in SAD. Acknowledgements This work was supported by Estonian Scientific Foundation grant no (J. S.), Estonian Ministry of Education target funding no (V. V.) and a research award from Lundbeck Eesti AS (J. S.). The citalopram solution was by courtesy of H. Lundbeck A/S (Copenhagen, Denmark). We thank study nurses Janika Pael, Merle Taevik and Moonika Soots for their valuable assistance. Statement of Interest None. Citalopram challenge in social anxiety disorder 181 References Attenburrow M-J, Mitter PR, Whale R, Terao T, Cowen PJ (2001). Low-dose citalopram as a 5-HT neuroendocrine probe. 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