Correspondence : Bum-Hee Yu, MD, PhD, Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Gangnam-gu, Seoul 135-710, Korea
Tel : +82-2-3410-3583, Fax : +82-2-3410-0050, E-mail : bhyu@smc.samsung.co.kr

Introduction

There have been some reports suggesting that panic disorder is associated with an increased risk of cardiovascular disorders.¹ Other studies have reported findings of increased cholesterol levels in patients with panic disorder.^2,3 In addition, patients with panic disorder have been reported to have higher than expected rates of mortality from diseases of the circulatory system.⁴ Currently SSRIs are widely used as a first line agent for panic disorder patients.⁵ Although SSRIs are known to be relatively safe drugs, panic disorder patients tend to have a chronic course,⁶ leading to long term effects on cardiovascular risks of great importance. A recent study reported that there is a possibility of serum cholesterol levels being increased after short-term pharmacotherapy with an SSRI.⁷
The relationship between serotonin and cholesterol is still under debate and largely unknown. In patients with major depressive disorder, high cholesterol levels might attenuate serotonin functions and lead to treatment resistance,⁸ whereas there might be a positive relationship between cholesterol levels and serotonergic functions in subjects who are not depressed.⁹ One study reported that panic patients with low cholesterol levels have a higher suicidal risk, which might be related to serotonin.¹⁰ In another study, an increased possibility of depressed mood, violence and suicide was found after cholesterol-lowering treatment, which may result from increased serotonin transporter activity.¹¹
Citalopram is known to be one of the most selective SSRIs,¹² and cause little drug interactions.¹³ Thus, it has fewer side effects and is considered as a relatively safe antipanic medication. The purpose of this study was to examine whether pharmacotherapy with citalopram has an effect on the cholesterol levels in panic disorder patients.

Methods

This study was a part of a prospective, multi-center, open labeled study involving Korean panic disorder patients, designed to examine the efficacy of citalopram, and its effect on quality of life.¹⁴ Patients were recruited from seven general hospitals in Korea, from November 2003 till December 2004. They were all over 18 years old and were diagnosed as having panic disorder according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria. The patients had no history of taking antidepressants/anxiolytics, or had an appropriate wash-out period of the medications before participating in this study.
Patients were excluded from the study when they had any of the following conditions; 1) a present or past history of any major axis i or ii psychiatric illnesses, 2) any serious medical illnesses, 3) the inability to discontinue current antidepressants/anxiolytics for one week, 4) any secondary anxiety disorders due to medical illnesses or substances, 5) a history of hypersensitivity to citalopram, 6) a high risk of suicide, 7) they were pregnant or breast-feeding women.
Patients with no history of taking antidepressants/anxiolytics regularly took citalopram from day 1, whereas those patients who had previously taken these psychotropic medications underwent a 'wash-out period' of at least one week (two weeks for fluoxetine or MAOIs). All psychotropic medications and propranolol were prohibited during the study period. The doses of citalopram were adjusted based on the clinical judgments of experienced physicians. Non-benzodiazepine sedatives (zolpidem, hydroxyzine) were allowed for the patients with severe insomnia.
The body weight, vital signs and a lipid profile battery including levels of serum total cholesterol, triglyceride, LDL-C, and HDL-C, were checked at baseline and week 24. The patients were repeatedly instructed not to change their eating patterns during the study period.
The clinical severities of panic disorder in the patients were measured using the Acute Panic Inventory (API), Panic Disorder Severity Scale (PDSS), Clinical Global Impression Scale (CGI), and Hamilton's Rating Scale for Anxiety (HAM-A). Hamilton's Rating Scale for Depression (HAM-D) was used to evaluate the depressive symptoms.
We analyzed the differences of body weight, lipid profiles, and psychological measures between baseline and week 24, using paired t-tests.

Results

Among the 73 patients who were recruited for the study, 33 completed the 24 weeks of citalopram treatment, whereas the remaining 40 dropped out prematurely. Four patients dropped out due to early symptom improvement, and 36 patients dropped out without any significant reason. The lipid profiles of twenty one patients (12 men and 9 women) were checked both at baseline and week 24. 
The mean levels of serum total cholesterol, triglyceride, and HDL-C showed no significant changes after treatment. The mean scores of API, PDSS, CGI, HAM-A, and HAM-D all showed a significant improvement after treatment. 
However, the mean levels of LDL-C showed a significant increase after treatment, along with a significant increase in the mean body weight (Table 1).
The levels of serum total cholesterol, triglyceride, HDL-C, and LDL-C were not associated with any of the psychological variables. 

Discussion

After the successful treatment with citalopram in the panic disorder patients, the mean serum LDL-C level was significantly increased, whereas the mean levels of total cholesterol, HDL-C, and triglyceride showed no increase. An increased LDL-C level is known to be a major predictor of cardiovascular diseases.
This finding is partly consistent with previous studies, which reported a significant increase in cholesterol levels in panic disorder patients after treatment with selective serotonin reuptake inhibitors.^7,15 Compared with these previous studies, this is a relatively longer follow-up study and showed a more specific LDL-C increase, rather than increases in general cholesterol levels. Due to the use of citalopram with its highly selective serotonin reuptake inhibition effect, this might be suggestive of a closer relationship between serotonin and serum LDL-C levels. However, the cause of this increase in LDL-C levels after SSRI treatment remains to be confirmed.
There have been reports that psychological stress might be a major risk factor for developing coronary artery disease as well as a high LDL-C level. In animal studies, it was found that acute stress triggers myocardial ischemia, promotes arrhythmogenesis, stimulates platelet function, and increases blood viscosity through hemoconcentration. In the presence of underlying atherosclerosis, acute stress also causes coronary vasoconstriction.¹ Since most patients in this study showed subclinical ranges of LDL-C levels after the treatment, it can be inferred that SSRIs may have more benefits than risks for the treatment of panic disorder.
Although serotonin is known to typically reduce carbohydrate intake,¹⁶ some studies paradoxically reported carbohydrate craving and weight gain after treatment with citalopram in major depressive disorder patients.¹⁷ A 10-year cohort study reported that weight gain had a significant association with increased LDL-C levels in subjects who were not overweight at baseline.¹⁸ Thus, the increased mean LDL-C level after treatment with citalopram might result from weight gain rather than a direct effect of citalopram, although, in another study, 3 months of paroxetine treatment caused increased cholesterol levels without weight gain in panic disorder patients.⁷
This study has some methodological limitations such as a small sample size, and lack of control of diet, body weight and exercise habits, A lack of plasma catecholamines and serum hematocrit levels could also be a limitation of this study, since plasma catecholamine levels could affect serum cholesterol levels, and there was a possibility of hemoconcentration occurring in situations of immediate stress such as panic attacks.¹⁹
Since panic disorder itself may cause a greater cardiovascular risk, citalopram should be used with caution when prescribed to panic patients with overt or covert cardiovascular diseases. Further studies are needed to determine whether increased mean LDL cholesterol level after SSRI treatment is specific to panic disorder, or applicable to other disorders in which SSRIs can be used as a therapeutic agent. In addition, long-term follow up studies might help determine whether SSRI treatments can increase cholesterol levels continuously up to a pathological level.

1. Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and the implications for therapy. Cardiology 1999;99:2192-2217.

2. Hayward C, Tayler CB, Roth WT, King R, Agras WS. Plasma lipid levels in patients with panic disorder or agoraphobia. Am J Psychiatry 1989;146:917-919.

3. Bajwa WK, Asnis GM, Sanderson WC, Irfan A, van Praaq HM. High Cholesterol levels in patients with panic disorder. Am J Psychiatry 1992;149:376-378.

4. Coryell W, Noyes R, House JD. Mortality among outpatients with anxiety disorders. Am J Psychiatry 1986;143:508-510.

5. Nutt D. The role of SSRIs in anxiety disorders. European Neuropsychopharmacology 1995;5:260-261.

6. Rosenbaum JF, Pollack MH, Pollack RA. Clinical issues in the longterm treatment of panic disorder. J Clin Psychiatry 1996;57:44-48.

7. Kim EJ, Yu BH. Increased cholesterol levels after paroxetine treatment in patients with panic disorder. J Clin Psychopharmacol 2005;25:597-599.

8. Fava M, Vuolo RD, Wright EC, Nierenberg AA, Alpert JE, Rosenbaum JF. Fenfluramine challenge in unipolar depression with and without anger attacks. Psychol Res 2000;94:9-18.

9. Terao T, Yoshimura R, Ohmori O, Takano T, Takahashi N, Iwata N, et al. Effect of serum cholesterol levels on meta-chlorophenylpiperazine-evoked neuroendocrine responses in healthy subjects. Biol Psychiatry 1997;41:974-978.

10. Ozer OA, Kutanis R, Agargun MY, Besiroglu L, Bal AC, Selvi Y, et al. Serum lipid levels, suicidality, and panic disorder. Compre Psychiatry 2004;45:95-98.

11. Vevera J, Fisar Z, Kvasnicka T, Zdenek H, Starkova L, Ceska R, et al. Cholesterol-lowering therapy evokes time-limited changes in serotonergic transmission. Psychiatry Res 2005;133:197-203.

12. Hyttel J, Arnt J, Sanchez C. The pharmacology of citalopram. Rev Contemp Pharmacother 1995;6:271-285.

13. Stahl SM. Not so selective serotonin reuptake inhibitors. J Clin Psychiatry 1998;59:343-344.

14. Lee IS, Yang JC, Choi YH, Kim JB, Lee SY, Lee SH, et al. The effect-tiveness of 6-month treatment with Citalopram in Korean panic disorder patients: a prospective, open-labeled, multi-center trial. Korean J Psychopharmacol 2006;17:203-211.

15. Bailey DL, Melledo JM. Effects of selective serotonin reuptake inhibitors on cholesterol levels in patients with panic disorder. J Clin Psychopharmacol 2003;23:317-318.

16. Leibowitz SF. The role of serotonin in eating disorders. Drugs 1990;35(suppl 3):33-48.

17. Bouwer CD, Harvey BH. Phasic craving for carbohydrate observed with citalopram. Int Clin Psychopharmacol 1996;11:272-278.

18. Norman JE, Bild D, Lewis CE, Liu K, Smith West D. The impact of weight change on cardiovascular disease risk factors on young black and white adults: the CARDIA study. International J Obesity 2003;27:369-376.

19. Brindley DN, McCann BS, Niaura R, Stoney CM, Suarez EC. Stress and lipoprotein metabolism. Metabolism 1993;42(9 suppl 1):3-15.