Psychosomatics 45:29-33, February 2004
© 2004 The Academy of Psychosomatic Medicine
Plasma Levels of Citalopram in Depressed Patients With Hepatitis C
Ondria C. Gleason, M.D.,
William R. Yates, M.D.,
Michelle A. Philipsen, B.A.,
M. Daniel Isbell, B.S., and
Bruce G. Pollock, M.D., Ph.D.
Received Aug. 23, 2002; revision received March 27, 2003; accepted April 15, 2003. From the Department of Psychiatry, University of Oklahoma College of Medicine—Tulsa; the University of Oklahoma College of Medicine, Oklahoma City; and the University of Pittsburgh, Western Psychiatric Institute and Clinic, Pittsburgh. Address reprint requests to Dr. Gleason, Department of Psychiatry, University of Oklahoma—Tulsa, 4502 E. 41st St., Tulsa, OK 74135-2512; ondria-gleason{at}ouhsc.edu (e-mail).
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ABSTRACT
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Hepatitis C affects an estimated 4 million Americans and 100 million people worldwide. Rates of depression are higher than that seen in the general population. Antidepressant therapy is often initiated at lower doses in patients with liver disease because of concerns about impaired metabolism and clearance. This study assessed plasma levels of citalopram in 15 subjects with hepatitis C and major depression during an 8-week trial. The mean citalopram dose at study completion was 26.67 mg/day. Mean plasma levels of citalopram, compared with levels previously reported, were lower than expected (at 10 mg/day [N=1]: 21 ng/ml [N=1]; at 20 mg/day [N=8]: mean=42.25 ng/ml, SD=18.38; at 30 mg/day [N=1]: 54 ng/ml; at 40 mg/day [N=5]: mean=76.2 ng/ml, SD=35.86). There was a tendency for lower plasma levels to be found in those subjects receiving interferon, although a statistically significant difference was not observed. Citalopram was well tolerated. The results of this study suggest that patients with major depression and hepatitis C, but without evidence of severe liver disease, may be able to tolerate usual recommended doses of citalopram, thus avoiding the potential for undertreatment of the depression.
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INTRODUCTION
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Hepatitis C affects an estimated 4 million Americans and an estimated 100 million people worldwide.1 Although the rates of depression among patients with hepatitis C have not been well established, depression appears to be more common in this group compared with the general population. Studies examining the prevalence of depression in patients with hepatitis C have found rates ranging from 22% to 28%,2–5 considerably higher than the 12.5% lifetime prevalence reported in the general population.6 Furthermore, interferon  , an approved treatment for hepatitis C, is known to induce psychiatric side effects, including depression and suicidal ideation,7–9 and depression is one of the most common reasons for discontinuation of interferon therapy. Management of depression is of critical importance in the treatment of patients with hepatitis C.
Liver disease can result in impaired drug metabolism and alterations in protein binding of drugs. These changes may result in alterations in plasma drug levels, which have the potential to increase the incidence of adverse effects and potentially dangerous drug-drug interactions. This study assessed the plasma levels of citalopram in subjects with concomitant hepatitis C and major depression during 8 weeks of treatment with citalopram. The hypothesis of the study was that citalopram blood levels would be higher in our patient group. Citalopram was chosen because of its favorable side effect profile, linear pharmacokinetics, and its limited interaction with cytochrome P450 enzymes. The objectives of the study were to 1) compare plasma levels of citalopram in subjects with hepatitis C with previously reported levels in subjects without hepatic disease, 2) estimate the antidepressant response rate, and 3) examine the effect of citalopram on quality of life measures and markers of hepatic function. The study group's clinical response to citalopram, with regard to improvements seen in Hamilton Depression Rating Scale scores and measures of quality of life, have been described in detail elsewhere.10
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METHOD
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Adult subjects between the ages of 18 and 65 with hepatitis C and major depression were recruited by advertisement and referred from local physicians. Subjects were instructed to call for a phone screen to determine eligibility. Subjects gave their written consent to participate after procedures and possible side effects were explained to them. The presence of major depressive disorder was confirmed with the Structured Clinical Interview for DSM-IV Axis I Disorders.11 Exclusion criteria were ongoing antidepressant or anxiolytic therapy, use of herbals for behavioral effects, evidence of cirrhosis (Child-Pugh stages B or C), evidence of liver failure, liver enzyme elevations greater than 2.5 times the upper limit of normal, evidence of cognitive impairment (demonstrated by scores of less than 23 on the Folstein Mini-Mental Status Examination12 or times on the Trails A and B tests indicating pathology), and active alcohol or substance abuse.
Subjects who met eligibility requirements were administered the Hamilton Depression Rating Scale,13 the Medical Outcomes Study 36-Item Short-Form Health Survey,14 and the SCL-90-R.15 Clinical Global Impression16 ratings were obtained, subjects underwent a physical examination, and blood samples were drawn to assess liver function.
Subjects were phoned within 2–3 days to inform them of the results of the laboratory studies. Subjects who met criteria for major depression and had acceptable laboratory values were instructed to begin a regimen of oral citalopram, 20 mg every morning. A telephone visit was done at 2 weeks to evaluate patient tolerability of the drug. Subjects returned to the clinic at weeks 4 and 8 for reassessment. Doses of citalopram were increased after week 4 for subjects not demonstrating adequate clinical response. One subject's dose was increased to 30 mg, and the doses of five subjects were increased to 40 mg. One subject's dose was decreased to 10 mg at week 4 because of sedation.
Drug compliance was assessed at each study visit. All subjects were at steady-state at the time of sample collection. Blood for plasma citalopram levels was collected at weeks 4 and 8. Blood was collected in a heparinized tube, centrifuged, and stored in a freezer until all subjects had completed the study. The samples were then sent by courier for analysis to the Psychopharmacology Lab at the Western Psychiatric Institute and Clinic at the University of Pittsburgh. The plasma levels for citalopram were analyzed by high-performance liquid chromatographic technique with a limit quantification of 5 ng/ml by ultraviolet detection.
Statistical analysis involved the calculation of correlation coefficients to compare relationships between two continuous variables. Student's t tests were calculated to compare the difference between two continuous variables. To compare our results for citalopram plasma levels with previously published samples, 95% confidence intervals for the means were calculated. Two means can be considered statistically different when the upper confidence interval of one mean is less than the lower confidence interval of the second mean. For all analyses, a p value of 0.05 or less was selected to designate statistical significance.
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RESULTS
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Study Group
Eighteen subjects entered the study and were started on regimens of citalopram. Three subjects were dropped before the second study visit because of noncompliance, patient choice, or being lost to follow-up, leaving 15 subjects in the study group (10 men and five women). Two subjects were lost after week 4, but data collected at week 4 was included in the statistical analysis by using the last-observation-carried-forward method. One subject presented for the final visit at week 8 but had discontinued citalopram at week 7 because of anorgasmia.
The mean age of the study group was 42.6 years (SD=6.4). Eight subjects had received interferon therapy at some time in their life, including three who were receiving interferon therapy at the time of enrollment and who continued receiving interferon during the course of the study. The other seven subjects had never been treated with interferon. Diagnoses of comorbid alcohol and drug abuse were common. Eleven subjects (73.3%) met diagnostic criteria for lifetime alcohol abuse at some time, and nine (60%) met criteria for abuse of another substance. No subject met diagnostic criteria for active alcohol or substance abuse because of study exclusion criteria. Albumin levels were within normal limits for all subjects.
Plasma Citalopram Levels
At the end of the study, eight subjects were receiving 20 mg/day of citalopram, five subjects were receiving 40 mg/day, one subject was receiving 10 mg/day, and one subject was receiving 30 mg/day. This resulted in a mean daily dose of 26.67 mg. All subjects were at steady-state at the time of the plasma level blood draws at weeks 4 and 8.
Mean plasma levels of citalopram and its metabolites are listed in Table 1. To compare our results with those previously published,17,18 95% confidence intervals for the means of our levels and those from published samples were calculated. We anticipated that our subjects with liver disease would have elevated mean plasma levels, similar to findings in geriatric patients, because of impaired metabolism and clearance. However, this was not observed when we compared our findings to the sample of Pollock et al.17 and found the differences to be statistically different. Conversely, we found no statistically significant difference between our findings and those of Montgomery et al.18
There was a correlation between citalopram plasma levels and daily citalopram dose values (r=0.61, df=13, p<0.02). This finding is consistent with citalopram's known linear pharmacokinetics. No correlation was observed between the change in Hamilton Depression Rating Scale Scores and plasma blood levels (r=–0.26, df=13, p<0.35), consistent with previous findings.18
Three subjects were receiving interferon during the study. All subjects on regimens of interferon received 20 mg/day of citalopram. This did not differ significantly from the average daily dose of those who did not receive interferon (mean=28.3 mg/day, SD=11.1) (t=1.26, df=13, p=0.23). However, there was a tendency for lower plasma levels to be found in the three subjects receiving interferon (mean=31.7 ng/ml, SD=17.5) than in subjects who were not (mean=56.5 ng/ml, SD=33.3), although this difference was not statistically significant (t=1.23, df=13, p<0.25).
Drug Tolerability
Overall, subjects tolerated the citalopram well. Of the 18 subjects who were initially enrolled in the study and started receiving study medication, one dropped out of the study because of sexual dysfunction. No other subjects ceased to participate because of adverse effects from the study medication.
The most commonly reported adverse effect was gastrointestinal dysfunction (Table 2). Five of these subjects complained of nausea, one reported constipation, and another reported diarrhea. Sexual dysfunction was reported in seven subjects; six of these subjects were male. Four of the male subjects complained of anorgasmia, one reported delayed ejaculation, and the other complaint was not further specified. The female subject complained of decreased libido.
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TABLE 2. Adverse Drug Reactions Reported by Patients With Hepatitis C (N=18) Receiving Citalopram for Treatment of Major Depression
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DISCUSSION
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Previous studies have shown increases in the half-life of citalopram in subjects with liver disease.19 On the basis of that observation, one might also expect elevations in plasma concentrations in subjects with liver disease. However, this was not observed in this study, where subjects demonstrated mean plasma levels of citalopram comparable to mean citalopram plasma levels in healthy adults.
General recommendations for antidepressant therapy in patients with liver disease include initiating the drug at lower than the usual recommended starting dose. This recommendation is in anticipation of impaired metabolism and clearance resulting in elevated plasma levels that may increase the patient's exposure to potential adverse effects. The results of this study suggest that patients with hepatitis C but without evidence of severe liver disease (defined as Child-Pugh stages B or C and elevated liver enzymes greater that 2.5 times the upper limit of normal) may be able to tolerate the usual recommended doses of citalopram. Thus, the clinician may avoid the potential for undertreatment of the patient's depression, an important condition to be managed in this population in which rates of depression are higher than that seen in the general population.
Limitations of this study include the lack of a placebo control group and a relatively small study group size. The study population is also not entirely representative of all patients with hepatitis C, since patients who had cirrhosis or evidence of severe liver disease were excluded from study participation. Plasma concentrations of citalopram reported were total drug concentrations, including both the free and bound drug. Patients with liver disease may have decreased levels of plasma proteins that can result in apparently low total drug concentrations. Further studies, preferably measuring free-drug levels, are needed to clarify the results observed in this study.
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ACKNOWLEDGMENTS
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Supported in part by a research grant from Forest Laboratories, Inc.
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REFERENCES
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- Alter MJ: Epidemiology of hepatitis C. Hepatology 1997; 26(3, suppl 1):62S-65S
- Kraus MR, Schäfer A, Csef H, Scheurlen M, Faller H: Emotional state, coping styles, and somatic variables in patients with chronic hepatitis C. Psychosomatics 2000; 41:377–384[Abstract/Free Full Text]
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M R Kraus, A Schafer, K Schottker, C Keicher, B Weissbrich, I Hofbauer, and M Scheurlen
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April 1, 2008;
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W. R. Yates
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ABSTRACT
INTRODUCTION
