human psychopharmacology Hum. Psychopharmacol Clin Exp 2007; 22: 477–482. Published online 24 July 2007 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/hup.864
Effectiveness and acceptability of sertraline and citalopram in major depressive disorder: pragmatic randomized open-label comparison Prithpal S. Matreja1, Dinesh K. Badyal1*,y, Prem Khosla1 and Randhir S. Deswal2 1 2
Department of Pharmacology, Christian Medical College and Hospital, Ludhiana, India Department of Psychiatry, Christian Medical College and Hospital, Ludhiana, India
Objective Citalopram and sertraline are widely prescribed selective serotonin reuptake inhibitors (SSRIs). There is no conclusive evidence to show superiority of citalopram or sertraline in terms of efficacy or tolerability. Hence this study was designed to compare short term efficacy and safety of citalopram and sertraline in major depressive disorder (MDD) in Indian patients. Methods In an open, randomized study, 100 patients were divided into two groups. In Group A (n ¼ 50) patients received citalopram (20–60 mg/day) for 6 weeks. In Group B (n ¼ 50) patients received sertraline (50–150 mg/day) for 6 weeks. Patients were evaluated at baseline and then at 1, 2, 3, 4, 5, and 6 weeks. Results There was significant improvement in Hamilton depression rating scale (HDRS), Montgomery and Asberg depression rating scale (MADRS) and Amritsar depressive inventory (ADI) scores ( p < 0.05) with both the drugs. However, the decrease in score was more with citalopram ( p < 0.05). Onset of action of citalopram was earlier as compared to sertraline ( p < 0.05). The number of responders and remitters was also more with citalopram ( p < 0.05). No serious adverse event was reported in either of the groups. Conclusion Citalopram had shown better efficacy, earlier onset of action and more number of responders and remitters as compared to sertraline in MDD in Indian patients. Copyright # 2007 John Wiley & Sons, Ltd. key words — depression; citalopram; sertraline
INTRODUCTION Major depressive disorder (MDD) is currently the fourth leading cause of disease and disability worldwide and is projected to rise to second in 2020. MDD accounts for 4.4% of the total overall global disease burden, a contribution similar to that of ischemic heart disease or diarrheal disease (WHO, 2002). Unfortunately many current therapies for depression provide remission in only approximately one third of patients (Simon et al., 2006). The current modalities of treatment of depression include tricyclic antidepressants (TCAs), monoamine * Correspondence to: Dr D. K. Badyal, Department of Pharmacology, Christian Medical College, Ludhiana-141008, India. Tel: þ91-98153-33776. Fax: þ91161-2609958. E-mail:
[email protected] y (Reader) Associate Professor.
Copyright # 2007 John Wiley & Sons, Ltd.
oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRIs). TCAs are not preferred these days because of their adverse effect profile, that is, anticholinergic effects, cardiac arrhythmias, and seizure precipitation. MAOIs are not preferred due to their dangerous food interactions. SSRIs are presently the most widely used antidepressants because of their better safety profile and tolerability. SSRIs selectively block neuronal transport of serotonin and increase synaptic availability of serotonin (Baldessarini, 2001). Sertraline and citalopram are commonly used SSRIs in treatment of depression. Various studies have reported differences in the efficacy and safety of sertraline and citalopram. Tucker et al. (2003) observed significant improvement in avoidance/ numbing symptoms in sertraline group than as compared to placebo and citalopram. Subjects on sertraline reported more gastrointestinal problems with early terminators having more insomnia. Early Received 7 January 2007 Accepted 13 June 2007
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terminators on citalopram group reported more fatigue and appetite changes than treatment groups with completers reporting more sexual dysfunction (Tucker et al., 2003). Another study demonstrated that SSRIs-related adverse events have a significant impact on the direct cost and cost effectiveness of treatment and showed that citalopram had a lower expected treatment cost and greater effectiveness when compared with sertraline (Sullivan et al., 2004). There is no conclusive evidence to show superiority of citalopram or sertraline in terms of efficacy or tolerability. Hence this study was designed to compare efficacy and safety of citalopram and sertraline in MDD in Indian patients. METHODS Patients We examined the patients during the period from August 2004 to December 2005. Patients suffering from MDD as per DSM-IV criteria were enrolled in the study (American Psychiatric Association, 2000). Those able to satisfy the following inclusion criteria were enrolled as subjects in the study. (1) Patients with HDRS (Hamilton depression rating scale-17 item) score > 18 (MDD) (Hamilton, 1960). (2) All individuals between the ages of 18–75 years. (3) Both males and females. A total of 100 patients were randomized into two groups as per random number table. Written informed consent was obtained form all patients and/or family members responsible for the patient before starting the antidepressant therapy. Institutional review board approval was obtained prior to the study.
Medication In this clinical, prospective, open-label, randomized study, treatment in Group A patients (n ¼ 50) was started with citalopram in the dose range of 20–60 mg/ day. Treatment in Group B patients (n ¼ 50) was started with sertraline in the dose range of 50–150 mg/ day. A fixed dose schedule was followed for each patient. After enrollment patients underwent a thorough clinical examination, including vital signs and systemic examination. Patients were evaluated at baseline and than at 1, 2, 3, 4, 5, and 6 weeks. Both the drugs were given either in single or divided doses. Compliance was checked by pill count method. Record of concomitant medication was maintained throughout the study. Copyright # 2007 John Wiley & Sons, Ltd.
ET AL.
Clinical measurement and safety assessment Changes in the severity of depression were assessed using the HDRS, Montgomery Asberg depression rating scale (MADRS), and Amritsar depressive inventory (ADI) scores (Montgomery and Asberg, 1979; Singh, 1974). HDRS, MADRS, and ADI scores were assessed every week for 6 weeks. Time to onset of action was defined as reduction of 40% or more in the score as compared to baseline (Thase, 2001). Responders were defined as patients who had 50% reduction in their scores as compared to baseline. Remission was defined as HDRS score 7 or MADRS score 12 at the end of 6 weeks (Nierenberg, 2001). In both the groups the vital parameters, that is, pulse, blood pressure, respiratory rate, and weight were monitored at the beginning of the study and at the end of 6 weeks. Secondary efficacy parameter was spontaneously reported adverse events. Statistical methods The data was tabulated as mean standard deviation (SD). The primary statistical analysis was intention to treat (ITT) analysis for all safety and efficacy variables with the last observation being carried forward (LOCF) for those patients who had at least 2 weeks data. Results were analyzed using nonparametric tests (Chi-Square, Friedman two way analyses, KruskalWallis test) and parametric tests (t-test). A p < 0.05 was considered as statistically significant. RESULTS Both citalopram and sertraline were generally well tolerated. All the patients continued the medication till the end of treatment. Table 1 summarizes the demographic and clinical characteristics of patients. The mean age of the patients in both the groups was comparable (39.6 years in Group A vs. 40.6 years in Group B). The patients comprised 22 men and Table 1. Demographic and baseline characteristics of patients in both groups at baseline Characteristics
Group A (citalopram)
Group B (sertraline)
Total number of patients 50 50 Age (years) (mean SD) 39.56 13.21 40.64 12.00 Sex (M:F) 28:22(56%:44%) 17:33(34%:66%) HDRS score (mean SD) 21.5 3.05 20.8 2.72 Duration of illness (months) 4.13 3.12 3.57 2.63 *p < 0.05 as compared to Group A.
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28 women in Group A (citaloparm). In Group B (sertraline) patients comprised 17 men and 33 women. The patient had similar clinical profile at baseline. Similarly, the mean HDRS score of patients (21.5 in Group A vs. 20.84 in Group B) was comparable at baseline. The mean duration of illness was (4.13 months in Group A vs. 3.57 month in Group B) also comparable. The mean dose of citalopram and sertraline used was 33 mg (SD 13) and 96 mg (SD 35) per day, respectively.
Primary efficacy variables
Figure 2. Mean score of MADRS in both the groups
The HDRS, MADRS, and ADI score reduced significantly at each visit as compared to baseline in both the groups. HDRS score (mean SD) at baseline was 21.5 3.05 which reduced significantly to 8.4 3.55 at the end of 6 weeks with citalopram. Similarly, HDRS score reduced significantly from 20.84 2.72 to 9.66 3.98 at the end of 6 weeks with sertraline (Figure 1). The MADRS score (mean SD) decreased significantly from 30.2 6.18 to 11.0 5.47 with citalopram and from 29.1 4.90 to 14 5.96 with sertraline at the end of 6 weeks (Figure 2). The ADI score (mean SD) decreased significantly from 19.1 2.34 to 6.5 2.77 with citalopram and from 19.3 2.20 to 8.2 3.76 with sertraline at the end of 6 weeks (Figure 3). The improvement with citalopram was significantly ( p < 0.05) more as compared to sertraline at 6th week in HDRS score (8.4 3.55 vs. 9.7 3.98), at 4th week (16.6 4.97 vs. 18.7 4.97), 5th week (13.7 5.11 vs. 16.5 5.11), and 6th week (11.0 5.47 vs. 14.0 5.96) in MADRS score and at 5th week (8.9 2.56 vs. 10.1 2.98) and 6th week (6.5 2.77 vs. 8.2 3.76) in ADI score.
Table 2 shows onset of action of citalopram and sertraline. Onset of action of citalopram and sertraline was at 5 weeks in HDRS score, but 4 weeks with citalopram and 5 weeks with sertraline in MADRS and ADI score. The number of responders was more in citalopram group as compared to sertraline group (Table 3). The difference was statistically significant at 5th week (32 vs. 17) and 6th week in HDRS (46 vs. 38). In ADI score also more patients responded at 5th (42 vs. 30) and 6th week (47 vs. 39). Similarly in MADRS score also there were more responders in citalopram group as compared to sertraline group on 4th week (19 vs. 7), 5th week (27 vs. 14), and 6th week (40 vs. 31). The number of remitters in our study was more in Group A as compared to Group B but this was statistically significant only in MADRS score at 6th week (37 vs. 26 Table 3). There was no significant difference in vital parameters at the end of 6 weeks as compared to baseline in both the groups. Neither was there any significant difference between both the
Figure 1. Mean score of HDRS in both the groups
Figure 3. Mean score of ADI in both the groups
Copyright # 2007 John Wiley & Sons, Ltd.
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Table 2. Time to onset of action in both groups Groups HDRS MADRS ADI
Mean base line score
Score after 40% reduction from mean base line score
21.5 20.8 30.2 29.1 19.1 19.3
12.9 12.48 18.12 17.46 11.46 11.58
A B A B A B
Time to reach 40% reduction (score) 5th 5th 4th 5th 4th 5th
week week week week week week
(10.9) (11.5) (16.6) (16.5) (10.9) (10.1)
Group A: citalopram; Group B: sertraline. Time to onset ¼ 40% reduction in score as compared to baseline.
groups. Baseline systolic blood pressure/diastolic blood pressure (SBP/DBP) was 124/88 and 120/ 80 mm of Hg in group 1 and group 2, respectively. The SBP/DBP at the end of treatment was 122/87 and 128/ 82 mm of Hg in group 1 and group 2, respectively.
Adverse events There was no serious adverse event reported in both the groups. These were no adverse event noted in patients in sertraline group. Two patients reported mild adverse events during treatment in citalopram group. Only one patient withdrew from the study that too in the citalopram group due to adverse event. No significant change was observed in ECG in any patient in both the groups. There was no hospitalization because of drugs in any group. No patient was lost to the follow-up.
DISCUSSION There was a significant decrease in the HDRS, MADRS, and ADI score from baseline to each subsequent visit in both the citalopram and sertraline group. The findings in our study are in agreement with the earlier studies which showed that both drugs produced a significant, sustained, and comparable improvement in depressive symptoms and in social functioning (Ekselius et al., 1997; Muijser et al., 2002; Rocca et al., 2005). There was significant improvement in the symptoms of depression and mean score in patients as early as 1–2 weeks in both the groups as per statistical analysis. This is in accordance to previous studies which have shown that significant reduction in both the groups as early as 2 weeks (Ekselius et al., 1997). However, onset of action can also be defined clinically as reduction of 40% in the mean score from baseline (Singh, 1974). Citalopram group showed an earlier onset of action (4 weeks) in MADRS and ADI
Table 3. Number (%) of responders and remitters in both groups Scales
Weeks
HDRS
Responders A B Remitters A B Responders A B Remitters A B Responders A B
MADRS
ADI
1
2
3
4
5
6
0 0
0 0
1 (2) 1 (2)
7 (14) 6 (12)
32a (64) 17 (34)
46a (92) 38 (76)
0 0
0 0
0 0
0 0
1 (2) 0
23 (46) 17 (34)
0 0
0 0
10 (20) 6 (12)
19a (38) 7 (14)
27a (54) 14 (28)
40a (80) 31 (62)
0 0
0 0
0 0
10 (20) 4 (8)
17 (34) 10 (20)
37a (74) 26 (52)
0 0
0 0
0 0
14 (28) 9 (18)
42a (84) 30 (60)
47a (94) 39 (78)
Group A: citalopram; Group B: sertraline. a p < 0.05 as compared to Group B.
Copyright # 2007 John Wiley & Sons, Ltd.
Hum. Psychopharmacol Clin Exp 2007; 22: 477–482. DOI: 10.1002/hup
citalopram and sertraline in depression score as compared to sertraline (5 weeks), whereas both citalopram and sertraline had comparable onset of action in HDRS score (5 weeks). Our findings are in agreement with the studies where significant improvement was observed at an earlier time point in the citalopram group (Sullivan et al., 2004). One study showed that there was no significant difference between the two drugs (Ekselius et al., 1997). This study also compares validity of ADI as compared to HDRS and MADRS. We could not find any other study comparing ADI with other depression scales (Pubmed, 2007). The results generated by ADI are comparable to results generated by HDRS and MADRS. Infact like MADRS, ADI was able to detect difference in onset of action 1 week earlier than HDRS. The percentage decrease in ADI score (66%) with citalopram was comparable to percentage decrease in HDRS (61%) and MADRS (64%) score. The percentage decrease in ADI score(58%) with sertraline was also comparable to percentage decrease in HDRS (54%) and MADRS (52%) score. The number of responders was more in citalopram group as compared to sertraline group. Citalopram had more number of patients responding to treatment than sertraline in most of other studies (Ekselius et al., 1997; Keene et al., 2005; Mullin et al., 2005). The number of remitters in our study was more in Group A as compared to Group B but this was statistically significant only in MADRS score at 6th week. The findings are contradictory to findings of Rocca et al. (2005), but in accordance with other studies in which more patients were benefited with citalopram than with sertraline (Ekselius et al., 1997; Rocca et al., 2005; Vinar et al., 1993). There was no serious adverse event reported in our study in any patient in both the groups. None of the patients in the sertraline group reported any adverse events during the treatment. Two patients reported mild adverse events during the total duration of the study in citalopram group. Of the patients who reported adverse events in citalopram group, one patient had sexual dysfunction which required reduction in the dose of citalopram. The sexual dysfunction was related to ejaculation. Ejaculatory dysfunction is common with citalopram (Ekselius et al., 1997). The other patient reported uneasiness which was severe enough to withdraw citalopram in that patient. Earlier studies have shown withdrawal rate of 15% with SSRIs (Micheal et al., 2002). In our study only one patient discontinued the treatment in the citalopram group (1%). No patient was lost to follow-up. Both the drugs have low incidence of Copyright # 2007 John Wiley & Sons, Ltd.
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adverse events and high safety profile in earlier studies also (American Psychiatric Association, 2000; Sullivan et al., 2004). There was no significant difference in vital parameter in both the groups. One study has shown that patients on citalopram had lower systolic and diastolic blood pressure whereas patients on sertraline group had significantly lower systolic blood pressure only (Tucker et al., 2003). Our findings contradict these findings, as there was no significant difference of blood pressure between the groups. May be over a prolonged period of time there might be a change in blood pressure, which needs to be confirmed by long-term studies. The results of this study should be seen keeping in view the open nature of the study and the fact that placebo control group was not used. We thought that giving placebo to MDD patients will not be ethical. In our study concomitant medication given was comparable in both the groups. Benzodiazepines were the most frequently prescribed adjunctive treatment along with citalopram and sertraline.
CONCLUSION Our study showed that both sertraline and citalopram were effective in reducing symptoms of depression in patients in Indian setup. However, citalopram showed earlier onset of action and was more effective in decreasing mean depression score as compared to sertraline. Number of responders and remitters were also more in citalopram group as compared to sertraline group. Sertraline in our study was found to be slightly safer than citalopram. Long duration studies may help us find out whether the adverse event reported could be present on long-term follow-up. In conclusion citalopram had better efficacy, earlier onset of action, more number of responders and remitters as compared to sertraline in MDD in Indian patients.
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