This study showed that approximately one third of the patients who had not responded to treatment with at least 20 mg of citalopram for at least 6 weeks achieved remission (MADRS ≤8) during the 34 weeks of treatment with doses of escitalopram at doses up to 50 mg. A further third did not complete the study for a range of reasons including intolerance of escitalopram. Thus, half of those who did complete the study achieved remission.
Entry to the study was based on a minimum treatment with citalopram for six weeks, but neither dosage regime nor length of treatment was recorded. This and the difference in remission criteria make comparisons with outcomes in other studies such as STAR-D difficult. The patients could not strictly be described as treatment resistant and so comparison with the initial phase patients in STAR-D may be appropriate. In STAR-D, a remission rate of 28% as assessed by HAM-D ≤7 was achieved with a mean citalopram dose of 41.8 mg prescribed by physicians for up to 14 weeks. In this study, 40.8% of patients were in remission (MADRS ≤8) at 16 weeks following an accelerated dosage programme at a mean dose of 41 mg escitalopram.
Factors such as gender, age group and history of anxiety may influence outcome and although none of the associations were statistically significant in this study, these should be investigated in further studies.
Patients who responded at 8 weeks were significantly more likely to achieve remission at the end of the study. Therefore, a response to 20 or 30 mg at 8 weeks of this regime may be a useful predictor for achieving MADRS remission.
Doses up to 40 mg were generally well tolerated by patients in this study, with doses above this less well tolerated. Although 26% of all patients were unable to tolerate doses of 45 to 50 mg, 38% of the 21 patients who achieved remission needed the 50 mg dose.
There were no unexpected safety issues arising from the use of the higher doses of escitalopram in this study and only a small weight gain was observed, which did not appear to be dose related. Further studies are needed to establish the role of dose escalation of escitalopram in the management of patients with MDD who have not responded to conventional treatment with escitalopram.
Limitations of the study were the open nature of the study design, the small number of male patients and the high mean BMI of the study population (30.8), which may have influenced weight changes during treatment. No formal attempt was made to assess compliance during the study. The data have also been presented using OC and BOCF approaches. A last observation carried forward (LOCF) approach was not used to provide data for the 18 patients who discontinued the study. The reasons for this were that 6 patients withdrew after the first visit and had no available efficacy data and 9 patients had large fluctuations in the patterns of MADRS scores (results not shown). An LOCF approach could be justified for the remaining 3 patients who all withdrew after week 8, based on the MADRS pattern, although 2 of these withdrew due to AEs and one was ineligible to continue.
The data obtained from this pilot study might be used for the design of any subsequent clinical development programme. In the sample size calculations for this study, the assumptions of an attrition rate of 10% and a MADRS remission rate of 70% were not met and should be revised in any future trials. The observed attrition rate of 30% was considerably higher than expected, whereas the remission rate of 50% achieved was lower than expected. The high drop-out rate was mainly due to patients discontinuing due to AEs and this was particularly evident in the first two weeks of treatment. Consideration should be given to how the drop-out rate could be limited in future trials, possibly by improving patient awareness of the transient nature of some side effects including worsening of depression/anxiety/low mood on changing to a low dose of another medication.