|DR.AK KALA AWARD PAPER
|Year : 2019 | Volume
| Issue : 1 | Page : 15-22
Comparison of efficacy and tolerability of escitalopram and venlafaxine in treatment-naïve patients with unipolar nonpsychotic depression: Is there a need to revisit the prescription patterns?
Harneet Kaur1, Ajeet Sidana2, Thiyam Kiran Singh3
1 Department of Psychiatry, Lady Hardinge Medical College, New Delhi, India
2 Department of Psychiatry, Government Medical College and Hospital, Chandigarh, India
3 Department of Psychology, Government Medical College and Hospital, Chandigarh, India
|Date of Web Publication||4-Jun-2020|
Department of Psychiatry, Lady Hardinge Medical College, New Delhi
Source of Support: None, Conflict of Interest: None
Background: Depression is a common mental illness for which guidelines recommend selective serotonin reuptake inhibitors as the first-line treatment. As per the Sequenced Treatment Alternatives to Relieve Depression trial, the first antidepressant needs to be chosen carefully so that the number of treatment changes and therefore treatment resistance can be reduced. This study compared the efficacy and tolerability of escitalopram and venlafaxine, in treatment-naïve patients with first-episode, nonpsychotic unipolar depression. Methodology: In this prospective, randomized, open-label study, 77 patients with the International Classification of Disease-10 Diagnostic Criteria for Research diagnosis of depression were inducted and randomly assigned using a computer-generated random table to receive either escitalopram (10–20 mg/day) or venlafaxine (75–225 mg/day) in therapeutic range for a period of 12 weeks. The assessments included the Hamilton Depression Rating Scale (HDRS) and physical investigations at baseline and weeks 2, 6, and 12. A total of 60 patients completed the study and were included in the final analysis. Results: Thirty patients in each group (n = 60) enrolled with comparable baseline assessment except significantly higher HDRS in the venlafaxine group (29.87 ± 10.58) compared to escitalopram group (21.80 ± 4.41). At 12 weeks, the reduction in HDRS was significantly early and higher in the venlafaxine group (26.3 ± 9.7) than the escitalopram group (21.3 ± 4.2). Common adverse effects in the venlafaxine group included Gastrointestinal (GI) activation and vivid dreams which were seen till 2 weeks; the escitalopram group included sexual dysfunction which lasted till the end of the study. Conclusions: Both the molecules lead to significant reduction in HDRS scores across assessment. However, venlafaxine demonstrated superior efficacy and transient adverse effects compared to escitalopram, despite having higher HDRS scores at baseline. The results of the current study indicate that serotonin–norepinephrine reuptake inhibitors such as venlafaxine should be prescribed more often in routine clinical practice.
Keywords: Depression, escitalopram, venlafaxine
|How to cite this article:|
Kaur H, Sidana A, Singh TK. Comparison of efficacy and tolerability of escitalopram and venlafaxine in treatment-naïve patients with unipolar nonpsychotic depression: Is there a need to revisit the prescription patterns?. J Mental Health Hum Behav 2019;24:15-22
|How to cite this URL:|
Kaur H, Sidana A, Singh TK. Comparison of efficacy and tolerability of escitalopram and venlafaxine in treatment-naïve patients with unipolar nonpsychotic depression: Is there a need to revisit the prescription patterns?. J Mental Health Hum Behav [serial online] 2019 [cited 2023 Feb 3];24:15-22. Available from: https://www.jmhhb.org/text.asp?2019/24/1/15/285989
| Introduction|| |
Depression is a mental illness with a massive socioeconomic impact. Moreover, the WHO estimates globally 350 million people of all ages suffering from it. The prevalence of major depressive disorder (MDD) in India ranges from 1.7 to 74 per thousand population., Therefore, to reduce the burden of depression, treatment that trims down hospitalization and potentially facilitates patients to return to active employment is needed. As per guidelines, selective serotonin reuptake inhibitors (SSRIs) are usually recommended as the first-line antidepressant. Still, up to 30%–50% of depressed patients have shown an inadequate response to the first antidepressant therapy. MDD has a high probability of recurrence; in addition, incomplete recovery from an index episode increases the risk of chronicity and recurrence, with 20% spending their remaining life in a depressive episode. Around 30% of such patients will experience further episodes of depression within 2 years of diagnosis and treatment with cumulative probability of recurrence of 13% after the first 6 months and 87% in 15 years.,
Numerous factors influence choosing antidepressant therapy. Recent findings suggest that psychiatrists choose antidepressants with more tolerable side effects and better treatment efficacy. This usually depends on the patient's preference, past experiences, previous response, and any concurrent medical comorbidity or drug therapy. The SSRIs are recommended first line because of their improved safety profile and better tolerability.,
However, the chance of remission of symptoms reduces significantly following a failure to respond to the initial antidepressant. Medication trial should be continued if there is even a modest (20%) reduction in symptoms at 6 weeks; hence, longer trials of pharmacotherapy are warranted. Venlafaxine, a serotonin–norepinephrine reuptake inhibitor (SNRI), was approved in 1994 and escitalopram, an SSRI, was approved in 2009 by the US Food and Drug Administration. The emergence of SSRIs and SNRIs has improved the treatment outcome in MDD but with lack of clarity regarding which antidepressant is better.
In India, the IPS multicentric study in 2013 evaluated the prescription pattern for antidepressants, and escitalopram was the most commonly prescribed antidepressant, comprising 40% of the total prescriptions. Overall, SSRIs formed 79.2% of all the prescriptions. SNRIs (venlafaxine, desvenlafaxine, and duloxetine) were prescribed to 11.3% of patients with equal share of venlafaxine and duloxetine. It was concluded that escitalopram is the most commonly prescribed antidepressant and SSRIs are the most commonly prescribed class of antidepressants.
It is evident that among SSRIs, escitalopram is the most commonly used, and among SNRIs, venlafaxine is the most used antidepressant. Although there are comparative studies of SSRIs and SNRIs, there is no head-to-head comparison of the two most commonly prescribed antidepressants (as per the IPS multicentric study), in India till date, to the best of our knowledge. The evidence present in the literature encompasses Western data largely and has certain methodological limitations such as shorter duration of the trial (≤8 weeks), more frequent comparison with fluoxetine (among SSRIs), and recruiting the treatment-resistant cases, so any overlap of the multiple medications used cannot be ruled out.,,,,,,,
Hence, the current study was planned to see the efficacy and tolerability of the two most commonly prescribed antidepressants, i.e., escitalopram and venlafaxine in unipolar nonpsychotic depression.
| Methodology|| |
Patients were inducted from those attending the outpatient clinic of the tertiary care teaching hospital of North India. The sample consisted of 77 consecutive patients with a diagnosis of nonpsychotic unipolar depression according to the International Classification of Disease-10 Diagnostic Criteria for Research. Patients were in the age group of 18–55 years of either gender, had given consent, and accompanied with reliable informant were included in the study. Patients with bipolar depression and recurrent depressive disorder, severe depressive episode with psychotic symptoms, comorbid substance-related disorders except nicotine and caffeine, and subnormal intelligence; pregnant and lactating patients; patients with any history of medical, surgical, or neurological complication/cognitive impairment or any other condition in which these medications are contraindicated; and actively suicidal patients were excluded from the study.
These patients were allotted to two different groups as per computer-generated random table. Group A received venlafaxine and Group B received escitalopram.
This was a comparative, open-label, prospective study with intent to treat analysis. After approval from the ethics committee, sociodemographic details and clinical details including treatment were recorded in the semi-structured pro forma, available in the department of psychiatry of the tertiary care teaching hospital of North India.
Patients were administered the Hamilton Depression Rating Scale (HDRS) at baseline and at weeks 2, 6, and 12. Other physical investigations – body mass index, lipid profile, random blood sugar (RBS), electrocardiogram (QT interval), hemogram, blood pressure (BP), thyroid profile, and cortisol levels – were also done at baseline and at the end of 12 weeks. A side effect checklist (nervousness, dry mouth, nausea, vomiting, restlessness, loss of libido, sexual dysfunction, any other/nightmares reported by venlafaxine group) was prepared and administered from time to time to record the side effects of two molecules. The patients were randomized into the escitalopram and venlafaxine groups as per computer-generated random table number. Patients were prescribed escitalopram in the dose of 10–20 mg/day and venlafaxine in the dose of 75–225 mg/day. The initial dose of escitalopram and venlafaxine was 10 mg and 75 mg, respectively. However, in patients who could not tolerate the starting dose, it was reduced to 5 mg and 37.5, respectively, and increased gradually, depending on the clinical improvement, and did reach 10 mg and 75 mg of escitalopram and venlafaxine, respectively, at the end of 2 weeks. In patients who showed inadequate (less than 50% reduction HDRS) response by the end of 2 weeks, dosages of respective molecule were increased gradually to maximum therapeutic level and was then observed for next 4 weeks. Patients who showed inadequate (<50% reduction HDRS) response at the end of 6 weeks were then dropped from the study and were treated as per standard protocol in the department. These patients were included in final analysis as nonresponder. Concomitant medications such as benzodiazepines (clonazepam) for sleep disturbances and beta-blockers for somatic anxiety were permitted, wherever required, and dosages of these medications were documented in both the groups. It was ensured that these concomitant medications were stopped well before the assessment at 6 weeks to minimize the effects of these medications on anxiety symptoms. To ensure compliance, escitalopram was dispensed from the hospital dispensary free of cost and venlafaxine was arranged by the investigator. The patients were asked to bring the empty strips of medication on follow-up visits. All the investigations were carried out at hospital free of cost. The various side effects of these medications were noted on the adverse event checklist prepared by the department of psychiatry and were properly documented in patients' record file. The trial was registered with Clinical Trials Registry-India (CTRI) (CTRI/2017/11/010347).
Data were analyzed using SPSS 17 (SPSS Inc., Chicago, IL, USA). Chi-square test was used for qualitative data, Student's t-test for comparing individual assessments, and repeated measures ANOVA and MANOVA for quantitative data. Significance level was P < 0.5.
| Results and Observations|| |
Seventy-seven patients were recruited in the current study. Of these, only sixty patients were able to complete a 12-week follow-up. In the current analysis, we included the sixty patients (thirty patients in each group) who were able to complete all the four assessments [Figure 1].
The mean age of the whole sample was 35.07 ± 11.7 years. Majority of the patients were male (66.7%), from rural background (63.3%), below matriculate (66.7%), and married (83.3%) in the escitalopram group as compared to higher proportion of females (76.7%), from urban background (63.3%), above matriculate (70%), and unmarried (43.3%) in the venlafaxine group. The groups were comparable with regard to other sociodemographic characteristics.
There was no statistically significant difference between the two groups with regard to biochemical profile except RBS (mg/dl) which was found to be 119 (14.45) in the escitalopram group and 109.5 (17.98) in the venlafaxine group [Table 1].
|Table 1: Comparison of biochemical profile at baseline and at the end of the study|
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A significant difference emerged on baseline HDRS score with mean score at baseline in the escitalopram group being 21.80 (4.405) and 29.87 (10.576) in the venlafaxine group. The total duration of illness was comparable.
Escitalopram was used in the range of 10–20 mg, mean dose being 15.16 mg.
Venlafaxine was used in the range of 75–225 mg, mean dose being 146.25 mg.
Benzodiazepine (clonazepam) was used in 63.3% of patients in the escitalopram group and 86.7% in the venlafaxine group. The average dose of clonazepam was 0.76 mg/day in the escitalopram group and 0.78 mg/day in the venlafaxine group. Chi-square analysis showed a significant difference in the use of benzodiazepine; it was required more in the venlafaxine group.
[Table 2] shows that HDRS score was significantly higher in the venlafaxine group than the escitalopram group at the baseline and the follow-up assessments over 12 weeks.
|Table 2: Effect of escitalopram and venlafaxine across each assessment on the Hamilton Depression Rating Scale|
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Both the molecules lead to reduction in HDRS score, and hence, improvement within the escitalopram and venlafaxine groups was statistically significant at every assessment [Table 3].
|Table 3: Effect of escitalopram and venlafaxine within the group assessments on the Hamilton Depression Rating Scale|
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The difference in reduction of HDRS score was statistically significant in both the groups after the first 2 weeks, mean reduction being 11.53 points in the venlafaxine group and 8.13 points in the escitalopram group. At the end of 6 weeks, the reduction in scores was comparable, whereas the reduction at the end of 12 weeks was significantly higher in the venlafaxine group than the escitalopram group [Table 4].
|Table 4: Cumulative reduction in the Hamilton Depression Rating Scale across the two groups|
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Both the escitalopram and venlafaxine groups were comparable in sociodemographic profile; however, it was observed that nonworking females comprised a higher proportion in responder subgroup in the venlafaxine group. The responders and nonresponders in the escitalopram and venlafaxine groups were comparable with respect to the clinical variables such as age, total duration of illness, and HDRS at baseline.
[Table 1] shows that all the biochemical parameters were comparable in both the groups (including cardiovascular status) at 12-week assessment.
[Table 5] shows the overall comparison of the escitalopram and venlafaxine on the adverse effects revealing common side effects of nausea, vomiting, dry mouth, and nervousness (seen only at 2 weeks) and a significant number of patients subjectively reporting nightmares in the venlafaxine group and erectile dysfunction, restlessness, and loss of libido in the escitalopram group at 12 weeks. Sexual dysfunction was seen in only two patients in the venlafaxine group.
|Table 5: Comparison of both the groups on adverse effects at 2 weeks and 12 weeks (only significant variation depicted in the table)|
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| Discussion|| |
The present study was conducted to evaluate the comparative efficacy and tolerability of escitalopram and venlafaxine during the first episode of nonpsychotic unipolar depression in treatment-naïve patients.
It was seen that the mean HDRS score was significantly higher indicating higher severity of depression in the venlafaxine group (29.87 ± 10.58) than the escitalopram group (21.80 ± 4.41) at baseline assessment. On comparison with the baseline, it can be concluded that there was a significant improvement within the groups at each follow-up visit. The overall improvement, when compared from the baseline to the end of the study, was higher in the venlafaxine group, thus proving that the response was early and higher in the venlafaxine group.
The analysis of cumulative reduction in the HDRS score across the two groups revealed that there was a significant difference in the rate of improvement in the first 2 weeks of the treatment, venlafaxine having a higher improvement in the severe depression. The improvement was comparable at week 6, with week 12 showing a higher improvement in the venlafaxine group than the escitalopram group.
Our finding that venlafaxine was significantly more effective than escitalopram (a SSRI) in improving depression, perhaps due to enhancing both serotonin and norepinephrine, is in favor of the current evidence present in the form of meta-analyses,,, and randomized controlled trials.,,, In our study, we have tried to cover the limitations such as shorter duration of the trial, comparison with most commonly prescribed SSRI, and enrolling treatment-naïve patients so that there is no treatment overlap.
As per the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial, the duration of adequate trial has not been well defined in the literature, but the traditional time frame of 4–6 weeks may not be most appropriate for many patients, as a substantial number who do not respond in the said time period may achieve remission at week 12. As the previously conducted study designs included duration of 8 weeks; therefore, a 12-week follow-up was included in our study to see the full response with both the molecules.
Reflecting upon the STAR*D trial, over the course of four levels of the treatment, HDRS remission rates were 28% in level 1 and ranged from 18% (sertraline switch) to 30% (buspirone augmentation) in level 2. HDRS remission rates ranged from 12% (mirtazapine switch) to 25% (T3 augmentation) and 7% (tranylcypromine switch) to 14% (venlafaxine XR + mirtazapine switch) in levels 3 and 4, respectively. It is evident that the rate of remission decreases as the number of changes in the treatment proceeds. Given the burden of the MDD (especially in low- and middle-income countries such as India) and the increasing prevalence of depression in both the genders, it is worth paying attention that the number of the treatment changes should be reduced.
Our findings are contrary to the previous studies conducted in comparison of escitalopram with venlafaxine, which either shows a comparable response for the two drugs prescribed in MDD,, or claiming escitalopram to have a higher improvement in depressive symptomatology as compared to venlafaxine,, where the studies which proposed a comparable response in escitalopram and venlafaxine were carried out for short duration;, the finding that escitalopram has higher efficacy was supported by a retrospective study conducted using computerized medical records.
We compared patients taking escitalopram and venlafaxine on the adverse effect checklist prepared by us in the department. Patients in the venlafaxine group reported significantly more nausea, vomiting, dry mouth, and nervousness in the first 2 weeks as compared to patients on the escitalopram group; however, the side effects were negligible after 2 weeks.
On the other hand, the escitalopram group reported restlessness, erectile dysfunction, and loss of libido as the main adverse effects. Erectile dysfunction and loss of libido were experienced by the patients till the end of the study. Sexual functioning is an important aspect of the quality of life. In the literature, some evidence suggests a range of 25%–75% prevalence of sexual dysfunction caused due to SSRI; others suggest that the exact prevalence is not well characterized due to underreporting on the part of the patient due to noncompliance and dropping out of the treatment and factors such as gender bias, lack of sex education, and cultural norms resulting in an underreporting of sexual side effects in general. Therefore, it can be inferred that escitalopram was better tolerated than venlafaxine, but sexual side effects were seen more commonly in the escitalopram group.
Our study findings are in keeping with the results of previous studies which report that escitalopram has a better tolerability profile as compared to venlafaxine.,,,,,,,,,,, It is noteworthy, however, that the evidence available is Western and the reported adverse effects in our checklist for both the molecules, has strengthened the present evidence in the literature, especially in an Indian context. It was seen that sexual dysfunction was negligible with venlafaxine which is in keeping with the evidence present in literature. There are no clinical trials that have taken into account the occurrence of nightmares while assessing the tolerability profile of venlafaxine and explored/reported the data on the same, but the significant reporting of nightmares in our study is in accordance with case reports in the literature that mention venlafaxine as a cause of vivid dreaming in patients receiving the concerned drug. Given that a significant number of patients complained about the nightmares, the same should be kept in mind while prescribing the molecule so that patients can be psychoeducated better and attrition can be minimized. Another important anticipated adverse effect is hypertension which is reported in 2%–6% of the patients, usually at higher dosages. Thase (1998) concluded, in a meta-analysis of 3744 patients, that clinically significant effect on systolic BP occurs only at higher dosages (>300 mg/day), and therefore, concerns about effects on BP should not deter the first-line use of this effective antidepressant. It is noteworthy that in our study, none of the patients developed hypertension and cardiovascular parameters were majorly unaltered.
The IPS multicentric study in 2013 evaluated the prescription pattern for antidepressants by psychiatrists for the treatment of first-episode depression. According to this study, escitalopram was the most commonly prescribed antidepressant, comprising 40% of the total prescriptions. Overall, SSRIs and SNRIs formed 79.2% of all the prescriptions. SNRIs (venlafaxine, desvenlafaxine, and duloxetine) were prescribed to 11.3% of patients with equal share of venlafaxine and duloxetine. This study concluded that escitalopram is the most commonly prescribed antidepressant and SSRIs are the most commonly prescribed class of antidepressants, given the better overall tolerability.
Why venlafaxine is prescribed in a meager manner?
The pattern of prescription is influenced by many factors, and tolerability is an important one. The literature strongly recommends SSRIs as a better-tolerated molecule as compared to SNRIs,,,,,,,,,, such as venlafaxine, but it is important to note that Indian data are lacking. It can be safely said that the anticipated early adverse effects including hypertension affect a clinician's prescription in routine clinical practice. This fear can be correlated with the fear of agranulocytosis with the clozapine also termed as clozaphobia which is mentioned in the literature, but nowadays, clinicians are much more comfortable with this molecule, and it is considered gold standard in the treatment-resistant schizophrenia. Here, the question arises could there be a similarly overlooked phobia toward venlafaxine that is prevailing?
Our study proposes that since the adverse effects associated with venlafaxine were transitory as compared to relatively enduring sexual dysfunction seen with escitalopram, a SSRI; and venlafaxine, an SNRI, provided better and early improvement in the depressive symptomatology, hence it deserves more number of prescriptions than the current prevailing practices.
In the present study, benzodiazepines were used in 19 (63.3%) patients in the escitalopram group and in 26 (86.7%) patients in the venlafaxine group. A significant difference was found in the frequency of prescribing clonazepam but not in the dosage, which was comparable in both the groups. Dropouts were observed more in the venlafaxine group (26.8%) than in the escitalopram group (16.7%) on account of poor tolerability. Combination of SRIs/SNRIs is frequently employed in clinical practice, but there is dearth of controlled research that explores how benzodiazepines and SSRIs/SNRIs may be usefully combined. A very recent cross-sectional study conducted in Brazil suggested that long-term benzodiazepine usage in patients taking antidepressants is seen more in SSRIs as compared to TCAs, but no such comparative study between SSRIs and SNRIs exists in literature till date.
Although the strengths of our study include a prospective design, longer follow-up duration, sound methodology, and stringent inclusion and exclusion criteria, the findings should be construed in the light of certain limitations which include small sample size, Placebo arm could not be included due to ethical considerations, nonblinded study, inability to do intent to treat analysis. Both the groups had differences on various sociodemographic variables, i.e., sex, area, and education; the study included sample of patients with similar race and cultural background; hence, generalization of these results should be done with caution.
| Conclusions|| |
The present study was conducted to evaluate the comparative efficacy and tolerability of escitalopram and venlafaxine during the first episode of nonpsychotic unipolar depression in treatment-naïve patients. Even though HDRS scores were higher in the venlafaxine group at baseline, nonetheless our findings show that venlafaxine was significantly more effective than escitalopram in treating depression and early reduction in HDRS score from baseline, although cumulative percentage of reduction in HDRS score in the escitalopram group was little higher than the venlafaxine group at the end of study when patients in both the groups were almost asymptomatic. Escitalopram had better short-term tolerability as venlafaxine caused adverse effects such as nausea, vomiting, dry mouth, and nervousness. Conversely, in the longer term (i.e., 12 weeks), the venlafaxine group did not show any major adverse effects; however, sexual side effects persist significantly more with escitalopram than with venlafaxine.
This study proposes that venlafaxine, an SNRI, providing better efficacy/remission and reasonable tolerability with transient side effects, should, therefore, be prescribed more often as first-line antidepressant in routine clinical practice. It is noteworthy that by this approach, the number of treatment changes could be reduced in MDD in order to increase chances of remission and therefore reduce treatment resistance. Probably, there is a need for more studies in this area to reconfirm or refute our findings and also revisit the prescription patterns for first-line antidepressant management of moderate-to-severe depression.
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Conflicts of interest
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]