|DR. AK KALA AWARD PAPER
|Year : 2015 | Volume
| Issue : 2 | Page : 48-54
Pattern of outcome with sertraline, imipramine, and des-venlafaxine in unipolar nonpsychotic depression
Abhishek Kapoor, Rohit Garg, Bir Singh Chavan, Paramleen Kaur
Department of Psychiatry, Government Medical College and Hospital, Chandigarh, India
|Date of Web Publication||20-Jan-2016|
Department of Psychiatry, Government Medical College and Rajindra Hospital, Patiala, Punjab
Source of Support: None, Conflict of Interest: None
Background: There is a scarcity of research on the temporal sequence of improvement with antidepressants and the differential effect of different antidepressants. Aims: To study the temporal sequence of improvement and differential pattern of outcome with antidepressants from different classes. Methods: 132 males and females from 18 to 65 years suffering from the first depressive episode were followed up at baseline, 3 rd day, 7 th day, 10 th day, 14 th day, 21 st day, 1 month, and 3 months using the 17 item Hamilton Rating Scale for Depression. Patients were randomized into three groups namely (1) sertraline (2) des-venlafaxine and (3) imipramine. Appropriate statistical analyses were applied. Results: The pattern of improvement was similar across the groups. The earliest improvement was seen in early insomnia (at day 3) followed by suicidal ideas and psychological anxiety (by day 7). Middle insomnia, late insomnia, and agitation improved by the 14 th day. Depressed mood improved significantly at day 14 th in the sertraline and imipramine groups and day 21 st in the des-venlafaxine group. Work and activities and retardation improved significantly in the sertraline and imipramine groups at 1 month. The last symptoms to improve were general somatic symptoms, genital symptoms, and guilt feeling. Conclusions: It is important to know the temporal sequence of symptomatic improvement with antidepressants as it will guide us to make important management decisions. It also helps to improve compliance as patients can be appropriately guided regarding expected course of treatment.
Keywords: Antidepressants, des-venlafaxine, imipramine, outcome, sertraline, temporal
|How to cite this article:|
Kapoor A, Garg R, Chavan BS, Kaur P. Pattern of outcome with sertraline, imipramine, and des-venlafaxine in unipolar nonpsychotic depression. J Mental Health Hum Behav 2015;20:48-54
|How to cite this URL:|
Kapoor A, Garg R, Chavan BS, Kaur P. Pattern of outcome with sertraline, imipramine, and des-venlafaxine in unipolar nonpsychotic depression. J Mental Health Hum Behav [serial online] 2015 [cited 2020 Feb 16];20:48-54. Available from: http://www.jmhhb.org/text.asp?2015/20/2/48/174590
| Introduction|| |
It was believed for long that antidepressants show the delayed effect and the initial improvement was considered due to placebo.  However, recently multiple studies and meta-analyses have proved that antidepressants start acting within the 1 st week itself and early improvement results in long-term stability. , Another long-held belief is that antidepressants are similar to each other in terms of efficacy, and the onset of action and the choice of antidepressant is determined by the side effect profile and cost of the drug.  However, there might be a difference in the temporal pattern of improvement with antidepressants owing to their variable mechanism of action. 
Response to antidepressants evolves over time. However, response and remission criteria defined by cut-off scores are used as outcome criteria ignoring the time course of symptom change.  These outcome criteria are considered by many as arbitrary and ill-suited to research applications since symptoms of depression lie on a continuum.  Dichotomization and categorization based on an end point score ignore the temporal pattern of change and rely on a single measurement.  The course of change in depressive symptoms that is usually discarded in favor of end point measures may help us understand how and for whom antidepressants work.  However, there is negligible research carried out in this area until date. Meta-analysis of Indian research on depression and antidepressants revealed no study on the topic from India. , From elsewhere, it has been found that sertraline starts improving anxiety symptoms from day 0 to 7, depressive symptoms from 7 to 21 and psychomotor retardation from 21 to 56 day  and somatic symptoms and psychomotor retardation improve late.  Similarly, the only studies carried out to assess the temporal pattern of symptom improvement with antidepressants showed that paroxetine improved anxiety symptoms early followed by depressive symptoms and finally psychomotor retardation while desipramine produced the opposite pattern and nortriptyline produced rapid improvement while escitalopram produced gradual improvement. ,
The aim of this study was to ascertain the temporal pattern of symptom improvement with three different drugs from three different classes namely sertraline (selective serotonin reuptake inhibitors), imipramine (tricyclic antidepressant) and desvenlafaxine (serotonin norepinephrine reuptake inhibitor). Another aim was to study the differential effect of the three drugs on symptoms of depression.
| Materials and Methods|| |
It was an open, randomized, nonblinded, longitudinal, follow-up, flexi-dose study.
Study settings and location
The study was done at the outpatient department (OPD) of a general hospital psychiatric unit of a tertiary care hospital in North India.
The enrolment was done from January to April 2011. Each patient was followed up for 3 months, and the study was concluded in August 2011.
It was a time bound study and the sample size was not predecided. However, it was decided to include at least 45 patients at baseline in each group so that data of at least 30 patients was available for analysis in each group after drop outs.
Patients were randomized into three groups by using computer generated random tables.
The study was conducted at the OPD of a general hospital psychiatry unit in a tertiary care hospital of north India from January to April 2011. 132 consecutive males and females suffering from the first episode of depression as per International Classification of Diseases-10  between 18 and 65 years were enrolled. Each patient was followed up for 3 months, and the study was completed in August 2011. Patients who were treatment naïve, accompanied by a close family member and willing to participate in the study were enrolled. Since there were frequent assessments, special care was taken that patient did not come from a far off place and could come to the OPD for subsequent assessments.
Patients who had a history of bipolar disorder, psychotic symptoms, co-morbid substance dependence except nicotine and caffeine, pregnant and lactating mothers, had a history of hypothyroidism or any other medical condition in which these medications were contraindicated, were excluded. Patients who needed in-patient facility due to suicidal risk were also excluded from the study. All the patients underwent detailed physical examination and biochemical investigations including hemogram, serum electrolyte, renal function test, thyroid function, lipid profile, electrocardiogram, and blood pressure to exclude patients with the co-morbid medical illness. Patients with a family history of bipolar disorder were also excluded. Patients with recurrent depressive disorder and chronic depression were excluded. Patients who had hypersensitivity to the study drugs or poor response to antidepressants in the past were excluded. Patients who required electroconvulsive therapy were excluded.
The confidentiality of the information obtained was maintained and the principles enunciated in the declaration of Helsinki were complied with.  Indian Council of Medical Research guidelines on biomedical research on human subjects were followed.  The study was approved by the ethics committee of the institution on 23 rd April 2010. The trial has been registered with the clinical trial registry India on 01.05.2015 vide registration number CTRI/2015/05/005735.
Treatment protocol (interventions)
Written informed consent from the patient and the family member accompanying the patient was taken. Patients were randomized to 3 different groups (Group A [sertraline], Group B [des-venlafaxine] and Group C [imipramine group]) using computer generated random tables. The dosages of medications were kept in the therapeutic range, i.e., 50-200 mg/day for sertraline, 50-100 mg/day for des-venlafaxine and 75-225 mg/day for imipramine. Doses were escalated as per the clinical judgment of the treating clinician. The dose at which the patient showed response was continued till the end of the study.
Assessments and rating scales (outcomes)
17-items Hamilton Depression Rating Scale (HDRS)  was used for the assessments. Each patient was rated at baseline, 3 rd day, 7 th day, 10 th day, 14 th day, 21 st day, 1 month, and 3 months. For study purpose, time to onset of response was taken as the 1 st time point at which the score on the HDRS decreased by 20% from the baseline.  Treatment response was taken as a 50% decrease in the HDRS score from baseline and remission was taken as final HDRS score of 7 or lower. ,
No psychotropics such as antipsychotics, mood stabilizers, or antidepressants were permitted except the study drugs. Intermediate-acting benzodiazepines (lorazepam) for sleep disturbances and beta-blockers for somatic anxiety were permitted, wherever required and doses of these medications were documented.
Maintaining compliance and follow-up
Since the study was done on an outpatient basis and required frequent assessments, maintaining compliance and follow-up was important. For this purpose, family members were instructed to supervise the medication by asking the patient to swallow the medication in their presence, and they were asked to accompany the patient for follow-up. The significance of maintaining compliance and follow-up even in case the patient improved and chances and consequences of relapse were explained to the patient and caregiver in detail. The investigator (AK) reminded the family member or patient telephonically 1 day before their appointment. The participants were told to return the empty medication strips to the investigator. After initial assessments on 3 rd , 7 th , 10 th , 14 th , and 21 st day, the assessment was carried out after 1 month and 3 months. However, patients were called for follow-up every 2 weeks to maintain a therapeutic relationship. It was observed that patients maintained an average of 80% of follow-up and no patient missed more than 5% of the doses.
The statistical analysis included Chi-square test for qualitative data and repeated measures ANOVA and MANOVA with repeated measures for quantitative data. t-test was applied to compare individual assessments. Data were analyzed by using SPSS version 13 (SPSS Inc., Chicago) and it was represented in mean and standard deviation, and where the data were heterogeneous, tests were applied after appropriate transformation.
| Results|| |
132 patients were included in the study (44 in each group) and out of them 42 patients (31.81%) dropped out. The 42 patients who dropped out were not statistically different from rest of the 90 patients on sociodemographic and baseline clinical variables. Out of dropped out cases, 14 patients were from the imipramine group, 12 were from the des-venlafaxine group, and 16 were from the sertraline group. Of these 42 patients who dropped out, 18 (5 from the sertraline group; 7 from the imipramine group; 6 from the des-venlafaxine group) did not return after the baseline visit, and thus, there is no information about their clinical status. Out of the rest of the 24 patients, 10 dropped out at 2 weeks and further 14 after 3 weeks. All these 24 patients had not shown the onset of action at the time of dropping out and were considered nonresponders. Hence, considering all these 42 patients as nonresponders, 63.38% of patients in our study showed the onset of action and response. Finally, data of remaining 90 patients who completed assessments and follow-up for 3 months were analyzed.
The three groups were similar to each other with regards to socio-demographic variables as shown in [Table 1].
[Table 2], [Table 3] and [Table 4] show the pattern of improvement with sertraline, des-venlafaxine and imipramine, respectively. From the tables, it can be concluded that the first symptoms to improve were insomnia, anxiety, and suicidal ideas followed by depressed mood and retardation followed by guilt, somatic symptoms, and genital symptoms.
As can be seen from the [Table 5], the pattern of improvement was similar across the three groups. The earliest significant improvement was seen in early insomnia (at day 3) followed by suicidal ideas and psychological anxiety (by day 7). Middle insomnia, late insomnia and agitation improved significantly by 14 th day in all the three groups. Depressed mood improved significantly at day 14 th in the sertarline and imipramine groups whereas it improved significantly in the des-venlafaxine group at 21 days. The reverse was true for somatic anxiety. Work and activities and retardation improved significantly in the sertraline and imipramine groups at 1 month follow-up whereas they improved later in the des-venlafaxine group. The last symptoms to improve were general somatic symptoms, genital symptoms, and guilt feeling.
|Table 5: Comparison of day of onset of improvement between sertraline, des-venlafaxine and imipramine|
Click here to view
50% of patients in the des-venlafaxine group required lorazepam in initial 1 month as compared to 36.67% in the sertraline group and 23.33% in the imipramine group, but the difference was nonsignificant (P = 0.321). Average doses of lorazepam in the three groups were almost same, i.e., 1.16 ± 0.661 mg/day, 1.13 ± 0.615 mg/day and 1.3 ± 0.728 mg/day respectively. 16.67% of patients in the sertraline and des-venlafaxine and 3.33% patients in the imipramine groups required propranalol for palpitations and other somatic symptoms of anxiety. Average 44 ± 8.944 mg/day of propranalol in sertraline group, 56 ± 16.733 mg/day of propranalol in des-venlafaxine and 40 ± 0.00 mg/day of propranalol in imipramine group was used (P = 0.336).
5 patients (17.86%) in sertraline and imipramine (16.67%) groups and 5 (15.62%) patients in des-venlafaxine group showed the onset of action by the 7 th day. 82.14% of patients in sertraline group had the onset of action by 14 days as compared to 50% in des-venlafaxine and 66.67% in imipramine group. At the end of the 1 st month, 82.14% patients of sertraline group showed a response (at least 50% reduction in Hamilton rating scale for depression score) as compared to 37.50% in des-venlafaxine and 60% in imipramine group. 46.63% of patients in the sertraline group showed remission at the end of 1 st month as compared to 12.5% in the des-venlafaxine and 33.3% in the imipramine groups.
| Discussion|| |
This study is the first Indian effort to investigate the temporal pattern of symptom improvement with antidepressants. We used 3 different antidepressants from 3 different classes to see the interclass difference between the antidepressants. The major strength of this study is the frequent follow-up which is required in a study aimed to assess the improvement on individual symptoms. No other study until date has made assessments on the 3 rd day after treatment initiation with an antidepressant. Another strength is the excellent compliance and follow-up rate which was possible because of the therapeutic relationship established by the investigator with the patient and family members and their psycho-education at the time of induction into the study.
Since the three groups were similar on sociodemographic and clinical variables like the severity of illness and duration of the episode, these variables were not responsible for the difference among the three drugs.
Early improvement in insomnia has been reported previously. , Insomnia is one of the most frequent symptoms in depression, may persist as a residual symptom and may be a precursor or prodrome symptom in relapse.  It has been found that persistent insomnia is an important risk factor for recurrence of depressive episode independent of other depressive symptoms and improvement in insomnia predicts greater improvement in depressive symptoms and quality of life ],[],[ Early improvement in insomnia can lead to early remission and prevent relapses, recurrences and chronicity in patients with depression.  Similarly, improvement in psychological anxiety early in the course of treatment seen in the present study has also been previously reported. , It has been previously shown that early improvement in psychological anxiety is a predictor of remission in depression. 
The present study also found that suicidal ideas improved early. Suicidal ideas have been linked with baseline anxiety levels in patients with depression.  Early improvement in anxiety in our study could be the reason for rapid improvement in suicidal ideas. Similarly, insomnia has been linked to suicidal thinking independently of depressed mood and anhedonia.  Anxiety and insomnia have been found to be the major symptoms that are distressing and bring the patient for treatment.  Early improvement in anxiety and insomnia could have instilled hope in the patients that their problems are treatable. This could have led to early improvement in suicidal ideas. The findings of our study refute the concern that antidepressants cause worsening of suicidal ideas. This concern was raised in the 1990s  but has always been an issue for debate and controversy, and no conclusion has been reached so far.  The findings of our study suggest that antidepressants do not cause or worsen suicidal ideas and clinicians should not hesitate to prescribe antidepressants in effective dosages to patients when they are clinically indicated.  There has also been a concern that early improvement in psychomotor retardation may increase the risk of a suicidal attempt.  However, the findings have been controversial and inconclusive.  Recently conducted treatment for adolescents with depression study concluded that most suicidal events occur due to persistent depression and insufficient improvement, and there was no evidence of medication-induced behavioral activation as a precursor to suicidal events.  This study also supports the finding that antidepressants do not increase the risk of suicidal ideas. This study found that guilt improves later than other symptoms. Persistent guilt could be the reason that persons with depression attempt or commit suicide in spite of treatment with antidepressants rather than antidepressants causing suicidal ideas.
The present study found that the general somatic symptoms (a headache, backache, painful somatic symptoms, and heaviness in the head) improved late. More than half of patients with depression report physical symptoms which can be a symptom, cause or consequence of depression.  They are often the presenting complaints and lead to missed diagnosis, unnecessary investigations and mismanagement. Higher physical symptoms at baseline predict poor response to treatment and poor quality of life.  Improvement in physical symptoms has been found to be a predictor of remission in patients with depression. 
Sexual symptoms (loss of libido) were among the last symptoms to improve in our study. It has been seen previously in studies on duloxetine that it does not produce improvement in sexual symptoms during acute treatment.  Another study found that after 1-month treatment with venlafaxine, anxiety, depressive, and somatic symptoms improved but sexual dysfunction did not improve. 
The finding of early improvement in insomnia, anxiety, and suicidal ideas followed by improvement in depressive symptoms and psychomotor retardation is in concordance with previous studies using sertraline and paroxetine. , It has been reported that sertraline starts improving anxiety symptoms from day 0 to 7, depressive symptoms from 7 to 21 and psychomotor retardation from 21 to 56 day  and somatic symptoms and psychomotor retardation improve late. 
This study found a similar pattern of improvement with all the three drugs. The only studies done on the issue until date showed that paroxetine improved anxiety symptoms early followed by depressive symptoms and finally psychomotor retardation while desipramine produced the opposite pattern  and nortryptiline produced rapid improvement while escitalopram produced gradual improvement. 
The pattern of outcome was almost similar across the three drugs. However, subtle differences were found. Des-venlafaxine improved late insomnia, agitation and somatic anxiety earlier than sertraline whereas the opposite was seen for depressed mood, work and activities and retardation. Imipramine showed a mixed pattern of response. It was similar to des-venlafaxine in terms of agitation. It was similar to sertraline in terms of late insomnia, depressed mood, somatic anxiety, work and activities and retardation. The difference seen in the pattern of outcome with the three antidepressants could be due to their variable mechanism of action. The mixed pattern seen with imipramine could be due to its effect on multiple receptors as compared to the other two drugs.
Though this study is the first of its kind from India and was conducted using sound methodology and strict inclusion and exclusion criteria, a few limitations are noteworthy. It was an open, nonblinded study. Hence, personal bias of information could not be ruled out. Although the three groups had almost 30 patients in each group, the sample size is still small considering the prevalence of depression. Use of lorazepam and propranolol which could have accounted for early improvement is another limitation. The absence of placebo group is another limitation.
| Conclusions and Clinical Implications|| |
- Insomnia, anxiety, and suicidal ideas are among the earliest symptoms to improve followed by depressed mood and psychomotor retardation
- Physical symptoms and sexual symptoms improve late
- The temporal sequence of symptomatic improvement seen in depression can help to predict the expected course of disease and to plan the management in a better way
- The three antidepressants namely sertraline, imipramine and des-venlafaxine produce a similar pattern of temporal improvement in depression except for some subtle differences.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Quitkin FM, Rabkin JD, Markowitz JM, Stewart JW, McGrath PJ, Harrison W. Use of pattern analysis to identify true drug response. A replication. Arch Gen Psychiatry 1987;44:259-64.
Posternak MA, Zimmerman M. Is there a delay in the antidepressant effect? A meta-analysis. J Clin Psychiatry 2005;66:148-58.
Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z. Early onset of selective serotonin reuptake inhibitor antidepressant action: Systematic review and meta-analysis. Arch Gen Psychiatry 2006;63:1217-23.
Avasthi A, Grover S, Aggarwal M. Research on antidepressants in India. Indian J Psychiatry 2010;52 Suppl 1:S341-54.
Uher R, Muthén B, Souery D, Mors O, Jaracz J, Placentino A, et al.
Trajectories of change in depression severity during treatment with antidepressants. Psychol Med 2010;40:1367-77.
Beunckens C, Molenberghs G, Verbeke G, Mallinckrodt C. A latent-class mixture model for incomplete longitudinal Gaussian data. Biometrics 2008;64:96-105.
Royston P, Altman DG, Sauerbrei W. Dichotomizing continuous predictors in multiple regression: A bad idea. Stat Med 2006;25:127-41.
Sarkar S, Grover S. A systematic review and meta-analysis of trials of treatment of depression from India. Indian J Psychiatry 2014;56:29-38.
Boyer P, Tassin JP, Falissart B, Troy S. Sequential improvement of anxiety, depression and anhedonia with sertraline treatment in patients with major depression. J Clin Pharm Ther 2000;25:363-71.
Shelton RC, Prakash A, Mallinckrodt CH, Wohlreich MM, Raskin J, Robinson MJ, et al.
Patterns of depressive symptom response in duloxetine-treated outpatients with mild, moderate or more severe depression. Int J Clin Pract 2007;61:1337-48.
Katz MM, Tekell JL, Bowden CL, Brannan S, Houston JP, Berman N, et al.
Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology 2004;29:566-79.
World Health Organization. ICD-10 Classifications of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: World Health Organization; 1992.
World Medical Association. Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. Seoul: World Medical Association; 2008.
Indian Council of Medical Research. Ethical Guidelines for Biomedical Research on Human Participants. New Delhi: Indian Council of Medical Research; 2008.
Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62.
Stassen HH, Angst J, Delini Stula A. Severity at baseline and onset of improvement in depression: Meta-analysis of imipramine and moclobemide versus placebo. Eur Psychiatry 1994;9:129-36.
Thompson C. Onset of action of antidepressants: Results of different analyses. Hum Psychopharmacol 2002;17 Suppl 1:S27-32.
Angst J, Deline A, Stassen HH. Is a cut off score a suitable measure of treatment outcome in short term trials in depression? Hum Psychopharmacol 1993;8:311-7.
Cho HJ, Lavretsky H, Olmstead R, Levin MJ, Oxman MN, Irwin MR. Sleep disturbance and depression recurrence in community-dwelling older adults: A prospective study. Am J Psychiatry 2008;165:1543-50.
Livingston WS, Rusch HL, Nersesian PV, Baxter T, Mysliwiec V, Gill JM. Improved sleep in military personnel is associated with changes in the expression of inflammatory genes and improvement in depression symptoms. Front Psychiatry 2015;6:59.
McCall WV, Blocker JN, D'Agostino R Jr., Kimball J, Boggs N, Lasater B, et al.
Insomnia severity is an indicator of suicidal ideation during a depression clinical trial. Sleep Med 2010;11:822-7.
Falussy L, Balla P, Frecska E. Relapse and insomnia in unipolar major depression. Neuropsychopharmacol Hung 2014;16:141-7.
Bitran S, Farabaugh AH, Ameral VE, LaRocca RA, Clain AJ, Fava M, et al.
Do early changes in the HAM-D-17 anxiety/somatization factor items affect the treatment outcome among depressed outpatients? Comparison of two controlled trials of St John's wort (Hypericum perforatum) versus a SSRI. Int Clin Psychopharmacol 2011;26:206-12.
Courtet P, Jaussent I, Lopez-Castroman J, Gorwood P. Poor response to antidepressants predicts new suicidal ideas and behavior in depressed outpatients. Eur Neuropsychopharmacol 2014;24:1650-8.
Garg R, Sidana A, Chavan BS. Factors associated with treatment lag in mental health care. J Ment Health Hum Behav 2011;16:12-7.
Teicher MH, Glod C, Cole JO. Emergence of intense suicidal preoccupation during fluoxetine treatment. Am J Psychiatry 1990;147:207-10.
Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry 2006;163:41-7.
Nischal A, Tripathi A, Nischal A, Trivedi JK. Suicide and antidepressants: What current evidence indicates. Mens Sana Monogr 2012;10:33-44.
Browning SM, Cowen PJ. Changes in mood, appetite and psychomotor retardation in depressed patients given ECT. Br J Psychiatry 1986;149:371-3.
Rich CL, Spiker DG, Jewell SW, Neil JF. Response of energy and suicidal ideation to ECT. J Clin Psychiatry 1986;47:31-2.
Vitiello B, Silva SG, Rohde P, Kratochvil CJ, Kennard BD, Reinecke MA, et al.
Suicidal events in the treatment for adolescents with depression study (TADS). J Clin Psychiatry 2009;70:741-7.
Schneider E, Linden M, Weigmann H, Wagner T, Quail D, Hundemer HP, et al
. Early reduction in painful physical symptoms is associated with improvements in long-term depression outcomes in patients treated with duloxetine. BMC Psychiatry 2011;11:150.
Novick D, Montgomery W, Kadziola Z, Moneta V, Peng X, Brugnoli R, et al
. Do concomitant pain symptoms in patients with major depression affect quality of life even when taking into account baseline depression severity? Patient Prefer Adherence 2013;7:463-70.
Lin CF, Juang YY, Wen JK, Liu CY, Hung CI. Correlations between sexual dysfunction, depression, anxiety, and somatic symptoms among patients with major depressive disorder. Chang Gung Med J 2012;35:323-31.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]