|Year : 2012 | Volume
| Issue : 2 | Page : 173-177
Efficacy and safety of add on low-dose mirtazapine in depression
Prithpal S Matreja1, Dinesh K Badyal2, Randhir S Deswal3, Arvind Sharma3
1 Department of Pharmacology, Gian Sagar Medical College and Hospital, Ram Nagar, District Patiala, India
2 Department of Pharmacology, Christian Medical College and Hospital, Ludhiana, India
3 Department of Psychiatry, Christian Medical College and Hospital, Ludhiana, India
|Date of Submission||31-Aug-2011|
|Date of Decision||18-Oct-2011|
|Date of Acceptance||17-Dec-2011|
|Date of Web Publication||16-Mar-2012|
Dinesh K Badyal
Department of Pharmacology, Christian Medical College and Hospital, Ludhiana
Source of Support: None, Conflict of Interest: None
Objectives: Although antidepressant medications are effective, they have a delayed onset of effect. Mirtazapine, an atypical antidepressant is an important option for add-on therapy in major depression. There is insufficient data on mirtazapine in Indian population; hence this study was designed to study the add-on effect of low-dose mirtazapine with selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder (MDD) in Indian population.
Materials and Methods: In an open, randomized study, 60 patients were divided into two groups. In Group A (n=30) patients received conventional SSRIs for 6 weeks. In Group B (n=30) patients received conventional SSRIs with low-dose mirtazapine 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) scores (P<0.05) in both groups. Mirtazapine in low dose as add on therapy showed improvement in scores, had earlier onset of action, and more number of responders and remitters as compared to conventional treatment (P<0.05). No serious adverse event was reported in either of the groups.
Conclusion: Low-dose mirtazapine as add-on therapy has shown better efficacy, earlier onset of action and more number of responders and remitters as compared to conventional treatment in MDD in Indian patients.
Keywords: Add-on, depression, mirtazapine, selective serotonin reuptake inhibitor
|How to cite this article:|
Matreja PS, Badyal DK, Deswal RS, Sharma A. Efficacy and safety of add on low-dose mirtazapine in depression. Indian J Pharmacol 2012;44:173-7
| » Introduction|| |
Depression is one of the leading causes of global disease burden and disability.  The consequences of underreporting of depression and lack of treatment for it are enormous. For instance, depression is the most important risk factor for suicide, which claims around 0.85 million lives annually, and is among the top three causes of death in young people ages 15-35. ,
The current modalities of treatment for depression include tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs) and selective serotonin reuptake inhibitors (SSRIs). TCAs and MAOIs are not preferred these days because of their adverse effect profile and dangerous food interactions respectively. SSRIs are presently the most widely used antidepressants because of their better safety and tolerability. 
Many current therapies for depression provide remission in only approximately one-third of patients and few have complete resolutions.  These antidepressant medications also have a delayed onset of therapeutic effect. This latency is problematic in that it prolongs the impairments associated with depression, leaves patients vulnerable to an increased risk of suicide, increases the likelihood that a patient will prematurely discontinue therapy and increases medical costs associated with severe depression.  Thus, there is continuous search for newer novel compounds that have better efficacy or can augment the effect of conventional antidepressants in these patients.
Mirtazapine, an atypical antidepressant is a noradrenergic and specific serotonergic antidepressant (NASSA) and is structural analogue of serotonin with potent antagonistic effects at several postsynaptic serotonin receptor types (including 5-HT2A, 5-HT2C, and 5-HT3 receptors) and can produce gradual down-regulation of 5-HT2A receptors. It also limits the effectiveness of inhibitory α2 adrenergic heteroceptors on serotonergic neurons as well as inhibitory α2 autoreceptors and 5-HT2A heteroceptors on noradrenergic neurons. This effect may enhance release of amines and contribute to the antidepressant effects. Mirtazapine is also a potent histamine H 1 receptor antagonist and is relatively sedating. Mirtazapine appears to be useful in patients with depression who present with anxiety symptoms and sleep disturbance. Its additional beneficial effects on the symptoms of anxiety and sleep disturbance associated with depression may reduce the need for concomitant anxiolytic and hypnotic medication seen with some antidepressants. It has low potential for interaction with drugs that are metabolized by CYP2D6, including antipsychotics, TCA and some SSRIs. It is also reported to be effective for augmentation or combination therapy in patients with refractory depression.  This makes mirtazapine an important option for the treatment of major depression in patients who require additional therapy. A few studies reported more number of responders at an earlier time period when mirtazapine was used as add on therapy. , However, most of the studies on mirtazapine as an add on therapy have been done on a small number of patients. This study is done to evaluate the effect of low-dose mirtazapine as add on therapy with SSRIs.
| » Materials and Methods|| |
This prospective, open, comparative, randomized, parallel group study was conducted in 60 patients suffering from major depressive disorder (MDD) as per ICD-10 and DSM-IV criteria. , Patients were enrolled in the study after an informed written consent. Patients of both sexes between the ages of 18-75 years with Hamilton Depression Rating Scale (HDRS-17 items) score ≥18 were included in the study.  The study plan was approved by the Institutional Ethics Committee.
Newly diagnosed patients, non-responders or partial responders to the earlier prescribed antidepressants and patients not tolerating earlier prescribed antidepressants were included in the study. Patients were screened at the beginning of the study. A detailed medical and psychiatry history was obtained. Mental status and physical examination was carried out. Patients with suicidal tendencies, schizoaffective disorder or bipolar disorder, seizure disorder, alcohol or substance abuse, concurrent major illness or systemic dysfunction involving hepatic and renal system were excluded. Pregnant women, lactating mothers and women not using contraceptives or desiring to have children were also excluded. Patients who qualified inclusion and exclusion criteria were enrolled in the study.
Patients were randomly divided into two groups using randomization table. Treatment in group A patients was started with SSRIs in the conventional dose range (escitalopram 10-30 mg, citalopram 20-60 mg, sertraline 50-150 mg, fluoxetine 20-40 mg, paroxetine 10-50 mg per day). Group B patients received SSRIs in the conventional dose range along with low-dose mirtazapine 7.5 mg per day. Both drugs were given either in single or divided doses based on the clinical improvement of the patient every week. Compliance was checked by pill count method. Record of concomitant medication was maintained throughout the study.
Clinical Measurement and Safety Assessment
Primary outcome measure was changes in total score of HDRS. The HDRS scale is the most commonly used scale focusing on somatic symptomatology. A 17-item version is used with score range from 0-50. A score of >8 indicates depression whereas a score of >23 means severe depression.  Secondary outcome measures included reduction in the score of Montgomery and Asberg depression rating scale (MADRS) and Amritsar depressive Inventory (ADI). , The MADRS score is designed to be sensitive to assess treatment effects. It has 10 items of core symptoms of depressive illness. Each item has a score range of 0-6., a score of >12 indicates depression.  The ADI scores are brief and effective psychological tool, easy to administer, and consists of 30 items with a total score of 30. A score in range of 5-13 indicates reactive depression and a score between 14 and 23 indicates endogenous depression.  Scores were recorded at baseline and then at 1, 2, 3, 4, 5 and 6 weeks after the treatment. Time to onset of action was defined as 40% reduction in the scores as compared to baseline.  Response to drugs was defined as decrease in HDRS, MADRS and ADI score of ≥50% from baseline. Remission was defined when the HDRS score was ≤7 and MADRS score was ≤12 , in a patient. Safety evaluation was based on spontaneously reported adverse effects and duration of hospitalization in the two groups. Laboratory investigations and ECG examination was also done at baseline and at the end of study i.e., 6 weeks.
The data was expressed as Mean±Standard Error (SE). 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, Kruskal Wallis test) and parametric tests (two-tailed test was used for t-test analysis). A P value of <0.05 was considered as statistically significant.
| » Results|| |
Both the groups tolerated the treatment. 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 (41.6 yrs in Group A vs. 38.6 in Group B). Similarly, the ratio of males and females was also comparable in both the groups (12:18 in Group A vs. 18:12 in Group B). The patient is both the groups had comparable HDRS score (20.76 in Group A vs. 20.53 in Group B). The mean duration of illness (3.82 in Group A vs. 3.6 in Group B) was comparable.
|Table 1: Demographic and baseline characteristics of patients in both groups at baseline|
Click here to view
The HDRS, MADRS and ADI score reduced significantly as compared to baseline in both groups. HDRS score (mean±SE) at baseline was 20.76 ± 0.32 which reduced significantly to 10.23 ± 0.71 at the end of 6 weeks in group A. Similarly, HDRS score reduced significantly from 20.53 ± 0.47 to 7.7 ± 0.54 at the end of 6 weeks in group B [Figure 1]. The MADRS score (mean±SE) decreased significantly from 28.42 ± 0.64 to 14.62 ± 0.96 in group A and from 28.67 ± 1.03 to 11.03 ± 0.94 in group B at the end of 6 weeks [Figure 2]. The ADI score (mean±SE) decreased significantly from 19.15 ± 0.34 to 8 ± 0.56 in group A and from 18.3 ± 0.33 to 6.33 ± 0.48 in group B at the end of 6 weeks [Figure 3].
|Figure 1: Mean score of HDRS in both groups. P<0.05 as compared to SSRI group|
Click here to view
|Figure 2: Mean score of MADRS in both groups. P<0.05 as compared to SSRI group|
Click here to view
|Figure 3: Mean score of ADI in both groups. P<0.05 as compared to SSRI group|
Click here to view
The improvement in group B was significantly (P<0.05) more as compared to group A from 2 nd week onwards in HDRS score (16.1 ± 0.27 vs. 17.5 ± 0.36), 2 nd week onwards in MADRS score (22.2 ± 0.68 vs. 23.9 ± 0.58) and at 3 rd week onward in ADI score (12.5 ± 0.29 vs. 13.2 ± 0.37).
[Table 2] shows onset of action in both groups. Onset of action was at 4 weeks in Group B and 5 weeks in group A in HDRS and MADRS score, but at 4 weeks in group B and Group A in ADI score. The number of responders was more in group B as compared to group A [Table 3]. The difference was statistically significant at 5 th week (22 vs. 9) in HDRS score. Similarly in MADRS score also there were more number of responders in group B as compared to group A at 6 th week (28 vs. 16). The number of remitters in our study was more in group B as compared to group A, this was statistically significant in HDRS score at 6 weeks (20 vs. 3) and at 5 weeks (10 vs. 3) and 6 weeks (23 vs. 15) in MADRS score [Table 3]. There was no significant difference in vital parameters at the end of 6 weeks as compared to baseline in both groups. There was no significant difference between the groups too. Baseline systolic blood pressure/diastolic blood pressure (SBP/DBP) was 119/79 and 123/82 mm of Hg in group A and group B respectively. The SBP/DBP at the end of treatment was 126/84 and 122/84 mm of Hg in group A and group B, respectively.
There was no serious adverse event reported in both the groups. Two patients reported somnolence in group B. Two patients reported mild adverse events during treatment in group A. One patient withdrew from the study from group A due to the complaint of impairment in ejaculation. No significant change was observed in ECG in any patient in both the groups. There was no prolongation of hospitalization in any patient. No patient was lost to the follow-up.
| » Discussion|| |
Although there are a number of therapeutic choices available for the treatment of major depression, it is generally acknowledged that current first line therapies provide less than satisfactory outcome in many instances. This is because nearly two-third of all patient are either partially or completely nonresponsive, only one-third experience full remission and many have tolerability concern that limit long-term treatment.  Thus the development of new agents that can meaningfully expand the expected therapeutic effect and tolerability of antidepressant therapy is an important medical need.
Mirtazapine is a α2 adrenergic antagonist produces a rapid increase in both noradrenergic and serotonergic transmission with enhance tonic activation of post synaptic serotonergic receptors. , Mirtazapine has shown significant improvement in depressed patients with anxiety and insomnia, including decreased sleep-onset latency, deeper sleep and fewer awakenings. , It is effective for augmentation or combination therapy in patients with refractory depression. 
In the present study, low dose add on mirtazapine therapy was very effective in improving HDRS score in patients of major depression. Low dose add on mirtazapine therapy also significantly improved MADRS and ADI scores in these patients. These results are in agreement with earlier studies which demonstrated a statistically significant improvement in the total score on the HDRS-17 and nearly all secondary efficacy measures, including remission, MADRS and ADI. , The response rate and number of remitters were significantly more with low dose add on mirtazapine therapy as compared to conventional therapy at the end of study. The HDRS-17 subset scores indicate that add on low-dose mirtazapine therapy was more effective in improving anxiety and somatic symptoms as compared to conventional therapy. These findings are in agreement with earlier studies. 
In this study, times to onset of action with low dose add on mirtazapine therapy, was earlier as compared to conventional therapy, with more responders at an earlier time period as seen with earlier studies. 
The most common adverse effects reported in our study with add on mirtazapine therapy was somnolence, whereas in the conventional group patients reported with nausea and sexual dysfunction. The adverse effect does not seem to be due to combination of mirtazapine with conventional therapy as the common adverse event reported with conventional therapy is insomnia, so both groups differ with respect to adverse events.
These results confirm and extend earlier finding, that mirtazapine, a dual action antidepressant is an effective and safe antidepressant in Indian patients of major depressive disorder for short-term augmentation and may be of more clinical utility in alleviation of anxiety symptoms and improvement of quality of life associated with depression. 
| » Conclusions|| |
Our study showed that both treatment groups showed significant decrease in HDRS, MADRS and ADI score in both groups as compared to baseline. However, patients treated with add on low-dose mirtazapine had earlier onset of action and more number of responders and remitters. None of the groups had severe adverse events. Long term studies may help us find out whether the adverse event documented could be present on long-term follow-up.
In conclusion, add-on therapy with mirtazapine had earlier onset of action, better efficacy and more number of responders and remitters as compared to conventional therapy in MDD in Indian patients.
| » References|| |
|1.||Hyman S, Chisholm D, Kessler R, Patel V, Whiteford H. Mental disorders. In: Jamison DT, Breman JG, Measham AR, Alleyne G, Claeson M, Evans DB, et al., editors. Disease Control Priorities in Developing Countries. 2 nd ed. New York: Oxford University Press for the World Bank; 2006. p. 605-25. |
|2.||World Health Organization. Mental and behavioural disorders, department of mental health [Online]. 2000. Available from: http://www.who.int/mental_health/media/en/59.pdf. [Last cited in 2011]. |
|3.||Aaron R, Joseph A, Abraham S, Muliyil J, George K, Prasad J, et al. Suicides in young people in rural southern India. Lancet 2004;363:1117-8. |
|4.||Baldessarini RJ. Drug therapy of depression and anxiety disorder. In: Brunton LL, Lazo JS, Parker KL, editors. The Pharmacological Basis of Therapeutics. 11 th ed. New York: McGraw-Hill; 2006. p. 429-60. |
|5.||Davidson JR, Meltzer-Brody SE. The under recognition and under treatment of depression: What is the breadth and depth of the problem? J Clin Psychiatry 1999;60:4-9. |
|6.||Whooley MA, Simon GE. Managing depression in medical outpatients. N Engl J Med 2000;343:1942-50. |
|7.||Carpenter LL, Jocic Z, Hall JM, Rasmussen SA, Price LH. Mirtazapine augmentation in the treatment of refractory depression. J Clin Psychiatry 1999;60:45-9. |
|8.||Papakostas GI, Homberger CH, Fava M. A meta-analysis of clinical trials comparing mirtazapine with selective serotonin reuptake inhibitors for the treatment of major depressive disorder. J Psychopharmacol 2008;22:843-8. |
|9.||Sartorius N. The classification of mental disorders in international classification of disease. In: Saddock BJ, Sadock VA, Ruiz P, editors. Kaplan and Sadocks Comprehensive Textbook of Psychiatry. 9 th ed., Vol. 1. Philadelphia: Lippincott Williams and Wilkins; 2009. p. 1139-51. |
|10.||American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder. 4 th ed. Text Revision (DSM-IV-TR). Washington D.C.: American Psychiatric Association; 2000. p. 356. |
|11.||Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62. |
|12.||Montgomery SA, Asberg MA. A new depression scale designed to be sensitive to change. Br J Psychiatry 1979;134:382-9. |
|13.||Singh G. A new depressive inventory (Amritsar Depressive Inventory). Indian J Psychiatry 1974;16:183-8. |
|14.||Thase ME. Methodology to measure onset of action. J Clin Psychiatry 2001;62 Suppl 15:18-21. |
|15.||Nierenberg AA. Do some antidepressants work faster than others? J Clin Psychiatry 2001;62 Suppl 15:22-5. |
|16.||Mulrow CD, William JW, Chiquette E, Aguilar C, Hitchcock-Noel P, Lee S, et al. Efficacy of newer medication for treating depression in primary care patients. Am J Med 2000;108:54-64. |
|17.||Haddjeri N, Blier P, de Montigny C. Noradrenergic modulation of central serotonergic neurotransmission: Acute and long-term actions of mirtazapine. Int Clin Psychopharmacol 1995;10 Suppl 4:11-7. |
|18.||Ruigt GS, Kemp B, Groenhout CM, Kamphuisen HA. Effect of the antidepressant Org 3770 on human sleep. Eur J Clin Pharmacol 1990;38:551-4. |
|19.||Sorensen M, Jorgensen J, Viby-Mogensen J, Bettum V, Dunbar GC, Steffensen K. A double-blind group comparative study using the new anti-depressant Org 3770, placebo and diazepam in patients with expected insomnia and anxiety before elective gynaecological surgery. Acta Psychiatr Scand 1985;71:339-46. |
|20.||Carpenter LL, Yasmina S, Pricea LH. A double-blind, placebo-controlled study of antidepressant augementation with mirtazapine. Biol Psychiatry 2001;51:183-8. |
|21.||Pallanti S, Quercioli L, Bruscoli M. Response acceleration with mirtazapine augmentation of citalopram in obsessive-compulsive disorder patients without comorbid depression: A Pilot Study. J Clin Psychiatry 2004;65:1394-9. |
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
|This article has been cited by|
||A systematic review and meta-analysis of trials of treatment of depression from India
| ||Sarkar, S., Grover, S. |
| ||Indian Journal of Psychiatry. 2014; 56(1): 29-38 |
||Effect of five-consecutive-day exposure to an anxiogenic stressor on sleep-wake activity in rats
| ||OæMalley, M.W., Fishman, R.L., Ciraulo Domenic A., D.A., Datta, S. |
| ||Source of the Document Frontiers in Neurology. 2013; 4 |