Safety and Efficacy of Add on Modafinil to Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder

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1 Original Article 282 Safety and Efficacy of Add on Modafinil to Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder A Sharma*, P. S. Matreja**, Rajdeep Kaur***, Arvind Sharma* Harhspunit Kaur**** *Department of Psychiatry, Christian Medical College and Hospital, Ludhiana, **Department of Pharmacology, Gian Sagar Medical College and Hospital,Ram Nagar, District Patiala, ***Civil Hospital, **** Gurdaspur, Punjab, Guru Nanak College of Nursing, Dhahan Kaleran, Distt. SBS Nagar Abstract Aim: Despite the efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depression, a significant number of patients show partial or no remission of symptoms. Although antidepressant medications are effective, they have a delayed onset of therapeutic effect. Modafinil is a novel psychostimulant that may be helpful in treating patients with residual symptoms of depression. The efficacy of modafinil as add-on therapy to SSRIs in depressed patients in Indian population is lacking; hence this study was designed to study the efficacy and safety of Modafinil as add-on therapy to SSRI in depressed patient in Indian Population.Methods: In an open, randomized study, 50 patients diagnosed with major depressive disorder (MDD) were divided into two groups. In Group A (n = 25) patients received conventional SSRIs with low dose Modafinil for 8 weeks. In Group B (n = 25) patients received conventional SSRIs for 8 weeks. Patients were evaluated at baseline and then at the end of 2, 4, 6, and 8 weeks. Results: There was significant improvement in Hamilton depression rating scale (HDRS), Epworth Sleepiness Scale (ESS), Fatigue severity Scale (FSS) and Clinical Global Improvement severity (CGI-S) Scale (p < 0.05) in both groups. Modafinil in low dose as add on therapy showed more decrease in scores, had earlier onset of action, as compared to conventional treatment (p < 0.05). No serious adverse event was reported in either of the groups. Conclusion: Low dose Modafinil as add-on therapy had shown better efficacy, earlier onset of action as compared to conventional treatment in MDD in Indian patients. Key words: Modafinil, SSRI s, Major Depressive Disorder. Introduction Depression is one of the leading causes of the global disease burden and disability worldwide 1. 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 850 million lives annually, and is among the top three causes of death in young people ages 15 to 35 2, 3. 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 profile and tolerability 4. Despite the better tolerability of SSRI s in treatment of Major Depressive Disorder, only a third of patients achieve remission and significant number of patients achieve no remission of symptoms 5, 6. Many patients treated with SSRI s

2 OCTOBER 2010 DELHI PSYCHIATRY JOURNAL Vol. 13 No. 2 have residual symptoms despite an overall antidepressant response 7. Fatigue being one of the core symptoms is present in 73% 97% of depressed patients and has a negative impact on their level of functioning and quality of life 8. Another residual symptom primarily comprises problem with sleep span (i.e., difficulty falling asleep, frequent awakenings during the night, and early morning wakefulness) is common in patients with depression 9. Modafinil, a wake-promoting agent was approved by the U.S. Food and Drug Administration in 1998 for the treatment of excessive daytime sleepiness (EDS) and to treat many conditions associated with fatigue, including depression. Modafinil action is possibly mediated through histamine receptors in the anterior hypothalamus with no affect on the dopamine pathways associated with dependence and reward usually targeted by the stimulants 10, 11. This makes modafinil an important option for the treatment of major depression in patients who require additional therapy for residual symptoms. A placebocontrolled study indicate that modafinil with SSRI s relieved excessive sleepiness, reduced fatigue, and improved patients overall clinical condition, including mood 7. Another study showed significant improvement in the overall clinical condition at all points of time it significantly reduced fatigue and improved wakefulness in patient with seasonal affective disorder and was well tolerated by the patients 8. However, the reports of Modafinil augmentation on Indian population are limited. Hence, we designed this study to evaluate the effect of low dose Modafinil as add on therapy with SSRIs. Patients and methods Patients This prospective, open, comparative, randomized, placebo-controlled, parallel group study was conducted in patients visiting the Department of Psychiatry, Christian Medical College and Hospital, Ludhiana. The duration of study was one year. A total of 50 patients suffering from major depressive disorder (MDD) as per ICD-10 and DSM-IV criteria were enrolled in the study after they signed an informed written consent 13, 14. Patients of both sexes between the ages of years with Hamilton depression rating scale (HDRS-17 items) score >17 were included in the study 15. The study was approved by the Institutional Ethics Committee (IEC) and was conducted as per ICH-GCP guidelines. 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 after they signed the written informed consent. Treatment Patients were divided into two groups using randomization as per random number table. Treatment in Group A patients was started with SSRIs in the conventional dose range (escitalopram mg, sertraline mg, paroxetine mg per day) along with low dose Modafinil mg per day. Group B patients received SSRIs in the conventional dose range along with placebo. Both drugs were given either in single or divided doses based on the clinical improvement of the patient every 2 week. Compliance was checked by pill count method. Record of concomitant medication was maintained throughout the study. Primary outcome measure was changes in total score of HDRS. Secondary outcome measures included reduction in the score of Epworth Sleepiness Scale (ESS) 16, Fatigue severity Scale (FSS) 17 and Clinical Global Improvement Severity (CGI- S) 18. Scores were recorded at baseline and then at 2, 4, 6 and 8 weeks after the treatment. Safety evaluation was based on spontaneously reported adverse effects and duration of hospitalization in the two groups. 283

3 Statistical Analysis 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 two weeks data. Results were analyzed using nonparametric tests (Chi-Square, Friedman two way analyses, Kruskal Wallis test) and parametric tests (two tailed t-test was used for analysis). A p-value of < 0.05 was considered as statistically significant. Results The patients in both groups had comparable demographic and clinical profile as shown in Table 1. The HDRS, ESS and FSS score reduced significantly as compared to baseline in both groups. HDRS score (Mean ± SD) at baseline was 18 ± 1.6 which reduced significantly to 11 ± 1 at the end of 8 weeks in Group A. Similarly, HDRS score reduced significantly from ± 1 to 15 ± 1.8 at the end of 8 weeks in Group B (Figure 1). The ESS score (Mean ± SD) decreased significantly from ± 0.76 to 9 ± 0.76 in Group A and from ± 0.71 to 9.4 ± 0.58 in Group B at the end of 8 weeks. The FSS score (Mean ± SD) decreased significantly from 5 ± 0.71 to 2.4 ± 0.5 in Group A and from 4.7 ± 0.74 to 4.3 ± 0.74 in Group B at the end of 8 weeks (Figure 2). duration of treatment. Figure 3 shows the Clinical Global Impression-Severity scores in both groups. There was significant reduction in the CGI-S score in both groups as compared to baseline scores (60 % reduction in Group A and 20% reduction in Group B) at the end of 8 weeks. There was significant reduction (p < 0.05) in CGI-S score in Group A as compared to Group B from 6 weeks onwards. Figure 1, Comparison of HDRS scores in both groups Table 1 Demographic profile at baseline Character Group A Group B Age (Range) Gender (M:F) 18:7 16:9 CGI-S Borderline 2 4 Slight 6 10 Moderate 15 9 Severe 2 2 ESS (Mean ± SD) ± ±.71 FSS (Mean ± SD) 5 ± ±.74 HDRS (Mean ± SD) 18 ± ± 1 No significant difference in both the groups at baseline (p>0.05) Figure 2, Comparison of ESS and FSS scores in both groups The improvement in Group A was significantly (p < 0.05) more as compared to Group B from 4th week onwards in HDRS score (13 ± 1 Vs 15 ± 0.95) and 2nd weeks onward in FSS score (4 ± 0.65 Vs 4.4 ± 0.58). There was no significant difference in the ESS score in both the groups during the entire 284 Figure 3, Comparison of CGI-S scores in both groups

4 OCTOBER 2010 DELHI PSYCHIATRY JOURNAL Vol. 13 No. 2 There was no serious adverse event reported in both groups. The incidence of adverse event reported in Group A was more as compared to Group B but none of the adverse event reported was severe that required termination of treatment. The adverse event reported in both groups did not require reduction in dose or any therapy for treatment of adverse events. Patients in both groups reported with nausea, vomiting, loss of appetite, headache, insomnia, nervousness, dry mouth, variation in blood pressure and improved sexual function. 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 non responsive, only onethird experience full remission and many have tolerability concern that limit long term treatment 19. Even those patients who have an overall antidepressant response with SSRI s they have residual symptoms 7. Thus the development of new agents that can meaningfully expand the expected therapeutic effect and tolerability of antidepressant therapy is an important medical need. In the present study, low dose add on Modafinil therapy was very effective in improving HDRS score in patients of major depression. Low dose add on Modafinil therapy also significantly improved ESS, FSS and CGI-S 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 measures, including FSS, ESS and CGI-S 7, 12. Modafinil as add-on with SSRI s relieved excessive sleepiness, reduced fatigue, and improved patients overall clinical condition significantly more with low dose add on Modafinil therapy as compared to conventional therapy at the end of study 7. The HDRS-17 subset scores indicate that add on low dose Modafinil therapy was more effective in improving anxiety and somatic symptoms as compared to conventional therapy. These findings are in agreement with earlier studies 4. The most common adverse effect reported in our study with add-on Modafinil was nausea, headache, insomnia, nervousness, and dry mouth whereas in the conventional group patients reported of nausea, diarrhea and dry mouth. The adverse effects reported are similar to those reported in earlier studies 12. None of the adverse event reported was severe that required termination of treatment or reduction in dose or any therapy for treatment of adverse events. These results confirm and extend earlier finding, that Modafinil, a wake-promoting agent 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 residual symptoms and improvement of quality of life associated with 8, 11 depression To conclude, patients in both groups tolerated the treatment. There was significant decrease in HDRS, FSS, ESS and CGI-S score in both groups as compared to baseline. However, Patients treated with add on low dose Modafinil had earlier response and the relief of residual symptoms was more as compared to conventional treatment. References 1. Hyman S, Chisholm D, Kessler R, Patel V, Whiteford H. Mental disorders. In: Disease Control Priorities in Developing Countries, Second Edition, eds Jamison DT, Breman JG, Measham AR, Alleyne G, Claeson M, Evans DB, Jha P, Mills A, Musgrove P, New York: Oxford University Press for the World Bank, 2006, World health organization. Mental and behavioural disorders, department of mental health [Online] available from: URL: 59.pdf 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: Baldessarini RJ. Depression and anxiety disorder. In: The pharmacological Basis of Therapeutics, 10th Edition, eds Hardman JG, 285

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