Effect of Botox Injection on Depression in Chronic Migraine
Effect of Botox Injection on Depression in Chronic Migraine
Onabot was beneficial in treating Chronic Migraine (CM) in the PREEMPT regulatory trials and in other studies. We set out to study PROs in CM patients receiving the PREEMPT protocol.
Although improvement on the PHQ9 was statistically significant, the magnitude of change, 0.7 points, was small. This may have been due to the fact that many of our CM patients displayed no symptoms of depression on their first visit; that is, these patients may not have been depressed at all. Therefore, on subsequent visits, when these patients returned, again without depression symptoms, no change in PHQ9 was observed. The difference between PHQ9 pre- and post-onabot injections was statistically significant when all patients were included; however, as a PHQ9 score of ≥10 has been shown in previous literature to have a sensitivity of 0.85 (95% CI 0.75–0.91) and a specificity of 0.89 (95% CI 0.83–0.92) for detecting at least moderate depression, we stratified our patients for PHQ9 scores of ≥10 only. This approach was to ensure that post-injection PHQ9 score-changes were measurable and to evaluate association of onabot with meaningful changes in PHQ9.
The mean changes in PHQ9 scores, stratified by pre-onabot treatment PHQ9 category, are displayed in Table 3. As depressive symptoms increased (as evidenced by higher pre-treatment scores), the improvement in PHQ9 was greater. Patients with a score of 20 or higher (severe depression) improved by an average of 6.6 points (Holm-adjusted P = .004). Thus, higher baseline PHQ9 scores (that is, worse depression) resulted in a greater reduction in postinjection PHQ9 scores. In other words, onabot injection had a greater impact in improving depression scores in those with a higher baseline PHQ9 score. It is not clear if this is entirely due to improvement of headache itself, or whether it is possible that onabot has anti-depressant properties.
Previous studies have implied that onabot injections for cosmetic purposes may improve depression scores. In a 24 week, randomized, double blind, placebo-controlled study, Magid et al analyzed whether a single treatment of onabot in the glabellar region could improve depression scores in patients with major depressive disorder (MDD). In that study, 30 patients received onabot injections (females received 29 units, males received 39 units). They reported that there was a significant reduction in MDD symptoms measured by PHQ9 compared to placebo, even when the cosmetic effects of onabot wore off at 12–16 weeks. At week 24, there was a 59% reduction in the PHQ9 scores (P < .0001). They concluded that the onabot injections in the glabellar region were associated with statistically significant changes in MDD symptoms as measured by PHQ9.
A similar study with 74 patients (29 units of onabot for females and 40 units of onabot for males) who received injections in the corrugator and procerus muscle (5 sites) also reported a reduction in depression symptoms. Similar findings have been reported in 3 other studies. A major difference between their studies and our study is the amount of onabot used and the number of injection sites. These other studies used a maximum of 40 onabot units for a total of 5 sites (corrugator and procerus muscles), whereas the PREEMPT protocol involves 155 units of onabot in 31 sites.
The significance of the dosage difference is not clear, but it is worth noting that previous prospective onabot studies for migraine that did not use at least 155 units did not reach their primary endpoints, raising the issue of a dose–response curve. For example, Elkind et al assessed the efficacy of onabot injection at doses 7.5 units, 25 units, and 50 units in 418 patients in series of 3 sequential, randomized, controlled studies. They reported no statistically significant differences in all treatment groups.
Evers et al also evaluated the efficacy of onabot injections with 16 units, 100 units, and placebo given in frontal and neck muscles in 60 patients with CM in a randomized, double blind, placebo-controlled study. The author reported that there were no statistically significant differences between the 3 groups in terms of migraine frequency or number of days with migraine (P = .921).
Mathew et al assessed the efficacy of onabot injections at 100 units in 279 patients in a randomized, double blind, placebo controlled study. They reported that at 180 days, the difference between the placebo and onabot injection groups was not statistically significant in terms of number of headache free days per 30-day period.
Patients in our study improved by a drop of 2.8 points on the HIT6, by 3.1 on the PDI, and by 0.4 for Headache Pain Level as well. Quality of Life scores increased by 0.03, and all changes were statistically significant (Table 2). For comparison, in the PREEMPT regulatory trials, the mean baseline HIT6 scores improved from 66 to 61.2 (P < .001) after 24 months (5 injections). Note that despite a shorter period of time and fewer injections in our study, the improvement in HIT6 in our study was statistically significant and not dissimilar to that seen in the Phase 3 trials.
One limitation in our study is its retrospective nature. Given that PROs are increasingly routinely collected, a hypothesis with prospective collection of data would be optimal for future research.
Some injectors in this study added an additional 45 units above 155 units for a total of 200 units of onabot for their CM patients, while others did not. These subsets were not analyzed due to small numbers and variations in individual preferences for this additional "follow-the-pain." As the FDA evaluation of the PREEMPT data did not find a significant difference with and without "follow-the-pain" additional injections beyond 155 units, we felt that the uniformity of the clinical PREEMPT protocol was sufficient for comparison purposes.
Our study suggests an association between onabot treatment via the PREEMPT protocol and decreased depression scores, but does not prove causation, that is, does not prove that onabot alleviates depression. Onabot treatment was associated with both improvements in depression and headache scores at the same time. As part of future research, it might be useful to give onabot versus onabot plus an antidepressant for moderate depression CM patients and prospectively evaluate the effect on depression scores. It also might be useful to evaluate PROs for other comorbid illnesses or habits after onabot injections.
Discussion
Onabot was beneficial in treating Chronic Migraine (CM) in the PREEMPT regulatory trials and in other studies. We set out to study PROs in CM patients receiving the PREEMPT protocol.
Although improvement on the PHQ9 was statistically significant, the magnitude of change, 0.7 points, was small. This may have been due to the fact that many of our CM patients displayed no symptoms of depression on their first visit; that is, these patients may not have been depressed at all. Therefore, on subsequent visits, when these patients returned, again without depression symptoms, no change in PHQ9 was observed. The difference between PHQ9 pre- and post-onabot injections was statistically significant when all patients were included; however, as a PHQ9 score of ≥10 has been shown in previous literature to have a sensitivity of 0.85 (95% CI 0.75–0.91) and a specificity of 0.89 (95% CI 0.83–0.92) for detecting at least moderate depression, we stratified our patients for PHQ9 scores of ≥10 only. This approach was to ensure that post-injection PHQ9 score-changes were measurable and to evaluate association of onabot with meaningful changes in PHQ9.
The mean changes in PHQ9 scores, stratified by pre-onabot treatment PHQ9 category, are displayed in Table 3. As depressive symptoms increased (as evidenced by higher pre-treatment scores), the improvement in PHQ9 was greater. Patients with a score of 20 or higher (severe depression) improved by an average of 6.6 points (Holm-adjusted P = .004). Thus, higher baseline PHQ9 scores (that is, worse depression) resulted in a greater reduction in postinjection PHQ9 scores. In other words, onabot injection had a greater impact in improving depression scores in those with a higher baseline PHQ9 score. It is not clear if this is entirely due to improvement of headache itself, or whether it is possible that onabot has anti-depressant properties.
Previous studies have implied that onabot injections for cosmetic purposes may improve depression scores. In a 24 week, randomized, double blind, placebo-controlled study, Magid et al analyzed whether a single treatment of onabot in the glabellar region could improve depression scores in patients with major depressive disorder (MDD). In that study, 30 patients received onabot injections (females received 29 units, males received 39 units). They reported that there was a significant reduction in MDD symptoms measured by PHQ9 compared to placebo, even when the cosmetic effects of onabot wore off at 12–16 weeks. At week 24, there was a 59% reduction in the PHQ9 scores (P < .0001). They concluded that the onabot injections in the glabellar region were associated with statistically significant changes in MDD symptoms as measured by PHQ9.
A similar study with 74 patients (29 units of onabot for females and 40 units of onabot for males) who received injections in the corrugator and procerus muscle (5 sites) also reported a reduction in depression symptoms. Similar findings have been reported in 3 other studies. A major difference between their studies and our study is the amount of onabot used and the number of injection sites. These other studies used a maximum of 40 onabot units for a total of 5 sites (corrugator and procerus muscles), whereas the PREEMPT protocol involves 155 units of onabot in 31 sites.
The significance of the dosage difference is not clear, but it is worth noting that previous prospective onabot studies for migraine that did not use at least 155 units did not reach their primary endpoints, raising the issue of a dose–response curve. For example, Elkind et al assessed the efficacy of onabot injection at doses 7.5 units, 25 units, and 50 units in 418 patients in series of 3 sequential, randomized, controlled studies. They reported no statistically significant differences in all treatment groups.
Evers et al also evaluated the efficacy of onabot injections with 16 units, 100 units, and placebo given in frontal and neck muscles in 60 patients with CM in a randomized, double blind, placebo-controlled study. The author reported that there were no statistically significant differences between the 3 groups in terms of migraine frequency or number of days with migraine (P = .921).
Mathew et al assessed the efficacy of onabot injections at 100 units in 279 patients in a randomized, double blind, placebo controlled study. They reported that at 180 days, the difference between the placebo and onabot injection groups was not statistically significant in terms of number of headache free days per 30-day period.
Patients in our study improved by a drop of 2.8 points on the HIT6, by 3.1 on the PDI, and by 0.4 for Headache Pain Level as well. Quality of Life scores increased by 0.03, and all changes were statistically significant (Table 2). For comparison, in the PREEMPT regulatory trials, the mean baseline HIT6 scores improved from 66 to 61.2 (P < .001) after 24 months (5 injections). Note that despite a shorter period of time and fewer injections in our study, the improvement in HIT6 in our study was statistically significant and not dissimilar to that seen in the Phase 3 trials.
One limitation in our study is its retrospective nature. Given that PROs are increasingly routinely collected, a hypothesis with prospective collection of data would be optimal for future research.
Some injectors in this study added an additional 45 units above 155 units for a total of 200 units of onabot for their CM patients, while others did not. These subsets were not analyzed due to small numbers and variations in individual preferences for this additional "follow-the-pain." As the FDA evaluation of the PREEMPT data did not find a significant difference with and without "follow-the-pain" additional injections beyond 155 units, we felt that the uniformity of the clinical PREEMPT protocol was sufficient for comparison purposes.
Our study suggests an association between onabot treatment via the PREEMPT protocol and decreased depression scores, but does not prove causation, that is, does not prove that onabot alleviates depression. Onabot treatment was associated with both improvements in depression and headache scores at the same time. As part of future research, it might be useful to give onabot versus onabot plus an antidepressant for moderate depression CM patients and prospectively evaluate the effect on depression scores. It also might be useful to evaluate PROs for other comorbid illnesses or habits after onabot injections.
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