Acute Treatment of Mania in Children and Adolescents
Acute Treatment of Mania in Children and Adolescents
Data from RCTs demonstrate that all SGAs that have been evaluated are more likely than placebo to induce a clinically significant reduction in core symptoms of mania in children and adolescents. The data are encouraging but some questions still remain. We do not have good information about expected time to response, nor do we know what proportion of those deemed nonresponders at study endpoint might be expected to respond with continuing treatment. Following on from this, we do not have data to inform the decision about when to switch to an alternative agent, or when to augment with a mood stabilizer. The trials have involved outpatients or a combination of inpatients and outpatients. It is uncertain whether the results generalize to populations of inpatients who have more severe illnesses.
As noted by Pavuluri, clinical trials have other limitations such as self-selection into studies, use of rescue medications which may mask the efficacy of the study drug, the impact of untreated comorbidities, and the probability that the blind will be broken due to the side-effect profiles of the treatment. None of the reviews published to date has examined the impact of the quality of the studies on the estimates of efficacy that are derived from their results.
There is little to separate the SGAs that have been evaluated in terms of efficacy, given the NNT estimates for optimal doses of each compound range from three to four. In the future, time to response analyses might separate the drugs, but we think that this is unlikely. In this situation our attention shifts naturally to the differential tolerability of medicines, and the data on some variables do separate the drugs. Most striking are the effects on weight gain, which are greatest for olanzapine and least for ziprasidone. However, during the relatively short period of acute stabilization of manic episodes, this should be of less concern than it is for continuing treatment of patients who have mania. Our own clinical experience has been that inpatients' weight gain can be minimized by ensuring that they remain active. We employ a sports psychologist to supervise their activity, and use secure outdoor areas in which patients can exercise. In addition, ward diets are optimized and patients have limited access to sugary snacks and drinks.
The NNTs of SGA versus mood stabilizer are similar to SGA versus placebo, and, to date, RCTs have not found mood stabilizers to separate statistically from placebo in terms of response rates. Thus the data do not support the use of mood stabilizer monotherapy in treating children and adolescents who have mania. Although there are no empirical data, combination therapy appears to be quite common in clinical practice. Available evidence indicates that SGA and lithium/valproate and perhaps lithium–valproate combinations are effective in the acute treatment of children and adolescents with mania. Clinicians may have other reasons for prescribing combination therapy during the acute phase of treatment, including, for example, initiating prophylaxis. Data for alternative and psychosocial treatments are too limited to allow comment on their role in acute treatment. Data are also limited for ECT, although our clinical experience has been positive for the one patient per year or so with refractory mania whom we treat with ECT. Of course, patients' improvements may be a result of factors other than the specific benefits of their treatment with medicines.
Discussion
Data from RCTs demonstrate that all SGAs that have been evaluated are more likely than placebo to induce a clinically significant reduction in core symptoms of mania in children and adolescents. The data are encouraging but some questions still remain. We do not have good information about expected time to response, nor do we know what proportion of those deemed nonresponders at study endpoint might be expected to respond with continuing treatment. Following on from this, we do not have data to inform the decision about when to switch to an alternative agent, or when to augment with a mood stabilizer. The trials have involved outpatients or a combination of inpatients and outpatients. It is uncertain whether the results generalize to populations of inpatients who have more severe illnesses.
As noted by Pavuluri, clinical trials have other limitations such as self-selection into studies, use of rescue medications which may mask the efficacy of the study drug, the impact of untreated comorbidities, and the probability that the blind will be broken due to the side-effect profiles of the treatment. None of the reviews published to date has examined the impact of the quality of the studies on the estimates of efficacy that are derived from their results.
There is little to separate the SGAs that have been evaluated in terms of efficacy, given the NNT estimates for optimal doses of each compound range from three to four. In the future, time to response analyses might separate the drugs, but we think that this is unlikely. In this situation our attention shifts naturally to the differential tolerability of medicines, and the data on some variables do separate the drugs. Most striking are the effects on weight gain, which are greatest for olanzapine and least for ziprasidone. However, during the relatively short period of acute stabilization of manic episodes, this should be of less concern than it is for continuing treatment of patients who have mania. Our own clinical experience has been that inpatients' weight gain can be minimized by ensuring that they remain active. We employ a sports psychologist to supervise their activity, and use secure outdoor areas in which patients can exercise. In addition, ward diets are optimized and patients have limited access to sugary snacks and drinks.
The NNTs of SGA versus mood stabilizer are similar to SGA versus placebo, and, to date, RCTs have not found mood stabilizers to separate statistically from placebo in terms of response rates. Thus the data do not support the use of mood stabilizer monotherapy in treating children and adolescents who have mania. Although there are no empirical data, combination therapy appears to be quite common in clinical practice. Available evidence indicates that SGA and lithium/valproate and perhaps lithium–valproate combinations are effective in the acute treatment of children and adolescents with mania. Clinicians may have other reasons for prescribing combination therapy during the acute phase of treatment, including, for example, initiating prophylaxis. Data for alternative and psychosocial treatments are too limited to allow comment on their role in acute treatment. Data are also limited for ECT, although our clinical experience has been positive for the one patient per year or so with refractory mania whom we treat with ECT. Of course, patients' improvements may be a result of factors other than the specific benefits of their treatment with medicines.
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