Evidence for clinicians
Atypical antipsychotics for psychosis in adolescents Derryck H Smith MD FRCPC
F
or the current issue of the Journal, we asked Dr Derryck H Smith to comment on and put into context the recent Cochrane review on the use of various atypical antipsychotic medications for adolescents with psychosis (1). Background Schizophrenia often presents in adolescence; however, current treatment guidelines are largely based on studies involving adults with psychosis. Over the past decade, the number of studies investigating treatment of adolescent-onset psychosis has increased. The present systematic review collates and critiques evidence obtained on the use of various atypical antipsychotic medications for adolescents with psychosis. Results Thirteen randomized controlled trials (RCTs) involving a total of 1112 participants were included. No data regarding service utilization, economic outcomes, behaviour or cognitive response were found. Trials were classified into the following groups: Atypical antipsychotics versus placebo: Only two studies compared one atypical antipsychotic medication with placebo. In one study, the number of nonresponders treated with olanzapine was not different from the number treated with placebo (one RCT, n=107; RR 0.84 [95% CI 0.65 to 1.10]); however, significantly more (57% versus 32%) individuals left the study early (one RCT, n=107; RR 0.56 [95% CI 0.36 to 0.87]) from the placebo group compared with the olanzapine group. With regard to adverse effects, young individuals treated with aripiprazole had significantly lower serum cholesterol levels compared with those given placebo (one RCT, n=302; RR 3.77 [95% CI 1.88 to 7.58]). Atypical antipsychotics versus typical antipsychotics: When the findings of all five trials comparing atypical antipsychotic medications with a typical antipsychotic medication were collated, no difference in the mean end point Brief Psychiatric Rating Scale (BPRS) score was noted between the two arms (five RCTs, n=236; mean difference −1.08 [95% CI −3.08 to 0.93]). With regard to adverse effects, the mean end point serum prolactin level was much higher than the reference range for treatment with risperidone, olanzapine and molindone in one of the studies. However, fewer adolescents who were receiving atypical antipsychotic medications left the study because of adverse effects (three RCTs, n=187; RR 0.65 [95% CI 0.36 to 1.15]) or for any reason (three RCTs, n=187; RR 0.62 [95% CI 0.39 to 0.97]). One atypical antipsychotic versus another atypical antipsychotic: The mean end point BPRS score was not significantly different for patients who received risperidone compared with those who received olanzapine; however, the above data were highly skewed. Overall, no difference was noted in the number of individuals leaving the studies early because of any adverse effects between each study arm in the three studies comparing olanzapine and risperidone
(three RCTs, n=130; RR 1.15 [95% CI 0.44 to 3.04]). Specific adverse events were not reported uniformly across the six different studies included in this section of the review; therefore, it was difficult to perform a head-to-head comparison of adverse events for different atypical antipsychotic medications. Lower-dose atypical antipsychotic versus standard/higher-dose atypical antipsychotic: Three studies reported comparisons of lower doses of the atypical antipsychotic medication with standard/ higher doses of the same medication. One study reported better symptom reduction with a standard dose of risperidone compared with a low dose (one RCT, n=257; RR −8.00 [95% CI −13.75 to −2.25]). In another study, no difference was reported in the number of participants not achieving remission between the group receiving 10 mg/day and those receiving 30 mg/day of aripiprazole (one RCT, n=196; RR 0.84 [95% CI 0.48 to 1.48]). Similarly, in the third study, authors reported no statistically significant difference in clinical response between the two groups receiving lowerdose (80 mg/day) and higher-dose (160 mg/day) ziprasidone, as reflected by the mean end point BPRS score (one RCT, n=17; mean difference −4.40 [95% CI −19.20 to 10.40]). Conclusions There is no convincing evidence to suggest that atypical antipsychotic medications are superior to typical medications for the treatment of adolescents with psychosis. However, atypical antipsychotic medications may be more acceptable to young individuals because fewer symptomatic adverse effects are observed in the short term. Little evidence is available to support the superiority of one atypical antipsychotic medication over another; however, side-effect profiles are different for different medications. Treatment with olanzapine, risperidone and clozapine is often associated with weight gain. Aripiprazole is not associated with increased prolactin or with dyslipidemia. Adolescents may respond better to standard-dose as opposed to lower-dose risperidone; however, for aripiprazole and ziprasidone, lower doses may be equally effective. Future trials should ensure uniform methods of reporting. The full text of the Cochrane Review is available in The Cochrane Library (1).
Expert Commentary
This is an important study and the results are self evident. I will raise more concerns over the issue of weight gain and metabolic monitoring in teens and, for that matter, children initially. Antipsychotic medications have been used in adolescents and children for many years, initially focusing on psychotic illness. Until recently, however, there have been no formal Health Canada approvals for the use of antipsychotic medications. Over the past several years, an increasing number of children and adolescents have been treated with antipsychotic medications for other conditions such as attention-deficit hyperactivity disorder
Correspondence: Dr Derryck H Smith, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia. Telephone 604-879-2200, fax 604-879-2248, e-mail [email protected] Accepted for publication July 16, 2014 Paediatr Child Health Vol 19 No 8 October 2014
©2014 Pulsus Group Inc. All rights reserved
405
Evidence for Clinicians
(ADHD), conduct disorder or oppositional defiant disorder – all diagnoses that feature prominent behavioural disturbances. By 2009, it was evident that although most of the prescriptions for antipsychotics were being written by psychiatrists (62%), the remainder of the prescriptions were being ordered by family physicians (2). In the same article, it was noted that 17% of the antipsychotics in Canada are prescribed for ADHD and the use of antipsychotic medications for ADHD in the United States varied from 29% to 61% of all prescriptions. The editorial concludes that “rapidly increasing antipsychotic treatment of children and adolescents stands in sharp contrast with the slow and steady accumulation of reliable efficacy information from controlled trials in this age group”. Patten et al (3) recently noted that antipsychotics are almost always prescribed off label. A single agent, aripiprazole, has recently received regulatory authorization for schizophrenia and bipolar illness. This report showed considerable differences in the use of atypical antipsychotics among studies and across various countries. Ninety-five percent of all prescribing of antipsychotics was for atypical antipsychotics and, internationally, most studies identified risperidone as the most widely prescribed agent. The increased use appears to be most often connected with treating ADHD, conduct and behavioural disturbances. Other authors have raised concern regarding growing evidence of weight gain and metabolic abnormalities, and the paucity of data supporting the efficacy of atypical antipsychotics for use in treating disruptive behaviour disorders (4). Concerns regarding metabolic side effects were highlighted by an article by Panagiotopoulos et al (5) in May 2010. At this point, there were no indications for the use of atypical antipsychotics in children or youth. A wide range of metabolic side effects were identified including weight gain, increased waist circumference, dysglycemia, dyslipidemia, hypertension and elevated hepatic transaminase and prolactin levels. The authors proposed several tools for metabolic monitoring (5). Finally, the Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children Group published specific monitoring and treatment recommendations if metabolic side effects are encountered (6). A specific handbook for physicians has been developed at the BC Children’s Hospital and can be downloaded from the Internet (www.bcchildrens.ca/NR/rdonlyres/45697169-42E2-45E6-B8700C1A8EC3C164/46605/metmonhb.pdf).
References
1. Kumar A, Datta SS, Wright SD, Furtado VA, Russell PS. Atypical antipsychotics for psychosis in adolescents. Cochrane Database Syst Rev 2013(10):CD009582. 2. Olfson M. Epidemiologic and clinical perspectives on antipsychotic treatment of children and adolescents. Can J Psychiatry 2012;57:715-6. 3. Patten SB, Waheed W, Bresee L. A review of pharmacoepidemiologic studies of antipsychotic use in children and adolescents. Can J Psychiatry 2012;57:717-21. 4. Pringsheim T, Gorman D. Second-generation antipsychotics for the treatment of disruptive behavior disorders in children: A systematic review. Can J Psychiatry 2012;57:722-7.
Based on the current review of the Cochrane Collaboration Review of atypical antipsychotics for adolescents, it is evident that there is no superiority of atypical antipsychotics over typical antipsychotics (also referred to as second-generation antipsychotics). It is evident in practice, however, that the vast majority of clinicians, particularly those whose training has been completed within the past 10 years, do not prescribe typical antipsychotics. Furthermore, it is evident that atypical antipsychotics have side effects that may be more disabling than the side effects observed with typical antipsychotics, specifically metabolic syndrome. My recommendations for the use of antipsychotic medications in adolescents would be as follows: • Given the risk-to-benefit ratio, these medications should primarily be used for treating psychotic disorders. The use of these medications for managing behavioural disruptions, anxiety or depression, or as sleeping aids should be minimized. • Patients should be on the lowest possible dose to manage their symptoms. There should be consistent follow-up provided to ensure that symptoms remain suppressed, particularly in psychotic disorders, and that the patients are not developing any signs of metabolic syndrome. • Community physicians, including family doctors and pediatricians, should be comfortable starting these medications when treating a psychotic illness, but should obtain a psychiatric consultation as soon as possible. • In choosing medications, the first line of treatment should be using medications with a more favourable metabolic side-effect profile such as aripiprazole and ziprasidone. Although olanzapine is a highly effective antipsychotic, its use should be minimized because it is the most likely to induce metabolic syndrome in my experience. Clozapine remains the most effective of all the antipsychotic medications, but requires special monitoring and should be reserved for patients who do not respond to first-line treatment. I would not hesitate using clozapine, however, in an adolescent patient with psychosis who has not responded to standard atypical treatment. • Children and adolescents should be screened for metabolic parameters before beginning treatment with atypical antipsychotics and should receive regular monitoring of these parameters, as outlined in the guidelines that have been referenced in the present report. 5. Panagiotopoulos C, Ronsley R, Elbe D, Davidson J, Smith DH. First do no harm: Promoting an evidence-based approach to atypical antipsychotic use in children and adolescents. J Can Acad Child Adolesc Psychiatry 2010;19:124-37. 6. Ho J, Panagiotopoulos C, McCrindle B, Grisaru S, Pringsheim T; CAMESA guideline group. Management recommendations for metabolic complications associated with second generation antipsychotic use in children and youth. J Can Acad Child Adolesc Psychiatry 2011;20:3.
The Evidence for Clinicians columns are coordinated by the Child Health Field of the Cochrane Collaboration (www.cochranechildhealth.org). To submit a question for upcoming columns, please contact us at [email protected].
406
Paediatr Child Health Vol 19 No 8 October 2014
Atypical antipsychotics for psychosis in adolescents Derryck H Smith MD FRCPC
F
or the current issue of the Journal, we asked Dr Derryck H Smith to comment on and put into context the recent Cochrane review on the use of various atypical antipsychotic medications for adolescents with psychosis (1). Background Schizophrenia often presents in adolescence; however, current treatment guidelines are largely based on studies involving adults with psychosis. Over the past decade, the number of studies investigating treatment of adolescent-onset psychosis has increased. The present systematic review collates and critiques evidence obtained on the use of various atypical antipsychotic medications for adolescents with psychosis. Results Thirteen randomized controlled trials (RCTs) involving a total of 1112 participants were included. No data regarding service utilization, economic outcomes, behaviour or cognitive response were found. Trials were classified into the following groups: Atypical antipsychotics versus placebo: Only two studies compared one atypical antipsychotic medication with placebo. In one study, the number of nonresponders treated with olanzapine was not different from the number treated with placebo (one RCT, n=107; RR 0.84 [95% CI 0.65 to 1.10]); however, significantly more (57% versus 32%) individuals left the study early (one RCT, n=107; RR 0.56 [95% CI 0.36 to 0.87]) from the placebo group compared with the olanzapine group. With regard to adverse effects, young individuals treated with aripiprazole had significantly lower serum cholesterol levels compared with those given placebo (one RCT, n=302; RR 3.77 [95% CI 1.88 to 7.58]). Atypical antipsychotics versus typical antipsychotics: When the findings of all five trials comparing atypical antipsychotic medications with a typical antipsychotic medication were collated, no difference in the mean end point Brief Psychiatric Rating Scale (BPRS) score was noted between the two arms (five RCTs, n=236; mean difference −1.08 [95% CI −3.08 to 0.93]). With regard to adverse effects, the mean end point serum prolactin level was much higher than the reference range for treatment with risperidone, olanzapine and molindone in one of the studies. However, fewer adolescents who were receiving atypical antipsychotic medications left the study because of adverse effects (three RCTs, n=187; RR 0.65 [95% CI 0.36 to 1.15]) or for any reason (three RCTs, n=187; RR 0.62 [95% CI 0.39 to 0.97]). One atypical antipsychotic versus another atypical antipsychotic: The mean end point BPRS score was not significantly different for patients who received risperidone compared with those who received olanzapine; however, the above data were highly skewed. Overall, no difference was noted in the number of individuals leaving the studies early because of any adverse effects between each study arm in the three studies comparing olanzapine and risperidone
(three RCTs, n=130; RR 1.15 [95% CI 0.44 to 3.04]). Specific adverse events were not reported uniformly across the six different studies included in this section of the review; therefore, it was difficult to perform a head-to-head comparison of adverse events for different atypical antipsychotic medications. Lower-dose atypical antipsychotic versus standard/higher-dose atypical antipsychotic: Three studies reported comparisons of lower doses of the atypical antipsychotic medication with standard/ higher doses of the same medication. One study reported better symptom reduction with a standard dose of risperidone compared with a low dose (one RCT, n=257; RR −8.00 [95% CI −13.75 to −2.25]). In another study, no difference was reported in the number of participants not achieving remission between the group receiving 10 mg/day and those receiving 30 mg/day of aripiprazole (one RCT, n=196; RR 0.84 [95% CI 0.48 to 1.48]). Similarly, in the third study, authors reported no statistically significant difference in clinical response between the two groups receiving lowerdose (80 mg/day) and higher-dose (160 mg/day) ziprasidone, as reflected by the mean end point BPRS score (one RCT, n=17; mean difference −4.40 [95% CI −19.20 to 10.40]). Conclusions There is no convincing evidence to suggest that atypical antipsychotic medications are superior to typical medications for the treatment of adolescents with psychosis. However, atypical antipsychotic medications may be more acceptable to young individuals because fewer symptomatic adverse effects are observed in the short term. Little evidence is available to support the superiority of one atypical antipsychotic medication over another; however, side-effect profiles are different for different medications. Treatment with olanzapine, risperidone and clozapine is often associated with weight gain. Aripiprazole is not associated with increased prolactin or with dyslipidemia. Adolescents may respond better to standard-dose as opposed to lower-dose risperidone; however, for aripiprazole and ziprasidone, lower doses may be equally effective. Future trials should ensure uniform methods of reporting. The full text of the Cochrane Review is available in The Cochrane Library (1).
Expert Commentary
This is an important study and the results are self evident. I will raise more concerns over the issue of weight gain and metabolic monitoring in teens and, for that matter, children initially. Antipsychotic medications have been used in adolescents and children for many years, initially focusing on psychotic illness. Until recently, however, there have been no formal Health Canada approvals for the use of antipsychotic medications. Over the past several years, an increasing number of children and adolescents have been treated with antipsychotic medications for other conditions such as attention-deficit hyperactivity disorder
Correspondence: Dr Derryck H Smith, Department of Psychiatry, University of British Columbia, Vancouver, British Columbia. Telephone 604-879-2200, fax 604-879-2248, e-mail [email protected] Accepted for publication July 16, 2014 Paediatr Child Health Vol 19 No 8 October 2014
©2014 Pulsus Group Inc. All rights reserved
405
Evidence for Clinicians
(ADHD), conduct disorder or oppositional defiant disorder – all diagnoses that feature prominent behavioural disturbances. By 2009, it was evident that although most of the prescriptions for antipsychotics were being written by psychiatrists (62%), the remainder of the prescriptions were being ordered by family physicians (2). In the same article, it was noted that 17% of the antipsychotics in Canada are prescribed for ADHD and the use of antipsychotic medications for ADHD in the United States varied from 29% to 61% of all prescriptions. The editorial concludes that “rapidly increasing antipsychotic treatment of children and adolescents stands in sharp contrast with the slow and steady accumulation of reliable efficacy information from controlled trials in this age group”. Patten et al (3) recently noted that antipsychotics are almost always prescribed off label. A single agent, aripiprazole, has recently received regulatory authorization for schizophrenia and bipolar illness. This report showed considerable differences in the use of atypical antipsychotics among studies and across various countries. Ninety-five percent of all prescribing of antipsychotics was for atypical antipsychotics and, internationally, most studies identified risperidone as the most widely prescribed agent. The increased use appears to be most often connected with treating ADHD, conduct and behavioural disturbances. Other authors have raised concern regarding growing evidence of weight gain and metabolic abnormalities, and the paucity of data supporting the efficacy of atypical antipsychotics for use in treating disruptive behaviour disorders (4). Concerns regarding metabolic side effects were highlighted by an article by Panagiotopoulos et al (5) in May 2010. At this point, there were no indications for the use of atypical antipsychotics in children or youth. A wide range of metabolic side effects were identified including weight gain, increased waist circumference, dysglycemia, dyslipidemia, hypertension and elevated hepatic transaminase and prolactin levels. The authors proposed several tools for metabolic monitoring (5). Finally, the Canadian Alliance for Monitoring Effectiveness and Safety of Antipsychotics in Children Group published specific monitoring and treatment recommendations if metabolic side effects are encountered (6). A specific handbook for physicians has been developed at the BC Children’s Hospital and can be downloaded from the Internet (www.bcchildrens.ca/NR/rdonlyres/45697169-42E2-45E6-B8700C1A8EC3C164/46605/metmonhb.pdf).
References
1. Kumar A, Datta SS, Wright SD, Furtado VA, Russell PS. Atypical antipsychotics for psychosis in adolescents. Cochrane Database Syst Rev 2013(10):CD009582. 2. Olfson M. Epidemiologic and clinical perspectives on antipsychotic treatment of children and adolescents. Can J Psychiatry 2012;57:715-6. 3. Patten SB, Waheed W, Bresee L. A review of pharmacoepidemiologic studies of antipsychotic use in children and adolescents. Can J Psychiatry 2012;57:717-21. 4. Pringsheim T, Gorman D. Second-generation antipsychotics for the treatment of disruptive behavior disorders in children: A systematic review. Can J Psychiatry 2012;57:722-7.
Based on the current review of the Cochrane Collaboration Review of atypical antipsychotics for adolescents, it is evident that there is no superiority of atypical antipsychotics over typical antipsychotics (also referred to as second-generation antipsychotics). It is evident in practice, however, that the vast majority of clinicians, particularly those whose training has been completed within the past 10 years, do not prescribe typical antipsychotics. Furthermore, it is evident that atypical antipsychotics have side effects that may be more disabling than the side effects observed with typical antipsychotics, specifically metabolic syndrome. My recommendations for the use of antipsychotic medications in adolescents would be as follows: • Given the risk-to-benefit ratio, these medications should primarily be used for treating psychotic disorders. The use of these medications for managing behavioural disruptions, anxiety or depression, or as sleeping aids should be minimized. • Patients should be on the lowest possible dose to manage their symptoms. There should be consistent follow-up provided to ensure that symptoms remain suppressed, particularly in psychotic disorders, and that the patients are not developing any signs of metabolic syndrome. • Community physicians, including family doctors and pediatricians, should be comfortable starting these medications when treating a psychotic illness, but should obtain a psychiatric consultation as soon as possible. • In choosing medications, the first line of treatment should be using medications with a more favourable metabolic side-effect profile such as aripiprazole and ziprasidone. Although olanzapine is a highly effective antipsychotic, its use should be minimized because it is the most likely to induce metabolic syndrome in my experience. Clozapine remains the most effective of all the antipsychotic medications, but requires special monitoring and should be reserved for patients who do not respond to first-line treatment. I would not hesitate using clozapine, however, in an adolescent patient with psychosis who has not responded to standard atypical treatment. • Children and adolescents should be screened for metabolic parameters before beginning treatment with atypical antipsychotics and should receive regular monitoring of these parameters, as outlined in the guidelines that have been referenced in the present report. 5. Panagiotopoulos C, Ronsley R, Elbe D, Davidson J, Smith DH. First do no harm: Promoting an evidence-based approach to atypical antipsychotic use in children and adolescents. J Can Acad Child Adolesc Psychiatry 2010;19:124-37. 6. Ho J, Panagiotopoulos C, McCrindle B, Grisaru S, Pringsheim T; CAMESA guideline group. Management recommendations for metabolic complications associated with second generation antipsychotic use in children and youth. J Can Acad Child Adolesc Psychiatry 2011;20:3.
The Evidence for Clinicians columns are coordinated by the Child Health Field of the Cochrane Collaboration (www.cochranechildhealth.org). To submit a question for upcoming columns, please contact us at [email protected].
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Paediatr Child Health Vol 19 No 8 October 2014
