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Individualising therapy using individual participant data
Comment
Individualising therapy using individual participant data Mania is the quintessence of bipolar disorder; indeed, diagnosis of the illness is contingent on the existence of mania, and its presence suggests specific therapeutic approaches are required. But in reality, such therapeutic precision is seldom the case, and a cursory examination of mania treatment guidelines reveals no consensus regarding optimal treatment strategies.1,2 A number of different drug options are available, with varying anti-manic efficacy and differential behavioural and cognitive effects.1 Remarkably, with respect to illness characteristics, little is known about the extent to which initial symptom severity determines treatment effectiveness.3 In this context, the novel study by Myrto Samara and colleagues in The Lancet Psychiatry4 provides some valuable insights. The analysis by Samara and colleagues determines the relationship between baseline severity of mania and the change in symptoms after treatment with olanzapine. Symptom scores were derived from ratings using the Young Mania Rating Scale (YMRS) and changes in scores were compared with placebo during a period of up to 3 weeks of treatment. The findings suggest that those individuals with greatest symptomatic severity at baseline benefit the most from olanzapine, whereas those with less severe symptoms benefit much less, but still endure side-effects to the same extent as those who were more severely ill to begin with. The mean estimated differences in YMRS score are 2·56 points for patients with a baseline score of 20–25, 4·74 points for a baseline score of 25–35, and 8·01 points for a baseline score of 35–60. Samara and colleagues elucidate these significant results by doing a sophisticated metaanalysis of individual participant data that are drawn from five double-blind, randomised controlled trials that compared the effects of olanzapine and placebo in a total of 939 patients with bipolar I disorder with acute mania. The findings of this study are immensely important because they highlight a crucial clinical issue—namely, if patients with mania who are mildly ill do not respond to the same extent as those who are severely ill when treated with antipsychotics (such as olanzapine), but still experience detrimental effects to the same degree (especially in the long term), then this difference in risk– benefit should be reflected in psychiatric practice and included in clinical treatment guidelines.
The authors are able to identify this nuance because of their use of individual participant data, which also safeguards against an ecological fallacy when inferring from their findings. Furthermore, as the authors themselves point out, by including a placebo comparison and examining specifically the difference in symptom improvement, they avoid the findings of the study being confounded by Wilder’s law of initial value. In short, the results are robust and meaningful. But what do the findings mean? Since the burden of treatment side-effects is the same for those who have a severe presentation of mania versus those who have a mild or modest presentation, the findings of the study
Lancet Psychiatry 2017 Published Online September 19, 2017 http://dx.doi.org/10.1016/ S2215-0366(17)30370-X See Online/Articles http://dx.doi.org/10.1016/ S2215-0366(17)30331-0
Acute Continuation Maintenance
Severe
Moderate
Mild
Time
Figure: Transitioned management of bipolar I disorder The circles represent changes in medication and the relative size of the circles reflects their side-effect burden. Severe, moderate, and mild refers to intensity or severity of symptoms or illness. In practice, management of the disorder should be reviewed and revised at each point of transition, from the acute phase of treatment to continuation, and then once again some time later when symptoms have fully remitted and the focus of management shifts to prophylaxis with maintenance therapy. For example, the treatment of acute full-blown mania could commence with olanzapine (in conjunction with a suitable benzodiazepine), and once the severity of acute symptoms has abated the antipsychotic could be switched to another antipsychotic (such as aripiprazole, which is somewhat better tolerated and poses fewer long-term risks than olanzapine). This approach could then be continued until manic symptoms fully remit and the goal of treatment progresses to prophylaxis with maintenance therapy (for example, with lithium).
www.thelancet.com/psychiatry Published online September 19, 2017 http://dx.doi.org/10.1016/S2215-0366(17)30370-X
1
Comment
suggest that drugs such as olanzapine, which have a poor tolerability profile, should be reserved for the treatment of more severe presentations, simply because this is where they have the potential to confer greatest benefit and concomitant side-effects can, to some extent, be justified. Clinically, this means that when the severity of mania symptoms is either mild or perhaps even moderate, alternative treatments could be considered from the outset. Even in cases of severe mania, where potent medications such as olanzapine clearly serve a purpose, once acute symptoms begin to subside the medication should be switched to one that is better tolerated.5 But implementation of such strategies is problematic because the management of severe manic symptoms usually requires an initial brief period of hospital admission, after which, as the patient improves and transfers to community care, the drug regimen commenced in hospital is often continued unchanged, with only dose and administration times being adjusted. This inertia in pharmacotherapeutic strategy means that once a drug is initiated, it may well remain part of the armamentarium— even when the symptom profile changes markedly. This is clearly poor practice because the treatment phases of bipolar disorder require different treatment strategies and should be regarded as separate stages of illness (figure). But switching medication might not be always necessary, especially if a tolerable drug has been used at the outset. In such cases (eg, mania of mild or moderate severity), changes could simply be alterations in drug dose, with downward titration geared to reducing side effects.
2
This study has led the way in individualising therapy from the outset, and the next step should be to extend this approach to other anti-manic drugs, and to determine the profile for drugs in relation to baseline severity of illness. Research should also target real-world populations as opposed to trial participants, to enhance generalisability of findings. The findings of this study should also inform clinical practice guidelines for the management of mood disorders, and in so doing ensure that treatment is tailored to symptom profile, illness severity, and the phase of management. Gin S Malhi Academic Department of Psychiatry, CADE Clinic, Royal North Shore Hospital, and Sydney Medical School, University of Sydney, Sydney 2065, NSW, Australia [email protected] I report grants from NHMRC, Ramsay Research and Teaching Fund, American Foundation for Suicide Prevention, and the NSW Agency for Clinical Innovation and NSW Ministry of Health, and personal fees from Astrazeneca, Elsevier, Lundbeck, Janssen-Cilag, and Servier. 1 2
3 4
5
Malhi GS, Bassett D, Boyce P, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust NZ J Psychiatry 2015; 49: 1087–1206. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2016; 30: 495–553. Tohen M, Chengappa RK, Suppes T, et al. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v mood stabiliser alone. Br J Psychiatry 2004; 184: 337–45. Samara MT, Goldberg Y, Levine SZ, et al. IInitial symptom severity of bipolar I disorder and the efficacy of olanzapine: a meta-analysis of individual participant data from five placebo-controlled studies. Lancet Psychiatry 2017; published online Sept 19. http://dx.doi.org/10.1016/S22150366(17)30331-0. Malhi G, Morris G, Hamilton A, Outhred T, Das P. Defining the role of SGAs in the long-term treatment of bipolar disorder. Bipolar Disord 2017; 9: 65–67.
www.thelancet.com/psychiatry Published online September 19, 2017 http://dx.doi.org/10.1016/S2215-0366(17)30370-X
Individualising therapy using individual participant data Mania is the quintessence of bipolar disorder; indeed, diagnosis of the illness is contingent on the existence of mania, and its presence suggests specific therapeutic approaches are required. But in reality, such therapeutic precision is seldom the case, and a cursory examination of mania treatment guidelines reveals no consensus regarding optimal treatment strategies.1,2 A number of different drug options are available, with varying anti-manic efficacy and differential behavioural and cognitive effects.1 Remarkably, with respect to illness characteristics, little is known about the extent to which initial symptom severity determines treatment effectiveness.3 In this context, the novel study by Myrto Samara and colleagues in The Lancet Psychiatry4 provides some valuable insights. The analysis by Samara and colleagues determines the relationship between baseline severity of mania and the change in symptoms after treatment with olanzapine. Symptom scores were derived from ratings using the Young Mania Rating Scale (YMRS) and changes in scores were compared with placebo during a period of up to 3 weeks of treatment. The findings suggest that those individuals with greatest symptomatic severity at baseline benefit the most from olanzapine, whereas those with less severe symptoms benefit much less, but still endure side-effects to the same extent as those who were more severely ill to begin with. The mean estimated differences in YMRS score are 2·56 points for patients with a baseline score of 20–25, 4·74 points for a baseline score of 25–35, and 8·01 points for a baseline score of 35–60. Samara and colleagues elucidate these significant results by doing a sophisticated metaanalysis of individual participant data that are drawn from five double-blind, randomised controlled trials that compared the effects of olanzapine and placebo in a total of 939 patients with bipolar I disorder with acute mania. The findings of this study are immensely important because they highlight a crucial clinical issue—namely, if patients with mania who are mildly ill do not respond to the same extent as those who are severely ill when treated with antipsychotics (such as olanzapine), but still experience detrimental effects to the same degree (especially in the long term), then this difference in risk– benefit should be reflected in psychiatric practice and included in clinical treatment guidelines.
The authors are able to identify this nuance because of their use of individual participant data, which also safeguards against an ecological fallacy when inferring from their findings. Furthermore, as the authors themselves point out, by including a placebo comparison and examining specifically the difference in symptom improvement, they avoid the findings of the study being confounded by Wilder’s law of initial value. In short, the results are robust and meaningful. But what do the findings mean? Since the burden of treatment side-effects is the same for those who have a severe presentation of mania versus those who have a mild or modest presentation, the findings of the study
Lancet Psychiatry 2017 Published Online September 19, 2017 http://dx.doi.org/10.1016/ S2215-0366(17)30370-X See Online/Articles http://dx.doi.org/10.1016/ S2215-0366(17)30331-0
Acute Continuation Maintenance
Severe
Moderate
Mild
Time
Figure: Transitioned management of bipolar I disorder The circles represent changes in medication and the relative size of the circles reflects their side-effect burden. Severe, moderate, and mild refers to intensity or severity of symptoms or illness. In practice, management of the disorder should be reviewed and revised at each point of transition, from the acute phase of treatment to continuation, and then once again some time later when symptoms have fully remitted and the focus of management shifts to prophylaxis with maintenance therapy. For example, the treatment of acute full-blown mania could commence with olanzapine (in conjunction with a suitable benzodiazepine), and once the severity of acute symptoms has abated the antipsychotic could be switched to another antipsychotic (such as aripiprazole, which is somewhat better tolerated and poses fewer long-term risks than olanzapine). This approach could then be continued until manic symptoms fully remit and the goal of treatment progresses to prophylaxis with maintenance therapy (for example, with lithium).
www.thelancet.com/psychiatry Published online September 19, 2017 http://dx.doi.org/10.1016/S2215-0366(17)30370-X
1
Comment
suggest that drugs such as olanzapine, which have a poor tolerability profile, should be reserved for the treatment of more severe presentations, simply because this is where they have the potential to confer greatest benefit and concomitant side-effects can, to some extent, be justified. Clinically, this means that when the severity of mania symptoms is either mild or perhaps even moderate, alternative treatments could be considered from the outset. Even in cases of severe mania, where potent medications such as olanzapine clearly serve a purpose, once acute symptoms begin to subside the medication should be switched to one that is better tolerated.5 But implementation of such strategies is problematic because the management of severe manic symptoms usually requires an initial brief period of hospital admission, after which, as the patient improves and transfers to community care, the drug regimen commenced in hospital is often continued unchanged, with only dose and administration times being adjusted. This inertia in pharmacotherapeutic strategy means that once a drug is initiated, it may well remain part of the armamentarium— even when the symptom profile changes markedly. This is clearly poor practice because the treatment phases of bipolar disorder require different treatment strategies and should be regarded as separate stages of illness (figure). But switching medication might not be always necessary, especially if a tolerable drug has been used at the outset. In such cases (eg, mania of mild or moderate severity), changes could simply be alterations in drug dose, with downward titration geared to reducing side effects.
2
This study has led the way in individualising therapy from the outset, and the next step should be to extend this approach to other anti-manic drugs, and to determine the profile for drugs in relation to baseline severity of illness. Research should also target real-world populations as opposed to trial participants, to enhance generalisability of findings. The findings of this study should also inform clinical practice guidelines for the management of mood disorders, and in so doing ensure that treatment is tailored to symptom profile, illness severity, and the phase of management. Gin S Malhi Academic Department of Psychiatry, CADE Clinic, Royal North Shore Hospital, and Sydney Medical School, University of Sydney, Sydney 2065, NSW, Australia [email protected] I report grants from NHMRC, Ramsay Research and Teaching Fund, American Foundation for Suicide Prevention, and the NSW Agency for Clinical Innovation and NSW Ministry of Health, and personal fees from Astrazeneca, Elsevier, Lundbeck, Janssen-Cilag, and Servier. 1 2
3 4
5
Malhi GS, Bassett D, Boyce P, et al. Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust NZ J Psychiatry 2015; 49: 1087–1206. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2016; 30: 495–553. Tohen M, Chengappa RK, Suppes T, et al. Relapse prevention in bipolar I disorder: 18-month comparison of olanzapine plus mood stabiliser v mood stabiliser alone. Br J Psychiatry 2004; 184: 337–45. Samara MT, Goldberg Y, Levine SZ, et al. IInitial symptom severity of bipolar I disorder and the efficacy of olanzapine: a meta-analysis of individual participant data from five placebo-controlled studies. Lancet Psychiatry 2017; published online Sept 19. http://dx.doi.org/10.1016/S22150366(17)30331-0. Malhi G, Morris G, Hamilton A, Outhred T, Das P. Defining the role of SGAs in the long-term treatment of bipolar disorder. Bipolar Disord 2017; 9: 65–67.
www.thelancet.com/psychiatry Published online September 19, 2017 http://dx.doi.org/10.1016/S2215-0366(17)30370-X