Journal Article Review Dr V K Sahu

Molecular PsychiatryOct 2015

Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following

remission of a manic episode: A CANMAT randomized double-blind trial

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OverviewNatural course of Bipolar - IArticle Proper

MethodStatisticsResultsDiscussionStrengthsLimitationsConclusion Critical analysis

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Natural course of Bipolar - I Bipolar disorder mostly starts as depression (75 % in women

and 67% in men).10-20 % only experience manic episodes.

Remission, and relapse of major depressive episodes, minor and subsyndromal depressive symptoms dominate long-term course by nearly a 3:1 ratio.

Manic episode has rapid onset (hours or days), but may evolve over few weeks.Sadock BJ,Sadock VA, Ruiz P, Course and Prognosis, Mood Disorder, Kaplana & Sadock’s synopsis of Psychiatry, 11th edition, 370-372

Judd LL, Akiskal HS, Schettler PJ, Endicott J, Maser J, Solomon DA et al. The longterm natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry 2002; 59: 530–537

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Natural course of Bipolar - I 90 % of people who had manic episode likely to have

another manic episode. 40-50 % have second episode within 2 years of first episode. As disorder progresses the time interval between episodes

decreases. After 5 episodes it stabilizes between 6-9 months.5-15 % have 4 or more episodes per year.7 % have no recurrences.45 % have more than one episode and 40% have chronic

disorder.

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Natural course of Bipolar - I• Patients may have 2 to 30 episodes, mean number is 9.• 40 % have more than 10 episodes.• So on long term follow up:

• 15 % are well• 45 % have multiple relapses • 30 % are in partial remission• 10 % are chronically ill.

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Molecular Psychiatry

Founded in 1997. Ranked as No.1 Journal in PsychiatryImpact factor :  14.496Editor - Julio Licinio

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Optimal duration of risperidone or olanzapine adjunctivetherapy to mood stabilizer following remission of a manicepisode: A CANMAT randomized double-blind trial

AuthorsLN YathamS Beaulieu A SchafferM Kauer-Sant’AnnaF KapczinskiB LaferV Sharma

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MethodsMulticenter randomized control trial

In 17 Canadian Network for Mood and Anxiety Treatments (CANMAT)-affiliated academic centers

In Canada and collaborating sites in Brazil

Study procedures were approved by the Research Ethics Boards

Written informed consent.

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Method (Contd…)• Subjects were > 17 years old were eligible if they met:

Inclusion Criteria:Diagnosed with Bipolar I disorderTreated within the previous 12 weeks, for a DSM-IV acute

manic or mixed episode. With a combination of mood stabilizer (lithium or valproate)

and atypical antipsychotic (risperidone or olanzapine)

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Method (Contd…)Inclusion criteria (Continued..)

In remission from the manic or mixed episode for at least 2 weeks and no more than 6 weeks based onClinical Global Impression Severity (CGI-S) score of 2

or less for 2 consecutive weeks orYoung Mania Rating Scale (YMRS) score of 8 or less Hamilton Rating Scale for Depression (HAM-D) 21- item

score of 8 or less for two consecutive weeks.

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Method (Contd…)Exclusion criteria:

Those taking other psychotropic medication with the exception of benzodiazepines were excluded

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Method (Contd…)Trial design and interventions:

multi-center three-parallel-group randomized double blind placebo-controlled trial.

Up to 52 weeks of follow-up.

Randomized to one of the three groups.

Randomizations were stratified by drug combination and by center.

Blinding : All except the trial statistician and the pharmacist were blinded.

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Method (Contd…)Trial design and interventions (Contd):

Three groups:

‘0-weeks’ group Tapered and discontinued risperidone or

olanzapine over 2 weeks beginning on the day of randomization

Received placebo substitution for the remaining50 weeks

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Method (Contd…)Trial design and interventions (Contd):

‘24-weeks’ group:Received risperidone or olanzapine for 24 weeks. Antipsychotic was tapered and discontinued over the next 2

weeks with the placebo substitution forthe remaining 26 weeks

‘52-weeks’ group:Continued risperidone or olanzapine for 52 weeks. All patients

continued the same mood stabilizer

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Method (Contd…)Trial design and interventions (Contd):The dose and type of atypical antipsychotic were

the same as the patient had been on at entry into the study.Dosages

Risperidone:1–6 mg per dayOlanzapine: 5–25 mg per day.

No other psychotropic medication except BZD for sedation and anti-parkinsonian medication for extrapyramidal side effects

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Method (Contd…)Trial design and interventions (Contd):

Patients were allowed to receive psychoeducation and counselling (as per clinical indication) for:

Sleep hygieneHealthy daily routines and rhythmsAlcohol and substance abuseAnxiety managementConflict resolutionProblem solving

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Method (Contd…)Study Outcomes:

Assessed biweekly until week 8 week.Every 4 weeks thereafter up to 52 week.Trained raters blind to treatment allocation using:

YMRSHAMDMontgomery-Asberg Depression Rating Scale MADRS).CGI-S Clinical Global Impression-Bipolar Severity (CGI-BP).Clinical Global Impression-Improvement (CGI-I)

(last 2 were assessed 2 week onwards)

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Method (Contd…)Study Outcomes (Continued):

Evaluation of safety and tolerability assessed at baseline and at monthly visits by:

Clinical observationUdvalg for Kliniske Undersøgelser Side Effect Rating Scale

(UKU)Extrapyramidal Symptoms Rating Scale (ESRS).Laboratory measurements on blood sera were obtained at

the screening visit and at weeks 12, 24, 36 and 52.

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Method (Contd…)Primary outcome measure:

Time to any mood episode, defined as any of the following events: YMRS score of 15 or greaterHAM-D 21-item score of 15 or greaterHAM-D suicide item score of 3 or greaterCGI-S score of 3 or greaterHospitalization for treatment of mood symptoms Suicide or suicide attempt.

Patients experiencing a primary event were removed from further study follow-up

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Method (Contd…)Secondary outcome measures :

Time to a manic episodeTime to a depressive episodeTime to premature discontinuation from the study

for any clinical reason Primary endpoint metDose change in risperidone or olanzapineNew interventionAdverse event.

Primary outcome events were classified as manic or depressive based on the CGI-BP, YMRS and HAM-D scores

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Method (Contd…)Sample size:

Planned sample size for the trial was 540 patients (180 per group). To ensure an overall type I error rate less than 5%) with80% power and allowing for a 25% drop-out rate.

Assumed event proportions: 55% in the 0-week group38% (that is, absolute reduction of 17%) in each of the

other two groups.

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Statistical AnalysisConducted on an intent-to-treat basis and included all

randomized patients.Kaplan–Meier cumulative incidence plots were used to

summarize the time to any mood episode by treatment group. For the primary analysis, a Cox proportional hazards model

with adjustment for the antipsychotic drug and for the mood stabilizer drug was used to compare the time to any mood episode across treatment groups.

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ResultsPatient Flow and Characteristics:

Total of 159 patients were randomized 52 to the 0-weeks group54 to the 24-weeks group 53 to the 52-weeks group

Patient characteristics were well-balanced across the groups except:0-weeks group had

higher percentage of womenlower mean weight lower percentage with a history of or currently active

psychiatric comorbidity

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ResultsPatient Flow and Characteristics (Continued):

Patients in the 24-weeks group had a lower percentage with alcohol/substance abuse

34 (21%) patients discontinued the study (8, 14 and 12 patients in the 0-weeks, 24-weeks and 52-

weeks groups, respectively)Mean follow-up times were 18, 25 and 24 weeks for the 0-weeks, 24-weeks and 52-weeks groups, respectively.

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Results

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ResultsTreatment Variables

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Results Primary outcomes:

39 primary events (depression = 25, mania = 14) among 52 patients in the 0-weeks group

29 events (depression = 23, mania = 6) among 54 patients in the 24-weeks group

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ResultsPrimary outcomes (Continued):

29 (depression = 22, mania = 7) events among 53 patients in the 52-weeks group.

time to any mood episode was longer in both 52-weeks and 24-weeks groups compared with the 0-weeks group.

time to any mood episode was similar between the 52-weeks and 24-weeks groups.

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ResultsHazard ratio (HR) for time to any mood episode

0.53 for the 24-weeks group relative to the 0-weeksgroup.

0.63 for the 52-weeks group relative to the 0-weeks group. HR for the 52-weeks group relative to the 24-weeks group

was 1.18 .Estimated 52-week event rates were 65%, 65% and 87%

in the 52-weeks, 24-weeks and 0-weeks groups, respectively.

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ResultsSecondary outcomes:

27 patients met criteria for a manic and 70 for a depressive event.

Time to a manic episode was longer in patients randomized to the 24-weeks and the 52-weeks groups compared with patients randomized to the 0-weeks group statistically significant for the 24-weeks group .

Not for the 52-weeks group

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ResultsSecondary outcomes (Continued):

Time to a manic episode was shorter in the 52-weeks group compared with the 24-weeks groups but the difference was not statistically significant.

Time to a depressive episode was also longer in the 24-weeks and 52-weeks groups compared with the 0-weeks group.This difference was not statistically significant for either group

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ResultsSecondary outcomes (Continued):

Time to a depressive episode was similar in the 52-weeks group compared with the 24-weeks group.

The time to discontinuation - longer in the 24-weeks and the 52-weeks groups compared with the 0-weeks group.Statistically significant only for the 24-weeks group but

not for the 52-weeks group.

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Results Secondary outcomes (Continued):

The time to discontinuation for any clinical reason was similar in the 52-weeks group compared with the 24-weeks group

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ResultsSubgroup analysis:

Olanzapine subgroupTime to any mood episode was longer in both the 24-

weeks and the 52-weeks groups compared with the 0-weeks group,statistical significance for the 52-week group

Time to any mood episode was longer but not statistically significant in the 52-weeks group compared with the 24-weeks group

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Adverse eventsonly serious adverse event recorded was the single death

from pneumonia.Rates of other adverse events were similar

across the three groups

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Discussion Subgroup analysis:

Risperidone subgroup

Time to any mood episode was longer in the 24-weeks group relative to 0-weeks group.Not statistically significant

Surprisingly, the time to any mood episode in the 52-week group was similar to that in the 0-weeks group and shorter than in the 24-weeks group.

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Results Patients in the 52-weeks group gained significantly more weight(also clinically significant weight gain ( 7% or more of baseline weight)⩾

Average change in glucose, cholesterol or triglycerides levels from baseline to last follow-up were similar in all three groups whether including all patients or in either antipsychotic subgroup

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ResultsAdverse events:

Only serious adverse event recorded was the single deathfrom pneumonia

Rates of other adverse events were similar across the three groups

Mean changes in the ESRS total score, Parkinsonism + Dystonia subscale and Dyskinesia subscale were similar across all three groups

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DiscussionFirst study to compare different durations of atypical

antipsychotic adjunctive therapy in the maintenance treatment of bipolar I disorder after remission from an acute manic or mixed episode.

The most important findings of the study are: Time to relapse of any mood episode was significantly

longer in the group that continued atypical antipsychotic adjunctive therapy for 24 weeks compared with the group that had their atypical antipsychotic discontinued at study entry.

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DiscussionThere was a trend for longer time to relapse of any mood

episode in the 52-weeks group compared with the 0-weeks group.

The time to relapse of any mood episode was similar in the 52-weeks group compared with the 24-weeks group; however, the sub-group analysis showed discordance in effects of risperidone and olanzapine beyond 24 weeks.

Weight gain was significantly greater and more patients gained 7% body weight with 52 weeks of continued ⩾antipsychotic use compared with 24 weeks.

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DiscussionAdjunctive atypical antipsychotic therapy was

beneficial for 24 weeks after the remission of an acute manicepisode, the benefits were not readily apparent beyond 24 weeks.

There were no differences in relapse rates between the24-weeks and 52–weeks groups.

More patients had depressive recurrences comparedwith manic recurrences (70 vs 27 events, respectively).

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Discussion• Prophylactic effect of risperidone was apparent only for mania

whereas for olanzapine, the benefit was seen mainly in preventing depression.

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Strengths of studyFirst study to compare different durations of atypical antipsychotic

adjunctive therapy in the maintenance treatment of bipolar I disorder after remission from an acute manic or mixed episode.

Stratified randomized controlled design.

Psychoeducation and counselling were continued during treatment.

Findings of this study are highly clinically relevant and valuable for the management of bipolar disorder.

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LimitationsTrial statistician and the pharmacist were not blinded to treatment arm

allocations.

Included only Olanzapine and risperidone amongst all antipsychotics.

Exclusion criteria not stringent.

Time period of conduct of study not mentioned.

Baseline severity or past history of mood disorders/relapse not mentioned.

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Limitations Final sample size was smaller than expected.Study was not adequately powered for analysis of the

antipsychotic subgroups.Number (or percentage) of patients gaining more weight was

not mentioned. Algorithm (if any) if patient relapse was not mentioned.Relapse rates in follow up of patients beyond 52 weeks can’t

be commented upon because of study design.

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Conclusion Patients on adjunctive risperidone or olanzapine therapy

are less likely to have a recurrence if these medications are continued for 24 weeks vs discontinuing soon after remission of mania. Benefits beyond 24 weeks are not apparent.

Risperidone & Olanzapine adjunctive therapy benefit was more apparent in preventing manic & depressive recurrences respectively.

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ConclusionContinued olanzapine use reduces the risk of recurrence, the

potential benefit should be weighed against a concomitant increased risk of weight gain.

Further studies are warranted to examine the applicability of these findings to other atypical antipsychotics that have less metabolic burden liability.

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Checklist for assessing the quality of quantitative studiesS.NO Criteria Yes (2) Partial

(1)No (0) NA

1 Question/ objective sufficiently described? √2 Study design evident & appropriate? √3 Method of subjective/comparison group selection

or source of information/ input variable describe and appropriate?

√4 Subject ( and comparison group, if applicable)

characteristics sufficiently described? √

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Checklist for assessing the quality of quantitative studies

S No Criteria Yes (2) Partial (1) No (0) NA5 If interventional and random allocation

was possible, was it described? √6 If interventional and blinding of

investigators was possible, was it reported?

√7 If interventional and blinding of subjects

was possible, was it reported? √8 Outcome and (if applicable) exposure

measures well-defined and robust to measurement/misclassification bias? Means of assessment reported

√

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Checklist for assessing the quality of quantitative studies

S No Criteria Yes (2) Partial (1) No (0) NA9 Sample size appropriate? √10 Analytic methods described/justified and

appropriate? √11 Controlled for confounding? √12 Results reported in sufficient detail? √13 Conclusions supported by the results? √

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Critique• Clear message: 4/5• Contribution to literature: 4/5• Potential to change thinking or practice: 4/5• Quality of manuscript: 4/5

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