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Table 1 Details of included studies

From: A systematic review of interventions in the early course of bipolar disorder I or II: a report of the International Society for Bipolar Disorders Taskforce on early intervention

Authors

Study design/comparison/population

Sample size

Age, yrs (M ± SD or median, range)

% Female

Outcome/s measured

Main findings

Comments

I. Interventions in early course of illness

Randomised controlled trials

Berk (2017)

RCT comparing maintenance treatment with quetiapine or lithium in patients with recently stabilised first-episode mania with psychotic features (15–25 yrs)

61

21.3 ± 2.3

22%

Symptomatic change, Global Illness Severity, Functioning, Quality of life

Continuation treatment with lithium rather than quetiapine resulted in more favorable mean levels of symptoms and functioning over a 1-year period

Planned secondary analysis and post-hoc analyses

Conus et al. (2015)

RCT comparing the efficacy of chlorpromazine vs olanzapine in patients with first episode of psychotic mania (15–25 yrs)

83

21.5 ± 2.9

32.4%

Efficacy (response on mania and depression scales)

Olanzapine was similar to chlorpromazine in achieving remission from manic symptoms

A priori primary hypothesis with adequate power

Detke et al. (2015)

RCT of Olanzapine-Fluoxetine (OFC) combination vs placebo in adolescents (10–17 yrs) with BD Depression

291

14.7 ± 2.3

49%

Depressive symptoms, adverse events

OFC combination was superior to placebo in adolescents in treating acute depression in the early course of BD

A priori primary hypothesis with adequate power

Kessing (2013)

Kessing et al. (2014a)

RCT comparing treatment in a specialized mood clinic vs standard care in early course of BD

158

Median 35.6 years, quartiles 27.7, 47.1

54.4%

Readmission to hospital,

Treatment satisfaction

Treatment in a specialized mood disorder clinic significantly reduced time to readmissions and improved treatment satisfaction compared with standard care. Those aged 18–25 years had a trend towards more pronounced benefit in specialized treatment increasing time to recurrence (p = 0.05)

A priori primary hypothesis with adequate power

Miklowitz et al. (2003)

RCT comparing Family Focused Psychoeducation (FFT) + pharmacotherapy or crisis management + pharmacotherapy among adults. A majority of the sample was in an early course of illness with ≤ 6 prior episodes

101

35.6 ± 10.2

63.3%

Time to relapse and symptom severity

A majority of participants were in early illness course. Participants receiving FFT had fewer relapses (35% vs 54%) and a longer time to relapse (74 weeks vs 53 weeks). FFT was also associated with better symptomatic control and improved medication adherence

A priori primary hypothesis with adequate power

Miklowitz et al. (2008)

RCT of FFT tailored for Adolescents (FFT-A) compared with Enhanced Care (EC) among adolescents, with both groups receiving pharmacotherapy. FFT was delivered over 21 sessions

58

14.5 ± 1.6

56.9%

Time to recovery and recurrence

There were no group differences on overall time to recovery and recurrence. FFT-A was associated with quicker recovery from depressive episodes and spent fewer weeks in depressive episodes

A priori primary hypothesis with adequate power

Miklowitz et al. (2014)

RCT of FFT-A among adolescents with BD I or II, compared with 3 session family psychoeducation, with both groups receiving pharmacotherapy

145

15.6 ± 1.4

54.5%

Time to recovery and recurrence

There were no group differences in time to recovery and recurrence. Those in FFT-A had greater improvements in manic symptoms particularly between 12 and 24 months

A priori primary hypothesis with adequate power

Patino et al. (2021)

RCT comparing lithium and quetiapine in acute treatment of mania among youth aged 10–17 years, with 85% of the sample having had fewer than 3 prior episodes

107

14.2–15.1 ± 1.9–2.1

57–63%

Response with respect to manic symptoms

Participants treated with quetiapine were more likely to respond (72.4%) than those treated with lithium (49%, p = 0.012). Remission rates did not differ between groups, and symptoms or CGI severity did not differ at end-point

A priori primary outcome was symptom change, response was secondary

Perry et al. (1999)

RCT examining efficacy of education regarding early warning signs of a relapse (psychoeducation). The sample had 5–6 median lifetime bipolar episodes indicating that a majority of the sample was in early illness course

69

44–45 (SD 11–13)

68–69%

Manic or depressive relapses

Time to first manic relapse was significantly longer with respect to manic episodes (25%, 65 wks in experimental group and 17 wks in control group). No significant differences noted for depressive relapses. Total number of manic episodes were fewer (2 vs 11 respectively)

A priori primary hypothesis with adequate power. Likely that predominantly hospitalised episodes were included in count of prior episodes

Strakowski et al. (2016)

Pseudo-Randomized Controlled Trial examining effect of quetiapine or lithium treatment for a first manic episode on brain activation changes. Participants could deviate from assigned intervention

42

18 ± 5 (13–25 years)

60%

Response on mania scales reported as a secondary outcome

Lithium numerically associated with higher response rate (58%) than quetiapine (43%), but this was not statistically significant

Incidental report on outcomes, likely insufficient power

Observational studies of interventions or non-randomised comparisons in RCTs

Craig et al. (2004)

Bromet et al. (2005)

Naturalistic 2-year follow-up study investigating antimanic use or non-use in a cohort of first admission BD (with psychotic features). Several baseline and time-varying confounders considered

Four-year follow up of the same cohort

155 (2 year follow up)

123 (4 year follow up)

–

29.5 ± 12.1

49.4%

52.8%

Global functioning, time in remission

Time to remission and time to relapse

Use of antimanic medications at baseline and 2 years (as well as less use of antipsychotics) associated with higher GAF and greater time in remission

Continuously taking antimanic medications or never using medications were associated with shorter time to remission compared to those who started and then discontinued medications

Possible residual confounding by indication

Hafeman et al. (2020)

Long term naturalistic follow up of youth with BD treated with lithium or Other Mood Stabilizers (OMS). Subgroup data extracted for those with ≤ 6 episodes

271 participants contributing to 1850 six-month treatment periods

12.3–12.6 ± 3.2–3.3

50–56%

Suicidality

Aggression

Functioning

During episodes prescribed lithium there were fewer suicide attempts, and participants had better psychosocial functioning and a lower risk of aggression

Confounding by indication possibly reduced by finding that those prescribed lithium were more unwell at baseline in a sub-proportion

Kessing et al. (2011)

Nationwide registry linkage cohort study comparing first use of lithium vs valproate in BD inpatients

4268

Median 50 years (Quartiles: 39, 60)

58%

Hospital re-admissions

Time to psychiatric hospital admissions was greater for lithium compared to valproate

Possible confounding by indication

Kessing et al. (2012)

Similar registry linkage cohort study to the above study comparing use of lithium vs lamotrigine after first hospitalization for BD

4248

Median 49 years (Quartiles: 48, 60)

59%

Readmissions to hospital, subgrouped by type of bipolar episode; switch to another medication

Switch to another medication, and readmissions were more common in the Lamotrigine group than in the lithium group

Possible confounding by indication

Macneil et al. (2012)

Open label comparative study examining pilot efficacy of CBT vs TAU in a subgroup of those participating in an acute treatment RCT (Conus 2015)

40

21.3–21.8 ± 2.1–2.6

35%

Symptoms, relapse, and functional outcome

Psychotherapy effective in improving functional outcome and reducing depression and overall symptom severity

Potential biases related to selection

Mander (1986)

Registry and medical record-based study of those treated with or without lithium after a first admission for a manic episode

98

35.2–37.5 years ± 13.8–14.3

58.2%

Time to relapse

No group differences for those treated with lithium vs those not treated with lithium. Patients discharged on lithium had longer duration of illness, more severe manic symptoms, and were more likely to be male and from middle class. Lithium treated episodes were associated with significantly greater time to relapse than the episodes where lithium was not used or discontinued

Confounding by indication moderated by the greater severity of symptoms in those prescribed lithium

II. Studies comparing interventions in early vs later course

Randomised controlled trials

Colom et al. (2010a, b)

Post-hoc exploratory sub-analysis of an RCT comparing those receiving psychoeducation vs non-structured group intervention, divided according to the number of previous episodes

120

Approx. 34 years

63.3%

Time to recurrence and time spent ill

Time to recurrence: Those with 6 or fewer episodes had significantly greater benefit with psychoeducation compared to control group

Time spent ill: Those with 6 or fewer (as well as 3 or fewer) episodes and receiving psychoeducation spent less time in any episode polarity compared with controls

Unplanned post-hoc analysis

Ketter et al. (2006)

Post-hoc analysis of RCT investigating the effectiveness of olanzapine vs lithium in preventing recurrence

431

42.3–42.5

 ± 12.3–13.1

52–53%

Recurrence to any mood episode, manic episode, depressive episode

Olanzapine resulted in lower recurrence rate compared to lithium in those with 2 or fewer previous episodes. This differential effect was not evident in those with more than 3 prior episodes

Likely adequate power, not clear if hypothesized A priori

Inder et al. (2015)

Post-hoc analysis of RCT examining the efficacy of Interpersonal and Social Rhythm Therapy (IPSRT) compared with Specialist Supportive Care among participants aged 15–36 years

100

26.6 ± 6.0

76%

Cumulative burden of depressive symptoms based on Psychiatric Status Ratings (PSR) from 6–18 months

There was no difference in the outcome between those with 6 or fewer lifetime mood episodes, compared with those with greater lifetime mood episodes

Unplanned post-hoc analysis

Scott et al. (2006)

RCT examining the effectiveness of CBT vs TAU in those with at least 1 episode in previous year

253

39.7–42.7 ± 10.3–11.4

63–67%

Time to recurrence and overall symptom severity

CBT plus treatment as usual (herewith referred to as CBT) was significantly more effective than treatment as usual alone in those with fewer than 6 prior episodes. Within the CBT group, those with less than 6 prior episodes had a lower risk of relapse compared with those with greater prior episodes

A priori planned post-hoc analysis

Swann et al. (1999)

RCT comparing treatment response in acute mania of lithium, divalproex, and placebo with respect to the number of previous episodes of affective disorders

154

39.1–40.4 ± 11.2–12.8 (based on original cohort of 179)

41.9% (for original cohort of 179)

Treatment response (SADS manic syndrome score)

Lithium and divalproex were significantly more effective than placebo for treating acute mania. Those with 5 (or 6) previous episodes did not have a better response with either medication or placebo

Post-hoc analysis describing continuous relationship between number of episodes and treatment response

Observational studies of interventions or non-randomised comparisons in RCTs

Kessing et al. (2014b)

Prospective registry-based linkage study comparing early vs late intervention with lithium in BD

4714

46.7–49.1 Quartiles- 34.2, 59.3

50.4–58.7%

Readmission to hospital following lithium prescription

Patients who purchased lithium after their first contact or first diagnosis had significantly decreased rates of non-response to lithium compared with the rate for patients starting lithium later

Possible confounding by indication

Pooled analysis of Olanzapine trials comparing early vs late course

Berk et al. (2011)

Pooled data from 12 mania, depression and maintenance studies of olanzapine looking at treatment response according to number of episodes

   

Recurrence and relapse (YMRS score, MADRS, HAMD21 and CGI-BP)

Response rates to olanzapine for mania, depression and maintenance were higher in those with ≤ 5 previous episodes compared to those with > 5 episodes

Pooled post-hoc analyses

Studies included within this analysis

Acute mania studies

• Tohen 1999

• Tohen 2000

• Tohen 2002a,b

• Tohen 2003

• Perlis 2006

Acute depression studies

• Tohen 2003

• Brown 2006

Maintenance studies

• Tohen 2003

• Tohen 2004

• Tohen 2005, Ketter 2006

• Brown 2009

1631

1243

1472

40.2 ± 12.3

40.3 ± 11.3

40.5 ± 11.9

62%

53%

56%

 

Acute mania studies

- Better response in YMRS and HAM-D scores for those with 1–5 episodes compared with > 10 lifetime episodes

Acute depression studies

- Greater response in MADRS scores in those with 1–5 episodes compared with > 10

Maintenance studies

- Lower OR and HR with respect to manic relapse after remission in those with 1–5 episodes compared with > 10 lifetime episodes

- Lower OR but not HR for depressive relapses after remission in those with 1–5 episodes

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