Authors | Study design/comparison/population | Sample size | Age, yrs (M ± SD or median, range) | % Female | Outcome/s measured | Main findings | Comments |
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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 50Â 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 49Â 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 | |||||||
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. 34Â 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 |  |