Bipolar depression: a major unsolved challenge

International Journal of Bipolar Disorders

Table 4 Placebo-controlled trials for acute depression in bipolar disorder

Treatments	Subjects (n)	Responders/subjects (%)		RR [95%CI]
Treatments	Subjects (n)	Drug	Placebo	RR [95%CI]
Anticonvulsants [10 trials, 3 agents]	1281	313/657 [47.6%]	181/624 [29.0%]	1.61 [1.39–1.87]
Antidepressants [12 trials, 11 agents]	1895	383/803 [48.9%]	419/1092 [38.4%]	1.32 [1.07–1.62]
Antipsychotics [13 trials, 6 agents]	6044	2135/3859 [55.3%]	904/2185 [41.4%]	1.28 [1.09–1.51]
Lithium [1 trial, 1 agent]	265	85/136 [62.5%]	72/129 [55.8%]	1.12 [0.92–1.37]
Pooled/totals [36 trials, 21 agents]	9485	2926/5455 [54.4%]	1576/4030 [39.4%]	1.37 [1.30–1.44]

Dropout rates (average: 32.9% [28.0–37.8]) were similar across treatments and with drug or placebo. Response typically involved ≥ 50% improvement in depression symptom ratings. By separate random-effects meta-analysis, antidepressants were statistically more effective than placebo (RR = 1.32 [1.07–1.87]; z = 2.65, p = 0.008), as were the other agents (RR = 1.34 [1.17–1.53]; z = 431, p < 0.0001). The overall weighted average drug vs. placebo difference (RR = 1.37) was highly significant (χ² = 196, p < 0.0001). Antidepressant dose averaged 172 [146–198] mg/day imipramine-equivalent (Baldessarini 2013). Antidepressant monotherapy trials yielded greater drug/placebo differences than with addition to a mood-stabilizer (RR = 1.64 [1.05–2.56] vs. 1.18 [0.96–1.46]). Of note, in 23/36 trials (63.9%) drug was not statistically superior to placebo. Results are ranked by drug/placebo Risk Ratios (RR). [References: Nemeroff et al. (2001); Tohen et al. (2003); Shelton and Stahl (2004); Agosti and Stewart (2008); McElroy et al. (2010); McGirr et al. (2016); Yatham et al. (2018); Vázquez et al. (2017a); Baldessarini et al. (2019b)]