Journal of Affective Disorders 308 (2022) 268–280

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Journal of Affective Disorders

journal homepage: www.elsevier.com/locate/jad

Review article

Lithium in the treatment of acute bipolar depression: A systematic review

and meta-analysis
Jeffrey J. Rakofsky *, Michael J. Lucido, Boadie W. Dunlop
Emory University, Atlanta, GA, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Objectives: To evaluate lithium in the treatment of acute bipolar depression.

Bipolar depression Methods: We conducted a systematic literature review for: 1) cross-over or parallel-group design studies
lithium comparing lithium response in bipolar versus unipolar depressed patients, and 2) parallel group studies of bipolar
meta-analysis
depressed patients comparing lithium versus placebo or other psychotropics. Meta-analyses using response rate
as the primary outcome were conducted to evaluate lithium's efficacy.
Results: The literature search yielded 947 records. Ultimately, 17 studies were included, totaling 1545 patients,
including 676 who received lithium. The overall summary effects reveal that there were no statistically signif­
icant differences between lithium versus antidepressants or placebo, however, lithium performed numerically
worse than antidepressants (RR = 0.61; 95%CI, 0.37–1.02; p = 0.06) but better than placebo (RR = 1.18; 95%CI,
0.99–1.41; p = 0.07). The specificity of lithium for bipolar versus unipolar depression was not supported in the
primary analysis of all trials, though an analysis limited to double-blinded, monotherapy, cross-over studies
revealed a statistically significant result supporting lithium's efficacy for those with bipolar depression.
Limitations: Limitations include study selection rules, the use of response rates rather than remission rates or
continuous score outcomes, and the small number of studies included in each meta-analysis.
Conclusions: These meta-analyses do not support lithium as a first-line treatment for acute bipolar depression.
However, the bipolar vs. unipolar sensitivity analysis and the modest, though non-significant advantage over
placebo suggest lithium may still be a viable treatment option. Larger and more rigorously-designed studies are
needed to determine lithium's full range of efficacy relative to placebo and other psychotropics.

1. Introduction
Bipolar disorder types I and II together affect 2.1% of the population
(Merikangas et al., 2007) and are associated with a markedly impaired
quality of life, (Michalak et al., 2005) significant disability, (Murray and
Lopez, 1997) and early mortality (Crump et al., 2013). Patients with
bipolar disorder experience depressive symptoms for 32–50% of the
time, (Judd et al., 2003; Judd et al., 2002) and these symptoms are
associated with social impairment (Judd et al., 2005) and an increased
risk of death by suicide (Baldessarini et al., 2019). There are few US
Food and Drug Administration (FDA) approved treatments for bipolar
depression, leaving patients with limited options and residual depressive
symptoms that predict poor functional recovery in those with multiple
previous episodes (Rosa et al., 2012).
Lithium carries an FDA marketing approval for the treatment of
manic episodes and maintenance treatment for bipolar I disorder but is
not approved for the treatment of depressive episodes for bipolar type I
or type II patients (Roxane Laboratories, 2011). Doubts surrounding
lithium's ability to treat bipolar depression originated from John Cade's,
1949 uncontrolled study reporting no antidepressant effect of lithium on
a small group of depressed patients (Cade, 1949). The controversy
continues today with ten treatment guidelines across the globe recom­
mending lithium as a first-line treatment for bipolar depression and five
not recommending lithium at all (Kelly, 2019). This review of the
guidelines argued that “woozle effects” (evidence based on repeated
citations over time), reference inflation (overstating findings of the
original studies), and belief preservation (maintaining beliefs despite
contradictory evidence) explain why lithium continues to be favored by
some guidelines in spite of relatively limited evidence of lithium's effi­
cacy. Unfortunately, there has only been one large, double-blind, ran­
domized controlled trial comparing lithium to placebo (Young et al.,
2010) and there are no such studies currently listed on trial registries,

* Corresponding author at: 12 Executive Park Drive, Atlanta, GA 30329, USA.

E-mail address: jrakofs@emory.edu (J.J. Rakofsky).

https://doi.org/10.1016/j.jad.2022.04.058
Received 26 December 2021; Received in revised form 4 April 2022; Accepted 10 April 2022
Available online 13 April 2022
0165-0327/© 2022 Elsevier B.V. All rights reserved.
J.J. Rakofsky et al.
such as Clinicaltrials.gov and the European Union Clinical Trials Reg­
ister. Consequently, addressing this controversy requires careful
consideration of the existing evidence base.
Several narrative reviews (Bhagwagar and Goodwin, 2002; Johnson,
1987; Mendels et al., 1979; Srisurapanont et al., 1995; Zornberg and
Pope, 1993) and four meta-analyses (Bahji et al., 2020; Selle et al., 2014;
Taylor et al., 2014; Vieta et al., 2010) of lithium monotherapy in the
treatment of acute bipolar depression have been published. Two other
meta-analyses examined the effect of lithium versus placebo for aug­
menting tricyclic antidepressants in mixed (i.e., unipolar and bipolar)
depressed patient populations (Austin et al., 1991; Bauer and Dopfmer,
1999). All four of the monotherapy meta-analyses included several
treatments for bipolar depression in addition to lithium and included no
more than 1–5 lithium trials depending on the publication. Selle et al.
had the most lithium studies and was the only one to show an advantage
over placebo. They had five placebo cross-over trials and conducted two
separate analyses of four trials each. One of their analyses compared
lithium to placebo among hospitalized patients and the other compared
lithium's effect in patients with bipolar depression versus unipolar
depression. These analyses revealed overall significantly larger effect
sizes for lithium over placebo and in bipolar depressed patients over
unipolar depressed. However, these results were considered to be sec­
ondary outcomes in the work by Selle et al. and the analyses suffered
from several concerns, including little explanation to justify the selec­
tion criteria for the analyzed studies and the lack of comparison of
lithium versus other active treatments. Since the publication of this
meta-analysis, two additional randomized controlled trials of lithium in
the treatment of bipolar depression studies have been reported (Altsh­
uler et al., 2017; Amsterdam et al., 2016), only one of which was
included in the most recent meta-analysis (Bahji et al., 2020).
Given the differences in methodology between previously published
lithium bipolar depression meta-analyses, the ongoing controversy
surrounding lithium's antidepressant efficacy, and the lack of well-
powered, high-quality lithium bipolar depression trials, additional
meta-analyses focused exclusively on lithium and utilizing a compre­
hensive search strategy are warranted. We undertook a systematic re­
view of the literature with the aim of conducting meta-analyses to
evaluate the efficacy of lithium versus: 1) placebo; 2) antidepressants; 3)
other mood stabilizers; and 4) antipsychotics. Additionally, we meta-
analyzed the specificity of lithium's efficacy in acutely depressed pa­
tients, evaluating studies that compared outcomes in bipolar versus
unipolar depressed patients.
2. Methods
This systematic review followed the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Moher
et al., 2009).
2.1. Eligibility criteria
All cross-over or parallel-group design studies comparing lithium
response in bipolar patients versus unipolar depressed patients, and all
parallel group studies of bipolar depressed patients comparing lithium
versus placebo pill or other psychotropics were included. Included
studies had to have enrolled bipolar I or II patients in the depressed
phase, initiated lithium during the course of the study, treated patients
in the lithium arm for at least one week, provided the raw numbers or
percentages of patients responding or improving, and must have re­
ported results separately for bipolar patients if the study included mixed
(bipolar and unipolar) depressed patient samples. Included studies must
also have been prospective in design and written in English. Studies that
enrolled patients diagnosed with ‘manic-depressive psychosis- circular
type’ were included as this term is synonymous with bipolar disorder
according to the ICD-8 (World Health Organization, 1968). This is in
distinction to ‘manic-depressive psychosis- depressed type’ and ‘non-
269
Journal of Affective Disorders 308 (2022) 268–280
cyclic depression’ which are synonymous with unipolar depression
(World Health Organization, 1968). For the lithium versus psychotropic
analyses, included studies must have enrolled two or more bipolar pa­
tients in each treatment arm, and patients must have been randomized
to receive the different treatments. However, the bipolar versus unipolar
studies were not required to use randomization as the two study groups
were categorized by disease rather than by treatment.
2.2. Information sources
Sources included OVID/Medline, PubMed, Embase, Google Scholar,
the ClinicalTrials.gov registry and the European Union Clinical Trials
Register (clinicaltrialsregister.eu). The database search occurred on
October 10th, 2021. Additionally, reference lists within bipolar disorder
treatment guidelines (American Psychiatric Association, 2010; Goodwin
et al., 2016; Grunze et al., 2010; Yatham et al., 2018), bipolar disorder
textbooks (Goodwin and Jamison, 1990; Goodwin et al., 2007), previous
meta-analyses (Austin et al., 1991; Bahji et al., 2020; Bauer and
Dopfmer, 1999; Selle et al., 2014; Taylor et al., 2014; Vieta et al., 2010),
and relevant review articles (Altshuler et al., 2003; Bhagwagar and
Goodwin, 2002; Johnson, 1987; Kelly, 2019; Mendels et al., 1979; Sri­
surapanont et al., 1995; Zornberg and Pope, 1993) were also identified
for possible inclusion.
2.3. Search
The following terms were used to search the databases, [Bipolar
disorder OR Manic-depression OR depression] AND [lithium] AND [All
clinical trials].
2.4. Study selection
The first author (JJR) screened the titles and abstracts of potential
studies to determine inclusion. Eligible studies were subsequently
confirmed by the second author (MJL) who independently checked the
full text of all retrieved articles. Disagreement was resolved through
discussion and consensus between JJR, MJL, and BWD.
2.5. Data collection process
One reviewer (JJR) extracted the following data from included
studies while the second author (MJL) checked the extracted data,
including author, year of publication, study design, sample size, name/
dose of interventions, lithium blood level, study duration, outcome
scale, and results. Disagreements were resolved by discussion between
JJR, MJL, and BWD.
2.6. Risk of bias in individual studies
Two reviewers (JJR, MJL) independently rated each eligible study,
using the modified Downs and Black quality assessment scale, (Downs
and Black, 1998) consisting of 27 questions that address study reporting,
external validity, and internal validity (bias and confounding). Each
question is worth one point. Studies with total scores of 14 or less are
considered to be of poor quality, 15–19 of fair quality, and 20 or greater
of good quality. Any disagreements in ratings were resolved by a third
reviewer (BWD).
2.7. Synthesis of results and risk of bias across studies
For the lithium versus placebo/psychotropic studies, results were
organized by drug class (placebo, antidepressants, mood stabilizers,
antipsychotics). Meta-analyses comparing the number of responders in
each treatment or diagnostic group were conducted when two or more
eligible publications were identified. Response rate was selected as the
primary outcome because it was the most frequently reported outcome
J.J. Rakofsky et al.
(i.e., more common than remission rate or standardized mean differ­
ence). For all meta-analyses, sensitivity analyses were conducted by
including only similarly designed studies. Specifically, for the lithium
versus placebo comparisons and the lithium versus antidepressant
comparisons, only monotherapy, double-blind, randomized-controlled
studies were included in the sensitivity analyses, and for the lithium
studies comparing bipolar and unipolar depressed patients, only double-
blind, monotherapy, cross-over studies were included. When there were
insufficient number of studies to conduct a meta-analysis, narrative
analyses were used to summarize response rates.
Studies varied in their definition and reporting of response and
improvement. For the analyses, all individuals who responded or
improved, regardless of degree and as defined by the study, were
counted as responders. However, in a few of the placebo-controlled,
cross-over studies, responders were classified as ‘unequivocal’ or
‘equivocal/probable’ based on whether they relapsed during placebo
phases after improving during lithium phases. For these studies, only
those who relapsed (unequivocal) were counted as responders.
Mantel Haenszel random-effects models were used to conduct all
meta-analyses and determine the mean effect size across studies (Deeks
et al., 2021). Results for each study were summarized as risk ratios (RR).
The overall mean effect size and 95% confidence intervals (CI) were
reported for each meta-analysis. To assess heterogeneity, T2, I2, Q, and P
values were reported. T2 is a measure of between-study variance and
when greater than zero, can be used to calculate prediction intervals
(PI). Prediction intervals include the range of effect sizes that have a
95% likelihood of falling within the population of all comparable
studies. I2 demonstrates the proportion of variance that is due to true
study effects rather than sampling error. The Q statistic is a test for the
presence of heterogeneity and is accompanied by a p-value that indicates
statistical significance (Borenstein et al., 2009).
For meta-analyses with ten or more studies, a random-effects meta-
regression analysis was conducted to look for moderators that might
explain the heterogeneity in effect sizes (Borenstein et al., 2009).
Similarly, measures of publication bias were conducted only for meta-
analyses containing ten or more studies (Ioannidis and Trikalinos,
2007). A funnel plot was created to investigate the presence of publi­
cation bias. If present, the “trim and fill” method was used to determine
the impact of the bias (Duval and Tweedie, 2000). RevMan 5.4 was used
for all meta-analysis calculations and to create forest plots for the main
and sensitivity analyses (The Cochrane Collaboration, 2020), while
Idenficaon
844 Records idenfied
through database/registry
search
Screening
947 Records screened by
tle and abstract
Eligibility
50 Full text arcles
assessed for eligibility
17 Arcles included in the
Included
qualitave/quantave
analysis (meta-analysis)
Fig. 1. Flow Diagram for Literature Search.
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Journal of Affective Disorders 308 (2022) 268–280
Comprehensive Meta-Analysis was used for the meta-regression and
publication bias analyses (Borenstein et al., 2013).
3. Results
3.1. Overall results
The literature search yielded a total of 947 records. Of those records,
50 were fully reviewed, and 33 were removed due to the following
reasons: did not provide responder rates for individual patients (n = 1),
cross-over study with no unipolar depression comparison group (n = 1),
did not break out results by mood disorder diagnosis (n = 6), did not
enroll bipolar patients (n = 5), less than one week of lithium treatment
(n = 1), too few bipolar patients (n = 4), did not indicate the number of
patients with bipolar disorder (n = 1), did not identify how many bipolar
patients were depressed at baseline (n = 2), case series (n = 9), retro­
spective (n = 2), review article (n = 1). See Fig. 1. Ultimately, there were
17 studies that met criteria, including a total of 1545 patients with 676
of those receiving lithium. Detailed descriptions of the included studies
are provided in Tables 1–5.
3.2. Lithium vs placebo
The search identified 3 publications (Arieli and Lepkifker, 1981;
Ebert et al., 1995; Young et al., 2010) that compared lithium to placebo
and met the inclusion criteria. See Table 1. Two of these studies (Arieli
and Lepkifker, 1981; Young et al., 2010) were monotherapy trials while
the other (Ebert et al., 1995) studied combination treatment: initiating
an antidepressant plus lithium simultaneously and comparing that to
simultaneous initiation of an antidepressant plus placebo. Young et al.
(2010) was the only study that recruited outpatients, excluded those
who failed antidepressants from 2 or more classes, and required the
duration of participants' major depressive episodes to be no less than 1
month and no longer than 1 year. On the other hand, Ebert et al. (1995)
enrolled only male patients, between 30 and 45 years old with a
melancholic depressive subtype. Mean lithium levels ranged from 0.61
mEq/L in two studies (Ebert et al., 1995; Young et al., 2010) to 1.27
mEq/L in the other (Arieli and Lepkifker, 1981). Attrition was only re­
ported in one of the studies and was equal between the treatment groups
(Young et al., 2010). Study duration ranged from 3 to 8 weeks. Only one
study (Young et al., 2010) explicitly defined response (50%
103 Studies idenfied through
addional hand search
864 Records excluded due
to duplicaon or
irrelevance
33 arcles excluded for:
Case series (9)
Results not reported by mood disorder (6)
No bipolar paents (5)
Too few bipolar paents (4)
Number of bipolar paents depressed at baseline
not reported (2)
Retrospecve (2)
No responder rates for individual paents (1)
Cross-over study with no MDD group (1)
Less than one week of lithium treatment (1)
Number of paents with bipolar disorder not
reported (1)
Review arcle (1)
J.J. Rakofsky et al. Journal of Affective Disorders 308 (2022) 268–280

Table 1
Lithium versus placebo in the treatment of bipolar depression.
Author, year Sample Dose Lithium level Duration Scale Results Notes
sizes

Young et al., Lithium: Lithium: 600–1800 Mean median in ITT was 0.61 8 weeks MADRS, Response rate (at least 50% -Double blind, parallel
2010 N = 136 mg mEq/L; 34.9% below 0.6 HAMD, reduction in baseline MADRS): group, RCT
Placebo: mEq/L; 25% had a median CGI Lithium- (85/136) 62.5%, -Bipolar I and II
N = 129 level of 0.8 mEq/L or greater Placebo- (72/129) 55.8% -Multicenter
-Outpatients
-Monotherapy
-Randomized 2:2:1:1
-MDE duration less than
1 year and 4 weeks or
more
-had not failed 2 or more
classes of antidepressants
Bias = 23 (Good)
Arieli and Lithium N Lithium: Mean = 1.27 mEq/L 3 weeks HAMD, Response rate (defined by JJR, -Double blind, parallel
Lepkifker, =3 2000–2500 mg CGI MJL, BWD as at least 50% group, RCT
1981 Placebo N reduction in baseline HAMD): -Hospitalized
=3 Lithium- (2/3) 66% -Single-site
Placebo- (1/3) 33% -Included MDD patients
as well
-One week placebo
washout
-Reported %
improvement on HAMD
Bias = 19 (Fair)
Ebert et al., Lithium N Lithium: 900 mg Mean (SD) at week 1, 2, 3 = 5 weeks HAMD, Improved or much improved -Double blind, parallel
1995 = 20 0.65 (0.16) mEq/L CGI (CGI): Lithium- (17/20) 85% group, RCT
Placebo N Amitriptyline: 225 -Augmentation
= 20 mg dosed to 200 ng/ Placebo- (12/20) 60% -Hospitalized
mL 0.66 (0.17) mEq/L -Single site
-All male
0.61 (0.15) mEq/L -30-45 years old
-Melancholic subtype
-All started on
Amitriptyline at the start
of trial
-1st 20 randomized, 2nd
20 matched on severity
and duration
Bias = 16 (Fair)

Key: CGI = Clinical Global Impression Scale, HAMD = Hamilton Depression Scale, ITT = Intent to treat sample, MADRS = Montgomery Asberg Depression Scale, MDE
= Major depressive episode, RCT = Randomized controlled trial, SD = Standard deviation.

improvement on the Montgomery Asberg Depression Rating Scale
(MADRS) (Montgomery and Asberg, 1979), while one provided Clinical
Global Impression (CGI) Improvement scores, (Ebert et al., 1995) and
the third provided percentage of improvement on the 17-item Hamilton
Depression Rating Scale (HAMD-17) (Hamilton, 1960) for each subject
(Arieli and Lepkifker, 1981). Bias scores were 16–23 and fell within the
‘Fair’ to ‘Good’ range depending on the study.
The meta-analysis found non-statistically significant higher response
rates with lithium versus placebo (3 studies, N = 311; RR = 1.18; 95%
CI, 0.99–1.41; p = 0.07) There was no evidence of heterogeneity (T2 = 0,
I2 = 0%, Q = 1.39, df = 2, p = 0.5). See Fig. 2A. When only monotherapy
studies were included, the sensitivity analysis revealed similar results (2
studies, N = 275; RR = 1.13; 95% CI, 0.92–1.38; p = 0.24; heteroge­
neity: T2 = 0, I2 = 0%, Q = 0.4, df = 1, p = 0.53). See Fig. 2B.
3.3. Lithium vs. antidepressants
The search identified four publications (Altshuler et al., 2017;
Amsterdam et al., 2016; Amsterdam and Shults, 2008; Arieli and Lep­
kifker, 1981) comparing lithium to antidepressants that met the inclu­
sion criteria. See Table 2. All studies except for one (Arieli and Lepkifker,
1981) included bipolar II depressed patients and were outpatient trials,
and all but one (Amsterdam and Shults, 2008) were double-blind. Three
studies (Altshuler et al., 2017; Amsterdam et al., 2016; Amsterdam and
Shults, 2008) excluded patients with a history of nonresponse to lithium
or the antidepressant. Mean lithium levels ranged from lows of 0.63
mEq/L and 0.64 mEq/L in Altshuler et al. (2017) and Amsterdam and
Shults (2008), respectively, to highs of 0.94 mEq/L (range = 0.3–2.4),
and 1.27 mEq/L in Amsterdam et al. (2016) and Arieli and Lepkifker
(1981), respectively. Antidepressants included venlafaxine, (Amsterdam
et al., 2016; Amsterdam and Shults, 2008) sertraline, (Altshuler et al.,
2017) and clomipramine (Arieli and Lepkifker, 1981). Attrition was
uneven in most of the studies with more patients dropping out of the
lithium group than the comparator. The attrition rate difference be­
tween groups ranged from 12.9% to 41.6% depending on the study.
Study duration ranged from as short as three weeks to as long as 16
weeks. To define response, all studies required a 50% score reduction in
the depression severity scale with two requiring additional items (a
decrease of </= 2 points on the (CGI)- Bipolar Depression Severity score
for at least two consecutive weeks (Altshuler et al., 2017); a final clinical
CGI-Severity score of 1 (not at all), 2 (borderline ill), or 3 (mildly ill)
(Amsterdam et al., 2016)). Bias scores were 19–23 which fell in the ‘Fair’
to ‘Good’ range.
The meta-analysis revealed that patients receiving lithium were less
likely to respond than those receiving antidepressants although the
result did not reach statistical significance (4 studies, N = 314; RR =
0.61; 95% CI, 0.37–1.02; p = 0.06), with significant heterogeneity
present (T2 = 0.19, I2 = 77%, Q = 13.3, df = 3, p = 0.004, PI = 0.07,
5.37). See Fig. 3A. A sensitivity analysis limited to the three double-
blind, randomized-controlled studies revealed a similar result (3
studies, N = 231; RR = 0.72; 95% CI, 0.44–1.16; p = 0.18; heteroge­
neity: T2 = 0.12, I2 = 72%, Q = 7.14, df = 2, p = 0.03, PI = 0.003,

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J.J. Rakofsky et al. Journal of Affective Disorders 308 (2022) 268–280

Table 2
Lithium versus antidepressants in the treatment of bipolar depression.
Author/year Sample sizes Dose Lithium level Duration Scale Results Notes

Arieli and Bipolar I Lithium: Mean = 1.27 mEq/ 3 weeks HAMD, CGI Response rate (defined by -Double blind, parallel group,
Lepkifker, depressed 2000–2500 mg L JJR,MJL, BWD as at least RCT
1981 patients 50% reduction in baseline -Hospitalized
Lithium N = 3 Clomipramine: NR HAMD): Lithium- (2/3) = -Single-site
66% -1 week placebo washout
Clomipramine Clomipramine- (4/5) = -Reported percent improvement
N=5 80% on HAMD
Bias = 19 (Fair)
Amsterdam Bipolar II Lithium mean (SD) Mean (SD) = 0.64 12 HAMD-28, Response rate (HAMD-17): -Open label
and Shults, depressed dose: 966.24 mg (0.265) mEq/L weeks HAMD-17, Lithium- (8/40) 20% -Single site
2008 patients (410.9) HAMD-17R, -Outpatients
CGI-S, CGI-C Venlafaxine- (25/43) -Monotherapy
Lithium N = 40 Venlafaxine mean Range = 0.29–1.5 58.1% -No hx of non-response to either
Venlafaxine N (SD) dose: 185.6 mg mEq/L drug WITHIN CURRENT MDE
= 43 (92.04) -Lithium grp had more prior
hypomanic episodes, prior MDEs,
earlier onset, longer current MDE
duration
-Response: 50% reduction in
HAM-D
− 62.5% drop out in li grp vs.
20.9% drop out in Ven grp
Bias = 20 (Good)
Amsterdam Bipolar II Lithium mean max Mean maximum 12 HAMD, CGI- Response rate (at least 50% -Double blind, parallel group,
et al., 2016 depressed dose (SD): 1180.85 (SD) = 0.94 (0.38) weeks S reduction in baseline RCT
patients mg (399.14) mEq/L HAMD): Lithium- (22/64) -Single center
34.4% -Outpatients
Lithium N = 64 Venlafaxine mean Range: 0.3–2.4 Venlafaxine- (44/65) -No hx of non-response to either
Venlafaxine N max dose (SD): mEq/L 67.7% drug WITHIN CURRENT MDE
= 65 265.55 mg (101.07) -Response: >50% reduction in
baseline HAMD AND a final CGI-
S of 1,2,or 3.
− 42% were rapid cyclers
− 43.8% (li) vs. 15.4% (ven)
withdrew prematurely
Bias = 23 (Good)
Altshuler Bipolar II Lithium: minimum Mean = Overall: 16 IDS-C, CGI- Response rate (at least 50% -Double blind, parallel group,
et al., 2017 depressed target dose 900 mg 0.63 mEq/L weeks BP reduction in baseline IDS- RCT
patients C): -Multicenter
Lithium N = 49 Sertraline: Responders: 0.61 Lithium- (33/49) 67.4% -Outpatients
minimum target mEq/L -Primary outcome was switch
dose 100 mg rate
Sertraline N = Nonresponders: Sertraline- (33/45) 73.3% -no mixed symptoms allowed
45 0.51 mEq/L -Response = Decrease of 50% or
more OR a decrease of 2 or more
points on CGI-BP depression x 2
consecutive visits over 2 weeks;
could not be due to hypomanic
switch.
− 41.6% were rapid cyclers
Bias = 22 (Good)

Key: CGI-BP = Clinical Global Impression Scale for Bipolar Disorder, CGI-I = Clinical Global Impression Improvement Scale, CGI-S = Clinical Global Impression
Severity Scale, HAMD = Hamilton Depression Scale, IDS-C = Inventory of Depression Symptomatology-Clinician Rated, MDE = Major depressive episode, NR = Not
reported, RCT = Randomized controlled trial, SD = Standard deviation.

Table 3
Lithium versus other mood stabilizers in the treatment of bipolar depression.
Author/ Sample sizes Dose Lithium Duration Scale Results Notes
year level

Suppes Bipolar II Lithium: 900 mg Median = 16 HAMD, Response rate (at least -Open label
et al., depressed over two weeks 0.8 mEq/L weeks MADRS, CGI- 50% reduction in baseline -Outpatients
2008 patients BP, GAF HAMD): -Single blind (raters blind)
Lithium = 54 Lamotrigine: 200 Lithium- (30/54) 55.1% − 2 studies with combined analysis
subjects mg over eight weeks -More rapid cyclers in the Lamotrigine
group
Lamotrigine = Lamotrigine- (30/44) -item analysis shows significant
44 subjects 67.5%, difference Li > LTG for HAM-D psychic
anxiety and MADRS pessimistic thoughts
Bias = 20 (Good)

Key: CGI-BP = Clinical Global Impression Scale for Bipolar Disorder, HAMD = Hamilton Depression Scale, MADRS = Montgomery Asberg Depression Scale.

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Table 4
Lithium versus second generation antipsychotics in the treatment of bipolar depression.
Author, Sample sizes Dose Li level
year
Young Bipolar I and Lithium: Mean in ITT was 0.61 mEq/L; 34.9%
et al., II patients 600–1800 mg below 0.6 mEq/L; 25% had a median
2010 level of 0.8 mEq/L or greater
Lithium N = QTP: 300 mg
136 or 600 mg
QTP 300 mg
N = 255
QTP 600 mg
N = 263
Key: CGI = Clinical Global Impression Scale, HAMD = Hamilton Depression Scale, ITT = Intent to treat sample, MADRS = Montgomery Asberg Depression Scale, MDE
= Major depressive episode, QTP = Quetiapine, RCT = Randomized controlled trial.
155.3). See Fig. 3B.
3.4. Lithium vs. mood stabilizers
Only one publication comparing lithium to another mood stabilizer
was identified. See Table 3. In that study, Suppes et al. (2008) combined
the results of two similarly-designed, randomized, 16-week studies
comparing lithium monotherapy to lamotrigine monotherapy in bipolar
II depressed outpatients. Forty-four patients were randomized to receive
lamotrigine and 54 were randomized to receive lithium. Lamotrigine
was titrated over eight weeks to 200 mg/day and could be increased to a
maximum dose of 400 mg/day (median dose was 250 mg/day). Lithium
was titrated to 900 mg/day by week two and was dosed to blood levels
from 0.8 to 1.2 mEq/L (median lithium level was 0.8 mEq/L). Patients
and physicians were unblinded while raters were blinded.
Response rates, defined as a 50% reduction on the HAMD-17, were
67.5% (30/44) for the lamotrigine group and 55.1% (30/54) in the
lithium group, revealing no significant difference (no p-values pro­
vided). The same was true of the primary outcome comparing change in
HAMD-17 scores between both treatment groups (F(7,402) = 0.54, p =
0.95). Limitations to this study included the lack of a placebo group, the
single-blind design, and a modest sample size. The study was signifi­
cantly underpowered as indicated by the authors' statement that over
10,000 subjects were needed to find a significant difference between the
groups. Additionally, there was a large number of participant drop-outs
with more individuals in the lithium group leaving the study prema­
turely (completer rate = lamotrigine 51% vs. lithium 39%, p = 0.29).
The bias score for this study was 20 which was in the ‘Good’ range.
3.5. Lithium vs. antipsychotics
Only one publication comparing lithium to an antipsychotic was
identified. See Table 4. In that study (known as EMBOLDEN I), Young
et al. (2010) compared two separate doses of quetiapine monotherapy to
lithium monotherapy and to placebo in an eight week, multisite study of
bipolar I and II outpatients with depression. As part of the inclusion
criteria, participants could not have failed two or more classes of anti­
depressants during the current episode and must have been depressed
for at least four weeks and no longer than one year. Patients were ran­
domized in a 2:2:1:1 manner resulting in 255 patients receiving que­
tiapine 300 mg/day, 263 receiving quetiapine 600 mg/day, 136 patients
receiving lithium, and 129 patients receiving placebo. Quetiapine was
titrated from a starting dose of 50 mg to target doses by day four (300
mg) and day eight (600 mg), while lithium was started at 600 mg/day
and increased to 900 mg/day by day four. Lithium was dosed to reach a
target lithium level between 0.6 and 1.2 mEq/L; however, the mean
median serum concentration was 0.61 mEq/L in the intent to treat
population and 34.9% had median levels below 0.6 mEq/L. Only a
quarter of the patients had a median lithium level that was 0.8 mEq/L or
273
Journal of Affective Disorders 308 (2022) 268–280
Duration Scale Results Notes
8 weeks MADRS, Response rate (at least -Double blind, parallel
HAMD, CGI 50% reduction in group, RCT
baseline MADRS): -Multicenter
Lithium- (85/136) 62.5% -Outpatients
-Monotherapy
-Randomized 2:2:1:1
QTP 300 mg- (175/255) -MDE duration less than 1
68.6%, year and 4 weeks or more
QTP 600 mg- (183/263) -had not failed 2 or more
69.6% classes of antidepressants
Bias = 23 (Good)
greater.
Response, which was based on a reduction of 50% or greater on the
MADRS score was 68.6% for quetiapine 300 mg (vs. placebo, p < 0.05),
69.6% for those receiving quetiapine 600 mg (vs. placebo, p < 0.01),
62.5% for those receiving lithium (vs. placebo, p = 0.279), and 55.8%
for those receiving placebo. The study was underpowered for a non-
inferiority comparison between quetiapine and lithium, and the au­
thors explicitly stated that no such power calculations were made.
Attrition from the study was similar for all treatment groups with
72–75% of patients completing the study depending on the treatment
group. The bias score for this study was 23 which was in the ‘Good’
range.
3.6. Bipolar depression vs. unipolar depression
The search identified ten publications (Baron et al., 1975; Donnelly
et al., 1978; Goodwin et al., 1969; Goodwin et al., 1972; Johnson, 1974;
Kramlinger and Post, 1989; Mendels, 1976; Mendels and Frazer, 1973;
Noyes et al., 1974; Price et al., 1986) that compared outcomes in pa­
tients with bipolar depression versus those with unipolar depression
receiving lithium. See Table 5. All except for two were monotherapy
studies (Kramlinger and Post, 1989; Price et al., 1986). All were double-
blinded except for one that was single-blinded (Johnson, 1974), one that
was blinded for only some of the patients (Price et al., 1986), and two
that provided no information about rater blinding (Mendels and Frazer,
1973; Noyes et al., 1974). All included hospitalized patients except for
one which included a mix of inpatients and outpatients (Price et al.,
1986), and all were cross-over, placebo-controlled studies except for two
that were parallel-group treatment studies (Mendels and Frazer, 1973;
Price et al., 1986). For many of these studies, the target range or actual
range of lithium levels was provided rather than a mean lithium level for
all subjects. Only one study (Price et al., 1986) had a range that was
lower than 0.7 mEq/L while seven studies (Donnelly et al., 1978;
Goodwin et al., 1969; Johnson, 1974; Mendels, 1976; Mendels and
Frazer, 1973; Noyes et al., 1974; Price et al., 1986) had a range that was
higher than 1.2 mEq/L. Duration of time on lithium ranged from ‘at least
10 days’ (Price et al., 1986) to ‘up to 28 days’ (Donnelly et al., 1978;
Mendels and Frazer, 1973). The number of placebo phases in the cross-
over trials varied from as few as one (Donnelly et al., 1978; Johnson,
1974; Kramlinger and Post, 1989) to as many as eight (Goodwin et al.,
1969). In three of those with multiple placebo phases (Baron et al., 1975;
Goodwin et al., 1969; Goodwin et al., 1972), response required
improvement during the lithium phase and then worsening during
subsequent placebo phases. All of the other studies (i.e., those with
multiple-placebo phases, single placebo phase, open-label) defined
response as improvement relative to baseline. The bias scores for these
studies were 10–16 which fell within the ‘Poor’ to ‘Fair’ range
depending on the study.
The meta-analysis showed a non-statistically significant benefit for
J.J. Rakofsky et al. Journal of Affective Disorders 308 (2022) 268–280

Table 5
Lithium in the treatment of bipolar depression vs major depressive disorder.
Author, year Sample sizes Dose Lithium level Duration Scale Results Notes

Goodwin 13 Manic- Lithium: Initial dose Target Range NR for Lithium or Bunney- Manic-depression: -Cross-over study (placebo- >
et al., 1969 depressive, 900–1800 mg = 0.8–1.3 placebo phase Hamburg Global (3/13) 23% Lithium- > 1–8 additional
depressed, mEq/L Rating Scale placebo periods)
Type-1 = 6, -Hospitalized
Type-II = 6 -Monotherapy
Recurrent Unequivocal/ -Complete and unequivocal =
MDEs = 1 complete response complete remission of
5 Non-cyclic Non-cyclic depressive symptoms within 2
depression depression: (0/5) weeks of Li and return of
0% symptoms during placebo
period
Unequivocal/ Bias = 13 (Poor)
complete response
Goodwin 40 Bipolar NR NR Lithium: At least 2 Bunney- Bipolar: (12/40) -Cross-over study (placebo- >
et al., 1972 weeks Hamburg 30% Unequivocal Lithium- > placebo +/−
response additional lithium period)
12 Unipolar Placebo: At least 6 Global Rating Unipolar: (2/12) -Hospitalized
days Scale 17% Unequivocal -Monotherapy
response -Unequivocal response = 3
point improvement on lithium
and relapse on placebo
Bias = 14 (Poor)
Mendels and Manic Lithium: mean dose Range = 4 weeks HAMD, BDI, Bipolar: (6/9) 60% -Open label study
Frazer, depression, 1200–2589 mg 0.78–1.37 nurses Improved -Hospitalized
1973 (bipolar) = 9 mEq/L observation -Biological study
Recurrent rating Unipolar: (1/4) -Monotherapy
depressive 25% Improved -Does not indicate whether
illness evaluators were blind to
(unipolar) = 4 diagnosis
-No comorbidities allowed
-One patient treated for two
separated episodes and
improved both times. We only
counted one of these episodes
in this analysis
-Improved = 70–75%
improvement on 2/3 rating
scales and ability to be
discharged home
Bias = 10 (Poor)
Johnson, 2 Manic- Lithium: initial dose Range = Lithium: at least 3 HAMD, Bipolar: (1/2) 50% -Cross-over study (placebo- >
1974 depressive 1000–1500 mg 0.7–1.9 mEq/L weeks psychiatrist's Marked response Lithium)
circular, clinical global but then became -Hospitalized pts
depressed phase impression hypomanic -Single Blind design
(bipolar) Bias = 14 (Poor)
6 Manic- Placebo: 9 days Unipolar and
depressive, depressive
depressed neurotics: (4/9)
(unipolar) 44% Marked
3 Depressive response
neurotics
Noyes et al., 6 Manic Lithium: 26 mg/kg Mean = 1.42 Lithium: at least 2 HAMD Bipolar: (6/6) -Cross-over study (placebo- >
1974 depressive, mEq/L weeks + time to 100% Responded Lithium- > placebo)
depressed phase reach plateau in -Hospitalized pts
improvement -Monotherapy
16 Unipolar Range = Placebo: 3–5 days Unipolar: (7/16) -Does not indicate whether
depressed 0.93–2.15 initially 44% Responded evaluators were blinded.
mEq/L -Does not define response
Bias = 16 (Fair)
Baron et al., 8 Bipolar Type- NR Mean = 0.87 Lithium: 19 days Bunney- Bipolar: (4/8) 50% -Cross-over study (placebo- >
1975 1 = 7 Type-II = mEq/L Hamburg Global Responded Lithium- > placebo)
1 Rating scale unequivocally -Hospitalized pts
-Monotherapy
10 Unipolar Range = Placebo: 1st − 1-2 Unipolar: (1/10) -Unequivocal response=
0.8–1.0 mEq/L weeks 2nd − 2 weeks 10% Responded 2 point improvement on
unequivocally lithium and 2 point worsening
on placebo
Bias = 16 (Fair)
Mendels, 13 Bipolar Lithium: Up to max Maximum = Lithium: 3 weeks HAMD, BDI, Bipolar: (9/13) -Cross-over study (placebo- >
1976 depressed blood level, clinical 1.5 mEq/L Bunney- 69% Responded Lithium- > placebo)
effect, or toxicity Hamburg -Hospitalized pts
8 Unipolar Placebo: 1st − 7-15 Global Rating Unipolar: (4/8) -Response = sufficient relief of
days, 2nd − 7-22 Scale 50% Responded symptoms that did not require
days any other form of active
(continued on next page)

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Table 5 (continued )
Author, year Sample sizes Dose Lithium level Duration Scale Results Notes

treatment and able to return to

premorbid level of function
Bias = 13 (Poor)
Donnelly 33 Bipolar Lithium: median dose Range = Lithium: 4 weeks Scale created by Bipolar: (21/33) -Cross-over study (placebo- >
et al., 1978 Type-1 = 17 1500 mg 0.9–1.3 mEq/L authors 64% Responded Lithium)
Type-II = 16 -Hospitalized pts
-Monotherapy
20 Unipolar Placebo: 5 days Unipolar: (8/20) -Responder = t value >2.26
40% Responded and a rating decrease of at
least 2 points on Lithium vs.
placebo
Bias = 16 (Fair)
Price et al., 11 Bipolar Lithium: initial dose Target range Lithium: at least 10 SCRS global Bipolar: (4/11) -Open label, augmentation
1986 900–1500 mg = 0.5–1.3 days depression item 36% Responded following antidepressant cross
mEq/L over (placebo <− >
Antidepressant)
73 Unipolar Antidepressant: 4–6 HAMD Unipolar: (43/73) -Hospitalized and outpatients
weeks 59% -Antidepressant: TCAs, SSRIs,
atypicals
Placebo: 2–3 weeks, Responded -Lithium augmentation for
those who did not respond to
antidepressant
-Only 15 patients were
blinded to Lithium
augmentation
-Response = global functional
improvement to permit
discharge from hospital or
research clinic and no major
med changes for inpatients 4
weeks after discharge
Bias = 12 (Poor)
Kramlinger 13 Bipolar Lithium: Mean (SD) Mean (SD) Lithium: 3 weeks Bunney- Bipolar: (6/13) -Cross-over following
and Post, Type-1 = 9 Responders = 975 Responders = Hamburg Global 46% Responded carbamazepine non-response
1989 Type-II = 4 (139) mg 0.67 (0.06) Rating Scale (placebo- > Lithium)
mEq/L -Hospitalized
2 Unipolar Non-responders = Non- Placebo: 1 week Unipolar: (2/2) -Continued carbamazepine
793 (248) mg responders = 100% Responded -Compared to historical
Carbamazepine: 0.69 (0.28) controls of mixed sample
mean dose 888 mg mEq/L treated with lithium alone
Target range -Good response = Mean
= 0.7–1.2 weekly decrease of 2 points or
mEq/L more from baseline placebo
week
Bias = 16 (Fair)

Key: SCRS = BDI = Beck Depression Inventory, HAMD = Hamilton Depression Scale, NR = Not reported, SD = Standard deviation, Short Clinical Rating Scale, SSRI =
Selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant.

Fig. 2. Forest Plot for Studies of Lithium versus Placebo in the Treatment of Acute Bipolar Depression. Key: A = Main analysis, B = Sensitivity analysis limited to
double-blinded, monotherapy, randomized controlled trials, Events = Number of patients who met response criteria.

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J.J. Rakofsky et al. Journal of Affective Disorders 308 (2022) 268–280

Fig. 3. Forest Plot for Studies of Lithium versus Antidepressants in the Treatment of Acute Bipolar Depression. Key: A = Main analysis, B = Sensitivity analysis
limited to double-blinded, monotherapy, randomized controlled trials, Events = Number of patients who met response criteria.

lithium in bipolar depression compared to unipolar depression patients
(10 studies, N = 307; RR = 1.33; 95% CI, 0.89–1.97; p = 0.16; hetero­
geneity: T2 = 0.13, I2 = 37%, Q = 14.4, df = 9, p = 0.11, PI = 0.51, 3.48).
See Fig. 4A. When only double-blinded, monotherapy, cross-over studies
were included, the sensitivity analysis revealed a statistically significant
greater response rate to lithium in bipolar depressed patients compared
to unipolar depression patients (5 studies, N = 162; RR = 1.65, 95% CI,
1.08–2.55; p = 0.02; heterogeneity: T2 = 0, I2 = 0%, Q = 1.7, df = 4, p =
0.79). See Fig. 4B.
A meta-regression analysis was performed on the original set of ten
studies and only one covariate, date of publication, was selected given
this small number of studies. This analysis revealed that date of publi­
cation had a negative impact on the overall effect size (B = − 0.0876;
95% CI, − 0.14 to − 0.04; p = 0.0005). See Fig. 5. The publication bias
assessment, also conducted on the original set of ten studies, revealed
that the effect size was larger in the smaller studies. See Fig. 6. The “trim
and fill” method was used to determine the effect size based on the
included studies and those that could have been missing, resulting in a
smaller overall effect size that still lacked statistical significance (RR =
1.20; 95% CI, 0.82–1.75).
4. Discussion
This systematic review and meta-analysis is the first to focus exclu­
sively on lithium in the treatment of acute bipolar depression. The
overall summary effects reveal that lithium performed numerically

Fig. 4. Forest Plot for Studies of Lithium in the Treatment of Bipolar Depressed versus Unipolar Depressed Patients. Key: A = Main analysis, B = Sensitivity analysis
limited to double-blinded, monotherapy, cross-over studies, BD = Bipolar disorder, UD = Unipolar depression Events = Number of patients who met
response criteria.

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J.J. Rakofsky et al. Journal of Affective Disorders 308 (2022) 268–280

3.00

2.50

2.00

1.50

1.00
Log risk ratio

0.50

0.00

-0.50

-1.00

-1.50

-2.00

-2.50

1963 1965 1968 1970 1973 1975 1978 1980 1983 1985 1988 1990 1993 1995

Date of Publication

Fig. 5. Meta-regression of Log Risk Ratio on Date of Publication for Studies of Lithium in the Treatment of Bipolar Depressed versus Unipolar Depressed Patients.

Funnel Plot of Standard Error by Log risk ratio

0.0

0.5
Standard Error

1.0

1.5

2.0

-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0

Log risk ratio

Fig. 6. Funnel Plot for Studies of Lithium in the Treatment of Bipolar Depressed versus Unipolar Depressed Patients.

worse than antidepressants but better than placebo, although neither of
these findings were statistically significant. Although the comparison of
lithium's efficacy for bipolar versus unipolar depression did not reveal
lithium to be statistically superior in bipolar patients, the sensitivity
analysis limited to double-blinded, monotherapy, cross-over studies
revealed a statistically significant result supporting lithium's superior
efficacy for those with bipolar depression. Too few studies were avail­
able to conduct a meta-analysis of lithium versus mood stabilizers or
lithium versus second generation antipsychotics.
Regarding the comparison with antidepressants, although the result
of the meta-analysis was not significant, nearly all of the values included
within the 95% confidence interval (0.37–1.02) were less than one. This
increases the likelihood that the true overall mean effect favors anti­
depressants and that a statistically significant result may well have been
achieved with greater statistical power. The sensitivity analysis limited
to double-blind randomized controlled trials resulted in a 95% confi­
dence interval (0.44–1.16) that was shifted rightward but still with a
majority of values below one, reinforcing the likelihood that the true
overall mean effect favors antidepressants. However, the majority of
these studies exclusively enrolled bipolar II patients and were conducted
in an outpatient setting, thereby limiting the ability to generalize these
results to either bipolar I patients or those severe enough to require
inpatient treatment. It is possible that lithium is inherently less effective
for bipolar II than bipolar I depression, but this remains to be proven.

277
J.J. Rakofsky et al.
The lithium levels were potentially inadequate for treatment of bipolar
depression, with mean levels <0.8 mEq/L in two of the four studies.
However, as of yet, there is no established range of lithium levels that
predict antidepressant response. Attrition rates were strikingly uneven
between treatment groups in most of the studies, with more lithium
treated patients withdrawing prematurely. Although intent to treat ef­
ficacy analyses take discontinuation into account, the higher attrition
rate may mask the degree of improvement achievable among patients
who are able to tolerate lithium adequately to complete the trial.
Completer analyses including patients who achieved effective lithium
blood levels may provide a clearer answer, but these data are not
available.
In addition, differences in manic induction and cycle acceleration by
the drug are a very important consideration when making judgments
about the relative value of lithium versus antidepressants. Although the
included studies found no differences in (hypo)manic symptom emer­
gence or cycle acceleration between groups, confidence in these results
is limited for several reasons: 1) nearly all of the subjects had bipolar
disorder type II, not type I (Altshuler et al., 2006), 2) the duration of the
trials was too brief to capture cycle acceleration, and 3) those patients
with a history of antidepressant-induced mood switching likely would
have declined participation in these studies. Only three antidepressants
were included in this meta-analysis, limiting generalizations to the many
other FDA-approved antidepressants available. It should be noted that
the current meta-analyses excluded one study (Fieve et al., 1968) that is
commonly included in reviews, which showed a stronger antidepressant
effect for imipramine than for lithium. Exclusion of this study was
justified because it enrolled patients with manic-depressive psychosis-
depressed type, a diagnosis which is synonymous with unipolar
depression and not bipolar disorder.
Compared to placebo, lithium showed a modest benefit though the
results were not statistically significant as the 95% confidence interval
(0.99–1.41) just barely crossed over one. The sensitivity analysis limited
to studies evaluating monotherapy treatment resulted in a 95% confi­
dence interval (0.93–1.38) that was shifted leftward only slightly,
reinforcing the likelihood that the true overall mean effect favors
lithium. Unfortunately, both analyses were comprised of only a few
studies and the majority of patients came from a single study. One study
(Stokes et al., 1971) that is often included in reviews and that showed
that lithium was not significantly more effective than placebo was
excluded from this meta-analysis because it was a cross-over study and
presented results in terms of percentage of treatment periods with
improvement.
Regarding the comparison between bipolar depression patients and
those with unipolar depression receiving lithium, the meta-analysis
favored bipolar depressed patients although the result was not statisti­
cally significant. On the other hand, the sensitivity analysis limited to
the more rigorous trials did find a significant difference in response
rates, likely resulting from greater homogeneity and methodological
quality of the included studies. This is reflected in I2 scores that dropped
from 35% in the meta-analysis to 0% in the sensitivity analysis. That
lithium has greater efficacy in patients with bipolar depression over
those with unipolar depression replicates the findings of an earlier meta-
analysis (Selle et al., 2014), and the conclusion of a review article
(Mendels et al., 1979), and two editions of a textbook (Goodwin and
Jamison, 1990; Goodwin et al., 2007) that addressed this question.
The bipolar depression versus unipolar meta-analysis was the only
one in this manuscript that contained ten or more studies, making a
meta-regression analysis and publication bias assessments appropriate.
The meta-regression suggested that date of publication might explain
some of the heterogeneity in individual study effect sizes which might be
due to differences in lithium dosing or study designs over time. The
publication bias assessment identified a risk of missing studies but the
trim and fill method did not change the overall result in a meaningful
way.
Regarding lithium vs. mood stabilizers, only one mood stabilizer,
278
Journal of Affective Disorders 308 (2022) 268–280
lamotrigine was compared and only one publication evaluating this
comparison was identified, thus precluding a meta-analysis. No signifi­
cant difference was seen between the treatment groups, although there
were a number of methodologic elements that might have led to this null
result. Regarding lithium versus second generation antipsychotics, only
one antipsychotic, quetiapine was compared and only one publication
evaluating this comparison was found, although there were two que­
tiapine treatment arms. The two quetiapine groups outperformed the
lithium group, but the sample sizes were uneven and only 25% of the
lithium-treated patients had a median lithium level of 0.8 mEq/L or
greater.
Taken together, these meta-analyses do not support the use of
lithium as a first-line treatment for acute bipolar depression. On the
other hand, the sensitivity analysis demonstrating lithium's specificity
for bipolar depression over unipolar depression, and the modest though
non-significant advantage over placebo suggest lithium may still be a
viable treatment option. Larger and more rigorously-designed studies
are needed to understand lithium's efficacy more definitively versus
placebo and its position relative to other psychotropics within the
treatment guidelines. Studies that explore the role of moderators such as
episode number (Swann et al., 1999), mixed features (Swann et al.,
1997), and depression polarity proneness (Popovic et al., 2012), may
shed further light on lithium's antidepressant effect as has been the case
regarding its anti-manic and prophylactic abilities.
Limitations to this work include the study selection rules, which
excluded publications that might have resulted in different overall
summary effects. However, these rules were established a priori to
identify publications that would be reasonably similar enough to
combine in a meta-analysis. The decision to focus on response rates
rather than remission rates or continuous score outcomes might have
influenced the results; however, response rates were more commonly
reported, allowing the authors to increase the number of included
studies. The number of studies included in each meta-analysis were
small, potentially leading to type I and II errors and precluding the au­
thors from using publication bias tests for most of the analyses. Within-
study bias ratings were low (Poor-Fair) for the studies included in the
bipolar versus unipolar depression comparisons but high (Fair to Good)
for the rest. Although there was evidence of heterogeneity in a few of the
meta-analyses, the PI's for the lithium versus antidepressant studies
suggest that the majority of studies within the population of comparable
studies would have effect sizes that favor antidepressants and align with
the overall summary effect. The PI's for the bipolar depression versus
unipolar depression studies included effect sizes favoring both bipolar
and unipolar depression groups, however, there was no significant
heterogeneity in the sensitivity analysis which included the more
rigorously conducted studies.
In summary, these meta-analyses demonstrated that lithium was
preferentially beneficial for patients with bipolar depression, was
numerically more efficacious than placebo, and numerically less effi­
cacious than antidepressants for bipolar II depressed outpatients. More
studies and additional meta-analyses are needed to confirm these results
and determine the full range of lithium efficacy in the treatment of acute
bipolar depression.
CRediT authorship contribution statement
JJR and MJL performed the literature search and data extraction.
All authors (JJR, MJL, BWD) participated in the interpretation of the
results.
JJR wrote the first draft of the manuscript and all authors (JJR, MJL,
BWD) contributed equally to subsequent revisions and have approved
the final draft.
Role of the funding source
This research did not receive any specific grant from funding
J.J. Rakofsky et al.
agencies in the public, commercial, or not-for-profit sectors.
Conflict of Interest
The authors have no affiliation with any organization with a direct or
indirect financial interest in the subject matter discussed in the
manuscript.
JJR- research support from Compass Pathways, Otsuka, consulting
fees from Eleven10, and honoraria from FOCUS and SMI: Clinical
Advisor.
MJL- none.
BWD- research support from Acadia, Compass, Aptinyx, NIMH, Sage,
Otsuka, and Takeda, and has served as a consultant to Greenwich Bio­
sciences, Myriad Neuroscience, Otsuka, Sage, and Sophren
Therapeutics.
Acknowledgments
None.
References
Altshuler, L.L., Frye, M.A., Gitlin, M.J., 2003. Acceleration and augmentation strategies
for treating bipolar depression. Biol. Psychiatry 53, 691–700.
Altshuler, L.L., Suppes, T., Black, D.O., Nolen, W.A., Leverich, G., Keck Jr., P.E., Frye, M.
A., Kupka, R., McElroy, S.L., Grunze, H., Kitchen, C.M., Post, R., 2006. Lower switch
rate in depressed patients with bipolar II than bipolar I disorder treated adjunctively
with second-generation antidepressants. Am. J. Psychiatry 163, 313–315.
Altshuler, L.L., Sugar, C.A., McElroy, S.L., Calimlim, B., Gitlin, M., Keck Jr., P.E., Aquino-
Elias, A., Martens, B.E., Fischer, E.G., English, T.L., Roach, J., Suppes, T., 2017.
Switch rates during acute treatment for bipolar II depression with lithium, sertraline,
or the two combined: a randomized double-blind comparison. Am. J. Psychiatry 174,
266–276.
American Psychiatric Association, 2010. Practice Guideline for the Treatment of Patients
With Bipolar Disorder, 2nd ed.
Amsterdam, J.D., Shults, J., 2008. Comparison of short-term venlafaxine versus lithium
monotherapy for bipolar II major depressive episode: a randomized open-label
study. J. Clin. Psychopharmacol. 28, 171–181.
Amsterdam, J.D., Lorenzo-Luaces, L., Soeller, I., Li, S.Q., Mao, J.J., DeRubeis, R.J., 2016.
Short-term venlafaxine v. lithium monotherapy for bipolar type II major depressive
episodes: effectiveness and mood conversion rate. Br. J. Psychiatry 208, 359–365.
Arieli, A., Lepkifker, E., 1981. The antidepressant effect of lithium. Curr. Dev.
Psychopharmacol. 6, 165–190.
Austin, M.P., Souza, F.G., Goodwin, G.M., 1991. Lithium augmentation in
antidepressant-resistant patients.A quantitative analysis. Br. J. Psychiatry 159,
510–514.
Bahji, A., Ermacora, D., Stephenson, C., Hawken, E.R., Vazquez, G., 2020. Comparative
efficacy and tolerability of pharmacological treatments for the treatment of acute
bipolar depression: a systematic review and network meta-analysis. J. Affect. Disord.
269, 154–184.
Baldessarini, R.J., Tondo, L., Pinna, M., Nunez, N., Vazquez, G.H., 2019. Suicidal risk
factors in major affective disorders. Br. J. Psychiatry 1–6.
Baron, M., Gershon, E.S., Rudy, V., Jonas, W.Z., Buchsbaum, M., 1975. Lithium
carbonate response in depression. Prediction by unipolar/bipolar illness, average-
evoked response, catechol-O-methyl transferase, and family history. Arch. Gen.
Psychiatry 32, 1107–1111.
Bauer, M., Dopfmer, S., 1999. Lithium augmentation in treatment-resistant depression:
meta-analysis of placebo-controlled studies. J. Clin. Psychopharmacol. 19, 427–434.
Bhagwagar, Z., Goodwin, G.M., 2002. The role of lithium in the treatment of bipolar
depression. Clin. Neurosci. Res. 2, 222–227.
Borenstein, M., Hedges, L., Higgins, J., Rothstein, H., 2009. Introduction to Meta-
analysis. John Wiley & Sons Ltd, West Sussex.
Borenstein, M., Hedges, L., Higgins, J., Rothstein, H., 2013. Comprehensive Meta-
analysis Version 3. Biostat, Englewood, NJ.
Cade, J.F., 1949. Lithium salts in the treatment of psychotic excitement. Med. J. Aust. 2,
349–352.
<collab>Roxane Laboratories, collab, 2011. Lithium Carbonate (Lithium Carbonate)
[package insert]. Roxane Laboratories, Inc., Columbus, Ohio.
Crump, C., Sundquist, K., Winkleby, M.A., Sundquist, J., 2013. Comorbidities and
mortality in bipolar disorder: a Swedish national cohort study. JAMA Psychiatry 70,
931–939.
Deeks, J.J., Higgins, J.P.T., Altman, D.G., 2021. Chapter 10: analysing data and
undertaking meta-analyses. In: Higgins, J.P.T., Thomas, J., Chandler, J.,
Cumpston, M., Li, T., Page, M.J., Welch, V.A. (Eds.), Cochrane Handbook for
Systematic Reviews of Interventions Version 6.2.
Donnelly, E.F., Goodwin, F.K., Waldman, I.N., Murphy, D.L., 1978. Prediction of
antidepressant responses to lithium. Am. J. Psychiatry 135, 552–556.
279
Journal of Affective Disorders 308 (2022) 268–280
Downs, S.H., Black, N., 1998. The feasibility of creating a checklist for the assessment of
the methodological quality both of randomised and non-randomised studies of
health care interventions. J. Epidemiol. Community Health 52, 377–384.
Duval, S., Tweedie, R., 2000. Trim and fill: a simple funnel-plot-based method of testing
and adjusting for publication bias in meta-analysis. Biometrics 56, 455–463.
Ebert, D., Jaspert, A., Murata, H., Kaschka, W.P., 1995. Initial lithium augmentation
improves the antidepressant effects of standard TCA treatment in non-resistant
depressed patients. Psychopharmacology 118, 223–225.
Fieve, R.R., Platman, S.R., Plutchik, R.R., 1968. The use of lithium in affective disorders.
I.Acute endogenous depression. Am. J. Psychiatry 125, 487–491.
Goodwin, F.K., Jamison, K.R., 1990. Manic-depressive Illness. Oxford University Press,
New York.
Goodwin, F.K., Murphy, D.L., Bunney Jr., W.E., 1969. Lithium-carbonate treatment in
depression and mania. A longitudinal double-blind study. Arch. Gen. Psychiatry 21,
486–496.
Goodwin, F.K., Murphy, D.L., Dunner, D.L., Bunney Jr., W.E., 1972. Lithium response in
unipolar versus bipolar depression. Am. J. Psychiatry 129, 44–47.
Goodwin, F.K., Jamison, K.R., Ghaemi, S.N., 2007. Manic-depressive Illness: Bipolar
Disorders And Recurrent Depression, 2nd ed. Oxford University Press, New York, N.
Y.
Goodwin, G.M., Haddad, P.M., Ferrier, I.N., Aronson, J.K., Barnes, T., Cipriani, A.,
Coghill, D.R., Fazel, S., Geddes, J.R., Grunze, H., Holmes, E.A., Howes, O.,
Hudson, S., Hunt, N., Jones, I., Macmillan, I.C., McAllister-Williams, H.,
Miklowitz, D.R., Morriss, R., Munafo, M., Paton, C., Saharkian, B.J., Saunders, K.,
Sinclair, J., Taylor, D., Vieta, E., Young, A.H., 2016. Evidence-based guidelines for
treating bipolar disorder: revised third edition recommendations from the British
Association for Psychopharmacology. J. Psychopharmacol. 30, 495–553.
Grunze, H., Vieta, E., Goodwin, G.M., Bowden, C., Licht, R.W., Moller, H.J., Kasper, S.,
WFSBP Taskforce on Treatment Guidelines for Bipolar Disorders, 2010. The World
Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the biological
treatment of bipolar disorders: update 2010 on the treatment of acute bipolar
depression. World J. Biol. Psychiatry 11, 81–109.
Hamilton, M., 1960. A rating scale for depression. J. Neurol. Neurosurg. Psychiatry 23,
56–62.
Ioannidis, J.P., Trikalinos, T.A., 2007. The appropriateness of asymmetry tests for
publication bias in meta-analyses: a large survey. CMAJ 176, 1091–1096.
Johnson, G., 1974. Antidepressant effect of lithium. Compr. Psychiatry 15, 43–47.
Johnson, G.F., 1987. Lithium in depression: a review of the antidepressant and
prophylactic effects of lithium. Aust. N. Z. J. Psychiatry 21, 356–365.
Judd, L.L., Akiskal, H.S., Schettler, P.J., Endicott, J., Maser, J., Solomon, D.A., Leon, A.C.,
Rice, J.A., Keller, M.B., 2002. The long-term natural history of the weekly
symptomatic status of bipolar I disorder. Arch. Gen. Psychiatry 59, 530–537.
Judd, L.L., Akiskal, H.S., Schettler, P.J., Coryell, W., Endicott, J., Maser, J.D.,
Solomon, D.A., Leon, A.C., Keller, M.B., 2003. A prospective investigation of the
natural history of the long-term weekly symptomatic status of bipolar II disorder.
Arch. Gen. Psychiatry 60, 261–269.
Judd, L.L., Akiskal, H.S., Schettler, P.J., Endicott, J., Leon, A.C., Solomon, D.A.,
Coryell, W., Maser, J.D., Keller, M.B., 2005. Psychosocial disability in the course of
bipolar I and II disorders: a prospective, comparative, longitudinal study. Arch. Gen.
Psychiatry 62, 1322–1330.
Kelly, T., 2019. Lithium and the Woozle effect. Bipolar Disord. 21, 302–308.
Kramlinger, K.G., Post, R.M., 1989. The addition of lithium to carbamazepine.
Antidepressant efficacy in treatment-resistant depression. Arch. Gen. Psychiatry 46,
794–800.
Mendels, J., 1976. Lithium in the treatment of depression. Am. J. Psychiatry 133,
373–378.
Mendels, J., Frazer, A., 1973. Intracellular lithium concentration and clinical response:
towards a membrane theory of depression. J. Psychiatr. Res. 10, 9–18.
Mendels, J., Ramsey, T.A., Dyson, W.L., Frazer, A., 1979. Lithium as an antidepressant.
Arch. Gen. Psychiatry 36, 845–846.
Merikangas, K.R., Akiskal, H.S., Angst, J., Greenberg, P.E., Hirschfeld, R.M.,
Petukhova, M., Kessler, R.C., 2007. Lifetime and 12-month prevalence of bipolar
spectrum disorder in the National Comorbidity Survey replication. Arch. Gen.
Psychiatry 64, 543–552.
Michalak, E.E., Yatham, L.N., Lam, R.W., 2005. Quality of life in bipolar disorder: a
review of the literature. Health Qual. Life Outcomes 3, 72.
Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., Group, P., 2009. Preferred reporting
items for systematic reviews and meta-analyses: the PRISMA statement. Ann. Intern.
Med. 151, 264–269. W264.
Montgomery, S.A., Asberg, M., 1979. A new depression scale designed to be sensitive to
change. Br. J. Psychiatry 134, 382–389.
Murray, C.J., Lopez, A.D., 1997. Global mortality, disability, and the contribution of risk
factors: Global Burden of Disease Study. Lancet 349, 1436–1442.
Noyes Jr., R., Dempsey, G.M., Blum, A., Cavanaugh, G.L., 1974. Lithium treatment of
depression. Compr. Psychiatry 15, 187–193.
Popovic, D., Reinares, M., Goikolea, J.M., Bonnin, C.M., Gonzalez-Pinto, A., Vieta, E.,
2012. Polarity index of pharmacological agents used for maintenance treatment of
bipolar disorder. Eur. Neuropsychopharmacol. 22, 339–346.
Price, L.H., Charney, D.S., Heninger, G.R., 1986. Variability of response to lithium
augmentation in refractory depression. Am. J. Psychiatry 143, 1387–1392.
Rosa, A.R., Gonzalez-Ortega, I., Gonzalez-Pinto, A., Echeburua, E., Comes, M., Martinez-
Aran, A., Ugarte, A., Fernandez, M., Vieta, E., 2012. One-year psychosocial
functioning in patients in the early vs. late stage of bipolar disorder. Acta Psychiatr.
Scand. 125, 335–341.
J.J. Rakofsky et al.
Selle, V., Schalkwijk, S., Vazquez, G.H., Baldessarini, R.J., 2014. Treatments for acute
bipolar depression: meta-analyses of placebo-controlled, monotherapy trials of
anticonvulsants, lithium and antipsychotics. Pharmacopsychiatry 47, 43–52.
Srisurapanont, M., Yatham, L.N., Zis, A.P., 1995. Treatment of acute bipolar depression:
a review of the literature. Can. J. Psychiatr. 40, 533–544.
Stokes, P.E., Shamoian, C.A., Stoll, P.M., Patton, M.J., 1971. Efficacy of lithium as acute
treatment of manic-depressive illness. Lancet 1, 1319–1325.
Suppes, T., Marangell, L.B., Bernstein, I.H., Kelly, D.I., Fischer, E.G., Zboyan, H.A.,
Snow, D.E., Martinez, M., Al Jurdi, R., Shivakumar, G., Sureddi, S., Gonzalez, R.,
2008. A single blind comparison of lithium and lamotrigine for the treatment of
bipolar II depression. J. Affect. Disord. 111, 334–343.
Swann, A.C., Bowden, C.L., Morris, D., Calabrese, J.R., Petty, F., Small, J., Dilsaver, S.C.,
Davis, J.M., 1997. Depression during mania. Treatment response to lithium or
divalproex. Arch. Gen. Psychiatry 54, 37–42.
Swann, A.C., Bowden, C.L., Calabrese, J.R., Dilsaver, S.C., Morris, D.D., 1999.
Differential effect of number of previous episodes of affective disorder on response to
lithium or divalproex in acute mania. Am. J. Psychiatry 156, 1264–1266.
Taylor, D.M., Cornelius, V., Smith, L., Young, A.H., 2014. Comparative efficacy and
acceptability of drug treatments for bipolar depression: a multiple-treatments meta-
analysis. Acta Psychiatr. Scand. 130, 452–469.
280
Journal of Affective Disorders 308 (2022) 268–280
The Cochrane Collaboration, 2020. Review Manager (RevMan) [Computer Program].
Version 5.4. The Cochrane Collaboration.
Vieta, E., Locklear, J., Gunther, O., Ekman, M., Miltenburger, C., Chatterton, M.L.,
Astrom, M., Paulsson, B., 2010. Treatment options for bipolar depression: a
systematic review of randomized, controlled trials. J. Clin. Psychopharmacol. 30,
579–590.
World Health Organization, 1968. International Classification of Diseases. Geneva.
Yatham, L.N., Kennedy, S.H., Parikh, S.V., Schaffer, A., Bond, D.J., Frey, B.N.,
Sharma, V., Goldstein, B.I., Rej, S., Beaulieu, S., Alda, M., MacQueen, G., Milev, R.V.,
Ravindran, A., O'Donovan, C., McIntosh, D., Lam, R.W., Vazquez, G., Kapczinski, F.,
McIntyre, R.S., Kozicky, J., Kanba, S., Lafer, B., Suppes, T., Calabrese, J.R., Vieta, E.,
Malhi, G., Post, R.M., Berk, M., 2018. Canadian Network for Mood and Anxiety
Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018
guidelines for the management of patients with bipolar disorder. Bipolar Disord. 20,
97–170.
Young, A.H., McElroy, S.L., Bauer, M., Philips, N., Chang, W., Olausson, B., Paulsson, B.,
Brecher, M., Investigators, E.I., 2010. A double-blind, placebo-controlled study of
quetiapine and lithium monotherapy in adults in the acute phase of bipolar
depression (EMBOLDEN I). J. Clin. Psychiatry 71, 150–162.
Zornberg, G.L., Pope Jr., H.G., 1993. Treatment of depression in bipolar disorder: new
directions for research. J. Clin. Psychopharmacol. 13, 397–408.