Molecular Psychiatry

https://doi.org/10.1038/s41380-018-0044-2

EXPERT REVIEW

Pharmacological treatment of adult bipolar disorder

Ross J. Baldessarini1,2 Leonardo Tondo3 Gustavo H. Vázquez4
● ●

Received: 12 February 2018 / Accepted: 19 February 2018

© Macmillan Publishers Limited, part of Springer Nature 2018

Abstract
We summarize evidence supporting contemporary pharmacological treatment of phases of BD, including: mania,
depression, and long-term recurrences, emphasizing findings from randomized, controlled trials (RCTs). Effective treatment
of acute or dysphoric mania is provided by modern antipsychotics, some anticonvulsants (divalproex and carbamazepine),
and lithium salts. Treatment of BD-depression remains unsatisfactory but includes some modern antipsychotics (particularly
lurasidone, olanzapine + fluoxetine, and quetiapine) and the anticonvulsant lamotrigine; value and safety of antidepressants
remain controversial. Long-term prophylactic treatment relies on lithium, off-label use of valproate, and growing use
of modern antipsychotics. Lithium has unique evidence of antisuicide effects. Methods of evaluating treatments for
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BD rely heavily on meta-analysis, which is convenient but with important limitations. Underdeveloped treatment for
BD-depression may reflect an assumption that effects of antidepressants are similar in BD as in unipolar major
depressive disorder. Effective prophylaxis of BD is limited by the efficacy of available treatments and incomplete
adherence owing to adverse effects, costs, and lack of ongoing symptoms. Long-term treatment of BD also is limited by
access to, and support of expert, comprehensive clinical programs. Pursuit of improved, rationally designed pharmacological
treatments for BD, as for most psychiatric disorders, is fundamentally limited by lack of coherent pathophysiology or
etiology.

Introduction to clear description by Kraepelin in the 1890s [2], followed

Bipolar disorder (BD) is both one of the oldest and
youngest of major, modern psychiatric disorders [1].
Whereas melancholia and irrational, excited states were
described from ancient times, the modern concept of
“manic-depressive illness” emerged over several centuries
Electronic supplementary material The online version of this article
(https://doi.org/10.1038/s41380-018-0044-2) contains supplementary
material, which is available to authorized users.
* Ross J. Baldessarini
rbaldessarini@mclean.harvard.edu
1 can change markedly over time, making their clinical
International Consortium for Bipolar & Psychotic Disorders
Research, Mailman Research Center, McLean Hospital, 115 Mill
Street, Belmont, MA 02478, USA
2
Department of Psychiatry, Harvard Medical School, 25 Shattuck
Street, Boston, MA, USA
3
Lucio Bini Mood Disorders Centers, Via Cavalcanti 28, 0918,
Cagliari and Via Crescenzio 42, Rome 00193, Italy
4
Department of Psychiatry, Queen’s University, 15 Arch Street,
Kingston, ON K763N6, Canada
by a century of debate about the breadth of the concept and
occurrence of clinically important subtypes. Even though
BD, with mania or hypomania (“[hypo]mania”) and a
separate melancholic or depressive syndrome were dis-
cussed for more than a century, formal distinction of BD
from “major depressive disorder” did not emerge until 1980
[3]. There followed a recognition of type-II BD (BD-II)
with depression and hypomania, as well as BD “mixed
states”, and of “mixed features” of opposite polarity in both
major depression and [hypo]mania [3]. BD types I (BD-I)
and II (BD-II) each show a prevalence of 0.5–1.0% [4, 5].
BD is highly inheritable, based on family studies and gene-
association analyses [6, 7].
Clinical manifestations of BD are many, complex, and
treatment especially challenging. There also are efforts to
extend the BD concept to include behavioral disorders of
children that may not follow the archetypical adult picture
of discrete episodes of [hypo]mania and major depression,
as well as depressive syndromes with subtle hypomanic
features, considered to fall within a “bipolar spectrum”
[8]. A related development is recently renewed interest
in mixed states or episodes with “mixed features” of

opposite polarity, or marked by prominent agitation in
depression and dysphoria in [hypo]mania [3]. Possibly
related cyclothymic disorder and cyclothymic or hyperthy-
mic temperament types are far less well developed as
clinical entities and not discussed here.
This review focuses on pharmacotherapy of BD in
adults, considering the following: [a] acute episodes of
[hypo]mania or [b] depression, and [c] efforts to limit their
risk of recurrence. This summary of contemporary ther-
apeutics for BD relies on research findings in recent, sys-
tematic, meta-analytic reviews, supplemented by systematic
literature searches through December 2017. Most available
research pertains to BD-I, with much less research on BD-II
(mostly pertaining to depression) and almost none on
cyclothymia. It is important to emphasize that most
randomized-controlled trials (RCTs) on the treatment of
acute depressive or [hypo]manic episodes in BD are time-
limited (typically weeks) for practical reasons and may not
adequately represent the clinical task of achieving full
remission, which often requires several months for mania
and often longer for depression, even with presumably
adequate treatment [9–12].
Treatment of mania
Acute mania can represent a medical emergency that often
leads to psychiatric hospitalization to protect patients from
hyperactive and impulsive activity, sometimes through the
intervention of law-enforcement agencies responding to
potentially dangerous behavior. The modern era of clinical
psychopharmacology can be dated from introduction of
lithium carbonate by John Cade in Melbourne in 1949 [13]
and early clinical use of chlorpromazine, the first effective
antipsychotic agent, in Paris in the early 1950s [14]. Both
initially were used to treat agitated-excited and usually
psychotic patients, many of whom probably would be
recognized now as having BD-I mania [13, 14]. Acceptance
of lithium in psychiatric therapeutics was slow initially,
owing to early case reports of toxicity among medically ill
patients who were given uncontrolled quantities of lithium
salts as a sodium chloride substitute [15]. In addition, lack
of patentability of this natural mineral greatly limited
pharmaceutical development, testing, and commercial pro-
motion of lithium as a treatment of demonstrated efficacy
[14]. An important conceptual impact of lithium as a
selectively antimanic treatment without antipsychotic
effects was to encourage interest in mania as a specific
diagnosis and therapeutic target [14, 16].
For several decades, lithium salts were a leading treat-
ment for acute mania, sometimes with initial use of first-
generation antipsychotic drugs (FGAs) and temporary
addition of sedatives, including potent benzodiazepines.
R. J. Baldessarini et al.
Most, if not all, effective antipsychotic agents also
have antimanic effects, which arise more rapidly than with
lithium, whose dosing is limited by a low margin of safety.
Of many FGAs widely employed empirically to treat acute
mania, only chlorpromazine has regulatory (FDA) approval
for this indication [14]. Currently, most modern, or “sec-
ond-generation” antipsychotics (SGAs) have regulatory
recognition of efficacy in acute mania, and many are also
approved for mixed states or dysphoric mania, usually
based on post-hoc, subgroup analyses of samples that
combined manic and mixed cases [17]. Among SGAs,
aripiprazole, asenapine, cariprazine, olanzapine, paliper-
idone, risperidone, and ziprasidone have solid evidence of
efficacy in mania, as does quetiapine in relatively high
doses [18–20].
Since the 1970s, some drugs developed primarily as
anticonvulsants also have proved useful for BD, notably
sodium divalproex (valproate) and carbamazepine; both
have regulatory approval for treatment of acute and dys-
phoric mania but not for long-term prophylaxis, for which
they are nevertheless used empirically, off-label. The
anticonvulsant analogs of carbamazepine, oxcarbazepine,
and licarbazepine probably are not effective for mania nor
are several other anticonvulsants, including gabapentin,
lamotrigine, and topiramate [18–22]. These inconsistent
effects indicate that antimanic effects are not characteristic
of anticonvulsants as a class, nor even those with similar
known action mechanisms [21].
RCTs for short-term treatment of acute mania have
been reviewed recently [18–20]. Table 1 summarizes their
relative response rates compared to placebo-treatment and
relative rates of all-cause early dropout, with meta-
analytically pooled data for agents that proved to be sta-
tistically more effective than placebo and have regulatory
approval for treatment of mania; all are widely employed
clinically, including antipsychotics, anticonvulsants, and
lithium. Ineffective in RCTs for mania include the antic-
onvulsants gabapentin, lamotrigine, licarbazepine, oxcar-
bazepine, and topiramate. Also not included is tamoxifen,
which has evidence of antimanic efficacy [23] but lacks
regulatory approval for use in mania, and may risk adverse
endocrinological effects.
Relative antimanic efficacy
Meta-analytic findings have been used to assess relative
efficacy among antimanic treatments, including by pooling
data from standard comparisons of drug vs. placebo, as
well increasingly, by multiple-comparison methods, which
attempt to make up for the striking dearth of head-to-head,
randomized comparisons of treatments (comparing trials of
different agents, which include a common treatment arm)
[18, 20, 24, 25]. Such efforts have not yielded consistent or
Pharmacological treatment of adult bipolar disorder

Table 1 Meta-analyses of randomized, placebo-controlled trials in mania

Drug Trials Subjects Mean Dose (mg/ Response (RR [95% Dropout (RR [95%
day) CI]) CI])

Risperidone 4 976 3.50 ± 0.00 2.66 [1.86–3.81] 0.60 [0.38–0.93]

Carbamazepine 2 427 700 ± 80.0 2.64 [1.60–4.30] 0.88 [0.51–1.56]a
Haloperidol 9 1663 9.45 ± 5.65 2.47 [1.89–3.25] 0.74 [0.53–1.04]a
Cariprazine 4 1198 7.12 ± 1.89 2.33 [1.56–3.53] 1.04 [0.63–1.73]a
Olanzapine 10 2031 13.4 ± 1.92 2.33 [1.82–3.02] 0.47 [0.35–0.63]
Aripiprazole 8 1982 22.5 ± 4.74 2.07 [1.56–2.77] 0.68 [0.48–0.96]
Quetiapine 6 1306 612 ± 118 2.05 [1.49–2.85] 0.63 [0.41–0.94]
Valproate 7 1299 1431 ± 954 2.05 [1.48–2.87] 0.67 [0.47–0.97]
Lithium 14 1981 1260 ± 251 1.92 [1.49–2.49] 0.94 [0.69–1.29]a
Paliperidone 5 1157 7.50 ± 3.87 1.72 [1.08–2.74] 0.60 [0.33–1.06]a
Asenapine 4 841 18.3 ± 0.14 1.61 [1.03–2.54] 0.88 [0.51–1.53]a
Ziprasidone 4 839 124 ± 7.21 1.47 [1.06–2.04] 0.93 [0.61–1.41]a
The data from 77 trials for 12 effective treatments involving a total of 15,500 acutely manic, BD-I subjects, adapted from Yildiz et al. [19, 20]
ranked by descending ratios of antimanic response to drug vs. placebo (RR). Note that CIs (ranging from 1.03 to 4.30) for all agents are
overlapping, and indicate caution in interpreting apparent relative efficacy. The following additional “ineffective” agents: lamotrigine,
licarbazepine, oxcarbazepine, and topiramate are not included nor is tamoxifen, an outlier in 2 trials with 74 subjects and a very high RR of 21.0
[4.50–180], in need of replication
RR relative rate of attaining clinical antimanic response or early dropout with drug/placebo
a
All-cause dropout rate is below that with placebo except for asenapine, carbamazepine, cariprazine, haloperidol, lithium, paliperidone, and
ziprasidone

Table 2 Controlled trials of treatment types for mania limitation of multiple-comparison meta-analysis is that
Treatment type Trials (n) Response rates (%) [95% CI] a fundamental assumption of the method often is not suf-
ficiently considered: fair indirect comparisons should
Antipsychotics 37 49.7 [47.0–52.5]
compare trials that are very similar in many details per-
Lithium carbonate 7 49.1 [42.8–55.3] taining to subject-selection, diagnosis, illness-severity, and
Anticonvulsants 8 48.4 [40.2–56.6] clinical rating methods [24, 25]. This assumption typically
All drugs 52 49.5 [47.3–51.7] is untested in reported multiple-comparison meta-analyses
Placebo 60 31.6 [29.3–33.8] of RCTs in psychopharmacology, leaving their conclusions
Overall drug/placebo RR 52 1.57 [1.50–1.64] less than secure.
On the basis of the data in Table 1 and in Yildiz et al. [20]
Limitations of treatment trials for mania

compelling rankings, which vary with the trials that are
compared. For example, based on 10 drugs considered both
in Table 1 and by Cipriani et al. [18], ranking by apparent
efficacy agreed only moderately (r = 0.618, p = 0.06).
Moreover, averaged results from 50 RCTs did not differ
significantly in their superiority to placebo among major
classes of effective agents (Table 2). Lack of important
differences among effective antimanic drugs also is appar-
ent in the overlapping confidence intervals of drug/placebo
response rate-ratios (RR; Table 1). It is not surprising that
available antimanic treatments would seem similar in effi-
cacy, given their regulatory approval for mania and wide
clinical employment. Of note, too, meta-analysis represents
averaged outcomes across several RCTs per agent, each of
which averages responses across many subjects, making the
likelihood of regression-to-mean effects high. Another
Most RCTs for mania have been relatively brief, typically
3–4 weeks, and rates of “response” are based on substantial
reductions of mania symptom ratings on standardized
scales, typically by ≥50%. Such outcomes have been
achieved, on an average, by just under half (49.5%) of
subjects given an effective drug, and by nearly a third
(31.6%) given placebo—a statistically highly significant
1.57-fold difference favoring active drugs (Tables 1 and 2)
[20]. The high response rates with placebo treatment in
mania may seem surprising, but many “nonspecific” but
helpful clinical and environmental elements favor reduction
of manic intensity and contribute to responses to placebo
and to drugs. Also of note, initial mania symptom-severity
ratings with the Young Mania Rating Scale (YMRS) [26] in
RCTs for mania averaged 29.5 points, or 49.2% of the scale
maximum of 60, indicating moderate illness-severity.

Within three weeks, these initial scores improved by 44.4%
with drugs and 27.4% among placebo-controls—a sig-
nificant, 1.62-fold difference. That is, available RCTs for
most clinically employed antimanic treatments have
demonstrated statistically superior symptomatic improve-
ment over placebo treatment in mania of moderate average
severity within three weeks, but have rarely followed sub-
jects to clinical remission. The few trials considering
remission, for example, defined as reduction of YMRS
scores to ≤12 (i.e., to ≤40.7% of initial scores of 29.5), leave
substantial symptomatic morbidity that is only slightly
greater than the average level of symptomatic improvement,
of 44.4% [20, 27]. Indeed, clinical recovery from an acute
episode of mania with commonly employed modern treat-
ments often requires many weeks [9]. Nevertheless, prac-
tical clinical improvement and discharge from hospital
typically are attained within the first weeks of treating
mania, with active treatment continued into outpatient
follow-up [11, 14]. To reiterate, studies of efficacy of
antimanic treatments have relied mainly on short-term
reductions of symptom-severity, with little attention to
attaining full clinical remission and virtually without con-
sidering functional recovery. This state of current knowl-
edge is understandable from the perspective of time, effort,
and cost considerations in trial designs, but it also under-
scores major differences in the aims of most sponsored trials
carried out to support drug licensing, with less emphasis on
developing information of interest and importance to clin-
icians and patients.
Secular trends in treatment trials for mania
An interesting secular trend was found in considering
changes in the outcomes of RCTs for mania over the years
[20, 28], similar to findings indicating loss of apparent
efficacy of antidepressants in trials for acute major depres-
sive episodes [29, 30], or trials of antipsychotic drugs in
acute psychosis [31]. Such secular trends appear to involve
rising rates of improvement with placebo but little change in
responses with active drugs over the years. In the trials for
mania reviewed here (Table 1) [20, 28], there was no sig-
nificant secular change in response to drugs between 1990
and 2014 (r = 0.04, p = 0.79), whereas response with
placebo-treatment increased highly significantly (r = 0.54,
p < 0.0001) with a consequent decline in apparent efficacy
(drug/placebo response rate ratio) over years (r = –0.58,
p < 0.0001). These secular changes may involve factors
tending to favor improvement with placebo treatment, such
as recruitment of less severely ill patients, and selective
dropout of more severely ill subjects randomized to pla-
cebo. However, baseline YMRS scores at trial-intake in
the same RCTs did not show significant changes over
years (r = 0.083, p = 0.46), whereas trial-size rose highly
R. J. Baldessarini et al.
significantly over the past two decades (r = 0.69, p <
0.0001) and, overall, averaged 237 [CI: 218–256] subjects/
trial. The increase in subject-counts, itself, may reflect
efforts to counteract declining effect-size. However, larger
trials, especially if conducted at multiple sites, can con-
tribute to heterogeneity of subject characteristics and to
increased clinical and measurement variance—all tending to
increase regression to average outcomes that may contribute
to greater apparent improvement in placebo trial-arms
[28–30, 32].
Treatment of bipolar depression
Depressive states are the major contributor to total illness-
burden in BD [10, 11]. In several longitudinal studies
from onset or in mid-course of BD, with ongoing clinical
treatment by community standards, the mean proportion
of weeks ill has averaged nearly 50%, and fully three-
quarters of that morbidity was accounted for by depression
[33, 34]. Depressive components are associated not only
with a high proportion of unresolved (“treatment-resistant”)
BD morbidity, but also with disability and suicide early,
later mortality from stress-sensitive medical illnesses—all
resulting in very high levels of clinical and economic bur-
dens [35, 36]. Despite high prevalence and major sig-
nificance of BD-depression, few treatments are proved to be
consistently effective in acute episodes, and long-term
protection from recurrences remains inadequately eval-
uated. In particular, the value and risks of antidepressant
drugs for BD-depression is controversial [37–39]. Lack of
highly effective treatments encourages widespread empiri-
cal trials of combinations of drugs (“polytherapy”) that are
largely untested for effectiveness and safety. Depressions in
BD and unipolar major depressive disorder differ (e.g., by
family history, sex-distribution, onset-age, long-term diag-
nostic stability, episode duration, recurrence rates, and
responses to particular treatments) [14, 40]. However,
despite limited evidence of efficacy and safety of anti-
depressants in BD-depression, the apparent ease and rela-
tive safety of treating depressive episodes with
antidepressants, combined with the wish to minimize or
avoid depression by BD patients and their clinicians, has
made antidepressants the leading form of treatment pro-
vided to BD patients in recent years [40–42].
The preceding considerations indicate that BD-
depression remains a major clinical problem, indeed, one
of the most critical, unsolved challenges for contemporary
psychiatric therapeutics [10–12, 14]. We summarized
research evidence concerning pharmacological treatments
for depressive components of BD, resulting from a sys-
tematic literature search as well as recent reviews on
Pharmacological treatment of adult bipolar disorder
antidepressants, anticonvulsants, lithium, and SGAs [12,
37–39, 43–48].
Antidepressants for bipolar depression
Knowledge of the value and potential risks of anti-
depressants to treat BD-depression is greatly constrained by
limited and inconsistent research-based information despite
more than a half-century of research and clinical use of
antidepressant drugs to treat “depression” [37, 49, 50].
Research is particularly limited regarding dysthymia and
dysphoria, depression with mixed features, depression in
BD-II, and long-term prophylaxis for BP-depression [12,
37, 48, 51–55].
Antidepressants in acute bipolar depression
Well-designed, controlled, monotherapy trials focusing on
efficacy of antidepressants for acute BD-depression are
surprisingly few, varied in size and quality, and have
yielded inconsistent findings (Table 3) [14, 38, 39, 44, 48–
54, 56]. Two large trials are often cited as indicating a
lack of efficacy of antidepressant treatment in BD-
depression. One, a 26-week, add-on trial found no
additional sustained remission of depressive symptoms
by adding paroxetine (10–40 mg/day) or bupropion
(150–375 mg/day) to already more-or-less clinically opti-
mized treatment of BD patients with mood-stabilizing
or antipsychotic drugs [52]. The second randomized
depressed BD-I and BD-II subjects to paroxetine (20 mg
per day) or placebo for 8 weeks, and found little additional
benefit with the antidepressant [53]. Two meta-analyses
included these and the few other relevant trials supported
possible efficacy of various antidepressants [38, 39];
another did not [49], and their findings are summarized
in Table 3. A naturalistic comparison of clinical responses
in large samples of depressed BD-I, BD–II, or recurrent
unipolar major depressive disorder patients found only
minor differences in rates of response or remission by
diagnostic type, after excluding patients who switched
into hypomania or showed agitation or subclinical hypo-
manic symptoms at baseline [44]. The impression that
antidepressants are less effective in BD-depression may
to some extent reflect worsening of agitation, anger,
or dysphoria with antidepressants [44]. Our tentative con-
clusion arising from available controlled trials is that
antidepressant treatment has yielded a significant, 32%
superiority over placebo in the treatment of acute BD-
depression, with a moderately high level of heterogeneity
among trials (Table 3). Despite limited and inconsistent
research support, it appears to be widely assumed clinically
that antidepressants may be appropriate for some BD
patients, perhaps especially BD-II patients who do not
become manic and therefore may be treated more safely
with antidepressants [37, 44].
Antidepressants and mood switching
There has been particular concern about pathological acti-
vation of mood and behavior during treatment with anti-
depressants, stimulants, or corticosteroids—either as a risk
specific to BD, or perhaps as a psychotoxic effect of such
drugs. As noted, risks particular to BD-I patients include
potentially severe reactions involving mania, psychosis,
aggression, or irresponsible risk-taking behavior, which are
dangerous for patients and may provoke liability concerns
to clinicians and investigators. However, the frequency and
severity of such reactions, as well as their expected pre-
vention by mood-stabilizing or antipsychotic drugs remain
incompletely resolved questions. One large study found a
risk of mood-switching in BD patients to be increased by
2.8-fold within 9 months of adding an antidepressant, but
not if a mood-stabilizing agent were also given [57].
However, in a comprehensive review, we found that risk of
spontaneous mania without antidepressants averaged 13.8%
in BD, and increased by only 1.5% with antidepressant
treatment [58]. Trial findings indicate that antidepressant-
types vary in association with mood-switching: risk is
especially high with tricyclic antidepressants (TCAs) and
the serotonin-norepinephrine reuptake inhibitor (SNRI)
venlafaxine and lower with monoaminoxidase inhibitors
and bupropion [58].
Importantly, prospective, randomized comparisons of
switching rates with versus without ongoing mood-
stabilizing or antipsychotic treatment are lacking, and
clinical evidence on the topic is probably confounded by
preferential use of a mood-stabilizer following mood-
switching or repeated episodes of mania [58].
There is an evident clinical consensus that anti-
depressants should be used in BD patients only cautiously,
briefly, with short-acting agents in moderate, slowly
increased doses, and in association with an effective mood-
stabilizing regimen, while monitoring closely for signs of
emerging hypomania [37]. Despite insufficient research on
the topic, it seems prudent that antidepressants, especially
TCAs and SNRIs, not be used for BD-depression, particu-
larly with a history of mood-switch during antidepressant
treatment, rapid-cycling, or current agitation or hypomanic
symptoms [37, 58].
Long-term use of antidepressants
The potential value and risks of long-term use of anti-
depressants in BD patients with the intent of limiting risk of
future depressive recurrences remains remarkably little-
investigated [40, 45, 51, 55, 59, 60]. The value and safety of
Table 3 Randomized, placebo-controlled trials of antidepressants in acute depression in bipolar disorders
Trial Bipolar types Duration Dropouts (%) Dose (IMI-eq mg/ Treatments Responders/Cases (n/N) [%] Meta-analytic RR
(weeks) day)
Antidepressant Placebo

Cohn et al. [eT3.1] I+II 6 53.9 50 [250] FLX vs. PBO [+Li] 26/30 (86.7%) 11/29 (37.9%) 2.28 [1.40–3.72]
Cohn et al. [eT3.1] I+II 6 53.9 188 [188] IMI vs. PBO {+Li] 17/30 (56.7%) 11/29 (37.9%) 1.49 [0.85–2.62]
Nemeroff et al. I+II 10 23.3 33 [165] PRX vs. PBO [+MS] 15/33 (45.5%) 15/43 (34.9%) 1.30 [0.75–2.27]
[eT3.2]
Nemeroff et al. I+II 10 23.3 167 [167] IMI vs. PBO [+MS] 14/31 (45.2%) 15/43 (34.9%) 1.29 [0.74–2.27]
[eT3.2]
Tohen et al. [eT3.3] I+II 8 33.9 39 [195] OFC vs. PBO 46/82 (56.1%) 108/355 (30.4%) 1.84 [1.44–2.36]
Shelton & Stahl I+II 12 40.2 28 [140] PRX vs. PBO [+MS + 5/20 (25.0%) 3/10 (30.0%) 0.83 [0.25–2.80]
[eT3.4] RSP]
Agosti& Stewart II 6 6.0 255 [255] IMI vs. PBO 13/23 (56.5%) 5/22 (22.7%) 2.49 [1.06–5.82]
[eT3.5]
Agosti& Stewart II 6 6.0 65 [162] PNZ vs. PBO 13/25 (52.0%) 5/22 (22.7%) 2.29 [0.97–5.39]
[eT3.5]
Sachs et al. [eT3] I+II 12 56.8 300 [165] or 30 BUP or PRX vs. PBO 42/179 (23.5%) 51/187 (27.3%) 0.86 [0.60–1.22]
[150] [+MS]
McElroy et al. I+II 8 33.9 20 [100] PRX vs. PBO 65/118 (55.1%) 64/121 (52.9%) 1.04 [0.82–1.32]
[eT3.7]
Ghaemi et al. [eT3.8] I+II 6 17.6 30 [150] CTP vs. PBO [+MS] 29/60 (48.3%) 27/59 (45.8%) 1.06 [0.72–1.55]
Yatham et al. [eT7.9] I 8 25.0 37.5 [150] AGO vs. PBO [+MS] 106/172 (61.6%) 104/172 (60.4%) 1.02 [0.86–1.21]
Overall [12 trials] I & II 8.2 [6.7–9.6] 31.1 [19.9–42.3] 172 [146–198] (IMI- ADs vs. PBO [±MS] 393/803 (48.9) 419/1092 (38.4) 1.32 [1.07–1.62]
[95%CI] eq) [45.4–52.5] [35.5–41.3]
BD-I and BD-II subjects usually were not considered separately, and most trials added antidepressant vs. placebo to a mood-stabilizer (MS: Li or VPA). In only 3/12 trials was antidepressant
significantly superior to placebo. The overall meta-analytically pooled RR of 1.32 was significant (z = 2.65, p = 0.008); NNT = 7.5 [4.4–25.3]; monotherapy trials yielded greater efficacy than
add-on trials (pooled RR = 1.64 [1.05–2.56] vs. 1.18 [0.96–1.46]). Crude response rates favored antidepressants by 1.27-fold (48.9%/38.4%; χ2 = 21.1, p < 0.0001), as did monotherapy (55.4%/
35.0% = 2.00-fold; χ2 = 28.2, p < 0.0001) but not polytherapy trials (45.8%/41.4% = 1.11-fold; χ2 = 2.15, p = 0.14). Overall heterogeneity is substantial (I2 = 66.9%). Most of these findings were
reviewed by Vázquez et al. [38] and McGirr et al. [39]. References are in eAppendix (as eT3.1–eT3.9)
ACs anticonvulsants, ADs antidepressants, AGO agomelatine, BUP bupropion, CTP citalopram, FLX fluoxetine, IMI imipramine; IMI-eq, imipramine-equivalent dose (mg per day), Li lithium
carbonate, MSs mood-stabilizers (Li or ACs), NNT number-needed-to-treat, OFC olanzapine-fluoxetine combination, PBO placebo, PNZ phenelzine, PRX paroxetine, RSP risperidone, VPA
valproate
R. J. Baldessarini et al.
Pharmacological treatment of adult bipolar disorder

long-term antidepressant treatment beyond the initial
months of recovery from an index episode of BD-depres-
sion—in contrast to recurrent unipolar major depression
[61]—remain uncertain. However, relatively long-term
use of antidepressants along with mood-stabilizers may be
appropriate in response to relapses after antidepressant
discontinuation, especially if this is gradual so as to avoid
provoking relapse by discontinuation itself [37, 62].
Two noteworthy RCTs of continuation of modern anti-
depressants involve “enrichment” by selecting subjects who
have had a favorable short-term response to the same
treatments, which may limit generalization. Both trials
suggest that a minority of patients may experience some
delay or reduced frequency of depressive recurrences, but
with increased risk of mood-switching [59, 63]. Rapidly-
cycling patients had far more recurrences with an anti-
depressant included, suggesting cycle-acceleration [37, 59].
Anticonvulsants and lithium
In recent decades, anticonvulsants have been used widely to
treat BD patients, based mainly on secure evidence of short-
term antimanic effects of carbamazepine and valproate, and
long-term effects of lamotrigine to limit risk of recurrences
of depressive episodes, but far less secure evidence of
prophylactic effectiveness of other anticonvulsants [14, 64,
65]. Use of anticonvulsants also has been encouraged by
seeming to be a clinically simpler treatment than lithium
[14]. Despite widespread use of anticonvulsants to treat
mania and to seek long-term protective effects in BD
patients, evidence concerning their value and risks for
treatment of acute BD-depression is limited, and evidence
concerning long-term effects, even more scarce [66].
Four small trials suggest some value of divalproex as a
monotherapy for acute BD-depression (Table 4) [67].
Lamotrigine also may have some benefit, based on pooling
inconsistent data from even individually failed trials
against placebo (Table 4) [68]. However, lamotrigine is
FDA-approved only for long-term prophylaxis in BD, with
effectiveness against recurrences of BD depression but
limited efficacy against acute or recurrent mania [69].
Moreover, the need for slow increments of doses to avoid
dermatological reactions limits the practicality of lamo-
trigine for acute depression. Evidence concerning carba-
mazepine is very limited (Table 4), and controlled trials for
other anticonvulsants have not supported efficacy in BD or
are lacking [45, 64].
Lithium has been a fundamental treatment for BD for
more than six decades, and is still considered a first-line
treatment in some expert guidelines [12, 43]. Surprisingly,

Table 4 Placebo-controlled trials for acute bipolar depression: lithium, anticonvulsants, antipsychotics
Treatments (trials) Subjects (n) Dropout (%) Drug/Placebo Responders/Subjects RR [95%CI]
Drug (%) Placebo (%)

Lithium
Lithium [Li] (1) 265 25.0/27.8 85/136 (62.5) 72/129 (55.8) 1.12 [0.92–1.37]*
Anticonvulsants
Carbamazepine [CBZ] (1) 70 26.5/40.0 30/47 (63.8) 8/23 (34.8) 1.84 [1.01–3.34]
Lamotrigine [LTG] (5) 1071 34.8/33.6 255/541 (47.1) 160/530 (30.2) 1.56 [1.33–1.83]
Valproate [VPA] (4) 140 41.1/47.9 28/69 (40.6) 13/71 (18.3) 2.22 [1.26–3.91]
Anticonvulsants (10) 1281 34.1/40.5 313/657 (47.6) 181/624 (29.0) 1.61 [1.39–1.87]
Antipsychotics
Aripiprazole [APZ] (2) 690 44.0/32.4 148/337 (43.9) 147/353 (41.6) 1.10 [0.81–1.48]*
Cariprazine[CAR] (1) 236 29.1/28.0 86/191 (44.4) 14/45 (31.1) 1.81 [0.91–3.62]*
Lurasidone [LUR] (1) 485 – 168/323 (52.0) 49/162 (30.2) 2.50 [1.68–3.73]
Olanzapine [ONZ] (2) 1220 36.9/45.0 317/694 (45.7) 185/526 (35.2) 1.55 [1.23–1.96]
Quetiapine [QTP] (5) 2485 34.4/35.1 1135/1760 (64.5) 322/725 (44.4) 2.27 [1.91–2.71]
Ziprasidone [ZPS] (2) 928 38.8/31.9 281/554 (50.7) 187/374 (50.0) 1.03 [0.79–1.34]*
Antipsychotics (13) 6044 36.6/35.1 2135/3859 (55.3) 904/2185 (41.4) 1.28 [1.09–1.51]
Pooled/totals (24) 7590 35.7/39.9 2533/4652 (54.4) 1157/2938 (39.4) 1.34 [1.17–1.53]
In individual RCTs or for specific agents, 14/24 (58.3%) trials failed, and [*] 4/10 agents failed. By random-effects meta-analysis: overall RR is
highly significant (z = 4.31, p < 0.0001), as is the difference in weighted-average response rate (54.4% with all drugs, 39.4% with placebo; χ2 =
164, p < 0.0001), but the overall drug superiority over placebo (34.0%) is modest. Agents with significant superiority to placebo were as follows:
CBZ (p = 0.02), LTG (p < 0.0001), VPA (p = 0.004), anticonvulsants (p = 0.001), LUR (p < 0.0001), ONZ (p = 0.0002), QTP (p < 0.0001),
antipsychotics (p < 0.0001). Numbers-needed-to-treat (NNT) for effective agents were as follows: CBZ (3.4 [CI: 1.9–19]), LTG (5.9 [4.4–8.9]),
VPA (4.5 [2.7–13]), anticonvulsants (5.5[4.3–7.7]), LUR (4.6 [3.3–7.8]), ONZ (9.5 [6.2–20]), QTP (5.0 [4.1–6.3]), antipsychotics (8.8 [5.3–27]).
Overall, heterogeneity is substantial (I2 = 79.4%). The data are provided in an eAppendix (in references eT4.1–eT4.23)

its use for BD-depression appears to be based on a single
RCT in which lithium was included as a third-arm of a trial
designed primarily to evaluate quetiapine (Table 4) [70].
Nevertheless, lithium may have some long-term benefits
against recurrences of BD-depression as well as more pro-
minent effects against [hypo]mania [14, 71]. Moreover,
lithium appears to reduce risk of suicide substantially in BD
patients [71–76]. Some experts, based mainly on research in
unipolar major depression, also recommend lithium to
augment effects of other treatments [77].
Second-generation antipsychotics
Modern or “second-generation” antipsychotic drugs
(SGAs), including olanzapine combined with fluoxetine, as
well as quetiapine and lurasidone, are currently the only
medicines with explicit FDA approval for short-term treat-
ment of acute major depressive episodes in BD patients [14,
45]. However, of these agents, only quetiapine has been
found to outperform placebo consistently in multiple trials,
though without dose-dependent differences in efficacy (with
300 vs. 600 mg/day); only the lower dose is FDA-approved
for acute BD-depression [53]. The FDA-approved combi-
nation of olanzapine + fluoxetine produced superior bene-
fits to placebo [78]. As both olanzapine and quetiapine have
antimanic properties, they have yielded somewhat lower
risks of mood-switching than with placebo [45]. Olanza-
pine + fluoxetine, quetiapine and lurasidone have yielded
favorable estimated number-needed-to-treat (NNT) values
below 6 (Table 4) [46–48], and were substantially more
effective than lamotrigine or olanzapine alone [78, 79].
Nevertheless, all of these responses in BD-depression have
been modest (Table 4).
Only some SGAs appear to reduce symptoms of acute
depression in BD patients so that such responses are evi-
dently not a class effect of all modern antipsychotics.
Notably, ziprasidone and aripiprazole were ineffective in
two trials for each [47], and cariprazine remains to be
evaluated adequately as only on a dose of 1.5 mg per day
has been found efficacious for the treatment of BD type I
depression, whereas the response rate with a lower (0.75 mg
per day) and higher (3 mg per day) dose was similar to
treatment with PBO [80] (Table 4).
In effective doses, antipsychotics risk adverse effects that
may not be well tolerated by some patients, particularly
excessive sedation and risk of akathisic restlessness [79,
81]. Although risks of tardive dyskinesia (TD) with most
modern antipsychotic drugs are far lower than with FGAs
[82, 83], the great increase in use and broadening indica-
tions for SGAs may risk increased numbers of cases of
even uncommon adverse effects [84]. Moreover, risks of
weight-gain, type 2 diabetes mellitus, and other features
of metabolic syndrome (hyperlipidemia, hypertension) are
R. J. Baldessarini et al.
encountered with some antipsychotics (particularly olanza-
pine and quetiapine), sometimes in less than 3 months [14,
70, 85]. These medically important adverse effects tend to
limit the potential, but unproved, value of SGAs for pro-
phylactic treatment against recurrences of BD-depression
[47, 48, 66]. In short, quetiapine and lurasidone as well
as olanzapine + fluoxetine and perhaps cariprazine at 1.5
mg/day appear to be efficacious in acute BD-depression,
although with some risks, and without compelling evidence
for long-term, prophylactic effects against BD-depression.
Alternative treatments
Acute BD-depression appears to be responsive to electro-
convulsive treatment (ECT), although maintenance treat-
ment with ECT may not prevent relapses or recurrences [86,
87]. ECT also has evidence of short-term suicide-preventive
effects in BD [88]. Several novel treatments also are under
investigation for BD-depression. They include the NMDA-
glutamate receptor antagonist ketamine (and better-tolerated
agents that affect glutamate neurotransmission), fatty acids,
anti-inflammatory agents, and probiotics [89].
Long-term treatment
Introduction
A critical characteristic of BD is its tendency to remit and
recur episodically in adults, with a cyclic course of alter-
nating and often complex affective and behavioral states
and changes of sleep-wake rhythms, perception, and cog-
nition, as well as long-term risks of substance abuse, self-
harm or injury, and socioeconomic consequences of dys-
function and disability [10, 11]. Single episodes of BD-
depression or mania are rare. Based on the data from the
placebo-arms of 13 long-term treatment trials, a new epi-
sode can be expected every 1–2 years, on average, in
untreated BD patients [90, 91]. Episodes of [hypo]mania
tend to be somewhat more frequent but shorter than of BD-
depression [3, 10, 11]. Many cases present multiphasic
cycles of depressive and [hypo]manic periods, separated by
more or less stable or euthymic intervals of varying length
[11, 33]. Such recurrence patterns, their sequencing, and
even the nature of first-lifetime episodes of BD have pow-
erful predictive value regarding future illness or responses
to treatment [92–94].
In general, the course of BD is variable between and
within individuals; episodes vary in frequency, severity,
duration, as well as in the sequencing of their polarities. The
hypothesis, dating from the work of Kraepelin, that BD
tends to be progressively more frequent with growing
recurrence count remains unproved as a generalization
Pharmacological treatment of adult bipolar disorder
[95, 96]. However, long-term patterns of morbidity in BD
appear to have considerable predictability. For example, the
polarity of first-lifetime episodes strongly predicts prevalent
types of future recurrences [92]. Moreover, some BD
patients tend to have an episode of elevated mood followed
by depression (Mania-Depression-euthymic Interval: MDI
pattern) and others tend to follow the opposite sequence
(DMI), whereas others may cycle at relatively high rates
(“rapid cycling”) or more or less continuously or erratically.
Those with a predominant DMI recurrence pattern, and
those with rapid cycling tend to have less favorable
responses to mood-stabilizing treatment, and are more likely
to switch mood when given an antidepressant [93]. Long-
term depressive morbidity in BD is, by far, the most pro-
minent and challenging aspect of treatment, and unresolved
BP-depressive morbidity is strongly associated with dis-
ability, substance abuse, and suicide [34, 40].
Routine recurrence in BD indicates that tolerable and
cost-effective, long-term, maintenance treatments aimed at
providing prophylaxis against future depressive and [hypo]
manic episodes are highly desirable. The decision to
recommend a potentially indefinitely prolonged program of
prophylactic treatment with one or more medicines as well
as psychosocial, educational, rehabilitative, and other sup-
portive interventions is not a simple one. Typically, treat-
ments found to be effective in an episode of BD are
continued for at least 6–12 months after initial clinical
remission to avoid early relapses [11, 14]. Thereafter,
treatment may or may not be continued indefinitely,
depending on assessment of many clinical factors, including
illness severity, occurrence of suicidal or other dangerous
behaviors, severe agitation, or psychotic features, assess-
ment of individual strengths and vulnerabilities, and con-
sideration of risks of adverse effects, logistical challenges,
and expense involved [12, 14]. Occasionally, long-term
prophylactic treatment is recommended after a single epi-
sode of BD, especially a severe or prolonged episode of
mania with psychotic features [12]. Typically, recommen-
dation of indefinitely pursued treatment with mood-altering
medicines that include lithium, certain anticonvulsants, or
modern antipsychotic drugs is deferred until there has been
either a severe episode or ≥2 recurrences of illness [14].
This strategy is supported by analysis of costs and benefits
associated with starting long-term treatment after one, two,
or more recurrences of BD [97]. Moreover, BD patients,
especially young and early in their experience of BD, often
are unwilling to undertake or adhere to indefinitely pro-
longed treatment. Successful prophylactic treatment in BD
is particularly remarkable in that the patient is expected to
continue taking medicine and to deal with its adverse effects
and expense for years, even when feeling and functioning
quite well. Despite routine recommendation of prophylactic
medical treatment for BD, high rates of non-adherence or of
stopping and restarting treatment are quite frequent. There is
a clinical suspicion that starting and stopping mood-
stabilizing treatments, itself, may contribute to emotional
and functional instability among BD patients. Efforts to
improve adherence to recommended long-term treatment
include supportive counseling, psychoeducation, family and
group therapies [98].
A final general point about establishing long-term treat-
ment for BD is that there is often a prolonged delay in
diagnosing the disorder and establishing appropriate treat-
ment. The delay from initial clinical presentation averages
6–8 years, internationally, and is even longer after onset in
childhood or adolescence, more delayed among women
than men, and in those eventually diagnosed with type-II
BD [99, 100]. Such delays probably are longer in patients
with less severe illness, but also reflect misdiagnosis of BD
as unipolar major depressive disorder or other conditions
[101, 102].
Treatments
Only a small number of medicines have support from long-
term controlled treatment trials aimed at preventing recur-
rences of BD [11, 12]. These include lithium salts, some
anticonvulsants, and some second-generation antipsychotic
drugs (SGAs). These medicinal agents have strong statis-
tical evidence of long-term effectiveness, although the
clinical impact on reduction of morbidity sometimes is quite
limited. These limitations probably reflect both the intrinsic
effectiveness of available medicines as well as unreliable
long-term adherence to prescribed drugs. Accordingly, it is
usual to include long-term psychosocial interventions and
support in efforts to optimize clinical outcomes.
Lithium
Lithium (usually as the carbonate) was introduced in 1949
by John Cade in Australia, primarily to treat acute mania,
but was also recognized as having possible preventive
benefits when continued long-term [13, 103]. Reflecting its
decades of clinical use, lithium has been particularly
extensively studied compared to most other modern alter-
natives. Safe dosing of lithium is supported by assays of
daily trough serum concentrations (morning samples ca. 12
h after a last dose), usually held in the range of 0.5–1.0
mEq/L, with approximately optimal balance of long-term
efficacy and safety at levels of 0.6–0.8 mEq/L, and use of
10–15% lower values for patients over age 60 [14, 104–
106]. Once appropriate dosing is established, it is usual to
monitor serum concentrations quarterly for a year, and then
2–3-times a year thereafter, typically along with assays of
renal and thyroid function [12, 14, 104, 106–108]. Although
lithium is effective in acute mania and poorly tested in acute

BP-depression, its relatively slowness of action, and its
narrow margin of safety which limits use of high doses,
have come to limit clinical use of lithium to aftercare
following near-remission of acute mania, as well as for
long-term prophylactic treatment. It is sometimes used long-
term in combination with a second agent with mood-
stabilizing properties, such as an anticonvulsant or modern
antipsychotc.
Table 5 summarizes findings from 15 long-term rando-
mized, placebo-controlled trials of lithium carried out for an
average of up to 18.9 months, and involving a total of
1888 subjects with BD or other recurring major mood dis-
orders [109]. Overall, the protection afforded by lithium
was highly statistically significant, but the reduction of risk
of recurrences averaged only 39.5% and protection aver-
aged 2.5-times greater against mania than depression.
Lithium appears to be less effective in cases of BD
characterized by: [a] prominent appearance of episodes of
dysphoric mania or with mixed features, [b] a rapid-cycling
course, as is the case with other mood-stabilizers, [c] pro-
minent psychotic symptoms, and [d] alcohol abuse [110]. A
particularly interesting effect of long-term lithium treatment
in BD is strong and consistent association with reduced
rates of suicide and attempts, probably even more effec-
tively than with mood-stabilizing anticonvulsants such as
valproate [76, 111–113]. There also is suggestive evidence
that long-term treatment with lithium may reduce risk of
cognitive dysfunction and dementia in older persons, not
necessarily with BD, although the optimal dosing for such
an effect is not clear [114–116]. Of some clinical impor-
tance, there is evidence that delay of starting treatment and
the number of previous episodes of BD may not reduce
responsiveness to long-term treatment with lithium [117–
119], and that discontinuing and restarting lithium may not
be associated with appreciable loss of benefit [120]. How-
ever, discontinuation of lithium can increase the risk of
early recurrences, especially if discontinuation is abrupt or
with dose-reduction over <14 days [121, 122].
Long-term use of lithium carries some risk of adverse
effects. These include decreased thyroid function (asso-
ciated with early increases of thyroid stimulating hormone
[TSH]), and concern about loss of renal function. In a
recent, international, multicenter study, we found that 18%
of 312 subjects treated with lithium and assessed for 8–14
years experienced ≥2 low values of estimated glomerular
filtration rate (eGFR) < 60 mL/min/1.73 m2; such cases were
associated with ≥15 years of treatment, starting after age 40,
and current age >55 years; no patients experienced end-
stage renal failure [106]. Mean serum creatinine rose only
from 0.87 to 1.17 mg/dL, BUN from 23.7 to 33.1 mg/dL,
glucose from 88 to 122 mg/dL, and BMI from 25.9 to 26.6
kg/m2. Independent factors associated with declining
eGFR ranked: longer lithium treatment, higher serum
R. J. Baldessarini et al.
lithium concentration, older age, and medical comorbidity.
A paradoxical finding was that eGFR was lower with lower
lithium doses, presumably as therapeutic serum concentra-
tions were maintained as age advanced and renal function
declined [106].
In conclusion, lithium remains a valuable, under-
appreciated long-term treatment option for BD patients.
However, its lack of patenting and commercial promotion,
associated with its potential toxicity without adequate
medical monitoring, as well as vigorous marketing of
alternative treatments have limited use of lithium to treat
BD in recent years.
Anticonvulsants
Anticonvulsants with regulatory approval for use in BD are
carbamazepine and divalproex for acute mania or mixed-
dysphoric mania, and lamotrigine for long-term protection
[14, 69, 123]. As noted, several other anticonvulsants have
received some research attention but appear to be ineffec-
tive in BD (gabapentin, oxcarbazepine, topiramate) or lack
research for psychiatric indications [14]. Curiously, only
some anticonvulsants have demonstrated mood-stabilizing
effects, whereas others with similar pharmacodynamic
effects did not. Currently, carbamazepine, lamotrigine, and
sodium valproate are used clinically for long-term preven-
tion of recurrences of mania or depression in BD [123, 124].
Of these, carbamazepine and valproate have regulatory
approval only for short-term treatment of acute mania or
mixed episodes of dysphoric mania, and their long-term use
with prophylactic intent remains an off-label indication that
lacks regulatory approval. Although lamotrigine is approved
only for long-term treatment of illness recurrences in BD, it
appears to be more effective against BD-depression.
For carbamazepine, we identified only one long-term
trial (up to 12 months) against placebo. Its protective effects
were not significant (despite 1.92-fold apparent superiority
to placebo) [124], and in two trials compared to lithium
[125, 126], long-term treatment with carbamazepine was
significantly inferior (Table 6). The main effect of carba-
mazepine appears to be to reduce recurrences of mania
selectively. For treatment of BD, carbamazepine typically is
dosed to serum concentrations of 4–12 µg/mL, mimicking
those found safe and effective for the treatment of epilepsy,
but not specifically optimized for BD. Its chemical analog,
oxcarbazepine, is not adequately tested for long-term
treatment in BD and lacks regulatory approval for any
indication in BD. Frequently observed adverse effects of
carbamazepine include: blurred vision, dizziness, sedation,
tremor, gastrointestinal symptoms, dermatological abnorm-
alities, and rare agranulocytosis. Notably, it also increases
metabolism and clearance of itself and many other medi-
cines, including antidepressants and contraceptive steroids.
Table 5 Long-term, placebo-controlled trials of lithium monotherapy for bipolar and other recurrent mood disorders
Study Months Total N Lithium Placebo RR [95% CI] Weight (%) M/D protection
New episodes Stable New episodes Stable

Baastrup et al. [eT5.1a] ≤5 50 0 28 12 10 0.03 [0.002–0.51] 0.49 —

Melia [eT5.2a] <24 15 4 3 6 2 0.76 [0.36–1.62] 4.61 —
Coppen et al. [eT5.3a] ≤6 38 3 14 20 1 0.19 [0.07–0.52] 2.92 5.58
Cundall et al. [eT5.4a] ≤6 38 4 8 10 2 0.40 [0.17–0.93] 3.98 —
Hullin et al. [eT5.5a] ≤6 36 1 17 6 12 0.17 [0.02–1.25] 0.90 —
Prien et al. [eT5.6] ≤24 205 43 58 84 20 0.53 [0.41–0.67] 11.6 —
Stallone et al. [eT5.7a] ≤28 52 11 14 25 2 0.48 [0.32–0.75] 8.09 2.70
Dunner et al. [eT5.8a] ≤36 40 10 6 18 6 0.83 [0.53–1.30] 8.25 4.67
Fieve et al. [eT5.9a] ≤53 53 12 12 24 5 0.60 [0.39–0.93] 8.42 —
Pharmacological treatment of adult bipolar disorder

Kane et al. [eT5.10] ≤24 11 1 3 5 2 0.35 [0.06–2.04] 1.16 0.79

Bowden et al. [eT5.11] ≤12 185 28 63 36 58 0.80 [0.54–1.20] 8.95 0.67
Bowden et al. [eT5.12] ≤12 116 18 28 49 21 0.56 [0.38–0.83] 9.10 2.28
Calabrese et al. [eT5.13] ≤12 242 56 65 66 55 0.85 [0.66–1.09] 11.5 1.85
Amsterdam & Shults [eT5.14] ≤12 53 15 11 14 13 1.11 [0.68–1.87] 9.10 —
Weisler et al. eT5.15] ≤24 768 95 269 208 196 0.51 [0.42–0.62] 12.4 1.36
Sums/Means [95%CI] (N = 15) ≤18.9 [11.5–26.4] 1888 301 599 583 405 0.605 [0.496–0.737]] 100 2.49 [1.58–3.42]
Overall efficacy (RR, as the rate of new episodes with drug/placebo) highly significantly favors lithium over placebo (z = 4.99, p < 0.0001). The pooled rate (%/month) of relapses or recurrences
was 1.76 with lithium and 3.15 with placebo. Number-needed-to-treat (NNT) = 3.2 [2.4–4.8]. I2 = 61.4%. M/D protection ratio = recurrence rate for depression/mania (ratio >1.0 favors mania)
a
Most older studies included subjects with various recurrent mood disorders, not all bipolar; their pooled efficacy was somewhat greater (lower RR = 0.474 [0.306–0.735]) than in more recent
trials (RR = 0.656 [0.525–0.820]). In meta-regression, efficacy declined with reporting year (rising RR), with little change in lithium-associated response, but an increase with placebo, and
efficacy was somewhat greater in larger trials, but did not differ with nominal trial duration. References, including a review by Cipriani et al. [eT7.16] are cited in an eAppendix (as T5.1–eT5.16)
 R. J. Baldessarini et al.

Table 6 Long-term trials of anticonvulsant monotherapy vs. lithium or placebo for bipolar disorders
Trials Months Total N Anticonvulsant Comparator RR [95%CI]
(AC vs other)
New episodes Stable % Failed New episodes Stable % failed

Carbamazepine vs. placebo

Okuma et al. [eT6.1] ≤12.0 22 5 7 41.7 8 2 80.0 0.52 [0.25–1.09]a
Carbamazepine vs. lithium
Greil et al. [eT6.2] ≤30 140 20 43 31.8 17 60 22.1 1.44 [0.83–2.50]
Hartong et al. [eT6.3] ≤24 53 14 16 46.7 3 20 27.3 3.58 [1.16–11.0]
Pooled ≤27.0 193 34 59 36.6 20 80 20.0 1.83 [1.12–2.99]b
Lamotrigine vs. placebo
Bowden et al. [eT6.4] ≤18 129 28 31 47.5 49 21 70.0 0.68 [0.50–0.92]
Calabrese et al. [eT6.5] ≤18 292 83 88 48.5 66 55 54.6 0.89 [0.71–1.11]
Koyama et al. [eT6.6] ≤6.0 103 20 25 44.4 37 21 63.8 0.70 [0.48–0.94]
Pooled ≤14.4 524 131 144 47.6 152 97 61.0 0.78 [0.65–0.94]c
Lamotrigine vs. lithium
Bowden et al. [eT6.4] ≤18 106 28 31 47.5 18 28 39.1 1.21 [0.77–1.90]
Calabrese et al. [eT5.5] <18 292 83 88 48.5 56 65 46.3 1.05 [0.82–1.35]
Pooled <18.0 398 111 119 48.3 74 93 44.3 1.08 [0.87–1.35]d
Valproate vs. placebo
Bowden et al. [eT6.7] ≤12.0 281 45 142 24.1 36 58 38.3 0.63 [0.44–0.90]e
Kemp et al. [eT6.8] ≤6.0 31 8 7 53.3 9 7 56.2 0.68 [0.49–1.80]
Pooled <9.0 312 53 149 26.2 45 65 40.9 0.68 [0.49–0.93]
Valproate vs. lithium
Bowden et al. [eT6.7] ≤12 278 45 142 24.1 28 63 30.8 1.28 [0.86–1.91]
Calabrese et al. [eT6.9] ≤20 60 14 14 50.0 18 14 56.2 1.12 [0.70–1.82]
Findling et al. [eT6.10] ≤18 60 20 10 66.7 18 12 60.0 0.90 [0.611–1.32]
Kemp et al. [eT6.8] ≤6 31 8 7 53.3 9 7 56.2 1.05 [0.56–2.00]
Geddes et al. [eT6.11] ≤24 220 76 34 69.1 65 45 59.1 1.45 [1.15–1.82]
Pooled ≤16.0 649 163 207 44.0 138 141 49.5 1.22 [1.01–1.47]f
By random-effects meta-analysis, lithium tended to be superior to all three anticonvulsants (pooled RR > 1.0), but all anticonvulsants provided
significantly more protection than placebo (RR < 1.0)
a
z = 1. 73, p = 0.08, NNT (number-needed-to-treat) = 2.6 [1.3–10]
Regarding relative protection against [hypo]mania vs. depression, data for carbamazepine and valproate are insufficient, but for lamotrigine (LTG)
vs. placebo, there was a larger effect against [hypo]mania than depression (ratio = 2.25 [0–8.44]), and for LTG vs. lithium, lithium was more
effective against [hypo]mania (LTG/Li benefit ratio = 2.07), but LTG was more effective for depression (ratio = 0.85). Data and references are
from Kemp et al. 2009 [eT6.8] Cipriani et al. [eT6.13] and Miura et al. [eT6], and as cited in an eAppendix (as references eT7.1–eT7.13)
b
z = 2.39, p = 0.02, NNT = 6.2 [3.5–26]
c
z = 2.63, p = 0.008, NNT = 7.0 [4.0–31]
d
z = 0.74, p = 0.46, NNT = 1.1 [0.9–1.4]
e
z = 2.52, p = 0.01; NNT = 7.0 [3.9–37]
f
z = 2.08, p = 0.02, NNT = 10.5 [5.8–56]

Lamotrigine is FDA-approved for prevention of recur-
rences in BD, although its main benefit appears to be
moderate and selective reduction of risk of recurrences
of depression in both BD-I and BD-II, perhaps more
effectively in BD-II patients [127]. Lamotrigine was sig-
nificantly protective against recurrences in BD compared
to placebo in three trials, reducing recurrence risk by
22% more than placebo, and it averaged, nonsignificantly,
8% less effective than lithium in two other trials (Table 6).
Recommended doses of lamotrigine are 50–200 mg/day,
usually initiated slowly, especially when combined with
valproate (which interferes with clearance of lamotrigine),
to limit risk of dermatological reactions [14]. Benign
rashes are not uncommonly associated with use of lamo-
trigine, especially early in treatment with rapidly increased
doses or in combination with valproate, and rarely necrosis
of skin and mucosae (Stevens-Johnson syndrome) has
occurred.
Pharmacological treatment of adult bipolar disorder

Sodium valproate has been widely used clinically as a

D) for all SGAs except quetiapine (QTP; ratio < 1.00 [D > M]). Data are re-analyzed by random-effects meta-analysis from raw data provided in an on-line appendix by Lindström et al. 2017,eT7.1
which also reports on several add-on trials that support long-term benefits for the agents shown as well as ziprasidone; and from reports by Szegredi et al. (2018) eT7.2 on asenapine, and by
RR = relative risk rate of having a new illness episode with drug/placebo during randomized follow-up, following initial treatment of acute index episodes for a mean of 10.8 [6.28–15.3] weeks

Note that only aripiprazole, olanzapine, and risperidone-LAI significantly outperformed placebo. Additional continuation trials showed benefits of adding an SGA to lithium or valproate:
quetiapine (Vieta et al., [eT7.4]), risperidone (Macfadden et al., [eT7.5]), quetiapine (Suppes et al., [eT7.6]), ziprasidone (Bowden et al., [eT7.7]); another found little difference between
Berwaerts et al. 2010 eT7.3 on paliperidone and olanzapine. Numbers-needed-to-treat (NNT) ranked: olanzapine (3.3 [2.7–4.0]), long-acting injected (LAI) risperidone (5.0 [3.6–8.0]), aripiprazole
(based on half of maxima). Trials that added an SGA vs. placebo to mood-stabilizers are excluded. Relative benefit (ratio of %-reduction of depressive [D]/manic [M] recurrences) was >1.0 (M >
mood-stabilizer, despite limited research support and lack of

Benefit ratio (M vs. D)

regulatory approval for this indication. Valproate reduced

M > D (except QTP)

recurrence risk significantly in BD by 32% in two long-term
trials, but was 22% less effective than lithium in five long-
term trials (Table 6). Usual therapeutic serum concentra-

(5.3 [3.0–23]), quetiapine (5.5 [2.2–∞]), paliperidone (12 [5.1–∞]), asenapine (14 [6.8–∞]); overall NNT = 5.0 [3.6–8.2]. Heterogeneity among trials was high (I2 = 91.0%)
2.68

1.72

0.57
3.27
tions are 50–125 μg/mL, at daily doses up to 10–20 mg/kg/

—
day. Common adverse effects include tremor, weight-gain,
ataxia. In addition valproate can decrease activity of some

p-value [z score]
hepatic oxidases to increase of plasma concentration of

<0.0001 [8.85]

<0.0001 [4.92]
<0.0001 [4.20]
some other medicines, notably including lamotrigine,

0.02 [2.40]
0.07 [1.78]

0.16 [1.40]
0.32 [1.00]
whereas carbamazepine increases the clearance of valproate
[128]. In general, the preceding findings indicate that all
three of the anticonvulsants considered have outperformed
placebo long-term; compared with lithium, carbamazepine

0.57 [0.36–0.90]
0.50 [0.23–1.07]
0.56 [0.49–0.63]
0.84 [0.67–1.07]
0.72 [0.38–1.37]
0.74 [0.65–0.83]
0.65 [0.53–0.80]
and valproate were significantly less effective and lamo-

RR [95%CI]
Table 7 Randomized controlled, long-term, monotherapy trials of second-generation antipsychotics versus placebo in bipolar disorder
trigine was similarly effective. Finally, to reiterate, long-
term use of valproate and carbamazepine for BD lacks
regulatory approval despite wide clinical use.

Stable
Antipsychotics

108
149

160
117
648
47

67

continuation of lithium or quetiapine (Weisler et al., [eT7.8]). References are in an eAppendix as [eT7.1–eT7.8].
First-generation antipsychotics (neuroleptics) are still
sometimes used to treat acute mania but rarely continued
New episodes

long-term, despite relatively low costs, owing largely to

Placebo

1125
risks of adverse neurological effects. Currently, some 304

539
151
36
18

77
second-generation antipsychotics (SGAs) are emerging as
useful for maintenance treatment in BD as well as for acute
Stable

1012
117
279

300
178
mania, mixed-states, and BD-depression. We identified 11
58

80

randomized, placebo-controlled, long-term trials of main-

tenance treatment of BD with six SGAs (aripiprazole [1
New episodes

trial], asenapine [1], olanzapine [4], paliperidone [1], que-

tiapine [2], and risperidone [2 trials]) that involved a total of
Drug

189

394

770

3555 subjects followed for an average of 1.38 years

19

66

93

Doses of 300 and 600 mg/day of quetiapine did not differ in efficacy
9

(Table 7).
Of six SGAs tested, only olanzapine and long-acting
injected (LAI) risperidone showed highly significant
1.38 [0.28–2.48]
Duration (years)

reductions of recurrences of BD (by 44 and 26%, respec-

tively), although aripiprazole yielded a similar and sig-
0.50
0.50
1.21
3.30
1.00
1.75

nificant level of reduction as with olanzapine with far fewer

subjects (Table 7). Only olanzapine was tested against
placebo in more than two trials. Three of the six drugs tested
Subjects (N)

were more effective against recurrences of mania than of

Both trials involved LAI-risperidone
1393

3555

depression; quetiapine was an exception with a greater

160
252
921
290

539

effect against BP-depression, but with only 28% overall

reduction of recurrences (not statistically significant;
Trials (n)

Table 7). Of note, in all of these trials, the degree of clinical

benefit was limited, averaging 35% reduction of risk of new
11
1
1
4
1
2
2

episodes.
Common characteristics of these long-term trials of
SGAs include “enrichment,” by requiring clinical response
b
Paliperidone
Aripiprazole

Total/means
Risperidone
Olanzapine

Quetiapine
Asenapine
Treatment

to initial treatment of an index episode of acute illness

before continuing into longer treatment. For this reason,
b
a

their findings may not generalize to all BD patients.
Moreover, most SGA trials involve relatively brief stabili-
zation after initial treatment, followed by random dis-
continuation of active treatment to placebo, usually without
defining the time of tapering off active treatment. Such
discontinuation designs risk artifactual enhancement of
drug–placebo differences owing to the stressful effects of
treatment discontinuation-to-placebo itself [14, 129]. In
addition, relatively brief periods of stabilization prior to
treatment-discontinuation may favor risk of relapse into
initial episodes rather than of independent, new episode
recurrences.
Adverse effects of continued use of SGAs (typically for
up to 6–18 months in reported trials [Table 7]) include risk of
weight-gain and metabolic syndrome associated with some
SGAs, notably olanzapine, quetiapine, and risperidone [14].
Except for moderate risk of restless akathisia (especially with
lurasidone and olanzapine) and potentially adverse emotional
overarousal (especially with aripiprazole, risperidone, and
ziprasidone), many of the traditional neurological adverse
effects of older neuroleptic drugs, notably acute dystonias
and parkinsonian bradykinesia, are far less prevalent with
SGAs [82, 130]. In addition, risk of tardive dyskinesias and
dystonias (TD) appears to be much lower with most SGAs
than with first-generation antipsychotics [131], although this
risk may rise as indications for use of SGAs continues to
expand, particularly with long-term exposure.
Clozapine, the original SGA, has been used to treat BD
patients largely on an empirical basis without support by
long-term RCTs, and especially when other treatments have
been insufficiently effective [132, 133]. Whether its anti-
suicidal effects in schizophrenia also apply to BD is not
known. Safe use of clozapine requires adequate medical
monitoring to avoid agranulocytosis, metabolic syndrome,
and cardiac toxicity [134, 135].
Antidepressants
Long-term treatment with antidepressants for BD patients
usually is discouraged [12, 37]. Long-term protection
against BP-depressive recurrences with an antidepressant
added, compared to mood-stabilizing drugs alone, though
poorly studied, appears to be minor, and much smaller than
increased risk of new episodes of [hypo]mania, and wor-
sening of rapid-cycling [51, 59]. Nevertheless, adjunctive
treatment with an antidepressant along with mood-stabilizers
appears to be a common, empirical, clinical practice, despite
lack of evidence of its efficacy or safety [12, 37].
ECT and rTMS
Electroconvulsive treatment (ECT) has evidence of efficacy
and safety in short-term applications in all types of episodes
R. J. Baldessarini et al.
of BD, with minimal risk of inducing destabilizing effects
or mania [86, 136–139]. However, support for the efficacy
and safety of maintenance ECT in BD is based on very few
studies, most of which are not well controlled or blinded,
and sometimes include some non-BD patients, without
control for effects of ongoing medicinal maintenance
treatments [86, 136–140]. Nevertheless, even anecdotal
reports may be instructive. One study involved 14 rapid-
cycling BD patients treated intermittently over 21 months;
58% did not relapse, but there was no control condition
[138]. A recent unblinded, mirror-image study found that
ECT at 1–2 treatments/month for 30 months reduced days-
in-hospital by 85% in 9 BD subjects, compared to the same
time-at-risk before starting ECT [140]. Less favorable
results were reported in a study that included 22 BD
patients, in whom hospitalization-days were decreased by
only 14% overall, though by 60% regarding full hospitali-
zation, but with a 3-fold greater use of partial hospitaliza-
tion [139]. In addition, there is suggestive evidence that
weekly repeated prefrontal transcranial magnetic stimula-
tion (rTMS) may reduce risk of recurrences of BP-
depression for up to a year [141].
Psychotherapies
Psychotherapy in BD can provide support and encourage-
ment and can help to identify and monitor early signs of
mood changes, manage stress and interpersonal difficulties,
develop relapse prevention plans, stabilize sleep and daily
routines, encourage medication adherence, and reduced use
of alcohol, drugs, and stimulants including caffeine [142–
146]. Psychoeducation techniques seem to be a particularly
well-supported psychotherapeutic intervention. Psycholo-
gical treatments as a contribution to maintenance or pre-
ventive treatments for BD appear to be effective, and
cognitive-behavioral therapy (CBT), family therapy, and
psychoeducation may be particularly useful against recur-
rences of BD-depression [98, 142, 144]. CBT may be
more effective than psychoeducation alone [144], whereas
interpersonal therapy (IPT) is reported to be particularly
helpful in improving interpersonal and social-role func-
tioning [145].
Conclusions: long-term treatment
In general, lithium continues to be a standard long-term
treatment for BD, and it appears to be at least as effective
as the leading anticonvulsant mood-stabilizers [60].
Modern antipsychotic drugs are being used increasingly,
but their long-term efficacy and safety require further
study. Even effective medicinal treatments have only partial
protective effects against recurrences of BD, especially
depressions. Their value can be enhanced by providing
Pharmacological treatment of adult bipolar disorder
cost-effective psychosocial supports, psychoeducation, and
group therapies.
Emerging approaches to treatment of
bipolar disorder
Innovative treatments
Fundamentally new types of treatments for mania are rare.
One possible lead is the anti-estrogen prodrug tamoxifen,
developed to pursue the common activity of lithium and
valproate as inhibitors of cerebral protein kinase C (PKC)
[147, 148]. A more challenging need is for highly effective
treatments for BD-depression. Proposals that have received
some research attention in BD include memantine, ketamine
and better-tolerated ketamine-like agents that affect gluta-
mate neurotransmission, as well as fatty acids, anti-
inflammatory agents, probiotics and exposure to intense
light [89, 149, 150]. For long-term treatment, there is strong
current interest in expanded and long-term use of SGAs, as
reviewed above.
Staging in bipolar disorder
An emerging concept with potential implications for treat-
ment is “staging” of BD [151–153]. It arises from clinical
observations that BD patients vary markedly in illness-
severity, treatment responsiveness and resulting disability,
and proposes that the illness tends to evolve over time
through rising levels of severity [154]. An associated
hypothesis is that timely intervention may improve long-
term outcome, arising from the assumption that many cases
of BD are “progressive,” routinely shifting from antecedent
states, through mild early presentations, to severe and
complex later illness. The concept of routine progression or
worsening in BD has remained controversial over the past
century, for example, based on the hypothesis that wellness
intervals may shorten as the number of episode recurrences
rises [95]. Such a progressive course may occur in a min-
ority of BD patients, but the overall pattern appears to be
random or chaotic and difficult to predict [96]. There also is
emerging evidence that prognosis in BD can be formulated
early in the illness-course, indeed, even based on the clin-
ical nature of the first-lifetime episode [92], on the presence
of mixed features [155], or considering the course sequence
of the disorder [93].
A related proposal that delay of treatment or a higher
recurrence count may predict poor treatment response is
also questionable and requires further testing, as does the
unproved proposal that early intervention may improve the
long-term course and outcome of BD [118, 119]. A source
of potential confusion is that early intervention involves
patients with a range of future courses—both favorable and
unfavorable, whereas later treatment tends to involve
patients who have history of illness and may well be more
disabled and less treatment responsive [156]. In addition,
the “staging” hypothesis may need modification if persons
with BD can be heavily affected by surrounding environ-
mental conditions, which in return can affect their occupa-
tional and social functioning. Despite these uncertainties, it
is clear clinically that prolonged and inadequately treated
BD illness can lead to severe disability. This possibility
makes timely and accurate diagnosis and early and con-
sistently sustained treatment and support very important.
Personalized treatment
Clinical and biological factors may help identify individuals
at high risk of developing BD, and contribute to formulating
prognoses of future illness and to predicting response to
particular treatments. Such clinical factors include family
history of BD, history of suicidal behavior, antecedent
psychopathological characteristics or events in childhood or
adolescence, age-at-onset, presence of mixed features, and
initial response to treatments [151, 154, 157]. In addition,
genetic markers and neuroimaging findings may be markers
of BD [158]. Personalized or precision psychiatry hopes to
tailor more highly individualized health care programs by
considering genetic information, including pharmacoge-
netics related to the metabolic clearance or actions of
medicines being considered, as well as other biomarkers,
clinical features, and environmental circumstances [158–
161]. Genetically based measures are of current research
interest, but remain to be tested as clinically compelling and
cost-effective methods of selecting and guiding treatment.
In addition, large collections of little-explored data con-
cerning potential clinical predictors of responses to parti-
cular treatments exist in data repositories of pharmaceutical
corporations and individual clinical investigators, and may
be of great clinical value. In general, the aim of predicting
treatment responses in individual BD patients is appealing
but requires a great deal of development and testing to be
reduced to routine clinical application.
Overall conclusions
Recent decades have brought major advances in the treat-
ment of mania, BD-depression, and long-term reduction of
risk of recurrences, especially of mania, in BD patients.
Nevertheless, major problems remain. These include a
tendency toward fragmentation of clinical management of
BD patients, excessively separate approaches to specific
dimensions of their illness (mania, depression, anxiety,
substance abuse), with lack of integration of overall clinical

management, as well as major structural and financial lim-
itations of access to expert clinical care [11, 162]. Particular
components of BD needing better treatment include
depression and dysthymia, rapid-cycling, mixed features,
cognitive impairments, and general dysfunction, as well as
co-occurring conditions such as anxiety syndromes and
highly prevalent substance abuse [11, 163–165]. There
continues to be a particularly remarkable disparity between
the seriousness of BD-depression and limited research effort
given to its clinical treatment over the past half-century.
Finally, methods of design and interpretation of clinical
trials need consideration: trials in acute episodes usually are
too brief to achieve full clinical remission; long-term trials
are brief compared to average cycling times and often
involve stressful discontinuation of treatment before secure
clinical remission; meta-analytic summaries are prone to
regression-to-mean outcomes and uncertain comparability
of trials included in multiple-comparison analyses, so as
to preclude confident assessment of possible differential
efficacy.
Acknowledgements Supported by a grant from the Bruce J. Anderson
Foundation and by the McLean Private Donors Psychiatry Research
Fund (to RJB), and an award from the Aretæus Foundation of Rome
(to LT). Sources of support had no influence on the conduct or
reporting of this review.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
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