REVIEW
Complex Combination Pharmacotherapy for Bipolar
Disorder: Knowing When Less Is More or More Is Better
Joseph F. Goldberg, M.D.
Combination pharmacotherapy for bipolar disorder is com-
monplace and often reflects the severity and complexity
of the illness and the comorbid conditions frequently asso-
ciated with it. Across treatment settings, about one-fifth of
patients with bipolar disorder appear to receive four or more
psychotropic medications. Practice patterns often outpace
the evidence-based literature, insofar as few systematic
studies have examined the efficacy and safety of two or
more medications for any given phase of illness. Most ran-
domized trials of combination pharmacotherapy focus on
the utility of pairing a mood stabilizer with a second-
generation antipsychotic for prevention of either acute
mania or relapse. In real-world practice, patients with bipolar
disorder often take more elaborate combinations of mood
Combination pharmacotherapy—sometimes derisively called
polypharmacy to connote drugs that are deemed unneces-
sary or inappropriate in a regimen—has long been a cor-
nerstone of treatment for complex medical conditions
ranging from hypertension to infectious disease to oncol-
ogy. Psychiatry has lagged behind other areas of medicine
by fostering the idea that psychiatric disorders somehow
ought to be treatable with only one medication, no matter
how complex the problem may be, and that the deliberate
juxtaposition of two or more drugs likely reflects shoddy
prescribing rather than the pursuit of pharmacodynamic
synergy. In the case of bipolar disorder, in which comorbid
conditions are more common than rare (1) and symptom
targets are often heterogeneous, the idea that one medi-
cation will reliably and effectively resolve all features of a
complex clinical presentation is often unrealistic and naïve.
In part, such fanciful expectations reflect a dubious as-
sumption that a single underlying neurobiological process
accounts for the entirety and diversity of psychopathology
features shown by people with bipolar disorder. Seldom
does one all-encompassing intervention ameliorate all
signs of psychopathology as comprehensively as an anti-
biotic for pneumonia treats cough, fever, weakness, and
dyspnea or a nitrate for angina eliminates chest pain,
nausea, diaphoresis, and weakness. Accordingly, in this
article, I provide an overview of the varied symptoms of
psychopathology for which patients with bipolar disorder
are prescribed medications so that practitioners can devise
218 focus.psychiatryonline.org
stabilizers, antipsychotics, antidepressants, anxiolytics, stim-
ulants, and other psychotropics for indefinite periods that do
not necessarily arise purposefully and logically. In this article,
I identify clinical factors associated with complex combi-
nation pharmacotherapy for patients with bipolar disorder;
describe approaches to ensuring that each component of a
treatment regimen has a defined role; discuss the elimina-
tion of unnecessary, ineffective, or redundant drugs in a
regimen; and address complementary, safe, rationale-based
drug combinations that target specific domains of psycho-
pathology for which monotherapies often provide inade-
quate benefit.
Focus 2019; 17:218–231; doi: 10.1176/appi.focus.20190008
regimens that are complementary, nonredundant, pur-
poseful, and evidence based.
TARGETS OF PHARMACOTHERAPY
Rather than speak of medications in a narrow fashion as
simply treating mania or depression, it is often more useful
to identify their utility for specific targets of pharmaco-
therapy according to dimensions of psychopathology, as
illustrated in Figure 1.
Ideally, a pharmacotherapy regimen for bipolar disorder
includes as many components as necessary to successfully
address all the relevant aspects of psychopathology de-
scribed in Figure 1. Elegant combination pharmacotherapy
is economical (making use of one drug with multiple effects
when feasible), purposeful (with every component serving
a definable function), and efficient (with dosing and the
number of drugs no higher than necessary to address the
intended targets). Less elegant are assemblages of medi-
cations that accrue over time without regard to intended
effects, lack of efficacy, mechanistic redundancies, phar-
macokinetic interactions, or ongoing relevance.
PREVALENCE OF PRESCRIPTION OF COMPLEX
COMBINATION PHARMACOTHERAPY
Cross-sectional descriptive studies have suggested that
about one-fifth (2) to one-third (3) of patients with bipolar
Focus Vol. 17, No. 3, Summer 2019
 GOLDBERG

disorder are taking four or more psychotropic medications FIGURE 1. Domains of psychopathology
at the time of hospitalization. Among 4,035 mostly out-
patient entrants to the National Institute of Mental Health
(NIMH) Systematic Treatment Enhancement Program for
Bipolar Disorder (STEP-BD), 18% were taking four or more
psychotropic drugs, and 40% took three or more (4). One
European study found that nearly 80% of outpatients with
bipolar disorder took a mean of 3.8 medications, most often
a mood stabilizer (92%), followed by an antidepressant
(59%), benzodiazepines (43%), antipsychotics (39%), and
thyroid hormone (21%; 5). Another report from the United
Kingdom found that, in 2009, nearly half of patients with
bipolar disorder were prescribed two or more psychotropic
drugs on an ongoing basis; nearly half of that group
chronically took lithium plus an antipsychotic drug (6).
Separate from merely counting how many medications a
patient takes is determining whether the components of
a pharmacotherapy regimen are appropriate and comple-
mentary (as opposed to inappropriate and pharmacologi-
cally conflictual). Considerations of drug appropriateness
include the following:
intended purpose, such as topiramate or gabapentin in
• Is the intended use of a drug aligned with its known
mania or paroxetine in bipolar depression, or an illogical
pharmacodynamic effects? For example, lamotrigine
rationale, such as use of modafinil or amphetamine for
would not be considered relevant to treat acute mania;
agitation or anxiety?
chronic sleep aids may be unnecessary and counter-
productive in patients with hypersomnia. • Have clinically important drug interactions gone un-
recognized? For example, carbamazepine and primidone
• Are the known pharmacodynamic effects of a drug
are potent inducers of cytochrome P450 enzymes and
contrary to current symptoms? Antidepressants gener-
may effectively reduce serum levels and pharmacody-
ally have no value during acute mania; and psychosti-
namic efficacy of drugs that undergo Phase I oxidative
mulants are likely counterproductive when treating
metabolism.
acute psychosis.
• Do the effects of one drug contradict or conflict with
those of another? An example is simultaneous use of an DO GUIDELINES OFFER GUIDANCE?
anticholinergic drug (such as benztropine) and a pro-
Practice guidelines convey only limited insight into the
cholinergic drug (such as donepezil).
utility of complex combination therapy. Beyond specifying
• Are current medications consistent with the patient’s episode features such as with versus without psychosis or
present clinical state? Antidepressants would be illogical mixed versus pure affective polarity, they tend to say little
during acute mania, as would be the absence of one or about contexts and comorbid conditions that typically in-
more antimanic drugs. fluence treatment decisions. Examples might include ma-
• Are adverse effects of one drug causing or mimicking nia in someone with or without metabolic syndrome, in
psychiatric symptoms? Akathisia can be mistaken for someone with or without substance misuse, or in a sexually
agitation; anticholinergics impair cognitive function; and active woman of child-bearing age or a person with bipolar
sleeplessness or loss of libido can be caused by a mono- depression with versus without prominent anxiety, with
aminergic antidepressant or by depression. Adverse ef- comorbid ADHD, or with suicidal features. For a patient
fects may also exacerbate a medical problem (e.g., beta with severe, acute mania, some guidelines advocate a
blockers worsening asthma; noradrenergic drugs driving combination of two drugs (usually lithium or divalproex
hypertension). plus an antipsychotic) as a first- (7–9) or second- (10) line
intervention. Some make no specific mention of combining
• Are medications being retained if they have been deemed three or more agents in any phase of bipolar disorder so
ineffective (and have all medications in a regimen re- much as replacing an ineffective medication with an al-
ceived an adequate trial and been deemed effective or ternative (e.g., the 2018 Canadian Network for Mood and
ineffective)? Anxiety Treatments Guidelines; 8). Others identify triple
• Are medications being used and retained even when they (or greater) therapy regimens as worthy of consideration
have an abundance of negative controlled trial data for an only after the failure of multiple single- or dual-drug

Focus Vol. 17, No. 3, Summer 2019 focus.psychiatryonline.org 219

COMPLEX COMBINATION PHARMACOTHERAPY FOR BIPOLAR DISORDER
TABLE 1. Factors associated with complex combination
pharmacotherapy for patients with bipolar disorder
Characteristic Findings
Sex Female (2)
Race or ethnicity White (2)
Age (years) .50 (16)
Psychosis Present (2)
Drug dosage Typically low (16)
Depressive illness burden High (4)
Comorbid personality Borderline personality disorder (2)
disorders
Comorbid psychiatric Posttraumatic stress disorder (2)
diagnoses Anxiety disorders (2, 3)
History of 1 or more suicide Present (3, 4)
attempts
Personality features Low ratings on openness,
extraversion, and
conscientiousness (17, 18)
therapy efforts for manic or mixed episodes (e.g., 9, 10), and
these regimens usually consist of two mood stabilizers plus
a first-generation antipsychotic or a second-generation
antipsychotic (SGA).
For acute bipolar depression, current guidelines have
not suggested a role for more than two drugs in combina-
tion (generally a mood stabilizer or SGA plus an anti-
depressant). Guidelines usually list novel agents (such as
pramipexole [11], inositol [12], anti-inflammatory or anti-
oxidant drugs [13], or thyroid hormone [14]) collectively as
last-step options, but without regard to the total net num-
ber of medications in a regimen. Most also seldom offer
explicit recommendations about when and how to dis-
continue a drug once it has been introduced into a regimen,
apart from often blanket discouragement of long-term use
of antidepressants for people with bipolar disorder (despite
a lack of consensus among experts and a limited evidence
base from which to inform decisions about deprescribing
antidepressants when they are acutely effective; 15).
No systematic studies have looked at combining two (or
more) monoaminergic antidepressants that have com-
plementary mechanisms as a strategy to treat bipolar
depression, unlike for major depressive disorder. The
relatively small handful of randomized trials that have
involved the use of traditional antidepressants to treat
bipolar depression have generally not demonstrated robust
efficacy—not unlike for treatment-resistant unipolar de-
pression. However, with no studies of the use of combi-
nation antidepressants in treating bipolar depression, the
potential utility of novel or multiple antidepressant ap-
proaches remains unknown. Clinical characteristics asso-
ciated with the use of combination therapy for bipolar
disorder are summarized in Table 1 (2–4, 16–18).
Polypharmacy has been identified as one of the biggest
contributors to guideline-discordant treatment of bipolar
disorder (18), yet herein lies a major dilemma for practi-
tioners: Guideline recommendations are based on tradi-
tional efficacy trials for specific phases of an illness rather
than on effectiveness studies with real-world populations.
220 focus.psychiatryonline.org
Snippets of guideline recommendations can be judged for
concordance with prescribed medications for specific ill-
ness phases of bipolar disorder (e.g., in the STEP-BD,
guideline-concordant treatments were prescribed for
more than 80% of manic-hypomanic, mixed, or depressive
episodes per se; 19), but most patients with bipolar disor-
der outside of clinical trials require treatment for more
than simply a current affective phase of illness. Clinician
surveys that examine guideline nonadherence in treating
bipolar disorder have pointed to the failure of guidelines to
address particular features of unique clinical populations
(20). Indeed, it would be difficult to craft an effective
guideline-driven drug regimen for a bipolar II depressed
patient with prominent anxiety, attentional complaints,
substance use comorbidity, chronic suicidal ideation,
metabolic syndrome, obstructive sleep apnea, and chronic
kidney disease.
Guidelines become less useful when diagnoses and ill-
ness phases do not conform neatly to DSM-5 criteria, pa-
tient priorities drive adherence, and prominent comorbid
conditions and complex features (e.g., trauma histories)
must be addressed. In addition, the clinical trials literature
does not indicate whether and when mono- or dual phar-
macotherapies yield better outcomes than more extensive
but thoughtfully devised combination regimens is largely
unknown. The shortcomings of current practice guidelines
for bipolar disorder are summarized in Box 1.
RATIONALES FOR PHARMACOTHERAPY
COMBINATIONS
From one perspective, combining diverse medications
makes sense with a disease entity in which known drug
mechanisms of action are complementary and related to the
pathophysiology of the underlying disease process. In the
case of bipolar disorder, such exactitude is unfortunately
largely unknown and may at best be speculative. Although a
systematic review of current theories about the pathogenesis
of bipolar disorder is beyond the scope of this article, theo-
ries that have been reviewed elsewhere (e.g., Manji et al.
[21]), ranging from the level of molecular-intracellular
function to neuronal networks, include the following:
monoaminergic dysregulation; elevated intracellular cal-
cium and abnormal calcium signaling (e.g., calcium channel
blockade); circadian dysrhythmias (e.g., light entrainment of
the circadian pacemaker; sleep-wake cycle perturbations);
dysfunction of purine metabolism (hyperuricemia in mania);
endocrinopathies (e.g., glucocorticoid receptor dysfunc-
tion, hypothalamic-pituitary-adrenocortical dysregulation,
hypothalamic-pituitary-thyroid axis dysfunction); abnormal
signal transduction (e.g., overactive inositol phosphate sig-
naling, elevated intracellular inositol or cyclic adenosine
monophosphate); immuno-inflammatory mechanisms, im-
paired neuronal plasticity, regulation of oxidative stress, and
neuroprotection against neuronal loss; and disrupted con-
nectivity of neural circuits.
Focus Vol. 17, No. 3, Summer 2019

Box 1. Limitations of current practice guidelines for bipolar disorder
Largely ignore the presence of psychiatric and medical
comorbid conditions.
Do not account for patients whose bipolar spectrum symptoms
may not fulfill traditional DSM-5 diagnostic criteria.
Often lump together recommendations for patients with bipolar
I vs. bipolar II disorder, those with vs. without rapid cycling, or
those with chronic vs. nonchronic presentations.
Do not account for risk-benefit situations (e.g., metabolic risk
vs. gravity of psychiatric disability when considering
clozapine).
Table 2 summarizes presumed neuronal and molecular-
cellular mechanisms of action for psychotropic drugs
commonly used to target mania, depressive symptoms, or
both in patients with bipolar disorder (22–55). The list of
potential mechanisms is far from complete due to the
limited knowledge about bipolar disorder’s basic patho-
physiology, along with emerging novel hypotheses that do
not yet clearly translate to any specific biological inter-
ventions (e.g., mitochondrial dysfunction, shortened telo-
mere length).
In addition, as noted in the table and its footnotes, in
many instances only preliminary animal or in vitro data
exist regarding the effects of specific psychotropic drugs on
possible receptor targets; these effects may not be so
straightforward or easily translated. For example, neither
lithium nor anticonvulsant mood stabilizers exert known
direct effects on specific serotonin receptors, but they
might exert indirect modulating effects; possible in vitro
effects of monoaminergic antidepressants on ion channels
may not translate to pharmacodynamic effects in humans.
Preclinical or in vitro receptor binding studies may not
necessarily provide information about regional anatomical
differences in drug effects. Existing treatments, for better
or worse, are geared more practically toward altering ob-
servable psychopathology rather than modifying an iden-
tified neurobiological process.
Some proposed mechanisms are likely more specific to
the treatment of depression than to that of mania (e.g.,
serotonin reuptake inhibition) or vice versa (e.g., protein
kinase C inhibition or inositol depletion), and even identi-
fied neuronal or molecular mechanisms do not necessarily
provide information about pharmacodynamic class effects
(e.g., mania may respond to some drugs that inhibit protein
kinase C inhibitors [e.g. tamoxifen; 56], but not all [e.g.,
omega-3 fatty acids; 57]). Existing knowledge about drug
mechanisms of action also does not specifically address
pharmacodynamic effects relevant to particular illness sub-
components (e.g., use of a drug for narrow purposes such as
putative antisuicide effects, such as lithium [58]), procogni-
tive effects (e.g., withania somnifera [59] or lurasidone [60]),
Focus Vol. 17, No. 3, Summer 2019
GOLDBERG
Minimally consider incorporating specific medications for
narrow intended purposes (e.g., lithium to reduce suicide risk;
topiramate solely for weight loss).
Do not account for multipurpose drugs with greater value in
unique situations (e.g., divalproex for patients with bipolar
disorder who experience migraines; bupropion for patients
with bipolar II depression and obesity, cigarette smoking, and
concerns about iatrogenic sexual dysfunction).
May blur opinion-based with evidence-based recommendations.
Provide little if any guidance on when and how to deprescribe.
anticraving effects (e.g., naltrexone), or targeting of impul-
sive aggression (e.g., divalproex; 61). It is also worth noting
that nuanced differences exist within the broad mechanisms
included in Table 2 whose depth is beyond the scope of this
article. For example, some anticonvulsant drugs (divalproex,
carbamazepine) are believed to exert antiglutamatergic ef-
fects only through N-methyl-D-aspartate receptor blockade,
whereas others (lamotrigine) appear to also affect a-amino-
3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors.
Calcium channel blocking effects of mood-stabilizing an-
ticonvulsants may occur through L-type calcium channels
(carbamazepine); L- and T-type calcium channels (dival-
proex); or L-, P/Q-, R-, and T-type calcium channels
(lamotrigine). Among SGAs, individual agents vary in their
specific receptor profiles and affinities, as well as in their
unique targets (e.g., 5-HT7 antagonism or D3 partial ago-
nism are not universally shared targets across SGAs, as
noted in Table 2).
COMPLEX COMBINATION PHARMACOTHERAPY
FOR BIPOLAR DISORDER AND CLINICAL
OUTCOMES
Almost no systematic studies have provided information
about whether and when a more extensive pharmacother-
apy regimen leads to a better or worse clinical outcome than
a simpler regimen. Such questions may never be answerable
because of the inherent complexities of controlled study
designs and the matching of drug regimens to individual
patient characteristics that in themselves influence medi-
cation choice. It is obviously also an oversimplification to
count the sheer number of medications someone takes
without regard to the appropriateness, responsivity, re-
dundancies, and purposefulness of each drug on a treatment
roster, as though counting instruments in an orchestra
without distinguishing woodwinds from brass or strings or
the composition of the overall ensemble. Specific medica-
tion choices in a given regimen, and their response likeli-
hoods, are also often made not just on the basis of an overall
Food and Drug Administration indication (e.g., acute
focus.psychiatryonline.org 221
COMPLEX COMBINATION PHARMACOTHERAPY FOR BIPOLAR DISORDER

TABLE 2. Putative mechanisms of action of antimanic and antidepressant drugsa

Mechanism Lithium DVPX CBZ LTG SGAs MADs
PKC inhibition P (22) P (23) 2 (24) 2 (25) ? ?
BDNF upregulation P (26) P (23) P (27) P (28, 29) P (30) P (31)
bcl–2 upregulation P (32) P (33) P (27) P (34) ?b ?c
GSK3b inhibition P (37) P (38) — — ?d ?e
MARCKS downregulation P (23) P (23) — — — —
GABA upregulation P (41) P (42) P (43) — — ?
Glutamate downregulation P (44) P (42) P (45) P (46) ? ?f
Na1 channel blockade P (48) P (49) P (50) P (51) ? Pg
Ca11 channel blockade — P P P — —
5-HT2A antagonism — — — — Ph Ph
5-HT1A partial agonism ? — — — Pi Pi
5-HT1B antagonism, partial agonism or ?j — — — Pk ?k
inverse agonism
D2 antagonism Pl Pl P lk — P —
D3 partial agonism — — — — Pm —
5-HT7 antagonism — — — — Pn Pn
a
P, predominantly robust positive published associations; 2, predominantly or solely negative published findings; ?, inadequate or inconclusive published
findings from which to draw associations; BDNF, brain-derived neurotrophic factor; CBZ, carbamazepine; DVPX, divalproex; GABA, gamma-aminobutyric
acid; LTG, lamotrigine; MARCKS, myristoylated alanine-rich C kinase substrate; MADs, monoaminergic antidepressants; PKC, protein kinase C.
b
Limited preclinical data suggest that olanzapine and clozapine may upregulate regional b-cell lymphoma 2 (bcl–2 mRNA) and protein expression in rat frontal
cortex and hippocampus (35).
c
Limited preclinical data show increased bcl–2 mRNA production in frontal and subcortical brain regions of rats stressed and then treated with fluoxetine,
reboxetine, tranylcypromine, or electroconvulsive seizures (36).
d
Preclinical data show that olanzapine or aripiprazole, but not haloperidol, may attenuate stress-induced downregulation of hippocampal glycogen synthase
kinase-3 (GSK3b) in rats subjected to immobilization stress (39).
e
A small preclinical database suggests that some antidepressants (notably, fluoxetine) may regulate neurogenesis through GSK3b signaling (40).
f
Preclinical (in vitro) studies suggest that selective serotonin reuptake inhibitors (SSRIs) may downregulate release of glutamate from microglia (47).
g
Tricyclics block sodium channels; effects of SSRIs or other monoaminergic antidepressants are less well established (52).
h
5-HT2A antagonism associated with all atypical antipsychotics, mirtazapine, nefzodone, and trazodone.
i
5HT1A partial agonism is associated with aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, lurasidone, olanzapine, quetiapine, ziprasidone,
nefazodone, vilazodone; it is associated with full agonism with vortioxetine. Over time, SSRIs downregulate 5-HTA1 somatodendritic autoreceptors.
j
Preliminary studies have suggested the possibility that 5-HT1B receptors may be a target of lithium (53).
k
5-HT1B antagonism is associated with asenapine, ziprasidone, and aripiprazole; partial agonism is associated with vortioxetine.
l
Lithium, divalproex and carbamazepine may each indirectly downregulate D2 receptor signaling via G-protein–coupled effects (22, 54, 55)
m
D3 partial agonists include aripiprazole, brexpiprazole, and cariprazine.
n
5-HT7 antagonism associated with several second-generation antipsychotics (SGAs; asenapine, clozapine, lurasidone, olanzapine, and ziprasidone; aripi-
prazole is a weak partial agonist) and antidepressants (amitriptyline, clomipramine, imipramine, and vortioxetine).

mania) but more precisely according to other characteris-
tics associated with more specific symptom domains (e.g.,
divalproex vs. lithium in mixed episodes; lamotrigine for
maintenance therapy in patients more prone to depressive
rather than manic recurrences) (62).
Existing randomized combination pharmacotherapy
trials for bipolar disorder focus mainly on the potential
utility of two medications versus one during either acute
manic or depressive phases of illness or during mainte-
nance and relapse prevention phases. This literature is
summarized in Tables 3-5, respectively, (63–88) for treat-
ment of acute bipolar manic or mixed episodes, acute bi-
polar depression, or bipolar maintenance and relapse
prevention, respectively. For acute bipolar depression,
Table 4 focuses on combinations of mood stabilizers or
adjunctive SGAs with mood stabilizers; I did not include
studies of traditional antidepressant or novel compounds
(e.g., pramipexole, modafinil, psychostimulants) added to a
mood stabilizer because such published studies generally
do not account for variability in inherent potential anti-
depressant properties among mood stabilizers.
Some naturalistic studies have suggested that patients
with bipolar disorder who take fewer medications (e.g.,
one) manifest more symptom stability (remain relapse-
free) over time than those on two, three, or more medi-
cations (5, 89); still others have suggested that when
medication regimens include certain core pharmacother-
apies such as lithium, there may be less need to add ad-
ditional medications (90). Open (nonrandomized) data
suggest that inpatients with mania who begin pharmaco-
therapy with a combination of lithium and divalproex at the
outset may incur a lesser dosage burden of antipsychotic
cotherapy than those who begin on lithium without dival-
proex (91). The NIMH Lithium Treatment Moderate Dose
Use Study (LiTMUS) trial found that cotherapy with sub-
therapeutic doses of lithium has not shown greater symp-
tomatic benefit than placebo (although a post hoc analysis
suggested that low-dose adjunctive lithium may be associated
with lower dosages of concomitant SGAs; 92). By contrast, use
of other medications (notably, chronic benzodiazepine use) in
a regimen for treatment of bipolar disorder may be associated
with higher recurrence rates and more severe overall illness

222 focus.psychiatryonline.org Focus Vol. 17, No. 3, Summer 2019


TABLE 3. Randomized trials of mono- vs. dual pharmacotherapies in acute bipolar manic or mixed episodes
Trial result and intervention
Positive trials
Allupurinol (N5218) or placebo
(N5215) plus mood stabilizers
(meta-analysis of five randomized
trials; 63)
Aripiprazole (N5253) or placebo
(N5131) plus lithium or divalproex
(64)
Asenapine (N5158) or placebo
(N5166) plus lithium or divalproex
(65)
Celecoxib (N523) or placebo
(N523) plus divalproex (66)
Olanzapine (N551) or placebo
(N548) plus lithium or divalproex
(67)
Olanzapine (N5100) or placebo
(N5101) plus lithium or divalproex
(68)
Risperidone (N552), haloperidol
(N553), or placebo (N551) plus
lithium or divalproex (69)
Quetiapine (N591) or placebo
(N5100) plus lithium or divalproex
(70)
Lithium (N5173) or placebo (N5182)
plus quetiapine XR (71)
Tamoxifen (N520) or placebo
(N520) plus lithium (72)
Negative trials
Olanzapine (N558) or placebo
(N560) plus carbamazepine
(73)
Focus Vol. 17, No. 3, Summer 2019
GOLDBERG
Duration Outcome Adverse effects
4–8 weeks Adjunctive allopurinol (dosed at 300– No significant differences from placebo
600 mg/day) was more effective
than placebo in reducing baseline
mania symptoms; greater effect in
pure than in mixed mania
6 weeks Adjunctive aripiprazole (mean More extrapyramidal symptoms with
dose519 mg/day) was more effective aripiprazole than with placebo, but no
than placebo; significantly greater significant differences in weight
reduction in mood elevation, changes or metabolic laboratory
hypersexuality, irritability, speech, parameters
aggression, insight); no significantly
greater reduction in depression
severity scores
12 weeks Adjunctive asenapine (mean More sedation and somnolence,
(primary dose511.8 mg/day) was more treatment-emergent depression,
efficacy at effective than placebo in reducing hypoesthesia, and weight gain with
week 3) mania symptoms; no between- asenapine than with placebo
groups differences in response or
remission rates or changes from
baseline in depression symptom
severity
6 weeks Adjunctive celecoxib (400 mg/day) No significant differences from placebo
was more effective than placebo in
reducing severity of mania symptoms
6 weeks Adjunctive olanzapine (mean modal Greater weight gain with combination
dose58.6 mg/day) was more than with monotherapy
effective than placebo in reducing
both manic and depressive symptoms
6 weeks Adjunctive olanzapine was more More weight gain and higher fasting
effective than placebo in reducing blood sugar with olanzapine than
both mania and depressive symptoms with placebo
3 weeks Adjunctive risperidone (mean Greater weight gain with adjunctive
dose53.8 mg/day) or haloperidol risperidone than placebo
(mean dose 6.2 mg/day) was more
effective than placebo in reduction in
mania symptom severity
3 weeks Adjunctive quetiapine (mean Greater somnolence and dry mouth
dose5504 mg/day) was more with adjunctive quetiapine than with
effective than placebo in reduction in placebo
mania symptom severity reduction
(greatest improvements in irritability,
aggression, sleep, and motor activity)
6 weeks Adjunctive lithium (mean modal More tremor, somnolence, dizziness,
dose51,085.5 mg/day, mean serum diarrhea, and vomiting with lithium
[Li1]50.72 mEq/L) was more effective than with placebo
than placebo in reduction in mania
symptom severity, psychosis,
agitation, aggression; no between-
group differences in reduction in
depressive symptom severity (mean
quetiapine dose5623.1 mg/day)
6 weeks Adjunctive tamoxifen (fixed dose 80 More fatigue with tamoxifen than with
mg twice daily) was more effective placebo
than placebo
6 weeks No significant between-groups Greater weight gain and higher
differences in mania symptom triglyceride levels with olanzapine
severity or response rates with than with placebo; carbamazepine is
adjunctive olanzapine plus known to reduce serum olanzapine
carbamazepine (mean levels by approximately 40%–50%
dose5617.5 mg/day) vs.
carbamazepine monotherapy (mean
dose5717.3 mg/day)
continued
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COMPLEX COMBINATION PHARMACOTHERAPY FOR BIPOLAR DISORDER

TABLE 3, continued
Trial result and intervention
Paliperidone ER (N5150) or placebo
(N5150) plus lithium or divalproex
(74)
Topiramate (N5143) or placebo
(N5144) plus divalproex or lithium
(75)
Ziprasidone (N5439) or placebo
(N5217) plus lithium or divalproex
(76)
Duration Outcome
6 weeks Adjunctive paliperidone (mean
dose58.1 mg/day) no different from
placebo
8 weeks Adjunctive topiramate (mean dose
254.7 mg/day) no different from
placebo
3 weeks Adjunctive ziprasidone (mean modal
dose560.1 mg/day in low-dose arm,
133.8 mg/day in high dose arm) no
different from placebo in changes
from baseline mania or levels of
depression symptom severity
Adverse effects
Greater somnolence, akathisia, weight
gain, and increased appetite with
paliperidone ER than with placebo
Paresthesias, diarrhea, and anorexia
more common with topiramate than
with placebo
More sedation and somnolence with
ziprasidone than with placebo

(93)—not necessarily in a causal fashion, but more likely be-
cause of the stigmata of pathology.
The literature on extensive polypharmacotherapy of
psychotropic drugs is largely more naturalistic and ob-
servational than randomized, which makes it hard to draw
causal inferences about treatment outcomes. In such
studies, medications are usually chosen on the basis of
patients’ individual conditions, leading to the problem of
confounding by indication. For example, some observa-
tional studies have attributed lower suicide attempts or
completions to the inclusion of lithium in a treatment
regimen over other mood stabilizers (94), but these studies
have not accounted for the possibility that clinicians might
avoid prescribing lithium to patients at a higher risk of
suicide (e.g., in the aftermath of an overdose or other at-
tempt), relegating prescription of lithium to a potential
marker or artifact of a better prognosis at baseline. Simi-
larly, some observational studies of rapid cycling have
concluded that prescription of antidepressants may lead to
more frequent episodes (95), without considering the re-
verse possibility that frequent depressive episodes may
cause more prescription of antidepressants. In any non-
randomized pharmacotherapy study (but especially in
those involving multidrug regimens), possible confound-
ing by indication poses obstacles to inferring causal drug
effects as a result of unrecognized and unaccounted-for
moderators and mediators of outcome (62).
A further dilemma when trying to assess extensive
combination pharmacotherapy regimens involves uncer-
tainties about within-class differences versus generaliz-
abilities among medications. For example, the relative
magnitude of antimanic efficacy across individual SGAs
appears comparable (96), although individual agents may
vary in their antidepressant, anxiolytic, or tolerability pro-
files. Similarly, monoaminergic antidepressants are often
lumped together as homogeneous entities, although the ab-
sence of placebo-controlled studies for most newer agents
(vortioxetine, vilazodone, desvenlafaxine, levomilnacipran,
mirtazapine) makes it difficult to generalize about within-
class efficacy or the potential for synergy from particular
antidepressant combinations.
WHAT ABOUT ANTIDEPRESSANT ADJUNCTS TO
MOOD STABILIZERS FOR BIPOLAR DISORDER?
Practice guidelines (7, 8, 10) and expert consensus state-
ments (15) emphasize the importance of avoiding antide-
pressant monotherapies in bipolar I depression (with
possibly greater leniency in bipolar II depression). Such
recommendations mainly reflect concerns about the poten-
tial for antidepressants to destabilize mood via a treatment-
emergent affective switch (TEAS). Consequently, guidelines
have advised using antidepressants only in tandem with
mood stabilizers in bipolar depression, mainly on the basis
of assumptions that mood stabilizers help safeguard against
TEAS outcomes rather than the perception that most mood
stabilizers exert meaningful intrinsic antidepressant effects
that synergize with antidepressant cotherapies. One often
cited example, the NIMH STEP-BD study, found only a
modest antidepressant response rate with mood stabilizer
monotherapy (about 24%) and no added benefit with anti-
depressant cotherapy (97). Said differently, the current ev-
idence base has suggested that neither mood stabilizers nor
monoaminergic antidepressants, nor their combination,
exert reliable and robust antidepressant effects on bipolar
depression. Yet, contemporary observational studies have
found that about one-third of patients with bipolar disorder
take antidepressants on a long-term basis (.90 days) as part
of their overall pharmacotherapy regimen (98). Such pre-
scribing habits notwithstanding, the Florida Medicaid
Guidelines (9) noted that “there is inadequate information
(including negative trials) to recommend adjunctive anti-
depressants . . . for bipolar depression.”
It is also worth noting that clinicians in real-world
practice settings may sometimes use selective serotonin
reuptake inhibitors (SSRIs) or other antidepressants for
their putative anxiolytic properties (in addition to, or pos-
sible entirely apart from, depression as an intended treat-
ment target). However, apart from one secondary analysis
from a negative randomized controlled trial of paroxetine
for bipolar depression (99), no prospective randomized
trials have demonstrated anxiolytic efficacy for mono-
aminergic antidepressants in bipolar disorder. Although

224 focus.psychiatryonline.org Focus Vol. 17, No. 3, Summer 2019

 GOLDBERG

TABLE 4. Randomized Trials of mono- versus dual pharmacotherapies for acute bipolar depression
Intervention
Lamotrigine (N564) or placebo
(N560) plus lithium (77)
Lamotrigine (N5101) or placebo
(N5101) plus quetiapine (78)
Lurasidone (N5183) or placebo
(N5165) plus lithium or divalproex
(79)
Ziprasidone (N5147) or placebo
(N5147) plus lithium or divalproex or
lamotrigine (80)
Duration Outcome Adverse effects
8 weeks Adjunctive lamotrigine (200 mg/day) None greater with adjunctive
was more effective than placebo lamotrigine than with lithium
monotherapy
12 weeks Adjunctive lamotrigine (200 mg/day) None greater with adjunctive
. placebo lamotrigine than with placebo
6 weeks Adjunctive lurasidone (mean dose Greater nausea, somnolence, tremor,
66.3 mg/day) was more effective than akathisia, and insomnia with
placebo adjunctive lurasidone than with
placebo
6 weeks Adjunctive ziprasidone (mean More nausea, fatigue, dizziness,
dose589.8 mg/day) no different from sedation, somnolence with adjunctive
placebo ziprasidone than with placebo

this absence of evidence is not evidence of absence and
does not negate the possibility of benefit, prescribers must
recognize that such assumptions have not been empirically
tested.
ANTIPSYCHOTIC COMBINATION
PHARMACOTHERAPY
The sustained use of two or more antipsychotic drugs,
although more often seen with patients with schizophre-
nia or schizoaffective disorder, has been observed in 15%2
20% of patients with bipolar disorder, often at prescribed
daily doses higher than those seen during monotherapy
(100). On entry into the STEP-BD, about 10% of patients
with bipolar disorder had been taking two or more anti-
psychotics (101). Psychosocial functioning and symptom
status were no different from those who were taking only
one antipsychotic, but side effect burden and service uti-
lization were both significantly more extensive. Practice
guidelines, such as the Texas Implementation of Medica-
tion Algorithms or the Florida Medicaid Guidelines, ex-
plicitly advise against the use of two (or more) SGAs,
mirroring the generally minimal, if any, benefit seen with
the use of antipsychotic combination pharmacotherapy
with people with schizophrenia.
TRIPLE THERAPY
Very few randomized trials have examined the use of three
(or more) psychotropic medications in any phase of bipolar
disorder. The existing literature is limited by methodo-
logical limitations such as small sample sizes, high drop-
out, and poor tolerability. For example, among rapid
cyclers whose symptoms had not stabilized after 16 weeks
of lithium plus divalproex, Kemp et al. (102) found no
advantage of the addition of lamotrigine over placebo but
suggested that the failure to demonstrate an advantage
may have been a Type II error because of the small number
of randomized participants. Other short-term open trials
with small sample sizes (i.e., N,10) or case series have
shown improvement among outpatients with bipolar dis-
order whose inadequate responses to dual-agent mood
stabilizers (lithium plus divalproex) improved with the
addition of a third (e.g., carbamazepine), but the lack of
larger trials or randomized study designs limits the ability
to distinguish multidrug interventions from possible out-
comes with alternative strategies, including longer trial
durations on existing regimens.
DEPRESCRIBING AND MAINTENANCE OF
PHARMACOLOGICAL HYGIENE
Surprisingly few randomized pharmacotherapy discontin-
uation trials exist in research on bipolar disorder. Although
such studies provide the most rigorous data about the
optimal treatment duration for any medication, that
information is especially important during combination
therapies, in which unnecessarily prolonged inclusion of a
drug jeopardizes overall treatment adherence and imposes
an additive side effect burden, cost, and risk for drug-drug
interactions. To the extent that randomized clinical trials
nowadays fall mainly under the auspices of pharmaceutical
industry sponsorship, there is little economic incentive for
commercial manufacturers to drive the deprescribing of
their products.
Give the scarcity of empirical information about when
a particular cotherapy may no longer be beneficial or
necessary, the components of a pharmacology regimen
can potentially accrue in a manner sometimes akin to
hoarding. Because pharmacotherapy per se is for most
patients with bipolar disorder an indefinite, open-ended
undertaking, it can be difficult to fathom specified end
points for stopping certain medications within a regimen.
One conspicuous exception is the frequent admonition
against long-term antidepressant use espoused in some
practice guidelines, based on theoretical concerns about
accelerated cycling frequency. In fact, however, random-
ized discontinuation trial data would suggest that, con-
trary to popular belief, cessation of an antidepressant after
an initial robust response may incur a greater risk for
depression relapse (103, 104), except in patients with past-
year rapid cycling, for whom long-term antidepressant
use has been associated with more depressive episodes
(104).

Focus Vol. 17, No. 3, Summer 2019 focus.psychiatryonline.org 225

COMPLEX COMBINATION PHARMACOTHERAPY FOR BIPOLAR DISORDER

TABLE 5. Randomized trials of mono- versus dual pharmacotherapies for bipolar maintenance and relapse prevention
Trial result and intervention
Positive trials
Aripiprazole (N5168) or placebo
(N5169) plus lithium or divalproex
(81)
Lithium plus divalproex combination 24 months
vs. either monotherapy
(BALANCE; 82)
Lithium or divalproex plus
aripiprazole of placebo (83)
Olanzapine (N551) or placebo
(N548) plus lithium or divalproex
(84)
Risperidone long-acting injectable
(N565) or placebo (N559) plus
treatment as usual (85)
Ziprasidone (N5127) or placebo
(N5113) plus lithium or divalproex
(86)
Negative trials
Lurasidone (N5246) or placebo 28 weeks
(N5250) plus lithium or divalproex
(87)
Oxcarbazepine (N526) or placebo
(N529) plus lithium (88)
Duration Outcome Adverse effects
12-week acute Lower 52-week relapse rate (any Comparable weight changes or
stabilization mood episode) with aripiprazole metabolic parameters with
followed by (mean dose 15.8–16.9 mg/day; 17%) aripiprazole or placebo
52-week than with placebo (29%); aripiprazole
maintenance was more effective than placebo for
mania but not depressive relapse
Lithium plus divalproex (N5110) was No significant differences in serious
more effective than divalproex adverse events among the treatment
monotherapy (N5110) but not arms
lithium monotherapy (N5110);
lithium was more effective than
divalproex for depressive relapses
12-week acute Adjunctive aripiprazole (mean More tremor with aripiprazole than
stabilization dose516.1 mg/day if index episode with placebo
followed by manic, 16.8 mg/day if mixed) was
52-week more effective than placebo for
maintenance prevention of manic but not mixed
episodes
18 months Adjunctive olanzapine (mean More weight gain and less insomnia
dose58.6 mg/day) was more with adjunctive olanzapine than with
effective than placebo for placebo
symptomatic but not syndromal
relapse for mania or depression (but
no significant differences for time to
mania relapse or time to depressive
relapse)
16-week open Adjunctive risperidone long-acting Tremor, insomnia, muscle rigidity, and
stabilization, injectable (modal dose 25 mg/day) mania more likely with risperidone
then 52 weeks was more effective than placebo for long-acting injectable than with
time to any mood episode placebo
8-week open Adjunctive ziprasidone (mean modal Incidence of tremor greater with
stabilization, doses of 80, 119, and 160 mg/day ziprasidone than placebo
then 16 weeks across three strata) was more
effective than placebo in time to any
mood episode and, separately, time
until a manic or until a depressive
relapse
No advantage for adjunctive lurasidone No clinically meaningful differences
over placebo in time until with lurasidone versus placebo
recurrence of a depressive, manic,
or mixed episode; if index episode
polarity was depressed, lurasidone
was more effective than placebo for
time until recurrence of any mood
episode
52 weeks No advantage for adjunctive Drowsiness, diarrhea, and tremor more
oxcarbazepine (mean modal dose common with oxcarbazepine than
1,200 mg/day) over placebo in time placebo
until recurrence of any mood
episode

Rapid cycling may represent a particular instance in
which monotherapy may rarely produce improvement. A
notable example is a randomized trial specifically with
patients with rapid-cycling bipolar disorder (105) in which
open-label dual therapy with lithium plus divalproex
was then converted to monotherapy with either agent.
Only one-quarter of 254 rapid-cycling patients initially
stabilized during combination therapy with lithium plus
divalproex (meaning that most rapid-cycling patients ei-
ther poorly tolerated or did not benefit from this combi-
nation); after subsequent randomization to either agent as
monotherapy, only about half of patients remained relapse
free over a 20-month period. Unfortunately, this study did
not examine whether the continued combination of lith-
ium plus divalproex might have prolonged the time until
relapse more than occurred with either pharmacotherapy.

226 focus.psychiatryonline.org Focus Vol. 17, No. 3, Summer 2019


It also did not examine whether the total number of re-
lapses per year among rapid-cycling patients was less after
randomization to either monotherapy than before.
In the case of adjunctive SGAs, Yatham and colleagues
(106) studied patients with manic or mixed bipolar episodes
who were stabilized on lithium or divalproex plus an SGA
(olanzapine or risperidone) and then compared time until
relapse among those randomized to continued combination
therapy versus mood stabilizer monotherapy for one year.
Relapse rates were significantly lower for those in the
combination condition than in the monotherapy condition
(hazard ratio50.53, 95% confidence interval50.33–0.86) up
to 24 weeks, but beyond that time frame the combination
provided no continued advantage in preventing relapse over
monotherapy. However, weight gain was significantly
greater with a continued adjunctive SGA beyond this time
(mean 3.2 kg gain vs. #0.1 kg gain, respectively).
A basic principle of psychopharmacological hygiene in-
volves discontinuing a psychotropic drug that exerts no
benefit after an adequate trial has elapsed. More ambiguous
can be knowing whether and when to stop ancillary phar-
macotherapies for bipolar disorder, such as benzodiazepines
or sleep aids, nonbenzodiazepine anxiolytics (buspirone,
hydroxyzine, anxiolytic anticonvulsants), psychostimulants
(particularly if used off label to counteract sedation, obesity,
or slowed attentional processing), beta blockers for social
anxiety or tremor, thyroid hormone in the absence of in-
trinsic thyroid disease (or safety concerns related to cardiac
arrhythmias or osteoporosis), and vitamins or nutritional
supplements.
Other tenets of basic pharmacological hygiene include
avoiding mechanistic redundancies, contradictory mecha-
nisms, and irrational strategies to avoid future events (e.g.,
maintaining antidepressants during an acute manic episode
on the basis of the notion that doing so may ward off a
subsequent depression); optimizing dosing of a first drug
before adding additional agents aimed at the same intended
symptom target; not maintaining sleep aids when hyper-
somnia is present; minimizing the number of new or ad-
ditive drug exposures during pregnancy, to the extent
feasible; and knowing why a prescribed drug was originally
introduced to a regimen and addressing its utility and on-
going relevance for a given patient.
As a practical matter, it can be helpful (as well as rapport
building) for patients and clinicians to conduct periodic
“performance evaluations” of a pharmacotherapy regimen
and review and mutually decide what value and cost each
drug brings to the patient’s treatment. Medications whose
relevance is uncertain can then be further assessed one by
one (thus changing only one variable at a time), either by
tracking intended target symptoms more closely and for-
mally or by dosage reduction or cautious elimination to de-
termine whether a unique benefit indeed exists.
Another useful practical rule of thumb involves the
concept of making no changes to a drug regimen for at least
four to six months once unequivocal wellness has been
Focus Vol. 17, No. 3, Summer 2019
GOLDBERG
established. This approach may also sometimes include
prolonging or suspending a cross-taper in progress. Al-
though “stalled” cross-tapers can leave patients on poten-
tially unnecessary or duplicative medications, and as such
are less than elegant, greater gains are sometimes accom-
plished by changing nothing once wellness is achieved and
letting patients accrue lengthier periods of euthymia before
embarking on efforts to prune a drug regimen.
The four- to six-month time frame corresponds to the
conventional time period that defines recovery, as noted
by nomenclature task forces of both the American College
of Neuropsychopharmacology (107) and the MacArthur
Foundation (108). Symptoms that arise within this time
frame after remission from an acute episode are generally
recognized as signs of relapse (i.e., the index episode itself
reignites), and symptoms that emerge beyond four to six
months of wellness are considered signs of a recurrence
(i.e., a new episode). Statistically, survivorship of four to six
months of wellness after an index episode categorically
places someone at a lesser risk for clinical deterioration and
consequently represents a logical and potentially safer time
to ask whether a particular component of a regimen is or is
not actually necessary to sustain wellness.
FUTURE DIRECTIONS
Several important unmet needs exist for which further
studies and guidelines can advance knowledge and clinical
practice about complex combination pharmacotherapy for
patients with bipolar disorder. These needs include exam-
ining sequential pharmacotherapies and specific augmentation-
versus-replacement strategies among patients whose
responses to core mood stabilizer monotherapies are in-
adequate; undertaking randomized discontinuation trials
to determine whether and when a particular medication
has a finite optimal duration of benefit (and at what point
diminishing returns might be expected); and conducting
formal studies designed specifically to treat common con-
ditions that are comorbid with bipolar disorder, including
anxiety disorders; alcohol and substance use disorders;
and adult ADD, ADHD, and cognitive dysfunction. Such
comorbid conditions contribute to combination pharma-
cotherapy, but the dearth of dedicated studies targeting
such presentations severely limits the evidence base for
differential therapeutics.
Other needs are identification of factors and clinical
circumstances in which augmentation strategies versus
switching from one drug to another produces better out-
comes and testing hierarchical treatment approaches as
a means to ultimately simplify pharmacotherapy regimens
in complex or comorbid presentations. For example, in
the case of bipolar disorder with comorbid obsessive-
compulsive disorder, some authors have argued that opti-
mization of mood stabilizers can adequately treat both
conditions, obviating the necessity of SSRI cotherapy (109);
in the case of mood disorder with concurrent alcohol use
focus.psychiatryonline.org 227
COMPLEX COMBINATION PHARMACOTHERAPY FOR BIPOLAR DISORDER
disorder, further studies are needed to determine whether
and when pharmacotherapy of mood symptoms alone may
simultaneously reduce excessive drinking (110).
CONCLUSIONS
Complex pharmacotherapy regimens can be elegant amal-
gams of complementary and synergistic elements in which
the pharmacodynamic whole becomes greater than the
sum of its parts, or they can represent more haphazard
collections of medications united by more arbitrariness
than purposeful intent. Good clinical practice involves
following a logical rationale and combining appropriate,
nonredundant drugs that serve identifiable functions and
avoid pharmacokinetic or pharmacodynamic hazards. With
diligent outcome tracking and a systematic approach to
medication changes, logical and strategic medication com-
binations can be devised to target key symptom domains
and minimize unnecessary exposure to redundant, in-
effective, or otherwise superfluous psychotropic agents.
AUTHOR AND ARTICLE INFORMATION
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New
York City. Send correspondence to Dr. Goldberg (joseph.goldberg@
mssm.edu).
Dr. Goldberg is a consultant with Neurocrine, Lundbeck, Otsuka,
Sunovion, and WebMD. He is with the speakers bureaus of Allergan,
Neurocrine, Otsuka, Sunovion, and Takeda-Lundbeck and receives
royalties from American Psychiatric Association Publishing.
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