Bipolar disorder in adults: Choosing maintenance treatment

Official reprint from UpToDate® www.uptodate.com

©2017 UpToDate®

Bipolar disorder in adults: Choosing maintenance treatment

Author: Robert M Post, MD
Section Editor: Paul Keck, MD
Deputy Editor: David Solomon, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Oct 03, 2017.

INTRODUCTION — Following remission of a bipolar mood episode, patients generally require maintenance
treatment to delay or prevent another episode. Standard maintenance treatment consists of pharmacotherapy
plus adjunctive psychotherapy. However, if psychotherapy is not available or is declined, pharmacotherapy
alone is reasonable.

Selecting maintenance treatment for bipolar disorder is reviewed here. The use of adjunctive psychotherapy
for maintenance treatment of bipolar disorder; management of poor adherence to maintenance
pharmacotherapy; pharmacotherapy for acute bipolar mood episodes; teratogenic risks and neonatal issues
involved in pharmacotherapy; and the epidemiology, clinical manifestations, and diagnosis of bipolar disorder
are discussed separately:

● (See "Bipolar disorder in adults: Psychoeducation and other adjunctive maintenance psychotherapies".)
● (See "Bipolar disorder in adults: Managing poor adherence to maintenance pharmacotherapy".)
● (See "Bipolar disorder in adults: Pharmacotherapy for acute mania and hypomania".)
● (See "Bipolar disorder in adults: Pharmacotherapy for acute depression".)
● (See "Teratogenicity, pregnancy complications, and postnatal risks of antipsychotics, benzodiazepines,
lithium, and electroconvulsive therapy".)
● (See "Bipolar disorder in adults: Epidemiology and pathogenesis".)
● (See "Bipolar disorder in adults: Clinical features".)
● (See "Bipolar disorder in adults: Assessment and diagnosis".)

DEFINITION OF BIPOLAR DISORDER — Bipolar disorder is a mood disorder that is characterized by

episodes of mania (table 1), hypomania (table 2), and major depression (table 3) [1]. The subtypes of bipolar
disorder include bipolar I and bipolar II. Patients with bipolar I disorder experience manic episodes, and nearly
always experience hypomanic and major depressive episodes. Bipolar II disorder is marked by at least one
hypomanic episode, at least one major depressive episode, and the absence of manic episodes. Additional
information about the clinical features and diagnosis of bipolar disorder is discussed separately. (See "Bipolar
disorder in adults: Clinical features" and "Bipolar disorder in adults: Assessment and diagnosis", section on
'Diagnosis'.)

Recurrent mood episodes — Bipolar disorder is characterized by recurrent mood episodes that can be life-
threatening. As an example, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD)
prospectively followed 858 patients who recovered from a mood episode, and found that within two years a
recurrent episode occurred in nearly 50 percent, despite receiving treatment at specialty mood disorder clinics
[2]. In addition, a meta-analysis of three studies lasting four years prospectively followed patients (n = 198)
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Bipolar disorder in adults: Choosing maintenance treatment
who recovered from an episode of mania and found that a recurrent mood episode occurred in 60 percent [3].
For each patient, manic and depressive episodes may recur in roughly equal proportions, or there may be a
predominant polarity [4].

Recurrence of bipolar mood episodes is associated with a greater number of suicide attempts [5-9], as well as
poorer social and occupational functioning [10] and cognitive impairment [11]. In addition, treatment
resistance for each episode appears to increase with each additional recurrence [12,13].

INDICATIONS — We suggest maintenance pharmacotherapy for every patient with bipolar disorder, and
observational studies support starting maintenance pharmacotherapy early in the course of illness [14].
Adjunctive psychotherapy during maintenance treatment is also indicated for all bipolar patients to prevent
relapses and enhance adherence. The goals for maintenance therapy are to reduce residual symptoms, delay
and prevent recurrence of new mood episodes, reduce the risk of suicide, and improve psychosocial
functioning. Maintenance pharmacotherapy for bipolar disorder is consistent with multiple practice guidelines
[15-18].

Although most maintenance pharmacotherapy studies have primarily or exclusively enrolled patients with
bipolar I disorder, we suggest maintenance treatment for bipolar II disorder as well. Patients with bipolar II
disorder are symptomatically ill more than 50 percent of their lives following onset of the illness and are at high
risk for suicide [19].

We also suggest maintenance pharmacotherapy for other specified bipolar disorder, based upon our clinical
experience. Although there are no controlled trials or observational studies to guide management [15,16], the
disorder is nevertheless a clinically significant syndrome that requires acute and maintenance treatment
[20,21].

Suicide attempts may be minimized by maintenance therapy. An observational study of 406 patients followed
for up to 22 years found that bipolar patients who received maintenance treatment had lower rates of suicide
deaths compared with those not treated (standardized mortality ratio 6 versus 27) [22].

In addition to preventing relapse in patients with bipolar disorder, maintenance pharmacotherapy may be
associated with reduced rates of violent behavior. A national registry study identified 494 convictions for
violent crime (eg, assault, robbery, or threats/intimidation) in 11,918 patients with bipolar disorder and
examined the time periods when patients were or were not prescribed mood stabilizers (eg, lithium, valproate,
lamotrigine, or carbamazepine) or antipsychotics [23]. The rate of violent behavior when mood stabilizers were
prescribed was 60 percent less, compared with times when mood stabilizers were not prescribed (hazard ratio
0.4, 95% CI 0.3-0.7). In addition, prescription of antipsychotics was associated with a 50 percent decrease in
interpersonal violence (hazard ratio 0.5, 95% CI 0.3-0.9). Additional information about violent behavior in
bipolar disorder is discussed separately. (See "Bipolar disorder in adults: Clinical features", section on
'Perpetration'.)

SELECTING A TREATMENT REGIMEN — Pharmacotherapy is essential for maintenance treatment of

bipolar disorder. The same medication regimen that was successfully used acutely is typically selected for
maintenance treatment. However, some medications are preferable for maintenance treatment due to their
demonstrated efficacy and tolerability. (See 'Choosing pharmacotherapy' below.)

In addition, we suggest combining pharmacotherapy with psychotherapy for maintenance treatment of bipolar
disorder. Multiple randomized trials indicate that adjunctive group psychoeducation reduces the rate of
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Bipolar disorder in adults: Choosing maintenance treatment
recurrent mood episodes and enhances medication adherence. Add-on cognitive-behavioral therapy and
family therapy can also improve adherence. (See 'Choosing adjunctive psychotherapy' below.)

However, it is reasonable to prescribe pharmacotherapy alone for maintenance treatment of bipolar disorder.
Psychotherapy may not be available and some patients decline it.

CHOOSING PHARMACOTHERAPY

First-line — Maintenance pharmacotherapy usually consists of the same regimen that successfully treated
the acute bipolar mood episode [15,17,24]. Studies that support this approach include the following:

● In a randomized trial of 148 acutely manic patients who initially remitted with open-label divalproex
(valproate) and were then assigned to maintenance treatment with divalproex, lithium (an efficacious
maintenance treatment), or placebo, time to recurrence was significantly longer with divalproex compared
with lithium or placebo [25]

● In a randomized trial in which 1172 patients with a manic or depressive episode were initially stabilized
with open-label quetiapine and then assigned to maintenance quetiapine, lithium, or placebo, time to
recurrence was significantly longer with quetiapine compared to lithium or placebo [26]

Nevertheless, medications can be distinguished as first, second, and third-line maintenance treatments,
based upon the quality and quantity of data that demonstrate the efficacy of each drug in preventing recurrent
bipolar mood episodes. Medications also vary in the type, frequency, and severity of adverse effects, which
influences clinician and patient preferences. As an example, a meta-analysis of six observational studies (n =
637 patients) found that the metabolic syndrome was present in more patients taking antipsychotics,
compared with patients not treated with antipsychotics (45 versus 32 percent) [27].

Clinicians should initially attempt to manage patients with monotherapy to enhance compliance and minimize
side effects and costs [4]. However, many patients require medication combinations for acute and
maintenance treatment [13]. (See 'Patients who relapse often' below and "Bipolar disorder in adults:
Pharmacotherapy for acute mania and hypomania", section on 'Severe manic episodes'.)

Second-line — For patients who do not tolerate first-line maintenance pharmacotherapy (ie, the regimen that
resolved the acute bipolar mood episode), the following medications are considered second-line monotherapy
because each has consistently demonstrated its efficacy in multiple randomized trials; the drugs are
presented in our general order of preference based upon the number of trials conducted, risk of side effects,
and cost:

● Lithium
● Valproate (divalproex)
● Quetiapine
● Lamotrigine

Use of lithium, valproate, quetiapine, or lamotrigine as maintenance treatment is consistent with multiple
practice guidelines [15-18,28].

Although we generally use valproate as a second line medication for maintenance treatment of bipolar
disorder, we regard valproate as a third line drug for female patients of childbearing potential. Many
pregnancies are unplanned, and the drug is teratogenic and associated with cognitive impairment in the
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Bipolar disorder in adults: Choosing maintenance treatment

offspring [29,30]. In addition, female patients with bipolar disorder who are treated with valproate are at
increased risk of polycystic ovary syndrome [31].

Lithium — Lithium has been more widely studied than any other maintenance treatment for bipolar
disorder. Using lithium reduces the risk of relapse by approximately 30 percent. Evidence for the efficacy of
lithium includes the following:

● A meta-analysis of five randomized trials (753 patients) that evaluated lithium for one to two years found
relapses occurred in fewer patients who received lithium compared with placebo (risk ratio 0.7, 95% CI
0.5-0.9) [32]. Lithium appeared especially effective in preventing manic recurrences. However,
discontinuation of treatment due to adverse events was three times greater with lithium than placebo (risk
ratio 3, 95% CI 1-8).

● A subsequent two-year randomized trial (n = 768) found that time to recurrence of mania or depression
were each significantly longer in patients treated with lithium than placebo [26]

The administration and side effects of lithium are discussed separately. (See "Bipolar disorder in adults and
lithium: Pharmacology, administration, and side effects".)

Reduced risk of suicide — High quality studies that included patients with unipolar depressive
disorders and patients with bipolar disorder have found that maintenance treatment with lithium reduces the
risk of suicide. (See "Suicidal ideation and behavior in adults", section on 'Pharmacotherapy'.)

In addition, a meta-analysis of 31 observational studies and randomized trials compared maintenance

treatment with lithium to treatment without lithium in patients with unipolar major depression, bipolar disorder,
or schizoaffective disorder (n >33,000) [33]. In the subgroup of bipolar patients (14 studies), suicide attempts
and completed suicides occurred less often in patients who received lithium than patients who did not
(relative risk 0.2, 95% CI 0.1-0.3). This was consistent with the finding in the total sample that suicide
attempts and deaths occurred in fewer patients who received maintenance lithium.

A subsequent study of self-harm used electronic health records from a nationally representative sample to
identify patients with bipolar disorder (n >6000) who received maintenance monotherapy with lithium,
valproate, olanzapine, or quetiapine [34]. Self-harm included any nonfatal act of self-injury, regardless of
suicidal intent. Propensity scoring was used to match the patients with regard to observed potential
confounders (eg, sex, comorbid disorders, and prior history of self-harm). The analyses found that time to
self-harm was longer with lithium, compared with valproate (hazard ratio 1.31, 95% CI 1.01-1.70), olanzapine
(hazard ratio 1.33, 95% CI 1.01-1.75), and quetiapine (hazard ratio 1.36, 95% CI 1.00-1.87). The rate of self-
harm was comparable for valproate, olanzapine, or quetiapine.

Valproate — Using valproate reduces the risk of relapse by approximately 30 percent. Evidence for the
efficacy of valproate as maintenance treatment includes a meta-analysis of six randomized trials (n = 876
euthymic bipolar patients) that evaluated valproate for 6 to 24 months; the primary findings were as follows
[35]:

● In two trials (n = 312) that compared valproate with placebo, fewer recurrent mood episodes occurred in
patients who received valproate (relative risk 0.7, 95% CI 0.5-0.9). Valproate appeared especially effective
in preventing depressive recurrences. However, weight gain, tremor, and alopecia were more common
with valproate than placebo, and discontinuation of treatment due to adverse effects was greater with

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Bipolar disorder in adults: Choosing maintenance treatment

valproate.

● Four trials (n = 618) compared valproate with lithium and found that recurrence was comparable (relative
risk 1.02, 95% CI 0.87-1.20). However, discontinuation of treatment due to intolerance or nonadherence
occurred less often with valproate (relative risk 0.7, 95% CI 0.5-0.9).

The administration and side effects (table 4 and table 5) of valproate are discussed separately. (See "Bipolar
disorder in adults: Pharmacotherapy for acute mania and hypomania", section on 'Valproate or divalproex'
and "Antiseizure drugs: Mechanism of action, pharmacology, and adverse effects", section on 'Valproate'.)

Quetiapine — Based upon multiple randomized trials, quetiapine is a second-line maintenance treatment
for bipolar disorder:

● A two-year trial randomly assigned patients (n = 1172) who were initially stabilized with open label
quetiapine to quetiapine (mean dose 546 mg per day), lithium (target trough serum concentration 0.6 to
1.2 mEq/L [0.6 to 1.2 mmol/L]), or placebo [26]. Time to recurrence of mania or depression was each
longer in patients who received quetiapine than placebo. In addition, time to recurrence of depression
was longer with quetiapine than lithium.

● A one-year randomized trial that compared quetiapine (300 or 600 mg per day) with placebo in 584
patients found that relapse occurred in fewer patients treated with quetiapine than placebo (24 versus 40
percent) [36]. Quetiapine appeared especially effective in preventing depressive recurrences.
Discontinuation of treatment due to adverse events in patients treated with quetiapine 300 mg per day,
quetiapine 600 mg per day, or placebo occurred in 8, 6, and 7 percent of patients.

In addition, quetiapine plus lithium or divalproex is beneficial as maintenance treatment for bipolar disorder.
(See 'Lithium or valproate plus a second-generation antipsychotic' below.)

The administration and side effects (table 6) of quetiapine are discussed separately. (See "Bipolar disorder in
adults: Pharmacotherapy for acute depression" and "Bipolar disorder in adults: Pharmacotherapy for acute
mania and hypomania", section on 'Second-generation'.)

Lamotrigine — Maintenance treatment with lamotrigine modestly reduces the risk of relapse by
approximately 16 percent, compared with placebo. In addition, the efficacy of lamotrigine appears to be
comparable to that for lithium; however, tolerability is better with lamotrigine than lithium.

Evidence for the efficacy of lamotrigine includes the following:

● A meta-analysis of three trials (n = 588) compared lamotrigine with placebo and found that lamotrigine
was superior (risk ratio 0.84, 95% CI 0.71-0.99) [32]. Lamotrigine appeared more effective in delaying or
preventing depression than mania or mood episodes with mixed features.

● In a meta-analysis of two trials (n = 387) that compared lamotrigine with lithium, efficacy was comparable
[32]. However, discontinuation of treatment due to adverse events occurred less often with lamotrigine
than lithium (risk ratio 0.5, 95% CI 0.3-0.8).

● A subsequent five year, open label, randomized trial (n = 155) compared lamotrigine with lithium and
found that efficacy was comparable, but that tolerability was better with lamotrigine [37].

The administration and side effects (table 4 and table 5) of lamotrigine are discussed separately. (See "Bipolar
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Bipolar disorder in adults: Choosing maintenance treatment

disorder in adults: Pharmacotherapy for acute depression" and "Antiseizure drugs: Mechanism of action,
pharmacology, and adverse effects", section on 'Lamotrigine'.)

Third-line — Third-line maintenance monotherapy for bipolar disorder includes:

● Aripiprazole (oral or long acting injectable formulations)

● Olanzapine
● Risperidone (oral or long acting injectable formulations)

The evidence for preventing recurrent mood episodes is less extensive and consistent for aripiprazole and
risperidone, compared with second-line drugs. The efficacy of olanzapine in preventing recurrence appears to
be comparable to that of second-line drugs, but the tolerability of olanzapine is poorer. Use of aripiprazole,
olanzapine, or risperidone as maintenance treatment is consistent with multiple practice guidelines
[15,16,18,28].

Aripiprazole — One randomized trial found that oral aripiprazole (mean dose 24 mg/day) was efficacious
as maintenance treatment for bipolar disorder. In the 100 week trial (n = 161 patients), there were fewer
recurrences in patients treated with aripiprazole than placebo (42 versus 63 percent) [38]. Common
aripiprazole side effects included tremor, akathisia, hypertension, dry mouth, weight gain, vaginitis, and flu
syndrome.

Randomized trials that studied aripiprazole as adjunctive maintenance treatment have yielded inconsistent
results. (See 'Patients who relapse often' below.)

The administration and side effects (table 6) of oral aripiprazole are discussed separately. (See "Bipolar
disorder in adults: Pharmacotherapy for acute mania and hypomania", section on 'Second-generation'.)

Long-acting injectable aripiprazole — Patients with bipolar disorder who are stabilized on daily oral
aripiprazole may prefer a regimen of long-acting injectable (depot) aripiprazole once every four weeks for
maintenance pharmacotherapy. However, many patients refuse depot aripiprazole because they dislike
receiving injections, and most clinicians and experts do not use depot medications [39]. In addition, long-
acting injectable antipsychotics do not necessarily improve adherence. (See "Bipolar disorder in adults:
Managing poor adherence to maintenance pharmacotherapy", section on 'Long-acting injectable
antipsychotics'.)

Evidence regarding the efficacy of long-acting injectable aripiprazole as maintenance treatment for bipolar
disorder includes a 52-week randomized trial that compared long-acting injectable aripiprazole with injectable
placebo in 266 patients [40]. Patients were enrolled during an episode of mania, stabilized on oral aripiprazole
(15 to 30 mg/day), then stabilized on long-acting injectable aripiprazole (either 300 mg or 400 mg every
month), and then randomly assigned to injectable aripiprazole or injectable placebo. Relapse of mood
episodes occurred in fewer patients treated with active drug than placebo (27 versus 51 percent). However,
during the stabilization phase prior to randomization, adverse events due to aripiprazole included akathisia (17
percent), weight increase (11 percent), insomnia (10 percent), and anxiety (7 percent). During the randomized
phase, these four side effects occurred more often with long-acting injectable aripiprazole than placebo;
nevertheless, it appeared that discontinuation of treatment due to side effects occurred less often with
aripiprazole than placebo (17 versus 26 percent of patients).

Olanzapine — Although multiple studies have consistently found that olanzapine delays or prevents
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recurrences of bipolar disorder [41,42], we use olanzapine as a third-line maintenance treatment because it
causes serious weight gain and may also cause diabetes mellitus [43-45].

Five randomized trials with different designs have studied olanzapine for maintenance treatment of bipolar
disorder [41,42]. As an example, a 48-week trial compared olanzapine (mean dose 13 mg per day) with
placebo in 361 patients and found that relapse occurred in fewer patients who received olanzapine than
placebo (47 versus 80 percent) [46]. Olanzapine appeared to delay or prevent mania more effectively than
major depression [41,42].

The administration and side effects (table 6) of olanzapine are discussed separately. (See "Bipolar disorder in
adults: Pharmacotherapy for acute mania and hypomania", section on 'Second-generation'.)

Risperidone — Risperidone may help prevent recurrence of bipolar mood episodes; when we prescribe
the drug, we typically use the daily oral formulation. Although long-acting injections every two weeks are a
reasonable alternative, many patients refuse depot risperidone because they dislike receiving injections, and
most clinicians and experts do not use depot risperidone [39]. In addition, long-acting injectable
antipsychotics do not necessarily improve adherence. (See "Bipolar disorder in adults: Managing poor
adherence to maintenance pharmacotherapy", section on 'Long-acting injectable antipsychotics'.)

No randomized trials have evaluated oral risperidone for maintenance treatment of bipolar disorder; however,
randomized trials have found that long-acting injectable (depot) risperidone may be efficacious. Also,
randomized trials with other second-generation antipsychotics, such as olanzapine and quetiapine, provide
indirect evidence that supports using oral risperidone.

Two randomized trials have evaluated long-acting injectable (depot) risperidone as maintenance treatment for
patients whose acute mania was initially stabilized with open label risperidone. Only one trial was positive:

● One two-year trial (n = 303) compared depot risperidone (generally 25 mg every two weeks) with placebo;
recurrent mood episodes occurred in fewer patients who received risperidone than placebo (29 versus 52
percent) [47]. Risperidone appeared more efficacious in delaying or preventing mania than major
depression.

● An 18-month trial (n = 398) compared depot risperidone (generally 25 mg every two weeks) plus oral
placebo, injectable placebo plus oral placebo, and injectable placebo plus oral olanzapine (10 mg per
day) [48]. Recurrence was comparable for depot risperidone plus oral placebo, compared with placebo
injection plus oral placebo (39 and 56 percent of patients). By contrast, recurrent mood episodes
occurred in fewer patients treated with placebo injection plus oral olanzapine, compared with placebo
injection plus oral placebo (24 versus 56 percent).

A third trial found that long-acting injectable risperidone plus lithium or divalproex was beneficial as
maintenance treatment for bipolar disorder. (See 'Lithium or valproate plus a second-generation antipsychotic'
below.)

The administration (table 7) and side effects (table 6) of long-acting injectable risperidone are discussed
separately in the context of schizophrenia. (See "Pharmacotherapy for schizophrenia: Long-acting injectable
antipsychotic drugs".)

Other options — For the many bipolar patients who are refractory to maintenance treatment with first,
second, or third-line medications, other options include asenapine, carbamazepine, lurasidone,
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oxcarbazepine, or paliperidone. However, the evidence supporting the use of these other options is less
compelling compared with second and third-line drugs, as well as certain medication combinations. (See
'Second-line' above and 'Third-line' above and 'Patients who relapse often' below.)

Asenapine — A 49-week extension study was conducted with patients who completed a three-week
randomized trial that compared asenapine with olanzapine for treatment of acute manic or mixed episodes;
the efficacy of asenapine as maintenance treatment appeared comparable to olanzapine [49]. The
administration and side effects (table 6) of asenapine are discussed separately.

Carbamazepine — A meta-analysis of four randomized maintenance trials (n = 464) compared

carbamazepine with lithium and found that prevention of recurrence or hospitalization was comparable;
however, none of the studies included a placebo arm [50]. Many clinicians attempt to achieve a target 12-hour
serum trough carbamazepine concentration of 4 to 8 mcg/mL, but there is no relationship between this blood
level range and efficacy for maintenance treatment of bipolar disorder. The administration and side effects
(table 4 and table 5) of carbamazepine are discussed separately. (See "Bipolar disorder in adults:
Pharmacotherapy for acute mania and hypomania", section on 'Carbamazepine' and "Antiseizure drugs:
Mechanism of action, pharmacology, and adverse effects", section on 'Carbamazepine'.)

Oxcarbazepine — A systematic review found insufficient evidence to recommend oxcarbazepine for

maintenance treatment of bipolar disorder [51]. However, oxcarbazepine is an alternative to carbamazepine,
based upon limited evidence of effectiveness in treating acute mood episodes and its structural similarity to
carbamazepine [52-54]. In addition, oxcarbazepine is generally better tolerated and is easier to prescribe
because it does not induce its own metabolism, as carbamazepine does. The administration and side effects
(table 4 and table 5) of oxcarbazepine are discussed separately. (See "Antiseizure drugs: Mechanism of
action, pharmacology, and adverse effects", section on 'Oxcarbazepine'.)

Paliperidone — A two year randomized maintenance trial compared paliperidone extended release
(median dose 6 mg per day) with placebo in 290 patients with bipolar disorder who initially remitted from
acute manic or mixed episodes with paliperidone [55]. The median time to recurrence was longer in patients
who received paliperidone than placebo (558 versus 283 days). The study also included 82 patients who
remitted with olanzapine and were maintained on it (median dose 10 mg per day). In this non-randomized arm,
time to recurrence was longer with olanzapine than in either the randomized paliperidone or placebo arms.

The administration and side effects (table 6) of paliperidone are discussed separately.

Patients who relapse often — Relapse frequently occurs in bipolar disorder despite maintenance
monotherapy. The evidence supports using medication combinations (polypharmacy) for acute and
maintenance treatment of these relapses [56].

Most patients with a past history of multiple (eg, three) recurrences are treated acutely for subsequent mood
episodes with a medication combination [57-59]; the combination should be continued for maintenance
treatment because the increased efficacy of medication combinations often outweighs the increased side
effects and costs [60]. In addition, for patients who have a partial but inadequate response to monotherapy
that is tolerated, we suggest adding a second medication. Among the many possible medications
combinations, we suggest lithium or divalproex plus a second-generation antipsychotic, which several trials
have found is more efficacious than either lithium or divalproex monotherapy [61-65]. Lithium plus valproate,
carbamazepine, or lamotrigine are reasonable alternatives.

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Bipolar disorder in adults: Choosing maintenance treatment

The majority of randomized trials that have tested medication combinations have initially treated the acute
mood episode with the combination. Following remission, patients were randomly assigned to maintenance
treatment with the combination or monotherapy (by substituting placebo for one of the medications in the
combination).

Clinicians prescribing medication combinations for maintenance therapy should try to follow certain principles
[56,66]:

● Attempt to prescribe only two medications, although three may be necessary

● The combination should not pose significantly greater safety or tolerability risks than monotherapy;
however, tolerability can be worse with combined treatments than monotherapy, especially if each drug is
not carefully titrated to below its side effects threshold

● The combined drugs should not have the same or opposing mechanisms of action

In addition, clinicians need to be aware of possible pharmacokinetic interactions. As an example, divalproex

(valproate) inhibits hepatic P450 enzymes and metabolism of concomitant medications. Conversely,
carbamazepine induces hepatic enzymes and metabolism of concomitant medications. Specific drug-drug
interactions can be determined using the drug interactions tool (Lexi-Interact Online) included in UpToDate.
This tool can be accessed from the UpToDate online search page or through the individual drug information
topics in the section on Drug interactions.

Lithium or valproate plus a second-generation antipsychotic — Randomized maintenance trials for

bipolar disorder have found that lithium or divalproex plus a second-generation antipsychotic is superior to
lithium or valproate monotherapy [61-65]. In order of preference, we suggest adjunctive quetiapine, long-
acting injectable risperidone (oral risperidone is a reasonable alternative), ziprasidone, olanzapine, or
aripiprazole:

● Quetiapine – Two similar randomized trials that each lasted two years compared adjunctive quetiapine
with placebo in patients receiving lithium or divalproex (total n = 1334) [61,62]. Relapse occurred in fewer
patients treated with adjunctive quetiapine compared with placebo (19 and 20 versus 49 and 52 percent).
Consistent with this finding, a pooled subgroup analysis of 445 patients who initially remitted from mood
episodes with mixed features prior to maintenance treatment found that there were fewer recurrences
with adjunctive quetiapine than placebo (21 versus 54 percent) [67].

● Long-acting injectable risperidone – In a one-year randomized trial (124 patients treated with lithium,
divalproex, and/or other medications), recurrence occurred in fewer patients who received adjunctive
long-acting injectable risperidone compared with placebo (23 versus 46 percent) [63].

● Ziprasidone – In a six-month randomized trial (240 patients treated with lithium or divalproex), the median
time to a mood episode was longer in patients who received adjunctive ziprasidone compared with
placebo (43 versus 27 days) [65].

● Olanzapine – In an 18-month randomized trial (68 asymptomatic patients treated with lithium or
valproate), the median time to relapse of symptoms was longer for adjunctive olanzapine compared with
placebo (163 versus 42 days) [64]. However, time to relapse of a mood syndrome (mania or depression)
was comparable for the two groups, as was the number of patients with syndromic relapse.

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Bipolar disorder in adults: Choosing maintenance treatment

● Aripiprazole – One maintenance trial of adjunctive aripiprazole found that the drug was efficacious,
whereas a smaller and shorter trial did not:

• A one-year randomized trial compared adjunctive aripiprazole with placebo in 337 patients treated
with lithium or valproate [68]. Recurrence occurred in fewer patients who received add-on
aripiprazole than placebo (17 versus 29 percent).

• A six-month randomized trial compared aripiprazole plus divalproex with placebo plus divalproex in
83 patients, and found that there was a trend for a longer time to relapse in patients treated with
adjunctive aripiprazole [69]

Additional information about lithium, divalproex, quetiapine, long-acting injectable risperidone, ziprasidone,
olanzapine, and aripiprazole is discussed separately. (See 'Lithium' above and 'Valproate' above and
'Quetiapine' above and 'Risperidone' above and 'Olanzapine' above and "Second-generation antipsychotic
medications: Pharmacology, administration, and side effects".)

Open-label prospective or retrospective studies suggest that clozapine added to any combination of lithium,
anticonvulsants, antidepressants, or anxiolytics may delay or prevent relapse of bipolar mood episodes [70-
72]. Clozapine can cause a potentially lethal agranulocytosis, and thus requires regular monitoring of white
blood cell counts every one or two weeks. In addition, clozapine should not be combined with carbamazepine
because they both adversely affect hematopoiesis. Additional information about the administration and side
effects (table 6) of clozapine is discussed separately.

For patients who respond to maintenance treatment with an adjunctive second-generation antipsychotic, we
suggest continuing the antipsychotic for a minimum of six months. Although maintaining the drug for longer
(eg, two years) is reasonable, if adverse effects such as weight gain intervene after six months, it is
appropriate to then taper and discontinue the antipsychotic over two to four weeks. Evidence supporting this
approach includes the randomized trials described immediately above. In addition, a study enrolled patients (n
= 159) who were successfully treated for mania with lithium (0.6 to 1.2 mmol/L) or valproate (350 to 830
micromol/L) plus olanzapine (5 to 25 mg/day) or risperidone (1 to 6 mg/day) [73]. After two to six weeks of
remission, patients were randomly assigned to placebo substitution for the antipsychotic at randomization
(monotherapy), placebo substitution for the antipsychotic at 6 months, or combination treatment for the entire
12 months of the study. Relapse occurred more often in the monotherapy group than the 6- and 12-month
groups, but was comparable for the 6- and 12-month groups. The estimated rate of relapse at one year in the
monotherapy, six-month, and 12-month groups was 85 versus 65 and 65 percent.

Additional information about duration of maintenance treatment is discussed elsewhere in this topic. (See
'Duration' below.)

Lithium plus an anticonvulsant — Lithium combined with an anticonvulsant is often more effective than
lithium monotherapy for maintenance treatment of bipolar disorder [74-76]:

● In a two-year, open label randomized trial (n = 220 patients), relapse occurred in fewer patients treated
with lithium plus valproate than valproate monotherapy (54 versus 69 percent) [77].

● In a one-year randomized trial (n = 52 patients), lithium plus carbamazepine led to fewer mood episodes
per year compared with lithium alone or carbamazepine alone (4.6 versus 6.3 and 6.7) [78].

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Bipolar disorder in adults: Choosing maintenance treatment
● A randomized trial compared lamotrigine plus lithium with placebo plus lithium in 124 patients and found
that the median time to relapse with adjunctive lamotrigine and placebo was 10 and 4 months [79].

● A one-year randomized trial (n = 55) compared oxcarbazepine plus lithium with placebo plus lithium and
found that recurrence with adjunctive oxcarbazepine and with placebo was 38 and 59 percent [80].
Although the difference was not statistically significant, a difference of this magnitude, if real, would be
clinically meaningful.

Other combinations — A one-year randomized trial (n = 351 patients) that compared aripiprazole plus
lamotrigine with placebo plus lamotrigine found that the estimated rate of relapse was comparable (11 and 23
percent of patients) [81].

Potentially problematic drugs

Antidepressants — There are some concerns that maintenance treatment with antidepressants may
destabilize patients with bipolar disorder. The use of antidepressants for maintenance treatment of bipolar
disorder is discussed separately. (See "Bipolar disorder in adults: Treating major depression with
antidepressants".)

Benzodiazepines — Benzodiazepines during maintenance treatment may be associated with an increased

risk of recurrence. An observational study from the Systematic Treatment Enhancement Program for Bipolar
Disorder (STEP-BD) examined 1365 patients who recovered from a mood episode [82]. After adjusting for
potential confounds, use of a benzodiazepine on a standing or as-needed basis following recovery was
associated with an increased risk of recurrence (hazard ratio 1.21, 95% CI 1.01-1.45). Comparable effects
were observed in additional analyses from the same study, including one that stratified the sample by
propensity score (a summary measure of the likelihood of receiving a benzodiazepine). However, patients with
a greater likelihood of suffering relapses may have been more likely to receive benzodiazepines.

MONITORING — We suggest regularly monitoring patients with self report rating scales during ongoing
treatment (often referred to as measurement based care). Although there is no evidence demonstrating that
this practice improves outcomes, possible benefits include identifying nonresponders, detecting residual or
prodromal symptoms, and helping patients recognize improvement. In addition, patients may become more
engaged in treatment as they take an active role, and may be able to relate specific behaviors with
symptomatic changes.

Measurement based care can be implemented with self report measures that are in the public domain (free),
require little additional time on the part of the clinician, and approximately 5 to 10 minutes for patients to
complete while waiting for their appointments [83]. Reasonable options in order of preference include the
following:

● The Life Chart Method (figure 1), with which patients rate their overall mood on a daily basis; the rating is
completed at the end of each day. A prospective study found preliminary evidence of good validity for
patient self reports [84]. Prior studies have established the reliability and validity of clinician ratings using
the instrument [85,86]. In addition, a manual that provides standardized instructions for patients is
available.

● The first 13 items of the Mood Disorder Questionnaire (table 8) to track symptoms of mania/hypomania
(validity has been established for clinician ratings but not for patient self reports) [87], as well as the nine-
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Bipolar disorder in adults: Choosing maintenance treatment
item Patient Health Questionnaire (table 9) to track symptoms of depression (this instrument is well

established for patients with unipolar depression) [88]. Patients can complete these instruments in
approximately 5 to 10 minutes while waiting for their appointments [83].

● A single Likert response item (form 1) that assesses mood on a daily basis, and is anchored on one end
with 0 for very sad, 10 on the other end for very happy, and 5 in the middle for normal mood (euthymia).

Other alternatives include the Internal State Scale [89] as well as instruments that can be downloaded from
the Depression and Bipolar Support Alliance website. In addition, My Mood Monitor is a 27-item instrument
that is used to screen for multiple psychiatric disorders including bipolar disorder [90]; the instrument can be
downloaded from My Mood Monitor or the journal website for longitudinal monitoring.

Additional information about measurement based care, including the Patient Health Questionnaire, is
discussed separately in the context of depression. (See "Using scales to monitor symptoms and treat
depression (measurement based care)".)

DURATION — The duration of maintenance treatment will vary for each patient. Most patients require
maintenance treatment for many years, and some patients require it their entire lives because medications are
not curative [91]. Maintenance treatment should last longer for patients with a more severe course of illness.
Factors to consider include the following:

● Number of years the patient has had bipolar disorder

● Lifetime number of mood episodes and hospitalizations, the length of time required to stabilize the
patient after each episode, and how many years have elapsed since the last episode

● Lifetime number of suicide attempts and their lethality

For female patients, the decision to conceive children may interrupt maintenance pharmacotherapy.
Intolerable side effects may truncate maintenance treatment altogether, but clinicians should first try to find
better tolerated alternatives.

Some patients are discouraged by the prospect of taking medications "forever" [4]. It is important to educate
patients about the course of illness in bipolar disorder and to emphasize that in the context of the long-term
relationship between the clinician and patient, the need for maintenance treatment will periodically be
reevaluated in light of the patient's progress in maintaining symptomatic and functional stability. It may also
help to point out that other chronic illnesses such as hypertension, diabetes mellitus, and asthma often require
lifetime medications. Additional information about adherence with maintenance medications for bipolar
disorder is discussed separately. (See "Bipolar disorder in adults: Managing poor adherence to maintenance
pharmacotherapy".)

Discontinuation — Most patients require maintenance treatment for many years, and some patients require it
for their entire lives. However, patients may want to stop maintenance medications because of side effects,
inadequate response, medical illness, pregnancy, or a wish to be medication-free after a prolonged period of
euthymia. Discontinuing stable treatment usually leads to a new mood episode:

● In a review of 14 lithium maintenance treatment studies that involved discontinuation of lithium in 257
patients who had previously been stable for a mean of 30 months, more than 50 percent of the patients

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Bipolar disorder in adults: Choosing maintenance treatment
suffered a recurrence within 10 weeks of discontinuing lithium, and about 90 percent relapsed within the
first year off of treatment [92].

● In a subsequent study, among 32 patients successfully treated with maintenance lithium for a minimum of
five years, 32 percent suffered a recurrence within one month of discontinuing lithium, and 62 percent
within one year [93].

Other risks of stopping maintenance treatment include hospitalization, persistent subsyndromal symptoms,
family and economic losses, and suicide. Psychoeducation may help discourage patients from discontinuing
effective maintenance treatment. (See "Bipolar disorder in adults: Managing poor adherence to maintenance
pharmacotherapy", section on 'Consequences' and "Bipolar disorder in adults: Psychoeducation and other
adjunctive maintenance psychotherapies", section on 'Group psychoeducation'.)

If patients insist on stopping treatment, we suggest slowly tapering one medication at a time, over a period of
several weeks to months. Clinicians should also monitor patients frequently for prodromal symptoms of early
recurrence. Prospective, open-label studies show that tapering maintenance medication more slowly is
associated with lower rates of recurrence, but that most patients suffer a recurrence despite the slower taper:

● In 78 patients who were effectively maintained on lithium for a mean of four years and then discontinued
it, recurrence within two years was significantly greater in patients who stopped lithium in less than two
weeks compared with discontinuation over two to four weeks (95 versus 69 percent) [94].

● In 64 patients who were stable on maintenance lithium for a mean of four years and then discontinued it,
recurrence within five years was significantly greater in patients who stopped lithium in less than two
weeks compared with discontinuation over two to four weeks (94 versus 53 percent) [95].

Based upon clinical experience, discontinuation of maintenance pharmacotherapy may be more successful
for patients who have established relationships with their clinicians, as well as patients who have relatively few
current psychosocial stressors such as relationship or occupational difficulties, getting married, or graduating
from school. It may also be helpful to educate patients about relapse prevention (eg, identifying prodromal
symptoms and avoiding risk factors for relapse such as substance abuse), and to develop a plan for patients
and families to follow should relapse occur.

CHOOSING ADJUNCTIVE PSYCHOTHERAPY — Although pharmacotherapy is the cornerstone of

maintenance treatment for bipolar disorder, adjunctive psychotherapy can help prevent relapses and improve
medication adherence. As an example, a meta-analysis of eight randomized trials (n = 830 patients) compared
psychotherapy (eg, group psychoeducation, cognitive-behavioral therapy, or family therapy) plus
pharmacotherapy with pharmacotherapy alone; the probability of relapse was lower in patients treated with
adjunctive psychotherapy (odds ratio 0.5, 95% CI 0.4-0.7) [96]. Adjunctive psychotherapy is typically
administered during maintenance treatment to euthymic patients, who are typically better able to participate in
psychotherapy than acutely ill patients [97].

However, if adjunctive psychotherapy is used during an acute mood episode, the same psychotherapy is
usually retained for maintenance treatment. This practice is supported by a randomized trial of 82 patients
with acute mood episodes who were stabilized for four weeks with pharmacotherapy plus one of two
randomly assigned adjunctive psychotherapies (either interpersonal and social rhythm therapy or the control
therapy, called intensive clinical management) [98]. Following stabilization, patients were randomly assigned
again to maintenance treatment with the same psychotherapy or to switch to the other psychotherapy.
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Bipolar disorder in adults: Choosing maintenance treatment
Relapse occurred in fewer patients who maintained the same therapy compared with those who switched (18
versus 40 percent).

Adjunctive psychotherapies can be distinguished as first and second-line maintenance treatments, based
upon the quality and quantity of data that demonstrate their efficacy in preventing recurrent bipolar mood
episodes, as well as their beneficial effects upon medication adherence.

First-line — For bipolar patients receiving maintenance pharmacotherapy, we suggest adjunctive group
psychoeducation as first-line psychotherapy. Psychoeducation is a structured, time-limited program that
teaches patients and family members about bipolar disorder, including its pathogenesis, clinical features,
course of illness, and treatment; the program also addresses detecting prodromal symptoms. Nearly all other
types of psychotherapy used for bipolar disorder include an element of psychoeducation because of its
demonstrated success and the ease of administration. Several randomized trials indicate that group
psychoeducation is efficacious both for preventing recurrent mood episodes and improving adherence to
pharmacotherapy. The efficacy, administration, and content of group psychoeducation are discussed
separately. (See "Bipolar disorder in adults: Psychoeducation and other adjunctive maintenance
psychotherapies", section on 'Group psychoeducation' and "Bipolar disorder in adults: Managing poor
adherence to maintenance pharmacotherapy", section on 'Group psychoeducation'.)

Second-line — Bipolar patients receiving maintenance pharmacotherapy may decline or not have access to
group psychoeducation, or may continue to demonstrate poor adherence despite treatment with group
psychoeducation. For these patients, we suggest either adjunctive cognitive-behavioral therapy (CBT) or
family therapy for enhancing poor medication adherence. Multiple randomized trials indicate that CBT and
family therapy are each efficacious for improving adherence. (See "Bipolar disorder in adults: Managing poor
adherence to maintenance pharmacotherapy", section on 'Specific interventions'.)

The efficacy of CBT and of family therapy for delaying or preventing recurrent bipolar mood episodes is not
clear, due to inconsistent results across different randomized trials. (See "Bipolar disorder in adults:
Psychoeducation and other adjunctive maintenance psychotherapies".)

ELECTROCONVULSIVE THERAPY — Maintenance electroconvulsive therapy (ECT) has been used for
patients who responded to ECT for treatment of acute mood episodes and failed many (eg, five) other
maintenance medication regimens and psychotherapies [16]. Most of the evidence supporting the
effectiveness and tolerability of maintenance ECT comes from small observational studies; the frequency of
maintenance ECT ranged from once a week to once a month [99-107]. Maintenance medications, including
anticonvulsants, are often prescribed in conjunction with maintenance ECT.

Additional information about using ECT for bipolar disorder, as well as an overview of ECT and the technique
for performing ECT, are discussed separately. (See "Bipolar disorder in adults: Indications for and efficacy of
electroconvulsive therapy (ECT)" and "Overview of electroconvulsive therapy (ECT) for adults" and "Technique
for performing electroconvulsive therapy (ECT) in adults".)

SELF-MANAGEMENT — Patients who are capable of taking responsibility for their health may benefit from
self-management strategies that include measures to [108]:

● Calm oneself and cope with stress (eg, scheduling relaxing activities or learning mindfulness-based
stress reduction).

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Bipolar disorder in adults: Choosing maintenance treatment
● Optimize medical management by adhering to treatment and being aware of prodromal signs. Regular
mood charting (figure 1) may be helpful. (See 'Monitoring' above.)

● Maintain hope (eg, understanding that bipolar disorder is a medical disorder that can be treated and if
current treatment is not working sufficiently, there are many other alternatives).

● Engage in physical activity and exercise (eg, bicycle riding or walking).

● Maintain a healthy diet.

GERIATRIC PATIENTS — Maintenance treatment for geriatric bipolar disorder is discussed separately. (See
"Geriatric bipolar disorder: Maintenance treatment".)

FEMALE PATIENTS — For female patients who are at high risk of unintended pregnancies (eg, become
hypersexual when manic or have a history of irregular use of contraceptives), we try to avoid using teratogenic
drugs, especially valproate, but also carbamazepine and lithium. The teratogenic and postnatal risks caused
by these drugs are discussed separately. (See "Teratogenicity, pregnancy complications, and postnatal risks
of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy" and "Risks associated with
epilepsy and pregnancy", section on 'Effect of antiseizure drugs on the fetus'.)

Pregnancy — Preconception and prenatal maintenance pharmacotherapy for bipolar patients, and
contraception and preconception counseling for bipolar disorder are discussed separately. (See "Bipolar
disorder in women: Preconception and prenatal maintenance pharmacotherapy" and "Bipolar disorder in
women: Indications for preconception and prenatal maintenance pharmacotherapy" and "Bipolar disorder in
women: Contraception and preconception assessment and counseling".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics”
and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed.
These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth
information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on “patient info” and the keyword(s) of interest.)

● Basics topics (See "Patient education: Bipolar disorder (The Basics)" and "Patient education: Reducing
the costs of medicines (The Basics)".)

● Beyond the Basics topics (See "Patient education: Bipolar disorder (manic depression) (Beyond the
Basics)" and "Patient education: Reducing the costs of medicines (Beyond the Basics)".)

These educational materials can be used as part of psychoeducational psychotherapy. (See 'First-line' above.)

The National Institute of Mental Health also has educational material explaining the symptoms, course of
illness, and treatment of bipolar disorder in a booklet entitled "Bipolar Disorder," which is available online at

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Bipolar disorder in adults: Choosing maintenance treatment
the website http://www.nimh.nih.gov/health/publications/bipolar-disorder/complete-index.shtml or through a
toll-free number, 866-615-6464. The web site also provides references, summaries of study results in
language intended for the lay public, and information about clinical trials currently recruiting patients.

More comprehensive information is provided in many books written for patients and family members,
including The Bipolar Disorder Survival Guide: What You and Your Family Need to Know, written by David J.
Miklowitz, PhD (published by The Guilford Press, 2002); An Unquiet Mind: A Memoir of Moods and Madness,
written by Kay Jamison, PhD (published by Random House, 1995); and Treatment of Bipolar Illness: A
Casebook for Clinicians and Patients, by RM Post, MD, and GS Leverich, LCSW (published by Norton Press,
2008).

The Depression and Bipolar Support Alliance (800-826-3632) is a national organization that educates
members about bipolar disorder and how to cope with it. Other functions include increasing public awareness
of the illness and advocating for more research and services. The organization is administered and maintained
by patients and family members, and has local chapters.

The National Alliance on Mental Illness (800-950-6264) is a similarly structured organization devoted to
education, support, and advocacy for patients with any mental illness. Bipolar disorder is one of their
priorities.

SUMMARY AND RECOMMENDATIONS

● Bipolar disorder is a highly recurrent illness. For patients with bipolar I disorder, we recommend
maintenance pharmacotherapy rather than no treatment (Grade 1A). We also suggest maintenance
treatment for patients with bipolar II disorder rather than no treatment (Grade 2C). Patients with other
specified bipolar disorder are likely to benefit from maintenance treatment as well. (See 'Indications'
above.)

● The goals for maintenance therapy are to reduce subsyndromal symptoms, delay or prevent recurrence
of new mood episodes, reduce the risk of suicide, and promote psychosocial functioning. (See
'Indications' above.)

● For most patients who respond to acute pharmacotherapy, we suggest maintenance treatment with the
same regimen, rather than switching medications (Grade 2B). (See 'First-line' above.)

● For patients who do not tolerate the initial course of maintenance pharmacotherapy and were not treated
with lithium, we suggest lithium monotherapy over other medication regimens (Grade 2B).

● For patients who do not respond to or tolerate lithium, we suggest valproate, quetiapine, or lamotrigine
rather than other medications (Grade 2B). For patients who do not respond to or cannot tolerate these
drugs, aripiprazole, olanzapine, or risperidone are reasonable alternatives. (See 'Second-line' above and
'Third-line' above.)

● For patients who have a history of multiple recurrences or have a partial but inadequate response to a
maintenance drug that is tolerated, we suggest adding a second medication (Grade 2B). Common
combinations include lithium or valproate, plus a second-generation antipsychotic, such as quetiapine,
long-acting injectable risperidone, ziprasidone, or olanzapine. Other combinations that are useful include
lithium plus valproate or carbamazepine. (See 'Patients who relapse often' above.)

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Bipolar disorder in adults: Choosing maintenance treatment
● Group psychoeducation as adjunctive treatment with pharmacotherapy can prevent recurrent mood
episodes and enhance medication adherence. For patients with bipolar disorder, we suggest adjunctive
psychoeducation for euthymic patients rather than no psychotherapy (Grade 2C). Adjunctive cognitive
behavior therapy or family therapy are each a reasonable alternative to psychoeducation for management
of poor adherence to pharmacotherapy. (See 'Choosing adjunctive psychotherapy' above.)

● Monitoring bipolar patients with rating scales during ongoing treatment may identify nonresponders,
detect residual symptoms, and help patients recognize improvement. Clinicians can track symptoms of
mania/hypomania with the first 13 items of the Mood Disorder Questionnaire (table 8), and symptoms of
depression with the nine-item Patient Health Questionnaire (table 9).

● Most patients require maintenance treatment for many years, and some patients require it their entire
lives. (See 'Duration' above.)

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