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## Complete Summary

#### GUIDELINE TITLE

Practice guideline for the treatment of patients with bipolar disorder
(revision).

#### BIBLIOGRAPHIC SOURCE(S)

Practice guideline for the treatment of patients with bipolar disorder
(revision). Am J Psychiatry 2002 Apr;159(4 Suppl):1-50. \[472
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11958165)

#### GUIDELINE STATUS

According to the guideline developer, this guideline is still considered
to be current as of November 2005. A Guideline Watch, which summarizes
significant developments in practice since the publication of the
original guideline, was published in November 2005 and is available from
the [American Psychiatric Association Web
site](http://www.psych.org/psych_pract/treatg/pg/Bipolar.watch.pdf) (see
also the \"Availability of Companion Documents\" field below).

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse (NGC)**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [December 12, 2007,
    Carbamazepine](http://www.fda.gov/medwatch/safety/2007/safety07.htm#carbamazepine):
    The U.S. Food and Drug Administration (FDA) has provided
    recommendations for screening that should be performed on specific
    patient populations before starting treatment with carbamazepine.

-   [May 2, 2007, Antidepressant
    drugs](http://www.fda.gov/medwatch/safety/2007/safety07.htm#Antidepressant):
    Update to the existing black box warning on the prescribing
    information on all antidepressant medications to include warnings
    about the increased risks of suicidal thinking and behavior in young
    adults ages 18 to 24 years old during the first one to two months of
    treatment.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Bipolar disorder, including:

-   Bipolar I disorder

-   Bipolar II disorder

-   Cyclothymic disorder

-   Bipolar disorder not otherwise specified (NOS)

#### GUIDELINE CATEGORY

Evaluation\
Management\
Treatment

#### CLINICAL SPECIALTY

Family Practice\
Internal Medicine\
Psychiatry

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

To assist the clinician faced with the task of implementing a specific
regimen for the treatment of a patient with bipolar disorder

#### TARGET POPULATION

Primarily adults (18 years of age or older) with bipolar disorder

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Psychiatric management**

1.  Diagnostic evaluation

2.  Evaluation of the safety of the patients and others and
    determination of a treatment setting

3.  Establishment and maintenance of a therapeutic alliance

4.  Monitoring of treatment response

5.  Patient and family education

6.  Measures to enhance treatment compliance

7.  Promotion of awareness of stressors and regular patterns of activity
    and sleep

8.  Work with patient to anticipate and address early signs of relapse

9.  Evaluation and management of functional impairments

**Somatic treatments**

1.  Pharmacologic agents:

> Classes of medications:

-   Antidepressants

    -   Monoamine oxidase inhibitors (MAOIs)

    -   Selective serotonin reuptake inhibitor (SSRI)

-   Antipsychotics

-   Benzodiazepines

> Specific medications:

-   Bupropion

-   Olanzapine

-   Carbamazepine

-   Clozapine

-   Lamotrigine

-   Lithium

-   Oxcarbazepine

-   Paroxetine

-   Risperidone

-   Valproate

-   Venlafaxine

2.  Electroconvulsive therapy (ECT)

3.  Combination therapies

*Concomitant psychosocial interventions* (psychoeducational,
interpersonal, family, group, social rhythm, psychodynamic, and
cognitive behavior therapies)

#### MAJOR OUTCOMES CONSIDERED

-   Efficacy of treatment as evidenced by morbidity and mortality
    associated with bipolar disorder

-   Adverse effects of treatment

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

A computerized search of the relevant literature from MEDLINE and
PsycINFO was conducted. Sources of funding were not considered when
reviewing the literature.

The first literature search was conducted by searching MEDLINE and
PsycINFO for the period from 1992 to 2000. Key words used were \"bipolar
disorder,\" \"bipolar depression,\" \"mania,\" \"mixed states,\" \"mixed
episodes,\" \"mixed mania,\" \"antimanic,\" \"hypomanic,\"
\"hypomania,\" \"manic depression,\" \"prophylactic,\"
\"pharmacotherapy,\" \"mood stabilizers,\" \"mood-stabilizing,\" \"rapid
cycling,\" \"maintenance,\" \"continuation,\" \"child and adolescent,\"
\"antidepressants,\" \"valproate,\" \"lithium,\" \"carbamazepine,\"
\"olanzapine,\" \"risperidone,\" \"gabapentin,\" \"topiramate,\"
\"lamotrigine,\" \"clonazepam,\" \"divalproex,\" \"psychotherapy,\"
\"family therapy,\" \"psychoeducation,\" \"course,\" \"epidemiology,\"
\"comorbidity,\" \"anxiety,\" \"anxiety disorders,\" \"attention
deficit,\" \"catatonia,\" \"elderly,\" \"family history,\" \"gender,\"
\"general medical conditions,\" \"life events,\" \"personality
disorders,\" \"pregnancy,\" \"psychosis,\" \"stress,\"
\"substance-related disorders,\" \"suicide,\" \"homicide,\" and
\"violence.\"

An additional MEDLINE search for the period from 1992 to 2001 used the
key words \"genetic counseling,\" \"family functioning,\"
\"cross-cultural issues,\" and \"pharmacokinetics.\" A search on PubMed
was also conducted through 2001 that used the search terms
\"electroconvulsive,\" \"intravenous drug abuse,\" \"treatment
response,\" \"pharmacogenetic,\" \"attention deficit disorder,\"
\"violence,\" \"aggression,\" \"aggressive,\" \"suicidal,\" \"cognitive
impairment,\" \"sleep,\" \"postpartum,\" \"ethnic,\" \"racial,\"
\"metabolism,\" \"hyperparathyroidism,\" \"overdose,\" \"toxicity,\"
\"intoxication,\" \"pregnancy,\" \"breast-feeding,\" and \"lactation.\"

Additional, less formal, literature searches were conducted by American
Psychiatric Association (APA) staff and individual members of the work
group on bipolar disorder.

#### NUMBER OF SOURCE DOCUMENTS

The first literature search yielded 3,382 citations

The additional MEDLINE search yielded 122 citations.

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Expert Consensus (Committee)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

Not applicable

#### METHODS USED TO ANALYZE THE EVIDENCE

Review of Published Meta-Analyses\
Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

Once a topic is chosen for guideline development, a work group is formed
to draft the guideline. By design, the work group consists of
psychiatrists in active clinical practice with diverse expertise and
practice experience relevant to the topic. Policies established by the
Steering Committee guide the work of systematically reviewing data in
the literature and forging consensus on the implications of those data,
as well as describing a clinical consensus. These policies, in turn,
stem from criteria formulated by the American Medical Association to
promote the development of guidelines that have a strong evidence base
and that make optimal use of clinical consensus.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

Each recommendation is identified at falling into one of three
categories of endorsement, indicated by a bracketed Roman numeral
following the statement. The three categories represent varying levels
of clinical confidence regarding the recommendation:

\[I\] Recommended with substantial clinical confidence.

\[II\] Recommended with moderate clinical confidence.

\[III\] May be recommended on the basis of individual circumstances.

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

This practice guideline was developed under the auspices of the American
Psychiatric Association Steering Committee on Practice Guidelines. The
development process is detailed in a document available from the
American Psychiatric Association Department of Quality Improvement and
Psychiatric Services: the \"American Psychiatric Association Guideline
Development Process\" (see \"Companion Documents\").

Key features of this process, relevant to review methodology, include
the following:

-   The production of multiple drafts with widespread review; seven
    organizations and more than 40 individuals (named in the original
    guideline document) submitted significant comments.

-   Approval by the American Psychiatric Association Assembly and Board
    of Trustees. This guideline was approved in December 2001.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

Each recommendation is identified as falling into one of three
categories of endorsement, indicated by a bracketed Roman numeral
following the statement. The three categories represent varying levels
of clinical confidence regarding the recommendation.

Definition of grades of recommendation \[I-III\] are presented at the
end of the \"Major Recommendations\" field.

**Psychiatric Management**

At this time, there is no cure for bipolar disorder; however, treatment
can decrease the associated morbidity and mortality **\[I\]**.
Initially, the psychiatrist should perform a diagnostic evaluation and
assess the patient´s safety and level of functioning to arrive at a
decision about the optimum treatment setting **\[I\]**. Subsequently,
specific goals of psychiatric management include establishing and
maintaining a therapeutic alliance, monitoring the patient´s psychiatric
status, providing education regarding bipolar disorder, enhancing
treatment compliance, promoting regular patterns of activity and of
sleep, anticipating stressors, identifying new episodes early, and
minimizing functional impairments **\[I\]**.

**Acute Treatment**

***Manic or Mixed Episodes***

The first-line pharmacological treatment for more severe manic or mixed
episodes is the initiation of either lithium plus an antipsychotic or
valproate plus an antipsychotic **\[I\]**. For less ill patients,
monotherapy with lithium, valproate, or an antipsychotic such as
olanzapine may be sufficient **\[I\]**. Short-term adjunctive treatment
with a benzodiazepine may also be helpful **\[II\]**. For mixed
episodes, valproate may be preferred over lithium **\[II\]**. Atypical
antipsychotics are preferred over typical antipsychotics because of
their more benign side effect profile **\[I\]**, with most of the
evidence supporting the use of olanzapine or risperidone **\[II\]**.
Alternatives include carbamazepine or oxcarbazepine in lieu of lithium
or valproate **\[II\]**. Antidepressants should be tapered and
discontinued if possible **\[I\]**. If psychosocial therapy approaches
are used, they should be combined with pharmacotherapy **\[I\]**.

For patients who, despite receiving maintenance medication treatment,
experience a manic or mixed episode (i.e., a \"breakthrough\" episode),
the first-line intervention should be to optimize the medication dose
**\[I\]**. Introduction or resumption of an antipsychotic is sometimes
necessary **\[II\]**. Severely ill or agitated patients may also require
short-term adjunctive treatment with a benzodiazepine **\[I\]**.

When first-line medication treatment at optimal doses fails to control
symptoms, recommended treatment options include addition of another
first-line medication **\[I\]**. Alternative treatment options include
adding carbamazepine or oxcarbazepine in lieu of an additional
first-line medication **\[II\]**, adding an antipsychotic if not already
prescribed **\[I\]**, or changing from one antipsychotic to another
**\[III\]**. Clozapine may be particularly effective in the treatment of
refractory illness **\[II\]**. Electroconvulsive therapy may also be
considered for patients with severe or treatment-resistant mania or if
preferred by the patient in consultation with the psychiatrist
**\[I\]**. In addition, electroconvulsive therapy is a potential
treatment for patients experiencing mixed episodes or for patients
experiencing severe mania during pregnancy **\[II\]**.

Manic or mixed episodes with psychotic features usually require
treatment with an antipsychotic medication **\[II\]**.

***Depressive Episodes***

The first-line pharmacological treatment for bipolar depression is the
initiation of either lithium **\[I\]** or lamotrigine **\[II\]**.
Antidepressant monotherapy is not recommended **\[I\]**. As an
alternative, especially for more severely ill patients, some clinicians
will initiate simultaneous treatment with lithium and an antidepressant
**\[III\]**. In patients with life-threatening inanition, suicidality,
or psychosis, electroconvulsive therapy also represents a reasonable
alternative **\[I\]**. Electroconvulsive therapy is also a potential
treatment for severe depression during pregnancy **\[II\]**.

A large body of evidence supports the efficacy of psychotherapy in the
treatment of unipolar depression **\[I\]**. In bipolar depression,
interpersonal therapy and cognitive behavior therapy may be useful when
added to pharmacotherapy **\[II\]**. While psychodynamic psychotherapy
has not been empirically studied in patients with bipolar depression, it
is widely used in addition to medication **\[III\]**.

For patients who, despite receiving maintenance medication treatment,
suffer a breakthrough depressive episode, the first-line intervention
should be to optimize the dose of maintenance medication **\[II\]**.

When an acute depressive episode of bipolar disorder does not respond to
first-line medication treatment at optimal doses, next steps include
adding lamotrigine **\[I\]**, bupropion **\[II\]**, or paroxetine
**\[II\]**. Alternative next steps include adding other newer
antidepressants (e.g., a selective serotonin reuptake inhibitor \[SSRI\]
or venlafaxine) **\[II\]** or a monoamine oxidase inhibitor (MAOI)
**\[II\]**. For patients with severe or treatment-resistant depression
or depression with psychotic or catatonic features, electroconvulsive
therapy should be considered **\[I\]**.

The likelihood of antidepressant treatment precipitating a switch into a
hypomanic episode is probably lower in patients with bipolar II
depression than in patients with bipolar I depression. Therefore,
clinicians may elect to recommend antidepressant treatment earlier in
patients with bipolar II disorder **\[II\]**.

Depressive episodes with psychotic features usually require adjunctive
treatment with an antipsychotic medication **\[I\]**. Electroconvulsive
therapy (ECT) represents a reasonable alternative **\[I\]**.

***Rapid Cycling***

As defined in DSM-IV-TR and applied in this guideline, rapid cycling
refers to the occurrence of four or more mood disturbances within a
single year that meet criteria for a major depressive, mixed, manic, or
hypomanic episode. These episodes are demarcated either by partial or
full remission for at least 2 months or a switch to an episode of
opposite polarity (e.g., from a major depressive to a manic episode).
The initial intervention in patients who experience rapid cycling is to
identify and treat medical conditions, such as hypothyroidism or drug or
alcohol use, that may contribute to cycling **\[I\]**. Certain
medications, particularly antidepressants, may also contribute to
cycling and should be tapered if possible **\[II\]**. The initial
treatment for patients who experience rapid cycling should include
lithium or valproate **\[I\]**; an alternative treatment is lamotrigine
**\[I\]**. For many patients, combinations of medications are required
**\[II\]**.

**Maintenance Treatment**

Following remission of an acute episode, patients may remain at
particularly high risk of relapse for a period of up to 6 months; this
phase of treatment, sometimes referred to as continuation treatment, is
considered in this guideline to be part of the maintenance phase.
Maintenance regimens of medication are recommended following a manic
episode **\[I\]**. Although few studies involving patients with bipolar
II disorder have been conducted, consideration of maintenance treatment
for this form of the illness is also strongly warranted **\[II\]**. The
medications with the best empirical evidence to support their use in
maintenance treatment include lithium **\[I\]** and valproate **\[I\]**;
possible alternatives include lamotrigine **\[II\]** or carbamazepine or
oxcarbazepine **\[II\]**. If one of these medications was used to
achieve remission from the most recent depressive or manic episode, it
generally should be continued **\[I\]**. Maintenance sessions of
electroconvulsive therapy may also be considered for patients whose
acute episode responded to electroconvulsive therapy **\[II\]**.

For patients treated with an antipsychotic medication during the
preceding acute episode, the need for ongoing antipsychotic treatment
should be reassessed upon entering maintenance treatment **\[I\]**;
antipsychotics should be discontinued unless they are required for
control of persistent psychosis **\[I\]** or prophylaxis against
recurrence **\[III\]**. While maintenance therapy with atypical
antipsychotics may be considered **\[III\]**, there is as yet no
definitive evidence that their efficacy in maintenance treatment is
comparable to that of agents such as lithium or valproate.

During maintenance treatment, patients with bipolar disorder are likely
to benefit from a concomitant psychosocial intervention---including
psychotherapy---that addresses illness management (i.e., adherence,
lifestyle changes, and early detection of prodromal symptoms) and
interpersonal difficulties **\[II\]**.

Group psychotherapy may also help patients address such issues as
adherence to a treatment plan, adaptation to a chronic illness,
regulation of self-esteem, and management of marital and other
psychosocial issues **\[II\]**. Support groups provide useful
information about bipolar disorder and its treatment **\[I\]**.

Patients who continue to experience subthreshold symptoms or
breakthrough mood episodes may require the addition of another
maintenance medication **\[II\]**, an atypical antipsychotic
**\[III\]**, or an antidepressant **\[III\]**. There are currently
insufficient data to support one combination over another. Maintenance
sessions of electroconvulsive therapy may also be considered for
patients whose acute episode responded to electroconvulsive therapy
**\[II\]**.

Refer to the original guideline document for a discussion of special
clinical features influencing the treatment plan.

**[Definitions]{.underline}**:

**Grades of Recommendations**:

I.  Recommended with substantial clinical confidence.

II. Recommended with moderate clinical confidence.

III. May be recommended on the basis of individual circumstances.

#### CLINICAL ALGORITHM(S)

None provided

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The recommendations are based on the best available data and clinical
consensus with regard to a particular clinical decision. The summary of
treatment recommendations is keyed according to the level of confidence
with which each recommendation is made (see the \"Major
Recommendations\" field). In addition, the following coding system is
used to indicate the nature of the supporting evidence in the
references:

\[A\] Randomized clinical trial\
\[B\] Clinical trial\
\[C\] Cohort or longitudinal study\
\[D\] Case-control study\
\[E\] Review of secondary analysis\
\[F\] Review\
\[G\] Other

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Benefits of treatment in general include decreased frequency,
    severity, and psychosocial consequences of episodes; and improved
    psychosocial functioning between episodes.

-   Potential benefits of psychiatric management include treatment of
    acute exacerbations; prevention of recurrences; improved
    interepisode functioning; the provision of assistance, insight, and
    support to the patient and family; and the reduction of the
    morbidity and sequelae of bipolar disorder.

-   Potential benefits of pharmacologic treatments include the effective
    treatment of acute episodes; decreased symptoms of mania or
    depression; the prevention of future episodes; and mood-stabilizing
    effects.

-   Electroconvulsive therapy (ECT) is efficacious in the treatment of
    both phases of bipolar disorder.

#### POTENTIAL HARMS

**Side effects and toxicities of medications**

-   *Lithium*. Dose-related side effects of lithium include polyuria,
    polydipsia, weight gain, cognitive problems (e.g., dulling, impaired
    memory, poor concentration, confusion, mental slowness), tremor,
    sedation or lethargy, impaired coordination, gastrointestinal
    distress (e.g., nausea, vomiting, dyspepsia, diarrhea), hair loss,
    benign leukocytosis, acne, and edema. Lithium may cause benign
    electrocardiogram (ECG) changes associated with repolarization. Less
    commonly, cardiac conduction abnormalities have been associated with
    lithium treatment. The most common renal effect of lithium is
    impaired concentrating capacity caused by reduced renal response to
    antidiuretic hormone (ADH), manifested as polyuria, polydipsia, or
    both. Although the polyuria associated with early lithium treatment
    may resolve, persistent polyuria (ranging from mild and well
    tolerated to severe nephrogenic diabetes insipidus) may occur. In
    addition to the other signs and symptoms of hypothyroidism, patients
    with bipolar disorder are at risk of developing depression or rapid
    cycling. Hyperparathyroidism has also been noted with lithium
    treatment. A small number of case reports have described
    exacerbation or first occurrences of psoriasis associated with
    lithium treatment. Approximately 10% to 20% of patients receiving
    long-term lithium treatment (i.e., for more than 10 years) display
    morphological kidney changes, usually interstitial fibrosis, tubular
    atrophy, and sometimes glomerular sclerosis. Additionally, several
    studies have shown that a small percentage of patients treated with
    lithium may develop rising serum creatinine concentrations after 10
    years or more of treatment.

> Signs and symptoms of early lithium intoxication (with levels above
> 1.5 meq/liter) include marked tremor, nausea and diarrhea, blurred
> vision, vertigo, confusion, and increased deep tendon reflexes. With
> lithium levels above 2.5 meq/liter, patients may experience more
> severe neurological complications and eventually experience seizures,
> coma, cardiac dysrhythmia, and permanent neurological impairment.

-   *Valproate*. Common dose-related side effects of valproate include
    gastrointestinal distress (e.g., anorexia, nausea, dyspepsia,
    vomiting, diarrhea), benign hepatic transaminase elevations,
    osteoporosis, tremor, and sedation. Mild, asymptomatic leukopenia
    and thrombocytopenia occur less frequently and are reversible upon
    drug discontinuation. Other side effects that are often bothersome
    to the patient include hair loss, increased appetite, and weight
    gain. Polycystic ovarian syndrome may be possible with valproate
    treatment. Rare, idiosyncratic, but potentially fatal adverse events
    with valproate include irreversible hepatic failure, hemorrhagic
    pancreatitis, and agranulocytosis. Signs of overdose include
    somnolence, heart block, and eventually coma. Deaths have been
    reported. Overdose can be treated with hemodialysis.

-   *Carbamazepine*. The most common dose-related side effects of
    carbamazepine include neurological symptoms, such as diplopia,
    blurred vision, fatigue, nausea, and ataxia. These effects are
    usually transient and often reversible with dose reduction. Less
    frequent side effects include skin rashes, mild leukopenia, mild
    thrombocytopenia, hyponatremia, and (less commonly) hypo-osmolality.
    Mild liver enzyme elevations occur in 5% to 15% of patients.
    Hyponatremia occurs in 6% to 31% of patients, is rare in children
    but probably more common in the elderly, occasionally develops many
    months after the initiation of carbamazepine treatment, and
    sometimes necessitates carbamazepine discontinuation. In addition,
    carbamazepine may decrease total and free thyroxine levels and
    increase free cortisol levels, but these effects are rarely
    clinically significant. Weight gain is also a common side effect of
    carbamazepine. Rare, idiosyncratic, but serious and potentially
    fatal side effects of carbamazepine include agranulocytosis,
    aplastic anemia, thrombocytopenia, hepatic failure, exfoliative
    dermatitis (e.g., Stevens-Johnson syndrome), and pancreatitis.
    Although these side effects usually occur within 3 to 6 months of
    carbamazepine initiation, they have also occurred after more
    extended periods of treatment. Other rare side effects include
    systemic hypersensitivity reactions, cardiac conduction
    disturbances, psychiatric symptoms (including sporadic cases of
    psychosis), and, very rarely, renal effects (including renal
    failure, oliguria, hematuria, and proteinuria). Carbamazepine may be
    fatal in overdose; deaths have been reported with ingestions of more
    than 6 grams. Signs of impending carbamazepine toxicity include
    dizziness, ataxia, sedation, and diplopia. Acute intoxication can
    result in hyperirritability, stupor, or coma. The most common
    symptoms of carbamazepine overdose are nystagmus, ophthalmoplegia,
    cerebellar and extrapyramidal signs, impaired consciousness,
    convulsions, and respiratory dysfunction. Cardiac symptoms may
    include tachycardia, arrhythmia, conduction disturbances, and
    hypotension. Gastrointestinal and anticholinergic symptoms may also
    occur.

-   *Olanzapine*. In placebo-controlled clinical trials, somnolence was
    the most common side effect associated with olanzapine. Other common
    side effects included constipation, dry mouth, increased appetite,
    and weight gain. Especially during initial dose titration,
    olanzapine may induce orthostatic hypotension associated with
    dizziness, tachycardia, and, in some patients, syncope. Syncope was
    reported in 0.6% of olanzapine-treated patients in phase II and III
    trials. In clinical trials, seizures occurred in 0.9% of
    olanzapine-treated patients. Transient elevations in plasma
    prolactin concentrations were also observed in short-term trials.
    Clinically significant hepatic transaminase elevations (Â³ 3 times
    the upper limit of the normal range) were observed in 2% of
    olanzapine-treated patients.

-   *Lamotrigine*. The most common side effects of lamotrigine in the
    treatment of depression are headache, nausea, infection, and
    xerostomia. The risk of serious rash, including Stevens-Johnson
    syndrome and toxic epidermal necrolysis, was approximately 0.3% in
    adults and approximately 1% in children in clinical trials for
    epilepsy. However, with a slow titration schedule, the risk of
    serious rash was reduced to 0.01% in adults, which is comparable to
    that of other anticonvulsant medications. Rash can occur at any time
    during treatment but is more likely to occur early in treatment. It
    may also be more likely if lamotrigine and valproate are
    administered concomitantly. Whenever lamotrigine is prescribed,
    patients should be apprised of the risk of rash and urged to contact
    the psychiatrist or primary care physician immediately if a rash
    occurs. At rash onset, it is difficult to distinguish between a
    serious and a more benign rash. Particularly worrisome are rashes
    accompanied by fever or sore throat, those that are diffuse and
    widespread, and those with prominent facial or mucosal involvement.
    In such circumstances lamotrigine (and concurrent valproate) should
    be discontinued. With concurrent valproate treatment,
    pharmacokinetic interactions lead to lamotrigine levels that are
    approximately twice normal. To minimize the risk of potentially
    serious rash in patients who are receiving valproate, the dose
    schedule should be cut in half (i.e., 12.5 mg/day or 25 mg every
    other day for 2 weeks, then 25 mg/day for weeks 3 and 4). Similarly,
    concurrent carbamazepine treatment leads to an increase in
    lamotrigine metabolism and requires dosing to be doubled.

**Note**: For information on side effects of electroconvulsive therapy
(ECT), refer to the American Psychiatric Association Task Force Report
on ECT (The practice of electroconvulsive therapy: recommendations for
treatment, training, and privileging: a Task Force report of the
American Psychiatric Association, 2nd ed. Washington \[DC\]: American
Psychiatric Press, 2001; Available from the [American Psychiatric
Association Web site](http://www.psych.org/clin_res/ect.cfm)).

For information on side effects of antidepressants, see the related
National Guideline Clearinghouse (NGC) summary of the American
Psychiatric Association guideline [Practice Guideline for the Treatment
of Patients With Major Depressive
Disorder](http://www.guideline.gov/summary/summary.aspx?view_id=1&doc_id=2605&nbr=1831).

**Subgroups Most Likely to be Harmed**:

-   Women taking lithium are more likely to experience hypothyroidism
    than men.

-   Patients taking valproate who have had or currently have hepatic
    disease may be at greater risk for hepatotoxicity when taking
    valproate.

-   Elderly patients may be more sensitive to side effects of
    carbamazepine.

-   Patients with a history of seizure disorder or in clinical
    conditions associated with lowered seizure threshold are more likely
    to experience seizures when taking olanzapine.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

This report is not intended to be construed or to serve as a standard of
medical care. Standards of medical care are determined on the basis of
all clinical data available for an individual case and are subject to
change as scientific knowledge and technology advance and practice
patterns evolve. These parameters of practice should be considered
guidelines only. Adherence to them will not ensure a successful outcome
in every case, nor should they be construed as including all proper
methods of care or excluding other acceptable methods of care aimed at
the same results. The ultimate judgment regarding a particular clinical
procedure or treatment plan must be made by the psychiatrist in light of
the clinical data presented by the patient and the diagnostic and
treatment options available.

This practice guideline has been developed by psychiatrists who are in
active clinical practice. In addition, some contributors are primarily
involved in research or other academic endeavors. It is possible that
through such activities some contributors have received income related
to treatments discussed in this guideline. A number of mechanisms are in
place to minimize the potential for producing biased recommendations due
to conflicts of interest. The guideline has been extensively reviewed by
members of American Psychiatric Association as well as by
representatives from related fields. Contributors and reviewers have all
been asked to base their recommendations on an objective evaluation of
available evidence. Any contributor or reviewer who has a potential
conflict of interest that may bias (or appear to bias) his or her work
has been asked to notify the American Psychiatric Association Department
of Quality Improvement and Psychiatric Services. This potential bias is
then discussed with the work group chair and the chair of the Steering
Committee on Practice Guidelines. Further action depends on the
assessment of the potential bias.

The cross-sectional (i.e., current clinical status) and longitudinal
(i.e., frequency, severity, and consequences of past episodes) context
of the treatment decision should guide the psychiatrist and bipolar
disorder patient in choosing from among various possible treatments and
treatment settings. Such treatment decisions must be based on knowledge
of the potential beneficial and adverse effects of available options
along with information about patient preferences. In addition, treatment
decisions should be continually reassessed as new information becomes
available, the patient´s clinical status changes, or both.

**Distinctions in Types of Bipolar Disorder**

Every effort has been made to identify and highlight distinctions
between bipolar I and bipolar II disorder in terms of patient response
to treatment. However, with few exceptions, data from large trials have
been presented in such a way that making such distinctions is difficult.
For the treatment of patients with major depressive disorder, see the
related National Guideline Clearinghouse (NGC) summary of the American
Psychiatric Association guideline [Practice Guideline for the Treatment
of Patients With Major Depressive
Disorder](../../../../../../../../summary/summary.aspx%3Fview_id=1&doc_id=2605&nbr=1831).

**Psychotherapy**

There have been no definitive studies to date of psychotherapy in lieu
of antidepressant treatment for bipolar depression.

**Treatment of Adolescents with Bipolar Disorder**

To date, there has been only one double-blind, placebo-controlled,
randomized study of pharmacotherapy in the treatment of adolescents with
bipolar disorder. The majority of information available about
pharmacological treatments for bipolar disorder in youth relies upon
open studies, case series, and case reports.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

The American Psychiatric Association develops derivative products
including patient guides, quick reference guides, and quality of care
indicators with research studies to evaluate the effectiveness of the
guideline.

#### IMPLEMENTATION TOOLS

Staff Training/Competency Material

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better

#### IOM DOMAIN

Effectiveness\
Patient-centeredness\
Safety

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Practice guideline for the treatment of patients with bipolar disorder
(revision). Am J Psychiatry 2002 Apr;159(4 Suppl):1-50. \[472
references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11958165)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

1994 Dec (revised 2002 Apr; reviewed 2005 Nov)

#### GUIDELINE DEVELOPER(S)

American Psychiatric Association - Medical Specialty Society

#### SOURCE(S) OF FUNDING

American Psychiatric Association (APA)

#### GUIDELINE COMMITTEE

Work Group on Bipolar Disorder

Steering Committee on Practice Guidelines

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Work Group on Bipolar Disorder*: Robert M.A. Hirschfeld, MD, Chair;
Charles L. Bowden, MD; Michael J. Gitlin, MD; Paul E. Keck, MD; Roy H.
Perlis, MD; Trisha Suppes, MD, PhD; Michael E. Thase, MD; Karen D.
Wagner, MD

*Steering Committee on Practice Guidelines*: John S. McIntyre, MD;
Chair; Sara C. Charles, MD; Vice-Chair; Kenneth Z. Altshuler, MD; Ian
Cook, MD; C. Deborah Cross, MD; Barry J. Landau, MD; Louis Alan Moench,
MD; Stuart W. Twemlow, MD; Sherwyn Woods, MD, PhD; Joel Yager, MD

*Consultants and Liaisons*: Paula Clayton, MD (Consultant); Marcia Goin,
MD, PhD (Liaison); Marion Goldstein, MD (Liaison); Sheila Hafter Gray,
MD (Consultant); Andrew J. Kolodny, MD (Liaison); Margaret T. Lin, MD
(Liaison); Grayson Norquist, MD (Consultant); Susan Stabinsky, MD
(Consultant); Robert Johnston, MD (Area I); James Nininger, MD (Area
II); Roger Peele, MD (Area III); Daniel Anzia, MD (Area IV); R. Scott
Benson, MD (Area V); Lawrence Lurie, MD (Area VI); R. Dale Walker, MD
(Area VII)

*Staff*: Rebecca M. Thaler, MPH, CHES, Senior Project Manager; Robert
Kunkle, MA, Project Manager; Althea Simpson, Project Coordinator; Laura
J. Fochtmann, MD, Medical Editor; Claudia Hart, Director, Department of
Quality Improvement and Psychiatric Services; Lloyd I. Sederer, MD,
Director, Division of Clinical Services

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

This practice guideline has been developed by psychiatrists who are in
active clinical practice. In addition, some contributors are primarily
involved in research or other academic endeavors. It is possible that
through such activities many contributors have received income related
to treatments discussed in this guideline. A number of mechanisms are in
place to minimize the potential for producing biased recommendations due
to conflicts of interest. The guideline has been extensively reviewed by
members of American Psychiatric Association (APA) as well as by
representatives from related fields. Contributors and reviewers have all
been asked to base their recommendations on an objective evaluation of
the available evidence. Any contributor or reviewer who has a potential
conflict of interest that may bias (or appear to bias) his or her work
has been asked to notify the APA Office of Research. This potential bias
is then discussed with the work group chair and the chair of the
Steering Committee on Practice Guidelines. Further action depends on the
assessment of the potential bias.

#### GUIDELINE STATUS

According to the guideline developer, this guideline is still considered
to be current as of November 2005. A Guideline Watch, which summarizes
significant developments in practice since the publication of the
original guideline, was published in November 2005 and is available from
the [American Psychiatric Association Web
site](http://www.psych.org/psych_pract/treatg/pg/Bipolar.watch.pdf) (see
also the \"Availability of Companion Documents\" field below).

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the [American Psychiatric Association
Web site](http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm).

Print copies: Available from the American Psychiatric Press, Inc (APPI),
1000 Wilson Boulevard, Suite 1825, Arlington, VA 22209-3901; (703)
907-7322; (800) 368-5777; Fax (703) 907-1091.

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   American Psychiatric Association practice guideline development
    process. In: practice guidelines for the treatment of psychiatric
    disorders: compendium 2000. Washington (DC): American Psychiatric
    Press, Inc (APPI), 2000.

-   Hirschfeld RMA. Guideline watch: practice guideline for the
    treatment of patients with bipolar disorder, 2nd edition. Arlington
    (VA): American Psychiatric Association; 2005 Nov. 9 p. Electronic
    copies available in Portable Document Format (PDF) from the
    [American Psychiatric Association Web
    site](http://www.psych.org/psych_pract/treatg/pg/Bipolar.watch.pdf).

Print copies: Available from the American Psychiatric Press, Inc (APPI),
1000 Wilson Boulevard, Suite 1825, Arlington, VA 22209-3901; (703)
907-7322; (800) 368-5777; Fax (703) 907-1091.

Additionally, a continuing medical education (CME) course is available
online at the [American Psychiatric Association Web
site](http://www.psych.org/cme/apacme/index.cfm).

#### PATIENT RESOURCES

None available

#### NGC STATUS

This summary was completed by ECRI on December 1, 1998. The information
was verified by the guideline developer on January 11, 1999. This
summary was updated by ECRI on April 17, 2002. The information was
verified by the guideline developer on July 24, 2002. This summary was
updated by ECRI on April 21, 2005 following the release of a public
health advisory from the U.S. Food and Drug Administration (FDA)
regarding Trileptal (oxcarbazepine). This summary was updated by ECRI on
August 15, 2005, following the U.S. Food and Drug Administration
advisory on antidepressant medications. This summary was updated by ECRI
on October 3, 2005, following the U.S. Food and Drug Administration
advisory on Paxil (paroxetine). This summary was updated by ECRI on
December 12, 2005, following the U.S. Food and Drug Administration
advisory on Paroxetine HCL - Paxil and generic paroxetine. This summary
was updated by ECRI on January 18, 2006, following the U.S. Food and
Drug Administration advisory on Clozaril (clozapine). This summary was
updated by ECRI on May 31, 2006 following the U.S. Food and Drug
Administration advisory on Paxil (paroxetine hydrochloride). This
summary was updated by ECRI on November 15, 2006, following the FDA
advisory on Lamictal (lamotrigine). This summary was updated by ECRI on
November 21, 2006, following the FDA advisory on Effexor (venlafaxine
HCl). This summary was updated by ECRI Institute on November 2, 2007,
following the U.S. Food and Drug Administration advisory on
Antidepressant drugs. This summary was updated by ECRI Institute on
January 10, 2008, following the U.S. Food and Drug Administration
advisory on Carbamazepine.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions. For further
information please contact the American Psychiatric Association, 1000
Wilson Boulevard, Suite 1825, Arlington, VA 22209-3901; (703) 907-7322.

### DISCLAIMER

#### NGC DISCLAIMER

The National Guideline Clearinghouse™ (NGC) does not develop, produce,
approve, or endorse the guidelines represented on this site.

All guidelines summarized by NGC and hosted on our site are produced
under the auspices of medical specialty societies, relevant professional
associations, public or private organizations, other government
agencies, health care organizations or plans, and similar entities.

Guidelines represented on the NGC Web site are submitted by guideline
developers, and are screened solely to determine that they meet the NGC
Inclusion Criteria which may be found at
<http://www.guideline.gov/about/inclusion.aspx> .

NGC, AHRQ, and its contractor ECRI Institute make no warranties
concerning the content or clinical efficacy or effectiveness of the
clinical practice guidelines and related materials represented on this
site. Moreover, the views and opinions of developers or authors of
guidelines represented on this site do not necessarily state or reflect
those of NGC, AHRQ, or its contractor ECRI Institute, and inclusion or
hosting of guidelines in NGC may not be used for advertising or
commercial endorsement purposes.

Readers with questions regarding guideline content are directed to
contact the guideline developer.

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Date Modified: 11/10/2008