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Treatment by phase: pharmacologic management of bipolar disorder.

Bipolar disorder is a lifelong illness with a broad spectrum of presentations. The overall goals of bipolar disorder treatment are to control acute episodes as quickly as possible, prevent or reduce further episodes, decrease or eliminate inter-episode symptoms, and provide support and education to the patient about management of the disorder. (1) Given the complex nature of bipolar disorder, it is difficult for the patient, who is experiencing depression and mania (sometimes concurrently), to manage and control the illness without the help of a strong and supportive therapeutic alliance. (2)

Pharmacologic therapy

The primary goal of pharmacologic treatment for bipolar disorder is mood stabilization. Drugs usually considered mood stabilizers include lithium and the anticonvulsants carbamazepine, valproic acid, and, more recently, lamotrigine; increasingly, second-generation antipsychotics (SGAs) are being prescribed for this purpose. First-generation antipsychotics may be effective primarily for mania but are not as well tolerated as the SGAs, and some studies suggest that they may exacerbate depressive symptoms. (3)

An ideal mood stabilizer would alleviate acute manic, mixed, and depressive symptoms; not induce the alternate mood symptoms; and prevent relapses into manic, mixed, or depressive episodes--all without causing significant side effects or toxicity. In reality, this is rarely accomplished by one medication alone. Successful treatment of bipolar disorder often requires use of either different drugs for different phases of the illness or a combination regimen. In one study of a voluntary registry of 457 patients with bipolar disorder, less than 20% of the group was receiving monotherapy for the disease. Half of those who were on a combination regimen were taking 3 or more medications, and almost one quarter of the patients in the survey were taking 4 or more drugs for their illness. (4)

Managing bipolar disorder is something of a balancing act. It is important to effectively treat acute episodes and current mood symptoms, and it is also essential to keep in mind the chronic and cyclical nature of the disease. (2) TABLE 1 lists medications currently approved by the US Food and Drug Administration (FDA) for treatment of the different phases of bipolar disorder.

The depressive phase

The issue of controlling the acute symptoms of a bipolar mood episode while also considering long-term management is particularly pronounced in the depressive phase of the illness, in which patients tend to spend a majority of time. (5) As mentioned previously, patients in the depressive phase of bipolar disorder are frequently misdiagnosed as having unipolar depression, an error that can have unwanted clinical consequences because the recommended treatments for the 2 disorders are substantially different. (6)

Antidepressants for unipolar depression may not be effective for the depressive symptoms of bipolar disorder. In a recent study by Sachs et al that is part of the Systemic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a large effectiveness trial funded by the National Institute of Mental Health, adjunctive antidepressant therapy did not significantly improve depressive symptoms of bipolar depression compared with mood stabilizers alone. (7) Furthermore, some studies have suggested that antidepressants can hasten manic episodes and contribute to rapid cycling in patients with bipolar disorder, although the findings of Sachs et al do not support this when antidepressants are used in conjunction with mood stabilizers. In addition, 2 European reviews have reported that patients with bipolar depression responded favorably to antidepressant therapy. (2,8,9) Still, it is considered prudent to prescribe an antidepressant for a patient with bipolar disorder only when other treatment strategies have failed and the benefits are determined to outweigh the risks. It is worth noting that, according to a small study by Altshuler et al, there may be a subset of patients for whom ongoing antidepressant use--together with a mood stabilizer regimen--is effective, does not precipitate mania, and conveys some protection against another depressive episode. (10) However, continued antidepressant efficacy in bipolar depression remains controversial and is considered by many to be unproven, especially in light of the longer-term risk of worsening cycling. It is generally recommended, therefore, that antidepressants be tapered and discontinued once bipolar depression is controlled. (2) Despite these recommendations, antidepressants are one of the most commonly prescribed classes of drugs for bipolar disorder in the United States. (11)

Traditional mood stabilizers have been shown to have only limited efficacy in the depressive phase of bipolar disorder. Lithium, for example, is somewhat effective, but its time to onset during bipolar depression is 6 to 8 weeks, and the response is less robust than that seen during mania. (1) Lamotrigine has been shown to be effective in both preventing and treating depressive episodes, and it has been recommended as first-line therapy for this phase of the disease. (12-15)

Important new options for treating bipolar depression are emerging from among the SGAs. Currently, quetiapine and an olanzapine/fluoxetine combination are the only medications with FDA approval for the treatment of patients with bipolar depression (TABLE 1). In placebo-controlled trials, both regimens have shown significant efficacy in improving depressive symptoms in patients in this phase of the disorder. Patients treated with the olanzapine/fluoxetine combination showed improvement compared with those taking placebo, starting at week 1 and continuing through the 8-week end point. Patients who received olanzapine alone also showed greater improvement than did those who received placebo during all 8 study weeks, but the response for olanzapine alone was numerically more modest than for the combination regimen. (16) Quetiapine at 300 and 600 mg/d was studied in patients with bipolar I and bipolar II depression in an 8-week, double-blind, placebo-controlled study. At both doses, quetiapine was superior to placebo from baseline through week 8, and these findings have recently been replicated. (17,18)

Two recent studies of aripiprazole showed that when the drug was administered as monotherapy (10 mg/day titrated to 5-30 mg/day) to patients with bipolar I disorder who were having a major depressive episode, it was no more effective than placebo, (19) Ziprasidone is under investigation by its manufacturer to determine whether clinical experience, case reports, and open-label work that suggest efficacy in bipolar depression can be reproduced in more stringent, blinded, multicenter trials.

The manic phase

The effectiveness of lithium in the manic phase of bipolar disorder has been documented over more than 50 years of testing. The use of valproate and carbamazepine is also supported by some 20 years of clinical study, (20) More recently, the SGAs have proven to be effective for treating the manic phase of this disorder. Aripiprazole, olanzapine, quetiapine, risperidone, and ziprasidone are FDA-approved for the treatment of bipolar manic episodes. All 5 medications have shown efficacy in treating acute manic episodes compared with placebo; however, their times to first separation from placebo range from 2 to 7 days. TABLE 2 presents each medication's earliest day of significant separation from placebo, measured in controlled studies. (21-31)

In cases of severe mania, it is often recommended that a combination of an antipsychotic with either lithium or valproate be used. (1) Benzodiazepines, while not thought to have an antimanic effect, can be a useful addition in the treatment of mania by providing extra sedation, restoring sleep patterns, and easing anxiety. (1,3)

Mixed episodes

Acute mood episodes that include significant symptoms of both depression and mania are categorized as mixed episodes. (32) These episodes are difficult to identify and present a particular challenge to both primary care providers (PCPs) and psychiatric clinicians. PCPs sometimes refer patients experiencing mixed episodes to psychiatrists for "treatment-refractory depression," as they do not always recognize these patients as having bipolar disorder.

Mixed states are common, troublesome, and underdiagnosed, and present unique treatment concerns. It is estimated that approximately 33% to 40% of patients with bipolar disorder experience mixed states. (33) Clinicians usually are able to identify depressive symptoms far more readily than manic symptoms in patients with bipolar disorder, but screening for both hypomania and mania, especially in the context of a depressed episode, is an important step in distinguishing mixed mood from pure depression. (2) Even when properly diagnosed and treated, patients who experience mixed episodes tend to have a slower recovery time and a shorter time to relapse than do patients with pure manic or depressive episodes. (33) For example, in a 5-year prospective study, median time to recovery for mixed episodes or rapid cycling episodes was 17 weeks, compared with 6 weeks for manic episodes and 11 weeks for depressive episodes. (34) The cumulative probability of relapse at 6 months after the first episode was 36% for patients with mixed episodes or rapid cycling, 20% for patients whose last episode was manic, and 33% for patients with depressive episodes. (34)

Patients who experience mixed episodes also have higher rates of both suicidality and substance abuse. For instance, in a pooled study of more than 500 patients with bipolar or other major affective disorders who had a history of at least 1 hospitalization,29.2% of patients with mixed episodes had had a recent suicide attempt, compared with 20.3% of patients with a depressive episode and 2% of manic patients (a statistically significant difference). (35) In addition, an incidence of substance abuse was observed in 38.2% of patients with mostly mixed episodes, compared with 30.3% in the rest of the bipolar population. (35)

Patients with mixed episodes respond more slowly to and experience less improvement with lithium than do patients experiencing pure mania). (3) Anticonvulsants such as valproate may be more effective than lithium for the treatment of mixed states. (1,33) Recent efforts to identify other treatment options that will rapidly relieve both the manic and the depressive symptoms of mixed episodes have led to the increased use of SGAs in this context. (33) As with mania, rapid control of mixed states is an important objective.

Treatment issues when psychotic symptoms are present

Psychotic features most frequently appear in manic episodes of bipolar disorder but may occur during any phase. More than half of manic episodes have psychotic features, and as many as 58% of patients with bipolar disorder have experienced at least 1 psychotic episode. (1,36) Psychotic symptoms that typically occur in bipolar disorder are grandiose delusions, such as an unrealistically inflated sense of worth, power, or knowledge, and depressive delusions, such as personal inadequacy and disease, paranoid and bizarre delusions, and hallucinations. Patients who experience psychotic symptoms during an acute episode may benefit from the use of an antipsychotic agent. (1)

Maintenance therapy

According to expert consensus guidelines, once an acute episode has been identified and controlled, the same medication should be continued at the same dose that achieved remission. (14) After a depressive episode, any antidepressants being used as adjunctive therapy should be tapered and discontinued when possible. (14)

Key points in the overall pharmacologic management of bipolar disorder

Several organizations publish treatment and medication algorithms for bipolar disorder (TABLE 3). (1,14,15,32,37) Thus, even if the first medication or dosage prescribed for a particular patient is not effective, there are many pharmacologic options and steps in the management of bipolar disorder. (38) Important management components to keep in mind are medication adherence, level of response to the treatment regimen, and possible adverse reactions.

Before changing therapies for a nonresponsive patient, the clinician must ensure that medications are being taken as directed. Nonadherence is high among patients with bipolar disorder, who have long periods of normal functioning and may be in denial about their illness. Patients with only hypomanic symptomatology may not consider their symptoms problematic, and those with mania may be reluctant to give up the euphoric feelings and high self-esteem that can come with it. (1) Thus, follow-up and patient education about medication adherence are vital.

If the patient is following medication schedules and directions correctly but improvement is still insufficient, optimizing dosing is the next step in pharmacologic management. TABLE 4 gives the recommended dosages of agents for various phases of bipolar disorder.

If response is still less than optimal, treatments may be switched or augmented. It is important during this process to keep patients hopeful, for example, by informing them that if they have not responded to a certain class of drugs, they may be more likely to respond to a different class. (38)

Most of the traditional mood stabilizers used for bipolar disorder can cause significant side effects; thus, periodic patient monitoring is crucial during long-term treatment. Interactions with other psychiatric and nonpsychiatric medications may push a mood stabilizer into either a subtherapeutic or a toxic range, and the consequences of overdosage can be serious and even lethal. (1) Therefore, serum levels of lithium, valproate, and carbamazepine should be checked regularly and dosages adjusted accordingly to ensure that they are in the therapeutic range. (20) Lithium treatment has been associated with weight gain and thyroid toxicity, (39) and renal and thyroid function should be checked every 6 months to 1 year during treatment. (1,39) Side effects of valproate can include transaminase elevations, hepatic failure (in pediatric patients), and, rarely, thrombocytopenia; while not required, it is recommended that tests of hematologic and hepatic function be performed every 6 months during valproate treatment. (1) Treatment with carbamazepine calls for complete blood cell counts, platelet measurements, and liver function tests every 2 weeks for the first 2 months of treatment. Thereafter, if laboratory results are normal, blood cell counts and liver function tests should be performed every 3 months. (1) Carbamazepine may decrease levels of valproate, lamotrigine, oral contraceptives, protease inhibitors, benzodiazepines, and certain antipsychotics and antidepressants; monitoring of serum levels of these drugs is, thus, required during carbamazepine therapy. (1)

After reviewing data on the metabolic implications of SGAs, the American Diabetes Association (ADA) and the American Psychiatric Association (APA) issued a joint consensus statement concluding that clozapine and olanzapine have a pronounced risk of metabolic syndrome, risperidone and quetiapine exhibit discrepancies in the data, and aripiprazole and ziprasidone show minimal impact on metabolic indices (TABLE 5). (40) The organizations nevertheless advocate that a patient taking any SGA be monitored for metabolic syndrome upon initiation of treatment and then periodically, as shown in TABLE 6. (40) An individual patient with an elevated level of risk may require more frequent monitoring. (40)

If a patient's metabolic condition deteriorates due to medication (eg, weight gain >5%, increased glycemia, or dyslipidemia), the ADA/APA consensus statement recommends switching to an SGA with a more favorable metabolic profile, thus reinforcing the importance of considering the overall health needs of a patient when choosing a treatment approach. (40) However, because antipsychotics are very different medications with distinctive receptor profiles, changing from one to another can be problematic. Therefore, it is prudent to follow a protocol for switching, such as the gradual approach recommended by the ADA/ APA consensus statement. It calls for cross-titration, avoidance of abrupt discontinuation of the current drug, and dosage determined by the profile of the new drug. (40) Also, there are times when switching may not be appropriate. For example, if the drug causing the metabolic problem is the only one to which the patient has responded clinically, efforts should be made to maintain symptom control and address metabolic concerns.

Beyond pharmacotherapy

Psychotherapy is another important component of bipolar treatment. Studies of several psychotherapeutic models have shown that family-focused, cognitive, psychoeducational, and interpersonal social rhythm therapies--which combines interpersonal therapy with simple techniques to help the patient follow daily routines--can all be effective in treating bipolar disorder. (1,41,42) These interventions allow for dialogue about ongoing disease management, educate the patient about medications and the need for adherence, and provide information about the importance of sticking to a routine and getting enough sleep. (11)

Psychotherapy can increase medication adherence, reduce relapse rates, shorten recovery times from depression, and improve overall patient functioning. (11) Although the best setting for psychotherapy is the office of a psychiatrist or psychologist (ideally one experienced in the treatment of bipolar disorder), the patient can benefit greatly if the PCP incorporates the messages from psychotherapy at key junctures during primary care visits. (41)

An especially important tool is daily mood charting, which enables the patient and the physician together to recognize subtle mood changes and symptoms, identify possible triggers and warning signs that might herald an acute episode, and graphically and efficiently monitor treatment response. Mood charts (available, for example, from html#) can provide the clinician with important and accurate information about a patient's disease course. (2,11)

A strong collaborative team that includes both the psychiatrist and the PCP is also needed to optimally address the psychiatric and medical comorbidities that occur in up to 70% of patients with bipolar disorder. (6) A particularly prevalent comorbidity in this patient population is obesity. In one multicenter study, 45% of patients with bipolar disorder were considered obese (based on body mass index) compared with 30.5% of the general population. (43) Obesity is a risk factor for many medical conditions, including diabetes and cardiovascular disease. In addition, obese patients can have significantly shorter times to recurrence of depressive episodes, more acute episodes over their lifetime (both manic and depressive), and more severe and difficult-to-treat index episodes. (44) It is important to keep in mind that many medications for bipolar disorder--including lithium, valproate, and many of the SGAs--are associated with weight gain. (40,45)

The prevalence of smoking (another risk factor for cardiovascular disease) is also high in the bipolar population: an estimated 54% to 68% compared with 21.5% in the general population. (46,47) Obesity and smoking are considered modifiable risk factors for cardiovascular disease and represent a target for intervention with exercise, nutrition, and lifestyle counseling. (43)


Optimal management of bipolar disorder involves maximizing patient functioning in both the short and the long term. Together with psychosocial interventions, today's pharmacologic treatment options for bipolar disorder offer greater possibilities for successful outcomes for these patients than ever before.


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Medications approved by the FDA for
the treatment of bipolar disorder

Phase                Medications

Depressive           Olanzapine/fluoxetine

Maintenance          Aripiprazole

Manic                Aripiprazole
                     Carbamazepine ER
                     Divalproex ER

Mixed                Aripiprazole
                     Carbamazepine ER
                     Divalproex ER

Manic and mixed      Aripiprazole
episodes with or     Divalproex ER
without psychotic    Olanzapine
symptoms             Risperidone

FDA, US Food and Drug Administration

Source: Manufacturers' US prescribing information for drugs listed.

Time to onset of effect of second-generation
antipsychotics in bipolar mania

                                  Onset of Effect *

                                              First Significant
Oral Medication    First Assessment           Separation from Placebo

Ziprasidone        Day 2 (21,22)              Day 2 (21,22)
Aripiprazole       Day 2 (23) or 4 (24)       Day 4 (23,24)
Risperidone        Day 3 (25,26) or 7 (27)    Day 3 (25) or 7 (26,27)
Olanzapine         Day 7 (28,29)              Day 7 (29) or 21 (28)
Quetiapine         Day 4 (30,31)              Day 4 (31) or 7 (30)

This table is not derived from head-to-head studies. It is derived from
the pivotal studies accepted by the US Food and Drug Administration in
support of the indication.

* Studies assessed first significant separation from placebo at
different days.


Guidelines and algorithms for
bipolar disorder treatment

American Psychiatric Association Practice Guideline for
Bipolar Disorder (1)

* Comprehensive

* For all aspects of treatment

Expert Consensus Guideline for Bipolar Disorder (14)

* Developed by an independent group of psychiatrists

* Focused primarily on psychopharmacology

* Survey of experts

Texas Implementation of Medication Algorithms for
Bipolar Disorder (15)

* Flowcharts as treatment algorithms for medication

Mt. Sinai Guidelines (37)

* Physical health monitoring of patients taking

Diagnostic and Statistical Manual of Mental Disorders,
Fourth Edition, Text Revision (DSM-IV-TR[R]) (32)

* Decision tree for differential diagnosis of mood
disorders, including bipolar disorder

Recommended dosage and administration of FDA-approved bipolar

Medication      Bipolar Depression               Continuation

Olanzapine/     * Take with or without food:     NA
fluoxetine      initiate 6 mg/25 mg capsule;
                adjust to optimal clinical
                response [less than or
                equal to] 18 mg/75 mg
                (once daily pm)

Quetiapine      * Take with or without food:     NA
                initiate 50 mg/d; adjust daily
                to reach 300 mg/d on day 4
                (once daily pm)

Divalproex      NA                               NA

Divalproex      NA                               NA

Lamotrigine     NA                               * Take with or without
                                                 food: escalate slowly;
                                                 target dose for mono-
                                                 therapy is 200 mg/d;
                                                 adjust downward or
                                                 upward during coad-
                                                 ministration with
                                                 other drugs; thera-
                                                 peutic plasma concen-
                                                 tration not estab-
                                                 lished; read pres
                                                 cribing infor-
                                                 mation carefully

Lithium         NA                               * Usually 900 to
                                                 1200 mg/d bid, tid or
                                                 qid; dosage must be
                                                 individualized and
                                                 serum levels monitored
                                                 at 1- or 2-week
                                                 intervals to
                                                 maintain optimal
                                                 clinical response
                                                 between 0.6
                                                 and 1.2 mEq/L;
                                                 during uncomplicated
                                                 remission, monitor
                                                 every 2 months

Aripiprazole    NA                               * Take once daily
                                                 with or without food:
                                                 15 or 30 mg/d in
                                                 patients whose acute
                                                 symptoms have been on
                                                 stabilized aripip-

Olanzapine      NA                               * Take once daily with
                                                 or without food: 5-20
                                                 mg/d in patients whose
                                                 acute symptoms have
                                                 been stabilized on

Carbamazepine   NA                               NA

Risperidone     NA                               NA

Ziprasidone     NA                               NA

Medication      Mania                            Mixed Episodes

Olanzapine/     NA                               NA

Quetiapine      * Take with or without           NA
                food: initiate 100 mg/d;
                adjust by 100 mg/d
                (max 400 mg/d on day
                4) and then by 200 mg/d
                (max 800 mg/d on day
                6) to optimal clinical
                response 400 to 800
                mg/d (divided dose)

Divalproex      * Take with food: initiate       NA
                750 mg/d (divided
                dose); adjust to optimal
                clinical response [less than
                or equal to] 60 mg/kg/d

Divalproex      * Take with food: initiate       * Take with food:
ER              25 mg/kg/d; adjust to            initiate 25 mg/kg/d;
                optimal clinical response        adjust to optimal
                [less than or equal to] 60       clinical re-
                mg/kg/d (once daily)             sponse [less than or
                                                 equal to] 60 mg/kg/d
                                                 (once daily)

Lamotrigine     NA                               NA

Lithium         * Usually 1800 mg/d in           NA
                divided doses; dosage
                must be individualized
                and serum levels
                monitored twice weekly
                until stabilized to optimal
                clinical response between
                1.0 and 1.5 mEq/L

Aripiprazole    * Take with or without food:     * Take with or without
                initiate 30 mg/d oral            food: initiate 30 mg/d
                tablets, 25 mg/d oral            oral tablets, 25 mg/d
                solution; may decrease           oral solution; may
                to 15 mg/d if not well           decrease to 15 mg/d if
                tolerated (once daily)           not well tolerated
                                                 (once daily)

Olanzapine      * Take with or without food:     * Take with or without
                initiate 10 to 15 mg/d;          food: initiate 10 to
                adjust by 5 mg/d to              15 mg/d; adjust by 5
                optimal clinical response        mg/d to optimal
                [less than or equal to] 20       clinical response
                mg/d (once daily)                [less than or equal
                                                 to] 20 mg/d (once

Carbamazepine   * Take with or without food:     * Take with or without
ER              initiate 400 mg/d; adjust        food: initiate 400
                by 200 mg/d to optimal           mg/d; adjust by 200
                clinical response [less          mg/d to optimal
                than or equal to] 1600           clinical response
                mg/d (divided dose)              [less than or equal
                                                 to] 1600 mg/d
                                                 (divided dose)

Risperidone     * Take with or without food:     * Take with or without
                initiate 2 to 3 mg/d; adjust     food: initiate 2 to 3
                by 1 mg/d to optimal             mg/d; adjust by 1 mg/d
                clinical response [less t        to optimal clinical
                han or equal to] 6 mg/d          response [less than or
                (once daily)                     equal to] 6 mg/d (once

Ziprasidone     * Take with food: initiate       * Take with food:
                80 mg/d; target 120 to           initiate 80 mg/d;
                160 mg/d by day 2                target 120 to 160
                (divided dose)                   mg/d by day 2 (divided
                NOTE: Absorption                 dose). Absorption
                doubles when taken               doubles when taken
                with food                        with food

NA. not applicable

Source: US Food and Drug Administration; Manufacturers' US prescribing
information for drugs listed.


Metabolic effects of
second-generation antipsychotics

                  Weight       Risk for     Worsening
Drug              Gain         Diabetes     Lipid Profile
Clozapine         +++          +            +
Olanzapine        +++          +            +
Risperidone       ++           D            D
Quetiapine        ++           D            D
Aripiprazole      +/-          -            -
Ziprasidone       +/-          -            -

+= increase effect; -= no effect; D = discrepant results

Copyright [C] 2004 American Diabetes Association.
From Diabetes Care[R], Vol. 27, 2004; 596-601.

Reprinted with permission from the American Diabetes Association

Monitoring schedule for patients taking second-generation antipsychotics

Assessment                   Start     4 Weeks     3 Weeks    12 Weeks

Personal/family history        X
Weight (BMI)                   X          X           X          X
Waist circumference            X
Blood pressure                 X                                 X
Fasting glucose                X                                 X
Fasting lipid profile          X                                 X

Assessment                  3 Month    Annually    5 Years

Personal/family history                   X
Weight (BMI)                   X
Waist circumference                       X
Blood pressure                            X
Fasting glucose                           X
Fasting lipid profile                                 X

BMI, body mass index.

Copyright [C] 2004 American Diabetes Association, Joint Consensus
Statement from Diabetes Care[R], Vol. 27. 2004; 596-601. Reprinted with
permission from the American Diabetes Association.
COPYRIGHT 2007 Quadrant Healthcom, Inc.
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2007 Gale, Cengage Learning. All rights reserved.

Article Details
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Title Annotation:PART 4
Publication:Journal of Family Practice
Article Type:Clinical report
Geographic Code:1USA
Date:Nov 1, 2007
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