Treatment by phase: pharmacologic management of bipolar disorder.
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)
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)
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.
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 http://www.manicdepressive.org/moodchart. 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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TABLE 1 Medications approved by the FDA for the treatment of bipolar disorder Phase Medications Depressive Olanzapine/fluoxetine Quetiapine Maintenance Aripiprazole Lamotrigine Lithium Olanzapine Manic Aripiprazole Carbamazepine ER Chlorpromazine Divalproex ER Divalproex Lithium Olanzapine Quetiapine Risperidone Ziprasidone Mixed Aripiprazole Carbamazepine ER Divalproex ER Olanzapine Risperidone Ziprasidone Manic and mixed Aripiprazole episodes with or Divalproex ER without psychotic Olanzapine symptoms Risperidone Ziprasidone FDA, US Food and Drug Administration Source: Manufacturers' US prescribing information for drugs listed. TABLE 2 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. TABLE 3 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 management Mt. Sinai Guidelines (37) * Physical health monitoring of patients taking antipsychotics 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 TABLE 4 Recommended dosage and administration of FDA-approved bipolar medications Maintenance/ 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 ER 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- razole Olanzapine NA * Take once daily with or without food: 5-20 mg/d in patients whose acute symptoms have been stabilized on olanzapine Carbamazepine NA NA ER Risperidone NA NA Ziprasidone NA NA Medication Mania Mixed Episodes Olanzapine/ NA NA fluoxetine 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 daily) 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 daily) 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. TABLE 5 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 TABLE 6 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.
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|Title Annotation:||PART 4|
|Publication:||Journal of Family Practice|
|Article Type:||Clinical report|
|Date:||Nov 1, 2007|
|Previous Article:||Clinical management of bipolar disorder: role of the primary care provider.|
|Next Article:||Recognizing bipolar disorder on initial presentation: a case study with decision points.|