Bipolar disorder, sometimes called manicdepressive

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1 XXASIN_2_4_p151_157 10/25/04 3:45 PM Page 151 ROLE OF ANTIPSYCHOTIC MEDICATIONS IN TREATING BIPOLAR DISORDER * Mary Jane Strong, APRN, MS, CS ABSTRACT Although no cure exists for bipolar disorder, treatment can decrease the associated morbidity and mortality. Nursing goals for patients experiencing a manic or mixed episode initially include injury prevention, maintenance of a safe environment, and patient assistance to meet basic needs and subsequently a return to normal levels of psychosocial functioning. Effective use of medications often in combination with psychotherapy enables most patients with manic depression to lead essentially normal lives. This article offers an overview of the role of antipsychotic medications in achieving this long-term goal and reviews indications for switching therapies. (Adv Stud Nurs. 2004;2(4): ) *Based on a presentation given by Ms Strong at a symposium held in conjunction with the 17th Annual Meeting of the American Psychiatric Nurses Association. Program Director, Psychiatric Clinical Research Center, University of Illinois Medical Center, Chicago, Illinois. Address correspondence to: Mary Jane Strong, APRN, MS, CS, Rush University Medical Center, Psychiatric Clinical Research Center, 1720 W Polk St, Chicago, IL jane_strong@rush.edu. Bipolar disorder, sometimes called manicdepressive order, is characterized during the mania phase primarily by an abnormally and persistently elevated, expansive, or irritable mood lasting for at least 1 week. Like depression, mania can vary in intensity. Episodes can range from moderate to severe manic states with psychotic features and suicidal ideation. 1 The wide variety of clinical presentations of this disorder make it particularly challenging for nurse clinicians to diagnose, assess, and intervene (Table 1). 2 According to conservative estimates, bipolar disorder/mania affects patients of both sexes across all cultures and ethnic backgrounds at the same rate: approximately 0.8% of the adult population, with estimates from community samples ranging between 0.4% and 1.6%. Although there is no cure for bipolar disorder, treatment can decrease the associated morbidity and mortality, and dedicated psychiatric nursing can make it possible for these patients to resume normal and fulfilling lives. Initially, the clinician should perform a diagnostic evaluation and assess the patient s safety and level of functioning in order to decide the optimum treatment setting. 3 Careful assessment of the patient s risk for suicide is critical; lifetime rates of completed suicide for individuals with bipolar disorder are as high as 10% to 15%. 3 Initial nursing goals include preventing injury, maintaining a safe environment, and meeting the patient s basic physiologic needs. The rapid control of agitation, aggression, and impulsivity is particularly important to ensure the safety of patients and of those around them (Table 2). 4 When the patient s agitation has subsided, the focus then is on achieving long-term goals for management Advanced Studies in Nursing 151

2 XXASIN_2_4_p151_157 10/25/04 3:45 PM Page 152 of this lifelong disorder. The American Psychiatric Association offers several strategies for long-term management, including establishing and maintaining a therapeutic alliance, monitoring treatment response, educating patients and their families, enhancing treatment compliance, and evaluating and managing functional impairments (see Sidebar on page 156). 5 APPROACHES TO TREATMENT Although no cure exists for bipolar disorder, treatment can decrease the associated morbidity and mortality. The primary goal of treatment for patients experiencing a manic or mixed episode is to control symptoms so patients can return to normal levels of psychosocial functioning. Effective use of medications, often in combination with psychotherapy, allows 75% to 80% of patients with manic depression to lead essentially normal lives. 2 Lithium, valproate, and antipsychotic medications have shown efficacy in the treatment of acute mania, although the time to onset of action for lithium may be somewhat slower than that for valproate or antipsychotics. 3 The evolution of therapies for treatment of acute mania and hypomania is presented in Figure 1. 6,7 Despite their widespread use, lithium and anticonvulsant therapies have not been extensively evaluated in bipolar disorder within the setting of controlled clinical trials. 8 Lithium and divalproex, however, are approved by the US Food and Drug Administration (FDA) for treatment of bipolar disorder. Among antipsychotic therapies, chlorpromazine, olanzapine, quetiapine, and risperidone are approved for the treatment of acute mania, and the FDA is currently reviewing other antipsychotic agents for use in bipolar disorder. These efforts to expand the current list of drug choices continue for many of the same reasons clinicians seek to expand the armamentarium for schizophrenia: atypical antipsychotic agents have been shown to reduce risks of extrapyramidal side effects (EPS), prolactin elevation, and tardive dyskinesia 6 while improving depressive symptoms. 7 For these reasons, the American Psychiatric Association recommends treatment with an atypical psychiatric medication during a manic or mixed episode. 5 Table 1. Behaviors Associated with Mania Affective Physiologic Cognitive Behavioral Elation or euphoria Dehydration Ambitiousness Aggressiveness Expansiveness Inadequate nutrition Denial of realistic Excessive spending Humorousness Needs little sleep danger Grandiose acts Inflated self-esteem Weight loss Distractibility Hyperactivity Intolerance of Flight of ideas Increased motor criticism Grandiosity activity Lack of shame or Illusions Irresponsibility guilt Lack of judgment Irritability or Loose associations argumentativeness Poor personal grooming Sexual overactivity Social activity Verbosity Reproduced with permission from Stuart GW. Emotional responses and mood disorders. In: Stuart GW, Laraia MT, eds. Principles and Practice of Psychiatric Nursing. 7th ed. St. Louis, Mo: Mosby, Inc; 2001: Table 2. Risk Factors and Nursing Interventions for Other- Directed Violence Risk Factors Restlessness Hyperactivity Agitation Hostile behavior Threatened or actual aggression toward self or others Low self-esteem Nursing Interventions Provide a safe environment Decrease environmental stimuli Administer drug therapy Provide a consistent, structured environment; set goals with the patient as soon as possible Give simple, direct explanations for routine actions, procedures, tests, etc. Do not argue with the patient Encourage the patient to verbalize feelings of anxiety, anger, or fear. Explore ways to relieve stress and tension with the patient as soon as possible. Encourage supervised physical activity Adapted with permission from Schultz et al. Lippincott s Manual of Psychiatric Nursing Care Plans. 6th ed. Philadelphia, Pa: Lipincott Williams & Wilkins; Vol. 2, No. 4 October 2004

3 XXASIN_2_4_p151_157 10/25/04 3:45 PM Page 153 Risperidone was approved by the FDA in December 2003 as monotherapy or combination therapy (with lithium or valproate) for the treatment of acute manic or mixed episodes. Several studies support this indication. Hirschfeld and colleagues reported significant improvements in Young Mania Rating Scale (YMRS) scores at day 3 and at each subsequent time point. 9 After 3 weeks of treatment, the YMRS score was reduced by 5 points in patients taking placebo versus 11 points in those patients taking risperidone (P <.001). Vieta and colleagues showed a surprising 73% response versus 36% with placebo. 10 Six controlled studies showed olanzapine to be effective, with some studies using placebo for control and others using more conventional therapies, such as haloperidol and divalproex One study showed a 68% response rate to olanzapine with a therapeutic dose of only 10 mg at the study s completion. 13 A summary of study findings regarding the efficacy of olanzapine for the treatment of acute mania is shown in Figure 2. Recent clinical research has also shown ziprasidone to be effective in half of the 216 subjects participating in a double-blind clinical trial. 17 In a study of combination therapy using quetiapine as adjunctive therapy with divalproex, a remarkable 87% response rate was reported in an adolescent population. 18 Efficacy was somewhat less pronounced in adults but nonetheless significant, with 53% of patients responding to this drug combination. 19 Aripiprazole has been shown in large-scale studies to achieve a response comparable to other atypical antipsychotic drugs (40% 20 ; 50% and 51% 21 ). The remarkable findings were that positive results were reported as soon as 4 days after initiation of therapy (Figure 3). 20,21 Psychiatric nurses with inpatient experience recognize the importance of obtaining immediate results for patients with acute mania, so this rapid onset of action is a significant finding. By day 10, a near-full response was reported and was sustained until the study s completion at week 3. 20,21 The safety profile for aripiprazole as reported in the studies for acute mania was, not surprisingly, similar to that reported in studies for schizophrenia: patients showed little weight gain and a decrease in prolactin levels. EPS were comparable to those seen with placebo; however, slight elevations in akathisia and insomnia have also been reported. In summary, aripiprazole has proven efficacy in acute mania in 2 placebo-controlled studies and in 1 study in which haloperidol was used as the control. This treatment has a demonstrated rapid onset of action, Figure 1.The Evolution of Therapies for Acute Mania/Hypomania *Approved for use for acute mania. ECT = electroconvulsive therapy. Data from Nemeroff 6 ; McElroy et al. 7 Figure 2. Efficacy of Olanzapine Monotherapy: Improvement in Mania Ratings Across Studies *Zajecka et al used the Schedule for Affective Disorders and Schizophrenia Change Version derived for mania ratings; other studies used the Young Mania Rating Scale. NS = not significant. Data from Tohen M et al 11,12,14 ; Zajecka et al. 15 Advanced Studies in Nursing 153

4 XXASIN_2_4_p151_157 10/25/04 3:45 PM Page 154 showing clinically meaningful improvement in symptoms based on YMRS findings with a favorable safety and tolerability profile in patients with bipolar disorder. SWITCHING ANTIPSYCHOTIC AGENTS Because there is no cure for bipolar disorder, most patients require lifelong medication. At some point during the course of a patient s treatment, the nurse clinician may consider questions about the patient s drug therapy. Is the patient still experiencing problematic symptoms? Are the medication s adverse effects jeopardizing the patient s physical health and/or significantly compromising quality of life? Is the patient able to follow the treatment regimen? Could the patient achieve better results with a different drug? Can a different medication achieve more of the therapeutic goals? These are questions to address with the patient and the family. When the clinician is considering a change in the patient s antipsychotic therapy, a structured clinician and patient worksheet may help to guide the discussion and the timing of the decision. Sometimes patients will decide for themselves that a medication is no longer tolerable by simply refusing to take it. Indications for switching antipsychotics from the perspective of the clinician, the patient, and the family are shown in Table Figure 3. Aripiprazole in Acute Mania: Mean Change in YMRS from Baseline *P <.01 vs placebo; last observation carried forward. YMRS = Young Mania Rating Scale. Data from Keck et al. 20 Table 3. Indications for Switching Antipsychotics from the Perspective of the Clinician, the Patient, and the Family* Clinician s Perspective Patient s Perspective Family s Perspective Persistent positive symptoms Distress from positive symptoms Disruptiveness and agitation Secondary anxiety and depression from positive symptoms Emotional and financial burden of caregiver role Persistent negative symptoms Inability to meet life s goals Dealing with multiple crises and setbacks Inability to function independently in community Persistent EPS and/or Dysphoria or distress from EPS Heartbreak of seeing loved one burdened by tardive dyskinesia akathisia or tardive dyskinesia Hyperprolactinemia Annoyance from increased complexity of regimen and Disappointment or frustration of sexual partner (galactorrhea and amenorrhea side effects from addition of anticholinergic medications in women, gynecomastia Disruption of self-image and self-esteem due to disturbances and impotence in men) in reproductive function *Assumes the patient is taking therapeutic doses of a conventional antipsychotic and that persistent symptoms are not attributable to compliance problems and/or substance abuse. Assumes the patient is taking treatment with optimal doses of a conventional antipsychotic and unsuccessfully attempted treatment with anti-parkinson or antiakathisia agents. EPS = extrapyramidal symptoms. Adapted with permission from Weiden et al. Switching antipsychotic medications. J Clin Psychiatry. 1997;58(suppl 10): Copyright 1997 Physicians Postgraduate Press Vol. 2, No. 4 October 2004

5 XXASIN_2_4_p151_157 10/25/04 3:45 PM Page 155 Figure 4. Algorithm for Mania/Hypomania* The rapid control of agitation, aggression, and impulsivity is particularly important to ensure the safety of patients and those around them. Once the patient s agitation has subsided, the focus becomes one of achieving longer-term goals for management of this lifelong disorder. *Aripiprazole was added to the list of atypical antipsychotics as this algorithm predates availability of this agent. Li = lithium; AC = anticonvulsant; DVP = divalproex; LTG = lamotrigine; OXC = oxcarbazepine; TPM = topiramate; AAP = antipsychotic; OLZ = olanzapine; RIS = risperidone; QTP = quetiapine; ZIP = ziprasidone; ARI = aripiprazole; ECT = electroconvulsive therapy. Adapted from the Texas Medication Algorithm Project. Algorithm for Mania/Hypomania. Texas Department of Mental Health and Mental Retardation. 25 There are major clinical concerns in changing patients antipsychotic medications: patients will become destabilized and perhaps relapse during the drug switch or they will suffer from new adverse effects. An interesting finding across studies is that patients who were changed to one of the first-line atypical antipsychotic agents improved regardless of whether their previous medication was conventional or atypical although investigator bias may have influenced these findings. 23 Differential efficacy, however, is consistent with the varied pharmacologic profiles seen across the spectrum of antipsychotic agents. One open-label phase 3 study evaluated the safety and tolerability of switching patients from other antipsychotic therapies to aripiprazole and whether there were any clinical differences between switching strategies. 24 A total of 311 patients with stable chronic schizophrenia were enrolled in the aripiprazole switching trial. These patients were taking stable doses of an antipsychotic agent (olanzapine, risperidone, or any conventional agent) for 1 month or longer. The reasons for switching therapies were not specified in the study design, and the decisions to switch were based on clinician opinion. In an 8-week trial, patients were randomly assigned to 1 of 3 groups with different switching strategies, using an open-label manner. Group 1 (immediate) initiated aripiprazole therapy at 30 mg daily while immediately discontinuing any previous antipsychotic drug. Group 2 (taper 1) initiated aripiprazole therapy at 30 mg daily and tapered off the other antipsychotic drug over a 2-week period. In group 3 (taper 2), aripiprazole was titrated over 2 weeks (from 10 to 30 mg daily), and the other antipsychotic Advanced Studies in Nursing 155

6 XXASIN_2_4_p151_157 10/25/04 3:45 PM Page 156 was tapered off over the same time period. Most patients were taking olanzapine (56%) or risperidone (36%) prior to switching; only 8% were receiving conventional agents (mainly haloperidol). A total of 224 patients (72%) completed the study: 69% in group 1, 66% in group 2, and 81% in group 3. The reasons for discontinuation were similar across treatment groups. Discontinuations for lack of efficacy or adverse events occurred with similar frequencies in the 3 treatment groups. Analyses were also performed after pooling all 3 groups and stratifying patients according to previous therapy (olanzapine, risperidone, or haloperidol). In this analysis, significant improvements from baseline in Positive and Negative Syndrome Scale (PANSS) total score were observed regardless of prior therapy. Baseline PANSS total scores were 69.4 among patients previously taking olanzapine, 69.9 among previous risperidone users, and 68.8 among those who switched from haloperidol. These findings suggest that clinicians should not become too complacent in their use of medications further improvement for patients may be within reach. FROM THEORY TO PRACTICE: CLINICAL IMPLICATIONS In the manic state, patients with bipolar disorder frequently demonstrate a propensity for being physically, emotionally, and/or sexually harmful to themselves or others. Initial nursing goals include preventing injury, maintaining a safe environment, and helping the patient meet basic needs, with a subsequent goal of the patient returning to normal levels of psychosocial functioning. Effective use of medications often in combination with psychotherapy enables most patients with bipolar disorder to lead essentially normal lives. An algorithm for medication management is presented in Figure Nursing Strategies for the Management of Bipolar Disorder ESTABLISH AND MAINTAIN A THERAPEUTIC ALLIANCE Over time, knowledge gained about the patient and the illness course allows early identification of usual prodromal symptoms and early recognition of new episodes. MONITOR TREATMENT RESPONSE Monitoring is especially important during manic episodes, when patient insight is often limited or absent. Be aware that small changes in mood or behavior may herald the onset of an episode. EDUCATE THE PATIENT AND FAMILY During different phases of illness, patients will vary in their ability to understand and retain information and accept and adapt to the need for longterm treatment. Education should be an ongoing process in which the nurse gradually but persistently introduces facts about the illness and its treatment. Printed and Internet material (eg, may be helpful. ENHANCE TREATMENT COMPLIANCE Ambivalence about treatment is often expressed as poor adherence to medication or other treatments. Causes of ambivalence include lack of insight about having a serious illness and even a reluctance to give up the experience of hypomania or mania. Other deterrents that need to be discussed include medication side effects, cost, and other demands of long-term treatment. Because many adverse effects can be corrected with careful attention to dosing, scheduling, and medication formulation (eg, sustained release, liquid), the psychiatric nurse plays an indispensable role by remaining vigilant of such issues. PROMOTE AWARENESS OF STRESSORS AND REGULAR PATTERNS OF ACTIVITY AND SLEEP Stressors commonly precede episodes in all phases of the illness. Social rhythm disruption with disrupted sleep-wake cycles may specifically trigger manic episodes. Patients and their families should be informed about the potential effects of sleep disruption in triggering manic episodes. Regular patterns for daily activities should be promoted, including sleeping, eating, physical activity, and social and emotional stimulation. WORK WITH THE PATIENT TO ANTICIPATE AND ADDRESS EARLY SIGNS OF RELAPSE As the clinician most likely to come into frequent contact with patients and their families, the psychiatric nurse should help patients, family members, and significant others recognize early signs and symptoms of manic or depressive episodes. Early markers of episode onset are often predictable across episodes for an individual patient. EVALUATE AND MANAGE FUNCTIONAL IMPAIRMENTS Assist the patient in scheduling absences from work or other responsibilities. Encourage the patient to avoid major life changes while in a depressive or manic state. Assess and address the needs of children of patients with bipolar disorder. Data from the American Psychiatric Association Vol. 2, No. 4 October 2004

7 XXASIN_2_4_p151_157 10/25/04 3:45 PM Page 157 REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Arlington, Va: American Psychiatric Association; Stuart GW. Emotional responses and mood disorders. In: Stuart GW, Laraia MT, eds. Principles and Practice of Psychiatric Nursing. 7th ed. St. Louis, Mo: Mosby, Inc; 2001: American Psychiatric Association Work Group on Bipolar Disorder. Practice Guideline for the Treatment of Patients with Bipolar Disorder. 2nd ed. Arlington, Va: American Psychiatric Association; Available at: visebook_index.cfm. Accessed January 22, Schultz JM, Videbeck SL. Lippincott s Manual of Psychiatric Nursing Care Plans. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; American Psychiatric Association. Treating Bipolar Disorder: A Quick Reference Guide. Arlington, Va: American Psychiatric Association; Available at: psych.org/psych_pract/treatg/quick_ref_guide/bipolar_di sorder_qrg9402.pdf. Accessed January 22, Nemeroff CB. An ever-increasing pharmacopoeia for the management of patients with bipolar disorder. J Clin Psychiatry. 2000;61(supp 13): McElroy SL, Keck PE Jr. Pharmacologic agents for the treatment of acute bipolar mania. Biol Psychiatry. 2000;48(6): Keck PE Jr, McElroy SL. Redefining mood stabilization. J Affect Disord. 2003;73(1-2): Hirschfeld RM, Keck PE, Karcher K, et al. Rapid antimanic effect of risperidone monotherapy: a 3-week, multicenter, double-blind, placebo-controlled trial. Presented at: American College of Neuropsychopharmacology 41st Annual Meeting; December 8-12, 2002; San Juan, Puerto Rico. 10. Vieta E, Khanna S, Van Kammen D, et al. Risperidone monotherapy in acute bipolar mania. Poster presented at: American College of Neuropsychopharmacology 41st Annual Meeting; December 8-12, 2002; San Juan, Puerto Rico. 11. Tohen M, Sanger TM, McElroy SL, et al. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am J Psychiatry. 1999;156(5): Tohen M, Jacobs TG, Grundy SL, et al. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. Olanzipine HGGW Study Group. Arch Gen Psychiatry. 2000;57(9): Tohen M, Chengappa KN, Suppes T, et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry. 2002;59(1): Tohen M, Baker RW, Altshuler LL, et al. Olanzapine versus divalproex in the treatment of acute mania. Am J Psychiatry. 2002;159(6): Zajecka JM, Weisler R, Sachs G, Swann AC, Wozniak P, Sommerville KW. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J Clin Psychiatry. 2002;63(12): Tohen M, Vieta E, Ketter T, et al. Olanzapine and olanzapine-fluoxetine combination (OFC) in the treatment of bipolar depression. Presented at: American College of Neuropsychopharmacology 41st Annual Meeting; December 8-12, 2002; San Juan, Puerto Rico. 17. Keck PE Jr, Versiani M, Potkin S, West SA, Giller E, Ice K. Ziprasidone in the treatment of acute bipolar mania: a three-week, placebo-controlled, double-blind, randomized trial. Ziprasidone in Mania Study Group. Am J Psychiatry. 2003;160(4): Delbello MP, Schwiers ML, Rosenberg HL, Strakowski SM. A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry. 2002;41(10): Sachs G, Mullen JA, Devine NA, Sweltzer DE. Quetiapine vs placebo as adjunct to mood stabilizers for treatment of acute mania. Presented at: 15th European College of Neuropsychopharmacology Congress; October 5-9, 2002; Barcelona, Spain. Eur Neuropsychopharmacol. 2002;12(suppl 3):S235. Abstract P Keck PE Jr, Marcus R, Tourkodimitris S, et al. A placebocontrolled, double-blind study of the efficacy and safety of aripiprazole in patients with acute bipolar mania. Am J Psychiatry. 2003;160(9): Bristol-Myers Squibb. Data on file. 22. Weiden PJ, Aquila R, Dalheim L, Standard JM. Switching antipsychotic medications. J Clin Psychiatry. 1997;58 (suppl 10): Weiden PJ. Establishing therapeutic goals in schizophrenia. Adv Stud Med. 2003;3(8C):S782-S Casey D, Kujawa M. Switching from other antipsychotics to aripiprazole [abstract]. Int J Neuropsychopharmacol. 2002;5(suppl 1):S Texas Department of Mental Health and Mental Retardation. Texas Medication Algorithm Project. Algorithm for mania/hypomania. Available at: mhmr.state.tx.us/centraloffice/medicaldirector/ timabd1algo.pdf. Accessed January 22, Advanced Studies in Nursing 157