As we have seen, bipolar disorder is a

LONG-TERM MOOD STABILIZATION: PHARMACOLOGIC TREATMENT STRATEGIES * Susan Simmons-Alling, MSN, APRN, BC ABSTRACT This article focuses primarily on the pharmacologic strategies recommended for bipolar disorder. Because a myriad of clinical states exist, ranging from mania to depression, with mixed states also possible, and with periods of euthymia in between, effective treatment poses a challenge. Mood stabilizers, including lithium, anticonvulsant medications, and antipsychotics, in conjunction with benzodiazepines when necessary, are preferred over antidepressants, even though the latter are frequently prescribed for these conditions. Armed with the knowledge that this is a lifelong illness, treatment goals include not only management of acute symptoms, but also maintenance of symptom-free remission. A collaborative relationship between patient and clinician has the best chance for success, whereby the patient is a full partner in decisions concerning medication regimens and is well educated as to potential side effects and options. (Adv Stud Nurs. 2005;3(2):49-53) *Based on a presentation given by Ms Simmons-Alling at a symposium held in conjunction with the Psychopharmacology for Advanced Practice Psychiatric Nurses Conference. Nurse Supervisor, Psych Effect, Red Bank, New Jersey. Address correspondence to: Susan Simmons-Alling, MSN, APRN, BC, 1204 Pond Rd, Spring Lake Heights, NJ 07762. E-mail: ssalling@msn.com. As we have seen, bipolar disorder is a complex syndrome, marked by diagnostic challenges, because of the spectrum of symptoms it presents with over time. Likewise, management of bipolar disorder may be equally challenging, since the goal is to temper the extremes of depression and mania that it can cause and to achieve remission. More specifically, the approach to treatment of bipolar disorder is to target not only the acute episodes, but to attempt to increase the well intervals between episodes and maintain a euthymic state for the individual. Of growing interest is the presence of roughening in the course of bipolar disorder. This may present as subsyndromal (in irritability, euphoria, or impulsivity), and may signal an impending episode. ISSUES AND GOALS IN PHARMACOLOGIC MANAGEMENT In terms of pharmacologic treatment, many individuals are improperly medicated with antidepressants because they are most likely to present to their healthcare providers in a depressed state, and unless a careful history is elicited, the patient may not articulate episodes or symptoms of mania and especially hypomania. The difficulty with prescribing medications meant for unipolar depression is that research and experience have determined that there is a significant danger for these patients of inducing mania. 1-4 In addition, there is evidence that delay of effective treatment for manic episodes results in an increase in frequency and severity of these attacks, which may then become refractory to treatment over time. 1,5,6 Indeed, the key property for mood stabilizing medications more appropriate for bipolar disorder may not be efficacy against both poles, but rather more neutrality to avoid initiating a switch process in suscepti- Advanced Studies in Nursing 49

ble patients. Thus, pharmacotherapy aims to treat the entire spectrum of the affective disorder, including the acute phase and maintenance phases, to prevent new syndromal roughening, to minimize the severity of impairment that occurs with subsyndromal episodes, and to curtail covert illness progression, violence, and suicide. As set forth by the American Psychiatric Association (APA) in 2002, 7,8 treatment objectives for bipolar disorder highlight the notion that this condition is a lifelong illness, with maintenance therapy as the core of management. Ideally, maintenance therapy will also have minimal adverse effects, financial burden, or inconvenience in terms of dosing schedule (see Sidebar). Treatment choice must be a collaborative effort between patient and practitioner and must also be tailored to the phase of illness with which the patient presents. For example, acute therapy must stabilize the acute episode with the goal of remission (see Sidebar). This sometimes requires hospitalization if the patient is out of control, and/or if he/she poses a danger to him/herself or others. Maintenance therapy should optimize protection against recurrence of acute symptoms. Concurrently, attention needs to be devoted to maximizing patient functioning (eg, by reinforcing the need for patients to avoid destabilizing agents such as alcohol, marijuana, steroids, and caffeine), and minimizing both subthreshold symptoms and the adverse effects of the treatments themselves. Treatment Principles for Bipolar Disorder Individually tailor guidelines Use proven treatments first Select medication that is Safe and tolerable Easiest to use (patient) Easiest to manage (provider) Aim for remission Measure outcomes No medication is panacea Do not give up Psychosocial restoration Family education and social rhythm therapy Source: Rush et al. Medication treatment for the severely and persistently mentally ill: the Texas Medication Algorithm Project. J Clin Psychiatry. 1999;60(5):284-291. Although this is an ambitious goal, and it is unlikely that the ideal mood stabilizer for all individuals with affective disorders exists, it is important to strive toward achieving these goals, because the consequences of not doing so are grave. For example, approximately 90% of patients have a relapse usually within the first 6 months, but 73% of patients have a relapse within 5 years. 9 Furthermore, a review of the literature reveals that an average of 19% of patients with bipolar disorder commit suicide 1 numbers that are much higher than among those with unipolar depression, and certainly higher than those in the general population. Indeed, whereas the lifetime risk of making at least 1 suicide attempt is estimated by the APA to be 15% for those with unipolar depression, suicidal ideation ranges from 25% to 50% among patients with bipolar disorder, with those patients suffering from mixed mania ranking among those in the highest percentages. 1,5 TARGETING THE BIOLOGICAL BASIS OF BIPOLAR DISORDER Selection of pharmacologic agents is intended to target the neural substrates that involve the circuits that are abnormal in bipolar disorder. For example, medications might target the neurotransmitters in the brain that are responsible for promoting executive functioning (problem solving and decision making), and controlling impulsivity and arousal that may be associated with irritability and agitation. Medications like lithium and valproate are believed to exert their effects on cytoprotective proteins within the brain; other theories suggest that mood stabilizers may prevent or delay apoptosis in the critical brain circuitry that regulates emotion. Still, other researchers propose that the key to treatment (and the explanation for the efficacy of anticonvulsants in affective disorders) lies with the fact that individuals with bipolar disorder have suffered a series of minor neurological insults (perhaps from environmental or behavioral stressors) similar to those that are related to seizure activity. 10 MEDICATION SELECTION The APA s Practice Guideline for the Treatment of Patients with Bipolar Disorder (Revision) sets forth recommendations for management of manic or mixed episodes, depressive episodes, rapid cycling, and maintenance. A comprehensive summary of the practice 50 Vol. 3, No. 2 February 2005

guideline for the treatment of patients with bipolar disorder from the APA is available online at: http://www.guidelines.gov/summary/summary.aspx?d oc_id=3302&nbr=2528&string=bipolar+and+disorder. First-line therapy, and a standard of care for many years, is lithium carbonate. Multiple mechanisms of action of lithium have been proposed, 11,12 including the theory that it stabilizes neuronal activities, supports neural plasticity, and provides neuroprotection. Lithium may play a role via messenger RNA changes in transcription and can help neurogenesis in the gray matter. Lithium decreases synaptic arousal responsible for impulsivity, thus, it tends to be slightly more effective in controlling the manic pole of bipolar disorder, although it has antidepressive effects as well. Lithium has a response rate of 79%, (although it may take weeks to up to 2 years to achieve effectiveness), may be more effective against suicide, and has been demonstrated to be more effective if there is no history of rapid cycling. 13-16 However, it has a significant side-effect burden, so screening for pre-existing cardiac and renal disorders, and the necessity of closely monitoring for therapeutic blood levels (maintenance levels between 0.8 and 1.0 meq/l), are suggested, 17 as it has a narrow window for toxicity and may interact with a number of other medications. More than 50% of individuals discontinue lithium due to adverse effects 18 the most serious of which include sick sinus syndrome and hypothyroidism, although poor tolerability is also an issue and patients may complain of weight gain, and gastrointestinal and cognitive side effects. Valproate/divalproex sodium, an anticonvulsant medication, is also recommended as first-line therapy for manic and mixed episodes, 8 and has a role in maintenance treatment with antidepressant effects over time. It may be used alone or in combination with lithium. Valproate acts at the sodium channels, decreases glutamate release, and enhances gammaaminobutyric acid transmission on the cellular level. 19 It is the most prescribed mood stabilizer, 19,20 perhaps because of its rapid onset of action, and its effectiveness for rapid cycling and for comorbid conditions that may accompany bipolar disorders, such as irritability, migraine, panic disorder, and alcohol abuse. However, like lithium, valproate/divalproex requires therapeutic monitoring and has rare serious adverse effects. It may cause hepatic toxicity, blood dyscrasias, and pancreatitis. Some drug-drug interactions may occur due to its inhibition of the cytochrome P-450 enzyme system, and thus, care should be exercised when adding valproate to any pre-existing drug regimen. A newer anticonvulsant, lamotrigine, has also been approved by the US Food and Drug Administration for maintenance therapy in bipolar disorder. It also has been APA approved as effective as first-line therapy for acute management of bipolar depression. It can be used for monotherapy and add-on therapy, in both bipolar I and bipolar II disorders, rapid cycling, but not for acute manic symptoms. 14 Lamotrigine seems to have fewer side effects than other medications used in the treatment of these disorders, except for the potentially fatal, but rare, Stevens-Johnson syndrome, which is a necrotic rash that appears to be present more commonly in individuals with epilepsy whose dose is increased too rapidly. Like other medications useful in bipolar disorder, it is believed that lamotrigine has an effect on sodium channels and the inhibition of glutamate and arousal. Atypical antipsychotic medications have been recommended as an adjunct to lithium or valproate therapy in those suffering from manic or mixed episodes. 8 Olanzapine was the first atypical antipsychotic approved for the treatment of acute bipolar I disorder as monotherapy or as an adjunct; it is also approved as maintenance therapy, and in combination with fluoxetine, it may be used for bipolar depression. Its mechanism of action appears to be involved with dopamine and serotonin antagonism in the mesolimbic circuits, as well as dampening the effects of glutamate on arousal. Because many individuals with bipolar disorder suffer from at least one psychotic episode in their life, atypical antipsychotics are certainly useful for this; however, they are effective regardless of whether there is coexisting psychosis. A potentially serious adverse class effect with atypicals (except aripirazole and ziaprisidone) is metabolic complications weight gain, diabetes, and dyslipidema, thus ongoing monitoring is necessary. Subjective patient tolerability of a medication is critical for achieving optimal outcomes. Receptor binding is what separates the client choice among these agents for dry mouth, dizziness, and drowsiness. Finally, benzodiazepines may be needed for the management of the acute phases of mania. As adjunctive agents they are useful because they act as a sedative and decrease agitation but may have a potential for addiction, so caution must be exercised in prescribing them. Thus, to summarize, the first-line pharmacologic treatments for acute mania are monotherapy with Advanced Studies in Nursing 51

lithium, valproate, or an atypical antipsychotic, most commonly olanzapine. Short-term adjunctive treatment with a benzodiazepine may also be necessary. For mixed episodes, combination therapy using valproate may be preferred over lithium, with an atypical antipsychotic preferred over a typical antipsychotic because of their more benign side-effect profile. Alternatives include carbamazepine or oxcarbazepine in lieu of lithium or valproate. Antidepressants should be tapered and discontinued if possible. 8 If a breakthrough episode occurs, the APA recommends optimizing the maintenance mood stabilizer first, then if necessary, add an atypical antipsychotic (especially if the patient displays psychotic symptoms) or a second mood stabilizer. Electroconvulsive therapy may also need to be considered. For episodes of depression, the first-line pharmacological treatment is the initiation of either lithium or lamotrigine. According to the APA, in patients with life-threatening conditions, such as inanition, suicidality, or psychosis, electroconvulsive therapy also represents a reasonable alternative. The use of antidepressants in bipolar depression is controversial, and if attempted, must be monitored carefully by an experienced clinician. If a patient has bipolar I or bipolar II disorder, a mood stabilizer should always be used first. For patients who have bipolar II disorder with rapid cycling, an antidepressant may be introduced at the lowest dose and only in combination with a mood stabilizer. The risk of switching (provoking a manic episode) is greatest when these medications are initiated during a euthymic period and also is most likely to occur within 5 weeks of beginning the antidepressant. 4 Prolonged use of antidepressants is controversial and may predispose patients to a manic period; however, once the decision is made to discontinue them, these medications should be slowly tapered. If patients experience 4 or more mood disturbances within a single year (marked by remission for at least 2 months prior to switching from one pole to another), they are considered to be undergoing rapid cycling. Certain medical conditions and drug use (including antidepressants, alcohol, and illicit substances) may predispose patients to this phenomenon and should be ruled out or eliminated. As with mania, treatment with lithium, valproate, or lamotrigine is indicated. 8 Once the acute phase of mania, depression, or rapid cycling has been stabilized, maintenance therapy should focus on the management of chronic illness and not on the control of episodes. Continued use of lithium, valproate, and lamotrigine or second-line options such as carbamazepine or oxcarbazepine are necessary. On the other hand, atypical antipsychotic medications should be discontinued, unless their continued use is needed due to persistent psychosis or high risk of recurrence of psychotic symptoms. 8 Since functional recovery lags behind syndromal recovery, patients with bipolar disorder continue to experience subthreshold or minor symptoms during interepisode intervals. 21 PRINCIPLES FOR REFRACTORY CASES We have seen that the armamentarium for treating bipolar disorder includes mood stabilizers such as lithium, anticonvulsants such as valproate and lamotrigine, atypical antipsychotics such as olanzapine, and benzodiazepines. In order to assure maximum efficacy and avoid having to manage refractory cases, it is important to try to treat from the onset with the goal of achieving remission. If the initial agent selected is well tolerated, it will be possible to increase the dose slowly to maximum efficacy while minimizing side effects, mania induction, and no acceleration. If symptoms are still present, then add a second drug, with combination synergy targeting varying mechanisms of action for the abnormal neural circuits within the brain. THE PRACTICAL ASPECTS OF INSTITUTING A MEDICATION TREATMENT PLAN Often, patients will require more than one medication for stabilization of their condition, and in fact, the average bipolar patient takes combination therapy with 4 medications. In selecting the proper drug or combination of drugs for each individual, the clinician should consider its efficacy, in particular for that patient s situation (eg, classic mania vs mixed states and rapid cycling). The other important consideration is the drug s efficacy for depression and the chance that it may worsen depressive symptoms. Last but not least, safety and tolerability are important considerations for medication selection. Patients will not comply with complex treatment regimens, drugs that cause side effects such as cognitive dulling, and most important, the clinician must ascertain if there is a risk of lifethreatening adverse events for the patient. For several of these medications, patients must be screened to identify the presence of certain comorbid conditions, and it must be determined if the patient will be compliant with necessary monitoring to assure safe and 52 Vol. 3, No. 2 February 2005

effective use of the therapy. Nurses can educate patients about side-effect profiles, and help them to make informed choices about what they can tolerate. It is also helpful to ease dosing by attempting to institute once-daily dosing, either in the morning or evening, and perhaps combining therapies to allow for lower doses of each, which in turn may lower the sideeffect burden. However, care must be exercised when switching therapies, as for example, in the case of switching to an extended-release formulation of the same medication, since the bioavailability of the medication may not be equivalent, and the patient s dose may need to be adjusted accordingly. Likewise, most medications need to be titrated upward when first introduced, and tapered slowly when discontinued. Although the emphasis here has been on medication based on the biological origins of affective disorders, nonpharmacologic therapies, particularly psychosocial counseling and various forms of psychotherapy, also may be extremely beneficial to patients and families coping with this group of disorders. These will be addressed in the next section. REFERENCES 1. Tugrul K. The nurse s role in the assessment and treatment of bipolar disorder. J Am Psychiatr Nurses Assoc. 2003; 9(6):180-186. 2. Altshuler L, Kiriakos L, Calcagno J, et al. The impact of antidepressant discontinuation versus antidepressant continuation on 1-year risk for relapse of bipolar depression: a retrospective chat review. J Clin Psychiatry. 2001; 62(8):612-616. 3. Calabrese JR, Bowden CL, Sachs GS, Ascher JA, Monaghan E, Rudd GD. A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I disorder. J Clin Psychiatry. 1999;60(2):79-88. 4. Ghaemi SN, Boiman EE, Goodwin FK. Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study. J Clin Psychiatry. 2000;61(10):804-808. 5. Goodman FK, Jamison KR. Suicide. In: Manic Depressive Illness. New York: Oxford University Press; 1990:227-246. 6. Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD. Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania. Am J Psychiatry. 1999;156(8):1264-1266. 7. Calabrese JR, Shelton MD, Rapport DJ, Kimmel SE, Elhaj O. Long-term treatment of bipolar disorder with lamotrigine. J Clin Psychiatry. 2002;63(suppl 10):18-22. 8. American Psychiatric Association. Practice guidelines for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50. 9. Keck PE. Clinical updates in bipolar depression: Novel therapy strategies to help you help your patient. Optima Education Solutions, Inc. Available at: http://www.optimaed.com. Accessed September 2004. 10. Soreff S, McInnes LA. Bipolar affective disorder. Available at: http://www.emedicine.com/med/topic229.htm. Accessed November 7, 2004. 11. Jefferson JW. Innovative treatment strategies with anticonvulsants: A focus on bipolar disorder. CME Home Study sponsored by Strategic Institute for Continuing Health Education. Wayne NJ. Accessed September 2004. 12. Manji HK. Genomic and Protemonic Studies Identify Novel Targets in Bipolar Disorder. NIMH Psychopharmacology Course: From Research to Practice Update 2003. Bethesda, Md ((publisher? YEAR?)). 13. Goodwin FK. Rationale for the long-term treatment of bipolar disorder and evidence for long-term lithium treatment. J Clin Psychiatry. 2002:63(suppl 10):52. Abstract. 14. Dunner DC, Fleiss JL, Fieve RR. Lithium carbonate prophylaxis failure. Br J Psychiatry. 1976;129:40-44. 15. Goodwin FK, Tondo L, Ghiani C, Albert M. Pharmacologic interventions in suicide prevention. J Clin Psychiatry. 2001;62(suppl 25):51-55. 16. Bowden CL. Rapid-cycling bipolar disorder: How to define it, how to treat it. J Bipolar Dis. 1998;2:14-18. 17. Bowden CL, Singh V. Long-term management of Bipolar disorder. Available at: www.medscape.com/view. Accessed December 2004. 18. Keck PE. Clinical updates in bipolar disorder: Novel strategies to help you to help your patients. Available at: http://www.optimaed.com. Accessed September 2004. 19. Stahl SM. Psychopharmacology of anticonvulsants: do all anticonvulsants have the same mechanism of action? J Clin Psychiatry. 2004;65(2):149-150. 20. Keck PE, Sachs G. New treatment options of bipolar mania. Distance Learning Network. Available at: http://www.dlnetwork.com/cactivs/listing_fullr.asp?id=17 0&Type=Enduring. Accessed February 2004. 21. Tohen M, Hennen J, Zarate CM Jr, et al. Two-year syndromal and functional recovery in 219 cases of first-episode major affective disorder with psychotic features. Am J Psychiatry. 2000;157(2):220-228. Advanced Studies in Nursing 53