Management of Acute Mania Management of Acute Mania Mauricio Tohen, M.D., Dr.P.H., and Starr Grundy, B.Sc.Pharm. Bipolar disorder is a lifelong episodic condition characterized by mood swings between mania and depression. In the United States alone, approximately 4 million people are affected by this disorder. © CopyrightPharmacologic treatment 2000 for acute Physicians manic episodes or as Postgraduatemaintenance therapy includes Press, lithium, val- Inc. proate, carbamazepine, and typical antipsychotics. However, many patients fail to respond to these treatments due to lack of efficacy or production of side effects leading to patient noncompliance. Non- compliance with pharmacologic treatment is indeed a major risk factor in bipolar disorder patients and needs to be managed with ongoing education, psychotherapy, and a simplified but effective pharma- cologic treatment regimen. Recently introduced novel antipsychotics show much promise as mood- stabilizing agents in bipolar patients, with minimal risk of treatment-emergent extrapyramidal symp- toms and tardive dyskinesia. Nonetheless, further research is warranted to help clarify the role of novel antipsychotics in the treatment of bipolar disorder. (J Clin Psychiatry 1999;60[suppl 5]:31–34) ipolar disorder is a highly prevalentOne personal condition copythat mayare bedifficult printed to estimate. However, in recent years an in- Bcauses a great deal of human suffering. First system- creasing number of patients have been hospitalized with atically described in the scientific literature in 1921,1 bi- affective disorders.5 This increase might be explained by polar disorder has an episodic nature, characterized by changes in diagnostic criteria. Another explanation is manic or depressive episodes followed by symptom-free treatment-orientated diagnostic bias, which occurs when periods. clinicians preferentially diagnose one condition over another when new pharmacologic treatments become EPIDEMIOLOGY available.5 The National Institute of Mental Health (NIMH) Epi- RISK FACTORS demiologic Catchment Area (ECA) Project estimates the lifetime prevalence of bipolar disorder to be 0.8%.2 The Evidence of genetic risk factors in bipolar disorder is 1-month point prevalence (the proportion of individuals ill well documented.6 Molecular genetics has made great at any single point in time) for bipolar disorder has been strides in recent years, with at least 2 groups providing estimated as 0.4%, which in 1996 would translate to ap- evidence suggesting that chromosome 18 carries the ge- proximately 1 million Americans. The National Comor- netic risk for bipolar disorder. bidity Survey (NCS) estimates the lifetime prevalence for Two controversial risk factors for bipolar disorder are bipolar disorder at 1.6%3; hence, 4 million Americans will socioeconomic class and gender. In one population-based suffer from bipolar disorder at some point in their life. study,7 bipolar disorder appears overrepresented in the Studies from countries outside the United States report higher socioeconomic classes. This finding is replicated in similar rates.4 neither the ECA nor the NCS studies, however. Similarly, Incidence rates, or the number of newly diagnosed most researchers report no gender differences with respect cases of bipolar disorder during a defined period of time, to bipolar disorder, although some studies show conflict- ing data in regard to gender prevalence.6 Stressful life events or trigger events (e.g., the death of a loved one) are considered contributing factors of bipolar From Harvard Medical School, McLean Hospital, Boston, disorder relapse early in the course of the illness. A cause- Mass. (Dr. Tohen), and Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Ind. (both and-effect association between these trigger events and re- authors). lapse in patients who have experienced fewer than 2 or 3 Presented at the symposium “The Use of Mood Stabilizers episodes is shown in a number of studies. This correlation for Treating Psychiatric Disorders,” which was held March 3, 6 1998, Amelia Island, Fla., and supported by an unrestricted has not been found in multiple-episode patients, as re- educational grant from Eli Lilly and Company. lapse in these patients is typically spontaneous. Hence, a Reprint requests to: M. Tohen, M.D., Dr.P.H., Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, clear cause-and-effect association between stressful Drop Code 0538, Indianapolis, IN 46285. events and relapse no longer exists. J Clin Psychiatry 1999;60 (suppl 5) 31 Tohen and Grundy COURSE AND OUTCOME acute mania. Another study included a 3-arm design com- paring divalproex, lithium, and placebo.18 Both active Bipolar disorder is a lifelong episodic condition with treatments were statistically significantly superior to pla- multiple episodes of mania or depression occurring in over cebo with no difference noted between the two. Regarding 90% of patients.8 In many cases, repeated episodes will patient satisfaction, 11% of patients discontinued lithium lead to a downhill course with progressively deteriorating due to adverse effects compared with only 6% of those levels of functioning and poor treatment response.6 Fur- taking divalproex. At least one study19 has suggested that thermore, as the frequency of episodes increases, the se- divalproex has a faster onset of action compared with verity of residual symptoms between episodes increases. lithium (10–14 days).15 Certain types of symptoms, specifically, mixed symptoms9 Valproate is also used as maintenance treatment for bi- and substance© Copyrightabuse,9 are recognized 2000 as predictors Physicians of in- polar Postgraduate disorder. A study conducted Press, in Europe Inc. compared creased episode length. valpromide (an amide derivative of valproate) with lithi- There are a number of predictors of relapse. An in- um in the treatment of bipolar disorder and showed no dif- creased number of previous episodes increases the risk of ference in terms of efficacy.20 Of 150 patients, 42 taking further relapses.6 Specific symptoms predicting relapse in- lithium relapsed compared with 39 taking valpromide. clude psychotic features, especially mood-incongruent The study design allowed patients to switch from one psychotic features,10 and depressive symptoms.11 Comor- treatment to the other in case of poor response or lack of bid conditions, specifically alcoholism and interepisode tolerability. Four patients switched from valpromide to subsyndromal symptoms, are also predictors of relapse.6 lithium and 10 from lithium to valpromide. Six of the 10 patients switching from lithium to valpromide did so due PSYCHIATRIC MANAGEMENT to lithium-induced adverse effects. One personal copy may Predictorsbe printed of poor response to lithium include mixed The American Psychiatric Association (APA) recently symptoms,2 a history of multiple episodes, and comorbid published practice guidelines addressing psychosocial and substance use disorders.15 In contrast, patients with mul- somatic interventions for the treatment of bipolar disor- tiple episodes and comorbid substance use disorders have der.12 Among psychosocial interventions, emphasis is demonstrated a good response to divalproex.15,18 placed on the establishment and maintenance of a thera- Other treatments currently not approved for bipolar dis- peutic alliance between the patient and a clinician who can order by the FDA have been used for the treatment of ma- provide a long-term supportive relationship. This relation- nia, including carbamazepine, typical and novel anti- ship should be established within the framework of a part- psychotics, lamotrigine, and gabapentin. While efficacy nership allowing the identification of significant trigger for the acute treatment of mania using carbamazepine is events or stressors, as well as interepisode subsyndromal well documented,15 maintenance studies show mixed re- symptoms that may affect the course of the illness. An im- sults.21–23 Due to its adverse effect profile, carbamazepine portant aspect of the therapeutic alliance is the clinician’s has low patient acceptability.24,25 The most common ad- role in providing education, not only to the patient but also verse effects include blood dyscrasia, headache, nausea, to the family.13,14 and skin rash.15,26 Also, due to its self-inducing metabo- lism, blood levels of carbamazepine need to be closely PHARMACOLOGIC TREATMENT monitored. Additionally, carbamazepine has many drug interactions with other mood stabilizers and several other In the early 1970s, the U.S. Food and Drug Administra- types of medications. tion (FDA) approved lithium carbonate for the treatment Typical antipsychotic agents are often used during of mania. The efficacy of lithium in acute and mainte- acute treatment of manic symptoms. They do not have a nance treatment of bipolar disorder has been clearly docu- large role in maintenance therapy, though, because of side mented.8 Although the risk of serious adverse effects (e.g., effects such as extrapyramidal symptoms (EPS) and tar- renal failure) is low, mild adverse effects (e.g., polydipsia dive dyskinesia. Furthermore, typical antipsychotics do and polyuria) with lithium appear to be quite common.15 not show adequate efficacy in the treatment or prevention Neurocognitive impairment represents the most frequent of depressive symptoms.27 The novel antipsychotic cloza- reason for patient noncompliance with lithium.8 Approxi- pine has demonstrated mood-stabilizing