Residents taught to use divalproex and atypicals to treat bipolar disorder are discovering lithium’s benefits
Melvin G. McInnis, MD, FRCPsych
Thomas B. and Nancy Upjohn Woodworth
Professor of Bipolar Disorder and Depression
University of Michigan Depression Center
Department of Psychiatry
Ann Arbor, Michigan
Is there an ideal lithium candidate?
Mood instability is the characteristic feature of a lithium responder. The instability may be over the course of the day, such as a dysregulated temperament that often is associated with DSM-IV personality categories, shorter-term fluctuations (within days with BD II), or in the context of episodic shifts of mood states over weeks and months, which are characteristic of BD I. The hallmark of mood instability is fluctuation from depression to elevated mood states and charged emotions with increased energy.
The patient considered ideal for lithium treatment has BD I with recurrent severe euphoric manic episodes, absence of significant comorbid disorders such as substance abuse, and a family history of lithium response. However, any patient with a clinically significant and unstable mood disorder, regardless of the DSM diagnosis, should be considered for lithium treatment.
When considering a lithium trial for a patient with significant mood instability, it is critical to establish the target symptoms and behavior that will help you gauge the efficacy of the intervention. Measurement-based care utilizes clinician and self-report instruments to provide data on the illness course and response to intervention. Commonly used clinician driven assessments include the Young Mania Rating Scale35 and the Quick Inventory of Depressive Symptoms,36 while the self-report assessments are the Patient Health Questionnaire37 and the Altman Self- Rating Mania Scale.38
During acute mania or depression, lithium often is used in combination with another medications such as an antipsychotic or antidepressant. Used in the outpatient and non-acute setting, lithium may be an “add-on” or monotherapy for preventing recurrence of episodes. Response in early acute manic symptoms are predictive of later response and remission.39
An initial problem with lithium is side effects that emerge when beginning treatment, which may discourage the patient and family from using this agent. Starting with 150 mg/d for the first 2 or 3 doses is unlikely to produce any adverse effects and can show the patient that there is a high likelihood that he will be able to tolerate the medication. Gradual titration over several days—or even weeks—to the target dosage and serum levels will enhance patient compliance. Rate of dosage increase is best guided by tolerance to the medication. The general consensus is that lithium is most effective at levels of 0.6 to 0.8 mEq/L,40 although a lower level (0.5 mEq/L) over a 2-year period also can be effective.41 Lithium may be used in to treat acute mania at higher serum levels (0.8 to 1.2 mEq/L), however, the acute phase often requires urgent management, usually with an antipsychotic.
Although there is a need to gather and analyze longer observational periods to clarify the clinical and biological characteristics of persons who respond to lithium, there are several points of consensus. Management will be guided by patient characteristics such as age, comorbidities, and other therapies. Most studies that address the effect of lithium level focus on high vs low serum levels. There are 3 categories of lithium serum levels, low (<0.6 mEq/L), mid-range (0.6 to 0.8 mEq/L), and high (>0.8 mEq/L), each has risk-benefit considerations.
The LiTMUS study42 compared low-level lithium augmentation with optimized personal treatment without lithium. Both groups had similar outcomes but the lithium-treated group had significantly lower use of atypical antipsychotics. This may be important when considering the long-term risk of the metabolic syndrome because the tolerability and side-effect profile of lithium at lower levels is more favorable than that of atypical antipsychotics. As lithium levels increase, there seems to be concomitant increase in efficacy and side effects. Many patients will benefit with low-level lithium use; yet clearly some individuals require higher dosages for effective maintenance therapy.
Dosing and monitoring. In patients age >50 or those with comorbid medical conditions, use a lower level of lithium (<0.6 mEq/L). Most individuals with BD likely will benefit from the mid-range level strategy (0.6 to 0.8 mEq/L); however, there will be those who require a higher level. When beginning lithium, start at a low dosage (150 mg/d) and increase as tolerated to the desired serum level. With acute mania, temporary use of an antipsychotic will be required.
There are no tests available to determine whether a patient will do well at any of these lithium serum levels. Breakthrough mania in an adherent patient with a serum lithium level of 0.7 mEq/L indicates the need to obtain a higher lithium level. A major deficit in lithium research is the lack of long-term data (>5 years) on outcomes, clinical and biological features with lithium levels because of a lack of pharmaceutical company support.3,17 Monitoring mood symptoms using detailed mood charts, whether clinician-administered or self-reported, is an effective way to monitor outcomes, provided the clinician uses the same scales or methods to record a patient’s moods. If a patient wants to discontinue lithium, taper the drug over an extended period (months) to minimize the likelihood of emerging manic or depressive episodes related to drug discontinuation.
Managing side effects
Consider lithium’s side effects in the context of their short-, intermediate-, and long-term presence (Table 2). Gradually increasing the lithium dosage often will prevent side effects that manifest in the short term. If side effects emerge at low dosages, proceed slowly with lithium and manage symptoms with other medications. When a patient shows a change in side effects, obtain lithium and electrolytes levels; a change in mental status with confusion will require an acute lithium level.