Lithium for bipolar disorder: A re-emerging treatment for mood instability

Lithium is among the most effective therapies for bipolar disorder (BD), and enthusiasm for this simple molecule is waxing. The his­tory of lithium is fascinating,¹ and recent considerations include that this element, the third on the periodic table, has few, if any, indus­try champions. The recent renaissance is caused by a groundswell of appreciation for the clinical efficacy of lithium and an increasing num­ber of providers who are willing to manage patients with lithium.

Target: Bipolar disorder
The target illness for lithium is BD, a spectrum of mood disorders with characteristic features of unstable mood and affect. Shifts in mood include recurrent episodes of mania, which are pathologically ener­gized states with misguided volition and behavior with intoxicating euphoria (or irritability).^₂ Psychomotor activity is elevated and out of character; speech and body movements are revved up, with a dimin­ished need for sleep. The social, personal, and vocational consequences often are disastrous.

The most common mood state of BD is depression. Depressive episodes consist of pathologically compromised energy and volition with a slowing of bodily functions, most prominently cognition and concentration; a pervasive depressed or sad mood is common but not always present. Presence of mixed states, when features of depression and mania are present simultaneously, is one of the many challenges of treating BD; an elevated volitional or energized state may occur with a depressed, dysphoric mood.

Evidence for lithium
Efficacy studies of lithium have focused on managing mood disorders, treating mania and depression, and prevention or main­tenance care.³ Most were performed dur­ing the 1970s and 1980s,³ but recent studies have been comparing lithium with other mood stabilizers^4-7 and searching for a genetic basis for lithium response.^8-10 Other researchers have examined the use of lith­ium to prevent suicide.¹¹ Some have sug­gested a neuroprotective effect of lithium, which may have profound implications for neuropsychiatry if valid.^12-14 Results of additional studies, which are at differ­ent stages of completion, will clarify lith­ium use,^15,16 and characterize the genetic makeup of individuals who respond to lithium.¹⁷ The primary evidence for lith­ium, however, is for maintenance treat­ment of BD and for preventing manic and depressive episodes.

Biochemistry and physiology of lithium. The biochemical and physiological effects of lithium are complex, wide-ranging, and likely to affect hundreds, if not thou­sands, of genes and gene products. The mechanisms of action remain a focus of aca­demic pursuit (for a review of hypotheses related to these mechanisms see Goodwin and Jamison² and Can et al¹⁸) Lithium is involved in cell signaling pathways that involve complex molecular mechanisms of inter- and intracellular communica­tion¹⁹; some neural receptors are down-regulated²⁰ and others show inhibition,²¹ which is thought to be a mechanism of lithium. The hypothesized neuroprotective effect of lithium²² may be mediated through an increased level of brain-derived neuro­trophic factor in brain tissue.¹⁴ Recently, investigators using induced pluripotent stem cell derived neurons have shown that patterns of calcium-related cell signaling in bipolar neurons are affected specifically by lithium in the culture media.²³ There likely are many mechanisms through which lithi­um’s effects are mediated, including a series of dynamic pathways that vary over time and in reaction to the internal and external environments of the cell and person.

The lithium renaissance
In the past decade, there has been an increase in interest and use of lithium because clinicians recognize its efficacy and advantages and can monitor serum levels and gauge the patient’s response and side effects²⁴ against the lithium level. This is important because balancing effi­ cacy and side effects depends on the serum level. Efficacy often is not immediate, although side effects may emerge early. All systems of the body may show effects that could be related to lithium use. It is helpful to be aware of the side effects in chronolog­ical order, because some immediate effects may be associated with starting at higher dosages (Table 1). Common side effects in the short term include:

• GI distress, such as nausea, vomiting, diarrhea, and abdominal discomfort
• a fine neurologic tremor, which may be seen with accentuation upon deliber­ate movement
• prominent thirst with polyuria
• drowsiness and clouded thinking, which can be upsetting to the patient and family.

In the longer term, adverse effects on kidney and thyroid function are common. Management must include monitoring of the serum level.

Lithium is FDA-approved for acute and maintenance treatment of mania in BD. There are reports that discuss most vari­ants of mood disorders, including BD I, BD II, unipolar depression, rapid cycling, and even alcohol abuse.^25-29 Lithium could help manage mood dysregulation in the context of temperament and personal­ity.³⁰ There is evidence that lithium has an antidepressant effect31-33 and has shown efficacy as an adjunctive treatment for depression.^31-33 There are data that sug­gest that lithium, with its neuroprotective mechanisms, may prevent progression of mild cognitive impairment.³⁴