Bipolar disorder (BD) is one of the most challenging illnesses to treat in psychiatry, especially bipolar depression. In older adults, changes in metabolism and medical comorbidities can result in a higher risk of side effects with first-line agents. Clinicians may therefore have to resort to second-line or third-line options for optimal treatment. This article will review the use of mood stabilizers, including lithium and anticonvulsants, in older adults. For an overview of these medications, see “Comparison of Mood Stabilizers in Older Adults” table).
Lithium is widely prescribed but can be difficult to use in older adults.
Lithium is a powerful antisuicide agent and reduces suicide risk at all ages—an important advantage given the high rate of completed suicides in older men. This effect is independent of its mood-stabilizing properties (D’Souza R et al, Curr Psychiatry Rep 2011;13(6):488–492).
Although prescriptions for divalproex (Depakote) have outpaced lithium in recent years, the two can still go toe to toe. In the Geri-BD study, 224 adults age 60 or older with BD type I whose most recent episode was manic, hypomanic, or mixed were given either lithium (0.80–0.99 mEq/L) or divalproex (80–99 mcg/mL) for nine weeks. Both lithium and divalproex were equally well tolerated, though patients on lithium experienced a slightly higher rate of tremors. Lithium was also associated with greater reduction in mania compared to divalproex (Young RC et al, Am J Psychiatry 2017;174(11):1086–1093).
Lithium might play a role in decreasing dementia risk even though high levels are associated with cognitive impairment. Lithium facilitates neurotrophic and protective responses in the brain. Even at subtherapeutic concentrations (0.25–0.5 mEq/L), after 24 months of treatment, older adults taking lithium had significantly better performance on memory and attention tests compared to patients on placebo (Forlenza OV et al, Br J Psychiatry 2019;215(5):668–674).
Older adults are at higher risk of lithium side effects and toxicity.
Higher lithium serum levels increase the risk of delirium, cognitive impairment, ataxia, weight gain, edema, tremor, and worsening of psoriasis. Increased urinary frequency or thirst are concerning signs of nephrogenic diabetes insipidus. Because it can contribute to hypothyroidism and nephrotoxicity, lithium should be used with caution in patients with kidney problems or thyroid disorders, which are common conditions in the older population. Clinicians should evaluate thyroid and kidney function prior to lithium initiation and every 6–12 months thereafter. Sick sinus syndrome (SSS), resulting in a heartbeat that is too slow, can be caused by lithium and is a relative contraindication. A physical exam focused on the thyroid, signs of tremor, and signs of renal failure or congestive heart failure can help determine a patient’s risk level. An ECG can help detect SSS, with the most common finding being T wave inversion. ECG findings in patients taking lithium may resemble hypokalemia and include depressed ST segments, T waves, and sometimes U waves.
Toxicity can develop rapidly in older adults due to dehydration or interference from other medications. These include thiazide diuretics, NSAIDs, angiotensin-receptor blockers, and angiotensin-converting enzyme inhibitors. The chances of toxicity are also increased by the reduced kidney elimination of lithium together with its longer half-life.
I recommend using doses 25%–50% lower than those for younger adults and aiming for lower serum levels (0.4–0.8 mEq/L) than the standard goal of 0.6–1.2 mEq/L. I often start at 150 mg or 300 mg PO QHS and increase in 150–300 mg increments weekly. After the patient has taken a dose of 600 mg QHS for five to seven days, I usually check their lithium level. I continue titration based on the level and the patient’s response and tolerance. Sustained-release preparations, including lithium ER (Lithobid) and lithium CR (Eskalith), and nighttime dosing can decrease peak levels, protecting the kidneys and improving tolerability. However, if the patient develops diarrhea, switching to immediate-release lithium (lithium carbonate) can resolve this problem.
Divalproex/valproic acid (VPA)
Prescription data show that divalproex has become a mainstay for the treatment of late-life BD.
Divalproex is well tolerated, even among patients with neurological and medical disorders. Because of its ease of use, it’s prescribed more often than lithium, but it hasn’t been shown to be the superior drug, with one exception: patients who experience rapid cycling.
The most common side effects are nausea, sedation, and weight gain. Less common are hair thinning, thrombocytopenia, Parkinsonism, ataxia, hepatotoxicity, and pancreatitis, with the last two less likely to occur in older age. Divalproex may also increase ammonia levels, which can result in hyperammonemic encephalopathy, characterized by confusion. Since this can occur in any patient on VPA—even a patient with normal liver function and normal serum VPA levels—it’s a good idea to obtain an ammonia level in all patients who develop altered mental status taking this medication. If a symptomatic patient has an elevated ammonia level, VPA dose reduction or discontinuation often results in complete recovery. L-carnitine supplementation and lactulose may lead to faster symptom resolution. In addition, be on alert for the rare urea cycle disorders (ornithine transcarbamylase deficiency being the most common)—patients with these disorders are very prone to high ammonia levels and should never be prescribed divalproex.
In older adults, more divalproex is free to circulate due to decreased protein binding, resulting in a longer half-life. Therefore, lower doses are recommended in this population. I suggest starting Depakote ER at 250 mg QD and increasing to 500 mg QD after one week in the outpatient setting (the dose can be titrated by 250–500 mg per day for mania in the inpatient setting). Dosing in the morning reduces daytime sedation, as peak levels occur after 12–15 hours. Additionally, morning dosing allows the obtaining of more accurate trough levels, which can be taken before the morning dose is due. A level should be obtained once steady state is achieved (between two and four days). The dose can be further increased based on response and tolerability to 1000 mg/day and targeting a therapeutic serum level of 65–90 mg/L (Chen ST et al, J Clin Psychiatry 1999;60(3):181–186). As Depakote ER only comes in 250 mg and 500 mg tablets, you might consider Depakote DR (which comes in 125, 250, and 500 mg tablets) when smaller dose titrations are required. Another important benefit is that other formulations, including sprinkles and liquid, are available for patients who have difficulty swallowing pills.
Carbamazepine (Tegretol) is a last resort in older adults because of its side effects and limited evidence of benefit (the closely related drug oxcarbazepine has even fewer data related to its efficacy in older adults).
Carbamazepine hasn’t been studied in older adults. It may help individuals with nonclassical features of BD. These include BD type II; continuous cycling; high irritability; substance use and anxiety comorbidity; mood-incongruent delusions; and a negative family history of mood disorders in first-degree relatives (Post RM, Psychiatr Clin N Am 2016;39(1):11–33).
Carbamazepine has autoinduction of metabolism, frequent drug-drug interactions, and possible neurotoxic effects. It’s a powerful inducer of CYP3A—one of the workhorses of human metabolism. CYP3A induction can reduce blood levels of an estimated 25% of all medications. On that list are several antipsychotics, antidepressants, and anticonvulsants, including carbamazepine itself (Ljubic N et al, Ann Gen Psychiatry 2021;20(1):45).
Neurotoxic effects like blurred vision, double vision, nystagmus, confusion, and agitation aren’t uncommon. Changes in blood counts (agranulocytosis, aplastic anemia) occur more frequently in older adults, so clinicians should obtain a complete blood cell count (CBC) when they check the patient’s serum level. Hyponatremia, rashes, and urinary retention are concerning adverse drug reactions to monitor. Carbamazepine has quinidine-like properties and has been associated with bradycardia and atrioventricular conduction delays.
Before initiating carbamazepine, check liver enzymes, electrolytes, a CBC, and an ECG. Carbamazepine may be started at 100 mg either once or twice daily and gradually increased every three to five days to 400–800 mg/day. Because of autoinduction, its dosage will need to be increased again after four to six weeks. Target serum levels are 4–12 mcg/mL and should be checked frequently in the first months (along with a CBC).
Lamotrigine’s niche in bipolar disorder is in depression and maintaining euthymia. The risk for rash warrants some caution.
Lamotrigine isn’t a true mood stabilizer. It isn’t very effective in treating or preventing mania. However, in older adults, lamotrigine has been shown to be significantly more effective than lithium and placebo in preventing bipolar depression. Conversely, lithium has been shown to perform much better than lamotrigine in preventing mania (Sajatovic M et al, Int J Geriatr Psychiatry 2007;22(10):945–950).
Overall, lamotrigine is well tolerated, although it comes with a rare but serious risk of skin rashes, like Stevens-Johnson syndrome (SJS). Its most common side effects are headache, insomnia, tremor, and somnolence. Lamotrigine has fewer negative effects on cognition than other anticonvulsants, which is appealing for older patients.
Lamotrigine and divalproex should be used cautiously when administered together, since divalproex doubles the plasma level of lamotrigine and lamotrigine lowers the concentration of VPA by 25%. This combination drastically increases the chance of SJS (Aziz R et al, Am J Geriatr Pharmacother 2006;4(4):347–364).
The overall research evidence for mood stabilizers in older adults is low. Lithium and divalproex are useful in all phases of BD, while lamotrigine is superior in bipolar depression. Carbamazepine should reserved as a last resort. Side effects and toxicities can be significant in older patients on any mood stabilizer, but they can be monitored for and avoided.
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