Mood Stabilizers

Mood stabilizers are generally taken to include lithium, divalproex (and valproic acid), carbamazepine, and lamotrigine. More liberal definitions extend to gabapentin, topiramate, and oxcarbazepine. Interestingly, the FDA doesn't recognize the existence of mood stabilizers, but rather the treatment of symptoms associated with exacerbations in mood disorders. By such a definition, the second-generation antipsychotics can be included in the mix.

Because drugs used as mood disorders are not actually a class in the sense that some antipsychotics are, they will each be covered separately.

Lithium

Lithium chloride has a colorful history as a salt substitute in the 1940s for people with cardiovascular disease. Apparently, it worked pretty well as a salt. When 7-Up was introduced in 1929, it contained lithium and continued to until 1950. Ironically, Coca Cola lost its cocaine in 1929.

Lithium has been in use over 50 years for the treatment of bipolar disorder. It has been proven effective in maintenance treatment of bipolar disorder, although it may be somewhat less effective in rapid-cycling variants of bipolar disorder (i.e., having four or more episodes in one year). Interestingly, lithium has been shown to in patients with bipolar disorder.

dosing

Lithium levels must be monitored to avoid lithium toxicity. In general therapeutic levels range from 0.6-1.2 mEq/L, but this can vary depending on the patient. Levels above 1.2 increase the risk of lithium toxicity. Many psychiatrists, however, tend to use lithium more as augmentation and maintain patients at the lower end of the therapeutic range.

A general pattern of dosing lithium would begin with 300 mg twice daily with subsequent increases tailored to serum levels and response. In acute mania, lithium can be started at 600 mg three times daily if using immediate release preparations or liquid. Extended release preparations of lithium can be started at 900 mg/day. ★Renal and thyroid function should be checked on all patients prior to beginning lithium. In moderate renal insufficiency, the lithium dose will need to be reduced 50-75%. ★For patients on dialysis, a typical dose is 300 mg after each dialysis session (lithium is removed during dialysis).

interactions & cautions

Lithium is cleared renally and not subject to hepatic metabolism. Although it is free of P450 interactions, nonsteroidal anti-inflammatory agents (ibuprofen, aspirin, etc) can significantly reduce lithium clearance and increase levels. ★It is worth noting that in patients with liver disease accompanied by ascites, the level may need to be monitored more closely because of fluctuations in fluid balance.

side effects

There are number of side effects of lithium, which is one reason why it is not as popular as it used to be. Less serious effects include nausea, vomiting, diarrhea, acne, and hair loss. However, weight gain, hypothyroidism, renal insufficiency, and diabetes insipidus are also possible side effects. Lithium is also rarely associated with first degree atrioventricular block and one should be cautious in at-risk patients. Patients with congestive heart failure require reduced doses of lithium because of salt restrictions and diuretics.

pregnancy

The use of lithium (and other mood stabilizers) during the first trimester of pregancy has been associated with a 4-12% incidence of Ebstein's anomaly. During pregnancy, lithium levels need to be monitored closely, as there is increased glomerular filtration during the third trimester. Lithium doses usually need to be lowered at the time of delivery because of a decreased glomerular filtration rate.

Preeclampsia and eclampsia patients are usually given a low sodium diet, which necessitates a decreased lithium dosage.

Valproate

Valproate is fairly commonly used as a mood stabilizer. There are several hypotheses regarding the mechanism of action of valproate, some of which involve GABA modulation. Some researchers have suggested that divalproex is more effective for rapid-cycling forms of bipolar disorder than lithium.

dosing

In acute mania, patients can be loaded with valproate at 20-30 mg/kg. There is a good case for not doing this, because the side effects of the loading dose can be more intense. Patients may then opt not to take the medication altogether. In California, patients can refuse treatment, so then this will lengthen their hospitalization. Thus, it is reasonable to begin at either 250 or 500 mg twice daily, except in frail older adults, where the starting dose should be lower.

interactions & cautions

Valproate undergoes extensive hepatic metabolism. In patients with hepatic disease, dosage should be reduced and levels monitored frequently, especially during the first six months of therapy. In patients with severe hepatic dysfunction, divalproex should be avoided.

side effects

Extended release preparations, such as Depakote ER, lessen some of the side effects of divalproex. Side effects include nausea/vomiting, sedation, weight gain, and cognitive slowing. ★There are warnings of fetal defects (relating to neural tube closure) as well as polycystic ovaries.

pregnancy

Valproate is associated with an increased incidence of neural tube defects, such as a 1-2% risk of spina bifida.

Lamotrigine

Lamotrigine is an anticonvulsant that has been approved for maintenance therapy in bipolar disorder. This is a rather odd approval, as it does not provide an indication of when lamotrigine should be started. Regardless, lamotrigine is effective for preventing mania and bipolar depression (though it isn't indicated for the latter use).

dosing

Lamotrigine should be gradually titrated, starting with 25 mg daily for two weeks, then 50 mg daily for 2 weeks, then 100 mg daily for 1 week to a maximum dose of 200 mg daily. If a patient is discontinuing lamotrigine, it should be tapered over two weeks.

interactions & cautions

The major caution for lamotrigine is the rare occurrence of Stevens-Johnson syndrome. Sometimes rapid titrations will lead to a rash that is not Stevens-Johnson. Slow titration minimizes the chance of rashes.

★It is important to remember that valproate will increase the lamotrigine level and carbamazepine will decrease it. Thus, the dose needs to be decreased by 50% when given with valproate and increased by 100% when given with carbamazepine, phenytoin, or phenobarbital.

side effects

Lamotrigine is generally very well tolerated, though about 10% of patients get a benign rash. The benign rash will develop in a few days, peak in about 10, and be spotty, nonconfluent, and nontender.

Carbamazepine

Carbamazepine was the first mood stabilizer shown to be effective in treating manic episodes. Presumably, carbamazepine acts through blocking voltage-sensitive sodium channels.

dosing

Carbamazepine is not an easy drug to dose and is not a preferred mood stabilizer in medically ill patients. If one does use it, the dose begins at 200 mg twice daily and is increased about 200 mg/day on a weekly basis. The maximum dose is often 1600 mg/day, though sometimes it is necessary to go higher.

interactions & cautions

Carbamazepine is a nightmare when it comes to medication interactions. In fact, it doesn't even play nicely with itself. Carbamazepine has many P450 interactions and undergoes extensive hepatic metabolism itself. In fact, it can induce its own metabolism, which makes achieving the therapeutic level in the range of 6-12 mEq/L a very tedious endeavor.

Carbamazepine should not be used in active liver disease, and some argue that it shouldn't be used at all. If one insists on using it, baseline liver function tests and periodic monitoring are necessary.

side effects

One serious side effect of carbamazepine is Stevens-Johnson syndrome in patients who have the HLA-B*1502 allele.

Carbamazepine is also associated with a 5-8x greater risk of aplastic anemia and agranulocytosis. Occasional fluctuations in WBC or platelets are not uncommon during carbamazepine therapy, but baseline measures should be obtained and if decreases are observed then closer monitoring is necessary. SIADH has been reported with carbamazepine as well.

pregnancy

Carbamazepine is associated with an increased risk of neural tube defects, such as spina bifida.

Oxcarbazepine

Yet another anticonvulsant that operates on voltage-sensitive sodium channels. It is not yet FDA approved for bipolar disorder, but it is often used as a mood stabilizer, most commonly to augment another mood stabilizer or second-generation antipsychotic.

dosing

A reasonable starting dose is 600 mg per day in two doses, increasing by 300 mg/day to reach a dose in the range of 1200-2400 mg/day. Oxcarbazepine doses are about 1/3 higher than carbamazepine doses for similar effects.

interactions & cautions

Oxcarbazepine can decrease levels of oral contraceptives. Though oxcarbazepine doesn't have other interactions itself, it is affected by P450 inducers.

side effects

The common side effects include sedation, headache, dizziness, nausea, vomiting.

Topiramate

Topiramate is not approved for use in bipolar disorder and is not widely thought of as effective. Like many drugs, it can cause sedation, nausea, and vomiting. Topiramate can be used as an adjunctive agent, but it increases the clearance of valproate.

Zonisamide

Zonisamide is not approved for use in bipolar disorder and may only work on a subset of patients. Its major side effects include sedation, depression, dizziness, headache. Zonisamide is metabolized through 3A4, so inhibitors can increase zonisamide levels. Some patients have developed serious rashes with zonisamide.

Gabapentin

You didn't really think I would discuss gabapentin, did you?