Treatment Options in Bipolar Disorder: Mood Stabilizers

Charles L. Bowden, MD

Medscape Psychiatry & Mental Health eJournal. 1997;2(4) 

In This Article

Mood-Stabilizing Agents: VPA

VPA, a branched-chain fatty acid, has been available commercially in the US since 1978 as an antiepileptic. A congener of VPA, valproate sodium, was introduced into clinical use a few years later. Because VPA and sodium valproate can commonly cause GI intolerance, a sustained-release formulation of the prodrug, divalproex sodium, which comprises a 1:1 ratio of VPA and valproate sodium, was later introduced into clinical use. Although VPA, valproate sodium, and divalproex sodium are 3 distinct compounds, the systemically absorbed and active component of each is VPA.[1,37]

Controlled and uncontrolled studies have demonstrated that VPA has therapeutic efficacy comparable to that of Li in acute mania.[1,37,38] VPA can be considered a therapy of choice in some patients with bipolar disorder, including those unable to tolerate Li and others for whom Li was not effective, such as those with rapid cycling and mixed states. VPA's faster onset of action (2 to 5 days with oral loading vs 7 to 14 days for Li) is, for some patients, a clinical advantage.[1,37,39,40]

The exact mechanism of action of VPA remains unclear. Some data suggest that the drug may be a gamma-aminobutyric acid (GABA) agonist, acting directly or indirectly by enhancing GABA receptor activity and/or inhibiting GABA metabolism. The drug may also facilitate chloride influx at the neuronal level.

Clinical data indicate that VPA is an effective agent for treating acute mania.[24] The findings of placebo-controlled, double-blind studies corroborate the findings of uncontrolled studies.[17,19,24,41,42,43,44,45] Pooled response rates from these studies showed significant improvement (at least partial remission or a greater than 50% reduction in manic symptoms) in 54% of patients. Rates for divalproex and Li were comparable.[18,19]

The available data on the efficacy of VPA for the prophylaxis of acute mania are derived from uncontrolled studies.[24] Although those results are positive, no randomized, comparative trials have been completed yet.[5] The open-label studies suggest that VPA may reduce the frequency and intensity of manic and depressive episodes over extended periods.

There have been no controlled studies reported for VPA in the treatment of acute depression. However, in open studies, divalproex appeared to be more effective in the treatment of acute mania than for treating depression.[24]

Studies of patients' response to treatment with divalproex have demonstrated that, unlike Li, divalproex is effective in patients with pure and mixed mania, rapid cycling, and comorbid substance abuse.[4]

A growing body of well-conducted clinical research indicates that VPA is well-tolerated and effective, especially for short-term (2- to 4-week) treatment of acute mania (Table III). Its short onset of action (2 to 5 days), particularly when a loading-dose strategy is used, is an advantage in the management of acutely manic patients. VPA's antimanic or mood-stabilizing effects may be augmented by concomitant use of Li, neuroleptics, CBZ, or thyroid hormone. Conversely, VPA may augment the antimanic effects of Li, neuroleptics, CBZ, or thyroid hormones. VPA can also reduce the frequency and intensity of recurrent episodes of both mania and depression over extended periods. Thus, it may especially benefit patients with rapid cycling, mixed (dysphoric) states, neurologic abnormalities (eg, EEG abnormalities, mental retardation), or histories of head trauma. Its antidepressant efficacy appears to be less robust than its antimanic effect, however.[1,36,37]

Another advantage of VPA is that multiple dosage formulations are available. This allows for appropriate dosage titration and individualization of therapy. Regardless of the dosage formulation used, VPA, in contrast to Li and CBZ, has less of an adverse effect on cognition and mental functioning.[1,37]

VPA tends to inhibit the hepatic metabolism of some other compounds. This can be disadvantageous for patients requiring polypharmacy with hepatically metabolized drugs. Hepatotoxicity is a concern with use of VPA. However, symptomatic liver dysfunction is rare and occurs almost exclusively in persons aged 2 years or younger.[46]

VPA is effective in the treatment of acute mania. The drug should also be considered--either alone or as an adjunct to Li or CBZ--for bipolar patients who cannot tolerate standard therapies or whose symptoms do not respond fully to them. It is also of use in patients with schizoaffective disorder, bipolar type. Patients with residual manic symptoms or rapid cycling, cyclothymia, mixed states, or neurologic or other organic abnormalities are also candidates for VPA.[1,36,37,47,48]

One recent study of the dose relationship to clinical improvement in acute mania indicated that greater improvement with good tolerance is achieved with concentrations of between 45 and 100-125mcg/mL.[49] A small number of patients may require substantially higher plasma concentrations. Initial dosage is usually 500 to 1000mg/day in 2 to 4 divided doses. Acutely agitated, hospitalized patients can be treated more aggressively, commencing with a 20mg/kg dose daily in 3 divided doses. This loading-dose strategy may speed early response in some patients. Trough (12-hour) serum VPA concentrations should then be measured every 2 to 4 days, while adjusting the dose upward until a favorable response within the therapeutic range is achieved. Once the patient is stabilized, the entire dosage may be taken in a single daily dose before sleep. This once-daily regimen can enhance compliance.[1,36,37]

If agents used previously appear partially therapeutic (eg, Li, neuroleptics), they usually can be continued while smaller initial doses of VPA are added to the regimen. When a favorable response to VPA is observed, the concurrently administered agents can be gradually withdrawn one at a time to assess the need for their continued use. Conversely, if mania or cycling persist with initial monotherapy with VPA, other agents can be added, including thyroid hormone, CBZ, Li, and neuroleptics. If depression ensues after adding these agents, Li or neuroleptics should be discontinued; if it persists, antidepressants should be considered.[1,36,37]

Some patients respond well to prophylactic monotherapy with VPA, while others need to continue with a combined drug regimen. Some will need the addition of neuroleptics or antidepressants only during breakthrough episodes of mania or depression, respectively.[1,36]

Because of the potential of VPA to cause neural tube defects, the drug should not be used during the first trimester of pregnancy. Pregnancy should be ruled out before the drug is started in a woman of child-bearing potential, and then she must use effective contraception after starting the drug.[36]

Four oral VPA formulations are available in the US: enteric-coated divalproex--a stable complex of VPA and sodium valproate in a 1:1 molar ratio; VPA; sodium valproate; and divalproex sodium sprinkle capsules. The latter is a hard, gelatin, pull-apart capsule that contains drug-coated sprinkles. The capsule can be swallowed intact or opened and sprinkled on soft foods. A rectal suppository is also available.[36]

The nonenteric oral preparations are rapidly absorbed from the stomach after ingestion, attaining peak serum concentrations within 2 hours. Divalproex sodium, actually the dimer of sodium valproate and VPA, is absorbed more slowly from the small intestine, reaching peak serum levels within 4 to 6 hours. Although it is better tolerated, the delayed absorption of the enteric tablet is somewhat less complete than that of the others. The sprinkle is absorbed more slowly than the nonenteric tablet, but it is quicker acting. Regardless of the formulation used, absorption can also be delayed if the drug is taken with food.[36]

It is important to note that the bioavailability of VPA (the pharmacologically active drug form) is essentially complete, regardless of the preparation administered. Once in the blood, VPA is rapidly distributed and highly bound (90%) to plasma proteins. The plasma elimination half-life ranges from 8 to 17 hours and can be reduced by the concomitant administration of hepatic microsomal enzyme-inducing drugs, such as phenytoin, barbiturates, and CBZ.[36]

VPA is generally well-tolerated. Common dose-related side effects include GI intolerance, sedation, tremor, and asymptomatic reduction in platelet count. VPA is less likely than Li to cause cognitive impairment. Tremors can be managed by lowering the dose or by adding propranolol to the regimen. Rare but potentially fatal effects include severe hepatic dysfunction, hemorrhagic pancreatitis, and agranulocytosis. Other serious side effects include neural-tube defects with first-trimester exposure and death from overdose. Platelet dysfunction, coagulopathies, and edema occur infrequently. Increased appetite, weight gain, and transient hair loss may occur.

Nausea or stomach cramping tends to occur early during the treatment course. These side effects often subside over time. The incidence varies among formulations, occurring more frequently with VPA and sodium valproate than with the enteric-coated divalproex sodium formulation: 15% to 20% versus 5% to 10%. To minimize GI side effects, VPA therapy should be started with divalproex. If GI effects do occur and persist, they usually can be managed by dose reduction. Persistent GI distress may be relieved by adding an H-2 receptor antagonist to the regimen or by switching to the sprinkle capsule.[36]

Sedation can be managed by reducing the daily dose of VPA. Hair loss can be kept to a minimum by multivitamin supplementation that contains zinc and selenium. If thrombocytopenia develops, the trough VPA level should be decreased to less than 80mcg/mL and the patient should be monitored.[36]

VPA may cause an increase in liver function tests (LFTs). Serum levels return to normal with dose reduction or discontinuation of treatment. Spontaneous resolution also occurs even if therapy is continued without altering the dose. Intervention is unwarranted unless patients become symptomatic, at which point the VPA dose should be decreased or discontinued.[36]

Potentially important drug interactions can occur with coadministration of VPA and CBZ. VPA inhibits CBZ metabolism thus raising serum CBZ concentrations. Conversely, CBZ increases the metabolism of VPA, thereby reducing blood levels of the latter. The 2 compete for protein-binding sites, potentially causing the concentration of "free" (pharmacologically active) drug to rise and promoting the risk of adverse effects and toxicity. Other drug interactions with VPA rarely result in clinically significant problems (Table IV).[36,50]


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.