Valproate mania

Until recently, most studies on antimanic agents were exclusively conducted in patients with bipolar I disorder and euphoric mania, resulting in firm evidence that lithium is especially effective in this type of mania. Valproate shows equal overall efficacy in mania however, fewer studies support its efficacy in euphoric mania compared with lithium. Valproate usually has a more rapid onset of action than lithium as its wide therapeutic window allows loading treatment strategies. Valproate may be the preferred choice in patients with numerous (more than eight) previous manic episodes or more than four depressive episodes, and who... 

The first mood stabilizer was lithium (its antimanic action being discovered in 1948) more recently the anticonvulsant drugs carbamazepine and valproate have been found to be effective in acute mania. Unfortunately these mood stabilizers are only successful in controlling mania to a limited extent and few patients are well enough to leave hospital at the end of 3 weeks of treatment using these drugs as monotherapy. It is increasingly common for combination treatment to be advocated, in which an antipsychotic dmg is combined with lithium or an anticonvulsant. 

Olanzapine Zyprexa 20, 30 mg Tablets 2.5, 5, 7.5, 10, 5-20 mg/day in 1 or 2 doses combination with lithium or valproate for the acute treatment of mania or mixed states for bipolar I disorder. Olanzapine and aripiprazole are approved for relapse prevention as well as for acute therapy... 

Divalproex sodium is comprised of sodium valproate and valproic acid. The delayed-release and extended-release formulations are converted in the small intestine into valproic add, which is the systemically absorbed form. It was developed as an antiepileptic drug, but also has efficacy for mood stabilization and migraine headaches. It is FDA-approved for the treatment of the manic phase of bipolar disorder. It is generally equal in efficacy to lithium and some other drugs for bipolar mania. It has particular utility in bipolar disorder patients with rapid cycling, mixed mood features, and substance abuse comorbidity. Although not FDA-approved for relapse prevention, studies support this use, and it is widely prescribed for maintenance therapy. Divalproex can be used as monotherapy or in combination with lithium or an antipsychotic drug.31... 

Introduced in clinical practice in the 1960s, lithium was the first mood stabilizer to be used in China. This was followed by carbamazepine and sodium valproate. For many years, these were the only treatment options available as mood stabilizers. Although lamotrigine was approved for maintenance treatment of bipolar I disorder in 2003 by FDA (Food and Drug Administration) in the USA, this indication has not yet been approved by the Chinese authorities. At present, only one atypical antipsychotic drug, risperidone, has been approved for treating acute mania (February 2005 by SFDA [State Food and Drug Administration]) in China (see Table 6.1). 

Turning to the pharmacotherapy for mania, for decades lithium was the only effective drug treatment. More recently, a number of antiepileptic drugs including carba maze pine, lamotrigine and valproate have been shown to also act as mood stabilisers and are becoming established for the treatment and prophylaxis of both unipolar mania and bipolar manic depressive disorders. 

Lithium, divalproex sodium (valproate), aripiprazole, olanzapine, que-tiapine, risperidone, and ziprasidone are currently approved by the FDA for treatment of acute mania in bipolar disorder. Lithium, olanzapine, and lamotrigine are approved for maintenance treatment of bipolar disorder. Quetiapine is the only antipsychotic that is FDA approved for bipolar depression. 

Lithium is the drug of choice for bipolar disorder with euphoric mania, whereas valproate has better efficacy for mixed states, irritable/dysphoric mania, and rapid cycling compared with lithium. 

Ari pi prazole, olanzapine, quetiapine, risperidone, and ziprasidone are effective as monotherapy or as add-on therapy to lithium or valproate for acute mania. Prophylactic use of antipsychotics can be needed for some patients with recurrent mania or mixed states, but the risks versus benefits must be weighed in view of long-term side effects (e.g., obesity, type 2 diabetes, hyperlipidemia, hyperprolactinemia, cardiac disease, and tardive dyskinesia). 

Use alone or in combination with other drugs (e.g., valproate, carba-mazepine, antipsychot-ics) for the acute treatment of mania and for maintenance treatment. 

Use in combination with other drugs (e.g, anti-psychotics, lithium, valproate) for the acute treatment of mania or mixed episodes. Use as a short-term adjunctive sedativehypnotic agent. Binds to the benzodiazepine site and augments the action of GABA/, by increasing the frequency of Cl" channel opening which causes hyperpolarization (a less excitable state) and inhibits neuronal firing. 

Lamotrigine is effective for the maintenance treatment of bipolar I disorder in adults. It has both antidepressant and mood-stabilizing effects, and it may have augmenting properties when combined with lithium or valproate. It has low rates of switching patients to mania. Although it is less effective for acute mania compared to lithium and valproate, it may be beneficial for the maintenance therapy of treatment-resistant bipolar I and II disorders, rapidcycling, and mixed states. It is often used for bipolar II patients. 

Valproate is as effective as lithium and olanzapine for pure mania, and it can be more effective than lithium for rapid cycling, mixed states, and bipolar disorder with substance abuse. It reduces the frequency of recurrent manic, depressive, and mixed episodes. 

Lithium, carbamazepine, antipsychotics, or benzodiazepines can augment the antimanic effects of valproate. Valproate can be added to lithium or carbamazepine to achieve synergistic effects. Atypical antipsychotics can be added to valproate for breakthrough mania or if there is partial response to antipsychotic monotherapy. 

Valproate (Depakote, Depakene). Valproate is an anticonvnlsant that has been demonstrated in multiple controlled clinical trials to be an effective mood stabilizer and, in fact, has obtained FDA approval for the treatment of acute mania. It appears to be particularly effective in bipolar patients who experience mixed episodes or rapid cycling or who have not responded well in the past to lithium. 

Carbamazepine (Tegretol, Equetro). Carbamazepine is another anticonvulsant with documented efficacy in treating BEAD, and was recently FDA approved for this indication. Like valproate, carbamazepine is usually preferred to lithium in cases of mixed mania or rapid cycling. 

Consequently, the choice for a primary mood stabilizer in acute therapy now includes lithium, valproate, carbamazepine, and the atypical antipsychotics. Among these, lithium and valproate remain first-line agents. Valproate and lithium are probably equally effective in the treatment of classic euphoric mania, but valproate and, for that matter, carbamazepine do not appear to provide the same degree of protec-... 

Numerous open studies, and seven controlled studies, have shown that valproate is effective in the treatment of acute mania. It has also been claimed to have an antidepressant action. Recent studies have shown that valproate is effective in the long-term treatment of bipolar disorder. 

Children See Warning Box. The safety and efficacy of divalproex sodium for the treatment of acute mania has not been studied in individuals younger than 18 years of age. Divalproex sodium extended-release tablets are not recommended in children. Use of valproate sodium injection has not been studied in children below 2 years of age. 

Valproic acid, valproate sodium, and (DVP) are carboxylic acid-derivative anticonvulsants. Divalproex sodium is a stable coordination compound consisting of valproic acid and valproate sodium in a 1 1 molar ratio (AHFS, 2000). It is a pro-drug of valproate, dissociating into valproate in the GI tract (AHFS, 2000), and a simple branched-chain carboxylic acid (w-dipropylacetic acid) with antiepileptic activity against a variety of types of seizures (Beydoun et al., 1997). Divalproex sodium has been approved for treating adults with simple and complex absence seizures (Mattson et al., 1992), and for mania. It has shown efficacy across a broad spectrum of BD subtypes (i.e., pure mania, mixed mania, and rapid cycling) (Pope et al., 1991 Bowden et al., 1994). 

Valproate, a simple branched-chain fatty acid, was first reported as a successful treatment for acute mania by Lambert and colleagues in 1966. Following this report, at least 16 uncontrolled trials consistently supported the observation that valproate has acute and long-term mood-stabilizing effects in patients with bipolar disorder (reviewed by Keck et al. 1992a). Recently, five double-blind controlled studies of valproate have been completed that provide definitive evidence of its efficacy in acute mania. 

In total, 61 (54%) of 113 patients with acute mania treated with valproate in controlled clinical trials showed moderate or better improvement. In those trials comparing it with placebo, valproate demonstrated significant efficacy. Further, when compared with lithium, no significant differences in response rates were observed. In summary, valproate has demonstrated considerable efficacy in the treatment of acute mania, although, as with lithium, 25%-50% of the patients in these trials did not respond. 

Lambert 1984 McElroy et al. 1988b] suggested that valproate may be a much better antimanic than antidepressant agent. In a study of 78 consecutively recruited patients with rapid-cycling bipolar disorder treated with open-label valproate alone or in combination with other psychotropic agents, Calabrese and colleagues [Calabrese and Delucchi 1990 Calabrese et al. 1992] reported a 54% valproate response in acute mania, an 87% response in acute mixed states, and a 19% response in acute depression. However, they did observe a prophylactic antidepressant effect in patients subsequently. Additional controlled studies are needed to clarify valproate s antidepressant efficacy. 

---