Valproate
For a more detailed discussion of this topic, see Valproate, Sec. 31.33, p. 3271, in Comprehensive Textbook of Psychiatry, 9th Edition.
Valproate (Depakene, Depakote), or valproic acid, is approved for the treatment of manic episodes associated with bipolar I disorder and is one of the most widely prescribed mood stabilizers in psychiatry. It has a rapid onset of action and is well tolerated, and numerous studies suggest that it reduces the frequency and intensity of recurrent manic episodes over extended periods of time.
Chemistry
Valproate is a simple-chain branch carboxylic acid. It is called valproic acid because it is rapidly converted to the acid form in the stomach. Multiple formulations of valproic acid are marketed. These include valproic acid (Depakene); divalproex sodium (Depakote), an enteric-coated delayed release 1:1 mixture of valproic acid and sodium valproate available in tablet and sprinkle formulation (can be opened and spread on food); and sodium valproate injection (Depacon). An extended-release preparation is also available. Each of these is therapeutically equivalent because at physiologic pH, valproic acid dissociates into valproate ion.
Pharmacologic Actions
Regardless of how it is formulated, valproate is rapidly and completely absorbed 1 to 2 hours after oral administration, with peak concentrations occurring 4 to 5 hours after oral administration. The plasma half-life of valproate is 10 to 16 hours. Valproate is highly protein bound. Protein binding becomes saturated at higher dosages, and concentrations of therapeutically effective free valproate increase at serum concentrations above 50 to 100 μg/mL. The unbound portion of valproate is considered to be pharmacologically active and can cross the blood–brain barrier. The extended-release preparation produces lower peak concentrations and higher minimum concentrations and can be given once a day. Valproate is metabolized primarily by hepatic glucuronidation and mitochondrial β oxidation.
The biochemical basis of valproate’s therapeutic effects remains poorly understood. Postulated mechanisms include enhancement of γ-aminobutyric acid (GABA) activity, modulation of voltage-sensitive sodium channels, and action on extrahypothalamic neuropeptides.
Therapeutic Indications
Valproate is currently approved as monotherapy or adjunctive therapy of complex partial seizures, monotherapy and adjunctive therapy of simple and complex absence seizures, and adjunctive therapy for patients with multiple seizures that include absence seizures. Divalproex has additional indications for prophylaxis of migraine.
Bipolar I Disorder
Acute Mania
About two-thirds of persons with acute mania respond to valproate. The majority of patients with mania usually respond within 1 to 4 days after achieving valproate serum concentrations above 50 μg/mL. Antimanic response is generally associated with levels greater than 50 μg/mL, in a range of 50 to 150 μg/mL. Using gradual dosing strategies, this serum concentration may be achieved within 1 week of initiation of dosing, but rapid oral loading strategies achieve therapeutic serum concentrations in 1 day and can control manic symptoms within 5 days. The short-term antimanic effects of valproate can be augmented with addition of lithium, carbamazepine (Tegretol), serotonin–dopamine antagonists (SDAs), or dopamine receptor antagonists (DRAs). Numerous studies have suggested that the irritable manic subtype respond significantly better to divalproex than lithium or placebo. Because of its more favorable profile of cognitive, dermatologic, thyroid, and renal adverse effects, valproate is preferred to lithium for treatment of acute mania in children and elderly persons.
Acute Bipolar Depression
Valproate possesses some activity as a short-term treatment of depressive episodes in bipolar I disorder, but this effect is far less pronounced than for treatment of manic episodes. Among depressive symptoms, valproate is more effective for treatment of agitation than dysphoria. In clinical practice, valproate is most often used as add-on therapy to an antidepressant to prevent the development of mania or rapid cycling.
Prophylaxis
Studies suggest that valproate is effective in the prophylactic treatment of bipolar I disorder, resulting in fewer, less severe, and shorter manic episodes. In direct comparison, valproate is at least as effective as lithium and is better tolerated than lithium. It may be particularly effective in persons with rapid-cycling and ultrarapid-cycling bipolar disorders, dysphoric or mixed mania, and mania caused by a general medical condition as well as in persons who have comorbid substance abuse or panic attacks and in persons who have not had complete favorable responses to lithium treatment.
Schizophrenia and Schizoaffective Disorder
Valproate may accelerate response to antipsychotic therapy in patients with schizophrenia or schizoaffective disorder. Valproate alone is generally less effective
in schizoaffective disorder than in bipolar I disorder. Valproate alone is ineffective for treatment of psychotic symptoms and is typically used in combination with other drugs in patients with these symptoms.
in schizoaffective disorder than in bipolar I disorder. Valproate alone is ineffective for treatment of psychotic symptoms and is typically used in combination with other drugs in patients with these symptoms.
Other Mental Disorders
Valproate has been studied for possible efficacy in a broad range of psychiatric disorders. These include alcohol withdrawal and relapse prevention, panic disorder, posttraumatic stress disorder, impulse control disorder, borderline personality disorder, and behavioral agitation and dementia. Evidence supporting use in these cases is weak, and any observed therapeutic effects may be related to treatment of comorbid bipolar disorder.
Precautions and Adverse Reactions
Although valproate treatment is generally well tolerated and safe, it carries quite a few black box warnings and other warnings (Table 33-1
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