Mood stabilizers valproic acid

Yuan PX, Huang LD, Jiang YM, Gutkind JS, Manji HK, Chen G (2001) The mood stabilizer valproic acid activates mitogen-activated protein kinases and promotes neurite growth. J Biol Chem 27 34) 31674-31683... 

Of the mood stabilizers, valproic acid (Depakene, Depakote) is the most widely used. Like the other mood stabilizers, its onset of action can be delayed by several days. Valproic acid is a reasonably well tolerated mood stabilizer. It does occasionally cause tremor, and it can on rare occasion lower platelet counts or cause liver problems. For this reason, blood monitoring is required when starting this medication. In addition, valproic acid can irritate the stomach lining, but this problem is largely overcome by using the buffered form sodium divalproex (Depakote or Depakote ER). Finally, valproic acid can also cause hair loss or drowsiness. 

To review the mechanism of action of lithium and five anticonvulsants used as mood stabilizers (valproic acid, carbamazepine, lamotrigine, gabapentin and topiramate). 

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... 

Agents that increase GABA activity or decrease glutamate activity are used for the treatment of mania and for mood stabilization (eg, benzodiazepines, lamotrigine, lithiurn, or valproic acid). 

Mood stabilizers (e.g., lithium, valproic acid, and carbamazepine) used as augmentation agents may improve labile affect and agitated behavior. A placebo-controlled trial supports fast symptom improvement when divalproex is combined with either olanzapine or risperidone. 

Peterson CL, Laniel MA (2004) Histones and histone modifications. Curr Biol 14 R546-R551 Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS (2001) Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J Biol Chem 276 36734-36741... 

Mood Stabilizers. Lithium (Eskalith, Lithobid), valproic acid (Depakene), sodium valproate (Depakote), and carbamazepine (Tegretol) are most often used by psychiatrists to treat the bipolar disorders. These so-called mood stabilizers are also used to treat impulsivity and agitation in a variety of psychiatric disorders including dementia, certain personality disorders, and the disruptive behavior disorders of childhood. 

Several anticonvulsant medications have mood-stabilizing properties. Valproic acid and carbamazepine are... 

There is strong evidence that bipolar disorder is associated with SUD in adolescents (Wilens et ah, 1999) and that pharmacological interventions are an effective treatment for youth with SUD and bipolar disorder. Two studies, including one randomized controlled study, have reported that mood stabilizers, specifically lithium and valproic acid (Depakote), significantly reduced substance use in bipolar youth (Donovan and Nunes, 1996 Geller et ah, 1998). In addition, these agents are considered effective agents for the treatment... 

In the Expert Consensus survey (Rush and Frances, 2000), respondents were asked to rate which classes of medication may be helpful for treating patients with severe and persistent physical aggression and those who destroyed property. The atypical antipsychotics were rated most highly, followed by anticonvulsant/ mood stabilizer. These were followed (with much lower priority) by antidepressants and beta-blockers. Among the atypical antipsychotics, risperidone was rated most highly, followed by olanzapine others had much lower ratings. Divalproex or valproic acid and carbamazepine were rated highest of the mood stabi-... 

Another group of mood-stabilizing drugs that are also anticonvulsant agents have become more widely used than lithium. These include carbamazepine and valproic acid for the treatment of acute mania and for prevention of its recurrence. Lamotrigine is approved for prevention of recurrence. Gabapentin, oxcarbazepine, and topiramate are sometimes used to treat bipolar disorder but are not approved by FDA for this indication. Aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone are approved by FDA for the treatment of manic phase of bipolar disorder. Olanzapine plus fluoxetine in combination and quetiapine are approved for the treatment of bipolar depression. 

Perhaps even more important in children is the issue of bipolar disorder. Mania and mixed mania have not only been greatly underdiagnosed in children in the past but also have been frequently misdiagnosed as attention deficit disorder and hyperactivity. Furthermore, bipolar disorder misdiagnosed as attention deficit disorder and treated with stimulants can produce the same chaos and rapid cycling state as antidepressants can in bipolar disorder. Thus, it is important to consider the diagnosis of bipolar disorder in children, especially those unresponsive or apparently worsened by stimulants and those who have a family member with bipolar disorder. These children may need their stimulants and antidepressants discontinued and treatment with mood stabilizers such as valproic acid or lithium initiated. 

FIGURE 7—35. Combination treatments for bipolar disorder (bipolar combos). Combination drug treatment is the rule rather than the exception for patients with bipolar disorder. It is best to attempt monotherapy, however, with first-line lithium or valproic acid, with second-line atypical antipsychotics, or with third-line anticonvulsant mood stabilizers. A very common situation in acute treatment of the manic phase of bipolar disorder is to treat with both a mood stabilizer and an atypical antipsychotic (atypical combo). Agitated patients may require intermittent doses of sedating benzodiazepines (benzo assault weapon), whereas patients out of control may require intermittent doses of tranquil-izing neuroleptics (neuroleptic nuclear weapon). For maintenance treatment, patients often require combinations of two mood stabilizers (mood stabilizer combo) or a mood stabilizer with an atypical antipsychotic (atypical combo). For patients who have depressive episodes despite mood stabilizer or atypical combos, antidepressants may be required (antidepressant combo). However, antidepressants may also decompensate patients into overt mania, rapid cycling states, or mixed states of mania and depression. Thus, antidepressant combos are used cautiously. 

The finding of abnormal cell growth stimulated by mood stabilizers is consistent with research showing that bipolar patients taking lithium and valproic acid have increased hippocampal regions measured on MRI. Beyer et al. (2004) found that this increase in hippocampal size correlated with the use of lithium. They also related it to the laboratory studies of neurogenesis. 

Of as yet unknown consequence to the brain and nervous system, there are many studies indicating that valproic acid promotes a variety of potentially dangerous viruses (e.g., Fan et al., 2005). Both valproic acid and carbamazepine cause a small increase in the rate of major congenital malformations in infants (Wide et al., 2004). Acute and potentially fatal pancreatitis has been reported with valproic acid (e.g., Grauso-Eby et al., 2003). Liver failure is a known problem as well. Valproic acid is known to cause hyperammonemia with encephalopathy (e.g., McCall et al., 2004). Severe and even lethal skin disorders can occur with all of the antiseizure medications now used as mood stabilizers. The various adverse effects of valproic acid and other mood stabilizers are not nearly as benign as physicians believe in their eagerness to switch patients from lithium. 

UGTs are responsible for the metabolism of many anxiolytics, antidepressants, mood stabilizers and antipsychotics. Inhibition of the metabolism of carbamazepine by valproic acid in part results from an effect on UGTs. Amitriptyline and clomipramine decrease the metabolism of morphine by affecting UGTs. 

Two anticonvulsants, carbamazepine (Tegretol) and valproic acid, also referred to as valproate (Depakote, Depakene), have proven mood-stabilizing properties (see figure 15-E). These agents are most useful when lithium is contraindicated or when a patient does not respond to or cannot tolerate lithium. Rapid cyclers, who often are poorly controlled with lithium, are good candidates for one of these alternative agents. Valproic acid appears to be indicated more for manic or mixed states of bipolar disorder, and is probably not as effective in depressed states. The anticonvulsants are often employed in conjunction with lithium. 

Anticonvulsants with antikindling properties are effective for stabilizing mood (e.g., carbamazepine, valproic acid). 

Jeong MR et al (2003) Valproic acid, a mood stabilizer and anticonvulsant, protects rat cerebral cortical neurons from spontaneous cell death a role of histone deacetylase inhibition. FEBS Lett 542(l-3) 74-78... 

Depakene or Depakote (sodium valproate or valproic acid) Medications commonly used as mood stabilizers for the following reasons (a) inadequate response or intolerance to antipsychotics or lithium (b) manic symptoms (c) rapid cycling of the condition (d) EEG abnormalities and... 

Evidence for the safety and the efficacy of lithium salts in the treatment of mania and the prevention of recurrent attacks of bipolar manic-depressive illness is both abundant and convincing. However, the limitations and adverse effects of lithium salts have become increasingly well appreciated, and efforts to find alternative antimanic or mood-stabilizing agents have intensified. The most successful alternatives or adjuncts to lithium to date are the anticonvulsants carbamazepine, lamotrigine, and valproic acid. 

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