Mood stabilizers - valproate

Legend Drugs that can increase the serum 1 levels/effects of 1 valproate s r Drugs whose serum levels/effects can be increased by 1 valproate ( ) Questionable interaction 

Rifampin is a prototype inducer of the cytochrome P450 enzyme CYP3A4. This induction of microsomal enzymes by rifampin is thought to increase the production of toxic metabolites, contributing to the potential of valproate to cause hepatotoxicity, although this clinical outcome is rare. Valproate inhibits glucuronidation of zidovudine and increased events from zidovudine are possible. 

The combined use of valproate and paroxetine has not been found to result in any significant drug-drug interaction. 

An interaction involving protein binding displacement may occur with aspirin. 

Children given antipyretic doses of aspirin co-administered with valproate were found to exhibit a decrease in protein binding and an inhibition of the metabolism of valproate. The common use of aspirin should alert to the need for caution if these drugs are co-administered. Interaction with other non-steroidal anti-inflammatory drugs (NSAIDs) may not be so prominent. 

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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. 

First, initiate and/or optimize mood-stabilizing medication lithium3 or lamotrigine6 Alternative anticonvulsants carbamazepine, oxcarbazepine, or valproate... 

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). 

Chen G, Jiang L et al. The mood stabilizing agents lithium and valproate robustly increase the expression of the neu-roprotective protein bcl-2 in the CNS. 

Wang JF, Young LT. Differential display PCR reveals novel targets for the mood-stabilizing dmg valproate including the molecular chaperone GRP78. Mol Pharmacol 1999 55 521-527. 

Chen, G., Huang, L. D., liang, Y. M. and Manji, H. K. The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. /. Neurochem. 72 1327-1330,... 

Divalproex sodium (sodium valproate) is now the most prescribed mood stabilizer in the United States. It is FDA approved only for the treatment of acute manic or mixed episodes, but it is often used as maintenance monotherapy for bipolar disorder. 

First, optimize current mood stabilizer or initiate mood-stabilizing medication lithium,0 valproate,0 or carba-mazepine0 Consider adding a benzodiazepine (lorazepam or clonazepam) for short-term adjunctive treatment of agitation or insomnia if needed Alternative medication treatment options carbam-azepine0 if patient does not respond or tolerate, consider atypical antipsychotic (e.g., olanzapine, quetiapine, risperidone) or oxcarbazepine. 

Approximately 20% to 50% of women with bipolar disorder relapse postpartum prophylaxis with mood stabilizers (e.g., lithium or valproate) is recommended immediately postpartum to decrease the risk of relapse. 

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 (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. 

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-... 

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. 

Mood stabilizers phenytoin, valproate, topiramate Sedative/anxiolytics diazepam, barbiturates Beta-blockers propranolol... 

Treatment of choice - mood stabilizer with or without an antidepressant (e.g. lithium, valproate, carbamazepine, lamotrigine). Antidepressants include an SSRI, venlafaxine, mirtazepine as possibilities but few controlled trials to substantiate choice. 

Alternate treatments. Mood-stabilization and control of manic or hy-pomanic episodes in some subtypes of bipolar illness may also be achieved with the anticonvulsants valproate and carbamazepine, as well as with calcium channel blockers (e.g., verapamil, nifedipine, nimodipine). Effects are delayed and apparently unrelated to the mechanisms responsible for anticonvulsant and cardiovascular actions, respectively. 

Diagnostic boundaries in juvenile-onset BD need to be defined, since children with hypomania or manic-like symptoms may be increasingly treated with mood stabilizers. In parallel, this would require more complex algorithms because very few controlled trials have been reported (Walkup, 1995). In contrast to the studies of adults reported in the literature, the pharmacological treatment of childhood bipolarity with anticonvulsants remains an understudied area. Carbamazepine appears to be less efficacious than valproate in adult rapid cycling, yet no studies have identified predictors of treatment response to CBZ or any other mood stabilizer (besides lithium) in a pediatric population. 

Differential effects of the three major mood stabilizers on phosphatase activity have been reported lithium blocks activity, carbamazepine increases activity, and valproate has no effect (Vadnal and Parthasarathy... 

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. 

Watson DG, Watterson JM, Lenox RH. Sodium valproate down-regulates the myristoylated alanine-rich C kinase substrate [MARCKS) in immortalized hippocampal cells a property unique to PKC-mediated mood stabilization J Pharmacol Exp Ther 285 307-316, 1998 Watson M, Roeske WR, Yamamura HI Cholinergic receptor heterogeneity, in Psychopharmacology The Third Generation of Progress. Edited by Meltzer HY. New York, Raven, 1987, pp 241-248... 

Although many mechanisms have been proposed, the basis for the mood-stabilizing effects of valproate is most likely concordant with... 

A related issue is the patient s ability to metabolize and eliminate drugs adequately. For example, lithium is excreted entirely by the kidneys, and if a patient suffers from significantly impaired renal function, high, potentially toxic levels could develop on standard doses. Although the dose could be adjusted to compensate for the decrease in drug clearance, it might be more appropriate to choose another mood stabilizer such as valproate or carbamazepine, because they are primarily metabolized through the liver. 

The possible differing mechanisms of action of three mood stabilizers (i.e., lithium, valproate, carbamazepine) are incorporated into a bidimensional model of mood regulation that postulates two gating zones (one for depression and one for mania). These zones are thought to be subserved by different neurochemical abnormalities, leading to a situation in which both could be impacted by certain agents (i.e., mood stabilizers) or, alternatively, could individually be affected by unidirectional compounds (e.g., HCAs). 

Post and Kramlinger (386) have also suggested that lithium added to carbamazepine may be useful in treatment-resistant mood-disordered patients. One possible basis for this approach is that carbamazepine, which has a tricyclic ring structure similar to imipramine, may sensitize postsynaptic serotonin receptors in a similar way to standard drugs such as imipramine. A mood stabilizer (e.g., lithium, valproate, carbamazepine) plus antidepressant may benefit some rapid cycling or mixed bipolar patients, attenuating the propensity to switch from mania to depression. 

ECT should be considered for more severe forms of depression (e.g., those associated with melancholic and psychotic features, particularly when the patient exhibits an increased risk for self-injurious behavior) or when there is a past, well-documented history of nonresponse or intolerance to pharmacological intervention. Limited data indicate that bipolar depressed patients may be at risk for a switch to mania when given a standard TCA. A mood stabilizer alone (i.e., lithium, valproate, carbamazepine, lamotrigine), or in combination with an antidepressant, may be the strategy of choice in these patients. Some elderly patients and those with acquired immunodeficiency syndrome may also benefit from low doses of a psychostimulant only (e.g., methylphenidate) (see also Chapter 14, The HIV-Infected Patient ). Fig. 7-1 summarizes the strategy for a patient whose depressive episode is insufficiently responsive to standard therapies. 

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