Valproic acid with carbamazepine

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. 

II.e. 5.2. Interactions between first and second generation AEDs. Felbamate raises plasma concentrations of phenytoin, valproic acid and carbamazepine. Clearance of tiagabine, topiramate and zon-isamide is increased in the presence of an enzyme inducer. Vigabatrin reduces phenytoin concentrations after 4-5 weeks of comedication (via an unknown mechanism). For tiagabine, the elimination half-life may be reduced by 2-3 hours in the presence of an enzyme-induction AED. Lamotrigine elimination is slower if given with valproic acid. Topiramate reduces elimination of phenytoin. 

According to the Expert Consensus Panel for Mental Retardation Rush and Frances, (2000), the mainstays of the pharmacological treatment of acute mania or bipolar disorder in adults are anticonvulsant medications (divalproex, valproic acid, or carbamazepine) or lithium. Both divalproex or valproic acid and lithium were preferred treatments for classic, euphoric manic episodes. Divalproex or valproic acid was preferred over lithium and carbamazepine for mixed or dysphoric manic episodes and rapid-cycling mania. For depressive episodes associated with bipolar disorder, the addition of an antidepressant (SSRI, bupropion, or venlafaxine) was recommended. According to the Expert Consensus Panel, the presence of MR does not affect the choice of medication for these psychiatric disorders in adults. 

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 case was a female who reported with complaints of increased incidence of muscle twitching episodes during daytime hours. These included slapping leg and turning head to right. Patient was on valproic acid and carbamazepine and St. John s wort was started 50 days prior to the occurrence of adverse events. No carbamazepine levels were reported. 

Hallucinogen persisting perception disorder is commonly called the flashback. While flashbacks are brief, usually lasting only a few seconds, these experiences often cause considerable anxiety and distress, due to the sudden, unanticipated onset of the episodes and the inability of the sufferer to control their occurrence. Psychotherapy is often sufficient treatment for anxiety and distress associated with flashbacks. Occasionally treatment with a long-acting tranquilizer, such as clonazepam, may be required. Anticonvulsant drugs, such as valproic acid and carbamazepine, have also been used to control flashbacks. However, antipsychotic drugs have been reported to exacerbate flashbacks and should not be prescribed. 

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. 

More modern anticonvulsants, such as valproic acid and carbamazepine, do not inhibit folate metabolism directly, and are not associated with megaloblastic anemia, although they are associated with increased risk of neural tube defects. They inhibit the glycine cleavage system (Section 10.3.1.1) and hence both reduce the pool of one-carbon substituted folates and also cause hyperglycinemia (Mortensen et al., 1980). 

THERAPEUTIC USE Topiramate is equivalent to valproic acid and carbamazepine in children and adults with newly diagnosed partial and primary generalized epilepsy the drug is also effective as monotherapy for refractory partial epilepsy and refractory generalized tonic-clonic seizures. Topiramate also is more effective than placebo against both drop attacks and tonic-clonic seizures in patients with Lennox-Gastaut syndrome. 

Castro-Gago M, G6mez-Lado C, Eirfs-Punal J, Dfaz-Mayo I, Castineiras-Ramos DE. Serum biotinidase activity in children treated with valproic acid and carbamazepine. J Child Neurol 2010 25 (1) 32-5. 

Rakic Ignjatovic A, Miljkovic B, Todorovic D, Timotijevic I, Pokrajac M. Moclobemide monotherapy vs. combined therapy with valproic acid or carbamazepine in depressive patients a pharmacokinetic interaction study. Br J Clin Pharmacol 2009 67(2) 199-208. 

The miscellaneous anticonvulsants are contraindicated in patients with known hypersensitivity to any of the dru. Carbamazepine is contraindicated in patients with bone marrow depression or hepatic or renal impairment and during pregnancy (Category D). Valproic acid is not administered to patients with renal impairment or during pregnancy (Category D). Oxcarbazepine (Trileptal), a miscellaneous anticonvulsant, may exacerbate dementia... 

When carbamazepine is administered with primidone, decreased primidone levels and higher carbamazepine serum levels may result. Cimetidine administered with carbamazepine may result in an increase in plasma levels of carbamazepine that can lead to toxicity. Blood levels of lamotrigine increase when the agent is administered with valproic acid, requiring a lower dosage of lamotrigine... 

Phenobarbitone was the first AED and was introduced in 1912. It was largely replaced in 1932 by phenytoin for the management of tonic-xilonic seizures and partial and secondary epilepsy. Carbamazepine followed, then ethosuximide for absence seizures and valproic acid. These remained, apart from the introduction of the benzodiazepines, the mainstay of therapy until the last decade. They were introduced solely on their ability to control experimentally induced seizures. Their mechanisms of action were unknown and no thought was given to the possibility of NT modification and in fact subsequent research has shown that with the exception of the benzodiazepines none of them work primarily through NT manipulation. They act directly on neuronal excitability. 

Epilepsy is a clinical disorder characterized by spontaneous, recurrent seizures arising from excessive electrical activity in certain parts of the brain [51]. Currently available drugs, such as phenytoin, carbamazepine, valproic acid, lamotrigine, and topiramate (for molecular structures see Fig. 6), provide symptomatic seizure suppression in only 60-70% of those receiving treatment [52-54]. These drugs are also associated with unwanted side... 

Anticonvulsant drugs such as carbamazepine, diazepam, valproic acid, and phenobarbital also slightly increased the duration of the initial AD. However, the effects of these drugs on the other associated seizure events were quite different from PCP and ketamine. The effects of carbamazepine and diazepam, typical of the four compounds, are illustrated in figure 4. These compounds either suppressed the rebound spiking (diazepam, valproic acid, and phenobarbital) or lengthened the total seizure duration with no rebound suppression (carbamazepine). 

Assess the AED serum concentration and adjust therapy as needed for agents with a defined therapeutic range (e.g., phenytoin, carbamazepine, valproic acid, and phenobarbital). Drug levels can also be used to determine adherence to medication regimens for agents that do not have defined ranges. 

Studies suggest that as monotherapy for partial seizures, lamotrigine is as effective as carbamazepine and phenytoin lamotrigine may be better tolerated. Clinical data suggest that oxcarbazepine is as effective as phenytoin, valproic acid, and immediate-release carbamazepine, with perhaps fewer side effects. 

Phenytoin, carbamazepine, phenobarbital, oxcarbazepine, and valproic acid may interfere with vitamin D metabolism, causing asymptomatic high-turnover bone disease with normal bone density or decreased bone mineral... 

Carbamazepine may interact with other drugs by inducing their metabolism. Valproic acid increases concentrations ofthe 10,11-epoxide metabolite without affecting the concentration of carbamazepine. The interaction of erythromycin and clarithromycin (CYP3A4 inhibition) with carbamazepine is particularly significant. 

Anticonvulsants. Carbamazepine and, to a lesser extent, valproic acid have been tried in attempts to reduce craving by interfering with kindling as well. Initial pilot studies were positive but more recent results have been unimpressive. 

Carbamazepine is believed to be effective in BPD, though the data is far less robust than with valproic acid. It is prescribed at doses up to 1200mg/day. Like valproic acid, it can also canse birth defects and requires laboratory monitoring including serum levels. For more information on the use of carbamazepine, please refer to the discussion of bipolar disorder treatment in Chapter 3. 

Distribution - Valproic acid is rapidly distributed. Volume of distribution of total or free valproic acid is 11 or 92 L/1.73 m, respectively. Valproic acid has been detected in CSF (approximately 10% of total concentrations) and milk (about 1% to 10% of serum concentrations). Therapeutic range is commonly considered to be 50 to 100 mcg/mL of total valproate. The plasma protein binding of valproate is concentration-dependent. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (eg, aspirin). Conversely, valproate may displace certain protein-bound drugs (eg, phenytoin, carbamazepine, warfarin, tolbutamide). 

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