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Depakote Review Article

 

An extended-release form of this drug, Depakote ER, is prescribed to prevent migraine headaches. The delayed-release tablets are also used for this purpose. Depakote, in both delayed-release tablet and capsule form, is used to treat certain types of seizures and convulsions. It may be prescribed alone or with other epilepsy medications. The delayed-release tablets are also used to control the manic episodes--periods of abnormally high spirits and energy--that occur in bipolar disorder (manic depression). Depakote is a prescription drug approved by the U.S. Food and Drugs Administration (US FDA) for the treatment of epileptic seizures, manic episodes of bipolar disorder (mania), and as prophylactic agent for chronic migraine. Depakote is a delayed release tablet, as opposed to its predecessor Depakene (Valproic acid) which is an immediate release tablet. Depakote is the only anti-epileptic drug approved for two non-epileptic conditions. Let us discuss each condition and relate the use of Depakote.


Seizures & Epilepsies Seizure is a disease symptom characterized by abnormal firing of neuronal impulses from the nervous system. Seizure is manifested in different forms such as altered mental state, momentary loss of senses, uncontrollable movements or even loss of consciousness. Seizure is caused by a disruption in the normal physiological state of a neuron caused by infection, stress, injury, intoxication, or an underlying disease. Continue reading...

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Its molecular structure is
Divalproex Sodium

Epilepsy, on the other hand, is a chronic neurological disorder characterized by recurrent seizure attacks without an identifiable cause such as those mentioned above. It is the result of disturbed electrical activity in the brain. Epileptic seizure attack is periodic yet unpredictable, which may or may not be accompanied by convulsions (violent involuntary contraction of muscles).

The prevalence of epilepsy is quite high. In the United States, there are approximately 2.5 million patients suffering from epilepsy, and nearly 50 million worldwide (WHO, 2009). Studies show that at least 10% of all people will experience seizure during their lifetime, with 3% getting a diagnosis of epilepsy (CDC). Annually $15.5 billion in direct and indirect medical costs are caused by this disease.

In the normal physiological state, neuronal activity is responsible for the release of inhibitory and excitatory neurotransmitter. Normal neuronal activity is made possible by adequate supply of glucose, oxygen, sodium, potassium, calcium, chlorides and amino acids in the brain. Normal pH, as well as normal receptor function is also needed. Excessive excitation or impairment of inhibitory function of neurons results in epilepsy.

The International Classification of Epileptic Seizures (ICES) have classified epilepsy according to seizures types:

• Partial Seizures - seizures which begin in only one hemisphere of the brain; includes simple partial seizures, complex partial seizures and secondarily generalized seizures

• Generalized Seizures – seizures which involve both hemispheres of the brain; includes several seizures like absence (characterized as blank stare), myoclonic (characterized with brief shock like muscular contractions), and others

• Unclassified Seizures – seizures which do not have fall on the other classficiations, like infantile spasms

• Status Epilepticus – seizures which lasts longer than 30 minutes

Depakote is used alone or administered together with other drugs for the treatment of complex partial seizures and generalized seizures.

Depakote’s mechanism of action has not been well established. However, several studies suggest that Depakote acts by potentiating the effects of gamma-amino butyric acid or GABA. As stated above, epilepsy is a condition that is caused by excessive excitation in the brain. GABA is a neurotransmitter that decreases this excitation – it antagonizes the effects of excitation. It is thought that Depakote either increases the concentration of GABA in the brain, or increases post synaptic responses to GABA.

Several studies have shown the effectiveness of Depakote for epilepsy, like studies by Coulter, Wu, & Allen in 1980, and more recently by Mattson and colleagues in 2002. Beydoun, Sackellares & Shu (1997) found that Depakote when used as a monotherapy is effective for reducing seizure attacks. In another study by Willmore, Shu, & Wallin (1994), they found Depakote is also effective when used together with carbamazepine or phenytoin.

In a review made by Davis, Peters & McTavish (1994) of the valproic acid (the acid form of Depakote), they said that the efficacy of Depakote as monotherapy is similar to that of carbamazepine, phenytoin, phenobarbital (in the treatment of generalized and partial seizures) and ethosuximide (treatment of absence seizures). They further stated that the several studies support the effectiveness of the drug as first line therapy for a wide range of seizure types. Another study found that valproic acid is effective for both adults and children (Coulter, Wu & Allen, 1980).

Migraine

Migraine is an episodic medical condition characterized by severe headache (Pubmed Health). The headache pain felt is described as a severe throbbing pain in the head or neck, which worsens upon exertion. The pain may last from 6 to 48 hours. Migraine is usually accompanied by symptoms such as sensitivity to light, sound or odors, nausea and vomiting. Migraine pain may vary in severity, frequency of attack, and duration but what is common is that patients’ normal functioning and quality of life is affected. According to the World Health Organization, migraine is the 19th disease with the highest disability adjusted life years (DALY) lost (DALY is the measure of total life years lost due to a disease or condition, in this case migraine).

According to the World Health Organization, there is an estimated of 3000 migraine attacks in a day per million population. In UK, there is an estimated 15% prevalence of migraine, while in the US, 18% of women are affected and 6% for men.

Migraine has not been well established, however, it is found that migraine is caused by an abnormal brain activity. Migraine attack may be triggered by several factors such as food, chemicals, stress, etc.

Valproic acid and divalproex sodium have been used in the treatment of migraine since the 1980s (Freitaq, 2003). Several studies have proven its effectiveness in preventive therapy of migraine (Mathew et al., 1995; Silberstein, 2002; Freitaq, 2003). These studies found a reduction in the frequency of attacks (>50% for Mathew et al.), reduction in the duration of an attack, and reduction in the intensity of pain. Accoding to Matthew and colleagues (1995), valproic acid is generally well tolerated among patients - only about 13% or less experience serious side effects, which make the drug intolerable for them.

The recommended dose of valproic acid for migraine prophylaxis is 500mg, once a day. This was proven in a dose controlled study by Klapper in 1997. Furthermore, he found that at higher doses of the drug, the adverse effects felt are intolerable. This finding was supported by Kinze and colleagues (2008), who recommended a dose range of only 500-600mg a day.

Depakote is the only antiepileptic drug approved for migraine treatment and prophylaxis.

Mania

Mania is a psychological condition in which there is an elevated or irritable mood that persists for at least one week. It is the opposite of depression. Patients report “elevated” symptoms such as grand ideations, excessively high self esteem, psychomotor agitations, and functional and social impairment. Episodes of mania and depression make up a bipolar disorder.

Bipolar disorder, or manic-depressive disorder, is a psychological condition wherein there is a cycle between depressive and manic mental states. These mental states may occur one after another quickly, or may even occur simultaneously, called a mixed state. (Pubmed Health). According to the World Health Organization, there is an estimated 2.4% of people worldwide suffering from this condition. Currently, bipolar disorder is the leading disease with the most disability adjusted life years.

Bipolar disorder has two episodes – mania and depression.

There have been four etiologies proposed for bipolar disorder - genetics (80-90% of cases have family history), presence of hyperactive G proteins, psychosocial and physical stressors, and catecholamine related activity. Catecholamines are neurotransmitters which are responsible for a lot of physiological functions, which include stimulation and neuromodulation. Recently, it has been found that during mood cycling, these neurotransmitters are very active. In manic episodes, there are elevated levels of norepinephrine, dopamine and acetylcholamine, while in depressive episodes there is a decrease in these hormones. Problems with GABA have also been found to be associated with bipolar disorder.

Depakote is an anticonvulsant approved for the treatment of manic episodes in bipolar disorder due to its effect on the neurotransmitter GABA, modulating its release and effects on receptors. It is becoming recognized as first line treatment for mania. Depakote is effective both as monotherapy and add-on therapy with Lithium.

The US FDA has provided two studies that prove the efficacy of Depakote for the treatment of acute mania in bipolar disorder. However, the safety and efficacy of use for more than 3 weeks has not been established.

In a study by Bowden et al. (2000), Depakote was compared against Lithium (first line therapy for bipolar disorder) and placebo. The group concluded that there was no significant difference between the two, though fewer patients discontinued Depakote than Lithium. In another study by Gyulai et al.(2003), they determined the efficacy of using Depakote as a maintenance therapy. The group found that Depakote together with an SSRI drug is more effective in preventing recurring depressive attack than SSRI alone. Another study found that Depakote in combination with quetiapine is more effective than monotherapy (Sachs, et al., 2004). Gyulai etal. concluded that at some points, Depakote was more effective than Lithium.

Cancer

Currently, Depakote is being studied for possible indications in cancer.

Cancer is a disease of unknown etiology but it is found that an aberration in DNA is the initial step in cancer. Histones are proteins that are found in DNA - when problems in histone occur, cancer develops. These problems in histone are mediated by histone modifying enzymes, such as histone deacetylase.

Histone deacetylase (HDAC) regulates the expression of proteins involved in cancer initiation and progression. HDAC removes acetyl groups from histones, enabling the transcription of genes necessary for cancer development (Glozak & Seto, 2007). Because HDAC is a potential drug target for cancer, drugs affecting it are being studied and considered for cancer therapy. Depakote is one drug affecting histones.

Phiel and colleagues (2001) have found that valproic acid has a direct inhibitory effect on histone deacetylase. Even at therapeutic levels, it mimics trichostatin A (the normal inhibitory protein for HCAD), causing inhibition on HDAC. A further studies made by Kramer et al. found that there are two classes of HDAC, numbered I and II. They found that aside from inhibiting HDAC I, Depakote also induces proteosomal degradation of HDAC II, stating two possible mechanisms for HDAC-based cancer therapy by Depakote. Several in vitro studies have proven the efficacy of Depakote against tumor cells, from varying stages - proliferation, differentiation, metastasis, immunogenicity, and angiogenesis (Kuendgen, et al, 2005). Though in vitro studies prove to be hopeful, it is yet to be established in clinical use as in vivo clinical trials in actual cancer patients are still lacking.

Teratogen

Depakote is well known to be a teratogen. The FDA has stated clearly that the drug can produce dangerous teratogenic effects like neural tube defects and spina bifida. FDA further states that women who have childbearing potential should be informed well and counseled regarding this adverse effect prior to use.

Several studies have been made to assess this adverse effect. In a study by Nau & Loscher published in 1986, they studied valproic acid and its metabolites for teratogenecity in mice. They found that at a dose of 600mg/kg was highly teratogenic – more than 60% of mouse fetus had neural tube defects. One year later, an update was published regarding the teratogenicity of this drug, stating that valproic acid has an absolute risk of 1-2% for spina bifida (Lammer, Sever & Oakley, 1987).

A more detailed elucidation of the teratogenic effect of valproic acid was done by Phiel et al. in 2001. They found that the valproic acid mimics the histone deacetylase inhibitor trichostatin A (as was mentioned above). Trichostatin A has teratogenic effects. Both valproic acid and trichostatin A showed similar teratogenic mechanism. Phiel et al. proposed that histone deacetylase inhibition is the mechanism by which valproic acid induces teratogenic effects.

Bybliography

BEYDOUN, A., SACKELLARES, J.C., & V. 1997. Safety and Efficacy of Divalproex Sodium Monotherapy in Partial Epilepsy. Retrieved from
http://www.neurology.org/content/48/1/182.short

BOWDEN, C.L., et al. 2000. A Randomized, Placebo-Controlled 12-Month Trial of Divalproex and Lithium in Treatment of Outpatients With Bipolar I Disorder. Retrieved from
http://archpsyc.ama-assn.org/cgi/content/abstract/57/5/481

COULTER, D.L., WU, H., ALLEN, R.J. 1980. Valproic Acid Therapy in Childhood Epilepsy. Retrieved from
http://jama.ama-assn.org/content/244/8/785.short

DAVIS, R., PETERS, D.H., & MCTAVISH, D. 1994. Valproic acid. A reappraisal of its pharmacological properties and clinical efficacy in epilepsy. Retrieved from
http://www.ncbi.nlm.nih.gov/pubmed/7512905

FREITAQ, F.G. 2003. Divalproex in the treatment of migraine. Retrieved from
http://www.ncbi.nlm.nih.gov/pubmed/15021865/

GLOZAK, M.A., & SETO, E. 2007. Histone deacetylase and cancer. Retrieved from
http://www.nature.com/onc/journal/v26/n37/abs/1210610a.html

GYULAI, L., et.al. 2003. Maintenance Efficacy of Divalproex in the Prevention of Bipolar Depression. Retrieved from
http://www.nature.com/?file=/npp/journal/v28/n7/full/1300190a.html

KINZE, S., et al. 2008. Valproic Acid Is Effective in Migraine Prophylaxis at Low Serum Levels: A Prospective Open-Label Study. Retrieved from
http://onlinelibrary.wiley.com/doi/10.1046/j.1526-4610.2001.01142.x/abstract

KLAPPER, J. 1997. Divalproex Sodium in Migraine Prophylaxis: A Dose-Controlled Study. Retrieved from
http://cep.sagepub.com/content/17/2/103.short

KRAMER, O.H. 2002. The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2. Retrieved from
http://www.nature.com/emboj/journal/v22/n13/abs/7595225a.html

KUENDGEN, A., et al. 2005. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Retrieved from
http://onlinelibrary.wiley.com/doi/10.1002/cncr.21552/full

LAMMER, E.J., SEVER, L.E. & OAKLEY, G.P. 1987. Teratogen update: valproic acid. Retrieved from
http://www.ncbi.nlm.nih.gov/pubmed/3114906/

MATHEW, N.T., et al. 1995. Migraine Prophylaxis With Divalproex. Retrieved from
http://archneur.ama-assn.org/cgi/content/abstract/52/3/281

MATTSON, R.H., CRAMER, J.A., WILLIAMSOM, P.D., & NOVELLY, R.A. 2002. Valproic acid in epilepsy: Clinical and pharmacological effects. Retrieved from
http://onlinelibrary.wiley.com/doi/10.1002/ana.410030105/abstract

NAU, H., & LOSCHER, W. 1986. Pharmacologic evaluation of various metabolites and analogs of valproic acid: Teratogenic potencies in mice. Retrieved from
http://www.sciencedirect.com/science/article/pii/0272059086901806

PHIEL, C.J., et al. 2001. Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen. Retrieved from
http://www.jbc.org/content/276/39/36734.short

SACHS G., et.a.l 2004. Quetiapine with lithium or divalproex for the treatment of bipolar mania: a randomized, double-blind, placebo-controlled study. Retrieved from
http://onlinelibrary.wiley.com/doi/10.1111/j.1399-5618.2004.00115.x/abstract

SILBERSTEIN, S.D. 2002. Divalproex Sodium in Headache: Literature Review and Clinical Guidelines. Retrieved from
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WILLMORE, L.J., SHU, V., WALLIN, B. 1994. Efficacy and safety of add-on divalproex sodium in the treatment of complex partial seizures. Retrieved from
http://www.neurology.org/content/46/1/49.short


 

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