Valproate (Depakote) | NAMI: National Alliance on Mental Illness

Brand names:

• Depakote®
  • Tablet (delayed release): 125 mg, 250 mg, 500 mg
  • Sprinkle capsule (delayed release): 125 mg
• Depakote ER®
  • Tablet (extended release): 250 mg, 500 mg
• Depakene® and Stavzor®: Discontinued

Generic names:

• Valproate (val PROE ate)
• Divalproex (dye val PRO ex) sodium
• Valproic (val PROE ik) acid

Note: Throughout this fact sheet, the medication will be referred to as valproate. Even though valproate is available in different names, strengths, and formulations, all provide the same active medicine.

All FDA black box warnings are at the end of this fact sheet. Please review before taking this medication.

What Is Valproate And What Does It Treat?

Valproate is a mood stabilizer medication that works in the brain. It is approved for the treatment of mania associated with bipolar disorder (also known as manic depression), seizures (epilepsy), and migraine headaches. Bipolar disorder involves episodes of depression and/or mania.

Symptoms of depression include:

• Depressed mood — feeling sad, empty, or tearful
• Feeling worthless, guilty, hopeless, or helpless
• Loss of interest or pleasure in normal activities
• Sleep and eat more or less than usual (for most people it is less)
• Low energy, trouble concentrating, or thoughts of death (suicidal thinking)
• Psychomotor agitation (‘nervous energy’)
• Psychomotor retardation (feeling like you are moving in slow motion)

Symptoms of mania include:

• Feeling irritable or “high”
• Having increased self esteem
• Feeling like you don’t need to sleep
• Feeling the need to continue to talk
• Feeling like your thoughts are too quick (racing thoughts)
• Feeling distracted
• Getting involved in activities that are risky or could have bad consequences (e.g. excessive spending)

Valproate may also be helpful when prescribed “off-label” for diabetic peripheral neuropathy, postherpetic neuralgia, status epilepticus, and some conditions related to a traumatic brain injury (agitation, aggression, and seizure prevention). “Off-label” means that it hasn’t been approved by the Food and Drug Administration for this condition. Your mental health provider should justify his or her thinking in recommending an “off-label” treatment. They should be clear about the limits of the research around that medication and if there are any other options.

What Is The Most Important Information I Should Know About Valproate?

Bipolar disorder requires long-term treatment. Do not stop taking valproate, even when you feel better. With input from you, your health care provider will assess how long you will need to take the medicine. Missing doses of valproate may increase your risk for a relapse in your mood symptoms.

Do not stop taking valproate or change your dose without talking to your healthcare provider first.

In order for valproate to work properly, it should be taken every day as ordered by your health care provider.

Periodically, your healthcare provider may ask you to provide a blood sample to make sure the appropriate level of medication is in your body and to assess for side effects, such as changes in blood cell counts.

Are There Specific Concerns About Valproate And Pregnancy?

If you are planning on becoming pregnant, notify your healthcare provider so that he/she can best manage your medications. People living with bipolar disorder who wish to become pregnant face important decisions. It is important to discuss the risks and benefits of treatment with your doctor and caregivers.

Valproate has been associated with an increased risk of spinal cord defects (spina bifida). Bleeding, liver problems, decreased IQ scores, developmental delays, and other birth defects have also been reported. There may be precautions to decrease the risk of these effects. Discontinuing mood stabilizer medications during pregnancy has been associated with a significant increase in symptom relapse.

Regarding breastfeeding, caution is advised since valproate does pass into breast milk in small amounts.

What Should I Discuss With My Healthcare Provider Before Taking Valproate?

• Symptoms of your condition that bother you the most
• If you have thoughts of suicide or harming yourself
• Medications you have taken in the past for your condition, whether they were effective or caused any adverse effects
• If you experience side effects from your medications, discuss them with your provider. Some side effects may pass with time, but others may require changes in the medication.
• Any other psychiatric or medical problems you have
• All other medications you are currently taking (including over the counter products, herbal and nutritional supplements) and any medication allergies you have
• Other non-medication treatment you are receiving, such as talk therapy or substance abuse treatment. Your provider can explain how these different treatments work with the medication.
• If you are pregnant, plan to become pregnant, or are breast-feeding
• If you drink alcohol or use illegal drugs

How Should I Take Valproate?

Valproate is usually is taken 1-3 times daily with or without food.

Typically patients begin at a low dose of medicine and the dose is increased slowly over several weeks.

The dose usually ranges from 1000 mg to 3500 mg or more. Only your health care provider can determine the correct dose for you, as sometimes the dose required is based on your weight.

Valproate tablets: Swallow whole. Do not crush, chew or split tablets.

Depakote Sprinkle® capsules: Swallow whole or sprinkle onto food, such as applesauce or pudding and eat immediately. Do not chew the sprinkle capsule or contents.

Valproate syrup: Measure with a dosing spoon or oral syringe that you can get from your pharmacy.

Use a calendar, pillbox, alarm clock, or cell phone alert to help you remember to take your medication. You may also ask a family member or a friend to remind you or check in with you to be sure you are taking your medication.

What Happens If I Miss A Dose Of Valproate?

If you miss a dose of valproate, take it as soon as you remember, unless it is closer to the time of your next dose. Discuss this with your health care provider. Do not double your dose or take more than what is prescribed.

What Should I Avoid While Taking Valproate?

Avoid drinking alcohol or using illegal drugs while you are taking valproate. They may decrease the benefits (e.g., worsen your condition) and increase adverse effects (e.g., sedation) of the medication.

What Happens If I Overdose With Valproate?

If an overdose occurs call your doctor or 911. You may need urgent medical care. You may also contact the poison control center at 1-800-222-1222.

A specific treatment to reverse the effects of valproate does not exist.

What Are Possible Side Effects Of Valproate?

Common side effects

• Nausea or vomiting
• Headache
• Drowsiness or dizziness
• Tremor
• Muscle weakness
• Insomnia
• Hair loss
• Weight gain
• Diarrhea or abdominal pain

Rare/serious side effects

• Liver problems
• Low platelets. Platelets help the blood to clot. Bruising easier than normal is a symptom of low platelets
• Pancreatitis (inflammation of the pancreas). Symptoms of pancreatitis include severe stomach pain, nausea, vomiting, and not feeling hungry
• Increased ammonia levels. If this happens, you may get confused, disoriented, or have difficulty thinking.

Studies have found that individuals who take antiepileptic medications including valproate have suicidal thoughts or behaviors up to twice as often than individuals who take placebo (inactive medication). These thoughts or behaviors occurred in approximately 1 in 500 patients taking the antiepileptic class of medications. If you experience any thoughts or impulses to hurt yourself, you should contact your doctor immediately.

Are There Any Risks For Taking Valproate For Long Periods Of Time?

To date, there are no known problems associated with long term use of valproate. It is a safe and effective medication when used as directed.

It is important to note that some of the side effects listed above (particularly changes in platelets, liver or pancreas problems, and suicidal thoughts) may continue to occur or worsen if you continue taking the medication. It is important to follow up with your doctor for blood work and to contact your doctor immediately if you notice abdominal pain, sudden nausea or vomiting, or changes in mood or behavior.

What Other Medications May Interact With Valproate?

Combining valproate with topiramate (Topamax®) may increase ammonia levels in your blood. If this happens, you may get confused, disoriented, or have difficulty thinking.

The following medications may increase the level and effects of valproate:

• Aspirin (high doses to treat fever or pain)

The following medications may decrease the level and effect of valproate:

• Anticonvulsant medications such as phenytoin (Dilantin®), carbamazepine (Tegretol®/Carbatrol®/Equetro®), and phenobarbital
• Rifampin (Rifadin®)
• Certain antibiotics, such as ertapenem (Invanz®) or meropenem (Merrem®)

Valproate may increase the level and effects of:

• Antidepressant medications such as amitriptyline (Elavil®) and nortriptyline (Pamelor®)
• Anticonvulsant medications such as phenytoin (Dilantin®), carbamazepine (Tegretol®/Carbatrol®/Equetro®), rufinamide (Banzel®), ethosuxamide (Zarontin®), and especially lamotrigine (Lamictal®).
• Diazepam (Valium®)

Valproate may decrease the level and effects of:

• Olanzapine (Zyprexa®)
• Oxcarbazepine (Trileptal®)

How Long Does It Take For Valproate To Work?

It is very important to tell your doctor how you feel things are going during the first few weeks after you start taking valproate. It will probably take several weeks to see big enough changes in your symptoms to decide if valproate is the right medication for you.

Mood stabilizer treatment is generally needed lifelong for persons with bipolar disorder. Your doctor can best discuss the duration of treatment you need based on your symptoms and illness.

Summary of FDA Black Box Warnings

Liver Damage

Serious and fatal liver damage has been associated with valproate, particularly during the first six months of treatment.

Mitochondrial Disease

Patients with mitochondrial disease caused by a certain DNA mutation are at an increased risk of acute liver failure and resultant death.

Birth Defects

Birth defects have been found in babies born to mothers who took valproate while pregnant.

Pancreatitis

Life threatening pancreatitis has been reported in children and adults who take valproate. Signs of pancreatitis include severe abdominal pain, nausea, vomiting and inability to keep food down.

Provided by

(September 2021)

©2021 The College of Psychiatric and Neurologic Pharmacists (CPNP) and the National Alliance on Mental Illness (NAMI). CPNP and NAMI make this document available under the Creative Commons Attribution-No Derivatives 4.0 International License. Last Updated: January 2016.

This information is being provided as a community outreach effort of the College of Psychiatric and Neurologic Pharmacists. This information is for educational and informational purposes only and is not medical advice. This information contains a summary of important points and is not an exhaustive review of information about the medication. Always seek the advice of a physician or other qualified medical professional with any questions you may have regarding medications or medical conditions. Never delay seeking professional medical advice or disregard medical professional advice as a result of any information provided herein. The College of Psychiatric and Neurologic Pharmacists disclaims any and all liability alleged as a result of the information provided herein.

Facts, Side Effects, Cost, Dosing

What is Depakote?
Depakote is a medication known as an anticonvulsant that is used to treat the manic symptoms of bipolar disorder. It is also used to treat seizures and prevent migraine headaches.

When did the U.S. Food and Drug Administration (FDA) approve the medication?
Depakote was first approved by the FDA in 1996.

Is there a generic version of Depakote?
Yes, the generic version is known as divalproex sodium and is sold in the U.S.

Are there any major differences between Depakote and other antipsychotics used to treat bipolar disorder?
Depakote belongs to the class of medications known as anticonvulsants. Anticonvulsants are sometimes taken to treat the manic episodes associated with bipolar disorder. Depakote is sometimes prescribed when patients experience rapid cycling of mood episodes and works by calming the hyperactivity of the brain during mania.

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Can children take Depakote?
Children under the age of two are at higher risk for liver damage when taking the medication. Talk to your child’s doctor about the risks of using the medication.

Are there potential interaction issues for people taking Depakote and any other drugs?
There are hundreds of drugs which are known to interact with Depakote in major, moderate, or mild ways, so let your doctor know what other medications you are taking before you begin taking the medication. Some of these include hepatic enzyme-inducing drugs, aspirin, carbapenem antibiotics, diazepam, ethosuximide, lamotrigine, phenytoin, amitriptyline, nortriptyline, warfarin, zidovudine, and topiramate.

Are there any other medical conditions that would make someone ineligible for Depakote therapy?
Talk to your doctor about other medical conditions before you take Depakote. Persons with liver disease, mitochondrial disease, and urea cycle disorders are typically advised not to take Depakote.

What is the typical dose that would be prescribed to someone taking Depakote?
The FDA recommends that dosage for treating mania begin at 750 mg daily. The maximum recommended dosage is 60mg/kg per day.

What do I do if I miss a dose?
Take the dose of Depakote when you remember, but skip the missed dose if it is almost time for your next dose. You should never take extra doses of the medication to make up for missed doses.

What side effects can Depakote cause?
The side effects of Depakote can include:
• headaches
• sleepiness
• nausea
• tremors
• fatigue
• vomiting
• dizziness
• blurred vision
• stomach pain
• diarrhea
• weight gain
• hair loss
• coordination problems

It also is recommended that you wait to drive or operate machinery until you know how the medication affects you. It is also recommended that people avoid alcohol and illegal drugs while on the medication, as they can worsen adverse effects. Report major side effects to your doctor immediately, which can include red or purple spots on skin, swelling or pain in joints, bruising, drowsiness, vomiting, change in mental status, drop in body temperature, fever, rash, hives, mouth sores, peelings of skin, swelling of face, and trouble swallowing or breathing. You can also report side effects to the FDA at 1-800-FDA-1088 or online.

What are the potential psychological side effects of taking Depakote?
Depakote causes suicidal thoughts in a small percentage of people who take the medication. Seek medical help if you experience these thoughts or other changes in your behavior or mood.

What are the potential long-term effects of taking Depakote?
Depakote can cause liver damage, and the risk is more likely to occur during the first 6 months of taking the medication. Signs might include nausea or vomiting, loss of appetite, abdominal pain, dark-colored urine, facial swelling, and yellowing of the skin or white of eyes. Cases of pancreatitis among children and adults taking the medication have also been reported.

Is it safe for a woman who is pregnant, about to become pregnant, or nursing to take Depakote?
Depakote can cause birth defects and fetal harm when taken during pregnancy. The drug can be transferred via breast milk and potentially harm a baby. Therefore, talk to your doctor if you are pregnant, planning to become pregnant, or are nursing before you take Depakote.

Can symptoms occur if Depakote is discontinued?
It’s important not to discontinue use of the drug before talking with your doctor. Withdrawal symptoms of Depakote can include irritability, anxiety, the return of manic or depressive symptoms, dizziness, and tremors.

What should I do if I overdose on Depakote?
An overdose of Depakote could be fatal, so seek immediate help or call the Poison Help Line at 1-800-222-1222 if you overdose. Overdose symptoms can include irregular heartbeat, sleepiness, and loss of consciousness resulting in a coma.

Is Depakote habit-forming?
Depakote has no habit-forming potential, but it is not recommended that you discontinue use of the drug before talking with your doctor, as withdrawal symptoms can occur.

How much does Depakote cost?
According to goodrx.com, 60 tables of 500 mg divalproex sodium cost approximately $170.

Are there any disadvantages to Depakote?
The biggest disadvantages of Depakote are potential side effects which include possible liver damage or pancreatitis. Pregnant women are also typically advised not to take the medication due to the risk of birth defects.

DISCLAIMER: The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. This article mentions drugs that were FDA-approved and available at the time of publication and may not include all possible drug interactions or all FDA warnings or alerts. The author of this page explicitly does not endorse this drug or any specific treatment method. If you have health questions or concerns about interactions, please check with your physician or go to the FDA site for a comprehensive list of warnings.

Article Sources

NIH – Depakote
FDA – Depakote

Last Updated: Aug 6, 2018

Mood Stabilizers for Bipolar Disorder

Bipolar disorder is often treated with medications referred to as mood stabilizers, such as lithium or Depakote (valproate) and Tegretol (carbamazepine).

These medications can be very effective in treating hypomania or mania and preventing the recurrence of bipolar episodes.

Types of Mood Stabilizers for Bipolar Treatment

Bipolar disorder is different in different people, and a treatment that can help someone else may not work for you, and vice versa.

But in general, mood stabilizers should always be used along with antidepressants to treat bipolar disorder in order to reduce the risk for mania, according to a 2014 study published in the American Journal of Psychiatry.

Mood-stabilizing medications that your doctor may recommend include:

Lithium. This drug can help balance out the emotional highs and lows of bipolar disorder.

“Lithium has this curious property of working both against mania and depression,” says Gary Sachs, MD, founding director of the Bipolar Clinic and Research Program at Massachusetts General Hospital in Boston and associate clinical professor of psychiatry at Harvard Medical School.

Lithium appears to work by helping to normalize brain activity. It also helps prevent both depression and mania relapses.

Valproate and carbamazepine. Valproate (also called valproic acid) and carbamazepine were first used to treat convulsions in people with epilepsy.

Researchers then found that these drugs could also help treat bipolar disorder symptoms. “Valproic acid and carbamazepine have, in fact, been shown to be efficacious for the treatment of acute mania,” says Dr. Sachs.

The two drugs work by calming the brain, resulting in a better and more stable mood.

These medications can help with bipolar episodes, especially the rapid-cycling variety in which moods change from mania to depression and back again over a period of hours or days.

Sachs says there is also evidence supporting the use of valproate to help prevent recurrences of bipolar episodes.

However, there’s limited evidence that valproate on its own is very effective as a long-term treatment, according to a 2013 research review by the Cochrane Database of Systematic Reviews.

Combination of medications. Lithium, valproate, and carbamazepine are often used together or in combination with dopamine-blocking medications for a more potent mood-stabilizing effect in bipolar treatment.

Special Considerations With Bipolar Treatment

Lithium is usually preferred for the treatment of bipolar disorder in children and adolescents because the safety of valproate and carbamazepine is still being evaluated in these groups.

For instance, numerous studies indicate that valproate puts girls and women at risk of hormonal abnormalities and polycystic ovary syndrome when the medication is taken before age 20.

In addition, if you are a woman with bipolar disorder you will need to talk with your physician about which medications are least risky to take when trying to conceive, during pregnancy, in the postpartum period, and while nursing.

All medicinal bipolar disorder treatments could harm a developing fetus or a breastfeeding baby, but your doctor may be able to tell you about new bipolar treatments that are thought to be safer during pregnancy and lactation.

Side Effects of Mood Stabilizers

Depending on the medication you are using, your doctor or pharmacist can tell you about side effects you could experience.

In general, lithium is commonly associated with:

Side effects of valproate and carbamazepine commonly include:

• Gastrointestinal problems
• Headache
• Double vision
• Dizziness
• Anxiety
• Confusion
• Liver problems

Any doctor can prescribe these medications, but it’s a good idea to see a psychiatrist, who’s trained to deal with mental illnesses such as bipolar disorder.

You will probably take these medications over the long term, and you may need to add medications if you have manic or depressive episodes that break through despite the treatment.

People with bipolar disorder usually need more than one medication. Over time, working with your psychiatrist, you can determine which bipolar treatment regimen works best for you.

Follow-Up Care Is Key With Bipolar Disorder

Although there are effective treatments for bipolar disorder, there is no cure. Because it’s a long-term illness, ongoing treatment is needed to control your symptoms.

Even if you are taking your medication as directed by your doctor, you may experience mood changes or lingering symptoms. If you have another mental illness, your treatment for bipolar disorder may also be more complicated.

Working closely and openly with your doctor is key to finding the treatment plan that is most effective for you.

Article updated by Mary Elizabeth Dallas and medically reviewed by Lindsey Marcellin, MD, MPH

Dosing for Bipolar Mania – Depakote® (divalproex sodium)

INDICATIONS

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Mania

DEPAKOTE^® ER (divalproex sodium) extended-release tablets, for oral use, is a valproate and is indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features.

DEPAKOTE^® (divalproex sodium) delayed-release tablets, for oral use, is a valproate and is indicated for the treatment of the manic episodes associated with bipolar disorder.

A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. A mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities).

The efficacy of DEPAKOTE ER is based in part on studies of DEPAKOTE in this indication, and was confirmed in a 3-week trial with patients meeting DSM-IV-TR criteria for bipolar I disorder, manic or mixed type, who were hospitalized for acute mania.

The efficacy of DEPAKOTE was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania.

The effectiveness of valproate for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use DEPAKOTE or DEPAKOTE ER for extended periods should continually reevaluate the long-term risk-benefits of the drug for the individual patient.

Epilepsy

DEPAKOTE ER is indicated as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures. DEPAKOTE ER is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older with multiple seizure types that include absence seizures.

DEPAKOTE is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. DEPAKOTE is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures.

Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.

Migraine

DEPAKOTE and DEPAKOTE ER are indicated for prophylaxis of migraine headaches. There is no evidence that DEPAKOTE ER or DEPAKOTE is useful in the acute treatment of migraine headaches.

Important Limitations

Because of the risk to the fetus of decreased IQ, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.

For prophylaxis of migraine headaches, DEPAKOTE and DEPAKOTE ER are contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception.

IMPORTANT SAFETY INFORMATION

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Warning: Life-Threatening Adverse Reactions

Hepatotoxicity

General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months.

Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When DEPAKOTE (divalproex sodium) delayed-release tablets, for oral use, or DEPAKOTE ER (divalproex sodium) extended-release tablets, for oral use, is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g., Alpers Huttenlocher Syndrome). DEPAKOTE and DEPAKOTE ER are contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and in children under two years of age who are clinically suspected of having a mitochondrial disorder. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, DEPAKOTE and DEPAKOTE ER should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with DEPAKOTE or DEPAKOTE ER for the development of acute liver injury, with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice.

Fetal Risk

Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores and neurodevelopmental disorders following in utero exposure.

Valproate is therefore contraindicated for prophylaxis of migraine headaches in pregnant women and in women of childbearing potential who are not using effective contraception [see Contraindications (4)]. Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.

Valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. In such situations, effective contraception should be used [see Warnings and Precautions (5.2, 5.3, 5.4)].

A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17)].

Pancreatitis

Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.

• Valproate should not be administered to patients with hepatic disease or dysfunction. Immediately discontinue drug if significant hepatic dysfunction is suspected or apparent. Progression of dysfunction has occurred in spite of discontinuation of valproate.
• Valproate is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers Huttenlocher Syndrome) and in children under two years of age who are suspected of having a POLG-related disorder. POLG-related disorder symptoms may include unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, ophthalmoplegia, or complicated migraine with occipital aura.
• DEPAKOTE and DEPAKOTE ER are contraindicated for use in prophylaxis of migraine headaches in women who are pregnant and in women of childbearing potential who are not using effective contraception.
• Valproate is contraindicated in patients with known hypersensitivity to the drug.
• Valproate is contraindicated in patients with known urea cycle disorders (UCDs). Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate. Symptoms of unexplained hyperammonemic encephalopathy during valproate therapy require prompt treatment (including discontinuation of valproate).
• Valproate can cause decreased IQ, neurodevelopmental disorders, neural tube defects, and other major congenital malformations (e.g., craniofacial defects, hypospadias, cardiovascular and limb malformations). In epileptic mothers, the rate of congenital malformations with in utero exposure is about four times higher compared to the rate with in utero exposure to other anti-seizure monotherapies. Lower cognitive test scores, including decreased IQ scores, were associated with in utero valproate exposure compared with in utero exposure to either another or no antiepileptic drug. Unless other medications have failed to provide adequate symptom control or are otherwise unacceptable, women of childbearing potential should not receive valproate.
• Valproate can increase the risk of suicidal thoughts or behavior. Patients treated with any AED should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or unusual changes in mood or behavior. Counsel patients and families to be alert for and to immediately report depression, any unusual changes in mood or behavior, or suicidal thoughts, behavior, or acts of self-harm.
• Thrombocytopenia is dose-related. Decreases in other cell lines and myelodysplasia have also been associated with valproate. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥110 ug/mL in females and ≥135 ug/mL in males or at 50 mg/kg/d. Check complete blood counts and coagulation times before starting therapy or surgery, at periodic intervals, and during pregnancy. Reduce dose or discontinue if hemorrhage, bruising, or hemostasis/coagulation disorder occur.
• Hyperammonemia has been associated with valproate; it may be present despite normal liver function tests and should be considered if hypothermia occurs. Asymptomatic elevations of ammonia are more common and require close monitoring. Discontinue valproate if ammonia increases.
• Concomitant administration of topiramate and valproate has been associated with hyperammonemia (with or without encephalopathy) in patients who have tolerated either drug alone.
• Hypothermia has been associated with valproate therapy both in conjunction with, and in the absence of, hyperammonemia. It can occur after starting topiramate treatment or after increasing the daily dose of topiramate. Consider stopping valproate if hypothermia develops.
• Drug Reaction with Eosinophilia and Systemic Syndrome (DRESS) / multi-organ hypersensitivity reactions have been reported and may be fatal or life-threatening. Patients typically present with fever, rash, and lymphadenopathy associated with other organ system involvement, e.g., hematologic abnormalities. Early symptoms may not include rash. Regardless, immediately evaluate and discontinue therapy for any signs of hypersensitivity.
• Carbapenem antibiotics (such as ertapenem, imipenem, meropenem) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control.
• In a clinical trial, somnolence was associated with valproate in some elderly dementia patients along with reduced nutritional intake; weight loss; and a trend to have a lower baseline albumin concentration, higher BUN, and lower valproate clearance. Discontinuation occurred in some patients.
• Valproate may interact with drugs capable of enzyme induction; check valproate and concomitant drug levels periodically in the early course of therapy.
• Rare reports of medication residue in the stool have occurred, some in patients with anatomic (ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times or in the context of diarrhea. If medication residue occurs, monitor plasma valproate levels and patient’s clinical condition; alternative treatment may be considered.

ADVERSE EVENTS

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• Most common adverse reactions (reported >5%) are abdominal pain, abnormal thinking, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, and weight loss.

Keep DEPAKOTE and all other medications where children cannot reach them.

Side Effects of Depakote ER (Divalproex Sodium), Warnings, Uses

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What is Depakote & What is It Used For?

Depakote is an anticonvulsant. Doctors prescribe it to treat conditions that affect the brain.

Depakote contains the active ingredient divalproex sodium. This is a combination of sodium valproate and valproic acid.

The medication comes in a white powder form. Drugmaker AbbVie Inc. makes it into a tablet.

Patients take Depakote by mouth. The drug’s maker tells patients to swallow Depakote whole, not to crush or chew it.

Valproate in Depakote is effective in managing and stabilizing moods. But the chemical substance can cause serious side effects.

Depakote lawsuits blame the drug for causing birth defects in children whose mothers took Depakote during pregnancy.

Depakote (Divalproex Sodium) Uses

The U.S. Food and Drug Administration approved Depakote in 1983 to treat epilepsy. Doctors may sometimes prescribe divalproex sodium with other medications to treat types of seizures.

The FDA expanded Depakote uses to include the treatment of manic episodes associated with bipolar disorder. Divalproex sodium also helps prevent migraines headaches.

What Depakote Does for the Brain

Divalproex sodium works by increasing the amount of gamma-aminobutyric acid (GABA) in the brain. The body produces GABA naturally. It is a chemical neurotransmitter — or brain messenger.

Faster than normal electrical impulses in the brain can cause erratic impulses. These impulses overstimulate the nerves. GABA helps to calm and relax nerves. Relaxing nerves can stabilize moods.

Increasing GABA can also prevent abnormal brain signals that lead to seizures.

Types of Depakote: Depakote DR vs Depakote ER vs Depakote Sprinkle Capsules

Divalproex sodium comes in Depakote tablets and Depakote ER (extended-release) tablets. It’s also available in Depakote Sprinkle Capsules (delayed-release capsules).

Depakote ER and the delayed-release formulation of Depakote are not interchangeable.

Depakote tablets are delayed release. They have a coating to keep the medication from dissolving too soon after it’s swallowed. These tablets come in three sizes: 125 mg, 250 mg and 500 mg. They are prescribed to be taken twice a day.

Depakote delayed release 250mg

Depakote delayed release 500mg

Depakote ER tablets are made to slowly deliver the medication over 24 hours. They are taken just once a day. They come in 250 mg and 500 mg. Depakote ER does not have a coating.

Depakote extended release 250mg

Depakote extended release 500mg

Depakote Sprinkle Capsules are approved only for the treatment of epilepsy. They are available in 125 mg. They work similar to Depakote delayed release, except that they are in capsules rather than tablets. Patients who have trouble swallowing may open the capsules and sprinkle the medication on soft food.

A closely related medication, Depakene (valproic acid), comes in capsule and liquid form. Another variety of valproic acid, Stavzor, is no longer manufactured.

In 2008, the FDA approved the first generic version of Depakote. Collectively, these medications are known as valproate products.

Depakote Dosages

Depakote dosage can vary. It depends on the patient and the condition for which a doctor prescribes it.

For example, when taken to control mania, the recommended initial dose is 750 mg a day taken in divided doses for Depakote. For Depakote ER, the recommended initial dose is 25 mg once a day, up to a maximum of 60 mg a day.

The initial Depakote therapy is 10 mg to 15 mg for treating epilepsy in patients age 10 and older. Doctors can then increase the dosage by 5 mg to 10 mg each week. This continues until the doctor determines that the medication is doing what it’s supposed to.

With Depakote ER, patients ages 10 and older should start the same with a maximum dose of 60 mg a day.

If a patient forgets to take Depakote at the usual time, he or she can take it upon remembering. But if it’s close to the next dose, patients can skip the forgotten dose and resume the normal schedule. Do not double up.

Depakote Interactions

Valporic acid in Depakote may interact with a number of different medications. Depakote interactions may increase or decrease the effects of the medications. Some can be fatal.

Valproic acid can increase the serum concentrations of diazepam in patients taking that medication. Antacids containing magnesium and aluminum hydroxide may increase valproic acid an average of 12 percent.

Patients with urea cycle disorders who are being treated with sodium phenylbutyrate should not receive valproic acid. This interaction can be fatal.

Supplements and food can also interact with Depakote. For example, high doses of folate can decrease the effectiveness of Depakote.

High doses of the herb Ginkgo biloba also could decrease the effectiveness of Depakote.

Drugs that can interact with Depakote include:

• Alprazolam
• 
  Amphetamine
• 
  Benzphetamine
• 
  Bupropion
• 
  Butabarbital
• 
  Carbamazepin
• 
  Cholestyramine
• 
  Darunavir
• 
  Doripenem
• 
  Ertapenem
• 
  Fosamprenavir
• 
  Haloperidol
• 
  Lamotrigine
• 
  Loxapin
• 
  Meropenem
• 
  Pemoline
• 
  Propofol
• 
  Ritonavir
• 
  Sodium Phenylbutyrate
• 
  Thiothixene
• 
  Vorinostat
• 
  Warfarin

Common Side Effects of Depakote

A common side effect of Depakote and Depakene is nausea, especially during the first month of treatment. This can be overcome by starting on a low dosage and slowly increasing the amount. Taking the medication on a full stomach can also help.

Common side effects associated with Depakote include:

• Nausea
• 
  Drowsiness
• 
  Abdominal pain
• 
  Diarrhea
• 
  Vomiting
• 
  Low platelet count
• 
  Tremors
• 
  Hair loss

These side effects may be mild or moderate. You should talk to your doctor about any side effects because they could be signs of something serious.

Depakote Serious Side Effects

Taking Depakote has been linked to some serious and even deadly side effects.

Liver damage is one of the side effects that may be fatal. This is especially true in children under 2. This risk is highest in the first months of taking the medication. The risk may still be present even after the Depakote medication is stopped.

Another potentially fatal side effect is inflammation of the pancreas, or pancreatitis. This is when digestive enzymes start digesting the pancreas itself.

When pregnant women take Depakote, their unborn babies are at risk of developing birth defects. These defects can affect the brain, spinal cord, heart, arms, legs and penis. These babies also risk developing lower intelligence. Women who are or may become pregnant should not take Depakote.

Depakote Black Box Warnings

The FDA requires that Depakote’s label have black box warnings. A black box warning is the agency’s most serious type of warning. It calls attention to serious or life-threatening risks.

Depakote’s boxed warnings are for hepatotoxicity, fetal risk and pancreatitis.

Depakote Precautions

Depakote manufacturer AbbVie warns that certain people should not take Depakote or Depakene. This includes people with liver problems, and women who are or may become pregnant.

Talk to your doctor before taking Depakote or Depakene if you:

• Have liver problems
• Have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome)
• Are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in Depakote or Depakene
• Have a genetic problem called urea cycle disorder
• Are or may become pregnant

Please seek the advice of a medical professional before making health care decisions.

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Extended-release divalproex in bipolar and other psychiatric disorders: A comprehensive review

Abstract

Bipolar disorder can be a devastating disease state for individuals with the disease and also for family members. Proper recognition and treatment is vital to the successful management of this disease state. Through increased community and practitioner awareness, along with efforts to increase awareness for proper assessment, the rate of diagnosed bipolar disorder is increasing. Recent years have brought about the introduction of several new medications with approved indications for the treatment of bipolar disorder. In addition to new agents, traditional mood stabilizing medications have also been released in different formulations to better enhance tolerability without jeopardizing efficacy. One particular product is extended-release divalproex sodium. In the following article, we review the clinical presentation of bipolar disorder, its epidemiology, and the pharmacokinetics and mechanism of action for divalproex. In addition, we specifically review the role of extended-release divalproex in bipolar disorder through a critical analysis of the currently available published primary literature.

Keywords: extended-release divalproex, divalproex, bipolar disorder, mania, depression

Bipolar disorder

Bipolar disorder is a psychiatric disease state manifesting as two different mood extremes, mania and depression. Manic symptoms often include hyperactivity, hyper-talkativeness, decreased need for sleep, grandiosity, increased risk taking, and being easily distracted (^{APA 2000}). Depression symptoms typically consist of a depressed mood, decreased energy, feelings of guilt, hopelessness, helplessness, crying, and even suicidal ideations (^{APA 2000}).

Symptoms of bipolar disorder typically present during late adolescence between the ages of 15 and 19 years, however it is not uncommon for proper diagnosis to be delayed for 5–10 years (^{Bowden et al 2002}). Bipolar I disorder is estimated to be prevalent in 1% of the US population, however recent findings from a large-scale survey suggest an adjusted prevalence rate near 3.7% (^{Bowden et al 2002; Hirschfeld, Calabrese et al 2003}). Additionally, it has been found through survey that there is often a gap of up to 10 years between the first visit and subsequent proper diagnosis, with the majority either not being diagnosed at all or inappropriately diagnosed with unipolar depression (^{Hirschfeld, Calabrese et al 2003; Hirschfeld, Lewis et al 2003}). Identification of which type of bipolar disorder is present is complicated by the fact that both bipolar I and bipolar II patients spend more time symptomatic in the depressed phase than the manic or hypomanic states (^{Judd et al 2002}). This is significant when considering the potential risk of switching a bipolar patient from a depressed state to manic state with antidepressant therapy. Contrary to this is that failure to address a depressive episode of bipolar disorder presents a dramatic increase in suicide risk. Additional things to consider when treating a patient with bipolar disorder are the high rates of concurrent substance abuse and anxiety disorders (^{Bowden et al 2002; McElroy 2004}).

Valproate mechanism

The mechanism by which valproate exerts its therapeutic effect is not well understood. Several hypotheses have been proposed concerning the mechanism of action in epilepsy and bipolar disorder. The most well studied and understood mechanism of valproate is its ability to potentiate or mimic the effects of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) (^{Loscher 2002; Casey et al 2003; Salloum et al 2005}). Indirectly, this potentiation of GABA has been hypothesized to produce inhibitory effects on central dopamine (Casey et al 2002; ^{Loscher 2002}). Some of the other and less well understood mechanisms involve the inhibition of neuronal excitability and a resultant anti-kindling effect (^{Loscher 2002}). One specific area of study has focused on the inhibition of protein kinase C epsilon (PKC-epsilon) (^{Brunello 2004; Toth 2005}). PKC-epsilon has been linked to the stimulation of intracellular calcium release and an increase in cortical excitation and instability. Valproate has also exhibited effects producing the blockade of voltage-dependent sodium channels (^{Loscher 2002; Owens and Nemeroff 2003}). Another proposed mechanism, though controversial, is one likening valproate to lithium as a potential inhibitor of inositol synthesis through inhibition of myo-inositol-1phosphate (MIP) (^{Harwood and Agam 2003; Shaltiel et al 2004; Harwood 2005}). It is not well understood if valproate inhibits MIP directly, but it has been shown to deplete inositol (^{Harwood and Agam 2003; Shaltiel et al 2004; Harwood 2005}).

Divalproex pharmacology

Delayed-release divalproex

Delayed-release divalproex (DR) is an enteric-coated compound consisting of sodium valproate and valproic acid in a 1:1 molar ratio (^{Abbott Laboratories 2006}). Divalproex is metabolized in the liver, primarily via glucuronidation to active metabolites, with the major active metabolite being Trans-2-en-valproate (^{Loscher 2002}). The estimated half-life of divalproex ranges from 9 to 16 hours (^{Abbott Laboratories 2006}). The usual dosing regimen for DR is on a two or three times daily schedule, often with the larger dose given at bedtime. The therapeutic range for divalproex sodium in acute mania according to primary literature suggests improvement is greatest at concentrations above 50 μg/mL and that adverse effects increase significantly at concentrations above 125 μg/mL (^{Bowden et al 2002}). The more common side effects of DR are transient nausea (31%), asthenia (20%), somnolence (17%), dyspepsia (13%), dizziness (12%), diarrhea (12%), vomiting (11%), and tremor (9%) (^{Abbott Laboratories 2006}). Some long-term side effects that have been associated with DR use are alopecia and weight gain. Therapeutic drug monitoring for valproic acid or any formulation of divalproex requires periodic monitoring of liver enzymes as serious liver toxicity has been reported, especially with use in children under the age of two and in patients receiving multiple antiepileptic medications. Valproic acid/divalproex have also been shown to produce a dose-related thrombocytopenia, thus periodic monitoring of platelets is also suggested. The primary advantage of the DR formulation over immediate release valproic acid (IR) is the enteric coating which helps reduce the incidence of gastrointestinal complaints. Prevalence of hepatic enzyme elevation, tremor, ataxia, increased appetite, weight gain, and alopecia have not been shown to be substantially different in clinical trials between DR and IR preparations.

Extended-release divalproex

The newest formulation of divalproex is in the form of an extended-release tablet, Depakote ER^® (ER), which provides a once-daily administration option for the treatment of acute manic or mixed episodes of bipolar disorder, independent of the presence of psychotic features (^{Abbott Laboratories 2006}). The ER formulation uses a hydrophilic polymer matrix controlled-release tablet system to provide controlled continued release of medication. After oral administration and entry into the stomach, the outer coating of the tablet dissolves and exposes the polymer matrix. The outer layer of the matrix becomes hydrated and forms a gel layer from which drug is released. In addition to bipolar disorder, ER is also approved for the prophylactic management of migraine headaches in adults, as well as monotherapy and adjunctive therapy in adults and children 10 years of age and older with complex partial seizures, adults and children 10 years of age or older with simple and complex absence seizures, and adults and children 10 years of age and older with multiple seizure types including absence seizures (^{Abbott Laboratories 2006}).

Comparative studies have shown that DR and ER are not bioequivalent products. The two primary kinetic differences are that the ER preparation results in an average bioavailability of 81%–89% relative to DR and ER has produces a 10%–20% lower fluctuation in peak serum concentration as compared to DR (^{Abbott Laboratories 2006}). These findings suggest that when converting patients from DR to ER that the ER dose may need to be increased between 8% and 20% to produce an equivalent serum concentration.

Further evidence for pharmacokinetic differences were supported in a study using a healthy adult population and comparing the bioavailability of unequal doses of DR and ER (^{Dutta et al 2002}). The results from this study determined that daily doses of ER dosed 14% and 20% higher than DR (1000 mg/day ER vs 875 mg/day DR and 1500 mg/day ER vs 1250 mg/day DR) produced equivalent serum concentrations as determined by area-under-the-curve (AUC) (^{Dutta and et al 2002}). The ER preparation resulted in a lower C_max than corresponding DR doses. Peak-to-trough a higher C_min fluctuations were 42%–48% lower for the ER preparation (^{Dutta et al 2002}). This study also showed that the increase in dose required with the ER dosage form was well tolerated (^{Dutta et al 2002}). While evidence is increasing, there continues to be a relative paucity of information available describing the use of ER in treating mood related symptoms within the psychiatric population.

Role of divalproex in bipolar disorder

There have been a number of recent additions to the list of approved medications for the treatment of bipolar disorder (see ). Despite these new advancements in drug delivery and efficacy for the treatment of bipolar disorder, DR continues to be a highly utilized mood stabilizer for the treatment of acute mania (^{Abbott Laboratories 2006}). In many instances, bipolar disorder treatment guidelines recommend valproate as a preferred agent, with DR usually being the suggested formulation of valproate/valproic acid (divalproex) due to the presumed improved tolerability (^{Zarate et al 1999; Bowden et al 2002; Keck et al 2004; Suppes et al 2005}). The disease states where evidence based guidelines support the use of valproate as a first-line choice include: acute manic exacerbations, euphoric mania, dysphoric or mixed mania, and in patients being treated for rapid cycling bipolar disorder (see ) (^{Bowden et al 2002; Keck et al 2004; Suppes et al 2005}). Valproate is also considered an appropriate agent for maintenance therapy, though it lacks the FDA maintenance indication (^{Taylor and Goodwin 2006}). Other FDA approved indications for DR include the treatment of complex partial, simple absence, and complex absence seizures in addition to prophylaxis of migraine headaches (^{Abbott Laboratories 2006}). DR is not FDA approved for aggression, though it is routinely used as monotherapy and is considered appropriate adjunct therapy to reduce hostility associated with schizophrenia (^{Citrome, Casey et al 2004; Lehman et al 2004}).

Table 1

FDA approved medications for the treatment of bipolar disorder and their approved indications

Table 2

Suggested first-line treatment strategies per available guidelines

Clinical trials – efficacy

In order to identify published, primary literature studying the ER formulation in bipolar disorder we conducted an Ovid Medline search. Our search terms included bipolar disorder, mania, depression, extended-release divalproex, delayed-release divalproex, divalproex, and schizophrenia. We did not include any information that was not published in primary literature form so any “Data on File” with Abbott Laboratories that is not published is not included in this review. Our search yielded a small number of clinical trials reporting on the use of extended-release divalproex in bipolar disorder. Three of the trials are open-label with a study enrollment ranging from 10 to 55 patients. The other three data sets included were published as “Letters to the Editor,” but were included for completeness of discussion. One additional study was included that examined the use of extended-release divalproex for mood stabilization and antipsychotic augmentation in schizophrenia.

The first trial discussed is an open-label, seven day study evaluating the efficacy and safety of converting psychiatric patients from DR to ER (^{Horne and Cunanan 2003}). The majority of participants carried a diagnosis of bipolar disorder or major depression, 36% and 27% respectively. Other psychiatric diagnosis included schizophrenia and schizoaffective disorder. A total of 55 patients were included in the conversion, 75% outpatients and 25% inpatients hospitalized for acute symptoms. Participants had been treated with DR from 2 days to >4 years at doses of 500 to 5,000 mg/day. Concomitant medications were described and included agents such as antipsychotics, antidepressants, and anxiolytics.

Following baseline measurements of plasma valproic acid concentrations, study participants were switched to ER at a dose equal to their total daily dose of DR. Subsequent therapeutic drug monitoring included assessment of plasma valproic acid concentrations which were obtained 10 to 12 hours after the last dose on study days 3, 5, and 7. Over half the patients in the study (58%) experienced an increase in valproic acid plasma concentration when switched from DR to ER dosage forms. In all but three cases, plasma concentrations remained within the therapeutic range of 50–125 μg/mL. In two of the cases the plasma levels increased following the initiation of the ER dosage form with no signs of toxicity and returned to values within therapeutic range with dosage reduction. In the third case, the patient’s serum valproic acid level decreased below the lower limit of normal but increased following dosage titration.

Efficacy was assessed with the Positive and Negative Syndrome Scale (PANSS) at baseline and endpoint. Upon analysis of the total patient population, a statistically significant improvement was observed in mean PANSS total score, positive subscale and general psychopathology subscale from baseline to endpoint. Mean total PANSS scores at baseline were 71.5 ± 21.4 with a mean change of −4.3 ± 11.1 at endpoint. While a statistical change was appreciated, clinical impact of improvement was most likely small.

Adverse events were assessed with the Udvalg for Kliniske Undersogelser (UKU) Side Effect Rating Scale. Patients reported a decrease in the number and severity of adverse effects at endpoint. Following the cessation of the study, 54 of the 55 participants choose to continue treatment with the ER formulation.

Statistical power was not discussed in the study design. This design characteristic becomes less of an issue for outcome measures in which statistical improvement is observed. Overall, conversion from DR to ER in this inpatient and outpatient psychiatric population was not associated with deterioration in mental status. In addition, a reduction in both the incidence and severity of adverse effects was appreciated with the ER dosing formulation, most likely thought to be the result of lower peak concentrations.

A second published, open-label study highlighted the conversion of DR to ER in ten subjects over a four-week time period (^{Stoner et al 2004}). Subjects were deemed eligible if they had been on DR at least 8 weeks and were considered “stable” in the two weeks preceding study enrollment. Subjects were also required to be experiencing two “mild” adverse events or one “moderate” adverse event that was considered a potential side effect of DR. All subjects were using DR for mood or behavioral related symptoms, with most diagnosed with schizophrenia, bipolar disorder, or schizoaffective disorder, bipolar type. Additionally, eight subjects had a history of substance abuse.

Seven of the ten subjects were converted on an equal milligram-per-milligram basis, while the other three received a 250 mg dose increase to 500 mg as at the time of the study only 500 mg ER tablets were available. The mean DR dose at baseline was 2,475 ± 1,010 mg/day with a slightly higher mean dose of ER observed at study endpoint, 2,550 ± 985 mg/day. The study group included six males and four females with an average age of 39.4 years and an average length of mental illness of 21.4 years. Subjects were diagnosed primarily with schizophrenia (n = 4), bipolar disorder (n = 2), and schizoaffective disorder (n = 2). Eight subjects had a history of substance abuse.

The primary outcome measure in this study was the 18-item Brief Psychiatric Rating Scale (BPRS), selected to identify any changes in psychiatric, behavioral, or mood related symptoms. The BPRS was completed at baseline and then at Days 7, 14, 21, and 28. The results from this study demonstrated that subjects maintained psychiatric and mood stability. Of particular interest, no significant changes were appreciated in weekly BPRS scores, although numerically the mean scores improved from baseline (29.10 ± 6.28) to endpoint (26.5 ± 7.14, p = 0.208). No individual BPRS items showed a statistically significant change, however a trend suggested a decrease in somatic complaints (p = 0.057).

Eleven-hour post-dose valproic acid serum concentrations were collected at Days 14 and 28. No statistically significant difference was found in DR baseline serum valproic acid concentrations (90.5 ± 29.11 μg/mL) and “Day 28” 11-hour post-dose ER valproic acid serum concentrations (95.50 ± 13.68; p = 0.493). Additional monitoring parameters included assessment of weight changes, and collection hematologic, renal, hepatic, electrolyte, lipid, and glucose labs at baseline and study endpoint. No significant changes in weight were observed between baseline and study endpoint. Serum chemistry monitoring showed statistically significant decreases in LDL cholesterol and potassium, although the decline in potassium was not clinically significant. There were no significant changes in platelet counts observed during the course of the study. Tolerability and adverse event assessment was as measured by the Systematic Assessment for Treatment Emergent Effects (SAFTEE) at baseline and then Days 7, 14, 21, and 28. SAFTEE results showed statistically significant reductions in complaints of sedation, stomach and abdominal discomfort, and tremor from baseline to study endpoint. This study was limited by a small sample size and the inclusion of only stable patients, thus not allowing the clinical application the ER findings to the acute phase of treatment. Additionally, the study subjects showed a broad variation of Axis I diagnosis, not limited to bipolar disorder. Despite these limitations, this study does provide some level of evidence that ER can be used in place of DR to help maintain psychiatric stability.

A third open-label, six day study was designed to compare the conversion of stable bipolar I or II or schizoaffective subjects (n = 12) from the DR to the ER formulation (^{Centorrino et al 2003}). Upon entry into the study, subjects were required to have baseline serum valproic acid levels within the therapeutic range of 50–120 μg/mL and had to have been receiving stable does of medications for at least four weeks prior to study initiation.

Participants were switched to ER with a goal of maintaining stable valproic acid serum concentrations. As the ER formulation was only available in the 500 mg tablet dosage form at the time of the study, doses were rounded to the nearest 500 mg/day. Serum valproic acid levels were collected at baseline, day 7, week 6, and one week following a medication adjustment. In this cohort of patients, it was observed that ER doses needed to be 20.7% higher than the previous DR doses to maintain serum valproic acid levels, a finding consistent with package labeling for ER.

Numerous efficacy measurements were evaluated at baseline and weekly thereafter and included the Young Mania Rating Scale (YMRS), the 17-Item Hamilton Depression Rating Scale (HAM-D 17), Clinical Global Impression of severity (CGI-S) and improvement (CGI-I), Global Assessment of Functioning Scale (GAF), and the 17-item Brief Psychiatric Rating Scale (BPRS). The mean baseline YMRS score was 3.00 ± 3.86 and at endpoint it increased to 3.42 ± 2.53. The baseline mean HAM-D 17 score was 11.2 ± 9.3 and at endpoint the mean improved to 7.67 ± 6.97. The mean CGI of severity score at baseline was 2.58 ± 0.79 and at endpoint was 2.75 ± 0.65. The mean baseline GAF score was 68.3 ± 6.2 and at endpoint improved marginally with a value of 69.2 ± 6.0. The baseline mean BPRS score was 39.8 ± 10.2 and at endpoint was 37.8 ± 7.82. None of the observed changes were deemed to be significant in regards to psychiatric stability.

Tolerability was assessed using the UKU Side Effect Rating Scale for adverse effects. The most commonly reported adverse effects at both baseline and endpoint were impaired concentration, fatigue, depression, and decreased salivation. The only statistically significant adverse event that was seen more frequently with the ER dosage form as compared to the DR was an increase in polyuria-polydipsia. All participants elected to continue treatment with the ER dosage formulation at the conclusion of the study. This study was also not without limitations, most notably a small sample size and the inclusion of only stable patients.

Three small studies which have been published as “Letter to the Editors” are useful in reporting conversions from DR to ER dosage formulations in psychiatric outpatients (^{Longo 2005; Minirth and Veal 2005; Jackson et al 2006}). In the first of these studies, a small, 12-week, open-label, pilot trial examined outpatients diagnosed with bipolar I or II disorder or schizoaffective disorder (^{Longo 2005}). The patients described in this study were being treated with the DR formulation, but were reporting associated adverse events. The dose conversion was carried out per package labeling which recommends up to a 20% dose increase in converting from DR to ER. No additional medication changes were allowed during the 12-week observation period. The primary outcome measures were the Clinical Global Impression Scale (CGI) and the Global Assessment of Functioning scales (GAF).

According to these outcome measures, 9 of 10 patients were considered to exhibit no change or slight improvement in their symptoms, while 5 of 10 reported improvements in adverse events. Baseline psychometric assessment scoring, dosing information, length of prior treatment, and therapeutic drug monitoring parameters were collected, however none of the values were reported. This study possesses several limitations, however it does provide some information regarding practical experience with converting patients.

The second of the “Letter to the Editor” publications described a retrospective chart review that focused on the evaluation of efficacy, tolerability, and impact on adherence when switching patients from DR to ER (^{Minirth and Veal 2005}). Psychiatric patients, including those diagnosed with bipolar disorder types I and II, were included. Participants eligible for enrollment had to have been taking DR for at least three months prior to the switch.

Patients were evaluated using the CGI-S scale on the day of the switch from DR to ER and again during the follow-up visit. Additional secondary assessments which were evaluated at baseline and endpoint included Self-Rating Report of Symptoms and review of clinician’s notes regarding patient symptomatology.

The study was conducted at a single study site and included the records of 32 patients. Doses of divalproex sodium DR ranged from 125 to 1000 mg/day and following the milligram-for-milligram switch patients were maintained on 500–2000 mg/day of ER.

While this report suggests clinical improvement, the ability to critically evaluate the study is limited by a lack of data showing baseline and endpoint scores for the outcome measures. Therapeutic drug monitoring, particularly serum valproic acid levels, were not mentioned in the design of the study and were not reported. Adherence, one of the secondary outcome measures, was patient rated and evaluated by a telephone interview conducted by the raters. Statistical analysis was not performed on the data collected.

The third “Letter to the Editor” briefly described the conversion of 52 patients stabilized on DR who were converted on an equal milligram-per-milligram basis to the ER formulation for up to 24 weeks (^{Jackson et al 2006}). Psychometric assessment measures included the HAM-D 21 (21-item scale) and YMRS. Utilizing the statistical method of repeated measures analysis, statistically significant improvement was noted from the time of conversion to study endpoint with both the HAM-D 21 and YMRS. No significant changes were identified in therapeutic drug monitoring lab values and overall patients reported improved tolerability of the ER formulation.

The use of ER in the management of psychiatric symptoms has not been limited to bipolar disorder alone. One 4-week, open-label DR to ER conversion study included thirty patients diagnosed with schizophrenia (^{Citrome, Tremeau et al 2004}). To be included in the study, patients had to be on a stable dose (1,000 to 3,000 mg/day) of DR for at least 4 weeks. Patients were converted at a 1:1 mg ratio (n = 12) for DR to ER if the baseline serum concentration of valproate was ⩾85 μg/mL and 1:1.2 mg ratio (n = 18) for DR to ER if the baseline serum concentration of valproate was <85 μg/mL. Dosing required the use of 500 mg increments due to the lack of availability of the 250 mg tablet at the time of the study. The BPRS was the primary outcome measure with side effects assessed with the UKU Side Effect Rating Scale.

Twenty-seven of 30 patients completed the 4-week study. The baseline mean BPRS total score was 37.9 ± 9.2 (n = 30) and the mean endpoint BPRS score was 35.7 ± 11.2 (n = 29), producing a significant mean reduction of 2.3 ± 5.4 points (p = 0.0322). Significant improvement was noted for the 1:1 mg conversion group (p = 0.0561), but not for the 1:1.2 mg group (p = 0.2223). Mean UKU scores also showed significant improvement, dropping from a mean of 8.8 ± 6.7 (n = 29) at baseline to 7.5 ± 5.8 (n = 28) at endpoint, though for patients with evaluable baseline and endpoint scores the mean change was a reduction of 2.2 ± 4.1 (n = 27, p = 0.0111).

The mean DR dose at study entry was 1,592 mg ± 498 mg/day which produced a mean baseline trough (12-hours post-dose) valproate concentration of 80.1 ± 20.4 μg/mL. The ER dosing at study endpoint was 1,950 mg ± 592 mg/day which produced a mean trough concentration (24-hours post-dose) of 73.1 ± 24.2 μg/mL. The 1:1 mg conversion group produced trough levels that were significantly lower at endpoint compared to baseline (p = 0.0006), though the difference in baseline and endpoint levels for the 1:1.2 conversion group were not (p = 0.7102).

The conversion of DR to ER was not associated with any reports of psychiatric decompensation. While the BPRS was noted to improve across the group, the small reduction should not be interpreted as being more effective as this study is limited by being open-label, small sample size, short duration, and the actual improvement was only a 6% reduction in total BPRS score. The improvement of UKU scores are consistent with other reports of improved tolerability associated with the ER formulation.

Clinical Study Mood Swings: Valproic Acid and Depakote ER – Clinical Trials Registry

Valproate as a maintenance therapy for people with bipolar disorder after episodes of mood disorder

Bipolar disorder is a disorder that manifests itself as manic and depressive conditions, and sometimes mixed.Depression is characterized by a decline in mood and energy, as well as an inability to experience joy, often in combination with other problems, such as sleep disturbance. Mania is the opposite – there is “too much” energy and problems with good mood or irritability. In mixed conditions, the symptoms of depression and mania are combined. These episodes of mood disorder usually occur several times in a person’s life, and therefore long-term treatment (supportive care) can play a very important role in preventing relapse.Since valproate is a drug that may be useful in the treatment of the acute phase of bipolar disorder, in this review we wanted to answer the following question: Is valproate useful as a supportive agent for bipolar disorder?

We searched for relevant studies (randomized controlled trials, or RCTs) of long-term treatment of people with bipolar disorder with valproate or any other mood stabilizer, antipsychotic drug, or placebo.Three of us reviewed RCTs to make sure the experiments were scientific. We extracted data from studies, pooled all the evidence together, and performed statistical analyzes to find meaningful results.

We searched up to January 11, 2013 and found six studies with 876 participants. The quality of the studies in terms of design was not very good, which means that the effects of some drugs could be overestimated. Pooled studies suggest that valproate may help prevent recurrence of bipolar disorder, especially depressive episodes.However, due to limited evidence, conclusions regarding valproate versus placebo and lithium (or other active agents) cannot be drawn with any reasonable degree of certainty. Lithium is an important comparison drug to valproate because it is known to be effective in preventing recurrence of bipolar disorder. When we pooled the results of all studies that compared valproate to lithium, the evidence was not superior to valproate or lithium in terms of efficacy.People who took valproate for a long time were more likely to continue taking their prescribed drugs than people who were given lithium. Clinicians and patients should consider the side effects of valproate, including alopecia, tremors, and weight gain.

We also found a study comparing valproate monotherapy with combination therapy (taking two drugs at the same time). This study compared people who took only lithium or valproate with those who took valproate and lithium at the same time.There is no evidence that the use of valproate and lithium compared with lithium alone resulted in greater patient adherence.

Bipolar Disorder Treatment | | Bipolar.su

Thanks to the right treatment, the majority of patients with bipolar disorder – even in its most severe forms – can stabilize mood swings and other symptoms of the disease. Because bipolar disorder is recurrent, preventive treatment is not only indicated but strongly recommended.Treatment that combines medication and psychotherapy is optimal to keep the disease under control.

In most cases, bipolar disorder can be controlled much more effectively if the patient does not interrupt the course of treatment, but constantly follows it. But even in these cases, episodes of mood swings are quite likely. In such cases, it is imperative to notify the attending physician. Timely changes in the course of treatment by the doctor can prevent a full-blown episode.
Treatment will be more effective by openly discussing any concerns and proposed treatment options with your doctor.
In addition, if the patient himself and his loved ones fill in the graph of mood symptoms, medication intake, sleep patterns, daily events every day, then they begin to better understand the disease. Schedules like these also help the treating doctor more effectively monitor the progress of illness and treatment.

Medication

Medication for bipolar disorder is prescribed by board certified psychiatrists – doctors of medicine (MD), specialists in the diagnosis and treatment of mental illness.Although a physician can also prescribe medication, it is strongly recommended that people with bipolar disorder be seen and treated by a psychiatrist.
For bipolar disorder, so-called mood stabilizers are usually prescribed. There are several types of them. Typically, people with bipolar disorder continue to take mood stabilizers for an extended period of time (years). Other drugs are given as needed, usually for a shorter period of time, to relieve episodes of mania or depression that may occur intermittently, even with mood stabilizers.

Lithium is the first mood stabilizing drug approved by the US Food and Drug Administration (FDA) for the treatment of mania. This medication is effective in controlling mania or preventing relapses of both manic and depressive episodes.

Anticonvulsants such as valproate (Depakote®) or carbamazepine (Tegretol®) also have mood-stabilizing effects and can be used in particularly difficult-to-treat cases of bipolar disorder.FDA approved valproate for the treatment of mania in 1995

New anticonvulsants such as lamotrigine (Lamictal®), gabapentin (Neurontin®), and topiramate (Topamax®) are under study to determine how well they work. to stabilize mood cycles
For maximum effect, several anticonvulsants may be prescribed at once, or they may be used in combination with lithium.

Children and adolescents with bipolar disorder are usually treated with lithium, but valproate and carbamazepine are also used.Scientists are investigating the safety and effectiveness of these and other psychotropic drugs for children and adolescents. Studies have shown that valproate can lead to hormonal changes in adolescent girls and polycystic ovarian syndrome in young women who start taking this drug before the age of 20.13 Therefore, young patients taking valproate should definitely be closely monitored by a doctor. …

Patients with bipolar disorder who wish to become pregnant or are already pregnant face difficult choices as mood stabilizers can have negative effects on the fetus or breastfeeding infant.14 Thus, before making a responsible decision, it is necessary to discuss with a specialist all the pros and cons of various methods of treatment. New drugs are currently being tested to significantly reduce risk during pregnancy or breastfeeding.

Treatment for Bipolar Disorder

Studies have shown that patients with bipolar disorder treated with antidepressants are at risk of developing mania, hypomania, or rapidly circulating disease.

Mood stabilizing medications, either in combination with antidepressants or on their own, are usually required to protect patients with bipolar disorder from these effects. Lithium and valproate are currently the most commonly used mood-stabilizing drugs. However, trials are ongoing to evaluate the effectiveness of new drugs for mood stabilization.
Atypical antipsychotics, including clozapine (Clozaril®), olanzapine (Zyprexa®), risperidone (Rispendal®), quetipine (Seroquel®), and ziprasidone (Geodon®), are being investigated for their use in the treatment of bipolar disorder.There is evidence that clozapine may help patients who do not respond to lithium or anticonvulsant treatment.
Other studies have confirmed that olanzapine is effective in acute mania and has recently been approved by the FDA for use in this capacity.17 Olanzapine has also been shown to help treat psychotic depression.18
Aripiprazole (Abilify®) is another atypical antipsychotic drug used to treat symptoms schizophrenia and manic or mixed (manic and depressive) episodes of bipolar I disorder.It comes in both tablets and liquid form. Injections are used to treat the symptoms of agitation in schizophrenia and manic or mixed episodes of bipolar I disorder.
If insomnia is a problem, highly effective benzodiazipine drugs such as clonazepam (Klonopin®) or lorazepam (Ativan®) can help. However, because these drugs are addictive, they are only prescribed for a short time. In some cases, sedatives such as zolpidem (Ambien®) are prescribed instead.
Over the course of treatment for bipolar disorder, medications have to be changed more than once in order to achieve the most effective treatment. All drug changes and dose changes should be made as directed by the attending psychiatrist.
Be sure to tell your psychiatrist about all medications you are taking, including over-the-counter medications, homeopathic remedies, vitamins, and other supplements. This is very important as some medications and supplements are incompatible and may cause adverse reactions.
In order to avoid relapse or a new episode, it is necessary to strictly adhere to the treatment plan. Talk to your doctor about any medication questions.

Thyroid function

Thyroid dysfunction is common in patients with bipolar disorder. Elevated or lowered thyroid hormone levels by themselves can have an impact on mood and energy changes. Therefore, it is very important that the thyroid gland parameters are under constant control of the attending physician.
The rapidly circulating form of bipolar is often associated with thyroid disease. In such cases, thyroid medications must be taken along with medications for bipolar disorder. It should also be borne in mind that in some patients, lithium can cause a decrease in the activity of the thyroid gland. At the same time, medications must be introduced into the course of treatment to regulate the function of the thyroid gland.

Drug side effects

Before starting new drugs, be sure to consult with your doctor and / or pharmacist about possible side effects.Depending on the drug, side effects may include weight gain, nausea, tremors, decreased sexual activity or ability, anxiety, hair loss, difficulty moving, and dry mouth. Be sure to tell your doctor about any side effects that appear while taking this or that medication. To remove or reduce side effects, the doctor may change the dosage of the drug or change it to another. Do not change medications or stop taking them without consulting a psychiatrist.

Psychosocial Methods

Psychosocial therapies are recommended along with medication, including some form of psychotherapy (or “talking” therapy). These methods help patients with bipolar disorder and their families understand the specifics of the disease and obtain the information they need. Research results have shown that psychosocial therapy helps stabilize mood, reduce hospitalizations and improve performance in various areas of human activity.

Typically, licensed psychologists and social service providers perform this therapy in coordination with the treating psychiatrist and collaboratively monitoring the patient’s health progress. The number of sessions, their frequency and duration depend on the individual needs of each patient.
Psychosocial treatments for bipolar disorder include cognitive behavioral therapy, psychological education, family therapy, and a new technique called interpersonal and social rhythmic therapy.Researchers at the National Institute of Mental Health (NIMH) are studying and comparing the effectiveness of these therapies when used in combination with various drugs to treat bipolar disorder:
Cognitive behavioral therapy helps patients with bipolar disorder understand and change negative or distorted thinking and behavior patterns associated with disease.
Psychological education provides patients with information about the disease and how to treat it, and helps them learn to recognize the signs of relapse so that they can seek early help and prevent a full-blown episode from occurring.Mental education is also useful for the family members of the patient.

Family therapy uses a strategy to reduce the level of tension in the family, which can aggravate the symptoms of the disease or provoked by them.
Interpersonal and social rhythm therapy helps patients with bipolar disorder improve interpersonal relationships and organize their daily routine. A regular schedule and regular sleep patterns can help prevent manic episodes.
As with medication, the prescribed course of treatment must be strictly adhered to in order to achieve successful psychosocial therapy results.

Other treatments

Electroconvulsive therapy (ECT) is used when drug therapy, psychosocial therapy, or a combination of both does not work, or is too slow to treat severe symptoms such as psychosis or suicidal symptoms. The use of ECT can also help during acute episodes when the patient’s physical condition (including pregnancy) does not allow the use of drugs.ECT is highly effective in the treatment of severe depression, manic and / or mixed episodes. The potential for long-term memory problems from ECT, which until recently was a major cause for concern, is now significantly reduced by the latest ECT techniques.
However, the pros and cons of ECT and other alternative therapies should be discussed in advance with the patient and, if necessary, with family or friends.
Herbs and natural supplements, such as St. John’s wort (Hypericum perforatum), are not well understood and there is little information available on their effects on bipolar disorder.Since FDA regulations do not apply to these products, different manufacturers of these supplements use different amounts of active ingredients. Before taking medicinal herbs or natural supplements, you should consult with your healthcare professional. There is evidence that St. John’s wort can reduce the effectiveness of certain drugs (see: www.nimh.nih.gov/events/stjohnwort.cfm) leaving the site’s OMH. 20 In addition, like prescription antidepressants, St. John’s wort can provoke mania in some people with bipolar disorder, especially when the patient is not on mood stabilizers.
Studies are being conducted on the efficacy of Omega-3s (fatty acids in fish oil) in the treatment of bipolar disorder, in combination with conventional medications or alone.

A chronic illness that can be treated very effectively

Although episodes of mania and depression tend to come and go, it must always be remembered that bipolar disorder is a chronic condition that currently has no cure. The only way to keep this disease under control is to constantly take medication, even during periods when you feel good.Only in this case can the chance of relapses and deterioration of the condition be reduced.

Comorbidities

Alcoholism and drug addiction are very common among patients with bipolar disorder. Studies have shown that there are a number of reasons for this, including self-medication, mood swings from alcohol or drug abuse, and risk factors that affect both the development of bipolar disorder and drug dependence.

Treatment for alcohol or drug addiction is an important part of the overall course of treatment.
Anxiety disorders such as post-traumatic stress disorder or obsessive-compulsive disorder (obsessive-compulsive disorder) are also common in bipolar disorder.

Comorbid anxiety disorders can sometimes be controlled by the same means as bipolar disorder, but in some cases special treatment is required.

Care for people with bipolar disorder and their families

People with bipolar disorder should be guided by an experienced psychiatrist who specializes in the diagnosis and treatment of the condition.Psychologists, social mental health workers, and mental health nurses help provide various aspects of treatment and care for patients and their families.

Help can be obtained at the following locations:

• Treatment programs at universities or medical schools
• In psychiatric wards of hospitals
• In private psychiatric offices and clinics
• In health care organizations (HMOs)
• In district offices or pediatricians
• Community mental health centers
• People with bipolar disorder may need help to get help

People with bipolar disorder often don’t realize how sick they are, or they do not see the cause of their illness in mental disorder, but in what Something else.
People with bipolar disorder may need encouragement and support from family and friends to seek help from a doctor. The therapist can play an important role in insisting on consultation with a psychiatrist.
Occasionally, a family member or friend may need to accompany a person with bipolar disorder to see a doctor and receive treatment.
Occasionally, a patient with an acute attack may need to be hospitalized for his / her own safety and treatment.In some cases, the patient has to be hospitalized against his / her will and without consent.
It is necessary to constantly support and encourage the patient after the start of treatment, because in some cases it may take quite a long time to find the right course of treatment.
In some cases, people with bipolar disorder in remission may negotiate a specific course of action in the event of a manic or depressive relapse in the future.

Like other serious illnesses, bipolar disorder affects spouses, family members, friends and employers.

Family members of a person with bipolar disorder often have to deal with serious behavioral problems, such as spending money rampant during episodes of mania or withdrawing from depression, and the long-term consequences of such behavior.

Many people with bipolar disorder are supported by support groups supported by various organizations such as the National Depression and Manic Depression Disorders Association (NDMDA), the National Mental Assistance Alliance (NAMI), and the National Mental Health Association (NMHA).These support groups also help families and friends of people with bipolar disorder. The coordinates of these organizations can be found in the Useful Information section of our brochure.

Source: http://www.omh.ny.gov/omhweb/russian/booklets/bipolar.html

Depakote

Depakote, which is commonly known as Valporic acid, is a drug used to treat migraines and schizophrenia. It is an anticonvulsant or mood stabilizer. It is manufactured by Abbott Laboratories for the United States markets and sold under alternative names like Depakene and Epival.
Valporic Acid was discovered over 100 years ago, but it was in 1983 that it became FDA approved to treat schizophrenia.It has also been used to treat epilepsy, bipolar disorder, and epilepsy.
Unfortunately, like many other drugs used to treat schizophrenia, Depakote has some very serious side effects. Perhaps most worrisome is the possibility of causing birth defects when pregnant women are prescribed this drug. For some reason, some doctors believe that it is an acceptable risk to prescribe Depakote to women who are in the middle of pregnancy without alerting these women to the potentially catastrophic birth defects that this drug might cause.
Depakote birth defects include (some are proven while others are speculated):
Skeletal Deformities
Spina Bifida
Neural Tube Deformity
Valporate Syndrome
Trigonocephaly
Low IQ
Epicanthic Folds Autism

Most healthcare providers suggest that women using this drug should switch to another drug as soon as they know they are pregnant. Depakote is believed to affect approximately 5% of pregnant women and cause mental birth defects.
However, Depakote also has many other negative effects associated with it that affect the taker than the offspring.
Depakote side effects include, but are not limited to:
Renal Impairment
Thrombocytopenia
Coagulation Polonged
Blood Dyscrasia
Impaired liver Fuction
Nausea
Weight gain
Hair loss
Shivering
Acne
· Hematological Toxicity
· Myelodysplasia
· Parkinson’s Signs
· Calm
· Peripheral Edema
· Overdose
In addition, there are many contraindications for this drug.If your doctor prescribed Depakote for you and knew that you had hepatitis, HIV / AIDS, metastatic cancer, or bone marrow depression, your doctor may be responsible for causing If you or one of your loved ones have been harmed in one of the many ways Depakote can cause serious injury,

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Bounce back with mood stabilizers

Mood stabilizers are not the same as antidepressants.Rather, as the name suggests, they act by mitigating the excessive mood swings that are common in manic-depressive illness. The classic mood stabilizer is lithium. Although some are similar

Dictionary of a Psychologist

Dysmorphophobic Disorder – severe preoccupation with minor or imaginary defects in the body, obsessive obsession with the body image.

Part 5> What is normal after all?

drugs are designed to relieve seizures, such as Tegretol and Depakot, they are also effective in stabilizing mood.

Lithium was the first and for a long time the only drug that had a beneficial effect in bipolar disease. It is most effective in relieving manic symptoms and less effective on the depressive side. It often reduces the frequency and severity of manic episodes, but does not necessarily eliminate them all.

Lithium is a mineral that is naturally produced in the body, but we do not know exactly what its role in manic depression is.According to one theory, lithium stabilizes the brain’s sensitivity to monoamines by inserting into the chain of amino acids (proteins) that are essential for life. The main problem with lithium is that, in high doses, it can cause serious side effects, including diarrhea, vomiting, and seizures. So, while taking it, it is necessary to regularly take blood or urine tests to avoid intoxication.

More recently, mood stabilizers have been used to treat other psychological conditions, with conflicting results.For example, lithium is somewhat effective in helping clients with explosions of uncontrolled aggression. It turns out that people with other “personality disorders” involving marked mood swings receive some relief from this remedy, although there is still debate about its long-term effectiveness.

Don’t worry, be happy: anti-anxiety drugs

Valium, Librium, barbiturates. These “minor tranquilizers,” as anti-anxiety drugs are often called, gained notoriety in the 1960s when more than 10% of US adults were taking them regularly.Unfortunately, these drugs made people feel good, but they were highly addictive. This dangerous combination led to very serious drug problems. Since then, their use has diminished significantly, although Valium remains the most popular tranquilizer in use today. Eight to nine million Americans take it daily.

See the Root

While mood stabilizers are most effective in treating the manic portion of manic-depressive disorders, epilepsy medications can help patients with bipolar depression.reparation.

Chapter 21 > Better Life With Chemistry

The anti-anxiety drugs (anxiolytics) prescribed today are much safer than their predecessors. Xanax and Klonopin are perhaps the most commonly used to control generalized anxiety and, to some extent, panic disorder. They work best when taken for a short time as they are still addictive. When it is time to stop taking the drug, the dose should be tapering off gradually to avoid unpleasant physical side effects.Among their unconditional advantages, it can be noted that they can save the lives of people whose anxiety is so great that it makes it impossible for them to cope with the experiences caused by the world around them.

The best “tranquilizers” are those that have the greatest anxiolytic effect with the least sedative effect. Buspar, a new anti-anxiety drug, appears to be safer and less addictive than older drugs. It has less sedative effect than benzodiazepines (Xanax, Klonopin), which replaced the old barbiturates.

Self-medicating people often use approved antihistamines (Benadryl) to combat anxiety or as a sleeping pill. While it’s certainly easier (and cheaper) to run to the pharmacy than go to the doctor, self-medication for anxiety is generally not a good idea. It is best to use regular exercise or relaxation techniques to deal with the problem yourself. Brand name drugs like Benadryl are not the most effective anti-anxiety medication, and they have more side effects than the benzodiazepines prescribed by your doctor.

Bipolar Personality Disorder (Manic Depressive Psychosis)

There are several types of bipolar disorder and related conditions. For each type, specific symptoms may vary from person to person. Bipolar I and II disorders can also be accompanied by some additional specific manifestations that can be added to the diagnosis based on specific symptoms and manifestations.

Criteria for Bipolar Disorder
The Diagnostic and Statistical Manual of Mental Disorders (DSM), published by the American Psychiatric Association, contains a list of criteria for the diagnosis of bipolar disorder and related disorders (DSM classification).This guide is used by psychiatrists to diagnose mental illness and by insurance companies to cover treatment costs.

Diagnostic criteria for bipolar disorder and related disorders are based on the characteristics of the disorder:

• Bipolar disorder I type. A history of bipolar I disorder should have at least one manic episode. It may follow or precede an episode of hypomania or major depressive episode.The symptoms of mania have a significant impact on the patient’s life and require hospitalization or are the cause of the development of psychosis, a condition in which behavior and perception of the real world are grossly disturbed.
• Bipolar disorder II type. To diagnose bipolar II disorder, there must be at least one major depressive episode lasting at least four days and no manic episodes at all.Major depressive episodes or unpredictable changes in mood and behavior can cause stress and difficulties in various areas of life.
• Cyclothymia. The history should be a period of at least two years (or one year in childhood or adolescence) of alternating multiple episodes of hypomania (less severe than an episode of hypomania) and periods of depression (less severe than major depressive episode). During this period, symptoms are present at least half the time and never go away for more than two months.Symptoms have a significant negative impact on important areas of life.
• Other types. This includes, for example, bipolar and related disorders associated with other medical conditions such as Cushing’s disease, multiple sclerosis, or stroke. Other types are called bipolar drug and substance use disorders.

Bipolar II disorder is not a milder form of type I disorder, but a separate condition.Although episodes of type I mania can be severe and dangerous, people with bipolar II disorder can be depressed for long periods of time, which significantly impairs their quality of life.

Criteria for episodes of mania and hypomania
The DSM-5 classification presents the following criteria for diagnosing episodes of mania and hypomania: at least one week (or less if hospitalization was necessary).This episode is also characterized by a constantly increased purposeful activity and a rise in energy.

To diagnose mania and hypomania, three or more of the symptoms described below must be present and significantly alter the normal behavior of a person against a background of agitation and a surge of energy (four if only irritability is present):

• Increased self-esteem and ideas of greatness (grandeur)
• Decreased need for sleep (for example, you feel rested after three hours of sleep)
• Increased talkativeness
• Speeding up the flow of thoughts (jump of ideas)
• Pathologically increased distraction
• Increased purposeful activity (whether social, at work or school, and sexual) or arousal
• Unusual behavior, the consequences of which can be potentially dangerous.For example, making a lot of senseless purchases, sexual promiscuity, or stupid enterprise.

To be considered an episode of mania:

• The mood disorder must be severe enough to result in marked difficulties in work, learning, social activities or relationships, or require hospitalization to prevent the person from harming themselves or others; or cause the development of psychosis – a condition in which the perception of the real world and behavior are grossly disturbed.
• Symptoms cannot be attributed to alcohol, drug use, medication, or any medical condition.

To be considered an episode of hypomania:

• Changes in mood and behavior must be abnormal for the person in their normal state and sufficiently pronounced for other people to notice them.
• The episode should not be so difficult as to cause difficulties in work, study, social activities or relationships.There should be no need for hospitalization and no signs of psychosis.
• Symptoms cannot be attributed to alcohol, drug use, medication, or any medical condition.

Criteria for a major depressive episode
The DSM-5 classification provides criteria for diagnosing a major depressive episode:

• The appearance of at least five of the following symptoms, resulting in marked changes in mood and personality functioning.The episode lasts at least two weeks.
• Description of symptoms can be based on the patient’s own feelings or observations of someone from the outside.

Symptoms should be expressed almost daily and include:

• Decreased mood, feelings of melancholy, emptiness, hopelessness, tearfulness. In children and adolescents, depression can manifest as irritability.
• Loss of pleasure or a marked decrease in interest in all or nearly all activities.
• Significant weight loss without diet, weight gain, decreased or increased appetite.
• Insomnia or increased drowsiness
• Excitement or lethargy noted or described by others
• Increased fatigue, weakness
• Feeling of own worthlessness or excessive guilt, aimlessness of existence, feeling of improbability of what is happening
• indecision.
• Constantly arising thoughts of death or suicide, attempts at suicide.

To be considered a major depressive episode:

• Symptoms must be severe enough to cause noticeable difficulty in daily activities such as school, work, social activity or relationships.
• Symptoms cannot be explained by alcohol, drug use, medication, or any medical condition
• Symptoms cannot be explained by a painful event, such as the loss of a loved one.

Other signs and symptoms of bipolar disorder

Symptoms and signs of bipolar I and II disorder may include:

• Anxious distress – anxiety, nervousness, tension, anxiety, trouble concentrating due to , fear that something terrible might happen, a feeling that you cannot control yourself.
• Mixed Bipolar Disorder – Criteria for a manic or hypomanic episode and some or all of the criteria for a major depressive episode are present at the same time.
• Melancholic depression – loss of pleasure from everything or almost everything that was previously pleasant. Lack of improvement even when good things happen.
• Atypical depression – its symptoms are not typical for a major depressive episode. For example, when something good happens, your mood improves dramatically.
• Catatonia – the state is characterized by a lack of response to external stimuli, freezing in an unusual posture, lack of speech contact and mimic reactions to addressed speech.
• Bipolar Disorder of Pregnancy and Postpartum Depression – Symptoms of bipolar disorder occur during pregnancy or in the first four weeks after childbirth.
• Seasonal Affective Disorders – episodes of mania, hypomania, or major depressive episodes occurring at certain times of the year.
• Rapid Cycle – At least four episodes of mania, hypomania, or major depressive episodes in one year with complete or partial remission of symptoms between episodes.
• Psychosis – severe episodes of mania or depression (but not hypomania), with impaired perception of reality, delusions and hallucinations.

Symptoms of Bipolar Disorder in Children and Adolescents
The criteria used to diagnose bipolar disorder in children and adolescents are the same as in adults.