Valproic Acid (Depakote)


Valproic Acid (Depakote)


HALF-LIFE: 9-16 hours
STARTING DOSE: 250mg-500mg per day
TARGET DOSING RANGE: 1000mg-1500mg PO daily
BEST TIME TO DOSE: Bedtime (for Extended release)
> Initial 250mg-500mg PO QHS. Increase rapidly to effective dose
> Alternatively: Initial 15-20 mg/kg/day (BID dosing)
> Target range 1000mg-1500mg PO daily
> Target serum level: 50mcg/mL – 125mcg/mL
> Max 4000mg/day
PREGNANCY: Avoid – Neural Tube Defects.
1) Seizures
2) Acute Mania associated with Bipolar Disorder
3) Migraine prophylaxis




  • Valproic acid (Valproate) is considered an anticonvulsant with mood stabilizing properties
  • Use of anticonvulsants in mood disorders developed out of research looking at the effects of anticonvulsants on seizure activity and the process of “kindling” in mice (i.e., repeatedly inducing seizures via electrical stimulation results in seizure activity even in the absence of any stimulation). 
  • Carbamazepine (Tegretol) was first tried in individuals with bipolar disorder
  • Carbamazapine (Tegretol) exerted both acute anti-manic and prophylactic effects on cycling rates
  • Valproic acid (Depakote) was used next and was found to be superior to lithium in type II bipolar illness and in rapid cycling illness (but anticonvulsants and lithium together showed additive benefits)
  • In manic patients, plasma levels greater than 45 ug/mL may be required for antimanic effects (levels up to 100-125 ug/mL are often tolerated in manic patients)
  • There is no consensus on the therapeutic plasma level range for valproic acid but likely between 50-100 ug/mL
  • Valproate inhibits Lamotrigine metabolism
    • Combination of valproate and lamotrigine increases lamotrigine levels and increases risk of rash and SJS/TEN
    • The dose of lamotrigine must be decreased by half the normal dose when given in combination with valproic acid (valproic acid inhibits lamotrigine metabolism).
  • Valproic acid associated with dose-related thrombocytopenia in ~24% of patients
  • Commonly associated with elevated liver enzymes
  • Valproic acid has been associated with encephalopathy, specifically from elevated ammonia levels
  • Valproic acid + Topiramate increases risk of encephalopathy
  • Valproic acid metabolized primarily by liver but by NonCYP450 enzymes
  • Valproic acid associated with Polycystic Ovarian Syndrome (10% of women)
  • Valproic acid has been shown to be effective in neuropathic pain


Proposed Mechanisms of Action:


  • Blocks voltage sensitive sodium channels
  • Increases brain concentrations of GABA
  • Unlike many other medications, lithium and the antiepileptics alter brain signal transduction by dampening axonal signal transmission and by inhibiting cellular response to excitatory signals.  Part of this is mediated by partial blockade of voltage-dependent sodium channels.  This property alone is not sufficient as anti-epileptics which DO NOT show benefit in bipolar illness also exhibit inhibitory effects at voltage-dependent sodium channels.  
  • To date, the property best correlated with prophylaxis of mood cycling has been depletion of the second-messenger, triphosphoinositol (IP3). 
  • Another candidate mechanism is increased guanine synthase kinase, type 3, activity.  This enzyme plays a role in modulating both voltage and ligand-gated sodium channels.


Common side effects:


  • Sedation
  • Tremor
  • Dizziness
  • Ataxia
  • Asthenia (muscle weakness) 
  • Headache
  • Abdominal Pain
  • Nausea
  • Vomiting
  • Weight gain
  • Alopecia


Prior to starting, obtain the following labs:


  • Pregnancy test
  • Liver function tests
  • Platelet count


Pregnancy risks:


  • Neural tube defects (spina bifida, anencephaly, etc)
  • Low IQ
  • Developmental delay
  • Valproic should not be used during pregnancy except in special cases (consult a perinatal psychiatrist)
  • There is actually little evidence that folate supplementation actually prevents or protects against neural tube defects (but it hasn’t been harmful so not a bad idea to use)




What Does “Mood” Mean?


Mood is defined as a person’s internal emotional state that is sustained over time. Mood is subjective and experienced by the person. Terms used to describe mood: Normal, Sad, Angry, Irritable, Anxious, Happy


What Does “Affect” Mean?


Affect is a term used to describe the outward expression of a mood state. In other words, an individual’s affect is visible to others. Healthcare providers obtain important information about an individual’s internal emotional experience (mood) based on their emotional expression (affect). Terms used to describe an individual’s affect: Dysphoric, Happy, Excited, Irritable, Angry, Tearful, Blunted, Euthymic, Flat, Blunted, Constricted, Restricted, Appropriate, Congruent.


What Are Mood Disorders?


Mood disorders are group of psychiatric disorders in which disturbances of mood or affect are severe and persistent enough to cause significant problems in an individual’s life. Moods by themselves are not pathological and many of us have experienced a wide range of mood states. When moods become severe and persistent enough to cause dysfunction and issues in an individual’s life, then we use the term “mood disorder.”  Mood disorders are better defined as syndromes consisting of a cluster of signs and symptoms that often “come and go” in “episodes” which persist for weeks, months, or even years. During these “episodes,” there is a significant change in the individual’s mood which may negatively impact work performance, relationships, or other important areas of functioning. The most common mood disorder is major depressive disorder (MDD), often referred to as “Unipolar depression.” Bipolar disorders are also mood disorders that differ from unipolar depression by the presence of elevated mood states called hypomania or mania.


What is Mania?


Mania is characterized by a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased goal-directed activity or energy, lasting at least 1 week and present most of the day, nearly every day (or any duration if hospitalization is necessary). During this period of elevated/expansive mood/energy, individuals may experience any combination of the following: Inflated self-esteem or grandiosity; Decreased need for sleep (e.g., feels rested after only 3 hours of sleep); More talkative than usual or pressure to keep talking; Flight of ideas or subjective experience that thoughts are racing; Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli), as reported or observed; Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation (i.e., puroseless non-goal-directed activity); Excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments). As with any “disorder,” the mood disturbance is sufficiently severe to cause marked impairment in social or occupational functioning or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. If the mood disturbance can be attribute dto a drug, medication, or medical condition then the term “manic episode” should not be used. 


What is Hypomania?


Hypomania is a less severe form of mania and is characterized by a distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least 4 consecutive days and present most of the day, nearly every day with the same symptoms that characterize mania (see above). 


Subtypes of Bipolar Disorder:

Bipolar 1 Disorder: Manic or Mixed episode +/- Major Depressive Episode (Only manic episode required) 

Bipolar 2 Disorder: Hypomanic episode + Major Depressive Episode (both are required)

With rapid cycling: 4 or more mood episodes in a 12-month period




Neurobiology of Bipolar Disorder 


The underlying biochemical abnormalities that cause or contribute to bipolar disorder remain unclear. However, studies have suggested neurobiological differences between unipolar and bipolar depression which is further supported by the relative lack of efficacy of classic antidepressant monotherapy in the treatment and prevention of bipolar depression. Human studies have found increased concentrations of noradrenaline (norepinephrine) and dopamine (DA) and decreasedconcentrations of serotonin (5-HT) in manic patients which suggests that norepinephrine and dopamine dysregulation may play a primary role in manic symptoms. In patients with unipolar depression, both serotonin (5-HT) and norepinephrine concentrations are low. Perhaps the imbalance partially explains bipolarity? Lastly, glutamate and GABA dysregulation have been implicated in the pathophysiology of bipolar disorder. Animals studies suggest increased glutamatergic neurotransmission via NMDA receptors in manic patients. In addition, the efficacy of anticonvulsants and benzodiazepines in the treatment of bipolar disorder suggests the likelihood that glutamate and GABA systems are involved in uncertain ways. 


It is likely that the combination of vulnerable genetics and environmental stressors lead to intracellular changes in transcription, signal transduction, and synaptic functioning that ultimately give rise (via poorly understood mechanisms) to symptoms of bipolar disorder.



Functional Imaging Studies


Functional Connectivity Studies have demonstrated or suggested


(1) Decreased connectivity between the amygdala and anterior cingulate cortex

(2) Increased connectivity between the amygdala and the supplemental motor area


Functional Neuroimaging Studies have demonstrated or suggested


(1) Decreased size and activity in the PFC of patients with bipolar disorder—similar to that found in patients with unipolar depression.

(2) Increased gray matter volume in bipolar patients after 4 weeks of lithium treatment (Note: Valproic acid (depakote) has not been shown to have the same effect.

(3) Amygdala are larger and more active in the bipolar patients.

(4) Bipolar disorder may be the result of abnormal interactions between the PFC and subcortical regions such as the amygdala—an abnormality not usually seen with unipolar depression.



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