Mood Stabilizers Flashcards
Asenapine
May act on nicotinic acetylcholine receptor and serotonin HT3.
The mechanism of its antidepressant effect is unclear.
Provides a rapid response (within 2-3 days) in patients who respond.
Little is known about the long-term efficacy.
Marketed as Zulresso (Schedule IV controlled substance).
Available only through a national registry.
Drawbacks:
Long administration time: 60-hour continuous IV infusion with slow dose increase.
High cost: ~$34,000 for a single dose, plus hospitalization costs, and not typically covered by insurance.
Mood Stabilizers: Lithium
Efficacy for mania and prophylactic treatment of manic-depressive disorder established in the early 1950s by John F.J. Cade.
FDA approved for mania treatment in 1970 and as maintenance therapy in 1974.
Used as an adjunctive medication in the treatment of MDD.
Lithium (Li) is a monovalent ion, a member of the group IA alkali metals.
Exists in nature as (7.42%) and (92.58%).
300 mg of lithium is contained in 1,597 mg of lithium carbonate ().
Pharmacologic Actions
Rapidly and completely absorbed after oral administration.
Peak serum concentrations: 1-1.5 hours with standard preparations, 4-4.5 hours with slow-release/controlled-release.
Does not bind to plasma proteins, is not metabolized, and is excreted through the kidneys.
Plasma half-life: initially 1.3 days, 2.4 days after administration for >1 year.
Slow passage across the blood-brain barrier.
Elimination half-life: 18-24 hours in young adults, shorter in children, prolonged in elderly.
Renal clearance decreased with renal insufficiency.
Equilibrium reached after 5-7 days of regular intake.
Obesity is associated with higher rates of lithium clearance.
Excretion increases during pregnancy but decreases after delivery.
Excreted in breast milk and insignificant amounts in feces and sweat.
Thyroid and renal concentrations higher than serum levels.
Mechanism of mood-stabilizing effects remains unclear; theories involve alterations of ion transport, effects on neurotransmitters/neuropeptides, signal transduction pathways, and second messenger systems.
Therapeutic Indications
Bipolar I Disorder
Manic Episodes
Controls acute mania and prevents relapse in ~80% of persons with bipolar I disorder.
Onset of antimanic effects takes 1-3 weeks; often administered with a benzodiazepine, DRA, SDA, or valproic acid initially.
Patients with mixed or dysphoric mania, rapid cycling, comorbid substance abuse, or organicity respond less well.
Bipolar Depression
Effective in treating depression associated with bipolar I disorder and as add-on therapy for severe MDD.
Augmentation with valproic acid or carbamazepine is usually well-tolerated.
Differential diagnosis for depressive episodes includes lithium-induced hypothyroidism, substance abuse, and non-compliance.
Can increase lithium concentration (up to 1-1.2 mEq/L) or augment with valproate or carbamazepine.
May add supplemental thyroid hormone (e.g., 25 µg a day of liothyronine [Cytomel]).
Antidepressants or ECT may be added judiciously.
After acute depressive episode resolves, taper other therapies in favor of lithium monotherapy.
Maintenance
Markedly decreases the frequency, severity, and duration of manic and depressive episodes in persons with bipolar I disorder.
More effective prophylaxis for mania than for depression; supplemental antidepressant strategies may be needed.
Lithium maintenance is almost always indicated after the first episode of bipolar I disorder, depression or mania, especially for adolescents or those with a family history.
Also beneficial for those with poor support systems, no precipitating factors for first episode, high suicide risk, sudden onset of first episode, or first episode of mania.
Reduces the incidence of suicide in bipolar I disorder patients six- or sevenfold.
Effective treatment for severe cyclothymic disorder.
Relapses are 28 times more likely after lithium discontinuation.
Continued maintenance treatment with lithium is often associated with increased efficacy and reduced mortality.
Supplemental treatment with carbamazepine or valproate may be useful if lithium loses effectiveness.
Maintenance lithium dosages can be adjusted to achieve lower plasma concentrations than for acute mania.
Abrupt discontinuation is associated with an increased risk of recurrence.
Major Depressive Disorder
Effective in long-term treatment, but not more so than antidepressant drugs.
Most common role is as an adjuvant to antidepressants in non-responders.
About 50-60% of antidepressant non-responders respond when lithium (300 mg three times daily) is added.
May see response within days, but most often needs several weeks.
Lithium alone may treat depressed persons with bipolar I disorder who have not yet had a manic episode.
Effective in persons with MDD with marked cyclicity.
Schizoaffective Disorder and Schizophrenia
Persons with prominent mood symptoms are likelier to respond to lithium than those with predominant psychotic symptoms.
Useful augmentation agent alongside SDAs and DRAs, even in the absence of a prominent mood disorder component.
Some persons with schizophrenia who cannot take antipsychotic drugs may benefit from lithium treatment alone.
Other Indications
Lithium has anti-aggressive activity separate from its effects on mood.
Aggressive outbursts, violent prison inmates, children with conduct disorder and aggression, or self-mutilation in persons with intellectual disability can sometimes be controlled with lithium.
Precautions and Adverse Effects
More than 80% of patients taking lithium experience side effects, emphasizing the need for monitoring blood levels and appropriate interventions.
Changes in body water and salt content can affect lithium excretion.
Excessive sodium intake lowers lithium concentrations, while too little sodium can lead to toxic concentrations.
Decreases in body fluid (e.g., excessive perspiration) can lead to dehydration and lithium intoxication.
Patients should report all other medications to avoid drug interactions affecting lithium concentrations.
Cardiac Effects
Can cause diffuse slowing, widening of the frequency spectrum, and potentiation and disorganization of background rhythm on ECG.
Bradycardia and cardiac arrhythmias may occur, especially in people with cardiovascular disease.
May reveal Brugada syndrome.
Clinicians should inquire about heart conditions, unexplained fainting, and family history of sudden unexplained death before starting lithium treatment.
Gastrointestinal Effects
GI symptoms (nausea, decreased appetite, vomiting, and diarrhea) can be diminished by dividing the dosage, administering with food, or switching to another lithium preparation.
Lithium citrate is least likely to cause diarrhea.
Some lithium preparations contain lactose, causing diarrhea in lactose-intolerant persons.
Diarrhea may respond to antidiarrheal preparations such as loperamide, bismuth subsalicylate, or diphenoxylate with atropine.
Weight Gain
Results from a poorly understood effect on carbohydrate metabolism.
Can also result from lithium-induced hypothyroidism or edema and excessive consumption of soft drinks and juices to quench lithium-induced thirst.
Neurologic Effects
Tremor
Lithium-induced postural tremor (8-12 Hz) is most notable in outstretched hands and during fine manipulations.
Can be reduced by dividing the daily dosage, using a sustained-release formulation, reducing caffeine intake, reassessing concomitant medications, and treating comorbid anxiety.
β-Adrenergic receptor antagonists (e.g., propranolol, 30-120 mg/day) and primidone (Mysoline, 50-250 mg/day) are usually effective.
Potassium supplementation may improve tremor in persons with hypokalemia.
Evaluate for lithium toxicity in cases of severe tremor.
Cognitive Effects
Lithium use has been associated with dysphoria, lack of spontaneity, slowed reaction times, and impaired memory.
The differential diagnosis for such symptoms should include depressive disorders, hypothyroidism, hypercalcemia, other illnesses, and other drugs.
Some persons report that fatigue and mild cognitive impairment decrease with time.
Other Neurologic Effects
Uncommon adverse effects include symptoms of mild parkinsonism, ataxia, and dysarthria (though the latter two may be due to lithium intoxication).
Rarely associated with peripheral neuropathy, benign intracranial hypertension, myasthenia gravis-like findings, and increased risk of seizures.
Renal Effect
The most common adverse effect is polyuria with secondary polydipsia (urine output >3 L/day in 25-35% of persons).
Primarily results from lithium antagonism to antidiuretic hormone effects, causing diuresis.
Evaluation includes assessment of renal function and 24-hour urine collections for creatinine clearance determinations.
Treatment involves fluid replacement, lowest effective lithium dosage, single daily dosing, and thiazide or potassium-sparing diuretics (e.g., amiloride, spironolactone).
Halve lithium dosage and wait 5 days before initiating diuretic treatment due to increased lithium retention.
Severe renal adverse effects (rare and associated with continuous use for ≥10 years) involve nonspecific interstitial fibrosis, gradual decreases in glomerular filtration rate, increases in serum creatinine, and, rarely, renal failure.
Lithium is occasionally associated with nephrotic syndrome and features of distal renal tubular acidosis.
MRI can demonstrate renal microcysts secondary to chronic lithium nephropathy.
Check serum creatinine, urine chemistries, and 24-hour urine volume at 6-month intervals.
If creatinine levels rise, consider more frequent monitoring and MRI.
Thyroid Effects
Lithium causes a generally benign and often transient diminution in the concentrations of circulating thyroid hormones.
Reports have attributed goiter (5%), benign reversible exophthalmos, hyperthyroidism, and hypothyroidism (7-10%) to lithium treatment.
Lithium-induced hypothyroidism is more common in women (14%) than in men (4.5%), with the highest risk during the first 2 years of treatment.
Persons taking lithium for bipolar disorder are twice as likely to develop hypothyroidism if they develop rapid cycling.
About 50% of persons receiving long-term lithium treatment have laboratory abnormalities, such as an abnormal TRH response, and about 30% have elevated concentrations of TSH.
If symptoms of hypothyroidism are present, replacement with levothyroxine (Synthroid) is indicated.
Some clinicians treat persons with significantly elevated TSH concentrations with levothyroxine even in the absence of hypothyroid symptoms.
TSH concentrations should be measured every 6-12 months.
Lithium-induced hypothyroidism should be considered when evaluating depressive episodes that emerge during lithium therapy.
Cardiac Effects
The cardiac effects of lithium resemble those of hypokalemia on ECG, due to the displacement of intracellular potassium by the lithium ion.
The most common changes on the ECG are T-wave flattening or inversion. The changes are benign and disappear after lithium is excreted from the body.
Lithium depresses the pacemaking activity of the sinus node, sometimes resulting in sinus dysrhythmias, heart block, and episodes of syncope.
Lithium treatment, therefore, is contraindicated in persons with sick sinus syndrome.
In rare cases, ventricular arrhythmias and congestive heart failure have been associated with lithium therapy.
Lithium cardiotoxicity is prevalent in persons on a low-salt diet, those taking certain diuretics or ACEIs, and those with fluid-electrolyte imbalances or any renal insufficiency.
Dermatologic Effects
Dermatologic effects may be dose-dependent and include acneiform, follicular, and maculopapular eruptions; pretibial ulcerations; and worsening of psoriasis.
Occasionally, aggravated psoriasis or acneiform eruptions may force discontinuation of lithium treatment.
Alopecia has also been reported.
Patients often respond favorably to changing lithium preparations and usual dermatologic measures.
Lithium concentrations should be monitored if tetracycline is used for acne treatment because it can increase lithium retention.
Lithium Toxicity and Overdoses
Early signs and symptoms include neurologic symptoms (coarse tremor, dysarthria, ataxia), GI symptoms, cardiovascular changes, and renal dysfunction.
Later signs and symptoms include impaired consciousness, muscular fasciculations, myoclonus, seizures, and coma.
Risk factors include exceeding the recommended dosage, renal impairment, low-sodium diet, drug interaction, and dehydration.
Elderly persons are more vulnerable to increased serum lithium concentrations.
The greater the degree and duration of elevated lithium concentrations, the worse are the symptoms of lithium toxicity.
Lithium toxicity is a medical emergency, potentially causing permanent neuronal damage and death.
In cases of toxicity, lithium should be stopped and dehydration treated.
Unabsorbed lithium can be removed from the GI tract by ingestion of sodium polystyrene sulfonate (Kayexalate) or polyethylene glycol solution (GoLYTELY), but not activated charcoal.
Ingestion of a single large dose may create clumps of medication in the stomach, which can be removed by gastric lavage with a wide-bore tube.
Value of forced diuresis is still debated.
In severe cases, hemodialysis rapidly removes excessive amounts of serum lithium.
Postdialysis serum lithium concentrations may increase as lithium is redistributed from tissues to the blood, so repeat dialysis may be needed.
Neurologic improvement may lag behind the clearance of serum lithium by several days because lithium crosses the blood-brain barrier slowly.
Adolescents
Serum lithium concentrations for adolescents are similar to those for adults.
Weight gain and acne associated with lithium use can be particularly troublesome.
Elderly Persons
Lithium is a safe and effective drug for elderly persons.
Treatment may be complicated by other medical illnesses, decreased renal function, special diets, and increased sensitivity to lithium.
Elderly persons should initially be given low dosages, their dosages should be switched less frequently than those of younger persons, and a longer time must be allowed for renal excretion to equilibrate with absorption before lithium can be assumed to have reached its steady-state concentrations.
Pregnant Women
Lithium should not be administered during the first trimester due to the risk of congenital disabilities, most commonly Ebstein anomaly of the tricuspid valves.
The risk of Ebstein malformation in lithium-exposed fetuses is 1 in 1,000, which is 20 times the risk in the general population.
Fetal cardiac anomalies can be evaluated with fetal echocardiography.
The teratogenic risk of lithium (4-12%) is higher than that for the general population (2-3%) but appears to be lower than that associated with valproate or carbamazepine.
Women who continue to take lithium during pregnancy should use the lowest effective dosage.
Maternal lithium concentration must be monitored closely during pregnancy, especially after pregnancy, because of the significant decrease in renal lithium excretion as renal function returns to normal in the first few days after delivery.
Adequate hydration can reduce the risk of lithium toxicity during labor.
Lithium prophylaxis is recommended for all women with bipolar disorder as they enter the postpartum period.
Lithium is excreted into breast milk and should be taken by a nursing mother only after careful evaluation of potential risks and benefits.
Signs of lithium toxicity in infants include lethargy, cyanosis, abnormal reflexes, and sometimes hepatomegaly.
Miscellaneous Effects
Lithium should be used with caution in diabetic persons, who should monitor their blood glucose concentrations carefully to avoid diabetic ketoacidosis.
Benign, reversible leukocytosis is commonly associated with lithium treatment.
Dehydrated, debilitated, and medically ill persons are most susceptible to adverse effects and toxicity.
Drug Interactions
Coadministration of higher dosages of a DRA and lithium may result in a synergistic increase in the symptoms of lithium-induced neurologic side effects and neuroleptic extrapyramidal symptoms.
In rare instances, encephalopathy has been reported with this combination.
The coadministration of lithium and carbamazepine, lamotrigine, valproate, and clonazepam may increase lithium concentrations and aggravate lithium-induced neurologic adverse effects.
Treatment should be initiated at slightly lower dosages than usual, and the dosages should be increased gradually.
Most diuretics (e.g., thiazide and potassium-sparing) can increase lithium concentrations; when treatment is stopped, the clinician may need to increase the person’s daily lithium dosage.
Osmotic and loop diuretics, carbonic anhydrase inhibitors, and xanthines (including caffeine) may reduce lithium concentrations to below therapeutic concentrations.
Whereas ACEIs may cause an increase in lithium concentrations, the AT1 angiotensin II receptor inhibitors losartan (Cozaar) and irbesartan (Avapro) do not alter lithium concentrations.
A wide range of NSAIDs can decrease lithium clearance, thereby increasing lithium concentrations. Aspirin and sulindac (Clinoril) do not affect lithium concentrations.
The coadministration of lithium and quetiapine (Seroquel) may cause somnolence but is otherwise well tolerated.
The coadministration of lithium and ziprasidone (Geodon) may modestly increase the incidence of tremors.
The coadministration of lithium and calcium channel inhibitors should be avoided because of potentially fatal neurotoxicity.
A person taking lithium who is about to undergo ECT should discontinue taking lithium 2 days before beginning ECT to reduce the risk of delirium.
Laboratory Interferences
Lithium does not interfere with any laboratory tests, but lithium-induced alterations include an increased WBC count, decreased serum thyroxine, and increased serum calcium.
Blood collected in a lithium–heparin anticoagulant tube will produce falsely elevated lithium concentrations.
Dosage and Clinical Guidelines
Initial Medical Workup
All patients should have a routine laboratory workup and physical examination before being started on lithium.
Laboratory tests should include serum creatinine concentration (or a 24-hour urine creatinine if the clinician has any reason to be concerned about renal function), electrolytes, thyroid function (TSH, T3, and T4), a CBC, ECG, and a pregnancy test in women of childbearing age.
Dosage Recommendations
Starting dosage for most adults is 300 mg of the regular-release formulation three times daily.
Starting dosage for elderly persons or persons with renal impairment should be 300 mg once or twice daily.
After stabilization, dosages between 900 and 1,200 mg a day usually produce a therapeutic plasma concentration of 0.6 to 1 mEq/L, and a daily dose of 1,200 to 1,800 mg usually produces a therapeutic concentration of 0.8 to 1.2 mEq/L.
Maintenance dosing can be given either in two or three divided doses of the regular-release formulation or in a single dosage of the sustained- release formulation equivalent to the combined daily dosage of the regular- release formulation.
The use of divided doses reduces gastric upset and avoids single high-peak lithium concentrations.
Discontinuation of lithium should be gradual to minimize the risk of early recurrence of mania and to permit recognition of early signs of recurrence.
Laboratory Monitoring
Regular monitoring of serum lithium concentrations is essential.
Lithium levels should be obtained every 2-6 months unless there are signs of toxicity, during dosage adjustments, and in persons suspected to be noncompliant.
Under these circumstances, levels may be done weekly.
Baseline ECG studies are essential and should be repeated annually.
When obtaining blood for lithium levels, patients should be at steady-state lithium dosing (usually after 5 days of constant dosing), preferably using a twice-daily or thrice-daily dosing regimen, and the blood sample must be drawn 12 hours (±30 minutes) after a given dose.
Lithium concentrations 12 hours postdose in people treated with sustained-release preparations are generally about 30% higher than those taking the regular-release preparations.
Factors that may cause fluctuations in lithium measurements include dietary sodium intake, mood state, activity level, body position, and use of an improper blood sample tube.
Laboratory values that do not seem to correspond to clinical status may result from the collection of blood in a tube with a lithium–heparin anticoagulant (which can give results falsely elevated by as much as 1 mEq/L) or aging of the lithium ion-selective electrode (which can cause inaccuracies of up to 0.5 mEq/L).
After the daily dose has been set, it is reasonable to change to the sustained-release formulation given once daily.
Effective serum concentrations for mania are 1.0 to 1.2 mEq/L, associated with 1,800 mg a day.
The recommended range for maintenance treatment is 0.4 to 0.8 mEq/L, which is usually achieved with a daily dose of 900 to 1,200 mg.
If there is no response after 2 weeks at a concentration that is beginning to cause adverse effects, then the person should taper off lithium over 1 to 2 weeks, and other mood-stabilizing drugs should be tried.
Patient Education
Lithium has a narrow therapeutic index, and many factors can upset the balance between lithium concentrations that are well tolerated and therapeutic and those that produce side effects or toxicity.
It is imperative that persons taking lithium be educated about signs and symptoms of toxicity, factors that affect lithium levels, how and when to obtain laboratory testing, and the importance of regular communication with the prescribing physician.
Lithium concentrations can be disrupted by common factors such as excessive sweating from ambient heat or exercise or the use of widely prescribed agents such as ACEIs or NSAIDs.
Patients may stop taking their lithium because they are feeling well or because they are experiencing side effects. They should be advised against discontinuing or modifying their lithium regimen.
Valproate
Approved for the treatment of manic episodes associated with bipolar I disorder.
One of the most widely prescribed mood stabilizers in psychiatry.
Rapid onset of action, well-tolerated, and reduces the frequency and intensity of recurrent manic episodes over extended periods.
Chemistry
Valproate is a simple-chain branch carboxylic acid.
It is called valproic acid because it is rapidly converted to the acid form in the stomach.
Multiple formulations: valproic acid (Depakene), divalproex sodium (Depakote), sodium valproate injection (Depacon).
Extended-release preparation is also available.
Each is therapeutically equivalent because valproic acid dissociates into valproate ion at physiologic pH.
Pharmacologic Actions
Rapidly and completely absorbed 1-2 hours after oral administration, with peak concentrations occurring 4-5 hours after oral administration.
The plasma half-life of valproate is 10-16 hours.
Highly protein-bound; concentrations of therapeutically effective free valproate increase at serum concentrations above 50-100 µg/mL.
The unbound portion of valproate is pharmacologically active and can cross the blood-brain barrier.
The extended-release preparation produces lower peak concentrations and higher minimum concentrations and can be given once a day.
Metabolized primarily by hepatic glucuronidation and mitochondrial β-oxidation.
Postulated mechanisms of action include enhancement of GABA activity, modulation of voltage-sensitive sodium channels, and action on extrahypothalamic neuropeptides.
Therapeutic Indications
Monotherapy or adjunctive therapy of complex partial seizures.
Monotherapy and adjunctive therapy of simple and complex absence seizures.
Adjunctive therapy for patients with multiple seizures that include absence seizures.
Divalproex has additional indications for prophylaxis of migraine.
Bipolar I Disorder
Acute Mania
About two-thirds of persons with acute mania respond to valproate.
The majority of patients with mania usually respond within 1 to 4 days after achieving valproate serum concentrations above 50 µg/mL.
The antimanic response is generally associated with levels greater than 50 µg/mL, in a range of 50 to 125 µg/mL.
The short-term antimanic effects of valproate can be augmented with the addition of lithium, carbamazepine (Tegretol), SDAs, or DRAs.
Because of its more favorable profile of cognitive, dermatologic, thyroid, and renal adverse effects, valproate is preferred to lithium for the treatment of acute mania in children and elderly persons.
Acute Bipolar Depression
Valproate possesses some activity as a short-term treatment of depressive episodes in bipolar I disorder, but this effect is far less pronounced than for the treatment of manic episodes.
Among depressive symptoms, valproate is more useful for the treatment of agitation than dysphoria.
In clinical practice, valproate is most often used as add-on therapy to an antidepressant to prevent the development of mania or rapid cycling.
Prophylaxis
Studies suggest that valproate is useful in the prophylactic treatment of bipolar I disorder, resulting in fewer, less severe, and shorter manic episodes.
In direct comparison, valproate is at least as effective as lithium and is better tolerated than lithium.
It may be particularly useful in persons with rapid-cycling and ultra-rapid-cycling bipolar disorders, dysphoric or mixed mania, and mania caused by a general medical condition as well as in persons who have comorbid substance use disorders or panic attacks and in persons who have not had complete favorable responses to lithium treatment.
Schizophrenia and Schizoaffective Disorder
Valproate may accelerate response to antipsychotic therapy in patients with schizophrenia or schizoaffective disorder.
Valproate alone is generally less effective in schizoaffective disorder than in bipolar I disorder.
Valproate alone is ineffective for the treatment of psychotic symptoms and is typically used in combination with other drugs in patients with these symptoms.
Other Mental Disorders
Valproate has been studied for possible efficacy in a broad range of psychiatric disorders. These include alcohol withdrawal and relapse prevention, panic disorder, PTSD, impulse control disorder, borderline personality disorder, and behavioral agitation and dementia.
Evidence supporting use in these cases is weak, and any observed therapeutic effects may be related to the treatment of a comorbid bipolar disorder.
Precautions and Adverse Reactions
Carries quite a few black box warnings and other warnings.
The two most serious adverse effects of valproate treatment affect the pancreas and liver.
Risk factors for potentially fatal hepatotoxicity include young age (younger than 3 years); concurrent use of phenobarbital; and the presence of neurologic disorders, especially inborn errors of metabolism.
The rate of fatal hepatotoxicity in persons who have been treated with valproate alone is 0.85 per 100,000 persons; no persons older than the age of 10 years have been reported to have died from hepatotoxicity. Therefore, the risk of this adverse reaction in adult psychiatric patients is low.
A modest increase in liver function test results does not correlate with the development of severe hepatotoxicity.
Rare cases of pancreatitis have been reported; they occur most often in the first 6 months of treatment, and the condition occasionally results in death. Pancreatic function can be followed by following amylase concentrations.
Other potentially severe consequences of treatment include hyperammonemia-induced encephalopathy and thrombocytopenia. Thrombocytopenia and platelet dysfunction occur most commonly at high dosages and result in the prolongation of bleeding times.
First-trimester use is associated with a 3-5% risk of neural tube defects.
In utero exposure may negatively affect cognitive development and increase the risk of autistic spectrum disorder.
Valproate is also associated with teratogenicity, most notably neural tube defects (e.g., spina bifida). The risk is about 1 to 4 percent of all women who take valproate during the first trimester of pregnancy. The risk of valproate-induced neural tube defects can be reduced with daily folic acid supplements (1 to 4 mg a day).
All women with childbearing potential who take the drug should be given folic acid supplements.
Infants breastfed by mothers taking valproate develop serum valproate concentrations 1 to 10 percent of maternal serum concentrations, but no data suggest that this poses a risk to the infant.
Valproate is not contraindicated in nursing mothers.
Cases of polycystic ovarian disease have been reported in women using valproate.
Common adverse effects include GI symptoms (nausea, vomiting, dyspepsia, and diarrhea), sedation, ataxia, dysarthria, and tremor. GI effects are common in the first month of treatment, especially if the dosage is increased rapidly.
Valproate-induced tremor may respond well to treatment with β-adrenergic receptor antagonists or gabapentin.
Weight gain is a common adverse effect, especially in long-term treatment, and can best be treated by strict limitation of caloric intake.
Hair loss may occur in 5 to 10 percent of all persons treated, and rare cases of complete loss of body hair have been reported. Some clinicians have recommended treatment of valproate-associated hair loss with vitamin supplements that contain zinc and selenium.
5 to 40 percent of persons experience a persistent but clinically insignificant elevation in liver transaminases up to three times the upper limit of normal, which is usually asymptomatic and resolves after discontinuation of the drug.
High dosages of valproate (above 1,000 mg a day) may rarely produce mild to moderate hyponatremia, most likely because of some degree of the syndrome of secretion of inappropriate antidiuretic hormone, which is reversible upon lowering of the dosage.
Drug Interactions
Commonly prescribed with other psychotropic agents.
The only consistent interaction with lithium is the exacerbation of drug-induced tremors, which can usually be treated with β-receptor antagonists.
The combination of valproate and DRAs may result in increased sedation and increased severity of extrapyramidal symptoms.
Valproate can usually be safely combined with carbamazepine or SDAs.
Valproate more than doubles lamotrigine concentrations, increasing the risk of a severe rash (Stevens–Johnson syndrome and toxic epidermal necrolysis).
Also, the plasma concentrations of phenytoin (Dilantin) and desipramine (Norpramin) may be decreased when they are combined with valproate.
The plasma concentrations of valproate may be decreased when the drug is coadministered with carbamazepine and may be increased when coadministered with guanfacine (Tenex), amitriptyline, or fluoxetine (Prozac).
Valproate can be displaced from plasma proteins by carbamazepine, diazepam, and aspirin.
Persons who are treated with anticoagulants (e.g., aspirin and warfarin [Coumadin]) should also be monitored when valproate use is initiated to assess the development of any undesired augmentation of the anticoagulation effects.