Valproic acid bipolar disorders

Divalproex sodium is comprised of sodium valproate and valproic acid. The delayed-release and extended-release formulations are converted in the small intestine into valproic add, which is the systemically absorbed form. It was developed as an antiepileptic drug, but also has efficacy for mood stabilization and migraine headaches. It is FDA-approved for the treatment of the manic phase of bipolar disorder. It is generally equal in efficacy to lithium and some other drugs for bipolar mania. It has particular utility in bipolar disorder patients with rapid cycling, mixed mood features, and substance abuse comorbidity. Although not FDA-approved for relapse prevention, studies support this use, and it is widely prescribed for maintenance therapy. Divalproex can be used as monotherapy or in combination with lithium or an antipsychotic drug.31... 

Anticonvulsants. Finally, several antiseizure medications have been tried. These include valproic acid (Depakote, Depakene), carbamazepine (Tegretol), Lamotrig-ine (Lamictal), and gabapentin (Neurontin). The anticonvulsants are effective treatments for bipolar disorder. Their use for major depression needs to be studied further. Please refer to Section 3.4 Bipolar Disorders. 

Mood Stabilizers. Lithium (Eskalith, Lithobid), valproic acid (Depakene), sodium valproate (Depakote), and carbamazepine (Tegretol) are most often used by psychiatrists to treat the bipolar disorders. These so-called mood stabilizers are also used to treat impulsivity and agitation in a variety of psychiatric disorders including dementia, certain personality disorders, and the disruptive behavior disorders of childhood. 

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

Valproic acid (dipropylacetic acid) is a single branched chain carboxylic acid that is structurally unlike any of the other drugs used in the treatment of bipolar disorder or epilepsy. The amide derivative, valproamide, is available in Europe as a more potent form of valproate. Valproate was first developed in Erance as an antiepileptic agent in 1963. As an antiepileptic agent, it was shown to be active against a variety of epilepsies without causing marked sedation. 

Bipolar disorder in patients receiving valproic acid PO 2 5 mg/day every other day for 2 wk, then 25 mg/day for 2 wk, then 50 mg/day for 1 wk, then 100 mg/day. Usual maintenance dose with valproic acid 100 mg/day. 

There is strong evidence that bipolar disorder is associated with SUD in adolescents (Wilens et ah, 1999) and that pharmacological interventions are an effective treatment for youth with SUD and bipolar disorder. Two studies, including one randomized controlled study, have reported that mood stabilizers, specifically lithium and valproic acid (Depakote), significantly reduced substance use in bipolar youth (Donovan and Nunes, 1996 Geller et ah, 1998). In addition, these agents are considered effective agents for the treatment... 

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

Two commonly used anticonvulsant medications for the treatment and prophylaxis of bipolar mood disorder in adults with MR are carbamazepine and valproic acid. Reid et al. (1981) compared carbamazepine to placebo in a double-blind, crossover fashion in 12 overactive adults with severe MR. Those described as having elevated moods and distractibility responded to treatment, while those without mood disturbance did not. Glue (1989) treated 10 adults with MR and rapidcycling bipolar mood disorder with lithium alone, lithium and carbamazepine, and carbamazepine alone. None of the patients treated with carbamazepine alone responded, while half of the patients showed partial or complete improvement with lithium alone or in combination with carbamazepine. 

The discovery of benzodiazepines is a story of serendipity and certainly one that is difficult to predictably reproduce as part of a drug discovery program. Regrettably (or fortuitously), this story of the benzodiazepines is not an isolated example. Valproic acid, an agent used to treat epilepsy, migraine, chronic pain, and bipolar affective disorder, was also discovered by accident. 

Several controlled trials have shown that lithium is efficacious in the maintenance treatment of bipolar disorder, with higher serum levels (0.8 1 mol/1) being more indicative of successful prophylaxis (Keck and McElroy. 2002). Valproic acid also appears to have efficacy in maintenance therapy, specifically in bipolar patients with mixed mania and rapid cycling (Bowden et al., 1995). The results concerning carbamazepine s efficacy as a maintenance medication are controversial (Stuppaeck et al., 1994). Other potential agents with some evidence of good maintenance value include clozapine and olanzapine. A combination of lithium and carbamazepine or other anticonvulsants is recommended under certain conditions if an adequate preventive effect cannot be obtained with the substances individually (Bauer et al., 2002). 

Antipsychotic drugs are also indicated for schizoaffective disorders, which share characteristics of both schizophrenia and affective disorders. No fundamental difference between these two diagnoses has been reliably demonstrated. They are part of a continuum with bipolar psychotic disorder. The psychotic aspects of the illness require treatment with antipsychotic drugs, which may be used with other drugs such as antidepressants, lithium, or valproic acid. The manic phase in bipolar affective disorder often requires treatment with antipsychotic agents, although lithium or valproic acid supplemented with high-potency benzodiazepines (eg, lorazepam or clonazepam) may suffice in milder cases. Recent controlled trials support the efficacy of monotherapy with atypical antipsychotics in the acute phase (up to 4 weeks) of mania, and olanzapine and quetiapine has been approved for this indication. 

Another group of mood-stabilizing drugs that are also anticonvulsant agents have become more widely used than lithium. These include carbamazepine and valproic acid for the treatment of acute mania and for prevention of its recurrence. Lamotrigine is approved for prevention of recurrence. Gabapentin, oxcarbazepine, and topiramate are sometimes used to treat bipolar disorder but are not approved by FDA for this indication. Aripiprazole, chlorpromazine, olanzapine, quetiapine, risperidone, and ziprasidone are approved by FDA for the treatment of manic phase of bipolar disorder. Olanzapine plus fluoxetine in combination and quetiapine are approved for the treatment of bipolar depression. 

Perhaps even more important in children is the issue of bipolar disorder. Mania and mixed mania have not only been greatly underdiagnosed in children in the past but also have been frequently misdiagnosed as attention deficit disorder and hyperactivity. Furthermore, bipolar disorder misdiagnosed as attention deficit disorder and treated with stimulants can produce the same chaos and rapid cycling state as antidepressants can in bipolar disorder. Thus, it is important to consider the diagnosis of bipolar disorder in children, especially those unresponsive or apparently worsened by stimulants and those who have a family member with bipolar disorder. These children may need their stimulants and antidepressants discontinued and treatment with mood stabilizers such as valproic acid or lithium initiated. 

Based on theories that mania may kindle further episodes of mania, a logical parallel with seizure disorders was drawn, since seizures can kindle more seizures. Thus, trials of several anticonvulsants, beginning with carbamazepine, have been conducted, and several are showing indications of efficacy in treating the manic phase of bipolar disorder (Table 7—1). Only valproic acid, however, is actually approved for this indication. 

The Depakote form of valproic acid is approved for the acute phase of bipolar disorder. It is also commonly used on a long-term basis, although its prophylactic effects have not been as well established. Valproic acid is now frequently used as a first-line treatment for bipolar disorders, as well as in combination with lithium for patients refractory to lithium monotherapy and especially for patients with rapid cycling and mixed episodes. Oral loading can lead to rapid stabilization, and plasma levels must be monitored to keep drug levels within the therapeutic range. 

Carbamazepine. The anticonvulsant carbamazepine was actually the first to be shown to be effective in the manic phase of bipolar disorder, but it has not been approved for this use by regulatory authorities such as the U.S. Food and Drug Administration (FDA). Its mechanism of action may be to enhance GABA function, perhaps in part by actions on sodium and/or potassium channels (Fig. 7—24). Because its efficacy is less well documented and its side effects can include sedation and hematological abnormalities, it is not as well accepted for first-line use in the treatment of mood disorders as either lithium or valproic acid. 

Combination treatment with two or more psychotropic medications is the rule rather than the exception for bipolar disorders (bipolar combos in Fig. 7—35). First-line treatment is with either lithium or valproic acid. When patients fail to stabilize in the acute manic phase on one of these first-line treatments, the preferred second-... 

FIGURE 7—35. Combination treatments for bipolar disorder (bipolar combos). Combination drug treatment is the rule rather than the exception for patients with bipolar disorder. It is best to attempt monotherapy, however, with first-line lithium or valproic acid, with second-line atypical antipsychotics, or with third-line anticonvulsant mood stabilizers. A very common situation in acute treatment of the manic phase of bipolar disorder is to treat with both a mood stabilizer and an atypical antipsychotic (atypical combo). Agitated patients may require intermittent doses of sedating benzodiazepines (benzo assault weapon), whereas patients out of control may require intermittent doses of tranquil-izing neuroleptics (neuroleptic nuclear weapon). For maintenance treatment, patients often require combinations of two mood stabilizers (mood stabilizer combo) or a mood stabilizer with an atypical antipsychotic (atypical combo). For patients who have depressive episodes despite mood stabilizer or atypical combos, antidepressants may be required (antidepressant combo). However, antidepressants may also decompensate patients into overt mania, rapid cycling states, or mixed states of mania and depression. Thus, antidepressant combos are used cautiously. 

Valproic acid (Depakene, Depakote, other trade names) is classified as a carboxylic acid, and is used primarily to treat absence seizures or as a secondary agent in generalized tonic-clonic forms of epilepsy. This drug is also used to treat bipolar disorder (manic-depression), especially during the acute manic phase (see Chapter 7). 

Q5 Carbamazepine or valproic acid can be used in treating bipolar disorder and are useful for patients who are unresponsive to lithium. Initially, carbamazepine may be given in a divided dose of 400 mg daily. The normal dosage range can increase to 600 mg daily in divided doses, although a maximum dose of 1600 mg daily may be needed in some patients. The initial dosage for valproic acid is 750 mg daily in two or three divided doses, increasing to 1 -2 g daily if necessary. 

A 19-year-old patient taking lithium therapy for bipolar I disorder developed a pityriasis rosea-like dermatitis, which resolved when valproic acid was substituted for lithium (403). The rash was defined as erythematous, sharply bordered oval and finely scaling lesions along skin cleavages on the trunk and proximal parts of the extremities. There was no evidence of a herald patch. 

A 47-year-old white man with a history of bipolar disorder, who was taking citalopram 40 mg/day and zolpidem 5 mg at bedtime, developed manic symptoms and was given valproic acid (50). Soon after this, he had episodes of somnambulism, which stopped when valproic acid was withdrawn. On rechallenge with valproic acid, the somnambulism returned. 

Since first reported by Cade in 1949, lithium has been the most frequently studied and used drug for the treatment of bipolar disorder. Recent trends in the United States have shifted to the use of anticonvulsants—mostly divalproex and valproic acid—although the rationale for this switch in emphasis arguably stands on tenuous scientific grounds. 

Friedman, S.D., Dager, S.R., Parow, A., Hirashima, F., Demopulos, C., Stoll, A.L., Lyoo, I.K., Dunner, D.L., and Renshaw, P.F., 2004, Lithium and valproic acid treatment effects on brain chemistry in bipolar disorder. Biol. Psychiatry 56 340-348. 

Macritchie KA, Geddes JR, Scott J, Haslam DR, Goodwin GM. Valproic acid, valproate and divalproex in the maintenance treatment of bipolar disorder. Cochrane Database Syst Rev. 2001 (3) CD003196. 

Valproic acid is the drug of first choice for prophylaxis of bipolar affective disorder in the United States, despite the lack of robust clinical trial evidence in support of this indication. But treatment with valproic acid is easy to initiate (especially compared to lithium), it is well tolerated and its use appears likely to extend if the evidence-base expands. As the semisodium salt, valproic acid is licenced for use in the treatment of acute mania unresponsive to lithium. (Note sodium valproate, see p. 420, is unlicenced for this indication.)... 

Two anticonvulsants, carbamazepine (Tegretol) and valproic acid, also referred to as valproate (Depakote, Depakene), have proven mood-stabilizing properties (see figure 15-E). These agents are most useful when lithium is contraindicated or when a patient does not respond to or cannot tolerate lithium. Rapid cyclers, who often are poorly controlled with lithium, are good candidates for one of these alternative agents. Valproic acid appears to be indicated more for manic or mixed states of bipolar disorder, and is probably not as effective in depressed states. The anticonvulsants are often employed in conjunction with lithium. 

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