Bipolar disorder maintenance treatments

The pharmacological management of bipolar disorder involves treatment of both the acute and the longer-term maintenance phase of the illness. Longterm maintenance is necessary to reduce or prevent the recurrence of the symptoms, and to minimize the risk of suicide. 

In the case of carbamazepine the evidence suggests that its prophylactic efficacy is less than that of lithium (Greil and Kleindienst, 1999). For valproate there is no placebo-controlled evidence as yet to support its efficacy in the prophylaxis of bipolar disorder. The only large-scale study designed to elucidate this action was a failed trial in which neither lithium nor valproate was more effective than placebo in maintenance treatment over 2 years (Bowden et al, 2000). 

Pharmacotherapy is the cornerstone of acute and maintenance treatment of bipolar disorder. Mood-stabilizing drugs are the usual first-choice treatments and include lithium, divalproex, carbamazepine, and lamotrigine. Atypical antipsychotics other than clozapine are also approved for treatment of acute mania. Lithium, lamotrigine, olanzapine, and aripiprazole are approved for maintenance therapy. Drugs used with less research support and without Food and Drug Administration (FDA) approval include topiramate and oxcarbazepine. Benzodiazepines are used adjunctively for mania. 

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... 

Lamotrigine is effective for the maintenance treatment of bipolar disorder. It is more effective for depression relapse prevention than for mania relapse. Its primary limitation as an acute treatment is the time required for titration to an effective dosage. In addition to maintenance monotherapy, it is sometimes used in combination with lithium or divalproex, although combination with divalproex increases the risk of rash, and lamotrigine dosage adjustment is required.37... 

Introduced in clinical practice in the 1960s, lithium was the first mood stabilizer to be used in China. This was followed by carbamazepine and sodium valproate. For many years, these were the only treatment options available as mood stabilizers. Although lamotrigine was approved for maintenance treatment of bipolar I disorder in 2003 by FDA (Food and Drug Administration) in the USA, this indication has not yet been approved by the Chinese authorities. At present, only one atypical antipsychotic drug, risperidone, has been approved for treating acute mania (February 2005 by SFDA [State Food and Drug Administration]) in China (see Table 6.1). 

Lithium, divalproex sodium (valproate), aripiprazole, olanzapine, que-tiapine, risperidone, and ziprasidone are currently approved by the FDA for treatment of acute mania in bipolar disorder. Lithium, olanzapine, and lamotrigine are approved for maintenance treatment of bipolar disorder. Quetiapine is the only antipsychotic that is FDA approved for bipolar depression. 

Lithium was the first established mood stabilizer and is still considered a first-line agent for acute mania and maintenance treatment of both bipolar I and II disorders. It is the only bipolar medication approved for adults and children 12 years and older. Long-term use of lithium reduces suicide risk. Patients with rapid cycling or mixed states may not respond as well to lithium monotherapy as to some anticonvulsants. 

Divalproex sodium (sodium valproate) is now the most prescribed mood stabilizer in the United States. It is FDA approved only for the treatment of acute manic or mixed episodes, but it is often used as maintenance monotherapy for bipolar disorder. 

Lamotrigine is approved for the maintenance treatment of bipolar I disorder. It has been used as monotherapy or add-on therapy for refractory bipolar depression. 

Depot antipsychotics (e.g., haloperidol decanoate, fluphenazine decanoate, and risperidone long-acting injection) can be used for maintenance therapy of bipolar disorder with noncompliance or treatment resistance. 

Lamotrigine is effective for the maintenance treatment of bipolar I disorder in adults. It has both antidepressant and mood-stabilizing effects, and it may have augmenting properties when combined with lithium or valproate. It has low rates of switching patients to mania. Although it is less effective for acute mania compared to lithium and valproate, it may be beneficial for the maintenance therapy of treatment-resistant bipolar I and II disorders, rapidcycling, and mixed states. It is often used for bipolar II patients. 

In contrast to the large number of studies that have investigated lithium as a maintenance treatment for bipolar disorder, relatively few studies have been made of divalproex sodium, despite its widespread use in the acute treatment of mania. There is evidence from one placebo-controlled study in which lithium was compared with divalproex sodium that the latter drug was better tolerated but that the prevention of relapse did not differ between the drugs. It would therefore appear that a switch to divalproex sodium may be particularly useful in bipolar patients who are experiencing... 

Despite the widespread use of neuroleptics in maintenance treatment of bipolar disorder, there have not been any systematic studies of their suitability for this role. Through clinical experience it has been widely accepted that neuroleptics are useful adjunctive treatments to lithium and related drugs. Treatment refractory patients frequently respond to atypical antipsychotics such as clozapine or risperidone. Such adverse effects as EPS, cognitive dysfunction and weight gain frequently limit the long-term use of classical neuroleptics. For this reason, the atypical neuroleptics such as olanzapine and risperidone should now be considered as alternatives for maintenance treatment. 

Monotherapy For the treatment of acute mixed or manic episodes associated with bipolar I disorder and for the maintenance monotherapy of bipolar disorder. 

Bipolar disorder For the maintenance treatment of Bipolar I Disorder to delay the time to occurrence of mood episodes (eg, depression, mania, hypomania, mixed episodes) in patients treated for acute mood episodes with standard therapy. 

Prevention or treatment of acute mania, manic phase of bipolar disorder (manic-depressive illness) PO 900-l,200mg/day. Maintenance 300mgtwiceaday. May increase by 300mg/dayqlwk. 

J.E, Cole, K., and Lavelle, J. (1998) Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med 321 1489-1493. 

Greil, W., and Kleindienst, N. (1999b) Lithium versus carbamazepine in the maintenance treatment of bipolar II disorder and bipolar disorder not otherwise specified. Int Clin Psychopharmacol 14 283-285. 

It is still debated whether patients with two previous episodes should receive maintenance treatment. Overall, maintenance treatment has been recommended for adult depressed patients with two episodes who have one or more of the following criteria (Depression Guideline Panel, 1993) (1) a family history of bipolar disorder or recurrent depression, (2) early onset of the first depressive episode (before age 20), and (3) both episodes were severe or life threatening and occurred during the past 3 years. Given that depression in youth has similar clinical presentation, sequelae, and natural course as in adults, these guidelines should probably be applied for youth with two previous major depressive episodes. 

Although adolescents who discontinue maintenance treatment have a high (92%) rate of relapse compared to those who maintain lithium treatment (37%) (Strober et al., 1990), reliable continuation of medication is a serious problem in bipolar adolescents, particularly those with comorbid behavior disorders (Carlson et al., 2000a). 

Sachs, G.S. and Thase, M.E. (2000) Bipolar disorder therapeutics maintenance treatment. Biol Psychiatry 48 573-581. 

The main indications for atypical antipsychotics are the acute and maintenance treatment of schizophrenic disorders, with an emphasis on the treatment of refractory and chronic disorders. However, because of the lower risk of EPS and in particular of tardive dyskinesia, there is a tendency toward a wider range of indications for some of the atypical neuroleptics. Favorable effects in drug-induced psychoses have been demonstrated for olanzapine. Clozapine seems effective in the treatment and relapse prevention of manic episodes and bipolar disorders, and risperidone has been shown to have good efficacy in conduct disorders and in the pervasive developmental disorders. 

EFFICACYOF LITHIUM IN MAINTENANCE TREATMENT OF BIPOLAR DISORDER... 

The most common indications for antipsychotic drugs are the treatment of acute psychosis and the maintenance of remission of psychotic symptoms in patients with schizophrenia. More recently, the atypical antipsychotics have become part of the standard repertoire for the treatment of bipolar disorder, as discussed in Chapter 5. Antipsychotic drugs also ameliorate psychotic symptoms associated... 

Aripiprazole has been approved for treatment of schizophrenia and acute manic or mixed episodes in bipolar disorder. This medication is also indicated for maintenance treatment in bipolar I disorder. The recommended starting and target dose for aripiprazole in patients with schizophrenia is 10 or 15 mg/day. This is a once-daily dose, and patients can take the medication with or without food. Although this medication has been shown to be effective in doses ranging from 10 to 30 mg/day, doses higher than 10-15 mg have not been shown to be more effective than 10- to 15-mg doses in patients with schizophrenia. The recommended starting dose for treatment of an acute manic or mixed episode is 30 mg the recommended dose for maintenance treatment in stable patients is 15 mg/day. The elimination half-life is 75 hours, and steady-state concentrations are reached within 2 weeks. Therefore, dose adjustments are recommended every 2 weeks, to allow time for clinical assessments of the medication s effects to be observed at steady-state concentration. Peak plasma concentrations occur within 3-5 hours. At equivalent doses, the plasma concentrations of aripiprazole from the solution were higher compared with plasma concentrations associated with the tablet form. 

Calabrese JR, Bowden CL, Sachs GS, et al A placebo-controlled 18-month trial of lamotrigine and lithium maintenance treatment in recently depressed patients with bipolar I disorder. Lamictal 605 Study Group. J Clin Psychiatry 64 1013-1024, 2003 Calabrese JR, Keck PE, Macfadden W, et al A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar 1 or 11 depression. Am J Psychiatry 162 1351-1360, 2005 Chen G, Manji HK, Hawver DB, et al Chronic sodium valproate selectively decreases protein kinase C alpha and epsilon in vitro. J Neurochem 63 2361-2364, 1994... 

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