Treatment of Mania or Mixed Episodes

Although mood stabilizers are effective therapeutic agents, their efficacy may not be apparent for 1-2 weeks, occasionally longer. Because agitation and behavioral dyscontrol are often prom- 

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Sprinkle capsule 15, 25 mg Atypical Antipsychotics FDA approved for use in bipolar disorder Aripiprazole Abilify Tablets 5, 10, 15, Dosage should be slowly increased to minimize adverse effects (e.g., 25 mg at bedtime for 1 week, then 25-50 mg/day increments at weekly intervals) 10-30 mg/day once daily acute treatment of mania or mixed episodes due to lack of efficacy used as an adjunctive agent with established mood stabilizers Use as monotherapy or in... 

Use in combination with other drugs (e.g, anti-psychotics, lithium, valproate) for the acute treatment of mania or mixed episodes. Use as a short-term adjunctive sedativehypnotic agent. Binds to the benzodiazepine site and augments the action of GABA/, by increasing the frequency of Cl" channel opening which causes hyperpolarization (a less excitable state) and inhibits neuronal firing. 

Lithium carbonate is completely absorbed by the gastrointestinal tract and reaches peak plasma levels in 1-2 hours. The elimination half-life is approximately 24 hours. Steady-state lithium levels are achieved in approximately 5 days. Therapeutic plasma levels range from 0.5 to 1.2 mEq/L. Lower plasma levels are associated with less troubling side effects, but levels of at least 0.8 mEq/L are often required in the treatment of acute manic episodes. Therefore, when intolerable side effects have not intervened, treatment of acute mania with lithium should not be considered a failure until plasma levels of 1.0-1.2 mEq/L have been reached and have been maintained for 2 weeks. As discussed at the end of this chapter (see Treatment of Mania or Mixed Episodes ), more severely ill patients may require combination treatment. 

Use in combination with other drugs (e.g., antipsychotics, lithium, valproate) for the acute treatment of mania or mixed episodes. Use as a short-term adjunctive sedative-hypnotic agent. 

Changes in the sleep-wake cycle or light-dark cycle can precipitate episodes of mania or depression. Bright light therapy can be used for the treatment of winter depression and can precipitate hypomania, mania, or mixed episodes. 

Combination therapies may be needed for the treatment of acute mania or mixed episodes, breakthrough depression, and rapid cycling Reassessment of combination and adjunctive therapies should be done routinely and unnecessary medications should be tapered off gradually and discontinued... 

Conventional antipsychotic drugs such as chlorpromazine and haloperidol have long been used in the treatment of acute mania. More recently, atypical antipsychotic drugs including aripiprazole, olanzapine, quetiapine, risperidone, and ziprasi-done have been approved for the treatment of bipolar mania or mixed mood episodes as monotherapy or in combination with mood-stabilizing drugs.25 Aripiprazole and olanzapine are also approved for maintenance therapy. The combination of olanzapine and fluoxetine is approved for treatment of bipolar depression. Quetiapine is approved for treatment of... 

Bipolar mania (ora only) - For the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. Schizophrenia - For the treatment of schizophrenia. 

Bipolar patients with substance abuse disorders are more likely to have an earlier onset of illness, mixed states, higher relapse rates, poorer response to treatment, higher suicide risk, and more hospitalizations. Approximately 10% to 15% of adolescents with recurrent major depressive episodes subsequently have an episode of mania or hypomania. 

For patients who experience a breakthrough episode, the medication dose should first be optimized. When first-line medications at optimal dose fail to control symptoms, recommended treatment options include the addition of another first-line medication. Alternative treatment options include adding carbamazepine or oxcarbazepine in lieu of an additional first-line medication, adding an antipsychotic if not already prescribed, or changing from one antipsychotic to another. Of the antipsychotics, clozapine may be particularly effective for treatment of refractory illness. Electroconvulsive therapy (ECT) may also be considered for patients with severe or treatment-resistant illness. In addition, ECT is a potential treatment for patients with mixed episodes or for severe mania experienced during pregnancy. 

It is common for both the depressive and manic phases to occur simultaneously in what is termed a mixed state or dysphoric mania. During these mixed episodes, the patient s mood is characterized by symptoms of both a depression and mania. Mixed episodes often have a poorer outcome than classic euphoric mania and, as a rule, respond better to certain anticonvulsants and atypical antipsychotic drugs than to lithium. As many as 50% of admissions to inpatient psychiatric facilities for the treatment of manic episodes appear to be for mixed manic states. The recognition... 

Lithium remains the treatment of choice for bipolar patients who experience classic euphoric episodes of mania. Current evidence suggests that those with mixed episodes or rapid cycling episodes respond preferably to anticonvulsants or atypical antipsychotic drugs. In addition to its use as a mood stabilizer, lithium is effective in converting unipolar antidepressant nonresponders to responders. Finally, lithium may also be an effective treatment for patients with clnster headaches. 

Valproate (Depakote, Depakene). Valproate is an anticonvnlsant that has been demonstrated in multiple controlled clinical trials to be an effective mood stabilizer and, in fact, has obtained FDA approval for the treatment of acute mania. It appears to be particularly effective in bipolar patients who experience mixed episodes or rapid cycling or who have not responded well in the past to lithium. 

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. 

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. 

Few randomized controlled trials have been done to evaluate different approaches for the treatment of acute and recurrent bipolar depression. Nonpharmacologic treatment that may have augmenting effects include phototherapy for seasonal-pattern depression and sleep deprivation for rapid cycling." The use of ECT for severe episodes of mania/mixed episodes, depression, psychotic features (e.g., hallucinations or delusions), or rapid cycling is still considered the best acute treatment approach for those patients who do not respond to first-line mood stabilizers such as lithium and valproate. " ... 

Olanzapine is an antipsychotic that controls psychotic symptoms throngh antagonism of selected dopamine and serotonin receptors in the central nervons system (CNS). It is indicated in the treatment of schizophrenia (oral) shortterm treatment of acnte mixed or manic episodes with bipolar I disorder (oral) in combination with lithium or valproate, for short-term treatment of acnte episodes associated with bipolar 1 disorder (oral) and treatment of agitation associated with schizophrenia and bipolar I mania (IM). 

The longitudinal course of bipolar illness is also characterized by many recurrent episodes, some predominantly depressive, some predominantly manic or hypomanic, some mixed with simultaneous features of both mania and depression (Fig. 5—5) some may even be rapid cycling, with at least four ups and/or downs in 12 months (Fig. 5—6). There is worrisome evidence that bipolar disorders may be somewhat progressive, especially if uncontrolled. That is, mood fluctuations become more frequent, more severe, and less responsive to medications as time goes on, especially in cases where there has been little or inadequate treatment. 

The combination of valproate and traditional neuroleptic drugs, a first-line treatment for mixed or rapid-cycling episodes or dysphoric mania with psychotic features, is associated with altered mental status and electroencepha-lographic abnormalities (641). 

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