Bipolar disorders mixed states

The total costs are likely to reflect the efficacy of treatment. In one industry-sponsored study (Keck et al, 1996b) treatment with lithium or valproate was compared in relation to classical, mixed and rapid-cycling disorder. Treatment with lithium was associated with lower costs than treatment with valproate for classical bipolar disorder, but treatment with valproate was associated with lower costs than treatment with lithium for mixed and rapid-cycling disorders. This is in keeping with the evidence that valproate is more effective than lithium for certain patients with rapid-cycling disorder and probably also for certain patients with mixed affective states. However, these associations are a guide to predicting response to treatment but are not very specific. 

Olanzapine Zyprexa 20, 30 mg Tablets 2.5, 5, 7.5, 10, 5-20 mg/day in 1 or 2 doses combination with lithium or valproate for the acute treatment of mania or mixed states for bipolar I disorder. Olanzapine and aripiprazole are approved for relapse prevention as well as for acute therapy... 

In depressed patients, cortical-hypothalamic-pituitary-adrenal axis hyperactivity can be explained by the hypersecretion of CRF, and secondary pituitary and adrenal gland hypertrophy. Impaired negative feedback at various CNS sites, including the hippocampus and pituitary are also likely to contribute. Downregulation of hippocampal mineralocorticoid receptors and expression is reported in depressed suicides [50]. In bipolar disorder, hyperactivity of the cortical-hypothalamic-pituitary-adrenal axis has been observed [51]. This increase in cortical-hypothalamic-pituitary-adrenal axis activity has also been observed in mixed mood states, mania and in depression in rapidcycling patients. Partial reversal of HPA overactivity is associated with treatment and recovery from depression. 

Two or more major depressive episodes Manic episode major depressive or mixed episode Major depressive episode + hypomanic episode Chronic subsyndromal depressive episodes Chronic fluctuations between subsyndromal depressive and hypomanic episodes (2 years for adults and 1 year for children and adolescents) Mood states do not meet criteria for any specific bipolar disorder... 

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. 

Lithium is the drug of choice for bipolar disorder with euphoric mania, whereas valproate has better efficacy for mixed states, irritable/dysphoric mania, and rapid cycling compared with lithium. 

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 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. 

Valproate is as effective as lithium and olanzapine for pure mania, and it can be more effective than lithium for rapid cycling, mixed states, and bipolar disorder with substance abuse. It reduces the frequency of recurrent manic, depressive, and mixed episodes. 

In the bipolar affective disorders (BPADs), periods of normal mood are interspersed with episodes of mania, hypomania, mixed states, or depression. BPAD differs from MDD in that there is a bidirectional natnre to the mood swings and, for many patients, the rate of cycling is more rapid in BPAD than MDD. The phases of BPAD inclnde mania, hypomania, and depression, though mixed states, the simultaneous presentation of symptoms of both mania and depression, are common. 

Lambert 1984 McElroy et al. 1988b] suggested that valproate may be a much better antimanic than antidepressant agent. In a study of 78 consecutively recruited patients with rapid-cycling bipolar disorder treated with open-label valproate alone or in combination with other psychotropic agents, Calabrese and colleagues [Calabrese and Delucchi 1990 Calabrese et al. 1992] reported a 54% valproate response in acute mania, an 87% response in acute mixed states, and a 19% response in acute depression. However, they did observe a prophylactic antidepressant effect in patients subsequently. Additional controlled studies are needed to clarify valproate s antidepressant efficacy. 

Although studies reviewed thus far support the efficacy of lithium treatment for acute mania, the presence of concurrent depression or depressive symptoms during mania, the so-called mixed state, has been associated with poor lithium response. In 1976, Himmelhoch et al. observed that patients with mixed states were significantly less likely to demonstrate a good treatment response than were manic patients [42% vs. 81%] in a retrospective chart review of 84 consecutively referred patients with bipolar disorder. Secunda et al. [1985] reported on 18 patients with mania studied as part of the Collaborative Study of the Psychobiology of Depression and found that patients with concomitant depression and mania [n = 8] had a significantly lower rate of... 

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. 

Recently, Calabrese (240) reviewed the use of topiramate in bipolar disorder and also presented the results of two additional studies. He noted that, thus far, topiramate had been studied in 12 open clinical trials involving a total of 224 patients, mainly in manic and mixed states, and generally as an augmentation strategy. 

Problems with mood are often called affective disorders. Depression and mania are often seen as opposite ends of an affective or mood spectrum. Classically, mania and depression are poles apart, thus generating the terms unipolar depression, in which patients just experience the down or depressed pole and bipolar disorder, in which patients at different times experience either the up (manic) pole or the down (depressed) pole. In practice, however, depression and mania may occur simultaneously, which is called a mixed mood state. Mania may also occur in lesser degrees, known as hypomania, or may switch so fast between mania and depression that it is called rapid cycling. ... 

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. 

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. 

Profound mood-stabilizing effects of the atypical antipsychotic drugs were observed once their antipsychotic effects were documented. These effects on mood appear to be quite independent of their effects on positive symptoms of psychosis. The most dramatic story may be how impressive the atypical antipsychotics are turning out to be for the treatment of bipolar disorder (Fig. 11 — 53). Although the best documented effect of these drugs is to reduce psychotic symptoms in the acute manic phase of bipolar disorder, it is clear that these agents also stabilize mood and can help in some of the most difficult cases, such as those marked by rapid cycling and mixed simultaneous manic-depressed states that are often nonresponsive to mood... 

A 26-year-old woman with bipolar I disorder took lithium and valproate, and sometimes additional risperidone and lamotrigine. Both risperidone and lamo-trigine produced dermatological adverse effects. Her serum lithium concentration was 0.82 mmol/1. Topiramate 75 mg/day was added. A week later, she continued to show a mixed state with mostly manic features and a raised lithium concentration of 1.24 mmol/1. The lithium concentration continued to increase over the next 4 days to 1.97 mmol/1 even though the lithium dosage was reduced from 900 to 750 mg/day. Lithium was withdrawn and the lithium concentration fell. Lithium was then restarted at half the admission dose to achieve a blood concentration of 0.67 mmol/1. Subsequent increases in the dose of topiramate resulted in further increases in the lithium concentration. 

Lithium was the original mood stabilizer and Is still a first-line treatment option but may be underutilized since It Is an older agent and Is less promoted for use In bipolar disorder than newer agents May be best for euphoric mania patients with rapid-cycling and mixed state types of... 

Valproate is a first-line treatment option that may be best for patients with mixed states of bipolar disorder or for patients with rapid-cycling bipolar disorder... 

Beginning with Kraepelin s (1921) systematic classification of dysphoric mania, considerable attention has been paid to mixed states of bipolar disorder. Kraepelin s model was based on variable symptom patterns expressed in three areas, mood, thought, and motor activity. Once considered to be uncommon, current estimates suggest that the prevalence rate for dysphoric, or mixed mania, is approximately 30 percent (McElroy et al. 1992). Debate continues regarding the status of mixed mania as a distinct affective state versus a form, or stage, of typical mania. However, there is convincing evidence to support the opinion that mixed episodes can be more severe, chronic, and difficult to treat than pure manic or depressive episodes (Clothier,... 

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. 

---