Atypical antipsychotic drugs bipolar disorder

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). 

Nonpsychotic persons also experience impaired performance as judged by a number of psychomotor and psychometric tests. Psychotic individuals, however, may actually show improvement in their performance as the psychosis is alleviated. The ability of the atypical antipsychotic drugs to improve some domains of cognition in patients with schizophrenia and bipolar disorder is controversial. Some individuals experience marked improvement and for that reason, cognition should be assessed in all patients with schizophrenia and a trial of an atypical agent considered, even if positive symptoms are well controlled by typical agents. 

For approximately 70% of patients with schizophrenia, and probably for a similar proportion of patients with bipolar disorder with psychotic features, typical and atypical antipsychotic drugs are of equal efficacy for treating positive symptoms. However, the evidence favors atypical drugs for benefit for negative symptoms and cognition, for diminished risk of tardivedyskinesia and other forms of EPS, and for lesser increases in prolactin levels. 

This chapter will explore the various drug treatments for psychotic disorders, with special emphasis on schizophrenia. Such treatments include not only conventional antipsychotic drugs but also the newer atypical antipsychotic drugs, which are rapidly replacing the older conventional agents. We will also take a look into the future at the drugs under development for psychosis, especially schizophrenia. Mood stabilizers for bipolar disorders were covered in Chapter 7. 

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... 

Atypical antipsychotic drugs (AADs), in addition to their application as a first-line treatment in schizophrenia, are also effective mood stabilizers. AADs are successfully used in unipolar and bipolar mood disorders, either as solo treatment or as adjuncts to SSRIs (Blier et al., 2005 Kennedy et al., 2001 Kennedy and Lam 2003 Papakostas et al., 2007 Simon and Nemeroff 2005 Tremblay and Blier 2006 Uzun et al., 2005). It has been suggested that the beneficial effect of AADs as adjuncts to SSRIs is explained, at least in part, by their ability to... 

The U.S. Food and Drug Administration today approved Risperdal (risperidone) for the treatment of schizophrenia in adolescents, ages 13 to 17, and for the short-term treatment of manic or mixed episodes of bipolar I disorder in children and adolescents ages 10 to 17. This is the first FDA approval of an atypical antipsychotic drug to treat either disorder in these age groups. 

During 2004 a number of clinical trials were reported involving acute and maintenance studies of lithium, mostly either comparing new atypical antipsychotic drugs with lithium in bipolar disorder or in combined treatment studies. Of the relatively few studies of the adverse effects of lithium, most clustered in the areas of cardiovascular effects and issues regarding lithium toxicity. 

Several modem, better-tolerated antipsychotic agents (olanzapine, quetiapine, and risperidone) have recently received FDA approval for use in acute mania. There is also evidence of antimanic efficacy for aripiprazole and ziprasidone. Olanzapine is FDA-approved for its long-term effectiveness in bipolar disorder 1. Other atypical antipsychotic drugs are under investigation for long-term prophylactic treatment of bipolar disorder. 

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. 

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. 

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. 

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... 

Lithium, several (but not all) anticonvulsants, and most of the atypical antipsychotic medications are approved by the U.S. Food and Drug Administration (FDA) for the treatment of one of more phases of bipolar disorder. These medications are referred to as mood stabilizers, and they are the foundation of treatment for bipolar disorders. However, the skillful treatment of bipolar disorder requires not only the knowledge of how to prescribe one or more of these medications but also the understanding that some medications are preferred for one phase of the illness but not the other or for long-term use but not necessarily acute use. In this chapter, we first review the clinical use of lithium and the anticonvulsants that are definite or probable mood stabilizers. The general properties of atypical anti-psychotics are reviewed in Chapter 4. In this chapter, we expand on the use of these compounds for the treatment of bipolar disorder. Discussion of the treatment of each phase of bipolar disorder concludes the chapter. 

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. 

Other mood stabilizers are arising from the group of drugs that were first developed as anticonvulsants and have also found an important place in the treatment of bipolar disorder. Several anticonvulsants are especially useful for the manic, mixed, and rapid cycling types of bipolar patients and perhaps for the depressive phase of this illness as well. Mood stabilizers will be discussed in detail in Chapter 7. An-tipsychotics, especially the newer atypical antipsychotics, are also useful in the treatment of bipolar disorders. 

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. 

Dunayevich E, McElroy SL. Atypical antipsychotics in the treatment of bipolar disorder pharmacological and clinical effects. CNS Drugs 2000 13 433-41. 

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