Treatment of non-schizophrenic disorders: focus on atypical antipsychotics

Antipsychotics are commonly used for conditions other than schizophrenia, yet support for such use in the literature is unclear. This article reviews the literature on the pharmacologic treatment of specific types of non-schizophrenic disorders: those associated with psychotic depression, obsessive-compulsive disorder, body dysmorphic disorder, bipolar disorder, and dementia. It focuses on the evidence for using antipsychotics in these conditions, placing emphasis on atypical antipsychotics. Medline/HealthStar and PsycInfo databases were used to identify published trials and reports of antipsychotics used specifically for non-schizophrenic disorders. Numerous studies were found supporting the use of atypical antipsychotics for non-schizophrenic disorders; however, with the exception of dementia, few randomized, double-blind controlled trials have been published examining the efficacy and safety of these agents in non-schizophrenic disorders. In general, most trials were restricted to short-term use as adjunctive therapy. The literature reviewed was primarily comprised of small open-label trials, thus making it difficult to draw definitive conclusions. Despite the limitations of the trials reviewed, atypical antipsychotics represent a promising treatment modality when considering their improved side effect profile compared to conventional agents. Appropriate dosing and the use of antipsychotics in combination with psychosocial treatments are important treatment considerations. Due to the frequent clinical use of atypical antipsychotics as adjunctive therapy, well-designed trials of these agents in non-schizophrenic disorders are necessary.     

Atypical antipsychotics in elderly patients with dementia or schizophrenia: review of recent literature

Atypical antipsychotics have become a common pharmacologic option for the treatment of various psychiatric and behavioral symptoms in older adults, although these medications have been officially approved by the U.S. Food and Drug Administration for use only in schizophrenia and bipolar disorder. Despite the widespread use of these agents, there is a relative shortage of rigorously conducted trials. This review focuses on recently published randomized, blinded, controlled trials involving the use of atypical antipsychotics in elderly patients with dementia (n = 9) or schizophrenia (n = 3), with some discussion of published large, open-label studies and a few unpublished controlled trials. In general, the studies of patients with dementia reported modest efficacy of atypical antipsychotics when compared to placebo and conventional antipsychotics. In addition, an advantage in terms of motor side effects was consistently noted with atypical antipsychotics when compared to conventional antipsychotics. The studies have also shown, however, a greater risk of mortality and adverse cerebrovascular events with several of these agents than with placebo in individuals with dementia. There are insufficient data comparing atypical antipsychotics to one another. In the trials involving elderly persons with schizophrenia, atypical antipsychotics were associated with significant improvements in psychopathology; differences in efficacy among atypical antipsychotics were unclear. A careful consideration of the risk-benefit ratio of atypical antipsychotics, as well as that of available alternative treatments, is needed for each individual elderly patient. Clinical judgment, caution, and consent should be the watchwords in this area of psychopharmacology.     

Atypical antipsychotics: newer options for mania and maintenance therapy

Atypical antipsychotics have been used to treat patients with schizophrenia for many years, but now there is increasing evidence of their utility in the treatment of bipolar disorder. In the past few years several atypical agents have received regulatory approval for use in bipolar mania. Through a review of randomized controlled trials for five commonly used atypical drugs, olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole, this article evaluates their efficacy in the acute and maintenance phases of bipolar disorder. The evidence shows that atypical antipsychotics are effective in the treatment of manic symptoms, either alone or in combination with traditional mood stabilizers such as lithium and divalproex. Although emerging data indicate that atypical antipsychotics will be a promising addition to those therapies that are currently available for managing patients during the maintenance phase of bipolar illness, their potential in the long-term management of bipolar disorder remains to be fully explored.
Atypical antipsychotics appear to have broadly similar efficacy against manic symptoms of bipolar disorder, but there are important differences in their tolerability profiles, which are likely to be of particular relevance during long-term treatment. A brief assessment of tolerability issues surrounding the use of atypical agents in bipolar disorder and other aspects of treatment that have impact on the clinical effectiveness of the therapy are considered.     

Atypical Antipsychotic Use in the Treatment of Psychosis in Primary Care

Atypical antipsychotics are a class of novel agents increasingly employed for the treatment of psychotic disorders. The pharmacodynamic properties of the atypicals appear to impact a broader spectrum of psychotic symptoms than had been appreciated with older generation antipsychotics. In addition, the atypical agents appear to have a reduced risk of neurologic side effects compared with conventional antipsychotic use. Both of these features enhance the appeal of the atypical antipsychotics and may be associated with enhanced patient compliance. The atypical antipsychotics appear to be effective for schizophrenia as well as other psychotic disorders, including schizoaffective disorder and mood disorders with psychotic features. Consequently, atypical antipsychotics are now considered to be the first-line treatment for schizophrenia, with the exception of clozapine, which is considered a second-line agent because of risks associated with its use. This review will discuss the literature on atypical antipsychotic efficacy in psychotic disorders. Issues related to antipsychotic use, dosing, adverse effects, and drug interactions are also discussed.     

Role of aripiprazole in treating mood disorders

Atypical antipsychotics have been used to treat patients with schizophrenia for many years, but now there is increasing evidence of their utility in the treatment of mood disorders. In the past few years, several atypical agents have received regulatory approval for use in mania. The evidence shows that atypical antipsychotics are effective in the treatment of manic symptoms, either alone or in combination with traditional mood stabilizers, such as lithium and divalproex. Although emerging data indicate that atypical antipsychotics will be a promising addition to those therapies that are currently available for managing patients during the maintenance phase of bipolar illness, their potential in the long-term management of bipolar disorder remains to be fully explored. Aripiprazole is a recently released antipsychotic medication that differs from other atypical antipsychotic agents by its mode of action as a dopamine D2 partial agonist. It is administered orally and has a long half-life. Randomized studies have demonstrated the efficacy of aripiprazole compared with placebo in the treatment of acute relapse of schizophrenia and schizoaffective disorder, maintenance treatment of schizophrenia, treatment of acute mania, and prevention of manic relapse in patients who responded to the drug during a manic episode. Further studies are ongoing in bipolar and unipolar depression. Aripiprazole is generally well tolerated compared with other antipsychotic medications, although commonly reported side effects include extrapyramidal symptoms and motoric activation similar to akathisia. Further studies and postmarketing data will be helpful in providing additional information regarding the comparative safety, efficacy and tolerability of aripiprazole in the treatment of affective disorders.     

The new and evolving pharmacotherapy of schizophrenia.

Based on the evidence presented here, the following tentative conclusions can be drawn. Atypical antipsychotics (except amisulpride) have shown superiority over placebo in acute schizophrenia. Compared with conventional antipsychotics, they are at least as effective. Generally, analyses employing conservative criteria (e.g., Cochrane reviews) report few efficacy differences between atypical and conventional agents. There are now many well-controlled studies indicating modest advantages for the atypical antipsychotics, however, particularly in specific symptom domains. For the treatment of negative symptoms, olanzapine and to a lesser extent amisulpride seem most promising. Risperidone, olanzapine, and quetiapine display advantages in improving cognitive and depressive symptoms. There are indications that the atypical antipsychotics are associated with decreased likelihood of rehospitalization and improved quality of life. In head-to-head comparisons of atypical antipsychotics, none have shown consistent efficacy advantages. In severely refractory samples, no atypical antipsychotics have consistently been shown to be as effective as clozapine or superior to conventional agents. There are indications, however, that risperidone, olanzapine, and quetiapine have advantages over conventional agents in less severely refractory patients. Few maintenance RCTs have been published, and efficacy advantages for atypical antipsychotics in prospective RCTs in first-episode schizophrenia have not been reported.     

Atypical antipsychotics in bipolar disorder: systematic review of randomised trials

Background

Atypical antipsychotics are increasingly used for treatment of mental illnesses like schizophrenia and bipolar disorder, and considered to have fewer extrapyramidal effects than older antipsychotics.

Methods

We examined efficacy in randomised trials of bipolar disorder where the presenting episode was either depression, or manic/mixed, comparing atypical antipsychotic with placebo or active comparator, examined withdrawals for any cause, or due to lack of efficacy or adverse events, and combined all phases for adverse event analysis. Studies were found through systematic search (PubMed, EMBASE, Cochrane Library), and data combined for analysis where there was clinical homogeneity, with especial reference to trial duration.

Results

In five trials (2,206 patients) participants presented with a depressive episode, and in 25 trials (6,174 patients) the presenting episode was manic or mixed. In 8-week studies presenting with depression, quetiapine and olanzapine produced significantly better rates of response and symptomatic remission than placebo, with NNTs of 5–6, but more adverse event withdrawals (NNH 12). With mania or mixed presentation atypical antipsychotics produced significantly better rates of response and symptomatic remission than placebo, with NNTs of about 5 up to six weeks, and 4 at 6–12 weeks, but more adverse event withdrawals (NNH of about 22) in studies of 6–12 weeks. In comparisons with established treatments, atypical antipsychotics had similar efficacy, but significantly fewer adverse event withdrawals (NNT to prevent one withdrawal about 10). In maintenance trials atypical antipsychotics had significantly fewer relapses to depression or mania than placebo or active comparator. In placebo-controlled trials, atypical antipsychotics were associated with higher rates of weight gain of ≥7% (mainly olanzapine trials), somnolence, and extrapyramidal symptoms. In active controlled trials, atypical antipsychotics were associated with lower rates of extrapyramidal symptoms, but higher rates of weight gain and somnolence.

Conclusion

Atypical antipsychotics are effective in treating both phases of bipolar disorder compared with placebo, and as effective as established drug therapies. Atypical antipsychotics produce fewer extrapyramidal symptoms, but weight gain is more common (with olanzapine). There is insufficient data confidently to distinguish between different atypical antipsychotics.     

Atypical uses of atypical antipsychotics

Atypical antipsychotic drugs are primarily indicated for the treatment of psychotic disorders such as schizophrenia and schizoaffective disorder. Recently, they have also been used for mood stabilization. This article reviews other, potentially therapeutically useful indications for these medications. In most cases, the evidence supporting these new uses is limited but provocative, and involves only case reports. It has not yet been determined whether the usefulness of atypical antipsychotics for nonpsychotic disorders outweighs their potential to cause serious side effects.     

The use of atypical antipsychotics in the treatment of catatonia.

PURPOSE: Evidence indicates that classical antipsychotics may aggravate non-malignant and malignant catatonia (MC). Atypical antipsychotics are less likely to cause movement disorders than classical antipsychotics and they are being frequently prescribed in disorders that can be associated with catatonia. Therefore, the important question that arises is whether atypical antipsychotics have a role to play in the treatment of catatonia. MATERIALS AND METHODS: A Medline search was performed to locate papers on the use of atypical antipsychotics in catatonia published between 1970 and 31st December 2004. RESULTS: The literature on the use of atypical antipsychotics in catatonia consists of case reports and retrospective studies. In most cases of non-MC a reduction of the catatonic symptoms is reported upon treatment with atypical antipsychotics. Cases of MC relate mainly to the neuroleptic malignant syndrome (NMS), which is considered as an iatrogenic stuporous variant of MC caused by antipsychotics. CONCLUSION: There are indications that atypical antipsychotics may be useful in non-MC. As a consequence, one should not only focus on the possible extrapyramidal and autonomic side effects of these drugs, but also on the possible beneficial effects on certain brain functions and on the catatonic symptomatology. However, randomized controlled trials are needed to evaluate the effect of these drugs, and caution is advisable, since cases of NMS have been linked to treatment with atypical antipsychotics. There is no evidence to prescribe atypical antipsychotics in MC.     

Pharmacotherapy for late-life depression

The 2001 expert consensus guidelines for treating major depressive disorder (MDD) in geriatric patients recommended antidepressant treatment in combination with psychotherapy. Recent evidence continues to support the use of selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors as first-line agents in the elderly, and although the transdermal monoamine oxidase inhibitor selegilene has shown promise in adult patients, it has not been studied in geriatric depression. Augmentation therapy with atypical antipsychotics or other agents may provide benefits for agitated, psychotic, or resistant MDD in the elderly. The few treatment studies that have been conducted in the geriatric population since the publication of the guidelines have had mixed results and high placebo response rates. More large controlled trials are needed.     

Generating evidence to inform policy and practice: the example of the second generation "atypical" antipsychotics

The introduction of the second generation "atypical" antipsychotics has been heralded as a major advance in the treatment of schizophrenia and other psychotic disorders. Systematic reviews have revealed only modest advantages over conventional antipsychotics and uncertainty about long-term efficacy and safety, yet the second generation antipsychotic drugs have been widely accepted into clinical practice. Although the existing evidence of the benefits and harms of atypical antipsychotics can facilitate decision making about individual patients, the randomized evidence remains inadequate to make valid and fully evidence-based policy statements such as clinical practice guidelines that are designed to apply to groups of patients. Further large randomized trials are needed, but these require patients and clinicians to be in equipoise, or substantially uncertain, about alternative therapies. Premature clinical practice guidelines or expert opinion can lead to changes in clinical practice that make it difficult or impossible to conduct the required trials and are therefore a disservice to patients.     

Atypical antipsychotic medications for borderline personality disorder: What’s the story?

Atypical antipsychotic medications have been approved for treatment of schizophrenia and broad efficacy has led to trials for other illnesses. For borderline personality disorder (BPD), traditional antipsychotics had been demonstrated to reduce symptoms, but were not well tolerated. This paper reviews the new data emerging from trials assessing safety and efficacy of the atypical antipsychotic medications risperidone, olanzapine, and quetiapine (studies of ziprasidone and aripiprazole have not been published). To date, the results of studies with atypical antipsychotics have shown reduction of symptoms from across a broad number of domains. Also, early placebo-controlled trials show an advantage for these agents. Taken together, these new studies are pointing to a positive direction and offer hope for the treatment of BPD.     

Antipsychotics in the treatment of mood disorders and risk of tardive dyskinesia

Psychosis occurs commonly in patients with mood disorders and has traditionally been treated with typical antipsychotics. Exposure to typical antipsychotics poses a risk for the emergence of tardive dyskinesia. Atypical antipsychotics may have advantages over typical agents in the treatment of patients with mood disorders complicated by psychotic features. The studies of typical and atypical antipsychotics in the treatment of mood disorders were reviewed. Similarly, studies regarding the risk of tardive dyskinesia from typical and atypical agents in patients with mood disorders were surveyed. Typical and atypical antipsychotics appear to be comparably effective in the treatment of acute mania. Limited data regarding these medications in psychotic depression are available. Advantages of atypical antipsychotics include, for most agents, minimal extrapyramidal and prolactin effects, inherent thymoleptic activity, and lower rates of tardive dyskinesia. Atypical antipsychotics appear to have a number of advantages over typical agents in the treatment of patients with psychotic mood disorders.     

Treatment of schizophrenia and delusional disorder in the elderly

With increasing longevity, greater numbers of patients with schizophrenia and delusional disorder will be surviving into advanced age. Antipsychotics form the core of the treatment for both of these psychotic disorders. Treatment of elderly patients with antipsychotics is, however, complicated by a much higher risk of adverse effects such as tardive dyskinesia. More is known about treating patients with schizophrenia than those with delusional disorder. The introduction of newer atypical antipsychotics may herald a new era in the pharmacotherapy of elderly psychotic patients. Nonetheless, judicious dosing is essential in the geriatric population. We discuss the benefits and limitations of the main forms of treatment.     

The Effects of Atypical Antipsychotics on Serum Prolactin Levels

Hyperprolactinemia may be a concern in the treatment of patients with schizophrenia. The side effects associated with high prolactin levels can have a negative impact on patient compliance with treatment. Atypical antipsychotics as a group cause less hyperprolactinemia than conventional antipsychotics, yet there is considerable variation among specific drugs. Risperidone at higher doses has been shown to produce increases in prolactin similar to conventional antipsychotics. At the other end of the spectrum, clozapine and quetiapine produce minimal sustained increases in prolactin that are no different from placebo. However, correlations between prolactin elevations and clinical symptoms have not been well-established. This paper reviews the published literature regarding prolactin levels in treated and untreated patients with schizophrenia and the relationship of prolactin and dopamine. It concludes with an overview of the effects of specific atypical antipsychotics on prolactin levels in patients with schizophrenia.     

Antipsychotic treatment in schizophrenia: atypical options and NICE guidance.

Following the reintroduction of clozapine, several atypical antipsychotics have become available for the treatment of schizophrenia. These drugs are at least as effective as conventional treatment. Although each has an individual pattern of affinities, new work suggests that the hallmark of atypicality is fast dissociation at the dopamine-2 receptor. Numerous novel drugs are in development, but it is not clear how these conform to this theory of therapeutic effect. Atypical antipsychotics cause less extrapyramidal side effects than conventional treatment, but other effects such as hyperprolactinaemia, weight gain, glucose dysregulation and prolonged QTc interval remain problematic for some. Current antipsychotic prescribing practice is far from ideal: the NICE guidance stresses that atypical treatments should be considered unless symptoms are well controlled and side effects are acceptable, or depot formulation is indicated. There is a welcome emphasis on drug treatment as part of an integrated package of care negotiated with patients and their carers.     

The chances of new atypical substances

Antipsychotic treatment with so-called "atypical" neuroleptics, as defined by the lack of extrapyramidal side effects in its strict sense, has made great advances in the last decades with the advent of newly developed antipsychotic agents. The first atypical neuroleptic drug was clozapine, also referred to as "dirty drug" or "rich drug" because of its broad receptor binding profile. Clozapine has been the starting point for several different, newly developed antipsychotics. Among these, the most prominent are olanzapine, risperidone, sertindol, ziprasidone, and amisulpride. All of these newly developed, atypical antipsychotics show a high degree of efficacy in the treatment of positive symptoms of schizophrenia in combination with a lack of or a reduced degree of extrapyramidal side effects (EPS). In addition, several atypical antipsychotics seem to have an additional impact on negative symptoms such as alogia, anhedonia, or avolition. However, apart from the clear advantage of clozapine in the treatment of otherwise treatment-resistant schizophrenia, differential indications for the different antipsychotics remain to be established.     

Managing treatment-resistant schizophrenia: evidence from randomized clinical trials

Clozapine was the first antipsychotic medication to be approved for the indication of treatment-refractory schizophrenia. This followed rigorous testing in patients who retrospectively and prospectively failed treatment trials of relatively high doses of conventional antipsychotics. In the past decade, other atypical antipsychotics have been approved, but they have not been designated specifically for patients with a history of prior poor treatment response. Better tolerated than clozapine, these new agents have been used with varying success in patients who would have otherwise received clozapine. Up until very recently there has not been a head-to-head controlled clinical trial comparing the two most commonly used atypical antipsychotics, risperidone and olanzapine, with clozapine in patients considered to have a suboptimal response to typical antipsychotics. This review summarizes the current advances made in the pharmacological management of these patients by examining recently published randomized controlled clinical trials that have measured psychopathology and cognition.     

The art and science of switching of antipsychotic medications, part 1

In the presentation "Prevalence of and Factors Influencing the Switching of Antipsychotic Medications," Weiden defines the recovery approach for the treatment of schizophrenia, focuses on reasons for switching antipsychotic medications, and offers recommendations for evaluating switch studies. In "Combining and Switching Medications in Bipolar Disorder," Young discusses the similarities and differences between schizophrenia and bipolar disorder, offers recommendations for switching medications in bipolar disorder, and evaluates studies of atypical antipsychotics in the treatment of bipolar disorder. Buckley's presentation, "Differential Pharmacology of Atypical Antipsychotics: Clinical Implications," examines response rates in patients with schizophrenia after switching antipsychotic medications, outlines receptor-binding profiles of atypical antipsychotics, highlights adverse events that may occur when switching antipsychotic medications, and offers recommendations for treating those adverse events.