Atypical antipsychotics in the treatment of affective symptoms: a review.

Atypical antipsychotics have demonstrated beneficial effects on affective symptoms, in addition to antipsychotic activity. Consequently, their role in the treatment of bipolar disorder and treatment-resistant or psychotic depression has been explored. Adjunctive atypical antipsychotic therapy appears to benefit patients experiencing manic episodes of bipolar disorder, and some studies suggest that monotherapy may also be efficacious. Clinical studies of patients with schizoaffective disorder and major depression support the use of atypical antipsychotics to treat depression. This review focuses on risperidone, olanzapine, quetiapine, and ziprasidone and provides evidence that these drugs demonstrate activity against manic episodes of bipolar disorder when used as adjunctive therapy and possibly as monotherapy and that depression in patients with schizoaffective disorder also responds to these agents.     

Clinical experience with quetiapine in elderly patients with psychotic disorders

Quetiapine fumarate is a recently marketed atypical antipsychotic medication proved to be effective in the treatment of schizophrenia and schizoaffective disorder in the younger population. There is a paucity of studies of this drug in the elderly and more data are needed on the effects of quetiapine in this population, especially those with comorbid medical illnesses. Quetiapine was used to treat seven elderly hospitalized patients between 61 and 72 years of age who manifested signs of psychosis related to schizophrenia, schizoaffective disorder, or bipolar disorder. All patients had been treated previously with conventional antipsychotics or other atypical antipsychotics. Response was assessed by observation of patient's behavior. Four patients responded to treatment; three did not respond. Positive symptoms decreased markedly in all four responders. Negative symptoms showed marked decrease in two patients and moderate decrease in one patient. Preexisting extrapyramidal symptoms (EPS) diminished in three patients. Transient hypotension, dizziness, and somnolence occurred in two patients. No other side effects were noted. No adverse consequences occurred when lithium, carbamazepine, valproic acid, or venlafaxine was given concurrently. The reduction of positive and negative symptoms of schizophrenia and lack of significant EPS and minimal sedative, hypotensive, and anticholinergic side effects indicate that quetiapine may be a safe and effective medication for the elderly.     

Ziprasidone-associated mania: a case series and review of the mechanism

Atypical antipsychotics are now commonly used in the treatment of bipolar disorder, as they have been shown to have effects on mania as well as psychosis. Shortly after the introduction of atypical antipsychotics, several cases of associated hypomania and mania were reported. Ziprasidone is an atypical antipsychotic recently approved by the Food and Drug Administration for the treatment of psychosis. Although ziprasidone has also been shown to be effective in treating mania, it may be associated with the induction of mania or hypomania. We report four cases of mania associated with initiation of ziprasidone, which, to our knowledge, are the first reported for this drug in bipolar patients. As ziprasidone has substantial serotonergic and noradrenergic action, we hypothesize, it may more likely induce mania than other atypical antipsychotics. We advocate future studies to evaluate ziprasidone's efficacy in treating bipolar disorder and caution clinicians that induction of mania or hypomania may be possible with this agent.     

Treatment of schizoaffective disorder and schizophrenia with mood symptoms.

OBJECTIVE: Patients with concurrent schizophrenic and mood symptoms are often treated with antipsychotics plus antidepressant or thymoleptic drugs. The authors review the literature on treatment of two overlapping groups of patients: those with schizoaffective disorder and those with schizophrenia and concurrent mood symptoms. METHOD: MEDLINE searches (from 1976 onward) were undertaken to identify treatment studies of both groups, and references in these reports were checked. Selection of studies for review was based on the use of specified diagnostic criteria and of parallel-group, double-blind design (or, where few such studies addressed a particular issue, large open studies). A total of 18 treatment studies of schizoaffective disorder and 15 of schizophrenia with mood symptoms were selected for review. RESULTS: For acute exacerbations of schizoaffective disorder or of schizophrenia with mood symptoms, antipsychotics appeared to be as effective as combination treatments, and there was some evidence for superior efficacy of atypical antipsychotics. There was evidence supporting adjunctive antidepressant treatment for schizophrenic and schizoaffective patients who develop a major depressive syndrome after remission of acute psychosis, but there were mixed results for treatment of subsyndromal depression. There was little evidence to support adjunctive lithium for depressive symptoms and no evidence concerning its use for manic symptoms in patients with schizophrenia. CONCLUSIONS: Empirical data suggest that both groups of patients are best treated by optimizing antipsychotic treatment and that atypical antipsychotics may prove to be most effective. Adjunctive antidepressants may be useful for patients with major depression who are not acutely ill. Careful longitudinal assessment is required to ensure identification of primary mood disorders.     

Ziprasidone-associated mania: a review and report of 2 additional cases

Although mania was not reported as an adverse event in the pivotal trials of ziprasidone, there have been 7 reports of ziprasidone-induced mania in 12 patients. We now report 2 additional cases wherein the introduction of ziprasidone resulted in new-onset manic episodes. In 1 case, the patient required hospitalization and lost his job. In the other, time to mania was 5 months, considerably longer than previously reported. Of the 14 cases, 9 were in a depressive episode when ziprasidone was prescribed, and 8 had a history of current or past exposure to antidepressants. Ziprasidone, like many antidepressants, can block reuptake of norepinephrine and serotonin, although mania has developed in patients treated with atypical antipsychotics that are less potent in this regard. However, ziprasidone and other atypical antipsychotics have in common a high ratio of 5-HT2a to D2 receptor blockade, which may also play a role in this phenomenon. Clinicians and patients need to be aware of the potential for the induction of mania with ziprasidone, even after lengthy exposure.     

Ziprasidone in the treatment of mania in bipolar disorder

Ziprasidone is an atypical antipsychotic with a unique receptor-binding profile. Currently, ziprasidone is approved by the US Food and Drug Administration for the acute treatment of psychosis in schizophrenia and mania in bipolar disorder. When compared to certain other atypical antipsychotics, ziprasidone appears to have a relatively benign side effect profile, especially as regards metabolic effects eg, weight gain, serum lipid elevations and glucose dysregulation. Taken together, these data suggest that ziprasidone may be a first line treatment for patients with bipolar mania. However, ziprasidone is a relatively new medication for which adverse events after long-term use and/or in vulnerable patient populations must be studied. Unstudied areas of particular importance include the efficacy and safety of ziprasidone in the treatment of bipolar depression and relapse prevention of mania as, well as in the subpopulations of pregnant women, the elderly and pediatric patients. The emergence of mania in patients taking ziprasidone is another topic for further study.     

The treatment of mixed states and the risk of switching to depression.

There are few controlled studies evaluating the treatment of bipolar mixed states. Evidence suggests that mixed states may be more responsive to some anticonvulsants than to lithium. Olanzapine alone or in combination with divalproate or lithium has been adequately evaluated in randomized clinical trials involving mixed-state patients, whereas risperidone and quetiapine have not. There is also some evidence demonstrating the efficacy of ziprasidone and aripiprazole. The risk of switching to depression is high in mixed states. Conventional antipsychotics, such as haloperidol, may be less efficacious at protecting against a switch to depression than atypical antipsychotics, divalproate or lithium. When choosing drugs for the treatment of mania, and especially for the treatment of mixed states, their efficacy against manic and depressive symptoms, and their safety in terms of the risk of switching to depression should be taken into account.     

A review of the effect of atypical antipsychotics on weight

Controlled research trials have shown that atypical antipsychotics have important advantages over standard antipsychotics, including a broader spectrum of efficacy and improved tolerability profile, particularly with regard to neurological adverse events such as extrapyramidal symptoms (EPS). Some atypical antipsychotics, however, tend to cause significant weight gain, which may lead to poor compliance and other adverse health effects. The mechanisms involved in antipsychotic drug-related weight gain are as yet uncertain, although serotoninergic, histaminic, and adrenergic affinities have been implicated along with other metabolic mechanisms. The atypical antipsychotics vary in their propensity to cause weight change with long-term treatment. Follow-up studies show that the largest weight gains are associated with clozapine and olanzapine, and the smallest with quetiapine and ziprasidone. Risperidone is associated with modest weight changes that are not dose related. Given the equivalent efficacy of atypical antipsychotics, weight-gain profile is a legitimate factor to consider when constructing an algorithm for treatment due to the serious medical consequences of obesity.     

Ziprasidone in the treatment of delayed carbon monoxide encephalopathy

Delayed carbon monoxide (CO) encephalopathy is a serious complication of acute CO poisoning. We present a case of successful treatment of ziprasidone, a newer atypical antipsychotic, in delayed CO encephalopathy. A 52-year-old depressed woman suffered acute CO intoxication after an attempt of suicide by burning charcoal. She was initially treated with hyperbaric oxygen (HBO) therapy for the acute intoxication. One week later, the patient developed neuropsychiatric symptoms including parkinsonism, tardive dyskinesia (TD), cognitive deterioration, urinary incontinence, gait disturbance, mutism, disorientation to time, place and person, and disorganized as well as disturbing behavior. During her psychiatric hospitalization, the patient had been treated with daily HBO therapy, bromocriptine (2.5 mg/day), the conventional antipsychotic sulpiride (600 mg/day), and atypical antipsychotics such as risperidone (5 mg/day) and quetiapine (400 mg/day). However, her delayed neuropsychiatric sequelae of CO intoxication persisted despite of these treatments. It was until she had been treated with ziprasidone (80 mg/day) for 10 days that her mental condition was improved. With ziprasidone therapy, the patient obtained substantial improvement in her neuropsychiatric symptoms, cognitive function, and daily activities. Our case indicates that ziprasidone can be used effectively in the treatment of delayed CO encephalopathy.     

The effect of a switch to ziprasidone in an adult population with autistic disorder: chart review of naturalistic, open-label treatment

BACKGROUND: The present investigation retrospectively assessed the effect of an open-label switch to ziprasidone from other atypical antipsychotics on behavior, weight, and lipid levels in an adult population with autistic disorder. METHOD: We conducted a chart review of 10 adults (mean +/- SD age = 43.8 +/- 6.0 years) with DSM-IV autistic disorder who were switched from other atypical antipsychotics to ziprasidone, primarily due to weight gain, but other reasons included hypercholesterolemia, maladaptive behaviors, drowsiness, and depression. They had been treated with ziprasidone for at least 6 months. Our review focused on frequency of maladaptive behaviors, weight, and lipid levels. RESULTS: The mean +/- SD daily dose of ziprasidone was 128 +/- 41 mg, and all 10 patients continued with this same treatment after completion of the 6-month trial. Seven patients were found to have an improvement or no change in their maladaptive behavior. Eight patients (80%) lost weight (mean change = -13.1 +/- 7.0 lb [-5.9 +/- 3.2 kg]), 4 (80%) of 5 patients had a decrease in total cholesterol level, and 3 (60%) of 5 had a decrease in triglyceride levels. Data on lipid levels were available for 5 of the 10 patients. Behavioral activation was not noted in this population. There were no significant adverse effects associated with ziprasidone. CONCLUSION: In adults with autism, a switch to ziprasidone from other atypical antipsychotics appears to have the potential for maintaining beneficial effect on behavior while improving major health indices including weight and lipid levels.     

Atypical antipsychotic augmentation of mood stabilizer therapy in bipolar disorder

Although monotherapy with lithium or divalproex is the recommended initial therapy for bipolar disorder, these agents are associated with prolonged favorable outcomes in only 30% of patients. Increasingly, the medical literature is demonstrating that augmentation of mood stabilizers with atypical antipsychotics is a more effective therapy. This form of combination therapy is recommended as first-line treatment for severe bipolar mania. Recent clinical studies have shown that augmentation therapy with the atypical antipsychotics risperidone, olanzapine, quetiapine, and ziprasidone is effective in long-term maintenance treatment, and preliminary evidence is emerging that use of atypicals with mood stabilizers can help control the depressive phase of bipolar disorder. The atypical antipsychotics also have relatively mild side effect profiles, although augmentation therapy with some antipsychotics and mood stabilizers has been associated with excessive weight gain.     

Comparing efficacy of first-line atypical antipsychotics: no evidence of differential efficacy between risperidone,olanzapine, quetiapine,ziprasidone, and aripiprazole

Objective

To evaluate the comparative efficacy of the first-line atypical antipsychotics risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole.

Methods

We reviewed published short-term, randomised, controlled clinical trials of first-line atypical antipsychotics in the treatment of schizophrenia or schizoaffective disorder that used the Positive and Negative Syndrome Scale to assess efficacy. We used a combined overview analysis to compare the extent of improvement in global symptoms and positive and negative symptoms. We did not analyse adverse event data.

Results

Although we found considerable variation in the degree of improvement with a particular atypical antipsychotic across different studies, the range and average improvement were similar among all first-line atypicals for all efficacy parameters considered. Dosage was a critical determinant of efficacy, although the most effective dose of each agent varied across studies. There were insufficient data for ziprasidone and aripiprazole to allow their inclusion in the formal overview comparison.

Conclusion

Despite confounding and methodological limitations, the data we reviewed do not support assertions of differential efficacy between the first-line atypical antipsychotics. Additional controlled comparative studies of the atypical antipsychotics should be of particular interest.     

Tardive dyskinesia in the era of typical and atypical antipsychotics. Part 2: Incidence and management strategies in patients with schizophrenia.

OBJECTIVE: Tardive dyskinesia (TD), the principal adverse effect of long-term conventional antipsychotic treatment, can be debilitating and, in many cases, persistent. We sought to explore the incidence and management of TD in the era of atypical antipsychotics because it remains an important iatrogenic adverse effect. METHODS: We conducted a review of TD incidence and management literature from January 1, 1965, to January 31, 2004, using the terms tardive dyskinesia, management, therapy, neuroleptics, antipsychotics, clozapine, olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. Additional articles were obtained by searching the bibliographies of relevant references. We considered articles that contributed to the current understanding of both the incidence of TD with atypical antipsychotics and management strategies for TD. RESULTS: The incidence of TD is significantly lower with atypical, compared with typical, antipsychotics, but cases of de novo TD have been identified. Evidence suggests that atypical antipsychotic therapy ameliorates long-standing TD. This paper outlines management strategies for TD in patients with schizophrenia. CONCLUSION: The literature supports the recommendation that atypical antipsychotics should be the first antipsychotics used in patients who have experienced TD as a result of treatment with conventional antipsychotic agents. The other management strategies discussed may prove useful in certain patients.     

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.     

Pharmacologic treatment of hospitalized patients with schizoaffective disorder.

This study examined changes in the pharmacologic treatment of 70 patients who were hospitalized with a diagnosis of schizoaffective disorder at some time during a six-year period. An increasing use of divalproex sodium and atypical antipsychotics instead of lithium and conventional antipsychotics was observed. The use of a combination of an antipsychotic and a thymoleptic medication was more common than monotherapy, and physicians tended to continue antidepressants if patients had a history of depression. Patients with a new diagnosis of schizoaffective disorder were stabilized less quickly than those with a previous diagnosis. The use of divalproex sodium and newer antipsychotics did not reduce the time to stabilization in routine clinical practice.     

Injectable atypical antipsychotics for agitation in borderline personality disorder

Agitation is relatively common among Borderline Personality Disorder (BPD) patients in Psychiatric Emergency Services (PES). New injectable atypical antipsychotics are indicated for treatment in agitated psychotic or maniac patients but not for agitated BDP patients. Twenty agitated BPD patients were treated with intramuscular atypical antipsychotics (olanzapine or ziprasidone). Results suggest intramuscular atypical antipsychotics may be effective, fast and safe for treating acute BPD patients.     

Rapid-acting IM ziprasidone in a psychiatric emergency service: a naturalistic study

Atypical antipsychotics have gained acceptance as first-line treatment for psychotic disorders. Rapid-acting intramuscular (IM) atypicals may supplant benzodiazepine and/or neuroleptic alternatives. IM atypical ziprasidone studies excluded severe psychiatric agitation (PSYCH), or that due to the abuse of alcohol (ETOH) or other substances (SUBS). We report Behavioral Activity Rating Scale agitation scores (range, 1-7) and duration of physical restraints in a naturalistic study in a psychiatric emergency service using IM ziprasidone 20 mg and various doses for conventional antipsychotics. Baseline scores were high for PSYCH, ETOH and SUBS patients (mean, 6.5, 6.9 and 6.6, respectively). Agitation decreased rapidly from baseline with ziprasidone [mean, 5.6, 5.3 and 5.8, respectively, at 15 min (P<.05 for all), and 4.2, 4.1 and 4.1, respectively, at 30 min (P<.01 for all)]. At 2 h, scores were 2.6, 2.1 and 2.3 (P<.01 for all versus baseline). For 9 patients receiving conventional IM antipsychotics, scores were 6.6 (baseline), 5.7 (15 min), 4.2 (30 min) and 2.9 (2 h) (P<.02 versus ziprasidone). Compared with restraint durations from 80 patients receiving conventional IM agents 1 month prior to this study, restraint duration decreased from 91+/-4 to 54+/-3 min with ziprasidone (n=77; P<.01) and varied with conventional IM agents (mean, 60+/-12 min; n=4; P=NS). None of the 19 ziprasidone patients who received electrocardiograms showed prolonged QTc; one had a dystonic reaction. IM ziprasidone appears effective for severe agitation, including agitation associated with alcohol or substance intoxication, and may reduce time in restraints.     

Augmentation of antidepressants with atypical antipsychotics: a review of the current literature

Studies have found that a large percentage of depressed patients may have limited response and remission rates when treated with traditional antidepressants. Options for augmenting antidepressant treatment include buspirone, lithium, and triiodothyronine. There are also increasing data concerning the use of atypical antipsychotics as augmenting agents in the treatment of unipolar, nonpsychotic, treatment-resistant depression. Aripiprazole has recently received an indication from the U.S. Food and Drug Administration (FDA) for adjunctive treatment in unipolar, nonpsychotic depression, the first indication of its kind, after two double-blind trials; doses were slightly lower than those recommended for monotherapy in schizophrenia or bipolar disorder. Olanzapine and risperidone have several controlled clinical trials indicating the efficacy of both of these agents, generally at low doses. One trial of quetiapine suggested that it may not be effective in the treatment of unipolar, nonpsychotic depression. One open-label trial of ziprasidone indicated some efficacy. According to these results, aripiprazole, olanzapine, and risperidone are reasonable choices as augmentation agents, with only aripiprazole currently having an FDA indication for this use. Given the preliminary results, double-blind, placebo-controlled trials with quetiapine and ziprasidone are needed, as well as studies comparing atypical antipsychotic agents with traditional augmentation agents in the treatment of depression.     

Anticonvulsants and antipsychotics in the treatment of bipolar disorder

Bipolar disorder is a complex medical condition, and up to the date there is no single treatment with proven efficacy in the control of all aspects of the illness. The available literature on the use of anticonvulsants (valproate, carbamazepine, oxcarbazepine, lamotrigine, gabapentin, topiramate, clonazepam) and atypical antipsychotics (clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) for acute and prophylactic treatment of bipolar disorder was reviewed. There is a large amount of evidence that lithium is efficacious in the prophylaxis of episodes and better for acute mania than for depressive episodes. Other data show that carbamazepine and valproate are effective in acute manic episodes. Lamotrigine has been shown to reduce cycling and effective in depressive episodes. Based on the available data, olanzapine was found to be the most appropriate atypical antipsychotic agent for the treatment of manic bipolar patients, although there are also studies suggesting the efficacy of risperidone, aripiprazole and clozapine. The preliminary data evaluating the efficacy of quetiapine and ziprasidone in bipolar disorder are still very limited. There is no consistent information supporting the prophylactic use of newer antipsychotics.     

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.