The promise of atypical antipsychotics

Fewer side effects mean enhanced compliance and improved functioning

Leslie Citrome, MD, MPH; Jan Volavka, MD, PhD

VOL 116 / NO 4 / OCTOBER 2004 / POSTGRADUATE MEDICINE

CME learning objectives

• To become familiar with the advantages that first-line second-generation antipsychotics have over first-generation antipsychotics
• To understand the different formulations and indications available for first-line second-generation antipsychotics
• To recognize that interindividual differences are important in the efficacy and tolerability of second-generation antipsychotics

Dr Citrome has consulted for, received honoraria from, and/or conducted clinical research supported by Abbott, AstraZeneca, Bristol-Myers Squibb, Lilly, Janssen, Novartis, Pfizer, and Repligen. Dr Volavka has received honoraria and/or research support from AstraZeneca, Bristol-Myers Squibb, Glaxo, and Lilly. The authors disclose no unlabeled uses of any product mentioned in this article.

Preview: Five new antipsychotic drugs introduced in the United States in the last decade offer physicians the ability to treat patients with schizophrenia and bipolar mania without the adverse effects of the first-generation antipsychotics. In this article, the authors discuss the advantages and side effects of these agents and present a guide to help physicians choose the optimal drug in the most favorable formulation for each patient.
Citrome L, Volavka J. The promise of atypical antipsychotics: fewer side effects mean enhanced compliance and improved functioning. Postgrad Med 2004;116(4):49-63

In the last decade, five new antipsychotic medications have been introduced in the United States: risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Geodon), and aripiprazole (Abilify). They are collectively placed in the class of atypical, or second-generation, antipsychotics because they share some advantages over the older, first-generation antipsychotics, such as chlorpromazine hydrochloride (Thorazine) and haloperidol (Haldol).

The newer agents have a lower tendency than the older medications to cause extrapyramidal side effects, such as rigidity, tremor, and akathisia. Because of this lower potential, adherence to the medication regimen is enhanced. They also have a lower risk of causing tardive dyskinesia. More recently, it has been shown that the newer agents favorably affect cognitive dysfunction and other symptoms that may be important in improving a patient's level of functioning.

Another recent development is the approval of these agents by the US Food and Drug Administration (FDA) for treatment of bipolar mania in addition to schizophrenia (table 1). Several new formulations have become available, including liquid risperidone, orally disintegrating tablets of olanzapine and risperidone, combination pills of olanzapine and fluoxetine (Symbyax), rapid-acting intramuscular preparations of ziprasidone and olanzapine, and a long-acting intramuscular preparation of risperidone (table 2).

On a cautionary note, second-generation antipsychotics have been associated with weight gain, which varies from medication to medication and patient to patient. In addition, the FDA has instructed the manufacturers of all second-generation antipsychotics to include a warning on their product label about the effects of these drugs on hyperglycemia and diabetes. In this article, we review the similarities and differences of the five first-line second-generation antipsychotics and place them in clinical perspective.

Clozapine: The first second-generation antipsychotic

Clozapine (Clozaril) was introduced commercially in the United States in 1989, heralding a new era in the treatment of patients whose schizophrenia did not respond adequately to the other agents available at that time (1). Moreover, clozapine was observed to cause few or none of the extra-pyramidal symptoms that have been the hallmark of such older agents as haloperidol. Because of the risk of agranulocytosis, clozapine use requires monitoring of the white blood cell count weekly for the first 6 months and then every other week for as long as the patient takes this medication.

Although clozapine is now also indicated for treatment of recurrent suicidal behavior in patients with schizophrenia (2), it is not usually considered a first-line second-generation antipsychotic because of the need for blood monitoring and such adverse effects as sedation (39%), hypersalivation (31%), tachycardia (25%), and seizures (5%). The newer second-generation antipsychotics are easier to administer, titrate, and tolerate. However, only risperidone and olanzapine have been compared directly with clozapine in randomized clinical trials (3).

First-line second-generation antipsychotics

The distinguishing clinical feature of second-generation antipsychotics is their low propensity for causing extrapyramidal side effects. Within the dose ranges commonly used, these agents do not generally cause the rigidity, tremor, or akathisia that is almost expected with such older agents as haloperidol. Moreover, these newer agents appear to have a broader spectrum of efficacy in that they are helpful not only in reducing positive symptoms (eg, hallucinations, delusions) but also in reducing negative symptoms (eg, amotivation, emotional and social withdrawal), cognitive impairment, mood problems, and perhaps even persistent aggressive behavior (4).

Initially FDA-approved for the treatment of patients with schizophrenia, most of these agents are also approved for the treatment of patients with bipolar mania as monotherapy (olanzapine, risperidone, quetiapine, and ziprasidone) and some as combination therapy (olanzapine, risperidone, and quetiapine) with lithium or valproic acid (Depacon, Depakene, Depakote) (5). The FDA has approved olanzapine for maintenance treatment of bipolar disorder and, in a combination pill with fluoxetine, for treatment of patients with depressive episodes associated with bipolar disorder.

How they work
The mechanism of action of these newer agents differs somewhat from that of the older antipsychotics. The second-generation antipsychotics have affinity for the serotonergic neurotransmitter system in addition to their effects on the dopamine D₂ receptor. This affinity may explain their clinical profile of lower extra-pyramidal symptoms and improvement in cognition, which is not observed with the older agents (6).

However, this explanation is a gross oversimplification because several dopaminergic pathways are involved. It is thought that the mesolimbic dopamine system mediates the positive symptoms of schizophrenia, the mesocortical system mediates the negative and cognitive symptoms, and serotonin antagonism reverses dopamine antagonism in the nigrostriatal pathway, resulting in fewer extrapyramidal side effects.

There are several other important components, such as glutamatergic neurotransmission and an array of receptor subtypes for both dopamine and serotonin. Although antipsychotics can also have antimuscarinic and antihistaminic properties and cause alpha₁-adrenergic and alpha₂-adrenergic blockade, these properties are thought to be related to different side effect profiles rather than to antipsychotic efficacy.

Traditionally, the efficacy of antipsychotics has been measured by psychopathology rating scales, and a 20% to 30% reduction from baseline classifies a person as a responder in clinical trials. These percentages may represent only a modest clinical improvement, and significant residual symptoms usually remain. In addition, psychopathology rating scales do not adequately assess cognition. This issue is particularly important because cognition is probably more clearly related to functioning than is the presence of hallucinations or delusions.

Differences in efficacy
It has been argued that all first-line second-generation antipsychotics have equal efficacy in reducing symptoms in schizophrenia. This argument is based on the observation that these agents have demonstrated superiority to placebo in randomized, double-blind registration trials. These clinical trials have strict inclusion and exclusion criteria, such that patients who have comorbid substance abuse or treatment resistance or are younger than 18 years are usually ineligible. Thus, the clinical experience with an agent in other patient populations (eg, those whose disorder may be refractory to treatment) may be quite different.

Differences in efficacy can also depend on what outcome measure is selected. For example, in a double-blind, randomized clinical trial comparing clozapine, risperidone, olanzapine, and haloperidol in patients with schizophrenia and a history of suboptimal response to first-generation antipsychotics who were hospitalized in state institutions (7), clozapine and olanzapine demonstrated superior reduction in psychopathology compared with haloperidol, but risperidone did not. But, in the same cohort and in comparison with haloperidol, improvement in cognition was seen among patients randomly assigned to receive either olanzapine or risperidone but not clozapine (8). Clozapine retained a significant advantage in reducing hostility (9).

Recent meta-analyses have provided conflicting information about the advantages of first-generation and second-generation antipsychotics. In one such study of 52 randomized trials (10), the investigators found that lower doses of first-generation antipsychotics resulted in the same efficacy as the newer agents. However, the meta-analysis included certain trials that allowed the doses of first-generation antipsychotics to vary according to "clinical judgment" (ie, flexible dosing). Thus, it is likely that higher doses were given to patients whose symptoms were not responding to the lower ones. This would invalidate the results. Nevertheless, these results are consistent with a clinical trial that compared olanzapine and haloperidol (11). Olanzapine did not demonstrate advantages over haloperidol (in combination with prophylactic benztropine mesylate) in compliance, symptoms, extrapyramidal symptoms, or overall quality of life; however, olanzapine was beneficial in reducing akathisia and improving cognition.

In contrast to the previously mentioned meta-analyses, a meta-analysis of 142 clinical trials (12) concluded that the efficacy of clozapine, risperidone, and olanzapine was greater than that of first-generation antipsychotics and that no difference in efficacy could be detected between risperidone and olanzapine. In this meta-analysis, quetiapine, ziprasidone, and aripiprazole were not statistically different in terms of efficacy when compared with first-generation antipsychotics. However, this lack of difference may be due to the paucity of studies available for analysis. Future research might show a difference. No evidence was found that the haloperidol dose used affected any of these results.

In practical terms, individual patients' symptoms may respond to one treatment but not another. The responses are not predictable. Thus, all antipsychotics should be available for sequential treatment trials to effectively manage symptoms. Interindividual differences in treatment response are greater than the interagent differences observed in randomized clinical trials. This individuality has parallels in other disease states and represents the art, rather than the science, of medicine.

Currently, based on the previously described meta-analysis (12), a reasonable first choice of a first-line second-generation antipsychotic is either risperidone or olanzapine. In patients with refractory symptoms, olanzapine has the edge for reducing psychopathology (7). However, both olanzapine and risperidone are equally likely to ameliorate cognitive dysfunction (8). After additional efficacy information is available comparing quetiapine, ziprasidone, and aripiprazole, it will be included in future meta-analyses, and this incorporation of data may lead to different recommendations. Other considerations include side effects, which may modify medication selection on the basis of individual patient profiles and preferences.

Differences in side effects
Although all first-line second-generation antipsychotics have a low propensity for causing extra-pyramidal side effects, they are not identical in this respect (table 3). In this class of medication, risperidone has the strongest tendency to cause parkinsonian symptoms. This tendency is dose-dependent and has led to a modification in the manufacturer's product labeling, which now recommends a lower dose range and a slower upward adjustment in dose for some patients (13). Dose-dependent extrapyramidal side effects can be seen with the other first-line second-generation antipsychotics but usually not within the dose range recommended by the manufacturer.

Endocrine and metabolic side effects have received a lot of attention within the last few years. These side effects include weight gain (14), diabetes (15), and hyperprolactinemia (16). It is becoming clear that patients with schizophrenia represent a group that is especially vulnerable to comorbid medical conditions.

Weight gain is more likely with olanzapine and quetiapine than with risperidone; it is least likely with ziprasidone and aripiprazole. A recent study (17) revealed that mean weight gain with olanzapine tends to plateau after about 40 weeks of treatment, and no further significant gain occurs for up to 3 years. About one third of patients lost weight. Higher baseline body mass index was predictive of a lower long-term weight gain, and dose was not a significant predictor of greater long-term weight change.

New onset of type 2 diabetes may be more likely for patients taking olanzapine, quetiapine, or risperidone, but differences among these agents are currently not quantifiable. Because ziprasidone and aripiprazole are relatively new, information about them is limited. It is likely that risk factors other than exposure to these agents, such as advancing age, family history of diabetes, nonwhite ethnicity, obesity, and lack of physical exercise, are far more important (15).

Schizophrenia appears to be an independent risk factor as well, and it is now included in the Canadian Diabetes Association's list of risk factors important for screening and prevention (18). The FDA has asked the manufacturers of all second-generation antipsychotics to include a new warning about hyperglycemia and diabetes on their product labels (15). The report from the Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes (19) contains valuable advice for the appropriate and prudent monitoring of patients who are at risk for type 2 diabetes (table 4). The report also notes the importance of monitoring serum lipid levels; available evidence suggests that changes in serum lipids are consistent with changes in body weight (19).

Table 4. Guidelines for assessing the impact of antipsychotic drugs on obesity and diabetes

At baseline, assess the following factors: Personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease Weight and height (calculate body mass index) Waist circumference (at the level of the umbilicus) Blood pressure Fasting plasma glucose Fasting lipid profile At follow-up visits, reassess the following factors: Weight (at 4, 8, and 12 wk and then quarterly) Fasting plasma glucose, fasting lipid profile, and blood pressure at 3 mo, fasting plasma glucose and blood pressure annually, and fasting lipid profile every 5 yr Adapted, with permission, from the American Diabetes Association, the American Psychiatric Association, the American Association of Clinical Endocrinologists, and the North American Association for the Study of Obesity (19).

Although prolactin levels are not routinely obtained, risperidone is more likely to be associated with hyperprolactinemia than the other second-generation antipsychotics (16). This association may have long-term consequences in terms of sexual functioning and bone mineral density loss, and further research is required to place this risk in clinical perspective.

The introduction of ziprasidone in the United States led to concerns about the risk of torsades de pointes. Because this agent has been associated with a measurable prolongation of the QT interval, several safeguards have been put in place, including the recommendation in the product labeling that the agent should not be administered to patients who have significant cardiovascular illness or electrolyte imbalance or are receiving other agents that may prolong the QT interval (20). This risk must be evaluated in the context of the fact that no deaths from ziprasidone overdose or torsades de pointes and no excess in sudden and unexpected deaths have been reported, even though by mid 2002 more than 150,000 patients had received long-term treatment (21).

Differences in dosing
As mentioned, the average daily dose of risperidone has been decreasing (22). However, the opposite trend has been observed for olanzapine and quetiapine (see table 2). The difference between what is recommended in the product labeling and what is being used in the clinical setting may reflect the reality that registration trials are not entirely representative of real-world populations (23). Furthermore, special populations, such as children, the elderly, and the medically infirm, may require a lower dose or a slower upward adjustment in dose than what is recommended in the product labeling for otherwise healthy adults.

Novel formulations
Risperidone is also available in a liquid preparation. Both risperidone and olanzapine are available in rapidly disintegrating tablets. These options may be particularly helpful in children, the elderly, other patients who may have difficulty swallowing pills, or those who are covertly noncompliant with medication. These preparations, which are absorbed in the lower gastrointestinal tract rather than the oral mucosa, are bioequivalent to the regular pill formulation.

Olanzapine is now also available in a combination formulation with fluoxetine. This combination pill has received FDA approval for the treatment of depressive episodes associated with bipolar disorder (24) and is available in several strengths (in the milligram equivalent of olanzapine to the milligram equivalent of fluoxetine): 6/25 mg, 6/50 mg, 12/25 mg, and 12/50 mg. It is noteworthy that 30% of patients presenting with depressive symptoms may actually have bipolar disorder, and antidepressants alone may not be optimal treatment for these patients (25).

Ziprasidone and olanzapine are available as rapid-acting intramuscular injections. This form of administration has substantial advantages in terms of speed of onset of action and guaranteed delivery (26). Ziprasidone is indicated for agitation associated with schizophrenia, for which the recommended dose is 10 or 20 mg per injection. Olanzapine is indicated for agitation associated with schizophrenia or bipolar mania, for which the recommended dose is 10 mg per injection. Both intramuscular ziprasidone and olanzapine can be smoothly transitioned to oral dosing.

Risperidone is now also available in a long-acting intramuscular preparation (27), which has advantages in terms of guaranteed delivery over the long term. However, it requires a transition period in which patients must have oral medication for 3 weeks after the first injection (28).

Choosing the optimal antipsychotic

Efficacy and tolerability are the two most important factors to consider when choosing a first-line second-generation antipsychotic. A history of treatment response in an individual patient to a given agent or agents can guide the prescriber. In the absence of such information, interindividual differences make it difficult--if not impossible--to predict either efficacy or tolerability in any given patient. Physicians often attempt several trials of different drugs to formulate the optimal treatment strategy for each patient.

Ease of use is partially dependent on dosing frequency, and here, the once-daily dosing available with risperidone, olanzapine, and aripiprazole has the advantage. Starting with a therapeutic dose on the first day of treatment (available with olanzapine and aripiprazole) is also a desirable characteristic. Having an oral rapidly disintegrating tablet (available with olanzapine and risperidone) rather than a standard pill is helpful for patients who have difficulty swallowing or who are covertly noncompliant. Rapid-acting intramuscular preparations for agitation are available for ziprasidone and olanzapine. Risperidone is the only first-line second-generation antipsychotic available in a long-acting formulation.

Although certain antipsychotics, such as olanzapine and quetiapine, have been associated with weight gain, not all patients taking these agents gain a significant amount of weight. Any weight gain must be balanced against the clinical efficacy observed. Appropriate interventions may include dietary modification, exercise, or switching to another agent if therapeutically possible.

The association between type 2 diabetes and olanzapine, risperi-done, and quetiapine is not clear. Pharmacoepidemiologic studies have not established that the choice of antipsychotic has any useful predictive value in terms of new-onset type 2 diabetes (15). Because ziprasidone and aripiprazole are relatively new and extended clinical experience is limited compared with other second-generation antipsychotics, information about the risk of diabetes with these newer agents as measured by pharmacovigilance studies is scarce. Regarding dyslipidemia, ziprasidone and aripiprazole, which are associated with the least amount of weight gain, do not seem to be associated with a worsening of serum lipid levels (19). Management of comorbid obesity, diabetes, and metabolic syndrome may require joint efforts on the part of primary care physicians, psychiatrists, and endocrinologists (29).

The cost of second-generation antipsychotics may also be a factor. Third-party payers and patient assistance programs operated by pharmaceutical companies are heavily relied on to support these costs. A 30-day supply of a second-generation antipsychotic in our local pharmacy (Rockland Psychiatric Center Pharmacy, Orangeburg, NY, May 2004) ranges from $220 for risperidone (4 mg daily) to $358 for olanzapine (15 mg daily). In comparison, the cost of a 30-day supply of haloperidol (10 mg daily) is $1.35, a small fraction of the cost of second-generation antipsychotics.

In addition, the cost of concomitant medications, such as other antipsychotics, mood stabilizers, and antidepressants, must be taken into consideration. In clinical reality, because some symptoms are difficult to treat and finding the right medication (or medications) can be a significant challenge, cost differences are relevant only if equal efficacy, safety, and quality of life with the agents used are actually achieved for the individual patient. The monetary cost of relapse and rehospitalization can wipe out any cost savings achieved if a less expensive medication did not adequately control symptoms for that particular patient.

Conclusion

First-line second-generation antipsychotics are used extensively. FDA-approved indications include schizophrenia and, more recently, bipolar mania. These agents have significant advantages over the first-generation antipsychotics, such as haloperidol, because they are less likely to cause extrapyramidal side effects and more likely to improve negative symptoms, cognition, and mood. Interindividual efficacy and tolerability are variable, and it is not unusual for patients to require multiple trials of different antipsychotics.

The dosing frequency and formulations available with second-generation antipsychotics can enhance compliance. Recent reports on weight gain, new-onset type 2 diabetes, and dyslipidemias require patients to receive ongoing monitoring for these conditions. Although there are differences in potential weight gain (and, consequently, dyslipidemias) among the second-generation antipsychotics, differences in risk for diabetes are not as easily quantifiable. Efficacy considerations for the individual patient will ultimately dictate treatment selection.

References

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Dr Citrome is director, clinical research and evaluation facility, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York, and professor of psychiatry, New York University School of Medicine, New York. Dr Volavka is chief, clinical research division, Nathan S. Kline Institute for Psychiatric Research, and professor of psychiatry, New York University School of Medicine. Correspondence: Leslie Citrome, MD, MPH, Nathan Kline Institute for Psychiatric Research, 140 Old Orangeburg Rd, Orangeburg, NY 10962. E-mail: citrome@nki.rfmh.org.

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