Schizophrenia: Atypical Antipsychotics

By | February 11, 2015

Many atypical antipsychotics are available. In addition to those reviewed in the following sections, atypical agents include perospirone (Sumitomo’s Lullan) and zotepine (Fujisawa’s Lodopin, Aventis’s Nipolept, Orion Pharma’ s Zoleptil, generics). These drugs are not discussed in detail here because their mechanisms of action are similar to those of other atypical agents, they are launched less extensively than other agents, and their prescription volume is lower than that of the atypical agents covered here.

No reliable data suggest that one atypical antipsychotic is significantly superior to another in overall efficacy. Although many comparator trials have been conducted, variations in study design (e.g., dosing regimen, statistical analysis) have led to conflicting results and prevented any conclusions from being drawn. The National Institute of Mental Health has funded a large, 18-month clinical study known as the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) to determine the long-term effects and usefulness of select atypical and typical antipsychotics in schizophrenia patients. Drugs included in the study are olanzapine, risperidone, quetiapine, ziprasidone, clozapine, and the typical antipsychotic perphenazine. Because atypical antipsychotics appear to be relatively similar in terms of efficacy, the true distinction lies in their compound attributes (i.e., dosing schedules and side-effect profiles).

Although atypical antipsychotics adequately treat the positive symptoms of schizophrenia, their effect on negative symptoms and cognitive deficits is less certain. Some trials of atypical antipsychotics show they improve negative symptoms to a greater extent than placebo or typical antipsychotics, but other studies were unable to duplicate these results. More confusing still, investigators are unsure whether atypical antipsychotics prevent secondary negative symptoms or independently improve primary negative symptoms. Primary negative symptoms are those arising as a result of schizophrenia-specific etiology or etiologies, whereas secondary negative symptoms arise from causes outside of disease etiology, such as medication, depression, or anxiety. In fact, it remains an open question whether the slight superiority documented for the atypical drugs over typical drugs in the treatment of negative symptoms reflects the former agents’ propensity to give rise to less extrapyramidal symptoms or whether an independent improvement in primary negative symptoms occurs. Typical antipsychotics’ association with a greater risk of extrapyramidal symptoms may increase the apparent negative symptoms directly by producing akinesia (which may mimic negative symptoms quite closely) and indirectly by causing depression due to having to cope with the medications’ side effects.

As for cognitive symptoms, preliminary research studies have shown improved cognitive function with atypical antipsychotics. Despite these promising results, definitive proof of atypical antipsychotics’ abilities to improve cognition is still lacking because many of these studies were small and poorly designed. Furthermore, it is unclear if atypical antipsychotics are independently able to improve cognition or if their propensity to cause less extrapyramidal symptoms leads to a small improvement in cognition compared with typical agents. Specifically, anticholinergic activity, either intrinsic to the antipsychotic agent or caused by drugs used to treat the parkinsonian side effects of antipsychotic drugs (such as extrapyramidal symptoms), may cause problems with memory, learning, and other cognitive functions. Because atypical antipsychotics are less likely than typical agents to cause extrapyramidal symptoms and require the addition of adjunctive anticholinergic medications, these drugs are likely associated with a minimal cognitive advantage over typical agents. Several studies supported this hypothesis. For example, in a randomized, double-blind study, the neurocognitive effects of low dose haloperidol (mean dose 5.21 mg daily) and olanzapine (mean dose 10.62 mg daily) was similar, suggesting that the superior cognitive efficacy of atypicals versus typicals in previous studies was partially attributable to the high doses of typical medications usually prescribed in these trials.

In summary, atypical antipsychotics appear to offer only modest relief of negative symptoms and cognitive dysfunction, and so treated patients are still considered impaired. In the future, atypical drugs will most likely be used in combination with emerging agents to treat these symptoms.

Mechanism Of Action

The atypical antipsychotics (i.e., serotonin-dopamine antagonists and dopamine partial agonists) all share a general mechanism of dual antagonism at serotonin and dopamine receptors. (Note that aripiprazole [Bristol-Myers Squibb/Otsuka Pharmaceutical’s Abilify] is the only approved dopamine partial agonist; all other atypical drugs discussed in the following sections are serotonin-dopamine antagonists.) Nevertheless, the individual drugs demonstrate different receptor-binding profiles (see Table Receptor Occupancy of Select Atypical Antipsychotics), biochemical profiles, and tolerability by patients. These variations may reflect different modes of action. One notable characteristic of all atypical antipsychotics is their complete lack of or much reduced motor side effects such as extrapyramidal symptoms or tardive dyskinesia compared with typical drugs. Theoretically, this lower risk of movement disorders could be the result of the blockade of 5-НТ2А receptors in addition to D2 receptors. This serotonin blockage prevents dopamine from being released in the mesolimbic dopamine pathway; hyperactivity of dopamine in this area is associated with extrapyramidal symptoms.

TABLE . Receptor Occupancy of Select Atypical Antipsychotics

Generic name D2 Occupancy 5-HT2 Occupancy
Clozapine 25% 90%
Risperidone 66-79% 78-88%
Olanzapine 59-63% 74-92%
Quetiapine Low High
Ziprasidone 65-75% 80-98%

Notes: Of the numerous dopamine receptors, the D2receptor is most clearly associated with psychosis, and the majority of antipsychotics are potent antagonists of this receptor. Serotonergic neurotransmission is thought to inhibit dopaminergic neurotransmission in the midbrain and fore-brain, and it appears that serotonin receptor antagonists disinhibit dopamine neurotransmission in the striatum and neurocortex. Importantly, 5-HT2A blockade seems to moderate the reduction in dopaminergic function caused by the D2antagonism of antipsychotics. It has been proposed (and debated) that a high affinity for 5-HT2receptors  —  particularly a higher affinity for 5-HT2versus D2receptors  — may be the key to atypicality, including efficacy in negative symptoms and the low propensity for extrapyramidal symptoms observed with newer antipsychotics. A D2occupancy of greater than 80% is associated with the induction of extrapyramidal symptoms. A D2occupancy of greater than 78% is associated with hyperprolactinemia. This table summarizes qualitative consensus of current thinking about the binding properties of these atypical antipsychotics at recommended doses. Binding properties vary greatly with technique and species and from one laboratory to another; data on such properties are continually revised and updated.

Atypical antipsychotics’ effect on positive symptoms is not well understood. The drugs are thought to improve positive symptoms by dual antagonism of D2 and 5-HT2A receptors. Dopamine hyperactivity is thought to be one of the main causes of psychosis. Based upon observations made during antipsychotic treatment, it appears that reduced dopaminergic neurotransmission eases the symptoms of schizophrenia. Importantly, 5-НТ2А blockade seems to moderate the reduction in dopaminergic function caused by the D2antagonism of antipsychotics. Furthermore, atypical antipsychotics demonstrate selectivity for mesolimbic over nigrostriatal regions of the brain in their effects on the dopamine system. This selectivity is important because dopamine deficiency in the nigrostriatal pathway of the brain can cause extrapyramidal symptoms while hyperactivity of dopamine in the mesolimbic pathways is thought to cause psychosis. However, given the many receptors these drugs affect, it may be that unknown biochemical mechanisms or receptors are at work.

Atypical antipsychotics’ effect on the negative symptoms and cognitive dysfunction associated with schizophrenia is also not well understood. Researchers have suggested that cortical dopamine deficiency and/or mesocortical dopamine blockade may be involved in the etiology of negative symptoms. Based on these theories, it has been further proposed that atypical antipsychotics reduce negative symptoms by their ability to block serotonin receptors in the mesocortical region, thereby increasing the release of cortical dopamine. Mesocortical release of dopamine associated with 5-HT2A antagonism is also hypothesized to be a factor in cognitive improvement associated with antipsychotic treatment. Atypical antipsychotics’ ability to increase acetylcholine release in the prefrontal cortex — a neurotransmission that is implicated in cognitive dysfunction in many illnesses such as Alzheimer’s disease — could be important in schizophrenia as well. Some researchers have proposed that the 5-HTia agonism activity of atypical antipsychotics may help alleviate depression, anxiety, negative symptoms, and cognitive dysfunction.

Formulations

Atypical antipsychotics are available in a wide variety of formulations. Oral formulations (e.g., orally disintegrating tablets and oral solutions) have been developed for use in extremely agitated patients who may refuse and spit out regular pills. Manufacturers have also developed intramuscular formulations of their atypical antipsychotics (ziprasidone and recently olanzapine). These agents are intended for emergency situations in which extremely agitated patients may refuse treatment yet need rapid drug therapy to prevent them from hurting themselves or others. Finally, manufacturers have developed long-acting depot formulations of atypical antipsychotics. (Currently only risperidone is available in this form, but olanzapine’s depot formulation is in Phase III trials.) This formulation is used in lieu of chronic oral therapy for patients who are extremely noncompliant. Depot formulations are injected biweekly or once monthly and ensure that these noncompliant patients receive the drug therapy they desperately need. Prior to the launch of the intramuscular form of ziprasidone (launched in its first market in March 2002) and the depot form of risperidone (launched in its first market in August 2002), only typical antipsychotics were available in these alternate forms.

Clozapine

A dibenzodiazepine derivative patented in 1960, clozapine (Novartis’s Clozaril/Leponex, generics) was the first atypical antipsychotic to be marketed for schizophrenia. In 1971, this drug was found to cause agranulocytosis, a potentially fatal reduction in white blood cell count, in approximately 2% of patients. It was subsequently withdrawn from most European markets (at that time, it was available in Europe but not in the United States) and was not submitted for FDA approval (although it still could be prescribed in the United States under compassionate-use protocols for highly refractory patients). Based on continued trials and efficacy results, clozapine was eventually reintroduced to the European markets and approved in the United States in 1990. Because of the risk of agranulocytosis, use is recommended only for the treatment of schizophrenic patients who are refractory to other compounds. In November 2002, clozapine’s labeling in the United States was expanded to include the treatment of emergent suicidal behavior in schizophrenic patients.

Like all serotonin-dopamine antagonists, clozapine has greater 5-НТ2 than D2 activity, a characteristic that researchers suggest may be key to its efficacy. In general, clozapine has a relatively high affinity for D1 and D4, muscarinic, and a-adrenergic receptors. The role these affinities have in contributing to clozapine’ s superior efficacy is unclear. Some researchers suggest that blockage of α1 -adrenoceptors may help alleviate positive symptoms, although it may also increase the risk of orthostatic hypotension. Blockage of аг-adrenoceptors (a prominent effect of clozapine) may be involved in the relief of negative and cognitive symptoms. Unlike most atypical antipsychotics, clozapine is associated with high antimuscarinic activity (particularly M4 receptors). This activity may explain the lack of extrapyramidal symptoms but may also be the cause of side effects such as constipation.

A double-blind, six-week study comparing clozapine and chlorpromazine demonstrated clozapine’s effectiveness in treatment-refractory schizophrenics. The criteria for a person’s disease being classified as refractory to treatment included the following: (1) at least three periods of antipsychotic treatment in the preceding five years for a period of six weeks, each without significant symptomatic relief, and (2) no period of good functioning within the preceding five years. Patients had to have a total Brief Psychiatric Rating Scale score of at least 45 plus a minimum Clinical Global Impression scale rate of 4 (moderately ill). The 319 schizophrenic patients were randomized to receive clozapine or chlorpromazine. Efficacy was measured by the Brief Psychiatric Rating Scale and Clinical Global Impression scale.

At the study end, the improvement in both the total Brief Psychiatric Rating Scale score and Clinical Global Impression scale was approximately three times greater in the clozapine-treated patients than in the chlorpromazine-treated patients, a difference that was statistically significant. In addition, clozapine was significantly superior to chlorpromazine in the treatment of positive and negative symptoms as measured by the subscales of Brief Psychiatric Rating Scale. Only 4% of patients treated with chlorpromazine were considered “responders” compared with 30% of clozapine-treated patients. Responders were defined as a > 20% reduction from baseline in Brief Psychiatric Rating Scale total score plus either a posttreatment Clinical Global Impression score of 3 (mild) or less or a posttreatment Brief Psychiatric Rating Scale total score of 35 or less. Clozapine caused significantly more fever (13% clozapine versus 4% chlorpromazine), salivation (13% versus 1%), and hypertension (12% versus 5%), while chlorpromazine resulted in significantly more hypotension (13% clozapine versus 38% chlorpromazine) and dry mouth (5% versus 20%).

Clozapine’s status as the most effective atypical antipsychotic is bolstered by its 2002 U.Spain. approval for the treatment of schizophrenic patients who are judged to be at chronic risk for suicidal behavior. As many as 13% of all patients with schizophrenia commit suicide — a rate that is 25 times the rate observed in the general population — and 25-50% of patients with schizophrenia make a suicide attempt during their lifetime. Clozapine’s regulatory approval for this indication was based largely on the Intersept study. This large, two-year, prospective, randomized trial compared the effectiveness of clozapine (300-900 mg) with that of olanzapine (10-20 mg) in reducing suicide attempts and hospitalizations to prevent suicide in 980 schizophrenic and schizoaffective patients who were considered to be at high risk for committing suicide. Primary end points included suicide attempts (including completions), hospitalizations to prevent suicide, and a rating of “much worsening of suicidality” from baseline on the Clinical Global Impression of Suicide Severity (Clinical Global Impression-SS) scale. Compared with olanzapine-treated patients, significantly fewer clozapine-treated patients attempted suicide (6.9% clozapine versus 11.2% olanzapine) or required hospitalization to prevent suicide (16.7% versus 21.8%) at the study end. Furthermore, significantly fewer clozapine-treated patients (24.5%) than olanzapine-treated patients (32.9%) were rated as “much worsening from baseline” on the Clinical Global Impression-SS scale.

Despite its impressive efficacy, clozapine is limited by its side-effect profile. In addition to the threat of agranulocytosis, clozapine can cause other significant side effects (albeit rarely and many of which are shared by all atypical antipsychotics) such as seizures, myocarditis, orthostatic hypotension with or without syncope, eosinophilia, tachycardia, neuroleptic malignant syndrome, and tardive dyskinesia. Clozapine is also associated with impaired glucose tolerance, significant weight gain, and increased lipid level — side effects that can lead to diabetes and cardiovascular disease. The FDA defines significant weight gain as an increase of at least 7% from baseline. Warnings regarding hyperglycemia and diabetes mellitus are found on clozapine’s label. One study suggests that the overall incidence of diabetes in patients taking this agent may rise to 37% in five years’ follow-up. A recent large cohort study (presented in abstract form) found a 48% increased risk of diabetes associated with clozapine over typical antipsychotics.

A further limitation is the need for strict monitoring of patients taking clozapine. Because of the risk of agranulocytosis, patients who are treated with clozapine must have a baseline white-blood count performed before initiation of treatment. Clozapine is available only through treatment systems that ensure a white-blood count testing prior to the delivery of the next supply of medication. During the first six months of therapy, patients are monitored once per week. After the first six months, patients may be monitored every other week.

Risperidone

Risperidone (Janssen Pharmaceutica’s Risperdal) is widely approved for the treatment of schizophrenia. In addition to its original tablet form, it is available in an oral liquid solution, orally disintegrating tablets (Risperdal M-Tab), and a long-acting depot formulation (Risperdal Consta). In the United States, risperidone is also approved as a monotherapy or for use in combination with lithium or valproate in the short-term treatment of acute manic or mixed episodes associated with bipolar disorder. Furthermore, the drug is under regulatory review in the United States for the treatment of autism in children and juveniles and in Europe for the treatment of psychosis in Alzheimer’s disease.

Unlike clozapine, this agent is a high-potency D2 receptor antagonist — 40-50 times more potent at the D2 receptor than clozapine (but it is only one-third to one-half as potent as haloperidol). Risperidone is also a very potent 5-HT2A blocker. Researchers suggest its serotonin-dopamine antagonism is important to its efficacy. The D2 receptor affinity of this atypical antipsychotic causes dose-dependent extrapyramidal symptoms, especially at doses above 6 mg daily. Risperidone also has high affinity for 5-HT7, β and α 2 adrenergic, and Hi histaminergic receptors. Blockage of a-adrenoceptors may help alleviate positive symptoms, negative symptoms, and cognitive dysfunction, although it may contribute to the risk of side effects such as orthostatic hypotension. Antagonism of histamine H1 receptors is thought to cause somnolence.

Risperidone has demonstrated an ability to relieve the positive and negative symptoms of schizophrenia. One study used to support its new drug application enrolled 388 hospital inpatients with schizophrenia. In this double-blind, fixed-dose, parallel-group, placebo-controlled trial, patients were randomized to receive four different doses of risperidone (2, 6, 10, and 16 mg), haloperidol (20 mg), or placebo for eight weeks. Because only a single dose of haloperidol was administered, the study’s methodology was not ideal for comparing the two drugs. The main efficacy variable was the Positive and Negative Syndrome Scale.

Clinical improvement at end point (defined as a 20% reduction in Positive and Negative Syndrome Scale total score) was shown by 22%, 35%, 57%, 40%, 51%, and 30% of patients receiving placebo, risperidone (2mg, 6mg, 10 mg, or 16 mg), and haloperidol, respectively. Overall, treatment with 6mg, 10 mg, and 16 mg of risperidone statistically reduced total Positive and Negative Syndrome Scale scores at the study end when compared with treatment with placebo. End point scores on the positive Positive and Negative Syndrome Scale subscale were also significantly lower in patients receiving risperidone (6mg, 10 mg, and 16 mg) than in the placebo-treated patients. Negative symptoms were significantly improved, relative to placebo, in patients receiving risperidone (6mg and 16 mg). Although treatment with haloperidol produced statistically significant reductions in total Positive and Negative Syndrome Scale score and positive Positive and Negative Syndrome Scale subscores at study end compared with that of placebo, the difference between haloperidol and placebo in negative Positive and Negative Syndrome Scale subscores was not statistically significant. Side effects that occurred significantly more often in risperidone patients than placebo patients included somnolence (3.2% in the 2mg risperidone group, 3.1% in the 6mg risperidone group, 3.1% in the 10 mg risperidone group, 9.4% in the 16 mg risperidone group, and 4.5% in the haloperidol group versus 0% in the placebo group), extrapyramidal symptoms (7.9%, 10.9%, 12.3%, 25%, and 25.8% versus 10.6%), headache (7.9%, 15.6%, 12.3%, 9.4%, and 7.6% versus 4.5%), and dizziness (3.2%, 9.4%, 1.5%, 10.9%, and 0% versus 0%).

In general, risperidone’s side-effect profile is similar to that of other atypical antipsychotics. It has the potential to cause neuroleptic malignant syndrome, tardive dyskinesia, orthostatic hypotension, and seizures. Its major limitations are the dose-related risks of hyperprolactine-mia and extrapyramidal symptoms. Atypical antipsychotics are generally free of sustained prolactin elevation, but risperidone has a relatively high incidence of this side effect, similar to that of typical agents, especially at doses larger than 6 mg. The consequences of persistent prolactin elevation in women can include menstrual cycle and reproductive disturbances, galactorrhea, hirsutism, vaginal dryness, and loss of libido; it may also cause obesity, reduce bone density, and increase the risk of breast cancer over the long term. In men, the most common problems associated with persistent prolactin elevation are erectile dysfunction, impotence, hypospermatogenesis, and loss of libido. In addition, doses higher than 6mg per day are associated with an increased incidence of extrapyramidal symptoms.

Risperidone is also associated with weight gain and increased triglyceride levels — though not as severely as olanzapine or clozapine — which may increase the risk of diabetes and coronary artery disease. In a pool of six- to eight-week, placebo-controlled trials, approximately 18% of risperidone-treated patients compared with 9% of placebo recipients experienced at least a 7% increase in body weight.

Warnings regarding hyperglycemia and diabetes mellitus were added to risperidone’s label in response to a September 2003 FDA recommendation that labeling of all atypical antipsychotics include this warning. This recommendation was based on a large cohort study (publicly available in abstract form) that found risperidone was associated with a 1.49 hazard ratio of developing diabetes compared with typical antipsychotics. Although this study found a higher risk of diabetes than others, other studies have found that risperidone is associated with less metabolic side effects than olanzapine and clozapine. Finally, risperidone appears to be associated with less hypertriglyceridemia than clozapine and olanzapine. The package insert states that fewer than 1/1,000 patients treated with risperidone experience this side effect.

Olanzapine

Olanzapine (Eli Lilly’s Zyprexa) is available for the treatment of schizophrenia in all of the major pharmaceutical markets. In addition to its original oral form, olanzapine is available in orally disintegrating tablets (Zyprexa Zydis) and a short-acting intramuscular formulation. Eli Lilly is also developing a depot formulation of olanzapine. Olanzapine is also approved as a monotherapy or in combination with lithium and valproate for the short-term treatment of acute mixed or manic episodes associated with bipolar disorder. Recently, this approval was extended in the United States and Europe to include maintenance monotherapy for bipolar patients.

Like all atypical antipsychotics, olanzapine demonstrates dual antagonism of D2 and 5-HT2A receptors, where the 5-НТ2А activity is greater than the D2 activity. This activity is theorized to be important to its antipsychotic effect. Olanzapine closely resembles clozapine in structure but exhibits a different receptor profile. It demonstrates significant 5-НТ2A, 5-HT2D, and 5-НТ6 receptor affinity as well as an increased ratio of D4 to D2 receptor affinity. Olanzapine also has a high affinity for muscarinic M1 — 5, histamine H1, and α1 adrenergic receptors. Although the therapeutic effect of olanzapine’s affinities has not been clearly defined, they most likely contribute to its side-effect profile. Its antagonism of muscarinic receptors (which may be partly responsible for its lower risk of extrapyramidal symptoms) may explain its anticholinergic effects, while its histamine receptor antagonism may explain the somnolence observed with this drug. Finally, its antagonism of α1 adrenergic receptors, which may enhance its antipsychotic efficacy, may explain the orthostatic hypotension.

Treatment with olanzapine relieves both positive and negative symptoms of schizophrenia. In the double-blind, multicenter HGAP study used to support regulatory filings, 152 schizophrenic patients were randomized to receive one of three treatments for six weeks: 1 mg olanzapine, 10 mg olanzapine, or placebo. Overall, patients manifested a clinically severe, mixed (positive and negative) symptom profile with a chronic longitudinal disease course, and their psychosis was relatively refractory to conventional antipsychotic therapy. The primary end points included improvement in overall psychopathology (as measured by Brief Psychiatric Rating Scale total score), positive psychotic symptoms (as measured by Positive and Negative Syndrome Scale-positive score), and negative psychotic symptoms (as measured by Positive and Negative Syndrome Scale-negative score).

Olanzapine treatment (10 mg) was statistically superior to placebo with regard to Brief Psychiatric Rating Scale-total score, Positive and Negative Syndrome Scale-positive score, and Positive and Negative Syndrome Scale-negative score. The HGAP study defined responders as subjects showing at least a 40% decline in the Brief Psychiatric Rating Scale total score or a final Brief Psychiatric Rating Scale total score of 18 or less after completing at least visit six (approximately three weeks) of therapy. Response rates were 9.5% for the placebo group, 11.9% for the 1 mg olanzapine group, and 27.9% for the 10 mg olanzapine group. The difference in response rate between the 10 mg olanzapine group and the placebo group was statistically significant. The most common adverse events that occurred numerically more often with olanzapine than with placebo in this study were hostility (18% 10 mg olanzapine, 9.6% 1 mg olanzapine, 14% for placebo), agitation (16%, 15.4%, 8%), headache (14%, 19.2%, 6%), rhinitis (14%, 1.9%, 8%), nervousness (10%, 11.5%, 8%), and abnormal thinking (10%, 1.9%, 6%). No side effects occurred significantly more in olanzapine patients than in placebo patients.

Like other atypical agents, olanzapine has the potential to cause neuroleptic malignant syndrome, tardive dyskinesia, orthostatic hypotension, and seizures. The most troublesome side effects associated with olanzapine are significant weight gain, diabetes, and increased glucose and triglyceride levels. Furthermore, olanzapine is associated with more sedation and anticholinergic side effects than some of its competitors.

According to olanzapine’s package insert, 29% of olanzapine-treated patients versus 3% of placebo-treated patients experienced significant weight gain in six-week trials. As mentioned earlier, significant weight gain is defined by the FDA as an increase of at least 7% from baseline. In addition, olanzapine increases glucose levels by approximately 21%, and increased glucose levels together with significant weight gain raise the risk of ketoacidosis and diabetes. According to Eli Lilly, diabetes was reported in 0.6% of patients in olanzapine premarketing trials. In the ten-month period following its 2001 launch in Japan, nine cases of diabetic ketoacidosis, coma, or hypoglycemia were reported, and the Japanese Ministry of Health, Labor, and Welfare (MHLW) ordered Lilly to revise its labeling to contraindicate the use of olanzapine in diabetic patients and those with a history of diabetes.

In September 2003, a warning was added to olanzapine’s label according to previously mentioned FDA recommendations. This warning is based on a study (publicly available in abstract form only) that found olanzapine was associated with a 27% increased risk for developing diabetes compared with typical antipsychotics. In April 2004, a law firm announced the filing of the first U.Spain. nationwide class action lawsuit against Eli Lilly on behalf of U.Spain. patients who have used olanzapine. The suit seeks compensation for patients who have been diagnosed with serious side effects (e.g., diabetes, pancreatitis) after taking olanzapine.

Olanzapine also negatively affects cholesterol, and many physicians now test lipid levels in olanzapine-treated patients. According to its package insert, the risk of increased triglycerides associated with olanzapine occurs infrequently (in approximately 1/100 to 1/1,000 patients). In clinical trials, olanzapine elevated triglyceride levels by an average of 39%; an increased level of triglycerides is a risk factor for coronary artery disease.

Quetiapine

Quetiapine (AstraZeneca’s Seroquel) is available for the treatment of schizophrenia in most of the major markets (France is an exception). Currently, only an oral tablet is available, but AstraZeneca is developing a sustained-release formulation of quetiapine and expected to file for U.Spain. and European approval in the second half of 2006. The company also expects to file for approval of a granule formulation of quetiapine in the United States and Europe after 2006. In January 2004, quetiapine was approved in the United States and the United Kingdom as monotherapy or in combination with lithium or valproate for the short-term treatment of manic or mixed episodes of bipolar disorder.

Like other atypical agents, quetiapine’s efficacy in schizophrenia is proposed to be mediated through a combination of D2 and 5-НТ2 antagonism. The compound’s D2 receptor occupancy is low, like that of clozapine; therefore, its primary mode of action likely involves more than D2 occupancy. Quetiapine exhibits relatively high binding affinity for serotonin receptors. It is also an antagonist of 5-HT1a, D1, histamine H1, α1-adrenergic, and α2-adrenergic receptors. Antagonism of the adrenergic receptors may improve its efficacy against positive and negative symptoms along with cognitive dysfunction but may also be responsible for the risk of orthostatic hypotension. Blockage of histamine may lead to somnolence.

Like other atypical agents, quetiapine has demonstrated an ability to relieve positive and negative symptoms of schizophrenia. In a six-week, double-blind, randomized, placebo-controlled trial used to support regulatory filing, 361 patients with acute exacerbation of chronic or subchronic schizophrenia were randomized to treatment with placebo, quetiapine (75 mg, 150 mg, 300 mg, 600 mg, or 750 mg), or haloperidol (12 mg). Because only a single dose (i.e., 12mg) of haloperidol was offered during this study, the study’s methodology was not ideal for comparing the two drugs. Efficacy was determined by changes in Brief Psychiatric Rating Scale, Clinical Global Impression, and Modified Scale for the Assessment of Negative Symptoms. Differences in Brief Psychiatric Rating Scale total and Brief Psychiatric Rating Scale-positive score changes from baseline were significant at end point between each of the four highest doses of quetiapine and placebo, whereas differences between quetiapine (all doses) and haloperidol were not (haloperidol was also statistically superior to placebo). Only 300 mg quetiapine and haloperidol showed a significant reduction in Scale for the Assessment of Negative Symptoms score when compared with placebo. The percentage of patients considered responders (>20% decline in Brief Psychiatric Rating Scale total score at end point) was 27%, 26%, 43%, 45%, 51%, 38%, and 16% for quetiapine (75mg, 150mg, 300mg, 600 mg, and 750 mg), haloperidol, and placebo, respectively. Overall, quetiapine was well tolerated. Only headache, constipation, and dyspepsia occurred at an incidence rate twice that of placebo, and none of these events led to withdrawal. Patients on haloperidol (37%) experienced more extrapyramidal symptoms than did patients treated with quetiapine (4-8%) and placebo (16%).

Quetiapine has the potential to cause neuroleptic malignant syndrome, tardive dyskinesia, orthostatic hypotension, and seizures. Other side effects include weight gain, hyperglycemia, and hyperlipi-demia. Changes in eye lenses have been observed in patients who took quetiapine for extended periods (at least six months), although a causal relationship has not been clinically proved. Nevertheless, a lens examination is recommended (at least in the United States) at the initiation of treatment and every six months thereafter.

The risk of weight gain, diabetes, and increases in glucose and lipid levels appears to be slightly less with quetiapine than with olanzapine and clozapine. According to quetiapine’s labeling, in a pool of four three- to six-week, placebo-controlled clinical trials, approximately 23% of quetiapine-treated patients, compared with 6% of placebo recipients, experienced at least a 7% increase in body weight. Like olanzapine, quetiapine was required by Japan’s MHLW to revise its labeling to reflect reports of diabetic ketoacidosis and diabetic coma resulting from increased blood glucose levels.

In September 2003, a warning was added to quetiapine’s U.Spain. label as a result of the previously mentioned FDA recommendations. This warning is based on a study (publicly available in abstract form only) that found quetiapine to be associated with an increased risk of diabetes compared with typical antipsychotics. According to the package inserts, the risk of increased triglycerides associated with quetiapine and olanzapine appears to be similar (occurring in approximately 1/100 to 1/1,000 patients). Quetiapine’s labeling also states that quetiapine-treated patients in schizophrenia trials experienced increases from baseline in cholesterol and triglycerides of 11% and 17%, respectively, compared with slight declines among placebo-treated patients.

Ziprasidone

Ziprasidone (Pfizer’s Geodon/Zeldox) is available for the treatment of schizophrenia in the United States, Germany, and Spain in both a pill and short-acting intramuscular formulation. In Japan, the oral form of ziprasidone is in Phase II trials for this indication.

Like other atypical agents, ziprasidone’s efficacy is proposed to be mediated via a combination of D2 and 5-НТгд antagonism. Chemically similar to risperidone, ziprasidone demonstrates a strong affinity for the D2, D3; 5-НТ2A, 5-HT1a, 5-НТ1D, and 1-adrenergic receptors. It shows a more moderate affinity for H1 histamine receptors. This receptor profile may contribute to its efficacy and its side-effect profile. Some researchers suggest that the inhibition of α1-adrenergic receptors may reduce the negative symptoms and cognitive dysfunction associated with schizophrenia, although this inhibition may also increase the risk of orthostatic hypotension. Blockade of histamine receptors may explain the somnolence observed with this drug. Ziprasidone’s agonism of 5-HTia receptors may provide some (albeit minimal) anxiolytic relief as well as improve negative symptoms, depressive symptoms, and cognitive dysfunction.

In one study used to support the regulatory filing, ziprasidone was found to be superior to placebo in the treatment of the positive and negative symptoms of schizophrenia. In this Phase III, six-week, placebo-controlled, randomized, parallel-group, fixed-dose study, 302 patients with an acute exacerbation of chronic or subchronic schizophrenia or schizoaffective disorder were randomized to receive ziprasidone (80 or 160 mg) or placebo for six weeks. The primary end points were changes in Positive and Negative Syndrome Scale total score, Positive and Negative Syndrome Scale-negative subscale score, and Clinical Global Impression of Severity of Illness (Clinical Global Impression-Spain) score. Researchers also measured Montgomery-Asberg Depression Rating Scale (MADRS) total scores. Responder rates were defined as a >30% decline in Positive and Negative Syndrome Scale total score from baseline to last observation.

At the study end, both doses of ziprasidone were significantly more efficacious than placebo in Positive and Negative Syndrome Scale total score, Positive and Negative Syndrome Scale-negative subscale score, and Clinical Global Impression-Spain score. Significantly more patients receiving 160 mg ziprasidone than placebo were defined as responders (31% 160 mg ziprasidone versus 18% placebo). Although more patients receiving 80 mg ziprasidone than placebo were defined as responders, this difference was not significant (29% versus 18%). This finding suggests that 80 mg ziprasidone is not a sufficient dose. Ziprasidone did not result in significant changes in MADRS score. However, when depressive symptoms were analyzed in a subgroup of patients with clinically important baseline depressive symptoms (defined as a MADRS score of 14 or greater), 160 mg ziprasidone produced a more statistically significant reduction in MADRS scores than did placebo (31% versus 13%, respectively). Nevertheless, the main end point score was still above 14, suggesting that even though ziprasidone reduced depressive symptoms, patients still had clinically important depressive symptoms at end point. The most frequently reported adverse events associated with ziprasidone were somnolence (19% 160 mg ziprasidone, 19% 80 mg ziprasidone, 5% placebo), dizziness (17%, 9%, 9%), dyspepsia (14%, 9%, 9%), and nausea (7%, 14%, 9%). There were no reports of weight gain in patients taking ziprasidone.

Like other atypical agents, ziprasidone has the potential to cause neuroleptic malignant syndrome, tardive dyskinesia, orthostatic hypotension, and seizures. Overall, the compound does not appear to be associated with many of the significant side effects that plague other atypical agents, such as hyperprolactinemia, weight gain, diabetes, and hyperlipidemia. According to its labeling, when groups of patients meeting a weight-gain criterion of 7% or more of body weight were compared in a pool of four- and six-week placebo-controlled clinical trials, researchers found a statistically significant greater incidence of weight gain with ziprasidone (10%) than with placebo (4%). The weight gain, however, was less than what is seen with atypicals such as olanzapine and risperidone.

Despite this “cleaner” side-effect profile, ziprasidone is typically reserved for second-line therapy, in part because of its risk of inducing QTc prolongation. The current package insert states that, in clinical trials, the electrocardiograms of 0.06% of all patients who received ziprasidone demonstrated QT intervals exceeding the potentially clinically relevant threshold of 500 milliseconds, a circumstance that has been associated with the occurrence of torsades de pointes (an atypical rapid ventricular tachycardia that could progress to ventricular fibrillation) and sudden unexplained death.

Aripiprazole

Aripiprazole (Bristol-Myers Squibb [BMS]/Otsuka Pharmaceutical’s Abilify) was the first dopamine partial agonist launched for the treatment of schizophrenia. The drug launched in the United States in 2002 and in Europe in 2004. In Japan, it is in Phase III trials. BMS and Otsuka received FDA approval for use of the drug in bipolar mania in 2004 and bipolar maintenance in 2005. BMS and Otsuka are also developing a short-acting, intramuscular formulation of aripiprazole.

Aripiprazole’s distinguishing characteristic is its mechanism of action. The drug is a partial agonist at dopamine D2 receptors and can act as a dopaminergic stabilizer, performing as a dopamine antagonist in conditions of dopamine hyperactivity and exhibiting dopamine agonist properties in states of hypoactivity. Such a profile may offer efficacy against the positive symptoms of schizophrenia while causing fewer dopamine-related side effects, most notably extrapyramidal symptoms and hyperprolactinemia. Aripiprazole also acts as a partial agonist at 5-HTia serotonin receptors and an antagonist at 5-НТг receptors. Some researchers suggest this mechanism may help combat the depression, cognitive dysfunction, and negative symptoms of schizophrenia. Furthermore, 5-НТгА receptor antagonism may improve negative symptoms and reduce the risk of developing extrapyramidal symptoms. Aripiprazole also has high affinity for D3 receptors and moderate affinity for D4, 5-НТ2B, 5-HT7, α1-adrenergic, and histamine Hi receptors. It does not have appreciable affinity for cholinergic muscarinic receptors. Its activity at α1-adrenergic receptors may contribute to its efficacy against the positive symptoms of schizophrenia but also increase the risk of orthostatic hypotension. Blockage of histamine receptors is associated with somnolence.

Available data suggest that aripiprazole offers relief from positive symptoms similar to that of typical and other atypical antipsychotics. A double-blind, randomized, placebo-controlled, multicenter Phase III study compared aripiprazole (15 mg or 30 mg) with haloperidol (10 mg) and placebo. The four-week study involved 414 patients hospitalized with a diagnosis of schizophrenia or schizoaffective disorder with acute relapse. The patients were extremely ill at baseline, with mean Positive and Negative Syndrome Scale scores of 100. Primary end points included Positive and Negative Syndrome Scale total, Positive and Negative Syndrome Scale-positive subscale, Positive and Negative Syndrome Scale-negative sub-scale, Clinical Global Impression-Spain score, and Clinical Global Impression of Improvement (Clinical Global Impression-I) score. The study found both doses of aripiprazole were superior to placebo based on the Positive and Negative Syndrome Scale total score, Positive and Negative Syndrome Scale-positive subscale score, Clinical Global Impression-Spain score, and Clinical Global Impression-I score. Aripiprazole 15mg also produced a significantly greater improvement in Positive and Negative Syndrome Scale-negative subscale score compared with placebo, although aripiprazole 30 mg produced an improvement that was numerically but not statistically superior to placebo. Approximately 35%, 28%, 26%, and 17% of patients responded (defined as a 30% reduction in total Positive and Negative Syndrome Scale score) to 15 mg aripiprazole, 30 mg aripiprazole, 10 mg haloperidol, or placebo, respectively. The response rates for both doses of aripiprazole were significantly better than for placebo (p = 0.002 and 0.050), while the response rate for haloperidol did not significantly differ from that of placebo (p = 0.089).

At the end of the study, the overall incidence of extrapyramidal symptoms in the aripiprazole groups was comparable to that in the placebo group and less than that in the haloperidol group. Clinically significant weight gain at four weeks was seen in approximately 7%, 4%, 10%, and 1% of patients receiving 15mg of aripiprazole, 30 mg of aripiprazole, 10 mg haloperidol, or placebo, respectively. Serum prolactin levels dropped from baseline in both aripiprazole groups and the placebo group over the course of the study; mean changes in QTc interval were not statistically different between any of the active treatment groups and placebo. The incidence of somnolence was 4%, 5%, 10%, and 13% in the placebo group, 15 mg aripipra-zole group, 30 mg aripiprazole group, and the haloperidol group, respectively. The incidence of nausea and vomiting was more common in aripiprazole-treated patients than in placebo- or haloperidol-treated patients, although no patients discontinued treatment because of these side effects. Nausea was reported by 7% of patients in the placebo group, 6% of patients in the haloperidol group, 15% of patients in the 15mg aripiprazole group, and 14% of patients in the 30 mg aripiprazole group. Vomiting was reported by 10% of patients in the placebo and haloperidol groups, 8% of patients in the 15mg aripiprazole group, and 17% of patients in the 30 mg aripiprazole group.

Like all atypical agents, aripiprazole increases the risk of developing neuroleptic malignant syndrome, tardive dyskinesia, orthostatic hypotension, and seizures. Overall, however, clinical data suggest that aripiprazole has a superior side-effect profile compared with that of other atypical antipsychotics. Specifically, data imply that aripiprazole does little to elevate weight, glucose, plasma prolactin, or lipids. In September 2003, the FDA recommended that a warning regarding an increased risk of elevated blood sugar levels and diabetes be added to the labeling of all atypical antipsychotics based on a large cohort study (publicly available in abstract form only) that found an increased risk of diabetes associated with olanzapine, risperidone, and quetiapine. In March 2004, this warning was added to aripiprazole’s label, although the warning is less severe and acknowledges that the studies used as the basis for the warning did not include aripiprazole and that aripiprazole may not, in fact, increase the risk of hyperglycemia-related adverse events. Although there have been no published reports of psychosis worsening with aripiprazole, several case studies have been noted. Furthermore, in a trial comparing aripiprazole, risperidone, and placebo, the most common adverse event that led to the discontinuation of medication was psychosis (5% in the aripiprazole 30 mg group, 10% in the aripiprazole 20 mg group, 5% in the risperidone group, and 8% in the placebo group). Researchers hypothesize that aripiprazole might exacerbate psychosis because of its partial dopamine agonist properties. Further research is needed to clarify any potential association.