Psychiatric Annals

ASCP SPEAKS OUT 

The New Antipsychotics and Their Therapeutic Potential

Paul E Keck, JR, MD; Susan L McElroy, MD

Abstract

Although the new atypical antipsychotic medications possess unique pharmacologic properties that distinguish them from standard antipsychotics, there have substantial pharmacologic and clinical differences. This review of olanzapine (Zyprexa, Lilly), sertindole (Serlect, Abbott), quetiapine (Seroquel, Zeneca), and ziprasidone (Pfizer) presents and discusses those differences with respect to their use in the treatment of schizophrenia and other psychotic disorders.

Information was drawn from a MedLine search of the published literature and from a BIOSIS Preview search of the abstracts from recent national and international psychiatric and psychopharmacologic meetings.

In the treatment of patients with schizophrenia, it is likely that all four medications covered in this article will represent an advantage over standard antipsychotics because, thus far, they appear to be comparably effective in the treatment of psychosis while having a low risk of both extrapyramidal side effects and elevation of serum prolactin concentrations. The more favorable side-effect profiles of these new agents may lead to improved compliance and better outcome.

Overall, the availability of olanzapine, sertindole, quetiapine, and ziprasidone should provide substantial therapeutic advances in the treatment of patients with schizophrenia. Much remains to be learned about these agents in clinical practice.

For over 40 years, standard antipsychotic agents (eg, chlorpromazine, haloperidol, fluphenazine, and others) have been the mainstay of treatment for patients with schizophrenia.1 These compounds, which are derived from a number of different chemical classes, are primarily effective in ameliorating the positive (overt) symptoms of psychosis (delusions, formal thought disorder, and hallucinations).2 However, these agents also share a number of limitations, including lack of efficacy in 30% to 40% of patients with schizophrenia,3,4 lack of efficacy in the treatment of negative (deficit) symptoms of psychosis (avolition, affective flattening, alogia),2 and troublesome neurological and other side effects. Standard antipsychotics may also produce secondary negative symptoms such as physical and psychic bradykinesia.5 In addition, there are no data indicating that the efficacy for any one drug or class of compounds is superior to any other.

Investigations into the mechanism of action of standard antipsychotics suggest that dopamine (DA) D2 receptor blockade in the mesolimbic system and depolarization blockade of ventral segmental dopamine neurotransmission account for their antipsychotic activity.6,7 Similarly, D2 blockade in the nigrostriatal dopamine system appears to account for the extrapyramidal side effects (EPS) associated with these medications.1 However, these pharmacologic actions are insufficient to account for their wide variation in efficacy and onset of action in patients with schizophrenia,8 their propensity for causing tardive dyskinesia with protracted exposure, or their lack of efficacy in treating negative symptoms, and, at times, exacerbating them.5 It was originally thought that the therapeutic and extrapyramidal effects of standard antipsychotics were inextricably linked by the nonspecific D2 receptor blockade in both brain dopamine systems.9 However, a few antipsychotics, eg, clozapine, produced lower rates of EPS while retaining antipsychotic activity. This difference in EPS liability led to the conceptualization of antipsychotics as being either typical (producing EPS) or atypical (producing minimal to no EPS).9

Table

The most common side effects that occurred significantly more frequently with sertindole than with placebo in short-term, placebo-controlled studies included nasal congestion, decreased ejaculatory volume, dry mouth, and dizziness. Rates of EPS-associated with sertindole at all dose ranges did not differ significantly from placebo but were significantly lower than those associated with haloperidol.

Turning to laboratory measures of safety, there was no significant difference in prolactin elevation between patients receiving sertindole and placebo. Hematologic data did not reveal any adverse effects related to sertindole treatment. In a small number of patients, sertindole was associated with mild, transient hepatic transaminase elevations that were not associated with clinical signs or symptoms or with…

Although the new atypical antipsychotic medications possess unique pharmacologic properties that distinguish them from standard antipsychotics, there have substantial pharmacologic and clinical differences. This review of olanzapine (Zyprexa, Lilly), sertindole (Serlect, Abbott), quetiapine (Seroquel, Zeneca), and ziprasidone (Pfizer) presents and discusses those differences with respect to their use in the treatment of schizophrenia and other psychotic disorders.

Information was drawn from a MedLine search of the published literature and from a BIOSIS Preview search of the abstracts from recent national and international psychiatric and psychopharmacologic meetings.

In the treatment of patients with schizophrenia, it is likely that all four medications covered in this article will represent an advantage over standard antipsychotics because, thus far, they appear to be comparably effective in the treatment of psychosis while having a low risk of both extrapyramidal side effects and elevation of serum prolactin concentrations. The more favorable side-effect profiles of these new agents may lead to improved compliance and better outcome.

Overall, the availability of olanzapine, sertindole, quetiapine, and ziprasidone should provide substantial therapeutic advances in the treatment of patients with schizophrenia. Much remains to be learned about these agents in clinical practice.

For over 40 years, standard antipsychotic agents (eg, chlorpromazine, haloperidol, fluphenazine, and others) have been the mainstay of treatment for patients with schizophrenia.1 These compounds, which are derived from a number of different chemical classes, are primarily effective in ameliorating the positive (overt) symptoms of psychosis (delusions, formal thought disorder, and hallucinations).2 However, these agents also share a number of limitations, including lack of efficacy in 30% to 40% of patients with schizophrenia,3,4 lack of efficacy in the treatment of negative (deficit) symptoms of psychosis (avolition, affective flattening, alogia),2 and troublesome neurological and other side effects. Standard antipsychotics may also produce secondary negative symptoms such as physical and psychic bradykinesia.5 In addition, there are no data indicating that the efficacy for any one drug or class of compounds is superior to any other.

Investigations into the mechanism of action of standard antipsychotics suggest that dopamine (DA) D2 receptor blockade in the mesolimbic system and depolarization blockade of ventral segmental dopamine neurotransmission account for their antipsychotic activity.6,7 Similarly, D2 blockade in the nigrostriatal dopamine system appears to account for the extrapyramidal side effects (EPS) associated with these medications.1 However, these pharmacologic actions are insufficient to account for their wide variation in efficacy and onset of action in patients with schizophrenia,8 their propensity for causing tardive dyskinesia with protracted exposure, or their lack of efficacy in treating negative symptoms, and, at times, exacerbating them.5 It was originally thought that the therapeutic and extrapyramidal effects of standard antipsychotics were inextricably linked by the nonspecific D2 receptor blockade in both brain dopamine systems.9 However, a few antipsychotics, eg, clozapine, produced lower rates of EPS while retaining antipsychotic activity. This difference in EPS liability led to the conceptualization of antipsychotics as being either typical (producing EPS) or atypical (producing minimal to no EPS).9

Table

TABLE 1Selected Differences in Neurotransmitter Interactions Between Clozapine and Standard Antipsychotics

TABLE 1

Selected Differences in Neurotransmitter Interactions Between Clozapine and Standard Antipsychotics

In patients with treatment-resistant schizophrenia, the prototypic atypical antipsychotic, clozapine, was found not only to differ from standard antipsychotics in producing little EPS, but also to be more effective than the standard antipsychotic, chlorpromazine, in reducing both positive and negative symptoms.10 Prolactin elevations also did not occur with clozapine use.10,11 Thus, the term "atypical" has subsequently been used to describe antipsychotic drugs that differ from standard agents in exerting antipsychotic activity at doses below those producing EPS; selectively interacting with mesolimbic over nigrostriatal dopamine pathways; interacting with different subtypes of DA and other neurotransmitter receptors (eg, subtypes of serotonin and glutamate receptors); producing fewer neurologic and endocrinologie side effects; exerting beneficial effects on negative symptoms; and/or possessing efficacy in patients with treatmentresistant schizophrenia.9*12

Recognition that these "atypical" features of clozapine were associated with a number of therapeutic advantages over available standard antipsychotics encouraged the search for new medications with a similar mechanism of action but devoid of clozapine's side effects (eg, sedation, hypotension, lowering of seizure threshold, and agranulocytosis).13,14 The development of such compounds has proved far from simple, however, in part because of the broad pharmacologic profile of clozapine. For example, clozapine has an affinity for a wide range of neurotransmitter receptors including, but not limited to, D1, D2, D4, 5-HT2, histamine H1, alpha-noradrenergic, and muscarinic receptors.15"17 Although it remains unclear which of these interactions or their combination confers clozapine's unique therapeutic properties, speculation has focused on a number of these actions as being potentially critical in underlying clozapine's unique properties. These differences in neurotransmitter receptor interactions between clozapine and standard antipsychotics are summarized in Table 1. First, although similar to other lowpotency standard antipsychotics in binding weakly to D2 receptors, clozapine differs from standard agents in binding to both D1 and D2 receptors with a similar affinity.18,19 Second, clozapine displays an especially high affinity for the D4 receptor, which is localized to cortical brain regions.20 Other available antipsychotics also share a high affinity for D4 receptors, but only clozapine possesses the combination of high D4 and low D2 binding.20 Third, one of the first recognized pharmacologic differences between clozapine and standard agents is clozapine's high affinity for serotonin receptors, including the 5-HT2 subtype.13 The combination of potent 5-HT2 blockade and relatively weak D2 antagonism, in particular, has been hypothesized to account for clozapine's lack of EPS and beneficial effect on negative symptoms.12,21 Blockade of 5-HT2 receptors may also confer thymoleptic activity.22,23 Fourth, clozapine's affinity for the M1 muscarinic receptor has also been proposed as a mechanism contributing to its atypical profile.24 Finally, noradrenergic receptor binding activity may also be relevant to clozapine's therapeutic actions. Clozapine differs from standard agents in its relatively potent affinity for alpha2 receptors, a mechanism that may confer antipsychotic and thymoleptic activity.25 Although clozapine does not differ from standard agents in its affinity for alphat receptors, antagonism at this receptor has also been hypothesized to exert antipsychotic effects.26

Risperidone, like clozapine, has a receptor binding affinity for both dopaminergic and serotonergic systems.27 However, risperidone is a more potent D2 and 5-HT2 antagonist than clozapine. Risperidone's dual D2 and 5-HT2 antagonism presumably accounts for the low incidence of EPS at doses *s6 to 8 mg/day.28 Unlike clozapine, risperidone causes elevation of serum prolactin concentrations,29 and it has yet to be proven definitively superior to standard agents in alleviating negative symptoms or in patients with treatment-resistant psychosis.30

The limitations of standard antipsychotics coupled with the therapeutic advantages of clozapine, in particular, and risperidone have fostered research into the development of new antipsychotics with greater efficacy and fewer side effects. Four new medications - olanzapine, sertindole, quetiapine, and ziprasidone - are expected to be available soon for clinical use in the United States. These agents join clozapine and risperidone in possessing unique pharmacologic properties that distinguish them from standard antipsychotics. Although the term "atypical antipsychotic" has been applied to these medications, there are substantial pharmacologic differences between them. These differences are important to understand because they may reflect differences in their therapeutic properties and side effects. The pharmacologic profiles and the available clinical data regarding the efficacy and safety of olanzapine, sertindole, quetiapine, and ziprasidone in the treatment of patients with schizophrenia and other psychotic disorders are reviewed below. In particular, we reviewed evidence regarding the efficacy of these agents in the treatment of positive and negative symptoms of psychosis, their likelihood of having a lower risk of EPS and other side effects, and their potential use in other disorders. It is important to note that the results of many studies have been reported only in abstract form at scientific meetings and have not yet been published in peer-reviewed journals.

Olanzapine

Olanzapine, a theinobenzodiazepine, has a high affinity for a number of different neurotransmitter receptors, binding potently to D1, D2, D4, 5-HT2, alphalf M1, and H1 receptors.31"34 This binding profile is very similar to that of clozapine, although olanzapine has somewhat higher affinity at all receptors except for alpha sites.32"34 This binding profile suggests that olanzapine will be less likely than clozapine to produce sedation and hypotension, side effects mediated by alpha blockade.18 Olanzapine also resembles clozapine in binding to 5-HT2 receptors more potently than to D2 receptors and in having a comparable binding affinity for the D1 and D2 receptors.32"34 The plasma elimination half-life of olanzapine is approximately 31 hours.

The results of one open-label35 and four double-blind, placebo-controlled, randomized trials36"39 of olanzapine in the treatment of patients with schizophrenia, schizophreniform, and schizoaffective disorder have been reported to date. The results of the controlled studies are summarized in Table 2. Data from these studies reveal a number of interesting findings. Regarding efficacy, the use of olanzapine at doses of 10 mg ± 2.5 mg/day or greater was superior to placebo and comparable in efficacy to haloperidol use in reducing positive symptoms of psychosis.36"39 In one study,38 patients receiving 12.5 to 17.5 mg/day of olanzapine displayed improvement in positive symptoms that was superior to that of the haloperidol (10 to 20 mg/day) group. Three controlled trials36,38,39 compared olanzapine at several dosage ranges to haloperidol in the reduction of negative symptoms. In all three studies, patients in the treatment groups given the higher dose range of olanzapine (10 to 20 mg/day) scored significantly better than patients in the haloperidol treatment group (10 to 20 mg/day). One of the studies was restricted to patients with firstepisode psychosis.40 Olanzapine was superior to haloperidol in the reduction of Brief Psychiatric Rating Scale (BPRS) total scores, BPRS negative scores, and Positive and Negative Syndrome Scale (PANSS) total scores.40 A recent head-to-head study of olanzapine and risperidone has shown numerically superior changes in positive and negative symptoms in favor of olanzapine.41

Turning to safety measures in these studies, olanzapine was generally well tolerated. Side effects occurring significantly more frequently with olanzapine than placebo were somnolence, dizziness (not correlated to postural hypotension), weight gain, and constipation. Importantly, rates of EPS and dystonias associated with olanzapine did not differ significantly from placebo but were significantly lower than those associated with haloperidol. Regarding laboratory measures, prolactin elevations were minimal in patients receiving olanzapine compared with patients receiving placebo,35"37 and significantly lower than those associated with haloperidol.36,38,39 Hematologic data did not reveal any adverse effects related to olanzapine therapy. Olanzapine was associated with a dose-dependent elevation in hepatic transaminase concentrations. These elevations were greater than those observed with haloperidol. However, the incidence of these elevations approximated those observed with clozapine and other antipsychotics in other studies.42,43

One controlled trial specifically examined the efficacy of olanzapine in the treatment of 300 patients with schizoaffective disorder (DSM-IIIR).44 In this study, olanzapine-treated patients with schizoaffective disorder (bipolar type) displayed significantly greater improvement in BPRS total, PANSS total, PANSS negative, Clinical Global Impressions (CGI) Severity of Illness, and Montgomery-Asburg Depression Rating Scale (MADRS) total scores from baseline to endpoint compared with the haloperidol-treated group. In patients with schizoaffective disorder (depressed type), the mean improvement on these same measures with olanzapine was significantly greater than in the haloperidoltreated group, but the magnitude of the difference was less robust than in the bipolar subtype. Because a large body of data from open trials suggests that clozapine exerts not only antipsychotic but also thymoleptic or mood-stabilizing effects in patients with schizoaffective disorder and treatment-resistant bipolar disorder, these findings have intriguing implications.23

Table

TABLE 2Efficacy and Safety of Olanzapine in Double-Blind, Randomized Trials

TABLE 2

Efficacy and Safety of Olanzapine in Double-Blind, Randomized Trials

Table

TABLE 3Efficacy and Safejyfl~ertindole in Double-Blind, Randomized Trials

TABLE 3

Efficacy and Safejyfl~ertindole in Double-Blind, Randomized Trials

Because schizophrenia is a chronic illness requiring maintenance and acute antipsychotic treatment,45 data regarding long-term olanzapine use are also of clinical importance.

Although no controlled trials of maintenance olanzapine treatment have been completed to date, one investigation46 has provided data from a double-blind extension study of 95 patients initially treated in an acute-phase, Qweek trial.36 Significantly more patients (44%) receiving olanzapine (12.5 to 17.5 mg/day) completed 1 year of treatment than patients receiving haloperidol (11%) or placebo (13%). Furthermore, survival analysis of relapse prevention indicated that a significantly greater proportion of patients treated with olanzapine (2.5 to 7.5 mg/day; 12.5 to 17.5 mg/day)- 91% and 88%, respectively - did not experience a relapse at any time, compared with patients in the placebo group (38%).

In a second double-blind extension study following an acute-phase trial,47 a survival analysis of time to relapse demonstrated that significantly fewer patients receiving olanzapine experienced relapse at any time over 1 year than did patients receiving haloperidol. Overall, no relapse occurred in 81% of patients receiving olanzapine compared with 72% of patients receiving haloperidol.

Because maintenance treatment with standard antipsychotics involves a risk of tardive dyskinesia,48 the incidence of such symptoms associated with olanzapine is of clinical importance. Cumulative data from long-term (1year) double-blind extension studies comparing haloperidol and olanzapine indicate the incidence of treatment-emergent dyskinetic symptoms associated with olanzapine is significantly lower than with haloperidol.48 Of 977 patients treated in the combined long-term studies, 65 (8.5%) of 763 patients receiving olanzapine displayed treatment-emergent dyskinetic movements compared with 37 (17.3%) of 214 patients receiving haloperidoi.

Similarly, using the Abnormal Involuntary Movement Scale (AIMS), 9 (1.2%) of 763 olanzapine-treated patients and 10 (4.7%) of 214 haloperidoi -treated patients met criteria for treatment-emergent dyskinetic movements on their final two assessments. In addition to studies in patients with schizophrenia, schizoaffective disorder, and schizophreniform disorder, olanzapine has also been reported to be effective in the treatment of patients with Parkinson's disease complicated by druginduced dopamimetic psychosis (DSM-IV).49 In this open trial involving 15 non-demented patients, olanzapine produced a significant reduction in BPRS total scores after 50 days compared with baseline. Notably, neurologic symptoms did not significantly deteriorate during olanzapine therapy. Fourteen of the Parkinson patients receiving optimal olanzapine treatment were then challenged with an increase in dopamimetic medication. In these patients, neurologic symptoms and BPRS total scores improved significantly compared with scores at day 50. The results of this pilot study suggest that olanzapine, like clozapine,50 may be effective in the treatment of dopamimetic psychosis in Parkinson's disease without significant exacerbation of neurologic symptoms.

Sertindole

Sertindole, one of a class of substituted indoles, has a high affinity for D2, 5-HT2, and alpha: receptors; a low affinity for D1, alpha2, and H1, receptors; and a negligible affinity for muscarinic receptors.51,52 The plasma elimination half-life of sertindole is 72 hours. Five double-blind, placebo-controlled, randomized studies of sertindole in the acute treatment of patients with schizophrenia or schizoaffective disorder (DSM-III-R; DSM-IV) have been reported to date.5367 These studies are summarized in Table 3.

Two studies comparing multiple doses of sertindole versus placebo found sertindole, at doses greater than 16 mg/day, to be significantly superior to placebo in reducing positive and negative symptoms of psychosis.53,67 Three placebo-controlled studies compared sertindole versus haloperidol54"56; one of these studies utilized a unique seven-arm design, comparing three doses of sertindole (12, 20, and 24 mg/day), three doses of haloperidol (4, 8, and 16 mg/day), and placebo.54 In this latter study,54 all doses of sertindole and haloperidol were comparably effective in reducing positive symptoms as measured by reduction in BPRS total, PANSS total, and PANSS positive subscale scores. Sertindole 20 mg/day was significantly more effective than placebo in reducing negative symptoms as measured by the Schedule for the Assessment of Negative Symptoms (SANS) and PANSS negative subscale scores. These findings were similar to those of another study that compared 20 or 24 mg/day of sertindole with 16 mg/day of haloperidol.55 In this study,55 both agents at all doses were comparably effective in reducing positive symptoms, but only 24 mg/day of sertindole produced significant reduction in negative symptoms as compared with placebo. One study that examined lower doses of sertindole (4, 12 mg/day) found no significant difference in efficacy compared with placebo at termination.56 However, 12 mg/day of sertindole was significantly more effective than placebo in reducing psychotic symptoms as measured by the PANSS total score in previous treatment weeks. A recent European dose-ranging study comparing four doses of sertindole and one dose of haloperidol found that the sertindole 8, 16, and 24 mg dose groups and the 10 nig haloperidol group showed significant improvement in efficacy with respect to the 8 mg sertindole group.58 There was a significant reduction in negative symptom ratings for the 16 mg sertindole group with respect to the 10 mg haloperidol group.

Table

TABLE 4Efficacy and Safety_of Quetiapine in Double-Blind, Randomized Trials

TABLE 4

Efficacy and Safety_of Quetiapine in Double-Blind, Randomized Trials

Table

TABLE 5Efficacy and Safety of Ziprasidone in Double-Blind, Randomized Trials

TABLE 5

Efficacy and Safety of Ziprasidone in Double-Blind, Randomized Trials

The most common side effects that occurred significantly more frequently with sertindole than with placebo in short-term, placebo-controlled studies included nasal congestion, decreased ejaculatory volume, dry mouth, and dizziness. Rates of EPS-associated with sertindole at all dose ranges did not differ significantly from placebo but were significantly lower than those associated with haloperidol.

Turning to laboratory measures of safety, there was no significant difference in prolactin elevation between patients receiving sertindole and placebo. Hematologic data did not reveal any adverse effects related to sertindole treatment. In a small number of patients, sertindole was associated with mild, transient hepatic transaminase elevations that were not associated with clinical signs or symptoms or with other laboratory abnormalities.66 Significant increases in QT and QTc intervals in the electrocardiograms (EKGs) of patients receiving sertindole compared with placebo or haloperidol were observed in all studies.5357 There were no occurrences of ventricular tachyarrhythmias associated with these prolongations.

The efficacy of sertindole in the treatment of patients with schizoaffective disorder was assessed in one open-label study.59 A total of 402 patients received sertindole; 281 (70%) received concurrent treatment with valproate for affective symptoms. Sertindole or the combination of sertindole and valproate produced an overall reduction in the CGI of two or greater by 2 months of treatment, a degree of improvement that was sustained throughout a 1-year followup period. Because of the concurrent administration of valproate, the potential thymoleptic activity of sertindole could not be specifically assessed in this open trial.

Two open-label long-term studies (1 to 2 years) have been reported examining the safety profile of sertindole.60,61 A total of 1070 patients were enrolled in these studies, with 200 completing 1 year or more of treatment. At the end of 1 year of sertindole treatment, there was no clinically significant increase in hepatic transaminase concentrations, no increase in prolactin levels, and a low incidence of EPS (similar to that of placebo-controlled maintenance studies). Side effects were consistent with those reported during acute treatment trials and included decreased ejaculatory volume, nasal congestion, and prolonged QT and QTc intervals. Again, no episodes of tachyarrhythmia were reported. Decreased ejaculatory volume, but with unimpaired libido, erection, and orgasm, was reported by 20% of men.62 This side effect is presumed to be caused by an alphaj blockade of pulsatile contractions of the vas deferens.62 There are no studies to our knowledge of sertindole in the treatment of dopamimetic psychosis in patients with Parkinson's disease, nor are data yet available regarding the incidence of treatment-emergent dyskinetic movements in patients treated with sertindole.

Quetiapine

Quetiapine, a dibenzothiazepine, has a high binding affinity for 5-HT2, alphaj, alpha2, and H1, receptors; a moderate affinity for D2 receptors; a low affinity for D, receptors; and, a negligible affinity for M1 receptors.63 The plasma elimination half-life of quetiapine is approximately 7 hours. To date, the efficacy and safety of quetiapine in the treatment of acute exacerbations of chronic and subchronic schizophrenia, schizoaffective disorder, and other psychotic disorders have been evaluated in one open-label64; four randomized, double-blind, placebocontrolled65'68; one low dose-controlled69; and two active-controlled studies.68,70 Results from controlled trials are summarized in Table 4. In all four of the placebo-controlled65"68 and in the subtherapeutic-therapeutic quetiapine study (also placebo-controlled),67 quetiapine was superior to placebo in reducing positive symptoms of psychosis. In one study,66 significant differences in favor of quetiapine over placebo were evident at weeks 2, 4, and 5 of treatment and were marginally significant at endpoint (week 6). In studies in which quetiapine was compared with a standard antipsychotic,67,68 both agents produced comparable reductions in positive symptoms. Dose response data suggest that quetiapine was effective in treating psychoses at a range of doses from 150 mg/day to 750 mg/day,68 and that twice-daily dosing is as effective as three-times daily dosing.69 Four studies65"68 also revealed superiority for quetiapine over placebo or subtherapeutic doses of quetiapine in the treatment of negative symptoms. However, quetiapine has not yet been demonstrated to have superior efficacy over standard antipsychotics in the treatment of negative symptoms.68,70 Further comparison studies with other antipsychotics are necessary to clarify whether quetiapine may have superior efficacy compared with standard antipsychotics.71

Regarding safety measures, quetiapine was generally well tolerated. The most commonly reported side effects, which usually occurred early in treatment during dose titration, were agitation, somnolence, headache, and insomnia71; weight gain also occurred significantly more frequently in quetiapine-treated patients than in patients receiving placebo.71 The incidence of EPS and akathisia was not significantly different in quetiapine-treated patients compared with those receiving placebo. The incidence of EPS among patients on quetiapine in the multiple fixed-dose study68 was no different than placebo across the entire dose range. Further, rates of EPS were significantly higher in patients receiving haloperidol than in patients treated with quetiapine.68 Mild, transient, reversible hepatic transaminase elevation was also associated with quetiapine treatment but was no more frequent than that associated with standard agents.68,70 In most patients, hepatic transaminase levels returned to normal ranges despite continued treatment. There were no significant hematologic or electrocardiographic abnormalities associated with quetiapine.71

Finally, quetiapine did not produce elevations in prolactin in patients treated for up to 6 weeks.72 Further, in the multiple fixed-dose study,68 there was no difference between quetiapine and placebo plasma prolactin levels across the entire dose range. In fact, in most studies, prolactin concentrations significantly decreased in patients receiving quetiapine.72

Ziprasidone

Ziprasidone, a benzisothiazolyl piperazine, has a high affinity for 5-HT2 and D2 receptors; a moderate affinity for H1 and alphaj receptors; and little affinity for D1, alpha2, and M1 receptors.73 Ziprasidone also has moderate potency for inhibiting serotonin and norepinephrine reuptake.73 The plasma elimination half-life of ziprasidone is approximately 5 hours.

Three double-blind, placebo-controlled, randomized studies of ziprasidone in the acute treatment of patients with schizophrenia or schizoaffective disorder have been reported to date.74"76 These studies are summarized in Table 5. The results of these studies indicate that ziprasidone, at doses of 80 mg/day or greater, is superior to placebo in reducing the positive and negative symptoms of psychosis,76 and, at 160 mg/day, is comparable with haloperidol in reducing positive symptoms of psychosis.76 However, ziprasidone has not yet been demonstrated to have superior efficacy over standard antipsychotics in the treatment of negative symptoms. Ziprasidone was remarkably well tolerated. In one study, there were no notable differences in the number of treatment-emergent adverse effects, laboratory abnormalities, or serious adverse events between ziprasidone at both doses and placebo except for agitation, which occurred more commonly in patients receiving placebo.75 Similarly, there were no notable treatment differences for EPS, akathisia, abnormal movements, or sedation in this study. Side effects associated with ziprasidone in other studies74"76 include somnolence, nausea, and constipation. Measures of prolactin levels have not been reported. No significant hematologic, hepatic, or electrocardiographic abnormalities have been reported in association with ziprasidone treatment to date. There are no data currently available regarding the long-term safety of ziprasidone, or separate analysis of its efficacy in patients with schizoaffective disorder.

DISCUSSiON

The results of clinical trials reported to date of olanzapine, sertindole, quetiapine, and ziprasidone reveal a number of encouraging findings. First, all four agents were effective in ameliorating positive symptoms of psychosis in patients with schizophrenia. Second, these agents were well tolerated and produce minimal to no EPS. Third, all four medications displayed little to no perturbation of plasma prolactin concentrations. Fourth, no significant adverse hematologic effects have been associated with these agents.

Some preliminary differences between these agents are apparent thus far. Although all four agents reduced negative symptoms compared with placebo, only olanzapine has been found to be superior in comparison to standard antipsychotics in reducing negative symptoms.36,38,39 This is an important distinction because the reduction in negative symptoms by these agents compared with placebo may be, in part, attributable to a reduction in EPS shared by all four compounds. Nevertheless, trends toward greater improvement in negative symptoms were associated with sertindole, quetiapine, and ziprasidone compared with standard antipsychotic controls.

Not surprisingly, there are other pharmacologic differences between these medications. First, the elimination half-lives differ between agents, with ziprasidone and quetiapine having the shortest half-lives (approximately 5 and 7 hours, respectively), and olanzapine and sertindole having the longest (31 and 72 hours, respectively). This suggests that once-daily dosing will be most appropriate for olanzapine and sertindole and, unless proven otherwise by further research, that twice - daily dosing will be indicated for most patients treated with quetiapine and ziprasidone.71 Second, there are differences in side effects between these medications. For olanzapine, somnolence, dizziness, constipation, weight gain, and mild, transient dose-related elevation in hepatic transaminase concentrations were the most commonly reported side effects.36" 39,44 Weight gain was also associated with sertindole and quetiapine.03,55'66-68 Other side effects associated with sertindole included nasal congestion, decreased ejaculatory volume, dizziness, dry mouth, and prolonged QT and QTc intervals, at times associated with increased heart rate.53-55 Thus far, no tachyarrhythmias have been reported in association with these sertindole-related cardiac conduction delays.5355 Side effects associated with quetiapine include somnolence, agitation, insomnia, headache, and mild, transient increases in hepatic transaminase concentrations.66,67,70 In studies reported to date, ziprasidone has been well tolerated. Side effects associated with ziprasidone include somnolence, nausea, and constipation.

In the treatment of patients with schizophrenia, it is likely that all four of these medications will represent an advantage over standard antipsychotics because, thus far, they appear to be comparably effective in the treatment of psychosis but have a low risk of EPS and elevation of serum prolactin concentrations. Because neurologic side effects are a common reason for noncompliance in patients with schizophrenia,77,78 and noncompliance is a major cause of relapse, the more favorable side effect profiles of these new agents may lead to improved compliance and better outcome. Further studies are needed to convincingly demonstrate their superiority over standard agents in the treatment of negative symptoms, although in three studies, 36,38,39 olanzapine 15 ±2.5 mg/day was superior to haloperidol. To date, none of these agents has been systematically studied in patients with treatment-refraetory psychosis. Such studies are greatly needed. Also unknown is whether the low rates of EPS associated with these agents will also be linked to lower rates of tardive (treatmentemergent) dyskinesia. Thus far, preliminary data for olanzapine are encouraging in this regard,47 but further long-term studies of the risk of tardive dyskinesia associated with all four agents are needed.

These agents also have potential treatment applications to other psychiatric disorders. A large number of open trials suggests that clozapine is a useful alternative in patients with treatment-refractory schizoaffective disorder and bipolar disorder.23,79-81 These studies also suggest that clozapine may possess not only antipsychotic but also thymoleptic activity. Thus far, patients with schizoaffective disorder have been treated in double-blind, randomized, placebo-controlled trials of olanzapine,39,44 sertindole,57,59 and ziprasidone.75,76 However, specific analysis of the response of both psychotic and affective symptoms has been conducted only for olanzapine44 to date. In this study,44 olanzapine, like clozapine, appeared to produce beneficial effects on both psychotic and affective symptoms. None of these agents has been examined to date in the treatment of psychotic mania in patients with bipolar disorder or in the treatment of psychotic depression.

Only olanzapine (in an open-label trial) has been studied in the treatment of dopamimetic psychosis in patients with Parkinson's disease.49 Again, like clozapine, olanzapine appeared to exert antipsychotic effects without significant exacerbation of Parkinson's disease. Further controlled studies of all four agents are needed in such patients.

CONCLUSIONS

Overall, the availability of olanzapine, sertindole, quetiapine, and ziprasidone should provide substantial therapeutic advances in the treatment of patients with schizophrenia. Much remains to be learned about these agents in clinical practice.

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TABLE 1

Selected Differences in Neurotransmitter Interactions Between Clozapine and Standard Antipsychotics

TABLE 2

Efficacy and Safety of Olanzapine in Double-Blind, Randomized Trials

TABLE 3

Efficacy and Safejyfl~ertindole in Double-Blind, Randomized Trials

TABLE 4

Efficacy and Safety_of Quetiapine in Double-Blind, Randomized Trials

TABLE 5

Efficacy and Safety of Ziprasidone in Double-Blind, Randomized Trials

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