Atypical Antipsychotics

Original Author: Paul Perry, Ph.D, BCPP
Latest Revisers: Paul Perry, Ph.D, BCPP, Brian C. Lund, Pharm.D.
Creation Date: 1996
Last Revision Date: October 2002
Peer Review Status: Internally Peer Reviewed

ATYPICAL PHARMACOLOGY

What makes an antipsychotic atypical?

The pharmacologic properties of clozapine differ in a number of ways from the typical antipsychotics. In addition to dopamine D2 antagonism, clozapine exhibits serotonergic antagonism and is therefore referred to as a serotonin-dopamine antagonist (SDA). Clozapine also differs from typical agents in several clinical aspects including (1) minimal, if any extrapyramidal side effects (EPSE), (2) essentially no tardive dyskinesia (TD), (3) minimal, if any increases in prolactin, (4) negative symptom efficacy, and (5) efficacy in treatment refractory populations (Stahl 1999). The newer atypical antipsychotics match these prototypical characteristics to a varying extent, which is summarized in Table 1. As shown in this table, none of the newer atypical agents fully match the clozapine prototype. The minimal definition for an atypical antipsychotic is therefore dual antagonism of serotonin 5-HT_2A and dopamine D2 and reduced propensity for EPSE (Stahl 1999).

Table 1. Characteristics of the atypical antipsychotics (adapted from Stahl 1999)
	Clozapine	Risperidone	Olanzapine	Quetiapine
Serotonin-dopamine antagonist	Yes	Yes	Yes	Yes
EPSE fewer than haloperidol	Yes	Yes	Yes	Yes
Patients essentially never get EPSE	Yes	No	Yes/No	Yes/No
Incidence of tardive dyskinesia less than typicals	Yes	Yes	Yes	Probably
Patients essentially never get tardive dyskinesia	Yes	No	No	No
Prolactin increase less than with haloperidol	Yes	No	Yes	Yes
Prolactin essentially never increases	Yes	No	No	Yes
Negative symptoms treated better than > 15 mg haloperidol	Yes	Yes	Yes	No
Effective in treatment-refractory populations	Yes	Maybe	Maybe	Unknown

Receptors and antipsychotic effects

It is well known that central serotonin agonists such as LSD and MCPP, as well as dopamine agonists such as amphetamine and cocaine, are capable of producing psychotic reactions (Huttunen 1995). On the other hand, ritanserin is a highly selective 5HT2A antagonist. Reyntgens et al (1986) administered ritanserin to schizophrenics and decreased the severity of their EPSE. Duinkerke et al (1993) administered ritanserin to schizophrenics who were receiving non-sedating antipsychotics such as haloperidol, fluphenazine and trifluoperazine. Negative symptoms showed significant improvement. Finally, Wiesel et al (1994) administered ritanserin 20 mg as monotherapy to acutely ill schizophrenics who were not receiving any antipsychotics. The ritanserin alone was able to produce significant improvement in both positive and negative symptoms. Thus, SDAs seem to be logical candidates for antipsychotic activity.

Figures 1 and 2 contrast the differing effects of the conventional antipsychotics and the SDA antipsychotics on the limbic and striatal areas of the brain. For the conventional antipsychotics, the antagonism of dopamine in the mesolimbic system relieves the positive symptoms of schizophrenia but at the same time, the blockade of transmission in the nigrostriatal system causes EPSE. Likewise for the SDAs, antagonism of dopamine in the mesolimbic system relieves the positive symptoms of schizophrenia. However, the dopamine (D2) blockade in the nigrostriatal system is inhibited by increased release of dopamine secondary to serotonin (5HT2) blockade in this area (Huttunen 1995). Additionally, serotonin (5HT2A) antagonism and reversal of the dopamine deficiency in the mesocortical tracts and mesolimbic tracts can result in improvement of the negative and positive symptoms of schizophrenia (Stahl 2000). Further, serotonin blockade prevents dopamine from increasing prolactin levels thereby relieving patients of the adverse effects of galactorrhea, amenorrhea, and gynecomastia (Stahl 2000).

Figure 1. Hypothetical mechanism of action of conventional neuroleptics.

Figure 2. Hypothetical mechanism of action of SDA neuroleptics.

Receptors and adverse effects

In addition to the serotonergic and dopaminergic systems, the atypical antipsychotics exhibit varying degrees of adrenergic, histamine, and acetylcholine receptor blockade (Meltzer et al 1989, Meltzer 1991). Table 2 presents a description of the relative receptor affinities of the atypical antipsychotics in contrast to the typical antipsychotic haloperidol (Bymaster et al 1996, Richelson 1999). Binding affinities to certain types of receptors have been associated with clinical effects, both intended (i.e. antipsychotic activity) and unintended (i.e. adverse effects). It is suggested that clozapine's low affinity for D2 receptors and high affinity for 5-HT2 receptors producing a high 5-HT/D2 ratio, is responsible for its' improved efficacy and decreased rate of extrapyramidal side effects (Meltzer et al 1991). Additionally, the intrinsic anticholinergic activity (M1) of clozapine and olanzapine may further reduce EPSE risk. However, the inhibition of muscarinic receptors can lead to cognitive impairment and confusion. Hypotension and sedation are probably related to the inhibition of a1 receptors and histamine (H1) receptors, respectively. There is also growing concern regarding weight gain with the atypical antipsychotics. This effect has been correlated with both 5HT2C and H1 activity. More detailed information regarding the specific adverse effects of the various atypicals can be found in the individual monographs.

Table 2. In vivo receptor binding affinities of the atypical antipsychotics and haloperidol (Ki - nM). Adapted from Bymaster et al 1996 and Richelson 1999.
Receptor*	Haloperidol	Clozapine	Risperidone	Olanzapine	Quetiapine
D2 (antipsychotic/EPSE)	1	125	3	11	160
5HT2A (anti-EPSE)	78	12	0.6	4	220
5HT2C (weight gain)	3085	8	26	11	615
a1 (sedation, hypotension)	46	7	2	19	7
H1 (sedation, weight gain)	3630	6	155	7	11
M1 (anti-EPSE, confusion)	1475	1.9	--	1.9	120
*D = dopamine, 5HT = serotonin, a = alpha adrenergic, H = histamine, M = muscarine

ATYPICALS AND NEGATIVE SYMPTOMS

The negative symptoms of schizophrenia include the spectrum of impoverished affect, alogia, avolition, anhedonia, and decreased attention. The ability of typical antipsychotics to improve negative symptoms is controversial. Early studies (Johnstone et al 1979, Angrist et al 1980) found that negative symptoms were resistant to treatment, though some more recent studies suggest a modest beneficial effect depending on the dose (Meltzer et al 1986, Coryell et al 1990). In contrast, atypical antipsychotics may yield specific improvements in negative symptoms.

Negative symptoms are often classified as primary and secondary negative symptoms. Secondary negative symptoms are those that can be attributed to psychosis, dysphoria, and antipsychotic ADRs. Thus it is expected that drugs that improve psychosis, reduce dysphoria, and have fewer ADRs (such as the atypical antipsychotics) could improve negative symptoms through a secondary mechanism. However, whether these drugs actually improve primary negative symptoms remains unknown. Clinical trials with risperidone demonstrate this confusion. The Canadian data of the North American study compared risperidone doses of 2, 6, 10 and 16 mg/d to haloperidol 20 mg/d and placebo. The authors concluded that only risperidone 6 mg/d was superior to haloperidol 20 mg/d in improving negative symptoms (Chouinard et al 1993). In contrast, the 15-country European study of 1,362 patients comparing the same risperidone doses to haloperidol 10 mg/d was not able to detect a significant difference in negative symptom response (Muller-Spahn et al 1992). These studies suggest that negative symptom efficacy, at least with risperidone, is explained by reduced EPSE liability. A meta-analysis of the seven studies investigating haloperidol concentration and therapeutic effect concluded that the optimum therapeutic response for haloperidol was achieved by dosing patients within a range of 5-18 ng/ml (Perry and Smith 1992). These data suggest that the negative symptom advantage of the atypical could be an artifact resulting from using too large a typical antipsychotic dose in the efficacy studies. It may well be that the effect on negative symptoms between haloperidol and the SDA antipsychotics is not significantly different if the haloperidol patients are all prospectively dosed into the therapeutic range of 5-18 ng/ml. A more recent study determined that the optimum haloperidol blood level to reduce negative symptoms was between 18-25 ng/ml (Coryell et al 1998). Levels outside of this range had nearly no effect on negative symptoms.

A more recent analysis of olanzapine treatment studies revisited the issue of atypical antipsychotics and primary negative symptoms (Tollefson and Sanger 1997). This study used a path analytic approach to analyze data from the HGAD olanzapine versus haloperidol and placebo trial (Beasley et al 1996). Briefly, this analysis found the difference in SANS change scores between high-dose olanzapine (12.5-17.5 mg/d) and haloperidol was 84% due to a primary negative symptom effect while 13% of the improvement was explained by changes in EPSE, psychosis, and depressive symptoms.

INTRODUCTION

Synthesized in 1960, clozapine (Clozaril‚) is a member of the dibenzodiazepine class of antipsychotics. The drug has a pharmacologic profile unlike standard antipsychotics and is labeled as an atypical antipsychotic. US marketing began in February 1990. The drug was synthesized in 1960 and the first clinical trial was completed in 1962. Clozapine was made available in Europe for clinical use in 1975 and for research purposes in the US the same year.

PHARMACOKINETICS

Clozapine is absorbed rapidly with peak plasma concentrations occurring within 1-4 hours. The drug is widely distributed in the body. The concentrations in the blood are relatively small in comparison to the liver, gall bladder, kidney, and lungs. The terminal elimination half-life in man is in the range of 5.5 - 33 hours (Lieberman et al 1989, Sayers and Amsler 1977).

An investigation of 148 patients receiving clozapine noted the effect of smoking, sex, and age on serum drug concentration (Haring et al 1989). Plasma concentrations in males were 69% of females' levels after adjusting for weight (p<0.001). The average plasma concentration for smokers was 82% of nonsmokers' concentrations (p=0.022). Male smoking patients reached mean plasma clozapine concentrations which were only 68% of the male non-smokers (p=0.008). Clozapine concentrations approximately doubled from the age cohort of 18-26 years to 45-54 years (p<0.01). Clozapine dose and plasma concentrations were reported to be directly related. Of clozapine-induced adverse effects only orthostatic hypotension is positively correlated with clozapine plasma concentrations (Ackenheil 1989).

A clozapine concentration of > 504 ng/ml is considered therapeutic (Perry and Miller 1993). This recommended plasma concentration threshold differs from their original recommendation of > 350 ng/ml (Perry et al 1991). This is because the original recommendation was based on the non-schizophrenic specific rating scale of the BPRS. The second recommendation of > 504 ng/ml is based on the Scale for the assessment of Positive Symptoms (SAPS) and Scale for the assessment of Negative Symptoms (SANS). The Brief Psychiatric Rating Scale (BPRS) suggested a lower limit of 397 ng/ml. However, the SAPS/SANS recommendation produces somewhat better sensitivity than the BPRS. The clozapine dosing recommendation has been replicated by three other studies (Hasegawa et al 1993, Potkin et al 1994, Kronig et al 1995).

EFFICACY

All typical antipsychotics available in the US are equally effective in the treatment of schizophrenia (Kane et al 1988). It is estimated 20 to 30% of people with schizophrenia do not respond to long-term treatment with these drugs (Kane et al 1988). It is recommended patients undergo trials of at least two antipsychotics to demonstrate "refractoriness" before they are considered candidates for clozapine (Marder and VanPutten 1988). By today's standards of care this would include either a typical or an atypical or two atypical antipsychotics.

Schizophrenia - Acute vs Chronic

Of the typical antipsychotics available in the US, clozapine has been compared to chlorpromazine (Thorazine), perphenazine (Trilafon), haloperidol (Haldol), and trifluoperazine (Stelazine) (Lieberman et al 1989, Marder and Van Putten 1988). Of these 12 studies, clozapine was more effective than the comparator antipsychotic in 8 studies according to clinical and/or statistical criteria. Three studies demonstrated equal efficacy and in one, clozapine was less effective than the standard antipsychotic. The drug is only approved in the US for the treatment of patients with refractory schizophrenia.

Antipsychotic-refractory patients with schizophrenia - Short-term treatment

Kane et al (1988) reported the results of a multi-center trial of clozapine in the treatment of antipsychotic-resistant schizophrenics (DSM-III). In the first phase of the study, 319 patients were enrolled. They had not responded to three different antipsychotic drug trials at doses of chlorpromazine >1000 mg/d or its equivalent for at least six weeks. The patients also had to have a BPRS score of >45 (range 18 - 126), a CGI score >4 out of 7 and moderate severity rating on two of the following: conceptual disorganization, suspiciousness, hallucinatory behavior, and unusual thought content to qualify for the study. The patients had a drug washout period ranging from 48 hours to two weeks. Haloperidol doses ranging from 40-120 (mean 61) mg/d plus benztropine 6 mg/d for six weeks were administered. Only 5 (1.6%) of these patients were responders. The nonresponders entered the second phase. Following a drug washout period of 48 hours to two weeks, the patients (N = 268) were treated with chlorpromazine 600-1800 mg/d plus benztropine 6 mg/d or clozapine 50-900 mg/d plus placebo for six weeks. Five (3.5%) of the chlorpromazine patients responded while 38 (30%) of the clozapine patients responded (p<0.001). Clozapine was more effective than chlorpromazine in the total BPRS score. On individual items of the BPRS, clozapine was more effective in the treatment of the positive symptoms of hallucinations, conceptual disorganization, suspiciousness and unusual thought content. Additionally, it was more effective than chlorpromazine in the treatment of negative symptoms (emotional withdrawal, blunted affect, and anergia). Significant improvement favoring clozapine over chlorpromazine occurred within 1 to 2 weeks.

Miller et al (1994a) analyzed the course of improvement of the positive and negative symptoms of 29 treatment refractory schizophrenics who were treated with clozapine up to 450 mg/d for 6 weeks. It was hypothesized that a portion of clozapine's effect on negative symptoms was related to improvement in positive (psychotic and disorganization) symptoms, a decrease in EPSE, and/or a decrease in depressive symptoms. Using the SANS to rate the patients' negative symptoms of affective flattening, anhedonia, asociality, avolition and alogia, all patients improved. Overall, there was a 31% improvement in psychotic symptoms, and a 35% improvement in disorganization according to the SAPS rating scale. The improvement in negative symptoms (SANS) correlated with the disorganization factor but not the psychotic factor on the SAPS, depression (HAM-D), or drug-induced EPSE (Simpson-Angus EPSE scale). It appears that at least a portion of clozapine's effect on core negative symptoms is mediated through a direct effect on the underlying pathophysiology of schizophrenia.

Antipsychotic-refractory patients with schizophrenia - Long-term effects

Two early Scandinavian retrospective reports of clozapine in refractory patients reported improvement ranging from 33-51% (Kuha and Mietenen 1986, Juul-Povlsen et al 1985).

Pickar et al (1992) in a double blind, placebo-controlled study treated 21 patients with schizophrenia (N=18) or schizoaffective disorder (N=3) that had failed >2 typical antipsychotic trials or had significant tardive dyskinesia or other EPSE. After discontinuation of typical antipsychotics, patients received an average fluphenazine dose of 28.9 (+/-21.2) mg/d for 45.8 (+/-15.8) days. After various time periods patients were changed to placebo for an average treatment time of 37.1 (+/-11.3) days. Clozapine was started and doses of 225 to 600 mg/d (average 373) were administered for at least 3 weeks (average 52 days). If the patient had a suboptimal response by criteria used in the Kane et al (1988) study, then doses were increased to 300 to 900 mg/d (average 542). This dose was maintained for an average of 106.5 (+/-35.1) days. Results indicated 10 (47.6%) patients responded equally to both drugs and 2 patients (9.5%) had a partial response to clozapine. However, 1 patient (4.8%) had a superior response to fluphenazine compared to clozapine, while 8 (38.1%) clozapine patients had a superior response compared to fluphenazine. Predictors of response to clozapine were a later age of onset of illness (21 vs 16 years), higher EPSE scores on typical antipsychotics, lower plasma HVA levels on clozapine, and lower HVA/5-HIAA ratios. BPRS scores in the clozapine responders decreased from an average score on typical antipsychotics of 62 to 49 on clozapine.

Mattes (1989) reported an open study of 14 patients treated with an average of 4.4 typical antipsychotics without a response before receiving clozapine. Eight of 14 patients treated for an average of 4.3 +/- 3.6 months experienced an average decrease in total BPRS score from 56 to 45. Six patients that continued to receive clozapine for 18 months had a BPRS score decrease from 52 to 39.7. It is important to note the latter group consists primarily of patients that responded or could tolerate clozapine.

Meltzer et al (1989) found that 31/51 treatment-resistant schizophrenics showed at least a 20% decrease in their BPRS scores at 10.8 +/-8.4 months (median 8.9). Of the 31 patients that improved, the improvement was first noted at 6 weeks (N=14), 3 months (N=9), 6 months (N=2), 9 months (N=5), and 12 months (N=1). This suggests a clozapine trial should be at least 3 to 6 months.

Owen et al (1989) reported in an open-label study that 50% of patients had improved significantly at 12 weeks of treatment. After 4-years of follow-up no significant further improvement in BPRS scores occurred.

Lindenmayer et al (1994) reported that improvement in positive and negative symptoms of schizophrenia at 12 weeks predicted improvement scores at 26 weeks. The authors concluded that response to clozapine could be determined at 3 months of treatment.

Cost-Benefit Analysis in schizophrenia - Effect on discharge rate/employment

The Battelle report (1989) commissioned by the manufacturer included 87 patients with schizophrenia that failed at least two typical antipsychotics. Of 64 patients that completed two years of clozapine, 64% were able to live independently yielding a cost savings of was $9,000 to $14,000 (range -$1,000 to $28,000) due to deinstitutionalization.

In a retrospective study by Lindstrom (1989) in Sweden, 96 patients with refractory schizophrenia or significant extrapyramidal side effects were treated with clozapine. At the end of one year 85% of patients were discharged from the hospital. Of those patients still receiving clozapine at two years (n=62), 24 (39%) were employed in full or part-time work. This compared to a 3% employment rate prior to clozapine.

In another open study Davies et al (1991) followed 24 patients initially evaluated as part of the Kane et al (1988) multi-center 6-week trial. Three patients never received clozapine and remained hospitalized for one year. Thirteen patients who discontinued clozapine because of inadequate therapeutic response or noncompliance also remained hospitalized at one year. However, 8 patients were still receiving clozapine at one year. Of these 8, 6 were discharged to the community and living in nonfamilial, supervised residential care facilities. Three of the 6 patients were attending school, though all were unemployed. Global assessment scores were available on 4 patients and indicated an average improvement of 44 points (on a 100-point scale).

Response predictors - Schizophrenia

Though one report suggests that the more treatment-resistant patients might respond better to clozapine (Osser 1990) as well as a later age of onset, presence of EPSE, and HVA/5-HIAA ratios (Pickar 1992), the majority of studies have been unable to identify predictors (Honigfeld 1989).

Schizoaffective disorder and psychotic mood disorders

McElroy et al (1991) reported in an open-label study that 25 patients with schizoaffective disorder and 14 with bipolar disorder with psychotic features had a better response rate (p = n.s.) than patients with schizophrenia based on final BPRS scores. In a retrospective study, it was reported that 45% of patients with schizophrenia compared to 65% of patients with schizoaffective disorder demonstrated marked or total improvement on clozapine (Naber et al 1989). A Medline search used to conduct a meta-analysis identified 315 psychotic or severe mood disorder patients treated with clozapine in either double-blind studies (n=2), open label trials (n=8), retrospective chart reviews (n=10), and case reports (n=10) (Zarate et al 1995). Ninety-four of the patients were acutely manic. Clinically significant improvement was reported in 71% (67/94) of the patients. This is not surprising since the typical antipsychotics, chlorpromazine, haloperidol, and pimozide achieved similar response rates when compared to lithium (Goodwin and Zis 1979, Chou 1991).

ADVERSE EFFECTS

Incidence

Several early studies have reported their experience with the adverse effects of clozapine (Clozapine Package Insert 1989, Kane et al 1988, Lieberman et al 1989). These are summarized in Table 3. Additionally Table 4 qualitatively contrasts the adverse effect profiles of the atypical antipsychotics to haloperidol.

Table 3. Comparison of Clozapine's Adverse Effects (%).
Adverse Effect	World-Wide	Manufacturer	US-Multicenter
	(n=13,000)	(n=842)	(n=268)
Sedation	9.0	39.0	21.0
Salivation	5.7	31.0	13.0
Tachycardia	25.0	5.3*	17.0
Dizziness/Vertigo	19.0	1.7	14.0
Constipation	1.9	14.0	16.0
Hypotension	2.2	9.0	13.0
Hyperthermia	3.3	5.0	13.0
Headache	0.86	7.0	10.0
Nausea/Vomiting	1.64	8.0	10.0
Weight Gain	0.73	0	N/R
Syncope	0.62	6.0	N/R
Seizures	0.36	3.0*	N/R
Leukopenia	0.26	3.0*	4.9
Agranulocytosis	N/R	1.0	0.0

* based on 1700 patients
N/R - Not Reported

Table 4. Adverse drug reaction profile for the atypical antipsychotics versus haloperidol.
ADR	HLP	CZP	RSP	OZP	QTP	ZPR
anticholinergic	0	+++	0	++	0	0
EPSE	+++	minimal	++	+	minimal	+
sedation	+	+++	+	++	++	++
Weight Increase	minimal	+++	++	+++	++	minimal
Orthostatic Hypotension	minimal	+++	+	+	+	+
Prolactin Increase	+++	0	++	+	0	+
HLP=haloperidol, CZP=clozapine, RSP=risperidone, OZP=olanzapine, QTP=quetiapine, ZPR=ziprazidone 0 = none, + = mild, ++ = moderate, +++ = severe

Cardiovascular

ECG. Reversible nonspecific ST-T wave changes, T wave flattening, or inversions have been infrequently reported. Sudden death has not been reported with clozapine.

Management. These effects are typically of no clinical significance.

Hypertension. This has been reported in approximately 4% of patients receiving clozapine. Blood pressure should be monitoring during the dose titration phase of clozapine dosing.

Management. Dose reduction and/or beta-blockers (i.e., atenolol) might be considered.

Hypotension/Dizziness. These side effects are primarily observed during the initiation of treatment and/or after dose escalation. The exact mechanism is unknown, but may be related to alpha-adrenergic blocking effects of clozapine. Tolerance usually develops to this effect within 3 to 4 weeks.

Management. Orthostatic blood pressure should be monitored, especially during the start of treatment and during dose titration. Dose increases may be slowed if blood pressure reductions are noted. Patients should be warned of dizziness and instructed how to arise from a lying or sitting position. The use of a liberal sodium diet and support stockings has been recommended. Although fludrocortisone (Florinef) has been suggested to benefit these patients, its use has not been extensively studied.

Syncope. Infrequent reports of a sudden loss of muscle tone without a loss of consciousness have been reported. This effect may be body-wide or limited to a specific muscle group. This effect has not been associated with auras, incontinence, or other signs of a seizure. It may be dose-related.

Management. Dose reduction should be considered. A history and work-up to rule out a seizure are also recommended. There is no specific treatment.

Tachycardia. An increase in heart rate occurs in most patients treated with clozapine. Though an increase of 20 - 25 bpm is typical, the rate may reach 120. It can occur in the supine as well as the standing position so it is not solely related to orthostatic blood pressure changes. Sometimes an orthostatic increase in pulse may occur without changes in blood pressure. The effect is dose-related and usually occurs within 7 days of initiation of treatment. Some degree of tolerance will occur to this effect in most patients; however it rarely completely reverses. It is probably related to the anticholinergic effect of the drug.

Management. If the patient is symptomatic (i.e., palpitations), dose reduction or the addition of beta-blocker with low CNS penetrability (i.e., atenolol 25 to 50 mg/d) is recommended. Blood pressure should be monitored for hypotensive effects of the combined use of atenolol and clozapine.

Pulmonary Embolism. The effects of clozapine on mortality rates were compared in 67,702 current and former users of the drug (Walker et al 1997). During 1991-1993, there were 396 deaths in 85,3999 person-years for patients ages 10-54 years. During clozapine use, there were elevations in mortality rates for less common causes of death, including pulmonary embolism. The relative risk for a pulmonary embolism during current exposure compared with past clozapine use was 5.23.

Management. Patients should be educated to discontinue the drug and contact their physician if the experience any symptoms of respiratory difficulty.

Central Nervous System

Anticholinergic

Tracy et al (1998) examined the anticholinergic burden and cognitive effects of clozapine and risperidone in 22 schizophrenics, mean age 44.7±8.4 years (range, 31-58). The Mini-Mental State Examination (MMSE) was used to assess cognitive impairment, with a score below 24 being reflective of impairment. The mean ± SD BPRS score was 38.8±8.2. Fifteen patients were taking clozapine, mean (±SD) dose was 489.3±190.5 mg/day (range 200-800 mg/day) and 7 were taking a mean dose of 4.7±2.1 risperidone. All patients had been taking stable doses for at least 30 days prior to the study and were not currently taking any other potentially anticholinergic agents. Blood samples were taken twice at two different time points. The anticholinergic assay measured the total antimuscarinic receptor binding potential in human serum and assayists were blind to the neuroleptic and the MMSE scores. The two groups differed in anticholinergic levels at both blood draw times. The anticholinergic levels in pmol/ml of atropine equivalents were 4.35 ± 2.38 for clozapine and 0.27±0.28 for risperidone for blood draw 1. There was no difference between the groups at blood draw 2, nor any difference between those done at time 1. The two groups did not differ significantly on MMSE scores. This suggests that clozapine stimulates higher human brain anticholinergic activity than risperidone, but not a difference in cognition. This study does not show a cognitive deficit that one might expect, which could be related to the tool used to assess changes in cognition. The MMSE may be too insensitive to detect anticholinergic effects. This age range was relatively young, mean age was 44.7 years. These anticholinergic drugs will have more of a deleterious effect on cognition in the elderly patients.

Delirium. Confusion or toxic delirium has been reported with clozapine (Szymanski et al 1991a). Onset occurred within 36 hours of a large initial dose (e.g., 400 mg/d) and presented with delirium. The delirium cleared within 9 hours. The patient tolerated a slightly lower dose of 300 mg/d, which was reached with gradual titration.

Management. Clozapine should be discontinued. After the delirium clears the drug may be reinstituted at a much smaller dose. Dose titration should be gradual.

Hypothermia. This mild effect occurs in 87% of patients (Safferman 1991). It is also reported with typical antipsychotics. The exact mechanism is unknown, but is believed to be a central effect.

Management. This is a benign effect that does not require any specific treatment.

Hyperthermia. Temperature elevations of 1-2 degrees F are noted within the first 5-20 days (average 10 days) of treatment in 5% of patients. The fever usually resolves within several days. The mechanism of clozapine-induced hyperthermia is unknown. The temperature increase might indicate a possible infection secondary to a leukopenia or, possibly, antipsychotic malignant syndrome (see below).

Management. Patients with hyperthermia should have a CBC and sedimentation rate done to rule out infection. They should be followed for signs of NMS. Typically, this is a benign effect that resolves without treatment or with clozapine discontinuation.

Sedation. This is a dose-related side effect, to which some degree of tolerance may develop with time in most patients and completely in some. This is probably related to clozapine's antihistaminic and antiadrenergic properties.

Management. Initiate treatment with doses of 12.5 mg once or twice daily. Increase doses by 25 - 50 mg/d, if tolerated, to a usual dose of 300 to 500 mg/d by the end of two weeks. A maximum dose of 900 mg/d is recommended, which might be accomplished within a five-week period. Administering most or the entire dose at bedtime may minimize this effect.

Seizures. A number of case reports have documented clozapine-induced tonic-clonic seizures. Clozapine related seizures were reviewed in 5,629 patients being monitored by the Clozaril Patient Management System (Pacia and Devinsky 1994). Of the 71 (1.3%) who had generalized tonic-clonic seizures, 24 (34%) of the patients had recurrent seizures. If patients with a seizure history are excluded, the percentage of patients with seizures at < 300 mg/d was 0.9%, 300-599 mg/d was 0.8%, and ³ 600 mg/d was 1.5%. Of the 37 patients who were rechallenged, 29 (78%) were able to continue the medication with dose reduction and more gradual titration, or with the addition of an antiepileptic.

Management. If a seizure occurs, clozapine should be discontinued. An EEG and neurology consult is advised. If the seizure work-up is unremarkable, then clozapine may be reintroduced at 50% of the dose at which the seizure occurred. If the work-up is abnormal and an anticonvulsant is started, clozapine maybe reinstituted after therapeutic levels of the anticonvulsant are achieved. See Drug Interaction section below.

Extrapyramidal Effects

Acute effects. Clozapine has not been associated with the usual acute extrapyramidal effects (e.g., dystonia, drug-induced parkinsonism) produced by typical antipsychotics (Ereshefsky 1989). Dystonic reactions have not been noted in US trials. Parkinsonian symptoms such as hypokinesia were not reported. Akathisia, tremor, and rigidity were reported in 6%, 3%, and 3% of patients, respectively (Safferman 1991). However, a recent blind survey reported a similar prevalence and severity of akathisia in clozapine-treated patients (9%) compared to patients receiving typical antipsychotics (14%) (Cohen et al 1991). However, this conclusion has been questioned indicating clozapine-treated patients may have manifested tardive akathisia, not acute-onset akathisia (Safferman et al 1992a).

EPSE rates for clozapine vs risperidone

The prevalence and severity of EPSE for patients treated with for three months of clozapine, risperidone or conventional antipsychotics was studied (Miller et al 1998). One blinded rater examined the patients using the BAS, and a modified version of the Simpson-Angus (subjective rating). One hundred six outpatients between 18-60 years were recruited, of which 41 were on clozapine, 23 with risperidone and 42 with conventional antipsychotics. Total time period of medication treatment was 45.3±40.2 months in the clozapine group, 13.4±6.6 months in the risperidone group and 92.5±158.9 months in those treated with conventional antipsychotics. The mean doses of antipsychotics (in chlorpromazine equivalents) were 425.6±197.1 mg/day in the clozapine group, 4.7±2.1 mg/day in the risperidone group and 476.5±476.9 mg/day in the conventional antipsychotic group. The point-prevalence of akathisia was 7.3% in the clozapine group, 13% in the risperidone group and 23.8% in the conventional group. The point-prevalence of rigidity and cogwheeling was 4.9% and 2.4%, respectively in the clozapine group, 17.4% and 17.4% in the risperidone group, and 35.7% and 26.2% in the conventional group. Twenty-four (57.4%) patients in the conventional group, 8 (34.8%) of the risperidone and one clozapine patient received antiparkinsonian medication.

Long-term effects. Most literature reviews indicate clozapine has not been clearly documented to produce tardive dyskinesia (Ereshefsky et al 1989, Lieberman et al 1989, Safferman et al 1991). However, one report has suggested clozapine to produce choreoathetoid dyskinesia and jaw dyskinesia in 2 cases (de Leon et al 1991). In one case the dyskinesia reversed within 3 days of clozapine discontinuation, reappeared within 4 days of the rechallenge, and reversed with drug discontinuation. In the second case jaw movements appeared 14 days after drug initiation and continued unchanged for 1 year. The drug was not discontinued and the dyskinesia did not respond to anticholinergic treatment.

Uncontrolled studies indicate clozapine may, like typical antipsychotics, produce a dose-dependent suppression of dyskinetic movements by >50% in approximately 43% of patients (Small et al 1987, Lieberman et al 1991). Dystonic features were said to be most responsive to clozapine. The 3-year trial by Lieberman et al (1991) found that TD disappeared in 33% of the clozapine treated patients whereas in typical antipsychotic treated patients it disappeared in only 8% (1800 mg/d chlorpromazine equivalents) to 20% (1200 mg/d chlorpromazine equivalents).

Neuroleptic malignant syndrome. Six cases of NMS have been reported with clozapine. Two early cases (Pope et al 1986, Muller et al 1988) were reported in patients receiving concurrent medication (e.g., lithium or carbamazepine), while 4 cases were receiving clozapine alone (Nopoulos et al 1990, Anderson and Powers 1991, Miller et al 1991a, Goates and Escobar 1992). Though two cases report NMS-type signs without rigidity, four cases report its presence.

Management. If a patient develops signs of rigidity, autonomic dysfunction (i.e., hypo- or hypertension), significant hyperthermia, a leucocytosis, and/or elevated CPK soon after initiation of clozapine, the drug should be discontinued. Supportive and, possibly, pharmacotherapy (i.e., bromocriptine) should be instituted. Rechallenge has been successfully completed (Goates and Escobar 1992).

Gastrointestinal

Constipation. This may be a significant problem in some patients. This is due to the anticholinergic properties of clozapine.

Management. Increased fluid intake, exercise, and/or the use of a bulk laxative (i.e., psyllium) are recommended. If constipation is significant, dose reduction might be considered. Prolonged stimulant (e.g., Exlax, Dulcolax) laxative use is not recommended.

Nausea/Vomiting. These effects usually occur after the patient has received clozapine for several weeks or months. Dopamine-blocking drugs are antiemetics and therefore it is unclear why clozapine would produce these effects. However, possible etiologies include gastric distention secondary to excessive salivation, excessive food intake, and/or delayed gastric emptying time secondary to anticholinergic effects.

Management. Dose reduction should be considered. Anecdotal reports suggest metoclopramide (Reglan) may be helpful.

Hypersalivation. Most patients on clozapine will experience some degree of excessive salivation. They may complain especially of significant drooling at night. Also complaints of difficulty swallowing saliva and gagging have been reported. The mechanism is unknown but may be related to increased peripheral adrenergic effects.

Management. Patients should be forewarned of this effect. Covering the pillow with a towel at night may decrease patient discomfort. Anticholinergic drugs (i.e., benztropine) have been reported to be partially effective or ineffective. One case reported suggested that chewing gum reduced a patient's drooling by 60% and was further improved with benztropine 2 mg/d (Bourgeois et al 1991). The author's suggested that chewing gum resulted in more frequent swallowing, which reduced the patients concern with the effect. One report of 4 patients reported that amitriptyline 75 to 100 mg/d resulted in a significant reduction of drooling, which was sustained (Copp et al 1991). Clonidine has been reported to markedly reduce salivation in 3/4 patients treated with a clonidine 0.1 mg transdermal patch every week (Grabowski 1992). However, in one patient tolerance developed within 2 weeks. Though the dose was increased to 0.2 mg q week tolerance again developed within 2 weeks. Dose reduction may be empirically tried. Though tolerance develops to some degree in 8 to 12 weeks of the last dose increase, rarely dose complete tolerance develop.

Hematologic

Agranulocytosis. In 1975, 16 cases of neutropenia (<1,000/mm3) were reported in Finland (Idanpaan-Heikkila et al 1977). Thirteen patients developed agranulocytosis (< 500/mm3) and 8 died from secondary infection.

Evidence is accumulating that suggests a genetic predisposition (i.e., Ashkenazi Jewish population) to this effect as HLA antigens in susceptible patients have been identified (Lieberman et al 1990, Joseph et al 1992). However, patients with these HLA have not developed agranulocytopenia on clozapine and conversely, patient without these antigens have.

The manufacturer mandates a baseline CBC and weekly WBCs. This monitoring schedule is based on the premise that the reduction in granulocytes is gradual. Therefore, advance warning of a potentially serious reduction would be possible. Between 2/90 and 12/94 99,502 patients were exposed to clozapine according to data from the Clozaril Patient Management System (Honigfeld et al 1998). Leukopenia (< 3500/mm3) occurred in 2,931 (2.95%) while agranulocytosis (< 500/ mm3) occurred in 382 (0.38%) of patients. The pre-marketing expected rate of agranulocytosis was estimated to be between 1-2%. Of these expected cases the fatality rate was predicted to be 15%. Thus based on the above population, there should have been between 149 and 298 deaths secondary to clozapine. However, only 12 deaths (0.012%) have occurred. Thus the Clozaril Patient Management System appears to have been highly successful in reducing the occurrence of clozapine-induced agranulocytosis and associated fatalities.

Management. Two baseline CBCs are required with a WBC count > 3500/mm3. The WBC count must be checked weekly for the first six months of treatment and then every other week until 4 weeks after discontinuation. If monitoring reveals a total WBC between 3000 and 3500/mm3 and a granulocyte count >1500/cu mm, then twice weekly WBC counts with differential should be performed. Likewise, if there is a pattern in which the patient's white count is decreasing from week to week, but remains above 3500/ mm3 a repeat WBC with differential is required. If the WBC falls below 3000/ mm3 or the granulocyte count <1500/ mm3, then clozapine should be discontinued and the patient monitored for an infectious process. Clozapine may be reinitiated if the above criteria are exceeded, but twice weekly counts should be obtained until the WBC exceeds 3500/ mm3.

If the WBC falls below 2000/mm3 or the granulocyte count <1500/cu mm, then clozapine should be discontinued and the patient should be admitted for observation and hematology and infectious disease consults obtained. The patient should not receive clozapine again. A review of 9 cases world-wide of leukopenia or agranulocytosis revealed recurrence of either condition. The average time to the event was 24.4 (+/-18.2) weeks for the first episode versus 14.6 (+/-33.6) weeks for the second (p=0.006) (Safferman et al 1992b). The interval between the 2 episodes ranged from 2 months to 2 years. This finding suggest the mechanism is immune-related, which is consistent with other reports (Pfister et al 1992). In recently reported cases (n = 7) of clozapine-induced agranulocytosis, granulocyte-macrophage colony-stimulating factor (G-CSF) 300 mcg/d reduced the time to recovery of granulocytes by 50% (Geibig and Marks 1993, Gerson et al 1992, Ryabik et al 1993, Weide et al 1992).

Eosinophilia. This is reported to occur in 1% of patients treated with clozapine. Onset has been reported between 1 and 5 weeks in 2 patients (Tiihonen and Paanila 1992, Stricker and Tielens 1991). In both cases reversal occurred within 1 week.

Management. Specific guidelines for eosinophilia have not been published. According to the authors of one case above, the drug should be discontinued if the count is >1.4 x 109/L

Leucocytosis. This has been reported in 0.6% of patients.

Management. This appears to be a benign condition.

Metabolic

Weight Gain. Similar to typical antipsychotics, clozapine has been associated with weight gain. The frequency of this effect is reported to vary from 13 to 85% of patients with the average gain varying from 9 to 25 lbs. Two reports have indicated the average weight gain to be around 14 lbs in 4 months (Leadbetter et al 1992) and 17 lbs in 6 months (Lamberti et al 1992). In these studies, the percent of patients that gained at least 10 lbs was 38 and 75, respectively. One study noted that the greatest improvement in symptoms occurred in patients with the greatest weight gain (Leadbetter 1992). Umbricht et al (1994) characterized the course of the weight gain in 82 patients who were followed for up to 90 months. Although the majority of the weight was gained during the first 6 to 12 months of treatment, it was a chronic problem continuing well into the third year of treatment. Over 50% of the patients became substantially overweight thereby posing a potential long-term health risk especially in those patients developing diabetes and hyperlipidemias. A recent review estimated the average weight gains for typical and atypical antipsychotics following 10 weeks of treatment (Allsion et al 1999). Among the atypicals, clozapine is associated with the greatest increases, i.e., clozapine, 4.45 kg; olanzapine, 4.15 kg; sertindole, 2.92 kg; risperidone, 2.10 kg; quetiapine, 2.18 kg; and ziprasidone, 0.04 kg. The antihistaminic and antiserotonergic effects of clozapine may be the responsible for this effect.

Clozapine's effect on body mass. A cohort consisting of patients treated with clozapine for at least 1 year was collected (Frankenburg et al 1998). Patients with medical illnesses that could affect weight, those eating disorders and those in which a pre-clozapine weight could not be determined were excluded. Forty-two patients were studied. The mean ± SD age of the women was 36.1±7.8 and 32.8±9.1 years for the men. The mean ± SD clozapine dose for women was 328±193 and for men was 348±170 mg/day. The women had been treated with clozapine for 37.1 ± 19.1 months, the men for 39.3 ±21 months. Concurrent medication use included: lithium (24%), divalproex sodium (14%), benzodiazepines (29%), fluoxetine (24%), sertraline (7%), paroxetine (7%), and other agents (24%). The female patients had an increase in their weight and their body mass index (BMI) from 62.8±15 to 79±17.4 kg (p=0.001) and from 23.2±5.2 to 29.1±5.5 kg/m2 (p=0.001), respectively. The male patients had an increase in their weight and their body mass index (BMI) from 83.6±18.2 to 94±12.4 kg (p=0.0001) and from 26.4±5.1 to 29.7±3.7 kg/m2 (p<0.001), respectively. The 3 variables found to be significantly associated with the follow-up BMI and accounted for half of the variance in the model were baseline BMI, dose and decrease in smoking (p=0.0001, p<0.0001, p<0.0001 respectively). The waist-to-hip ratio (WHR) for the female patients after clozapine treatment was 0.83±0.07 and for the males was 0.93±0.05. It has been proposed that a WHR value of 0.8 for women and 1.0 for men as the cutoff for separating persons at low risk for cardiovascular disease. Other risk factors for these women include those with BMIs of 29 kg/m2 have a relative risk of coronary heart disease of 3.56 and also those women who gained weight as adults were also at greater risk of developing coronary heart disease.

Management. Patients should be informed of this adverse effect. Caloric restriction and/or increased activity should be considered. It is unknown if this responds to dose reduction.

Non-insulin dependent Diabetes Mellitus. Since 1994, 27 cases of clozapine-induced or exacerbated diabetes mellitus (DM) or diabetic ketoacidosis have been reported (Wehring et al 2000). Insulin resistance in the peripheral tissues and an insulin secretory defect of beta cells characterizes Type 2 DM. It is the most common form of DM and is generally associated with a family history of the disorder, older age, obesity and the lack of exercise.

Lund et al (2001) compared medical and pharmacy claims from the Iowa Medicaid program to determine the incidence rates for diabetes, hyperlipidemia, and hypertension. The study group consisted of 552 patients receiving clozapine and 2,461 patients receiving conventional antipsychotics (e.g. haloperidol, chlorpromazine, etc.), using a retrospective cohort design. Exposure to the individual drug averaged 24 to 25 months in both groups. Logistic regression was used to compare incidence rates adjusting for age, gender, and duration of available follow-up. No significant differences in overall incidence rates for diabetes, hyperlipidemia or hypertension were observed in patients receiving clozapine versus conventional antipsychotics. However, among younger patients (ages 20-34 years), clozapine administration was associated with a significantly increased relative risk of diabetes (R.R. 2.5 (95% confidence interval 1.2-5.4)) and hyperlipidemia (R.R. 2.4 (95% confidence interval 1.1-5.2)), but not hypertension (R.R. 0.9 (95% confidence interval 0.4-2.0)). These data suggest that clozapine may not be an independent cause of diabetes or hyperlipidemia, but instead acts as an effect modifier in susceptible populations by increasing weight or affecting insulin secretion and resistance. This finding requires confirmation in other settings and patient populations and with the other atypical antipsychotics (risperidone, olanzapine and quetiapine).

Management. Due to the increasing numbers of case reports of DM and IGT with clozapine and other atypical antipsychotics, patients should be carefully monitored for signs and symptoms of glucose intolerance and diabetes mellitus.

Urogenital

Reports to the manufacturer indicate these may occur in approximately 6% of clozapine-treated patients (Safferman 1991). However, it is believed these are underreported. Amenorrhea, galactorrhea, gynecomastia have not been reported with clozapine, probably because the drug does not increase prolactin levels. In one case a male patient had reversal of gynecomastia when clozapine was substituted for typical antipsychotics (Uehlinger and Baumann 1991).

Enuresis, frequency/urgency, hesitancy, urinary retention. Patients with prostatic hypertrophy may be most susceptible to these effects. These may occur secondary to anticholinergic effects.

Management. Dose reduction may empirically be tried. Drug discontinuation may be required.

Anorgasmia, ejaculatory dysfunction, impotence, decreased libido. These effects are probably related to anti-adrenergic effects.

Management. Dose reduction or drug discontinuation may be required to alleviate these effects.

Priapism. Two cases have been reported with onset occurring in 3 and 10 weeks, respectively, of initiation of treatment (Seftel et al 1992, Zeigler and Behar 1992). In one case multiple rechallenges lead to recurrence of priapism and in the second, permanent impotence resulted.

Withdrawal Effects

"Rebound Psychosis." Cases of rapid return of psychotic symptoms after clozapine discontinuation have been reported (Safferman et al 1991). However, other reports indicate the return of psychotic symptoms is not any faster with clozapine compared to typical antipsychotics (Safferman et al 1991). A recent case suggests return of psychotic symptoms is faster with clozapine than haloperidol (Alphs and Lee 1991).

Cholinergic Rebound. It has been suggested that abrupt discontinuation of clozapine can result in withdrawal symptoms such as diaphoresis, diarrhea, restlessness, and insomnia (Safferman et al 1991).

Management. If possible, clozapine should be tapered over a 7 to 10 day period of time when discontinuation is possible.

DRUG INTERACTIONS

Benzodiazepines. Two cases of patients that received lorazepam 2 or 3 mg plus clozapine that resulted in lethargy, pale appearance, drooling, and ataxia have been reported (Cobb et al 1991). Neither patient had experienced this reaction while receiving typical antipsychotics and lorazepam previously. No clozapine serum levels were reported. In addition, 4 cases of the combination of several different benzodiazepines and clozapine that resulted in severe sedation, hypersalivation, hypotension, toxic delirium, collapse, loss of consciousness, and respiratory arrest have been reported (Grohmann et al 1989). A review of 39 patients who received clozapine monotherapy and clozapine plus benzodiazepines revealed an increased incidence of collapse, drug fever, sedation, and dizziness with the combination (Sassim and Grohmann 1988). These effects occurred with 48 hours of the combination and the patients were receiving high doses of clozapine. These cases stimulated the manufacturer to issue a separate warning on the combination of clozapine and benzodiazepines. They estimated the reaction occurs in about 1:2,000 to 1:6,000 patients.

Cimetidine. In a case report cimetidine 800 mg/d increased clozapine serum levels form 1081 ng/ml to 1701 ng/ml, while ranitidine 300 mg/d plus clozapine did not significantly affect clozapine concentrations (Szymanski et al 1991b). The patient on the combination of clozapine and cimetidine experienced marked diaphoresis, dizziness, vomiting, generalized weakness, and sever lightheadedness on standing. These symptoms were not present while the patient was receiving clozapine plus ranitidine.

Carbamazepine. Hepatic enzyme induction of CYP3A4 results in significant decreases in clozapine plasma levels (Drug Interaction Facts 2000). This may result in patients developing subtherapeutic clozapine concentrations thereby predisposing them to an acute psychotic relapse.

Fluoxetine. Case reports and controlled trials indicate that fluoxetine (mean 76%), sertraline (mean 76%), and fluvoxamine (mean 3-fold) cause clinically significant increases in clozapine plasma concentrations (Drug Interaction Facts 2000).

Phenytoin. Two cases are reported in which the addition of phenytoin to clozapine resulted in significant decreases in clozapine concentrations and worsening of psychosis (Miller 1991b). In one patient, phenytoin concentrations of approximately 9 ng/ml reduced the clozapine concentration from 295.9 ng/ml on 400 mg/d to 92.6 ng/ml on 500 mg/d. The second patient's clozapine concentrations decreased from 940.5 ng/ml on clozapine 250 mg/d to 334.7 ng/ml on the same dose. Her phenytoin concentration was 12.4 ng/ml at steady-state.

CONCLUSION

It is important to emphasize that clozapine is not a "miracle cure" for all patients with schizophrenia. Because of the severity of the adverse effect profile, the drug is usually regarded as the "drug of last resort" in the treatment of the psychotic patient. Some patients who have not responded to different typical or atypical antipsychotics will improve significantly on this drug. Because of this it is recommended that a trial of at least 3 to 6 months be given to patients placed on this medication.

_____

RISPERIDONE

INTRODUCTION

Risperidone is a benzsoxazole derivative that was marketed in the U.S. in February 1994. The drug is indicated in the treatment of schizophrenia.

PHARMACOLOGY

Risperidone is a potent 5HT2A and D2 antagonist. In addition, it antagonizes alpha1, alpha2 and H1 receptors. It does not bind to cholinergic receptors. The drug produces dose-related increases in prolactin levels nearly equal to that of haloperidol (Cohen 1994). In animal testing based on the ratio of serotonin/dopamine blocking effects, risperidone is classified as an atypical antipsychotic at low doses, but a typical antipsychotic at high doses based on its ability to produce extrapyramidal side effects.

PHARMACOKINETICS

Risperidone is rapidly absorbed after oral administration, reaching a peak plasma level within 2 hours (Cohen 1994). The drug can be given with or without food, as extent of absorption is not affected. The half-life of risperidone is 15 hours; however, the total parent drug plus 9-hydroxyrespiridone active metabolite has a half-life of 23 hours (Borison et al 1994) thereby making single daily dosing practical. Risperidone and hydroxyrisperidone are 89% and 77% plasma protein bound, respectively. Plasma concentrations of both are dose proportional in the range of 1 to 16 mg/d. A therapeutic range has not been established. Though hepatic insufficiency doesn't change the half-life of risperidone, a more pronounced effect may occur due to more unbound risperidone (Livingston 1994). However, the half-life is longer in the elderly patient and in patients with renal insufficiency.

EFFICACY

Summary

Song (1997) evaluated the relative effectiveness and adverse effects of risperidone as compared with typical antipsychotics in the treatment of schizophrenia, in a meta-analysis of 11 double-blind, randomized controlled trials. The proportion of patients showing clinical improvement, use of medications for EPSE, the treatment drop-out rates, and the changes in negative PANSS scores were measured. Compared with conventional antipsychotics, slightly more patients in the risperidone group showed clinical improvement (57 vs 52%). The use of concomitant medications for EPSE was significantly less frequent in the risperidone group than in the typical antipsychotic group (22.8 vs 38.4%). The overall dropout rate was lower in the risperidone group than in the other antipsychotic group (29.1 vs 33.9%). The absolute difference in changes in negative PANSS score between the risperidone and the haloperidol group was -0.74 Weight gain and tachycardia were more common in patients treated with risperidone. The short-term efficacy of risperidone is comparable to other antipsychotics in the treatment of schizophrenia. It is associated with significantly less EPSE than conventional antipsychotics (mainly haloperidol) at doses less than or equal to 6 mg/day.

Clinical Studies - Individual review

Risperidone versus clozapine. In a 1991 comparative study by Heinrich et al, 60 schizophrenic patients were treated with either risperidone or clozapine (Heinrich et al 1991). After a 7-day drug dose titration period, the patients received a fixed dose of 4 mg/day or 8 mg/day of risperidone or 400 mg/day of clozapine for an additional 21 days. Patients in both risperidone groups and those in the clozapine group experienced similar improvements on BPRS scores. However, improvement on the Clinical Global Impression scale was better in the risperidone 4 mg/day group than in the risperidone 8 mg/day group or the clozapine group. The authors concluded that risperidone was as effective as clozapine in non-treatment-resistant patients.

Risperidone versus haloperidol. In a large, multicenter, fixed-dose trial conducted in the United States and Canada, 523 schizophrenic patients were treated with 2, 6, 10, or 16 mg/day of risperidone, 20 mg/day of haloperidol, or placebo for 8 weeks (Chouinard et al 1993, Marder et al 1994). The Positive and Negative Syndrome Scale (PANSS) was used for clinical assessments.

Patients receiving 6, 10, or 16 mg/day of risperidone had a greater reduction in negative symptoms than those treated with risperidone 2 mg/d, haloperidol or placebo. A similar pattern of response was seen in a subgroup of patients classified as having type 2, or negative-type, schizophrenia. Improvement in negative symptoms was seen as early as week 2 in the patients treated with risperidone, but not until week 6 in those receiving haloperidol. Improvement in positive symptoms was seen by week 1 in patients treated with risperidone 6 mg/day. In the haloperidol group, significant improvement in positive symptoms was not apparent until week 4.

The incidence of EPSE with risperidone 2, 6, and 10 mg/day was similar to that seen with placebo, and less than that seen with haloperidol 20 mg/day. Patients in the 6-mg/day risperidone group showed an improvement in negative symptoms without an increasing need for medication to treat EPSE or parkinsonian side effects.

The investigators concluded that 6 mg/day is the optimal dose of risperidone. The suggested titration schedule for reaching this dose is 1 mg BID for 1 day, 2 mg BID for 1 day, and 3 mg/BID thereafter. This titration period is shorter than that of clozapine, which, in one study averaged 11 days to reach 400 mg/day (Perry et al 1991). Thus it is likely that risperidone will have a faster onset of action than clozapine, because less time is needed to reach the optimal dose.

Risperidone in treatment-resistant patients.

In a study conducted in Italy in 1990, Bersani et al treated 30 treatment-refractory patients with risperidone for a total of 4 weeks. Patients received risperidone 2 mg/day for 1 week, 4 mg/day for 1 week, and 6 mg/day for the final 2 weeks (Bersani et al 1990). Significant improvement in BPRS and SANS scores was seen by week 1, and the changes remained significant throughout the 4-week study period. Scores on the Mindham EPSE scale also were significantly improved at weeks 1 through 4. These preliminary data demonstrate that risperidone was effective in treatment-resistant patients.

Perry et al 1993 compared the SANS data from their clozapine trial with that from the Bersani et al 1990 risperidone study (Bersani et al 1990, Perry et al 1993). The effect of both drugs on SANS scores was reasonably similar.

Bondolfi et al 1998 studied 86 chronic schizophrenics (DSM-III-R) who had previously failed to respond to or were intolerant to at least two different classes of typical antipsychotics given in appropriate doses for at least 4 weeks each. None of the participants had received clozapine in the past. Patients were randomly assigned double-blind treatment to risperidone or clozapine for 8 weeks. The baseline Positive and Negative Syndrome Scale (PANSS) score was 106.3 (SD 11.7) for the clozapine group and 100.4 (SD 15.2) for the risperidone group. The CGI baseline scores were 4.3 in both groups. The dose of risperidone was increased to 6 mg/day and the dose of clozapine to 300 mg/day during the first 7 days of the study, mean doses at day 42 were 6.4 mg/day for risperidone (range 3-10) and 291.2 mg/day for clozapine (range 150-400). At the end of the eight weeks 67% (29/43) of the risperidone patients and 65% (28/43) of the clozapine patients were clinically improved according to the CGI. For both drugs, the PANSS scores decreased significantly, 78.9 (SD 23.6) for risperidone and 77.2 (SD 21.5). No significant differences between treatments were seen on the CGI scales, nor the positive and negative symptom subscales of the PANSS. Plasma clozapine concentrations were measured at week 8 in 23 of 43 patients. The mean concentrations were 292 ng/ml (SD=255, range=102-670) in the nonresponders (N=4) and 281 ng/ml (SD=195, range 87-826) in the responders (N=24). There were no differences between responders and nonresponders when plasma concentrations of risperidone and of its metabolite were considered. The Extrapryamidal Symptom Rating Scale measured parkinsonism, dystonia and dyskinesia. Fifty-four percent of the risperidone group and 37% of the clozapine group scored 0 on the Extrapyramidal Symptom Rating Scale total score, those scoring 0 on the parkinsonism total score were 61% and 37%, respectively, 95% and 98% on the dystonia total score, and both groups had 84% score a 0 on the dyskinesia total score. The only significant adverse event difference between the two drugs was asthenia/lassitude/increased fatigability in which 28% of the risperidone group and 51% of the clozapine group experienced this (p<0.05).

Wirshing et al (1999) contrasted the effectiveness of risperdione to haloperidol in 67 patients with treatment-refractory schizophrenia. Risperidone demonstrated clinical efficacy superior to that of haloperidol on the BPRS after the first 4 weeks of treatment. However, risperidone did not show any advantage over haloperidol after an additional 4 weeks. Risperidone-treated subjects were significantly less likely than haloperidol-treated subjects to require concomitant anticholinergic medication after 4 weeks (20% versus 63%).

Azorin in a much larger patient population of 273 schizophrenics found clozapine more effective than risperidone on nearly every comparative measure. In a 12-week study, a 6 mg/d median dose (range 2-15 mg/d) of risperidone was compared to clozapine 600 mg/d (range=200-900 mg/d). Clozapine was more effective than risperidone according to the BPRS (total, positive, and negative symptoms subscales), CGI, Calgary Depression Scale, Psychotic Depression Scale and the Psychotic Anxiety Scale. Additionally, when response was defined as either a 20%, 30%, 40%, or 50% BPRS change score, clozapine was always superior to risperidone. Thus this very large study suggests that clozapine is more effective than risperidone in the treatment of acutely ill non-treatment refractory patients.

ADVERSE EFFECTS

Extrapyramidal.

In comparison to haloperidol 10 to 20 mg/d risperidone 6 mg/d or less cause fewer EPSS. The incidence and severity increases proportionally in the dosage range studied (1 to 16 mg/d) (Cohen et al 1994). In the Canadian study, at 6 mg/d the rate of anticholinergic use in the risperidone and placebo groups was 32% and 23%, respectively (Chouinard et al 1993). At risperidone 2 mg and 10 mg/d, the use rate was 25% and 46%, respectively. This compared to a 74% rate with haloperidol-treated patients. The U.S. multicenter study reported similar percentages, except the rate with risperidone 16 mg/d was 38%, which compared to a haloperidol 20 mg/d rate of 46% (Marder and Meibach 1994).

Tardive dyskinesia.

Several case reports have been published implicating risperidone in the development of TD (Buzan 1996, Woerner et al 1996). Since risperidone is reported to produce less acute EPSE than haloperidol it may be less likely to produce tardive dyskinesia (Cohen 1994). In several studies the tardive dyskinesia rating scores were lower on risperidone than placebo. It is possible that with the initiation of risperidone, as with typical antipsychotics, dyskinetic movements may be temporarily suppressed. However, since EPSE is a primary risk factor for the development of TD, it is likely that patients who experience EPSE from risperidone are at increased risk of developing TD.

Other effects.

At 6 mg/d, common risperidone adverse effects that occurred in 10 to 15% of patients included insomnia, agitation, headache, dizziness, and rhinitis (Marder et al 1994). Approximately 9% of patients treated with risperidone in phase 2-3 studies discontinued treatment because of adverse effects, compared to 10% of haloperidol-treated patients and 7% of placebo-treated patients (Cohen 1994). EPSE was the most common reason for discontinuing treatment with risperidone (2.1%).

Overdose.

In one case of an approximate 240 mg overdose a patient experienced ECG and electrolyte abnormalities. He recovered without sequelae (Cohen 1994).

Drug interactions.

As risperidone is metabolized by the P-450 enzyme system, it is possible that it might interact with other hepatically transformed drugs (Cohen 1994)

____

OLANZAPINE

INTRODUCTION

Olanzapine is a thienobenzodiazepine approved by the FDA in 1996 for the treatment of schizophrenia.

PHARMACOLOGY

Olanzapine displays significant affinity for dopamine D1, D2, D4, serotonin 5HT2A, 5HT2C, 5HT3, a1-adrenergic, histamine H1 and multiple muscarinic receptors (Bymaster et al 1996).

PHARMACOKINETICS

Olanzapine reaches peak plasma levels at around 6 hours after administration and has an elimination half-life of approximately 30 hours (Zyprexa insert, Kassahun et al 1997). The major metabolites was olanzapine-N-glucuronide, other metabolites being olanzapine-N-oxide and N-desmethyl olanzapine (Kassahun et al 1997)

EFFICACY

Olanzapine vs. Placebo. Patients were randomized to receive one of three double-blind treatments: olanzapine 1mg, olanzapine 10mg, or placebo (Beasley et al 1996a). Efficacy measures were based on changes seen in the Brief Psychiatric Rating Scale (BPRS); total, positive, and negative scores, Positive and Negative Syndrome Scale (PANSS); total, positive, and negative, and a Clinical Global Impression-Severity of Illness. There were no statistically significant changes seen in any of the symptom scales between 1mg olanzapine and placebo. Olanzapine, 10 mg was statistically significantly superior to placebo on the BPRS-total and the PANSS-total scores.

Olanzapine vs. Haloperidol vs. Placebo. Patients were randomized to one of five double-blind treatments: olanzapine 2.5,5, or 7.5 mg/day (low dose group), olanzapine 7.5,10,or 12.5 mg/day (medium dose group), or 12.5, 15, or 17.5 mg/day (high dose group), haloperidol 10, 15, or 20 mg/day, or placebo (Beasley et al 1996b). The two higher dosages of olanzapine and haloperidol were superior to placebo in total improvement on the BPRS-total, these treatments showing similar findings when compared between one another. The low and high dose of olanzapine were significantly superior to placebo and the high dose was superior to haloperidol on the SANS.

Olanzapine vs Risperidone. A recently reported multi-center international double-blind placebo controlled trial in 339 patients with either schizophrenia, schizophreniform, or schizoaffective illness (DSM-IV) contrasted the efficacy of olanzapine 10-20 mg/d to risperidone 4-12 mg/d over 28 weeks (Tran et al 1997). Overall, according to the BPRS and PANSS rating scales change scores there was no difference in the effectiveness of the two drugs. However, the negative symptom response as measured by the SANS rating scale demonstrated a difference favoring olanzapine (p=0.02). Additionally, the Kaplan-Meier survival curves at 28 weeks favored olanzapine (~90%) over risperidone (~70%). A greater number of suicide attempts occurred in the risperidone (4.2%) than the olanzapine (0.6%) treatment group. Finally, the adverse drug reactions favored olanzapine in that fewer patients experience extrapyramidal side effects, sexual dysfunction, and drooling.

Treatment-Resistant Schizophrenia. Conley et al (1998) studied 103 treatment-resistant schizophrenics. Subjects could have been on clozapine in the past but not resistant. An open six week trial of haloperidol 10-40 mg/day and 4 mg/day of benztropine was given to all patients and a failure to respond was defined as less than a 20% decrease in total BPRS score, endpoint >35 and CGI>4 for those completing at least 2 weeks. Eighty-four qualified for the study by showing no response to haloperidol. Patients were randomly assigned to an 8-week fixed-dose, double-blind trial with either olanzapine 25 mg/day or chlorpromazine 1200 mg/day plus benztropine 4 mg/day (if randomized to chlorpromazine). All patients received 25 mg/day of olanzapine and the mean dose of chlorpromazine was 1173 mg/day (SD=125). Subjects remained hospitalized throughout the study. Thirty of the 42 (71%) olanzapine patients and 29 of the 42 (69%) chlorpromazine patients completed the study. Three of 42 (7%) olanzapine and no chlorpromazine patients met response criteria during the study (p=0.24). Response criteria was defined as at least a 20% reduction in total BPRS score compared to baseline, a post-treatment CGI of ²3 or a post-treatment BPRS score ² 35. Chlorpromazine caused more dry mouth, postural hypotension, unsteady gait, and extrapyramidal adverse effects. Twenty-one of the patients that did not respond to olanzapine were treated with clozapine. Eleven of these 21 (52%) have had a 20% improvement.

Volavka et al (2002) contrasted the efficacy of olanzapine, risperidone, and clozapine and haloperidol in a NIMH sponsored 14-week study of 157 severely ill treatment-resistant schizophrenic or schizoaffective patients. The target doses for the first eight weeks of the study were clozapine 500 mg/d (mean=402 mg/d), olanzapine 20 mg/d (mean=20 mg/d), risperidone 8 mg/d (mean=8 mg/d), and haloperidol 20 mg/d (mean=19 mg/d). The maximum doses for the final six weeks of the study were clozapine 800 mg/d (mean=527 mg/d), olanzapine 40 mg/d (mean=30 mg/d), risperidone 16 mg/d (mean=12 mg/d), and haloperidol 30 mg/d (mean=26 mg/d). Statistically significant within treatment improvement on total PANSS scores were observed for all the atypical antipsychotics. At the end of 14 weeks the PANSS (total) change scores for clozapine and olanzapine were greater than haloperidol. There were no differences in the effectiveness of the 4 drugs for the treatment of positive symptoms. All three atypicals produced change scores on the PANSS (negative) that were greater than haloperidol. The most robust changes consistently occurred with clozapine.

Negative Symptoms. Tollefson and Sanger (1997) investigated whether primary negative symptoms of schizophrenia are enduring or treatment-responsive. Previously, a double-blind, random-assignment trial of the novel antipsychotic olanzapine (in low, medium, and high dose ranges), placebo, or haloperidol (10-20 mg/day) for 335 schizophrenic inpatients was conducted for up to 52 weeks. Changes in the treatment groups from baseline to endpoint in summary scores on the Scale for the SANS and several secondary measures were compared. A path analysis to determine to what extent the total treatment effect on negative symptoms was direct or indirect (i.e., mediated by differential effects on positive symptoms, extrapyramidal symptoms, or mood). More improvement was achieved with high-dose olanzapine than with placebo or haloperidol. Olanzapine had a significantly greater direct effect than placebo on all SANS dimensions except anhedonia-asociality. Olanzapine also demonstrated a significantly greater direct effect than haloperidol on negative symptoms, especially on the dimensions of affective flattening and avolition-apathy. These results suggest that the negative symptoms of schizophrenia are directly responsive to treatment. The significantly greater direct and indirect effects of olanzapine than of haloperidol on negative symptoms are likely related to olanzapine's pleotrophic pharmacology, which includes dopaminergic, serotonergic, muscarinic, and adrenergic activities. The results contribute to the hypothesis that negative symptoms may be under the influence of several neurotransmitters within one or more neuroanatomic circuits.

Agitation. Wright et al (2001) evaluated the comparative efficacy of IM dosage formulations olanzapine 7.5 mg and haloperidol 10 mg versus placebo in 291 agitated patients diagnosed with schizophrenia, schizophreniform disorder, or schizoaffective disorder. According to the excitement item scores on the PANSS, olanzapine reduced agitation to greater extent than haloperidol at 15, 30, and 45 minutes after the first injection. No olanzapine patients experienced a dystonic reaction in contrast to 7% of the haloperidol patients.

ADVERSE EFFECTS

In the two above multicenter trials totaling approximately 480 patients showed that anticholinergic side effects, such as constipation and dry mouth showed an increase in relationship to dosage. Unlike clozapine, no leukopenia or agranulocytosis has been seen with olanzapine. Olanzapine was shown to be associated with increases in hepatic transaminases (ALT, AST, GGT) in a dose-dependent manner. In the high dose olanzapine group an increase in ALT of 24.3±93.5u/l seen in 9.2% of the patients, with some patients discontinuing therapy and transaminases returning to normal and others remaining on olanzapine and transaminases normalizing after continued therapy (Beasley et al 1996b).

Extrapyramidal symptoms. In the placebo study (Beasley et al 1996a), there were no significant differences in changes from baseline in symptom scores for parkinsonism (Simpson-Angus), akathisia (Barnes), and dyskinesias (AIMS). In the olanzapine-haloperidol-placebo trial (Beasley 1996b) these three symptom scales improved in the olanzapine groups with statistically significant changes in the Simpson-Angus score and a worsened score in the haloperidol-treated groups.

Weight gain. Weight gain was seen in both trials. In the 10 mg olanzapine trial subjects gained 2.2±4 kg vs. a loss of 0.4±3.1 kg in the placebo group (Beasley et al 1996a). In the trial using high doses of olanzapine ranging up to 17.5 mg, mean increase in weight was 3.5±3.9 kg (Beasley et al 1996b).

____

QUETIAPINE

INTRODUCTION

Quetiapine, brand name Seroquel® is a dibenzothiazepine. Quetiapine was approved in October 1997 and is indicated for the management of psychotic disorders.

PHARMACOLOGY

Quetiapine is an antagonist at 5HT1A and 5HT2,dopamine D1 (low) and D2, (not as high as haloperidol, comparable to clozapine) histamine H1 and adrenergic a1 (comparable to haloperidol, clozapine, olanzapine) and a2. Quetiapine has no appreciable affinity at cholinergic muscarinic receptors.

PHARMACOKINETICS

Quetiapine is rapidly absorbed after oral administration, reaching peak plasma concentration in 1.5 hours. Quetiapine is 100% bioavailable relative to solution. The bioavailability of quetiapine is marginally affected by the administration with food, with Cmax and AUC values increased by 25% and 15%, respectively. The liver extensively metabolizes quetiapine. The mean terminal half-life is about 6 hours within the proposed clinical dose range. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. The cytochrome P4503A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite.

EFFICACY

Summary

The efficacy of quetiapine for the management of psychotic disorders was established in 3 short-term 6-week studies.

Quetiapine vs. Chlorpromazine

Peuskens and Link (1997) studied 201 schizophrenics and schizophreniform patients in a 6-week, double-blind, randomized, multicenter, parallel-group study. Patients had to score at least 27 on the BPRS (0-6 scale), a score of at least 3 on 2 or more of the positive items of the BPRS, and score at least 4 on the CGI. The mean daily dose of quetiapine was 407 mg, for chlorpromazine was 384 mg. The mean change in BPRS total scores from baseline to day 42 was -18.4 for quetiapine and -18 for chlorpromazine. The difference between the groups was not statistically significant at any time-point. The CGI scores also improved at day 42, -1.23 for quetiapine and -1.09 for chlorpromazine. Sixty-five percent of the quetiapine patients met the response criteria (a reduction of >50% in BPRS total score) compared with 52% in the chlorpromazine group, this was significant (p=0.04). Each group experienced somnolence, 14% in the quetiapine group and 16% in the chlorpromazine group. Each group also experienced insomnia, 10% in the quetiapine group vs 16% in the chlorpromazine. Eighteen percent of the chlorpromazine patients experienced postural hypotension.

Quetiapine vs Haloperidol vs Placebo

Three hundred sixty-one chronic schizophrenic patients from 26 North American centers entered a dose-response study to compare the efficacy and tolerability of quetiapine vs placebo and haloperidol (Arvanitis et al 1997). Patients were required to have met the entry criteria described in the above-mentioned trial. There was a one-week placebo lead-in and eligible patients were randomized to one of seven treatments: 75, 150, 300, 600, or 750 mg of quetiapine daily, 12 mg of haloperidol daily, or placebo. Treatment was equally divided into three doses. Mean baseline BPRS total scores ranged from 44-47, CGI from 4.9-5.1 and SANS scores from 13.9-15.5. Significant differences (p<0.05) were seen in the four highest doses of quetiapine and haloperidol for mean adjusted changes in the BPRS total score, BPRS positive-symptom cluster, and CGI severity of illness score. There was also a significant difference between quetiapine 300 mg and placebo for the SANS summary score. There were no differences between quetiapine and haloperidol.

Copolov et al (2000) conducted a 6-week multi-center trial (n=55) multi-national (n=14) trial comparing the efficacy of quetiapine to haloperidol in 448 acutely ill schizophrenic inpatients. Quetiapine was titrated to a maximum effective dose between 300-800 mg/d (mean=455) while haloperidol was titrated to a dose between 6-16 mg/d (mean=8 mg/d). At day 42, the mean total PANSS score was reduced by 19 in the quetiapine group and 22 in the haloperidol group. The response (30% decrease in PANSS) rates also did not differ between the two drugs, 44% for quetiapine and 47% for haloperidol. No information was provided regarding the effect of the drugs on negative symptoms.

High vs Low Dose Study

Another dose optimization study was conducted by Small et al (1997) which involved 286 schizophrenics. This was a 6-week randomized, multicenter, double-blind, parallel-group with the same entry criteria as the above-mentioned studies. Patients were randomized to 1 of 3 treatments, high dose quetiapine (maximum daily dose 750 mg), low-dose quetiapine (maximum 250 mg) or placebo. The BPRS total score at end point for the high-dose group was -8.7 (p<0.001 vs placebo) compared with -4.2 in the low-dose group and -1.0 in the placebo group (NS). The change in SANS scores for the high dose quetiapine group was -1.7+/-0.47 (p<0.02 vs placebo) vs the low dose group was 0.3+/-0.48 (p<0.004 vs haloperidol) and -0.1+/-0.46 for the placebo.

Quetiapine appears to be no more effective than haloperidol for the treatment of the positive and negative symptoms of schizophrenia.

ADVERSE EFFECTS

Hypotension

Quetiapine may induce orthostatic hypotension associated with dizziness, tachycardia and in some patients syncope, especially during the initial dose-titration period. Syncope was reported in 1% (22/162) of the patients treated with quetiapine. This risk is minimized by limiting the initial dose to 25 mg bid.

Cataracts

The development of cataracts was observed in association with quetiapine treatment in chronic dog studies. Lens changes have also been observed in patients during long-term treatment. Examination of the lens by methods such as slit lamp is recommended at initiation of treatment and at 6-month intervals during chronic treatment.

Liver

Asymptomatic, transient and reversible elevation in serum transaminases (primarily ALT) has been reported. In the clinical trials the proportions of patients with transaminase elevations of >3 times the upper limit were 6% vs 1% for placebo.

Somnolence

During the clinical trials 18% of the quetiapine patients compared to 11% of placebo patients experienced this.

Extrapyramidal Symptoms

There was no difference between quetiapine and placebo treatment groups in the incidence of EPSE in 3 placebo-controlled clinical trials using variable doses of quetiapine.

NMS

Two possible cases of NMS (2/2387 (0.1%) have been reported in the quetiapine clinical trials described above.

____

ZIPRASIDONE

INTRODUCTION

Ziprasidone is a new atypical antipsychotic approved by the FDA in 2000.

PHARMACOLOGY

Ziprasidone is a very potent 5HT2A receptor antagonist and a potent D2 receptor antagonist (8-fold variation favoring 5HT2A receptor). It is also a potent antagonist at the 5HT1D and the 5HT2C receptors, a potent agonist at the 5HT1A receptor, and a moderate inhibitor of the synaptic re-uptake of 5HT and norepinephrine. It has negligible affinity for the muscarinic receptors and only modest affinity for the H1 and a1 receptors (Canton et al 1990).

PHARMACOKINETICS

Ziprasidone displays linear pharmacokinetics in the recommended dose range of 8-160 mg/d. Its mean half-life 0s 6.6 hours. Food increases ziprasidone bioavailability up to 2-fold and reduces the variability of absorption. In multi-dose studies, Cmax occurs at about 6 hours after the dose in the fed state. Using a twice-daily dosing schedule, steady-state levels in the fed state occur within 1-3 days. The drug is extensively metabolized by aldehyde oxidase and the CYP450 3A4 hepatic oxidase enzyme. One metabolite, S-methyl-dihyroziprasidone (M9) may be pharmacologically active. Co-administration of CYP4503A4 inhibitors or inducers with ziprasidone results in (`35%) increases/decreases respectively in ziprasidone plasma concentration.

EFFICACY

Ziprasidone vs. placebo Study 114.

Ziprasidone 80 mg/d and 160 mg/d was compared to placebo in a 6-week double blind controlled study in 302 hospitalized patients who had an acute exacerbation of either schizophrenia or schizoaffective disorder. Patients were evaluated with the PANSS, BPRS, CGI, and MADRS. Separation from placebo on all the ratings scales occurred at week 1. The drug was found to be effective in the treatment of the positive, negative and depressive symptoms of schizophrenia and schizoaffective disorder (Anonymous 2000).

Ziprasidone vs. Haloperidol Study 115.

Ziprasidone 40, 120, 200 mg/d were compared to haloperidol 15 mg/d and placebo in a 6-week double blind controlled study in 419 hospitalized patients who had an acute exacerbation of either schizophrenia or schizoaffective disorder. All treatments were more effective than placebo according to PANSS, BPRS and CGI ratings. On the PANNS negative symptom subscale only ziprasidone 200 mg/d and haloperidol 15 mg/d were more effective than placebo (Anonymous 2000).

Ziprasidone vs. Placebo Study 303

Ziprasidone 40, 80, 160 mg/d were compared to placebo in a 52-week double blind controlled study in 293 schizophrenic to assess the drug's prophylactic effectiveness. The relapse rates were 38% (82/218) for the ziprasidone groups and 71% (53/75) for the placebo group. All doses were more effective than placebo according to PANSStotal, PANSSnegative, CGI-severity and GAF ratings (Anonymous 2000).

ADVERSE EFFECTS

The most frequent ADRs associated with ziprsidone vs placebo in short-term clinical trials were transient sedation (14% vs 7%), and a cold-like respiratory disorder (8% vs 3%). In the 52-week trial only asthenia occurred more often than placebo (6% vs 0%. The rating scales utilized to assess EPSE demonstrated similar changes for both placebo and ziprasidone. Unlike the other atypical antipsychotics, weight gain is not associated with ziprasidone. In the 52-week (Study 303) patients actually lost between 1 to 3 kg, depending on the dose (Anonymous 2000).

ATYPICALS and PHARMACOECONOMICS

Based on Medicaid data from the state of Iowa for fiscal year 1994-1995, 19,875 prescriptions for clozapine 100 mg were written for approximately 382 patients (Perry et al 1995). The mean cost for the drug alone, not including dispensing fees or other charges, was $110.13/week or $5727/year. The total annual cost of drug was almost $2,188,039. Additionally, the cost of weekly blood counts must be factored into the final bill. A survey of 3 laboratories and 8 hospitals in eastern Iowa found that a complete blood count (CBC) ranged in cost from $13.50 to $44.70 (mean = $31.83). Phlebotomy charges in 6 hospitals ranged from $4.20 to $6.95 (mean = $5.93). Thus the annual charge for CBCs and phlebotomy added an additional $920 to $2686 to the clozapine bill. Therefor, adding a prescription dispensing fees, the annual clozapine bill can range from approximately $7000 to $9000. On the other hand, risperidone 1 mg, 2 mg, 3 mg, and 4 mg accounted for 11,017 prescriptions for approximately 918 patients at total annual cost of $1,697,677. Thus the annual patient cost of risperidone is approximately $1850/year.

Miller et al (1994) has recently completed a 2-1/2 year follow-up of clozapine patients. A survey of the 2-1/2 years prior to the start of clozapine and the 2-1/2 years after the start of clozapine, the patients annual number of hospital days decreased 88% from 74 ± 75 days to 9 ± 24 days per day. Similar data can be extrapolated from the Canadian risperidone study (Chouinard et al 1993). Addington reported that hospital days decreased by 20% per year in 27 patients treated with risperidone per year (Addington et al 1993). However, if the 6 risperidone patients who were chronically institutionalized are removed from the database the figures are quite similar to Iowa clozapine data base. The annualized hospital days decreased from 32 ± 11 days before risperidone to 11 ± 20 days after risperidone. Thus, when the indirect cost of hospital days are considered along with the direct costs of the drugs, health care costs of treating schizophrenia are reduced.

Rosenheck et al (1999) examined the relationship between pretreatment hospital use and the cost-effectiveness of clozapine in the treatment of refractory schizophrenia. Data from a 15-site randomized clinical trial were used to compare clozapine with haloperidol in hospitalized VA patients with refractory schizophrenia (n=423). Clozapine treatment resulted in greater reduction in hospital use among high hospital users (35 days less than controls, P=0.02) than among low users (21 days less than controls, P=0.05). Patients taking clozapine also had lower health care costs; after including the costs of both medications and other health services, costs were $7134 less than for controls among high hospital users (P=0.14) but only $759 less than for controls among low hospital users (P=0.82). Clinical improvement in the domains of symptoms, quality of life, EPSS, and a synthetic measure of multiple outcomes favored clozapine in both high and low hospital user groups. Substantial 1-year cost savings with clozapine are observed only among patients with very high hospital use prior to initiation of treatment while clinical benefits are more similar across groups. Cost-effectiveness evaluations, and particularly studies of expensive treatments, cannot be generalized across type of use groups.

Overall, the use of the more effective, better-tolerated newer antipsychotics over the short-term appears to reduce the cost to society of schizophrenia and improve patients' quality of life. However, since more recent studies are suggesting that atypical antipsychotic -induced weight gain in predisposed patients is causing earlier onset of medical illnesses such as diabetes and hyperlipidemia, all cost-savings generalizations need to be put on hold.

CONCLUSION

Clozapine is more effective than typical antipsychotics in the treatment of non-refractory and refractory patients. It produces significantly less EPSE than high-potency typical antipsychotics. Risperidone has not consistently been shown to be more effective than haloperidol in non-refractory patients. However, it has been shown to be more effective than haloperidol and equal to clozapine for treatment of refractory schizophrenics. The EPSS rate with risperidone is similar to placebo at doses ² 6 mg/, but higher doses have similar EPSS rates as haloperidol 20 mg/d. Unlike clozapine, risperidone increases prolactin levels at therapeutic doses. The effectiveness of quetiapine for treating the positive and negative symptoms of schizophrenia is similar to haloperidol. However, the drug causes minimal EPSS in contrast to haloperidol at all doses. Compared to haloperidol, olanzapine has similar effects on the positive symptoms of schizophrenia but is more effective in treating the negative symptoms. Olanzapine appears more effective than risperidone for treating the negative symptoms of schizophrenia. It remains to be proven whether olanzapine is as effective as clozapine for the treatment of refractory schizophrenics. At doses ² 17.5 mg/d EPSS rates for olanzapine are quite minimal. However, rates may be dose dependent as with risperidone. Ziprasidone appear to have similar effectiveness to haloperidol in the treatment of the positive and negative symptoms of schizophrenia. However, the drug causes fewer EPSS than haloperidol. Finally, unlike all of the atypical antipsychotics, ziprasidone does not cause weight gain. This is an important issue since the weight gain increases the rate of onset of diabetes and hyperlipidemias in schizophrenic patients predisposed to these diseases. The beneficial pharmacoeconomic effects of the atypical antipsychotics must now be regarded as debatable. Long-term weight gain may have profound effects on the purported positive pharmacoeconomic effects of the atypical antipsychotics. However, this issue remains to be settled

REFERENCES

Ackenheil M (1989). Clozapine: pharmacokinetic investigations and biochemical effects. Psychopharmacology 99:S32-7.

Addington DE, Jones B, Bloom D, et al (1993). Reduction of hospital days in chronic schizophrenic patients treated with risperidone: a retrospective study. Clin Ther 5:917-26.

Allison DB, Mentore J, Moonseong H, et al (1999). Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry156:1686-96.

Alphs LD, Lee HS (1991). Comparison of withdrawal of typical and atypical antipsychotic drugs: a case study. J Clin Psychiatry 52:346-8.

Anden NE, Stock G (1973). Effect of clozapine on the turnover of dopamine in the corpus striatum and in the limbic system. J Pharm Pharmacol 25:346-8.

Anderson ES, Powers PS (1991). Antipsychotic malignant syndrome associated with clozapine use. J Clin Psychiatry 52:102-4.

Angrist B, Rotrosen J, Gershon S. (1980). Differential effects of amphetamine and antipsychotics on negative versus positive symptoms in schizophrenia. Psychopharmacology 72:17-9.

Anonymous (1995). Seroquel: A putative atypical antipsychotic drug with serotonin- and dopamine-receptor antagonist properties. Preclinical and early clinical trials in schizophrenia. J Clin Psychiatry 56:438-45.

Anonymous (2000). Briefing document for Zeldox (ziprasidone). FDA Psychopharmacological Drug Advisory Committee, July 19.

Azorin JM, Spiegel R, Remington G, et al (2001). A double &endash;blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am J Psychiatry 158:1305-13.

Beasley CM, Sanger T, Satterlee W, et al (1996a). Olanzapine versus placebo: results of a double-blind, fixed-dose olanzapine trial. Psychopharmacology 124:159-167.

Beasley CM, Tollefson G, Tran P et al (1996b). Olanzapine versus placebo and haloperidol: acute phase results of the North American double-blind olanzapine trial. Neuropsychopharmacology 14:111-123.

Bersani G, Bressa GM, Meco G, et al (1990). Combined serotonin-5-HT2 and dopamine-D2 antagonism in schizophrenia: Clinical, extrapyramidal and neuroendocrine response in a preliminary study with risperidone (R 64-766). Hum Psychopharmacol 5:225-231.

Bondolfi G, Dufour H, Patris M, et al (1998). Risperidone versus clozapine in treatment-resistant chronic schizophrenia: A randomized double-blind study. Am J Psychiatry 155:499-504.

Borison RL, Diamond B, Pathiraja, et al (1994). Pharmacokinetics of risperidone in chronic schizophrenic patients. Psychopharmacol Bull 30:193-7.

Borison RL (1995). Clinical efficacy of serotonin-dopamine antagonists relative to classic antipsychotics. J Clin Psychopharmacol 15[suppl 1]:24S-9S.

Bourgeois JA, Drexler KG, Hall MJ (1991). Hypersalivation and clozapine (letter). Hosp Comm Psychiatry 42:1174.

Buzan RD (1996). Risperidone-induced tardive dyskinesia. Am J Psychiatry 153:734.

Bymaster FP, Calligaro DO, Falcone FJ et al (1996). Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14:87-96.

Campbell M (1999). Risperidone-induced tardive dyskinesia in first-episode psychotic patients. J Clin Psychopharmacol 19:276-7.

Canton H, Verriele L, Colpaert FC (1990). Binding of typical and atypical antipsychotics to 5HT1C and 5HT2 sties: clozpaine totently interacts with 5HT1C sties. Eur J Pharmacol 191:93-6.

Chou J C-Y (1991). Recent advances in treatment of mania. J Clin Psychopharmacol 11:3-21.

Chouinard G, Jones B, Remington G, et al (1993). A Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 13:25-40.

Clozapine. Package Insert: 1989. Sandoz Pharmaceuticals.

Cobb CD, Anderson CB, Seidel DR (1991). Possible interaction between clozapine and lorazepam (letter). Am J Psychiatry 148:1606-7.

Cohen BM, Keck PE, Satlin A, et al (1991). Prevalence and severity of akathisia in patients on clozapine. Biol Psychiatry 29:1215-9.

Cohen, LJ (1994). Risperidone. Pharmacotherapy 14:253-65.

Conley RR, Tamminga CA, Bartko JJ, et al (1998). Olanzapine compared with chlorpromazine in treatment-resistant schizophrenia. Am J Psychiatry 155:914-920.

Copolov DL, Link CGG, Kowalcyk B (2000). A multicenter, double-blind, randomized comparison of quetiapine (ICI 204,636), 'Seroquel') and haloperidol in schizophrenia. Psychological Med 30:95-105.

Copp PJ, Lament R, Tennent TG (1991). Amitriptyline in clozapine-induced sialorrhoea (letter). Br J Psychiatry 159:166.

Coryell WH, Kelly MW, Perry PJ, et al (1990). Haloperidol plasma levels in acute clinical change in schizophrenia. J Clin Psychopharmacol 10:397-402.

Coryell WH, Miller DD, Perry PJ (1998).. Haloperidol plasma levels and dose optimization. Am J Psychiatry155:48-53.

Cost effectiveness of clozapine for treatment-resistant schizophrenics. Prepared for Sandoz Laboratories by Battelle Human Affairs Research Centers (#CLO-1002):Washington, DC. July 1989.

Davies MA, Conley RR, Schulz SC, et al (1991). One-year follow-up of 24 patients in a clinical trial of clozapine. Hosp Comm Psychiatry 42:628-9.

de Leon J, Moral L, Camunas C (1991). Clozapine and jaw dyskinesia: a case report. Am J Psychiatry 52:494-5.

Duinkerke DJ, Botter PA, Janssen AAI, et al (1993). Ritanserin, a selective 5HT2/1c antagonist, and negative symptoms in schizophrenia: a placebo-controlled double-blind trial. Br J Psychiatry 163:451-5.

Ereshefsky L, Watanabe MD, Tran-Johnson TK (1989). Clozapine: an atypical antipsychotic agent. Clin Pharm 8:691-709.

Farde L, Nordstrom AL, Wiesel FA, et al (1992). Positron emission tomographic analysis of central D1 and D2 receptor occupancy in patients treated with classical antipsychotics and clozapine. Arch Gen Psychiatry 49:538-44.

Frankenburg FR, Zanarini MC, Kando J, et al (1998). Clozapine and body mass change. Biol Psychiatry 43:520-524.

Geibig CB, Marks LW (1993). Treatment of clozapine- and molindone-induced agranulocytosis with granulocyte colony-stimulating factor. Ann Pharmacother 27:1190-2.

Gerson SL, Gullion G, Yeh H, et al (1992). Granulocyte colony-stimulating factor for clozapine-induced agranulocytosis (letter). Lancet 340:1097.

Gerson SL, Lieberman JA, Friedenberg WR, et al (1991). Polypharmacy in fatal clozapine-associated agranulocytosis (letter). Lancet 338;262-3.

Goates MG, Escobar JI (1992). An apparent antipsychotic malignant syndrome without extrapyramidal symptoms upon initiation of clozapine therapy: report of a case and results of a clozapine rechallenge (letter). J Clin Psychopharmacol 12:139-40.

Goodwin FK, Zis AP (1979). Lithium in the treatment of mania. Comparison with neuroleptics. Arch Gen Psychiatry 36:840-4.

Grabowski J (1992). Clonidine treatment of clozapine-induced hypersalivation (letter). J Clin Psychopharmacol 12:69-70.

Grohmann R, Ruther E, Sassim N, Schmidt LG (1989). Adverse effects of clozapine. Psychopharmacology 99(Suppl):101-4.

Haring C, Meise U, Humpel C, et al (1989). Dose-related plasma levels of clozapine: influence of smoking behavior, sex and age. Psychopharmacol 99:W38-W40.

Hasegawa M, Gutierrez-Esteinou R, Way L, et al (1993). Relationship between clinical efficacy and clozapine concentrations in plasma in schizophrenia: effect of smoking. J Clin Psychopharmacol 13:383-90.

Heinrich K, Klieser E, Lehmann E, Kinzler E. Experimental comparison of the efficacy and compatibility of risperidone and clozapine in acute schizophrenia. In: Kane JM, ed. Risperidone: Major progress in antipsychotic treatment. Satellite Symposium at the 17th Congress of Collegium Internationale Neuropharmacologicum. Oxford: Oxford Clinical Communications, 1991.

Honigfeld G, Patin J (1989). Predictors of response to clozapine therapy. Psychopharmacology 99:S64-S67.

Honigfeld G, Arellano F, Sethi J, et al (1998). Reducing clozapine-related morbidity and mortality: 5 years experience with the clozaril national registry. J Clin Psychiatry 59(suppl 3):3-7.

Huttunen M (1995). The evolution of the serotonin-dopamine antagonist concept. J Clin Psychopharmacol 15(suppl 1):4S-10S.

Hyttel J, Arnt J, Costall B et al (1992). Pharmacological profile of the atypical antipsychotic sertindole. Clin Neuropharm 15 (suppl 1):267A-268A.

Idanpaan-Heikkila J, Alhava E, Olkinuora M, Palva IP (1977). Agranulocytosis during treatment with clozapine. Eur J Clin Pharmacol 11:193-8.

Johnstone EC, Crow TJ, Frith CE et al (1979). Mechanism of the antipsychotic effect in the treatment of acute schizophrenia. Lancet 1:848-51.

Joseph G, Nguyen V, Smith JD (1992). HLA-B38 and clozapine-induced agranulocytosis (letter). Ann Int Med 116:605.

Juul Povlsen U, Noring U, Fog R, et al (1985). Tolerability and therapeutic effect of clozapine: a retrospective investigation of 216 patients treated with clozapine for up to 12 years. Acta Psychiatr Scand 71:176-85.

Kane JM, Honigfeld G, Singer J, et al (1988). Clozapine for the treatment- resistant schizophrenic. Arch Gen Psychiatry 45:789-96.

Kane JM, Taminga CA, Schooler NR, et al (1996). Choosing among old and new antipsychotics. J Clin Psychiatry 57:427-38.

Kassahun K, Mattiuz E, Nyhart E, et al (1997). Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drug Metab Dispos 1997 25:81-93.

Keks NA (1997). Impact of newer antipsychotics on outcomes in schizophrenia. Clin Therap 19:148-58.

Kinon BJ, Lieberman JA (1996). Mechanisms of action of atypical antipsychotic drugs: a critical analysis. Psychopharmacology 124(1-2):2-34.

Kronig MH, Munne RA, Szymanski S, et al (1995). Plasma clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry. 152:179-82.

Kuha S, Mietinen E (1986). Long-term effect of clozapine in schizophrenia: a retrospective study of 108 chronic schizophrenics treated with clozapine for up to seven years. Nord Psykiatr Tidsfkr 40:225-30.

Lamberti JS, Bellnier T, Schwarzkopf SB (1992). Weight gain among schizophrenic patients treated with clozapine. Am J Psychiatry 149:689-90.

Leadbetter R, Shutty M, Pavalonis D, et al (1992). Clozapine-induced weight gain: prevalence and clinical relevance. Am J Psychiatry 149:68-72.

Lieberman JA, Kane JM, Johns CA (1989). Clozapine: guidelines for clinical management. J Clin Psychiatry 50:329-38.

Lieberman JA, Yunis J, Egea E, et al (1990). HLA-B38, DR4, DQw3 and clozapine-induced agranulocytosis in Jewish patients with schizophrenia. Arch Gen Psychiatry 47:945-8.

Lieberman JA, Saltz BL, Johns CA, et al (1991). The effects of clozapine on tardive dyskinesia. Br J Psychiatry 158:503-10.

Lindenmayer JP, Grochowski S, Mabugat L (1994). Clozapine effects on positive and negative symptoms: a six-month trial in treatment-refractory schizophrenics. J Clin Psychopharmacol 14:201-4.

Lindstrom LH (1989). A retrospective study on the long-term efficacy of clozapine in 96 schizophrenic and schizoaffective patients during a 13-year period. Psychopharmacol 99:S84-S86.

Livingston MG. Risperidone. Lancet 1994;343:457-60.

Lund BC, Perry PJ, Brook JM et al. Clozapine use in patients with schizophrenia and the risk of diabetes, hyperlipidemia, and hypertension: a claims-absed approach. Arch Gen Psychiatry (in press).

Marder SR, Meibach RC. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994;151:825-35.

Marder SR, Van Putten T (1988). Who should receive clozapine? Arch Gen Psychiatry 45:865-7.

Mattes JA (1989). Clozapine for refractory schizophrenia: an open study of 14 patients treated for up to 2 years. J Clin Psychiatry 50:389-91.

McElroy SL, Dessain EC, Pope HG, et al (1991). Clozapine in the treatment of psychotic mood disorders, schizoaffective disorder, and schizophrenia. J Clin Psychiatry 52:411-4.

Meltzer HY (1991). The mechanism of action of novel antipsychotic drugs. Schizophrenia Bull 1991;2:263-87.

Meltzer HY, Bastani B, Ramirez L, Matsubara S (1989). Clozapine: new research on efficacy and mechanism of action. Eur Arch Psychiatr Neural Sci 238:332-9.

Meltzer HY, Sommer AA, Luchins DJ (1986). The effect of antipsychotic and other psychotropic drugs on negative symptoms in schizophrenia. J Clin Psychopharmacol 6:329-38.

Miller CH, Mohr F, Umbricht D, et al (1998). The prevalence of acute extrapyramidal signs and symptoms in patients treated with clozapine, risperidone, and conventional antipsychotics. J Clin Psychiatry 59:69-75.

Miller DD, Sharafuddin MJA, Kathol R (1991a). A case of clozapine-induced antipsychotic malignant syndrome. J Clin Psychiatry 52:99-101.

Miller DD (1991b). Effect of phenytoin on plasma clozapine concentrations in two patients. J Clin Psychiatry 52:23-5.

Miller DD, Perry PJ, Cadoret RJ, et al (1994a). Clozapine's effect on negative symptoms in treatment-refractory schizophrenics. Compr Psychiatry 35:8-15.

Miller DD, Fleming F, Holman TL, et al (1994b). Plasma clozapine concentrations as a predictor of clinical response: a follow-up study. J Clin Psychiatry 55(suppl B):117-21.

Muller T, Becker T, Fritze J (1988). Antipsychotic malignant syndrome after clozapine plus carbamazepine. Lancet 31:1499-1500.

Muller-Spahn F, the International Risperidone Research Group (1992). Risperidone in the treatment of chronic schizophrenic patients. An international double-blind parallel-group study versus haloperidol. Clin Neuropharmacol 15[suppl 1]:90A-1A.

Naber D, Leppig M, Grohmann R, et al (1989). Efficacy and adverse effects of clozapine in the treatment of schizophrenia and tardive dyskinesia: a retrospective study of 387 patients. Psychopharmacology 99(Suppl):73-6.

Nopoulos P, Flaum M, Miller DD (1990). Atypical antipsychotic malignant syndrome with an atypical antipsychotic: clozapine-induced NMS without rigidity. Ann Clin Psychiatry 2:251-3.

Osser DN (1990). Is clozapine response different in antipsychotic nonresponders vs partial responders? Arch Gen Psychiatry 47:189.

Owen RR. Beake BJ. Marby D. Dessain EC. Cole JO (1989). Response to clozapine in chronic psychotic patients. Psychopharmacol Bull. 25:253-6.

Pacia SV, Devinsky O (1994). Clozapine-related seizures: Experience with 5,629 patients. Neurology 44:247-9.

Perry PJ, Miller DD, Arndt SV, et al (1991). Clozapine and norclozapine plasma concentrations and clinical response in treatment-refractory schizophrenics. American Journal of Psychiatry148:231-5.

Perry PJ, Miller DD (1993). The clinical utility of clozapine plasma concentrations. In: Marder S, Davis J, eds. The clinical use of neuroleptic plasma levels, Washington, DC: American Psychiatric Association Press.

Perry, PJ, Pursel M (1995). Analysis of clozapine Medicaid cost data for fiscal year 1992-1993 for the State of Iowa. Iowa Medicaid Drug Utilization Review Commission.

Pfister GM, Hanson DR, Roerig JL, et al (1992). Clozapine-induced agranulocytosis in a native american: HLA typing and further support for an immune-mediated mechanism. J Clin Psychiatry 53:242-44.

Pickar D (1995). Prospects for pharmacotherapy of schizophrenia. Lancet 345:557-62.

Pickar D, Owen RR, Litman FE, et al (1992). Clinical and biologic response to clozapine in patients with schizophrenia. Arch Gen Psychiatry 49:345-53.

Pope HG, Cole JO, Choras PT, Fulviler CE (1986). Apparent antipsychotic malignant syndrome with clozapine and lithium. J Nerv Ment Disorders 174:493-5.

Potkin SG, Bera R, Gulasekaram B, et al (1994). Plasma clozapine concentrations predict clinical response in treatment-resistant schizophrenia. J Clin Psychiatry 55[suppl B]:133-6.

Reyntgens A, Gelders YG, Hoppenbrouwers JA, et al (1986). Thymosthenic effects of ritanserin, a centrally acting serotonin S2 receptor blocker. Drug Dev Res 8:205-11.

Richelson E (1999). Receptor pharmacology of neuroleptics: relation to clinical effects. J Clin Psychiatry 60(suppl 10):5-14.

Rosenheck R, Cramer J, Allan E et al (1999). Cost-effectiveness of clozapine in patients with high and low levels of hospital use. Arch Gen Psychiatry. 56:565-572.

Ryabik BM, Nguyen VT, Mann RN, et al (1993). Clozapine-induced agranulocytosis and colony-stimulating cytokines. Gen Hosp Psychiatry 15:263-5.

Safferman AZ, Lieberman JA, Kane JM, et al (1991). Update on the clinical efficacy and side effects of clozapine. Schizophrenia Bull 17:247-61.

Safferman AZ, Lieberman JA, Pollack S, Kane JM (1992a). Clozapine and akathisia (letter). Biol Psychiatry 31:749-54.

Safferman AZ, Lieberman JA, Alvir JMJ, Howard A (1992b). Rechallenge in clozapine-associated agranulocytosis (letter). Lancet 339:1296-7.

Sassim N, Grohmann R (1988). Adverse drug reactions with clozapine and simultaneous application of benzodiazepines. Pharmacopsychiatry 21:306-7.

Sayers AC, Amsler HA (1977). Clozapine. Pharmacol Biochem Prop Drug 1:1-31.

Seftel AD, De Tejada IS, Szetela B, et al (1992). Clozapine-induced priapism: a case report. J Urology 147:146-8.

Small JG, Milstein V, Marhenke JD, et al (1987). Treatment outcome with clozapine in tardive dyskinesia, antipsychotic sensitivity, and treatment-resistant psychosis. J Clin Psychiatry 48:263-7.

Song F (1997).. Risperidone in the treatment of schizophrenia: a meta-analysis of randomized controlled trials. J Psychopharmacol 11:65-71.

Spivak B, Mester R, Abesgaus J, et al (1997). Clozapine treatment for neuroleptic-induced tardive dyskinesia, parkinsonism, and chronic akathisia in schizophrenic patients. J Clin Psychiatry 58:318-322.

Stahl SM (1999). Selecting an atypical antipsychotic by combining clinical experience with guidelines from clinical trials. J Clin Psychiatry 60(suppl 10):31-41.

Stahl SM (2000). Antipsychotic Agents In Essential Psychopharmacology. Cambridge University Press, New York: 401-58.

Stricker BH, Tielens JAE (1991). Eosinophilia with clozapine (letter). Lancet 338:1520-1.

Szymanski S, Jody D, Leipzig R, et al (1991a). Anticholinergic delirium caused by retreatment with clozapine (letter). Am J Psychiatry 148:1752.

Szymanski S, Lieberman JA, Picou D, et al (1991b). A case report of cimetidine-induced clozapine toxicity. J Clin Psychiatry 52:21-22.

Tatro DS (2000). Drug Interaction Facts. Facts and Comparisons, St Louis.

Tiihonen J, Paanila J (1992). Eosinophilia associated with clozapine (letter). Lancet 339:488.

Tollefson GD, Beasley CM, Tran PV, et al (1994). Olanzapine: a novel antipsychotic with a broad spectrum profile (abstract). Biol Psychiatry 35:746-747.

Tollefson GD, Sanger TM (1997). Negative symptoms: a path analytic approach to a double-blind, placebo- and haloperidol-controlled clinical trial with olanzapine. Am J Psychiatry. 154:466-74.

Tracy JI, Monaco CA, Abraham G, et al (1998). Relation of serum anticholinergicity to cognitive status in schizophenia patients taking clozapine or risperidone. J Clin Psychiatry 59:184-188.

Tran PV, Beasley CM, Tollefson GD, et al (1995). Olanzapine: a promising "atypical" antipsychotic agent (abstract). Schizo Res 15:169.

Tran PV, Tollefson GD, Andersen SW, et al (1997). Olanzapine versus risperdione in the treatment of psychosis. Presented at the Anual meeting of the American Psychiatric Association, San Diego, CA, May, 1997.

Uehlinger C, Baumann P (1991). Clozapine as an alternative treatment for antipsychotic-induced gynecomastia (letter). Am J Psychiatry 148:392-3.

Umbricht DS, Pollack S, Kane JM (1994). Clozapine and weight gain. J Clin Psychiatry 55(suppl B):157-60.

Volavka J, Czobor P, Sheitman B, et al (2002). Clozpine, olanzapine, risperidone, and haloperidol in the treatment of patients with chronic schizophrenia and schizoaffective disorder. Am J Psychiatry 159:255-62.

Walker AM, Lanza, LL, Arellano F, et al (1997). Mortality in current and former users of clozapine. Epidemiology 8:671-7.

Wehring H, Alexander B, Perry PJ (2000). Diabetes mellitus associated with clozapine therapy. Pharmacotherapy 20:844-7.

Weide R, Koppler H, Heymanns J, et al (1992). Successful treatment of clozapine-induced agranulocytosis with granulocyte colony stimulating activity (letter). Br J Haematol 4:5579.

Wiesel FA, Norstrom AL, Farde L, et al (1994). An open clinical and biochemical study of ritanserin in acute patients with schizophrenia. Psychopharmacology 114:31-8.

Wirshing DA. Marshall BD Jr. Green MF et al (1999). Risperidone in treatment-refractory schizophrenia. Am J Psychiatry. 156:1374-9.

Woerner MG, Sheitman BB, Lieberman JA, Kane JM (1996). Tardive dyskinesia induced by risperidone? Am J Psychiatry 153:843.

Wright P, Birkett M, David SR, et al (2001). Double-blind, placebo-controlled comparison of intramuscular olanzapine and intramuscular haloperidol in the treatment of acute agitation in schizophrenia. Am J Psychiatry 158:1149-51.

Zeigler J, Behar D (1992). Clozapine-induced priapism (letter). Am J Psychiatry 149:272-3.

Zyprexa package insert (1998). Eli Lilly and Company.

Title Page