Olanzapine: Preclinical and Clinical Profiles of a Novel Antipsychotic Agent

Transcription

1 CNS Drug Reviews Vol. 6, No. 4, pp Neva Press, Branford, Connecticut Olanzapine: Preclinical and Clinical Profiles of a Novel Antipsychotic Agent Gary D. Tollefson and Cindy C. Taylor Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA Key Words: Antipsychotic agent Dopamine antagonist Olanzapine Schizophrenia Serotonin antagonist. ABSTRACT The novel antipsychotic agent olanzapine (Zyprexa, Eli Lilly and Company) is a thienobenzodiazepine analog marketed for the treatment of schizophrenia. Olanzapine s diverse receptor binding profile and greater affinity for serotonin receptors over dopamine receptors is thought to impart antipsychotic efficacy with a low incidence of serious extrapyramidal symptoms (EPS). With once daily dosing steady-state plasma concentrations reached within approximately 1 week. Olanzapine is extensively metabolized by the liver, is mostly excreted in the urine, and has few drug intractions. In clinical trials, the efficacy of olanzapine for treating schizophrenia is better than placebo and haloperidol and comparable to risperidone. Olanzapine may also ameliorate some comorbid symptoms including negative symptoms, depression, anxiety, substance abuse, and cognitive dysfunction, and it is effective in the long-term maintenance of response, treatment-resistance, and improving quality of life. The overall direct costs are lower with olanzapine treatment compared with haloperidol or risperidone treatment. In clinical trials, olanzapine demonstrates a favorable safety profile. The most frequently reported treatment-emergent adverse events are somnolence, schizophrenic reaction, insomnia, headache, agitation, rhinitis, and weight gain. Significantly fewer EPS (based on formal rating scales) and incidences of tardive dyskinesia have been reported for olanzapine compared with haloperidol. Olanzapine has not been associated with persistent elevations of prolactin above the upper limit of normal nor has it been associated with clinically significant changes in cardiac QT c interval. Fewer incidences of suicide attempts have been reported with olanzapine compared with placebo, haloperidol, or risperidone treatments. There is evidence that olanzapine may be effective in the treatment of mood disorders, psychosis associated with Address correspondence and reprint requests to Dr. Gary Tollefson, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Drop Code 2033, Indianapolis, IN 46285, USA. Telephone: +1 (317) ; Fax: +1 (317) tollefson_gary_d@lilly.com, myers_suzanne@lilly.com 303

2 304 G. D. TOLLEFSON AND C. C. TAYLOR Alzheimer s disease, obsessive-compulsive disorder, pervasive developmental disorders, and delirium. Patients with schizophrenia have been successfully switched from other antipsychotics to olanzapine. In conclusion, olanzapine offers a significantly improved risk-to-benefit profile compared with haloperidol and possibly risperidone, and thus should be considered an important treatment option for schizophrenia and related disorders. INTRODUCTION Schizophrenia is the most debilitating of mental disorders. While the classical manifestation is a loss of contact with reality typically characterized by delusions, hallucinations, and disorganized behaviors, victims of schizophrenia exhibit a heterogeneity of clinical symptoms (Table 1). It is estimated that each year 1 in 10,000 adults (12 to 60 years of age) are diagnosed with schizophrenia (106), and at any given time, approximately 1% of the worldwide population is afflicted with this disease (63). In addition to extensive medical costs, the indirect burden of schizophrenia includes homelessness (136,185), substance abuse (36,68), criminal behavior (166,267), and a high rate of suicide (42,159). The objective of contemporary pharmacological therapy for schizophrenia is to alleviate both the positive symptoms (e.g., delusions, hallucinations, and disorganized speech and behavior) and negative or deficit symptoms (e.g., affective flattening, alogia, apathy or avolition, and anhedonia). To this aim, conventional or typical antipsychotic agents, such as haloperidol and chlorpromazine, which act through the selective antagonism of dopamine (D 2 ) receptors, are principally effective in treating the positive symptoms of schizophrenia (35). These agents have demonstrated minimal benefit for the core negative features of schizophrenia (176). Moreover, residual symptoms experienced by these patients, such as concurrent mood dysregulation, cognitive deficits, and anxiety, are oftentimes more disturbing to the patient with schizophrenia than their positive symptoms. These nonpositive disease features tend to be more persistent and, as a result, may significantly compromise the patient s quality of life and social functioning (177). An estimated 30% of patients with schizophrenia are treatment-resistant to conventional antipsychotic agents (118). Even among those patients receiving some degree of therapeutic response, noncompliance characterizes at least half of individuals, with experience of one or more adverse events being a chief causative factor (44,264). For example, TABLE 1. Schizophrenia symptom complexes and comorbid symptoms Condition Symptoms Psychosis Hallucinations, delusions, thought disorders, bizarre behavior Deficit syndrome Poverty of speech and speech content, blunted affect, social isolation, apathy, lack of motivation, anhedonia, attention impairment Comorbid Depressive Suicidal ideation Symptoms Comorbid anxiety Somatic symptoms Cognitive deficit Dissociative thinking, disorganization of thoughts, attention impairment Motor abnormality Abnormal movements, catatonia

3 OLANZAPINE 305 the occupation of striatal dopamine (D 2 ) receptors by conventional antipsychotic agents results in potentially serious EPS including dystonia, pseudoparkinsonism, akathisia, and tardive dyskinesia (103). Blockade of hypothalamic dopamine (D 2 ) receptors can also lead to hyperprolactinemia, which, in turn, has been associated with gynecomastia, amennorhea, and sexual dysfunction (96). These side effects, and the ensuing noncompliance characterizing a conventional antipsychotic regimen, frequently result in a relapse of psychotic symptoms with increased morbidity and mortality (264). A clear opportunity exists to better the risk-to-benefit profile characteristic of these older agents. Potential innovations in antipsychotic therapy had to first challenge the existing dopamine hypothesis of schizophrenia that postulated that an overactivity of dopamine was responsible for the symptoms of schizophrenia (64). The incomplete clinical efficacy of dopamine receptor antagonists, such as the inability to effectively ameliorate the negative symptoms of schizophrenia, alluded to the limitations of this hypothesis. Early observations that the serotonin (5-hydroxytryptamine; 5-HT) agonist lysergic acid diethylamide (LSD) could induce schizophrenia-like hallucinations implicated the serotonergic system in the pathophysiology of schizophrenia (110). Subsequently, clozapine, an agent with higher affinity for the serotonin 5-HT 2 receptor subtype relative to the dopamine D 2 receptor subtype, was reported efficacious for both the positive and negative symptoms of schizophrenia and in individuals historically refractory to conventional neuroleptics (79). Additionally, a lower relative dopamine D 2 receptor occupancy resulted in a lower incidence of EPS and hyperprolactinemia. These findings suggested that serotonin is likely to play an important role in the pathophysiology of schizophrenia and catalyzed the development of a second generation of so-called atypical antipsychotic agents. However, the use of clozapine has been limited to severely ill, treatment-resistant patients because of its associated risk of agranulocytosis (97,139). Hence, recent research efforts have focused on at least matching some of the benefits of clozapine in the context of a wider safety margin. To date, the published clinical trial experience with olanzapine (Zyprexa, Eli Lilly and Company) would appear to have reached this objective. PHYSICAL CHARACTERISTICS Chemistry Olanzapine is a thienobenzodiazepine analog (Fig. 1) with the chemical name of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno(2,3-b )(1,5)benzodiazepine (72). The molecular formula of olanzapine is C 17 H 20 N 4 S and it has a molecular weight of Olanzapine is a nearly water-insoluble yellow crystalline solid. Formulation Olanzapine is currently available only as an oral tablet in dosages of 5, 7.5, and 10 mg. A small preliminary study has been conducted on an oral lyophilisate of olanzapine, which is an orally disintegrating tablet that dissolves on contact with saliva (48). In 11 patients with schizophrenia, this orally disintegrating tablet formulation has a dissolution profile that is practical for use in patients who are unwilling or unable to swallow olanzapine in the traditional oral tablet form. Studies are also underway to examine the efficacy,

4 306 G. D. TOLLEFSON AND C. C. TAYLOR N N H N CH 3 N CH 3 Fig. 1. The chemical structure of olanzapine, 2-methyl-4-(4- methyl-1-piperazinyl)-10h-thieno(2,3-b )(1,5)benzodiazepine. S safety, pharmacodynamics, and pharmacokinetics of a short-acting intramuscular formulation of olanzapine (25,274,275). Preclinical Studies In vitro receptor selectivity Historically, the efficacy of antipsychotic agents has been attributed to the antagonism of dopamine D 2 receptors in mesolimbic regions (59,224). As a class, the atypical agents exhibit greater in vitro radioligand binding affinity for the serotonin 5-HT 2A receptor subtype than the dopamine D 2 receptor subtype, distinguishing them from the typical dopamine D 2 blockers (Table 2) (158,160,161). Among the new generation of antipsychotic agents, olanzapine exhibits binding activity most similar to clozapine. In addition to dopamine D 2 and serotonin 5-HT 2A receptor affinity, olanzapine demonstrates appreciable in vitro binding affinity for D 1,D 3,D 4, 5-HT 2C, 5-HT 3, 5-HT 6, histamine H 1, 1 -adrenergic, and M 1 M 4 muscarinic receptors (38). Olanzapine also has low affinity for 2 -adrenergic, histamine H 3, -aminobutyric acid A (GABA A ), benzodiazepine, and -adrenergic receptors. This in vitro binding profile is similar in both the rat and human brain. Recently, in cell lines transfected selectively with receptor subtypes and in receptor-selective isolated tissue studies, olanzapine was a particularly potent antagonist at 5-HT 2A, 5-HT 2B, 5-HT 2C, 1 - adrenergic, and histamine H 1 receptors (40). Additionally, olanzapine was demonstrated to have moderate antagonist activity at D 1 and weak activity at M 1 M 5 receptors. The ratio of D 2 -like (D 2,D 3,D 4 ) receptor affinity relative to D 1 -like (D 1,D 5 ) receptor affinity for olanzapine is much lower than that for haloperidol and similar to clozapine, demonstrating that olanzapine has dopamine binding activity more similar to clozapine than haloperidol (41). Furthermore, both olanzapine and clozapine bind relatively nonselectively to the subtypes of dopamine receptors. The D 2 D 1 receptor ratio has implications for the safety of a particular agent, as a higher D 2 D 1 receptor ratio suggests a greater propensity for inducing EPS (5). The serotonin binding profile of olanzapine is also diverse. Olanzapine exhibits strong affinity for the 5-HT 2A, 5-HT 2B, 5-HT 2C, and the recently characterized 5-HT 6 serotonin receptor subtypes, moderate affinity for the 5-HT 3 and 5-HT 7 subtypes, and low affinity for the 5-HT 1 and 5-HT 4 subtypes (38). By comparison, conventional neuroleptics, such as haloperidol, exhibit much lower affinity for each of these serotonin receptors, suggesting higher EPS potential. Affinity for the 5-HT 2A receptor has also been implicated for efficacy in the treatment of the negative symptoms of schizophrenia (142,201). Even less well understood, olanzapine s affinity for 5-HT 3 receptors is hypothesized to contribute to its antipsychotic activity by interacting with the dopamine system (57,202) and the high affinity for 5-HT 6 receptors has been suggested to imply a low propensity for EPS (212).

5 OLANZAPINE 307 Thus, serotonergic activity is likely an important contributor to the novel antipsychotic pharmacology of olanzapine. The importance of muscarinic receptor activity of antipsychotic agents is not fully understood, although it has been proposed that they may be involved in normal motor function and movement (14). Affinity for muscarinic receptors is unique to olanzapine and clozapine among the atypical antipsychotic agents (30). Although olanzapine has demonstrated both agonist and antagonist activity for the muscarinic receptors in vitro (40,278), the relatively minimal incidence of anticholinergic adverse events in clinical trials (17,19) suggests a comparatively weak muscarinic antagonist activity of olanzapine in vivo. Although it is not presently clear whether or not adrenergic or histamine receptors contribute to the therapeutic effects of antipsychotic agents, their possible role in adverse events has been suggested. Antagonism of 1 -adrenergic receptors may play a role in the large increases in norepinephrine and dopamine in the prefrontal cortex produced with olanzapine (33,143), which may, in turn, function in arousal, increased cognition, and elevated mood. Additionally, antagonism of 1 -adrenergic receptors may cause hypotension, dizziness, and a reflex form of tachycardia (206). Histamine H 1 receptor antagonism may contribute to weight gain and sedation (163). In Vivo Pharmacology In vivo functional assays One functional assay of in vivo dopamine receptor antagonism is the measurement of the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC). In rodent brain, olanzapine increases DOPAC consistent with dopamine receptor blockade (39). Both dopamine and serotonin receptor antagonism by olanzapine can be demonstrated in vivo by the blockade of peroglide (D 2 )-induced and quipazine (5-HT 2 )-induced increases in serum corticosterone levels (84). In this assay, olanzapine showed a greater potency at antagonizing 5-HT 2 -mediated than D 2 -mediated increases in serum corticosterone (an approximate 5:1 ratio). This profile is intermediate to either clozapine (5-HT 2 preference) or haloperidol (D 2 preference). Thus, in vivo functional assays support the in vitro data demonstrating the af- TABLE 2. Pharmcological profile (K i [nm]) of olanzapine vs. comparator antipsychotic agents a K i (nm) Compound D 1 D 2 D 4 5-HT 1 A 5-HT 2A 5-HT 2C 1 2 H 1 M 1 Olanzapine > Clozapine Risperidone >10,000 Haloperidol a From Bymaster et al. (38).

6 308 G. D. TOLLEFSON AND C. C. TAYLOR finity of olanzapine for both D 2 and 5-HT 2 receptors, with higher affinity for 5-HT 2 over D 2 receptors. In a recent study, in mice depleted of their dopamine stores, olanzapine was shown to have partial D 2 agonist activity and strong D 1 antagonist activity (181). Although further studies are necessary to confirm these findings, the atypical clinical effect of olanzapine may be explained by this pharmacological duality at the dopamine receptor subtypes. Finally, in vivo, olanzapine stimulated histamine H 3 neuron activity via blockade of the 5-HT 2A receptor (173). One possible discrepancy between the olanzapine in vitro and in vivo studies is that while olanzapine binds to muscarinic receptors in vitro, in vivo it does not induce a deficit in spatial memory, as measured by the Morris Water Maze Test (172). As mentioned previously, this may suggest that olanzapine has some muscarinic agonist properties. Clearly, further studies are necessary to fully define the muscarinic profile of olanzapine and implications for its pharmacological characteristics. C-fos The elevation of the fast gene c-fos indicates neuronal activity. Typical antipsychotic agents elevate c-fos in both the dorsolateral striatum and the nucleus accumbens (70). The induction of c-fos in the dorsolateral striatum suggests a propensity to induce EPS (70), whereas induction in the nucleus accumbens likely reflects antipsychotic activity since c-fos expression is increased in this region by all antipsychotic agents tested to date (66,180,211). Olanzapine preferentially elevates c-fos in the nucleus accumbens and lateral septal nucleus in a dose-dependent manner (210). Olanzapine-induced increases in the dorsolateral striatum, which are considerably smaller in magnitude than those produced in the nucleus accumbens, suggest olanzapine s regional selectivity and predict antipsychotic potential with minimal EPS. Moreover, olanzapine also increases c-fos expression in the medial prefrontal cortex (210), a property not typical of the conventional neuroleptic agents (209). This prefrontal profile is suggestive of clinical activity in both the negative and cognitive symptoms of schizophrenia (91,265,270). Recently, cross-tolerance was observed between the c-fos responses of olanzapine and haloperidol in the rostral part of the cingulate cortex, the dorsomedial and dorsolateral striatum, the nucleus accumbens, and the lateral septum, whereas cross-tolerance between olanzapine and clozapine was observed in the prefrontal cortex, the lateral septum, the hypothalamic paraventricular nucleus, and the amygdala (223). The interactions of olanzapine, clozapine, and haloperidol in the lateral septum, another important component of the limbic system, suggest that it might also be a target for the antipsychotic efficacy of these agents. Microdialysis Microdialysis experimentation has demonstrated that olanzapine increases both extracellular dopamine and norepinephrine levels in a dose-dependent fashion in the nucleus accumbens, striatum, and prefrontal cortex (143). This is an effect not seen with the conventional neuroleptic agents and several of the newer compounds. The greatest olanzapine-related increases in dopamine and norepinephrine occurred in the prefrontal cortex and were significantly larger than those observed in the nucleus accumbens or striatum (Fig. 2). The authors suggest that the enhancement of dopaminergic and noradrenergic transmission in the prefrontal cortex may contribute to an understanding of olanzapine s clinical effects on negative and mood symptoms. Furthermore, increased dopamine release in the prefrontal cortex has been related also to enhancement of cognitive function (221). In order of magnitude, the dopamine and norepinephrine increases in the prefrontal

7 OLANZAPINE Prefrontal cortex Nucleus accumbens Striatum 400 % of baseline Dopamine Norepinephrine Fig. 2. Comparison of the change from baseline extracellular levels of dopamine and norepinephrine in the prefrontal cortex, nucleus accumbens, and striatum induced by 10 mg kg olanzapine. Data from Li et al. (143). cortex induced by olanzapine were slightly higher than those of clozapine, while haloperidol-related prefrontal cortex effects were negligible (Fig. 3). The similar induction of dopamine release by olanzapine in the nigrostriatal and mesolimbic dopamine areas may contribute to its lower incidence of EPS. In a recent study on the effects of antipsychotic agents on extracellular dopamine levels, olanzapine and risperidone produced comparable increases in extracellular dopamine levels in the medial prefrontal cortex and the nucleus accumbens (135). For olanzapine (10 mg kg), greater effects were observed in the medial prefrontal cortex than the nucleus accumbens. In comparison, haloperidol significantly increased extracellular dopamine levels in the nucleus accumbens, but not the medial prefrontal cortex. Thus, the ability of antipsychotic agents to increase extracellular dopamine levels in the medial prefrontal cortex compared to the nucleus accumbens appears to be positively correlated with the affinities for 5-HT 2A and D 2 receptors. Olanzapine (1 and 10 mg kg) and haloperidol, unlike clozapine and risperidone, had no significant effect on extracellular 5-HT levels in the medial prefrontal cortex or the nucleus accumbens (112). These findings suggest that the release of 5-HT by antipsychotic agents in these regions is not directly related to their affinity for 5-HT 2A receptors. While both are effective in treating the negative symptoms of schizophrenia, the inability of these agents to increase extracellular levels of 5-HT in the nucleus accumbens suggests that the ability to improve negative symptoms by these agents is not mediated by a serotonergic mechanism. Electrophysiology Electrophysiological studies have also demonstrated the regional selectivity of olanzapine. In one study, a decrease in the number of spontaneously active dopaminergic neurons in both the mesolimbic (A10) and nigrostriatal (A9) tracts occurred following chronic exposure to typical neuroleptic drugs, such as haloperidol (268). In contrast, olan-

8 310 G. D. TOLLEFSON AND C. C. TAYLOR % of baseline Olanzapine Clozapine Haloperidol 0 Dopamine Norepinephrine Fig. 3. Comparison of the change from baseline prefrontal cortex extracellular levels of dopamine and norepinephrine by olanzapine (10 mg kg), clozapine (10 mg kg), and haloperidol (2 mg kg). Data from Li et al. (143). zapine selectively decreased the number of spontaneously active A10, but not A9, dopamine cells (236,268). The A10 neurons project primarily to limbic and cortical regions (associated with psychosis), whereas A9 neurons project primarily to striatum (associated with EPS). The previously described ability of olanzapine to increase dopamine levels in the prefrontal cortex may reduce dopamine hypofrontally in this area, which may be associated with its efficacy for the negative symptoms of schizophrenia, whereas olanzapine s ability to attenuate dopamine hyperactivity in the nucleus accumbens may be important for its positive symptom efficacy. Neurotensin The neuropeptide neurotensin has been hypothesized to play a role in modulation of the dopamine system. Furthermore, biochemical and behavioral studies suggest that neurotensin has inherent antipsychotic activity (28). Low cerebrospinal fluid (CSF) concentrations of neurotensin are associated with higher levels of psychopathology (225). In addition, patients treated with antipsychotic agents exhibit increased CSF neurotensin levels corresponding with improvements in overall psychopathology, particularly negative symptoms (225). Interestingly, neurotensin is differentially synthesized within the brain following administration of atypical compared to typical antipsychotic agents (165). Furthermore, clinically effective antipsychotic agents selectively increase expression of neurotensin mrna in the nucleus accumbens, whereas only the typical neuroleptic agents also increase neurotensin mrna expression in the dorsolateral striatum. This latter effect in the extrapyramidal region primarily involved in motor control (164) is predictive of EPS (165). In rats, chronic olanzapine treatment (21 days) has been shown by in vivo microdialysis to preferentially increase neurotensin mrna expression within the nucleus accumbens (200), attesting to its atypicality (i.e., antipsychotic potential with low EPS potential). Haloperidol, in contrast, increased neurotensin release in both the striatum and nucleus accumbens. Of note, c-fos expression precedes the increases in neurotensin mrna levels in the dorsolateral striatum following administration of antipsychotic agents (165), suggesting that c-fos plays a role in regulating neurotensin transcription in this brain region.

9 OLANZAPINE 311 Non-Human Behavioral Pharmacology Amphetamine-induced hyperactivity As discussed previously, the selectivity of olanzapine for mesolimbic A10 over striatal A9 dopamine receptors suggests antipsychotic activity with decreased EPS. An in vivo behavioral assay for mesolimbic activity is the inhibition of stimulant-induced hyperactivity. Olanzapine significantly reduces cocaine-induced hyperactivity (indicating activity at mesolimbic dopamine receptors), while having no effect on amphetamine-induced hyperactivity (indicating negligible activity at striatal dopamine receptors) (171). Catalepsy The induction of catalepsy (CAT) in animal models is indicative of EPS, whereas the blockade of the conditioned avoidance response (CAR) is used to predict antipsychotic potential (8,73,273). Olanzapine induces catalepsy at a dose more than twice that required to block the conditioned avoidance response (170). In contrast, haloperidol exhibits less separation between the dose that inhibits avoidance responding and the dose that induces catalepsy (CAT CAR ratio: olanzapine = 8.4 vs. haloperidol = 2.2) (172). In a recent study, olanzapine (0.25 and 0.5 mg kg) did not induce a decrease in spontaneous locomotor activity and did not induce catalepsy (182). PCP-induced social withdrawal The noncompetitive NMDA antagonist phencyclidine (PCP) induces psychoses that resemble both the positive and negative symptoms of schizophrenia in human subjects (114). The ability of an agent to block PCP-induced social withdrawal in rodents is a behavioral model suggesting efficacy for alleviating the negative symptoms of schizophrenia. Olanzapine significantly reversed this behavior. On the contrary, haloperidol, chlorpromazine, and risperidone failed to block this response in doses up to those inducing significant motor impairment (55). In addition, olanzapine antagonizes dizocilpine (MK-801)-induced hyperlocomotion and falling behavior, but not stereotypy (55,182). Oral dyskinesia and dystonia The induction of oral dyskinesias, including vacuous chewing movements, represents an animal model of dyskinesia. Chronic administration of olanzapine did not produce a significant incidence of haloperidol-like vacuous chewing movements, and the movement rating with olanzapine was not significantly different from placebo (85). In contrast, haloperidol produced a 60% prevalence of vacuous chewing movements, which was significantly increased compared with placebo. The frequency of lapping behavior, another movement disorder model, was not altered with olanzapine, whereas it was decreased with haloperidol (61). Finally, in sensitized Cebus monkeys, the dystonia threshold dose for olanzapine is 0.08 mg kg compared with 0.01 mg kg for haloperidol (88). Paw Test A paw test was conducted in rats in which hindlimb reaction time (a measure of antipsychotic activity) was measured against forelimb reaction time (predictive of EPS) for various atypical antipsychotic agents (54). All atypical neuroleptics increase hindlimb reaction time at doses that are much smaller than those that increase forelimb reaction time.

10 312 G. D. TOLLEFSON AND C. C. TAYLOR For olanzapine, the minimum effective dose for forelimb reaction time was approximately 20 times greater than for hindlimb reaction time, compared with a ratio of 10:1 for risperidone or sertindole. Furthermore, olanzapine potently inhibited the locomotor activity induced by dopamine injections into the olfactory tubercle, but did not inhibit locomotor activity induced by ergometrine injections into the nucleus accumbens (54). These results demonstrate that, like other atypical agents, olanzapine preferentially acts in the olfactory tubercle. In Vivo Human Pharmacology In vivo imaging techniques such as positron emission tomography (PET) and single photon emission computed tomography (SPECT) have been used to detect the displacement of a radioligand by an antipsychotic agent. Using PET, classical antipsychotic agents typically demonstrate a high degree (70 to 89%) of striatal D 2 dopamine receptor occupancy consistent with the induction of EPS (76). In contrast, PET studies of subjects receiving low to moderate doses of clozapine (150 to 300 mg) show a striatal D 2 dopamine receptor occupancy in the range of 38 to 63% (76). This is coupled with a higher 5-HT 2 cortical receptor occupancy of 85 to 90% (184). Single dose PET studies following administration of olanzapine (10 mg) in three healthy volunteers showed receptor occupancies of 74 to 92% for 5-HT 2 receptors and 59% to 63% for D 2 receptors (186). Another study investigated olanzapine s binding to 5-HT 2 and D 2 receptors in patients with schizophrenia (n = 12) treated with clinically relevant doses (5, 10, 15, and 20 mg day) (121). Olanzapine induced near saturation of 5-HT 2 sites at all doses in this study, with all patients showing >90% occupancy. The D 2 receptor occupancy was dose-related with an average of 55% occupancy with 5 mg day, 73% with 10 mg day, 75% with 15 mg day, and 76% with 20 mg day. For three patients who received doses of 30 to 40 mg day of olanzapine, D 2 receptor occupancy was 83 to 88%. Results of these studies suggest that routine clinical doses of olanzapine displace significant 5-HT 2 binding to cortical receptors, while only modestly displacing striatal D 2 receptors binding. These results predict little or no EPS. A more recent PET comparative study in 44 patients with schizophrenia reported D 2 receptor occupancy with clozapine to be 16 to 68%, with risperidone to be 63 to 89%, and with olanzapine to be 43 to 89%, at clinically relevant doses of these drugs (120). D 2 receptor occupancies were equal with 5 mg day of risperidone and 20 mg day of olanzapine. Furthermore, in this study, all three atypical agents demonstrated greater 5-HT 2 than D 2 receptor occupancy at all doses studied. It has been suggested that a D 2 receptor occupancy of 60 to 70% is necessary to elicit antipsychotic activity (except with clozapine), occupancy beyond 70% is associated with hyperprolactinemia, and levels exceeding 80% increase the risk for EPS. A SPECT study in patients with schizophrenia who have responded over 6 weeks of acute drug treatment revealed a striatal D 2 receptor occupancy with olanzapine that was not significantly different from clozapine, albeit significantly lower than that observed in patients receiving either haloperidol or risperidone (193). Recently, striatal D 2 receptor occupancy was measured by [ 123 I] iodobenzamide (IBZM) SPECT imaging in patients with schizophrenia treated with olanzapine (10 to 25 mg day, n = 6), clozapine (300 to 600 mg day, n = 6), or haloperidol (5 to 20 mg day, n = 10) (240). Mean striatal D 2 receptor occupancy was 75% (range 63 to 85%) with olanzapine, 84% (range 67 to 94%) with haloperidol, and 33% (range <20 to 49%) with clozapine. In this study, there was no

11 OLANZAPINE 313 correlation between the degree of striatal D 2 receptor occupancy and clinical improvement, although the incidence and severity of EPS were correlated with the higher striatal D 2 receptor occupancy of haloperidol. Some methodological differences between these two SPECT studies may account for the apparently discrepant results. Finally, it has been proposed that the affinity of olanzapine for 5-HT 2 and muscarinic receptors may be responsible for the low incidence of EPS in olanzapine-treated patients, notwithstanding its relatively high D 2 receptor occupancy (240). Furthermore, although the typical D 2 receptor occupancy for olanzapine was above 70%, which is thought to be associated with hyperprolactinemia, olanzapine treatment has not been associated with persistent prolactin elevations above the upper limit of normal (58). Summary of the Preclinical Evidence for Low EPS Potential with Olanzapine Preclinical studies with olanzapine have provided biochemical and behavioral evidence to support antipsychotic efficacy with a favorable EPS safety profile (Table 3). In vitro binding studies have shown that olanzapine has a diverse neurotransmitter receptor binding profile, with preferential affinity for the 5-HT receptors conferring low EPS potential. The receptor selectivity of olanzapine has been confirmed using PET and SPECT analysis in humans. Furthermore, olanzapine preferentially induces neuronal activity in the nucleus accumbens (antipsychotic activity) vs. the striatum (EPS potential). Behavioral studies with rats and nonhuman primates further suggest that the dose necessary for antipsychotic-like activity is widely separated from the dose that produces motor disturbances. PHARMACOKINETICS Table 4 summarizes the pharmacokinetic properties of olanzapine. Olanzapine is completely absorbed following oral administration, reaching peak plasma concentrations within 5 to 8 h. In six healthy male subjects, a single oral 12.2 mg dose resulted in a maximum plasma concentration (C max )of11 1ng ml, which occurred h following administration (188). The C max and areas under the concentration time curve (AUC) are proportional to the dose administered (24). The volume of distribution of olanzapine is approximately 1000 L, indicating that it is widely distributed in tissues (72). Olanzapine is highly bound to plasma proteins (93%), largely albumin and 1 -acid glycoprotein. In humans, olanzapine is extensively metabolized by the liver, resulting in the production of several metabolites, primarily a glucuronide (see below). Olanzapine is eliminated mostly in the urine (52% of a radiolabeled dose) following a single oral dose (188). The elimination half-life (t 1 2 ) of olanzapine is approximately 30 h, and systemic clearance is L h (72,188). Assuming that steady-state is attained in five halflives, olanzapine steady-state concentrations are reached within approximately 1 week. At steady-state, plasma olanzapine concentrations typically vary only 4- to 5-fold, whereas some other antipsychotic agents result in up to 30-fold or greater differences in patient blood levels (75). Women and elderly subjects demonstrate a modestly increased t 1 2 and decreased clearance (191); however, this alone is usually not sufficient to require a change in dose (24). Smokers have a clearance of olanzapine that is approximately 40% higher

12 314 G. D. TOLLEFSON AND C. C. TAYLOR TABLE 3. Biochemical and behavioral characteristics of olanzapine suggesting low EPS potential Study Characteristic Bymaster et al. (38) D 2 D 1 binding affinity ratio of 3:1 Bymaster et al. (38); Fuller and Snoddy (84) Roth et al. (212) Bolden et al. (30) Robertson and Fibiger (210) Li et al. (143) Stockton and Rasmussen (236) Merchant and Dorsa (165) Radke et al. (200) Selectivity for the serotonin 5-HT 2A receptor over the dopamine D 2 receptor both in vivo and in vitro Affinity for the 5-HT 6 receptor Affinity for muscarinic receptors Olanzapine-induced increases in c-fos expression in the dorsolateral striatum are considerably smaller than in the nucleus accumbens Similar induction of dopamine release in the nigrostriatal and mesolimbic dopamine areas Chronic administration of olanzapine selectively inhibits A10 relative to A9 dopamine cells Increased expression of neurotensin mrna in the nucleus accumbens, but not in the dorsolateral striatum Chronic olanzapine treatment (21 days) in rats preferentially increases neurotensin mrna expression within the nucleus accumbens Moore et al. (171) Significantly reduces cocaine-induced hyperactivity (a measure of mesolimbic dopamine receptors) while having no effect of amphetamine-induced hyperactivity (a measure of striatal dopamine receptors) Moore et al. (170) Induces catalepsy at a dose more than twice that required to block the conditioned avoidance response Ninan and Kalkarni (182) Does not induce a decrease in spontaneous locomotor activity and did not induce catalepsy Gao et al. (85) Vacuous chewing movements (VCM) minimally induced following 6 months of continuous treatment Das and Fowler (61) Inhibits licking rhythm while inhibition of within-session decrements in lapping behavior is not affected Gerlach and Peacock (88) In sensitized Cebus monkeys, the dystonia threshold dose for olanzapine is 0.08 mg kg compared with 0.01 mg kg for haloperidol Cools et al. (54) Increases hindlimb retraction time (predictive of antipsychotic activity) at doses 20 times lower than those necessary to increase forelimb retraction time (predictive of EPS) Nyberg et al. (186); Kapur et al. (120); Kapur et al. (121) Tauscher et al. (240) Pilowsky et al. (193) PET analysis reveals D 2 receptor occupancy less than 80%. Greater 5-HT 2 than D 2 receptor occupancy at all clinically relevant doses By SPECT, affinity for 5-HT 2 and muscarinic receptors By SPECT, 6 weeks of acute drug treatment revealed a striatal D 2 receptor occupancy not significantly different from clozapine, albeit significantly lower than haloperidol or risperidone

13 OLANZAPINE 315 than nonsmokers, but adjustments in dosage are not routinely recommended based on smoking status alone (72). The available pharmacokinetic data indicate that dosage adjustment based on the degree of renal or hepatic impairment alone is not required (72). In humans, olanzapine is extensively metabolized after oral administration to yield some 10 metabolites, all of which appear to be behaviorally inactive. Olanzapine undergoes N-glucuronidation, allylic hydroxylation, N-oxidation, and N-demethylation. Only two of the resulting metabolites, 10-N-glucuronide olanzapine (44% olanzapine concentration at steady state) and 4-N-desmethyl olanzapine (31% olanzapine concentration at steady state) (122) are present in concentrations that potentially could be clinically relevant. Both metabolites lack pharmacological activity at the concentrations studied (72). Characterization in human liver slices confirmed both phase I and phase II metabolism of olanzapine in the liver (179). Although the oxidative metabolic profile of olanzapine in mice, dogs, and rhesus monkeys is similar to that found in humans, these species do not form appreciable amounts of the principle human metabolite, 10-N-glucuronide olanzapine (154). The enzymes responsible for the oxidation of olanzapine are the human cytochrome P450 isoenzymes CYP1A2 (apparent K i 36 M), CYP2D6 (apparent K i 89 M), and the flavin-containing monooxygenase system (208). The dominance of the N-glucuronide pathway of olanzapine metabolism has been demonstrated. Given the relatively low affinity that olanzapine possesses for the cytochrome P450 family (micromolar), routine clinical dosing would not be predicted to inhibit metabolism of most concomitantly administered drugs degraded through these pathways (Table 5) (207,208). In fact, it has been demonstrated that olanzapine does not affect the kinetics of imipramine or desipramine, and therefore does not show a metabolic drug interaction involving CYP2D6 (43). The Pharmacokinetic Property TABLE 4. Pharmacokinetic Properties of Olanzapine Specific Olanzapine Value(s) Comments Peak plasma concentration (C max ) 11 g L After a single 12.2 mg dose; proportional to dose administered Time to peak plasma concentration 5 to 8 h Absorption unaffected by food intake AUC 227 g L h After a single 12.2 mg dose; proportional to dose administered Volume of distribution L kg Widely distributed in tissues L kg a Major metabolic route Hepatic Several metabolites are formed having no clinically significant activity Inhibition of drug-metabolizing enzyme routes Elimination half-life Clearance Weak 21 to 54 h (median = 31 h) Excretion Urinary (52%) Fecal (23%) a Aged years. Magnitude suggests few clinically important drug-drug interactions Clearance is modestly lower in females, nonsmokers, and those aged L h L h a Allowing for once daily dosing regimen Clearance not significantly different for those patients with severe renal failure

14 316 G. D. TOLLEFSON AND C. C. TAYLOR pharmacokinetics of olanzapine is altered by concomitant treatment with carbamazepine, resulting in a more rapid clearance, most likely due to the induction of CYP1A2 by carbamazepine (148). This interaction results in increased first-pass and systemic metabolism of olanzapine, but is not thought to be of clinical significance. Coadministration of olanzapine with fluvoxamine, a potent inhibitor of CYP1A2, may also lead to a small increase in the steady-state plasma levels of olanzapine. These results further confirm the significant role of CYP1A2 in the clearance of olanzapine. Ethanol (45 mg 70 kg, single dose) or warfarin (20 mg, single dose) did not affect olanzapine pharmacokinetics (72). The coadministration of olanzapine with either diazepam or ethanol may potentiate the orthostatic hypotension observed with olanzapine. EFFICACY PROFILE The efficacy of olanzapine in treating schizophrenia has been evaluated in several open-label studies and placebo-controlled, double-blind clinical trials (Table 6). The double-blind clinical trials include those that have directly compared the efficacy of olanzapine with placebo and or typical neuroleptics (haloperidol, fluphenazine) or atypical antipsychotic agents (risperidone). Efficacy measurements in these studies have typically been based on the last-observation-carried-forward (LOCF) change score on the Positive and Negative Syndrome Scale (PANSS) (123) and or the Brief Psychiatric Rating Scale total (BPRS; items extracted from the PANSS and scored 0 to 6) (189). Secondary measurements have included the PANSS factors or BPRS subscales (189), the Scale for the Assessment of Negative Symptoms (SANS) (6), the Montgomery-Åsberg Depression Rating Scale (MADRS) (169), and the Clinical Global Impression-Severity of Illness (CGI-S) (98). More recently, studies have also examined the efficacy of olanzapine versus clozapine and haloperidol in treatment-resistant schizophrenia, vs. placebo in the treatment of bipolar disorder, vs. haloperidol and risperidone in comorbid cognitive dysfunction, and vs. fluphenazine for comorbid anxiety. Open-Label Studies The first clinical experience with olanzapine was a 4-week trial involving 10 patients with schizophrenia who received olanzapine 5 to 30 mg day (12). In this study, 5 of the 10 TABLE 5. Inhibition of metabolizing enzymes (apparent K i [ M]) a by olanzapine and clozapine b Enzyme Olanzapine Clozapine CYP3A CYP2D CYP2C CYP2C a K i S.E. of the parameter estimate. b From Ring et al. (207).

15 TABLE 6. Olanzapine (OLZ) in clinical trials of schizophrenia and related disorders Study Study Design Comparator(s) Duration (weeks) Total (N ) Summary of Results Open-label (12) Open-label, 5 30 mg day None of 10 patients responded vs. PLC (17) Multicenter, fixed-dose PLC OLZ (10 mg day) was significantly superior to PLC on BPRS total, (1 mg day or 10 mg day), PANSS total score, BPRS positive symptom, PANSS positive symptom, randomized (1:1) PANSS negative symptom, and CGI-S scale; fewer EPS with OLZ than PLC vs. PLC and HAL (19) Randomized (1:1), parallel, multicenter; 5,10, or 15 mg day vs. HAL (250) International, randomized (2:1) multicenter, double-blind, 5 20 mg day vs. HAL (16) Multicenter, randomized (1:1); 5,10,15 mg day vs. RIS (256) International, randomized (1:1) multicenter, double-blind, parallel, mg day vs. RIS (241) Multicenter, double-blind, randomized, mg day vs. FLU (113) vs. CHL (147) Treatmentresistance (153) Multicenter, double-blind randomized, parallel; 5 20 mg day Double-blind, randomized (2:1); 5 20 mg day Open-label (15 25 mg day) PLC; HAL 15 mg day) HAL (5 20 mg day) HAL (15 mg day) RIS (4 12 mg day) RIS (4 8 mg day) FLU (6 21 mg day) CHL ( mg day) OLZ medium and high dose and HAL were significantly superior to PLC on BPRS total; OLZ high dose was numerically superior to HAL and significantly superior to PLC on SANS OLZ was significantly superior to HAL on BPRS total, CGI-S, PANSS negative symptom, BPRS negative, and MADRS total OLZ high dose was significantly superior to OLZ low dose; no significant difference between OLZ and HAL as measured by BPRS total Significant improvements with OLZ and RIS on PANSS, BPRS, SANS, and CGI-S; OLZ significantly superior to RIS in improvement on SANS summary score and PANSS mood item OLZ and RIS had equivalent efficacy on improvements in general psychopathology; OLZ was significantly superior to RIS on BPRS total and PANSS General Psychopathology at 30 weeks 6, Numerical improvements with both OLZ and FLU on the PANSS, BPRS, and CGI; OLZ significantly superior to FLU on the CGI-S; after 22 weeks, OLZ significantly superior to FLU on the PANSS positive 6 41 OLZ was significantly superior to CHL on PANSS total score, PANSS general psychopathology, PANSS mood, BPRS total, and BPRS positive None 6 25 Statistically significant improvements from baseline in positive and negative symptoms Abbreviations: olanzapine (OLZ); placebo (PLC); haloperidol (HAL); risperidone (RIS); fluphenazine (FLU); chlorpromazine (CHL); clozapine (CLZ); Brief Psychiatric Rating Scale (BPRS; extracted from PANSS, 0 6 scale); Positive and Negative Syndrome Scale (PANSS); Clinical Global Impression-Severity (CGI-S); Scale for the Assessment of Negative Symptoms (SANS); Montgomery Åsberg Depression Rating Scale (MADRS); extrapyramidal symptoms (EPS). OLANZAPINE 317

16 318 G. D. TOLLEFSON AND C. C. TAYLOR patients responded with a decrease in the mean BPRS total score ranging from 66 to 87%. BPRS negative symptom item scores (blunted affect, emotional withdrawal, psychomotor retardation) decreased on average by 81% at week 4 of treatment, with 7 of the 10 patients achieving a reduction in BPRS negative symptom items of 40%. Five subsequent 6- or 8-week open-label studies showed similar results with mean decreases in BPRS total scores of approximately 10 to 20 points. Double-Blind Comparator Studies Olanzapine vs. placebo This was a multicenter, 6-week, fixed-dose, randomized study conducted in the United States (17). Patients with DSM-III-R diagnosis of schizophrenia and a BPRS total score of 24 (n = 152) were randomized to placebo, or olanzapine 1 or 10 mg day. The approximate mean baseline scores were 38 for BPRS total score and 25 for the PANSS negative symptom scale. Olanzapine 10 mg day was statistically significantly superior to placebo in BPRS total score (P = 0.04) and PANSS (P = 0.006) symptomatic improvement, including BPRS positive symptom (P = 0.011), PANSS positive symptom (P = 0.013), PANSS negative symptom (P = 0.02) subscales, and on the CGI-S scale (P = 0.013). Olanzapine 1 mg day did not significantly separate from placebo, suggesting it has minimal activity in schizophrenia. The response rates ( 40% decrease in BPRS total score from baseline or a final BPRS total score of 18 following at least 3 weeks of therapy) were 9.5% with placebo, 11.9% with olanzapine 1 mg day, and 27.9% with olanzapine 10 mg day. Olanzapine vs. haloperidol and placebo This study was a randomized, parallel, active- and placebo-controlled study conducted at 22 sites in the United States and Canada (19). This study compared the efficacy of three fixed dosage ranges of olanzapine (5 2.5 mg day [Olz-L], mg day [Olz-M], mg day [Olz-H]) with haloperidol (15 5mg day) and placebo in 335 schizophrenic patients (DSM-III-R) with a baseline BPRS score of 24. The mean baseline BPRS total score was approximately 42 (items scored 0 to 6) and the mean baseline SANS composite score was approximately 44, indicating relatively severe overall psychopathology and severe negative symptomatology. After 6 weeks of acute treatment, Olz-M and Olz-H and haloperidol resulted in statistically significant improvements (P 0.01) over placebo in BPRS total scores. Moreover, Olz-M and Olz-H, like haloperidol, separated from placebo on positive symptoms as measured by the BPRS positive symptom subscale (P 0.05). On baseline to endpoint SANS improvement, significant superiority over placebo was observed with both Olz-L (P 0.05) and Olz-H (P 0.001), whereas haloperidol did not separate from placebo. When compared against each other, Olz-H was also significantly more effective than haloperidol in SANS score improvement (P 0.05). Olanzapine vs. haloperidol (17 countries) This study was a 6-week, international, multicenter, double-blind trial designed to compare the therapeutic effects of olanzapine versus the conventional antipsychotic agent

17 OLANZAPINE 319 haloperidol across a flexible dose range (250). A total of 1996 inpatients or outpatients with a DSM-III-R diagnoses of schizophrenia (83%), schizophreniform disorder (2%), or schizoaffective disorder (15%) (data on file) were enrolled from 174 sites in Europe and North America. Patients were required to have a BPRS total score of 18 and or be intolerant to their most recent therapy (excluding haloperidol). A total of 76.7% of the olanzapine-treated patients and 77.6% of the haloperidol-treated patients either had to discontinue or were unresponsive to their last course of antipsychotic therapy. The mean baseline BPRS total score was approximately 33 and the mean baseline PANSS negative symptom score was approximately 24. Patients were blindly randomized 2:1 to either olanzapine (n = 1336) or haloperidol (n = 660) and initiated therapy at 5 mg of study drug. Thereafter, their dosage could be individually titrated by the research physician in accordance with the protocol across a 5 to 20 mg day dose range. The mean modal dose was mg day for olanzapine and mg day for haloperidol. The primary outcome, baseline to endpoint change on the BPRS total score, demonstrated the statistically significant superiority of olanzapine over haloperidol (P < 0.02). Olanzapine-treated patients also had statistically significantly greater improvements than haloperidol-treated patients on the PANSS total (P = 0.05). Secondarily, olanzapinetreated patients demonstrated statistically significant improvements on BPRS negative symptom (P = 0.002), PANSS negative symptom (P = 0.03), CGI-S (P < 0.03), and MADRS (P = 0.001) scores (data on file). A trend favored olanzapine over haloperidol on PANSS positive symptom improvement as well (P = 0.06). Furthermore, there was a significantly higher response rate ( 40% improvement in BPRS total score from baseline and at least three study weeks completed) among olanzapine-treated (52% [ ]) than haloperidol-treated patients (34% [ ]; P < 0.001), reflecting the robustness of olanzapine. First-episode of schizophrenia A retrospective examination of a subpopulation of trial patients (250) in their firstepisode of schizophrenia (n = 83) was performed (219). Olanzapine was significantly superior to haloperidol in the reduction of schizophrenic symptomatology (BPRS total mean change from baseline = ; P = 0.011). Clinical response ( 40% improvement in BPRS total from baseline), which was again statistically significantly greater (P = 0.003) with olanzapine (67%) than haloperidol (29%) treatment, revealed an even more robust separation than was observed among the multiepisode subjects. Moreover, EPS with haloperidol was increased, in contrast to a decrease with olanzapine, among these first-episode patients relative to their multiepisode counterparts. The results of this analysis suggest that olanzapine should be considered as a first-line strategy among firstepisode patients with schizophrenia. Geriatric schizophrenia A post hoc stratification by age of this study (250) evaluated the efficacy of olanzapine (n = 44) vs. haloperidol (n = 15) in a subset of 59 patients aged 65 years compared with those aged <65 years (239). Among the aged 65-year-old cohort, olanzapine-treated subjects experienced numerically greater symptomatic improvement (PANSS total, PANSS negative symptom, MADRS, CGI-S) and a higher rate of response (defined a priori as a 40% change among subjects with a BPRS 0 6 total score 18 at baseline and who had been treated at least 3 weeks) than haloperidol-treated patients (53 vs. 38%).