Atypical Antipsychotics Assessed At Acnp

2004 Psychiatric Times. All rights reserved.

Atypical Antipsychotics Assessed at ACNP by Kenneth J. Bender, Pharm.D., M.A. Psychiatric Times February 1997 Vol. XIV Issue 2

(This article is based on selected presentations at the 35th Annual Meeting of the American College of Neuropsychopharma-cology [ACNP], San Juan, P.R., Dec. 9 to 13, 1996.) Do people like the term atypical? This question was asked by David Pickar, M.D., chief of the National Institute of Mental Health's Experimental Therapeutics Branch, who chaired the symposium "Tracking the Next Generation of Antipsychotic Drugs." "It's a term that has outlived its usefulness," rejoined the symposium moderator, John Kane, M.D., department of psychiatry, Hillside Hospital, Glen Oaks, N.Y. "What about 'novel?'" quipped Nina Schooler, Ph.D., professor of psychiatry and director of the Psychosis Research Program, University of Pittsburgh, amid discussion that quickly achieved consensus that new antipsychotic agents which offer therapeutic advantages over older neuroleptics will, themselves, soon become typical. Kane then put semantics and categorizations aside, and challenged the psychopharmacologists to conduct investigations of the new compounds that will assist clinicians in choosing an optimal antipsychotic for a particular patient at a particular stage in that patient's illness. "I think we're going to be increasingly hard-pressed to develop a data base that's going to assist us in answering those questions," Kane said. As the utility of the "typical" neuroleptics is now being questioned, Kane indicated, so should the typical clinical research paradigms be reconsidered. One limitation of the current antipsychotic research data base, Kane recounted, is that subject populations have invariably comprised patients with chronic, entrenched illness. "The patient population that we're studying in most of the antipsychotic drug development programs is really one segment of the population," said Kane, who is professor of psychiatry at Albert Einstein College of Medicine. "We have to make some decisions and choices based on the data that are generated by those particular trials." Kane then recommended investigating the therapeutic potential of atypical antipsychotic compounds in patients experiencing their first onset of illness, before they are exposed to typical neuroleptics. "That has implications," Kane said, "not only in looking at the broad and immediate clinical effects of these

drugs, but also setting the stage for actually attempting to study the impact of antipsychotic drugs on the evolution of the illness itself." He elaborated, "The evolution of negative symptoms, deficit state and a variety of other issues really can't be studied in patients given putative atypical compounds when they've already been treated with conventional drugs for 10 or 12 years." Kane also asserted the continued need for placebo-control arms in antipsychotic clinical trials, while acknowledging the growing concern about the use of placebo in investigating medical conditions for which there is proven, effective treatment (Rothman and Michels). Placebo control is a valuable component of antipsychotic efficacy research, Kane argued, because of the variable, often marginal response associated with schizophrenia. "Without having these comparative groups," he said, "it's difficult to know the responsiveness of the population you're studying, and we can draw erroneous conclusions about a new compound." The measures of drug response most frequently employed in antipsychotic trials may also be inadequate, Kane suggested, to discern the scope of therapeutic benefit or track fundamental aspects of a patient's progress. Efficacy measures should extend beyond quantifying symptom reduction to include functional outcomes, Kane recommended. "We're ultimately interested in where patients end up," he said. "What patients improve slightly or not at all? Were differences found between the new drug and comparators clinically as well as statistically significant?" Other areas that Kane hopes can be elucidated in future clinical trials include: whether one antipsychotic offers sufficient therapeutic advantage to justify switching from another agent; the extent to which such adverse effects as akinesia and akathisia confound measures of clinical response; the optimal doses of study drugs and comparators from investigations with multiple dosage arms of each; and whether maintenance antipsychotic regimens can be evaluated for long-term efficacy, safety and compliance. Kane also questioned the use of typical neuroleptic comparators to repeatedly demonstrate the efficacy of new, atypical antipsychotics. After initial studies have shown the therapeutic advantages of a new compound, Kane suggested, subsequent direct comparisons between atypical compounds could yield data that is more helpful to clinicians. To underscore the extent to which new antipsychotics have demonstrated advantage over older neuroleptics, John M. Davis, M.D., Psychiatric Institute, University of Illinois, Chicago, offered the results of his recent meta-analysis of the olanzapine (Zyprexa)-haloperidol (Haldol) and the risperidone (Risperdal)-haloperidol comparative trials (Davis and others). He included all such studies published or presented prior to this ACNP meeting. He based the drug effect size comparison on the reported Positive and Negative Syndrome Scale (PANSS) and/or Brief Psychiatric Rating Scale (BPRS) score reductions associated with haloperidol or the newer antipsychotics, calculated as: mean

reduction (new drug) less mean reduction (haloperidol comparator) divided by pool standard deviation. For the olanzapine studies, Davis related finding the difference in effect size favoring olanzapine to be highly statistically significant. "It's established," said Davis, "that olanzapine is better than haloperidol." Davis found the data for risperidone more complicated to evaluate because of the large number of (and occasionally heterogeneous) studies. "But taken in toto," Davis concluded, "I feel risperidone is significantly and quite substantially better than standard neuroleptics." Where there is such evident advantage over typical neuroleptics, Schooler concurred with Kane that further distinctions between the atypical antipsychotics and their relative advantages in particular subsets of patients can be best ascertained through direct comparison. She suggested that an NIMH collaborative effort could facilitate these comparisons; others indicated that such studies are already underway, including a comparison of olanzapine and risperidone scheduled for presentation later in the ACNP proceedings. The interim report of this olanzapine-risperidone comparison is described below, as are the studies presented during the ACNP meeting which addressed the issues from this symposium of earlier treatment of schizophrenia, the switching of antipsychotic agents to improve response and broadening efficacy measures to include improvement of deficit states and function. Directly Comparing Atypicals Pierre Tran, M.D., clinical research physician with Lilly Research Laboratories, presented interim results from Lilly's comparison of olanzapine and risperidone in the treatment of patients with schizophrenia, schizophreniform disorder and schizoaffective disorder (Tran and others). Tran indicated that his group intended not only to distinguish between the two drugs in measures of efficacy and safety, but to judge the extent to which each met the criteria for an "atypical" antipsychotic. "With the introduction of these atypical agents," Tran said, "we have set a new level of expectations for these [antipsychotic] compounds." The three criteria set forth by the investigators to judge atypicality relative to the effects of typical neuroleptics were: fewer extrapyramidal symptoms (EPS); broader efficacy, especially in treating negative symptoms; and less effect on the dopamine-sensitive hormone prolactin. Tran indicated that the development of olanzapine and risperidone to achieve this atypical antipsychotic profile has followed different paths, and resulted in the two compounds having distinctly different chemical structures, receptor-binding affinities, animal neuropharmacology, pharmacokinetics and clinical riskbenefit profiles. This first large-scale head-to-head comparison of two putative atypical antipsychotics was conducted in randomized, double-blind parallel manner by

41 investigators at centers in nine countries. The study was statistically powered to enable an interim comparative analysis of safety and efficacy after at least 250 patients completed a washout period and began receiving either study medication. At the time of this preliminary report, 297 had been randomly assigned to receive either olanzapine or risperidone in a 1:1 ratio for eight weeks of acute therapy and 20 weeks of maintenance. Two hundred and twenty-six patients completed the eight-week acute phase, with no statistically significant differences between the treatment groups in completion of this phase. Of the 77 that completed the entire 28-week study period, statistically significantly more olanzapine-treated patients completed than did risperidonetreated patients. The severity of the patients' psychotic disorders at their entry into the study was quantified as a minimum BPRS score of 24 (BPRS extracted from the PANSS, items 0 to 6). Approximately two-thirds of the study population was male; the average age of the entire study population was 36 years; and their illness onset had occurred at an average age of 23 years. The starting dose of olanzapine was 15 mg once daily for the first week; and 1 mg risperidone twice daily, increased by 1 mg per dose daily to 3 mg twice daily for days 3 through 7, in accordance with the approved labeling. Each drug was thereafter titrated for optimal effect within the respective daily dose ranges of 5 mg to 20 mg olanzapine and 4 mg to 12 mg risperidone. The resultant daily mean modal dose of olanzapine was 16.9 mg at eight weeks and 17.1 mg by 28 weeks; and the daily mean modal dose of risperidone was 7.3 mg at both times. Critical discussion at the study presentation included an observation that the risperidone dosage required by this study population was higher than the average risperidone dose that marketing data indicate is used in the United States. At the doses employed, olanzapine best met the investigators' first criteria for atypicality by having less EPS liability than risperidone; as monitored with the Simpson-Angus Scale (SAS) for parkinsonism, the Barnes Akathisia Scale (BAS), the Abnormal Involuntary Movement Scale (AIMS) and in the frequency of use of anti-EPS medications. A statistically significantly smaller proportion of patients receiving olanzapine (17.9%) requested one or more doses of anticholinergic medication during the eight-week acute treatment phase than the 31.5% of patients receiving risperidone who required anti-EPS medication during that period. In addition, statistically fewer olanzapine-treated patients experienced elevated prolactin levels after both eight weeks and 28 weeks than did those receiving risperidone. The question of whether this difference, albeit statistically significant, is clinically significant was among those arising in the discussion of this study report. That question, along with unknown long-term effects of relative levels of prolactinemia awaits further study. In efficacy measures at week 8, olanzapine and risperidone were comparable in reducing overall positive and negative symptoms of schizophrenia, although olanzapine achieved numerically superior mean changes on six of eight

measures, and statistically significant superiority to risperidone in the PANSS mood subscore at both eight and 28 weeks. In addition, at 28 weeks, a statistically significant advantage with olanzapine was evident among patients who had achieved at least a 30% improvement on the PANSS total score. Fewer patients receiving olanzapine experienced relapse (4% at three months and 9% at six months) than did those treated with risperidone (9% at three months and 29% at six months). Relapse, a key measure of maintenance efficacy, was defined as a 20% or greater worsening in PANSS total score along with a Clinical Global Impression-Severity of Illness (CGI-S) score equal to or greater than 3. In seeking a broader measure of antipsychotic efficacy than reduction of overt symptoms, the investigators also applied the Heinrichs-Carpenter Quality of Life Scale (QLS) at baseline and week 28. The effect of the agents appeared comparable by this measure, although the patients receiving olanzapine demonstrated significantly better scores in the subscale for maintaining positive interpersonal relations. Tran summarized from this 28-week trial that olanzapine evidenced the key criteria for atypical antipsychotic effects more often and to a greater degree than risperidone. Olanzapine was associated with fewer side effects, less elevation of prolactin and greater efficacy in mood symptoms. At the dosages employed, he concluded, olanzapine was statistically significantly more likely than risperidone to evoke greater initial therapeutic response and less likely to be associated with relapse during maintenance therapy. Risperidone and Haloperidol Risperidone, in turn, was reported by other investigators at the ACNP to have demonstrated favorable advantage over the typical neuroleptic comparator, haloperidol. In an analysis of combined data from two eight-week, doubleblind, placebo-controlled trials of risperidone conducted in phase III, prior to market approval, Stephen Marder, M.D., department of psychiatry at West Los Angeles Veterans Affairs Medical Center, reported that patients treated with risperidone in daily doses ranging from 6 mg to 16 mg evidenced significantly greater response than those who had received 20 mg daily haloperidol (Marder 1996a). The investigators' factor analysis of data from a total of 523 hospitalized patients diagnosed with chronic schizophrenia revealed an advantage with risperidone that was greatest for treatment of negative symptoms, uncontrolled hostility/excitement and anxiety/depression. In addition, there was a statistically significant advantage for risperidone in the treatment of positive symptoms and disorganized thought. Haloperidol was not, however, found to differ significantly from placebo in the treatment of either negative symptoms or anxiety/depression. The specific PANSS items that improved most significantly with risperidone in relation to the response with haloperidol were passive social withdrawal, active social avoidance, depression, emotional withdrawal and hostility. Since these are not the factors usually associated with

the psychotic component of schizophrenia, the investigators suggest that risperidone showed a qualitatively different therapeutic effect than haloperidol. Marder indicated that he finds relatively small differences between the new antipsychotics and typical neuroleptics in treating positive symptoms of schizophrenia, and posits that their therapeutic advantages arise from other properties. "I think, now, people are beginning to look in much more refined ways at the activities of the drugs," Marder commented. "In the past, clinicians focused on positive symptoms. Now there is a greater focus on negative symptoms, cognitive symptoms and mood." Treating the First Episode The possibility mentioned by Kane that an atypical antipsychotic, with greater efficacy and lower side-effect liability than typical neuroleptics, might exert even greater benefit when used early in the course of schizophrenia illness was examined further by Jeffrey Lieberman, M.D., professor and vice chairman of psychiatry at the University of North Carolina, Chapel Hill, as chair of another ACNP symposium, "Atypical Antipsychotic Drug Treatment of First-Episode and Recent-Onset Schizophrenia." Lieberman described the pattern and course of schizophrenia and the rationale for early intervention with atypical anti-psychotics. Lieberman presented data from a pilot study of risperidone and clozapine (Clozaril) in first-episode schizophrenia, which he conducted with colleagues from Hillside Hospital Research Department (poster presentation by Delbert Robinson, M.D., and others). Lieberman explained that most patients with schizophrenia experience their acute onset by early adulthood; and many, after initial improvement, then follow an undulating, deteriorating course with increased, seemingly accumulating morbidity of both persisting symptoms and declining function. Lieberman pointed out that the deterioration process invariably commences in the early phase of illness, often prior to psychotic symptoms and within five years of the first episode. The treatment response during the first episode has been found to be distinct from that observed later in the course of illness, Lieberman explained, with patients in this early stage often having both a better therapeutic response to an antipsychotic and more sensitivity to its side effects (Lieberman 1996; McEvoy and others). The apparently greater therapeutic response at this stage of illness has then been associated with improved levels of recovery, as well as better long-term functioning (Wyatt). The atypical antipsy-chotics may have particular utility at this early stage, Lieberman suggested, not only for their increased efficacy, but because they are more likely to be tolerated in therapeutic doses than neuroleptics with greater EPS liability.

Lieberman posits an association between the duration of psychosis and poorer treatment response and outcome. He suggested that the pathophysiologic process underlying the psychiatric illness, when left unabated by incomplete antipsychotic effect or delayed treatment, progresses to cause the persistent morbidity of schizophrenia. The first episode of the illness is then, he proposed, the most opportune time for therapeutic intervention. Lieberman suggested that the question of "whether there is any added value" from employing atypical antipsychotics earlier in illness onset should be assessed with measures of antipsychotic efficacy beyond drug effects on positive and negative symptoms. He urged assessment of the possible antipsychotic benefit for cognitive deficits, affective symptoms, functional impairment, as well as their effectiveness in preventing relapse and subsequent deterioration. In their pilot study of atypical agents in first-episode, 16 patients (eight men and eight women, mean age 25.8 years) were treated with risperidone; and 30 patients (17 men and 13 women, mean age 22.6 years) were treated with clozapine. Inclusion criteria included a lifetime treatment history of previous anti-psychotic medication treatment of 12 weeks or less, a diagnosis of schizophrenia or schizoaffective disorder and current severity of psychotic symptoms to achieve a rating of 4 or more on at least one psychotic item on the Schedule for Affective Disorders and Schizophrenia-Change Version with psychotic and disorganization items (SADS-C+PD). Initially in the pilot study, patients were offered risperidone, and as the study progressed, patients were then offered clozapine first, and risperidone if clozapine was refused. Robinson related that there was wide variation from the clozapine mean daily dose of 230 mg, with some patients requiring less than 100 mg per day as a result of these first-episode patients being particularly sensitive to its side effects. "For clozapine [these reactions include] sedation and orthostatic hypotension. The end result is that many people [first episode] responded at dosages that are much lower than what we're used to with clozapine for treatment-refractory patients," Robinson said. "So you have to start at a very low dose and gradually build up." Robinson reported that the onset of response to either risperidone or clozapine was similar to that of fluphenazine (Prolixin), as was the degree of improvement in such positive symptoms as hallucinations and delusions. Fifteen of the 22 patients treated with clozapine (68%) and nine of the 13 patients receiving risperidone (69%) for more than six weeks met the response criteria of a rating of mild or less on the four psychotic symptom items of the SADS-C+PD, and a much or very much improved rating on the CGI. Robinson reported that clozapine-treated patients improved more on depression and negative symptoms than did patients treated with risperidone or fluphenazine. Patients receiving either risperidone or clozapine experienced, as expected, less EPS than those who had received fluphenazine. Robinson indicated that a more rigorous study design with parallel comparison of first-episode patients

receiving clozapine or a typical neuroleptic should be conducted to confirm the apparent advantage of clozapine. Olanzapine and Haloperidol Lieberman had also collaborated with Lilly Research Laboratories scientists Todd Sanger, Ph.D., and Gary Tollefson, M.D., Ph.D., in extracting and examining the data for olanzapine and haloperidol in treatment of first-episode psychosis from the larger data base generated in the international, multicenter double-blind parallel trial in 1,996 patients with schizophrenia, schizophreniform disorder and schizoaffective disorder. Sanger, lead author of that study, briefly described it to the participants of the symposium chaired by Lieberman, and presented it in the subsequent poster session (Sanger and others). Of the 1,996 patients enrolled in the comparative trial of olanzapine and haloperidol, 83 were determined to be in their first episode of psychosis. The random allocation of medication had originally been in the ratio of two olanzapine to one haloperidol, with 59 of the first-episode patients receiving olanzapine, 24 receiving haloperidol. The illness characteristics and demographics of the groups were similar: 67.8% of the olanzapine patients were male; 32.2% were female. The average age of those receiving olanzapine was 29 years and had been 27.5 years at illness onset; the average length of illness episode was 390 days. In the olanzapine group, 28.8% had not previously received antipsychotics. The haloperidol group was 70.8% male, 29.2% female, with average age of 27 years and 26.3 years age at illness onset; the average length of episode was 389 days; and 29.2% had not previously received antipsychotics. Dosing in this trial was somewhat naturalistic, each drug initiated at 5 mg daily, and subsequently titrated to optimal effect within the range of 5 mg to 20 mg in single daily dose. The resultant mean modal dose of olanzapine found most effective for treating first-episode patients was 11.6 mg, lower than the 12.7 mg utilized for the multiepisode cohort. In contrast, the 10.8 mg haloperidol dose found necessary for the first-episode patients was essentially the same as the 11 mg required by multiepisode patients. Tollefson suggested in the symposium on first-episode treatment that the greater sensitivity to antipsychotic drug effect than is anticipated in these patents relative to those with chronic, multiepisode schizophrenia was demonstrated by this disparate dose requirement of olanzapine, but was not evident with haloperidol. A possible indication that olanzapine exerted greater efficacy and was better tolerated than haloperidol was the higher number of olanzapine-treated patients completing the six-week acute phase of the trial (72.9%) than did the 37.5% of those treated with haloperidol. Analysis of the reasons patients dropped out of the study revealed that 33.3% of haloperidol patients left the study due to lack of drug efficacy, in comparison to 13.6% of those receiving olanzapine; and 16.7% of haloperidol-treated patients left because of adverse events, compared to 1.7% of those receiving olanzapine.

The adverse events prompting patients receiving haloperidol to leave the study were one report each of akathisia, hypertonia, abnormal thoughts and EPS, while depression was the adverse condition reported by the single olanzapinetreated patient to leave the study for any treatment-emergent event. Analysis of all treatment-emergent adverse events in the first-episode cohort during the six-week acute phase revealed that 18.6%, 15.3% and 15.3% of olanzapinetreated patients, respectively, experienced somnolence, asthenia and headache while no haloperidol-treated patients experienced these events. In turn, 8.3% of haloperidol patients experienced agitation, 8.3% experienced movement disorder and 16.7% experienced hypokinesia, reactions that did not occur in patients receiving olanzapine. An approximate 29% incidence each of hypertonia and of akathisia was associated with haloperidol compared to an 8.5% incidence of hypertonia and 5.1% incidence of akathisia associated with olanzapine. In efficacy measures, olanzapine was found to be significantly superior to haloperidol in reduction of BPRS total and negative scores and in the PANSS total and negative score. The investigators concluded that olanzapine was both more effective than haloperidol and better-tolerated by these patients with firstepisode psychosis. Patients receiving olanzapine were 2.3 times more likely to respond than haloperidol-treated patients, and were significantly more improved on total, positive and negative psychopathology. The response rate to olanzapine was higher, and the superiority of that response to that associated with haloperidol was greater in first-episode patients than in patients with multiepisodes. The response rate to haloperidol was approximately the same in both first-episode and multiepisode patients. "This tells me," said Sanger, "that the first-episode [patients, in contrast to those having multiple episodes] have a much greater advantage in going on the atypical olanzapine, than a typical [neuroleptic]." Treatment-Resistant Patients Evidence that increased therapeutic benefit can occur from either changing from a typical neuroleptic regimen to an atypical anti-psychotic or switching one atypical antipsychotic compound for another is most pertinent for patients who have not previously responded to treatment. Both olanzapine and risperidone were investigated for their efficacy in treatment-resistant patients, and these results were reported at the ACNP. Stephen Erhart, M.D., research fellow at the West Los Angeles Veterans Affairs Medical Center, presented the poster of a comparison of risperidone and haloperidol in patients with treatment-resistant schizophrenia conducted by his colleagues (Ames and others). In their trial, 67 patients with schizophrenia were identified with a history of nonresponse to typical neuroleptics. After administering placebo during a one-week washout period, these patients were randomly assigned in a double-blind manner to two four-week treatment phases. In the initial month, patients received fixed daily doses of either 6 mg risperidone or 15 mg haloperidol. In the subsequent month, their clinicians could adjust their dose within ranges of between 3 mg and 15 mg of

risperidone and 5 mg to 30 mg of haloperidol. The patients were then evaluated weekly during the two months of treatment with measures of psychopathology, neurotoxicity, mood, obsessive-compulsive symptoms and subjective response. The investigators found that risperidone was associated with greater improvement than haloperidol from baseline on measures of overall psychopathology. While the subjective response to haloperidol was predominantly dysphoria, it was largely positive to risperidone, with risperidone showing no significant liability for either obsessive-compulsive or depressive symptoms. As expected, a significantly greater percentage of patients treated with haloperidol (61%) required medication to treat EPS side effects than did those receiving risperidone (21%). "There was a notable difference, which we didn't expect at all," commented Erhart, "in eight risperidone patients of a total of 32, who showed a diminution of their baseline BPRS scores of between 40% and 80%." Two investigations of olanzapine in treatment-refractory patients with schizophrenia employed particularly stringent inclusion criteria defining treatment resistance. In one study (Conley and others), Robert Conley, M.D., and Carol Tamminga, M.D., of the Psychiatric Research Center, University of Maryland, Baltimore, and Charles Beasley, M.D., Lilly Research Laboratories, applied the same rigorous criteria that Kane had developed (Kane and others) to test clozapine's effectiveness. These investigators contrasted the effect of olanzapine and chlorpromazine (Thorazine) in patients who had failed to achieve greater than 20% improvement on BPRS in two trials with adequate dose and duration of different neuroleptics exclusive of haloperidol (1000 mg daily of chlorpromazine equivalent for six weeks each); and then failed to improve in their own six-week prospective trial on haloperidol at daily doses of 10 mg to 40 mg, along with benztropine (Cogentin) up to 4 mg daily. At the time Conley reported their interim results to the ACNP, 89 patients had met the inclusion criteria for treatment resistance and had been titrated over one week to either olanzapine 25 mg daily or chlorpromazine 1200 mg daily, and maintained on these fixed- dose regimens for seven additional weeks. Fifty-six patients completing the blinded trial then opted to continue, after a washout period, in an open study of olanzapine treatment at an initial daily dose of 10 mg for the first week, then titrated for optimal benefit and tolerance up to 25 mg daily at the discretion of the investigator clinician. If responsive after seven weeks of open olanzapine therapy, patients could continue on olanzapine maintenance. The results were that 48% of the patients were found improved, with a 20% or greater reduction in total BPRS scores or CGI scores of less than or equal to 3 or a 1 point fall on the CGI. While the data on the olanzapine-chlorpromazine comparison remained blinded at the time of his interim report, Conley indicated that there was improvement in the overall study group, which was lost in the washout period preceding the open olanzapine study phase. Improvement was resumed, however, by week 4 of the open olanzapine treatment, with significant

reduction in BPRS total and positive symptom scores and anxiety factor. This improvement on olanzapine appeared persistent throughout a 27-week followup period during which olanzapine was well-tolerated. Dry mouth was reported by approximately 20% of the patients, dizziness in approximately 5%, and there was an occasional report of blurred vision. EPS was infrequent, with only one patient experiencing treatment-emergent EPS associated with olanzapine. Another study evaluated the response to olanzapine in patients who had histories of being unresponsive to typical neuroleptics and who had also failed a well-defined, four-month course of treatment with clozapine (Birkett and others). The study population was drawn from patients who failed to improve during their participation in the Cooperative Demonstration Project of Clozapine for Neuroleptic Nonresponsive Patients, administered at five centers in Israel under the auspices of the Israeli Ministry of Health. After a washout period of five to nine days, 50 patients were enrolled for openlabel treatment with olanzapine initiated at 15 mg per day, and titrated for optimal benefit within a daily dose range of 5 mg to 25 mg for a treatment period of up to 18 weeks. Forty-five patients continued participation (64% male, 36% female, mean age 38.7 years) and were evaluated for drug efficacy weekly for the first six weeks and monthly for the remaining 12 weeks. On average, these patients experienced a 13% reduction in PANSS total score and a 14% reduction in BPRS total score during the first six weeks. Approximately half of these previously unresponsive patients showed at least minimal improvement on the CGI scale at endpoint. Seventeen patients (37.8%) evidenced response to olanzapine in meeting the criteria of at least a 20% reduction in PANSS total score; and 20 patients (44.4%) were deemed responsive by achieving that same reduction in their BPRS total score. Tollefson commented on his colleagues' study, pointing out that olanzapine was well-tolerated by the study population with few treatment-emergent events or patients leaving the study. "Neutrophils weren't a problem," he pointed out. "Even in patients who had previously taken clozapine and had some hematological complications, they were able to tolerate olanzapine." Tollefson added, "They actually improved from baseline in their EPS scores, so the drug [olanzapine], even up to 25 mg, appeared not to be inducing a lot of motor side effects." The investigators concluded that olanzapine demonstrated efficacy in some patients who had previously been unresponsive to typical neuroleptics and to clozapine; and that olanzapine was both safe and well-tolerated. Tollefson observed, "It would suggest that if you've done two [neuroleptic] treatments and you've moved on to a trial with clozapine, and the patient is either not tolerating clozapine or hasn't responded, then you've got approximately a 2 out of 5 chance that you'll see some improvement with olanzapine." Future Treatment Targets

Cognitive deficits associated with schizophrenia have proved to be elusive targets in the treatment of the illness. On the closing day of the ACNP meeting, the progress and prospects for mitigating neurocognitive deficits and improving functional outcome in schizophrenia were considered in a symposium chaired by William Carpenter, M.D., Maryland Psychiatric Research Center, Baltimore, and Richard Mohs, Ph.D., professor, Mt. Sinai School of Medicine, New York. The dilemma, as Carpenter described it, is that neurocognitive deficit appears to be independent, or has minimal relationship to any of the symptom complexes which have, to some extent, responded to traditional neuroleptics. "At least [there is] the lack of relationship in the context of clinical trials or clinical change," he explained. "That is, you can get large changes in symptoms of schizophrenia without getting changes in the various cognitive measures." In his address to the symposium, Michael Green, Ph.D., UCLA Research Center, Camarillo State Hospital, Camarillo, Calif., credited Lieberman with making the comparison, and said, "neurocognition of schizophrenia is to the 1990s what negative symptoms were to the '80s." Barbara Cornblatt, Ph.D., Hillside Hospital, Glen Oaks, N.Y., described her research findings which indicate that attentional deficits are independent of the clinical symptoms of schizophrenia (Cornblatt and others). Her evidence, which counters the traditional view that impaired attention is a component of the schizophrenia clinical syndrome, includes a longitudinal study of more than 350 subjects at high and low risk for schizophrenia in which attentional dysfunctions followed a different developmental course from the onset of psychotic symptoms. Cornblatt also cited a number of additional studies which indicate that impaired attention is a core feature of schizophrenia, from its earliest stages in adolescence through chronic illness in adults. Furthermore, in many studies, attention does not appear to improve with neuroleptic treatment, even though clinical symptoms diminish--again supporting the independence of attentional functioning from clinical state. In contrast with typical neuroleptics, however, Cornblatt suggested that attention may improve with amphetamines as indicated in a preliminary study of patients with schizotypal personality disorders (Kirrane and others). Cornblatt has focused on developing measures to identify subjects at high risk for schizophrenia and is hopeful that early detection of deficits that appear well before clinical symptoms may enable intervention and favorably affect illness progression. "Standard neuroleptic treatment is quite beneficial for the clinical symptoms," she said, "resulting in a lower amount of hospital time and, hopefully, reduced relapses. It therefore has a beneficial effect on outcomes." This responsiveness

of clinical symptoms contrasts, however, with the lack of effect of neuroleptics on the neurocognitive domain which is critical to how well a patient can function in a community setting. "What I'm calling for," Cornblatt said, "is an effort to develop a treatment that will focus on the neurocognitive pathway of the illness." While there is little correlation between neurocognitive deficits and the clinical syndrome of schizophrenia, Green summarized several studies which have ascertained associations between specific deficits and patients' lack of functioning (Green). For example, verbal memory is associated with all types of functional outcomes; the level of vigilance is related to social problem solving and skill acquisition. Measures of executive functioning relate to community functioning, but not social problem-solving. And the negative symptoms of schizophrenia are associated with social problem-solving, but not skill acquisition. Green emphasized the importance of addressing specific neurocognitive capacities such as verbal memory and vigilance, which are correlated with functional outcomes, noting that this will require novel therapies, since conventional neuroleptics have minimal effect in these domains. "If we're going to start talking about the treatment of neurocognition and psychotic symptoms--then it challenges the definition of treatment efficacy," he said. "It raises the question of whether or not 'symptom reduction,' narrowly defined, should be broadened to include something more akin to 'disability reduction.'" The possibility that new antipsychotics may have greater utility in the neurocognitive domain of schizophrenia than older neuroleptics was posed at this symposium by separate studies related, respectively, by Marder and by Dilip Jeste, M.D., professor of psychiatry and neuroscience, University of California, San Diego, and the San Diego VAMC. Marder's group at the West Los Angeles VAMC and at Camarillo State Hospital reported differential effects of risperidone and haloperidol on both the spatial and verbal working memory of patients with schizophrenia (Marder and others 1996b). The study concluded that benztropine, which is more frequently administered to patients taking haloperidol, has a negative effect on spatial working memory. The relative benefit from risperidone appeared greatest among those patients having the poorest initial performance on verbal working memory measures. Jeste reported comparing the results of a global cognitive test--i.e., the MiniMental State Examination (MMSE) in middle-aged and elderly patients with schizophrenia and other psychotic disorders receiving risperidone in one study and haloperidol and other conventional neuroleptics in another (Jeste and others). While acknowledging that this comparison was not double-blinded, Jeste indicated that there was a significant improvement in MMSE score with risperidone which did not occur with older neuroleptics. The investigators wrote in their conclusion, "It is not clear, however, whether atypical antipsychotics such as risperidone produce cognitive enhancement directly, as the effect might have been secondary to a greater improvement in

psychopathology along with fewer extrapyramidal symptoms compared to typical neuroleptics." Tollefson had earlier described the expanded efficacy of antipsychotics that fulfill the "atypical" pharmacological criteria as potentially preventing further cognitive deterioration in schizophrenia and/or improving performance (Tollefson). He related that the clinical effects of olanzapine on cognitive and psychomotor functions are now being investigated in elderly subjects. In one study in progress, the effects of olanzapine and haloperidol were compared in 14 healthy, elderly volunteers. While both antipsychotics were associated with some impaired efficiency in cognitive function after the first day's dose, those subjects receiving olanzapine returned to pretreatment levels by the next day, while cognitive deficits associated with haloperidol increased during subsequent days of treatment. While it is uncertain whether these disparate effects of olanzapine and haloperidol can be related to relative benefit for primary cognitive deficits of schizophrenia, Tollefson pointed to the relative benefit of olanzapine not exhibiting a sustained or increased impairment of cognition or psychomotor function. Although little evidence exists of the direct effects of atypical antipsychotics on neurocognition, Tollefson described one experimental model for this domain, and the demonstrated activity of olanzapine and clozapine. A diminished prepulse inhibition (PPI) of startle response has been found to be characteristic of patients with schizophrenia, and was recently modeled in animals by administration of N-methyl-D-aspartate (NMDA) antagonists, phencyclidine (PCP) or the investigational compound MK-801. Clozapine has previously been found to block the attenuation of normal PPI by NMDA antagonists, while the typical neuroleptic haloperidol did not. Tollefson related that olanzapine was also recently found to antagonize this PPI disruption by NMDA antagonists, and did so to a comparable degree to clozapine (Bakshi and others). Tollefson concluded, "Cognitive impairment in schizophrenia greatly impedes psychosocial performance and eventual reintegration into society." The cognitive features of schizophrenia, then, "become key targets in the development of new therapeutic modalities."

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