Abstracts

Green MF, Nuechterlein KH, Kern RS, Baade LE, Fenton WS, Gold JM, Keefe RS, Mesholam-Gately R, Seidman LJ, Stover E, Marder SR

Objective: During the consensus meetings of the National Institute of Mental Health Measurement and Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS) Initiative, the U.S. Food and Drug Administration took the position that a drug for this purpose should show changes on 1) an accepted consensus cognitive performance measure and 2) an additional measure (i.e., a co-primary) that is considered functionally meaningful. The goal of the current study was to describe steps to evaluate four potential co-primary measures for psychometric properties and validity. Method: As part of the five-site MATRICS Psychometric and Standardization Study (PASS), two measures of functional capacity and two interview-based measures of cognition were evaluated in 176 patients with schizophrenia (167 of these patients were retested 4 weeks later). Results: Data are presented for each co-primary measure for test-retest reliability, utility as a repeated measure, relationship to cognitive performance, relationship to functioning, tolerability/practicality, and number of missing data. Conclusions: Psychometric properties of all of the measures were considered acceptable, and the measures were generally comparable across the various criteria, except that the functional capacity measures had stronger relationships to cognitive performance and fewer missing data. The development and evaluation of potential co-primary measures is still at an early stage, and it was decided not to endorse a single measure for clinical trials at this point. The current findings offer the initial steps to identify functionally meaningful co-primary measures in this area and will help to guide further evaluation of such measures.

Keefe RS, Bilder RM, Davis SM, Harvey PD, Palmer BW, Gold JM, Meltzer HY, Green MF, Capuano G, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Davis CE, Hsiao JK, Lieberman JA; CATIE Investigators; Neurocognitive Working Group

Context: Neurocognitive impairment in schizophrenia is severe and is an important predictor of functional outcome. The relative effect of the second-generation (atypical) antipsychotic drugs and older agents on neurocognition has not been comprehensively determined. Objective: To compare the neurocognitive effects of several second-generation antipsychotics and a first-generation antipsychotic, perphenazine. Design: Randomized, double-blind study of patients with schizophrenia assigned to receive treatment with olanzapine, perphenazine, quetiapine fumarate, or risperidone for up to 18 months as reported previously by Lieberman et al. Ziprasidone hydrochloride was included after its approval by the Food and Drug Administration. Setting: Fifty-seven sites participated, including academic sites and treatment mental health facilities representative of the community. Patients: From a cohort of 1460 patients in the treatment study, 817 completed neurocognitive testing immediately prior to randomization and then after 2 months of treatment. Main Outcome Measures: The primary outcome was change in a neurocognitive composite score after 2 months of treatment. Secondary outcomes included neurocognitive composite score change at 6 months and 18 months after continued treatment and changes in neurocognitive domains. Results: At 2 months, treatment resulted in small neurocognitive improvements of z = 0.13 for olanzapine (P<.002), 0.25 for perphenazine (P<.001), 0.18 for quetiapine (P<.001), 0.26 for risperidone (P<.001), and 0.12 for ziprasidone (P<.06), with no significant differences between groups. Results at 6 months were similar. After 18 months of treatment, neurocognitive improvement was greater in the perphenazine group than in the olanzapine and risperidone groups. Neurocognitive improvement predicted longer time to treatment discontinuation, independently from symptom improvement, in patients treated with quetiapine or ziprasidone. Conclusions: After 2 months of antipsychotic treatment, all groups had a small but significant improvement in neurocognition. There were no differences between any pair of agents, including the typical drug perphenazine. These results differ from the majority of previous studies, and the possible reasons are discussed.

Turetsky BI, Calkins ME, Light GA, Olincy A, Radant AD, Swerdlow NR

In an effort to reveal susceptibility genes, schizophrenia research has turned to the endophenotype strategy. Endophenotypes are characteristics that reflect the actions of genes predisposing an individual to a disorder, even in the absence of diagnosable pathology. Individual endophenotypes are presumably determined by fewer genes than the more complex phenotype of schizophrenia and would, therefore, reduce the complexity of genetic analyses. Unfortunately, despite there being rational criteria to define a viable endophenotype, the term is sometimes applied indiscriminately to characteristics that are deviant in affected individuals. Schizophrenia patients exhibit deficits in several neurophysiological measures of information processing that have been proposed as candidate endophenotypes. Successful processing of sensory inputs requires the ability to inhibit intrinsic responses to redundant stimuli and, reciprocally, to facilitate responses to less frequent salient stimuli. There is evidence to suggest that both these processes are “impaired” in schizophrenia. Measures of inhibitory failure include prepulse inhibition of the startle reflex, P50 auditory evoked potential suppression, and antisaccade eye movements. Measures of impaired deviance detection include mismatch negativity and the P300 event-related potential. The purpose of this review is to systematically evaluate the endophenotype candidacy of these key neurophysiological abilities. For each candidate, we describe typical experimental procedures, the current understanding of the underlying neurobiology, the nature of the abnormality in schizophrenia, the reliability, stability and heritability of the measure, and any reported gene associations. We conclude with a discussion of the few studies thus far that have employed a multivariate approach with these candidates.

Murphy BP, Chung YC, Park TW, McGorry PD

Background: Optimal treatment of primary negative symptoms is important because their presence is associated with poor outcome. Aims: To systematically review all studies dealing with the efficacy of pharmacological agents on primary negative symptoms. Method: A comprehensive search of the relevant literature was undertaken using electronic database, reference lists and personal contact. Results: There is a lack of standardized research designs. Amisulpride is the most extensively studied drug with respect to efficacy against primary negative symptoms. At low doses it demonstrates a consistent, modest effect compared to placebo, though not to conventional antipsychotics and has yet to be tested against other atypicals. Evidence from multiple studies that used simple statistical analyses and inclusion criteria for patients with primary negative symptoms does not support a direct effect for clozapine. Path-analysis studies support the direct effects of risperidone, olanzapine, sertindole and aripiprazole, however, different statistical analyses of the same risperidone study produced conflicting results and the direct effects of olanzapine were not confirmed in selected patients with primary negative symptoms. There are no studies supporting the use of ziprasidone or quetiapine. The effects of typical antipsychotics on primary negative symptoms are inconclusive and likely to depend on drug dosages. Selective serotonin reuptake inhibitors (SSRIs), mirtazepine and NMDA agonists show early promise but require further study. Novel agents such as selegiline, naltrexone, dehydroepiandrosterone, galantamine, Ginkgo, nitric oxide, L-deprenyl and pergolide show positive effects on general negative symptoms but remain untested against primary negative symptoms. Conclusions: Further studies using standardized selective inclusion criteria and controlling for chronicity are needed. Research guidelines are discussed.

Olfson M, Blanco C, Liu L, Moreno C, Laje G

Context: Although there are indications that antipsychotic drugs are increasingly used to treat children and adolescents, little is known about the characteristics of those who receive them. Objective: To examine national trends and patterns in antipsychotic treatment of youth seen by physicians in office-based medical practice. Design: Analysis of national trends of visits (1993-2002) that included prescription of antipsychotics, and comparison of the clinical and demographic characteristics of visits (2000-2002) that included or did not include antipsychotic treatment. Setting: Outpatient visits to physicians in office-based practice. Participants: Patient visits by persons 20 years and younger from the National Ambulatory Medical Care Surveys from 1993 to 2002. Main Outcome Measures: Visits that included prescription of antipsychotics. Results: In the United States, the estimated number of office-based visits by youth that included antipsychotic treatment increased from approximately 201,000 in 1993 to 1,224,000 in 2002. From 2000 to 2002, the number of visits that included antipsychotic treatment was significantly higher for male youth (1913 visits per 100,000 population) than for female youth (739 visits per 100,000 population), and for white non-Hispanic youth (1515 visits per 100,000 population) than for youth of other racial or ethnic groups (426 visits per 100,000 population). Overall, 9.2% of mental health visits and 18.3% of visits to psychiatrists included antipsychotic treatment. From 2000 to 2002, 92.3% of visits with prescription of an antipsychotic included a second-generation medication. Mental health visits with prescription of an antipsychotic included patients with diagnoses of disruptive behavior disorders (37.8%), mood disorders (31.8%), pervasive developmental disorders or mental retardation (17.3%), and psychotic disorders (14.2%). Conclusions: There has been a sharp national increase in antipsychotic treatment among children and adolescents in office-based medical practice. Second-generation antipsychotics are being widely prescribed, and emerging empirical evidence provides a base of support that is limited to short-term safety and efficacy.

McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK; CATIE Investigators

Objective: When a schizophrenia patient has an inadequate response to treatment with an antipsychotic drug, it is unclear what other antipsychotic to switch to and when to use clozapine. In this study, the authors compared switching to clozapine with switching to another atypical antipsychotic in patients who had discontinued treatment with a newer atypical antipsychotic in the context of the Clinical Antipsychotic Trials for Interventions Effectiveness (CATIE) investigation. Method: Ninety-nine patients who discontinued treatment with olanzapine, quetiapine, risperidone, or ziprasidone in phase 1 or 1B of the trials, primarily because of inadequate efficacy, were randomly assigned to open-label treatment with clozapine (N=49) or blinded treatment with another newer atypical antipsychotic not previously received in the trial (olanzapine [N=19], quetiapine [N=15], or risperidone [N=16]). Results: Time until treatment discontinuation for any reason was significantly longer for clozapine (median=10.5 months) than for quetiapine (median=3.3), or risperidone (median=2.8), but not for olanzapine (median=2.7). Time to discontinuation because of inadequate therapeutic effect was significantly longer for clozapine than for olanzapine, quetiapine, or risperidone. At 3-month assessments, Positive and Negative Syndrome Scale total scores had decreased more in patients treated with clozapine than in patients treated with quetiapine or risperidone but not olanzapine. One patient treated with clozapine developed agranulocytosis, and another developed eosinophilia; both required treatment discontinuation. Conclusions: For these patients with schizophrenia who prospectively failed to improve with an atypical antipsychotic, clozapine was more effective than switching to another newer atypical antipsychotic. Safety monitoring is necessary to detect and manage clozapine's serious side effects.

Honer WG, Thornton AE, Chen EY, Chan RC, Wong JO, Bergmann A, Falkai P, Pomarol-Clotet E, McKenna PJ, Stip E, Williams R, MacEwan GW, Wasan K, Procyshyn R; Clozapine and Risperidone Enhancement (CARE) Study Group

Background: The treatment of schizophrenia with multiple antipsychotic drugs is common, but the benefits and risks are not known. Methods: In a randomized, double-blind study, we evaluated patients with schizophrenia and a poor response to treatment with clozapine. The patients continued to take clozapine and were randomly assigned to receive eight weeks of daily augmentation with 3 mg of risperidone or with placebo. This course of treatment was followed by an optional 18 weeks of augmentation with risperidone. The primary outcome was reduction in the total score for severity of symptoms on the Positive and Negative Syndrome Scale (PANSS). The secondary outcomes included cognitive functioning. Results: A total of 68 patients were randomly assigned to treatment. In the double-blind phase, the mean total score for the severity of symptoms decreased from baseline to eight weeks in both the risperidone and the placebo groups. There was no statistically significant difference in symptomatic benefit between augmentation with risperidone and placebo: 9 of 34 patients receiving placebo and 6 of 34 receiving risperidone responded to treatment (P=0.38). The mean difference in the change in PANSS scores from baseline to eight weeks between those receiving risperidone and those receiving placebo was 0.1 (95 percent confidence interval, -7.3 to 7.0). The verbal working-memory index showed a small decline in the risperidone group and a small improvement in the placebo group (P=0.02 for the comparison between the two groups in the change from baseline). The increase in fasting blood glucose levels was mildly greater in the risperidone group than in the placebo group (16.2 vs. 1.8 mg per deciliter [0.90 vs. 0.10 mmol per liter], P=0.04). The incidence and severity of other side effects did not differ between the two groups. Conclusions: In this short-term study, the addition of risperidone to clozapine did not improve symptoms in patients with severe schizophrenia.

Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators

Background: The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study. Methods: A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments. Results: Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects. Conclusions: The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism.

Jablensky AV, Morgan V, Zubrick SR, Bower C, Yellachich LA

Objective: This study ascertained the incidence of complications during pregnancy, labor, and delivery and the neonatal characteristics of infants born to women with schizophrenia, bipolar disorder, or major depression in a population-based cohort. Method: Based on records linkage across a psychiatric case register and prospectively recorded obstetric data, the study comprised women with schizophrenia or major affective disorders who had given birth to 3,174 children during 1980-1992 in Western Australia. A comparison sample of 3,129 births to women without a psychiatric diagnosis was randomly selected from women giving birth during 1980-1992. Complications were scored with the McNeil-Sjöström Scale. Odds ratios were calculated for specific reproductive events. Results: Both schizophrenic and affective disorder patients had increased risks of pregnancy, birth, and neonatal complications, including placental abnormalities, antepartum hemorrhages, and fetal distress. Women with schizophrenia were significantly more likely to have placental abruption, to give birth to infants in the lowest weight/growth population decile, and to have children with cardiovascular congenital anomalies. Neonatal complications were significantly more likely to occur in winter; low birth weight peaked in spring. Complications other than low birth weight and congenital anomalies were higher in pregnancies after psychiatric illness than in pregnancies preceding the diagnosis. Conclusions: While genetic liability and gene-environment interactions may account for some outcomes, maternal risk factors and biological and behavioral concomitants of severe mental illness appear to be major determinants of increases in reproductive pathology in this cohort. Risk reduction in these vulnerable groups may be achievable through antenatal and postnatal interventions.

Asarnow JR, Tompson MC, McGrath EP

Background: In the past 10 years, there has been increased research on childhood-onset schizophrenia and clear advances have been achieved. Method: This annotation reviews the recent clinical and treatment literature on childhood-onset schizophrenia. Results: There is now strong evidence that the syndrome of childhood-onset schizophrenia exists and there are several similarities between childhood- and later-onset schizophrenia. Schizophrenia in youth can be reliably diagnosed using the same criteria employed with adults, and childhood-onset schizophrenia is predictive of schizophrenia or schizophrenia spectrum disorders in adulthood. Data is accumulating to guide pharmacological treatment strategies, and practice parameters have been developed to guide clinical care. Conclusions: Despite significant advances, there remains an urgent need for additional research on treatment and service delivery strategies. Promising work with adults highlights the importance of attending to psychosocial as well as pharmacologic treatment strategies, and the potential value of preventive interventions.