With growing knowledge of disease

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1 PHARMACOLOGIC STRATEGIES IN THE MANAGEMENT OF COGNITIVE SYMPTOMS Terry E. Goldberg, PhD* ABSTRACT Cognitive dysfunction is considered a major determinant and predictor of long-term disability and has, therefore, been viewed for well over a decade as an important therapeutic target. Although the effects of typical antipsychotic drugs on cognition have been studied for several decades, increasing evidence indicates that atypical antipsychotics have a more pronounced impact on this domain. Still, there is an unmet treatment need because atypical agents only modestly improve the considerable cognitive deficits seen in patients with schizophrenia. This article provides a comprehensive review of cognition trials that have involved first- and secondgeneration antipsychotics, in addition to current strategies for improving research protocols involving investigational agents that target cognitive function. Also included are the accomplishments of the National Institute of Mental Health-sponsored program, Measurement and Treatment Research to Improve Cognition in Schizophrenia, in regard to overcoming research barriers, devising a cognitive battery for use in clinical trials, and reaching a consensus on clinical trial design. Potential therapeutic targets and a network that focuses on identifying promising compounds for studies also are discussed. (Adv Stud Med. 2007;7(3):85-90) *Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, New York. Address correspondence to: Terry E. Goldberg, PhD, Division of Psychiatry Research, Zucker Hillside Hospital, rd Street, Glen Oaks, NY tgoldber@nshs.edu. With growing knowledge of disease processes and the ever-expanding availability of sophisticated drugs, it becomes increasingly apparent that in order to make a substantial impact on an illness, one must comprehensively address all its aspects. This point is particularly valid with a disorder such as schizophrenia, in which it is critical to treat cognitive impairment in addition to other symptoms in order to significantly influence long-term functional outcomes. Now recognized as an enduring core feature of schizophrenia, cognitive dysfunction is considered a major determinant and predictor of long-term disability, as discussed in an earlier article by David J. Schretlen, PhD, ABPP, and therefore, has been viewed for well over a decade as an important therapeutic target. IMPACT OF CURRENT ANTIPSYCHOTIC AGENTS ON COGNITIVE FUNCTION Although the focus in more recent years has been on atypical antipsychotic agents, typical or first-generation neuroleptic drugs (ie, haloperidol and chlorpromazine) have been studied for their effects on cognition since their introduction in the 1950s. Although earlier literature suggested that these drugs may enhance specific cognitive functions (ie, sustained and selective attention), the growing consensus had been that typical neuroleptic treatment had little or no appreciable effects on most aspects of higher-level cognitive function, especially when compared with atypical antipsychotic drugs. Most studies have narrowed the therapeutic effects of typical neuroleptics to positive symptoms, with substantially less impact on negative symptoms, mood symptoms, and cognitive impairment. However, a recent meta-analysis raised the question of whether typical neuroleptic treatment improves patients cognitive functioning when compared with no treatment at all or baseline after a washout period. 1 Researchers found that typical antipsychotic agents provided modest gains (effect Johns Hopkins Advanced Studies in Medicine 85

2 size =.22) in multiple cognitive domains when compared to no treatment. Nevertheless, there is continuing concern over their tendency to cause impairment in extrapyramidal systems and memory problems, perhaps on the basis of adjunctive anticholinergic treatment. Moreover, recent investigations suggest that haloperidol may interfere with specific cognitive skills, such as processing speed and procedural learning. 2,3 With the introduction of atypical or second-generation antipsychotic agents, several studies have been devoted to their possible cognitive-enhancing effects, which may be related to pharmacologic features that are not shared by typical antipsychotics. The newer agents are associated with increased release of dopamine (DA) and acetylcholine (ACh) in the prefrontal cortex and hippocampus, antagonism of various 5-hydroxytryptamine (5-HT) receptors (ie, 5-HT 2A, 5-HT 2C, or 5-HT 6 ), and stimulation of 5-HT 1A receptors. 4 Increased release of DA may lead to particular stimulation of D1 and D3 receptors, which may have beneficial effects on cognition, assuming that these receptors are understimulated in schizophrenia. Increased release of ACh may lead to enhancement of muscarinic (M) subtype 1 and M4 receptors or α-7 nicotinic acid postsynaptic signaling, which has been implicated in cognitive impairment in schizophrenia. 4 Some evidence also suggests that blockade of α2-adrenoceptors (a prominent effect of clozapine and, to some extent, risperidone) may be involved in attenuation of negative and cognitive symptoms. 5 Two earlier quantitative reviews of published studies up to the year 2000 identified significant gains with atypical agents in several cognitive domains including verbal fluency, vigilance, selective attention, secondary memory, and visuomotor skills. 6,7 However, the improvements were modest relative to the magnitude of cognitive deficits seen in patients with schizophrenia. Moreover, the results can only be extrapolated to clozapine and risperidone, because they were the primary focus of the studies. A more recent meta-analyses examining clozapine, olanzapine, quetiapine, and risperidone found the agents to be superior to typical neuroleptics in improving overall cognitive function, particularly in learning and processing speed, but the magnitude of these effects was considered to be at the low end of the medium range. 4 It is important to note that not all research on atypical antipsychotics has found positive effects on cognition. Some studies suggest that certain atypical agents have negative effects on working memory (delayed response in oculomotor tasks). 8 Nevertheless, atypical antipsychotics hold several advantages over typical agents, including a lower potential to produce extrapyramidal symptoms, improved effectiveness against negative symptoms, and availability in longer-acting, depot formulations or formulations with improved pharmacokinetics (ie, risperidone and paliperidone). These dosage forms are usually used in maintenance treatment to ensure compliance and to eliminate bioavailability problems related to absorption and first-pass metabolism. UNMET NEEDS IN THE TREATMENT OF COGNITIVE FUNCTION Current treatments appear most robust in effecting psychosis, yet they fall short in producing substantial improvements in those aspects of schizophrenia that appear to account for poor functional outcomes. In this regard, impaired cognition represents an unmet therapeutic need and challenges the field for innovation and discovery. 9 In an effort to advance the development of drugs for treating cognitive impairment, the National Institute of Mental Health (NIMH) developed a program titled, Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS). In collaboration with industry, academia, the US Food and Drug Administration (FDA), and NIMH leaders, MATRICS identified several obstacles that are likely to interfere with drug development, including a lack of consensus on how cognition should be measured, differing opinions on the most promising pharmacologic approaches, challenges in clinical trial design, concerns over the US FDA s approach to drug approval for this indication, and issues in developing a research infrastructure for carrying out clinical trials. 10 The first 3 barriers involved the US FDA and were addressed through a series of activities that began with the awarding of a contract to the University of California, Los Angeles, the convening of a series of consensus conferences, the implementation of a multi-site psychometric study of candidate measures, and the evaluation of all resulting information by a national panel of experts. Perhaps the most important result of the MATRICS effort was the US FDA s provisional consent to allow registration of an adjunctive drug that potentially improves cognition in patients with schizophrenia. IDENTIFYING TARGETS FOR INTERVENTION AND CREATING INSTRUMENTS TO TEST FOR EFFICACY One proposal for new therapeutics in schizophrenia 86 Vol. 7, No. 3 March 2007

3 is to dissect the Diagnostic and Statistic Manual of Mental Disorders entity into component symptom complexes (eg, negative symptoms, positive symptoms, and cognitive deficits) and to develop treatments for narrower clinical targets, rather than trying to develop a monotherapy for what is essentially a heterogeneous disorder. 11,12 In attempting to improve cognitive abnormalities, there has been some focus on drugs that target several 5-HT receptor subtypes, receptors within the central cholinergic system (nicotinic and muscarinic), and glutaminergic and noradrenergic pathways (Table 1). 11 These pathways are of particular interest because of their putative role in Table 1. Summary of Cognitive Enhancing Research Agent Effects on Cognition Type of Evidence Neuroleptics First-generation antipsychotic Very modest gains on most aspects of higher-level cognitive Quantitative reviews agents function Second-generation Superior to typical neuroleptics in improving overall cognitive Meta-analysis antipsychotic agents function, particularly in learning and processing speed, but the magnitude of these effects was considered to be at the low end of the medium range Adjunctive treatment Guanfacine Some preliminary benefit in reversing working memory deficits Studies of nonhuman primates and limited and distractibility studies of patients with schizophrenia Modafinil Improves cognitive function in some studies, but not in others Small open-label studies in healthy control subjects and patients with schizophrenia Donepezil and galantamine See central cholinergic system Open-label and placebo-controlled studies Modest cognitive improvements in some studies, but not in others Tolcapone Drugs that inhibit COMT may improve working memory and Preliminary studies in healthy control subjects executive function. Promising receptors/systems Central cholinergic system Alterations in the central cholinergic system of patients with Preclinical and limited clinical studies schizophrenia, such as reduced numbers of M and nicotinic receptors in the cortex and hippocampus, may contribute to the cognitive impairment of schizophrenia. Therefore, agents that enhance central cholinergic function, such as M1/M5 agonists (eg, norclozapine) and α-7 nicotinic receptor agonists (eg, varenicline), may improve specific functions, such as diminished auditory sensory gating and working memory. 5-HT receptor subtypes Serotonergic mechanisms are of particular relevance because of Preclinical and limited clinical literature (ie, 5-HT 1A, 5-HT 2A, their modulation of dopaminergic transmission and their key role 5-HT 6 selective compounds for cognition 5-HT 4, and 5-HT 6 ) in the control of mood, cognition, memory, and motor behavior. enhancement are in late-stage clinical trials. If add-on therapy is contemplated, antipsychotic drugs with 5-HT 4 compounds have not yet been weak affinities for serotonin receptors should be used to avoid tested in humans for cognition enhancement. confounds. Glutaminergic receptors PCP and other antagonists of NMDA-mediated neurotrans- Limited human trials of patients (NMDA and AMPA mission induce symptoms and cognitive deficits that closely with schizophrenia receptors) resemble those of schizophrenia, indicating a potentially critical Limited human trials of patients role of NMDA receptors in the etiopathology of primary with schizophrenia with conflicting evidence negative symptoms. D-serine, an NMDA receptor agonist, improved positive, negative, and cognitive symptoms. AMPA receptor enhancers have been shown to produce improvements in memory, attention, and cognition. 5-HT = 5-hydroxytryptamine; AMPA= α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid; COMT = catechol-o-methyltransferase; M = muscarinic; NMDA = N- methyl-d-aspartate; PCP = phencyclidine. Johns Hopkins Advanced Studies in Medicine 87

4 working memory, attentional function, learning and memory, and gating. 5 Despite the desirability of interventions that target cognitive deficits, there is no standard, easily administered test battery that specifically and efficiently assesses the important cognitive deficits in patients with schizophrenia (see previous article by Dr Schretlen). 13 Currently, there are 2 distinct approaches to measuring cognition in schizophrenia; one is based on clinical neuropsychology and the other is based on experimental cognitive psychology. Clinical neuropsychology uses batteries of standardized tests with generally wellestablished psychometric properties to measure cognitive abilities. Individual test scores are often combined to make composite scores based on factor analyses, and cognitive domains are identified using this empirical approach. In contrast, experimental cognitive psychology uses highly refined tasks that have been developed to examine the function of specific cognitive systems. 14 These theoretical model systems have been validated through extensive experimentation, in which task parameters are varied and performance is measured to test predictions arising from the models. Because this experimental approach involves constantly designing and modifying tasks, there is no standardization of task design or administration and relatively little has been done to understand the measurement properties of experimental cognitive tasks. The majority of tasks included in the MATRICS battery are clinical neuropsychological measures and have many desirable properties, including stable testretest reliability, a relative lack of floor and ceiling effects, and tests that reflect distinct functional domains. But despite the reliability of clinical neuropsychology, there are several compelling reasons for establishing a dialogue between cognitive and clinical neuropsychological approaches in regard to moving drug discovery for the treatment of cognitive deficits forward. The use of tasks from experimental cognitive psychology allows researchers to examine the integrity of specific cognitive systems and apply these tasks in noninvasive neuroimaging (eg, functional magnetic resonance imaging or fmri) studies that directly measure the effects of drugs on cognition-related brain activity. The approach offers many advantages, including isolation of specific cognitive systems that may be conserved across species, controlling for confounding effects of generalized performance deficits (eg, poor motivation or sedation), and providing a direct translational bridge from studies using animal models of cognition to patient-based research using fmri. 14 DEVISING A BLUEPRINT FOR DEVELOPMENT OF NOVEL COGNITIVE AGENTS The lack of consensus on a clinical trial design to establish efficacy of a cognition-enhancing agent has been a formidable barrier to drug development. In 2004, a joint meeting of the US FDA, NIMH, MATRICS investigators, and experts from academia and the pharmaceutical industry was convened to develop evidence-based guidelines for establishing therapeutic efficacy of 2 general types of potential procognitive agents: adjunctive/co-treatment agents and broad-spectrum agents. Although adjunctive/co-treatment agents have cognitive impairments as their primary indication, broad-spectrum agents have cognitive impairments and other symptoms of schizophrenia as co-primary indications. At a workshop held several years ago, experts addressed specific questions relating to clinical trial design and reached consensus on inclusion criteria, use of co-primary outcome measures, statistical approaches, diagnostic and concomitant medication, inclusion criteria, and the use of cognitive screening measures. 15 Major points that were agreed on are listed in Table 2. One underappreciated issue that complicates design and interpretation of clinical trials is the observance of a practice or repetition effect. For example, a recent study compared patients with first episode schizophrenia receiving second-generation antipsychotic agents with healthy control subjects and found that patients with first episode schizophrenia were only able to demonstrate greater changes (compared to healthy controls) in 2 of the 16 cognitive measures assessed. 16 Researchers found that the cognitive improvements observed among patients with first episode schizophrenia were consistent in magnitude to practice effects observed in healthy control subjects, suggesting that practice effects, rather than the medication, produced the limited cognitive change. This study raises concerns over several previous trials, in which the magnitude of cognitive improvement may not have been greater than the practice effect demonstrated by the healthy control group in this study. At face value, practice effects may be clinically advantageous, because optimal performance of activities in daily life is dependent on practice or repetition. 88 Vol. 7, No. 3 March 2007

5 Table 2. Consensus on Clinical Trial Design for Neurocognitive Drugs Studies of potential cognitive enhancers should initially include only patients with schizophrenia. Studies should be limited to patients who have been clinically stable and in the residual (nonacute) phase of their illness for a specified period of time (eg, 8 12 weeks), with no more than a moderate severity rating on positive and negative symptoms and a minimal level of extrapyramidal symptoms and depressive symptoms. Patients should be maintained on 1 current antipsychotic and other concomitant therapy for a specified period of time (eg, 6 8 weeks) and on the current dose for a specified time period (eg, 2 4 weeks). In stage I research, concomitant use of drugs with interactions between the adjunctive/co-treatment agent and the antipsychotic or concomitant medication should be avoided. Stage 2 research should evaluate the impact of potential pharmacodynamic or pharmacokinetic interactions with a larger, stratified sample and with minimal restrictions on allowed medication. Patients should be excluded from a trial only if their cognitive impairment severity compromises the validity of the cognitive outcome measures or if their level of cognitive functioning is so high that they perform at or near ceiling and, therefore, cannot demonstrate improvement. If a screening assessment must be used for inclusion based on the level of cognitive impairment, then during the trial, a different assessment should be used to evaluate cognitive outcome. If US FDA requires a co-primary measure; the measure should assess a clinically relevant functional outcome, but not necessarily community functioning, which is highly dependent on factors that are usually beyond the control of clinical trials. Co-primary measure should have good face validity for patient improvement, be expected to change in close temporal proximity to changes on cognitive performance, not be heavily dependent on range of rehabilitation opportunities and level of social support, and be practical and tolerable. Co-primary proxy measures should have good test-retest reliability, demonstrated associations with cognitive performance measures, and demonstrated associations with community functional status. Primary outcome should be a pre-specified, single, reliable, and valid primary cognitive outcome measure. It should be global or domain-specific and be based on its psychometric properties and results of pilot studies. FDA = Food and Drug Administration. However, there is little evidence that improvements in practiced tasks can be generalized to other tasks, because a practice effect is either paradigm specific (eg, familiarity with testing instructions and demands) or item specific (eg, words on a list). As a result, practice effects may not reflect changes in the compromised neurobiology that are necessary for improvement in broad domains of cognition. Furthermore, practice effects will not compensate for baseline differences between patients with schizophrenia and healthy control subjects who also practice. Possible ways of minimizing practice effects in research include using crossover study designs, incorporating a healthy control group for assessment of practice effects in cognition, and using tests that are not prone to practice effects. CREATING A NATIONAL NETWORK TO TEST THE EFFICACY OF NEW COMPOUNDS In an effort to foster a clinical research network where clinical studies of potential cognitive-enhancing agents can be investigated, the NIMH established the Treatment Units for Research on Neurocognition and Schizophrenia (TURNS) program. Some of the goals of the program include identifying promising compounds for studies, defining optimal experimental designs, and developing opportunities for industry/ academia/government collaboration in testing promising compounds. In looking at potential cognitiveenhancing drugs under development, there has been significant interest in α-amino-3-hydroxy-5- methylisoxazole-4-propionic acid receptor enhancers, which have been shown in some trials to produce improvements in memory, attention, and cognition. 17,18 Other promising cognitive-enhancing agents include nicotinic α-7 receptor partial agonists, D1 agonists, and 5-HT 6 receptor antagonists (Table 1). CONCLUSIONS Advances in pharmacologic treatment have had a major impact on positive and negative symptoms of schizophrenia. However, improved cognition remains an unmet treatment goal, because currently available drugs have marginal effects on the clinical relevance of Johns Hopkins Advanced Studies in Medicine 89

6 cognition. Large-scale, government-funded efforts, such as the MATRICS program and TURNS, have encouraged the collaboration of academia, government, and industry in hopes of turning the promise of cognitive-enhancing therapy into reality. REFERENCES 1. Mishara A, Goldberg TE. A meta analysis of the effects of typical neuroleptic medications on cognition: reopening the book. Biol Psychiatry. 2004;55: Purdon SE, Woodward N, Lindborg SR, Stip E. Procedural learning in schizophrenia after 6 months of double-blind treatment with olanzapine, risperidone, and haloperidol. Psychopharmacology (Berlin). 2003;169: Stevens A, Schwarz J, Schwarz B, et al. Implicit and explicit learning in schizophrenics treated with olanzapine and with classic neuroleptics. Psychopharmacology (Berlin). 2002;160: Woodward ND, Purdon SE, Meltzer HY, Zald DH. A metaanalysis of neuropsychological change to clozapine, olanzapine, quetiapine, and risperidone in schizophrenia. Int J Neuropsychopharm. 2005;8: Svensson TH. Alpha-adrenoceptor modulation hypothesis of antipsychotic atypicality. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27: Keefe RS, Silva SG, Perkins DO, Lieberman JA. The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr Bull. 1999;25: Harvey PD, Keefe RS. Studies of cognitive change in patients with schizophrenia following novel antipsychotic treatment. Am J Psychiatry. 2001;158: Reilly JL, Harris MS, Keshavan MS, Sweeney JA. Adverse effects of risperidone on spatial working memory in first-episode schizophrenia. Arch Gen Psychiatry. 2006;63: Carpenter W. Unmet therapeutic needs. Schizophr Bull. 2005;31: Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS). Available at: edu/matrics-overview-frame. htm. Accessed January 17, Hyman SE, Fenton WS. What are the right targets for psychopharmacology? Science. 2003;299: Green Mf, Nuechterlein KH, Gold JM, et al. Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biol Psychiatry. 2004;56: Keefe RSE, Goldberg TE, Gold J, Harvey P. The Brief Assessment of Cognition in Schizophrenia: reliability, sensitivity and comparison with a standard neuropsychological battery. Schizophr Res. 2004;68: Carter CS. Applying new approaches from cognitive neuroscience to enhance drug development for the treatment of impaired cognition in schizophrenia. Schizophr Bull. 2005;31: Buchanan R, Davis M, Goff D, et al. A summary of the FDA- NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull. 2005;31: Goldberg TE, Goldman R, Burdick KE, et al. Cognitive improvement after treatment with second generation antipsychotic medications in first episode schizophrenia: is it a practice effect? Neuropsychopharmacology. 2006;(Suppl). 17. Eye On Schizophrenia. CenterWatch (clinical trial listing service). Available at: Accessed January 22, Marenco S, Egan MF, Goldberg TE, et al. Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series. Schizophr Res. 2002;57: Vol. 7, No. 3 March 2007