Efficacy of Cognitive Remediation in Patients With Schizophrenia or Schizoaffective Disorder Stabilized on Lurasidone

Schizophrenia Clinical Trial

Official title:

Clinical and Biomarker Assessment of Efficacy of Cognitive Remediation in Patients With Schizophrenia or Schizoaffective Disorder Stabilized on Lurasidone

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT01173874
• Other study ID #: TENETS01
• Status: Recruiting
• Phase: Phase 3
• First received: July 8, 2010
• Last updated: October 3, 2012
• Start date: July 2010
• Est. completion date: December 2013

Study information

• Verified date: October 2012
• Source: University of California, Los Angeles
• Contact: Marlene M. Carlson
• Phone: 212-543-5678
• Email: mcarlson[@]pi.cpmc.columbia.edu
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

The investigators hypothesize that cognitive remediation will be superior to the active control group on the change from baseline to study end point of cognitive remediation phase on both co-primary outcome measures (standardized composite MATRICS score and Cognitive Assessment Interview).

Description:

OVERVIEW & SPECIFIC AIMS Marked cognitive impairment underlies much of the social & occupational dysfunction associated with schizophrenia. Currently available antipsychotic medications are primarily effective in treating psychotic symptoms & have demonstrated only limited potential in ameliorating cognitive deficits in schizophrenia patients.

Lurasidone is a novel compound synthesized by SEPRACOR, Inc.for the treatment of patients with schizophrenia & bipolar disorder. It possesses high affinity for dopamine D2, serotonin 5-HT2A, 5-HT7, 5-HT1A & noradrenaline α2C receptors. Compared with other atypical antipsychotics, lurasidone demonstrates similar binding affinities for the D2 & 5-HT2A receptors, but greater affinity for serotonin 5-HT1A receptors. Lurasidone displays no affinity for histamine H1 or acetylcholine M1 receptors. In animal studies, lurasidone significantly reversed memory impairment induced by MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, in a rat step-through type passive avoidance task. The maximum inhibitory effects of lurasidone were greater than those observed with risperidone, quetiapine, & olanzapine, while aripiprazole was not effective in reversing the impairment induced by MK-801. Additionally, lurasidone significantly reversed memory impairment induced by the anticholinergic drug scopolamine in the passive avoidance task. The reversal of pharmacologically induced cognitive deficits in rats by lurasidone is promising & warrants specific investigation in subjects with schizophrenia, given the prominence of cognitive deficits in this disorder.

From a different therapeutic perspective, the utility of cognitive remediation in ameliorating cognitive deficits & improving functional outcomes in schizophrenia has recently been evaluated in several studies. A meta-analysis of these trials found effect sizes for improvement in cognitive & psychosocial functioning in the low to moderate range (McGurck 2007). The best outcomes in psychosocial functioning were evident when cognitive remediation was combined with teaching of psychosocial skills.

Given the recalcitrant nature of cognitive deficits in schizophrenia & their impact on functional capacity we felt that in designing a study to test the effectiveness of cognitive remediation we should maximize the likelihood of therapeutic benefit by administering cognitive remediation in the context of pharmacotherapy that may have potential for precognitive effects. By so doing we could possibly boost the effect sizes seen with cognitive remediation alone. In this study we will transition patients with schizophrenia (in whom a change in antipsychotic therapy is clinically warranted) from their current antipsychotic to lurasidone - clinicians will have eight weeks to complete the switch. Subjects who are successfully switched to lurasidone will then be randomized to receive either cognitive remediation or a non-specific mental activity control condition two times/week for a total of 30 sessions over a 4-6 month period. Our goal is to have 140 patients complete the cognitive remediation phase.

A subset of the sample will participate in 2 biomarker studies. Event related potentials & fMRI will be done in these subjects at baseline & study completion.

This study will be done as an Investigator initiated trial (J. Lieberman, M.D. - PI) under a separate IND.

Primary Aim: We hypothesize that cognitive remediation will be superior to the active control group on the change from baseline to study end point of cognitive remediation phase on both co-primary outcome measures (standardized composite MATRICS score & Cognitive Assessment Interview).

Additional aims

1. To compare cognitive remediation to active control on functional outcome as assessed by the change in UCSD Performance-Based Skills Assessment (UPSA-Brief) from baseline to end point of cognitive remediation phase.

2. To compare cognitive remediation to active control on changes from lurasidone stabilized baseline to end point in indices of functional brain activation (ERP & fMRI) during cognitive activation tasks.

3. Evaluate the effect of 8 weeks of lurasidone treatment on cognitive & functional outcomes as assessed by changes from baseline in the MATRICS composite score, CAI, & UPSA-Brief.

4. Evaluate the effect of cognitive remediation compared to nonspecific mental activity on cognitive & functional outcomes as assessed by changes from lurasidone stabilized baseline to end of cognitive remediation phase in the MATRICS composite score, CAI, & UPSA-Brief.

5. Evaluate the efficacy, safety, & tolerability of lurasidone in patients with schizophrenia as assessed by the change from baseline to week 8 & to end of cognitive remediation phase in the PANSS total score, Side Effect Checklist, AIMS, SAS, BAS, & frequency of abnormal laboratory values.

BACKGROUND & SIGNIFICANCE

A broad range of neurocognitive abnormalities characterizes patients with schizophrenia. These include impairments in attention (including abnormalities in sensory gating), visual & verbal learning & memory, working memory, processing speed, social cognition, & executive function, (Nuechterlein et al, 2004), & are major determinants of poor functional outcome (Green, 1996; Green et al, 2004). Conventional antipsychotics have limited effects on these impairments. Second generation antipsychotics may have modest benefits for cognitive function although recent literature does not support an advantage over first generation antipsychotics (Davidson et al, 2009). Regardless, most patients continue to exhibit pronounced cognitive impairment despite adequate antipsychotic treatment & these deficits result in much of the social & occupational dysfunction associated with schizophrenia.

A number of investigations have examined the impact of cognitive remediation on cognition in schizophrenia subjects. A recent meta-analysis of cognitive remediation trials (McGurck et al. 2007) found a low to moderate effect size for improvement in cognitive performance (effect size 0.41), & psychosocial functioning (effect size 0.36). Interestingly, the effects of cognitive remediation on psychosocial functioning were significantly greater in those studies that provided adjunctive psychiatric rehabilitation (effect size 0.47) than in those that provided cognitive remediation alone (effect size 0.05). In other words, a basic cognition-enhancing strategy had to be combined with the teaching of psychosocial skills & strategies to see clinically meaningful effects in psychosocial functioning (which is the ultimate goal of any cognitive remediation intervention).

Of all the cognitive deficits in schizophrenia, verbal learning & memory are among the most abnormal. Abnormalities are present at the earliest stages of auditory processing as evidenced by the abnormally low amplitudes of the mismatch negativity response obtained during the pre-attentive detection of auditory stimuli. Reduced mismatch negativity responses are significantly associated with impaired verbal memory, with the inability to decode semantic & emotional aspects of speech, & with poor functional status. These findings suggest that efficient auditory processing is crucial for the successful encoding & retrieval of verbal information & that disturbance in these elemental processes are related to higher-order cognitive dysfunction in schizophrenia (Fisher et al 2009).

Based on this body of evidence & on data from animal experiments in the basic neuroscience of learning-induced neuroplasticity, a cognitive training program that targets both early auditory processing & working memory operations was developed by Posit Science with the goal of improving verbal memory performance in patients with schizophrenia. Interim findings from an ongoing study to evaluate the effectiveness of this approach were recently published (Fisher et al 2009). 55 patients with schizophrenia who were clinically stable on various antipsychotics were assigned either to the cognitive training program developed by Posit Science (50 sessions administered 5X/week over 10 weeks), or to a computerized game control condition to mimic the time & concentration at a computer required in the cognitive training program. Primary outcome was the change from baseline in the Measurement & Treatment Research to Improve Cognition in Schizophrenia (MATRICS) test battery. The group that received cognitive training showed impressive & significantly larger improvements than the control group on global cognition, verbal working memory, & verbal learning & memory at effect sizes in the medium to large range (.56 to .86). Important questions not addressed by this study were the optimal dose & duration of the cognitive remediation intervention, the tolerability & efficacy of the intervention in below average IQ schizophrenia populations, the persistence (or lack thereof) of the improvement in cognitive function after cessation of the cognitive remediation, the functional significance of the gains in cognitive function, & the contribution, if any, of the type of antipsychotic therapy. Additionally, it is unlikely that patients in typical clinical settings would be able to comply with such a rigorous daily cognitive remediation program without the financial incentives that were provided to subjects in this study.

As noted above, studies of cognitive remediation have thus far included subjects on whatever antipsychotic they were taking at study entry. It is well known that the antihistaminergic & antimuscarinic properties of antipsychotics may further impair cognitive processes in schizophrenia patients. Additionally, antipsychotics vary considerably in their EPS liability, which can affect cognitive processing & motor speed. Thus, choice of antipsychotic therapy would appear to be an important consideration in the design of cognitive remediation trials in schizophrenia patients although no studies thus far have attempted to control for this important variable.

Lurasidone is a novel compound synthesized by Sepracor for the treatment of patients with schizophrenia & bipolar disorder. It possesses high affinities for dopamine D2, serotonin 5-HT2A, 5-HT7, 5-HT1A & noradrenaline α2C receptors. Compared with other atypical antipsychotics, lurasidone demonstrates similar binding affinities for the D2 & 5-HT2A receptors, but greater affinity for serotonin 5-HT1A receptors. Lurasidone displays no affinity for histamine H1 or acetylcholine M1 receptors. As of September 02, 2008, approximately 1560 people had received lurasidone in various types of clinical studies (e.g., single doses ranging from 0.1-100 mg, repeated doses up to 600 mg/day for less than one week, & repeated doses up to 120 mg/day for 6 weeks of treatment & up to 80 mg/day for 12 months of treatment). This included approximately 263 healthy volunteers & 1309 schizophrenic or schizoaffective disorder subjects. Another 600 subjects are currently enrolled in ongoing, placebo-, & active comparator controlled Phase 3 studies. Double-blind placebo-controlled & open label studies lasting 6-8 weeks in patients with acute exacerbation of schizophrenia, were suggestive of a therapeutic dose range of lurasidone of 40mg/day to120 mg/day given once daily.

Of special interest in animal studies was the observation that lurasidone significantly reversed memory impairment induced by MK-801, an N-methyl-D-aspartate (NMDA) receptor antagonist, in a rat step-through type passive avoidance task. The maximum inhibitory effects of lurasidone were greater than those of risperidone, quetiapine, & olanzapine, while aripiprazole was not effective in reversing the impairment induced by MK-801. Additionally, lurasidone significantly reversed memory impairment induced by the anticholinergic drug scopolamine in the passive avoidance task. The reversal of pharmacologically induced cognitive deficits in rats by lurasidone & the differences observed from other antipsychotics is promising & warrants specific investigation in subjects with schizophrenia.

In this study we propose to build on the important work done thus far in cognitive remediation in schizophrenia by addressing some of the limitations of previous studies. All subjects will be stabilized on lurasidone prior to initiation of cognitive remediation. This will provide a uniform foundation of antipsychotic therapy with an agent that might have pro-cognitive effects. Cognitive remediation initiated in schizophrenia patients stabilized on lurasidone treatment could potentially provide a synergistic benefit on cognition & functioning. At a minimum, lurasidone would not be expected to worsen cognitive functioning, as it has no M1 or H1 antagonist activity. The cognitive remediation intervention will be administered in small group settings twice weekly for 30 sessions & will utilize computerized & verbal group training exercises to address basic skills such as auditory processing, attention, processing speed, & verbal working memory & learning, as well as intermediate & complex skills such as deductive reasoning, planning & sequencing, set shifting, & complex problem solving. Software exercises from Posit Science will be used to address the deficits in basic cognitive skills. Cognitive remediation sessions will include a 55 minute session in which the subject engages in cognitive exercises on the computer followed by a 20 minute "bridging" component in which participants gather in a circle to discuss skills practiced, how they might use that skill in real world tasks, & to learn other non-computer based techniques to enhance their cognitive & psychosocial skills in order to meet their overall recovery goals. Outcome measures include improvement in cognition as assessed by the MATRICS & CAI, & functional outcome using UPSA-B. Two biomarker assessments (ERP & fMRI) will also be conducted in a subset of subjects at baseline & study completion.

Our goal in this study is to conduct a scientifically rigorous clinical trial that optimizes the likelihood of meaningful improvement in cognitive & psychosocial functioning in patients with schizophrenia. An important consideration in the study design is that the intervention is practical & can be implemented in regular clinical settings. Biomarker assessments will provide valuable information on neuroanatomical & pathophysiological substrates of cognitive impairment & the effect of therapeutic interventions.

PHARMACOLOGIC TREATMENTS

The daily dose of lurasidone will be flexibly dosed at 40, 80 or 120 mg based solely on clinical considerations & investigator judgment. All these doses have been demonstrated in large double-blind placebo-controlled trials to be effective in the management of acute exacerbation as well as maintenance treatment of schizophrenia.

COGNITIVE REMEDIATION

The Cognitive Remediation program has two principal parts: (1) individualized computer-based cognitive training allows participants to hone their cognitive skills through repeated exercises which gradually increase in difficulty & complexity (2) "bridging" group therapy sessions facilitate the transfer & application of newly learned cognitive skills to everyday situations & recovery goals. A building block approach to session planning will be used, with learning blocks increasing in complexity from Basic to Intermediate to Complex. Three dimensions determine complexity of the tasks:

• Cognitive skill emphasized by the activity (one versus multiple skills)

• Cognitive load of the activity (difficulty of task)

• Goal properties of the tasks (proximal versus distal, highly specific versus complex)

Within each learning block are sessions that introduce an assortment of computerized cognitive exercises, which build upon previous skills learned, but are not reliant on achieving 100% accuracy before progressing. Thus foundation skills need to be completely mastered to progress onto more complicated tasks. The overarching training model is to introduce basic cognitive skills in the beginning block, with tasks that target one or two cognitive skills, have proximal goals, & low cognitive load. In addition to exercising the requisite basic cognitive skills, this facilitates self-efficacy & task valuation, which in turn enhances motivation. Increasingly tasks become more complex & touch upon various cognitive domains. In this manner, multiple domains are engaged simultaneously - as is the case when the participant must navigate everyday life outside the laboratory setting.

The "building block" approach allows the participant to gradually train each cognitive skill necessary for higher order executive functioning. The ultimate goal is to teach memory techniques & the problem-solving skills to successfully steer through tasks not only on the computer but in everyday life

Non-specific mental activity Active Control Group (ACG). Participants will be enrolled in twice weekly group that works on various computerized puzzles & mentally stimulating exercises for total of 30 hours within a 6 month timeframe. Commercially available puzzles games that provide engaging but non-specific mental stimulation will be used as the active control training exercises. Participants will follow similar session timeframe as CR groups followed by healthy lifestyle groups.

Structured Clinical Interview for DSM-IV-Clinical Trial (SCID-CT) The Structured Clinical Interview for DSM-IV Clinical Trial Version (SCID-CT) will be used to confirm the diagnosis of schizophrenia. The SCID-CT is a semi-structured interview designed to evaluate DSM-IV Axis I diagnoses. It enables trained clinical raters to reliably determine Axis I diagnoses in diverse patient populations.

Clinician-Rated Side-Effect Scales Patients are to be assessed for extrapyramidal symptoms such as bradykinesia, rigidity, tremor, hyperkinesias, dystonia, akathisia, involuntary muscle contractions, athetosis, & chorea.

EPS-related side effects will be evaluated with the standardized scales of AIMS, SAS & BAS.

Abnormal Involuntary Movement Scale (AIMS) The AIMS consists of 12 items, 10 to be rated on a 4-point scale of severity & 2 to be rated as yes or no.

Simpson-Angus Scale (SAS) The SAS is a rating scale used to measure EPS & consists of a list of 10 symptoms, each to be rated on a 5-point scale of severity.

Barnes-Akathisia Rating Scale (BARNES) The Barnes Akathisia Rating Scale will be used to assess the presence & severity of akathisia before treatment (baseline) & at the scheduled visits. This scale consists of 4 items (objective observation of akathisia by the investigator, subjective feelings of restlessness by the patient, patient distress due to akathisia, an global evaluation of akathisia). To complete this scale, subjects should be observed while they are seated & then standing (for a minimum of two minutes in each position). Symptoms observed in other situations (e.g., while engaging in neutral conversation, engaging in activity) may also be rated. Subjective phenomena should be elicited by direct questioning.

The Positive & Negative Syndrome Scale (PANSS) The Positive & Negative Syndrome Scale (PANSS) will be the primary assessment instrument for psychopathology.

The PANSS contains 30 items that assess symptoms of psychotic disorders including positive, negative & general psychopathology. The PANSS was chosen because of its widespread use in clinical studies of psychosis, & its demonstrated reliability in assessing psychopathology across diverse patient populations. The PANSS includes items from the Brief Psychiatric Rating Scale (BPRS), with additional items from the Psychopathology Rating Schedule.

Clinical Global Impressions Severity Scale (CGI-S) The Clinical Global Impressions (CGI) Severity Scale will be used for repeated evaluations of global psychopathology. The CGI-S scale is widely used in schizophrenia research & is a single Likert scale rating severity of psychopathology on a scale of 1 (normal, not ill) to 7 (very severely ill).

Calgary Depression Scale for Schizophrenia (CDSS) The CDSS is a nine-item scale specifically developed for assessment of depression in patients with schizophrenia. Compared with the HAM-D, there is less overlap between positive & negative psychopathology. Items do not focus on weight change & initial insomnia, both of which can be confounded by the drug treatment of schizophrenia. All items are rated on a four-point scale: 0=absent; 1=mild; 2=moderate; 3=severe.

Columbia Suicide-Severity Rating Scale (CSSRS) The CSSRS is a low-burden, clinician-administered tool that covers the wide spectrum of suicidality from ideation to behavior. With suicide attempts too infrequent to serve as an outcome parameter, this suicide assessment scale provides a validated measure of such related variables as impulsivity, poor frustration tolerance, sadness, & hopelessness.

Service Utilization & Resources Form -Short Form (SURFs) The Service Use & Resources Form for Schizophrenia (SURFs) is a multi-item self-report form that comprehensively documents use of mental health & non-mental health service use, including the number & duration of contacts & the specific types of agencies from which services were obtained.

BIOMARKER STUDIES

A total of 72 subjects (36 per group) will participate in each biomarker study (ERP & fMRI). However we still anticipate a 50% total attrition from baseline to end point & will therefore have to conduct baseline biomarker assessments in 144 subjects to yield 72 completers & 58 subjects with good data.

EVENT RELATED POTENTIALS

Verbal episodic memory processing will be examined by measuring event-related brain potentials (ERPs) during a continuous word recognition test, & behavioral measures of verbal working memory will be obtained using a word serial position test (WSPT), both of which we have extensively used in our studies of schizophrenia (Bruder et al., 2004; Kayser et al., 1999; Kayser et al., 2006; Kayser et al., 2009). We have chosen to use the auditory version of both tests because ERP deficits were found to be particularly evident for spoken words (Kayser et al., 2009) & this will enable assessment of changes in auditory processing following the cognitive remediation with Posit Science auditory training. ERP & behavioral assessments will be conducted at baseline (on previous antipsychotic prior to switching to lurasidone) & at study end point upon completion of cognitive remediation.

ERPs During Verbal Episodic Memory: Studies using neuropsychological tests have found that patients with schizophrenia display a selective deficit in verbal learning & memory (Saykin et al., 1991). Neuroimaging studies have linked the verbal episodic memory deficits in schizophrenia to left inferior frontal & medial temporal lobe structures (Gur et al., 1994; Mozley et al., 1996). PET studies indicate that left inferior frontal cortex is involved in both encoding & retrieval of words in a recognition memory task, & schizophrenic patients show reduced activation of this region during both stages of episodic memory (Ragl& et al., 2001).

Episodic memory processes have also been examined by measuring brain ERPs during a continuous word recognition memory task (Friedman, 1990b). Subjects view or hear a series of words, some of which are repeated after a number of intervening words, & their task is to decide whether each word is new (not previously presented) or old (previously presented). A robust, replicable finding in healthy adults has been greater ERP positivity to "old" as compared to "new" words about 250 to 800 ms after word onset, referred to as the 'old-new effect.' The old-new effect has been interpreted as a neurophysiologic representation of retrieval processes involved in consciously discriminating old from new words. Intracranial ERP recordings in & around medial temporal lobe structures of epilepsy patients have revealed similar old-new effects, suggesting that the hippocampus, parahippocampal gyrus or amygdala may contribute to the scalp recorded effects (Elger et al., 1997).

We have used a continuous word recognition paradigm to assess neurophysiologic correlates of episodic memory deficits in schizophrenic patients & healthy controls (Kayser et al., 1999). In our most recent study (Kayser et al., 2009), schizophrenic patients showed poorer accuracy of word recognition, which is consistent with findings of impaired verbal memory in schizophrenia. Patients showed marked reductions the ERP old-new effect over lateral-parietal sites. Patients also lacked the left-greater-than-right hemispheric asymmetry typically observed for healthy adults. Impairments of these electrophysiologic correlates of episodic memory were most robust for auditory stimuli, which suggests a left-lateralized deficit in encoding &/or retrieval of phonological information. Patients also showed reduced left-parietal P3 & response-related mid-frontal negativity, likely associated with performance monitoring & anterior cingulate cortex.

We propose to record ERPs using essentially the same auditory word recognition task as in our prior study (Kayser et al., 2009). Words synthesized for a male voice (484 ms median duration) are presented binaurally through headphones at a comfortable level of about 70 dB SPL. A constant 2.5 s stimulus onset asynchrony & a fixation cross to minimize eye movements are used. The words are selected from a dictionary of 925 nouns. Words are arranged in two lists of 80 items, pseudo-randomly assigning items to the lists with the constraint that item features (e.g., concreteness or imagery norms for words) are balanced across lists. For each list, an item sequence is constructed so that an equal number of words (n = 17) are repeated once following either a short lag (8 intervening items) or a long lag (24 intervening items). Thus, each sequence has 34 words that repeat once, 17 at each lag, & 46 filler words that do not repeat, yielding a total of 114 items per sequence. Items that are repeated are considered new items at the first presentation, & old items at the second presentation, & these repeated items would form the basis for the subsequent data analysis. In contrast, never-repeated words are considered filler items & not included in the data analysis. Word presentation order is pseudo-randomized within each sequence to yield an equal distribution of short & long lags. Participants are instructed to respond to every word as quickly & accurately as possible by pressing one of two buttons on a response pad to indicate whether the word was "new" (never presented in the series) or "old" (previously presented). Prior to the first block, practice trials are administered with stimuli not used in the test to ensure that subjects understand the task & are responding appropriately. Each session will consist of two blocks of 114 trials with a 5 min rest interval between blocks. The retest session will also consist of two blocks, but with different words. Each session will take about one hour including electrode preparation. ERP & behavioral data will be acquired at each site & sent to NYSPI for processing & analyses.

Verbal Working Memory & Tone Discrimination Tests: There is now considerable evidence that working memory is impaired in schizophrenia (Goldman-Rakic, 1991; Park & Holzman, 1992; Carter et al., 1998). We have found that schizophrenic patients, who performed as well as healthy controls on a tone discrimination test of perception & attention, showed poorer performance than controls on an auditory verbal WM test, i.e., the Word Serial Position Test (WSPT), which requires short-term storage of the serial position of a series of four words (Bruder et al., 2004; Wexler et al., 1998). Moreover, when recording ERPs during this working memory test we found that patients having schizophrenia had reduced amplitude of P3 source over left inferior parietotemporal region (Kayser et al., 2006).

The WSPT & a tone discrimination screening test will be administered behaviorally after the ERP measures & take about 30 min. In the WSPT (Wexler et al., 1998), each trial begins with a series of four nouns spoken in a male voice followed after a delay interval of 9 sec by one of these words. The subject's task is to remember the four words in the order presented & to indicate the position of the probe word in the sequence. There are a total of 36 trials. Schizophrenic patients show poorer performance than healthy controls on this verbal working memory test (Bruder et al., 2004; Wexler et al., 1998). Moreover, patients who perform poorly on the tone screening test of auditory discrimination & attention have a particularly marked deficit on the WSPT & episodic memory tests, & may benefit most from the auditory training approach to cognitive remediation (Posit Science). The tone discrimination task is simply to judge whether two pure tones separated by 100 ms are the same or different in pitch. There are 10 practice trials & 60 test trials consisting of 30 trials where the tone pairs are the same pitch & 30 trials where the tones are different, with 6 trials at each of five frequency ratios. The auditory ERP, WSPT, & tone discrimination test may be of particular value as predictors of improvement in cognitive function following auditory training & also for monitoring changes during cognitive remediation.

fMRI OF WORKING MEMORY & EPISODIC MEMORY

Rationale: Working memory (WM), or the ability to hold information "on line" for short periods of time & often (but not always) to manipulate that information (Baddeley 1992), is considered to be one of the most fundamental cognitive impairments in schizophrenia. It is closely related to the construct of executive dysfunction. Deficits in both working memory & executive processing have been related particularly to dysfunction of the prefrontal cortex (PFC) (Goldman-Rakic 1999; Weinberger 2001). The exemplar of the executive WM task, is the "N-back" task (Cohen 1994). The "N-Back" task requires "continuous updating & order memory." It has been used to assess WM function in schizophrenia in several neuroimaging studies & has shown sensitivity to change as a function of pharmacological challenge in healthy controls (Mattay 2003) & cognitive rehabilitation in individuals with schizophrenia (Wykes, 2002). Because of the relative simplicity of the N-back paradigm, activation can be measured in a shorter time period & with fewer complexities than the Sternberg type task, & is likely to yield robust data in a "blocked" design format in a substantially shorter time period than storage tasks.

Episodic (Declarative) Memory Assessment Rationale: Episodic (declarative) memory will be assessed using intentional word encoding followed by a yes/no recognition test. Tests of this type robustly activate a range of brain regions known to be involved in the pathophysiology of schizophrenia, including inferior frontal cortex, parahippocampus, thalamus, parietal cortex & hippocampus. Individuals with schizophrenia are impaired on episodic memory tasks, & on tasks of this nature specifically. The paradigm chosen for this task is straightforward, easy for almost all individuals with schizophrenia to complete, relatively easy to implement in a multisite study, & will allow for the assessment of both basic components of episodic encoding & retrieval, as well as proactive interference effects in secondary analyses.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 140
• Est. completion date: December 2013
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 55 Years

Eligibility

Inclusion Criteria:

• Male or female between 18-55 years of age who meet DSM-IV-TR criteria for schizophrenia or schizoaffective disorder confirmed by the Structured Clinical Interview for DSM-IV Clinical trial version (SCID-CT version). Duration of illness > 1 year. Outpatient status.

• Change in antipsychotic medication is clinically warranted as evidenced by

• persistent psychosis despite adequate dose and duration of antipsychotic, or * inability to achieve therapeutic dose because of dose-limiting side effects,

• persistent side effects that either cause significant subjective distress or significantly increase medical risks, such as substantial weight gain or metabolic disturbances, or

• patient preference to switch and treating psychiatrist is in agreement.

• No behaviors suggesting potential danger to self or others over the 6 months prior to participation.

• For the last 2 weeks of lurasidone stabilization phase, a score of 4 or less on PANSS items of conceptual disorganization, hallucinations, suspiciousness and unusual thought content items.

• At end of lurasidone stabilization phase, Simpson-Angus Scale total score <

• At end of lurasidone stabilization phase, Calgary Depression Scale total score <10.

• No acute medical problems; any chronic medical condition (e.g. hypertension) consistently treated and stable during the 1 month prior to participation.

• Able to provide signed informed consent and to cooperate with all study procedures.

• Able to attend twice weekly sessions (each lasting approximately 75 minutes) for cognitive remediation or active control sessions for the ~6 month duration of the cognitive remediation phase of the study.

• Must meet the following cognitive performance criteria:

• Able to complete the baseline MATRICS validly at baseline as assessed by NP tester.

• Raw score of 12 or greater on the WTAR (Wechsler Test of Adult Reading) at screening.

• Women who can become pregnant must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the study in such a manner that the risk of pregnancy is minimized. Acceptable methods include oral, injectable or implanted contraceptives, intrauterine devices or barrier methods such as condoms, diaphragm and spermicides. Women who can become pregnant must have a negative urine pregnancy test at the Screening Visit. Women who can become pregnant include anyone who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy), or is not postmenopausal (defined as amenorrhea 12 consecutive months).

Exclusion Criteria:

• Documented history of learning disability.

• Hearing or visual impairment; not fluent in English.

• Current treatment with clozapine or history of treatment resistance as evidenced by failure to improve (in the judgment of the investigator) with 2 or more adequate dose antipsychotic trials of at least 6 weeks duration in preceding 1 year.

• Concomitant or anticipated treatment with potent CYP 3A4 inhibitor such a cimetidine, cyclosporine, erythromycin or erythromycin-like drugs (e.g., azithromycin, clarithromycin except short term acute treatment for 1 week or less), diltiazem, itraconazole, ketoconazole or other systemic antifungal agents in the azole class, nefazodone; or potent CYP3A4 inducer including: carbamazepine, modafinil, Phenobarbital, phenytoin, rifampin, St. Johns Wort, and troglitazone.

• Current treatment with psychotropic agents known to affect cognition such as amphetamines, topiramate.

• History of treatment with electroconvulsive therapy within the 6 months prior to participation or expectation that patient may require ECT during the study.

• History of neurological or neuropsychiatric conditions (e.g. stroke, traumatic brain injury, epilepsy, etc).

• Subjects with a history of clinically significant neurological, metabolic, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, and/or urological disorders (e.g. unstable angina, decompensate congestive heart failure, CNS infection or history of HIV seropositivity), which would pose a risk to the patient if they were to participate in the study or that might confound the results of the study. Active medical conditions that are minor or well controlled are not exclusionary if they do not affect risk to the patient of the study results. For example, the following are not exclusionary: a) stable and well-controlled hypertension; b) asthma (no serious attacks in the past year); c) hypothyroidism (TSH within normal limits).

• A positive test for Hepatitis C antibody with concurrent evidence of impaired hepatic function (increased AST or ALT greater than 2 times the upper limit of normal) or positive tests for Hepatitis A antibody IgM fraction or Hepatitis B surface antigen, irrespective of the AST or ALT values.

• History of alcohol or substance abuse or dependence during the 6 months prior to participation.

• Participation in a clinical trial involving an investigational medication within 3 months prior to participation or 2 or more investigational drug trials in the preceding 12 months.

• Pregnant women or women of child-bearing potential who are not using adequate birth control.

• Woman who are breast feeding.

• Individuals who: a) received any cognitive remediation in the 6 months prior to study entry or b)received more than 6 hours of cognitive remediation in the 12 months prior to study entry or c) received more than 15 hours in the 24 months prior to study entry. Cognitive remediation is defined as any behavioral intervention consisting of training activities that aim to target impairments in cognitive domains of sensory processing, attention, memory, processing speed, working memory, and executive functioning.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Psychotic Disorders
• Schizophrenia

Intervention

Drug:
• Cognitive Remediation
Cognitive remediation intervention will be administered in small group settings twice weekly for 30 sessions and will utilize computerized and verbal group training exercises to address basic skills such as auditory processing, attention, processing speed, and verbal working memory and learning, as well as intermediate and complex skills such as deductive reasoning, planning and sequencing, set shifting, and complex problem solving.

Locations

Country	Name	City	State
United States	Medical College of Georgia	Augusta	Georgia
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Duke University Medical Center	Butner	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Rush University Psychiatric Clinical Research Center	Chicago	Illinois
United States	University of Missouri	Columbia	Missouri
United States	University of Texas Southwestern Medical Center at Dallas	Dallas	Texas
United States	San Fernando Mental Health Center	Granada Hills	California
United States	Indiana University	Indianapolis	Indiana
United States	University of Miami Department of Psychiatry	Miami	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	Yale University	New Haven	Connecticut
United States	Columbia University	New York	New York
United States	Psychopharmacology Research Unit- Nathan KIine Institute for Psychiatric Research	New York	New York
United States	University of California - Irvine	Orange	California
United States	University of Texas Health Science Center, San Antonio	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
University of California, Los Angeles

Country where clinical trial is conducted

United States, 

References & Publications (38)

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* Note: There are 38 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Cognitive Function/Assessment	The NIMH MATRICS Neuropsychological Battery will be used to assess cognitive function. The NIMH MATRICS Neuropsychological Battery is comprised of measures of: a) working memory; b) attention/vigilance; c) verbal memory; d) visual memory; e) processing speed; f) problem solving; and g) social cognition. The MATRICS battery takes 90 minutes or less to complete.; Co-primary outcome measure is the Cognitive Assessment Interview (CAI). The CAI is a rating scale designed to elicit information from the subject and informant on the level of cognitive related function of the subject.	4-6 month period	No
Secondary	Functional Levels	The key secondary outcome measures are functional level as assessed by the UCSD Performance-Based Skills Assessment (UPSA-Brief), efficacy (change in PANSS score), Side Effect Checklist, AIMS, SAS, BAS, study completion rates, and frequency of abnormal laboratory values.	4-6 month period	No