The treatment of cognitive impairment in schizophrenia.

Abstract

Cognitive deficits are major contributors to disability in schizophrenia. Many pharmacologic targets have been identified for cognitive enhancing agents, including receptors involved in dopaminergic, glutamatergic, GABAergic, serotonergic and cholinergic neurotransmission. In addition, new approaches to drug development have been directed towards neuroprotection and the facilitation of neuroplasticity. While several pharmacologic agents and cognitive remediation have shown promise in early trials, no treatment has yet demonstrated efficacy in large replication trials. The experience with different pharmacologic targets is reviewed and methodologic issues are discussed with recommendations for future research.

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The treatment of cognitive impairment in schizophrenia
Donald C. Goff, Michele Hill, Deanna Barch
PII:
DOI:
Reference:
S0091-3057(10)00347-3
doi: 10.1016/j.pbb.2010.11.009
PBB 71044
To appear in:
Pharmacology
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Accepted date:
9 September 2010
5 November 2010
12 November 2010
Please cite this article as:
treatment of cognitive impairment in schizophrenia, Pharmacology (2010),
10.1016/j.pbb.2010.11.009
Goff Donald C., Hill Michele, Barch Deanna, The
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The treatment of cognitive impairment in schizophrenia








Donald C. Goff1

Michele Hill1

Deanna Barch2





1 The Schizophrenia Program, Massachusetts General Hospital and Harvard Medical School

2 Washington University, Departments of Psychology, Psychiatry and Radiology






Corresponding author:
Donald Goff, MD
Freedom Trail Clinic
25 Staniford St.
Boston, MA 02114

617 912 7862
Fax: 617 723 3919
goff@psych.mgh.harvard.edu

Supported by MH002025 (DG)

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experience impairments in cognitive function, including first degree relatives (Delawalla et al.,
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1. Introduction:

1.1 Cognitive Deficits in Schizophrenia:


The field of psychopathology research has increasingly come to recognize the importance of
cognitive deficits in understanding etiology, course and outcome in schizophrenia (Green et al.,
2000; Keefe, 2008), one of the most debilitating of psychiatric disorders. The range of cognitive
impairments in individuals with schizophrenia is broad, with the more robust and replicable
deficits typically found in the domains of processing speed, episodic memory, working memory,
and executive function. Impairments in these domains are associated with alterations in the
neural systems known to support these cognitive functions, including impairments in the
function of the medial temporal lobes (Heckers, 2001; Reichenberg and Harvey, 2007), the
prefrontal cortex (Minzenberg et al., 2009), and a range of neurotransmitter systems known to be
important for intact cognitive function. These cognitive impairments are typically present prior
to the onset of the illness (Cornblatt et al., 1999; Niendam et al., 2003), and there is even some
data to suggest that the degree of impairment in certain aspects of cognition predicts the
subsequent onset of schizophrenia (Cornblatt et al., 1999; Sorensen et al., 2006). Importantly,
individuals who share unexpressed genetic components of vulnerability to schizophrenia also
2006; Snitz et al., 2006) and individuals with schizotypal personality disorder (Barch et al., 2004;
Dickey et al., 2005; Voglmaier et al., 2000). In addition, some evidence suggests that the
stronger the genetic risk, the greater the impairment in cognitive function in first-degree relatives
(Glahn et al., 2003; Tuulio-Henriksson et al., 2003). These cognitive deficits persist throughout
the course of the illness in individuals with schizophrenia (Heaton et al., 2001; Irani et al.), and
may be important in constraining functional outcome and quality of life (Gold et al., 2002; Green

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efficacy for cognition in schizophrenia, an active control condition is not available to provide a
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et al., 2004). Thus, it is a high priority to identify the biological underpinnings of cognitive
deficits in schizophrenia and to develop effective treatments.


1.2 Trial Design for Agents to Treat Cognitive Deficits in Schizophrenia:


In 2003, experts from academia, industry, and the FDA were brought together by the NIMH-
funded “Measurement and Treatment Research to Improve Cognition in Schizophrenia”
(MATRICS) project to develop guidelines for clinical trials of cognitive enhancing drugs for
schizophrenia (Buchanan et al., 2005). One of several accomplishments by this group was the
creation of the MATRICS consensus cognitive battery (MCCB), which tests seven domains of
cognition intended to represent functionally-significant areas of impairment in schizophrenia that
may be amenable to pharmacologic treatment (Nuechterlein and Green, 2006); the MCCB has
become the standard assessment tool for clinical trials. Although cognitive tests were selected to
minimize practice effects, experience with the MCCB indicates that small practice effects may
complicate the interpretation of results and so a placebo control is necessary in clinical trials
(Buchanan et al., 2010b). However, this issue of practice effects is not unique to the MCCB and
will be an issue with almost any cognitive battery. In addition, because no agent has established
measure of assay sensitivity (i.e., the ability of the trial to differentiate active drug from placebo).
As a result, negative trials of cognitive enhancing agents can’t be differentiated reliably from
failed trials, in which an effective agent would also fail to separate from placebo.

Several other issues were raised during the MATRICS discussion of clinical trial design,
including a concern on the part of the Food and Drug Administration (FDA) about

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“pseudospecificity”, or the possibility that cognitive function might be improved indirectly by a
drug that primarily improves psychosis, agitation, apathy, Parkinsonism or mood. Precautions to
avoid secondary causes of cognitive impairment in participants were recommended, such as
restricting study samples to patients who are stable, without significant psychosis, depression,
Parkinsonism, negative symptoms or use of drugs that impair cognition, such as anticholinergics
and benzodiazepines. It remains unclear whether common neurobiologic mechanisms may
underlie both cognitive deficits and negative symptoms of schizophrenia, and so the wisdom of
excluding patients with negative symptoms is debated (Buchanan et al., 2010b). The consensus
view of experts at the MATRICS meeting was that most patients with schizophrenia have
experienced some decrement in cognitive functioning associated with the illness; hence the only
restrictions regarding cognitive functioning in subject selection are that participants are not at the
“ceiling” level for a test nor too impaired to provide valid results. Because the second
generation antipsychotics bind to a wide range of receptors, potential pharmacodynamic
interactions may complicate add-on trials of cognitive enhancing agents. Drugs known to
possess the potential for pharmacodynamic or pharmacokinetic interactions with the
experimental agent may be best excluded at early stages of clinical development prior to
embarking on an “all-comers” approach to enrollment.

A common problem with trials of cognitive enhancing agents has been the analysis in small
subject samples of more than one cognitive test score without correction for multiple
comparisons, thus increasing the likelihood of false positive results. As such, it is recommended
that investigators use a single composite cognitive score or, if a priori evidence supports it, a
single domain score, as the primary outcome measure. If the composite cognitive score