Work Proceeds to Address Cognitive Impairment in Schizophrenia

The better-known symptoms of schizophrenia are devastating enough: hallucinations, delusions, agitated body movements, the inability to experience pleasure. Yet even when these facets are controlled with antipsychotic drugs, cognitive deficits that make it hard to maintain relationships or hold a job can still consign patients to a life in the shadows, with few friends or little contact with family.

Those impairments — which include things like working memory, processing speed, or the ability to interpret the emotion on someone’s face – affect 98% of schizophrenia patients to varying degrees, according to a study¹ cited at Sunday’s lunchtime session, “Recognizing Cognitive Impairment in Schizophrenia: Neurobiology and Clinical Implications,” part of the US Psychiatric and Mental Health Congress in Orlando, Florida.

Speakers Henry A. Nasrallah, MD, chairman of the Department of Neurology and Psychiatry, St. Louis University School of Medicine; Richard S.E. Keefe, PhD, professor of Psychiatry, Department of Psychiatry and Behavioral Science, Duke University Medical Center; and John M. Kane, MD, chairman, Department of Psychiatry, Hofstra North Shore-LIJ School of Medicine; discussed background, implications, and current research efforts by academia and the pharmaceutical community to find treatments for cognitive impairment in schizophrenia.

Cognitive impairment is a core feature of schizophrenia, not a secondary element of the disease, Dr Nasrallah said. Its near universal appearance among patients is made more complicated by the fact that fewer than half are aware of these deficits, and thus interactions with everyone from family, to strangers, to prospective employers are marked by failures to connect. “They may interpret a neutral facial expression as threatening,” Dr Nasrallah said.

For decades, schizophrenia research focused on managing symptoms that could cause the patient immediate harm, or harm to others. Only in the 1990s did cognition come back into focus, Dr Nasrallah said, and it’s long overdue, for these are the deficits that keep patients from fully taking their place in the world.

“It’s a huge unmet need,” he said; if this area is not addressed, most schizophrenia patients will remain on disability.

For years, there was debate whether cognitive deficits were caused by the disease or antipsychotic drugs that controlled its symptoms. That has been settled, Dr Nasrallah said. Cognitive decline is present early, and it picks up speed in the period before psychosis occurs,^2,3 although improper dosing of some therapies can make the deficits worse.

Dr Nasrallah and the later speakers suggested the knowledge of how early cognitive decline happens, and the fact that the loss of brain tissue at the onset of schizophrenia has now been documented, could provide an opportunity for clinician and researchers to create therapies to halt the worst effects. The ultimate goal, Dr Kane said later, would be to tailor treatment to a patient’s genetic profile.

Why is treating cognitive impairment just as important as treating symptoms like hallucinations? As Dr Keefe explained, these deficits contribute to functional outcomes, and they are the reason why schizophrenia is third-leading cause of life-years on disability for persons aged 15 to 44 years old. (The first is unipolar depression, the second is alcoholism).

Data are compelling and sad. “Two-thirds of these patients never marry,” Dr Keefe said. Some 20% are homeless at any one time. Fewer than 15% hold competitive employment. Most chilling, 40% of individuals with severe mental illness are incarcerated, Dr Keefe said. (A study in The American Journal of Managed Care earlier this year linked prior authorization policies in Medicaid in certain states with higher incarceration rates for persons with schizophrenia.)⁴ Cognitive impairment, Dr Keefe said, cause persons with schizophrenia to lead, “impoverished, challenging lives.”

As an example, he discussed how if an average person is given 16 words, he can remember 10, while a person with schizophrenia can only recall 6. “Try developing an intimate relationship when you can’t remember the things that the other person told you, things that are keys to your intimacy,” Dr Keefe said.

MATRICS. As Dr Kane explained, the age of onset of schizophrenia comes as a patient’s peers are moving into the world, making connections, finding jobs, and getting married. “All of that is delayed in someone with cognitive impairment,” Dr Kane said.

Right now, there aren’t any FDA approved treatments for cognitive impairment, but much work is going on to change that. Promoted by the National Institute of Mental Health, the MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) project seeks to speed up the process of developing therapies to treat cognitive impairment in schizophrenia.

According to Dr Kane, MATRICS represents a collaboration among government, academia, and the pharmaceutical sector; it was also described in a 2006 journal article as a “consensus-building” process to agree not only on what are the best molecular targets and the best targets for drug development, but also what the standards should be for measuring progress in cognition.⁵ The project developed the MATRICS Consensus Cognitive Battery, or MCCB, which takes 75 minutes to complete and measures not only cognition but also functional improvement as a co-primary endpoint.

As for therapies, Dr Kane said, "Pharmacologic interventions that target molecular mechanisms beyond dopamine are in development to address cognitive impairment."

Numerous potential therapies are being studied:

• α₇-Nicotinic receptor agonists
• Dopamine D₁ receptor agonists
• AMPA glutamatergic receptor agonists
• α₂-adrenergic receptor agonists
• NMDA glutamatergic receptor agonists
• Metabotropic glutamate receptor agonists
• Glycine reuptake inhibitorsM₁
• muscarinic receptor agonists
• GABA_A R subtype selective agonists⁵

^References

1. Keefe, RS, Eesley CE, Poe MP, Defining a cognitive function decrement in schizophrenia. Biol Psychiatry. 2005;57(6):688-691.
2. Woodberry KA, Giuliano AJ, Seidman LJ. Premorbid IQ in schizophrenia: a meta-analytic review. Am J Psychiatry 2008;165(5):579-587.
3. Carrion RE, Goldberg TE, McLaughlin D, Auther AM, Correll CU, Cornblatt BA. Impact of neurocognition on social and role functioning in individuals at clinical high risk for psychosis.Am J Psychiatry 2011;168(8):806-813.
4. Goldman D, Fastenau J, Dirani R, et al. Medicaid prior authorization policies and imprisonment among patients with schizophrenia. Am J Manag Care. 2014;20(7):577-586.
5. Marder SR. The NIMH-MATRICS project for developing cognition-enhancing agents for schizophrenia. Dialogues Clin Neurosci 2006;8(1):109-113

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