Locus Coeruleus Neuroimaging of Antipsychotic/Modafinil Interactions on Cognition in Schizophrenia

Michael M. Minzenberg, M.D.

University of California, Davis

Grant Program:

David Mahoney Neuroimaging Program

Funded in:

September 2011, for 3 years

Funding Amount:


Lay Summary

fMRI may reveal how antipsychotic medications interfere with cognitive control in schizophrenia patients

Investigators will use fMRI to assess the extent to which two commonly used antipsychotic drugs interfere with cognitive control functions in patients with schizophrenia. They also will determine how these drugs may limit the effectiveness of medications intended to enhance cognitive functioning.

People with schizophrenia have disordered thought processes (such as difficulties with memory, paying attention, and making sense of information) in addition to their psychiatric symptoms which can include delusions, hallucinations, disorganized behavior, loss of interest, and social withdrawal. Currently there are no effective drugs for treating patients’ cognitive problems. Moreover, the two commonly used antipsychotic drug therapies—aripiprazole and risperidone—may adversely affect cognitive functions by lowering activity in the brain system involved in cognitive control. This system is composed of neural networks in the brain’s prefrontal cortex and the neurotransmitter norepinephorine, used by the network’s cells to communicate. Similarly, the two antipsychotic drugs may limit the effectiveness of therapeutic agents that are designed to enhance cognitive control through neural network activation. One such agent is modafinil (Provigil®). Currently approved by the Food and Drug Administration to treat sleep-related disorders, modafinil has shown some promise in improving attention and memory.

Based on their preliminary research, the investigators hypothesize that apriprazole interferes less with prefrontal cortex system activation compared to risperidone. They also hypothesize that apriparazole, compared to risperidone, will interfere less with modafinil’s potential activation of the prefrontal cortex to improve network connectivity. They will use fMRI to test these hypotheses in 40 patients with early course schizophrenia. Each patient will be randomly assigned to receive either apiprazole or risperidone. Patients will undergo an fMRI scan while undertaking cognitive tasks prior to starting treatment, and again after eight weeks of treatment. Additionally, during the last few days of treatment, patients in both groups will be treated with modafinil on one day and with a placebo on the next day. Investigators will see whether patients treated with apiprazole show greater neural connectivity and cognitive task performance compared to patients treated with risperidone, and whether this difference is maintained or increased while patients also receive modafinal compared to placebo.

Significance: This research could lead to development of new types of antipsychotics and pro-cognitive agents that together would improve cognitive functioning in patients with schizophrenia.