Tim Piser, PhD, Chief Scientific Officer at Cadent Therapeutics

Most people with schizophrenia have difficulty with concentrating, remembering, maintaining attention, or making decisions, even when they are not experiencing auditory or visual hallucinations. For example, they may not remember a phone number they were just told, or they may feel “foggy” and can’t focus their attention on the task at hand. These difficulties are called “cognitive deficits” [1]. These deficits start before people with schizophrenia develop their first psychotic episode that leads to psychiatric hospitalization [2]. Those deficits also persist even when the most severe symptoms of schizophrenia have been brought under control with antipsychotic medication. Difficulties in thinking and processing routine information clearly make it hard to get and hold a good job, live independently, or develop social relationships. If you or a family member has schizophrenia, it’s important to be aware of these challenges in cognitive brain function.

Brain research has found that oscillations in electrical brain activity are important for normal thinking. Scientists have determined that the electrical brain activity that occurs in people with schizophrenia while they listen and respond to sounds is different than the brain activity recorded in people who don’t have schizophrenia [3-5]. These differences are also present before people with schizophrenia are first hospitalized for treatment [6-8]. The available medications that can help reduce delusions and hallucinations do not reverse these differences in brain activity, and the greater these differences are, the more challenging it is for people with schizophrenia to think clearly. Some scientists believe that the differences in brain activity in people with schizophrenia cause their difficulties in thinking rationally [9]. Measurement of brain electrical activity with electroencephalography (EEG) may prove useful in the development of new medicines to help people with schizophrenia think more clearly.

Cognitive remediation therapy may help people with schizophrenia think more clearly [10]. These treatments typically involve computer-based, social, and life skills training several times a week over several months. This kind of training may reshape the brain activity of people with schizophrenia so they can experience improvement in their cognitive functions during the activities of their daily lives. People with schizophrenia and their families should talk to their doctor or social worker about the possible benefits of a program of cognitive remediation therapy to improve their thinking.

Medicines currently used to treat people with schizophrenia, called antipsychotic drugs, do not reverse these differences in brain activity. Instead, they mostly modify the functions of several brain chemicals, especially dopamine and serotonin. Fluctuations of these brain chemicals in various brain regions are thought to cause some symptoms of schizophrenia, like hearing voices that aren’t there, or acting on beliefs that aren’t true. However, in people with schizophrenia, there are changes in the function of other brain chemicals that are not affected by these medications. For example, the most common brain chemical involved in thinking is called glutamate, and one of the brain proteins activated by glutamate is called the NMDA receptor. Yet, most medicines currently used to treat people with schizophrenia do not directly affect glutamate or the NMDA receptor, which is believed to have low activity in schizophrenia.

In healthy individuals who don’t have schizophrenia, drugs of abuse that block glutamate’s activation of the NMDA receptor, such as ketamine and phencyclidine (PCP), can suddenly trigger several symptoms of schizophrenia [11]. Also, in people who don’t have schizophrenia, these drugs change electrical brain activity and cause cognitive difficulties that are very similar to those in people with schizophrenia [12]. Some scientists believe that reduced activation of the glutamate NMDA receptor may produce the symptoms of schizophrenia [13].

One medicine that is available for some people with schizophrenia is clozapine (Clozaril). Clozapine may improve symptoms of schizophrenia that persist even after receiving several of the other medicines used to treat schizophrenia [14]. Some scientists think that clozapine may help improve the severe symptoms of schizophrenia by indirectly increasing activation of the NMDA receptor by glutamate [15]. Unfortunately, clozapine is not used very often because it can produce several serious side effects in some patients and requires weekly blood draws to measure the white blood cells.

New treatments are in development to try to restore cognitive functions like memory and attention and making daily plans in people with schizophrenia. For example, Cadent Therapeutics is developing CAD-9303, a drug that increases activation of NMDA receptors by glutamate. Cadent has already started clinical studies of CAD-9303 involving people with schizophrenia.



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