A New Way of Thinking about Schizophrenia

At a Glance

  • Researchers are using neuro-physiological methods and functional brain imaging to investigate the role of NMDA receptors in sensory processes, and compare the contributions of sensory dysfunctions to impairments in higher-level processes in schizophrenia.
  • Applying low level currents over motor regions of the brain using tDCS dramatically alters the brain response and improves motor learning in those with schizophrenia.

“This is an entirely new way of thinking about schizophrenia. It is exciting to be at Columbia because here we have the right tools for the intersection of cognitive neuroscience and psychiatry. The new model transmitter system is changing the way we think about the experience and thoughts of the individuals with symptoms. And this leads to new treatments.”

Daniel C. Javitt, MD, PhD

For more than 20 years, Daniel C. Javitt, MD, PhD, Director of the Division of Experimental Therapeutics and Professor of Psychiatry and Neuroscience at Columbia University Medical Center, has been building an alternative conceptual approach for schizophrenia that withdraws from the one-size-fits-all antipsychotic treatment options traditionally given to patients since the 1950s. Schizophrenia was first described over a century ago, and for the past 60 years compounds developed based on dopamine models that focus on controlling hyperactivity and hallucinations, such as chlorpromazine, haloperidol, risperidone, or olanzapine, have remained the only FDA-approved treatments for schizophrenia.

Dr. Javitt, who is also the Director of Schizophrenia Research at the Nathan Kline Institute for Psychiatric Research, is using neuro-physiological methods and functional brain imaging to investigate the role of N-methyl-D-asparate (NMDA) receptors in sensory processes and compare the contributions of sensory dysfunctions in attention, perception, social cognition, and reading to impairments in higher-level processes in schizophrenia. NMDA receptors are “responsible for forming new connections and rehearsing old skills,” and are among several types of receptors for the neurotransmitter glutamate – the primary neurotransmitter for balancing mood in the brain.

“There is no medication to improve cognition, yet cognition is the most important part of the disease in terms of predicting outcome of quality of life,” says Dr. Javitt. “This is an entirely new way of thinking about schizophrenia. It is exciting to be at Columbia because here we have the right tools for the intersection of cognitive neuroscience and psychiatry. The new model transmitter system is changing the way we think about the experience and thoughts of the individuals with symptoms. And this leads to new treatments.”

An early symptom, he explains, includes losing the ability to read fluently. “If you don’t have the right model of the disease, you don’t think about it. If you don’t think about it, you don’t test it. If you don’t test it, you don’t find it,” Dr. Javitt says, emphasizing the importance of asking a patient exhibiting symptoms to read aloud and gauging their ability to pronounce words at their previously held reading level. “Those regions of the brain actually degenerate; we were able to find that many people lose four school grades worth of reading ability.

“Individuals also lose the ability to pick up intonation and inflection,” continues Dr. Javitt. “They don’t detect when people are being sarcastic, and they don’t detect the emotion in their voices and on their faces. If they are not able to understand the social cues, it leads them to withdraw from the social scene, which, in turn, feeds into paranoia.”

Application of low level currents over motor regions of the brain using tDCS (shown by dot) dramatically alters the brain response and improves motor learning in both healthy individuals and those with schizophrenia. The improvements are linked to an improved ability of individuals to increase activity in frontal brain regions (red), a critical first step in motor learning.

In addition to exploring what is needed for treatment at the basic cognitive level, Dr. Javitt’s most recent research investigates the role of brain oscillations in cognition, and on the ability of brain stimulation techniques, such as transcranial direct current stimulation (tDCS), to modulate normal and abnormal brain activity by stimulating and inhibiting regions and remapping its functions. “Noninvasive brain stimulation has the power to remodel and resculpt the brain, and only treat the necessary areas,” says Dr. Javitt, who supports a multipronged team-based approach to managing schizophrenia.

Researchers in the brain stimulation program of the Division of Experimental Therapeutics also conduct studies using multiple modalities. In addition to tDCS, these include deep brain stimulation, transcranial magnetic stimulation, magnetic seizure therapy, and electroconvulsive therapy. In describing the difference between these stimulation modalities, Dr. Javitt explains tDCS is meant specifically for rebuilding deficient activity. These research and treatment options, he emphasizes having recently discovered unexpected crossover, have vast opportunities for overlap with depression, bipolar disorder, cancer, Parkinson’s disease and more.

“Paradoxically, one of the most immediate benefits to emerge from the glutamate story on schizophrenia is its role in depression,” notes Dr. Javitt. “In schizophrenia, you want to stimulate the NMDA receptors and restore plasticity, but in depression it turns out that blocking NMDA receptors is useful for patients who don’t respond to the traditional antidepressants. In fact, it has had dramatic effects on depressive symptoms. So instead of stimulating glutamate, we’re antagonizing glutamate to treat depression instead of schizophrenia. The ultimate target may not always be where you thought it was, but more importantly, we are understanding new ways to interact with and manipulate the brain,” says Dr. Javitt. “It is learning behaviors, unlearning behaviors, and tweaking brain circuits with personalized approaches.”

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