Research Discovers New Ways Of Treating Schizophrenia

Although it is a widely mediatized condition, there is surprisingly little that is known about schizophrenia. In fact, there’s no objective test to determine whether a person suffers from it and diagnosis is based on psychiatrists’ analysis of symptoms.

In addition, standard drugs to treat schizophrenia work in only half the cases and tend to lose their effect over time.

Now, Professor Illana Gozes of Tel Aviv University has discovered a new pathological symptom of schizophrenia, which may shed more light on the condition. Gozes found that an important cell-maintenance process called autophagy is reduced in the brains of schizophrenic patients.

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“We discovered a new pathway that plays a part in schizophrenia,” Gozes said. “By identifying and targeting the proteins known to be involved in the pathway, we may be able to diagnose and treat the disease in new and more effective ways.”

Kick-starting the cell’s cleaning process

Autophagy is like the cell’s housekeeping service, cleaning up unnecessary and dysfunctional cellular components. The process — in which a membrane engulfs and consumes the clutter — is essential to maintaining cellular health. But when autophagy is blocked, it can lead to cell death. Several studies have tentatively linked blocked autophagy to the death of brain cells seen in Alzheimer’s disease.

Brain-cell death also occurs in schizophrenics, so Gozes and her colleagues set out to see if blocked autophagy could be involved in the progression of that condition as well. They found evidence of decreased levels of the protein beclin 1, which is central to initiating autophagy. Its deficit suggests that the process is indeed blocked in schizophrenia patients. Developing drugs to boost beclin 1 levels and restart autophagy could offer a new way to treat schizophrenia, the researchers say.

“It is all about balance,” Gozes said. “Paucity in beclin 1 may lead to decreased autophagy and enhanced cell death. Our research suggests that normalizing beclin 1 levels in schizophrenia patients could restore balance and prevent harmful brain-cell death.”

Finding schizophrenia in the blood

Next, the researchers looked at protein levels in the blood of schizophrenia patients. They found no difference in beclin 1 levels, suggesting that the deficit is limited to the affected area of the brain. But the researchers also found increased levels of another protein, activity-dependent neuroprotective protein (ADNP), discovered by Gozes and shown to be essential for brain formation and function, in the patients’ white blood cells. Previous studies have shown that ADNP is also deregulated in the brains of schizophrenia patients.

The researchers think the body may boost ADNP levels to protect the brain when beclin 1 levels fall and autophagy is derailed. ADNP, then, could potentially serve as a biomarker, allowing schizophrenia to be diagnosed with a simple blood test.

The first of many discoveries

Prof. Gozes discovered ADNP in 1999 and carved a protein fragment, NAP, from it. NAP mimics the protein nerve cell protecting properties. In follow-up studies Prof. Gozes helped develop the drug candidate davunetide (NAP). In Phase II clinical trials, davunetide (NAP) improved the ability of schizophrenic patients to cope with daily life. The researchers hope NAP will be just the first of their many discoveries to improve understanding and treatment of schizophrenia.

Gozes is the Lily and Avraham Gildor Chair for the Investigation of Growth Factors, the director of the Adams Super Center for Brain Studies at the Sackler Faculty of Medicine, and a member of the Sagol School of Neuroscience at Tel Aviv University. Graduate students Avia Merenlender-Wagner, Anna Malishkevich, and Zeev Shemer of TAU, Professor Brian Dean and colleagues of the University of Melbourne, and Professor Galila Agam and Joseph Levine of Ben Gurion University of the Negev and Beer Sheva’s Psychiatry Research Center and Mental Health Center collaborated on the research. The findings were published in Nature’s Molecular Psychiatry.

Photo: Caste