LAS VEGAS – By ignoring schizophrenia’s symptomatology and focusing instead on its biomarkers and other implicated factors, researchers are homing in on treatments and interventions for the disease, according to an expert.

“The developmental model of schizophrenia suggests ... the field is now moving toward treatments better targeted to causes,” Dr. Matcheri S. Keshavan said at the annual psychopharmacology update held by the Nevada Psychiatric Association.

Clinicians need to understand that the disease is not homogeneous but more like a syndrome that can present in a variety of ways, according to Dr. Keshavan, Stanley Cobb Professor of Psychiatry at Harvard Medical School, Boston.

The stars emerging in the constellation many researchers are now using to chart the disease’s etiology range from neurobiologic disruptions, to drug use, to genetics, and several other possible factors. Reductions in stress, preventing drug use, and proactive cognitive support, as well as the development of targeted pharmacologic interventions are all currently being explored as ways to mitigate the disease.

‘Pathophysiological hits’

Whereas an excess of dopamine and hypersensitive dopamine receptors in the limbic region of the brain previously were thought to increase the risk for schizophrenia, Dr. Keshavan said the latest thinking is that there also might be cortical dopamine deficits, leading to a variety of symptoms, including psychosis. “Too little cortical dopamine might account for cognitive impairments and medical symptoms, whereas too much limbic dopamine might account for psychosis,” Dr. Keshavan said.

Beyond dopamine dysfunction, Dr. Keshavan said he and others have observed that higher levels of brain glutamate in adolescents correlate with more schizotypal symptoms, leading him to consider that there might be a problem with cortical glutaminergic regulation.

The pathophysiology of these changes is still uncertain, but Dr. Keshavan said several novel pharmacologic intervention trials are now underway, including some intended to reverse cognitive deficits by targeting GABA allosteric modulators to help correct glutaminergic dysfunction.

Also occurring in adolescence, both preceding and during schizophrenia’s prodromal phase, is a depletion of gray matter in the brain, particularly in boys. Also, a decrease in the brain’s plasticity because of exaggerated synaptic pruning by the adolescent brain, an otherwise normal function, has been cited as a risk factor for schizophrenia. Additionally, research into disruptions of the adolescent’s maturing stress response system has shown that for some, prolonged periods of stress can lead to an imbalance of cortical cognitive control.

Such brain imbalances often are thought to be related to a series of “pathophysiological hits” as Dr. Keshavan called them.

“It’s possible that in the premorbid phase, there is already a failure in brain development which is followed by a steep decline [in its integrity] due to excessive pruning, and there might be a post-illness onset of decline as well. That might be related to neuroinflammation, excitotoxicity, oxidative stress, and antipsychotic effects.”

Inflammation and genetics

If these so-called hits are implicated, Dr. Keshavan said it might be possible to remediate high levels of oxidative stress that otherwise can lead to toxicity, damaging neurons and mitochondria, and contributing to functional decline after the onset of illness.

Finding ways to reduce brain inflammation also could lead to treatment. “There is an increasing amount of evidence that shows proinflammatory cytokines like [interleukin-6] and tumor necrosis factor–alpha are increased in people who are psychotic or in the prodromal phase of the illness,” Dr. Keshavan said. “As they get better, their inflammation is reduced. Therefore, I think working with anti-inflammatory hormones could have value.”

The highly heritable nature of schizophrenia is long established, but recent genetic research has helped identify multiple etiologic factors, particularly when it comes to the implication of more common genes that have a small impact and rarer ones that have a greater effect. These discoveries have shown how several mental illnesses such as autism, bipolar disorder, and ADHD overlap, but the way in which they manifest is determined by how one’s genes are either triggered or influenced by the environment or by neurochemical influences. “The picture is becoming more and more clear that schizophrenia is not one disease,” Dr. Keshavan said. “It’s a combination of a lot of physiological processes.”

Predictors for the development of psychosis include a family history of psychosis, cognitive impairment, schizotypal symptoms, childhood trauma, and cannabis use, Dr. Keshavan said.

Prevention may not be complicated

As the various etiologies of this disease are being mapped, so too are new approaches that combine existing and emerging therapies. For primary prevention and secondary interventions, Dr. Keshavan said that, particularly in those in whom a risk for the illness already has been identified, reducing stress, enhancing cognitive abilities, and preventing drug use was key. In the near future, he anticipates that these kinds of behavioral interventions will be combined with cognitive-behavioral therapies, along with dopamine blockers, neuroprotective agents, and glutaminergic modulation, and perhaps even fish oil for its omega-3 fatty acids, as well as common anti-inflammatory agents such as aspirin.

By seeing schizophrenia not as “one disease but one of heterogeneity, we can better classify, stratify, and divide and conquer it,” Dr. Keshavan said.

Dr. Keshavan disclosed he has financial relationships with Sunovion and Otsuka.

wmcknight@frontlinemedcom.com

On Twitter @whitneymcknight

Schizophrenia prevention opportunities are emerging