Frontiers of Psychiatry: Prevention, Personalized Treatment

The need to rethink mental illness in neuroscience terms was the dominant note of the 27^th annual New York Mental Health Research Symposium of the Brain and Behavior Research Foundation.

In investigations ranging from epidemiology to nanotechnology, a couple of  tantalizing if elusive themes emerged: preventive strategies and personalized treatment.

Robert Freedman, professor and chairman of psychiatry at University of Colorado, Denver, described research exploring a hallmark deficit of schizophrenia—the inability to screen out irrelevant sensory stimuli, resulting in a barrage of data that fuels hallucinations and delusions.

The neurobiological fault, he suggested, is in a nicotinic receptor that normally inhibits response to stimuli. The gene for the receptor, CHRNA7, is apparently “one of the most depleted of all in schizophrenia,” Freedman said. Research to develop drugs to redress this deficit has been promising, and some compounds are in phase III trials.

But the most exciting possibility, he suggested, is prevention. Infants of nonpsychotic mothers already display normal inhibition at one month, while those of psychotic mothers often do not. “We suspect they will carry [this physiological flaw] for the rest of their lives,” he said.

Cerebral inhibition, he explained, begins in the months before birth, as some excitatory neurons become inhibitory. High concentrations of choline in amniotic fluid are essential to the process.

Freedman proposed that phosphatidylcholine, a nutritional supplement, might overcome the   deficit in children genetically predisposed to it. He described a controlled study where prenatal and neonatal choline supplementation was associated with more robust inhibition at four months.

At four years of age, a subgroup of the supplemented children showed better attention and less social withdrawal than controls.

If safety and effectiveness are confirmed, doctors might recommend that all pregnant women take choline supplementation to reduce schizophrenia risk, much as they now take folic acid to prevent neural tube defects, he said.

Prevention: a combined approach

Michael Berk’s presentation also offered hope for prevention. He addressed the need for novel pharmacotherapy for psychiatric disorders, grounded in an understanding of their underlying pathophysiology.

“Drug discovery in mental health has reached pretty much of a standstill,” said Berk, professor of psychiatry at Deakin University, Australia. “There are no new, interesting drugs—not what one would have predicted at the outset of the decade of the brain.”

The drugs he discussed were not new, although their psychiatric applications are still being investigated.

Inflammation has recently garnered particular attention in psychiatric research. “It’s the New Jerusalem…. all mental disorders are apparently characterized by increased inflammation, often present before the onset of symptoms,” Berk said.

The relationship has been particularly well documented in depression, although findings from trials of anti-inflammatory treatment are “not impressive,” he said.

Preventive efforts may be more rewarding. “One group of medications I’m interested in are statins,” he said. These drugs, primarily prescribed to prevent heart attack, are “robustly anti-inflammatory,” and their efficacy in reducing depression risk has been suggested in epidemiological studies. In a study of 193 patients hospitalized for acute coronary conditions, those on statins were 79 percent less likely to be depressed 9 months later.

Controlled clinical trials are under way. In one pilot study, statins combined with the antidepressant escitalopram (Lexapro) reduced depression in patients who had been hospitalized for heart disease  better than either drug alone. “This study may well be transformative for the field,” Berk said.

For preventive strategies generally, “it’s not appropriate to look at schizophrenia, depression, or bipolar disorder in isolation. Because they share many risk factors with medical diseases like diabetes and heart disease, we need a common, integrative framework,” he said.  “To target large numbers of individuals and have an impact, we need to work with physicians across the disease spectrum.”

As a case in point, Berk described the ongoing  ASPREE study, whose primary goal is to see if low-dose aspirin extends quality and length of life in older people. The trial will track depression along with cardiovascular disease, dementia, and colon cancer. “With 19,000 participants, this would be the largest study ever done in preventive psychiatry,” he said.

Tailoring treatment

B.J. Casey, professor of psychology, psychiatry, and neuroscience at Weill Cornell Medical Center, discussed how a neuroscience-driven modification of anxiety therapy could benefit a group at particular risk: adolescents.

Mental illnesses peak around adolescence, and “understanding how developmental processes may go awry” then could help optimize treatments “to get them back on track,” said Casey, who is a member of the Dana Alliance for Brain Initiatives.

Anxiety disorders affect as many as one in five adolescents, but the best validated treatment, cognitive behavior therapy (CBT), is less effective for them than for children or adults.

An explanation, Casey suggested, might be found in the uneven rate at which connections develop across the brain. Adolescence is characterized by an imbalance between emotional centers like the limbic system and prefrontal cortex (PFC) circuits that regulate emotions.

CBT for anxiety relies on fear extinction—the person is gradually desensitized by exposure to the feared object in a safe environment. The process, she explained, does not actually erase fear conditioning, but adds a safer alternative memory, which the prefrontal cortex allows to win out.

The relative weakness of the PFC in adolescents subverts this process, she said.

Casey described a “tweak” in CBT that takes advantage of the dynamic nature of memory: for   10 minutes to 3 hours after a memory is aroused, “we can update it,” she said.

In the modified therapy, fear is triggered by a cue, and the extinction process initiated after a brief delay to allow for reconsolidation. The manipulation in timing did lead to fear extinction in adolescent rodents. In preliminary trials with humans, it seems effective as well.

“This illustrates how understanding the biological state of the developing brain may help us get better traction for more individualized, precise treatment,” she said.

Jianping Zhang of Zucker-Hillside Hospital in New York described a different route to individualized medicine: pharmacogenomics, the study of the role of genetics in drug response. “Antipsychotics are the mainstay of schizophrenia treatment, but there are no good predictors [of response],” he said. Pharmacotherapy is often an arduous trial and error process, and 30 to 40 percent of patients respond poorly to first-line drugs.

Genetic information has proven useful in treatment planning in areas of medicine like oncology. “It’s emerging in psychiatry,” Zhang said.

Genes regulating neurotransmitters and their receptors would potentially affect how well antipsychotics work. “By studying DNA sequence we ideally can figure out which patient will respond to which medication.”

Research in his lab has addressed genetic variations affecting the dopamine receptor DRD2, a common site of antipsychotic action. A meta-analysis of 6 studies involving 700 patients found associations between variants in this gene and drug response.

In a recently published clinical trial, patients with two copies of one polymorphism had a 10 percent better improvement in positive symptoms of schizophrenia (such as fewer hallucinations), compared with those with the other variant. These patients were also more liable to certain side effects, he said.

In other studies, variations in the gene for brain-derived neurotrophic factor (BDNF) predicted which patients could be stabilized on first-line antipsychotics and which would need clozapine, which is reserved for resistant cases.

The genes regulating liver enzymes that metabolize antipsychotics have also been identified, and Zhang is involved in two clinical trials exploring whether this information can effectively guide drug choice and dosage.

“No single polymorphism is powerful enough to be clinically useful,” Zhang said.  “In the future, we’ll want to combine multiple genetic and other biomarkers to predict treatment response.”

Nanoscale insights

Markita Patricia Landry of the department of chemical engineering at Massachusetts Institute of Technology described research that might someday advance both prevention and individualized treatment: sensors to track neurotransmitter release at the level of single neurons and synapses.

“We need a tool that is small, non-disruptive to the functioning brain, and able to emit signals that can penetrate tissue and bone,” she said. “Neurotransmitter release occurs in milliseconds, repeatedly. The sensors must be reversible.”

Carbon nanotubes represent such a tool, Landry suggested: these molecules can attach to a library of polymers that respond selectively to biologically active substances like inflammatory mediators and hormones, emitting light of distinctive intensity and wave length in their presence.

A nanotube molecule that she helped develop responds to dopamine. Adding microscopy techniques, Landry and colleagues used the sensor to study individual neurons in the mouse brain, tracking dopamine release and the growth of projections over a period of weeks.

“We want to take this a step further, to study how the neuron changes shape when the animal is exposed to different environmental stimuli, and how brain cells talk to each other.  Here, the dopamine sensor can be useful to link neuroplasticity and chemical neurotransmission throughout the life course of the animal.”

Ultimately, techniques like these could “get at the question, at the single molecular level, of how brain cells interact differently for patients with normal and abnormal brain function,” Landry said.