Early Detection and Prevention of Schizophrenia

The Sunday morning session at the NAMI 2008 convention featured two psychiatrists working on the cutting-edge of research and treatment for schizophrenia: Ed Scolnick, M.D., director, Psychiatry Initiative, the Broad Institute, Cambridge, MA and William Cook, Ph.D., director, Psychiatry Research, Maine Medical Center, Portland, ME.  First, I'll report on the information presented about research, and then look at the promising results of an early intervention program.

Scolnick offered this hope: "We're in a different era for the first time ever understanding complex human genetic diseases."  Medicines in development are based on neuroscience research.  The single largest risk for schizophrenia is the sequence of letters in genes.  Identical twin studies indicate if one person has schizophrenia, the other has a 50 to 80 percent chance of getting it.  Indeed, your risk goes up tenfold if someone genetically related to you has the illness.

The goal is to find all the genes for schizophrenia.  New approaches to finding a schizophrenia gene include whole-genome association studies.  The biological implications being evaluated will be clues to underlying causal pathways.  For the first time in the history of the field there is a way forward that can lead to significant improvements in diagnosis and treatment.

Since 2003, when the human genome was first mapped, researchers have been tracking the patterns of genes and gene interactions to unlock the complex condition that is schizophrenia.  This task may also offer genomic information to aid in treatment tailored to the individual.  Possible new drugs include these kinds of agents:

• Glu 2,3 agonist
• D-cycloserine
• N-desmethylclozapine
• M1 allosteric agonists
• Gaba alpha 2,3 agonist
• PDE-10 inhibitors
• Alpha-7 nicotinic agonists

This brings hope, as N-desmethylclozapine, the Gaba alpha and Alpha-7 are all agents believed to work on cognitive deficits.  D-cycloserine is a novel regimen used with psychotherapy.  The ultimate goal is to teach patients new behaviors and paradigms to increase the rate at which they learn to cope so medication isn't life-long.  It has proven helpful in acrophobia (fear of heights) and anxiety.  The difference is it is not a dopamine or serotonin agent. 

The truth is I wouldn't want to take a drug unless I absolutely had to, and I'm sure you would feel that way, too.  The sentiment is that in five to 10 years the research will lead to a much greater molecular understanding.  In one study, there was an excess of DNA deletions in genes in samples of patients versus controls.  Larger samples are needed to detail where the deletions are.  However, this discovery won't make treatment harder; it's an optimistic finding.  For the first time, new methods in genetic research are rapidly developing more detailed maps.  While it's too early to expect a cure or a vaccine, this news dovetails with the words of Stephen M. Goldfinger, M.D., who I interviewed and who spoke about the benefits of new drugs as early as three years away.

William Cook, Ph.D., the second speaker, talked about a creative program funded by the Robert Wood Johnson Foundation that uses families to indentify and reduce the severity of psychotic illness.  The Early Intervention Project showed how families can be instrumental in changing the course of the schizophrenia.

The PIER program was a randomized clinical trial of family-aided assertive community treatment, supported by the National Institute of Mental Health (NIMH).  Patients were moved into treatment before the onset of psychosis.  It is a revolutionary idea about how we think about psychosis and its prevention.  

Biological risk factors include genetic risk, non-genetic biological risks, pre-natal infections (influenza) and pre-natal toxic exposure (lead), birth complications and traumatic events (head trauma from perinatal up to adolescence).

Cook suggested, "Genetics loads the gun and environment pulls the trigger."  The relationship between the Mom and Dad is a chronic source of stress for young children, such as arguing with each other.

A study of the effects of genetic risk and family functioning on eventual schizophrenia-spectrum disorders is telling.  In a study of adopted children, some had a genetic link, some did not have the risk of schizophrenia.  The incidence was dramatically larger in stress in family if there was an underlying biological component.

Cook repeated the prevailing wisdom, "The earlier you intervene, the better the prognosis."  If episodes increase, functioning appears to be lost and there's less recovery to be gained.  The goal is to reduce the duration of untreated illness to prevent an episode.

So how do we identify young people at ultra-high risk?  The Schedule of Prodromal Syndromes Scale (SPSS) lists these criteria:

• Delusions
• Grandiosity
• Perceptual abnormalities
• Hallucinations
• Disorganized communication
• Unusual thought content.