Even so, schizophrenia continues to be a conundrum. On one hand, we know that it is a major cause of morbidity, mortality, and personal and societal cost. While a class of medicines can treat the major signs and symptoms effectively, particularly hallucinations and delusions, we also know that their benefits are incomplete and inconsistent.
For far too many people, these medicines work only partially or occasionally, not at all. This lack of knowledge is not the result of a lack of studies. Schizophrenia has been studied intensively by several generations of scientists using the best methods and technologies available to them at those times. After a lot of excitement and high-profile papers, researchers determined that the pink spot merely was a nonspecific lifestyle difference. Another example was the observation that psychotic symptoms improved after hemodialysis suggesting a blood-borne toxin.
A New Way of Thinking about Schizophrenia
Unfortunately, subsequent double-blind studies could not replicate initial findings. Genetics was no exception. In the past 25 years, perhaps a dozen genetic associations with schizophrenia received considerable attention but have not withstood the test of time and replication. Thus, the origins of madness are elusive. The lack of fundamental knowledge has a major consequence: If we do not know the biological processes fundamental to schizophrenia, we can only make guesses about how to design better therapeutic and intervention strategies.
But encouraging results from recent research have us entering a different and more productive phase in schizophrenia research. To date, the development of antipsychotic medications—the backbone of treatment for many people with schizophrenia—has been serendipitous the first in the class, chlorpromazine, was developed as a surgical premedication in the s.
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Most subsequent approved antipsychotics were just variants on a theme add a chlorine here, remove a methyl group there. On one list, three of the top ten best-selling medications in history were antipsychotics.
But following some failures and patent expirations, the antipsychotic drug development pipeline went dry. Many believe that the lack of new and better medications for schizophrenia is the direct result of a lack of knowledge of its basic biology, which we need not only for medications but also to understand exactly who is at risk, to understand the impact of nondrug therapies e. Many studies have involved family history, adoption, and twins.
Taken together, these studies tell us that schizophrenia has a definite tendency to run in families and that it does so mostly via inheritance. But because the lifetime risk of schizophrenia in the overall population is around 1 percent, only about 10 percent of the relatives of a person with schizophrenia will become ill—the majority of people with a relative with schizophrenia will not develop this illness. In fact, only a small proportion of people with schizophrenia have a relative with the illness.
So the genetic processes involved are probably subtle. The genetic risks for schizophrenia are more complex—probabilistic, not deterministic. This suggests that the biological processes underlying schizophrenia are relatively understated. It also is consistent with the clinical course of schizophrenia: a waxing and waning illness with preservation of basic neurological and higher cognitive functions and without an inexorable decline to dementia, intractable seizures, coma, and death. Genetics is thus a major etiologic clue.
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In parallel, knowledge of the genome and the technologies to query the genome have made marked advances. It is now possible to do genetic assays with speed, throughput, and accuracy that would have been nearly inconceivable ten or 20 years ago. Past impediments were human and structural. Typical approaches in psychiatric genetics were based on siloed research groups.
There were a couple dozen research groups, and they tended not to work collaboratively. One would gather a sample and study it to the best of its ability. We needed a new way to work.
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For true progress, we needed to find ways to cooperate in order to put together much larger samples than any single group could attain, and to introduce extremely high degrees of rigor. In , I was part of a group of psychiatrists, psychologists, and geneticists that founded the Psychiatric Genomics Consortium PGC on the principles of cooperation, democracy, and participation, and dedication to rapid progress and open sharing of results.
These studies were for schizophrenia, bipolar disorder, major depressive disorder, and attention deficit hyperactivity disorder ADHD , and it seemed clear to us that we should try to become a trusted clearinghouse for conducting large and careful genetic analyses within and between these disorders. The PGC has since become the largest consortium in the history of psychiatry, and arguably its most successful biological experiment.
The PGC currently consists of more than scientists from 36 countries. We currently have about , individuals in analysis and are in the process of adding about , more. We have published 17 major papers and 31 secondary-analysis or methods-development papers, and at least 75 other papers have made major use of our results. Schizophrenia is one of nine psychiatric disorders whose genetic basis PGC researchers are studying carefully.
This paper increased the number of intriguing genome locations by a factor of five. The paper had more than authors and represented the concerted efforts of dozens of people for about three years. The findings make a lot of sense. For example, one key genetic result was near the dopamine type 2 receptor gene.
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 s. 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.
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. An early symptom, he explains, includes losing the ability to read fluently.
ignamant.cl/wp-includes/34/1629-rastrear-un-numero.php 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. 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.
Light joined Drs. Braff in and Dr. Swerdlow in They had a theory that the disabling deficits in cognitive function seen in people with schizophrenia are caused, at least in part, by problems receiving or analyzing signals that enter the brain through the senses. Whatever the reasons for cognitive deficiencies, the results were evident to all who worked with patients: most were isolated from other people, often profoundly—a painful if infrequently discussed aspect of living with schizophrenia.
In early papers focused on the auditory neuroscience of schizophrenia, Dr. Sophia Vinogradov, whose BBRF Independent Investigator grant had supported research on using computers to train schizophrenia patients to improve their results on cognitive tests. This research also produced a big surprise: those patients with the lowest scores in the MMN test had the greatest impairments in social functioning.
Beyond the financial assistance he received, Dr. Light says part of the BBRF boost came in the form of validation, for there was plenty of resistance within the scientific community, early on, to his suggestion that MMN measurements could be used to predict how well people could function socially. His second Young Investigator award in and concurrent federal funding enabled Dr. Light to replicate his earlier results and to test the concept that MMN could predict which patients stood to benefit from cognitive training.
He would test this concept in a variety of clinical settings. In the most recent test, in the facility outside San Diego where he tested TCT in medicated patients with longstanding, chronic illness, not only did TCT provide a real, measurable benefit to two-thirds of these patients in the form of improved results on cognitive tests.
The research also demonstrated that MMN measured after the very first hour of training accurately predicted which patients were going to benefit from the full 4-week program. This was confirmed once the training course was completed. Light and colleagues still are not sure why some respond to TCT and others do not, but they speculate that MMN and possibly other measures of brain activity one is called auditory steady-state response are able to show which patients have sufficient plasticity in their neural circuitry to benefit from this particular type of training—which, in essence, is a form of learning.