Topics and Speakers Stephen Rayport, MD, PhD
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Synopsis
Formerly known as dementia praecox, or early deterioration of the intellect, schizophrenia still remains a mysterious disease that affects 1% of the population globally. In this lecture, Dr Stephen Rayport discusses the symptoms, the genetic etiology and surprising environmental components to the illness, the neurobiological differences between healthy and schizophrenic brains, and, finally, pharmacotherapy.
Schizophrenia is defined by what physicians refer to as positive and negative symptoms. The former are properties that manifest themselves as abnormal, such as hallucinations, hearing voices, and delusions including that the television set is sending coded messages. Negative symptoms are "key aspects of our normal functioning which are lacking," such as an inability to take care of hygiene, poverty of speech, and flattened affect.
There is no doubt that schizophrenia is a heavily genetic disease. A handful of chromosomes have been identified as being abnormal in schizophrenics, including chromosome 1, chromosome 8, and chromosome 22, which is also known as COMT and is involved in dopamine metabolism. It is the abnormalities of the structure of these genes, especially COMT, which has made doctors define the illness as a synaptic disorder. For instance, it has been proven through knockout mouse studies, that if COMT is activity deficient (that is, there is an overproduction of dopamine), then the result is hyperactivity and poor performance on tests requiring working memory.
However, there are surprising environmental factors which can affect whether a person genetically at risk will develop the disease. The first factor deals with whether the person was exposed to influenza in utero. Another surprising factor is the age of the father. The risk for the disease triples from young to older fathers. It is hypothesized that some genetic mutations occur over the lifespan of the gametes (i.e., sperm), which then translates as a risk for the illness.
Neurobiologically, the brains of schizophrenics differ widely from healthy brains. Working memory is controlled by the prefrontal cortex, which does not come "online" until the late teenage years, and which explains why so many schizophrenics have their first episodes when they go off to college. The genes that are in charge of the dopaminergic, glutamatergic, and GABAergic system are abnormal too, which in turn suggests an abnormality in cortical circuitry. Also, imaging studies of monozygotic twins show that schizophrenics have larger ventricles when compared to the healthy twin. Other abnormalities, like reduction in hippocampal volume and a deficit in gray matter, are also discussed.
Finally, because of the overactivity of the dopamine system in schizophrenics, medication has been targeted to suppress the neurotransmitter. Thorazine was the first neuroleptic to regulate the dopamine system. Its drawback were dystonic effects. Second-generation or atypical neuroleptics, such as Seroquel and Zyprexa, now also affect the serotonergic system, with less dystonic effects. While all these drugs control the positive symptoms, they have been unable to treat the negative symptoms of schizophrenia. Therefore, current research is focused on drugs that can alleviate negative symptoms.
