The Latest Theories on the Neurobiology of Schizophrenia

John J. Spollen III, MD

For many years, the science of schizophrenia seemed stuck at the level of neurotransmitters and receptors. Decades of research had apparently proven the singular importance of dopamine and dopamine receptors to the understanding of schizophrenia and its treatment. Unfortunately, this awareness had brought us only so far in understanding the underlying pathophysiology and the ways in which we could improve outcomes in our patients. While the positive symptoms of schizophrenia, including hallucinations, delusions, and disorganized thinking, were often effectively ameliorated with typical antipsychotics -- with a singular mechanism action of D2 blockade, the negative and cognitive symptoms were left untouched and understudied.

The identification of clozapine as an effective treatment for previously untreatable patients with schizophrenia brought a paradigm shift in several important areas. First, other neurotransmitters, specifically serotonin, became important in the understanding of schizophrenia. Second, the benefits of clozapine for negative and cognitive symptoms led to an increased realization of their importance in affecting quality of life and other important outcomes. The evolution in understanding of the pathophysiology of schizophrenia, however, remained at the level of neurotransmitters and their receptors.

Analogous to the era of phrenology, the "bumps" that were seen on neurons only hinted at the dysfunction in the flesh below. With advances in techniques of molecular genetics, functional neuroimaging, and other research methods, the calvaria has been removed and the underlying function of the brain is becoming increasingly better understood. An emerging theme in schizophrenia research that was evident at this year's American Psychiatric Association annual meeting is that parallel lines of research are rapidly progressing beyond the level of simple transmitters to define neuroanatomical and neurophysiological circuits that lie at the heart of cerebral dysfunction in schizophrenia.

Nicotinic Receptor Model
To further broaden the number of neurotransmitters found to be important in understanding the pathophysiology and the complex neurocircuitry in schizophrenia, research over the last several years has provided clues to the impact of dysfunction of both cholinergic and glutamatergic neurotransmitter systems. The work of Robert Freedman, MD,[1] Chairman of the Department of Psychiatry at the University of Colorado Health Sciences Center, Denver, has progressed from early studies showing deficits in auditory information processing in schizophrenia to a well-described model of cortical dysfunction in schizophrenia related to dysfunction of a specific nicotinic receptor using molecular genetic techniques. By tracing the deficits in auditory information processing through families that included patients with schizophrenia and unaffected relatives, Dr. Freedman's group was able to show that a relatively common genetic mutation in nicotinic receptors, found in 10% of the population, caused difficulties in sensory gating and could be a predisposing factor for the impaired cognition and psychosis seen in schizophrenia. His research indicates a deficit in inhibitory interneuronal function, involving the alpha7-nicotinic receptor, as an integral feature of the altered neurocircuitry in schizophrenia. Such impaired nicotinic receptor function could be at the heart of the dramatically increased use of nicotine in patients with schizophrenia.

Glutamate Model
With all the emphasis in psychiatric research on neurotransmitters, it seems odd that the most prevalent and possibly most important neurotransmitter of them all was ignored. Glutamate, by virtue of the fact that it is found in high concentrations in the brain with much of it not acting as a neurotransmitter, was difficult to see as a neurotransmitter at all. However, it is now widely understood that glutamate is the most prevalent excitatory neurotransmitter in the brain and that dysfunction of glutamate receptors, which are likely present on every cell in the brain, lies at the heart of many neurologic, and possibly psychiatric, diseases.

Carol Tamminga, MD,[2] Professor of Psychiatry and Pharmacology at the University of Maryland School of Medicine, Baltimore, has published several studies measuring effects of certain compounds on a specific glutamate receptor, the NMDA receptor. The NMDA receptor is most known for its involvement as a mechanism of action of the hallucinogenic properties of phencyclidine, or PCP. Dr. Tamminga and colleagues have used PCP and ketamine in humans as a model of the pathophysiology of schizophrenia. PCP and ketamine were both initially used as anesthetic agents, and ketamine is still commonly used in dental procedures. Both PCP and ketamine antagonize the action of the NMDA receptor by blocking the ion channel and can cause perceptual disturbance and cognitive dysfunction similar to that seen in schizophrenia. In addition, when these compounds are given to patients with schizophrenia their symptoms are magnified. Using positron emission tomography (PET) studies, Dr. Tamminga's group has shown that ketamine increases regional cerebral blood flow in the anterior cingulate cortices and decreases flow in the hippocampus and cerebellum, all areas that had previously been shown to be abnormal in schizophrenia. A hypoglutamatergic state beginning in the hippocampus could inhibit excitatory transmission to the anterior cingulate and temporal cortex. The complicated neurocircuitry could include GABA and cholinergic interneurons that regulate pyramidal cell firing as well, thereby expanding pharmacological targets for treatment to glutamatergic, cholinergic, and GABA-ergic modulators.

Role of Dopamine
Returning to the importance of dopamine in the pathophysiology of schizophrenia, Daniel Weinberger, MD,[3] Chief of the Clinical Brain Disorders Branch at the National Institute of Mental Health, has conducted research into the importance of catechol-O-methyl transferase, or COMT, in the pathophysiology of schizophrenia. COMT is an enzyme that degrades dopamine in the synaptic cleft. Interestingly, unlike the striatum, the prefrontal cortex has no dopamine transporters. Dopamine transporters are reuptake sites similar to those found on serotonin receptors. When these reuptake sites are blocked, like with serotonin reuptake inhibitors, or don't exist, as is the case in the prefrontal cortex for dopamine, the effects of neurotransmitter-degrading enzymes are extremely important. Hence the contraindication of concurrent serotonin reuptake inhibitors and monoamine oxidase inhibitor use. Therefore, the effect of COMT in the action of dopamine in the prefrontal cortex is substantial. In fact, animal studies have shown that COMT is responsible for more than 60% of dopamine degradation in the prefrontal cortex. And dopamine action in the prefrontal cortex is supremely important for cognition. Dopamine activity in the prefrontal cortex, through studies done in patients with Parkinson's disease, has been shown to dramatically increase the "efficiency" of neurocognitive performance. This, in essence, allows the brain to focus more of its energy on brain regions that are important for processing information. This effect of dopamine, and its disruption, is possibly responsible for the deficits in attention and executive functioning commonly found in patients with schizophrenia.

Genetic Techniques
Using molecular genetic techniques similar to those used by Dr. Freedman, Dr. Weinberger and colleagues[3] have shown that a single point mutation in the COMT gene causes a 75% reduction in the activity of COMT. This genetic "defect," which increases dopamine activity in the prefrontal cortex, has been shown, using the Wisconsin Card Sort Test, to significantly improve executive functioning. In fact, this "defect," which is responsible for 4% of the human variation of attention and executive functioning and is not found in great apes, was proposed as a potential factor in the evolution of the cortex, and, therefore, of mankind itself. And the gene encoding the more effective form of COMT has been shown to be significantly more prevalent in patients with schizophrenia than in normal controls. This line of evidence makes a convincing argument that the gene encoding the more effective form of COMT is a susceptibility gene for schizophrenia. With the elucidation of the importance of COMT, another target for psychopharmacology is delineated.

Glia and White Matter
With all the focus on neurons, it is easy to forget that the vast majority of the cells in our brains are not neurons, but glia. Glia, including astrocytes and oligodendrocytes, make up more than half the brain's weight and outnumber neurons by a factor of more than 101. Their actions of support to neurons are crucial to proper brain function. Astrocytes are believed to provide structural support for the neurons of the brains and aid in the repair of neurons following damage to the brain. Oligodendrocytes produce myelin, which surrounds the axons of many neurons and is the identifying component of white matter. Taking the research into the pathophysiology of schizophrenia into a heretofore-neglected area, Kenneth L. Davis, MD,[4] Chairman of the Department of Psychiatry at Mount Sinai School of Medicine, New York, NY, presented data indicating that alterations in white matter may be intimately involved.

Moving forward from an atheoretical presupposition, measuring gene expression changes detected by microarray DNA-chip analysis of postmortem tissue from the dorsolateral prefrontal cortex of patients with schizophrenia -- analogous to a scientifically sound "fishing expedition" into altered genetic expression, Dr. Davis found that one can differentiate schizophrenic from normal brains solely on the basis of expression of myelin genes. Following this exciting finding, several investigators have utilized different methods to show the dramatic damage to oligodendrocytes in the brains of patients with schizophrenia. Not only are oligodendrocyte counts in functionally important areas of the cortex significantly reduced, but electron microscope findings show that such areas exhibit abnormal inclusions between myelin sheath lamellae, showing evidence for cellular dysfunction. Anisotropy, a measure of the coherence of white matter, has also been shown to be reduced in frontal and temporal lobes of patients with schizophrenia. Such "frayed wires" are further evidence for altered neuronal structure and connectivity in schizophrenia.

Given this, dramatic alterations in oligodendrocyte function appear to be present in schizophrenia, with reduced numbers, impaired function, and disrupted cytoarchitecture. Decades of research have consistently shown increased ventricular size in the brains of people with schizophrenia, but reductions in gray matter volume have been small and inconsistently found, outside of specific thalamic nuclei. Could it be that, all along, the lost brain volume in schizophrenia has come from loss of white matter?

One exciting possibility that could link several of these parallel lines of research involves glutamate hyperactivity. Bita Moghaddam, PhD,[5] Associate Professor in Psychiatry at Yale University, New Haven, Connecticut, published an important paper in 1997 showing that ketamine, an NMDA antagonist, actually increased glutamate outflow in the prefrontal cortex to non-NMDA receptors. Overactivation of AMPA and kainate receptors, 2 important non-NMDA glutamate receptors, has been linked to subsequent excitotoxic oligodendroglial death.[6] Thus, endogenous alterations in the glutamate system, mimicked by drugs such as PCP and ketamine as in the work by Dr. Tamminga, could lead to excessive glutamate release onto oligodendrocytes -- leading to impaired function, cell death, and loss of white matter.

Such a model that includes both known neurophysiological and neuroanatomical deficits found in the brains of people with schizophrenia offers hope that we are ever closer to answering a question deserving of the Nobel prize: what is the pathophysiology of schizophrenia and how do we treat it?

Freedman R. Nicotinic receptors and the genetics of schizophrenia and bipolar disorder. Program and abstracts of the American Psychiatric Association 155th Annual Meeting; May 18-23, 2002; Philadelphia, Pennsylvania. Industry-supported Symposium No. 24B.
Tamminga CA. Glutamatergic transmission in schizophrenia. Program and abstracts of the American Psychiatric Association 155th Annual Meeting; May 18-23, 2002; Philadelphia, Pennsylvania. Industry-supported Symposium No. 24C.
Weinberger DR. Molecular biology and genetics of cortical function in schizophrenia. Program and abstracts of the American Psychiatric Association 155th Annual Meeting; May 18-23, 2002; Philadelphia, Pennsylvania. Industry-supported Symposium No. 24E.
Davis KL. White-matter abnormalities in schizophrenia. Program and abstracts of the American Psychiatric Association 155th Annual Meeting; May 18-23, 2002; Philadelphia, Pennsylvania. Industry-supported Symposium No. 24D.
Moghaddam B, Adams B, Verma A, Daly D. Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex. J Neurosci. 1997;17:2921-2927.
McDonald JW, Althomsons SP, Hyrc KL, Choi DW, Goldberg MP. Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity. Nat Med. 1998;4:291-297.



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