by Elaine Weiner, M.D.
[September 1996; Vol. 23 No. 3]
The Maryland Psychiatric Research Center (MPRC), internationally recognized for its pioneering work in the investigation of schizophrenia and related brain diseases is located on the Spring Grove Hospital Center campus in Catonsville. The research mission of the MPRC is to gain greater understanding of the etiology, pathophysiology, course and treatment of schizophrenia and related disorders. A joint effort between the University of Maryland at Baltimore, School of Medicine, Department of Psychiatry and the State of Maryland, Department of Health and Mental Hygiene (DHMH), the center provides state-of-the-art clinical services to patients throughout Maryland, educational opportunities to University trainees and continuing education programs to professionals in the community.
Under the direction of Dr. William Carpenter since 1977, the MPRC has four scientific programs, an NIMH Clinical Research Center, and the Maryland Brain Collection. The Inpatient Research Program, overseen by Carol Tamminga, M.D., consists of the Residential Research Unit, headed by Adrienne Lahti, M.D. and the Treatment Research Unit, headed by Robert Conley, M.D. Dr. Lahti’s unit focuses on the early development of experimental medication and functional PET studies. Dr. Conley’s unit tests new therapies for treatment-resistant patients and studies brain correlates of drug response.
The MPRC directs two outpatient programs. In the Schizophrenia Related Disorders program, Drs. Gunvant Thaker and David Ross test innovative treatments for tardive dyskinesia and investigate biologic correlates in family members with schizophrenia spectrum disorders. The Outpatient Research Program, headed by Robert W. Buchanan, M.D., has a DHMH licensed CMHC that focuses on treatments hypothesized to be more effective for partially responsive patients and for primary negative symptoms. Psychopathology studies conducted by Drs. Buchanan, Brian Kirkpatrick, Royce Waltrip, James Gold, and William Carpenter involve brain imaging and neuropsychology and the investigation of etiologic factors to further the understanding of schizophrenia.
In the Neuroscience Program an eclectic faculty directed by Robert Schwarcz, Ph.D. uses basic science knowledge to further the progress toward the center’s research goals. State-of-the-art laboratories are equipped to study brain chemistry, neuroanatomy, neuronal physiology, developmental neurobiology, and the neurobiology of stress.
One of the major scientific tasks undertaken at the MPRC has been the investigation of the heterogeneity of schizophrenia. Considering how this work has been accomplished helps to illustrate how work proceeds at the MPRC.
To date, much of the work on the heterogeneity of schizophrenia has focused on patients who exhibit prominent negative symptomatology. The theoretic framework built on Kraepelin’s description of the dissolution of the personality in patients with schizophrenia: there is “a weakening of those emotional activities which permanently form the mainspring of volition ... the result of this part of the morbid process is emotional dullness, loss of mastery over volition, of endeavor, and of ability for independent action”. Researchers at the MPRC term these symptoms which are presumed to be an essential part of schizophrenia, “the deficit syndrome”. As it is defined, deficit symptoms include restricted affective expression, diminished emotional range, poverty of speech, curbing of interests, diminished sense of purpose, and diminished social drive. These symptoms are a major cause of the social and occupational impairments that characterize chronic schizophrenic patients. Such impairments are often a major factor preventing patients from leaving the hospital and becoming integrated into the community and may contribute to much of the human and economic costs of schizophrenia.
Because these symptoms are so debilitating, investigators at the MPRC have emphasized the importance of identifying negative symptoms which are secondary to other causes and therefore may be responsive to treatment. Secondary negative symptoms may be due to a variety of causes. Untreated or residual psychosis may lead to autistic withdrawal, paranoid guardedness, or a need to retreat from sensory overload. Traditional antipsychotic medication may lead to dysphoria, akinesia, sedation, and a wooden or “glassed-in” feeling. Dysphoric affect may be also caused by depression, demoralization and social anxiety. Additionally, secondary social withdrawal may be caused by a lack of social stimulation due to living in isolation or in situations where there is no shared experience.
The work on the deficit syndrome has advanced along a number of scientific fronts. Several investigators have worked to clarify the underlying neuroanatomical substrates of the syndrome. In the Outpatient Research Program, Dr. Buchanan and others found that patients with the deficit syndrome are more neurologically impaired and to do more poorly than their schizophrenic controls on neuropsychological tests that assess frontal and parietal lobe functioning. Additionally, MRI scans of deficit and nondeficit patients revealed a number of brain areas that differ in size and symmetry. Drs. Thaker and Ross, in the Schizophrenia Related Disorder program demonstrated that schizophrenic patients have abnormal eye movements and that the abnormalities are particularly pronounced in deficit syndrome patients. In particular, deficit patients as compared to nondeficit patients exhibit increased volitional saccadic latency, an eye-tracking measure sensitive to frontal and parietal lobe impairment. Positron emission studies performed in the Residential Research Program by Drs. Tamminga, Lahti, Henry Holcomb, Buchanan and Carpenter have demonstrated reduced glucose utilization in the frontal and parietal cortices at rest and during performance of simple attentional tasks. These findings, along with other findings performed in other research centers around the country point, to the frontal and parietal lobes and/or the connections between these areas as part of the neural substrate underlying deficit symptoms.
Brian Kirkpatrick, M.D., and others in the Outpatient Research Program are working to more clearly define and describe the deficit syndrome. Dr. Kirkpatrick developed a structured interview (The Schedule for the Deficit Syndrome (SDS)) that operationalizes criteria for defining the deficit syndrome, thereby enabling researchers to separate out groups of patients who suffer from primary versus secondary negative symptoms. Using the information obtained from the SDS, Dr. Kirkpatrick found differences in the course of illness and associated clinical findings between deficit and nondeficit patients. Compared to nondeficit schizophrenic patients, deficit patients are less likely to have histories of depression and suicide, delusions with social content, or substance abuse and are less likely to have insight into their impairments. He and Dr. Buchanan found that deficit patients are more likely to have histories of asocial development.
Other studies at the MPRC have focused on differences in the risk factors and etiology for patients who develop the deficit syndrome. Dr. Kirkpatrick has a preliminary finding suggesting an increased frequency of summer births in patients with the deficit syndrome. This finding is in contradistinction to the more universally accepted association of an increase in winter births among schizophrenic patients. Royce Waltrip II, M.D., also in the Outpatient Research Program, is investigating the presence of circulating antibodies to Borna virus, a virus known to infect the central nervous system. When blood samples of patients with deficit and nondeficit schizophrenia were compared, he found half of the deficit patients and none of the nondeficit patients had antibodies to Borna virus. This finding suggests there may be an increased risk of a viral etiology for patient’s with the deficit form of schizophrenia.
The implications of the work reviewed above-that there are possibly different neural circuits, and possibly different pathophysiologies and etiologies for the deficit form of schizophrenia, suggest that there might be differential treatments for the syndrome, as well. A number of studies support the limited ability of traditional neuroleptics to treat deficit symptoms. There was much hope that clozapine would be more efficacious in treating these symptoms. Unfortunately, data from the Outpatient Research Program's clozapine study, one of the most important longterm outpatient studies of clozapine, did not support this outcome. When the outcomes of patients with primary versus secondary negative symptoms were compared, the degree of improvement was attributable to improvement in secondary negative symptoms. Stated in another way, it did not appear that clozapine was having any efficacy in the treatment of deficit symptomatology. Data from the Treatment Research Unit's inpatient clozapine study supported this finding. Interest in exploring new drug treatments for the deficit syndrome, therefore, became a major priority after completion of the clozapine study.
Today, in the Outpatient Research Program, Drs. Buchanan and Carpenter are investigating the use of medications that might activate the frontal and parietal areas of the brain-those areas that are thought possibly to be the neural substrate for the deficit syndrome. Mazindol, a dopamine reuptake inhibitor that is somewhat selective in its activation of the frontal lobes, is currently being studied as an adjunct to either traditional neuroleptics or clozapine. Following a protocol similar to many of the drug studies performed in the Outpatient Research Program, symptom based behavioral assessments are performed weekly, with neuropsychological testing performed at specified intervals during the study. Outcomes studied relate not only to drug efficacy but also to differential response between deficit and nondeficit groups.
The information presented here is typical of how the work at the MPRC progresses. From a theoretical idea based on careful observation to the collection of descriptive data, the development of new measurement techniques, the measurement of behavioral correlates and within group differences, and the development of new treatment strategies aimed not only on symptom reduction but also improved functioning, MPRC investigators strive to make meaningful contributions to the understanding of the complex illness that is schizophrenia.
Dr. Weiner is the Program/Medical Director in the Outpatient Research Program, performing clinical services and administering the CMHC component of the program.