Progress
Report
Progress
with the studies of the relationship between antipsychotic plasma concentrations
and clinical response and determination of dosing requirements
Progress
with examining the effect of antipsychotics on the symptom dimensions of schizophrenia
Progress
with studies determining the effect of antipsychotics on cognitive function
and cerebral blood flow
Progress
with the study of the use of MRI to examine the long-term effects of antipsychotics
on brain plasticity
References
DIRECTOR: Del D. Miller, Pharm.D., M.D.
CO-DIRECTORS: Paul J. Perry, Ph.D., Susan K. Schultz, M.D.
Overall Aims
1. To examine the effects of typical and atypical antipsychotics on the neuroanatomic
substrates of schizophrenia and determine their relative effects on cognitive
performance.
2. To examine the effects of typical and atypical antipsychotics on functional
measures of cerebellar activity while performing motor tasks.
3. To examine the influence of gene expression at the CYP2D6 liver enzymes
on pharmacokinetics of antipsychotic medications and apply principles of pharmacokinetics
to identify optimum antipsychotic doses.
4. To explore the efficacy of typical and atypical antipsychotics in the treatment
of the psychotic, disorganized, and negative symptom dimensions in schizophrenia.
5. To determine whether receptor polymorphisms at the 5-HT2A and 5-HT2C receptors
predict therapeutic response to atypical antipsychotics.
6. To explore why some patients with schizophrenia develop neuroleptic induced
motor disturbances, such as tardive dyskinesia (TD) and to determine the relative
influences of various risk factors for TD.
7. To use MR imaging to examine the long-term effects of antipsychotics on
brain plasticity through the assessment of subtle structural changes in a longitudinal
design.
Background and Rationale: It has been argued that the development of antipsychotic drugs has been the single most important event in the history of schizophrenia since its original definition by Kraepelin. These medications have substantially improved the quality of life of patients suffering from schizophrenia by reducing the presence and severity of symptoms, decreasing the duration of hospitalization, and permitting most chronically ill persons suffering with schizophrenia to live outside of chronic institutions. The effectiveness of the antipsychotics in treating the symptoms of schizophrenia has also furthered our understanding regarding the underlying neurobiological aspects of the disorder. As all the clinically effective antipsychotic agents have some degree of dopamine receptor blocking activity, the dopamine hypothesis of schizophrenia has remained the primary heuristic model for the study of the pathophysiological basis of schizophrenia. This tradition has persisted despite the lack of definitive direct disturbance in dopamine function. Postmortem studies measuring brain dopamine receptors, in vivo positron emission tomography (PET) studies examining dopamine receptor concentrations, and studies which have analyzed dopamine concentrations (or dopamine metabolites) in blood or spinal fluid have not consistently demonstrated evidence of hyperdopaminergic activity in schizophrenia.
The discovery and development of the atypical antipsychotics such as clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and sertindole have challenged the simplicity of the dopamine hypothesis and broadened our understanding of the pathophysiological basis of schizophrenia. These agents have been shown to be effective for positive and negative symptoms, to improve cognitive impairment, and have low rates of extrapyramidal side effects. In fact they appear to be more effective for the negative symptoms of schizophrenia than typical antipsychotics (Kane et al 1988a; Marder et al 1994; Tollefson et al 1997; Arvanitis et al 1997; Zimbroff et al 1997; Gunn et al 1996) and there are suggestions that they may be more effective than the typical antipsychotics in stabilizing and/or reversing the cognitive impairment associated with schizophrenia (Goldberg et al 1993; Hagger et al 1993; Buchanan et al 1994a; Hoff et al 1996; Green et al 1997). While these new compounds all block dopamine D2 receptors, they are less potent than the typical antipsychotics. In addition, the atypical antipsychotics have varying degrees of activity at the dopamine (D1, D3 and D4), serotonin (5-HT2A, 5-HT2C), histamine (H1), adrenergic (a1), and muscarinic receptors. Thus, although it appears that blockade of dopaminergic receptors is necessary to produce an antipsychotic effect, it is now recognized that other neurotransmitters such as serotonin, glutamate, norepinephrine, acetylcholine, and GABA may play important roles in the pathophysiology and treatment of schizophrenia. Much like the dopamine hypothesis, however, there is currently no direct evidence supporting the role of these neurotransmitters.
Clearly there remains much to be learned regarding the critical elements necessary for therapeutic efficacy among the antipsychotic agents. Likewise, despite over four decades of clinical use, the optimal dose of antipsychotics has not yet been established. Clinical fashions tend to fluctuate between recommending high and low doses, these recommendations generally being based more on impressions than on science. In recent decades there has been a concerted effort to examine the utility of antipsychotic plasma concentrations to guide antipsychotic dosing and optimize the treatment of persons with schizophrenia. There is now research data on several antipsychotics showing a relationship between plasma concentrations and clinical response (Perry et al 1991; Miller et al 1994a; Coryell et al 1998; and many others). Unfortunately there remains an inadequate fund of basic information about this class of pharmacological agents and there is a great need for more and better information concerning the pharmacology of their antipsychotic action. This information is essential to then determine factors that predict response to various agents and for the development of dosing guidelines to optimize clinical response.
In the previous application of this grant, the Neuropharmacology Research Unit proposed a project to explore peripheral and central measures of neurotransmitters and their metabolites in an effort to increase our understanding of the pharmacology of antipsychotics. Subsequent analysis of the literature revealed that data from other laboratories was disappointingly inconsistent. We therefore elected to utilize the availability of functional imaging that allows for more direct study of the effects of antipsychotic medications on the physiologic substrates of schizophrenia, in lieu of directing resources toward neurochemical studies. The major purpose of our MH-CRC has been to consolidate our research efforts on the relationship between the clinical picture of schizophrenia and its underlying biological mechanisms. The results of our functional imaging (i.e., PET) studies of patients with schizophrenia are surprisingly convergent, in that the majority of them indicate flow abnormalities in interconnected CCTCC circuits, which are relatively independent of the task. These observations have led to our hypothesis of a fundamental cognitive deficit, cognitive dysmetria. The relationship between this fundamental deficit and the effects of treatment awaits further exploration, however. For example, the relative effects of typical and atypical antipsychotics on the CCTCC abnormalities await exploration, as well as the extent to which these effects are related to improvement in clinical symptoms and in cognitive performance. Project 1 continues our ongoing work to examine the effect of antipsychotics on the neuroanatomic substrates of schizophrenia using PET, with an emphasis on examining specific nodes on the CCTCC. Project 2 proposes to utilize functional MRI to examine the effects of antipsychotic medications on cerebellar blood flow while performing simple and complex motor tasks in patients with schizophrenia and to examine the relationship between clinical response to antipsychotics and patterns of cerebellar flow.
The Basic and Clinical Neuropharmacology Research Unit has continued to be very involved in studying ways to optimize antipsychotic treatment. Several funded projects have been conducted examining the relationship between plasma concentration and clinical response with haloperidol. In Project 3 this area of investigation is further explored from a genetics approach by genotyping patients with schizophrenia for the P-450 2D6 enzyme system, which is the major enzyme involved in the metabolism of many antipsychotic drugs. This will determine whether genotyping of the enzyme correlates with rates of drug metabolism and/or steady-state plasma concentrations of haloperidol. These measures will also determine whether genotyping may be related to clinical response and/or adverse effects from the medications.
There is increasing evidence that blockade of serotonin receptors is involved in the unique properties of the atypical antipsychotics, and there is now some data to suggest that poor response to atypical antipsychotics may be associated with polymorphisms of serotonin receptors. Therefore Project 4 will explore receptor polymorphisms of specific serotonin receptors to determine whether certain polymorphisms are associated with a non-response to atypical antipsychotics. These studies combine two possible predictors of antipsychotic response, those being therapeutic plasma concentrations and receptor polymorphisms. As many of the subjects receiving olanzapine in Project 1 will also be involved in the Projects 4 and 5, we will also be able to examine any possible relationships between polymorphisms of the serotonin receptors and the effect that olanzapine has on rCBF in the CCTCC and on cerebellar activation.
In addition to the beneficial effects of atypical antipsychotics on symptoms, these agents have also been of substantial benefit due to their more desirable side effect profile. Serotonin antagonism is the probable mediator of the relative decrease in expression of extrapyramidal side effects among atypical agents in contrast to typical antipsychotics. Through blockade of serotonin-mediated inhibition of dopaminergic activity in the motor thalamus, the novel antipsychotic risperidone is thought to induce less early onset extrapyramidal effects, which may further translate into a lower likelihood of the development of tardive dyskinesia. Thus the newer antipsychotics afford the opportunity for investigators to rethink not only the mechanisms involved in the production of psychosis but also the mechanisms inducing motor abnormalities in schizophrenia. Certainly clozapine led the way in provoking a reappraisal of the dopamine hypothesis with its diffuse target receptor profile. With its similar target receptor profile, olanzapine will also be utilized in our proposed projects as a measure of atypical antipsychotic effects on functional imaging measures.
Despite extensive research in neuroleptic-induced movement disorders, the precise risk factors for the development of tardive dyskinesia (TD) remain poorly defined. Even the advent of novel agents does not detract from this problem given the substantial number of young and middle-aged adults with schizophrenia who have already experienced a decade or more of typical neuroleptic exposure. Project 5 will seek to better understand the arbitrary nature of tardive dyskinesia by incorporating a longitudinal study of risk factors for TD, including magnitude of neuroleptic exposure and other proposed risk factors such as diabetes mellitus and phenylalanine exposure. By combining this longitudinal data regarding risk factors and abnormal involuntary movement (AIMS) measures in Project 5 with detailed structural imaging data obtained through the use of neural network technology (Project 6), these projects will help to define the neural substrates responsible for the development of abnormal movements in schizophrenia. This will provide the foundation for understanding the long-term impact and potential benefits of the use of the novel antipsychotic agents.
We have chosen to utilize haloperidol as the representative typical antipsychotic, since it is the most widely used typical antipsychotic, and clozapine and olanzapine as atypical antipsychotics. As many different types of pharmacological studies are potentially affected by antipsychotic medication, the MH-CRC has provided us with an enormous benefit by providing us with a facility where we can withdraw patients from medications and study patients in a drug-free environment. In this setting we have been able to study the effects of antipsychotic medications on brain blood flow using PET and fMRI, the influence of medications of negative and positive symptoms and cognitive performance, etc.
Our overall goal remains to increase our understanding of the mechanism by which antipsychotics exert their effect and optimize treatments for patients suffering from schizophrenia in order to decrease the morbidity and mortality involved with this illness.
Progress Report
The Basic and Clinical Neuropharmacology Research Unit has made substantial
progress over the past five years, resulting in over 20 publications as well
as numerous presentations and abstracts. In addition, several of the projects
initiated through the Basic and Clinical Neuropharmacology Research Unit
have resulted in independent grant funding through the National Institutes
of Health, pharmaceutical industry and private foundations.
During the previous funding period the Psychopharmacology Research Laboratory moved from the old University of Iowa Psychiatric Hospital into a new 1000 square feet wet laboratory located in the College of Pharmacy Building, adjacent to the hospital. This laboratory is equipped with High Performance Liquid Chromatographic (HPLC) equipment with an ultraviolet (UV) and Electrochemical (EC) detectors capable of accurately measuring plasma concentrations of various antipsychotic medications and their metabolites. Urine drug screens and other general chemistry tasks are also performed in this laboratory. The Basic and Clinical Neuropharmacology Research Unit in cooperation with the College of Pharmacy has also developed the Pharmacogenetics Laboratory. This is a 500 square feet wet laboratory located in the College of Pharmacy Building equipped with a Digital Imaging System capable of performing allele-specific polymerase chain reaction (PCR) assays and restriction fragment length polymorphism (RFLP) analysis. Dr. Ellingrod has set up the Pharmacogenetics Laboratory to perform allele-specific polymerase chain reaction (PCR assays and restriction fragment length polymorphism (RFLP) analysis to determine mutations in the hepatic enzyme, cytochrome P-450 2D6 and to look for polymorphisms of neurotransmitter receptor genes).
Progress with the studies of the relationship between antipsychotic
plasma concentrations and clinical response and determination of dosing
requirements
During the current funding period Dr. William Coryell's RO1-funded study, "Response
Prediction and Haloperidol Plasma Concentrations in Schizophrenia" was completed
(see Appendices). During this time period an additional study on the effect
of smoking on the pharmacokinetics of haloperidol was conducted (see Perry
et al 1993). Highlights of the key findings of these investigations are listed
below:
Progress with examining the effect of antipsychotics on
the symptom dimensions of schizophrenia
In the past, most of the emphasis of the antipsychotics' therapeutic effect
has stressed their alleviation of hallucinations and delusions with little,
if any, attention given to negative symptoms. The issue of clinical responsivity
of negative symptoms to antipsychotic treatment is an important question with
major implications both clinically and for understanding the basic mechanisms
of negative symptoms. During the current funding period the members of Basic
and Clinical Neuropharmacology Research Unit have interacted closely with investigators
in the Diagnosis and Phenomenology Research Unit. Together we have looked
at the effects of both typical and atypical antipsychotics (i.e., clozapine)
on the symptom dimensions of schizophrenia (i.e., psychotic, disorganized and
negative symptoms) and how changes in these various dimensions affect changes
in other symptom dimensions. The principal focus of these studies has been
whether typical and atypical antipsychotics affect "primary" negative symptoms
of schizophrenia (see Miller et al 1994a, b). Our progress in this area includes
the findings highlighted below:
Progress with studies determining the effect of antipsychotics
on cognitive function and cerebral blood flow
The recent focus of the Basic and Clinical Neuropharmacology Research Unit
has been to study the effects of antipsychotic medications on cerebral blood
flow, specifically examining their effects on the various nodes of the CCTCC.
During the current funding period we have completed a SPECT study (see Miller
et al1997a, b) that are directing our future work in this area. Briefly, our
progress with functional imaging includes the following findings listed below:
Progress with the study of the use of MRI to examine the
long-term effects of antipsychotics on brain plasticity
There is evidence that persons suffering from schizophrenia may have an increase
in basal ganglia structures over time. It was initially thought that this volume
increase was related to the disease process. Recent work has suggested that
this increase may be secondary to antipsychotic induced neuronal plasticity.
While typical antipsychotics have been reported to be associated with increased
basal ganglia volume, there is evidence that atypical antipsychotics are associated
with a relative decrease. This issue has been addressed by our center by examining
volume changes during the time interval between initial baseline structural
imaging and follow-up MR imaging in a group of patients with schizophrenia-spectrum
illness followed in the Iowa Prospective Study of Recent-Onset Psychoses to
examine the long-term effects of antipsychotics on brain plasticity (Westmoreland
et al submitted). The following are some of our key findings:
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