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SCHIZOPHRENICS & GENETIC MODIFICATION.
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Discusses symptoms & etiology of the disorder, genetic evidence & potential for modification. Bioethical issues.... More...
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Paper Abstract:
Discusses symptoms & etiology of the disorder, genetic evidence & potential for modification. Bioethical issues.
Paper Introduction:
Should Genetic Modification Be Advocated for Schizophrenia
Introduction
There are two main issues to consider in any discussion of genetic modification in relationship to schizophrenia. The first issue is a scientific issue, related to the etiology of schizophrenia and the available evidence regarding a genetic component. The second issue is a bio-ethical issue regarding the ethics of gene modification in human beings, including the initial experimentation involved.
Schizophrenia
The major symptoms of schizophrenia are described in the DSM-IV as involving several areas of the person's functioning,
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Psychiatry, 45(3), 247-253. The zygosity diagnoses were based onmolecular genetic methodology plus a zygosity questionnaire. Essentially, the authors,and other researchers involved, used patients with schizophrenia asexperimental subjects to determine if D4 antagonists would be effectivetreatments. The question here, then, is whether intercession would be desired inall instances, since not all individuals with this genetic propensity woulddevelop schizophrenia. Davison, G.C. The American Journal ofPsychiatry, 155(1), 76-83. The main support for genetic involvement has come from family, twin,and adoption studies, which provide strong, indirect support for geneticvulnerability as an aspect of the etiology of the disorder (Waldo andFreedman, 1999) (or disorders, since Shastry (1999) and Murray and Fearon(1999), among others, indicate that schizophrenia may actually be severaldifferent diseases). There is still need for identification and completecharacterization of these genes before effective treatments can be devised. Dickerson, F.B., Boronow, J.J., Ringel, N., Parente, F. Some medications reduce symptoms for somepeople some of the time, but medication compliance is an important problem. (1999). Murray and Fearon (1999), too, contend that there is no single causefor schizophrenia, but that an appropriate etiological model involves bothmultiple genes and multiple environmental risk factors. Instead, more research is needed in several areas, includingresearch on differences between the subtypes, research determining whetherthe current diagnosis of schizophrenia actually represents severaldifferent diseases or disorders (with differential genetic involvement),and research more carefully pinpointing genetic vulnerability. (1999). Basic symptoms include such things as disorganized speech,hallucinations, delusions, bizarre behavior, avoltion, alogia, anhedonia,blunted affect, and asociality (Davison and Neal, 1998). (1996). Further, Lesch (1999) indicated, there is increased knowledge of thestructure and development of gene promoters and regulatory systems. Abnormal psychology. Genetic and non-geneticvulnerability factors in schizophrenia: The basis of the "two hithypothesis". This disease directly affects 1 percent of thepopulation of the United State, causing great suffering and economic costsof approximately $73 billion (Backlar, 1998). Their subjects were all twinsin the region of Lower Franconia, Germany who were born after 193 andhospitalized for psychiatric disease. psychiatry,4(6), 529-38. (1999) also discussed both the clinical and ethicalimplications of genetic investigations. These then interact with inherited personalitytraits of the schizotypal type to lead the child toward a more solitary anddeviant lifestyle. Schizophrenia: Areview of genetic studies. In looking at their results, in combination with other studies, theauthors concluded that schizophrenia spectrum psychoses may, and probablydo, consist of clinically and etiologically heterogenous subgroups withdifferent genetic backgrounds (Franzek and Beckmann, 1998). Waldo, M.C. Neurogenetics, 2(3), 149-154. It recommended more research - not surprisingly - and alsoacknowledged the ethical challenges that need to be more fully discussedregarding genetic alteration of a human being, or manipulation of the humangenome. Again, this raises ethical issues. Genetic modification and ethical issues One of the problems with this is that much of what would pass forgenetic "treatment" or genetic "modification" of schizophrenia is reallymore appropriately termed research trials. In other words, theindividual may not be capable of informed consent as we understand itbecause of being unable to distinguish between important concepts involvedwith treatment and research (Dickerson et al., 1997). Biol. Murray, R.M. This is a very complicated model that would make genetic interventiondifficult, since the authors implicate more than one gene. Psychiatry, 56(6), 549-552. In addition, there was noevidence that these subjects had increased obstetrical complications orinordinate environmental stress. Inaddition, in the case of cycloid psychoses and conditions such asschizophreniform, schizoaffective, and delusional disorders, and psychoticdisorders not otherwise specific, the affected twins had sufferedsignificantly more severe birth complications than their healthy twins(Franzek and Beckmann, 1998). At thispoint, there is an increasing level of sophistication in gene transferstrategies that impact such disorders as Parkinson's and Alzheimer;s, aswell as disorders like schizophrenial. and Freedman, R. The assumption is that identification of those geneswill then impact diagnosis, prevention, and treatment of the diseases.However, the working group noted that there were a number of problems stillto be addressed before molecular psychiatry or psychiatric genetics becamea field that was able to effectively work with such problems asschizophrenia. In looking at this problem, the study by Franzek and Beckmann (1998)is instructive. and Fearon, P. The second issue is abio-ethical issue regarding the ethics of gene modification in humanbeings, including the initial experimentation involved. The first issue is ascientific issue, related to the etiology of schizophrenia and theavailable evidence regarding a genetic component. In their model,genetic and/or early environmental risk factors lead to the development ofanomalous neural networks. (1999). However, I would recommend continuedresearch to identify pathways of pathology, ethical research with patientswith disorders on the schizophrenic spectrum that made use of transgenesand minor genetic modifications, and ongoing dialogue about the subject ofthe human genome and its potential widescale modification. (2 ).Sensory gating deficits assessed by the P5 event-related potential insubects with schizotypal personality disorder. Nicolson, R. BMJ, 319(7223), 1498-1499. Recent developments in the genetics ofschizophrenia. Nicolson and Rapoport (1999) recommend studying the population ofindividuals with schizophrenia who have the childhood-onset version.Although this is rarer than adolescent, or adult-onset schizophrenia, theynote that the characteristics of the population make it worth studying forgenetic involvement. (1999). This is both aspiritual and ethical issue that requires public dialogue that is not yettaking place. Clearly, too, there is insufficient knowledgeabout what other functions the P5 sensory gating might impact. Lesch, K.P. Genetic evidence and potential for modification Much recent emphasis has been on genetic vulnerability as thefoundation for schizophrenia. Journal of Psychiatric Research,33(6), 491-495. This, to them, pointed a way tounderstanding the pathogenesis of schizophrenia by indicating that earlydamage to these structures could produce behavioral, morphological, andneuropharmacological abnormalities associated with pathology in adultschizophrenics. Theylooked specifically at the damage to rat amygdala or the hippocampus 48hours after birth which led to smaller structures as adults, larger lateralventricles, and problems with cerebral cortex, prefrontal cortex, andhippocampal volumes and functions. The results were complex, but one salient fact is that not one of the37 monozygotic twins was diagnosed as having systematic schizophrenia,whereas six of the 25 dizygotic index twins were so diagnosed. Still, it seems clear that researchers are beginning to understandthe complex of pathways that lead to disorders on the schizophrenicspectrum. Bayer et al. As each of these pathways is more clarified, it should bepossible to design transgenes or transcriptional apparatus to the brain inorder to regulate development and manage expression of certain geneproducts. Thiscan be associated with either schizophrenia or the development of aschizotypal personality disorder. (1998). Approximately 1 percent of people withschizophrenia commit suicide. Ethics in community mental health care.Community Mental Health Journal, 34(3), 229-24 . Ethics in mental health care and treatment Although Backlar (1998) indicated that now is a good time foremphasizing research with subjects, like schizophrenics, who havefluctuating cognitive impairments (and consequently impaired decision-making and choice-making), she also noted that the guidelines for ensuringtheir safety and well-being as research subjects are currently inadequate.She recommended that guidelines be changed to allow for the appointment ofsurrogate decision-makers during those times of fluctuating impairment.She also recommended use of research advance directives which clearlydelineate other safeguards for the research subjects. and Rapoport, J.L. Brain Res., 1 7(1-2), 71-83. At some point, the individual passes a threshold forexpression of schizophrenia, often through either drug abuse or socialadversity that are precipitating factors in the initial psychosis. (1999). Journal of Psychiatric Research, 33(6), 497-499. With the knowledge already available, efforts have been made to treatschizophrenia. This greater familial vulnerability could lead tomore fruitful genetic studies providing more pinpointed etiologicinformation on areas of genetic vulnerability. (1999). Gene transfer to the brain: Emergingtherapeutic strategy in psychiatry? The 49 patients examined by the National Institute ofMental Health exhibited more severe premorbid neuro-developmentalabnormalities, higher rates of cytogenetic anomalies, and a higher rate offamilial schizophrenia and spectrum disorders. They measured the response to each oftwo auditory clicks. To look more closely at just one aspect of one gene that has beenassociated with the schizophrenia spectrum of problems, Cadenhead et al.(2 ) explored attention and information processing by testing suppressionof the P5 event-related potential. Psychiatry, 46(1 ): 1418-1428. There is no known cure. However,Shastry continued on to say that linkage analyses do suggest thatsusceptibility genes may be present on chromosomes 5q, 6p, ip, 13q, 18p,and 22q. and Baldessarini, R.J. Mentally disabled research subjects: theenduring policy issues. Hanlon, F.M. An agenda for psychiatric genetics. (1999). Franzek, E. For example, Lesch (1999) noted that public concerns might arisebecause developing techniques of gene transfer could be utilized not onlyto treat brain disorders, but to enhance normal CNS functioning. Mol. These policies generallyrest upon the informed consent process which requires that the researchsubject freely agrees to participate in research which they are completelyinformed about and understand (Sachs et al., 1994). They specifically emphasize6p, 8p, and 22q as having the most significant backing for involvement inthe etiology of schizophrenia. Neurobiological abnormalitiesin the relatives of schizophrenics. The ethical issues are harder to solve, in some ways. (1999). To begin with, there is theethical issue of labeling the individual as potentially schizophrenic.There are several problems with this, including the possibility ofostracism of the child, differential treatment by school districts,unnecessary genetic manipulation, problems with health insurance and healthcare provision, and genetic manipulation leading to unknown, andunpredictable, consequences for the child. At the same time, the authors recommended testing these on patients withother psychiatric disorders in the hope of ameliorating certain psychoticconditions. Even those working in neurogenetics indicate that schizophrenia iscomplex and multifactorial and genetic intervention may be difficultbecause etiology is not clearly understood (Shastry, 1999). The National Institute of Mental Health has recently convened aworking group to facilitate identification of the genes that influencemental disorders. Moncrieff, J. Bayer, T.A., Falkai, P., Maier, W. and Beckmann, H. There is a tangle of causes,including genetic vulnerability, and a number of gene sites that have beenimplicated in one or more study. They caution thatconsistent results have not yet been obtainable, but that there issufficient evidence to support an assertion that there are areas ofvulnerability at certain chromosomal sites. This is a biological disorder that affects almost every area of theperson's life, including their mental ad emotional activity, and theirinterpersonal relationships. ethical aspects of dementia research: Informed consent andproxy consent. and Sutherland, R.J. She also asserted thatindividuals with such extreme cognitive impairments that they are unable toestablish advance directives or appoint a proxy decision-maker should notbe permitted to participate in research protocols. Psychiatric Services,48(2), 195-199. Dopamine D4 receptors:Significance for molecular psychiatry at the millennium. (1997). Bleuler, however, disagreed with Krapaelin'sconceptualization, devising the term schizophrenia to cover what he viewedas the split mind, or split personality of clients (Davison and Neal,1998). (1994). Conclusions The most positive argument for genetic modification in the treatmentor prevention of schizophrenia was made by Lesch (1999); most of the otherwriters were more cautious about what remains unknown. Behav. Dressler, R. At the present time, there arethree subtypes of the disorder discussed in the DSM-IV, includingdisorganized, catatonic, and paranoid (DSM-IV, 199 ). Cadenhead, K.S., Light, G.A., Geyer, M.A., and Braff, D.L. The information they had to work with was inconclusiveregarding the relationship of Dopamine D4 receptors to schizophrenia.This trial-and-error approach - which Tarazi and Baldessarini recommend andseem to support as the future of molecular psychiatry - is ethicallyproblematic, particularly for patients who may not really be able to giveinformed consent for such very experimental procedures. However, the problem with schizophrenia is that the individual maylack insight into his or her own disease and suffer from importantcognitive impairments even when psychotic episodes are under control, andhallucinations and delusions have been treated. Etiology has been attributed to early trauma, bad parenting,chemical disorders, neonatal damage, inappropriate brain development, andgenetic propensities. There is less harm likely to be done to subjectsunder these changed conditions. In normal subjects the P5 wave following the secondclick was suppressed, or "gated", while in schizophrenic subjects and theirrelatives, the second P5 wave showed significantly less suppression.Deficits in P5 wave suppression show linkage to the alpha-7 subunit of thenicotinic cholinergic receptor gene, and they have high heritability. Biol. Childhood-onsetschizophrenia: Rare but worth studying. Arch.Gen. (1998). Although Krapaelin describedmany of the symptoms, he did not attempt to search for causes, norcategorize symptom groups. (1999). Shastry, B.S. References Backlar, P. Tarazi, F.I. and Neal, J.M. Barondes, S.H. For example, D4 antagonists have been utilized in treatingschizophrenia, but have proven ineffective (Tarazi and Baldessarini, 1999). Another major problem with genetic modification for schizophrenia isthat there still remains controversy about the etiology, or pathogenesis ofthe disease. Thus, it seems reasonable toexpect the development of recombinant transcriptional designs which couldtailor development and restrict expression in order to avoid unwanted sideeffects of the gene product. Journal of the American Medical Association, 276,67-72. Sachs, G.A., Stocking, C.B., Stern, R., cox, D.M., Hougham, G., Sachs,R.S. It also raisesethical issues, since it seems to imply that not every person with specificgenes would become schizophrenic. Thus, genetic modification would beunnecessary in many cases and the need for genetic modificationunpredictable given the multiplicity of factors involved. Backlar (1998) noted that there are so many more sophisticatedmethods for working with the human genome, and non-invasive methods ofimaging brain function, that the climate is positive for working onschizophrenia research. Thus, this relatively homogenouspopulation with onset of schizophrenia before age 12 may indicate greaterfamilial vulnerability. The challenge is to create policies that allowfor promising lines of research to continue, while also developingprotocols that safeguard the rights and welfare of the individualsparticipating in the studies (Dressler, 1996). Backlar(1998) provided an excellent design for performing research withindividuals with disorders on the schizophrenic spectrum, starting with anadvance directive and a proxy decision-maker for unanticipated situations.More difficult to resolve are the general bioethical issues of theappropriateness of modifying human beings genetically. Lackof insight among outpatients with schizophrenia. Different genetic background ofschizophreia spectrum psychoses: A twin study. Until this dialogue occurs, I would not advocate widespreadgenetic modification of human genes, even in cases of diseases likeschizophrenia and Parkinson's. Tsuang, M.T., Stone, W.S., Faraone, S.V. For example, Hanlon and Sutherland (2 ) described the problem asone of limbic damage in early development which then cases aberrantmaturation of brain structures leading to adult behavioral problems. (1999), however, have proposedwhat they term the "two hit hypothesis" meaning that neither genetic nornon-genetic factors solely account for the onset of the disease, but thatboth genetic and non-genetic vulnerability factors are required in orderfor it to develop. Journal of Psychiatric Research, 33(6), 543-548. Changes in adult brain andbehavior cased by neonatal limbic damage: Implications for the etiology ofschizophrenia. For example, Moncrieff (1999) asserted that clinical reviewof current studies overstates the genetic case for schizophrenia, and thatthe inconsistency of results does not lead toward a cure based on geneticmodification. In other words, there is no easy intervention with the modificationof one or more genes always called for and always successful in preventingthe disorders of the schizophrenia spectrum. Tsuang et al. The changes in the concept can be traced through changes indiagnostic criteria in DSM-I, DSM-II, DSM-III, and up to DSM-IV (AmericanPsychiatric Assn., 1952; 1968; 1975; 199 ). Schizophrenia The major symptoms of schizophrenia are described in the DSM-IV asinvolving several areas of the person's functioning, including thought,perception, motor behavior, affect, and basic daily functioning. There are still problems, however, not least of which is thatindividuals with schizophrenia may not be able to give truly informedconsent in many instances. There are also theunaddressed ethical concerns. Harvard Review of Psychiatry, 7(4), 185-2 7. Clinical Research, 42, 4 3-412. American Journal ofPsychiatry, 157(1), 55-9. There is noresolution to this dilemma, but Backlar (1998) seems to support thecreation of advance directives with potential appointment of a proxydecision-maker as the most ethical procedure. Etiology of the disorder Etiology, too, has been the source of much discussion, revision, andcontroversy. (1999). The problem with this study, of course, is that it focusedexclusively on rats. The authors conducted a systematic twin study of indextwins with schizophrenia spectrum psychoses. (1998). AsDavison and Neal (1998) indicated, however, no one symptom is definitiveand this means that schizophrenic patients can differ radically from eachother. The developmental Ôrisk factorÕmodel of schizophrenia. Clinical review overstates genetic case forschizophrenia. NY: JohnWiley & Sons, Inc. Transgees can be delivered directlyto brain cells and transplant techniques have been developed for neuronal,non-neuronal, and progenitor cells that have been genetically modified tocreate and distribute therapeutic gene products in the brain. These are significant bioethical issues. Should Genetic Modification Be Advocated for Schizophrenia Introduction There are two main issues to consider in any discussion of geneticmodification in relationship to schizophrenia. In general,schizophrenics are isolated people who have poor social skills, fewfriends, and intermittent awareness of their disease, their isolation, andthe non-reality of the voices and hallucinations that often torment them. (2 ). Thereis an assumption that the brain has the capability for more modification,and modularity, than had been anticipated. History of the concept In looking at the history of the concept of schizophrenia, it isapparent that it has confused researchers. Tsuang et al (1999) provided an excellent review of genetic studies,looking not only at family studies, but at genetic linkage studiesindicating progress toward identifying the specific genes or gene aspectscontributing to the development of schizophrenia.
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