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Online Discussions

Updated 10 January 2006 E-mail discussion
Printable version

Live Discussion: Identifying Phenotypes and Endophenotypes in Schizophrenia (Psychosis) Research


Irv Gottesman

Mayada Akil

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Irving Gottesman (University of Minnesota) and Mayada Akil (NIMH) led our first live discussion on 10 January 2006. You can also read Dr. Gottesman's introductory text, as well as well as a brand new Genes, Brain, and Behavior paper coauthored with Todd Gould of NIMH (Gould and Gottesman, 2006). We welcome your comments on the live discussion materials and the transcript.
View the full text of Irv Gottesman and Todd Gould's (NIMH) well-known American Journal of Psychiatry endophenotype paper from 2003 (Gottesman and Gould, 2003), and see citation from David Braff's group on prepulse inhibition and facilitation (Hsieh et al., 2005).

Our thanks to Genes, Brain and Behavior for free access to Gould and Gottesman (2006): Psychiatric endophenotypes and the development of valid animal models, and to the American Journal of Psychiatry for free access to the Gould and Gottesman (2003) pdf: The Endophenotype Concept in Psychiatry: Etymology and Strategic Intentions.

See also the related SRF news story on a paper by Greg Price and colleagues describing a multivariate electrophysiological endophenotype, with commentary by Danielle Dick, Robert Freedman, and Elvira Bramon, along with a response by Price and Assen Jablensky.

Postscript: We would like to direct readers to the January issue of Schizophrenia Bulletin, which has a number of articles devoted to endophenotypes and schizophrenia research, edited by guest editor David Braff.

View Transcript of Live Discussion — Posted 23 February 2006

View Comments By:
Paul Patterson — Posted 2 January 2006
Elaine Chaika — Posted 6 January 2006
Michael Owen — Posted 6 January 2006
Patricia Estani — Posted 7 January 2006
Deborah Levy — Posted 8 January 2006
Edward Scolnick — Posted 8 January 2006
Daniel Weinberger — Posted 9 January 2006
Margit Burmeister — Posted 9 January 2006
David A. Hay — Posted 10 January 2006
Irwin Waldman — Posted 10 January 2006
Kurt Salzinger — Posted 14 January 2006
Ritushree Kukreti — Posted 30 January 2006


Background
by Irving Gottesman

Welcome to this experimental and still-evolving discussion in cyberspace. Our objective is to host a lively exchange of ideas among researchers pursuing a better understanding of the serious afflictions of the human mind, with the goal of amelioration sooner, rather than later, by optimizing strategies. In our live discussion in January, a few well-informed users of the endophenotype strategy will kick off the chat from the introductory paragraphs, with remarks, raising and answering questions, and providing further discussion points.

The endophenotype concept has reemerged as an important tool in neuropsychiatric research strategies after a long latency since its introduction to psychopathology by Gottesman and Shields (1972) and its reawakening (e.g., Gottesman and Gould, 2003). A quick peek into PubMed reveals more than 614 articles mentioning the concept, and all but 17 since January 1999. This emergence is due to many factors, including the limited reproducibility of genetic and neurobiological studies directed toward etiologies of the disorders in the DSM and an improved appreciation for the complex relationships between genes and behavior.

Endophenotypes are not discernible to the unaided eye or ear—they are not the signs or symptoms of medical practice. The prototype of an endophenotype that Gottesman and Shields had in mind 35 years ago was the role played by an abnormal glucose tolerance test, after glucose challenge to the phenotypically normal co-twins and close relatives of Type 1 diabetics, in identifying those at greatest genetic risk in the context of a multifactorial (polygenic) threshold model of etiology. Disease heterogeneity is often guaranteed, rather than simplified, through our current (DSM) diagnostic system; inherent benefits of endophenotypes include more specific disease concepts and process definitions. Endophenotypes for psychopathology can be neurophysiological, biochemical, endocrinological, neuroanatomical, cognitive, or neuropsychological in nature. Heritability and stability (independent of state) represent key components of any useful endophenotype. Importantly, they characterize an approach that reduces the complexity of symptoms and multifaceted behaviors resulting in units of analysis that are more amenable to being modeled in the laboratory (e.g., cell culture or animal studies). There exists a need for increased collaboration between clinicians and basic scientists, mediated by the conceptual framework embedded in the endophenotype story (depicted in Figs. 1 and 2 below in a very condensed format), the net result of which should be to improve diagnosis, classification, and treatment on one end, and to increase the construct relevance of preclinical/animal models on the other. Although focused on schizophrenia for this Schizophrenia Research Forum chat (Braff and Freedman, 2002; Egan and Goldberg, 2003; Lenzenweger, 1999; Hsieh et al., 2005), the endophenotype strategy is being applied to bipolar disorder (Glahn et al., 2004; Hasler et al., 2006; Lenox et al., 2002), major depression (Hasler et al., 2004; Ogden et al., 2004), ADHD (Waldman, 2005), childhood onset schizophrenia (Skuse, 2001; Sporn et al., 2003), coronary artery disease (Rodin et al., 2005 [.pdf]), autism (Belmonte et al., 2004), alcohol dependence (Dick et al., 2005), and other complex, genetically influenced conditions. Hopefully, the discussion to follow will clarify how the still-evolving definition of an endophenotype makes it distinct from broader terms such as biomarkers or biological markers—as well as from the undefined term, intermediate phenotype. Improvements in defining and deploying the concept are needed and welcomed.

Figure 1. Biological markers (A.K.A. subclinical traits, vulnerability markers) may be primarily environmental, epigenetic, or multifactorial in origin. For this reason, criteria useful for the identification of endophenotypes—a special subset of such markers for studies in psychiatric genetics—have been proposed, adapted, and refined over time (see Gottesman and Gould, 2003; Hasler et al., in press; Leboyer et al., 1998; Lenox et al., 2002; Shields and Gottesman, 1973). Current criteria for an endophenotype, to be distinguished from biological markers, are designed to direct clinical research in psychiatry toward genetically and biologically meaningful conclusions.

Figure 2. Endophenotypes are characterized by simpler neurobiological and genetics antecedents than are psychiatric disorders. The schizophrenia phenotype, as an example, is associated with a number of candidate genes and chromosomal regions, the influence of which can be observed at the levels of either behavior or endophenotypes. Endophenotypes, located closer to genes in the pathway from genes to behaviors, have fewer genes associated, and thus are more amenable to genetic investigations and studies in model systems. This skeleton (genes to endophenotypes to behaviors), allowing for epigenetic, "environmental," and purely stochastic influences upon clinical observations, can be applied to other diseases with complex genetics using the input of disease-specific candidate genes/regions, SNPs, and endophenotypes (Gottesman, 1997; Gottesman and Gould, 2003; Hasler et al., in press; Manji et al., 2003; Sing et al., 1996; Sing et al., 1994). © 2005 I.I. Gottesman and used by permission.

References:

Only three short papers (Gottesman and Gould, 2003; Gould and Gottesman, 2005; Hsieh et al., 2005 have been selected as a starting background to the discussion. A suggested Reading List with more relevant items follows.

Belmonte MK, Cook EH Jr, Anderson GM, Rubenstein JL, Greenough WT, Beckel-Mitchener A, Courchesne E, Boulanger LM, Powell SB, Levitt PR, Perry EK, Jiang YH, DeLorey TM, Tierney E. Autism as a disorder of neural information processing: directions for research and targets for therapy. Mol Psychiatry. 2004 Jul;9(7):646-63. Review. Abstract

Braff DL, Light GA. The use of neurophysiological endophenotypes to understand the genetic basis of schizophrenia. Dialogues Clin Neurosci. 2005; 7(2):125-35. Abstract

Braff DL, Freedman R. (2002) Endophenotypes in studies of the genetics of schizophrenia. In Davis, K.L., Charney, D.S., Coyle, J.T. and Nemeroff, C. (eds), Neuropsychopharmacology: the fifth generation of progress. Lippincott Williams and Wilkens, Philadelphia, pp. 703-716.

Castellanos FX, Tannock R. Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes. Nat Rev Neurosci. 2002 Aug;3(8):617-28. Review. No abstract available. Abstract

Crusio WE. Flanking gene and genetic background problems in genetically manipulated mice. Biol Psychiatry. 2004 Sep 15;56(6):381-5. Review. Abstract

Dick DM, Jones K, Saccone N, Hinrichs A, Wang JC, Goate A, Bierut L, Almasy L, Schuckit M, Hesselbrock V, Tischfield J, Foroud T, Edenberg H, Porjesz B, Begleiter H. Endophenotypes Successfully Lead to Gene Identification: Results from the Collaborative Study on the Genetics of Alcoholism. Behav Genet. 2005 Dec 10;:1-15 [Epub ahead of print] Abstract

Doyle AE, Willcutt EG, Seidman LJ, Biederman J, Chouinard VA, Silva J, Faraone SV. Attention-deficit/hyperactivity disorder endophenotypes. Biol Psychiatry. 2005 Jun 1;57(11):1324-35. Review. Abstract

Egan MF, Goldberg TE. Intermediate cognitive phenotypes associated with schizophrenia. Methods Mol Med. 2003 ;77():163-97. Abstract

Gershon ES, Goldin LR. Clinical methods in psychiatric genetics. I. Robustness of genetic marker investigative strategies. Acta Psychiatr Scand. 1986 Aug;74(2):113-8. Abstract

Geyer MA, McIlwain KL, Paylor R. Mouse genetic models for prepulse inhibition: an early review. Mol Psychiatry. 2002;7(10):1039-53. Review. Abstract

Glahn DC, Bearden CE, Niendam TA, Escamilla MA. The feasibility of neuropsychological endophenotypes in the search for genes associated with bipolar affective disorder. Bipolar Disord. 2004 Jun;6(3):171-82. Review. Abstract

Gottesman II. Twins: en route to QTLs for cognition. Science. 1997 Jun 6;276(5318):1522-3. No abstract available. Abstract

Gottesman II, Erlenmeyer-Kimling L. Family and twin strategies as a head start in defining prodromes and endophenotypes for hypothetical early-interventions in schizophrenia. Schizophr Res. 2001 Aug 1;51(1):93-102. Review. Abstract

Gottesman II, Shields J. Genetic theorizing and schizophrenia. Br J Psychiatry. 1973 Jan;122(566):15-30. No abstract available. Abstract

Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003 Apr;160(4):636-45. Review. Abstract

Gottesman II, Shields J. (1972) Schizophrenia and Genetics; a Twin Study Vantage Point. Academic Press, Inc., New York.

Gould TD, Manji HK. The molecular medicine revolution and psychiatry: bridging the gap between basic neuroscience research and clinical psychiatry. J Clin Psychiatry. 2004 May;65(5):598-604. Review. Abstract

Hasler G, Drevets WC, Gould TD, Gottesman II, Manji HK. (in press) Toward constructing an endophenotype strategy for bipolar disorders.

Hasler G, Drevets WC, Manji HK, Charney DS. Discovering endophenotypes for major depression. Neuropsychopharmacology. 2004 Oct;29(10):1765-81. Review. Abstract

Hsieh MH, Swerdlow NR, Braff DL. Effects of Background and Prepulse Characteristics on Prepulse Inhibition and Facilitation: Implications for Neuropsychiatric Research. Biol Psychiatry. 2005 Sep 16. Abstract

Kirov G, O'Donovan MC, Owen MJ. Finding schizophrenia genes. J Clin Invest. 2005 Jun;115(6):1440-8. Review. Abstract

Leboyer M, Bellivier F, Nosten-Bertrand M, Jouvent R, Pauls D, Mallet J. Psychiatric genetics: search for phenotypes. Trends Neurosci. 1998 Mar;21(3):102-5. Review. Abstract

Lenox RH, Gould TD, Manji HK. Endophenotypes in bipolar disorder. Am J Med Genet. 2002 May 8;114(4):391-406. Review. Erratum in: Am J Med Genet 2002 Jul 8;114(5):592. Abstract

Lenzenweger MF. Schizophrenia: refining the phenotype, resolving endophenotypes. Behav Res Ther. 1999 Mar;37(3):281-95. Review. Abstract

Manji HK, Gottesman II, Gould TD. Signal transduction and genes-to-behaviors pathways in psychiatric diseases. Sci STKE. 2003 Nov 4;2003(207):pe49. Review. Abstract

Miguel EC, Leckman JF, Rauch S, do Rosario-Campos MC, Hounie AG, Mercadante MT, Chacon P, Pauls DL. Obsessive-compulsive disorder phenotypes: implications for genetic studies. Mol Psychiatry. 2005 Mar;10(3):258-75. Review. Abstract

Niculescu AB 3rd, Akiskal HS. Proposed endophenotypes of dysthymia: evolutionary, clinical and pharmacogenomic considerations. Mol Psychiatry. 2001 Jul;6(4):363-6. Review. Abstract

Petryshen TL, Kirby A, Hammer Jr RP, Purcell S, Singer JB, Hill AE, Nadeau JH, Daly MJ, Sklar P. Two QTLs for prepulse inhibition of startle identified on mouse chromosome 16 using chromosome substitution strains. Genetics. 2005 Jul 5; [Epub ahead of print] Abstract

Rodin A, Mosley TH, Clark AG, Sing CF, Boerwinkle E. Mining genetic epidemiology data with Bayesian networks application to APOE gene variation and plasma lipid levels. J Comput Biol. 2005 Jan 1;12(1):1-11. Abstract; .pdf

Shields J, Gottesman II. (1973) Genetic studies of schizophrenia as signposts to biochemistry. In Iversen, L.L. and Rose, S.P.R. (eds), Biochemistry and mental illness, Vol 1. Biochemical Society, London, pp. 165-174.

Sing CF, Haviland MB, Reilly SL. Genetic architecture of common multifactorial diseases. Ciba Found Symp. 1996;197:211-29; discussion 229-32. Review. Abstract

Sing CF, Zerba KE, Reilly SL. Traversing the biological complexity in the hierarchy between genome and CAD endpoints in the population at large. Clin Genet. 1994 Jul;46(1 Spec No):6-14. Review. Abstract

Skuse DH. Endophenotypes and child psychiatry. Br J Psychiatry. 2001 May 1;178():395-6. Abstract

Sporn AL, Greenstein DK, Gogtay N, Jeffries NO, Lenane M, Gochman P, Clasen LS, Blumenthal J, Giedd JN, Rapoport JL. Progressive brain volume loss during adolescence in childhood-onset schizophrenia. Am J Psychiatry. 2003 Dec ;160(12):2181-9. Abstract

Swerdlow NR, Geyer MA, Braff DL. Neural circuit regulation of prepulse inhibition of startle in the rat: current knowledge and future challenges. Psychopharmacology (Berl). 2001 Jul;156(2-3):194-215. Review. Abstract

Waldman ID. Statistical approaches to complex phenotypes: evaluating neuropsychological endophenotypes for attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005 Jun 1;57(11):1347-56. Abstract


Comments on Online Discussion
Comment by:  Paul Patterson
Submitted 2 January 2006 Posted 2 January 2006

I'm interested in the maternal infection risk factor, and curious if others have followed up on this report on subsets of schizophrenia and risk: Parental transmission (genetic) is prominent in periodic catatonia cases, while mid-gestation infection is prominent in the systemic catatonia phenotype (Stober et al., 2002). Is the distinction between periodic and systemic catatonia made in the USA? Could differential endophenotypes tell us something about the causes of schizophrenia?

View all comments by Paul Patterson


Comment by:  Elaine Chaika
Submitted 6 January 2006 Posted 6 January 2006

Gottesman's noting of the importance of eye-tracking dysfunction in schizophrenics seems very on-target to me. In an early paper, "A unified explanation for the diverse structural deviations reported for adult schizophrenics with disrupted speech," (Chaika, 1982), later summarized in my 1990 book Understanding Psychotic Speech: Beyond Freud and Chomsky (Chas. C. Thomas, Springfield, Ill; pp 44-5; 190-1), I showed that the speech syndrome long identified uniquely as schizophrenic, when diagrammed, shows the same pathway deviations that the eye-tracking dysfunction manifests. Both the saccades and spiky type movement (of visual tracking) are analogous to schizophrenic utterances. The saccades show lack of focusing ability, a deficit in tracking. The spiky type movement represents perseverations in associative pathways. It should also be noted that the initial utterances of speech-disordered schizophrenics, such as responses to questions, are usually correct. However, they veer off...  Read more


View all comments by Elaine Chaika

Comment by:  Michael Owen, SRF Advisor
Submitted 6 January 2006 Posted 6 January 2006

Irv Gottesman and colleagues are to be congratulated on their lucid and thoughtful championing of the use of endophenotypes in schizophrenia research. Like many, I agree that this would appear to have massive face validity, given that it is clear that the clinical diagnosis of schizophrenia is syndromic and relies upon the detection and measurement of symptoms and signs that are to a large extent heterophenomenological in nature. However, I believe that there are a number of issues that need to be carefully considered before genetics researchers rush headlong into the widespread use of endophenotypes. To my mind, the most important of these are as follows.

1. How well do currently advocated endophenotypes really satisfy the criteria laid out clearly by Gould and Gottesman? In particular, it is often not clear to the outsider just how state-independent most of the measures proposed really are, with the potential for contamination not just by fluctuations in course and drug treatment, but also by factors such as smoking.

2. How much inter-laboratory variation...  Read more


View all comments by Michael Owen

Comment by:  Patricia Estani
Submitted 7 January 2006 Posted 7 January 2006

The current and clinical classifications of schizophrenia are completely phenomenological. These classifications are not useful for the research dissection of the variables implicated in the disease. New directions, such as those given by the idea of endophenotypes, must be used in the research of schizophrenia. The concept of endophenotype, as it is defined by Dr. Gottesman, is extremely important (Gottesman and Gould, 2003). The idea of endophenotype is a useful tool to design experimental approaches, not only in the field of animal research, but also in the clinical and genetic research of this disease.

In reply to the comment of Dr. Owen, I think that the concept delimited by Dr. Gottesman is clear and well defined. In this way, many factors, such as smoking, could affect an endophenotype, but a specific endophenotype is not altered by all factors in an easy way. In this sense, the concept is very robust and clear.

References:
Gottesman II, Gould TD. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry. 2003 Apr 1;160(4):636-45. Abstract

View all comments by Patricia Estani


Comment by:  Deborah Levy
Submitted 8 January 2006 Posted 8 January 2006

I want to follow up on several comments made by Dr. Owen, who wrote, "Is the genetic architecture of the relevant endophenotype simpler than that of the genetic architecture of schizophrenia, to a sufficient degree to offset the greater difficulty in collecting large samples?"

I agree with Dr. Owen that this is a fundamental question. What has made it difficult to provide compelling evidence for the potentially simpler genetic architecture of endophenotypes? One cause is that existing methods to evaluate power (e.g., the elegant work of Risch) apply when a symmetrical ascertainment design is being used (probands are ascertained for having trait x and relatives are examined for recurrence on the same trait). In such a design, power is largely determined by relative risk (the “Risch λ”) (Risch, 1990). It has not been widely appreciated that studies of endophenotypes are based on an asymmetrical ascertainment design—probands are ascertained on the basis of schizophrenia and relatives are...  Read more


View all comments by Deborah Levy

Comment by:  Edward Scolnick
Submitted 8 January 2006 Posted 8 January 2006

I suggest anyone participating in this discussion read Chapter 12 of Genetics in Medicine by Nussbaum et al. I suggest they learn about Hutchinson Gilford progeria, San Fillippo syndrome, Hurler's and Scheie syndrome, and the work of Lifton in a metabolic syndrome in which all family memebrs have the identical mutation in a tranfer RNA with meager overlap in the members for the constellation of the symptoms and signs of the syndrome. Is the right strategy more detailed endophenotyping now? Or much larger samples with already available defintions and more detailed endophenotyping once real risk genes have been discovered?

References:
Nussbaum RL. McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine. 6th ed. Philadelphia: Saunders, 2004. ISBN: 0721602444

View all comments by Edward Scolnick


Comment by:  Daniel Weinberger, SRF Advisor
Submitted 9 January 2006 Posted 9 January 2006

If we accept that schizophrenia genes, or for that matter any genes for psychiatric disorders, do not encode for hallucination and delusions, or thought disorder, or panic attack, or the like, then it is hard to escape the conclusion that biologic traits related to the emergence of these behavioral phenomena will show greater penetrance of gene effects, that is, greater effect sizes, than will the behavioral phenomena. In my view, this is of even greater relevance when the genetic defects do not result in truncated or dysfunctional proteins, but likely in variation in gene regulation at critical times of development. Many individuals will harbor risk haplotypes in candidate genes and not show the behavioral associations. If we had the intermediate phenotypes related to the risk haplotypes robustly characterized, we would not need such huge samples to show clinical association to meaningful behavioral syndromes.

I think a clear example of this is the data that have emerged with the 5'HTTLPR variant and mood and temperament. Effects of this variant on function (and likely...  Read more


View all comments by Daniel Weinberger

Comment by:  Margit Burmeister
Submitted 9 January 2006 Posted 9 January 2006

Regarding Mike Owen's point: "I think the crucial question is as follows: Is the genetic architecture of the relevant endophenotype simpler than that of the genetic architecture of schizophrenia, to a sufficient degree to offset the greater difficulty in collecting large samples?"

That isn't quite the point. There are two advantages with most endophenotypes:

1. They are usually quantitative, and if we believe that most of the genes change things quantitatively, incrementally, it is better to use a quantitative trait than a dichotomous diagnosis—there are quantitations of that advantage (e.g., Allison et al., 1998)—even if the heritability and complexity of the phenotype was the same as of the disorder.

2. For some endophenotypes (e.g., neuroticism), it is easier to collect samples, in part because one can measure them in a population sample—it is possible to measure N in 10,000 people, and some have done that; it is much easier than finding 5,000 depressed people and...  Read more


View all comments by Margit Burmeister

Comment by:  David A. Hay
Submitted 10 January 2006 Posted 10 January 2006

Hi, Irv. Sorry I can't join your discussion but it will be 1 a.m. Wednesday morning our time. A few points from our discussions over the last few years in Steve Faraone's NIMH ADHD group and Joe Sergeant's European ADHD group which I think apply to all endophenotypes.

1. There have been very few studies of the heritabilities of endophenotypes, and those show less genetic variation than for the actual disorders. While it may seem these are closer to the genes, a key point in the Hsieh paper is that these methods are quite equipment-specific. In fact, when we met about a common set of endophenotype techniques for ADHD, we all felt our "own" set-up was the way to go, and even though there was some agreement on what to measure, there was much less on how to measure it.

2. Even less clear is the evidence on bivariate heritability of endophenotypes with the disorder. Certainly in ADHD, the one example we have is one of the measures used by Jonna Kuntsi and Jim Stevenson. This raises another question about whether these endophenotypes really are across the whole...  Read more


View all comments by David A. Hay

Comment by:  Irwin Waldman
Submitted 10 January 2006 Posted 10 January 2006

It is worth noting that several researchers have systematized and extended the criteria enumerated by Gottesman and Gould and others (e.g., Almasy and Blangero, 2001; Castellanos and Tannock, 2002; Cornblatt and Malhotra, 2001; Doyle et al., 2005; Waldman, 2005; Waldman et al., in press) in such a way that they can be used to evaluate the validity and utility of putative endophenotypes for molecular genetic studies. Criteria for the validity of endophenotypes include its relation to the disorder in the population and within families, its expression in probands’ unaffected relatives, its heritability and common genetic influences with the disorder, and to a lesser extent, its psychometric...  Read more


View all comments by Irwin Waldman

Comment by:  Kurt Salzinger
Submitted 13 January 2006 Posted 14 January 2006

I was delighted to read the two Gottesman and Gould articles on endophenotypes because of the behavioral mechanism that I have posited for a number of years (Salzinger and Feldman, 1966; Salzinger, 1984; Salzinger and Serper, 2004). The behavioral mechanism is the Immediacy Mechanism. It states basically that the behavior of schizophrenia patients is largely controlled by stimuli immediate in the patient's environment. In the reviews cited above, many areas of schizophrenic functioning lent themselves to such an interpretation. Thus, a deficit in working memory could be explained in terms of the patient's inability to respond to stimuli (old words or numbers) not in their immediate environment. The Continuous Performance Test has shown that when schizophrenia patients are given the task of responding to stimulus X only when preceded by the stimulus A, as the interval between A and X increases, the performance deteriorates precipitously for schizophrenia patients, compared to normal or other psychotic patients. We have also been able to show that their tangential speech could...  Read more


View all comments by Kurt Salzinger

Comment by:  Ritushree Kukreti
Submitted 30 January 2006 Posted 30 January 2006

The multifactorial etiology of schizophrenia makes it a complex interaction of symptoms. A network model of the interaction/crosstalk between the neurotransmitter signaling systems is presented in our recent paper (Gupta et al., 2006) to emphasize the importance of the genes in the molecular mechanisms of the disease and drug response. These genes may serve as potential susceptibility genes and drug targets for schizophrenia. The crucial point for the identification of a significant biological marker(s) includes the experimental validation of the genes involved in the neurotransmitter signaling systems, and coupling of our knowledge of genetic polymorphisms with clinical response data (endophenotypes) promises a bright future for rapid advances in personalized medicine.

References:
Gupta S, Jain S, Brahmachari SK, Kukreti R. Pharmacogenomics: a path to predictive medicine for schizophrenia. Pharmacogenomics. 2006 Jan ; 7(1):31-47. Abstract

View all comments by Ritushree Kukreti

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