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Clarifying the nature of olfaction deficits in the schizophrenia-prone: “Clinical high-risk state” versus “vulnerability”
Schizophrenia Research 139 (2012) 262–263
Contents lists available at SciVerse ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Clarifying the nature of olfaction deficits in the schizophreniaprone: “Clinical high-risk state” versus “vulnerability”
Dear Editors,
We very much appreciate the comments made by the authors of “Olfaction and Schizophrenia Clinical Risk Status: Just the Facts,” as well as the opportunity by the editor of Schizophrenia Research to clarify our position. We agree wholeheartedly with each of Turetsky et al. (in press) “facts” outlined in their letter, and agree with the authors' conclusions that olfaction appears to be a promising “viable biomarker of the psychosis clinical high-risk state.” Further, we do not believe that their conclusions are in contradiction with any of the conclusions discussed in Cohen et al. (2012) – notably that “conducting further studies examining a gross deficit(s) in olfaction functioning across schizotypy, broadly defined, is not a particularly promising endeavor.” We believe there is an important distinction to be made between the terms appearing in our article – “vulnerability marker” and “schizotypy” and the term used by Turetsky et al. (in press) – “Clinical risk status.” Vulnerability is a foundational term in schizophrenia research and forms a critical basis of the vulnerability-stress model of schizophrenia (e.g., Walker et al., 2004). The notion is that genetic, environmental and other factors confer a vulnerability to schizophrenia pathology — but that it is the interaction with other factors that “unlock” phenotypic expression. From this neurodevelopmental perspective, the majority of individuals with vulnerability to schizophrenia do not meet criteria for a schizophrenia-spectrum disorder at any point during their lifetime despite showing a host of subclinical schizophrenia-like characteristics. Some heuristic neurodevelopmental models suggest that this vulnerable population, often described in terms of “schizotypy,” is quite large (e.g., 10% of the population; Meehl 1962). A number of operational definitions have been advanced to objectify the term “vulnerability marker,” at least in regards to biological or genetic factors. These definitions generally require a candidate marker to show evidence of heritability as well as manifestation, albeit attenuated in magnitude, in unaffected biological relatives of patient probands (e.g. Gottesman and Gould 2003; Calkins et al., 2007). In this regard, there were two findings from our meta-analysis that are inconsistent with the notion that olfaction deficits reflect a vulnerability marker for schizophrenia-spectrum pathology. First, unaffected biological family members of patients showed an effect size difference from controls on the order of one-fifth of a standard deviation. For point of reference, of the five studies examining biological family members reporting all items from the University of Pennsylvania Smell Identification Test reviewed in our meta-analysis (UPSIT; Doty et al., 1984), family members of patients scored, on average, .50 of a single item (of 40 total items possible) lower than family members of controls. Second, individuals with psychometrically-defined schizotypy, identified based on self-report of subclinical schizophrenia-like symptoms/traits, showed negligible differences in olfaction 0920-9964/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2012.04.010
identification compared to controls. To help clarify our position, we offer the following: Are olfaction deficits important for understanding schizophrenia? Unquestionably yes. The results of our meta-analysis (also see Moberg et al., 1999; Turetsky et al., 2009) provide clear evidence that olfaction deficits are profound in patients with schizophrenia. Are olfaction deficits predictive of clinical risk status? The results of our meta-analysis and the author's letter provide compelling evidence that individuals at “ultra-high” risk for developing schizophrenia show pronounced olfaction deficits. In light of this, and the longitudinal data discussed in Turetsky et al.'s (in press) letter, olfaction deficits may reflect a marker differentiating individuals most likely to develop schizophrenia symptoms from the larger vulnerable population. Are olfaction deficits a vulnerability marker of schizophrenia-spectrum pathology? Insofar as biological family members of patients with schizophrenia and individuals with psychometrically-defined schizotypy do not show meaningful levels of olfaction identification deficits, we believe it is difficult to make the case that olfaction deficits are a meaningful vulnerability marker for schizophrenia-spectrum pathology. Caveats — It is important to highlight limitations of the existing literature (see Cohen et al., 2012 for elaboration of each these points), notably that: a) existing measures of olfaction ability may be insufficiently sensitive for detecting deficits in higher functioning populations, b) olfaction acuity, as opposed to identification, may be impaired in schizotypy, c) subjective appraisal of olfactory stimuli may be abnormal in vulnerable populations, and d) schizotypy and schizophrenia are heterogeneous constructs. In sum, we stand by our conclusion that “conducting further studies examining a gross deficit(s) in olfaction functioning across schizotypy, broadly defined, is not a particularly promising endeavor”. An equally important conclusion, noted in our article, is that “olfaction deficits may be useful in teasing out relative risk for individuals vulnerable to schizophrenia-pathology” (p. 155) (Cohen et al., 2012). Sincerely, Alex Cohen, Laura Brown, Tracey Auster. P.S. Please note that the effect sizes reported in Cohen et al. (2012) were Hedges d values computed using MetaWin software (Rosenberg et al., 2000). Presumably, the authors computed Cohen's d values, which may explain the minor discrepancies. References Calkins, M.E., Dobie, D.J., Cadenhead, K.S., Olincy, A., Freedman, R., Green, M.F., Greenwood, T.A., Gur, R.E., Gur, R.C., Light, G.A., Mintz, J., Nuechterlein, K.H., Radant, A.D., Schork, N.J., Seidman, L.J., Siever, L.J., Silverman, J.M., Stone, W.S., Swerdlow, N.R., Tsuang, D.W., Tsuang, M.T., Turetsky, B.I., Braff, D., 2007. The consortium on the genetics of endophenotypes in schizophrenia: model recruitment, assessment, and endophenotyping methods for a multisite collaboration. Schizophr. Bull. 33 (1), 33–48. Cohen, A.S., Brown, L.A., Auster, T.L., 2012. Olfaction, “olfiction” and the schizophreniaspectrum. Schizophr. Res. 135, 152–157. Doty, R.L., Shaman, P., Dann, M., 1984. University of pennsylvania smell identification test: a standard microencapsulated test of olfactory function. Physiol. Behav. 32 (3), 489–502. Gottesman, I.I., Gould, T.D., 2003. The endophenotype concept in psychiatry: etymology and strategic intentions. Am. J. Psychiatry 160 (4), 636–645.
Letter to the Editor Meehl, P., 1962. Schizotaxia, schizotypy, schizophrenia. Am. Psychol. 17, 827–838. Moberg, P.J., Agrin, R., Gur, R.E., Gur, R.C., Turetsky, B.I., Doty, R.L., 1999. Olfactory dysfunction in schizophrenia: a qualitative and quantitative review. Neuropsychopharmacology 21 (3), 325–340. Rosenberg, M.S., Adams, D.C., Gurevitch, J., 2000. MetaWin: Statistical Software for Meta-Analysis. Sinauer Associates, Inc., Sunderland, Massachusetts. Turetsky, B.I., Hahn, C.G., Borgmann-Winter, K., Moberg, P.J., 2009. Scents and nonsense: olfactory dysfunction in schizophrenia. Schizophr. Bull. 35 (6), 1117–1131. Turetsky, B.I., Kamath, V., Calkins, M.E., Brewer, W.J., Wood, S.J., Pantelis, C., Seidman, L.J., Malaspina, D., Good, K.P., Kopala, L.C., Moberg, P.J., in press. Olfaction and schizophrenia clinical risk status: just the facts. Schizophr. Res. Walker, E., Kestler, L., Bollini, A., Hochman, K.M., 2004. Schizophrenia: etiology and course. Annu. Rev. Psychol. 55, 401–430.
263
Alex S. Cohen* Laura A. Brown Tracey L. Auster Department of Psychology, Louisiana State University, United States ⁎Corresponding author at: Department of Psychology, Louisiana State University, 206 Audubon Hall, Baton Rouge, LA 708080, United States. E-mail address: [email protected] (A.S. Cohen). 2 April 2012
Contents lists available at SciVerse ScienceDirect
Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Letter to the Editor Clarifying the nature of olfaction deficits in the schizophreniaprone: “Clinical high-risk state” versus “vulnerability”
Dear Editors,
We very much appreciate the comments made by the authors of “Olfaction and Schizophrenia Clinical Risk Status: Just the Facts,” as well as the opportunity by the editor of Schizophrenia Research to clarify our position. We agree wholeheartedly with each of Turetsky et al. (in press) “facts” outlined in their letter, and agree with the authors' conclusions that olfaction appears to be a promising “viable biomarker of the psychosis clinical high-risk state.” Further, we do not believe that their conclusions are in contradiction with any of the conclusions discussed in Cohen et al. (2012) – notably that “conducting further studies examining a gross deficit(s) in olfaction functioning across schizotypy, broadly defined, is not a particularly promising endeavor.” We believe there is an important distinction to be made between the terms appearing in our article – “vulnerability marker” and “schizotypy” and the term used by Turetsky et al. (in press) – “Clinical risk status.” Vulnerability is a foundational term in schizophrenia research and forms a critical basis of the vulnerability-stress model of schizophrenia (e.g., Walker et al., 2004). The notion is that genetic, environmental and other factors confer a vulnerability to schizophrenia pathology — but that it is the interaction with other factors that “unlock” phenotypic expression. From this neurodevelopmental perspective, the majority of individuals with vulnerability to schizophrenia do not meet criteria for a schizophrenia-spectrum disorder at any point during their lifetime despite showing a host of subclinical schizophrenia-like characteristics. Some heuristic neurodevelopmental models suggest that this vulnerable population, often described in terms of “schizotypy,” is quite large (e.g., 10% of the population; Meehl 1962). A number of operational definitions have been advanced to objectify the term “vulnerability marker,” at least in regards to biological or genetic factors. These definitions generally require a candidate marker to show evidence of heritability as well as manifestation, albeit attenuated in magnitude, in unaffected biological relatives of patient probands (e.g. Gottesman and Gould 2003; Calkins et al., 2007). In this regard, there were two findings from our meta-analysis that are inconsistent with the notion that olfaction deficits reflect a vulnerability marker for schizophrenia-spectrum pathology. First, unaffected biological family members of patients showed an effect size difference from controls on the order of one-fifth of a standard deviation. For point of reference, of the five studies examining biological family members reporting all items from the University of Pennsylvania Smell Identification Test reviewed in our meta-analysis (UPSIT; Doty et al., 1984), family members of patients scored, on average, .50 of a single item (of 40 total items possible) lower than family members of controls. Second, individuals with psychometrically-defined schizotypy, identified based on self-report of subclinical schizophrenia-like symptoms/traits, showed negligible differences in olfaction 0920-9964/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2012.04.010
identification compared to controls. To help clarify our position, we offer the following: Are olfaction deficits important for understanding schizophrenia? Unquestionably yes. The results of our meta-analysis (also see Moberg et al., 1999; Turetsky et al., 2009) provide clear evidence that olfaction deficits are profound in patients with schizophrenia. Are olfaction deficits predictive of clinical risk status? The results of our meta-analysis and the author's letter provide compelling evidence that individuals at “ultra-high” risk for developing schizophrenia show pronounced olfaction deficits. In light of this, and the longitudinal data discussed in Turetsky et al.'s (in press) letter, olfaction deficits may reflect a marker differentiating individuals most likely to develop schizophrenia symptoms from the larger vulnerable population. Are olfaction deficits a vulnerability marker of schizophrenia-spectrum pathology? Insofar as biological family members of patients with schizophrenia and individuals with psychometrically-defined schizotypy do not show meaningful levels of olfaction identification deficits, we believe it is difficult to make the case that olfaction deficits are a meaningful vulnerability marker for schizophrenia-spectrum pathology. Caveats — It is important to highlight limitations of the existing literature (see Cohen et al., 2012 for elaboration of each these points), notably that: a) existing measures of olfaction ability may be insufficiently sensitive for detecting deficits in higher functioning populations, b) olfaction acuity, as opposed to identification, may be impaired in schizotypy, c) subjective appraisal of olfactory stimuli may be abnormal in vulnerable populations, and d) schizotypy and schizophrenia are heterogeneous constructs. In sum, we stand by our conclusion that “conducting further studies examining a gross deficit(s) in olfaction functioning across schizotypy, broadly defined, is not a particularly promising endeavor”. An equally important conclusion, noted in our article, is that “olfaction deficits may be useful in teasing out relative risk for individuals vulnerable to schizophrenia-pathology” (p. 155) (Cohen et al., 2012). Sincerely, Alex Cohen, Laura Brown, Tracey Auster. P.S. Please note that the effect sizes reported in Cohen et al. (2012) were Hedges d values computed using MetaWin software (Rosenberg et al., 2000). Presumably, the authors computed Cohen's d values, which may explain the minor discrepancies. References Calkins, M.E., Dobie, D.J., Cadenhead, K.S., Olincy, A., Freedman, R., Green, M.F., Greenwood, T.A., Gur, R.E., Gur, R.C., Light, G.A., Mintz, J., Nuechterlein, K.H., Radant, A.D., Schork, N.J., Seidman, L.J., Siever, L.J., Silverman, J.M., Stone, W.S., Swerdlow, N.R., Tsuang, D.W., Tsuang, M.T., Turetsky, B.I., Braff, D., 2007. The consortium on the genetics of endophenotypes in schizophrenia: model recruitment, assessment, and endophenotyping methods for a multisite collaboration. Schizophr. Bull. 33 (1), 33–48. Cohen, A.S., Brown, L.A., Auster, T.L., 2012. Olfaction, “olfiction” and the schizophreniaspectrum. Schizophr. Res. 135, 152–157. Doty, R.L., Shaman, P., Dann, M., 1984. University of pennsylvania smell identification test: a standard microencapsulated test of olfactory function. Physiol. Behav. 32 (3), 489–502. Gottesman, I.I., Gould, T.D., 2003. The endophenotype concept in psychiatry: etymology and strategic intentions. Am. J. Psychiatry 160 (4), 636–645.
Letter to the Editor Meehl, P., 1962. Schizotaxia, schizotypy, schizophrenia. Am. Psychol. 17, 827–838. Moberg, P.J., Agrin, R., Gur, R.E., Gur, R.C., Turetsky, B.I., Doty, R.L., 1999. Olfactory dysfunction in schizophrenia: a qualitative and quantitative review. Neuropsychopharmacology 21 (3), 325–340. Rosenberg, M.S., Adams, D.C., Gurevitch, J., 2000. MetaWin: Statistical Software for Meta-Analysis. Sinauer Associates, Inc., Sunderland, Massachusetts. Turetsky, B.I., Hahn, C.G., Borgmann-Winter, K., Moberg, P.J., 2009. Scents and nonsense: olfactory dysfunction in schizophrenia. Schizophr. Bull. 35 (6), 1117–1131. Turetsky, B.I., Kamath, V., Calkins, M.E., Brewer, W.J., Wood, S.J., Pantelis, C., Seidman, L.J., Malaspina, D., Good, K.P., Kopala, L.C., Moberg, P.J., in press. Olfaction and schizophrenia clinical risk status: just the facts. Schizophr. Res. Walker, E., Kestler, L., Bollini, A., Hochman, K.M., 2004. Schizophrenia: etiology and course. Annu. Rev. Psychol. 55, 401–430.
263
Alex S. Cohen* Laura A. Brown Tracey L. Auster Department of Psychology, Louisiana State University, United States ⁎Corresponding author at: Department of Psychology, Louisiana State University, 206 Audubon Hall, Baton Rouge, LA 708080, United States. E-mail address: [email protected] (A.S. Cohen). 2 April 2012