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Understanding the pathophysiology of schizophrenia: Are we on the wrong or on the right track?
Schizophrenia Research 127 (2011) 20–21
Contents lists available at ScienceDirect
Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Invited Commentary
Understanding the pathophysiology of schizophrenia: Are we on the wrong or on the right track? Mario Maj Department of Psychiatry, University of Naples SUN, Naples, Italy
There is at present a remarkable disenchantment and skepticism among clinicians and the general public worldwide about the perspective that a solid understanding of the pathophysiology of schizophrenia be achieved in the near future. Too much has been promised along the years; too many findings and theories have been presented as major breakthroughs to be then rapidly dismissed or forgotten. The huge mass of “data” or “evidence” which is being accumulated in this area is not perceived anymore as an indication of a continuing increase of “knowledge”. Rather, this mass of data, with its inconsistencies and with the postulated involvement of so many different cerebral structures, neuronal circuits and neurotransmitters, is increasingly seen as a sign of uncertainty and confusion. What is even worse, carers of people with schizophrenia do not follow pathophysiological research on the disease with the same attention and hope as carers of people with chronic and disabling physical diseases. They either do not believe in that research (being continuously reinforced in this attitude by the inputs of the media and of part of the psychiatric profession) or do not expect that research to generate in the near future anything which may help them in any way. A superficial reading of the comprehensive and informative paper by Keshavan et al. (2011) may reinforce the above perceptions and attitudes. The unsophisticated reader, comparing the meager list of “facts” on schizophrenia presented in Table 1 with the huge list of “extant models” of the disease summarized in Table 2, may conclude that several decades of research, with a substantial investment of financial and human resources, have produced a very modest outcome. The listed “facts” about schizophrenia mostly pertain to its clinical picture, course and epidemiology, whereas the “facts” concerning etiology or pathogenesis are very few, not specific and certainly not an outcome of recent research. A pessimistic view of this situation is that we are on the wrong track. Perhaps there is not a disease entity
E-mail address: [email protected]. 0920-9964/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2011.01.002
corresponding to what we call schizophrenia; or several disease entities with a different etiology and/or pathogenesis are being subsumed under that heading; or there is indeed a disease entity, but the relevant phenotype is not appropriately delineated; or there is a disease entity, but the biological level at which our current research efforts are being displayed (e.g., neuronal circuits, neurotransmitters) is very far from the one at which a convincing explanation of the disease is likely to be found; or brain dysfunctions can only account for a vulnerability to something which emerges at the interface between the brain and the world of interpersonal relationships (so that many different brain dysfunctions can be found in patients with schizophrenia, but the essence of the disease cannot be delineated at that level). Each of these options, and possibly several others, deserve to be better articulated and carefully explored. An optimistic view is that we are on the right track, but we are dealing with a condition that is very complex, much more than those which are the subject of investigation of the other branches of medicine. The functions which are perturbed in schizophrenia are the most complex of human beings. Most of them involve an interaction between such a composite organ as the brain and the even more composite world of interpersonal relationships in which all of us are immersed. It is not surprising that research is progressing so slowly and that many alternative avenues are being pursued. Our current technology and modeling may not be adequate to address that complexity, and the future may bring about very important advances in this respect. Furthermore, we cannot expect a single model to explain all the constituents of the complex picture: “decomposing” the disease in its various elements may be very helpful. On the other hand, the many extant models of the disease should not be regarded as mutually exclusive: they may address different levels of the complexity and may turn out to be consistent with each other. Trying to integrate the models and the pieces of evidence, or “connecting the dots”, may be a useful exercise, but premature or unwarranted “connections” should be avoided, because they may be perceived as less convincing
M. Maj / Schizophrenia Research 127 (2011) 20–21
than the pieces of evidence they try to integrate, thus reinforcing rather than lessening the above-mentioned disenchantment and skepticism. In any case, current operational diagnostic criteria for schizophrenia are not proving to be an adequate basis for research efforts. Schizophrenia is defined in these criteria by what it is not, rather than by what it is (Maj, 1998). The symptomatological, chronological and functional criteria, taken together, can be fulfilled by several cases of major depression, mania or dementia. The exclusion criterion becomes, therefore, decisive for the diagnosis. A patient selection essentially based on an exclusion criterion is unlikely to generate really homogeneous samples for research. The addition of a dimensional characterization to the categorical diagnosis is not likely to substantially modify this situation. What is probably needed is a reformulation of the prototype of schizophrenia, on the basis of classical descriptions and more recent acquisitions (e.g., those concerning the psychopathology of intersubjectivity). Patients could be classified on the basis of their degree of typicality, and pathophysiological research could focus on the most typical cases, or its findings could be correlated with the degrees of typicality. A reformulation of the prototype of schizophrenia could also allow the correction of some inadequacies of the current psychopathological
21
characterization of the disease (e.g., the conceptualization of passivity experiences as delusions) and help to bridge the gap between a biological research which often lacks psychopathological sophistication and a psychopathological inquiry which sometimes pays too little attention to empirical validation. Role of funding source There was no funding source.
Contributors Prof. Mario Maj is the only author.
Conflict of interest Prof. Maj has no conflict of interest to declare.
Acknowledgement None.
References Keshavan MS, Tandon R, Nasrallah HA., 2011. Schizophrenia, "Just the Facts" 6. Moving ahead with the schizophrenia concept: From the elephant to the mouse. Schizophr Res. 127, 3-13 (this issue). Maj, M., 1998. Critique of the DSM-IV operational diagnostic criteria for schizophrenia. Br. J. Psychiatry 172, 458–460.
Contents lists available at ScienceDirect
Schizophrenia Research j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / s c h r e s
Invited Commentary
Understanding the pathophysiology of schizophrenia: Are we on the wrong or on the right track? Mario Maj Department of Psychiatry, University of Naples SUN, Naples, Italy
There is at present a remarkable disenchantment and skepticism among clinicians and the general public worldwide about the perspective that a solid understanding of the pathophysiology of schizophrenia be achieved in the near future. Too much has been promised along the years; too many findings and theories have been presented as major breakthroughs to be then rapidly dismissed or forgotten. The huge mass of “data” or “evidence” which is being accumulated in this area is not perceived anymore as an indication of a continuing increase of “knowledge”. Rather, this mass of data, with its inconsistencies and with the postulated involvement of so many different cerebral structures, neuronal circuits and neurotransmitters, is increasingly seen as a sign of uncertainty and confusion. What is even worse, carers of people with schizophrenia do not follow pathophysiological research on the disease with the same attention and hope as carers of people with chronic and disabling physical diseases. They either do not believe in that research (being continuously reinforced in this attitude by the inputs of the media and of part of the psychiatric profession) or do not expect that research to generate in the near future anything which may help them in any way. A superficial reading of the comprehensive and informative paper by Keshavan et al. (2011) may reinforce the above perceptions and attitudes. The unsophisticated reader, comparing the meager list of “facts” on schizophrenia presented in Table 1 with the huge list of “extant models” of the disease summarized in Table 2, may conclude that several decades of research, with a substantial investment of financial and human resources, have produced a very modest outcome. The listed “facts” about schizophrenia mostly pertain to its clinical picture, course and epidemiology, whereas the “facts” concerning etiology or pathogenesis are very few, not specific and certainly not an outcome of recent research. A pessimistic view of this situation is that we are on the wrong track. Perhaps there is not a disease entity
E-mail address: [email protected]. 0920-9964/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.schres.2011.01.002
corresponding to what we call schizophrenia; or several disease entities with a different etiology and/or pathogenesis are being subsumed under that heading; or there is indeed a disease entity, but the relevant phenotype is not appropriately delineated; or there is a disease entity, but the biological level at which our current research efforts are being displayed (e.g., neuronal circuits, neurotransmitters) is very far from the one at which a convincing explanation of the disease is likely to be found; or brain dysfunctions can only account for a vulnerability to something which emerges at the interface between the brain and the world of interpersonal relationships (so that many different brain dysfunctions can be found in patients with schizophrenia, but the essence of the disease cannot be delineated at that level). Each of these options, and possibly several others, deserve to be better articulated and carefully explored. An optimistic view is that we are on the right track, but we are dealing with a condition that is very complex, much more than those which are the subject of investigation of the other branches of medicine. The functions which are perturbed in schizophrenia are the most complex of human beings. Most of them involve an interaction between such a composite organ as the brain and the even more composite world of interpersonal relationships in which all of us are immersed. It is not surprising that research is progressing so slowly and that many alternative avenues are being pursued. Our current technology and modeling may not be adequate to address that complexity, and the future may bring about very important advances in this respect. Furthermore, we cannot expect a single model to explain all the constituents of the complex picture: “decomposing” the disease in its various elements may be very helpful. On the other hand, the many extant models of the disease should not be regarded as mutually exclusive: they may address different levels of the complexity and may turn out to be consistent with each other. Trying to integrate the models and the pieces of evidence, or “connecting the dots”, may be a useful exercise, but premature or unwarranted “connections” should be avoided, because they may be perceived as less convincing
M. Maj / Schizophrenia Research 127 (2011) 20–21
than the pieces of evidence they try to integrate, thus reinforcing rather than lessening the above-mentioned disenchantment and skepticism. In any case, current operational diagnostic criteria for schizophrenia are not proving to be an adequate basis for research efforts. Schizophrenia is defined in these criteria by what it is not, rather than by what it is (Maj, 1998). The symptomatological, chronological and functional criteria, taken together, can be fulfilled by several cases of major depression, mania or dementia. The exclusion criterion becomes, therefore, decisive for the diagnosis. A patient selection essentially based on an exclusion criterion is unlikely to generate really homogeneous samples for research. The addition of a dimensional characterization to the categorical diagnosis is not likely to substantially modify this situation. What is probably needed is a reformulation of the prototype of schizophrenia, on the basis of classical descriptions and more recent acquisitions (e.g., those concerning the psychopathology of intersubjectivity). Patients could be classified on the basis of their degree of typicality, and pathophysiological research could focus on the most typical cases, or its findings could be correlated with the degrees of typicality. A reformulation of the prototype of schizophrenia could also allow the correction of some inadequacies of the current psychopathological
21
characterization of the disease (e.g., the conceptualization of passivity experiences as delusions) and help to bridge the gap between a biological research which often lacks psychopathological sophistication and a psychopathological inquiry which sometimes pays too little attention to empirical validation. Role of funding source There was no funding source.
Contributors Prof. Mario Maj is the only author.
Conflict of interest Prof. Maj has no conflict of interest to declare.
Acknowledgement None.
References Keshavan MS, Tandon R, Nasrallah HA., 2011. Schizophrenia, "Just the Facts" 6. Moving ahead with the schizophrenia concept: From the elephant to the mouse. Schizophr Res. 127, 3-13 (this issue). Maj, M., 1998. Critique of the DSM-IV operational diagnostic criteria for schizophrenia. Br. J. Psychiatry 172, 458–460.