Thomas A. Ban
Neuropsychopharmacology in Historical Perspective
Education in the Field in the Post-Neuropsychopharmacology Era
Background to An Oral History of the First Fifty Years 

Towards a genetic era in neuropsychopharmacology*

Bulletin 76

        During the 1980s diagnoses, based on consensus-based classifications, became the clinical end-points for neuropsychopharmacological research and clinical investigations with psychotropic drugs. Nevertheless, the dissatisfaction with these clinical end points in biological research rapidly grew to the extent that a re-conceptualizations of mental illness in genetically meaningful “discrete neurobiological deficits,” also referred to as “alternative phenotypes,” was proposed in order to replace these diagnoses.  One such an “alternative phenotype” for schizophrenia considered was the “abnormality of smooth pursuit eye movement” linked to a locus on the short arm of chromosome 6 (Arolt, Lencer, Nolte et al. 1996; Holzman, Kringlen, Mathysse et al. 1988). Another “alternative phenotype” considered was the “P-50 evoked response deficit” linked to the α₁-nicotinic acid receptor on the long arm o chromosome 15 (Freedman, Adler and Leonard 1997; Freedman, Coon, Myles–Worseley et al. 1999). Nevertheless, by the late 1990s it was recognized that the usefulness of these “alternative phenotypes” in biological research in schizophrenia was questionable; both “alternative phenotypes” were encountered several times more frequently in the general population than in patients with the diagnosis of schizophrenia (Faraone, Tsuang and Tsuang 1999).

        It has also been suggested replacing traditional classifications of mental illness by a classification rooted in genetics that would assign patients into categories that “correspond with their genes.” While such a classification, as Faraone, Tsuang and Tsuang pointed out, might focus attention on overlaps between certain traits, e.g., depression and anxiety, it would group together individuals who fully qualify for a particular disease and individuals who, despite carrying the genes for the disease, are symptom free (Faraone, Tsuang and Tsuang 1999).

        Recognition that to date there is no alternative methodology to psychopathology for classifying mental pathology in a clinically relevant manner  stimulated interest in linear regression equations for the identification of the treatment responsive form(s) of illness within the currently used diagnoses (Ban 2002). However, findings with linear regression analyses of rating scale scores -- generated in clinical drug trials designed for the demonstration of therapeutic efficacy -- were inconsistent (Ban 1987; Roth and Barnes 1981).

        Rating scales constructed for the assessment of change in the severity of psychopathology are sensitized by the omission of psychopathological symptoms that are not influenced by treatment or by the retention of only those symptoms that show the largest changes (Ban 1999). While sensitized scales are eminently suited for the demonstration of the efficacy of a drug in the shortest possible time in the smallest number of patients, they preclude the possibility of finding any relevant information for the identification of treatment-responsive forms of illness by meta-analyses of the data generated in randomized clinical trials with psychotropic drugs (Ban 2002).

References:

Arolt V, Lence  R, Nolte A, Müller-Myhsok B, Purmann S, Schürmann M, Leutelt J, Pinnow M, Schwinger E. Eye tracking dysfunctions is a putative phenotypic susceptibility marker of schizophrenia and maps to a locus on chromosome 6p in families with multiple occurrence of the disease. Am. J. Med. Genet. 1996; 67, 564-9.

Ban TA. Prolegomenon to the clinical prerequisite: Psychopharmacology and the classification of mental disorders. Progress in Neuro-Psychopharmacology & Biological Psychiatry 1987; 11, 527-80.

Ban TA. Selective drugs versus heterogenous diagnoses towards a new methodology in neuropsychopharmacological research. Psiqiatria Biologica 1999; 7: 177-89.

Ban TA. Neuropsychopharmacology: the interface between genes and psychiatric nosology. In: Lerer B, editor. Pharmacogenetics of Psychotropic Drugs. Cambridge: Cambridge University Press; 2002, pp. 36-56.

Faraone SV, Tsuang M.T, Tsuang DW. Genetics of Mental Disorders. New York: Guilford Press; 1999.

Freedman R, Adler LE, Leonard S. Alternative phenotypes for the complex genetics of schizophrenia. Biol. Psychiatry 1999; 45: 551-8.

Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A, Polymeropoulos M, Holik J, Hopkins J, Hoff M, Rosenthal J, Waldo MC, Reimherr F, Wender P, Yaw J, Young DA, Breese CR, Adams C, Patterson D, Adler LE, Kruglyak L, Leonard S, Byerley W. Linkage of neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci U S A. 1997 Jan 21;94(2):587-92.

Holzman PS, Kringlen E, Mathysse S, Flanagan SD, Lipton RB, Cramer G, Levin S, Lange K, Levy DL. A single dominant gene can account for eye tracking dysfunctions and schizophrenia in offspring of discordant twins. Arch Gen Psychiatry 1988; 45: 641-7.

Roth M, Barnes TRE. The classification of affective disorders: A synthesis of old and new concepts. Compr. Psychiatry 1981; 22: 54-77.

* Based on Thomas A. Ban’s chapter entitled, “Neuropsychopharmacology: the interface between genes and psychiatric nosology,”  in Bernard B. Lerer’s book, “Pharmacogenetics of Psychotropic Drugs,” published by Cambridge University Press in 2002 (pages from 36 to 56).

July 11, 2019