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Wednesday, 01.04.2020

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

Update (Volume Nine): 1. Pharmacogenetics and Genetics and Neuropsychopharmacology

(Bulletin 69)

 

            In the first eight volumes of this 10-volume series interviewees reflect on their contributions to the development of neuropsychopharmacology. Volume One: Starting Up (behavioural pharmacology); Volume Two: Neurophysiology (electrophysiology & brain imaging); Volume Three: Neuropharmacology; Volume Four: Psychopharmacology; Volume Five: Neuropsychopharmacology; Volume Six: Addiction; Volume Seven: Special Areas (child psychiatry, geriatric psychiatry, diagnosis and pharmacokinetics); Volume Eight: Diverse Topics (Ban 2011). Volume Nine (Update) differs from all prior volumes in that it includes a second interview that complements and updates the information in the first interviews. These second interviews were not planned; they were done on request of the interviewees or others, most often for the purpose of adding to the information covered in the first interview (Blackwell 2011).

            In Volume Nine, interviewees contributed to diverse areas of research in neuropsychopharmacology. Hence, in the same way as in Volume Eight (Diverse Topics), the information in the transcripts provides the prime material for an overview of the changes which have taken place in neuropsychopharmacology since the 1950s.  

            During its first 50 years neuropsychopharmacology was a rapidly evolving field. In the 1960s behavioral pharmacology was replaced by neuropharmacology in the screening and preclinical development of psychotropic drugs. In the 1970s research in neuropharmacology was extended from cerebral monoamines to neurotransmitter modulators, peptides and prostaglandins; interest shifted from pre-synaptic to post-synaptic mechanisms; and studies of neurotransmitter biochemistry were supplemented with studies on receptor affinities (Carlsson 2000). In the 1980s electrophysiological studies were complemented by studies of brain metabolism with the employment of brain imaging and research studies on the effect of drugs on “wiring transmission” by studies on the effect of drugs on “volume transmission” (Agnati, Fuxe, Zoli et al. 1986; Ban and Ucha Udabe 2006). 

            In the 1990s, with the sequencing of the human genome from 1989 to 2004, a molecular genetic (pharmacogenetic) approach emerged and in a decade replaced the “traditional” biochemical approach in the study of the biology of mental illness (Waterson, Lauder and Sulston 2002). By the dawn of the 21st century, the neurotransmitter era, the first epoch in the history of neuropsychopharmacology was succeeded by a molecular genetic era, opening up a new perspective for developing psychotropic drugs.

            The subject matter of this volume is the charting of this rapid transformation of the field in the thoughts, writings and research of the interviewees.

            As in all prior volumes in this series, the first part of the Preface provides orientation points for placing interviewees’ contributions into a historical context and the last part reviews personal contributions. Although there are some overlaps, the vignettes in this volume on interviewees’ contributions differ from the vignettes in prior volumes. In Volume Nine the vignettes are based primarily on what interviewees themselves consider their most important contributions to neuropsychopharmacology, whereas in the other volumes they are based on editor’s judgment about interviewees’ contributions to the particular area of research covered in the volume.  Another difference is that in Volume Nine special attention is paid to early and most recent contributions (Ban 2011b).   

 

Pharmacogenetics   

 

            The term “pharmacogenetics” was coined by Friedrich Vogel in 1959, about six years after James Watson and Francis Crick proposed (in 1953) the “double helix” as the structure of the human DNA (deoxyribonucleic acid) (Lerer 2001; Vogel 1958; Watson and Crick 1958).

            The roots of pharmacogenetics are in Archibald Garrod’s recognition in the first decade of the 20th century that genetic factors “direct” the chemical transformation (metabolism) of drugs in the body (Garrod 1902, 1909; Motulsky 1957). The first systematic account on pharmacogenetics was published in 1962 by Werner Kalow (Kalow 1962).

            Pharmacogenetics studies inter-individual differences in response to drugs. The objective is to identify and characterize genetic factors that underlie differential responsiveness to drugs between groups and between individuals within a group. Accordingly, one area of pharmacogenetic research is focused on the responses of patients with different psychiatric diagnoses to the pharmacodynamic properties of the same drug, whereas another area of research is focused on genetically-based pharmacokinetic differences between members of the same diagnostic group in responding to the same drug (Evans, Manley and McKusick 1960; Evans and White 1969; Lerer 2002).

            The genetics of pharmacokinetic differences entered psychiatric pharmacotherapy in 1960 with Evans and associates’ recognition that the rate of acetylation of isoniazid is under genetic control (Ban 1969). In 1964 they reported that patients who metabolize phenelzine at a relatively lower rate, as measured by the ratio of acetylated to free sulfapyridine in urine after sulfamethazine administration, developed more side effects (Evans, Davidson and Pratt 1964). These findings were complemented by the work of Johnstone who reported in 1966 that “slow acetylators” respond more favorably (Johnstone 1966). Nevertheless, the relationship between acetylator status and response to treatment has remained tenuous; Robinson and associates found no difference between slow and fast acetylators in therapeutic response, side effects and platelet monoamine oxidase inhibition in patients treated with phenelzine (Ravaris, Nies, Robinson et al. 1967; Robinson, Nies, Ravaris et al. 1978). Phenelzine is a monoamine oxidase inhibitor antidepressant that shares with isoniazid and iproniazid a hydrazine moiety.

            The genetics of pharmacodynamic differences entered psychiatry in the 1990s in molecular genetic studies of schizophrenia and manic-depressive illness. On the basis of the mode of action of drugs with demonstrated therapeutic efficacy, various genes which encode transporters (e.g., the serotonin transporter, the dopamine transporter), receptors (e.g., the serotonin-5HT2A receptor, the dopamine-D2 and D3 receptors) and enzymes (e.g., monoamine oxidase, dopamine-β-hydroxylase, catechol-methyl-transferase), have been implicated in the pathophysiology of these diseases. Genetic “association studies,” however, have failed to detect consistent differences in mutations in the implicated genes between normal volunteers and patients with either of these diseases (Heiden, Schussler, Itzlinger et al. 2000; Malhotra and Goldman 1999).

 

Genetics and Neuropsychopharmacology

 

            The observation that mental illness runs in families has been documented since the mid-18th century; the first genetic theory of mental illness was formulated by Morel in the mid-1850s (Battie 1758; Shorter 1997). It was based on the assumption of “degeneration,” the notion that mental disease is the result of an “innate biological defect” that becomes manifest in increasingly severe mental syndromes in “lineal descents” (Morel 1857). Morel’s degeneration theory was replaced by Moebius’ “endogeny theory” in the 1890s which implicated a “constitutionally determined predisposition” for developing mental illness (Moebius 1893). 

              The heredity of mental illness received substantial support in epidemiologic genetic studies. The risk of developing schizophrenia for relatives of patients with schizophrenia and manic-depressive illness was found to be consistently higher than in the general population; the risk of developing the respective illness in both diagnostic groups was found to be higher for first than for second degree relatives (Key 1978; Slater and Cowie 1971). Furthermore, children of schizophrenic biological parents adopted into the  families of non-schizophrenic foster parents  were found to develop schizophrenia at a much higher rate than adopted away children of normal parents and mental illness was found to occur also at a much higher rate in the biological than in the adoptive families  of adopted schizophrenic and manic-depressive children (Heston 1966; Mendlewicz,  and Rainer  1977; Moldin 1999; Wender, Kety, Rosenthal et al.  1986).

            In spite of evidence that mental illness runs in families, molecular genetic studies using “linkage analysis,” “positional cloning” and “genome scanning” yielded inconsistent findings. Susceptibility loci for schizophrenia and manic-depressive illness were reported on various chromosomes (for schizophrenia on 1q, 3p, 5q, 5p, 8q, 9p, 10q, 12q, 13p, 14p, 15q, 20p and 22q; and for manic-depressive illness on chromosomes 4p, 5p, 6p, 18q, 20p, 21q and 22q);  the findings in one group of patients, however, could not be replicated in others (Ban 2002). Failure to replicate findings in a similar diagnostic population from one study to the next indicates genetic heterogeneity within the diagnostic groups. Thus, the heterogeneity within diagnoses interfered with molecular genetic research in mental illness (Ban 2002).

            The inconsistent findings in molecular genetic research lead to growing dissatisfaction with consensus-based classifications (Ban 2001). The unhappiness was such   that in 1999 Steven Hyman, at the time the Director of the US National Institute of Mental Health (NIMH), pointed out that “it would be foolish to think” that diagnostic criteria in classifications like the DSM-IV would “select anything that maps into the genome” (Hyman 1999). It was also recognized that without a re-evaluation of diagnostic concepts in psychiatry it would be futile to employ either a pharmacogenetic or a pharmacogenomic approach to psychotropic drug development (Potter, Van Lone and Altstiel 2002; Shalom and Darvas 2002).

            The problem created by the genetic, pharmacological and psychopathological heterogeneity within diagnoses was compounded by the vanishing from view by the end of the 20th century of the two disciplines of psychiatry, psychopathology and psychiatric nosology, that dealt with the delineation and classification of  “psychiatric diseases.”

 

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Ban TA. Psychopharmacology of Depression. Basel: Karger; 1981. p. 41-2.

Ban TA. From DSM-III to DSM-IV: progress or standstill. In Franzek E, Ungvari T, Ruther E, Beckmann H, editors.  Progress in Differentiated Psychopathology. Hong Kong: Contemporary Development Company; 2001. p. 1-11. 

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

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May 9, 2019