Tuesday, 18.05.2021

Philip Seeman and Mary Seeman: The Dopamine Hypothesis of Schizophrenia in Historical Perspective


George Awad’s comment


       The early observations by Jacques M. von Rossum (1967) about the impact of enhanced dopaminergic activities in the brain exacerbating psychotic state and which could be reversed by such dopamine blocking agents as chlorpromazine, proved to be the key for the subsequent evolvement of the “dopamine hypothesis.”

       The hypothesis was subsequently confirmed, refined and expended by the important and extensive contributions by Phil Seeman and colleagues demonstrating that all antipsychotics could block specific dopamine receptors in direct relation to their clinical potency (Seeman, Chau-Wong, Tedesco and Wong 1975). Though Seeman et al initially noted only a small increase, about 6%, in dopamine receptors in the postmortem brains of patients with schizophrenia, more recent studies reported higher figures, about 11%. By now it is clear that baseline dopamine functioning in specific regions of the brain of non-medicated patients with schizophrenia can be markedly variable. We had come to such conclusion in the major neuroimaging study about “neuroleptic induced dysphoria” by Dr. Lakshimi Voruganti and me using a depletion SPECT approach and simultaneously quantifying the baseline striatal dopamine function with (123)IBZM-SPECT imaging (Voruganti, Slomka, Zabel et al. 2001; Voruganti and Awad 2006). Mary Seeman had kindly served as a member of the supervisory committee for Voruganti’s PhD thesis.

       Over the years, the dopamine hypothesis has gained wide support and continued its popularity as the only hypothesis that stood the test of time. Not only that the dopamine hypothesis has shaped the development of broad range of antipsychotic medications based on the principal of dopamine blockade, the dopamine hypothesis has reached beyond the development of medications as it got also implicated in the pathophysiology of psychotic states including schizophrenia. Though it was envisaged by von Rossum (1967) that antipsychotic medications like chlorpromazine could alleviate symptoms across the three dimensions of symptoms, positive, negative and cognitive, such optimistic prediction did not fully materialize.

       As it became widely recognized, antipsychotic medications, old and new, proved effective for the treatment of positive psychotic symptoms but much less or none against negative and cognitive symptoms dimensions. Furthermore, recent research findings, including ours, raised the question of whether the three dimensions, positive, negative and cognitive, though frequently associated, are independent of each other pointing to the possibility of different etiological neuro-psychopathology. Such new thinking has at last opened the door after long resistance from the FDA to accept the development of specific medications for the treatment of a single dimension as negative or cognitive.

       As I argue in my forthcoming book, I do believe that several major studies in schizophrenia may have ended in failure or just been partly successful as a result of using the DSM formula of three dimensions as the starting point of selecting the samples.

       I do believe that deconstructing schizophrenia and using a dimensional approach has better chance of leading to success, particularly that psychotic symptoms cut across several conditions with different diagnoses such as dementia or drug induced… etc.

       If such approach gets validated and accepted by researchers, maybe the time has come to do without the frightening title of schizophrenia. Though I am not in favor of historical revisionism, in this case it may be worth the effort.



Seeman P, Chau-Wong M, Tedesco J, Wong K. Brain Receptors for antipsychotic drugs and dopamine: direct binding assays. Proc Natl Acad Sci USA, 1975;72:4376-80. 

Van Rossum JM. The significance of dopamine-receptor blockade for the action of neuroleptic drugs. In: Brill H, Cole JO, Deniker P, Hippius H, Bradley PB, editors. Neuro-Psycho-Pharmacology, Proceeding of the Fifth International Congress of the Collegium Internationale Neuro-Psycho-Pharmacologicum, March 1966. Amsterdam: Excerpta Medica Foundation;1967, pp. 321-9. 

Voruganti L, Slomka P, Zabel P, Costa G, So A, Mattar A, Awad AG. Subjective Effects of AMPT-Induced Dopamine Depletion in Schizophrenia: Correlation between Dysphoric and Striatal D2 Binding Ratio on SPECT Imaging. Neuro-Psycho-Pharmacology, 2001;25:642-50. 

Voruganti LNP, Awad AG. Subjective and Behavioral Consequences of Striatal Dopamine Depletion in Schizophrenia- finding from an in-vivo SPECT study. Schizophren Res, 2006;88:179-86.


April 1, 2021