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


Gary Remington’s Comments 


       The dopamine hypothesis fundamentally changed schizophrenia in many ways. It is hard to believe now, but the introduction of chlorpromazine and the subsequent research related to “neuroleptics” represented a cornerstone in establishing this illness as, at least in part, biological, a position that was still debated at that time. As pointed out in their perspective, the D2 model has certainly stood the test of time in terms of hypotheses forwarded to explain psychosis.

       This said, it has faced challenges. Briefly summarizing, the evolution of these drugs quickly transitioned from low, e.g., chlorpromazine, to high potency D2 antagonists, haloperidol the prototype. From a clinical perspective, however, both groups of agents still remained ineffective in a number of patients (Remington, Agid, Foussias et al. 2015). This called into question the D2 hypothesis, at least for a subpopulation of those with schizophrenia, a question that would be complicated further when clozapine was reintroduced in the 1980s and found to be effective in what would come to be called “treatment resistant schizophrenia” (TRS) (Kane, Honigfeld, Singer and Meltzer 1998).

       Access to neuroimaging would add to (and complicate) this story. By the early 1990s, evidence indicated that both clinical response and risk of extrapyramidal symptoms (EPS) could be linked to D2 thresholds (Kapur and Remington 1996). At the same time, it was confirmed that non-response was not the result of suboptimal D2 occupancy (Wolkin, Barouche, Wolf et al. 1989). Moreover, clozapine itself challenged the D2 threshold findings (Kapur, Zipursky and Remington 1999).

       By the late 1990s, the merit of the D2 hypothesis and whether D2 occupancy is necessary was being questioned (Pickar 1998). Seminal work coming out of Dr. Seeman’s lab would force us to revisit this (Kapur and Seeman 2001; Seeman and Tallerico 1998), leading to the position that high and sustained D2 occupancy is not necessary to maintain response (Seeman and Remington 2012). By this point, though, other lines of investigation had us looking beyond dopamine for different reasons. Schizophrenia had transitioned and was now framed as a heterogeneous illness with multiple symptom domains, e.g., positive, negative, cognitive (Remington, Agid, Foussias et al. 2015). This, of course, opened the door for numerous other models that might explain facets of schizophrenia beyond psychosis.

       If we only focus on psychosis, though, there is still the issue of limited response. As many as 30% of patients demonstrate a suboptimal response to non-clozapine antipsychotics (Brenner, Dencker, Goldstein, et al. 1990), and even in those with TRS, clozapine efficacy is in the range of 60% (Siskind, Siskind and Kisely 2017).

       Greater consideration is now given to the notion that psychosis may not be unitary. Certainly, we know that symptoms within this framework can respond differentially and the case has been made that psychosis and its pharmacological response can vary one condition to another (Goldman, Vaughan and Goetz 2011; Kircher, Brohl, Meier and Engelen 2018). To this last point, it is worth noting that the U.S. FDA recently approved a serotonin 5-HT inverse agonist, pimavanserin, for the psychosis of Parkinson’s disease (Patel, Bhela, Tahir et al. 2019).

       Summarizing, there is still much to learn about psychosis, and in this context it is critical that we acknowledge that antipsychotics are not anti-schizophrenia drugs (Remington, Foussias, Agid et al. 2012). In terms of psychosis specifically, whether “all roads” lead to dopamine (Seeman 2011) remains a work in progress and research related to elevation of D2High receptors, particularly from the standpoint of neuroimaging, represents an important line of investigation that needs to be addressed.



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June 3, 2021