A challenge to the dopamine orthodoxy in schizophrenia?
The hypothesis has formed a useful drug discovery paradigm to the extent that all currently approved treatments can be considered to conform to a dopaminergic view of schizophrenia/antipsychotic drug action.
Abstract
According to Kuhn’s argument science progresses by ‘paradigm shifts’ (Kuhn, 1962), an expression now so accepted that it has become entrenched in the lexicon of multiple disciplines. Kuhn’s classic examples included the shift from the Ptolemaic geocentric view of the planetary system to the Copernican heliocentric notion. On the horizon for the treatment of schizophrenia are non-dopaminergic acting agents which, if primary pharmacological actions mean anything at all, sit uncomfortably within the prevailing dopamine paradigm of antipsychotic drug action. Does the advent of such agents herald a Kuhnian ‘revolution’ in the understanding of antipsychotic drug action with an attendant ‘paradigm shift’ from the dopamine hypothesis of schizophrenia? When introduced into clinical practice seven decades ago, chlorpromazine was rightly considered a breakthrough treatment for schizophrenia. It enabled many patients, who would otherwise have been confined long-term to mental hospitals, to be discharged to the community. While there were significant therapeutic benefits, these were offset by the associated neurological side effects (Stroup et al., 2000). The intervening years have resulted, arguably, in little in the way of improved efficacy with respect to the pharmacological treatment of the positive and negative symptoms, but current medications have a somewhat more benign neurological side effect profile (Stroup et al., 2000). Nevertheless, like the prototypical phenothiazine antipsychotic medications, current drugs are believed to derive their therapeutic benefits, at least in part, by antagonism/partial agonism at the dopamine D2 class of receptors (this includes D2-Short, D2-Long, D3 and D4 receptors) (Ginovart and Kapur, 2012). Recognition of the pharmacological actions of medications contributed significantly to an initial formulation of a dopamine hypothesis of schizophrenia. A more sophisticated iteration of the hypothesis focussed on the activity of dopamine within specific neuronal circuits. Overactivity of dopamine within the mesolimbic pathway is postulated to be responsible for positive symptoms of the disorder, while underactivity in meso-cortical pathways is posited to be responsible for negative and cognitive symptoms (Stahl, 2004). Within this framework of the modified hypothesis, alterations of the activity of other neurotransmitter systems (most notably a hypoactive glutamatergic system) have been accommodated. Although the hypothesis has been criticised as too reliant on the inference from drug effects to underlying disease process (Moncrieff, 2009), it nevertheless remains a plausible explanation of some symptoms of the disorder. The hypothesis has formed a useful drug discovery paradigm to the extent that all currently approved treatments can be considered to conform to a dopaminergic view of schizophrenia/antipsychotic drug action. Pre-clinical and early phase studies indicate that molecules without a primary dopamine D2-antagonist/partial agonist effect may be effective for the treatment of schizophrenia. At face value, the efficacy of such compounds questions the continuing utility of the dopamine hypothesis. A case in point is that of ulotaront (SEP-363856), which is in the preliminary stages of clinical evaluation. Ulotaront is a trace amine-associated receptor (TAAR-1) and 5HT1A agonist. In pre-clinical studies the molecule blocked phencyclidine (PCP)-induced hyperactivity, pre-pulse inhibition and PCP-induced deficits in social interaction and cognition, widely used mouse phenotypes for antipsychotic drug discovery (Dedic et al., 2019). A short-term (4-week) double-blind, placebo-controlled trial showed superiority for the active compound in treating relapse of schizophrenia (Koblan et al., 2020). In the open label continuation phase of this study ulotaront maintained efficacy over 6 months (Correll et al., 2021). Clearly, further clinical evaluations are necessary to robustly establish clinical efficacy. Nevertheless, taken together the two parts of this study offer preliminary validation of non-dopaminergic mechanisms as A challenge to the dopamine orthodoxy in schizophrenia?