Revisiting the Concept of Subjective Tolerability to Antipsychotic Medications in Schizophrenia and its Clinical and Research Implications: 30 Years Later.

Schizophrenia is a long-term psychiatric disorder that impacts important mental functions and requires indefinite treatment, as well as psychosocial and economic support. The introduction of chlorpromazine, the first antipsychotic, and the subsequent development of a long list of similar dopamine-blocking antipsychotic medications, has changed the treatment of schizophrenia as medications have become the cornerstone of clinical management. The enthusiasm that greeted the introduction of antipsychotics was soon tempered by the realisation that they induced significant side effects, such as extrapyramidal and autonomic symptoms. A less-recognized side effect at the time was the emergence of subtle subjective side effects that led patients to dislike medications and eventually discontinue them, with serious consequences of frequent relapses requiring hospitalization, poor outcomes and more health costs. The development of our dedicated programme for research into subjective tolerability to medications over the past 30 years has allowed us to establish the validity of the construct of 'subjective tolerability' to antipsychotics, applying research methodologies that are required for any scientific inquiry. We clarified definitions, developed reliable measuring tools, and constructed psychosocial and neurobiological conceptual models. We also documented the serious consequences of negative subjective tolerability to antipsychotics: poor medication adherence behaviour, impaired quality of life, and worse clinical and functional outcomes. More recently, using neuroimaging techniques, we and other international research groups were able to clearly elucidate the neurobiology of dysphoric negative subjective responses, linking it to low dopamine functioning in the striatal region of the brain. Such a discovery for the first time allowed us to also link the development of comorbid drug abuse in schizophrenia, which is a common occurrence, to the development of neuroleptic dysphoria, since both relate to the low dopamine function in the striatum. As an already validated scientific concept that has serious consequences, subjective tolerability to antipsychotics can serve as a model for patient-centered outcomes that really matter. Our long-serving research programme also illustrates the value of clinical observations to the development of important clinical research studies, i.e. from the bedside to the research bench, and back to the bedside.