Central nervous system (CNS) drugs are the mainstay of treatment for many patients with psychiatric disorders. However, the pathophysiology of psychiatric disorders in terms of brain function still remains poorly understood, receptor pharmacology of CNS drugs insufficiently explains their effects in psychiatric disease and reliable response- and treatment biomarkers of CNS function for use in psychiatric drug development and -treatment are lacking. In addition, a sizeable proportion of patients only respond partially or do not respond at all to currently registered drugs. Although the reasons for individual differences in drug response in psychiatry remain speculative, heterogeneity of populations with the same psychiatric diagnosis, interindividual variation in terms of neurotransmitter system function and differences in pharmacokinetics (PK) due to comorbid medical illness, age and polypharmacy probably play an important role.
As a psychiatrist I examine individuals with unusual perceptions, frightening or overly rigid ideas, uncontrollable urges and/or extreme emotions on a daily basis. Psychiatrists are trained to identify psychiatric symptoms and to consider them in the context of psychological-, general medical-, epidemiological and social factors. Symptoms that cluster together and are associated with common predisposing factors and/or a specific clinical course, are classified into clinical syndromes as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM), resulting in psychiatric diagnoses such as schizophrenia or generalized anxiety disorder. In contrast to other medical specialties, psychiatric diagnoses do not require the application of objective diagnostic methodologies like blood tests, a lumbar puncture or neuroimaging of the brain since no putative/experimental biomarkers yet reliably discriminate individuals who display a certain psychiatric symptom from healthy individuals. Diagnoses in psychiatry are therefore symptom-based and arguably depend on the psychiatrist’s professional interpretation of additional contextual information. Nonetheless, psychiatrists like other physicians, ultimately want reduce suffering and improve general well-being of patients, and are trained to apply both evidence-based psychotherapy and drug treatments for this purpose. Thus, the modern-day psychiatrist is 1) forced to make diagnoses that lack an objectifiable neurobiological basis, 2) constrained to prescribe drugs without knowing whether they influence a brain mechanism that is relevant to the patient’s disease, 3) not able to measure drug effects reliably, and at the same time, 3) obliged to consider PK factors that may influence drug response. This is a daunting task that often ends in advising patients to take CNS drugs in order to “restore a chemical imbalance”, while most psychiatrists would agree that although paracetamol is effective in treating headache, its therapeutic effect does not reflect the restoration of a paracetamol imbalance in the human brain. A puzzling phenomen that probably reflects a Freudian defence mechanism in the form of avoidance to cope with feelings of professional doubt or even incapacity.
When oncology was faced with similar challenges in the 60’s and 70’s of the previous century, academia did not concede and pressurized government until president Nixon and the US National Cancer Institute declared “the war on cancer” in 1971. Billions of dollars were subsequently invested in cancer research, resulting in the elucidation of the pathophysiological pathways of many types of cancer, and culminating in state-of-the-art 21st century “personalized medicine” in terms of diagnosis and treatment. Clearly, psychiatry could benefit by taking an example from oncology, abandoning the Freudian “black box” approach to the brain and move forward by applying a mechanistic rather than a phenomenological approach. In this context, CHDR has an established history in innovative CNS drug development and has hitherto focused on developing reliable functional CNS biomarkers to quantify the pharmacodynamics (PD) effects of novel CNS compounds in healthy volunteers. Currently, we are expanding our activities to routinely perform trials with compounds that display innovative PD mechanisms in different psychiatric patient populations, and to include drug-sensitive biomarkers that are translatable from preclinical data to healthy volunteers and patients in such trials. By doing this, we aim to stimulate collaboration between pharma, academia, mental health institutions and patient organizations, and to provide an impetus for mechanism-based, innovative drug research in psychiatry in the Netherlands. At the same time, CHDR is involved in neurology and psychiatry residency teaching programmes where it provides clinical pharmacology as a basis for pharmacotherapy by specialists in the near future. Developing reliable biomarkers and innovative, effective drugs for brain disorders is time-consuming, but in the meantime, sound knowledge of the principles of clinical pharmacology could render current psychopharmacotherapy in psychiatry more effective.
Author: Gabriel Jacobs