Biomarkers of Mood Disorders and Ketamine's Antidepressant Effect: a neuropsychopharmacological approach to test current hypotheses of depression

Mood disorders are rising globally amid radical changes in the ecosystem, economic uncertainties, and social inequalities. These psychiatric conditions, characterized by dysfunctional emotional responses to external stimuli, profoundly impact individuals' daily lives. Among them, depressive disorders stand out as a prevalent and debilitating condition, ranking second in terms of disease burden worldwide. For decades, the development of new pharmacological interventions to address the mental health epidemic had mainly produced insignificant variations of old drugs with limited efficacy. By the turn of the millennium, the resurgence of scientific interest in hallucinogenic psychoactive compounds represents one of the most promising avenues for research within the field of psychiatry. This development was marked by the discovery of ketamine's rapid and long-lasting antidepressant properties. However, the aetiology of depressive disorders and the mechanisms underlying ketamine efficacy remain poorly understood. Current models suggest that the manifestation of depressive symptoms stems from neurophysiological alterations. Key theories include the "serotonin (5-HT) deficiency", "excitatory/inhibitory imbalance", and "neural atrophy" hypotheses. Psychoactive substances like ketamine, serving both as interventions and tools to perturb brain function, offer an ideal neuropsychopharmacological model to examine these hypotheses and explore novel therapeutic mechanisms in humans. The present thesis presents three original research studies utilizing psychoactive compounds in conjunction with state-of-the-art neuroimaging methods to test current neurobiological theories of the aetiology of depression. Furthermore, it incorporates a narrative review summarizing available evidence on the acute and subacute mechanisms of action of ketamine. In the first study, a direct assessment of the "5-HT deficiency" theory of depression was achieved using an amphetamine challenge to probe the state of the 5-HT system imaged through the Positron Emission Tomography (PET) radioligand [11C]Cimbi-36 in patients with depression and healthy subjects. The results yielded compelling evidence indicating a reduced 5-HT release capacity in individuals with depression compared to healthy controls. Moreover, the study uncovered an intriguing difference in baseline 5-HT type 2A (5-HT2A) receptor availability between depressed patients and control subjects. Within the patient group, higher 5-HT2A receptor availability was associated with lower connectedness, a psychological trait of an individual's connection with themselves, others, and the environment. In the second study, the acute neurophysiological effects of the novel rapid-acting antidepressant ketamine were investigated using a portable EEG apparatus in a population of hospitalized patients with bipolar depression. The administration of ketamine resulted in notable alterations in rhythmic and arrhythmic components of the EEG signal, suggesting an underlying shift in cortical excitability in accordance with the "excitatory/inhibitory imbalance" hypothesis of depression. Remarkedly, the magnitude of the modulation of EEG parameters induced by ketamine, specifically of the arrhythmic components, was found to differentiate between early and late responders to ketamine therapy. The third study examined the neuroplastic effects of ketamine using the PET tracer [11C]-UCBJ to image synaptic density in healthy individuals. Contrary to initial expectations, robust evidence for an increase in neuroplasticity was not observed. However, a trend toward an increase was reported, which exhibited a correlation with acute and subacute psychological outcomes. Given the considerable body of pre-clinical evidence supporting the neuroplasticity-promoting effects of ketamine, the absence of significant results in the study may be attributed to methodological limitations inherent to the applied technique or dosing regimen and individual variability in drug response. Overall, the multifaceted findings obtained from the various studies, which implicate different neurotransmitter systems at a brain-wide level, indicate that depression is characterized by alterations across numerous brain regions and circuits. This highlights the need for a non-reductionist and multidisciplinary approach to studying brain function and dysfunction. Notably, consistent results across the three studies underscore the crucial role of variability and individual predisposition in response to psychoactive drugs. This variability manifests in various ways: from differences in the state of the 5-HT system between healthy individuals and patients, and within depression endophenotypes, to the distinct neurophysiological response to ketamine treatment observed between early and late responders, and the relative insensitivity to neuroplastic changes of ketamine in healthy subjects. The concept of individual variability adds another layer to the well-recognized factors of "set" and "setting" in influencing therapeutic outcomes of psychoactive medications. If the neurophysiological and therapeutic trajectories triggered by psychoactive medications vary based on individual brain architecture, mental state, and physical and interpersonal environment (both current and past), then a purely biological explanation of depression and antidepressant response is inadequate. Achieving a comprehensive understanding of mental well-being requires a unified framework that integrates biological, psychological, and environmental factors — a biopsycho-social model.