Neurobiology of Mood Disorders

This essay analyzes possible underlying assumptions and provides bridge laws between various levels of complexity of brain processes. A short historical introduction on the main trends in neuropsychiatry over the last century is given. Then Kendler’s philosophical agenda are discussed. The central question is: what kind of relationships between mental and neurobiological levels of complexity is or could become useful in the psychiatric practice? The philosophical analysis based on general systems theory and on Searle’s concept, assuming the mind as a biological property of the brain. Consequently the individually unique mind exists in a similarly unique brain, containing all information acquired during life. Clinical investigations show that the occurrence and time course of some psychiatric conditions, such as depression, can best be described in stochastic models. Diagnostic systems and research agenda’s should take into account for such uncertainties, that are not due to a lack of scientific knowledge, but might be inherent to the neurobiology of the brain, instead. The probabilistic nature of the brain, together with the possible involvement of multiple genes and other molecules may pose limitations on both the biological understanding of mental disorders and evidence based psychiatric practice.

From anesthetized rats in the 90s to conscious wild-type or knockout mice today, intracerebral in vivo microdialysis provided important information about the brain mechanism of action of psychotropic drugs such as antidepressants. The principle of microdialysis technique is based on the balance between the release of neurotransmitters (e.g., serotonin 5-HT, norepinephrine, dopamine) and re-uptake by selective transporters (e.g., SERT for 5-HT). Complementary to electrophysiology, this technique reflects presynaptic monoamines release and intrasynaptic events corresponding to ≈ 80% of whole brain tissue content. It has been proposed that the inhibitory role of 5-HT_1A and 5-HT_1B serotonergic receptor sub-types that limit somatodendritic and nerve terminal 5-HT release, respectively, plays a key role in the mechanism of action of Selective Serotonin Reuptake Inhibitors (SSRI). This hypothesis is based partially on results of microdialysis experiments performed in naïve, non stressed Rodents. Examples from our own experience and from relevant publications from key investigators in this field will illustrate this statement. The present chapter will first remind the principle and methodology of the microdialysis technique when performed in mice. We will also underline the crucial need of developing animal models displaying behavioral, neurochemical and brain morphological phenotypes reminiscent of depression and anxiety in Human. Recently developed genetic mouse models have been generated to independently manipulate 5-HT_1A autoreceptor and heteroreceptor populations and microdialysis helped to clarify the role of the presynaptic component, i.e., by measuring extracellular levels of neurotransmitters in serotonergic nerve terminal regions and raphe nuclei. The last two paragraphs will summarize main advantages and drawbacks of using microdialysis in mice through recent examples obtained in knockouts or alternatives such as infusion of a small-interfering RNA (siRNA) suppressing receptor functions in the mouse brain. Finally, by using drug infusion through the probe, correlation of microdialysis changes with behavioural data can be obtained, e.g., with the antidepressant-like activity.

There is considerable evidence for circuit dysfunction anxiety disorders, but our basic knowledge of the complex neural pathways that underlie emotional behavior remains incomplete. A more complete understanding of these systems promises both to facilitate a fuller understanding of anxiety disorder pathogenesis as well as suggest novel therapeutic strategies for unmet psychiatric needs. Classically, researchers have used correlational imaging techniques, gross lesion or electrical stimulation to delineated the brain structures involved in generating affective responses. While these studies have provided a wealth of information describing the structures involved in the generation of emotional behavior, in many instances they lack sufficient regional or temporal specificity. This chapter will review recent studies using optogenetic methodologies for delineating the circuits that underlie emotional behavior. First, I will review the suite of available tools for optical inhibition and excitation, and their utility for modulating activity in a cell-type and projection-specific manner. Then, I will highlight recent experiments using these tools to dissect the circuitry that underlies emotional behavior. As anxiety disorders are increasingly being viewed as a circuit-based dysfunction, optogenetics proves to be a powerful method for identifying the circuits that generate emotional responses, and will provide essential insight for development of novel therapies.

The serotonergic (5-HT) system consists of a complex network of neurons, originating in the midbrain raphe nuclei and projecting to almost every brain region. Serotonin is involved in various processes and behavioural functions through the involvement of at least 15 pre- and postsynaptic receptors belonging to 7 receptor families. Synthesis, vesicular storage and reuptake are crucially involved in the release and extracellular levels of the monoamine 5-HT from nerve terminals.Serotonin has been implicated in many different behaviours and pathologies, which is reflected by the intensive research into this monoamine. Serotonin function is believed to play a pivotal role in the pathology and treatment of affective disorders, but its role is still far from clear. Efficacy of antidepressant and antipsychotic medications is likely related to different aspects of 5-HT function, including synthesis and 5-HT_1A and 5-HT_2A receptor function. So far Positron Emission Tomography (PET) has the best prospects to investigate these aspects of 5-HT function in humans in a relatively non invasive manner. Through kinetic modelling of the imaging data valuable information like receptor binding potential, enzymatic activity or receptor occupancy can be acquired. PET tracers are available for some of the components of the serotonergic system, but some of them are not optimal and a large part of the system can not yet be visualised with imaging techniques. However, as more tracers become available and imaging techniques improve, PET can play a major role in research and the development of new pharmacological agents.

Major depressive disorder (MDD) is an emergent cause of personal and socioeconomic burden, since its high lifetime prevalence (16.2%) and the unsatisfying response rate of the available antidepressant drugs. Among modulators of treatment outcome, genetic polymorphisms are thought to explain a significant share of the inter-individual variability, according to a complex multi-loci model.

Given the described scenario, the present chapter aims to summarize and compare the main pharmacogenetic findings regarding antidepressant treatment outcome, including both candidate gene studies and genome-wide association studies.

The literature provided replicated evidence of association between several genes (in particular, SLC6A4, HTR1A, HTR2A, COMT, MAOA, BDNF, GNB3, and MDR1) and antidepressant efficacy, but findings were mainly contradictory. Despite the inconsistent pharmacongetic results obtained so far, the increasing knowledge about MDD pathogenesis and antidepressant mechanisms of action, together with better awareness of the limitations of previous pharmacogenetic studies, may lead to the confirmations required to produce clinical applications. Technical improvement in genotyping procedures may help to translate the increasing theoretic knowledge into practical applications.

There are number of lines of evidence that the neurotransmitter norepinephrine (NE) might be very important in pathophysiology of anxiety and mood disorders. Firstly, NE projections innervate the limbic system, suggesting the involvement of NE in the regulation of emotions and cognition. Secondly, NE interacts with serotonin (5-HT) and dopamine (DA) systems, which also play very important roles in the regulation of mood. Thirdly, it has been shown that various agents for increasing NE availability, such as NE reuptake inhibitors, are also effective antidepressant drugs. And fourthly, the depletion of NE can result in the relapse of depression after successful treatment with antidepressant drugs. All these pieces of evidence suggest that the stimulation of NE transmission can be beneficial in the treatment of affective disorders. However, different psychiatric medications have distant effects on NE transmission. The current chapter analyses the effect of psychiatric medications on NE system and proposes how the treatment outcome might be improved.

The serendipitous discovery of the antidepressant potential of inhibitors of monoamine oxidase (MAO, protein facilitating catabolism of the monoamines) in 1950 led to the development of the monoamine theory of depression. This theory was based on the correlation between the buildup of monoamines serotonin (5-HT), norepinephrine (NE) and dopamine (DA) in CNS, achieved with blockade of their cellular degradation by the above pharmacological agents, and the observed antidepressant effect. While the role of norepinephrine and serotonin in the pathophysiology and/or treatment of depression received a significant attention and was studied in detail in years following that discovery, DA remained a ‘forgotten child’ for some time. In past two decades, however, the relationship between the function/state of the DA system and depression has been studied from various perspectives.

This section will be devoted to the review of evidence suggesting the important role of the DA system in pathophysiology and/or treatment of depression. The main features of DA system neuroanatomy and neurotransmission, critical for the proper understanding of physiological basis of depression, its treatment and applicable research methods, will be outlined. The focus will be made on the principal findings elucidating the involvement of DA in etiology of mood disorders, particularly depression. The findings from both clinical and animal studies will be discussed.

The prefrontal cortex represents the brain region with the highest hierarchical level among the association cortices and stands as the most evolved cortex, responsible of the superior mental functions. The representation, planning and execution of actions, cognition, behavior and emotional control, adaptation to the environment and the working memory are dependent on the integrity of the prefrontal cortex and its interconnections with cortical and subcortical areas. Schizophrenia and depression generate profound changes in the patient’s behavior, disabling them for a normal adaptation to society. In addition, treatments are far from being optimal for both illnesses; their effectiveness has a high degree of variation, and severe secondary effects usually emerge. Alterations of higher brain functions can be observed, thus indicating that depression and schizophrenia have in common a damage or dysfunction of the prefrontal cortex circuitry. Particularly, disruption of prefrontal neurotransmission of serotonin and dopamine is a shared feature. Furthermore, both psychiatric diseases present marked mood alterations. Hence, the characteristic negative symptoms of schizophrenia (apathy, lack of motivation) are key features of depression.In the present chapter we review the changes and alterations observed in the prefrontal cortex of patients of depression and schizophrenia in terms of cytoarchitecture, connections and functions, and how they are disrupted in both disorders. Some important preclinical findings are also reviewed. We also discuss how different treatments normalize the altered cortical neurotransmission and how this could be reflected by an improvement of the patient’s symptomatology.

We review the major findings of the Hypothalamic-Pituatary-Adrenal (HPA) axis and depression. We give an overview of the HPA axis organization and its component parts, including cortisol, CRF and CRFBP, and interpret findings from the dexamethasone suppression test, dex/CRF and CRF-provocation tests in relation to depression. CRF appears to mediate the neuroendocrine, autonomic, immune and behavioral responses to stress; the CRF1 Receptor (CRF1R) plays a central role in the stress response, while CRF2R exerts a modulating effect on the CRF1R. The CRF hypothesis of depression suggests that CRF is hypersecreted in depressed subjects and persistently elevated CSF CRF may serve as a marker for depressive vulnerability and early relapse. Pharmacological data support the view that chronic antidepressant treatment may decrease CRF sensitivity to stress. Our group’s findings, and others’, on the nexus of childhood trauma, depression and HPA axis disruption are explored; data are highly suggestive of far-reaching CNS changes associated with a history of childhood trauma that may underlie increased vulnerability to future depression. A distinct biological subtype of depression with a history of childhood trauma is proposed for future investigation. Gender differences in response to the triad of early life trauma, depression and HPA axis disruption are reviewed, as are gene studies for the CRF1R, CRHBP and FKBP5. A variant of the CRF1R gene may exert a protective effect in men. Studies of CRF1R antagonists as novel antidepressants have been inconclusive, yet the studies haven’t sub-typed the depressed patients with a history of childhood trauma. Mefipristone and other glucocorticoid receptor antagonists may be effective in the treatment of psychotic depression.

Depression and anxiety are psychiatric illnesses that are major burdens on society and affect as much as 7% of the world’s population. Here we review common approaches used to model depression in rodents such as chronic mild stress (CMS), social defeat, and chronic corticosterone treatment. We discuss the pros and cons of these different approaches. Furthermore, we provide a detailed review of adult hippocampal neurogenesis, including the distinct phases that a cell passes through when transitioning from precursor to neuron. Finally, we discuss at length the experiments that have related adult hippocampal neurogenesis to treatments of depression and anxiety, and why neurogenesis might be necessary for these treatments. We end by revisiting the neurogenesis hypothesis of depression and by providing suggestions for future research directions.

It has been proposed that triple reuptake inhibitors (TRIs) that enhance serotonin, norepinephrine and dopamine extracellular levels in the brain may produce greater antidepressant effects than single- or dual-acting agents. This hypothesis is mainly based on the observations that drugs stimulating dopaminergic neurotransmission produce antidepressant effects or attenuate some side effects observed with selective serotonin reuptake inhibitors. Although preclinical data clearly establish the beneficial effects of TRIs in animal paradigms used to screen antidepressant-like effects, there are two limitations of these studies. On one hand, the effects of TRIs have been tested mainly after acute administration. However, given the functional and reciprocal interactions between monoaminergic neurons, it is conceivable that counter-productive effects occur when the treatment is prolonged. On the other hand, the relevance of TRIs in antidepressant-like activity is based exclusively on the forced swim and tail suspension tests in naïve animals which do not reproduce the complex biological and psychological changes associated with depression. In human, clinical evidence for antidepressant activity of TRIs and more particularly their ability to produce a greater efficacy than currently available agents remains equivocal. The present chapter synthesizes the preclinical and clinical data emphasizing the interest of increasing dopaminergic activity with the other two monoamines in the treatment of major depression and related symptoms such as pain.

Depression is a severe psychiatric disorder, in which a third of patients do not achieve remission, despite the wide variety of therapeutic strategies that are currently available. Vagus nerve stimulation (VNS) has shown promise in treating resistant-depressed patients, and it has been approved as an adjunctive treatment for resistant depression. However, the mechanism of action by which VNS exerts its antidepressant effects has remained elusive. The present chapter was aimed first at introducing VNS, beginning from the anatomy of the vagus nerve, the surgical procedure of the stimulator implantation, and the rationale leading to the use of VNS for the treatment of resistant depression. A second goal of this chapter was to review what has been done so far in clinical and preclinical research, from neuroimaging, neurochemical, molecular and electrophysiological studies, in order to understand the mechanism of action of VNS. These studies reported an effect of VNS on brain regions, such as limbic structures, involved in mood regulation. Furthermore an influence of VNS on all three central monoamine systems (serotonin, norepinephrine, and, dopamine) implicated in the pathophysiology of depression and that are especially targeted by antidepressant medications has been revealed, contributing to the clinical efficacy of this approach. Finally, this chapter described the stimulation parameters of this therapy and the results of different studies aimed at characterizing the optimal VNS parameters to treat resistant depression and to potentially minimize and/or even prevent stimulation-related side effects, thus improving patients’ quality of life.