Open questions in current models of antidepressant action

Abstract

Research on depression and antidepressant drugs is necessary, as many patients display poor response to therapy. Different symptomatic and pathophysiological features have been proposed as end points of the depressive phenotype and of the antidepressant action, including anhedonia, depressed mood, alterations in morphology and activity of some brain areas (amygdala, nucleus accumbens, hippocampus, prefrontal cortex and cingulate cortex), modifications in the connectivity between brain structures, changes in neurotransmitters (serotonin, noradrenaline, glutamate and neuropeptides), brain plasticity (neurogenesis, neurotrophins) and abnormal function of the hypothalamic-pituitary adrenal axis. However, few models have been proposed to describe how these end points could induce the depressive phenotype and are involved in the mechanism of action of antidepressants. Here we propose a connectionist-inspired network of depression and antidepressant action, in which the different aetiological factors participating in the release of a depressive episode are represented by input nodes, the different symptomatic as well as pathophysiological end points are represented by an intermediate layer, and the onset of depression or of comorbid disease is represented by the output node. The occurrence of depression and the mechanism of the antidepressant action thus depend upon the weight of the interactions between the different end points, none of them being per se crucial to the onset of a depressive phenotype or to the antidepressant action. This model is heuristic to draw future lines of research concerning new antidepressant therapies, designing new animal models of depression and for a better understanding of the depressive pathology and of its comorbid pathology such as anxiety disorders.

Figure 1

Representation of aetiological factors involved in depression. Examples of triggers in humans are given in blue boxes. Examples of experimental models used in animals to reproduce these triggers are given in purple boxes. These aetiological factors are thought to induce changes in pathophysiological end points precipitating a depression. Antidepressant treatments may act by reversing these changes. BDNF, brain-derived neurotrophic factor; MDD, major depressive disorder; MDMA, methylenedioxymethamphetamine.

Figure 2

Theoretical model of depression and antidepressant effects based on a connectionist inspired network. Blue arrows represent normal interactions between nodes. Red arrows represent pathological interactions. Antidepressant effects are indicated by green arrows. Increased weight/interaction between nodes is represented by bold arrows. Filled red nodes indicate a pathological change of state, while filled green nodes represent an antidepressant-induced reversal from a pathological state to a normal state. Core behavioural/cognitive traits relevant to the depression diagnostic (hedonic behaviour and mood) are indicated by plain nodes while dashed nodes represent secondary traits (stress coping or cognitive processing). Different colours of the output correspond to the state of the subject (green: normal, red; depressed, purple: comorbid pathology). (A) Normal state, (B) depressive episode induced by dys-regulation of a single end point leading to a core behavioural impairment (e.g. mood), (C) depressive disorder induced by dys-regulation of multiple end points leading to impairments in multiple psychological functions together mediating symptoms of depression, (D) comorbid pathological state induced by dys-regulation of a single secondary end point, (E) hypothetical effects of an antidepressant treatment in scenario 2B, (F) hypothetical effects of an antidepressant in scenario 2B, (G) hypothetical effects of a cognitive behavioural therapy or an emotional regulation therapy on a subject displaying profile 2C and (H) hypothetical view proposing that depression can be recapitulated by a crucial process, neuroplasticity.