Treatment of Major Depressive Disorder (MDD) in many cases, offers less than optimal results, resulting in loss of function and remaining impairment. In recent years, there has been an accumulation of evidence demonstrating substantial etiopathological heterogeneity and overlap both within and across a variety of psychiatric disorders including depression [1]. While initial research was conducted to gain insight into genetic risk, much of the current research has focused on attempting to develop more effective treatments. This has proven to be difficult, in part, due to the varying degree of etiological heterogeneity of symptoms associated with MDD. Moving beyond genetics, towards an understanding of specific neural pathways and distinct disruptions that may result in related, but different, symptomatic presentation, could lead to a more accurate appraisal and definition of disorders. Still, at present, there is no consensus on how to identify relevant and disease-specific pathology with the specific neural circuits given our current limited understanding of disease pathophysiology.
 
Hence, the purpose of this paper is to gain insight and to propose a common link between symptoms and related disorders in association with specific dysfunction of known neural circuits, in order to account for the increased likelihood of developing treatmentresistant depression in a subgroup of depressed patients. This paper will specifically attempt to present the question as to whether low hedonic tone is a risk factor for Attention Deficit Hyperactivity Disorder (ADHD) and for developing comorbid depression. Furthermore, this paper will present the hypothesis that low hedonic tone and associated specific neurobiologic correlates predict the presence of ADHD in MDD, thus who is at risk for poorer outcomes with selective Serotonin Reuptake Inhibitors (SSRIs).
 
Brain Regions and Circuits
 
Eleven key areas of the brain have been highlighted in part by their specific neurotransmitter projections of which alteration in neurotransmitter innervation has been hypothesized to create disruptions in information processing and consequently specific psychological symptoms [2]. Linking each of these functional areas is a network of neuron projections or neurotransmitter pathways from the brainstem. It is posited that when a neurotransmitter-carrying neuron projects into a specific area, it has the capacity to modulate the physiological processes of the associated circuit [2]. Thus these pathways form the substrates that “tune” the neurons within each circuit, thereby affecting the function of the specific brain areas they innervate. Furthermore, it is hypothesized that these neural circuits are linked together in functional loops allowing various regions of the brain to communicate chemically via neurotransmission. In some instances, for example in cortex-to-cortex circuits, cortical areas are “tuned” by bottom-up neurotransmission, whereas other cortical circuits including a variety of Cortico-Striatal-Thalamic-Cortical Circuits (CSTC), allow information to be sent downstream by way of top-down mediation [3]. Whenever there is malfunction or even hypofunction in these circuits, the effects are felt throughout the loop and thus may mediate specific psychological symptoms.

Citation: Sternat T, Lodzinski A, Katzman MA (2014) Hedonic Tone: A Bridge between the Psychobiology of Depression and its Comorbidities. J Depress Anxiety 3:147. doi: 10.4172/2167-1044.1000147

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