**2.2 Depression and monoamine axon degeneration**

Further evidence has been provided using animal models of depression to show that axonal degeneration of monoamine neurons is involved in the pathophysiology of depression. The rat model of depression, which was developed by repeated exposure to forced walking stress for 2 weeks, showed depressive behaviors including prolonged inactivity, seclusion, aggression, motor retardation, lack of coupling behavior, fitful sleep, weight loss, and hypersensitivity to light and sound [12]. Subsequent

#### *Perspective Chapter: Depression as a Disorder of Monoamine Axon Degeneration May Hold… DOI: http://dx.doi.org/10.5772/intechopen.102340*

studies have demonstrated that this stress-induced depression model reveals the degeneration of NA axons in the cerebral cortex [8]. In this depression model with NA axon degeneration, imipramine (intraperitoneal injections for 20 days) could induce regeneration of cortical NA axons and ameliorate the depression-like behaviors [8]. A most recent study showed that in a mouse model of poststroke depression with degeneration of NA- and 5-HT axons, chronic treatment with fluoxetine reversed depression-like behaviors and a loss of 5-HT axons, but not NA axons [11]. Furthermore, light deprivation was found to induce a loss of NA axons, but not 5-HT axons, in the frontal cortex and depression-like behaviors in rats, while desipramine improved the NA axon loss and depressive behaviors [10]. Postnatal isolation rearing, which induced depressive behavior in adolescent/young adult rats, reduced the density of 5-HT axons, but not NA axons, in the hippocampus and amygdala [13]. A recent study has shown that exposure to 1-bromopropane, an alternative to ozonedepleting solvents, which is known to induce depressive symptoms in a subset of people exposed to this chemical, induced the degeneration of NA axons, but not 5-HT axons, in the adult rat [14]. It has also been presented that repeated electroconvulsive shock that is most effective in the treatment of clinical depression promotes the regeneration of 5-HT axons of the rat hippocampus damaged by the 5-HT specific neurotoxin [15]. In the chronic social defeat stress model of depression with reduced 5-HT innervation in the hippocampal dentate gyrus (DG) and ventromedial prefrontal cortex (vmPFC) of mice, chronic deep brain stimulation of vmPFC reversed depression-like behavior and restored 5-HT innervation in the DG and vmPFC [16]. Further evidence for the involvement of the degeneration of monoamine axons in the pathophysiology of depression has been reported: Interferon-α, which is widely used for the treatment of cancers and viral illnesses, is known to frequently induce depressive symptoms [17], reduces the density of NA and 5-HT axons in the frontal cortex, hippocampus, and amygdala of rats [18]. Finally, human brain imaging studies have shown evidence that the degeneration of monoamine axons is associated with depressive symptoms [19–21]. In these studies, the density of axon terminals of monoamine neurons was measured by positron emission tomography using radiotracers of presynaptic monoamine transporters. Although scant in number and limited to Parkinson's diseases with depressive symptoms, the imaging studies have provided evidence to support the involvement of loss of monoamine axons in the occurrence of depressive symptoms. Importantly, a recent imaging study reported that depressed patients showing the improvement of depressive symptoms after cognitive behavioral therapy revealed an overall increase in cerebral 5-HT transporter availability, suggesting the occurrence of 5-HT axon regeneration/sprouting after depression treatment [22]. Furthermore, in depressed suicide victims, immunohistochemistry using an antibody to serotonin transporters showed a localized decrease in the density of 5-HT axons in the PFC [23].

All these studies support the view that depressive symptoms are caused by the loss of monoamine axons and antidepressants exert their effects by inducing the regeneration of monoamine axons. Thus, the delayed onset of antidepressant efficacy can be explained by the time required for the regeneration of monoamine axons.

### **3. Plausible causes of treatment-resistant depression**

Based on the view that depression is a neurodegenerative disease, the possible causes of treatment-resistant depression are considered due to (1) mismatch of impaired

monoamines and prescribed antidepressant drugs, (2) severe degeneration or cell death, (3) persistent inflammation, and (4) omega-3 fatty acid deficiency. Obviously, we cannot exclude other causes of treatment-resistant depression (**Figure 1**).
