**3.2 Severe degeneration or cell death**

Another likely cause of treatment-resistant depression may be attributable to the possibility that the degeneration of monoamine axons is not localized at axon terminals, but extends further from the terminals. In the most severe case, retrograde axonal degeneration may result in the degeneration of the neuron soma (cell death).

#### **Figure 1.**

*Plausible causes of treatment-resistant depression. The causes of resistance to antidepressant drugs may be 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. Others may include deficiency of signaling pathways or molecules related to regeneration of monoamine axons.*

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

In fact, a great loss of NA neurons in the locus coeruleus has been reported to be associated with depressive symptoms in patients without dementia as well as those with Alzheimer's disease or Parkinson's disease [24, 25]. A loss of 5-HT neurons in the raphe nucleus is also reported to be associated with depressive symptoms of patients with Parkinson's disease [26]. Depressive symptoms due to the loss of monoamine neurons can hardly be treated with the administration of conventional antidepressant drugs as well as electroconvulsive shock therapy. It is noted that at the early stages of Parkinson's disease and Alzheimer's disease the degeneration of the distal axons occurs first, and in the late stages, persistent axonal degeneration finally results in the degeneration of the neuron soma [27–29]. This implies that in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, possibly including depression, the degeneration of the distal axons precedes the loss of the neuron soma. Postmortem and imaging studies have shown that in Parkinson's disease about 30% of DA neurons of the substantia nigra compacta (SNc) and about 50–70% of striatal DA axon terminals are lost by the time of motor symptom onset [30, 31]. The reason for making the distal axons more vulnerable to insults than the neuron soma can be explained by the fact that the distal portions of axons are most remote from the cell body that supplies proteins and chemicals required for the survival and growth of axons.

Whether distal axon degeneration is prone to cell death or not could be dependent on the length of axons from the neuron soma to the distal axon terminal and the morphological features of axon terminals (**Figure 2**). In Parkinson's disease, motor symptoms occur due to the degeneration of SNc DA neurons projecting to the dorsal striatum. Since the distance between the two brain regions is relatively short, retrograde axon degeneration of SNc DA neurons is considered to result in cell death more easily. In contrast, NA neurons of the locus coeruleus and 5-HT neurons of the raphe nucleus send their axons to long distances from the brainstem to the cerebral cortex [32], thus taking a long time to cause soma degeneration. On the other hand, it has been reported that DA neurons of the ventral tegmental area (VTA), which project their axons to the ventral striatum (nucleus accumbens) and are responsible for reward-related behavior, are involved in the pathophysiology of depression [33, 34]. Similar to SNc DA neurons, VTA DA neurons project relatively short axons to the nucleus accumbens. Although the axon length of both DA neurons is almost the same, however, DA neurons of the SNc are more prone to cell death in Parkinson's disease, compared to DA neurons of the VTA [35, 36]. A single-neuron tracing study demonstrated that a single DA neuron of the SNc forms highly overlapping innervation with extremely dense axonal arborizations in the dorsal striatum [37], while that of the VTA has much smaller axonal arbors in the ventral striatum (**Figure 2**) [27, 36]. A large and dense axonal arborization in the terminal field is considered to contribute to cell death of DA neurons of the SNc in Parkinson's disease [36]. Thus, in addition to axonal length, the spread and size of terminal axon arbors may play a pivotal role in vulnerability to neuronal cell death. It is also noted that because 5-HT, NA, and DA axons all have a great capacity to spontaneously regenerate or sprout in response to damage in the adult brain [38–41], the competition between degenerative and regenerative mechanisms may occur after axonal damage, finally resulting in either axonal regeneration or cell death.

#### **3.3 Persistent inflammation**

In recent years much evidence has been accumulating that inflammation is a key player in the pathogenesis of neurodegenerative diseases, such as Parkinson's disease

#### **Figure 2.**

*Retrograde axonal degeneration and cell death of monoamine neurons depend on axonal length and morphological features of axon terminals. NA neurons of the locus coeruleus and 5-HT neurons of the raphe nucleus have long axons, rarely causing cell death, and depressive symptoms can occur predominantly due to axonal degeneration without cell death. In contrast, DA neurons of the VTA and SNc have relatively short axons. Although the axon length of both DA neurons is almost the same, DA neurons of the SNc are more prone to cell death in Parkinson's disease, compared to DA neurons of the VTA. A single DA neuron of the SNc forms highly overlapping innervation with extremely dense axonal arborizations, while that of the VTA has much smaller axonal arbors. A large and dense axonal arborization in the terminal field is considered to contribute to cell death of DA neurons of the SNc in Parkinson's disease. NA: Noradrenaline, 5-HT: Serotonin, DA: Dopamine, VTA: Ventral tegmental area, and SNc: Substantia nigra compacta.*

and Alzheimer's disease [42, 43]. Many researchers also reported that inflammation plays an important role in the occurrence of depressive symptoms and is associated with treatment-resistant depression [4, 5, 44, 45]. A subset of patients with depression and animal models of depression revealed increased levels of pro-inflammatory cytokines in the periphery and brain, including IL-1β, IL-6, and TNF-α, and a variety of stresses including psychosocial stress could induce activation of key inflammatory pathways to elevate the serum levels of pro-inflammatory cytokines such as IL-6 [44–48]. Based on these findings, as mentioned previously, long-term repeated intraperitoneal injection of the pro-inflammatory cytokine interferon-α induces the degeneration of 5-HT and NA axons in the rat brain, though there is no apparent change in the number and shape of 5-HT and NA neuronal somata [18]. Accordingly, it is reasonable to assume that prolonged inflammation and persistent release of proinflammatory cytokines produce the degeneration of 5-HT and/or NA axons without cell death, resulting in the occurrence of depressive symptoms. If inflammation as a cause of the axonal degeneration of monoamine neurons persists without antiinflammatory treatment during repeated administration of antidepressants, patients are likely to suffer from treatment-resistant depression.

#### **3.4 Omega-3 fatty acid deficiency**

Chronic treatment with antidepressants is reported to cause the downregulation of β-adrenergic receptors [49]. On the other hand, the denervation of cortical NA axons with the neurotoxin 6-OHDA causes upregulation (supersensitivity) in cortical

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

β-adrenergic receptors [50]. As upregulation of β-adrenergic receptors is associated with NA axon degeneration, it is possible that downregulation of β-adrenergic receptors results from regeneration or sprouting of NA axons. If upregulation of β-adrenergic receptors occurs due to the degeneration of NA axons in the brains of patients with depression, antidepressants could normalize the sensitivity of β-adrenergic receptors by the downregulation following the regeneration of NA axons. Further studies have shown that downregulation of β-adrenergic receptors following repeated application of β-adrenergic agonists or chronic stress treatment is blocked by phospholipase A2 (PLA2) inhibitors, while this downregulation can be induced by the activation of PLA2 [51, 52]. Moreover, it has been demonstrated that PLA2 activation is involved in the downregulation of β-adrenergic receptors induced by chronic desipramine treatment [53]. A possible link between the downregulation of β-adrenergic receptors and the regeneration of NA axons raised the possibility that PLA2 is involved in the molecular mechanisms of the antidepressant-induced regeneration of NA axons. Based on these findings, the PLA2 inhibitor mepacrine or 4-bromphenacyl bromide could attenuate the regeneration of NA axons induced by desipramine, while the PLA2 activator melittin induced NA axon regeneration [54]. These findings suggested that the PLA2 signaling pathway is involved in the pathophysiology of depression.

PLA2 generates the omega-6 polyunsaturated fatty acid arachidonic acid (AA) and omega-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) by acting on membrane phospholipids. PLA2 enzymes are subdivided into several groups and among them, two groups of PLA2, cytosolic PLA2 (cPLA2) and calcium-independent PLA2 (iPLA2), play a major role in the release of AA, EPA, and DHA from the cell membrane [42, 55]. PLA2 and its products, omega-3 and omega-6 fatty acids, reveal the capacity to produce axon outgrowth of adult mouse sensory neurons *in vitro*, aged rat sensory neurons in culture, and cultured hippocampal and PC12 cells [56–58]. Importantly, acute administration of DHA is reported to induce sprouting of 5-HT axons as well as corticospinal axons in an adult rat model of spinal cord injury [59]. A recent study also reported that in the damaged cornea of the adult mouse, DHA induces axonal regeneration of trigeminal sensory nerves via the iPLA2 activity of the receptors of the neuroprotective molecule pigment epithelium-derived factor [60]. Furthermore, using iPLA2β-knockout mice, the impairment of iPLA2β was found to cause widespread degeneration of axons in the central and peripheral nervous systems, including nigrostriatal DA axons, although the changes were not observed in developing and young mice, but became evident in older mice [61, 62]. All these findings suggest that PLA2 and its products play a key role in the degeneration and regeneration of axons in the periphery and brain, including monoamine axons in the adult brain.

Recently, many reports have shown lower levels of EPA and/or DHA being associated with depression [63–66]. Animal studies demonstrated that administration of EPA and DHA had an antidepressant-like effect, reducing immobility in the forced swim test [67, 68]. Moreover, it has been reported that the antidepressant effect of maprotiline, an NA reuptake inhibitor, is mediated by DHA released by activation of iPLA2 in the mouse prefrontal cortex [69]. Notably important is that EPA and DHA are essential fatty acids and must be obtained from the diet. Consequently, if patients with depression do not get enough of these fatty acids from their diet during the administration of antidepressant drugs, they may suffer from treatment-resistant depression. Notably, in adolescents with SSRI-resistant depression who exhibited robust DHA deficits, DHA supplementation with fish oil increased DHA status and enhanced the antidepressant effects of SSRI [70].
