The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications

Abstract

In some patients with major depressive disorder (MDD), individual illness characteristics appear consistent with those of a neuroprogressive illness. Features of neuroprogression include poorer symptomatic, treatment and functional outcomes in patients with earlier disease onset and increased number and length of depressive episodes. In such patients, longer and more frequent depressive episodes appear to increase vulnerability for further episodes, precipitating an accelerating and progressive illness course leading to functional decline. Evidence from clinical, biochemical and neuroimaging studies appear to support this model and are informing novel therapeutic approaches. This paper reviews current knowledge of the neuroprogressive processes that may occur in MDD, including structural brain consequences and potential molecular mechanisms including the role of neurotransmitter systems, inflammatory, oxidative and nitrosative stress pathways, neurotrophins and regulation of neurogenesis, cortisol and the hypothalamic–pituitary–adrenal axis modulation, mitochondrial dysfunction and epigenetic and dietary influences. Evidence-based novel treatments informed by this knowledge are discussed.

Introduction

Although some patients with major depressive disorder (MDD) suffer from only one depressive episode, many display characteristics of a progressive illness. In progressive illness, outcomes1, 2, 3 and treatment efficacy4, 5 are inversely correlated with earlier disease onset and increased number and length of depressive episodes.6 Longer and more frequent depressive episodes appear to increase vulnerability to further relapses,7 facilitating an accelerating and progressive illness course associated with functional decline. For example, the number of past depressive episodes is associated in a dose-dependent manner with memory decline (2–3% per episode; up to 4),1 and increased dementia risk (13% per episode).3 It is probable that depressive episodes cause brain tissue damage and altered physiological functioning through a variety of mechanisms that underpin patient symptomatology and functional decline over time. Evidence from neuroimaging and molecular studies appears to support this model. This understanding is key to informing new treatment strategies. This paper reviews current knowledge of the neuroprogressive processes that may occur in MDD, its structural consequences and molecular basis, and evidence-based novel treatments.

Materials and methods

Data for this review were sourced from electronic databases PUBMED, EMBASE and PsycInfo and were not limited by language or date of publication.

Results and Discussion

Clinical sequelae and structural consequences of MDD

MDD may be associated with stage-related structural brain changes potentially resulting from toxic or adaptive effects produced during depressive episodes. Structural changes are inconsistently found during the first episode; however, they appear more commonly in severe, protracted illness.8 For example, meta-analysis of available data suggests reduced hippocampal volume, a common9, 10, 11, 12, 13 but not universal finding in MDD, is consistently present in patients with illness duration >2 years and in those with >1 depressive episode.9 Hippocampal volume change in MDD is influenced by patient age, gender, illness duration, age of onset, episode frequency, comorbidity, depression subtype and genotype.12 Consistent with trial data,14, 15, 16, 17 a meta-analysis confirmed a direct correlation between increasing episode number and decreased hippocampal volume.18 Length of untreated illness has also been correlated with degree of hippocampal volume reduction,19 although this is not consistently replicated.15 Although some evidence supports early volume reduction (that is, commencing after the first episode)20 not all studies support differential volume reduction in first vs multi-episode patients.21 In fact, most studies including first episode adult patients fail to demonstrate relative volumetric hippocampal changes.20, 22 Correlates of hippocampal atrophy might present themselves in functional consequences of MDD. For example, lower verbal memory scores were associated with decreased hippocampal volumes in patients with recurrent depressive episodes.20 It is important, however, to consider that a number of factors could underpin hippocampal volume change in MDD, including changes in neuronal density, altered fluid content and neuropil.23

Structural alterations in other brain regions including the amygdala,24, 25, 26, 27, 28 orbitofrontal cortex,14, 16, 29 anterior cingulate cortex, basal ganglia and pituitary have been reported in MDD. Most evidence does not support a correlation between MDD characteristics (severity, duration, episode frequency) and volumetric changes in these regions. Exceptions include an inverse correlation between left putamen volume and length of MDD,30 and decreased anterior cingulate cortex volume in currently depressed31, 32 but not euthymic or less depressed patients.33, 34

Biochemical basis of neuroprogression in MDD

Clinical features suggestive of neuroprogression35, 36 have been noted as early as the work of Kraepelin,37 and include increased illness severity over time,38 reduced inter-episode duration as a function of increasing number and length of episodes,39 increasing illness autonomy facilitating spontaneous episodes later in the course7 and underlying genetic risk.7 Two differing pathophysiological models have been utilized to explain these clinical findings; a ‘sensitization model’ and ‘kindling model’.36 Sensitization suggests repeated administration of diverse stimuli causes progressive amplification of neuronal responses over time.40 In this model, psychological or organic stressors causes time-dependent sensitization leading to susceptibility to re-stress that increases progressively.41, 42, 43 The kindling model is based on observations that exogenous substances that induce seizures facilitate brain alterations leading to endogenous seizures in animals. Over time, repeated illness episodes can permanently alter neuronal activity, leading to increased susceptibility to further episodes—akin to the clinical observations of patients with MDD. It is likely these changes are underpinned by altered neuronal gene expression, which could reinforce the maladaptive changes facilitating longer term susceptibility.36

Numerous neurobiological mechanisms contribute to the pathogenesis and neuroprogression of MDD, mediating changes in conjunction with dynamic environmental influences (Figure 1). Major pathways include neurotransmitter systems, inflammatory, oxidative and nitrosative stress (IO&NS), neurotrophins and neurogenesis, cortisol and hypothalamic–pituitary–adrenal axis (HPA) modulation, mitochondrial dysfunction, epigenetic influences and dietary factors (Figure 2).

Figure 1
figure1

Neuroprogression in MDD. Psychosocial and physical stressors combine with pre-existing MDD vulnerability to precipitate a first depressive episode. Biochemical factors including inflammatory, O&NS, mitochondrial dysfunction, epigenetic alterations, HPA axis dysregulation and disturbance to neutrophic function interact to cause cellular damage, stimulate apoptosis and decrease neuronal growth and survival. These effects render the individual increasingly treatment resistant and more vulnerable to further episodes. Each episode is associated with progressive cognitive and functional decline, and associated structural brain changes. HPA, hypothalamic–pituitary–adrenal; MDD, major depressive disorder; O&NS, oxidative and nitrosative stress.

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Figure 2
figure2

Pathways to neuroprogression. Multiple biochemical pathways, not all of which are shown here, interact simultaneously to cause cellular damage that underwrites neuroprogression in MDD. Pathways include (1) inflammatory and cell-mediated immune effects on neurotransmitter metabolism, the HPA axis, receptor functioning, mitochondria and DNA; (2) O&NS-mediated damage to cellular components; (3) disturbance to mitochondrial energy production and cell survival mechanisms; and (4) alterations to gene transcription. As a representative example, increased levels of PICs and CMI cytokines lead to increased HPA axis activation, activation of IDO, and exert direct effects on cytokine receptors and normal gene expression. Induction of IDO leads to preferential production of TRYCATs, which exert direct effects on mitochondria increasing oxidative stress and impairing mitochondrial energy production, and decreased synthesis of 5-HT, impairing anti-oxidant defenses. Direct activation of particular cytokine receptors can lead to activation of caspase-9-dependent pathways inducing mitochondrial dysfunction, facilitating increased production of ROS and RNS. All of these effects lead to impaired cell survival and neurogenesis, potentially contributing to neuroprogression in MDD. 5-HT, 5-hydroxytryptophan; 5-HTTLPR, serotonin transporter-linked polymorphic region; CMI, cell-mediated immune; GPX, glutathione peroxidase; HPA, hypothalamic–pituitary–adrenal; IDO, indoleamine 2,3-dioxygenase; IFN-γ, interferon-gamma; IL-1, interleukin-1; MDD, major depressive disorder; NMDA, N-methyl-D-aspartate; NO, nitric oxide; NOS, nitric oxide synthase; NR3C1, nuclear receptor subfamily 3, group C, member 1; O&NS, oxidative and nitrosative stress; PIC, pro-inflammatory cytokine; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-alpha; TRYCAT, tryptophan catabolite.

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Pathways to neuroprogression

Serotonergic system

The serotonergic system is tightly coupled to depression onset,44 stage and neuroprogression. Serotonin (5-hydroxytryptophan (5-HT)) acts as a neurotrophic factor; stimulating neurogenesis and brain-derived neurotrophic factor (BDNF) expression45 that in turn promotes 5-HT neuronal survival. The lowered metabolism of 5-HT in depression may contribute to reduced neurogenesis and subsequent neuroprogression. 5-HT is produced from tryptophan, an essential amino acid catabolized by indoleamine 2,3-dioxygenase (IDO). Cell-mediated immune (CMI) cytokines (for example, interferon gamma (IFN-γ)) can activate IDO leading to tryptophan and 5-HT depletion, and synthesis of tryptophan catabolites (TRYCATs) including kynurenine and quinolinic acid in the plasma and brain. Similarly, some evidence suggests depression is accompanied by IDO activation, lowered plasma tryptophan and relative increases in detrimental TRYCATs and/or decreases in neuroprotective TRYCATs, such as kynurenic acid (for a review, see Maes et al.).46 There are multiple consequences of IDO activation. Reduced tryptophan and 5-HT impairs antioxidant defenses as both are strong antioxidants. Some TRYCATs increase oxidative stress (for example, 5-hydroxyanthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic and quinolinic acid)46 and are involved in processes that facilitate neurodegeneration. TRYCATs, such as kynurenic acid, 3-hydroxyanthranilic acid and/or 3-hydroxykynurenine, impair mitochondrial energy metabolism including adenosine triphosphate production and reduce mitochondrial respiratory mechanisms.47, 48 IFN-γ-induced IDO activity increases synthesis of neurotoxic TRYCATs.46 Quinolinic acid, for example, exerts agonistic effects at N-methyl-D-aspartate receptors a process that leads to excitotoxicity;49 inhibits glutamate uptake;50 and may cause degeneration of nerve cells; hippocampal cell death; destruction of postsynaptic elements; and reduction in central cholinergic functioning.51, 52, 53 All these mechanisms potentially underpin neuroprogression.

Anti-serotonin antibody titers appear significantly higher in MDD patients (54.1%), particularly those with melancholia (82.9%), compared with controls (5.7%).54 Autoimmune responses may interfere with 5-HT neurotransmission, in part helping to explain 5-HT hyporesponsivity in depression,44 which may in turn be involved in lowered neurogenesis and changes in postsynaptic receptor expression and function. Importantly, autoimmune activity directed against 5-HT is significantly associated with the number of previous depressive episodes; patients with >3 depressive episodes had a higher frequency of 5-HT autoimmunity than those with 1 or 2 prior episodes. These findings suggest each depressive episode may progressively increase the propensity to develop autoimmune responses to 5-HT. The latter in turn will increase the risk of new depressive episodes and to sequelae of reduced 5-HT, such as neuroprogression. All in all, the findings show that progressive autoimmune responses against 5-HT contribute to the sensitization or kindling of depression.

Noradrenergic (NA) and dopaminergic (DA) systems

NA alterations are strongly associated with depression. Post-mortem and functional imaging studies reveal altered density and sensitivity of α-2 adrenoreceptors, which modulate noradrenaline release, in prefrontal cortices of depressed suicidal victims.55, 56 Peripheral markers of altered central NA function (decreased platelet α-2 adrenoreceptor density) has also been found in depressed patients.57 Decreased axonal density of NA neurons appears to be induced by IFN-alpha (IFN-α),58 suggesting a potential connection between depressive symptoms and inflammatory mediated effects on the NA system. Antidepressants appear to increase axonal regeneration of cortical NA neurons.59

Alterations in DA function may partially underpin the delayed effects of antidepressants.60 Individuals with MDD have decreased turnover of homovanillic acid, the primary metabolite of dopamine.61, 62 This correlates with a lower DA tone in MDD, a finding consistent with depressogenic effects of DA depletion in depressed patients.63 Greater D-amphetamine responses in patients with MDD are possibly mediated by augmented postsynaptic responses secondary to low basal DA tone.60 Repeated stress may lead to sensitization of the mesolimbic DA system via increased glucocorticoids,64 as glucocorticoids themselves may selectively facilitate DA transmission in the nucleus accumbens.

The role of dopamine in pathogenesis may partially explain incomplete response rates to standard antidepressants,60 reflecting the failure of increased 5-HT and NA neurotransmission to appropriately modify DA signalling. Supporting this, responders to selective serotonin reuptake inhibitors (SSRIs), but not non-responders, exhibit increased dopamine binding to striatal D2 receptors,60 with degree of increased D2 binding correlated with improvement in depressive symptoms.

Inflammation and CMI activation

MDD is characterized by chronic inflammation and CMI activation independent of pathogen response.65, 66 The evidence is underscored by three recent meta-analyses demonstrating increased levels of pro-inflammatory cytokines (PICs) including interleukins (IL-1, IL-6), tumor necrosis factor-alpha (TNF-α)67, 68 and T-cell activation indicated by increased serum levels of soluble IL-2 receptors69 in MDD. Another consistent finding is increased neopterin, indicating increased IFN-γ-mediated macrophage activation.66 Increased production of PICs and CMI-related cytokines (for example, IFN-γ, IL-2) elicits depressive- and anxiety-like behaviors,70 with even small concentration changes consistently associated with the cardinal symptoms of depression. Moderate increments in cytokine levels may cause depression in individuals vulnerable to inflammatory changes (for example, patients receiving hemodialysis or IFN-α-based immunotherapy, post-partum women).71 Vulnerability to inflammatory triggers in depression is determined by factors including decreased levels of immunologically active peptidases (dipeptidylpeptidase IV and prolylendopeptidase) and by polymorphisms in cytokine and oxidative and nitrosative stress (O&NS) genes.70

Changes in inflammatory markers appear related to the number of depressive episodes. Neopterin is significantly increased in patients with 2 depressive episodes compared with those with 1 episode,72 and neopterin, IL-1 and TNF-α are significantly higher in patients with 3 depressive episodes.73 These findings suggest prior depressive episodes sensitize PIC responses and IFN-γ-induced mechanisms, potentially increasing vulnerability for further depressive episodes. Additionally, patients with a lifetime history of MDD showed increased IL-6 and soluble IL-1 receptor antagonist (indicating monocytic activation) in the early puerperium, suggesting prior depression sensitizes inflammatory responses.74 PICs and IFN-γ-related mechanisms mediate central sensitization in behavioral responses to maternal separation75 and may at least partially mediate the above sensitization.

Increased levels of PICs and CMI-related cytokines may contribute to neuroprogression.76 Increased IFN-γ production stimulates IDO and increases production of neurotoxic TRYCATs. Moreover, IFN-γ sensitizes cortical and cerebellar neurons to neurotoxic peptides, increases neuronal death, participates in neuronal loss and exacerbates neurotoxicity in neurodegenerative disorders.77, 78 IL-2 potentiates the effects of N-methyl-D-aspartate and has a role in reactive astrogliosis, myelin damage and neuronal loss in many brain regions.79, 80 IL-1β has neurotoxic effects on astrocytes and endothelial cells, thereby causing increased production of free radicals and metaloproteinases, which together may cause neuronal death, and exacerbates cell death by increasing seizure activity and N-methyl-D-aspartate receptor functions.81, 82, 83, 84, 85 Moreover, increased IL-1 production impairs hippocampal neurogenesis and cytogenesis; reduces BDNF expressions at both the messenger ribonucleic acid and protein level; reduces neurotrophin TrK receptor expression in the hippocampus and increases p75 receptor expression, subsequently impairing neuronal survival.86, 87, 88

TNF-α influences neuroprogressive processes such as silencing of cell survival signals, activation of caspase-dependent mechanisms and potentiation of glutamate neurotoxicity.89 Neopterin, in turn, potentiates the effects of reactive oxygen species (ROS), such as hydrogen peroxide.90, 91 Neopterin also triggers inducible nitric oxide synthase gene expression enhancing nitric oxide (NO) production.92 Therefore, neopterin may have a role in activating O&NS pathways observed in depression.93 Moreover, neopterin may elicit programmed cell death caused by PICs and O&NS.92, 94

Taken together, inflammation and CMI activation may contribute to the staging or recurrence of MDD. Exposure to previous depressive episodes magnifies the responses of depressogenic cytokines, potentially increasing the likelihood of new depressive episodes. These PICs, CMI-related cytokines and compounds such as neopterin induce neuroprogressive processes facilitate staging of depression.

Corticotrophin-releasing hormone (CRH) and the HPA axis

Numerous lines of evidence support a role of CRH and HPA axis alteration in MDD (for a review, see Swaab et al.).95 Many depressive symptoms can be induced by intracerebroventricular injections of CRH,96 and patients with MDD exhibit higher CRH neuronal activation and raised salivary, plasma and urinary cortisol compared with aged matched controls.97 It is postulated that HPA axis hyperactivity may result from early life programming.98 Events that sensitize the HPA axis in utero including maternal stress or smoking, and early bereavement or abuse in childhood lead to a higher risk of developing MDD later in life. An enduring sensitivity of CRH neurons is commonly seen in depressed individuals, and may reflect a state of glucocorticoid resistance, which facilitates increased exposure to glucocorticoids throughout the brain and body.99 Chronic use of antidepressants upregulate glucocorticoid receptor (GR) expression and function, leading to increased negative feedback and subsequent decreases in HPA axis reactivity.100 In addition, the GR has a key role in mediating antidepressant-induced hippocampal neurogenesis.101 Alteration of action appears to include inhibitory effects on cell membrane steroid transporters (for example, P-glycoprotein), leading to decreased glucocorticoid expulsion and higher intracellular concentrations (increasing GR function), and activation of GR translocation from cytoplasm to the nucleus, decreasing GR expression and function.100

The HPA axis is activated by PICs involved in depression and neuroprogression, including IL-6, TNFα, IL-1β and IFN-γ.102, 103 Maes et al.104 showed that HPA axis hyperactivity, either increased baseline activity or glucocorticoid resistance, is associated with increased production of PICs. There is evidence that glucocorticoid resistance in depression is caused by IL-2 and IL-1β-related mechanisms.105 The increased production of PICs and CMI-related cytokines could thus induce HPA axis hyperactivity by causing glucocorticoid resistance and increased baseline hormonal activity.98, 104, 105, 106

Changes in gene expression may additionally underlie environmentally mediated HPA axis hyperactivity susceptibility. Patients suffering from MDD or bipolar depression have been demonstrated to exhibit decreased GR messenger ribonucleic acid levels in the frontal cortex, amygdala and hippocampus.107, 108 Polymorphisms (rs6198, rs6191 and rs33388) of the nuclear receptor subfamily 3, group C, member 1 gene (which codes for the GR) and FK506 binding protein 5 (FKBP5) gene are associated in mediating environmentally induced onset of depressive risk.109, 110 FKBP5, which is found in both the cytoplasm nucleus,111 is a co-chaperone of heat shock protein 90 that modulates GR sensitivity. Increased expression of FKBP5, through gene polymorphism-induced upregulation, appears related to increased GR resistance. FKBP5 binding lowers GR affinity for cortisol, reducing negative feedback and its expression is actually induced by steroids. In this respect, increased environmental stressors, facilitating increased glucocorticoid expression, may induce FKBP5 expression and further GR resistance (for a review, see Binder),112 which may increase risk for MDD.

O&NS and mitochondrial dysfunctions

Oxidative stress: Inflammatory and mitochondrial processes can increase production of ROS and reactive nitrogen species (RNS) including superoxide, NO, peroxynitrite and peroxides. Under normal conditions, the potentially damaging effects of increased ROS and RNS on lipids, proteins, deoxyribonucleic acid (DNA) and mitochondria are counterbalanced by defense systems, including antioxidants and antioxidant enzymes. Activation of O&NS pathways occurs when excess of ROS/RNS and/or compromised antioxidant defenses are present. Beside damage to fatty acids, proteins, DNA and mitochondria, damage by O&NS may initiate autoimmune responses. Thus, oxidative stress may damage fatty acids that in turn cause lipid peroxidation and damage to cell membranes. Increased production of NO and peroxynitrite may cause nitration and nitrosylation of proteins. These O&NS processes alter the chemical structure of endogenous fatty acids and proteins, potentially rendering them immunogenic, inducing immunoglobulin-mediated autoimmune responses directed against fatty acid and protein neoepitopes.

MDD is accompanied by lowered antioxidant levels, including coenzyme Q10, vitamin E, zinc, glutathione; and reduced antioxidant enzyme activities, such as glutathione peroxidase (for a review, see Maes et al.).113 Increased O&NS damage is indicated by signs of lipid peroxidation, including increased plasma levels of malondialdehyde, a by-product of polyunsaturated fatty acid (PUFA) peroxidation, arachidonic acid and increased 4-hydroxynonenal expression in the anterior cingulate cortex of bipolar patients (for a review, see Maes et al.).113 Damage to DNA is indicated by increased levels of 8-hydroxy-2-deoxyguanosine, a mutagenic DNA lesion, in the urine or plasma of depressed patients. There is also evidence for immunoglobulin-G and immunoglobulin-M mediated autoimmune responses against neoepitopes including oxidized low-density lipoprotein, the three major anchorage molecules (palmitic and myristic acid, and S-farnesyl-L-cysteine) and NO-adducts, including NO-phenylalanine and NO-tyrosine.113

Damage by O&NS and subsequent autoimmune responses are major causes of disease progression, as demonstrated by the contributory roles of lipid peroxidation and oxidative damage to proteins in neurodegenerative disorders.114, 115, 116 Pathophysiological mechanisms include activation of the Janus kinase/signal transducer and activator of transcription pathway (influencing DNA transcription) in glia and astroglia, lowered expression of neurofilaments, reduced neuronal viability and increased cell necrosis via mitochondrial dysfunction, membrane destabilization and ion dysregulation.117, 118, 119 Moreover, lipid peroxidation products exert specific neuroprogressive effects.

For example, malondialdehyde inhibits the nucleotide excision repair system, sensitizing mutagenesis and damaging DNA,120 and causes mitochondrial damage by increasing mitochondrial ROS, inhibiting mitochondrial respiratory processes and reducing the mitochondrial membrane potential and mitochondrial antioxidant levels.121 4-Hydroxynonenal induces inflammation and neuronal cell death via apoptotic pathways, leads to accumulation of peroxides in astrocytes, impairments in axon regeneration, aberrant axonal functioning, loss of active mitochondria and suppressed mitochondrial respiration.122, 123, 124, 125, 126

The immunoglobulin-M mediated autoimmune responses in depression not only amplify inflammatory reactions but target molecules involved in cell signalling pathways. The three major anchorage molecules (palmitic acid, myristic acid and S-farnesyl-L-cysteine) bind hundreds of functional proteins and receptors to the inner cell membrane, determining proper functioning of these proteins and receptors. Palmitoylation, myristoylation and farnesylation are therefore required for intracelluar signal transduction, cellular architecture, cellular differentiation, DNA synthesis and cell growth.127, 128, 129

Autoimmune responses targeting the three anchorage molecules and other key components may lead to aberrations in cell signaling functions in depression. Further, these findings demonstrate autoimmune responses directed against functionally active neo-epitopes confer increased risk to developing chronic depression, as autoimmune processes amplify inflammatory reactions and interfere with critical cell signaling pathways that activate disease pathways involved in the pathophysiology of chronic depression.

NO production and nitrosative stress: Disturbed NO production appears related to the pathogenesis of depression.130, 131, 132 Endogenous hippocampal NO production is associated with the pathophysiology of MDD,133, 134 and agents that block NOS can produce antidepressant effects. SSRIs (for example, paroxetine) have been demonstrated to act as a NOS inhibitors, and the NO inhibitor methylene blue has putative antidepressant effects.135

NO has roles in immune, neuronal, paracrine and endocrine regulation, and exerts influences over numerous neurotransmitter systems. NO may inhibit the basal and potassium-stimulated release of NA136 and potentially inhibits reuptake of noradrenaline by influencing cyclic guanosine monophosphate (cGMP)-mediated uptake processes.137

Inhibition of NOS decreases 5-HT turnover in the frontal cortex138 and fluoxetine down regulates hippocampal NOS139 and striatal NO production.140 Activation of 5-HT1a receptors appears inversely related to NOS expression.139 NO also influences DA transmission134 and interacts with the excitatory glutamatergic system. Animal models suggest NO, via altering the level of cGMP, can produce depression-like states.141 cGMP is metabolized via phosphodiesterase enzymes, and drugs that affect the phosphodiesterase enzyme cGMP functions may be useful in MDD.142 In addition, N-1-acetyl-5-methoxylkyuramine, a brain metabolite of melatonin, inhibits NOS,143 which is consistent with an antidepressant function of melatonin receptor-1 and melatonin receptor-2 melatonergic receptor agonist agomelatine.144

The increased immunoglobulin-M mediated immune responses directed against NO-adducts indicate increased nitrosylation and chronically elevated NO levels in depression.93 The conversion of organic compounds into nitroso derivatives (NO-formation) provides an index of ROS and RNS production. Results suggest increased ROS and RNS enables nitrosation of proteins facilitating autoimmune responses against these nitrosated neo-epitopes (nitrosyls).

Mitochondrial dysfunction: MDD is associated with decreased brain energy generation.145 Dysfunctional mitochondrial energy production is associated with depression146, 147, 148, 149, 150 and may contribute to pathogenesis through influencing neurogenesis and cell survival.151 Stress induces robust inhibition of mitochondrial energy generation152 and damages mitochondrial ultrastructure. Changes in mitochondrial size, distribution and function are observed in MDD.153 Antidepressants and lithium upregulate mitochondrial energy generation,154 and N-acetylcysteine (NAC) enhanced mitochondrial function and cognition in an animal model of mitochondrial dysfunction.4 Mitochondrial dysfunction impairs neural progenitor cell function155 and can result from action of various inflammatory mediators including TNF-α, IL-6 and ROS.151 TNF-α suppresses pyruvate dehydrogenase156 and mitochondrial complexes I and IV.157

As the high metabolic rate of the brain strongly depends on mitochondrial adenosine triphosphate production, dysfunctional mitochondria have a key role in neurodegenerative disorders.158 Dysfunctional mitochondria together with the IO&NS pathways synergistically contribute to the neurodegenerative processes in Parkinson's disease, Alzheimer's dementia, Huntington's disorder and amyotrophic lateral sclerosis.159, 160 Mitochondrial-derived hyperproduction of ROS and the mitochondrial apoptotic pathway controlling caspase-9 and release of cytochrome c are critical in the neurodegenerative processes.

Neurotrophins and neurogenesis

The importance of neurogenesis for hippocampal function161 is supported by the high rate of ongoing neuronal generation in the dentate gyrus.162 Neurotrophins are key mediators of normal neurogenesis, and numerous findings support the role of neurotrophins and neurogenesis in MDD. In animal models, stress reduces neurogenesis in the subgranular zone of the dentate gyrus and the subventricular zone of the lateral ventricle, potentially resulting in neuronal atrophy, neurotoxicity and increased vulnerability to insults. This hippocampal damage appears driven by increased glucocorticoids, although 5-HT, N-methyl-D-aspartate and neurotrophins are also implicated. Glucocorticoids have a role in allostatic regulation function, modulating the potentially noxious effects of excitatory amino-acid neurotransmitters in response to environmental changes as well as impacting neuronal excitability involved in learning and memory.

Neurotrophins regulate neurogenesis in the hippocampus, and affect cell survival via inhibition of apoptotic pathways. MDD is characterized by altered levels of neurotrophins BDNF,163 vascular endothelial growth factor,164 insulin growth factor,165, 166 fibroblast growth factors,167 S100 calcium-binding protein B (s100b),168 B-cell lymphoma 2 and glial cell line-derived neurotrophic factor.169 Administration of these factors produces antidepressant effects in animal models,170, 171 and traditional antidepressant medications may alter neurotrophin levels.172

Decreased BDNF appears correlated with severity and recurrent MDD,173, 174, 175 although this was not replicated in a recent study.176 Molendijk et al.176 demonstrated normalization of BNDF lags symptomatic improvement, noting that a wide variety of factors influence BDNF levels. BDNF concentration appears to be lower in untreated depressed patients compared with those on antidepressant therapy,173 but the effect of increasing BDNF appears mostly related to 5-HT modulation.176 Neurogenesis appears increased by treatment with antidepressant drugs as well as electroconvulsive therapy, although this may also be explained by mistaking induced dematurated granule cells for new neurons.161

Exposure to neonatal stress can lead to decreased levels of hippocampal BDNF177, 178 through altered gene expression. Altered BDNF expression may produce disease vulnerability as consequence of a smaller neuronal reserve and decreased neuronal survival.179 Besides the hippocampus, altered levels of BDNF and the TRkB receptors to which they bind may occur in DA pathways projecting from the ventral tegmental area in the midbrain to the nucleus accumbens.36, 180 Progressively decreasing BDNF expression may underpin the larger alterations in brain region volume associated with an increased number of depressive episodes.9, 181 Such a possibility would fit with a neuroprogressive model of MDD.

Other neurotrophins appear to experience greater derangement with increasing episode frequency. For example, levels of S100B, a calcium-binding protein that exerts a variety of neurotrophic and neurotoxic effects, are higher in patients with recurrent MDD compared with first episode or controls.168 S100B exerts complicated effects at both an intracellular and extracellular level, and is known to be potentially toxic at higher concentrations through activation of the receptor for advanced glycation end product.182

Inhibition of neurogenesis appears to block the effects of antidepressants, although it does not necessarily produce depression-like behavior or increase sensitivity to chronic stress. An additional caveat is that the effects of chronic stress and antidepressants on depression models seem more tightly correlated the density of the dendritic arbor of pyramidal and granule cells than with neurogenesis. For this reason, the relationship between hippocampal neurogenesis and MDD requires further elucidation, although perturbations in the degree of neurogenesis does appear to be critically related to MDD pathogenesis.161

Epigenetic influences

Epigenetic modification of gene function may be related to MDD pathogenesis183 although this is a nascent field. Levels of methylation of genes associated with depression, including nuclear receptor subfamily 3, group C, member 1 and 5-HTTLPR (serotonin transporter-linked polymorphic region) may be altered by early life events and might be amenable to pharmacological intervention.184, 185, 186 Recently, chronic administration of escitalopram normalized methylation of the P11 gene in a rodent model of depression leading to increased P11 expression.187 Potential inter-relationships exist between modulation of gene methylation and inflammatory processes in pathogenesis of depression,183 including alterations in activities related to tryptophan metabolism. Modification of the epigenetic profile of neuronal DNA is gaining recognition as a mechanism for activity-dependent epigenetic regulation in the adult nervous system.188 Necessarily, studies in humans often focus on epigenetic changes in peripheral tissues as biomarkers, which may or may not be representative of epigenetic changes in neuronal cells. Epigenetics provides a mechanism for environmental stressors to impact on gene expression and exploration of epigenetic influences presents an appealing approach to explain MDD neuropathogenesis, although the currently available empirical data has numerous limitations.

Neuroprotection and antidepressants

Antidepressants influence pathways involved in MDD neuroprogression. As previously mentioned, antidepressants may modulate neurotrophin levels including BDNF.189, 190, 191 Antidepressants interact directly with the TrkB receptor192 independent of BDNF or monoamine neurotransmitters193 systems, potentially through alternative pathways including ion channel regulation, Sigma-1 receptors and adenosine reuptake protein modulation. Interestingly, antidepressant activation of TrkB does not occur in vitro (for example, in isolated cell lines), suggesting an in context network may underpin this effect.193 Given this, agents that interact directly with TrkB194 are being developed, with early findings suggesting potential antidepressant and anxiolytic properties.195, 196

Antidepressants exert anti-inflammatory properties, potentially through modulating levels of pro and anti-inflammatory cytokines. For example, the initially increased levels of CMI cytokines and PICs (for example, IL-12, IFN-γ) are decreased by SSRIs. In addition, SSRIs increase anti-inflammatory cytokine (for example, IL-10, IL-4, transforming growth factor-β1) levels in depressed patients.197, 198 Other non-SSRI antidepressants appear to modulate levels of inflammatory cytokines199, 200 leading to an anti-inflammatory effect. For example, the tricyclic desipramine may decrease neuronal production of TNF-α, an effect that over time alters NA transmission,201 potentially by modifying expression or function of α2-adrenergic receptors

New therapeutic targets

Anti-inflammatory drugs

Anti-inflammatory agents may be beneficial in MDD.202 Acetylsalicylic acid (aspirin) augments ROS reduction when combined with fluoxetine,203 and has demonstrated faster antidepressant effects in combination than fluoxetine alone in animal models204 and an open-label clinical study.205 Aspirin augmentation may be have particular potential in treatment-resistant populations.206 Celecoxib, a COX-2 inhibitor, has demonstrated benefit in reducing depressive symptoms in randomized placebo-controlled trials when combined with reboxetine207 and fluoxetine.208 Similarly, the tetracylic antibiotic agent minocycline, which enhances neurogenesis and exhibits strong anti-inflammatory effects,209 appears to augment antidepressant effects of desipramine in rat behavior,210 although few other trial data exist.211 Erythropoietin, which shows neuroprotective and neurotrophic properties in hypoxic-ischemic, traumatic, excitotoxic and inflammatory models, appears to be effective in animal as well as proof-of-concept human depression studies.212

The role of specific PIC antagonists has also been explored in special populations. For example, TNF-α antagonists etanercept and infliximab may improve depressive symptoms in patients suffering from psoriasis.213, 214 Agents that induce release of PICs such as IFN-α, used in treatment of viral illness's including hepatitis C, can induce MDD symptoms;215, 216 this may be prevented by pre-administration of SSRIs.217

Statins

Statins impact regulation of IO&NS. Statins had anti-IO&NS effects in a model of spontaneously hypertensive rats218 and in patients with hypertension and dyslipidemia.219 Following an acute cardiac event, statins were associated with reductions of TNF-α and IFN-γ generation in stimulated T-lymphocytes.220 Statins also upregulate glutathione synthesis,221 decrease lipid peroxidation222 and reduce oxidized low-density lipoprotein accumulation, potentially through stimulating superoxide dismutase 1, a free radical scavenging enzyme. Clinical studies suggest statins may reduce the risk of depression in at risk populations,223, 224 which may be ascribed to their anti-IO&NS effects, and may be a promising therapeutic avenue.224, 225

Diet, including PUFAs

Certain dietary measures and regular physical activity are associated with reduced depressive symptoms that may be partially mediated through regulation of IO&NS. Poorer quality diets (characterized by large proportion of processed foods high in fat and sugars) are associated with increased likelihood of depression.226 Consumption of such highly palatable foods potentially mediates increased ROS227 and inflammatory cytokines. Certain dietary items such as PUFAs, zinc, selenium and magnesium appear to exhibit anti-inflammatory properties and are potential therapeutic modalities. Deprivation of omega-3 PUFAs increased depressive symptoms in a rat model, and supplementation can exert antidepressant-like effects.228, 229, 230, 231 Omega-3 PUFAs exert anti-inflammatory effects88 in both animals232, 233 and humans,234 although data in depressed populations are limited. In addition, Omega-3 is positively associated with grey matter volume and deficiency impairs astrocyte-mediated neuron-vascular coupling.235, 236 Supplemental omega-3 PUFAs appear to be effective for depressive symptoms, but study heterogeneity is limiting.237, 238

Antioxidants

Specific antioxidants may exert antidepressant effects. NAC augmentation improved depressive symptoms in bipolar disorder,239 and administration of NAC decreases immobility time in depression models of male Wistar rats.240 NAC is a potent antioxidant that increases glutathione241 and that additionally has anti-inflammatory effects, promotes neurogenesis and neuronal survival, and reverses models of mitochondrial toxicity.239, 242, 243 These findings are corroborated by studies on the effects of ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one), a compound that mimics the antioxidant and neuroprotective activity of glutathione peroxidase.244, 245 Similar to NAC, ebselen also yields antidepressant effects246 and prevents the activation induction of IO&NS pathways that accompany immobilization stress.247

Conclusion

MDD is a complex disorder. Understanding pathways aiding pathogenesis and neuroprogression provides opportunities for improving treatment outcomes. Emphasis on relapse prevention is supported by the concept of MDD as a neuroprogressive disorder with each episode precipitating increased functional impairment and sensitivity for further episodes. It is, however, necessary to emphasize the bidirectional nature of the process, and that substantial plasticity and remodelling can occur. A number of potential novel treatment pathways are emerging out of the rapidly expanding research base.

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Acknowledgements

The authors wish to gratefully acknowledge the assistance of Dr Harris Eyre in the preparation of this manuscript.

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All authors are responsible for the design, content and research used in this manuscript. All authors have approved all manuscript contents.

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Correspondence to S Moylan.

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Dr S Moylan, Professor NR Wray and Professor M Maes declare no conflict of interest. Professor M Berk has received Grant/Research Support from Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Geelong Medical Research Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Organon, Novartis, Mayne Pharma and Servier, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvayand Wyeth, and served as a consultant to Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck and Servier.

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Moylan, S., Maes, M., Wray, N. et al. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry 18, 595–606 (2013). https://doi.org/10.1038/mp.2012.33

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Keywords

  • cytokines
  • depression
  • inflammation
  • neuroprogression
  • nitrosative stress
  • oxidative stress

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