The Neuroprogressive Nature of Major Depressive Disorder: Pathways to Disease Evolution and Resistance, and Therapeutic Implications

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

S Moylan1, M Maes2,NRWray3 and M Berk1,4,5,6

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.

Molecular Psychiatry (2013) 18, 595--606; doi:10.1038/mp.2012.33; published online 24 April 2012 Keywords: cytokines; depression; inﬂammation; neuroprogression; nitrosative stress; oxidative stress

INTRODUCTION RESULTS AND DISCUSSION Although some patients with major depressive disorder (MDD) Clinical sequelae and structural consequences of MDD suffer from only one depressive episode, many display character- MDD may be associated with stage-related structural brain istics of a progressive illness. In progressive illness, outcomes1--3 changes potentially resulting from toxic or adaptive effects and treatment efficacy4,5 are inversely correlated with earlier produced during depressive episodes. Structural changes are disease onset and increased number and length of depressive inconsistently found during the first episode; however, they episodes.6 Longer and more frequent depressive episodes appear appear more commonly in severe, protracted illness.8 For to increase vulnerability to further relapses,7 facilitating an example, meta-analysis of available data suggests reduced accelerating and progressive illness course associated with hippocampal volume, a common9--13 but not universal finding functional decline. For example, the number of past depressive in MDD, is consistently present in patients with illness duration episodes is associated in a dose-dependent manner with memory 42 years and in those with 41 depressive episode.9 Hippocam- decline (2--3% per episode; up to 4),1 and increased dementia risk pal volume change in MDD is influenced by patient age, gender, (13% per episode).3 It is probable that depressive episodes cause illness duration, age of onset, episode frequency, comorbidity, brain tissue damage and altered physiological functioning depression subtype and genotype.12 Consistent with trial data,14--17 through a variety of mechanisms that underpin patient sympto- a meta-analysis confirmed a direct correlation between increasing matology and functional decline over time. Evidence from episode number and decreased hippocampal volume.18 Length of neuroimaging and molecular studies appears to support this untreated illness has also been correlated with degree of model. This understanding is key to informing new treatment hippocampal volume reduction,19 although this is not consistently strategies. This paper reviews current knowledge of the neuropro- replicated.15 Although some evidence supports early volume gressive processes that may occur in MDD, its structural reduction (that is, commencing after the first episode)20 not all consequences and molecular basis, and evidence-based novel studies support differential volume reduction in first vs multi- treatments. 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 MATERIALS AND METHODS themselves in functional consequences of MDD. For example, Data for this review were sourced from electronic databases PUBMED, lower verbal memory scores were associated with decreased EMBASE and PsycInfo and were not limited by language or date of hippocampal volumes in patients with recurrent depressive 20 publication. episodes. It is important, however, to consider that a number

1School of Medicine, Deakin University, Geelong, VIC, Australia; 2Piyavate Hospital, Bangkok, Thailand; 3Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia; 4Orygen Youth Health Research Centre, Centre for Youth Mental Health, Parkville, VIC, Australia; 5The Mental Health Research Institute of Victoria, Parkville, VIC, Australia and 6Department of Psychiatry, Melbourne University, Parkville, VIC, Australia. Correspondence: Dr S Moylan, School of Medicine, Deakin University, C/o Swanston Centre, Barwon Health, Geelong, VIC 3220, Australia. E-mails: [email protected] and [email protected] Received 12 January 2012; revised 21 February 2012; accepted 19 March 2012; published online 24 April 2012 Neuroprogressive nature of major depressive disorder S Moylan et al 596 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 -- 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 pathophysiolo- Figure 1. Neuroprogression in MDD. Psychosocial and physical gical models have been utilized to explain these clinical findings; a stressors combine with pre-existing MDD vulnerability to precipitate 36 a first depressive episode. Biochemical factors including in- ‘sensitization model’ and ‘kindling model’. Sensitization suggests flammatory, O&NS, mitochondrial dysfunction, epigenetic altera- repeated administration of diverse stimuli causes progressive 40 tions, HPA axis dysregulation and disturbance to neutrophic amplification of neuronal responses over time. In this model, function interact to cause cellular damage, stimulate apoptosis and psychological or organic stressors causes time-dependent sensitiza- decrease neuronal growth and survival. These effects render the tion leading to susceptibility to re-stress that increases progres- individual increasingly treatment resistant and more vulnerable to sively.41--43 The kindling model is based on observations that further episodes. Each episode is associated with progressive cog- exogenous substances that induce seizures facilitate brain altera- nitive and functional decline, and associated structural brain chan- tions leading to endogenous seizures in animals. Over time, ges. HPA, hypothalamic--pituitary--adrenal; MDD, major depressive repeated illness episodes can permanently alter neuronal activity, disorder; O&NS, oxidative and nitrosative stress. 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 neurodegeneration. TRYCATs, such as kynurenic acid, 3-hydro- could reinforce the maladaptive changes facilitating longer term xyanthranilic acid and/or 3-hydroxykynurenine, impair mitochon- susceptibility.36 drial energy metabolism including adenosine triphosphate Numerous neurobiological mechanisms contribute to the production and reduce mitochondrial respiratory mechanisms.47,48 IFN-g-induced IDO activity increases synthesis of pathogenesis and neuroprogression of MDD, mediating changes 46 in conjunction with dynamic environmental influences (Figure 1). neurotoxic TRYCATs. Quinolinic acid, for example, exerts agonistic effects at N-methyl-D-aspartate receptors a process that Major pathways include neurotransmitter systems, inflammatory, 49 50 oxidative and nitrosative stress (IO&NS), neurotrophins and leads to excitotoxicity; inhibits glutamate uptake; and may neurogenesis, cortisol and hypothalamic--pituitary--adrenal axis cause degeneration of nerve cells; hippocampal cell death; destruction of postsynaptic elements; and reduction in central (HPA) modulation, mitochondrial dysfunction, epigenetic influ- 51 -- 53 ences and dietary factors (Figure 2). cholinergic functioning. All these mechanisms potentially underpin neuroprogression. Anti-serotonin antibody titers appear significantly higher in Pathways to neuroprogression MDD patients (54.1%), particularly those with melancholia (82.9%), Serotonergic system. The serotonergic system is tightly coupled to compared with controls (5.7%).54 Autoimmune responses may depression onset,44 stage and neuroprogression. Serotonin interfere with 5-HT neurotransmission, in part helping to explain (5-hydroxytryptophan (5-HT)) acts as a neurotrophic factor; 5-HT hyporesponsivity in depression,44 which may in turn be stimulating neurogenesis and brain-derived neurotrophic factor involved in lowered neurogenesis and changes in postsynaptic (BDNF) expression45 that in turn promotes 5-HT neuronal survival. receptor expression and function. Importantly, autoimmune The lowered metabolism of 5-HT in depression may contribute to activity directed against 5-HT is significantly associated with the reduced neurogenesis and subsequent neuroprogression. 5-HT is number of previous depressive episodes; patients with 43 produced from tryptophan, an essential amino acid catabolized by depressive episodes had a higher frequency of 5-HT autoimmunity indoleamine 2,3-dioxygenase (IDO). Cell-mediated immune (CMI) than those with 1 or 2 prior episodes. These findings suggest each cytokines (for example, interferon gamma (IFN-g)) can activate IDO depressive episode may progressively increase the propensity to leading to tryptophan and 5-HT depletion, and synthesis of develop autoimmune responses to 5-HT. The latter in turn will tryptophan catabolites (TRYCATs) including kynurenine and increase the risk of new depressive episodes and to sequelae of quinolinic acid in the plasma and brain. Similarly, some evidence reduced 5-HT, such as neuroprogression. All in all, the findings suggests depression is accompanied by IDO activation, lowered show that progressive autoimmune responses against 5-HT plasma tryptophan and relative increases in detrimental TRYCATs contribute to the sensitization or kindling of depression. and/or decreases in neuroprotective TRYCATs, such as kynurenic acid (for a review, see Maes et al.).46 There are multiple Noradrenergic (NA) and dopaminergic (DA) systems. NA alterations consequences of IDO activation. Reduced tryptophan and 5-HT are strongly associated with depression. Post-mortem and impairs antioxidant defenses as both are strong antioxidants. functional imaging studies reveal altered density and sensitivity Some TRYCATs increase oxidative stress (for example, 5-hydro- of a-2 adrenoreceptors, which modulate noradrenaline release, in xyanthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic and prefrontal cortices of depressed suicidal victims.55,56 Peripheral quinolinic acid)46 and are involved in processes that facilitate markers of altered central NA function (decreased platelet a-2

Molecular Psychiatry (2013), 595 -- 606 & 2013 Macmillan Publishers Limited Neuroprogressive nature of major depressive disorder S Moylan et al 597

Figure 2. 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 antioxidant 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-g, 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-a, tumor necrosis factor-alpha; TRYCAT, tryptophan catabolite.

adrenoreceptor density) has also been found in depressed patients with MDD are possibly mediated by augmented patients.57 Decreased axonal density of NA neurons appears to postsynaptic responses secondary to low basal DA tone.60 be induced by IFN-alpha (IFN-a),58 suggesting a potential Repeated stress may lead to sensitization of the mesolimbic DA connection between depressive symptoms and inflammatory system via increased glucocorticoids,64 as glucocorticoids them- mediated effects on the NA system. Antidepressants appear to selves may selectively facilitate DA transmission in the nucleus increase axonal regeneration of cortical NA neurons.59 accumbens. Alterations in DA function may partially underpin the delayed The role of dopamine in pathogenesis may partially explain effects of antidepressants.60 Individuals with MDD have decreased incomplete response rates to standard antidepressants,60 reflect- turnover of homovanillic acid, the primary metabolite of ing the failure of increased 5-HT and NA neurotransmission to dopamine.61,62 This correlates with a lower DA tone in MDD, a appropriately modify DA signalling. Supporting this, responders to finding consistent with depressogenic effects of DA depletion in selective serotonin reuptake inhibitors (SSRIs), but not non- 63 depressed patients. Greater D-amphetamine responses in responders, exhibit increased dopamine binding to striatal D2

& 2013 Macmillan Publishers Limited Molecular Psychiatry (2013), 595 -- 606 Neuroprogressive nature of major depressive disorder S Moylan et al 598 receptors,60 with degree of increased D2 binding correlated with depressive episodes magnifies the responses of depressogenic improvement in depressive symptoms. cytokines, potentially increasing the likelihood of new depressive episodes. These PICs, CMI-related cytokines and compounds such Inflammation and CMI activation. MDD is characterized by chronic as neopterin induce neuroprogressive processes facilitate staging inflammation and CMI activation independent of pathogen of depression. response.65,66 The evidence is underscored by three recent meta- analyses demonstrating increased levels of pro-inflammatory Corticotrophin-releasing hormone (CRH) and the HPA axis. Numer- cytokines (PICs) including interleukins (IL-1, IL-6), tumor necrosis ous lines of evidence support a role of CRH and HPA axis alteration factor-alpha (TNF-a)67,68 and T-cell activation indicated by increased in MDD (for a review, see Swaab et al.).95 Many depressive serum levels of soluble IL-2 receptors69 in MDD. Another consistent symptoms can be induced by intracerebroventricular injections of finding is increased neopterin, indicating increased IFN-g-mediated CRH,96 and patients with MDD exhibit higher CRH neuronal macrophage activation.66 Increased production of PICs and CMI- activation and raised salivary, plasma and urinary cortisol related cytokines (for example, IFN-g, IL-2) elicits depressive- and compared with aged matched controls.97 It is postulated that anxiety-like behaviors,70 with even small concentration changes HPA axis hyperactivity may result from early life programming.98 consistently associated with the cardinal symptoms of depression. Events that sensitize the HPA axis in utero including maternal Moderate increments in cytokine levels may cause depression in stress or smoking, and early bereavement or abuse in childhood individuals vulnerable to inflammatory changes (for example, lead to a higher risk of developing MDD later in life. An enduring patients receiving hemodialysis or IFN-a-based immunotherapy, sensitivity of CRH neurons is commonly seen in depressed post-partum women).71 Vulnerability to inflammatory triggers in individuals, and may reflect a state of glucocorticoid resistance, depression is determined by factors including decreased levels of which facilitates increased exposure to glucocorticoids throughout immunologically active peptidases (dipeptidylpeptidase IV and the brain and body.99 Chronic use of antidepressants upregulate prolylendopeptidase) and by polymorphisms in cytokine and glucocorticoid receptor (GR) expression and function, leading to oxidative and nitrosative stress (O&NS) genes.70 increased negative feedback and subsequent decreases in HPA Changes in inflammatory markers appear related to the number axis reactivity.100 In addition, the GR has a key role in mediating of depressive episodes. Neopterin is significantly increased in antidepressant-induced hippocampal neurogenesis.101 Alteration patients with X2 depressive episodes compared with those of action appears to include inhibitory effects on cell membrane with p1 episode,72 and neopterin, IL-1 and TNF-a are signifi- steroid transporters (for example, P-glycoprotein), leading to cantly higher in patients with X3 depressive episodes.73 decreased glucocorticoid expulsion and higher intracellular These findings suggest prior depressive episodes sensitize PIC concentrations (increasing GR function), and activation of GR responses and IFN-g-induced mechanisms, potentially increasing translocation from cytoplasm to the nucleus, decreasing GR vulnerability for further depressive episodes. Additionally, patients expression and function.100 with a lifetime history of MDD showed increased IL-6 and The HPA axis is activated by PICs involved in depression and soluble IL-1 receptor antagonist (indicating monocytic activation) neuroprogression, including IL-6, TNFa, IL-1b and IFN-g.102,103 Maes in the early puerperium, suggesting prior depression sensitizes et al.104 showed that HPA axis hyperactivity, either increased inflammatory responses.74 PICs and IFN-g-related mechanisms baseline activity or glucocorticoid resistance, is associated with mediate central sensitization in behavioral responses to maternal increased production of PICs. There is evidence that glucocorticoid separation75 and may at least partially mediate the above resistance in depression is caused by IL-2 and IL-1b-related sensitization. mechanisms.105 The increased production of PICs and CMI-related Increased levels of PICs and CMI-related cytokines may cytokines could thus induce HPA axis hyperactivity by causing contribute to neuroprogression.76 Increased IFN-g production glucocorticoid resistance and increased baseline hormonal stimulates IDO and increases production of neurotoxic TRYCATs. activity.98,104 --106 Moreover, IFN-g sensitizes cortical and cerebellar neurons to Changes in gene expression may additionally underlie envir- neurotoxic peptides, increases neuronal death, participates in onmentally mediated HPA axis hyperactivity susceptibility. Patients neuronal loss and exacerbates neurotoxicity in neurodegenerative suffering from MDD or bipolar depression have been demon- 77,78 disorders. IL-2 potentiates the effects of N-methyl-D-aspartate strated to exhibit decreased GR messenger ribonucleic acid levels and has a role in reactive astrogliosis, myelin damage and in the frontal cortex, amygdala and hippocampus.107,108 Poly- neuronal loss in many brain regions.79,80 IL-1b has neurotoxic morphisms (rs6198, rs6191 and rs33388) of the nuclear receptor effects on astrocytes and endothelial cells, thereby causing subfamily 3, group C, member 1 gene (which codes for the GR) and increased production of free radicals and metaloproteinases, FK506 binding protein 5 (FKBP5) gene are associated in mediating which together may cause neuronal death, and exacerbates cell environmentally induced onset of depressive risk.109,110 FKBP5, 111 death by increasing seizure activity and N-methyl-D-aspartate which is found in both the cytoplasm nucleus, is a co-chaperone receptor functions.81 -- 85 Moreover, increased IL-1 production of heat shock protein 90 that modulates GR sensitivity. Increased impairs hippocampal neurogenesis and cytogenesis; reduces expression of FKBP5, through gene polymorphism-induced upre- BDNF expressions at both the messenger ribonucleic acid and gulation, appears related to increased GR resistance. FKBP5 binding protein level; reduces neurotrophin TrK receptor expression in the lowers GR affinity for cortisol, reducing negative feedback and its hippocampus and increases p75 receptor expression, subse- expression is actually induced by steroids. In this respect, increased quently impairing neuronal survival.86 -- 88 environmental stressors, facilitating increased glucocorticoid ex- TNF-a influences neuroprogressive processes such as silencing pression, may induce FKBP5 expression and further GR resistance of cell survival signals, activation of caspase-dependent mechan- (for a review, see Binder),112 which may increase risk for MDD. isms and potentiation of glutamate neurotoxicity.89 Neopterin, in turn, potentiates the effects of reactive oxygen species (ROS), such O&NS and mitochondrial dysfunctions as hydrogen peroxide.90,91 Neopterin also triggers inducible nitric Oxidative stress: Inflammatory and mitochondrial processes can oxide synthase gene expression enhancing nitric oxide (NO) increase production of ROS and reactive nitrogen species (RNS) production.92 Therefore, neopterin may have a role in activating including superoxide, NO, peroxynitrite and peroxides. Under O&NS pathways observed in depression.93 Moreover, neopterin normal conditions, the potentially damaging effects of increased may elicit programmed cell death caused by PICs and O&NS.92,94 ROS and RNS on lipids, proteins, deoxyribonucleic acid (DNA) and Taken together, inflammation and CMI activation may con- mitochondria are counterbalanced by defense systems, including tribute to the staging or recurrence of MDD. Exposure to previous antioxidants and antioxidant enzymes. Activation of O&NS

Molecular Psychiatry (2013), 595 -- 606 & 2013 Macmillan Publishers Limited Neuroprogressive nature of major depressive disorder S Moylan et al 599 pathways occurs when excess of ROS/RNS and/or compromised NO production and nitrosative stress: Disturbed NO production antioxidant defenses are present. Beside damage to fatty acids, appears related to the pathogenesis of depression.130 -- 132 proteins, DNA and mitochondria, damage by O&NS may initiate Endogenous hippocampal NO production is associated with the autoimmune responses. Thus, oxidative stress may damage fatty pathophysiology of MDD,133,134 and agents that block NOS can acids that in turn cause lipid peroxidation and damage to cell produce antidepressant effects. SSRIs (for example, paroxetine) membranes. Increased production of NO and peroxynitrite may have been demonstrated to act as a NOS inhibitors, and the NO cause nitration and nitrosylation of proteins. These O&NS inhibitor methylene blue has putative antidepressant effects.135 processes alter the chemical structure of endogenous fatty acids NO has roles in immune, neuronal, paracrine and endocrine and proteins, potentially rendering them immunogenic, inducing regulation, and exerts influences over numerous neurotransmitter immunoglobulin-mediated autoimmune responses directed systems. NO may inhibit the basal and potassium-stimulated against fatty acid and protein neoepitopes. release of NA136 and potentially inhibits reuptake of noradrenaline MDD is accompanied by lowered antioxidant levels, including by influencing cyclic guanosine monophosphate (cGMP)- coenzyme Q10, vitamin E, zinc, glutathione; and reduced mediated uptake processes.137 antioxidant enzyme activities, such as glutathione peroxidase Inhibition of NOS decreases 5-HT turnover in the frontal (for a review, see Maes et al.).113 Increased O&NS damage is cortex138 and fluoxetine down regulates hippocampal NOS139 indicated by signs of lipid peroxidation, including increased and striatal NO production.140 Activation of 5-HT1a receptors plasma levels of malondialdehyde, a by-product of polyunsatu- appears inversely related to NOS expression.139 NO also influences rated fatty acid (PUFA) peroxidation, arachidonic acid and DA transmission134 and interacts with the excitatory glutamatergic increased 4-hydroxynonenal expression in the anterior cingulate system. Animal models suggest NO, via altering the level of cGMP, cortex of bipolar patients (for a review, see Maes et al.).113 Damage can produce depression-like states.141 cGMP is metabolized via to DNA is indicated by increased levels of 8-hydroxy-2-deoxygua- phosphodiesterase enzymes, and drugs that affect the phospho- nosine, a mutagenic DNA lesion, in the urine or plasma of diesterase enzyme cGMP functions may be useful in MDD.142 In depressed patients. There is also evidence for immunoglobulin-G addition, N-1-acetyl-5-methoxylkyuramine, a brain metabolite of and immunoglobulin-M mediated autoimmune responses against melatonin, inhibits NOS,143 which is consistent with an anti- neoepitopes including oxidized low-density lipoprotein, the three depressant function of melatonin receptor-1 and melatonin major anchorage molecules (palmitic and myristic acid, and receptor-2 melatonergic receptor agonist agomelatine.144 S-farnesyl-L-cysteine) and NO-adducts, including NO-phenylala- The increased immunoglobulin-M mediated immune responses nine and NO-tyrosine.113 directed against NO-adducts indicate increased nitrosylation Damage by O&NS and subsequent autoimmune responses are and chronically elevated NO levels in depression.93 The conversion major causes of disease progression, as demonstrated by the of organic compounds into nitroso derivatives (NO-formation) contributory roles of lipid peroxidation and oxidative damage to provides an index of ROS and RNS production. Results proteins in neurodegenerative disorders.114 -- 116 Pathophysiologi- suggest increased ROS and RNS enables nitrosation of proteins cal mechanisms include activation of the Janus kinase/signal facilitating autoimmune responses against these nitrosated neo- transducer and activator of transcription pathway (influencing epitopes (nitrosyls). DNA transcription) in glia and astroglia, lowered expression of neurofilaments, reduced neuronal viability and increased cell Mitochondrial dysfunction: MDD is associated with decreased brain necrosis via mitochondrial dysfunction, membrane destabilization energy generation.145 Dysfunctional mitochondrial energy pro- and ion dysregulation.117 -- 119 Moreover, lipid peroxidation production is associated with depression146 -- 150 and may contribute ducts exert specific neuroprogressive effects. to pathogenesis through influencing neurogenesis and cell For example, malondialdehyde inhibits the nucleotide excision survival.151 Stress induces robust inhibition of mitochondrial repair system, sensitizing mutagenesis and damaging DNA,120 and energy generation152 and damages mitochondrial ultrastructure. causes mitochondrial damage by increasing mitochondrial ROS, Changes in mitochondrial size, distribution and function are inhibiting mitochondrial respiratory processes and reducing the observed in MDD.153 Antidepressants and lithium upregulate mitochondrial membrane potential and mitochondrial antioxidant mitochondrial energy generation,154 and N-acetylcysteine (NAC) levels.121 4-Hydroxynonenal induces inflammation and neuronal enhanced mitochondrial function and cognition in an animal cell death via apoptotic pathways, leads to accumulation of model of mitochondrial dysfunction.4 Mitochondrial dysfunction peroxides in astrocytes, impairments in axon regeneration, impairs neural progenitor cell function155 and can result from aberrant axonal functioning, loss of active mitochondria and action of various inflammatory mediators including TNF-a, IL-6 suppressed mitochondrial respiration.122 -- 126 and ROS.151 TNF-a suppresses pyruvate dehydrogenase156 and The immunoglobulin-M mediated autoimmune responses in mitochondrial complexes I and IV.157 depression not only amplify inflammatory reactions but target As the high metabolic rate of the brain strongly depends on molecules involved in cell signalling pathways. The three major mitochondrial adenosine triphosphate production, dysfunctional 158 anchorage molecules (palmitic acid, myristic acid and S-farnesyl-L- mitochondria have a key role in neurodegenerative disorders. cysteine) bind hundreds of functional proteins and receptors to the Dysfunctional mitochondria together with the IO&NS pathways inner cell membrane, determining proper functioning of these synergistically contribute to the neurodegenerative processes in proteins and receptors. Palmitoylation, myristoylation and farnesy- Parkinson’s disease, Alzheimer’s dementia, Huntington’s disorder lation are therefore required for intracelluar signal transduction, and amyotrophic lateral sclerosis.159,160 Mitochondrial-derived cellular architecture, cellular differentiation, DNA synthesis and cell hyperproduction of ROS and the mitochondrial apoptotic pathway growth.127 --129 controlling caspase-9 and release of cytochrome c are critical in Autoimmune responses targeting the three anchorage mole- the neurodegenerative processes. cules and other key components may lead to aberrations in cell signaling functions in depression. Further, these findings demon- Neurotrophins and neurogenesis. The importance of neurogenesis strate autoimmune responses directed against functionally active for hippocampal function161 is supported by the high rate of neo-epitopes confer increased risk to developing chronic depres- ongoing neuronal generation in the dentate gyrus.162 Neurotro- sion, as autoimmune processes amplify inflammatory reactions phins are key mediators of normal neurogenesis, and numerous and interfere with critical cell signaling pathways that activate findings support the role of neurotrophins and neurogenesis in disease pathways involved in the pathophysiology of chronic MDD. In animal models, stress reduces neurogenesis in the depression. subgranular zone of the dentate gyrus and the subventricular

& 2013 Macmillan Publishers Limited Molecular Psychiatry (2013), 595 -- 606 Neuroprogressive nature of major depressive disorder S Moylan et al 600 zone of the lateral ventricle, potentially resulting in neuronal escitalopram normalized methylation of the P11 gene in a rodent atrophy, neurotoxicity and increased vulnerability to insults. This model of depression leading to increased P11 expression.187 hippocampal damage appears driven by increased glucocorti- Potential inter-relationships exist between modulation of gene coids, although 5-HT, N-methyl-D-aspartate and neurotrophins are methylation and inflammatory processes in pathogenesis of also implicated. Glucocorticoids have a role in allostatic regulation depression,183 including alterations in activities related to trypto- function, modulating the potentially noxious effects of excitatory phan metabolism. Modification of the epigenetic profile of neuronal amino-acid neurotransmitters in response to environmental DNA is gaining recognition as a mechanism for activity-dependent changes as well as impacting neuronal excitability involved in epigenetic regulation in the adult nervous system.188 Necessarily, learning and memory. studies in humans often focus on epigenetic changes in peripheral Neurotrophins regulate neurogenesis in the hippocampus, and tissues as biomarkers, which may or may not be representative of affect cell survival via inhibition of apoptotic pathways. MDD is epigenetic changes in neuronal cells. Epigenetics provides a characterized by altered levels of neurotrophins BDNF,163 vascular mechanism for environmental stressors to impact on gene endothelial growth factor,164 insulin growth factor,165,166 fibroblast expression and exploration of epigenetic influences presents an growth factors,167 S100 calcium-binding protein B (s100b),168 appealing approach to explain MDD neuropathogenesis, although B-cell lymphoma 2 and glial cell line-derived neurotrophic the currently available empirical data has numerous limitations. factor.169 Administration of these factors produces antidepressant effects in animal models,170,171 and traditional antidepressant medications may alter neurotrophin levels.172 Neuroprotection and antidepressants. Antidepressants influence Decreased BDNF appears correlated with severity and recurrent pathways involved in MDD neuroprogression. As previously MDD,173 -- 175 although this was not replicated in a recent study.176 mentioned, antidepressants may modulate neurotrophin levels Molendijk et al.176 demonstrated normalization of BNDF lags including BDNF.189 -- 191 Antidepressants interact directly with the symptomatic improvement, noting that a wide variety of factors TrkB receptor192 independent of BDNF or monoamine neurotrans- influence BDNF levels. BDNF concentration appears to be lower in mitters193 systems, potentially through alternative pathways includ- untreated depressed patients compared with those on anti- ing ion channel regulation, Sigma-1 receptors and adenosine depressant therapy,173 but the effect of increasing BDNF appears reuptake protein modulation. Interestingly, antidepressant activation mostly related to 5-HT modulation.176 Neurogenesis appears of TrkB does not occur in vitro (for example, in isolated cell lines), increased by treatment with antidepressant drugs as well as suggesting an in context network may underpin this effect.193 Given electroconvulsive therapy, although this may also be explained by this, agents that interact directly with TrkB194 are being developed, mistaking induced dematurated granule cells for new neurons.161 with early findings suggesting potential antidepressant and Exposure to neonatal stress can lead to decreased levels of anxiolytic properties.195,196 hippocampal BDNF177,178 through altered gene expression. Antidepressants exert anti-inflammatory properties, potentially Altered BDNF expression may produce disease vulnerability as through modulating levels of pro and anti-inflammatory cytokines. consequence of a smaller neuronal reserve and decreased For example, the initially increased levels of CMI cytokines and neuronal survival.179 Besides the hippocampus, altered levels of PICs (for example, IL-12, IFN-g) are decreased by SSRIs. In addition, BDNF and the TRkB receptors to which they bind may occur in DA SSRIs increase anti-inflammatory cytokine (for example, IL-10, IL-4, pathways projecting from the ventral tegmental area in the transforming growth factor-b1) levels in depressed patients.197,198 midbrain to the nucleus accumbens.36,180 Progressively decreasing Other non-SSRI antidepressants appear to modulate levels of BDNF expression may underpin the larger alterations in brain inflammatory cytokines199,200 leading to an anti-inflammatory region volume associated with an increased number of depressive effect. For example, the tricyclic desipramine may decrease episodes.9,181 Such a possibility would fit with a neuroprogressive neuronal production of TNF-a, an effect that over time alters NA model of MDD. transmission,201 potentially by modifying expression or function of Other neurotrophins appear to experience greater derange- a2-adrenergic receptors. ment 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 New therapeutic targets recurrent MDD compared with first episode or controls.168 S100B Anti-inflammatory drugs. Anti-inflammatory agents may be bene- exerts complicated effects at both an intracellular and extracellular ficial in MDD.202 Acetylsalicylic acid (aspirin) augments ROS level, and is known to be potentially toxic at higher concentrations reduction when combined with fluoxetine,203 and has demon- through activation of the receptor for advanced glycation end strated faster antidepressant effects in combination than fluox- product.182 etine alone in animal models204 and an open-label clinical Inhibition of neurogenesis appears to block the effects of study.205 Aspirin augmentation may be have particular potential antidepressants, although it does not necessarily produce depres- in treatment-resistant populations.206 Celecoxib, a COX-2 inhibitor, sion-like behavior or increase sensitivity to chronic stress. An has demonstrated benefit in reducing depressive symptoms in additional caveat is that the effects of chronic stress and randomized placebo-controlled trials when combined with antidepressants on depression models seem more tightly corre- reboxetine207 and fluoxetine.208 Similarly, the tetracylic antibiotic lated the density of the dendritic arbor of pyramidal and granule agent minocycline, which enhances neurogenesis and exhibits cells than with neurogenesis. For this reason, the relationship strong anti-inflammatory effects,209 appears to augment anti- between hippocampal neurogenesis and MDD requires further depressant effects of desipramine in rat behavior,210 although few elucidation, although perturbations in the degree of neurogenesis other trial data exist.211 Erythropoietin, which shows neuropro- does appear to be critically related to MDD pathogenesis.161 tective and neurotrophic properties in hypoxic-ischemic, trau- matic, excitotoxic and inflammatory models, appears to be Epigenetic influences. Epigenetic modification of gene function effective in animal as well as proof-of-concept human depression may be related to MDD pathogenesis183 although this is a nascent studies.212 field. Levels of methylation of genes associated with depression, The role of specific PIC antagonists has also been explored in including nuclear receptor subfamily 3, group C, member 1 and special populations. For example, TNF-a antagonists etanercept 5-HTTLPR (serotonin transporter-linked polymorphic region) may be and infliximab may improve depressive symptoms in patients altered by early life events and might be amenable to pharmaco- suffering from psoriasis.213,214 Agents that induce release of logical intervention.184 --186 Recently, chronic administration of PICs such as IFN-a, used in treatment of viral illness’s including

Molecular Psychiatry (2013), 595 -- 606 & 2013 Macmillan Publishers Limited Neuroprogressive nature of major depressive disorder S Moylan et al 601 hepatitis C, can induce MDD symptoms;215,216 this may be Foundation, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Organon, Novartis, prevented by pre-administration of SSRIs.217 Mayne Pharma and Servier, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pﬁzer, Statins. Statins impact regulation of IO&NS. Statins had anti-IO&NS Sanoﬁ Synthelabo, Servier, Solvayand Wyeth, and served as a consultant to Astra 218 Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck effects in a model of spontaneously hypertensive rats and in and Servier. patients with hypertension and dyslipidemia.219 Following an acute cardiac event, statins were associated with reductions of 220 TNF-a and IFN-g generation in stimulated T-lymphocytes. ACKNOWLEDGEMENTS Statins also upregulate glutathione synthesis,221 decrease lipid 222 The authors wish to gratefully acknowledge the assistance of Dr Harris Eyre in the peroxidation and reduce oxidized low-density lipoprotein preparation of this manuscript. accumulation, potentially through stimulating superoxide dismu- tase 1, a free radical scavenging enzyme. Clinical studies suggest Author contributions statins may reduce the risk of depression in at risk populations,223,224 which may be ascribed to their anti-IO&NS effects, and All authors are responsible for the design, content and research used in this manuscript. All authors have approved all manuscript contents. may be a promising therapeutic avenue.224,225

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