Skip to main content
NCBI home page
Dialogues in Clinical Neuroscience logoLink to Dialogues in Clinical Neuroscience
. 2013 Mar;15(1):77–85. doi: 10.31887/DCNS.2013.15.1/bbewernick

Chronic depression as a model disease for cerebral aging

La depresión crónica como modelo de enfermedad del envejecimiento cerebral

La depression chronique, un modèle pathologique du vieillissement cérébral

Bettina H Bewernick 1, Thomas E Schlaepfer 2,*
PMCID: PMC3622471  PMID: 23576891

Abstract

Conceptualizations of the underlying neurobiology of major depression have changed their focus from dysfunctions of neurotransmission to dysfunctions of neurogenesis and neuroprotection. The “neurogenesis hypothesis of depression” posits that changes in the rate of neurogenesis are the underlying mechanism in the pathology and treatment of major depression. Stress, neuroinflammation, dysfunctional insulin regulation, oxidative stress, and alterations in neurotrophic factors possibly contribute to the development of depression. The influence of antidepressant therapies, namely pharmacotherapy and neuroprotectants, on cellular plasticity are summarized. A dysfunction of complex neuronal networks as a consequence of neural degeneration in neuropsychiatric diseases has led to the application of deep brain stimulation. We discuss the way depression seen in the light of the neurogenesis hypothesis can be used as a model disease for cerebral aging. A common pathological mechanism in depression and cerebral aging—a dysfunction of neuroprotection and neurogenesis—is discussed. This has implications for new treatment methods.

Keywords: depression, cerebral aging, plasticity, neuroprotectant, neurodegeneration, Alzheimer's disease, Parkinson's disease, neuroinflammation, antidepressant therapy, deep brain stimulation, neuroplasticity

Traditional conceptualization of neurobiology of depression

Development of traditional pharmacological treatments for major depression has been based on the monoamine hypothesis of depression, inferring a depletion in the levels of serotonin, norepinephrine, and dopamine in the central nervous system as the underlying pathophysiology of depression This hypothesis is supported by the mechanism of action of antidepressants, although the mechanism of action is not precisely understood and only about 50% of patients respond to antidepressants with this action.1 Thus, new types of antidepressants (eg, κ-receptor antagonists, melatonin receptor agonists, cytokines) are the subject of active research.1 The antidepressant effect of neuromodulation approaches (eg, vagus nerve stimulation therapy, deep brain stimulation) have also challenged the monoamine hypothesis and favored the network hypothesis of depression. This hypothesis assumes that dysfunctions of large neuronal networks in the brain can be normalized through a modulation of one node of the respective network.

In this article, we will rely on another explanatory approach to depression, namely on the neurogenesis hypothesis of depression.2 This hypothesis posits that changes in the rate of neurogenesis are the underlying mechanism in the pathology and treatment of major depression.3 We then discuss in what way depression according to the neurogenesis hypothesis can be used as model disease for cerebral aging, and possible implications for new treatment methods.

Current knowledge on neurobiological effects of depression

In current concepts, depression is seen as a chronic disease with recurrent episodes in the majority of cases. About 30% of patients do not profit from conventional antidepressant treatments (psychotherapy, pharmacological, electroconvulsive therapy),4 which leads to a chronic manifestation of the disease.

The neurogenesis hypothesis of depression assumes that neurogenesis is influenced negatively by stressful experiences and positively by antidepressant treatment. Alterations in neurogenesis are believed to play a decisive role in the pathology and treatment of major depression3,5; this view is supported by several converging lines of research.

Neurodegeneration and neurogenesis

Imaging and postmortem studies have demonstrated cellular loss in several brain areas, eg, in the prefrontal cortex and amygdala6-9 and in the paraventricular nucleus of the hypothalamus10 in depressed patients.10 High lacunar volume in white matter has been observed in latelife mood disorders,11 as has reduced hippocampal volume.12,13 A negative correlation of the hippocampal volume and the length of the untreated depression, as well as a normalization of the hippocampal volume in remission, have been demonstrated.13

Neurogenesis and cellular plasticity

Adult neurogenesis was demonstrated in 1965 in rats and some years later in the human dentate gyrus of the hippocampus14 and in the subventricular zone of the lateral ventricle.

It has been demonstrated that neurogenesis can be inhibited by physical and social stress, depression, and antidepressant treatment. Modulating factors seem to be novelty, fear, and learning.3

Possible mechanisms of action relating depression to a dysfunction in neurogenesis are psychological stress, glucose and insulin regulation, oxidative stress, a reduction in brain-derived neurotrophic factor (BDNF), and telomere shortening.

Psychological stress and neuroinflammation

Psychological stress and neuroinflammation lead to an activation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis and proinflammatory cytokines are released. It has been proven that inflammatory cytokines can induce neurodegeneration in depression.15-18 For example, in 2009, Maes and colleagues concluded that chronic stress may exacerbate the release of proinflammatory cytokines and precipitate depressive episodes.15 The administration of high levels of proinflammatory cytokines can cause changes in behavior similar to depression, and the attenuation of an inflammatory response can reduce depressive symptoms.19-20

Glucose and insulin regulation

Depression is often associated with higher levels of the stress-related hormone cortisol. In depressive patients suffering from hypercortisolemia, glucose and insulin regulation are abnormal. High levels of Cortisol have an anti-insulin effect. In a comprehensive review, Rasgon and colleagues21 have described how prolonged exposure to glucose intolerance and insulin resistance is associated with accelerated biological aging. Neurotoxic effects of hypercortisolemia have also been described.22

Oxidative stress

Oxidative stress and inflammation are also called the “evil twins” of brain aging. It has been shown that oxidative stress increases with aging while antioxidant activities decrease with higher age.23 Oxidative stress is seen in depression and Alzheimer's disease (AD).24

Brain-derived neurotrophic factor

Brain derived neurotrophic factor (BDNF) seems to play an important role in the neurogenesis hypothesis of depression. BDNF also has anti-inflammatory and antioxidant effects. Diminished hippocampal BDNF activity impairs stem cells in the dentate gyrus, an effect related to depression.25 Unmedicated depressive patients have decreased hippocampal serum concentrations of BDNF.26

Telomeres

Telomeres are DNA protein complexes that protect DNA from damage. The length of the telomeres is one marker of biological age and genotoxic and cytotoxic processes The effect of depression on telomeres has also been under research. Patients suffering from depression show premature telomere shortening,27 probably due to inflammatory processes. In this relationship, the enzyme telomerase is thought to have anti-aging or cell-promoting effects. Telomerase has been shown to be increased in unmedicated depressed patients,22 possibly a compensatory response to telomere shortening. High levels of cortisol lead to a downregulation of telomerase.28

An open question remains as to whether dysfunction in neuronal plasticity is the cause, the consequence, or a correlate of depression.

In the following section, we will summarize evidence for a positive effect of different antidepressant therapies on neuroplasticity.

The effect of antidepressant therapies on neuroplasticity and neuroprotection

Antidepressants

The effect of antidepressants on neuroplasticity has been under research.29 The shrinkage of neurons in the hippocampus can be reversed with antidepressants in animal models.30-31 Treatment with antidepressants promotes neurogenesis, thus normalizing hippocampal volume.12-13 The appearance of new cells in the hippocampus after treatment with antidepressants32 has been discussed as the mechanism by which antidepressants overcome stressinduced atrophy. In animal models, hippocampal neurogenesis plays a role in the action of antidepressants,33 but its clinical relevance for the pathogenesis of depression in humans remains to be established. A putative mechanism could be that antidepressants decrease oxidative stress,24 reduce proinflammatory cytokines20,34 or lead to a BDNF-dependent increase in cell proliferation.

Although the effect on neuroprotection and neurogenesis of antidepressants in animal models has been proven, studies are needed to assess this effect in humans. Currently, neurogenesis is considered as one major aspect, but other factors possibly add to the pathophysiology of depression and to pharmacological treatment effects.3

Neuroprotectants

Neuroprotectants are drugs acting to protect against or help repair the damaging effects of a disease an insult to the brain.

Excessive nicotine consumption35,36 as well as withdrawal37,38 has been proven to induce depression. In depressed patients, nicotine has an effect on anhedonia and mood.39,40 The neuroprotective effect of nicotine has been demonstrated, possibly by activation of nicotinergic receptors.41,42 Nicotine has a neuroprotective effect for example in Parkinson's disease (PD).43-45 Consequently, it has been proposed to use nicotinic agonists for the treatment of neurodegenerative diseases and depression.46-48

Alcohol and depression are highly comorbid, and high doses of alcohol induce depressive -like behaviors in normal rats,49,50 but antidepressant effects of low doses of alcohol in a rat model of depression has been demonstrated. Light to moderate drinkers have a reduced risk of dementia and cognitive decline compared with nondrinkers,51 and low doses of alcohol are thought to provide neuroprotection through a dampening of inflammatory processes.51-53 The exact mechanism of neuroprotection is not known.

Other substances have antidepressant as well as neuroprotective properties, eg, the antioxidant resveratrol (for example, in red grapes) has proven antidepressant effects in a preclinical study54 and also reduces the risk of AD and PD,55-57 possibly through a mediation of neuroinflammation.58 Curcumin, another antioxidant has proven anti-inflammatory59,60 and antidepressant61,62 properties, and has been proposed in the treatment of neurodegenerative disease.63

Ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, has anxiolytic and antidepressant effects in preclinical and clinical studies,64-66 but its application in depression and neurodegenerative disorder remains to be determined.

Taken together, the first evidence exists that neuroprotection could also have an antidepressant and anti-aging effect, but large clinical studies are needed to further evaluate their potential in clinical practice.

Deep brain stimulation

Deep brain stimulation (DBS) is a surgical treatment. It involves the implantation of a brain pacemaker, which constantly stimulates specific structures in the brain with electrical impulses. DBS is currently under research for the treatment of chronic, therapy-resistant depression, and other psychiatry disorders. The exact mechanism of action is not fully understood, but possibly, DBS modulates neuronal networks for emotional processing and reward, which are dysfunctional in depression. Four targets are evaluated.

DBS to the subgenual cingulate cortex (Cg25) was hypothesized to exert an antidepressant effect by modulating the depression network through a reduction of Cg25 hyperactivity.67 Observations from historical lesion studies (eg, anterior capsulotomy) and antidepressant effects seen in patients with obsessive-compulsive disorder who were stimulated in the anterior limb of the internal capsule/the ventral striatum,68 led to a study in which the anterior limb of the internal capsule/ventral striatum (ALIC).69 Converging evidence from animal, pharmacological, and neuroimaging studies points toward a nucleus accumbens (NAcc) dysfunction in patients suffering from depression; this led to the hypothesis that DBS to the NAcc would lead to antidepressant effects by modulating the depression network.70

For all three targets (Cg25, ALIC, NAcc), similar longterm antidepressant effects have been published.69,71-76 Response (defined as a reduction of minimum 50% in the Hamilton Rating Scale of Depression or the Montgomery-Asperg Depression Rating Scale) varied between 40% and 60%, 69,71-76 but small study sizes do not yet allow the selection of a favorite target.

Very recently, the supero-lateral branch of the medial forebrain bundle (slMFB) has also been proposed as a target.77,78 The slMFB is anatomically and functionally connected with the above described DBS targets in depression (Cg25, ALIC and NAcc) and electric field stimulation as well as probabilistic fiber tracking have demonstrated a possible involvement of the slMFB in DBS of the current targets.77-79 In a recent slMFB-DBS pilot study, six out of seven patients showed a fast and sustained antidepressant response.80

The clinical effect of DBS has been explained as a modulation of neuronal excitability and as a direct activation of neurons.81,82 Effects of DBS on neurogenesis and neuroprotection as studied in animal models will be addressed here in more detail.

High-frequency DBS to the anterior thalamic nuclei leads has increased neural progenitors in the dentate gyrus of the hippocampus and increased number of new neurons in mice.83 Also in rats, high-frequency (130 Hz) DBS to the same nucleus has increased hippocampal neurogenesis and restored prior experimentally suppressed neurogenesis. Low-frequency (10 Hz) DBS did not have the same effect.84 Increased neurogenesis has been associated with enhanced behavioral performance in other studies. For example, DBS to the fornix in mice promoted proliferation in the dentate gyrus and ameliorated water maze memory after 6 weeks. This effect was missing when neurogenesis was experimentally blocked. This suggests a causal relationship between stimulation-induced promotion of adult neurogenesis and enhanced spatial memory.85

These animal data suggest that hippocampal neurogenesis seems a strong correlate of cognitive and emotional processes.83 Hippocampal neurogenesis may possibly be as sensitive indicator of limbic circuitry activation induced by DBS, antidepressants (fluoxetine) and physical exercise.83

In a PD rat model, chronic high-frequency stimulation of the subthalamic nucleus increased cell survival in the striatum and promoted the recovery of the dopaminergic system.86 In another study, continuous high-frequency DBS to the subthalamic nucleus for several days demonstrated delayed behavioral and cellular effects, suggesting progressive functional reorganization in the corticobasal ganglia-cortical loop circuits.87 Preclinical studies in both rats and monkeys have demonstrated that DBS to the subthalamic nucleus can prevent the degeneration of nigral dopaminergic neurons from the insult produced by dopamine-depleting neurotoxins.88-91

Although human studies are missing, subthalamic nucleus DBS in animals has demonstrated significant neuroprotective and neuroplastic properties. Thus, the initiation of DBS earlier in the course of PD has been suggested.92 This is assumed to provide added neuroprotective benefits in addition to symptomatic relief. Currently, several studies are under way exploring the neuroprotective potential of early DBS in PD (ClinicalTrials.gov identifier: NCT00282152, NCT01274832, NCT00354133). Results from these studies will be important for the discussion of an early intervention in other diseases, for example in depression.

Overall, deep brain stimulation has contributed to a novel view of depression — away from a synaptocentric view to a conceptualization of dysfunctional brain networks for the processing of emotions.93 It has become evident that several neuropsychiatric disorders might be associated with network dysfunctions.94 Initial studies have demonstrated a positive effect of DBS on neuroplasticity and neuroprotection. Future studies are required to explore long-term effects of DBS on neuroneogenesis and neuroprotection.

Aging and dementia

AD is the most common neurodegenerative disease featuring progressive impairments in memory, cognition, and behaviour, and half of the cases of dementia are caused by AD. The neurodegenerative hallmarks of AD include the accumulation amyloid-β, the deposition of amyloid plaques and the formation of neurofibrillary tangles.95

Similar to the monoamine theory on depression, the cholinergic hypothesis of dementia was proposed in 1982 by Bartus et al who believed that functional disturbances in cholinergic activity occurred in the brains of healthy older adults and demented patients.96,97

This hypothesis has been supported by positive effects of cholinesterase inhibitors on cognition in patients suffering from AD.98 Although much clinical development research on cholinergic agents has followed, the clinical effects are limited99 and no therapeutic strategy for AD has demonstrated long-term efficacy to date.100 Thus, new concepts and therapeutic approaches are required.

The role of inflammation (eg, cytokines) and telomerase activity, which leads to neuronal degeneration94,98 have also been suggested in the neurogenesis theory of depression. These factors lead to a dysregulation of brain networks.99 It is unclear whether amyloid-β itself by its ability to alter synaptic (glutamatergic) transmission and to impair the induction of long-term potentiation.99 A disruption of the connectivity of memory networks have been observable in early AD and asymptomatic individuals with high amyloid burden.100

Novel concepts of aging and dementia as a dysfunction of neuronal networks led to the application of deep brain stimulation in patients suffering from AD.103 Current studies targeting the fornix or the nucleus basalis of Meynert will show whether deep brain stimulation will be superior to pharmacological treatment (ClinicalTrials.gov identifier NCT01559220, NCT01094145, NCT01608061) and if the modulation of neuronal networks as suggested effective in the treatment of depression can be extended to dementia.

Evidence for a common mechanism in depression and aging

Several lines of evidence suggest that depression and neurodegenerative diseases such as AD underlie common neurodegenerative processes, and thus depression, can be seen as a model disease for (pathological) neuronal aging.

Clinical evidence

About 50% of patients suffering from AD have comorbid depression.104 This is especially the case in elderly patients. Many medical comorbid diseases seen in depression are diseases of advanced age (eg, heart disease, stroke).22 In addition, both depression and AD are associated with cognitive decline.

Pathophysiology

An increase in neurodegeneration, coupled with a reduction of neuroprotection and neuronal repair, is proposed as the unifying mechanism of depression and cerebral aging.105,106 Dysregulation of BDNF107 and neuroinflammatory processes (eg, a dysregulation of cytokines) has been proposed as a unifying factor in depression and AD.15 Certain cytokines increase as a function of age; this could be one cause for age-related dementia and depression.108 A positive feedback loop between neuroinflammation, neurodegeneration, and depression has been suggested109 and an increase in glucocorticoid level may be the initial pathological marker of depression and dementia.105,106

Treatment

Neuroprotectants (eg, ketamine, curcumin, resveratrol, and nicotine) seem to have antidepressant properties as well as an effect on neurodegenerative diseases (AD, PD). Electroconvulsive therapy is known to have better results in elderly patients, although the reasons are not yet understood. Therapies (eg, pharmacotherapy, deep brain stimulation) interfering with detrimental consequences of neuronal degeneration are promising treatments both for mood disorders and cerebral aging.

Conclusion and outlook

Current concepts of depression and cerebral aging have been changed from a dysfunction of neurotransmission to a dysfunction of neurogenesis and neuroprotection. As underlying mechanisms of pharmacological treatment effects in depression and dementia, a restoration of neuroprotection and neurogenesis have been suggested. Converging evidence exists for the dysfunction of complex neuronal networks as consequence of neural degeneration in neuropsychiatric diseases, leading to the application of deep brain stimulation. Future studies using deep brain stimulation in combination with neuroimaging, electrophysiology, and cognitive behavioral experiments are required to underline the hypothesis of dysfunctional neuronal networks.

Contributor Information

Bettina H. Bewernick, Department of Psychiatry and Psychotherapy, University Hospital, Bonn, Germany.

Thomas E. Schlaepfer, Department of Psychiatry and Psychotherapy, University Hospital, Bonn, Germany; Departments of Psychiatry and Mental Health, The Johns Hopkins University, Baltimore, USA.

REFERENCES

  • 1.Berton O., Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci. 2006;7:137–151. doi: 10.1038/nrn1846. [DOI] [PubMed] [Google Scholar]
  • 2.Castren E. Is mood chemistry? Nat Rev Neurosci. 2005;6:241–246. doi: 10.1038/nrn1629. [DOI] [PubMed] [Google Scholar]
  • 3.Hanson ND., Owens MJ., Nemeroff CB. Depression, antidepressants, and neurogenesis: a critical reappraisal. Neuropsychopharmacology . 2011;36:2589–2602. doi: 10.1038/npp.2011.220. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Rush AJ., Trivedi MH., Wisniewski SR., et al Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–1917. doi: 10.1176/ajp.2006.163.11.1905. [DOI] [PubMed] [Google Scholar]
  • 5.Manji HK., Drevets WC., Charney DS. The cellular neurobiology of depression. Nat Med. 2001;7:541–547. doi: 10.1038/87865. [DOI] [PubMed] [Google Scholar]
  • 6.Cotter D., Mackay D., Landau S., Kerwin R., Everall I. Reduced glial cell density and neuronal size in the anterior cingulate cortex in major depressive disorder. Arch Gen Psychiatry. 2001;58:545–553. doi: 10.1001/archpsyc.58.6.545. [DOI] [PubMed] [Google Scholar]
  • 7.Rajkowska G. Cell pathology in mood disorders. Semin Clin Neuropsychiatry. 2002;7:281–292. doi: 10.1053/scnp.2002.35228. [DOI] [PubMed] [Google Scholar]
  • 8.Rosso IM. Review: hippocampal volume is reduced in people with unipolar depression. Evid Based Ment Health. 2005;8:45. doi: 10.1136/ebmh.8.2.45. [DOI] [PubMed] [Google Scholar]
  • 9.Rosso IM., Cintron CM., Steingard RJ., Renshaw PF., Young AD., Yurgelun-Todd DA. Amygdala and hippocampus volumes in pediatric major depression. Biol Psychiatry. 2005;57:21–26. doi: 10.1016/j.biopsych.2004.10.027. [DOI] [PubMed] [Google Scholar]
  • 10.Manaye KF., Lei DL., Tizabi Y., Davila-Garcia Ml., Mouton PR., Kelly PH. Selective neuron loss in the paraventricular nucleus of hypothalamus in patients suffering from major depression and bipolar disorder. J Neuropathol Exp Neurol. 2005;64:224–229. doi: 10.1093/jnen/64.3.224. [DOI] [PubMed] [Google Scholar]
  • 11.Lavretsky H., Zheng L., Weiner MW., et al The MRI brain correlates of depressed mood, anhedonia, apathy, and anergia in older adults with and without cognitive impairment or dementia. Int J Geriatr Psychiatry. 2008;23:1040–1050. doi: 10.1002/gps.2030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Czeh B., Lucassen PJ. What causes the hippocampal volume decrease in depression? Are neurogenesis, glial changes and apoptosis implicated? Eur Arch Psychiatry Clin Neurosci. 2007;257:250–260. doi: 10.1007/s00406-007-0728-0. [DOI] [PubMed] [Google Scholar]
  • 13.Sheline Yl., Gado MH., Kraemer HC. Untreated depression and hippocampal volume loss. Am J Psychiatry. 2003;160:1516–1518. doi: 10.1176/appi.ajp.160.8.1516. [DOI] [PubMed] [Google Scholar]
  • 14.Eriksson PS., Perfilieva E., Bjork-Eriksson T., et al Neurogenesis in the adult human hippocampus. Nat Med. 1998;4:1313–1317. doi: 10.1038/3305. [DOI] [PubMed] [Google Scholar]
  • 15.Maes M., Yirmyia R., Noraberg J., et al The inflammatory & neurodegenerative (l&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis. 2009;24:27–53. doi: 10.1007/s11011-008-9118-1. [DOI] [PubMed] [Google Scholar]
  • 16.Maes M. The immunoregulatory effects of antidepressants. Hum Psychopharmacol. 2001;16:95–103. doi: 10.1002/hup.191. [DOI] [PubMed] [Google Scholar]
  • 17.Raison CL., Capuron L., Miller AH. Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends Immunol. 2006;27:24–31. doi: 10.1016/j.it.2005.11.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Schiepers OJ., Wichers MC., Maes M. Cytokines and major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2005;29:201–217. doi: 10.1016/j.pnpbp.2004.11.003. [DOI] [PubMed] [Google Scholar]
  • 19.Capuron L., Miller AH. Cytokines and psychopathology: lessons from interferon-alpha. Biol Psychiatry. 2004;56:819–824. doi: 10.1016/j.biopsych.2004.02.009. [DOI] [PubMed] [Google Scholar]
  • 20.Pollak Y., Yirmiya R. Cytokine-induced changes in mood and behaviour: implications for 'depression due to a general medical condition', immunotherapy and antidepressive treatment. Int J Neuropsychopharmacol. 2002;5:389–399. doi: 10.1017/S1461145702003152. [DOI] [PubMed] [Google Scholar]
  • 21.Rasgon NL., Kenna HA. Insulin resistance in depressive disorders and Alzheimer's disease: revisiting the missing link hypothesis. Neurobiol Aging. 2005;26(suppl 1):103–107. doi: 10.1016/j.neurobiolaging.2005.09.004. [DOI] [PubMed] [Google Scholar]
  • 22.Wolkowitz OM., Reus VI., Mellon SH. Of sound mind and body: depression, disease, and accelerated aging. Dialogues Clin Neurosci. 2011;13:25–39. doi: 10.31887/DCNS.2011.13.1/owolkowitz. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Joseph JA., Shukitt-Hale B., Casadesus G., Fisher D. Oxidative stress and inflammation in brain aging: nutritional considerations. Neurochem Res. 2005;30:927–935. doi: 10.1007/s11064-005-6967-4. [DOI] [PubMed] [Google Scholar]
  • 24.Cumurcu BE., Ozyurt H., Etikan I., Demir S., Karlidag R. Total antioxidant capacity and total oxidant status in patients with major depression: impact of antidepressant treatment. Psychiatry Clin Neurosci. 2009;63:639–645. doi: 10.1111/j.1440-1819.2009.02004.x. [DOI] [PubMed] [Google Scholar]
  • 25.Duman RS., Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006;59:1116–1127. doi: 10.1016/j.biopsych.2006.02.013. [DOI] [PubMed] [Google Scholar]
  • 26.Groves JO. Is it time to reassess the BDNF hypothesis of depression? Mol Psychiatry. 2007;12:1079–1088. doi: 10.1038/sj.mp.4002075. [DOI] [PubMed] [Google Scholar]
  • 27.Hartmann N., Boehner M., Groenen F., Kalb R. Telomere length of patients with major depression is shortened but independent from therapy and severity of the disease. Depress Anxiety. 2010;27:1111–1116. doi: 10.1002/da.20749. [DOI] [PubMed] [Google Scholar]
  • 28.Choi J., Fauce SR., Effros RB. Reduced telomerase activity in human T lymphocytes exposed to Cortisol. Brain Behav Immun. 2008;22:600–605. doi: 10.1016/j.bbi.2007.12.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.D'Sa C., Duman RS. Antidepressants and neuroplasticity. Bipolar Disord. 2002;4:183–194. doi: 10.1034/j.1399-5618.2002.01203.x. [DOI] [PubMed] [Google Scholar]
  • 30.Magarinos AM., McEwen BS., Flugge G., Fuchs E. Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews. J Neurosci. 1996;16:3534–3540. doi: 10.1523/JNEUROSCI.16-10-03534.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.McEwen BS. Stress and hippocampal plasticity. Annu Rev Neurosci. 1999;22:105–122. doi: 10.1146/annurev.neuro.22.1.105. [DOI] [PubMed] [Google Scholar]
  • 32.Malberg JE., Eisch AJ., Nestler EJ., Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000;20:9104–9110. doi: 10.1523/JNEUROSCI.20-24-09104.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Santarelli L., Saxe M., Gross C., et al Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805–809. doi: 10.1126/science.1083328. [DOI] [PubMed] [Google Scholar]
  • 34.Zunszain PA., Hepgul N., Pariante CM. Inflammation and depression. Curr Topics Behav Neurosci. In press. doi: 10.1007/7854_2012_211. [DOI] [PubMed] [Google Scholar]
  • 35.Parrott AC. Cigarette-derived nicotine is not a medicine. World J Biol Psychiatry. 2003;4:49–55. doi: 10.3109/15622970309167951. [DOI] [PubMed] [Google Scholar]
  • 36.Steuber TL., Danner F. Adolescent smoking and depression: which comes first? Addict Behav. 2006;31:133–136. doi: 10.1016/j.addbeh.2005.04.010. [DOI] [PubMed] [Google Scholar]
  • 37.Edward SJ., Stevens AJ., Braunholtz DA., Lilford RJ., Swift T. The ethics of placebo-controlled trials: a comparison of inert and active placebo controls. World J Surg. 2005;29:610–614. doi: 10.1007/s00268-005-7621-7. [DOI] [PubMed] [Google Scholar]
  • 38.Glassman AH., Covey LS., Stetner F., Rivelli S. Smoking cessation and the course of major depression: a follow-up study. Lancet. 16 2001;357:1929–1932. doi: 10.1016/S0140-6736(00)05064-9. [DOI] [PubMed] [Google Scholar]
  • 39.Cook JW., Spring B., McChargue D. Influence of nicotine on positive affect in anhedonic smokers. Psychopharmacology (Berl). 2007;192:87–95. doi: 10.1007/s00213-006-0688-5. [DOI] [PubMed] [Google Scholar]
  • 40.McClernon FJ., Hiott FB., Westman EC., Rose JE., Levin ED. Transdermal nicotine attenuates depression symptoms in nonsmokers: a double-blind, placebo-controlled trial. Psychopharmacology (Berl). 2006;189:125–133. doi: 10.1007/s00213-006-0516-y. [DOI] [PubMed] [Google Scholar]
  • 41.Copeland RL., Jr, Das JR., Kanaan YM., Taylor RE., Tizabi Y. Antiapoptotic effects of nicotine in its protection against salsolinol-induced cytotoxicity. Neurotoxicity Res. 2007;12:61–69. doi: 10.1007/BF03033901. [DOI] [PubMed] [Google Scholar]
  • 42.Copeland RL., Jr, Leggett YA., Kanaan YM., Taylor RE., Tizabi Y. Neuroprotective effects of nicotine against salsolinol-induced cytotoxicity: implications for Parkinson's disease. Neurotoxicity Res. 2005;8:289–293. doi: 10.1007/BF03033982. [DOI] [PubMed] [Google Scholar]
  • 43.Ross GW., Petrovitch H. Current evidence for neuroprotective effects of nicotine and caffeine against Parkinson's disease. Drugs Aging. 2001;18:797–806. doi: 10.2165/00002512-200118110-00001. [DOI] [PubMed] [Google Scholar]
  • 44.Thacker EL., O'Reilly EJ., Weisskopf MG., et al Temporal relationship between cigarette smoking and risk of Parkinson disease. Neurology. 2007;68:764–768. doi: 10.1212/01.wnl.0000256374.50227.4b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Baron JA. Beneficial effects of nicotine and cigarette smoking: the real, the possible and the spurious. Br Med Bull. 1996;52:58–73. doi: 10.1093/oxfordjournals.bmb.a011533. [DOI] [PubMed] [Google Scholar]
  • 46.Cui WY., Li MD. Nicotinic modulation of innate immune pathways via alpha7 nicotinic acetylcholine receptor. J Neurolmmune Pharmacol. 2010;5:479–488. doi: 10.1007/s11481-010-9210-2. [DOI] [PubMed] [Google Scholar]
  • 47.Piao WH., Campagnolo D., Dayao C., Lukas RJ., Wu J., Shi FD. Nicotine and inflammatory neurological disorders. Acta pharmacologica Sinica. 2009;30:715–722. doi: 10.1038/aps.2009.67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Shi FD., Piao WH., Kuo YP., Campagnolo Dl., Vollmer TL., Lukas RJ. Nicotinic attenuation of central nervous system inflammation and autoimmunity. J Immunol. 2009;182:1730–1739. doi: 10.4049/jimmunol.182.3.1730. [DOI] [PubMed] [Google Scholar]
  • 49.Getachew B., Hauser SR., Taylor RE., Tizabi Y. Alcohol-induced depressivelike behavior is associated with cortical norepinephrine reduction. Pharmacol Biochem Behav. 2010;96:395–401. doi: 10.1016/j.pbb.2010.06.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Hauser SR., Ding ZM., Getachew B., et al The posterior ventral tegmental area mediates alcohol-seeking behavior in alcohol-preferring rats. J Pharmacol Exp Ther. 2011;336:857–865. doi: 10.1124/jpet.110.168260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Collins MA., Neafsey EJ., Mukamal KJ., et al Alcohol in moderation, cardioprotection, and neuroprotection: epidemiological considerations and mechanistic studies. Alcohol Clin Exp Res. 2009;33:206–219. doi: 10.1111/j.1530-0277.2008.00828.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52.Belmadani A., Zou JY., Schipma MJ., Neafsey EJ., Collins MA. Ethanol pre-exposure suppresses HIV-1 glycoprotein 120-induced neuronal degeneration by abrogating endogenous glutamate/Ca2+-mediated neurotoxicity. Neuroscience. 2001;104:769–781. doi: 10.1016/s0306-4522(01)00139-7. [DOI] [PubMed] [Google Scholar]
  • 53.Park HJ., Lee PH., Ahn YW., et al Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action. Eur J Neurosci. 2007;26:79–89. doi: 10.1111/j.1460-9568.2007.05636.x. [DOI] [PubMed] [Google Scholar]
  • 54.Xu Y., Wang Z., You W., et al Antidepressant-like effect of trans-resveratrol: involvement of serotonin and noradrenaline system. Eur Neuropsychopharmacol. 2010;20:405–413. doi: 10.1016/j.euroneuro.2010.02.013. [DOI] [PubMed] [Google Scholar]
  • 55.Chen LW., Wang YQ., Wei LC., Shi M., Chan YS. Chinese herbs and herbal extracts for neuroprotection of dopaminergic neurons and potential therapeutic treatment of Parkinson's disease. CNS Neurol Disord Drug Targets. 2007;6:273–281. doi: 10.2174/187152707781387288. [DOI] [PubMed] [Google Scholar]
  • 56.Tredici G., Miloso M., Nicolini G., Galbiati S., Cavaletti G., Bertelli A. Resveratrol, map kinases and neuronal cells: might wine be a neuroprotectant? Drugs Exp Clin Res. 1999;25:99–103. [PubMed] [Google Scholar]
  • 57.Vingtdeux V., Dreses-Werringloer U., Zhao H., Davies P., Marambaud P. Therapeutic potential of resveratrol in Alzheimer's disease. BMC Neurosci. 2008;9(suppl 2):S6. doi: 10.1186/1471-2202-9-S2-S6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Zhang F., Wang H., Wu Q., et al Resveratrol protects cortical neurons against microglia-mediated neuroinflammation. Phytother Res. In press. doi: 10.1002/ptr.4734. [DOI] [PubMed] [Google Scholar]
  • 59.Aggarwal BB., Harikumar KB. Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases. Int J Biochem Cell Biol. 2009;41:40–59. doi: 10.1016/j.biocel.2008.06.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Jurenka JS. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Alt Med Rev. 2009;14:141–153. [PubMed] [Google Scholar]
  • 61.Bhutani MK., Bishnoi M., Kulkarni SK. Anti-depressant like effect of curcumin and its combination with piperine in unpredictable chronic stressinduced behavioral, biochemical and neurochemical changes. Pharmacol Biochem Behav. 2009;92:39–43. doi: 10.1016/j.pbb.2008.10.007. [DOI] [PubMed] [Google Scholar]
  • 62.Kulkarni SK., Bhutani MK., Bishnoi M. Antidepressant activity of curcumin: involvement of serotonin and dopamine system. Psychopharmacology (Berl). 2008;201:435–442. doi: 10.1007/s00213-008-1300-y. [DOI] [PubMed] [Google Scholar]
  • 63.Darvesh AS., Carroll RT., Bishayee A., Novotny NA., Geldenhuys WJ., Van der Schyf CJ. Curcumin and neurodegenerative diseases: a perspective. Expert Opin Investig Drugs. 2012;21:1123–1140. doi: 10.1517/13543784.2012.693479. [DOI] [PubMed] [Google Scholar]
  • 64.Berman RM., Cappiello A., Anand A., et al Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–354. doi: 10.1016/s0006-3223(99)00230-9. [DOI] [PubMed] [Google Scholar]
  • 65.Zarate CA., Jr, Singh JB., Carlson PJ., et al A randomized trial of an Nmethyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–864. doi: 10.1001/archpsyc.63.8.856. [DOI] [PubMed] [Google Scholar]
  • 66.Maeng S., Zarate CA., Jr, Du J., et al Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63:349–352. doi: 10.1016/j.biopsych.2007.05.028. [DOI] [PubMed] [Google Scholar]
  • 67.Mayberg HS. Limbic-cortical dysregulation: a proposed model of depression. J Neuropsychiatry Clin Neurosci. 1997;9:471–481. doi: 10.1176/jnp.9.3.471. [DOI] [PubMed] [Google Scholar]
  • 68.Greenberg BD., Gabriels LA., Malone DA., Jr, et al Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience. Mol Psychiatry. 2010;15:64–79. doi: 10.1038/mp.2008.55. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Malone DA., Jr, Dougherty DD., Rezai AR., et al Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression. Biol Psychiatry. 2009;65:267–275. doi: 10.1016/j.biopsych.2008.08.029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Schlaepfer T., Lieb K. Deep brain stimulation for treatment refractory depression. Lancet. 2005;366:1420–1422. doi: 10.1016/S0140-6736(05)67582-4. [DOI] [PubMed] [Google Scholar]
  • 71.Bewernick BH., Hurlemann R., Matusch A., et al Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatmentresistant depression. Biol Psychiatry. 2010;67:110–116. doi: 10.1016/j.biopsych.2009.09.013. [DOI] [PubMed] [Google Scholar]
  • 72.Bewernick BH., Kayser S., Sturm V., Schlaepfer TE. Long-term effects of nucleus accumbens deep brain stimulation in treatment-resistant depression: evidence for sustained efficacy. Neuropsychopharmacology. 2012;37:1975–1985. doi: 10.1038/npp.2012.44. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Holtzheimer PE., Kelley ME., Gross RE., et al Subcallosal cingulate deep brain stimulation for treatment-resistant unipolar and bipolar depression. Arch Gen Psychiatry. 2012;69:150–158. doi: 10.1001/archgenpsychiatry.2011.1456. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Kennedy SH., Giacobbe P., Rizvi SJ., et al Deep brain stimulation for treatment-resistant depression: follow-up after 3 to 6 years. Am J Psychiatry. 2011;168:502–510. doi: 10.1176/appi.ajp.2010.10081187. [DOI] [PubMed] [Google Scholar]
  • 75.Lozano AM., Giacobbe P., Hamani C., et al A multicenter pilot study of subcallosal cingulate area deep brain stimulation for treatment-resistant depression. J Neurosurg. 2012;116:315–322. doi: 10.3171/2011.10.JNS102122. [DOI] [PubMed] [Google Scholar]
  • 76.Puigdemont D., Perez-Egea R., Portella MJ., et al Deep brain stimulation of the subcallosal cingulate gyrus: further evidence in treatment-resistant major depression. Int J Neuropsychopharmacol. 2011:1–13. doi: 10.1017/S1461145711001088. [DOI] [PubMed] [Google Scholar]
  • 77.Coenen VA., Panksepp J., Hurwitz TA., Urbach H., Madler B. Human medial forebrain bundle (MFB) and anterior thalamic radiation (ATR): imaging of two major subcortical pathways and the dynamic balance of opposite affects in understanding depression. J Neuropsychiatry Clin Neurosci. 2012;24:223–236. doi: 10.1176/appi.neuropsych.11080180. [DOI] [PubMed] [Google Scholar]
  • 78.Coenen VA., Schlaepfer TE., Maedler B., Panksepp J. Cross-species affective functions of the medial forebrain bundle-implications for the treatment of affective pain and depression in humans. Neurosci Biobehav Rev. 2011;35:1971–1981. doi: 10.1016/j.neubiorev.2010.12.009. [DOI] [PubMed] [Google Scholar]
  • 79.Coenen VA., Schlaepfer TE., Maedler B., Panksepp J. Cross-species affective functions of the medial forebrain bundle-Implications for the treatment of affective pain and depression in humans. Neurosci Biobehav Rev. 2011;35:1971–1981. doi: 10.1016/j.neubiorev.2010.12.009. [DOI] [PubMed] [Google Scholar]
  • 80.Schlaepfer T., Bewernick B., Kayser S., Madler B., Coenen VA. Rapid effects of deep brain stimulation for treatment resistant major depression. Biol Psychiatry. In press. doi: 10.1016/j.biopsych.2013.01.034. [DOI] [PubMed] [Google Scholar]
  • 81.Deniau JM., Degos B., Bosch C., Maurice N. Deep brain stimulation mechanisms: beyond the concept of local functional inhibition. Eur J Neurosci. 2010;32:1080–1091. doi: 10.1111/j.1460-9568.2010.07413.x. [DOI] [PubMed] [Google Scholar]
  • 82.Mclntyre CC., Savasta M., Kerkerian-Le Goff L., Vitek JL. Uncovering the mechanism(s) of action of deep brain stimulation: activation, inhibition, or both. Clin Neurophysiol. 2004;115:1239–1248. doi: 10.1016/j.clinph.2003.12.024. [DOI] [PubMed] [Google Scholar]
  • 83.Encinas JM., Hamani C., Lozano AM., Enikolopov G. Neurogenic hippocampal targets of deep brain stimulation. J Comp Neurol. 2011;519:6–20. doi: 10.1002/cne.22503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84.Toda H., Hamani C., Fawcett AP., Hutchison WD., Lozano AM. The regulation of adult rodent hippocampal neurogenesis by deep brain stimulation. J Neurosurg. 2008;108:132–138. doi: 10.3171/JNS/2008/108/01/0132. [DOI] [PubMed] [Google Scholar]
  • 85.Stone SS., Teixeira CM., Devito LM., et al Stimulation of entorhinal cortex promotes adult neurogenesis and facilitates spatial memory. J Neurosci. 2011;31:13469–13484. doi: 10.1523/JNEUROSCI.3100-11.2011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 86.Khaindrava V., Salin P., Melon C., Ugrumov M., Kerkerian-Le-Goff L., Daszuta A. High frequency stimulation of the subthalamic nucleus impacts adult neurogenesis in a rat model of Parkinson's disease. Neurobiol Dis. 2011;42:284–291. doi: 10.1016/j.nbd.2011.01.018. [DOI] [PubMed] [Google Scholar]
  • 87.Gubellini P., Eusebio A., Oueslati A., Melon C., Kerkerian-Le Goff L., Salin P. Chronic high-frequency stimulation of the subthalamic nucleus and L-DOPA treatment in experimental parkinsonism: effects on motor behaviour and striatal glutamate transmission. Eur J Neurosci. 2006;24:1802–1814. doi: 10.1111/j.1460-9568.2006.05047.x. [DOI] [PubMed] [Google Scholar]
  • 88.Harnack D., Meissner W., Jira JA., Winter C., Morgenstern R., Kupsch A. Placebo-controlled chronic high-frequency stimulation of the subthalamic nucleus preserves dopaminergic nigral neurons in a rat model of progressive Parkinsonism. Exp Neurol. 2008;210:257–260. doi: 10.1016/j.expneurol.2007.10.002. [DOI] [PubMed] [Google Scholar]
  • 89.Maesawa S., Kaneoke Y., Kajita Y., et al Long-term stimulation of the subthalamic nucleus in hemiparkinsonian rats: neuroprotection of dopaminergic neurons. J Neurosurg. 2004;100:679–687. doi: 10.3171/jns.2004.100.4.0679. [DOI] [PubMed] [Google Scholar]
  • 90.Temel Y., Visser-Vandewalle V., Kaplan S., et al Protection of nigral cell death by bilateral subthalamic nucleus stimulation. Brain Res. 2006;1120:100–105. doi: 10.1016/j.brainres.2006.08.082. [DOI] [PubMed] [Google Scholar]
  • 91.Wallace BA., Ashkan K., Heise CE., et al Survival of midbrain dopaminergic cells after lesion or deep brain stimulation of the subthalamic nucleus in MPTP-treated monkeys. Brain. 2007;130:2129–2145. doi: 10.1093/brain/awm137. [DOI] [PubMed] [Google Scholar]
  • 92.Spieles-Engemann AL., Collier TJ., Sortwell CE. A functionally relevant and long-term model of deep brain stimulation of the rat subthalamic nucleus: advantages and considerations. Eur J Neurosci. 2010;32:1092–1099. doi: 10.1111/j.1460-9568.2010.07416.x. [DOI] [PubMed] [Google Scholar]
  • 93.Krishnan V., Nestler EJ. The molecular neurobiology of depression. Nature. 16 2008;455:894–902. doi: 10.1038/nature07455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 94.Insel TR. Faulty circuits. Scientific American. 2010;302:44–51. doi: 10.1038/scientificamerican0410-44. [DOI] [PubMed] [Google Scholar]
  • 95.Atri A. Effective pharmacological management of Alzheimer's disease. Am J Managed Care. 2011;17(suppl 13):S346–355. [PubMed] [Google Scholar]
  • 96.Bartus RT., Dean RL., 3rd, Beer B., Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982;217:408–414. doi: 10.1126/science.7046051. [DOI] [PubMed] [Google Scholar]
  • 97.Dumas JA., Newhouse PA. The cholinergic hypothesis of cognitive aging revisited again: cholinergic functional compensation. Pharmacol Biochem Behav. 2011;99:254–261. doi: 10.1016/j.pbb.2011.02.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Hansen RA., Gartlehner G., Webb AP., Morgan LC., Moore CG., Jonas DE. Efficacy and safety of donepezil, galantamine, and rivastigmine for the treatment of Alzheimer's disease: a systematic review and meta-analysis. Clin interv Aging. 2008;3:211–225. [PMC free article] [PubMed] [Google Scholar]
  • 99.Dumas JA., Newhouse PA. The cholinergic hypothesis of cognitive aging revisited again: cholinergic functional compensation. Pharmacol Biochem Behav. 2011;99:943–951. doi: 10.1016/j.pbb.2011.02.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 100.Nelson PT., Head E., Schmitt FA., et al Alzheimer's disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies. Acta Neuropathology. 2011;121:571–587. doi: 10.1007/s00401-011-0826-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101.Gleichmann M., Mattson MP. Alzheimer's disease and neuronal network activity. Neuromol Med. 2010;12:44–47. doi: 10.1007/s12017-009-8100-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Sperling RA., Dickerson BC., Pihlajamaki M., et al Functional alterations in memory networks in early Alzheimer's disease. Neuromol Med. 2010;12:27–43. doi: 10.1007/s12017-009-8109-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Laxton AW., Tang-Wai DF., McAndrews MP., et al A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann Neurol. 2010;68:521–534. doi: 10.1002/ana.22089. [DOI] [PubMed] [Google Scholar]
  • 104.de Souza MB., de Lemos RR., da Cunha JE., de Lima Filho JL., de Oliveira JR. Searching for new genetic risk factors for neuropsychiatric disorders in expression databases. J Mol Neurosci. 2010;41:193–197. doi: 10.1007/s12031-009-9321-5. [DOI] [PubMed] [Google Scholar]
  • 105.Leonard BE. Inflammation, depression and dementia: are they connected? Neurochem Res. 2007;32:1749–1756. doi: 10.1007/s11064-007-9385-y. [DOI] [PubMed] [Google Scholar]
  • 106.Leonard BE., Myint A. The psychoneuroimmunology of depression. Hum Psychopharmacol. 2009;24:165–175. doi: 10.1002/hup.1011. [DOI] [PubMed] [Google Scholar]
  • 107.Krabbe KS., Mortensen EL., Avlund K., et al Brain-derived neurotrophic factor predicts mortality risk in older women. J Am Geriatr Soc. 2009;57:1447–1452. doi: 10.1111/j.1532-5415.2009.02345.x. [DOI] [PubMed] [Google Scholar]
  • 108.Wilson CJ., Finch CE., Cohen HJ. Cytokines and cognition-the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc. 2002;50:2041–2056. doi: 10.1046/j.1532-5415.2002.50619.x. [DOI] [PubMed] [Google Scholar]
  • 109.Hurley LL., Tizabi Y. Neuroinflammation, neurodegeneration, and depression. Neurotoxicity Res. 2013;23:131–144. doi: 10.1007/s12640-012-9348-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Dialogues in Clinical Neuroscience are provided here courtesy of Taylor & Francis

RESOURCES