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Is depression an inflammatory condition? A review of available evidence.

Byline: Ali Madeeh Hashmi, Zeeshan Butt and Muhammad Umair


The current review examines the relationship between depression and the inflammatory immune response. Mood disorders are a significant cause of morbidity and the etiology of depression is still not clearly understood. Many studies have shown links between inflammatory cytokines and mood disorders, including elevated level of cytokines like tumour necrosis factor-alpha (TNF a), Interleukins (IL-1,IL-6) and others. Raised levels of cytokines have been shown to increase depressive behaviour in animal models, while many anti-depressants reverse this behaviour alongside reducing the Central Nervous System (CNS) inflammatory response and reduction in the amounts of inflammatory cytokines. Cytokines reduce neurogenesis, Brain Derived Neurotrophic Factor (BDNF) and neuronal plasticity in the CNS, while many anti-depressants have been shown to reverse these processes.

The considerations of anti-depressants as anti-inflammatory agents, and implication of other anti-inflammatory therapeutics for the treatment of depression are pointed out.

Keywords: Depression, Inflammation, Cytokines.


Mood disorders, especially depressive disorders are prevalent, hard to treat and cause considerable morbidity. There is a bidirectional relationship between mood disorders, especially depression and markers of the inflammatory immune response, such as Interleukins and Interferons. In the last 25 years several new classes of anti-depressant medications have become available for the treatment of these debilitating conditions. While the in vitro effects of these medications have been clearly elucidated, their exact mechanisms of in-vivo action are still disputed. Animal models of depression including measurement of cytokine levels, have provided some clues about both the pathophysiology of depression as well as the mechanism of action of commonly used anti-depressant medication.

In this paper we review the available evidence about the role of inflammatory cytokines in the etiology of depression and the relationship between anti-depressant medication and cytokine levels in the body both before and after treatment.

The Burden of Depression

Depression is a complex illness that is associated with substantial disability and reduced quality of life for the person with depression, as well as a significant social burden. Major depressive disorder (MDD) is the occurrence of one or more episodes of major depression. A Major Depressive Episode (MDE) is defined as a period of at least 2 weeks that is characterised either by depressed mood and/or markedly diminished interest or pleasure in all, or almost all, activities in addition to at least four other symptoms.1 Dysthymic disorder is characterised by a chronically depressed mood and at least two other depressive symptoms that occur most of the day, more days than not, for at least 2 years.

Mood disorders, including MD, affect as many as one in five individuals and are the most prevalent psychiatric conditions.2 The World Health Organisation (WHO) projects that MD will be the second leading cause of disability worldwide by 2020.3 The lifetime risk of MDD in the USA is 7% to 12% for men and 20% to 25% for women.4

There are no, large, well-designed population-based studies of the incidence and prevalence of depression in Pakistan. However, the available studies indicate a prevalence of MDD in Pakistan to be between 10% and 50%.5-7 Most individuals with MDD have a chronic or recurrent course, often with considerable symptomatology and disability even between episodes.8-10 Approximately one-third of MDD are refractory to any kind of anti-depressant treatment, including selective serotonin reuptake inhibitors (SSRIs), tricyclic anti-depressants (TCAs), monoamine oxidase inhibitors (MAOIs), and electroconvulsive therapy (ECT).11

Depression has a significantly negative impact on occupational functioning. In one study, comparing workers with depression and workers with rheumatoid arthritis, depressed workers had significantly greater performance deficits than the controls. This included performing mental tasks, time management, output tasks, and physical tasks.12 Depressed employees are also almost five times as likely to lose their jobs as those with arthritis.13

Depression negatively impacts physical health as well; it reduces compliance with medical treatment14 and increases the likelihood of risk factors such as obesity,15 smoking16 and a sedentary lifestyle.17

MDD can also be associated with multiple medical conditions, including cardiovascular disease18 endocrine and neurological diseases, and a general increase in chronic disease incidence.19 Mortality rates in MDD are also high; approximately four per cent of people with a mood disorder commit suicide and about two-thirds of suicides are preceded by depression.20

Untreated depression in adolescents results in significant decline in school performance, interpersonal relationships, risk of early pregnancy and impaired social and family functioning.21 It also impairs occupational adjustment and increases the risk of suicidal behaviour and completed suicide.22

Cytokines and Depression

It has become clear that the inflammatory immune system is altered during the course of clinical depression. Most of the evidence that links inflammation and MDD comes from three observations:23

1. MDD (even in the absence of medical illness) is associated with raised inflammatory markers.

2. Inflammatory medical illnesses, both CNS and peripheral, are associated with greater rates of major depression.

3. Patients treated with cytokines for various illnesses are at increased risk of developing major depressive illness.

Acute stress enhances immune function while chronic stress suppresses it through the Hypothalamic-Pituitary-Adrenal (HPA) axis.24 Elevated glucocorticoids released in response to acute stress activate the \'delayed-type hypersensitivity\' (DTH) response; so called because it occurs 24-72 hours after an environmental threat.25 Chronic stress leads to habituation of the HPA axis response and thus impairs the DTH response.25

Various psychological stressors can induce neurotransmitter changes which include disturbed functioning of the adaptive immune system, including T and B lymphocytes, as well as innate immune cells, particularly natural killer (NK) cells and macrophages.26 Although the blood-brain barrier (BBB), as well as other inhibitory mechanisms, within the brain, normally tightly regulate the flow and level of immune factors within the brain, increasing evidence-indicates that several neurological disorders, including multiple sclerosis, Alzheimer\'s and Parkinson\'s disease, have a prominent neuro-inflammatory component.27-29

In addition to direct entry into the brain parenchyma, immune factors can influence CNS functioning through activation of receptors located on peripheral organs or the BBB.30

Cytokines are soluble low-molecular-weight glycoprotein messengers secreted by lymphoid cells which act as signallers to other lymphoid cells. They can be classified into various groups, including Interferons (released by infected cells and induce anti-viral resistance), Interleukins (abbreviated as IL; produced mostly by T-cells and involved in directing other cells to divide and differentiate), Colony stimulating factors (direct division and differentiation of bone marrow stem cells) and other cytokines such as tumor necrosis factors (TNF) which mediate inflammation and cytotoxic reactions.31 Cytokines are often divided into pro-inflammatory (including IL-1, IL-6 and TNF) or anti-inflammatory (IL-4, IL-10, IL-13).32

Cytokines influence brain functioning in a variety of ways. They can bind to receptors located on the liver or spleen or the nodose ganglion and trigger neural firing from these sites, which can then signal the CNS.33 They can also interact directly with BBB receptors to induce cyclooxygenase-2 (COX2) inflammatory signalling within the brain parenchyma.34,35 There is also evidence that they are produced in CNS glial cells.36

Cytokines are important for a subset, but not all depressive symptoms. It is helpful to view cytokines as being a very important trigger that acts together with psychosocial challenges to provoke the onset of MDD. They have potent sickness-inducing effects (so called \'sickness behaviour\' including social withdrawal, reduced appetite and low energy), which are often taken to reflect some form of depression.37,38 On the other hand, the melancholia typical of MDD is harder to model in animals and might be somewhat independent from cytokine effects.

Classes of Anti-Depressant Drugs and Their Actions

Most anti-depressants enhance noradrenergic and/or serotonergic neurotransmission following acute administration.39 For the most widely used anti-depressants, including TCAs, SSRIs), norepinephrine reuptake inhibitors (NRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs), this results from reuptake inhibition of norepinephrine or serotonin in the neuronal synapse.40-43 Some drugs enhance monoaminergic neurotransmission by other mechanisms such as inhibition of monoamine oxidase,44,45 or antagonism of presynaptic alpha-2 adrenergic receptors.46-48 The exact relationship between synaptic monoamine neurotransmission and the efficacy of antidepressant medications remains unclear. Although monoamine levels begin to rise within hours of the first administration of the drug, its therapeutic effects develop gradually over time with repeated treatment.49,50 This discrepancy has focused research on non-monoamine mechanisms that may lead to more effective anti-depressants.39

Animal Models of Depression

In addition to being a major public health problem, the treatments available for depression leave much to be desired. Even if MDD is accurately diagnosed and adequately treated with excellent compliance, remission rates with standard anti-depressants vary from 30-40%.39,40 In contrast other chronic disorders such as diabetes mellitus can be adequately treated with successful prevention of complications in a large majority of patients.41

This has been presumed to be because of several factors. First, the diagnosis of depressive episodes is based primarily on \'check lists\' of certain vaguely defined clinical symptoms (e.g., depressed mood, anhedonia, sleep changes, appetite changes, guilt, etc.) for a 2-week period. There are no objective diagnostic tools available such as neuroimaging, genetic variations, biomarkers, or biopsies. Depression is heterogeneous (atypical vs. melancholic vs. psychotic, etc.),42 but little is known about the pathophysiological or etiological differences between these subtypes. Most current theories of depression are based largely on animal models of the disease.

Some of the core symptoms of depression in humans such as guilt, suicidal ideation and sad mood obviously cannot be assessed in animals. However, other aspects of the depressive syndrome have been replicated and in several instances ameliorated with anti-depressant treatment in laboratory animals. These include measures of helplessness, anhedonia, behavioural despair and other neuro-vegetative changes such as alterations in sleep and appetite patterns.

Animal models of depression can be categorised into those that provoke acute stress such as the Forced Swim Test (FST),46 the Tail Suspension Test (TST)47 or the Learned Helplessness (LH) Model, following an uncontrollable stress such as exposure to inescapable electric shocks. So called \'secondary depression\' is mediated through the HPA Axis and can be secondary to external stress or iatrogenic, the effects of both of which can be studied in mice.49,50

Cytokines have been shown to induce depression-like behaviour in rodents and primates.51,52 However, simply inducing \'sickness behaviour\' by strong immune stimuli such as lipopolysaccharide (LPS)53 overlooks other core symptoms of depression in humans that cannot be modelled in animals such as guilt, suicidal thoughts or melancholia.

Chronic mild stress (CMS), better described as Chronic Unpredictable Stress (CUS), involves the application of intermittent physical stresses (water deprivation, cage tilt, continuous light, white noise, damp bedding etc.) applied randomly over a relatively prolonged time period (between 1 and 7 weeks). This model has been recently used to phenotype mouse mutants, study gender differences in stress responses, and validate novel anti-depressants.54-56

Despite advances in our understanding of some of the mechanisms of depression, new anti-depressants slightly vary from their predecessors in side-effect profiles only, with little or no improvements in efficacy. Clinicians are often forced to initiate multiple anti-depressant medications simultaneously, or rely on adjunct medications like thyroid hormone, anti-psychotic agents or psychostimulants to boost the anti-depressant response. The animal models of depression discussed so far can expand our understanding of mechanisms in depression.

Anti-Depressants and Cytokines Levels in Animal Models

Extensive work has been done on the effects of anti-depressant drugs on cytokine production in animal and in-vitro studies. The common approach in such studies in animals was to induce sickness behaviour by administration of bacterial LPS or by using animal models that replicate the features of depression seen in humans, as mentioned earlier, e.g., FST, TST and CMS. Another approach is use of olfactory bulbectomised (OB) rats which demonstrate increased production of pro-inflammatory cytokines.57

In a recent study, administration of TNF-a in mice resulted in depressive behaviour in FST and TST models. These depressive symptoms were attenuated by administration of Fluoxetine, Imipramine, and Desipramine.58 In another study, coronary arteries of rats were blocked to produce myocardial infarction (MI). This resulted in depression-like symptoms similar to post-MI depression in humans. Administration of Escitalopram decreased despair, anhedonia and levels of TNF-a, prostaglandin E2 (PGE2,) and IL-1.59

Kubera et al showed that chronic administration of imipramine in CMS model reversed anhedonia and elevated production of pro-inflammatory cytokines like IL-1 and IL-2. Chronic administration of SSRIs and TCA in OB rats reversed the rise in acute phase reactants.57 Many studies have shown that sickness behaviour in animals produced by administration of bacterial LPS can be reversed by chronic administration of different anti-depressant drugs.60,61

Human blood monocytes are widely used in in-vitro studies to evaluate the effects of anti-depressants on cytokine production. Kubera M et al have shown that pro-inflammatory cytokine production by human monocytes induced by bacterial LPS is inhibited by anti-depressants.62 In another study, Fluoxetine and Citalopram were added to culture of synovial membrane cells from patients of rheumatoid arthritis. They reduced production of TNF-a, IL-6, interferone INF-g inducible protein 10.63

Microglial activation in brain plays an important role in pathophysiology of depression because microglia produce pro-inflammatory cytokines when stimulated. In a recent study, fluoxetine was added to LPS-stimulated microglial cells. Fluoxetine inhibited production of TNF-a, IL-6, and nitric oxide (NO) and decreased messenger Ribonucleic acid (mRNA) levels of these cytokines (Figure-1) and inducible Nitric Oxide Synthase (iNOS).64 This demonstrates that interventions aiming at microglial activation may be a therapeutic possibility in depression. In another study, microglia were activated by administering IFN-g. Subsequent administration of Paroxetine and Sertraline reduced production of NO and TNF-a by inhibiting IFN-g induced raised intracellular calcium[65] (Figure-1).

Studies of the CNS of animals have also shown that increased levels of inflammatory cytokines have implications in development of depression due to disturbed neuronal synaptic plasticity and disturbances in the levels of different neurotrophic factors especially BDNF in the hippocampus.62,64 Moreover, these increased levels of cytokines have been shown to reduce neurogenesis in the hippocampus,62,63 while studies by Wang Y et al have shown that the administration of Fluoxetine (an SSRI) increases neurogenesis in the hippocampus by antagonising the effects of cytokines.65 This fact is also supported by studies of the ablation of hippocampal neurogenesis, which attenuated the behavioural effects of the anti-depressants.62

SSRIs have also been shown to potentiate the effects of neurotrophic factor BDNF in reducing the release of NO (an inflammatory cytokine, and an agent of oxidative stress) from activated rodent microglia.66 Thus anti-depressants may play a role in reducing the release of inflammatory cytokines by glia cells, independent of their role in neurogenesis (Figure-2).

Human Studies

Studies in humans are less conclusive than those in animals or those in-vitro. Hannestad J recently conducted a meta-analysis of 22 studies done in humans in which cytokine levels were measured before and after treatment with anti-depressants for major depression. The study concluded that TNF-a is not affected by anti-depressants, but anti-depressants reduce IL-1b and possibly IL-6 levels as expected. All classes of anti-depressants reduce symptoms of depression.67 Anti-depressants do not reduce cytokine levels in healthy subjects. In a study by the same author on healthy subjects, it was found that pre-treatment with Citalopram did not reduce elevated levels of IL-6 and TNF-a induced by low dose endotoxin administration, but depression severity was reduced by 50%.68 In another study, Fluoxetine reduced IL-1b levels in respondents only.69 Studies have shown that addition of anti-inflammatory drugs to anti-depressants in humans results in greater degree of reduction in cytokine levels and depression symptoms.

In a recent randomised controlled trial (RCT), the Celecoxib plus Sertraline group had greater reduction in levels of IL-6 and symptoms of depression than the Sertraline only group.70 In another RCT, Celecoxib plus Fluoxetine markedly reduced depression severity compared to Fluoxetine alone.71 The use of anti-inflammatory agents in the adjunctive treatment of depression is in need of further research and exploration before any suggestion can be made regarding their clinical use, considering that current anti-inflammatory drugs often have serious side effects of their own.

Mechanisms of Immunomodulatry Effects of Anti-Depressants

Anti-depressants may be involved in modulating pro-inflammatory states at both micro and macro-levels. These may include alterations in hypothalamic-pituitary-adrenal (HPA) axis, glucocorticoid receptor (GR) signalling, synaptic plasticity, neuronal regeneration, increased production of neurotrophic factors, alterations in melatonin production, changes in microglial proton channels and astrocytes favouring an anti-inflammatory state.

As described previously, decreased sensitivity of GR and disturbances in HPA axis are important in the pathophysiology of depression. Elevated cytokines in depression reduce the negative feedback control in HPA axis72 and reduce GR expression.73 A recent review concluded that anti-depressants up-regulate and increase GR expression, thereby restoring the negative feedback control system in HPA axis. Moreover, they also normalise serum glucocorticoid levels.74

As described previously, microglia produce pro-inflammatory cytokines and anti-depressants reduce microglial activation and thus production of pro-inflammatory cytokines. Anti-depressants may do this by blocking proton channels in microglia that are important in production of cytokines. In a recent study, it was found that imipramine inhibited the release of TNF-a from LPS-stimulated murine microglia cells at concentrations comparable to those that blocked microglial proton channels.75

Depressed patients have decreased melatonin levels and anti-depressant drugs increase melatonin production.74 Melatonin is important in maintaining normal circadian rhythms and sleep-wake cycles in humans. Another mechanism by which anti-depressants may modulate effects of pro-inflammatory cytokines is their inhibitory effect on iNOS, thus resulting in decreased production of NO and PGE2.57

Structural changes in neuronal synapses and increased hippocampal neurogenesis after chronic administration of anti-depressant drugs has been consistently observed in animal models of depression.76,77 Mice treated with Methyl-phenyl-tetrahydropyridine (MPTP) are used as an animal model of Parkinson\'s disease because MPTP administration results in neuronal damage in the nigrostriatal pathway. In a recent study, fluoxetine prevented this neuronal damage by decreasing the production of pro-inflammatory cytokines and reducing activity of nicotinamide adenine dinucleotide phosphate NADPH Oxidase, thus decreasing the generation of free radicals and reactive oxygen species.78 Anti-depressants also promote production of neurotrophic growth factors and modulate signalling cascade in microglia.79 It is still unknown whether changes in synaptic plasticity and neurogenesis persist after discontinuation of anti-depressants.


Variations in the levels of pro- and anti-inflammatory cytokines are central to the pathophysiology of depression. Treatment with anti-depressant medication helps normalise these variations and may play a key role in recovery from depressive illness. The exact mechanism of the immunomodulatory effects of anti-depressants is unknown, but it may involve normalisation of glucocortocoid negative feedback control, increased neurogenesis and production of neurotrophic factors and decreased microglia activation in the CNS. Cytokines are important biological markers in elucidating the mechanism and pathophysiology of depression as well as helping with diagnosis, treatment selection and long-term screening. In the light of data suggesting that immuneprocesses may interact with the pathophysiologic pathways known to contribute to depression, novel approaches to the treatment of depression may target relevant aspects of the immune response.

Further research is needed, particularly on the clinical effects of cytokine antagonists and cytokine synthesis inhibitors on the pathophysiological and psychological features of MDD. The cytokine hypothesis also presents a novel opportunity for the development of a new generation of effective anti-depressants.


1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders IV. Washington, DC:American Psychiatric Publishing, Inc; 1994.

2. Kessler RC, Angermeyer M, Anthony JC, de Graaf R, Demyttenaere K, Gasquet I, et al. Lifetime prevalence and age-of-onset distributions of mental disorders in the World Health Organization\'s World Mental Health Survey Initiative. World Psychiatry 2007; 6:168-76.

3. Murray CJ, Lopez AD. Evidence-based health policy - lessons from the global burden of disease study. Science 1996; 274:740-3.

4. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289:3095-105.

5. Dodani S, Zuberi RW. Center-based prevalence of anxiety and depression in women of the northern areas of Pakistan. J Pak Med Assoc 2000; 50:138-40.

6. Rasheed S, Khan MA, Khan B, Khan MY. Depression in medical in-patients. Pak Armed Forces Med J 2003; 53:132-5.

7. Shah S, Hassan SS, Ahmed M, Shah H, Ali R. Anxiety and depression in patients and controls. J Rawal Med Coll 2006; 10:86-9.

8. Kocsis JH, Klein DN (eds.). Diagnosis and Treatment of Chronic Depression. New York: Guilford Press; 1995.

9. Schulberg HC, Katon W, Simon GE, Rush AJ. Treating major depression in primary care practice: an update of theagency for health care policy and research practice guidelines. Arch Gen Psychiatry 1998; 55:1121-7.

10. Akiskal HS, Akiskal K. Cyclothymic, hyperthymic and depressive temperaments as subaffective variants of mood disorders. In: Tasman A, Riba MB, (eds.). Annual Review of Psychiatry. Vol. 11. Washington, DC: American Psychiatric Press; 1992.

11. Warden D, Rush AJ, Trivedi MH, Fava M, Wisniewski SR. The STAR*D Project results: a comprehensive review of findings. Curr Psychiatry Rep 2007; 9:449-59.

12. Adler DA, McLaughlin TJ, Rogers WH, Chang H, Lapitsky L, Lerner D. Job performance deficits due to depression. Am J Psychiatry 2006; 163:1569-76.

13. Lerner D, Adler DA, Chang H, Berndt ER, Irish JT, Lapitsky L, et al. The clinical and occupational correlates of work productivity loss among employed patients with depression. J Occup Environ Med 2004; 46 (suppl 6): S46-55.

14. Ciechanowski PS, Katon WJ, Russo JE. Depression and diabetes: impact of depressive symptoms on adherence, function, and costs. Arch Intern Med 2000; 160:3278-85.

15. McIntyre RS, Soczynska JK, Konarski JZ, Kennedy SH. The effect of antidepressants on glucose homeostasis and insulin sensitivity: synthesis and mechanisms. Expert Opin Drug Saf 2006; 5:157-68.

16. Murphy JM, Horton NJ, Monson RR, Laird NM, Sobol AM, Leighton AH. Cigarette smoking in relation to depression: historical trends from the Stirling County Study. Am J Psychiatry 2003; 160:1663-9.

17. van Gool CH, Kempen GI, Penninx BW, Deeg DJ, Beekman AT, van Eijk JT. Relationship between changes in depressive symptoms and unhealthy lifestyles in late middle aged and older persons: results from the Longitudinal Aging Study Amsterdam. Age Ageing 2003; 32:81-7.

18. Taylor CB, Youngblood ME, Catellier D, Veith RC, Carney RM, Burg MM, et al. Effects of antidepressant medication on morbidity and mortality in depressed patients after myocardial infarction. Arch Gen Psychiatry 2005; 62:792-8.

19. Patten SB, Williams JV, Lavorato DH, Modgill G, Jette N, Eliasziw M. Major depression as a risk factor for chronic disease incidence: longitudinal analyses in a general population cohort. Gen Hosp Psychiatry 2008; 30:407-13.

20. Seguin M, Lesage A, Chawky N, Guy A, Daigle F, Girard G, et al. Suicide cases in New Brunswick from April 2002 to May 2003: the importance of better recognizing substance and mood disorder comorbidity. Can J Psychiatry 2006; 51:581-6.

21. US Preventive Services Task Force. Screening and treatment for major depressive disorder in children and adolescents: US preventive services task force recommendation statement. Pediatrics 2009;123:1223-8.

22. Bridge JA, Goldstein TR, Brent DA. Adolescent suicide and suicidal behavior. J Child Psychol Psychiatry 2006; 47:372-94.

23. Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther 2011; 130:226-38.

24. McEwen BS. The neurobiology of stress: from serendipity to clinical relevance. Brain Res 2000; 886:172-89.

25. Dhabhar FS. Acute stress enhances while chronic stress suppresses skin immunity. The role of stress hormones and leukocyte trafficking. Ann N Y Acad Sci 2000; 917:876-93.

26. Griffiths J, Ravindran AV, Merali Z, Anisman H. Dysthymia: a review of pharmacological and behavioral factors. Mol Psychiatry 2000; 5:242-61.

27. Wheeler RD, Owens T. The changing face of cytokines in the brain: perspectives from EAE. Curr Pharm Des 2005; 11:1031-7.

28. Czlonkowska A, Kurkowska-Jastrzebska I, Czlonkowski A, Peter D, Stefano GB. Immune processes in the pathogenesis of Parkinson\'s disease - a potential role for microglia and nitric oxide. Med Sci Monit 2002; 8:RA165-77.

29. Cotter RL, Burke WJ, Thomas VS, Potter JF, Zheng J, Gendelman HE. Insights into the neurodegenerative process of Alzheimer\'s disease: a role for mononuclear phagocyte-associated inflammation and neurotoxicity. J Leukoc Biol 1999; 65:416-27.

30. Goehler LE, Erisir A, Gaykema RP. Neural-immune interface in the rat area postrema. Neuroscience 2006; 140:1415-34.

31. Roitt I, Brostoff J, Male D. Immunology. 4th ed. London: Mosby; 1996.

32. Dinan TG. Inflammatory markers in depression. Curr Opin Psychiatry 2009;22:32-6.

33. Cunningham ET Jr., De Souza EB. Interleukin 1 receptors in the brain and endocrine tissues. Immunol Today 1993; 14:171-6.

34. Rivest S. How circulating cytokines trigger the neural circuits that control the hypothalamic-pituitary-adrenal axis. Psychoneuroendocrinology 2001; 26:761-88.

35. Hayley S, Mangano E, Strickland M, Anisman H. Lipopolysaccharide and a social stressor influence behaviour, corticosterone and cytokine levels: divergent actions in cyclooxygenase-2 deficient mice and wild type controls. J Neuroimmunol 2008; 197:29-36.

36. Buttini M, Boddeke H. Peripheral lipopolysaccharide stimulation induces interleukin-1 beta messenger RNA in rat brain microglial cells. Neuroscience 1995; 65:523-30.

37. Anisman H, Gibb J, Hayley S. Influence of continuous infusion of interleukin-1beta on depression-related processes in mice: corticosterone, circulating cytokines, brain monoamines, and cytokine mRNA expression. Psychopharmacology (Berl) 2008; 199:231-44.

38. Dantzer R, O\'Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9:46-56.

39. Millan MJ. Multi-target strategies for the improved treatment of depressive states: conceptual foundations and neuronal substrates, drug discovery and therapeutic application. Pharmacol Ther 2006; 110:135-370.

40. Beyer CE, Boikess S, Luo B, Dawson LA. Comparison of the effects of antidepressants on norepinephrine and serotonin concentrations in the rat frontal cortex: an in-vivo microdialysis study. J Psychopharmacol 2002; 16:297-304.

41. Katz MM, Tekell JL, Bowden CL, Brannan S, Houston JP, Berman N, et al. Onset and early behavioral effects of pharmacologically different antidepressants and placebo in depression. Neuropsychopharmacology 2004; 29:566-79.

42. Morilak DA, Frazer A. Antidepressants and brain monoaminergic systems: a dimensional approach to understanding their behavioural effects in depression and anxiety disorders. Int J Neuropsychopharmacol 2004; 7:193-218.

43. White KJ, Walline CC, Barker EL. Serotonin transporters: implications for antidepressant drug development. AAPS J 2005; 7:E421-33.

44. Laux G, Volz H, Muller H. Newer and older monoamine oxidase inhibitors. A comparative profile. CNS drugs 1995; 3:145-58.

45. Lopez-Munoz F, Alamo C, Juckel G, Assion HJ. Half a century of antidepressant drugs: on the clinical introduction of monoamine oxidase inhibitors, tricyclics, and tetracyclics. Part I: monoamine oxidase inhibitors. J Clin Psychopharmacol 2007; 27:555-9.

46. Charney DS, Price LH, Heninger GR. Desipramine-yohimbine combination treatment of refractory depression. Implications for the beta-adrenergic receptor hypothesis of antidepressant action. Arch Gen Psychiatry 1986; 43:1155-61.

47. Dickinson S. Alpha2-adrenoceptor antagonism and depression. Drug News Perspect 1990;4:197-203.

48. Millan MJ, Gobert A, Rivet JM, Adhumeau-Auclair A, Cussac D, Newman-Tancredi A, et al. Mirtazapine enhances frontocortical dopaminergic and corticolimbic adrenergic, but not serotonergic, transmission by blockade of alpha2-adrenergic and serotonin2C receptors: a comparison with citalopram. Eur J Neurosci 2000; 12:1079-95.

49. Frazer A, Benmansour S. Delayed pharmacological effects of antidepressants. Mol Psychiatry 2002; 7(suppl 1):S23-8.

50. Nelson JC, Mazure CM, Jatlow PI, Bowers MB Jr., Price LH. Combining norepinephrine and serotonin reuptake inhibition mechanisms for treatment of depression: a double-blind, randomized study. Biol Psychiatry 2004; 55:296-300.

51. Rapaport MH, Schneider LS, Dunner DL, Davies JT, Pitts CD. Efficacy of controlled-release paroxetine in the treatment of late-life depression. J Clin Psychiatry 2003; 64:1065-74.

52. Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006; 163:28-40.

53. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature 2008; 455:894-902.

54. Rush AJ. The varied clinical presentations of major depressive disorder. J Clin Psychiatry 2007; 68(suppl 8):4-10.

55. Sloman L. A new comprehensive evolutionary model of depression and anxiety. J Affect Disord 2008; 106:219-28.

56. Nesse RM. Is depression an adaptation? Arch Gen Psychiatry 2000; 57:14-20.

57. Castanon N, Leonard BE, Neveu PJ, Yirmiya R. Effects of antidepressants on cytokine production and actions. Brain Behav Immun 2002; 16:569-74.

58. Kaster MP, Gadotti VM, Calixto JB, Santos AR, Rodrigues AL. Depressive-like behavior induced by tumor necrosis factor-alpha in mice. Neuropharmacology 2012;62:419-26.

59. Bah TM, Benderdour M, Kaloustian S, Karam R, Rousseau G, Godbout R. Escitalopram reduces circulating pro-inflammatory cytokines and improves depressive behavior without affecting sleep in a rat model of post-cardiac infarct depression. Behav Brain Res 2011; 225:243-51.

60. Castanon N, Bluthe RM, Dantzer R. Chronic treatment with the atypical antidepressant tianeptine attenuates sickness behavior induced by peripheral but not central lipopolysaccharide and interleukin-1beta in the rat. Psychopharmacology (Berl) 2001;154:50-60.

61. Yirmiya R, Pollak Y, Barak O, Avitsur R, Ovadia H, Bette M, et al. Effects of antidepressant drugs on the behavioral and physiological responses to lipopolysaccharide (LPS) in rodents. Neuropsychopharmacology 2001;24:531-44.

62. Kubera M, Kenis G, Bosmans E, Scharpe S, Maes M. Effects of serotonin and serotonergic agonists and antagonists on the production of interferon-gamma and interleukin-10. Neuropsychopharmacology 2000;23:89-98.

63. Sacre S, Medghalchi M, Gregory B, Brennan F, Williams R. Fluoxetine and citalopram exhibit potent antiinflammatory activity in human and murine models of rheumatoid arthritis and inhibit toll-like receptors. Arthritis Rheum 2010;62:683-93.

64. Liu D, Wang Z, Liu S, Wang F, Zhao S, Hao A. Anti-inflammatory effects of fluoxetine in lipopolysaccharide(LPS)-stimulated microglial cells. Neuropharmacology 2011;61:592-9.

65. Horikawa H, Kato TA, Mizoguchi Y, Monji A, Seki Y, Ohkuri T, et al. Inhibitory effects of SSRIs on IFN-gamma induced microglial activation through the regulation of intracellular calcium. Prog Neuropsychopharmacol Biol Psychiatry 2010;34:1306-16.

66. Masi G, Brovedani P. The hippocampus, neurotrophic factors and depression: possible implications for the pharmacotherapy of depression. CNS Drugs 2011; 25:913-31.

67. Hannestad J, DellaGioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 2011;36:2452-9.

68. Hannestad J, DellaGioia N, Ortiz N, Pittman B, Bhagwagar Z. Citalopram reduces endotoxin-induced fatigue. Brain Behav Immun 2011;25:256-9.

69. Song C, Halbreich U, Han C, Leonard BE, Luo H. Imbalance between pro- and anti-inflammatory cytokines, and between Th1 and Th2 cytokines in depressed patients: the effect of electroacupuncture or fluoxetine treatment. Pharmacopsychiatry 2009;42:182-8.

70. Abbasi SH, Hosseini F, Modabbernia A, Ashrafi M, Akhondzadeh S. Effect of celecoxib add-on treatment on symptoms and serum IL-6 concentrations in patients with major depressive disorder: randomized double-blind placebo-controlled study. J Affect Disord 2012; 141:308-14.

71. Akhondzadeh S, Jafari S, Raisi F, Nasehi AA, Ghoreishi A, Salehi B, et al. Clinical trial of adjunctive celecoxib treatment in patients with major depression: a double blind and placebo controlled trial. Depress Anxiety 2009;26:607-11.

72. Karaoulanis SE, Angelopoulos NV. The role of immune system in depression. Psychiatrike 2010;21:17-30.

73. Pace TW, Miller AH. Cytokines and glucocorticoid receptor signaling. Relevance to major depression. Ann N Y Acad Sci 2009;1179:86-105.

74. Antonioli M, Rybka J, Carvalho LA. Neuroimmune endocrine effects of antidepressants. Neuropsychiatr Dis Treat 2012;8:65-83.

75. Song JH, Marszalec W, Kai L, Yeh JZ, Narahashi T. Antidepressants inhibit proton currents and tumor necrosis factor-alpha production in BV2 microglial cells. Brain Res 2012;1435:15-23.

76. Wang Y, Cui XL, Liu YF, Gao F, Wei D, Li XW, et al. LPS inhibits the effects of fluoxetine on depression-like behavior and hippocampal neurogenesis in rats. Prog Neuropsychopharmacol Biol Psychiatry 201;35:1831-5.

77. Chiou SH, Chen SJ, Peng CH, Chang YL, Ku HH, Hsu WM, et al. Fluoxetine up-regulates expression of cellular FLICE-inhibitory protein and inhibits LPS-induced apoptosis in hippocampus-derived neural stem cell. Biochem Biophys Res Commun 2006;343:391-400.

78. Chung YC, Kim SR, Park JY, Chung ES, Park KW, Won SY, et al. Fluoxetine prevents MPTP-induced loss of dopaminergic neurons by inhibiting microglial activation. Neuropharmacology 2011;60:963-74.

79. Kovaru H, Pav M, Kovaru F, Raboch J, Fiserova A. Cell signalling in CNS and immune system in depression and during antidepressant treatment: focus on glial and natural killer cells. Neuro Endocrinol Lett 2009;30:421-8.
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Publication:Journal of Pakistan Medical Association
Date:Jul 31, 2013
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