Will finding the depression−inflammation link lead to tailored treatments for MDD?

There is an association between inflam­mation and depression: Patients with a major depressive disor­der (MDD) have elevated levels of pro-inflammatory cytokines interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). Abnormal cell-mediated immunity and lymphocyte proliferation also have been reported in patients with MDD^1-2 (Box).^1,3-7

What remains unclear is whether inflammation is causative in affective ill­ness,^1-4 and how the association might be exploited for the benefit of a subset of MDD patients.

Underpinnings of pathophysiology
Immune system activation leads to pro­duction of cytokines, which 1) influences the synthesis, reuptake, and release of neu­rotransmitters and 2) stimulates the mani­festations of depression.^1,2 Interferon-γ and TNF-α are involved in neuronal degen­eration and inhibition of neurogenesis in the brain, especially the hippocampus— thereby explaining observed cognitive deficits in depression.

Production of cytokines in serum and cerebrospinal fluid can be triggered by psychosocial stress, administration of interferon-α or IL-2, and acute stimula­tion of the immune system after vacci­nation; this production of cytokines is associated with development of MDD.^1-3 Inflammatory disorders raise a person’s vulnerability to MDD; affective illness is the most common psychiatric condition seen in association with multiple sclerosis, for example.² 

Principal receptor targets
Glucocorticoid receptors. Synchrony between the hypothalamic-pituitary-adrenal axis and adrenal function occurs during stressful circumstances.² Down-regulation, or reduced activity, of glucocorticoid recep­tors in depression leads to glucocorticoid resistance, resulting in hyperactivity of this axis. TNF-α is associated with glucocorti­coid resistance by its action in opposing the influx of the cortisol-glucocorticoid recep­tor complex into the nucleus and inhibiting its linkage with DNA. Cytokines increase levels of corticotropin-releasing hormone and adrenocorticotrophic hormone, leading to a higher-than-normal cortisol concentra­tion in depressed patients.⁸

N-methyl-d-aspartate (NMDA) receptors are involved in the monoamine and glu­tamatergic pathways that are associated with depression.² NMDA-receptor acti­vation raises the intracellular calcium con­centration, causing neuronal cell death. Inflammatory mediators, including TNF-α, induce activation of the kyneurin pathway. Thus, instead of serotonin production, tryp­tophan is diverted to the synthesis of the NMDA-receptor agonists kynurenine and quinolinic acid, which leads to apoptosis.

The glutamatergic pathway involves binding of IL-1β and IL-1R complexes to hippocampal NMDA receptors.² Persistent activation of these receptors results in calcium toxicity and neuronal death. Reuptake inhibition of neurotransmit­ters is explained by the action of IL-1β on reuptake of glutamate, which enhances its availability to stimulate NMDA-receptor activation.

Any prospects for therapeutics?
As described, an association exists between inflammation and depression. Psychosocial stresses initiate inflammatory responses that might result in affective illness. In treat­ing depression and preventing its relapse, the question is whether psychotherapy provides clinical efficacy through stress reduction, thereby leading to potential anti-inflammatory action.¹

Inflammation has a detrimental influence in a subset of MDD cases.⁹ Identification of those patients through genetic research is ongoing, with the goal of establishing spe­cific anti-inflammatory or antidepressant therapies.

Anti-inflammatory drugs such as aspi­rin, celecoxib, and etanercept do induce antidepressant effects and augment the antidepressant response to other thera­pies.^1,3 In the future, anti-inflammatory treatments might become an option for select MDD patients.


Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

There is an association between inflam­mation and depression: Patients with a major depressive disor­der (MDD) have elevated levels of pro-inflammatory cytokines interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). Abnormal cell-mediated immunity and lymphocyte proliferation also have been reported in patients with MDD^1-2 (Box).^1,3-7

What remains unclear is whether inflammation is causative in affective ill­ness,^1-4 and how the association might be exploited for the benefit of a subset of MDD patients.

Underpinnings of pathophysiology
Immune system activation leads to pro­duction of cytokines, which 1) influences the synthesis, reuptake, and release of neu­rotransmitters and 2) stimulates the mani­festations of depression.^1,2 Interferon-γ and TNF-α are involved in neuronal degen­eration and inhibition of neurogenesis in the brain, especially the hippocampus— thereby explaining observed cognitive deficits in depression.

Production of cytokines in serum and cerebrospinal fluid can be triggered by psychosocial stress, administration of interferon-α or IL-2, and acute stimula­tion of the immune system after vacci­nation; this production of cytokines is associated with development of MDD.^1-3 Inflammatory disorders raise a person’s vulnerability to MDD; affective illness is the most common psychiatric condition seen in association with multiple sclerosis, for example.² 

Principal receptor targets
Glucocorticoid receptors. Synchrony between the hypothalamic-pituitary-adrenal axis and adrenal function occurs during stressful circumstances.² Down-regulation, or reduced activity, of glucocorticoid recep­tors in depression leads to glucocorticoid resistance, resulting in hyperactivity of this axis. TNF-α is associated with glucocorti­coid resistance by its action in opposing the influx of the cortisol-glucocorticoid recep­tor complex into the nucleus and inhibiting its linkage with DNA. Cytokines increase levels of corticotropin-releasing hormone and adrenocorticotrophic hormone, leading to a higher-than-normal cortisol concentra­tion in depressed patients.⁸

N-methyl-d-aspartate (NMDA) receptors are involved in the monoamine and glu­tamatergic pathways that are associated with depression.² NMDA-receptor acti­vation raises the intracellular calcium con­centration, causing neuronal cell death. Inflammatory mediators, including TNF-α, induce activation of the kyneurin pathway. Thus, instead of serotonin production, tryp­tophan is diverted to the synthesis of the NMDA-receptor agonists kynurenine and quinolinic acid, which leads to apoptosis.

The glutamatergic pathway involves binding of IL-1β and IL-1R complexes to hippocampal NMDA receptors.² Persistent activation of these receptors results in calcium toxicity and neuronal death. Reuptake inhibition of neurotransmit­ters is explained by the action of IL-1β on reuptake of glutamate, which enhances its availability to stimulate NMDA-receptor activation.

Any prospects for therapeutics?
As described, an association exists between inflammation and depression. Psychosocial stresses initiate inflammatory responses that might result in affective illness. In treat­ing depression and preventing its relapse, the question is whether psychotherapy provides clinical efficacy through stress reduction, thereby leading to potential anti-inflammatory action.¹

Inflammation has a detrimental influence in a subset of MDD cases.⁹ Identification of those patients through genetic research is ongoing, with the goal of establishing spe­cific anti-inflammatory or antidepressant therapies.

Anti-inflammatory drugs such as aspi­rin, celecoxib, and etanercept do induce antidepressant effects and augment the antidepressant response to other thera­pies.^1,3 In the future, anti-inflammatory treatments might become an option for select MDD patients.


Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

There is an association between inflam­mation and depression: Patients with a major depressive disor­der (MDD) have elevated levels of pro-inflammatory cytokines interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP). Abnormal cell-mediated immunity and lymphocyte proliferation also have been reported in patients with MDD^1-2 (Box).^1,3-7

What remains unclear is whether inflammation is causative in affective ill­ness,^1-4 and how the association might be exploited for the benefit of a subset of MDD patients.

Underpinnings of pathophysiology
Immune system activation leads to pro­duction of cytokines, which 1) influences the synthesis, reuptake, and release of neu­rotransmitters and 2) stimulates the mani­festations of depression.^1,2 Interferon-γ and TNF-α are involved in neuronal degen­eration and inhibition of neurogenesis in the brain, especially the hippocampus— thereby explaining observed cognitive deficits in depression.

Production of cytokines in serum and cerebrospinal fluid can be triggered by psychosocial stress, administration of interferon-α or IL-2, and acute stimula­tion of the immune system after vacci­nation; this production of cytokines is associated with development of MDD.^1-3 Inflammatory disorders raise a person’s vulnerability to MDD; affective illness is the most common psychiatric condition seen in association with multiple sclerosis, for example.² 

Principal receptor targets
Glucocorticoid receptors. Synchrony between the hypothalamic-pituitary-adrenal axis and adrenal function occurs during stressful circumstances.² Down-regulation, or reduced activity, of glucocorticoid recep­tors in depression leads to glucocorticoid resistance, resulting in hyperactivity of this axis. TNF-α is associated with glucocorti­coid resistance by its action in opposing the influx of the cortisol-glucocorticoid recep­tor complex into the nucleus and inhibiting its linkage with DNA. Cytokines increase levels of corticotropin-releasing hormone and adrenocorticotrophic hormone, leading to a higher-than-normal cortisol concentra­tion in depressed patients.⁸

N-methyl-d-aspartate (NMDA) receptors are involved in the monoamine and glu­tamatergic pathways that are associated with depression.² NMDA-receptor acti­vation raises the intracellular calcium con­centration, causing neuronal cell death. Inflammatory mediators, including TNF-α, induce activation of the kyneurin pathway. Thus, instead of serotonin production, tryp­tophan is diverted to the synthesis of the NMDA-receptor agonists kynurenine and quinolinic acid, which leads to apoptosis.

The glutamatergic pathway involves binding of IL-1β and IL-1R complexes to hippocampal NMDA receptors.² Persistent activation of these receptors results in calcium toxicity and neuronal death. Reuptake inhibition of neurotransmit­ters is explained by the action of IL-1β on reuptake of glutamate, which enhances its availability to stimulate NMDA-receptor activation.

Any prospects for therapeutics?
As described, an association exists between inflammation and depression. Psychosocial stresses initiate inflammatory responses that might result in affective illness. In treat­ing depression and preventing its relapse, the question is whether psychotherapy provides clinical efficacy through stress reduction, thereby leading to potential anti-inflammatory action.¹

Inflammation has a detrimental influence in a subset of MDD cases.⁹ Identification of those patients through genetic research is ongoing, with the goal of establishing spe­cific anti-inflammatory or antidepressant therapies.

Anti-inflammatory drugs such as aspi­rin, celecoxib, and etanercept do induce antidepressant effects and augment the antidepressant response to other thera­pies.^1,3 In the future, anti-inflammatory treatments might become an option for select MDD patients.


Disclosures
The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.