In the last two decades, the resurgence of interest in the molecular basis of inflammation, and its points of control, has fueled an intense research effort for the development of new anti-inflammatory drugs. Although this movement has not yet penetrated the field of inflammation-associated subjective health complaints, the potential of research and development is certainly worthwhile. Abandoning this opportunity to the many unfulfilled promises of over-the-counter drugs and the vagaries of alternative and complementary medicine would be unfortunate.
Andrew Miller (Atlanta, Georgia) reviewed the possible targets for intervention in the chain of events linking inflammation and depression. The production and action of proinflammatory cytokines represent the most obvious target since they are at the beginning of the chain. Modulation of cytokine production and action can be achieved by administration of cytokine synthesis inhibitors, anti-inflammatory cytokines and soluble receptors. Proinflammatory cytokines often act in synergy, via activation of common intracellular signaling pathways involving either MAP kinases, MyD88 or NFκB. MAP kinases and NFκB represent interesting targets since their activation mediates not only the induction of effector genes in the action of proinflammatory cytokines on their cell targets but also the synthesis of proinflammatory cytokines by themselves. In particular, binding of pathogen-associated molecular patterns to Toll-like receptors activates the synthesis of proinflammatory cytokines such as IL-1 and TNFα in a NFκB dependent manner. Binding of IL-1 and TNFα to their cogent receptors activates the NFκB signaling pathway, which mediates for instance the anti-apoptotic effect of TNFα and the transcription of IL-1 inducible genes such as cyclo-oxygenase 2 that is responsible for the synthesis of prostaglandins E2. Michael May (Philadelphia, Pennsylvania) reported on the ability to specifically block the activation of this pathway upstream of NFκB activation, at the level of the IκB-kinase complex, using an inhibitor of the regulatory protein NEMO (NFκB essential modifier) coupled to a cell permeable peptide (May et al., 2000
). Such blockade abrogates inflammation in various in vivo animal models, including cytokine-induced sickness behavior (Nadjar et al., 2005
). Activation of stress-activated protein/mitogen-activated protein kinase (SAPK/MAPK) pathways also plays an important role in inflammation. As pointed out by Charles Malemud (Cleveland, Ohio), inhibitors of MAP kinases have potent anti-inflammatory activity and several of them are under Phase I clinical trials (Malemud, 2007
). A target of choice could be the c-Jun N-terminal kinase (JNK) since inhibition of JNK by a cell penetrating peptide that blocks TNFα-induced IGF-I resistance (Strle et al., 2006
) protects against excitotoxicity and cerebral ischemia (Borsello et al., 2003
) and abrogates TNFα-induced sickness behavior (Palin et al., 2007
). However, even if blockade of SAPK/MAPK signaling pathway helps to ameliorate inflammation, this does not necessarily imply that it will abrogate inflammation-associated depression. Indeed, there is evidence that acute inhibition of an upstream kinase in this pathway, MAPK kinase (MEK), actually produces depressive-like behavior and blocks the effects of several conventional antidepressants (Duman et al., 2007
Several cytokine antagonists are already in clinical use or under advanced development stages, including the IL-1 receptor antagonist (Anakinra), several TNF-α blockers (including etanercept (Enbrel), infliximab (Remicade), adalimumab (Humira)), and the anti-inflammatory cytokine IL-10. Indeed, during the last few years, preliminary clinical studies pointed to the potential of this approach. For example, 618 patients with moderate to severe psoriasis who were treated with etanercept for 12 weeks displayed a marked improvement in depression scores independently of any ameliorating effect of the treatment on skin condition and joint pain (Tyring et al., 2006
). In a study of the tolerability of high dose chemotherapy in cancer patients, etanercept was found to significantly decrease the incidence of asthenia and fatigue while at the same time preserving the maintenance of dose intensive chemotherapy (Monk et al., 2006
). However, increased sensitivity to infections could represent a serious side effect of any treatment targeting the antagonism of proinflammatory cytokines.
Proinflammatory cytokines induce the production of several downstream inflammatory mediators, such as prostaglandins and nitric oxide, which could constitute appropriate targets for antidepressant medication. Indeed, a recent prospective, double-blind study demonstrated that administration of the non-steroidal anti-inflammatory drug celecoxib, a specific inhibitor of Cox-2, significantly improved the therapeutic efficacy of the conventional antidepressant drug reboxetine in patients with major depression (Muller et al., 2006
). Another secondary process that has been implicated in inflammation-associated depression is tryptophan depletion, as a consequence of activation of IDO (Capuron and Dantzer, 2003
). It is still unknown whether activation of IDO leads to depression because of the reduction in serotonergic neurotransmission that results from tryptophan depletion or because of an increased production of kynurenine, which in microglia can be converted to the neurotoxic compound quinolinic acid (Schwarcz, 2004
). The possibilities of modulating kynurenine actions in the brain were discussed by Robert Schwarcz (Baltimore, Maryland). Specific inhibitors of IDO, as well as some recently discovered modulators of kynurinergic pathways (Schwarcz, 2004
), may represent interesting strategies for treating inflammation-associated depression.
Proinflammatory cytokines and other inflammatory mediators are produced by accessory immune cells, such as macrophages and monocytes in the periphery and microglia within the central nervous system. As pointed out in the previous section, targeting cell trafficking into the central nervous system is unlikely to be a very useful approach since symptoms of sickness and depression are dependent on the activation of brain cytokine signaling independently of any blood cell recruitment. However, it is possible to decrease the production of brain proinflammatory cytokines by down-regulating brain macrophage-like cells and microglia. This can be achieved by using the tetracycline derivative minocycline (e.g., (Fan et al., 2007
)) or by blockers of NADPH oxidase activation, although this last mechanism is predominantly implicated in the damaging effects of microglia on neurons, as demonstrated by Michelle Block (Research Triangle Park, North Carolina) (Block et al., 2007
). Microglial activation that takes place during inflammation induced-neuronal death is a two-edge sword. Its inhibition is beneficial early in the process but deleterious later. Whether the same balance between injury and repair applies to functional rather than structural alterations in neurons as a consequence of microglial activation is still unknown. Another strategy that applies to inflammatory processes both at the periphery and in the brain is to dampen cytokine production by enhancing cholinergic neurotransmission (Pollak et al., 2005
; Tracey, 2007
Instead of simply applying to the field of inflammation and depression therapeutic strategies already developed for more traditional inflammatory disorders, it might be useful to define specific steps for the rational design of new therapies. These steps are as follows:
- Identify possible candidates in the form of inflammatory-related processes or molecules that are altered in the brains (post-mortem), CSF or blood of depressed patients (begin by examining patients with clear indication of inflammation-induced depression, and then assess other populations of clinically-depressed patients).
- Find similar inflammatory-related processes or molecules in animal models of depression.
- Assess the effects of conventional antidepressants (e.g., tricyclic antidepressants or selective serotonin reuptake inhibitors) on these process or molecules.
- Study the effects of specific inhibitors of these processes or molecules in animal models of depression.
- Examine the effects of these inhibitors in clinical trials – first in populations of depressed patients in which inflammation is likely to play an important role, such as IFN-α treated patients and patients with autoimmune disorders, and then with other depressed patient populations, such as treatment-resistant depression.
In the intervention studies defined in steps 4 and 5, it is important to measure markers of the inflammatory processes that are supposed to be modulated, that is, confirm that there are basal changes in this processes in the treated population (either in an animal model or in depressed patients) and verify that the treatment is indeed having the expected effect on these processes.
Most current anti-inflammatory compounds target peripheral immune processes, whereas depressive symptoms are obviously generated within the brain. Nevertheless, novel anti-inflammatory antidepressants may work even if their effects are restricted to the periphery, for the following reasons. If the source of the depressive condition is peripheral (e.g., following acute or chronic peripheral infection, surgery, trauma, myocardial infarction), the rationale for using a peripherally active drug is obvious. This is particularly important since peripheral infections can also sensitize or exaggerate existing brain inflammatory processes (Perry et al., 2007
). Furthermore, there is evidence that even subclinical daily fluctuations in immune activation can elicit depressive symptoms (Reichenberg et al., 2001
). Finally, although in most depressive conditions there is no obvious source of peripheral (or central) immune stimulation, the levels of peripheral inflammatory markers can be elevated in many patients (Raison et al., 2006
). Whatever their cause, elevated cytokine levels in blood have the potential to reverberate and activate central inflammatory systems. Therefore, while future studies should focus on development of centrally active anti-inflammatory drugs, the more widely available peripheral anti-inflammatory treatments could still be beneficial for alleviating inflammation-associated depression.
In conclusion, mounting evidence for the involvement of inflammatory processes in depression indicates that various anti-inflammatory approaches could be beneficial for patients with several forms of depression. Thus, in parallel to basic research aimed at elucidating the mechanisms of inflammation-associated depression, clinical studies should be carried out to examine novel approaches for treatment of symptoms of depression.