Side effect profile similarities shared between antidepressants and immune-modulators reveal potential novel targets for treating major depressive disorders

In this study, we’ve explored the space of drug side effect profile similarities between immune-modulators/anti-inflammatory medications and antidepressants. Side effect profiles contain complex phenotypic information related to the underlying physiological pathways affected by medications. Similarities in side effect profiles indicate that drugs share common targets or off-targets, or perturb common downstream pathways. Thus this could provide us new insights as to how the immune system may influence mood and vice versa. The immune-modulators and anti-inflammatory drugs sharing side effects with antidepressants in our study fall into two different categories: one targeting pathways such as glucocorticoid signaling, which is known to affect both immune and nervous systems; the other targeting mainly pro-inflammatory mediators such as cytokines, TNF-α and calcineurin, which may then influence the nervous system through a bidirectional communication route between the immune and the nervous system.

Four glucocorticoids showed side effect similarity with antidepressant venlafaxine while another three showed similarity with lithium in our study. One of them, alclometasone induced expression profiles in human cells similar to that induced by antidepressants fluvoxamine and citalopram, suggesting that glucocorticoids and antidepressants may induce common molecular pathways. Glucocorticoids exert their anti-inflammatory effect by binding to glucocorticoid receptor (GR), which then suppress the transcription of pro-inflammatory cytokines such as IL-6, IL-12, COX-2 and TNFα [35]. GR has also been proposed to play pivotal role in depression and antidepressant treatment [36]. Under normal physiological conditions, glucocorticoid activated GR mediates a negative feedback loop to maintain low glucocorticoid levels in the brain. However, this negative feedback loop is impaired in some depressed patients, resulting in chronic high levels of glucocorticoids and constant hyperactivity of the hypothalamus-pituitary-adrenal (HPA) axis [37]. Studies in rodent models have shown that chronic glucocorticoid treatment induces depression and anxiety-like behavior, and reduction of adult hippocampal neurogenesis [38]. Treatment with antidepressants could normalize HPA axis hyperactivity, possibly by restoring GR function [36]. Interestingly, glucocorticoids such as prednisolone, dexamethasone and cortisol have been reported to have antidepressant-like effects in MDD patients, possibly by restoring the negative feedback loop on the HPA axis [39–41]. Taken together, these suggest that the glucocorticoid receptor is involved in both immune regulation and depression, and may be a viable target for treating depressed patients with HPA axis hyperactivity.

Another example is glatiramer acetate (GA), which has a dual anti-inflammatory and neuroprotective role in treating multiple sclerosis (MS) [42]. GA is a synthetic polypeptide mixture containing amino acids glutamic acid, lysine, alanine and tyrosine in a molar ratio of 1.4 : 3.4: 4.2 : 1.0 assembled in a random order into polypeptide chains with 40 ~ 100 amino acids [43]. Peripheral GA treatment (either by subcutaneous injections or by oral administration) induces GA-specific T cells in the peripheral immune system, which can cross the blood brain barrier to accumulate in the CNS. These T cells are type 2 T helper (Th2) cells that secrete anti-inflammatory cytokines such as IL-4, IL-10 and TGF-β, thus blocking the immune response in the CNS. In addition, Th2 cells also produce neurotrophic factors such as BDNF, which helps to rescue degenerating neurons and promote neural regeneration [44]. Furthermore, GA-specific T cells also induced a “bystander effect” on CNS resident cells to produce anti-inflammatory cytokines and neurotrophic factors [43]. It is interesting to observe that among the immune-modulators we studied, GA is the only one that shows side effect profile similarity with multiple antidepressants. However, it is unknown to us whether these similarities were the result of anti-inflammatory effect of GA or its neuroprotective effect, or both. Because antidepressant treatment, like GA, can also restore the decreased BDNF function in MDD patients up to the normal level [45]. According to this evidence, the dual effect of GA treatment may also benefit patients with depressive symptoms and is worth further study.

Rapamycin, also known as sirolimus, may also have dual functions regulating both the immune and nervous system. Rapamycin forms a complex with FK-binding protein 12 (FKBP12) and then inhibits the mTOR pathway by binding directly to mTOR complex 1. The mTOR pathway is involved in both immune response regulation [46] and synaptic plasticity [47] by acting as a bridge between extracellular signals and translation machinery. Inhibition of mTOR by rapamycin can block the response to IL-2, thus suppressing immune system. Interestingly, blocking the mTOR pathway by intracerebroventricular infusion of rapamycin could inhibit the rapid antidepressant activity of ketamine [34], whereas chronic and partial inhibition of mTOR by rapamycin could reduce anxiety and depressive-like behavior in mice throughout their lifespan, possibly by stimulating the production of major monoamines (norepinephrine, dopamine and 5-hydroxytrptamine) [33]. Our study showed that at both the clinical level and cellular level, rapamycin shared phenotypic similarities with antidepressants targeting monoamines: monoamine oxidase B (MAO-B) inhibitor, selegiline, which prevents the breakdown of monoamines; as well as monoamine reuptake inhibitors, which helps increase the extracellular concentrations of the monoamine neurotransmitters. Besides the regulation of monoamine levels, another possible link between MAO-B activity and rapamycin is mitochondria turnover. One study has found that age or neurodegenerative disorder related brain MAO-B level elevation could contribute to the accumulation of damaged mitochondrial and neurodegeneration. Treatment by rapamycin could counteract this process by enhancing autophagic removal of damaged mitochondria [48]. Based on current knowledge, the immune suppressant activity and antidepressant-like activity of rapamycin may both depend on its ability to inhibit the mTOR pathway. Further analyses are needed to reveal whether the antidepressant-like activity of rapamycin is dependent on its immune suppressant activity.

In our study, most of the immune-modulators sharing side effect profile similarities with antidepressants do not seem to have dual functions like GA and rapamycin. They suppress the immune response by targeting pro-inflammatory mediators. These immune-modulators had side effect profiles similar to antidepressants targeting the dopamine pathway. Four of them had side effect similarities with Pramipexole, a dopamine receptor agonist with antidepressant-like activity. Another drug, montelukast, a leukotriene receptor antagonist, showed side effect similarities with antidepressant bupropion, which is a norepinephrine-dopamine reuptake inhibitor. Dopamine has been proposed as one of the key neurotransmitters bridging the nervous and immune systems, since dopamine and its receptor are expressed not only by the central and peripheral nervous cells, but also by different immune cells [49]. Communication between CNS and the peripheral immune system may be carried out by dopamine activated T cells crossing the blood brain barrier [50]. A recent study showed that electroacupuncture at the sciatic nerve of mice could induce dopamine production in the adrenal medulla, which then leads to the inhibition of cytokine production by dopamine, confirming the dopaminergic regulation of immune response [51]. Interestingly, studies have shown that changes in the expression of dopamine receptors and their signaling pathways, especially in T cells, are associated with altered immune functions in schizophrenia and Parkinson’s disease [52, 53]. The similarities in the side effect profiles as observed by us may be a reflection of the communication between immune system and nervous system through dopamine. Even though deficiencies in dopamine, serotonin and noradrenaline are thought to underpin MDD pathophysiology, treating MDD with drugs targeting dopamine pathway is under-recognized currently [54]. Considering the role that dopamine plays in both mood and immune response, it may provide viable treatment options for MDD patients who are resistant to treatments with SSRI, and who have elevated immune activation, perhaps indicated by CRP levels.

Like dopamine, serotonin has also been shown to be able to act as signaling agents between immune cells, helping to enhance T cell activation [55, 56]. There is also evidence supporting that CNS serotonin neurons are direct or indirect targets for the communication from the immune system to the brain via both humoral and neuronal mechanisms [57]. The pro-inflammatory cytokine IL-1β could increase extracellular levels of serotonin in the brain as well as serotonin transporter (SERT) activity, which may reflect a coordinated serotonergic response to immune activation, and disruption of this homeostatic mechanism may be a risk for diseases such as depression or autism [57]. Seven COX inhibitors in our study showed side effect similarities with antidepressants, which targets the serotonin signaling (Table 2). Our results seem to indicate that COX inhibitors targeting the synthesis of prostanoids and immune-modulators targeting other pro-inflammatory mediators may interact with nervous systems through different communication routes. Whether this is related to differences between the serotonergic and dopaminergic systems needs further explorations.

Interestingly, studies have shown that antidepressants also have anti-inflammatory effects, possibly through increasing production of IL-10 [58] and suppressing the expression of TNF-α and IL-6 [59]. This is consistent with our findings that antidepressants and immune-modulators may affect similar molecular mechanisms and thus share common physiological effects, and further supports the idea that serotonin and other monoamines targeted by antidepressants may play an important role in the communication between the immune and nervous system. Several immune-modulators and anti-inflammation medications have also shown antidepressant-like effects [14]. For example, IL-12/23 inhibitor ustekinumab improves symptoms of depression and anxiety in patients with psoriasis [10]. COX 2 inhibitors such as celecoxib have been reported to benefit MDD patients when used together with other antidepressants but not when using alone [11, 13]. TNF-α inhibitor infliximab could reduce depressive symptoms in treatment-resistant MDD patients having relatively more severe inflammation symptoms [9]. In our analysis, ustekinumab showed side effect similarities with antidepressants, but celecoxib and infliximab did not. This could mean that antidepressants in our study share limited common molecular mechanisms with celecoxib and infliximab. But it could also due to incomplete side effect profiles captured by the drug labels of these drugs. Even though we analyzed the side effects of over 1000 drugs, it is by no means a comprehensive survey of all marketed drugs. Additional similarities between antidepressants and immune related medications may be revealed with a bigger drug-side effect database. A more comprehensive survey of the side effects reported from more patients such as those stored in the FDA adverse reporting system may help resolve this question in the future. Another approach is to extend the side effect profiles using in silico side effect prediction methods based on correlation between side effect and drug structure [60] or based on predicted interactions between drugs and key metabolic enzymes such as cytochrome P450 [61].The value of repurposing drugs has to be explored in the context of the side-effect risk associated with the repurposed compound; for example biologics are often associated with higher risk of infections, such as pneumonia [62]; therefore the value proposition for the patient would be based on having failed to respond to safer compounds, and ideally the ability to enrich for patients likely to respond. Identifying that cohort is beyond the scope or capability of this study, but an essential next step. Nevertheless, results from our side-effect profile similarities suggest that the antidepressant potential of several novel candidates such as Siltuximab and Pimecrolimus may worth further exploration, as may the re-evaluation of dopaminergic antidepressants among MDD patients with high levels of inflammation.