sign in sign up
<<
Home , Quinolinic acid

REVIEW ARTICLE Psychiatry and Clinical Psychopharmacology 2020;30(1):71-80 DOI: 10.5455/PCP.20200215032026 , Insulin Resistance and the Pathophysiology of Depression: Implications for Novel Developments

Brian E. Leonarda, Feyza Aricioglub a Department of Pharmacology and Therapeutics,National University of Ireland, Galway, b Department of Pharmacology and Psychopharmacology Research Unit University of Marmara, Istanbul, Turkey

Abstract This review summarises the impact of chronic low grade inflammation as a causative factor in the pathophysiology of major depression. Evidence is presented to show that proinflammatory both directly, and indirectly by increasing hypercortisolaemia, desensitise insulin receptors and thereby ARTICLE HISTORY decrease the transport of glucose into the (the diabetic brain). In addition, the proinflammatory Received: May 30, 2019 cytokines activate the - pathway which results in the synthesis of the NMDA- Accepted: Jan 29, 2020 quinolinic acid. This acts as a and facilitates neuronal . As metabolic changes initiated by low grade inflammation underlie the pathophysiology of depression, drugs which attenuate the inflammatory cascade may present an approach to the KEYWORDS: inflammation, novel development of . The review concludes with a summary of drugs which might insulin resistance, depression be considered for their novel therapeutic activity. Key points are; i)Chronic low grade inflammation commonly occurs in major depression and contributes to adverse changes in brain energy by decreasing insulin receptor function and thereby reducing glucose transport into the brain. ii) Low grade inflammation initiates an increase in the tryptophan- which enhances the NMDA-glutamate receptor function and thereby increases neuronal apoptosis, iii) As many of the pathophysiological changes in depression result from dysfunctional brain metabolism caused by chronic low grade inflammation, it is concluded that drugs targeting the inflammatory pathways may offer new possibilities for the development of novel antidepressants.

INTRODUCTION

In recent years there has been more attention directed disorder and the anxiety disorders [4,5,6]. In addition to towards a more holistic view of depression in which the the proinflammatory cytokines, prostaglandin E2 (PGE2), immune and endocrine systems play a significant role. and peroxidation also increase The potential importance of the immune system in in depression in response to stress. Thus proinflammatory the pathology of major depression led Smith, in 1991, cytokines can interact with virtually all pathophysiological to formulate the theory of depression changes that characterise major depression and thereby [1] in which he summarised the clinical evidence of influence function, synaptic plasticity inflammation due to the overactivity of peripheral and and ultimately neuronal structure. This could result in central as an important causal factor. Since increased apopotosis and contribute to dementia in later then, evidence has accumulated to indicate that chronic life (Figure 1). low grade inflammation is an important contributor to 2. The link between inflammation and insulin resistance the pathophysiology of depression [2]. For example, Dowlati and colleagues [3], in a detailed meta-analysis Inflammation has emerged as a major pathophysiological of raised proinflammatory cytokines in major depression, link between major depression and the metabolic syndrome confirmed that interleukin-6 (IL-6) and tumour necrosis [7]. Both conditions, irrespective of the underlying factor-alpha (TNF-alpha) were consistently raised. psychiatric disorder, are characterised by an increase in These proinflammatory cytokines are raised in response proinflammatory cytokines and the development of insulin to stress and have been demonstrated to occur in other and glucocorticoid receptor resistance. While it may appear major psychiatric disorders such as , bipolar to be contradictory that stress induced hypercortisolaemia

Corresponding author: Brian E. Leonard, E-Mail: [email protected] To cite this article: Leonard BE, Aricioglu F. Inflammation, Insulin Resistance and the Pathophysiology of Depression: Implications for Novel Antidepressant Developments.Psychiatry and Clinical Psychopharmacology 2020;30(1):71-80, DOI: 10.5455/PCP.20200215032026 Leonard B. & Aricioglu F.

co-exists with elevated proinflammatory cytokines, in due to the internalisation for the receptors from the cell depression and in chronic stressful situations the peripheral surfaces, changes which arise from the excessive activation and central glucocorticoid receptors become insensitive of the receptors by the elevated glucocorticoids [8].

Figure 1. The link between inflammation and insulin resistance. Sites of action of putative antidepressants: targets linked to disrupted brain metabolism. PUFA’s=polyunsaturated fatty acids; ROS=rapid oxygen species; NSAID’s=non steroidal antiinflammatory drugs; (+) activation; (-) inhibition.

Functional insulin insensitivity arises as a consequence of the 2,3 dioxygenase, located in the brain and many peripheral glucocorticoids decreasing the insulin mediated expression tissues, andby tryptophan dioxygenase which is activated by of the glucose transporter GLUT4. This results in a reduction glucocorticoids and located in the liver. In depression, and in the transport of glucose into both peripheral and, most under stressful situations, these are activated and importantly, the brain [9]. Further changes in insulin result in the metabolism of tryptophan to kynurenine and receptor signalling arise due to the cortisol induced release kynurenine metabolites [12,13]. Kynurenine is a substrate of fatty acids from cellular lipoproteins while the increased for both kynureninase and kynurenine aminotransferase. proinflammatory cytokines also directly contribute to the In depression the former is activated leading to the desensitisation of the insulin receptors [10]. formation of quinolinic acid, an agonist at N-methyl-D-aspartate These adverse changes in the insulin receptor signalling are (NMDA) glutamate receptors, and the diabetogenic kynurenine usually offset by the activity of the adipokine, adiponectin, metabolites anthranilic acid and 3-hydroxyanthranilic acid. which can reactivate the desensitised receptor. However, By reducing the activity of insulin, these substrates further the concentration of adiponectin is decreased in depression contribute to the reduction in the availability of glucose for and as a consequence of the metabolic syndrome thereby sustaining brain metabolism [14,15]. This neurodegenerative, compounding the reduction in insulin receptor function diabetogenic pathway is normally balanced under non-stress [11]. Thus the key metabolic changes initiated by conditions by the synthesis of the NMDA glutamate agonist, hypercortisolaemia and chronic low grade inflammation , which is formed by the action of kynurenine are instrumental in causing insulin receptor dysfunction. As aminotransferase. This neuroprotective pathwayis decreased in a consequence, glucose transport is impeded which would depression while the neurodegenerative arm of the tryptophan- have a significant impact on brain glucose metabolism. kynurenine pathway is increased [13]. However, in depression a chronic decrease in high energy 3. The contribution of the tryptophan-kynurenine substrates resulting from a deficit in glucose and essential pathway to decreased insulin receptor function. cofactors in depression may also be of importance in causing In recent years there has been a renewed interest in the role of the increase in neuronal apoptosis [16]. The situation is the tryptophan-kynurenine pathway in depression. In depression, further complicated by the increase in oxygen free radicals the free plasma tryptophan concentration is decreased caused by xanthenuric acid and 3-hydroxykynurenine which thereby reducing its availability for the synthesis of . damage the mitochondrial membranes thereby resulting in This effect is linked to the increase in the metabolism of a reduction in the synthesis of triphosphate and tryptophan by proinflammatory activated indoleamine other high energy intermediates [17] (Figure 2).

72 Psychiatry and Clinical Psychopharmacology

Figure 2. Illustration of the integration of the changes in tryptophan-kynurenine pathway with the changes in the immune and endocrine systems which are relevant to the development of novel psychotropic drugs.

4. Inflammation, insulin insensitivity and reduced brain reasonable to expect such drugs to alleviate the impact of energy metabolism in depression: could the link provide chronic low grade inflammation associated with depression a guide for the development of novel antidepressants? and other psychiatric disorders in which inflammation contributes. The search for novel psychotropic drugs has, with few exceptions, largely depended on the extension of currently Of the NSAID’s available, aspirin is still the most widely available drugs into areas for which they were not used largely on grounds of efficacy and cost. However, initially developed. For example, many second generation the adverse effects of long term use are well known and antipsychotics are now used as adjunctive treatments for attributed to the inhibition of the synthesis of PGE2 by therapy resistant depression or even in some cases such as cyclooxygenase-1 in the wall of the gastric mucosa. For this quetiapine as a single agent for treating depression. Anti- reason, a new generation of NSAID’s have been developed have been used for several decades to treat that selectively inhibit cyclooxygenase-2, an enzyme that while the SSRI antidepressants are widely is induced by inflammatory cytokines acting on used to treat anxiety disorders and pain syndromes. Clearly particularly in the and cortex [20]. On the classification of psychotropic drugs according to the heoretical grounds, a centrally acting COX-2 inhibitor therapeutic category of their clinical use (antidepressants, should enable the inflammation hypothesis of depression antipsychotics, anti-manic etc) is becoming increasingly to be tested as the inhibition of COX-2 should result in meaningless as the complexity in the understanding of the reduction of PGE2 synthesis, particularly in the brain. their pharmacology becomes apparent. This situation has Experimental studies have demonstrated that the selective led to the establishment of new classification guidelines by COX-2 inhibitor celecoxib reduces the stress response and the “Neuroscience based Nomenclature Committee” which cognitive deficits in the rat [21] and also the behavioural was established recently with representatives from the and immune changes in the olfactory bulbectomised rat main world neuropsychopharmacological societies under model of depression [22]. the chairmanship of Zohar [18]. In clinical studies, (open and randomised, double-blind However, despite the therapeutic benefits that have arisen trails) there are positive results to demonstrate that from the extension of the newer psychotropic drugs there celecoxib enhances the response of antidepressants is no evidence that they are significantly improved on their (fluoxetine, reboxetine, sertraline and mood stabilisers) predecessors. Perhaps it is timely to consider an approach given concurrently [23,24,25,26]. There is also an “open” based on drugs which act as anti-inflammatory agents. study showing that aspirin enhances the antidepressant effects of fluoxetine [27]. 4a. Anti-inflammatory drugs as potential antidepressants Adjunctive treatment of celecoxib with an antidepressant In addition to the proinflammatory cytokines, has also been shown to be beneficial in patients with prostaglandin E2 (PGE2) is also increased in the blood and bipolar disorder. Thus Nery and coworkers [28] showed that of patients with major depression [19]. celecoxib treatment produced a rapid onset antidepressant As inflammation, commonly associated with arthritis and response and similar findings have been reported by Halaris other inflammatory disorders, is attenuated by treatment et al (in preparation) in a group of treatment resistant with non steroidal anti-inflammatory drugs (NSAID’s) it is bipolar patients given escitalopram and celecoxib. A

73 Leonard B. & Aricioglu F.

meta-analysis of the efficacy of adjunctive celecoxib could also be beneficial in reducing the transition from treatment for patients with major depression showed depression to dementia. However, such beneficial effects that the combined treatment resulted in better remission depend on the absence of Apo E 4 carrier status. Thus and response rates compared to those receiving the Rosenbloom and colleagues [37], in a single dose pilot antidepressant plus a placebo [29]. A recent meta-analysis trial of intranasal rapid-acting insulin in Apo E4 carriers by Koehler and coworkers [20] supported this conclusion. with mild to moderate Alzheimer’s disease, found that Despite the appeal of these clinical results, it must be insulin failed to have an effect on memory performance. emphasised that the potential links between inflammation These preliminary results, if replicated in a larger cohort and depression are highly complex and the results of of patients, suggest that intranasal insulin, or drugs such the clinical trials are so far limited [30]. Not all studies as liraglutide which sensitise insulin receptors, may have shown the beneficial effects of adjunctive celecoxib be beneficial for subgroups of depressed or demented with SSRI antidepressants while Maes [31] has raised a patients who lack the ApoE4 genotype. number of questions regarding the theoretical limitations At present, it is uncertain whether intranasal insulin could of PGE2 inhibitors. In addition to clinical and theoretical have a beneficial effect in correcting the adverse metabolic limitations there remains the risk of severe cardiovascular changes which also characterise major depression. events which have been recognised for COX-2 inhibitors However, there is experimental evidence that insulin-like [32].Thus as a precaution, the adjunctive treatment of growth factor increases hippocampal neurogenesis and antidepressants with celecoxib should be confined largely insulin signalling within the brain; it has also been shown to younger patients with few depressive episodes and a to exhibit antidepressant-like activity in rodent models of low a priori risk of cardiovascular disease. Furthermore, depression [38]. Clearly it is now important to consider if it still remains to be demonstrated that selective COX-2 these preliminary experimental and clinical observations inhibitors given alone are safe and effective long-term can be translated into therapeutic strategies for the treatments for depression without causing major adverse treatment of major depression. central and peripheral side effects [31]. In addition to the direct application of insulin, one obvious area to explore is the role of anti-diabetic drugs and their 4b. Drugs which target insulin and glucose transporters effects on brain function. Of the numerous types of orally As insulin resistance appears to play a crucial role in the active drugs used for the treatment of type 2 diabetes metabolic changes associated with major depression it is (DM2), metformin is one of the most intensively used for a timely to consider if the insulin receptor could provide first line oral therapy. a target for the development of novel antidepressants. The mode of action of metformin depends on the cellular This seems particularly pertinent as the adverse changes ratio of AMP/ATP. The reduction in the peripheral glucose in insulin function are triggered by inflammation level occurs due to the inhibition of liver gluconeogenesis and hypercortisolaemia which frequently accompany and a reduction in available glycogen. Metformin also depression. inhibits mitochondrial function resulting in defective Insulin plays such a crucial role in brain metabolism and cyclic AMP synthesis and signalling. There insulin resistance is a critical feature of major depression is also evidence that metformin increases the sensitivity it would be anticipated that the administration of insulin of insulin receptors and stimulates AMP-activated protein might reverse the consequences of insulin resistance. kinase [39]. There is evidence that patients with major depression Metformin is lipophilic and therefore has easy access to the and Alzheimer’s disease have a reduced insulin receptor brain. In vitro studies have demonstrated that metformin sensitivity [33]. In addition, particularly those patients can prevent the formation of beta and with Alzheimer’s disease have a hypophosphorylation of the hyperphosphorylation of [40], both of the insulin receptor and the insulin receptor substrate which are increased in the brain of elderly depressed [34]. An increase in insulin signalling improves memory patients but of greater density in those with dementia. in cognitively normal healthy humans [35]. Thus it was Experimentally it has also been shown that metformin shown that the intranasal administration of insulin increases neurogenesis and reduces the effects of oxidative over a period of 8 weeks improved the performance stress [41]. However, treatment with metformin did not on a declarative memory task, an effect which counteract experimentally induced cognitive decline even primarily involved improved hippocampal function [35]. though it attenuated insulin resistance and reduced the Furthermore, verbal memory, which depends on the impact of a high fat diet on the increase in body weight activation of the frontal cortex, was shown to improve [42] following the intranasal application of insulin [36]. While 4c. Polyunsaturated fatty acids as complimentary such studies have not yet been reported in patients with treatment for major depression major depression, Freiherr and coworkers [36] have reviewed the studies on the use of intranasal insulin in Polyunsaturated fatty acids, also known as essential fatty the treatment and prevention of Alzheimer’s disease and acids, are important components of membrane structures concluded that strategies for enhancing insulin signalling and essential for the development and function of the

74 Psychiatry and Clinical Psychopharmacology . These are long chain fatty acids the reduction in the concentration of n-3 fatty acids in and the two types which are of major importance for brain erythrocyte membranes reflects the frequency of previous function are eicosapentanoeic and docosahexanoeic acids. depressive episodes in elderly patients [57]. Besides to These fatty acids are classified as n-3 or omega-3 fatty the epidemiological evidence that a deficit in dietary acids as the carbon chain contains 3 unsaturated double n-3 fatty acids is associated with episodes of depression bonds. In addition to their role in membrane structure, there is also clinical evidence that enriching the diet with the n-3 fatty acids are also involved in the maintenance n-3 fatty acid containing foods are beneficial to recovery of membrane fluidity, expression and in neuronal [56,57]. Since the publication of these preliminary “open” development [43]. As there is both experimental and clinical studies, some 30 studies have been published. Of clinical evidence that the n-3 fatty acids have anti- these, 15 showed no overall difference between the n-3 inflammatory properties [44] there has been considerable group and those on placebo while 15 studies showed that interest in exploring the effects of diets rich in these fatty the n-3 fatty acid group experienced a reduction in the acids and in determining if their deficiency is associated symptoms of depression to varying extents [51]. with cognitive and affective changes [45,46]. The heterogeneity of the results could be a consequence A deficiency of n-3 fatty acids associated with chronic of the differences in the study designs, the duration of the inflammatory diseases such as cardiovascular disease studies, the number of subjects studied (in the analysis and autoimmune disease which often coexist with major of the studies by Saah et al [51] these varied from 7 to depression [48]. 2,501 but there was no difference in the outcome relative In contrast to the n-3 fatty acids which are anti- to the number of subjects in the study!) and the doses of inflammatory, the long chain n-6 fatty acids, such as n-3 fatty acids given (these varied between 1 and 4 g daily) linolenic acid, are pro-inflammatory in their action [43]. [51]. Differences in the concurrent treatments also varied The structural difference between the n-3 and n-6 fatty between the studies. acids lies in the location of the double bonds in the carbon Despite the limitations of the clinical studies, the results do skeleton. The n-6 fatty acids can act as antagonists to the suggest that there is a sub-population of depressed patients n-3 fatty acids. As both the n-3 and n-6 fatty acids are who may benefit from n-3 fatty acids given concurrently essential components of neuronal membranes, dietary or with the usual antidepressant medication. There is also a disease initiated changes in their membrane composition suggestion from the clinical studies that such treatments can have a profound effect on neuronal, glial and immune may be beneficial in treating the early stages of cognitive function [47]. decline in elderly depressed patients. The dietary importance of the n-3 and n-6 fatty acids has been the focus of important epidemiological 4d. The role of polyamines as modulators of inflammation studies. Populations with a high intake of n-3 fatty and acids (fatty fish for example) have a lower frequency and are examples of endogenous of chronic inflammatory and cardiovascular disease and polyamines found in . Of these, agmatine is a slower rate of cognitive decline in old age than those synthesised from the arginine by arginase populations with a poor n-3 fatty acid diet [49]. Thus as decarboxylase. It is widely distributed in mammals and the ratio of the n-3: n-6 fatty acids have decreased due is specifically transported into neurons by a cationic to the increasing consumption of grain based diets, not amino acid transporter. In the brain, agmatine is further only has the frequency of inflammation linked diseases metabolised by synthase to nitric oxide and increased but the frequency of depression in later life has by a separate pathway to spermidine and [58]. also increased [50,51]. However, supplementation of the Thus agmatine is important in the brain as a source of diet with n-3 fatty acids has so far had a disappointing nitric oxide and the polyamines spermidine and spermine, outcome and the therapeutic benefits of n-3 fatty acids in addition to its possible neurotransmitter function and in patients with inflammatory disorders remains doubtful ability to interact with other neurotransmitter pathways [51]. [59]. Despite the largely negative results of the dietary From the therapeutic perspective, agmatine is of supplementation studies experimental studies have potential importance because experimentally it has shown that the supplementation of the diet of rats been demonstrated that it has antidepressant, anti- with the polyunsaturated omega-3 (n-3) fatty acid can anxiety, and cognitive enhancing properties which normalise changes in the inflammatory state and reduce reflect its broad neuroregulatory effects by modulating the stress induced hyperactivity of the HPA axis [52,53]. neurotrophic pathways [60]. Agmatine dose dependently The result of such studies support the view that n-3 fatty reduces the deficits in memory and learning induced acids might be useful in the adjunctive treatment for in rodents by scopolamine [61]. It has been also shown major depression. that agmatine might have modulatory effect of on Clinical studies have shown that a dietary deficiency cognitive functions during vascular dementia through in n-3 fatty acids is associated with a higher frequency eNOS and BDNF expression [62]. At the cellular level, of major depression [54,55]. In addition, the extent of agmatine has a high affinity for alpha 2 receptors and

75 Leonard B. & Aricioglu F.

imidazoline binding sites [63] and, in addition, has as TNF-alpha, which are raised in depression and chronic affinity for nicotinic cholinergic receptors, serotonin inflammatory disorders such as psoriasis and rheumatoid 5HT3 receptors and by acting as an antagonist at ligand arthritis, can attenuate not only the symptoms associated gated cationic channels particularly on NMDA glutamate with joint pain and skin but also reduce the symptoms receptors. Agmatine also reduces hypoxia induced neuronal damage in vitro and protects the integrity of fatigue and depression which are frequently associated of mitochondria from . In neuronal with inflammatory disorders. Of the clinical trials which cultures, agmatine reduces the neurotoxic effects of support the evidence that monoclonal antibodies have activated NMDA glutamate receptors which contribute potential antidepressant activity associated with the to its neuroprotective profile [64,65]. With such a broad reduction in inflammation, etanercept [74], influximab effect on so many neurotransmitter and neuroregulatory [75] and adalimumab [76] have been noted for their pathways it is surprising that relatively little interest has been shown in its therapeutic potential. There is clinical activity in reducing the depressive symptoms concurrently evidence that the plasma concentration of agmatine is with the reduction in the inflammatory cytokines. Of the reduced in depression and normalised following effective clinical studies cited, that by Raison and colleagues [75] antidepressant treatment [66]. Agmatine has been shown is particularly pertinent as it indicated that the anti-TNF to have anti-stress effect in sub-chronic restrain stress- alpha monoclonal antibody infliximab produced a positive through Nod-like Receptor Protein 3 (NLRP3) activation antidepressant response in a group of patients with therapy and cytokine response [67]. It has been also shown that antidepressant effect of agmatine is via modulation resistant depression. Apart from the unacceptably high cost of neuroinflammation and this modulation is not only of monoclonal antibody therapy, these results indicate that through NLRP3 but also through NLRP1 in a validated direct immunomodulation of proinflammatory cytokines is animal model of depression [68, 69,70]. worthy of consideration when developing a new generation Despite the paucity of clinical data, experimental of antidepressants. data does suggest that agmatine, or agmatine-like , an antibiotic with anti inflammatory compounds could provide a series of novel psychotropic drugs not only for the treatment of depression but also properties: Minocycline is a tetracycline antibiotic that for neurological disorders, such as Parkinson’s disease, crosses the blood-brain barrier and has shown both anti- epilepsy and , in which neuroinflammatory and inflammatory and anti-oxidant effects in experimental neurodegenerative components play a role [71]. As the and clinical studies [77]. Experimentally minocycline has biologically active polyamines spermine and spermidine been shown to increase neurogenesis, reduce the release are synthesised in the brain from agmatine, it seems of proinflammatory cytokines from activated and reasonable to speculate that they also play an important to have anti-oxidant activity. It inhibits the activation, role in the maintenance of neuronal health. It has been known for decades that caloric restriction in rodents migration and/or proliferation of T-cells, neutrophils and and non-human primates improves longevity and health, microglia and inhibits the release of proinflammatory changes which reflect the spermidine levels. The cytokines. The anti-inflammatory effects of minocycline, potential importance of spermidine has been the subject which have been reported experimentally and clinically, of a review by Moretti and coworkers [71]. Conversely, are independent of its antibiotic properties [78]. the age-associated reduction in spermidine is associated with genomic instability, changes in diet selection, Over 20 years ago there was a suggestion in the clinical mitochondrial dysfunction and chronic inflammation. literature that minocycline may have an antidepressant Spermidine displays pleiotropic effects that have been profile [79]. Later, in an open label study, minocycline was shown experimentally to counteract many of these changes shown to have antidepressant effects in a group of patients associated with ageing, depression-like behaviour etc. with unipolar psychotic depression [80]. A double-blind, This is due to the increase in autophagy which ensures cellular homeostasis and proteostasis, degrades harmful placebo controlled, randomised trial of minocycline for protein aggregates and increases effects [72]. mild to moderate depression in HIV patients demonstrated As experimental studies have shown that spermidine has a antidepressant effects [81] while in a major clinical trial low toxicity and high efficacy it, or a synthetic analogue, in bipolar disorder, it was concluded that while there was could be considered for clinical investigation as a novel no significant effect of the drug on the MADRS sores across psychotropic agent [73]. the treatment period, minocycline may be an efficacious 4e. Some miscellaneous drugs and compounds which adjunctive treatment for bipolar depression [82]. From have immunomodulating properties these preliminary clinical results it may be concluded Monoclonal antibodies as putative antidepressants: that minocycline is worth consideration as an adjuctive There is experimental and clinical evidence to suggest treatment for depression, particularly in the subgroup of that antibodies to the proinflammatory cytokines such patients in which proinflammatory changes are apparent.

76 Psychiatry and Clinical Psychopharmacology

The statins for the adjunctive treatment of depression: is lower in patients with major depression [90] so that a The statins are a group of HMG-CoA reductase inhibitors further reduction in the concentration by a statin could which are widely used to reduce high cholesterol levels and have major adverse consequences. thereby prevent serious cardiovascular events. In addition While there may be a use for statins as adjunctive to their effects on cholesterol metabolism, statins have treatments for depression in the future, based on the anti-inflammatory effects and have been used successfully current clinical evidence it would appear that other as adjunctive treatments for major depression [83]. A approaches to the development of novel antidepressants, meta-analysis has indicated that statins are effective in already discussed above, deserve priority consideration. enhancing the antidepressant efficacy of different types of antidepressants [84]. 5. CONCLUSION However, in recent years concerns have been raised The purpose of this review was to consider some of the regarding the side effects of the statins, in particular the major metabolically related changes in major depression increase in irritability, anxiety and depression [85]. The which could provide novel targets for psychotropic drugs. cause of these side effects is still uncertain but it is known As these targets ultimately involve changes in brain energy that cholesterol plays a significant role in metabolism, it is reasoned that the restoration of normal and that low cholesterol levels impact on serotonin brain metabolic activity will be reflected in an improvement receptor function [86]. The reduction in cholesterol by in depression. As chronic low grade inflammation appears statins has been shown experimentally to affect the to play a crucial role in the pathophysiology of major function of 5HT1A [87] and 5HT7 [88] receptors. However, depression, the primary target for novel antidepressants the causal relationship between the use of statins and is the inflammatory mediators and their cellular origins. the frequency of depressive symptoms is unclear. The A more direct target affecting brain metabolism is the statins affect the activity of cytochrome P 2C9 which insulin receptor and the glucose transporter mechanisms could impact on the efficacy of antidepressants such as associated with the receptor. Some of the approaches, and sertraline and fluvoxamine. In addition, the high density their targets, mentioned in this review are shown in Figure lipoprotein fraction of cholesterol (“good” cholesterol) 3.

Figure 3. Some of the approaches, and their targets. Figure 3. Some of the approaches, and their targets. 77

Leonard B. & Aricioglu F.

While these approaches do not directly involve targeting [13] Myint AM. Inflammation, and psychiatric specific , it is certain that any changes disorders. Mod Trends Pharmacopsychiat. 2013; 28: 61- leading to the improvement in brain energy metabolism 74. will have an impact on most other cellular pathways. [14] Kotaki Y, Ueda T, Mori T et al. Abnormal tryptophan Major depression, like all other major psychiatric disorders metabolism and experimental diabetes by xanthenuric affects the whole body and a fundamental improvement in acid. Acta Vitaminol Enzymol. 1975; 29: 236-239. brain energy metabolism could provide a useful target for [15] Hattori M, Kotake Y. Studies on the urinary excretion of drug development. xanthenuric acid in diabetes. Acta Vitaminol Enzymol. 1989; 36: 221-228. Compliance with ethical standards: No external sources [16] Moudrian MM, Heyes MP, Pan JB et al. No change in of funding were obtained for the writing of this review. central quinolinic acid levels in Alzheimer’s disease. The authors has no conflict of interest with any of the Neurosci Lett 1989; 105: 233-238. citations quoted in this review. [17] Sofic E, Halket J, Pryzborowska A et al. Brain quinolinic acid in Alzheimer’s dementia. Eur Arch Psychiat Neurol REFERENCES Sci. 1989; 239: 171-179. [18] Zohar J, Stahl S, Moeller HJ et al. Neuroscience based nd [1] Smith R.S. The macrophage theory of depression. Med. nomenclature, 2 edition, ECNP, 2017. Hypoth. 1991; 298-306. [19] Calabrese JR, Skwerer RG, Barna, B et al. Depression, [2] Leonard B.E. Inflammation and depression: a causal immunocompetence and prostaglandins of the e series. or a co-incidental link to pathophysiology? Acta Psychiat Res.1986; 17:41-47. Neuropsychiat. 2017; 23: 1-16. [20] Kohler O, Krogh J, Mors O, Benros ME. Inflammation [3] Dowlati Y, Herrmann N, Swardfager W et al. A meta- in depression and the potential for ant i-inflammation analysis of cytokines in major depression. Biol Psychiat. treatment. Curr Neuropharmac. 2016; 14: 732-742. 2010;67: 446-457. [21] Casolini P, Catalami A, Zuena AR. Inhibition of [4] Watanabe Y, Someya T, Nawa H. Cytokine hypothesis of cyclooxygenase 2 reduces the age dependent increase schizophrenia:evidence from human studies in animal in hippocampal inflammatory markers, corticosterone models. Psychiat Clin Neurosci. 2010; 64:217-230. secretion and behavioral impairments in rats. J Neurosci Res.2002; 68: 337-343. [5] Vogelzanga N, Beckman ATF, de Jonge P, Peaninx BWJH. Anxiety disorders and inflammationin a large adult [22] Myint AM, Steinbusch HW, Geoghegan L et al. Effect of cohort. Transl Psychiat. 2013; 3: e249. the COX-2 inhibitor celecoxib on behaviour and immune changes in the olfactory bulbectomised rat model of [6] Munkholm K, Vinberg M, Vedel Kessing L. Cytokines in depression. Neuroimmunomodulation 2007; 14: 65-71. bipolar disorder: a systematic review and meta-analysis. J Affect Dis. 2013; 144: 16-27. [23] Mueller N, Schwarz MJ, Dehning S et al. The cyclooxygenase inhibitor celecoxib has therapeutic [7] Shelton RC, Miller AH. Eating ourselves to death (and effects in major depression. Mol Psychiat 2006; 11: 680- despair): the contribution of adiposity and inflammation 684. to depression. Prog Neurobiol. 2010; 59: 275-299. [24] Mueller N. Immunomodulationas a therapeutic [8] Miller GF, Cheu E, Sze J et al. A functional genomic approach in schizophrenia depression: state of the finger print of chronic stressing humans: blunted art. In: Immunology and Psychaitry; Current topics in glucocorticoids and increased NF-kB signalling. Biol 8. (Eds. Mueller N, Myint AM, Schwarz MJ.) Psychiat 2008; 64: 266-272. Sringer Int. 2015; pp.351-369. [9] Weinstein SP, Paquin T, Pritske A, Haber RS. Glucocorticoid [25] Akhondzadeh S, Tabatabace M, Amini H et al. Celecoxib induced insulin resistance: dexamethasone inhibits the as an adjunctive therapy in schizophrenia: a double blind activation of glucose transportin rat skeletal musclke randomised controlled trial. Schizophren Res. 2007; 90: by both insulin and non insulin related stimuli. Diabetes 179-185. 1995; 44: 441-445. [26] Abbasi SH, Hosseini F, Modabbernia A et al. Effect of [10] Solomon SS, Odunsi O, Carrigan D et al. TNF-alpha celecoxib add-on treatment on symptoms and serum inhibits insulin action on liver and adipose tissue: a IL-6 concentration in patients with major depressive model of the metabolic syndrome. Hormone Metab. disorder: a randomised, placebo controlled study. J 2010; 42(2):115-121. Affect Dis. 2012; 18: 308-314. [11] Maeda N, Takahashi M, Funehashi I et al. PPAR-gamma [27] Mendlewicz J, Kriwin P, Oswald P et al. Shortened onset ligands increase expression and plasma concentrations of action of antidepressants in major depression using of adiponectin, an adipose derived protein. Diabetes aspirin augmentation; a pilot, open-label study. Int Clin 2001; 50: 2094-2099. Psychopharmac. 2006; 21: 227-231. [12] Steiner J, Bielau H, Brisch R et al. Immunological aspects [28] Nery FG, Monkul ES, Hatch JP, et al. Celecoxib as an in the neurobiology of suicide: elevated microglial adjunct in the treatment of depression and mixed density in schizophrenia and depression is associated epidodes of bipolar disorder. Hum Psychopharmac. 2008; with suicide. J Psychiat Res. 2008; 42: 151-157. 23: 87-94.

78 Psychiatry and Clinical Psychopharmacology

[29] Boufidou F, Halaris A. Pharmacological and non [45] Song C, Zhang XY, Manku M. Increased phospholipid pharmacological interventions to arrest neuroprogression A2 activity and inflammatory response but decreased in psychiatric disorders. Mod Trends Pharmacopsychiat. NGF expression in olfactory bulbectomised rat model 2017; 31: 162-176. of depression: effect of chronic eicosapaenoic acid [30] Maes M. Targeting cyclooxygenase 2 in depression treatment. J Neurosci. 2009; 29: 14-22. in depressionis not a viable approach and may even [46] Calder PC. Polyunsaturated fatty acids and inflammation. aggrevate the pathophysiological underpinning of Biochem S Trans. 2005; 33: 423-427. depression. Metab Brain Res. 2012; 27: 405-413. [47] Lagishetty CV, Naik SR. Polyamines: potential anti- [31] Eyre HA, Stuart MJ, Baune BT. A phase specific inflammatoryagents and their possible mechanisms of neuroimmune model of clinical depression. Prog. action. Indian J Pharmacol. 2008; 40: 121-125. Neuropsychopharmac. Biol Psychiat. 2014; 54: 265-274. [48] Yates CM, Colder PC, Rainger E. Pharmacology and [32] Solomon SD, McMurray JJ, Pfeffer MA, et al. therapeutics of omega 3 polyuunsaturated fatty acids in Cardiovascular risk associated with celecoxib in a chronic inflammatory disease. Prostaglandin. Leukot Ess clinical trial for colorectal adenoma prevention. N Eng J Fatty Ac. 2004; 71: 171-176. Med. 2005; 352: 1071-1080. [49] Fitten LJ, Ortiz F, Fairbanks L et al. Depression, diabetes [33] 33.Talbot K, Wang HY, Kazi H et al. Demonstrated and metabolic-nutritional factors in elderly. Hispanics J brain insulin resistance in Alzheimer’s disease patients Nutrit Health Aging. 2008; 12: 634-640. associated with IGF-1 resistance, IRS-1 deregulation and [50] Hibbeln JR. Fish consumption and major depression. cognitive decline. J Clin Invest. 2012; 122: 1316-1338. Lancet 1998; 351: 1213. [34] Steen E, Terry BM, Rivera EJ et al. Impaired insulin Saah T, Garlow SJ, Rapport MH. Polyunsaturated fatty and insulin-like growth factor expression and signaling [51] acids in adult psychiatric disorders: a comprehensive mechanisms in Alzheimer’s disease: is this type 3 overview. Immunol and Psychiat Curr Topics in diabetes? J Alzheim Dis. 2005; 7: 63-80. Neurotoxicity (Eds. Mueller N, Myint AM, Schwarz MJ) [35] Benedict C, Hallschmid M, Schultes B et al. Intranasal 2015; pp: 371-395. insulin improves memory function in humans. Song C, Li X, Leonard BE, Horrobin DF. Effects of dietary Neuroendocrinol. 2007; 86: 136-142. [52] n-3 and n-6 fatty acids on IL-1 beta induced anxiety, [36] Freiherr J, Hallschmid M, Frey WK et al. Intranasal stress and inflammatory responses in rats. J Lipid Res. insulin as a treatment for Alzheimer’s disease: a review 2003; 44: 1984-1991. of basic research and clinical evidence. CNS Drugs 2013; 27: 505-514. [53] Song C, Phillips AG, Leonard BE, Horrobin DF. Eicosapaentanoic acid prevents corticosterone-mediated [37] Rosenbloom H, Barclay TR, Pyle M et al. A single dose memory impairment induced by central administration pilot trial of intranasal rapid acting insulin in ApoE4 of IL-1 beta in rats. Mol Psychiat. 2004; 9: 630-638. carriers with nild to moderate Alzheimer’s disease. CNS Drugs 2014; 28: 1185-1189. [54] Freemen MP, Rapoport M. Omega 3 fatty acids and depression: from cellular mechanisms to clinical care. J Malberg JE, Platt B, Rivat C et al. Increasing levels of [38] Clin Psychiat. 2011; 72: 258-259. insulin-like growth factor – 1 by insulin growth factor binding protein inhibitor produces anxiolytic and [55] Chiu CC, Huang SY, Chen, CC et al. Omega 3 fatty acids antidepressant-like effects. Neuropsychopharmac. 2007; are more beneficial in depressive phase than manic 32: 2360-2368. phase in patients with bipolar disorder. J Clin Psychiat. 2005; 66: 1613-1614. [39] Pernicova I, Korbonits M. Metformin mode of action and clinical implications for diabetes and cancer. Nat Rev [56] Peet M, Horrobin DF. A dose ranging study of the effects Endocrinol. 2014; 10: 143-156. of eicosapaentenoic acid in patients with ongoing depression despite apparently adequate treatment with [40] Gupta A, Bisht B, Dey CS. Peripheral insulin-sensitizer standard drugs. Arch Gen Psychiat. 2002; 59: 913-919. drug metformin ameliorates neuronal insulin resistance and Alzheimer disease-like changes. Neuropharmac. [57] Peet M, Stokes C. Omega 3 fatty acids in the treatment 2011; 60: 910-920. of psychiatric disorders. Drugs 2005; 65:1051-1059. [41] HwangI K, Kim IY, Joo EJ et al. Metformin normalizes [58] Moretti M, Matheus F, de Olivereira PA et al. Role of type 2 diabetes induced decrease in cell proliferation agmatine in neurodegenerative diseases and epilepsy. and neuroblast differentiation in the rat dendate gyrus. Front Bioscience, 2014; E6: 341-359. Neurochem Res. 2010; 35: 645-650. [59] Reis DJ, Regunathan S. Agmatine, a novel [42] McNelly AD, Williamson R Balfour DJ et al. A high fat diet neurotransmitter? Adv Pharmacol. 1998; 42: 645-649. induced cognitive deficient in rats that is not prevented [60] Zhu MY, Wang WP, Cai ZW et al. Exogenous agmatine by improving insulin sensitivity with metformin. has neuroprotective effects against restraint induced Diabetalogia 2012; 55: 3061-3070. structural changes in the rat brain. Eur JNeurosci. 2008; [43] Perica MM, Delas I. Essential fatty acids and psychiatric 27: 1320-1332. disorders. Natr Clin Pract. 2014; 26: 409-425. [61] Moosavi M, Khale GY, Abbasi L et al. Agmatine protects [44] Freeman MP. Omega 3 fatty acids in major depressive against scopolamine induced water maze performance disorder. J Clin Psychiat. 2009; 70 (suppl 5): 7-11. impairment and hippocampal ERK and Akt activation.

79 Leonard B. & Aricioglu F.

Neuropharmacol. 2002; 62: 2018-2023. [75] Raison CL, Rutherford RE, Woolwine BJ et al. A [62] Li G, Regunathan S, Barrow CJ et al. Agmatine: an randomized controlled trial of the TNF antagonist endogenous clonidine-displacing substance in the brain. infliximab for treatment of resistant depression: role Science,1994; 263: 966-969. of baseline inflammatory biomarkers. JAMA, Psychiat. 2013; 70: 31-41. [63] Bağcı B, Utkan T, Yazir Y, Aricioglu F, Öztürk GS, Sarioglu Y. Effects of agmatine on cognitive functions during [76] Menter A, Augustin M, Signorovitch J et al.The effect vascular dementia in biological aging through eNOS and of adalimumab on reducing symptoms of depression in BDNF expression. Psychiatry Clin. Psychopharmacol., patients with moderate-severe psoriasis. J Amer Acad 2017; 27(2): 106-115. Dermatol. 2010; 62: 457-465. [64] Wang WP, Iyo AH, Miguel-Hidago S, et al. Agmatine [77] Soczynska JK, Mansur RB, Brietzke E, et al. Novel protects against cell damage induced by NMDA and therapeutiuc targets in depression: minocycline as a glutamate in cultured hippocampal neurons. Brain Res. candidate treatment. Behav Brain Res. 2012; 235: 302- 2006; 1084: 210-216. 317. [65] Binnetoglu D, Hacimuftuoglu A, Aricioglu F. [78] Savitz JB, Misaki M, Wurfel BE, et al. Treatment of Neuroprotective effects of agmatine in antineoplastic bipolar disorder with minocycline and/or aspirin. Trans drugs induced neurotoxicity: In vitro study. Life Sci. Psychiat. 2018; 8: 73-77. 2019; 221:311-318. [79] Levine J, Cholestoy A, Zimmerman J. Possible [66] Halaris A, Zhu H, Feng Y, Piletz JE. Plasma agmatine and antidepressant effects of minocycline. Am J Psychiat. platelet imidazoline receptors in depression. Ann NY 1996; 153,582. Acad Sci. 1999; 881: 445-451. [80] Miyaoke T, Wake R, Furuya Met al. Minocycline as an [67] Sahin C, Albayrak O, Akdeniz TF, Akbulut Z, Yanikkaya adjunctive therapy in patients with unipolar psychotic Demirel G, Aricioglu F. Agmatine Reverses Sub-Chronic depression. Prog. Neuropsychopharmac. Biol Psychiat. Stress-induced Nod-like Receptor Protein 3 (NLRP3) 2012; 37: 222-226. Activation and Cytokine Response in Rats.Basic Clin [81] Emadi-Kouchok H, Mohammadinegad P, Asadotlah- Pharmacol Toxicol. 2016; 119(4): 367-375. Amin A et al. Therapeutic effects of minocycline in [68] Şahin-Özkartal C, Aricioglu F, Tüzün E, Keleş R, mild to moderate depression in HIV patiants: a double Kandemir C, Şirvancı S, Küçükali CI. Agmatine blind, randomized placebo-controlled trial. Int Clin produces antidepressant effect via modulation of Psychopharmac. 2016; 31: 20-26. neuroinflammation in chronic unpredictable mild stress Weitz-Schmidt G. Statins as an anti-inflammatory agent. model of rats: Implication in inflammatory perspective [82] Trends Pharmacol Sci. 2002; 23: 482-486. of depression. Psychiatry Clin. Psychopharmacol., 2017; 27 (suppl 1): 184-188. [83] Salagre E, Fernandez BS, Dodd S et al. Statins for the treatment of depression: a meta-analysis of randomised, [69] Sahin Ozkartal C, Aricioglu F, Tuzun E, Kucukali CI. Chronic mild stress-induced anhedonia in rats is coupled double-blind controlled trials. J Affect Dis. 2016; 200: with the upregulation of inflammasome sensors: a 235-242. possible involvement of NLRP1. [84] You H, Lu W, Zhao S et al. The relationship between [70] Sahin Ozkartal C, Tuzun E, Ismail Kucukali C, Ulusoy statins and depression: a review of the literature. Exp C, Giris M, Aricioglu F. Antidepressant-like effects of Opin Pharmacotherap. 2013; 14: 1467-1476. agmatine and NOS inhibitors in chronic unpredictable [85] Vevera J, Fisar Z, Kvasnicka T et al. Cholesterol lowering mild stress model of depression in rats: The involvement therapy evokes time-limited changes in serotonin of NLRP inflammasomes Brain Res. 2019;1725: 146438. transmission. Psychiat Res. 2005; 133: 197-203. [71] Moretti M, Matheus FC, de Oliveira P et al. Role of [86] Shrivastava S, Pucadyll TJ, Palla YD et al. Chronic agmatine in neurodegenerative diseases and epilepsy. cholesterol depletion using statins impairs the function Front Biosci. 2014; E6: 341-359. and dynamics of human 5HT1A receptors. Biochem. [72] Madeo F, Eisenberg T, Pietrocola F, Kromer G. Spermidine 2010; 49: 5426-5435. in health and disease. Science 2018; 359: 410. [87] Sjogren B, Csoregh L, Svenningsson P. Cholesterol [73] Lovaas E, Carlin G. Spermidine, an antioxidant and anti- depletion reduces serotonin binding and signalling via inflammatory agent. Free Rad Biol Med. 1991; 11: 655- human 5HT7 receptors. Eur J Pharmac. 2006; 552: 1-10. 661. [88] Maes M, Smith R, Christophe A et al. Lower serum HDL- [74] Tyring S, Gottlieb A, Papp K et al. Etanercept and clinical cholesterol in major depression and depressed men with outcome, fatigue syndrome, and depression in psoriasis: serious suicidal attempts: relationship with immune a double-blind, placebo controlled randomized trial. inflammatory markers. Act Psychiat Scand. 1997; 95: Lancet 2006; 367: 29-35. 212-221.

80