Is Autophagy Involved in the Diverse Effects of Antidepressants





Theo Rein

Max Planck Institute of Psychiatry, Munich 80804, Germany;; Tel.: +49-89-30622531


Received: 15 December 2018; Accepted: 9 January 2019; Published: 12 January 2019

Abstract: Autophagy has received increased attention as a conserved process governing cellular energy and protein homeostasis that is thus relevant in a range of physiological and pathophysiological conditions. Recently, autophagy has also been linked to depression, mainly through its involvement in the action of antidepressants. Some antidepressant drugs and psychotropic medication have been reported to exert beneficial effects in other diseases, for example, in cancer and neurodegenerative diseases. This review collates the evidence for the hypothesis that autophagy contributes to the effects of antidepressants beyond depression treatment.

Keywords: autophagy; antidepressants; depression; cancer; FKBP51

1. Autophagy

The continuous synthesis and degradation of (macro)molecules to keep internal entropy low is a hallmark of life [1]. While in its first decades, molecular biology focused on the discovery of the fascinating principles of synthetic processes, the equally important mechanisms of degradation are now also the subjects of intense research. Two distinct pathways have evolved for intracellular degradation: the ubiquitin–proteasome system and the autophagy–lysosome system [2]. Over the past couple of years, it has become increasingly evident that the two pathways influence each other [3]. Originally described as a response to calorie restriction [4,5], autophagy is now generally known as a degradative process promoting energy, organelle and protein homeostasis. This essential cellular homeostasis mechanism is described in detail in several excellent reviews [6–9] and thus will be introduced here only briefly.

The different types of degradative autophagy include macroautophagy, chaperone-mediated autophagy (CMA) and microautophagy. The autophagic machinery is also involved in non-degradative processes, such as the secretion of complex cytoplasmic cargo, referred to as secretory autophagy [10]. Macroautophagy is the most investigated form of autophagy. It is a step-wise mechanism leading to the formation of a double membrane vesicular structure (called autophagosome) that enwraps to be degraded cytosolic material and is then fused with lysosomes to form autolysosomes. This process is enacted by an array of proteins encoded by autophagy related genes (ATGs). The key proteins are the ATG1/ULK complex (ULK1/2 are mammalian homologs of the yeast ATG1 protein), which initiates autophagy by the isolation of membrane material, and Beclin1/ATG6, as part of the nucleation complex that begins the formation of the double membrane phagophore structures. Both ULK and Beclin1 are under the control of the nutrient sensor AMPK (adenosine monophosphate-activated protein kinase), directly and also indirectly through the mTOR complex [11]. The expansion of the phagophore into the autophagosome requires two conjugation systems, ATG7 and ATG10, which catalyze the conjugation of ATG12 with ATG5, and then promote the lipidation of LC3B/ATG8 (conjugation with phosphatidylethanolamine) to form LC3BII. More details of the various steps of the autophagic pathways from membrane isolation to fusion of the autophagosome with the lysosome are provided in various reviews [6–9,11,12]. Of note, it is increasingly recognized that there is considerable

Cells 2019, 8, 44; doi:10.3390/cells8010044

Cells 2019, 8, 44 2 of 18

redundancy of autophagic proteins. Under certain circumstances, autophagy can also be observed in the absence of genes originally considered to be essential for the autophagic pathway such as ATG5, ATG7 or Beclin1 [9].

While a broad spectrum of cargo—e.g., damaged proteins, organelles, and pathogens—can be degraded by macroautophagy, CMA is confined to proteins [13]. In essence, CMA degrades proteins with a specific motif at their N-terminus [14]; the chaperone, HSC70, binds to this motif and delivers the protein to the lysosome through interaction with the lysosomal LAMP-2A protein [13,15]. Microautophagy is a much less investigated non-selective lysosomal degradation mechanism that involves enwrapping cytosolic material by the lysosomal membrane and delivery into the lysosomal lumen upon membrane scission [16]. Based on membrane dynamics and the molecular machinery involved, three types of microautophagy are distinguished: microautophagy with lysosomal protrusion, microautophagy with lysosomal invagination and microautophagy with endosomal invagination [17]. There is mechanistic overlap between the different types of degradative autophagy. For example, the binding of HSC70 to the N-terminal amino acid motif of the cargo protein is part of both CMA and endosomal microautophagy [18]. Related to the cross-talk between different forms of autophagy, particular physiological conditions can cause more than one type of autophagy. For example, amino acid depletion has recently been shown to not only induce bulk macroautophagy, but also endosomal microautophagy [19,20].

2. Antidepressants

Since autophagy is a fundamental physiological process that is also involved in several pathologies, increasing efforts are being devoted to deciphering pharmacological ways of addressing the autophagic pathway [21–23]. Concomitantly, several compounds and drugs were discovered to impact autophagy, including antidepressant drugs [24–29]. In general, currently used antidepressant drugs were developed based on the monoamine deficiency hypothesis of depression [30,31]. This hypothesis stipulates a shortage of monoaminergic neurotransmitters in the synaptic cleft. The theory was derived from the observation of the effects of tricyclic antidepressants (TCAs), with imipramine being the first TCA to have been introduced more than 60 years ago [32]. In the following, this hypothesis has stimulated the development of more selectively acting drugs, for example selective serotonin re-uptake inhibitors (SSRIs) [33]. These newly developed drugs exhibit fewer side effects, but no better treatment efficacy [34]. Furthermore, there is some evidence for a sex difference in the effectiveness of these two classes of antidepressants, with men responding better to TCAs than women, while women appear to better respond to SRRIs than men [35].

Efforts to improve drug development based on neurobiological findings have had limited success so far, despite promising developments. For example, one of the most established findings in molecular psychiatry is the association of depression with a dysfunctional hypothalamic–pituitary–adrenocortical (HPA) axis [36–39]. Therefore, drugs that target components of the HPA axis, such as the glucocorticoid receptor and the receptors for corticotrophin-releasing hormone or arginine vasopressin, have been tested. Overall, controlled large-scale studies are still needed to prove the clinical usefulness of these compounds [40–43]. It should be noted here that another avenue of HPA axis-derived drug development in depression targets the glucocorticoid receptor inhibitor FK506 binding protein (FKBP) 51 [44,45], which has recently been linked to autophagy [26,27,46]. Furthermore, the N-methyl-D-aspartate receptor (NMDAR) antagonist, ketamine, which has demonstrated efficacy as an antidepressant [47–49], has also been linked to NMDAR-independent effects [50], including impacts on autophagy [51,52].

The discovery of the first antidepressants in the 1950s was fortuitous since these compounds were originally developed for a different clinical application [32]. Conversely, following the concept of drug repositioning [53,54], antidepressant drugs are now being explored for their usefulness in diseases beyond depression, for example, in cancer treatment [55]. The following sections survey the reported

Cells 2019, 8, 44 3 of 18

effects of antidepressants in different clinically relevant conditions with particular consideration of the potential involvement of autophagy.

3. Autophagy in the Action of Antidepressants

There are quite a number of publications which report that antidepressants impact autophagy, as has been collated very recently [56]. The majority of these studies report the induction of autophagy, mostly based on the increase in abundance of autophagic markers, typically LC3II/I. However, this conclusion might be premature, as inhibiting functional autophagy by blocking the fusion between autophagosome and lysosome also produces increased levels of this marker. Therefore, the guidelines for the use and interpretation of assays for monitoring autophagy call for the use of methods that determine protein-turnover [57]. The studies employing these methods mostly report increased autophagy upon treatment with antidepressants [26–29,58], but impaired autophagy has also been reported [25]. Collectively, these studies point to the diverse and cell-type-dependent effects of antidepressants on autophagy.

The molecular mechanism of the autophagy-modulating function of antidepressants is largely unexplored. Nevertheless, an interesting recent study provides evidence for an autophagy-inducing mechanism involving the inhibition of acid sphingomyelinase (ASM) [58], which has long been considered a potential target for antidepressant action [59–62]. The antidepressants amitriptyline and fluoxetine lead to the gradual accumulation of sphingomyelin in the lysosomes and of ceramide in the endoplasmic reticulum, which stimulates autophagy via protein phosphatase 2A, ULK, Beclin and LC3B [58]. Another study reported the involvement of the stress protein FKBP51 [45,63], Akt1 and Beclin1 in the effect of antidepressants on autophagy and behavior [26,27]. Given the multitude of the cellular effects of antidepressants beyond monoaminergic neurotransmission, and the plethora of at least partially redundant autophagy proteins [9], it will be challenging to pinpoint the exact mechanisms that evoke the autophagic response. Their characteristic as cationic amphiphilic chemicals might play a role [61,64], and new tools to decipher novel molecules directly interacting with antidepressants should also contribute to elucidating their molecular mode of action [64,65].

3.1. Depression

In general, it is difficult to unequivocally prove the causal involvement of a particular molecular pathway in the effect of a drug in a clinical setting. Virtually all studies on antidepressants and autophagy in depression have been performed in murine or cellular models, with the known limitations [66] of modeling such a complex disease in animals. The expression of the autophagy initiator and regulator protein Beclin1 [67] in peripheral blood mononuclear cells (PBMCs) of depressed patients was positively correlated with clinical treatment success [26,27]. Moreover, the induction of the autophagic markers Beclin1, pAkt and LC3II/I in response to treatment of these PBMCs with antidepressants was predictive of the clinical treatment response [26,27]. Of the published investigations, this study comes closest to clinical settings, but it cannot prove the causal involvement of autophagy in clinical antidepressant action. It should also be mentioned that the sample size was between 30 and 50, and “only” the antidepressants amitriptyline, paroxetine and fluoxetine were investigated. While the autophagy types were not differentiated, the effects were linked to the Hsp90 co-chaperone FKBP51 [26,27], which is relevant in stress adaptation and depression, as well as in homeostatic pathways in many ways [45,63,68].

In animal studies, it is possible to employ genetic or pharmacological inhibition of autophagy to more rigorously test for a causal contribution of autophagy to the effect of antidepressants in depression-like behavior. In a recent example, deletion of the autophagy regulator ATG5 in microglia did not significantly change the effects of the antidepressant fluoxetine on depression-like effects in a chronic unpredictable mild stress paradigm in mice [69]. On the other hand, the pharmacological inhibition of Beclin1 abrogated the beneficial cellular and behavioral effects of the antidepressants, amitriptyline and fluoxetine, in mice [58]. Further studies testing causalities are awaited. A great

Cells 2019, 8, 44 4 of 18

number of studies report the effects of antidepressants or antidepressant-like compounds on autophagy, as surveyed very recently [56].

3.2. Cell Proliferation, Differentiation and Cancer

3.2.1. Autophagy and Cancer

In general, autophagy is known as a beneficial, cell-protective process [6–9]. However, excessive autophagy has also been linked to cell death under certain circumstances. This is referred to as type II programmed cell death, which is distinct from apoptosis (type I programmed cell death); several interrelations between apoptosis and autophagy are known [8,70,71]. Furthermore, as discussed elsewhere [22], the observation of massively enhanced autophagy around cell death per se does not prove causality, but often may indicate the final adaptive efforts of the cell. Nevertheless, autophagic cell death has been documented in some cases; for example, deletion of autophagy genes interfered with cell death during Drosophila melanogaster larvae development [72].

Reflecting the potentially dual role of autophagy in cell proliferation and cell death, there is no general rule for the best approach in using autophagy inducers or autophagy inhibitors for cancer treatment [22,73,74]. The development of straightforward concepts may need to take into consideration the stage and the type of tumor, and this is further complicated by the fact that autophagy is intertwined with the immune system that is relevant for the surveillance and suppression of tumor cells [75–78]. The double-edged function of autophagy is illustrated, for example, by the tissue-specific genetic blockade of autophagy in mice: the progression of lung tumors was markedly impaired, but the onset was accelerated [79]. The promotion of tumor progression by autophagy was also concluded very recently in a murine model of acute myeloid leukemia (AML) where deletion of the autophagy receptor p62 impaired the expansion and colony-forming ability of leukemia cells [80]. Several other preclinical studies support the hypothesis that autophagy inhibitors might be useful in fighting cancer [81–83]. Nevertheless, the clinical trials revealed no beneficial effect of the autophagy inhibitors chloroquine and hydroxychloroquine in cancer treatment [22,84].

Conversely, it has been documented in several animal models that autophagy inhibits malignant transformation. For example, blocking autophagy in mice through the systemic mosaic deletion of Atg5 or the deletion of Atg7 in the liver led to the development of multiple liver tumors [85]. Moreover, the heterozygous loss of Beclin1 in mice led to propensity for the development of lung and liver tumors as well as mammary hyperplasia later in life [86,87]. Furthermore, very recent data suggest that annexin A1 suppresses autophagy, thereby promoting migration, invasion and metastasis of nasopharyngeal carcinoma cells [88]. Along these lines, several chemical autophagy inducers are either approved for cancer treatment or in clinical trial [89]. Mimetics of caloric restriction, tapping into prototypic autophagy induction, were shown to enhance the effect of established antitumor drugs and radiotherapy in mice [84,90,91]. Taken together, autophagy appears to show a Janus face in its role in cancer cell survival and death by, on the one hand, inhibiting malignant transformation that may involve its effects on immune surveillance, and on the other hand, accelerating tumor progression in certain cases [22,79,92,93].

3.2.2. Antidepressants and Cancer

Tricyclic antidepressants (TCAs), due to their putative genotoxicity [94] and a few reports of their potential tumor promoting effects in animal models [95–97], have raised some concerns in the past about their potential action as carcinogens. These concerns, however, could not be substantiated in several studies. For example, a case-control study using the General Practice Research Database (GPRD) and examining a total of 31,953 cases of cancer (matched to controls) concluded that lung, breast and prostate cancers were largely unaffected, while TCAs may actually display preventive effects for colorectal cancer and glioma [98]. Furthermore, analysis of 7878 cases of epithelial ovarian

Cells 2019, 8, 44 5 of 18

cancer and 73,913 controls revealed no association between antidepressant use and the risk for this type of cancer [99]. Likewise, antidepressant use was not correlated with a recurrence of breast cancer [100]. Several preclinical studies in cells and animals report anticancer effects of tricyclic

antidepressants [24,101–107]. More recently, a drug repositioning approach revealed the inhibitory effects of TCAs on small cell lung cancer and other neuroendocrine tumors [108]. The involvement of autophagy in the anticancer effects of antidepressants is suggested by several reports. Another and very recent drug repurposing study found that sertraline acts as a sensitizer of non-small cell lung cancer cells to drug (erlotinib) treatment by inducing autophagy [55]. More specifically, treatment of cells with sertraline, erlotinib, or their combination, elevates autophagic flux through reciprocally regulating the AMPK/mTOR pathway and pharmacological or genetic interference with autophagy decreases the anticancer efficacy of sertraline or the combination of sertraline and erlotinib [55]. Similarly, using ATG7 knock down, the tumor growth inhibition by imipramine in combination with another autophagy inducer could be linked to its autophagy promoting effect [109]. Furthermore, sertraline both induces autophagy and inhibits cell growth in the cell lines and primary cells of acute myeloid leukemia, while employing bafilomycin A1 (BafA1) as an inhibitor of autophagy attenuates these effects [110]. In U-87MG human glioma cells, the TCA imipramine exhibited antitumor effects, which were abrogated using siRNA directed against Beclin1 [111]. Likewise, in drug-resistant Burkitt’s lymphoma, the antidepressants maprotiline and fluoxetine induced Type II autophagic cell death, which was diminished by the autophagy inhibitors 3-methyl-adenine (3-MA) or BafA1 [112]. Similarly, fluoxetine induced autophagy and decreased the proliferation and adipogenic differentiation of human adipose-derived stem cells [113]. Autophagy as well as the anti-proliferative effect was attenuated by 3-MA [113]. Fluoxetine was also found to induce autophagic cell death in triple negative breast cancer [114,115], and this effect was also diminished by 3-MA [114].

There are also studies that report the anti-proliferative effects of antidepressants in co-occurrence with autophagy induction, which thus do not attempt to establish causality but suggest a functional link. For example, plant lectins extracted from Dioclea violacea display antidepressant-like and antitumor effects and induce autophagy [116]. The antidepressant indatraline was reported to induce autophagy and to inhibit smooth muscle cell proliferation and restenosis in a rat model [117]. In HepG2 cells, amitriptyline induced autophagy, mitophagy and cell death [118]. Finally, inhibition of the autophagic flux by antidepressants has also been reported in conjunction with the inhibition of cell proliferation: the TCA amitriptyline not only inhibits autophagic flux but also endothelial cell proliferation and tube formation [119].

3.3. Infectious Diseases, Inflammation and the Immune System

3.3.1. The Role of Autophagy in Infectious Diseases, Inflammation and the Immune System

As alluded to in Section 3.2. on cancer, autophagy exerts non-cell autonomous antitumor effects through the immune system. It enhances the processing and presentation of tumor antigens and also diminishes tumor-promoting inflammation [120]. Autophagy is further established as a defense mechanism in the infection of several bacteria [121–124]. As an evolutionary response to this host defense, bacteria developed strategies to evade autophagic degradation [121,125–127]. Autophagy inducing agents were reported to fight bacterial infection [22]. However, as another evolutionary adaptation, some bacteria enhance autophagy in their hosts for their own metabolic benefit [128,129]. Accordingly, autophagy inhibitors displayed some treatment effects [130]. Likewise, autophagy also plays both pro- and anti-microbial roles in plants [131,132].

Similar observations have been made for viral infections. On the cell-autonomous level, autophagy leads to the efficient degradation of viral particles (also referred to as virophagy) [133–138]. Accordingly, some viruses evolved mechanisms to reduce or evade autophagy [22,135,139], and autophagy inducers were shown to fight infection of several viruses [22,134,135]. As with bacteria, some viruses evolved strategies to use autophagy for their own benefit [135,140–142]. A more recently described mechanism

Cells 2019, 8, 44 6 of 18

has been found for enteroviruses that use and partly remodel autophagy for their replication and secretion through secretory autophagy [143–149]. In line, autophagy suppressing compounds, the natural substance berberine and synthetic derivatives thereof, were reported to exhibit antiviral potency against enteroviruses [150].

3.3.2. Antidepressants and Infectious Diseases, Inflammation and the Immune System

Evidence for a role of inflammatory reactions and the immune system in the pathophysiology of depression has accumulated for several decades [151,152]. For example, psychosocial stress and other adverse events, particularly early in life, which are established risk factors for the development of depression [153–155], provoke an immune response involving several molecular pathways in mononuclear lymphocytes and inflammation [156,157]. While the exact inflammatory profile depends on the specific type of trauma [157], elevated inflammation generally correlates with a higher likelihood of developing depression and with its severity [158,159]. Elevated levels of inflammation impact physiology and behavior through several mechanisms involving, for example, synaptic neurotransmission in several brain circuits and the stress hormone axis [160,161].

The inflammatory status has also been linked to treatment response in depression and thus the action of antidepressants. A meta-analysis examining data from 35 studies suggests that increased inflammation contributes to treatment resistance [162]. Very recently, a genetic disposition to both inflammation and antidepressant treatment response was discovered, which differed between the antidepressants escitalopram and nortriptyline [163]. It has been suggested that treatment-resistant depression in particular is linked to elevated inflammation, leading to the proposal to explore the potential of anti-inflammatory treatment in depression [160,161,164,165].

Since antidepressants impact both inflammation and autophagy, and since inflammation is relevant for depression treatment, it appears plausible to hypothesize that antidepressants act through regulating autophagy on inflammation and the immune system. Currently, however, there are very few studies that directly address this question. Using a mouse model of depression, it was reported that several antidepressants not only reduce depression-like behavior, but also inhibit the NLRP3-inflammasome in an autophagy-dependent manner [166]. The deletion of ATG5 in cells abolished the effect of antidepressants on both autophagy and the inflammasome [166]. The anti-inflammatory effects of fluoxetine were also assessed in a brain injury model in rats: fluoxetine induced autophagy as evidenced by the increased levels of Beclin1 and attenuated the activation of the NLRP3 inflammasome [167]. Administration of the autophagy inhibitor 3-MA reversed the beneficial effects of fluoxetine [167].

Linkages between viral diseases and depression have been described on several levels, often suggesting mutual causation [168]. Fluoxetine, which has been reported in numerous studies to induce autophagy, is a potent inhibitor of coxsackievirus replication and other enteroviruses [169–171]. However, enteroviruses are reported to make use of autophagy for their secretion, as mentioned above. Thus, the involvement of autophagy in this antiviral effect of fluoxetine is not clear. It is possible that autophagy might be induced to a level that clears out the viral particles before they can exit. Similarly, a potential contribution of autophagy to the other antiviral effects of fluoxetine, such as for hepatitis C and Dengue virus, has not been examined [172,173]

3.4. Neurodegeneration

A hallmark of neurodegenerative diseases such as Alzheimer’s, Huntingtin’s and Parkinson’s disease is the accumulation of dysfunctional and aggregation-prone proteins, and it is thus not surprising that autophagy, or rather impairment of autophagy, has been linked to neurodegeneration in numerous studies, as documented in several excellent reviews [22,174–176]. Accordingly, the pharmacological induction of autophagy is considered a promising approach and several studies reported beneficial effects in various models [22,174,175,177–179].

Cells 2019, 8, 44 7 of 18

Antidepressants and other psychotropic medication are frequently prescribed to patients suffering from Alzheimer’s, Huntingtin’s, Parkinson’s and other neurodegenerative diseases [180–182]. While these drugs are frequently prescribed to treat co-morbid mood disorders, neuroprotective effects have also been reported, typically in preclinical models. For example, in a mouse model of Huntington’s disease that uses ectopic expression of mutant huntingtin (various models are reviewed in [183]), treatment with a combination of the mood stabilizers, lithium and valproate, produced multiple beneficial effects [184]. In related neuronal and non-neuronal cell models, lithium protected against polyglutamine toxicity [185]. Lithium also mitigated beta-amyloid and associated pathologies in a mouse model of Alzheimer’s disease [186]. This study also found enhanced autophagy upon treatment with lithium [186], like several other researchers in diverse cell and animal models [187,188]. Similarly, in a mouse model of Parkinson’s disease, beneficial effects along with the induction of autophagy were observed upon treatment with lithium in combination with valproate [189]. Of note, these authors also pre-treated the animals with the autophagy inhibitor wortmannin, which dampened the protective effects of lithium and valproate [189]. Similarly, clearance of protease-resistant prion proteins in prion-infected cells by lithium was abolished by the autophagy inhibitor 3-MA [190]. Based on these and other results documenting the neuroprotective and autophagy-inducing actions of lithium, this drug was proposed as a candidate drug for the treatment of neurodegenerative diseases in general [191]. In fact, lithium delayed disease progression in patients suffering from amyotrophic lateral sclerosis (ALS) [192]. The same study also reported neuroprotection in a mouse model of ALS concomitant with autophagy induction [192]. However, as pointed out elsewhere, large controlled trials are required to firmly establish the effect of lithium in neurodegenerative diseases [193]. In addition, there is also evidence for autophagy inhibition by lithium through the inhibition of kinase GSK3β [194]. Thus, it has been reasoned that treatment with lithium should be complemented by the application of rapamycin to ensure autophagy induction [194].

The effects of antidepressants in animal models of neurodegenerative diseases [180–182,195,196], for example, the slowdown in disease progression in mouse models of Huntington’s disease [197,198], may also be linked to autophagy. However, in the absence of experimental proof, this remains a hypothesis.

3.5. Aging/Longevity

The beneficial effect of autophagy on healthy aging and longevity is well documented in dozens of publications, as surveyed recently [89]. It is very likely that this is not independent of the regulation of disease and metabolic processes, but rather a consequence of it. Similarly, antidepressants may contribute to healthy aging through their effects on various disease conditions. A screen of 88,000 diverse chemicals revealed serotonin receptor antagonists, also used as antidepressants in the clinic, as efficient in extending lifespan in adult Caenorhabditis elegans [199]. Even though autophagy has not been investigated in this study, the authors point out that lifespan extension is achieved by blocking certain types of neurotransmission that are implicated in food sensing, thus possibly leading to a state of perceived starvation [199]. As mentioned above, caloric restriction is the prototypic inducer of autophagy restriction [4,5] and has been shown to extend lifespan in several laboratories [200–202]. Nevertheless, this does not prove that antidepressants extend lifespan through the induction of autophagy in Caenorhabditis elegans. In humans, an analysis of 357 adults with Down syndrome indicated a positive correlation of antidepressant medication with longevity [203]. However, this retrospective study could not establish causality, and autophagy was not assessed.

4. Conclusions

Autophagy still enjoys growing attention, not least for its link to a broad spectrum of physiological and pathological conditions. In addition, more and more compounds that modulate autophagy are being revealed, both new molecules and FDA-approved drugs such as antidepressants and other psychotropic drugs. Thus, autophagy induction may be seen as a non-specific side effect of many

Cells 2019, 8, 44 8 of 18

drugs, including antidepressants. Therefore, it is important to include pharmacological or genetic loss of function approaches to prove the relevance of autophagy in the action of antidepressants or any other drug in future studies. Distinguishing the types of autophagy would also greatly improve our understanding of the role of autophagy in antidepressant action. It should further be noted that not all studies report the induction of autophagy by psychotropic drugs; lithium and tricyclic antidepressants appear to be able to inhibit autophagy in some cases. Thus, wherever possible, turnover-assays need to be performed. Moreover, it appears challenging in several cases to come up with a coherent picture of the physiological events. For example, antidepressants are reported to exert beneficial effects on depression, in part through down-regulating immune function and inflammation. At first glance, this is difficult to reconcile with the beneficial effects in cancer, where intact immune surveillance would be advantageous. In such situations, it is usually argued that the effects are context-dependent. Finally, evidence suggests that autophagy is intimately linked to other cellular processes involving membrane re-organization. Therefore, markers of autophagy might actually be indicators of related mechanisms requiring membrane fusion and scission, such as synaptic neurotransmission. It will be interesting to further advance our understanding of the complexity in this exciting area of research.

Funding: This research received no external funding.
Conflicts of Interest: The author declares no conflict of interest.


1. Schrödinger, E. What Is Life? The Physical Aspect of the Living Cell; University Press: Cambridge, UK, 1944.

2. Dikic, I. Proteasomal and Autophagic Degradation Systems. Annu. Rev. Biochem. 2017, 86, 193–224.
[CrossRef] [PubMed]

3. Nam, T.; Han, J.H.; Devkota, S.; Lee, H.W. Emerging Paradigm of Crosstalk between Autophagy and the
Ubiquitin-Proteasome System. Mol. Cells 2017, 40, 897–905. [PubMed]

4. De Duve, C. The lysosome. Sci. Am. 1963, 208, 64–73. [CrossRef] [PubMed]

5. Bagherniya, M.; Butler, A.E.; Barreto, G.E.; Sahebkar, A. The effect of fasting or calorie restriction on
autophagy induction: A review of the literature. Ageing Res. Rev. 2018, 47, 183–197. [CrossRef] [PubMed]

6. Nakamura, S.; Yoshimori, T. Autophagy and Longevity. Mol. Cells 2018, 41, 65–72. [PubMed]

7. Mizushima, N.; Komatsu, M. Autophagy: Renovation of cells and tissues. Cell 2011, 147, 728–741. [CrossRef]

8. Kroemer, G.; Marino, G.; Levine, B. Autophagy and the integrated stress response. Mol. Cell 2010, 40, 280–293.

9. Galluzzi, L.; Baehrecke, E.H.; Ballabio, A.; Boya, P.; Bravo-San Pedro, J.M.; Cecconi, F.; Choi, A.M.; Chu, C.T.;
Codogno, P.; Colombo, M.I.; et al. Molecular definitions of autophagy and related processes. EMBO J. 2017,
36, 1811–1836. [CrossRef]

10. Ponpuak, M.; Mandell, M.A.; Kimura, T.; Chauhan, S.; Cleyrat, C.; Deretic, V. Secretory autophagy. Curr. Opin.
Cell Biol. 2015, 35, 106–116. [CrossRef]

11. Tamargo-Gomez, I.; Marino, G. AMPK: Regulation of Metabolic Dynamics in the Context of Autophagy.
Int. J. Mol. Sci. 2018, 19, 3812. [CrossRef]

12. Nakamura, S.; Yoshimori, T. New insights into autophagosome-lysosome fusion. J. Cell Sci. 2017, 130,
1209–1216. [CrossRef] [PubMed]

13. Kaushik, S.; Cuervo, A.M. The coming of age of chaperone-mediated autophagy. Nat. Rev. Mol. Cell Biol.
2018, 19, 365–381. [CrossRef] [PubMed]

14. Dice, J.F. Peptide sequences that target cytosolic proteins for lysosomal proteolysis. Trends Biochem. Sci. 1990,
15, 305–309. [CrossRef]

15. Kaushik, S.; Cuervo, A.M. Chaperone-mediated autophagy: A unique way to enter the lysosome world.
Trends Cell Biol. 2012, 22, 407–417. [CrossRef] [PubMed]

16. Li, W.W.; Li, J.; Bao, J.K. Microautophagy: Lesser-known self-eating. Cell. Mol. Life Sci. 2012, 69, 1125–1136.
[CrossRef] [PubMed]

Cells 2019, 8, 44 9 of 18

17. Oku, M.; Sakai, Y. Three Distinct Types of Microautophagy Based on Membrane Dynamics and Molecular Machineries. Bioessays 2018, 40, e1800008. [CrossRef] [PubMed]

18. Tekirdag, K.; Cuervo, A.M. Chaperone-mediated autophagy and endosomal microautophagy: Joint by a chaperone. J. Biol. Chem. 2018, 293, 5414–5424. [CrossRef]

19. Mejlvang, J.; Olsvik, H.; Svenning, S.; Bruun, J.A.; Abudu, Y.P.; Larsen, K.B.; Brech, A.; Hansen, T.E.; Brenne, H.; Hansen, T.; et al. Starvation induces rapid degradation of selective autophagy receptors by endosomal microautophagy. J. Cell Biol. 2018, 217, 3640–3655. [CrossRef]

20. Olsvik, H.L.; Svenning, S.; Abudu, Y.P.; Brech, A.; Stenmark, H.; Johansen, T.; Mejlvang, J. Endosomal microautophagy is an integrated part of the autophagic response to amino acid starvation. Autophagy 2019, 15, 182–183. [CrossRef]

21. Rubinsztein, D.C.; Bento, C.F.; Deretic, V. Therapeutic targeting of autophagy in neurodegenerative and infectious diseases. J. Exp. Med. 2015, 212, 979–990. [CrossRef]

22. Galluzzi, L.; Bravo-San Pedro, J.M.; Levine, B.; Green, D.R.; Kroemer, G. Pharmacological modulation of autophagy: Therapeutic potential and persisting obstacles. Nat. Rev. Drug Discov. 2017, 16, 487–511. [CrossRef] [PubMed]

23. Levine, B.; Kroemer, G. Autophagy in the pathogenesis of disease. Cell 2008, 132, 27–42. [CrossRef] [PubMed]

24. Daley, E.; Wilkie, D.; Loesch, A.; Hargreaves, I.P.; Kendall, D.A.; Pilkington, G.J.; Bates, T.E. Chlorimipramine: A novel anticancer agent with a mitochondrial target. Biochem. Biophys. Res. Commun. 2005, 328, 623–632.
[CrossRef] [PubMed]

25. Rossi, M.; Munarriz, E.R.; Bartesaghi, S.; Milanese, M.; Dinsdale, D.; Guerra-Martin, M.A.; Bampton, E.T.;
Glynn, P.; Bonanno, G.; Knight, R.A.; et al. Desmethylclomipramine induces the accumulation of autophagy
markers by blocking autophagic flux. J. Cell Sci. 2009, 122, 3330–3339. [CrossRef]

26. Gassen, N.C.; Hartmann, J.; Schmidt, M.V.; Rein, T. FKBP5/FKBP51 enhances autophagy to synergize with
antidepressant action. Autophagy 2015, 11, 578–580. [CrossRef] [PubMed]

27. Gassen, N.C.; Hartmann, J.; Zschocke, J.; Stepan, J.; Hafner, K.; Zellner, A.; Kirmeier, T.; Kollmannsberger, L.;
Wagner, K.V.; Dedic, N.; et al. Association of FKBP51 with Priming of Autophagy Pathways and Mediation of Antidepressant Treatment Response: Evidence in Cells, Mice, and Humans. PLoS Med. 2014, 11, e1001755. [CrossRef]

28. Zschocke, J.; Zimmermann, N.; Berning, B.; Ganal, V.; Holsboer, F.; Rein, T. Antidepressant drugs diversely affect autophagy pathways in astrocytes and neurons—Dissociation from cholesterol homeostasis. Neuropsychopharmacology 2011, 36, 1754–1768. [CrossRef] [PubMed]

29. Zschocke, J.; Rein, T. Antidepressants encounter autophagy in neural cells. Autophagy 2011, 7, 1247–1248. [CrossRef]

30. Woolley, D.W.; Shaw, E. A Biochemical and pharmacological suggestion about certain mental disorders. Proc. Natl. Acad. Sci. USA 1954, 40, 228–231. [CrossRef]

31. Schildkraut, J.J. The catecholamine hypothesis of affective disorders: A review of supporting evidence. Am. J. Psychiatry 1965, 122, 509–522. [CrossRef]

32. Lopez-Munoz, F.; Alamo, C. Monoaminergic neurotransmission: The history of the discovery of antidepressants from 1950s until today. Curr. Pharm. Des. 2009, 15, 1563–1586. [CrossRef] [PubMed]

33. Wong, M.L.; Licinio, J. From monoamines to genomic targets: A paradigm shift for drug discovery in depression. Nat. Rev. Drug Discov. 2004, 3, 136–151. [CrossRef] [PubMed]

34. Steffens, D.C.; Krishnan, K.R.; Helms, M.J. Are SSRIs better than TCAs? Comparison of SSRIs and TCAs: A meta-analysis. Depress. Anxiety 1997, 6, 10–18. [CrossRef]

35. LeGates, T.A.; Kvarta, M.D.; Thompson, S.M. Sex differences in antidepressant efficacy. Neuropsychopharmacology 2019, 44, 140–154. [CrossRef] [PubMed]

36. Holsboer, F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000, 23, 477–501. [CrossRef]

37. Ising, M.; Horstmann, S.; Kloiber, S.; Lucae, S.; Binder, E.B.; Kern, N.; Kunzel, H.E.; Pfennig, A.; Uhr, M.; Holsboer, F. Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression—A potential biomarker? Biol. Psychiatry 2007, 62, 47–54. [CrossRef] [PubMed]

38. De Kloet, E.R.; Joels, M.; Holsboer, F. Stress and the brain: From adaptation to disease. Nat. Rev. Neurosci. 2005, 6, 463–475. [CrossRef]

Cells 2019, 8, 44 10 of 18

39. Fries, G.R.; Moreno, M.P.V.; Gubert, C.; Santos, B.T.M.Q.; Sartori, J.; Eisele, B.; Ferrari, P.; Fijtman, A.; Rüegg, J.; Gassen, N.C.; et al. Hypothalamic-pituitary-adrenal axis dysfunction and illness progression in bipolar disorder. Int. J. Neuropsychopharmacol. 2014, in press. [CrossRef]

40. Schüle, C.; Baghai, T.C.; Eser, D.; Rupprecht, R. Hypothalamic-pituitary-adrenocortical system dysregulation and new treatment strategies in depression. Expert Rev. Neurother. 2009, 9, 1005–1019. [CrossRef]

41. Zalachoras, I.; Houtman, R.; Atucha, E.; Devos, R.; Tijssen, A.M.; Hu, P.; Lockey, P.M.; Datson, N.A.; Belanoff, J.K.; Lucassen, P.J.; et al. Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator. Proc. Natl. Acad. Sci. USA 2013, 110, 7910–7915. [CrossRef]

42. Katz, D.A.; Locke, C.; Greco, N.; Liu, W.; Tracy, K.A. Hypothalamic-pituitary-adrenal axis and depression symptom effects of an arginine vasopressin type 1B receptor antagonist in a one-week randomized Phase 1b trial. Brain Behav. 2017, 7, e00628. [CrossRef] [PubMed]

43. Spierling, S.R.; Zorrilla, E.P. Don’t stress about CRF: Assessing the translational failures of CRF1antagonists. Psychopharmacology 2017, 234, 1467–1481. [CrossRef] [PubMed]

44. Gaali, S.; Kirschner, A.; Cuboni, S.; Hartmann, J.; Kozany, C.; Balsevich, G.; Namendorf, C.; Fernandez-Vizarra, P.; Sippel, C.; Zannas, A.S.; et al. Selective inhibitors of the FK506-binding protein 51 by induced fit. Nat. Chem. Biol. 2015, 11, 33–37. [CrossRef] [PubMed]

45. Wochnik, G.M.; Ruegg, J.; Abel, G.A.; Schmidt, U.; Holsboer, F.; Rein, T. FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells. J. Biol. Chem. 2005, 280, 4609–4616. [CrossRef] [PubMed]

46. Attwood, B.K.; Bourgognon, J.M.; Patel, S.; Mucha, M.; Schiavon, E.; Skrzypiec, A.E.; Young, K.W.; Shiosaka, S.; Korostynski, M.; Piechota, M.; et al. Neuropsin cleaves EphB2 in the amygdala to control anxiety. Nature 2011, 473, 372–375. [CrossRef] [PubMed]

47. Berman, R.M.; Cappiello, A.; Anand, A.; Oren, D.A.; Heninger, G.R.; Charney, D.S.; Krystal, J.H. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 2000, 47, 351–354. [CrossRef]

48. Diazgranados, N.; Ibrahim, L.; Brutsche, N.E.; Newberg, A.; Kronstein, P.; Khalife, S.; Kammerer, W.A.;
Quezado, Z.; Luckenbaugh, D.A.; Salvadore, G.; et al. A randomized add-on trial of an N-methyl-D-aspartate
antagonist in treatment-resistant bipolar depression. Arch. Gen. Psychiatry 2010, 67, 793–802. [CrossRef]

49. Murrough, J.W.; Iosifescu, D.V.; Chang, L.C.; Al Jurdi, R.K.; Green, C.E.; Perez, A.M.; Iqbal, S.; Pillemer, S.; Foulkes, A.; Shah, A.; et al. Antidepressant efficacy of ketamine in treatment-resistant major depression:
A two-site randomized controlled trial. Am. J. Psychiatry 2013, 170, 1134–1142. [CrossRef]

50. Zanos, P.; Moaddel, R.; Morris, P.J.; Georgiou, P.; Fischell, J.; Elmer, G.I.; Alkondon, M.; Yuan, P.; Pribut, H.J.; Singh, N.S.; et al. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature
2016, 533, 481–486. [CrossRef]

51. Shan, Z.; Wei, L.; Yu, S.; Jiang, S.; Ma, Y.; Zhang, C.; Wang, J.; Gao, Z.; Wan, F.; Zhuang, G.; et al. Ketamine
induces reactive oxygen species and enhances autophagy in SV-HUC-1 human uroepithelial cells. J. Cell.
Physiol. 2019, 234, 2778–2787. [CrossRef]

52. Zanos, P.; Gould, T.D. Mechanisms of ketamine action as an antidepressant. Mol. Psychiatry 2018, 23, 801–811.
[CrossRef] [PubMed]

53. Ashburn, T.T.; Thor, K.B. Drug repositioning: Identifying and developing new uses for existing drugs.
Nat. Rev. Drug Discov. 2004, 3, 673–683. [CrossRef] [PubMed]

54. Chong, C.R.; Sullivan, D.J., Jr. New uses for old drugs. Nature 2007, 448, 645–646. [CrossRef] [PubMed]

55. Jiang, X.; Lu, W.; Shen, X.; Wang, Q.; Lv, J.; Liu, M.; Cheng, F.; Zhao, Z.; Pang, X. Repurposing sertraline
sensitizes non-small cell lung cancer cells to erlotinib by inducing autophagy. JCI Insight 2018, 3, 98921.
[CrossRef] [PubMed]

56. Gassen, N.C.; Rein, T. Role of autophagy in depression and antidepressant action. Front. Psychiatry
2019, submitted.

57. Klionsky, D.J.; Abdelmohsen, K.; Abe, A.; Abedin, M.J.; Abeliovich, H.; Acevedo, A.A.; Adachi, H.;
Adams, C.M.; Adams, P.D.; Adeli, K.; et al. Guidelines for the use and interpretation of assays for monitoring
autophagy (3rd edition). Autophagy 2016, 12, 1–222. [CrossRef]

58. Gulbins, A.; Schumacher, F.; Becker, K.A.; Wilker, B.; Soddemann, M.; Boldrin, F.; Muller, C.P.;
Edwards, M.J.; Goodman, M.; Caldwell, C.C.; et al. Antidepressants act by inducing autophagy controlled by sphingomyelin-ceramide. Mol. Psychiatry 2018, 23, 2324. [CrossRef]

Cells 2019, 8, 44 11 of 18

59. Gulbins, E.; Palmada, M.; Reichel, M.; Luth, A.; Bohmer, C.; Amato, D.; Muller, C.P.; Tischbirek, C.H.; Groemer, T.W.; Tabatabai, G.; et al. Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs. Nat. Med. 2013, 19, 934–938. [CrossRef]

60. Kornhuber, J.; Medlin, A.; Bleich, S.; Jendrossek, V.; Henkel, A.W.; Wiltfang, J.; Gulbins, E. High activity of acid sphingomyelinase in major depression. J. Neural Transm. (Vienna) 2005, 112, 1583–1590. [CrossRef]

61. Rhein, C.; Lober, S.; Gmeiner, P.; Gulbins, E.; Tripal, P.; Kornhuber, J. Derivatization of common antidepressant drugs increases inhibition of acid sphingomyelinase and reduces induction of phospholipidosis. J. Neural Transm. (Vienna) 2018, 125, 1837–1845. [CrossRef]

62. Albouz, S.; Le, S.F.; Wenger, D.; Hauw, J.J.; Baumann, N. Modifications of sphingomyelin and phosphatidylcholine metabolism by tricyclic antidepressants and phenothiazines. Life Sci. 1986, 38, 357–363. [CrossRef]

63. Rein, T. FK506 binding protein 51 integrates pathways of adaptation: FKBP51 shapes the reactivity to environmental change. Bioessays 2016, 38, 894–902. [CrossRef] [PubMed]

64. Vater, M.; Mockl, L.; Gormanns, V.; Schultz, F.C.; Mallmann, A.M.; Ziegart-Sadowska, K.; Zaba, M.; Frevert, M.L.; Brauchle, C.; Holsboer, F. New insights into the intracellular distribution pattern of cationic amphiphilic drugs. Sci. Rep. 2017, 7, 44277. [CrossRef] [PubMed]

65. Kirmeier, T.; Gopalakrishnan, R.; Gormanns, V.; Werner, A.M.; Cuboni, S.; Rudolf, G.C.; Hofner, G.; Wanner, K.T.; Sieber, S.A.; Schmidt, U.; et al. Azidobupramine, an Antidepressant-Derived Bifunctional Neurotransmitter Transporter Ligand Allowing Covalent Labeling and Attachment of Fluorophores. PLoS ONE 2016, 11, e0148608. [CrossRef] [PubMed]

66. Nestler, E.J.; Hyman, S.E. Animal models of neuropsychiatric disorders. Nat. Neurosci. 2010, 13, 1161–1169. [CrossRef] [PubMed]

67. Levine, B.; Liu, R.; Dong, X.; Zhong, Q. Beclin orthologs: Integrative hubs of cell signaling, membrane trafficking, and physiology. Trends Cell Biol. 2015, 25, 533–544. [CrossRef] [PubMed]

68. Binder, E.B.; Salyakina, D.; Lichtner, P.; Wochnik, G.M.; Ising, M.; Putz, B.; Papiol, S.; Seaman, S.; Lucae, S.; Kohli, M.A.; et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat. Genet. 2004, 36, 1319–1325. [CrossRef]

69. Tan, X.; Du, X.; Jiang, Y.; Botchway, B.O.A.; Hu, Z.; Fang, M. Inhibition of Autophagy in Microglia Alters Depressive-Like Behavior via BDNF Pathway in Postpartum Depression. Front. Psychiatry 2018, 9, 434. [CrossRef]

70. Booth, L.A.; Tavallai, S.; Hamed, H.A.; Cruickshanks, N.; Dent, P. The role of cell signalling in the crosstalk between autophagy and apoptosis. Cell Signal. 2014, 26, 549–555. [CrossRef]

71. Thorburn, A. Apoptosis and autophagy: Regulatory connections between two supposedly different processes. Apoptosis 2008, 13, 1–9. [CrossRef]

72. Berry, D.L.; Baehrecke, E.H. Growth arrest and autophagy are required for salivary gland cell degradation in Drosophila. Cell 2007, 131, 1137–1148. [CrossRef] [PubMed]

73. Huang, T.; Song, X.; Yang, Y.; Wan, X.; Alvarez, A.A.; Sastry, N.; Feng, H.; Hu, B.; Cheng, S.Y. Autophagy and Hallmarks of Cancer. Crit. Rev. Oncog. 2018, 23, 247–267. [CrossRef] [PubMed]

74. Amaravadi, R.; Kimmelman, A.C.; White, E. Recent insights into the function of autophagy in cancer. Genes Dev. 2016, 30, 1913–1930. [CrossRef] [PubMed]

75. Galluzzi, L.; Pietrocola, F.; Bravo-San Pedro, J.M.; Amaravadi, R.K.; Baehrecke, E.H.; Cecconi, F.; Codogno, P.; Debnath, J.; Gewirtz, D.A.; Karantza, V.; et al. Autophagy in malignant transformation and cancer progression. EMBO J. 2015, 34, 856–880. [CrossRef] [PubMed]

76. Puleston, D.J.; Zhang, H.; Powell, T.J.; Lipina, E.; Sims, S.; Panse, I.; Watson, A.S.; Cerundolo, V.; Townsend, A.R.; Klenerman, P.; et al. Autophagy is a critical regulator of memory CD8(+) T cell formation. Elife 2014, 3. [CrossRef] [PubMed]

77. Pua, H.H.; Dzhagalov, I.; Chuck, M.; Mizushima, N.; He, Y.W. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp. Med. 2007, 204, 25–31. [CrossRef] [PubMed]

78. Michaud, M.; Martins, I.; Sukkurwala, A.Q.; Adjemian, S.; Ma, Y.; Pellegatti, P.; Shen, S.; Kepp, O.; Scoazec, M.; Mignot, G.; et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 2011, 334, 1573–1577. [CrossRef]

Cells 2019, 8, 44 12 of 18

79. Rao, S.; Tortola, L.; Perlot, T.; Wirnsberger, G.; Novatchkova, M.; Nitsch, R.; Sykacek, P.; Frank, L.; Schramek, D.; Komnenovic, V.; et al. A dual role for autophagy in a murine model of lung cancer. Nat. Commun. 2014, 5, 3056. [CrossRef]

80. Nguyen, T.D.; Shaid, S.; Vakhrusheva, O.; Koschade, S.E.; Klann, K.; Thoken, M.; Baker, F.; Zhang, J.; Oellerich, T.; Surun, D.; et al. Loss of the selective autophagy receptor p62 impairs murine myeloid leukemia progression and mitophagy. Blood 2018. [CrossRef]

81. Guo, J.Y.; Xia, B.; White, E. Autophagy-mediated tumor promotion. Cell 2013, 155, 1216–1219. [CrossRef]

82. White, E.; Mehnert, J.M.; Chan, C.S. Autophagy, Metabolism, and Cancer. Clin. Cancer Res. 2015, 21,
5037–5046. [CrossRef] [PubMed]

83. White, E. The role for autophagy in cancer. J. Clin. Investig. 2015, 125, 42–46. [CrossRef] [PubMed]

84. Galluzzi, L.; Bravo-San Pedro, J.M.; Demaria, S.; Formenti, S.C.; Kroemer, G. Activating autophagy to
potentiate immunogenic chemotherapy and radiation therapy. Nat. Rev. Clin. Oncol. 2017, 14, 247–258.
[CrossRef] [PubMed]

85. Takamura, A.; Komatsu, M.; Hara, T.; Sakamoto, A.; Kishi, C.; Waguri, S.; Eishi, Y.; Hino, O.; Tanaka, K.;
Mizushima, N. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 2011, 25, 795–800.
[CrossRef] [PubMed]

86. Yue, Z.; Jin, S.; Yang, C.; Levine, A.J.; Heintz, N. Beclin 1, an autophagy gene essential for early embryonic
development, is a haploinsufficient tumor suppressor. Proc. Natl. Acad. Sci. USA 2003, 100, 15077–15082.
[CrossRef] [PubMed]

87. Qu, X.; Yu, J.; Bhagat, G.; Furuya, N.; Hibshoosh, H.; Troxel, A.; Rosen, J.; Eskelinen, E.L.; Mizushima, N.;
Ohsumi, Y.; et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene.
J. Clin. Investig. 2003, 112, 1809–1820. [CrossRef] [PubMed]

88. Zhu, J.F.; Huang, W.; Yi, H.M.; Xiao, T.; Li, J.Y.; Feng, J.; Yi, H.; Lu, S.S.; Li, X.H.; Lu, R.H.; et al. Annexin
A1-suppressed autophagy promotes nasopharyngeal carcinoma cell invasion and metastasis by PI3K/AKT
signaling activation. Cell Death Dis. 2018, 9, 1154. [CrossRef]

89. Leidal, A.M.; Levine, B.; Debnath, J. Autophagy and the cell biology of age-related disease. Nat. Cell Biol.
2018, 20, 1338–1348. [CrossRef]

90. Pietrocola, F.; Pol, J.; Vacchelli, E.; Rao, S.; Enot, D.P.; Baracco, E.E.; Levesque, S.; Castoldi, F.; Jacquelot, N.;
Yamazaki, T.; et al. Caloric Restriction Mimetics Enhance Anticancer Immunosurveillance. Cancer Cell 2016,
30, 147–160. [CrossRef]

91. Di Biase, S.; Lee, C.; Brandhorst, S.; Manes, B.; Buono, R.; Cheng, C.W.; Cacciottolo, M.; Martin-Montalvo, A.;
de Cabo, R.; Wei, M.; et al. Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor
Cytotoxicity. Cancer Cell 2016, 30, 136–146.

92. Strohecker, A.M.; Guo, J.Y.; Karsli-Uzunbas, G.; Price, S.M.; Chen, G.J.; Mathew, R.; McMahon, M.; White, E.
Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors.
Cancer Discov. 2013, 3, 1272–1285. [CrossRef] [PubMed]

93. Rosenfeldt, M.T.; O’Prey, J.; Morton, J.P.; Nixon, C.; MacKay, G.; Mrowinska, A.; Au, A.; Rai, T.S.; Zheng, L.;
Ridgway, R.; et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature
2013, 504, 296–300. [CrossRef] [PubMed]

94. Van, S.N.; Graf, U. Genotoxicity evaluation of five tricyclic antidepressants in the wing somatic mutation
and recombination test in Drosophila melanogaster. Mutat. Res. 1991, 260, 99–104.

95. Brandes, L.J.; Arron, R.J.; Bogdanovic, R.P.; Tong, J.; Zaborniak, C.L.; Hogg, G.R.; Warrington, R.C.; Fang, W.; LaBella, F.S. Stimulation of malignant growth in rodents by antidepressant drugs at clinically relevant doses.
Cancer Res. 1992, 52, 3796–3800. [PubMed]

96. Hilakivi-Clarke, L.; Wright, A.; Lippman, M.E. DMBA-induced mammary tumor growth in rats exhibiting
increased or decreased ability to cope with stress due to early postnatal handling or antidepressant treatment.
Physiol. Behav. 1993, 54, 229–236. [CrossRef]

97. Iishi, H.; Tatsuta, M.; Baba, M.; Taniguchi, H. Enhancement by the tricyclic antidepressant, desipramine,
of experimental carcinogenesis in rat colon induced by azoxymethane. Carcinogenesis 1993, 14, 1837–1840.
[CrossRef] [PubMed]

98. Walker, A.J.; Card, T.; Bates, T.E.; Muir, K. Tricyclic antidepressants and the incidence of certain cancers:
A study using the GPRD. Br. J. Cancer 2011, 104, 193–197. [CrossRef]

Cells 2019, 8, 44 13 of 18

99. Huo, Y.L.; Qiao, J.M.; Gao, S. Association between antidepressant medication use and epithelial ovarian cancer risk: A systematic review and meta-analysis of observational studies. Br. J. Clin. Pharmacol. 2018, 84, 649–658. [CrossRef]

100. Chubak,J.;Bowles,E.J.;Yu,O.;Buist,D.S.;Fujii,M.;Boudreau,D.M.Breastcancerrecurrenceinrelationto antidepressant use. Cancer Causes Control 2016, 27, 125–136. [CrossRef]

101. Arimochi,H.;Morita,K.CharacterizationofcytotoxicactionsoftricyclicantidepressantsonhumanHT29 colon carcinoma cells. Eur. J. Pharmacol. 2006, 541, 17–23. [CrossRef]

102. Xia, Z.; Bergstrand, A.; DePierre, J.W.; Nassberger, L. The antidepressants imipramine, clomipramine, and citalopram induce apoptosis in human acute myeloid leukemia HL-60 cells via caspase-3 activation. J. Biochem. Mol. Toxicol. 1999, 13, 338–347. [CrossRef]

103. Levkovitz, Y.; Gil-Ad, I.; Zeldich, E.; Dayag, M.; Weizman, A. Differential induction of apoptosis by antidepressants in glioma and neuroblastoma cell lines: Evidence for p-c-Jun, cytochrome c, and caspase-3 involvement. J. Mol. Neurosci. 2005, 27, 29–42. [CrossRef]

104. Tsuruo,T.;Iida,H.;Nojiri,M.;Tsukagoshi,S.;Sakurai,Y.Potentiationofchemotherapeuticeffectofvincristine in vincristine resistant tumor bearing mice by calmodulin inhibitor clomipramine. J. Pharmacobiodyn. 1983, 6, 145–147. [CrossRef] [PubMed]

105. Merry,S.;Hamilton,T.G.;Flanigan,P.;Freshney,R.I.;Kaye,S.B.Circumventionofpleiotropicdrugresistance in subcutaneous tumours in vivo with verapamil and clomipramine. Eur. J. Cancer 1991, 27, 31–34. [CrossRef]

106. Reddy, K.K.; Lefkove, B.; Chen, L.B.; Govindarajan, B.; Carracedo, A.; Velasco, G.; Carrillo, C.O.; Bhandarkar, S.S.; Owens, M.J.; Mechta-Grigoriou, F.; et al. The antidepressant sertraline downregulates Akt and has activity against melanoma cells. Pigment Cell Melanoma Res. 2008, 21, 451–456. [CrossRef] [PubMed]

107. Pommerenke,E.W.;Volm,M.Reversalofdoxorubicin-resistanceinsolidtumorsbyclomipramine.InVivo
1995, 9, 99–101. [PubMed]

108. Jahchan,N.S.;Dudley,J.T.;Mazur,P.K.;Flores,N.;Yang,D.;Palmerton,A.;Zmoos,A.F.;Vaka,D.;Tran,K.Q.;
Zhou, M.; et al. A drug repositioning approach identifies tricyclic antidepressants as inhibitors of small cell
lung cancer and other neuroendocrine tumors. Cancer Discov. 2013, 3, 1364–1377. [CrossRef]

109. Shchors,K.;Massaras,A.;Hanahan,D.DualTargetingoftheAutophagicRegulatoryCircuitryinGliomas with Repurposed Drugs Elicits Cell-Lethal Autophagy and Therapeutic Benefit. Cancer Cell 2015, 28, 456–471.

110. Xia, D.; Zhang, Y.T.; Xu, G.P.; Yan, W.W.; Pan, X.R.; Tong, J.H. Sertraline exerts its antitumor functions
through both apoptosis and autophagy pathways in acute myeloid leukemia cells. Leuk. Lymphoma 2017, 58,
1–10. [CrossRef]

111. Jeon,S.H.;Kim,S.H.;Kim,Y.;Kim,Y.S.;Lim,Y.;Lee,Y.H.;Shin,S.Y.Thetricyclicantidepressantimipramine
induces autophagic cell death in U-87MG glioma cells. Biochem. Biophys. Res. Commun. 2011, 413, 311–317.

112. Cloonan,S.M.;Williams,D.C.TheantidepressantsmaprotilineandfluoxetineinduceTypeIIautophagiccell
death in drug-resistant Burkitt’s lymphoma. Int. J. Cancer 2011, 128, 1712–1723. [CrossRef]

113. Sun,B.K.;Kim,J.H.;Choi,J.S.;Hwang,S.J.;Sung,J.H.FluoxetineDecreasestheProliferationandAdipogenic Differentiation of Human Adipose-Derived Stem Cells. Int. J. Mol. Sci. 2015, 16, 16655–16668. [CrossRef]

114. Sun,D.;Zhu,L.;Zhao,Y.;Jiang,Y.;Chen,L.;Yu,Y.;Ouyang,L.Fluoxetineinducesautophagiccelldeath
via eEF2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer. Cell Prolif. 2018, 51, e12402.
[CrossRef] [PubMed]

115. Bowie, M.; Pilie, P.; Wulfkuhle, J.; Lem, S.; Hoffman, A.; Desai, S.; Petricoin, E.; Carter, A.; Ambrose, A.;
Seewaldt, V.; et al. Fluoxetine induces cytotoxic endoplasmic reticulum stress and autophagy in triple
negative breast cancer. World J. Clin. Oncol. 2015, 6, 299–311. [CrossRef] [PubMed]

116. Nascimento,A.P.M.;Knaut,J.L.;Rieger,D.K.;Wolin,I.A.V.;Heinrich,I.A.;Mann,J.;Juarez,A.V.;Sosa,L.D.V.; De Paul, A.L.; Moreira, C.G.; et al. Anti-glioma properties of DVL, a lectin purified from Dioclea violacea.
Int. J. Biol. Macromol. 2018, 120, 566–577. [CrossRef] [PubMed]

117. Cho,Y.S.;Yen,C.N.;Shim,J.S.;Kang,D.H.;Kang,S.W.;Liu,J.O.;Kwon,H.J.Antidepressantindatraline
induces autophagy and inhibits restenosis via suppression of mTOR/S6 kinase signaling pathway. Sci. Rep. 2016, 6, 34655. [CrossRef] [PubMed]

Cells 2019, 8, 44 14 of 18

118. Villanueva-Paz, M.; Cordero, M.D.; Pavon, A.D.; Vega, B.C.; Cotan, D.; De la, M.M.; Oropesa-Avila, M.; cocer-Gomez, E.; de La Mata, M.; Garrido-Maraver, J.; et al. Amitriptyline induces mitophagy that precedes apoptosis in human HepG2 cells. Genes Cancer 2016, 7, 260–277.

119. Guan,Y.;Li,X.;Umetani,M.;Boini,K.M.;Li,P.L.;Zhang,Y.Tricyclicantidepressantamitriptylineinhibits autophagic flux and prevents tube formation in vascular endothelial cells. Basic Clin. Pharmacol. Toxicol. 2018. [CrossRef]

120. Zhong,Z.;Sanchez-Lopez,E.;Karin,M.Autophagy,Inflammation,andImmunity:ATroikaGoverning Cancer and Its Treatment. Cell 2016, 166, 288–298. [CrossRef]

121. Tattoli,I.;Sorbara,M.T.;Vuckovic,D.;Ling,A.;Soares,F.;Carneiro,L.A.;Yang,C.;Emili,A.;Philpott,D.J.; Girardin, S.E. Amino acid starvation induced by invasive bacterial pathogens triggers an innate host defense program. Cell Host Microbe 2012, 11, 563–575. [CrossRef]

122. Thurston,T.L.;Ryzhakov,G.;Bloor,S.;von,M.N.;Randow,F.TheTBK1adaptorandautophagyreceptor NDP52 restricts the proliferation of ubiquitin-coated bacteria. Nat. Immunol. 2009, 10, 1215–1221. [CrossRef] [PubMed]

123. Gutierrez,M.G.;Master,S.S.;Singh,S.B.;Taylor,G.A.;Colombo,M.I.;Deretic,V.Autophagyisadefense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell 2004, 119, 753–766. [CrossRef] [PubMed]

124. Travassos, L.H.; Carneiro, L.A.; Ramjeet, M.; Hussey, S.; Kim, Y.G.; Magalhaes, J.G.; Yuan, L.; Soares, F.; Chea, E.; Le, B.L.; et al. Nod1 and Nod2 direct autophagy by recruiting ATG16L1 to the plasma membrane at the site of bacterial entry. Nat. Immunol. 2010, 11, 55–62. [CrossRef] [PubMed]

125. Choy,A.;Dancourt,J.;Mugo,B.;O’Connor,T.J.;Isberg,R.R.;Melia,T.J.;Roy,C.R.TheLegionellaeffector RavZ inhibits host autophagy through irreversible Atg8 deconjugation. Science 2012, 338, 1072–1076. [CrossRef] [PubMed]

126. Dong,N.;Zhu,Y.;Lu,Q.;Hu,L.;Zheng,Y.;Shao,F.StructurallydistinctbacterialTBC-likeGAPslinkArf GTPase to Rab1 inactivation to counteract host defenses. Cell 2012, 150, 1029–1041. [CrossRef] [PubMed]

127. Yoshikawa, Y.; Ogawa, M.; Hain, T.; Yoshida, M.; Fukumatsu, M.; Kim, M.; Mimuro, H.; Nakagawa, I.; Yanagawa, T.; Ishii, T.; et al. Listeria monocytogenes ActA-mediated escape from autophagic recognition. Nat. Cell Biol. 2009, 11, 1233–1240. [CrossRef] [PubMed]

128. Gutierrez, M.G.; Vazquez, C.L.; Munafo, D.B.; Zoppino, F.C.; Beron, W.; Rabinovitch, M.; Colombo, M.I. Autophagy induction favours the generation and maturation of the Coxiella-replicative vacuoles. Cell. Microbiol. 2005, 7, 981–993. [CrossRef]

129. Niu,H.;Xiong,Q.;Yamamoto,A.;Hayashi-Nishino,M.;Rikihisa,Y.Autophagosomesinducedbyabacterial Beclin 1 binding protein facilitate obligatory intracellular infection. Proc. Natl. Acad. Sci. USA 2012, 109, 20800–20807. [CrossRef]

130. Raoult,D.;Houpikian,P.;Tissot,D.H.;Riss,J.M.;rditi-Djiane,J.;Brouqui,P.TreatmentofQfeverendocarditis: Comparison of 2 regimens containing doxycycline and ofloxacin or hydroxychloroquine. Arch. Intern. Med. 1999, 159, 167–173. [CrossRef]

131. Üstün,S.;Hofius,D.Anti-andpro-microbialrolesofautophagyinplant-bacteriainteractions.Autophagy 2018, 14, 1465–1466. [CrossRef]

132. Üstün,S.;Hafren,A.;Liu,Q.;Marshall,R.S.;Minina,E.A.;Bozhkov,P.V.;Vierstra,R.D.;Hofius,D.Bacteria Exploit Autophagy for Proteasome Degradation and Enhanced Virulence in Plants. Plant Cell 2018, 30, 668–685. [CrossRef]

133. Campbell,G.R.;Spector,S.A.VitaminDinhibitshumanimmunodeficiencyvirustype1andMycobacterium tuberculosis infection in macrophages through the induction of autophagy. PLoS Pathog. 2012, 8, e1002689. [CrossRef] [PubMed]

134. Shoji-Kawata, S.; Sumpter, R.; Leveno, M.; Campbell, G.R.; Zou, Z.; Kinch, L.; Wilkins, A.D.; Sun, Q.; Pallauf, K.; MacDuff, D.; et al. Identification of a candidate therapeutic autophagy-inducing peptide. Nature 2013, 494, 201–206. [CrossRef]

135. Dong, X.; Levine, B. Autophagy and viruses: Adversaries or allies? J. Innate Immun. 2013, 5, 480–493. [CrossRef]

136. Orvedahl,A.;Sumpter,R.,Jr.;Xiao,G.;Ng,A.;Zou,Z.;Tang,Y.;Narimatsu,M.;Gilpin,C.;Sun,Q.;Roth,M.; et al. Image-based genome-wide siRNA screen identifies selective autophagy factors. Nature 2011, 480, 113–117. [CrossRef] [PubMed]

Cells 2019, 8, 44 15 of 18

137. Liang, X.H.; Kleeman, L.K.; Jiang, H.H.; Gordon, G.; Goldman, J.E.; Berry, G.; Herman, B.; Levine, B. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J. Virol. 1998, 72, 8586–8596. [PubMed]

138. Sumpter, R., Jr.; Sirasanagandla, S.; Fernandez, A.F.; Wei, Y.; Dong, X.; Franco, L.; Zou, Z.; Marchal, C.; Lee, M.Y.; Clapp, D.W.; et al. Fanconi Anemia Proteins Function in Mitophagy and Immunity. Cell 2016, 165, 867–881. [CrossRef]

139. Orvedahl,A.;Alexander,D.;Talloczy,Z.;Sun,Q.;Wei,Y.;Zhang,W.;Burns,D.;Leib,D.A.;Levine,B.HSV-1 ICP34.5 confers neurovirulence by targeting the Beclin 1 autophagy protein. Cell Host Microbe 2007, 1, 23–35. [CrossRef]

140. Shi,J.;Luo,H.Interplaybetweenthecellularautophagymachineryandpositive-strandedRNAviruses. Acta Biochim. Biophys. Sin. (Shanghai) 2012, 44, 375–384. [CrossRef]

141. Jackson,W.T.Poliovirus-inducedchangesincellularmembranesthroughoutinfection.Curr.Opin.Virol. 2014, 9, 67–73. [CrossRef]

142. Alirezaei,M.;Flynn,C.T.;Wood,M.R.;Whitton,J.L.Pancreaticacinarcell-specificautophagydisruption reduces coxsackievirus replication and pathogenesis in vivo. Cell Host Microbe 2012, 11, 298–305. [CrossRef] [PubMed]

143. Bird, S.W.; Maynard, N.D.; Covert, M.W.; Kirkegaard, K. Nonlytic viral spread enhanced by autophagy components. Proc. Natl. Acad. Sci. USA 2014, 111, 13081–13086. [CrossRef]

144. Chen,Y.H.;Du,W.;Hagemeijer,M.C.;Takvorian,P.M.;Pau,C.;Cali,A.;Brantner,C.A.;Stempinski,E.S.; Connelly, P.S.; Ma, H.C.; et al. Phosphatidylserine vesicles enable efficient en bloc transmission of enteroviruses. Cell 2015, 160, 619–630. [CrossRef] [PubMed]

145. Robinson,S.M.;Tsueng,G.;Sin,J.;Mangale,V.;Rahawi,S.;McIntyre,L.L.;Williams,W.;Kha,N.;Cruz,C.; Hancock, B.M.; et al. Coxsackievirus B exits the host cell in shed microvesicles displaying autophagosomal markers. PLoS Pathog. 2014, 10, e1004045. [CrossRef] [PubMed]

146. Jackson,W.T.;Giddings,T.H.,Jr.;Taylor,M.P.;Mulinyawe,S.;Rabinovitch,M.;Kopito,R.R.;Kirkegaard,K. Subversion of cellular autophagosomal machinery by RNA viruses. PLoS. Biol. 2005, 3, e156. [CrossRef] [PubMed]

147. Mutsafi, Y.; tan-Bonnet, N. Enterovirus Transmission by Secretory Autophagy. Viruses 2018, 10, 139. [CrossRef]

148. Corona,A.K.;Saulsbery,H.M.;CoronaVelazquez,A.F.;Jackson,W.T.EnterovirusesRemodelAutophagic Trafficking through Regulation of Host SNARE Proteins to Promote Virus Replication and Cell Exit. Cell Rep. 2018, 22, 3304–3314. [CrossRef]

149. Corona,A.K.;Mohamud,Y.;Jackson,W.T.;Luo,H.Oh,SNAP!Howenterovirusesredirectautophagictraffic away from degradation. Autophagy 2018, 14, 1469–1471. [CrossRef]

150. Wang,Y.X.;Yang,L.;Wang,H.Q.;Zhao,X.Q.;Liu,T.;Li,Y.H.;Zeng,Q.X.;Li,Y.H.;Song,D.Q.Synthesisand Evolution of Berberine Derivatives as a New Class of Antiviral Agents against Enterovirus 71 through the MEK/ERK Pathway and Autophagy. Molecules 2018, 23, 2084. [CrossRef]

151. Miller,A.H.;Raison,C.L.Theroleofinflammationindepression:Fromevolutionaryimperativetomodern treatment target. Nat. Rev. Immunol. 2016, 16, 22–34. [CrossRef]

152. Medina-Rodriguez, E.M.; Lowell, J.A.; Worthen, R.J.; Syed, S.A.; Beurel, E. Involvement of Innate and Adaptive Immune Systems Alterations in the Pathophysiology and Treatment of Depression. Front. Neurosci. 2018, 12, 547. [CrossRef] [PubMed]

153. Herzog, J.I.; Schmahl, C. Adverse Childhood Experiences and the Consequences on Neurobiological, Psychosocial, and Somatic Conditions across the Lifespan. Front. Psychiatry 2018, 9, 420. [CrossRef] [PubMed]

154. Nanni,V.;Uher,R.;Danese,A.Childhoodmaltreatmentpredictsunfavorablecourseofillnessandtreatment outcome in depression: A meta-analysis. Am. J. Psychiatry 2012, 169, 141–151. [CrossRef] [PubMed]

155. Cougle, J.R.; Timpano, K.R.; Sachs-Ericsson, N.; Keough, M.E.; Riccardi, C.J. Examining the unique relationships between anxiety disorders and childhood physical and sexual abuse in the National Comorbidity Survey-Replication. Psychiatry Res. 2010, 177, 150–155. [CrossRef] [PubMed]

156. Bierhaus,A.;Wolf,J.;Andrassy,M.;Rohleder,N.;Humpert,P.M.;Petrov,D.;Ferstl,R.;von,E.M.;Wendt,T.; Rudofsky, G.; et al. A mechanism converting psychosocial stress into mononuclear cell activation. Proc. Natl. Acad. Sci. USA 2003, 100, 1920–1925. [CrossRef] [PubMed]

Cells 2019, 8, 44 16 of 18

157. Baumeister, D.; Akhtar, R.; Ciufolini, S.; Pariante, C.M.; Mondelli, V. Childhood trauma and adulthood inflammation: A meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-alpha. Mol. Psychiatry 2016, 21, 642–649. [CrossRef] [PubMed]

158. Aschbacher, K.; Epel, E.; Wolkowitz, O.M.; Prather, A.A.; Puterman, E.; Dhabhar, F.S. Maintenance of a positive outlook during acute stress protects against pro-inflammatory reactivity and future depressive symptoms. Brain Behav. Immun. 2012, 26, 346–352. [CrossRef]

159. Köhler-Forsberg,O.;Buttenschon,H.N.;Tansey,K.E.;Maier,W.;Hauser,J.;Dernovsek,M.Z.;Henigsberg,N.; Souery, D.; Farmer, A.; Rietschel, M.; et al. Association between C-reactive protein (CRP) with depression symptom severity and specific depressive symptoms in major depression. Brain Behav. Immun. 2017, 62, 344–350. [CrossRef]

160. Kopschina, F.P.; Doorduin, J.; Klein, H.C.; Juarez-Orozco, L.E.; Dierckx, R.A.; Moriguchi-Jeckel, C.M.; de Vries, E.F. Anti-inflammatory treatment for major depressive disorder: Implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy. J. Psychopharmacol. 2017, 31, 1149–1165. [CrossRef]

161. Felger,J.C.RoleofInflammationinDepressionandTreatmentImplications.Handb.Exp.Pharmacol.2018. [CrossRef]

162. Strawbridge,R.;Arnone,D.;Danese,A.;Papadopoulos,A.;Herane,V.A.;Cleare,A.J.Inflammationand clinical response to treatment in depression: A meta-analysis. Eur. Neuropsychopharmacol. 2015, 25, 1532–1543. [CrossRef] [PubMed]

163. Zwicker,A.;Fabbri,C.;Rietschel,M.;Hauser,J.;Mors,O.;Maier,W.;Zobel,A.;Farmer,A.;Aitchison,K.J.; McGuffin, P.; et al. Genetic disposition to inflammation and response to antidepressants in major depressive disorder. J. Psychiatr. Res. 2018, 105, 17–22. [CrossRef] [PubMed]

164. Köhler, O.; Krogh, J.; Mors, O.; Benros, M.E. Inflammation in Depression and the Potential for Anti-Inflammatory Treatment. Curr. Neuropharmacol. 2016, 14, 732–742. [CrossRef]

165. Schmidt,F.M.;Kirkby,K.C.;Lichtblau,N.InflammationandImmuneRegulationasPotentialDrugTargets in Antidepressant Treatment. Curr. Neuropharmacol. 2016, 14, 674–687. [CrossRef] [PubMed]

166. cocer-Gomez, E.; Casas-Barquero, N.; Williams, M.R.; Romero-Guillena, S.L.; Canadas-Lozano, D.; Bullon, P.; Sanchez-Alcazar, J.A.; Navarro-Pando, J.M.; Cordero, M.D. Antidepressants induce autophagy dependent-NLRP3-inflammasome inhibition in Major depressive disorder. Pharmacol. Res. 2017, 121, 114–121. [CrossRef]

167. Li, J.R.; Xu, H.Z.; Nie, S.; Peng, Y.C.; Fan, L.F.; Wang, Z.J.; Wu, C.; Yan, F.; Chen, J.Y.; Gu, C.; et al. Fluoxetine-enhanced autophagy ameliorates early brain injury via inhibition of NLRP3 inflammasome activation following subrachnoid hemorrhage in rats. J. Neuroinflammation. 2017, 14, 186. [CrossRef] [PubMed]

168. Coughlin, S.S. Anxiety and Depression: Linkages with Viral Diseases. Public Health Rev. 2012, 34, 7. [CrossRef]

169. Zuo,J.;Quinn,K.K.;Kye,S.;Cooper,P.;Damoiseaux,R.;Krogstad,P.Fluoxetineisapotentinhibitorof coxsackievirus replication. Antimicrob. Agents Chemother. 2012, 56, 4838–4844. [CrossRef]

170. Ulferts,R.;deBoer,S.M.;vander,L.L.;Bauer,L.;Lyoo,H.R.;Mate,M.J.;Lichiere,J.;Canard,B.;Lelieveld,D.; Omta, W.; et al. Screening of a Library of FDA-Approved Drugs Identifies Several Enterovirus Replication Inhibitors That Target Viral Protein 2C. Antimicrob. Agents Chemother. 2016, 60, 2627–2638. [CrossRef]

171. Benkahla,M.A.;Alidjinou,E.K.;Sane,F.;Desailloud,R.;Hober,D.Fluoxetinecaninhibitcoxsackievirus-B4 E2 in vitro and in vivo. Antivir. Res. 2018, 159, 130–133. [CrossRef]

172. Young,K.C.;Bai,C.H.;Su,H.C.;Tsai,P.J.;Pu,C.Y.;Liao,C.S.;Lin,Y.M.;Lai,H.W.;Chong,L.W.;Tsai,Y.S.; et al. Fluoxetine a novel anti-hepatitis C virus agent via ROS-, JNK-, and PPARbeta/gamma-dependent pathways. Antivir. Res. 2014, 110, 158–167. [CrossRef]

173. Medigeshi, G.R.; Kumar, R.; Dhamija, E.; Agrawal, T.; Kar, M. N-Desmethylclozapine, Fluoxetine, and Salmeterol Inhibit Postentry Stages of the Dengue Virus Life Cycle. Antimicrob. Agents Chemother. 2016, 60, 6709–6718. [CrossRef] [PubMed]

174. Menzies,F.M.;Fleming,A.;Caricasole,A.;Bento,C.F.;Andrews,S.P.;Ashkenazi,A.;Fullgrabe,J.;Jackson,A.; Jimenez, S.M.; Karabiyik, C.; et al. Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. Neuron 2017, 93, 1015–1034. [CrossRef] [PubMed]

Cells 2019, 8, 44 17 of 18

175. Frake,R.A.;Ricketts,T.;Menzies,F.M.;Rubinsztein,D.C.Autophagyandneurodegeneration.J.Clin.Investig. 2015, 125, 65–74. [CrossRef] [PubMed]

176. Metaxakis,A.;Ploumi,C.;Tavernarakis,N.AutophagyinAge-AssociatedNeurodegeneration.Cells2018,7, 37. [CrossRef] [PubMed]

177. Ashkenazi,A.;Bento,C.F.;Ricketts,T.;Vicinanza,M.;Siddiqi,F.;Pavel,M.;Squitieri,F.;Hardenberg,M.C.; Imarisio, S.; Menzies, F.M.; et al. Polyglutamine tracts regulate beclin 1-dependent autophagy. Nature 2017, 545, 108–111. [CrossRef] [PubMed]

178. Ashkenazi,A.;Bento,C.F.;Ricketts,T.;Vicinanza,M.;Siddiqi,F.;Pavel,M.;Squitieri,F.;Hardenberg,M.C.; Imarisio, S.; Menzies, F.M.; et al. Polyglutamine tracts regulate autophagy. Autophagy 2017, 1–2. [CrossRef]

179. Sarkar,S.;Davies,J.E.;Huang,Z.;Tunnacliffe,A.;Rubinsztein,D.C.Trehalose,anovelmTOR-independent
autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein. J Biol. Chem. 2007,
282, 5641–5652. [CrossRef]

180. Lauterbach,E.C.NeuroprotectiveeffectsofpsychotropicdrugsinHuntington’sdisease.Int.J.Mol.Sci.2013,
14, 22558–22603. [CrossRef]

181. Lauterbach, E.C. Six psychotropics for pre-symptomatic & early Alzheimer’s (MCI), Parkinson’s, and
Huntington’s disease modification. Neural Regen. Res. 2016, 11, 1712–1726.

182. Jamwal, S.; Kumar, P. Antidepressants for neuroprotection in Huntington’s disease: A review. Eur. J.
Pharmacol. 2015, 769, 33–42. [CrossRef] [PubMed]

183. Rubinsztein, D.C. Lessons from animal models of Huntington’s disease. Trends Genet. 2002, 18, 202–209.

184. Chiu, C.T.; Liu, G.; Leeds, P.; Chuang, D.M. Combined treatment with the mood stabilizers lithium
and valproate produces multiple beneficial effects in transgenic mouse models of Huntington’s disease.
Neuropsychopharmacology 2011, 36, 2406–2421. [CrossRef] [PubMed]

185. Carmichael,J.;Sugars,K.L.;Bao,Y.P.;Rubinsztein,D.C.Glycogensynthasekinase-3betainhibitorsprevent
cellular polyglutamine toxicity caused by the Huntington’s disease mutation. J. Biol. Chem. 2002, 277,
33791–33798. [CrossRef] [PubMed]

186. Habib, A.; Sawmiller, D.; Li, S.; Xiang, Y.; Rongo, D.; Tian, J.; Hou, H.; Zeng, J.; Smith, A.; Fan, S.; et al.
LISPRO mitigates beta-amyloid and associated pathologies in Alzheimer’s mice. Cell Death Dis. 2017, 8,
e2880. [CrossRef] [PubMed]

187. Sarkar,S.;Floto,R.A.;Berger,Z.;Imarisio,S.;Cordenier,A.;Pasco,M.;Cook,L.J.;Rubinsztein,D.C.Lithium
induces autophagy by inhibiting inositol monophosphatase. J. Cell Biol. 2005, 170, 1101–1111. [CrossRef]

188. Motoi, Y.; Shimada, K.; Ishiguro, K.; Hattori, N. Lithium and autophagy. ACS Chem. Neurosci. 2014, 5,
434–442. [CrossRef]

189. Li,X.Z.;Chen,X.P.;Zhao,K.;Bai,L.M.;Zhang,H.;Zhou,X.P.Therapeuticeffectsofvalproatecombined
with lithium carbonate on MPTP-induced parkinsonism in mice: Possible mediation through enhanced
autophagy. Int. J. Neurosci. 2013, 123, 73–79. [CrossRef]

190. Heiseke,A.;Aguib,Y.;Riemer,C.;Baier,M.;Schatzl,H.M.Lithiuminducesclearanceofproteaseresistant
prion protein in prion-infected cells by induction of autophagy. J. Neurochem. 2009, 109, 25–34. [CrossRef]

191. Forlenza,O.V.;De-Paula,V.J.;Diniz,B.S.Neuroprotectiveeffectsoflithium:Implicationsforthetreatment of Alzheimer’s disease and related neurodegenerative disorders. ACS Chem. Neurosci. 2014, 5, 443–450.

192. Fornai,F.;Longone,P.;Cafaro,L.;Kastsiuchenka,O.;Ferrucci,M.;Manca,M.L.;Lazzeri,G.;Spalloni,A.;
Bellio, N.; Lenzi, P.; et al. Lithium delays progression of amyotrophic lateral sclerosis. Proc. Natl. Acad.
Sci. USA 2008, 105, 2052–2057. [CrossRef] [PubMed]

193. Morlet,E.;Hozer,F.;Costemale-Lacoste,J.F.Neuroprotectiveeffectsoflithium:Whataretheimplicationsin
humans with neurodegenerative disorders? Geriatr. Psychol. Neuropsychiatr. Vieil. 2018, 16, 78–86.

194. Sarkar, S.; Krishna, G.; Imarisio, S.; Saiki, S.; O’Kane, C.J.; Rubinsztein, D.C. A rational mechanism for combination treatment of Huntington’s disease using lithium and rapamycin. Hum. Mol Genet. 2008, 17,
170–178. [CrossRef] [PubMed]

195. Lauterbach, E.C.; Shillcutt, S.D.; Victoroff, J.; Coburn, K.L.; Mendez, M.F. Psychopharmacological
neuroprotection in neurodegenerative disease: Heuristic clinical applications. J. Neuropsychiatry Clin. Neurosci. 2010, 22, 130–154. [CrossRef] [PubMed]

Cells 2019, 8, 44 18 of 18

196. Lauterbach, E.C.; Victoroff, J.; Coburn, K.L.; Shillcutt, S.D.; Doonan, S.M.; Mendez, M.F. Psychopharmacological neuroprotection in neurodegenerative disease: Assessing the preclinical data. J. Neuropsychiatry Clin. Neurosci. 2010, 22, 8–18. [CrossRef] [PubMed]

197. Duan,W.;Peng,Q.;Masuda,N.;Ford,E.;Tryggestad,E.;Ladenheim,B.;Zhao,M.;Cadet,J.L.;Wong,J.; Ross, C.A. Sertraline slows disease progression and increases neurogenesis in N171-82Q mouse model of Huntington’s disease. Neurobiol. Dis. 2008, 30, 312–322. [CrossRef] [PubMed]

198. Peng,Q.;Masuda,N.;Jiang,M.;Li,Q.;Zhao,M.;Ross,C.A.;Duan,W.Theantidepressantsertralineimproves the phenotype, promotes neurogenesis and increases BDNF levels in the R6/2 Huntington’s disease mouse model. Exp. Neurol. 2008, 210, 154–163. [CrossRef]

199. Petrascheck,M.;Ye,X.;Buck,L.B.AnantidepressantthatextendslifespaninadultCaenorhabditiselegans. Nature 2007, 450, 553–556. [CrossRef]

200. Morselli,E.;Maiuri,M.C.;Markaki,M.;Megalou,E.;Pasparaki,A.;Palikaras,K.;Criollo,A.;Galluzzi,L.; Malik, S.A.; Vitale, I.; et al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death Dis. 2010, 1, e10. [CrossRef]

201. Colman,R.J.;Beasley,T.M.;Kemnitz,J.W.;Johnson,S.C.;Weindruch,R.;Anderson,R.M.Caloricrestriction reduces age-related and all-cause mortality in rhesus monkeys. Nat. Commun. 2014, 5, 3557. [CrossRef]

202. Lopez-Otin,C.;Galluzzi,L.;Freije,J.M.P.;Madeo,F.;Kroemer,G.MetabolicControlofLongevity.Cell2016, 166, 802–821. [CrossRef] [PubMed]

203. Tsiouris,J.A.;Patti,P.J.;Flory,M.J.Effectsofantidepressantsonlongevityanddementiaonsetamongadults with Down syndrome: A retrospective study. J. Clin. Psychiatry 2014, 75, 731–737. [CrossRef] [PubMed]
© 2019 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (

Leave a Reply

Fill in your details below or click an icon to log in: Logo

You are commenting using your account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

<span>%d</span> bloggers like this: