Elsevier

Journal of Affective Disorders

Volume 213, 15 April 2017, Pages 35-43
Journal of Affective Disorders

Review article
Ceramides and depression: A systematic review

https://doi.org/10.1016/j.jad.2017.02.008Get rights and content

Highlights

  • Aberrant sphingolipid metabolism is commonly present in depression.

  • Ceramides have been implicated in depression due to pro-apoptotic characteristics.

  • Ceramides C18:0 and C20:0 are most strongly linked to depression in humans.

  • Pharmacologic reduction of certain ceramide species should be explored as treatment.

Abstract

Background

Major depressive disorder is a significant contributor to global disability and mortality. The mechanisms of depression are vast and not fully understood, and as a result current treatment of depression is suboptimal. Aberrant sphingolipid metabolism has been observed in some cases of depression, specifically alterations in ceramide concentrations. The role of ceramides and other sphingolipids in depression is a novel concept. This review summarizes and evaluates the current state of evidence for a role of ceramides in depression pathophysiology and the potential for novel depression pharmacotherapies targeting ceramide metabolism.

Methods

Medline, Embase, and PsycINFO databases were searched through October 2016 for English-language studies using combinations of the search terms: ceramide, depression, sphingolipid, and depressive symptoms.

Results

Of the 489 articles screened, 14 were included in the qualitative synthesis of this review article. Pre-clinical and clinical evidence suggest that ceramide species may contribute to depression pathophysiology. In human studies, ceramides C18:0 and C20:0 are the species most strongly linked to depression. Evidence for altered ceramide metabolism in depression is present, but data for a causal role of ceramides in depression are lacking.

Limitations

This review was limited by potential reporting bias. Furthermore, a lack of specificity of which ceramides were altered in depression was common.

Conclusions

Pharmacotherapy targeting ceramide metabolism may be a novel treatment option for depression. A number of pharmacological targets exists for ceramide reduction and a number of currently approved medications inhibit ceramide production. More evidence, pre-clinical and clinical, is warranted to determine the extent and consistency of the role of ceramides in depression.

Introduction

Major depressive disorder (MDD) is defined by persistent feelings of sadness and reduced responsiveness to pleasurable stimuli, affecting how people think, feel and behave (Belmaker and Agam, 2008). MDD can also consist of somatic symptoms, such as insomnia, poor appetite, and weight loss or gain (Belmaker and Agam, 2008). Approximately 1 in every 10 individuals will experience depression in their lifetime (Lepine and Briley, 2011). MDD is the second leading cause of disability worldwide, as measured by years lived with disability, and a major contributor to the burden of suicide (Ferrari et al., 2013). Beyond suicide-related mortality, depression also increases risk of mortality due to other medical illnesses (Rovner et al., 1991, Wulsin et al., 1999). Dysthymia and depressive symptoms, psychological constructs related to depression but of a severity less than that of MDD, are also important illnesses that result in disability and economic costs (Akiskal, 1994, Ruo et al., 2003). Depression and its related disorders are important, and understanding their mechanisms will help us develop enhanced treatments for these disorders, alleviating the burden of these diseases.

Currently, the main treatment options for depression include psychotherapy, pharmacotherapy, and electroconvulsive therapy (Fava and Kendler, 2000). More than half of all individuals with MDD will not achieve remission after initial treatment with an antidepressant, and of this group, 30–50% will not respond at all to initial antidepressant treatment (Mrazek et al., 2014). Moreover, approximately half of all cases of MDD will not achieve remission after multiple trials of antidepressant treatment (McIntyre et al., 2014). This has given rise to the term treatment-resistant depression (TRD), describing individuals who do not respond to conventional antidepressant treatments or psychotherapy (McIntyre et al., 2014). Individuals with TRD contribute a disproportionately high burden of illness compared to those with depression who respond to treatment (Mrazek et al., 2014). Low response rates to current antidepressants and other conventional depression treatments, along with high rates of TRD, have motivated the search for new pharmacotherapies and other treatments for depression. A better understanding of the etiology and mechanisms of depression, as well as its biological correlates, is needed to inform new pharmacotherapies for the treatment of depression.

Sphingolipids, in particular ceramides, have been suggested as a novel therapeutic target for depression due to their potential roles in its pathophysiology (Kornhuber et al., 2014, Kornhuber et al., 2009). Ceramides have been linked to multiple pathophysiological mechanisms of depression including neurodegeneration and elevated inflammation (Bieberich, 2012, Kornhuber et al., 2014). This review will summarize and evaluate the current state of evidence for a role of ceramides in depression and the potential for novel pharmacotherapies for depression targeting ceramide metabolism.

Section snippets

Search strategy

English-language studies published through October 2016 were identified using Medline, Embase, and PsycINFO databases. The following search terms were used for all databases using the operator AND: ceramide, sphingolipid, depression, depressive symptoms (e.g. ceramide AND depression, sphingolipid AND depressive symptoms, etc.). Reference sections of identified articles were examined to attempt to identify articles not captured by this search. Abstracts of all articles identified in the search

Sphingolipids and depression

Sphingolipids are a major lipid class that make up a significant portion of brain membrane lipids (Muller et al., 2015, Vajn et al., 2013). Different classes of sphingolipids exist, including ceramides, sphingomyelins, cerebrosides, gangliosides, and sphingosines (Abe and Norton, 1974). In addition to their structural role as a physical barrier between the intracellular and extracellular environment, sphingolipids can alter the localization, oligomerization, and function of proteins, including

Ceramides

Ceramides, a family of sphingolipids, consist of a sphingoid base linked to a fatty acid via an amide bond (Bikman and Summers, 2011). They are formed as key intermediates in the biosynthesis of all complex sphingolipids such as sphingomyelins, cerebrosides, and gangliosides (Gangoiti et al., 2010). Ceramides are produced via three different pathways. They can be generated by de novo synthesis starting from palmitoyl-CoA and serine in a multi-step pathway (Chaurasia and Summers, 2015, Jenkins

Potential neurobiological mechanisms

Preclinical (Grassme et al., 2015, Gulbins et al., 2016, Gulbins et al., 2013, Jernigan et al., 2015, Kornhuber et al., 2014, Kornhuber et al., 2009, Muller et al., 2015, Oliveira et al., 2016, Schneider et al., 2016) and clinical (Demirkan et al., 2013, Gracia-Garcia et al., 2011, Kornhuber et al., 2005, Mielke et al., 2013, Rhein et al., 2016, Xing et al., 2016b) evidence implicates ceramides as having a potential role in the pathophysiology of depression. A common feature of depression is a

Potential for treatment

If specific ceramides are found to be implicated in depression, novel pharmacotherapies aimed at reducing their concentrations may be an effective strategy in treating depression and depressive symptoms. Already, candidate drugs that reduce ceramide concentrations exist (Cinar et al., 2014, Kornhuber et al., 2010, Miyake et al., 1995). Myriocin, an antibiotic derived from certain fungi, has been shown to be a potent inhibitor of serine palmitoyltransferase (SPT), an important enzyme in the de

Limitations

Although evidence that ceramide metabolism is aberrant in depression is promising, little evidence exists for a causal role of ceramides in depression pathophysiology. Some animal evidence exists that increases in C16:0 concentration in the brain may cause depression-like behavior (Gulbins et al., 2013); however, this effect has only been reported by one research group and thus must be replicated by other groups to evaluate its validity and consistency. Most evidence for a role of ceramides in

Conclusions

Evidence in both animals and humans has accumulated that suggests abnormal ceramide concentrations may play a role in the initiation and/or progression of depression. In particular, ceramides C18:0 and C20:0 appear to be promising candidates for a pathophysiological role in depression. The potential neurobiological mechanisms by which ceramides may cause depression are biologically plausible and focus on ceramide-induced neuro-inflammation and neurodegeneration as well as modification of cell

Acknowledgements

The authors acknowledge operating funds from the Ontario Mental Health Foundation and the Canadian Institutes of Health Research (CIHR) MOP 114913 to KLL and NH. All authors report no competing or financial interests.

References (123)

  • P. Gangoiti et al.

    Control of metabolism and signaling of simple bioactive sphingolipids: implications in disease

    Prog. Lipid Res.

    (2010)
  • D. Gebreselassie et al.

    Sigma-2 receptors are specifically localized to lipid rafts in rat liver membranes

    Eur. J. Pharm.

    (2004)
  • F.M. Goni et al.

    Sphingomyelinases: enzymology and membrane activity

    FEBS Lett.

    (2002)
  • H. Grassme et al.

    CD95 signaling via ceramide-rich membrane rafts

    J. Biol. Chem.

    (2001)
  • H. Grassme et al.

    Molecular mechanisms of ceramide-mediated CD95 clustering

    Biochem Biophys. Res. Commun.

    (2001)
  • F.A. Henn et al.

    Neurogenesis and depression: etiology or epiphenomenon?

    Biol. Psychiatry

    (2004)
  • T. Herget et al.

    Production of ceramides causes apoptosis during early neural differentiation in vitro

    J. Biol. Chem.

    (2000)
  • M.R. Hojjati et al.

    Effect of myriocin on plasma sphingolipid metabolism and atherosclerosis in apoE-deficient mice

    J. Biol. Chem.

    (2005)
  • M. Jafurulla et al.

    Effect of sphingomyelinase treatment on ligand binding activity of human serotonin1A receptors

    Biochim. Biophys. Acta

    (2008)
  • S. Jayadev et al.

    Role for ceramide in cell cycle arrest

    J. Biol. Chem.

    (1995)
  • G.M. Jenkins et al.

    Acute activation of de novo sphingolipid biosynthesis upon heat shock causes an accumulation of ceramide and subsequent dephosphorylation of SR proteins

    J. Biol. Chem.

    (2002)
  • J. Kornhuber et al.

    The ceramide system as a novel antidepressant target

    Trends Pharm. Sci.

    (2014)
  • K. Leidl et al.

    Mass spectrometric analysis of lipid species of human circulating blood cells

    Biochim. Biophys. Acta

    (2008)
  • G. Liebisch et al.

    Quantitative measurement of different ceramide species from crude cellular extracts by electrospray ionization tandem mass spectrometry (ESI-MS/MS)

    J. Lipid Res.

    (1999)
  • R.S. McIntyre et al.

    Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach

    J. Affect Disord.

    (2014)
  • D.P. McKernan et al.

    "Killing the blues": a role for cellular suicide (apoptosis) in depression and the antidepressant response?

    Prog. Neurobiol.

    (2009)
  • G.L. Ming et al.

    Adult neurogenesis in the mammalian brain: significant answers and significant questions

    Neuron

    (2011)
  • Y. Miyake et al.

    Serine palmitoyltransferase is the primary target of a sphingosine-like immunosuppressant, ISP-1/myriocin

    Biochem. Biophys. Res. Commun.

    (1995)
  • C.P. Muller et al.

    Brain membrane lipids in major depression and anxiety disorders

    Biochim. Biophys. Acta

    (2015)
  • T. Okazaki et al.

    Sphingomyelin turnover induced by vitamin D3 in HL-60 cells. role in cell differentiation

    J. Biol. Chem.

    (1989)
  • A. Olivera et al.

    Differential effects of sphingomyelinase and cell-permeable ceramide analogs on proliferation of Swiss 3T3 fibroblasts

    Biochim. Biophys. Acta

    (1997)
  • T.S. Park et al.

    Serine palmitoyltransferase inhibitor myriocin induces the regression of atherosclerotic plaques in hyperlipidemic ApoE-deficient mice

    Pharm. Res.

    (2008)
  • B.J. Pettus et al.

    Ceramide in apoptosis: an overview and current perspectives

    Biochim Biophys. Acta

    (2002)
  • C.L. Raison et al.

    Cytokines sing the blues: inflammation and the pathogenesis of depression

    Trends Immunol.

    (2006)
  • E.L. Riddle et al.

    Ceramide-induced alterations in dopamine transporter function

    Eur. J. Pharm.

    (2003)
  • P.P. Ruvolo et al.

    Ceramide induces Bcl2 dephosphorylation via a mechanism involving mitochondrial PP2A

    J. Biol. Chem.

    (1999)
  • T. Abe et al.

    The characterization of sphingolipids from neurons and astroglia of immature rat brain

    J. Neurochem.

    (1974)
  • J.M. Adams et al.

    Ceramide content is increased in skeletal muscle from obese insulin-resistant humans

    Diabetes

    (2004)
  • A. Adibfar et al.

    Potential biomarkers for depression associated with coronary artery disease: a critical review

    Curr. Mol. Med.

    (2016)
  • H.S. Akiskal

    Dysthymia: clinical and external validity

    Acta Psychiatr. Scand. Suppl.

    (1994)
  • J. Altman et al.

    Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats

    J. Comp. Neurol.

    (1965)
  • Babenko, N., Hassouneh, L., Budvytiene, M., Liesiene, J., Geilen, C., 2010. Natural C18:0-ceramide induces cellular...
  • N. Beckmann et al.

    Inhibition of acid sphingomyelinase by tricyclic antidepressants and analogons

    Front Physiol.

    (2014)
  • R.H. Belmaker et al.

    Major depressive disorder

    N. Engl. J. Med.

    (2008)
  • E. Bieberich

    It's a lipid's world: bioactive lipid metabolism and signaling in neural stem cell differentiation

    Neurochem. Res.

    (2012)
  • B.T. Bikman et al.

    Ceramides as modulators of cellular and whole-body metabolism

    J. Clin. Invest.

    (2011)
  • S. Chiantia et al.

    Raft domain reorganization driven by short- and long-chain ceramide: a combined AFM and FCS study

    Langmuir

    (2007)
  • W. Christie

    Ceramides

    (2014)
  • R. Cinar et al.

    Hepatic cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing de novo synthesis of long-chain ceramides

    Hepatology

    (2014)
  • S. Elmore

    Apoptosis: a review of programmed cell death

    Toxicol. Pathol.

    (2007)
  • Cited by (0)

    View full text