Review articleCeramides and depression: A systematic review
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)
- et al.
FAN, a novel WD-repeat protein, couples the p55 TNF-receptor to neutral sphingomyelinase
Cell
(1996) - et al.
Ceramide: a common pathway for atherosclerosis?
Atherosclerosis
(2008) - et al.
Ceramide-induced inhibition of Akt is mediated through protein kinase Czeta: implications for growth arrest
J. Biol. Chem.
(2002) - et al.
Depression and cortisol responses to psychological stress: a meta-analysis
Psychoneuroendocrinology
(2005) - et al.
Ceramides - lipotoxic inducers of metabolic disorders
Trends Endocrinol. Metab.
(2015) Sphingolipids: players in the pathology of metabolic disease
Trends Endocrinol. Metab.
(2009)- et al.
Plasma phosphatidylcholine and sphingomyelin concentrations are associated with depression and anxiety symptoms in a Dutch family-based lipidomics study
J. Psychiatr. Res.
(2013) - et al.
Ceramide stimulates a cytosolic protein phosphatase
J. Biol. Chem.
(1992) - et al.
A meta-analysis of cytokines in major depression
Biol. Psychiatry
(2010) - et al.
Major depressive disorder
Neuron
(2000)