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Review
. 2021 Sep 2;14(9):894.
doi: 10.3390/ph14090894.

New Molecular Targets for Antidepressant Drugs

Johannes Kornhuber  1 , Erich Gulbins  2   3
Affiliations
Review

New Molecular Targets for Antidepressant Drugs

Johannes Kornhuber et al. Pharmaceuticals (Basel). .

Abstract

Major depressive disorder (MDD) is a common and severe mental disorder that is usually recurrent and has a high risk of suicide. This disorder manifests not only with psychological symptoms but also multiple changes throughout the body, including increased risks of obesity, diabetes, and cardiovascular disease. Peripheral markers of oxidative stress and inflammation are elevated. MDD is therefore best described as a multisystem whole-body disease. Pharmacological treatment with antidepressants usually requires several weeks before the desired effects manifest. Previous theories of depression, such as the monoamine or neurogenesis hypotheses, do not explain these characteristics well. In recent years, new mechanisms of action have been discovered for long-standing antidepressants that also shed new light on depression, including the sphingolipid system and the receptor for brain-derived neurotrophic factor (BDNF).

Keywords: FIASMA; acid sphingomyelinase; antidepressant drug; autophagy; brain-derived neurotrophic factor (BDNF); ceramide; hippocampus; lysosome; neurogenesis; sphingomyelin.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
MDD is a risk factor for the development of multiple disorders and diseases, such as metabolic syndrome, osteoporosis, and cardiovascular disease. MDD can therefore be conceptualized as a multisystem, whole-body disease.
Figure 2
Figure 2
In recent years, two new molecular targets of antidepressants have been discovered. Many antidepressants functionally inhibit ASM, causing a reduction in ceramide in the cell membrane as a forward effect and a slow increase in sphingomyelin as a backward effect. Sphingomyelin increases autophagy via intermediate steps. Because ceramide in the cell membrane displaces cholesterol, antidepressants increase cholesterol by lowering ceramide levels. Cholesterol enhances TRKB dimerization and, thus, antidepressant binding. The BDNF-TRKB pathway induces autophagy, and so both signaling pathways converge here. A reduction in autophagy is observed in many of the phenomena associated with MDD, and increasing the rate of autophagy is likely to be useful in treating patients with MDD. Abbreviations: ASM, acid sphingomyelinase; BDNF, brain-derived neurotrophic factor; TRKB, tyrosine kinase receptor 2.
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