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. 2023 Jun 2;12(6):1208.
doi: 10.3390/antiox12061208.

Different Effects of SSRIs, Bupropion, and Trazodone on Mitochondrial Functions and Monoamine Oxidase Isoform Activity

Matej Ľupták  1 , Zdeněk Fišar  2 , Jana Hroudová  1   2
Affiliations

Different Effects of SSRIs, Bupropion, and Trazodone on Mitochondrial Functions and Monoamine Oxidase Isoform Activity

Matej Ľupták et al. Antioxidants (Basel). .

Abstract

Mitochondrial dysfunction is involved in the pathophysiology of psychiatric and neurodegenerative disorders and can be used as a modulator and/or predictor of treatment responsiveness. Understanding the mitochondrial effects of antidepressants is important to connect mitochondria with their therapeutic and/or adverse effects. Pig brain-isolated mitochondria were used to evaluate antidepressant-induced changes in the activity of electron transport chain (ETC) complexes, monoamine oxidase (MAO), mitochondrial respiratory rate, and ATP. Bupropion, escitalopram, fluvoxamine, sertraline, paroxetine, and trazodone were tested. All tested antidepressants showed significant inhibition of complex I and IV activities at high concentrations (50 and 100 µmol/L); complex II + III activity was reduced by all antidepressants except bupropion. Complex I-linked respiration was reduced by escitalopram >> trazodone >> sertraline. Complex II-linked respiration was reduced only by bupropion. Significant positive correlations were confirmed between complex I-linked respiration and the activities of individual ETC complexes. MAO activity was inhibited by all tested antidepressants, with SSRIs causing a greater effect than trazodone and bupropion. The results indicate a probable association between the adverse effects of high doses of antidepressants and drug-induced changes in the activity of ETC complexes and the respiratory rate of mitochondria. In contrast, MAO inhibition could be linked to the antidepressant, procognitive, and neuroprotective effects of the tested antidepressants.

Keywords: ATP; antidepressants; mitochondrial respiration; monoamine oxidase; oxidative phosphorylation; reactive oxygen species.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Diagram of the electron transport chain and the structure of ATP synthase. Reduced nicotinamide adenine dinucleotide (NADH) donates electrons (blue arrows) that pass through complex I via flavin mononucleotide (FMN) and iron-sulfur (Fe-S) clusters. Together with two protons, they bind to oxidized coenzyme Q (CoQ) to form reduced coenzyme Q (CoQH2). This electron flow allows four H+ (red arrows) to be transported into the intermembrane space. Complex II is the electron side entrance, as electrons from succinate pass through oxidized flavin adenine dinucleotide (FAD+) and Fe-S before forming CoQH2. Electrons then flow from CoQH2 to complex III, and through cytochrome c (Cyt c) to complex IV. In total, ten H+ are transported into the intermembrane space for each NADH or six H+ for each FADH2. The stator (blue) and the rotor (green) form complex V. The FO domain of ATP synthase consists of three a subunits, three b subunits, and ten c subunits forming the c-ring. The a subunit contains the H+ ion half-channel, which is responsible for mediating proton movement across the membrane. The α and β subunits of F1 form a hexamer on the top of the γ subunit, which is inserted into the c-ring. Adapted from Ľupták et al. [3].
Figure 2
Figure 2
Enzymatic reactions catalyzed by monoamine oxidase (adapted from Fišar et al.) [23]. Monoamines (e.g., dopamine, serotonin, or norepinephrine) are metabolized by oxidative deamination (along with oxygen and water) catalyzed by monoamine oxidase (MAO) to form aldehyde, ammonia, and hydrogen peroxide. Subsequently, aldehyde dehydrogenase oxidizes aldehydes into carboxylic acids, and hydrogen peroxide can be further converted to hydroxyl radical.
Figure 3
Figure 3
SSRI-induced changes in the activity of electron transport chain (ETC) complexes (complex I, complex II + III and complex IV, (A–C), respectively). Relative activity is expressed as the percentage difference from the activity of the control sample, with the mean value and standard deviation (SD) calculated from at least three independent measurements. A one-sample t-test was performed to assess statistical significance, with the mean control value set at 100% and is expressed as * p ˂ 0.05. ** p ˂ 0.01. *** p ˂ 0.001. Drug concentrations are expressed in µm/L. ESC—escitalopram, FLUV—fluvoxamine, PAR—paroxetine, SER—sertraline.
Figure 3
Figure 3
SSRI-induced changes in the activity of electron transport chain (ETC) complexes (complex I, complex II + III and complex IV, (A–C), respectively). Relative activity is expressed as the percentage difference from the activity of the control sample, with the mean value and standard deviation (SD) calculated from at least three independent measurements. A one-sample t-test was performed to assess statistical significance, with the mean control value set at 100% and is expressed as * p ˂ 0.05. ** p ˂ 0.01. *** p ˂ 0.001. Drug concentrations are expressed in µm/L. ESC—escitalopram, FLUV—fluvoxamine, PAR—paroxetine, SER—sertraline.
Figure 4
Figure 4
Bupropion- and trazodone-induced changes in the activity of electron transport chain (ETC) complexes (complex I, complex II + III and complex IV, (A–C), respectively). Relative activity is expressed as the percentage difference from the activity of the control sample, with the mean value and standard deviation (SD) calculated from at least three independent measurements. A one-sample t-test was performed to assess statistical significance, with the mean control value set at 100% and is expressed as * p ˂ 0.05. ** p ˂ 0.01. *** p ˂ 0.001. Drug concentrations are expressed in µm/L. BUP—bupropion, TRA—trazodone.
Figure 4
Figure 4
Bupropion- and trazodone-induced changes in the activity of electron transport chain (ETC) complexes (complex I, complex II + III and complex IV, (A–C), respectively). Relative activity is expressed as the percentage difference from the activity of the control sample, with the mean value and standard deviation (SD) calculated from at least three independent measurements. A one-sample t-test was performed to assess statistical significance, with the mean control value set at 100% and is expressed as * p ˂ 0.05. ** p ˂ 0.01. *** p ˂ 0.001. Drug concentrations are expressed in µm/L. BUP—bupropion, TRA—trazodone.
Figure 5
Figure 5
Effect of antidepressants on respiration in isolated mitochondria (complex I-linked respiration, complex II-linked respiration, (A,B), respectively). The dose-response curves are represented by the oxygen consumption rate plotted against drug concentration. The respiratory rate of the sample titrated with the antidepressants is relative to the control sample titrated with the DMSO (solvent). Four different measurements were used to calculate the plot points. Statistical significance was tested using a one-sample t-test with a mean control value of 100%, indicated as * p ˂ 0.05. ** p ˂ 0.01. *** p ˂ 0.001. Table 1 shows the half-maximal inhibitory concentration (IC50), Hill slope, and the residual activity calculated using a four-parameter logistic function. BUP—bupropion, ESC—escitalopram, FLUV—fluvoxamine, PAR—paroxetine, SER—sertraline, TRA—trazodone.
Figure 6
Figure 6
Antidepressant-induced changes in complex I-linked ATP content and kinetics (ATP content, ATP kinetics, (A,B), respectively). Relative activity is expressed as the percentage difference from the activity of the control sample (100% corresponded to the production of (A) 160 nmol of ATP per 1 mg of protein and (B) 282 nmol of ATP per 1 mg of protein per 1 min), with the mean value and standard deviation (SD) calculated from at least six independent measurements. A one-sample t-test was performed to assess statistical significance, with the mean control value set at 100% and is expressed as * p ˂ 0.05. ** p ˂ 0.01. Drug concentrations are expressed in µm/L. BUP—bupropion, ESC—escitalopram, FLUV—fluvoxamine, PAR—paroxetine, SER—sertraline, TRA—trazodone.
Figure 7
Figure 7
Antidepressant-induced changes in complex II-linked ATP content and kinetics (ATP content, ATP kinetics, (A,B), respectively). Relative activity is expressed as the percentage difference from the activity of the control sample (100% corresponded to the production of (A) 291 nmol of ATP per 1 mg of protein and (B) 1289 nmol of ATP per 1 mg of protein per 1 min), with the mean value and standard deviation (SD) calculated from at least six independent measurements. A one-sample t-test was performed to assess statistical significance, with the mean control value set at 100% and is expressed as * p ˂ 0.05. ** p ˂ 0.01. Drug concentrations are expressed in µm/L. BUP—bupropion, ESC—escitalopram, FLUV—fluvoxamine, PAR—paroxetine, SER—sertraline, TRA—trazodone.
Figure 8
Figure 8
Antidepressant-induced inhibition of MAO activity (MAO-A, MAO-B, (A,B), respectively). Relative activity is expressed as the percentage difference from the activity of the control sample. A one-sample t-test was performed to evaluate statistical significance with the mean control value set at 100% and is expressed as * p ˂ 0.05. ** p ˂ 0.01. *** p ˂ 0.001. Table 2 shows the calculated half-maximal inhibitory concentration (IC50), Hill slope, and the residual activity. Drug concentrations are expressed in μmol/L. BUP—bupropion, ESC—escitalopram, FLUV—fluvoxamine, PAR—paroxetine, SER—sertraline, TRA—trazodone.
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