Plasma acetyl-l-carnitine and l-carnitine in major depressive episodes: a case–control study before and after treatment
TL;DR: A decreased mitochondrial metabolism of l-carnitine into ALC during MDE is restored after a 6-month antidepressant treatment and the magnitude of mitochondrial dysfunction may predict remission after 3 months of antidepressant treatment.
Abstract: BACKGROUND
Major depressive disorder (MDD) is the main cause of disability worldwide, its outcome is poor, and its underlying mechanisms deserve a better understanding. Recently, peripheral acetyl-l-carnitine (ALC) has been shown to be lower in patients with major depressive episodes (MDEs) than in controls. l-Carnitine is involved in mitochondrial function and ALC is its short-chain acetyl-ester. Our first aim was to compare the plasma levels of l-carnitine and ALC, and the l-carnitine/ALC ratio in patients with a current MDE and healthy controls (HCs). Our second aim was to assess their changes after antidepressant treatment.
METHODS
l-Carnitine and ALC levels and the carnitine/ALC ratio were measured in 460 patients with an MDE in a context of MDD and in 893 HCs. Depressed patients were re-assessed after 3 and 6 months of antidepressant treatment for biology and clinical outcome.
RESULTS
As compared to HC, depressed patients had lower ALC levels (p < 0.00001), higher l-carnitine levels (p < 0.00001) and higher l-carnitine/ALC ratios (p < 0.00001). ALC levels increased [coefficient: 0.18; 95% confidence interval (CI) 0.12-0.24; p < 0.00001], and l-carnitine levels (coefficient: -0.58; 95% CI -0.75 to -0.41; p < 0.00001) and l-carnitine/ALC ratios (coefficient: -0.41; 95% CI -0.47 to -0.34; p < 0.00001), decreased after treatment. These parameters were completely restored after 6 months of antidepressant. Moreover, the baseline l-carnitine/ALC ratio predicted remission after 3 months of treatment (odds ratio = 1.14; 95% CI 1.03-1.27; p = 0.015).
CONCLUSIONS
Our data suggest a decreased mitochondrial metabolism of l-carnitine into ALC during MDE. This decreased mitochondrial metabolism is restored after a 6-month antidepressant treatment. Moreover, the magnitude of mitochondrial dysfunction may predict remission after 3 months of antidepressant treatment. New strategies targeting mitochondria should be explored to improve treatments of MDD.
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TL;DR: In this paper , the authors identify serum, plasma and erythrocyte biomarkers of oxidative stress in major depressive disorder patients according to disease stage and clinical features, and identify modifications to antioxidant enzymes (mainly glutathione peroxidase and superoxide dismutase) in MDD patients.
Abstract: Major depressive disorder (MDD) is currently the main cause of disability worldwide, but its pathophysiology remains largely unknown, especially given its high heterogeneity in terms of clinical phenotypes and biological characteristics. Accordingly, its management is still poor. Increasing evidence suggests that oxidative stress, measured on various matrices such as serum, plasma or erythrocytes, has a critical role in MDD. The aim of this narrative review is to identify serum, plasma and erythrocyte biomarkers of oxidative stress in MDD patients according to disease stage and clinical features. Sixty-three articles referenced on PubMed and Embase between 1 January 1991, and 31 December 2022, were included. Modifications to antioxidant enzymes (mainly glutathione peroxidase and superoxide dismutase) in MDD were highlighted. Non-enzymatic antioxidants (mainly uric acid) were decreased in depressed patients compared to healthy controls. These changes were associated with an increase in reactive oxygen species. Therefore, increased oxidative damage products (principally malondialdehyde, protein carbonyl content and 8-hydroxy-2′-deoxyguanosine) were present in MDD patients. Specific modifications could be identified according to disease stages and clinical features. Interestingly, antidepressant treatment corrected these changes. Accordingly, in patients in remission from depression, oxidative stress markers were globally normalized. This narrative review suggests the particular interest of oxidative stress biomarkers for MDD care that may contribute to the heterogeneity of the disease and provide the opportunity to find new therapeutic targets.
2 citations
TL;DR: In this article , the authors assessed metabolomic profiles of 38 acylcarnitines in patients with major depression before and after treatment compared to healthy controls (HCs) and found that depressed patients had lower levels of medium-and long-chain acyl-carmitines.
Abstract: Abstract Background Major depression is associated with changes in plasma L-carnitine and acetyl-L-carnitine. But its association with acylcarnitines remains unclear. The aim of this study was to assess metabolomic profiles of 38 acylcarnitines in patients with major depression before and after treatment compared to healthy controls (HCs). Methods Metabolomic profiles of 38 plasma short-, medium-, and long-chain acylcarnitines were performed by liquid chromatography-mass spectrometry in 893 HCs from the VARIETE cohort and 460 depressed patients from the METADAP cohort before and after 6 months of antidepressant treatment. Results As compared to HCs, depressed patients had lower levels of medium- and long-chain acylcarnitines. After 6 months of treatment, increased levels of medium- and long-chain acyl-carnitines were observed that no longer differed from those of controls. Accordingly, several medium- and long-chain acylcarnitines were negatively correlated with depression severity. Conclusions These medium- and long-chain acylcarnitine dysregulations argue for mitochondrial dysfunction through fatty acid β -oxidation impairment during major depression.
TL;DR: Depression score decreased in both groups over time, and Supplementation of L-carnitine to sertraline in patients with MDD did not show a significant effect on the improvement of depression severity.
Abstract:
Despite the various treatment approaches proposed for major depressive disorder (MDD), the right treatment protocol for different patients is not the same. Supplementation of L-carnitine to antidepressants has been recommended in some studies; however, different results have been reported. This study aimed to evaluate the effectiveness of adding L-carnitine to sertraline in the treatment of patients diagnosed with MDD.
This double-blind randomized controlled trial was conducted on 60 patients with MDD. The severity of the depressive disorder, as the primary research outcome, was assessed using the Beck depression inventory. The intervention group received 1000 mg of daily L-carnitine oral capsule along with 100 mg of sertraline; and the control group received a placebo (oral capsule containing 1000 mg of starch), along with 100 mg of sertraline every day. The primary outcome was assessed at baseline, the 3rd, and the 6th week.
Although depression score decreased in both groups over time, the difference between the two groups was not significant (P = 0.634). Three patients reported adverse side effects; however, the difference between the two groups was not significant (P = 0.554).
Supplementation of L-carnitine to sertraline in patients with MDD did not show a significant effect on the improvement of depression severity.
References
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TL;DR: The present scale has been devised for use only on patients already diagnosed as suffering from affective disorder of depressive type, used for quantifying the results of an interview, and its value depends entirely on the skill of the interviewer in eliciting the necessary information.
Abstract: Types of Rating Scale The value of this one, and its limitations, can best be considered against its background, so it is useful to consider the limitations of the various rating scales extant. They can be classified into four groups, the first of which has been devised for use on normal subjects. Patients suffering from mental disorders score very highly on some of the variables and these high scores serve as a measure of their illness. Such scales can be very useful, but have two defects: many symptoms are not found in normal persons; and less obviously, but more important, there is a qualitative difference between symptoms of mental illness and normal variations of behaviour. The difference between the two is not a philosophical problem but a biological one. There is always a loss of function in illness, with impaired efficiency. Self-rating scales are popular because they are easy to administer. Aside from the notorious unreliability of self-assessment, such scales are of little use for semiliterate patients and are no use for seriously ill patients who are unable to deal with them. Many rating scales for behaviour have been devised for assessing the social adjustment of patients and their behaviour in the hospital ward. They are very useful for their purpose but give little or no information about symptoms. Finally, a number of scales have been devised specifically for rating symptoms of mental illness. They cover the whole range of symptoms, but such all-inclusiveness has its disadvantages. In the first place, it is extremely difficult to differentiate some symptoms, e.g., apathy, retardation, stupor. These three look alike, but they are quite different and appear in different settings. Other symptoms are difficult to define, except in terms of their settings, e.g., mild agitation and derealization. A more serious difficulty lies in the fallacy of naming. For example, the term "delusions" covers schizophrenic, depressive, hypochrondriacal, and paranoid delusions. They are all quite different and should be clearly distinguished. Another difficulty may be summarized by saying that the weights given to symptoms should not be linear. Thus, in schizophrenia, the amount of anxiety is of no importance, whereas in anxiety states it is fundamental. Again, a schizophrenic patient who has delusions is not necessarily worse than one who has not, but a depressive patient who has, is much worse. Finally, although rating scales are not used for making a diagnosis, they should have some relation to it. Thus the schizophrenic patients should have a high score on schizophrenia and comparatively small scores on other syndromes. In practice, this does not occur. The present scale has been devised for use only on patients already diagnosed as suffering from affective disorder of depressive type. It is used for quantifying the results of an interview, and its value depends entirely on the skill of the interviewer in eliciting the necessary information. The interviewer may, and should, use all information available to help him with his interview and in making the final assessment. The scale has undergone a number of changes since it was first tried out, and although there is room for further improvement, it will be found efficient and simple in use. It has been found to be of great practical value in assessing results of treatment.
29,488 citations
TL;DR: The response and remission rates in this highly generalizable sample with substantial axis I and axis III comorbidity closely resemble those seen in 8-week efficacy trials.
Abstract: OBJECTIVE: Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat depression, but the rates, timing, and baseline predictors of remission in “real world” patients are not established. The authors’ primary objectives in this study were to evaluate the effectiveness of citalopram, an SSRI, using measurement-based care in actual practice, and to identify predictors of symptom remission in outpatients with major depressive disorder. METHOD: This clinical study included outpatients with major depressive disorder who were treated in 23 psychiatric and 18 primary care “real world” settings. The patients received flexible doses of citalopram prescribed by clinicians for up to 14 weeks. The clinicians were assisted by a clinical research coordinator in the application of measurement-based care, which included the routine measurement of symptoms and side effects at each treatment visit and the use of a treatment manual that described when and how to modify medication doses based on these measures....
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TL;DR: The QIDS-SR(16) has highly acceptable psychometric properties, which supports the usefulness of this brief rating of depressive symptom severity in both clinical and research settings.
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TL;DR: Recommendations suggest that symptom ratings that measure all nine criterion symptom domains to define a major depressive episode are preferred as they provide a more certain ascertainment of remission.
582 citations
TL;DR: This study focused on characterizing AcylCN profiles in human plasma from individuals with obesity and T2DM during fasting and insulin‐stimulated conditions, suggesting that more fatty acids can enter mitochondria.
Abstract: Dysregulation of fatty acid oxidation (FAO) is recognized as important in the pathophysiology of obesity and insulin resistance (IR). However, demonstrating FAO defects in vivo in humans has entailed complex and invasive methodologies. Recently, the identification of genetic blocks in FAO has been vastly simplified by using tandem mass spectrometry (MS/MS) of dried bloodspots to specify acylcarnitine (AcylCN) alterations characteristic for each disorder. This technology has recently been applied to examine FAO alterations in human and animal models of obesity and type 2 diabetes mellitus (T2DM). This study focused on characterizing AcylCN profiles in human plasma from individuals with obesity and T2DM during fasting and insulin-stimulated conditions. Following an overnight fast, plasma was obtained from lean (n = 12), obese nondiabetic (n = 14), and T2DM (n = 10) participants and analyzed for AcylCN using MS/MS. Plasma samples were also obtained at the end of a 4-h insulin-stimulated euglycemic clamp. In obesity and T2DM, long-chain AcylCNs were similarly significantly increased in the fasted state; free-CN levels were also elevated. Additionally, T2DM subjects of comparable BMI had increased short- and medium-chain AcylCNs, both saturated and hydroxy, as well as increased C(4)-dicarboxylcarnitine (C(4)DC-CN) that correlated with an index of poor glycemic control (HbA(1c); r = 0.74; P < 0.0001). Insulin infusion reduced all species of plasma AcylCN but this reduction was blunted in T2DM. Plasma long-chain AcylCN species are increased in obesity and T2DM, suggesting that more fatty acids can enter mitochondria. In T2DM, many shorter species accumulate, suggesting that they have a generalized complex oxidation defect.
531 citations