Certain metabolites may be predictive indicators for persons at risk for recurrent major depressive disorder

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Researchers at University of California San Diego School of Medicine, in collaboration with Dutch scientists, have found that certain metabolites – small molecules produced by the process of metabolism – may be predictive indicators for persons at risk for recurrent major depressive disorder.

The findings were published in the January 11, 2021 online issue of Translational Psychiatry.

“This is evidence for a mitochondrial nexus at the heart of depression,” said senior author Robert K. Naviaux, MD, Ph.D., professor of medicine, pediatrics and pathology at UC San Diego School of Medicine.

“It’s a small study, but it is the first to show the potential of using metabolic markers as predictive clinical indicators of patients at greatest risk – and lower risk – for recurring bouts of major depressive symptoms.”

Recurrent major depressive disorder (in lay terms, clinical depression) is a mood disorder characterized by multiple symptoms in combination: feelings of sadness or hopelessness, anger or frustration, loss of interest, sleep disturbances, anxiety, slowed or difficulty thinking, suicidal thoughts and unexplained physical problems, such as back pain or headaches.

Major depressive disorder (MDD) is among the most common mental illnesses in the United States, with an estimated lifetime prevalence of 20.6 percent, meaning one in five Americans will suffer at least one episode during their lives.

For patients who have recurrent MDD (rMDD), the five-year recurrence risk is up to 80 percent.

For their study, Naviaux and colleagues in The Netherlands recruited 68 subjects (45 females, 23 males) with rMDD who were in antidepressant-free remission and 59 age- and gender-matched controls.

After collecting blood from patients who were in remission, the patients were followed prospectively for two-and-a-half years.

Results showed that a metabolic signature found when patients were well could predict which patients were most likely to relapse up to two-and-a-half years in the future.

The accuracy of this prediction was more than 90 percent. Analysis of the most predictive chemicals found they belong to certain kinds of lipids (fats that included eicosanoids and sphingolipids) and purines.

Purines are made from molecules, such as ATP and ADP – the major chemicals used for energy storage in cells, but which also play a role in communications used by cells under stress, known as purinergic signaling.

The researchers found that in subjects with rMDD, changes in specific metabolites in six identified metabolic pathways resulted in fundamental alterations of important cellular activities.

“The findings revealed an underlying biochemical signature in remitted rMDD that set diagnosed patients apart from healthy controls,” said Naviaux.

“These differences are not visible through ordinary clinical assessment, but suggest that the use of metabolomics – the biological study of metabolites – could be a new tool for predicting which patients are most vulnerable to a recurrence of depressive symptoms.”

The authors noted that their initial findings require validation in a larger study of at least 198 females and 198 males (99 cases and 99 controls each).


Major depressive disorder (MDD) is one of the most common and serious neuropsychiatric disorders with a current prevalence rate of approximately 2.2% in men and 3.3% in women in the general population of China [1]. Among individuals suffering from MDD, an estimated 15% have suicide ideation while as many as 6% is attempt suicide [2].

Most of the individuals with suicide attempts may meet the diagnostic criteria for MDD [3]. Although there are several dedicated suicide risk assessment instruments in clinical practice, such as Beck Hopelessness Scale and Suicide Ideation Scale, it is very difficult to predict and distinguish the individuals who are vulnerable to suicide [4].

An improved understanding of the pathophysiology of suicide risk in patients with MDD is critical for developing specific targeted strategies for prevention and intervention.

Strong evidence has indicated that there are biochemical and morphological abnormalities in certain brain regions of MDD patients and suicide victims [5,6,7]. The purinergic system, which includes not only extracellular nucleosides and nucleotides, such as adenosine and adenosine triphosphate (ATP), but also various receptor subtypes, such as adenosine A1 and A2A receptors, is widely expressed in the central nervous system (CNS) [8].

Several experimental studies have indicated that dysregulation of the purinergic system might play an important role in the pathophysiology of suicide [9,10,11,12] .

Uric acid (UA), as an easily detectable marker, is the final compound generated from the catabolism of purines in humans [13]. As a powerful endogenous antioxidant, UA accounts for more than 60% of free radical scavenging capacity in human blood [14, 15]. Notably, the CNS is considered to be one of the main sites of UA antioxidation [16].

Recently, numerous clinical data suggest that UA might be one of the potential contributing factors in behavioural and neuronal responses. For example, abnormal serum UA levels have been reported in individuals with cognitive dysfunction, dementia, schizophrenia, bipolar disorder, and sleep disorder [17,18,19,20].

The potential involvement of oxidative/antioxidant function in MDD has been demonstrated [21]. Unfortunately, investigations about the causal relationship between UA and MDD have produced inconsistent results and there is still no conclusive evidence [22,23,24].

To date, few studies have been designed to explore the association between UA and suicide. Recently, promising findings from Bartoli and his team have shown an inverse relationship between UA levels and severity of suicidal ideation in individuals with major affective disorders [25, 26] . However, some confounding factors such as glucose and lipid metabolism, renal function and prescribed medications were not controlled in these studies.

In consideration of the relationship between UA levels and MDD or suicide risk remains poorly understood, we carried out this study aimed at investigating and comparing serum UA levels in MDD patients with or without suicide risk. It is well known that females are more likely to suffer from depression and to attempt suicide [27, 28] than males, and sex is one of the most important factors affecting serum UA levels.

Previous evidence indicates that UA levels in men are higher than those in women in both the normal population and MDD patients [26]. Moreover, antidepressant treatment may significantly affect serum UA levels [29]. Therefore, only untreated female subjects were allowed to participate in the present study. Based on existing data, we generated the following hypotheses: 1) serum UA levels in the patient groups would be significantly lower than those in the healthy control group [2]; there would be a significant relationship between decreased serum UA levels and suicide risk in patients with MDD.

reference link : https://bmcpsychiatry.biomedcentral.com/articles/10.1186/s12888-020-02891-8


More information: Roel J. T. Mocking et al. Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence, Translational Psychiatry (2021). DOI: 10.1038/s41398-020-01182-w

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