Serum copper and zinc levels correlate with biochemical metabolite ratios in the prefrontal cortex and lentiform nucleus of patients with major depressive disorder

Liu, Xuanjun; Zhong, Shuming; Li, Zhinan; Chen, Junhao; Wang, Ying; Lai, Shunkai; Miao, Haofei; Jia, Yanbin

doi:10.1016/j.pnpbp.2019.109828

Cited by 25 publications

(12 citation statements)

References 66 publications

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“…Previous analyses of 1 H-MRS-derived NAA levels in MDD found no convincing evidence of cerebral NAA alterations in MDD (22,23). Contrary to what we show here, two previous reports could not demonstrate a reduction of NAA levels in the frontal lobe of patients with MDD as compared to HC, either because their analysis lacked power (n = 8 and n = 11 versus n = 26) or because more negative effect sizes emerged from more recent studies (77,86). Our findings expand and confirm their negative findings within the BG (23).…”

Section: Discussioncontrasting

confidence: 99%

Proton magnetic resonance spectroscopy of N-acetyl aspartate in first depressive episode and chronic major depressive disorder: a systematic review and meta-analysis

Saccaro

Tassone

Tozzi

et al. 2022

Preprint

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Background: N-acetyl aspartate (NAA) is a marker of neuronal integrity and metabolism. Deficiency in neuronal plasticity and hypometabolism are implicated in the pathophysiology of Major Depressive Disorder (MDD). To test if cerebral NAA concentrations decrease progressively over the MDD course, we conducted a meta-analysis of Proton Magnetic Resonance Spectroscopy (1H-MRS) studies comparing NAA concentrations in chronic MDD (cMDD) and first episode of depression (FED) to healthy controls. Methods: We searched Scopus and Web of Knowledge; using search terms related to depression and NAA. Hedges' g was used as effect size measure, together with heterogeneity analyses, test of moderators and publication bias and quality assessment. The protocol is pre-registered in PROSPERO (CRD42020221050). Sixty-two studies were included and meta-analyzed using a random-effect model for each brain region. Results: NAA concentrations were significantly reduced in cMDD compared to healthy controls within the frontal lobe (Hedges' g =-0.330; p=0.018), the occipital lobe (Hedges' g=-0.677; p=0.007), the thalamus (Hedges' g=-0.673; p=0.016) and the frontal (Hedges' g=-0.471; p=0.034) and periventricular white matter (Hedges' g=-0.478; p=0.047). We highlighted a gap of knowledge regarding NAA levels in FED. Sensitivity analyses indicated that antidepressant treatment may reverse NAA alterations in the frontal lobe. None of the clinical or 1H-MRS-related methodological moderators had a significant impact on the effect sizes. Conclusions: Our findings are in line with the hypometabolism hypothesis of MDD. Future studies should assess NAA alterations in the early stages of the illness and their longitudinal progression, also considering the modifying effect of antidepressant treatment.

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Section: Discussioncontrasting

confidence: 99%

Proton magnetic resonance spectroscopy of N-acetyl aspartate in first depressive episode and chronic major depressive disorder: a systematic review and meta-analysis

Saccaro

Tassone

Tozzi

et al. 2022

Preprint

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“…ApoE is a polymorph protein involved in the transformation and metabolism of lipoproteins, and its gene can regulate many biological functions that have been existed as a risk factor in mental diseases, such as depression [ 28 ]. Additionally, the disturbance of Cu metabolism can cause neuropsychiatric symptoms, such as depression [ 29 ]. Therefore, ApoE4 mice showed aggravation of depression-like behavior under Cu exposure.…”

Section: Discussionmentioning

confidence: 99%

Low‐Dose Copper Exposure Exacerbates Depression‐Like Behavior in ApoE4 Transgenic Mice

Zhang

et al. 2021

Oxidative Medicine and Cellular Longevity

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Depression is one of the most common neuropsychiatric disorders. Although the pathogenesis of depression is still unknown, environmental risk factors and genetics are implicated. Copper (Cu), a cofactor of multiple enzymes, is involved in regulating depression-related processes. Depressed patients carrying the apolipoprotein ε4 allele display more severe depressive symptoms, indicating that ApoE4 is closely associated with an increased risk of depression. The study explored the effect of low-dose Cu exposure and ApoE4 on depression-like behavior of mice and further investigates the possible mechanisms. The ApoE4 mice and wild-type (WT) mice were treated with 0.13 ppm CuCl2 for 4 months. After the treatment, ApoE4 mice displayed obvious depression-like behavior compared with the WT mice, and Cu exposure further exacerbated the depression-like behavior of ApoE4 mice. There was no significant difference in anxiety behavior and memory behavior. Proteomic analysis revealed that the differentially expressed proteins between Cu-exposed and nonexposed ApoE4 mice were mainly involved in the Ras signaling pathway, protein export, axon guidance, serotonergic synapse, GABAergic synapse, and dopaminergic synapse. Among these differentially expressed proteins, immune response and synaptic function are highly correlated. Representative protein expression changes are quantified by western blot, showing consistent results as determined by proteomic analysis. Hippocampal astrocytes and microglia were increased in Cu-exposed ApoE4 mice, suggesting that neuroglial cells played an important role in the pathogenesis of depression. Taken together, our study demonstrated that Cu exposure exacerbates depression-like behavior of ApoE4 mice and the mechanisms may involve the dysregulation of synaptic function and immune response and overactivation of neuroinflammation.

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“…Our study agrees with previous data from a study of a homogeneous MDD population [ 17 ], indicating no correlation between copper ion concentrations and the stage of the disease or the treatment outcome. Liu et al [ 18 ] found that there were no significant correlations between the depression severity scores (based on the Hamilton Depression Scale-24 version) or disease course and abnormal copper levels in patients with MDD. However, another study [ 19 ] demonstrated that children and adolescents with moderate and severe depression had significantly higher copper levels.…”

Section: Discussionmentioning

confidence: 99%

Copper Concentrations in Ketamine Therapy for Treatment-Resistant Depression

et al. 2020

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Changes in serum copper concentration are observed in patients with depressive symptoms. Unmet needs in contemporary antidepressant treatment have increased interest in non-monoaminergic antidepressants, such as ketamine, an anaesthetic drug that has demonstrated a rapid antidepressant effect in patients with treatment-resistant depression (TRD). The purpose of this study was to examine whether serum copper concentrations change during ketamine treatment and whether there is an association between the copper concentrations and treatment response measured using psychometric scale scores. Moreover, the interlink between somatic comorbidities and copper concentration was studied. Patients with major depressive disorder or bipolar disorder were rated weekly by a clinician using the Montgomery–Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS). Copper level assessments were carried out weekly before the start of ketamine treatment and then after every second infusion and one week after the last ketamine infusion. The serum concentration of copper before ketamine treatment was significantly higher than that after the fifth infusion (p = 0.016), and the serum concentration after the treatment was significantly higher than that after the fifth infusion (p = 0.048). No significant correlations between changes in the copper serum concentrations and MADRS or YMRS were found. The serum copper level was not associated with somatic comorbidities during the course of treatment. This study provides data on the role of copper in short-term intravenous ketamine treatment in TRD, although no clear evidence of a connection between the copper level and treatment response was found.

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Serum copper and zinc levels correlate with biochemical metabolite ratios in the prefrontal cortex and lentiform nucleus of patients with major depressive disorder

Cited by 25 publications

References 66 publications

Proton magnetic resonance spectroscopy of N-acetyl aspartate in first depressive episode and chronic major depressive disorder: a systematic review and meta-analysis

Proton magnetic resonance spectroscopy of N-acetyl aspartate in first depressive episode and chronic major depressive disorder: a systematic review and meta-analysis

Low‐Dose Copper Exposure Exacerbates Depression‐Like Behavior in ApoE4 Transgenic Mice

Copper Concentrations in Ketamine Therapy for Treatment-Resistant Depression

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