Electroconvulsive Stimulation in Rats Induces Alterations in the Hippocampal miRNome: Translational Implications for Depression.

MicroRNAs (miRNAs) may contribute to the development of depression and its treatment. Here, we used the hypothesis-neutral approach of next-generation sequencing (NGS) to gain comprehensive understanding of the effects of a course of electroconvulsive stimulation (ECS), the animal model equivalent of electroconvulsive therapy (ECT), on rat hippocampal miRNAs. Significant differential expression (p < 0.001) of six hippocampal miRNAs was noted following NGS, after correcting for multiple comparisons. Three of these miRNAs were upregulated (miR-132, miR-212, miR-331) and three downregulated (miR-204, miR-483, miR-301a). qRT-PCR confirmed significant changes in four of the six miRNAs (miR-132, miR-212, miR-204, miR-483). miR-483 was also significantly reduced in frontal cortex, though no other significant alterations were noted in frontal cortex, cerebellum, or whole blood. Assessing the translatability of the results, miR-132 and miR-483 were significantly reduced in whole blood samples from medicated patients with depression (n = 50) compared to healthy controls (n = 45), though ECT had no impact on miRNA levels. Notably, pre-ECT miR-204 levels moderately positively correlated with depression severity at baseline and moderately negatively correlated with mood score reduction post-ECT. miRNAs were also examined in cerebrospinal fluid and serum from a separate cohort of patients (n = 8) treated with ECT; no significant changes were noted post-treatment. However, there was a large positive correlation between changes in miR-212 and mood score post-ECT in serum. Though replication studies using larger sample sizes are required, alterations in miRNA expression may be informative about the mechanism of action of ECS/ECT and in turn might give insight into the neurobiology of depression.

Whole blood mitochondrial DNA copy number in depression and response to electroconvulsive therapy.

Mitochondrial dysfunction may play a role in various psychiatric conditions. Mitochondrial DNA copy number (mtDNAcn), the ratio of mitochondrial DNA to nuclear DNA, represents an attractive marker of mitochondrial health that is easily measured from stored DNA samples, and has been shown to be altered in depression. In this study, we measured mtDNAcn in whole blood samples from medicated patients with depression (n = 100) compared to healthy controls (n = 89) and determined the relationship between mtDNAcn and depression severity and the therapeutic response to electroconvulsive therapy (ECT). We also explored the relationship between mtDNAcn and telomere length and inflammatory markers. Our results show that mtDNAcn was significantly elevated in blood from patients with depression when compared to control samples, and this result survived statistical adjustment for potential confounders (p = 0.002). mtDNAcn was significantly elevated in blood from subgroups of patients with non-psychotic or unipolar depression. There was no difference in mtDNAcn noted in subgroups of ECT remitters/non-remitters or responders/non-responders. Moreover, mtDNAcn was not associated with depression severity, telomere length, or circulating inflammatory marker concentrations. Overall, our results show that mtDNAcn is elevated in blood from patients with depression, though whether this translates to mitochondrial function is unknown. Further work is required to clarify the contribution of mitochondria and mtDNA to the pathophysiology of depression and the therapeutic response to antidepressant treatments.

PARP1 and OGG1 in Medicated Patients With Depression and the Response to ECT.

BACKGROUND: Oxidative stress and oxidation-induced DNA damage may contribute to the pathophysiology of depression. Two key mediators of base excision repair (BER) in response to oxidative damage of DNA are OGG1 and PARP1. Few studies have examined changes in OGG1 or PARP1 mRNA in patients with depression or following antidepressant treatment. We examined PARP1 and OGG1 mRNA levels in patients with depression at baseline/pre-electroconvulsive therapy (baseline/pre-ECT) vs in healthy controls and in patients following a course of ECT. METHODS: PARP1 and OGG1 were examined in whole blood samples from medicated patients with depression and controls using quantitative real-time polymerase chain reaction. Exploratory subgroup correlational analyses were performed to determine associations between PARP1 and OGG1 and mood (Hamilton Depression Rating Scale 24-item version) scores as well as with vitamin B3, SIRT1, PGC1α, and tumor necrosis factor alpha levels, as previously reported on in this cohort. RESULTS: PARP1 levels were reduced in samples from patients with depression vs controls (P = .03), though no difference was noted in OGG1. ECT had no effect on PARP1 or OGG1. Higher baseline PARP1 weakly correlated with greater mood improvement post ECT (P = .008). Moreover, PARP1 positively correlated with SIRT1 at baseline and post ECT, and positive correlations were noted between change in PARP1 and change in OGG1 with change in tumor necrosis factor alpha post ECT. CONCLUSIONS: To our knowledge, this is the first study to examine the effect of ECT on BER enzymes. A better understanding of BER enzymes and DNA repair in depression could unearth new mechanisms relevant to the pathophysiology of this condition and novel antidepressant treatments.

Blood cell ratios in mood and cognitive outcomes following electroconvulsive therapy.

Systemic inflammation is commonly reported in depression, with dysregulation of both the innate and adaptive arms of the immune system documented. Obtaining ratios of neutrophils, platelets, and monocytes to counts of lymphocytes (NLR, PLR, MLR, respectively) represents a low-cost and easily reproducible measure of an individual's inflammatory burden that can be calculated effortlessly from routine clinical full white blood cell counts. Electroconvulsive therapy (ECT) remains the most effective acute antidepressant treatment for depression but is often limited by its cognitive side-effects. Here, we examined differences in blood cell ratios in subgroups of depressed patients (unipolar/bipolar, psychotic/non-psychotic, early-onset/late-onset) and ECT-related subgroups (responder/non-responder, remitter/non-remitter). We also explored the relationships between blood cell ratios and depression severity and immediate cognitive outcomes post-ECT. Our results show baseline NLR was raised in patients with psychotic depression. In the entire group of patients, significant negative correlations were noted between the PLR and SII and baseline HAM-D24 score, signifying that lower systemic inflammation is associated with more severe depressive symptoms. Significant positive correlations were noted between various blood cell ratios and mean time to recovery of orientation in the entire group of patients and in depression subgroups, indicating that increased peripheral inflammation is linked to worse cognitive outcomes post-ECT. Overall, our results suggest that assessment of blood cell ratios could be useful for predicting mood changes in patients at risk of developing depressive episodes or relapse following successful treatment or for identifying those at risk for cognitive side-effects following ECT.

Peripheral blood inflammatory markers in depression: Response to electroconvulsive therapy and relationship with cognitive performance.

The inflammatory response may play a role in depression and the response to antidepressants. Electroconvulsive therapy (ECT), the most acutely powerful antidepressant treatment, can also affect the innate immune system. Here, we determined circulating blood concentrations of the inflammatory mediators C-reactive protein (CRP), IL-1ß, IL-6, IL-10, and TNF-α in depressed patients compared to healthy controls and assessed the effect of ECT on their concentrations. Relationships between inflammatory mediator concentrations and mood/cognition scores were also explored. Plasma CRP, IL-1ß, IL-6, IL-10, and TNF-α concentrations were examined in 86 depressed patients and 57 controls. Relationships between inflammatory mediators and clinical or cognitive outcomes following ECT were assessed using correlation and linear regression analyzes, respectively. CRP, IL-6, IL-10, and TNF-α were elevated in patients at baseline/pre-ECT compared to controls. However, only IL-6 and TNF-α survived adjustment for potential confounders. IL-1ß was undetectable in most samples. ECT did not significantly alter plasma concentrations of any of the inflammatory mediators. No relationship was identified between CRP, IL-6, IL-10, and TNF-α and mood or neurocognitive scores. Overall, our data do not support a major role for these four inflammatory markers in clinical outcomes following ECT or in cognition.

Interrogating Associations Between Polygenic Liabilities and Electroconvulsive Therapy Effectiveness.

BACKGROUND: Electroconvulsive therapy (ECT) is the most effective treatment for severe major depressive episodes (MDEs). Nonetheless, firmly established associations between ECT outcomes and biological variables are currently lacking. Polygenic risk scores (PRSs) carry clinical potential, but associations with treatment response in psychiatry are seldom reported. Here, we examined whether PRSs for major depressive disorder, schizophrenia (SCZ), cross-disorder, and pharmacological antidepressant response are associated with ECT effectiveness. METHODS: A total of 288 patients with MDE from 3 countries were included. The main outcome was a change in the 17-item Hamilton Depression Rating Scale scores from before to after ECT treatment. Secondary outcomes were response and remission. Regression analyses with PRSs as independent variables and several covariates were performed. Explained variance (R2) at the optimal p-value threshold is reported. RESULTS: In the 266 subjects passing quality control, the PRS-SCZ was positively associated with a larger Hamilton Depression Rating Scale decrease in linear regression (optimal p-value threshold = .05, R2 = 6.94%, p < .0001), which was consistent across countries: Ireland (R2 = 8.18%, p = .0013), Belgium (R2 = 6.83%, p = .016), and the Netherlands (R2 = 7.92%, p = .0077). The PRS-SCZ was also positively associated with remission (R2 = 4.63%, p = .0018). Sensitivity and subgroup analyses, including in MDE without psychotic features (R2 = 4.42%, p = .0024) and unipolar MDE only (R2 = 9.08%, p < .0001), confirmed the results. The other PRSs were not associated with a change in the Hamilton Depression Rating Scale score at the predefined Bonferroni-corrected significance threshold. CONCLUSIONS: A linear association between PRS-SCZ and ECT outcome was uncovered. Although it is too early to adopt PRSs in ECT clinical decision making, these findings strengthen the positioning of PRS-SCZ as relevant to treatment response in psychiatry.

Microglia and their LAG3 checkpoint underlie the antidepressant and neurogenesis-enhancing effects of electroconvulsive stimulation.

Despite evidence implicating microglia in the etiology and pathophysiology of major depression, there is paucity of information regarding the contribution of microglia-dependent molecular pathways to antidepressant procedures. In this study, we investigated the role of microglia in a mouse model of depression (chronic unpredictable stress-CUS) and its reversal by electroconvulsive stimulation (ECS), by examining the effects of microglia depletion with the colony stimulating factor-1 antagonist PLX5622. Microglia depletion did not change basal behavioral measures or the responsiveness to CUS, but it completely abrogated the therapeutic effects of ECS on depressive-like behavior and neurogenesis impairment. Treatment with the microglia inhibitor minocycline concurrently with ECS also diminished the antidepressant and pro-neurogenesis effects of ECS. Hippocampal RNA-Seq analysis revealed that ECS significantly increased the expression of genes related to neurogenesis and dopamine signaling, while reducing the expression of several immune checkpoint genes, particularly lymphocyte-activating gene-3 (Lag3), which was the only microglial transcript significantly altered by ECS. None of these molecular changes occurred in microglia-depleted mice. Immunohistochemical analyses showed that ECS reversed the CUS-induced changes in microglial morphology and elevation in microglial LAG3 receptor expression. Consistently, either acute or chronic systemic administration of a LAG3 monoclonal antibody, which readily penetrated into the brain parenchyma and was found to serve as a direct checkpoint blocker in BV2 microglia cultures, rapidly rescued the CUS-induced microglial alterations, depressive-like symptoms, and neurogenesis impairment. These findings suggest that brain microglial LAG3 represents a promising target for novel antidepressant therapeutics.

PBMC telomerase activity in depression and the response to electroconvulsive therapy.

Telomerase, the DNA polymerase responsible for maintaining telomere length, has previously been implicated in depression and the response to antidepressant drugs. In this study, we aimed to compare telomerase activity in peripheral blood mononuclear cells between patients with severe depression recruited as part of the KEEP-WELL Trial (Ketamine for Depression Relapse Prevention Following ECT; NCT02414932) and age- and sex-matched healthy volunteers both at baseline/pre-ECT and at follow-up 1 month later for controls or in patients after a course of ECT. We found no differences in telomerase activity between patients with depression (n = 20) compared to healthy controls (n = 33) at baseline/pre-ECT, or between patients treated with ECT compared to controls at follow-up. In patients, telomerase activity was not associated with mood, as assessed by the 24-item Hamilton Rating Scale for Depression, or the duration of the current depressive episode. Additionally, we found no significant relationship between telomerase activity and exposure to recent or childhood adversity in either the patient or control groups. Overall, our results suggest that telomerase activity is not associated with depression, the therapeutic response to ECT, or exposure to adversity.

Vascular endothelial growth factor and pigment epithelial-derived factor in the peripheral response to ketamine.

BACKGROUND: Ketamine is a rapid-acting antidepressant but its mechanism remains unclear. Vascular endothelial growth factor growth factor (VEGF) has been reported in the antidepressant action of ketamine in rodents. VEGF and pigment epithelial-derived factor (PEDF) signalling are closely linked and both are dysregulated in depression. We explored the effect of a single infusion of ketamine, with midazolam as comparison, on peripheral whole blood mRNA levels of vascular endothelial growth factor A (VEGFA) and PEDF, and the VEGFA/PEDF ratio, in patients with depression. METHODS: Twenty-five patients with depression were randomised to either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) infusions over 40 min. Blood plasma samples were taken 1 h before the first infusion and 4 h after the infusion start. mRNA was extracted and qRT-PCR performed to analyse gene expression. RESULTS: Single infusions of ketamine and midazolam both decreased depression scores (F(1,21) = 102.40, p < 0.000). There was a significant group × time interaction for VEGFA mRNA levels (F(1, 21) = 5.207, p = 0.029), with ketamine increasing VEGFA levels. There was no significant effect of either ketamine or midazolam on PEDF levels. There was a significant group × time interaction for VEGFA/PEDF mRNA ratio, with ketamine alone increasing this ratio (F(1, 11) = 12.085, p = 0.005). LIMITATIONS: Patients were on psychotropic medication and continued treatment as usual throughout the study. CONCLUSIONS: These preliminary results support a role for VEGF in the action of ketamine and suggest a novel role for VEGF/PEDF in the molecular response to ketamine.

Blood plasma B vitamins in depression and the therapeutic response to electroconvulsive therapy.

A growing body of research has indicated a role for B vitamins in depression, with some previous studies suggesting that B vitamin status in patients with depression can impact on antidepressant response. Here we aimed to investigate B vitamin plasma concentrations in medicated patients with depression (n â€‹= â€‹94) compared to age- and sex-matched healthy controls (n â€‹= â€‹57), and in patients with depression after electroconvulsive therapy (ECT) in a real-world clinical setting. Our results show that nicotinamide (vitamin B3), N1-methylnicotinamide (vitamin B3 metabolite), and pyridoxal 5'-phosphate (PLP; vitamin B6) concentrations were significantly reduced in patients with depression compared to controls. The Cohen's d effect sizes for nicotinamide, N1-methylnicotinamide, and PLP were moderate-large (-0.47, -0.51, and -0.59, respectively), and likely to be of clinical relevance. Functional biomarkers of vitamin B6 status (PAr index, 3-hydroxykynurenine: hydroxyanthranilic acid ratio, 3-hydroxykynurenine: xanthurenic acid ratio, and HKr) were elevated in depressed patients compared to controls, suggestive of reduced vitamin B6 function. Over 30% of the patient cohort were found to have low to deficient PLP concentrations, and exploratory analyses revealed that these patients had higher IL-6 and CRP concentrations compared to patients with PLP levels within the normal range. Treatment with ECT did not alter B vitamin concentrations, and B vitamin concentrations were not associated with depression severity or the therapeutic response to ECT. Overall, reduced plasma PLP, nicotinamide, and N1-methylnicotinamide concentrations could have wide ranging effects on pathways and systems implicated in depression. Further studies are required to understand the reasons why patients with depression present with low plasma B vitamin concentrations.

Telomere length in depression and association with therapeutic response to electroconvulsive therapy and cognitive side-effects.

BACKGROUND: Electroconvulsive therapy (ECT) is the most acutely effective treatment for severe treatment-resistant depression. However, there are concerns about its cognitive side-effects and we cannot yet confidently predict who will experience these. Telomeres are DNA-protein complexes that maintain genomic integrity. In somatic cells, telomeres shorten with each cell division. Telomere length (TL) can thus provide a measure of 'biological' aging. TL appears to be reduced in depression, though results are mixed. We sought to test the following hypotheses: (1) that TL would be shorter in patients with depression compared to controls; (2) that TL would be a predictor of response to ECT; and (3) that shorter TL would predict cognitive side-effects following ECT. METHOD: We assessed TL in whole blood DNA collected from severely depressed patients (n = 100) recruited as part of the EFFECT-Dep Trial and healthy controls (n = 80) using quantitative real-time polymerase chain reaction. Mood and selected cognitive measures, including global cognition, re-orientation time, and autobiographical memory, were obtained pre-/post-ECT and from controls. RESULTS: Our results indicate that TL does not differ between patients with depression compared to controls. TL itself was not associated with mood ratings and did not predict the therapeutic response to ECT. Furthermore, shorter baseline TL is not a predictor of cognitive side-effects post-ECT. CONCLUSIONS: Overall, TL assessed by PCR does not represent a useful biomarker for predicting the therapeutic outcomes or risk for selected cognitive deficits following ECT.

Tryptophan metabolite concentrations in depressed patients before and after electroconvulsive therapy.

Tryptophan and kynurenine pathway (KP) metabolites are implicated in the pathophysiology of depression. We aimed to investigate their plasma concentrations in medicated patients with depression (n = 94) compared to age- and sex-matched healthy controls (n = 57), and in patients with depression after electroconvulsive therapy (ECT) in a real-world clinical setting, taking account of co-variables including ECT modality and heterogenous psychopathology. Depression severity was assessed using the Hamilton Depression Rating Scale (HAM-D24). Tryptophan (TRP) and kynurenine (KYN) metabolite concentrations [anthranilic acid (AA), 3-hydroxyanthranilic acid (3HAA), picolinic acid (PA), kynurenic acid (KYNA), and xanthurenic acid (XA)] and KYNA/KYN and KYNA/quinolinic acid (QUIN) ratios were lower in patients compared to controls. For the total group there was no significant change in KP metabolites post-ECT or correlations with mood ratings. However, improvements in mood score were correlated with increased KYN, 3-hydroxykynurenine (3HK), 3HAA, QUIN, and KYN/TRP in a subgroup of unipolar depressed patients. Additionally, in remitters baseline KYN, 3HK, and QUIN were associated with baseline HAM-D24 scores, and changes in 3HK and 3HAA concentrations post-ECT correlated with improvement in mood. KYN, KYNA, AA, 3HK, XA, PA, and QUIN were increased in a smaller 3-month follow-up group (n = 19) compared to pre-ECT concentrations. Overall, the results indicate that ECT mobilizes the KP, where a moderate association between selected metabolites and treatment response in unipolar depressed patients is evident.

Low Circulating Levels of GR, FKBP5, and SGK1 in Medicated Patients With Depression Are Not Altered by Electroconvulsive Therapy.

OBJECTIVES: Hypothalamic-pituitary-adrenal axis dysregulation is frequently observed in patients with depression, with increased levels of the glucocorticoid (GC) cortisol commonly reported. Hypothalamic-pituitary-adrenal axis dysregulation may be a consequence of impaired feedback inhibition due to GC receptor (GR) impairments or dysfunction, termed "glucocorticoid resistance." Here, our objective was to assess mRNA levels of GC-related markers (GR, FKBP5, serum glucocorticoid kinase 1 [SGK1]) in patients with depression versus controls and in patient samples after electroconvulsive therapy (ECT). We also examined the relationship between these GC-related markers and 24-item Hamilton Depression Rating Scale (HAM-D24) scores to assess the utility of using them as biological markers for depression or the therapeutic response to ECT. METHODS: GR, FKBP5, and SGK1 mRNA levels were examined in whole blood samples from 88 medicated patients with depression pre-/post-ECT and 63 controls using quantitative real-time polymerase chain reaction. Exploratory subgroup correlational analyses were performed to determine the relationship between GR, FKBP5, and SGK1 and 24-item Hamilton Depression Rating Scale scores. RESULTS: GR, FKBP5, and SGK1 mRNA levels were significantly lower in medicated patients with depression compared with controls (P < 0.001, P = 0.03, P < 0.001, respectively), but ECT did not alter their levels (all P > 0.05). There was no relationship between GR, FKBP5, or SGK1 and 24-item Hamilton Depression Rating Scale scores. CONCLUSIONS: GR, FKBP5, and SGK1 do not seem to be involved in the peripheral molecular response to ECT and do not represent useful biomarkers for predicting the therapeutic response to ECT in a real-world clinical setting.

Dexamethasone attenuates inflammatory-mediated suppression of ß2-adrenoceptor expression in rat primary mixed glia.

ß2-adrenoceptors are G-protein coupled receptors expressed on both astrocytes and microglia that play a key role in mediating the anti-inflammatory actions of noradrenaline in the CNS. Here the effect of an inflammatory stimulus (LPS + IFN-γ) was examined on glial ß2-adrenoceptor expression and function. Exposure of glia to LPS + IFN-γ decreased ß2-adrenoceptor mRNA and agonist-stimulated production of the intracellular second messenger cAMP. Pre-treatment with the synthetic glucocorticoid and potent anti-inflammatory agent dexamethasone prevented the LPS + IFN-γ-induced suppression of ß2-adrenoceptor mRNA expression. These results raise the possibility that inflammation-mediated ß2-adrenoceptor downregulation in glia may dampen the innate anti-inflammatory properties of noradrenaline in the CNS.

Peripheral blood GILZ mRNA levels in depression and following electroconvulsive therapy.

Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA)-axis is commonly observed in patients with depression. The delayed feedback system that mediates inhibition of HPA-axis activation is regulated by glucocorticoid receptors (GRs) found in stress-responsive areas of the brain. Glucocorticoid-induced leucine zipper (GILZ) is a key molecule in glucocorticoid biology and is thought to mediate the downstream anti-inflammatory effects of GRs. Previous reports suggest that GILZ levels are altered in the blood and brains of patients with, and animal models of, depression. However, no study has yet investigated the effects of antidepressant treatment on GILZ. Therefore, our aim was to examine peripheral blood GILZ mRNA levels in patients with depression (n = 88) compared to age- and sex-matched healthy controls (n = 63), and in patients with depression following treatment with a course of electroconvulsive therapy (ECT). We also assessed the relationship between GILZ and mood and clinical outcomes following ECT. GILZ mRNA levels were assessed using qRT-PCR. GILZ levels were found to be significantly lower in patients with depression compared to controls (p < 0.002), and ECT further decreased GILZ levels (p = 0.05). Both of these results survived adjustment for potential covariates. However, we found no association between GILZ and mood scores. Overall, these results suggest that GILZ is involved in the pathophysiology of depression and the peripheral molecular response to ECT.

Peripheral blood E2F1 mRNA in depression and following electroconvulsive therapy.

The E2F transcription factors are a group of proteins that bind to the promotor region of the adenovirus E2 gene. E2F1, the first family member to be cloned, is linked to functions including cell proliferation and apoptosis, DNA repair, cell senescence and metabolism. We recently performed a deep sequencing study of micro-RNA changes in whole blood following ECT. Two micro-RNAs (miR-126-3p and miR-106a-5p) were identified and gene targeting analysis identified E2F1 as a shared target of these miRNAs. To our knowledge, no studies have examined E2F1 mRNA levels in patients with depression. Peripheral blood E2F1 mRNA levels were therefore examined in patients with depression, compared to healthy controls, and the effects of a course of ECT on peripheral blood E2F1 mRNA was investigated. Depressed patient and healthy control groups were balanced on the basis of age and sex. E2F1 mRNA levels were significantly lower in depressed patients in comparison to controls (p = .009) but did not change with ECT. There was no relationship between baseline E2F1 levels and depression severity, response to treatment, presence of psychosis or polarity of depression. There were no significant correlations between E2F1 levels and mood scores based on the HAM-D24. These results indicate that reduced peripheral blood E2F1 mRNA could be a trait feature of depression.

Peroxisome proliferator-activated receptor gamma co-activator-1 alpha in depression and the response to electroconvulsive therapy.

BACKGROUND: The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC-1α), termed the 'master regulator of mitochondrial biogenesis', has been implicated in stress and resilience to stress-induced depressive-like behaviours in animal models. However, there has been no study conducted to date to examine PGC-1α levels in patients with depression or in response to antidepressant treatment. Our aim was to assess PGC-1α mRNA levels in blood from healthy controls and patients with depression pre-/post-electroconvulsive therapy (ECT), and to examine the relationship between blood PGC-1α mRNA levels and clinical symptoms and outcomes with ECT. METHODS: Whole blood PGC-1α mRNA levels were analysed in samples from 67 patients with a major depressive episode and 70 healthy controls, and in patient samples following a course of ECT using quantitative real-time polymerase chain reaction (qRT-PCR). Exploratory subgroup correlational analyses were carried out to determine the relationship between PGC-1α and mood scores. RESULTS: PGC-1α levels were lower in patients with depression compared with healthy controls (p = 0.03). This lower level was predominantly accounted for by patients with psychotic unipolar depression (p = 0.004). ECT did not alter PGC-1α levels in the depressed group as a whole, though exploratory analyses revealed a significant increase in PGC-1α in patients with psychotic unipolar depression post-ECT (p = 0.045). We found no relationship between PGC-1α mRNA levels and depression severity or the clinical response to ECT. CONCLUSIONS: PGC-1α may represent a novel therapeutic target for the treatment of depression, and be a common link between various pathophysiological processes implicated in depression.

Peripheral blood SIRT1 mRNA levels in depression and treatment with electroconvulsive therapy.

Sirtuins are a family of nicotinamide adenine dinucleotide (NAD+) dependent enzymes that regulate cellular functions through deacetylation of protein targets. They have roles in both the periphery and central nervous system and have been implicated in depression biology. A recent genome-wide association study has identified a locus for major depression in the Sirtuin1 gene (SIRT1) and lower blood levels of SIRT1 mRNA in patients with depression have also been observed in two studies. To our knowledge, no studies have examined the effect of treatment on SIRT1 levels in patients with depression. We therefore examined SIRT1 mRNA levels in a well characterised group of patients with depression, compared to healthy controls, and characterised the effects of a course of electroconvulsive therapy (ECT) on peripheral blood SIRT1 mRNA. Depressed patients (n = 91) were matched to healthy controls (n = 85) on the basis of age and sex. In line with previous studies, blood SIRT1 mRNA levels were lower in depressed patients in comparison to controls (p = 0.005). However, ECT had no effect on SIRT1 levels (p = 0.67). There was no relationship between baseline pre-ECT SIRT1 levels and depression severity, change in mood scores, suicidality, depression polarity, presence of psychosis, or response to treatment. There was a trend for a negative association between an increase in SIRT1 mRNA and a decrease in HAM-D24 scores in ECT responders and remitters. These results indicate that reduced peripheral blood SIRT1 mRNA could be a trait feature of depression.

Vascular endothelial growth factor plasma levels in depression and following electroconvulsive therapy.

Both animal and human studies have implicated the neurotrophic and angiogenic mediator vascular endothelial growth factor (VEGF) in depression, with meta-analyses, indicating that protein levels are raised in patients with depression. In line with this, we have previously shown that VEGFA mRNA levels are higher in whole blood from patients with depression compared to controls, in particular in patients with psychotic unipolar depression, and that treatment with electroconvulsive therapy (ECT) alters VEGFA mRNA levels. The aim of the present study was, therefore, to extend this previous work by assessing plasma VEGF protein levels in patients with depression compared to healthy controls, and in patients following treatment with ECT. We found that there was no difference between controls and patients with depression with regard to plasma VEGF (p = 0.59), and that VEGF levels were unaltered by ECT (p = 0.09) after correction for potential covariates. We found no correlation between VEGF protein and mRNA levels. Within the subgroup of patients receiving treatment with bitemporal ECT (n = 34), we identified a moderate negative correlation (ρ = - 0.54, p = 0.001) between the change in VEGF and the change in depression severity following treatment; however, no other association between VEGF and mood, responder/remitter status, polarity of depression, or presence of psychosis were found. Overall, our results indicate that the measurement of VEGF protein is not a useful marker for depression or response to treatment, and suggest that the measurement of VEGFA mRNA may prove more useful.