Risk Phenotypes, Comorbidities, Pharmacotherapy, and Electroconvulsive Therapy (ECT) in a Cohort with Difficult-to-Treat Depression in Comparison to an Unmedicated Control Group.

BACKGROUND: Approximately 15-25% of depressed patients suffer from difficult-to-treat depression (DTD). Patients with DTD require a thorough examination to avoid the oversight of treatable (psychiatric/somatic) comorbidities or (pseudo-)resistance to antidepressant drugs (ADs). Polymorphisms of the cytochrome P450 (CYP) enzymes 2D6 and 2C19, which play a major role in the metabolism of ADs, may contribute to resistance to ADs. Patients with DTD might benefit from electroconvulsive therapy (ECT). METHODS: We enrolled 109 patients with DTD and 29 untreated depressed controls (UDC). We assessed risk phenotypes, comorbidities, and treatment, including ECT. We also performed pharmacokinetic analyses of CYP2D6 and CYP2C19. RESULTS: DTD patients significantly more often suffered from comorbid psychiatric diseases, especially ICD-10: F40-F48 (DTD:40.4%, UDC:17.2%, OR 11.87, p=0.011) than UDC patients. DTD patients receiving ECT were more likely to achieve remission (37.7% vs. 11.8%, OR=3.96, p=0.023). Treatment with ADs did not differ between remitters and non-remitters. No significant differences were observed in the distribution of CYP2D6 and CYP2C19 variants between both groups. CONCLUSION: Patients with DTD appear to experience comorbid neurotic stress and somatoform disorders (ICD-10: F40 - F48) more frequently. Therefore, a comprehensive differential diagnosis is crucial when patients do not respond sufficiently to antidepressant medication. Genotyping CYP2D6 and CYP2C19 should be considered.

DNA Methylation of POMC and NR3C1-1F and Its Implication in Major Depressive Disorder and Electroconvulsive Therapy.

INTRODUCTION: Precision medicine in psychiatry is still in its infancy. To establish patient-tailored treatment, adequate indicators predicting treatment response are required. Electroconvulsive therapy (ECT) is considered one of the most effective options for pharmacoresistant major depressive disorder (MDD), yet remission rates were reported to be below 50%. METHODS: Since epigenetics of the stress response system seem to play a role in MDD, we analyzed the DNA methylation (DNAm) of genes encoding the glucocorticoid receptor (NR3C1) and proopiomelanocortin (POMC) through Sanger Sequencing. For analysis, blood was taken before and after the first and last ECT from MDD patients (n=31), unmedicated depressed controls (UDC; n=19, baseline), and healthy controls (HC; n=20, baseline). RESULTS: Baseline DNAm in NR3C1 was significantly lower in UDCs compared to both other groups (UDC: 0.014(±0.002), ECT: 0.031(±0.001), HC: 0.024(±0.002); p<0.001), whereas regarding POMC, ECT patients had the highest DNAm levels (ECT: 0.252(±0.013), UDC: 0.156(±0.015), HC: 0.162(±0.014); p<0.001). NR3C1m and POMCm decreased after the first ECT (NR3C1: p<0.001; POMC: p=0.001), and responders were less methylated compared to non-responders in NR3C1(p<0.001). DISCUSSION: Our findings indicate that both genes might play a role in the chronification of depression and NR3C1 may be relevant for ECT response prediction.

Neurological soft signs are increased in major depressive disorder irrespective of treatment.

The significance of neurological soft signs (NSS) in major depressive disorder (MDD) remains unclear and the stability of NSS in relation to antidepressant treatment has never been investigated. We hypothesized that NSS are relatively stable trait markers of MDD. We thus predicted that patients show more NSS than healthy controls, irrespective of illness duration and antidepressant treatment. To test this hypothesis, NSS were assessed in chronically depressed, medicated MDD patients before (n = 23) and after (n = 18) a series of electroconvulsive therapy (ECT). In addition, NSS were assessed once in acutely depressed, unmedicated MDD patients (n = 16) and healthy controls (n = 20). We found that both chronically depressed, medicated MDD patients and acutely depressed, unmedicated MDD patients showed more NSS than healthy controls. The degree of NSS in both patient groups did not differ. Importantly, we found no change in NSS after on average eleven sessions of ECT. Thus, the manifestation of NSS in MDD seems to be independent of illness duration and pharmacological and electroconvulsive antidepressant treatment. From a clinical perspective, our findings corroborate the neurological safety of ECT.

Overlooking the obvious? Influence of electrolyte concentrations on seizure quality parameters in electroconvulsive therapy.

Clinical response to electroconvulsive therapy (ECT) depends on eliciting a generalized seizure. Though there are multiple ictal and other parameters to assess seizure quality, factors that influence these parameters have only been identified to a limited extend in antecedent studies (e.g., stimulus dosage, age). In the context of ECT, electrolyte concentrations have hardly been investigated so far-although hyponatremia is one well-known clinical factor to increase the risk of spontaneous seizures. In 31 patients with unipolar or bipolar depressive disorder, blood concentrations of sodium (Na), potassium (K), and calcium (Ca) were measured immediately prior to repeated sessions of maintenance ECT. Generalized linear mixed models were used to analyze the influence of Na, K, and Ca on seven seizure quality parameters: postictal suppression index (PSI), maximum sustained coherence (MSC), midictal amplitude, average seizure energy index, seizure duration (EEG/motor), and peak heart rate. Results show a statistically significant relationship between the serum sodium level and MSC: in the model, a reduction of 1 mmol/l led to an increase in interhemispheric coherence of 0.678%. The further markers remained unaffected by changes in electrolyte concentrations. This finding provides first evidence that a lower blood concentration of sodium could enhance the quality of ECT-induced seizures in terms of higher interhemispheric coherence.

Serum neurofilament light chain (NFL) remains unchanged during electroconvulsive therapy.

Objectives: Although there is consistent evidence that electroconvulsive therapy (ECT) is safe and well tolerated by the majority of patients, some authors still accuse ECT to inevitably cause brain damage and permanent memory loss, assertions that may increase patients' worries about a useful treatment. Recently, the measurement of neurofilament light chain (NFL) in peripheral blood was technically implemented, permitting longitudinal analysis of this biomarker for axonal damage. NFL is part of the axonal cytoskeleton and is released into the CSF and peripheral blood in the context of neuronal damage.Methods: In our study, blood from 15 patients with major depressive disorder receiving ECT was collected before the first ECT as well as 24 h and seven days after the last ECT, respectively. NFL concentrations were analysed using the ultrasensitive single molecule array (Simoa) technology.Results: NFL concentrations did not differ between patients and healthy controls, and there was no significant change in NFL levels in the course of ECT. On the contrary, we even found a slight decrease in absolute NFL concentrations.Conclusions: Our study confirms the safety of ECT by using a most sensitive method for the detection of NFL in peripheral blood as a biomarker of neuronal damage.