The influence of pharmacological mineralocorticoid and glucocorticoid receptor blockade on the cortisol response to psychological stress.

The glucocorticoid cortisol is the end product of the hypothalamic-pituitary-adrenal (HPA) axis and crucial for the stress response in humans. Cortisol regulates numerous biological functions by binding to two different types of receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Both receptors are found in the brain where they are crucially involved in various mental functions and in feedback inhibition of cortisol release. The precise role of both receptors in the human stress response is not completely understood. In this study, we examined the effects of pharmacological blockade of the MR or the GR on stress-induced cortisol release in a sample of 318 healthy young men (M = 25.42, SD = 5.01). Participants received the MR antagonist spironolactone (300 mg), the GR antagonist mifepristone (600 mg), or a placebo and were subjected 90 min later to a social-evaluative stressor (Trier Social Stress Test) or a non-stressful control condition. We found significantly higher stress-induced cortisol release in the spironolactone group, whereas participants after mifepristone administration did not differ from the control groups. These results suggest that MR blockade results in attenuated fast negative feedback processes and emphasize the important role of the MR during the early phase of the stress response.

Causes, clinical characteristics, and outcomes of high lithium levels and intoxications: Retrospective analysis of patient records.

BACKGROUND: The mood stabilizer lithium has a narrow therapeutic index with a relevant risk of intoxication. We used real-world hospital data to identify causes, treatment courses, and outcomes of high lithium levels and intoxications. METHODS: Retrospective chart review of patients with a lithium concentration of ⩾1.1 mmol/L, who were treated at Charité University Medical Center Berlin. RESULTS: We identified 136 patients (58% women; mean age: 54.7 years) with high lithium levels or intoxication. 66.9% were chronic (stable lithium dose but changes in other variables such as co-medication). 40.4% took at least one risk medication with a relative contraindication for concurrent lithium treatment. 11.1% of the cases with a high therapeutic level showed moderate to severe intoxications. Feverish infections were significantly associated with severe intoxications. Overall, 97.1% (132/136) of patients fully recovered, two had residual but mild symptoms and two died during hospitalization (unlikely related to the intoxication). In 37.5% of patients, no psychiatrist was involved in the management of high lithium levels or intoxication. In these patients, lithium treatment was adjusted or discontinued in 37.3% of the cases compared to 64.7% when a psychiatrist was involved (χ²(1) = 9.683, p = 0.002). CONCLUSIONS: Patients and medical doctors should be aware of the increased risk of lithium intoxication already within the high therapeutic range and should consider alternative medications without relative contraindications for concurrent lithium use. Involving psychiatrists during or after an intoxication event is associated with more frequent adjustment of the maintenance lithium dose and should be considered in most cases.

No influence of mineralocorticoid and glutamatergic NMDA receptor stimulation on spatial learning and memory in individuals with major depression.

BACKGROUND: Major depressive disorder (MDD) is associated with impairments in spatial learning and memory and with altered functioning of central mineralocorticoid receptors (MR) and glutamatergic N-methyl-D-aspartate receptors (NMDA-R). Both receptors are highly expressed in the hippocampus and prefrontal cortex - brain areas that are critical for spatial learning and memory. Here, we examined the effects of separate and combined MR and NMDA-R stimulation on spatial learning and memory in individuals with MDD and healthy controls. METHODS: We used a randomized, double-blind, placebo-controlled between-group study design to examine the effects of separate and combined stimulation of the MR (with 0.4 mg fludrocortisone) and NMDA-R (with 250 mg D-cycloserine) in 116 unmedicated individuals with MDD (mean age: 34.7 ± 13.3 years; 78.4% women) and 116 age-, sex-, and education-matched healthy controls. Participants were randomly assigned to one of four conditions: 1) placebo; 2) MR stimulation; 3) NMDA-R stimulation; and 4) combined MR/NMDA-R stimulation. Three hours after drug administration, spatial learning and memory were assessed using a virtual Morris Water Maze task. RESULTS: Individuals with MDD and healthy controls did not differ in spatial learning and memory performance. Neither separate nor combined MR or NMDA-R stimulation altered measures of spatial performance. CONCLUSION: In this study of relatively young, predominantly female, and unmedicated individuals, we found no effect of MDD and no effect of separate or combined MR and NMDA-R stimulation on spatial learning and memory.

Selective attention to emotional stimuli and emotion recognition in patients with major depression: The role of mineralocorticoid and glutamatergic NMDA receptors.

BACKGROUND: Mineralocorticoid receptors (MR) are highly expressed in limbic brain areas and prefrontal cortex, which are closely related to selective attention to emotional stimuli and emotion recognition. Patients with major depressive disorder (MDD) show alterations in MR functioning and both cognitive processes. MR stimulation improves cognitive processes in MDD and leads to glutamate release that binds upon N-methyl-D-aspartate receptors (NMDA-R). AIMS: We examined (1) whether MR stimulation has beneficial effects on selective attention to emotional stimuli and on emotion recognition and (2) whether these advantageous effects can be improved by simultaneous NMDA-R stimulation. METHODS: We examined 116 MDD patients and 116 healthy controls matched for age (M = 34 years), sex (78% women), and education in the following conditions: no pharmacological stimulation (placebo), MR stimulation (0.4 mg fludrocortisone + placebo), NMDA-R stimulation (placebo + 250 mg D-cycloserine (DCS)), MR + NMDA-R stimulation (fludrocortisone + DCS). An emotional dot probe task and a facial emotion recognition task were used to measure selective attention to emotional stimuli and emotion recognition. RESULTS: Patients with MDD and healthy individuals did not differ in task performance. MR stimulation had no effect on both cognitive processes in both groups. Across groups, NMDA-R stimulation had no effect on selective attention but showed a small effect on emotion recognition by increasing accuracy to recognize angry faces. CONCLUSIONS: Relatively young unmedicated MDD patients showed no depression-related cognitive deficits compared with healthy controls. Separate MR and simultaneous MR and NMDA-R stimulation revealed no advantageous effects on cognition, but NMDA-R might be involved in emotion recognition.

Approach-avoidance tendencies in depression and childhood trauma: No effect of noradrenergic stimulation.

Adverse childhood experiences (ACE) are a major risk factor for major depressive disorder (MDD) in later life. Both conditions are characterized by dysregulations in the noradrenergic system related which again could represent a mediating mechanism for deficits in affective processing and behavioral functioning. In this double-blind, placebo-controlled study we tested the hypothesis that ACE and MDD are characterized by aberrant approach-avoidance (AA) tendencies and that these are mitigated after noradrenergic stimulation with yohimbine. In a mixed-measures, fully crossed design, participants (N = 131, 73 women) with/without MDD and with/without ACE received a single-dose of yohimbine or placebo on different days, followed by an AA task. We found modulation of AA tendencies by the emotional valence of target images, yet there were no effects of group or treatment. From these results, we conclude that AA tendencies are not critically affected by MDD or ACE and that the noradrenergic system is not substantially involved in this behavior.

Simvastatin add-on to escitalopram in patients with comorbid obesity and major depression (SIMCODE): study protocol of a multicentre, randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Major depressive disorder (MDD) and obesity are both common disorders associated with significant burden of disease worldwide. Importantly, MDD and obesity often co-occur, with each disorder increasing the risk for developing the other by about 50%-60%. Statins are among the most prescribed medications with well-established safety and efficacy. Statins are recommended in primary prevention of cardiovascular disease, which has been linked to both MDD and obesity. Moreover, statins are promising candidates to treat MDD because a meta-analysis of pilot randomised controlled trials has found antidepressive effects of statins as adjunct therapy to antidepressants. However, no study so far has tested the antidepressive potential of statins in patients with MDD and comorbid obesity. Importantly, this is a difficult-to-treat population that often exhibits a chronic course of MDD and is more likely to be treatment resistant. Thus, in this confirmatory randomised controlled trial, we will determine whether add-on simvastatin to standard antidepressant medication with escitalopram is more efficacious than add-on placebo over 12 weeks in 160 patients with MDD and comorbid obesity. METHODS AND ANALYSIS: This is a protocol for a randomised, placebo-controlled, double-blind multicentre trial with parallel-group design (phase II). One hundred and sixty patients with MDD and comorbid obesity will be randomised 1:1 to simvastatin or placebo as add-on to standard antidepressant medication with escitalopram. The primary outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 12. Secondary outcomes include MADRS response (defined as 50% MADRS score reduction from baseline), MADRS remission (defined as MADRS score <10), mean change in patients' self-reported Beck Depression Inventory (BDI-II) and mean change in high-density lipoprotein, low-density lipoprotein and total cholesterol from baseline to week 12. ETHICS AND DISSEMINATION: This protocol has been approved by the ethics committee of the federal state of Berlin (Ethik-Kommission des Landes Berlin, reference: 19/0226-EK 11) and by the relevant federal authority (Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), reference: 4043387). Study findings will be published in peer-reviewed journals and will be presented at (inter)national conferences. TRIAL REGISTRATION NUMBERS: NCT04301271, DRKS00021119, EudraCT 2018-002947-27.

No association between major depression with and without childhood adversity and the stress hormone copeptin.

Background: Adverse childhood experiences (ACE) are associated with an increased risk of major depressive disorder (MDD) and hypothalamic-pituitary-adrenal (HPA) axis dysregulation. Within the HPA axis, corticotropin-releasing hormone and vasopressin (AVP) synergistically stimulate the release of adrenocorticotropic hormone, which promotes cortisol release. The cleavage product copeptin is produced during AVP synthesis and is a surrogate marker of AVP release. Children with ACE and young adults with depressive symptoms have higher levels of copeptin than healthy controls. Objective: To uncover the effects of MDD and ACE on copeptin levels in adult females. Methods: We recruited 94 women (mean age: 34.0 ± 3.6 years): 23 with MDD and ACE, 24 with MDD without ACE, 22 with ACE without MDD, and 25 healthy controls. ACE was defined as repeated sexual or physical abuse at least once a month over at least one year before the age of 18 years. MDD was defined by the DSM-IV criteria. Copeptin plasma levels were measured with an immunoluminometric assay. Results: The four groups did not differ in demographic variables. We found a significant negative correlation between body mass index (BMI) and copeptin plasma levels (r = -.21; p = .045). Copeptin plasma levels did not differ between the four groups after controlling for BMI. Conclusion: Neither MDD nor ACE was associated with altered plasma copeptin levels. Thus, copeptin does not seem to play a major role in MDD and ACE in adult females.

Antecedentes: Las experiencias adversas de la infancia (EAI) se asocian con un mayor riesgo de trastorno depresivo mayor (TDM) y desregulación del eje hipotalámico-pituitario-adrenal (HPA). Dentro del eje HPA, la hormona liberadora de corticotropina y la vasopresina (AVP) estimulan sinérgicamente la liberación de la hormona adrenocorticotrópica, que promueve la liberación de cortisol. El producto de escisión copeptina se produce durante la síntesis de AVP y es un marcador sustituto de la liberación de AVP. Los niños con EAI y los adultos jóvenes con síntomas depresivos tienen niveles más altos de copeptina que los controles sanos.Objetivo: Descubrir los efectos del TDM y la EAI en los niveles de copeptina en mujeres adultas.Métodos: Se reclutaron 94 mujeres (edad media: 34,0 ± 3,6 años): 23 con TDM y EAI, 24 con TDM sin EAI, 22 con EAI sin TDM y 25 controles sanos. La EAI se definió como abuso sexual o físico repetido al menos una vez al mes durante al menos un año antes de los 18 años. El TDM fue definido por los criterios del DSM-IV. Los niveles plasmáticos de copeptina se midieron con un ensayo inmunoluminométrico.Resultados: Los cuatro grupos no difirieron en las variables demográficas. Encontramos una correlación negativa significativa entre el índice de masa corporal (IMC) y los niveles plasmáticos de copeptina (r = −.21; p = .045). Los niveles plasmáticos de copeptina no difirieron entre los cuatro grupos después de controlar el IMC.Conclusión: Ni el TDM ni la EAI se asociaron con niveles alterados de copeptina plasmática. Por tanto, la copeptina no parece desempeñar un papel importante en el TDM y la EAI en mujeres adultas.

Cognitive and emotional empathy after stimulation of brain mineralocorticoid and NMDA receptors in patients with major depression and healthy controls.

Mineralocorticoid receptors (MR) are predominantly expressed in the hippocampus and prefrontal cortex. Both brain areas are associated with social cognition, which includes cognitive empathy (ability to understand others' emotions) and emotional empathy (ability to empathize with another person). MR stimulation improves memory and executive functioning in patients with major depressive disorder (MDD) and healthy controls, and leads to glutamate-mediated N-methyl-D-aspartate receptor (NMDA-R) signaling. We examined whether the beneficial effects of MR stimulation can be extended to social cognition (empathy), and whether DCS would have additional beneficial effects. In this double-blind placebo-controlled single-dose study, we randomized 116 unmedicated MDD patients (mean age 34 years, 78% women) and 116 age-, sex-, and education years-matched healthy controls to four conditions: MR stimulation (fludrocortisone (0.4 mg) + placebo), NMDA-R stimulation (placebo + D-cycloserine (250 mg)), MR and NMDA-R stimulation (both drugs), or placebo. Cognitive and emotional empathy were assessed by the Multifaceted Empathy Test. The study was registered on clinicaltrials.gov (NCT03062150). MR stimulation increased cognitive empathy across groups, whereas NMDA-R stimulation decreased cognitive empathy in MDD patients only. Independent of receptor stimulation, cognitive empathy did not differ between groups. Emotional empathy was not affected by MR or NMDA-R stimulation. However, MDD patients showed decreased emotional empathy compared with controls but, according to exploratory analyses, only for positive emotions. We conclude that MR stimulation has beneficial effects on cognitive empathy in MDD patients and healthy controls, whereas NMDA-R stimulation decreased cognitive empathy in MDD patients. It appears that MR rather than NMDA-R are potential treatment targets to modulate cognitive empathy in MDD.

Steroid hormone secretion after stimulation of mineralocorticoid and NMDA receptors and cardiovascular risk in patients with depression.

Major depressive disorder (MDD) is associated with altered mineralocorticoid receptor (MR) and glucocorticoid receptor function, and disturbed glutamatergic signaling. Both systems are closely intertwined and likely contribute not only to the pathophysiology of MDD, but also to the increased cardiovascular risk in MDD patients. Less is known about other steroid hormones, such as aldosterone and DHEA-S, and how they affect the glutamatergic system and cardiovascular disease risk in MDD. We examined salivary cortisol, aldosterone, and DHEA-S secretion after stimulation of MR and glutamatergic NMDA receptors in 116 unmedicated depressed patients, and 116 age- and sex-matched healthy controls. Patients (mean age = 34.7 years, SD = ±13.3; 78% women) and controls were randomized to four conditions: (a) control condition (placebo), (b) MR stimulation (0.4 mg fludrocortisone), (c) NMDA stimulation (250 mg D-cycloserine (DCS)), and (d) combined MR/NMDA stimulation (fludrocortisone + DCS). We additionally determined the cardiovascular risk profile in both groups. DCS had no effect on steroid hormone secretion, while cortisol secretion decreased in both fludrocortisone conditions across groups. Independent of condition, MDD patients showed (1) increased cortisol, increased aldosterone, and decreased DHEA-S concentrations, and (2) increased glucose levels and decreased high-density lipoprotein cholesterol levels compared with controls. Depressed patients show profound alterations in several steroid hormone systems that are associated both with MDD pathophysiology and increased cardiovascular risk. Prospective studies should examine whether modulating steroid hormone levels might reduce psychopathology and cardiovascular risk in depressed patients.

Noradrenergic system and cognitive flexibility: Disentangling the effects of depression and childhood trauma.

Stress plays a fundamental role in the development and maintenance of major depressive disorder (MDD). Importantly, maladaptive changes in the physiological stress regulation systems have been demonstrated. In the locus coeruleus-noradrenergic (LC-NA) system, up-regulated central alpha2-adrenergic receptors in patients with MDD affect cognitive functions. Although cognitive deficits are core symptoms of MDD, the relationship between the LC-NA system and cognitive processes has rarely been investigated in depressed patients. The aim of our study was to investigate whether noradrenergic stimulation affects cognitive flexibility in MDD. In addition, we aimed to further disentangle the effects of MDD and adverse childhood experiences (ACE), such as physical or sexual abuse on cognitive function. In a double-blind placebo-controlled study, MDD patients with ACE, MDD patients without ACE, healthy participants with ACE and healthy control participants without MDD or ACE were tested with a task switching task (total N = 125). Participants were tested twice after treatment with either 10 mg yohimbine or a placebo. Switch costs (differences between switch and repetition trials) in reaction times and accuracy served as the independent variables. We found higher switch costs in MDD patients as compared with controls, while ACE did not affect task performance. Yohimbine administration had no effect on task switching. The results of this study contribute to a better understanding of the role of the LC-NA system as a neurobiological mechanism of cognitive processes in patients with MDD.

Enhanced noradrenergic activity by yohimbine and differential fear conditioning in patients with major depression with and without adverse childhood experiences.

Major depressive disorder (MDD) has been associated with changes in the biological stress systems, including the locus coeruleus-noradrenergic system. Accumulated evidence suggests an upregulation of central alpha2-receptors, leading to decreased noradrenergic activity on a central level in MDD patients. Adverse childhood experiences (ACE) such as physical or sexual abuse might contribute to those changes. Furthermore, noradrenaline can affect cognitive processes, e.g. learning and memory. Cognitive dysfunctions constitute an important symptom of MDD. We aimed to investigate the relationship of alpha2-receptor dysregulation with learning processes in MDD by conducting a differential fear conditioning paradigm after double-blind administration of the alpha2-receptor antagonist yohimbine versus placebo. To investigate the role of ACE systematically, we included four groups of healthy participants and MDD patients with and without ACE (MDD-/ACE-: N = 44, MDD-/ACE+: N = 26, MDD+/ACE-: N = 24, MDD+/ACE+: N = 24; without antidepressant medication). We found increased noradrenergic activity after yohimbine administration across groups as measured by alpha-amylase and blood pressure. Overall, fear responses were higher after yohimbine as indicated by skin conductance responses and fear-potentiated startle responses. While we found no significant MDD effect, ACE had significant impact on the ability to discriminate between both conditioned stimuli (CS+ predicting an aversive stimulus, CS- predicting none), depending on drug condition. After yohimbine, CS discrimination decreased in individuals without ACE, but not in individuals with ACE. Differences in the response to yohimbine might be explained by aberrant alpha2-receptor regulation in individuals with ACE. Impaired discrimination of threat and safety signals might contribute to enhanced vulnerability following ACE.

Inhibition of monoamine oxidase activity by repetitive transcranial magnetic stimulation: implications for inter-train interval and frequency.

Repetitive transcranial magnetic stimulation (rTMS) is a neuromodulation technique that stimulates cortical regions via time-varying electromagnetic fields; in several countries this technique has been approved as a treatment for major depressive disorder. One empirically established target in antidepressant pharmacotherapy is the flavin-containing monoamine oxidoreductase (MAO). The function of MAO enzymes is based on oxidation processes that may be sensitive towards strong electromagnetic fields. Therefore, we hypothesized that rTMS-induced electromagnetic fields impact the activity of this enzyme. Using crude synaptosomal cell preparations from human SH-SY5Y neuroblastoma cells and rat cortex as well as viable cells, we assessed the effects of rTMS on MAO-A and -B activity in a well-controlled in vitro set up. In short, samples were stimulated at maximal intensity with an equal number of total stimuli at frequencies of 5, 20, and 100 Hz. Sham stimulation was performed in parallel. Treatment at frequencies of 5 and 20 Hz significantly decreased mainly MAO-B activity in all tissue preparations and species, whereas 100 Hz stimulation remained without effect on any MAO activity. Our results support the hypothesis, that rTMS-induced electromagnetic fields affect MAO activity and provide further evidence for intracellular effects possibly contributing to therapeutic effects of this neuromodulatory method. On a cautionary note, however, our findings are solely based on in vitro evidence.

Childhood trauma and diagnosis of major depression: Association with memory and executive function.

Cognitive function is often impaired in patients with major depressive disorder (MDD). Childhood trauma is a risk factor for developing MDD and is also associated with cognitive impairments in later life. We aimed to investigate the effects of childhood trauma on cognitive function in MDD. 68 medication-free MDD patients and 75 healthy controls (HC) participated. We tested cognitive function with the Autobiographical Memory Test, Auditory Verbal Learning Test (AVLT), Trail Making Test A and B, Rey-Osterrieth/Taylor Complex Figure Test, and Digit Span Backward. Childhood trauma was assessed with the Childhood Trauma Questionnaire (CTQ). Patients and HC did not differ with respect to age, sex, education. Mean CTQ sum scores differed significantly for depressed and HC with mean 47.8 (19.2) and 31.0 (6.8), respectively. Depressed patients and HC (without taking childhood trauma into account) differed only in AVLT performance. When childhood trauma was considered, this group difference disappeared. Subsequent regression analyses revealed that higher CTQ scores but not a diagnosis of MDD were associated with less specific autobiographical memories. Associations of CTQ with other cognitive domains failed significance after correction for multiple testing. Our results suggest that cognitive function is influenced by childhood trauma in MDD. However, the effects are small.

Mineralocorticoid receptor stimulation improves cognitive function and decreases cortisol secretion in depressed patients and healthy individuals.

Memory and executive function are often impaired in patients with major depression, while cortisol secretion is increased. Mineralocorticoid receptors (MR) are abundantly expressed in the hippocampus and in the prefrontal cortex, brain areas critical for memory, executive function, and cortisol inhibition. Here, we investigated whether MR stimulation with fludrocortisone (1) improves memory and executive function and (2) decreases cortisol secretion in depressed patients and healthy individuals. Twenty-four depressed patients without medication and 24 age-, sex-, and education-matched healthy participants received fludrocortisone (0.4 mg) or placebo in a randomized, double-blind, within-subject cross-over design. We measured verbal memory, visuospatial memory, executive function, psychomotor speed, and salivary cortisol secretion during cognitive testing between 1400 and 1700 hours. For verbal memory and executive function, we found better performance after fludrocortisone compared with placebo across groups. No treatment effect on other cognitive domains emerged. Depressed patients performed worse than healthy individuals in psychomotor speed and executive function. No group effect or group × treatment interaction emerged on other cognitive domains. Fludrocortisone decreased cortisol secretion across groups and there was a significant correlation between cortisol inhibition and verbal memory performance. Our data suggest a crucial role of MR in verbal memory and executive function and demonstrate the possibility to improve cognition in depressed patients and healthy individuals through MR stimulation.