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Recent observations suggest a role of the volume of the cerebral ventricle volume, corpus callosum (CC) segment volume, in particular that of the central-anterior part, and choroid plexus (CP) volume for treatment resistance of major depressive disorder (MDD). An increased CP volume has been associated with increased inflammatory activity and changes in the structure of the ventricles and corpus callosum. We attempt to replicate and confirm that these imaging markers are associated with clinical outcome in subjects from the EMBARC study, as implied by a recent pilot study. The EMBARC study is a placebo controlled randomized study comparing sertraline vs. placebo in patients with MDD to identify biological markers of therapy resistance. Association of baseline volumes of the lateral ventricles (LVV), choroid plexus volume (CPV) and volume of segments of the CC with treatment response after 4 weeks treatment was evaluated. 171 subjects (61 male, 110 female) completed the 4 week assessments; gender and age were taken into account for this analyses. As previously reported, no treatment effect of sertraline vs. placebo was observed, therefore the study characterized prognostic markers of response in the pooled population. Change in depression severity was identified by the ratio of the Hamilton-Depression rating scale 17 (HAMD-17) at week 4 divided by the HAMD-17 at baseline (HAMD-17 ratio). Volumes of the lateral ventricles and choroid plexi were positively correlated with the HAMD-17 ratio, indication worse outcome with larger ventricles and choroid plexus volumes, whereas the volume of the central-anterior corpus callosum was negatively correlated with the HAMD-17 ratio. Responders (n = 54) had significantly smaller volumes of the lateral ventricles and CP compared to non-responders (n = 117), whereas the volume of mid-anterior CC was significantly larger compared to non-responders (n = 117), confirming our previous findings. In an exploratory way associations between enlarged LVV and CPV and signs of lipid dysregulation were observed. In conclusion, we confirmed that volumes of lateral ventricles, choroid plexi and the mid-anterior corpus callosum are associated with clinical improvement of depression and may be indicators of metabolic/inflammatory activity.

The renin–angiotensin–aldosterone system and its hormone receptors, i.e. the angiotensin and mineralocorticoid receptor (MR), have emerged as important targets for central nervous system disorders and in particular for major depression. We have recently characterized baseline MR function as a predictor for treatment outcome with standard antidepressants. The aims of this study are (i) to characterize how strongly an early biomarker change (after 2 weeks) is related to outcome and (ii) whether these biomarker changes are related to the final outcome, that is, could serve as surrogate markers for response. Twenty-four of 30 patients with unipolar major depression completed the observational trial. MR-related biomarkers were assessed at baseline, 2 weeks, and 6 weeks of standard antidepressant treatment. These biomarkers included slow wave sleep (SWS), salivary cortisol and aldosterone after awakening, heart rate variability measured as respiratory sinus arrhythmia (RSA), systolic blood pressure, salt taste intensity (STI), salt pleasantness (SP), and plasma electrolytes. The Hamilton depression rating scale with 21 items was primarily used to determine depression severity. In the overall sample, STI increased and SP decreased significantly with treatment without a clear relationship with treatment outcome. No other significant changes were observed. Reductions in cortisol and aldosterone after 2 weeks of treatment were significantly related to improvement after 6 weeks (P<0.05). SWS increase after 2 and 6 weeks was by trend (P<0.08) correlated to clinical improvement after 6 weeks. Systolic blood pressure differentiated responders and nonresponders at baseline (P<0.05), but did not change significantly during treatment. We earlier identified a relationship between clinical outcome and baseline values of STI, SP, and RSA only in male patients; therefore, changes in this subgroup were analyzed separately: in male treatment responders, a trend toward an increase in SWS occurred after 2 (P<0.07) and 6 (P<0.07) weeks. Further, a trend toward RSA reduction (P<0.07) was observed. Changes in STI and SP were similar to the total group, but did not reach levels of significance. Early changes in central MR-related biomarkers appear to influence the outcome of standard antidepressant treatment: reduced salivary cortisol, increased SWS, and reduced RSA are linked to a better treatment outcome. These features point to a mechanism involving increased central MR activation in responders to standard antidepressants, but not in nonresponders.

A close association between vegetative regulation and affect is common knowledge. Recently, the role of aldosterone and the activity of its receptor [mineralocorticoid receptor (MR)] in the clinical outcome for treatment with standard antidepressants has been shown including low systolic blood pressure and a low concentration of plasma sodium (Na+), both of which appear to be related to therapy resistance to standard antidepressants. We carried out a retrospective analysis of a double-blind placebo-controlled trial of St John’s wort extract LI160 in 247 outpatients with major depression. The study did not show a difference between the treatment groups; therefore, a pooled dataset of the 6-week completer population of the trial was analyzed. The focus was on the moderating effect of blood pressure and electrolytes on clinical outcome (relative change in Montgomery–Asberg Depression Rating Scale). Low Na+/K+ratio and high K+at screening predicted worse outcome after 6 weeks as measures with the Montgomery–Asberg Depression Rating Scale (P<0.01). Systolic blood pressure at the same time point did not influence the treatment outcome. In conclusion, signs of reduced peripheral MR sensitivity, as reflected by a lower plasma Na+/K+ratio and/or higher K+concentration, predict worse outcome. This is in line with our recent data as well as neuroendocrine findings. The data indicate that widely collected biomarkers, which are related to MR activity, may be useful to identify patients, who are at risk of nonresponse to antidepressant treatment.

This study looks to compare the antidepressant efficacy and safety of a standardized extract of St John's wort with both placebo and fluoxetine.

Selective serotonin reuptake inhibitors (SSRIs) are widely used as effective pharmacological agents to treat depressive disorders. In contrast to the SSRIs, which block the presynaptic serotonin (5-HT) transporter and by this route increase the concentration of serotonin in the synaptic cleft, the antidepressant tianeptine enhances the presynaptic neuronal reuptake of 5-HT and thus decreases serotonergic neurotransmission. Both SSRIs and tianeptine are clinically effective; however, their opposite modes of action challenge the prevailing concepts on the need of enhancement of serotonergic neurotransmission. To better understand the differences between these two opposite pharmacological modes of action, we compared the changes induced by tianeptine and paroxetine on psychopathology, the hypothalamic-pituitary-adrenocortical (HPA) system, and cognitive functions in a double-blind, randomized, controlled trial including 44 depressed inpatients over a period of 42 days. Depressive symptomatology significantly improved in all efficacy measures, with no significant differences between tianeptine and paroxetine. There was a trend toward better response to the SSRI among women. Assessment of the HPA system showed marked hyperactivity before the beginning of treatment, which then normalized in most of the patients, without significant differences between the two antidepressants. Cognitive assessments showed no significant differences between the two drugs investigated. The results of the current study suggest that the initial effect, i.e., enhancement or decrease of 5-HT release, is only indirectly responsible for antidepressant efficacy, and they support the notion that downstream adaptations within and between nerve cells are crucial. The normalization of the HPA system as a common mode of action of different antidepressants seems to be of special interest.

Walther, Christian, Klaus E. Zittlau, Harald Murck, and Karlheinz Voigt.Resting membrane properties of locust muscle and their modulation. I. Actions of the neuropeptides YGGFMRFamide and proctolin. J. Neurophysiol.80: 771–784, 1998. The resting K+conductance (GK,r) of locust jumping muscle and its modulation by two neuropeptides, proctolin (Arg-Tyr-Leu-Pro-Thr) and YGGFMRFamide (Tyr-Gly-Gly-Phe-Met-Arg-Phe-NH2), were investigated using the two-electrode voltage clamp. At a physiological [K+]oof 10 mM, GK,raccounts for ∼90% of the membrane resting conductance, and the resting membrane potential differs by ≤1 mV from EK(mean: −74 mV). There is a K+conductance that slowly activates on hyperpolarization (GK,H) and that seems to be largely located in the transverse tubules. Steady-state activation of GK,Hwas analyzed by tail current measurements. GK,His activated partially at EKbut accounts for probably ≤50% of total resting K+conductance. Raising [K+]ocaused a large increase in GK,rand in maximal steady state GK,Hwithout shifting the voltage sensitivity of GK,H. YGGFMRFamide and proctolin reduce GK,H, mainly affecting the maximal steady-state conductance. The voltage-insensitive component of the resting K+conductance is also reduced. The conductance suppressed by the peptides exhibited an outwardly rectifying instantaneous current/voltage-characteristic that is quite similar to that of GK,H. The actions of the two peptides appeared to be identical, but proctolin was by some two orders of magnitude more potent than YGGFMRFamide. The effects of both peptides are mediated by G proteins. They are mimicked by phorbol esters but do not seem to be initiated by either branch of the phospholipase C-dependent intracellular pathways. The properties of the resting K+conductance in locust muscle and other invertebrate muscles are compared. The biological significance of peptide-induced reduction in resting K+conductance is discussed in view of the known property of proctolin to support tonic force as opposed to FMRFamide-peptides that support quick leg movements.

With increasing age, sleep becomes more shallow and fragmented and sleep-associated growth hormone (GH) release declines. GH secretion is regulated physiologically by opposite actions of GH-releasing hormone (GHRH) and somatostatin (SRIF). The administration of GHRH promotes sleep in both young and elderly controls, whereas SRIF does not induce sleep-EEG changes in young subjects. Because the influence of peripheral SRIF administration on sleep EEG in the elderly is unknown, we administered 50 μg SRIF-14 every hour between 2200 and 0100 hours to controls with an age range from 60 to 73 years (mean ± SD 67.4 ± 5.1 years). After SRIF administration, total sleep time and rapid eye movement (REM) sleep decreased significantly, and more time was spent awake in the first sleep cycle, suggesting that SRIF induces sleep deterioration in the elderly. The peptide may become more effective on sleep EEG in older than in younger subjects, because of the decline of GHRH–GH axis activity, which may contribute to sleep disturbances in aging. The increased efficacy of SRIF in the elderly also may be explained by enhanced leakage of the blood-brain barrier.

Hypericum extract (HE) might be favourably active in depressed patients with reversed vegetative signs (RVS). Therefore, we performed an exploratory subgroup analysis of a three-armed study to compare HE, fluoxetine, and placebo in patients with major depressive disorder (MDD) in a 12 wk trial. A total of 135 patients were randomized to 12 wk treatment with HE LI 160 (900 mg/d), fluoxetine (20 mg/d), or placebo. Patients with RVS were defined in two steps, according to DSM-IV. First, patients with melancholy-related vegetative signs were excluded. Secondly, patients had to have at least one score of 2 for the items 22–26 of the HAMD-28 scale, which are related to hypersomnia and hyperphagia. Twenty-seven patients remained in the group. Analysis of covariance (ANCOVA) was applied using the HAMD-17 score. Secondly a ?2 test for response was performed, using the same and further an adapted criterium as in recently published studies. ANCOVA revealed a trend to a global difference. Post-hoc analysis showed a trend to superiority of HE compared to placebo and to fluoxetine, but a very large effect size for both differences. Fluoxetine was not different from placebo. The adapted response criterium showed a significant global difference as well as a significant superiority of HE over placebo and over fluoxetine. These data are based on a small sample size and must be considered tentative. A characterization of vegetative features of patients with depression could lead to an overall increased effect size in the treatment with HE.

Preliminary evidence shows that ethyl-eicosapentaenoate (E-EPA) has a marked clinical effect when used as an adjunct in therapy-refractory depression. EPA belongs to the class of polyunsaturated omega-3 fatty acids. The mechanism of its action in depression is not fully understood. There are two related fields where the pathophysiology of refractory depression meets the effect of EPA. First, a general immunosuppressive effect of EPA meets a general immunoactivation in severe depression, especially an increase in CD4/CD8 ratio, neutrophilia, and an increase in interleukins (IL)-6 and IL-12 and of prostaglandin E2 (PGE2). Secondly, a resistance to dexamethasone (Dex) suppression of the HPA axis meets the effects of EPA on multidrug resistance reversing and HPA axis suppression. The effects of EPA on the immune system, the HPA axis, and multidrug resistance are connected through the action of a transport protein called p-glycoprotein (p-gp). Physiological and synthetic steroids such as cortisol and Dex are substrates of p-gp, and so Dex resistance in depression may be related to dysfunction of this protein. In addition, expression of p-gp is induced by PGE2, and EPA inhibits the synthesis of PGE2. The reversal of drug resistance by EPA may be mediated via this immunological mechanism and lead to its antidepressive efficacy. In addition, antidepressants such as amitriptyline, which have special efficacy in severe depression, decrease p-gp function. EPA may, furthermore, enhance the action of antidepressants, like many SSRIs that are p-gp substrates, which are actively transported out of the intracerebral space at the level of the bloodbrain barrier.