Therapy-refractory Depression Research Articles

Vagus nerve stimulation for conservative therapy-refractive epilepsy and depression.

Numerous studies confirm that the vagus nerve stimulation (VNS) is an efficient, indirect neuromodulatory therapy with electrically induced current for epilepsy that cannot be treated by epilepsy surgery and is therapy-refractory and for drug therapy-refractory depression. VNS is an established, evidence-based and in the long-term cost-effective therapy in an interdisciplinary overall concept.Long-term data on the safety and tolerance of the method are available despite the heterogeneity of the patient populations. Stimulation-related side effects like hoarseness, paresthesia, cough or dyspnea depend on the stimulation strength and often decrease with continuing therapy duration in the following years. Stimulation-related side effects of VNS can be well influenced by modifying the stimulation parameters. Overall, the invasive vagus nerve stimulation may be considered as a safe and well-tolerated therapy option.For invasive and transcutaneous vagus nerve stimulation, antiepileptic and antidepressant as well as positive cognitive effects could be proven. In contrast to drugs, VNS has no negative effect on cognition. In many cases, an improvement of the quality of life is possible.iVNS therapy has a low probability of complete seizure-freedom in cases of focal and genetically generalized epilepsy. It must be considered as palliative therapy, which means that it does not lead to healing and requires the continuation of specific medication. The functional principle is a general reduction of the neuronal excitability. This effect is achieved by a slow increase of the effectiveness sometimes over several years. Responders are those patients who experience a 50% reduction of the seizure incidence. Some studies even reveal seizure-freedom in 20% of the cases. Currently, it is not possible to differentiate between potential responders and non-responders before therapy/implantation.The current technical developments of the iVNS generators of the new generation like closed-loop system (cardiac-based seizure detection, CBSD) reduce also the risk for SUDEP (sudden unexpected death in epilepsy patients), a very rare, lethal complication of epilepsies, beside the seizure severity.iVNS may deteriorate an existing sleep apnea syndrome and therefore requires possible therapy interruption during nighttime (day-night programming or magnet use) beside the close cooperation with sleep physicians.The evaluation of the numerous iVNS trials of the past two decades showed multiple positive effects on other immunological, cardiological, and gastroenterological diseases so that additional therapy indications may be expected depending on future study results. Currently, the vagus nerve stimulation is in the focus of research in the disciplines of psychology, immunology, cardiology as well as pain and plasticity research with the desired potential of future medical application.Beside invasive vagus nerve stimulation with implantation of an IPG and an electrode, also devices for transdermal and thus non-invasive vagus nerve stimulation have been developed during the last years. According to the data that are currently available, they are less effective with regard to the reduction of the seizure severity and duration in cases of therapy-refractory epilepsy and slightly less effective regarding the improvement of depression symptoms. In this context, studies are missing that confirm high evidence of effectiveness. The same is true for the other indications that have been mentioned like tinnitus, cephalgia, gastrointestinal complaints etc. Another disadvantage of transcutaneous vagus nerve stimulation is that the stimulators have to be applied actively by the patients and are not permanently active, in contrast to implanted iVNS therapy systems. So they are only intermittently active; furthermore, the therapy adherence is uncertain.

"The Heart Asks Pleasure First"-Conceptualizing Psychiatric Diseases as MAINTENANCE Network Dysfunctions through Insights from slMFB DBS in Depression and Obsessive-Compulsive Disorder.

More than a decade ago, deep brain stimulation (DBS) of the superolateral medial forebrain bundle (slMFB), as part of the greater MFB system, had been proposed as a putative yet experimental treatment strategy for therapy refractory depression (TRD) and later for obsessive–compulsive disorders (OCD). Antidepressant and anti-OCD efficacy have been shown in open case series and smaller trials and were independently replicated. The MFB is anato-physiologically confluent with the SEEKING system promoting euphoric drive, reward anticipation and reward; functions realized through the mesocorticolimbic dopaminergic system. Growing clinical experience concerning surgical and stimulation aspects from a larger number of patients shows an MFB functionality beyond SEEKING and now re-informs the scientific rationale concerning the MFB’s (patho-) physiology. In this white paper, we combine observations from more than 75 cases of slMFB DBS. We integrate these observations with a selected literature review to provide a new neuroethological view on the MFB. We here formulate a re-interpretation of the MFB as the main structure of an integrated SEEKING/MAINTENANCE circuitry, allowing for individual homeostasis and well-being through emotional arousal, basic and higher affect valence, bodily reactions, motor programing, vigor and flexible behavior, as the basis for the antidepressant and anti-OCD efficacy.

The potential pathophysiological role of aldosterone and the mineralocorticoid receptor in anxiety and depression – Lessons from primary aldosteronism

High levels of aldosterone appear to be related to depressive and anxiety related behavior as demonstrated in therapy refractory depression and primary aldosteronism (PA). We analyzed data from a large register of patients with PA in order to clarify mediators and moderators of this influence. Up to 624 subjects were analyzed, however not all subjects had a complete dataset. Due to the known gender differences in subjects with PA we performed the analyses adjusted for gender. We compared subjects with (PHQ-9 ≥ 5) vs. no depressive symptomatology. 56% of men and 61% of women met this depression criterion. In women aldosterone concentration was significantly higher in depressed patients and renin levels were significantly increased with higher anxiety scores. This was not found in men. Depressive symptoms in men and women were significantly associated to BMI (men: dep vs non-dep: 29.6 vs. 28.4, p < 0.05; women: 26.9 vs. 24.5) and body weight (p < 0.05). Neither blood pressure nor electrolytes were different between depression groups. The relationship of these parameters to anxiety was less pronounced and partially unexpected: only in men higher anxiety (GAD ≥ 5) was related to lower systolic blood pressure. In conclusion, higher aldosterone appears to be associated with depressive symptoms in women, but less so in men with PA. BMI appears to be strongly and independently associated with depressive symptoms in patients with PA, independent of gender. Further studies are required to clarify the causal relationship.

S76. Under Pressure – Is Therapy Refractory Depression a Disorder of CSF-Secretion?

Increased aldosterone (Aldo) levels and central mineralcorticoid-receptors (MR) activation are linked to therapy resistance to antidepressants. Apart from regulating of slow-wave-sleep, heart-rate-variability, salt preference, aldosterone affect the secretion of cerebrospinal fluid.

Target-based biomarker selection – Mineralocorticoid receptor-related biomarkers and treatment outcome in major depression

Aldosterone and mineralocorticoid receptor (MR)-function have been related to depression. We examined central and peripheral parameters of MR-function in order to characterize their relationship to clinical treatment outcome after six weeks in patients with acute depression.30 patients with a diagnosis of major depression were examined 3 times over a 6 week period. Aldosterone and cortisol salvia samples were taken at 7.00 a.m. before patients got out of bed. Easy to use e-devices were used to measure markers of central MR function, i.e. slow wave sleep (SWS) and heart-rate variability (HRV). Salt-taste intensity (STI) and salt pleasantness (SP) of a 0.9% salt solution were determined by a newly developed scale. In addition, systolic blood pressure (SBP) and plasma electrolytes were determined as markers for peripheral MR activity. The relationship between the levels of these biomarkers at baseline and the change in clinical outcome parameters (Hamilton depression rating scale (HDRS)-21, anxiety, QIDS and BDI) after 6 weeks of treatment was investigated. A higher aldosterone/cortisol ratio (Aldo/Cort) (n = 17 due to missing values; p < 0.05) and lower SBP (n = 24; p < 0.05) at baseline predicted poor outcome, as measured with the HDRS, independent of gender. Only in male patients higher STI, lower SP, lower SWS (all n = 13) and higher HRV (n = 11) at baseline predicted good outcome p < 0.05). Likewise, in male patients low baseline sodium appears to be predictive for a poor outcome (n = 12; p = 0.05; based on HDRS-6). In conclusion, correlates of higher central MR-activation are associated with poorer clinical improvement, particularly in men. This contrasts with the finding of a peripheral MR-desensitization in more refractory patients. As one potential mechanism to consider, sodium loss on the basis of dysfunctional peripheral MR function and additional environmental factors may trigger increased aldosterone secretion and consequently worse outcome. These markers deserve further study as potential biological correlates for therapy refractory depression.

Electroconvulsive therapy increases hippocampal and amygdala volume in therapy refractory depression: A longitudinal pilot study

Electroconvulsive therapy (ECT) is the most potent biological therapy in depression. Animal studies suggest that ECT acts via neuroplasticity effects on limbic structures involved in the pathophysiology of depression but in vivo evidence at the human system level is scarce. Therefore, the aim of the present study was to investigate the effect of ECT on hippocampus and amygdala volume in 15 antidepressant-free patients with treatment refractory depression (seven males, range 42–63 years). ECT treatment was successful as indexed by a significant decrease in depressive symptoms (t14=13.6; p<0.001). Analysis of normalized volumetric data before and after ECT treatment revealed a significant volume increase of both hippocampus and amygdala (minimum p<0.005) with no evidence for a change in global brain volume. Though this change in volume cannot be clearly related to treatment effects, ECT is associated with broader neurotrophic effects other than mere adult neurogenesis in the hippocampus, which has been previously suggested as a core mechanism on the basis of animal data.

P 107. Performance of electroconvulsive therapy in a patient with clipping of the middle intracerebral artery (Yasargil titanium clip) without major complications

Little is known regarding the risks of electroconvulsive therapy (ECT) in patients with clippings of intracerebral aneurysms. Currently, literature merely provides few anecdotal reports ( Najiar and Guttmacher, 1998 ) and manufacturers of such clipping systems (usually made of titanium) refrain from any suggestions concerning the safety during the performance of ECT. Thus, clinicians facing the coincidence of therapy-refractory depression (suggesting performance of ECT) and presence of intracerebral clips have to trade of possible benefits of ECT against theoretical risks in the complete absence of any guidelines or recommendations. Indeed, titanium is principally inert and the application of electric current should therefore not result in significant warming (with the risk of damaging surrounding brain tissue). However, the indication of ECT under these conditions must be confirmed meticulously. A case report is presented in order to to contribute to the available experience concerning this clinical situation. We present the case of a 55-year old female patient who successfully underwent clipping (Yasargil Titanium Clip, Aesculap®) of the left middle cerebral artery (MCA) due to MCA-aneurysm three years prior. The patient suffered from treatment-refractory major depressive disorder (recurrent type). Taking into account that various pharmacologic treatment attempts failed, ECT was considered. The patient was comprehensively informed about possible risks of the procedure related to the titanium clip. Before ECT CT-angiography was performed showing no re-development of the surgically treated aneurysm or development of new aneurysms. 12 cycles of right-unilateral ECT were performed without any complications despite ECT-related tachycardia. During ECT the patient was treated with esmolol. Subsequently, the patient’s clinical situation significantly improved. Though clear guidelines or suggestions of manufacturers of neurosurgical clips regarding safety during ECT are absent we did not observe any major complications during ECT in a patient with an intracerebral Yasargil titanium clip. However, the material behaviour of titanium during application of electric current remains to be studied systematically in order to rule out problematic warming with the risk of tissue damage.

Partial Status Epilepticus after Electroconvulsive Therapy and Medical Treatment with Bupropion

Electroconvulsive therapy (ECT) is the most effective treatment for therapy-refractory depression. Usually, prior antidepressant medication will be continued during ECT. However, the seizure threshold may be influenced by psychotropic drugs. We report a patient who received right unilateral ECT under concomitant treatment with bupropion, a selective noradrenaline- and dopamine-reuptake inhibitor. After the fourth session, a focal status epilepticus occurred, which was pharmacoresistant for the duration of 12 days. We assume that the induction of a status may be facilitated by a lowering of the seizure threshold due to bupropion. An evaluation of drug therapy and control of EEG before and during ECT are recommended, especially when the drug treatment has an influence on the seizure threshold.

Ethyl-EPA and dexamethasone-resistance in therapy-refractory depression

Ethyl-EPA and dexamethasone-resistance in therapy-refractory depression

Ethyl-eicosapentaenoate and dexamethasone resistance in therapy-refractory depression

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 blood-brain barrier.