Brain stimulation for treatment-resistant depression.

Depression is one of the main public health problems in the world, having a high prevalence and being considered the main cause of disability. An important portion of patients does not respond to treatment with the initial trial of conventional antidepressants in the current depressive episode of moderate to severe intensity, which characterizes treatment-resistant depression. In this context, non-invasive neuromodulation procedures use an electric current or magnetic field to modulate the central nervous system, and they represent a new option for patients with treatment-resistant depression.

A Clinical Case Series of Acute and Maintenance Home Administered Transcranial Direct Current Stimulation in Treatment-Resistant Depression.

OBJECTIVES: Transcranial direct current stimulation (tDCS) is a noninvasive neurostimulation technique being translated clinically for the treatment of depression. There is limited research documenting the longer-term effectiveness and safety of tDCS treatment. This case series is the first report of remotely supervised, home-administered tDCS (HA-tDCS) for depression in a clinical setting. METHODS: We report clinical, cognitive, and safety outcomes from 16 depressed patients who received acute and/or maintenance HA-tDCS. We retrospectively examined clinical data from up to 2.5 years of treatment. Descriptive statistics are reported to document patient outcomes. RESULTS: Twelve patients received acute treatment for a current depressive episode and 4 commenced tDCS maintenance therapy after responding to ECT or repetitive transcranial magnetic stimulation (rTMS). The cohort was highly treatment-resistant wherein 15 of 16 patients failed 3 trials or more of antidepressant medication in the current episode, and 6 patients failed to gain significant benefit from prior ECT or rTMS. Five of 12 patients responded to acute tDCS within 6 weeks, and 9 patients who received tDCS for more than 12 weeks maintained improvements over several months. Cognitive tests showed no evidence of impairments in cognitive outcomes after up to 2 years of treatment. Two patients were withdrawn from treatment because of blurred vision or exacerbation of tinnitus. Transcranial direct current stimulation was otherwise safe and well tolerated. CONCLUSIONS: Transcranial direct current stimulation given for at least 6 weeks may be of clinical benefit even in treatment-resistant depression. Results provide support for long-term effectiveness, safety, and feasibility of remotely supervised HA-tDCS and suggest a role for maintenance tDCS after acute treatment with tDCS, rTMS, or ECT.

Cerebral Small Vessel Disease and Depression Among Intracerebral Hemorrhage Survivors.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is an acute manifestation of cerebral small vessel disease (CSVD), usually cerebral amyloid angiopathy or hypertensive arteriopathy. CSVD-related imaging findings are associated with increased depression incidence in the general population. Neuroimaging may, therefore, provide insight on depression risk among ICH survivors. We sought to determine whether CSVD CT and magnetic resonance imaging markers are associated with depression risk (before and after ICH), depression remission, and effectiveness of antidepressant treatment. METHODS: We analyzed data from the single-center longitudinal ICH study conducted at Massachusetts General Hospital. Participants underwent CT and magnetic resonance imaging imaging and were followed longitudinally. We extracted information for neuroimaging markers of CSVD subtype and severity. Outcomes of interest included pre-ICH depression, new-onset depression after ICH, resolution of depressive symptoms, and response to antidepressant treatment. RESULTS: We followed 612 ICH survivors for a median of 47.2 months. Multiple CSVD-related markers were associated with depression risk. Survivors of cerebral amyloid angiopathy-related lobar ICH were more likely to be diagnosed with depression before ICH (odds ratio, 1.68 [95% CI, 1.14-2.48]) and after ICH (sub-hazard ratio, 1.52 [95% CI, 1.12-2.07]), less likely to achieve remission of depressive symptoms (sub-hazard ratio, 0.69 [95% CI, 0.51-0.94]), and to benefit from antidepressant therapy (P=0.041). Cerebral amyloid angiopathy disease burden on magnetic resonance imaging was associated with depression incidence and treatment resistance (interaction P=0.037), whereas hypertensive arteriopathy disease burden was only associated with depression incidence after ICH. CONCLUSIONS: CSVD severity is associated with depression diagnosis, both before and after ICH. Cerebral amyloid angiopathy-related ICH survivors are more likely to experience depression (both before and after ICH) than patients diagnosed with hypertensive arteriopathy-related ICH, and more likely to report persistent depressive symptoms and display resistance to antidepressant treatment.

Relationship between childhood physical abuse and clinical severity of treatment-resistant depression in a geriatric population.

INTRODUCTION: We assessed the correlation between childhood maltreatment (CM) and severity of depression in an elderly unipolar Treatment-Resistant Depression (TRD) sample. METHODS: Patients were enrolled from a longitudinal cohort (FACE-DR) of the French Network of Expert TRD Centres. RESULTS: Our sample included 96 patients (33% of the overall cohort) aged 60 years or above, with a mean age of 67.2 (SD = 5.7). The majority of the patients were female (62.5%). The Montgomery and Asberg Depression Rating Scale (MADRS) and Quick Inventory Depression Scale-Self Report (QIDS-SR) mean scores were high, 28.2 (SD = 7.49) [MADRS score range: 0-60; moderate severity≥20, high severity≥35] and 16.5 (SD = 4.94) [IDS-SR score range: 0-27; moderate severity≥11, high severity≥16], respectively. Mean self-esteem scores were 22.47 (SD = 6.26) [range 0-30]. In an age- and sex-adjusted model, we found a positive correlation between childhood trauma (CTQ scores) and depressive symptom severity [MADRS (ß = 0.274; p = 0.07) and QIDS-SR (ß = 0.302; p = 0.005) scores]. We detected a statistically significant correlation between physical abuse and depressive symptom severity [MADRS (ß = 0.304; p = 0.03) and QIDS-SR (ß = 0.362; p = 0.005) scores]. We did not observe any significant correlation between other types of trauma and depressive symptom severity. We showed that self-esteem (Rosenberg scale) mediated the effect of physical abuse (PA) on the intensity of depressive symptoms [MADRS: b = 0.318, 95% BCa C.I. [0.07, 0.62]; QIDS-SR: b = 0.177, 95% BCa C.I. [0.04, 0.37]]. Preacher & Kelly's Kappa Squared values of 19.1% (k2 = 0.191) and 16% (k2 = 0.16), respectively for the two scales, indicate a moderate effect. CONCLUSION: To our knowledge, this is the first study conducted in a geriatric TRD population documenting an association between childhood trauma (mainly relating to PA) and the intensity of depressive symptoms.

Large falcine meningioma presented as treatment-resistant depression: A case report.

Large intracranial tumour may present only with psychiatric symptoms without any neurological deficits. Delay in surgical treatment may significantly affect the quality of life in these patients. We report a case of a young engineering student who was diagnosed as treatment-resistant depression without initial neuroimaging study. Further neuroimaging studies revealed he has a large falcine meningioma. His psychiatric symptoms resolved following surgical resection of the tumour. We emphasized the importance of initial neuroimaging study in young patients presenting with psychiatric symptoms.

Reversal of a Treatment-Resistant, Depression-Related Brain State with the Kv7 Channel Opener Retigabine.

Neuroinflammation is associated with increased vulnerability to diverse psychiatric conditions, including treatment-resistant major depressive disorder (MDD). Here we assessed whether high fat diet (HFD) induced neuroinflammation may be suitable to model a treatment-resistant depressive-like brain state in mice. Male and female mice were fed a HFD for 18 weeks, followed by quantitation of glucose tolerance, inflammatory markers of brain tissue (TNFα, IL-6, IL-1ß, Iba-1), neural excitability in the prelimbic cortex (PLC), as well as assessment of emotional reactivity and hedonic behavior in a battery of behavioral tests. In addition, we assessed the behavioral responsiveness of mice to fluoxetine, desipramine, ketamine, and the Kv7 channel opener and anticonvulsant retigabine. HFD exposure led to glucose intolerance and neuroinflammation in male mice, with similar but non-significant trends in females. Neuroinflammation of males was associated with anxious-depressive-like behavior and defects in working memory, along with neural hyperexcitability and increased Ih currents of pyramidal cells in the PLC. The behavioral changes were largely resistant to chronic treatment with fluoxetine and desipramine, as well as ketamine. By contrast, retigabine (also known as ezogabine) normalized neural excitability and Ih currents recorded from slices of HFD-treated animals and significantly ameliorated most of the behavioral impairments, without effects in control diet exposed animals. Thus, treatment resistant depressive-like brain states that are associated with chronic neuroinflammation may involve hyperexcitability of pyramidal neurons and may be effectively treated by retigabine.

Sleep-related breathing disturbances in adolescents with treatment resistant depression.

OBJECTIVE/BACKGROUND: A considerable subgroup of adolescents does not respond to standard antidepressant treatments. There are some indications that sleep disordered breathing may contribute to refractory depression in adults, but little is known about how it may relate to the course of depressive disorders in adolescents. Focussing on a group of Canadian adolescents with treatment resistant depression (TRD), this study aimed to investigate how the severity of residual depressive symptoms following unsuccessful antidepressant trials relates to breathing disturbances during sleep. PATIENTS/METHODS: A retrospective chart review was conducted at a tertiary mental health facility. Polysomnography, the Beck Depression Inventory-II (BDI-II), and the Epworth Sleepiness Scale (ESS) were collated from 18 adolescents (15-18 years old, 44% females) patients with depressive disorders who did not respond to at least two 4-week trials of antidepressant medications. RESULTS: Of this sample, 39% reported at least mild levels of excessive daytime sleepiness, and 55% had an apnea/hypopnea index ≥1. Worse depressive symptoms correlated with higher RDI (r = 0.53, p = 0.022). This was mainly driven by respiratory effort-related arousals occurring during NREM sleep (r = 0.52, p = 0.029). No significant correlation was found between depressive symptoms and other respiratory or sleep variables. Higher daytime sleepiness correlated significantly with lower minimum oxygen desaturation (r = -0.51, p = 0.030). CONCLUSIONS: These results suggest that even subtle respiratory disturbances during sleep may play a role in persistent depressive symptoms and treatment resistance. Early screening for sleep-related breathing disturbances in adolescents with TRD may be relevant, since previous work suggests that treating sleep-related breathing disturbances can attenuate depressive symptoms.

International Union of Basic and Clinical Pharmacology CIV: The Neurobiology of Treatment-resistant Depression: From Antidepressant Classifications to Novel Pharmacological Targets.

Major depressive disorder is one of the most prevalent and life-threatening forms of mental illnesses and a major cause of morbidity worldwide. Currently available antidepressants are effective for most patients, although around 30% are considered treatment resistant (TRD), a condition that is associated with a significant impairment of cognitive function and poor quality of life. In this respect, the identification of the molecular mechanisms contributing to TRD represents an essential step for the design of novel and more efficacious drugs able to modify the clinical course of this disorder and increase remission rates in clinical practice. New insights into the neurobiology of TRD have shed light on the role of a number of different mechanisms, including the glutamatergic system, immune/inflammatory systems, neurotrophin function, and epigenetics. Advances in drug discovery processes in TRD have also influenced the classification of antidepressant drugs and novel classifications are available, such as the neuroscience-based nomenclature that can incorporate such advances in drug development for TRD. This review aims to provide an up-to-date description of key mechanisms in TRD and describe current therapeutic strategies for TRD before examining novel approaches that may ultimately address important neurobiological mechanisms not targeted by currently available antidepressants. All in all, we suggest that drug targeting different neurobiological systems should be able to restore normal function but must also promote resilience to reduce the long-term vulnerability to recurrent depressive episodes.

The habenula in neurosurgery for depression: A convergence of functional neuroanatomy, psychiatry and imaging.

BACKGROUND: The habenula is a small, mostly underrated structure in the pineal region. Multidisciplinary findings demonstrate an underlying complex connectivity of the habenula with the rest of the brain, subserving its major role in normal behavior and the pathophysiology of depression. These findings suggest the potential application of "habenular psychosurgery" in the treatment of mental disorders. OBJECTIVE/HYPOTHESIS: The remission of two patients with treatment-resistant major depression treated with deep brain stimulation of the habenula supported the hypothesis that the habenula is an effective target for deep brain stimulation and initiated a surge of basic science research. This review aims to assess the viability of the deep brain stimulation of the habenula as a treatment option for treatment resistant depression. METHODS: PubMed and the Cochrane Library databases were searched with no chronological restrictions for the identification of relevant articles. RESULTS: The results of this review are presented in a narrative form describing the functional neuroanatomy of the human habenula, its implications in major depression, findings of electrode implantation of this region and findings of deep brain stimulation of the habenula for the treatment of depression. CONCLUSION: Data assessing the hypothesis are scarce. Nonetheless, findings highlight the major role of the habenula in normal, as well as in pathological brain function, particularly in depression disorders. Moreover, findings of studies utilizing electrode implantation in the region of the habenula underscore our growing realization that research in neuroscience and deep brain stimulation complement each other in a reciprocal relationship; they are as self-reliant, as much as they depend on each other.

Refractory Depression, Fatigue, Irritable Bowel Syndrome, and Chronic Pain: A Functional Medicine Case Report.

INTRODUCTION: Single-disorder or single-organ-system clinical practice guidelines are often of limited usefulness in guiding effective management of patients with chronic multidimensional signs and symptoms. The presence of multiple long-standing medical problems in a given patient despite intensive medical effort suggests that addressing systemic core imbalances could complement more narrowly focused approaches. CASE PRESENTATION: A 72-year-old man experiencing longstanding depression, fatigue, irritable bowel syndrome, and chronic pain in the context of additional refractory illnesses was assessed and treated, guided by a system-oriented approach to underlying core imbalances termed functional medicine. This patient was referred from a team of clinicians representing primary care, cardiology, gastroenterology, hematology, and psychology. Prior treatment had been unsuccessful in managing multiple chronic comorbidities. Diagnostic assessment included comprehensive stool and nutritional/metabolic laboratory testing. RESULTS: The blood-, urine-, or stool-based measurements of relevant markers for multiple systemic issues, including digestion/absorption, inflammation, oxidative stress, and methylation, identified previously unrecognized root causes of his constellation of symptoms. These functional measurements guided rational recommendations for dietary choices and supplementation. The patient experienced steady and significant improvement in his mental health, fatigue, chronic pain, and irritable bowel syndrome-as well as the unexpected resolution of his chronic idiopathic pancytopenia. CONCLUSION: The success in this case suggests that other patients with chronic, complex, and treatment-refractory illness may benefit from a system-oriented assessment of core imbalances guided by specialized nutritional/metabolic and digestive laboratory testing.

The influence of prescription opioid use duration and dose on development of treatment resistant depression.

Long-term prescription opioid use is associated both with new-onset and recurrence of depression. Whether chronic opioid use interferes with depression management has not been reported, therefore we determined whether patients' longer duration of opioid use and higher opioid dose are associated with new-onset treatment resistant depression (TRD) after controlling for confounding from pain and other variables. Data was obtained from Veteran Health Administration (VHA) de-identified patient medical records. We used a retrospective cohort design from 2000-2012. Eligible subjects (n=6169) were 18-80years of age, free of cancer and HIV, diagnosed with depression and opioid-free for the 24-month interval prior to the observation period. Duration of a new prescription for opioid analgesic was categorized as 1-30days, 31-90days and >90days. Morphine-equivalent dose (MED) during follow-up categorized as ≤50mg versus >50mg per day. Pain and other sources of confounding were controlled by propensity scores and inverse probability of treatment weighting. Cox proportional hazard models were computed to estimate the association between duration and dose of opioid and onset of TRD. After controlling for confounding by weighting data, opioid use for 31-90days and for >90days, compared to 1-30days, was significantly associated with new onset TRD (HR=1.25; 95% CI: 1.09-1.45 and HR=1.52; 95% CI: 1.32-1.74, respectively). MED was not associated with new onset TRD. The risk of developing TRD increased as time spent on opioid analgesics increased. Long-term opioid treatment of chronic pain may interfere with treatment of depression.

[Primary and secondary arterial hypertension - update 2016]. / Primäre und sekundäre arterielle Hypertonie - Update 2016.

In patients with hypertension without diabetes and with an increased risk of cardiovascular complications a blood pressure of below 130 mmHg should be targeted. Hypertensive patients with an age above 80 years should be treated in the same way as younger hypertensive patients if they are otherwise healthy and functionally independent. On the other hand frail elderly patients could have an increased morbidity and mortality with intensive blood pressure control. In patients with resistant hypertension spironolactone was the most effective drug when given in addition to their baseline drugs (ACE-inhibitor/angiotensin receptor antagonist, calcium channel blocker and thiazide diuretic).

Socio-demographic and clinical predictors of treatment resistant depression: A prospective European multicenter study.

BACKGROUND: Few studies investigated socio-demographic and clinical predictors of non response and remission in treatment resistant depression (TRD) in the case of failure of more than two adequate antidepressant (AD) trial. The primary aim of this study was to investigate socio-demographic and clinical predictors of TRD defined as the lack of response to at least three adequate AD treatments, two of which prospectively evaluated. As secondary aims, we also investigated predictors of non response and remission to: (1) at least two adequate AD treatment (one of which prospectively assessed); (2) at least one adequate and retrospectively assessed AD treatment. METHODS: In the context of a European multicenter project, 407 major depressive disorder (MDD) patients who failed to respond to a previous AD treatment were recruited for a 2 stage trial, firstly receiving venlafaxine and then escitalopram. MINI, HRSD, MADRS, UKU, CGI-S and CGI-I were administered. RESULTS: Ninety eight subjects (27.61%) were considered as resistant to three AD treatments. Clinical predictors were: longer duration and higher severity of the current episode (p=0.004; ES=0.24; p=0.01; RR=1.41, respectively), outpatient status (p=0.04; RR=1.58), higher suicidal risk level (p=0.02; RR=1.49), higher rate of the first/second degree psychiatric antecedents (MDD and others) (p=0.04; RR=1.31, p=0.03; RR=1.32 respectively) and side effects during treatments (p=0.002; RR=2.82). Multivariate analyses underlined the association between TRD and the severity of the current episode (p=0.04). As for secondary outcomes, predicting factors were partially overlapping. LIMITATIONS: The limited sample size and specific drugs used limit present findings. CONCLUSION: Subjects with a high degree of resistance to AD treatments show specific features which may guide the clinicians to the choice of more appropriate therapies at baseline.

The Role of Anger/Hostility in Treatment-Resistant Depression: A Secondary Analysis From the ADAPT-A Study.

Major depressive disorder is often accompanied by elevated levels of anger, hostility, and irritability, which may contribute to worse outcomes. The present study is a secondary analysis examining the role of anger/hostility in the treatment response to low-dose aripiprazole added to antidepressant therapy in 225 patients with major depressive disorder and inadequate response to antidepressant treatment. Repeated-measures model demonstrated no drug-placebo difference in treatment response across levels of anger/hostility. However, within-group analyses showed significantly lower placebo response rates in patients with high anger/hostility and a trend for lower drug response rates in patients with high anger/hostility. Pooled response rates across phases and treatments revealed a lower response rate among patients with high anger/hostility. Depressed patients with high anger/hostility demonstrate greater illness severity and lower depressive treatment response rates than patients with low anger/hostility, suggesting that patients with high anger/hostility may have poorer outcomes in response to adjunctive treatment.

Determinants of Treatment-Resistant Depression: The Salience of Benzodiazepines.

Treatment-resistant depression (TRD) lacks consensus regarding its definition, despite being common in clinical practice. This study was designed to identify factors contributing to TRD in patients diagnosed with a major depressive disorder. Patients were grouped into "low," "medium," and "high" treatment-resistant (TR) groups based on the number of medications that had been prescribed for their depression. We identified a number of factors linked to TRD. The high TR group was generally older, had a longer depressive episode duration, a higher number of comorbid medical and anxiety disorders, a lower education, and were less likely to be in full-time employment. They also reported less trait irritability and were more likely to view medication as being a contributor to their current depression. Some differences between non-melancholic and melancholic subsets were evident and point to the benefits in research on TRD analyzing the two diagnostic groups separately. The most striking finding was benzodiazepine use, which was significantly more common in the high TR group and within both the melancholic and non-melancholic subsets. Some potential explanations for this finding are offered.

Translating clinical science into effective therapies.

Identifying a patient with treatment-resistant depression involves ensuring that at least 2 evidence-based antidepressant trials from two different pharmacologic classes have been undertaken and determining their impact on patients' symptoms, functioning, quality-of-life and social relationships as outcomes. When assessing depressive symptoms throughout the course of treatment, clinical judgment should be supplemented by using standardized tools such as the 9-item Patient Health Questionnaire (PHQ-9) and the Quick Inventory of Depressive Symptomatology (QIDS). Adjunctive treatment strategies preserve the benefits of first-line antidepressants in partial responders and potentially enhance the initial antidepressant's effect through complementary mechanisms of action. Novel "multimodal" pharmacotherapies with diverse potentially beneficial mechanisms of action are in development, which have varying degrees of activity across multiple monoamine systems including those regulated by serotonin, dopamine, and glutamate.

The biology of depression in cancer and the relationship between depression and cancer progression.

The prevalence of depressive symptoms in patients with cancer exceeds that observed in the general population and depression is associated with a poorer prognosis in cancer patients. The increased prevalence is not solely explained by the psychosocial stress associated with the diagnosis. Pro-inflammatory cytokines, which induce sickness behaviour with symptoms overlapping those of clinical depression, are validated biomarkers of increased inflammation in patients with cancer. A growing literature reveals that chronic inflammatory processes associated with stress may also underlie depression symptoms in general, and in patients with cancer in particular. Therapeutic modalities, which are frequently poorly tolerated, are used in the treatment of cancer. These interventions are associated with inflammatory reactions, which may help to explain their toxicity. There is evidence that antidepressants can effectively treat symptoms of depression in cancer patients though the database is meager. Novel agents with anti-inflammatory properties may be effective alternatives for patients with treatment-resistant depression who exhibit evidence of increased inflammation.