Revisiting the interleukin 17 family of cytokines in psoriasis: pathogenesis and potential targets for innovative therapies.

Psoriasis is a common chronic inflammatory skin disease, associated with substantial comorbidity. TH17 lymphocytes, differentiating under the influence of dendritic cell-derived IL-23, and mediating their effects via IL-17A, are believed to be central effector cells in psoriasis. This concept is underlined by the unprecedented efficacy of therapeutics targeting this pathogenetic axis. In recent years, numerous observations made it necessary to revisit and refine this simple "linear" pathogenetic model. It became evident that IL-23 independent cells exist that produce IL-17A, that IL-17 homologues may exhibit synergistic biological effects, and that the blockade of IL-17A alone is clinically less effective compared to the inhibition of several IL-17 homologues. In this review, we will summarize the current knowledge around IL-17A and its five currently known homologues, namely IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25) and IL-17F, in relation to skin inflammation in general and psoriasis in particular. We will also re-visit the above-mentioned observations and integrate them into a more comprehensive pathogenetic model. This may help to appreciate current as well as developing anti-psoriatic therapies and to prioritize the selection of future drugs' mode(s) of action.

Investigational Therapies for Gunshot Wounds to the Spine: A Narrative Review.

STUDY DESIGN: This was a narrative review. OBJECTIVE: The objective of this study was to review the standards of care and triage protocol for gunshot wounds to the spine, highlighting innovative future treatment options that may be implemented in patients with spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: With the increased availability of firearms among the United States population, gunshot wounds to the spine are becoming a clinically relevant and devastating issue. Such injuries result in severe and diverse complications. SCIs due to gunshot wounds are the leading cause of morbidity and mortality, as they often result in complete or incomplete paraplegia. Current standards of care focus on preventing further damage rather than total cure or treatment of SCI. METHODS: A literature review was performed on the standards of care, triage protocol, associated conditions, current therapeutic options, and innovative treatment options for patients with gunshot wounds to the spine. RESULTS: The general standards of care for spinal gunshot wounds involve maintaining or renewal of mechanical spinal steadiness and neurological activity while limiting complications of treatment. Current treatment options include management of mean arterial pressure goals, drug therapies consisting of antibiotics, and surgical approaches. With recent innovations in molecular biology and cell transplantation, potentially new and promising treatment options for patients with SCI exist. These options include cell transplantation therapies, platelet-rich plasma administration, exosomal treatments, and mitochondrial-targeted therapeutics. Stem cell transplantation is promising, as several clinical studies have been completed. However, loss-to-follow-up, lack of long-term evaluation, and questionable randomization has limited the use of stem cells in the standard of care practice. Although not studied on human models to a gunshot wound, exosomal and mitochondrial-based treatment options have been studied both in vitro and in animal models with SCI. CONCLUSION: Newly emerging molecular and cellular therapy modalities for SCI contribute to the recovery process and may be utilized in conjunction with the current modalities for better outcomes.

Academic Physician Specialists' Approaches to Counseling Patients Interested in Unproven Stem Cell and Regenerative Therapies-A Qualitative Analysis.

OBJECTIVE: To explore the experiences, approaches, and challenges of physicians consulting patients about experimental stem cell and regenerative medicine interventions (SCRIs). PARTICIPANTS AND METHODS: From August 21, 2018, through July 30, 2019, semistructured interviews of 25 specialists in cardiology, ophthalmology, orthopedics, pulmonology, and neurology were conducted and qualitatively analyzed using modified grounded theory. RESULTS: All specialists used informational approaches to counsel patients, especially orthopedists. Informational approaches included explaining stem cell science, sharing risks, and providing principles. Several specialists also used relational counseling approaches including emphasizing that physicians want what is best for patients, acknowledging suffering, reassuring continued care, empathizing with patients and families, and underscoring that patients have the final decision. Many specialists reported being comfortable with the conversation, although some were less comfortable and several noted challenges in the consultation including wanting to support a patient's decision but worrying about harms from unproven SCRIs, navigating family pressure, and addressing stem cell hype and unrealistic expectations. Specialists also desired that additional resources be available for them and patients. CONCLUSION: Physicians relied more heavily on providing patients with information about SCRIs than using relational counseling approaches. Efforts should be directed at helping physicians address the informational and relational needs of patients, including providing tools and resources that inform physicians about the unproven SCRI industry, building skills in empathic communication, and the creation and dissemination of evidence-based resources to offer patients.

Gastrointestinal toxicity of high-dose melphalan in autologous hematopoietic stem cell transplantation: identification of risk factors and a benchmark for experimental therapies.

Gastrointestinal side effects are the dose-limiting toxicity of high-dose melphalan (HDM) in autologous hematopoietic stem-cell transplantation, but there are limited contemporary data on the incidence and severity of gastrointestinal toxicity associated with this regimen. We retrospectively studied 100 consecutive patients who received HDM alone or in combination with other conditioning agents. Patients had a median age of 56 (range 20-73); underlying diseases were myeloma (42%), lymphoma (42%), or amyloidosis (16%) and melphalan dosages were 200 (40%), 140 (59%), or 100 mg/m2 (1%). Ninety-seven percent of patients experienced diarrhea with a range of 1-18 bowel movements per day, 88% developed nausea, and 60% experienced vomiting. Abdominal CT scans rarely altered patient management, but stool studies were useful in identifying a treatable infectious source. Grade ≥ 2 diarrhea was associated with longer duration of diarrhea, longer length of stay, worse hypoalbuminemia, higher use of antibiotics, abdominal imaging, electrolyte repletions, and anti-diarrheal agents. Risk factors for severe diarrhea were female sex, melphalan dose, age > 50, creatinine clearance < 60 ml/min, and having a plasma cell neoplasm as opposed to lymphoma. Female sex was also associated with more severe nausea and vomiting. In summary, diarrhea remains an important toxicity of HDM and novel therapies for chemotherapy-induced diarrhea for patients undergoing stem-cell transplantation are needed. Grade 2 or higher diarrhea is associated with significant clinical consequences and should be used as the primary endpoint in prospective clinical trials.

Cost-Effectiveness and Efficacy of a Novel Combination Regimen in Acromegaly: A Prospective, Randomized Trial.

CONTEXT: Combination therapy with somatostatin receptor ligand (SRL) plus pegvisomant for patients with acromegaly is recommended after a maximizing dose on monotherapy. Lower-dose combination regimens are not well studied. OBJECTIVE: To compare cost-effectiveness and efficacy of 3 lower-dose combination regimens in controlled and uncontrolled acromegaly. DESIGN AND SETTING: Prospective, randomized, open-label, parallel arm study at a tertiary referral pituitary center. PATIENTS: Adults with acromegaly regardless of response to prior SRL and biochemical control status at baseline, stratified by an SRL dose required for insulin-like growth factor (IGF)-I normalization during any 3-month period within 12 months preceding enrollment. INTERVENTION: Combination therapy for 24 to 32 weeks on arm A, high-dose SRL (lanreotide 120 mg/octreotide long-acting release [LAR] 30 mg) plus weekly pegvisomant (40-160 mg/week); arm B, low-dose SRL (lanreotide 60 mg/octreotide LAR 10 mg) plus weekly pegvisomant; or arm C, low-dose SRL plus daily pegvisomant (15-60 mg/day). MAIN OUTCOME MEASURE: Monthly treatment cost in each arm in participants completing ≥ 24 weeks of therapy. RESULTS: Sixty patients were enrolled and 52 were evaluable. Fifty of 52 (96%) demonstrated IGF-I control regardless of prior SRL responsiveness (arm A, 14/15 [93.3%]; arm B, 22/23 [95.7%]; arm C, 14/14 [100%]). Arm B was least costly (mean, $9837 ±â€…1375 per month), arm C was most expensive (mean, $22543 ±â€…11158 per month), and arm A had an intermediate cost (mean, $14261 ±â€…1645 per month). Approximately 30% of patients required pegvisomant dose uptitration. Rates of adverse events were all < 10%. CONCLUSIONS: Low-dose SRL plus weekly pegvisomant represents a novel dosing option for achieving cost-effective, optimal biochemical control in patients with uncontrolled acromegaly requiring combination therapy.

Drug interactions: a review of the unseen danger of experimental COVID-19 therapies.

As global health services respond to the coronavirus pandemic, many prescribers are turning to experimental drugs. This review aims to assess the risk of drug-drug interactions in the severely ill COVID-19 patient. Experimental therapies were identified by searching ClinicalTrials.gov for 'COVID-19', '2019-nCoV', '2019 novel coronavirus' and 'SARS-CoV-2'. The last search was performed on 30 June 2020. Herbal medicines, blood-derived products and in vitro studies were excluded. We identified comorbidities by searching PubMed for the MeSH terms 'COVID-19', 'Comorbidity' and 'Epidemiological Factors'. Potential drug-drug interactions were evaluated according to known pharmacokinetics, overlapping toxicities and QT risk. Drug-drug interactions were graded GREEN and YELLOW: no clinically significant interaction; AMBER: caution; RED: serious risk. A total of 2378 records were retrieved from ClinicalTrials.gov, which yielded 249 drugs that met inclusion criteria. Thirteen primary compounds were screened against 512 comedications. A full database of these interactions is available at www.covid19-druginteractions.org. Experimental therapies for COVID-19 present a risk of drug-drug interactions, with lopinavir/ritonavir (10% RED, 41% AMBER; mainly a perpetrator of pharmacokinetic interactions but also risk of QT prolongation particularly when given with concomitant drugs that can prolong QT), chloroquine and hydroxychloroquine (both 7% RED and 27% AMBER, victims of some interactions due to metabolic profile but also perpetrators of QT prolongation) posing the greatest risk. With management, these risks can be mitigated. We have published a drug-drug interaction resource to facilitate medication review for the critically ill patient.

Avatar Therapy for people with schizophrenia or related disorders.

BACKGROUND: Many people with schizophrenia do not achieve satisfactory improvements in their mental state, particularly the symptom of hearing voices (hallucinations), with medical treatment. OBJECTIVES: To examine the effects of Avatar Therapy for people with schizophrenia or related disorders. SEARCH METHODS: In December 2016, November 2018 and April 2019, the Cochrane Schizophrenia Group's Study-Based Register of Trials (including registries of clinical trials) was searched, review authors checked references of all identified relevant reports to identify more studies and contacted authors of trials for additional information. SELECTION CRITERIA: All randomised clinical trials focusing on Avatar Therapy for people with schizophrenia or related disorders. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and 95% confidence intervals (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and 95% CIs. We employed a fixed-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. Our main outcomes of interest were clinically important change in; mental state, insight, global state, quality of life and functioning as well as adverse effects and leaving the study early. MAIN RESULTS: We found 14 potentially relevant references for three studies (participants = 195) comparing Avatar Therapy with two other interventions; treatment as usual or supportive counselling. Both Avatar Therapy and supportive counselling were given in addition (add-on) to the participants' normal care. All of the studies had high risk of bias across one or more domains for methodology and, for other risks of bias, authors from one of the studies were involved in the development of the avatar systems on trial and in another trial, authors had patents on the avatar system pending. 1. Avatar Therapy compared with treatment as usual When Avatar Therapy was compared with treatment as usual average endpoint Positive and Negative Syndrome Scale - Positive (PANSS-P) scores were not different between treatment groups (MD -1.93, 95% CI -5.10 to 1.24; studies = 1, participants = 19; very low-certainty evidence). A measure of insight (Revised Beliefs about Voices Questionnaire; BAVQ-R) showed an effect in favour of Avatar Therapy (MD -5.97, 95% CI -10.98 to -0.96; studies = 1, participants = 19; very low-certainty evidence). No one was rehospitalised in either group in the short term (risk difference (RD) 0.00, 95% CI -0.20 to 0.20; studies = 1, participants = 19; low-certainty evidence). Numbers leaving the study early from each group were not clearly different - although more did leave from the Avatar Therapy group (6/14 versus 0/12; RR 11.27, 95% CI 0.70 to 181.41; studies = 1, participants = 26; low-certainty evidence). There was no clear difference in anxiety between treatment groups (RR 5.54, 95% CI 0.34 to 89.80; studies = 1, participants = 19; low-certainty evidence). For quality of life, average Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (QLESQ-SF) scores favoured Avatar Therapy (MD 9.99, 95% CI 3.89 to 16.09; studies = 1, participants = 19; very low-certainty evidence). No study reported data for functioning. 2. Avatar Therapy compared with supportive counselling When Avatar Therapy was compared with supportive counselling (all short-term), general mental state (Psychotic Symptom Rating Scale (PSYRATS)) scores favoured the Avatar Therapy group (MD -4.74, 95% CI -8.01 to -1.47; studies = 1, participants = 124; low-certainty evidence). For insight (BAVQ-R), there was a small effect in favour of Avatar Therapy (MD -8.39, 95% CI -14.31 to -2.47; studies = 1, participants = 124; low-certainty evidence). Around 20% of each group left the study early (risk ratio (RR) 1.06, 95% CI 0.59 to 1.89; studies = 1, participants = 150; moderate-certainty evidence). Analysis of quality of life scores (Manchester Short Assessment of Quality of Life (MANSA)) showed no clear difference between groups (MD 2.69, 95% CI -1.48 to 6.86; studies = 1, participants = 120; low-certainty evidence). No data were available for rehospitalisation rates, adverse events or functioning. AUTHORS' CONCLUSIONS: Our analyses of available data shows few, if any, consistent effects of Avatar Therapy for people living with schizophrenia who experience auditory hallucinations. Where there are effects, or suggestions of effects, we are uncertain because of their risk of bias and their unclear clinical meaning. The theory behind Avatar Therapy is compelling but the practice needs testing in large, long, well-designed, well-reported randomised trials undertaken with help from - but not under the direction of - Avatar Therapy pioneers.

Long-term outcomes of the Ovation Stent Graft System investigational device exemption trial for endovascular abdominal aortic aneurysm repair.

OBJECTIVE: The objective of this study was to report the 5-year outcomes of the Food and Drug Administration investigational device exemption clinical trial of endovascular aneurysm repair (EVAR) with the Ovation stent graft (Endologix, Irvine, Calif) for elective treatment of abdominal aortic aneurysm (AAA). METHODS: The study comprised 161 patients who underwent EVAR as part of the prospective, international, multicenter pivotal Ovation stent graft trial. The main inclusion criteria were AAA diameter ≥5 cm, proximal neck length ≥7 mm, neck angulation ≤60 degrees, and bilateral iliac fixation length ≥10 mm. The primary end point was a composite outcome of primary clinical success at 5 years. Primary clinical success was defined in accordance with the Society for Vascular Surgery guidelines as successful aneurysm exclusion without aneurysm-related death, type I or type III endoleak, graft infection or thrombosis, aneurysm expansion, aneurysm rupture, graft migration, or conversion to open repair. Secondary end points included freedom from reintervention, all-cause mortality, and aneurysm-related mortality. RESULTS: Patients were predominantly male (87.6%) and elderly with a mean age of 73 ± 7.7 years; 66 patients (41%) had challenging anatomy and would be considered outside the instructions for use with other stent grafts, 26 (16.2%) had a proximal neck length <10 mm, and 53 (33%) had a minimum access vessel diameter <6 mm. Technical success was 100%. Of 126 surviving patients, 84 (66.7%) completed 5-year follow-up. The 5-year primary clinical success rate was 78%, aneurysm-related mortality was 1% (one patient), and all-cause mortality was 25%. The AAA-related death resulted from AAA post-EVAR rupture at 49 months in a patient who refused treatment for a type IB endoleak. Freedom from type I or type III endoleak was 95.1%. Freedom from secondary interventions was 80.2%. Most of the reinterventions were performed for type II endoleak (24 [63.1%]) or for limb thrombosis or stenosis (7 [18.4%]). There was no graft migration. None of the patients required open conversion. CONCLUSIONS: Five-year results from the Ovation pivotal and continued access investigational device exemption trials demonstrate excellent long-term durability of this endograft despite that 41% of patients had anatomy unfit for other stent grafts. There were no migrations or conversions to open repair and 99% freedom from aneurysm-related mortality. These results suggest a less invasive on-label endovascular option for patients with challenging anatomy who may otherwise require hybrid or open repair.

Chemoradiation phase II trials: re-exploring a world of missed opportunities.

Background: Phase II trials are designed to assess the efficacy/toxicity ratio of experimental treatments and select those worth being tested in phase III trials. Although crucial limitations were identified when concurrent chemoradiation (cCRT) phase III trials characteristics were assessed, features of cCRT phase II trials have never been reported. The objective was to describe features of all cCRT phase II trials. Methods and material: Requests were performed in the Medline database (via PubMed). The latest update was performed in April 2016, using the following MESH terms: 'clinical trials: phase II as topic', 'chemoradiotherapy'. Results: Four hundred and fifty-eight cCRT phase II trials were identified. They were mainly multicenter (51.5%), single arm studies (77.7%) published after 2011 (55.0%). The median number of included patients was 52. Primary endpoints were mainly response rate (20.5%), pathological complete response (14.4%) and overall survival (12.6%). The primary endpoint was not defined in 22% of studies. Tumors were mostly lung (23.1%), head and neck (20.3%), colorectal (16.6%) and esophagogastric cancer (14.6%) treated at a locally advanced setting (81.7%). 55.2% of trials used 3D-conformal radiotherapy and 9.1% intensity-modulated radiotherapy, mainly with normo-fractionation (82.0% of the 573 arms with radiotherapy). Radiation technique was not reported in 19.9% of studies. Associated anticancer drugs (563 arms) were mainly conventional chemotherapies (559 arms): cisplatin (46.2%) and 5-fluorouracil (28.3%). Non cytotoxic agents (targeted therapies, immunotherapies) were tested in 97 arms (17%). With a median follow-up of 31 months, acute grades 3-5 were reported in 98.5% of studies and late toxicities in 44.5%. Follow-up was not reported in 17% of studies. Conclusions: cCRT phase II trials featured severe limitations, with outdated radiation techniques, insufficient reporting of crucial data and a small number of included patients. This certainly limited the impact of conclusions and hindered the development of successful phase III trials.

Cost Estimate of Immune-Related Adverse Reactions Associated with Innovative Treatments of Metastatic Melanoma.

BACKGROUND AND OBJECTIVE: Immuno-oncology therapies represent a new treatment opportunity for patients affected by metastatic melanoma. The purpose of this study was to estimate the costs of immune-related adverse events (irAEs) associated with the new anti-PD1 immuno-oncology therapies, with the anti-CTLA-4 immuno-oncology therapy and with the combined therapy (CTLA4 + anti-PD1) in patients affected by metastatic melanoma. MATERIALS AND METHODS: A probabilistic cost-of-illness (COI) model was developed to estimate the management costs of grade ≥ 3 adverse events associated with the new anti-PD1 therapies (pembrolizumab and nivolumab), the anti-CTLA-4 therapy (ipilimumab) and the combined therapy CTLA4 + anti-PD1 (nivolumab + ipilimumab) for the treatment of patients with metastatic melanoma from the National Health Service (NHS) perspective in Italy. Identification of the epidemiological and cost parameters was carried out through a systematic literature review (SLR). Univariate and probabilistic sensitivity analyses were performed to account for uncertainty and variation in the model results. RESULTS: The model estimated a cost associated with the management of grade ≥ 3 immune-related adverse events in patients with metastatic melanoma equal to €176.2 (95% CI 63.5-335.0) for anti-CTLA-4 therapy, €48.6 (95% CI 40.1-58.5) for the new anti-PDI therapies and €276.8 (95% CI 240.4-316.2) for the combined therapy. Among the innovative therapies for the considered metastatic melanoma, the combined therapy was the most expensive innovative treatment in terms of event management of immune-related grade ≥ 3 adverse events. CONCLUSION: This study may represent a useful tool to understand the economic burden associated with the management of irAEs associated with patients affected by metastatic melanoma.

Cutaneous toxicities of new treatments for melanoma.

New drugs against advanced melanoma have emerged during last decade. Target therapy and immunotherapy have changed the management of patients with metastatic disease. Along with its generalized use, drug toxicities have appeared and the skin is the target organ of a significant part of them. This revision summarizes the most common side effects and consensus management to improve the compliance of therapies and patients' quality of life. Among the BRAF inhibitors, main cutaneous side effects are photosensitivity, plantar hyperkeratosis, and the appearance of verrucal keratosis or squamous cell carcinoma. Special attention must be paid to the development of new primary melanomas or changes on nevi during BRAF inhibitor therapy. The most common cutaneous side effects of immunotherapy are rash, pruritus, and vitiligo. It remains controversial the possible role of these toxicities as markers of response to therapy.

Investigational procedures in benign prostatic hypertrophy.

PURPOSE OF REVIEW: As benign prostatic hypertrophy (BPH) becomes a more common disease, there has been a dramatic rise in the number of investigational procedures being developed to manage it. We seek to present an overview of the most recently developed treatments and present clinical data related to application wherever available. RECENT FINDINGS: As a greater number of treatments become available for BPH, improved diagnostic testing could prove beneficial in helping guide patient selection. Efforts are underway to identify serum biomarkers associated with BPH as well as new classifications strategies, specifically with MRI, to determine both the anatomy of BPH as well as its histologic distribution. Outpatient-based procedures for BPH currently being developed include the temporary implantable nitinol device as well as intraprostatic injections such as Botox and PRX302. Aquablation is a novel technique that uses robotically guided high-pressured saline to ablate prostate tissue. Early data suggests noninferiority compared with TURP. Finally, efforts are underway to apply robotics to BPH with the advent of a robotic transurethral platform being designed for prostate enucleation. SUMMARY: Many new techniques are poised to be introduced to the BPH market over the coming years. The unique risk/benefit profiles as well as associated clinical outcomes of each will need to be studied in detail in order to help identify proper roles in the management of patients with symptomatic disease.

New horizons for focused ultrasound (FUS) - therapeutic applications in neurodegenerative diseases.

Access to the CNS and delivery of therapeutics across the blood-brain barrier remains a challenge for most treatments of major neurological diseases such as AD or PD. Focused ultrasound represents a potential approach for overcoming these barriers to treating AD and PD and perhaps other neurological diseases. Ultrasound (US) is best known for its imaging capabilities of organs in the periphery, but various arrangements of the transducers producing the acoustic signal allow the energy to be precisely focused (F) within the skull. Using FUS in combination with MRI and contrast agents further enhances accuracy by providing clear information on location. Varying the acoustic power allows FUS to be used in applications ranging from imaging, stimulation of brain circuits, to ablation of tissue. In several transgenic mouse models of AD, the use of FUS with microbubbles reduces plaque load and improves cognition and suggests the need to investigate this technology for plaque removal in AD. In PD, FUS is being explored as a way to non-invasively ablate the brain areas responsible for the tremor and dyskinesia associated with the disease, but has yet to be utilized for non-invasive delivery of putative therapeutics. The FUS approach also greatly increases the range of possible CNS therapeutics as it overcomes the issues of BBB penetration. In this review we discuss how the characteristics and various applications of FUS may advance the therapeutics available for treating or preventing neurodegenerative disorders with an emphasis on treating AD and PD.

Neurosurgery of the future: Deep brain stimulations and manipulations.

Important advances are afoot in the field of neurosurgery-particularly in the realms of deep brain stimulation (DBS), deep brain manipulation (DBM), and the newly introduced refinement "closed-loop" deep brain stimulation (CLDBS). Use of closed-loop technology will make both DBS and DBM more precise as procedures and will broaden their indications. CLDBS utilizes as feedback a variety of sources of electrophysiological and neurochemical afferent information about the function of the brain structures to be treated or studied. The efferent actions will be either electric, i.e. the classic excitatory or inhibitory ones, or micro-injection of such things as neural proteins and transmitters, neural grafts, implants of pluripotent stem cells or mesenchymal stem cells, and some variants of gene therapy. The pathologies to be treated, beside Parkinson's disease and movement disorders, include repair of neural tissues, neurodegenerative pathologies, psychiatric and behavioral dysfunctions, i.e. schizophrenia in its various guises, bipolar disorders, obesity, anorexia, drug addiction, and alcoholism. The possibility of using these new modalities to treat a number of cognitive dysfunctions is also under consideration. Because the DBS-CLDBS technology brings about a cross-fertilization between scientific investigation and surgical practice, it will also contribute to an enhanced understanding of brain function.

The future of psychiatry: brain devices.

Recent advances in deep brain stimulators and brain-machine interfaces have greatly expanded the possibilities of neuroprosthetics and neuromodulation. Together with advances in neuroengineering, nanotechnology, molecular biology and material sciences, it is now possible to address fundamental questions in neuroscience in new, more powerful ways. It is now possible to apply these new technologies in ways that range from augmenting and restoring function to neuromodulation modalities that treat neuropsychiatric disorders. Recent developments in neuromodulation methods offer significant advantages and potential clinical benefits for a variety of disorders. Here we describe the current state of the art in neuromodulation methods, and some advances in brain-machine interfaces, describing the advantages and limitations of the clinical applications of each method. The future applications of these new methods and how they will shape the future of psychiatry and medicine, along with safety and ethical implications, are also discussed.