Prescrire Int. 2011 May;20(116):128-33.

Treatment-resistant depression: no panacea, many uncertainties. Adverse effects are a major factor in treatment choice.

[No authors listed]

Abstract

At least 50% of patients with depression do not enter remission after several weeks of antidepressant therapy. To determine the treatment options and their respective risk-benefit balances in this setting, we reviewed the literature using the standard Prescrire methodology. Clinical trials and epidemiological studies show that depression should only be considered drug-resistant after at least 6 weeks of therapy. After assessing residual symptoms and their impact on the patient's quality of life, a search should be made for factors responsible for the persistence of depression, such as the patient's environment, a psychiatric or somatic disorder, and drug intake or addiction. Increasing the dose of the first-line antidepressant is only based on weak evidence. Trials comparing continuing the first-line antidepressant versus switching to another pharmacological class have yielded conflicting results. A switch may benefit some patients, but the elimination half-life of the discontinued drug must be taken into account to limit the risk of interactions during the transition. Combining two antidepressants mainly increases the risk of adverse effects, without a tangible clinical benefit. Two meta-analyses suggest that adding a so-called atypical neuroleptic to ongoing antidepressant therapy leads to 1 extra remission per 7 to 10 treated patients, but also to treatment cessation due to adverse effects in 8% to 9% of cases. Older neuroleptics have not been properly evaluated in this setting. Comparative trials suggest that lithium may have a certain antidepressant effect in this setting, but there is no firm evidence that adding lithium increases the chances of remission. Lithium has a narrow therapeutic margin and overdose can be fatal; the blood lithium concentration must therefore be monitored. Adding an antiepileptic or a psychostimulant is more harmful than beneficial. Adding a thyroid hormone, a benzodiazepine, buspirone or pindolol has no proven antidepressive effect. Four trials, each including fewer than 20 patients, have assessed the efficacy of psychotherapy in patients with treatment-resistant depression. Two of them provided positive results. Electroconvulsive therapy is probably effective for some patients with refractory depression but it necessitates general anaesthesia and carries a risk of memory disorders. Vagal nerve electrostimulation has no proven efficacy. Transcranial magnetic stimulation seems to have some efficacy and few adverse effects, but its optimal modalities remain to be determined. In practice, when the patient and doctor decide to attempt second-line therapy for treatment-resistant depression, adverse effects must be taken into account in the choice of drug(s). Maintaining a good quality relationship between patient and doctor may be more important than attempting to obtain remission "at any cost".

PMID:

21648180

[PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/21648180

J Neurosurg Pediatr. 2011 Jun;7(6):671-5.

Vagal nerve stimulator infection: a lead-salvage protocol.

Wozniak SE, Thompson EM, Selden NR.

Source

Department of Neurological Surgery, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA.

Abstract

OBJECT:

Vagal nerve stimulator (VNS) hardware infections are fraught with difficult management decisions. As with most implanted medical device-related infections, standard practice traditionally involves complete hardware removal, systemic antibiotic therapy, and subsequent reimplantation of the device. To avoid the potential morbidity of 2 repeat left carotid sheath surgical dissections, the authors have implemented a clinical protocol for managing VNS infections that involves generator removal and antibiotic therapy without lead removal.

METHODS:

A prospective, single-surgeon database was compared with hospital billing records to identify patients who underwent primary implantation or reimplantation of a VNS lead, generator, or both, from January 2001 to May 2010, at Oregon Health & Science University. From these records, the authors identified patients with VNS hardware infections and characterized their management, using a lead salvage protocol.

RESULTS:

In their review, the authors found a matching cohort of 206 children (age 3 months-17 years) who met the inclusion criteria. These children underwent 258 operations (including, in some children, multiple operations for generator end of life and/or lead malfunction). Six children experienced a single postimplantation infection (2.3% of the 258 operative cases), and no child experienced repeated infection. A lead-salvage protocol was used in 4 of 6 infected patients and was successful in 3 (75%), with clinical follow-up ranging from 10 months to 7.5 years. The fourth patient subsequently underwent lead removal and later reimplantation in standard fashion, with no adverse sequelae.

CONCLUSIONS:

Vagal nerve stimulator lead salvage is a safe and potentially advantageous strategy in the management of VNS-related infection. Further study is necessary to validate appropriate patient selection, success rates, and risks of this approach.

PMID:

21631207

[PubMed - indexed for MEDLINE]

http://www.ncbi.nlm.nih.gov/pubmed/21631207

J Neurosurg Pediatr. 2011 Jun;7(6):671-5.

Vagal nerve stimulator infection: a lead-salvage protocol.

Wozniak SE, Thompson EM, Selden NR.

Source

Department of Neurological Surgery, Oregon Health & Science University, 3303 SW Bond Avenue, Portland, OR 97239, USA.

Abstract

OBJECT:

Vagal nerve stimulator (VNS) hardware infections are fraught with difficult management decisions. As with most implanted medical device-related infections, standard practice traditionally involves complete hardware removal, systemic antibiotic therapy, and subsequent reimplantation of the device. To avoid the potential morbidity of 2 repeat left carotid sheath surgical dissections, the authors have implemented a clinical protocol for managing VNS infections that involves generator removal and antibiotic therapy without lead removal.

METHODS:

A prospective, single-surgeon database was compared with hospital billing records to identify patients who underwent primary implantation or reimplantation of a VNS lead, generator, or both, from January 2001 to May 2010, at Oregon Health & Science University. From these records, the authors identified patients with VNS hardware infections and characterized their management, using a lead salvage protocol.

RESULTS:

In their review, the authors found a matching cohort of 206 children (age 3 months-17 years) who met the inclusion criteria. These children underwent 258 operations (including, in some children, multiple operations for generator end of life and/or lead malfunction). Six children experienced a single postimplantation infection (2.3% of the 258 operative cases), and no child experienced repeated infection. A lead-salvage protocol was used in 4 of 6 infected patients and was successful in 3 (75%), with clinical follow-up ranging from 10 months to 7.5 years. The fourth patient subsequently underwent lead removal and later reimplantation in standard fashion, with no adverse sequelae.

CONCLUSIONS:

Vagal nerve stimulator lead salvage is a safe and potentially advantageous strategy in the management of VNS-related infection. Further study is necessary to validate appropriate patient selection, success rates, and risks of this approach.

PMID:

21631207

[PubMed - indexed for MEDLINE]

Electrical stimulation outside the heart

"In the previous paragraphs, we have discussed the application of electrical stimulation on the heart, which has the advantage of avoiding possible adverse side-effects as regularly encountered with pharmacological therapies. The therapies discussed below are applied outside the heart and usually are applied continuously throughout the cardiac cycle (see Fig. 1). Their benefit may be that the stimulation is affecting a much more integrated system. Studies of these therapies clearly show cardiac benefit, but in most cases, the exact mechanism is unknown. This is likely due to multi-organ and central nervous system pathways.

Vagal nerve stimulation

There has been extensive research demonstrating that acute vagus nerve stimulation results in a decrease in various measures of ventricular function including contractility. Lewis et al. showed that in the human and pig heart, stimulation of the left vagus nerve can profoundly decrease contractility of the left ventricular myocardium, independent of its braducardic effect [54]. This decrease in ventricular contractility during vagal stimulation (VNS) appears to be mediated by the parasympathetic ganglia located in the cranial medial ventricular fat pad [55, 56]. However, at low sympathetic tone, the negative inotropic effect of vagal stimulation is attributable primarily to its negative chronotropic effect [57]. This suggests that the effect of VNS on contractility is mediated via an interaction with the sympathetic system.

It may seem counterintuitive that a reduction in contractility by VNS may be beneficial to patients with heart failure. However, several pre-clinical studies have shown benefit in chronic vagus nerve stimulation in models of systolic heart failure [58]. Recently, Zhang et al. evaluated VNS in a canine high-rate pacing-induced model of heart failure. VNS at an intensity that reduced sinus rate by approximately 20 bpm was delivered in the VNS group. After 4 and 8 weeks, both left ventricular end-diastolic and end-systolic volumes were lower, and left ventricular EF was higher in the VNS group than in the control group [59]. Li et al. showed that VNS markedly improved the long-term survival of chronic heart failure rats through the prevention of pumping failure, remodeling, and increasing contractility [60]. Very recently, the same group showed that VNS applied immediately after MI attenuated LV remodeling, which may be related to the decreased acute inflammatory response or to the reduction in infarct size induced by VNS [61], since the remodeling process increases with a larger infarct."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074071/

J Neurosurg. 2011 Aug 12. [Epub ahead of print]

Vagus nerve stimulation for epilepsy: a meta-analysis of efficacy and predictors of response.

Englot DJ, Chang EF, Auguste KI.

Source

Department of Neurological Surgery, University of California, San Francisco, California.

Abstract

Vagus nerve stimulation (VNS) was approved by the US FDA in 1997 as an adjunctive treatment for medically refractory epilepsy. It is considered for use in patients who are poor candidates for resection or those in whom resection has failed. However, disagreement regarding the utility of VNS in epilepsy continues because of the variability in benefit reported across clinical studies. Moreover, although VNS was approved only for adults and adolescents with partial epilepsy, its efficacy in children and in patients with generalized epilepsy remains unclear. The authors performed the first meta-analysis of VNS efficacy in epilepsy, identifying 74 clinical studies with 3321 patients suffering from intractable epilepsy. These studies included 3 blinded, randomized controlled trials (Class I evidence); 2 nonblinded, randomized controlled trials (Class II evidence); 10 prospective studies (Class III evidence); and numerous retrospective studies. After VNS, seizure frequency was reduced by an average of 45%, with a 36% reduction in seizures at 3-12 months after surgery and a 51% reduction after > 1 year of therapy. At the last follow-up, seizures were reduced by 50% or more in approximately 50% of the patients, and VNS predicted a ≥ 50% reduction in seizures with a main effects OR of 1.83 (95% CI 1.80-1.86). Patients with generalized epilepsy and children benefited significantly from VNS despite their exclusion from initial approval of the device. Furthermore, posttraumatic epilepsy and tuberous sclerosis were positive predictors of a favorable outcome. In conclusion, VNS is an effective and relatively safe adjunctive therapy in patients with medically refractory epilepsy not amenable to resection. However, it is important to recognize that complete seizure freedom is rarely achieved using VNS and that a quarter of patients do not receive any benefit from therapy.

PMID:

21838505

[PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/21838505

CYBERONICS ANNOUNCES HOLD ON SHIPMENT AND RETRIEVAL OF INVENTORY OF AspireHC™ AND AspireSR™ GENERATORS

For Release Monday, August 15, 2011; 8:00 AM ET

CYBERONICS ANNOUNCES HOLD ON SHIPMENT AND RETRIEVAL OF INVENTORY OF AspireHC™ AND AspireSR™ GENERATORS

COMPANY AFFIRMS FINANCIAL GUIDANCE FOR FISCAL 2012

HOUSTON, Texas August 15, 2011 -- Cyberonics, Inc. (NASDAQ:CYBX), a global leader in devices for epilepsy management, announced today that it has voluntarily stopped shipment and is retrieving field inventory of its Aspire platform generators, Models 105 and 106.  The company does not believe that the generators pose a health risk to patients, but initiated this action when it discovered that stimulation output current delivered to patients can be less than the output current programmed by a physician.  Instructions will be provided to physicians regarding management of the approximately 118 patients worldwide who have been implanted with an AspireHC or AspireSR generator.  Cyberonics has also suspended enrollment in its E-36 clinical trial pending resolution of this hardware-related design issue.

“Patient safety is our first priority.  We are working expeditiously to resolve this problem.  Our product development team has identified what we believe to be the cause of the problem, as well as several potential hardware solutions,” said Dan Moore, President and Chief Executive Officer.  “Our goal is to implement and validate a solution and submit for regulatory approvals by no later than the end of the fiscal year.”

The company, which completed the first quarter of fiscal 2012 on July 29, 2011 and will report financial results on August 25, 2011, does not currently anticipate a change to guidance for fiscal year 2012 as a result of this action. The previously provided guidance remains at $212 million to $215 million for net sales, and $54 million to $57 million for income from operations.  Sales for the AspireHC (Model 105) generator comprised approximately 9% of worldwide revenue in the recently completed first quarter, and the company believes that the availability of alternate models provides physicians and patients with appropriate additional options for the treatment of refractory epilepsy.

About Cyberonics, Inc. and the VNS Therapy^® System

Cyberonics, Inc. is a medical technology company with core expertise in neuromodulation.  The company developed and markets the VNS Therapy System, which is FDA-approved for the treatment of refractory epilepsy and treatment-resistant depression.  The VNS Therapy System uses a surgically implanted medical device that delivers electrical pulsed signals to the vagus nerve.  Cyberonics markets the VNS Therapy System in selected markets worldwide.

Additional information on Cyberonics and the VNS Therapy System is available at www.cyberonics.com.

Epilepsy Behav. 2011 Aug 4. [Epub ahead of print]

Severe new seizures after initiation of vagus nerve stimulation therapy.

Murr NI, Azar NJ.

Abstract

Vagus nerve stimulation is considered to be a safe and effective adjunctive therapy for patients with drug-resistant epilepsy. Contrary to some antiepileptic drugs, vagus nerve stimulation is not known to precipitate or aggravate new or preexisting seizures. We describe the emergence of a new type of disabling, recurrent partial seizure immediately after initiation of vagus nerve stimulation in a 51-year-old man with a known history of refractory partial epilepsy. Discontinuation of vagus nerve stimulation therapy and multiple antiepileptic drug interventions were required to abort these unexpected new seizures. We conclude that vagus nerve stimulation may induce paradoxical seizures, similarly to some antiepileptic drugs.

PMID:

21820359

[PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/21820359

Pain Med. 2011 Aug 3. doi: 10.1111/j.1526-4637.2011.01203.x. [Epub ahead of print]

Safety and Efficacy of Vagus Nerve Stimulation in Fibromyalgia: A Phase I/II Proof of Concept Trial.

Lange G, Janal MN, Maniker A, Fitzgibbons J, Fobler M, Cook D, Natelson BH.

Source

Departments of Radiology Psychiatry Neuroscience, UMDNJ-New Jersey Medical School, Newark, New Jersey Department of Veterans Affairs, New Jersey Health Care System, East Orange, New Jersey Departments of Neurosurgery Pain Medicine & Palliative Care, Beth Israel Medical Center, New York, New York Department of Epidemiology and Health Promotion, College of Dentistry, New York University, New York, New York William S. Middleton Memorial Veterans Hospital and the Department of Kinesiology, University of Wisconsin, Madison, Wisconsin, USA.

Abstract

Objective.  We performed an open-label Phase I/II trial to evaluate the safety and tolerability of vagus nerve stimulation (VNS) in patients with treatment-resistant fibromyalgia (FM) as well as to determine preliminary measures of efficacy in these patients. Methods.  Of 14 patients implanted with the VNS stimulator, 12 patients completed the initial 3-month study of VNS; 11 patients returned for follow-up visits 5, 8, and 11 months after start of stimulation. Therapeutic efficacy was assessed with a composite measure requiring improvement in pain, overall wellness, and physical function. Loss of both pain and tenderness criteria for the diagnosis of FM was added as a secondary outcome measure because of results found at the end of 3 months of stimulation. Results.  Side effects were similar to those reported in patients treated with VNS for epilepsy or depression and, in addition, dry mouth and fatigue were reported. Two patients did not tolerate stimulation. At 3 months, five patients had attained efficacy criteria; of these, two patients no longer met widespread pain or tenderness criteria for the diagnosis of FM. The therapeutic effect seemed to increase over time in that additional participants attained both criteria at 11 months. Conclusions.  Side effects and tolerability were similar to those found in disorders currently treated with VNS. Preliminary outcome measures suggested that VNS may be a useful adjunct treatment for FM patients resistant to conventional therapeutic management, but further research is required to better understand its actual role in the treatment of FM.
Wiley Periodicals, Inc.

PMID:

21812908

[PubMed - as supplied by publisher]

http://www.ncbi.nlm.nih.gov/pubmed/21812908

Unsuccessful use of DBS...

It is with much sadness that I recently read of a DBS (Deep Brain Stimulation) patient who has not obtained efficacy from her involvement in the research program.  Also of interest to me were the comments made by Dr. John O'Reardon.  That in turn led my thoughts back to my coining of the phrase "The Trial and Error Approach to Wellness" over 4 decades ago.  There simply are no guarantees of efficacy and the only way to know for sure is to try.

Here's the link to the blog.  Pay careful attention to the posting of April 2011 and especially the two audio presentations:

http://whyy.org/cms/news/health-science/special-features/2010/02/03/living-with-chronic-depression/7912

Herb