1. Vagus Nerve Stimulation: A New Treatment for Severe Depression VNS@UW UW Health /Meriter Hospital Department of Psychiatry February 1, 2006

2. CHRONIC DEPRESSION WHAT IS IT, HOW WE TREAT IT AND THE ROLE OF VAGUS NERVE STIMULATION Stephen J. Weiler, M.D. U.W. Health Psychiatry

3. DEPRESSION: WHAT IS IT? DSM-IV CRITERIA DEPRESSED MOOD DEPRESSED MOOD ANHEDONIA ANHEDONIA CHANGE IN APPETITE OR WEIGHT CHANGE IN APPETITE OR WEIGHT INSOMNIA OR HYPERSOMNIA INSOMNIA OR HYPERSOMNIA PSYCHOMOTOR RETARDATION OR AGITATION PSYCHOMOTOR RETARDATION OR AGITATION DECREASE ENERGY DECREASE ENERGY GUILT OR FEELINGS OF WORTHLESSNESS GUILT OR FEELINGS OF WORTHLESSNESS DECREASED CONCENTRATION DECREASED CONCENTRATION RECURRENT THOUGHTS OF DEATH OR SUICIDAL IDEATION RECURRENT THOUGHTS OF DEATH OR SUICIDAL IDEATION

4. Depression is a common illness Depression affects 18 million Americans at any one time; 2/3 are female Depression affects 18 million Americans at any one time; 2/3 are female 20% to 35% of people with depression (at least 4 million Americans) have long-lasting or repeated episodes of depression that do not respond or respond only temporarily to several antidepressant treatments 20% to 35% of people with depression (at least 4 million Americans) have long-lasting or repeated episodes of depression that do not respond or respond only temporarily to several antidepressant treatments

5. THE “COST” OF DEPRESSION 4 TH MOST DISABLING CONDITION WORLDWIDE; MOST DISABLING CONDITION FOR FEMALES IN U.S. 4 TH MOST DISABLING CONDITION WORLDWIDE; MOST DISABLING CONDITION FOR FEMALES IN U.S. LOSS OF PRODUCTIVITY IN WORK AND FAMILY ROLES LOSS OF PRODUCTIVITY IN WORK AND FAMILY ROLES WORSENS OTHER MEDICAL CONDITIONS WORSENS OTHER MEDICAL CONDITIONS INCREASES RISK FOR DEVELOPING OTHER MEDICAL CONDITIONS INCREASES RISK FOR DEVELOPING OTHER MEDICAL CONDITIONS WORSE OUTCOMES WORSE OUTCOMES HIGHER COSTS HIGHER COSTS

6. CHRONIC AND RECURRENT DEPRESSION Chronic depression: depression that lasts 2 years or more without relief Chronic depression: depression that lasts 2 years or more without relief Recurrent depression: 2 or more episodes of depression over time Recurrent depression: 2 or more episodes of depression over time

7. WHAT IS TREATMENT RESISTANT DEPRESSION? BASICALLY DEPRESSIVE STATES THAT DO NOT RESPOND TO TREATMENT STAGE 0:No single adequate trial of meds STAGE 1: Failure to respond to 1 med trial STAGE 2: Failure to respond to 2 different med trials STAGE 3: Stage 2 + 1 augmentation trial STAGE 4: Stage 3 + 2 augmentation trials STAGE 5: Stage 4 + failure to respond to ECT

8. How effective are current treatments? Mild to moderate depression: meds and psychotherapy about equal with >60% response rates Mild to moderate depression: meds and psychotherapy about equal with >60% response rates Moderate to severe depression: psychotherapy alone ineffective Moderate to severe depression: psychotherapy alone ineffective RECENT RESEARCH RECENT RESEARCH 35% COMPLETE RESPONSE TO 1 SSRI 35% COMPLETE RESPONSE TO 1 SSRI 50% SIGNIFICANT IMPROVEMENT 50% SIGNIFICANT IMPROVEMENT ECT: ~80% RESPONSE RATE ECT: ~80% RESPONSE RATE BUT HIGH RELAPSE RATE (64% in 24 weeks) BUT HIGH RELAPSE RATE (64% in 24 weeks)

9. VAGUS NERVE STIMULATION A COMPLETELY NEW TREATMENT APPROACH (more on this with Dr Halverson) A COMPLETELY NEW TREATMENT APPROACH (more on this with Dr Halverson) INDICATIONS (FDA Criteria) INDICATIONS (FDA Criteria) VNS Therapy is indicated for the adjunctive long- term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments.

10. EXCLUSIONARY CONSIDERATIONS FOR VNS CURRENT STATE THAT IS WITH HIGH IMMEDIATE RISK (SUICIDE, SUBSTANCE ABUSE, PROBLEMS WITH BEHAVIORAL CONTROL)CURRENT STATE THAT IS WITH HIGH IMMEDIATE RISK (SUICIDE, SUBSTANCE ABUSE, PROBLEMS WITH BEHAVIORAL CONTROL) HISTORY OF BRAIN SURGERY OR PROGRESSIVE NEUROLOGICAL D/O HISTORY OF BRAIN SURGERY OR PROGRESSIVE NEUROLOGICAL D/O H/O SURGERY ON VAGUS NERVE H/O SURGERY ON VAGUS NERVE SOME MEDICAL CONDITIONS SOME MEDICAL CONDITIONS OTHER FORMS OF CNS STIMULATION DEVICES OTHER FORMS OF CNS STIMULATION DEVICES

11. Vagus Nerve Stimulation Therapy What is it and how does it work? Jerry L. Halverson, M.D. University of Wisconsin Department of Psychiatry Meriter Hospital February 1, 2006

14. FDA Indication INTENDED USE/INDICATIONS – UNITED STATES VNS Therapy is indicated for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments.

15. What is VNS Therapy? VNS Therapy stands for “Vagus Nerve Stimulation” The vagus nerve: –Is one of the primary communication pathways from the major organs of the body to the brain –Appears to communicate with areas of the brain involved in regulating mood –Does not contain pain fibers

16. How VNS Therapy works –VNS Therapy is delivered by a pulse generator—a device like a pacemaker –The pulse generator sends mild, intermittent pulses through a thin, flexible wire leading to electrodes attached to the left vagus nerve –Because the vagus nerve does not contain pain fibers, VNS Therapy is typically painless –VNS Therapy is regular, automatic, and generally unnoticeable –VNS Therapy is added to your current antidepressant medications

17. What is the pulse generator? The device delivers very mild intermittent brief pulses to the left vagus nerve. 30s/5m The pulses that are delivered to the left vagus nerve are transmitted to the central nervous system, and they appear to go to specific areas in the central nervous system that control mood, motivation, sleep, appetite, and other symptoms that are relevant to depression. VNS Therapy targets specific areas of the brain that affect the production or activity of neurotransmitters, such as serotonin and norepinephrine.

18. What does the pulse generator look like?

19. Why use VNS in depression? FDA approved for use in epilepsy in 1997 More than 32,000 patients have been treated worldwide with VNS for epilepsy. Clinical experience with comorbid patients Trials since the mid nineties FDA approval in July 2005

20. Why use VNS? Adding VNS Therapy has been shown to succeed when other antidepressant treatments have not. The effectiveness of VNS Therapy improves over time and lasts. – After 1 year, 1 in 3 people receiving VNS Therapy experienced significant mood improvements, compared with 1 in 8 people receiving only other antidepressant treatments. – Many people who did not respond immediately to VNS Therapy did experience improvement over time. – Most people who responded to VNS Therapy maintained improvement for at least two years. –For some people, VNS Therapy reduces the need for antidepressant medications over time.

21. Clinical Trials and Published Studies #1 Patients included in VNS trials are typically excluded from other antidepressant studies Patients were experiencing long term chronic or recurrent, treatment resistant depression that had not responded to multiple antidepressant treatment trials including adequate medication trials, therapy and electroconvulsive therapy

22. Thumbnail of the “average” trial patient Experienced depression for more than 25 years Had current major depressive episode for longer than four years Experienced more than 12 unsuccessful clinical treatments for their depression 53% were previously treated with ECT

23. Clinical Trials and Published Studies #2 In studies published in peer reviewed journals, after two years of adjunctive use of VNS –More than 50% realized at least a meaningful clinical benefit –Approximately 1/3 had realized at least a 50% improvement in their depressive symptoms –One out of every six patients were depression free

24. Clinical Trials and Published Studies #3 In this treatment resistant, difficult to treat population between 60 and 70% of patients achieving response at 3 months or one year maintained this response This durability of response is unprecedented in other antidepressant treatments, particularly in this difficult to treat population

25. Quality-of-life benefits In addition to improvements in mood, many people receiving VNS Therapy and their physicians also report significant and lasting improvements in: –Vitality—increased energy –Social functioning—increased interaction with family and/or friends –Emotional well-being—better function at work and in daily activities –Mental health—more positive feelings

26. Cost Considerations Chronic Depression is a very costly problem, both to the patient’s quality of life and in the cost of the treatments Many insurance companies are in the process of determining coverage for VNS therapy for chronic depression VNS Therapy has been paid for by insurance companies on a case-by-case basis Cyberonics actively assists in this process Research and indigent programs

27. VNS Implant Surgery P. Charles Garell, MD Director of Functional Neurosurgery Chief of Neurosurgery, VA Hospital

28. Surgical evaluation Meet with surgeon to review Meet with surgeon to review Health history Health history Physical exam Physical exam Benefits of surgery Benefits of surgery Risks of surgery Risks of surgery Details of the procedure Details of the procedure

29. You decide on surgery Talk to others who have had surgery. Talk to others who have had surgery. Talk to insurance company. Talk to insurance company. Talk to friends and family. Talk to friends and family. Talk to psychiatrist (again), or medical doctor. Talk to psychiatrist (again), or medical doctor.

30. Work up Meet nurse practitioner. Meet nurse practitioner. Have blood work done. Have blood work done. Maybe chest x-ray and EKG. Maybe chest x-ray and EKG. Meet anesthesiologist. Meet anesthesiologist. Confirm surgical date Confirm surgical date

31. Surgery In the OR you will be under general anesthesia (completely asleep). In the OR you will be under general anesthesia (completely asleep). You will be positioned with your neck and upper chest scrubbed with antibacterial soap. You will be positioned with your neck and upper chest scrubbed with antibacterial soap. Sterile drapes will cover all but your left neck and left upper chest. Sterile drapes will cover all but your left neck and left upper chest. Incision will be marked. Incision will be marked. You will receive antibiotics. You will receive antibiotics.

32. Surgery Neck incision will expose the vagus nerve and surrounding structures. Neck incision will expose the vagus nerve and surrounding structures. Upper chest incision will create a “pocket” for the “battery pack.” Upper chest incision will create a “pocket” for the “battery pack.” A wire will be passed under the skin from the neck to the chest incision. A wire will be passed under the skin from the neck to the chest incision.

33. Surgery The wire (electrode) will be wrapped around the vagus nerve. The other end will be connected to the battery pack (internal pulse generator). The wire (electrode) will be wrapped around the vagus nerve. The other end will be connected to the battery pack (internal pulse generator). The system will be tested. The system will be tested. Both incisions will be sutured closed. Both incisions will be sutured closed.

34. The VNS Therapy ™ procedure is straightforward Actual implant procedure takes about 1 hour Actual implant procedure takes about 1 hour Usually performed under general anesthesia Usually performed under general anesthesia Usually an outpatient procedure—no overnight hospital stay Usually an outpatient procedure—no overnight hospital stay Two small incisions: Two small incisions: One in the left chest area, below the collarbone for the pulse generator One in the left chest area, below the collarbone for the pulse generator One in a natural crease on the left side of the neck to connect with the left vagus nerve One in a natural crease on the left side of the neck to connect with the left vagus nerve The incisions heal in about a week The incisions heal in about a week The small scars fade over time, becoming barely noticeable for many people The small scars fade over time, becoming barely noticeable for many people 3 months post procedure

35. In-hospital recovery You will wake up in the recovery room, then transfer to the hospital ward. You will wake up in the recovery room, then transfer to the hospital ward. Bandages will be checked, pain will be treated, and you will receive more antibiotics. Bandages will be checked, pain will be treated, and you will receive more antibiotics. You will stay overnight and be discharged the next morning. You will stay overnight and be discharged the next morning.

36. At-home recovery You will be given pain medications to take by mouth. You will be given pain medications to take by mouth. You will change you bandage at 3 days. You will change you bandage at 3 days. You will remove you bandage at 6 days. You will remove you bandage at 6 days. You will be sore and tired but able to do most normal activities. You will be sore and tired but able to do most normal activities.

37. Follow up At two weeks you will see Dr. Halverson to activate your VNS system. At two weeks you will see Dr. Halverson to activate your VNS system. At six weeks you will see me to assess healing progress. At six weeks you will see me to assess healing progress.

38. Long-term Battery pack currently last about 5 years (depends on stimulation parameters). At 5 years it will need to be replaced if you want (if it was helpful). Battery pack currently last about 5 years (depends on stimulation parameters). At 5 years it will need to be replaced if you want (if it was helpful). Battery replacement requires surgery, however, this is done as an outpatient, with only one incision. Battery replacement requires surgery, however, this is done as an outpatient, with only one incision.

39. After the implant

40. Management We will work with your psychiatrist to help you feel, and stay, better. We will work with your psychiatrist to help you feel, and stay, better. VNS@UW will manage your implant, your primary psychiatrist will continue to work with your medications. VNS@UW will manage your implant, your primary psychiatrist will continue to work with your medications. Two weeks after the implant, you will be seen in our clinic for activation of the implant Two weeks after the implant, you will be seen in our clinic for activation of the implant You will be seen weekly and your dose titrated higher until your VNS is at a therapeutic level You will be seen weekly and your dose titrated higher until your VNS is at a therapeutic level

41. Implant Interrogation and Dosage Adjustments Interrogation of the implant and titration of dose is done in the office Usually finished within 15 minutes Simple and Painless

42. Side effects of VNS Therapy are mild to moderate and typically decrease over time –Side effects typically occur only during stimulation and may include: Temporary hoarseness or changes in voice tone, cough, tickling in the throat, or a feeling of shortness of breath during exertion Some may complain of no side effects –The side effects can be lessened by dose adjustments –The side effects typically decrease over time –VNS Therapy works with your other treatments without undesired interactions –VNS Therapy has not been associated with sexual dysfunction or memory impairment, common side effects of other antidepressant treatments 1 –The incidence of sleep disturbance and weight gain (also commonly reported side effects of other antidepressant treatments) is less than 2%

43. If necessary, you can control any troublesome stimulation-related side effects of VNS Therapy The VNS Therapy System includes a small magnet that can temporarily control any troublesome side effects. You can hold or place the magnet over your VNS Therapy pulse generator to stop stimulation temporarily during situations or activities when even mild side effects are troublesome. For example: –Public speaking –Singing –Exercise or other strenuous activity