Vagus Nerve Vagus Nerve Stimulation:Stimulation:

A New Treatment A New Treatment for Severe for Severe DepressionDepression

VNS@UWVNS@UWUW Health /Meriter Hospital UW Health /Meriter Hospital

Department of PsychiatryDepartment of PsychiatryFebruary 1, 2006February 1, 2006

CHRONIC CHRONIC DEPRESSIONDEPRESSIONWHAT IS IT, HOW WE TREAT IT WHAT IS IT, HOW WE TREAT IT

ANDANDTHE ROLE OF VAGUS NERVE THE ROLE OF VAGUS NERVE

STIMULATIONSTIMULATION

Stephen J. Weiler, M.D.Stephen J. Weiler, M.D.U.W. Health PsychiatryU.W. Health Psychiatry

DEPRESSION:DEPRESSION:WHAT IS IT? DSM-IV WHAT IS IT? DSM-IV

CRITERIACRITERIA DEPRESSED MOODDEPRESSED MOOD ANHEDONIAANHEDONIA CHANGE IN APPETITE OR WEIGHTCHANGE IN APPETITE OR WEIGHT INSOMNIA OR HYPERSOMNIAINSOMNIA OR HYPERSOMNIA PSYCHOMOTOR RETARDATION OR AGITATIONPSYCHOMOTOR RETARDATION OR AGITATION DECREASE ENERGYDECREASE ENERGY GUILT OR FEELINGS OF WORTHLESSNESSGUILT OR FEELINGS OF WORTHLESSNESS DECREASED CONCENTRATIONDECREASED CONCENTRATION RECURRENT THOUGHTS OF DEATH OR RECURRENT THOUGHTS OF DEATH OR

SUICIDAL IDEATIONSUICIDAL IDEATION

Depression is a common Depression is a common illnessillness

Depression affects 18 million Depression affects 18 million Americans at any one time; 2/3 are Americans at any one time; 2/3 are femalefemale

20% to 35% of people with 20% to 35% of people with depression (at least 4 million depression (at least 4 million Americans) have long-lasting or Americans) have long-lasting or repeated episodes of depression that repeated episodes of depression that do not respond or respond only do not respond or respond only temporarily to several temporarily to several antidepressant treatmentsantidepressant treatments

THE “COST” OF THE “COST” OF DEPRESSIONDEPRESSION

44THTH MOST DISABLING CONDITION MOST DISABLING CONDITION WORLDWIDE; MOST DISABLING WORLDWIDE; MOST DISABLING CONDITION FOR FEMALES IN U.S.CONDITION FOR FEMALES IN U.S.

LOSS OF PRODUCTIVITY IN WORK LOSS OF PRODUCTIVITY IN WORK AND FAMILY ROLESAND FAMILY ROLES

WORSENS OTHER MEDICAL WORSENS OTHER MEDICAL CONDITIONSCONDITIONS INCREASES RISK FOR DEVELOPING INCREASES RISK FOR DEVELOPING

OTHER MEDICAL CONDITIONSOTHER MEDICAL CONDITIONS WORSE OUTCOMESWORSE OUTCOMES HIGHER COSTSHIGHER COSTS

CHRONIC AND CHRONIC AND RECURRENT DEPRESSIONRECURRENT DEPRESSION

Chronic depression: Chronic depression: depression that lasts 2 years depression that lasts 2 years or more without reliefor more without relief

Recurrent depression: 2 or Recurrent depression: 2 or more episodes of depression more episodes of depression over timeover time

WHAT IS TREATMENT WHAT IS TREATMENT RESISTANT DEPRESSION?RESISTANT DEPRESSION?BASICALLY DEPRESSIVE STATES THAT BASICALLY DEPRESSIVE STATES THAT DO NOT RESPOND TO TREATMENTDO NOT RESPOND TO TREATMENT

STAGE 0:STAGE 0: No single adequate trial of medsNo single adequate trial of meds

STAGE 1: Failure to respond to 1 med trialSTAGE 1: Failure to respond to 1 med trial

STAGE 2: Failure to respond to 2 different STAGE 2: Failure to respond to 2 different med trialsmed trials

STAGE 3: Stage 2 + 1 augmentation trialSTAGE 3: Stage 2 + 1 augmentation trial

STAGE 4: Stage 3 + 2 augmentation trialsSTAGE 4: Stage 3 + 2 augmentation trials

STAGE 5: Stage 4 + failure to respond to STAGE 5: Stage 4 + failure to respond to ECTECT

How effective are current How effective are current treatments?treatments?

Mild to moderate depression: meds Mild to moderate depression: meds and psychotherapy about equal with and psychotherapy about equal with >60% response rates>60% response rates

Moderate to severe depression: Moderate to severe depression: psychotherapy alone ineffectivepsychotherapy alone ineffective

RECENT RESEARCH RECENT RESEARCH 35% COMPLETE RESPONSE TO 1 SSRI35% COMPLETE RESPONSE TO 1 SSRI 50% SIGNIFICANT IMPROVEMENT50% SIGNIFICANT IMPROVEMENT

ECT: ~80% RESPONSE RATEECT: ~80% RESPONSE RATE BUT HIGH RELAPSE RATE (64% in 24 BUT HIGH RELAPSE RATE (64% in 24

weeks)weeks)

VAGUS NERVE VAGUS NERVE STIMULATIONSTIMULATION

A COMPLETELY NEW TREATMENT A COMPLETELY NEW TREATMENT APPROACH (more on this with Dr APPROACH (more on this with Dr Halverson)Halverson)

INDICATIONS (FDA Criteria)INDICATIONS (FDA Criteria)

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

EXCLUSIONARY EXCLUSIONARY CONSIDERATIONS FOR CONSIDERATIONS FOR

VNSVNS•• CURRENT STATE THAT IS WITH CURRENT STATE THAT IS WITH

HIGH IMMEDIATE RISK (SUICIDE, HIGH IMMEDIATE RISK (SUICIDE, SUBSTANCE ABUSE, PROBLEMS SUBSTANCE ABUSE, PROBLEMS WITH BEHAVIORAL CONTROL)WITH BEHAVIORAL CONTROL)

HISTORY OF BRAIN SURGERY OR HISTORY OF BRAIN SURGERY OR PROGRESSIVE NEUROLOGICAL D/OPROGRESSIVE NEUROLOGICAL D/O

H/O SURGERY ON VAGUS NERVEH/O SURGERY ON VAGUS NERVE SOME MEDICAL CONDITIONSSOME MEDICAL CONDITIONS OTHER FORMS OF CNS OTHER FORMS OF CNS

STIMULATION DEVICESSTIMULATION DEVICES

Vagus Nerve StimulationTherapy

What is it and how does it work?

Jerry L. Halverson, M.D.University of Wisconsin

Department of PsychiatryMeriter Hospital

February 1, 2006

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.

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

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

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.

What does the pulse generator look like?

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

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.

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

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

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

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

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

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

VNS Implant VNS Implant SurgerySurgery

P. Charles Garell, MDP. Charles Garell, MD

Director of Functional Director of Functional NeurosurgeryNeurosurgery

Chief of Neurosurgery, VA Chief of Neurosurgery, VA HospitalHospital

Surgical evaluationSurgical evaluation

Meet with surgeon to reviewMeet with surgeon to review Health historyHealth history Physical examPhysical exam Benefits of surgeryBenefits of surgery Risks of surgeryRisks of surgery Details of the procedureDetails of the procedure

You decide on surgeryYou 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 Talk to psychiatrist (again), or

medical doctor.medical doctor.

Work upWork 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 dateConfirm surgical date

SurgerySurgery

In the OR you will be under general In the OR you will be under general anesthesia (completely asleep).anesthesia (completely asleep).

You will be positioned with your neck You will be positioned with your neck and upper chest scrubbed with and upper chest scrubbed with antibacterial soap.antibacterial soap.

Sterile drapes will cover all but your Sterile drapes will cover all but your left neck and left upper chest.left neck and left upper chest.

Incision will be marked.Incision will be marked. You will receive antibiotics.You will receive antibiotics.

SurgerySurgery

Neck incision will expose the vagus Neck incision will expose the vagus nerve and surrounding structures.nerve and surrounding structures.

Upper chest incision will create a Upper chest incision will create a “pocket” for the “battery pack.” “pocket” for the “battery pack.”

A wire will be passed under the skin A wire will be passed under the skin from the neck to the chest incision.from the neck to the chest incision.

SurgerySurgery

The wire (electrode) will be wrapped The wire (electrode) will be wrapped around the vagus nerve. The other around the vagus nerve. The other end will be connected to the battery end will be connected to the battery pack (internal pulse generator).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.

The VNS TherapyThe VNS Therapy™™ procedure is procedure is

straightforwardstraightforward Actual implant procedure takes about 1 hourActual implant procedure takes about 1 hour Usually performed under general anesthesiaUsually performed under general anesthesia Usually an outpatient procedure—no overnight Usually an outpatient procedure—no overnight

hospital stayhospital stay Two small incisions:Two small incisions:

One in the left chest area, below the collarbone for One in the left chest area, below the collarbone for the pulse generatorthe pulse generator

One in a natural crease on the left side of the neck One in a natural crease on the left side of the neck to connect with the left vagus nerveto connect with the left vagus nerve

The incisions heal in about a weekThe incisions heal in about a week The small scars fade over time, becoming barely The small scars fade over time, becoming barely

noticeable for many peoplenoticeable for many people

3 months post procedure

In-hospital recoveryIn-hospital recovery

You will wake up in the recovery You will wake up in the recovery room, then transfer to the hospital room, then transfer to the hospital ward.ward.

Bandages will be checked, pain will Bandages will be checked, pain will be treated, and you will receive be treated, and you will receive more antibiotics.more antibiotics.

You will stay overnight and be You will stay overnight and be discharged the next morning.discharged the next morning.

At-home recoveryAt-home recovery

You will be given pain medications to You will be given pain medications to take by mouth.take by mouth.

You will change you bandage at 3 You will change you bandage at 3 days.days.

You will remove you bandage at 6 You will remove you bandage at 6 days.days.

You will be sore and tired but able to You will be sore and tired but able to do most normal activities.do most normal activities.

Follow upFollow up

At two weeks you will see Dr. At two weeks you will see Dr. Halverson to activate your VNS Halverson to activate your VNS system.system.

At six weeks you will see me to At six weeks you will see me to assess healing progress.assess healing progress.

Long-termLong-term

Battery pack currently last about 5 Battery pack currently last about 5 years (depends on stimulation years (depends on stimulation parameters). At 5 years it will need parameters). At 5 years it will need to be replaced if you want (if it was to be replaced if you want (if it was helpful).helpful).

Battery replacement requires Battery replacement requires surgery, however, this is done as an surgery, however, this is done as an outpatient, with only one incision.outpatient, with only one incision.

After the implantAfter the implant

ManagementManagement We will work with your psychiatrist to We will work with your psychiatrist to

help you feel, and stay, better.help you feel, and stay, better. VNS@UW will manage your implant, your VNS@UW will manage your implant, your

primary psychiatrist will continue to work primary psychiatrist will continue to work with your medications.with your medications.

Two weeks after the implant, you will be Two weeks after the implant, you will be seen in our clinic for activation of the seen in our clinic for activation of the implantimplant

You will be seen weekly and your dose You will be seen weekly and your dose titrated higher until your VNS is at a titrated higher until your VNS is at a therapeutic leveltherapeutic level

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

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 treatments1

– The incidence of sleep disturbance and weight gain (also commonly reported side effects of other antidepressant treatments) is less than 2%

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