VAGUS NERVE STIMULATION/BEHAVIORAL ADDICTIONS
| VAGUS NERVE STIMULATION: WHAT IT IS AND WHEN TO CONSIDER IT— A. John Rush, MD, Vice
Chair, Department of Clinical Sciences; Professor of Psychiatry; Betty Jo Hay Distinguished Chair in Mental Health;
and the Rosewood Corporation Chair in Biomedical Science, University of Texas Southwestern Medical Center, Dallas
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| Rationale for using vagus nerve stimulation (VNS) for treatment of depression: approved by Food and
Drug Administration (FDA) as antiepileptic treatment; in epilepsy studies, VNS showed evidence of mood improvement
independent of seizure control; neuroanatomy of vagus nerve known, including fact that it distributes
messages to structures involved in depression; VNS is anticonvulsant, and some anticonvulsants known to affect
mood; antidepressant activity of VNS demonstrated in animal model
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| What is VNS? implantable device placed under left axilla and wired to left vagus nerve; when switched on, device
supplies automatic intermittent stimulation to vagus nerve; device lightweight and relatively straightforward to implant
(outpatient surgery typically takes 1 to 1.5 hr; can be done under local anesthesia, but “there’s a tendency for
[surgeons] to use general anesthesia”; battery life 3 to 8 yr; implanted in >32,000 patients with epilepsy, so short-
and long-term safety well known; few contraindications; surgical complications—no deaths reported; asystole occurs
in 0.1%, but only in operating room with first pulse; no asystole has occurred in physicians’ offices when devices
turned on; infection rate 1.7%; if surgeon follows creases in neck, cosmetic result acceptable
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| Studies: short-term results of pivotal study—statistical significance not achieved in primary efficacy measure; statistically
significant improvement in treatment group seen in some secondary outcome measures; consistent numerical
trends provide additional support for effectiveness of VNS therapy in treatment-resistant depression (TRD); immediate
safety of implant procedure and VNS therapy confirmed; immediate tolerability confirmed; long-term results
of pivotal study—statistically significant improvement in response and remission rates seen over 1 yr; of individuals
who responded at 3 mo, about two thirds still showed response at 1 yr and 2 yr; comparative study—patients as
closely matched to those in pivotal study as possible, but none in comparative group received VNS; patients in
VNS pivotal study showed benefit roughly twice that in comparative group; results favored adjunctive VNS therapy
on primary analysis; statistically and clinically significant differences confirmed by secondary analyses using
multiple outcome measures
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| Safety and tolerability of VNS: approved by FDA for TRD; restricted to individuals who have failed ≥4 lifetime
treatment modalities and to patients who need long-term treatment; side effects—all related to when device turned
on (duty cycle typically turns device on for 30 sec, off for 5 min); ≈50% of patients experience voice alteration due
to activation of left recurrent laryngeal nerve; when device turned off, voice returns to normal; ≈50% of those who
experience voice alteration can stop it with magnet, but for all, problem still present after 1 yr; other side effects include
increased coughing, dyspnea, neck pain, dysphagia, and paresthesias in neck; advantages—90% continuation
rate at 1 yr; few discontinue due to adverse events; VNS does not cause weight gain, neuropsychologic impairment,
or insomnia; obviously does not have drug-drug interactions; other considerations—manic and hypomanic reactions
do occur, mostly in those who have history of manic or hypomanic episodes; most manic or hypomanic reactions
controlled by reducing current or by changing pulse-stimulation parameters; outcomes identical in unipolar
and bipolar depression; no indication VNS causes suicidal ideation; well tolerated; impossible to overdose; easily
added to other treatments without adding to side-effect burden; short- and long-term effects well known from epilepsy
experience
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| Patient selection: follow FDA guidelines, which say VNS “indicated for the adjunctive long-term treatment of
chronic or recurrent depression for patients 18 yr of age and older who are experiencing a major depressive epi
sode and have not had adequate response to 4 or more adequate antidepressant treatments”; trials did not include
patients with psychosis, schizoaffective disorder, or rapid cycling, so those patients excluded under current FDA
guidelines; “adequate antidepressant treatments” must have been well conducted, adhered to, wisely administered,
and carefully done; patient must be in need of long-term treatment
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| Which patients respond? “the short answer to this is nothing predicts”; in search of predictors, speaker’s group
considered unipolar vs bipolar depression, severity of symptoms, experience with electroconvulsive therapy (ECT),
dose-adjustment parameters, sex, age, and number of unsuccessful trials in current episode, and none of these variables
predicted response; appropriate candidates include patients—with unipolar or bipolar disorder with current
major depressive episode; with long-term (≥2 yr) major depressive episode; with recurrent depression; with or
without history of ECT; who are currently experiencing major depressive episode and have not had adequate response
to ≥4 adequate treatments
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| Device programming: speaker observes, “I am a computer fool, I am a computer failure; I can do this”; device relatively
simple to use, all parameters set by menu; company that manufactures device provides training for clinician
and patient’s family, and representative will even make house visit to help in using and adjusting device; current is
variable most frequently dealt with, and “it’s dosed up to a tolerable level” (optimal dose unknown); other parameters
that can be adjusted include signal frequency, pulse width, and on and off times (optimal settings for these parameters
also unknown)
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| Bottom line: “it’s the darndest treatment to use because you know about tolerability early but you don’t know about
efficacy until later”; may take up to 1 yr for effectiveness to be seen
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| PATHOLOGICAL GAMBLING AND OTHER BEHAVIORAL ADDICTIONS —Jon E. Grant, JD, MD, Associate
Professor of Psychiatry, University of Minnesota Medical School, Minneapolis, and Editor-in-Chief, Journal of Gambling
Studies
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| Impulse-control disorders: pathologic gambling, kleptomania, and skin picking classified as impulse-control disorders
in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV); recognized for several
centuries; speaker’s study found that ≈30% of psychiatric inpatients had at least one comorbid impulse-control
disorder, but very few mentioned it on admission
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 | Core features: repetitive or compulsive engagement in behavior despite adverse consequences; diminished control
over that behavior; appetitive urge or craving state before engagement in that behavior; hedonic quality to performing
that behavior
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| Core qualities: tolerance; withdrawal; repeated unsuccessful attempts to cut back or to stop; impairment in major
areas of life functioning
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| Dynamics of multiple addictions: switching (replacing one addiction with another); alternating (cycling from one
addiction to another in patterned, systematic way); intensification (using addictive patterns simultaneously to intensify
overall experience); numbing (using addiction to medicate shame and pain due to another addiction); disinhibiting (using
one addiction to lower inhibitions for other addictive acting out)
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| Family history: first-degree relative with substance-use disorder found in 25% of patients with compulsive buying
and 20% of those with kleptomania; among those with pathologic gambling, 52% have first-degree relative with alcohol-use
disorder
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| Pathologic gambling: DSM-IV criteria largely borrowed from substance dependence; defined as persistent and recurrent
maladaptive gambling behavior as indicated by ≥5 of following: 1) preoccupation with gambling; 2)
needing to gamble with increasing amounts of money to achieve desired level of excitement; 3) repeated unsuccessful
efforts to control, cut back, or stop gambling; 4) restlessness or irritability when attempting to cut down
or stop; 5) gambling to escape from problems; 6) chasing losses (ie, returning to gambling site to try to make up
losses from previous evening or several evenings); 7) lying; 8) committing illegal acts; 9) jeopardizing or losing
significant relationship, job, or educational or career opportunity; 10) relying on others for money
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| Epidemiology: ≈4% of adults in United States have gambling problem; rates similar in Sweden, Switzerland, Britain,
Australia, South Africa, Japan, and Korea; numbers may be increasing due to proliferation of Internet gambling sites
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| Characteristics: usually begins in early adulthood; men tend to start at earlier age than women; 32% of problem gamblers
women, 62% men; “telescoping phenomenon” describes phenomenon in which women become addicted at
later age, but addiction gets out of control more rapidly
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| Personal consequences: pathologic gamblers lie, cheat, steal, and may do things “that are drastically out of character
to feed their addiction”; high levels of distress; attempted suicide rate 24%
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| Social consequences: family dysfunction, marital problems, and domestic violence; significant financial problems;
criminal behavior
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| Adolescent gambling: 3.2% to 8.4% of adolescents may have gambling problem (most adolescent gambling done
over Internet, making estimates difficult; speaker interested in discovering how many adolescents will become
adults with gambling addiction)
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| Pharmacologic treatment: in trials, 195-mg dose of fluvoxamine more effective than placebo, as was 52-mg dose of paroxetine;
other medications that have produced improvement include naltrexone and lithium; no difference found between
olanzapine and placebo; nalmefene has shown efficacy in Europe, but not available in United States
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| Cognitive behavioral therapy (CBT): speaker prefers always to augment medications with CBT; all trials from
Canada or Europe, none done yet in United States, but those trials showed efficacy of CBT
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| Kleptomania: DSM-IV criteria include recurrent failure to resist impulse to steal unneeded objects, increasing sense
of tension before committing theft, experience of pleasure, gratification, or release at time of committing theft,
and stealing not being done out of anger or vengeance and not due to psychosis; people with kleptomania in great
distress because their behavior contrary to social mores (“thou shalt not steal”)
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| Clinical characteristics: onset usually in late adolescence or early adulthood; 63% women; steal 2 to 3 times/wk; unsuccessful
attempts to stop; patients feel shame and guilt; majority never discuss problem with anyone, even spouses; all report
urges to steal; up to 18% have personality disorder
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| Consequences: 63% of people with kleptomania hoard items; 64% apprehended; 23% serve jail time; 27% have
psychiatric hospitalization (often due to suicide attempt); 18% contemplate suicide
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| Pharmacologic treatment: “we’ve got nothing for this”; no medications approved by FDA for kleptomania; speaker’s
trial showed naltrexone helpful in “a small number of people” (only 13 people in trial)
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| Psychotherapy: case reports only; some success reported with covert sensitization combined with exposure and response
prevention and with imaginal desensitization; speaker prefers in vivo exposure therapy
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| Skin picking: also called neurotic excoriation and pathologic skin picking; defined as repetitive, ritualistic, impulsive
picking at skin that leads to tissue damage; many people pick occasionally at cuticles or other areas, pathology
lies in duration, focus, and extent of behavior; ≈4% of college students found to have pathologic skin
picking; sufferers comprise ≈2% of dermatology patients; 80% to 90% of patients women; may be seen in people
who abuse methamphetamine and in cocaine addicts
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| Clinical characteristics: patients pick at any part of body; use hands, fingernails, tweezers, knives, pins, and other
things to pick; urge to pick may worsen in evenings; patients may pick for up to 12 hr/day; suicide risk high
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| Assessment: patients need thorough medical examination (they often do not tell mental health provider extent of
skin damage); is condition caused by dermatologic or other medical condition? by psychiatric disorder (eg, body
dysmorphic disorder, obsessive-compulsive disorder, delusions of parasitosis, dermatitis artefacta)?
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| Treatment: dermatologic examination and treatment of excoriations; treat underlying psychiatric disorder if one exists;
if independent impulse-control disorder, use pharmacotherapy plus habit reversal; fluoxetine and fluvoxamine
showed some efficacy in double-blind trials, sertraline in open-label trial, but medication alone does not
resolve problem; psychotherapy and habit reversal needed; habit reversal involves psychoeducation, keeping
picking diary to foster awareness of behavior, learning emotion-regulation skills, learning competing behaviors
to keep hands busy, and cognitive restructuring to deal with urges to pick
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Educational Objectives
| The goal of this program is to educate the listener about using vagus nerve stimulation (VNS) as treatment for depression
and about treating some of the impulse-control disorders. After hearing and assimilating this program, the clinician
will be better able to:
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| Discuss the rationale for using VNS as adjunctive treatment in treatment-resistant depression.
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| Identify appropriate candidates for VNS.
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| State the core features and qualities that impulse-control disorders have in common.
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| Determine when common activities such as gambling and skin picking become pathologic.
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| Diagnose and treat pathologic gambling, kleptomania, and pathologic skin picking.
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Discussed on This Program
Escitalopram oxylate (Lexapro)
Fluoxetine hydrochloride [Prozac, Sarafem]
Fluvoxamine maleate
Lithium carbonate [Eskalith, Eskalith CR, Lithobid, Lithonate, Lithotabs]
Nalmefene hydrochloride [Revex]
Naltrexone hydrochloride [ReVia]
Olanzapine [Zyprexa]
Suggested Reading
Christensen RC: Olanzapine augmentation of fluoxetine in the treatment of pathological skin picking. Can J Psychiatry
49:788, 2004; Deckersbach T et al: Cognitive-behavior therapy for self-injurious skin picking. A case series. Behav
Modif 26:361, 2002; Elger G et al: Vagus nerve stimulation is associated with mood improvements in epilepsy patients.
Epilepsy Res 42:203, 2000; George MS et al: A one-year comparison of vagus nerve stimulation with treatment as usual
for treatment-resistant depression. Biol Psychiatry 58:364, 2005; Goodnick PJ et al: Vagus nerve stimulation in depression.
Expert Opin Pharmacother 2:1061, 2001; Grant JE et al: Multicenter investigation of the opioid antagonist
nalmefene in the treatment of pathological gambling. Am J Psychiatry 163:303, 2006; Grant JE et al: Paroxetine treatment
of pathological gambling: a multi-centre randomized controlled trial. Int Clin Psychopharmacol 18:243, 2003; Grant JE,
Kim SW, Grosz RL: Perceived stress in kleptomania. Psychiatr Q 74:251, 2003; Grant JE, Kim SW: An open-label
study of naltrexone in the treatment of kleptomania. J Clin Psychiatry 63:349, 2002; Grant JE, Williams KA, Kim
SW: Update on pathological gambling. Curr Psychiatry Rep 8:53, 2006; Grant JE: Outcome study of kleptomania patients
treated with naltrexone: a chart review. Clin Neuropharmacol 28:11, 2005; Harden CL et al: A pilot study of mood in epilepsy
patients treated with vagus nerve stimulation. Epilepsy Behav 1:93, 2000; Keuthen NJ et al: The Skin Picking Impact
Scale (SPIS): scale development and psychometric analyses. Psychosomatics 42:397, 2001; Krahl SE et al: Vagus
nerve stimulation (VNS) is effective in a rat model of antidepressant action. J Psychiatr Res 38:237, 2004; Marangell LB
et al: Vagus nerve stimulation (VNS) for major depressive episodes: one-year outcomes. Biol Psychiatry 51:280, 2005; Nahas
Zet al: Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. J Clin Psychiatry
66:1097, 2005; Papakostas GI et al: Hopelessness and suicidal ideation in outpatients with treatment-resistant
depression: prevalence and impact on treatment outcome. J Nerv Ment Dis 191:444, 2003; Rowan PJ et al: Depressive
symptoms predict medical-care utilization in a population-based sample. Psychol Med 32:903, 2002; Rush AJ et al: Effects
of 12 months of vagus nerve stimulation in treatment-resistant depression: a naturalistic study. Biol Psychiatry 58:355, 2005;
Rush AJ et al: Vagus nerve stimulation for treatment-resistant depression: a randomized, controlled acute phase trial. Biol
Psychiatry 58:347, 2005; Sackeim HA et al: A prospective, randomized, double-blind comparison of bilateral and right
unilateral electroconvulsive therapy at different stimulus intensities. Arch Gen Psychiatry 57:425, 2000; Sackeim HA et
al: Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome. Neuropsychopharmacology
25:713, 2001; Thase ME, Rush AJ: When at first you don’t succeed: sequential strategies for antidepressant
nonresponders. J Clin Psychiatry 58(Suppl 13):23, 1997.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
Dr. Rush reported that he has grant/research support from the National Institute of Mental Health and the Stanley
Medical Research Institute; he is a consultant/advisor for Bristol-Myers Squibb Company, Cyberonics, Inc., Eli Lilly
and Company, Forest Laboratories, Inc., GlaxoSmithKline, Merck and Company, Inc., and Organon, Inc. (Akzo);
and he is on the Speakers’ Bureau of Cyberonics, Inc., Eli Lilly and Company, and Forest Laboratories, Inc. Dr.
Grant disclosed that he is a consultant for Somaxon Pharmaceuticals and receives grant/research support from Forest
Pharmaceuticals and Ortho-McNeil Pharmaceuticals. Dr. Grant discussed off-label uses for several medications.
Dr. Rush was recorded at The 11th Annual Psychopharmacology Update, held February 16-19, 2006, in Las Vegas, NV,
and sponsored by the American Psychiatric Association and the Nevada Psychiatric Association. Dr. Grant was recorded
at An Entertaining and Eclectic Elucidation of Psychiatric Erudition, held September 19-20, 2005, in Minneapolis,
MN, and sponsored by the University of Minnesota Medical School. The Audio-Digest Foundation thanks the speakers
and the sponsors for their cooperation in the production of this program.
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