Anxiety Disorders

From Update in Anxiety Disorders, presented by the Medical University of South Carolina

Educational Objectives

The goal of this program are to improve the management of depression and anxiety through the use of neuromodula­tion, and to improve treatment of anxiety with comorbid alcohol abuse. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe neuromodulation techniques used in psychiatry.

2.   Discuss the mechanism by which transcranial magnetic stimulation is hypothesized to modulate mood disor­ders.

3.   Assess the applicability of neuromodulation techniques to different mood disorders.

4.   Summarize the complicated relationship between anxiety disorders and alcohol use.

5.   Explain the importance of decreasing alcohol use to patients with social anxiety disorders.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. George is a consultant to GlaxoSmithKline, Jazz Pharmaceuticals, Brainsonix, Brainsway, Cephos, Cy­beronics, Neurinetics, Neuropace, NeoStim, and PureTech Ventures. Dr. George has also received research support from Brainsway. Dr. Book and the planning committee reported nothing to disclose. In his lecture, Dr. George dis­cusses off-label or investigational use of a therapy, product, or device.

Acknowledgements

Drs. George and Book were recorded at Update in Anxiety Disorders, held July 31, 2009, in Charleston, SC, and sponsored by the Medical University of South Carolina (MUSC). The Audio-Digest Foundation thanks the speakers and MUSC for their cooperation in the production of this program.

Neuromodulation for Anxiety

Mark S. George, MD, Distinguished Professor of Psychiatry, Radiology and Neuroscience; Director, Medical University of South Carolina (MUSC) Center for Advanced Imaging Research; Director, Brain Stimulation Lab­oratory; MUSC Director, South Carolina Brain Imaging Center of Excellence, Charleston

Introduction: many new techniques for focal electrical stimulation of brain; these techniques and brain imaging technology changing understanding of how brain works in health and disease; over time, largely forgotten that “the brain is an electrical organ, and electricity is the currency of the brain”)

Definition of neuromodulation: using electricity to stimulate specific areas of brain; therapeutic changes possible with brain stimulation that cannot be achieved with medications; brain stimulation techniques can act on individual neurons, groups of neurons, or brain regions; can selectively prime firing of neurons in one region, while blocking firing in another; electroconvulsive therapy (ECT) oldest technology and one with most data

Transcranial magnetic stimulation (TMS): electricity passing through electromagnet creates powerful magnetic field, which passes unimpeded through tissue and induces electrical current in brain (“electrodeless electrical stimulation”); magnetic field penetrates skull noninvasively; used alone, provides neuropsychologic localization and measure of cortical excitability, and can modify specific region of brain; coupled with imaging techniques, TMS can noninvasively monitor circuit activity and behavior; because of principles of physics, magnetic field drops off quickly from coil, and only superficial cortex can be stimulated; however, if connections of cortex un­derstood, cortical stimulation can be used transsynaptically to modify other brain regions; group in Israel cur­rently using new coil that provides deep brain stimulation (down to level of amygdala)

Side effects: primarily, discomfort or pain; however, clinical trial shows patients rate pain as lower at end of proce­dure than at beginning, and as less severe over 3 wk of treatment; occasional headache (»1 in 5 sessions), relieved by aspirin or acetaminophen

How does TMS work? prefrontal cortex (PFC) responsible for nonspecific functions (eg, working memory, hopes, dreams, planning for future); speaker believes main function of PFC to be regulation of deeper limbic region (nu­cleus accumbens, hippocampus, and amygdala); constant interplay between primary emotional drive (from lim­bus) and modulation by PFC in mentally healthy individuals; however, this feedback hypothesized to be dysfunctional in depression and some anxiety disorders; focal repetitive TMS (rTMS) changes neurohormones and mood

Clincal data: 62 published studies of rTMS show efficacy for treatment of depression; speaker’s study  —  sponsored by National Institutes of Mental Health (industry-free); improved sham (no unblinding); data accepted and em­bargoed for upcoming publication; Food and Drug Administration (FDA) approval granted in 2008 for use in medication-free unipolar major depression; not yet covered by all insurance providers; studies demonstrate cost-effectiveness of TMS

TMS for anxiety disorders: in posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), panic dis­order, and obsessive-compulsive disorder (OCD), results “decidedly mixed”; (eg, 3 positive and 3 negative trials for PTSD, 2 positive and 4 negative trials for OCD); speaker opines that mixed results obtained because delivery of TMS to modify involved circuits therapeutically not yet fully understood; in animal studies of learned help­lessness, animals with control over electric shock did not get rat equivalent of PTSD, while those without control did; recent studies indicate that control involves intermittent signal from PFC to dorsal raphe nucleus; with inter­mittent stimulation to PFC, rats do not develop PTSD (allows development of sense of control despite shocks); studies suggest that stimulation of these connections during re-exposure to source of anxiety or to pain might give patients greater sense of control (ie, less anxiety and pain)

Vagus nerve stimulation (VNS): first introduced as treatment for epilepsy, but also found to improve depression; pacemaker-like device implanted in chest wall, wire threaded subcutaneously to vagus nerve in neck; device sends intermittent signal to vagus nerve that travels to base of brain; first study to determine whether VNS could be useful in treatment-resistant depression underpowered and failed to show statistical significance; however, fol­low-up study showed that individuals with depression had improved outcomes, compared to treatment-as-usual group; based on that study, FDA approved it for treatment of treatment-resistant depression

VNS for anxiety: open pilot study of 9 patients with OCD, PTSD, or panic disorder, or combination of those; Ham­ilton Anxiety Scale (Ham-A; used to measure severity of anxiety), showed »50% response at 1 yr in 7 patients with OCD; study not yet replicated

Deep brain stimulation (DBS): newest and most invasive of brain stimulation technologies; originally introduced to treat Parkinson disease; high-frequency stimulation (>50 Hz) immediately improves rigidity, akinesia, and tremor; pacer placed in chest wall, with subcutaneous electrodes going into brain (however, insertion of elec­trodes into incorrect region of brain produces thoughts of crying, despair, and suicidal ideation); newest model for use in epilepsy monitors for preseizure signal (change in electroencephalography [EEG] that predicts onset of seizure); if change in EEG detected, device fires with advance neuromodulatory inhibitory signal; clinical trials just completed, but results not yet released

DBS in OCD: surgical ablation of anterior limb of internal capsule produces improvement in OCD, but creates per­manent lesion; open controlled study showed that inserting DBS electrodes in anterior limb of internal capsule and keeping them constantly “on” produced similar but slow improvement (over weeks to months); lesion not permanent; treatment group showed »50% improvement; even though double-blind studies have not been done, FDA granted humanitarian exemption for device for treatment of treatment-resistant OCD

Conclusions: TMS, VNS, DBS, and ECT have been used largely for treatment of depression; now finding greater ap­plication for treatment of anxiety disorders; other technologies that use electricity to stimulate brain currently under development

Anxiety and Alcohol

Sarah W. Book, MD, Associate Professor of Behavioral and Neurosciences, Center for Drug and Alcohol Pro­grams, Charleston Research Center, Medical University of South Carolina, Charleston

Introduction: relationship between anxiety and alcohol complicated; individuals with anxiety use alcohol to cope and may go on to develop alcohol problem; conversely, individuals with alcohol problems can be anxiogenic (ie, may develop anxiety in response to alcohol use and chronic alcohol withdrawal)

Speaker’s model: posits that anxiety precedes alcohol use; hallmark of social anxiety disorder  —  excessive or unrea­sonable fear of scrutiny in social situations; situations endured or avoided to reduce anxiety; epidemiologic surveys show social anxiety disorder generally begins in mid teenage years and alcohol use generally starts later; »1 in 5 people with social anxiety disorder go on to develop alcohol abuse or dependence

Measuring severity of social anxiety

Liebowitz Social Anxiety Scale Self-Report (LSAS-SR): used to measure severity of anxiety disorders; available on paper or online at (www.anxietyhelp.org/information/liebowitz.html); speaker uses it as initial screening tool and as tool to monitor ongoing efficacy of treatment; consists of 24 social situations; patient rates his or her anx­iety in each situation on scale of 0 to 3; online version scores results automatically

Attentional bias: individuals with social phobia known to have increased attentional bias to angry faces; hypothe­sized that if alcohol helps reduce anxiety in individuals with social anxiety disorder, then giving them alcohol should lessen attentional bias to angry faces; hypothesis borne out by “2 by 2” study (comparing participants with social anxiety disorder to those without, and participants given alcohol to sober participants)

Does excessive alcohol use interfere with treatments for anxiety? much more complicated to answer; in one study, subjects sorted into 4 groups consisting of regular group therapy for social anxiety disorder, therapist-assisted bibliotherapy, bibliotherapy alone, and waiting list; subjects in all groups improved, but subgroup analysis showed that those with alcohol problems did not do as well as those without alcohol problems; speaker opines that “the vast majority of people with alcohol problems don’t do well in therapy”

Speaker’s study: based on premise that individuals with social anxiety disorder who use alcohol to cope at risk for developing alcohol problems; if treatment for social anxiety disorder reduced or eliminated social anxiety, quan­tity and frequency of alcohol use should decrease; in randomized, placebo-controlled trial, subjects with social anxiety disorder and alcohol abuse or dependence treated with paroxetine for 16 wk; age of onset of social anxi­ety disorder 11 to 13 yr, onset of alcohol use disorder almost decade later; subjects drank average of 15 to 18 drinks per week, 5 to 7 drinks per drinking day; results showed that social anxiety did indeed decrease in subjects who took paroxetine

Drinking-to-cope survey: showed that paroxetine decreased drinking to cope; those taking paroxetine reported less drinking to cope and less avoidant behavior before and during social situations, as compared to those on placebo; no change seen in overall quantity or frequency of alcohol use; speaker realized that drinking did not decrease because subjects “had no idea they had an alcohol problem”, and were therefore unconcerned about their alcohol use; participants had not sought treatment for alcohol abuse, but for their anxiety; speaker concluded that these people needed counseling about consequences of alcohol use

Treatment for alcohol abuse and dependence: book from National Institutes of Health (NIH; Helping Patients Who Drink Too Much: A Clinician’s Guide); available on paper or online (www.niaaa.nih.gov/guide); provides guidelines for clinicians to use in assessing and providing brief intervention for patients with alcohol problems; booklet discusses whether “drinking is good for you,” how much alcohol is too much, definitions of standard drinks, and other subjects often raised by patients; problem drinking defined as men having ³5 drinks in any one day in past year or women hav­ing ³4; if screen positive, determine how much patient drinks per week (men should not have >14 drinks per week, women and individuals >65 yr of age should not have >7); in nonjudgmental manner, counsel positive patients about cutting down on their drinking; encourage patients to set goal by asking them what decrease would be realistic and if they think cutting down “worth it”; second NIH booklet, Rethinking Drinking, written for patients and clients; speaker finds information on associated website (www.rethinkingdrinking.niaaa.nih.gov) superior to that in booklet

Summary: alcohol use can complicate presentation and treatment of anxiety symptoms and syndromes; screen for at-risk drinking and consider brief intervention

Suggested Reading

Ansari S et al: Vagus nerve stimulation: indications and limitations. Acta Neurochir Suppl 97:281, 2007; Book SW et al: Paroxetine reduces social anxiety in individuals with a co-occurring alcohol use disorder. J Anxiety Disord 22:310, 2008; Book SW et al: Social anxiety impacts willingness to participate in addiction treatment. Addict Behav 34:474, 2009; Clark CR et al: Evidence-based medicine evaluation of electrophysiological studies of the anxiety disorders. Clin EEG Neurosci 40:84, 2009; Dempsey JP et al: Treatment of social anxiety with paroxetine: media­tion of changes in anxiety and depression symptoms. Compr Psychiatry 50:135, 2009; George MS et al: Brain stim­ulation for the treatment of psychiatric disorders. Curr Opin Psychiatry 20:250, 2007; Higgins ES, George MS: The Neuroscience of Clinical Psychiatry: The Pathophysiology of Behavior and Mental Illness. Baltimore: Lippincott, Williams & Wilkins, 2007; Le Fauve CE et al: Pharmacological treatment of alcohol abuse/dependence with psychi­atric comorbidity. Alcohol Clin Exp Res 28:302, 2004; Lisanby SH et al: Daily left prefrontal repetitive transcranial magnetic stimulation in the acute treatment of major depression: clinical predictors of outcome in a multisite, ran­domized controlled clinical trial. Neuropsychopharmacology 34:522, 2009; Helping Patients Who Drink Too Much: A Clinician’s Guide). Washington, DC: U.S. Department of Health and Human Services, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, 2005; Rethinking Drinking: Alcohol and Your Health. Washing­ton, DC: National Institutes of Health, U.S. Department of Health and Human Services, 2009; Pallanti S, Bernardi S: Neurobiology of repeated transcranial magnetic stimulation in the treatment of anxiety: a critical review. Int Clin Psychopharmacol 24:163, 2009; Rapee RM: Overcoming Shyness and Social Phobia: A Step-by-Step Guide (Clini­cal Application of Evidence-Based Psychotherapy). Lanham, MD: Jason Aronson, 1998; Rapee RM et al: Treatment of social phobia through pure self-help and therapist-augmented self-help. Br J Psychiatry 191:246, 2007; Smith JP, Book SW: Comorbidity of generalized anxiety disorder and alcohol use disorders among individuals seeking outpa­tient substance abuse treatment. Addict Behav. Aug 7, 2009 [Epub ahead of print]; Thomas SE et al: A complex rela­tionship between co-occurring social anxiety and alcohol use disorders: what effect does treating social anxiety have on drinking? Alcohol Clin Exp Res 32:77, 2008; Watts BV: Electroconvulsive therapy for comorbid major depressive disorder and posttraumatic stress disorder. J ECT 23:93, 2007.