MENTAL HEALTH MATTERS

Treating Depression with Transcranial Direct Current Stimulation When medication is not enough—will this experimental treatment ­present a cure? this disorder to share with them and that we understand when referral to a mental health professional is indicated. This column will provide an overview of depression and its existing treatment modalities—focusing particularly on an experimental therapy known as transcranial direct current stimulation (tDCS). Recently discussed in the New York Times,3 this therapy exposes patients’ brains to low levels of electric current. This article will also provide an examination of the evidence surrounding tDCS and its use as a tool in the fight against depression.

Photo by James Cheng.

TYPES AND SYMPTOMS OF DEPRESSION

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t’s not unusual to experience periods of feeling sad or even hopeless, times when we have less energy and interest in our surroundings. While such feelings can occur for no apparent reason, in certain situations they may be a normal response to an abnormal situation. This is often true for patients who are dealing with illness or threats to their health. Many are able, eventually, to move out of this depression and return to their prior level of functioning. However, this is not always the case. When a person is unable to function and many areas of life are negatively affected, it can be a sign of a clinical depression that requires intervention and treatment. The global burden of depression is on the rise; in the United States, it’s estimated that the 12-month prevalence of major depression is about 7%.1, 2 As health care professionals, nurses will undoubtedly encounter people who either are experiencing or have questions about depression. It’s important that we have basic information about 66

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There are several forms of depression, including major depressive disorder (MDD) and persistent depressive disorder (PDD), formerly known as dysthymic disorder. For detailed information on depressive disorders, readers are referred to the Diagnostic and Statistical Manual of Mental Disorders: DSM-5.1 A diagnosis of MDD requires that a person experience certain symptoms of depression for at least two weeks and that there is a noticeable and measurable change in the person’s ability to function and enjoy life. In addition to experiencing either a “depressed mood” or a “loss of interest or pleasure,” the person must have at least four other symptoms, which may include a loss of energy, a change in appetite, difficulty thinking or concentrating, and possible thoughts of death or suicide.1 For MDD criteria as established by the American Psychiatric Association, see Diagnostic Criteria for Major Depressive Disorder.1 A diagnosis of PDD requires that a person experience “a depressed mood for most of the day, for more days than not,” for at least two years (one year for children or adolescents).1 While the symptoms are similar to those of MDD, they are less intense, ranging from mild to moderate. People with PDD don’t experience the same level of dysfunction or impairment as those with MDD. For PDD criteria as established by the American Psychiatric Association, see Diagnostic Criteria for Persistent Depressive Disorder.1 ajnonline.com

By Donna Sabella, PhD, MEd, MSN, CRNP, PMHNP-BC

TALK AND PHARMACOLOGIC THERAPY

Depression can negatively affect quality of life and, at its worst, cause serious impairment in a person’s ability to love, work, play, and generally function. In addition, there is always the risk of suicide. Regardless of the type of setting nurses work in, it’s reasonable to expect that at some time we will work with patients experiencing depression who may turn to us for answers regarding treatment options. Talk therapy, conducted by a trained therapist, is one form of treatment for depression. Cognitive behavioral therapy and interpersonal therapy are among the clinical modalities proven to help patients with depression. Cognitive behavioral therapy helps people change negative thinking patterns, enabling them to view and react to the world in more positive ways. The goal of interpersonal therapy is to help people improve their relationships, particularly those that may be part of the reason for the depression. Research has shown that combining medication with some form of talk therapy is effective in treating depression and that the majority of people who seek and receive treatment can improve.4 Pharmacologic approaches. The most common approach to treatment involves medication, and there are several categories of medications available to treat depression. Antidepressants work by correcting imbalances in a variety of neurotransmitters. Because it can be four to six weeks before antidepressants take effect, patients may have to wait weeks before depression lessens. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants; others include tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). However, it’s not uncommon for a single medication to be ineffective. It may be necessary to augment treatment with atypical antipsychotics such as aripiprazole (Abilify), quetiapine (Seroquel), or olanzapine (Zyprexa).5 The adverse effects of these medications can include weight gain, diabetes, dyslipidemia, or metabolic syndrome.6 SSRIs are currently the first choice for treating depression. They have fewer adverse effects than other antidepressants, and these tend to be mild, especially when compared with those of the TCAs and MAOIs. The most common adverse effects include nausea, insomnia, headache, and sexual dysfunction. The most serious adverse effect is serotonin syndrome, which occurs when SSRIs are combined with other serotonergic drugs, such as MAOIs, and excessive serotonin is released in the brain. Symptoms include increased body temperature, diarrhea, restlessness, and nausea. If untreated, death can occur. Examples of SSRIs include fluoxetine (Prozac), paroxetine (Paxil, Pexeva), sertraline (Zoloft), and citalopram (Celexa). [email protected]



TCAs and MAOIs, the oldest categories of antidepressants, have a number of adverse effects that, in some cases, can be fatal. Although they are usually not clinicians’ first-choice drugs in treating depression, they are effective for some people and cost less than the newer SSRIs. TCAs are known to cause cardiac problems in some patients.7 Before beginning TCA therapy, people with a history of, or risk factors for, cardiac problems may require an electrocardiogram.6 A TCA overdose can be fatal, so clinicians must closely monitor a patient for suicidal ideation. Examples of TCAs include amitriptyline, imipramine (Tofranil), and nortriptyline (Pamelor). MAOIs are associated with the life-threatening condition known as hypertensive crisis, which causes a sudden increase in blood pressure, severe headache, sweating, fever, palpitations, and chest pain.8 If left untreated, hypertensive crisis can cause intracerebral bleeding and death. It can occur when people taking MAOIs ingest food or drinks with tyramine, such as but not limited to sausage, alcohol, yogurt, aged cheese, and anything with monosodium glutamate.8 Combining MAOIs with nasal and sinus decongestants can also cause hypertensive crisis. Examples of MAOIs include phenelzine (Nardil), tranylcypromine

Diagnostic Criteria for Major Depressive Disorder Updated guidelines from the DSM-5.

Major depressive disorder can be diagnosed when five or more of the following symptoms, including either a depressed mood or loss of interest or pleasure (and clearly unrelated to another medical condition), exist for at least two weeks: • depressed mood most of the time • loss of interest or pleasure in all or most activities • significant unintentional weight loss or gain • insomnia or sleeping too much • psychomotor agitation or retardation noticed by others • fatigue or loss of energy • feelings of worthlessness or excessive guilt • diminished ability to think or concentrate, or indecisiveness • recurrent thoughts of death or suicide Source: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013.1

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Diagnostic Criteria for Persistent Depressive Disorder Updated guidelines from the DSM-5.

Persistent depressive disorder can be diagnosed when a depressed mood exists for most of the day, more days than not, for at least two years, along with two or more of the following symptoms that cause clinically significant impairment in social, work, or other important areas of functioning: • poor appetite or overeating • insomnia or sleeping too much • low energy or fatigue • low self-esteem • poor concentration or indecisiveness • feelings of hopelessness Source: American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Washington, DC: American Psychiatric Publishing; 2013.1

(Parnate), and isocarboxazid (Marplan). In 2006, the Food and Drug Administration approved a oncedaily transdermal MAOI patch containing selegiline (Emsam). While the patch requires less attention to dietary restrictions, patients will still need to avoid medications that negatively interact with MAOIs.9 While medications are typically the first line of treatment for depression and are often effective, they don’t work for everyone. Antidepressants may present safety risks in certain populations, especially pregnant women, geriatric patients, and adolescents. It can also take weeks to months for antidepressants to take effect, and they can increase the risk of suicidal ideation and suicide attempts, especially in children and young adults. There is also the issue of availability and cost, especially for those with no insurance. Finally, not all patients will be adherent, especially those who are prescribed several medications. For these reasons, researchers are eager to add more tools to the fight against depression.

ELECTROTHERAPY

For people who have been diagnosed with MDD and still have symptoms of depression after trying at least two antidepressants, physicians may suggest a form of electrotherapy.10 Far from a modern-day concept, electrotherapy—applying electricity to the brain to allay the effects of behavioral disorders— was first used in the early 1800s by the Italian physicist Giovanni Aldini.11 The process and procedure have evolved over time; today electrotherapy is available in several forms. 68

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Electroconvulsive therapy (ECT) is perhaps the best-known form of electrotherapy for depression. Formerly known as electroshock therapy, today’s ECT is safer and has none of the adverse sequelae (such as broken bones) of former years. Patients are placed under anesthesia and given a muscle relaxant, then an electric current induces a controlled seizure. The belief is that the electrical stimulation helps to regulate the person’s chemical balance and brain function. While patients require medical clearance for ECT, adverse effects tend to be minimal, most noticeably short-term memory loss and mild disorientation. Treatments are administered several times a week over the course of a few weeks. ECT has been shown to work fairly well for patients with either unipolar or bipolar depression.12-14 Repetitive transcranial magnetic stimulation (rTMS) does not induce seizures like ECT, nor does it require sedation or have many adverse effects. A small magnet is applied to the forehead and triggers mild electric currents in the brain. Sessions are typically four to five times per week for 40 minutes each; treatment may last for two to six weeks.10 Although not a well-known treatment modality, rTMS is approved for clinical use in the United States, Israel, Canada, and Brazil.15 tDCS. Unlike ECT, tDCS does not require anesthesia, and it uses a milder current to stimulate the brain. Two saline-soaked sponge electrodes, a cathode and an anode, are placed over the scalp and a weak direct current is administered. Patients remain conscious and alert. There are no set guidelines for the intensity and range of delivery of the current, the number of minutes per session, or how many weeks treatment should last. However, patients generally undergo tDCS for 20 to 30 minutes several times a week for several weeks.15, 16 A number of studies have reported the benefits of tDCS on chronic pain disorders17-19 and migraines.20 The therapy has also been noted to improve attention and concentration21, 22 and cognitive ability.23 While tDCS is still considered an experimental form of treatment, with early studies showing mixed results,24 there is cautious optimism among researchers regarding its viability as a treatment for depression.

tDCS: WHAT THE RESEARCH SAYS

Since 2006, a number of studies have reported encouraging findings. When comparing tDCS with sham treatment, both Fregni and colleagues and Boggio and colleagues found tDCS more effective in relieving subjects’ depression.25, 26 (It should be noted that participants didn’t take antidepressant medication before or during either of these studies.24, 25) A double-blind, shamcontrolled trial of 64 people experiencing depression ajnonline.com

found significantly greater improvement in those who underwent tDCS.27 The researchers also noted that those who received tDCS experienced improvements in attention and working memory after only one session. In this trial, participants continued taking antidepressant medications throughout the study. One of the largest and most recent trials comes to us from São Paulo, Brazil.15 Unlike previous studies, this one compared the efficacy of tDCS with that of an antidepressant—in this case the SSRI sertraline. Participants were assigned to one of the following four groups: sham tDCS and placebo, sham tDCS and sertraline, active tDCS and placebo, and active tDCS and sertraline. The researchers hypothesized that the use of tDCS plus sertraline would be more effective than either tDCS or sertraline alone. Participants included 120 patients with moderate to severe, nonpsychotic, unipolar MDD who were not taking antidepressants. Findings revealed that combined tDCS and sertraline treatment had a significantly greater effect on MDD than placebo; the combination was also significantly more effective than either tDCS or sertraline alone, raising the possibility that each intervention has an additive effect on the other. The researchers concluded that the results confirmed the clinical efficacy of tDCS in treating depression and demonstrated that tDCS has similar effects to those of sertraline. While the literature points to the efficacy and safety of tDCS,27, 28 more research and future trials are called for. In their meta-analysis of six randomized controlled trials of tDCS use in depression, Kalu and colleagues found a significant reduction in the severity of depressive symptoms with active tDCS compared with sham tDCS.16 However, they noted that many of the studies had small sample sizes, and they encouraged readers to consider results in terms of both the placebo effect and the variability of the patient population (for example, subjects took antidepressants in some studies but not in others and there were variations in symptom severity among study participants at baseline). Questions to be raised in future studies include which brain areas should be targeted to achieve optimal treatment efficacy. In terms of safety, while headache and itchiness and redness at the stimulation site were the more common adverse effects in one trial,27 hypomanic episodes after tDCS treatment have also been reported.15, 27 In their article on establishing safety limits for tDCS, Bikson and colleagues call for “continued vigilance in examining potential hazards.”29 They argue that tDCS “represents a constellation of technologies and approaches,” that may require protocol-specific safety standards dependent on details such as the intensity and duration of electrical impulses, the placement of electrodes, and the salinity of sponges. [email protected]



Others point out that tDCS stimulation is widespread within the brain, and that while this may be an advantage in certain instances, it can also yield unexpected adverse effects; researchers need to bear this in mind when conducting further trials.22 As Brunoni and colleagues point out, while tDCS appears to be safe, with mild and transient adverse effects, many tDCS trials have been conducted in healthy people in single-session studies.30 What will be the consequences of multiple treatments in patients who are not in the best of health? They call for a more active examination of tDCS’s adverse effects to ensure that the treatment is as safe as many believe it to be. As a final word of caution, people need to be warned against trying tDCS on themselves at home. As word has spread about the possible benefits and ease of use of this treatment, a number of companies are selling kits online, a practice that could cause more harm than good.31 There is a tremendous need for MDD treatment that is readily accessible, affordable, effective, and safe. Hopefully, future research will determine whether tDCS will be a contender in the ongoing fight against this life-altering disorder. ▼ Donna Sabella is a mental health nurse and assistant clinical professor and director of global studies at the Drexel University College of Nursing and Health Professions in Philadelphia. She also coordinates Mental Health Matters: [email protected] The author has disclosed no potential conflicts of interest, financial or otherwise.

REFERENCES 1. American Psychiatric Association, DSM-5 Task Force. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Washington, DC: American Psychiatric Publishing; 2013. 2. World Health Organization, Media Centre. Depression. Fact sheet number 369. 2012 Oct. http://www.who.int/mediacentre/ factsheets/fs369/en. 3. Belluck P. Promising depression therapy. New York Times 2013 Feb 11. http://well.blogs.nytimes.com/2013/02/11/ promising-depression-therapy. 4. National Institute of Mental Health. Depression. Bethesda, MD: National Institutes of Health 2011. http://www.nimh. nih.gov/health/publications/depression/depression-booklet.pdf. 5. WebMD. Recognizing and treating depression: treatments for depression. 2012. http://www.webmd.com/depression/ symptoms-depressed-anxiety-12/treating-depression. 6. Stahl SM. The Prescriber’s Guide: Stahl’s Essential Psychopharmacology. 3rd Ed. New York City: Cambridge University Press, 2009. 7. Hamer M, et al. Antidepressant medication use and future risk of cardiovascular disease: the Scottish Health Survey. Eur Heart J 2011;32(4):437-42. 8. Flockhart DA. Dietary restrictions and drug interactions with monoamine oxidase inhibitors: an update. J Clin Psychiatry 2012;73(Suppl 1):17-24. 9. U.S. Food and Drug Administration. FDA approves Emsam (selegiline) as first drug patch for depression [press release]. FDA news release 2006 Feb 28. http://www.fda.gov/newsevents/ newsroom/pressannouncements/2006/ucm108607.htm.

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10. Agency for Healthcare Research and Quality, Effective Health Care Program. Therapies for treatment-resistant depression: a review of the research. Rockville, MD; 2012 Mar. Consumer guides on health conditions; http://effectivehealthcare.ahrq. gov/ehc/products/76/1011/ref_dep_cons_fin_to_post.pdf. 11. Parent A. Giovanni Aldini: from animal electricity to human brain stimulation. Can J Neurol Sci 2004;31(4):576-84. 12. Dierckx B, et al. Efficacy of electroconvulsive therapy in bipolar versus unipolar major depression: a meta-analysis. Bipolar Disord 2012;14(2):146-50. 13. National Institute of Mental Health. Brain stimulation therapies. National Institutes of Health. n.d. http://www.nimh. nih.gov/health/topics/brain-stimulation-therapies/brain-­ stimulation-therapies.shtml. 14. Pagnin D, et al. Efficacy of ECT in depression: a meta-analytic review. J ECT 2004;20(1):13-20. 15. Brunoni AR, et al. The sertraline vs. electrical current therapy for treating depression clinical study: results from a factorial, randomized, controlled trial. JAMA Psychiatry 2013; 70(4):383-91. 16. Kalu UG, et al. Transcranial direct current stimulation in the treatment of major depression: a meta-analysis. Psychol Med 2012;42(9):1791-800. 17. DosSantos MF, et al. Immediate effects of tDCS on the muopioid system of a chronic pain patient. Front Psychiatry 2012;3:93. 18. Fregni F, et al. A randomized, sham-controlled, proof of principle study of transcranial direct current stimulation for the treatment of pain in fibromyalgia. Arthritis Rheum 2006;54(12):3988-98. 19. Riberto M, et al. Efficacy of transcranial direct current stimulation coupled with a multidisciplinary rehabilitation program for the treatment of fibromyalgia. Open Rheumatol J 2011;5:45-50. 20. Dasilva AF, et al. tDCS-induced analgesia and electrical fields in pain-related neural networks in chronic migraine. Headache 2012;52(8):1283-95.

21. Chi RP, Snyder AW. Brain stimulation enables the solution of an inherently difficult problem. Neurosci Lett 2012;515(2): 121-4. 22. Loo CK, Martin DM. Could transcranial direct current stimulation have unexpected additional benefits in the treatment of depressed patients? Expert Rev Neurother 2012; 12(7):751-3. 23. Brunoni AR, et al. Clinical research with transcranial direct current stimulation (tDCS): challenges and future directions. Brain Stimul 2012;5(3):175-95. 24. Nitsche MA, et al. Treatment of depression with transcranial direct current stimulation (tDCS): a review. Exp Neurol 2009;219(1):14-9. 25. Boggio PS, et al. A randomized, double-blind clinical trial on the efficacy of cortical direct current stimulation for the treatment of major depression. Int J Neuropsychopharmacol 2008;11(2):249-54. 26. Fregni F, et al. Treatment of major depression with transcranial direct current stimulation. Bipolar Disord 2006;8(2): 203-4. 27. Loo CK, et al. Transcranial direct current stimulation for depression: 3-week, randomised, sham-controlled trial. Br J Psychiatry 2012;200(1):52-9. 28. Poreisz C, et al. Safety aspects of transcranial direct current stimulation concerning healthy subjects and patients. Brain Res Bull 2007;72(4-6):208-14. 29. Bikson M, et al. Establishing safety limits for transcranial direct current stimulation. Clin Neurophysiol 2009;120(6): 1033-4. 30. Brunoni AR, et al. A systematic review on reporting and assessment of adverse effects associated with transcranial direct current stimulation. Int J Neuropsychopharmacol 2011; 14(8):1133-45. 31. Novella S. Brain stimulation for the masses. Science-Based Medicine 2013 Jul 10. http://www.sciencebasedmedicine.org/ brain-stimulation-for-the-masses.

Treating depression with transcranial direct current stimulation.

When medication is not enough-will this experimental treatment present a cure?...
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