April 2013 Volume 8 Issue 4

Inside In This Issue 2 Moral Injury: An Emerging Concept in Combat Trauma George Loeffler, M.D. 4 Methoxetamine: The Rise of a Ketamine Analogue “Legal High” Cassandra Craig, B.Sc. George Loeffler, M.D. 6 Depression, Suicide, and Ketamine John Burger, M.D. George Loeffler, M.D. 9 Use of “Bath Salts” Among Members of the United States Military: A Case Report With Discussion Daniel G. Allen, M.D. Wander S. Segura, M.D. Rebecca R. Burson, D.O. 11 Deployment Stress, Dextro­ This issue of the Residents’ Journal focuses on the theme of military psychiatry. The methorphan, Ketamine, and issue begins with an article by the Guest Section Editor, George Loeffler, M.D., on the Pharmacologic Interactions: emerging concept of moral injury. In a case report, Daniel G. Allen, M.D., Wander S. A Multifactorial Presentation Segura M.D., and Rebecca R. Burson, D.O., describe the effects of methylenedioxypy- of Mania rovalerone use in an active-duty service member, as well as the unique challenges use Philip Y.T. Liu, M.D. of this substance presents to both service members and military health care providers. Rebecca R. Burson, D.O. Philip Y.T. Liu, M.D., and Dr. Burson present a case report of first-episode sub- stance-induced mania with psychotic features in a decorated soldier evacuated from a 13 Virtual Reality Exposure combat-stressed environment. Ryan Richmond, B.S., discusses virtual reality exposure Therapy for the Treatment of therapy for treatment of combat posttraumatic stress disorder. Last, Nicole Garber, Combat Posttraumatic Stress M.D., presents data on the effects of military deployment on children. Disorder Ryan Richmond, B.S. Editor-in-Chief Guest Section Editor Monifa Seawell, M.D. George Loeffler, M.D. 15 Effects of Military Senior Editor Editors Emeriti Deployment on Children Sarah M. Fayad, M.D. Sarah B. Johnson, M.D. Molly McVoy, M.D. Nicole Garber, M.D. Associate Editor Arshya Vahabzadeh, M.D. Joseph M. Cerimele, M.D. 16 Editor’s Note Staff Editor Angela Moore Moral Injury: An Emerging Concept in Combat Trauma

George Loeffler, M.D.

Since antiquity, it has been recognized that ories of trauma. Their hypothesis was imagined conversation with a benevolent military combat can result in psychological most heavily drawn from social cogni- moral authority or fellow junior service damage. In his landmark book Achilles in tive theories of PTSD. According to this member who is similarly “stuck.” The goal Vietnam, Jonathan Shay (1) powerfully ar- theory, PTSD is a result of a traumatic is to “get service members and veterans to gues that the Iliad can be read as just such event conflicting with an individual’s be- articulate ideas about the capacity to do an account. In his book’s subtitle, “Combat liefs, such as “the world is benevolent,” good, talk about being forgiven and the Trauma and the Undoing of Character,” “the world is meaningful,” and “the self need for self-forgiveness, even if they don’t Shay intimates the profound way the war is worthy.” Moral injury fits this mold. initially accept these ideas.” fighter’s experiences shape him or her. The psychological difficulties result from He introduces the phrase “moral injury” a combat experience conflicting with an Description of Adaptive Disclosure to describe how “the moral dimension of individual’s ethical beliefs. Adaptive disclosure is a manualized trauma destroys virtue, undoes good char- intervention consisting of six 90-min- acter,” considering it “an essential part of The Moral Injury Construct ute sessions designed specifically to any combat trauma that leads to a lifelong treat active-duty service members with Drescher et al. (3) assumed the task of psychological injury” (1, p. 20) combat-related PTSD. Details of this beginning to operationalize and clinically approach are described elsewhere (2, 4, Training in a military hospital, I have situate the concept of moral injury. With 5). Acknowledging the challenges active- seen that the consequences of combat are the goal of exploring “professional opin- duty service members face participating ubiquitous. In my own clinical experience, ion as to the presence, the utility, and the in protracted courses of treatment, the I have found that neither the diagnosis phenomenology of the construct of moral goal of this brief intervention is explicitly of posttraumatic stress disorder (PTSD) injury,” they conducted semistructured identified as “initiat[ing] a process experi- nor the current trauma-focused psycho- interviews of 23 experts in mental health entially rather than expecting full system therapies adequately address the ethical and chaplaincy. remission, in effect ‘planting seeds’” (5). dimension of combat trauma. These ethi- Experts were unanimous in the expressed cal and existential concerns are the focus The first session consists of an intro- need for the concept of moral injury. This of moral injury. duction to adaptive disclosure and extended to the belief that the current identification of the index event. The next Emergence of the Moral conception of PTSD has failed to ade- four sessions delve into this event. The Injury Construct quately capture this dimension of combat event is described in significant detail trauma. so as to emotionally engage the patient. Litz et al. (2) wrote an article, published Treating Moral Injury Following this, based on the nature of in 2009, on the understanding and treat- the event and the patient’s reaction, the ment of combat trauma. Using the phrase therapist guides the patient in addressing Theoretical Considerations “moral injury,” the authors postulated a one of three experiences: life threat, loss, Litz et al. (2) outlined an approach de- distinct syndrome arising from the com- or moral injury. signed to treat moral injuries. They bat experience. They defined moral injury identified two routes to healing moral To address moral injury, the therapist uses as “perpetrating, failing to prevent, bear- injury: the psychological and emotional the empty chair technique in guiding the ing witness to, or learning about acts processing of the memory and meaning of patient through an imagined conversa- that transgress deeply held moral be- the moral transgression and corrective life tion with a benevolent authority figure. liefs and expectations.” They also stated experience. Focusing on the first, Litz et al. The patient describes his or her guilt and that, “moral injury requires an act of drew from a number of psychotherapeutic shame and then offers what the authority transgression that severely and abruptly interventions. From exposure therapy, they figure might say in turn. The therapist is contradicts an individual’s personal or suggested a raw and emotional reliving of encouraged to be highly directive in elic- shared expectation about the rules or the the morally transgressive experience, fol- iting “forgiveness-related content. code of conduct, either during the event lowed by a critical examination of implicit In the sixth and final session, the patient or at some point afterward.” appraisals. Recognizing the rigidity and is instructed to reflect on gains and to Litz et al. situated the notion of moral resistance to disconfirmation of these neg- prepare for future struggles. injury within a number of current the- ative appraisals, the authors proposed an

The Residents’ Journal 2 Open Trial of Adaptive Disclosure that it contains some measure of univer- While it has long been known that not Gray et al. (5) described the initial proof sality that binds or compels an individual. all combat wounds are physical, the moral of concept trial of adaptive disclosure, The Golden Rule appeals to a special set of dimension of psychological injury re- which was conducted at the Marine beliefs that bind both oneself and others mains largely unexplored, at least within Corps Base Camp Pendleton in San with a special force. While these ethical mainstream mental health. The work Diego and funded by the Navy Bureau beliefs are embedded in the particular done to understand and treat moral in- of Medicine and Surgery. This was an history and psychology of an individual, jury, while preliminary, provides hope for uncontrolled open-clinical trial of 44 ac- at the same time they originate and apply those suffering from these unseen scars tive-duty Marines. All participants met beyond the individual. I do not feel that and those charged with helping them. criteria for PTSD from deployment ex- these elements of moral injury have thus Dr. Loeffler is a fourth-year psychiatry periences in Iraq or Afghanistan. far been sufficiently addressed. resident at the Naval Medical Center San Results of this brief intervention were To adequately do so would be part of a Diego. He is also an active-duty Lieutenant encouraging. The primary outcome mea- larger project to draw together insights in the United States Navy. sure, PTSD symptoms as measured by from many different fields. Within psy- The author thanks Eileen Delaney for her the PTSD Checklist–Military version, chology, in addition to the cognitive, support and guidance. The author also thanks revealed that there was nearly a 10-point behavioral, and gestalt schools, I would Eric Baker, Marc Capobianco, Warren Klam, improvement in symptoms, represent- include existential psychotherapy, affect George Loeffler, Sr., Robert McLay, David ing an effect size of 0.79 (Cohen’s d) in theory, moral psychology, and psycho- Oliver, Christopher Streeter, and Sarah Yas- the large range. Improvement of depres- dynamics, particularly as it relates to utake for their assistance with this article. sive symptoms was also in the large effect object-relations and super-ego function- size range (Cohen’s d=0.71, p=0.001). Of ing, to name just a few. As my mentor The views presented in this article are solely note, these results were for all three arms Christopher Streeter once pointed out, that of the author’s and do not necessar- of the intervention pooled and not exclu- developmental theories, such as Erik- ily reflect the official policy or position of the sively for the moral injury intervention. son’s psychosocial stages, are also relevant, United States Federal Government, Depart- ment of Defense, or Department of the Navy. Gray at al. (5) acknowledged a number of especially in light of the fact that many limitations to the study, however, includ- combat veterans are in their late teens References ing small sample size, lack of long-term and early twenties, falling somewhere be- follow up, and lack of random assign- tween identity versus role diffusion and 1. Shay J: Achilles in Vietnam: Combat ment for the comparison group. Another intimacy versus isolation. Trauma and the Undoing of Character. limitation was the absence of a rating in- Additionally, we need to reach beyond New York, Scribner, 1995 strument to directly assess moral injury, psychology. Ethics, the branch of philoso- 2. Litz BT, Stein N, Delaney E, Lebowitz L, subsequently addressed by Nash et al. phy through which we seek to understand Nash WP, Silva C, Maguen S: Moral in- with the Moral Injury Event Scale (6). good conduct and the good in human life, jury and moral repair in war veterans: a preliminary model and intervention strat- is also necessary. Including religion, the- egy. Clin Psychol Rev 2009; 29:695–706 Future Directions ology, and spirituality is important as well. 3. Drescher KD, Foy DW, Kelly C, Lesh- In a few short years, Litz and his col- Much clinical research must also be done. nerA, Schutz K, Litz B: An exploration of laborators have laid the conceptual and The adaptive disclosure pilot study is an the viability and usefulness of the con- clinical foundation for the concept of important first step. The Naval Center struct of moral injury in war veterans. moral injury. Nevertheless, much work for Combat and Operational Stress Con- Traumatology 2011; 17:8–13 remains to be done. trol is planning an expanded follow-up 4. Steenkamp MM, Litz BT, Gray MJ, Leb- study. We need to apply other treatment Part of the theoretical work will involve owitz L, Nash W, Conoscenti L, Amidon modalities to moral injury, in addition to A, Lang AJ: A brief exposure-based inter- further clarifying what moral injury is. I developing new ones. The Moral Injury vention for service members with PTSD. believe that it is a more challenging, even Event Scale offers the necessary cur- Cogn Behav Practice 2011; 18:98–107 murkier, concept than other concepts rency by which to compare these various 5. Gray MJ, Schorr Y, Nash W, Lebowitz L, in mental health because of its inherent approaches. Amidon A, Lansing A, Maglione M, inclusion of the philosophical domain Lang AJ, Litz BT: Adaptive disclosure: an Of course, this all must be translated of morality. At once we are trying to open trial of a novel exposure-based inter- describe the subjective psychological ex- into clinical practice. I see recognition vention for service members with combat- perience of an individual, something we of moral injury permeating the hospital related psychological stress injuries. Behav are accustomed to in mental health, as where I train. For example, the residential Ther 2012; 43:407–415 treatment program for active-duty service well as the individual’s conception of mo- 6. Nash W, Carper T, Mills M, Au T, Baker rality, something I believe that we are less members with combat PTSD has added D, Goldsmith A, Litz B: Psychometric accustomed to. What separates morality a weekly moral injury group. evaluation of the Moral Injury Event from mere opinion of likes and dislikes is Scale. (in press)

The Residents’ Journal 3 Methoxetamine: The Rise of a Ketamine Analogue “Legal High” Cassandra Craig, B.Sc. George Loeffler, M.D.

“Legal highs,” or “designer drugs,” are group with an N-ethyl group prolongs methoxetamine is also ingested rectally novel psychoactive substances that are the duration of action while preventing and through intramuscular and intravas- designed to elicit a psychoactive response the occurrence of chronic bladder toxic- cular injection (10). similar to that of commonly available ity associated with long-term ketamine Users describe euphoria, increased empa- substances of abuse while eluding legal use (6, 7). However, recent evidence from thy, a pleasant intensification of sensory control (1). They are principally synthetic a study conducted in mice demonstrated experience (especially music), vivid visual chemicals but may also include plant or significant kidney and bladder damage hallucinations, and transient antidepres- fungal material (1). In recent years, we following daily methoxetamine adminis- sant effects (6). Untoward effects include have seen migration to the United States tration over a 3-month period (8). dizziness, confusion, time distortion, of synthetic cannabinoid receptor ago- Although the mechanism of action of aphasia, and psychomotor agitation (6). nists and synthetic cathinones, commonly methoxetamine has not been formally Reported withdrawal symptoms include known as “spice” and “bath salts,” respec- determined, its close structural similarity low mood, cognitive impairment, and tively (2). Both substance classes presented to ketamine suggests that it is also an N- in­som­nia, as well as a single anecdotal re- in continental Europe and the United methyl-d-aspartate receptor blocker and port of attempted suicide (6). Kingdom about 2 years prior to emerging a dopamine reuptake inhibitor (6). The in the United States (2). Methoxetamine Individuals presenting with acute meth­ properties of methoxetamine and ket- ox­etamine toxicity exhibit ketamine-like (or 3-MeO-2-Oxo-PCE), an analogue amine are presented in Figure 1. of ketamine (which is a dissociative anes- dissociation, including derealization, de- thetic), was first identified as a new “legal personalization, or even a catatonic-like high” in November 2010 by the European Clinical Presentation state (6). In contrast to acute ketamine toxicity, individuals may also exhibit Monitoring Centre for Drugs and Drug Methoxetamine (also known as “MXE,” Addiction (3). In Europe, methoxetamine sympatho­ mimetic­ features, including “m-ket,” “K-max,” or “mexxy”) can be tachycardia, hypertension, and pyrexia, has risen to become a prominent substance readily purchased over the Internet or in of abuse. It is widely discussed in the pop- as well as marked agitation and aggres- head shops. It is sometimes labeled “fish sion (6, 7, 11, 12). A series of three cases ular media and has a small but growing tank cleaner” and may include the “not presence in the European peer-reviewed in the United Kingdom identified sig- for human consumption” disclaimer com- nificant cerebellar toxicity associated literature. While to date there are few re- monly placed on other designer drugs. It ports concerning methoxetamine abuse in with methoxetamine use. The patients is a white powder and is frequently sold in presented with cerebellar ataxia, inco- the United States, this may change in the small, colorful packets (6, 9). near future if it conforms to the 2-year lag ordination, dysarthria, and horizontal time of prior designer drugs migrating The most common methods of adminis­ nystagmus, although rotary nystagmus from Europe, especially from the United tration are orally and insufflation, although has also been described (9, 10). Creatine Kingdom. FIGURE 1. Methoxetamine and Ketamine Properties Pharmacology Methoxetamine is a 3-methoxy, N- Cl ethyl derivative of ketamine in the arylcyclohexylamine class (4). It has been O O described as having a higher potency than ketamine, with a longer duration of ac- NH NH tion (2–3 hours), as well as a longer delay in the onset of its effects (10–20 minutes) when taken by insufflation (nasally) (5). This delayed onset has reportedly led to re- O peated dosing and unintentional overdose by users (6). It has been suggested that Methoxetamine Ketamine the substitution of ketamine’s N-methyl

The Residents’ Journal 4 kinase levels may also be elevated, peak- doses of ketamine have shown great KM, Ceschi A: Ketamine-like effects after ing several hours after drug consumption promise, and Coppola and Mondola (14) recreational use of methoxetamine. Ann (9). Autonomic symptoms tend to re- hypothesize that methoxetamine may Emerg Med 2012; 60:97–99 solve within 2 to 3 hours, while cerebellar prove even better. 6. Corazza O, Schifano F, Simonato P, Fer- gus S, Assi S, Stair J, Corkery J, Trincas G, symptoms may take up to 4 days. Except Methoxetamine appears to be the first for one reported overdose death in which Deluca P, Davey Z, Blaszko U, Demetrov- and most prominent in a collection of ics Z, Moskalewicz J, Enea A, di Melchi- autopsy results demonstrated the pres- ketamine-based compounds. The initial ence of methoxetamine in addition to orre G, Mervo B, di Furia L, Farre M, handful of spice and bath salt compounds Flesland L, Pasinetti M, Pezzolesi C, three synthetic cannabinoids, complete rapidly proliferated into dozens if not Pisarska A, Shapiro H, Siemann H, Skutle resolution has been described in all other hundreds of new compounds, emerging in A, Enea A, di Melchiorre G, Sferrazza E, reported cases (5, 7, 9, 10, 13). waves in response to legislation and drug Torrens M, van der Kreeft P, Zummo D, Because methoxetamine has only recently detection capability (2). True to this pat- Scherbaum N: Phenomenon of new drugs emerged, we still do not have a clear clinical tern, 3-methoxy-PCP, 4-methoxy-PCP, on the Internet: the case of ketamine de- rivative methoxetamine. Hum Psycho- picture of its acute toxicity, not to mention 2-methoxy-ketamine, and N-ethyl-nor- pharmacol Clin Exp 2012; 27:145–149 the effects of chronic use. Methoxetamine ketamine have arrived on the market is marketed to recreational drug users as a recently (3). Relative to ketamine, even 7. Wood DM, Davies S, Puchnarewicz M, “bladder-friendly alternative to ketamine,” less is known about these compounds. Johnston A, Dargan PI: Acute toxicity as- sociated with recreational use of the ket- although no studies in humans have been Cassandra Craig is a third-year medical stu- amine derivative methoxetamine. Eur J conducted, and preliminary data from an- dent at the Uniformed Services University Clin Pharmacol 2012; 68:853–856 imal studies indicate significant bladder of the Health Sciences School of Medicine, 8. North American Congress of Clinical and kidney toxicity (8). Bethesda, Md. She is also an active-duty Toxicology: From the Proceedings of the While no specific recommendations exist Second Lieutenant in the United States Air 2012 Annual Meeting of the North for the acute treatment of methoxetamine Force. Dr. Loeffler is a fourth-year psychi- American Congress of Clinical Toxicol- toxicity, given its similarity to ketamine atry resident at the Naval Medical Center ogy, Las Vegas, October 1–6, 2012 and phencyclidine (PCP), it would be rea- San Diego. He is also an active-duty Lieu- 9. Shields JE, Dargan PI, Wood DM, Puch- sonable to infer management from these tenant in the United States Navy. narewicz M, Davies S, Waring WS: better known compounds, i.e., supportive Methoxetamine associated reversible cer- The views presented in this article are solely ebellar toxicity: three cases with analytical care with benzodiazepines, antiemetics, that of the authors’ and do not necessarily and intravenous fluids with respiratory confirmation. Clin Toxicol 2012; reflect the official policy or position of the 50:438–440 support as required (11). United States Federal Government, Depart- 10. Ward J: Methoxetamine: a novel ketamine The Future ment of Defense, Air Force, or Department analog and growing health-care concern. of the Navy. Clinical Toxicol 2011; 49:874–875 Although the United Kingdom appears References 11. Rosenbaum CD, Carreiro SP, Babu KM: to be the primary market for methoxet- Here today, gone tomorrow…and back amine at present, the confluence of easy 1. Gibbons S: “Legal Highs”: novel and again? a review of herbal marijuana alter- availability over the Internet, low cost, emerging psychoactive drugs: a chemical natives (K2, spice), synthetic cathionones and a perceived absence of federal regu- overview for the toxicologist. Clin Toxicol (bath salts), kratom, Salvia divinorum, lations make the United States a fertile 2012; 50:15–24 methoxetamine, and piperazine. J Med Toxicol 2012; 8:15–32 potential market. 2. Loeffler G, Hurst D, Penn A, Yung K: To date, discussion of methoxetamine Spice, bath salts, and the U.S. military: the 12. Wood DM, Dargan PI: Novel psychoac- in the medical literature has principally emergence of synthetic cannabinoid re- tive substances: how to understand the acute toxicity associated with the use of been presented in either toxicological or ceptor agonists and cathinones in the U.S. armed forces. Military Med 2012; these substances. Ther Drug Monit 2012; case reports. As was the case when spice 177:1041–1048 34:363–367 and bath salts initially emerged, we need a more robust literature describing clinical 3. Advisory Council on the Misuse of Drugs 13. Wikström M, Thelander G, Dahlgren M, (ACMD) Methoxetamine Report. http:// Kronstrand R: An accidental fatal intoxi- presentation and management. We also www.homeoffice.gov.uk/publications/ cation with methoxetamine. J Anal Toxi- need an understanding of the pharmacol- agencies-public-bodies/acmd1/methoxet- col 2013; 37:43–46 ogy of methoxetamine, since we currently amine2012 (Accessed January 2013) 14. Coppola M, Mondola R: Methoxetamine: are limited to inferring properties based 4. Hays PA, Casale JF, Berrier AL: The char- from drug of abuse to rapid-acting antide- on structural similarities to ketamine and acterization of 2-(3-methoxyphenyl)-2- pressant. Med Hypotheses 2012; PCP. (ethylamino) cyclohexanone (methox­ eta­ ­ 79:504–507 Interestingly, it has been suggested that mine). Microgram J 2012; 9: 3–17 methoxetamine may be efficacious as 5. Hofer KE, Grager B, Müller DM, Rau- a clinical antidepressant. Subanesthetic ber-Lüthy C, Kupferschmidt H, Rentsch

The Residents’ Journal 5 Depression, Suicide, and Ketamine John Burger, M.D. George Loeffler, M.D.

Over the past 50 years, monoamines this effect lasted 3 days postinfusion. In toms was noted within 40 minutes, with have remained the target of treatment for a subsequent study, Zarate et al. (7) used 42% of patients meeting response criteria depression, despite only one-third of pa- a single dose of ketamine in 17 patients within 24 hours. Zarate et al. (15) per- tients achieving remission with standard with treatment-resistant depression. At formed a similar study of 15 patients with antidepressant therapy, while taking 4 to 110 minutes postinfusion, 50% of the pa- treatment-resistant bipolar depression. 6 weeks to do so (1). A novel, rapid, and tients exhibited significant improvement Within 40 minutes, significant decreases effective therapeutic target has emerged in depressive symptoms, and this postin- in both depressive symptoms and suicidal with modulators of the glutamatergic fusion improvement increased to 71% of ideation were observed, and these de- system, in particular, the N-methyl-d- patients at 24 hours. For 35% of patients, creases remained 3 days postinfusion. aspartate (NMDA) antagonist ketamine. this effect lasted >7 days. These studies were repeated with similar outcomes (8, Ketamine and Suicidal Preclinical Research 9). Aan het Rot et al. (10) examined the Ideation efficacy of administering five subsequent Glutamate is the primary excitatory ketamine infusions following the ini- Price et al. (16) conducted an open-label neurotransmitter of the brain and helps tial dose. Eight of the nine patients who study demonstrating the rapid antisuicidal regulate plasticity of neurons involved in achieved remission relapsed within 19 effect of ketamine 24 hours after a single learning and memory (2). Initial research days of the sixth infusion, although one dose in 26 patients with treatment-resis- began with the observation that mood patient maintained remission for 45 days. tant depression. This was corroborated in disorders were correlated with altered an open-label study conducted by Phelps Other studies have examined related glutamate levels in both plasma (3) and et al. (17) who found that patients with questions. Ibrahim et al. (11) found that brain tissue (4). Research using animal treatment-resistant depression who had patients with treatment-resistant de- models revealed that NMDA receptor a family history of alcohol dependence pression refractory to ECT responded antagonists, such as ketamine, reversed responded significantly more than those to ketamine. Kranaster et al. (12) exam- symptoms of depression. One study dem- without a family history of alcohol de- ined retrospectively whether the use of onstrated that depressive behavior in rats pendence. DiazGranados et al. (18) ketamine as an anesthetic for ECT in was relieved for up to 10 days following a conducted an open-label study of 33 treatment-resistant depression offered single dose of ketamine (5). These obser- patients with treatment-resistant depres- any added benefit. Compared with pa- vations led to clinical trials of ketamine to sion. They reported a significant decrease tients not receiving ketamine, those who treat depression in humans. in suicidal ideation scores within 40 received ketamine exhibited not only a minutes after infusion, which remained Ketamine and Unipolar significant decrease in depressive symp- significant up to 4 hours postinfusion. toms, but they also required fewer ECT Depression Larkin et al. (19) confirmed these results treatments. in another open-label study, which was The initial study of ketamine to treat Kudoh et al. (13) added ketamine as conducted in an emergency department depression in humans was a random- an induction agent for patients with setting. The Zarate et al. (15) study of bi- ized double-blinded placebo-controlled major depressive disorder undergoing polar depression was the first controlled cross-over study conducted by Berman et surgery and found that they had sig- study to demonstrate this effect. al. (6). All seven participants with treat- nificantly lower depressive scores 1 day ment-resistant depression receiving a postoperatively. Risks and Side Effects single infusion of ketamine at a subanes- thetic dose (0.5 mg/kg) exhibited a rapid Ketamine and Bipolar Ketamine is best known clinically for its and significant antidepressant effect. Depression use as an anesthetic, but it is also an es- Within 72 hours, participants receiving tablished substance of abuse. In addition treatment had a 14-point (SD=10) im- In the wake of the promising effects of to sedation, 20% of patients receiving an- provement in scores on the Hamilton ketamine on unipolar depression, Diaz- aesthetic doses (2 mg/kg administered Depression Rating Scale (HAM-D), Granados et al. (14) tested a single dose in over 5 to 10 minutes) have psychoto- whereas those receiving placebo showed patients with treatment-resistant bipolar mimetic/dissociative effects, including no improvement (HAM-D score, 0 depression who were receiving valpro- depersonalization, derealization, confu- [SD=12]). Furthermore, for four par- ate or lithium maintenance therapy. A sion, and hallucinations. In their 2006 ticipants in the active treatment group, significant decrease in depressive symp- study, Zarate et al. (7) reported a higher

The Residents’ Journal 6 occurrence of perceptual disturbances, The views presented in this article are solely action. Int J Neuropsychopharmacol 2011; confusion, elevations in blood pressure, that of the authors’ and do not necessarily 7:1–19 euphoria, dizziness, and increased libido reflect the official policy or position of the 10. Aan het Rot M, Collins KA, Murrough in a ketamine group. Notably, the side ef- United States Federal Government, De- JW, Perez AM, Reich DL, Charney DS, fects reported subsided within 80 minutes partment of Defense, or Department of the Mathew SJ: Safety and efficacy of re- postinfusion. Navy. peated-dose intravenous ketamine for treatment-resistant depression. Biol Psy- Future Directions References chiatry 2010; 67:139–145 11. Ibrahim L, DiazGranados N, Lucken- Ketamine’s rapid antidepressant and an- 1. Trivedi MH, Rush AJ, Wisniewski SR, baugh DA, Machado-Vieira R, Baumann tisuicide properties in treatment-resistant Nierenberg AA, Warden D, Ritz L, J, Mallinger AG, Zarate CA Jr: Rapid de- Norquist G, Howland RH, Lebowitz B, unipolar and bipolar depression are im- crease in depressive symptoms with an N- McGrath PJ, Shores-Wilson K, Biggs portant. Not only may ketamine alleviate methyl-d-aspartate antagonist in MM, Balasubramani GK, Fava M; ECT-resistant major depression. Prog depressive and suicidal symptoms in min- STAR*D Study Team: Evaluation of out- Neuropsychopharmacol Biol Psychiatry utes to hours, use of this drug also opens comes with citalopram for depression us- 2011; 35:1155–1159 vast new vistas in the understanding of ing measurement-based care in STAR*D: depression. implications for clinical practice. Am J 12. 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Francis PT, Poynton A, Lowe SL, Naj­ New avenues of research into the patho- 14. DiazGranados N, Ibrahim L, Brutsche lerahim A, Bridges PK, Bartlett JR, NE, Newberg A, Kronstein P, Khalife S, physiology of depression go hand in hand Procter AW, Bruton CJ, Bowen DM: Kammerer WA, Quezado Z, Lucken- with the development of novel com- Brain amino acid concentrations and baugh DA, Salvadore G, Machado-Vieira pounds. The clinical success of ketamine Ca2+-dependent release in intractable de- R, Manji HK, Zarate CA Jr: A random- has already spurred a number of hypoth- pression assessed antemortem. Brain Res eses and preclinical studies. One of the 1989; 494:315–324 ized add-on trial of an N-methyl-d-as- partate antagonist in treatment-resistant most tantalizing is the relationship be- 5. Yilmay A, Schulz D, Aksoy A, Cambeyli bipolar depression. Arch Gen Psychiatry tween depression and synaptic plasticity. R: Prolonged effect of an anesthetic dose 2010; 67:793–802 We still, however, do not know which of ketamine on behavioral despair. Phar- macol Biochem Behav 2002; 71:341–344 15. Zarate Jr CA, Brutsche NE, Ibrahim L, patients and what settings and routes of Franco-Chaves J, Diazgranados N, Crav- administration, doses, and dosing regi- 6. Berman RM, Cappiello A, Anand A, chik A, Selter J, Marquardt CA, Liberty V, mens are most appropriate. Furthermore, Oren DA, Heninger GR, Charney DS, Luckenbaugh DA: Replication of ket- ketamine is a substance of abuse with Krystal JH: Antidepresant effects of ket- amine’s antidepressant efficacy in bipolar amine in depressed patients. Biol Psychia- known safety concerns, especially in the depression: a randomized controlled add- try 2000; 47:351–354 setting of chronic use. While results to on trial. Biol Psychiatry 2012; 71:939–946. date have been promising, larger-scale 7. Zarate CA Jr, Singh JB, Carlson PJ, studies are needed before the use of ket- Brutsche NE, Ameli R, Luckenbaugh 16. Price RB, Nock MK, Charney DS, DA, Charney DS, Manji HK: A random- amine as an antidepressant can enter Mathew SJ: Effects of intravenous ket- ized trial of an N-methyl-d-aspartate an- amine on explicit and implicit measures of mainstream clinical practice. tagonist in treatment-resistant major suicidality in treatment-resistant depres- Dr. Burger is a third-year psychiatry resident depression. Arch Gen Psychiatry 2006; sion. Biol Psychiatry 2009; 66:522–526 63:856–864 at the Naval Medical Center San Diego. 17. Phelps LE, Brutsche N, Moral JR, Luck- He is also an active-duty Lieutenant in the 8. Valentine GW, Mason GF, Gomez R, Fa- enbaugh DA, Manji HK, Zarate CA Jr: United States Navy. Dr. Loeffler is a fourth- sula M, Watzl J, Pittman B, Krystal JH, Family history of alcohol dependence and year psychiatry resident at the Naval Medical Sanacora G: The antidepressant effect of initial antidepressant response to an N- Center San Diego. He is also an active-duty ketamine is not associated with changes in methyl-d-aspartate antagonist. Biol Psy- Lieutenant in the United States Navy. occipital amino acid neurotransmitter chiatry 2009; 65: 181–184 content as measured by 1H-MRS. Psychi- The authors thank Ben Boche, Rob Lovern, atry Res 2011; 191:122–127 18. DiazGranados N, Ibrahim LA, Brutsche and Robert McLay for their support and as- NE, Ameli R, Henter ID, Luckenbaugh 9. Bunney BG, Bunney WE: Rapid-acting DA, Machado-Vieira R, Zarate CA Jr: sistance with this article. antidepressant strategies: mechanisms of Rapid resolution of suicidal ideation after

The Residents’ Journal 7 a single infusion of an N-methyl-d-aspar- 19. Larkin GL, Beautrais AL: A preliminary 20. Strayer RJ, Nelson LS: Adverrse events tate antagonist in patients with treatment- naturalistic study of low-dose ketamine associated with ketamine for procedural resistant major depressive disorder. J Clin for depression and suicide ideation in the sedation in adults. Am J Emerg Med Psychiatry 2010; 71:1605–1611 emergency department. Int J Neuropsy- 2008; 26:985–1028 cholpharmacol 2011; 14:1127–1131

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The Residents’ Journal 8 Case Report Use of “Bath Salts” Among Members of the United States Military: A Case Report With Discussion Daniel G. Allen, M.D. Wander S. Segura, M.D. Rebecca R. Burson, D.O.

The military is not immune to substance medical workup was performed, and he “ivory wave.” He reported obtaining the misuse, especially substances that are was medically cleared. A follow-up with substance from a gas station. Following not readily detectible or explicitly illegal. mental health was recommended. Further legal advice from the area defense council, Until recently, methylenedioxypyrova- interview revealed symptoms and behav- he declined to further discuss his sub- lerone (MDPV), the key psychoactive iors such as memory difficulties, decreased stance use. As a result of his misconduct, constituent of “bath salts,” was not a motivation, paranoia (in the form of being he was demoted and assigned extra duty, banned substance. MDPV intoxication suspicious of superiors), agitation, irrita- and he continued to have legal difficulties is known to cause hallucinations, agita- bility, anger, public physical altercations, related to his behaviors while intoxicated. tion, and aggressive behavior. Despite and domestic violence. These symptoms Despite his initial reluctance to engage subsequent state and federal prohibitions, and behaviors led to his difficulty studying in treatment, the patient experienced MDPV remains easily accessible and for promotion, threatening violence at the resolution of his irritability as well as ag- affordable, and detection of its use is dif- work place, failure to attend mandatory gression and experienced improvement in ficult. Given the military’s demographic functions, and criminal misconduct. His his depression symptoms coincident with overlap with that of MDPV users and symptoms and behaviors again appeared treatment adherence, including cessation the occupational risks of intoxication, the consistent with an adjustment reaction, of MDPV use. military should have a vested interest in since all other axis I conditions were ruled both the identification of and treatment out. Psychotherapy and sertraline were Discussion for MDPV users. We present a case dem- initiated, but he was not fully compliant Understanding the mechanisms of action, onstrating the effects of MDPV use in an with this treatment regimen. use patterns, and consequences of MDPV active-duty serviceman. The patient continued to have worsened is essential for health care providers. This Case symptoms and occupational dysfunction substance is a synthetic cathinone and as his marriage ended in divorce. This was relatively unknown until 2008 (1). “Mr. A” is a 25-year-old active-duty ser- culminated in an episode in which he re- Animal studies have suggested that MD- viceman with a history of alcohol abuse. ported to work late with altered mental PV’s mechanism of action is mostly that The patient presented to the mental status and new-onset suicidal ideation. of dopamine and norepinephrine reup- health clinic complaining of dysthymia, He then revealed to his supervisor that take and agonism, as well as serotonin insomnia, and anxiety. These symptoms he had been using bath salts. He was reuptake, although to a lesser degree preceded his presentation by several transported to the emergency department (2). MDPV’s mechanism of action and months and were related to occupational where physical examination and routine effect share similarities with that of stress and marital discord. At the time, laboratory examination (complete blood methamphetamine, cocaine, and ecstasy. he denied alcohol and illicit substance count, metabolic profile, thyroid-stimu- Physiologically, this results in sympatho- use. Thus, his symptoms were conceptu- lating hormone, urine drug screen) were mimetic manifestations such as elevated alized as an adjustment reaction, and he negative, and he was admitted voluntarily blood pressure and tachycardia. Psychi- was diagnosed with adjustment disorder to inpatient psychiatry for safety concerns. atric manifestations include elevated with mixed anxiety and depressed mood. After a brief hospitalization, he transi- anxiety, agitation, paranoia, hallucina- He began weekly psychotherapy and tioned to a 28-day inpatient rehabilitation tions, and aggressive behavior (3). Health disengaged from treatment after partial program. Following this program, he en- care providers should keep substance improvement. gaged in individual and group therapy intoxication on their differential when and was referred to the Air Force Alcohol Five months later, the patient presented these symptoms are observed. However, and Drug Abuse Prevention and Treat- to the emergency department with short- MDPV is undetectable on a urine drug ment program. While in the treatment ness of breath, chest pain, and worsening screen and must be requested separately. program, he revealed that in the months of his depressed mood and anxiety in the Those who are reported to have the high- prior to his hospitalization, he had used context of ongoing relational stressors. A est rates of MDPV use are young adults an MDPV-containing product called

The Residents’ Journal 9 with a mean age of 25 years, as reported military personnel at a time of high op- References in a study conducted in the United King- erational tempo. The relatively lower rate dom (4), and 28 years, as reported in a of illicit substance use is attributed to the 1. Uchiyama N, Kikura-Hanajiri R, Kawa- hara N, Goda Y: Analysis of designer study conducted in Michigan (5). De- military’s policy of random drug screen- drugs detected in the products purchased spite its elicit status since 2010, MDPV ing. This deterrent is not likely effective in fiscal year 2006. J Pharm Soc Japan can still be obtained at gas stations, head in the case of substances that are not cur- 2008; 128:1499–1505 shops, and adult book stores camouflaged rently detectable by routine screening 2. Baumann MH, Partilla JS, Lehner KR, under names such as research chemicals, tests. Despite efforts to develop a screen- Thorndike EB, Hoffman AF, Holy M, plant food, and insect repellant (6). De- ing tool (11), no tool as cost-effective as Rothman RB, Goldberg SR, Lupica CR, spite the popular name bath salts, there the urine drug screen exists to assist with Sitte HH, Brandt SD, Tella SR, Cozzi is no relation to the self-care product. the identification of substance misuse NV, Schindler CW: Powerful cocaine-like Additionally, it is inexpensive compared when a patient presents with unexplained actions of 3,4-methylenedioxypyrova- with other street drugs, costing about symptoms. Thus, detection of MDPV is lerone (MDPV), a principal constituent of $10 per use (6). MDPV has psychomi- dependent on the admission of the user. psychoactive ‘bath salts’ products. Neuro- metic effects between 5 mg and 20 mg, Despite the protections allotted to service psychopharmacology 2013; 38:552–562 with reports of use as high as 200 mg members that promote help-seeking be- 3. Ross EA, Reisfield GM, Watson MC, (3). Its routes of administration include havior (12), our patient’s self-disclosure Chronister CW, Goldberger BA: Psycho- oral, intramuscular, rectal, and sublingual; resulted in serious adverse action. Therein active “bath salts” intoxication with meth- however, most users inhale or snort the lies a dilemma for a service member suf- ylenedioxypyrovalerone. Am J Med 2012; 125:854–858 powder-like substance (6). Much of the fering from addiction disorders: to seek evidence of reported MDPV intoxica- help at the risk of one’s livelihood or to 4. Winstock AR, Mitcheson LR, Deluca P, tion symptoms is anecdotal. For instance, risk further dysfunction but continue to Davey Z, Corazza O, Schifano F: Me- phedrone, new kid for the chop? Addic- news outlets have reported paranoid de- meet financial obligations. On the part of tion 2011; 106:154–161 lusions in a mother who left her child in the physician, this also presents a dilemma the highway after using MDPV and a unique to the military: to treat the patient 5. Report MW: Emergency department vis- its after use of a drug sold as “bath salts”: 21-year-old who died of a self-inflicted and keep the confidentiality or to disclose Michigan, November 13, 2010–March 31, gunshot wound following 5 days of acute the substance use as mandated (12). One 2011. MMWR Morb Mortal Wkly Rep psychosis due to a single MDPV use (7, can argue that in the military, such action 2011; 60:624–627 8). One study of 236 MDPV users seen is necessary given the real security and 6. Slomski A: A trip on “bath salts” is cheaper in an emergency department found that safety risks inherent in the armed forces. than meth or cocaine but much more dan- 12% and 21% were admitted to an inpa- Balancing the protection of the fighting gerous. JAMA 2012; 308:2445–2447 tient psychiatric unit or critical care unit, force and the health of the individual 7. KFVS: Children found on road, mom respectively, with stays as long as 2 weeks remains a difficult task expected of mili- snorted bath salts. http://www.kfvs12. (9). Given the ease of access, affordabil- tary psychiatrists. The military will likely com/Global/story.asp?S=14163078 ity, and nondetectability in routine drug benefit from routinely available screen- 8. Marder J: The drug that never lets go. screens, MDPV has gained popularity, ing tools for MDPV and the removal of http://www.pbs.org/newshour/multime- resulting in both individual and commu- disincentives to reporting and treatment. dia/bath-salts/ nity consequences. For the same reasons, Until then, health care providers must be it is suspected that similar problems exist aware of the use of MDPV in the form of 9. Spiller HA, Ryan ML, Weston RG, Jan- sen J: Clinical experience with and ana- within the military. Currently, MDPV is bath salts in order to provide both educa- lytical confirmation of “bath salts” and a banned substance for both U.S. military tion and treatment. “legal highs” (synthetic cathinones) in the service members as well as civilians. Dr. Allen is a third-year resident, Dr. Se- United States. Clin Toxicol (Phila) 2011; While the prevalence of illicit substance gura is a third-year resident, and Dr. Burson 49:499–505 use in the U.S. military is lower than is a fourth-year resident in the University of 10. Sirratt D, Ozanian A, Traenkner B: Epi- that in the civilian population (2.3% and Texas Health Science Center San Antonio- demiology and prevention of substance 8.9%, respectively), the use of nonillicit Lackland Air Force Base Joint Psychiatry use disorders in the military. Military Med substances, such as alcohol (military, 26% Residency Program. All authors also hold 2012; 177(suppl 8):21–28 compared with civilian, 16%), tobacco the rank of Captain in the United States Air 11. Leonhart MM, Bersin AD: Schedules of (military, 44% compared with civilian, Force. controlled substances: temporary place- ment of three synthetic cathinones into 39.4%), and prescription medication The views presented in this article are solely (military, 10% compared with civilian, Schedule I. Fed Register 2011; 76: that of the authors’ and do not necessarily 65371–65373 2.5%) is higher (10). It is believed that reflect the official policy or position of the 12. Green CB, Collier JD: Alcohol and Drug the increased use of nonillicit substances United States Federal Government, De- and the misuse of prescription medica- Abuse Prevention and Treatment Program: partment of Defense, or Air Force. Operations Manual Air Force Instruction tion are related to the increased physical 44-121. Washington, DC, US Department and psychological demands placed on of the Air Force, 2011, pp 16–9

The Residents’ Journal 10 Case Report Deployment Stress, Dextromethorphan, Ketamine, and Pharmacologic Interactions: A Multifactorial Presentation of Mania Philip Y.T. Liu, M.D. Rebecca R. Burson, D.O.

Although military standards exclude the facility, the patient continued to exhibit day) and lorazapam (2 mg by mouth at entrance of individuals with previous af- thought and behavioral disturbances that bedtime). He exhibited improvement, fective and psychotic disorders, this does required involuntary hospitalization. He with reduced manic symptoms, includ- not ensure that military service members referred to himself as a millionaire, the ing improved sleep (8 hours nightly), are not at risk (1). Epidemiologic findings recipient of the Congressional Medal increased mood stability, and decreased suggest that males are at increased risk for of Honor, and a successful film writer agitation and irritability. On day 7 of his experiencing a first episode of mania or and claimed to have many “can’t lose” hospitalization, the patient no longer met psychosis before age 25 years, often re- investment schemes. His medical his- involuntary hospitalization criteria and sulting in the development of a primary tory revealed a combat patrol accident 3 requested to be discharged. Although he mood or thought disorder (2, 3). Given months prior, in which he sustained frag- continued to exhibit rapid speech and ex- that the vast majority of the military ment injuries from an explosion without pansive affect at discharge, he regained overlaps with this age and sex demo- evidence of traumatic brain injury or cog- insight and was able to reflect on his re- graphic, in addition to stressors unique to nitive impairment. Since then, he had cent behavior as being “out of character.” the military, it is not surprising that every sought behavioral health treatment for year numerous service members experi- “anxiety,” which resulted in treatment for Discussion ence a first-break psychotic episode. We combat and operational stress reactions; This case demonstrates the importance of present a case of first-episode substance- no medications were prescribed. During understanding the unique role that mili- induced mania with psychotic features in intake admission, he endorsed continued tary psychiatrists play in the treatment of a young soldier. nightmares and hypervigilance relating to active-duty service members in the unnat- improvised explosive device incidence but ural environment of a war zone. Not only Case did not display or endorse any dissocia- must active-duty psychiatrists have an tive or avoidance symptoms. Collateral “Mr. M” is a 29-year-old decorated soldier immediate understanding of emergency obtained from his parents confirmed no evacuated from a combat-stressed envi- psychiatry, gene-environment interac- previous diagnosis of a primary mood or ronment for “psychotic” and “manic-like” tions, and pharmacologic interactions, thought disorder; however, he did have a behaviors after recreationally ingesting they must also have knowledge of how history of extensive cannabis and alcohol 2½ 4-ounce bottles of dexromethorphan deployment stress influences all of the misuse. Furthermore, the patient’s father hydrobromide (with active guaifenesin) aforementioned variables. The concept of had a diagnosis of bipolar I disorder and within a 24-hour window. Overnight, he the biopsychosocial model is highly rel- benzodiazepine dependence. Organic exhibited acute and persistent grandios- evant to the above case. The patient had a work-up, including CT scan of the brain, ity, pressured speech, impaired reality history significant for presumed abuse of were all within normal limits. There were testing (claiming to be a unicorn and both alcohol and cannabis, thus making no abnormal physical findings. The pa- other forms of identity confusion), im- him more at risk for a potential psychotic tient’s mental status examination revealed pulsivity and agitation (posturing and experience (4). His acute and recent en- increased psychomotor activity, pressured throwing chairs), distractibility, decreased vironmental contributions included his speech, euphoric and expansive affect, sleep, and increased energy. He was then exposure to combat, recent explosive tangential thoughts with loose associa- air-evacuated from Afghanistan for fur- trauma, poor sleep, removal of primary tions, and delusions of grandeur. ther mental health evaluation and care support, a deployed environment, and in the United States. In order to ensure During the first 3 days of admission, limited mental health care resources. The safety while in transport, he was admin- he was difficult to redirect and required various stressors that the patient experi- istered ketamine (400 mg intravenously), emergency medications of olanzapine (10 enced both in the past and recently likely haloperidol (10 mg intravenously), and mg by mouth) and lorazapam (2 mg by interacted with his probable genetic load- lorazepam (2 mg intravenously). mouth) on three different occasions. Over ing for a primary mood disorder, thus the next 4 days, he became agreeable to Upon arrival to the inpatient psychiatry resulting in psychotic presentation (5). scheduled olanzapine (10 mg twice a ward at a stateside military treatment The Residents’ Journal 11 Secondly, ketamine and dexrometho- patic metabolism, both have metabolites. United States Federal Government, De- rphan were also important variables in These metabolites are likely processed partment of Defense, or Air Force. this case. Ketamine has gained attention hepatically, and thus the 2D6 pathway in the literature because it has demon- may have been overburdened in our pa- References strated mood-elevating effects and rapid tient. Because of the pharmacological 1. Stanley CL: Medical Standards for Ap- antidepressant properties (4). In fact, the similarities between ketamine and dexro- pointment, Enlistment, or Induction in psychotropic tendencies of ketamine are methorphan, the effects resulting from the Military Services. http://www.dtic. so prominent that it is proposed to in- the combination may have reacted syner- mil/whs/directives/corres/pdf/613003p. duce schizophrenia and manic-like states gistically. However, this would need to be pdf in animal models (6). It is postulated elucidated at the molecular and clinical 2. Loranger AW: Sex difference in age at on- that noncompetitive N-methyl-d-aspar- levels to further account for our patient’s set of schizophrenia. Arch Gen Psychiatry tate (NMDA) receptor antagonism and presentation. 1984; 41:157–161 sigma-1 opiate receptor agonism play a 3. Yildiz A, Sachs GS: Age onset of psy- role in mediating ketamine’s mood-ele- Conclusions chotic versus non-psychotic bipolar illness vating effects (7). Because it is common This case demonstrates the unique vari- in men and in women. J Affect Disord practice to screen for manic symptoms 2003; 74:197–201 ables that military psychiatry is tasked before starting a patient on antidepres- to account for in austere settings. The 4. Stefanis NC, Dragovic M, Power BD, sants to prevent mania induction, it is contribution of dexromethorphan and Jablensky A, Castle D, Morgan VA: Age conceivable that the rapid antidepressant ketamine, in addition to the genetic and at initiation of cannabis use predicts age at properties of ketamine contributed to our onset of psychosis: the 7- to 8-year trend. environmental factors at play, represent patient’s acute presentation. Similarly, Schizophr Bull 2013: 39: 251–2545 the multifactorial presentation of this dexromethorphan also has psychoto- patient. Furthermore, with the increas- 5. van Winkel R, Stefanis NC, Myin-Ger- mimetic properties. In fact, high-dose meys I: Psychosocial stress and psychosis: ing use of ketamine in various treatment dexromethorphan has been described a review of the neurobiological mecha- modalities for mood disorders, anesthe- to have effects similar to those of ket- nisms and the evidence for gene-stress in- sia, and pain management, as well as the amine and other recreational drugs, such teraction. Schizophr Bull 2008; ease of accessibility of dexromethorphan, as phencyclidine (8). The patient’s mo- 34:1095–1105 it is important to remain vigilant of the tivation to use dexromethorphan was to 6. Ghedim FV, Fraga Dde B, Deroza PF, various consequences these drugs can me- achieve a “high” feeling given his lim- Oliveira MB, Valvassori SS, Steckert AV, diate. This case represents the importance ited access to other forms of intoxication. Budni J, Dal-Pizzol F, Quevedo J, Zugno of a holistic approach that appreciates Pharmacologically, this over-the-counter AI: Evaluation of behavioral and neuro- complex biological, psychological, and medication shares many properties with chemical changes induced by ketamine in social factors in order to aid in optimal rats: implications as an animal model of ketamine, including NMDA antagonism diagnosis and treatment. Military psy- mania. J Psychiatr Res 2012; and sigma-1 agonism (9). It is likely that chiatry is often offered the challenge of 46:1569–1575 the high dexromethorphan dosage con- deciphering such complex variables. 7. Robson MJ, Elliott M, Seminerio MJ, sumed by the patient contributed to his Matsumoto RR: Evaluation of sigma (s) Dr. Liu is a first-year resident, and Dr. manic symptoms similar to the mecha- receptors in the antidepressant-like effects nisms that underlie ketamine’s rapid Burson is a fourth-year resident at the Uni- of ketamine in vitro and in vivo. Eur Neu- antidepressant properties. versity of Texas Health Science Center San ropsychopharmacol 2012; 22:308–317 Antonio-Lackland Air Force Base Joint As demonstrated, ketamine and dexro- 8. Romanelli F, Smith KM: Dextromethor­ Psychiatry Residency Program. Dr. Burson methorphan individually played roles in phan abuse: clinical effects and manage- is also an active-duty Captain in the United this presentation. Furthermore, the effect ment. J Am Pharm Assoc 2009; States Air Force. of these two medications in combina- 49:e20–e5 tion as well as the addition of haloperidol The authors thank Dr. Victor Torres-Collazo 9. Klein M, Musacchio JM: High affinity brings up the importance of pharmaco- for his teaching and mentorship in this case. dextromethorphan binding sites in guinea pig brain: effect of sigma ligands and other logic interactions. Although ketamine The views presented in this article are solely and haloperidol were administered agents. J Pharmacol Exp Ther 1989; that of the authors’ and do not necessarily 251:207–215 intravenously, thus bypassing initial he- reflect the official policy or position of the

The Residents’ Journal 12 Virtual Reality Exposure Therapy for the Treatment of Combat Posttraumatic Stress Disorder Ryan Richmond, B.S.

The United States has been involved in those used in cognitive-behavioral ther- Each therapy trial ultimately focuses on multiple wars for over a decade. This has apy (CBT), and may involve confronting addressing the four primary symptoms resulted in more than 2 million service- anxiety-provoking situations in everyday of PTSD (including combat-related men and women who have been subject life (in vivo exposure). Exposure therapy PTSD): avoidance, re-experiencing, hy- to long multiple and harsh deployments also involves imaginal exposure, a tech- perarousal, and the presence of trauma. (1).War-related mental illnesses are not nique in which the patient relives and commonly seen by most civilian mental talks through traumatic events (5). There Does VRET Work? health care providers. This makes disor- are some limitations in traditional expo- The PTSD Checklist–Military version ders such as combat posttraumatic stress sure therapy. For example, some patients has been used to evaluate patients for di- disorder (PTSD) difficult to treat except are not able to complete the therapy, re- agnosis of PTSD (1, 6–8). This checklist is for in an extremely individualized manner. porting problems with willingness and a widely accepted method of categorizing Additionally, treatment is complicated by ability to engage in the imaginal exposure. PTSD symptoms (6). Other clinician- the large numbers of people affected by One strategy in VRET is to circumvent rated and self-reported measures that war-related mental illnesses. Between 4% this obstacle by providing a more realistic have been used include the Clinician- and 45% of U.S. troops deployed to Iraq experience, for example, detailing simu- Administered PTSD Scale, the Mini and Afghanistan have met criteria for lated convoys, dismounted patrols, attacks International Neuropsychiatric Interview, PTSD-related disorders, and treatments and ambushes, small-arms fire, rocket fire, the Patient Health Questionnaire–9, the such as exposure therapy, which includes and human remains (3, 6). Newer tech- Beck Anxiety Inventory, the Combat Ex- virtual reality exposure therapy (VRET), nology has moved virtual therapy to a posure Scale, and the Blast Assessment have been shown to have one of the best realistic therapy modality (2). (7). These clinical instruments are used to therapeutic efficacies (1, 2). VRET can be conducted in many differ- analyze how patients with depression and The purpose of this article is to provide ent ways, and most trials include therapy anxiety disorders respond to various mo- an overview and exploration of VRET involving an average of 10 sessions lasting dalities of treatment. and its relation to combat-related PTSD between 90 and 120 minutes. During the In a recent open-label, single-group study, and how it compares to previously estab- session, the patient is placed in the simu- McLay et al. (8) aimed to develop and test lished traditional therapy, as well as where lator. Some simulators have the capacity a method for applying VRET, using the this technology is going today and why to produce only virtual images, while oth- PTSD Checklist–Military version, the knowledge of the therapy is important for ers can add auditory and olfactory stimuli. Patient Health Questionnaire–9, and the civilian and military physicians alike. The most common equipment includes Beck Anxiety Inventory as outcome mea- movement that is controlled with a joy- sures. The authors reported statistically What Is VRET? stick, allowing the patient to interact in significant results, with an average reduc- a virtual reality environment simulating First documented in 1994 in a case study tion in PTSD symptom scores by 50%, his or her specific trauma (6). The graph- of a single Vietnam veteran suffering depression scores by 47%, and anxiety ics have been described as being “similar from PTSD, exposure therapy has been scores by 36% (8). In addition, these re- to what might be experienced in a high- used to treat survivors of various trau- sults were maintained 3 months after the quality, modern videogame” (5). The mas, including automobile accidents and completion of VRET treatment. The data sessions are facilitated by a therapist who the September 11, 2001, terrorist attacks. were analyzed using last-observation- works with the patient, guiding him or her Exposure therapy has also been used for carried forward and intention-to-treat through the environment and controlling treatment of severe phobias and anxiety analyses. These results are consistent with the amount of exposure received. Inter- disorders (3, 4). This form of therapy was prior studies, which also demonstrated the estingly, there have been recent advances developed under the assumption that efficacy of VRET in combat PTSD (4, 6). in and additions to the VRET platform. confrontation with the feared stimu- For example, virtual reality-graded ex- In an earlier randomized, unblinded lus would desensitize the patient to the posure therapy has been introduced and study, McLay et al. (5) reported that stimulus, resulting in reduction in anxiety involves psychophysical measurements, seven out of 10 patients showed a 30% symptoms. Exposure therapy includes be- such as skin conductance, finger tem- reduction (p<0.05) in symptoms after havioral modification techniques, such as perature, respiration rate, and heart rate. receiving virtual reality-graded exposure The Residents’ Journal 13 therapy, compared with one out of 9 pa- combat-related PTSD (3). Additionally, ders: a meta-analysis. J Anxiety Disord tients who received normal standard of most of the investigations conducted to 2008; 22:561–569 care (p<0.001) (5). These results are simi- date consist of small sample sizes, are 4. Rothbaum B, Hodges L, Alarcon R, lar to those found in studies of traditional often not blinded, are not randomized, Ready D, Shahar F, Graap K, Pair J, He- VRET techniques (6, 8). However, the and do not include a comparison group. bert P, Gotz D, Wills B, Baltzell D: Vir- study was limited due to its small sample Despite these factors, VRET and virtual tual reality exposure therapy for PTSD size and wide variability in the patients’ reality-graded exposure therapy appear to Vietnam veterans: a case study. J Trauma response to treatment. In a case report, be promising, and, if properly developed, Stress 1999; 12:263–271 Wood et al. (7) reported similar results for could be an efficacious means of treating 5. McLay R, Wood D, Webb-Murphy J, a patient receiving virtual reality-graded combat-related PTSD. Spira J, Wiederhold M, Pyne J, Wieder- exposure therapy, with the patient’s score hold B: A randomized, control trial of vir- Ryan Richmond is a third-year medical stu- tual reality-graded exposure therapy for on the PTSD Checklist–Military ver- dent at the Uniformed Services University post-traumatic stress disorder in active sion indicating a decrease in symptoms of the Health Sciences School of Medicine, duty service members with combat-re- (baseline score, 55; follow-up score, 45). Bethesda, Md. He is also an active-duty lated post-traumatic stress disorder. Cy- This same patient did not exhibit any Second Lieutenant in the United States Air berpsychol Behav Soc Netw 2011; notable changes in depressive or anx- Force. 14:223–229 ious symptoms as indicated by scores on The views presented in this article are solely 6. Reger G, Holloway K, Candy C, Roth- the Patient Health Questionnaire–9 and baum B, Rizzo A, Gahm G: Effectiveness Beck Anxiety Inventory. However, there that of the author’s and do not necessarily of virtual reality exposure therapy for ac- was no mention of any statistical analysis reflect the official policy or position of the tive duty soldiers in a military mental in this case. United States Federal Government, De- health clinic. J Trauma Stress 2011; partment of Defense, or Air Force. 24:93–96 What Does the Future Hold? 7. Wood D, Murphy J, Center K, McLay R, References Reeves D, Pyne J, Shilling R, Wiederhold Currently, there are many modalities for B: Combat-related post-traumatic stress treating combat-related PTSD, includ- 1. Wood D, Webb-Murphy J, McLay R, Wiederhold B, Spira J, Johnston S, Koff- disorder: a case report using virtual reality ing traditional CBT, exposure therapy, man R, Wiederhold M, Pyne J: Reality exposure therapy with physiologic moni- prolonged exposure, and VRET. At the graded exposure therapy with physiologic toring. Cyberpsychol Behavior 2007; present time, however, VRET has not monitoring for the treatment of combat 10:309–315 been shown to be superior to other mo- related post-traumatic stress disorder: a 8. McLay R, Graap K, Spira J, Perlman K, dalities such as CBT, eye movement pilot study. Stud Health Technol Inform Johnston S, Rothbaum B, Difede J, Deal desensitization, and reprocessing and re- 2011; 163:696–702 W, Oliver D, Baird A, Bordnick P, Spital- laxation therapy (8), and this hinders its 2. Rizzo A, Reger G, Gahm G, Difede J, nick J, Pyne J, Rizzo A: Development and use in large population cohorts. While Rothbaum B: Virtual reality exposure testing of virtual reality exposure therapy there is a meta-analysis examining VRET therapy for combat related PTSD. The for post-traumatic stress disorder in active for the treatment of anxiety disorders Neurobiology of PTSD. duty service members who served in Iraq and Afghanistan. Military Med 2012; and phobias, there is no meta-analysis 3. Powers MB, Emmelkamp PM. Virtual re- 177:635–642 examining VRET in the treatment of ality exposure therapy for anxiety disor-

Residents, fellows, and students are invited to attend this year’s American Journal of Psychiatry Residents’ Journal workshop, to take place at the Annual Meeting in San Francisco. This year’s workshop title is “The American Journal of Psychiatry Residents’ Journal: How to be Involved.” Bring your thoughts and ideas about the Residents’ Journal; hear a brief presentation about the Journal’s new developments; meet with Residents’ Journal editors and edito- rial staff as well as the American Journal of Psychiatry Editor-in-Chief Robert Freedman, M.D. The workshop is scheduled for Wednesday, May 22nd, from 1:30 to 3:00 p.m. in Room 226, Moscone South, East Mezzanine. For further in- formation please contact [email protected].

The Residents’ Journal 14 Effects of Military Deployment on Children Nicole Garber, M.D.

Since the September 2001 terrorist at- home; it is often marked with excitement, Emotional and Behavioral tacks, there have been over 2 million U.S. anticipation, and stress over preparing for Adjustments troops deployed in Operations Endur- the return. The postdeployment phase is ing Freedom and Iraqi Freedom (1), and often a period of transition for the family, Chandra et al. (6) collected informa- more than 900,000 troops with children a period marked by joy but also a need to tion from families that attended a camp have been deployed (2). We know that renegotiate the family life and roles. This called Operation Purple, a free camp for deployment can affect the service mem- can be a particularly challenging time for military-dependent children ages 7 to ber, with known complications being children of all ages. Children less than 1 17 years old to help them deal with the posttraumatic stress disorder, depression, year old may not remember the parent stress of having a parent deployed. A total substance abuse, and traumatic brain in- and may cry when held by the return- of 1,507 families participated in a com- jury, but less has been known about the ing parent. Toddlers may be apprehensive puter-assisted telephone interview with impact of deployment on children in mil- initially around the returning parent, and the children and their nondeployed par- itary families. preschoolers may feel guilty about the ent. The study examined child wellness, separation. School-age children may seek which included academic performance, Cycle of Deployment and desire a lot of attention from the par- peer and family relationships, general ent, and adolescents may act as though In 1987, Kathleen Logan (3) postulated emotional difficulties, and problem be- the return of the parent is not a big deal. the “emotional cycle of deployment,” haviors. Chandra et al. compared answers Other research has specifically focused which initially examined the effects of from this survey with data from the 2001 on the deployment and postdeployment deployment on military wives only. More National Health Interview Survey, which phases (4). recently, this concept has been adapted to provided population norms. The study examine how the cycle of deployment af- Child Maltreatment found statistically significant higher fects military families. Logan identified scores, indicating higher levels of dis- five stages in the cycle of deployment: One study used the Central Army Regis- tress, for all measures among children in predeployment, deployment, sustainment, try database to examine the rate of child Operation Purple compared with scores redeployment, and postdeployment. The maltreatment in Army families in which for their age- and gender-matched peers predeployment stage is marked by antici- a parent was deployed compared with the in the general population. The study re- pation of the loss of the loved one and rate in which no parent was deployed. The vealed some associations based on age; denial of the situation. This tends to be study found that the rate of child mal- for example, peer relationships improved a busy time for family members as they treatment was 42% higher when a family with increasing age, and anxiety symp- try to prepare for the impending depar- member was deployed compared with toms decreased with increasing age. Some ture. Parents may be distracted during when no family member was deployed. behaviors and functioning worsened with this phase, and this may lead children The study also examined different forms increasing age, such as fighting, drink- to wonder whether their parents will be of abuse to determine whether there were ing, and academic engagement. There was able to take care of them. Children may patterns between different types of abuse also an association between self-reported also wonder whether the deployed parent and deployment status. Rates of neglect caregiver mental health and the child’s will return home. The deployment pe- were almost twice as high in families with academic engagement and relationship riod is often marked with worry by the a deployed member compared with fami- strengths. The study also examined the nondeployed spouse. Younger children lies in which no one was deployed. Abuse postdeployment period and found that may have stronger emotions, cry, regress, was more likely to be committed by the older children had more difficulties with complain of body aches, and have irri- female civilian in families with a deployed reintegration. A possible explanation for table and sad moods, and teenagers may family member. One possible reason for this, as proposed by the investigators, may isolate themselves or engage in risky ac- this may be that most of the at-home be that older children are likely to take on tivities, such as drug and alcohol abuse. caregivers were women, and most of the more responsibilities while the deployed Sustainment is typically the period in deployed family members were men. parent is away and therefore may expe- which the family adjusts to the deploy- Male and female children were equally rience greater role transitions when the ment and feels empowered that they can likely to be abused during deployments, parent returns. cope adequately with the challenges. The but children between 2 and 5 years old Chartrand et al. (7) examined 169 fam- redeployment phase is the period of time were most at risk (5). ilies with children ages 18 months to 5 about a month before the solider returns years old who attended daycare on a Ma-

The Residents’ Journal 15 rine Corps base. They divided the families agnostic Scale, and Posttraumatic Stress need to be continued services for families into two groups: those with a deployed Disorder Checklist–Military version were after deployment. There are several re- parent and those without a deployed par- used to measure outcomes in parents. On sources that exist to prepare children for ent. The Child Behavior Checklist–parent the Multidimensional Anxiety Scale for the different phases of deployment (www. and teacher report was used to evalu- Children, those with a currently deployed realwarriors.net and www.myarmyone- ate children, and the Parenting Stress parent had increased ratings, indicating source.com). Such resources can help Index–short form and Center for Epi- higher levels of distress (mean boys score, children and families better cope with the demiological Studies Depression Scale 56.21; mean girls score, 53.62), compared stresses of deployment. were used to evaluate caregivers. At this with community norms (mean boys score, Dr. Garber is a second-year child and ado- particular base, the mean time of deploy- 42.06; mean girls score, 49.12). Children lescent psychiatry fellow in the Department ment was 3.9 months. Children 3 to 5 with a recently returned parent also had of Psychiatry, Baylor College of Medicine, years old had higher total scores as well as increased ratings (mean boys score, 56.18; Houston. higher scores for externalizing behaviors mean girls score, 54.79). The increased (such as tantrums) on the Child Behavior ratings were primarily for separation References Checklist parent report form and higher anxiety and physical manifestations of scores for externalizing behaviors on the anxiety. The study found that 31.9% of 1. Tan M: 2 million troops have deployed teacher report form. No such correlation children with a recently returned par- since 9/11. Marine Corps Times, Dec 18, was found for children 18 months to 3 ent and 24.7% with a currently deployed 2009 years old. This suggests that older chil- parent had clinically significant anxiety 2. Zoroya G: Troops’ kids feel war toll. USA dren respond differently from younger symptoms. The two groups did not have Today, June 25, 2009 children to the deployment of a parent. elevated scores for the other measures 3. Logan K: The Emotional Cycle of De- The authors hypothesized that this may compared with community norms. With ployment. (http://www.usni.org) be because in most cases the deployed regard to sex differences, girls were found 4. Pincus SH, House R, Christensen J, Adler parent was the father and that often the to be at higher risk for externalizing be- LE: The emotional cycle of deployment: a primary attachment of the child is to the haviors while a parent was deployed, military family perspective. J Army Med mother. Therefore, the youngest children compared with community norms, but Department 2005; 615–623 in the study may have been protected by had ratings similar to those found in the 5. Gibbs D, Martin S, Kupper L, Johnson R: the secure attachment with their mothers, community when the parent was recently Child maltreatment in enlisted soldiers’ and that during their fathers’ deployment returned. Boys exhibited the opposite families during combat-related deploy- they were actually able to spend more pattern, with increased externalizing be- ment. JAMA 2007; 298:528–535 time with the preferred attachment figure. haviors when the parent was recently 6. Chandra A, Lara-Cinisomo S, Jaycox L, A total of 171 Army and Marine families returned. Taniellian T, Burns R, Ruder T, Han B: participated in a study examining anxiety Children on the homefront: the experi- Conclusions ence of children from military families. in children with a deployed parent (8). Pediatrics 2010; 125:16–25 The families included 163 nondeployed This study can help guide possible inter- parents, 65 parents who were currently 7. Chartrand M, Frank D, White L, Shope ventions that may help increase resiliency T: Effects of parents’ wartime deployment deployed or who had recently returned among military families. The studies dis- on the behavior of young children in mili- from deployment, and 272 children. The cussed reveal that children with a deployed tary families. Arch Pediatr Adolesc Med average length of deployment for the parent are more likely to experience child 2008; 162:1009–1014 Army and Marine families was 12 months maltreatment, receive more outpatient 8. Lester P, Peterson K, Reeves J, Knauss L, and 7 months, respectively. The Child Be- services, and have behavioral maladjust- Glover D, Mogil C, Duan N, Saltzman W, havior Checklist, Children’s Depression ments. The studies also reveal that certain Pynoos R, Wilt K, Beardslee W: The long Inventory, and Multidimensional Anxiety populations are more vulnerable, particu- war and parental combat deployment: ef- Scale for Children were used to mea- larly children ages 3 to 5 years old, when fects on military children and stay at home sure outcomes in children, and the Brief a parent is deployed and that there may spouses. J Am Acad Child Adolesc Psy- Symptom Inventory, Posttraumatic Di- chiatry 2010; 49:310–320

Editor’s Note: We would like to acknowledge Harita Raja, M.D., for her contribution to the Residents’ Journal as Guest Section Ed- itor for the March 2013 issue.

The Residents’ Journal 16 In preparation for the PRITE and ABPN Board examinations, test your knowledge with the following questions (answers will appear in the next issue). This month’s questions are courtesy of Venkata B. Kolli, M.D., a third-year resident at the Nebraska Medical Center, Omaha, Nebraska.

Question 1. A 25-year-old male patient with paranoid schizophrenia presents with another relapse following a long history of noncompliance with oral antipsychotic agents. With the intention of transitioning the patient to depot haloperidol decanoate, oral haloperidol was initiated. The patient tolerates the oral haloperidol well. What is the utility of an intramuscular test dose administration? A. Test for extrapyramidal side effects B. Test for sensitivity reactions C. Test the degree of psychological resistance D. Test dosing does not have any advantages

Question 2. The patient in question #1 is started on haloperidol decanoate (100 mg, intramus- cular, 4 weekly doses). When should the depot dose be evaluated following the first In preparation for the PRITE and ABPN Board dose administration? examinations, test your knowledge with the A. At 1 week following questions. B. At 2 weeks (answers will appear in the next issue) C. At 4 weeks D. At 6 weeks

ANSWERS TO March QUESTIONS

Question #1. Question #2. Answer: D. Moclobemide Answer A. Tranylcypromine Moclobemide is a reversible inhibitor of monoamine oxidase type A MAO inhibitors not only inhibit MAO, but may also block MAO uptake. (MAO-A) (1). Tranylcypromine is a nonhydrazine irreversible MAOI. Tranylcypromine is believed to have the most potent blockade of MAO It increases the concentration of norepinephrine, epinephrine, and uptake (1). Isocarboxazid, phenelzine, and selegiline may have MAO 5-HT in the CNS. It also has a mild stimulant effect. Isocarboxazid is uptake blockade but to a lesser extent than tranylcypromine (1). an irreversible hydrazine MAOI. Phenelzine is a substrate as well as Reference an irreversible MAOI. 1. Schatzberg A: Monoamine oxidase inhibitors, in The American Psychiat- Reference ric Publishing Textbook of Psychopharmacology, 4th ed. Washington, 1. Schatzberg A: Monoamine oxidase inhibitors, in The American Psychiat- DC, American Psychiatric Publishing, 2009 ric Publishing Textbook of Psychopharmacology, 4th ed. Washington, DC, American Psychiatric Publishing, 2009

We are currently seeking residents who are interested in submitting Board-style questions to appear in the Test Your Knowledge feature. Selected residents will receive acknowledgment in the issue in which their questions are featured. Submissions should include the following: 1. Two to three Board review-style questions with four to five answer choices. 2. Answers should be complete and include detailed explanations with references from pertinent peer-reviewed journals, textbooks, or reference manuals. *Please direct all inquiries and submissions to Dr. Vahabzadeh: [email protected].

The Residents’ Journal 17 Author Information for The Residents’ Journal Submissions The Residents’ Journal accepts manuscripts authored by medical students, resident physicians, and fellows; manuscripts authored by members of faculty cannot be accepted. To submit a manuscript, please visit http://mc.manuscriptcentral.com/appi-ajp, and select “Residents” in the manuscript type field.

1. Commentary: Generally includes descriptions of recent events, opinion pieces, or narratives. Limited to 500 words and five references.

2. Treatment in Psychiatry: This article type begins with a brief, common clinical vignette and involves a description of the evaluation and management of a clinical scenario that house officers frequently encounter. This article type should also include 2-4 multiple choice questions based on the article’s content. Limited to 1,500 words, 15 references, and one figure.

3. Clinical Case Conference: A presentation and discussion of an unusual clinical event. Limited to 1,250 words, 10 references, and one figure.

4. Original Research: Reports of novel observations and research. Limited to 1,250 words, 10 references, and two figures.

5. Review Article: A clinically relevant review focused on educating the resident physician. Limited to 1,500 words, 20 references, and one figure.

6. Letters to the Editor: Limited to 250 words (including 3 references) and three authors. Comments on articles published in The Residents’ Journal will be considered for publication if received within 1 month of publication of the original article.

7. Book Review: Limited to 500 words and 3 references.

Abstracts: Articles should not include an abstract.

Upcoming Issue Themes Please note that we will consider articles outside of the theme.

June 2013 August 2013 Section Theme: Psychiatry and Social Justice David Hsu, M.D. Guest Section Editor: Megan Testa, M.D. Section Theme: Geriatric Psychiatry [email protected] [email protected]

July 2013 September 2013 Section Theme: Open Section Theme: Open E-mail Editor: Arshya Vahabzadeh, M.D. E-mail Editor: Arshya Vahabzadeh, M.D. [email protected] [email protected]

October 2013 Section Theme: Global Psychiatry Misty Richards, M.D., M.S. [email protected]

The Residents’ Journal 18