THE AMERICAN JOURNAL OF PSYCHIATRY RESIDENTS’ JOURNAL

March 2015 Volume 10 Issue 3

Inside In This Issue 2 Major Depressive Disorder: The Renewed Search for New Targets and Treatments Samuel T. Wilkinson, M.D. 3 Recent Literature on Electroconvulsive Therapy Techniques for the Treatment of Depression Sandarsh Surya, M.B.B.S. Neil Mori, M.D. 6 Ketamine Infusion for the Treatment of Depression Mahalia L. Way, M.D., Ph.D. 9 Low-Field Magnetic Stimulation: The Next Big Thing? Stanley Lyndon, M.D. 11 A Question of Balance: Preventing Relapse This issue of the Residents’ Journal focuses on the topic of advances in antidepressant of Psychotic Depression therapy. In an editorial, Samuel T. Wilkinson, M.D., discusses the renewed search for Laurel D. Pellegrino, M.D. new targets and treatments for major depressive disorder. In a review article, Sandarsh Surya, M.B.B.S., and Neil Mori, M.D., examine recent evidence for methods designed to 14 DRESS Syndrome Induced by maximize the therapeutic benefit of ECT, minimizing side effects and preventing relapse. Antidepressant Sertraline Mahalia L. Way, M.D., Ph.D., analyzes clinical trials of the use of ketamine infusion for Meredith Brandon, M.D. the treatment of depression. Stanley Lyndon, M.D., explores low-field magnetic stimu- lation as a potential treatment modality. In a treatment in psychiatry article, Laurel D. 16 When Parents Kill: A Review of Pellegrino, M.D., outlines current recommendations for treating major depression with Infanticide psychotic features, including discussion of relapse rates with antidepressant monotherapy Samuel J. House, M.D. and with antipsychotic therapy, as well as ongoing research. Lastly, Meredith Brandon, M.D., describes a case of drug reaction with eosinophilia and systemic symptoms during 20 Residents’ Resources sertraline and aripiprazole treatment in an adolescent patient.

Editor-in-Chief Associate Editors Editors Emeriti Misty Richards, M.D., M.S. Ijeoma Chukwu, M.D., M.P.H. Sarah B. Johnson, M.D. Kathleen Mary Patchan, M.D. Senior Deputy Editor Molly McVoy, M.D. Rajiv Radhakrishnan, M.B.B.S., M.D. Media Editor Joseph M. Cerimele, M.D. Deputy Editor Holly S. Peek, M.D., M.P.H. Sarah M. Fayad, M.D. Tobias Wasser, M.D. Monifa Seawell, M.D. Staff Editor Guest Section Editor Angela Moore Samuel T. Wilkinson, M.D. Editorial Major Depressive Disorder: The Renewed Search for New Targets and Treatments

Samuel T. Wilkinson, M.D.

Major depressive disorder is the most bination of multimodal therapies. For common mental illness and accounts There is an urgent example, D-cycloserine, which enhances for significant morbidity and mortality extinction learning, has been shown to throughout the United States and the need for the enhance cognitive-behavioral therapy world (1). Results from the Sequenced development of (CBT) of anxiety disorders, but its effects Treatment Alternatives to Relieve De- are greatest when given within a specific pression trials have demonstrated that our better and faster time frame relative to CBT (4). Combin- most commonly used treatments are only ing biological treatments with social and marginally effective and generally take treatments. psychological interventions that assist in weeks before any antidepressant effects the delivery of care in a methodical way are experienced. Hence, there is an urgent may prove to be more effective than the need for the development of better and continued search for the “magic bullet” faster treatments. To this end, the National Fast-Fail Trials initiative, which aims to (5). Institute of Mental Health (NIMH) has expedite the development of medications Major depressive disorder causes sig- funded the Rapidly-Acting Treatments used to treat major depressive disorder nificant morbidity, and there remains an for Treatment-Resistant Depression ini- and other disorders. Because so many urgent need for improved treatments. It is tiative, a multicenter research project drugs are simply modifications of existing hoped that renewed efforts on the part of aimed at developing faster therapies to therapies that utilize the same mechanism NIMH and other investigators will lead relieve depression. The Rapidly-Acting (i.e., increasing synaptic concentrations of to the discovery of more rapid and effec- Treatments for Treatment-Resistant monoamine neurotransmitters), the proj- tive therapies. Depression project involves advancing ect will also attempt to identify new brain our understanding and potential utility targets for potentially novel therapeutic Dr. Wilkinson is a third-year resident in of ketamine (trial NCT01920555), an mechanisms. The consortium hopes to the Department of Psychiatry, Yale School of N-methyl-d-aspartic acid (NMDA) re- accomplish these objectives by utilizing Medicine, New Haven, Conn. ceptor antagonist that has powerful and relatively small clinical trials (N=10–30) rapid antidepressant effects (2). Low- and by studying candidate compounds References field magnetic stimulation, a noninvasive in humans, rather than animals. One of 1. Kessler RC, Berglund P, Demler O, et al: form of brain stimulation that has been the first such trials involves investigating The epidemiology of major depressive dis- shown to induce rapid elevation of mood the potential of a kappa opioid receptor order: results from the National Comor- in bipolar depression with minimal side agonist (trial NCT02218775) in treating bidity Survey Replication (NCS-R). effects (3), is also being studied as part anhedonia. JAMA 2003; 289:3095–3105 of the Rapidly-Acting Treatments for Another potential approach to combat- 2. Krystal JH, Sanacora G, Duman RS: Rapid-acting glutamatergic antidepres- Treatment-Resistant Depression initia- ing major depressive disorder involves tive (trial NCT01654796). This initiative sants: the path to ketamine and beyond. the concept that some biological treat- Biol Psychiatry 2013; 73:1133–1141 aims to investigate the potential of a ments induce a state of neuroplasticity or number of other compounds with novel an opportune time during which neural 3. Rohan ML, Yamamoto RT, Ravichandran CT, et al: Rapid mood-elevating effects of mechanisms, including thyrotropin-re- circuitry might potentially be altered (4). leasing hormone, allosteric modulators low field magnetic stimulation in depres- It is hoped that by combining neuroplas- sion. Biol Psychiatry 2014; 76:186–193 of alpha-amino-3-hydroxy-5-methyl- ticity-inducing treatments with cognitive isoxazole-4-propionate receptors, and and behavioral interventions, the latter 4. Krystal JH, Tolin DF, Sanacora G, et al: Neuroplasticity as a target for the phar- other NMDA receptor antagonists, as might harness the time-limited window macotherapy of anxiety disorders, mood well as nonpharmacologic mechanisms of neuroplasticity to rewire potentially (i.e., sleep deprivation, electroconvulsive disorders, and schizophrenia. Drug Dis- pathological neural circuits. While using cov Today 2009; 14:690–697 therapy). biological and behavioral interventions 5. Narayan VA, Mohwinckel M, Pisano G, Historically, the development of drugs simultaneously is not new in psychiatry, et al: Beyond magic bullets: true innova- has been expensive and time-consuming. the concept of neuroplasticity implies tion in health care. Nat Rev Drug Discov Hence, the NIMH is also sponsoring the a synergistic rather than additive com- 2013; 12:85–86

The American Journal of Psychiatry Residents’ Journal 2 Article Recent Literature on Electroconvulsive Therapy Techniques for the Treatment of Depression

Sandarsh Surya, M.B.B.S. Neil Mori, M.D.

Electroconvulsive therapy (ECT) is been used since the origin of ECT and domized controlled trial of 59 patients the most effective treatment for both is still considered the gold standard when with a major depressive episode reported unipolar and bipolar depression, with re- comparing efficacy and side effects with that bifrontal ECT had better therapeu- sponse rates of 80%–90% when used as other types of montages (2). In bitem- tic efficacy compared with bitemporal first-line therapy and 50%–60% in treat- poral ECT, electrodes are placed on both and right unilateral ECT (4). However, ment-resistant depression. ECT is often temples of the skull, which correspond further study in a recent large random- considered the best option for severe de- to the point just above the midpoint on ized controlled trial of 230 patients with pression, particularly for depression with an imaginary line connecting the outer unipolar and bipolar depression did not psychotic or catatonic features refractory canthus of an eye and the external au- replicate the findings and found that the to pharmacotherapy and psychotherapy ditory meatus (Figure 1A). Cognitive speed of response was greater in the bi- because of its potential for rapid allevia- impairment is the major limitation asso- temporal group (5). In terms of cognitive tion of symptoms (1). Additionally, ECT ciated with bitemporal ECT, thought to profile, a meta-analysis reported that bi- is one of a short list of treatments that be due to the direct effect on the domi- frontal ECT had a small but statistically can significantly reduce suicidality. ECT nant medial temporal lobe. In the 1970s, significant benefit regarding global cog- can be considered a first-line treatment d’Elia introduced right unilateral ECT nition scores compared with bitemporal option for patients with severe depression to minimize cognitive side effects, and it ECT and an effect comparable to right coupled with psychotic features, catato- is now the second most commonly used unilateral ECT (6). Additionally, bifron- nia, suicide risk, or food refusal leading montage (2). In right unilateral ECT, tal ECT had a smaller decline in visual to nutritional compromise, for patients one electrode is placed on a point just memory, greater decline in immediate for whom a rapid antidepressant response to the right of the point of intersection verbal memory, and no difference in fron- is required, for patients who have pre- between a perpendicular line connecting tal executive functioning compared with viously shown a positive response, and two external auditory canals and a line right unilateral ECT. for patients who prefer it (1). Pregnant connecting the nasion and inion, and the women with pharmacotherapy-resistant second electrode site is similar to that of Left Anterior Right Temporal ECT depression with psychotic or catatonic bitemporal ECT on the right side (Fig- Swartz and Nelson (7) introduced the features and pregnant women who pre- ure 1B). The initially proposed “low-dose” left anterior right temporal montage, in fer the treatment can be offered ECT (1). energy setting used with right unilateral which the right-side electrode is placed Severe depression with comorbid general ECT is associated with poor antidepres- at the right bitemporal electrode site and medical conditions that preclude the use sant response rates, and current literature the left-side electrode is placed 5 cm an- of antidepressants should also be consid- suggests that high-dose right unilateral terior to the left bitemporal electrode site ered for ECT (1). ECT has a comparable efficacy to mod- (Figure 1D). In small studies, left ante- rior right temporal ECT had comparable The practice of ECT has been progres- erate-dose bitemporal ECT and retains cognitive advantages (3). Some of the efficacy to bitemporal ECT, with better sively evolving since its initial emergence cognitive profiles (7). In a case series, three in the 1930s. In the present review, we new montages being explored to retain the efficacy of the treatment and dimin- patients with chronic late-life depression, discuss recent evidence for methods to whose symptoms were not responsive to maximize ECT’s therapeutic benefit, ish cognitive side effects are discussed below, although the data are limited. previously effective ECT treatments with minimize its side effects, and prevent bitemporal, right unilateral, or bifrontal relapse. Bifrontal ECT montages, successfully responded to left Electrode Placement Bifrontal ECT became popular in the anterior right temporal ECT (8). Chang- 1990s and is now the third most com- ing to the left anterior right temporal monly used montage. The bifrontal montage during the maintenance phase Bitemporal ECT montage involves placing the electrodes also prevented relapse, improved quality The position of the electrodes used to 5 cm above the lateral angle of the or- of life, and, interestingly, improved the deliver energy has a significant impact bits (Figure 1C) (4). Studies exploring seizure quality in all three patients. on both efficacy and side effects of the the efficacy of bifrontal ECT have treatment. The bitemporal montage has yielded mixed results. One initial ran- The American Journal of Psychiatry Residents’ Journal 3 FIGURE 1. Diagram of Electrode Placement lower width of 0.5 ms–2 ms (Figure 1F), which is one of the proposed reasons for its improved cognitive profile (2). Recent research explores the use of stimulus with pulse widths of 0.2 ms–0.5 ms, termed ultra-brief pulse (Figure G). There is some controversy concerning the value of ultra-brief pulse, with several studies suggesting that it may be less efficacious or require more treatments to achieve re- mission when compared with standard brief pulse stimulation (11), and this dif- ference seems to nullify when high-dose ultra-brief pulse stimulation is used and retains cognitive benefits (12, 13). Anesthesia Methohexital is generally considered the gold-standard induction agent in ECT anesthesia due to its rapid onset, short duration, good hemodynamic profile, low cost, and relatively low potential to increase seizure threshold (2). Propo- fol is the second most commonly used of cognitive impairment (2). Sine wave- Focal Electrically induction agent for ECT, with higher form stimulus was the original waveform Administered Seizure anticonvulsant properties but lower in- used in ECT but has long been aban- cidence of postictal agitation compared Therapy doned due to its inferior efficacy and with methohexital (2). Emerging evi- dramatically worse cognitive side effects dence suggests that low-dose ketamine Focal electrically administered seizure (2). Alternating current pulses are con- infusion has an independent rapid anti- therapy is a novel form of ECT that dif- ventionally used, and unidirectional direct depressant effect that lasts 2–3 days (14). fers from other montages in several ways current pulses are now being explored in As a result, several studies have exam- (9). Two different-sized electrodes are the focal electrically administered seizure ined the use of ketamine as an induction used. A smaller anode (0.75 inches) is therapy technique (9, 10). placed above the center of the right eye- agent for ECT and whether it can offer brow, and a larger cathode (1×2.5 inches) Stimulus dose is a product of pulse am- an adjunctive antidepressant effect. A is placed tangential to the midline and plitude, pulse width, pulse frequency, and meta-analysis of four trials with 118 pa- extended across the right supplementary stimulus duration. Evidence suggests that tients receiving ECT for unipolar and motor cortex (Figure 1E). The stimulus stimulus dose is the strongest predictor bipolar depressive illness reported signifi- used is a unidirectional direct current of treatment outcome (2). Irrespective cantly greater improvement of depression that flows from anode to cathode (Figure of the values of other parameters, higher scores among patients receiving ketamine 1H). With this technique, the subcal- stimulus dose tends to have better efficacy anesthesia compared with thiopental or losal cingulate gyrus and frontal pole, and poorer cognitive outcome compared propofol (14). However, ketamine admin- neuroanatomical targets of depression, with lower stimulus dose (2). Current istered in anesthetic doses is associated are stimulated while avoiding the tem- guidelines recommend determining a with higher rates of nausea, dizziness, poral lobes implicated in the cognitive threshold dose that can induce an EEG psychotomimetic phenomena, and car- impairment associated with ECT (10). seizure of a 30-second duration for the diovascular excitement. A longitudinal In a feasibility study, focal electrically first treatment (1). For subsequent treat- crossover study of 20 patients reported administered seizure therapy was safe, ments, recommended doses are 1.5–2.5 that ketamine inductions resulted in in- well-tolerated, and effective in the treat- times the threshold for bitemporal ECT creased side effects, more subject drop out, ment of depression (10). and 5–8 times the threshold for right and longer reorientation times compared unilateral ECT (2). with methohexital (15). Given the small Stimulus Parameters One aspect of the sine waveform be- sample sizes and heterogeneity of current lieved to contribute to its poor cognitive evidence, it is premature to make conclu- Stimulus parameters, such as waveform side effects is its prolonged pulse width sions about the benefit-to-risk ratio of and total dose, can independently influ- of 8.33 ms–10 ms (2). Brief pulse has a the use of ketamine for ECT anesthesia. ence the efficacy of ECT and the severity

The American Journal of Psychiatry Residents’ Journal 4 Relapse Prevention ment of patients with Major Depressive 11. Spaans H-P, Verwijk E, Comijs HC, et al: Disorder [Internet]. Third Edit. 2010. Efficacy and cognitive side effects after It has been well established that an acute Available from: http://bit.ly/1vfiPwe brief pulse and ultrabrief pulse right uni- course of ECT without any form of con- 2. American Psychiatric Association: The lateral electroconvulsive therapy for major tinuation treatment is associated with a Practice of Electroconvulsive Therapy: depression: a randomized, double-blind, high likelihood of depression relapse, es- Recommendations for Treatment, Train- controlled study. J Clin Psychiatry 2013; 74:e1029–e1036 timated to be up to 80% within 6 months ing, and Privileging: A Task Force Report (16). With continuation pharmacother- of the American Psychiatric Association. 12. Mayur P, Byth K, Harris A: Acute antide- apy, relapse rates drop to nearly 40% in Edited by Weiner R. Washington, DC, pressant effects of right unilateral ultra- 6 months and 50% in 12 months, and a American Psychiatric Association, 2001 brief ECT: a double-blind randomised 3. Sackeim HA, Dillingham EM, Prudic J, controlled trial. J Affect Disord 2013; recent meta-analysis reported that main- 149:426–429 tenance ECT resulted in similar 6-month et al: Effect of concomitant pharmaco- relapse rates (16). With respect to medi- therapy on electroconvulsive therapy out- 13. Loo CK, Katalinic N, Smith DJ, et al: A comes: short-term efficacy and adverse randomized controlled trial of brief and cation strategies after successful ECT, a effects. Arch Gen Psychiatry 2009; ultrabrief pulse right unilateral electro- randomized controlled trial of 290 pa- 66:729–737 convulsive therapy. Int J Neuropsycho- tients with unipolar depression found pharmacol 2014; 18(1) a 6-month relapse rate of 39% among 4. Letemendia FJ, Delva NJ, Rodenburg M, et al: Therapeutic advantage of bifrontal 14. Fond G, Loundou A, Rabu C, et al: Ket- patients receiving a combination of nor- electrode placement in ECT. Psychol Med amine administration in depressive disor- triptyline and lithium, compared with a 1993; 23:349–360 ders: a systematic review and meta-analysis. rate of 60% in the nortriptyline-alone Psychopharmacology (Berl) 2014; group and 84% in the placebo group (17). 5. Kellner CH, Tobias KG, Wiegand J: Elec- trode placement in electroconvulsive ther- 231:3663–3676 A retrospective study reported an impres- apy (ECT): a review of the literature. J 15. Yen T, Khafaja M, Lam N, et al: Post-elec- sive 16% relapse rate within 6 months ECT 2010; 26:175–180 troconvulsive therapy recovery and reori- of successful ECT when an antidepres- entation time with methohexital and sant plus lithium combination was used, 6. Dunne RA, McLoughlin DM: System- atic review and meta-analysis of bifrontal ketamine: a randomized, longitudinal, whereas other combinations, such as an- electroconvulsive therapy versus bilateral crossover design trial. J ECT (Epub ahead tidepressants plus antipsychotics (75% and unilateral electroconvulsive therapy in of print, April 21, 2014) relapse rate), antidepressants plus mood depression. World J Biol Psychiatry 2012; 16. Jelovac A, Kolshus E, McLoughlin DM: stabilizers other than lithium (69% re- 13:248–258 Relapse following successful electrocon- lapse rate), and antidepressants only (60% 7. Swartz CM, Nelson AI: Rational electro- vulsive therapy for major depression: a relapse rate) (18), seemed to offer no ad- convulsive therapy electrode placement. meta-analysis. Neuropsychopharmacol- ditional benefit. Psychiatry (Edgmont) 2005; 2:37–43 ogy 2013; 38:2467–2474 Dr. Surya is a fourth-year resident and 8. Weiss AM, Hansen SM, Safranko I, et al: 17. Sackeim HA, Haskett RF, Mulsant BH, Chief Resident in the Department of Psychi- Effectiveness of left anterior right tempo- et al: Continuation pharmacotherapy in the prevention of relapse following elec- atry and Health Behavior, Medical College ral electrode placement in electroconvul- sive therapy: 3 case reports. J ECT (Epub troconvulsive therapy: a randomized con- of Georgia, Georgia Regents University, trolled trial. JAMA 2001; 285:1299–1307 Augusta, Ga. Dr. Mori is a second-year resi- ahead of print, May 14, 2014) 18. Atiku L, Gorst-Unsworth C, Khan BU, et dent in the Department of Psychiatry and 9. Spellman T, Peterchev AV, Lisanby SH: Focal electrically administered seizure al: Improving relapse prevention after suc- Health Behavior, Medical College of Geor- cessful electroconvulsive therapy for pa- gia, Georgia Regents University. therapy: a novel form of ECT illustrates the roles of current directionality, polarity, tients with severe depression: completed The authors thank Drs. Peter Rosenquist and electrode configuration in seizure in- audit cycle involving 102 full electrocon- and Vaughn McCall for their mentorship duction. Neuropsychopharmacology vulsive therapy courses in West Sussex, and support. 2009; 34:2002–2010 United Kingdom. J ECT (Epub ahead of print, July 15, 2014) 10. Nahas Z, Short B, Burns C, et al: A feasi- References bility study of a new method for electri- 1. Galenberg AJ, Freeman MP, Markowitz cally producing seizures in man: focal JC, et al: Practice guidelines for the treat- electrically administered seizure therapy [FEAST]. Brain Stimul 2013; 6:403–408

The American Journal of Psychiatry Residents’ Journal 5 Article Ketamine Infusion for the Treatment of Depression

Mahalia L. Way, M.D., Ph.D.

Ketamine is a noncompetitive antago- terval [CI]=1.21–4.14), and ketamine confusion, hypertension, euphoria, diz- nist of the N-methyl-d-aspartic acid resulted in lowered scores on the Mont- ziness, and increased libido, all of which (NMDA) receptor that has been repeat- gomery-Åsberg Depression Rating Scale resolved by 110 minutes (1, 2). Studies edly shown to have rapid but temporally by almost 8 points more than midazolam of ketamine for bipolar depression have limited antidepressant effects in both (7.95 points, 95% CI=3.20–12.71), rep- shown a similar array of transient adverse unipolar and bipolar depression. The resenting a large effect size (Cohen’s events, with no shifts to mania (6, 7). present study is a review of the results of d=0.81). The Montgomery-Åsberg De- More concerning than the adverse events clinical trials of ketamine, the obstacles to pression Rating Scale scores of both associated with infusion are the unknown the widespread use of ketamine, and the groups (ketamine, midazolam) began long-term consequences of chronic use evolving understanding of its mechanism. increasing with time around day 3, with and the potential for ketamine abuse, similar trajectories, and by day 7 scores Efficacy given its history as a club drug (8, 4). on the Montgomery-Åsberg Depression When abused, ketamine is associated Rating Scale and Quick Inventory of De- The first clinical trial of ketamine for with cystitis and biliary dilation, but users pressive Symptomatology-Self Report no the treatment of depression was a small, are often taking multiple drugs at once longer demonstrated any statistically sig- randomized placebo-controlled cross- and using ketamine at higher and more nificant differences between the groups. over trial of a single subanesthetic dose frequent doses than what is normally used By day 17 postinfusion, 60% of the ket- (0.5 mg/kg) administered intravenously for depression (9). Ketamine is known to amine responders had relapsed, but the over 40 minutes. The study found a ro- have opioid receptor activity, but animal rest maintained some improvement bust antidepressant effect developing studies of whether it is reinforcing, re- through day 30. Trials of ketamine for over 3 days following infusion, with lev- sulting in drug-seeking behaviors, have bipolar depression have found similar re- els returning to baseline in 1–2 weeks. been mixed (10, 8). The S-enantiomer of sults, with antidepressant effects generally These antidepressant effects temporally ketamine appears to have less psychoto- not lasting more than 1–2 weeks (6, 7). outlasted the euphoric effects of ket- mimetic effects than the R-enantiomer, amine, which resolved within hours (1). Safety but it is unclear whether this would de- Similar results were found in a slightly crease its abuse potential (8). larger crossover study conducted in 2006 In the largest placebo-controlled study that tracked the timing of response more to date (5), the most common adverse Increasing Duration closely (2). The study found significant events in the ketamine group were diz- Attempts to increase the duration of ket- improvement within 110 minutes after ziness, blurred vision, headache, nausea, amine’s antidepressant effects have been infusion, with 71% of participants meet- dry mouth, poor coordination, poor con- met with only modest success. Although ing response criteria and 29% meeting centration, and restlessness. Seventeen open-label case reports have found that remission criteria at 24 hours. These ef- percent of the ketamine patients experi- repeated ketamine infusions can extend fects were maintained for at least a week enced significant dissociative symptoms benefits for several months (11), larger in 35% of responders. Numerous small immediately after infusion, but these studies have shown more modest re- studies have reported similarly robust re- symptoms resolved within 2 hours, and sults. A small study of responders who sults, with response rates ranging from none experienced psychotic symptoms. received five additional infusions on a 25% to 85% at 24 hours and 14% to 72% Infusion was halted for two patients: schedule similar to that for ECT found at 72 hours (3, 4), but all of these stud- one of whom experienced elevated blood that 8/9 relapsed within 30 days (12), and ies used inert placebos, which may have pressure unresponsive to beta block- Murrough et al. (13) found that antide- interfered with blinding and lowered ers (maximum, 187 mmHg/91 mmHg), pressant effects lasted an average of 18 placebo response scores. The largest trial while the other experienced transient days. Attempts to follow ketamine infu- to date was a two-site randomized con- hypotension and bradycardia, which sion with oral riluzole, which modulates trolled trial examining 72 patients with resolved without intervention. Tran- glutamate and increases neuroplasticity, treatment-resistant major depression sient cardiovascular effects are common, were unsuccessful (4, 14). Which oral using midazolam (0.045 mg/kd) as an and at most academic research centers antidepressants work best following ket- active placebo (5). At 24 hours postinfu- the patient’s vital signs are monitored amine treatment is unknown and may be sion, the response rate to ketamine was throughout the infusion. In the two small difficult to determine, given the fact that 74%, while that of midazolam was 28% crossover studies discussed above, adverse most patients receiving ketamine have al- (odds ratio=2.18, 95% confidence in- events included perceptual disturbances, ready failed multiple antidepressant trials. The American Journal of Psychiatry Residents’ Journal 6 Ketamine for Suicidal Rodent models have demonstrated a antidepressant effects that begin after its Ideation three-stage response to ketamine. First, psychotomimetic effects have worn off, ketamine blocks the presynaptic NMDA lasting 1–2 weeks after a single infusion. The limited duration of ketamine’s receptors that would normally inhibit Attempts to prolong the antidepressant antidepressant effects, the unknown con- the release of glutamate. The resulting effects of ketamine by repeated infusions sequences of its chronic use, and known glutamate surge increases activation of and the use of adjunctive medications abuse potential are obstacles to intra- postsynaptic AMPA receptors, which have met with mixed results. Although venous ketamine becoming a common in turn activate neuroplasticity-related the side effects of subanasthetic doses of treatment for depression. However, its signaling pathways resulting in synap- ketamine are mild and transient, the un- rapid onset and robust antidepressant ef- togenesis and potentiation (17). The known consequences of prolonged use, fects after a single dose, with relatively mammalian target of rapamycin com- the ephemeral nature of its antidepres- mild, transient adverse effects, make it plex 1 (mTORC1), which regulates the sant properties, and its history as a drug a good candidate for the acute treat- initiation of protein synthesis, and brain- of abuse are obstacles to it becoming a ment of suicidality. All of the studies derived neurotrophic factor (BDNF) are mainstream treatment for depression. discussed above found a statistically sig- essential components of these pathways However, its rapid, robust action may nificant decrease in the suicidal ideation and necessary for the antidepressant be useful in the treatment of acute sui- items of their depression instruments effects of ketamine to take place. Block- cidality and as a bridging strategy while used. Diazgranados et al. (15) found ing AMPA receptors, interfering with awaiting the effects of longer-acting tra- that the suicidal ideation score, as mea- mTORC1, or interfering with the ef- ditional antidepressant therapies. Our sured by the Scale for Suicidal Ideation, fectiveness of BDNF all can prevent the growing knowledge of the mechanism dropped within 40 minutes of infu- rapid antidepressant effects of ketamine of ketamine presents new targets for the sion and remained improved for up to in animal models (17–20). Li et al. (18) development of future antidepressants, 4 hours. Other studies have found that showed that when these pathways are including AMPA receptors, mTOR, suicidal ideation remained significantly intact, ketamine induces the rapid induc- BDNF, and other proteins involved in lower for several weeks (12), potentially tion of mature spines in layer V pyramidal the restoration of the neuronal circuitry long enough to allow other interven- neurons in the prefrontal cortex. It also impaired by depression. tions to have an effect. To the best of causes an increase in the frequency and Dr. Way is a third-year resident in the De- our knowledge, there has been only one amplitude of the 5-HT and hypocretin- partment of Psychiatry, Emory University trial of intravenous ketamine for suicidal induced excitatory postsynaptic currents Hospital, Atlanta. ideation in an emergency department to that mark increases in corticocortical and date (16), but this study was conducted thalamocortical connections. In the Li References without controls, making it difficult to et al. study, these neuroplastic changes compare ketamine with other potential lasted about 7 days and were accompa- 1. Berman RM, Cappiello A, Anand A, et al: Antidepressant effects of ketamine in de- interventions. Several other studies eval- nied by improvements on several different rodent models of depression and anxiety. pressed patients. Biol Psychiatry 2000; uating ketamine for suicidal ideation in 47:351–354 emergent settings are in process (Clini- This correlation of neuroplastic and be- 2. Zarate Jr CA, Singh JB, Carlson PJ, et al: calTrials.gov identifiers: NCT01209845, havioral changes in animals is consistent with postmortem findings in humans, A randomized trial of N-methyl-D-as- NCT01892995, NCT02183272). partate antagonist in treatment resistant in which depression is associated with major depression. Arch Gen Psychiatry Mechanism of Action decreased prefrontal synaptic connectiv- 2006; 63:856–864 ity and neuronal atrophy and synaptic From its earliest studies, the timing of depression in the prefrontal cortex and 3. Fond G, Londou A, Rabu C, et al: Ket- amine administration in depressive disor- ketamine’s effects has suggested that hippocampus. Patients with depression ders: a systematic review and meta-analysis. events downstream of the initial NMDA have also been found to have lower levels receptor blockade were responsible for its Psychopharmacology 2014; of central and peripheral BDNF, and at- 231:3663–3676 antidepressant action. Ketamine’s psy- tenuating polymorphisms in the BDNF 4. Naughton M, Clarke G, O’Leary OF, et chotomimetic and dissociative effects receptor are also associated with depres- peak around 30–40 minutes postin- al: A review of ketamine in affective disor- sion. Since traditional antidepressants ders: current evidence of clinical efficacy, fusion but no longer exist before its increase BDNF and synaptogenesis, it is limitations of use, and pre-clinical evi- antidepressant effects emerge (1, 2, 4, 17). not surprising that a rapid-acting antide- dence of proposed mechanisms of action. J Experiments interrupting the cascade pressant would do the same (17). Affect Disord 2014; 156:24–35 of events initiated by NMDA receptor 5. Murrough JW, Iosifescu DV, Chang LC, blockade have begun to shed light on the Summary et al: Antidepressant efficacy of ketamine mechanism of ketamine’s antidepressant in treatment-resistant major depression: a Ketamine is a rapid-acting noncom- effect and offer new avenues for research. two-site randomized controlled trial. Am petitive NMDA antagonist with robust J Psychiatry 2013; 170:1134–1142

The American Journal of Psychiatry Residents’ Journal 7 6. Diazgranados N, Ibrahim L, Brutsche tions of ketamine for depression. Biol Psy- 16. Larkin GL, Beautrais AL: A preliminary NE, et al: A randomized add-on trial of chiatry 2012; 72:e11–e12 naturalistic study of low-dose ketamine an N-methyl-D-aspartate antagonist in 12. Aan het Rot M, Collins KA, Murrough for depression and suicide ideation in the treatment resistant bipolar depression. JW, et al: Safety and efficacy of repeated emergency department. Int J Neuropsy- Arch Gen Psychiatry 2010; 67:793–803 dose intravenous ketamine for treatment- chopharm 2011; 14:1127–1131 7. Zarate Jr CA, Brutsch NE, Ibrahim L, et resistant depression. Biol Psychiatry 2010; 17. Abdallah CG, Sanacora G, Duman RS, et al: Replication of ketamine’s antidepres- 67:139–145 al: Ketamine and rapid acting antidepres- sant efficacy in bipolar depression: a ran- 13. Murrough JW, Perez AM, Stern J, et al: sants: a window into a new neurobiology domized controlled add-on trial. Biol Rapid and longer-term antidepressant ef- for mood disorder therapeutics. Annu Rev Psychiatry 2012; 71:939–946 fects of repeated ketamine infusions in Med 2015; 66:509–523 8. Sancora G, Schatzberg AF: Ketamine: treatment-resistant depression. Biol Psy- 18. Li N, Lee B, Liu RJ, et al: m-TOR-depen- promising path or false prophesy in the chiatry 2013; 74:250–256 dent synapse formation underlies the development of novel therapeutics for 14. Mathew SJ, Murrough JW, aan het Rot rapid antidepressant effects of NMDA mood disorders? Neuropsychopharmacol- M, et al: Riluzole for relapse prevention antagonists. Science 2010; 329:959–964 ogy 2015; 40:259–267 following intravenous ketamine in treat- 19. Liu RJ, Lee FS, Li XY, et al: Brain-de- 9. Krystal JH, Sanacora G, Duman RS: ment-resistant depression: a pilot rived neurotrophic factor Val66Met allele Rapid-acting glutamatergic antidepres- randomized, placebo-controlled continu- impairs basal and ketamine-stimulated sants: the path to ketamine and beyond. ation trial. Int J Neuropsychopharmacol synaptogenesis in prefrontal cortex. Biol Biol Psychiatry 2013; 73:1133–1141 2010; 13:71–82 Psychiatry 2012; 71:996–1005 10. Parise EM, Alcantara LF, Warren BL: 15. Diazgranados N, Ibrahim LA, Brutsche 20. Maeng S, Zarate CA, Du J, et al: Cellular Repeated ketamine exposure induces an NE, et al: Rapid resolution of suicidal ide- mechanisms underlying the antidepres- enduring resilient phenotype in adoles- ation after a single infusion of an N- sant effects of ketamine: role of alpha- cent and adult rats. Biol Psychiatry 2013; methyl-D-aspartate antagonist in patients amino-3-hydroxyl-5-methylisoxazole- 74:750–759 with treatment resistant major depressive 4-propionic acid receptors. Biol Psychiatry 11. Blier P, Zigman D, Blier J: On the safety disorder. J Clin Psychiatry 2010; 2008; 63:349–352 and benefits of repeated intravenous injec- 71:1605–1611

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The American Journal of Psychiatry Residents’ Journal 8 Article Low-Field Magnetic Stimulation: The Next Big Thing?

Stanley Lyndon, M.D.

Depression has a lifetime prevalence of (8). Following these successes, a portable tive and Negative Affect Schedule. The approximately 17% in the United States low-field magnetic stimulation device authors found that low-field magnetic (1), and approximately 30% of patients do that produced the same time-varying stimulation produced an immediate not achieve remission after four different electromagnetic fields that were within improvement on all scales except the adequate and sequential antidepressant clinical MRI guidelines but that differed Positive and Negative Affect Schedule treatment trials (2). Many of the cur- in waveform, frequency, and strength negative affect (changes in the Positive rently available treatment modalities, from MRI was built and used by Rohan and Negative Affect Schedule positive including medications, electroconvulsive et al. (5) in their recent study involving affect scores were significant) across the therapy (ECT), and repetitive transcra- patients with a current depressive episode. combined population of depressed pa- nial magnetic stimulation (rTMS), have The stimulation paradigm utilized con- tients compared with sham treatment. one major common limitation: a very sisted of a 1-kHz oscillating magnetic The significance of the results is ampli- slow onset of therapeutic effect (3, 4). field, adapted from the component of the fied by the notable advantage of low-field Although rapid relief (within hours) has original MRI protocol, producing electric magnetic stimulation compared with the been reported with intravenous ketamine fields of 1 V/m or less. This differs sig- other neuromodulation techniques: the and deep brain stimulation, studies to nificantly from the other electromagnetic absence of any physical sensation with date have shown either that these rapid treatments currently used for the treat- stimulation, enabling excellent blinding responses are transient (in the case of ment of depression. For instance, ECT (the mild operational sounds produced by ketamine) or the treatment involves sub- produces electric fields larger than 200 the magnetic coil are easily duplicated in stantial perioperative risks, including V/m, while rTMS and deep brain stimu- the sham arm). Low-field magnetic stim- intracranial infection or hemorrhage (in lation produce fields of approximately 100 ulation is also completely noninvasive, the case of deep brain stimulation). Low- V/m, which are of sufficient magnitude to with no known adverse effects. field magnetic stimulation is a fairly new directly induce neuronal depolarization However, there are a number of issues potential treatment modality that uses a (9). The oscillations in rTMS and deep that cloud the significance of the results. small, portable tabletop device to achieve brain stimulation are also at the much Most importantly, the study was not de- rapid improvements in mood in as little lower frequencies of 10 Hz and 120 Hz, signed to measure the durability of mood as 20 minutes (5). While the durability of respectively; ECT has a frequency of ap- improvement but rather to isolate the these effects is yet to be studied, and the proximately 40 Hz–60 Hz. That low-field electromagnetic field responsible for the preliminary results need to be interpreted magnetic stimulation would have similar earlier observations of rapid mood el- with utmost caution, the rapidity of mood clinical effects as the other electromag- evating effects of low-field magnetic elevation achieved using a portable device netic treatments despite inducing a stimulation. Mood changes were evalu- that could someday be used by an acutely drastically different field is another reason ated immediately after the intervention, depressed and suicidal patient at home to be excited, as it could not only provide and although the participants were con- with at least temporary relief provides us methods to influence neuronal activity tacted 1 week later to assess for adverse much cause for excitement at this time. without directly depolarizing neurons but effects, no subsequent assessments were Rapid improvements in mood were first also help us gain better insight into the conducted to determine whether the an- observed fortuitously when patients with pathophysiology of depression, an entity tidepressant effects persisted after the first bipolar depression underwent an experi- still not fully understood. hour. Also concerning is the unclear va- mental magnetic resonance spectroscopic In the most recent study by Rohan et al. lidity of the scales used to measure mood imaging procedure (6). A small, sham- (5), low-field magnetic stimulation was changes over very short periods of time. controlled pilot study was then designed applied in a double-blind sham-con- HAM-D, for instance, has several items to check whether the findings could be trolled design in a group of 63 patients that require the observer to assess the sub- replicated in patients with bipolar depres- with a current episode of depression and ject’s symptoms of depression over the past sion, and it showed promising results (7). a diagnosis of either major depressive 1 week. The scale has not been validated Antidepressant-like behavioral effects of disorder or bipolar depression. Effects for shorter periods of time, and it is diffi- low-field magnetic stimulation were then on mood were assessed primarily using cult to know what the reported changes in demonstrated using the forced swim test a self-rated visual analog scale and the those items actually mean when adminis- in rats, which is one of the animal mod- observer-rated 17-item Hamilton De- tered less than an hour apart. els traditionally used to demonstrate pression Rating Scale (HAM-D) and Another criticism of the Rohan et al. responses to antidepressant treatments secondarily using the self-rated Posi- study is the relatively small size and The American Journal of Psychiatry Residents’ Journal 9 heterogeneity of the tested population, mechanisms of action, as well as deter- major depressive disorder. Int J Neuropsy- considering that the study included pa- mining whether or not applying a global chopharmacol 2011; 14:1417–1431 tients with bipolar disorder as well as magnetic field that affects a wide group 4. Merkl A, Heuser I, Bajbouj M: Antide- major depressive disorder, as defined by of important cortical brain structures is pressant electroconvulsive therapy: mech- DSM. The initial analysis with the groups warranted over identifying the specific anism of action, recent advances and stratified into the two disorders also did regions responsible for the observed ef- limitations. Exp Neurol 2009; 219:20–26 not show statistical significance with fects and applying the field only to those 5. Rohan ML, Yamamoto RT, Ravichandran treatment, and the authors had to com- regions, is ultimately necessary moving CT, et al: Rapid mood-elevating effects of bine data across the diagnostic groups forward. low field magnetic stimulation in depres- sion. Biol Psychiatry 2014; 76:186–193 for the results to reach statistical signifi- Despite the uncertainties, however, the cance. However, considering the recent results described in the Rohan et al. (5) 6. Posse S, Dager SR, Richards TL, et al: In vivo measurement of regional brain meta- criticisms of the nosological approach of study are fascinating, especially consider- DSM (10) and the National Institute of bolic response to hyperventilation using ing the uniqueness of low-field magnetic magnetic resonance: proton echo planar Mental Health’s strong push toward Re- stimulation among the neuromodulatory search Domain Criteria over DSM (11), spectroscopic imaging (PEPSI). Magn techniques in terms of the mechanism Reson Med 1997; 37:858–865 as well as the small number of subjects in and the effects. And as it is unclear the stratified groups that could impede 7. Rohan M, Parow A, Stoll AL, et al: Low- whether the various neuromodulatory field magnetic stimulation in bipolar de- gaining meaningful correlations, this crit- techniques exert their antidepressant ef- icism may be unwarranted. pression using an MRI-based stimulator. fects through a common mechanism or Am J Psychiatry 2004; 161:93–98 Unlike rTMS and deep brain stimula- multiple mechanisms, there is also the 8. Carlezon WA, Rohan ML, Mague SD, et tion, low-field magnetic stimulation does possibility of combining various methods al: Antidepressant-like effects of cranial not target a specific region of the brain. of neuromodulation in the treatment of stimulation within a low-energy magnetic Because of this widespread approach, it depression in the future. Other potential field in rats. Biol Psychiatry 2005; is difficult to determine the exact mech- areas of research include testing combina- 57:571–576 anism by which low-field magnetic tions of neuromodulation, psychotherapy, 9. Silva S, Basser PJ, Miranda PC: Elucidat- stimulation exerts its effects. It is also im- and pharmacological therapy in the treat- ing the mechanisms and loci of neuronal portant to assess whether or not specific ment of depression, while at the same excitation by transcranial magnetic stimu- neuroanatomical structures or networks time observing the neural networks and lation using a finite element model of a might be mediating the observed effects, substrates modulated by them during the cortical sulcus. Clin Neurophysiol 2008; since identifying them would be the sine treatment to understand the underlying 119:2405–2413 qua non of transitioning to larger clinical disease process better. If the preliminary 10. Carpenter WT: RDoC and DSM-5: trials to assess treatment efficacy, at least results of low-field magnetic stimulation what’s the fuss? Schizophr Bull 2013; according to NIMH’s recent guidelines could be replicated in larger, independent 39:945–946 requiring future trial proposals to identify studies, preferably with a durable effect, 11. Insel T, Cuthbert B, Garvey M, et al: Re- a defined neurobiologic target or me- low-field magnetic stimulation could very search domain criteria (RDoC): toward a diator. It was postulated that the effects well become the “next big thing” in the new classification framework for research seen in low-field magnetic stimulation treatment of depression. on mental disorders. Am J Psychiatry 2010; 167:748–751 may stem from changes in the membrane Dr. Lyndon is a first-year resident in the potentials of the dendritic neurons in Department of Psychiatry and Behavioral 12. Price JL, Drevets WC: Neurocircuitry of mood disorders. Neuropsychopharmacol- layers 5 and 6 of the cortex, since these Medicine, Medical College of Wisconsin, ogy 2010; 35:192–216 were shown to be involved in mood reg- Milwaukee. ulation (12). As acknowledged by the 13. Volkow ND, Tomasi D, Wang G-J, et al: authors, these possibilities regarding the References Effects of low-field magnetic stimulation mechanism and site of action are only on brain glucose metabolism. NeuroImage speculative until tested. Another study 1. Kessler RC, McGonagle KA, Zhao S, et 2010; 51:623–628 showed significant reductions in the glu- al: Lifetime and 12-month prevalence of 14. Sheline YI, Price JL, Yan Z, et al: Resting- cose metabolism in several regions of DSMIII-R psychiatric disorders in the state functional MRI in depression un- United States: results from the National the cerebral cortex following exposure to masks increased connectivity between Comorbidity Survey. Arch Gen Psychia- networks via the dorsal nexus. Proc Natl low-field magnetic stimulation compared try 1994; 51:8–19 with sham treatment in healthy volun- Acad Sci USA 2010; 107:11020–11025 2. Rush AJ, Trivedi MH, Wisniewski SR, et teers (13). Connectivity between cortical 15. Perrin JS, Merz S, Bennett DM, et al: al: Acute and longer-term outcomes in regions most strongly penetrated by low- Electroconvulsive therapy reduces frontal depressed outpatients requiring one or cortical connectivity in severe depressive field magnetic stimulation fields has also several treatment steps: a STAR*D report. been shown to be increased in depres- disorder. Proc Natl Acad Sci USA 2012; Am J Psychiatry 2006; 163:1905–1917 109:5464–5468 sion (14) and decreased with treatment 3. Dupuy JM, Ostacher MJ, Huffman J, et al: (15). Therefore, further research into the A critical review of pharmacotherapy for The American Journal of Psychiatry Residents’ Journal 10 Treatment in Psychiatry A Question of Balance: Preventing Relapse of Psychotic Depression

Laurel D. Pellegrino, M.D.

Case Ideal maintenance alone, and these studies found variable rates of relapse, from 27% to 70%. The A man with major depression and sui- treatment would highest rate (70%) was found in a study cidal ideation is treated for psychotic of patients maintained on stable doses of symptoms. balance … opposing antidepressant therapy for a mean of 3.5 “Mr. E” is a 35-year-old man who was years following ECT treatment of the ini- admitted to the inpatient psychiatric unit factors while keeping tial episode (7). Two other studies found for a major depressive episode and suicidal the patient well. rates of about 50%. One of these stud- ideation with a plan to overdose (he had ies followed 19 patients who were treated stock-piled pills). His presentation was with nortriptyline for 2 years, and 47.4% notable for significant psychomotor retar- of these patients had either a relapse or dation. He was cooperative but guarded, high morbidity and mortality. Compared a recurrence (2). The second study found citing a need to maintain his privacy. The with patients with nonpsychotic depres- a relapse rate of 50% among 32 patients patient was started on mirtazapine (15 sion, those with psychotic symptoms taking antidepressants (primarily tricy- mg) for depression and insomnia. On the experience a higher depressive symptom clics) for 1 year following ECT treatment third day of hospitalization, he expressed burden, a longer time to recovery (1), a (8). Finally, the study with the lowest re- worry that his dreams were coming true. higher rate of relapse (2), and a mortal- lapse rate (27%) was a prospective study Before being hospitalized, he had a dream ity rate that is twice as high (3). One of 30 adults treated with fluoxetine and that involved being back in the military, large epidemiologic study estimated that perphenazine, then maintained on fluox- being tortured, winding up in a hospital, almost 20% of people with major depres- etine alone for 1 year (9). and facing a large spider. Because he was sion have psychotic symptoms (4). This now in the hospital, he was afraid that percentage is even higher in the elderly, Factors Associated With Relapse other parts of his dream might also come estimated in one study to be 47% (5). Several factors explain the variability in true. On the fourth day of hospitalization, observed relapse rates. First, studies with Current APA practice guidelines for longer follow-up tended to report more he admitted hearing voices telling him to treatment of psychotic depression recom- leave the hospital and take his life. Ar- relapse events, which may represent the mend acute-phase treatment with either course of this illness over time. More ipiprazole was added to his regimen and electroconvulsive therapy (ECT) or a titrated up to 10 mg; his psychotic symp- standardized follow-up periods in future combination of an antidepressant and an studies could correct for this problem. toms and mood improved after 5 days of antipsychotic (6). However, less evidence treatment. The patient was discharged Second, the choice of antidepressants exists to support recommendations for used during the maintenance phase may and scheduled to follow-up in the outpa- maintenance treatment or the choice of tient clinic within a week. have affected relapse rates. Fluoxetine medication and length of therapy fol- was the antidepressant used in the study If you were Mr. E’s outpatient provider, lowing remission of acute symptoms. with the lowest relapse rate, while the how long would you continue treating him Unnecessary treatment with antipsychot- studies with higher relapse rates tended with aripiprazole? He was already over- ics disposes patients to potentially serious to use tricyclic antidepressants. In non- weight and had an elevated lipid profile, side effects, but undertreatment of this psychotic depressed patients who have and thus treating him for longer than nec- serious disorder poses the risk of relapse. been treated with ECT, treatment with essary could compromise his physical health. Ideal maintenance treatment would bal- paroxetine was more protective against On the other hand, discontinuing aripip- ance these opposing factors while keeping relapse than imipramine (10); it is pos- razole too soon could result in relapse of his the patient well. sible that the same is true for psychotic depressive and psychotic symptoms, as well Relapse depression. Third, the choice of treat- as his suicidality. ment during the acute phase may have influenced outcomes during mainte- Relapse Rates With Factors to Weigh nance treatment. Pharmacotherapy was Antidepressant Monotherapy the choice of acute-phase treatment in Major depression with psychotic features Four studies have followed patients the study with the lowest relapse rate (9), is a debilitating form of depression, with maintained on antidepressant therapy while ECT was used in the studies with The American Journal of Psychiatry Residents’ Journal 11 higher rates (2, 7, 8). In fact, when Flint with an antipsychotic outweighed the Recommendations for et al. (2) broke down patients by acute- benefits for a given population. Treatment phase treatment, those treated with ECT It would perhaps be most efficacious to had a 53.3% rate of relapse, while those determine whether there are character- Because of the many unanswered ques- treated with pharmacotherapy had a rate istics of individuals that determine who tions about maintenance treatment of of 25% (although the difference between needs to be treated longer and who does psychotic depression, outpatient provid- these two groups was not statistically not. Toward this end, Rothschild et al. (9) ers could follow an algorithm for treating significant). One explanation for this identified some characteristics of patients psychotic depression created by Dr. Roth- phenomenon is that ECT tends to be re- who relapsed. They found that patients schild (15) that is based on existing served for more severely ill patients, and who relapsed on antidepressant therapy research. His recommendations for main- thus patients initially treated with ECT alone tended to have had longer initial tenance treatment include continuing the may have had a poorer prognosis. depressive episodes and more frequent administration of an antipsychotic for 4 months following remission of symp- Relapse Rates When Antipsychotic past episodes. Along similar lines, Spiker toms, followed by a very gradual taper. Therapy is Prolonged et al. (8) found that patients who relapsed In an example, he treats a patient with One small study (N=10) suggests that tended to have longer initial episodes, sertraline (150 mg) and olanzapine (15 long-term combination pharmacotherapy but this finding did not reach statistical mg). He monitors psychotic symptoms can prevent relapse. Of patients followed significance. with the Brief Psychotic Rating Scale for a mean duration of 11 months, 80% Ongoing Research and depressive symptoms with the Ham- maintained remission on a combina- ilton Depression Rating Scale. After 4 tion of antidepressant and antipsychotic The STOP-PD II (Sustaining Remis- months of treatment following remission treatment. The patients who relapsed did sion of Psychotic Depression II) group of symptoms, he tapers olanzapine by 5 so after discontinuing their medications is currently addressing the best approach mg every 4 weeks. However, if a patient (11). This finding is limited by the lack to maintenance treatment, which will be experiences significant side effects during of a control group and the variability of the largest maintenance study to date. An treatment, he suggests starting the taper medications and doses used. earlier STOP-PD study (13) compared sooner. He continues sertraline indefi- There is only one randomized controlled acute-phase treatments of olanzapine nitely (15). trial comparing antidepressant mainte- (target dose 15 mg–20 mg) and sertra- Dr. Pellegrino is a second-year resident in nance treatment alone with combination line (target dose 150 mg–200 mg) with the Department of Psychiatry, University of treatment with an antipsychotic. For this olanzapine and placebo and found that Washington, Seattle. study, 28 older adults (age 50–84 years) combination treatment was associated were randomly assigned to maintenance with higher rates of remission (41.9% vs. The author thanks Joseph Cerimele, M.D., treatment with either nortriptyline (tar- 23.9%). for his support, encouragement, and assis- get blood concentration, 50 ng/ml–150 The current STOP-PD II study is evalu- tance with this article. ng/ml) and perphenazine (target dose 12 ating maintenance treatment following References mg–16 mg) or nortriptyline and placebo 20 weeks of acute-phase treatment (14). for 26 weeks. About 25% of patients in Subjects whose symptoms remit will be 1. Maj M, Pirozzi R, Magliano L, et al: Phe- both groups experienced a relapse, with randomly assigned to receive either ser- nomenology and prognostic significance no difference between groups. These re- traline and olanzapine or sertraline and of delusions in major depressive disorder: sults were surprising, since the authors placebo for 36 weeks (at the same doses a 10-year prospective follow-up study. J anticipated that the group receiving com- used for acute treatment). The primary Clin Psychiatry 2007; 68:1411–1417 bination treatment would have a lower outcome to be measured is relapse rate, 2. Flint AJ, Rifat SL: Two-year outcome of rate of relapse. It is unclear whether this with relapse defined as a subject expe- psychotic depression in late life. Am J Psy- finding pertains only to older adults or riencing a resurgence of depressive or chiatry 1998; 155:178–183 would be true for younger adults as well, psychotic symptoms, a suicide plan or 3. Vythilingam M, Chen J, Bremner JD, et and thus more data are needed. attempt, mania or hypomania, or psy- al: Psychotic depression and mortality. An additional finding of this study was chiatric hospitalization due to any of Am J Psychiatry 2003; 160:574–576 that the group receiving combination the above. Metabolic changes will be 4. Ohayon MM, Schatzberg AF: Prevalence treatment experienced a higher degree examined as a secondary outcome. Ad- of depressive episodes with psychotic fea- of side effects with significant morbidity, ditionally, the authors will investigate tures in the general population. Am J Psy- including extrapyramidal side effects, tar- age and genetic polymorphisms as pos- chiatry 2002; 159:1855–1861 dive dyskinesia, and falls (12). Thus, this sible predictors of variability in response 5. Meyers BS, Greenberg R: Late-life delu- study serves as a good example of a case to treatment, which could potentially lead sional depression. J Affect Disord 1986; in which the risks of longer treatment to more personalized treatment. 11:133–137

The American Journal of Psychiatry Residents’ Journal 12 6. Gelenberg AJ, Freeman MD, Markowitz 10. Lauritzen L, Odgaard K, Clemmesen L, sion: the study of pharmacotherapy of JC, et al: Practice Guideline for the Treat- et al: Relapse prevention by means of par- psychotic depression (STOP-PD). Arch ment of Patients With Major Depressive oxetine in ECT-treated patients with ma- Gen Psychiatry 2009; 66:838–847 Disorder, 3rd ed. Washington, DC, Amer- jor depression: a comparison with 14. Flint AJ, Meyers BS, Rothschild AJ, et al: ican Psychiatric Association, 2010 imipramine and placebo in medium-term Sustaining remission of psychotic depres- continuation therapy. Acta Psychiatr 7. Aronson TA, Shukla S, Hoff A: Continu- sion: rationale, design and methodology Scand 1996; 94:241–251 ation therapy after ECT for delusional of STOP-PD. BMC Psychiatry 2013; depression: a naturalistic study of prophy- 11. Clower CG: Recurrent psychotic unipolar 13:38 lactic treatments and relapse. Convuls depression. J Clin Psychiatry 1983; 15. Rothschild AJ: Major depressive disorder, Ther 1987; 3:251–259 44:216–218 severe with psychotic features, in How to 8. Spiker DG1, Stein J, Rich CL: Delusional 12. Meyers BS, Klimstra SA, Gabriele M, et Practice Evidence-Based Psychiatry. depression and electroconvulsive therapy: al: Continuation treatment of delusional Washington, DC, American Psychiatric one year later. Convuls Ther 1985; depression in older adults. Am J Geriatr Publishing, 2010 1:167–172 Psychiatry 2001; 9:415–422 9. Rothschild AJ, Duval SE: How long 13. Meyers BS, Flint AJ, Rothschild AJ, et al: should patients with psychotic depression A double-blind randomized controlled stay on the antipsychotic medication? J trial of olanzapine plus sertraline vs olan- Clin Psychiatry 2003; 64:390–396 zapine plus placebo for psychotic depres-

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The American Journal of Psychiatry Residents’ Journal 13 Case Report DRESS Syndrome Induced by Antidepressant Sertraline

Meredith Brandon, M.D.

Selective serotonin reuptake inhibi- ment of the rash. On presentation to the the causative agent because there are no tors (SSRIs) are associated with notable emergency department, her vital signs reports of associated rash with aripipra- side effects, including gastrointestinal were stable and her laboratory results zole in the literature (7, 8). Furthermore, disturbances, headaches, sexual dysfunc- were significant for a leukocytosis of 15 DRESS syndrome has been associated tion, insomnia or sedation, sweating, 200/mm3 and eosinophilia of 11.5%. with the use of antidepressants such as and bleeding. Less commonly, however, During her hospitalization, she was desipramine, amitriptyline, and fluox- are dermatologic symptoms. In cases of treated with intravenous prednisone, di- etine (9). treatment-resistant depression, SSRIs are phenhydramine, and hydroxyzine and combined with atypical antipsychotics underwent daily hydrotherapy. Based on Conclusions such as aripiprazole or quetiapine, which her clinical presentation and histologi- DRESS syndrome is a potentially life- also carry little to no risk of dermato- cal confirmation, she was diagnosed with threatening adverse drug reaction that logic reactions. The present case involves DRESS syndrome. After 6 days, the rash can be infrequently induced by some of a 14-year-old adolescent who developed improved, and the patient was discharged the most commonly prescribed antide- drug reaction with eosinophilia and sys- home. pressant medications. This case highlights temic symptoms (DRESS) syndrome that although antidepressants such as during the use of sertraline and aripip- Discussion SSRIs are considered to be relatively be- razole. To the best of our knowledge, DRESS syndrome is a rare, poten- nign in terms of side effects, it is essential there are no other documented cases of tially life-threatening drug-induced that clinicians are still able to recognize DRESS syndrome induced by either ser- hypersensitivity reaction that includes more serious side effects. Perhaps more traline or aripiprazole. skin eruption, hematologic abnormalities research in dermatologic manifestations Case (eosinophilia and atypical lymphocyto- of antidepressant medications and greater sis), lymphadenopathy, and internal organ information availability on the potential “Meghan” is a healthy 14-year-old ado- involvement (liver, kidney, and lung) (1– dermatologic side effects would help re- lescent with a psychiatric history of 3). The diagnosis of DRESS syndrome duce such occurrences. depression and anxiety, who was hospi- is based upon the combination of clini- Dr. Brandon is a third-year resident at talized after presenting with complaints cal features (history of drug exposure), Rutgers-New Jersey Medical School, New- of a new-onset generalized, erythema- cutaneous findings, systemic findings ark, N.J. tous, and pruritic rash. The rash started (fever, lymphadenopathy, and visceral in- 2 weeks prior to admission and initially volvement), laboratory findings such as References only involved her thighs but then spread leukocytosis with eosinophilia >700/mi- to her arms, face, back, and abdomen. croL and/or atypical lymphocytosis, and 1. Bocquet H, Bagot M, Roujeau JC: Drug- She also developed bilateral hand swell- histologic findings. DRESS syndrome is induced pseudolymphoma and drug hy- ing and paresthesias in her hands and primarily a drug-specific immune reac- persensitivity syndrome (drug rash with eosinophilia and systemic symptoms: feet. The patient reported that sertraline tion caused by latent viral reactivation of DRESS). Semin Cutan Med Surg 1996; (100 mg daily) was started 4 months ear- various herpes viruses (4). The reaction 15:250–257 lier for depression, and approximately 1 usually begins 2–6 weeks after the ini- 2. Husain Z, Reddy BY, Schwartz RA: month later, aripiprazole (2 mg daily) tiation of the offending medication (5, DRESS syndrome, part I: clinical per- was added to the regimen for antide- 6). Antiepileptic agents and allopurinol spectives. J Am Acad Dermatol 2013; pressant augmentation. After evaluation are the most frequently reported causes. 68:693.e1–e14 by an outpatient dermatologist and fol- Identification and prompt withdrawal 3. Husain Z, Reddy BY, Schwartz RA: lowing a biopsy, she was diagnosed with of the offending drug is the mainstay of DRESS syndrome, part II: management dermohypersensitivity, most likely due to treatment (3). and therapeutics. J Am Acad Dermatol an allergic reaction from sertraline and/ In the above case, the diagnosis of 2013; 68:709.e1–e9 or aripiprazole. Because the patient was DRESS syndrome was confirmed both 4. Takahashi R, Kano Y, Yamazaki Y, et al: tapered off both medications by her out- clinically and histologically. The anti- Defective regulatory T cells in patients patient psychiatrist, she was also treated depressant sertraline was most likely with severe drug eruptions: timing of the with oral prednisone, with no improve- dysfunction is associated with the patho- The American Journal of Psychiatry Residents’ Journal 14 logical phenotype and outcome. J Immu- tion of drug reaction with eosinophilia 9. Criado PR, Avancini J, Santi CG, et al: nol 2009; 182:8071–8079 and systemic symptoms (DRESS). Br J Drug reaction with eosinophilia and sys- 5. Kardaun SH, Sekula P, Valeyrie-Allanore Dermatol 2014; 170:866–873 temic symptoms (DRESS): a complex in- L, et al: Drug reaction with eosinophilia 7. Spigset O: Adverse reactions of selective teraction of drugs, viruses and the immune and systemic symptoms (DRESS): an serotonin reuptake inhibitors: reports system . IMAJ 2012; 14:577–582 original multisystem adverse drug reac- from a spontaneous reporting system. tion: results from the prospective RegiS- Drug Safety 1999; 20:277–287 CAR Study. Br J Dermatol 2013; 8. Dunner DL: Safety and tolerability of 169:1071–1080 emerging pharmacological treatments for 6. Chi MH, Hui RC, Yang CH, et al: Histo- bipolar disorder. Bipolar Discord 2005; pathological analysis and clinical correla- 7:307–325

The American Journal of Psychiatry Residents’ Journal 15 Article When Parents Kill: A Review of Infanticide

Samuel J. House, M.D.

Infanticide, the intentional killing of a of the one-child policy in China suggest to use drowning, negligence, and poison- child less than 1 year of age, has been that the additional pressures of popula- ing as methods (10). In a sample of 110 practiced throughout history for a va- tion control may lead to additional cases Italian women who committed infanti- riety of reasons, including presence of of homicide (1). cide, Ciani et al. (11) found that mothers disability, gender selection, and popula- Infant age also contributes to the risk for who committed infanticide were more tion control (1). In 2011, the Centers homicide. Of Japanese murder victims likely to have had psychopathology (most for Disease Control and Prevention esti- under the age of 15 years, children under commonly major depressive disorder of mated the number of infant deaths due 1 year are at the greatest risk (7). Over- those pathologies that could be identi- to homicide to be at 7.3 per 100,000, peck et al. (8) examined the murders of fied), to have engaged in violent killing excluding those deaths in which inten- 2,776 infants in the United States and of the infant, to have committed or at- tion was unknown (2). Additionally, the found that 5% of homicides occurred on tempted suicide after the homicide, and World Health Organization estimated the first day of life, 25% by 2 months of to have made no attempt to conceal the the international rate of deaths due to age, 50% by 4 months of age, and 66% by bodies of the infants. While most women violence against children ages 0 to 4 years 6 months of age. who commit infanticide do not suffer to be 136 per 100,000 in 2008, excluding from postpartum psychosis, the incidence deaths occurring during war (3). The con- Perpetrators of suicide or infanticide among women tinued gravity of this issue and potential Describing perpetrators of infanticide with this psychopathology nears 5% (12). involvement of parental mental illnesses could also prove invaluable to risk assess- Fathers who commit child homicides are warrant examination of infanticide litera- ment. Children are more likely to be killed more likely to kill older children than in- ture to familiarize practitioners with this by their caretaker than a stranger (5). In fants (10, 13). In an analysis of fathers issue for the purposes of improved risk the aforementioned landmark analysis who commit child homicides, research- analysis, prevention, detection, and treat- of infanticide risk factors in the United ers found that only 20% of the 458 child ment of perpetrators, as well as the legal States, Overpeck et al. found that young, homicide victims were infants (excluding implications that arise. Because neonati- multiparous mothers were more likely to neonates), and only 1.5% of the victims cide, the intentional killing of a child less commit infanticide than other parents, were neonates (13). Research indicates than one day old, presents unique risk and the authors also reported the follow- that fathers who commit infanticide are factors compared with infanticide, this ing additional risk factors: maternal age more likely to cause shaking/beating in- topic is also reviewed. <19 years, maternal education <12 years juries, and the infant is more likely to be (confounded by age), unmarried, African taken to the hospital (5). Infanticide American or American Indian race, first prenatal visit after 6 months gestation The risk of infanticide in families in- Victims or no prenatal care, and gestational age cluding adopted and step children is still As with other violent acts, risk analysis <28 weeks at delivery (8). However, these debated (14, 15). While there may or may of infanticide could provide a means of findings do not separate neonaticide from not be a relationship between blended prevention. Foremost among risk factors infanticide, and other studies show that families and infanticide risk, step parents for infanticide is a history of previous mothers who commit infanticide tend to do commit these crimes. Murders by step abuse (4). In a study of infanticides in the be married or living with their partner, parents are more likely to involve anger, United States, Fujiwara et al. (5) found >25 years old, and suffer from psychopa- rage, ongoing abuse, and death by beating that 39 of 71 cases of infanticide had thology (9). rather than use of a weapon, drowning, or evidence of previous physical abuse. Fur- poison (16). Similarly, a review of child homicides thermore, fatal abuse has been noted to Other factors that may increase the risk of occur in “young, unwanted children” (6). occurring between 1995 and 2005 in Austria and Finland found that 51% of committing infanticide include increased Infant sex is also a risk factor for homi- child homicides committed by mothers rates of economic stress (4, 17) and inter- cide. Evidence suggests that male infants were infant victims, compared with a rate actional problems between parents (17). are more likely to be victims of infanti- of 7% of infant victims by paternal per- Neonaticide cides in Western cultures (5). However, petrators (10). Compared with fathers, female infanticide is a more common mothers were less likely to have a history The intentional killing of an infant less practice in Asian cultures, potentially of violent offenses, were more likely to than 1 day old, or neonaticide, appears secondary to “son preference,” and critics conceal their crimes, and were more likely to have different risk factors for the vic- The American Journal of Psychiatry Residents’ Journal 16 TABLE 1. Characteristics of Infanticide and Neonaticide Victims and status. However, some have argued that Perpetrators and Risk Assessment and Prevention Strategies this should be the case, given the preva- Victim Characteristics lence of postpartum mental illness (19). • History of previous abuse Arguments against infanticide statutes • Gender include a focus on redundancy if insanity –– Neonaticide - ♀ = ♂ –– Infanticide - ♀ < ♂a defense standards already exist, inherent • Unwanted child gender bias, diminished value of infant • Age – 2/3 by 6 months life, and the fact that maternal mental ill- Perpetrator Characteristics ness continues after a child reaches 1 year • Fathers of age (20). It is recommended that prac- –– Less likely to kill infants compared with mothers titioners familiarize themselves with the –– History of violent offenses compared with mothers –– Less likely to conceal crime mental health laws in their state. –– Violent means of crime (shaking, beating) • Mothers of Infants >1 day old Risk Assessment and –– Psychopathology present –– Age ≥25 Prevention –– Married or living with partner –– More likely to kill infants compared with fathers Having considered the epidemiology and –– No violent offense history compared with fathers risk factors of infanticide, one key ques- –– Drowning, poisoning, and negligence as means of crime tion remains: How can clinicians help –– Less likely to conceal crimes compared with mothers of neonates • Mothers of Neonates (≤1 day old) prevent infanticides? Primarily, a com- –– Psychopathology absent prehensive risk assessment for potential –– <20 years of age harm to the infant should be performed. –– Single Some suggest that clinicians should per- –– Low income –– Less violent means of crime (such as abandonment) form in-depth risk assessments when –– More likely to conceal crime compared with mothers of older infants evaluating patients, similar to a suicide risk assessment, and it has been shown Risk Assessment • Direct questioning of potential perpetrators regarding thoughts, plan, and intent to harm that during risk assessments, practitio- infant ners are more likely to ask about general • Look for warning signs in perpetrators including: homicidal thoughts rather than spe- –– Depressive symptoms cific harm to children (4) Friedman and –– Suicidal thoughts –– Feelings of insufficiency Resnick (4) suggested direct question- –– Relationship strain ing about thoughts, plans, and intent to –– History of mental illness harm children, with low thresholds for –– History of abusing children hospitalization of mothers contemplat- –– Significant infant illness –– Lack of prenatal treatment ing harm (4). Similarly, clinicians should be wary of warning signs in mothers and Prevention • Very low threshold for hospitalization fathers, including depressive symptoms, • Early identification and treatment underlying mental illness suicidal thoughts, feelings of insuffi- • Refer to marital counseling ciency, relationship strain, and history of • Refer to domestic violence support groups abusing children (17). Additionally, his- • Close, regular follow-up • Report suspected child abuse to appropriate authority tory of mental illness, domestic violence, significant infant illness, and lack of pre- a Except in Asian cultures, including India, where ♀ > ♂. natal treatment should be added to this list of red flags. tim and the perpetrator. The incidence tempted to conceal the bodies. Similarly, Another aspect of the prevention of in- of neonaticide is equal among male and a series of 32 documented neonaticides fanticide lies with the practitioner’s ability female neonates (6), unlike the incidence describes mothers as having no psychopa- to adequately treat any modifiable risk of infanticide. Mothers who commit thology and seeking little to no prenatal factors. For example, treatment of under- neonaticide tend to present in a differ- care and concealing or even denying the lying mental illness could help reduce the ent fashion. Putkonen et al. (10) found existence of the pregnancy (18). risk of infanticide. Examples of treatment that mothers were more likely to commit include couples counseling, hospitaliza- neonaticide than fathers. Ciani et al. (11) Legal Considerations tion, referral to domestic violence support reported that mothers who committed groups, and close follow-up. Finally, re- Currently in the United States, parents neonaticide were without psychopathol- ferral to the Department of Human who kill their infants are able to plead not ogy, young, single, poor, used nonviolent Services for suspected child abuse is guilty by reason of insanity, and there is means (such as abandonment), and at- not only recommended but mandatory no special consideration for postpartum The American Journal of Psychiatry Residents’ Journal 17 in many jurisdictions. Characteristics 2. Child Trends: Infanticide. Child Trends Kaplan and Sadock’s Comprehensive of perpetrators and victims and risk as- Databank, 2014. http://www.childtrends. Textbook of Psychiatry, 9th ed. Edited by sessment and prevention strategies are org/? indicators=infant-homicide Sadock BJ, Sadock VA, Ruiz P. Philadel- summarized in Table 1. 3. World Health Organization: Causes of phia, Lippincott, Williams, and Wilkins, Death 2008 Summary Tables. Geneva, 2009 Summary World Health Organization. http://www. 13. West SG, Friedman SH, Resnick PJ: Fa- who.int/evidence/bod thers who kill their children: an analysis of The killing of infants, sometimes thought 4. Friedman SH, Resnick J: Child murder by the literature. J Forensic Sci 2009; to be a problem of the ancient world, mothers: patterns and prevention. World 54:463–468 is still practiced across the globe today. Psychiatry 2007; 6:137–141 14. Daly M, Wilson MI: Violence against Multiple studies have investigated the 5. Fujiwara T, Barber C, Schaechter J, et al: stepchildren. Curr Dir Psychol Sci 1996; various risk factors in the infant and per- Characteristics of infanticides: findings 5:77–81 petrator, which can be used to perform from a U.S. multisite reporting system. 15. Malkin CM, Lamb ME: Child maltreat- risk assessments. Mental health profes- Pediatrics 2009; 124:e210–e217 ment: a test of sociobiological theory. J sionals are often asked to perform risk 6. Bourget D, Grace J, Whithurst L: A re- Comp Fam Stud 1994; 25:121–133 assessments for violence, including risk view of maternal and paternal filicide. J 16. Harris GT, Hilton NZ, Rice ME, et al: of infanticide and neonaticide. It is im- Am Acad Psychiatry Law 2007; Children killed by genetic parents versus portant for consultants to consider the 35:74–82 stepparents. Evol Hum Behav 2007; age of the child when assessing the risk 7. Yasumi K, Kageyama J: Filicide and fatal 28:85–95 of homicide, as differences between the abuse in Japan, 1994–2005: temporal 17. Rohde A, Raic D, Varchmin-Schultheiss possible perpetrators exist. Because of the trends and regional distribution. J Foren- K, et al: Infanticide: sociobiographical legal implications of this issue, practitio- sic Leg Med 2009; 16:70–75 background and motivational aspects. ners should familiarize themselves with 8. Overpeck M, Brenner RA, Trumble AC, Arch Womens Ment Health 1998; the legal statutes governing their jurisdic- et al: Risk factors for infanticide in the 1:125–130 tions. Using these suggested strategies for United States. New Engl J Med 1998; 18. Vellut N, Cook JM, Tursz A: Analysis of risk assessment, prevention could inform 339:1211–1216 the relationship between neonaticide and the treatment of possible perpetrators 9. Craig M: Perinatal risk factors for neonat- denial of pregnancy using data from judi- and prevention of homicides. icide and infant homicide: can we identify cial files. Child Abuse Neglect 2012; 36:553–563 Dr. House is a fourth-year resident in the those at risk? J R Soc Med 2004; Department of Psychiatry, University of 97:57–61 19. Friedman SH, Sorrentino R: Commen- Arkansas for Medical Sciences, Little Rock, 10. Putkonen H, Amon S, Eronen M, et al: tary: Postpartum psychosis, infanticide, and insanity: implications for forensic Ark. Gender differences in filicide offense characteristics: a comprehensive register- psychiatry. J Am Acad Psychiatry Law Dr. House thanks Robert Forrest, M.D., based study of child murder in two Euro- 2012; 40:326–332 and Zachary Stowe, M.D., for their super- pean countries. Child Abuse Neglect 20. Friedman SH, Cavney J, Resnick PJ: vision and assistance during the writing of 2011; 35:319–328 Mothers who kill: evolutionary underpin- this article. 11. Ciani ASC, Fontanesi L: Mothers who nings and infanticide law. Behav Sci Law kill their offspring: testing evolutionary 2012; 30:585–597 References hypothesis in a 110-case Italian sample. 1. Schwartz LL, Isser NK: Endangered Child Abuse Neglect 2012; 36:519–527 Children: Neonaticide, Infanticide, and 12. Berga SL, Parry BL, Moses-Kolko EL: Filicide. New York, CRC Press, 2000 Psychiatry and reproductive medicine, in

The American Journal of Psychiatry Residents’ Journal 18

Test Your Knowledge Has Moved

Our Test Your Knowledge feature, in preparation for the PRITE and ABPN Board examinations, has moved to our Twitter (www.twitter.com/AJP_ResJournal) and Facebook (www.facebook.com/AJPResidentsJournal) pages.

We are currently seeking residents who are interested in submitting Board- style questions to appear in the Test Your Knowledge feature. Selected resi- dents will receive acknowledgment for their questions. 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 ref- erences from pertinent peer-reviewed journals, textbooks, or reference manuals.

*Please direct all inquiries to Rajiv Radhakrishnan, M.B.B.S., M.D., Senior Deputy Editor ([email protected]).

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The American Journal of Psychiatry Residents’ Journal 19 Residents’ Resources We would like to welcome all our readers to this new feature of the Journal! Here we hope to highlight upcoming national oppor- tunities for medical students and trainees to be recognized for their hard work, dedication, and scholarship. *To contribute to the Residents’ Resources feature, contact Tobias Wasser, M.D., Deputy Editor ([email protected]). April Deadlines

Fellowship/Award Organization Brief Description Eligibility Contact Website and Deadline

Rappeport Fellowship American The fellowship offers an opportunity PGY-III in a general pro- Phone: http://www.aapl.org/ Academy of for outstanding residents with interests gram, or PGY-IV in a child 800-331-1389 rappeport.htm Deadline: Psychiatry and in psychiatry and the law to develop or geriatric subspecialty April 1, 2015 the Law (AAPL) their knowledge and skills. Fellows training program. e-mail: will attend the Annual Meeting of [email protected] AAPL and AAPL’s annual Forensic Psychiatry Review Course, which precedes the meeting.

American College of ACNP The ACNP annually selects distin- Eligible applicants may Kelly Phy http://www.acnp.org/ Neuropsychopharma- guished young scientists in the field be no more than 5 years e-mail: annualmeeting/ cology (ACNP) Travel of neuropsychopharmacology to be posttraining. (Posttraining [email protected] travelawards.aspx Awards a part of the Travel Award Program. for MDs will be counted These awards offer an opportunity to from the final year of their or Deadline: attend an outstanding scientific pro- residency. Posttraining for April 30, 2015 gram in clinical and basic research PhDs will be counted from Laura Hill on brain-behavior-drug interactions; the last year of postdoc- e-mail become aware of the most recent, toral training.) [email protected] and often unpublished, advances in psychopharmacology; and meet and interact with internationally distin- guished researchers and scientists.

American Academy of AACAP and Offers a stipend for child and Candidates must be Board Phone: http://www.aacap.org/ Child and Adolescent the Elaine adolescent psychiatry residents and eligible/certified in child 202-587-9664 AACAP/Awards/ Psychiatry (AACAP) Pi- Schlosser Lewis junior faculty who have an interest and adolescent psychia- Resident_and_ECP_ lot Research Award for Fund in beginning a career in child and try, or enrolled in a child e-mail: Awards/AACAP_Pilot_ Learning Disabilities adolescent mental health research. By psychiatry residency or [email protected] Research_Award_for_ providing one award to a child and fellowship program. Learning_Disabilities.aspx Deadline: adolescent psychiatry junior faculty April 30, 2015 member or resident for pilot research Candidates must have a on learning disabilities, we support a faculty appointment in an young investigator at a critical stage, accredited medical school encouraging a future career in child or be in a fully accred- and adolescent psychiatry research. ited child and adolescent psychiatry clinical research or training program.

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The American Journal of Psychiatry Residents’ Journal 20 Author Information for The Residents’ Journal Submissions

Editor-in-Chief Senior Deputy Editor Deputy Editor Misty Richards, M.D., M.S. Rajiv Radhakrishnan, M.B.B.S., M.D. Tobias Wasser, M.D. (UCLA) (Yale) (Yale) 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.

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Please note that we will consider articles outside of the theme. Personality Disorders Biological Psychiatry If you have a submission related to this If you have a submission related to this theme, contact the Section Editors, theme, contact the Section Editor, Miguel Alampay, M.D., J.D. Adarsh S. Reddy, M.D., Ph.D. ([email protected]) ([email protected]) Robert Johnson, M.D., J.D., L.L.M. ([email protected]) Pediatric Neuropsychiatry If you have a submission related to this theme, contact the Section Editor, Aaron J. Hauptman, M.D. ([email protected])

*If you are interested in serving as a Guest Section Editor for the Residents’ Journal, please send your CV, and include your ideas for topics, to Misty Richards, M.D., M.S., Editor-in-Chief ([email protected]). The American Journal of Psychiatry Residents’ Journal 21