Letters base on interventions for women with perinatal mental disorders who are experiencing domestic violence.

COMMENT & RESPONSE

Association Among Posttraumatic Stress Disorder, Adverse Birth Outcomes, and Domestic Violence To the Editor Research on perinatal mental disorders other than postnatal depression is long overdue; therefore, we were pleased to see the study by Yonkers et al,1 which reported a 4-fold elevated risk for preterm birth in women who had a likely diagnosis of posttraumatic stress disorder or a major depressive episode. However, we were concerned by the omission of any measure of domestic violence in the study, as domestic violence is a correlate of posttraumatic stress disorder and major depression in pregnancy2 and of adverse pregnancy outcomes including preterm birth.3 The prevalence of antenatal domestic violence is about 4% to 9% in high-income settings.4 In a systematic review of domestic violence and perinatal mental disorders, we reported that women with antenatal depression and posttraumatic stress disorder had high prevalence (15%-30%) and raised odds (3fold to 6-fold) of domestic violence experiences within the past year or during pregnancy. There were a few longitudinal studies, confined to postpartum depression, providing evidence for a bidirectional relationship between domestic violence and postpartum depression. Therefore, domestic violence is potentially important both as a trigger and a consequence of antenatal and postnatal mental disorders. The mechanisms linking domestic violence with adverse pregnancy outcomes3 include poor antenatal care; chronic gynecological problems; behavioral risk factors, such as substance misuse; direct effects of physical trauma; and poor mental health.3 Domestic violence has broader implications for mother and child beyond poor pregnancy outcomes including increased risks for maternal death and child abuse.3,4 The high prevalence of domestic violence among pregnant women with mental disorders, and its association with adverse maternal and fetal outcomes, has important clinical implications. Routine antenatal care provides an opportunity for health care professionals to identify domestic violence and to offer interventions or refer as necessary. A systematic review of interventions for domestic violence during pregnancy found some preliminary evidence that psychological therapy, domestic violence advocacy, and home visiting may be effective in reducing violence and/or pregnancy outcomes.5 Therefore, maternity and mental health professionals need to be trained on how to identify domestic violence in pregnancy safely and should have appropriate referral and care pathways for pregnant women experiencing domestic violence. We would also recommend that researchers include measures of domestic violence in epidemiological studies of perinatal mental disorders and build on the small evidence 94

Hind Khalifeh, MRCPsych Gene Feder, PhD Louise M. Howard, PhD Author Affiliations: Mental Health Sciences Unit, University College London, London, England (Khalifeh); Centre for Academic Primary Care, School of Social and Community Medicine, University of Bristol, Bristol, England (Feder); King’s College London, London, England (Howard). Corresponding Author: Louise M. Howard, PhD, King’s College London, De Crespigny Park, London SE5 8AF, England ([email protected]). Conflict of Interest Disclosures: None reported. 1. Yonkers K, Smith MV, Forray A, et al. Pregnant women with posttraumatic stress disorder and risk of preterm birth. JAMA Psychiatry. 2014;71(8):897-904. 2. Howard LM, Oram S, Galley H, Trevillion K, Feder G. Domestic violence and perinatal mental disorders: a systematic review and meta-analysis. PLoS Med. 2013;10(5):e1001452. 3. Shah PS, Shah J; Knowledge Synthesis Group on Determinants of Preterm/LBW Births. Maternal exposure to domestic violence and pregnancy and birth outcomes: a systematic review and meta-analyses. J Womens Health (Larchmt). 2010;19(11):2017-2031. 4. Devries KM, Kishor S, Johnson H, et al. Intimate partner violence during pregnancy: analysis of prevalence data from 19 countries. Reprod Health Matters. 2010;18(36):158-170. 5. Jahanfar S, Janssen PA, Howard LM, Dowswell T. Interventions for preventing or reducing domestic violence against pregnant women. Cochrane Database Syst Rev. 2013;2:CD009414.

Ketamine for Posttraumatic Stress Disorder To the Editor The Feder et al1 study published in JAMA Psychiatry found that a single infusion of ketamine was more efficacious in reducing symptoms of posttraumatic stress disorder than midazolam. However, midazolam was rather successful in its own right, being associated with approximately 50% reductions in posttraumatic stress disorder severity scores at 24 hours postinfusion. A similarly designed ketamine vs midazolam study in depression from the same research group2 found midazolam was associated with a 28% response rate at 24 hours postinfusion, a rather substantial improvement, although ketamine was better. In both studies, midazolam was referred to as psychoactive placebo while the effects of ketamine were couched as involving the N-methyl-D-aspartate receptor complex. A more circumspect consideration of the data leaves the investigators with several possible explanations: (1) ketamine effects are due to inherent neurobiological actions and those of midazolam mere placebo; (2) midazolam and ketamine effects are both due to inherent neurobiologic actions; and (3) both ketamine and midazolam effects are related to expectational phenomena (ie, placebo effect) and ketamine is a better placebo than midazolam. There may be both placebo and an inherent neurobiologic mechanism to explain ketamine effects. However, the same could be true of midazolam.

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Letters

To explore expectational effects, Feder et al1 could have analyzed the correlation between rise in dissociative symptom scores and reduction in posttraumatic stress disorder severity scores. Would it not be interesting if such an analysis found that drug effect disappeared after controlling for dissociative adverse effects? This would suggest the seeming superiority of ketamine is merely due to increased adverse effects of that drug with attendant patient expectation of benefit, that is, that ketamine is a better placebo than midazolam. The point I am making is that if one only takes away from these 2 studies the message that ketamine beats midazolam, with resultant single-minded focus on N-methyl-Daspartate function, then important lessons are potentially being missed about the ultimate mechanism of action of both compounds. It is time for modern psychiatry to embrace active study of expectationally mediated effects rather than ignoring them. Keith G. Rasmussen, MD Author Affiliation: Department of Psychiatry and Psychology, Mayo Clinic, Rochester, Minnesota. Corresponding Author: Keith G. Rasmussen, MD, Mayo Clinic, Department of Psychiatry and Psychology, 200 First St SW, Rochester, MN 55905 (rasmussen [email protected]). Conflict of Interest Disclosures: None reported. 1. Feder A, Parides MK, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2014;71(6):681-688. 2. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-1142.

In Reply In his correspondence referencing our published proofof-concept randomized clinical trial of intravenous ketamine for chronic posttraumatic stress disorder (PTSD)1 and another study published by our research group,2 Dr Rasmussen remarks that our comparison drug, midazolam, also had some beneficial effects on PTSD symptom levels. He also noted that the beneficial effects of both ketamine and midazolam might be explained by a placebo effect. Furthermore, Dr Rasmussen stated that if the extent of dissociative effects of ketamine were found to be related to its mitigating effects on PTSD symptoms, it may be concluded that the reduction in PTSD symptom levels associated with ketamine is due to “patient expectation of benefit, that is, that ketamine is a better placebo than midazolam.” Dr Rasmussen invites the readers to consider 3 potential alternative accounts of ketamine and midazolam in the context of our study: (1) that ketamine effects are due to neurobiological actions while midazolam effects are “mere placebo,” (2) that ketamine and midazolam effects are both due to neurobiological actions, or (3) that both ketamine and midazolam effects are placebo effects and that ketamine is a better placebo than midazolam. We find this formulation somewhat arbitrary and potentially misleading. Clearly, the first option is not correct because both ketamine and midazolam have inherent neurobiological actions, and expectation effects (ie, placebo) make up a component of all treatment jamapsychiatry.com

responses.3 The second alternative is true but is not helpful in disentangling drug/placebo effects. The third option does not make sense because both drugs have inherent neurobiological effects and have been previously found to be clinically active in mood or anxiety disorders.4-6 We agree with Dr Rasmussen that midazolam was associated with some initial reduction in PTSD symptom levels in our published study. As discussed in the article, the choice of midazolam as the comparison condition likely strengthened our study design, as we expected that it would be more challenging to show differential efficacy of ketamine compared with midazolam rather than compared with saline in patients with PTSD because midazolam has known anxiolytic effects. We acknowledge that psychoactive placebo is perhaps not an ideal label for the comparator. What we meant to convey was that the comparator is known to have psychoactive effects in the absence of hypothesized specific anti-PTSD effects. We would like to point out that while in our study, midazolam was associated with a sizeable reduction (but less pronounced than ketamine) in PTSD severity scores at 24 hours, only 1 patient remained significantly improved 2 weeks after midazolam infusion. In contrast, 7 patients remained improved 2 weeks after ketamine infusion. While it would be interesting to examine our data for a potential correlation between dissociative adverse effects and reduction in PTSD symptom severity, we disagree with Dr Rasmussen on what such a finding might mean. Such correlation, if found, could have several alternative interpretations, eg, that higher plasma levels of ketamine in some patients led to both higher dissociative symptoms and more pronounced PTSD symptom reduction (higher bioavailability) or that a different common cause of higher dissociative symptoms and more pronounced PTSD symptom reduction was at work such as a functional polymorphism in a glutamate receptor gene. As just noted, we do not disagree with the fact that symptom improvement after administration of any drug can be partially due to a placebo effect, which incidentally has its own underlying neurobiology.3 Indeed, while randomized clinical trials are required to control for ever-present expectational and other nonspecific effects of treatment, these factors are often optimized in the service of patient care. Adriana Feder, MD James W. Murrough, MD Author Affiliations: Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York (Feder, Murrough); Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York (Murrough); Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York (Murrough). Corresponding Author: Adriana Feder, MD, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Pl, PO Box 1230, New York, NY 10029 ([email protected]). Conflict of Interest Disclosures: Dr Feder and Mount Sinai have been named on a use patent application on ketamine for the treatment of posttraumatic stress disorder. If ketamine were shown to be effective in the treatment of depression or posttraumatic stress disorder, Dr Feder and Mount Sinai could benefit financially. No other disclosures were reported.

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Letters

1. Feder A, Parides MK, Murrough JW, et al. Efficacy of intravenous ketamine for treatment of chronic posttraumatic stress disorder: a randomized clinical trial. JAMA Psychiatry. 2014;71(6):681-688. 2. Murrough JW, Iosifescu DV, Chang LC, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170(10):1134-1142. 3. Jubb J, Bensing JM. The sweetest pill to swallow: how patient neurobiology can be harnessed to maximise placebo effects. Neurosci Biobehav Rev. 2013;37 (10, pt 2):2709-2720. 4. Caddy C, Giaroli G, White TP, Shergill SS, Tracy DK. Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Ther Adv Psychopharmacol. 2014;4(2):75-99. 5. Young CC, Prielipp RC. Benzodiazepines in the intensive care unit. Crit Care Clin. 2001;17(4):843-862. 6. Möhler H. The rise of a new GABA pharmacology. Neuropharmacology. 2011; 60(7-8):1042-1049.

CORRECTION Typographical Error in Text: In the article titled “Placebo Response in Antipsychotic Clinical Trials: A Meta-analysis” published in the December issue of JAMA Psychiatry (2014;71[12]:1409-1421. doi:10.1001/jamapsychiatry.2014.1319), a typographical error was made in the text. The last 2 sentences of the second paragraph of the Discussion should read: “Although we did not directly test the relationship between the type and the number of study sites with placebo response, we did find that the standardized mean change for placebo-treated patients was significantly associated with sample size (Pearson r = 0.48, n = 39, P = .002). Because a larger sample size generally requires a greater number of study sites, this finding appears consistent with the findings of Agid et al.4” This article was corrected online.

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Error in Figure: In the Original Investigation entitled “Association of Poor Subjective Sleep Quality With Risk for Death by Suicide During a 10-Year Period: A Longitudinal, Population-Based Study of Late Life,” published in the October 2014 issue of JAMA Psychiatry (2014;71[10]:1129-1137. doi:10.1001/jamapsychiatry .2014.1126), the y-axis of Figure 1 on page 1133 was incorrectly labeled. This article was corrected online. Incorrect Value in Table 2: In the article titled “Telemedicine-Based Collaborative Care for Posttraumatic Stress Disorder: A Randomized Clinical Trial,” published online November 19, 2014, and also in the January 2015 print issue of JAMA Psychiatry (doi:10.1001/jamapsychiatry.2014.1575), an incorrect value appeared in Table 2. The mean (SD) distance to the closest Department of Veterans Affairs Medical Center for the TOP (Telemedicine Outreach for Posttraumatic Stress Disorder) patient group should have been given as 91.0 (40.8) km. This article was corrected online and in print. Incorrect Sentences in Abstract: In the article titled “Telemedicine-Based Collaborative Care for Posttraumatic Stress Disorder: A Randomized Clinical Trial,” published online November 19, 2014, and also in the January 2015 print issue of JAMA Psychiatry (doi:10.1001/jamapsychiatry.2014.1575), errors occurred in the Abstract. The second and third sentences of the Abstract’s Results section should have read as follows: “Patients in the TOP arm had significantly larger decreases in Posttraumatic Diagnostic Scale scores (from 35.0 to 29.1) compared with those in the UC arm (from 33.5 to 32.1) at 6 months (β = −3.81; P = .002). Patients in the TOP arm also had significantly larger decreases in Posttraumatic Diagnostic Scale scores (from 35.0 to 30.1) compared with those in the UC arm (from 33.5 to 31.7) at 12 months (β = −2.49; P = .04).” In an earlier correction of this article, Table 2 was revised to report the mean (SD) distance to the closest Department of Veterans Affairs Medical Center for the TOP (Telemedicine Outreach for Posttraumatic Stress Disorder) patient group as 91.0 (40.8) km. This article was corrected online and in print.

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