Letters

considered as continuous and categorical variables. The association of tobacco use with oral HPV-16 was explored using logistic regression. All multivariable models included variables considered significant (2-sided P < .05) in bivariable analysis and important factors based on the literature.2 Analyses were performed using SUDAAN software version 11.0.1 (RTI International). Results | Among 6887 participants, 2012 (28.6%; 95% CI, 26.5%-30.9%) were current tobacco users and 63 (1.0%; 95% CI, 0.8%-1.3%) had oral HPV-16 detected. Current tobacco users were more likely than nonusers to be male, younger, less educated, and to have a higher number of lifetime oral sexual partners (Table 1). In bivariable analysis, selfreported and biological measures of tobacco exposure as well as oral sexual behavior were significantly associated with prevalent oral HPV-16 infection (Table 2). Oral HPV-16 prevalence was greater in current tobacco users (2.0%; 95% CI, 1.3%-3.1%) compared with never or former tobacco users (0.6%; 95% CI, 0.4%-0.9%) (P = .004). Mean cotinine (157.7 ng/mL vs 57.2 ng/mL, P = .002) and NNAL levels (0.36 ng/mL vs 0.12 ng/mL, P = .02) were higher in individuals with vs without oral HPV-16 infection. All biomarkers of tobacco exposure remained associated with oral HPV-16 infection after adjustment for other factors (Table 2). Significant dose-response relationships were observed between cotinine (P = .02 for trend) or NNAL (P = .01 for trend) levels and odds of oral HPV-16 infection (Table 2). Each log increase in cotinine, approximating 3 cigarettes per day, was independently associated with oral HPV-16 prevalence (adjusted odds ratio, 1.31; 95% CI, 1.07-1.60). Each log increase in NNAL, approximating 4 cigarettes per day, was independently associated with oral HPV-16 prevalence (adjusted odds ratio, 1.68; 95% CI, 1.23-2.28). Discussion | In this large cross-sectional, population-based study, we demonstrated statistically significant dose-response relationships between behavioral and objective biomarkers of current tobacco use and oral HPV-16 infection. Tobacco use is an established co-factor for the development of cervical cancer, for which HPV infection is a necessary cause.5 Tobacco use has local and systemic immunosuppressive effects6; however, the specific biological mechanisms underlying our observed associations are unknown. Tobacco use may alter determinants of oral HPV-16 prevalence, such as incidence, persistence, or reactivation of infection. These findings highlight the need to evaluate the role of tobacco in the natural history of oral HPV-16 infection and progression to malignancy. Although adjusted for sexual behavior, we cannot entirely exclude the possibility that tobacco use is a marker for risky behavior. Additional limitations include some unstable estimates and a cross-sectional study design that precludes our ability to determine temporality or causation. Carole Fakhry, MD, MPH Maura L. Gillison, MD, PhD Gypsyamber D’Souza, PhD, MS, MPH

Author Affiliations: Johns Hopkins University School of Medicine, Baltimore, Maryland (Fakhry); Ohio State University Comprehensive Cancer Center, Columbus (Gillison); Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (D’Souza). Corresponding Authors: Gypsyamber D’Souza, PhD, MS, MPH, Johns Hopkins Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205 ([email protected]); and Carole Fakhry, MD, MPH ([email protected]). Author Contributions: Dr D’Souza had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Fakhry, D’Souza. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Fakhry, D’Souza. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Fakhry, D’Souza. Obtained funding: All authors. Administrative, technical, or material support: Fakhry, D’Souza. Study supervision: Fakhry, D’Souza. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Drs Gillison and D’Souza reported receiving previous research support from Merck Inc. Dr Gillison also reported serving as an unpaid consultant to GlaxoSmithKline. No other disclosures were reported. Funding/Support: This study was supported by grants P50DE019032, R01DE021395, R01DE023175 from the National Institute of Dental and Craniofacial Research and funding from the Milton J. Dance Head and Neck Center and Merck. Role of the Funder/Sponsor: The National Institute of Dental and Craniofacial Research, the Milton J. Dance Head and Neck Center, and Merck had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Additional Contributions: Timothy S. McNeel, BA (Information Management Services Inc), assisted with statistical analyses and received compensation. 1. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol. 2011;29(32): 4294-4301. 2. Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA. 2012;307(7):693-703. 3. Chaturvedi AK, Graubard BI, Pickard RK, Xiao W, Gillison ML. High-risk oral human papillomavirus load in the US population, National Health and Nutrition Examination Survey 2009-2010. J Infect Dis. 2014;210(3):441-447. 4. US Centers for Disease Control and Prevention. 2009-2010 and 2011-2012 National Health and Nutrition Examination Survey data. http://www.cdc.gov /nchs/nhanes.htm. Accessibility verified September 15, 2014. 5. Bosch FX, de Sanjosé S. The epidemiology of human papillomavirus infection and cervical cancer. Dis Markers. 2007;23(4):213-227. 6. Sopori M. Effects of cigarette smoke on the immune system. Nat Rev Immunol. 2002;2(5):372-377.

COMMENT & RESPONSE

Antipsychotic Medications for Schizophrenia To the Editor Dr McEvoy and colleagues1 reported a clinical trial comparing old- and new-generation depot antipsychotic medications and found no significant difference in efficacy failure for paliperidone palmitate compared with haloperidol decanoate. However, they neglected to discuss that only approximately one-third of the randomized patients completed the trial, which limits the generalizability of their findings. Some of the criteria to assess efficacy failure, such as the statement that “oral antipsychotic medication could not be discontinued within 8 weeks after starting the longacting injectable,” may not directly reflect “inadequate con-

jama.com

JAMA October 8, 2014 Volume 312, Number 14

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Purdue University User on 05/18/2015

1467

Letters

trol of the psychopathology.” Their relapse rates (32.4% for haloperidol decanoate and 33.8% for paliperidone palmitate) are considerably higher than those of recently published phase 3 trials and meta-analyses,2-4 which may in part be explained by the patient population they chose to study. All measures of extrapyramidal adverse events point to a disadvantage with haloperidol decanoate, although some did not reach statistical significance due to low power. I would also be interested in a comparison of injection site complications, given that haloperidol depot is an oily preparation and paliperidone long-acting injectable is an aqueous solution. The comparison of their data with a clinical trial that analyzed relapse rates in patients taking oral haloperidol and risperidone 5 is confusing. The study by Csernansky et al5 did not use haloperidol decanoate, which is misstated in the article. Relapse rates between the 2 trials are not similar; they were lower with risperidone use than with haloperidol use (34% vs 60%, respectively) in the study by Csernansky et al.5 The trial by McEvoy et al1 underscores both the methodological challenges of studying the long-term treatment of patients with schizophrenia as well as the fact that there is still considerable room for improvement in managing treatment. W. Wolfgang Fleischhacker, MD Author Affiliation: Department of Psychiatry and Psychotherapy, Medical University Innsbruck, Innsbruck, Austria. Corresponding Author: W. Wolfgang Fleischhacker, MD, Medical University Innsbruck, Department of Psychiatry and Psychotherapy, Anichstrasse 35, 6020 Innsbruck, Austria ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving research grants from Otsuka, Pfizer, Janssen, and Reckitt-Benckiser; receiving consulting honoraria from Lundbeck, Roche, Bristol-Myers Squibb, Otsuka, Richter, Janssen, Pfizer, MedAvante, Sunovion, Takeda, Endo, Targacept and Vanda; receiving speaker honoraria from Lundbeck, Janssen, Otsuka, Roche, and Takeda; and holding stock in MedAvante. 1. McEvoy JP, Byerly M, Hamer RM, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA. 2014;311(19):1978-1987. 2. Fleischhacker WW, Gopal S, Lane R, et al. A randomized trial of paliperidone palmitate and risperidone long-acting injectable in schizophrenia. Int J Neuropsychopharmacol. 2012;15(1):107-118. 3. Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012;73 (5):617-624. 4. Leucht S, Tardy M, Komossa K, et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet. 2012;379(9831):2063-2071. 5. Csernansky JG, Mahmoud R, Brenner R; Risperidone-USA-79 Study Group. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med. 2002;346(1):16-22.

To the Editor Pharmacological treatment of schizophrenia in the real world is frequently challenging. Dr McEvoy and colleagues1 compared paliperidone palmitate with haloperidol decanoate in patients with schizophrenia deemed at high risk of destabilization. 1468

McEvoy et al1 found that paliperidone palmitate was not significantly different from haloperidol decanoate in the rate of efficacy failure (33.8% vs 32.4%, respectively), with some differences in tolerability. Several issues need to be taken into account in interpreting their clinically relevant findings. First, the dose of paliperidone palmitate (mean monthly dose, 129-169 mg) was higher than that of haloperidol decanoate (mean monthly dose, 67-83 mg). It has been suggested that 100 mg equivalent paliperidone (or paliperidone palmitate 156 mg) is equivalent to 50 mg of risperidone long-acting injectable, which is equipotent to 150 mg of haloperidol decanoate given every 4 weeks or a daily dose of 20 mg of olanzapine, 10 mg of haloperidol, or 600 mg of chlorpromazine.2 The comparable dose of typical vs atypical agents is frequently an important consideration and typical antipsychotic agents have usually been tested at higher doses than atypical agents.3 Although the dose-response relationship of antipsychotic medications is not necessarily linear, the relative dose of palperidone palmitate was about 2 times higher in this study. Second, although the study targeted patients who were at risk of efficacy failure and likely to benefit from long-acting antipsychotic medications, the mean scores at baseline were 73 and 70 on the Positive and Negative Syndrome Scale (PANSS) and 4.0 and 3.8 on the Clinical Global Impressions Severity scale in patients treated with paliperidone palmitate and haloperidol decanoate, respectively, indicating moderate illness severity. For reference, the PANSS score was higher at approximately 80 in a prior study.4 Third, information about medications used before entering the study was unknown. For instance, it could be complicated to compare patients previously treated with clozapine, a medication reserved for treatment-resistant schizophrenia, with patients who were antipsychotic-free for some time at baseline. Furthermore, prior use of oral paliperidone or haloperidol may theoretically favor patients in that group, at least in terms of tolerability, generating a survivorship bias. Even though the inability to discontinue oral antipsychotic medications within 8 weeks represented treatment failure, whether other adjunctive psychotropic medications were allowed was unclear. This is important because some augmentation strategies (with mood stabilizers for instance) might occasionally be effective in the management of challenging cases in patients with schizophrenia.5 Takefumi Suzuki, MD, PhD Author Affiliation: Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan. Corresponding Author: Takefumi Suzuki, MD, PhD, Department of Neuropsychiatry, Keio University School of Medicine, Shinanomachi 35, Shinjuku-ku, Tokyo 160-8582, Japan ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and reported receiving manuscript or speaker’s fees from Astellas, Dainippon Sumitomo, Eli Lilly, Elsevier Japan, Janssen, Meiji Seika, Novartis, Otsuka, and Weily Japan.

JAMA October 8, 2014 Volume 312, Number 14

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Purdue University User on 05/18/2015

jama.com

Letters

1. McEvoy JP, Byerly M, Hamer RM, et al. Effectiveness of paliperidone palmitate vs haloperidol decanoate for maintenance treatment of schizophrenia: a randomized clinical trial. JAMA. 2014;311(19):1978-1987. 2. Gardner DM, Murphy AL, O’Donnell H, Centorrino F, Baldessarini RJ. International consensus study of antipsychotic dosing. Am J Psychiatry. 2010; 167(6):686-693. 3. Geddes J, Freemantle N, Harrison P, Bebbington P. Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ. 2000;321(7273):1371-1376. 4. Rosenheck RA, Krystal JH, Lew R, et al; CSP555 Research Group. Long-acting risperidone and oral antipsychotics in unstable schizophrenia. N Engl J Med. 2011;364(9):842-851. 5. Suzuki T, Uchida H, Takeuchi H, et al. Augmentation of atypical antipsychotics with valproic acid: an open-label study for most difficult patients with schizophrenia. Hum Psychopharmacol. 2009;24(8):628-638.

In Reply Dr Fleischhacker suggests that high dropout rates limit the generalizability of our findings. This effectiveness study included participants that clinicians selected as candidates for long-acting injectable antipsychotic medications (ie, they were expected to benefit from depot treatment because they were at risk of poor outcomes due to a history of poor adherence or substance abuse). Thus the findings should be generalizable to typical patients for whom treatment with long-acting injectable antipsychotics is considered. Fleischhacker speculates that some differences in extrapyramidal symptom ratings did not reach statistical significance due to low power. With a large enough sample, all such differences become statistically significant; however, we agree that small differences in adverse events may be clinically important for individuals. Any results that did not meet statistical significance must be considered relative to clinically and statistically significant differences (eg, the mean 2 kg weight gain with paliperidone palmitate vs the 1 kg weight loss with haloperidol decanoate). We plan to investigate possible differences in injection site pain, but it is already clear that any effect favoring one of the drugs did not result in an overall effectiveness advantage. Fleischhacker correctly points out that oral haloperidol rather than oral haloperidol decanoate was the comparator in the haloperidol-risperidone trial mentioned in our article. A correction accompanies this letter. Dr Suzuki suggests that the mean doses of paliperidone used for maintenance treatment in our trial may have been too high. His analysis, which initiated from a study about relative doses of antipsychotics that did not include paliperidone palmitate, suggests that the mean maintenance dose of paliperidone palmitate in our study should have been approximately 50 mg per month. We are aware of no evidence to support this as a typical maintenance dose, which is less than half the recommended maintenance dose found in the paliperidone palmitate package insert. Because our study was not restricted to people with an acute exacerbation, it is not surprising that the participants were on average moderately ill. We used randomization to address measured and unmeasured factors, including baseline medications, that might theoretically advantage one group. Adjunctive psychotropics, excluding the sustained need for antipsychotic medications after 8 weeks,

were allowed throughout the trial, and we found similar rates of starting new medications in the 2 groups for the following indications: anxiety (16.6% for paliperidone vs 15.2% for haloperidol); depression (19.3% for paliperidone vs 17. 2% for haloperidol); agitation, exc itement, or mania (8.3% for paliperidone vs 4.8% for haloperidol); aggression or violence (1.4% for paliperidone vs 0.7% for haloperidol); and insomnia (22.1% for paliperidone vs 24.8% for haloperidol). The study found that paliperidone palmitate and haloperidol decanoate were similar in avoiding efficacy failure. We could not rule out a clinically meaningful difference favoring one of the drugs, but did find significant differences in akathisia favoring paliperidone palmitate and in weight and prolactin levels favoring haloperidol decanoate. T. Scott Stroup, MD, MPH Joseph P. McEvoy, MD Robert M. Hamer, PhD Author Affiliations: Columbia University College of Physicians and Surgeons, New York, New York (Stroup); Georgia Regents University, Augusta, Georgia (McEvoy); University of North Carolina, Chapel Hill (Hamer). Corresponding Author: T. Scott Stroup, MD, MPH, Department of Psychiatry, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, 1051 Riverside Dr, New York, NY 10032 ([email protected] .columbia.edu). Conflict of Interest Disclosures:The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Stroup reported receiving a grant from the National Institute of Mental Health; and participating in CME activities funded by Genentech. Dr McEvoy reported receiving grants from the National Institute of Mental Health, Ameritox, Auspex, GlaxoSmithKline, Otsuka, Merck, Psychogenics, Roche/Genentech, and Sunovion; receiving consulting fees from Ameritox, Alkermes, Envivo, Jazz, Otsuka, and Merck; receiving honoraria for promotional programs from Lilly, Merck, and Sunovion; receiving fees for CME programs from Roche/Genentech; and serving as an expert witness for Pfizer. Dr Hamer reported receiving a grant from the National Institute of Mental Health; and receiving personal fees for serving on data and safety monitoring boards for Novartis, Roche, Protein Sciences, Alkermes, Allergan, Abbot-Abvie, Bioline, and Columbia University, for clinical trial consulting from Lilly, AstraZeneca, Duke University, Cenerx, and National University of Singapore/Duke, for serving as an expert witness from Winston and Strawn, Sheppard Mullin, Rakoczy Molino Mazzochi Siwik, and Goldberg Segalla, for working on a grant review panel from the US Department of Veterans Affairs, and for serving on a mock advisory panel from Titan and Neurogex.

Use of Hemodynamic Algorithm After Gastrointestinal Surgery To the Editor The pragmatic, multicenter, randomized, observer-blinded Optimisation of Cardiovascular Management to Improve Surgical Outcome (OPTIMISE) trial1 found that a cardiac output–guided hemodynamic treatment algorithm did not result in a statistically significant improvement in outcomes compared with usual care in high-risk patients undergoing major gastrointestinal surgery. An updated meta-analysis on perioperative goal-directed therapy, which was part of the same article, came to the opposite conclusion. We believe the reason for this diversity is a misinterpretation of pragmatic. The main determinants of hemodynamic goal-directed therapy are fluids and pharmacological

jama.com

JAMA October 8, 2014 Volume 312, Number 14

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://jama.jamanetwork.com/ by a Purdue University User on 05/18/2015

1469

Antipsychotic medications for schizophrenia--reply.

Antipsychotic medications for schizophrenia--reply. - PDF Download Free
74KB Sizes 0 Downloads 7 Views