Forget the myths and help your psychiatric patients quit smoking

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The National Ambulatory Medical Care Survey^1,2 (NAMCS) indicates that less than 1 out of 4 (23%) psychiatrists provide smoking cessation counseling to their patients, and even fewer prescribe medications.

What gives? How is it that so many psychiatrists endorse having recently helped a patient quit smoking when the data from large-scale surveys^1,2 indicate they do not?

From the “glass is half-full” perspective, the discrepancy might indicate that psychiatrists finally have bought into the message put forth 20 years ago when the American Psychiatric Association first published its clinical practice guidelines for treating nicotine dependence.³ Because the figures I cited from NAMCS reflect data from 2006 to 2010, it is possible that in the last 5 years more psychiatrists have started to help their patients quit smoking. Such an hypothesis is further supported by the increasing number of research papers on smoking cessation in individuals with mental illness published over the past 8 years—a period that coincides with the release of the second edition of the Treating tobacco use and dependence clinical practice guideline from the U.S. Agency for Healthcare Research and Quality, which highlighted the need for more research in this population of smokers.⁴

Regardless of the reason, the fact that my informal surveys indicate a likely uptick in activity among psychiatrists to help their patients quit smoking is welcome news. With nearly 1 out of 2 cigarettes sold in the United States being smoked by individuals with psychiatric and substance use disorders,⁵ psychiatrists and other mental health professionals play a vital role in addressing this epidemic. That our patients smoke at rates 2- to 4-times that of the general population and die decades earlier than their non-smoking, non-mentally ill counterparts⁶ are compelling reasons urging us to end our complacency and help our patients quit smoking.

EAGLES trial results help debunk the latest myth about smoking cessation

In an article that I wrote for Current Psychiatry 11 years ago,⁷ I attempted to debunk 3 myths that might have influenced some psychiatrists’ approach and motivation to intervene in tobacco dependence. Since that article appeared, a fourth myth has been promulgated—that the non-nicotine smoking cessation medications, bupropion and varenicline, are unsafe to use in patients with stable psychiatric disorders and cause serious neuropsychiatric adverse events (AEs) including suicide. Indeed, that is one implication of the “black-box” warning both of these medications received in July 2009, which caution that, “the risks of Zyban^®/Chantix^® should be weighed against the benefits of [their] use.”^8,9 For an illness that causes 480,000 deaths each year in the United States,¹⁰ and nearly 6 million across the globe,¹¹ tobacco treatment specialists find themselves in a quandary when 2 of the only 3 approved medications available—nicotine replacement therapy being the third—carry such a stern warning.

In addition to applying the “black-box” warning, the FDA issued a post-marketing requirement to the manufacturers of bupropion and varenicline to conduct a large randomized controlled trial—Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES)—the top-line results of which were published in The Lancet this spring.¹²

EAGLES is the largest, placebo-controlled trial of first-line smoking cessation medications conducted to date with more than 8,000 participants randomly assigned to 1 of 2 cohorts: those with histories of or current DSM-IV-TR¹³ disorders (n = 4,166), including primary mood (71%), anxiety (19%), psychotic (9%), and borderline personality (<1%) disorders, and 4,028 smokers without a psychiatric disorder (Table^14-17).

Key results of the EAGLES trial

The researchers found no significant increase in serious neuropsychiatric AEs—a composite measure assessing depression, anxiety, suicidality, and 13 other symptom clusters—attributable to varenicline or bupropion compared with placebo or the nicotine patch in smokers with or without psychiatric disorders. The study did detect a significant difference—approximately 4% (2% in non-psychiatric cohort vs 6% in psychiatric cohort)—in the rate of serious neuropsychiatric AEs regardless of treatment condition. In both cohorts, varenicline was more effective than bupropion, which had similar efficacy to the nicotine patch; all interventions were superior to placebo. Importantly, all 3 medications significantly improved quit rates in smokers with and without psychiatric disorders. Although the efficacy of medications in smokers with or without psychiatric disorders was similar in terms of odds ratios, overall, those with psychiatric disorders had 20% to 30% lower quit rates compared with non-psychiatrically ill smokers.

The EAGLES study results, when viewed in the context of findings from other clinical trials and large-scale observational studies, provide further evidence that smokers with stable mental illness can use bupropion and varenicline safely. It also demonstrates that moderate to severe neuropsychiatric AEs occur during a smoking cessation attempt regardless of the medication used, therefore, monitoring smokers—especially those with psychiatric disorders—is important, a role that psychiatrists are uniquely poised to play.

That all 3 smoking cessation medications are effective in patients with mood, anxiety, and psychotic disorders is good news for our patients. Combined with the EAGLES safety findings, there is no better time to intervene in tobacco dependence

References

1. Rogers E, Sherman S. Tobacco use screening and treatment by outpatient psychiatrists before and after release of the American Psychiatric Association treatment guidelines for nicotine dependence. Am J Public Health. 2014;104(1):90-95.

2. Himelhoch S, Daumit G. To whom do psychiatrists offer smoking-cessation counseling? Am J Psychiatry. 2003;160(12):2228-2230.
3. Practice guideline for the treatment of patients with nicotine dependence. American Psychiatric Association. Am J Psychiatry. 1996;53;153(suppl 10):1-31.
4. U.S. Department of Health and Human Services. Treating tobacco use and dependence: 2008 update. Clinical practice guideline. http://www.ahrq.gov/sites/default/files/wysiwyg/professionals/clinicians-providers/guidelines-recommendations/tobacco/clinicians/update/treating_tobacco_use08.pdf. Published May 2008. Accessed September 12, 2016.
5. Grant BF, Hasin DS, Chou SP, et al. Nicotine dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry. 2004;61(11):1107-1115.
6. Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006;3(2):A42.
7. Anthenelli RM. How—and why—to help psychiatric patients stop smoking. Current Psychiatry. 2005;4(1):77-87.
8. Zyban [package insert]. Research Triangle Park, NC; GlaxoSmithKline; 2016.
9. Chantix [package insert]. New York, NY: Pfizer; 2016.
10. U.S. Department of Health and Human Services. The health consequences of smoking – 50 years of progress: a report of the surgeon general, 2014. Rockville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2014.
11. World Health Organization. WHO report on the global tobacco epidemic, 2011: warning about the dangers of tobacco. http://www.who.int/tobacco/global_report/2011/en/index.html. Published 2011. Accessed December 1, 2015.
12. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomized, placebo-controlled clinical trial. Lancet. 2016;18;387(10037):2507-2520.
13. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
14. First MB, Spitzer RL, Gibbon M, et al. Structured clinical interview for DSM-IV-TR axis I disorders, research version, patient edition (SCID-I/P). New York, NY: Biometrics Research, New York State Psychiatric Institute; 2002.
15. First M, Gibbon M, Spitzer RL, et al. Structured clinical interview for DSM-IV axis II personality disorders (SCID-II). Washington, DC: American Psychiatric Press, Inc.; 1997.
16. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361-370.
17. Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2001;168(12):1266-1277.

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Dr. Anthenelli is Professor and Executive Vice Chair, Department of Psychiatry, and Director, Pacific Treatment and Research Center, University of California, San Diego, Health Sciences, San Diego, California.

Disclosure

Dr. Anthenelli has received grant support from Pfizer and Alkermes, and he provides consulting and advisory board services to Pfizer, Arena Pharmaceuticals, and Cerecor.

Dr. Anthenelli’s writing of this editorial was supported, in part, by National Institute on Alcohol Abuse and Alcoholism grant numbers U01 AA013641 and R01 AA019720; and National Institute on Drug Abuse/Veterans Cooperative Studies 1031 and 1032.

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Current Psychiatry

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Robert M. Anthenelli, MD

Author(s)

Robert M. Anthenelli, MD

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Dr. Anthenelli is Professor and Executive Vice Chair, Department of Psychiatry, and Director, Pacific Treatment and Research Center, University of California, San Diego, Health Sciences, San Diego, California.

Disclosure

Dr. Anthenelli has received grant support from Pfizer and Alkermes, and he provides consulting and advisory board services to Pfizer, Arena Pharmaceuticals, and Cerecor.

Dr. Anthenelli’s writing of this editorial was supported, in part, by National Institute on Alcohol Abuse and Alcoholism grant numbers U01 AA013641 and R01 AA019720; and National Institute on Drug Abuse/Veterans Cooperative Studies 1031 and 1032.

Author and Disclosure Information

Dr. Anthenelli is Professor and Executive Vice Chair, Department of Psychiatry, and Director, Pacific Treatment and Research Center, University of California, San Diego, Health Sciences, San Diego, California.

Disclosure

Dr. Anthenelli has received grant support from Pfizer and Alkermes, and he provides consulting and advisory board services to Pfizer, Arena Pharmaceuticals, and Cerecor.

Dr. Anthenelli’s writing of this editorial was supported, in part, by National Institute on Alcohol Abuse and Alcoholism grant numbers U01 AA013641 and R01 AA019720; and National Institute on Drug Abuse/Veterans Cooperative Studies 1031 and 1032.

Article PDF

CP01510023.PDF

Article PDF

CP01510023.PDF

The National Ambulatory Medical Care Survey^1,2 (NAMCS) indicates that less than 1 out of 4 (23%) psychiatrists provide smoking cessation counseling to their patients, and even fewer prescribe medications.

What gives? How is it that so many psychiatrists endorse having recently helped a patient quit smoking when the data from large-scale surveys^1,2 indicate they do not?

From the “glass is half-full” perspective, the discrepancy might indicate that psychiatrists finally have bought into the message put forth 20 years ago when the American Psychiatric Association first published its clinical practice guidelines for treating nicotine dependence.³ Because the figures I cited from NAMCS reflect data from 2006 to 2010, it is possible that in the last 5 years more psychiatrists have started to help their patients quit smoking. Such an hypothesis is further supported by the increasing number of research papers on smoking cessation in individuals with mental illness published over the past 8 years—a period that coincides with the release of the second edition of the Treating tobacco use and dependence clinical practice guideline from the U.S. Agency for Healthcare Research and Quality, which highlighted the need for more research in this population of smokers.⁴

Regardless of the reason, the fact that my informal surveys indicate a likely uptick in activity among psychiatrists to help their patients quit smoking is welcome news. With nearly 1 out of 2 cigarettes sold in the United States being smoked by individuals with psychiatric and substance use disorders,⁵ psychiatrists and other mental health professionals play a vital role in addressing this epidemic. That our patients smoke at rates 2- to 4-times that of the general population and die decades earlier than their non-smoking, non-mentally ill counterparts⁶ are compelling reasons urging us to end our complacency and help our patients quit smoking.

EAGLES trial results help debunk the latest myth about smoking cessation

In an article that I wrote for Current Psychiatry 11 years ago,⁷ I attempted to debunk 3 myths that might have influenced some psychiatrists’ approach and motivation to intervene in tobacco dependence. Since that article appeared, a fourth myth has been promulgated—that the non-nicotine smoking cessation medications, bupropion and varenicline, are unsafe to use in patients with stable psychiatric disorders and cause serious neuropsychiatric adverse events (AEs) including suicide. Indeed, that is one implication of the “black-box” warning both of these medications received in July 2009, which caution that, “the risks of Zyban^®/Chantix^® should be weighed against the benefits of [their] use.”^8,9 For an illness that causes 480,000 deaths each year in the United States,¹⁰ and nearly 6 million across the globe,¹¹ tobacco treatment specialists find themselves in a quandary when 2 of the only 3 approved medications available—nicotine replacement therapy being the third—carry such a stern warning.

In addition to applying the “black-box” warning, the FDA issued a post-marketing requirement to the manufacturers of bupropion and varenicline to conduct a large randomized controlled trial—Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES)—the top-line results of which were published in The Lancet this spring.¹²

EAGLES is the largest, placebo-controlled trial of first-line smoking cessation medications conducted to date with more than 8,000 participants randomly assigned to 1 of 2 cohorts: those with histories of or current DSM-IV-TR¹³ disorders (n = 4,166), including primary mood (71%), anxiety (19%), psychotic (9%), and borderline personality (<1%) disorders, and 4,028 smokers without a psychiatric disorder (Table^14-17).

Key results of the EAGLES trial

The researchers found no significant increase in serious neuropsychiatric AEs—a composite measure assessing depression, anxiety, suicidality, and 13 other symptom clusters—attributable to varenicline or bupropion compared with placebo or the nicotine patch in smokers with or without psychiatric disorders. The study did detect a significant difference—approximately 4% (2% in non-psychiatric cohort vs 6% in psychiatric cohort)—in the rate of serious neuropsychiatric AEs regardless of treatment condition. In both cohorts, varenicline was more effective than bupropion, which had similar efficacy to the nicotine patch; all interventions were superior to placebo. Importantly, all 3 medications significantly improved quit rates in smokers with and without psychiatric disorders. Although the efficacy of medications in smokers with or without psychiatric disorders was similar in terms of odds ratios, overall, those with psychiatric disorders had 20% to 30% lower quit rates compared with non-psychiatrically ill smokers.

The EAGLES study results, when viewed in the context of findings from other clinical trials and large-scale observational studies, provide further evidence that smokers with stable mental illness can use bupropion and varenicline safely. It also demonstrates that moderate to severe neuropsychiatric AEs occur during a smoking cessation attempt regardless of the medication used, therefore, monitoring smokers—especially those with psychiatric disorders—is important, a role that psychiatrists are uniquely poised to play.

That all 3 smoking cessation medications are effective in patients with mood, anxiety, and psychotic disorders is good news for our patients. Combined with the EAGLES safety findings, there is no better time to intervene in tobacco dependence

The National Ambulatory Medical Care Survey^1,2 (NAMCS) indicates that less than 1 out of 4 (23%) psychiatrists provide smoking cessation counseling to their patients, and even fewer prescribe medications.

What gives? How is it that so many psychiatrists endorse having recently helped a patient quit smoking when the data from large-scale surveys^1,2 indicate they do not?

From the “glass is half-full” perspective, the discrepancy might indicate that psychiatrists finally have bought into the message put forth 20 years ago when the American Psychiatric Association first published its clinical practice guidelines for treating nicotine dependence.³ Because the figures I cited from NAMCS reflect data from 2006 to 2010, it is possible that in the last 5 years more psychiatrists have started to help their patients quit smoking. Such an hypothesis is further supported by the increasing number of research papers on smoking cessation in individuals with mental illness published over the past 8 years—a period that coincides with the release of the second edition of the Treating tobacco use and dependence clinical practice guideline from the U.S. Agency for Healthcare Research and Quality, which highlighted the need for more research in this population of smokers.⁴

Regardless of the reason, the fact that my informal surveys indicate a likely uptick in activity among psychiatrists to help their patients quit smoking is welcome news. With nearly 1 out of 2 cigarettes sold in the United States being smoked by individuals with psychiatric and substance use disorders,⁵ psychiatrists and other mental health professionals play a vital role in addressing this epidemic. That our patients smoke at rates 2- to 4-times that of the general population and die decades earlier than their non-smoking, non-mentally ill counterparts⁶ are compelling reasons urging us to end our complacency and help our patients quit smoking.

EAGLES trial results help debunk the latest myth about smoking cessation

In an article that I wrote for Current Psychiatry 11 years ago,⁷ I attempted to debunk 3 myths that might have influenced some psychiatrists’ approach and motivation to intervene in tobacco dependence. Since that article appeared, a fourth myth has been promulgated—that the non-nicotine smoking cessation medications, bupropion and varenicline, are unsafe to use in patients with stable psychiatric disorders and cause serious neuropsychiatric adverse events (AEs) including suicide. Indeed, that is one implication of the “black-box” warning both of these medications received in July 2009, which caution that, “the risks of Zyban^®/Chantix^® should be weighed against the benefits of [their] use.”^8,9 For an illness that causes 480,000 deaths each year in the United States,¹⁰ and nearly 6 million across the globe,¹¹ tobacco treatment specialists find themselves in a quandary when 2 of the only 3 approved medications available—nicotine replacement therapy being the third—carry such a stern warning.

In addition to applying the “black-box” warning, the FDA issued a post-marketing requirement to the manufacturers of bupropion and varenicline to conduct a large randomized controlled trial—Evaluating Adverse Events in a Global Smoking Cessation Study (EAGLES)—the top-line results of which were published in The Lancet this spring.¹²

EAGLES is the largest, placebo-controlled trial of first-line smoking cessation medications conducted to date with more than 8,000 participants randomly assigned to 1 of 2 cohorts: those with histories of or current DSM-IV-TR¹³ disorders (n = 4,166), including primary mood (71%), anxiety (19%), psychotic (9%), and borderline personality (<1%) disorders, and 4,028 smokers without a psychiatric disorder (Table^14-17).

Key results of the EAGLES trial

The researchers found no significant increase in serious neuropsychiatric AEs—a composite measure assessing depression, anxiety, suicidality, and 13 other symptom clusters—attributable to varenicline or bupropion compared with placebo or the nicotine patch in smokers with or without psychiatric disorders. The study did detect a significant difference—approximately 4% (2% in non-psychiatric cohort vs 6% in psychiatric cohort)—in the rate of serious neuropsychiatric AEs regardless of treatment condition. In both cohorts, varenicline was more effective than bupropion, which had similar efficacy to the nicotine patch; all interventions were superior to placebo. Importantly, all 3 medications significantly improved quit rates in smokers with and without psychiatric disorders. Although the efficacy of medications in smokers with or without psychiatric disorders was similar in terms of odds ratios, overall, those with psychiatric disorders had 20% to 30% lower quit rates compared with non-psychiatrically ill smokers.

The EAGLES study results, when viewed in the context of findings from other clinical trials and large-scale observational studies, provide further evidence that smokers with stable mental illness can use bupropion and varenicline safely. It also demonstrates that moderate to severe neuropsychiatric AEs occur during a smoking cessation attempt regardless of the medication used, therefore, monitoring smokers—especially those with psychiatric disorders—is important, a role that psychiatrists are uniquely poised to play.

That all 3 smoking cessation medications are effective in patients with mood, anxiety, and psychotic disorders is good news for our patients. Combined with the EAGLES safety findings, there is no better time to intervene in tobacco dependence

References

1. Rogers E, Sherman S. Tobacco use screening and treatment by outpatient psychiatrists before and after release of the American Psychiatric Association treatment guidelines for nicotine dependence. Am J Public Health. 2014;104(1):90-95.

2. Himelhoch S, Daumit G. To whom do psychiatrists offer smoking-cessation counseling? Am J Psychiatry. 2003;160(12):2228-2230.
3. Practice guideline for the treatment of patients with nicotine dependence. American Psychiatric Association. Am J Psychiatry. 1996;53;153(suppl 10):1-31.
4. U.S. Department of Health and Human Services. Treating tobacco use and dependence: 2008 update. Clinical practice guideline. http://www.ahrq.gov/sites/default/files/wysiwyg/professionals/clinicians-providers/guidelines-recommendations/tobacco/clinicians/update/treating_tobacco_use08.pdf. Published May 2008. Accessed September 12, 2016.
5. Grant BF, Hasin DS, Chou SP, et al. Nicotine dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry. 2004;61(11):1107-1115.
6. Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006;3(2):A42.
7. Anthenelli RM. How—and why—to help psychiatric patients stop smoking. Current Psychiatry. 2005;4(1):77-87.
8. Zyban [package insert]. Research Triangle Park, NC; GlaxoSmithKline; 2016.
9. Chantix [package insert]. New York, NY: Pfizer; 2016.
10. U.S. Department of Health and Human Services. The health consequences of smoking – 50 years of progress: a report of the surgeon general, 2014. Rockville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2014.
11. World Health Organization. WHO report on the global tobacco epidemic, 2011: warning about the dangers of tobacco. http://www.who.int/tobacco/global_report/2011/en/index.html. Published 2011. Accessed December 1, 2015.
12. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomized, placebo-controlled clinical trial. Lancet. 2016;18;387(10037):2507-2520.
13. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
14. First MB, Spitzer RL, Gibbon M, et al. Structured clinical interview for DSM-IV-TR axis I disorders, research version, patient edition (SCID-I/P). New York, NY: Biometrics Research, New York State Psychiatric Institute; 2002.
15. First M, Gibbon M, Spitzer RL, et al. Structured clinical interview for DSM-IV axis II personality disorders (SCID-II). Washington, DC: American Psychiatric Press, Inc.; 1997.
16. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361-370.
17. Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2001;168(12):1266-1277.

References

1. Rogers E, Sherman S. Tobacco use screening and treatment by outpatient psychiatrists before and after release of the American Psychiatric Association treatment guidelines for nicotine dependence. Am J Public Health. 2014;104(1):90-95.

2. Himelhoch S, Daumit G. To whom do psychiatrists offer smoking-cessation counseling? Am J Psychiatry. 2003;160(12):2228-2230.
3. Practice guideline for the treatment of patients with nicotine dependence. American Psychiatric Association. Am J Psychiatry. 1996;53;153(suppl 10):1-31.
4. U.S. Department of Health and Human Services. Treating tobacco use and dependence: 2008 update. Clinical practice guideline. http://www.ahrq.gov/sites/default/files/wysiwyg/professionals/clinicians-providers/guidelines-recommendations/tobacco/clinicians/update/treating_tobacco_use08.pdf. Published May 2008. Accessed September 12, 2016.
5. Grant BF, Hasin DS, Chou SP, et al. Nicotine dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry. 2004;61(11):1107-1115.
6. Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006;3(2):A42.
7. Anthenelli RM. How—and why—to help psychiatric patients stop smoking. Current Psychiatry. 2005;4(1):77-87.
8. Zyban [package insert]. Research Triangle Park, NC; GlaxoSmithKline; 2016.
9. Chantix [package insert]. New York, NY: Pfizer; 2016.
10. U.S. Department of Health and Human Services. The health consequences of smoking – 50 years of progress: a report of the surgeon general, 2014. Rockville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2014.
11. World Health Organization. WHO report on the global tobacco epidemic, 2011: warning about the dangers of tobacco. http://www.who.int/tobacco/global_report/2011/en/index.html. Published 2011. Accessed December 1, 2015.
12. Anthenelli RM, Benowitz NL, West R, et al. Neuropsychiatric safety and efficacy of varenicline, bupropion, and nicotine patch in smokers with and without psychiatric disorders (EAGLES): a double-blind, randomized, placebo-controlled clinical trial. Lancet. 2016;18;387(10037):2507-2520.
13. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000.
14. First MB, Spitzer RL, Gibbon M, et al. Structured clinical interview for DSM-IV-TR axis I disorders, research version, patient edition (SCID-I/P). New York, NY: Biometrics Research, New York State Psychiatric Institute; 2002.
15. First M, Gibbon M, Spitzer RL, et al. Structured clinical interview for DSM-IV axis II personality disorders (SCID-II). Washington, DC: American Psychiatric Press, Inc.; 1997.
16. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand. 1983;67(6):361-370.
17. Posner K, Brown GK, Stanley B, et al. The Columbia-Suicide Severity Rating Scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2001;168(12):1266-1277.