International Journal of Psychiatry in Clinical Practice, 2006; 10(Suppl 3): 25 31
ORIGINAL ARTICLE
Closing the antidepressant efficacy gap between clinical trials and real patient populations
Int J Psych Clin Pract Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/21/14 For personal use only.
ALAN G. WADE CPS Research, Todd Campus, West of Scotland Science Park, Glasgow, UK
Abstract Overall, patient outcomes in the primary care of depression are seldom as good as those achieved in clinical trials the ‘‘efficacy gap’’. Many factors contribute to this, including poor patient compliance, poor family and social support and negative media reporting of antidepressants. Indeed, negative media reporting has had far more impact on physicians’ prescribing of antidepressants than have regulatory agencies, partly as a result of changing public attitudes. Negative media reports linking SSRIs to increased child suicide rates have also resulted in a decline in the prescribing of SSRIs to this age group, but with no concomitant increase in the prescribing of fluoxetine, the only antidepressant recommended for the treatment of children. There are also inadequacies in the guidelines available to primary care givers that might contribute to the efficacy gap. Guidelines can be too specific for clinical practice especially where depression coexists with anxiety disorders and too passive, resulting in delayed or inadequate intervention. Evidence suggests that many physicians prefer to be more proactive. In the recent AHEAD survey, physicians identified faster resolution of symptoms as the property most desirable for improving antidepressant therapy. There is recent evidence that structured long-term therapy and easilyimplemented measurement-based care procedures can improve remission rates and help bridge the efficacy gap. If these can be allied with greater public/media understanding of depression and its treatment, along with improved guidelines, then significant progress can be anticipated in the management of mood disorders.
Key Words: Depression, SSRIs, guidelines, media
Introduction The long-term care interests of patients with affective disorders are not served by an approach of just treating the symptoms. Patients need to be returned to health: ‘‘a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity’’ (as defined by the World Health Organization [1]). For patients with chronic depression, this is best achieved with a long-term care plan involving maintenance of treatment to reduce the likelihood of relapse. Failure to apply maintenance treatment is often associated with poor patient outcome. For primary care givers, however, longterm treatment for depression represents a major challenge. Consequently, it is unsurprising that patient outcomes among ‘‘real populations’’ in the primary care setting tend to be inferior to those obtained by the cohorts of controlled clinical trials of depression therapies. This article discusses some of the barriers to effective long-term therapy in primary care that contribute to this ‘‘efficacy gap’’, and
considers evidence that structured care plans can help bridge this gap. Efficacy studies versus clinical practice: Bridging the gap At present, a discrepancy exists between the proven efficacy of antidepressants in clinical trials and their effectiveness in the general patient population. The reasons for this (Figure 1) are implicit in the challenges faced by physicians, which include inadequate guidelines (which may be too specific or too general), poor patient compliance and understanding, and negative media attitudes towards depression. Physicians can also contribute to this efficacy gap by poor clinical and consultation techniques, devoting insufficient time to the patient and poor knowledge of the illness and/or the patient. Physicians have a responsibility to make the best treatment choice, based on the available evidence and guidelines can assist with this [2,3].
Correspondence: Alan G. Wade, CPS Research, Todd Campus, West of Scotland Science Park, Glasgow G20 0XA, UK. Tel: /44 141 9467888. E-mail: [email protected]
ISSN 1365-1501 print/ISSN 1471-1788 online # 2006 Taylor & Francis DOI: 10.1080/13651500600934982
Int J Psych Clin Pract Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/21/14 For personal use only.
26
A. G. Wade
Figure 1. The efficacy/effectiveness gap.
The efficacy of treatment for depression in randomized controlled trials has been demonstrated many times. Pooled analyses illustrate overall response and remission rates up to 65 and 58%, respectively, for SSRIs (selective serotonin reuptake inhibitors) such as escitalopram (now referred to as an ASRI allosteric serotonin reuptake inhibitor, due to its unique mode of action [4]), with improvement in symptoms (]/20% reduction from baseline in MADRS score) after just 1 week in one-third of patients [5,6]. There is further evidence from another metaanalysis, which included data from seven randomized controlled trials of SSRIs (fluoxetine, sertraline and paroxetine) in patients with moderate-to-severe major depressive disorder (21-item HAM-D minimum score 18 20), Here, the overall remission rate (5/7 on first 17 items of HAM-D at end of trial) was found to be 47% in studies lasting from 6 to 16 weeks [7]. Combined psychotherapy and antidepressant treatment has proven particularly effective in trials. In a systematic review of 16 randomized clinical trials, a combination of antidepressant treatment and psychological intervention was associated with a higher response rate than antidepressant monotherapy [8]. Combined therapy was also found to have a positive effect on decreasing the dropout rate. In studies longer than 12 weeks, there was a significant reduction in the number of dropouts in patients who received combined therapy, compared with those who received pharmacotherapy alone (rate difference: /12.9%; 95% CI: /13.6 to /12.2%). Furthermore, this was achieved without an increase in the rate of non-responders, which was similar between treatment arms (rate difference: 0.4%; 95% CI: /6.2 to 7.0%) [8]. In contrast, the efficacy of usual physician care in a primary setting is largely inadequate [9]. Current primary care provision models are inefficient, in that lack of time and gaps in treatment result in poor patient outcomes [10]. A study of primary physicians’ self-reports and prescription data found that
treatment for mild-to-moderate depression was particularly inadequate (assessed by the Antidepressant Treatment and History Form ATHF), and was associated with specific treatments, such as sertraline and fluoxetine [11]. One 8-month study investigated the efficacy of standardized treatments for major depression, and compared it with usual primary care [12]. Patients received either pharmacotherapy (nortriptyline; n /91) or interpersonal psychotherapy (n /93) within well-structured parameters, or physician’s usual care (n /92). The severity of symptoms was more rapidly and more effectively reduced in patients who were randomized to pharmacotherapy or psychotherapy, compared with patients who received physician’s usual care. The proportion of patients deemed to have ‘‘recovered’’ after 8 months was 70 vs. 20%, respectively [12]. Even when remission from major depression is achieved, few patients in primary care receive maintenance treatment for the recommended 6 9 months, and this is also the case for patients with recurrent or chronic depression who are at high risk of relapse [13,14]. From the patient perspective, there are obvious issues of compliance: a treatment can only be effective if it is actually taken by the patient. Compliance is influenced by many factors including patients’ negative attitudes to, or lack of understanding of, depression, perhaps exacerbated by negative media reporting. Family and social support is important in encouraging compliance and at present this is undermined by the stigma associated with all mental disorders, and this stigma is also enhanced by negative media coverage. The doctor, the regulator and the media Prescribing by physicians is controlled by the regulatory framework within which they operate. Nevertheless, the pattern of medication use is heavily influenced by media pressure, both directly and by its influence on patient and public attitudes. This is particularly true in the use of antidepressant drugs where the media influence has, in general, been negative. The relative impact of the regulatory agencies and the media (in this case Panorama television programmes in the UK a current affairs documentary series) on physician behavior has been compared by assessing the timing of spontaneous adverse event reporting of paroxetine relative to regulatory advice and media events [15]. There is little doubt that the media had a considerably greater effect (Figure 2). It seems likely that the impact on patient attitudes would have been equally profound. Media campaigns can also provoke regulatory action with sometimes unintended consequences. The issue of suicidality in children being prescribed antidepressants is of interest in this respect. This is
Int J Psych Clin Pract Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/21/14 For personal use only.
Antidepressant efficacy gap
27
Figure 2. Suspected adverse drug reactions to paroxetine (yellow-card reports) per 100,000 paroxetine prescriptions correlated with Panorama programmes (solid arrows) and regulatory communications (dashed arrows) between 2001 and 2004. Reprinted with permission from [15], copyright Blackwell Publishing.
an area where only limited data are available, but advice was given in newspaper articles (Daily Express , UK, 9 February 2006; The Independent , UK, 9 February 2006) that the benefit of fluoxetine outweighed the risks and that this was the only recommended SSRI for use in children. The result has been a reduction in the prescription of other SSRIs, but no concomitant increase in fluoxetine prescribing to this age group in the UK. A study by Simon et al. [16] looked at the number of reported serious suicide attempts (based on hospital discharge data) in a large population database. Suicide attempts and the number of antidepressant prescriptions written by primary care physicians representing ‘‘real-life’’ data were analyzed. If the risk/benefit of SSRIs in relation to suicide was negative, it would be expected that in the month following prescription, there would be an increase in the number of suicide attempts reported. The data concerning suicide attempts relative to first prescription do not support the notion that SSRIs are increasing suicidality (Figure 3). Indeed, the numbers of suicide attempts are highest prior to treatment and decline in the first month after starting treatment. The figures for patients less than 18 years old show similar trends to those in older patients [16]. The relative decline in the prescribing of antidepressants to children in the UK has coincided with the March 2006 report from ChildLine (the UK child support helpline) reporting an increase in the number of children expressing suicidal thoughts. In the year from April 1, 2004 to March 31, 2005, a total of 1039 children and young people called ChildLine primarily about feeling suicidal, representing an increase of 14% compared with the previous year [17].
The patient and the media Public understanding of depression has changed little over the years. After a substantial public education campaign (the UK ‘‘Defeat Depression Campaign’’), Paykel et al. [18] reported that it had negligible influence on patients’ attitude to depression and its treatment. This contrasts sharply with the significant impact asserted on patients and physicians by a small number of television programmes and newspaper articles. The influence of the media cannot be overestimated. Perhaps there should be less emphasis on formulating and adhering to guidelines, and more on improving public relations and getting media support for the treatment of mood disorders. Closing the efficacy gap There is new evidence that treatment efficacy in primary care can be improved, and the efficacy gap narrowed. The recent naturalistic Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study demonstrated that measurement-based care procedures can help improve remission rates [19]. Here, the effectiveness of citalopram, a selective serotonin reuptake inhibitor (SSRI), was evaluated and baseline predictors of symptom remission in patients with major depressive disorder (moderateto-severe defined by a score /21 on the 17-item Hamilton Depression [HAM-D] rating scale) were identified. A total of 2976 outpatients (23 psychiatric settings, 18 primary care settings) received flexible doses of citalopram for up to 14 weeks. Measurement-based care throughout treatment was applied, including the routine measurement of symptoms and side effects at each treatment visit
Int J Psych Clin Pract Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/21/14 For personal use only.
28
A. G. Wade
Figure 3. Rates of suicide attempts during the 3 months before, and 6 months after, initial antidepressant prescription. Adapted and reprinted with permission from [16], copyright of the American Psychiatric Association.
by a clinical research coordinator. Guidelines (not rigidly enforced) in the form of a treatment manual were also used, which described when and how to modify treatment doses in response to these measures. Citalopram treatment averaged 10 weeks and patients who achieved HAM-D remission remained in treatment for a mean of 12 weeks. The mean dose of citalopram (41.8 mg/day) was comparable for patients who did or did not achieve remission and also for patients in primary care and psychiatric settings. The overall response rate was 47% (n / 1343), defined as a reduction of ]/50% from baseline in Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) score at the last assessment. Remission rates were 28% (n /790) with the HAM-D definition (exit score 5/7; primary outcome) and 33% (n /943) with the QIDS-SR definition (last observed score 5/5). In the STAR*D study, pharmacotherapy augmented with a measurement-based care approach may have contributed to these response and remission rates, and the authors suggest that these methods could be easily implemented in real practice [19]. Although some form of enhanced care allied to pharmacotherapy can be effective in the treatment of major depression, not all approaches have yielded consistent benefits. In a summary of 12 trials of enhanced care in primary care settings, Von Korff and Goldberg [20] found that interventions including treatment guidelines, enhanced patient education, and screening for depression were not always effective. In contrast, the incorporation of some form of case management integrated with mental health specialist support was found to be consistently successful at improving patient outcomes. Here, case management included taking responsibility for following-up patients, determining whether patients were continuing the prescribed treatment as intended, assessing the improvement of depressive
symptoms, and taking action when patients were not adhering to guideline-based treatment or not showing expected improvement. In many of the included trials, the case management services were provided over the telephone at low cost and therefore may be easily implemented in real-life clinical practice [20]. Case management is important to make treatment more pro-active and enhance longterm compliance in patients. Are guidelines too specific for real patients? Inadequate diagnosis and treatment guidelines may be another factor compromizing patient outcomes. The complexity of comorbid depression and anxiety illustrates the difficulty in publishing guidelines that are applicable to every case. Comorbidity of major depressive disorder with anxiety disorders is common (Figure 4) [2126]. Even at the sub-syndromal level, feelings of excessive worry and guilt are common findings in patients with anxiety [27] and it is rare to find patients who present with depression as their only symptom. The presence of comorbidity may affect outcome [26], by hindering recovery and increasing the likelihood of relapse [28]. For these reasons, the use of clinical guidelines specific to a single, isolated disorder alone may be an inflexible approach for those patients with both anxiety and depression. Indeed, the National Comorbidity Survey in the United States found that it is not uncommon for adults to present with three or more comorbid psychiatric disorders [29], making accurate diagnosis and treatment extremely difficult. Are guidelines too passive? With mild and newly-diagnosed anxiety disorders, guidelines recommend ‘‘watchful waiting’’ [3]. The
Int J Psych Clin Pract Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/21/14 For personal use only.
Antidepressant efficacy gap
29
Figure 4. Prevalence comorbid depression among the major anxiety disorders. Up to 70% of patients with social anxiety disorder (SAD) report a history of depression; other percentages refer to the proportion of patients that will suffer at least one major depressive episode in their lifetime. 1Kessler et al. [21]; 2APA [22]; 3Brawman-Mintzer et al. [23]; 4Rasmussen & Eisen [24]; 5Dunner et al. [25]. Reprinted with permission from [26], copyright Taylor & Francis.
rationale behind this approach is that it allows time to accurately diagnose specific disorders and comorbid depression. Ideally, appropriate treatment would then follow recommended treatments for different disorders are based on different evidence. However, this monitoring process does not help the patient if, meanwhile, symptoms are increasing in severity. Perhaps physicians should be more proactive in the treatment of depression and anxiety, and evidence suggests that many prefer this approach. The AHEAD survey [30], which examined 1017 physicians’ responses to factors that would most improve satisfaction with new antidepressant treatment, found that faster resolution of symptoms was the most frequently chosen characteristic (Figure 5).
Furthermore, expectations are already high: 50 60% of physicians expected SSRIs and non-selective drugs to start acting within 2 weeks. The benefits of structured care Based on the discussions above, it seems that improved care management, rather than new drugs, is the way forward to get more patients to remission. A multifaceted care programme involving primary physicians and collaboration with psychiatrists, in which relapse prevention intervention is included, has been shown to give prolonged improvement in depressive outcomes [31,32]. Structured treatment for depression in primary care can get 50% of
Figure 5. Physician responses to factors that would most improve satisfaction with new antidepressant treatment. The largest proportion (37%) of physicians want antidepressants to work faster. Adapted from [30].
Int J Psych Clin Pract Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/21/14 For personal use only.
30
A. G. Wade
patients to full remission in 6 months, with a further 30% in partial remission [12,33]. Unfortunately, comprehensive structured depression therapy is the exception rather than the rule in primary care [34]. A major part of the treatment strategy must be long-term care. In a 12-month study by Wade et al. [35], patients were treated with the ASRI, escitalopram, in primary care centers across Europe. Escitalopram was proven to be safe and effective in the long-term treatment of depression; the number of patients in full remission increased from 46% at baseline to 86% at week 52. Long-term remission is also likely to be associated with compliance. Combined psychotherapy and pharmacotherapy has been shown to help keep patients with depression in treatment [36] and is often necessary for patients with chronic OCD, following successful inpatient treatment, to maintain long-term improvement [37]. The same may be true for other mood disorders. Conclusion Guidelines can only go part of the way towards promoting optimal efficacy in the treatment of anxiety and depression, leaving a considerable efficacy/effectiveness gap between controlled studies and clinical practice. This emphasizes, among other issues, an urgent and increasing need for proactivity, not only in public health education, but in physicians’ relationships with the media so that they can help to redress the commonly promoted misconceptions about depression and its treatment. Together with improved guidelines and long-term maintenance therapy, these measures should allow significant progress in the management of mood disorders.
macology, including H. Lundbeck A/S, who sponsored the symposium.
References [1] World Health Organization. Preamble to the Constitution of the World Health Organization as adopted by the International Health Conference, New York, 19 22 June, 1946; signed on 22 July 1946 by the representatives of 61 States (Official Records of the World Health Organization, no. 2, p. 100) and entered into force on 7 April 1948. [2] Depression Guideline Panel. Clinical Practice Guideline, No. 5. Depression in Primary Care, Vol 2 AHCPR Publication No. 93-0551 Treatment of Major Depression. 1993; Rockville, MD: Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research. [3] Baldwin DS, Anderson IM, Nutt DJ, et al. British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2005;19(6):567 96. [4] Sa´nchez C. The pharmacology of citalopram enantiomers: the antagonism by R-citalopram on the effect of S-citalopram. Basic Clin Pharmacol Toxicol 2006;99:91 5. [5] Kasper S, Spadone C, Verpillat P, Angst J. Onset of action of escitalopram compared with other antidepressants: results of a pooled analysis. Int Clin Psychopharmacol 2006;21(2): 105 10. [6] Kennedy SH, Andersen HF, Lam RW. Efficacy of escitalopram in the treatment of major depressive disorder compared with conventional selective serotonin reuptake inhibitors and venlafaxine XR: a meta-analysis. J Psychiatry Neurosci 2006; 31(2):122 31. [7] Thase ME, Haight BR, Richard N, et al. Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials. J Clin Psychiatry 2005; 66(8):974 81. [8] Pampallona S, Bollini P, Tibaldi G, Kupelnick B, Munizza C. Combined pharmacotherapy and psychological treatment for depression: a systematic review. Arch Gen Psychiatry 2004;61(7):714 9. [9] Paykel ES. Depression: major problem for public health. Epidemiol Psichiatr Soc 2006;15(1):4 10. [10] Reiss-Brennan B, Briot P, Cannon W, James B. Mental health integration: rethinking practitioner roles in the treatment of depression: the specialist, primary care physicians, and the practice nurse. Ethn Dis 2006;16(2 Suppl 3):S337 43. [11] Joo JH, Solano FX, Mulsant BH, Reynolds CF, Lenze EJ. Predictors of adequacy of depression management in the primary care setting. Psychiatr Serv 2005;56(12):1524 8. [12] Schulberg HC, Block MR, Madonia MJ, et al. Treating major depression in primary care practice. Eight-month clinical outcomes. Arch Gen Psychiatry 1996;53(10):913 9. [13] Simon G, Von Korff M, Wagner E, Barlow W. Patterns of antidepressant use in community practice. Gen Hosp Psychiatry 1995;53:399 408. [14] Lin EH, Katon WJ, VonKorff M, et al. Relapse of depression in primary care. Rate and clinical predictors. Arch Fam Med 1998;7(5):443 9. [15] Martin RM, May M, Gunnell D. Did intense adverse media publicity impact on prescribing of paroxetine and the notification of suspected adverse drug reactions? Analysis of routine databases, 2001 2004. Br J Clin Pharmacol 2006; 61(2):224 8. [16] Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry 2006; 163(1):41 7. /
/
. There is a clinically significant gap between the treatment efficacy seen in controlled trials of antidepressant drugs and that achieved in everyday primary care for depression . Patient education, the influence of the media and other external factors should be considered when trying to bridge this gap . Consequently, treatment guidelines alone are likely to be insufficient to optimize the treatment of depression and anxiety disorders . Guidelines may fail if they are too specific or too passive . Structured, long-term therapy is necessary to get more patients to sustained remission Statement of interest
/
/
/
/
/
/
Key points
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
The author sits on advisory boards and has received research funding and lecture fees from many companies active in the field of neuropsychophar-
/
/
/
31
Antidepressant efficacy gap [17] ChildLine Report 2006 [http://www.childline.org.uk/Sharp riseinsuicidecallswarnsChildLine.asp]. [18] Paykel ES, Hart D, Priest RG. Changes in public attitudes to depression during the Defeat Depression Campaign. Br J Psychiatry 1998;173:519 22. [19] Trivedi MH, Rush AJ, Wisniewski SR, et al. STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006;163(1):28 40. [20] Von Korff M, Goldberg D. Improving outcomes in depression. Br Med J 2001;323(7319):948 9. [21] Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 1995;52(12):1048 60. [22] APA. Diagnostic and statistical manual of mental disorders. 4th ed. Text revision. Washington, DC: American Psychiatric Association; 2000. [23] Brawman-Mintzer O, Lydiard RB, Emmanuel N, et al. Psychiatric comorbidity in patients with generalized anxiety disorder. Am J Psychiatry 1993;150(8):1216 8. [24] Rasmussen SA, Eisen JL. The epidemiology and differential diagnosis of obsessive compulsive disorder. J Clin Psychiatry 1992;53(Suppl):4 10. [25] Dunner DL. Management of anxiety disorders: the added challenge of comorbidity. Depress Anxiety 2001;13(2):57 71. [26] Kasper S. Anxiety disorders: under-recognised and insufficiently treated. Int J Psychiatry Clin Pract 2006;10(Suppl 1): 3 9. [27] Coplan JD, Gorman JM. Treatment of anxiety disorder in patients with mood disorders. J Clin Psychiatry 1990; 51(Suppl):9 13; discussion 14 7. [28] Hirschfeld RM. The comorbidity of major depression and anxiety disorders: recognition and management in primary /
/
Int J Psych Clin Pract Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/21/14 For personal use only.
/
/
/
/
/
/
[29]
/
/
/
[30] [31]
/
[32]
[33]
/
/
[34]
/
[35]
/
/
/
/
/
/
/
/
/
/
/
care. Prim Care Companion J Clin Psychiatry 2001;3(6): 244 54. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994;51(1):8 19. Wade A. Poster presented at DURG/British Society for Pharmacoepidemiology, 2005. Katon W, Rutter C, Ludman EJ, et al. A randomized trial of relapse prevention of depression in primary care. Arch Gen Psychiatry 2001;58(3):241 7. Katon W, Russo J, Von Korff M, et al. Long-term effects of a collaborative care intervention in persistently depressed primary care patients. J Gen Intern Med 2002;17(10): 741 8. Katon W, Von Korff M, Lin E, et al. Stepped collaborative care for primary care patients with persistent symptoms of depression: A randomized trial. Arch Gen Psychiatry 1999; 56:1109 15. Valenstein M, Vijan S, Zeber JE, Boehm K, Buttar A. The cost-utility of screening for depression in primary care. Ann Intern Med 2001;134(5):345 60. Wade A, Despiegel N, Heldbo Reines E. Escitalopram in the long-term treatment of major depressive disorder. Ann Clin Psychiatry 2006;18(2):83 9. Terry CM, Kohlenberg RJ. Review: long term psychotherapy in combination with antidepressants increases compliance and response rates in people with depression. Evid Based Ment Health 2005;8(1):12. Rufer M, Hand I, Alsleben H, et al. Long-term course and outcome of obsessive-compulsive patients after cognitivebehavioral therapy in combination with either fluvoxamine or placebo: a 7-year follow-up of a randomized double-blind trial. Eur Arch Psychiatry Clin Neurosci 2005;255(2):121 8. /
/
[36]
/
/
/
[37]
/
/
/
ORIGINAL ARTICLE
Closing the antidepressant efficacy gap between clinical trials and real patient populations
Int J Psych Clin Pract Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/21/14 For personal use only.
ALAN G. WADE CPS Research, Todd Campus, West of Scotland Science Park, Glasgow, UK
Abstract Overall, patient outcomes in the primary care of depression are seldom as good as those achieved in clinical trials the ‘‘efficacy gap’’. Many factors contribute to this, including poor patient compliance, poor family and social support and negative media reporting of antidepressants. Indeed, negative media reporting has had far more impact on physicians’ prescribing of antidepressants than have regulatory agencies, partly as a result of changing public attitudes. Negative media reports linking SSRIs to increased child suicide rates have also resulted in a decline in the prescribing of SSRIs to this age group, but with no concomitant increase in the prescribing of fluoxetine, the only antidepressant recommended for the treatment of children. There are also inadequacies in the guidelines available to primary care givers that might contribute to the efficacy gap. Guidelines can be too specific for clinical practice especially where depression coexists with anxiety disorders and too passive, resulting in delayed or inadequate intervention. Evidence suggests that many physicians prefer to be more proactive. In the recent AHEAD survey, physicians identified faster resolution of symptoms as the property most desirable for improving antidepressant therapy. There is recent evidence that structured long-term therapy and easilyimplemented measurement-based care procedures can improve remission rates and help bridge the efficacy gap. If these can be allied with greater public/media understanding of depression and its treatment, along with improved guidelines, then significant progress can be anticipated in the management of mood disorders.
Key Words: Depression, SSRIs, guidelines, media
Introduction The long-term care interests of patients with affective disorders are not served by an approach of just treating the symptoms. Patients need to be returned to health: ‘‘a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity’’ (as defined by the World Health Organization [1]). For patients with chronic depression, this is best achieved with a long-term care plan involving maintenance of treatment to reduce the likelihood of relapse. Failure to apply maintenance treatment is often associated with poor patient outcome. For primary care givers, however, longterm treatment for depression represents a major challenge. Consequently, it is unsurprising that patient outcomes among ‘‘real populations’’ in the primary care setting tend to be inferior to those obtained by the cohorts of controlled clinical trials of depression therapies. This article discusses some of the barriers to effective long-term therapy in primary care that contribute to this ‘‘efficacy gap’’, and
considers evidence that structured care plans can help bridge this gap. Efficacy studies versus clinical practice: Bridging the gap At present, a discrepancy exists between the proven efficacy of antidepressants in clinical trials and their effectiveness in the general patient population. The reasons for this (Figure 1) are implicit in the challenges faced by physicians, which include inadequate guidelines (which may be too specific or too general), poor patient compliance and understanding, and negative media attitudes towards depression. Physicians can also contribute to this efficacy gap by poor clinical and consultation techniques, devoting insufficient time to the patient and poor knowledge of the illness and/or the patient. Physicians have a responsibility to make the best treatment choice, based on the available evidence and guidelines can assist with this [2,3].
Correspondence: Alan G. Wade, CPS Research, Todd Campus, West of Scotland Science Park, Glasgow G20 0XA, UK. Tel: /44 141 9467888. E-mail: [email protected]
ISSN 1365-1501 print/ISSN 1471-1788 online # 2006 Taylor & Francis DOI: 10.1080/13651500600934982
Int J Psych Clin Pract Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/21/14 For personal use only.
26
A. G. Wade
Figure 1. The efficacy/effectiveness gap.
The efficacy of treatment for depression in randomized controlled trials has been demonstrated many times. Pooled analyses illustrate overall response and remission rates up to 65 and 58%, respectively, for SSRIs (selective serotonin reuptake inhibitors) such as escitalopram (now referred to as an ASRI allosteric serotonin reuptake inhibitor, due to its unique mode of action [4]), with improvement in symptoms (]/20% reduction from baseline in MADRS score) after just 1 week in one-third of patients [5,6]. There is further evidence from another metaanalysis, which included data from seven randomized controlled trials of SSRIs (fluoxetine, sertraline and paroxetine) in patients with moderate-to-severe major depressive disorder (21-item HAM-D minimum score 18 20), Here, the overall remission rate (5/7 on first 17 items of HAM-D at end of trial) was found to be 47% in studies lasting from 6 to 16 weeks [7]. Combined psychotherapy and antidepressant treatment has proven particularly effective in trials. In a systematic review of 16 randomized clinical trials, a combination of antidepressant treatment and psychological intervention was associated with a higher response rate than antidepressant monotherapy [8]. Combined therapy was also found to have a positive effect on decreasing the dropout rate. In studies longer than 12 weeks, there was a significant reduction in the number of dropouts in patients who received combined therapy, compared with those who received pharmacotherapy alone (rate difference: /12.9%; 95% CI: /13.6 to /12.2%). Furthermore, this was achieved without an increase in the rate of non-responders, which was similar between treatment arms (rate difference: 0.4%; 95% CI: /6.2 to 7.0%) [8]. In contrast, the efficacy of usual physician care in a primary setting is largely inadequate [9]. Current primary care provision models are inefficient, in that lack of time and gaps in treatment result in poor patient outcomes [10]. A study of primary physicians’ self-reports and prescription data found that
treatment for mild-to-moderate depression was particularly inadequate (assessed by the Antidepressant Treatment and History Form ATHF), and was associated with specific treatments, such as sertraline and fluoxetine [11]. One 8-month study investigated the efficacy of standardized treatments for major depression, and compared it with usual primary care [12]. Patients received either pharmacotherapy (nortriptyline; n /91) or interpersonal psychotherapy (n /93) within well-structured parameters, or physician’s usual care (n /92). The severity of symptoms was more rapidly and more effectively reduced in patients who were randomized to pharmacotherapy or psychotherapy, compared with patients who received physician’s usual care. The proportion of patients deemed to have ‘‘recovered’’ after 8 months was 70 vs. 20%, respectively [12]. Even when remission from major depression is achieved, few patients in primary care receive maintenance treatment for the recommended 6 9 months, and this is also the case for patients with recurrent or chronic depression who are at high risk of relapse [13,14]. From the patient perspective, there are obvious issues of compliance: a treatment can only be effective if it is actually taken by the patient. Compliance is influenced by many factors including patients’ negative attitudes to, or lack of understanding of, depression, perhaps exacerbated by negative media reporting. Family and social support is important in encouraging compliance and at present this is undermined by the stigma associated with all mental disorders, and this stigma is also enhanced by negative media coverage. The doctor, the regulator and the media Prescribing by physicians is controlled by the regulatory framework within which they operate. Nevertheless, the pattern of medication use is heavily influenced by media pressure, both directly and by its influence on patient and public attitudes. This is particularly true in the use of antidepressant drugs where the media influence has, in general, been negative. The relative impact of the regulatory agencies and the media (in this case Panorama television programmes in the UK a current affairs documentary series) on physician behavior has been compared by assessing the timing of spontaneous adverse event reporting of paroxetine relative to regulatory advice and media events [15]. There is little doubt that the media had a considerably greater effect (Figure 2). It seems likely that the impact on patient attitudes would have been equally profound. Media campaigns can also provoke regulatory action with sometimes unintended consequences. The issue of suicidality in children being prescribed antidepressants is of interest in this respect. This is
Int J Psych Clin Pract Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/21/14 For personal use only.
Antidepressant efficacy gap
27
Figure 2. Suspected adverse drug reactions to paroxetine (yellow-card reports) per 100,000 paroxetine prescriptions correlated with Panorama programmes (solid arrows) and regulatory communications (dashed arrows) between 2001 and 2004. Reprinted with permission from [15], copyright Blackwell Publishing.
an area where only limited data are available, but advice was given in newspaper articles (Daily Express , UK, 9 February 2006; The Independent , UK, 9 February 2006) that the benefit of fluoxetine outweighed the risks and that this was the only recommended SSRI for use in children. The result has been a reduction in the prescription of other SSRIs, but no concomitant increase in fluoxetine prescribing to this age group in the UK. A study by Simon et al. [16] looked at the number of reported serious suicide attempts (based on hospital discharge data) in a large population database. Suicide attempts and the number of antidepressant prescriptions written by primary care physicians representing ‘‘real-life’’ data were analyzed. If the risk/benefit of SSRIs in relation to suicide was negative, it would be expected that in the month following prescription, there would be an increase in the number of suicide attempts reported. The data concerning suicide attempts relative to first prescription do not support the notion that SSRIs are increasing suicidality (Figure 3). Indeed, the numbers of suicide attempts are highest prior to treatment and decline in the first month after starting treatment. The figures for patients less than 18 years old show similar trends to those in older patients [16]. The relative decline in the prescribing of antidepressants to children in the UK has coincided with the March 2006 report from ChildLine (the UK child support helpline) reporting an increase in the number of children expressing suicidal thoughts. In the year from April 1, 2004 to March 31, 2005, a total of 1039 children and young people called ChildLine primarily about feeling suicidal, representing an increase of 14% compared with the previous year [17].
The patient and the media Public understanding of depression has changed little over the years. After a substantial public education campaign (the UK ‘‘Defeat Depression Campaign’’), Paykel et al. [18] reported that it had negligible influence on patients’ attitude to depression and its treatment. This contrasts sharply with the significant impact asserted on patients and physicians by a small number of television programmes and newspaper articles. The influence of the media cannot be overestimated. Perhaps there should be less emphasis on formulating and adhering to guidelines, and more on improving public relations and getting media support for the treatment of mood disorders. Closing the efficacy gap There is new evidence that treatment efficacy in primary care can be improved, and the efficacy gap narrowed. The recent naturalistic Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study demonstrated that measurement-based care procedures can help improve remission rates [19]. Here, the effectiveness of citalopram, a selective serotonin reuptake inhibitor (SSRI), was evaluated and baseline predictors of symptom remission in patients with major depressive disorder (moderateto-severe defined by a score /21 on the 17-item Hamilton Depression [HAM-D] rating scale) were identified. A total of 2976 outpatients (23 psychiatric settings, 18 primary care settings) received flexible doses of citalopram for up to 14 weeks. Measurement-based care throughout treatment was applied, including the routine measurement of symptoms and side effects at each treatment visit
Int J Psych Clin Pract Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/21/14 For personal use only.
28
A. G. Wade
Figure 3. Rates of suicide attempts during the 3 months before, and 6 months after, initial antidepressant prescription. Adapted and reprinted with permission from [16], copyright of the American Psychiatric Association.
by a clinical research coordinator. Guidelines (not rigidly enforced) in the form of a treatment manual were also used, which described when and how to modify treatment doses in response to these measures. Citalopram treatment averaged 10 weeks and patients who achieved HAM-D remission remained in treatment for a mean of 12 weeks. The mean dose of citalopram (41.8 mg/day) was comparable for patients who did or did not achieve remission and also for patients in primary care and psychiatric settings. The overall response rate was 47% (n / 1343), defined as a reduction of ]/50% from baseline in Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) score at the last assessment. Remission rates were 28% (n /790) with the HAM-D definition (exit score 5/7; primary outcome) and 33% (n /943) with the QIDS-SR definition (last observed score 5/5). In the STAR*D study, pharmacotherapy augmented with a measurement-based care approach may have contributed to these response and remission rates, and the authors suggest that these methods could be easily implemented in real practice [19]. Although some form of enhanced care allied to pharmacotherapy can be effective in the treatment of major depression, not all approaches have yielded consistent benefits. In a summary of 12 trials of enhanced care in primary care settings, Von Korff and Goldberg [20] found that interventions including treatment guidelines, enhanced patient education, and screening for depression were not always effective. In contrast, the incorporation of some form of case management integrated with mental health specialist support was found to be consistently successful at improving patient outcomes. Here, case management included taking responsibility for following-up patients, determining whether patients were continuing the prescribed treatment as intended, assessing the improvement of depressive
symptoms, and taking action when patients were not adhering to guideline-based treatment or not showing expected improvement. In many of the included trials, the case management services were provided over the telephone at low cost and therefore may be easily implemented in real-life clinical practice [20]. Case management is important to make treatment more pro-active and enhance longterm compliance in patients. Are guidelines too specific for real patients? Inadequate diagnosis and treatment guidelines may be another factor compromizing patient outcomes. The complexity of comorbid depression and anxiety illustrates the difficulty in publishing guidelines that are applicable to every case. Comorbidity of major depressive disorder with anxiety disorders is common (Figure 4) [2126]. Even at the sub-syndromal level, feelings of excessive worry and guilt are common findings in patients with anxiety [27] and it is rare to find patients who present with depression as their only symptom. The presence of comorbidity may affect outcome [26], by hindering recovery and increasing the likelihood of relapse [28]. For these reasons, the use of clinical guidelines specific to a single, isolated disorder alone may be an inflexible approach for those patients with both anxiety and depression. Indeed, the National Comorbidity Survey in the United States found that it is not uncommon for adults to present with three or more comorbid psychiatric disorders [29], making accurate diagnosis and treatment extremely difficult. Are guidelines too passive? With mild and newly-diagnosed anxiety disorders, guidelines recommend ‘‘watchful waiting’’ [3]. The
Int J Psych Clin Pract Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/21/14 For personal use only.
Antidepressant efficacy gap
29
Figure 4. Prevalence comorbid depression among the major anxiety disorders. Up to 70% of patients with social anxiety disorder (SAD) report a history of depression; other percentages refer to the proportion of patients that will suffer at least one major depressive episode in their lifetime. 1Kessler et al. [21]; 2APA [22]; 3Brawman-Mintzer et al. [23]; 4Rasmussen & Eisen [24]; 5Dunner et al. [25]. Reprinted with permission from [26], copyright Taylor & Francis.
rationale behind this approach is that it allows time to accurately diagnose specific disorders and comorbid depression. Ideally, appropriate treatment would then follow recommended treatments for different disorders are based on different evidence. However, this monitoring process does not help the patient if, meanwhile, symptoms are increasing in severity. Perhaps physicians should be more proactive in the treatment of depression and anxiety, and evidence suggests that many prefer this approach. The AHEAD survey [30], which examined 1017 physicians’ responses to factors that would most improve satisfaction with new antidepressant treatment, found that faster resolution of symptoms was the most frequently chosen characteristic (Figure 5).
Furthermore, expectations are already high: 50 60% of physicians expected SSRIs and non-selective drugs to start acting within 2 weeks. The benefits of structured care Based on the discussions above, it seems that improved care management, rather than new drugs, is the way forward to get more patients to remission. A multifaceted care programme involving primary physicians and collaboration with psychiatrists, in which relapse prevention intervention is included, has been shown to give prolonged improvement in depressive outcomes [31,32]. Structured treatment for depression in primary care can get 50% of
Figure 5. Physician responses to factors that would most improve satisfaction with new antidepressant treatment. The largest proportion (37%) of physicians want antidepressants to work faster. Adapted from [30].
Int J Psych Clin Pract Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/21/14 For personal use only.
30
A. G. Wade
patients to full remission in 6 months, with a further 30% in partial remission [12,33]. Unfortunately, comprehensive structured depression therapy is the exception rather than the rule in primary care [34]. A major part of the treatment strategy must be long-term care. In a 12-month study by Wade et al. [35], patients were treated with the ASRI, escitalopram, in primary care centers across Europe. Escitalopram was proven to be safe and effective in the long-term treatment of depression; the number of patients in full remission increased from 46% at baseline to 86% at week 52. Long-term remission is also likely to be associated with compliance. Combined psychotherapy and pharmacotherapy has been shown to help keep patients with depression in treatment [36] and is often necessary for patients with chronic OCD, following successful inpatient treatment, to maintain long-term improvement [37]. The same may be true for other mood disorders. Conclusion Guidelines can only go part of the way towards promoting optimal efficacy in the treatment of anxiety and depression, leaving a considerable efficacy/effectiveness gap between controlled studies and clinical practice. This emphasizes, among other issues, an urgent and increasing need for proactivity, not only in public health education, but in physicians’ relationships with the media so that they can help to redress the commonly promoted misconceptions about depression and its treatment. Together with improved guidelines and long-term maintenance therapy, these measures should allow significant progress in the management of mood disorders.
macology, including H. Lundbeck A/S, who sponsored the symposium.
References [1] World Health Organization. Preamble to the Constitution of the World Health Organization as adopted by the International Health Conference, New York, 19 22 June, 1946; signed on 22 July 1946 by the representatives of 61 States (Official Records of the World Health Organization, no. 2, p. 100) and entered into force on 7 April 1948. [2] Depression Guideline Panel. Clinical Practice Guideline, No. 5. Depression in Primary Care, Vol 2 AHCPR Publication No. 93-0551 Treatment of Major Depression. 1993; Rockville, MD: Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research. [3] Baldwin DS, Anderson IM, Nutt DJ, et al. British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological treatment of anxiety disorders: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2005;19(6):567 96. [4] Sa´nchez C. The pharmacology of citalopram enantiomers: the antagonism by R-citalopram on the effect of S-citalopram. Basic Clin Pharmacol Toxicol 2006;99:91 5. [5] Kasper S, Spadone C, Verpillat P, Angst J. Onset of action of escitalopram compared with other antidepressants: results of a pooled analysis. Int Clin Psychopharmacol 2006;21(2): 105 10. [6] Kennedy SH, Andersen HF, Lam RW. Efficacy of escitalopram in the treatment of major depressive disorder compared with conventional selective serotonin reuptake inhibitors and venlafaxine XR: a meta-analysis. J Psychiatry Neurosci 2006; 31(2):122 31. [7] Thase ME, Haight BR, Richard N, et al. Remission rates following antidepressant therapy with bupropion or selective serotonin reuptake inhibitors: a meta-analysis of original data from 7 randomized controlled trials. J Clin Psychiatry 2005; 66(8):974 81. [8] Pampallona S, Bollini P, Tibaldi G, Kupelnick B, Munizza C. Combined pharmacotherapy and psychological treatment for depression: a systematic review. Arch Gen Psychiatry 2004;61(7):714 9. [9] Paykel ES. Depression: major problem for public health. Epidemiol Psichiatr Soc 2006;15(1):4 10. [10] Reiss-Brennan B, Briot P, Cannon W, James B. Mental health integration: rethinking practitioner roles in the treatment of depression: the specialist, primary care physicians, and the practice nurse. Ethn Dis 2006;16(2 Suppl 3):S337 43. [11] Joo JH, Solano FX, Mulsant BH, Reynolds CF, Lenze EJ. Predictors of adequacy of depression management in the primary care setting. Psychiatr Serv 2005;56(12):1524 8. [12] Schulberg HC, Block MR, Madonia MJ, et al. Treating major depression in primary care practice. Eight-month clinical outcomes. Arch Gen Psychiatry 1996;53(10):913 9. [13] Simon G, Von Korff M, Wagner E, Barlow W. Patterns of antidepressant use in community practice. Gen Hosp Psychiatry 1995;53:399 408. [14] Lin EH, Katon WJ, VonKorff M, et al. Relapse of depression in primary care. Rate and clinical predictors. Arch Fam Med 1998;7(5):443 9. [15] Martin RM, May M, Gunnell D. Did intense adverse media publicity impact on prescribing of paroxetine and the notification of suspected adverse drug reactions? Analysis of routine databases, 2001 2004. Br J Clin Pharmacol 2006; 61(2):224 8. [16] Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry 2006; 163(1):41 7. /
/
. There is a clinically significant gap between the treatment efficacy seen in controlled trials of antidepressant drugs and that achieved in everyday primary care for depression . Patient education, the influence of the media and other external factors should be considered when trying to bridge this gap . Consequently, treatment guidelines alone are likely to be insufficient to optimize the treatment of depression and anxiety disorders . Guidelines may fail if they are too specific or too passive . Structured, long-term therapy is necessary to get more patients to sustained remission Statement of interest
/
/
/
/
/
/
Key points
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
The author sits on advisory boards and has received research funding and lecture fees from many companies active in the field of neuropsychophar-
/
/
/
31
Antidepressant efficacy gap [17] ChildLine Report 2006 [http://www.childline.org.uk/Sharp riseinsuicidecallswarnsChildLine.asp]. [18] Paykel ES, Hart D, Priest RG. Changes in public attitudes to depression during the Defeat Depression Campaign. Br J Psychiatry 1998;173:519 22. [19] Trivedi MH, Rush AJ, Wisniewski SR, et al. STAR*D Study Team. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry 2006;163(1):28 40. [20] Von Korff M, Goldberg D. Improving outcomes in depression. Br Med J 2001;323(7319):948 9. [21] Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 1995;52(12):1048 60. [22] APA. Diagnostic and statistical manual of mental disorders. 4th ed. Text revision. Washington, DC: American Psychiatric Association; 2000. [23] Brawman-Mintzer O, Lydiard RB, Emmanuel N, et al. Psychiatric comorbidity in patients with generalized anxiety disorder. Am J Psychiatry 1993;150(8):1216 8. [24] Rasmussen SA, Eisen JL. The epidemiology and differential diagnosis of obsessive compulsive disorder. J Clin Psychiatry 1992;53(Suppl):4 10. [25] Dunner DL. Management of anxiety disorders: the added challenge of comorbidity. Depress Anxiety 2001;13(2):57 71. [26] Kasper S. Anxiety disorders: under-recognised and insufficiently treated. Int J Psychiatry Clin Pract 2006;10(Suppl 1): 3 9. [27] Coplan JD, Gorman JM. Treatment of anxiety disorder in patients with mood disorders. J Clin Psychiatry 1990; 51(Suppl):9 13; discussion 14 7. [28] Hirschfeld RM. The comorbidity of major depression and anxiety disorders: recognition and management in primary /
/
Int J Psych Clin Pract Downloaded from informahealthcare.com by QUT Queensland University of Tech on 11/21/14 For personal use only.
/
/
/
/
/
/
[29]
/
/
/
[30] [31]
/
[32]
[33]
/
/
[34]
/
[35]
/
/
/
/
/
/
/
/
/
/
/
care. Prim Care Companion J Clin Psychiatry 2001;3(6): 244 54. Kessler RC, McGonagle KA, Zhao S, et al. Lifetime and 12month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gen Psychiatry 1994;51(1):8 19. Wade A. Poster presented at DURG/British Society for Pharmacoepidemiology, 2005. Katon W, Rutter C, Ludman EJ, et al. A randomized trial of relapse prevention of depression in primary care. Arch Gen Psychiatry 2001;58(3):241 7. Katon W, Russo J, Von Korff M, et al. Long-term effects of a collaborative care intervention in persistently depressed primary care patients. J Gen Intern Med 2002;17(10): 741 8. Katon W, Von Korff M, Lin E, et al. Stepped collaborative care for primary care patients with persistent symptoms of depression: A randomized trial. Arch Gen Psychiatry 1999; 56:1109 15. Valenstein M, Vijan S, Zeber JE, Boehm K, Buttar A. The cost-utility of screening for depression in primary care. Ann Intern Med 2001;134(5):345 60. Wade A, Despiegel N, Heldbo Reines E. Escitalopram in the long-term treatment of major depressive disorder. Ann Clin Psychiatry 2006;18(2):83 9. Terry CM, Kohlenberg RJ. Review: long term psychotherapy in combination with antidepressants increases compliance and response rates in people with depression. Evid Based Ment Health 2005;8(1):12. Rufer M, Hand I, Alsleben H, et al. Long-term course and outcome of obsessive-compulsive patients after cognitivebehavioral therapy in combination with either fluvoxamine or placebo: a 7-year follow-up of a randomized double-blind trial. Eur Arch Psychiatry Clin Neurosci 2005;255(2):121 8. /
/
[36]
/
/
/
[37]
/
/
/
