Focus Points   • Evidence-based mental health guidelines exist within the framework of evidence-based medicine, are simple, specific, and user-friendly, focus on key clinical decisions, are based on research evidence, and present recommendations in a concise, accessible format. • Evidence-based mental health programs require education, time, and improved effort. • Guidelines can inform practitioner decision making, but administrators of drug formularies may regard themselves as primarily being responsible for limiting costs and access to certain medications, even if these decisions are at odds with guideline recommendations.

Abstract

Evidence-based medicine (EBM) enables clinicians to justify decision making, enhances the quality of medical practice, identifies unanswered research questions, and ensures the efficient practice of medicine. Implementation of evidence-based mental health programs requires education, time, and improved effort by administration, regulatory, and clinical professionals. Essential to these efforts are consistent incentives for change, effective training materials, and clear clinical guidelines. Guidelines exist within the framework of EBM. Good guidelines are simple, specific, and user friendly, focus on key clinical decisions, are based on research evidence, and present evidence and recommendations in a concise and accessible format. Potential limitations of guidelines to improve clinical outcomes in anxiety disorders are the widespread distribution of anxiety symptoms in primary care, health inequalities across patient groups, persistent misconceptions regarding psychotropic drugs, and low confidence in using simple psychological treatments. Clinical guidelines generally specify therapeutic areas covered and not covered, but often there is no mention of cost or cost effectiveness of treatment. Guidelines can inform clinical decision making, but administrators of drug formularies may regard themselves as being primarily responsible for limiting costs and access to certain medications, even if these decisions are at odds with guideline recommendations.

Introduction

The advance of evidence-based medicine (EBM) in the 1990s has exerted major influences on current clinical practice in mental health. Key stakeholders in the field such as policy formers, health service managers, advocates, researchers, and physicians generally agree that the primary goal of clinical practice is to provide the most effective mental health treatments to the greatest number of people in need, at the lowest price. The implementation of evidence-based mental health practices in routine treatment settings has become integral to this effort.

The conundrum faced by many health professionals is how to implement evidence-based treatment in mental health settings where existing practice seems suboptimal. Implementation of evidence-based mental health programs requires a broad range of activities, including patient and professional education (eg, workbooks, videos, self-learning, manuals, and symposia), goodwill, time, and the improved and coordinated involvement of all stakeholders. Essential to this effort are consistent incentives for change, effective training materials, and the incorporation of clear evidence-based clinical guidelines.¹ The objective of this narrative review is to outline approaches, treatments, and outcomes in anxiety disorders, to discuss the value of clinical guidelines for practice in this area of mental health, to describe the principal results of studies that utilized clinical guidelines, and to provide a brief perspective on cost-effectiveness of treatment.

Approaches to Improve Clinical Outcomes

Some general observations about clinical outcomes in anxiety disorders can be made. Full symptomatic remission is comparatively rare, sub-syndromal cases often become syndromal when followed-up,² and most disorders typically follow a chronic course.³ Most anxiety disorders are associated with increased morbidity and mortality.⁴ Furthermore, treatment responsiveness may diminish with further episodes of illness, emphasizing the need for long-term treatment.⁵ Given these observations, it is disappointing that existing standards of care are so often suboptimal. For example, a study by Stein and colleagues⁶ demonstrated that for anxiety disorder patients at outpatient clinics in the western United States, fewer than one third received either psychotherapy or pharmacotherapy that met a criterion for quality care. Even when the appropriate therapy was used, the duration of treatment was often too short.

Several possible approaches exist to improve clinical outcomes in anxiety disorders. One approach is to use existing treatments in a more concerted fashion. Existing approaches could be enhanced via combination with pharmacologic treatments or structured psychotherapies. These findings highlight the need for evidence-based guidelines and guidelines with supplementary algorithms for anxiety disorders in primary care to enhance the use of existing treatments.⁶

There could be modifications to existing pharmacologic or psychological treatments.⁷ Novel targets for pharmacotherapy include 5-HT₁ and 5-HT₂ receptor antagonists, melatonin receptor agonists, antagonists at the substance P (NK-1) receptor, metabotropic glutamate receptor antagonists, cholecystokinin antagonists, neuropeptide Y agonists, and adenosine A1 and A2A receptor agonists. Furthermore, treatment approaches could be customized through pharmacogenetic methods to develop more personalized treatments.⁸

The “ideal” anxiolytic should meet a number of criteria: it should be effective across the full range of anxiety disorders and across the spectrum of symptom severity; it should be effective across the age range; it should help achieve symptomatic remission in acute treatment and prevent relapse and recurrence with continued treatment; it should be rapid in onset, require only once-daily dosage, possess minimal adverse effects, and interfere minimally with everyday life. In addition, tolerance should not develop with prolonged use and the compound should have no discontinuation symptoms. Finally, the therapeutic agent should be suitable in the physically ill, free from interactions, and safe in overdose.

The Role of Evidence-based Medicine

The conscientious and judicious use of current best evidence in making clinical decisions about the care of individual patients has been termed EBM.⁹ The practice of EBM enables clinicians to justify their decision making, may enhance the quality of medical care, can identify unanswered research questions, and should ensure cost-effective clinical practice.

Clinical Guidelines

Clinical guidelines exist within the framework of EBM.¹⁰ Good guidelines are simple, specific, and user-friendly, should have a focus on key clinical decisions, must be able to demonstrate their origin in research evidence, and should present the relevant research evidence and resulting clinical recommendations in a concise and accessible format.¹⁰ Guidelines are often disseminated through an educational program and are implemented with patient-specific reminders, but it is claimed that they are more likely to be adopted if “grassroots” in nature, with local clinicians involved in their development conferring a resulting sense of “ownership.” Guidelines can be improved by involving all the relevant stakeholders, continually updating the guidelines according to the evidence base, having a local champion, and making the material available in a multitude of formats.¹⁰

In order to overcome barriers to adopt guidelines, both those involved in their development and local practitioners should emphasize the priority of the clinical topic, and enhance the understanding of both the patient and the clinician of the need for change in current practice. A range of methods for dissemination should be explored and wherever possible utilized.

Evidence-based clinical guidelines include a set of systematic statements, based upon current best research evidence, with the aim of  helping practitioners and patients make appropriate decisions about health care for specific circumstances.¹¹ Current guidelines for anxiety disorders have been produced by numerous organizations including the International Consensus Group on Depression and Anxiety, the World Federation of Societies of Biological Psychiatry, the World Council on Anxiety Disorders, the National Institute for Clinical Excellence, and the British Association for Psychopharmacology.

Potential limitations associated with the use of guidelines to improve outcomes of anxiety disorders are as follows: the widespread distribution of anxiety symptoms in primary care, health inequalities across patient groups, persistent public and professional misconceptions regarding the risks and benefits of psychotropic drugs, and low physician confidence in using even simple psychological treatment approaches.

What Has Been Learned From Randomized Controlled Interventions in Depressive Disorders in Primary Care?

Many randomized controlled trials (RCTs) of interventions designed to improve outcomes for depression in primary care have been undertaken, but results have been mixed. In “positive” studies (ie, those in which a controlled intervention has been associated with an improved outcome),^12-18 several common factors can be detected. In all these studies, evidence-based guidelines were used, there was enhanced patient education and varying forms of case management, and a mental health specialist was involved in nearly all studies.

It is uncertain whether the addition of algorithms to guidelines might result in improved outcomes in anxiety disorders. Trivedi and colleagues¹⁹ undertook a prospective study that focused on treatment effectiveness in depressive disorders, using an intent-to-treat comparison of clinics offering algorithm-guided treatment (ALGO) versus those providing “treatment as usual” for depression. There was a greater reduction in depressive symptom severity (observer rated and patient rated) in the ALGO group, and significantly greater improvement in the mental health summary score of the medical outcomes study (short form) (MOS-SF Health Survey) with ALGO (P=.046), suggesting algorithms can enhance clinical outcomes.

Two research groups have attempted to establish whether guidelines can improve clinical outcomes in anxiety disorders. Thomas and colleagues²⁰ performed an RCT of computer generated patient-specific treatment recommendations versus locally agreed guidelines. Patients (n=762) with “common mental health problems” (principally mixed anxiety and depressive disorders of low severity) in five UK general practices were included. Increased intervention was not associated with improved outcomes, although methodological features may explain this finding. For example, participation was not restricted to incident cases. Treatment recommendations resulted from a clinical interview schedule (revised) (CIS-R) score, and there was no information gathered on the process of clinical care.²⁰

In a second study, Van Boeijen and colleagues²¹ undertook an RCT in Dutch primary care patients (n=154) with panic disorder or generalized anxiety disorder. Clinical guidelines were compared to manualized self-help and cognitive behavior therapy (CBT), the latter being offered in secondary care. There were no significant differences in clinical outcomes at 12, 24, or 52 weeks. However, the general practitioners (GPs) adhered to guidelines only poorly because they felt unable to carry out even a simplified form of CBT and considered that the time investment in offering this treatment option was too great.²¹

A number of RCTs of interventions for depression in primary care have been performed in which increased intervention has not been associated with improved clinical outcomes.^16,22-24 For example, the Hampshire Depression Project²⁴ was a pragmatic RCT involving the implementation of the “Defeat Depression” guideline for the recognition and treatment of depressive illness. The central hypothesis was that education would improve recognition and clinical outcome²⁴ based on assumptions that the behavior of health professionals could be modified, that cases of depression can be reliably identified, and that effective treatment can be applied.

In this study, 60 of 232 approached practices volunteered to take part. The program consisted of educational components with seminars (4 hours), discussion of guidelines, and listing of local resources.²⁴ Although 80% of the participants thought that this education would change their management of depression,²⁴ the intervention and control groups did not differ in sensitivity or specificity in the recognition of depression. There was some evidence of an improved outcome at 6 weeks in recognized cases in the “educated” group (post hoc analysis), but no differences in 6-month follow-up rates or outcomes.²⁴ Several reasons were proffered for these disappointing results: the guidelines themselves provided only a limited evidence base for the management of depression in primary care; there was a possible ceiling effect on recognition of depression in participants; both incident (new) and prevalent (previously known) cases could be recruited; the education component consisted of a one-off intervention; the study design allowed for study nonparticipants within the practice; and finally there were no interview-based case definitions.²⁴

In a similar study, Croudace and colleagues²² undertook an RCT of the World Health Organization International Classification of Diseases (ICD-10) primary health care diagnostic and management guidelines to evaluate the effect of local adaptation and dissemination of these guidelines within the context of UK primary medical care. The study was a pragmatic, pair-matched, cluster RCT consisting of 30 practices and 2,328 patients. Practices were stratified according to a social deprivation score. Outcome measures included the sensitivity of detecting minor psychiatric morbidity and 3-month clinical outcomes using the General Health Questionnaire (GHQ)-12, EuroQoL, and Brief Disability Scale. As in the Hampshire Depression Project, the results indicated that patients treated through the guideline did not differ from other patients on GHQ scores and there were no significant differences in secondary outcomes.²² The researchers concluded that guidelines that attempt to influence clinician behavior are unlikely to alter detection rates or outcomes.²²

The disappointing nature of the findings from these two studies led some to address the question, “Why can’t GPs follow guidelines on depression?”²⁵ In this analysis several reasons emerged. The first was the recognition that the diagnosis of depression is not easy to make in primary care because depressive symptoms are distributed continuously in the general practice patient population. In addition, it was noted that many GPs doubt the effectiveness of antidepressants when prescribed in the face of social problems. This is supported by the observation in the Hampshire Depression Project that recovery from depression was slower in the presence of social adversity. Finally, it was acknowledged that most patients are reluctant to take antidepressant drugs for the right duration at the right dose.²⁵

Based on the outcomes of the positive and negative studies, a consensus has emerged on how to improve depression outcomes. It consists of enhanced patient education, some involvement of mental health services, and case management, ie, assuming responsibility for patient follow-up, asking whether symptoms are improving, determining patients’ treatment compliance, intervening when patients are not responding, and intervening when physicians are departing from guidelines.

There are several implications of these studies of depression and anxiety: there is a need for clarity in case definition; an emphasis needs to be placed on treatment, even in the absence of depression; guidelines should be supported by case management; a focus on engaging patients from all ethnic groups should be undertaken; competence-based training in simplified psychological treatments should be performed; and current misunderstandings about psychotropic drug treatment need to be corrected.

What Are the Implications for Decisions Regarding Cost Effectiveness?

Clinical guidelines generally specify the areas covered and those not covered. Guidelines will normally recommend use of medicines within licensed indications, but occasionally, where the evidence supports it, may recommend use outside a treatment’s licensed indications. In most guidelines there is no mention of costs of illness or cost effectiveness of treatment. Guidelines can inform clinical decision making, but administrators of drug formularies may regard themselves as being primarily responsible for limiting cost and access to certain medications.

In the previous sections it was noted that the practice of EBM and use of clinical guidelines may enable clinicians to justify their decision making, enhance the quality of medical practice, identify unanswered research questions, and ensure the efficient practice of medicine. However, a key question is, “At what price?” The traditional patient-physician dynamic excluded cost issues from the decision-making process when considering treatment options. However, from a public health perspective, there is clearly a need to provide the most cost-effective care to the largest number of patients. Does the public health medicine approach limit the treatment options for physicians treating individual patients? And how is this reconciled within clinical guidelines?

To answer these questions we need to look at how health service providers and payers make formulary decisions. In an effort to provide services to large populations in an environment of increasing numbers of treatment medication options with their concomitant increased prices, payers are forced to examine the relative cost effectiveness of various medications. In economic terms this often translates into assessing what is the incremental increased benefit associated with an incremental increased cost compared with the current standard of care at the time. Pragmatic RCTs in primary care settings provide the means to assess the relative cost effectiveness and value of differing treatment approaches.²⁶ With this form of analysis, formulary decision makers may feel more confident in allowing access to medications that can demonstrate some incremental cost-effectiveness ratio over current treatments.

In instances in which “any” incremental increase in effectiveness is the standard for inclusion of new medications in a formulary, more treatment options will be available for clinicians and patients. However, if the required standard for inclusion of new medications in a formulary is, for example, 10%, then fewer medications will jump this hurdle and medications would therefore not be included in a formulary. This in turn limits the access (through preauthorizations, increased copays, or coinsurance) of individual providers to prescribe medications for their patients.

For example, the State of Oregon has legislated that the Oregon Prescription Drug Program will develop a Preferred Drug List (PDL) that participating groups may choose to adopt for beneficiaries of their prescription drug benefit program. The Oregon Prescription Drug Program will, in effect, decide what drugs are included in their formulary through consultations with Oregon Health and Science University (OHSU).²⁷ The OHSU Drug Effectiveness Review Project provides information on the safety and effectiveness of medications.²⁸ The Oregon Legislature notes that the PDL shall include the most effective prescription drugs at the lowest possible prices, taking into account negotiated price discounts and available rebates. However, there is no indication of what is an adequate balance between clinical guidelines, drug effectiveness, and price to justify formulary inclusion.²⁹ A recent OSHU review of second-generation antidepressants noted the evidence supports the general efficacy of sertraline; however, there was insufficient evidence of the effectiveness of citalopram, fluoxetine, fluvoxamine, mirtazapine, duloxetine, bupropion, and nefazodone for generalized anxiety disorder treatment.³⁰

Conclusion

Evidence-based clinical guidelines include a systematic set of statements based on current best research evidence. These mental health clinical guidelines are built upon the foundation of EBM, which enables clinicians to justify their decision making. Useful guidelines are simple, specific, and user friendly. They focus on key clinical decisions and are easily traced back to original research. Guidelines should gradually evolve with accumulating research evidence. The lack of consideration of cost effectiveness in many existing clinical guidelines is unfortunate and can lead to disagreements between clinicians and health service and formulary managers.

References

1. Drake RE, Torrey WC, McHugo GJ. Strategies for implementing evidence-based practices in routine mental health settings. Evid Based Ment Health. 2003;6:6-7.
2. Wittchen HU, Lieb R, Pfister H, Schuster P. The waxing and waning of mental disorders: evaluating the stability of syndromes of mental disorders in the population. Compr Psychiatry. 2000;41:122-132.
3.  Yonkers KA, Bruce SE, Dyck IR, Keller MB. Chronicity, relapse, and illness-course of panic disorder, social phobia, and generalized anxiety disorder: Findings in men and women from 8 years of follow-up. Depress Anxiety. 2003;17:173-179.
4. Roose SP. Depression, anxiety, and the cardiovascular system: the psychiatrist’s perspective. J Clin Psychiatry. 2001;62(suppl 8):19-22.
5. Maina G, Albert U, Bogetto F. Relapses after discontinuation of drug associated with increased resistance to treatment in obsessive-compulsive disorder. Int Clin Psychopharmacol. 2001;16:33-38.
6. Stein MB, Sherbourne CD, Craske MG, et al. Quality of care for primary care patients with anxiety disorders. Am J Psychiatry. 2004;161:2230-2237.
7. Stahl SM, Grady MM. Differences in mechanism of action between current and future antidepressants. J Clin Psychiatry. 2003;64(suppl 13):13-17.
8. Wong ML, Licinio J. From monoamines to genomic targets: a paradigm shift for drug discovery in depression. Nat Rev Drug Discov. 2004;3:136-151.
9. Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS. Evidence based medicine: what it is and what it isn’t. BMJ. 1996;312:71-72.
10. Jackson R, Feder G. Guidelines for clinical guidelines. BMJ. 1998;317:427-428.
11. Field MJ, Lohr KN. Guidelines for Clinical Practice: From Development to Use. Washington, DC: National Academies Press; 1992.
12. Hunkeler EM, Meresman JF, Hargreaves WA, et al. Efficacy of nurse telehealth care and peer support in augmenting treatment of depression in primary care. Arch Fam Med. 2000;9:700-708.
13. Katon W, Von Korff M, Lin E, et al. Collaborative management to achieve treatment guidelines. Impact on depression in primary care. JAMA. 1995;273:1026-1031.
14. 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;56:1109-1115.
15. Katzelnick DJ, Simon GE, Pearson SD, et al. Randomized trial of a depression management program in high utilizers of medical care. Arch Fam Med. 2000;9:345-351.
16. Peveler R, George C, Kinmonth AL, Campbell M, Thompson C. Effect of antidepressant drug counselling and information leaflets on adherence to drug treatment in primary care: randomised controlled trial. BMJ. 1999;319:612-615.
17. Rost K, Nutting P, Smith J, Werner J, Duan N. Improving depression outcomes in community primary care practice: a randomized trial of the quEST intervention. Quality Enhancement by Strategic Teaming. J Gen Intern Med. 2001;16:143-149.
18. Wells KC, Pelham WE, Kotkin RA, et al. Psychosocial treatment strategies in the MTA study: rationale, methods, and critical issues in design and implementation. J Abnorm Child Psychol. 2000;28:483-505.
19. Trivedi MH, Rush AJ, Crismon ML, et al. Clinical results for patients with major depressive disorder in the Texas Medication Algorithm Project. Arch Gen Psychiatry. 2004;61:669-680.
20. Thomas HV, Lewis G, Watson M, et al. Computerised patient-specific guidelines for management of common mental disorders in primary care: a randomised controlled trial. Br J Gen Pract. 2004;54:832-837.
21. van Boeijen CA, van Oppen P, van Balkom AJ, et al. Treatment of anxiety disorders in primary care practice: a randomised controlled trial. Br J Gen Pract. 2005;55:763-769.
22. Croudace T, Evans J, Harrison G, et al. Impact of the ICD-10 Primary Health Care (PHC) diagnostic and management guidelines for mental disorders on detection and outcome in primary care. Cluster randomised controlled trial. Br J Psychiatry. 2003;182:20-30.
23. Dowrick C, Buchan I. Twelve month outcome of depression in general practice: does detection or disclosure make a difference? BMJ. 1995;311:1274-1276.
24. Thompson C, Kinmonth AL, Stevens L, et al. Effects of a clinical-practice guideline and practice-based education on detection and outcome of depression in primary care: Hampshire Depression Project randomised controlled trial. Lancet. 2000;355:185-191.
25. Kendrick T. Why can’t GPs follow guidelines on depression? We must question the basis of the guidelines themselves. BMJ. 2000;320:200-201.
26. Kendrick T, Peveler R, Longworth L, et al. Cost-effectiveness and cost-utility of tricyclic antidepressants, selective serotonin reuptake inhibitors and lofepramine: randomised controlled trial. Br J Psychiatry. 2006;188:337-345.
27. Senate Bill 329. Oregon State Legislature Web site. Available at: http://www.leg.state.or.us/05reg/measures/sb0300.dir/sb0329.intro.html. Accessed April 19, 2006.
28. Oregon Health and Science University. Drug Effectiveness Review Project. Available at: http://www.ohsu.edu/drugeffectiveness/. Accessed April 19, 2006.
29. State of Oregon Department of Administrative Services. Office for Oregon Health Policy and Research Prescription Drug Program. Available at: http://egov.oregon.gov/DAS/OHPPR/OPDP/docs/OPDPadminrules.pdf. Accessed April 19, 2006.
30. Gartlehner G, Hansen RA, Kahwati L, Lohr KN, Gaynes B, Carey T. Drug Class Review on Second Generation Antidepressants. [Oregon Health and Science University Web site]. March 2006. Available at: http://www.ohsu.edu/drugeffectiveness/reports/documents/Antidepressants%20 Final%Report%20Update%202.pdf.  Accessed April 19, 2006.