The Diagnosis of and Treatment Recommendations for Anxiety Disorders

Background: Anxiety disorders (panic disorder/agoraphobia, generalized anxiety disorder, social phobia, and specific phobias) are the most common mental illnesses. For example, the 12-month prevalence of panic disorder/agoraphobia is 6%.

Methods: This guideline is based on controlled trials of psychotherapy and pharmacotherapy, retrieved by a systematic search for original articles that were published up to 1 July 2013. Experts from 20 specialty societies and other organizations evaluated the evidence for each treatment option from all available randomized clinical trials and from a synthesis of the recommendations of already existing international and German guidelines.

Results: 403 randomized controlled trials were evaluated. It was concluded that anxiety disorders should be treated with psychotherapy, psychopharmacological drugs, or both. Response rates to initial treatment vary from 45% to 65%. Cognitive behavioral therapy is supported by higher-level evidence than any other psychotherapeutic technique. Psychodynamic therapy is recommended as a second-line treatment. Among anxiolytic drugs, the agents of first choice are selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors. The patient’s preference should be considered in the choice of treatment. Drug treatment should be continued for 6 to 12 months after remission. If psychotherapy or drug treatment is not adequately effective, then the treatment should be switched to the other form, or to a combination of both.

Conclusion: The large amount of data now available from randomized controlled trials permits the formulation of robust evidence-based recommendations for the treatment of anxiety disorders. Future work should more closely address the necessary duration of psychotherapy and the efficacy of combined psychotherapy and drug treatment.

Anxiety disorders are the most common mental illnesses (1). Women are much more frequently affected than men. Specific phobias, with a 12-month prevalence of 10.3%, are the most common type of anxiety disorder (2), although persons suffering from them rarely seek treatment. The next most common type is panic disorder/agoraphobia (6.0%), followed by social phobia (2.7%) and generalized anxiety disorder (2.2%). Anxiety disorders have not become more common in recent years and decades (3, 4). They often arise in combination with other anxiety disorders, major depression, somatoform disorders, and addictive disorders (5). They are now thought to originate from an interaction of psychosocial, genetic, and neurobiological factors.

The S3 guideline on anxiety disorders

The S3 guideline on anxiety disorders (6) is available free of charge, in both short and long versions, on the website www.awmf.org/leitlinien (in German). S3 guidelines are required to meet the highest qualitative requirements of the DELBI criteria (7). This guideline was issued by 20 specialty societies and other organizations (eTable 1). It was created over the period 2008–2014 by a guideline committee of 36 persons, including specialists, general practitioners, and patient representatives (eTable 2). After ten working sessions, the final text of the guideline was created by a steering committee (B. Bandelow, M. Beutel, T. Lichte, S. Rudolf) and put to a vote of the remaining participants in two consensus conferences. Each participating group had one vote; recommendations were accepted if they received at least 75% of all votes cast. The resulting guideline was presented to the boards of the participating societies. Professor Ina Kopp of the Association of Scientific Medical Societies in Germany (Arbeitsgemeinschaft der wissenschaftlichen medizinischen Fachgesellschaften, AWMF) assisted in the creation of the guideline and moderated all working sessions and consensus conferences.

This guideline, like other guidelines, is explicitly not intended to serve a regulatory function; it neither mandates nor forbids anything. Rather, it provides important contextual information for individual treatment decisions, which should also properly depend on the treating person’s experience and

Table 1

Brief descriptions of the main anxiety disoders according to ICD-10

Table 2

Summary of recommendations on the treatment of anxiety disorders

eTable 1

Participating medical societies, professional associations, and other organizations

eTable 2

Members of the consensus group and of the steering committee (designated with an asterisk); abbreviations as in eTable 1

on the preference of the patient.

It is planned that this guideline will be disseminated through presentations by members of the guideline committee at scientific conferences and at continuing medical education sessions, and by providing a patient version (www.awmf.org/leitlinien). An update in 5 years is projected.

Because of the large number of clinical trials evaluated for the guideline, references will not be given for every statement in this article; rather, the reader is referred to the long version of the S3 guideline (in German only) for more information.

Methods

Already existing guidelines on the subject were sought by electronic search. Guidelines meeting the specified quality criteria were selected in a peer-review process (eTable 3). The guideline committee performed its own literature searches when discrepancies between existing guidelines were found, when subject areas were not adequately covered, or when new trials potentially resulting in different evidence levels were found to have been published since the appearance of the reference guidelines. All available randomized controlled trials (RCTs) on the treatment of anxiety disorders published up to 1 July 2013 were examined. The inclusion criteria were: original publication in a peer-reviewed journal; therapeutic trials of anxiety disorders defined according to ICD or DSM (panic disorder/agoraphobia, generalized anxiety disorder, social phobia, or specific phobia) in adults; not exclusively subgroup analysis; use of a control group (for drug trials, a placebo or reference drug; for psychotherapy trials, a waiting list, an active control [i.e., a supportive conversation with the patient, without applying specific therapeutic techniques], or treatment as usual [TAU]); for drug trials, use of a commercially available and approved drug.

As an example, the literature search on panic disorder/agoraphobia was carried out in the following way, according to the PRISMA Statement (8): PubMed search algorithm: ([“panic disorder”{Title}] OR [“agoraphobia”{Title}]) AND [“randomized”{All fields}] AND [“t

Table 3

Stepwise plan for alternative drug treatment if the drug initially used to treat an anxiety disorder is ineffective or poorly tolerated

eTable 3

Existing guidelines on the treatment of anxiety disorders that were used in the creation of the present guideline, in order of publication date. The four columns at right indicate which of the four disorders discussed in the present guideline (panic disorder, generalized anxiety disorder, social phobia, specific phobia) were covered by the guideline in question.

reatment” OR “therapy”{All fields}]; date: 1980/01/01 to present; in ISI Web of Science: Title=[panic disorder OR agoraphobia] AND Topic=[randomized] AND Topic=[therapy]; timespan: >1979; Search language=English, German). 1296 publications were retrieved by this search, and 21 further ones were identified by a manual search. Of the 1317 publications found in total, 1100 were excluded after screening of the titles and abstracts. The full texts of the remaining 217 articles were obtained. 48 were excluded because they met specifically defined exclusion criteria (e.g., double publication, subgroup analysis only, sample size <10 for each arm at study baseline, and lack of an adequate control group, among others); 169 were included in the analysis. A similar procedure was followed for the remaining anxiety disorders (see the long version of the guideline). Finally, a total of 403 RCTs were evaluated for the guideline.

The quality of each trial was evaluated according to the criteria enunciated in the SIGN Statement (9). Methodological flaws led to the exclusion of trials or to downgrading of their evidence level. Common reasons for downgrading the evidence level included small sample size (particularly in non-inferiority comparisons), failure to state the primary efficacy measure, or respectively failure to apply a Bonferroni correction for multiple testing, and inappropriate methods of statistical analysis.

Decisions to base guideline recommendations on the results of RCTs alone have often met with criticism in the past, and, indeed, in the case of the present guideline, this decision was controversial within the guideline committee itself. It was pointed out that RCTs generally involve a selected group of patients: patients with comorbidities are often excluded, and suicidal patients are as a rule excluded. Yet an analysis of psychotherapy and drug trials evaluated for the guideline did not indicate that these types of treatment differed systematically with respect to the inclusion of comorbid patients. In uncontrolled studies, it cannot be determined whether an observed improvement was due to the treatment itself or to spontaneous remission, tendency of regression to the mean, or non-specific attention effects; therefore, the guideline committee agreed that the recommendations should, essentially, be based on the results of RCTs. Although, according to the protocol, results from open studies, case series, and single case reports were also admissible, there was no concrete case in which a decision about an evidence level had to be made on the basis of such publications. This was due to the lack of sufficiently informative non-randomized studies, and the sufficient availability of controlled trials.

While the evidence categories were based exclusively on the efficacy of the various treatments studied, the recommendation grades also took risks into account, e.g., drug adverse effects (eTable 4).

Diagnosis

In Germany, anxiety disorders are evaluated in the outpatient and inpatient settings according to the 10^th edition of the International Classification of Diseases in its German modification (ICD-10 GM) (10; see brief description in Table 1

eTable 4

Evidence levels (from Eccels and Mason, 2001 [28]) and recommendation grades

). In primary care, the diagnosis “mixed anxiety and depressive disorder” (ICD-10 F41.2) is often made; according to ICD-10, however, this diagnosis is impermissible if either anxiety or depression is severe enough to merit being diagnosed in itself. As no clinical trials have been conducted on the treatment of this entity according to its proper, restricted definition, the present guideline does not contain any recommendations about its treatment.

Anxiety disorders often go unrecognized, partly because patients frequently complain of pain, sleep disturbances, or other somatic problems as their main symptom, rather than of the underlying anxiety (11). The differential diagnosis of anxiety disorders must include other common mental disorders, such as other anxiety disorders, major depression, and somatoform disorders, as well as somatic diseases such as coronary heart disease, bronchial asthma, and others (Table 2).

Health care provision

The primary care physician is often the first doctor contacted by the patient, and therefore plays a major role in its care. Some 15% of patients remain exclusively under the treatment of their primary care physicians and do not consult a specialist (12). Psychotherapy is provided by psychotherapists, who can be either physicians or certified psychologists in Germany. If the symptoms fail to improve sufficiently, if the patient becomes suicidal, or if other complications arise, the patient should be referred to a psychiatrist. Anxiety disorders can usually be treated on an outpatient basis. Indications for hospitalization include suicidality, lack of further options for outpatient management, very severe anxiety, and marked comorbidity.

Treatment recommendations

The accepted indications for treatment are: the presence of an anxiety disorder as defined by ICD-10 GM, moderate to severe subjective distress as perceived by the patient, and psychosocial problems and other complications resulting from the anxiety disorder (e.g., substance abuse). The treatment recommendations are summarized in Table 2 (for a more detailed version, cf. Table 1 in the text of the guideline [in German]). Anxiety disorders can be treated with psychotherapy and/or drug treatment and other interventions. In meta-analyses, both psychotherapy and medication have been found to have moderate to high effect sizes in pre–post comparisons and in comparisons with control groups. Response rates for the form of treatment initially chosen are in the range of 45% to 65%.

The treatment plan should be chosen after careful consideration of individual factors (the patient’s preference, previous treatment attempts, severity, comorbidity including substance abuse, suicide risk, and others). All interventions should be performed on the basis of a functioning and sustainable therapeutic relationship. Treating physicians and psychologists must inform patients of the diagnosis and the likelihood of improvement with each potential treatment, in the light of the available evidence. They must also inform them of the alternatives when multiple treatments, any of which may be indicated, are associated with markedly different burden of distress, risks, or chances of improvement.

The patients’ relatives should be integrated into the treatment, and the economic aspects of treatment should also be considered. A detailed discussion of the treatment of generalized anxiety disorder can be found in Bandelow et al. (2013) (13).

Psychotherapy

The large number of RCTs of cognitive behavioral therapy (CBT) carried out to date for each of the four types of anxiety disorder have documented the efficacy of CBT in comparison to active controls and to waiting lists. CBT should be based on empirically validated treatment protocols (manuals). Patients with avoidance behavior (e.g., agoraphobic patients) should receive CBT with exposure, i.e., confrontation with anxiety-inducing situations. Exposure therapy was found to be more effective when the patient was accompanied by the therapist (14).

As psychodynamic methods have rarely been considered in previous guidelines due to a lack of studies, the guideline group carried out an independent literature search in order to integrate recently published studies of manualized short-term psychodynamic therapy. The RCTs on psychodynamic therapy were markedly fewer in number, and lower in quality, than those on CBT, and some comparison studies have shown CBT to be superior. It is thus recommended that patients with panic disorder/agoraphobia, generalized anxiety disorder, or social phobia should be offered psychodynamic psychotherapy if CBT is ineffective or unavailable, or if the (adequately informed) patient expresses a preference for psychodynamic treatment. For specific phobias, the available studies are exclusively of behavioral therapy, which should be performed as exposure treatment.

The current state of the data does not permit any valid generalization about the necessary duration of psychotherapy, as most trials were conducted for periods of 10 to 24 weeks, and only a few of them involved a comparison of the efficacy of treatment when carried out for a shorter or longer time. The duration of treatment should be planned individually depending on the severity of illness, comorbidities, and the overall psychosocial situation. For specific phobias, the available studies show that exposure treatment can be performed successfully in a few sessions.

The guideline committee also investigated nontherapist-supported techniques that are performed via computer or over the Internet. Many studies of such treatments have been published in the last few years, but there is, as yet, insufficient evidence to conclude that they are as effective as individual CBT. Moreover, treatments without personal contact are not reimbursable by the statutory health insurance carriers in Germany. Medicolegal problems can also arise (e.g., in case of suicidality), and the matter of data privacy has not yet been adequately addressed. Patients with panic disorder/agoraphobia can be offered therapist-unsupported interventions based on CBT and involving books, audio material, computers, or the Internet as a form of self-help, to bridge the time interval before therapy is scheduled to begin or as adjunctive treatment to face-to-face therapy.

Group CBT has also been studied in randomized controlled trials, but there is still too little evidence to conclude that group CBT is as effective as individual treatment. It seems reasonable, however, to conduct self-assurance training in groups, e.g., for patients with social phobia; in such cases, the treatment should involve both individual and group therapy. Offering group therapy is also justified if individual therapy is unavailable.

The guideline committee found too little evidence to support any recommendation about other forms of psychotherapy (applied relaxation, interpersonal therapy, client-centered therapy, others).

Pharmacotherapy

Grade A recommendations were issued for drugs from two categories: the selective serotonin reuptake inhibitors (SSRI) and the serotonin-norepinephrine reuptake inhibitors (SNRI). Grade B recommendations were issued for the tricyclic antidepressant clomipramine (for panic disorder) and for pregabalin (for generalized anxiety disorder). Benzodiazepines, though effective, should not be prescribed, as they have major side effects (including the development of dependence). Only in exceptional cases—e.g., in the setting of severe heart disease, contraindications for the standard drugs, suicidality, and other situations—benzodiazepines can be given for short-term use after their risks and benefits have been carefully weighed.

Drug treatment should be conducted according to generally accepted medical standards. The patient must be informed about adverse effects, possible interactions, contraindications, and warnings; the prescriber should obtain this information from the current summary of product characteristics for the drug in question. Patients starting treatment with antidepressants should be told that they generally take effect after a latency period of about two weeks (range, 1 to 6 weeks).

SSRI and SNRI have a relatively flat dose-response curve, i.e., about 75% of patients respond to the initial (low) dose. For some patients, it is reasonable to begin treatment at half of the usually recommended dose. Dose adjustment may be necessary in patients with impaired hepatic function. To prevent agitation and insomnia at the start of treatment, the drug should be given in the morning or at midday. Some patients will need doses at the upper end of the indicated range and should be given them if necessary. Treatment with an SSRI or an SNRI should be continued as maintenance therapy at the same dose that was successful in acute treatment. Once remission has been achieved, pharmacotherapy should be continued for 6 to 12 months, or even longer if drug discontinuation leads to recurrent anxiety, if the anxiety disorder is especially severe, or if the patient's history indicates that prolonged treatment may be needed. The dose should be slowly tapered at the end of treatment to avoid discontinuation syndromes.

There is too little evidence to support any recommendation for drug treatment for specific phobias.

Combined psychotherapy and drug treatment, and the management of refractory anxiety

There have been a number of comparative studies of psychotherapy, drug treatment, and a combination of both in the treatment of panic disorder; most have indicated that a combination is superior to monotherapy of either type. For generalized anxiety disorder, studies of this type are lacking; for social phobia, the evidence is inconsistent. No study indicated that combination therapy was worse. If either psychotherapy or drug treatment is ineffective in an individual case, there should be a switch to the other type of treatment, or to a combination of the two. If there is no response to the first drug after 4 to 6 weeks of treatment, a second standard drug should be given instead. In case of a partial response, raising the dose can be considered first. Table 3 contains a stepwise plan for drug treatment options in case of drug inefficacy or intolerance. If a switch to a different standard drug is unsuccessful, there can be another switch to drugs recommended as a second-line treatment, e.g., tricyclic antidepressants or pregabalin. Medicolegal issues should be considered whenever drugs that have not been approved for the treatment of anxiety (e.g. quetiapine [in Europe]) are given off label.

The treatment of anxiety disorders in older patients

The treatment of older patients has been studied only in generalized anxiety disorder, probably because the other anxiety disorders are less commonly seen in older patients. The few available studies on CBT in persons over age 65 have shown a lower degree of efficacy than in adults aged 18 to 65. As for drug treatment in older patients, a few studies have shown efficacy for duloxetine, venlafaxine, pregabalin, and quetiapine. In older patients, possible drug interactions and contraindications must be considered carefully, along with the following additional factors: increased sensitivity to anticholinergic effects, the increased risk of orthostatic hypotension and ECG changes, the increased risk of falling, and possible paradoxical reactions to benzodiazepines.

Pregnancy and breastfeeding

For pregnant women, the risk of an untreated anxiety disorder must be weighed against the risk of damage to the unborn child as a result of treatment. The physician should consider whether psychotherapy may be preferable to drug treatment for this reason. Some authors report increased risks with antidepressant drugs (15–17), which should, therefore, be given with caution. Likewise, a risk assessment has to be done when the patient is breast feeding.

Exercise

Exercise is recommended as a treatment for panic disorder (aerobic training, e.g., jogging 5 km three times a week). There is, however, too little evidence to support a recommendation for exercise as monotherapy. In the studies performed to date, exercise was less effective than a drug (18) and no more effective than relaxation as a control treatment (19).

Self-help groups

Patients should be informed about self-help and family support groups and encouraged to participate if appropriate.

Conflict of interest statement
All participants in the creation of this guideline have declared their conflicts of interest (e.g., having received lecture honoraria from drug companies or having been an advocate for a particular form of treatment). The guideline committee tried to base its recommendations exclusively on objective evaluation of the scientific evidence despite these potentially distorting influences. Participants with a relevant conflict of interest abstained when recommendations were put to a vote.

Prof. Bandelow has served as a paid consultant to Lilly, Lundbeck, Otsuka, and Pfizer and has received reimbursement of meeting participation fees and of travel and accommodation expenses from Pfizer and Servier. He has received honoraria for lectures at scientific meetings and continuing medical education events from AstraZeneca, Glaxo, Janssen, Lilly, Lundbeck, Meiji-Seika, Otuska, Pfizer, and Servier.

Prof. Beutel has received payment from Pfizer, Servier, and Boehringer-Ingelheim for preparing scientific meetings and continuing medical education events.

Dr. Rudolf, Prof. Lichte, and PD Wiltink declare that no conflict of interest exists.

Manuscript submitted on 13 May 2014, revised version accepted on
22 May 2014.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Prof. Dr. med. Borwin Bandelow, Dipl.-Psych.
Klinik für Psychiatrie und Psychotherapie
Universitätsmedizin Göttingen
von-Siebold-Str. 5
37075 Göttingen, Germany

@eTables:
www.aerzteblatt-international.de/14m0473

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