Volume 14 Supplement 1

Canadian Anxiety Disorders Guidelines Initiative: Clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders

Open Access

Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders

  • Martin A Katzman1Email author,
  • Pierre Bleau2,
  • Pierre Blier3,
  • Pratap Chokka4,
  • Kevin Kjernisted5,
  • Michael Van Ameringen6 and
  • the Canadian Anxiety Guidelines Initiative Group on behalf of the Anxiety Disorders Association of Canada/Association Canadienne des troubles anxieux and McGill University
BMC Psychiatry201414(Suppl 1):S1

DOI: 10.1186/1471-244X-14-S1-S1

Published: 2 July 2014

Abstract

Background

Anxiety and related disorders are among the most common mental disorders, with lifetime prevalence reportedly as high as 31%. Unfortunately, anxiety disorders are under-diagnosed and under-treated.

Methods

These guidelines were developed by Canadian experts in anxiety and related disorders through a consensus process. Data on the epidemiology, diagnosis, and treatment (psychological and pharmacological) were obtained through MEDLINE, PsycINFO, and manual searches (1980–2012). Treatment strategies were rated on strength of evidence, and a clinical recommendation for each intervention was made, based on global impression of efficacy, effectiveness, and side effects, using a modified version of the periodic health examination guidelines.

Results

These guidelines are presented in 10 sections, including an introduction, principles of diagnosis and management, six sections (Sections 3 through 8) on the specific anxiety-related disorders (panic disorder, agoraphobia, specific phobia, social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder), and two additional sections on special populations (children/adolescents, pregnant/lactating women, and the elderly) and clinical issues in patients with comorbid conditions.

Conclusions

Anxiety and related disorders are very common in clinical practice, and frequently comorbid with other psychiatric and medical conditions. Optimal management requires a good understanding of the efficacy and side effect profiles of pharmacological and psychological treatments.

Keywords

guidelines recommendations anxiety disorders panic disorder agoraphobia specific phobia social anxiety disorder generalized anxiety disorder GAD obsessive-compulsive disorder OCD posttraumatic stress disorder PTSD pharmacotherapy psychotherapy special populations

Introduction

Anxiety and related disorders are among the most common of mental disorders. Lifetime prevalence of anxiety disorders is reportedly as high as 31%; higher than the lifetime prevalence of mood disorders and substance use disorders (SUDs) [15]. Unfortunately, anxiety disorders are under-diagnosed [6] and under-treated [5, 7, 8].

These guidelines were developed to assist clinicians, including primary care physicians and psychiatrists, as well as psychologists, social workers, occupational therapists, and nurses with the diagnosis and treatment of anxiety and related disorders by providing practical, evidence-based recommendations. This guideline document is not focused on any individual type of clinician but rather on assessing the data and making recommendations. Subsequent “user friendly” tools and other initiatives are planned.

The guidelines include panic disorder, agoraphobia, specific phobia, social anxiety disorder (SAD), generalized anxiety disorder (GAD), as well as obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD). Also included are brief discussions of clinically relevant issues in the management of anxiety and related disorders in children and adolescents, women who are pregnant or lactating, and elderly patients, and patients with comorbid conditions.

Methods

These guidelines are based on a thorough review of the current literature and were developed by a panel of Canadian experts in anxiety and related disorders through a consensus process. Data on the epidemiology, diagnosis, and treatment (psychological and pharmacological) were obtained through MEDLINE searches of English language citations (1980–2012), using search terms encompassing the specific treatments and specific anxiety and related disorders. These searches were supplemented with data from PsycINFO and manual searches of the bibliographies of efficacy studies, meta-analyses, and review articles. Treatment strategies were rated on strength of evidence for the intervention (Table 1). A clinical recommendation for each intervention was then made, based on global impression of efficacy in clinical trials, effectiveness in clinical practice, and side effects, using a modified version of the periodic health examination guidelines (Table 2).
Table 1

Levels of evidence

1

Meta-analysis or at least 2 randomized controlled trials (RCTs) that included a placebo condition

2

At least 1 RCT with placebo or active comparison condition

3

Uncontrolled trial with at least 10 subjects

4

Anecdotal reports or expert opinion

Levels of evidence do not assume positive or negative or equivocal results, they merely represent the quality and nature of the studies that have been conducted.

Level 1 and Level 2 evidence refer to treatment studies in which randomized comparisons are available. Recommendations involving epidemiological or risk factors primarily arise from observational studies, hence the highest level of evidence for these is usually Level 3. Recommendations, such as principles of care, reflect consensus opinion based on evidence from various data sources, and therefore are primarily Level 4 evidence.

Table 2

Treatment recommendation summary

First-line

Level 1 or Level 2 evidence plus clinical support for efficacy and safety

Second-line

Level 3 evidence or higher plus clinical support for efficacy and safety

Third-line

Level 4 evidence or higher plus clinical support for efficacy and safety

Not recommended

Level 1 or Level 2 evidence for lack of efficacy

The guidelines were initiated prior to the introduction of the American Psychiatric Association’s (APA) fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the committee was sensitive to potential changes to the nosology of anxiety and related disorders and its impact on the guidelines. However, it was agreed that, since the evidence for treatment is based on studies using DSM-IV criteria (or earlier), the introduction of the DSM-5 would not fundamentally alter the evidence and recommendations at this time. Whether using DSM-5 diagnostic criteria for the inclusion patients in clinical trials in the future will have an impact on outcomes, remains to be seen.

The panel of Canadian experts in anxiety and related disorders responsible for the development of these guidelines via consensus process included 10 psychiatrists and seven psychologists who were organized into subpanels based on their expertise in particular anxiety or related disorders as well as in treating specific patient populations. Preliminary treatment recommendations and the evidence upon which they had been based were reviewed at a meeting of the panel in December 2012; subsequently, draft guidelines were prepared by the subpanels which were then circulated to the entire group for consensus ratification during 2013. Preliminary recommendations were also presented to the Canadian psychiatric community for input in September 2012 at the Canadian Psychiatric Association annual conference.

These guidelines are presented in 10 sections, the first of which is this introduction. In the following section, the principles of diagnosis and management of anxiety and related disorders are covered. That section provides an overview of the differential diagnoses associated with anxiety and related disorders in general, discusses issues that affect all anxiety disorders, and presents the general advantages and disadvantages of psychological treatment and pharmacotherapy options. In the subsequent six sections (Sections 3 through 8), the specific diagnosis and management of the individual anxiety and related disorders (panic disorder, specific phobia, SAD, OCD, GAD, and PTSD) are reviewed and recommendations are made for psychological and pharmacological treatments. Section 9 discusses issues that may warrant special attention pertaining to anxiety and related disorders in children and adolescents, pregnant or lactating women, and the elderly. The last section of these guidelines addresses clinical issues that may arise when treating patients with anxiety and related disorders who are also diagnosed with comorbid psychiatric conditions such as major depressive disorder (MDD), bipolar disorder, or other psychoses, and attention deficit/hyperactivity disorder (ADHD), or medical comorbidities, such as pain syndromes, cardiovascular disease, and diabetes/metabolic syndrome.

Principles of diagnosis and management of anxiety and related disorders

Epidemiology

Prevalence and impact

Anxiety and related disorders are among the most common mental disorders, with lifetime prevalence rates as high as 31% [15] and 12-month prevalence rates of about 18% [3, 4]. Rates for individual disorders vary widely. Women generally have higher prevalence rates for most anxiety disorders, compared with men [4, 5, 9]. Anxiety and related disorders are associated with an increased risk of developing a comorbid major depressive disorder [1012].

Anxiety and related disorders put a significant burden on patients and their family members [13]. They are associated with substantial functional impairment, which increases as the severity of anxiety [14] or the number of comorbid anxiety disorders increases [7, 15]. In addition, studies have demonstrated quality of life impairments in patients with various anxiety and related disorders [16, 17]. Anxiety has a considerable economic impact on society as well, being associated with greater use of health care services [5, 18] and decreased work productivity [18, 19].

Importantly, studies report that about 40% of patients diagnosed with anxiety and related disorder are untreated [5, 7].

Suicide risk

In large surveys, anxiety and related disorders were independently associated with a significant 1.7-2.5 times increased risk of suicide attempts [2023]; however, data are conflicting as to whether the risk is moderated by gender [20, 23]. Increased risk of suicide attempts or completed suicide has been reported for patients with panic disorder, PTSD [20, 24], and GAD [24], even in the absence of a comorbid mood disorder. These data indicate that patients with an anxiety disorder warrant explicit evaluation for suicide risk. The presence of a comorbid mood disorder significantly increases the risk of suicidal behavior [22, 25].

Initial assessment of patients with anxiety

The management of patients presenting with anxiety symptoms should initially follow the flow of the five main components outlined in Table 3.
Table 3

Overview of the management of anxiety and related disorders

• Screen for anxiety and related symptoms

• Conduct differential diagnosis (consider severity, impairment, and comorbidity)

• Identify specific anxiety or related disorder

• Psychological and/or pharmacological treatment

• Perform follow-up

Screen for anxiety and related symptoms

Anxiety and related disorders are generally characterized by the features of excessive anxiety, fear, worry, and avoidance. While anxiety can be a normal part of everyday life, anxiety disorders are associated with functional impairment; as part of the key diagnostic criteria for anxiety disorders is the requirement that the symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning [26].

Asking patients if they are feeling nervous, anxious or on edge, or whether they have uncontrollable worry, can be useful to detect anxiety in patients in whom the clinician suspects an anxiety or related disorder [7]. The DSM-5 suggests the questions shown in Table 4 for the identification of anxiety-related symptoms; items scored as mild or greater may warrant further assessment [26]. If anxiety symptoms are endorsed, they should be explored in more detail by including questions about the onset of the anxiety symptoms, associations with life events or trauma, the nature of the anxiety (i.e., worry, avoidance, or obsession), and the impact they have had on the patient’s current functioning.
Table 4

General screening questions

• During the past two weeks how much have you been bothered by the following problems?

     Feeling nervous, anxious, frightened, worried, or on edge

     Feeling panic or being frightened

     Avoiding situations that make you anxious

Adapted from reference [26].

Table 5 presents suggested screening questions for individual anxiety and related disorders, from various validated screening tools [2730], some of which are freely available online (e.g., http://www.macanxiety.com/online-anxiety-screening-test).
Table 5

Screening questions for specific anxiety and related disorders

Panic disorder – MACSCREEN [29, 30]

• Do you have sudden episodes/spells/attacks of intense fear or discomfort that are unexpected or out of the blue?

If you answered "YES" then continue

• Have you had more than one of these attacks?

• Does the worst part of these attacks usually peak within several minutes?

• Have you ever had one of these attacks and spent the next month or more living in fear of having another attack or worrying about the consequences of the attack?

SAD (Based on Mini-SPIN [28])

• Does fear of embarrassment cause you to avoid doing things or speaking to people?

• Do you avoid activities in which you are the center of attention?

• Is being embarrassed or looking stupid among your worst fears?

GAD [31]

• During the past 4 weeks, have you been bothered by feeling worried, tense, or anxious most of the time?

• Are you frequently tense, irritable, and having trouble sleeping?

OCD – MACSCREEN [29, 30]

Obsessions:

• Are you bothered by repeated and unwanted thoughts of any of the following types:

     Thoughts of hurting someone else

     Sexual thoughts

     Excessive concern about contamination/germs/disease

     Preoccupation with doubts (“what if” questions) or an inability to make decisions

     Mental rituals (e.g., counting, praying, repeating)

     Other unwanted intrusive thoughts

• If you answered "YES" to any of the above… Do you have trouble resisting these thoughts, images, or impulses when they come into your mind?

Compulsions:

• Do you feel driven to perform certain actions or habits over and over again, or in a certain way, or until it feels just right? Such as:

     Washing, cleaning

     Checking (e.g., doors, locks, appliances)

     Ordering/arranging

     Repeating (e.g., counting, touching, praying)

     Hoarding/collecting/saving

• If you answered "YES" to any of the above… Do you have trouble resisting the urge to do these things?

PTSD – MACSCREEN [29, 30]

• Have you experienced or seen a life-threatening or traumatic event such as a rape, accident, someone badly hurt or killed, assault, natural or man-made disaster, war, or torture?

If you answered "YES" then continue

• Do you re-experience the event in disturbing (upsetting) ways such as dreams, intrusive memories, flashbacks, or physical reactions to situations that remind you of the event?

Conduct differential diagnosis

The differential diagnosis of anxiety and related disorders should consider whether the anxiety is due to another medical or psychiatric condition, is comorbid with another medical or psychiatric condition, or is medication-induced or drug-related [32].

When a patient presents with excessive or uncontrollable anxiety it is important to identify other potential causes of the symptoms, including direct effects of a substance (e.g., drug abuse or medication) or medical condition (e.g., hyperthyroidism, cardiopulmonary disorders, traumatic brain injury), or another mental disorder [26]. However, since comorbid conditions are common, the presence of some of these other conditions may not preclude the diagnosis of an anxiety or related disorder.

Certain risk factors have been associated with anxiety and related disorders and should increase the clinician’s index of suspicion (Table 6) [4, 9, 3337]. A family [33] or personal history of mood or anxiety disorders [34, 35] is an important predictor of anxiety symptoms. In addition, family history is associated with a more recurrent course, greater impairment, and greater service use [33]. A personal history of stressful life events is also associated the development of anxiety and related disorders [36, 37], in particular, childhood abuse [37].
Table 6

Common risk factors in patients with anxiety and related disorders

• Family history of anxiety [33]

• Personal history of anxiety or mood disorder [34, 35]

• Childhood stressful life events or trauma [36, 37]

• Being female [4, 9]

• Chronic medical illness [34, 40]

• Behavioral inhibition [41, 42]

Women generally have higher prevalence rates across all anxiety and related disorders, compared with men [4, 5, 9]. The median of age of onset is very early for some phobias and for separation anxiety disorder (seven to 14 years), but later for GAD, panic disorder, and PTSD (24-50 years) [1, 2].

Loneliness [38], low education [38], and adverse parenting [39], as well as chronic somatic illnesses, such as cardiovascular disease, diabetes, asthma, and obesity may increase the risk for a lifetime diagnosis of anxiety [34, 40].

Comorbid medical and psychiatric disorders

Anxiety and related disorders frequently co-occur with other psychiatric disorders [3]. More than half of patients with an anxiety disorder have multiple anxiety disorders [3, 15], and almost 30% will have three or more comorbid anxiety or related disorders [3]. Anxiety is often comorbid with substance use and mood disorders [3, 40]. An estimated 52% of patients with bipolar disorder [43], 60% of patients with MDD [44], and 47% of those with ADHD [45] will have a comorbid anxiety or related disorder. Therefore, anxiety disorders should be considered in these patients.

The high frequency of comorbidity must be considered when diagnosing anxiety and related disorders since this can have important implications for diagnosis and treatment [32]. Anxiety disorders comorbid with other anxiety or depressive disorders are associated with poorer treatment outcomes, greater severity and chronicity [4649], more impaired functioning [46], increased health service use [50], and higher treatment costs [51]. The impact tends to increase with an increasing number of comorbid conditions [46].

Patients with anxiety disorders have a higher prevalence of hypertension and other cardiovascular conditions, gastrointestinal disease, arthritis, thyroid disease, respiratory disease, migraine headaches, and allergic conditions compared to those without anxiety disorders [16, 52]. Comorbid anxiety and related disorders have a significant impact on quality of life (QoL) in patients with medical conditions [52].

Baseline assessment
Baseline assessment should include a review of systems, prescribed medications, over-the-counter agents, alcohol use, caffeine intake, and illicit drug use, in addition to evaluation of the anxiety symptoms and functioning [32]. Table 7 lists potential investigations that can be considered based on an individual patient’s presentation and specific symptoms (e.g., dizziness or tachycardia). Ideally, a physical examination and baseline laboratory investigations should be performed before pharmacotherapy is initiated, with repeat assessments according to best practice guidelines [32]. Patients with anxiety and related disorders should be monitored initially every one to two weeks and then every four weeks for weight changes and adverse effects of medications, as this is a major factor contributing to discontinuation of medication.
Table 7

Considerations for baseline laboratory investigations (as needed based on patient’s presenting symptoms)

Basic lab tests

 

• Complete blood count

• Fasting glucose

• Fasting lipid profile (TC, vLDL, LDL, HDL, TG)

• Thyroid-stimulating hormone

• Electrolytes

• Liver enzymes

If warranted

 

• Urine toxicology for substance use

 

Adapted from references [32, 53]. HDL = high density lipoprotein; LDL = low density lipoprotein; TC = total cholesterol; TG = triglyceride; vLDL = very low density lipoprotein.

Closer monitoring may be required in children younger than 10 years of age, older or medically ill patients, patients on medications associated with metabolic changes, and those on multiple medications [32].

Identify specific anxiety or related disorder

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) has been finalized by the American Psychiatric Association (APA) [26]. The new DSM-5 provides diagnostic criteria for psychiatric disorders based on scientific reviews of the literature, field trial data, internal evaluations, public comments, and a final review by APA’s Board of Trustees.

The “anxiety disorders” chapter now includes panic disorder, agoraphobia, GAD, selective mutism, separation anxiety disorder, SAD (social phobia), specific phobia, substance/medication-induced anxiety disorder, as well as anxiety disorder due to another medical condition or not elsewhere classified. OCD and PTSD have been moved to separate chapters on obsessive-compulsive and related disorders and trauma- and stressor-related disorders, respectively [26].

Table 8 provides a brief summary of the key DSM-5 diagnostic features of the anxiety and related disorders that are included in these guidelines [26]. While the DSM-5 is the most up-to-date diagnostic criteria, it is important to note that the evidence for treatment is based on studies using DSM-IV criteria (or earlier) for inclusion of patients. However, most of the diagnostic criteria have not changed substantially (see Sections 3–9 for more information on diagnosis); the exception being agoraphobia, which is now designated as a separate diagnosis.
Table 8

Key features of specific anxiety and related disorders

Disorder

Key features

Panic disorder

• Recurrent unexpected panic attacks, in the absence of triggers

• Persistent concern about additional panic attacks and/or maladaptive change in behavior related to the attacks

Agoraphobia

• Marked, unreasonable fear or anxiety about a situation

• Active avoidance of feared situation due to thoughts that escape might be difficult or help unavailable if panic-like symptoms occur

Specific phobia

• Marked, unreasonable fear or anxiety about a specific object or situation, which is actively avoided (e.g., flying, heights, animals, receiving an injection, seeing blood)

Social anxiety disorder (SAD)

• Marked, excessive or unrealistic fear or anxiety about social situations in which there is possible exposure to scrutiny by others

• Active avoidance of feared situation

Generalized anxiety disorder (GAD)

• Excessive, difficult to control anxiety and worry (apprehensive expectation) about multiple events or activities (e.g., school/work difficulties)

• Accompanied by symptoms such as restlessness/feeling on edge or muscle tension

Obsessive–compulsive disorder (OCD)

• Obsessions: recurrent and persistent thoughts, urges, or images that are experienced as intrusive and unwanted and that cause marked anxiety or distress

• Compulsions: repetitive behaviors (e.g., hand washing) or mental acts (e.g., counting) that the individual feels driven to perform to reduce the anxiety generated by the obsessions

Posttraumatic stress disorder (PTSD)

• Exposure to actual or threatened death, serious injury, or sexual violation

• Intrusion symptoms (e.g., distressing memories or dreams, flashbacks, intense distress) and avoidance of stimuli associated with the event

• Negative alterations in cognitions and mood (e.g., negative beliefs and emotions, detachment), as well as marked alterations in arousal and reactivity (e.g., irritable behavior, hypervigilance)

Adapted from reference [26].

Specific individual anxiety and related disorders should be diagnosed with the DSM-5 criteria in the sections devoted to each anxiety disorder. An accurate diagnosis is important to help guide treatment.

Psychological and pharmacological treatment

Treatment options for anxiety and related disorders include psychological and pharmacological treatments. All patients should receive education about their disorder, efficacy (including expected time to onset of therapeutic effects) and tolerability of treatment choices, aggravating factors, and signs of relapse [32]. Information on self-help materials such as books or websites may also be helpful.

The choice of psychological or pharmacological treatment depends on factors such as patient preference and motivation, ability of the patient to engage in the treatment, severity of illness, clinicians’ skills and experience, availability of psychological treatments, patient’s prior response to treatment, and the presence of comorbid medical or psychiatric disorders [32].

A brief overview of psychological and pharmacological treatments is provided below, with more specific recommendations in the individual sections for each anxiety and related disorder.

Overview of psychological treatment

Psychological treatments play an important role in the management of anxiety and related disorders. Regardless of whether formal psychological treatment is undertaken, patients should receive education and be encouraged to face their fears. Meta-analyses have demonstrated the efficacy of psychological treatments in group and individual formats in patients with panic disorder [5456], specific phobia [57], SAD [58, 59], OCD [6063], GAD [55, 64, 65], or PTSD [6669], particularly exposure-based and other cognitive behavioral therapy (CBT) protocols [70, 71], as well as mindfulness-based cognitive therapy (MBCT) [72]. When choosing psychological treatments for individual patients, the forms of therapy that have been most thoroughly evaluated in the particular anxiety or related disorder should be used first.

CBT is not a single approach to treatment, but rather a process that focuses on addressing the factors that caused and maintain the individual patient’s anxiety symptoms [73]. Some of the core components of CBT are shown in Table 9 [73].
Table 9

Components of cognitive behavioral interventions

Exposure

• Encourage patients to face fears

• Patients learn corrective information through experience

• Extinction of fear occurs through repeated exposure

• Successful coping enhances self-efficacy

Safety response inhibition

• Patients restrict their usual anxiety-reducing behaviors (e.g., escape, need for reassurance)

• Decreases negative reinforcement

• Coping with anxiety without using anxiety-reducing behavior enhances self-efficacy

Cognitive strategies

• Cognitive restructuring, behavioral experiments, and related strategies target patients’ exaggerated perception of danger (e.g., fear of negative evaluation in SAD)

• Provides corrective information regarding the level of threat

• Can also target self-efficacy beliefs

Arousal management

• Relaxation and breathing control skills can help patient control increased anxiety levels

Surrender of safety signals

• Patient relinquishes safety signals (e.g., presence of a companion, knowledge of the location of the nearest toilet)

• Patients learn adaptive self-efficacy beliefs

Adapted from reference [73].

CBT can be effectively delivered as individual or group therapy for most anxiety and related disorders. In addition, a variety of self-directed or minimal intervention formats (e.g., bibliotherapy/self-help books, or internet/computer-based programs with or without minimal therapist contact) have demonstrated significant improvements in anxiety symptoms [7479]. Meta-analyses have also shown that exposure therapy can be effectively administered in a virtual reality format [80, 81]. These strategies may be particularly useful in cases where real-life exposure is difficult due to inconvenience, expense, or patient reluctance.

Psychotherapy and pharmacotherapy generally demonstrate about equivalent efficacy for the treatment of most anxiety and related disorders [71, 82]. Results with combination therapy vary for the different anxiety disorders, and results have been conflicting [82, 83] (see Sections 3–9 for evidence and references regarding combination therapy). Therefore, current evidence does not support the routine combination of CBT and pharmacotherapy as initial treatment. However, when patients do not benefit from CBT or have a limited response, a trial of pharmacotherapy is advisable. Similarly, patients who show limited benefit from pharmacotherapy may benefit from CBT. All patients being treated with pharmacotherapy should be instructed to gradually face their fears (exposure to decrease avoidance).

Overview of pharmacological treatment

This section provides a general overview of some of the commonly recommended pharmacological agents. Evidence and recommendations for specific medications are described in the individual sections for each of the anxiety and related disorders.

Table 10 shows medications that have Health Canada approved indications for use in different anxiety and related disorders [84], and dosing suggestions are shown in Additional file 1. Various antidepressants including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and reversible inhibitors of monoamine oxidase A (RIMAs) have demonstrated some efficacy in the treatment of anxiety and related disorders (see Sections 3–9 for evidence and references). SSRIs and SNRIs are usually preferred as initial treatments, since they are generally safer and better tolerated than TCAs or MAOIs [32].
Table 10

Medications with Health Canada–approved indications for anxiety and related disorders

 

Anxiety disorders

Panic disorder

Social anxiety disorder

Obsessive–compulsive disorder

Generalized anxiety disorder

Posttraumatic stress disorder

ANTIDEPRESSANTS

      

SSRIs

      

Escitalopram (Cipralex®)

   

X

X

 

Fluoxetine (Prozac®)

   

X

  

Fluvoxamine (Luvox®)

   

X

  

Paroxetine (Paxil®)

 

X

X

X

X

X

Paroxetine CR (Paxil® CR)

 

X

X

   

Sertraline (Zoloft®)

 

X

 

X

  

TCAs

      

Clomipramine

   

X

  

Other antidepressants

      

Venlafaxine XR (Effexor® XR)

 

X

X

 

X

 

Duloxetine (Cymbalta®)

    

X

 

AZAPIRONES

      

Buspirone (BuSpar®, Buspirex®)

    

X

 

BENZODIAZEPINES*

X

     

Data from respective Canadian product monographs [84].

*Multiple generic and brand name products, consult product monographs: alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, lorazepam, and oxazepam are indicated for anxiety disorders; alprazolam is also indicated for panic disorder.

CR = controlled release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release.

Benzodiazepines may be useful as adjunctive therapy early in treatment, particularly for acute anxiety or agitation, to help patients in times of acute crises, or while waiting for onset of adequate efficacy of SSRIs or other antidepressants [32]. Due to concerns about possible dependency, sedation, cognitive impairment, and other side effects, benzodiazepines should usually be restricted to short-term use, and generally dosed regularly rather than as-needed [32].

Several anticonvulsants and atypical antipsychotics have demonstrated efficacy in some anxiety and related disorders, but for various reasons, including side effects, as well as limited randomized controlled trial (RCT) data and clinical experience, these agents are generally recommended as second-line, third-line, or adjunctive therapies (see Sections 3–9 for evidence and references).

The choice of medication should take into consideration the evidence for its efficacy and safety/tolerability for the treatment of the specific anxiety and related disorder, as well as for any comorbid conditions the patient might have, in both acute and long-term use.

Safety and side effects

Antidepressants: The most common side effects seen with SSRIs and SNRIs include headache, irritability, gastrointestinal complaints, insomnia, sexual dysfunction, weight gain, increased anxiety, drowsiness, and tremor [8588]. Patients report that the most common bothersome side effects are sexual dysfunction, drowsiness, fatigue, and weight gain [87, 88]. Most side effects occur early and transiently during the first two weeks of treatment, but others, such as sexual dysfunction and weight gain, may persist for the duration of treatment [85, 87, 89].

Use of SSRIs or SNRIs has been associated with an increased risk of upper gastrointestinal bleeding, particularly when used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) [90, 91]. SSRI use has also been associated with low bone mineral density [92, 93], as well as an increased risk of fractures [94] and hyponatremia [95].

Abrupt discontinuation of SSRIs or SNRIs can lead to a discontinuation syndrome with gastrointestinal, psychiatric, vasomotor, and other symptoms [85, 96].

Health Canada and the US Food and Drug Administration (FDA) require antidepressants to include a warning regarding an increased risk of suicidal ideation and behavior in children and adolescents [97, 98]. The increased risk of suicidal behavior reported in pediatric patients [99] does not appear to be seen in adults, and may in fact be decreased [99, 100]. Careful monitoring for evidence of self-harming or suicidal thoughts or behaviors is important in both adult and pediatric patients.

SSRIs and SNRIs are generally better tolerated and safer than TCAs and MAOIs, having less anticholinergic effects, toxicity, lethality, and psychomotor or cognitive impairment [85, 101]. MAOIs are generally reserved for second- or third-line treatment because of side effects, drug interactions, and dietary restrictions [32].

Anxiolytics: The most common side effects associated with benzodiazepines include primarily sedation, fatigue, ataxia, slurred speech, memory impairment, and weakness [85]. Benzodiazepines are associated with withdrawal reactions, rebound, and dependence, with the risk being greater with short- and intermediate-acting compared to long-acting agents [102]. These agents should be used with caution in patients with SUDs [85, 103]. Older patients (generally over 65 years of age) may be at high risk for falls and fractures due to psychomotor impairment associated with benzodiazepines [104, 105]. Cognitive impairment has been reported [106], some of which may persist after cessation of therapy [107]. In particular, memory impairment has been associated with high-dose or high-potency benzodiazepines, particularly in older people [102, 107].

Reported side effects of azapirones (buspirone) include dizziness, drowsiness, and nausea [32, 108].

Atypical antipsychotics: Atypical antipsychotics are associated to varying degrees with weight gain, diabetes, and other metabolic side effects, including alterations in glucose and lipid levels [109116]. Metabolic disturbances generally appear to be higher with olanzapine, intermediate with risperidone and quetiapine, and lower with aripiprazole, asenapine, lurasidone, and ziprasidone [109114].

Atypical antipsychotics have varying sedative effects, with quetiapine, clozapine, asenapine, and olanzapine generally causing more sedation than ziprasidone, risperidone, lurasidone, or aripiprazole [111, 115]. Data on cognitive effects are conflicting, with some studies suggesting improvements [111], while other data suggest greater cognitive dysfunction in patients using, versus those not using, antipsychotics [117].

Because of the risks of diabetes and weight gain, and the fact that there is limited RCT evidence of the efficacy of these agents in anxiety and related disorders, atypical antipsychotics are generally recommended as second-line, third-line, or adjunctive therapies (see Sections 3–9 for evidence and references).

Anticonvulsants: Anticonvulsants are associated with gastrointestinal side effects, somnolence, weight gain, tremor, as well as dermatologic and hematologic side effects [111, 118]. In addition, several anticonvulsants have a potential risk of serious rash, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis [111]. Regular monitoring of serum medication levels and liver function is required for patients on divalproex [84, 111].

Follow-up

Anxiety and related disorders are often chronic and a systematic approach to treatment should include patient education, assessment of comorbidities, and evidence-based pharmacological and psychological interventions with adequate monitoring and duration. Pharmacological treatment is often associated with a delay of about two to eight weeks in onset of symptom relief, with full response taking up to 12 weeks or more. Longer-term therapy has been associated with continued symptomatic improvement and the prevention of relapse, and therapy should be continued for at least 12-24 months for most patients [32].

Medication should be initiated at low doses and titrated to the recommended dosage range at one- to two-week intervals over four to six weeks. Once the therapeutic range has been achieved, improvement is usually seen over the next four to eight weeks. Follow-up should occur at two-week intervals for the first six weeks and monthly thereafter [32].

For a patient undergoing psychotherapy, the treatment schedule is structured around weekly contact with a therapist for about 12-20 weeks, although shorter protocols and minimal intervention programs have also proven effective (see Sections 3–9 for evidence and references). A follow-up appointment four weeks later and then every two to three months is usually sufficient [32].

Assessing response to treatment

Therapy should seek to improve symptoms and distress. The optimal goal is full remission of symptoms and return to a premorbid level of functioning [32, 85]. However, goals may need to be individualized for some patients with disorders that have been present since childhood as they may never have had adequate premorbid functioning. A response to therapy is often defined as a percentage reduction in symptoms (usually 25-50%) on an appropriate scale. Remission is often defined as loss of diagnostic status, a pre-specified low score on an appropriate disorder-specific scale, and no functional impairment in fully recovered patients as measured by a scale such as the Sheehan Disability Scale or SF-36 [32, 119, 120].

Objective scales can be used to help assess a patient’s progress. The Clinical Global Impression (CGI) scale is brief, comprehensive, and can easily be used at each appointment to assess improvement. The clinician-rated Hamilton Anxiety Rating Scale (HARS) can assess anxiety symptoms in general and is often used in clinical trials but is less practical in clinical practice. A variety of self-report and clinician-rated scales are available to assess the specific anxiety or related disorder.

Panic disorder and agoraphobia

Epidemiology

The lifetime and 12-month prevalence of panic disorder have been estimated at 4.7-5.1% and 2.1-2.8%, respectively [121, 122]. The estimated prevalence of panic attacks is considerably greater at 28.3% (lifetime) and 6.4-11.2% (12-month) [121, 123]. Youth with panic attacks (which often do not meet diagnostic criteria for panic disorder) will frequently have or develop other psychiatric disorders including mood disorders (bipolar disorder and MDD), other anxiety or related disorders, SUDs, eating disorders, psychotic disorders, and personality disorders [122, 124, 125]. Annually, 8-10% of the general public will have a panic attack without ever developing any identifiable psychopathology [126]. About 40-70% of patients with panic disorder experience nocturnal panic (waking from sleep in a state of panic) [127]. Rates of 12-month and lifetime agoraphobia (without panic) are quite low, at 0.8% and 1.4%, respectively [2, 3].

The risk of panic disorder and agoraphobia is higher in women than men, and patients who are middle-aged, widowed/divorced, and those of low income [122]. In the Canadian Community Health Survey 1.2 (CCHS 1.2) there were no differences in the rates of panic disorder or agoraphobia in urban versus rural settings [128].

Panic disorder has a negative impact on both psychological and physical functioning, and puts a substantial burden on the patient’s family [13]. Patients with panic disorder have more QoL impairment and dissatisfaction [16, 17], greater likelihood of suicide attempts [20], and increased cognitive and emotional dysfunction [129133] compared to healthy controls. Panic disorder is also associated with substantial societal costs [134], both in terms of health care utilization [135] and loss of workplace productivity [136]. In a 2012 survey, panic disorder conferred a substantial rate of work absenteeism (mean: 36.0 days/year) [136].

Comorbidity

Patients with panic disorder, or those experiencing panic attacks, have significantly increased odds of being diagnosed with a comorbid disorder, including another anxiety or related disorder, mood disorder, impulse-control disorder, or SUD [121, 137]. MDD is very common, occurring in an estimated 35-40% of patients with panic disorder [121]. Panic disorder also frequently co-occurs with agoraphobia [138].

Panic disorder is more prevalent in patients with medical conditions, including thyroid disease, cancer, chronic pain, cardiac disease, irritable bowel syndrome, migraine, as well as allergic and respiratory diseases compared with the general population [85, 139141]. The presence of medical comorbidity is associated with greater severity of panic disorder symptoms and disability [140, 142].

Diagnosis

For a diagnosis of panic disorder, a patient must have had recurrent, unexpected panic attacks (Table 11), followed by at least one month of persistent concern or worry about further attacks or their consequences, or a significant maladaptive behavioral change related to attacks (Table 12) [26].
Table 11

DSM-5 criteria for panic attacks

• An abrupt surge of intense fear or intense discomfort that reaches a peak within minutes, and includes ≥4 of the following symptoms:

(1) Palpitations, pounding heart, or accelerated heart rate

(2) Sweating

(3) Trembling or shaking

(4) Sensations of shortness of breath or smothering

(5) Feelings of choking

(6) Chest pain or discomfort

(7) Nausea or abdominal distress

(8) Feeling dizzy, unsteady, light-headed, or faint

(9) Chills or heat sensations

(10) Paresthesias (numbness or tingling sensations)

(11) Derealization (feelings of unreality) or depersonalization (being detached from oneself)

(12) Fear of losing control or going crazy

(13) Fear of dying

Adapted from reference [26].

Table 12

DSM-5 diagnosis of panic disorder

• The person has experienced both of the following:

     Recurrent unexpected panic attacks

     ≥1 of the attacks followed by ≥1 month of 1 or both of the following:

        • Persistent concern or worry about additional panic attacks or their consequences

        • Significant maladaptive change in behavior related to the attacks

Adapted from DSM-5 [26].

A panic attack continues to be considered a noncodable event in the DSM-5, with only minor revisions, including removal of the “10-minute” window, changing “hot flushes” to “heat sensations,” and the re-ordering of the list of symptoms to increase clinical utility [26, 143].

Compared to the DSM-IV-TR [144], changes to the diagnostic criteria for panic disorder largely consisted of minor phrasing changes to improve clinical utility, with the most substantial change being the title of the disorder [26, 143]. The DSM-5 now lists agoraphobia (anxiety about having a panic attack in certain situations, which are avoided or endured with marked distress) as a separate codable disorder, whereas previously panic disorder could be diagnosed as “panic disorder with agoraphobia” or “panic disorder without agoraphobia” [26, 145].

For a diagnosis of agoraphobia, a patient must have intense fear about at least two different types of situations, with the fear resulting from thoughts that escape may be difficult or help may be unavailable if panic-like symptoms occur (Table 13) [26, 145]. The situations provoke anxiety and are avoided or endured with intense fear or anxiety, or may require that a companion be present. The resultant fear or anxiety is out of proportion to any actual danger from the situation, causes substantial functional impairment, and usually lasts for six months or longer [26].
Table 13

DSM-5 diagnosis of agoraphobia

• Marked fear or anxiety about ≥2 of the following 5 groups of situations:

(1) Public transportation (e.g., traveling in automobiles, buses, trains, ships, or planes)

(2) Open spaces (e.g., parking lots, market places, or bridges)

(3) Being in shops, theatres, or cinemas

(4) Standing in line or being in a crowd

(5) Being outside of the home alone in other situations

• The individual fears or avoids these situations due to thoughts that escape might be difficult or help might not be available in the event of panic-like symptoms

• The agoraphobic situations almost always provoke fear or anxiety

• The situations are actively avoided, require presence of a companion, or endured with marked fear or anxiety

• The fear or anxiety is out of proportion to actual danger posed by agoraphobic situation

• The fear, anxiety, or avoidance is persistent, typically lasting ≥6 months

• The fear, anxiety, and avoidance cause clinically significant distress or functional impairment

Adapted from DSM-5 [26].

While the most up-to-date DSM-5 diagnostic criteria are presented here, the treatment data described within this section are based on studies involving patients meeting DSM-IV panic criteria (or older).

Establishing the context in which panic attacks occur, and whether there is any prior history of recurrent, unexpected panic attacks, is important for accurate diagnosis. Panic attacks frequently occur in other psychiatric disorders (e.g., MDD, PTSD), and medical conditions (e.g., cardiac, respiratory), and the DSM-5 has identified panic attacks as a specifier to be used in the absence of a diagnosable panic disorder [85]. Another disorder may better account for the panic attacks; for example, panic attacks in social situations may be SAD, those related to defined phobic objects or situations may be specific phobia, those related to reminders of traumatic events may be PTSD [26, 85], and those related to being kidnapped by extraterrestrials may be schizophrenia [26]. Some medical conditions that can be associated with panic symptoms include hyper- or hypothyroidism, hypoglycemia, seizure disorders, and cardiac conditions [26, 85]. Panic attacks may also be associated with intoxication or withdrawal from drugs of abuse, medications such as decongestants, stimulants, or beta-adrenergic agonist inhalers, or caffeine [85].

Psychological treatment

CBT has been extensively studied, and is an efficacious psychological treatment for panic disorder (Level 1) [56, 70, 146, 147]. In fact, CBT was significantly favored over medications for the treatment of panic disorder in a meta-analysis [71]. In a meta-analysis of 42 studies, exposure and combinations of exposure, cognitive restructuring and other CBT techniques had the most consistent evidence of efficacy for the treatment of panic disorder [56]. Strategies that included exposure were the most effective for panic measures. For measures of agoraphobia, combined strategies were more effective than single techniques, which did not result in significant improvements. Factors that improved the effectiveness of treatments were the inclusion of homework and a follow-up program [56]. Another meta-analysis also found that CBT that included interoceptive exposure was superior to relaxation therapy for panic symptoms [55]. CBT can be effectively delivered in both individual and group settings [56, 148, 149]. Conducting exposure in virtual reality appears to be effective when used as part of a CBT protocol [150154].

Minimal intervention formats, such as self-help books (bibliotherapy) [75, 76, 155158], treatment via telephone/videoconferencing [75, 159161], and internet-based CBT (ICBT) [75, 79, 162169] have been shown to be more effective than wait-list or relaxation controls, as effective as face-to-face CBT, and may be cost-effective options particularly for agoraphobic patients who are unwilling or unable to attend a clinic. When using bibliotherapy, providing information all at one time was as effective as pacing [157], and therapist support does not appear to be essential [75, 158]. Most ICBT programs have some therapist contact by either telephone or email, and once weekly contact appeared to be as effective as more frequent contact [168].

CBT panic disorder protocols usually involve 12-14 weekly sessions, but briefer strategies of six to seven sessions have been shown to be as effective [148, 149, 170]. In addition, compressing the duration of therapy by administering 13 sessions over three weeks has also been shown to be as effective as traditional weekly CBT [171]. Patients with higher baseline severity, disability, or comorbidity may have better outcomes with standard CBT [172]. CBT programs sometimes include one or more follow-up or “booster” sessions [170, 173].

Predictors of decreased response to CBT were severity of panic disorder, strength of blood/injury fears, earlier age of initial onset of panic symptoms, comorbid social anxieties, and degree of agoraphobic avoidance [174, 175]. Changes in symptoms are preceded by changes in beliefs during therapy [176], and change in beliefs and avoidance behaviors are considered key process variables [170, 176].

Eye movement desensitization and reprocessing (EMDR) does not appear to offer advantages over the same strategy without the eye movement component for the treatment of panic disorder [177, 178].

Combined psychological and pharmacological treatment

A meta-analysis of 21 trials found that combination psychotherapy and pharmacotherapy with antidepressants was superior to CBT or pharmacotherapy alone during the acute treatment phase and while medication was continued [179, 180]. After termination of treatment, combined therapy was more effective than pharmacotherapy alone and was as effective as psychotherapy [179, 180]. Prior meta-analyses have reported similar findings [54, 146, 181], suggesting that CBT alone or CBT combined with pharmacotherapy should be considered as first-line treatment.

A meta-analysis of the combination of psychotherapy and benzodiazepines included only three trials, and found no benefit to combination therapy compared with psychotherapy or medication alone [182]. The follow-up data suggested that the combination might be inferior to behavior therapy alone [182].

Adding self-administered CBT to SSRI therapy did not result in significant improvements overall, but patients did report a significantly greater rate of decline in fear of bodily sensations compared to medication alone [183]. Early results suggest a benefit of MBCT as an adjunct to pharmacotherapy in relieving anxiety and depressive symptoms in patients with panic disorder [184, 185].

Providing CBT sessions around the time of medication discontinuation was associated with a lower relapse rate during follow-up among patients treated with antidepressants [186]. In addition, CBT has been shown to be helpful in facilitating benzodiazepine discontinuation [187, 188].

A cost-effectiveness study found that combined CBT and pharmacotherapy was associated with a robust clinical improvement compared to usual care, with only a moderate increase in costs [189].

In a RCT, buspirone enhanced the effects of CBT in the short-term, but had no significant benefit over CBT alone during long-term follow-up [190].

Data on the efficacy of d-cycloserine as an adjunct to CBT are conflicting, with one study suggesting significant benefits at posttreatment and one-month follow-up [191], while another found an acceleration of symptom reduction in severely ill patients but no significant improvement in outcomes overall [192] compared to CBT plus placebo. Another compound acting at the N-methyl-D-aspartate (NMDA) receptor, Org 25935, demonstrated no benefit over placebo in augmenting CBT for panic disorder [193].

Long-term effects of psychological treatment

In naturalistic long-term follow-up studies, the benefits of CBT were maintained for up to three years [148, 169, 170, 188]. At two-year follow-up, individual, group, and brief CBT were associated with lower relapse rates compared to the wait-list control [148]. A long-term follow-up study of patients who had become panic-free with exposure therapy found that 93% remained in remission after two years and 62% after 10 years [194].

A meta-analysis found that at six to 24 months follow-up, remission/response rates with the combination of psychotherapy and antidepressants continued to be superior to antidepressants alone, or to psychotherapy as long as therapy was continued [179, 180].

Pharmacological treatment

The management of patients with panic disorder should follow the principles discussed in Section 2. Pharmacological interventions that have good evidence for efficacy in treating panic disorder include SSRIs, TCAs, and other antidepressants, as well as benzodiazepines. Treatments that have been investigated for use in panic disorder have been assessed according to the criteria for strength of evidence (Tables 1 and 2) and are summarized in Tables 14 and 15.
Table 14

Strength of evidence for pharmacotherapy for panic disorder

Agent

Level of evidence

Agent

Level of evidence

Antidepressants

SSRIs

 

TCAs

 

Citalopram [198200]

1

Clomipramine [199, 211, 213, 232, 233]

1

Fluoxetine [201204]

1

Imipramine [207, 224, 233240]

1

Fluvoxamine [195, 205210]

1

MAOIs and RIMAs

 

Paroxetine [211219]

1

Phenelzine [240]

2

Sertraline [183, 220224]

1

Moclobemide [204, 232, 241, 242]

1*

Escitalopram [198]

2

Tranylcypromine [243]

3

Paroxetine CR [225]

2

Other antidepressants

 

SNRIs

 

Reboxetine [200, 219, 244]

1

Venlafaxine XR [215, 216, 227229]

1

Mirtazapine [203, 245, 246]

2

Duloxetine [230]

3

Bupropion SR [247, 248]

3*

Milnacipran [231]

3

  

Other therapies

Anxiolytics

 

Atypical antipsychotics

 

    Benzodiazepines

 

Risperidone [217, 267]

2

      Alprazolam [234, 249254]

1

Olanzapine [268]

3

      Clonazepam [218, 250, 255258]

1

Quetiapine [267]

3

      Lorazepam [251, 259, 260]

1

Adjunctive aripiprazole [269]

3

      Diazepam [261263]

1

Adjunctive olanzapine [270]

3

      Adjunctive clonazepam [264, 265]

1

Adjunctive risperidone [271]

3

      Adjunctive alprazolam ODT [266]

3

Anticonvulsants

 

Other treatments

 

Divalproex [272275]

3

Buspirone [254, 282]

1 (-ve)

Levetiracetam [276]

3

Trazodone [283]

2 (-ve)

Gabapentin [277]

2 (-ve)

Propranolol [262, 284, 285]

2 (-ve)

Tiagabine [278, 279]

2 (-ve)

Adjunctive pindolol [286]

2

Carbamazepine [280]

3 (-ve)

  

Adjunctive divalproex [281]

3

*Conflicting data. No significant superiority over placebo in overall population, but significant benefits in subgroup of more severely ill patients. CR = controlled release; MAOI = monoamine oxidase inhibitor; ODT = orally disintegrating tablets; RIMA = reversible inhibitor of monoamine oxidase A; SNRI = serotonin–norepinephrine reuptake inhibitor; SR = sustained release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release; (-ve) = negative.

Table 15

Recommendations for pharmacotherapy for panic disorder

First-line

Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, paroxetine CR, sertraline, venlafaxine XR

Second-line

Alprazolam, clomipramine, clonazepam, diazepam, imipramine, lorazepam, mirtazapine, reboxetine

Third-line

Bupropion SR, divalproex, duloxetine, gabapentin, levetiracetam, milnacipran, moclobemide, olanzapine, phenelzine, quetiapine, risperidone, tranylcypromine

Adjunctive therapy

Second-line: alprazolam ODT, clonazepam

Third-line: aripiprazole, divalproex, olanzapine, pindolol, risperidone

Not recommended

Buspirone, propranolol, tiagabine, trazodone

CR = controlled release; ODT = orally disintegrating tablets; SR = sustained release; XR = extended release.

First-line agents

SSRIs: Evidence from meta-analyses [195197] and RCTs supports the use of the SSRIs citalopram [198200], fluoxetine [201204], fluvoxamine [195, 205210], paroxetine [211219], and sertraline [183, 220, 221, 223, 224] (all Level 1), as well as escitalopram [198] and paroxetine controlled-release (CR) [225] (both Level 2) for the treatment of panic disorder. In meta-analyses, SSRIs demonstrated significant improvements in panic symptoms, agoraphobic avoidance, depressive symptomatology, and general anxiety [195197, 226]. Effect sizes for SSRIs and TCAs are similar [195, 196], although dropout rates may be lower with SSRIs [195].

SNRIs: Venlafaxine extended-release (XR) has been shown to be useful in reducing the severity of panic disorder symptoms in RCTs (Level 1) [215, 216, 227229]. Two studies found significantly greater rates of panic-free patients compared with placebo [215, 216] while two did not [228, 229].

Second-line agents

TCAs: There is good evidence from RCTs to support the use of the TCAs clomipramine [199, 211, 213, 232, 233] and imipramine [207, 224, 233240] in panic disorder (Level 1). In meta-analyses, TCAs have demonstrated efficacy for the treatment of panic symptoms and agoraphobia [195197, 226]. Efficacy is generally equivalent to SSRIs, however, since TCAs tend to be less well tolerated and have higher discontinuation rates than SSRIs [195], they are recommended as second-line options.

Other antidepressants: Although there is level 1 evidence to support the use of reboxetine [200, 219, 244], limited experience with this agent in Canada, and its side effect profile, which includes dry mouth, constipation, and insomnia [244], led to its recommendation as a second-line option. Mirtazapine has demonstrated efficacy for the treatment of panic disorder in several open trials [245, 246] and one small RCT [203] (Level 2). It appears to be as effective as fluoxetine [203] and may be a useful second-line choice.

Benzodiazepines: Alprazolam [234, 249254], clonazepam [218, 250, 255258], lorazepam [251, 259, 260], and diazepam [261263] have demonstrated efficacy for the treatment of panic disorder (Level 1). While it has been suggested that alprazolam may be more effective, a meta-analysis found no evidence that it was superior to other benzodiazepines for the treatment of panic disorder [252]. Although benzodiazepines are second-line options, they may be useful at any time during therapy for the short-term management of acute or severe agitation or anxiety. They may also be useful at the initiation of SSRI treatment to hasten response (Level 1) [264266].

Third-line agents

MAOIs and RIMAs: Results with moclobemide for the management of panic disorder have been conflicting (Level 1). In clinical trials, moclobemide demonstrated efficacy similar to that of clomipramine and fluoxetine [204, 232], but was not superior to placebo [241, 242]. However, significant efficacy in more severely ill patients [241], suggests it may be useful in treatment-resistant patients. In a RCT, phenelzine was more effective than placebo and as effective as imipramine (Level 2) [240]. In a small randomized, uncontrolled trial, tranylcypromine demonstrated efficacy for patients with comorbid panic and social anxiety disorders (Level 3) [243].

Atypical antipsychotics: There is some evidence that atypical antipsychotics may have some benefits in the treatment of patients with refractory panic disorder [217, 267, 268]. In a RCT, risperidone monotherapy was as effective as paroxetine (Level 2) [217]. Open-label data also support the use of risperidone [267], olanzapine [268], and quetiapine [267]. There are also open-label data supporting the use of some atypical antipsychotics as adjunctive therapy (see below).

Other therapies: The antidepressants duloxetine [230], milnacipran [231], and bupropion sustained release (SR) [247, 248] have shown some efficacy in open trials, as have the anticonvulsants divalproex [272275] and levetiracetam [276] (all Level 3). In a RCT, gabapentin was superior to placebo in patients who were more severely ill, but not in the overall group (Level 2, negative) [277]. These agents are recommended only as third-line options in patients with refractory panic disorder.

Adjunctive therapy

There is good evidence that adjunctive clonazepam [264, 265] (Level 1), and open-label evidence that adjunctive alprazolam orally-disintegrating tablet (ODT) [266] (Level 3), used short-term (<8 weeks including taper) at the initiation of SSRI treatment, can lead to a more rapid response [264266].

In a RCT, pindolol added to fluoxetine therapy in patients with treatment-resistant panic disorder was associated with significant improvement in panic disorder symptoms compared with fluoxetine plus placebo (Level 2) [286]. Open-label data also support the use of the atypical antipsychotics aripiprazole [269], olanzapine [270], and risperidone [271] (all Level 3), as well as the anticonvulsant divalproex [281], as adjunctive strategies for patients with treatment-resistant panic disorder.

Not recommended

Buspirone (Level 1, negative) [254, 282], propranolol (Level 2, negative) [262, 284, 285], tiagabine [278, 279] (Level 2, negative), and trazodone (Level 2, negative) [283] have not demonstrated efficacy and are not recommended for the treatment of panic disorder. Carbamazepine (Level 3, negative) [280] also does not appear to be effective in this disorder.

Maintenance pharmacological treatment

In long-term, open, follow-up studies, citalopram [287, 288], fluoxetine [204, 288], fluvoxamine [288], paroxetine [288290], and moclobemide [204], as well as clomipramine [287, 289] and imipramine [291, 292] demonstrated maintenance of benefits and continued improvements over six months to three years of ongoing treatment. In a RCT, sertraline and imipramine were equally effective over a six month period [224]. However, in another RCT, imipramine was not superior to placebo in the proportion of panic-free patients after eight months of therapy [293].

Venlafaxine XR [294] and imipramine [295] have been shown to prevent relapse in randomized, placebo-controlled, discontinuation studies. After three months of acute treatment, relapse rates were significantly lower with ongoing venlafaxine XR [294] or imipramine [295] therapy compared with switching to placebo during six to 12 months of follow-up.

Benzodiazepines are generally recommended for short-term use only. However, several trials have demonstrated the benefits of up to two years of alprazolam maintenance therapy [291, 293]. There was no evidence of tolerance, but up to one-third of patients were unable to discontinue therapy [293]. The efficacy of clonazepam was maintained over a three-year course of treatment [290], and patients who had been asymptomatic for at least one year were able to successfully discontinue the medication, using a slow tapering strategy over four to seven months, and improvement in panic disorder was maintained [296].

Biological and alternative therapies

Biological therapies: In open-label case series, noninvasive brain stimulation using a radioelectric asymmetric conveyor (REAC) demonstrated efficacy for panic symptoms and agoraphobia (Level 3) [297, 298]. A small case series suggested repetitive transcranial magnetic stimulation (rTMS) could improve panic and anxiety in patients with panic disorder with comorbid MDD (Level 4) [299]. However, a small RCT found no additional benefit of rTMS compared to sham rTMS as an add-on to SSRI therapy in patients with panic disorder (Level 2, negative) [300].

Alternative therapies: In a RCT, capnometry-assisted respiratory training was as effective as cognitive training in reducing panic symptom severity and panic-related cognitions and improving perceived control (Level 2) [301]. However, breathing training did not significantly improve reactivity or recovery after a respiratory challenge in another small trial (Level 2, negative) [302]. In a RCT, patients with panic disorder randomized to the exercise groups (plus paroxetine or placebo) had a trend toward better improvement compared to relaxation training, but this was not significant (Level 2, negative) [303]. However, in an open cross-over study, acute aerobic exercise was found to reduce anxiety as well as panic attack frequency and intensity in patients with panic disorder compared to a quiet rest condition (Level 3) [304]. These therapies may be useful for some patients; however, more data are needed.

Summary

As much as 40% of the general population has experienced a panic attack at some point in their lifetime. However, patients with actual panic disorder experience recurrent, unexpected panic attacks as well as persistent concern or behavioral change around further attacks.

Data support pharmacotherapy, CBT alone, and CBT combined with pharmacotherapy as initial treatments for panic disorder. CBT alone may be insufficient in patients with comorbid moderate-to-severe major depression, or in those with severe, frequent panic attacks, or rapid worsening of agoraphobia, and/or suicidal ideation, as well as in situations where one might consider initial rescue treatment with a benzodiazepine to minimize or stop the panic attacks while waiting the 4-12 weeks for the first-line pharmacotherapy to become effective. Also there are patients who are not motivated to participate in CBT (preferring medication as initial treatment) or are too fearful to engage in any kind of exposure before being treated with a first-line pharmacotherapeutic agent. At the very least, if agoraphobic distress or avoidance persists, these patients need instruction and support to engage in exposure exercises. For panic symptoms, strategies should include exposure; and combined strategies should be considered for patients with agoraphobia. CBT can be effectively delivered in both individual and group settings, as well as via self-help books, virtual reality, and internet-based programs. The benefits of CBT are maintained during follow-up. In addition, data suggest that combination of psychotherapy and pharmacotherapy may be superior to pharmacotherapy alone during follow-up.

Pharmacotherapeutic approaches should begin with a first-line agent. If response to optimal dosing is inadequate or the agent is not tolerated, treatment should be switched to another first-line agent before considering second-line medications. First-line options for the treatment of panic disorder include citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine XR, escitalopram, or paroxetine CR. Second-line choices include the TCAs (clomipramine and imipramine), mirtazapine, reboxetine, or benzodiazepines (alprazolam, clonazepam, lorazepam, and diazepam).

Patients who do not respond to first- or second-line agents are considered to have treatment-refractory illness. In such patients it is important to reassess the diagnosis and consider comorbid medical (e.g., ischemic heart disease) and psychiatric conditions (e.g., SUDs) that may be affecting response to therapy. Third-line agents, adjunctive therapies, as well as biological and alternative therapies may be useful when patients fail to respond to an optimal treatment trial of first- and second-line therapies used alone and in combination.

Specific phobia

Epidemiology

A specific phobia is an intense fear of a specific object or situation and is usually associated with avoidance of the feared object. The most prevalent phobia types include animal (e.g., insects, snakes), natural environment (e.g., heights, storms, water), situational (e.g., flying, enclosed spaces), and blood-injection-injury (B-I-I) (e.g., blood, dentists, hospitals) [305, 306]. Large US and European epidemiologic surveys report lifetime prevalence estimates of 10-13% and 12-month prevalence rates of 7-9% [2, 3, 305, 307]. Rates among adolescents may be particularly high with lifetime prevalence estimates of 36.5% and 12-month prevalence rates of 27.3% being reported [308]. Specific phobias are more common in women than men [306]. Age of onset is usually in the range of five to 12 years (median: seven years) [2]; however, this varies by type of phobia. Animal and B-I-I phobias generally begin in childhood, whereas situational phobias (e.g., driving phobia, claustrophobia) have a later onset, typically during late adolescence or early adulthood [306].

Specific phobias are associated with significant distress, regardless of the number of feared stimuli reported [305]. Specific phobias have a negative impact on social/occupational functioning and lead to restriction of usual daily activities, which increases with an increasing number of fears [305].

Comorbidities

Specific phobias tend to co-occur with other specific phobias, with less than 10% of patients having only one fear [305]. The mean number of fears, in one survey, was three [305]. In addition, specific phobias are frequently comorbid with other psychiatric disorders, including SUDs, mood disorders, and other anxiety or related disorders (particularly panic disorder, SAD, and GAD), as well as personality disorders [305, 309, 310].

Diagnosis

To receive a DSM-5 diagnosis of specific phobia a patient must experience marked (intense) fear or anxiety about a specific object or situation, which is associated with significant distress or functional impairment (Table 16) [26]. The object or situation will be actively avoided or endured with intense anxiety. Compared to the DSM-IV-TR criteria for specific phobia [144], few changes were made in the DSM-5 [26, 306]. Of note, recognition that the fear is excessive or unreasonable has been removed and a new criterion stating “the fear or anxiety is out of proportion to danger posed” has been added. Avoidance has been clarified as “actively avoided” to distinguish the avoidance seen in specific phobias from passive avoidance that may occur for other reasons [26, 306].
Table 16

DSM-5 diagnosis of specific phobia

• Marked fear or anxiety about a specific object or situation (e.g., flying, seeing blood)

• The phobic object or situation almost always provokes immediate fear or anxiety and is actively avoided or endured with marked fear or anxiety

• The fear or anxiety is out of proportion to the actual danger posed by the specific object or situation

• The fear, anxiety, or avoidance is persistent, typically ≥6 months

• There is marked distress or functional impairment

Adapted from DSM-5 [26].

While the most up-to-date DSM-5 diagnostic criteria are presented here, it is important to note that most of the treatment data described within this section are based on patients meeting DSM-IV criteria (or older).

Specific phobias are delineated into five types: animal type, natural environment type, B-I-I type, situational type, or other type (Table 17) [26]. The fear of contracting an illness has been removed because of high relatedness to OCD and anxiety disorder related to medical condition [26].
Table 17

Specific phobia specifiers in DSM-5

Specifier

Examples

Animal

Spiders, insects, dogs

Natural environment

Heights, storms, water

Blood-injection-injury

Needles, invasive medical procedures

Situational

Airplanes, elevators, enclosed spaces

Other

Choking or vomiting. In children, loud sounds or costumed characters

Adapted from DSM-5 [26].

Specific phobias can be difficult to distinguish from panic disorder [311]. It is important to consider the focus of apprehension (e.g., fear of crashing while on an airplane versus fear of having a panic attack on an airplane), the types of panic attacks experienced (e.g., expected versus unexpected), and the range of situations associated with fear and avoidance [311].

Psychological treatment

Psychosocial interventions, particularly exposure-based treatments, are the treatments of choice and are associated with a high degree of success in providing remission of specific phobias [311]. Both in vivo exposure and virtual reality exposure (VRE) can be effective [57, 311, 312], with in vivo exposure being shown to be superior to alternative types (e.g., imaginal, virtual reality, etc.) at posttreatment but not at follow-up [57].

In general, exposure-based therapy has been shown to be more effective if: sessions are grouped closely together; exposure is prolonged, real (not imagined), and provided in multiple different settings; and there is some degree of therapist involvement (not entirely self-directed) [32, 311]. While one-session treatments have demonstrated efficacy [313], a meta-analysis found that a greater number of sessions predicted more favorable outcomes [57].

There is no evidence that either flooding or gradual exposure is more effective [314], however, progressive exposures are generally more tolerable to patients [311]. An example of graded exposure in a patient with arachnophobia would be to look at pictures of spiders, hold a rubber spider, look at a live spider in a jar, touch the jar containing the spider, stand two feet from a live spider, and finally touch a live spider. This approach can be used to guide exposure depending on the patient’s symptom severity and tolerance to each level of exposure.

While a meta-analysis of 33 RCTs of psychological approaches found that treatment outcomes were not moderated by type of specific phobia [57], studies have suggested that certain subtypes may respond more favorably to specific types of treatment (Table 18).
Table 18

Psychological treatments with demonstrated efficacy in specific phobias

Psychological treatment

Phobia

Exposure-based treatments

All specific phobias [57, 311, 312]

Virtual reality exposure

Heights [327329], flying [319, 321324], spiders [331, 332], claustrophobia [330]

Computer-based self-help programs

Spiders [334, 335], flying [323], small animals [336, 337]

Applied muscle tension (exposure combined with muscle tension exercises)

Blood-injection-injury type [311, 315, 316]

Cognitive therapy and exposure

Dental [318], flying [319, 320]

For patients with B-I-I phobias, exposure therapy combined with muscle tension exercises (applied tension) designed to prevent fainting [311] has been shown to be effective [315, 316]. Use of stress-reducing medical devices, such as decorated butterfly needles and syringes, has been shown to significantly reduce needle phobia and stress in both pediatric and adult patients [317]. CBT reduced avoidance of oral injections and decreased anxiety in patients with dental phobias [318].

Fear of flying has been effectively treated with group CBT [319, 320]. In addition, computer-generated VRE has demonstrated efficacy [319, 321324], which was comparable to standard exposure therapy in several studies [322, 324], and can have long-term benefits [325, 326]. Bibliotherapy was found to be less effective than VRE or CBT for patients with fear of flying [319]. VRE has also been shown to be effective for patients with a fear of heights [327329], and those with claustrophobia [330]. This approach may also be useful for treating fears for which in vivo exposure may not be practical (e.g., fear of storms) [32].

Arachnophobia has been successfully treated with in vivo[331] and VR [331, 332] exposure, with little difference between the two modalities [331]. A spiderless form of VRE, which presented images that were not spiders, but had some of the characteristics of spiders, was shown to be useful in patients with severe arachnophobia who were reluctant to undergo direct exposure or VRE [333]. An internet-based self-help program was associated with improvement, but was not as effective as one session of in vivo exposure at the post-treatment assessment, although results were similar at follow-up [334]. However, even one session of VRE was associated with greater fear reduction compared to a control group, and may be a useful self-help intervention to reduce fear of spiders [335]. Computer-based self-help has also shown promise for other small-animal phobias (e.g., cockroaches, mice) [336, 337].

Combined psychological and pharmacological treatment

It has been speculated that d-cycloserine, a partial agonist at the NMDA receptor, may improve extinction of fear in patients with phobias undergoing behavioral exposure therapy [338]. In a RCT (n=28), d-cycloserine as an adjunct to VRE resulted in significantly larger reductions of acrophobia symptoms compared with VRE alone [338]. In another study (n=100), adjunctive d-cycloserine did not improve the reduction of spider fears compared to exposure-based therapy alone, however, patients had heightened, but subclinical, spider fears [339].

In two RCTs, use of adjunctive cortisol, a glucocorticoid, significantly enhanced the benefits of exposure therapy compared with placebo in patients with acrophobia (n=40) [340] and arachnophobia (n=20) [341], with evidence suggesting that cortisol may facilitate the extinction of phobic fear at follow-up.

Enhanced emotional memory may be stimulated through elevated noradrenaline levels, and data suggest that yohimbine hydrochloride, a noradrenaline agonist, can facilitate fear extinction. In RCTs, there were no significant VRE-enhancing effects with adjunctive yohimbine compared with placebo in patients with fear of flying (n=48) [342] or claustrophobia (n=24) [343]. However, in the claustrophobia study, patients treated with yohimbine showed greater improvements in outcomes at the one-week follow-up [343].

In contrast, naltrexone was found to render one-session exposure therapy less effective compared with placebo or no treatment in 15 patients with specific phobias (animals) [344].

Long-term effects of psychological treatment

Long-term treatment of specific phobia is rare. As discussed above, CBT and exposure therapies have demonstrated sustained benefits at long-term follow-up assessments [325, 326].

Pharmacological treatment

There is a minimal role for pharmacotherapy in the treatment of specific phobias, largely due to the lack of research on medications in this condition, and the success of exposure-based therapies [32, 311].

Antidepressants have been investigated in two small RCTs [345, 346]. In a small RCT, paroxetine was significantly more effective than placebo in resolving anxiety in patients with specific phobias (n=11) [345]. Similarly, escitalopram was associated with a strong treatment effect in a small RCT (n=12); however, the trial was under-powered to show statistically significant superiority over placebo on the primary outcome [346]. In addition, cases of successful treatment of flying phobias with fluoxetine [347], and storm phobia with fluvoxamine [348], have been reported.

Benzodiazepines have usually been assessed as adjuncts to exposure therapy, and these studies have found no additional benefit with medication [349351]. Benzodiazepines are often used in clinical practice to provide acute symptom relief when it is necessary for a patient with a specific phobia to face a feared situation (e.g., dental procedure, magnetic resonance imaging [MRI], unexpected flight) [32]. Nasal midazolam has proven useful in facilitating MRI in claustrophobic patients [352, 353].

Summary

Specific phobia is quite common, particularly among adolescents. Patients with specific phobia exhibit an intense fear or anxiety about a specific object or situation which is associated with significant distress or functional impairment. The most prevalent phobia types include animal, natural environment, situational, and B-I-I.

Exposure-based techniques, including virtual exposure, are highly effective, and are the foundation of treatment for specific phobias. Pharmacotherapy is generally unproven, and thus not a recommended treatment for most cases.

Social anxiety disorder

Epidemiology

SAD is one of the most common anxiety disorders, with lifetime prevalence estimates ranging from 8-12% among the international general population [2, 354356]. It is more common in women than men [355, 357360], and higher rates have been reported in developed (6.1%) versus developing (2.1%) countries [361]. SAD has an early age of onset, typically during adolescence (mean 12 years), and tends to have a chronic and unremitting course [2, 362, 363]. Factors such as low educational achievement, low socioeconomic status, being single or separated, and having comorbid MDD have been associated with a higher prevalence of SAD in epidemiological studies [359, 360, 364].

SAD is associated with significant impairments including problems with educational and occupational performance, family functioning, and an overall reduced QoL [14, 15, 17, 354, 363, 365369]. SAD also confers a substantial economic burden upon afflicted individuals and society in terms of work days missed and health care costs [370, 371]. Canadians with SAD were twice as likely to report at least one disability day in the past two weeks, compared to those without SAD [356].

Psychiatric comorbidity

SAD is associated with significant comorbidity, with up to 72% of patients reporting criteria for another psychiatric disorder [372]. The highest rates of comorbidity have been found with MDD and other anxiety or related disorders [355, 356, 360]. Avoidant personality disorder [373], body dysmorphic disorder [374, 375], SUD [356, 376], ADHD [377, 378], and schizophrenia [379] also commonly occur with SAD.

Diagnosis

SAD is characterized by a persistent fear that in social and performance situations the individual will say or do something that will lead to humiliation, embarrassment, or negative evaluation by others (Table 19) [26]. Social situations are actively avoided or endured with distress, and the individual recognizes the fears as excessive or unreasonable. The avoidance or anxiety induced by these fears incurs significant functional impairment and distress [144]. Compared to the DSM-IV-TR [144], changes to the diagnostic criteria for SAD in the DSM-5 have been minimal, largely consisting of minor phrasing changes to improve clinical utility [26]. The criterion that the “person recognizes that the fear is excessive or unreasonable” has been changed to “out of proportion to the actual threat posed by the social situation.” Since patients with SAD are often unable to recognize that their fear may be excessive the clinician may be in a better position to judge this.

Table 19

DSM-5 diagnosis of SAD (social phobia)

• Marked fear or anxiety about social situations in which the person may be exposed to scrutiny by others

• Fear that actions or showing anxiety symptoms will cause negative evaluation (e.g., embarrassment, humiliation) or offend others

• The social situation:

     Almost always provokes fear or anxiety

     Is actively avoided or endured with marked fear or anxiety

• The fear, anxiety, or avoidance:

     Is out of proportion to the actual threat posed by the social situation

     Is persistent, typically ≥6 months

     Causes significant distress or functional impairment

• If another medical condition is present (e.g., stuttering, obesity), the disturbance is unrelated or out of proportion to it

• Specify “performance only” if the fear is restricted to speaking or performing in public

Adapted from DSM-5 [26].

The DSM-IV-TR criteria excluded social fears/avoidance associated with and secondary to medical conditions, however, the DSM-5 recognizes that SAD may be secondary to a medical condition. Some patients experience excessive social anxiety about their medical symptoms (e.g., stuttering, tremulousness from Parkinson’s disease, obesity, disfigurement from burns or injury), and may experience disability due to their social anxiety [26].

In addition, the “generalized” subtype specifier included in DSM-IV-TR has been removed, while the “performance only” specifier has been added [26, 380] for DSM-5. This change was made because there was little supporting evidence for the generalized specifier, and the evidence that SAD symptoms fall along a continuum of severity characterized by the number of fears [380]. The “performance only” specifier appears to represent a subset of SAD patients typically experiencing impairment from performance fears primarily related to their professional lives [26].

While the most up-to-date DSM-5 diagnostic criteria are presented here, it is important to note that all of the treatment data described within this section are based on patients meeting DSM-IV criteria (or older).

Psychological treatment

Psychological treatment, in the form of CBT, is considered to be the gold-standard nonpharmacological treatment in SAD. Cognitive techniques involved in CBT for SAD include restructuring and challenging of maladaptive thoughts, while the behavioral component is typically in the form of exposure therapy. The efficacy of CBT compared with placebo, treatment-as-usual, or wait-list conditions, is supported by many RCTs as well as meta-analytic evidence [58, 59, 70, 71, 381]. Although results vary, several studies of acute SAD treatment have also found a similar efficacy between CBT and pharmacotherapy [382387]. Some reports suggest that after treatment discontinuation, gains achieved with CBT may persist longer than those achieved with pharmacotherapy [388, 389]. CBT for SAD can be administered in group or individual formats. Although some studies have reported that individual CBT is superior to group CBT [390, 391], meta-analyses have failed to find significant differences in efficacy between the two modalities [58, 59, 381].

The treatment literature has also examined the efficacy of the individual components of CBT. There is evidence to support the effectiveness of exposure therapy alone [389, 392], however the efficacy of exposure alone compared with CBT is equivocal in the current treatment literature [392395].

There are several variants of CBT that have been examined in the literature. For example, videotaped feedback was not shown to enhance the effects of exposure-based treatment [396]. However, CBT with VRE was found to be more effective than wait-list control and as effective as CBT with imaginal or in vivo exposure according to two meta-analyses [80, 150].

A form of CBT focused on interpersonal behavior found similar improvements in social anxiety compared to standard CBT but also increased relationship satisfaction and social approach behaviors [397]. Evidence to support interpersonal therapy (IPT) in SAD is conflicting [398400]; while some results have been negative [398], it is likely that IPT is more effective than wait-list control [399], but less effective than traditional CBT [399, 400].

Similarly, while less effective than traditional CBT, mindfulness-based therapy (MBT) has been associated with improvements in symptoms of SAD [401]. In addition, small studies of attentional bias training suggest there may be some benefit associated with training patients to disengage from negative social cues, but data are conflicting [402, 403].

ICBT is a newer treatment that may increase the availability of CBT for anxiety and mood disorders in the future. Studies have evaluated this treatment in comparison to individual and group CBT. ICBT has demonstrated efficacy in RCTs of SAD, significantly improving social anxiety symptoms compared to wait-list control conditions [404410]. Most ICBT programs include minimal therapist contact via email [404410] or telephone [405, 409]. Many programs involve a component of interaction with other participants through the use of internet discussion groups [411]. However, it remains unclear whether the therapist component is necessary, and studies comparing guided with unguided ICBT have yielded conflicting results. In one RCT, clinician-assisted ICBT was more effective than a self-guided ICBT, and the self-guided ICBT was not significantly better than the wait-list condition [406]. Similarly, a self-help program augmented with minimal therapist contact was more useful than a pure self-help strategy [412]. However, several other RCTs have found that unguided ICBT self-help was as effective as ICBT with therapist involvement [410, 411]. A few ICBT programs included face-to-face in vivo exposure sessions [409, 413], but one RCT found that adding this component did not significantly improve outcomes versus ICBT with self-directed exposure [413]. In addition, several RCTs have shown ICBT (with minimal therapist contact) to be as effective as face-to-face CBT [414, 415], while being more cost-effective [416]. As with other RCTs, research on ICBT has involved pre-screening of participants in-person or by telephone, with posttreatment and follow-up assessments by telephone or through self-report measures. Little is known about the effectiveness of self-administered treatments (ICBT or self-help books) used with no pre-screening or planned follow-up contacts.

Combined psychological and pharmacological treatments

When used in combination, pharmacotherapy has not been shown to add to the benefits of CBT in some studies [387, 417], while one study found the combination of phenelzine and CBT superior to either modality alone [418]. D-cycloserine has also been found to enhance treatment outcomes when used during exposure exercises as an adjunct to exposure alone [419, 420]. In addition, a study of psychodynamic group therapy with or without the addition of clonazepam also found combination treatment to be superior to clonazepam treatment alone [421].

Long-term effects of psychological treatment

The benefits of CBT have been found to be maintained at six to 12 month follow-up visits [58, 382, 390, 393, 409, 413, 422, 423], with sustained improvement being reported at five years posttreatment [424, 425]. Long-term assessments post-ICBT have shown sustained improvement at one to five years follow-up [409, 413, 423, 424]. Long-term benefits with psychotherapy appear to be more enduring than those of pharmacotherapy after treatment discontinuation [388, 389].

Pharmacological treatment

The management of patients with SAD should follow the principles discussed in Section 2. Pharmacological interventions that have good evidence for efficacy in treating SAD include SSRIs, SNRIs, anticonvulsants, and benzodiazepines. Treatments that have been investigated for use in SAD have been assessed according to the criteria for strength of evidence (Tables 1 and 2) and are summarized in Tables 20 and 21.
Table 20

Strength of evidence of pharmacotherapy for SAD

Agent

Level of evidence

Agent

Level of evidence

Antidepressants

SSRIs [58, 426429]

1

TCAs

 

Escitalopram [430432]

1

Clomipramine [458, 459]

3

Fluvoxamine [433435]

1

Imipramine [460]

3 (-ve)

Fluvoxamine CR [436, 437]

1

MAOIs and RIMAs

 

Paroxetine [431, 438444]

1

Phenelzine [384, 386, 418, 461, 462]

1

Sertraline [445448]

1

Moclobemide [417, 462466]

1*

Fluoxetine [382, 387, 449]

1*

Other antidepressants

 

Citalopram [450, 451]

2

Mirtazapine [467, 468]

1*

Paroxetine CR [452]

2

Bupropion SR [469]

3

Adjunctive paroxetine [453]

3

  

SNRIs

   

Venlafaxine XR [439, 441, 454, 255, 456]

1

  

Duloxetine [457]

2

  

Other therapies

Anxiolytics

 

Anticonvulsants

 

    Benzodiazepines

 

Pregabalin [474, 475]

1

      Clonazepam [385, 470, 471]

1

Gabapentin [476, 477]

2

      Alprazolam [386]

2

Levetiracetam [478480]

2 (-ve)

      Bromazepam [472]

2

Divalproex [481]

3

      Adjunctive clonazepam [473]

2 (-ve)

Tiagabine [477, 482]

3

  

Topiramate [483]

3

Other treatments

 

Atypical antipsychotics

 

Atenolol [461, 484]

1 (-ve)

Olanzapine [493]

2

Buspirone [383, 485]

1 (-ve)

Quetiapine [494, 495]

2 (-ve)

Atomoxetine [486, 487]

1*

Adjunctive aripiprazole [496]

3

Propranolol [488]

2 (-ve)

Adjunctive risperidone [271]

3

Selegiline [489]

3

  

Pergolide [490]

3 (-ve)

  

Adjunctive buspirone [491]

3

  

Adjunctive pindolol [492]

2 (-ve)

  

*Conflicting data. CR = controlled release; MAOI = monoamine oxidase inhibitor; RIMA = reversible inhibitor of monoamine oxidase A; SNRI = serotonin–norepinephrine reuptake inhibitor; SR = sustained release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release; (-ve) = negative.

Table 21

Recommendations for pharmacotherapy for SAD

First-line

Escitalopram, fluvoxamine, fluvoxamine CR, paroxetine, paroxetine CR, pregabalin, sertraline, venlafaxine XR

Second-line

Alprazolam, bromazepam, citalopram, clonazepam, gabapentin, phenelzine

Third-line

Atomoxetine, bupropion SR, clomipramine, divalproex, duloxetine, fluoxetine, mirtazapine, moclobemide, olanzapine, selegiline, tiagabine, topiramate

Adjunctive therapy

Third-line: aripiprazole, buspirone, paroxetine, risperidone

Not recommended: clonazepam, pindolol

Not recommended

Atenolol*, buspirone, imipramine, levetiracetam, propranolol*, quetiapine

CR = controlled release; SR = sustained release; XR = extended release.

*Beta-blockers have been successfully used in clinical practice for performance situations such as public speaking.

Note: although there is limited evidence for citalopram in SAD, it is likely as effective as the other SSRIs, in contrast there are negative trials of fluoxetine in SAD suggesting it may be less effective than other SSRIs [382, 449].

First-line agents

Antidepressants: Meta-analyses demonstrate that SSRIs and SNRIs are significantly more effective than placebo [58, 426429] and RIMAs [426, 428] for the treatment of SAD. There is level 1, RCT evidence supporting the use of the SSRIs escitalopram [430, 431], fluvoxamine [433435], fluvoxamine CR [436, 437], paroxetine [431, 438444], and sertraline [445448], as well as the SNRI venlafaxine XR [439, 441, 454456], for the first-line treatment of SAD. There is also good evidence for the efficacy of paroxetine CR (Level 2) [452].

Pregabalin: Pregabalin has also demonstrated efficacy versus placebo for the treatment of SAD in RCTs at higher (600 mg/day) but not lower dose levels (150-300 mg/day) (Level 1) [474, 475]. Although there is Level 1 evidence for pregabalin, it is not clear how its efficacy compares to that of SSRIs. In addition, SSRIs may have a broader spectrum of efficacy for common comorbid conditions.

Second-line agents

Benzodiazepines: In RCTs, the benzodiazepines clonazepam (Level 1) [470][385, 471], alprazolam [386], and bromazepam [472] (both Level 2) have demonstrated efficacy in the treatment of SAD.

Although, a meta-analysis found benzodiazepines to be as effective as SSRIs [58], these agents are recommended as second-line options because of the lack of effect on common comorbidities and the potential for abuse/dependence in individuals with a history of SUDs.

Antidepressants: In RCTs, citalopram was found to be significantly more effective than placebo [451], and as effective as moclobemide [450] (Level 2). Although there is limited evidence for citalopram in SAD, it is likely as effective as the other SSRIs.

The efficacy of phenelzine has been established in multiple RCTs (Level 1) [384, 386, 418, 461, 462]; however, this agent is recommended as a second-line option because of concerns regarding dietary restrictions, drug interactions, and the potential for hypertensive crisis.

Anticonvulsants: Gabapentin was significantly more effective than placebo in a RCT [476], and as effective as tiagabine in a small cross-over study (Level 2) [477].

Third-line agents

Antidepressants: Results with fluoxetine have been mixed (Level 1, conflicting) [382, 387, 449]. A large RCT found that fluoxetine was more effective than placebo and as effective as CBT [387]. However, in two other small RCTs, fluoxetine alone or when added to self-exposure showed no benefit over placebo, with or without self-exposure [382, 449]. These negative trials with fluoxetine suggest it may be less effective than other SSRIs [382, 449].

Similarly, results with moclobemide have also been mixed (Level 1, conflicting) [417, 462466], with some RCTs demonstrating significantly higher response rates with moclobemide compared with placebo (Level 1) [462464], while others have not [465, 466]. Moclobemide was found to be superior to CBT early in treatment; however, after six months CBT was found to be superior.

Data from two small RCTs assessing mirtazapine were also mixed (Level 1, conflicting), with one showing significant improvements over placebo [468] and the other showing no differences [467].

In a dose-finding study in which patients treated with open-label duloxetine 60 mg/day were randomized to continue or double their dose, both doses improved symptoms, but there was no significant advantage to the higher dose (Level 2) [457].

Small open-label trials have also suggested that bupropion SR [469] and clomipramine [458, 459] (both Level 3) may be effective in patients with SAD.

Anticonvulsants: Open-label studies have demonstrated some efficacy with divalproex [481], topiramate [483], and tiagabine [482] (all Level 3). In addition, tiagabine was comparable to gabapentin in a small RCT, crossover study in eight adults [477].

Other treatments: Olanzapine was effective in a small RCT (Level 2) [493], and selegiline demonstrated efficacy in a small, open-label trial (Level 3) [489]. In a RCT, atomoxetine significantly improved SAD symptoms compared with placebo [487]; however, in a another small RCT, atomoxetine showed no significant difference in outcomes compared with placebo (Level 1, conflicting) [486].

All of these agents are recommended as third-line options, and may be useful in refractory patients after first- and second-line monotherapies and adjuncts have been unsuccessful.

Adjunctive therapy

Adjunctive strategies have generally been studied in patients who have had an inadequate response to antidepressant therapy and can be considered for patients with treatment-resistant SAD.

Third-line adjunctive therapies: Open-label studies and case series have suggested that patients with refractory SAD may benefit from adjunctive therapy with aripiprazole [496], risperidone [271], buspirone [491], or paroxetine [453] (all Level 3).

Not recommended adjunctive or combination therapies: In RCTs, clonazepam [473] combined with paroxetine and pindolol augmentation of paroxetine [492] (both Level 2, negative) were not significantly superior to placebo in augmenting the effects of SSRI treatment for SAD.

Not recommended

In RCTs there was no evidence of benefits with the beta-blockers atenolol (Level 1, negative) [461, 484] or propranolol (Level 2, negative) [488], or for the following treatments: buspirone [383, 485], levetiracetam [478480] (both Level 1, negative), or quetiapine (Level 2, negative) [494, 495]. These agents are not recommended for SAD. Imipramine [460] and pergolide (both Level 3, negative) [490] also do not appear to be effective in this disorder.

Maintenance pharmacological treatment

Long-term therapy has been evaluated in relapse prevention and naturalistic follow-up studies. Relapse-prevention studies are those in which responders to medication are randomized to continued active treatment or placebo. A meta-analysis of four relapse prevention studies included 760 patients with SAD and found a highly significant reduction in relapse rates with continued SSRI treatment compared with placebo over three to six months. The relative risk (RR) for relapse was 0.39 (95% CI 0.30–0.49) and number needed to treat (NNT) was 3.57 (95% CI 2.94–4.76) [497]. The anticonvulsant pregabalin has also demonstrated reductions in relapse rates over six months [498].

In RCTs, escitalopram [431], fluvoxamine CR [499], and venlafaxine XR [456] have demonstrated continued improvement compared with placebo over approximately six months. Additional open follow-up data support the long-term efficacy of moclobemide over six to 24 months [464, 500].

Biological and alternative therapies

Biological therapies: In an open-label study, neuro psycho physical optimization-radio electric asymmetric conveyor (NPPO-REAC) (a brain stimulation technique) was as effective as sertraline for the treatment of SAD (Level 3) [501].

Alternative therapies: St John’s wort failed to demonstrate superiority over placebo, and is not recommended for the treatment of SAD (Level 2, negative) [502].

Summary

SAD is one of the most common anxiety disorders, occurring more often in women than men. SAD has a negative impact on QoL, functional and occupational outcomes, and is often associated with other comorbid disorders, including MDD and other anxiety and related disorders. SAD is characterized by intense fear or anxiety relating to social or performance situations where the individual is exposed to scrutiny by others. These situations are often actively avoided.

CBT and exposure therapy alone are effective first-line options for the treatment of SAD, although limited data suggest that CBT may be more effective in maintaining benefits during follow-up. VRE and internet-based programs have also demonstrated efficacy. The benefits of CBT are maintained over one to five years of follow-up. CBT and pharmacotherapy appear to have similar efficacy for the acute treatment of SAD, but after treatment discontinuation, gains achieved with CBT appear to persist longer than those achieved with pharmacotherapy. In most studies, adding pharmacotherapy has not been shown to increase the benefits of CBT.

Pharmacotherapeutic approaches should begin with a first-line antidepressant such as escitalopram, fluvoxamine, fluvoxamine CR, paroxetine, paroxetine CR, sertraline, or venlafaxine XR, or the anticonvulsant pregabalin. If response to optimal doses is inadequate or the agent is not tolerated, therapy should be switched to another first-line agent before considering a second-line medication. Second-line choices include the benzodiazepines alprazolam, bromazepam, and clonazepam, as well as citalopram, gabapentin, and phenelzine. Pregabalin has also been shown to maintain benefits and prevent relapse in a six-month study.

Patients who do not respond to several medication trials and/or CBT are considered to have treatment-refractory illness. In such patients it is important to reassess the diagnosis and consider comorbid medical and psychiatric conditions that may be affecting response to therapy. Third-line agents and adjunctive therapies may be useful when patients fail to respond to optimal treatment trials of first- and second-line therapies used alone and in combination.

Generalized anxiety disorder

Epidemiology

The estimated 12-month prevalence of GAD ranges from 1-4%, and the lifetime prevalence is approximately 6% [2, 3, 16, 503]. GAD is more frequent in Caucasians compared to other groups [504]. The usual age of onset varies and may be bimodal with the median age of onset being approximately 31 years [2] and mean age of onset being 32.7 years [505]. The prevalence of GAD is estimated to be 3% in children and 10.8% in adolescents [506], with the age of onset for children and adolescents being between ages 10 and 14 [507]. Some data suggest that women may be two to three times more likely to suffer from GAD than men [16, 508], and GAD may be more common in older adults [509, 510]. This disorder is reportedly frequently under-recognized with less than one-third of patients being adequately treated [511, 512]. This is further complicated in children because of the previous designation of Overanxious Disorder of Childhood and its possible differentiation of childhood GAD from GAD in adults.

GAD is associated with functional [15, 511, 513], occupational [511], and QoL impairments [16, 511], as well as substantial economic costs [511, 514]. In addition, in primary care 60-94% of patients with GAD report painful physical symptoms [515, 516], and these were the main reason for initial presentation to a physician in 72% of cases [516].

Comorbidity

GAD is associated with high rates of comorbid psychiatric conditions including other anxiety or related disorders and MDD [16]. The risk of medical conditions is also elevated [16], including pain syndromes [16, 517], hypertension [16], as well as cardiovascular and gastric conditions [16, 518]. The presence of comorbid depression increases the severity of illness, functional impairment [519], and economic costs [514].

Diagnosis

GAD is characterized by excessive anxiety and worry about multiple events or activities such as school or work difficulties, which is apparent on a majority of days over the previous six months (Table 22) [26]. In addition, GAD is associated with restlessness, muscle tension, fatigue, concentration difficulties, irritability, and sleep issues [26].
Table 22

DSM-5 diagnosis of GAD

• Excessive anxiety and worry (apprehensive expectation) about a number of events or activities (e.g., school/work performance)

• The individual finds it difficult to control the worry

• Excessive anxiety and worry are associated with ≥3 of the following symptoms (with at least some occurring more days than not for ≥6 months):

     Restlessness or feeling keyed-up or on edge, being easily fatigued, difficulty concentrating, irritability, muscle tension, or sleep disturbance

• The disturbance causes clinically significant distress or functional impairment

Adapted from DSM-5 [26].

The diagnostic criteria for GAD underwent one minor revision in the DSM-5 [26] compared to the DSM-IV-TR [144], the requirement that the disturbance not occur exclusively during a mood, psychotic, or pervasive developmental disorder was removed. However, it remains important to note that most of the treatment data described within this section are based on patients meeting DSM-IV criteria (or older).

Psychological treatment

Meta-analyses clearly demonstrate that CBT significantly reduces GAD symptoms and is markedly more effective than placebo or wait-list control conditions for GAD (Level 1) [55, 64, 65, 70, 520]. Few studies have compared CBT and pharmacotherapy alone in the same trial, but the magnitude of benefits appear to be comparable for both groups [521523]. Individual and group therapy appear to be equally effective in terms of anxiety symptom reduction, but individual therapy may lead to earlier improvement in worry and depression symptoms [65, 520].

The intensity of therapy was assessed in a meta-analysis of 25 studies [65]. Regimens including fewer than eight sessions were as effective as those of eight or more for anxiety symptoms, but the more intense regimens were more effective in improving symptoms of worry and depression compared with fewer sessions [65].

Several studies have demonstrated the utility of internet-based or computer-based CBT programs [79, 524526]. ICBT has been shown to be significantly more effective than wait-list control [79, 524, 525], with benefits being maintained at long-term follow-up [525]. In addition, a peer-to-peer cognitive self-therapy program was as effective as treatment-as-usual, with a decreased need for therapist contact [527].

A meta-analysis of five trials found no significant differences between CBT and relaxation therapy [55]. However, more recent studies suggest that applied relaxation has limited efficacy [528530]. One RCT found little evidence that patients with GAD can learn to relax in therapy or that a decrease in activation is associated with a reduction in anxiety [529]. Balneotherapy, a relaxation therapy involving spa-related treatments, demonstrated potential advantages over SSRI pharmacotherapy in improving anxiety scores and response rates in patients with GAD in a large RCT [531]; however, while this study may be interesting, concerns pertaining to blinding and potential bias indicate further study is needed [531].

Several research-based variables have been specifically identified among individuals with GAD in order to generate evidence-based CBT protocols for GAD, including: intolerance of uncertainty, poor problem-solving confidence, as well as positive and negative metacognitive beliefs about the function or utility of worry [532]. Specific psychotherapeutic protocols based upon models of the disorder that target variables underlying GAD have been developed to individualize therapy. Acceptance-based behavior therapy [533], meta-cognitive therapy [528, 534], CBT targeting intolerance of uncertainty [530], and adjunctive MBCT [184] have demonstrated efficacy for the treatment of GAD. Targeting worry and relaxation [535], as well as looming vulnerability (the tendency to generate and maintain internal scenarios of increasing risk and danger) [536], may also be beneficial.

Psychodynamic therapy may also be of benefit, however the research findings to date are unclear. A RCT found that short-term psychodynamic psychotherapy was as effective as CBT in improving anxiety scores, but CBT was superior on measures of worry and depression [537]. Another study found no significant differences between brief psychodynamic therapy, pharmacotherapy, or the combination [523].

No significant benefits were found with the addition of interpersonal and emotional processing therapy to CBT when compared with CBT plus supportive listening [538]. However, pretreatment motivational interviewing as an adjunct to CBT was shown to help reduce resistance to therapy, improve homework compliance, and improve worry outcomes — this strategy may be particularly useful in more severe cases [539, 540].

In clinical practice, the approach may need to be individualized to the problems experienced by the patient.

Psychological and pharmacological treatment

Few data are available on the use of combined psychological and pharmacological treatment. A meta-analysis concluded that combination pharmacotherapy and CBT was more effective than CBT alone at posttreatment but not at six-month follow-up [83]. While large effect sizes were found for GAD, data were available from only two studies, and these compared CBT plus diazepam or buspirone with CBT alone [83]. Compared to pharmacotherapy alone, the few studies that have assessed the benefits of adjunctive psychotherapy have been conflicting [184, 523, 541, 542]. One study suggested benefits of the combination [184], while two other studies did not [523, 541]. However, adjunctive CBT was shown to facilitate benzodiazepine tapering in patients with GAD [542].

There is no current evidence to support the routine combination of CBT and pharmacotherapy. However, as in other anxiety and related disorders, when patients do not benefit from CBT or have a limited response, a trial of pharmacotherapy is advisable. Similarly, patients who show limited benefit from pharmacotherapy may benefit from CBT.

Long-term effects of psychological treatment

Long-term follow-up data from a meta-analysis [520] and RCTs [523, 525, 535, 543] suggest that benefits of psychological treatments are maintained at one to three years follow-up after treatment.

Pharmacological treatment

The management of patients with GAD should follow the principles discussed in Section 2. Pharmacological interventions that have good evidence for efficacy in treating GAD include SSRIs, SNRIs, TCAs, benzodiazepines, pregabalin, quetiapine XR, and other therapies. Treatments that have been investigated for use in GAD have been assessed according to the criteria for strength of evidence (Tables 1 and 2) and are summarized in Tables 23 and 24.
Table 23

Strength of evidence for pharmacotherapy for GAD

Agent

Level of evidence

Agent

Level of evidence

Antidepressants

SSRIs

 

TCAs

 

Escitalopram [544552]

1

Imipramine [553, 581583]

1

Paroxetine [546, 547, 553558]

1

Other antidepressants

 

Sertraline [556, 559561]

1

Agomelatine [584, 585]

1

Citalopram [562]

3

Vortioxetine [586, 587]

1*

Fluoxetine [563]

3

Bupropion XL [549]

2

Paroxetine CR [564, 565]

3

Trazodone [583]

2

SNRIs

 

Mirtazapine [588]

3

Duloxetine [566571]

1

  

Venlafaxine XR [548, 553, 570580]

1

  

Other therapies

Anxiolytics

 

Atypical antipsychotics

 

    Benzodiazepines

 

Quetiapine XR [551, 557, 602, 603]

1

      Alprazolam [589593]

1

Adjunctive quetiapine [565, 604, 605]

1*

      Bromazepam [589, 594]

1

Adjunctive risperidone [606, 607]

1*

      Diazepam [583, 589, 595, 596]

1

Adjunctive olanzapine [608]

2

      Lorazepam [589, 593, 597601]

1

Adjunctive aripiprazole [269, 609]

3

  

Adjunctive quetiapine XR [610]

3

  

Adjunctive or monotx ziprasidone [611, 612]

2 (-ve)

Anticonvulsants

 

Other treatments

 

Pregabalin [576, 577, 592, 593, 597, 613]

1

Buspirone [108, 561, 572, 589, 598, 618, 619]

1

Divalproex chrono [614]

2

Hydroxyzine [594, 619, 620]

1

Tiagabine [615, 616]

1 (-ve)

Pexacerfont [552]

2 (-ve)

Adjunctive pregabalin [617]

2

Propranolol [621]

2 (-ve)

  

Memantine [622]

4 (-ve)

*Conflicting data. SNRI = serotonin–norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XL = extended release; XR=extended release; (-ve) = negative.

Table 24

Recommendations for pharmacotherapy for GAD

First-line

Agomelatine, duloxetine, escitalopram, paroxetine, paroxetine CR, pregabalin, sertraline, venlafaxine XR

Second-line

Alprazolam*, bromazepam*, bupropion XL*, buspirone, diazepam*, hydroxyzine, imipramine, lorazepam*, quetiapine XR*, vortioxetine

Third-line

Citalopram, divalproex chrono, fluoxetine, mirtazapine, trazodone

Adjunctive therapy

Second-line: pregabalin

Third-line: aripiprazole, olanzapine, quetiapine, quetiapine XR, risperidone

Not recommended: ziprasidone

Not recommended

Beta blockers (propranolol), pexacerfont, tiagabine

CR = controlled release; XL = extended release; XR=extended release.

*Note: These have distinct mechanisms, efficacy and safety profiles. Within these second-line agents, benzodiazepines would be considered first in most cases, except where there is a risk of substance abuse, while bupropion XL would likely be reserved for later. Quetiapine XR remains a good choice in terms of efficacy, but given the metabolic concerns associated with atypical antipsychotic, it should be reserved for patients who cannot be provided antidepressants or benzodiazepines. Please refer to text for further rationale for the recommendations.

First-line agents

Antidepressants (SSRIs & SNRIs): Evidence from RCTs supports the use of SSRIs including escitalopram [544552] and sertraline [556, 559561], as well as the SNRIs duloxetine [566571] and venlafaxine XR [548, 553, 570580] (all Level 1) for the first-line treatment of GAD. Similar evidence exists for paroxetine [546, 547, 553558] supporting its use as a first-line option. Paroxetine CR has a similar active ingredient, and although there are less data supporting its use, it is likely interchangeable with paroxetine as a first-line agent (Level 3) [564, 565]. In head-to-head comparisons, the efficacy of SSRIs and SNRIs appear to be similar [546, 547, 549, 556, 558, 570, 571]. Some data suggest that escitalopram may be less effective than venlafaxine XR [548] or quetiapine XR [551]. Efficacy of venlafaxine was similar to pregabalin in one RCT [576], but less effective in another [577].

Other antidepressants: In two 12-week, double-blind RCTs, agomelatine was found to be more effective than placebo (Level 1) [584, 585], and as effective as escitalopram [585].

Pregabalin: The anticonvulsant pregabalin was more effective than placebo in RCTs [576, 577, 592, 593, 597, 613] and as effective as benzodiazepines [592, 593, 597] in patients with GAD (Level 1). Pregabalin was more effective than venlafaxine XR in one RCT [577], but equivalent in another [576].

Second-line agents

Benzodiazepines: Alprazolam [589593], bromazepam [589, 594], diazepam [583, 589, 595, 596], and lorazepam [589, 593, 597601] all have demonstrated efficacy for the treatment of GAD (all Level 1). While these agents have level 1 evidence for efficacy, they are recommended as second-line therapy, and usually only for short-term use, because of side effects, dependence, and withdrawal issues.

TCAs and other antidepressants: In RCTs, imipramine was superior to placebo and as effective as benzodiazepines for the treatment of GAD (Level 1) [553, 581583]. However, because of side effects and potential toxicity in overdose, imipramine is recommended as a second-line option. While there are little data on bupropion XL (Level 2), in a 12-week RCT in patients with GAD it was as effective as escitalopram (a first-line option), supporting its use as a second-line option [549].

Vortioxetine is a so-called "serotonin modulator" because of its activity in a variety of serotonin receptors. Results from two similar, eight-week, placebo-controlled RCTs with vortioxetine were conflicting, with one trial being positive [587] and the other negative (Level 1, conflicting) [586]. The differences in outcomes may be related to differences in recruitment between the two studies [623], and data suggest that vortioxetine may be useful in GAD.

Quetiapine XR: There is good evidence for the efficacy of quetiapine XR for the management of GAD (Level 1) [551, 557, 602, 603]. Two meta-analyses [115, 116] concluded that quetiapine was significantly superior to placebo and equivalent to antidepressants [115] for the treatment of GAD. However, quetiapine was associated with more weight gain and sedation, and higher dropout rates due to adverse events compared with placebo or antidepressants [115, 116]. Due to tolerability and long-term safety concerns with atypical antipsychotics, this treatment is recommended as a second-line option for patients who cannot be provided antidepressants or benzodiazepines.

Other treatments: Buspirone was more effective than placebo and as effective as benzodiazepines in several RCTs (Level 1) [108, 561, 572, 589, 598, 618, 619]. There are limited data comparing buspirone to antidepressants, with it being less effective than venlafaxine XR in one study [572], but as effective as sertraline in another [561]. Limited effectiveness in clinical practice relegates buspirone to a second-line agent.

Hydroxyzine has demonstrated efficacy superior to placebo and similar to benzodiazepines and buspirone in RCTs (Level 1) [594, 619, 620]; however, clinical experience with this agent in the treatment of GAD remains limited.

Third-line agents

The following agents are recommended as third-line options because of limited data, side effects, or lack of clinical experience as a primary therapy for the treatment of GAD.

Antidepressants: In open-label studies or case series, the antidepressants citalopram [562], fluoxetine [563], paroxetine CR [564, 565], and mirtazapine [588] have demonstrated efficacy in patients with GAD (all Level 3). In a RCT, trazodone was as effective as diazepam (Level 2) [583].

Other treatments: Divalproex chrono was superior to placebo for the treatment of GAD (Level 2) [614], however this formulation is not widely available.

Adjunctive therapy

Adjunctive strategies have generally been studied in patients who have had an inadequate response to SSRI therapy, and can be considered for patients with treatment-resistant GAD.

Second-line adjunctive therapies: Adjunctive pregabalin demonstrated good efficacy in a large RCT in patients with GAD who had an inadequate response to prior treatments (Level 2) [617].

Third-line adjunctive therapies: A meta-analysis of five RCTs of adjunctive atypical antipsychotics found no significant improvement in response rates but higher discontinuation rates versus placebo in patients with refractory GAD [116].

Two RCTs suggest that adjunctive risperidone (Level 1, conflicting) [606, 607] may be useful in some patients, but in the larger RCT it demonstrated superiority over placebo only in patients with moderate to severe residual symptoms at baseline [607]. Similarly, data on adjunctive quetiapine have been inconsistent (Level 1, conflicting) [565, 604, 605], with one RCT being negative [565], while another, unblinded RCT showed some, but limited benefits [605]. Adjunctive olanzapine demonstrated efficacy in a small RCT in patients who remained symptomatic after six weeks of SSRI therapy [608]. Adjunctive treatment with quetiapine XR [610] or aripiprazole [269, 609] (both Level 3) also had some benefit in open trials.

Because of the limited evidence for efficacy and their potential for weight gain and metabolic side effects, atypical antipsychotics should be reserved for highly treatment-refractory cases of GAD, and other than quetiapine XR, used only as an adjunctive treatment.

Not recommended adjunctive therapies: Ziprasidone does not appear to be effective as adjunctive therapy (Level 2, negative) [611].

Not recommended

Propranolol [621] and pexacerfont [552] (both Level 2, negative) have not demonstrated efficacy and are not recommended in the treatment of GAD. While a small randomized, open-label trial suggested that tiagabine was as effective as paroxetine, the results of three placebo-controlled RCTs do not support the efficacy of tiagabine in patients with GAD (Level 1, negative) [615, 616]. Memantine also does not appear to be effective in this disorder (Level 4, negative) [622].

Maintenance pharmacological treatment

Long-term therapy has been evaluated in relapse prevention and naturalistic follow-up studies. Relapse-prevention studies are those in which responders to SSRI therapy are randomized to continued active treatment or placebo. A meta-analysis of three relapse prevention studies included 1342 patients with GAD and found a highly significant reduction in relapse rates with continued SSRI treatment compared with placebo over six to 12 months (odds ratio for relapse was 0.20) [497].

In RCT discontinuation studies, duloxetine [624], escitalopram [625], paroxetine [626], and venlafaxine XR [627] have demonstrated significantly lower relapse rates over six to 18 months in the range of 10-20% with active treatment compared to 40-56% with placebo. Pregabalin [628] and quetiapine XR [629] have also demonstrated significantly lower relapse rates over six to 12 months of continued treatment in discontinuation trials.

In long-term RCT studies, escitalopram [546], paroxetine [546], and venlafaxine XR [578, 579] have demonstrated continued improvement compared with placebo over approximately six months.

Biological and alternative therapies

In general, these therapies may be useful for some patients; however, more data are needed.

Biological therapies: In a small open trial, rTMS was effective as monotherapy or as an adjunct to SSRIs in patients with GAD (Level 3) [630], and improvements were largely maintained six months after treatment [631].

Alternative therapies: Several herbal preparations have demonstrated efficacy comparable to lorazepam for the treatment of GAD including silexan (lavender oil) (Level 1) [600, 632] and Galphimia glauca extract (Level 2) [601]. Cochrane meta-analyses found two studies of passiflora (passion flower) indicating it was as effective as benzodiazepines (Level 2) [633], and one study of valerian which found no significant differences between placebo, valerian, or diazepam (Level 2, negative) [634, 635]. Unfortunately, because these preparations are poorly standardized and have substantial variation in proportion of the active ingredient in different products, they cannot be widely recommended.

A RCT of adjunctive resistance training (weightlifting) or aerobic exercise found significant symptomatic improvements compared to a wait-list condition (Level 2) [636]. A systematic review included four studies of acupuncture in GAD or anxiety neurosis, and while all trials reported positive findings, methodological details were lacking and the authors concluded that there was insufficient evidence to determine efficacy (Level 2) [637]. Open-label studies suggest that adjunctive meditation and yoga-based treatments may be useful in patients with GAD (Level 3) [638, 639].

Not recommended alternative therapy: In a RCT, there were no significant improvements with bright light therapy compared with placebo (Level 2, negative) [640], and this treatment is not recommended.

Summary

The lifetime prevalence of GAD is approximately 6%, it is more frequent in women than in men, with age of onset reflecting a bimodal distribution (onset in late-teens to early-twenties, and again in the 30s and 40s). GAD is associated with substantial functional impairment and a high prevalence of comorbid psychiatric and medical disorders. According to DSM-5 criteria, GAD is characterized by excessive anxiety and worry about multiple situations and is associated with restlessness, muscle tension, and behavioral changes.

CBT is an effective first-line option for the treatment of GAD and is as effective as pharmacotherapy. Internet-based and computer-based CBT have also demonstrated efficacy. Evidence does not support the routine combination of CBT and pharmacotherapy, but when patients do not benefit from CBT, a trial of pharmacotherapy is advisable, and vice versa.

Pharmacotherapeutic approaches should begin with one of the first-line options including an SSRI such as escitalopram, paroxetine, or sertraline, an SNRI such as duloxetine or venlafaxine XR, or other antidepressant such as agomelatine. The anticonvulsant pregabalin is also a recommended first-line therapy.

If response to optimal doses is inadequate or the agent is not tolerated, therapy should be switched to another first-line agent before considering second-line medications. Second-line choices include bupropion XL, buspirone, hydroxyzine, imipramine, quetiapine XR, vortioxetine, as well as the benzodiazepines, alprazolam, bromazepam, diazepam, and lorazepam.

Patients who do not respond to multiple courses of therapy are considered to have treatment-refractory illness. In such patients it is important to reassess the diagnosis and consider comorbid medical and psychiatric conditions that may be affecting response to therapy. Third-line agents, adjunctive therapies, as well as biological and alternative therapies may be useful when patients fail to respond to an optimal treatment trial of first- and second-line therapies used alone and in combination.

Obsessive-compulsive disorder

Epidemiology

OCD is a relatively uncommon, yet severe, mental disorder, with an estimated lifetime and 12-month prevalence of 1.0-2.3% and 0.7%-1.2% in adults, respectively [2, 3, 641, 642]. Mean age of onset of OCD is ~20 years of age, but symptoms can occur below the age of 10, with few new cases after the early 30s [2, 641, 643]. Rates of treatment-seeking have been estimated to be only about 14-56% of patients, suggesting that OCD may be under-recognized and under-treated [644, 645]. Social isolation, history of physical abuse, and negative emotionality are risk factors for the development of OCD [646].

OCD is associated with a substantial negative impact on QoL for both patients [647, 648] and their caregivers [649]. Patients experience cognitive, social, and occupational impairments [642, 645, 650, 651]. In addition, up to one-quarter of patients with OCD have attempted suicide [645, 652]. OCD symptoms are associated with increased rates of health care utilization compared to those without OCD symptoms [642], with health care costs estimated at $10.6 billion/year (2005) in the US [653].

Comorbidity

About 60-90% of patients with OCD also have a comorbid disorder [641, 645]. Patients with OCD or OCD symptoms have a three-times higher rate of comorbidity compared to those without OCD symptoms [642]. Common comorbidities include mood, anxiety, and somatoform disorders, as well as SUDs, psychotic disorders, and bipolar disorders [641, 642, 645].

Diagnosis

A diagnosis of OCD requires the presence of obsessions and/or compulsions (Table 25) [26]. Obsessions are defined as recurrent, persistent, and intrusive thoughts, images, or urges that cause marked anxiety, and compulsions are defined as repetitive behaviors or mental acts that the patient feels compelled to perform to reduce the obsession-related anxiety [26]. The obsessions or compulsions are time consuming and cause significant impairment in social or occupational functioning.
Table 25

DSM-5 diagnosis of OCD

• Presence of either obsessions, compulsions, or both

     Obsessions are defined by the following:

        • Recurrent and persistent thoughts, urges, or images that are experienced as intrusive and unwanted and that cause marked anxiety or distress

        • The individual attempts to ignore or suppress such thoughts, urges, or images, or to neutralize them with other thoughts or actions

     Compulsions are defined by the following:

        • Repetitive behaviors (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the individual feels driven to perform in response to an obsession or according to rigid rules

        • Compulsions are aimed preventing or reducing anxiety or preventing some dreaded situation or event; however, they are not connected in a realistic way with what they are designed to neutralize or are clearly excessive

• The obsessions or compulsions are time-consuming (e.g., take >1 h/day) or cause clinically significant distress or functional impairment

• Specify patient’s degree of insight as to reality of OCD beliefs:

     Good or fair insight (i.e., definitely or probably not true)

     Poor insight (i.e., probably true)

     Absent insight (i.e., completely convinced beliefs are true)

• Specify if "tic-related" OCD

Adapted from DSM-5 [26].

In the DSM-5, OCD has been moved from the “anxiety disorders” [144] to a new diagnostic category called “obsessive-compulsive and related disorders.” In addition to OCD, this new category also includes diagnostic criteria for body dysmorphic disorder, hoarding disorder, hair-pulling disorder (trichotillomania), and skin picking disorder [26].

Most of the other modifications to the OCD diagnostic criteria in the DSM-5 were minor wording changes designed to enhance clarity or further operationalize concepts that were considered too vague [26]. In particular, the definitions of obsessions and compulsions were clarified and simplified [26, 654]. The requirement that the patient recognizes that the obsessions or compulsions are “excessive or unreasonable” has been deleted, since these terms are subject to interpretation and patients can have varying levels of insight. As a result, the previous DSM-IV-TR specifier of “poor insight” has been expanded to include: good or fair, poor, and absent insight [26]. Finally, a specifier of "tic-related" OCD has been added [26].

While the most up-to-date DSM-5 diagnostic criteria are presented here, it is important to note that most of the treatment data described within this section are based on patients meeting DSM-IV criteria (or older).

Psychological treatment

Meta-analyses support the beneficial effects of psychological treatment for OCD, mainly CBT, generally including exposure with response prevention (ERP) [6063, 70, 71, 655657]. CBT is equivalent or superior to pharmacotherapy [71, 658660]. Results with CBT were generally similar in comparisons of interventions with an emphasis on ERP and those with an emphasis on cognitive elements [60, 63, 655]. A treatment specifically designed to address fear of contamination with infectious substances, using a cognitive intervention that includes no direct exposure (“danger ideation reduction therapy, DIRT”), was found to be more efficacious than ERP [661, 662]. Cognitive interventions may be important in patients who do not have overt compulsions, which can make ERP more difficult. One meta-analysis found that exposure in vivo combined with imaginal exposure was better than exposure in vivo alone [60].

Several meta-analyses have demonstrated no significant differences in efficacy between group and individual CBT [60, 62, 663]. However, results of head-to-head trials are conflicting, with some RCTs finding no significant differences in efficacy between group and individual therapy [663, 664], and others showing individual therapy to be superior [665667]. Differences in results may be explained by the fact that in individual therapy the therapist may have the advantage of being more aware of the patient’s dysfunctional beliefs, however, the group therapy setting may offer the advantages of group encouragement, reciprocal support, imitation, and interpersonal learning which may result in an increased motivation and reduced discontinuation of treatment [62].

An important practical question concerns the intensity and duration of treatment. The intensive ERP program described by Foa’s group involves 15 two-hour sessions scheduled five days a week over three weeks [658, 668]. A similar program administered twice-weekly (a more practical approach for many patients and therapists) was as effective at the end of follow-up as the intensive five-days/week strategy [669]. A step-care approach in which patients received six weeks of low-intensity counseling with ERP bibliotherapy followed by standard ERP for non-responders only was found to be as effective as initial therapy with standard ERP (17 sessions twice weekly), but was significantly less costly [670].

Other techniques that may be useful include acceptance and commitment therapy (ACT) [671], modular cognitive therapy (CT) addressing OCD beliefs [672, 673], CT addressing obsessional doubt [674], organizational training [675, 676], and mindfulness training [677]. RCTs on the benefits of adding motivational interviewing to CBT have been conflicting, with one showing no additional benefits [678], while another demonstrated improved symptom reduction and remission rates compared with CBT alone [679]. While EMDR was more effective than an SSRI in a RCT [680], data are limited and this technique is not generally recommended for patients with OCD.

Data suggest that therapist-guided exposure is better than self-exposure [60]. While both treatment conditions showed significant symptom reduction, therapist-administered ERP was superior to self-administered ERP in improving OCD symptoms and self-reported functional impairment [681]. Other data suggest that ERP delivered by telephone is equivalent to face-to-face ERP [682]. Bibliotherapy in the form of self-help manuals delivered to patients via email has demonstrated significantly greater improvements in OCD symptoms compared with wait-list control groups in two RCTs [683, 684].

ICBT is an easily accessible treatment that has the potential to reach untreated patients and motivate them for face-to-face psychotherapy if necessary [684, 685]. Several RCTs have demonstrated that ICBT programs are significantly more effective than supportive therapy or relaxation control strategies [685687]. ICBT was as effective as therapist-led CBT only when patients completed at least one self-exposure session [687]. ICBT was associated with significantly better outcomes when it included brief, scheduled, therapist-initiated telephone support compared with on-demand phone support [688].

Family accommodation (i.e., family members taking part in the performance of rituals, avoidance of anxiety-provoking situations, or modification of daily routines to assist a relative with OCD) has been associated with poorer response to both behavioral and pharmacological treatments [689]. Clinicians may want to consider targeting family accommodation in order to improve treatment outcomes for some patients.

Although hoarding disorder is now a separate diagnosis [690], the limited data available on the treatment of hoarding will be mentioned in this section on OCD. One RCT found that group CBT significantly reduced hoarding and depression symptoms while bibliotherapy alone was associated with very limited improvements [691]. The addition of posttreatment, nonclinician, home assistance did not significantly improve outcomes.

Combined psychological and pharmacological treatment

The combination of psychological and pharmacological treatment has been shown to be superior to medication alone [657, 658, 692694], but not to CBT alone [83, 658, 692, 694, 695]. These findings suggest that if pharmacotherapy is required or preferred, adding CBT to pharmacological treatment of OCD may enhance response rates and reduce relapse rates. Unlike in some anxiety and related disorders, there does not appear to be any contraindication to combining CBT with medications in patients with OCD [696], and combined treatment may improve relapse prevention [697].

Adding d-cycloserine may hasten the onset of improvements with ERP, with significant benefits over placebo during the first four or five ERP sessions [698700], but this effect has not been seen in all studies [701].

Long-term effects of psychological treatment

Follow-up studies suggest that the benefits of CBT are maintained at one to five years of follow-up [664, 695, 702704].

Pharmacological treatment

The management of patients with OCD should follow the principles discussed in Section 2. SSRIs are recommended first-line pharmacological interventions for OCD, while SNRIs, clomipramine, and other antidepressants are recommended second- and third-line treatments. Treatments that have been investigated for use in OCD have been assessed according to the criteria for strength of evidence (Tables 1 and 2) and are summarized in Tables 26 and 27.
Table 26

Strength of evidence of pharmacotherapy for OCD

Agent

Level of evidence

Agent

Level of evidence

Antidepressants

SSRIs

 

MAOIs

 

Escitalopram [705709]

1

Phenelzine [737, 738]

2*

Fluoxetine [660, 710716]

1

Tranylcypromine [739]

4

Fluvoxamine [711, 713, 714, 717719]

1

TCAs

 

Paroxetine [705, 720722]

1

Clomipramine [658, 711, 713, 714, 716718, 720, 724, 740, 741]

1

Sertraline [659, 710, 711, 713, 714, 723725]

1

IV clomipramine [742744]

2

Citalopram [680, 726728]

2

Desipramine [723, 745]

2 (-ve)

IV citalopram [729]

3

Adjunctive clomipramine [746, 747]

2 (-ve)

Adjunctive citalopram [730]

3

Other antidepressants

 

SNRIs

 

Mirtazapine [748]

2

Venlafaxine XR [721, 731733]

2

Bupropion [749]

3 (-ve)

Duloxetine [734736]

4

Adjunctive mirtazapine [727]

3

Other therapies

Antipsychotics

 

Anxiolytics

 

Adjunctive aripiprazole [750755]

1

    Benzodiazepines

 

Adjunctive risperidone [755761]

1*

      Clonazepam [771]

2 (-ve)

Adjunctive olanzapine [760, 762, 763]

1*

      Adjunctive clonazepam [772]

2 (-ve)

Adjunctive quetiapine [728, 746, 747, 764768]

1*

Other treatments

 

Adjunctive haloperidol [758, 769]

2

Clonidine [773]

2 (-ve)

Adjunctive amisulpride [770]

3

Adjunctive pindolol [774776]

1*

Adjunctive ziprasidone [767]

4

Adjunctive celecoxib [777]

2

Anticonvulsants

 

Adjunctive granisetron [778]

2

Adjunctive topiramate [795798]

1*

Adjunctive IV ketamine [779, 780]

2

Adjunctive lamotrigine [799, 800]

2

Adjunctive memantine [622, 781783]

2

Adjunctive pregabalin [801, 802]

3

Adjunctive ondansetron [784, 785]

2

Adjunctive gabapentin [803, 804]

3 (-ve)

Adjunctive N-acetylcysteine [786, 787]

2

Opioids

 

Adjunctive riluzole [788, 789]

3

Tramadol [805, 806]

4

Adjunctive lithium [790, 791]

1 (-ve)

Naltrexone [807]

3 (-ve)

Adjunctive buspirone [792, 793]

2 (-ve)

Adjunctive morphine [808]

2

Adjunctive minocycline [794]

4 (-ve)

*Conflicting data. IV = intravenous; MAOI = monoamine oxidase inhibitor; SNRI = serotonin–norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release; (-ve) = negative.

Table 27

Recommendations for pharmacotherapy for OCD

First-line

Escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline

Second-line

Citalopram, clomipramine, mirtazapine, venlafaxine XR

Third-line

IV citalopram, IV clomipramine, duloxetine, phenelzine, tramadol, tranylcypromine

Adjunctive therapy

First-line: aripiprazole, risperidone

Second-line: memantine, quetiapine, topiramate

Third-line: amisulpride, celecoxib, citalopram, granisetron, haloperidol, IV ketamine, mirtazapine, N-acetylcysteine, olanzapine, ondansetron, pindolol, pregabalin, riluzole, ziprasidone

Not recommended: buspirone, clonazepam, lithium, morphine

Not recommended

Clonazepam, clonidine, desipramine

IV = intravenous; XR = extended release.

First-line agents

SSRIs: Evidence from RCTs and meta-analyses support the use of SSRIs, including escitalopram [705709], fluoxetine [660, 710716], fluvoxamine [711, 713, 714, 717719], paroxetine [705, 720722], and sertraline [659, 710, 711, 713, 714, 723725] (all Level 1), in the treatment of OCD. In meta-analyses, response rates with SSRIs are generally twice those of placebo [809], at 40-60% with treatment versus <20% with placebo [711, 713, 714, 740, 741]. Pooled response rates are not significantly different between SSRIs [809]. In meta-analyses and head-to-head trials, compared with clomipramine, the SSRIs fluoxetine, fluvoxamine, paroxetine, and sertraline had similar efficacy but better tolerability [711, 713, 714, 716718, 720, 724].

Dimensional analyses have suggested that symmetry/hoarding symptoms may be associated with a poorer response to SSRI therapy [810, 811], while aggressive/religious/sexual symptoms may predict better outcomes [810, 812]. It has been hypothesized that the symmetry/hoarding symptom dimension may be mediated by the dopamine system and aggressive behaviors by the serotonin system [810, 812].

Second-line agents

Clomipramine: There is good evidence to support the use of clomipramine in the treatment of OCD (Level 1) [658, 711, 713, 714, 716718, 720, 724, 740, 741]. Clomipramine has efficacy similar to SSRIs, but SSRIs are generally better tolerated [711, 713, 714, 716718, 720, 724]. Side effects and safety are issues with clomipramine and therefore it is recommended as a second-line choice. Common adverse effects include anticholinergic effects such as dry mouth, constipation, and blurred vision, as well as urinary retention, orthostatic hypotension, weight gain, and sedation [813, 814]. The major safety concerns are cardiac arrhythmias, seizures, drug interactions, and toxicity in overdose [813, 814].

Antidepressants: In RCTs, citalopram was more effective than placebo but less effective than psychotherapy (Level 2) [680, 726]. Additional data from augmentation studies support the efficacy of citalopram for the treatment of OCD [727, 728]. However, given that other SSRIs have much stronger evidence, citalopram was designated a second-line option. The only RCT data on the use of mirtazapine in OCD are from a discontinuation study in which continued mirtazapine was associated with continued improvement (Level 2) [748]. There is some evidence to support the use of venlafaxine XR for the treatment of OCD (Level 2) [721, 731733]. In RCTs, venlafaxine XR was more effective than placebo [732], and as effective as paroxetine [721] and clomipramine [731]. In a double-blind extension of a RCT [721], paroxetine was more efficacious than venlafaxine in the treatment of non-responders to previous treatment with the alternate antidepressant [733].

Third-line agents

Intravenous clomipramine: In a RCT, intravenous (IV) clomipramine was more effective than placebo in patients with OCD (Level 2) [742]. Initiating therapy with IV then switching to oral therapy does not appear to be associated with greater benefit compared with oral therapy alone [743, 744].

Other agents: IV citalopram [729] (Level 3), as well as duloxetine [734736], tramadol [805, 806], and tranylcypromine [739] (all Level 4) have demonstrated some efficacy in open trials or case reports. Results with phenelzine have been inconsistent. In one RCT, phenelzine was not significantly better than placebo [738], but in another it was as effective as clomipramine (Level 2) [737]. In the placebo-controlled trial, post-hoc analysis suggested that phenelzine may be beneficial in patients with symmetry or other atypical obsessions [738].

These agents are recommended as third-line options, and may be useful in refractory patients after first- and second-line monotherapies and adjuncts have been unsuccessful.

Adjunctive therapy

Adjunctive strategies have generally been studied in patients who have had an inadequate response to SSRI therapy, and can be considered for patients with treatment-resistant OCD. A meta-analysis demonstrated that response rates with adjunctive medication were twice those of placebo, however these were still quite low (31.8% versus 13.6%) [815]. Meta-analyses of RCTs found that adding risperidone (and possibly quetiapine) to antidepressants increased efficacy but decreased tolerability, while adjunctive olanzapine did not improve response rates [816, 817].

First-line adjunctive therapies: In RCTs, adjunctive aripiprazole was significantly more effective than placebo (Level 1) [750, 754], and may be as effective as risperidone [755]. Additional open-label data also support the beneficial effects of adjunctive aripiprazole [751753].

As adjunctive therapy for treatment-resistant OCD, risperidone was more effective than placebo (Level 1) [756759] and as effective as olanzapine [760] and aripiprazole overall [755]. Compared with aripiprazole, risperidone may provide greater improvement in obsessions [755]. Risperidone was also as effective as haloperidol for obsessions, but less so for compulsions, however it was better tolerated [758]. More recently an open, randomized study found that while augmentation with ERP was superior to risperidone or pill placebo, risperidone was not significantly more effective than placebo [761]. However, patients in this study had some response to SSRI therapy and may have been less refractory compared to those in other studies. Considering the tolerability concerns of atypical antipsychotics, these data reinforce that this augmentation strategy should be reserved for patients with treatment-resistant OCD.

Second-line adjunctive therapies: RCT evidence demonstrated that adjunctive memantine was superior to placebo (Level 2) [783]. Additional open-label data also support this therapy [622, 781, 782]. Another option which may be useful as an adjunctive therapy in those with refractory OCD is the atypical antipsychotic quetiapine (Level 1, conflicting) [728, 746, 747, 764766, 768].

Data from small RCTs suggest that topiramate may be a useful adjunctive therapy, but data are conflicting (Level 1) [796, 797]. In one RCT, adjunctive topiramate significantly improved Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores compared with placebo [797], while in another trial, adjunctive topiramate significantly improved compulsions but not obsessions [796]. Additional open-label data support the use of adjunctive topiramate [795, 798].

Third-line adjunctive therapies: The agents discussed below are recommended as third-line adjunctive options, since some data are available to suggest they may be useful but there is conflicting or inadequate evidence to warrant stronger recommendations. These agents may be useful for some patients, but more data are needed.

Other atypical antipsychotics have been assessed as adjunctive therapies in patients with refractory OCD, including olanzapine (Level 1, conflicting) [760, 762, 763], amisulpride (Level 3) [770], and ziprasidone (Level 4) [767].

There is level 2 evidence to support the use of adjunctive haloperidol in patients with refractory OCD [758, 769], and although it may be as effective as adjunctive risperidone, it is a third-line choice because it was less well tolerated [758].

Adjunctive mirtazapine was associated with an earlier onset of response of OCD symptoms compared with citalopram alone, but there was no advantage of the combination over time (Level 2) [727]. Some data also support the efficacy of adjunctive citalopram for treatment-resistant OCD (Level 3) [730].

Adjunctive anticonvulsants may be useful for some patients with refractory illness [799802]. In a small RCT, adjunctive lamotrigine improved both obsessions and compulsions compared to SSRI therapy (Level 2) [799]. Open-label data also suggest that adjunctive pregabalin may be useful (Level 3) [801, 802].

Other agents that have been studied as adjunctive therapy for treatment-resistant OCD include celecoxib [777], granisetron [778], IV ketamine [779, 780], ondansetron [784, 785], N-acetylcysteine [786, 787] (all Level 2), and riluzole (Level 3) [788, 789]. There is little clinical experience with these agents for refractory OCD, therefore they are recommended as third-line adjunctive options only.

Results with pindolol augmentation have been inconsistent, with significant improvements in one small RCT [774], but not in other randomized or open trials (Level 1, conflicting) [775, 776].

In two randomized, quetiapine-controlled trials, adjunctive clomipramine was not superior to SSRI therapy (Level 2, negative) [746, 747]. Clinical experience suggests that some patients may benefit from adjunctive clomipramine; however, plasma levels should be monitored because of the risk of drug interactions with SSRIs [747, 813].

Not recommended

Clonazepam [771], clonidine [773], and desipramine (all Level 2, negative) [723, 745] have not demonstrated efficacy and are not recommended in the treatment of OCD. Bupropion [749] and naltrexone (both Level 3, negative) [807] also do not appear to be effective in this disorder.

Adjunctive buspirone [