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Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1 REVIEW Open Access Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders Martin A Katzman1*, Pierre Bleau2, Pierre Blier3, Prat...

Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1 REVIEW Open Access Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders Martin A Katzman1*, Pierre Bleau2, Pierre Blier3, Pratap Chokka4, Kevin Kjernisted5, Michael Van Ameringen6, the Canadian Anxiety Guidelines Initiative Group on behalf of the Anxiety Disorders Association of Canada/ Association Canadienne des troubles anxieux and McGill University 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. 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) [1-5]. 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, * Correspondence: [email protected] 1 Department of Psychiatry, University of Toronto, Toronto, ON, M5S 1A1, Canada Full list of author information is available at the end of the article 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. © 2014 Katzman et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1 Page 2 of 83 Methods Table 2 Treatment recommendation summary 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). 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 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 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. Not Level 1 or Level 2 evidence for lack of efficacy recommended 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% [1-5] and 12-month prevalence rates of about 18% [3,4]. Rates for individual disorders vary widely. Women generally have higher prevalence rates Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1 Page 3 of 83 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 [10-12]. 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]. 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 5 presents suggested screening questions for individual anxiety and related disorders, from various validated screening tools [27-30], some of which are freely available online (e.g., http://www.macanxiety.com/ online-anxiety-screening-test). Suicide risk Conduct differential diagnosis In large surveys, anxiety and related disorders were independently associated with a significant 1.7-2.5 times increased risk of suicide attempts [20-23]; 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]. 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) [4,9,33-37]. 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]. 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 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. 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]. 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 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]. Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1 Page 4 of 83 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? 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], 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] 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 [46-49], 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, Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1 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-thecounter 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. 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 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. Page 5 of 83 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. 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 [54-56], specific phobia [57], SAD [58,59], OCD [60-63], GAD [55,64,65], or PTSD [66-69], 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 Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1 Page 6 of 83 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]. caused and maintain the individual patient’s anxiety symptoms [73]. Some of the core components of CBT are shown in Table 9 [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 [74-79]. 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). Table 9 Components of cognitive behavioral interventions Exposure • • • • 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 Encourage patients to face fears Patients learn corrective information through experience Extinction of fear occurs through repeated exposure Successful coping enhances self-efficacy 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]. Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1 Page 7 of 83 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]. 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 [85-88]. 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, 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 Escitalopram (Cipralex®) X X Fluoxetine (Prozac®) X Posttraumatic stress disorder ANTIDEPRESSANTS SSRIs Fluvoxamine (Luvox®) X Paroxetine (Paxil®) X X Paroxetine CR (Paxil® CR) X X Sertraline (Zoloft®) X X X X X TCAs Clomipramine X Other antidepressants Venlafaxine XR (Effexor® XR) X Duloxetine (Cymbalta®) X X X AZAPIRONES Buspirone (BuSpar®, Buspirex®) BENZODIAZEPINES* X 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. Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1 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 [109-116]. Metabolic disturbances generally appear to be higher with olanzapine, intermediate with risperidone and quetiapine, and lower with aripiprazole, asenapine, lurasidone, and ziprasidone [109-114]. 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 Page 8 of 83 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 evidencebased 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. Followup 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 followup 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 Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1 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. Page 9 of 83 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 [85,139-141]. The presence of medical comorbidity is associated with greater severity of panic disorder symptoms and disability [140,142]. Panic disorder and agoraphobia Epidemiology Diagnosis 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 [129-133] 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]. 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]. 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 Comorbidity Patients with panic disorder, or those experiencing panic attacks, have significantly increased odds of being diagnosed with a comorbid disorder, including another anxiety 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]. Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1 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]. 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]. 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 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]. Page 10 of 83 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 [150-154]. Minimal intervention formats, such as self-help books (bibliotherapy) [75,76,155-158], treatment via telephone/ videoconferencing [75,159-161], and internet-based CBT (ICBT) [75,79,162-169] 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 Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1 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 Page 11 of 83 [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 followup, 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. First-line agents SSRIs: Evidence from meta-analyses [195-197] and RCTs supports the use of the SSRIs citalopram [198-200], fluoxetine [201-204], fluvoxamine [195,205-210], paroxetine [211-219], 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 [195-197,226]. 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) [215,216,227-229]. Two studies found significantly greater rates of panicfree 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] Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1 Page 12 of 83 Table 14 Strength of evidence for pharmacotherapy for panic disorder Agent Level of evidence Agent Level of evidence Antidepressants SSRIs TCAs Citalopram [198-200] 1 Clomipramine [199,211,213,232,233] 1 Fluoxetine [201-204] 1 Imipramine [207,224,233-240] 1 Fluvoxamine [195,205-210] 1 MAOIs and RIMAs Paroxetine [211-219] 1 Phenelzine [240] 2 Sertraline [183,220-224] 1 Moclobemide [204,232,241,242] 1* 3 Escitalopram [198] 2 Tranylcypromine [243] Paroxetine CR [225] 2 Other antidepressants SNRIs Reboxetine [200,219,244] 1 Venlafaxine XR [215,216,227-229] 1 Mirtazapine [203,245,246] 2 Duloxetine [230] 3 Bupropion SR [247,248] 3* Milnacipran [231] 3 Other therapies Anxiolytics Benzodiazepines Alprazolam [234,249-254] 1 Atypical antipsychotics Risperidone [217,267] 2 Olanzapine [268] 3 Clonazepam [218,250,255-258] 1 Quetiapine [267] 3 Lorazepam [251,259,260] 1 Adjunctive aripiprazole [269] 3 Diazepam [261-263] 1 Adjunctive olanzapine [270] 3 Adjunctive clonazepam [264,265] 1 Adjunctive risperidone [271] 3 Adjunctive alprazolam ODT [266] 3 Anticonvulsants Other treatments Buspirone [254,282] 1 (-ve) Divalproex [272-275] Levetiracetam [276] 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 3 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. and imipramine [207,224,233-240] in panic disorder (Level 1). In meta-analyses, TCAs have demonstrated efficacy for the treatment of panic symptoms and agoraphobia [195-197,226]. 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 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,