Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for the treatment of panic disorder, social anxiety disorder and generalised anxiety disorder

The qualitative synthesis ultimately included 143 quantitative studies.

“This resulted in exclusion of 388 articles, leaving a final 143 quantitative studies to be included in the qualitative synthesis.”

Well-designed studies have not compared CBT self-help books with dCBT or face-to-face CBT for these anxiety disorders.

“the comparative efficacy of CBT self-help books with dCBT or face-to-face CBT in the treatment of these anxiety disorders has not been assessed in appropriately designed studies.”

Data are lacking for estimating suicide risk in these three disorders.

“There were insufficient data to estimate the risk of suicide associated with these three disorders.”

Those with panic disorder, SAD or GAD have a 50% higher likelihood of suicidal thoughts and attempts.

“found that people with panic disorder, SAD and GAD were 50% more likely to experience suicidal ideation and suicide attempts.”

• cites Bentley et al., 2016Not checked yet

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Evidence comparing treatments for refractory anxiety is very sparse.

“There is very limited evidence for the comparative efficacy of treatment options to manage treatment-refractory anxiety.”

Abrupt discontinuation of tricyclic antidepressants may cause symptoms similar to selective serotonin reuptake inhibitor or serotonin-noradrenaline reuptake inhibitor discontinuation syndrome.

“Abrupt discontinuation of TCAs may cause similar symptoms.”

Overall evidence does not indicate that any one of these medications is to be preferred.

“Overall, evidence does not indicate that any one of these medications is to be preferred”

In a review of 96 studies of antidepressants in depression, pill placebo effect sizes assessed by rating scales were three times greater than those from self-report scales.

“In a review of 96 studies of antidepressants in depression (Rief et al., 2009), the pill placebo effect sizes assessed by rating scales were three times greater than those from self-report scales.”

• cites Rief et al., 2009Not checked yet

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There is potential for abuse of benzodiazepines.

“There is also a potential for abuse (Williams et al., 2017).”

• cites Williams et al., 2017Not checked yet

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Some patients who have not responded to lower doses may respond to higher doses within the therapeutic dose range.

“However, some patients who have not responded to lower doses may respond to higher doses within the therapeutic dose range.”

Studies in anxiety disorders that compare medication and cognitive-behavioural therapy with the same control group, whether pill placebo or wait-list, are rare and somewhat atypical.

“Studies in anxiety disorders that compare medication and CBT with the same control group, whether pill placebo, or wait-list, are rare and somewhat atypical.”

Irreversible monoamine oxidase inhibitors have proven efficacy in social anxiety disorder and panic disorder.

“The irreversible monoamine oxidase inhibitors (MAOIs) have proven efficacy in SAD and panic disorder.”

Use of irreversible monoamine oxidase inhibitors in social anxiety disorder and panic disorder has been limited due to significant potential adverse effects, the need for dietary restrictions, toxicity in overdose and important pharmacokinetic interactions.

“However, their use in the treatment of these disorders has been limited, due to significant potential adverse effects, the need for dietary restrictions, toxicity in overdose and important pharmacokinetic interactions.”

When ceasing some selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors, especially paroxetine and venlafaxine, many individuals experience a discontinuation syndrome with flu-like symptoms, shocklike sensations, dizziness, insomnia, vivid dreams, irritability and crying spells, as well as excessive sweating and myalgia.

“When ceasing some SSRIs and SNRIs (especially paroxetine and venlafaxine), many individuals experience a discontinuation syndrome, with flu-like symptoms, shocklike sensations, dizziness, insomnia, vivid dreams, irritability and crying spells, as well as excessive sweating, and myalgia.”

There is inconsistent evidence for a dose-response relationship for antidepressants in anxiety disorders.

“There is inconsistent evidence for a dose-response relationship.”

Selective serotonin reuptake inhibitors and serotonin-noradrenaline reuptake inhibitors can have adverse effects including initial exacerbation of anxiety, particularly where there is a history of panic attacks, nausea, headache, sleep disruption and sexual dysfunction.

“SSRI and SNRI antidepressants can have adverse effects including initial exacerbation of anxiety (particularly where there is a history of panic attacks), nausea, headache, sleep disruption and sexual dysfunction.”

Trials have not been done in Indigenous or other locally relevant culturally and linguistically diverse groups.

“In addition, no trials have been conducted in Indigenous populations or other locally relevant culturally and linguistically diverse populations.”

Digital cognitive-behavioural therapy programmes for people with mixed or comorbid anxiety and depressive disorders that have been shown effective in practice are available from mindspot.org.au and thiswayup.org.au.

“dCBT programmes for people with mixed or comorbid anxiety and depressive disorders that have been shown to be effective in practice are available from https://mindspot.org.au a and https://thiswayup.org.aub .”

For about half of participants in clinical trials of selective serotonin reuptake inhibitors or serotonin-noradrenaline reuptake inhibitors, symptoms improve to the point that they no longer meet criteria for the disorder.

“For about half of the participants in clinical trials of SSRIs or SNRIs, symptoms improve to the point that they no longer meet criteria for the disorder.”

The body of evidence suggests that cognitive-behavioural therapy delivered face-to-face by an experienced clinician or as guided digital cognitive-behavioural therapy produces no serious adverse effects.

“However, the body of evidence suggests that CBT (delivered face-to-face by an experienced clinician or as guided digital CBT) produces no serious adverse effects.”

• AssumptionRests on an assumption: The potential risks of cognitive-behavioural therapy have not been systematically evaluated in the published literature.

A narrative review found the combination of medication and cognitive-behavioural therapy to be equal to cognitive-behavioural therapy in the longer term for generalised anxiety disorder.

“In contrast, a narrative review (Würz and Sungur, 2009) found the combination of medication and CBT to be equal to CBT in the longer term.”

• cites Würz and Sungur, 2009Not checked yet

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Panic disorder often follows a chronic course with waxing and waning.

“Panic disorder often follows a chronic course with waxing and waning.”

A meta-analysis found that the combination of medication and cognitive-behavioural therapy was better than cognitive-behavioural therapy in the treatment of generalised anxiety disorder.

“A meta-analysis investigating the benefits of adding pharmacotherapy to CBT in the treatment of anxiety disorders (Hofmann et al., 2009) found that the combination of medication and CBT was better than CBT in the treatment of GAD.”

• cites Hofmann et al., 2009Not checked yet

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Four studies, including two meta-analyses and two randomised controlled trials, found that the combination of selective serotonin reuptake inhibitors and cognitive-behavioural therapy was better than selective serotonin reuptake inhibitors alone in the treatment of panic disorder.

“Four studies, including two meta-analyses (Bandelow et al., 2007;Cuijpers et al., 2014a) and two RCTs (Roy-Byrne et al., 2005;Van Apeldoorn et al., 2013) found that the combination of SSRIs and CBT was better than SSRIs alone in the treatment of panic disorder.”

• cites Bandelow et al., 2007Not checked yet

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• cites Cuijpers et al., 2014aNot checked yet

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• cites Roy-Byrne et al., 2005Not checked yet

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In the treatment of panic disorder and agoraphobia, social anxiety disorder or generalised anxiety disorder, available evidence does not consistently support the use of higher doses of antidepressant medicines than those recommended as standard for the treatment of depression.

“In the treatment of panic disorder and agoraphobia, SAD or GAD, available evidence does not consistently support the use of higher doses of antidepressant medicines than those recommended as standard for the treatment of depression.”

Only a few people have complete, sustained remission without relapse.

“Only a few people have complete, sustained remission without relapse (Andersch and Hetta, 2003;Roy-Byrne et al., 2006;Swoboda et al., 2003).”

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• cites Roy-Byrne et al., 2006Not checked yet

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• cites Swoboda et al., 2003Not checked yet

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A meta-analysis found that the combination of medication and cognitive-behavioural therapy was better than either single treatment in the treatment of social anxiety disorder.

“A meta-analysis of RCTs comparing psychopharmacological and psychological treatment for anxiety disorders (Bandelow et al., 2007) found that the combination of medication and CBT was better than either single treatment in the treatment of SAD.”

• cites Bandelow et al., 2007Not checked yet

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Response times for antidepressants in anxiety are longer than for depression.

“Response times are longer than for depression.”

Evidence suggests that panic disorder is undertreated in both primary and secondary care.

“Yet, evidence suggests that panic disorder is undertreated in both primary (Stein et al., 2004) and secondary care (Bruce et al., 2003;Burton et al., 2011;Goisman et al., 1999).”

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• cites Bruce et al., 2003Not checked yet

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• cites Burton et al., 2011Not checked yet

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There is currently limited evidence to support the routine combination of cognitive-behavioural therapy and pharmacotherapy for anxiety disorders.

“Despite its common use in clinical practice, there is currently limited evidence to support the routine combination of CBT and pharmacotherapy for anxiety disorders.”

It is uncommon for an anxiety disorder to first appear after age 40.

“Developing an anxiety disorder after the age of 40 years is uncommon”

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• cites McEvoy et al., 2011Not checked yet

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Adequate treatment reaches only a minority of those with anxiety disorders.

“yet only a minority of people with anxiety disorders get adequate treatment (Harris et al., 2015).”

• cites Harris et al., 2015Not checked yet

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Anxiety disorders frequently co-occur with other anxiety and depressive disorders.

“There are high rates of comorbidity between an anxiety disorder and other anxiety and depressive disorders (Andrews et al., 2002;Brown et al., 2001;Comer et al., 2011).”

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• cites Brown et al., 2001Not checked yet

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• cites Comer et al., 2011Not checked yet

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Under half of those with anxiety disorders consult a health professional for treatment.

“Fewer than half seek treatment by visiting a health professional.”

• cites Boyce et al., 2015Not checked yet

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• cites Harris et al., 2015Not checked yet

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Subthreshold cases do warrant treatment.

“Subthreshold cases do warrant treatment”

• cites Goldberg et al., 2009Not checked yet

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• cites Newby et al., 2015Not checked yet

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Major depression, panic and phobias, GAD, OCD and PTSD all improve with similar therapies.

“the internalising disorders (major depression, panic and phobias, GAD, OCD and PTSD) do respond to similar therapies (Goldberg et al., 2009)”

• cites Goldberg et al., 2009Not checked yet

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As few as 30-60% of primary care patients with an anxiety disorder may get treatment considered adequate.

“perhaps only 30-60% of people who see their GP for an anxiety disorder receive a treatment regarded as adequate (Slade et al., 2009b;Stein et al., 2004b).”

• cites Slade et al., 2009bNot checked yet

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• cites Stein et al., 2004bNot checked yet

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Four established diagnostic interviews yield reliable and valid diagnoses.

“There are four well-established diagnostic interviews that generate a reliable and valid diagnosis:”

• cites First et al., 1997Not checked yet

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• cites Brown and Barlow, 2014Not checked yet

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• cites Kessler and Üstün, 2004Not checked yet

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In major depression, evidence suggests some patients improve only with CBT and others only with antidepressants.

“Literature on the treatment of major depressive disorder (but not yet on the treatment of these three anxiety disorders) supports the idea that, while patient preference is important to adherence, some patients will only respond to CBT and others only to antidepressants.”

• cites Cuijpers et al., 2014bNot checked yet

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• cites Dunlop et al., 2017Not checked yet

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• cites Karyotaki et al., 2016Not checked yet

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dCBT seems as helpful as therapist-delivered CBT, producing similar gains in symptoms, disability and quality of life.

“Compared with CBT with a therapist, dCBT appears to be equally beneficial, with equivalent reductions in symptoms and disability and equivalent improvement in quality of life”

• cites Andrews et al., 2010aNot checked yet

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• cites Andrews et al., 2018Not checked yet

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• cites Olthuis et al., 2016Not checked yet

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Every disorder lies on a continuum from subthreshold to severe.

“all disorders exist on a dimension from subthreshold to severe cases.”

• cites Helzer et al., 2009Not checked yet

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Each included study had its evidence level rated using the Australian NHMRC intervention classification.

“For each included study, the level of evidence was assessed according to the Australian National Health and Medical Research Council (NHMRC) classification for intervention studies (Table 1;National Health and Medical Research Council, 2009).”

• cites National Health and Medical Research Council, 2009Not checked yet

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A single RCT found a CBT self-help book and dCBT had similar effects in depression.

“Although one RCT has reported that the use of a CBT self-help book was equivalent to dCBT in the treatment of depression (Smith et al., 2017)”

• cites Smith et al., 2017Not checked yet

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Internalising disorders respond to transdiagnostic therapies.

“and to transdiagnostic therapies (Newby et al., 2015).”

• cites Newby et al., 2015Not checked yet

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Anxiety is under-recognised in general practice.

“anxiety is under-recognised in general practice (Jameson and Blank, 2010)”

• cites Jameson and Blank, 2010Not checked yet

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Direct study comparisons are hindered by differing outcome measures.

“The use of different outcome measures makes direct comparisons between studies difficult”

In medication trials, substantial placebo improvement is a major limitation that can make drug effects look smaller.

“A significant limitation of the pharmacological research is the degree of improvement that occurs with pill placebo that tends to underestimate the effect of medication.”

It has been difficult to compare the benefits of medication versus pill placebo assessed by rating scales with the benefits of cognitive-behavioural therapy versus wait-list controls assessed by self-report.

“Therefore, it has been difficult to compare the benefits of medication versus pill placebo assessed by rating scales, with the benefits of CBT versus wait-list controls assessed by self-report.”

Digital cognitive-behavioural therapy appears comparable in efficacy and effectiveness to face-to-face cognitive-behavioural therapy for panic disorder, social anxiety disorder and generalised anxiety disorder.

“Thus, dCBT appears to be comparable in efficacy and effectiveness to face-to-face CBT for panic disorder, SAD and GAD.”

Toxic levels or increased adverse effects may result if other drugs substantially metabolised via CYP2D6, such as tricyclic antidepressants, some antiarrhythmic agents and beta blockers, are used concomitantly with fluoxetine or paroxetine.

“As a result, toxic levels or increased adverse effects may result if other drugs that are substantially metabolised via this pathway (e.g.TCAs, some antiarrhythmic agents and beta blockers) are used concomitantly.”

Shifts in recruitment and population trends can make trial samples unrepresentative of clinical populations.

“Changes in clinical trial recruitment strategies and secular trends in the general population over recent decades may result in samples that do not accurately reflect the clinical population.”

Comparing medication with psychotherapies using control groups specific to the intervention could put medication at a disadvantage.

“Accordingly, comparing medication with psychotherapies using control groups specific to the intervention could well put medication at a disadvantage.”

Antidepressants, especially selective serotonin reuptake inhibitors and to a lesser extent serotonin-noradrenaline reuptake inhibitors, are first-line medications for panic disorder, social anxiety disorder and generalised anxiety disorder on the basis of efficacy evidence from pill placebo-controlled randomised controlled trials, overall safety and low misuse potential.

“Antidepressants, especially the SSRIs and, to a lesser extent the SNRIs, are the first-line medications for panic disorder, SAD and GAD on the basis of efficacy evidence from pill placebo-controlled RCTs (Craske and Stein, 2016;Ravindran and Stein, 2010), overall safety and low misuse potential”

• cites Craske and Stein, 2016Not checked yet

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• cites Ravindran and Stein, 2010Not checked yet

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In the management of depression, nonspecific elements are more important than specific elements, as reflected in the response to pill placebo.

“In the management of depression, it is clear that the nonspecific elements are more important than the specific elements, as reflected in the response to pill placebo.”

Improvement after digital cognitive-behavioural therapy treatment was maintained 36 months later.

“The improvement post treatment was maintained 36 months later.”

Systematic reviews of studies in depressed patients suggest that the serotonin-noradrenaline reuptake inhibitors duloxetine and venlafaxine may be less well tolerated than selective serotonin reuptake inhibitors.

“systematic reviews of studies in depressed patients suggest that the SNRIs, duloxetine and venlafaxine, may be less well tolerated than the SSRIs (Cipriani et al., 2012;Schueler et al., 2011).”

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• cites Schueler et al., 2011Not checked yet

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When seeking help, people with panic disorder often go to medical specialists or emergency departments, probably because of the predominance of physical symptoms and catastrophic concerns about these.

“When seeking help, people often go to medical specialists or emergency departments, probably because of the predominance of physical symptoms and the catastrophic concerns about these (Deacon et al., 2008;Fleet et al., 1998;Gerdes et al., 1995;Katerndahl and Realini, 1995).”

• cites Deacon et al., 2008Not checked yet

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• cites Fleet et al., 1998Not checked yet

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• cites Gerdes et al., 1995Not checked yet

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Panic disorder is often comorbid with other mental health disorders, particularly other anxiety disorders, mood disorders, psychotic disorders, and substance use disorders.

“Panic disorder is often associated with comorbidity with other mental health disorders, particularly other anxiety disorders, mood disorders, psychotic disorders and substance use disorders (Roy-Byrne et al., 2006).”

• cites Roy-Byrne et al., 2006Not checked yet

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The Panic Disorder Severity Scale and the Panic and Agoraphobia Scale assess components of panic disorder including panic attacks, anticipatory anxiety, avoidance, health-related concerns, and disability.

“Two scales have been developed that assess the components of panic disorder (panic attacks, anticipatory anxiety and avoidance, health related concerns and disability): the Panic Disorder Severity Scale (Houck et al., 2002) and the Panic and Agoraphobia Scale (Bandelow, 1995).”

• cites Houck et al., 2002Not checked yet

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• cites Bandelow, 1995Not checked yet

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Major depressive disorder in people with panic disorder can result in poorer outcome.

“Major depressive disorder is common, occurring in approximately 35-40% of people with panic disorder (Kessler et al., 2006), is associated with greater impairment in functioning and can result in poorer outcome (Scheibe and Albus, 1994).”

• cites Scheibe and Albus, 1994Not checked yet

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Panic disorder has significant comorbidity with medical disorders, particularly thyroid disease, cardiac disease, respiratory conditions, migraine, irritable bowel syndrome, arthritis, allergies, chronic pain, and cancer.

“There is also significant comorbidity with medical disorders, particularly thyroid disease, cardiac disease, respiratory conditions, migraine, irritable bowel syndrome, arthritis, various allergies, chronic pain and cancer (Korczak et al., 2007;Roy-Byrne et al., 2006;Yamada et al., 2011).”

• cites Korczak et al., 2007Not checked yet

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• cites Roy-Byrne et al., 2006Not checked yet

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• cites Yamada et al., 2011Not checked yet

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In a study with 2-14 years follow-up (median 8 years), only 23% had a relapse at any time over this period.

“A study in which participants were followed up for 2-14 years (median, 8 years) reported that only 23% had a relapse at any time over this period (Fava et al., 2001b).”

• cites Fava et al., 2001bNot checked yet

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Interoceptive exposure is superior to relaxation for panic disorder.

“Interoceptive exposure has been shown to be superior to relaxation (Siev and Chambless, 2007).”

• cites Siev and Chambless, 2007Not checked yet

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Effect sizes for panic disorder treatments are generally moderate.

“Effect sizes are generally moderate.”

Alcohol use and dependence may complicate treatment of panic disorder.

“Alcohol use and dependence have been associated with panic disorder and may also complicate treatment (Kessler et al., 1997;Otto et al., 1992).”

• cites Kessler et al., 1997Not checked yet

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• cites Otto et al., 1992Not checked yet

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Meta-analyses report that the efficacy of CBT is equivalent to that of pharmacotherapy for panic disorder.

“Meta-analyses (Bandelow et al., 2007;Cuijpers et al., 2013;Mitte, 2005b) report that the efficacy of CBT is equivalent to that of pharmacotherapy.”

• cites Bandelow et al., 2007Not checked yet

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• cites Cuijpers et al., 2013Not checked yet

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• cites Mitte, 2005bNot checked yet

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A meta-analysis of 19 studies reported large effect sizes of CBT versus control on measures of both panic disorder and agoraphobia.

“A meta-analysis of 19 studies that assessed the efficacy of CBT for panic disorder compared with control (waitlist, psychological control or pill placebo) reported large effect sizes on measures of both panic disorder and agoraphobia (Sanchez-Meca et al., 2010).”

• cites Sanchez-Meca et al., 2010Not checked yet

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The average dropout rate for CBT from meta-analyses was 12.7%.

“The average dropout rate for CBT from meta-analyses was 12.7%.”

CBT has been shown to be efficacious in the treatment of panic disorder.

“CBT has been shown to be efficacious in the treatment of panic disorder.”

Major depressive disorder in people with panic disorder is associated with greater impairment in functioning.

“Major depressive disorder is common, occurring in approximately 35-40% of people with panic disorder (Kessler et al., 2006), is associated with greater impairment in functioning and can result in poorer outcome (Scheibe and Albus, 1994).”

• cites Scheibe and Albus, 1994Not checked yet

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The benefits of CBT for panic disorder are long lasting.

“The benefits of CBT have been shown to be long lasting (Barlow et al., 2000;Brown et al., 1995;Clark et al., 1999;Fava et al., 1995;Marchand et al., 2009;Ruwaard et al., 2010).”

• cites Barlow et al., 2000Not checked yet

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• cites Brown et al., 1995Not checked yet

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• cites Clark et al., 1999Not checked yet

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Alcohol use and dependence are associated with panic disorder.

“Alcohol use and dependence have been associated with panic disorder and may also complicate treatment (Kessler et al., 1997;Otto et al., 1992).”

• cites Kessler et al., 1997Not checked yet

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• cites Otto et al., 1992Not checked yet

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Medical comorbidity is not associated with poorer outcomes across anxiety disorders.

“However, medical comorbidity is not associated with poorer outcomes across anxiety disorders (Olatunji et al., 2010).”

• cites Olatunji et al., 2010Not checked yet

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Exposure treatment as a component of CBT reduces panic and agoraphobic symptoms.

“Several studies support the efficacy of exposure treatment as a component of CBT, in reducing panic and agoraphobic symptoms (Ito et al., 2001;Marks et al., 1993;Ost et al., 1993;Swinson et al., 1995).”

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• cites Marks et al., 1993Not checked yet

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• cites Ost et al., 1993Not checked yet

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Intensive CBT treatment has been shown to be effective for panic disorder.

“Intensive treatment has also been shown to be effective (Bohni et al., 2009;Deacon and Abramowitz, 2006).”

• cites Bohni et al., 2009Not checked yet

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• cites Deacon and Abramowitz, 2006Not checked yet

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Current evidence does not support recommending one SSRI over another, or venlafaxine over an SSRI, in terms of efficacy, onset of action, side effect profile, or dropout rates.

“Current evidence does not support the recommendation of one SSRI over another, or venlafaxine over an SSRI in terms of efficacy, onset of action, side effect profile or dropout rates.”

Meta-analyses report equivalent efficacy for SSRIs, TCAs, and benzodiazepines in panic disorder.

“Meta-analyses report equivalent efficacy for SSRIs, TCAs and benzodiazepines.”

There is insufficient evidence from meta-analyses specific to panic disorder to make conclusions about mindfulness and Acceptance and Commitment Therapy.

“However, there is insufficient evidence from meta-analyses specific to panic disorder to make conclusions at this time.”

Imipramine and clomipramine have demonstrated efficacy in panic disorder with an effect size of 0.41 (NNT = 6; 95% CI [5, 8]), similar to SSRIs.

“Imipramine and clomipramine have demonstrated efficacy in panic disorder, with an effect size of 0.41 (NNT = 6; 95% CI = [5, 8]; Mitte, 2005b), which is similar to those seen with SSRIs.”

• cites Mitte, 2005bNot checked yet

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One study examined long-term outcomes over 3 years and reported no evidence of relapse in the first year after dCBT.

“One study examined long-term outcomes over 3 years and reported no evidence of relapse in the first year (Ruwaard et al., 2010).”

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MAOI use in panic disorder is limited by safety and tolerability profile.

“MAOIs are effective in managing the symptoms of panic disorder (Batelaan et al., 2012), but their use is limited by their safety and tolerability profile.”

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MAOIs are effective in managing the symptoms of panic disorder.

“MAOIs are effective in managing the symptoms of panic disorder (Batelaan et al., 2012), but their use is limited by their safety and tolerability profile.”

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Medication with SSRIs, SNRIs, TCAs, and benzodiazepines has been shown to be efficacious in the treatment of panic disorder.

“Medication with SSRIs, SNRIs, TCAs and benzodiazepines has been shown to be efficacious in the treatment of panic disorder.”

Moderate effect sizes (0.41, NNT = 8; 95% CI [6, 11]) have been reported for all SSRIs in panic disorder.

“Moderate effect sizes (0.41, NNT = 8; 95% CI = [6, 11]) have been reported for all SSRIs (Mitte, 2005b).”

• cites Mitte, 2005bNot checked yet

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These studies also reported increased treatment response with increased duration of treatment.

“They have also reported increased treatment response with increased duration of treatment (Lecrubier and Judge, 1997).”

• cites Lecrubier and Judge, 1997Not checked yet

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Group CBT is comparable to individual therapy for panic disorder.

“Studies of CBT delivered in group formats report that group CBT was comparable to individual therapy (Lidren et al., 1994;Néron et al., 1995;Telch et al., 1993).”

• cites Lidren et al., 1994Not checked yet

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• cites Néron et al., 1995Not checked yet

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• cites Telch et al., 1993Not checked yet

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Other meta-analyses have reported similar outcomes for dCBT.

“Other meta-analyses have reported similar outcomes (Olthuis et al., 2016).”

• cites Olthuis et al., 2016Not checked yet

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Long-term open-label follow-up studies over 6 months to 3 years demonstrated maintenance of improvements with continued use of citalopram, fluoxetine, sertraline, fluvoxamine, and paroxetine.

“Long-term, open-label follow-up studies over 6 months to 3 years have demonstrated maintenance of improvements with continued use of citalopram (Dannon et al., 2007;Lepola et al., 2003), fluoxetine (Tiller et al., 1999), sertraline (Lepola et al., 2003), fluvoxamine and paroxetine (Dannon et al., 2007;Lecrubier et al., 1997;Nardi et al., 2012).”

• cites Dannon et al., 2007Not checked yet

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• cites Lepola et al., 2003Not checked yet

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• cites Tiller et al., 1999Not checked yet

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Three studies comparing dCBT with face-to-face CBT showed no difference in efficacy.

“Three of the studies included a comparison with face-to-face CBT and showed no difference in efficacy (Andrews et al., 2018).”

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Studies have shown an increase in overall treatment response with increased duration of treatment from 12 to 52 weeks.

“Studies have also shown that there is an increase in overall treatment response with increased duration of treatment from 12 to 52 weeks (Ballenger et al., 1998;Batelaan et al., 2012).”

• cites Ballenger et al., 1998Not checked yet

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• cites Batelaan et al., 2012Not checked yet

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Some people with panic disorder are very sensitive to medication side effects and anxiety exacerbation at treatment initiation.

“Some people with panic disorder are very sensitive to medication side effects and anxiety exacerbation at treatment initiation (Mavissakalian and Perel, 1985;Zitrin et al., 1983).”

• cites Mavissakalian and Perel, 1985Not checked yet

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• cites Zitrin et al., 1983Not checked yet

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Randomised fixed-dose studies reported superior efficacy for paroxetine and fluoxetine than for citalopram and venlafaxine.

“Randomised fixed-dose studies have reported superior efficacy for some SSRIs and SNRIs (paroxetine, fluoxetine; Ballenger et al., 1998;Michelson et al., 1998) than others (citalopram, venlafaxine;Pollack et al., 2007a;Wade et al., 1997).”

• cites Ballenger et al., 1998Not checked yet

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• cites Michelson et al., 1998Not checked yet

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• cites Pollack et al., 2007aNot checked yet

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Long-term open-label follow-up studies over 6 months to 3 years demonstrated maintenance of improvements with clomipramine and imipramine.

“Long-term, open-label follow-up studies over 6 months to 3 years have demonstrated maintenance of improvements with both clomipramine (Lecrubier et al., 1997;Lepola et al., 1998) and imipramine (Curtis et al., 1993;Mavissakalian and Perel, 1992).”

• cites Lecrubier et al., 1997Not checked yet

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• cites Lepola et al., 1998Not checked yet

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• cites Curtis et al., 1993Not checked yet

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Two studies observed no difference in rates of panic-free patients between venlafaxine treatment and placebo groups.

“However, two of these studies observed no difference in the rates of panic-free patients in the treatment and placebo groups (Bradwejn et al., 2005;Liebowitz et al., 2009;Pollack et al., 2007aPollack et al., , 2007b)).”

• cites Bradwejn et al., 2005Not checked yet

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• cites Liebowitz et al., 2009Not checked yet

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• cites Pollack et al., 2007aNot checked yet

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On average, rates of response to medication for panic disorder are 50-70%.

“On average, rates of response to medication are 50-70%.”

Meta-analyses, systematic reviews, and RCTs support the use of SSRIs as first-line pharmacotherapy for panic disorder.

“Meta-analyses (Andrisano et al., 2013;Bakker et al., 2002;Otto et al., 2001), systematic reviews (Batelaan et al., 2012) and RCTs support the use of SSRIs as first-line pharmacotherapy for panic disorder.”

• cites Andrisano et al., 2013Not checked yet

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• cites Bakker et al., 2002Not checked yet

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• cites Otto et al., 2001Not checked yet

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Panic-focused psychodynamic psychotherapy delivered twice a week in a 12-week manualised treatment programme has been shown to be effective in one RCT.

“Panic-focused psychodynamic psychotherapy delivered twice a week in a 12-week manualised treatment programme has been shown to be effective in one RCT (Milrod et al., 2007).”

• cites Milrod et al., 2007Not checked yet

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Several RCTs demonstrated that extended-release venlafaxine reduced the severity of panic disorder symptoms.

“Several RCTs have demonstrated that the SNRI, extended-release venlafaxine, reduced the severity of panic disorder symptoms (Bradwejn et al., 2005;Liebowitz et al., 2009;Pollack et al., 1996aPollack et al., , 2007aPollack et al., , 2007b)).”

• cites Bradwejn et al., 2005Not checked yet

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• cites Liebowitz et al., 2009Not checked yet

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• cites Pollack et al., 1996aNot checked yet

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There are no differences in attrition and dropout rates for SSRIs (23.1%), TCAs (23.5%), and benzodiazepines (17.7%) in panic disorder.

“These studies also report no differences in attrition and dropout rates for the different medications (SSRIs 23.1%, TCAs 23.5% and benzodiazepines 17.7%).”

There is a lack of clear evidence for what constitutes an adequate trial of medication for panic disorder.

“Although there is lack of clear evidence for what constitutes an adequate trial of medication, consensus expert recommendation is to wait for at least 6 weeks with at least 2 weeks at the full dose (Lecrubier et al., 1997;National Institute for Health and Care Excellence, 2011a;Stein et al., 2009a), however the recently updated British Association of”

Few studies have addressed the optimal dose of TCAs for panic disorder.

“Few studies have addressed the optimal dose of TCAs.”

A controlled combination study reported equivalent outcomes at 3 months for CBT, imipramine, and the combination of CBT and imipramine compared with placebo.

“A controlled combination study (Barlow et al., 2000), which compared imipramine, CBT, placebo, the combination of CBT and placebo, and the combination of CBT and imipramine, reported equivalent outcomes at 3 months for CBT, imipramine, and the combination of CBT and imipramine, compared with placebo.”

• cites Barlow et al., 2000Not checked yet

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A Cochrane review of second-generation antipsychotic agents reported no clear benefits for their use in panic disorder.

“A Cochrane review of second-generation (atypical) antipsychotic agents (Depping et al., 2010) reported no clear benefits for their use in panic disorder.”

• cites Depping et al., 2010Not checked yet

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Two-thirds of people relapse over the course of 3 years after discontinuation of antidepressant medication.

“Relapse rates after discontinuation vary, with about a third of people relapsing within 6 months of discontinuation of antidepressant medication (Mavissakalian and Perel, 2002) and two-thirds over the course of 3 years (Toni et al., 2000).”

• cites Toni et al., 2000Not checked yet

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Better outcomes are achieved when medication is discontinued only after attaining remission of symptoms, rather than just improvement.

“Better outcomes are achieved when medication is discontinued only after attaining remission of symptoms, rather than just improvement.”

Evidence to support dose escalation after an initial lack of response to lower doses is limited or negative.

“However, the evidence to support Australian & New Zealand Journal of Psychiatry,52(12) dose escalation after an initial lack of response to lower doses is only limited (Michelson et al., 2001) or negative (Simon et al., 2009).”

• cites Michelson et al., 2001Not checked yet

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• cites Simon et al., 2009Not checked yet

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There is limited evidence supporting the use of these medications as monotherapies or adjunctive therapies for panic disorder.

“There is limited evidence supporting the use of these medications either as monotherapies or adjunctive therapies.”

The optimal duration of treatment with SSRIs, SNRIs, and TCAs has not been well studied.

“The optimal duration of treatment has not been well studied.”

A greater number of people may relapse after discontinuation of benzodiazepines.

“A greater number may relapse after discontinuation of benzodiazepines (Noyes et al., 1991).”

• cites Noyes et al., 1991Not checked yet

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About a third of people relapse within 6 months of discontinuation of antidepressant medication.

“Relapse rates after discontinuation vary, with about a third of people relapsing within 6 months of discontinuation of antidepressant medication (Mavissakalian and Perel, 2002) and two-thirds over the course of 3 years (Toni et al., 2000).”

• cites Mavissakalian and Perel, 2002Not checked yet

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Combination treatment does not appear to be significantly superior to standard monotherapies for most people with panic disorder.

“Combination treatment does not, therefore, appear to be significantly superior to standard monotherapies for most people.”

At 12-month follow-up after treatment withdrawal, CBT had a greater response rate than CBT plus imipramine.

“At 12-month follow-up, after treatment withdrawal, CBT was found to have a greater response rate than CBT plus imipramine (Barlow et al., 2000).”

• cites Barlow et al., 2000Not checked yet

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Combination treatment may provide benefits in relapse prevention following combination therapy, especially following medication withdrawal.

“It may provide benefits in relapse prevention following combination therapy especially following medication withdrawal.”

A systematic review of 23 controlled studies (21 involving behavioural therapy or CBT) compared combined treatment with psychotherapy alone or antidepressants alone.

“A systematic review of all controlled studies (23 in total, of which 21 involved behavioural therapy or CBT) compared combined treatment with psychotherapy alone or antidepressants alone (Furukawa et al., 2007).”

• cites Furukawa et al., 2007Not checked yet

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A primary care study showed that CBT plus pharmacotherapy was more effective than pharmacotherapy alone.

“A study in primary care showed that CBT plus pharmacotherapy was more effective than pharmacotherapy alone (Craske et al., 2005;Roy-Byrne et al., 2005).”

• cites Craske et al., 2005Not checked yet

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• cites Roy-Byrne et al., 2005Not checked yet

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Use of benzodiazepines in combination with CBT has potentially detrimental effects.

“Their use in combination with CBT also has potentially detrimental effects.”

Benzodiazepines may be infrequently required short term to reduce exacerbation of anxiety associated with initiation of SSRI treatment, which usually lasts from a few days to 2 weeks.

“They may also be infrequently required short term to reduce any exacerbation of anxiety associated with the initiation of SSRI treatment, which usually lasts from a few days to 2 weeks.”

Traditional MAOIs have been shown to be effective in the treatment of panic disorder.

“Traditional MAOIs have been shown to be effective in the treatment of panic disorder (Batelaan et al., 2012), but are not recommended as first-line antidepressants because of poor tolerability, the requirement for dietary restrictions, interactions and risks in overdose.”

• cites Batelaan et al., 2012Not checked yet

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Medications with less empirical support for panic disorder include mirtazapine, duloxetine, milnacipran, moclobemide, bupropion, divalproex, levetiracetam, and gabapentin.

“Medications for which there is less empirical support include the antidepressants mirtazapine (Ribeiro et al., 2001), duloxetine (Simon et al., 2009), milnacipran (Blaya et al., 2007), moclobemide (Kruger and Dahl, 1999) and bupropion (Simon et al., 2003), and the anticonvulsants divalproex (Baetz and Bowen, 1998;Keck et al., 1993;Primeau et al., 1990;Woodman and Noyes, 1994), levetiracetam (Baetz”

• cites Ribeiro et al., 2001Not checked yet

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• cites Simon et al., 2009Not checked yet

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• cites Blaya et al., 2007Not checked yet

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These benefits were sustained for as long as medication continued.

“These benefits were sustained for as long as medication continued.”

• cites Furukawa et al., 2007Not checked yet

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For patients with moderate or severe agoraphobia, the combination of CBT plus SSRI was associated with more rapid improvement than either treatment alone.

“The same authors reported that for patients with moderate or severe agoraphobia, the combination of CBT plus SSRI was associated with more rapid improvement than either treatment alone (Van Apeldoorn et al., 2013).”

• cites Van Apeldoorn et al., 2013Not checked yet

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Those on SSRIs (alone or with CBT) showed maintenance of gains to the same extent as those treated with CBT at 1 year after discontinuation.

“Those on SSRIs (again whether alone or in combination with CBT) showed maintenance of gains to the same extent as those treated with CBT at 1 year after discontinuation (van Apeldoorn et al., 2010).”

• cites van Apeldoorn et al., 2010Not checked yet

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Adding medication to patients unsuccessfully treated with CBT alone has been found to be beneficial.

“Adding in medication to patients unsuccessfully treated with CBT alone has also been found to be beneficial (Hoffart and Martinsen, 1993;Kampman et al., 2002).”

• cites Hoffart and Martinsen, 1993Not checked yet

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• cites Kampman et al., 2002Not checked yet

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There is often a long delay of 9 to 28 years between the start of SAD symptoms and seeking professional help.

“There is frequently a long delay (9-28 years) between developing symptoms of SAD and seeking professional help (Green et al., 2012;Thompson et al., 2008), with a median of 16 years reported in the US National Comorbidity Survey Replication (Wang et al., 2005) and 28 years in Te Rau Hinengaro: The New Zealand Mental Health Survey (Oakley Browne et al., 2006;Wells, 2006).”

• cites Green et al., 2012Not checked yet

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• cites Thompson et al., 2008Not checked yet

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The addition of CBT to medication has been shown to be beneficial in patients with panic disorder resistant to medication treatment alone.

“The addition of CBT to medication has been shown to be beneficial in patients with panic disorder that are resistant to medication treatment alone (Heldt et al., 2003;Pollack et al., 1994).”

• cites Heldt et al., 2003Not checked yet

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• cites Pollack et al., 1994Not checked yet

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The amount of distress, disability and impairment rises as the number of social fears increases.

“The level of distress, disability and impairment increases with the number of social fears (Acarturk et al., 2008;Ruscio et al., 2008).”

• cites Acarturk et al., 2008Not checked yet

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• cites Ruscio et al., 2008Not checked yet

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People with greater symptom severity before treatment tend to have lower endstate functioning than those who start treatment less impaired.

“Individuals with greater symptom severity at pre-treatment tend to show lower endstate functioning than those who begin treatment less impaired (Eskildsen et al., 2010).”

• cites Eskildsen et al., 2010Not checked yet

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Severity is relevant when informing treatment expectations.

“Thus, severity is relevant in informing treatment expectations.”

Subthreshold illness is associated with impairment in social and occupational functioning.

“Even subthreshold illness has been associated with impairment in social and occupational functioning (Fehm et al., 2008).”

• cites Fehm et al., 2008Not checked yet

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The Harvard Brown Anxiety Disorders Research Programme found a 0.63 probability that participants had remained in the index episode of SAD 12 years after intake.

“The Harvard Brown Anxiety Disorders Research Programme found a 0.63 probability that participants had remained in the index episode of SAD 12 years after intake (Bruce et al., 2005).”

• cites Bruce et al., 2005Not checked yet

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Only 30-40% of people with SAD received a treatment likely to be effective.

“Only 30-40% received a treatment likely to be effective (Issakidis and Andrews, 2002;Issakidis et al., 2004).”

• cites Issakidis and Andrews, 2002Not checked yet

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• cites Issakidis et al., 2004Not checked yet

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The median delay from SAD onset to help-seeking in Te Rau Hinengaro: The New Zealand Mental Health Survey is 28 years.

“and 28 years in Te Rau Hinengaro: The New Zealand Mental Health Survey (Oakley Browne et al., 2006;Wells, 2006).”

• cites Oakley Browne et al., 2006Not checked yet

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• cites Wells, 2006Not checked yet

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Shyness does not appear to be associated with comorbid psychiatric conditions or substance use disorders.

“but shyness does not appear to be associated with comorbid psychiatric conditions or substance use disorders (Burstein et al., 2011;Heiser et al., 2009).”

• cites Burstein et al., 2011Not checked yet

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• cites Heiser et al., 2009Not checked yet

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About 62% of Australians with SAD had sought help at some time in the previous 12 months.

“Australian epidemiological data identified that about 62% of those with SAD had sought help at some time in the previous 12 months.”

• cites Issakidis and Andrews, 2002Not checked yet

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• cites Issakidis et al., 2004Not checked yet

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Comorbidity with alcohol use disorders does not appear to be related to SAD severity.

“Comorbidity with alcohol use disorders does not appear to be related to the severity of SAD (El-Gabalawy et al., 2009;Fehm et al., 2008;Ruscio et al., 2008).”

• cites El-Gabalawy et al., 2009Not checked yet

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• cites Fehm et al., 2008Not checked yet

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• cites Ruscio et al., 2008Not checked yet

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Delays in seeking help for SAD are likely longer in rural and regional areas.

“It is likely that delays are longer in rural and regional areas (Green et al., 2012).”

• cites Green et al., 2012Not checked yet

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High rates of SAD are found among people who stutter.

“High rates of SAD are found among people who stutter (Craig and Tran, 2006;Iverach and Rapee, 2014).”

• cites Craig and Tran, 2006Not checked yet

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• cites Iverach and Rapee, 2014Not checked yet

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Only about 21% of people with SAD were receiving treatment at the time of the Australian survey.

“only about 21% were currently receiving treatment at the time of the survey.”

• cites Issakidis and Andrews, 2002Not checked yet

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• cites Issakidis et al., 2004Not checked yet

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Patients with comorbid depression may not engage well with CBT.

“Patients with comorbid depression may not engage well with CBT (Ledley et al., 2005).”

• cites Ledley et al., 2005Not checked yet

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A comorbid diagnosis of avoidant personality disorder can be made in about one-third of individuals with SAD.

“A comorbid diagnosis of avoidant personality disorder can be made in about one-third of individuals (Lampe and Sunderland, 2015)”

• cites Lampe and Sunderland, 2015Not checked yet

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SAD most commonly precedes comorbid disorders.

“SAD most commonly precedes comorbid disorders (Fehm et al., 2008), as would be expected from its relatively early age of onset.”

• cites Fehm et al., 2008Not checked yet

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Avoidant personality disorder may be associated with greater impairments in interpersonal functioning, self-identity, self-esteem, and greater attachment pathology.

“However, studies suggest that avoidant personality disorder may be associated with greater impairments in interpersonal functioning, selfidentity and self-esteem, and greater attachment pathology (Lampe, 2016).”

• cites Lampe, 2016Not checked yet

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People with SAD show high levels of comorbidity with other disorders.

“People with SAD show high levels of comorbidity with other disorders (Ruscio et al., 2008).”

• cites Ruscio et al., 2008Not checked yet

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Co-occurrence of another anxiety disorder was increased when major depressive disorder was present, at 65.2%.

“Co-occurrence of another anxiety disorder was increased when a major depressive disorder was present (65.2%).”

• cites Ohayon and Schatzberg, 2010Not checked yet

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The median delay from SAD onset to help-seeking in the US National Comorbidity Survey Replication is 16 years.

“with a median of 16 years reported in the US National Comorbidity Survey Replication (Wang et al., 2005)”

• cites Wang et al., 2005Not checked yet

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The likelihood of comorbid anxiety and mood disorders, and of suicidal ideation, increases with the number of social fears.

“The likelihood of having comorbid anxiety and mood disorders, and suicidal ideation, increases with the number of social fears (El-Gabalawy et al., 2009;Ruscio et al., 2008).”

• cites El-Gabalawy et al., 2009Not checked yet

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• cites Ruscio et al., 2008Not checked yet

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The effects of self-help CBT for SAD have not been shown to be superior to psychological placebo.

“However, effects have not been shown to be superior to psychological placebo (Mayo-Wilson et al., 2014).”

• cites Mayo-Wilson et al., 2014Not checked yet

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Psychological treatments for SAD have large overall effects compared with wait-list, with an effect size of 0.86 and NNT of 2.19.

“Overall effects are large when psychological treatments are compared with wait-list (effect size = 0.86; NNT = 2.19).”

• cites Acarturk et al., 2009Not checked yet

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• cites Powers et al., 2008Not checked yet

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Combining CBT with medication for SAD is superior to medication alone.

“A systematic review and meta-analysis found that the combination of CBT plus medication for SAD was superior to medication alone, and the combination of CBT plus medication for SAD was superior to CBT alone.”

• cites Bandelow et al., 2007Not checked yet

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• cites Würz and Sungur, 2009Not checked yet

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CBT and antidepressant pharmacotherapy with SSRIs, SNRIs or MAOIs are effective for SAD according to a large body of level I evidence.

“CBT and antidepressant pharmacotherapy with SSRIs, SNRIs or MAOIs have been demonstrated to be effective by a large body of level I evidence.”

Digital CBT accessed by computer, tablet or smartphone is effective for SAD.

“There is also evidence that dCBT (accessed by computer, tablet or smartphone application) is effective.”

Mindfulness, supportive therapy and interpersonal therapy have not shown effects significantly better than wait-list for SAD.

“Other psychological therapies, including mindfulness, supportive therapy and interpersonal therapy, have failed to show effects that are significantly better than wait-list (combined effect size = 0.36, NNT = 5.00; separate effect size = 0.26-0.43;Mayo-Wilson et al., 2014).”

• cites Mayo-Wilson et al., 2014Not checked yet

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Individual therapy is superior to group CBT for SAD.

“A meta-analysis of treatments for anxiety disorders (Bandelow et al., 2015) found that individual therapy was superior to group CBT for SAD.”

• cites Bandelow et al., 2015Not checked yet

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An analysis of four datasets found that medication reduced relapse risk compared with placebo in SAD, with a relative risk of 0.33 and NNT of 3.7-5.7.

“Some studies have also demonstrated protection against relapse in the longer term: an analysis of four datasets (Stein et al., 2000) calculated the RR of relapse compared with placebo at 0.33 (95% CI = [0.22,0.49]; NNT = 3.7-5.7).”

• cites Stein et al., 2000Not checked yet

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There is no clear dose-response relationship for pharmacotherapy in SAD.

“Given the absence of a clear dose-response relationship, pharmacotherapy should be given at the minimum therapeutic dose for an initial period of 4-6 weeks before assessing response.”

The benefits of guided dCBT for SAD were evident at a mean follow-up of 9.8 months post treatment.

“The benefits were evident at a mean follow-up of 9.8 months post treatment (Andrews et al., 2018).”

• cites Andrews et al., 2018Not checked yet

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Numerous RCTs demonstrate the efficacy of pharmacological agents in short-term treatment of SAD, typically 12-14 weeks.

“Numerous RCTs demonstrate the efficacy of pharmacological agents in the short-term (typically 12-14 weeks) treatment of SAD.”

Effect sizes for self-help CBT are generally slightly larger for therapist-assisted self-help than for pure self-help.

“Effect sizes are generally slightly larger for therapist-assisted self-help (effect size = 0.86, NNT = 2.19) than for pure self-help (effect size = 0.75, NNT = 2.48).”

Combining CBT with medication for SAD is superior to CBT alone.

“A systematic review and meta-analysis found that the combination of CBT plus medication for SAD was superior to medication alone, and the combination of CBT plus medication for SAD was superior to CBT alone.”

• cites Bandelow et al., 2007Not checked yet

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• cites Würz and Sungur, 2009Not checked yet

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Individual CBT is significantly more efficacious than psychodynamic therapy for SAD.

“However, a more recent analysis showed that individual CBT was significantly more efficacious than psychodynamic therapy (effect size = 0.56, NNT = 3.25; Mayo-Wilson et al., 2014).”

• cites Mayo-Wilson et al., 2014Not checked yet

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Applied relaxation and social skills training are associated with smaller effects than exposure plus cognitive restructuring for SAD.

“One meta-analysis showed that applied relaxation (effect size = 0.51, NNT = 3.55) and social skills training (effect size = 0.64, NNT = 2.86) were associated with smaller effects than exposure plus cognitive restructuring (effect size = 0.84, NNT = 2.23; Fedoroff and Taylor, 2001).”

• cites Fedoroff and Taylor, 2001Not checked yet

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Self-help CBT delivered over the internet or through printed materials shows significant benefits for SAD.

“Self-help CBT, either delivered over the internet or through printed materials, has also shown significant benefits for SAD (Cuijpers et al., 2009, Mayo-Wilson et al., 2014).”

• cites Cuijpers et al., 2009Not checked yet

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• cites Mayo-Wilson et al., 2014Not checked yet

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CBT is efficacious in reducing SAD symptoms in the longer term, with an effect size of 0.95 and NNT of 2.01.

“and longer term (effect size = 0.95, NNT = 2.01; Fedoroff and Taylor, 2001;Gil et al., 2001).”

• cites Fedoroff and Taylor, 2001Not checked yet

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• cites Gil et al., 2001Not checked yet

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CBT is efficacious in reducing SAD symptoms immediately after treatment, with effect sizes of 0.61-1.19 and NNT of 1.67-2.99.

“Overall, CBT is efficacious in the reduction of SAD symptoms, both immediately following treatment (effect size = 0.61-1.19,NNT = 1.67-2.99;Acarturk et al., 2009;Fedoroff and Taylor, 2001;Gil et al., 2001;Mayo-Wilson et al., 2014;Powers et al., 2008)”

• cites Acarturk et al., 2009Not checked yet

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• cites Fedoroff and Taylor, 2001Not checked yet

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• cites Gil et al., 2001Not checked yet

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Meta-analyses have failed to show consistent differences between different CBT components for SAD.

“Unsurprisingly, meta-analyses have failed to show consistent differences between these components.”

An analysis of three trials found little difference in dropout rates between active treatment and placebo in SAD.

“Analysis of three trials that reported dropout rates (Stein et al., 2000) showed little difference between dropout rates among patients who received active treatment and those who received placebo (RR = 0.61; 95% CI = [0.27,1.36]).”

• cites Stein et al., 2000Not checked yet

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Studies have generally been unable to draw conclusions about comparative efficacy between medications for SAD.

“Studies were generally unable to draw conclusions about comparative efficacy between medications.”

Meta-analyses including phenelzine generally conclude that it may be the most effective agent for SAD, with the highest effect sizes or standardized mean differences against placebo.

“Meta-analyses that included trials of phenelzine generally conclude that it may be the most effective agent in treating SAD, with the highest effect sizes or SMDs against placebo (Canton et al., 2012;Davis et al., 2014;Stein et al., 2000).”

• cites Canton et al., 2012Not checked yet

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• cites Davis et al., 2014Not checked yet

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• cites Stein et al., 2000Not checked yet

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A systematic review reported substantial variation in number needed to harm between individual medicines and classes for SAD: 87.2 for moclobemide, 83.1 for phenelzine, 14.9 for SSRIs, 10.1 for venlafaxine and 9.3 for brofaromine.

“A systematic review of pharmacotherapy for SAD reported that the number needed to harm showed substantial variation between individual medicines and pharmacological classes: 87.2 for moclobemide, 83.1 for phenelzine, 14.9 for SSRIs, 10.1 for venlafaxine and 9.3 for brofaromine (Ipser et al., 2008).”

• cites Ipser et al., 2008Not checked yet

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Moclobemide has been reported to be less effective than venlafaxine, phenelzine and paroxetine for SAD.

“It has been reported to be less effective than venlafaxine (effect size = 0.23, NNT = 7.7), phenelzine and paroxetine (Davis et al., 2014).”

• cites Davis et al., 2014Not checked yet

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A large body of RCT evidence suggests that non-responders at 8-12 weeks may become responders with continuation of the same medication over 6-12 months in SAD.

“A large body of evidence from RCTs suggests that non-responders at 8-12 weeks may become responders with continuation of the same medication over 6-12 months (Ipser et al., 2008;Lader et al., 2004;Stein et al., 2003Stein et al., , 2005;;Versiani et al., 1997).”

• cites Ipser et al., 2008Not checked yet

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• cites Lader et al., 2004Not checked yet

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• cites Stein et al., 2003Not checked yet

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Current evidence does not support differences in efficacy between individual SSRIs for SAD.

“Current evidence does not support differences in efficacy between individual SSRIs for the treatment of SAD.”

Moclobemide was not more effective than placebo in one meta-analysis for SAD.

“Moclobemide was not more effective than placebo in one meta-analysis (Bandelow et al., 2015).”

• cites Bandelow et al., 2015Not checked yet

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Two meta-analyses found stronger evidence of efficacy for SSRIs than for phenelzine in SAD.

“Two meta-analyses (Blanco et al., 2003;Canton et al., 2012) found stronger evidence of efficacy for the SSRIs than for phenelzine.”

• cites Blanco et al., 2003Not checked yet

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• cites Canton et al., 2012Not checked yet

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A comparatively large number of trials have evaluated SSRIs and venlafaxine in SAD.

“A comparatively large number of trials have evaluated SSRIs (total n = 3677) and venlafaxine (total n = 1318) in the treatment of SAD.”

A long-term trial of moclobemide with a good response rate showed high rates of symptom recurrence when the medication was discontinued after 12-20 months.

“However, a long-term trial of moclobemide, in which there was a good response rate, demonstrated high rates of symptom recurrence when the medication was discontinued after 12-20 months of treatment (Versiani et al., 1997).”

• cites Versiani et al., 1997Not checked yet

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SSRIs are effective in treating comorbid depression in SAD.

“SSRIs are also effective in treating comorbid depression (Stein et al., 2000).”

• cites Stein et al., 2000Not checked yet

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Post-treatment standardized mean differences for second-generation antidepressants in SAD were calculated for paroxetine, fluvoxamine, sertraline, fluoxetine and venlafaxine.

“Post-treatment SMDs on various outcome measures were calculated for paroxetine (-0.31 to -0.63; NNT = 2.9-5.7),fluvoxamine (-0.28 to -0.67; NNT = 2.7-6.4),sertraline (-0.29 to -0.85; NNT = 2.2-6.1),fluoxetine (0.03 to -0.57; NNT ⩾3.1), and venlafaxine (-0.40 to -0.63; NNT = 2.9-4.5).”

• cites de Menezes et al., 2011Not checked yet

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Reliable conclusions could not be drawn about relative efficacy between second-generation antidepressants for SAD.

“Reliable conclusions could not be drawn about relative efficacy between the agents.”

• cites de Menezes et al., 2011Not checked yet

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A systematic review and meta-analysis concluded there is no evidence of differential effectiveness between medication classes in SAD.

“Another systematic review and meta-analysis (Mayo-Wilson et al., 2014) concluded that there is no evidence of differential effectiveness between medication classes in the treatment of SAD.”

• cites Mayo-Wilson et al., 2014Not checked yet

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A systematic review and meta-analysis reported efficacy for paroxetine, sertraline, escitalopram, fluoxetine and fluvoxamine in SAD, with odds ratios ranging from 1.98 to 3.43.

“A systematic review and meta-analysis (Canton et al., 2012) reported efficacy for paroxetine (odds ratio [OR] = 3.43; 95% CI = [2.51,4.69]; NNT = 2.97-11.6),sertraline (OR = 2.48; 95% CI = [1.82,3.37]; NNT = 8.2-10.6),escitalopram (OR = 2.0; 95% CI = [1.47,2.86]; NNT = 12.2-14.1),fluoxetine (OR = 1.98; 95% CI = [1.0,3.67]; NNT = 10.3-18.2) and fluvoxamine (OR = 2.73; 95% CI = [1.67,4.48]; NNT = 4.”

• cites Canton et al., 2012Not checked yet

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A meta-analysis of second-generation antidepressants in SAD found active treatment associated with a 62% increase in treatment response compared with placebo, with a relative risk of 1.62.

“A meta-analysis of second-generation antidepressants in the treatment of SAD (de Menezes et al., 2011), in which three quarters of the included studies evaluated SSRIs, reported that active treatment overall was associated with a 62% increase in treatment response (defined as final CGI <2), compared with placebo (RR = 1.62; 95% CI = [1.44,1.81]).”

• cites de Menezes et al., 2011Not checked yet

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Moclobemide appears to be only modestly efficacious in treating SAD.

“Moclobemide, a RIMA, appears to be only modestly efficacious in the treatment of SAD.”

It is not possible to draw conclusions about the efficacy of antipsychotics in treating SAD.

“It is not possible to draw conclusions about the efficacy of antipsychotics in the treatment of SAD.”

• cites Canton et al., 2012Not checked yet

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Studies have failed to show superiority of beta blockers over placebo for social anxiety.

“However, studies have failed to show superiority over placebo (Steenen et al., 2016).”

• cites Steenen et al., 2016Not checked yet

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A systematic review reported five trials that compared medication plus CBT with medication alone or with CBT alone.

“Five trials comparing medication plus CBT with medication alone, or with CBT alone, were reported in a systematic review (Canton et al., 2012).”

• cites Canton et al., 2012Not checked yet

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Some studies have reported that combining CBT with medication was better than medication alone or CBT alone for social anxiety disorder.

“Some studies have reported that the combination of CBT plus medication was superior to either medication alone or CBT alone in the treatment of SAD (Bandelow et al., 2007;Canton et al., 2012).”

• cites Bandelow et al., 2007Not checked yet

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• cites Canton et al., 2012Not checked yet

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Two meta-analyses found SSRIs significantly more effective than RIMAs, including moclobemide and brofaromine, for SAD.

“Two meta-analyses - Stein et al. (2000) and Blanco et al. (2003) -found that SSRIs were significantly more effective than RIMAs, including moclobemide and brofaromine.”

• cites Stein et al., 2000Not checked yet

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• cites Blanco et al., 2003Not checked yet

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A systematic review and meta-analysis identified only five trials evaluating the combination of CBT and medication.

“Another systematic review and meta-analysis (Mayo-Wilson et al., 2014) identified only five trials evaluating the combination of CBT and medication.”

• cites Mayo-Wilson et al., 2014Not checked yet

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The use of d-cycloserine for SAD remains experimental.

“The use of d-cycloserine remains experimental at this stage.”

Another systematic review reported three positive RCTs of alpha-2 delta ligands (pregabalin and gabapentin) for SAD, with a combined odds ratio of 3.11 and NNT of 6.8-8.3.

“Another systematic review (Canton et al., 2012) reported three positive RCTs of alpha-2 delta ligands (pregabalin and gabapentin), with a combined OR of 3.11 [1.92, 5.04]; NNT = 6.8-8.3.”

• cites Canton et al., 2012Not checked yet

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Another meta-analysis estimated a combined standardized mean difference of -0.81 for five trials of anticonvulsants in SAD.

“Another meta-analysis (Mayo-Wilson et al., 2014) estimated the combined SMD as -0.81 (-1.36 to -0.28) for five trials of anticonvulsants (one each for gabapentin and levetiracetam, and three studies of pregabalin).”

• cites Mayo-Wilson et al., 2014Not checked yet

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Anticonvulsants were superior to placebo in treating SAD in a small number of studies.

“Anticonvulsants were superior to placebo in the treatment of SAD in a small number of studies.”

A systematic review and meta-analysis concluded that mirtazapine was not superior to wait-list for SAD.

“A systematic review and meta-analysis (Mayo-Wilson et al., 2014) concluded that mirtazapine was not superior to wait-list.”

• cites Mayo-Wilson et al., 2014Not checked yet

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One meta-analysis reported that pregabalin was not superior to placebo for SAD.

“One metaanalysis reported that pregabalin was not superior to placebo (Davis et al., 2014).”

• cites Davis et al., 2014Not checked yet

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The onset of anxiolytic effects for alpha-2 delta ligands was reported to occur within the first week of treatment.

“The onset of anxiolytic effects was reported to occur within the first week of treatment.”

• cites Canton et al., 2012Not checked yet

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One study of clonazepam estimated an effect size of 0.97 and NNT of 1.97 for SAD.

“One study of clonazepam estimated an effect size of 0.97 (95% CI = [0.49,1.44]; NNT = 1.97;Davidson et al., 1993).”

• cites Davidson et al., 1993Not checked yet

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The benzodiazepines clonazepam, bromazepam and alprazolam were reported to be superior to placebo in treating SAD in a meta-analysis including one trial of each agent.

“The benzodiazepines clonazepam, bromazepam and alprazolam were all reported to show superiority over placebo in the treatment of SAD in a meta-analysis that included one trial of each agent (Canton et al., 2012).”

• cites Canton et al., 2012Not checked yet

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People with GAD report spending much more time per day worrying than non-clinical populations.

“People with GAD report spending much more time per day worrying than non-clinical populations (Andrews et al., 2016) and, although many people worry when there is a problem, people with GAD worry about the future even when things are going well (e.g.worrying about the health of children even when they are not sick).”

• cites Andrews et al., 2016Not checked yet

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Treatment for GAD tends to be sought for comorbid somatic, panic, or depressive disorders or painful physical symptoms.

“Even then, treatment tends to be sought for comorbid somatic, panic, or depressive disorders or painful physical symptoms (Campayo et al., 2012;Judd et al., 1998;Kessler and Wittchen, 2002).”

• cites Campayo et al., 2012Not checked yet

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• cites Judd et al., 1998Not checked yet

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• cites Kessler and Wittchen, 2002Not checked yet

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The number of studies comparing CBT with other psychotherapies was too small to draw conclusions about comparative effectiveness.

“The number of studies comparing CBT with other psychotherapies (e.g.applied relaxation) was too small to draw conclusions about comparative effectiveness.”

• cites Cuijpers et al., 2014bNot checked yet

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Overall, medical comorbidity across anxiety disorders is not associated with poorer outcomes.

“Overall, medical comorbidity across anxiety disorders is not associated with poorer outcomes (Olatunji et al., 2010), and there is evidence that people with and without comorbid disorders respond similarly to face-to-face CBT and dCBT (Johnston et al., 2013;McEvoy and Nathan, 2007;Norton et al., 2008).”

• cites Olatunji et al., 2010Not checked yet

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People with GAD worry about the future even when things are going well.

“People with GAD report spending much more time per day worrying than non-clinical populations (Andrews et al., 2016) and, although many people worry when there is a problem, people with GAD worry about the future even when things are going well (e.g.worrying about the health of children even when they are not sick).”

• cites Andrews et al., 2016Not checked yet

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Limited evidence from four low-quality studies suggests that CBT regimens with 5-8 sessions had a better effect on symptoms than regimens with 9 or more sessions.

“Limited evidence (four studies with low methodological quality) suggests CBT regimens with 5-8 sessions had better effect on symptoms than those of 9 or more sessions.Hunot et al. (2007)”

• cites Hunot et al. (2007)Not checked yet

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The risk of comorbid medical conditions in GAD is elevated, including pain syndromes, hypertension, cardiovascular conditions, and gastric conditions.

“The risk of comorbid medical conditions in GAD is also elevated including pain syndromes, hypertension, cardiovascular and gastric conditions (Comer et al., 2011;Teesson et al., 2011).”

• cites Comer et al., 2011Not checked yet

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• cites Teesson et al., 2011Not checked yet

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People with GAD who seek treatment do so on average 10 years after onset.

“While GAD is the most common anxiety disorder in primary care (Maier et al., 2000;Üstün and Sartorius, 1995;Wittchen, 2002), those who seek treatment only do so an average of 10 years after the onset (Wang et al., 2005).”

• cites Wang et al., 2005Not checked yet

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GAD is the most common anxiety disorder in primary care.

“While GAD is the most common anxiety disorder in primary care (Maier et al., 2000;Üstün and Sartorius, 1995;Wittchen, 2002), those who seek treatment only do so an average of 10 years after the onset (Wang et al., 2005).”

• cites Maier et al., 2000Not checked yet

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• cites Üstün and Sartorius, 1995Not checked yet

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• cites Wittchen, 2002Not checked yet

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There are high rates of comorbidity between GAD and other anxiety and depressive disorders.

“There are high rates of comorbidity between GAD and other anxiety and depressive disorders (Andrews et al., 2002;Brown et al., 2001;Comer et al., 2011).”

• cites Andrews et al., 2002Not checked yet

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• cites Brown et al., 2001Not checked yet

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• cites Comer et al., 2011Not checked yet

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GAD is comorbid with other disorders more often than not.

“GAD is comorbid with other disorders more frequently than not (Brown and Barlow, 1992;Brown et al., 2001;Hunt et al., 2002).”