foreword general general Six Persimmons 六柿圖 other modalities of treatments by evidence or impression? anxiety disorders drugs benzodiazepines

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1 Clinical Updates Management of Anxiety Disorders John So - Psychiatrist foreword Six Persimmons 六柿圖 MuqiFachang 牧谿法常 after Zen meditation mindfulness other trends of psychotherapy other modalities of treatments by evidence or impression? anxiety disorders general normal emotion disorders becoming disabling reducing quality of life characteristics different types prone to have co-morbidities prone to be chronic drugs benzodiazepine antidepressant (SSRI SNRI) others other antidepressants other agents general rapid symptomatic relief pooled analysis showed less risk of treatment discontinuation due to lack of efficacy as compared to placebo (Martin JL et al, 2007) rapid symptomatic relief recommendation only for severe, disabling or extremely distressing anxiety dependence, withdrawal risks lowest effective dose shortest period (maximum 4/52) caution with substance misuse

2 rapid symptomatic relief real world over-prescription Harvard / Brown Anxiety Research Project (HARP) naturalistic, longitudinal, multisite study of adults with anxiety disorders (BenítezCI et al, 2008; VasileRG et al, 2005) psychiatric setting rapid symptomatic relief real world over-prescription Harvard / Brown Anxiety Research Project (HARP) Clonazepam 1.6mg Alprazolam 2.0mg Lorazepam 2.8mg Diazepam 13.0mg rapid symptomatic relief real world over-prescription should not be denied a very small number of patients with severely disabling anxiety may benefit from long-term benzodiazepine (12 th Maudsley Guidelines, 2015) (Tan KR et al, 2011)

3 SSRI antidepressant efficacious first-line drug broad spectrum short and long term generally well tolerated SSRI / SNRI (Tan KR et al, 2011) (Baldwin D et al, 2014) SSRI antidepressant efficacious first-line drug SNRI antidepressant SSRI / SNRI venlafaxine and duloxetine short and long term for GAD venlafaxine acute treatment and relapse prevention in panic disorder (Baldwin D et al, 2014) some have initial worsening of anxiety (Scott A et al, 2001) normal dosage as tolerated predictors: severity and duration of symptoms, (neuroimaging?) response within 6 weeks, continues to increase over time (Ballenger JC, 2004, Baldwin DS et al, 2006, 2011) 4 th wee k

4 at least 1 year treatment optimal duration undetermined (Baldwin DS et al, 2014, Davidson JR et al, 2010) longer continuation treatment (Baldwin DS et al, 2011) GAD Rx responders R treatment placebo (Baldwin DS et al, 2011) at least 1 year treatment optimal duration undetermined (Baldwin DS et al, 2014, Davidson JR et al, 2010) longer continuation treatment (Baldwin DS et al, 2011) at least 1 year treatment optimal duration undetermined longer continuation treatment may prevent depression; drug tx NOT associated with depression (Goodwin RD & Gorman JM, 2002) drug choice (Baldwin D et al, 2011b) Fluoxetine probably most effective Sertraline probably best tolerated Rank Response reduction of HAM-score 50% Remission final HAM-A score 7 Withdrawal for adverse events 1 Fluoxetine Fluoxetine Sertraline 2 Lorazepam Escitalopram Pregabalin 3 Duloxetine Venlafaxine Fluoxetine 4 Sertraline Paroxetine Paroxetine 5 Paroxetine Sertraline Tiagabine 6 Pregabalin Duloxetine Venlafaxine 7 Venlafaxine Tiagabine Escitalopram 8 Escitalopram N/A Duloxetine 9 Tiagabine N/A Lorazepam (Baldwin D et al, 2011b)

5 Efficacy of drug treatments for GAD: systematic review and meta-analysis. Efficacy of drug treatments for GAD: systematic review and meta-analysis. Systematic review of RCT: 3249 citations 46 randomised controlled trials 27 with sufficient or appropriate data Systematic review of RCT: 3249 citations 46 randomised controlled trials 27 with sufficient or appropriate data Primary Bayesian probabilistic mixed treatment meta-analyses allowed pharmacological treatments to be ranked for effectiveness for each outcome measure, given as percentage probability of being the most effective treatment. (Baldwin D et al, 2011b) (Baldwin D et al, 2011b) (i.e. less withdrawal for adverse events) drug choice (Baldwin D et al, 2011b) Fluoxetine probably most effective Sertraline probably best tolerated (Baldwin D et al, 2011b) drug choice (Baldwin D et al, 2011b) Fluoxetine Sertraline please note unpublished data, sponsorships, publication bias, methodology GAD highly variable, racial disparities SSRI / SNRI x others SSRI / SNRI x panic disorder (12 th MaudsleyGuidelines, 2015) bottom antidepressant range paroxetine may need higher dose response as long as 6 weeks

6 SSRI / SNRI x others SSRI / SNRI x panic disorder (12 th MaudsleyGuidelines, 2015) at least 8 months optimal duration undetermined (Rickels K & Schweizer E, 1998) evidence of benefit for at least 3 years (ChoyY et al, 2007) SSRI / SNRI x others SSRI / SNRI x panic disorder media n 5.67 yr media n 1.17 yr SSRI / SNRI x others SSRI / SNRI x panic disorder (12 th MaudsleyGuidelines, 2015) drug choice SSRI first line clonazepam augmentation may lead to more rapid response, but not greater overall response (Pollack HM et al, 2003) controversies (Davidson JR, 2004, NICE Guidelines CG113, 2011) Disorder GAD Panic Disorder Social Phobia OCD PTSD Dosing half starting dose titrate to normal dose half starting dose titrate to normal dose standard dose titration may not be required higher licensed dose but standard dose may suffice lower starting dose high dose often required SSRI / SNRI x others Response (week) Minimum (month) to to 12 6 (12 th Maudsley Guidelines, 2015) other antidepressants TCA efficacious in some anxiety disorders more side effects (Baldwin DS et al, 2014) clomipramine augmentation OCD cases (Koran LM et al, 2007) other antidepressants agomelatine melatonergic and serotonergic MT(1), MT(2), 5-HT(2C) receptors efficacious in GAD, RCT vs placebo, fu 12 weeks and 6 months (Stein DJ et al, 2008, 2012) less sexual or withdrawal side effects; liver function monitor (Baldwin DS et al, 2014)

7 Results of AMSP a Drug Surveillance Program (Friedrich ME et a, 2016) SSRI TCA & Tetra Results of AMSP ** a Drug Surveillance Program (Friedrich ME et a, 2016) Arzneimittelsicherheit in der Psychiatrie in-patients on antidepressants (from 1993 to 2011) n = DILI = 149 (0.08%) other antidepressants mirtazapine (Baldwin DS et al, 2014) NorAdrenergicand Specific Serotonergic Antidepressant limited and inconsistent evidence probably less frequent sexual dysfuction other antidepressants bupropion (Baldwin DS et al, 2014) noradrenergic, dopaminergic non-specific anxiolyticeffect, pilot study support concomitant s are necessary (Coplan JD et al, 2015) other antidepressants TCA agomelatine mirtazapine bupropion other agents pregabalin Ca channel α2δ subunit ligand efficacious in GAD (Baldwin DS et al, 2015, Pollack MH, 2009) initial dose 150mg comparable onset with ; abrupt stop may cause rebound anxiety and seizures (12 th Maudsley Guidelines, 2015)

8 other agents quetiapine atypical antipsychotic efficacious in GAD, acute treatment, relapse prevention (Maneeton N et al, 2016, Katzman MA et al, 2011) dose from 50 to 150 or 300mg low acceptability and tolerability, generally for non-response cases (Baldwin DS et al, 2011) other agents buspirone azapirone anxiolytic 5-HT1A, 5-HT2A, D2, α1- adrenergic and α2-adrenergic receptors efficacious in GAD, not superior to, not as acceptable as (Chessick CA et al, 2006) other agents hydroxyzine 1 st generation antihistamine efficacious in GAD, also tolerable, may be as effective as chlordiazepoxide or buspirone (noting study limits) (Guaiana G et al, 2010) other agents flupentixol-melitracen (Wang L et al, 2015) Deanxit chronic somatic diseases associated anxiety symptoms RCT response rates favouring addition to sertralineto lower anxiety for first two weeks potential tardive dyskinesia risk drug other agents flupentixol-melitracen (Wang L et al, 2015) SSRI / SNRI fluoxetine sertraline benzodiazepine other antidepressants TCA agomelatine mirtazapine bupropion other agents pregabalin quetiapine buspirone hydroxyzine flupentixolmelitracen

9 drug treatments anxiety disorders noting other modalities generally, SSRI first line temporarily, coverage response around 6 to 12 weeks prone chronic and co-morbid drug treatments limits anxiety disorders evidence issues access to data, publication bias, methodology limits cultural and biological differences side effects and withdrawals guideline issues drug treatments limits inherent issues anxiety disorders anxiety disorders highly variable prone chronic and co-morbid residual symptoms and resistant cases Reference 12th MaudsleyGuidelines (2015). The MaudsleyPrescribing Guidelines in Psychiatry, 12th Edition. April 2015, Wiley-Blackwell. Baldwin D et al (2011b). Efficacy of drug treatments for generalised anxiety disorder: systematic review and meta-analysis. BMJ Mar 11;342:d1199. Baldwin DS et al (2006). Escitalopramand paroxetinein the treatment of generalised anxiety disorder: randomised, placebo-controlled, doubleblind study. Br J Psychiatry Sep;189: Baldwin DS et al (2011). Evidence-based pharmacological treatment of generalized anxiety disorder. IntJ Neuropsychopharmacol Jun;14(5): Baldwin DS et al (2014). Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessivecompulsive disorder: a revision of the 2005 guidelines from the British Association for Psychopharmacology. J Psychopharmacol May;28(5): Baldwin DS et al (2015). Efficacy and safety of pregabalin in generalised anxiety disorder: A critical review of the literature. J Psychopharmacol Oct;29(10): Reference Ballenger JC (2004). Remission rates in patients with anxiety disorders treated with paroxetine. J Clin Psychiatry Dec;65(12): BenítezCI et al (2008). Use of benzodiazepines and selective serotonin reuptake inhibitors in middle-aged and older adults with anxiety disorders: a longitudinal and prospective study. Am J GeriatrPsychiatry Jan;16(1):5-13. ChessickCA et al (2006). Azapironesfor generalized anxiety disorder. Cochrane Database Syst Rev Jul 19;(3):CD Choy Y et al (2007). Three-year medication prophylaxis in panic disorder: to continue or discontinue? A naturalistic study. ComprPsychiatry Sep-Oct;48(5): CoplanJD et al (2015). Treatingcomorbidanxiety and depression: Psychosocial and pharmacological approaches. World J Psychiatry.2015 Dec 22;5(4): Davidson JR et al (2010). A psychopharmacological treatment algorithm for generalisedanxiety disorder (GAD). Davidson JR (2004). Use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and posttraumatic stress disorder. J Clin Psychiatry. 2004;65 Suppl 5: Reference Friedrich ME et al (2016). Drug-Induced Liver Injury during Antidepressant Treatment: Results of AMSP, a Drug Surveillance Program. IntJ Neuropsychopharmacol Apr 20;19(4). Goodwin RD & Gorman JM (2002). Psychopharmacologic treatment of generalized anxiety disorder and the risk of major depression. Am J Psychiatry Nov;159(11): GuaianaG et al (2010). Hydroxyzinefor generalisedanxiety disorder. Cochrane Database SystRev.2010 Dec 8;(12):CD Katzman MA et al (2011). Extended release quetiapine fumarate (quetiapinexr) monotherapyas maintenance treatment for generalized anxiety disorder: a long-term, randomized, placebo-controlled trial. Int Clin Psychopharmacol Jan;26(1): Koran LM et al (2007). Practice guideline for the treatment of patients with obsessive-compulsive disorder. Am J Psychiatry.2007 Jul;164(7 Suppl):5-53. ManeetonN et al (2016). Quetiapinemonotherapyin acute treatment of generalized anxiety disorder: a systematic review and meta-analysis of randomized controlled trials. Drug Des Devel Ther Jan 12;10:

10 Reference Martin JL et al (2007). Benzodiazepines in generalized anxiety disorder: heterogeneity of outcomes based on a systematic review and metaanalysis of clinical trials. J Psychopharmacol Sep;21(7): Montgomery et al (2002). Characterization of the longitudinal course of improvement in generalized anxiety disorder during long-term treatment with venlafaxine XR. J Psychiatr Res Jul-Aug;36(4): NICE Guidelines CG113 (2011). GeneralisedAnxiety Disorder in Adults. Management in Primary, Secondary and Community Care. NICE Clinical Guidelines, No. 113 Leicester (UK): British Psychological Society; Pollack MH et al (2003). Combined paroxetine and clonazepam treatment strategies compared to paroxetinemonotherapyfor panic disorder. J Psychopharmacol Sep;17(3): Pollack MH (2009). Refractory generalized anxiety disorder. J Clin Psychiatry. 2009;70 Suppl 2:32-8. RickelsK & SchweizerE (1998). Panic disorder: long-term pharmacotherapy and discontinuation. J ClinPsychopharmacol Dec;18(6 Suppl 2):12S-18S. Rudolph U et al (2011). Beyond classical benzodiazepines: novel therapeutic potential of GABAA receptor subtypes. Nat Rev Drug Discov Jul 29;10(9): Reference Scott A et al (2001). Antidepressant drugs in the treatment of anxiety disorders. Advances in Psychiatric Treatment (2001), vol. 7, pp Stein DJ et al (2008). Efficacy of agomelatinein generalized anxiety disorder: a randomized, double-blind, placebo-controlled study. J Clin Psychopharmacol Oct;28(5): Stein DJ et al (2012). Agomelatineprevents relapse in generalized anxiety disorder: a 6-month randomized, double-blind, placebo-controlled discontinuation study. J ClinPsychiatry Jul;73(7): Tan KR et al (2011). Hooked on benzodiazepines: GABAA receptor subtypes and addiction. Trends Neurosci April ; 34(4): VasileRG et al (2005). Results Of A Naturalistic Longitudinal Study Of Benzodiazepine And SSRI Use In The Treatment Of Generalized Anxiety Disorder And Social Phobia. Depress Anxiety. 2005; 22(2): Wang L et al (2015). Sertralineplusdeanxitto treat patients with depression andanxietyin chronic somatic diseases: a randomized controlled trial. BMC Psychiatry.2015 Apr 14;15:84.