Clinical Updates

Management of Anxiety Disorders

John So - Psychiatrist

foreword

• Six Persimmons 《六柿圖》

• Muqi Fachang 牧谿法常

• after Zen meditation

•mindfulness

• other trends of psychotherapy

• other modalities of treatments

• by evidence or impression?

general

• anxiety disorders

• normal emotion � disorders

•becoming disabling

•reducing quality of life

• characteristics

•different types

•prone to have co-morbidities

•prone to be chronic

general

• drugs

• benzodiazepine

• antidepressant (SSRI SNRI)

• others

•other antidepressants

•other agents

BZ

• benzodiazepines

• rapid symptomatic relief

•efficacy

• pooled analysis showed less risk

of treatment discontinuation due

to lack of efficacy as compared to

placebo (Martin JL et al, 2007)

BZ

• benzodiazepines

• rapid symptomatic relief

•efficacy

•recommendation

• only for severe, disabling or

extremely distressing anxiety

• dependence, withdrawal risks

• lowest effective dose

• shortest period (maximum 4/52)

• caution with substance misuse

BZ

• benzodiazepines

• rapid symptomatic relief

• real world…

•over-prescription

• Harvard / Brown

Anxiety Research Project (HARP)

• naturalistic, longitudinal, multisite

study of adults with anxiety

disorders (Benítez CI et al, 2008; Vasile RG

et al, 2005)

• psychiatric setting

BZ

• benzodiazepines

BZ

• benzodiazepines

BZ

• benzodiazepines

• 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

BZ

• benzodiazepines

• 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” (12th Maudsley

Guidelines, 2015) (Tan KR et al, 2011)

(Tan KR et al, 2011)

SSRI / SNRI

• SSRI antidepressant

• efficacious first-line drug

•“broad spectrum”

•short and long term

•generally well tolerated

(Baldwin D et al, 2014)

SSRI / SNRI

• SSRI antidepressant

• efficacious first-line drug

• SNRI antidepressant

• venlafaxine and duloxetine

•short and long term for GAD

• venlafaxine

•acute treatment and relapse

prevention in panic disorder

(Baldwin D et al, 2014)

SSRI / SNRI x GAD

• SSRI / SNRI x GAD

• dosing

•1 / 2 normal starting dose

• some have initial worsening of

anxiety (Scott A et al, 2001)

SSRI / SNRI x GAD

• SSRI / SNRI x GAD

• dosing

•1 / 2 normal starting dose

•titration upwards

• 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)

SSRI / SNRI x GAD

• SSRI / SNRI x GAD

4th

wee

k

SSRI / SNRI x GAD

• SSRI / SNRI x GAD

• dosing

•1 / 2 normal starting dose

•titration upwards

•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)

R

GAD Rx responders

treatment

placebo

(Baldwin DS et al, 2011)

SSRI / SNRI x GAD

• SSRI / SNRI x GAD

• dosing

•1 / 2 normal starting dose

•titration upwards

•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)

SSRI / SNRI x GAD

• SSRI / SNRI x GAD

• dosing

•1 / 2 normal starting dose

•titration upwards

•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)

SSRI / SNRI x GAD

• SSRI / SNRI x GAD

• dosing

• drug choice (Baldwin D et al, 2011b)

•Fluoxetine

• probably most effective

•Sertraline

• probably best tolerated

Rank Responsereduction of

HAM-score ≥ 50%

Remissionfinal

HAM-A score ≤ 7

Withdrawalfor

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)

(Baldwin D et al, 2011b)

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

(Baldwin D et al, 2011b)

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

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)

(i.e. less withdrawal for adverse events)

SSRI / SNRI x GAD

• SSRI / SNRI x GAD

• dosing

• drug choice (Baldwin D et al, 2011b)

•Fluoxetine

• probably most effective

•Sertraline

• probably best tolerated

SSRI / SNRI x GAD

• SSRI / SNRI x GAD

• dosing

• 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

• dosing (12th Maudsley Guidelines, 2015)

•1 / 2 normal starting dose

•titration upwards

• bottom antidepressant range

• paroxetine may need higher dose

• response as long as 6 weeks

SSRI / SNRI x others

• SSRI / SNRI x panic disorder

• dosing (12th Maudsley Guidelines, 2015)

•1 / 2 normal starting dose

•titration upwards

•at least 8 months

• optimal duration undetermined (Rickels K & Schweizer E, 1998)

• evidence of benefit for at least 3

years (Choy Y et al, 2007)

SSRI / SNRI x others

• SSRI / SNRI x panic disorder

media

n

1.17 yr

media

n

5.67 yr

SSRI / SNRI x others

• SSRI / SNRI x panic disorder

• dosing (12th Maudsley Guidelines, 2015)

• drug choice

•SSRI first line

•clonazepam augmentation

• may lead to more rapid

response, but not greater overall

response (Pollack HM et al, 2003)

• BZ controversies (Davidson JR, 2004, NICE

Guidelines CG113, 2011)

SSRI / SNRI x others

Disorder DosingResponse

(week)

Minimum

(month)

GADhalf starting dose

titrate to normal dose6 12

Panic

Disorder

half starting dose

titrate to normal dose6 8

Social

Phobia

standard dose

titration may not be required8 12

OCDhigher licensed dose

but standard dose may suffice10 to 12 12

PTSDlower starting dose

high dose often required8 to 12 6

(12th Maudsley Guidelines, 2015)

etc

• other antidepressants

• TCA

•efficacy

• efficacious in some anxiety

disorders

• more side effects (Baldwin DS et al, 2014)

•clomipramine augmentation

• OCD cases (Koran LM et al, 2007)

etc

• other antidepressants

• agomelatine

•melatonergic and serotonergic

• MT(1), MT(2), 5-HT(2C) receptors

•efficacy

• 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)

Results of AMSPa Drug Surveillance Program(Friedrich ME et a, 2016)

TCA &

Tetra

SSRI

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 = 184 234

DILI = 149 (0.08%)

etc

• other antidepressants

• mirtazapine (Baldwin DS et al, 2014)

•NorAdrenergic and Specific

Serotonergic Antidepressant

•efficacy

• limited and inconsistent

evidence

• probably less frequent sexual

dysfuction

etc

• other antidepressants

• bupropion (Baldwin DS et al, 2014)

•noradrenergic, dopaminergic

•efficacy

• non-specific anxiolytic effect,

pilot study support

• concomitant BZs are necessary (Coplan JD et al, 2015)

etc

• other antidepressants

• TCA

• agomelatine

• mirtazapine

• bupropion

etc

• other agents

• pregabalin

•Ca channel α2δ subunit ligand

•efficacy

• efficacious in GAD (Baldwin DS et al,

2015, Pollack MH, 2009)

• initial dose 150mg

• comparable onset with BZ;

abrupt stop may cause rebound

anxiety and seizures (12th Maudsley

Guidelines, 2015)

etc

• other agents

• quetiapine

•atypical antipsychotic

•efficacy

• 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)

etc

• other agents

• buspirone

•azapirone anxiolytic

• 5-HT1A, 5-HT2A, D2, α1-

adrenergic and α2-adrenergic

receptors

•efficacy

• efficacious in GAD, not superior

to BZ, not as acceptable as BZ (Chessick CA et al, 2006)

etc

• other agents

• hydroxyzine

•1st generation antihistamine

•efficacy

• efficacious in GAD, also tolerable,

may be as effective as

chlordiazepoxide or buspirone

(noting study limits) (Guaiana G et al,

2010)

etc

• other agents

• flupentixol-melitracen (Wang L et al, 2015)

•“Deanxit”

•efficacy

• chronic somatic diseases

associated anxiety symptoms

• RCT response rates favouring

addition to sertraline to lower

anxiety for first two weeks

• potential tardive dyskinesia risk

etc

• other agents

• flupentixol-melitracen (Wang L et al, 2015)

drug

• SSRI / SNRI

• fluoxetine

• sertraline

• other

antidepressants

• TCA

• agomelatine

• mirtazapine

• bupropion

• benzodiazepine

• other

agents

• pregabalin

• quetiapine

• buspirone

• hydroxyzine

• flupentixol-

melitracen

anxiety disorders

• drug treatments

• noting other modalities

• generally, SSRI first line

• temporarily, BZ coverage

• response around 6 to 12 weeks

• prone chronic and co-morbid

anxiety disorders

• drug treatments

• limits

• evidence issues

•access to data, publication bias,

methodology limits

• cultural and biological differences

•side effects and withdrawals

• “guideline” issues

anxiety disorders

• drug treatments

• limits

• inherent issues

• anxiety disorders

•highly variable

•prone chronic and co-morbid

•residual symptoms and

resistant cases

Reference

• 12th Maudsley Guidelines (2015). The Maudsley Prescribing 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. 2011 Mar

11;342:d1199.

• Baldwin DS et al (2006). Escitalopram and paroxetine in the treatment of

generalised anxiety disorder: randomised, placebo-controlled, double-

blind study. Br J Psychiatry. 2006 Sep;189:264-72.

• Baldwin DS et al (2011). Evidence-based pharmacological treatment of

generalized anxiety disorder. Int J Neuropsychopharmacol. 2011

Jun;14(5):697-710.

• Baldwin DS et al (2014). Evidence-based pharmacological treatment of

anxiety disorders, post-traumatic stress disorder and obsessive-

compulsive disorder: a revision of the 2005 guidelines from the British

Association for Psychopharmacology. J Psychopharmacol. 2014

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• Baldwin DS et al (2015). Efficacy and safety of pregabalin in generalised

anxiety disorder: A critical review of the literature. J Psychopharmacol.

2015 Oct;29(10):1047-60.

Reference

• Ballenger JC (2004). Remission rates in patients with anxiety disorders

treated with paroxetine. J Clin Psychiatry. 2004 Dec;65(12):1696-707.

• Benítez CI et al (2008). Use of benzodiazepines and selective serotonin

reuptake inhibitors in middle-aged and older adults with anxiety

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2008 Jan;16(1):5-13.

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Reference

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Reference

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Reference

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