foreword

Clinical Updates
Management of Anxiety Disorders • Six Persimmons 《六柿圖》
John So - Psychiatrist • Muqi Fachang 牧谿 法常
• after Zen meditation
•mindfulness
• other trends of psychotherapy

• other modalities of treatments

• by evidence or impression?

general general
• anxiety disorders • drugs
• normal emotion
disorders • benzodiazepine
•becoming disabling • antidepressant (SSRI SNRI)
•reducing quality of life • others
• characteristics •other antidepressants
•different types •other agents
•prone to have co-morbidities
•prone to be chronic

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 BZ
• benzodiazepines • 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 BZ
• benzodiazepines • 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)
 SSRI / SNRI
• SSRI antidepressant
• efficacious first-line drug
•“broad spectrum”
•short and long term
•generally well tolerated

(Baldwin D et al, 2014)

(Tan KR et al, 2011)

SSRI / SNRI SSRI / SNRI x GAD

• SSRI antidepressant • SSRI / SNRI x GAD
• efficacious first-line drug • dosing
• SNRI antidepressant •1 / 2 normal starting dose
• venlafaxine and duloxetine • some have initial worsening of
anxiety (Scott A et al, 2001)
•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

• SSRI / SNRI x GAD • SSRI / SNRI x GAD
• dosing
•1 / 2 normal starting dose
•titration upwards
• normal dosage as tolerated
• predictors: severity and duration
4th
of symptoms, (neuroimaging?) wee
• response within 6 weeks, k

continues to increase over time

(Ballenger JC, 2004, Baldwin DS et al, 2006, 2011)
 SSRI / SNRI x GAD GAD Rx responders
treatment

placebo

• SSRI / SNRI x GAD

• dosing
•1 / 2 normal starting dose
•titration upwards R

•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)

(Baldwin DS et al, 2011)

SSRI / SNRI x GAD SSRI / SNRI x GAD

• SSRI / SNRI x GAD • SSRI / SNRI x GAD
• dosing • dosing
•1 / 2 normal starting dose •1 / 2 normal starting dose
•titration upwards •titration upwards
•at least 1 year treatment •at least 1 year treatment
• optimal duration undetermined • optimal duration undetermined
(Baldwin DS et al, 2014, Davidson JR et al, 2010)
• longer continuation treatment
• longer continuation treatment
(Baldwin DS et al, 2011) • may prevent depression; drug tx
NOT associated with depression
(Goodwin RD & Gorman JM, 2002)

SSRI / SNRI x GAD Rank Response Remission Withdrawal

reduction of final for
• SSRI / SNRI x GAD HAM-score ≥ 50% HAM-A score ≤ 7 adverse events

• dosing 1 Fluoxetine Fluoxetine Sertraline

• drug choice (Baldwin D et al, 2011b) 2 Lorazepam Escitalopram Pregabalin
•Fluoxetine 3 Duloxetine Venlafaxine Fluoxetine
• probably most effective 4 Sertraline Paroxetine Paroxetine
5 Paroxetine Sertraline Tiagabine
•Sertraline
6 Pregabalin Duloxetine Venlafaxine
• probably best tolerated
7 Venlafaxine Tiagabine Escitalopram
8 Escitalopram N/A Duloxetine
9 Tiagabine N/A Lorazepam
(Baldwin D et al, 2011b)
Efficacy of drug Efficacy of drug
treatments for GAD: treatments for GAD:
systematic review and systematic review and
meta-analysis. meta-analysis.

Systematic review of RCT: Systematic review of RCT:

3249 citations 3249 citations
46 randomised controlled trials 46 randomised controlled trials
27 with sufficient or appropriate data 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)

SSRI / SNRI x GAD

(i.e. less withdrawal for adverse events)
• SSRI / SNRI x GAD
• dosing
• drug choice (Baldwin D et al, 2011b)
•Fluoxetine
• probably most effective
•Sertraline
• probably best tolerated

(Baldwin D et al, 2011b)

SSRI / SNRI x GAD SSRI / SNRI x others

• SSRI / SNRI x GAD • SSRI / SNRI x panic disorder
• dosing • dosing (12 Maudsley Guidelines, 2015)
th

• drug choice (Baldwin D et al, 2011b) •1 / 2 normal starting dose

•Fluoxetine •titration upwards
•Sertraline • bottom antidepressant range
• paroxetine may need higher dose
•please note…
• response as long as 6 weeks
• unpublished data, sponsorships,
publication bias, methodology…
• GAD highly variable, racial
disparities…
 SSRI / SNRI x others SSRI / SNRI x others
• SSRI / SNRI x panic disorder • SSRI / SNRI x panic disorder
• dosing Maudsley Guidelines, 2015)
(12th

•1 / 2 normal starting dose

media
•titration upwards n
5.67 yr
•at least 8 months
• optimal duration undetermined
(Rickels K & Schweizer E, 1998)

• evidence of benefit for at least 3

media
years (Choy Y et al, 2007) n
1.17 yr

SSRI / SNRI x others SSRI / SNRI x others

Response Minimum
• SSRI / SNRI x panic disorder Disorder Dosing
(week) (month)
• dosing (12 Maudsley Guidelines, 2015)
th
half starting dose
GAD 6 12
• drug choice titrate to normal dose
Panic half starting dose
•SSRI first line 6 8
Disorder titrate to normal dose
•clonazepam augmentation Social standard dose
8 12
• may lead to more rapid Phobia titration may not be required
response, but not greater overall higher licensed dose
OCD 10 to 12 12
response (Pollack HM et al, 2003) but standard dose may suffice
lower starting dose
• BZ controversies (Davidson JR, 2004, NICE PTSD 8 to 12 6
Guidelines CG113, 2011)
high dose often required
(12th Maudsley Guidelines, 2015)

etc etc
• other antidepressants • other antidepressants
• TCA • agomelatine
•efficacy •melatonergic and serotonergic
• efficacious in some anxiety • MT(1), MT(2), 5-HT(2C) receptors
disorders •efficacy
• more side effects (Baldwin DS et al, 2014) • efficacious in GAD, RCT vs
•clomipramine augmentation placebo, fu 12 weeks and 6
• OCD cases (Koran LM et al, 2007) months (Stein DJ et al, 2008, 2012)
• less sexual or withdrawal side
effects; liver function monitor
(Baldwin DS et al, 2014)
Results of AMSP Results of AMSP **
a Drug Surveillance Program a Drug Surveillance Program
(Friedrich ME et a, 2016) (Friedrich ME et a, 2016)

TCA & Arzneimittelsicherheit in der Psychiatrie

Tetra
in-patients on antidepressants
(from 1993 to 2011)
n = 184 234
SSRI
DILI = 149 (0.08%)

etc etc
• other antidepressants • other antidepressants
• mirtazapine (Baldwin DS et al, 2014) • bupropion (Baldwin DS et al, 2014)
•NorAdrenergic and Specific •noradrenergic, dopaminergic
Serotonergic Antidepressant •efficacy
•efficacy • non-specific anxiolytic effect,
• limited and inconsistent pilot study support
evidence • concomitant BZs are necessary
(Coplan JD et al, 2015)
• probably less frequent sexual
dysfuction

etc etc
• other antidepressants • other agents
• TCA • pregabalin
• agomelatine •Ca channel α2δ subunit ligand
• mirtazapine •efficacy
• bupropion • 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 etc
• other agents • other agents
• quetiapine • buspirone
•atypical antipsychotic •azapirone anxiolytic
•efficacy • 5-HT1A, 5-HT2A, D2, α1-
• efficacious in GAD, acute adrenergic and α2-adrenergic
treatment, relapse prevention receptors
(Maneeton N et al, 2016, Katzman MA et al, 2011) •efficacy
• dose from 50 to 150 or 300mg • efficacious in GAD, not superior
• low acceptability and tolerability, to BZ, not as acceptable as BZ
generally for non-response cases (Chessick CA et al, 2006)
(Baldwin DS et al, 2011)

etc etc
• other agents • other agents
• hydroxyzine • flupentixol-melitracen (Wang L et al, 2015)
•1st generation antihistamine •“Deanxit”
•efficacy •efficacy
• efficacious in GAD, also tolerable, • chronic somatic diseases
may be as effective as associated anxiety symptoms
chlordiazepoxide or buspirone • RCT response rates favouring
(noting study limits) (Guaiana G et al, addition to sertraline to lower
2010)
anxiety for first two weeks
• potential tardive dyskinesia risk

etc drug
• other agents • SSRI / SNRI • benzodiazepine
• fluoxetine
• flupentixol-melitracen (Wang L et al, 2015)
• sertraline

• other • other
antidepressants agents
• TCA • pregabalin
• agomelatine • quetiapine
• mirtazapine • buspirone
• bupropion • hydroxyzine
• flupentixol-
melitracen
 anxiety disorders anxiety disorders
• drug treatments • drug treatments
• noting other modalities • limits
• generally, SSRI first line • evidence issues
• temporarily, BZ coverage •access to data, publication bias,
• response around 6 to 12 weeks methodology limits
• prone chronic and co-morbid • cultural and biological differences
•side effects and withdrawals
• “guideline” issues

anxiety disorders Reference

• 12th Maudsley Guidelines (2015). The Maudsley Prescribing Guidelines in
• drug treatments Psychiatry, 12th Edition. April 2015, Wiley-Blackwell.
• Baldwin D et al (2011b). Efficacy of drug treatments for generalised
• limits 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
• inherent issues generalised anxiety disorder: randomised, placebo-controlled, double-
blind study. Br J Psychiatry. 2006 Sep;189:264-72.
• anxiety disorders • Baldwin DS et al (2011). Evidence-based pharmacological treatment of
generalized anxiety disorder. Int J Neuropsychopharmacol. 2011
Jun;14(5):697-710.
•highly variable • Baldwin DS et al (2014). Evidence-based pharmacological treatment of
anxiety disorders, post-traumatic stress disorder and obsessive-
•prone chronic and co-morbid compulsive disorder: a revision of the 2005 guidelines from the British
Association for Psychopharmacology. J Psychopharmacol. 2014
•residual symptoms and May;28(5):403-39.
• Baldwin DS et al (2015). Efficacy and safety of pregabalin in generalised
resistant cases 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
disorders: a longitudinal and prospective study. Am J Geriatr Psychiatry.
2008 Jan;16(1):5-13.
• Chessick CA et al (2006). Azapirones for generalized anxiety disorder.
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• Choy Y et al (2007). Three-year medication prophylaxis in panic disorder:
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• Coplan JD et al (2015). Treating comorbid anxiety and depression:
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Reference
• Friedrich ME et al (2016). Drug-Induced Liver Injury during
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 Reference
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