Microsoft powerpoint - pharmacological treatments for anxiety disorders- razavi-final [compatibility mode]

Pharmacological Treatmen
Anxiety Disord
Keming Gao, M.D
o, M.D., Ph.D
Review pharmacological treatments for
“pure” anxiety disorders
Discuss pharmacological treatments for
“treatment-refractory” anxiety disorders
Discuss challenges of pharmacological
treatments for “comorbid” anxiety disorders
Anxiety Disorders: DSM-IV
DSM-IV Anxiety
DSM-IV Anxiety Disorders
Substance Due to
Other Anxiety Disorders
APA (1994), Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, D.C.:

Current Pharmacotherapies Approved by
FDA or EC for Anxiety Disorders
Disorder Antidepressants Benzodiazepines
or antipsychotic

Escitalopram, Paroxetine
Venlafaxine XR, Duloxetine
Clomipramine, Fluoxetine
CR, Paroxetine, Sertraline

Alprazolam, Clonazepam
Paroxetine/Paroxetine CR
Sertraline Venlafaxine,

Paroxetine, Sertraline
Paroxetine/Paroxetine CR,
Venlafaxine XR, Fluvoxamine-

Sheehan & Sheehan Psychopharmacol Bull 2007; Gao et al., 2009 Other Pharmacological Options for
Generalized Anxiety Disorder
Other SSRIs, TCAs ( imipramine); Opipramol; MAOIs; Trazodone,
nefazodone, mirtazapine, and others
Agomelatine (melatonin agonist and 5-HT 2c antagonist) short – and
Other benzodiazepines
Other 5-HT1A agonist/partial agonists
Ipsapirone, PRX-00023
Serotonin Modulator and stimulator – Vortiosetine (Lu AA 21004)
Other anticonvulsants
Tiagabline (not superior to placebo); Valproate – superior to
placebo in a small study
Antipsychotics, trifluoperazine (FDA-approved), quetiapine-XR
Other alternative medicines
Ginkgo Biloba, matricaria recutita (Chamoline)
Baldwin DS, 2005; Rickels K, et al., 1993; Stein DJ, et al., 2008; 2012; Fontaine R, et al., 1983; 1986; Scarpini E, et al., 1988; Casacchia M, et al., 1990; Bassi S, et al., 1989; Boyer WF and Feighner JP, 1993; Rickels K, et a., 2008; 2012; Pollack MH, et al., 2008; Aliyev NA and Aliyev ZN, 2008; Pollack MH, et al., 1997; Lydiard RB, et al., 1997; Moller HJ, et al., 2001; Czobor P, et al., 2010); Rothschild AJ, et al., 2012; Amsterdam JD, et al., 2009; Woelk H et al., 2007) Other Options for Panic disorder
Other selective serotonin reuptake inhibitors
– Escitalopram as effective as citalopram and superior to placebo • Other antidepressants
– Reboxetine, a selective norepinepherine reuptake inhibitor, was • Other benzodiazepines
– Gabapentin (300 – 3600 mg/d), overall not effective, but effective in Stahl SM, et al., 2003; Noyes R Jr, et al., 1996; Pande AC, et al., 2000; Boyer W, 1995 Other Options for Generalized Social
Anxiety Disorder (GSAD)
Other selective serotonin reuptake inhibitors
– Short- and long-term studies showed escitalopram superior to placebo – Fluoxetine was as effective as Flu/CBT, CBT/placebo and superior to • Other antidepressants
– Nefazodone; Mirtazapine (1 small study was negative, 1 was positive in – MAOIs: Moclobemide ,Phenelzine, Brofaromine, were superior to placebo • Anticonvulsants
– Pregabalin, especially at 600 mg/d was superior to placebo in acute Gabapentin (300 – 3600 mg/d) was superior to placebo – Levetiracetam was not superior to placebo in GSAD • Other treatments
– Paroxetine+clonazepam > paroxetine alone– Pindolol+paroxetine not superior to paroxetine + placebo– Buspirone not superior to placebo – Quetiapine not superior o placebo Lader M, et al., 2004; Kasper S, et al., 2005; Montgomery SA, et al., 2005; Davidson JR, et al., 2004; Feltner DE, et al., 2011;Pande AC, et al., 2004; Greist JH, et al., 2011; Pande AC, et al., 1999; Stein MB, et al., 2010 Other Options for Treatment of
Obsessive-Compulsive Disorder (OCD)
Citalopram and escitalopram;
Mirtazapine – superior to placebo from 2 to 6
weeks only in a 12 week study
Clomipramine+nortriptyline > clomipramine
High doses of SSRIs are superior to medium
(NNT=13) and low doses (NNT=14) doses
Stein DJ, et al., 2008; 2007; Montgomery SA, et al., 2001; Fineberg NA, et al., 2006; Antipsychotic Adjunctive Therapy in Treatment
– Refractory Generalized Anxiety Disorder
∆ Difference in HAMA P value
Relative to Placebo

Risperidone (0.5 – 1.5 mg/d) n=19
Placebo n=12
Risperidone (total n=417)

Olanzapine n=9
Placebo n=12
Quetiapine IR (25 – 400 mg/d) n=11
Placebo n=11
Quetiapine-IR 50 mg/d n=10

Placebo n=10
Ziprasidone (20 – 80 mg/d) n=41
Placebo n=21
Gao K, et al., 2009; Altamura AC, et al., 2011; Lohoff FW, et al., 2010 Options for Treatment-Refractory
Obsessive-Compulsive Disorder (OCD)
Adjunctive antipsychotics (risperidone, quetiapine,
aripiprazole, olanzapine, haloperidol), overall 1/3
benefit from adjunctive treatment , but risperidone
had the best evidence and should be used as the first-
Adjunctive anticonsulsants
Lamotrigine, topiramate
Adjunctive 5-HT3 antagonists
Ondansetron, granisetron
Adjunctive morphine, celecoxib
Adjunctive pindolol, lithium, D-cycloserine,
clonazepam, naltrexone – ineffective,
Bold M et al., 2012; Fineberg NA, et al., 2006; Denys D, et al., 2007; Koran LM, et al., 2005; Askari N, et al., 2012; Soltani F, et al., 2010; Sayyah M, et al., 2011; Mundo E, et al., 1998; McDougle CJ, et al., 1991; Storch EA, et al., 2007; 2010; Crockett BA, et al., 2004; Hollander E, et al., 2003; Amiaz R, et al., 2008; Noorbala AA, et al., 1998; Pallanti S, et al., 2004; Bloch MH, et al., 2010; Berlin HA, et al., 2011; Bruno A, et al., 2012; Mowla A, et al., 2010; Muscatello MR, et al., 2011; Diniz JB, et al., 2011; Vulink NCC, et al., 2009.
How to Choose a Medications for
Anxiety Disorders
First-line treatments for these disorders are
selective serotonin reuptake inhibitors (SSRIs),
serotonin-noradrenaline reuptake inhibitors (SNRIs)
and the calcium channel modulator pregabalin.

Tricyclic antidepressants (TCAs) are equally
effective for some disorders, but many are less well
tolerated than the SSRIs/SNRIs.

In treatment-resistant cases, benzodiazepines may
be used when the patient does not have a history of
substance abuse disorders.

In most cases, combination psychotherapy with
medication is better than either treatment alone
Bandelow B, et al., 2008; 2012; Roy-Byrne P, et al., 2006 Choose a Medication Based on
Effect Size (numerical data)
Effect Size = (Change in active
treatment arm – change in placebo
arm)/pooled standard deviation
Effect Sizes of Medications in Treatment
of Generalized Anxiety Disorder
Based on Change in Hamilton Anxiety Scale
Large (0.8)
SSRIs: Paroxetine, sertraline, fluvoxamine, escitalopram CA: Complementary or alternative medicine (Kava-kava, homeopathic preparation Medium (0.5)
Small (0.2)
* A pooled analysis of 4 studies showed: the effect size was less than 0.4 if the dose was less than 150 mg/d and exceeded 0.4 if the dose was from 200 – 450 mg/d, but no increase in effect size with max does 600 mg/d.
Small Sample Size Study is Likely to
Produce a Larger Effect Size
No. of Patients
Effect Size
0.65 – 0.89
(4 studies)

0.49 – 0.68
(3 studies)

0.23 -0.61
(2 studies)

0.37 – 0.45
(3 studies)
Otto MW, et al., AJP 2001; Michelson D, et al., BJP 2001 Choose a Medication Based on
Number Needed to Treat
(categorical data)
Calculation of Number Needed to
Number needed to treat to benefit (NNT)
= 1/ARR (absolute risk reduction)
Absolute Risk Reduction (ARR)
= active treatment event rate - placebo
event rate
Jaeschke et al., 1995; McQuay et al., 1997, Guyatt et al., 2002. Altman DG, 1998; Gao et al., 2008; 2011 Number Needed to Treat (NNT) for
Response in Treatment of GAD
o 4

er Need 2
Nu 1

Allgulander C, et al., 2008; Davidson JR, et al., 2004 The Challenges and Unmet Needs
for Treatment of Anxiety Disorders
The duration of most studies was short
More than half of patients continued having symptoms
even with current “effective” treatments
Majority of studies were done in patients with “pure”
anxiety disorder. Therefore, generalizability is limited.
Only 20-30% of patients met the inclusion criteria.

The rating scales used in the studies may not reflect
the core symptoms of anxiety disorder
There is lack of data to guide clinicians sequentially to
use different medications
Study of treating different comorbid anxiety disorder is
an urgent unmet need.
Gao K, et al., 2010; Baldwin DA and Tiwari N, et al., 2009; Hoertel N, et al., 2012 Lifetime Co-occurrence of Anxiety
Disorders in Bipolar Disorders is Common
(n=102) (n=223)
Panic D/O
Specific P
Merikangas et al., Arch Gen Psychiatry, 2007; Kessler et al., JAMA 2003 atien
f P 10

BP only DD
Gao et al., APA 2010
Concurrent Anxiety Has a Negative
Impact on Patients with Mood Disorders
Earlier onset of bipolar disorder
Increased symptom severity
More frequent episodes, depressive relapses
Decreased response to treatment
Longer time to remission
Higher incidence of substance abuse
Higher incidence of suicide
More likely to have side effects
Lish et al. J Affect Dis 1994;31:281-94; Feske et al. Am J Psych 2000;157:956-62; McElroy et al. Am J Psych 2001;158:420-6; Young et al. J Affect Dis 1993;29:49-52; Chen, Dilsaver. Psych Res 1995;59:57-64. Fava M, et al., AJP 2008; Fava M, et al., Psycho Med 2004; Davis LL, et al. Am J Addict 2006. Papakostas GI, et al., 2008: Gaynes BN 2007, Howland RH, et al., 2009; Davis LL, et al., 2010; Gao K, et al., 2009 Challenges in Treatment of Comorbid
Anxiety Disorders with Mood Disorders
No efficacy study
Antidepressants - mania/hypomania in
bipolar disorder
Benzodiazepines – abuse/dependence in
patients with history of substance use
Some anticonvulsants – may be useful, but
no large study in comorbid population
Antipsychotics – may be viable alternatives,
but also no good-quality data in comorbid
Keck PE, et al., JCP 2006; . Chun & Dunner, BPD 2004; Gijsman HJ, et al., AJP 2004; Goldberg & Whiteside JCP 2002; Manwani SG, et al., JCP 2006; Martin A, et al. APAM 2004; Leverich GS, et al., AJP 2006; Brunette et al. Psychiatric Serv 2003; Gao K, et al. JCP 2006 Efficacy ≠ Effectiveness
Change in HAM-A from Baseline in Bipolar Study Week
Mean Change From Baseline
P<0.01; §P<0.001 vs placebo Change in HAM-A Total Score From Baseline
to End of Study in Bipolar Disorder with
Lifetime Panic Disorder and/or GAD
Quetiapine-XR (n=47) Divalproex-ER (n=46)
Placebo (n=51)
Sheehan DV, et al., J Affect Disord, in press Change in HAM-A Total Score From Baseline
to End of Study in Bipolar Disorder Current
GAD with or without SUD
Quetiapine-XR (n=46)
Placebo (n=44)
SSRIs should be considered as first-line treatment for all
anxiety disorders
SNRIs should be considered as first-line treatment for
all anxiety disorder with the exception of OCD
Pregabalin should be considered first-line agent for GAD
TCAs and other antidepressant may be considered for
second-line agents
Benzodiazepine can also be considered as second-line
Antipscyhotics may be used for adjunctive therapy
Combination psychotherapy with medications is
Treatment of comorbid anxiety is an urgent unmet need


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