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

Pharmacological Treatmen
Anxiety Disord
Keming Gao, M.D
o, M.D., Ph.D
Objectives
• 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
Classification
DSM-IV Anxiety
DSM-IV Anxiety Disorders
Disorders
Substance Due to
Other Anxiety Disorders
disorder
disorders
Conditions
Specific
Agoraphobia
disorder
disorder
APA (1994), Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Washington, D.C.:
APA
Current Pharmacotherapies Approved by
FDA or EC for Anxiety Disorders
Disorder Antidepressants Benzodiazepines
Anticonvulsants
or antipsychotic
Escitalopram, Paroxetine
Alprazolam
Pregabalin
Venlafaxine XR, Duloxetine
Trifluoperazine
Clomipramine, Fluoxetine
Fluvoxamine/Fluvoxamine-
CR, Paroxetine, Sertraline
Fluoxetine,
Alprazolam, Clonazepam
Paroxetine/Paroxetine CR
Sertraline Venlafaxine,
citalopram
Paroxetine, Sertraline
Paroxetine/Paroxetine CR,
Sertraline
Venlafaxine XR, Fluvoxamine-
CR
Buspirone
Sheehan & Sheehan Psychopharmacol Bull 2007; Gao et al., 2009 Other Pharmacological Options for
Generalized Anxiety Disorder
• Antidepressants
– Other SSRIs, TCAs ( imipramine); Opipramol; MAOIs; Trazodone,
nefazodone, mirtazapine, and others
– Agomelatine (melatonin agonist and 5-HT 2c antagonist) short – and
long-term
• 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
• Anticonvulsants
– 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
Fluvoxamine
0.65 – 0.89
(4 studies)
Paroxetine
0.49 – 0.68
(3 studies)
Citalopram
Fluoxetine
0.23 -0.61
(2 studies)
Sertraline
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
5
reat
T
o 4
er Need 2
mb
Nu 1
Escitalopram
Duloxetine
Venlafaxine
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
Any BPD BPI
Sub BPD MDD
(n=102) (n=223)
(n=1530)
Agoraphobia
Panic D/O
Specific P
Merikangas et al., Arch Gen Psychiatry, 2007; Kessler et al., JAMA 2003 atien
f P 10
BP only DD
BP+AD+AUD
DD+AD+AU
BP+AD+AUD+DUD AD
BP+AD+AUD
BP+AD+AUD+DUD+ADHD
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
• Misdiagnosis
• 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
disorder
• 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
population
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)
Conclusions
• 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
treatments
• Antipscyhotics may be used for adjunctive therapy
• Combination psychotherapy with medications is
essential.
• Treatment of comorbid anxiety is an urgent unmet need

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