Evidence-Based Pharmacotherapy for
OCD: An Update.
Naomi A Fineberg
Highly Specialised Service for Obsessive
Compulsive an...
Declaration of interests
I have received sponsorship for:
• Consultancy work, from Servier, Lundbeck, Glaxo-Smith
Kline, A...
Aims of lecture
• What are the first-line treatments?
• Does pharmacotherapy improved health-related
quality of life?
• Ho...
DSM5: Obsessive-Compulsive and Related Disorders.
APA, May 4th 2011
Diagnostic category, Obsessive-Compulsive and Movement...
Anxiety Disorders Guidelines covering OCD
• International Consensus Group on Depression and
Anxiety (2000, 2003)
• World F...
Hierarchy of evidence
Level Type of evidence
I Evidence from a single randomised controlled trial or a meta-
analysis of r...
Exclusion criteria in standard RCTs
• suicide risk and a history of self harm
• severe depression
• chronic depression
• r...
National Institute for Clinical Excellence (NICE)
OCD Guideline
Key Priorities
• Awareness of OCD as major lifespan disord...
Who is responsible for care?
STEP 6 Inpatient care or intensive treatment
programmes (national).
STEP 5 Multidisciplinary ...
First - Line Treatments in OCD
A. Behaviour therapy; exposure and response
prevention (>16h; in vivo)
B. Pharmacotherapy; ...
The pharmacological specificity of OCD
Effective
• Potent SRIs eg:
clomipramine
fluvoxamine
fluoxetine
sertraline
paroxeti...
16
18
20
22
24
26
28
30
32
0 1 2 3 4 5 6 7 8
desipramine (n=19)100-
300mg
fluvoxamine (n=21) 100-
300 mg
Are all antidepre...
Definitions of response for OCD
Depends on dose and duration of treatment
Response = 35% improvement in YBOCS (? Full)
OR ...
Which SRI?
Controlled studies comparing SSRIs with clomipramine (CMI)
DRUG
STUDY
n DESIGN
OUTCOME
Efficacy Tolerability
Fluoxetine (F...
For paroxetine, n= 399 cases / 387 controls, mean change 2.73kg (0.78 – 4.68)
based on 5 trials (2 major depression, 3 anx...
Which dose?
Fixed – dose escitalopram study: primary analysis
Stein DS et al Curr. Med. Res. and Opinion 2007
0
* p<0.05, **p<0.01; di...
Placebo-controlled comparator studies of fixed-doses of SSRI
DRUG
STUDIES
FIXED
DOSE
n DURATION
Positive dose-
response
re...
Dose-titration
• address common concerns about taking medication
with the patient e.g. potential side effects including
wo...
Definitions of remission and recovery for OCD
Remission is a period during which sufficient improvement has
occurred that ...
Patients in remission (Y-BOCS < 10)
Stein DS et al Curr. Med. Res. and Opinion 2007
0
5
10
15
20
25
30
35
40
45
1 2 4 6 8 ...
Does SSRI improve health related disability
and quality of life?
Mean baseline SF-36 scores for each of 8 dimensions (pooled FAS n =
921) in comparison to published U.S. norms and baselin...
Mean change in SF-36 from baseline to end of double-
blind period (OC, ANCOVA)
-14
-12
-10
-8
-6
-4
-2
0
2
4
6
8
Physical
...
Does adding CBT improve
outcomes?
Does adding CBT to SRI improve outcomes?
Randomised Studies
Three controlled
studies suggest adding
SRI to CBT improves
ou...
Cognitive-Behavioral Therapy vs Risperidone for Augmenting Serotonin
Reuptake Inhibitors in OCD: A Randomized Clinical Tri...
How long to remain on treatment?
Definitions of relapse for OCD
Relapse = Y-BOCS worsened by 25%
by 50%
by 100%
by 5 points
Y-BOCS > 20
CGI-I = 6
CGI-S wor...
Esc vs placebo:Time to relapse
Fineberg et al. Eur Neuropsychopharmacol. 2007
ESC N=163; Relapses: 38 (23.5%)
PBO N=157; R...
Double-blind studies of relapse prevention in OCD
STUDY DRUG
Duration
prior drug
treatment
n in
discont.
phase
Follow-
up ...
Meta-analysis of SSRI relapse prevention studies in
adults with OCD
Fineberg et al Int Clin Psychopharmacol 2007
Mean SF-36 scores at last assessment for relapsed (n=119)
and non-relapsed (n=201) patients (relapse-prevention
study). (H...
Sustained Response Versus Relapse: The
Pharmacotherapeutic Goal For OCD.
Fineberg NA et al Int Clin Psychopharmacol 2007
•...
Definitions of treatment non-response and resistance
Depends on dose and duration of treatment
Non-response = <25% improve...
SRI-resistant OCD: Predictors of non-response
Adults Children
• Longer illness duration Comorbid ADHD
• Early age of onset...
Comorbidity in UK refractory OCD; cross sectional
survey of systematic data. N=25
Disorder n Disorder n
TS 5 BPD 2
Tic dis...
Do specific OCD symptoms predict treatment-
response?
Symmetry/Hoarding predicts poor outcome to
escitalopram.
Stein D et al; CNS Spectr. 2008 Jun;13(6):492-8.
• 466 OCD patien...
SRI-resistant OCD: a pharmacological algorithm
First-line treatment
SSRI, maximal dose, 12 weeks
Switch SSRI or clomiprami...
Switching SSRIs in OCD.
• Delay switching until at least 12 weeks (March et al 1997)
• 11-33% patients not responding to o...
SRI-resistant OCD: a pharmacological algorithm
First-line treatment
SSRI, maximal dose, 12 weeks
Switch SSRI or clomiprami...
Randomised controlled studies in SRI-Resistant OCD
Appear effective:
Adding haloperidolb
Adding risperidone
Adding quetiap...
Higher-dose SSRI monotherapy for resistant OCD?
Ninan et al J Clin Psych 2006
• 66 OCD non-responders to 16 weeks of sertr...
SRI Usual Max
Dose (mg/day)
Occasionally
Prescribed Max
Dose (mg/day)
citalopram 40 120
clomipramine 250 -
escitalopram 20...
High-dose SSRIs in OCD: a systematic retrospective
case notes survey of 192 outpatients.
Pampaloni I et al J Psychopharm. ...
Antipsychotics as monotherapy in OCD
• Early open-label studies with first generation
antipsychotics fail modern standards...
Antipsychotic augmentation of SRIs in resistant OCD
Skapinakis P et al. Eur Neuropsychopharmacol 2007; 17: 79-93
haloperid...
8-week, single-blind, randomized trial comparing
risperidone (1-3mg) versus olanzapine (2.5-10mg)
augmentation of serotoni...
Who is responsible for care?
STEP 6 Inpatient care or intensive treatment
programmes (national).
STEP 5 Multidisciplinary ...
Does intensive CBT (ERP plus cognitive restructuring)
improve severe, refractory OCD? A 24 week naturalistic
study of 52 i...
SRI-resistant OCD: a pharmacological algorithm
First-line treatment
SSRI, maximal dose, 12 weeks
Switch SSRI or clomiprami...
Intravenous SSRI / clomipramine?
• Pulse loading with IV (but not oral) clomipramine produced an early
and rapid decrease ...
Combine clomipramine and SSRI?
• Caution is required if clomipramine is combined with SSRIs that
potentially interact at t...
SRI-resistant OCD: a pharmacological algorithm
First-line treatment
SSRI, maximal dose, 12 weeks
Switch SSRI or clomiprami...
Compound Study Study design Outcome
M
O
N
O
T
H
E
R
A
P
Y
D-amphetamine
(single dose)
Insel et al 1983
Joffe et al 1991
Do...
Somatic treatments in highly refractory OCD.
ECT: Insufficient evidence to recommend ECT for OCD, given potential
associat...
Neurosurgery for OCD: Inclusion criteria
1.Legal status: both patients detained under the mental health act and those who
...
Neurosurgery for OCD; Exclusion criteria
1.Age <20 years.
2.Failure to fulfill ICD-10 criteria for F42.0-F42.9.
3.Incapaci...
Conclusions
• Treatment effect on SSRI partial and dose and time
dependent
• Long-term SSRI protects against relapse
• Com...
International College of Obsessive Compulsive
Spectrum Disorders (ICOCS)
Committee: J Menchon ( Chair)
N. Fineberg ( Sec)
...
Opiate agonist and antagonists in OCD
• Morphine>placebo in a 2-week, randomised
double-blind crossover study of once week...
N-methyl D-aspartate (NMDA)-receptors, glutamate and
OCD
Reviewed in: Pittenger C et al. NeuroRx. 2006 Jan;3(1):69-81).
• ...
Differential Efficacy of Memantine for OCD vs.
Generalized Anxiety Disorder: An Open-Label Trial.
Feusner JD et al Psychop...
Does D-cycloserine improve CBT outcomes in OCD?
Author n Duration
(wk)
design Outcome
on D-cyc
Storch et al
2007
24 12 wee...
Cognitive Enhancers – a role in OCD?
D-Amphetamine :
• Two placebo-controlled single-dose studies (n=12, n=11) showed
impr...
Conclusions
• Treatment effect on SSRI partial and dose
and time dependent
• Long-term SSRI protects against relapse
• Com...
Daily Mail, 3rd April 2006
“Beckham said: 'I have got this obsessive compulsive disorder
where I have to have everything i...
Common obsessions Common compulsions
Fear of causing harm to someone
Fear of self-harm
Fear of behaving unacceptably
Fear ...
Anxiety disorders – epidemiology
(Wittchen & Jacoby, Eur Neuropsychopharmacol 2005)
Diagnostic group 12-month estimate
% (...
Age at onset of OCD
Rasmussen SA et al J Clin Psych 1990
0
5
10
15
20
25
30
35
40
6y-9y 10y-
12y
13y-
15y
16y-
19y
20y-
24...
Aetiology of OCD: cognitive theories
(Beck A. Arch Gen Psych 2005):
Biassed information processing leads to overestimation...
Thought- action fusion
Rachman (1976)
• Inflated sense of responsibility may derive from false assumptions
about thoughts ...
Aetiology of OCD: behavioural theories
Marks I , 1969, Rachman and Hodgson 1980
– Obsessions are anxiogenic
– Compulsions ...
Anxiety
Time
Anxiety
rises
Feeling
‘contaminated’
Anxiety reduces
- only a little
- not for long
Ritualisation
Behavioural...
Anxiety
initially
rises
Breaking the cycle -
self -imposed response prevention
Anxiety eventually reduces -
it falls highe...
DEFINITION OF CLINICAL RESPONSE
DRUG
[duration weeks]
much or very much
improved on CGI-I
(Criterion A)
>25% improved on
b...
Escitalopram 10mg, 20mg vs paroxetine 40mg and
placebo: 24 weeks study.
Stein DS et al Curr. Med. Res. and Opinion 2007
Do...
Drug
(duration,
wk)
Study n
Dose (mg/day)
[mean dose]
Response
criteria
Response rate
on active
drug
Placebo
response
rate...
Open-label, high-dose escitalopram in resistant OCD
Rabinowitz I et al., Int J Psychopharmacol 2008
• 67 patients received...
• JAMA Psychiatry. 2013 Nov 1;70(11):1190-9. doi: 10.1001/jamapsychiatry.2013.1932.
• Cognitive-Behavioral Therapy vs Risp...
Antipsychotic augmentation for treatment resistant
OCD : what if antipsychotic is discontinued?
Maina G et al. Int Clin Ps...
Does adding CBT to SRI protect against
relapse after drug discontinuation?
No properly controlled, blinded studies
Biondi et al (2005)
- 10/20 SRI-responders non-randomly allocated CBT timed to end...
Defining OCD - ICD-10
A. Either obsessions or compulsions (or both) [present on
most days for a period of at least two wee...
Obsessive-compulsive
disorders
BDD
TS
OCD
Affective
disorders
Autism
Addiction
Depressive
disorders
Anxiety disorders
Tric...
Dra. Naomi A. Fineberg - Simposio Internacional ' La enfermedad de la duda: el TOC'
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Dra. Naomi A. Fineberg - Simposio Internacional ' La enfermedad de la duda: el TOC'

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El 14 de noviembre de 2013, la Fundación Ramón Areces organizó y acogió en su sede un Simposio Internacional sobre 'La enfermedad de la duda: el TOC'. El Trastorno Obsesivo-Compulsivo (TOC) es un problema de salud pública, poco conocido, que afecta a un porcentaje de la población en torno a un 1-2% y que la Organización Mundial de la Salud ha situado entre las diez entidades que producen más discapacidad.

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  • The eurpoean conceptualisation of OCD as a disorder unto itself is back in the ascendancy, and as many of you already know, the Apa has recently proposed a new stad alone category including OCd and related spectrum disorders, all of which are characterised by the inability to restrain repetitive thought sna d acts. This emphasis on disinhibited behaviour, as opposed to anxiety and emotional dysregulation per se , marks a paradigm shift and it is to be hoped will generate new and exciting deveoplments in treatment and prevention of this most disbaling of diseases. So this is a most exciting time to be researching ocd.
  • NOTES FOR PRESENTERS
    Refer to QRG (page 7) NICE guideline –
    Section 1.2
    Each step introduces additional interventions: the higher steps normally assume interventions in the previous step have been offered and/or attempted but there are situations where an individual may be referred to any appropriate level.
    The guidance follows the steps in the figure
  • Christine:
    Please use Hlu set-up
    Change venlafaxine to venlafaxine XR
    Add journal reference
    Sustained remission
    Meeting remission criteria from this time point on for the rest of the study
    Dose
    ESC 10-20mg
    VFL 75-150mg = lower dose range
  • NOTES FOR PRESENTERS
    Starting the treatment – refer to NICE guideline section 1.5.3.1
    Choice of drug treatment – refer to NICE guideline section 1.5.3.8 to 1.5.3.19
    Initial SSRI should be one of the following: Fluoxetine, fluvoxamine, paroxetine, sertraline or citalopram.
    Apart from SSRIs and clomipramine, other anti-depressants are generally not helpful.
    Drugs not recommended for OCD:
    The following should not normally be used without comorbidity –
    Tricyclic antidepressants (except clomipramine)
    Tricyclic-related antidepressants
    SNRIs (including venlafaxine)
    MAOIs
    Anxiolytics (except cautiously for short periods to counter early activation of SSRIs)
    Antipsychotics as monotherapy should not normally be used for OCD
  • Log-rank p=1.48 E-07
  • How long then should treatment be continued?
  • NOTES FOR PRESENTERS
    Refer to QRG (page 7) NICE guideline –
    Section 1.2
    Each step introduces additional interventions: the higher steps normally assume interventions in the previous step have been offered and/or attempted but there are situations where an individual may be referred to any appropriate level.
    The guidance follows the steps in the figure
  • These novel compounds have been subjected to prliminary clinical trials in OCD. blue= db rcts with a positive outcome.
    Mention koran- d amphet
    Also, Pasquini &amp; Biondi 2006 Poyurovsky et al 2005 positive case reprts on memnatine,
    Mirtaz=Double-blind discontinuation in MIR responders
    Glycine
    Greenberg et al 2009
    Open-label case reports
    Improvement
    Biol Psychiatry. 2012 Dec 1;72(11):964-70. doi: 10.1016/j.biopsych.2012.05.028. Epub 2012 Jul 10.
    Effects of ketamine in treatment-refractory obsessive-compulsive disorder.
    Bloch MH, Wasylink S, Landeros-Weisenberger A, Panza KE, Billingslea E, Leckman JF, Krystal JH, Bhagwagar Z, Sanacora G, Pittenger C.
    Source
    Yale Child Study Center, Yale University School of Medicine, New Haven, Connecticut, USA. michael.bloch@yale.edu
    Abstract
    BACKGROUND:
    Treatments for obsessive-compulsive disorder (OCD) usually lead to incomplete symptom relief and take a long-time to reach full effect. Convergent evidence suggests that glutamate abnormalities contribute to the pathogenesis of OCD. Ketamine is a potent noncompetitive antagonist of the N-methyl-D-aspartate glutamate receptor. Trials have reported rapid antidepressant effects after low-dose ketamine infusion.
    METHODS:
    We conducted an open-label trial of ketamine (.5 mg/kg IV over 40 min) in 10 subjects with treatment-refractory OCD. Response was defined as &amp;gt;35% improvement in OCD symptoms and &amp;gt;50% improvement in depression symptoms from baseline at any time between 1 and 3 days after infusion.
    RESULTS:
    None of 10 subjects experienced a response in OCD symptoms in the first 3 days after ketamine. Four of seven patients with comorbid depression experienced an antidepressant response to ketamine in the first 3 days after infusion. Both OCD and depression symptoms demonstrated a statistically significant improvement in the first 3 days after infusion compared with baseline, but the OCD response was &amp;lt;12%. The percentage reduction in depressive symptoms in the first 3 days after ketamine infusion was significantly greater than the reduction in OCD symptoms.
    CONCLUSIONS:
    Ketamine effects on OCD symptoms, in contrast to depressive symptoms, did not seem to persist or progress after the acute effects of ketamine had dissipated.
    Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
    Riluzole
    Coric V et al 2003, 2005
    Pittenger et al 2008
    Open-label case reports
    Open-label case reports
    Improvement
    Improvement
    Amphetamine has been identified as a potent agonist of trace amine-associated receptor 1 (TAAR1) (aka &amp;quot;TAAR1&amp;quot;), a GPCR, discovered in 2001, that is important for regulation of monoaminergic systems in the brain.[33] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits dopamine transporter function.[33][34][35][36]
    Amphetamine exerts its behavioral effects by modulating neurotransmitters in the brain, with the majority of amphetamines effects being exerted on the catecholamine neurotransmitters.[37] Beyond this, amphetamine has broader influence on the brain neurotransmission and the central nervous system, including but not limited to effects on dopamine,[38] serotonin,[38] norepinephrine,[38] acetylcholine,[39] glutamate,[40][41] and histamine,[42] through various mechanisms. However, the activity of amphetamine throughout the brain appears to be site-specific;[43] certain receptors that respond to amphetamine in some regions of the brain tend not to do so in other regions. For instance, dopamine D2 receptors in the hippocampus, a region of the brain associated with forming new memories, appear to be unaffected by the presence of amphetamine.[43] It is believed that this is due to the presence, or lack thereof, of TAAR1 localization with the associated monoamine transporters.[38] As of 2010, co-localization of TAAR1 and the dopamine transporter (aka &amp;quot;DAT&amp;quot;) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (aka &amp;quot;NET&amp;quot;) and the serotonin transporter (aka &amp;quot;SERT&amp;quot;) has only been evidenced by mRNA expression.[38]
    The major neural systems affected by amphetamine are largely implicated in the reward (mesolimbic) pathway and executive function (mesocortical) pathway of the brain.[37] More specifically, the concentrations of the primary neurotransmitters involved in reward circuitry, dopamine, and executive functioning, dopamine and norepinephrine, are known to be markedly increased in a dose-dependent manner by amphetamine.[37] It is hypothesized that d-amphetamine acts primarily on the dopaminergic systems, while l-amphetamine is primarily noradrenergic. The primary reinforcing and behavioral-stimulant effects of amphetamine, however, are linked to enhanced dopaminergic activity, primarily in the mesolimbic pathway
    Amphetamine has been identified as a potent agonist of trace amine-associated receptor 1 (TAAR1) (aka &amp;quot;TAAR1&amp;quot;), a GPCR, discovered in 2001, that is important for regulation of monoaminergic systems in the brain.[33] Activation of TAAR1 increases cAMP production via adenylyl cyclase activation and inhibits dopamine transporter function.[33][34][35][36]
    Amphetamine exerts its behavioral effects by modulating neurotransmitters in the brain, with the majority of amphetamines effects being exerted on the catecholamine neurotransmitters.[37] Beyond this, amphetamine has broader influence on the brain neurotransmission and the central nervous system, including but not limited to effects on dopamine,[38] serotonin,[38] norepinephrine,[38] acetylcholine,[39] glutamate,[40][41] and histamine,[42] through various mechanisms. However, the activity of amphetamine throughout the brain appears to be site-specific;[43] certain receptors that respond to amphetamine in some regions of the brain tend not to do so in other regions. For instance, dopamine D2 receptors in the hippocampus, a region of the brain associated with forming new memories, appear to be unaffected by the presence of amphetamine.[43] It is believed that this is due to the presence, or lack thereof, of TAAR1 localization with the associated monoamine transporters.[38] As of 2010, co-localization of TAAR1 and the dopamine transporter (aka &amp;quot;DAT&amp;quot;) has been visualized in rhesus monkeys, but co-localization of TAAR1 with the norepinephrine transporter (aka &amp;quot;NET&amp;quot;) and the serotonin transporter (aka &amp;quot;SERT&amp;quot;) has only been evidenced by mRNA expression.[38]
    The major neural systems affected by amphetamine are largely implicated in the reward (mesolimbic) pathway and executive function (mesocortical) pathway of the brain.[37] More specifically, the concentrations of the primary neurotransmitters involved in reward circuitry, dopamine, and executive functioning, dopamine and norepinephrine, are known to be markedly increased in a dose-dependent manner by amphetamine.[37] It is hypothesized that d-amphetamine acts primarily on the dopaminergic systems, while l-amphetamine is primarily noradrenergic. The primary reinforcing and behavioral-stimulant effects of amphetamine, however, are linked to enhanced dopaminergic activity, primarily in the mesolimbic pathway.[medical citation neede
    Bupropion affects a number of neurotransmitter systems, and its mechanisms of action are only partly understood. The primary pharmacological action of the drug is as a mild dopamine reuptake inhibitor and also a much weaker norepinephrine reuptake inhibitor as well as a nicotinic acetylcholine receptor antagonist. Chemically, bupropion belongs to the class of aminoketones and is similar in structure to stimulants such as cathinone and amfepramone, and to phenethylamines in general
    Neuropsychopharmacology. 2013 Jun 19. doi: 10.1038/npp.2013.150. [Epub ahead of print]
    Randomized Controlled Crossover Trial of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept.
    Rodriguez CI, Kegeles LS, Levinson A, Feng T, Marcus SM, Vermes D, Flood P, Simpson HB.
    Source
    1] New York State Psychiatric Institute, New York, NY, USA [2] Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY, USA.
    Abstract
    Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2-3 months lag time before clinically meaningful improvement. New medications with faster onset are needed. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, we tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid anti-obsessional effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n=15) with near-constant obsessions received two 40-min intravenous infusions, one of saline and one of ketamine (0.5 mg/kg), spaced at least 1-week apart. The OCD visual analog scale (OCD-VAS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were used to assess OCD symptoms. Unexpectedly, ketamine&amp;apos;s effects within the crossover design showed significant (p&amp;lt;0.005) carryover effects (ie, lasting longer than 1 week). As a result, only the first-phase data were used in additional analyses. Specifically, those receiving ketamine (n=8) reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo (n=7). One-week post-infusion, 50% of those receiving ketamine (n=8) met criteria for treatment response (35% Y-BOCS reduction) vs 0% of those receiving placebo (n=7). Rapid anti-OCD effects from a single intravenous dose of ketamine can persist for at least 1 week in some OCD patients with constant intrusive thoughts. This is the first randomized, controlled trial to demonstrate that a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an SRI and is consistent with a glutamatergic hypothesis of OCD
    Mirtazapine. Antagonization of the α2-adrenergic receptors, which function largely as autoreceptors and heteroreceptors enhances adrenergic and serotonergic neurotransmission, the notable ones being central 5-HT1A receptor-mediated transmission in the dorsal raphe nucleus and hippocampus; hence, mirtazapine&amp;apos;s classification as a NaSSA. Indirect α1-adrenoceptor-mediated enhancement of 5-HT cell firing and direct blockade of inhibitory α2-heteroreceptors located on 5-HT terminals are held responsible for the increase in extracellular 5-HT.[2][3][75][76][77] Because of this, mirtazapine has been said to be a functional &amp;quot;indirect agonist&amp;quot; of the 5-HT1A receptor.[76] Increased activation of the central 5-HT1A receptor is thought to be a major mediator of efficacy of most antidepressant drugs.[78] Unlike most conventional antidepressants, however, at clinically used doses mirtazapine has no appreciable affinity for the serotonin, norepinephrine, or dopamine transporters and thus lacks any significant effects as a reuptake inhibitor of these neurotransmitters,[79] nor does it have any significant inhibitory effects on monoamine oxidase.[80]
  • The inhibitory effect of rTMS on the increased neuronal activity in the prefrontal subcortical circuits is hypothesized to be beneficial in the treatment of OCD (Blom et al 2011).
    rTMS modulates neuronal activity by inducing a magnetic field pulse. The inhibitory effect of rTMS on the increased neuronal activity in the prefrontal subcortical circuits is hypothesized to be beneficial in the treatment of OCD (Blom et al 2011). A systematic review of studies investigating the efficacy of rTMS in OCD between 1996 and 2010 (Jaafari et al 2012) and a recently published meta-analysis (Berlim et al 2013) suggested promising results in comparison to sham rTMS with target areas such as the orbitofrontal cortex and the supplementary motor area. rTMS is generally a safe and non invasive from of treatment. Rarely, high frequency rTMS may induce seizures. Other reported side effects include localized pain, paraesthesias, hearing changes, thyroid stimulating hormone and blood lactate level changes and hypomania; however these problems are usually transient (Blom et al 2011). In summary, there is presently insufficient evidence to support the use of rTMS as a treatment for OCD, and it remains an experimental procedure.
    Deep brain stimulation (DBS)
    Deep brain stimulation (DBS) is a neurosurgical treatment which involves the implantation of electrodes that send electrical impulses to specific locations in the brain, with areas selected according to the type of symptoms to be addressed. This approach permits focal, relatively low risk and relatively reversible modulation of brain circuitry. DBS may bring about therapeutic effects in OCD by modulating the cortico-striatal neurocircuitry that is widely proposed to mediate OCD (Bourne et al 2012). Stimulation of the ventral capsule/ventral striatum appears to improve mood, obsessions and compulsions whereas stimulation of the sub-thalamic nucleus may selectively improve compulsions (Milan et al 2010). Small studies with at best partially controlled designs have reported significant overall average Y-BOCS decreases ranging from 6.8 to 31 points (in severely ill patients with baseline Y-BOCS scores usually exceeding 30), and the average overall responder rate is 50%. The procedure is reported to be “relatively safe” with limited side effects (de Koning et al 2011). However, adverse events have been reported. In a study (Greenberg et al 2006) that followed up the 3-year outcomes following bilateral stimulation of ventral capsule/ventral striatum areas in 10 adult OCD patients meeting stringent criteria for severity and treatment resistance, the following surgical adverse effects were reported: asymptomatic haemorrhage, a single seizure, and superficial infection. Psychiatric adverse effects included transient hypomanic symptoms and worsening of depression and OCD when DBS was interrupted. Acute adverse effects of DBS included transient sadness, anxiety, and euphoria or giddiness. Anxiety was more frequent with monopolar than with bipolar stimulation. Suicide events were not noted when DBS was interrupted, and cognitive events were described as relatively benign. At the present time, DBS remains an experimental treatment, with evidence largely based on case series.
    Ablative neurosurgery
    Modern ablative neurosurgical procedures are stereotactically guided, resulting in small and accurately placed lesions. This is most commonly achieved using thermal stimuli although there is ongoing research into the use of radio surgical techniques such as the gamma knife. There are two procedures that are offered by the international centers involved in the provision of such therapies. Anterior cingulotomy, involving lesions placed in the dorsal anterior cingulate cortex (Sheth et al 2013) and anterior capsulotomy, involving lesions placed within the inferior fronto-thalamic connections within the anterior limb of the internal capsule (Ruck et al 2003), are the most common procedures. Both procedures are believed to modulate functioning within the cortico-striatal-thalamic circuitry. Overall the available evidence suggests that such procedures offer significant therapeutic benefits to 30-60% of patients with otherwise highly refractory OCD. Serious adverse effects are uncommon, but have been reported with both procedures (e.g. intracranial hemorrhage, recurrent seizures). Anterior cingulotomy appears to offer a superior safety profile to that of anterior capsulotomy. The quality of evidence supporting each procedure is reflective of neurosurgery as a whole. There are no randomized controlled trials and most data is derived from prospective case series and small un-blinded cohort studies. Surgical intervention is therefore reserved for patients with severe, incapacitating OCD who have failed an exhaustive array of expertly delivered medication trials and intensive psychological (including behavioural) treatments. The inclusion and exclusion criteria for neurosurgery in the UK are listed in Table 1. The authors recommend that readers refer to the website of the Advanced Interventions Service, Dundee (UK), for information on psychopharmacological and psychological treatments deemed ‘essential’ (in the UK) before proceeding to surgery.
  • European
  • Christine:
    Please use Hlu set-up
    Change venlafaxine to venlafaxine XR
    Add journal reference
    Sustained remission
    Meeting remission criteria from this time point on for the rest of the study
    Dose
    ESC 10-20mg
    VFL 75-150mg = lower dose range
  • Dra. Naomi A. Fineberg - Simposio Internacional ' La enfermedad de la duda: el TOC'

    1. 1. Evidence-Based Pharmacotherapy for OCD: An Update. Naomi A Fineberg Highly Specialised Service for Obsessive Compulsive and Related Disorders, Hertfordshire Partnership NHS University Foundation Trust and University of Hertfordshire, Queen Elizabeth II Hospital, Welwyn Garden City, Hertfordshire AL7 4HQ
    2. 2. Declaration of interests I have received sponsorship for: • Consultancy work, from Servier, Lundbeck, Glaxo-Smith Kline, Astra-Zeneca and Bristol-Myers Squibb. • Lectures, from Astra-Zeneca, Jazz Pharmaceuticals • Educational support, from Janssen, Lundbeck, Bristol- Myers Squibb, Wyeth, Servier, Jazz.
    3. 3. Aims of lecture • What are the first-line treatments? • Does pharmacotherapy improved health-related quality of life? • How do we evaluate clinical response and relapse? • How long should treatment continue? • Can we predict treatment outcomes? • What is the management of treatment-refractory OCD?
    4. 4. DSM5: Obsessive-Compulsive and Related Disorders. APA, May 4th 2011 Diagnostic category, Obsessive-Compulsive and Movement-Related Disorders. Contains diagnoses that were listed in DSM-IV under Anxiety Disorders, Somatoform Disorders and Impulse-Control Disorders Not Elsewhere Classified. 300.3 Obsessive-Compulsive Disorder a Specify if: Tic-related 300.7 Body Dysmorphic Disordera Specify if: With muscle dysmorphia 300.3 Hoarding Disorder a Specify if: With excessive acquisition 312.39 Hair-Pulling Disorder (Trichotillomania) 698.4 Skin Picking (Excoriation) Disorder --.-- Substance-Induced Obsessive-Compulsive or Related Disorders 294.8 Obsessive-Compulsive or Related Disorder Associated with a Known General Medical Condition 300.3 Other Specified Obsessive-Compulsive or Related Disorders 300.3 Unspecified Obsessive-Compulsive or Related Disorders a Specify if: With good or fair insight, With poor insight, With absent insight/delusional beliefs
    5. 5. Anxiety Disorders Guidelines covering OCD • International Consensus Group on Depression and Anxiety (2000, 2003) • World Federation of Societies of Biological Psychiatry (2002, 2008, 2012) • World Council on Anxiety Disorders (2003) • National Institute for Clinical Excellence (UK) (2006; Evidence Update 2013) • British Association for Psychopharmacology (2005, 2013 in press) • American Psychiatric Association (2007)
    6. 6. Hierarchy of evidence Level Type of evidence I Evidence from a single randomised controlled trial or a meta- analysis of randomised controlled trials IIa Evidence from at least one well-designed controlled study without randomisation IIb Evidence from at least one other well-designed quasi- experimental study III Evidence from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies IV Evidence from expert committee reports or opinions and/or clinical experiences of respected authorities Adapted from Eccles M & Mason J (2001), Mann T (1996) P Pharmacological evidence from pre-clinical studies Anderson and Edwards (2001)
    7. 7. Exclusion criteria in standard RCTs • suicide risk and a history of self harm • severe depression • chronic depression • recurrent depression • treatment-resistant depression • inpatients • medical illnesses • concurrent medication • other psychiatric co-morbidity • alcohol / substance misuse • major social difficulties / chaotic lifestyles • not taking contraception
    8. 8. National Institute for Clinical Excellence (NICE) OCD Guideline Key Priorities • Awareness of OCD as major lifespan disorder • Access to specialist services according to stepped care model • Availability of behavioural cognitive therapies (incl ERP) and pharmacotherapies (SSRIs & CMI) • Behaviour therapy or pharmacotherapy 1st line for adults • Behaviour therapy 1st line; pharmacotherapy 2nd line for children • Combined behaviour therapy & pharmacotherapy in more severe cases www.nice.org.uk (Feb 2006)
    9. 9. Who is responsible for care? STEP 6 Inpatient care or intensive treatment programmes (national). STEP 5 Multidisciplinary teams with specific expertise in management of OCD (regional). STEP 4 local multidisciplinary care (GP or psychiatrist). STEP 3 GPs and primary care team, primary care mental health worker, family support team. STEP 2 GPs, practice nurses, school health advisors STEP 1 Individuals, public organisations, NHS STEPPED CARE MODEL
    10. 10. First - Line Treatments in OCD A. Behaviour therapy; exposure and response prevention (>16h; in vivo) B. Pharmacotherapy; serotonin reuptake inhibitors (clomipramine or SSRI); higher doses; extended duration- minimum 12 weeks; adjunctive DA antagonists C. Combination of A+B BUT Up to 40% fail to respond Relapse is common Better treatments are needed Fineberg NA, Brown, A, Reghunandanan S, Pampaloni I. Evidence-Based Pharmacotherapy of Obsessive-Compulsive Disorder. Int J Neuropsychopharmacol. 2012 Jan 9:1-19
    11. 11. The pharmacological specificity of OCD Effective • Potent SRIs eg: clomipramine fluvoxamine fluoxetine sertraline paroxetine citalopram escitalopram Effective in combination with SRIs (unlicensed for OCD): 1st generation antipsychotics eg haloperidol 2nd generation antipsychotics eg risperidone, quetiapine, olanzapine, aripiprazole Ineffective • Tricyclics (apart from clomipramine) • Monoamine oxidase inhibitors • Lithium • Benzodiazepines • Buspirone • Electroconvulsive therapy
    12. 12. 16 18 20 22 24 26 28 30 32 0 1 2 3 4 5 6 7 8 desipramine (n=19)100- 300mg fluvoxamine (n=21) 100- 300 mg Are all antidepressants also anti-obsessive? Randomised, double-blind, parallel-group study Mean Y-BOCS score Goodman et al (1990) Arch Gen Psychiatry 47:577-585 Weeks
    13. 13. Definitions of response for OCD Depends on dose and duration of treatment Response = 35% improvement in YBOCS (? Full) OR 25% (? Partial) AND/OR CGI-I Score 1 or 2 (Pallanti et al 2002, Simpson et al 2006) Standardised definitions of meaningful OCD response could be improved using combined clinical databases, as for other anxiety disorders (Bandelow et al. 2006). By correlating post-baseline Y-BOCS improvements with CGI-I scores, changes smaller than those representing ‘much improved’ could be considered as ‘partial response’. Fineberg NA et al J Psychopharmacol 2007
    14. 14. Which SRI?
    15. 15. Controlled studies comparing SSRIs with clomipramine (CMI) DRUG STUDY n DESIGN OUTCOME Efficacy Tolerability Fluoxetine (FLX) Piggott et al (1990) Lopez-Ibor et al (1996) 11 30 vs 24 CMI (50-250mg) vs FLX (20-80mg) CMI 150mg vs FLX 40mg CMI=FLX CMI=FLX on primary criterion CMI>FLX on other criteria FLX > CMI FLX = CMI Fluvoxamine (FLV) Smeraldi et al (1992) Freeman et al (1994) Koran et al (1996) Milanfranchi et al (1997) Rouillon (1998) 10 30 vs 34 42 vs 37 13 vs 13 105 vs 112 CMI 200mg vs FLV 200mg CMI (150-250mg) vs FLV (150-250mg) CMI (100-250mg) vs FLV (100-250mg) CMI (50-300mg) vs FLV (50-300mg) CMI (150-300mg) vs FLV (150-300mg) CMI=FLV CMI=FLV CMI=FLV CMI=FLV CMI=FLV FLV = CMI FLV > CMI (on severe effects) FLV = CMI FLV = CMI FLV > CMI. Paroxetine (PAR) Zohar and Judge (1996) 99 vs 201 vs 99 CMI (50-250mg) vs. PAR (20-60mg) vs PLACEBO CMI>PLACEBO PAR>PLACEBO PAR > CMI Sertraline (SER) Bisserbe et al (1997) 82 vs 86 CMI (50-200mg) vs. SER (50-200mg) SER=CMI SER > CMI Citalopram (CIT) Pidrman & Tuma (1998) 24 CIT vs. CMI CIT=CMI CIT = CMI
    16. 16. For paroxetine, n= 399 cases / 387 controls, mean change 2.73kg (0.78 – 4.68) based on 5 trials (2 major depression, 3 anxiety disorders) Serretti A, Mandelli, L J Clin Psych 2010; 71 (10): 1259-1272 Weight Gain Meta-analysis of 116 trials of ACUTE and/or MAINTENANCE Rx WITH ANTIDEPRESSANTS
    17. 17. Which dose?
    18. 18. Fixed – dose escitalopram study: primary analysis Stein DS et al Curr. Med. Res. and Opinion 2007 0 * p<0.05, **p<0.01; difference versus placebo 0 Adjustedmeanchangefrombaseline Y-BOCStotalscore 4 8 12 16 20 24 -4 -2 -6 -8 -10 -12 -14 * * * * * ** ** ** * * * * ** ** Escitalopram 10 mg n = 114 Placebo Escitalopram 20 mg n=114 Paroxetine 40 mg n=116 n=113 ** Treatment week (LOCF)
    19. 19. Placebo-controlled comparator studies of fixed-doses of SSRI DRUG STUDIES FIXED DOSE n DURATION Positive dose- response relationship? Fluoxetine Montgomery et al (1993) Tollefson et al (1994) 20/40/60mg 20/40/60mg 214 355 8weeks 13 weeks YES 1 NO Sertraline Greist et al (1995) 50/100/200mg 324 12 weeks NO Paroxetine Hollander et al (2003) 20/40/60mg 348 12 weeks YES Citalopram Montgomery et al (2001) 20/40/60mg 352 12 weeks YES2 Escitalopram Stein et al 2007 10/20mg 457 12 weeks 24 weeks YES YES 1 marginally significant benefit for medium and higher doses on primary analysis (total Y-BOCS; p = 0.059); significant on ‘responder’ analysis (p<0.05). 2 60mg significantly better than placebo and 20mg on secondary analyses
    20. 20. Dose-titration • address common concerns about taking medication with the patient e.g. potential side effects including worsening anxiety • explain that OCD responds to drug treatment in a slow and gradual way and that improvements may take weeks or months • Start with standard antidepressant dose and titrate upwards slowly according to clinical response toward remission
    21. 21. Definitions of remission and recovery for OCD Remission is a period during which sufficient improvement has occurred that the individual no longer has syndromal OCD. Remission = YBOCS < 16 OR YBOCS < 12 OR YBOCS < 10 OR YBOCS < 7 (Simpson et al., 2006, Stein et al 2007) Recovery is a sustained period of remission (? >6 months) Includes moving forward and rebuilding one’s life and incorporating improvements in areas such as quality of life and psychosocial function.
    22. 22. Patients in remission (Y-BOCS < 10) Stein DS et al Curr. Med. Res. and Opinion 2007 0 5 10 15 20 25 30 35 40 45 1 2 4 6 8 10 12 16 20 24 Treatment week (LOCF) Remission(Y-BOCS<10)rate(%) PBO PAR40 ESC10 ESC20 * * * * * ** * * * p<0.05 vs PBO, ** p<0.01 vs PBO Stein et al. Poster presented at APA 2006
    23. 23. Does SSRI improve health related disability and quality of life?
    24. 24. Mean baseline SF-36 scores for each of 8 dimensions (pooled FAS n = 921) in comparison to published U.S. norms and baseline data from two published studies of impact of OCD on SF-36 scores. 0 10 20 30 40 50 60 70 80 90 100 Physical Functioning Role physical limitations Bodily pain General health Vitality Social functioning Role emotional Mental health SF-36score(0-100) Baseline U.S. normsa Koran et al., 1996 Mancebo et al., 2008 (OCD + disability)b Mancebo et al., 2008 (OCD no disability)b 0 10 20 30 40 50 60 70 80 90 100 Physical Functioning Role physical limitations Bodily pain General health Vitality Social functioning Role emotional Mental health SF-36score(0-100) Baseline U.S. normsa Koran et al., 1996 Mancebo et al., 2008 (OCD + disability)b Mancebo et al., 2008 (OCD no disability)b Baseline U.S. normsa Koran et al., 1996 Mancebo et al., 2008 (OCD + disability)b Mancebo et al., 2008 (OCD no disability)b
    25. 25. Mean change in SF-36 from baseline to end of double- blind period (OC, ANCOVA) -14 -12 -10 -8 -6 -4 -2 0 2 4 6 8 Physical Functioning Role-Physical Bodily Pain General Health Vitality Social Functioning Role- Emotional Mental Health PBO ESC * * * * * * * * * p<0.05 vs PBO, ** p<0.01 vs PBO, *** p<0.001 vs PBO
    26. 26. Does adding CBT improve outcomes?
    27. 27. Does adding CBT to SRI improve outcomes? Randomised Studies Three controlled studies suggest adding SRI to CBT improves outcome over CBT given alone. One controlled study suggests adding ERP to SSRI improves outcome over SSRI given alone (in partially SRI-resistant OCD). STUDY DURATION (weeks) OUTCOME COMMENTS Rachman et al (1979)27 3 CMI+EXP = CMI+REL CMI+EXP = PLAC+EXP OC scales No ITT Marks et al (1980)28 8 CMI+EXP > PLAC+EXP Rituals & depression No ITT Cottraux et al (1990)29 24 FLV+EXP > PLAC+EXP Rituals & depression No ITT Hohagen et al (1998)30 9 FLV+CBT > PLAC+CBT Multimodal CBT Foa et al (2005)31 12 CMI+ERP > CMI > PLAC No ERP control Tenneij et al (2006)32 52 SSRI+CBT > SSRI 12 wk SRI responders Simpson et al (2008)33 8 ERP+SSRI > stress Mx+SSRI After 12 wks SSRI: YBOCS>16 responder analysis
    28. 28. Cognitive-Behavioral Therapy vs Risperidone for Augmenting Serotonin Reuptake Inhibitors in OCD: A Randomized Clinical Trial Simpson HB et al, JAMA 2013.1932 Epub Change in Symptom Severity During Augmentation OCD of at least moderate severity despite a therapeutic SRI dose<= 12 wk. SSRI+Risperidone n = 40; SSRI+EX/RP n = 40; SSRI+ placebo n = 20. N=86 (86%) completed the trial. EX/RP= 17 twice-weekly 90-minute sessions, daily homework (at least 1 hour of self-directed exposures daily), and between session telephone check-ins.
    29. 29. How long to remain on treatment?
    30. 30. Definitions of relapse for OCD Relapse = Y-BOCS worsened by 25% by 50% by 100% by 5 points Y-BOCS > 20 CGI-I = 6 CGI-S worsened by 1 point Using different methodologies and criteria, relapse rates following drug discontinuation range from 24% over 28 weeks (Koran et al 2002) to 89% over 7 weeks (Pato et al 1988). (Pallanti et al 2002, Simpson et al 2006, Fineberg et al 2007)
    31. 31. Esc vs placebo:Time to relapse Fineberg et al. Eur Neuropsychopharmacol. 2007 ESC N=163; Relapses: 38 (23.5%) PBO N=157; Relapses: 81 (52.6%) Hazard ratio = 2.74 N=320 (ESC 163, PBO 157 ) Kaplan-Meier 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 0 28 56 84 112 140 168 Days ESC PBO Log-rank test: p < 0.001 *** Esc N=163: Relapses 38 (23.5%) PBO N=157: Relapses 81 (52.6%) Hazard ration = 2.74 Log rank test: P<0.001 ***
    32. 32. Double-blind studies of relapse prevention in OCD STUDY DRUG Duration prior drug treatment n in discont. phase Follow- up after discont. OUTCOME Romano et al (1998) fluoxetine 20 weeks 71 52 wks Relapse rate on plac = pooled fluox Relapse rate on plac > fluox 60mg Koran et al (2002) sertraline 52 weeks 223 28 wks Relapse rate on plac = sert Acute exacerb of OCD on plac > sert Dropout due to relapse on plac > sert b Geller et al (2003) paroxetine 16 weeks 193 16 wks Relapse rate on plac = parox Hollander et al (2003) paroxetine 12 weeks 105 36 wks Relapse rate on plac > parox Fineberg et al (2006) escitalopra m 16 weeks 322 24 wks Time to relapse on esc > plac Relapse rate on plac > esc b in children and adolescents
    33. 33. Meta-analysis of SSRI relapse prevention studies in adults with OCD Fineberg et al Int Clin Psychopharmacol 2007
    34. 34. Mean SF-36 scores at last assessment for relapsed (n=119) and non-relapsed (n=201) patients (relapse-prevention study). (Hollander E et al, J Clin Psychiatry, Jun;71(6):784-92. 2010.) p<0.05, **p<0.01, ***p<0.001 vs. placebo (ANCOVA) 0 10 20 30 40 50 60 70 80 90 100 Physical Functioning Role physical limitations Bodily pain General health Vitality Social functioning Role emotional Mental health Relapse Non-relapse SF-36score(0to100) ** ** ** ** ** ** ** * **p<0.001 * p<0.01 0 10 20 30 40 50 60 70 80 90 100 Physical Functioning Role physical limitations Bodily pain General health Vitality Social functioning Role emotional Mental health Relapse Non-relapse SF-36score(0to100) ** ** ** ** ** ** ** * **p<0.001 * p<0.01 SF-36score(0to100) ** ** ** ** ** ** ** * **p<0.001 * p<0.01
    35. 35. Sustained Response Versus Relapse: The Pharmacotherapeutic Goal For OCD. Fineberg NA et al Int Clin Psychopharmacol 2007 • ‘’OCD is a chronic disorder. On the basis of current evidence, long-term treatment with SSRIs is indicated to protect against relapse for most cases and treatment should not be discontinued. • Clinicians need to inform their patients about the risks of relapse, so that collaborative decisions about maintenance treatment can be agreed.’’
    36. 36. Definitions of treatment non-response and resistance Depends on dose and duration of treatment Non-response = <25% improvement in Y-BOCS (Pallanti et al 2002, Simpson et al 2006) Treatment-resistance = non-response to two trials of 12 weeks SRI at therapeutic dose (Fineberg et al 2007)
    37. 37. SRI-resistant OCD: Predictors of non-response Adults Children • Longer illness duration Comorbid ADHD • Early age of onset Comorbid tics • Chronic course Comorbid oppositional • Compulsive rituals defiant disorder • Comorbid tics Comorbid autism • Comorbid PD (OCPD) • Previous SRI treatment • Sub-clinical depression • Hoarding • Higher OFC activity and lower right caudate activity on PET (Rauch et al 2002, Saxena et al 2003) • Venlafaxine- response associated with S/L genotype of 5-HTTLPR polymorphism; Paroxetine- response with G/G genotype of 5-HT2A polymorphism (Denys D et al J Clin Psych 2007) Largescale prospective longitudinal studies of response- predictors
    38. 38. Comorbidity in UK refractory OCD; cross sectional survey of systematic data. N=25 Disorder n Disorder n TS 5 BPD 2 Tic disorder 5 Anorexia N 2 Aspergers 5 SAD 2 OCPD 3 Depression 2 Trich/skin picking 3 BDD 1 Bipolar AD 3 Schizotypal 1 Depersonalis ation 2 Alcohol dep 1
    39. 39. Do specific OCD symptoms predict treatment- response?
    40. 40. Symmetry/Hoarding predicts poor outcome to escitalopram. Stein D et al; CNS Spectr. 2008 Jun;13(6):492-8. • 466 OCD patients in an 12 week RCT of escitalopram. • Exploratory factor analysis of individual Y-BOCS items yielded 5 factors (contamination/cleaning, harm/checking, hoarding/symmetry, religious/sexual, and somatic/hypochondriacal). • Analyses of covariance for overall group demonstrated escitalopram more effective than placebo. • A significant interaction for “hoarding/symmetry” was associated with a poorer treatment response (p<0.001). • Hoarding/symmetry may characterise an early-onset group of OCD patients, with involvement of neurotransmitters other than serotonin. • Further work is needed to delineate of OCD subtypes and their underlying neurobiology and treatment responsivity.
    41. 41. SRI-resistant OCD: a pharmacological algorithm First-line treatment SSRI, maximal dose, 12 weeks Switch SSRI or clomipramine, maximal dose, 12 weeks Increase dose beyond formulary limits Add second generation antipsychotic Add haloperidol Combine clomipramine and SSRIs Intravenous SSRI or clomipramine Novel agents Review diagnosis
    42. 42. Switching SSRIs in OCD. • Delay switching until at least 12 weeks (March et al 1997) • 11-33% patients not responding to one SSRI show a clinically meaningful response to another, with declining likelihood of subsequent response to other agents (Fineberg et al 2006) • Two small open label studies suggesting benefit from a change to venlafaxine (Hollander et al 2002, 2003) and one to duloxetine (Dell Osso et al 2008) were counterbalanced by a double-blind study showing a significantly more favourable response for patients switched from venlafaxine to paroxetine (56%) than vice versa (19%) (Denys et al 2004).
    43. 43. SRI-resistant OCD: a pharmacological algorithm First-line treatment SSRI, maximal dose, 12 weeks Switch SSRI or clomipramine, maximal dose, 12 weeks Increase dose beyond formulary limits Add second generation antipsychotic Add haloperidol Combine clomipramine and SSRIs Intravenous SSRI or clomipramine Novel agents Review diagnosis
    44. 44. Randomised controlled studies in SRI-Resistant OCD Appear effective: Adding haloperidolb Adding risperidone Adding quetiapine Adding olanzapine Adding aripiprazole High dose sertraline Intravenous clomipraminea Apparently ineffective: Adding lithium, topiramate Adding buspirone Adding triiodothyronine (liothyronine) Adding desipramine Adding inositol Adding clonazepam Adding naltrexone Adding oxytocin a. Remains investigational in many countries b. Primarily in 'tic-related' OCD Class 1a
    45. 45. Higher-dose SSRI monotherapy for resistant OCD? Ninan et al J Clin Psych 2006 • 66 OCD non-responders to 16 weeks of sertraline, randomly assigned: • 12 weeks high-dose sertraline (250-400 mg/day, mean = 357mg, N = 30) showed significantly greater improvement than 200mg/day (N = 36) on YBOCS, NIMH Global OC Scale, CGI-I. • Responder rates not significantly different between groups, either on completer analysis ( 34% vs. 52%) or endpoint analysis (33% vs. 40%). • Both treatments showed similar adverse event rates. • Higher than labelled SSRI doses may be a treatment option for OCD patients who fail to respond to standard acute treatment.
    46. 46. SRI Usual Max Dose (mg/day) Occasionally Prescribed Max Dose (mg/day) citalopram 40 120 clomipramine 250 - escitalopram 20 60 fluoxetine 80 120 fluvoxamine 300 450 paroxetine 60 100 sertraline 200 400 American Psychiatric Association. (2007).Practice guideline for the treatment of patients with obsessive-compulsive disorder. Arlington (VA): Koran L et al; American Psychiatric Association (APA); 96 p.
    47. 47. High-dose SSRIs in OCD: a systematic retrospective case notes survey of 192 outpatients. Pampaloni I et al J Psychopharm. Epub. April 7th 2009 • 26 (13.5%) received high-dose SRI for 3–364 wks (mean 81.5 wks) • At the last assessment, high-dose SSRI showed sig. within-group improvements from baseline (Y-BOCS 25.4 vs. 21.0) • Endpoint scores for the high-dose group remained sig. higher than controls treated for a matched period (Y-BOCS 21.0 vs. 15.5), suggesting they showed enduring treatment-resistance. • Frequency of AEs (@50%) did not sig. differ between high and non- high dose groups. Severe AEs observed in one case with ASD. • Sustained high-dose SRI was associated with clinical improvement and was well-tolerated in a particularly refractory OCD sample. • AE monitoring advisable, with special care in comorbid cases.
    48. 48. Antipsychotics as monotherapy in OCD • Early open-label studies with first generation antipsychotics fail modern standards for clinical trial methodology (eg Trethowan and Scott 1955, Altschuler 1962, Hussein and Ahad 1970, O’Regan 1970, Rivers-Bulkeley and Hollender 1982) • Open-label clozapine was ineffective in 12 SRI- resistant cases (McDougle et al 1995b) • Open-label aripiprazole was ineffective in 7 cases including SRI- naive and resistant individuals (Connor et al 2005)
    49. 49. Antipsychotic augmentation of SRIs in resistant OCD Skapinakis P et al. Eur Neuropsychopharmacol 2007; 17: 79-93 haloperidol risperidone olanzapine quetiapine Favours control Favours treatment
    50. 50. 8-week, single-blind, randomized trial comparing risperidone (1-3mg) versus olanzapine (2.5-10mg) augmentation of serotonin reuptake inhibitors in treatment-resistant obsessive-compulsive disorder. Maina G et al. Eur Neuropsychopharmacol. 2008 May;18(5):364-72. • N = 50 • Significant within-group improvements in both groups • No differences between the two treatment groups • No differences emerged for the proportion of patients reporting at least one adverse event • Profiles of adverse experiences differed significantly; risperidone associated with amenorrhoea and olanzapine with weight gain.
    51. 51. Who is responsible for care? STEP 6 Inpatient care or intensive treatment programmes (national). STEP 5 Multidisciplinary teams with specific expertise in management of OCD (regional). STEP 4 local multidisciplinary care (GP or psychiatrist). STEP 3 GPs and primary care team, primary care mental health worker, family support team. STEP 2 GPs, practice nurses, school health advisors STEP 1 Individuals, public organisations, NHS STEPPED CARE MODEL
    52. 52. Does intensive CBT (ERP plus cognitive restructuring) improve severe, refractory OCD? A 24 week naturalistic study of 52 inpatients. Significant within-group differences between total Y-BOCS scores at admission, 12 weeks, and 24 weeks (ANOVA; P<.001). Follow-up comparisons between consecutive measurements demonstrated significant falls in total Y-BOCS scores from admission to 12 weeks (P<.001) and between the 12-week and 24-week assessments (P<.001).
    53. 53. SRI-resistant OCD: a pharmacological algorithm First-line treatment SSRI, maximal dose, 12 weeks Switch SSRI or clomipramine, maximal dose, 12 weeks Increase dose beyond formulary limits Add second generation antipsychotic Add haloperidol Combine clomipramine and SSRIs Intravenous SSRI or clomipramine Novel agents Review diagnosis
    54. 54. Intravenous SSRI / clomipramine? • Pulse loading with IV (but not oral) clomipramine produced an early and rapid decrease in symptoms but the advantage was not sustained (Koran et al 1997) • Two double blind trials supported the efficacy of IV clomipramine in resistant OCD (Fallon et al 1998, Koran et al 1997) • An open label study of IV citalopram hinted at efficacy (Pallanti et al 2002)
    55. 55. Combine clomipramine and SSRI? • Caution is required if clomipramine is combined with SSRIs that potentially interact at the hepatic microsomes. • Clomipramine plasma levels and ECG monitoring are usually recommended • Citalopram, escitalopram and to a lesser extent sertraline may be less likely to interact and therefore to be preferred. • An open label study of citalopram with clomipramine (Pallanti et al 1999) requires replication under controlled conditions.
    56. 56. SRI-resistant OCD: a pharmacological algorithm First-line treatment SSRI, maximal dose, 12 weeks Switch SSRI or clomipramine, maximal dose, 12 weeks Increase dose beyond formulary limits Add second generation antipsychotic Add haloperidol Combine clomipramine and SSRIs Intravenous SSRI or clomipramine Novel agents Review diagnosis
    57. 57. Compound Study Study design Outcome M O N O T H E R A P Y D-amphetamine (single dose) Insel et al 1983 Joffe et al 1991 Double blind RCT Double blindRCT D-amphet >placebo D-amphet >placebo; methylphenidate=pla c Buproprion Vulink et al 2005 Open-label bimodal; 8/11 worse Morphine Koran L et al (2005) Double-blind RCT Morphine > Placebo Naltrexone Keuler et al (1996) Amiaz R et al (2008) Double-blind RCT Double-blind RCT No effect No effect Ketamine (IV) (single dose) Bloch et al (2012) Rodriguez et al 2013 Open-label Double-blind RCT No responders at 3d Ketamine>plac et 7d Mirtazapine Koran LM et al 2005 Double-blind discontin MIR>placebo COMBINATIO N D-cycloserine & CBT Storch et al 2007 Kushner et al 2007 Wilhelm et al 2008 D-cyc + BT vs pla + BT NS NS NS AUGMENTATIO N OF SRI D-amphetamine + SSRI vs caffeine+SSRI Koran et al 2009 Double-blind RCT >50% Responders in both groups at 1 wk Topiramate + SSRI Berlin HA et al 2010 Double-blind RCT Compulsions sig, Total Y-BOCS NS Lamotrigine + SSRI Bruno et al (2012) Double-blind RCT Lamotrigine>placebo Memantine +SRI Haghigi et al 2013 Double – blind RCT Memantine>placebo N-acetyl cysteine Afshar et al, 2012 Double – blind RCT N-AC > placebo
    58. 58. Somatic treatments in highly refractory OCD. ECT: Insufficient evidence to recommend ECT for OCD, given potential associated risks (APA Practice Guidelines on OCD; Koran et al 2007) . rTMS: A systematic review of rTMS studies in OCD (1996 – 2010; Jaafari et al 2012) and a meta-analysis (Berlim et al 2013) suggest promising results in comparison to sham rTMS with target areas such as orbitofrontal cortex and supplementary motor area. Though promising, rTMS remains experimental. DBS: stimulating ventral striatum/ventral capsule or subthalamic nucleus may produce therapeutic effects by modulating the cortico-striatal neurocircuitry that is widely proposed to mediate OCD (Bourne et al 2012). Though promising, DBS remains experimental. Ablative neurosurgery; (ant. cingulotomy, ant. capsulotomy) remains the last resort for very severely ill patients who do not respond to expert delivered trials of pharmacotherapy and CBT of optimal dosage/content, duration, and mode of delivery as assessed by experienced experts in specialty treatments for OCD.
    59. 59. Neurosurgery for OCD: Inclusion criteria 1.Legal status: both patients detained under the mental health act and those who voluntarily seek treatment can be considered. 2.Confirmation of diagnosis: individuals will normally fulfill criteria for a primary diagnosis according to ICD-10 F42.0-F42.9. Individuals with treatment-refractory obsessional and/or compulsive symptoms in the presence of other comorbid mental disorder (e.g. depression, schizophrenia) can be considered for surgery but additional criteria for adequacy of treatment will be applied. 3.Duration of illness: an absolute minimum of 3 years, with at least 2 years of unremitting symptoms despite intensive psychopharmacological and psychological treatment. Only in exceptional circumstances would a duration of illness of <5 years be considered. 4.Consent: the patient must be considered capable of providing sustained, informed consent. 5.Age>20 years
    60. 60. Neurosurgery for OCD; Exclusion criteria 1.Age <20 years. 2.Failure to fulfill ICD-10 criteria for F42.0-F42.9. 3.Incapacity to give informed consent. 4.A current diagnosis of substance misuse fulfilling criteria for ICD-10 F10-F19, ‘Mental and behavioural disorders due to psychoactive substance use’. 5.A diagnosis of organic brain syndrome fulfilling criteria for ICD-10 F00-F09, including Alzheimer’s disease, vascular and other dementias. 6.A diagnosis of disorder of adult personality fulfilling criteria for ICD-10 F60-F69. 7.A diagnosis of pervasive developmental disorder fulfilling criteria for ICD-10 F84. 8.Absence of an adequate therapeutic trial of psychological treatment methods. 9.Absence of adequate therapeutic trials of psychopharmacological treatment methods.
    61. 61. Conclusions • Treatment effect on SSRI partial and dose and time dependent • Long-term SSRI protects against relapse • Combining SSRI + ERP may confer added benefit • Treatment resistance is poorly understood and may require specialised teams. • Developing role for antipsychotics • New, more highly effective treatments targeting core symptoms desirable
    62. 62. International College of Obsessive Compulsive Spectrum Disorders (ICOCS) Committee: J Menchon ( Chair) N. Fineberg ( Sec) M Figee E. Hollander C Ruck R Shavitt D. Stein J. Zohar www.ICOCS.org
    63. 63. Opiate agonist and antagonists in OCD • Morphine>placebo in a 2-week, randomised double-blind crossover study of once weekly oral morphine, lorazepam and placebo1 . • 2 randomised trials showed lack of efficacy or worsening on naltrexone 2,3, • 1 Koran L et al (2005) • 2 Keuler et al (1996) • 3 Amiaz R et al (2008)
    64. 64. N-methyl D-aspartate (NMDA)-receptors, glutamate and OCD Reviewed in: Pittenger C et al. NeuroRx. 2006 Jan;3(1):69-81). • NMDA receptors important for neurodevelopment, synaptic plasticity and excito-toxicity. • Postsynaptic NMDA receptors activated by glutamate only in presence of co-transmitters glycine, d-serine. • Elevated glutamate in caudate, and reduced glutamate in ACC on MRS in OCD (Rosenberg DR et al., 2004) • Abnormally high glutamatergic concentrations in children with OCD decreased in line with symptom severity during SSRI treatment (Rosenberg DR, et al. 2000). • Open-label case reports of improvement on riluzole (Coric V et al 2003, 2005, Swedo et al 2008), memantine (Pasquini &Biondi 2006, Poyurovsky et al 2005) and N-acetyl cysteine (la Fleur et al 2006) which act via glu-antagonism, and glycine (Greenberg et al 2009).
    65. 65. Differential Efficacy of Memantine for OCD vs. Generalized Anxiety Disorder: An Open-Label Trial. Feusner JD et al Psychopharmacol Bull. 2009;42(1):81-93 Method 10 OCD and 7 GAD subjects received 12 weeks open-label memantine 10 mg BD, as monotherapy or augmentation of existing medication. Results: At endpoint OCD - significant reduction in YBOCS (mean 40.6%, p < 0.001). 3/10 OCD subjects classified as responders, and 7 / 10 experienced a >/= 45% reduction in Y-BOCS. GAD - reduction in HARS scores (mean 22.4%, p = 0.012). No responders, and none experienced a >/= 50% reduction in HARS. Memantine was well tolerated, and there were no serious AEs Conclusions: Memantine may have preferential efficacy in OCD vs. GAD.
    66. 66. Does D-cycloserine improve CBT outcomes in OCD? Author n Duration (wk) design Outcome on D-cyc Storch et al 2007 24 12 weekly BT sessions D-cyc 250mg (+4h) + BT vs. plac + BT NS Kushner et al 2007 25 10 twice-weekly BT sessions D-cyc 125mg (+2h) + BT vs. plac + BT NS (at S4; sig improvement in distress) Wilhelm et al 2008 23 10 twice-weekly BT sessions D-cyc 100mg (+1h) + BT vs. plac +BT D-cyc>plac on Y- BOCS at S5 and on BDI at S10, but not at 1 month
    67. 67. Cognitive Enhancers – a role in OCD? D-Amphetamine : • Two placebo-controlled single-dose studies (n=12, n=11) showed improvement on CPRS-OCS. One study showed improvements on an attentional task. Methylphenidate: • A placebo controlled single-dose study (n=12)showed no effect on CPRS-OCS. • One case report of OCD worsening with methylphenidate treatment (but not with d-amphetamine). • Another report of emergence of OC symptoms in 3 cases. Modafinil: • 2 reports of cases : exacerbation of obsessions in 2 patients with SRI- responsive OCD; dose-related exacerbation of anxiety and improvement in an attentional task in one SRI-resistant OCD case (Insel TR, et al: Psychopharmacology (Berl) 1983; Joffe RT, et al: J Clin Psychopharmacol 1991; Woolley JB and Heyman I. Am J Psychiatry ,2003. Serby M. CNS Spectr. 2003; Kotsopoulos S, Spivak M. Can J Psychiatry 2001; Kouris S, J Am Acad Child Adolesc Psychiatry 1998, Tan et al Prim Care Companion J Clin Psychiatry 2008, Padhi et al Int J Psychiatry in Clinical Practice,
    68. 68. Conclusions • Treatment effect on SSRI partial and dose and time dependent • Long-term SSRI protects against relapse • Combining SSRI + ERP may confer added benefit • New, more highly effective treatments targeting core symptoms desirable
    69. 69. Daily Mail, 3rd April 2006 “Beckham said: 'I have got this obsessive compulsive disorder where I have to have everything in a straight line or everything has to be in pairs.' 'I'll put my Pepsi cans in the fridge and if there's one too many then I'll put it in another cupboard somewhere.’ Beckham reportedly spends hours straightening the furniture, apparently buys exactly 20 packets of Super Noodles on each visit to the supermarket and wears a new pair of football boots for every match. His wife Victoria, 31, has said: 'Everything has to match in the house. If there are three cans of Diet Pepsi, he'd throw one away because it's uneven.‘”
    70. 70. Common obsessions Common compulsions Fear of causing harm to someone Fear of self-harm Fear of behaving unacceptably Fear of contamination Fear of making a mistake Need for symmetry or exactness A. Behaviours Cleaning Hand washing Checking Asking for reassurance Ordering and arranging Hoarding B. Mental acts Counting Making mental lists Repeating words silently
    71. 71. Anxiety disorders – epidemiology (Wittchen & Jacoby, Eur Neuropsychopharmacol 2005) Diagnostic group 12-month estimate % (95% CI) Lifetime estimate % (95% CI) Any (without PTSD) 12.0 (11.1 – 13.0) 21.1 (20.5 – 21.6) Panic Disorder (+/- agoraphobia) 2.3 (1.9 – 2.8) 3.8 (3.1 – 4.5) Agoraphobia (without panic) 2.0 (1.7 – 2.5) 3.8 (3.1 – 4.5) GAD 1.5 (1.2 – 1.9) 5.1 (4.3 – 5.9) Social Anxiety Disorder 2.0 (1.6 – 2.5) 5.8 (5.1 – 6.5) Specific phobia 7.6 (6.9 – 8.5) 13.2 (12.8 – 13.6) OCD 0.7 (0.5 – 1.0) 0.8 (0.6 – 1.1) PTSD 1.2 (0.9 – 1.3) Not established
    72. 72. Age at onset of OCD Rasmussen SA et al J Clin Psych 1990 0 5 10 15 20 25 30 35 40 6y-9y 10y- 12y 13y- 15y 16y- 19y 20y- 24y 25y- 29y males females
    73. 73. Aetiology of OCD: cognitive theories (Beck A. Arch Gen Psych 2005): Biassed information processing leads to overestimation of threat (cognitive distortion). Danger-oriented cognitive schemas predispose individuals to narrow their attention to threat, make catastrophic interpretations of amibiguous stimuli and engage in dysfunctional ‘safety behaviours’ eg compulsions, avoidance – Irrational thoughts and beliefs inadequately challenged by OCD patients (Ellis, 1962) – Overinflated ideas of personal responsibility (Salkovskis, 1999) – Exaggerated danger expectancies (Menzies et al., 2000)
    74. 74. Thought- action fusion Rachman (1976) • Inflated sense of responsibility may derive from false assumptions about thoughts and actions, eg: - Having a thought about an action is equivalent to doing the action - Failing to prevent harm is the same as causing harm - Failing to neutralise an aggressive obsession is tantamount to wanting to harm others - One should control one’s thoughts • Supportive evidence: sense of responsibility predicted level of distress over obsessions (Scarabelotti et al 1995) and reducing responsibility lessened distress and urge to ritualise (Ladouceur et al 1995). • However, some question over the link between responsibility and OCD (Freeston et al 1993)
    75. 75. Aetiology of OCD: behavioural theories Marks I , 1969, Rachman and Hodgson 1980 – Obsessions are anxiogenic – Compulsions are anxiolytic – Anxiety is a re-inforcer Solomon R (1953): Dog + shock+ light anxiety escape Dog + light anxiety escape (ritual/avoidance) Dog + light anxiety no escape (ERP) extinction Victor Meyer (1966): Prolonged exposure and response prevention for OCD; 10/15 responded. Distress about intrusive cognitions appears linked to attempts to remove them ( Freeston M et al 1991)
    76. 76. Anxiety Time Anxiety rises Feeling ‘contaminated’ Anxiety reduces - only a little - not for long Ritualisation Behavioural Theories of OCD
    77. 77. Anxiety initially rises Breaking the cycle - self -imposed response prevention Anxiety eventually reduces - it falls higher than when ritualisation occurs Anxiety Time Behavioural Theories of OCD
    78. 78. DEFINITION OF CLINICAL RESPONSE DRUG [duration weeks] much or very much improved on CGI-I (Criterion A) >25% improved on baseline Y-BOCS (Criterion B) >35% improved on baseline Y-BOCS Criteria A & B STUDY Fluvoxamine [8] 9/21 Goodman et al (1989) Fluvoxamine [10] 33.3% Goodman et al (1996) Fluvoxamine CR [12] 34% from graph 63% 45% Hollander et al (2003) Fluvoxamine [10] 42% (CY-BOCS) Riddle et al (2001) Sertraline [12] 41% Kronig et al (1999) Sertraline [12] 38.9% Greist et al (1995a) Sertraline [12] 42% March et al (1998) Fluoxetine 20mg [8] 40mg [8] 60mg [8] 36% 48% 47% Montgomery et al 1993) Fluoxetine 20mg [13] 40mg [13] 60mg [13] 32% 34% 35% Tollefson et al (1994) Fluoxetine [13] 55% Geller et al (2001) Fluoxetine [16] 57% Leibowitz et al (2002) Paroxetine [12] Clomipramine [12] 55.1% 55.3% Zohar and Judge (1996) Citalopram 20mg[12] 40mg [12] 60mg [12] 57.4% 52% 65% Montgomery et al 2001) Escitalopram 20m[24] Paroxetine 40mg [24] 70.2% 67.2% Stein et al 2007 Rates of clinical response in placebo controlled studies of SSRIs for patients with OCD
    79. 79. Escitalopram 10mg, 20mg vs paroxetine 40mg and placebo: 24 weeks study. Stein DS et al Curr. Med. Res. and Opinion 2007 Double-blind treatmentBaseline Down- tapering Safety follow-up W eek 1 W eek 2 W eek 28 W eek 25 W eeks 3–24 Placebo Escitalopram 10 mg Escitalopram 20 mg Paroxetine 20 mg Paroxetine 30 mg Paroxetine 40 mg
    80. 80. Drug (duration, wk) Study n Dose (mg/day) [mean dose] Response criteria Response rate on active drug Placebo response rate Risperidone McDougle et al. (2000)47 36 1 titrated to 6 as tolerated [2.2] Marked=3 of a,c,e Partial=2 of a,c,e 4/18 (22%) 5/18 (28%) 0/15 (0%) Risperidone Hollander et al. (2003)48 16 0.5-3.0 b, d 4/10 (40%) 0/6 (0%) Risperidone Li et al. (2005)49 16 1 not defined not reported not reported Olanzapine Bystritsky et al. (2004)50 26 up to 20 [11.2] b 6/13 (46%) 0/13 (0%) Olanzapine Shapira et al. (2004)51 44 5-10 [6.1] not defined 5/22 (23%)a 9/22 (41%)b 4/22 (18%)a 9/22 (41%)b Quetiapine Denys et al. (2004)52 40 300 a, d 8/20 (40%) 2/20 (10%) Quetiapine Carey et al. (2005)53 41 300 b, d 8/20 (40%) 10/21 (47%) Quetiapine Fineberg et al. (2005)54 21 400 [215] b 3/11 (27%) 1/10 (10%) Quetiapine Kordon et al. (2008)55 40 400-600 a 6/20 (33%) 3/20 (15%) Quetiapine Vulink et al. (2009)56 76 300-450 a, d 22/39 (56%) 15/37 (41%) Aripiprazole Muscatello et al. (2011) 40 15 a, b 7 (35%), 11 (55%) 0/20 (0%) a ≥35% improvement in YBOCS; b ≥25% improvement in YBOCS; c Final YBOCS score <16; d CGI of “much improved” or “very much improved”; e consensus opinion of investigators
    81. 81. Open-label, high-dose escitalopram in resistant OCD Rabinowitz I et al., Int J Psychopharmacol 2008 • 67 patients received escitalopram 10-20 mg/day for 4 weeks, • 64 patients who did not achieve a > or =25% Y-BOCS reduction from baseline continued on higher doses of escitalopram (mean dose, 33.8 mg/day; maximum 50 mg/day) for 12 weeks. • At endpoint, high-dose escitalopram had significantly improved the OCD symptoms (Y-BOCS score) and all the other efficacy measures (P<0.001), compared with baseline. • Escitalopram was also well tolerated, with no discontinuations during the 12-week high-dose phase. The only reported adverse drug reactions were dry mouth (n=8, 12.1%) and decreased sexual desire (n=21, 31.8%). • Randomized, blinded studies are needed to reinforce these findings.
    82. 82. • JAMA Psychiatry. 2013 Nov 1;70(11):1190-9. doi: 10.1001/jamapsychiatry.2013.1932. • Cognitive-Behavioral Therapy vs Risperidone for Augmenting Serotonin Reuptake Inhibitors in Obsessive-Compulsive Disorder: A Randomized Clinical Trial. • Simpson HB, Foa EB, Liebowitz MR, Huppert JD, Cahill S, Maher MJ, McLean CP, Bender J Jr, Marcus SM, Williams MT, Weaver J, Vermes D, Van Meter PE,Rodriguez CI, Powers M, Pinto A, Imms P, Hahn CG, Campeas R. • Source • Department of Psychiatry, Columbia University, New York, New York2New York State Psychiatric Institute, New York, New York. • Abstract • IMPORTANCE Obsessive-compulsive disorder (OCD) is one of the world's most disabling illnesses according to the World Health Organization. Serotonin reuptake inhibitors (SRIs) are the only medications approved by the Food and Drug Administration to treat OCD, but few patients achieve minimal symptoms from an SRI alone. In such cases, practice guidelines recommend adding antipsychotics or cognitive-behavioral therapy consisting of exposure and ritual prevention (EX/RP). OBJECTIVE To compare the effects of these 2 SRI augmentation strategies vs pill placebo for the first time, to our knowledge, in adults with OCD. DESIGN, SETTING, AND PARTICIPANTS A randomized clinical trial (conducted January 2007-August 2012) at 2 academic outpatient research clinics that specialize in OCD and anxiety disorders. Patients (aged 18-70 years) were eligible if they had OCD of at least moderate severity despite a therapeutic SRI dose for at least 12 weeks prior to entry. Of 163 who were eligible, 100 were randomized (risperidone, n=40; EX/RP, n=40; and placebo, n=20), and 86            completed the trial. INTERVENTIONS While continuing their SRI at the same dose, patients were randomized to the addition of 8 weeks of risperidone (up to 4 mg/d), EX/RP (17 sessions delivered twice weekly), or pill placebo. Independent assessments were conducted every 4 weeks. MAIN OUTCOME AND MEASURE The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) to measure OCD severity. RESULTS Patients randomized to EX/RP had significantly greater reduction in week 8 Y-BOCS scores based on mixed-effects models (vs risperidone: mean [SE], -9.72 [1.38]; P&lt;.001 vs placebo: mean [SE], -10.10 [1.68]; P&lt;.001). Patients receivingrisperidone did        not significantly differ from those receiving placebo (mean [SE], -0.38 [1.72]; P=.83). More patients receiving    EX/RP responded (Y-BOCS score decrease ≥25%: 80% for EX/RP, 23% for risperidone, and 15% for placebo; P  &lt;.001). More patients receiving EX/RP achieved minimal symptoms (Y-BOCS score ≤12: 43% for EX/RP, 13%  for risperidone, and 5% for placebo; P=.001). Adding EX/RP was also superior torisperidone and placebo in    improving insight, functioning, and quality of life. CONCLUSIONS AND RELEVANCE Adding EX/RP to SRIs was superior to both risperidone and pill placebo. Patients with OCD receiving SRIs who continue to have clinically significant symptoms should be offered EX/RP before antipsychotics given its superior efficacy and less negative adverse effect profile. TRIAL REGISTRATION clinicaltrials.gov Identifier:
    83. 83. Antipsychotic augmentation for treatment resistant OCD : what if antipsychotic is discontinued? Maina G et al. Int Clin Psychopharmacol. 2003 Jan;18(1):23-8 • Retrospective chart review of 18 OCD patients who responded to addition of antipsychotic to SRI, and then discontinued antipsychotic. • Follow-up = 1 year. • 15 patients (83.3%) ‘relapsed’ after antipsychotic discontinuation, with a mean worsening of Y-BOCS of 6.6 +/- 1.7 points • 13 patients relapsed by week 8 after discontinuation. Two subjects relapsed at the end of the 1-year follow-up. • Conclusions: Initial evidence that antipsychotic may need to be maintained for patients who respond to this strategy because the majority who discontinue antipsychotic relapse within 2 months.
    84. 84. Does adding CBT to SRI protect against relapse after drug discontinuation?
    85. 85. No properly controlled, blinded studies Biondi et al (2005) - 10/20 SRI-responders non-randomly allocated CBT timed to end after SRI openly discontinued - Time to relapse sig longer for CBT+SRI (p<0.001) Simpson et al (2005) - Post-hoc survival analysis of acute-phase responders - CMI (N=13), CMI+ERP (N=15), ERP (N=18) placebo (N=2) - Following open discontinuation (wk12-24): [ERP and CMI+ERP] > CMI on proportion and time to relapse on some but not all relapse criteria
    86. 86. Defining OCD - ICD-10 A. Either obsessions or compulsions (or both) [present on most days for a period of at least two weeks B. Obsessions (thoughts, images or ideas) and compulsions share the following features, all of which must be present: • Acknowledged as originating in the mind of the individual • Repetitive and unpleasant; at least one recognised as excessive or unreasonable • At least one must be unsuccessfully resisted (although resistance may be minimal in some cases) • Carrying out the obsessive thought or compulsive act is not intrinsically pleasurable
    87. 87. Obsessive-compulsive disorders BDD TS OCD Affective disorders Autism Addiction Depressive disorders Anxiety disorders Trichotillomania Hypochondriasis ICDs PG Hollander et al. CNS Spectrums 2007;12:5–13 The obsessive compulsive spectrum

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