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TREATMENT

RESISTANT
OCD
Chairperson: Dr. P. John Mathai
Presenter: Dr. Wilona

Introduction
Common & disabling mental disorder
Twice as common as schizophrenia &
bipolar disorder
Largely underdiagnosed
Inadequately treated
Presents for the 1st time in
adolescence

Introduction
Considerable progress in
understanding & treatment
SSRIs & CBT
Still 40 60% pts do not show
satisfactory improvement
Only 10% cases show complete
remission

Adequacy of treatment

Patient should be treated with:


Adequate dosages
Appropriate treatment
Adequate duration
Compliant with the treatment
Adequate trial of an SSRI: at least
10-12 weeks of treatment with at least
46 weeks at the highest comfortably
tolerated dosage

Optimum dosages used in OCD


Drug used

Dosage usual mg/ day

Dosage maximum mg/day

Citalopram

40 80

120

Clomipramine

100 250

250

Escitalopram

20 40

60

Fluoxetine

40 80

120

Fluvoxamine

200 300

450

Paroxetine

40 60

100

Sertraline

50 200

400

CBT
Only other evidence based treatment
Cognitive Behaviour Therapy
CBT trial before adding other drugs
No clear consensus
Minimum of 12 weekly sessions
incorporating:
- Psychoeducation about anxiety and
OCD and
- Exposure & response prevention

CBT
CBT experts
1320 sessions of weekly outpatient
CBT with daily homework or
Weekday daily CBT for 3 weeks
About 50 hours, half therapist
guided, half homework
Adequate dose

Response
Acute phase treatment of OCD: response as a
decrease of more than 25% or 35% of the
YBOCS score
AND
a CGI-I score of 1 (very much improved)
or 2 (much improved)
More emphasis on functional improvement
Total score < 16

What is treatment resistant


OCD?
Defined operationally by different
investigators
Various synonomous terms: treatment
resistant, treatment refractory and non
responders
Resistance defined using:
- Yale Brown Obsessive Compulsive Symptom
Severity Scale (YBOCS) and
- Clinical Global Impression Severity &
Improvement scales (CGI-S & CGI- I)

Treatment resistant OCD


Failure to respond to one adequate
SSRI trial.
Failure to respond to at least 2 adequate
SRIs used consecutively
Failure to respond to 2 SRIs one of which
should be clomipramine or a
combination of SSRI with clomipramine
with/ without behaviour therapy

Treatment resistant OCD


Pallanti et al in 2002
Non response: less than 25%
reduction in the YBOCs score and a
CGI-I of 4 i.e. no change or more.
Refractory OCD is defined as failure
to respond to all available treatments.

Treatment resistant OCD


Shetti et al (2005)
Study of the predictors of non
response in OCD
Non-responders as patients who
failed to show a CGI-I score of 1 or 2
after adequate trials of SSRIs.
Hollander et al (2002) treatment
refractory.

Treatment resistant OCD


Krebs et al (2009)
Treatment refractory OCD
Failure to respond to trials of two or more
SSRIs
Failure to respond to two or more
adequate courses of CBT.
Treatment resistance was defined as
inadequate response to the same
treatment

Predictors of poor response


to pharmacotherapy

Early age at onset


Longer duration of OCD
Presence of sexual obsession
Presence of washing compulsions
Hoarding
Poor insight
Prior treatment with medications
Personality disorders: borderline, avoidant & OCPD
Psychotic disorders
Neurological disorders: Tic disorders

Predictors of poor response


to behaviour therapy
Concomitant depression
Use of central nervous system depressants, which may
inhibit the ability to habituate to anxiety
Lack of insight
Poor compliance with homework, resulting in
inadequate exposure
Poor compliance on the part of the therapist in enforcing
the behavioral paradigm
Personality disorders: borderline, avoidant & OCPD
Psychotic disorders
Neurological disorders: Tic disorders

Initial treatment: unsatisfactory


Problems in the therapeutic alliance;
Interference by co-occurring conditions
inadequate patient adherence to treatment
Presence of psychosocial stressors
Level of family members accommodation
to the OC symptoms
Inability to tolerate an adequate trial of
psychotherapy or the maximum
recommended drug doses

Management
Review:
Diagnosis
Treatment
Compliance: both with
pharmacotherapy and psychotherapy

Reviewing diagnosis
Co-morbid psychiatric conditions:
-

Major depression
Bipolar disorder
Panic disorder
Social phobia
Schizophrenia
Substance use disorders
Autism & Aspergers syndrome
Personality disorders

Reviewing diagnosis

Neurological disorders:
Chronic motor tics
Tourettes disorder
Brain trauma
Stroke
Encephalitis
Temporal lobe epilepsy
Prader-Willi syndrome
Sydenhams chorea
Poisoning CO & Mn
Neurodegenerative diseases such as Parkinsons disease
and Huntingtons disease

Reviewing diagnosis
Rule out general medical conditions:
Investigations
- Routine blood tests: CBC, LFT, RFT,
TFT
- ECG
- EEG
- Neuroimaging

Reviewing diagnosis

Psychosocial co-morbidities:
Family dysfunction
Stressful events
Negative family interactions
High levels of expressed emotions
Predictive of poorer response
May exacerbate residual OCD symptoms
May trigger a relapse in those who have
already achieved remission

Reviewing treatment
Based on definition of adequate trial
of medications and CBT
Treatment of co-morbidities

Reviewing compliance

Patient compliance:
Medications
CBT
Follow ups
Therapist compliance

Therapeutic approaches

High dose SSRI therapy


Switching
Augmentation
Combination
Other strategies

High dose SSRI therapy


Available trial data suggest that
higher SSRI doses produce a
somewhat higher response rate and
somewhat greater magnitude of
symptom relief
Nonresponders: raising the dose
associated with enhanced response

High dose SSRI therapy


A multi centre double blind study showed
that high dose sertraline (250 400
mg/day) was more effective than
continuation with the same drug
Pts showed greater symptomatic
improvement rather than a fall in the
YBOCS scores
Also noted to be effective in citalopram
Best considered in selected patients in
specialized centres

Switching strategies
Switching to another SSRI:
For patients who do not respond to their first SRI
Evidence does not allow one to predict the
patients chance of response to the new SRI
Clinical experience suggests that response rates
to a second SRI trial are close to 50%
Recommended that switching to another SSRI is
a potentially effective strategy that must be tried
in all cases

Switching strategies
Switching from an SSRI to Clomipramine:
Consistently found to be superior to other SSRIs in
meta-analytical studies both in adults as well as
children.
Studies comparing clomipramine to newer drugs
have found it to have comparable efficacy
Associated with more adverse effects.
APA guidelines recommend switching over to
clomipramine if patients do not respond to
their first trial of an SSRI.

Augmentation strategies
Preferred in patients who have had a
partial response to the initial treatment
Modest evidence supports augmentation
of SRIs with antipsychotic medications or
other SRIs
Response rates in the range of 40% to 55%
Best evidence base is available for
risperidone and it should be the first
drug of choice for augmentation.

Augmentations strategies
Augmentation with SRIs
Should be done with less than optimal dose
of the medication
Patients with inadequate response to
clomipramine showed improvement when 50
mg/day of sertraline was added rather than
when clomipramine was increased
Also pts had fewer side-effects
Clomipramine at low doses (25 50 mg/
day) when added to ongoing treatment with
fluoxetine was found to be effective

Augmentation strategies
Augmentation with Venlafaxine
Open trial study
Venlafaxine was effective in 76% of nonresponders to SSRI treatment
Comparision studies with paroxetine and
clomipramine: equally efficacious but not
superior to either
Better side effect profile as compared with
clomipramine.

Augmentation strategies
Augmentation with Mirtazepine:
Supported by one open pilot study and a
double-blind discontinuation trial
Open label study: 53.3% of patients were
responders to a 12 week trial of
mirtazepine (30- 60 mg/day)
Continuation phase data also showed
improvement
Sufficient data to support its use in
treatment resistant cases is lacking.

Augmentation strategies
Other antidepressants:
MAOIs:
Weak evidence for use in OCD
Phenelzine: 60 mg/day
Predictor: symmetry obsessions & strong
anxiety symptoms
TCAs
- Limited investigations
- No efficacy

Augmentation strategies

Other antidepressants:
Trazodone:
Found to be effective
Dose: 300 600 mg/day
Alleviates anxiety, sleep disturbance

Augmentation strategies

Drugs tried but with insufficient evidence to


support their routine use:
-

Nicotine
Carbamazepine
Lamotrigine
Gabapentin
Reboxetine
N-acetyl cysteine
D-amphetamine
Ondansetron

- Lithium
- Buspirone

Augmentation strategies

Drugs that have been found to be ineffective and


should not be used:
- Fenfluramine
- Inositol
- Thyroid hormone
- Older nor-adrenergic antidepressants
- L-tryptophan
- St. Johns wort
- Bupropion

Augmentation strategies
Many questions remain unanswered,
including:
- the optimal dose for each drug
- long-term tolerability
- when and how to discontinue treatment
- the drugs relative augmentation efficacy
- the reasons that only some patients
benefit.

Augmentation strategies
Most augmentation trials are short term
trials lasting a maximum of 8 weeks.
If the desired response has not been
produced by the augmenting agent by 6
8 weeks, it is preferable to discontinue it
and proceed to another treatment
approach.
Once a patient has responded, it is not
clear how long augmentation should be
continued.

Augmentation strategies
Chart review study found that
discontinuing successful augmentation
after 112 months resulted in relapse for
more than 80% (15/18) of patients, most
within 2 months of discontinuation.
Maina et al: augmentation treatment
should be continued as long as the SSRI
treatment to prevent relapse

Combination strategies
SSRI & Clomipramine:
Two case series, RCT & several open
label trials
Combination should use optimal
doses of both the drugs used for
treatment

Combination strategies
Results of the RCT showed that
combination therapy with
clomipramine was superior to
monotherapy or switching strategies.
Care must be taken to avoid
precipitating the serotonin syndrome
and doses should be titrated carefully
with appropriate monitoring
Risk of precipitating seizures

Combination strategies
SSRI & behaviour therapy:
CBT and SSRIs are of comparable efficacy
in treating OCD
Multicentre RCT, patients treated with a
combination of ERP & clomipramine
showed a better response as compared to
clomipramine alone
Combined therapy may be superior to
medication alone in medication nonresponders.

Combination strategies
Useful as an add on therapy in patients who
show partial response to medications.
Another multicentre study suggested that the
combination of CBT with medication yielded a
higher response rate and decreased obsessions
more effectively than CBT alone
Sustained efficacy even upto 5 yrs
Wise to choose combination therapy as an
effective approach in patients who fail to
respond to either form of monotherapy.

Other strategies
Intravenous clomipramine
Residential treatment
Family therapy
Psychodynamic psychotherapy
Psychosurgery
Repetitive transcranial magnetic
stimulation
Deep brain stimulation
Electroconvulsive therapy

Intravenous clomipramine
Administer clomipramine intravenously
Higher immediate plasma levels by avoiding
first-pass liver metabolism
Placebo controlled trial: non-responders to oral
clomipramine
IV clomipramine: 14 consecutive infusions at
doses of upto 250 mg/day
Associated with a response rate of 43%.
Potential cardiac and neurological side effects
require close monitoring
Plasma concentration should be kept below 500
ng/ml to avoid toxicity

Residential treatment
Intensive residential therapy/ IRT
Involves inpatient or day care therapy by a
multidisciplinary team.
Includes pharmacotherapy, daily CBT (2-4
hrs), group therapy
Specifically developed for management of
treatment refractory OCD pts
Promising treatment option

Residential treatment
A recent study from a specialised IRT unit
in Massachusets which used the YBOCS
as one of its outcome measures, found that
IRT administered over a period of 3
months produced a mean fall in YBOCS
scores of 30% in a largely treatment
refractory sample.

Residential treatment
Predictors of good response include:
female gender
better psychological adjustment
lower baseline OCD severity
absence of tic disorders
IRT appears to be a safe, tolerable and efficacious
method
Should be considered in patients where other
strategies have failed.
Expertise required for successful IRT may not be
readily available which limits its applicablility

Family therapy
Family factors often play a role in the
management of OCD
Expressed emotions from care givers
Family accommodation to compulsive
rituals
Negative impact on treatment outcome
Families can be involved in the therapeutic
process as co therapists

Family therapy
Available evidence suggests that the
efficacy of behavioural and group oriented
family approaches is good
May be effective in treatment refractory
patients
Should be addressed as they may impede
response to other treatments.

Psychodynamic psychotherapy
Indicated in patients with co-morbid personality
disorders: OCPD
Helped by a more psychoanalytically oriented
approach
Salzman ( 1983 ) and MacKinnon and Michels
( 1971 )
Encouraged to take risks and
Learn to feel comfortable with, or at least less
anxious about making mistakes and
To accept anxiety as a natural and normal part of
human experience

Psychosurgery

Selectively and judiciously applied


Safe and effective
Stereotactical techniques
4 specific procedures:
Anterior capsulotomy
Anterior cingulotomy
Sub-caudate tractotomy
Limbic leucotomy
Gamma knife capsulotomy

Psychosurgery
Patient selection criteria:
Diagnosis of OCD by standard criteria
Severe OCD causing significant suffering
and marked impairment of psychosocial
function
Long standing illness
Prior trials of all effective drug treatments
Adequate trial of behaviour therapy
Symptomatic improvement of less than
25% in YBOCS following treatment

Psychosurgery
Contra-indications:
Organic mental disorders
Age <18 or >65yrs
Certain axis I comorbid disorders such as
psychosis, severe bipolar disorder,
personality disorders, substance use
disorders
Presence of brain pathology that would
contraindicate surgery

Psychosurgery
Adverse effects following surgery include:
Post operative delirium
Fatigue
Weight gain
Seizures
Headache
Urinary incontinence
Cognitive deficits
Cerebral hemorhage
Personality changes of the frontal lobe type
Suicide

Psychosurgery
Response:
A recent published study used B/L
anterior cingulotomy
Found a response rate of 43% with no
enduring cognitive or other deficits
Long term outcome has also been
examined with response rates of 28% after
26 months and 32% after 32 months in
patients who underwent cingulotomy

Repetitive transcranial
magnetic stimulation

rTMS: non invasive method of stimulating the


cerebral cortex using a pulsed magnetic field
Based on functional neuroimaging evidence of
frontal hyperactivity in untreated OCD patients
rTMS to the right prefrontal cortex of patients
with OCD
Greenberg et al : significantly reduced symptoms
in 12 OCD pts.
Only one trial found evidence of efficacy
Larger studies are needed to answer this
question definitively

Deep brain stimulation


Targets for DBS include:
Anterior capsule
Nucleus accumbens
Caudate nucleus
Subthalamic nucleus
Evidence from case reports & case series
May be beneficial in the acute phase in
some but not all patients

Deep brain stimulation


Response rates were between 25% to 66%
Well tolerated by subjects
S/E: weight gain, nausea, diarrhoea and
throbbing or tingling sensations
Potentially reversible
Benefits appear to be sustained in the long
run
Demonstrated in a 3 yr follow up of 8 pts
where a response rate of 50 % was noted.

Deep brain stimulation


The latest study in this field examined 12
pts with treatment refractory OCD and
found that 8 of them had a fall of 35% or
greater on the YBOCS score.
High cost
Inaccessible to majority of the patients

Electroconvulsive Therapy
Case series and several individual cases:
effectiveness
Frequent Axis I comorbidity among
subjects
Lack of standard outcome measures
Absence of blinded trials
Need for repeated anesthesia
Side effects of ECT

Electroconvulsive Therapy
Evidence limited to a single case
series
Using a nonstandard form of ECT
ECT cannot be recommended for the
treatment of OCD
May be considered for treating cooccurring conditions

Treatment in children
Treatment: CBT or CBT + SRI
ERP efficacious in children (45% response)
Three SSRIs and clomipramine are FDAapproved
Caution and frequent clinical monitoring:
advisable
Increase in suicidal thinking or behaviors
Using SRIs may be necessary and should
not be avoided

Treatment in elderly
No studies published
Lower starting doses of medication
More gradual approach to dose increases
Older patients: more sensitive to adverse
drug effects
More likely to be taking medications for
general medical conditions

Conclusions
Single most challenging problem facing
clinicians treating OCD
First line treatments effective but majority
patients show inadequate response
Various modalities of treatment are
available further research about their
effectiveness is required
Research into predictors of response to
treatment may yield new approaches in
the management

Future directions
Efficacy of venlafaxine &
mirtazepine?
Novel augmentation strategies?
Neurosurgery: controlled trials?

THANK
YOU