SEMINAR: TREATMENT RESISTANTOBSESSIVE COMPULSIVE DISORDER

INTRODUCTION-

Obsessive and Compulsive Disorder (OCD) is a

chronic and severely disabling condition characterized

by presence of obsessions and/or compulsions which

Are usually identified by the patient as ego-dystonic, are

time consuming and cause marked impairment of

patient’s psycho-social functioning.

Obsessions are persistent thoughts, impulses, or images that are experienced as intrusive and in-appropriate and that cause marked anxiety or distress.

Typical Obsessions include—

Aggressive obsessions, contamination obsessions, sexual obsessions, hoarding/saving obsessions, religious obsessions, somatic obsessions, obsession with need for symmetry or exactness.

INTRODUCTION-

INTRODUCTION-

Compulsion are repetitive behaviours the goal of which is to prevent or reduce anxiety or distress arising out of obsessions.

Typical compulsions include—

Cleaning/washing compulsions, checking compulsions, repeating rituals, counting compulsions, ordering/ arranging compulsions, hoarding/collecting compulsions.

DEFINING THE PROBLEM

STUDY LIFETIME

PREVALENCE

POINT PREVALENCE

ECA Study 2.5% 1.6%(6m)

NCS Study: 2.3% 1.2%(12m)

CNC Study 1.9-2.5% 1.1--1.8%

(12m)

PREVALENCE OF OCD

DEFINING THE PROBLEM

AGE- Peak onset 20 yrs , early

In males. 65% before 25 yrs &

85% before 35 yrs.

EARLY ONSET <8 YRSLATE ONSET >65 YRS

SEX- Ratio equalize with age

Children M>F

DEFINING THE PROBLEM

High economic burden.

40-60% Respond to SSRI.

30% are resistant to first-line treatment.

DEFINING TREATMENT RESISTANCE- Certain Terms described- (Goodman, 1999). Treatment Non-response- In a SRI trial less

than 25% improvement in YBOCS rating of OC symptoms severity has been considered as cut off for non-responders and failure to achieve this as treatment non-response.

Partial Response- In a SRI trial those achieving 25-35% improvement in YBOCS rating of OC symptoms severity has been considered as partial-responders and achievement of this much improvement as Partial Response.

Treatment Refractory- cases are those which

do not show any change (neither improve nor deteriorate) with all available therapies

DEFINING TREATMENT RESISTANCE-

In defining treatment resistance, there is less uniformity in setting criteria for adequate trial regarding number of SSRI trial, doses used, minimum duration of each trial (10-12 week), inclusion or exclusion of Clomipramine, behaviour therapy, etc. As a result we come across various definitions in literature and lack a single operationalised one.

DEFINITIONS

Failure of 2 SSRI trial for 12 weeks with 20 hrs ERP <25% Improve in (Y-BOCS) score (Jenike and Rauch, 1994).

35% or greater reduction in YBOCS score similar criteria for adequacy of trial (McDougle et al., 2000).

Failure to respond to at least 3 SSRIs , at the maximum recommended dosages for 12 weeks (Walsh and McDougle, 2004; Pallanti et al, 2004).

DEFINITIONS

Include Clomipramine and/or BT (ERP >20 hours )with 3 SRI to fail before labelling treatment resistant (Mishra et al., 2007).

A clinical trial (McDougle et al.1995) included: (1) failure to respond to SSRIs/ clomipramine, (2) a 4-week augmentation trial with a typical antipsychotic, and (3) a trial of adjunctive BT.

DEFINITION CRITERIA

STAGE I RECOVERY Less than 8 on YBOCS

STAGE II REMISSION Less than 16 on YBOCS

STAGE III FULL RESPONSE

35% > Reduction of YBOCS & CGI 1 OR 2

STAGE IV PARTIAL RESPONSE

>25% - <35% Reduction of YBOCS

STAGE V NONRESPONSE <25% Reduction of YBOCS & CGI 4

STAGE VI RELAPSE Symptom return after 3+ m 25% increase of YBOCS &CGI 6 above remission

STAGE VII REFRACTORY No change, no worsening with all available therapies

LEVELS OF NON RESPONSE

LEVELS OF

NONRESPONSE

DESCRIPTION

I SSRI OR CBT

II SSRI AND CBT

III 2 SSRIs tried and CBT

IV At least 3 SSRIs tried plus CBT

V At least 3 SRIs including Clomipramine tried plus CBT

LEVELS OF NONRESPONSE

DESCRIPTION

VI At least 3 SRIs including Clomipramine augmentation & CBT

VII At least 3 SRIs including Clomipramine tried plus CBT plus psycho-education and other classes of medication (BZD, MOOD STABILISERS, NEUROLEPTICS)

VIII At least 3 SRIs including IV Clomipramine plus CBT plus psycho-education

LEVELS OF

NONRESPONSE

DESCRIPTION

IX At least 3 SRIs including Clomipramine tried plus CBT plus psycho-education and other classes of antidepressants (NSRI, MAOI)

X All above treatment, Neurosurgery

NEUROBIOLOGY OF TREATMENT RESISTANCE-

NEURO-ANATOMY- abnormalities in the orbitofrontal cortex,

anterior cingulate cortex, and structures of the basal ganglia and thalamus.

NEURO-CHEMISTRY- A) serotonergic system (5HT Hypothesis) B) dopaminergic system C) dysregulation of glutamate

neurotransmission (RECENT)

NEUROBIOLOGY OF TREATMENT RESISTANCE-

GENETICS-Preliminary association with the NMDA

glutamate receptor subunit GRIN2B100.A negative association with a particular allele of

tGRIK2 kainate receptor gene.An association between diagnosis of OCD and

polymorphisms in the genes encoding the 5HT1Dß and 5HT2A receptor subtypes & the 5HT transporter.

positive association between polymorphisms in the gene coding for D4 dopamine receptor and OCD.

CAUSES FOR TREATMENT RESISTANCE

DIAGNOSTIC ISSUES

1. Major depression 2. Bipolar disorders 3.Panic disorder 4.Generalised anxiety disorder 5.Simple phobia & social phobia 6.Psychotic disorders 7. Organic mental disorders 8. Eating disorders 9. OCPD 10. Schizotypal disorder11. Tourette’s syndrome12.Trichotillomania 13. body dysmorphic disorder

SUBTYPES OF OCD

Certain varities show atypicalities in presentation, response and mode of treatment-

OCD with sexual and religious obsessions, obsessions

of symmetry and OCD with severe hoarding behaviour.Highly anxious obsessional subject .Post-partive onset of OCD. Late onset OCD Early onset OCD Acquired OCD OCD in Tourette’s syndrome OCD with co-morbid Bipolar illness

COMORBIDITY

1. Affective disorder bipolar or depressive 2. Other anxiety disorders 3. Organic mental disorders like seizure disorders and substance use disorders 4. Personality disorders5. Tics disorder 6. Co-morbid axisII diagnosis of borderline,

schizotypal and avoidant personality disorder ,OCPD 7. Co-existant neurological soft signs

INADEQUATE TRIAL

IMPROPER COMPLIANCE

PSYCHO-SOCIAL ISSUES

ASSESSMENT OF TREATMENT RESISTANCE-

YALE BROWN OBSESSIVE COMPULSIVE RATING SCALE-YBOCSMAUDSLEY OBSESSIONAL-COMPULSIVE INVENTORY-MOCILYNFIELD OBSESSIONAL-COMPULSIVE QUESTIONNARIES Leyton Obsessional Inventory PADUA INVENTORY

ASSESSMENT OF TREATMENTRESISTANCE-

OTHER SCALES- useful in evaluating OC symptoms are University of Hamburg Obsession-Compulsion

Inventory Screening Form Thought Control Questionnarie

Scales not measuring OC symptoms but widely used

for global assessment are- Clinical Global Improvement Scale (Guy, 1976), Health Related Quality of Life (Koran, 2000)

TREATMENT STRATEGIES-

1. Early screening for the illness by

Primary care physicians to identify early onset OCD.2. Considering a differential diagnosis if required.3. Maximising the effectiveness of the first trials

of either pharmacotherapy or behaviour therapy or both.4. Conducting a systematic search for and

identifying co-morbidities.5. Addressing the psychosocial issues.6. Better utilisation of the available non-drug

treatments (multimodal CBT, Intensive individual and/or group therapy.)

Basically there are 3 main modes of management

of treatment resistant OCD –

PHARMACO-THERAPYBEHAVIOUR THERAPY

EXPERIMENTAL MODES

PHARMACOTHERAPY

FIRST-LINE PHARMACOTHERAPY- Till date,5-HT theory of causation and pharmacotherapy

of OCD holds good and serotonin reuptake inhibitors

form the mainstay of treatment of OCD. Drugs found to

be useful in various trials compared against placebo are

Clomipramine and SSRIs namely Fluvoxamine,

Paroxetine,Fluoxetine, Sertraline and Citalopram and

Escitalopram.

DRUG DOSE EFFICACY CHANGE IN YBOCS

SIDE EFFECTS

CLOMIPRAMINE

250-300 mg/d

40-50% DIFF-8.2 Seizure,arrhythmia, orth. HypoTN,

FLUVOXAMINE

150-300 mg/d

30-40% 8.5/5.4 Nausea,headache, sleep disturbance

FLUOXETINE

20-80 mg/d

25-30% DIFF-1.6 Sexual dysfunction, insomnia, headache, tremors.

DRUG DOSE EFFICACY CHANGE IN YBOCS

SIDE EFFECTS

SERTRALINE

50-200 mg/d

Upto 400 mg

-- DIFF- 2.5 Sexual dysfuncn, insomnia, somnolence,

PAROXETINE

40-60 mg/d

-- 7.8/3.6 Sexual dysfunc, yawning, rhinitis, sleep disturb.

DRUG DOSE EFFICACY CHANGE IN YBOCS

SIDE EFFECTS

CITALOPRAM

40-60 mg/d

-- 10.4/5.6 Delayed ejaculation, SIADH, somnolence

ESCITALOPRAM

20-40 mg/d

-- -- Delayed ejaculn. somnolence, insomnia,

PARTIAL RESPONSE TO SSRI—40-60% of

patients do not respond adequately to SSRI

treatment alone .

STRATEGIES –

1)SWITCHING DRUG-Venlafaxine (225-300mg/d), Clomipramine

(125-225mg/d) were found effective in patients

who failed to 2 SSRI trials.42% non-responders benefit from cross over to

another antidepressant and Paroxetine was found

more efficacious than Venlafaxine.

2)AUGMENTATION STRATEGIESAugmentation means enhancement of activity or

efficacy of one drug by adding another drug (which is not known to be used in that particular disorder) simultaneously with it. This strategy is one of the main-stay of treating treatment resistant OCD. The various drugs used as augmenting agents are-

NEUROLEPTICSNON-NEUROLEPTICS

DRUG DOSE RESPONSE SIDE EFFECT

PIMOZIDE 6.5 mg/d 53% EPS

HALOPERIDOL

2-4 mg/d 65% TD & EPS.

TYPICAL ANTIPSYCHOTICS

DRUG DOSE RESPONSE SIDE EFFECT

RISPERIDONE

0.5-3 mg/d

50% Increased appetite, restlessness, sedation, ameno rrhoea,galactorrhoea.

OLANZAPINE

5-20 mg/d

46% Sedation, altered glucose tolerance & lipidprofile,weight gain

QUETIAPINE

100-400 mg/d

71% nausea, sedation, dizziness, and cataract.

ATYPICAL ANTIPSYCHOTICS

clozapine

No efficacy in augmenting SSRI in resistant OCD Induce or aggravate OC symptoms in psychotics

NON-NEUROLEPTICS

Augmenting

AgentDose Mechanism Side Effects

Clonazepam .5-2 mg TID

Up regulation of 5HT1 &5HT2 receptors

Depression, irritability, intoxication.

Lithium SLE-0.4-1.0 mEq/l.

Enhancement of 5HT transmission

Toxicity

Buspirone 30-60 mg/d

Partial 5HT1A receptor agonist

Irritability, forgetfulness

NON-NEUROLEPTICS

Augmenting

AgentDose Mechanism Side Effects

L-tryptophan

3-9g/d Amino-acid precursor of 5HT

Serotonin syndrome

Trazodon 50-100mg/d

5HT2A antagonist Sedation and priapism

Pindolol 2.5-5 mg TID

pre-synaptic 5HT1A and 5HT1B antagonist

major CVS side effects

NON-NEUROLEPTICS

OTHER AUGMENTING AGENTS like INOSITOL,

SUMATRIPTAN, CLONIDINE , PHENELZINE ,

GABAPENTINE and FENFLURAMINE have also been

tried.

COMBINATION STRATEGIES

Another effective strategy in treating treatment

resistant OCD is by combining two different groups

of anti-obsessional drugs to work in unison.

CLOMIPRAMINE WITH SSRI: CLOMIPRAMINE WITH MAOIVENLAFAXINE WITH SSRI

DRUGS DOSE MECHANISM LIMITATION

CLOMIPRAMINE & SSRI

75-150 mg/d

CMI

Enhanced inhibition of 5HT re-uptake.

Serotonin syndrome

CLOMIPRAMINE &MAOI

Low dose CMI

Enhancement of synaptic 5HT neurotransmission

serotonin syndrome

VENLAFAXINE & SSRI

200-300 mg/d VNF

inhibiting 5HT reuptake and enhancing serotonin transmission

Hypertension at higher doses.

ALTERNATIVE MONO-THERAPY

Other drugs used in treatment of resistant OCD used as monotherapy has fewer data to establish efficacy. However some of them are enumerated below—

VENLAFAXINE:RILUZOLE:

These 2 drugs have been established as alternate monotherapy in OCD.

Some other drugs tried are-Inositol,Tramadol hydrochloride,Mitrazapine,Aripprazole,Ondansetron,Nicotine,St. John’s wort .

BEHAVIOURAL INTERVENTIONS

BEHAVIOUR THERAPY

CATEGORIES

PURE OBSESSIONS

COMPULSIONS

INTERVENTIONS

Thought Stopping, Rubber-band Technique, Habituation Training,

Distraction Technique,

Paradoxical Intervention.

Exposure and Response Prevention (ERP) by prevention of compulsive un-doing behaviour.

COGNITIVE THERAPYCOGNITIVE THERAPY: is initiated with assessment

of the belief domains in OCD, which includes responsibility,

threat estimation, perfectionism, over-importance of thoughts,

control over thoughts and tolerance of ambiguity. Intrusive

thoughts are considered as stimuli, automatic negative thoughts

are identified and challenged to convert distressing thoughts to

non-distressing ones. The treatment is basically based on 3

cognitive models—

Model of Carr (Carr, 1974) Model of McFall (McFall and Wollersheim, 1979) Model of Salkovskis (Salkovskis, 1989) .

In combination with ERP, Cognitive therapy has 84%

success rate (Gail, 2002) as also effective in patients who

cannot tolerate anxiety when exposedto ERP.

Other newer techniques found effective in resistant OCD

Are—

Danger Ideation Reduction Therapy (DIRT) Acceptance and commitment therapy (ACT)

EXPERIMENTAL MODE OF TREATMENT

Newer research findings and techniques in fields of

treatment resistant OCD which are currently in

experimental level are to be implemented in suitable

cases with the view of future development in treating Treatment Resistant OCD.Some of them are —

Intrvenous SSRI (Clomipramine and Citalopram)Electroconvulsive Therapy (ECT) r TMSDeep brain stimulation (DBS)Vagal nerve stimulation (VNS) Psychosurgery

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