SEMINAR: TREATMENT RESISTANT OBSESSIVE 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 patients psycho-social functioning.

INTRODUCTION-

Obsessions are persistent thoughts, impulses, or

images that are experienced as intrusive and inappropriate 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-

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

PREVALENCE OF OCD
STUDY ECA Study NCS Study:
LIFETIME PREVALENCE POINT PREVALENCE

2.5% 2.3%

1.6%(6m) 1.2%(12m)

CNC Study

1.9-2.5%

1.1--1.8% (12m)

DEFINING THE PROBLEM

AGE- Peak onset 20 yrs , early

In males. 65% before 25 yrs & 85% before 35 yrs.

EARLY ONSET <8 YRS LATE 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 RESISTANCECertain 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
STAGE I RECOVERY

CRITERIA
Less than 8 on YBOCS
Less than 16 on YBOCS 35% > Reduction of YBOCS & CGI 1 OR 2 >25% - <35% Reduction of YBOCS <25% Reduction of YBOCS & CGI 4 Symptom return after 3+ m 25% increase of YBOCS &CGI 6 above remission No change, no worsening with all available therapies

STAGE II REMISSION STAGE III FULL RESPONSE STAGE IV PARTIAL RESPONSE STAGE V NONRESPONSE STAGE VI RELAPSE

STAGE VII REFRACTORY

LEVELS OF NON RESPONSE

LEVELS OF NONRESPONSE I II III IV V

DESCRIPTION

SSRI OR CBT SSRI AND CBT 2 SSRIs tried and CBT At least 3 SSRIs tried plus CBT At least 3 SRIs including Clomipramine tried plus CBT

LEVELS OF NONRESPONSE VI

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

VII

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)

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-CHEMISTRYA) serotonergic system (5HT Hypothesis) B) dopaminergic system C) dysregulation of glutamate

neurotransmission (RECENT)

NEUROBIOLOGY OF TREATMENT RESISTANCEGENETICS 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 5HT1D 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

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 disorder

ISSUES

11. Tourettes syndrome

12.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 Tourettes 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 disorders 5. 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-YBOCS MAUDSLEY OBSESSIONAL-COMPULSIVE INVENTORY-MOCI LYNFIELD OBSESSIONAL-COMPULSIVE QUESTIONNARIES Leyton Obsessional Inventory PADUA INVENTORY

ASSESSMENT OF TREATMENT RESISTANCEOTHER 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 STRATEGIES1. 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-THERAPY BEHAVIOUR THERAPY EXPERIMENTAL MODES

PHARMACOTHERAPY

FIRST-LINE PHARMACOTHERAPYTill 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 SIDE IN EFFECTS YBOCS

DIFF-8.2 Seizure,arrhy thmia, orth. HypoTN, Nausea,he adache, sleep disturbance Sexual dysfunction, insomnia, headache,

CLOMIPRA 250-300 MINE mg/d

40-50%

FLUVOXA MINE

150-300 mg/d

30-40%

8.5/5.4

FLUOXETI NE

20-80 mg/d

25-30%

DIFF-1.6

DRUG

DOSE

EFFICACY

CHANGE SIDE IN EFFECTS YBOCS DIFF- 2.5 Sexual dysfuncn, insomnia, somnolen ce, 7.8/3.6 Sexual dysfunc, yawning, rhinitis, sleep disturb.

SERTRAL 50-200 INE mg/d Upto 400 mg PAROXE TINE 40-60 mg/d

--

--

DRUG

DOSE

EFFICACY

CHANGE SIDE IN EFFECTS YBOCS

CITALOP 40-60 RAM mg/d

--

10.4/5.6

ESCITAL OPRAM

20-40 mg/d

--

--

Delayed ejaculatio n, SIADH, somnolen ce Delayed ejaculn. somnolen ce, insomnia,

PARTIAL RESPONSE TO SSRI40-60% of patients do not respond adequately to SSRI treatment alone .

STRATEGIES 1)SWITCHING DRUGVenlafaxine (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 STRATEGIES
Augmentation 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-

NEUROLEPTICS

NON-NEUROLEPTICS

TYPICAL ANTIPSYCHOTICS
DRUG DOSE RESPONSE SIDE EFFECT 53% EPS

PIMOZIDE 6.5 mg/d

HALOPERI 2-4 mg/d DOL

65%

TD & EPS.

ATYPICAL ANTIPSYCHOTICS
DRUG DOSE RESPONSE SIDE EFFECT 50%
Increased appetite, restlessness, sedation, ameno rrhoea,galactorrhoea. Sedation, altered glucose tolerance & lipidprofile,weight gain nausea, sedation, dizziness, and cataract.

RISPERIDO 0.5-3 NE mg/d

OLANZAPI NE

5-20 mg/d

46%

QUETIAPIN 100-400 E mg/d

71%

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

NON-NEUROLEPTICS
Augmenting Agent

Dose
.5-2 mg TID

Mechanism
Up regulation of 5HT1 &5HT2 receptors

Side Effects
Depression, irritability, intoxication.

Clonazepam

Lithium

SLEEnhancement of Toxicity 0.4-1.0 5HT transmission mEq/l. 30-60 mg/d Partial 5HT1A receptor agonist Irritability, forgetfulness

Buspirone

NON-NEUROLEPTICS
Augmenting Dose Agent

Mechanism

Side Effects

Ltryptophan Trazodon

3-9g/d

Amino-acid precursor of 5HT

Serotonin syndrome Sedation and priapism

major CVS side effects

505HT2A antagonist 100mg/ d

2.5-5 pre-synaptic mg TID 5HT1A and 5HT1B antagonist

Pindolol

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 MAOI VENLAFAXINE WITH SSRI

DRUGS CLOMIPRA MINE & SSRI CLOMIPRA MINE &MAOI VENLAFAXI NE & SSRI

DOSE MECHANISM 75150 mg/d CMI Low dose CMI 200300 mg/d VNF Enhanced inhibition of 5HT re-uptake.

LIMITATION Serotonin syndrome

Enhancement of serotonin synaptic 5HT syndrome neurotransmission inhibiting 5HT reuptake and enhancing serotonin 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. Johns wort .

BEHAVIOURAL INTERVENTIONS

BEHAVIOUR THERAPY
CATEGORI PURE ES OBSESSIONS INTERVEN Thought Stopping, TIONS Rubber-band Technique, Habituation Training, Distraction Technique, Paradoxical Intervention. COMPULSIONS

Exposure and Response Prevention (ERP) by prevention of compulsive undoing behaviour.

COGNITIVE THERAPY
COGNITIVE 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 Salkovskis (Salkovskis, 1989) .

Model of McFall (McFall and Wollersheim, 1979

 In combination with ERP, Cognitive therapy has 84%

success rate (Gail, 2002) as also effective in patients wh 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 TMS Deep brain stimulation (DBS) Vagal nerve stimulation (VNS) Psychosurgery

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