current pharmacological treatments for obsessive-compulsive disorder

251Essent Psychopharmacol 5:4, 2004

Current Pharmacological Treatments for

Obsessive-Compulsive DisorderAlexander Bystritsky, MD

Dr. Bystritsky is Professor of Psychiatry and Biobehavioral Sciences and Director of Anxiety and Treatment-resistant OCD Program, Neuropsychiatric Institute,

David Geffen School of Medicine, University of California, Los Angeles.

Introduction

Obsessive-Compulsive Disorder (OCD) is a severe, chronic condition that affects 2% to 3% of theUnited States population, or 4 million to 7 million people.

1The illness is characterized by recur-

rent thoughts, images, feelings, or behaviors that persist against the patient’s wishes to suppressthem and are usually accompanied by marked anxiety. These symptoms are often associated withmarked impairment of function.

2OCD affects people regardless their cultural background or

socio-economic status.3

OCD was listed as the tenth leading cause of disability worldwide by arecent World Health Organization study. The total cost of the disorder in the US is estimated to bemore than $8 billion.

4OCD is a treatable condition with 50% to 60% of patients responding to

first line of treatment, which includes pharmacological and/or psychological intervention.5,6

How-ever, about one-third of the patients improve only partially, and roughly 20% do not respond toconventional treatment strategies.

7The situation is complicated by the fact that many health pro-

fessionals are not educated about the appropriate treatments that can be offered to OCDpatients.

8

This review summarizes the available literature on the pharmacological treatments of OCD.We discuss the factors affecting the treatment choices for this disorder. We discuss tolerability, sideeffects, dosing, and the safety of medications used in the treatment of OCD. In addition, manage-ment of partial response to medications is reviewed, and the available interventions for refractoryOCD are considered. Finally, while we will not be reviewing extensively the psychological treat-ments of OCD, we will discuss the interplay between the therapeutic and pharmacological inter-ventions that can be used to maximize the treatment.

The Expert Consensus Guidelines on the treatment of obsessive-compulsive disorder, pub-lished in 1997, provided the first guidance for clinicians on the management of this often-vexingcondition.

9Several recent reviews are available on the subject of the treatment of OCD.

10,11Our

review focuses on a practical approach to the treatment of OCD with front-line medications and

F E A T U R E A R T I C L E

psychotherapeutic interventions as well astreatment of resistant cases.

Factors Affecting Treatment

The decision to administer treatment for a par-ticular patient usually requires the clinician toanalyze multiple factors. These include thepresence of a diagnosis of OCD or OCD Spec-trum disorders and comorbid conditions,interplay of biological, genetic, and psycholog-ical factors, and the stage of the disorder. Theclinician also has to balance available data,from experience and literature, on efficacy,pharmacodynamics, and side effects of particu-lar medications. If several medications areused, drug interactions need to be considered.

Diagnosis and Assessment:

Diagnosis of OCD frequently presents diffi-culty. DSM IV calls for the presence of recur-rent and persistent thoughts, images, orimpulses that are perceived by a person astheir own and that are causing anxiety or dis-tress (obsessions) and actions or rituals aimedat reducing the anxiety (compulsions) (Table1).

12In fact, the OCD picture can be far more

complex with mental rituals, reassurances,avoidances, and covert behaviors, which donot easily fit into the category of obsessions orcompulsions. OCD is one of the most complexmental illnesses. If we consider the main assess-ment tool for OCD, the Yale Brown ObsessiveCompulsive Scale (Y-BOCS),

13and specifically

the Y-BOCS Checklist, which lists most of knownobsessions and compulsions, we find that itconsists of more than 60 different types ofsymptoms. There have been attempts to clusterthese symptoms together.

14,15 Principal compo-

nent analysis has revealed an existence of fivemain types of OCD.

15They include:

• violent/aggressive

• images/checkers

• contamination fears/washers

• symmetry and exactness/arrangers

• hoarders/savers.

However, some of the patients’ presenta-tions do not fit into these clusters. Diagnosiscan be even more complicated due to the exis-tence of OCD Spectrum disorders or disordersthat mimic OCD, in that the main presenta-tion of these disorders is the repetitive actionsor behaviors.

16,17In addition, a variety of neuro-

logical conditions and personality disorders,including Obsessive Compulsive PersonalityDisorder (OCPD) and other anxiety disorders,could be confused with OCD.

18,19 It is under-

standable that with the presence of such a vari-ety of syndromes with similar features thescreening for this disorder is difficult. Initialquestions for obsessions (“Do you have unpleas-ant thoughts that keep coming into your mind, eventhough you don’t want them?”) and compulsions(“Do you have to do things over and over, eventhough you don’t want to?”) often lead to over-diagnosing OCD. This problem resulted in theexclusion of OCD from most of the recent epi-demiological surveys.

A Multi-faceted, Evolving Process:

The clinician who wants to assess this disordershould not simply look for the presence ofobsessions and compulsions, but rather under-stand the condition as a multifaceted, evolvingprocess that starts with initial anxieties andfears, and faulty coping strategies that lead toperpetuating the fears and behaviors (Table

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Essential Psychopharmacology

Table 1

DSM-IV CRITERIA FOR OBSESSIVE-COMPULSIVE DISORDER

1. Obsessions and/or compulsions

2. recognized as excessive or unreasonable

3. Causes marked distress, time-consuming

(> 1 hour/day), or interferes with functioning

4. Content not due to another Axis I disorder

5. Not due to a substance or general med-ical condition

Current Pharmacological Treatments for Obsessive-Compulsive Disorder

2). The disorder typically starts with an initialfright or gradually increasing anxiety (of conta-mination, for example). The person attemptsto eliminate anxiety by worrying about thesource in an attempt to analyze and solve theproblem. Initially, this strategy helps as itwould for any normal person to eliminate ordecrease anxiety and fear (e.g., “Germs are prob-ably dead”). However, because the specificthinking patterns of OCD require an absolute,fault-proof solution that is impossible (“Whatif they are not dead?”), the worry persists andbecomes obsession or anxious, uncontrollableworry. The persistence of anxiety calls formore active coping strategies. As a result, theperson takes certain actions that could elimi-nate or suppress fears and obsessions (e.g.,washing). Washing initially eliminates orreduces the fear of contamination. However,since absolute assurance of safety is impossiblein OCD patients, they keep repeating the com-pulsive ritual invariably retriggering fears. Usu-ally this ritual continues until the patient givesup. Giving up also initially helps to reduce anx-iety, but as it leads to the eventual decrease orelimination of certain normal activities (such

as washing or showering), or causes delay inbeginning normal activities or lateness, usuallythe end result is further deterioration in func-tioning. The pressures associated with func-tional impairment lead to even more stressand anxiety, translating into more fear andrekindling the vicious cycle of OCD, frequentlyleading to despair and depression. It is impor-tant for a clinician to understand this progres-sive development of OCD symptoms becausepatients in different stages may respond differ-entially to medications or to behavioral ther-apy, which I will discuss later.

Comorbid Conditions:

Another important factor governing the treat-ment is the presence of comorbid psychiatricconditions, which are not infrequent in OCD.

20

It is especially important to consider the pre s-ence of other anxiety disorders, such as so c i a lanxiety disord e r, frequently overlooked inOCD, that can affect the functional impro v e-ment of the patients.

2 1Mood disorders includ-

ing major depression and bipolar disorder arev e ry important for administration of both phar-

macological and psychological tre a t-m e n t s .

2 2The presence of Posttraumatic

S t ress Disorder (PTSD) is also fre q u e n t l yoverlooked and needs to be assessed.

2 3

In our OCD Treatment-resistant Pro-gram, approximately one-quarter of thepatients can trace the onset of theirOCD to some traumatic or very stressfulevent in their lives.

24

Biological Mechanisms:

Biological mechanisms responsible forthe vicious cycles in OCD are not fullyunderstood.

25However, OCD is one of

the few disorders for which we havesome idea of what neuroanatomical cir-cuits participate in psychopathology.

26As

we explained above, two processes arelikely to participate in OCD. The first isrelated to fear and anxiety formation

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Bystritsky

Table 2

INTERPLAY BETWEEN ANXIETY AND OCD SYMPTOMS

Stages of OCD Fear and Anxiety

1. Initial stress and anxiety 5

2. Worry, thinking, problem solving 6

3. Obsessions 5

4. Initial compulsions (including mental) 6

5. Extensive compulsions 5

6. Abandonment of Compulsions (withdrawl) 6

7. Avoidance 6 then 5

8. Depression 5

and emotional regulation, and the second isspecific cognitive processes that include infor-mation processing of the threat, decision-mak-ing, and facilitation of thoughts and behaviors.Limbic circuits that are usually thought to reg-ulate the fear formation and other emotionalresponses include amygdala, cingulumhypocampal and parahypocampal, and someorbital and temporal cortical areas.

27Some of

the studies of OCD patients reveal abnormali-ties in these circuits, specifically in cingulum.

28

However, most of the neuroanatomical studiesusing neuroimaging and other techniques indi-cate the presence of abnormalities in cortico-stiriato-thalamic-cortical circuits that seem tohave a broad function of modulating and coor-dinating emotional and cognitive processes inhumans.

29-31Impairment in these circuits,

caused by either a neurological condition(strokes, Tourette’s syndrome and Hunting-ton’s disorder) or autoimmune disorders suchas Sydenham’s chorea frequently have OCD-like symptoms.

32

Neurochemically, OCD has been mostassociated with the serotonergic system.

33

Results of studies of static measures of seroton-ergic function in obsessive-compulsive disor-der have, however, been inconsistent, andother work has focused on more informativedynamic measures.

34,35For example, adminis-

tration of the serotonin (5-HT2) agonist

m-chlorophenylpiperazine (mCPP) has beenaccompanied by exacerbation of obsessive-compulsive disorder symptoms and a bluntedneuroendocrine response.

36After treatment

with a serotonin reuptake inhibitor, behavioraland neuroendocrine responses to mCPP seemto be normal.

37This work leads to questions

about the role of specific 5-HT subreceptors inobsessive-compulsive disorder. Effects ofmCPP on the postsynaptic 5-HT2C receptormay be especially relevant in OCD.

38Pre-clini-

cal and clinical data also suggest that the 5-HT1D terminal autoreceptor plays an impor-tant part; desensitization of this receptor inthe orbitofrontal cortex needs high durationand high dose administration of serotonin

reuptake inhibitors.39

Preliminary challenge,pharmacological, genetic, and imaging datalend support to a role for the 5-HT1B and 1Dreceptors in obsessive-compulsive disorder.

40,41

Although work on the role of the sero-tonin system in mediation of obsessive-compul-sive disorder is important, to date no specificabnormality in the serotonin system has beenidentified as a cause.

42Another neurotransmit-

ter system that could be especially importantin mediation of obsessive-compulsive disorderin some patients is dopamine.

43In pre-clinical

studies, administration of dopamine agonistsleads to stereotypic behavior, whereas inhuman beings such agents can exacerbatesymptoms and tics of obsessive-compulsive dis-order. Conversely, dopamine blockers, such ashaloperidol, are used in treatment ofTourette’s syndrome, one of the spectrum ofobsessive-compulsive disorders.

44Further-

more, augmentation of serotonin reuptakeinhibitors with such agents can be useful intreatment-refractory obsessive-compulsive dis-order.

45It seems that dopamine and serotonin

systems maintain a sort of balance with eachother and many other systems, including gluta-mate neurotransmission, some neuropeptides,and gonadal steroids that all may be playing apart.

46-50Ultimately, the role of second and

third messenger pathways in obsessive-compul-sive disorder will need to be explored.

Interplay of Biological, Genetic,and Psychological Factors

It is important to understand the psychopathol-ogy of OCD as interplay of biological, genetic,and psychological factors.

Recent family, twin, and other geneticstudies indicate that at least some types ofOCD can be transmitted possibly in autosomaldominant or recessive fashion.

5 1Patients who

are genetically vulnerable to OCD usuallydevelop their symptoms very early, betweeneight and 14 years of age, often without thepresence of major stressors.

5 1Different hypothe-

ses exist on what exactly is transmitted, m o s t l y


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focusing on components of the serotonergics y s t e m .

5 2 , 5 3Some genetic theories focus on neu-

roimmunology or genetic vulnerability toautoimmune reactions.

5 4Early reports of an

association between obsessive-compulsive dis-order and Sydenham’s chorea were confirmedin a systematic investigation leading to consid-eration of whether some cases of obsessive-compulsive disorder resulted from autoim-mune processes that disrupted cortico-striatal-thalamic-cortical circuits.

55A syndrome of

autoimmune neuropsychiatric disorder associ-ated with streptococcal infections, or PAN-DAS, has been proposed to describe childrenwho have acute onset of obsessive-compulsivedisorder symptoms with or without tics afterstreptococcal infection.

56In patients with PAN-

DAS, their obsessive-compulsive disorder andtic symptoms respond to immunomodulatoryinterventions such as plasma exchange andintravenous immunoglobulin.

57Long-term fol-

low-up showed continued improvement ofsymptoms for most patients, especially whenantibiotic prophylaxis had been effective inprevention of recurrent streptococcal infec-tions.

58In some studies, expression of D8/17, a

B lymphocyte antigen and marker of suscepti-bility to development of sequelae after strepto-coccal infection, was increased in patients withobsessive-compulsive disorder.

59

Biological assaults on the brain andspecifically lesions in orbito-frontal-cortico-striato-thalamic circuits are also capable ofproducing OCD symptoms.

60These includes

strokes, head injuries, illicit drug use, andbrain infections such as encephalitis. Strongtraumatic events have been described to leadto OCD in patients without any known biologi-cal or genetic predisposition.

61In the majority

of adult patients, by the time they reach treat-ment, their clinical picture invariably repre-sents a mixture of biological and psychologicalfactors. Early onset of OCD creates and perpet-uates stress by disrupting the social, family, andwork or school function of the patients. Thisfrequently forces them to miss normal develop-mental stages; this generates additional stress,

which in turn worsens their OCD.62

Knowing the factors described above canhelp the clinician to make appropriate choicesregarding the treatment of patients sufferingfrom OCD.

Pharmacological Treatment

General Principals of Pharmacological Treatment for OCD:

It is important to be aware of the specific diffi-culties of the pharmacological management ofOCD patients. Treatment of an OCD patient isoften difficult because of the specific attitudethis population has about taking medication.OCD patients, by nature of their illness, havean inflated need for control and are suspiciousand doubtful. Taking medication presentsthese patients with a sensation of loss of con-trol. Both a patient and a psychopharmacolo-gist need to pay attention to these feelings tobe able to assure compliance. On the otherhand, some patients with OCD are prone todevelop a magical thinking toward a medica-tion and believe that a particular medicationmay cure them, only to become disappointedlater on. Early discussion of realistic expecta-tions regarding the effectiveness of the medica-tion will help to solve this problem. Anotherproblem that may occur with this population isthat medication may become a part of thep a t i e n t ’s ritual. Some patients can take medica-tion only on certain days, in certain numbers ofpills, or have fears associated with the color,name, or “chemical purity” of the pill. Also,while the majority of OCD patients are notprone to develop side effects, a subgroup ofsomatically and environmentally concernedOCD patients may exhibit difficulty swallowingpills or multiple somatic symptoms. It is veryimportant to assess early in the treatmentwhether any of the patient’s fears or ritualsi n t e rfere with compliance. We recommend ini-tially to see those patients frequently and toprovide them with good access to a clinician forpossible discussion of the problems associated

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with the beginning of the treatment. Some-times it is even permissible to yield to ritualsand to reassure the patient in order to preserv ethe collaboration and compliance in the initialstages of the treatment. The last principle isthat a psychopharmacologist needs to be awareof new scientific developments in the field ofOCD and of psychological and alternative treat-ments. This group of patients frequently doestheir “homework” by thoroughly investigatingthe Internet and other informational resourcesand, absence of knowledge on the part of theclinician, raises their level of suspiciousness. Werecommend, if possible, collaborating with apsychologist or other trained therapist who hastraining in Cognitive-Behavioral Treatment forOCD. Providing the patient with comprehen-sive treatment may improve both complianceand outcome.

The treatment of OCD patients usuallyproceeds as a step-by-step approach, which isbriefly listed in Table 3.

Serotonin-Reuptake Inhibitors:

Serotonin-reuptake inhibitors, or SRIs, havebeen considered the first line of drug treat-ment for OCD.

63SRIs, or agents that inhibit

the reuptake of serotonin back into the nerveterminal, were introduced in late 1980s andearly 1990s for the treatment of depressionand almost immediately began to be used inOCD. At the present time, each of five selec-tive SRIs (fluoxetine [Prozac], paroxetine [Paxil],fluvoxamine [Luvox], sertraline [Zoloft], andcitalopram [Celexa]) have shown efficacy forOCD in randomized controlled trials.

64-68

Although antidepressants without this seroton-ergic action have occasionally been describedas effective in small, uncontrolled studies andcase reports, possibly because they alleviatedcomorbid depression, controlled head-to-headcomparisons have consistently shown them tobe less efficacious than SRIs.

69,70It is not clear

why SRIs work in OCD. Earlier theories pro-posed that OCD is caused by a decreased sero-tonin neurotransmission improved by SRIs.

71

This introduces faulty logic that may lead oneto believe that a fever may be caused by aspirininsufficiency in the body. In fact, neurochemi-cal and neuroendocrinological studies havenot led to a coherent etiologic model of sero-tonin dysfunction in OCD.

72Recent theories

suggest that SRIs, through their effect on sero-tonin neurotransmission, modulate dysfunc-tional neural circuits, possibly changing a bal-ance between several neurotransmitters.

72,73

SRIs quickly became the first choice of medica-tional treatment of OCD because of their effi-cacy, tolerability, and safety.

66,67As yet, we have

no predictors based on symptom patterns oron side effect profiles to guide SRI choice.

74

The best assumption, at the current state ofscience, is that the SRIs all are equivalent interms of efficacy. The meta-analyses of random-ized placebo-controlled trials to date have allfound little difference in efficacy among them.

7 4 , 7 5

In the majority of studies, 40% to 60% ofpatients were “much” or “very much” impro v e don clinical global impression ratings. Completeresponse is unusual, and most patients havesome residual symptoms. Patients who do notrespond to an initial SRI are less likely torespond to subsequent ones, but further trialsa re wort h w h i l e .

7 6Usually it is recommended to

t ry at least two, or occasionally three, SRIs beforeswitching to a different class of drug.

9

Dosing and Initiation of the Treatment

Recommended dosing levels are detailed inTable 4. For elderly patients, and for anyonewho has a history of sensitivity to medication oris anxious about side effects, starting with a lowdose (e.g., 10 mg of p a ro x e t i n e or f l u o x e t i n e , o r25 mg of sertraline) and increasing it moreslowly than usual (e.g., raising it every 10 to 14days instead of every five to seven days) is best.Hasty dose increases are usually unnecessaryand can be counterproductive. We recommendcontinuing to increase the dose if no change inanxiety and affective symptoms occur to themaximum tolerated (or until the upper limitfor that drug is reached). If anxiety, worry, or


256


obsessive thinking isreduced, the dose increasemay be stopped, and thephysician may wait untilweek six of the treatmentwhen outcome should bereassessed and a furtherdose increase proposed ifn e c e s s a ry. Specific atten-tion should be given to flu-oxetine, which became ap r i m a ry agent on many for-mularies since it is avail-able in generic form. F l u o x-etine has the longest half-life,and blood levels of the dru gmay continue to rise foranother two weeks followingthe dose adjustment.

Most patients do notexperience benefit inreducing obsessive-com-pulsive symptoms beforesix weeks, and at least sixweeks at the maximum tol-erated dose is required foran adequate therapeutictrial.

63The most effective

dose is often (but notalways) higher than thatused for depression, andpatients may well respondto higher doses whenlower ones have failed.The majority of the studiesdemonstrated that maxi-mum benefit usuallyoccurs by the twelfth weekof treatment. Improve-ment may continue for sev-eral months after the ini-tial response, and lastingbenefit is seen with long-term continuation inresponders.

77

Start treatment with alow dose of an SRI that

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Table 3

CURRENT ALGORITHM FOR THE TREATMENT OF OCD

1. The first step in the treatment of Obsessive-Compulsive disorder is toadminister either medications or cognitive behavioral therapy.If drugtreatment is to be used, it is advisable to start with an SSRI.

2. If there is no response, or the SRI is not tolerated, another SRI shouldbe used with or without psychological treatment. The SSRI should betried in an appropriate dose for at least six weeks.

The patient may be considered treatment resistant. Subsequent steps a re much more obscure, and very little re s e a rch exists to guide ust h rough the process. The treatment choice is ususally guided by

physician experience, familiarity with medications, and side eff e c t s .Patient knowledge and pre f e rences also play a major role.

A psychiatrist should guide tre a t m e n t .

3. If there is no response, the ususal recommendation is to try anotherSSRI (under some circumstances all five of them may be tried) or switch to clomipramine.

4. If there is parital response to SRIs, augmentation strategies can beattempted. These usually include buspiron, lithium, clonazepam or a novel neuro l e p t i c .

5. If the response is inadequate, or there is no response despite followingsteps 1 through 4, SNRIs such as venlafaxine, nefazadone, or mitrazap-ine may be tried ususally with an SSRI orsome other form of pharmaco-logical augmentation.

The patient may be considered “treatment refractory.” Treatment at this stage should mostly be conducted by a specialized

OCD center or with guidance from such a center.

6. Treatment in a specialized program usually include intensive behavior modifications administered in outpatient, partial hospital, inpatientunits, or residential facilities.

7. Stimulants, tricyclics, MAOIs, or ECT could be considered as the nextstep, but these strategies have low rate of response.

8. Experimental pharmacological strategies such as such as intravenousclomipramine or weekly oral morphine could be tried.

9. Non-pharmacological experimental strategies could be considered, such as Transcranial Magnetic Stimulation (TMS), Deep Brain Stimula-tion (DBS), or Vagus Nerve Stimulation (VNS). Efficacy and parametersof these treatments still remain to be explored.

10.Finally, if symptoms remain severe and incapacitating, patients mayconsider neurosurgery. This may be considered right after step 7,bypassing experiemental treatments.

you are most familiar with and that is the leastexpensive on the patient’s insurance formu-lary. Increase the dose once a week to a mid-range dose, or as tolerated, and wait till weeksix of the treatment before gradually increas-ing the dose to maximum, or as tolerated, over

the next two to four weeks. If patient has noresponse or low tolerance, switch to anotherSRI. If there is a 30% decrease in symptomsand the dose is at maximum and well toler-ated, begin augmentation. If the patient doesnot respond to two SRIs, you can add or switch


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Table 4

RECOMMENDED DOSING REGIMEN AND SIDE EFFECT PROFILE OF SRIS

Dose (OCD) Half-life (with DrugMedication mg metabolites) Interaction Side Effects

+Advantage/Difference Management Comments

Citalopram 20 – 120 35 low Sx w Mostly specific SRI Good for elderly andSE ww Kidney metabolism medically ill due to lowIns 0 Does not affect sleep drug interaction. Can beWt w used in liver impaired

(alcoholics?)

Clomipramine 25 – 300 32 high Sx www Best in obsessional thoughts Needs blood level SE www Sleep inducing, stops diarrhea; monitoring (and tri-Ins 0 Affects many neurotransmitter cyclics); problematic inWt www systems and could be more elderly and ill, specific-

effective in some cases. ally with liver or heartproblems. Beware ofseizures.

Fluoxetine 20 – 120 92 + mod Sx ww Cheapest and longest existing Watch out for drugSE w SRI. Because of long half-life interactions. May be inIns w gives little withdrawl. Good patient’s blood threeWt ww safety record including to four weeks after

pregnancy. Most activating SRI discontinuation

Fiuvoxamine 50 – 600 14 high Sx w Most short acting SRI, sedates Some advantage inSE www at night, least likely to cause combination withIns 0 activation or agitation. 3A4 clomipramine due toWt ww metabolism (different drug metabolism. Good

interaction from other SRI) efficacy in panic and OCD

Paroxetine 20 – 120 16 high Sx www Some norepinephrine reuptake Strongest withdrawlSE www Very effective in a variety of Negative publicityIns w anxiety symptoms (known to Side effectsWt www PCP) Convenient in use Problematic in elderly

(usually no tiration) and ill

Sertraline 25 – 400 62 + low Sx www Second most activating Good in medically illSE w Low drug interaction due to low drug Ins ww Some dopamine activity interactionWt ww Needs titration

+Side effects: Sx = sexual SE = sedation Ins = insomnia Wt = weight gain

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Table 5

RECOMMENDED DOSING REGIMEN AND SIDE EFFECT PROFILE OF OTHER MEDICATIONS

Dose (OCD) Half-life (with DrugMedication mg metabolites) Interaction Side Effects

+Advantage/Difference Management Comments

Venlaflaxine 25 – 450 16 low Sx w SNRI (blocks Good for elderly andSE ww Norepinefrine Reuptake) medically ill due to lowIns w drug interaction. GoodWt w efficacy in many anxiety

d i s o rders. Needs titration

Mirtazapine 7.5 – 45 30 mod Sx w NE reuptake blocker; Sedative agent in elderly SE wwww Serotonin 5HT2 and 3 Rapid weight gainIns 0 receptor agonist In larger doses actuallyWt wwww activate

Nefazadone 100 – 400 4 mod Sx 0 NE reuptake blocker Liver test monitoringSE www Serotonin 5Ht2 receptor is needed; sedative Ins 0 agonist; short acting agent in elderly, canWt 0 provoke anxiety in some

p a t i e n t s

Trazadone 50 – 300 7 mod Sx 0 Serotonin 5Ht2 receptor Sedative agent in elderlySE www agonist Short acting; can pro-Ins 0 voke anxiety in some Wt 0 patients. Marginally

effective in depression

Valproate 250 – 1000 8 mod Sx w GABA-ergic AE drug Needs blood levels,SE ww Liver metabolism ammonia levels monitor-Ins 0 ing; slow titration andWt www w i t h d r a w l

Gabapentin 100 – 3600 6 low Sx 0 GABA-ergic AE drug Slow titration and SE ww Kidney metabolizes withdrawl; seizures Ins 0 possible with rapidWt w withdrawl

Clonazepam 0.5 – 8 16 mod Sx w Benzodiazepine Slow titration and SE ww Long-acting withdrawl; seizures Ins 0 possible with rapidWt 0 withdrawl

Lorazepam 0.5 – 8 8 low Sx w Benzodiazepine Slow titration and SE ww Long-acting withdrawl; seizures Ins 0 possible with rapidWt 0 withdrawl; dependency

forming

+Side effects: Sx = sexual SE = sedation Ins = insomnia Wt = weight gain

to clomipramine. On occasions, one or two tri-als of other SRIs could be justified.

Side-Effects Management

Management of pharmacological interventionand side effects in OCD patients should beperformed very carefully and throughout thetreatment. Although side-effect rates differslightly among the SRIs, the majority ofpatients are able to tolerate all of these med-ications.

78The side effects and other proper-

ties of SRIs that can assist with the treatmentchoice are summarized in Table 4. SRIs arevery safe medications for almost all OCDpatients except for those with severe hepaticor renal impairment. They are generally safein overdose.

79However, most SRIs significantly

inhibit various isoenzymes of the cytochromeP450 system, which is central to the hepaticmetabolism of many commonly used drugs.

80

By this mechanism, they can increase bloodlevels of all tricyclic antidepressants (includingclomipramine), many antipsychotics (includingclozapine, thioridazine, haloperidol, andrisperidone), beta-blockers, opiates, and sev-eral antiarrhythmics (type 1C). Citalopram onlyweakly inhibits cytochrome P450 and usually ispreferred in cases where drug interaction is ofconcern.

81

Gastrointestinal disturbance is common.However, it normally subsides within a few daysand can be reduced by taking the medicationwith the main meal of the day, at night, ortogether with an antacid. The last methodmay, however, interfere with drug absorption.Hyperactivity and an increase in anxiety, ner-vousness, and agitation are also common butusually abate within the first two weeks oftreatment. These SRI-induced symptoms areless frequent in OCD patients than in otheranxiety disorder patients. However, patientsneed to be informed of the possibility ofincreased anxiety, and those who develop itneed to be seen once a week through the firsttwo weeks of the treatment. Four of the sideeffects that, once started, usually persistthrough the treatment are sexual difficulties,

sedation, weight gain, and insomnia.82

They arethe most frequent reasons for premature dis-continuation of the medication several monthsinto the treatment. Sexual side effects, rangingfrom delayed orgasm to anorgasmia to com-plete loss of libido, are very common withSRIs. They occur in 20% to 40% of patientstaking these medications. Brief drug holidaysor dose reduction for a few days before sexualactivity may be effective, except in the case offluoxetine, which has a long half-life. Co-administration of buspirone (Buspar), bupropion(Wellbutrin), mirtazapine (Remeron), trazodone(Desyrel), stimulants, and sildenafil (Viagra)was helpful in case reports but no definitivetreatment is available for this problem.

83Other

side effects include Serotonin Syndrome whenSRIs are combined with other drugs thatenhance serotonergic neurotransmission(especially monoamine-oxidase inhibitors[MAOIs]). Moreover, care is needed whenswitching agents, particularly switching fromfluoxetine—again, because of its long half-life.

79While SRIs appear to be non-terrato-

genic and safe in the neonatal period, theyhave been shown to be quite effective and arepreferable during pregnancy.

84The decision of

continuing or stopping SRIs during pregnancyis a difficult, one and risks and benefits shouldbe thoroughly discussed with the patient.

Treatment Course and Discontinuation

The duration of the treatment is usually indefi-nite since relapse occurs in 80% to 90% ofpatients upon full discontinuation.

77Early dis-

cussion of the chronic course of OCD mayhelp to ameliorate anxiety associated withlong-term medication use. If discontinuation isdesirable, it should be gradual and slow for allSRIs except fluoxetine in order to avoid a dis-continuation reaction.

85With fluoxetine, some

patients are able to tolerate more rapid with-drawal without much problem. Such reactionsare characterized by anxiety, dizziness, insom-nia, irritability, fin-like symptoms, feelings ofdetachment, and sensations resembling elec-


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tric shocks. Withdrawal from paroxetine seemsto carry the greatest risk because of its shorthalf-life. Symptoms are usually self-limitingand are rapidly relieved by reinstating the drugor by switching to another SRI with longerhalf-life. Occasionally, very slow reductionsmay be required over several weeks even withfluoxetine. Concurrent competent cognitivebehavioral therapy may reduce relapse rateand assist discontinuation, but this remains tobe confirmed in randomized trials.

Clomipramine:

When two SRIs have failed to improve OCDsymptoms, the next logical step is a trial ofclomipramine (Anafranil). It is a tricyclic antide-pressant with strong SRI properties.Clomipramine may either be added to an SRI,in patients with partial response, or usedinstead of SRIs. Clomipramine was actually thefirst antiobsessive medication introduced tothe US market.

86Early trials demonstrated its

considerable efficacy of clomipramine. Morethan 35% of the patients were nearly symptomfree and more than 60% of patients experi-enced significant improvement in their symp-toms, while only a few patients improved onplacebo. However, due to an unfavorable side-effect profile and cumbersome monitoring,SRIs quickly replaced clomipramine as a firstchoice medication for OCD.

64,65

Clomipramine may be slightly more effec-tive than SRIs. Greist and coworkers con-ducted a meta-analysis of four large multicen-ter, randomized controlled trials comparingclomipramine, fluoxetine, sertraline, and fluvoxam-ine with placebo.

74They found an approxi-

mately 66% chance of improvement with any-one of the SRIs compared to an 83% chancewith clomipramine. Similarly, Piccinelli andcoworkers’ meta-analysis of 47 randomizedcontrolled trials conducted in Europe found a61% reduction in Yale-Brown Obsessive-Compul-sive Scale (Y-BOCS) scores with clomipraminecompared to a 22% to 28% reduction with thesame three SRIs.

75In contrast, head-to-head

comparisons have not shown clomipramine tobe superior to SRIs.

87-89However, most of these

trials had methodological flaws and biaseddesign. Thus, the comparative studies to dateare inconclusive; and large, well-conducted tri-als are required to confirm or refute the find-ings of meta-analyses of placebo-controlled tri-als. Clomipramine and its metabolitedesmethyl-clomipramine affect, to somedegree, norepinephrine and dopaminergic sys-tem as do most of the tricyclics, which mayexplain the different degree of efficacy. Whilethe relationship of norepinephrine anddopamine reuptake blocking properties toantiobsessive efficacy is doubtful, it may relateto additional decrease in anxiety and depres-sion causing overall greater improvement ofthe patient.

Safety, Tolerability, and Side Effects

Clomipramine affects histamine and manyother receptors and, as a result, has more sideeffects than do the SRls.

8 7On the contrary, in

meta-analytic studies dropout rates withclomipramine were significantly lower thanwith SRIs.

7 4 , 7 5Rasmussen has suggested that in

early trials there was no effective alternative toclomipramine, so patients were more likely topersist with treatment.

9 0In comparative stud-

ies in which clomipramine was started at therecommended dose of 25 mg, dropout rateswere comparable to those of SRIs.

8 7 - 8 9S o

although more likely to cause side effects,clomipramine, if prescribed correctly andtitrated slowly, seems to be tolerated almost aswell as SRIs. Clomipramine can also causefatal cardiac arrhythmias in overdose andshould not be prescribed to patients with a sig-nificant suicidal risk. It should also be avoidedin patients with cardiac instability, part i c u l a r l yif conduction defects are present, and shouldbe used with caution in persons at risk for uri-n a ry retention and those with narro w - a n g l eglaucoma or significant hepatic or re n a li m p a i rm e n t . Sedative, anticholinergic (e.g.,d ry mouth, constipation) and antiadrenergic

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(e.g., postural hypotension) effects are com-mon. When combination with SRIs, neurolep-tics, or other medications is indicated, thisshould be done carefully with knowledge ofadditive effects and drug interactions.Clomipramine treatment alone or in combina-tion with other medications should be doneonly under careful blood level and ECG moni-t o r i n g . This monitoring should be started witha baseline assessment and followed initially bymonthly blood levels and bimonthly EEG anda f t e rwards by repeated monitoring every six toeight months.

Practical Recommendations

Clomipramine can be added an SRI if noresponse or partial response to that SRI isobserved. This should be done under carefulmonitoring of ECG, cardiovascular parameters(pulse and blood pressure) and blood levels ofclomipramine because of possible pharmaco-dynamic interaction and toxicity. This is espe-cially important with older or physically com-promised people. An SRI can later be taperedoff and blood levels of clomipraminerechecked.

Augmentation Strategies in Treatment-resistant OCD

Since 40% to 60% of patients do not respondadequately to SRI or clomipramine treatments,clear strategies are needed for treating thosewho show partial or little response. At thisstage, we are entering initial management oftreatment-resistant cases. We strongly recom-mend, if the patient is being treated by a pri-mary care physicians, a consultation from apsychiatrist who is more familiar with augmen-tation strategies should be done. Unfortu-nately, the literature does not offer any well-validated solutions. For patients with severeresidual symptoms following an adequate trialof an SRI (i.e., a therapeutic dose for 12 weeksor more with full compliance), several optionscan be considered. If cognitive behavioral

therapy (CBT) has not been tried, it should beoffered at this time or at least a consultationwith a trained therapist should be sought. Theinterplay between medication and therapy willbe discussed in the next section. If CBT treat-ment is not available or if it is not feasiblebecause of cost or time constraints, the admin-istration of drug combinations should be tried.Polypharmacy has been widely used in practiceand is currently a rule rather than exceptionfor this stage of OCD treatment. However,none of the combined or augmentation strate-gies summarized briefly below has been con-clusively validated in controlled trials.

Venlafaxine (Effexor):

While there are no controlled trials demon-strating the efficacy of venlaflaxine alone inthe treatment of OCD, there are several casereports suggesting that combining SRIs withvenlaflaxine, which is also a norepinephrinereuptake blocker, may be helpful.

91,92However,

combination may be more tolerable, and incontrast to clomipramine, there is very littleadditional drug interaction. Dose ranges up to450 mg of venlaflaxine have been used. Sideeffects are similar to those of SRIs, specificallyin higher doses.

Clonazepam (Klonopin):

While adding clonazepam may not be desir-able at early stages of the treatment because ofdependency and withdrawal issues, by thisstage of OCD management (which is severalmonths of unsuccessful medicational trials),most of the patients are so needy and desper-ate that physicians are compelled to institute abenzodiazepine treatment. Clonazepam hasmore evidence for efficacy as an adjunct agentin OCD than do other benzodiazepines.

93The

advantages of clonazepam include long half-life that permits once-daily use (often beforesleep) and possible serotonergic system upreg-ulation that provides more specific anti-obses-sional effect. Clonazepam is probably ineffec-


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tive when used alone except that it decreasesoverall anxiety.

94Side effects may be limiting

and include depression, cognitive deficits, irri-tability, and intoxication. Should not be used“as needed,” especially if CBT is instituted.

Atypical Antipsychotics:

Antagonists of both D2 and 5-HT2 receptorshave been emerging within the last decade aspivotal treatments for treatment-resistantO C D .

9 3In his early reviews, Jenike suggested

that conventional neuroleptics have been betterthan any other agent in the augmentation ofthe SRIs’ effects.

9 5Interaction of dopamine and

serotonergic systems was proposed as a possiblemechanism of action. However, their use wasprecluded by the possibility of extrapyramidalside effects and tardive diskinesia.

The atypical neuroleptics with additiveeffect on the serotonergic system are lackingthose side effects, at least in lower doses. How-ever, there are reports of these atypical agentsexacerbating OCD in patients with comorbidschizophrenia when used alone.

96Contrary to

that, in combination with SRIs they seem tohave a therapeutic effect.

Risperidone (Risperdal) has shown to beeffective in open trials and in case series.

97In a

randomized, controlled trial that was con-ducted on 36 patients with SRI-refractoryOCD,

98fifty percent of those taking risperi-

done, but none of those taking placebo, were“much” or “very much” improved on the Clini-cal Global Impression scale. Two open trialshave been conducted using olanzapine(Zyprexa) in patients showing partial responseto an SRI.

99,100Recently, our group conducted a

double blind, placebo-controlled trial usingolanzapine in 26 patients with OCD; 46% ofpatients in the olanzapine group showed aresponse and only 3% showed a response inthe placebo group. Clozapine has not beeninvestigated as an augmentation agent, butMcDougle and colleagues found that none of10 patients with treatment-refractory OCD

responded to clozapine used alone.101

Giventhe relative toxicity of this agent, its use inOCD cannot be justified at present. There areongoing trials with other atypical neuroleptics(e.g., ziprazadone [Geodon] and quitaiapine[Seroquel]), but no results are available.Approximately 50% of response in very resis-tant patients is remarkable, and atypical neu-roleptics in combination with an SRI should beconsidered as one of better ways of manage-ment of non-responders to SRI treatment. Thecombination of SRIs and atypical antipsy-chotics is generally well tolerated. Theresponse tends to occur at lower doses (risperi-done, two to six mg daily; olanzapine, five to 20mg daily), and a four-week therapeutic trial atthe maximum tolerated dose is considered suf-ficient. However, there are some limitations tothe use of this combination. SRIs may reducethe breakdown of risperidone and olanzapineand this requires cautious dosing. Additionalside effects such as sedation, weight gain, orthe possibility of extrapyramidal effects may betroublesome. Moreover, it’s not clear whichpatients respond to this combination. Thereare some indications those patients withsevere, bizarre obsessions, low insight, and ticsare less responsive to SRIs alone. For thesepatients, early addition of atypical neurolepticsmay be indicated.

Lithium or Other Mood Stabilizers:

Lithium enhances serotonin transmission and,in combination, may work where SRIs alonefailed. However, despite promising casereports, lithium alone was not efficacious intwo double-blind, placebo controlled trials.

1 0 2 , 1 0 3

There is another reason to use lithium or, infact, other mood stabilizers such as v a l p ro a t e o rg a b a p e n t i n in this population. T h e re is emerg-ing data on increased comorbidity with bipolard i s o rder in tre a t m e n t - resistant OCD. In addi-tion, SRIs are capable of causing mood instabil-ity and hypomania that could go unnoticed for

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a long time. The dose range of lithium andother agents is similar to that used in mood sta-b i l i z a t i o n and monitoring of blood levels, andl i v e r, kidney, and other parameters need to bedone where appropriate to monitor toxicity.

Other Agents:

B u s p i ro n e (BuSpar), a partial 5-HT 1A recep-tor agonist, has been used for over a decade.Case reports were promising. However, f o u rc o n t rolled trials have yielded disappointingre s u l t s .

1 0 4The low toxicity and benign side

effect profile made it a popular choice, butthe use of buspirone for SRI augmentation isnot warranted by either clinical data or byexperience. Case reports suggest that thismedication can counteract sexual side effectsof SRIs and, if confirmed, this may serve asjustification for an occasional use of bus-pirone/SRIs combination.

Many other augmentation strategies andmedications or herbal combinations havebeen used, including l-tryptophan, inositol,f e n f l u r a m i n e (Pondimin), p i n d o l o l ( V i s k e n ) ,oxytocin, trazodone (Desyrel), and an andro-gene antagonist. None of these has shown suf-ficient promise.

1 0 5 - 1 1 0

In summary, begin augmentation withvenlaflaxine unless definitive hypersensitivityto SRIs exist. Then add clonazepam or, ifthere is a history of drug abuse, a GABAergicmood stabilizer such as gabapentin can beadded. If there is no response within two tofour weeks, a trial of an atypical neuroleptic iswarranted. This trial may be followed by anaugmentation with buspirone, trazodone, fen-fluramine, or l-triptophane, depending onyour level of comfort with the drug and theside effect profile of the combination. Behav-ior therapy should be tried at the same timeor in sequence.

Combining CBT with Medication

Cognitive-Behavioral Therapy (CBT) was thefirst psychotherapy for which careful empiricalsupport was obtained and is a standard treat-ment for OCD in adults and children.

6T h e

most important component of behavioral ther-apy is Exposure and Response Pre v e n t i o n( E R P ) .

1 1 1It consists of confrontation with the

feared stimuli combined with prevention offaulty coping behaviors such as compulsions oravoidance. The cognitive component of thetreatment or correction of faulty beliefs (includ-ing inflated responsibility, over-importance ofthoughts, excessive concern about the impor-tance of controlling thoughts, and overestima-tion of threat) might be less important andprobably works only in combination with ERP.Some researchers, however, believe that cogni-tive approaches are as effective as exposure pro-cedures. The therapy, just like medications, can eff e c tchanges in the brain, specifically in the orbital fro n t a lc o rtex and striatum.

1 1 2H o w e v e r, the true mecha-

nism of these changes is unknown. There is thepossibility of different targets of CBT versuspharmacological intervention.

Metha-analytic studies have demonstratedthat one of predictors of poor response to SRIsis severity of compulsive and avoidant behavior(see stages four through seven in Table 2),w h e reas the most noticeable predictor of non-response to CBT is severity of worry and anxi-ety and an inability to tolerate these stro n ga ff e c t s (see stages one through three in Ta b l e2). It is possible that psychopharmacologicali n t e rventions cause improvement of anxiety,depression, and obsessiveness while only effect-ing secondary changes in coping behaviorssuch as compulsions and avoidance. CBT, onthe contrary, modifies coping behaviors andonly later causes the resetting of the thresholdof anxiety and modification of abnormal think-ing. In our OCD Treatment-resistant program,we frequently see patients whose anxiety andobsessive thinking was improved by medica-tions but who considered themselves to bemedication non-responders because their com-


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pulsions did not improve and who stoppedmedication for that reason. When CBT wasinstituted, these patients greatly benefited froma combined approach.

U n f o r t u n a t e l y, only a few studies haveassessed how best to sequence or combinepharmacotherapy and psychotherapy forobsessive-compulsive disorder with mixed out-come results.

1 1 3 , 1 1 4In clinical practice, it would

seem sensible to routinely encourage patientswho receive pharmacological treatment to alsounderstand and adhere to the principles ofcognitive-behavioral therapy. The therapy canbe administered individually, in groups, or byself-help computer instruction. Because symp-toms of obsessive-compulsive disorder cangreatly affect the patient’s family, assessmentof such an effect and inclusion of the patient’spartner or family in development of a treat-ment strategy is appropriate in some cases.Psychodynamic psychotherapy for obsessive-compulsive disorder is generally ineffective,and there are no data to support its use. How-e v e r, it can be successfully implemented as anadditional therapy when significant personal-ity deficiencies exist.

Management of Treatment-refractory Cases

When both psychological and pharmacologicalapproaches (including adequate trials of eachSRI, with and without augmentation) have beenunsuccessful, other options must be considered.It is important at that point to reassess and toreview the diagnosis for the presence of anycomorbid conditions such as drug dependency,o rganic conditions, psychosis, or a mood disor-der and to explore psychosocial stressors or sec-o n d a ry gain issues that my be participating inmaintaining symptoms. We would re c o m m e n dat that point that a general psychiatrist get aconsultation from a clinician specializing in thet reatment of OCD. There is usually a listing ofthese clinicians available from patient advocacygroups or foundations (e.g., OCD Foundation:

w w w.ocdfoundation.org; Anxiety DisordersAssociation of America: www.adaa.org). Thereare many specialty treatment centers for treat-ment-resistant OCD. These centers can offer apackage of intensive cognitive behavior ther-apy, psychoeducation, family intervention, andpharmacological treatment administered onan inpatient unit, in a partial hospital, or in aresidential facility. This treatment is frequentlyeffective even in severe OCD patients that donot respond to any other treatment strategy.Four- and five-year follow up studies are avail-able documenting how improvement acquiredin these programs has a tendency to persist.

Psychopharmacological Strategies:

When medication strategies listed in the previ-ous sections are exhausted, non-standardapproaches could be used. Monoamine oxi-dase inhibitors had been used for the treat-ment of OCD before the introduction ofclomipramine and SRIs. A randomized, con-trolled trial compared phenelzine (Nardil)with clomipramine (Anafranil) and found thetwo to be equally efficacious.

115A more recent

placebo-controlled comparison of phenelzinewith fluoxetine, however, found fluoxetine tobe significantly superior except for obsessionsregarding symmetry, which responded well tophenelzine.

116

Traditional antipsychotics also can betried at this point. Comorbidity with schizo-phrenia is common in OCD.

117Obsessions and

compulsions are surprisingly common in schiz-ophrenia, with studies estimating rates of 8%to 46%. We suggest that trials of antiobses-sional drugs begin only after psychotic symp-toms have been stabilized with medication; wealso urge caution with respect to drug interac-tion since many SSRIs increase blood levels ofantipsychotics. In OCD with a comorbid tic dis-order that fails to respond to an SRI, the addi-tion of haloperidol (Haldol) or pimozide (Orap)in doses up to 2 to 10 mg has been associatedwith higher response rates than would be

expected from changing to another SRI. Inthese studies, tics were also reduced.

118Inhibi-

tion of excess dopaminergic activity in thebasal ganglia via D2 receptor blockade is theputative mechanism of action.

There is some evidence for the efficacyand safety of intravenous clomipramine, whichmay become the optimal strategy in treatment-resistant cases. Researchers have suggestedthat the ratio of clomipramine to its metabo-lite desmethylclomipramine (which alsoinhibits noradrenaline reuptake) is increasedwith parenteral treatment through reductionof first-pass hepatic metabolism and that thisexplains the greater tolerability and efficacy ofthe intravenous form of the drug.

119In a dou-

ble-blind, randomized, controlled trial inpatients with treatment-refractory OCD, Fallonand coworkers found that nine of 21 patientstreated with 14 days of clomipramine infusionsand seven days of oral treatment were respon-ders, compared with none of 18 in the placebogroup. Improvement was maintained to theend of blind ratings at three weeks, and theregimen was well tolerated.

120

Even experienced psychopharmacologistsmay be reluctant to administer some of theprospective treatments. A once-a-week opioidreceptor agonist trial in OCD patients hasshown some success and is underinvestigation.

77Since potential adversities of

these treatments are high, they should proba-bly still be conducted only in specialized cen-ters under scrutiny of researchers and withexplicit informed consents until more evi-dence is gathered.

Non-Pharmacological Strategies:

Electroconvulsive therapy (ECT) has a role incases of treatment-refractory OCD compli-cated by severe comorbid depression, but it isnot believed to be consistently effective forprimary treatment-refractory OCD. In oneuncontrolled case series, the majority ofpatients with treatment-refractory OCDimproved considerably for a year following

such therapy.121

Although the response wasassociated with improved depression ratings,the authors suggested an independent effecton obsessional symptoms.

Non-pharmacological experimental treat-ment strategies are under development andtesting, including: Deep Brain Stimulation(DBS), Vagus Nerve Stimulation (VNS), andRepetitive Transcranial Magnetic Stimulation(rTMS).

Bilateral Deep Brain Stimulation (DBS) hasbeen used successfully for essential tremor andP a r k i n s o n ’s disease (PD) since about 1995 andutilizes the Medtronic Activa Tremor ControlS y s t e m .

1 2 2Significant adverse events from the

DBS procedure have included equipment fail-ure or lead wire breakage, intracranial hemor-rhage, infection, seizures, and paresis. In 1999, ateam of Swedish and Belgian physiciansapproached refractory OCD through DBSrather than bilateral capsulotomy.

1 2 3T h e

selected stimulation targets for the chronic stim-ulation were identical to those aimed for in ac a p s u l o t o m y. In four patients with severe treat-ment-resistant OCD, quadripolar electrodeswere stereotactically bilaterally implanted in theanterior limbs of the internal capsule. Beneficialeffects were seen in three patients.

The vagus nerve (10th cranial nerve) isbest known for its efferent function withparasympathetic inervation to organs such asthe heart and gut. However, approximately80% of vagal nerve fibers are afferent sensoryfibers and relay information from the body tothe brain.

124 These afferent fibers project via

the nucleus tractus solitarii (NTS) to the locusceruleus (LC) and parabracial nucleus (PB).The LC and PB project to all levels of the fore-brain, including the hypothalamus, orbitalfrontal cortex, amygdala, and bed nucleus ofthe stria terminalis. In theory, direct stimula-tion of the vagus afferent fibers could affectsensory input to limbic, brain stem, and corti-cal areas known to be involved in mood andanxiety disorders. Vagus Nerve Stimulation(VNS) has had an excellent safety record in


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seizure patients.125

The most common adverseevent related to implantation is mild pain atthe incision site that typically resolves over thetwo weeks following surgery. There are cur-rently seven patients with obsessive-compulsivedisorder, two patients with PTSD, and onepanic disorder patient implanted with thedevice. Acute and long-term data are not yetavailable on these patients.

126

Barker and coworkers introduced Tran-scranial Magnetic Stimulation (rTMS) in 1985 asa non-invasive means of stimulating the cere-bral cortex.

127It involves placing an electro-

magnetic coil on the scalp and passing arapidly alternating high-intensity currentthrough the coil. This sets up a magnetic field,which passes through the cranium and induceslocal electrical changes on the surface of thecortex. Therapeutically, rTMS has received themost attention with treatment-resistant depres-sion.

128,129Greenberg and coworkers treated 12

patients with OCD and found that a single ses-sion of right prefrontal rTMS decreased com-pulsive urges for 8 hours, but there was noeffect on obsessions.

130However, Alonso and

coworkers, who randomly assigned 18 patientswith OCD to real or sham rTMS, did not findany difference between the treatmentgroups.

131

With the failure to find effective therapiesfor OCD over the past three decades, psy-chosurgery has become an intervention of lastresort.

132It is important to balance the risks of

nonintervention (social, physical, and psycho-logical complications, including suicide)against those of surgery (frontal lobe dysfunc-tion and psychological complications, includ-ing personality alteration, substance abuse,and suicide), which are not excessive with cur-rent techniques.

133Unfortunately, in the

absence of a controlled comparison with“sham” surgery, efficacy remains unproven.Follow-up studies from the 1960s and 1970sshowing improvement in more than 80% ofpatients need to be viewed with caution,because many patients would not meet currentcriteria for treatment resistance or therapeuticresponse.

134More-recent retrospective and

prospective studies have reported response in30% to 60% of patients. A “gamma knife”using cobalt 60 has been used in some centersto create surgical lesions without opening theskull, making a controlled comparison withsham surgery feasible.

135The procedures

favored across various centers include cingulo-tomy, subcaudate tractotomy, capsulotomy, andlimbic leucotomy (cingulotomy plus subcau-date tractotomy).

136No conclusive data exist on

comparative efficacy or safety. Further researchis needed to identify the best target sites. Forthese procedures, a “stereotactic” frame isused, and target sites are visualized with mag-netic resonance imaging. Occasionally, sur-geons will reoperate if clinically indicated. It ishypothesized that such lesions disrupt dysfunc-tional neural circuits by severing connectionsbetween the orbitomedial frontal lobes andlimbic or thalamic structures. However, theobservation that most patients take weeks ormonths to improve suggests that secondaryeffects such as nerve degeneration may beimportant. If the patient seems to be suitable,the next step is to contact the multidisciplinaryreview committee at an institution specializingin this form of neurosurgery for further detailsabout their criteria for treatment and admis-sion. Surgery should only be used as anabsolutely last resort and performed in special-ized centers.

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