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Brief treatment 3:2

Biological, Pharmacological, and Somatic
Treatments for Obsessive-Compulsive

Michele T. Pato, MD
Katharine A. Phillips, MD
For many patients, obsessive-compulsive disorder is a lifelong illness extending from early childhood into adulthood. However, pharmacological and behavioral treatments at adequate doses and duration offer a majority of patients improvement in symptomsand functioning. At the present time, there are a number of effective medications withrelatively tolerable side effects. Experimental biological treatments for the truly treatmentrefractory, such as neurosurgery, deep brain stimulation, and vagal nerve stimulation, arebeing developed and refined, and may ultimately offer new hope to patients who do notrespond to traditional treatments. [Brief Treatment and Crisis Intervention 3:275–290(2003)] KEY WORDS: pharmacotherapy, serotonin, obsessions, compulsions, neuroimaging, neurochemical, serotonin reuptake inhibitors, SRIs, treatment refractory, neurosurgery.
A growing understanding of the pathophysiol- Biological Mechanisms in OCD
ogy of obsessive-compulsive disorders (OCDs)has been helpful in stimulating the development Neuroanatomical and Neuroimaging
of biologic treatments. Neuroimaging studies Considerations
and research on neuroreceptors implicate sero-tonin and certain brain circuits in OCD’s patho- An increasing number of studies have been genesis. The purpose of this article is to review done with structural and functional neuroimag- some of the theoretical underpinnings of biolog- ing. Structural imaging uses computerized tomo- ical treatments and to present evidence for the graphy (CT) and magnetic resonance imaging efficacy of these treatments in OCD.
(MRI) (Robinson et al., 1995; Szeszko et al.,1999); functional imaging uses positron emis-sion tomography (PET), single photon emission From the Department of Psychiatry at SUNY Upstate Med-ical University and the Center for Psychiatric and Molecular Genetics and VAMC Syracuse (Pato) and the Department magnetic resonance imaging (fMRI), and mag- of Psychiatry and Human Behavior at the Brown UniversitySchool of Medicine and the Body Dysmorphic Disorder Pro- netic resonance spectroscopy (MRS). These studies have shown abnormalities in patients Contact author: Michele T. Pato, MD, 750 East Adams with OCD at rest and with symptom provocation Street, IHP, Center for Psychiatric and Molecular Genetics,Syracuse, New York 13210. E-mail:
paradigms (Breiter et al., 1996; Cottraux & Ger- ard, 1998; Rauch et al., 1994; Saxena, Brody, Schwartz, & Baxter, 1998). Some studies have the SRIs is unclear, it appears that serotonin re- even shown a “normalization” of brain func- uptake is followed by a cascade of changes both tioning following successful pharmacotherapy presynaptically and postsynaptically (Blier & de and cognitive-behavioral therapy (CBT) (Baxter Montigny, 1999). A role for serotonin is also sup- et al., 1992a; Benkelfat et al., 1990; Hoehn-Saric, ported by studies measuring neurotransmitter Pearlson, Harris, Machlin, & Camargo, 1991; or metabolite concentration in the central and peripheral nervous systems, as well as pharma- The majority of these studies have implicated cological challenge paradigms that measure be- abnormalities in the orbitofrontal cortex, ante- havioral and neuroendocrine effects produced rior cinglulate cortex, and structures of the by acute administration of pharmacological basal ganglia (especially the caudate nucleus) and thalamus. These structures were originally Other neurotransmitters, such as dopamine, proposed to be linked in a neuroanatomical cir- have also been implicated as playing a role in cuit by Insel (1992) and Baxter (1992b). More OCD. When dopamine antagonists (neurolep- elaborated models by Saxena and colleagues tic agents; also called antipsychotics) are added (1998) and Blier and de Montigny (1999) pro- pose a complicated balance, involving the neuro- cially in patients with comorbid tics or co- transmitter serotonin, within a three-way cir- morbid schizotypal personality disorder (Good- cuit between the orbitofrontal cortex, head of man et al., 1990a; Koran, Ringold, & Elliott, the caudate nucleus, and the thalamus (Baxter 2000; McDougle, Epperson, Pelton, Wasylink, et al., 1987, 1988, 1992b; Blier & de Montigny, & Price, 2000; Saxena, Wang, Bystritsky, & Bax- 1999; Nordahl et al., 1989; Saxena, Brody, ter, 1996; Stein, Bouwer, Hawkridge, & Emsley, Schwartz, & Baxter, 1998; Swedo et al., 1989).
1997). Given the complex interactions and over- Successful treatment with various pharmaco- lap among various receptors in the brain, it is logical agents (clomipramine, fluoxetine, and likely that additional neurotransmitters are in- paroxetine) and with CBT has been shown to re- volved in OCD’s pathophysiology and etiology.
sult in a decrease in glucose metabolism in the Drawing from conflicting results, Baumgarten caudate nucleus (indicating change in the activ- ity of this circuit) (Saxena et al., 1998).
orbitofronto/cingulo-striatal projections are in-volved in adapting behavior to changing exter-nal demands and internal emotional status, a Neurochemical Considerations
core problem in OCD. The effect of long-term There are also several lines of evidence from a treatment with SRIs may not only be to change neurochemical perspective that support a role the ratio of dopamine to serotonin turnover, but for the neurotransmitter serotonin in OCD. The to decrease the sensitivity of various serotonin hypothesis that OCD involves an abnormality in receptors. Ongoing research will be needed to serotonin transmission has been called the sero- tonin hypothesis. Data supporting this hypothe-sis come from several different sources. First,agents that effectively treat OCD affect serotonin Somatic Treatments
(the serotonin reuptake inhibitors [SRIs]), with aspecific action on the presynaptic reuptake of General Considerations
serotonin into the serotonin-releasing neuron(Greist, Jefferson, Kobak, Katzelnick, & Serlin, Many forms of somatic therapy—e.g., pharma- 1995a). While the exact mechanism of action of cological, neurosurgical—have been shown to Brief Treatment and Crisis Intervention / 3:2 Summer 2003
be effective for OCD. Behavior therapy is dis- phase of treatment is often most difficult be- cussed elsewhere in this issue; thus, the focus cause an adequate therapeutic alliance may not here will be on pharmacotherapy and other bio- have yet developed. Both risk aversion and a need to be in control may make it difficult for a The general goals of treatment are to reduce patient to take medication. Preparing the pa- the frequency and intensity of symptoms, such tient, in advance, about side effects and delayed as obsessions and compulsions, and to minimize onset of therapeutic action often helps the pa- interference in functioning caused by the symp- tient feel more in control and able to continue toms. Although a majority of patients experi- treatment. The gradual onset of improvement, ence improvement in symptoms with pharma- although in some cases frustrating, may actually cotherapy, relatively few patients experience be reassuring to patients who might feel out of complete remission. Thus, even with treatment, control if improvement occurred too rapidly.
OCD tends to be a chronic illness with a waxingand waning course. Symptoms often worsen Pharmacological Treatments
during times of psychosocial stress, even whenpatients are on medication. Thus, anticipating The principal pharmacological agents used to with the patient what stressors may make the treat OCD prominently affect the serotonin sys- symptoms worse can be helpful in long-term tem and include clomipramine, fluoxetine, flu- voxamine, sertraline, paroxetine, and citalo- Compliance, both short- and long-term, can be greatly facilitated by considering how the na- medications because it has major direct effects ture of the illness affects the use of various treat- on noradrenergic neurotransmitters, which ment modalities. For instance, at the core of OCD some argue may make it more effective (see be- are the concepts of obsessional doubt, risk aver- low). Because of its direct effects on neurotrans- sion, and a need to feel in control of one’s envi- mitters other than serotonin, it is often referred ronment. These three features affect both phar- to as an SRI; the other agents, which work more macological and behavioral treatment. In the selectively on the serotonin system, are called initial phases of treatment, to address patients’ selective serotonin reuptake inhibitors (SSRIs) tendency to doubt and be risk aversive, extra (although the term SRI applies to the SSRIs as time often must be spent conveying the poten- well). The SRIs are antidepressants that are tial efficacy of treatment and lack of serious side effective for OCD in addition to depression and effects. Cognitive distortions about both behav- many other psychiatric disorders. It appears ior therapy and pharmacological treatment need that non-SRI antidepressants, which also are to be addressed as well. Patients with contami- effective for depression and other disorders, are nation obsessions and somatic obsessions often have numerous questions about drug safety and It is critically important to measure symptom may be hesitant to take medication. The clini- severity before and after treatment to judge cian must consider this obsessional worry when describing side effects and take special care with worked. The standard measure for OCD treat- the detail with which certain side effects are ment is the Yale-Brown Obsessive Compulsive described, being thorough but not obsessional.
Scale (Y-BOCS; Goodman et al., 1989a), a reliable It is important when discussing side effects to and valid 10-item, 40-point semistructured in- present an objective assessment of the relative strument that assesses the severity of obses- frequency and severity of various side effects.
sions and rituals during the preceding week.
Most studies that have been conducted since Brief Treatment and Crisis Intervention / 3:2 Summer 2003
1989 have used the Y-BOCS as one of the major constipation (which may lead to fecal impac- outcome measures. Typically a Y-BOCS score of tion), forgetfulness, and mental cloudiness, 16 to 20 is used as a study entry criterion, indi- which might be confused with dementia. Thus, cating the presence of clinically significant lower doses may be recommended. The cardiac OCD, although it has been argued that higher conduction effects of tricyclic antidepressants scores (e.g., 20 to 21) might reduce the increas- may preclude use of clomipramine completely ing placebo response rates in OCD studies in patients with preexisting cardiac conduction (Greist et al., 1995b). A 25–35% or greater re- problems, especially atrioventricular block.
Some recent studies of intravenous (IV) clo- generally considered to represent response to mipramine and citalopram (Pallanti, Quercioli, treatment (Goodman et al., 1993). The National & Koran, 2002) have been particularly promis- Institute of Mental Health Global Obsessive- ing. IV administration can produce quicker on- Compulsive Scale is another frequently used set of action and fewer side effects than the oral outcome measure. This scale provides a global form and may be effective even in patients who measure of symptom severity on a 1–15 scale do not respond to oral clomipramine. Like the (from minimal to very severe) (Pato & Pato, other SRIs, oral clomipramine usually takes a minimum of 4–6 weeks to produce a clinicallysignificant response. In contrast, in at least one Clomipramine (Anafranil) The tricyclic anti-
study by Koran, which used IV pulse dosing, depressant clomipramine is perhaps the most patients showed a response within 4.5 days extensively studied medication in the treatment (Fallon et al., 1998; Koran, Sallee, & Pallanti, of OCD. The 1991 report of the Clomipramine 1997). The reasons for this rapid response are Collaborative Study Group, which contained an not fully understood, but it is postulated that extensive review of earlier studies and also re- the IV preparations avoid first-pass liver and ported the findings of the largest double-blind, gastrointestinal metabolism, thus leading to in- placebo-controlled trial of clomipramine in creased bioavailability of the parent compoundOCD (N = 520 patients at 21 sites), found that (i.e., clomipramine). This may in turn play a clomipramine led to significantly greater im- role in rapidly desensitizing serotonergic recep- provement in OCD symptoms than did placebo.
tors or initiating changes in postsynaptic sero- Duration of treatment was 10 weeks, and the tonergic neurons, which brings about a more mean dosage was approximately 200 mg/day, rapid clinical response. These preparations are with the majority of patients (69%) taking 150 still not approved by the U.S. Food and Drug to 250 mg/day. More than half (51–60%) of Administration for clinical use in the United patients receiving clomipramine experienced a 35% or greater reduction in symptoms as mea-sured by the Y-BOCS, compared with only 7– Fluoxetine (Prozac) Fluoxetine was the first
7.5% of the placebo group. The most common SSRI available in the United States. While re- side effects were those typical of most tricyclic searchers were hopeful that fluoxetine would be antidepressants: dry mouth, dizziness, tremor, more efficacious than clomipramine, controlled fatigue, somnolence, constipation, nausea, in- double-blind trials have shown it to be equally, creased sweating, headache, mental cloudiness, but not more, effective than clomipramine and sexual dysfunction. It should be noted that (Greist et al., 1995a; Pigott et al., 1990; Wood, elderly patients may be more prone to tricyclic side effects, such as orthostatic hypotension, The fixed-dose trials of fluoxetine are partic- Brief Treatment and Crisis Intervention / 3:2 Summer 2003
ularly noteworthy (Tollefson, Birkett, Koran, & trial of clomipramine or fluoxetine did respond Genduso, 1994; Tollefson, Rampey, et al., 1994).
These studies indicated that dosages of 20, 40, All of the fluvoxamine studies showed a simi- and 60 mg/day were all effective for OCD when lar side effect profile. Interestingly, insomnia compared with placebo, but there was a trend and nervousness tended to occur early in treat- for 60 mg/day to be more effective. Some patients ment, whereas fatigue and somnolence occurred who did not respond to lower doses responded with ongoing treatment. Other side effects in- to higher doses, and others who responded to a cluded nausea, headache, and sexual dysfunc- lower dose showed further improvement on a tion (Goodman et al., 1989b, 1990b, 1997; higher dose (Tollefson, Rampey, et al., 1994; Jenike, Hyman, et al., 1990; Mallya et al., 1992).
Wood et al., 1993). Furthermore, patients main- Overall, however, a small number of patients, tained their improvement or experienced in- only 10–15%, experienced side effects that re- creased improvement during the 5- to 6-month follow-up period (Levine, Hoffman, Knepple, & Kenin, 1989; Tollefson, Rampey, et al., 1994).
Sertraline (Zoloft) Similar to other SRIs, ser-
These were some of the first studies to support traline, in a multicenter, fixed-dose, placebo- long-term treatment of OCD (see Table 1).
controlled study of 324 patients, was signifi- Fluoxetine has fewer side effects than clo- cantly more effective than placebo, with effi- mipramine, perhaps reflecting its more selective cacy similar to that demonstrated for fluoxetine mechanism of action. The most common side and fluvoxamine in other studies (Greist et al., effects are headache, nausea, insomnia, de- 1995a, 1995b). As in the fluoxetine studies, creased appetite, anorexia, dry mouth, somno- there was a trend toward higher doses of sertra- lence, nervousness, tremor, and diarrhea; these line (200 mg/day being more effective than 50 side effects tend to be dose related (Tollefson, mg/day or 100 mg/day). There was a low drop- out rate from side effects (10%); typical sideeffects included nausea, headache, diarrhea, in- Fluvoxamine (Luvox) Fluvoxamine became
available in the United States in 1995. A number A recent study compared the efficacy of ser- of systematic trials have demonstrated fluvox- traline to the non-SRI antidepressant desipra- amine’s effectiveness in treating OCD (Goodman mine for patients with OCD and comorbid de- et al., 1989b; Goodman et al., 1990b; Jenike, Hy- pression. Although these medications were sim- man, et al., 1990; Mallya, White, Waternaux, ilarly effective for depression, sertraline was & Quay, 1992). As has been demonstrated with more effective for OCD symptoms. Furthermore, most oral forms of SRIs, a relatively long treat- even though desipramine improved depressive ment trial (at least 8–10 weeks) is indicated be- symptoms, a significantly greater number of fore concluding that an SSRI is ineffective for patients treated with sertraline achieved remis- OCD (Goodman et al., 1989b). In studies of flu- sion from their depression as well as from OCD voxamine, failure to respond at 4 or 6 weeks did not predict response at 10 weeks. In the largeststudy of fluvoxamine (Goodman, Ward, Kab- Paroxetine (Paxil) Paroxetine is yet another
linger, & Murphy, 1997), even though failure to SSRI with proven efficacy in OCD. Results of a respond to a previous SSRI was associated with fixed-dose, multicenter trial of 348 patients dem- a lower likelihood of responding to fluvoxam- onstrated paroxetine’s effectiveness. As was sug- ine, 6 of 31 patients who had failed a previous gested in the sertraline and fluoxetine studies Brief Treatment and Crisis Intervention / 3:2 Summer 2003
(Greist et al., 1995b; Tollefson, Rampey, et al., ical percentage of patients responding (52% to 1994), higher doses (40 or 60 mg/day) may be 65%) in the three dosage groups compared with needed because 20 mg/day was no more effec- placebo. The placebo response rate, however, tive than placebo (Wheadon, Bushnell, & was rather high (37%), as has been seen in more Steiner, 1993). Paroxetine’s efficacy has been recent OCD medication trials. Similar to other noted to be comparable to that of other SRIs SRIs, there was a trend for a higher dose to have with similar side effects, including lethargy, dry a higher response rate, although there was no mouth, nausea, insomnia, somnolence, tremor, statistical difference between the three dosages sexual dysfunction, and decreased appetite (Zo- used (20, 40, and 60 mg/day). Initial side effects har & Judge, 1996). However, there are also re- included fatigue, sweating, dry mouth, ejacu- ports of an acute discontinuation syndrome with lation failure, nausea, and insomnia, although paroxetine, which can include general malaise, many patients habituated to these side effects asthenia, dizziness, vertigo, headache, myalgia, in 4 to 6 weeks. Thus, citalopram may be an ex- loss of appetite, nausea, diarrhea, and abdomi- cellent choice for OCD treatment because of its nal cramps. Occasional patients may experience side effect profile and low probability of caus- some of these symptoms when their dose is de- ing drug-drug interactions (Montgomery, Kas- layed by only a few hours. Thus, if the medica- per, Stein, Bang Hedegaard, & Lemming, 2001; tion is discontinued, a more gradual reduction in dose than is typically used with other SRIs isrecommended (Barr et al., 1994; Bryois, Rubin,Zbinden, & Baumann, 1998; Dominguez & Choosing an SRI?
Goodnick, 1995; Keuthen et al., 1994).
An important question is whether one SRI is Citalopram (Celexa) Citalopram has also been
more effective for OCD than the others. To in- shown to be effective for OCD. The chemical vestigate this question, a number of studies have structure of citalopram consists of two mirror directly compared the efficacy of different SRIs; images, an S (active) form and an R (inactive) meta-analyses have also been done. Head-to- form (these forms are known as enantiomers).
head SRI comparison studies have involved The S form of citalopram, escitalopram, has re- clomipramine, fluoxetine (Lopez-Ibor et al., cently become available (Lexapro). This S form 1996; Pigott et al., 1990), fluvoxamine (Freeman, is purported to have fewer side effects and mayhave a quicker onset of action in the treatment Table 1. Summary Points in Somatic Treatment of OCD
of depression (Burke, Gergel, & Bose, 2002), al-though research is needed to determine whether these potential advantages apply to OCD.
2. Trials should be at least 10–12 weeks in duration Citalopram is unique in its selectivity for sero- tonin reuptake compared with the other SRIs.
3. Higher doses than those typically needed for Its minimal effect on liver metabolism probably makes it safer than other SRIs when combined augmentation medications (such as neuroleptics) with other medications, and it therefore might to the SRI as long as there has been some response be an ideal choice for the elderly, who often take medications for other ailments as well. A 5. CBT, including exposure and response prevention, multicenter, fixed-dose, placebo-controlled trial is an effective augmentation strategy tosomatotherapy with 401 patients with OCD showed the typ- Brief Treatment and Crisis Intervention / 3:2 Summer 2003
Trimble, Deakin, Stokes, & Ashford, 1994; Ko- ran et al., 1996), paroxetine (Zohar & Judge, symptom profiles might help to predict re- 1996), sertraline (Bisserbe, Lane, & Flament, sponse to a particular SRI. However, to date, 1997), and citalopram (Mundo, Bianchi, & Bel- little relevant data are available. Nonetheless, lodi, 1997). All found that the SRIs studied were existing data suggest that certain clinical char- equally efficacious, although all but one (Bis- acteristics, such as early age of OCD onset, pres- serbe et al., 1997) may have been underpow- ence of schizotypal personality disorder, and ered, due to small sample size, to detect differ- presence of hoarding, predict poor response to medication (Ackerman, Greenland, Bystritsky, However, meta-analyses of OCD trials (Greist Morgenstern, & Katz, 1994; Alonso et al., 2001; et al., 1995a; Greist & Jefferson, 1998; Jenike, Baer et al., 1992; Eisen et al., 2001; Erzegovesi et Baer, & Greist, 1990), which compare SRIs across al., 2001; Goodman et al., 1997; Mataix-Cols, large placebo-controlled multicenter trials, lend Rauch, Manzo, Jenike, & Baer, 1999; Ravizza et some support to the notion that clomipramine al., 1995; Stein, Seedat, Shapira, & Goodman, might be more effective than the more selective agents. In one such study, a four-way (clomipra- In general, SRIs are well tolerated, although mine, fluoxetine, fluvoxamine, and sertraline) differences in side effect profiles can be consid- meta-analysis computed effect sizes by compar- ered when choosing one drug over another in ing the average change in Y-BOCS scores pooled particular patients. For instance, potential car- over various studies (Griest et al., 1995a). Clo- diac arrhythmias can make clomipramine dan- mipramine had the largest effect size. However, gerous in overdose or in those with preexisting like most meta-analyses, these studies are flawed cardiac arrhythmias. Of all the SRIs, clomipra- by various factors, including variations in the mine is most likely to cause constipation, which study protocol, sample size, and the number of can be a particular problem in the elderly. All treatment-resistant and treatment-naive sub- these agents have the potential to cause sexual jects. Nonetheless, before considering a patient side effects, ranging from anorgasmia to diffi- to be treatment resistant, these meta-analyses culty with ejaculatory function. Such side support use of clomipramine in all patients who effects may cause noncompliance and yet may do not respond to the more selective SSRIs.
not be readily volunteered by patients. It istherefore important for clinicians to ask aboutsexual side effects. There are a number of treat- Table 2. Medications Used as Primary Somatic Therapy
ment strategies for sexual side effects, including dosage reduction, transient drug holidays, and Usual Dosage
switching to another SRI. Adding certain med- Generic Name
Brand Name
ications to the SRI (e.g., stimulants, buspirone,sildenafil [Viagra]) may be helpful for some pa- tients. Perhaps most reassuring to patients is that these sexual side effects are not permanent; once the medication is stopped, baseline sexual function returns. In addition, clinical experi- ence suggests that SRIs may lead to improved *A new form of citalopram made up of the S-enantiomer (escitalo- sexual functioning in some patients, as a result pram) has recently been marketed as Lexapro, but has not yet been tested in OCD. † Not presently FDA approved for OCD treatment.
have been interfering with sexual functioning.
Brief Treatment and Crisis Intervention / 3:2 Summer 2003
Most of the controlled treatment trials re- ever, a careful treatment history, which includes viewed above have been performed in adults the patient’s report as well as review of old aged 18 to 65. While there are few controlled records, often reveals that the patient has not studies in older and younger populations, ex- been adequately treated. An adequate trial of tensive clinical experience indicates that these any single pharmacological agent should be a treatments are effective for patients of all ages.
minimum of 10 to 12 weeks and should reach the In general, children and the elderly tolerate turer, if this dose is tolerated by the patient. It changes and side effects should be carefully at- should also be determined whether poor com- tended to. It is generally recommended that, in pliance may have compromised past pharma- children, doses be considered based on body cotherapy trials, making them less than ade- weight and thus lower. For instance, a recom- quate. It is also important to determine that past mended dosage of clomipramine for children is therapy consisted of adequately performed ex- up to 150 mg/day (3 mg/kg/day) versus the 250 posure and response prevention for a minimum mg/day often recommended for adults. Simi- of sessions with good compliance (e.g., comple- larly, lower doses should be considered for the elderly, because their decreased ability to me- When assessing treatment resistance, it is also tabolize medications can increase the risk of side important to assess the patient’s diagnosis.
effects, especially when dose is combined with Schizotypal personality disorder, borderline other medicines they may be taking (Pato & personality disorder, avoidant personality dis- Steketee, 1997; Pato & Zohar, 2001) (see Table 2).
order, and obsessive-compulsive personalitydisorder seem to be associated with poorer re-sponse to pharmacotherapy, particularly if the Treatment for Refractory OCD
personality disorder is the primary diagnosis(Goodman et al., 1993; Jenike, Baer, Minichiello, The definition of treatment resistance, or treat- Schwartz, & Carey, 1986; Stein et al., 2001). Co- ment refractoriness, has been discussed at some morbid depression may inhibit the ability to length in the literature (Goodman et al., 1993; learn and to habituate to anxiety (Jenike, 1993), Jenike, 1993; March, Frances, Carpenter, & and thus may make a patient with comorbid de- Kahn, 1997; Stein, 2001). For treatment plan- pression less likely to respond to behavior ther- ning, it is critically important to determine apy until the depression is treated.
whether a particular patient is truly treatmentresistant or has simply received inadequate Augmentation Strategies
treatment. A reasonable definition of treatmentresistance is failure to respond to several (e.g., When patients partially respond to an SRI, it 3–4) adequate (in terms of dose and duration) may be reasonable to augment this response SRI trials without at least 25–35% improvement with another agent or CBT, rather than switch- in Y-BOCS scores, even when augmenting med- ing to a different SRI (March et al., 1997). How- ication or CBT has been added. In such cases, ever, it is generally thought that if no response nonpharmacological somatic approaches, such occurs with a particular SRI, there is no effect to as certain neurosurgical approaches, might be augment, and therefore switching to another considered (see below, “Neurosurgery and agent should be attempted. No augmentation Other Somatic Interventions”), although it is agent has been firmly established as efficacious.
also reasonable to first try additional SRIs. How- Many appeared promising in open trials, only to Brief Treatment and Crisis Intervention / 3:2 Summer 2003
fail in more methodically rigorous trials (Good- morbid depressive symptoms if present, because man et al., 1993). Many questions about aug- patients may then be more amenable to experi- mentation remain unanswered, including the encing the anxiety that will be evoked by the be- optimal duration of augmentation, comparative havioral challenges they perform. There is no ev- efficacy of different agents, predictors of re- idence that SRIs interfere with the learning that sponse, and mechanism of action (Jenike, 1992, occurs with behavioral therapy (see Table 1).
1993). However, since these agents do help somepatients significantly, their use should be con- Neurosurgery and Other Somatic
One potentially effective strategy in augmen- tation is to choose agents that are effective for Some patients have intractable OCD symptomsan existing comorbid condition. For instance, a even with adequate medication, augmentation, patient with comorbid psychosis or tic disorder and CBT. In these cases, more aggressive treat- may be helped by pimozide (Orap) 1–3 mg/ ment may be warranted. Promising, yet still in- day, haloperidol (Haldol) 2–10 mg/day, and adequately tested, experimental treatments in- other neuroleptic agents (risperidone [Risper- clude neurosurgery and other procedures, such dal] 2–8 mg/day, olanzapine [Zyprexa] 2.5–10 mg/ as deep brain stimulation (DBS) and vagal nerve day) (Goodman et al., 1993; Koran et al., 2000; stimulation (VNS). At present, strict criteria are McDougle et al., 1990, 2000; Saxena et al., 1996; employed to determine who is eligible for such procedures and to obtain informed consent toperform them (Mindus & Jenike, 1992).
Behavioral Therapy This issue contains an ex-
The neurosurgical procedures interrupt brain tensive review of the use of cognitive and be- tracts involved in the serotonin system and im- havioral therapy in the treatment of OCD, done plicated in the pathophysiology of OCD. The in individual, group, and family settings. Yet it surgical procedures used include anterior cap- would be an oversight to not mention the effi- sulotomy, cingulotomy, and limbic leucotomy, cacy of CBT as a pharmacotherapy augmenting which all aim to interrupt the connection be- agent. Adding CBT to an SRI can improve re- tween the cortex and the basal ganglia and re- sponse to the SRI (Direnfeld, Pato, & Gunn, lated structures (see Neuroanatomical and Neu- 2000). Research is beginning to show that com- roimaging Considerations above). These proce- bined treatment may be even more effective than dures involve making a small lesion of 10–20 mm either pharmacotherapy or behavioral therapy with either radiofrequency-heated electrodes or, alone, although these findings are still prelimi- more recently, gamma knife techniques. Gamma nary (Cottraux et al., 1990; Foa, 1994; Marks, knife procedures focus individual gamma rays Stern, Mawson, Cobb, & McDonald, 1980; Simp- deep in the brain without causing damage to the son, Gorfinkle, & Liebowitz, 1999). Some studies skull or surrounding brain tissue through have begun to indicate that pharmacotherapy which they pass. DBS and VNS interrupt similar may be particularly helpful in reducing obses- brain tracts; however, these procedures use sions, whereas compulsions may respond better electrical overstimulation rather than ablation of to behavior therapy (Direnfeld et al., 2000; Ho- the nerve cells. Data compiled from a number of hagen et al., 1998). Clinically, it may be advisable small studies have yielded success rates of 25% to have patients begin treatment with medica- to 84% with neurosurgical treatments (Mindus tion to reduce the intensity of their OCD symp- & Jenike, 1992; Jenike, 1998), which is promis- toms (especially if symptoms are severe) and co- ing given the treatment-refractory nature of the Brief Treatment and Crisis Intervention / 3:2 Summer 2003
patients who received these treatments. Results experienced a decrease in symptoms when the from DBS and VNS are still not available for medication dose was increased from the previ- ous, unsuccessful dose. Similar to previous re- ports in smaller samples of patients taking flu- Several important findings have come from one oxetine (Fontaine & Chouinard, 1989; Frenkel, of the largest prospective neurosurgical long- Rosenthal, Nezu, & Winston, 1990; Levine et al., term follow-up studies to date, in which all 44 1989), this study suggested that symptom im- patients received the same neurosurgical pro- provement was maintained over time and, even cedure (cingulotomy) (Dougherty et al., 2002).
more importantly, that further improvement oc- Clinical improvement occurred in 32% to 45% curred with longer treatment duration and/or of patients, and the average effect size was 1.27 (Cohen’s d ), comparable to that seen in pharma- In another study, of 85 patients who had been cotherapy trials (d = 1.09–1.53). However, these treated with a variety of SRIs, follow-up was changes were not immediately apparent postop- done between one year and 3.5 years after initial eratively, when most patients were encouraged treatment (Orloff et al., 1994). Not only were to receive pharmacotherapy and/or behavioral 94% of the patients still taking medication, but therapy. Thus, it is unlikely that this response 87% had maintained previous gains or achieved was due to the surgical procedure alone. Be- further improvement. Thus, from a clinical cause of the longitudinal follow-up, which had point of view, it seems wise to continue medi- a mean duration of 32 months, researchers were cation for an extended period, perhaps for 6 able to assess the longer-term impact of the pro- months to a year or longer after initiating treat- cedure. Particularly noteworthy is that patients ment, because not only is improvement main- continued to show improvement for up to 29 tained during this period, but some patients months after surgery without receiving further may experience further improvement. Further- more, the Orloff study noted that this extendedduration of treatment did not result in worsen-ing side effects; in fact, in most cases patients Duration and Discontinuation
habituated to side effects. The side effects that of Treatment
tend to persist with SRI treatment appear to be The question of how long to continue effective fatigue, weight gain, and sexual dysfunction medication requires consideration of data from (Rasmussen, Eisen, & Pato, 1993). Similar results studies of long-term efficacy, maintenance dos- have been found with sertraline. In a study of 38 ing, and treatment discontinuation. This area patients on sertraline that included a follow-up has received less research attention than has period of 2 years, the medication showed con- treatment efficacy. One of the largest studies of tinued efficacy and produced fewer side effects extended pharmacological treatment used flu- with longer-term treatment (Rasmussen, Hack- oxetine (Tollefson, Rampey, et al., 1994). In this study, two groups comprising 268 patients (70 While improvement may persist, or even in- who had responded to fluoxetine, and 198 who crease, with longer-term treatment, the question had not responded during an acute 13-week remains whether doses lower than that at which trial) were given the opportunity to continue response occurred can be used in the long term medication for another 6 months. At the end of to minimize cost and side effects. Another im- the 6 months, most of the 70 patients who had portant question is whether the medication can responded initially continued to do well, and be discontinued completely. Only a few studies over half of the 198 in the nonresponder group are available that address these issues. Koran et Brief Treatment and Crisis Intervention / 3:2 Summer 2003
al. (2002) assessed a large group of patients (N = Thus, for patients unable to tolerate medication 223) who had been successfully treated with discontinuation, it may be possible to decrease single-blind sertraline for 52 weeks and were the SRI dose in longer-term treatment. However, then randomized in a double-blind manner to clinical experience indicates that dose reduction continued treatment for another 6 months with may lead to worsening of symptoms, in which sertraline or placebo. One third (35%) of the pa- case it may be necessary to raise the dose again.
tients in the placebo group relapsed, whereasonly 12% of the sertraline group experiencedexacerbation. Although the relapse rate was Conclusion
higher with the switch to placebo than sertra-line, the relapse rate in the placebo group was For many patients, OCD is a lifelong illness ex- surprisingly lower than in earlier studies. Ear- tending from early childhood into adulthood.
lier studies in which clomipramine was abruptly However, pharmacotherapy, either alone or in discontinued or replaced had relapse rates that combination with behavioral treatment, at ade- were above 90% (Leonard et al., 1991; Pato, quate doses and duration, offers the majority of Zohar-Kadouch, Zohar, & Murphy, 1988). The patients notable improvement in symptoms and authors offered a number of plausible explana- functioning. Other biological procedures for the tions for the sertraline study results, including truly treatment refractory patient are currently the possibility that one year of effective treat- being investigated and remain experimental at ment may provide sustained benefit for patients, this time. More research is needed to identify and that patients may have engaged in self- predictors of treatment response to various directed behavior therapy, which was not read- medications and to better guide clinicians in ily available when the clomipramine discontinu- choosing a single treatment modality versus a ation studies were done. They also noted that combination of medications and CBT. Further while OCD symptom ratings did not worsen in research is also needed on effective SRI augmen- the placebo-treated group as a whole, quality- tation strategies and on optimal doses and treat- of-life measures showed significant deteriora- ment duration to prevent relapse and symptom tion. This finding points to the need for more sensitive and comprehensive measures of pa-tient improvement in the further exploration oflong-term treatment efficacy.
Of interest, some anecdotal data suggest that it Acknowledgment
may be possible to decrease the dose of medica-tion over the longer term without subsequent Special thanks to Amy Eisener, BS, for all her assis- relapse (Pato, Hill, & Murphy, 1990). Two more tance in the preparation of the manuscript.
recent studies have more systematically ad-dressed this issue. In one study by Mundo et al.
(1997), patients were treated with one third or References
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CANINE DISTEMPER IN FERRETS This handout reviewed by Dr. Mark Burgess of Southwest Animal Hospital in Beaverton, Oregon (503) 643-2137. Transmission Canine (dog) distemper is an airborne virus that can be transmitted from direct or indirect contact with an infected animal. It can be transmitted from your clothing, shoes, or from your skin for at least 8 hours after exposure. In other


IL SECONDO RINASCIMENTO IL SECONDO RINASCIMENTO I capitani dell’avvenire ARMANDO VERDIGLIONE 18 maggio 1996, dalla conferenza del sabato ELISABETTA COSTA Perché molti subiscono il fascino della morte? A.V. È affascinato dalla morte chi presume di conoscerla, chi presume che la conoscenza sia conoscenza della morte e l’accetta, chi l’assume, pertanto chi si abbatte, chi si

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