INDEX OF CONTRIBUTIONS INDEX OF CONTRIBUTIONS LECTURES Roger Sheldon Enzymatic Conversions under Non-Natural Conditions Willem P.C. Stemmer Molecular Breeding of Enzymes, Pathways and Organisms Friedrich Lottspeich Proteomics - A Powerful Tool for Functional Analysis Dick B. Janssen Engineered Biocatalysts for the Production of Chiral Epoxides and Alcohols Donald Hilvert C
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Greg Hajcak ● Jonathan D. Huppert ● Edna B. Foa W H AT I S O B S E S S I V E – C O M P U L S I V E D I S O R D E R ( O C D ) ?
OCD is defined by recurrent obsessions and/or compulsions that significantlyimpair functioning (American Psychiatric Association, 1994). Obsessions involveintrusive thoughts, images, or impulses that cause significant distress. Commonobsessions include preoccupation with contamination, concerns about harmingoneself or others, intrusive sexual thoughts, fear of throwing possessions away, andpreoccupation with things not being “just right.” Compulsions can be either men-tal or physical behaviors that people have a difficult time resisting; functionally,over 90% of patients with OCD report that they perform compulsions to reduce thedistress associated with obsessions (Foa et al., 1995). Common compulsions includewashing, checking, reviewing, hoarding, reassurance seeking, and repeating actsuntil they feel as if they have been performed correctly. Although DSM-IV criteriado not require the presence of both obsessions and compulsions, only 2% ofpatients in the DSM-IV field study reported obsessions alone (Foa et al., 1995).
Covert mental actions, such as repeating a phrase mentally, or replacing an anxiety-provoking thought or image with a neutralizing thought or image, are important toidentify as they can be overlooked in favor of more overt compulsive behaviors.
When patients do not recognize that their obsessions and compulsions are exces-sive or unreasonable, they are given the diagnosis of OCD “with poor insight.” Fromthe standpoint of cognitive behavioral therapy, it is crucial to identify the functionalrelationship between obsessive thoughts and ritualistic behaviors, and to note thepresence of poor insight.
B A S I C FA C T S A B O U T O C D
OCD is a relatively common disorder, estimated to occur in approximately. 5–3% ofthe population (Andrews, Henderson, & Hall, 2001; Rasmussen & Eisen, 1992).
OCD can be observed in childhood, and has been reported as young as age 2(Rapoport, Swedo, & Leonard, 1992), although it more commonly begins in earlyadolescence and young adulthood (Rasmussen & Eisen, 1992). In adult samples,approximately 50% of patients with OCD are female (Rasmussen & Tsuang, 1986).
Consistent with the finding that OCD has an earlier age of onset in males (Lochneret al., 2004), reports indicate OCD in twice as many males as females in some pedi-atric samples (Swedo, Rapoport, Leonard, Lenane, & Cheslow, 1989).
Most patients with OCD experience a chronic course with waning and waxing symptoms (Rasmussen & Eisen, 1992). OCD has been associated with significantcomorbid psychiatric illnesses, especially depression and other anxiety disorders(Denys Tenny, van Megen, de Geus, & Westenberg, 2004, LaSalle et al., 2004). Infact, these studies indicate that between one-third and two-thirds of patients withOCD meet criteria for major depressive disorder. There also appear to be high ratesof comorbidity between OCD and tic disorders (Eichstedt & Arnold, 2001), as well Hajack, G., Huppert, J. D., & Foa, E. B. (in press). Obsessive–compulsive disorder. In J. E. Fisher & W. T.
O’Donohue (Eds.), Practitioner’s guide to evidence-based psychotherapy. New York: Springer.
as potentially higher rates of comorbidity with other impulse-control disorders (cf,Foa & Franklin, 2001). In terms of impact on quality of life and functioning, OCDhas been found to adversely affect employment, social functioning, physical func-tioning, and general quality of life (Quilty, Van Ameringen, Mancini, Oakman, &Farvolden, 2003; Bijl & Rivelli, 2000).
W H AT C A U S E S O C D ?
There is no single cause that currently explains why some people develop OCD.
There are, however, a number of theoretical accounts regarding the developmentand maintenance of OCD. Dollard & Miller (1950) suggest that fear associated withobsessions begins via classical conditioning (e.g., the experience of fear is pairedwith a cue such as a dirty bathroom or an intrusive thought), and rituals are main-tained through operant conditioning (e.g., avoiding dirty places or performing rit-uals reduces anxiety associated with the obsession). More cognitive theories focuson the false assumptions commonly found in patients with OCD, especially exag-gerated personal responsibility (Salkovskis, 1985). Foa and Kozak (1985) proposedthat patients with OCD overestimate threat because they fail to take the absence ofdanger as a signal of safety.
Although data indicates that there is some type of familial transmission of OCD (Nestadt et al., 2000), this also appears to be the case for most anxiety disorders(Nestadt et al., 2001). A number of genes believed to be involved in OCD have beenidentified; however, progress in this area seems to be hampered because of the clin-ical heterogeneity of OCD (Pato, Pato, & Pauls, 2002). For instance, recent studieshave suggested that gender, neurobiological differences, comorbidity, and symp-tom types may all contribute to etiological heterogeneity in OCD. Specifically, oneOCD phenotype appears to involve earlier onset, being male, a more chroniccourse, higher incidence of tic-related disorders, higher familial incidence of OCsymptoms, and may be associated with distinct genetic susceptibility (Eichstedt &Arnold, 2001; Lochner et al., 2004).
A subset of pediatric patients develop OCD more following streptococcal infec- tion, and these cases are referred to as Pediatric Autoimmune NeuropsychiatricDisorders Associated with Strep (PANDAS; Swedo et al., 1998). Hallmark featuresof PANDAS include a relatively sudden onset and symptom exacerbations andreductions that follow the course of step infections. Few data are available to dateto establish the prevalence of PANDAS within patients with OCD, but our clinicalexperience suggests a small percentage of patients follow the hallmark features.
In terms of the neural substrates of OCD, recent neuroimaging studies have implicated hyperactivity in frontostriatal circuits, including the orbitofrontal cor-tex, anterior cingulate cortex, and structures of the basal ganglia (Saxena, Brody,Schwartz, & Baxter, 1998). Evidence suggests that symptom reduction followingeither psychotherapy or psychopharmacology is reliably related to reductions inactivity in these areas of the brain. Functionally, the frontostriatal circuit has beenfound to be involved in action monitoring. Consistent with both OCD symptomsand OCD-related abnormalities of these areas, recent studies have reported hyper-active brain activity related to response monitoring in Obsessive–Compulsive sub-jects (Gehring, Himk, & Nisenson, 2000; Hajcak & Simons, 2002; Ursu, Stenger, [Au1]Shear, Jones, & Carter, 2003). Although neuropsychological findings vary some-what from study to study, patients with OCD may show deficits in some memorytasks and tasks that assess executive functions such as organization (cf, Kuelz,Hohagen, & Volderholzer, 2004).
O B S E S S I V E – C O M P U L S I V E D I S O R D E R W H AT I S I N V O LV E D I N E F F E C T I V E A S S E S S M E N T ?
OCD symptom severity can be assessed with either clinical interviews or self-reportmeasures. Although structured clinical interviews can be used to determinewhether or not patients meet DSM-IV criteria for OCD, the semistructured Yale-Brown Obsessive–Compulsive Scale (Y-BOCS; Goodman et al., 1989a, 1989b) isconsidered the gold standard in OCD assessment. The Y-BOCS is a semistructuredclinician-administered interview that involves both a symptom checklist thatassesses the presence of 40 obsessions and 29 compulsions, and a measure of symp-tom severity. Severity of obsessions and compulsions are calculated separately,where each are rated for time occupied, interference, distress, resistance, and con-trol. The Y-BOCS total score is the sum of both the obsession and compulsion sever-ity scales. The total scores run from 0 to 40, with the average patient in most studiesranging between a 24 and 28, and a clinical cut-score of 14.
There are several self-report instruments including the Maudsley Obsessive–Compulsive Inventory (Hodgson & Rachman, 1977), the PaduaInventory—Washington State University Revision (Burns, Keortge, Formea, &Sternberger, 1996), and the Vancouver Obsessive–Compulsive Inventory (in press).
One of the most recent, and easy to administer, is the Obsessive–CompulsiveInventory—Revised (OCI-R; Foa, Huppert, et al., 2002), an 18-item self-reportmeasure that assesses the distress associated with obsessions and compulsions. Inaddition to the total score, separate subscale scores can be calculated for Washing,Checking, Ordering, Obsessing, Hoarding, and Neutralizing. Foa, Huppert, et al.
(2002) report excellent psychometric properties for the OCI-R in clinical patientswith a range of anxiety disorders and nonanxious controls; excellent psychometricproperties have also been reported in a nonclinical sample (Hajcak, Huppert,Simons, & Foa, 2004).
W H AT S H O U L D B E R U L E D O U T ?
Because of the high rates of psychiatric comorbidity in patients with OCD, it can bedifficult to differentiate OCD from other disorders with related symptoms.
Specifically, obsessions should be differentiated from depressive rumination andpathological worry characteristic of MDD and generalized anxiety disorder (GAD),respectively. These related symptoms can often be differentiated in the followingway: the content of worry is usually verbally based, typically involves real-world con-cerns (e.g., the health of older parents, money in difficult financial times, etc.) andis experienced as appropriate or ego-syntonic. Ruminations generally surroundnegativistic thoughts about the past and the self and/or world, and depressedpatients rarely struggle to suppress ruminations. On the other hand, obsessionsgenerally involve magical or unrealistic thinking and images that are experiencedas ego-dystonic; furthermore, patients with OCD continually attempt to suppressobsessions (cf, Foa & Franklin, 2001).
W H AT T R E AT M E N T S A R E E F F E C T I V E ?
Behavior therapy that involves both exposure and response prevention (EX/RP)are considered the first-line treatment for OCD by experts (Greist et al., 2003).
EX/RP entails exposing patients to feared stimuli in a hierarchical fashion, andhaving patients completely refrain from ritualizing. Exposures can be in vivo(e.g., touching contaminated objects) and/or imaginal (e.g., thinking about spreading contamination). Imaginal exposures should be utilized, in particular,to confront patients with their unrealistic feared catastrophes that cannot and/orshould not be produced in reality (e.g., finding out that one has a brain tumor).
Importantly, both imaginal and in vivo exposures must be long enough andrepeated frequently enough to allow for anxiety habituation (cf, Foa & Franklin,2001). During the course of EX/RP, patients learn that they do not need to ritu-alize to reduce their anxiety—that anxiety habituates on its own. Importantly,they learn that the feared disasters they anticipate do not materialize and there-fore they do not need to protect themselves by ritualizing or avoiding feared sit-uations.
A number of studies have shown EX/RP to be superior to a number of control treatments (Abramowitz, 1997). Furthermore, many studies have demonstratedthat treatment gains following EX/RP are maintained over long periods of time—up to 5 years in one study (see Marks, 1997). Studies examining whether the bene-ficial effects of EX/RP generalize beyond therapy delivered by experts in researchsettings have found support for the general effectiveness of EX/RP in both nonre-search and private practice settings (Franklin, Abromawitz, Kozak, Levitt, & Foa,2000; Warren & Thomas, 2001), as well as in ethnically diverse populations(Friedman et al., 2003). Importantly, EX/RP also appears generally effective forpatients with comorbid depression (Abramowitz, Franklin, Street, Kozak, & Foa,2000; Overbeek, Schruers, Vermetten, Griez, 2002) and personality disorders(Franklin, Harap, & Herbert, 2004), further suggesting the generalizability ofEX/RP as an effective treatment.
Many studies have also found that psychopharmacological treatment with selec- tive serotonin reuptake inhibitors (SSRIs) results in significantly greater OCDsymptom reduction relative to placebo (for a review, see Dougherty, Rauch, &Jenike, 2002). However, when the medicine is discontinued, some studies havereported high rates of relapse (Koran et al., 2002), although longer-term treatmentmay reduce rates of relapse somewhat (Hollander et al., 2003). Relatively few stud-ies have directly compared therapy with SSRI with EX/RP; however, the availableevidence suggests that EX/RP is at least as effective if not superior to existing SSRIs(Dougherty et al., 2002). In a recent study, EX/RP was superior to clomipramine,and the combined treatment outcome was superior to medication only, but equiv-alent to EX/RP only (Foa et al, in press). Thus, although there is some evidencethat the combination of SSRI and EX/RP produces slightly better outcome thanEX/RP alone (Hohagen et al., 1998), their combination does not appear to havereliable synergistic effects (cf, Foa, Franklin, & Moser, 2002). Alternative treatmentsfor intractable cases of OCD have also been evaluated. Notably, deep-brain stimu-lation (cf, Kopell, Greenberg, & Rezai, 2004) and the surgical removal of the cin-gulate have shown to improve some treatment-resistant cases (Dougherty et al.,2002).
W H AT P R E D I C T S T R E AT M E N T O U T C O M E ?
Most patients that get adequate treatment with either EX/RP or pharmacotherapywill experience significant reductions in symptom severity. However, there are anumber of factors that appear related to poor outcome following therapy. Somestudies have found that specific patterns of pretreatment brain activity differentiallypredict positive treatment response to both pharmacotherapy and behavior therapy(cf, Hurley, Saxena, Rauch, Hoehn-Saric, & Taber, 2002). An early study suggestedthat OCD patients that have obsessions in the absence of overt rituals may fare O B S E S S I V E – C O M P U L S I V E D I S O R D E R more poorly than patients with overt rituals (Rachman & Hodgson, 1980); however,this difference may have resulted from early failures to identify and target covertmental rituals (cf, Abramowitz, Franklin, Schwartz, & Furr 2003). Subsequent stud-ies suggest that poor insight is associated with poorer outcome with EX/RP(Abramowitz et al., 2003). Additionally, a number of studies have reported thathoarding is related to poorer outcome following both cognitive-behavioral therapy(Abramowitz et al., 2000; Mataix-Cols, Marks, Greist, Kobak, & Baer, 2002), andpharmacotherapy (Mataix-Cols, Rauch, Manzo, Jenike, & Baer, 1999). Severedepression may also be associated with a somewhat attenuated treatment response(Abramowitiz et al., 2000; Overbeek, Schruers, Vermetten, & Griez, 2002).
W H AT D O W E S T I L L N E E D T O K N O W ?
OCD is a heterogeneous disorder, and further progress may depend on researchthat focuses on particular symptom subtypes (cf, Calamari et al., 2003). Forinstance, whether hoarding represents a distinct subtype of OCD or should be con-sidered a separate but related disorder should be a topic of future studies (seeSteketee & Frost, 2003). Similarly, the OCD with childhood-onset should be inves-tigated with respect to OCD that begins later in life. Within the latter subtype, itsrelationship to tic-related disorders is another area that requires further study.
Identifying distinct phenotypes is a necessary step toward better understandingOCD at the level of molecular mechanisms, including the involvement of bothspecific genes and neurotransmitters.
In addition to furthering our understanding of basic psychopathology and mechanisms underlying the subtypes of OCD, more research will be needed toguide practitioners in terms of how to treat treatment-resistant patients (i.e., thosewho do not respond to SSRIs or EX/RP), how to maintain treatment gains, andhow to treat patients to full remission. Finally, how to best export the most effectivetreatments to the community and ensure that more patients are receiving adequatetreatment also requires further examination.
W H AT A R E S O M E H E L P F U L R E S O U R C E S ?
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[Au1]: Ursu et al. (2004) has been changed to Ursu et al. (2003) in accord to the list. Please check[Au2]: Please update Foa (in press)[Au3]: Bibliographic year has been inserted from the text. Please check[Au4]: Thordarson et al. (2004) is listed but not cited. Please check.
This information sheet is a short guide to tacrolimus ointment (also known as Protopic). Itcontains information, which will help in understanding what tacrolimus ointment does, how it works,how it is used and what the possible side effects might be. Tacrolimus ointment is an ointment applied to the skin. It is not a steroid. Tacrolimus ointment is animmunomodulatory drug, which means it mod