Neurobiological Models of Obsessive-Compulsive Disorder

Review Article Neurobiological Models of Obsessive-Compulsive Disorder SCOTT L. RAUCH, M.D. MICHAEL A. JENIKE, M.D.

The authors review current neurobiological models of obsessive·compulsive disorder (OCD). The rationale for anatomically based models is outlined and selected brain regions of interest are discussed. The authors conclude that there is abundant evidence to implicate multiple brain regions as sites ofabnormality in OCD. A review of neuropharmacological concepts related to the serotonergic (5-HT) hypothesis of OCD is also presented. The authors conclude that antiobsessional agents may well have therapeutic effects via the 5-HT system, yet there is little unequivocal evidence to suggest an underlying abnormality in the 5-HT system. A comprehensive neurobiological model of OCD must acknowledge the interrelationship between multiple transmitter systems and integrate anatomical with neuropharmacological concepts.

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bsessive.compulsive disorder (OCD) is characterized by recurrent obsessions or compulsions that are sufficiently severe to cause marked distress, be time consuming, or otherwise significantly interfere with normal daily functioning.' Individuals with OCD typically retain insight and recognize their obsessions as products of their own mind, which distinguishes obsessions from delusions. Guilt and shame often accompany their thoughts and actions, causing great emotional pain beyond the decrement in daily functioning that is attributable to the OCD symptoms themselves. These patients sometimes seek to hide their condition for fear that they will be thought "crazy." PerReceived April 10, 1991; revised July 22. 1991; accepted July 29. 1991. From the Department of Psychiatry. Massachusetts General Hospital. and Harvard Medical School. Boston. MA. Address reprint requests to Dr. Rauch. Obsessive-Compulsive Disorders Unit, 9th Roor. MGHEast. Bid. 149, 13th St., Charlestown Navy Yard, Charlestown, MA02129. Copyright © 1993 The Academy of Psychosomatic Medicine. 20

haps for this reason, the prevalence of OCD was previously underestimated; currently, lifetime prevalence is estimated at 2%-3% of the adult population? In the middle ages, symptoms suggestive of OCD were attributed to demonic possession and treated by exorcism. Not until the beginning of the twentieth century had the disorder been described formally and psychological theories developed. 3 Freud4•s was responsible for several early case reports and the application of psychoanalytic theory in an effort to understand and treat what he termed "obsessive-compulsive neurosis." Despite a lack of evidence to suggest efficacy, psychodynamic psychotherapy remained a popular treatment for OCD through the 1970s. Meanwhile, behavioral models were developed and led to treatment strategies that proved somewhat effective, especially for patients with compulsions. 6 More recently, advances in the neurosciences, including innovative technologies and pharmacotherapies, have prompted investigators to construct neurobiological models of OCD. The following is a PSYCHOSOMATICS

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review of these models, which is organized in two parts: I) anatomical concepts and 2) neuropharmacological concepts. PART I: ANATOMICAL CONCEPTS The clinical neurosciences have a rich tradition of correlating clinical presentation with site of pathology. In OCD, however, no pathognomonic structural lesion has been identified, yet it remains intuitively appealing to search for underlying localized pathology. With the advent of MRI and PET scanning and conventional and computerized EEG, it has become possible to locate regional abnormalities that belie gross anatomical inspection. The following is a review of the data generated using these various paradigms that presents convergent evidence about putative sites of dysfunction in OCD. Brain Regions of Interest There are currently several brain regions that are prime candidates as possible sites of dysfunction in OCD: I) basal ganglia (BG), 2) frontal cortex, and 3) limbic structures including cingulum, septum, hippocampus, and temporal cortex. Basal ganglia. The BG are subcortical nuclei that comprise the extrapyramidal system and are closely associated with cortical and limbic structures. The BG consist of caudate nucleus, putamen, and globus pallidus (the three together form the corpus striatum), plus the amygdaloid complex. Historically, the BG have been attributed a role in the modulation of corticospinal outflow or movement. Consequently, there has been great interest in this area in relation to the movement disorders. There is some evidence linking BG dysfunction with Tourette syndrome (TS)7.s as well as Sydenham's chorea9 and several other movement disorders, to which are closely associated with OCD. TS is a disorder that typically develops in childhood and is characterized by tics manifested as involuntary movements or vocalVOLUME 34· NUMBER \ • JANUARY - FEBRUARY 1993

izations. The tics, like compulsions of OCD, tend to be exacerbated in times of stress and can be suppressed temporarily during which time a subjective sense of tension escalates. Patients with TS frequently have concurrent symptoms of OCD as well as a disproportionately high incidence of OCD-affected relatives. II Reciprocally, subjects with OCD are more likely than controls to have tics as are their families. 12 A genetic relationship between the two disorders has been suggested, and the two clinical entities may represent different phenotypic expressions of the same genetic anomaly. 13.14 Patients with Sydenham's chorea, a movement disorder that afflicts up to 20% of patients with rheumatic fever, have a higher prevalence of OCD symptoms than control patients who have had rheumatic fever without Sydenham's chorea. 9 The etiology of Sydenham's chorea is thought to be related to antibodies to BG. The BG are implicated in OCD beyond a mutual relationship with movement disorders. IS In part, BG nuclei participate in cognitive aspects of behavior, a role consistent with the finding that the striatum receives inputs from the entire neocortex. 16 Whereas the motor functions of the BG are carried out predominantly by the putamen, the cognitive functions are thought to be carried out by the caudate nuc1eus. 16 Thus the BG are involved in thought, and perhaps abnormalities in these areas ca:: result in obsessions and repetitive patterns of behavior. CT studies have suggested structural differences between the brains of OCD subjects and normal control subjects. Ventricular/brain ratios have been shown to be enlarged in OCD subjects, I? and caudate volume has been found to be reduced compared with normal control subjects. IS However, Kellner et al. 19 did not find reduced caudate volumes in a study using a more accurate modality: MRI. In case reports, OCD patients have been found to have focal lesions involving the caudate and putamen as determined by MRI. 20•21 PET has revealed increased metabolic activity at the head of the caudate bilaterally in the brains of OCD subjects compared with control subjects. 22 Taken 2\

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together, these data are compelling and suggest striatal abnormality in OCD. They do not, however, address whether the abnormal findings are reflective of primary pathology vs. some compensatory or secondary process. The clinical relationship between OCD and TS combined with mutual evidence for BO involvement has prompted theories of related underlying pathophysiology. Cummings and Frankel 23 suggested that whereas tics may represent aberrant "simple motor programs," the symptoms of OCD are "more complex motor programs" and both are initiated via similar anomalous activity. Tics are not preceded by the normal bereitschaftspotentials that precede usual voluntary movements. 24 ,2S Determinations of bereitschaftspotentials in 44 OCD subjects vs. 40 normal control subjects demonstrated increased bereitschaftspotential latency in the OCD subjects. 26 The authors concluded that this indicates an abnormality in complex motor programming, which is likely reflective of combined cortical and subcortical dysfunction. There is much to be learned about normal BO function and its interrelationships with other neural networks. Elaborate experiments performed with cats entailing bilateral caudate lesions have led to a model of the striatum as "a fine tuner of the brain.'t27 Acaudate cats exhibit stereotypy, deficits in postural adjustments, perseveration, hyperreactivity, and "compulsive approaching behavior." These investigators 27 concluded that, among other functions, the striatum plays an integrative role and influences the sequencing of behaviors and the capacity for cognitive discrimination. From a neuroethological perspective, one theory suggests that the 80 are responsible for elaborating fixed action patterns, whereas the frontal cortex is responsible for selectively inhibiting such actions. 9.28 In another review,29 the BO are conceptualized as having a sensory gating function. In this way, the BO govern attention shifting and, when lesioned, leave the animal unable to shift appropriately, hence perseverating. Yet another review 30 describes the BO as a funnel through which information between thalamus 22

and cortex must pass. In this context, the BO separately influence five different corticostriate pathways, each via a corresponding BOthalamocortical circuit (Le., motor, oculomotor, dorsolateral prefrontal, lateral orbitofrontal, and anterior cingulate). Again, the complexity and wide-ranging influence of the BO is emphasized. In summary, the BO were formerly conceptualized as subserving a circumscribed motor function, but recent evidence also implicates these structures in cognitive processes. The BO had been implicated in a range of movement disorders. There is compelling evidence from various imaging modalities to suggest BO abnormalities in OCD as well, but there are insufficient data to distinguish whether these abnormalities are primary or secondary. Animal studies suggest that caudate lesions may produce deficits reminiscent of OCD symptoms. Further, an evolving understanding of BO acknowledges a previously unrecognized complexity of function and interrelationship with cortical and limbic circuits. These data together implicate the 80 in the pathophysiology of OCD. In keeping with more comprehensive anatomical models ofOCD,31 it is likely that multiple brain regions are affected in this disorder.

Frontal cortex. The frontal lobes are associated with neuropsychological functions of programming, regulating, controlling, and verifying behaviors. Thus frontal lobe pathology is correlated with inflexibility, decreased response inhibition, perseveration, and stereotypy,32 characteristics reminiscent of OCD symptomatology. Some neuropsychological studies of OCD subjects have implicated frontal lobe dysfunction;,·33-3S whereas another study failed to demonstrate frontal findings (Otto et aI., unpublished observations, 1991) but did find subtle memory deficits. A controlled electrophysiological study of OCD subjects demonstrated frontal cortical abnormalities in evoked potentials,3s and case reports have noted EEO abnormalities consistent with frontal epileptic focL 36 PSYCHOSOMATICS

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On the other hand, radiological studies have not revealed gross structural pathology in the frontal lobes of OCD subjects. 17.37.38 There is, however, evidence suggesting subtle metabolic or compositional abnormalities in the frontal lobes. Garber et aI.,39 comparing nuclear magnetic resonance brain images of 32 OCD subjects and 14 normal controls, found that OCD subjects had prolonged T. signals in right frontal white matter and increased right-left frontal white matter T•. Further, right-left T, for orbitofrontal cortex correlated with OCD symptom severity in the subset of patients who were untreated or who had positive family histories of OCD. The authors acknowledged that elevated T. is a nonspecific finding that may reflect increased free water or decreased molecular binding of water. Such differences can be related to compositional changes in extracellular, membrane, or cytoplasmic compartments or be a consequence of cerebrospinal fluid (CSF) averaging or differences in local blood flow. Therefore, the underlying pathophysiological significance of these frontal findings is unknown. Nonetheless, the finding of a localized abnormality that correlates with symptom severity stands as evidence for frontal involvement. Again, the distinction between primary lesion vs. secondary or compensatory phenomenon cannot be made. PET studies have consistently shown increased frontal cortical metabolism in OCD subjects compared with controls. PET analysis of 10 OCD subjects and 10 controls demonstrated increased metabolism in orbital gyrus and orbital gyrus/ipsilateral hemispheric ratio bilaterally in OCD patients. 40 These findings have been replicated!' Similarly, PET investigation of 18 adult childhood-onset OCD subjects vs. control subjects revealed increased metabolism in bilateral prefrontal areas and an increase in left orbitofrontal cortex. 28 Discrepancies between this and previous studies could be attributable to variations in the test conditions. In this study, for instance, subjects were scanned at rest under conditions of reduced auditory and visual stimulation. Despite some variability in the findings, the radiological VOLUME 34· NUMBER I • JANUARY - FEBRUARY 1993

evidence does speak for frontal, specifically orbitofrontal, hyperactivity in OCD. The available data support theories of frontal cortical dysfunction in OCD!2 Findings of asymmetry suggest that OCD may be a consequence of abnormal laterality of function.2 6.J.4 An analysis of neurological soft signs revealed a preponderance of signs consistent with right hemispheric dysfunction,43 whereas studies of event-related potentials44 and neuroimaging data have implicated left hemispheric involvement. The evidence for dual involvement of BG and frontal cortex has prompted several hypotheses that rely on the interrelationship between multiple brain regions. One theory suggests that the primary defect in OCD is striatal hypofunction and that cortical hyperactivity is a secondary response that, while serving a compensatory function, simultaneously produces OCD symptoms. 4• PET analysis of OCD patients after successful pharmacological treatment has demonstrated normalization of glucose metabolic rates in both frontal cortex and caudate. 4s However, such findings do not solve the question of primary vs. secondary abnormalities. Other models go beyond these two brain regions to incorporate other structures of interest, including the tracts that connect them. 31 The significance of psychosurgery data is best interpreted in this context. The psychosurgical literature provides evidence for attenuation of OCD symptoms following leucotomy, cingulotomy, thalamotomy, and anterior capsulotomy,46-48 procedures that entail interruption of the frontothalamic axis. As discussed earlier, this axis is modulated by the BG. Certainly, the success of surgical procedures is consistent with a role for frontal cortex and BG in elaborating the symptoms of OCD. The role of the cingulum will be discussed. Limbic structures. The limbic system consists of several interconnected structures that are thought to serve as the neural substrate for drive-related and emotional behavior. Limbic structures include the septal area, hippocampus, cingulum, amygdala, and portions of the temporal lobe, particularly the parahippocampal 23

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gyrus. The limbic system has widespread connections to neocortex and outflow through the hypothalamus via the medial forebrain bundle. Animal models of OCD include bilateral hippocampectomized rats that exhibit repetitive behaviors, invariability, excessiveness, and enhanced avoidance. 49-S0 One theory suggests that the septohippocampal system serves as a "comparator." In this role, the septohippocampus interacts with cortical inputs to compare sensory information with anticipated conditions then, via inhibitory output, modulates behavior accordingly.sl The comparator responds to novel or threatening stimuli with behavioral inhibition and enhanced attention and arousal. Therefore, experiencing anxiety in innocuous situations and repetitive or checking behaviors such as those seen in OCD could be explained as a consequence of comparator malfunctions. Interestingly, other authors have attributed a comparator function to the BG. IS The cingulum is closely associated with the septohippocampal system and thalamocortical tracts. Clinical observations have suggested that electrical stimulation of the cingulum causes stereotypy that is accompanied by a subjective quality similar to that of compulsive urges. S2 PET analysis has shown OCD subjects to have increased metabolic activity bilaterally in the anterior cingulate cortex. 28 Cingulate lesions have been shown to ameliorate OCD symptoms in some patients4 6-48.s3-ss and may act by disrupting thalamocortical tracts as in leukotomy.s6.s1 Thus, it has been hypothesized that cingulate hyperactivity causes compulsive behavior.S8 The temporal lobes were initially implicated in OCD as a consequence of clinical similarities between OCD and temporal lobe epilepsy. Complex partial seizures, typically involving the temporal lobe, are characterized by protean behavioral manifestations, including the reported experience of "forced thinking" that is almost indistinguishable from obsessional thinking. S9 In addition, there are several reports that demonstrate temporal lobe EEG abnormalities coinciding with OCD.60-62 How24

ever, there have been other large series that have not found significant EEG differences between OCD subjects and controls. 63.64 There have been anecdotal reports of OCD treatment efficacy with the anticonvulsant agent clonazepam,6s.66 whereas others report little success with Carbamazepine.6O•61 SUMMARY There is some evidence that implicates particular brain regions in the pathophysiology of OCD. Pathological lesions in BG have occasionally been associated with OCD. Radiological investigations reveal structural/metabolic abnormalities in BG, frontal cortex, and cingulum. Electrophysiological data suggest that abnormal activity in frontal cortex, cingulum, or temporal lobes can produce symptomatology characteristic of OCD, and a variety of paradigms point to lateralized dysfunction. Surgical lesions at several different locations can reduce OCD symptoms. This body of evidence that implicates multiple regions could be viewed as divergent and supportive of a pathophysiological heterogeneity of OCD. Indeed, clinically it seems likely that heterogeneity exists in this population. Nonetheless, these findings should be accepted as a testament to the complexity ofthe brain and with it the concept that the underlying pathophysiology of OCD may involve multiple brain regions. There is, as yet, no compelling evidence for a solitary primary lesion underlying this disorder. It also remains to be determined which findings will be consistently replicated and which, if any, regional abnormalities are secondary or compensatory. Progress in understanding OCD depends on comprehensive models that reconcile the full scope of available data. Ambitious attempts to develop such a model, such as that recently proposed by Modell et al.,31 may serve to stimulate and direct future research. A complete model will also require an accounting of the neurochemistry and pharmacology along with anatomy and physiology. PSYCHOSOMATICS

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PART II: NEUROPHARMACOLOGICAL CONCEPTS There has been a tendency in neuroscience to associate each neuropsychiatric disorder with a single transmitter system and hypotheses depending on a regional diminution or excess. This approach has met with some success, such as in the case of nigrostriatal dopaminergic depletion in Parkinson's disease. One must wonder, however, to what degree other disorders can be understood with this simplistic approach. Similarly troubling is the practice of inferring specific transmitter involvement based on the pharmacology of efficacious treatments. As the dopamine hypothesis of schizophrenia was born out of the treatment efficacy of dopaminergic antagonists, so too was the serotonergic hypothesis of OCD derived from the beneficial effects of clomipramine (CMI). Subsequently, the serotonergic (5-HT) hypothesis has stimulated much investigation of 5-HT systems and their relationship to OCD. The following is a review of that evidence as well as a discussion regarding the possible role of other transmitter systems. Response to Serotonergic Medications There is evidence that selective 5-HT reuptake inhibitors are efficacious in the treatment of OCD. In 1980, Thoren et a1. 68 ,69 published the results of a double-blind, controlled study in which 24 patients with OCD underwent an initial treatment with placebo followed by random assignment to treatment with CMI or nortriptyline. Only CMI was significantly superior to placebo in reducing OCD symptoms. Further, treatment response to CMI was strongly correlated with posttreatment reductions in CSF concentrations of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA). Six subjects also met Research Diagnostic Criteria for major depression. Those with concomitant depressive disorder did not differ from the nondepressed group in terms of treatment response. Subsequent to the above study, CMI was given openly to 22 subjects and 50% were responders. VOLUME 34· NUMBER I • JANUARY - FEBRUARY 1993

When CMI was later discontinued, the symptoms returned. In this study, nortriptyline was chosen for comparison because of its relative selectivity for noradrenergic reuptake blockade. Thus, these results were taken to support the notion that I) CMI is an efficacious treatment for OCD and 2) that CMI's superiority to nortriptyline might be a consequence of its differential selectivity for 5-HT vs. noradrenergic receptors. CMI was compared with the monoamine oxidase inhibitor (MAO!) clorgyline in the treatment of 13 OCD subjects using a doubleblind, placebo-controlled crossover paradigm.70 CMI treatment significantly reduced OCD symptoms compared with both clorgyline and placebo. Again, improvement on CMI correlated with plasma concentration and was not dependent on concurrent depression. Clorgyline was no more effective than placebo in reducing OCD symptoms. Swedo et al. 71 compared CMI with desipramine (a noradrenergic uptake inhibitor) in the treatment of 48 children and adolescents with OCD. A double-blind crossover paradigm was used, and again CMI was found to be clearly superior to desipramine. Sixty-four percent of the patients who derived benefit from initial treatment with CMI relapsed when switched to desipramine. Again, though there was comorbidity with major depression, the depressed subjects showed no difference in their response to treatment in terms of OCD measures. The conclusions from this study parallel those of Thoren et al. 68 ,69 Several other controlled trials have demonstrated the efficacy of CMI compared with placebo. 72- 76 Open77 and double-blind7~ trials of the selective 5-HT uptake inhibitor fluvoxamine and an open trial of another selective 5-HT uptake inhibitor fluoxetine 8\ have yielded similar beneficial results. There have been anecdotal reports of OCD patients benefiting from treatment with other antidepressants 82 or MAOIs;83 the response rate for these was not as robust as in the above studies. Therefore, several agents that selectively 25

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block 5-HT uptake ameliorate OCD symptoms in children and adults, whereas pharmacologically similar agents, which do not have this 5-HT selectivity, have not been shown to be nearly as effective. This suggests that manipulation of 5-HT systems may be the mechanism through which these agents have their therapeutic effects. Still, evidence of baseline 5-HT dysfunction in OCD is required to strongly implicate 5-HT systems in the pathophysiology of the disorder. Serotonergic Indices in OCD Insel et al. 84 studied several indices of5-HT function in 16 OCD patients and normal control subjects. Tritiated-imipramine ([3H]IMI) binding and 5-HT uptake in platelets were assayed along with CSF concentrations of 5-HIAA. They demonstrated no significant difference in imipramine binding or 5-HT uptake in platelets between the OCD and normal groups; CSF 5-HIAA was, however, found to be significantly elevated in the OCD group. These findings imply a higher rate of 5-HT turnover in the brains of the OCD patients. A second phase of this study entailed a placebo-controlled, double-blind comparison between desipramine and zimelidine. Zimelidine was chosen because of its extreme selectivity as a 5-HT uptake inhibitor. Interestingly, although CSF 5-HIAA levels were significantly reduced after zimelidine treatment, neither zimelidine nor desipramine was clinically effective in reducing OCD symptoms. However, another controlled study demonstrated effective treatment of OCD with zimelidine.8s Insel et al. 'S84 findings refute the notion that a reduction in CSF 5-HIAA is sufficient to effectively treat OCD; such a change may be necessary, although it may not be sufficient. Weizman et al. 86 studied a mixed population of 18 adult and adolescent OCD subjects vs. an age-matched control group in which platelet [3H]IMI binding and 5-HT uptake were compared. They replicated the above findings, with the exception that the Bmax determined by [3H]IMI binding was significantly reduced in 26

the OCD population compared with controls, regardless of age. This suggests a lower density of 5-HT receptors in the OCD population and would be inconsistent with the hypothesis that treatment with 5-HT uptake inhibitors has its effect via down-regulation of 5-HT receptors (see later section). Moreover, this highlights one of the chief difficulties in model building, namely, the task of reconciling seemingly contradictory data. Flament et a1. 8? studied 29 childhood OCD subjects and 31 age-matched normal controls. They found no differences in platelet 5-HT binding, MAO activity, or plasma epinephrine or norepinephrine concentrations between the two groups. A placebo-controlled trial of CMI replicated previous studies confirming efficacy in the treatment of OCD for this age group. In addition, treatment with CMf resulted in decreased platelet 5-HTbinding. Of greatest interest were the findings that pretreatment platelet 5-HT binding and MAO activity correlated with CMI response as did posttreatment reductions in platelet 5-HT binding and MAO activity. The authors concluded that this represented further evidence that CMf has its therapeutic effect via action at 5-HT uptake sites. Studies of various indices of 5-HT function support some aspects of the 5-HT hypothesis of OCD, specifically, that the correlation between changes in platelet 5-HT binding, MAO activity, and CSF 5-HIAA as well as baseline levels are consistent with the notion that known 5-HT uptake blocking agents may have therapeutic action via alterations in the 5-HT system. There is a limited amount ofevidence, however, to implicate 5-HT dysregulation as the underlying lesion in OCD, and that evidence is equivocal. Serotonergic Agonist Challenges Given that there is little direct evidence of grossly abnormal 5-HT function in OCD patients, is there evidence that 5-HT perturbations could produce symptoms of OCD? M-chlorophenylpiperazine (mCPP) is a metabolite of the antidepressant trazodone and has been shown to PSYCHOSOMATICS

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be a 5-HT agonist. 88 Administered intraperitoneally to rats, mCPP decreases brain 5-HIAA, presumably reflecting decreased 5-HT turnover via feedback or presynaptic inhibition. 88 In rats, behavioral and neuroendocrine effects include an increase in serum cortisol and a marked decrease in milk drinking. These effects are blocked by treatment with the 5-HT antagonist metergoline, further supporting mCPP's 5-HT mode of action. Human studies with mCPP have shown similar neuroendocrine and behavioral effects, including elevations in cortisol, prolactin, adrenocorticotrophic hormone, and body temperature as well as decreased food intake and gross locomotor activity. Again, treatment with metergoline was shown to block these effects.89 There have been seemingly contradictory findings as to the effects of mCPP on OCD subjects. Acomparison of the effects of intravenously administered mCPP and tryptophan was performed on 21 OCD subjects and 21 normal control subjects. 9O Interestingly, the baseline prolactin level and the prolactin rise after mCPP administration in female OCD subjects was significantly reduced compared with female control subjects. No significant difference was shown between subjects and control subjects with respect to tryptophan-stimulated prolactin rise or other neuroendocrine parameters. Neither tryptophan nor mCPP produced an exacerbation of OCD symptoms in this study. Still, the differential baseline prolactin levels and response to mCPP may be the best existing evidence for actual 5-HT dysregulation in a population of OCD patients. This conclusion is tempered by the fact that the difference is only evident in females and by the fact that prolactin levels are not uniquely governed by the 5-HT system. Perhaps most surprising was the finding that 5-HT agonists did not acutely alter OCD symptoms, which seemingly contradicts the 5-HT hypothesis. The effects of orally administered mCPP were studied in a double-blind, placebo-controlled study comparing 12 OCD subjects with 20 normal control subjects. 91 OCD subjects VOLUME 34· NUMBER I • JANUARY - FEBRUARY 1993

treated with mCPP suffered exacerbation of their OCD symptoms and became significantly more anxious, depressed, and dysphoric compared with control subjects. It is difficult to explain the disparity between these findings and those of Charney et al. 9O above. Possibilities include the differential route of administration (i.e., oral vs. intravenous) or some difference in the population of OCD subjects studied (e.g., severity of OCD symptoms, Hollander E., personal communication, 1991). In the Zohar et al. study,91 this behavioral effect was selective inasmuch as there were no significant differences between OCD subjects and controls in mCPP's neuroendocrine effects. OCD subjects were more sensitive than normals to the psychiatric sequelae of mCPP treatment but did not demonstrate a global hypersensitivity to mCPP's action. The authors recognized their failure to include a parallel control group with other psychiatric disorders as a limitation of the study. Therefore, the possibility remains that mCPP exacerbates OCD nonspecifically via an anxiogenic or dysphorogenic mechanism. The authors argue against this conclusion, however, citing studies that found no exacerbation of OCD following treatment with known anxiogenic agents. 92 .93 As a corollary to the above experiment, Zohar et aI.94 studied the effects of oral mCPP vs. placebo in 9 OCD subjects, challenged in a double-blind crossover paradigm, before and during (after 4 months) a trial ofCMI treatment. The baseline effects of mCPP replicated their previous findings. After 4 months of CMI, mCPP no longer exacerbated OCD symptoms but continued to have its neuroendocrine effects except for an attenuation of thermal changes. The finding of blunted response to mCPP after CMI treatment was consistent with the hypothesis that CMI acts via down-regulation of 5-HT receptors. These results likewise supported the notion that the psychiatric manifestations of mCPP were independent of the neuroendocrine changes. This in tum implies that CMI has a preferential effect on a select part of the 5-HT system rather than causing global hyporesponsivity. 27

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The 5-HT system is not homogeneous. There is evidence to suggest that mCPP is a selective 5-HT 1B agonist,9~ It has been theorized that 5-HT 1A and 5-HT2 receptors mediate anxiolysis, whereas 5-HT 'B mediates anxiogenesis.96 In this context, 8 OCD subjects were administered oral mCPP, fenfluramine, placebo, and intravenous c10nidine or placebo in a double-blind comparison study.97 The exacerbation of OCD symptoms with oral mCPP was replicated. Fenfluramine, a nonspecific 5-HT uptake blocker and 5-HT releasing agent, did not have a significant effect on OCD measures. Further, c1onidine, an alpha-2 agonist, had an impressive and significant acute beneficial effect on 6 of 6 OCD subjects studied. These findings underscore the heterogeneity of the 5-HT system. Moreover, we are reminded that the 5-HT system does not function in a vacuum; rather, there are other transmitter systems that may play an equal1y important role in OCD. In vitro studies of mCPP binding to human brain membranes suggest that its high affinity for 5-HT III may not be as selective as once thought,98 This first comprehensive study of mCPP's pharmacological profile in human brain revealed comparable affinities for all 5HT receptor subtypes, as wel1 as alpha-2 receptors. In addition, pharrnacological1y significant, though lesser, affinities were found for muscarinic cholinergic, dopaminergic, alpha-I, and beta-adrenergic receptors. Multiple Transmitter System Models A comprehensive model of OCD must consider multiple transmitter systems. Findings such as the clinical ineffectiveness of zimelidine, as described earlier, and the anxiolytic 5HT1aA partial agonist buspirone99 are difficult to explain within a strictly 5-HT model. Although evidence has been presented to suggest that 5-HT uptake inhibitors have their beneficial effects via changes in that system, this is not the only possibility. In animal studies, fluoxetine administered intraperitoneal1y not only resulted in down-regulation of 5-HT receptors, but beta-adrenergic receptors as wel1. loo 28

Fluoxetine, fluvoxamine, and CMI are touted as superior to other cyclic antidepressant agents in the treatment of OCD. Currently, they have been distinguished, from desipramine and nortriptyline for example, on the basis of their selectivity for 5-HT uptake blockade. However, zimelidine, an agent with an order of magnitude of lesser affinity for adrenergic receptors, has been shown to be ineffective. One possibility is that a balance of adrenergic and 5-HT action is necessary. Other data run contrary to the hypothesis that the 5-HT system is the only neurotransmitter system involved in the pathophysiology of OCD. In a comparison offour studies of various 5-HT agents (i.e., fluvoxamine, sertraline, fluoxetine, CMf) in OCD patients performed by the same investigators by means of metaanalysis, it appeared that among agents with selective and potent effects on 5-HT reuptake, greater effect size (i.e., improvement in OCD symptoms) was actual1y associated with less 5-HT selectivity.80 There is intuitive appeal to the notion that cholinomimetic agents might be effective in the treatment ofOCD. Authors have speculated that subtle neuropsychiatric deficits in memory accompany OCDIOI.I02 (and Otto et aI., unpublished observations, 1991) and account for symptoms of uncertainty or chronic doubting. IOJ Cholinergic system lesions (e.g., Alzheimer's disease) have been implicated in memory deficits. The role of the anticholinesterase physostigmine, available in an oral form for experimental purposes, could be explored in OCD patients who have great difficulty with feelings of uncertainty (Le., checkers). Moreover, nicotine has been shown anecdotally to be effective in treating some cases ofTS 104 and has not yet been studied in OCD. The efficacy of high-potency dopaminergic antagonists in the treatment ofTS, OCD-related disorders, IO~ and subpopulations of OCD patients 106 argues for further exploration of the dopaminergic system. Indeed, reviewers have hypothesized that a relative excess of BG dopaminergic activity underlies compulsive behaviors. I~ PSYCHOSOMATICS

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CONCLUSION The 5-HT hypothesis of OCD was initially developed in response to the finding that 5-HT uptake inhibitors effectively treated OCD. Although these agents do act via the 5-HT system, they act via other transmitter systems as well. Therapeutic benefit from these agents may in part depend on down-regulation of 5-HT receptors, but, down-regulation, possibly reflected by decreased CSF 5-HIAA, does not seem to be sufficient to ameliorate OCD symptoms. Treatment with some, but not other, 5-HT agonists exacerbates OCD symptoms, but does not seem to produce such symptoms in normal control

subjects. Further, mCPP-stimulated OCD exacerbation is attenuated by CMI treatment. There is little unequivocal evidence to suggest a baseline dysregulation of 5-HT function in OCD. Rather, data suggest that manipulation of the 5-HT system plays some role in effectively treating the disorder. The finding that 5-HT uptake inhibitors effect changes in non-5HT receptors speaks to the need for any neurochemical model of OCD to include multiple transmitter systems. This notion parallels the evolution of anatomical models that have come to reflect the complexity of systems that mediateOCD.

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