2008年1月27日星期日

Biological Factors in Obsessive-Compulsive Disorders

表單的頂端

Biological Factors in Obsessive-Compulsive Disorders

[Review Articles]

Turner, Samuel M.1,2; Beidel, Deborah C.1; Nathan, R Swami1

1Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine

2Requests for reprints should be sent to Samuel M. Turner, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, 8311 O'Hara, Pittsburgh, PA 15213.

The authors wish to express their appreciation to Rolf G. Jacob, Richard Stiller, and Ralph E. Tarter for their helpful comments on an earlier version of this article.

Received Date: November 1, 1983; Revised Date: November 19, 1984

Abstract

Biological variables in obsessive-compulsive disorder are reviewed. In several areas of inquiry, aberrations in obsessive-compulsive patients have been noted. Biological areas of inquiry include genetic, neuroanatomical, neurophysiological, neuropsychological, and biochemical factors. The available data at this time point to a chronic overaroused state in the obsessive-compulsive. However, they are too preliminary at this juncture to formulate one specific hypothesis. In addition, a diathesis-stress model is called for to accommodate the available data. Finally, it is suggested that the hypothesis of chronic overarousal implicated in this condition can serve a valuable heuristic function.




In recent years, there has been a reemergence of interest in biological approaches to psychopathology. This is particularly true with respect to schizophrenia and affective disorders. More recently, there has been increased interest in biological parameters associated with anxiety disorders, including obsessive-compulsive disorders (OCD). The purpose of this article is to review the major findings from genetic, neuroanatomical, neurophysiological, neuropsychological, and biochemical studies of OCD. Although these findings in many instances are rather disparate, they suggest intriguing possibilities, and some suggestions for future research are put forth.

Obsessive-compulsive disorder is a relatively rare, extremely debilitating condition which is highly refractory to treatment; see the Diagnostic and Statistical Manual of Mental Disorders (DSM-III; American Psychiatric Association [APA], 1980). The syndrome is manifested in cognitive and motoric components and may be accompanied by mood disorders such as anxiety and depression. The DSM-III (APA, 1980) definition of obsessive-compulsive disorder is:

Obsessions are recurrent, persistent ideas, thoughts, images or impulses that are ego-dystonic; that is, they are not experienced as voluntarily produced, but rather as thoughts that invade consciousness and are experienced as senseless or repugnant. Attempts are made to ignore or suppress them. Compulsions are repetitive and seemingly purposeful behaviors that are performed according to certain rules or in a stereotyped fashion. The behavior is not an end in itself, but is designed to produce or prevent some future event or situation. (p. 234)

Salzman and Thaler (1981) noted several consistent characteristics of the disorder: (a) thoughts or actions over which an individual believes there is a lack of voluntary control; (b) the presence of anxiety due to the ego-dystonic nature of the thoughts; and (c) knowledge that the thoughts and actions are senseless and unreasonable, which nevertheless does not alter the need to perform the compulsive acts.

Obsessions are intrusive and unwanted thoughts, and the content is usually senseless and/or repulsive. Fears include worry over germs or contamination, over contracting an illness such as cancer, or about being responsible for someone's death or injury. Compulsions are repetitive, excessive, and unnecessary overt acts, which are the result of strong subjective urges, although strictly speaking the behaviors are under the individual's voluntary control. Two common forms of compulsions are excessive checking (e.g., oven gas jets, windows and locks, personal articles) and cleaning or washing of one's person or domicile (Turner & Michelson, 1984). Some individuals experience cognitive rituals (Sturgis & Meyer, 1981), in which a discrete number of steps must be performed for the act to be successfully completed. If there is any deviation, the individual must begin the sequence again. An example of a cognitive ritual would be the recitation of a series of statements or numbers. Regardless of form, rituals usually serve an anxiety-reducing function. In addition, obsessive-compulsives sometimes attribute magical qualities to their rituals, thinking the rituals have the power to ward off undesirable events. The compulsions can become so overwhelming that other activities become restricted because of time spent engaged in the compulsive behavior. In addition, family members are often drawn into the rituals and must likewise perform certain circumscribed acts. The course of obsessive-compulsive disorder is considered chronic with periodic exacerbation and diminution of the symptoms (DSM-III; APA, 1980).

Epidemiology

As is the case for all of the anxiety disorders, extensive epidemiological data are not available for obsessive-compulsive disorder. Thus, we know little about its incidence and prevalence or cultural patterns. As noted, obsessive-compulsive disorder is rare; it is estimated to affect 3% of the neurotic population or 0.05% of the general population (Sturgis & Meyer, 1981). Onset usually occurs in early adulthood (DSM-III; APA, 1980), and social behavior may be markedly impaired. Obsessives are reported to have celibacy rates as high as 72% (Coryell, 1981), to marry later, and to have lower rates of fertility (Turner & Michelson, 1984). Similarly, other epidemiological investigations (deSilva, Rachman, & Seligman, 1977; Hare, Rice, & Slater, 1971) reported high celibacy rates, particularly among men; they suggested this is proportional to severity of the illness. This pattern may be related either to specific obsessions (fear of contamination or infection) or to social isolation accompanying the secretive nature of the disorder and the restrictive rituals. Also, this pattern may be specific to Western cultures. Akhtar (1978) investigated marriage, celibacy, and fertility patterns in a sample of Indian obsessive-compulsive patients. In comparison with Indians suffering from generalized anxiety disorder and with obsessionals from other countries, the Indian obsessionals demonstrated lower rates of bachelorhood and celibacy. The obsessionals reported higher fertility rates than either comparison group. Akhtar attributed this discrepancy to the cultural demands and social taboos in India and the obsessional's inability to resist the pressures of conformity.

Relation to Other Psychiatric Disorders

Obsessive-compulsive symptoms are often found in other psychiatric conditions. The disorders known to have obsessional features are Lesch-Nyhaus Syndrome, anorexia nervosa, mental retardation, organic brain syndrome, epilepsy, head trauma, Parkinson's Disease, depression, schizophrenia, and Tourette's Syndrome. This list indicates there are a number of disorders with obsessional features similar to those found in obsessive-compulsive disorders. Moreover, a number of biological hypotheses regarding etiology of these disorders have been postulated, suggesting OCD might also have biological underpinnings. Before discussing biological abnormalities in OCD, we present evidence for the similarities of the symptom features between these disorders and OCD. In a later section, we evaluate the evidence for a shared biological base between these disorders and OCD where there has been sufficient research.

Schizophrenics often experience delusional thoughts and hallucinations that may be considered obsessional. For the most part, these are easily distinguishable, because the schizophrenic does not believe these thoughts are senseless and therefore they are not experienced as ego-dystonic (DSM-III; APA, 1980). Individuals who experience closed head injuries are sometimes reported to develop ritualistic or stereotypic behavior that may resemble compulsions. In these cases, the ritualistic behavior of the organically impaired group is more likely the result of impaired cognitive processes that prevent integration of new learning or the ability to vary performance on a particular task. On a clinical basis, the stereotypic behaviors do not appear to serve an anxiety-reducing function, nor do they appear to be purposeful in any fashion as in the case of obsessive-compulsive behavior. Moreover, organically impaired individuals do not appear to experience such behavior as being problematic (Turner & Michelson, 1984).

The existence of obsessive-compulsive symptoms in Tourette's disorder is striking, and this has been suggested as supporting a link between the two conditions (Elkins, Rapoport, & Lipsky, 1980). Various reports in the literature have indicated that obsessive-compulsive symptoms occur in the range of 33% to 89% of patients diagnosed as suffering from Tourette's syndrome (Cohen, Detlor, Young, & Shaywitz, 1980; Nee, Caine, Polinsky, Eldridge, & Ebert, 1980; Yaryura-Tobias, 1977). Additionally, obsessive-compulsive symptoms often appear in first-degree relatives of patients with Tourette's disorder (Montgomery, Clayton, & Friedhoff, 1982). In both disorders there are motoric manifestations. The behaviors are quite different, however. In Tourette's disorder, the uncontrollable behaviors consist of circumscribed body movements such as tics, extremity jerks, or involuntary vocalizations such as barks or grunts. This differs from OCD patients in two ways: First, the behaviors of the OCD patient are not limited to specific body movements and tend to be related to specific obsessive ideation. Further, rituals in OCD patients may be strictly cognitive. Second, rituals seen in OCD serve a purpose (e.g., compulsive handwashing prevents the possibility of infection). Nevertheless, the high percentage of Tourette's individuals who suffer concomitant OCD symptomatology is important in view of the proposed neurochemical aberration in Tourette's disorder. Pharmacological interventions such as L-dopa can precipitate Tourette's (Feinberg & Carroll, 1979), and some neuroleptics (such as Haloperidol) improve the condition, presumably by blocking dopamine receptors (Shapiro, Shapiro, Bruun, & Sweet, 1978). Because L-dopa and Haloperidol affect dopamine levels in the brain, and Tourette's syndrome patients and OCD patients have a number of similarities, the question arises as to the relation of the neurotransmitter dopamine in these disorders. We discuss the possible role of dopamine in OCD in a later section.

There is considerable evidence of an association between OCD and depression (Turner & Michelson, 1984). A significant proportion of individuals experience both disorders simultaneously. Gittelson (1966) reviewed the case histories of 398 patients with a diagnosis of psychotic depression. Thirty-one percent of the cases exhibited obsessional thoughts during the depressive episode. Kendal and Discipio (1970) reported high scores on the Leyton Obsessional Inventory for patients during a depressive episode. Interestingly, these scores were not substantially reduced after recovery from the depressive disorder. In addition, these authors reported that patients with obsessional personality features prior to a depressive episode were more likely to manifest obsessional thoughts during their illness. As further support that there is some overlap in these conditions, the incidence of depressive symptoms in OCD has been reported to range from 17% to 35% (Vaughn, 1976) to 34% (Sturgis & Meyer, 1981) to 66% (Solyom, Zamanyadeh, Ledwich, & Kenny, 1971). In a more recent study, Turner (1984) reported that 79% of a sample of 43 OCD patients requesting outpatient treatment in the Anxiety Disorders Clinic at Western Psychiatric Institute and Clinic over a 2-year period scored 17 or above on the Beck Depression Inventory, indicating a significant degree of depression. In a sample of 22 obsessive-compulsives, 91% scored a t score of 70 or above on the MMPI Depression scale. Thus, it is clear that depressive symptoms are part of the clinical picture in many OCD cases.

Because some level of depression often accompanies OCD, determining a primary diagnosis is sometimes difficult. One method used is to establish an etiological time line for the two disorders. In most OCD cases, patients report the appearance of depressive symptomatology after the onset of OCD (Sturgis & Meyer, 1981). Rachman and Hodgson (1980) reported that although 55% of their patients did not feel depressed at the onset of their obsessive-compulsive behaviors, there were many cases of secondary depression over the course of the illness. Similarly, Welner, Reich, Robins, Fishman, and Van Doren (1976) found that the pattern of OCD followed by depression was three times as likely to occur as that of an initial depression followed by OCD. Insel, Kalin, Guttmacher, Cohen, and Murphy (1982) reported the case of a woman diagnosed as OCD who, 3 months after onset of the disorder, developed depressive symptoms. Twelve years before, this woman had suffered a major depressive disorder unaccompanied by obsessive-compulsive symptoms. The woman was able to differentiate the two depressive episodes by describing the depressive feelings accompanying her OCD as being entirely different from the subjective quality of “being totally blue” that she experienced as part of her major depressive episode. Although speculation on the link between OCD and depression has existed for some time, it is clear that both conditions can and do occur independently. This example seems to indicate that a patient can discriminate depression associated with OCD from a separate depressive illness. However, the covariation of the symptom picture, and the hypothesized involvement of similar neurotransmitters in both conditions, make this a fertile area for further inquiry.

Genetic and Family Studies

As early as 1868, Griesinger reported obsessional symptoms in relatives of obsessive-compulsive patients (Inouye, 1972). The difficulty in determining a genetic or biological predisposition for OCD is similar to that for other psychiatric disorders. It is necessary to control or determine the influence of environmental factors.

Investigators examining genetic predisposition in OCD have used two major approaches: Family studies and twin studies. A major difficulty in all of these studies is the lack of consistent diagnosis of the disorder. Inouye (1965) described four pairs of twins in which the index cases were diagnosed as obsessive-compulsive disorder. The behaviors exhibited by one male proband included tics, uncontrollable yelling and blinking, and feeling compelled to stick needles into his body. These behaviors were first observed to have occurred at the age of 7. The behaviors of a second proband began at the age of 9 and included tics, coprolalia, grimacing, yelling, and moving of extremities. Using DSM-III criteria, both of these cases would appear to be consistent with a diagnosis of Tourette's Syndrome rather than OCD. Similarly, Tarsh (1978) described a pair of dizygotic twins in which one twin exhibited symptoms specifically about her body weight. She felt she was grossly overweight, which was factually incorrect. She worried constantly about her weight and refused to be weighed. In addition, she reportedly spent a great deal of time standing in front of a mirror counting her ribs. Although no information about actual weight loss was provided, the symptom pattern is suggestive of an eating disorder, perhaps anorexia nervosa, rather than obsessive-compulsive disorder.

Thus, in reviewing the genetic and family studies, clear determination of the diagnosis of OCD is somewhat difficult. Similar difficulties arise in determining whether relatives have obsessive-compulsive disorder or compulsive personality traits. Certain individuals may exhibit behaviors resembling symptoms of obsessive-compulsive disorder. However, they do not manifest true obsessions and compulsions. Rather they are perfectionistic and preoccupied with trivial details, rules, and order; they lack the ability to express warm and tender emotions; they insist that others submit to their way of doing things; they are excessively devoted to work and productivity; and they are indecisive (DSM-III; APA, 1980). The similarities between obsessive-compulsive disorder and the compulsive personality style are such that it may, at times, be difficult to clearly differentiate the two conditions. Therefore, concordance rates may vary dependent upon the definition used (Carey & Gottesman, 1981). Finally, most information has been gathered from case records rather than actual interviews with the probands and relatives. With these precautions in mind, evidence for a genetic basis in OCD is presented.

In one recent study of family patterns of OCD symptomatology, 27 patients with obsessive-compulsive disorder and their biological parents were interviewed (Insel, Hoover, & Murphy, 1983). The patients did not report any OCD symptoms in their parents. One proband, however, did report a son who had compulsive checking behavior. Additionally, there was evidence of affective and depressive spectrum disorder in a subset of the parents. A second method of assessing OCD was the administration of the Leyton Obsessional Inventory to a subset of 10 patients' parents. Three of the 20 parents (2 parents for each patient) who completed the inventory scored more than two standard deviations above the mean. These parents appeared to have obsessional features without the corresponding resistance and interference noted in OCD patients. In effect, while exhibiting similar behaviors, the parents did not view their own behavior as maladaptive or interfering in their daily lives. The authors suggested that obsessional behavior could represent an inheritable “obsessional factor” which under certain environmental conditions might be manifested in symptomatic behavior.

Carey and Gottesman (1981) examined family patterns in relatives of OCD patients. They reported 6.2% of parents, 3.2% of siblings, and 6.2% of the children of index cases suffered an identifiable obsessive-compulsive illness, whereas 8.3% of parents, 6.4% of siblings, and 9.3% of children had obsessional features to their personalities. Although these incidence rates are higher than those found in the general population, such family studies do not rule out the effects of modeling or other psychological factors in the development of the disorder. The stronger weight given to twin studies over family incidence reports rests on the assumption that the environment affects twins equally; therefore, different concordance rates for MZ and DZ twins should reflect genetic inheritance. In evaluating concordance, rates must be compared with that produced by chance alone. Marks, Crowe, Drewe, Young, and Dewhurst (1969) calculated the chance concordance rate for OCD in MZ twins as follows: Accepting the .05% frequency of OCD in the general population and the estimate that 1 in 200 adults is an identical twin, then 1 in 400,000 could be expected to be a MZ twin with OCD. Thus, 1 in 800 million would be the expected probability of a pair of MZ twins with the same disorder. In fact, the concordance rate for OCD far exceeds this chance probability. The incidence of concordance and discordance for MZ and DZ twins in which the proband is diagnosed as OCD is presented in Table 1.


Graphic
[Help with image viewing]
[Email Jumpstart To Image]

Table 1 Incidence of Concordance for MZ and DZ Twins for Proband Diagnosed as Obsessive-Compulsive Disorder


In a review of 15 early studies of incidence of OCD in twins, Inouye (1972) reported 27 MZ pairs concordant and 8 pairs discordant for OCD, whereas for DZ twins the rates were zero concordant and 7 discordant pairs. However, due to discrepancies in diagnoses and brevity of some of the case records, caution is advised in interpreting these data.

Carey and Gottesman (1981) reported a high concordance rate for OCD in monozygotic twins. The investigators reviewed 30 years of hospital case records (1948–1979) at the Maudsley and Bethlehem hospitals in England, selecting individuals who upon admission were diagnosed as obsessional neurosis or phobic neurosis. Fifty one twin probands (30 obsessional and 21 phobic), their twins, and their first-degree relatives agreed to personal interviews. All probands in the sample met DSM-III criteria for obsessive-compulsive disorder or phobic disorder. The interview included developmental and marital history, psychiatric status as measured by the Present State Examination, the Leyton Obsessional Inventory, and a list of 20 common phobias. Two types of concordance rates were reported: Concordance for a twin receiving treatment for OCD and concordance for obsessional symptomatology with or without concomitant treatment. Concordance rates for those twins receiving treatment were 33% for MZ twins and 7% for DZ twins. For obsessional behaviors with or without treatment, the rates were 87% and 47%, respectively. This study also used a comparison group of unspecified phobic probands and established concordance rates in the twins for this disorder. Rates for the phobic twin receiving treatment was 13% for MZ and 8% for DZ twins.

There are no adoptive studies for OCD similar to those used in examining biological components of schizophrenia and affective disorders (Carey & Gottesman, 1981). However, McGuffin and Mawson (1980) described two pairs of MZ twins concordant for OCD but who had been separated for several years prior to onset of the disorder. In addition, each twin did not have knowledge of the other's illness prior to development of their own symptoms. Despite this separation, there was a remarkable similarity in symptoms within each pair. In view of their separation before symptom onset, this report is significant in that obsessive-compulsive behavior in each twin cannot be attributed to modeling or other psychological processes.

It appears that the higher concordance rate in MZ twins would implicate more than environmental factors in the development of OCD (Carey & Gottesman, 1981). However, it is also clear that there is little evidence for a Mendelian or sex-linked transmission. Therefore, one might postulate decreased gene penetrance (McGuffin & Mawson, 1980) or a vulnerability model in which, given a sufficient level, environmental stressors would combine with a genetic predisposition to precipitate the disorder. There is need for further research, however, before any definitive conclusions regarding genetic hypotheses or a vulnerability model can be reached.

In addition to genetic predisposition, Snowdon (1979) observed that mean family size of obsessionals is smaller than for a matched group of controls. This is apparently due to the tendency for some obsessive-compulsives to engage in low-frequency sexual contact, probably due to contamination fears. If obsessional symptoms do in fact run in families, this could explain lower fertility rates noted in families of individuals with OCD.

In determining evidence for a genetic basis in a disorder, gene linkage and genetic marker studies are often useful in postulating the location of the gene on a particular chromosome. Linkage is a term used to suggest that the gene alleles of two specific conditions may be found on the same chromosome. Suggestion of gene linkage is based on a high degree of covariance in phenotypic expression of two conditions. If the two conditions do covary, and the location of one of the alleles is known, one type of gene linkage would suggest that the loci of the second phenotypic condition is on the same chromosome. Thus, the particular site of an abnormality is identified. For example, the gene for a certain type of bipolar depressive condition has been posited to be located on the X chromosome between the locations for Xg blood group and certain forms of color blindness (Depue & Monroe, 1978). These conditions appear in tandem with bipolar affective states. An investigation of blood types and anancastic (obsessive) symptoms (Rinieris, Stefanis, Rabavilas, & Vaidakis, 1978) produced evidence of a significant association between blood group phenotype A and obsessional behavior. Patients with OCD had a significantly higher incidence of type A (p < .001) and a significantly lower incidence of type O (p < .01) than the general population. Depressives free of anancastic symptoms also demonstrated differences from normals, having a lower incidence of blood type A (p < .05) and a higher incidence of blood type O (p < .05). In comparison, schizophrenics and depressives with anancastic symptomatology did not differ from normal controls in incidence of blood type. One might hypothesize a continuum based on anancastic symptoms with phenotype A and identifiable OCD at one extreme, obsessional symptoms in depression and schizophrenia and perhaps decreased gene penetrance at the center, and depressive disorders without anancastic characteristics and a higher incidence of blood type O at the other end. Although reminiscent of the bipolar linkage studies, the research in OCD is at a comparatively crude stage, and any conclusions drawn must be regarded as tenuous.

In summary, the studies reviewed thus far present some basis for hypothesizing a biological predisposition for the development of OCD. This predisposition may take the form of a genetic aberration or some type of structural weakness. The lack of adoption studies, however, makes it difficult to evaluate the impact of the environment in the development of the disorder. In addition, the rare occurrence of the disorder has no doubt prevented the large-scale investigations necessary to provide confirmation of these suppositions.

Neurophysiological and Neuropsychological Studies

Evoked Potential Studies

In an effort to establish neurophysiological correlates of OCD, Ciesielski, Beech, and Gordon (1981) recorded average evoked potentials on three types of visual stimulation tasks for a group of obsessional patients and a matched group of nonpsychiatric controls. They postulated that an abnormality of the central nervous system (CNS), leading to more rapid and fixed learning than considered normal, may explain the rigidity of behavior often seen in OCD. The OCD patients did not experiment with various response strategies as did nonpsychiatric controls. The authors suggested that instability in the arousal system could affect learning in this way, but they did not propose a specific anatomical site responsible for this instability. It is important to note, however, that this rigid style is characteristic of OCD patients and may be a result of the disorder, and not necessarily an antecedent. Variation in information processing was demonstrated in the obsessive group but only when the stimulus was complex (e.g., a patterned stimulation as opposed to a flash projection). The OCD group exhibited smaller amplitude of evoked potentials (EPs) and shorter latencies in pattern discrimination. This coincides with the findings of other investigators who have suggested that the nature of the OCD abnormality stems from an ability to become aroused in response to low levels of stimulation (e.g., Beech, 1971). As a possible explanation for this increased arousal potential, Ciesielski et al. (1981) suggested that the faster latencies observed in the OCD group could reflect an abnormality of neurotransmitter inhibitory processes.

A follow-up investigation (Beech, Ciesielski, & Gordon, 1983) with 16 subjects—8 OCD patients and 8 controls—essentially confirmed the earlier Ciesielski et al. (1981) report. Obsessionals had shorter latencies and smaller amplitudes than normals, and this difference became more apparent as task difficulty increased. This study presents findings contradictory to Beech's (1971) suggestion of enhanced arousal in OCD because increased arousal should result in higher peak amplitudes. In addition, a theory of reduced inhibition as a basis of OCD based solely on evoked potentials is somewhat speculative as differences in information processing have been demonstrated in other psychiatric disorders (cf. Spring & Zubin, 1978). It is unclear at this juncture if the EP differences noted in this study can be attributed to some type of generalized deficit associated with the psychopathological state in general.

EEG Studies

The results of several studies have suggested cerebral dysfunction in anxiety-disorder patients based on electroencephalogram (EEG) recordings. In an early study, using a mixed group of anxiety patients, Crighel and Solomonovici (1968) reported EEG abnormalities in two groups of psychiatric patients, the first suffering from neurasthenia and the second group of neurotic patients also evidencing symptoms of anxiety and/or depression. Patients in the second group evidenced a significantly higher number of recordings characterized as containing EEG alterations. The abnormalities were of two types: (a) alterations of the temporal leads either unilaterally on the left side or bilaterally or (b) temporal spikes in addition to a fast and ample rhythm. The authors observed that these abnormalities usually indicate overexcitability of the temporo-amygdala complex. Because this complex is integral in the regulation of emotional behavior, abnormalities are likely to be reflected in altered mood states. Thus, one might expect the anxiety disorders (including OCD) to show the same pattern of abnormality. Further studies using EEG technology could help to clarify the role of the temporoamygdala complex in OCD as well as all of the anxiety disorders.

In contrast to the previously mentioned study, which sampled patients with unspecified anxiety symptoms, others have restricted their investigations to EEG patterns in OCD patients. Epstein and Bailine (1971) described the sleep EEG patterns of three obsessionals, noting that abnormalities in the form of theta waves and spiking were localized to the temporal region and were similar to patterns of temporal lobe epileptics, again implicating possible amygdala or limbic dysfunction. Further, the authors suggested that these similarities may be reflected in the abnormal behavior patterns evidenced in each group (i.e., the stereotyped repetitive behavior seen in psychomotor epilepsy and the rituals of the obsessive-compulsive patient). Additionally, the authors hypothesized that dream imagery may be similar to obsessional symptomatology, as dreams are not felt to be under conscious control. However, in this assessment, dream imagery was unrelated to obsessional ideation. Therefore, it appears that a waking state is necessary for appearance of OCD symptoms. The authors suggested that while a waking state is necessary, it may not be identical to a normal waking state. An alteration in arousal mechanisms, creating an altered waking state, might allow the release of normally inhibited ideas or behaviors manifesting in forced, uncontrollable thoughts. This study is limited by the small sample size, and thus conclusions drawn from these data must be regarded as tenuous, but they do suggest that EEG technology might be useful in exploring brain functioning in OCD patients.

Flor-Henry, Yeudall, Koles, and Howarth (1979) studied 11 OCD and 11 control patients, recording EEG levels during resting periods and two cognitive tasks. The subjects also participated in neuropsychological testing. Unlike the results of other studies (Crighel & Solomonovici, 1968; Epstein & Bailine, 1971), there were no statistically significant differences in EEG recordings between groups other than reduced left-temporal variability in OCD patients during the resting situation. Neuropsychological testing was consistent with a dominant frontal lobe dysfunction in 10 of the 11 patients. However, this study is subject to major methodological difficulties. Control subjects were not recruited for this particular study. Rather, hospital case records were reviewed and patients were matched on the variables of age, education, and full-scale IQ. No further description of the control group was provided. Thus, it is unknown if the control group comprised normal individuals or a group of psychiatric patients. If it was the latter, the control group's neuropsychological performance might not be representative of that of a nonpsychiatric sample. Also, although there were significant differences between groups on some of the neuropsychological variables, results were not consistent within the obsessive group and therefore cannot be considered characteristic of the entire sample.

In summary, the previously mentioned studies present some evidence for abnormal EEG patterns in obsessive-compulsive patients. The abnormalities are inconsistent and do not present a clear indication of the location of the disturbance. Several authors hypothesized that overarousal (Crighel & Solomonovici, 1968) or altered waking states (Epstein & Bailine, 1971) may be a contributory factor in the disorder. Such disturbances might implicate a dysfunction in one of the known arousal systems, although mere overactivity cannot explain the primary OCD behavior. However, a chronic state of overarousal might well leave one more vulnerable to the development of OCD. Therefore, the overarousal hypothesis is worthy of further study, and EEG technology is one way this might be done.

Neuroanatomical Studies

Although twin studies and diffuse EEG abnormalities provide some evidence for a genetic or biological predisposition for OCD, such hypotheses are limited as they do not specify an anatomical site that might be implicated in the disorder. In comparison with OCD, the etiology of several of the disorders previously listed (epilepsy, head trauma, organic brain syndrome, and Parkinson's Disease) which also have some characteristics similar to OCD, can be associated with the malfunction of specific neuroanatomical regions. The association of brain region to disorder is clearest in the case of Parkinson's Disease, where the basal ganglia have been identified as the malfunctioning anatomical site. Certain forms of epilepsy, in particular temporal lobe epilepsy, or psychomotor epilepsy, are associated with seizure foci in the temporal lobe. In each of these disorders, the symptoms include motoric stereotypy and repetition that resembles the repetitive, ritualistic acts of the obsessive-compulsive. There is some indirect evidence from the animal literature relating OCD-like behaviors to specific areas of the brain. Pitman (1982) provided the following case description of a hippocampectomized rat.

He is remarkable for his intense and rigid behavior, which others find difficult to modify…. At work on a task, he often overdoes it and persists beyond the point at which others would give up. His behavior is sometimes quite peculiar in that he engages in odd rituals, which bear no relation to the task at hand. These [behaviors] often appear superstitious. (p. 139)

Pitman (1982) noted the behavior of these rats with damaged limbic structures was similar to the behavioral style characteristic of OCD patients.

Similar behavior in rats with hippocampal lesions has been reported by Devenport, Devenport, and Holloway (1981) and Morris, Garrud, Rawlins, and O'Keefe (1982). Thus, these data suggest a starting place in the search for a specific CNS site which may be involved in the disorder. In addition, hypotheses of neurophysiological dysfunction have been suggested as a means of explaining some of the more puzzling aspects of OCD, including the observation that performance of the rituals sometimes serves to increase rather than decrease anxiety (Turner & Michelson, 1984) or why alterations in mood rather than environmental events seem to precipitate the behavior (Ciesielski et al., 1981).

Leucotomies

The rationale for the use of psychosurgery to alleviate OCD evolved from animal studies in which bilateral frontal lobe ablations in chimpanzees resulted in decreases in levels of experimentally induced anxiety and frustration (Kelly, 1973). Spurred by these reports, Moniz (1936, cited in Kelly, 1973) suggested that similar psychosurgical procedures could be effective in patients exhibiting anxiety and obsessions. In further support of the importance of the cingulate regions, it has been reported that anterior capsulotomy (involving the cingulate region) was useful in relieving symptoms of OCD (Fodstad, Strandman, Karlsson, & West, 1982). The limbic system, long acknowledged as an anatomical site for emotional behavior (Papez, 1937), has been the target of surgical intervention in the treatment of OCD. The object of leucotomy operations has been to disconnect the orbital and medical frontal cortex from the limbic circuit (Kelly, 1973). Although early leucotomies were performed without much regard for precise anatomical location, later efforts were targeted at the lower medial quadrant of the frontal lobes, orbital convexity, and cingulate gyri. Kelly (1973) reported 17 cases of obsessional neurosis treated by limbic leucotomy. Seventy-five percent were reported as much improved or improved 6 weeks after their operations. Self-report measures used to assess psychological changes included the Maudsley Personality Inventory, the Beck Depression Inventory, the Hamilton Depression Scale, the Taylor Manifest Anxiety Scale, and the Middlesex Hospital Questionnaire. Following the surgery, decreases were reported in neuroticism, depression, anxiety, and obsessions. There were concomitant decreases in physiological arousal evidenced by a reduction in forearm blood flow, heart rate, and blood pressure. There was no decrease in intellectual functioning as measured by the Wechsler Adult Intelligence Scale. Symptomatology of the other 25% was unchanged postoperatively. At 1-year follow-up, all treatment gains had been maintained. It is important to note that no specific measures of obsessions and compulsions were used in this study. Thus, this places some limitations on the findings. For a discussion of measurement issues in OCD, see Turner (1982) and Mavissakalian and Barlow (1981).

Kelly, Walter, and Sargant (1966) examined the physiological effects of leucotomy on psychiatric patients with various diagnoses. Forty consecutive patients selected for psychosurgery were assessed pre- and postoperatively. Diagnostic categories included recurrent or agitated depression, chronic anxiety, phobic anxiety state, obsessional neurosis, and schizophrenia. However, the specific patient selection criteria and the procedures used to arrive at their diagnosis were not described. Bilateral frontal leucotomies or orbital undercutting techniques were used. Again, 75% of the patient group showed improvement and 25% remained unchanged. Preoperative baseline measures of physiological arousal were within normal limits for blood pressure and blood flow. Heart rate was slightly accelerated at 95 beats per min. At 6 weeks after treatment, all patients demonstrated significant decreases in all resting physiological measures. Those patients suffering from agitated depression and chronic anxiety improved the most, as measured by reductions in level of forearm blood flow, heart rate and blood pressure during resting periods, and stressful mental arithmetic tasks. In addition, self-reported levels of anxiety and scores on the Taylor Manifest Anxiety Scale significantly decreased. Patients suffering from schizophrenia, obsessional neurosis, and phobias did not evidence the same level of improvement 6 weeks postoperatively as those suffering from agitated depression and chronic anxiety. At 18-month follow-up (Kelly, Walter, Michell-Heggs, & Sargant, 1972), 50% of the obsessional patients showed a decrease in symptoms resulting from the leucotomy. The authors attributed this delayed improvement to the gradual relearning process the obsessional must undergo. They postulated that anxiety concomitant with OCD is limited to particular events (in comparison with generalized anxiety), and that the individual must have the opportunity to be repeatedly engaged in the idiosyncratic, previously anxiety-provoking situation before the beneficial effects of the leucotomy become evident. Again, no specific measures of obsessive ideation or compulsive behavior were used. Also, delayed improvement could be attributed to exposure to anxiety-provoking situations that occurred after treatment.

In a retrospective comparison of the effects of psychosurgery and other treatment interventions, Tan, Marks, and Marset (1971) compared the effect of bimedial leucotomy with other treatments for OCD in patients matched for sex, age, symptom duration, onset age, and OCD symptom severity. Although the exact nature of the other treatments was not delineated, the authors listed several interventions including drugs, electro-convulsive therapy (ECT), insulin, hypnosis, abreaction, and behavioral and dynamic psychotherapy. All subjects were diagnosed as suffering from obsessive-compulsive disorder. This study is also remarkable for its 5-year follow-up period. Categories of improvement included obsessions and compulsions, general anxiety, depression, and work adjustment. Independent ratings of improvement were made from hospital records using a 5-point rating scale used by two independent judges. After treatment, obsessions were significantly reduced in the leucotomy group but not in the control group. This difference held constant even at the 5-year follow-up period. For generalized anxiety, findings were again in favor of the leucotomy group during the first 3 months. However, at 5-year follow-up, the control subjects also were improved, thus negating the differences between the groups. Both groups also improved on the variable of depression. Work and social adjustment improved significantly more in the leucotomy group throughout the course of follow-up.

Decreases in OCD symptoms following dissociation of frontal-limbic neurons may make psychosurgery appear beneficial. However, the side effects of leucotomy can range from minimal to quite severe. Immediate side effects included urinary incontinence, headache, and transient confusion. Long-range side effects included poor memory and concentration, apathy, one case each of psychosis and epilepsy, sexual disorders, weight gain, and social disinhibition. The authors did point out that treatment gains were not “bought at the expense of a vegetable existence” (Tan et al., 1971, p. 160). Those who were unable to work adequately when assessed at the 5-year follow-up were those who retained their symptoms.

Leucotomy is an extremely controversial procedure and not widely accepted as an appropriate treatment intervention for OCD. The use of leucotomies in treatment of OCD, however, highlights the intractable nature of the disorder and the frustration that often accompanies the treatment of these individuals. In at least one study, the author emphasized that leucotomy was not the treatment of first choice, that selection of candidates was made with extreme caution, and that leucotomies were considered only in severely refractory, long-term cases where psychosurgery was preferable to continued life with the severely debilitating condition. To our knowledge, in the United States psychosurgery is not used in the treatment of obsessive-compulsive disorders. Advances in pharmacologic (antidepressants) and behavioral therapies (e.g., flooding and response prevention) have added new techniques to the treatment armamentarium for OCD such that treatment prognosis is now quite good (Turner & Michelson, 1984). Thus, it does not appear that the use of psychosurgical procedures is necessary.

In summary, the findings of neuroanatomical studies suggest that cerebral dysfunction might well be a factor in obsessive-compulsive disorders. The results of the leucotomy studies have demonstrated that ablations of sections of the limbic system, or the association areas, reduce the severity of OCD symptoms. The direct mechanism through which this occurs is unknown. If the defective inhibitory ability in the arousal system of OCD patients, as proposed by the “alternate waking state hypothesis” put forth by Epstein and Bailine (1971) or the evoked potential deviation noted by Ciesielski et al. (1981) are correct, the effect of leucotomies may be to alter a chronically overaroused state.

A recent article by Bear (1983), equating areas of hemispheric dysfunction with specific emotional and behavioral patterns, may be useful in helping to synthesize the results of these disparate studies. Bear suggested that there are characteristic emotional patterns for temporal lobe epileptics dependent upon the involved hemisphere. Right-sided foci are characterized by an impulsive, aggressive pattern, whereas controlled, reflective profiles are typical for left-sided lesions. Left temporal lobe lesions show “ideative traits including religiosity, philosophic interests, sense of personal destiny, paranoid concerns, and hypergraphia” (Bear, 1983, p. 197). These behavioral characteristics, in many instances, are not unlike the style of OCD patients, and it is interesting to note that some EEG studies of anxiety and OCD patients have documented abnormal activity in the left temporal region (Crighel & Solomonovici, 1968; Epstein & Bailine, 1971). In addition to left-right asymmetry, Bear (1983) discussed what he refers to as complementary parietofrontal and temporofrontal systems, each with independent limbic connections and specific functions. Although the temporofrontal system is important for the processing of affective information and autonomic responses, the parietofrontal system is responsible for emotionally appropriate arousal including recognition of threat. Within this second system, there is limbic input from the cingulate gyrus to the inferior parietal lobule and back to the cingulate. It appears this circuit mediates emotional arousal and rapid selective attention to stimuli important for goal attainment. Lesions in this area could interfere with surveillance, orientation, and arousal, with deficits manifesting as neglect, apathy, or abulia (Bear, 1983). If one can speculate on overstimulation in this area, then it might be expected to lead to overconcern as opposed to neglect or apathy, and abulia might be replaced by rigidity. If this is so, the function of this system might explain the success of cingulate leucotomies in ameliorating OCD systems.

Although these studies suggest potential sites for cerebral dysfunction in OCD patients, they do not specify the mechanism by which the symptoms occur. Moreover, a recent study comparing OCD patients with normals revealed no differences in gross anatomical features (Insel, Donnelly, Lalakea, Alterman, & Murphy, 1983). However, studies designed to examine the brain at a more basic level (i.e., neuronal concentrations) will need to be conducted before definitive statements can be made. In this regard, reliance upon post-mortem evaluations might be necessary.

Biochemical and Pharmacological Studies

Because mood disturbance has been noted as a feature of OCD, two biological tests used to assess for depression are worthy of note. These are the Dexamethasone Suppression Test (DST) and sleep studies.

Dexamethasone Suppression Test

The Dexamethasone Suppression Test (DST) consists of orally administering dexamethasone (1 mg) at 11 p.m. followed by measurement of plasma cortisol levels the following day at 8 a.m. and 4 p.m. In normal individuals, plasma cortisol remains suppressed for 24 hr following dexamethasone administration. Lack of suppression of plasma cortisol levels is thought to be a biological marker of depression. The DST has been suggested as one objective diagnostic test to identify major depressive disorder (Carrol et al., 1981). Although reports regarding the specificity of the test are inconsistent, approximately 40% to 60% of the patients with major depressive disorder show a pattern of cortisol nonsuppression (>5 micrograms/dl) after administration of dexamethasone (1 mg) the previous night (11 p.m.; Carroll et al., 1981). The DST has recently been used in the assessment of obsessive-compulsive patients. The DST was administered to 16 OCD patients, 7 of whom had secondary depressive symptoms (Insel, Kalin, Guttmacher, Cohen, & Murphy, 1982). In each of the 7 cases, depressive symptoms were secondary to the obsessive-compulsive disorder. Six (37.5%) of the 16 patients treated had an abnormal DST response. This percentage is approximately equivalent to the 40–60% figure of sensitivity cited in the literature for the number of depressed individuals who fail to suppress (Brown, Johnston, & Mayfield, 1979; Carrol et al., 1981). In OCD patients, there was a trend for those patients who had higher scores on a depression rating scale, and a family history of affective illness, to be DST nonsuppressors, again suggesting the possibility of a shared biological substrate for the two disorders. In another study, Åsberg, Thorén, and Bertilsson (1982) used the DST to assess 17 OCD patients in the manner recommended by Carrol et al. (1981). Seven of the 17 patients (41%) were found to be nonsuppressors. The authors contended that some cases of melancholia and obsessive-compulsive disorder may have the same biochemical disturbance, despite the apparent differences in the clinical picture.

Sleep Studies

Sleep patterns and sleep EEG recordings of OCD patients were contrasted with those of patients exhibiting primary depression and a group of matched normal controls (Insel, Gillin, et al., 1982). Seven of the fourteen OCD patients evidenced sufficient depressive symptoms to meet DSM-III criteria for major depressive disorder. However, in all OCD subjects, appearance of depressive symptoms was subsequent to onset of OCD. Results indicated that the OCD patients differed from the normal subjects on 8 of 17 sleep variables. In comparison with the normals, the EEG “disclosed a pattern of shallow, interrupted, insufficient, and shortened sleep.” (Insel, Gillen, et al., 1982, p. 1375). Of particular interest was the reduction of Rapid Eye Movement (REM) latency and Stage 4 sleep in OCD patients, similar to the pattern noted in primary depressives. There was also a reduction of REM efficiency in patients with OCD, resulting from the intrusion of NREM or awake time. Sleep pattern of the OCD patients was similar to that of depressed patients, possibly providing further evidence of a link between the two disorders. These results, however, are tempered by reports of extreme anxiety on the part of the OCD patients regarding the sleep-monitoring procedure. Of the 18 patients invited to participate in the research, four refused because of concerns about contamination. Of the remaining 14, the authors related:

For many of the patients, particularly those with cleaning rituals, the sleep-recording procedures were a source of considerable distress. Two patients refused to allow recordings in their regular hospital bed for fear of contamination. Others insisted that they shower just before and after the sleep recordings. One patient who reluctantly consented to the sleep study withdrew after 2 nights amid intense preoccupations that the electrodes had contaminated her bed. (p. 1374)

Thus, the pattern of shallow, interrupted sleep could be attributed to either characteristics of OCD or a reaction to the sleep-monitoring procedure.

Although current research would suggest that behavioral strategies are the most effective treatments for obsessions and compulsions, drugs also play an important role in certain cases. For example, Foa (1978) reported that for at least one subcategory of OCD, attempts at remediation of obsessional behavior will be ineffective until the depressive mood has been alleviated. Thus, pharmacological intervention has been accepted as an integral component in the treatment of OCD when depression is a particularly prominent feature. In addition to the antidepressants, other drugs frequently used in the treatment of OCD include antianxiety agents and neuroleptics.

Antianxiety Agents

Because of the severe anxiety often concomitant with OCD, anxiolytic agents have been widely used. Numerous studies have demonstrated that the performance of rituals is associated with decreased levels of anxiety or discomfort caused by the obsessions (e.g., Hodgson & Rachman, 1972; Rachman, 1976; Roper & Rachman, 1976; Roper, Rachman, & Hodgson, 1973). Therefore, reduction of anxiety might be expected to correlate with reduced OCD symptoms. However, Lader (1974) demonstrated that although physiological arousal and anxiety are often confused, level of physiological arousal does not always correlate with the subjectively perceived experience of anxiety. In particular, although anxiety may initially develop as a result of an increased level of arousal, diminution of the arousal does not necessarily result in decreased subjective feelings of anxiety. For example, anxiety patients treated with diazepam evidenced a decreased level of physiological arousal but no concomitant changes in perceived level of anxiety (Lader, 1974). In addition, propanolol (a betablocker) has been found to produce reduction in physiological arousal in OCD patients (Rabavilas, Boulougouris, Perissaki, & Stefanis, 1979). However, clinical ratings of symptoms did not decrease, and patients did not report themselves as less anxious or more content when using the drug. As Ananth (1976) concluded, although certain preparations may decrease arousal levels, they are ineffective in decreasing the primary symptoms of obsessions and compulsions. Thus, it does not appear that anxiolytic agents are effective in the treatment of OCD, indicating the disorder is considerably more complex than simple increased level of arousal.

Neuroleptics and L-Dopa

Biochemical bases have been suggested for three of the final four disorders previously listed. Parkinson's Disease, schizophrenia, and Tourette's Syndrome all encompass behavior which, superficially or otherwise, resembles OCD. In these disorders the similarity pertains to the stereotypic, repetitive movements, except that the movements are assumed to be involuntary in these conditions. The hypothesized biochemical abnormality in each of the latter three conditions is aberrant dopaminergic functioning, with increased or excessive activity in the case of schizophrenia (Neale & Oltmanns, 1980) and Tourette's Syndrome (Shapiro et al., 1978) and decreased dopaminergic functioning in Parkinson's Disease (Iversen, 1977). Part of the effectiveness of neuroleptic medications is their ability to alter dopamine levels. Neuroleptics have been successfully used to treat schizophrenia and Tourette's Syndrome, and L-dopa has been found to eliminate the stereotypic and repetitive movements of Parkinson's Disease. As described, these conditions have behaviors similar to those seen in OCD. Thus, the possibility of dopamine involvement in OCD is raised. However, to our knowledge, there have been no studies investigating dopamine function in OCD.

Antidepressants

In 1977, Yaryura-Tobias proposed a serotonin hypothesis for obsessive-compulsive disorders. The serotonin hypothesis states there are decreased functional levels of serotonin available at the synaptic cleft of OCD patients when compared with normals. Among the antidepressants, the drug clomipramine, which has a potent serotonergic action component, has been reported to be particularly effective in the treatment of this disorder (Thorén, Åsberg, Cronholm, Jörnestedt, & Träskman, 1980; Yaryura-Tobias, Berbirian, Neziroglu, & Bhagavan, 1977). Ananth, Solyom, Bryntwick, and Krishnappa (1979) reported that clomipramine resulted not only in a decrease in anxiety and depression, but also a significant reduction in the severity of obsessions. Although most of the clomipramine studies suffer from methodological inadequacies including the uncontrolled nature of the clinical reports, use of mixed diagnostic groups, different dose ranges and methods of administration of clomipramine, varying duration of treatment and absence of objective measures of the primary symptoms (Turner & Michelson, 1984), the preliminary results nevertheless raise the question that neurotransmitter deficits similar to those posited in some biological theories of depression may be operating in OCD.

Because many OCD patients report feelings of depression, various antidepressants have been used in treatment. The amine hypothesis of affective disorders suggests a decreased availability of functional amines, including serotonin (5-HT) and norepinephrine (NE) in the brain, specifically at the neural synapses. Functional deficits of these neurotransmitters at the synaptic clefts have been suggested as being related to depressive states. There is evidence to suggest reduced serotonergic function in depressed patients. First, reduction in 5-HT levels or its metabolites has been noted in the cerebral spinal fluid (CSF) and blood of some depressed patients (Coppen & Wood, 1982). Similarly, a reduction has been observed in 5-HT levels in platelets of depressed patients (Meltzer, Arora, Baker, & Tricou, 1981; Tuomsito & Tukiainen, 1976). Antidepressants that affect the neurotransmitters serotonin and norepinephrine have been reported to have varying degrees of effectiveness in treating OCD. For a review of pharmacological interventions in OCD, see Ananth (1976, in press).

Of all the antidepressants, clomipramine has been demonstrated to be the most effective, with apparent antiobsessive properties discovered in an accidental fashion (Ananth, in press). The drug, being tested in depressed patients, was reported effective in eliminating secondary obsessional features. Several reviews of clomipramine as a treatment for OCD have been published (Ananth, 1976, in press; Turner & Michelson, 1984). This article highlights the biochemical mechanisms that have been implicated as being responsible for its treatment efficacy.

Similar to the action of other antidepressants, clomipramine's action is thought to hinge on its ability to block the reuptake of certain neurotransmitters. The particular effectiveness of clomipramine in OCD treatment in comparison with other antidepressants has been linked to its preference for blocking serotonin reuptake, especially when administered intravenously. Clomipramine is a potent inhibitor of serotonin (5-HT) reuptake, with a lesser, but concurrent effect on norepinephrine (Waldmeier, Baumann, Grungrass, & Maitre, 1976). This is in contrast to other antidepressants (e.g., imipramine and amitriptyline) that are less selective for serotonin. Selectivity of clomipramine for 5-HT reuptake, coupled with its clinical effectiveness in reducing symptoms of OCD, could indicate a 5-HT disturbance in obsessive-compulsive disorder, which is the basis of the serotonin hypothesis discussed earlier (Yaryura-Tobias, 1977). In a test of the serotonin hypothesis, Yaryura-Tobias et al., (1977) examined blood serotonin levels in drug-free OCD patients and controls. Twenty patients diagnosed as suffering from obsessive-compulsive disorder and 11 normal control subjects recruited from the clinic staff participated in the research. In the first part of the study, baseline blood 5-HT and urinary 5-hydroxyindoleactic acid (5-HIAA) levels were collected. The OCD patients had significantly lower levels of blood serotonin, and there was no significant difference in urinary excretion of the serotonin metabolite 5-HIAA. This suggests some disturbance in the synthesis of serotonin in OCD patients. In the second part of the experiment, OCD patients were administered clomipramine, 50 mg twice daily for 2 weeks. Blood and urine levels were collected again at the end of this period. In addition, clinicians rated improvement in symptoms at posttreatment. Following treatment with clomipramine, there was a further significant decrease in 5-HT, but no change in urinary 5-HIAA levels. The authors suggested this further reduction in 5-HT levels, but stable 5-HIAA excretion, could be explained by increased circulating levels of 5-HT being rapidly oxidized in the blood. Other studies also reported improvement in obsessional symptoms to be positively correlated with increased levels of clomipramine in the blood plasma, indicating increased availability for synthesis (Insel, Murphy, et al., 1983; Stern, Marks, & Mawson, 1980). In addition, the antiobsessional effect of clomipramine was reported to be significantly correlated with decreases in the levels of the serotonin metabolite 5-HIAA in the CSF, once again suggesting increased availability of serotonin for synthesis (Åsberg et al., 1982). The evidence provided by these investigations, including differing baseline serotonin levels, further decreases in blood platelet levels as a result of blocked reuptake, and decreased obsessions, lend support for the role of the serotonergic neurotransmitter system in OCD.

Depletion of CNS 5-HT in laboratory animals may provide evidence for a model of behavior associated with decreased serotonergic transmission. In cats, decreased availability of 5-HT by reserpine reduces 5-HT storage by acting on the storage vessicles and allowing increased intracellular catabolism, thus interfering with Stage-II sleep and reduction in REM efficiency (Jouvet, 1978). In Insel, Gillin, et al. (1982), OCD sleep study, Stage-II sleep and decreased REM efficiency were two of the variables found to differ between OCD patients and normals. In addition, serotonergic depletion in animals has been demonstrated to be related to stereotypic, repetitive behaviors. As one example, Abel (1974) administered p-chlorophenylalanine (p-CPA) which selectively depletes cerebral 5-HT in rats. Following administration of p-CPA, he observed hyperaggressivity and compulsive sexual activity in the males. He reported similar behavior in cats and rabbits. Abel (1974) hypothesized that 5-HT pathways may exert an inhibitory influence over sexual behavior, although it remains unclear if this is a result of an increase in general arousal or a direct effect on the mechanism of sexual behavior. Additional evidence to suggest that serotonergic neurons might play a role in limitation of behavior is provided by Shillitoe (1970). Depletion of 5-HT by p-CPA was associated with excessive grooming behavior in rats to the point where they experienced total baldness. Although admittedly speculative, there appears to be some evidence of behavioral repetition in rats correlated with changes in levels of the neurotransmitter serotonin. The behaviors previously described are clearly reminiscient of behavior seen in OCD.

Further clinical studies using clomipramine have provided some support for the serotonin hypothesis. Thorén, Åsberg, Bertilsson, et al. (1980) examined CSF levels of 5-HIAA (a serotonin metabolite), homovanillic acid (HVA; a dopamine metabolite), and a noradrenergic metabolite 4-hydroxy-3 methoryphenyl glycol (MHPG) in OCD patients before and after treatment with clomipramine. It should be noted that this study examined CSF levels of 5-HIAA and not urinary excretion levels as in the Yaryura-Tobias et al. (1977) study. CSF levels are thought to be a more direct indication of CNS activity. Twenty-four patients diagnosed as suffering from obsessive-compulsive disorder and 37 paid, healthy volunteers participated in the study. OCD patients were treated with one of three medications: clomipramine, 50 mg three times per day; nortriptyline, 50 mg twice daily; or a placebo. Treatment lasted for 6 weeks. Lumbar punctures were performed at pre- and posttreatment. Prior to treatment, mean concentrations of CSF 5-HIAA and CSF HVA did not differ between the OCD and control group. The level of CSF MHPG was more variable within the OCD group than the controls; 5 of the patients had higher levels of MHPG than any of the controls. In the nortriptyline group, treatment resulted in reduction in MHPG levels. After treatment with clomipramine, there was a significant reduction in both 5-HIAA and MHPG levels in the CSF and a slight but significant increase in HVA. In addition, there was an inverse relation between 5-HIAA and HVA levels; the more 5-HIAA decreased, the more HVA increased. With nortriptyline both levels increased, indicating that these two pharmacological agents differ in their effect on serotonin and dopamine receptors. This study also examined clomipramine responders and nonresponders. Responders were differentiated by significantly higher pretreatment levels of both CSF HVA and CSF 5-HIAA, whereas MHPG did not differ between these two groups. There was a significant negative correlation between 5-HIAA level during the fifth week of treatment and obsessional symptom scores, indicating those patients with a marked reduction in 5-HIAA were the ones who improved clinically. There was also a significant negative correlation between plasma concentrations of clomipramine and reduction in scores on the Leyton Obsessional Inventory.

In contrast to 5-HT pretreatment differences found in blood platelets in the Yaryura-Tobias et al. (1977) study, CSF pretreatment levels of 5-HIAA, HVA, and MHPG in the Thorén, Åsberg, Bertilsson, et al. (1980) study did not differ between OCD patients and healthy controls. However, high pretreatment CSF 5-HIAA levels in the Thorén, Åsberg, Bertilsson, et al. (1980) study were correlated with improvement in obsessional behavior. They noted that there may be some evidence for biological subcategories of OCD similar to those proposed in the depression literature (cf. Depue & Monroe, 1978). They further noted that in depression there is a bimodal distribution of CSF 5-HIAA levels, and these two modes are representative of two distinct biological subgroups. Although the small sample size of this study with the OCD patients prevents the drawing of a similar conclusion with respect to OCD, the distribution of 5-HIAA CSF levels appears similarly bimodal. Therefore, there may be subclasses of OCD patients with different biological underpinnings that may lead to differential responsivity to treatment. Thorén, Åsberg, Bertilsson, et al. (1980) suggested this may explain why the high 5-HIAA group was more responsive to clomipramine. Finally, there was a U-shaped dosage response curve in which plasma drug levels below or exceeding 300n mole/L resulted in decreased effectiveness. One explanation for this is that above this level clomipramine may begin to block serotonin receptors in addition to blocking reuptake. On the basis of all the evidence, the authors concluded that the strong correlation between reduction in CSF level of 5-HIAA and diminution of obsessive symptoms is indicative of an antiobsessive effect of clomipramine, and that this effect is related to its capacity to inhibit serotonin reuptake.

Further evidence of a role for serotonin in OCD is supported by research showing the 5-HT precursor amino-acid, L-tryptophan to be effective in treatment of OCD (Yaryura-Tobias & Bhagavan, 1977). Administration of this precursor is an alternative approach to clomipramine treatment in increasing steady-state levels of serotonin. Synthesis of serotonin is reulated by the amount of available L-tryptophan. Thus, increasing the precursor should result in an increase in the availability of serotonin for synthesis. Seven obsessive-compulsive patients were treated with 3 to 9 g of L-tryptophan in divided doses. Although criteria for improvement were not described, patients were reported to evidence considerable improvement after 1 month on the medication, and they continued to improve for up to 5 months afterward.

In summarizing the response to pharmacological intervention in obsessive-compulsive disorders, there appears to be some basis for a serotonin hypothesis. Differences in 5-HT blood plasma levels between OCD patients and normals and more variable CSF levels of MHPG within the OCD patient group have been reported. A high pretreatment level of 5-HIAA in one study was predictive of responsivity to clomipramine treatment. In addition, the decrease in CSF 5-HIAA and blood plasma 5-HT levels after clomipramine treatment indicates that increasing available levels of serotonin are correlated with a decrease in symptoms. However, thus far the biochemical evidence for this hypothesis is limited to peripheral measures of bioamine activity. Cerebral spinal fluid and blood and urine assessments are not without limitations. Exact relations between these peripheral measures and brain concentrations of the same substances have yet to be established. However, CSF metabolite concentration is considered to approximate more accurately brain concentration levels. Even if the levels were identical, there is no evidence to suggest neurotransmitter function is the same at both sites (Green & Costain, 1981). If the exact relation of peripheral neurotransmitter levels to CNS functioning was understood, this still would not clearly delineate their role in the pathogenesis of OCD. Differences in levels may be pathogenic factors, or they may be secondary effects of the disorder and have no role in causality.

Despite the existence of some evidence for the role of serotonin in obsessive-compulsive disorders, there are difficulties in validating the hypothesis with current approved antidepressive drugs. The reason for this is that clomipramine and other widely used antidepressants also have an effect on the neurotransmitter norepinephrine. Hence, norepinephrine and serotonin are affected when these drugs are used. The clomipramine metabolite, demethylclomipramine, has been demonstrated to have effects on norepinephrine. Thus, the effect of clomipramine cannot entirely be attributed to its effect on serotonin. In a recent study using zimelidine, a specific serotonin blocker that has been withdrawn from use by the Food and Drug Administration, and desipramine (which preferentially inhibits norepinephrine reuptake), Insel and Mueller (1984) reported that neither zimelidine or desipramine had a significant effect on clinical ratings of obsessionality in 13 OCD patients. However, when these patients were treated with clomipramine, they showed significant improvement on a global obsessional scale. The authors noted that CSF 5-HIAA did not significantly differ between zimelidine and clomipramine treatment. This indicates the ineffectiveness of zimelidine (a selective serotonin blocker) when compared with clomipramine (a serotonin and norepinephrine blocker) and raises questions regarding a singular central role for serotonin in OCD. Of course, these data are preliminary, and further studies with other antidepressants selective for serotonin (e.g., fluoxetine) will be necessary to delineate more explicitly the possible role of serotonin in OCD.

Summary and Discussion

It is clear from the previous discussion that we are not at a point where an integrated biological theory of OCD can be proposed. Although, the findings reviewed here consistently suggest that biological factors are correlated with OCD, a truly integrated discussion of these findings would be premature. From the data discussed, it does not appear that OCD is strictly a biological abnormality. Rather, the data suggest some type of biological predisposition that leaves an individual more vulnerable to the development of OCD, perhaps as a result of psychological stress.

The high concordance rate observed in monozygotic twins as opposed to dizygotic twins is comparable with concordance rates obtained in studies of schizophrenia and seems to suggest some type of genetic transmission. However, the absence of adoptive studies makes it impossible to rule out psychogenic or environmental factors. Moreover, the data that are available do not support a straightforward genetic model. It may well be that what is inherited is the tendency toward chronic elevated arousal or a tendency to respond in an overaroused fashion. It has long been noted that neurotic patients are subject to chronic overarousal which has been referred to as anxiety proneness (e.g., Carey & Gottesman, 1981). There is also some evidence that such individuals demonstrate resistance to habituation. In fact, Eysenck (1979) described a tendency for vulnerable individuals to show increases in arousal on repeated presentation of feared stimuli rather than extinction. This is known as the incubation effect or paradoxical enhancement of anxiety. If OCD patients are congenitally overaroused, this might explain their tendency to worry excessively and to overrespond to threatening stimuli, and the ability of such stimuli to elicit anxiety responses. In vulnerable individuals, such a process could be set off under circumstances such as the stress of giving birth or interpersonal conflict.

These significant events have been noted to be related to onset of OCD (Turner & Michelson, 1984). In a diathesis-stress model such as the one just described, the nature of psychological stress would determine the particular symptomatic expression in each individual. A recent study by Torgersen (1983) also provides evidence for genetic transmission of proneness to anxiety. Torgersen studied a subsample of 32 MZ and 53 DZ adult twins of the same sex who were part of a nationwide study of neurotic and borderline psychotic adult same-sex twins treated in Norway during the 1970s. The study was reported to have included almost all adult same-sex twin patients born between 1910 and 1955 and who were admitted to an institution before 1977. Two hundred and ninety-nine pairs were personally interviewed. In 19 pairs, both twins were probands. Therefore, the total number of probands was 318. Among the findings reported by Torgersen was that no MZ twin had the same disorder as the corresponding proband. That is, the MZ twin had a high incidence of anxiety disorder but not necessarily the same disorder as the proband. The concordance for an anxiety disorder in the twin was higher in MZ than in DZ pairs in all the twin proband groups except generalized anxiety. These data lend further support for a genetic transmission of anxiety proneness rather than a specific anxiety disorder.

One caveat with respect to the genetic studies is in order. In examining these studies, caution is advised because of differential diagnostic procedures used to determine anxiety disorders. As we noted, it is unclear in some of the studies whether the symptoms manifested by first-degree relatives were true obsessive-compulsive disorder symptoms or compulsive personality characteristics. A distinction has been made based on this dichotomy (Slade, 1974).

As was previously discussed, the findings from neuropsychological and neurophysiological investigations and studies of the effects of leucotomies suggest possible neuroanatomical abnormalities in OCD. These aberrations include altered EEG patterns, differences in averaged evoked potential, and suggestions of dominant frontal lobe dysfunction. However, all of these studies have major methodological difficulties including small sample size, lack of comparison groups, and lack of information regarding base rates for these abnormalities in the general population. In addition, psychosurgical procedures involving lesions in certain sites have been shown to reduce symptoms of OCD. These results also point to an organism that is in a chronically overaroused state.

Serotonin has been the subject of considerable study in relation to OCD. Clinical studies of the antidepressant clomipramine have been used to support the role of serotonin. However, the major flaw in all of these studies is that they do not have adequate measurement of OCD behaviors. In particular, there are no direct measures of obsessions and compulsions per se. Thus, it is difficult to assess the antiobsessive effect independent of mood. Moreover, the best designed study using the most sophisticated assessment strategy failed to reveal an antiobsessive effect for clomipramine. Rather, the effect was found only on measures of mood (Rachman et al., 1979). Biochemical abnormalities are found not only in studies of serotonin level, however. Recent reports have suggested that OCD patients also exhibit differing levels of norepinephrine when compared with normals. Thus, at this juncture, it is impossible to suggest a single biochemical factor as responsible for the disorder.

In view of the evidence presented, it would appear premature to attempt an explanation of OCD based on a single etiological hypothesis. It is possible that genetic predisposition, neuroanatomical involvement, and biochemical abnormalities (including serotonin and norepinephrine) may contribute to the pathogenesis of obsessive-compulsive disorders, each in varying degrees. It is also possible that the manifestations seen in these various systems are reflective of the same pathological process. The one unifying theme is that the disturbance in these systems is related in some way to emotional overarousal. Finally, it was also noted that a diathesis-stress model is called for to explain fully the current findings. At present, we know little about the complex interaction of these biological and environmental factors.

References

Abel, E. L. (1974). Drugs and behavior: A primer in neuropsychopharmacology. New York: Wiley. [Context Link]

Akhtar, S. (1978). Obsessional neurosis, marriage, sex and fertility: Some transcultural comparisons. International Journal of Social Psychiatry, 24, 164–166. [Context Link]

American Psychiatric Association (1980). Diagnostic and statistical manual of mental disorders (3rd ed.). Washington, DC: Author. [Context Link]

Ananth, J. (1976). Treatment of obsessive-compulsive neurosis: Pharmacological approach. Psychosomatics, 17, 180–184. Bibliographic Links [Context Link]

Ananth, J. (in press). Clomipramine in obsessive neurosis: A review. In M. Mavissakalian, S. M. Turner, & L. Michelson (Eds.), Psychological and pharmacological treatment of obsessive-compulsive disorder. New York: Plenum. [Context Link]

Ananth, J., Solyom, L., Bryntwick, S., & Krishnappa, U. (1979). Clomipramine therapy for obsessive-compulsive neurosis. American Journal of Psychiatry, 136, 700–701. [Context Link]

Åsberg, M., Thorén, P., & Bertilsson, L. (1982). Clomipramine treatment of obsessive-disorder: Biochemical and clinical aspects. Psychopharmacology Bulletin, 18, 13–21. [Context Link]

Bear, D. M. (1983). Hemispheric specialization and the neurology of emotion. Archives of Neurology, 40, 195–202. [Context Link]

Beech, H. R. (1971). Ritualistic activity in obsessional patients. Journal of Psychosomatic Research, 15, 417–422. Bibliographic Links [Context Link]

Beech, H. R., Ciesielski, K. T., & Gordon, P. K. (1983). Further observations of evoked potentials in obsessional patients. British Journal of Psychiatry, 142, 605–609. Bibliographic Links [Context Link]

Brown, W. A., Johnston, R., & Mayfield, D. (1979). The 24-hour dexamethasone suppression test in a clinical setting: Relationship to diagnosis, symptoms, and response to treatment. American Journal of Psychiatry, 136, 543–547. Bibliographic Links [Context Link]

Carey, G., & Gottesman, I. I. (1981). Twin and family studies of anxiety, phobic, and obsessive disorders. In D. F. Klein & J. G. Rabkin (Eds.), Anxiety: New research and changing concepts (pp. 117–135). New York: Raven. [Context Link]

Carrol, B. J., Feinberg, M., Greden, J. F., Toriska, J., Albal, A. A., Hachet, R. F., James, M., Kronfal, Z., Lohr, N., Steiner, M., deVigine, J. P., & Young, E. (1981). A specific laboratory test for the diagnosis of melancholia: Standardization, validation and clinical utility. Archives of General Psychiatry, 38, 15–22. [Context Link]

Ciesielski, K. T., Beech, H. R., & Gordon, P. K. (1981). Some electrophysiological observations in obsessional states. British Journal of Psychiatry, 138, 479–484. Bibliographic Links [Context Link]

Cohen, D. J., Detlor, J., Young, J. G., & Shaywitz, B. A. (1980). Clonidine ameliorates in Gilles de la Tourette Syndrome. Archives of General Psychiatry, 37, 1350–1357. [Context Link]

Coppen, A., & Wood, K. (1982). 5 Hydroxytriptamine in the patogenesis of affective disorders. In B. T. Ho, J. C. Schoolar, & E. Usdin (Eds.), Serotonin in biological psychiatry (pp. 249–258). New York: Raven. [Context Link]

Coryell, W. (1981). Obsessive-compulsive disorder and primary unipolar depression: Comparison of background, family history, course, and mortality. Journal of Nervous and Mental Disease, 164, 220–224. [Context Link]

Crighel, E., & Solomonovici, A. (1968). Electroclinical correlations in neurosis with anxiety and depression. Psychiatrica Clinica, 7, 143–151. [Context Link]

Depue, R. A., & Monroe, S. M. (1978). The unipolarbipolar distinction in the depressive disorders. Psychological Bulletin, 85, 1001–1029. [Context Link]

deSilva, P., Rachman, S., & Seligman, M. E. P. (1977). Prepared phobias and obsessions: Therapeutic outcome. Behaviour Research and Therapy, 15, 54–77. [Context Link]

Devenport, C. D., Devenport, J. A., & Holloway, F. A. (1981). Reward induced stereotype: Modulation by the hippocampus. Science, 212, 1288–1289. [Context Link]

Elkins, R., Rapóport, J. L., & Lipsky, A. (1980). Obsessive-compulsive disorder of childhood and adolescence. Journal of the American Academy of Child Psychiatry, 19, 511–524. [Context Link]

Epstein, A. W., & Bailine, S. H. (1971). Sleep and dream studies in obsessional neurosis with particular reference to epileptic states. Biological Psychiatry, 3, 149–158. Bibliographic Links [Context Link]

Eysenck, H. J. (1979). The conditioning model of neurosis. Behavioral and Brain Sciences, 2, 155–199. [Context Link]

Feinberg, M., & Carroll, B. J. (1979). The effects of dopamine agonists and antagonists in Tourette's disease. Archives of General Psychiatry, 36, 979–988. [Context Link]

Flor-Henry, P., Yeudall, L. T., Koles, Z. J., & Howarth, B. G. (1979). Neuropsychological and power spectral EEG investigations of the obsessive-compulsive syndrome. Biological Psychiatry, 14, 119–130. Bibliographic Links [Context Link]

Foa, E. B. (1978). Failure in treating obsessive-compulsives. Behaviour Research and Therapy, 17, 169–176. [Context Link]

Fodstad, H., Strandman, E., Karlsson, B., & West, K. A. (1982). Treatment of stereotactic anterior capsulotomy or cingulotomy. Acta Neurochiurgia, 62, 1–23. [Context Link]

Gittelson, N. L. (1966). The fate of obsessions in depressive psychosis. British Journal of Psychiatry, 112, 705–708. [Context Link]

Green, A. R., & Costain, D. W. (1981). Pharmacology and biochemistry of psychiatric disorders. New York: Wiley. [Context Link]

Hare, E., Rice, J., & Slater, E. (1971). Age distribution of schizophrenia and neurosis: Findings in a national sample. British Journal of Psychiatry, 119, 445–458. [Context Link]

Hodgson, R., & Rachman, S. (1972). The effects of contamination and washing in obsessional patients. Behaviour Research and Therapy, 10, 111–117. [Context Link]

Inouye, E. (1965). Similar and dissimilar manifestations of obsessive-compulsive neurosis in monozygotic twins. American Journal of Psychiatry, 21, 1171–1175. [Context Link]

Inouye, E. (1972). Genetic aspects of neurosis: A review. International Journal of Mental Health, 1, 176–189. [Context Link]

Insel, T. R., Donnelly, E. F., Lalakea, M. L., Alterman, I. S., & Murphy, D. L. (1983). Neurological and neuropsychological studies of patients with obsessive-compulsive disorder. Biological Psychiatry, 18, 741–751. Bibliographic Links [Context Link]

Insel, T. R., Gillin, C., Moore, A., Mendelson, W. B., Lowenstein, R. J., & Murphy, D. L. (1982). The sleep of patients with obsessive-compulsive disorder. Archives of General Psychiatry, 39, 1372–1377. [Context Link]

Insel, T. R., Hoover, C., & Murphy, D. L. (1983). Parents of patients with obsessive-compulsive disorder. Psychological Medicine, 13, 807–811. [Context Link]

Insel, T. R., Kalin, N. H., Guttmacher, L. B., Cohen, R. M., & Murphy, D. L. (1982). The dexamethasone suppression test in patients with primary obsessive-compulsive disorder. Psychiatry Research, 6, 153–160. Bibliographic Links [Context Link]

Insel, T. R., & Mueller, E. A. (1984). The psychopharmacologic treatment of obsessive-compulsive disorder. In T. R. Insel (Ed.), New findings in obsessive-compulsive disorder (pp. 72–88). Washington, DC: American Psychiatric Press. [Context Link]

Insel, T. R., Murphy, D. L., Cohen, R. M., Alterman, I., Kilts, C., & Linnoila, M. (1983). Obsessive-compulsive disorder: A review of supporting evidence. American Journal of Psychiatry, 122, 509–522. [Context Link]

Iversen, S. D. (1977). Brain dopamine systems and behavior. In L. L. Iversen, S. D. Iversen, & S. H. Snyder. Handbook of psychopharmacology (Vol. 8, pp. 333–384). New York: Plenum. [Context Link]

Jouvet, M. (1978). Neuropharmacology of the sleep waking cycle. In L. L. Iversen, S. D. Iversen, & S. H. Snyder (Eds.), Handbook of psychopharmacology (pp. 233–331). New York: Plenum. [Context Link]

Kelly, D. (1973). Therapeutic outcome in limbic leucotomy in psychiatric patients. Psychiatria, Neurologia, Neurochirurgia, 76, 353–363. [Context Link]

Kelly, D., Walter, C. J. S., Mitchell-Heggs, N., & Sargant, W. (1972). Modified leucotomy assessed clinically, physiologically and psychologically at six weeks and eighteen months. British Journal of Psychiatry, 120, 19–29. Bibliographic Links [Context Link]

Kelly, D. H. W., Walter, C. J. S., & Sargant, W. (1966). Modified leucotomy assessed by forearm blood flow and other measurements. British Journal of Psychiatry, 112, 871–881. Bibliographic Links [Context Link]

Kendal, R. E., & Discipio, W. J. (1970). Obsessional symptoms and obsessional personality traits in patients with depressive illnesses. Psychological Medicine, 1, 65–72. [Context Link]

Lader, M. (1974). The peripheral and central role of the catecholamines in the mechanisms of anxiety. International Journal of Pharmacopsychiatric Medicine, 9, 125–137. [Context Link]

Marks, I., Crowe, M., Drewe, E., Young, J., & Dewhurst, W. (1969). Obsessive-compulsive neurosis in identical twins. British Journal of Psychiatry, 115, 991–998. Bibliographic Links [Context Link]

Mavissakalian, M., & Barlow, D. H. (1981). Assessment of obsessive-compulsive neurosis. In D. H. Barlow (Ed.), Behavioral assessment of adult disorders (pp. 209–238). New York: Guilford. [Context Link]

McGuffin, P., & Mawson, D. (1980). Obsessive-compulsive neurosis: Two identical twin pairs. British Journal of Psychiatry, 137, 285–287. Bibliographic Links [Context Link]

Meltzer, H. Y., Arora, R. C., Baker, R., & Tricou, B. J. (1981). Serotonin uptake in blood platelets of psychiatric patients. Archives of General Psychiatry, 38, 1322–1326. Bibliographic Links [Context Link]

Montgomery, M. A., Clayton, P. J., & Friedhoff, A. J. (1982). Psychiatric illness in Tourette Syndrome patients and first degree relatives. In A. J. Friedhoff & T. N. Chase (Eds.), Gilles de la Tourette Syndrome (pp. 335–339). New York: Raven. [Context Link]

Morris, R. G. M., Garrud, P., Rawlins, J. N. P., & O'Keefe, J. (1982). Place navigation impaired in rats with hippocampal lesions. Nature, 297, 681–683. [Context Link]

Neale, J. M., & Oltmanns, T. F. (1980). Schizophrenia. New York: Wiley. [Context Link]

Nee, L. E., Caine, E. D., Polinsky, R. J., Eldridge, R., & Ebert, M. H. (1980). Gilles de la Tourette Syndrome: Clinical and family studies of 50 cases. Annals of Neurology, 7, 41–49. [Context Link]

Papez, J. W. (1937). A proposed mechanism of emotion. Archives of Neurology and Psychiatry, 38, 725–743. [Context Link]

Pitman, R. K. (1982). Neurological etiology of obsessive-compulsive disorders. American Journal of Psychiatry, 139, 139–140. [Context Link]

Rabavilas, A. D., Boulougouris, J. C., Perissaki, C., & Stefanis, C. (1979). The effect of peripheral beta-blockade on psychophysiologic responses in obsessional neurotics. Comprehensive Psychiatry, 20, 378–383. [Context Link]

Rachman, S. (1976). Obsessional-compulsive checking. Behaviour Research and Therapy, 14, 269–277. [Context Link]

Rachman, S., Cobb, J., Grey, S., McDonald, B., Mawson, D., Sartory, G., & Stern, R. (1979). The behavioral treatment of obsessional-compulsive disorders, with and without Clomipramine. Behaviour Research and Therapy, 17, 467–478. [Context Link]

Rachman, S., & Hodgson, R. (1980). Obsessions and compulsions. Englewood Cliffs, NJ: Prentice-Hall. [Context Link]

Rinieris, P. M., Stefanis, C. N., Rabavilas, A. D., & Vaidakis, N. W. (1978). Obsessive-compulsive neurosis, anancastic symptomatology and ABO blood types. Acta Psychiatrica Scandanavica, 57, 377–381. Bibliographic Links [Context Link]

Roper, G., & Rachman, S. (1976). Obsessional-compulsive checking: Experimental replication and development. Behaviour Research and Therapy, 14, 25–32. [Context Link]

Roper, G., Rachman, S., & Hodgson, R. (1973). An experiment on obsessional checking. Behaviour Research and Therapy, 11, 271–277. [Context Link]

Salzman, L., & Thaler, F. H. (1981). Obsessive-compulsive disorders: A review of the literature. American Journal of Psychiatry, 138, 286–296. Bibliographic Links [Context Link]

Shapiro, A. K., Shapiro, E. S., Bruun, R. D., & Sweet, R. D. (1978). Gille de la Tourette's Syndrome. New York: Raven. [Context Link]

Shillitoe, E. E. (1970). The effect of parachlorphenylalanine on social interaction of male rats. British Journal of Pharmacology, 38, 305–315. [Context Link]

Slade, P. D. (1974). Psychometric studies of obsessional illness and obsessional personality. In H. R. Beech (Ed.), Obsessional states (pp. 95–109). London: Methuen. [Context Link]

Snowdon, J. (1979). Family size and birth order in obsessional neurosis. Acta Psychiatrica Scandanavica, 60, 121–128. Bibliographic Links [Context Link]

Solyom, L., Zamanyadeh, D., Ledwich, B., & Kenny, F. (1971). Aversion relief treatment of obsessional neurosis. In R. Rubin (Ed.), Advances in behavior therapy (pp. 93–109). London: Academic Press. [Context Link]

Spring, B. J., & Zubin, J. (1978). Attention and information processing as indicators of vulnerability of schizophrenic episodes. Journal of Psychiatric Research, 14, 289–301. Bibliographic Links [Context Link]

Stern, R. S., Marks, I. M., & Mawson, D. (1980). Clomipramine and exposure for compulsive rituals: Plasma levels, side effects and outcome. British Journal of Psychiatry, 136, 161–166. Bibliographic Links [Context Link]

Sturgis, E. T., & Meyer, V. (1981). Obsessive-compulsive disorders. In S. M. Turner, K. S. Calhoun, & H. E. Adams (Eds.), Handbook of clinical behavior therapy (pp. 68–102). New York: Wiley. [Context Link]

Tan, E., Marks, I. M., & Marset, P. (1971). Bimedial leucotomy in obsessive-compulsive neurosis: A controlled serial inquiry. British Journal of Psychiatry, 118, 155–164. [Context Link]

Tarsh, M. J. (1978). Severe obsessional illness in dizygotic twins treated by leucotomy. Comprehensive Psychiatry, 19, 165–169. Bibliographic Links [Context Link]

Thorén, P., Åsberg, M., Bertilsson, L., Mellström, B., Sjoqvist, F., & Traskman, L. (1980). Clomipramine treatment of obsessive-compulsive disorders: II. Biochemical aspects. Archives of General Psychiatry, 37, 1289–1294. Bibliographic Links [Context Link]

Thorén, P., Åsberg, M., Cronholm, B., Jörnestedt, L., & Träskman, L. (1980). Clomipramine treatment of obsessive-compulsive disorder: I. A controlled clinical trial. Archives of General Psychiatry, 37, 1281–1285. Bibliographic Links [Context Link]

Torgersen, S. (1983). Genetic factors in anxiety disorders. Archives of General Psychiatry, 40, 1085–1089. [Context Link]

Tuomsito, J., & Tukiainen, R. (1976). Decreased uptake of 5-hydroxytryptamine in blood platelets from depressed patients. Nature, 262, 596–598. [Context Link]

Turner, S. M. (1982). Behavioral assessment of drug effects in obsessive compulsive disorders. Psychopharmacology Bulletin, 18, 41–43. Bibliographic Links [Context Link]

Turner, S. M. (1984). Patterns of depression and anxiety in patients with anxiety disorders. Unpublished manuscript, University of Pittsburgh. [Context Link]

Turner, S. M., & Michelson, L. (1984). Obsessive-compulsive disorders. In S. M. Turner (Ed.), Behavioral theories and treatment of anxiety (pp. 239–277). New York: Plenum. [Context Link]

Vaughn, M. (1976). The relationships between obsessional personality, obsessions and depression, and symptoms of depression. British Journal of Psychiatry, 129, 36–39. [Context Link]

Waldmeier, P. C., Baumann, P., Grungrass, P. M., & Maitre, L. (1976). Effects of clomipramine and other tricyclic antidepressants on biogenic amine uptake and turnover. Postgraduate Medicine Journal Supplement, 52, 33–39. [Context Link]

Welner, A., Reich, T., Robins, E., Fishman, R., & Van Doren, T. (1976). Obsessive-compulsive neurosis: Record, follow-up and family studies: I. Inpatient record study. Comprehensive Psychiatry, 17, 527–539. Bibliographic Links [Context Link]

Yaryura-Tobias, J. A. (1977). Obsessive-compulsive disorders: A serotonergic hypothesis. Journal of Orthomolecular Psychiatry, 6, 317–326. [Context Link]

Yaryura-Tobias, J. A., Berbirian, R. J., Neziroglu, F. A., & Bhagavan, H. N. (1977). Obsessive-compulsive disorders as a sertonergic defect. Research Communications in Psychology, Psychiatry and Behavior, 2, 279–286. [Context Link]

Yaryura-Tobias, J. A., & Bhagavan, H. N. (1977). L-Tryptophan in obsessive-compulsive disorders. American Journal of Psychiatry, 134, 1298–1299. Bibliographic Links [Context Link]



Accession Number: 00006823-198505000-00005

表單的底部

Copyright (c) 2000-2007 Ovid Technologies, Inc.
Version: rel10.5.8, SourceID 1.13281.2.32.1.0.2.197.1.4.1.5

沒有留言: