Elsevier

Psychoneuroendocrinology

Volume 24, Issue 1, 1 January 1999, Pages 1-24
Psychoneuroendocrinology

Possible role of neuropeptides in obsessive compulsive disorder

https://doi.org/10.1016/S0306-4530(98)00046-8Get rights and content

Abstract

The most consistent finding in clinical research of obsessive compulsive disorder (OCD) is the significant treatment advantage of potent serotonin uptake inhibitors (SUIs) over other classes of antidepressant and antianxiety drugs. Clinical neurobiological studies of OCD, however, have yielded limited and inconsistent evidence for significant fundamental abnormalities in monoamine systems including serotonin, norepinephrine and dopamine. Furthermore, one-third to one-half of OCD patients do not experience a clinically meaningful improvement with SUI treatment. Investigation beyond the monoamine systems may be necessary in order to more fully understand the pathophysiology of obsessive–compulsive symptoms and develop improved treatments. Evidence from preclinical studies suggests that neuropeptides may have important influences on memory acquisition, maintenance and retrieval; grooming, maternal, sexual and aggressive behavior; fixed action patterns; and stereotyped behavior; these phenomena may relate to some features of OCD. In addition, extensive interactions have been identified in the brain between neuropeptidergic and monoaminergic systems, including co-localization among specific populations of neurons. The purpose of this review is to present the current knowledge of the role of neuropeptides in the clinical neurobiology of children, adolescents and adults with OCD focusing primarily on results from pharmacological challenge and cerebrospinal fluid studies. Where evidence exists, developmentally regulated differences in neuropeptide function between children and adolescents versus adults with OCD will be emphasized; these data are intended to underscore the potential importance of establishing the age of symptom onset (childhood versus adult) in individual patients with OCD participating in clinical neurobiological investigations. Likewise, where information is available, differences in measures of neuropeptides between patients with non-tic-related OCD versus tic-related OCD will be highlighted; these data will demonstrate the critical value of diagnostic precision, as these two particular subtypes of OCD may have different neurochemical underpinnings.

Introduction

Clinical observation of the efficacy of potent serotonin (5-hydroxytryptamine; 5-HT) uptake inhibitors (SUIs) in the treatment of obsessive compulsive disorder (OCD) initially focused attention on the role 5-HT may play in the mediation of obsessive–compulsive (OC) symptoms (Insel et al., 1985). The differential efficacy of the SUIs, when directly compared with agents that inhibit norepinephrine (NE) uptake (Zohar and Insel, 1987, Leonard et al., 1989, Goodman et al., 1990a), supports the hypothesized importance of 5-HT in the treatment of OC symptoms. Furthermore, preliminary support for association and linkage disequilibrium between a polymorphism in the promoter region of the gene (SLC6A4) encoding the 5-HT transporter protein and OCD has recently been described (McDougle et al., 1998). Results from pharmacologic challenge studies employing the mixed 5-HT receptor agonist/antagonist m-chlorophenylpiperazine (mCPP) (Zohar et al., 1988, Hollander et al., 1991) and the nonselective 5-HT receptor antagonist metergoline (Benkelfat et al., 1989a) in OCD patients improved following SUI treatment suggest that SUIs may ‘stabilize’ dysregulated 5-HT neuronal function. Fluoxetine (Hollander et al., 1991) and clomipramine (Zohar et al., 1988) treatment abolished the pretreatment mCPP-induced exacerbation of OC symptoms, whereas metergoline (Benkelfat et al., 1989a) administration resulted in a nonsignificant increase in OC symptoms. Although inconsistent, a relationship between SUI-induced changes in biological markers of the 5-HT system and drug treatment response has been identified in some studies (Thorén et al., 1980, Flament et al., 1987).

Despite these advances, other lines of evidence suggest that investigation beyond the 5-HT system will be necessary in order to more fully understand the pathophysiology of OC symptoms and develop improved treatments (Goodman et al., 1990b). Between 33 and 50% of OCD patients do not experience clinically meaningful improvement with SUI monotherapy (McDougle et al., 1993a). In these patients, addition of other drugs active upon the 5-HT system, such as lithium (McDougle et al., 1991, Pigott et al., 1991) and buspirone (Pigott et al., 1992, Grady et al., 1993, McDougle et al., 1993b), to ongoing SUI treatment does not generally enhance response. Furthermore, pharmacologic challenge studies in drug-free OCD patients have identified no consistent abnormality in 5-HT function (Barr et al., 1992, Goodman et al., 1995), and some evidence suggests that SUIs may produce downstream effects not immediately reversed by reductions in central 5-HT. For example, the acute tryptophan depletion paradigm, designed to rapidly lower brain 5-HT levels, does not exacerbate OC symptoms in SUI-remitted OCD patients (Barr et al., 1994).

Other studies have linked OCD and the chronic tic disorder, Tourette's syndrome (TS) (Pitman et al., 1987, McDougle et al., 1994a). Involvement of the dopamine (DA) system has been hypothesized in the pathophysiology of TS based on the efficacy of DA receptor antagonists in suppressing tics (Shapiro et al., 1989), and on neuropathological (Singer et al., 1991) and neuroimaging (Malison et al., 1995, Wolf et al., 1996) studies which demonstrate differences in DA innervation in the basal ganglia between patients and matched healthy controls. Recent trials of combined SUI and typical neuroleptic treatment indicate that DA receptor antagonism may further reduce OC symptom severity in OCD patients with comorbid chronic tic disorders (McDougle et al., 1990, McDougle et al., 1994b). Moreover, results from open-label studies suggest that the addition of the atypical neuroleptic risperidone to SUIs may be a useful approach for OCD patients with (McDougle et al., 1995) and without (Saxena et al., 1996) comorbid chronic tics.

We will now review preclinical evidence linking neuropeptides to repetitive behavior in animals, as well as results from initial clinical investigations of neuropeptides in OCD patients. Arginine vasopressin (AVP), oxytocin, adrenocorticotropic hormone (ACTH), corticotropin releasing factor (CRF), somatostatin, and the possible role of the opioid system in the modulation of OC symptoms will be reviewed.

Section snippets

Arginine vasopressin

Arginine vasopressin (AVP), along with oxytocin, is a hormonal peptide secreted by the posterior lobe of the pituitary gland. AVP increases distal renal tubule permeability, thus enhancing the capacity of the kidney to retain free water. AVP acts peripherally as a vasoconstrictor, particularly during periods of hypovolemia. AVP-containing neurons in the suprachiasmatic and paraventricular nuclei project to limbic areas (Buijs, 1978), including the hippocampus, the subiculum, the ventral nucleus

Oxytocin

Oxytocin has been called the ‘amnesic’ neuropeptide because of its action to attenuate memory consolidation and retrieval (Bohus et al., 1978). It appears to facilitate the extinction of an active avoidance response and attenuates passive avoidance behavior (Kovács and Telegdy, 1985). Importantly, postmortem studies of Alzheimer's patients have found elevated oxytocin concentrations in the hippocampus and temporal cortex compared with controls (Mazurek et al., 1987). It may be that pathological

Adrenocorticotropic hormone

The relationship between adrenocorticotropic hormone (ACTH)-induced fixed action patterns (inborn, internally coordinated behavior sequences) and OC symptoms has been reviewed previously (Swedo, 1989). ACTH administration has been associated with grooming behavior in rats typical of that seen when they are placed in novel and presumably stressful situations. ACTH-induced grooming is thought to be independent of the endocrine system (Gispen et al., 1975) and is altered by pretreatment with

Corticotropin releasing factor

Corticotropin releasing factor (CRF) acts on the anterior pituitary to stimulate ACTH release. CRF-containing neurons are present in the paraventricular nucleus, the median eminence, the preoptic areas, the bed nucleus of the stria terminalis, the amygdala, the locus coeruleus, and the prefrontal and cingulate cortex. For a comprehensive review of neurotransmitter regulation of hypothalamic CRF the reader is referred to the excellent review by Owens and Nemeroff (1991).

Preclinical studies

Somatostatin

Somatostatin inhibits both release of growth hormone by the pituitary and the pancreatic release of insulin and glucagon. Somatostatin is concentrated in the mediobasal hypothalamus; smaller amounts are present in dorsal root ganglia, intestine, amygdala and neocortex (Cooper et al., 1996). Brain somatostatin exists in three forms and these peptides may be stored in separable subcellular compartments (Cooper et al., 1996). Somatostatin-containing neurons overlap with GABA-ergic neurons in the

Opioids

The role of opioids in the mediation of reward signals suggests a possible role for these neuropeptides in OCD (Insel and Pickar, 1983). The ongoing ‘self-doubt’ that many OCD patients experience may be explained by a deficiency in the neural mechanisms involved in finishing thoughts or resolving indecision. For instance, the OCD patient who repeatedly returns to a door to check the lock may have an alteration in the mechanisms that signal successful task completion. This signal may be mediated

Conclusion

The purpose of this review was to discuss preclinical evidence linking neuropeptides to repetitive behavior in animals and to review initial clinical investigations of neuropeptides in patients with OCD (Table 1). Data regarding the possible memory-enhancing and -attenuating effects of AVP and oxytocin, respectively, were reviewed, as were CSF studies of these neuropeptides in children, adolescents and adults with OCD. That CSF levels of AVP and oxytocin appear to be developmentally regulated

Acknowledgements

This work was supported by a National Alliance for Research on Schizophrenia and Depression Independent Investigator Award (Dr McDougle), the Stanley Foundation Research Program (Drs McDougle and Price), the State of Connecticut Department of Mental Health and Addiction Services, and National Institutes of Health grants MH49351, MH30929, and MH25642. The authors wish to thank Kathryn A. Czarkowski, B.S., and Elizabeth Kyle, A.S., for their assistance in the preparation of the manuscript.

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