The role of neurotransmitters and neurohormones in obsessive-compulsive disorder

Summary

There is considerable evidence that serotonergic systems modulate obsessive-compulsive disorder (OGD) symptomatology. The strongest such data are the antiobsessional effects of serotonin reuptake inhibitors (SRIs), unique among antidepressants. Although the mechanisms underlying the effectiveness of SRI treatment remain largely unknown, the available data support the position that enhanced 5-HT synaptic availability, resulting from a combination of effects on serotonin release and transport, is necessary for the therapeutic efficacy of SRI treatment. The ability of the serotonergic probe mCPP to exacerbate OCD symptoms in untreated patients, and findings that potent 5-HT receptor antagonists may reverse SRI-induced therapeutic benefits, also support serotonergic modulation of OCD symptomatology. There is as yet little evidence that dysregulation in serotonergic systems might be etiologically important in OCD. Although evidence that other neurotransmitter or neuropeptide systems are involved in OCD is considerably more preliminary than that implicating serotonergic mechanisms, there are some indications that such systems may be involved. Studies of the role of these systems, and how they may interact with serotonergic mechanisms, may be particularly helpful in further elucidating the neuropharmacology of OCD and in identifying potential new treatments.

Introduction

A considerable body of evidence suggests that OCD is related in important ways to the functioning of brain serotonin (5-HT) systems. Although numerous clinical and preclinical studies also implicate serotonergic mechanisms in other neuropsychiatric disorders (Coccaro & Murphy, 1990; Sandler et al., 1991), it is in OCD that changes in serotonin subsystem function and symptomatology have been most closely linked. This review will consider the possibility that 5-HT dysregulation may be etiologically important in the disorder, as well as the better established hypothesis that changes in serotonergically-mediated functions produced by pharmacologic agents that affect neurotransmitters and neurohormones can modulate OCD symptoms, both beneficially and adversely. Agents with initial actions on 5-HT systems, particularly the serotonin reuptake inhibitors (SRIs), have been those with the greatest clinical effects in OCD. It is important to note at the outset, however, that it may be the interaction between serotonergic mechanisms and other brain systems that is critical to the changes in symptomatology observed (Insel et al., 1985; Murphy et al., 1989). It seems particularly likely that the time-dependent therapeutic effects of serotonin reuptake inhibiting antidepressants (SRIs) depend upon adaptive changes, both within serotonergic subsystems and possibly in other neurotransmitter or neuropeptide mechanisms; these adaptive changes could take place at sites distant from the SRIs' initial action on the 5-HT transporter. In this regard, we will consider evidence from clinical and preclinical studies which potentially implicates different neurotransmitter and neuropeptide systems in OCD.

Therapeutic effects of serotonin reuptake inhibitors in OCD

The first evidence for a role of brain 5-HT systems in OCD came from studies of the therapeutic effects of agents which are potent inhibitors of the serotonin transporter. The antiobsessional action of the SRIs was serendipitously discovered in studies of the antidepressant effects of clomipramine, which found that obsessive-compulsive symptoms in depressed patients improved, sometimes even more strikingly than the antidepressant effects observed (Fernandez & Lopez-Ibor, 1967). Subsequently, the antiobsessional action of SRIs has been well established in a number of placebo-controlled studies. For clomipramine, these include both individual trials (reviewed in McTavish & Benfield, 1990; Murphy & Pigott, 1990) and multicentre studies (Clomipramine Collaborative Study Group, 1991; DeVeaugh-Geiss et al., 1992). As noted in the earliest, as well as subsequent, studies, clomipramine's antiobsessional effects did not depend on its antidepressant action, since OCD patients who were not depressed responded as well as those with depressive symptoms (Katz & DeVeaugh-Geiss, 1990).

Controlled studies of SRIs which act more selectively on the 5-HT transporter than the broader-spectrum tricyclic, clomipramine, demonstrated that they also have therapeutic effects in OCD. Fluvoxamine was the first of these shown effective in both single-site (Cottraux et al., 1990; Goodman et al., 1989; Perse et al., 1987) and multicentre trials (Greist, 1992; Montgomery & Manceaux, 1992). Single site (Pigott et al., 1990) and multicentre trials of fluoxetine (Greist et al., 1995; Montgomery et al., 1993; Wood et al., 1993) and sertraline (Montgomery et al., 1993; Wood et al., 1993) demonstrate that these agents are also efficacious. Multicentre trials showing that paroxetine is also effective in OCD have only been partially published (Wheadon et al., 1993).

The proportion of patients reported to be `much improved' or `very much improved' after treatment with clomipramine and the more selective agents ranges from approximately 25-60% across studies. Meta-analyses of multicentre studies have suggested that clomipramine may be somewhat more effective than fluoxetine, fluvoxamine and sertraline (Greist et al., 1995a; Greist et al., 1995b; Piccinelli et al., 1995; Stein et al., 1995). Studies directly comparing clomipramine and the more selective agents, however, have reported equal efficacy for clomipramine and fluoxetine (Pigott et al., 1990), clomipramine and fluvoxamine (Freeman et al., 1994; Koran et al., 1995) and clomipramine and paroxetine (Zohar & Judge, in press). Thus, the issue of the relative efficacy of clomipramine versus more selective SRIs remains unsettled. Possible reasons for this include differences in patient samples from the earliest studies using clomipramine, which included patients with severe OCD of long duration, and later trials with the more selective agents, which included some patients who had been poorly responsive to clomipramine or fluoxetine. The higher rate of placebo response in some later studies compared to the very low placebo response rate in the earliest studies also suggests differences in patient samples.

Nevertheless, it is clear that the potent SRIs produce at least some clinical benefit in most patients with OCD. These therapeutic effects of SRIs in OCD are in marked contrast to those of non-SRI antidepressants. Clomipramine is more effective than desipramine, a norepinephrine uptake inhibitor, when the two are directly compared (Leonard et al., 1989; Zohar & Insel, 1987). Likewise, fluvoxamine was superior to desipramine in OCD (Goodman et al., 1990). And although one study found the monoamine oxidase inhibitor phenelzine to be as effective as clomipramine (Vallejo et al., 1992), the preponderance of studies find monoamine oxidase inhibitors to be ineffective in OCD (reviewed in Den Boer & Westenberg, 1996; Murphy & Pigott, 1990). Taken together, these data are especially noteworthy in that they distinguish OCD from both depressive and anxiety disorders which are successfully treated by a variety of antidepressants with differing pharmacological actions.

As noted above, most patients respond to SRIs with only a partial reduction in symptoms, and a substantial subgroup of OCD patients fails to benefit significantly from SRI monotherapy. This indicates that SRI treatment only partly compensates for dysfunctions underlying OCD in many patients, and further suggests that brain mechanisms not significantly affected by SRIs are involved in maintaining OCD symptomatology in other patients. The need for better treatments in OCD patients poorly responsive to SRIs has led to studies of adjuvant agents added to SRI monotherapy, some of which are discussed later in this review.

Functional state of serotonergic mechanisms in OCD

Baseline measures in unmedicated OCD patients Studies aimed at identifying abnormalities in 5-HT systems in untreated OCD patients studied at baseline have on the whole been disappointing. For example, although a few earlier studies hinted at abnormal cerebrospinal fluid levels of the 5-HT metabolite, 5-hydroxyindoleacetic acid (5-HIAA), later studies with larger patient samples reported normal 5-HIAA levels (Altemus et al., 1992; Leckman et al., 1995). Peripheral markers of 5-HT function, including levels of platelet 3H-imipramine or ³H-paroxetine binding sites and whole blood or platelet 5-HT content, have likewise generally failed to suggest abnormalities in OCD patients compared to healthy individuals (reviewed in Barr et al., 1992; Bastani et al., 1991; Nelson et al., 1995). However, one study of children and adolescents with severe OCD found higher whole blood 5-HT levels in patients with a family history of OCD compared to both health controls and to OCD patients without a family history (Hanna et al., 1991). Since studies indicate that OCD may have a heritable component (Leonard et al., 1992; Pauls et al., 1995), the finding that some familial cases of OCD may have an abnormality in serotonergic measure (Hanna et al., 1991) raises the possibility that an inherited dysregulation of 5-HT systems might predispose at least some individuals to OCD. Direct investigations or candidate genes encoding serotonergic or other neurotransmitter receptors, transporters or synthetic enzymes have not yet revealed any abnormalities in patients with OCD (Altemus et al., in press; Brett et al., 1995; Catalano et al., 1994; Novelli et al., 1994).

Serotonergic probes in unmedicated OCD patients

The lack of clear evidence of abnormalities in 5-HT systems in OCD when baseline markers of serotonergic functioning are obtained, has led to the use of pharmacologic challenge paradigms to test various hypotheses of functional brain 5-HT alterations in OCD. One such hypothesis is that a presynaptic dysfunction leading to reduced serotonin availability is involved in the etiology or modulation of OCD symptoms. In that case, producing a further reduction in either synaptic availability of 5-HT or in stimulation of postsynaptic 5-HT receptors might be expected to intensify OCD symptoms. However, attempts to reduce brain 5-HT availability by acute depletion of dietary tryptophan, which has been shown in humans to reduce plasma tryptophan and presumably central 5-HT levels, did not acutely worsen symptoms in a relatively small sample (n = 8) of unmedicated OCD patients (Delgado et al., 1988). Similarly, the potent 5-HT antagonist metergoline, which would be expected to markedly reduce postsynaptic stimulation of a number of 5HT receptor subtypes, also produced no acute OCD symptom worsening in untreated patients (Zohar & Insel, 1987). We have recently replicated the latter finding in an additional unmedicated OCD patient group (Greenberg et al., unpublished observations). While it remains possible that there is a reduction in 5-HT availability in OCD due to presynaptic factors, it appears thus far that acutely reducing 5-HT neurotransmission does not exacerbate OCD symptoms in unmedicated patients.

Another approach, using pharmacologic probes with 5-HT agonist effects to assess the functional status of central serotonergic pathways in OCD, has been more widely used (reviewed in Bart et al., 1993; Kahn & Wetzler, 1991; Murphy et al., 1996). A number of studies have focused on neuroendocrine effects of serotonin agonist probes, which can produce increases in plasma prolactin, cortisol and ACTH (Murphy, 1991a; Murphy, 1991b), or other systemic effects such as an increase in temperature (Schwartz et al., 1995) both in neuropsychiatric patients and in healthy volunteers. Some studies have found that OCD patients have a blunted physiological response to serotonin agonist challenge using one or more of these measures, but a fully consistent pattern of effects has not emerged (reviewed in Murphy et al., 1996). It should be noted that, although these studies were intended to provide physiological evidence of serotonergic dysregulation in OCD, what they actually measure is the responsivity of hypothalamic-pituitary structures to direct and indirect serotonergic modulation. It is very possible that serotonergic modulation of behaviors, including OCD symptoms, occurs at different neuroanatomical locations and via different subpopulations of 5-HT receptors.

Behavioral effects of serotonin agonist probes in OCD

A number of investigations have found evidence of enhanced behavioral responsivity to a serotonergic partial agonist challenge in OCD. Studies using the partial serotonergic agonist m-chlorophenylpiperazine (mCPP), a metabolite of the antidepressant trazodone, have generated the most interest. Although mCPP has a number of actions on different serotonin receptor mechanisms (Benjamin et al., 1996; Kahn & Wetzler, 1991), recent studies using transgenic knockout mice demonstrate that some of mCPP's physiologic and behavioral effects require stimulation of 5-HT2C receptors (Tecott et al., 1995). Studies in animal models suggest that the anxiogenic effects of mCPP are also mediated by agonist effects at 5-HT2C receptors (Curzon & Kennett, 1990), with some qualifications (reviewed in Murphy, 1991b). mCPP is anxiogenic when administered to healthy volunteers (Benjamin et al., 1996; Mueller et al., 1985; Murphy et al., 1989). The view that behavioral effects of mCPP involve an action on 5-HT2C receptors is consistent with a study showing that the 5-HT2A/2C selective antagonist ritanserin reduced the anxiogenic effects of mCPP in healthy volunteers (Seibyl et al., 1991). Another study, showing attenuation of mCPP's anxiogenic effects in healthy volunteers by the 5-HT3 selective antagonist ondansetron (Broocks et al., in press), suggests that the effects of mCPP may be modulated by other serotonergic subsystems as well.

In the earliest studies in OCD, which were carried out by our research group, mCPP administered to unmedicated patients produced transiently increased anxiety and, in some patients, brief exacerbations of OCD symptoms (Zohar & Insel, 1987). This demonstration that mCPP administered to unmedicated OCD patients could provoke a transient symptomatic exacerbation led to this agent becoming the most studied serotonergic probe in OCD. A number of subsequent studies in our group and elsewhere had results consistent with the initial finding of symptomatic exacerbation (Broocks et al., 1992; Hollander et al., 1988; Hollander et al., 1992; Pigott et al., 1993; Zohar et al., 1988). Evidence that this effect of mCPP was mediated by serotonergic mechanisms came from studies showing that pretreatment with the potent 5-HT antagonist metergoline blocked the behavioral effects of mCPP in OCD patients (Pigott et al., 1991; Pigott et al., 1993). In OCD patients, chronic treatment with clomipramine (Zohar et al., 1988) or fluoxetine (Hollander et al., 1991) attenuated the behavioral effects of mCPP. This suggests that a therapeutic SRI regimen may produce adaptive changes in 5HT mechanisms which result in reduced sensitivity to mCPP's behavioral effects.

However, it is important to note that in other studies (Charney et al., 1988; Goodman et al., 1995, mCPP did not exacerbate obsessions or compulsive urges in OCD patients, despite being anxiogenie in both of these studies (Charney et al., 1988; Goodman et al., 1995). In addition, the early observation that the anxiogenic effects of mCPP in OCD patients were greater than those seen in healthy individuals (Zohar & Insel, 1987; Zohar et al., 1987), suggesting that serotonergic systems mediating anxiety-related behaviors may be abnormally sensitive in OCD, was not replicated in two subsequent studies (Charney et al., 1988; Hollander et al., 1992). Methodological differences, including dose, route and rate of administration, and drug challenge setting (see Hollander, 1995 and Pigott et al., 1993 for a general discussion) may help explain variations in mCPP's behavioral effects across these studies (Goodman et al., 1995) (reviewed in Barr et al., 1993; Murphy et al., 1996). The possible existence of an mCPP-responsive OCD patient subgroup might also be important. Still, no fully satisfactory explanation for these discrepant findings has yet emerged.

Possible mechanisms of SRI action in OCD: modulation of serotonergic neurotransmission

Studies in animals have found that chronic treatment with SRIs leads to increased extracellular concentrations of 5-HT, consistent with electro-physiological evidence that SRIs given chronically enhance 5-HT release through desensitization of inhibitory 5-HT autoreceptors located both on the cell body and on terminals of serotonergic neurons (Blier et al., 1990). There is also evidence that repeated administration of the SRI paroxetine may lead to a further reduction in activity of the 5-HT transporter itself (Pineyro et al., 1994). This effect may be due to reduced transporter gene transcription, which has been observed after chronic treatment with fluoxetine (Lesch et al., 1993). Two weeks of fluoxamine treatment produced a larger increase in the extracellular serotonin concentration in rat frontal cortex than that seen after a single dose (Bel & Artigas, 1993). In addition, chronic treatment with SRIs has been reported to increase the electrically-stimulated overflow of 3H-5-HT in both the cell body-containing dorsal raphe nucleus (O'Connor & Kruk, 1994) and 5-HT terminal fields, including the suprachiasmatic nucleus (after fluoxetine treatment) (O'Connor & Kruk, 1994) and hypothalamus (after citalopram treatment) (Moret & Briley, 1990). Thus, there is a body of preclinical evidence consistent with the view that chronic SRI administration produces time-dependent changes in serotonergic neurons, leading to increased levels of 5-HT in terminal regions (Blier et al., 1990). It seems likely that such a prolonged elevation in synaptic serotonin concentrations could result in changes in 5-HT receptor-linked signal transducing mechanisms, which may be important in the antiobsessional effects of SRIs, as well as in their antidepressant actions.

There may, however, be differences in the mechanisms underlying the antidepressant and the antiobsessional actions of SRIs. SRI treatment of OCD may require longer duration of treatment than is typically necessary in treating depression (Fineberg et al., 1992; Montgomery & Manceaux, 1992). Clinical practice suggests that higher SRI doses are needed for optimum treatment of OCD compared with depression, although this has not been definitively established (Tollefson et al., 1994). In addition, stopping SRI treatment results in a rapid return of symptoms in OCD (Pato et al., 1988), a phenomenon less regularly observed in depression. Also, most functional neuroimaging studies find that patterns of cerebral activity associated with OCD and depression also differ, both before and after treatment (including treatment with SRIs). Increased metabolism or perfusion in prefrontal cortex and basal ganglia, most commonly those regions comprising the `lateral orbitofrontal circuit', is consistently observed in untreated OCD patients (reviewed by Hoehn-Saric & Greenberg, this issue). In contrast, in depression most evidence supports hypofunction of anterior brain structures (reviewed by Ketter et al., in press). Both of these aberrant patterns of cerebral activity tend to normalize as patients become less symptomatic.

Preclinical research may shed some light on possible differences in mechanisms underlying antiobsessional and antidepressant effects of SRIs. A recent animal study found that prolonged (eight weeks) and higher dose treatment with paroxetine was required to increase electrically-evoked 5-HT release in the guinea pig analog of human orbital frontal cortex. Briefer (three weeks) treatment with paroxetine increased 5-HT release only in non-orbital prefrontal cortex (El Mansari et al., 1995). This effect appeared to be due to an SRI-induced desensitization of 5-HT1D autoreceptors on serotonergic terminals, which are similar to autoreceptors on serotonergic afferents in human cerebral cortex. These findings are particularly interesting in that orbitofrontal cortex is the prefrontal region most commonly implicated in OCD (Baxter et al., 1992; Benkelfat et al., 1990b; Schwartz et al., 1996; Swedo et al., 1992), and suggest that modulation of orbitofrontal activity by chronic SRI treatment might be specifically important for therapeutic benefit in OCD.

Pharmacologic challenges reducing serotonin availability or transmission in SRI-treated OGD patients

One approach used to characterize possible therapeutically-relevant adaptive changes in serotonergic transmission in SRI-responsive OCD patients has been to produce an acute reduction in serotonin synthesis. Acute tryptophan depletion (ATD), a technique producing a transient decrease in plasma 5-HT and presumably in brain 5-HT synthesis, has been shown to reactivate depressive symptoms in SRI-responsive patients with major depression (Delgado et al., 1990). ATD has been applied to OCD in one study. This investigation (Barr et al., 1994), found that ATD, which markedly reduced plasma tryptophan, produced a modest increase in depression ratings but not in OCD symptoms in SRI-responsive OCD patients. The results suggested that a transient reduction in serotonin availability did not lead to an acute OCD exacerbation. They also provided more evidence of important differences in serotonergic modulation of OCD and of depressive symptoms.

Another research strategy to reduce serotonergic transmission in OCD patients who have improved on SRIs is administration of 5-HT receptor blockers. A study by our research group used repeated administration of metergoline, a potent serotonin antagonist, to produce a more sustained decrease in 5-HT transmission in clomipramine-responsive OCD patients. While a single dose of metergoline had no acute effect on OCD symptoms, four days of repeated metergoline administration tended to exacerbate them (Benkelfat et al., 1989). In a recent study designed to further explore this finding in OCD patients treated with fluoxetine, a more selective SRI, we found that a single higher metergoline dose did not produce any acute effects other than sedation relative to placebo; however, an increase in anxiety and obsessive-compulsive symptoms appeared more than 24 hours after metergoline but not placebo administration (Greenberg et al., 1994). Depression ratings, in contrast, did not increase over the same period.

That metergoline did not acutely worsen OCD symptoms in SRI-treated patients in two studies (Benkelfat et al., 1989; Greenberg et al., 1994) is consistent with the lack of an effect of acute tryptophan depletion in SRI-treated OCD patients (Bart et al., 1994), indicating that acute interventions which reduce 5-HT transmission do not produce a rapid exacerbation of OCD symptoms. A time-dependent process thus appears necessary for the delayed OCD symptom exacerbation after metergoline administration in SRI-treated OCD patients (Benkelfat et al., 1989; Greenberg et al., 1994). These results are consistent with a study finding that 14 days of treatment with ritanserin, a selective 5-HT 2A/2C antagonist, produced a worsening of symptoms in a small number of fluovoxamine-responsive OCD patients (Erzegovesi et al., 1992).

Pharmacologic strategies to augment serotonergic transmission or 5-HT availability in SRI-treated OCD patients

As discussed above, SRI treatment is only partly effective in many OCD patients. This has led to attempts to enhance therapeutic effectiveness of SRI treatment using adjuvant medications. Some of these efforts have involved drugs thought to have additional actions on 5-HT systems, based on the hypothesis that further enhancing serotonergic transmission might result in better therapeutic effects in OCD. Case reports and uncontrolled studies suggested that some patients responded to adjuvant lithium (Feder, 1988; Golden et al., 1988; Rasmussen, 1984), fenfluramine (Hollander et al., 1990), L-tryptophan (Rasmussen, 1984; Yaryura-Tobias & Bhagavan, 1977), and buspirone (Jenike et al., 1991; Markovitz et al., 1990). Controlled studies, however, have been disappointing, both for adjuvant lithium (McDougle et al., 1991; Pigott et al., 1991) and for adjuvant buspirone (Grady et al., 1993; Pigott et al., 1992b).

The lack of effectiveness of lithium and buspirone augmentation of SRI treatment in controlled studies in OCD patients might indicate that their sites of action had already been saturated by the primary medication. It seems likely that many agents with effects on serotonergic systems might not prove useful in OCD, since numerous 5-HT receptor subtypes have been identified which appear to have distinct anatomical and cellular distributions (reviewed in Glennon & Dukat, 1995). Therapeutically relevant changes are likely to involve only a subset of these receptors, possibly only in distinct brain regions, together with the signal transduction mechanisms to which they are coupled. Thus, lithium addition to SRI treatment might be generally ineffective in OCD because it fails to act at the relevant sites. For example, although lithium has been shown to enhance 5-HT release in the spinal cord, hypothalamus and hippocampus, studies have failed to show an effect of lithium on 5-HT release in cerebral cortex. In addition, electrically evoked release of 5-HT was actually decreased by lithium treatment in the striatum (brief review in Blier & de Montigny, 1992). Since both frontal cortex and striatum are implicated in OCD by functional neuroimaging studies (reviewed by Hoehn-Saric & Greenberg, this issue), lithium's failure to increase 5-HT availability in these regions when used as a single agent may relate to its lack of therapeutic benefit when combined with SRIs.

In contrast, there is preliminary evidence that other strategies for further augmenting 5-HT availability might have therapeutic effects in SRI-treated OCD patients. Pindolol, a 5-HT1A and fi-receptor antagonist, was added to SRI treatment in OCD patients who were refractory to SRI monotherapy (Blier & Bergeron, 1995). The rationale for this study was that antagonism of somatodendritic 5-HT1A receptors by pindolol would increase firing rates of serotonergic neurons, resulting in a further increase in 5-HT availability in terminal fields. Although pindolol addition produced no further benefit in these patients, subsequent addition of L-tryptophan to the combined SRI and pindolol regimen, which might further increase 5-HT availability, did produced clinical improvement (Blier & Bergeron, 1995). An earlier open study reported that tryptophan addition to clomipramine treatment was also of benefit (Rasmussen, 1984). These preliminary findings, if replicated in controlled studies, would indicate that manipulations designed to further enhance 5-HT availability may be clinically useful in OCD. In addition, a case study (Cohen et al., 1987) and a controlled trial (Pigott et al., unpublished observations) of adjuvant clonazepam in SRI-treated OCD patients suggest that clonazepam addition may be beneficial in OCD. This finding is interesting in light of evidence that clonazepam has effects on serotonergic mechanisms not shared by other benzodiazepines (reviewed in Lima, 1991; Lima et al., 1993).

Possible roles of other neurotransmitter and neuropeptide mechanisms in OCD

Dopamine systems

Dopamine (DA) receptor antagonist drugs have not in general been viewed as effective when used as monotherapy for OCD (McDougle et al., 1994b; Zohar et al., 1992). Similarly, clozapine, an antipsychotic with antagonist actions at several 5-HT as well as at DA receptor subtypes, was ineffective as a single-drug therapy in an open trial in OCD patients resistant to SRI treatment (McDougle et al., 1995). Thus, the available data indicate that DA receptor antagonism is likely insufficient to produce therapeutic benefit in OCD. In contrast, addition of conventional neuropleptics to SRI treatment was of benefit in an open study (McDougle et al., 1990) and a controlled trial (McDougle et al., 1994a). The latter study found that haloperidol addition to fluvoxamine treatment was especially effective in patients with comorbid chronic tic disorders, suggesting that tic-related OCD is clinically meaningful subtype. It has also been suggested that the combination of SRIs and DA antagonists may be useful when OCD and schizophrenia-spectrum disorders are comorbid conditions (McDougle et al., 1994b). These clinical findings point to the importance of interactions between 5-HT and DA mechanisms in modulating symptoms of OCD. This is perhaps not surprising, given the evidence implicating basal ganglia mechanisms in OCD (Baxter & Brody, 1996; Insel, 1992). Such a 5-HTDA interaction could involve serotonergic modulation of dopaminergic systems, either directly or via serotonergic influences on areas of the cerebral cortex and thalamus functionally related to the basal ganglia.

The novel antipsychotic risperidone has also been reported to reduce OCD symptoms when used to augment SRI treatment in two open studies (Jacobsen, 1995; Saxena et al., 1996). These trials found that benefit was not restricted to patients with tic-related OCD. Interestingly, one of these studies (Saxena et al., 1996) found that patients with intrusive violent obsessions were particularly likely to benefit. The relationship of neurotransmitter systems affected by the newer antipsychotics to OCD symptoms is complex, however. Clozapine and risperidone have both been reported to exacerbate or provoke obsessive-compulsive patients in schizophrenic patients (Baker et al., 1992; Patil, 1992; Sultan & Chouinard, 1996). It is interesting that in some of these cases those obsessive-compulsive symptoms associated with clozapine or risperidone administration in schizophrenia have responded to subsequent SRI treatment.

Neuropeptide systems

A number of central neuropeptides, including corticotrophin-releasing hormone, vasopressin, oxytrocin and somatostatin have been studied in OCD. Neuropeptides have been shown to modulate stereotyped and other behaviors in animals which have been proposed as potential animal models of OCD (Altemus & Murphy, 1996). Clinical studies of cerebrospinal (CSF) fluid neuropeptide levels have found levels of corticotrophin-releasing hormone, vasopressin and somatostatin to be elevated in untreated OCD patients (Altemus et al., 1992; Altemus et al., 1993; Kruesi et al., 1990). All three of these peptides are arousal producing and released centrally in response to stress. These CSF neuropeptide concentrations were reduced after chronic SRI treatment (Altemus et al., 1994; DeBellis et al., 1993a; 1993b), suggesting an interaction of serotonergic and neuropeptide mechanisms that might relate to the antiobsessional actions of SRIs. However, another study of OCD patients using a less specific vasopressin assay did not find elevations in CSF vasopressin, while concentrations of oxytocin, a neuropeptide with more anxiolytic behavioral effects in animal models, were higher than those in controls (Leckman et al., 1994). Interestingly, oxytocin was elevated only in patients with non-tic-related OCD.

Endocrine axis observations and pharmacological probes

Hypothalamic-pituitary-adrenal (HPA) axis

Because cortisol readily enters the brain, peripheral HPA axis activity might modulate systems potentially involved in OCD, including central 5-HT receptor function (Kuroda et al., 1994), and autoimmune (Swedo et al., 1994) and neuropeptide systems (Altemus et al., 1994; Leckman et al., 1994). In addition, there is an intriguing single case report that the nonselective steroid synthesis inhibitor aminoglutethimide was of benefit when added to SRI treatment in OCD (Chouinard et al., 1995).

Studies of HPA axis activity in OCD patients have produced mixed results. One study of multiple urinary free cortisol measures in unmedicated OCD patients found evidence of cortisol hypersecretion only in patients with new onset illness (Altemus et al., in press), while another study found that urinary free cortisol elevations at an initial time point were not sustained (Gehris et al., 1990). Another group reported elevated cortisol levels in nondepressed OCD patients, using 24-hour plasma sampling, (Monteleone et al., 1994). In contrast, another study using repeated evening plasma sampling found elevated plasma cortisol only in new onset patients (Altemus et al., in press).

There have been a fairly large number of studies assessing HPA axis function in OCD using the dexamethasone suppression test. In general, these studies find that rates of nonsuppression after dexamethasone administration are comparable in OCD patients and in healthy individuals (reviewed by Altemus, 1995). Other studies have used infusion of corticotropin-releasing hormone to probe endocrine function in OCD. One study (Bailly et al., 1994) found blunted adrenocorticotropin and normal cortisol responses to CRH infusion, while in another study the effects of corticotropin-releasing hormone did not differ between OCD patients and controls (Altemus et al., in press). Methodological issues which may be important in explaining these discrepant results across studies are discussed in a recent review (Altemus, 1995). There has been little study of stress responsivity in OCD. One study did find enhanced vasopressin secretion in response to hypertonic saline infusion (Altemus et al., 1992).

Hypothalamic-pituitary-gonadal axis

Anecdotal evidence suggests that gonadal steroids may exacerbate OCD symptoms. Onset or worsening of OCD has been reported in association with pregnancy and polycystic ovary disease (Buttolph & Holland, 1990; Nezeroglu et al., 1992; Weiss et al., 1995). Open case studies in OCD have found temporary benefit from treatments which produce nonspecific suppression of gonadal steroid activity (Casas et al., 1986; Chouinard et al., 1995; Leonard et al., 1989; Weiss et al., 1995). While the selective androgen antagonist flutamide had therapeutic effects in one Tourette's syndrome patient with comorbid OCD (Peterson et al., 1993), a larger open study did not find benefit from flutamide monotherapy in OCD (Altemus et al., unpublished observations). These results suggest that estrogen receptor mechanisms might play a more important role than androgen receptor systems in gonadal steroid modulation of OCD symptoms.

Second messenger systems

A recent study has raised the intriguing possibility that neurotransmitter second messenger systems might be an important pharmacological target in OCD. Inositol, an essential component of posphotidylinositol signal transduction mechanisms linked to many neurotransmitter receptors, was therapeutically effective when used as monotherapy in a controlled study in OCD (Levine & Belmaker, 1996). It is interesting that 5-HT2A and 2C-linked receptors, serotonin receptor subtypes implicated in the modulation of OCD symptoms (see above), are posphotidylinositol-linked.

Conclusions

This review has considered the possibility that dysregulation in serotonergic systems might be etiologically important in OCD, an hypothesis for which there is as yet little direct evidence. In contrast, evidence that serotonergic systems modulate OCD symptomatology is much stronger. Such evidence includes the unique antiobsessional effects of SRIs, the ability of the serotonergic probe mCPP to exacerbate OCD symptoms in untreated patients, and findings from a few studies that potent 5-HT receptor antagonists may reverse SRI-induced therapeutic benefits. Although the mechanisms underlying the effectiveness of SRI treatment remain largely unknown, the available data support the position that enhanced 5-HT synaptic availability, resulting from a combination of effects on serotonin release and transport, is necessary for therapeutic efficacy after SRI treatment. Although aspects of serotonergic regulation of OCD symptoms remain controversial, there is general agreement that further investigations of the role(s) of brain serotonin subsystems in OCD, using more sophisticated pharmacological probes and techniques, promise to enhance our understanding of the response to treatment and possibly of pathophysiology as well. Such research methods could include the use of more selective serotonergic probes for challenge studies both before and after treatment. Functional neuroimaging studies with ligands specific for particular components of brain 5-HT pathways would also be very helpful. Although evidence that other neurotransmitter or neuropeptide systems are involved in OCD is considerably more preliminary than that implicating serotonergic mechanisms, there are initial indications that such systems may be involved. Studies of the role of these systems, and how they may interact with serotonergic mechanisms, may be particularly helpful in further elucidating the neuropharmacology of OCD and in identifying potential new treatments.

Correspondence to: Benjamin Greenberg, M.D., Laboratory of Clinical Science, National Institute of Mental Health, Bldg. 10, Rm. 3D41, 10 CENTER DR MSC 1264, Bethesda, MD 20892-1264, USA. Tel: + 1 (301) 496 3421. Fax: + 1 (301) 402 0188.

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By BENJAMIN D. GREENBERG, MARGARET ALTEMUS & DENNIS L. MURPHY, Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, USA