This clinical supplement is supported by funding from Lundbeck

Faculty Affiliations and Disclosures

Dr. Westenberg is professor in the Section Psychiatric Phenotypes of Biological Psychiatry at the Rudolf Magnus Institute of Neuroscience and the Department of Psychiatry at the University Medical Center Utrecht in The Netherlands. Dr. Fineberg is consultant psychiatrist and visiting professor at the University of Hertfordshire, Queen Elizabeth II Hospital in Welwyn Garden City, United Kingdom. Dr. Denys is psychiatrist and head of the anxiety clinic of the Department of Psychiatry at the University Medical Center Utrecht in The Netherlands.

Disclosure: Dr. Westenberg has been a speaker for AstraZeneca and Solvay; and has received grants from AstraZeneca. Dr. Fineberg has been a speaker for AstraZeneca, Bristol-Myers Squibb, Janssen, Lundbeck, and Wyeth; and has received grants/honoraria from AstraZeneca, Bristol-Myers Squibb, Cephalon, GlaxoSmithKline, Lundbeck, and Wyeth. Dr. Denys has been a speaker for AstraZeneca.

Submitted for publication: October 10, 2006; Accepted December 27, 2006.

Please direct all correspondence to: Herman G. M. Westenberg, PhD, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Department of Psychiatry, PO Box 85500, 3508 GA Utrecht, The Netherlands. Tel: +31-30-250-9019; Fax: +31-30-212-9205; E-mail h.g.m.westenberg@umcutrecht.nl.
 

Focus Points   • Uncertainty is an important feature of obsessive-compulsive disorder (OCD). • Dopaminergic and serotonergic pathways play a role in the genesis and maintenance of OCD symptoms. • Some phenomenological characteristics of OCD may be understood within the conceptual framework “behavioral addiction.” • Phenotypic heterogeneity of OCD should be taken into account when studying the neurobiology of OCD.

Abstract

The evidence for the involvement of the serotonergic system in the pathogenesis of obsessive-compulsive disorder (OCD) is circumstantial at best, despite being the focus for most pathophysiological research over the last 2 decades. This hypothesis was initially motivated by the observed differential efficacy of selective serotonin reuptake inhibitors (SSRIs) in alleviating OCD symptoms. Direct evidence that serotonergic perturbations are implicated in the pathophysiology of OCD is still sparse. There is growing evidence, from both preclinical and clinical studies, that the dopamine system may also be involved in the pathogenesis of OCD, and that dopaminergic and serotonergic pathways play a role in the genesis and maintenance of obsessive-compulsive symptoms. The complex interactions between both systems, the phenotypic heterogeneity of the disorder, and the limitations of the available tests to probe both systems, make it as yet impossible to draw firm conclusions as to how these systems are implicated. Further studies with more selective pharmacologic agents and neurocognitive probes in humans, studies using deep brain stimulation in combination with neuroimaging, and the development of better animal models for OCD may further our understanding of this disabling condition.

Introduction

Obsessive-compulsive disorder (OCD) is a psychiatric condition characterized by recurring obsessions and compulsions that significantly interfere with patient’s daily functioning. Over the past two decades, efforts to elucidate the neurobiology of OCD have centered largely on the role of serotonin (5-HT). The 5-HT hypothesis was initially motivated by the observed differential efficacy of selective serotonin reuptake inhibitors (SSRIs) in alleviating OCD symptoms. These findings, although attesting to the therapeutic versatility of serotonin transporter inhibition in OCD, do not necessarily reflect the existence of a neurobiological abnormality in the central serotonergic system in OCD; a reasoning referred to as an ex juvantibus argument. SSRIs may modulate serotonin via an intact serotonergic system to compensate for the underlying pathogenesis. Direct evidence that serotonergic perturbations are implicated in the pathophysiology of OCD is still sparse, but some recent studies suggest that it might play a role. There is now also growing evidence from both preclinical and clinical studies that the dopamine system may be involved in the pathogenesis of OCD.¹ The role of dopamine is intriguing in view of its role in decision-making—compulsive individuals are habitually indecisive—and because the basal ganglia, which are heavily endowed with dopaminergic fibres, are an important substrate for OCD symptoms. In this article, the preclinical and clinical evidence supporting the role for serotonin and dopamine in the pathophysiology of OCD will be reviewed.

Animal Models and the Role of Serotonin and Dopamine

Animal models of OCD are inevitable based solely on alteration in motor behavior mimicking compulsive rituals, because aberrant “thoughts,” if present at all, are not verifiable in animal models. Most of these animal models of OCD are based on pharmacologic, behavioral, or genetic manipulations. Several investigators have shown that 5-HT receptor agonists are able to induce compulsive-like behavior in animals.

Chou-Green and colleagues² tested the 5-HT_2C receptor knockout (KO) mice, which was first described as a model for obesity. They report that this KO mouse showed increased chewing on non-nutritive clay with a distinct “neat” pattern and a reduced habituation of head dipping activity as compared to the wild type.  They concluded that the 5-HT_2C receptor null mutant mouse provide a putative model for compulsive behavior. The data point towards a role of the 5-HT_2C receptor in the pathophysiology of this behavior, but the predictive validity of this model for OCD has not been assessed properly. Tsaltas and colleagues³ have described a model based on persistence in the context of rewarded spatial alternation. Using this behavioral model, they have shown that 5-HT_2C receptors are implicated in the mechanism underlying the “compulsive” behavior in this animal model for OCD. Acute administration of meta-chlorophenylpiperazine (mCPP), a non-selective 5-HT receptor agonist acting mainly at the 5-HT_2C receptors but with some affinity also for the 5-HT_1B, 5-HT_1A and α₂-adrenergic receptors, increased “compulsive” behavior. An effect could be prevented by chronic pretreatment with fluoxetine, but not with diazepam or desipramine. The selective 5-HT_1B receptor agonist naratriptan was not effective in this animal model, supporting the role of 5-HT_2C receptors underlying the effect of mCPP.

In another behavioral model, rats undergoing extinction of lever-pressing for food after the attenuation of an external feedback for this behavior, exhibit excessive lever-pressing unaccompanied by an attempt to collect a reward. This behavior may be analogous to the excessive and unreasonable behavior seen in OCD. Using this model, Joel and colleagues⁴ found that lesions to the rat orbital frontal cortex led to “compulsive” lever pressing, which was paralleled by an increase in striatal 5-HT transporter density, suggesting that compulsive behavior in this model is mediated or accompanied by alterations in the (striatal) serotonergic system.  The predictive validity of this model is, however, questionable, because it responds to acute treatment with SSRIs. Administration of the D₁ receptor antagonist SCH 23390 also reduced the number of compulsive lever-presses without affecting the number of lever-presses followed by an attempt to collect a reward. On the basis of electrophysiological data, Joel and Doljansky⁵ suggested that compulsive lever-pressing depends on a phasic decrease in stimulation of D₁ receptors. Campbell and colleagues6 have investigated the behavioral consequences of transgenic stimulation of a regional subpopulation of the dopamine neurons that express the D₁ receptor in the cortex and amygdala, by generating mice that express an intracellular form of cholera toxin (CT). The study suggests that chronic stimulation of these D₁ expressing neurons induces complex compulsive behavior that resembles symptoms of OCD in humans. Although these mice were resistant to behavioral inhibition by a D₁ receptor antagonist and supersensitive to the D₂ receptor antagonist sulpiride, Campbell and colleagues⁶ suggested that chronic stimulation of cortical and limbic D₁ expressing neurons may cause obsessive-compulsive behaviors.

In a pharmacologic animal model for OCD, in which rats are chronically treated with the selective D_2/3 receptor agonist quinpirole (QNP), a ritual-like set of behavioral acts resembling OCD checking behavior has been observed.⁷ This “compulsive” behavior is dependent on QNP administration, because it rapidly returns to normal behavior when QNP administration is discontinued.⁸ Postmortem analyses in these animals revealed increased dopamine tissue levels in the nucleus accumbens and right prefrontal cortex. A recent microdialysis study revealed a significant blunting of the QNP induced decrease in dopamine release in the nucleus accumbens (H.G.M. Westenberg, unpublished data, 2007). This effect was maintained up to 2 weeks after cessation of QNP administration and suggests a long-term sensitization of the dopamine D₂ autoreceptors.  Although this model shows face validity, the predictive validity has not been tested properly; it has only been validated with clomipramine, which has shown to partially and transiently reduce compulsive checking.

In summary, these data animal models for OCD suggest a role for dopamine, in particular of the D₁ and D₂ receptors, and serotonin, most likely the 5-HT_2C receptors, in the mechanism underlying compulsive behavior in animals.

Serotonin and Metabolite Concentrations in Humans

The notion that SSRIs work in OCD by a serotonergic mechanism was supported by early studies showing a  positive correlation between improvement and  the drug-induced decrease in 5-hydroxyindoleacetic acid (5-HIAA) levels, the major metabolite of 5-HT,  in cerebrospinal fluid.⁹ However, baseline 5-HIAA levels in the cerebrospinal fluid (CSF) of OCD patients have not been found to be reliably different from controls. Insel and colleagues¹⁰ found higher CSF 5-HIAA levels in OCD patients than in controls, but Leckman and colleagues¹¹ found no difference. Two studies have examined urinary 5-HIAA levels in patients with Tourette’s syndrome with and without OCD. One study reported a correlation between urinary 5-HIAA and OCD symptoms, but the other did not.^12,13

Concerning peripheral markers of 5-HT in OCD, the data are equivocal as well. Blood and platelet levels of 5-HT in patients with OCD are, not surprisingly, by and large normal.^10,14-20 The binding capacity of the serotonin transporter (5-HTT) of the platelets has consistently been reported to be reduced in OCD patients.^21-24 The 5-HT_2A binding sites on platelets were not different between patients and controls.¹⁶ Given the questionable relationship between peripheral and central 5-HT transporter binding sites the meaning of these data is far from clear.

Dopamine and Metabolite Concentrations in Humans

Baseline measures of dopamine and its metabolite homovanillic acid (HVA) in psychotropic naïve patients may provide also direct evidence for a role of dopamine in OCD. Thoren and colleagues⁹ assessed HVA in CSF levels before and after three weeks of treatment with clomipramine, but did not find any change. Benkelfat and colleagues²⁵ found no differences between the mean plasma HVA level of 13 medication-free patients with OCD and 29 normal controls. Swedo and colleagues,²⁶ examining CSF levels of HVA in 43 children with primary OCD, reported that CSF HVA levels were not significantly related to OCD symptoms and did not correlate with improvement following 5 weeks of treatment with clomipramine. Hollander and colleagues,²⁷ on the other hand, observed a significant decrease in plasma HVA in 12 OCD patients relative to 10 controls following fenfluramine treatment, and Zahn and colleagues²⁸ showed that CSF metabolites of serotonin and dopamine, but not of norepinephrine, were positively correlated with electrodermal responsivity in a reaction time task in 43 adolescents and children with OCD. Marraziti and colleagues²⁴ measured platelet sulfotransferase activity in 17 drug-free OCD patients and an equal number of healthy controls. Sulfotransferase is an enzyme involved in the catabolism of catecholamines such as dopamine and has similar kinetic characteristics in brain and platelets. Their results showed a higher level of sulfotransferase activity in OCD patients compared with control subjects, suggesting an increased dopaminergic neurotransmission in OCD.

In summary, the neurochemical studies on the role of dopamine metabolites in OCD patients have, by and large, yielded no evidence for an abnormal dopamine function in OCD.

Pharmacologic Challenge Tests

Another approach to assess the functioning of the serotonergic and dopaminergic system is the evaluation of behavioral and neuroendocrine effects to administration of indirect or direct serotonin or dopamine receptor agonists.

Serotonin

By using mCPP as a serotonergic probe, Zohar and colleagues²⁹ were the first to show a transient exacerbation of obsessive-compulsive (OC) symptoms in OCD patients. This effect could be prevented by long-term pretreatment with clomipramine,³⁰ an anti-obsessive drug.  This effect of mCPP on OC symptoms has been replicated in some, but not all studies.^29,31-35 Because mCPP affects several 5-HT receptors, challenge tests with more selective agents have been conducted to dissect the possible mechanism underlying the purported induction of OC symptoms in OCD patients. Ipsapirone, a selective 5-HT_1A receptor agonist, was not effective,³⁶ while sumatriptan,^34,37,38 a selective 5-HT_1B receptor agonist, induced an exacerbation of OC symptoms in OCD patients in some, but not all studies. Similarly, zolmitriptan,³⁹ a selective 5-HT_1B receptor agonist with a better penetration of the blood-brain barrier than sumatriptan, did not cause an increase in OC symptoms. Neuroendocrine responses to mCPP challenge are also inconsistent. Some studies reported a blunted prolactin and/or cortisol response following mCPP administration, suggesting hyporesponsive 5-HT receptor in the brain regions controlling the neuroendocrine response, while other studies could not replicate this finding. 

Fenfluramine interacts with both the 5-HTT and dopamine transporter (DAT). Some studies report a blunted prolactin or cortisol response, while other did not found behavioral or neuroendocrine effects.^31,40-42 Differences in design, heterogeneity of the patient population, and small number of subjects in most studies, may account for these discrepant findings. The nonselectivity of the probes used in the studies further hamper the interpretation of the data.

Dopamine

Cocaine, a  DAT blocker, elevates synaptic dopamine levels and increases the DAT density.⁴³ It has been reported that chronic use of cocaine may be associated with stereotyped examining, searching and sorting behaviors, and an exacerbation of obsessive-compulsive symptoms.^44-48 Moreover, cocaine-abusing patients are at increased risk for the later development of OCD.⁴⁹ Methylphenidate and amphetamine have been reported to exacerbate or induce as well as to improve OCD symptoms.^48,50-54 A limitation of the use of cocaine, methylphenidate, and amphetamine as dopaminergic probes is that they also release serotonin and norepinephrine. Pitchot and colleagues⁵⁵ assessed the growth hormone response to 0.5 mg apomorphine) in eight drug-free OCD patients and eight healthy male volunteers. No difference in mean GH peak response was found, suggesting that the dopaminergic function was not altered in OCD. In contrast, Brambilla and colleagues^56,57 studying 15 patients with OCD and 15 age/sex-matched controls, found a blunted GH responses to apomorphine  in OCD patients, hinting at  a  postsynaptic dopamine receptor subsensitivity. In the same sample, however, cortisol responses to stimulation with apomorphine were not different between the two groups. Longhurst and colleagues⁵⁸ examined the effects of catecholamine depletion in six drug-free patients with the tyrosine hydroxylase inhibitor a-methyl-para-tyrosine and found no significant changes in OC symptom severity as compared with placebo. Although bromocriptine, a selective dopamine receptor agonist, has been shown to induce stereotypies in animals, one report describes an improvement in OC symptoms in of OCD patients.⁵⁹ Results from pharmacologic challenge studies with dopamine receptor agonist in OCD are as yet inconsistent, but there are indications that OC symptoms may be related to increased dopamine neurotransmission.

Pharmacotherapy

Indirect evidence for a role of serotonin and dopamine in OCD comes from treatment studies using pharmacologic agents that modulate the serotonergic and dopaminergic activity in the brain.

Serotonin Reuptake Inhibitors

The 5-HT hypothesis of OCD has emerged from the observation that only antidepressants that preferentially block the 5-HTT are efficacious in OCD. A comparison of the clinical efficacy of clomipramine, fluvoxamine, and sertraline with that of desipramine, an antidepressant that selectively blocks the uptake of norepinephrine, supports the notion that inhibition of the 5-HTT is required for antidepressants to be efficacious in OCD.^60-63 Denys and colleagues⁶⁴ have shown that venlafaxine and paroxetine are equally efficacious in OCD, suggesting that inhibition of the norepinephrine uptake does not contribute to the effect of antidepressants as well. As mentioned previously, this finding does not necessarily point to an abnormal serotonergic system in OCD. On the contrary, several observation lend support to the idea that inhibition of the 5-HTT, although required for antidepressants to work in OCD, is not causally related to the genesis of the disorder. First, the mean response rate in OCD is 50% or less,⁶⁵ indicating that for a substantial number of patients 5-HTT inhibition is insufficient to alleviate OC symptoms. Phenotypic heterogeneity may partly explain this phenomenon as patients with contamination fear respond more favorably to SSRIs than patients from the subtype symmetry/perfectionism/hoarding.⁶⁶ Second, the doses of antidepressants necessary for OCD are substantially higher than those for depression or anxiety disorders and also substantially higher than necessary to completely block the 5-HTT.⁶⁷ Third, the synthesis of 5-HT depends on the availability of tryptophan in the brain. Depletion studies in depression have shown deterioration in patients on antidepressants in remission,⁶⁸ but no worsening of symptoms was seen in patients with OCD who underwent a tryptophan depletion paradigm.⁶⁹ Fourth, the therapeutic effects in OCD are usually not seen within 8 weeks of treatment, which is much later than in patients with depression. El Mansari and colleagues⁷⁰ have argued on the basis of their electrophysiological work that this difference in onset of action between depression and OCD can be accounted for by a greater delay in effect of SSRIs on 5-HT release in the orbital frontal cortex (OFC), a brain region supposedly implicated in OCD, as compared to other brain regions. According to these investigators, this delay in effect in the OFC might be explained by a slower desensitization of the 5-HT_1B autoreceptors in the OFC. They also used this finding as an argument to explain why in OCD larger doses of SSRIs are needed. In line with this finding, Dannon and colleagues⁷¹ have reported pindolol, a non-selective 5-HT_1B receptor antagonist, to hasten the effect of SSRIs in OCD patients. They also suggest that the effect of SSRIs in OCD might be explained by the delayed stimulation of the postsynaptic 5-HT_2A receptors in the OFC. If this were to be true, one would expect mirtazapine, which among others is a 5-HT_2A receptor antagonist, and atypical antipsychotics that also have antagonistic effects at this receptor, to attenuate the effect of SSRIs. Clinical studies with these drugs, however, have shown the opposite. Mirtazapine, although not effective by itself, has shown to hasten the effect of paroxetine⁷² and several studies have shown that atypical antipsychotics augment the effects of SSRIs in refractory OCD patients.⁷³ Moreover, mCPP, a nonselective 5-HT₂ receptor agonist is either not effective or causes a worsening of OC symptoms after acute administration.^31-35 The effects of SSRIs in OCD can also be explained by taking into account the serotonin-dopamine interaction and the effects of SSRIs on dopamine release.

Dopamine Antagonists

McDougle and colleagues⁷⁴ assessed the efficacy of clozapine monotherapy in 12 adults with refractory OCD in a 10-week, open-label trial with clozapine but found no significant change. Until now there have been no placebo-controlled trials with atypical antipsychotics, such as risperidone, olanzapine, quetiapine, or ziprasidone, as monotherapy for OCD. It is of note that de novo emergence or exacerbation of OCD symptoms during treatment with antipsychotics has been described extensively in patients with psychotic disorders. Lykouras and colleagues⁷⁵ have recently reviewed the reported cases of OCD symptoms induced by atypical antipsychotics.

Several studies have recently been published on the efficacy of antipsychotics in combination with SSRIs. Addition of pimozide and haloperidol to SSRIs proved effective for patients who were refractory to treatment, in particular for patients with comorbid chronic tic disorders or schizotypal personality disorders.⁷⁶ Following the successful combination of typical antipsychotics to SSRIs for treatment refractory patients, there are a number of studies combining atypical antipsychotics with SSRIs.^1,73 Although, two negative studies have been published,^77-80 risperidone, olanzapine, and quetiapine appear to be efficacious in addition to SSRIs for therapy-refractory patients at low doses within 6–8 weeks.^73,81 Recently, we found that low doses of quetiapine also augment the effect of citalopram in newly diagnosed OCD patients, indicating that this effect is not restricted to therapy-refractory cases (Vulink and colleagues, unpublished data, 2007). In an open trial, Metin and colleagues⁸² evaluated the efficacy of amisulpiride 325 mg/day, a selective dopamine D^2/3  receptor antagonist, to augment the effect of SSRI treatment in 20 patients with treatment-resistant OCD and observed a significant improvement in 95% of the patients. It is intriguing why antipsychotics in monotherapy lack efficacy in OCD, while they are capable to induce de novo OCD symptoms in patients psychotic disorders, and are efficacious in combination with SSRIs in patients with OCD without psychotic features. It has been proposed that 5-HT^2A receptor antagonism exacerbates OC symptoms by increasing the firing rate of the dopamine neurons, whereas D₂ receptor antagonism reduces OC symptoms through inhibition of the dopamine neurons,⁸³ but preclinical data do not support the assumption that 5-HT_2A receptor antagonists increase dopamine release in the prefrontal cortex.84 Differences in neurobiological substrate among patients with psychotic disorders with and without comorbid OCD and patients with OCD without psychotic features may account for these discrepant findings. Zhang and colleagues^85,86 have shown in rats that the combination of olanzapine and fluoxetine may increase synergistically extracellular dopamine and norepinephrine levels in the prefrontal cortex, and Denys and colleagues⁸⁷ found that the combination of quetiapine and fluvoxamine may cause a synergistic dopamine increase in the prefrontal cortex and thalamus. Additional research is warranted to determine whether changes in extracellular dopamine levels may account for the clinical efficacy of the augmentation strategy with atypical antipsychotics in OCD.

Neuroimaging

Serotonin Receptor Binding

The development of radioligands for neuroimaging techniques has facilitated studies of the central neurotransmitter systems. In vivo neuroimaging of the 5-HTT offers a unique tool to probe the 5-HT function. [¹²³I]-2β-carbomethoxy-3β-(4-iodophenyl)tropane ([¹²³I]β-CIT) is a radiotracer suitable for single photon emission computer tomography (SPECT) imaging that can be used to visualize 5-HTT and DAT in the human brain.⁸⁸ Differences in binding characteristics for the DAT and 5-HTT make temporal separation of the transporter occupancy possible. Using this tool, Pogarell and colleagues⁸⁹ reported elevated 5-HTT density in the midbrain region of OCD patients. Stratification of the patients by age of onset of the disorder revealed that this effect was fully accounted for by patients with an early age of onset. Patients and controls in this study were, however, not fully matched by age and gender. In contrast to this finding, Hesse and colleagues⁹⁰ using the same radioligand recently reported a significant reduced 5-HTT density in the midbrain and thalamus of OCD patients. They do not report the age of onset of OCD symptoms in their patients, but subjects were matched by age and gender. They also found a negative correlation between 5-HTT density and symptom severity. A reduced 5-HTT density in OCD patients as compared to control subjects has also been described by Stengler-Wenzke and colleagues⁹¹ using SPECT [¹²³I]β-CIT imaging. Similarly, Müller-Vahl and colleagues⁹² found a significant reduction in 5-HTT binding in patients with Tourette’s syndrome with OCD compared with age matched controls using this tool. Finally, van der Wee and colleagues⁹³ using [¹²³I]β-CIT SPECT with MRI co-registration found no difference in 5-HTT binding density in drug-naïve OCD patients and age and gender matched healthy controls. Thus far only one study reports on the 5-HTT density in OCD, using positron emission tomography (PET). Simpson and colleagues,⁹⁴ using [¹¹C]McN 5652 as radioligand, found no significant differences between OCD patients and control subjects was found.

Adams and colleagues⁹⁵ investigated the 5-HT_2A receptor binding in untreated OCD patients and age and gender matched healthy controls using [¹⁸F]altanserin and PET. The 5-HT_2A binding potential in the caudate nucleus of untreated OCD patients was significantly higher compared to controls. Subsequent treatment with SSRIs had no effect on the binding potential in OCD patients. The increased 5-HT_2A binding density might result from a lack of 5-HT in the basal ganglia.

In conclusion, the 5-HTT binding studies have yielded mixed results as yet and one study into the density of the 5-HT_2A receptors suggests an upregulation in the basal ganglia of OCD patients.  Although equivocal, the data do suggest that an impaired 5-HT function might play a role in the pathogenesis of OCD. The higher 5-HT_2A receptor binding may hint at a reduced serotonergic output into the basal ganglia. If this explanation were to be true, one would also expect a lower 5-HTT binding density in this region to compensate for the lack of 5-HT. With the exception of the PET study, that found no difference, all SPECT studies report only on 5-HTT binding in other brain regions

Dopamine Receptor Binding

SPECT and PET imaging have also been used to probe dopamine function in OCD. Van der Wee and colleagues⁹³ found higher binding ratios of [¹²³I]β-CIT to the DAT in the left basal ganglia in 15 drug naïve patients with OCD. Kim and colleagues⁹⁶ found also an increased DAT binding ratio in the right basal ganglia and a tendency towards an increased DAT binding ratio in the left basal ganglia with [¹²³I] IPT SPECT in 15 OCD patients. Pogarell and colleagues,⁹⁷ on the other hand, did not detect significant differences in striatal DAT [¹²³I]β-CIT binding between 7 patients and 10 controls and Hesse and colleagues⁹⁰ reported a reduced DAT availability in the basal ganglia. Sawle and colleagues⁹⁸ did not find an alteration in [¹⁸F]-6-Fluorodopa uptake into the caudate and putamen in a small (PET) study involving six OCD patients with obsessional slowness. A decrease in [¹⁸F]-6-Fluorodopa uptake is believed to reflect a reduction in the number of nigrostriatal dopaminergic neurons. Finally, Denys and colleagues99 observed in 10 OCD patients a decreased [^123I] IBZM binding in the left caudate, suggesting a down regulated dopamine D₂ receptor. Altogether, these findings indicate that the dopamine system in the basal ganglia could be involved in OCD. Higher DAT densities, in tandem with a down-regulation of the D2 receptor, suggests higher synaptic concentrations of dopamine in the basal ganglia in OCD.

Genetic studies
Serotonin
In view of the purported role of the 5-HTT in the mechanism of action of SSRIs, several studies have investigated the possible role for polymorphism in the promoter region of the 5-HTT gene (5-HTTPR) in relation to OCD. However, studies conducted so far have generated conflicting results. Some studies reported that the L-allele of 5-HTTPR was associated with OCD, but many others did not find an association between 5-HTTPR and OCD. Recently, Denys and colleagues¹⁰⁰ found an association between the S-allele and OCD in female patients. The S-allele is associated with a relatively lower expression of the 5-HTT and a higher frequency of this allele would suggest a lower density of the 5-HTT in female OCD patients. This finding is compatible with some of the neuroimaging studies showing a reduced density of the 5-HTT density. The notion that this effect was only present in female patients raises the question whether the phenotypic heterogeneity of OCD complicates interpretation of biological findings. In general, women are reported to have more contamination obsessions and cleaning rituals, while men tend to have more symmetry/ordering and sexual obsessions. Kim and colleagues¹⁰¹ studied the 5-HTTPR polymorphism in association with phenotypic characteristics of OCD using the principal component analysis and found that the L-genotype had higher scores for religious and somatic obsessions. Cavallini and colleagues¹⁰² performed a principal component analysis on the Yale-Brown Obsessive-Compulsive Scale checklist and found that patients who were homozygote for the l-allele more often could be classified as symmetry/ordering subtype OCD patients.
The polymorphism of the 5-HT_1B receptor gene has been studied by Mundo and colleagues,103 who found a significant association between OCD and G861C polymorphism of this gene in a large Canadian family-based sample. The G-allele was associated with OCD and predicted OC severity. A subsequent study confirmed the association between severity of symptoms and the G-allele, but other studies have failed to find an association between OCD and the 5-HT_1B receptor gene.

The -1438G/A polymorphism of the 5-HT_2A receptor gene has also been linked to OCD. Enoch and colleagues¹⁰⁴ reported an association between the A allele and female OCD patients, and Walitza and colleagues¹⁰⁵ reported an association between the A allele and children and adolescents with OCD. Denys and colleagues¹⁰⁰ reported an association between the G-allele and patients with a positive family history and an early onset of OCD. Difference in OCD phenotype may explain these discrepant findings. The 5-HT_2A receptor is of particular relevance to OCD as 5-HT_2A receptor binding characteristics may discriminate between affected and unaffected subjects in families with OCD¹⁵ and because imaging studies have revealed an increased 5-HT_2A receptor binding in the caudate nucleus of OCD patients.

Finally, Camarena and colleagues¹⁰⁶ reported a higher frequency of allele1, a silent mutation on exon 14 (EcoRV polymorphism), of the MAO gene in female OCD patients. This finding suggests that female OCD patients have a lower MAO activity than males.

Dopamine

A number of candidate gene studies have been conducted in order to elucidate the contribution of the dopamine system in OCD. Investigations on the role of the DAT and dopamine D₃ receptor showed no significant association between a particular allele and OCD.^107-110 Except for the TAQ I A2 allele that was found to be associated with OCD patients and tics in male patients,^109,111 no statistically significant differences in allele frequencies or genotype between OCD patients and controls was found with regard to dopamine D₂ receptor.^112,113 Cruz and colleagues¹¹⁴ and Millet and colleagues¹¹⁵ found an association for the dopamine D₄ receptor, but other reports were negative.^{107,108,113,116} The role of catechol-O-methyl transferase (COMT) has been extensively investigated in OCD since COMT is an enzyme that has a crucial role in the elimination of dopamine and higher dopamine levels may be implicated in OCD. Karayiorgou and colleagues^117,118 found evidence for an association between the low-activity COMT allele and OCD in male OCD patients, in a case-control study and a family-based study, whereas Alsobrook and colleagues¹¹⁹ found evidence pointing to an association between the low-activity COMT allele and OCD in female OCD patients. Niehaus and colleagues¹²⁰ reported a preponderance of COMT high/low heterozygotes in an Afrikaner population of 54 OCD patients, but did not observe gender differences. Schindler and colleagues¹²¹ did not find an association between any particular allele and OCD, but found a tendency for an association with homozygosity at the COMT locus. Ohara and colleagues¹²² did not find any association in a small sample of 24 Japanese patients and neither did Erdal and colleagues¹²³ in a sample of 59 Turkish patients. In line with the study of  Karayiorgou and colleagues,¹¹⁸ Denys and colleagues¹¹¹ found a higher frequency of the low-activity COMT in male OCD patients. On the other hand, a recent meta-analysis of the COMT gene in 144 OCD patients and 337 controls showed insufficient evidence to support an association.¹²⁴

The Neuroanatomy of OCD

There is no known locus of neuronal degeneration in OCD, although some studies have shown decreased volumes in the OFC and basal ganglia.^125-127 However, functional imaging studies suggest that there is an abnormal neuronal activity in the OFC, the anterior cingulate, dorsolateral prefrontal cortex (DLPFC), caudate nucleus and thalamus in OCD patients (for review see Friedlander and Desrocher¹²⁸). These findings have been described in the context of several models to explain the relationship between the neuroimaging results and OCD symptomatology. Most models are based on the so-called cortico-striato-thalamic circuits first proposed by Modell¹²⁹ and adapted by others.^130,131 The function of the striatum in this working model of OCD is to process information automatically, without conscious representation. It integrates inputs arriving from the cortex and uses this information to select certain motor and cognitive programs. It sends information on to thalamus through two different pathways—a direct route via the globus pallidus pars interna and an indirect pathway involving the globus pallidus pars externa and the subthalamic nuclei. An important function of the basal ganglia in this model is to use reinforcement signals and learning rules to reduce the dimensionality of sparse cortical information. Several functional circuits connecting the basal ganglia with the cortex and thalamus have been described, each playing a specific role in processing information.^132,133 The OFC is connected to the ventral part of the caudate nucleus and seems to be implicated in behavioral planning and decision-making.^134,135 It appears critical in integrating affective information and signaling some types of reward.  The second loop involves the anterior cingulate cortex (ACC) which is linked to the nucleus accumbens and amygdala and thought to play a role in cognitive processes such as attention, reward and error detection, motivation, and action planning.¹³⁶ The third loop connects the DLPFC with the dorsolateral part of the caudate nucleus. The DLPFC enables temporal information processing and holding relevant information on-line.^137,138 It is believed to mediate working memory and executive functions. The basal ganglia are thought to project back to these cortical areas through the medial dorsal and anterior nuclei of the thalamus. Neuroimaging data suggest that this cortico-striato-thalamic circuit may be dysfunctional in OCD and therefore crucial in the pathogenesis of the disorder.^139-146

The hallmark of OCD is doubt and uncertainty regarding the consequences or results of certain acts or decisions. Drawing on this notion, Sachdev and Malhi¹⁴⁷ have proposed a decision-making model for OCD. They suggest that pathological indecisiveness in OCD patients leads to prolonged deliberations before a decision is made and repetition of an act because of uncertainty of the reward. Recent studies have identified the DLPFC, OFC, and ACC as regions that play a pivotal role in decision-making.^148-151 Functional imaging studies suggest that the OFC and ACC subserve error detection processes and planning of behavior on the basis of reward. Dysfunctions in these regions may facilitate basal ganglia activity and the emergence of aberrant behavioral manifestations.¹⁵²

Neuropsychology

Neurocognitive studies have also shown evidence of impairment in systems thought to be subserved by dorsal and ventral corticostriatal circuitry.¹⁵³ Individuals with OCD perform poorly on tests of neurocognitive function including executive, memory, and visuospatial abilities. Neuropsychological tests have only a limited localizing capability, but executive function appears disrupted on tests thought to tap DLPFC (eg, set-shifting, spatial working memory) and OFC (eg, alternation, decision making). However, problems with small sample sizes, comorbidity, and phenotypic heterogeneity have confounded studies to date. Impairment in OCD may reflect failures in behavioral inhibition and strategy formation.¹⁵⁴ A recent study of non-comorbid OCD patients demonstrated impaired cognitive flexibility and impulsivity, but intact decision-making for both probands and unaffected first-degree relatives as compared to healthy controls, implying a true neurocognitive endophenotype.¹⁵⁵ Studies on decision-making abilities using gambling tasks in OCD have yielded discrepant findings; some studies reveal an impaired performance,^156,157 while others do not.^153,158,159 Phenotypic heterogeneity may partly explain these discrepancies.¹⁶⁰ Another test thought to tap the OFC function is the  probabilistic learning an reversal test. Chamberlain and colleagues¹⁵³ found an intact performance on this task in OCD patients of whom most were on treatment with SRIs, while Remijnse and colleagues161 reported an impaired performance associated with an abnormal OFC-striatal neuronal activity in drug-free OCD patients. Abnormalities in decision-making have also been reported for OCD spectrum disorders.^162,163 Poor performance on decision-making tasks was associated with a poor response to SRI monotherapy,¹⁵⁶ though not to SRI with added risperidone.¹⁶⁴ In contrast, set-shifting impairment, reflecting DLPFC circuitry, predicted a better outcome to SRIs.¹⁶⁵ Poorer overall cognitive function was associated with a poorer response to CBT in some¹⁶⁶ but not all¹⁶⁷ studies. The effect of treatment on cognitive performance in OCD is unclear; evidence of limited improvements on WCST from SRI^168,169 and on the Iowa gamble task from SRI plus risperidone,164 were not supported by a study by Nielen and Den Boer¹⁵⁸  where DLPFC related executive deficits endured despite 12 weeks of fluoxetine treatment, again suggesting they may represent endophenotypic trait markers for OCD.

A neurocognitive study comparing trichotillomania with OCD suggested more limited and specific failures of behavioral inhibition in the former using tests sensitive to cortical function.¹⁷⁰ Another study comparing OCD with Tourette’s syndrome (TS) reported that TS and OCD show both differences (recognition memory, decision-making) and similarities (set-shifting) in selected profiles of cognitive function.¹⁵⁹ A controlled study of early-onset Huntington’s disease reported similar impairments to those reported for OCD, with impaired visuospatial planning (dorsolateral prefrontal circuitry), but normal  decision-making (OFC task).¹⁷¹

Dopamine-Serotonin Interaction

Dopaminergic pathways to cortical and subcortical regions are thought to play a central role in signaling reward and controlling reward prediction. Overactivity of the dopaminergic system projecting to these cortical and subcortical regions may result in uncertainty with regard to the expected outcome and therefore in the emergence of obsessional thoughts about the predictability of the event or act.^172,173  Through the basal ganglia it may also be implicated in the production of compulsive behavior aimed at reducing the distress resulting from these intrusive thoughts.
 
Serotonergic activity may be expected to modulate obsessive-compulsive symptoms at least in part through a dopamine-serotonin interaction.¹⁷⁴

Amargos-Bosch and colleagues¹⁷⁴ have shown that about 60% of the neurons in the rat and mouse prefrontal cortex express 5-HT_1A and/or 5-HT_2A receptor mRNA, which are highly co-localized (~80%). Stimulation of the 5-HT_2A receptors causes excitation of the pyramidal cells, while stimulation of the 5-HT_1A receptors had an opposite effect. This finding indicates that 5-HT_1A and 5-HT_2A receptors have a prominent modulatory role in prefrontal cortical function because of their presence on a high proportion of the pyramidal cells and the opposite nature of their activity. Atypical antipsychotic are, in addition to their effects on dopamine D₁ and D₂ receptors, also potent 5-HT2A receptor antagonists and have some agonistic activity at the 5-HT_1A receptors.^176,177  This suggests that they, by virtue of these effects, may reduce cortical output to the basal ganglia by neurons expressing these serotonergic receptors.

It is also well know that 5-HT fibers can modulate the activity and functioning of dopaminergic neurons. This modulation is complex, involving both excitatory and inhibitory influences. Dopamine release can be affected by 5-HT both at the level of cell bodies and at the level of the nerve terminals. Bortolozzi and colleagues¹⁷⁷ have shown that stimulation of the 5-HT_2A receptors in the prefrontal cortex stimulate the dopamine release in the prefrontal cortex and ventral tegmental area (VTA). Stimulation of the 5-HT_2A receptors also augments the amphetamine-induced dopamine release in the prefrontal cortex and nucleus accumbens of the rat.⁸⁴ Most atypical antipsychotics have, in addition to their antagonistic effects on dopamine receptors, also high affinity for the 5-HT_2A, 5-HT_2C, 5-HT_1B, and 5-HT_1A receptors.¹⁷⁷ Atypical antipsychotics are potent 5-HT_2A receptor antagonists and weak 5-HT_1A receptor agonists. Several studies have shown that these drugs can stimulate dopamine release in the prefrontal cortex and nucleus accumbens, probably by stimulating the 5-HT1A receptors on neurons projecting to the VTA.^87,179 There is also substantial evidence that activation of the 5-HT_1B receptors in the VTA and nucleus accumbens can increase dopamine release in the nucleus accumbens.¹⁸⁰ Similar effects may be expected in other projection areas of the VTA. Serotonin 5-HT_1B receptor agonists alter by this mechanism the rewarding properties of psychostimulants such as cocaine.^181,182 Stimulation of the 5-HT_2C receptors, on the other hand, inhibits dopamine release in the striatum, nucleus accumbens and prefrontal cortex of the rat.¹⁸³ 

Interaction between 5-HT and dopamine can also take place at level of vesicular uptake. Zhou and colleagues^184,185 have shown that competition between dopamine and 5-HT for the DAT may reduce the signaling of the former neurotransmitter. They have shown that treatment with SSRIs may affect dopaminergic release through co-release of dopamine and serotonin from dopamine terminals in the striatum.

These preclinical data articulate that effects of 5-HT and dopamine selective or non-selective agents in OCD cannot be easily taken as evidence for a role of dopamine or serotonin in the mechanism underlying the effects. Interactions between 5-HT and dopamine should be taken into account when interpreting the data. These interactions between 5-HT and dopamine may also explain why atypical antipsychotics augment the effects of SSRIs. Depending on the brain region this may result in either stimulation or inhibition of the dopamine release.

Discussion

Despite some inconsistencies, in general, the results from most studies hint at an association between OCD and increased midbrain dopamine neurotransmission. The hypothesis of increased dopamine neurotransmission in the basal ganglia is in agreement with various working hypotheses of the pathophysiology of OCD such as the hyperactive cortico-striato-thalamic model or the model of behavioral addiction in OCD.^1,186  The cortico-striato-thalamic working model of OCD suggests an imbalance of the direct versus indirect pathway that produces a hyperactive circuit responsible for the repetitive behaviors seen in OCD.¹⁴² Since D₁ preferentially activates the direct and D₂ the indirect pathway, and the density of D₁ receptors in the basal ganglia is higher than the density of D₂ receptors, increased concentrations of dopamine are most likely to result in a dominant D₁-regulated direct circuit, and consequently in a hyperactive cortico-striatal system. Another way to understand OCD is that the normal cortical inhibition of the amygdala is malfunctioning, and that the anxiety responses induced by the amygdala become more intrusive and chronic in patients with OCD. Rosenkranz and colleagues¹⁸⁷ demonstrated that the response of the amygdala to cortical inhibition is potently affected by alterations of the mesolimbic dopaminergic system. When dopamine is increased, the ability of the prefrontal cortex to suppress the affective responses generated in the amygdala is attenuated. A number of phenomenological characteristics of OCD such as loss of voluntary control, repetitiveness, compulsiveness, reinforcement of behavior, aberrant habit learning and uncertainty resemble addictive behavior and may be understood within the conceptual framework “behavioral addiction”. In particular, ritualistic-compulsive actions share similarities with addictive behavior.¹⁸⁸ There is little doubt that midbrain dopamine has positive reinforcing properties, and it is liable that the reinforcing nature of compulsions originates from increased dopamine transmission. Recently, Fiorillo and colleagues1⁷² demonstrated that dopamine neurons show increased firing during prolonged periods of uncertainty. Subjective uncertainty is a main feature of pathological gambling and plays a major role in OCD. 

There is convincing evidence for the role of 5-HT in the treatment of OCD. However, the role of 5-HT in the pathophysiology of OCD is less clear.  Studies in putative animal models for OCD suggest a role for the 5-HT_2C receptors, whereas imaging studies, challenge tests with nonselective agents, and genetic studies in men have implicated a role for the 5-HT_2A and probably the 5-HT_1B receptors. The observation that atypical antipsychotics, which have high affinity for these receptors, can augment the effect of SSRIs underscores the possible role of these receptors in the mechanism of action of antidepressants.

Another feature of OCD patients is that they are habitually indecisive. Converging evidence implicates the role of the OFC, ACC, and DLPFC in decision-making and reversal learning. The OFC maintains a representation of the reward history, the ACC monitors decision outcomes, and the DLPFC is substrate for deliberation and execution of actions. Bilateral lesions of the OFC produce severe impairment in reward-related reversal learning.¹⁸⁹ Abnormal OFC activity can lead to prolonged deliberation before decisions are made, because of reward uncertainty. The OFC is strongly connected to the VTA, nucleus accumbens and amygdala.  Neuroimaging studies have shown hyperactivity in the OFC of OCD patients.¹⁴⁶ Hyperactivity, although not consistently, has also been found in the ACC.130 Electrophysiological studies have shown significantly greater error-related activation of the ACC in OCD patients, suggesting abnormal error detection leading to repetition of the behavior and uncertainty of the outcome.^190-192 Anterior cingulotomy have shown to exert beneficial effects in severe OCD patients.^193,194 Error-related activity is strongly influenced by dopaminergic activity.¹⁹⁵ Schultz and colleagues¹⁵² have suggested that dopamine neurons might serve as error signals used to correct the behavioral response. The ascending 5-HT and dopamine neurons have a modulatory role in these processes. Tryptophan depletion, which results in a diminished availability of 5-HT, impairs decision-making in healthy volunteers,^196,197 suggesting that 5-HT mediates decision-making perhaps in the orbital frontal cortex by modulating the processing of reward cues. Comparable effects have been observed after manipulation of the dopaminergic system by using the l-dopa withdrawal technique in patients with Parkinson’s disease.¹⁹⁸

These finding implicate a role for both 5-HT and dopamine in decision making.

Conclusion

There is circumstantial evidence that dopaminergic and serotonergic pathways play a role in the genesis and maintenance of obsessive-compulsive symptoms. The complex interactions between both monoaminergic systems, the phenotypic heterogeneity of the disorder and the limitations of the available tests to probe both systems, make it as yet impossible to draw firm conclusions as to how these systems are implicated. Although this review focused predominantly on serotonin and dopamine, other neurotransmitter systems, such as norepinephrine and g-aminobutyric acid, might play a role also and deserve further investigation. Studies with more selective agents in humans,  studies using deep-brain stimulation in combination with neuroimaging and  the development of better animal models for OCD may also further our understanding of this disabling condition.

References

1. Denys D, Zohar J, Westenberg HG. The role of dopamine in obsessive-compulsive disorder: preclinical and clinical evidence. J Clin Psychiatry. 2004;65(suppl 14):11-17.
2. Chou-Green JM, Holscher TD, Dallman MF, et al. Compulsive behavior in the 5-HT_2C receptor knockout mouse. Physiol Behav. 2003;78:641-649.
3. Tsaltas E, Kontis D, Chrysikakou S, et al. Reinforced spatial alternation as an animal model of obsessive-compulsive disorder (OCD): investigation of 5-HT_2C and 5-HT_1D receptor involvement in OCD pathophysiology. Biol Psychiatry. 2005;57:1176-1185.
4. Joel D, Doljansky J, Schiller D. ‘Compulsive’ lever pressing in rats is enhanced following lesions to the orbital cortex, but not to the basolateral nucleus of the amygdala or to the dorsal medial prefrontal cortex. Eur J Neurosci. 2005;21:2252-2262.
5. Joel D, Doljansky J. Selective alleviation of compulsive lever-pressing in rats by D₁, but not D₂, blockade: possible implications for the involvement of D₁ receptors in obsessive-compulsive disorder. Neuropsychopharmacology. 2003;28:77-85.
6. Campbell KM, de Lecea L, Severynse DM, et al. OCD-Like behaviors caused by a neuropotentiating transgene targeted to cortical and limbic D1+ neurons. J Neurosci. 1999;19:5044-5053.
7. Eilam D, Szechtman H. Psychostimulant-induced behavior as an animal model of obsessive-compulsive disorder: an ethological approach to the form of compulsive rituals. CNS Spectr. 2005;10:191-202.
8. Sullivan RM, Talangbayan H, Einat H, et al. Effects of quinpirole on central dopamine systems in sensitized and non-sensitized rats. Neuroscience. 1998;83:781-789.
9. Thoren P, Asberg M, Bertilsson L, et al. Clomipramine treatment of obsessive-compulsive disorder. II. Biochemical aspects. Arch Gen Psychiatry. 1980;37:1289-1294.
10. Insel TR, Mueller EA, Alterman I, et al. Obsessive-compulsive disorder and serotonin: is there a connection? Biol Psychiatry. 1985;20:1174-1188.
11. Leckman JF, Goodman WK, Anderson GM, et al. Cerebrospinal fluid biogenic amines in obsessive compulsive disorder, Tourette’s syndrome, and healthy controls. Neuropsychopharmacology. 1995;12:73-86.
12. Bornstein RA, Baker GB. Urinary indoleamines in Tourette syndrome patients with obsessive-compulsive characteristics. Psychiatry Res. 1992;41:267-274.
13. de Groot CM, Bornstein RA, Baker GB. Obsessive-compulsive symptom clusters and urinary amine correlates in Tourette syndrome. J Nerv Ment Dis. 1995;183:224-230.
14. Cath DC, Spinhoven P, Landman AD, et al. Psychopathology and personality characteristics in relation to blood serotonin in Tourette’s syndrome and obsessive-compulsive disorder. J Psychopharmacol. 2001;15:111-119.
15. Delorme R, Betancur C, Callebert J, et al. Platelet serotonergic markers as endophenotypes for obsessive-compulsive disorder. Neuropsychopharmacology. 2005;30:1539-1547.
16. Delorme R, Chabane N, Callebert J, et al. Platelet serotonergic predictors of clinical improvement in obsessive compulsive disorder. J Clin Psychopharmacol. 2004;24:18-23.
17. Brewerton TD, Flament MF, Rapoport JL, et al. Seasonal effects on platelet 5-HT content in patients with OCD and controls. Arch Gen Psychiatry. 1993;50:409.
18. Flament MF, Rapoport JL, Murphy DL, et al. Biochemical changes during clomipramine treatment of childhood obsessive-compulsive disorder. Arch Gen Psychiatry. 1987;44:219-225.
19. Hanna GL, Yuwiler A, Cantwell DP. Whole blood serotonin in juvenile obsessive-compulsive disorder. Biol Psychiatry. 1991;29:738-744.
20. Hanna GL, Yuwiler A, Coates JK. Whole blood serotonin and disruptive behaviors in juvenile obsessive-compulsive disorder. J Am Acad Child Adolesc Psychiatry. 1995;34:28-35.
21. Sallee FR, Richman H, Beach K, et al. Platelet serotonin transporter in children and adolescents with obsessive-compulsive disorder or Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry. 1996;35:1647-1656.
22. Weizman A, Mandel A, Barber Y, et al. Decreased platelet imipramine binding in Tourette syndrome children with obsessive-compulsive disorder. Biol Psychiatry. 1992;31:705-711.
23. Marazziti D, Rossi A, Gemignani A, et al. Decreased platelet 3H-paroxetine binding in obsessive-compulsive patients. Neuropsychobiology. 1996;34:184-187
24. Marazziti D, Hollander E, Lensi P, et al. Peripheral markers of serotonin and dopamine function in obsessive-compulsive disorder. Psychiatry Res. 1992;42:41-51.
25. Benkelfat C, Mefford IN, Masters CF, et al. Plasma catecholamines and their metabolites in obsessive-compulsive disorder. Psychiatry Res. 1991;37:321-331.
26. Swedo SE, Leonard HL, Kruesi MJ, et al. Cerebrospinal fluid neurochemistry in children and adolescents with obsessive-compulsive disorder. Arch Gen Psychiatry. 1992;49:29-36.
27. Hollander E, Stein DJ, Saoud JB, et al. Effects of fenfluramine on plasma HVA in OCD. Psychiatry Res. 1992;42:185-188.
28. Zahn TP, Kruesi MJ, Swedo SE, et al. Autonomic activity in relation to cerebrospinal fluid neurochemistry in obsessive and disruptive children and adolescents. Psychophysiology. 1996;33:731-739.
29. Zohar J, Mueller EA, Insel TR, et al. Serotonergic responsivity in obsessive-compulsive disorder. Comparison of patients and healthy controls. Arch Gen Psychiatry. 1987;44:946-951.
30. Zohar J, Insel TR, Zohar-Kadouch RC, et al. Serotonergic responsivity in obsessive-compulsive disorder. Effects of chronic clomipramine treatment. Arch Gen Psychiatry. 1988;45:167-172.
31. Hollander E, DeCaria CM, Nitescu A, et al. Serotonergic function in obsessive-compulsive disorder. Behavioral and neuroendocrine responses to oral m-chlorophenylpiperazine and fenfluramine in patients and healthy volunteers. Arch Gen Psychiatry. 1992;49:21-28.
32. Charney DS, Goodman WK, Price LH, et al. Serotonin function in obsessive-compulsive disorder. A comparison of the effects of tryptophan and m-chlorophenylpiperazine in patients and healthy subjects. Arch Gen Psychiatry. 1988;45:177-185.
33. Goodman WK, McDougle CJ, Price LH, et al. m-Chlorophenylpiperazine in patients with obsessive-compulsive disorder: absence of symptom exacerbation. Biol Psychiatry. 1995;38:138-149.
34. Gross-Isseroff R, Cohen R, Sasson Y, et al. Serotonergic dissection of obsessive compulsive symptoms: a challenge study with m-chlorophenylpiperazine and sumatriptan. Neuropsychobiology. 2004;50:200-205.
35. Ho Pian KL, Westenberg HG, den Boer JA, et al. Effects of meta-chlorophenylpiperazine on cerebral blood flow in obsessive-compulsive disorder and controls. Biol Psychiatry. 1998;44:367-370.
36. Lesch KP, Hoh A, Schulte HM, et al. Long-term fluoxetine treatment decreases 5-HT_1A receptor responsivity in obsessive-compulsive disorder. Psychopharmacology (Berl). 1991;105:415-420.
37. Ho Pian KL, Westenberg HG, van Megen HJ, et al. Sumatriptan (5-HT1D receptor agonist) does not exacerbate symptoms in obsessive compulsive disorder. Psychopharmacology (Berl). 1998;140:365-370.
38. Stein DJ, Van Heerden B, Wessels CJ, et al. Single photon emission computed tomography of the brain with Tc-99m HMPAO during sumatriptan challenge in obsessive-compulsive disorder: investigating the functional role of the serotonin auto-receptor. Prog Neuropsychopharmacol Biol Psychiatry. 1999;23:1079-1099.
39. Boshuisen ML, den Boer JA. Zolmitriptan (a 5-HT1B/1D receptor agonist with central action) does not increase symptoms in obsessive compulsive disorder. Psychopharmacology (Berl). 2000;152:74-79.
40. McBride PA, DeMeo MD, Sweeney JA, et al. Neuroendocrine and behavioral responses to challenge with the indirect serotonin agonist dl-fenfluramine in adults with obsessive-compulsive disorder. Biol Psychiatry. 1992;31:19-34.
41. Hewlett WA, Vinogradov S, Martin K, et al. Fenfluramine stimulation of prolactin in obsessive-compulsive disorder. Psychiatry Res. 1992;42:81-92.
42. Lucey JV, O’Keane V, Butcher G, et al. Cortisol and prolactin responses to d-fenfluramine in non-depressed patients with obsessive-compulsive disorder: a comparison with depressed and healthy controls. Br J Psychiatry. 1992;161:517-521.
43. Little KY, Zhang L, Desmond T, et al. Striatal dopaminergic abnormalities in human cocaine users. Am J Psychiatry. 1999;156:238-245.
44. McDougle CJ, Goodman WK, Delgado PL, et al. Pathophysiology of obsessive-compulsive disorder. Am J Psychiatry. 1989;146:350-1351.
45. Rosse RB, Fay-McCarthy M, Collins JP, Jr., et al. The relationship between cocaine-induced paranoia and compulsive foraging: a preliminary report. Addiction. 1994;89:1097-1104.
46. Rosse RB, Fay-McCarthy M, Collins JP Jr, et al. Transient compulsive foraging behavior associated with crack cocaine use. Am J Psychiatry. 1993;150:155-156.
47. Koizumi HM. Obsessive-compulsive symptoms following stimulants. Biol Psychiatry. 1985;20:1332-1333.
48. Satel SL, McDougle CJ. Obsessions and compulsions associated with cocaine abuse. Am J Psychiatry. 1991;148:947.
49. Rosse RB, McCarthy MF, Alim TN, et al. Saccadic distractibility in cocaine dependent patients: a preliminary laboratory exploration of the cocaine-OCD hypothesis. Drug Alcohol Depend. 1994;35:25-30.
50. Kouris S. Methylphenidate-induced obsessive-compulsiveness. J Am Acad Child Adolesc Psychiatry. 1998;37:135.
51. Kotsopoulos S, Spivak M. Obsessive-compulsive symptoms secondary to methylphenidate treatment. Can J Psychiatry. 2001;46:89.
52. Frye PE, Arnold LE. Persistent amphetamine-induced compulsive rituals: response to pyridoxine(B6). Biol Psychiatry. 1981;16:583-587.
53. yo M, Sekine Y, Matsunaga T, et al. Methamphetamine-associated obsessional symptoms and effective risperidone treatment: a case report. J Clin Psychiatry. 1999;60:337-338.
54. Lemus CZ, Robinson DG, Kronig M, et al. Behavioral responses to a dopaminergic challenge in obsessive-compulsive disorder. J Anxiety Disorders. 1991;5:369-273.
55. Pitchot W, Hansenne M, Moreno AG, et al. Growth hormone response to apomorphine in obsessive-compulsive disorder. J Psychiatry Neurosci. 1996;21:343-345.
56. Brambilla F, Perna G, Bussi R, et al. Dopamine function in obsessive compulsive disorder: cortisol response to acute apomorphine stimulation. Psychoneuroendocrinology. 2000;25:301-310.
57. Brambilla F, Bellodi L, Perna G, et al. Dopamine function in obsessive-compulsive disorder: growth hormone response to apomorphine stimulation. Biol Psychiatry. 1997;42:889-897.
58. Longhurst JG, Carpenter LL, Epperson CN, et al. Effects of catecholamine depletion with AMPT (alpha-methyl-para-tyrosine) in obsessive-compulsive disorder. Biol Psychiatry. 1999;46:573-576.
59. Ceccherini-Nelli A, Guazzelli M. Treatment of refractory OCD with the dopamine agonist bromocriptine. J Clin Psychiatry. 1994;55:415-416.
60. Goodman WK, Price LH, Delgado PL, et al. Specificity of serotonin reuptake inhibitors in the treatment of obsessive-compulsive disorder. Comparison of fluvoxamine and desipramine. Arch Gen Psychiatry. 1990;47:577-585.
61. Zohar J, Insel TR. Obsessive-compulsive disorder: psychobiological approaches to diagnosis, treatment, and pathophysiology. Biol Psychiatry. 1987;22:667-687.
62. Leonard HL, Swedo SE, Rapoport JL, et al. Treatment of obsessive-compulsive disorder with clomipramine and desipramine in children and adolescents. A double-blind crossover comparison. Arch Gen Psychiatry. 1989;46:1088-1092.
63. Hoehn-Saric R, Ninan P, Black DW, et al. Multicenter double-blind comparison of sertraline and desipramine for concurrent obsessive-compulsive and major depressive disorders. Arch Gen Psychiatry. 2000;57:76-82.
64. Denys D, van der WN, van Megen HJ, et al. A double blind comparison of venlafaxine and paroxetine in obsessive-compulsive disorder. J Clin Psychopharmacol. 2003;23: 568-575
65. Denys D, van Megen H, Westenberg H. The adequacy of pharmacotherapy in outpatients with obsessive-compulsive disorder. Int Clin Psychopharmacol. 2002;17:109-114.
66. Denys D, de Geus F, van Megen HJ, et al. Use of factor analysis to detect potential phenotypes in obsessive-compulsive disorder. Psychiatry Res. 2004;128:273-280.
67. Kent JM, Coplan JD, Lombardo I, et al. Occupancy of brain serotonin transporters during treatment with paroxetine in patients with social phobia: a positron emission tomography study with 11C McN 5652. Psychopharmacology (Berl). 2002;164:341-348.
68. Neumeister A. Tryptophan depletion, serotonin, and depression: where do we stand? Psychopharmacol Bull. 2003;37:99-115.
69. Berney A, Sookman D, Leyton M, et al. Lack of effects on core obsessive-compulsive symptoms of tryptophan depletion during symptom provocation in remitted obsessive-compulsive disorder patients. Biol Psychiatry. 2006;59:853-857.
70. El Mansari M, Blier P. Mechanisms of action of current and potential pharmacotherapies of obsessive-compulsive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:362-373.
71. Dannon PN, Sasson Y, Hirschmann S, et al. Pindolol augmentation in treatment-resistant obsessive compulsive disorder: a double-blind placebo controlled trial. Eur Neuropsychopharmacol. 2000;10:165-169.
72. Pallanti S, Quercioli L, Bruscoli M. Response acceleration with mirtazapine augmentation of citalopram in obsessive-compulsive disorder patients without comorbid depression: a pilot study. J Clin Psychiatry. 2004;65:1394-1399
73. Bloch MH, Landeros-Weisenberger A, Kelmendi B, et al. A systematic review: antipsychotic augmentation with treatment refractory obsessive-compulsive disorder. Mol Psychiatry. 2006;11:622-632.
74. McDougle CJ, Barr LC, Goodman WK, et al. Lack of efficacy of clozapine monotherapy in refractory obsessive-compulsive disorder. Am J Psychiatry. 1995;152:1812-1814.
75. Lykouras L, Alevizos B, Michalopoulou P, et al. Obsessive-compulsive symptoms induced by atypical antipsychotics. A review of the reported cases. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:333-346.
76. McDougle CJ, Goodman WK, Price LH, et al. Neuroleptic addition in fluvoxamine-refractory obsessive-compulsive disorder. Am J Psychiatry. 1990;147:652-654.
77. Shapira NA, Ward HE, Mandoki M, et al. A double-blind, placebo-controlled trial of olanzapine addition in fluoxetine-refractory obsessive-compulsive disorder. Biol Psychiatry. 2004;55:553-555.
78. Sevincok L, Topuz A. Lack of efficacy of low doses of quetiapine addition in refractory obsessive-compulsive disorder. J Clin Psychopharmacol. 2003;23:448-450.
79. Fineberg NA, Sivakumaran T, Roberts A, et al. Adding quetiapine to SRI in treatment-resistant obsessive-compulsive disorder: a randomized controlled treatment study. Int Clin Psychopharmacol. 2005;20:223-226.
80. Carey PD, Vythilingum B, Seedat S, et al. Quetiapine augmentation of SRIs in treatment refractory obsessive-compulsive disorder: a double-blind, randomised, placebo-controlled study [ISRCTN83050762]. BMC Psychiatry. 2005;5:5.
81. Fineberg NA, Stein DJ, Premkumar P, et al. Adjunctive quetiapine for serotonin reuptake inhibitor-resistant obsessive-compulsive disorder: a meta-analysis of randomized controlled treatment trials. Int Clin Psychopharmacol. 2006;21:337-343.
82. Metin O, Yazici K, Tot S, et al. Amisulpiride augmentation in treatment resistant obsessive-compulsive disorder: an open trial. Hum Psychopharmacol. 2003;18:463-467.
83. Ramasubbu R, Ravindran A, Lapierre Y. Serotonin and dopamine antagonism in obsessive-compulsive disorder: effect of atypical antipsychotic drugs. Pharmacopsychiatry. 2000;33:236-238.
84. Kuroki T, Meltzer HY, Ichikawa J. 5-HT2A receptor stimulation by DOI, a 5-HT_2A/2C receptor agonist, potentiates amphetamine-induced dopamine release in rat medial prefrontal cortex and nucleus accumbens. Brain Res. 2003;972:216-221.
85. Zhang W, Bymaster FP. The in vivo effects of olanzapine and other antipsychotic agents on receptor occupancy and antagonism of dopamine D₁, D₂, D₃, 5HT_2A and muscarinic receptors. Psychopharmacology (Berl). 1999;141:267-278,
86. Zhang W, Perry KW, Wong DT, et al. Synergistic effects of olanzapine and other antipsychotic agents in combination with fluoxetine on norepinephrine and dopamine release in rat prefrontal cortex. Neuropsychopharmacology. 2000;23:250-262.
87. Denys D, Klompmakers AA, Westenberg HG. Synergistic dopamine increase in the rat prefrontal cortex with the combination of quetiapine and fluvoxamine. Psychopharmacology (Berl). 2004;176:195-203.
88. Ryding E, Lindstrom M, Bradvik B, et al. A new model for separation between brain dopamine and serotonin transporters in ¹²³I-beta-CIT SPECT measurements: normal values and sex and age dependence. Eur J Nucl Med Mol Imaging. 2004;31:1114-1118.
89. Pogarell O, Hamann C, Popperl G, et al. Elevated brain serotonin transporter availability in patients with obsessive-compulsive disorder. Biol Psychiatry. 2003;54:1406-1413.
90. Hesse S, Muller U, Lincke T, et al. Serotonin and dopamine transporter imaging in patients with obsessive-compulsive disorder. Psychiatry Res. 2005;140:63-72.
91. Stengler-Wenzke K, Muller U, Angermeyer MC, et al. Reduced serotonin transporter-availability in obsessive-compulsive disorder (OCD). Eur Arch Psychiatry Clin Neurosci. 2004;254:252-255.
92. Muller-Vahl KR, Meyer GJ, Knapp WH, et al. Serotonin transporter binding in Tourette Syndrome. Neurosci Lett. 2005;385:120-125.
93. van der Wee NJ, Stevens H, Hardeman JA, et al. Enhanced dopamine transporter density in psychotropic-naive patients with obsessive-compulsive disorder shown by [¹²³I]{beta}-CIT SPECT. Am J Psychiatry. 2004;161:2201-2206.
94. Simpson HB, Lombardo I, Slifstein M, et al. Serotonin transporters in obsessive-compulsive disorder: a positron emission tomography study with [(¹¹)C]McN 5652. Biol Psychiatry. 2003;54:1414-1421.
95. Adams KH, Hansen ES, Pinborg LH, et al. Patients with obsessive-compulsive disorder have increased 5-HT_2A receptor binding in the caudate nuclei. Int J Neuropsychopharmacol. 2005;8:391-401.
96. Kim CH, Koo MS, Cheon KA, et al. Dopamine transporter density of basal ganglia assessed with [123I]IPT SPET in obsessive-compulsive disorder. Eur J Nucl Med Mol Imaging. 2003;30:1637-1643.
97. Pogarell O, Poepperl G, Mulert C, et al. SERT and DAT availabilities under citalopram treatment in obsessive-compulsive disorder (OCD). Eur Neuropsychopharmacol. 2005;15:521-524.
98. Sawle GV, Hymas NF, Lees AJ, et al. Obsessional slowness. Functional studies with positron emission tomography. Brain. 1991;114(Pt 5):2191-2202.
99. Denys D, van der WN, Janssen J, et al. Low level of dopaminergic D₂ receptor binding in obsessive-compulsive disorder. Biol Psychiatry. 2004;55:1041-1045.
100. Denys D, Van Nieuwerburgh F, Deforce D, et al. Association between serotonergic candidate genes and specific phenotypes of obsessive compulsive disorder. J Affect Disord. 2006;91:39-44.
101. Kim SJ, Lee HS, Kim CH. Obsessive-compulsive disorder, factor-analyzed symptom dimensions and serotonin transporter polymorphism. Neuropsychobiology. 2005;52:176-182.
102. Cavallini MC, Di Bella D, Siliprandi F, et al. Exploratory factor analysis of obsessive-compulsive patients and association with 5-HTTLPR polymorphism. Am J Med Genet. 2002;114:347-353.
103. Mundo E, Richter MA, Zai G, et al. 5HT1Dbeta Receptor gene implicated in the pathogenesis of obsessive-compulsive disorder: further evidence from a family-based association study. Mol Psychiatry. 2002;7:805-809.
104. Enoch MA, Kaye WH, Rotondo A, et al. 5-HT_2A promoter polymorphism -1438G/A, anorexia nervosa, and obsessive-compulsive disorder. Lancet. 1998;351:1785-1786.
105. Walitza S, Wewetzer C, Warnke A, et al. 5-HT_2A promoter polymorphism -1438G/A in children and adolescents with obsessive-compulsive disorders. Mol Psychiatry. 2002;7:1054-1057.
106. Camarena B, Cruz C, de LF, Jr., et al. A higher frequency of a low activity-related allele of the MAO-A gene in females with obsessive-compulsive disorder. Psychiatr Genet. 1998;8:255-257.
107. Frisch A, Michaelovsky E, Rockah R, et al. Association between obsessive-compulsive disorder and polymorphisms of genes encoding components of the serotonergic and dopaminergic pathways. Eur Neuropsychopharmacol. 2000;10:205-209.
108. Hemmings SM, Kinnear CJ, Niehaus DJ, et al. Investigating the role of dopaminergic and serotonergic candidate genes in obsessive-compulsive disorder. Eur Neuropsychopharmacol. 2003;13:93-98.
109. Nicolini H, Cruz C, Camarena B, et al. DRD2, DRD3 and 5HT2A receptor genes polymorphisms in obsessive-compulsive disorder. Mol Psychiatry. 1996;1:461-465.
110. Catalano M, Sciuto G, Di Bella D, et al. Lack of association between obsessive-compulsive disorder and the dopamine D3 receptor gene: some preliminary considerations. Am J Med Genet. 1994;54:253-255.
111. Denys D, Van Nieuwerburgh F, Deforce D, et al. Association between the dopamine D2 receptor TaqI A2 allele and low activity COMT allele with obsessive-compulsive disorder in males. Eur Neuropsychopharmacol. 2006;16:446-450.
112. Novelli E, Nobile M, Diaferia G, et al. A molecular investigation suggests no relationship between obsessive-compulsive disorder and the dopamine D2 receptor. Neuropsychobiology. 1994;29:61-63.
113. Billett EA, Richter MA, Sam F, et al. Investigation of dopamine system genes in obsessive-compulsive disorder. Psychiatr Genet. 1998;8:163-169.
114. Cruz C, Camarena B, King N, et al. Increased prevalence of the seven-repeat variant of the dopamine D4 receptor gene in patients with obsessive-compulsive disorder with tics. Neurosci Lett. 1997;231:1-4.
115. Millet B, Chabane N, Delorme R, et al. Association between the dopamine receptor D4 (DRD4) gene and obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet. 2003;116:55-59.
116. Di Bella D, Catalano M, Cichon S, et al. Association study of a null mutation in the dopamine D4 receptor gene in Italian patients with obsessive-compulsive disorder, bipolar mood disorder and schizophrenia. Psychiatr Genet. 1996;6:119-121.
117. Karayiorgou M, Altemus M, Galke BL, et al. Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proc Natl Acad Sci U S A. 1997;94:4572-4575.
118. Karayiorgou M, Sobin C, Blundell ML, et al. Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Biol Psychiatry. 1999;45:1178-1189.
119. Alsobrook JP, Zohar AH, Leboyer M, et al. Association between the COMT locus and obsessive-compulsive disorder in females but not males. Am J Med Genet. 2002;114:116-120.
120. Niehaus DJ, Kinnear CJ, Corfield VA, et al. Association between a catechol-o-methyltransferase polymorphism and obsessive-compulsive disorder in the Afrikaner population. J Affect Disord. 2001;65:61-65.
121. Schindler KM, Richter MA, Kennedy JL, et al. Association between homozygosity at the COMT gene locus and obsessive compulsive disorder. Am J Med Genet. 2000;96:721-724.
122. Ohara K, Nagai M, Suzuki Y, et al. No association between anxiety disorders and catechol-O-methyltransferase polymorphism. Psychiatry Res. 1998;80:145-148.
123. Erdal ME, Tot S, Yazici K, et al. Lack of association of catechol-O-methyltransferase gene polymorphism in obsessive-compulsive disorder. Depress Anxiety. 2003;18:41-45.
124. Azzam A, Mathews CA. Meta-analysis of the association between the catecholamine-O-methyl-transferase gene and obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet. 2003;123:64-69.
125. Kang DH, Kim JJ, Choi JS, et al. Volumetric investigation of the frontal-subcortical circuitry in patients with obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci. 2004;16:342-349.
126. Szeszko PR, Robinson D, Alvir JM, et al. Orbital frontal and amygdala volume reductions in obsessive-compulsive disorder. Arch Gen Psychiatry. 1999;56:913-919.
127. Robinson D, Wu H, Munne RA, et al. Reduced caudate nucleus volume in obsessive-compulsive disorder. Arch Gen Psychiatry. 1995;52:393-398.
128. Friedlander L, Desrocher M. Neuroimaging studies of obsessive-compulsive disorder in adults and children. Clin Psychol Rev. 2006;26:32-49.
129. Modell JG, Mountz JM, Curtis GC, et al. Neurophysiologic dysfunction in basal ganglia/limbic striatal and thalamocortical circuits as a pathogenetic mechanism of obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci. 1989;1:27-36.
130. Aouizerate B, Guehl D, Cuny E, et al. Pathophysiology of obsessive-compulsive disorder: a necessary link between phenomenology, neuropsychology, imagery and physiology. Prog Neurobiol. 2004;72:195-221.
131. Schwartz JM. Neuroanatomical aspects of cognitive-behavioural therapy response in obsessive-compulsive disorder. An evolving perspective on brain and behaviour. Br J Psychiatry Suppl. 1998;131:38-44.
132. Albin RL, Young AB, Penney JB. The functional anatomy of disorders of the basal ganglia. Trends Neurosci. 1995;18:63-64.
133. Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci. 1986;9:357-381.
134. Krawczyk DC. Contributions of the prefrontal cortex to the neural basis of human decision making. Neurosci Biobehav Rev. 2002;26:631-664.
135. Elliott R, Dolan RJ, Frith CD. Dissociable functions in the medial and lateral orbitofrontal cortex: evidence from human neuroimaging studies. Cereb Cortex. 2000;10:308-317.
136. Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain. 1995;118(Pt 1):279-306.
137. Goldman-Rakic PS. Working memory and the mind. Sci Am. 1992;267:110-117.
138. Dubois B, Verin M, Teixeira-Ferreira C, et al. Ho to study frontal lobe functions in humans. In: Thierry A-M, Glowinsky J, Goldman-Rakic PS, et al, eds. Motor and Cognitive Functions of the Prefrontal Cortex. Berlin: Springer-Verlag; 1994:1-16.
139. Garber HJ, Ananth JV, Chiu LC, et al. Nuclear magnetic resonance study of obsessive-compulsive disorder. Am J Psychiatry. 1989;146:1001-1005.
140. Baxter LR, Jr., Schwartz JM, Mazziotta JC, et al. Cerebral glucose metabolic rates in nondepressed patients with obsessive-compulsive disorder. Am J Psychiatry. 1988;145:1560-1563.
141. Saxena S, Brody AL, Schwartz JM, et al. Neuroimaging and frontal-subcortical circuitry in obsessive-compulsive disorder. Br J Psychiatry Suppl. 1998:35;26-37.
142. Swedo SE, Schapiro MB, Grady CL, et al. Cerebral glucose metabolism in childhood-onset obsessive-compulsive disorder. Arch Gen Psychiatry. 1989;46:518-523.
143. Nordahl TE, Benkelfat C, Semple WE, et al. Cerebral glucose metabolic rates in obsessive compulsive disorder. Neuropsychopharmacology. 1989;2:23-28.
144. Martinot JL, Allilaire JF, Mazoyer BM, et al. Obsessive-compulsive disorder: a clinical, neuropsychological and positron emission tomography study. Acta Psychiatr Scand. 1990;82:233-242.
145. Rauch SL, Jenike MA, Alpert NM, et al. Regional cerebral blood flow measured during symptom provocation in obsessive-compulsive disorder using oxygen 15-labeled carbon dioxide and positron emission tomography. Arch Gen Psychiatry. 1994;51:62-70.
146. Breiter HC, Rauch SL. Functional MRI and the study of OCD: from symptom provocation to cognitive-behavioral probes of cortico-striatal systems and the amygdala. Neuroimage. 1996;4(suppl):S127-S138.
147. Sachdev PS, Malhi GS. Obsessive-compulsive behaviour: a disorder of decision-making. Aust N Z J Psychiatry. 2005;39:757-763.
148. Critchley HD, Mathias CJ, Dolan RJ. Neural activity in the human brain relating to uncertainty and arousal during anticipation. Neuron. 2001;29:537-545.
149. Rolls ET. The orbitofrontal cortex and reward. Cereb Cortex. 2000;10:284-294.
150. Schnider A, Treyer V, Buck A. The human orbitofrontal cortex monitors outcomes even when no reward is at stake. Neuropsychologia. 2005;43:316-323.
151. Prabhakaran V, Narayanan K, Zhao Z, et al. Integration of diverse information in working memory within the frontal lobe. Nat Neurosci. 2000;3:85-90.
152. Schultz W. Behavioral theories and the neurophysiology of reward. Annu Rev Psychol. 2006;57:87-115.
153. Chamberlain SR, Blackwell AD, Fineberg NA, et al. The neuropsychology of obsessive compulsive disorder: the importance of failures in cognitive and behavioural inhibition as candidate endophenotypic markers. Neurosci Biobehav Rev. 2005;29:399-419.
154. Chamberlain SR, Blackwell AD, Fineberg NA, et al. Strategy implementation in obsessive-compulsive disorder and trichotillomania. Psychol Med. 2006;36:91-97.
155. Chamberlain SR, Fineberg NA, Menzies LA, et al. Impaired cognitive flexibility and motor inhibition in unaffected first-degree relatives of OCD patients: on the trail of endophenotypes. Am J Psychiatry. 2007. In press.
155. Cavedini P, Riboldi G, D’Annucci A, et al. Decision-making heterogeneity in obsessive-compulsive disorder: ventromedial prefrontal cortex function predicts different treatment outcomes. Neuropsychologia. 2002;40: 205-211.
156. Cavallaro R, Cavedini P, Mistretta P, et al. Basal-corticofrontal circuits in schizophrenia and obsessive-compulsive disorder: a controlled, double dissociation study. Biol Psychiatry. 2003;54:437-443.
157. Nielen MM, den Boer JA. Neuropsychological performance of OCD patients before and after treatment with fluoxetine: evidence for persistent cognitive deficits. Psychol Med. 2003;33:917-925.
158. Watkins LH, Sahakian BJ, Robertson MM, et al. Executive function in Tourette’s syndrome and obsessive-compulsive disorder. Psychol Med. 2005;35:571-582.
159. Lawrence NS, Wooderson S, Mataix-Cols D, et al. Decision making and set shifting impairments are associated with distinct symptom dimensions in obsessive-compulsive disorder. Neuropsychology. 2006;20:409-419.
160. Remijnse PL, Nielen MM, van Balkom AJ, et al. Reduced orbitofrontal-striatal activity on a reversal learning task in obsessive-compulsive disorder. Arch Gen Psychiatry. 2006;63:1225-1236.
161. Cavedini P, Riboldi G, Keller R, et al. Frontal lobe dysfunction in pathological gambling patients. Biol Psychiatry. 2002;51:334-341.
162. Cavedini P, Zorzi C, Bassi T, et al. Decision-making functioning as a predictor of treatment outcome in anorexia nervosa. Psychiatry Res. 2006;7(145 suppl 2-3):179-187.
163. Cavedini P, Bassi T, Zorzi C, et al. The advantages of choosing antiobsessive therapy according to decision-making functioning. J Clin Psychopharmacol. .2004;24:628-631.
164. Fontenelle L, Marques C, Engelhardt E, et al. Impaired set-shifting ability and therapeutic response in obsessive-compulsive disorder. J Neuropsychiatry Clin Neurosci. 2001;13:508-510.
165. Moritz S, Kloss M, Jacobsen D, et al. Neurocognitive impairment does not predict treatment outcome in obsessive-compulsive disorder. Behav Res Ther. 2005;43:811-819.
166. Bolton D, Raven P, Madronal-Luque R, et al. Neurological and neuropsychological signs in obsessive compulsive disorder: interaction with behavioural treatment. Behav Res Ther. 2000;38:695-708.
167. Abbruzzese M, Ferri S, Scarone S. Wisconsin Card Sorting Test performance in obsessive-compulsive disorder: no evidence for involvement of dorsolateral prefrontal cortex. Psychiatry Res. 1995;58:37-43.
168. Mataix-Cols D, Alonso P, Pifarre J, et al. Neuropsychological performance in medicated vs. unmedicated patients with obsessive-compulsive disorder. Psychiatry Res. 2002;109:255-264.
169. Chamberlain SR, Fineberg NA, Blackwell AD, et al. Motor inhibition and cognitive flexibility in obsessive-compulsive disorder and trichotillomania. Am J Psychiatry. 2006;163:1282-1284.
170. Watkins LH, Rogers RD, Lawrence AD, et al. Impaired planning but intact decision making in early Huntington’s disease: implications for specific fronto-striatal pathology. Neuropsychologia. 2000;38:1112-1125.
171. Fiorillo CD, Tobler PN, Schultz W. Discrete coding of reward probability and uncertainty by dopamine neurons. Science. 2003;299:1898-1902.
172. Horvitz JC. Mesolimbocortical and nigrostriatal dopamine responses to salient non-reward events. Neuroscience. 2000;96:651-656.
173. Kapur S, Remington G. Serotonin-dopamine interaction and its relevance to schizophrenia. Am J Psychiatry. 1996;153:466-476.
174. Amargos-Bosch M, Bortolozzi A, Puig MV, et al. Co-expression and in vivo interaction of serotonin1A and serotonin2A receptors in pyramidal neurons of prefrontal cortex. Cereb Cortex. 2004;14:281-299.
175. Seeman P. Atypical antipsychotics: mechanism of action. Can J Psychiatry. 2002;47:27-38.
176. Marek GJ, Carpenter LL, McDougle CJ, et al. Synergistic action of 5-HT2A antagonists and selective serotonin reuptake inhibitors in neuropsychiatric disorders. Neuropsychopharmacology. 2003;28:402-412.
177. Bortolozzi A, Diaz-Mataix L, Scorza MC, et al. The activation of 5-HT receptors in prefrontal cortex enhances dopaminergic activity. J Neurochem. 2005;95:1597-1607.
178. Ichikawa J, Ishii H, Bonaccorso S, et al. 5-HT(2A) and D(2) receptor blockade increases cortical DA release via 5-HT(1A) receptor activation: a possible mechanism of atypical antipsychotic-induced cortical dopamine release. J Neurochem. 2001;76:1521-1531.
179. Hallbus M, Magnusson T, Magnusson O. Influence of 5-HT1B/1D receptors on dopamine release in the guinea pig nucleus accumbens: a microdialysis study. Neurosci Lett. 1997;225:57-60.
180. O’Dell LE, Parsons LH. Serotonin1B receptors in the ventral tegmental area modulate cocaine-induced increases in nucleus accumbens dopamine levels. J Pharmacol Exp Ther. 2004;311:711-719.
181. Neumaier JF, Vincow ES, Arvanitogiannis A, et al. Elevated expression of 5-HT1B receptors in nucleus accumbens efferents sensitizes animals to cocaine. J Neurosci. 2002;22:10856-10863.
182. De Deurwaerdere P, Navailles S, Berg KA, et al. Constitutive activity of the serotonin2C receptor inhibits in vivo dopamine release in the rat striatum and nucleus accumbens. J Neurosci. 2004;24:3235-3241.
183. Zhou FC, Lesch KP, Murphy DL. Serotonin uptake into dopamine neurons via dopamine transporters: a compensatory alternative. Brain Res. 2002;942:109-119.
184. Zhou FM, Liang Y, Salas R, et al. Corelease of dopamine and serotonin from striatal dopamine terminals. Neuron. 2005;46:65-74.
185. Potenza MN. The neurobiology of pathological gambling. Semin Clin Neuropsychiatry. 2001;6:217-226.
186. Rosenkranz JA, Grace AA. Dopamine-mediated modulation of odour-evoked amygdala potentials during pavlovian conditioning. Nature. 2002;417:282-287.
187. Holden C. ‘Behavioral’ addictions: do they exist? Science. 2001;294:980-982.
188. Manes F, Sahakian B, Clark L, et al. Decision-making processes following damage to the prefrontal cortex. Brain. 2002;125:624-639.
189. van V, V, Carter CS. The anterior cingulate as a conflict monitor: fMRI and ERP studies. Physiol Behav. 2002;77:477-482.
190. Fitzgerald KD, Welsh RC, Gehring WJ, et al. Error-related hyperactivity of the anterior cingulate cortex in obsessive-compulsive disorder. Biol Psychiatry. 2005;57:287-294.
191. Hajcak G, Simons RF. Error-related brain activity in obsessive-compulsive undergraduates. Psychiatry Res. 2002;110:63-72.
192. Jung HH, Kim CH, Chang JH, et al. Bilateral anterior cingulotomy for refractory obsessive-compulsive disorder: Long-term follow-up results. Stereotact Funct Neurosurg. 2006;84:184-189.
193. Kim CH, Chang JW, Koo MS, et al. Anterior cingulotomy for refractory obsessive-compulsive disorder. Acta Psychiatr Scand. 2003;107:283-290.
194. Nieuwenhuis S, Ridderinkhof KR, Talsma D, et al. A computational account of altered error processing in older age: dopamine and the error-related negativity. Cogn Affect Behav Neurosci. 2002;2:19-36.
195. Talbot PS, Watson DR, Barrett SL, et al. Rapid tryptophan depletion improves decision-making cognition in healthy humans without affecting reversal learning or set shifting. Neuropsychopharmacology. 2006;31:1519-1525.
196. Rogers RD, Tunbridge EM, Bhagwagar Z, et al. Tryptophan depletion alters the decision-making of healthy volunteers through altered processing of reward cues. Neuropsychopharmacology. 2003;28:153-162.
197. Pessiglione M, Czernecki V, Pillon B, et al. An effect of dopamine depletion on decision-making: the temporal coupling of deliberation and execution. J Cogn Neurosci. 2005;17:1886-1896.