Quetiapine augments the effect of citalopram in non-refractory obsessive-compulsive disorder: a randomized, double-blind, placebo-controlled study of 76 patients.
ABSTRACT To assess the efficacy of quetiapine addition to citalopram in treatment-naive or medication-free obsessive-compulsive disorder (OCD) patients.
Seventy-six patients who met DSM-IV criteria for OCD and who were drug-free or drug-naive at entry were randomly assigned in a 10-week, double-blind trial with citalopram (60 mg/day) plus quetiapine (300-450 mg/day) or placebo; treatment-refractory OCD patients were excluded. Of the 76 eligible patients, 66 patients completed the trial-31 in the quetiapine and 35 in the placebo group. The change from baseline to endpoint on the total Yale-Brown Obsessive Compulsive Scale (YBOCS) and the response to treatment in the quetiapine addition compared with the placebo addition group were the primary outcome measures. Response was defined as a 35% or greater reduction on the YBOCS and a Clinical Global Impressions-Improvement (CGI-I) score at endpoint of 1 or 2. The study was conducted from November 2003 to June 2005 at the University Medical Centre Utrecht, The Netherlands.
As measured by the mean reduction in YBOCS scores following an intent-to-treat, last-observation-carried-forward analysis, quetiapine addition (11.9) was significantly superior to placebo (7.8; p = .009). Quetiapine addition was also significantly superior to placebo on the CGI-I scale, with a mean +/- SD CGI-I score of 2.1 +/- 1.3 versus 1.4 +/- 1.2, respectively (p = .023). Quetiapine addition (N = 22, 69%) was also associated with a significantly greater number of patients responding to treatment compared with placebo addition (N = 15, 41%; p = .019). More patients receiving quetiapine (N = 8) than placebo (N = 2; NS) discontinued treatment due to adverse events.
The combination of quetiapine and citalopram was more effective than citalopram alone in reducing OCD symptoms in treatment-naive or medication-free OCD patients.
www.trialregister.nl Identifier NTR116.
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ABSTRACT: Obsessive-compulsive disorder is a chronic psychiatric disorder related to dysfunctional dopaminergic neurotransmission. Deep brain stimulation (DBS) targeted at the nucleus accumbens (NAc) has recently become an effective treatment for therapy-refractory obsessive-compulsive disorder, but its effect on dopaminergic transmission is unknown. We measured the effects of NAc DBS in 15 patients on the dopamine D2/3 receptor availability in the striatum with [(123)I]iodobenzamide ([(123)I]IBZM) single photon emission computed tomography. We correlated changes in [(123)I]IBZM binding potential (BP) with plasma levels of homovanillic acid (HVA) and clinical symptoms. Acute (1-hour) and chronic (1-year) DBS decreased striatal [(123)I]IBZM BP compared with the nonstimulated condition in the putamen. BP decreases were observed after 1 hour of stimulation, and chronic stimulation was related to concurrent HVA plasma elevations, implying DBS-induced dopamine release. BP decreases in the area directly surrounding the electrodes were significantly correlated with changes in clinical symptoms (45% symptom decrease). NAc DBS induced striatal dopamine release, which was associated with increased HVA plasma levels and improved clinical symptoms, suggesting that DBS may compensate for a defective dopaminergic system.Biological psychiatry 08/2013; · 8.93 Impact Factor
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ABSTRACT: Tourette syndrome (TS) and obsessive-compulsive disorder (OCD) both are neuropsychiatric disorders associated with abnormalities in dopamine neurotransmission. Aims of this study were to quantify striatal D2/3 receptor availability in TS and OCD, and to examine dopamine release and symptom severity changes in both disorders following amphetamine challenge. Changes in [(11)C]raclopride binding potential (BPND) were assessed using positron emission tomography before and after administration of d-amphetamine (0.3mgkg(-1)) in 12 TS patients without comorbid OCD, 12 OCD patients without comorbid tics, and 12 healthy controls. Main outcome measures were baseline striatal D2/3 receptor BPND and change in BPND following amphetamine as a measure of dopamine release. Voxel-based analysis revealed significantly decreased baseline [(11)C]raclopride BPND in bilateral putamen of both patient groups vs. healthy controls, differences being more pronounced in the TS than in the OCD group. Changes in BPND following amphetamine were not significantly different between groups. Following amphetamine administration, tic severity increased in the TS group, which correlated with BPND changes in right ventral striatum. Symptom severity in the OCD group did not change significantly following amphetamine challenge and was not associated with changes in BPND. This study provides evidence for decreased striatal D2/3 receptor availability in TS and OCD, presumably reflecting higher endogenous dopamine levels in both disorders. In addition, it provides the first direct evidence that ventral striatal dopamine release is related to the pathophysiology of tics.European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 07/2013; · 3.68 Impact Factor
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ABSTRACT: Anxiety and related disorders are among the most common mental disorders, with lifetime prevalence reportedly as high as 31%. Unfortunately, anxiety disorders are under-diagnosed and under-treated.BMC Psychiatry 07/2014; 14(Suppl 1):S1. · 2.24 Impact Factor
Feelings of Incompleteness
Studies on dopamine in obsessive-compulsive disorder
Studies naar dopamine bij de obsessieve-compulsieve stoornis
(met een samenvatting in het Nederlands)
ter verkrijging van de graad van doctor aan de Universiteit Utrecht op
gezag van de rector magnificus, prof. dr. J.C. Stoof, ingevolge het besluit
van het college voor promoties in het openbaar te verdedigen op maandag
26 oktober 2009 des ochtends te 10.30 uur
Nienke Cornelia Christina Vulink
geboren op één januari 1976 te Deventer
Promotoren: Prof. dr. H.G.M. Westenberg
Prof. dr. D. Denys
Feelings of Incompleteness - Studies on dopamine in obsessive-compulsive disorder
Cover Skrik, Edvard Munch, 1893, Oil, tempera and pastel on cardboard, 91 x 73,5 cm.
© The Munch Museum / The Munch-Ellingsen Group, c/o Pictoright Amsterdam 2009
Lay-out Eric Jansen
Print Gildeprint Drukkerijen
© N.C.C. Vulink, Utrecht, 2009
“Les sentiments d’incomplétude” (feelings of incompleteness) were introduced by Pierre
Janet as the core problem in patients with obsessive-compulsive disorder (Janet P. Les
obsessions et la psychasthénie. 2nd ed. volumes 1 and 2. Paris: Alcan; 1903). Janet located
sensations of incompleteness in what he called the psychasthenic state, characterized by
subjective appraisals of the inadequacy of one’s performance and perceptions, together with
elusiveness of feelings of satisfaction: “psychasthenics are continually tormented by an inner
sense of imperfection” (Pitman, 1987). Feelings of incompleteness, the need for experiences
to conform to precise, yet often indefinable criteria, like for example using exact the right
words to express one’s thoughts or leaving the house only after strict ordering of one’s
belongings, is a specific dimension in OCD which is being increasingly recognized by
subsequent authors. Rasmussen and Eisen (1991, 1992) distinguished obsessive-compulsive
disorder (OCD) characterized by abnormal risk assessment, pathological doubt, and
incompleteness. These authors described that patients with OCD characterized by feelings of
incompleteness experience “an inner drive to have things perfect, absolutely certain, or
completely under control” in the absence of any concerns related to harm. Foa et al. (1995)
suggested that approximately 40 percent of participants with OCD in the DSM-IV field trial
did not involve a feared consequence. These patients feel that actions they perform are
incompletely achieved or do not produce enough satisfaction. Their inability to achieve
“closure” of actions/ perceptions leads to what Coles et al. (2003) described as “not just right
experiences”. A need to perform compulsions to quell feelings of things being not just right
is reported by over half of clinical OCD patients (Summerfeldt, 2007) and positively correlates
with symptom severity and feelings of tension or discomfort (Leckman, 1995; Pietrefesa and
Coles, in press). In summary, several pieces of evidence suggest that feelings of
incompleteness are associated with OCD. This core dimension of incompleteness or like Janet
proposed “an inner sense of imperfection” is also highly recognizable in patients with Body
Dysmorphic Disorder (BDD). Patients with BDD are tormented by continuous feelings of
looking ugly, though no defects or only small physical flaws are seen. They have to check
their appearance in every mirror or reflecting surface and will do anything to hide or
camouflage the imagined defect. In 2004 we initiated research on BDD firstly assessing the
half-year prevalence of BDD on the outpatient clinics of Dermatology, Plastic Surgery and
Maxillofacial surgery of the University Medical Center Utrecht. Our study showed a high
prevalence of BDD (3.2-10%) of all patients presenting on outpatients clinics, supporting
dermatologists, plastic and maxillofacial surgeons to further explore distress and dysfunction
of their patients and to consult a psychiatrist when patients have significant distress and
moderate to severe behavioral impairment. We then elaborated our research with SPECT
scan imaging, questionnaires and epidemiologic studies in private clinics and general
psychiatric hospitals to extend knowledge on BDD.
General Introduction 5
Sexual pleasure in women with obsessive-compulsive disorder? 23
Female hormones affect symptom severity in obsessive–
compulsive disorder 33
Positron emission tomography imaging of amphetamine-induced
dopamine release in drug-free patients with obsessive-
compulsive disorder: preliminary findings 43
Bupropion for patients with obsessive compulsive disorder: an
open-label, fixed-dose study 57
Are atypical antipsychotics effective in anxiety? 65
Quetiapine augments the effect of citalopram in non-refractory
obsessive-compulsive disorder: a randomized, double-blind,
placebo-controlled study of 76 patients 89
Catechol-O-MethylTranferase gene expression predicts response
to citalopram in obsessive-compulsive disorder 105
Serotonin-related genes predict response to quetiapine
augmentation of citalopram in drug naive patients with
obsessive-compulsive disorder 117
Summary, discussion and furure research 129
Nederlandse Samenvatting 137
Curriculum Vitae 147
“In the previous months I’ve become completed fixated on my saliva. Hour by hour I’m
aware of my saliva production and I need to spit it out in order to arrange it in bins and
glasses. Swallowing is forbidden otherwise my parents or sister will die in a horrible traffic
accident. Despite my awareness of the ridiculous nature of these thoughts, I have to obey
them otherwise agitation, anxiety and black despair will take over control.”
“When I walk out of the door the conviction about a weird appearance of my mouth pops
up in my attention and I’m convinced it makes me a very ugly person as everybody is looking
at it. I will do anything to hide my mouth and pictures of my face are a worst nightmare. In
the end I know my mouth is looking rather normal, but I have to check it in every mirror or
“During the last years I’m spending increasing amounts of time when leaving the house or
going to bed with checking if I switched off every device like television, computer, mp3
player, vacuum cleaner, and iron until it feels right. I have to be sure every machine is turned
off, otherwise I will be responsible for short circuit and fire.”
These words are part of the intriguing histories of patients with obsessive-compulsive
disorder or body dysmorphic disorder, who inspired me to start clinical research on this
topic. Almost everybody recognizes some of the content of obsessions as it shares overlap
with the content of childish rituals and superstitious beliefs (e.g. your path being crossed by
a cat while leaving the house predicts evil) experienced by most healthy people1;2. But what
if these thoughts persist, emerge again and again, elicit resistance, distress and/or restrict
your daily functioning3?
If motivated by a feeling of incompleteness, naturalist tenacity appears not as an inability to
carry out the realist ideal of narrative completion, but as an excessive investment in that
ideal that reveals its fundamental impossibility. These people suffer from obsessive-
compulsive disorder (OCD).
When obsessions are confined to the subject of imaginary ugliness and occasionally pass into
delusions of being as ugly as sin, symptoms belong to the diagnosis body dysmorphic
Although obsessive-compulsive disorders have been subject to intense multimodal research,
their pathogeneses are yet to be fully understood. However, increasing evidence from both
preclinical and clinical studies support a role for dopamine in OCD. The major aim of this
research project was to elaborate knowledge on the role of dopamine in OCD. Will
bupropion, which is a preferential dopamine and norepinephrine reuptake inhibitor, be
effective in the treatment of OCD? Are atypical antipsychotics effective in the treatment of
OCD patients? Can we find abnormalities of presynaptic dopamine release in OCD patients
in a PET-scan experiment? Can dopamine genes predict response to pharmacotherapy of
Short history and phenomenology
Obsessive-compulsive disorder (OCD) is a severely incapacitating mental illness characterized
by recurrent, disturbing, intrusive thoughts (obsessions) and overt repetitive and invariant
motor actions or mental acts (compulsions)3. Listed amongst the top 10 most debilitating
illnesses by the World Health Organization4;5. In terms of loss of income and decreased
quality of life, OCD is thought to affect 0.5-3% of the general population6;7, though there is
great diversity in findings due to methodological limitations. Little is known about
prevalence of subsyndromal symptoms, though a recent study reported that 28% of the
population experienced obsessions or compulsions at some time in their lives7.
Psychopathological concepts of obsessions and compulsions underwent fundamental
changes during the past two centuries8;9. The French psychopathologists Esquirol (1772-1840,
1838), Falret (1794-1870), Morel (1809-1873, 1866), and Legrand du Saulle (1830-1886, 1875)
described obsessions and compulsions as respectively “délire partiel”, “délire du toucher”,
“délire émotif”, “folie de doute avec délire de toucher’ and “sentiment d’íncompletude”. In
Germany, von Krafft-Ebing introduced “Zwangvorstellungen” (1840-1902, 1867) and pointed
to an affective basis for obsessions (melancholic mood) which determine the contents of
thoughts and images, with the subject being unable to challenge them in a reflexive and
evaluating manner10. Westphal (1833–1890) proposed an ‘intellectual’ view in 1877 and
assumed OCD (“Zwangvorstellungen”) as primary dysfunctions of cognition11. He was the
first author that distinguishes OCD from psychosis (‘Verrücktheit’, ‘Wahnidee’) and he
defined obsessions as thoughts which comes to the foreground of consciousness in spite of
and contrary to the will of the patient and which he is unable to suppress, although he
recognizes them as abnormal and not characteristic of himself. According to Kurt Schneider
(1939) an obsession is when someone can not repress contents of consciousness although he
judges them as being nonsensical or dominating for no reason. He furthermore reasoned
that the I think accompanies all perceptions, images and thoughts, so that mental life is
personalized, receiving the quality of “mine”. Obsessive phenomena as reflexive phenomena
therefore always have the character of mineness in contrast to delusions12.
In the beginning of the nineteenth century, elaborate observation and description of
mentally ill was combined with a zeal in the search for specific disease entities and
underlying neuroanatomical and physiological explanations. In 1769 Cullen introduced the
term neurosis which covered various nervous disorders and symptoms that could not be
explained physiologically. As the twentieth century opened, both Janet (1859-1947, 1903) and
Freud (1856-1939) isolated OCD from neurasthenia. Beard’s original description of
neurasthenia dated to 1869 (literal translation is absence of nerve strength) and included
symptoms as tenderness of the scalp, backache and spinal tenderness, tinnitus, hypophonia,
inability to concentrate, mental irritability, dilated pupils, insomnia, sexual dysfunction, and
In his highly regarded work, Les Obsessions et la Psychasthenie, Janet proposed that
obsessions and compulsions arise in the third stage of psychasthenia. According to Janet,
patients with psychasthenia (diminution of psychic energy) reported indecisiveness, lack of
confidence, obsessional thoughts, fears, and self-scrutiny. Because the individual lacks
sufficient psychological tension to complete higher-level mental activities, nervous energy is
diverted into more primitive psychological operations that include obsessions and
compulsions. He summarized the essence of the struggle of an obsessive patient as an
ongoing oscillation between a sense of achieved completeness and a disarranging doubt.
Freud (1896) proposed several theories for obsessions, while in his famous “Rat Man”, he
defined obsessions as “transformed self-reproaches which have re-emerged from repression
and which always relate to some sexual act that was performed with pleasure in childhood”.
Until the beginning of the 20th century, but partly even nowadays, the definition of
obsession has been challenged by the concept of obsession in the everyday sense of the
word that has lead to an uncontrolled broadening of the concept. Hallucinations, emotions
and affects were converted into obsessive hallucinations, obsessive emotions and obsessive
affects. Loewenfeld and Friedmann already identified more than 20 different types of
obsessions, including overvalued ideas and phobias, obsessive affects like rage, anger, love,
impulsive acts like suicide and homicide, pyromania, kleptomania, dromomania, sexual
impulses 13-15. In addition, Kraepelin colligates symptoms like passivity phenomena, delusion
and catatony under the heading of obsessive phenomena in the 4th and 5th editions of his
manual of psychiatry16;17.
Nowadays, the presence of insight in obsessions, which was implied in its definition, is
questioned and evidence suggests that obsessions can be accompanied by poor or absent
insight and can become delusional. Insel and Akiskal hypothesized insight in OCD on a
continuum with at the severe end of this spectrum, loss of insight when a patient’s
resistance to the intrusive thoughts is abandoned18.
Similarly, research into BDD showed that non-delusional and delusional variants of BDD are
likely to constitute a single disorder encompassing a spectrum of insight, with the entire
spectrum characterized by obsessional thinking19. This spectrum of insight may range from
good (obsessions), to poor (overvalued ideas), to absent (delusions). However,
differentiating between obsessions and delusions by the presence or absence of insight is
too simplified and other characteristics should be taken into account, such as the form and
content of both ways of thinking, just as the behavioral consequences20.
As the twenty-first century started, advances in pharmacology, neuroanatomy,
neurophysiology and learning theory have allowed us to reach new conceptualizations of
OCD. Current neuroanatomical models are mostly based on the corticostriatal model of
Baxter21;22. On the one hand, patients with OCD show behavioral impairment compared to
controls on neurocognitive tasks which challenge activity in brain structures involved in the
cortico-striato-thalamo-cortical circuit with aberrant activity in implicated brain regions23;24.
On the other hand, from a phenomenological point of view, the heart of obsessions could
be viewed as (1) pathological doubt or failure to reach certainty25, (2) deficits of response
control and inhibition3, or (3) the subject's underlying impression that "something is
wrong"26-28. Error recognition or performance monitoring have been linked to the basal
ganglia and anterior cingulated cortex (ACC), while set-shifting and response inhibition are
linked to respectively the dorsolateral prefrontal cortex (DLPFC) and the orbitofrontal cortex
(OFC). Actually, these brain areas (basal ganglia, ACC, DLPFC and OFC) are part of the
cortico-striato-thalamo circuit and show abnormal activity in OCD patients compared to
controls29-32. In summary, current models of OCD are trying to integrate phenomenological
characteristics of OCD patients linked to aberrant activity in associated brain regions, with
the hypothesis of dysfunctional orbitofronto-striato-thalamic circuits in OCD.
Current conceptualizations of OCD further emphasize a dimensional approach as well as
viewing OCD as part of a larger spectrum of disorders including BDD, tic disorders and
trichotillomania33. According to a dimensional approach, OCD is composed of temporally
stable symptom dimensions. Bloch et al. (2008) included 21 factor analytic studies (n=5124
OCD patients) of the 13 major symptom categories of the Y-BOCS symptom checklist, which
generated four factors: (1) symmetry: symmetry obsessions and repeating, ordering, and
counting compulsions; (2) forbidden thoughts: aggressive, sexual, religious, and somatic
obsessions and checking compulsions; (3) cleaning: contamination obsession and cleaning
compulsion, and (4) hoarding: hoarding obsessions and compulsions34. These symptom
dimensions have been associated with distinct patterns of comorbid psychiatric disorders35,
various patterns of heritability36 or genetic polymorphisms37, divergent neural activity on
functional brain imaging studies38 , and differential response to treatment39;40.
Etiology and course of OCD
The etiology of OCD is likely to involve both genetic and environmental factors. Although
there is convincing evidence that genetic factors can increase an individual’s vulnerability to
OCD, the specific nature of this vulnerability is still uncertain41. Estimates of heritability and
aggregation differ due to methodological differences across studies in patient populations,
criteria/ measures of OCD (symptoms), and use of a comparison group42. In a conservative
meta-analysis of Hettema et al. (2001), in which 5 family studies were reviewed, an
unadjusted aggregate risk of 8.2% to first degree relatives (n=1209) of OCD probands was
observed, compared to 2.0% in relatives of comparisons (n=746)43. In a more recent review
of Pauls (2008), he concluded that the rate of OCD among relatives of adults with OCD was
approximately two times that among controls, while the rate of OCD among relatives of
children and adolescents with OCD was increased almost tenfold in those studies where
comparison to controls was possible. When examining twin studies with dimensional
assessment of OCD symptoms, genetic liability ranges from 27 to 47% in adults and 45-65%
Bienvenu et al. (2000) explored OCD-spectrum disorders among relatives of the proband and
found significantly higher rates of BDD (odds ratio=5.4) and all spectrum disorders combined
(odds ratio=2.7)45. Five segregation analyses have been published to date which reported
different genetic models. Apparently, OCD is an oligogenic disorder with several genes
important for the expression of the syndrome44. Furthermore, over 60 candidate gene
studies were published during the last decade, which revealed varying results with regard to
genetic associations between OCD and genes in the serotonergic and dopaminergic
pathways44;46. The glutamate transporter gene (SCL1A1) is the only candidate gene, which
has been consistently replicated47-49. Two genome-wide linkage studies of OCD have been
published, but none of the studies yielded genome-wide significance. However, both studies
suggested regions of interest (9p, 3q) for further research50;51. Therefore, a whole genome
association study in a sufficient large sample is warranted.
As twin studies consistently show that the concordance rate for monozygotic twins is always
less than 1.0, environmental/ cultural (non-genetic) factors also influence the development
of behaviour36. Environmental triggers for OCD are largely unknown, although the
frequency of stressful or traumatic life events is significantly higher during the year prior to
onset of OCD in both children and adults compared to normal controls52-55. Further, some
studies showed that exposure to an extremely upsetting event or emotional trauma
comorbid OCD can emerge in addition to the onset of post-traumatic stress disorder56;57. Yet,
other studies did not report such differences58.
In addition, family studies have revealed that parents of children with OCD suffer from
poorer mental health and have fewer coping strategies than parents of healthy children59.
Perinatal risk factors, such as edema or other illnesses during pregnancy requiring medical
care, prolonged or induced labor, forceps delivery have been reported to increase the risk of
Originally, Freud conceptualized adult neurosis as rooted in repressed sexual fantasies or
desires. He hypothesized that sexual conflict is a causal factor in the development of
obsessive compulsive disorder63 . Impaired sexuality is still frequently reported in patients
with OCD, but its significance largely neglected since it is nowadays thought to be
exclusively related to drug treatment. In chapter two we assessed attitude of OCD patients
towards sexuality and sexual functioning and the possible influence of medication.
A major limitation in previous studies on environmental factors and OCD is the fact that they
are correlational in design and therefore cannot provide conclusive evidence on causation.
Furthermore, previous risk factors are non-specific, as perinatal problems and sexual abuse in
childhood has been linked to several psychiatric diseases (e.a. Hyun (2000)64; Morrison
(1989)65; Moncrieff (1996)66).
Stronger causal inferences comes from: (1) the development of OCD following brain injury,
(2) neurosurgical lesions that attenuate OCD and (3) pediatric autoimmune neuropsychiatric
disorders associated with streptococcal infection (PANDAS)67. Many case studies report onset
of OCD after (traumatic) brain lesions in the basal ganglia68;69, OFC70;71 and frontal cortex69;72.
On the other hand, 2 case reports of lesions in the basal ganglia show an improvement of
pre-existing OCD symptoms73;74. In line with these results are promising results of
neurosurgical lesions which interrupt connections between OFC, ACC and subcortical
structures75 or deep brain stimulation of structures of the cortico-striatal-pallido-
thalamocortical loop in patients with treatment-resistant OCD76;77. Observations of a subset
of patients with rheumatic fever who had Sydenham’s chorea manifesting with OCD
symptoms have suggested a possible etiological link between group-A beta-hemolytic
Streptococcus pyogenes infection (GABHS) and a subset of OCD patients. In a case-control
study of Mell et al (2005), streptococcal infection seemed to double the risk for a first
diagnosis of OCD, TS, or tic disorder within the 3 months after infection, and multiple
infections seemed to approximately triple the risk for a first diagnosis within 12 months'
Besides triggering the onset of OCD, GABHS has been linked to exacerbations of OCD
symptoms79-81. Although, in a recent prospective, blinded case-control study of children who
met published diagnostic criteria for PANDAS, it was reported that while the rate of
exacerbations temporally linked to GABHS infections exceeded that expected by chance, the
large majority of clinical exacerbations could not be linked to antecedent GABHS infection82.
Some other factors hypothesized to moderate the waxing and waning course of OCD are
stressful life events and hormonal events. Rasmussen and Eisen (1991) found that patients
reported a worsening of OCD symptoms when experiencing every-day stressful life events83.
Similarly, children with OCD experienced significantly more daily stress when compared to
nonclinical controls84. The presence of one or more traumatic life events is associated with
increased OCD symptom severity, and specifically associated with compulsive hoarding85.
Hormonal events like premenstruum, pregnancy and postpartum period have also been
linked to exacerbations of OCD symptoms86-88. Preclinical evidence supports a role of ovarian
hormones in two rat models of OCD, which show fluctuation of perseveration and
compulsive lever pressing during the estrous cycle89;90. We were the first to carry out
prospectively an assessment of the reproductive cycle events and OCD symptom severity,
described in chapter three.
Neuroimaging and pathophysiology
Findings from neuroimaging, neuropsychological and neurosurgical studies in OCD patients
emphasize the role of the frontal cortex and the striatum. Parallel organizations of
functionally segregated circuits, which connect cortex, thalamus and striatum, have been the
basis of several neuroanatomical models of OCD91;92. Baxter and Modell introduced the
corticostriatal model of OCD in which positive feedback loops between the cortex and
thalamus accounted for obsessions, while the striatum was responsible for fixed action
patterns or compulsions21;22. During the last two decades, imaging studies elaborated the
evidence emphasizing abnormalities in the orbitofronto-striato-thalamic circuits in OCD
patients. In summary, results from recent quantative meta-analyses showed (1)
hypermetabolism in the orbital gyrus and head of the caudate nucleus (see meta-analysis
Whiteside 2004: 23-13 PET and SPECT studies)93, (2) reduced volume of the orbitofrontal
cortex (OFC) and anterior cingulated cortex (ACC, see meta-analysis Rotge, 2009: 41-21 MRI
studies)94, (3) increased thalamic volumes94-97 and (4) abnormal activation patterns of the
OFC, lateral frontal, ACC and parietal cortices during fMRI compared to controls (see meta-
analysis Menzies et al., 2008: 15 MRI studies)98. Less consistent results have been found for
the caudate nucleus with no changes in volume94;99, while functional studies showed only
increased activity in the head of the caudate compared to controls93.
However, many imaging studies have reported additional brain areas in OCD including the
parietal cortex and DLPFC31;100-102. Contemporary neuroimaging modalities using voxel-based
morphometry or diffusion tensor imaging support the corticostriatal model with grey matter
abnormalities involving orbitofrontal, thalamic, and striatal regions103-105, though
abnormalities were reported in additional brain areas as the anterior cingulate, and
temporolimbic cortex98;104;106;107. Hence, experts proposed a revised model for OCD in which
the underlying pathology involves the orbitofronto-striatal loop, together with the
amygdala, anterior cingulated loop and the dorsolateral prefronto-striatal circuit 98;108.
Increasing evidence shows that dopamine plays a pivotal role in the function of the
orbitofronto-striatal circuit109-111. The medial prefrontal cortex (mPFC), the OFC and the
nucleus accumbens are innervated by dopaminergic neurons of the ventral tegmental area,
which modulate reward processing and reversal learning112-115. Reversal learning is disturbed
in OCD patients and imaging studies show differential frontal-striatal and paralimbic activity
during reversal learning in patients with OCD compared to controls23;24. Furthermore,
abnormalities of the dopamine system, have been found in several imaging studies with
OCD patients, which show higher dopamine transporter (DAT) densities116-118 in tandem with
a down-regulation of the D2 receptor in the basal ganglia of OCD patients119;120. In addition,
one [(11)C]-SCH23390 PET study of Olver et al. (2008) showed reduced striatal D1 receptor
binding in OCD patients compared to controls121. Decreased availability of striatal D1 and D2
receptors in tandem with increased striatal DAT availability, which was found in 2 out of 3
SPECT studies in OCD patients compared to controls, confirm increased dopamine levels in
patients with OCD116;118. In addition, in a recent study of Wong et al. patients with Tourette
syndrome (TS) and comorbid OCD showed significantly increased dopamine release
compared to controls and higher dopamine levels than that seen in TS patients without
OCD122. These neuroimaging data together with data from animal studies, pharmacologic
challenge studies, genetic studies and pharmacotherapy studies allude to increased midbrain
dopamine neurotransmission123;124. However, direct observation of abnormalities in
dopamine function has remained elusive. In order to test the hypothesis that dopamine
release may be increased in OCD, amphetamine-induced changes in [11C]raclopride BPND were
assessed in drug-free patients with OCD compared to healthy controls in chapter four. The
theory of an increased level of dopamine is in line with the corticostriatal model of Baxter as
described earlier, since increased dopamine most likely results in a dominant D1- regulated
direct circuit in the basal ganglia, which net effect is excitatory. Successful treatment,
whether it be pharmacologic, behavioral, or by means of deep brain stimulation is
associated with a normalization of their metabolic activity125-128.
Cognitive behavioral therapy (CBT) and selective serotonin reuptake inhibitors (SSRIs) are the
only established first-line treatment options for OCD. In two recent meta-analyses it was
reported that patients receiving different types of cognitive and/or behavioral treatments
exhibited significantly fewer symptoms post-treatment than those on a waiting list129;130.
Addition of SSRIs or clomipramine to previous started CBT in patients with OCD did not
increase response rates131-134. On the other hand, augmentation of exposure and ritual
prevention in patients not responding to SSRI pharmacotherapy, did reduce OCD
symptoms135. A promising treatment option for facilitating extinction learning is D-
cyclosporine, which is a cognitive enhancer that stimulates the N-methyl-D-aspartate
(NMDA)-glutamate synapses to support short-term learning and memory when it is used in
combination with CBT136;137.
The discovery of antiobsessional properties of SSRIs and clomipramine implicated a key piece
of evidence of the brain serotonin (5-HT) system in the treatment of OCD. Currently, SSRIs
are the drug treatment of choice for OCD and a recent meta-analysis of Soomro et al. (2008)
demonstrated overall superiority of SSRIs compared to placebo in the short term (6-13
weeks), without significant differences between individual SSRIs138. Furthermore, another
review reported that SSRIs are effective long-term treatments (24 weeks) and prevent
relapse among adult treatment-responders139. Thus, inhibition of the serotonin transporter
(5-HTT) is required for antidepressants to be effective in the treatment of OCD. When
treatment was switched from clomipramine, a potent 5-HT reuptake inhibitor, to
desipramine, which is a noradrenergic reuptake inhibitor, relapse of OCD symptoms was
seen140. In addition, venlafaxine, which is a serotonergic and noradrenergic reuptake
inhibitor, showed similar efficacy to paroxetine141;142. However, inhibition of the 5-HTT does
not appear to be causally related to OCD. First, a major part of patients with OCD (40-60%)
do not respond to SSRIs. Symmetry and hoarding were associated with poorer treatment
outcome and initial severity of OCD was related to greater posttreatment severity of
OCD143;144. Second, high doses of SSRIs are necessary to reach maximum clinical effect in OCD
patients, with doses higher than needed to completely block the 5-HTT145;146. Third, the
synthesis of 5-HT in the brain depends on tryptophan availability, though no worsening of
OCD symptoms was seen after tryptophan depletion147-149. Fourth, it takes 6-12 weeks for
SSRIs to decrease obsessive-compulsive symptoms, whereas in depression therapeutic effects
can be seen earlier150;151. Time course of desensitisation of the 5-HT1B autoreceptor in OFC
corresponds with the delayed therapeutic response in OCD and higher doses of SSRIs are
needed to obtain the effect152;153. Finally, previous attempts to enhance serotonergic activity
to further improve OCD symptoms generally have not been successful. Of four studies
evaluating augmentation of SRIs with pindolol154-157, three produced negative results, as did
one study evaluating clonazepam158, one of two studies evaluating buspirone159;160, two
studies evaluating lithium161;162 and two studies evaluating inositol163;164. However,
augmentation with citalopram to clomipramine decreased OCD symptoms in approximately
50% of patients in an open-label trial165. Apparently, serotonin is not the only
neurotransmitter involved in OCD. As suggested in the previous paragraph, neuroimaging
data together with data from animal studies, pharmacologic challenge studies, and genetic
studies allude to increased midbrain dopamine neurotransmission123;124. These findings
prompted us to study the efficacy and tolerability of bupropion, which is a preferential
dopamine and norepinephrine reuptake inhibitor, in patients with OCD in chapter five.
Additional evidence confirming the role of dopamine in patients with OCD are beneficial
trials of atypical antipsychotics in OCD patients166. Therefore we conducted a narrative
review in chapter six to resume efficacy and tolerability of atypical antipsychotics in
monotherapy and add-on therapy in patients with primary and comorbid anxiety disorders.
Yet, previous trials mostly included treatment-refractory OCD patients, who may constitute a
subgroup of OCD patients. The results of augmentation trials in refractory OCD patients can
therefore not readily be expanded to all OCD populations. Consequently, in chapter seven,
we assessed the efficacy of quetiapine addition to citalopram in treatment-naïve or
medication-free OCD patients. However, addition with antipsychotics did not result in
complete symptom resolution in all OCD patients. Obviously, predictors of response may
help to tailor made treatment by reducing non response and unnecessary exposure to side
effects. One of the factors probably involved in explaining individual variations of response
to drugs are genetic differences. We determined in chapter eight and chapter nine whether
polymorphisms of the catechol-O-methyl-transferase (COMT), dopamine D2 receptor (DRD2),
serotonin transporter, 5-HT2A, and 5-HT1B receptor genes affect the efficacy of citalopram
plus quetiapine or placebo in 64 patients with OCD, who were drug-free or drug-naïve at
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