© Springer International Publishing Switzerland 2015
Lieuwe De Haan, Frederike Schirmbeck and Mathias Zink (eds.)Obsessive-Compulsive Symptoms in Schizophrenia10.1007/978-3-319-12952-5_99. Obsessive-Compulsive Symptoms in Schizophrenia: Neurophysiological and Neuroimaging Findings
(1)
DST-INSPIRE Faculty, Centre for Neuroscience, Indian Institute of Science, Bangalore, Karnataka, India
(2)
Department of Psychiatry & Translational Psychiatry Laboratory, The Schizophrenia Clinic, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, Karnataka, 560029, India
Abbreviations
ACC
Anterior cingulate cortex
CSF
Cerebrospinal fluid
DLPFC
Dorsolateral prefrontal cortex
LSD
Lysergic acid diethylamide
MRI
Magnetic resonance imaging
MRS
Magnetic resonance spectroscopy
NMDA
N-methyl-D-aspartate
OCD
Obsessive-compulsive disorder
OCS
Obsessive-compulsive symptoms
OFC
Orbitofrontal cortex
PET
Positron emission tomography
9.1 Introduction
Although schizophrenia and obsessive-compulsive disorder (OCD) are distinct nosological entities, obsessive-compulsive symptoms (OCS) and schizophrenia symptoms frequently coexist in a substantial proportion of patients; the prevalence of OCS in schizophrenia has been reported to range from 8 to 46 % (Eisen et al. 1997; Poyurovsky et al. 2004). Considering the lifetime prevalence of these two illnesses [(1–1.5 % for schizophrenia (Bland et al. 1987) and 2–3 % for obsessive-compulsive disorder (OCD) (Karno et al. 1988)], this co-occurrence of OCS and schizophrenia cannot be explained by mere chance (Tibbo and Warneke 1999). However, whether this co-occurrence is a co-morbidity or represents a distinct entity remains controversial. Nonetheless, some researchers have proposed a schizo-obsessive subgroup of schizophrenia as a separate diagnostic entity (Poyurovsky et al. 2012). This controversy is mainly based on clinical findings and only few studies have examined the neurobiology of OCS in schizophrenia. These studies have reported both overlapping and distinct neurobiological findings between schizophrenia patients with OCD and without OCD (Venkatasubramanian et al. 2009). In this chapter we will review the relation between schizophrenia and OCD in the context of neuroanatomical, neurochemical and neurodevelopmental abnormalities. Initially we will review the neuroimaging and neurophysiological findings in OCD and schizophrenia per se and later summarize the current knowledge regarding co-morbid OCS in schizophrenia.
9.2 Neuroimaging and Neurophysiological Findings in OCD and Schizophrenia
9.2.1 Neuroimaging Findings in OCD
Over the past two decades, different studies have indicated abnormalities of cortico-striato-thalamo-cortical circuits in the pathogenesis of OCD. Whereas increased regional grey matter volumes in basal ganglia structures – namely, bilateral lenticular nuclei, caudate nuclei and putamen – are reported in different meta-analyses (Peng et al. 2012; Radua and Mataix-Cols 2009), one meta-analysis did not find volumetric differences within the basal ganglia (Rotge et al. 2009). Increased grey matter volume has also been reported in the parietal lobule (Peng et al. 2012) and thalami (Rotge et al. 2010). On the other hand, a reduced volume of cortical regions – namely, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC) – has consistently been reported in all meta-analysis (Rotge et al. 2009, 2010; Peng et al. 2012; Radua et al. 2010). It is important to note that these regional differences are observed in the absence of global grey matter volume differences.
In addition to grey matter volume abnormalities, a recent meta-analysis also reported white matter abnormalities in the form of lower fractional anisotropy (FA) in the cingulum bundles, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, corpus callosum and anterior limb of the internal capsule and increased FA in the left uncinate fasciculus in OCD patients, again suggesting abnormality of frontal cortex connections (Peng et al. 2012; Koch et al. 2014). Positron emission tomography (PET) studies reported increased metabolic rates in the orbitofrontal cortex (OFC) and cingulate cortex in patients with OCD (Baxter et al. 1990; Saxena et al. 2001, 2004; Nordahl et al. 1989). Single photon emission computed tomography (SPECT) studies have reported equivocal findings with some reporting hyperactivity (Lacerda et al. 2003; Alptekin et al. 2001), whereas others did not find any changes (Crespo-Facorro et al. 1999; Busatto et al. 2000). Low metabolic rates in the striatum and thalamus have been reported in most (Saxena et al. 1999; Nordahl et al. 1989; Rauch et al. 2001) but not all studies (Perani et al. 1995).
In summary, these studies substantially support assumed abnormalities in the cortico-striato-thalamo-cortical circuitry in patients with OCD. The proposed circuit arises in the frontal cortex and projects sequentially to ventromedial areas of caudate nucleus, globus pallidus and mediodorsal thalamus before projecting back to the cortex (Bonelli and Cummings 2007). Increased excitatory output from the orbitofrontal/cingulate cortex and increased caudate activity are postulated to cause inhibition of the dorsal thalamus which in turn leads to decreased disinhibition and increased cortical activation (Baxter et al. 1992).
9.2.2 Neuroimaging Findings in Schizophrenia
Established concepts about the mechanisms of schizophrenia postulate a disruption in distributed functional circuits rather than an abnormality in a single brain region such as the prefrontal cortex (Keshavan et al. 2008). In addition to the frontal cortex, brain abnormalities in schizophrenia have been demonstrated in the basal ganglia, the thalamus and the cerebellum (Schultz and Andreasen 1999; Konick and Friedman 2001; Heckers 1997; Keshavan et al. 2008; Andreasen and Pierson 2008). Thalamus abnormalities have been reported in both structural and functional imaging studies (Hazlett et al. 1999; Rao et al. 2010); patients with schizophrenia had smaller thalamic volumes compared to healthy controls (Rao et al. 2010). Studies investigating the volume of the caudate nucleus are controversial with some finding enlarged volumes in schizophrenic patients (Swayze et al. 1992; Breier et al. 1992) and others finding decreased volumes (Keshavan et al. 1998; Shihabuddin et al. 1998). No difference in the size of striatal structures has also been reported (DeLisi et al. 1997). While the majority of studies in schizophrenia have focused on the DLPFC, only a few studies have focused on the OFC; both increased (Hoptman et al. 2005) and decreased volumes (Goldstein et al. 1999) have been reported in schizophrenia compared to healthy controls. Similarly findings are inconclusive with respect to anterior cingulate cortex; both decreased (Haznedar et al. 1997) and increased activation (Catafau et al. 1994) have been reported as well as both decreased volume (Noga et al. 1995) and the absence of differences (Nordahl et al. 1996). Andreasen et al. (1998) have hypothesized a prefrontal-thalamic-cerebellar-prefrontal pathway to explain the symptoms of schizophrenia. It is argued that the thalamus filters out unnecessary information and forwards only relevant information, and the deficit of this function may lead to positive symptoms in schizophrenia (Andreasen 1997). This theory of ‘input overload’ in schizophrenia has similarity to that proposed for OCD (Tibbo and Warneke 1999).
In summary, abnormalities of the frontal lobe, the basal ganglia, the thalamus and the cerebellum have been demonstrated both in schizophrenia and in OCD. Thus, reviewing literature on neuroanatomical circuits in schizophrenia and OCD reveals more similarities than differences. In fact, recent studies implicate comparable abnormalities in both schizophrenia and OCD (Kang et al. 2008; Kwon et al. 2003). Similarities between OCD and schizophrenia also emerge if one considers the gating or filtering of sensory information as playing a role in either illness.
9.3 Neuroimaging Findings of OCS in Schizophrenia
While a number of studies have examined the clinical characteristics and epidemiological features of OCS in schizophrenia, neuroimaging literature is sparse. Few studies have examined structural and functional abnormalities as possible distinct neurobiological underpinnings of a schizo-obsessive disorder. A study by Aoyama et al. revealed significantly reduced volumes of the left hippocampus, frontal lobes and anterior horn of the lateral and third ventricles in schizophrenia patients with OCS compared to those without OCS (Aoyama et al. 2000). The same study also found an inverse correlation between illness duration and frontal lobe size in schizo-obsessive patients but not in schizophrenia patients. These findings were replicated in another study which also demonstrated enlarged anterior horn of the lateral ventricle and the third ventricle in schizo-obsessive patients compared to schizophrenia only (Iida et al. 1998).
Similar to structural magnetic resonance imaging (MRI) studies, one functional MRI study reported the effect of OCS on brain activation; schizo-obsessive patients exhibited a negative correlation between activation of the left dorsolateral prefrontal cortex and OCS severity (Levine et al. 1998). However, a recent study did not report differences between schizo-obsessive and schizophrenia patients; authors examined working memory tasks in schizo-obsessive, schizophrenia and matched healthy volunteers and reported reduced activation in the right DLPFC and right caudate, as well as decreased functional connectivity (FC) in both schizo-obsessives and schizophrenia compared to healthy controls (Bleich-Cohen et al. 2014). Another recent functional MRI study utilized response inhibition and working memory paradigms to elucidate the effects of second-generation antipsychotic medication on the neural systems related to OCS in schizophrenia (Schirmbeck et al. 2014) (see Chap. 10). Altered brain activation (especially increased activation of OFC during response inhibition) related to the antipsychotic treatment might be a pathogenic mechanism in the development of antipsychotic-induced OCS in schizophrenia (Schirmbeck et al. 2014).
9.4 Neuropsychological Profile of OCS in Schizophrenia
Similar to neuroimaging studies, a possible neuropsychological profile of schizo-obsessive disorder has been investigated. The results are inconsistent when comparing findings to schizophrenia and OCD (for details, see Chap. 7). While few studies have reported deficits in different cognitive domains, namely, set shifting (Hwang et al. 2000; Lysaker et al. 2002; Patel et al. 2010), sustained attention (Lysaker et al. 2002), visuospatial perception, visual memory (Schirmbeck et al. 2013) and delayed visual memory (Berman et al. 1998), other studies have reported better performance on attention and psychomotor speed (Borkowska et al. 2003), set shifting (Borkowska et al. 2003), verbal fluency (Lee et al. 2009) and immediate visual recall (Lysaker et al. 2002) in patients with a schizo-obsessive disorder compared to schizophrenia. No difference between schizo-obsessive disorder and schizophrenia is also reported in attention (Berman et al. 1998; Tumkaya et al. 2009), response inhibition (Berman et al. 1998; Tumkaya et al. 2009; Lee et al. 2009; Patel et al. 2010), set shifting (Borkowska et al. 2003; Berman et al. 1998; Hermesh et al. 2003; Tumkaya et al. 2009), verbal fluency (Berman et al. 1998; Borkowska et al. 2003), planning and decision-making (Hermesh et al. 2003; Patel et al. 2010), visual memory (Tumkaya et al. 2009; Lee et al. 2009) and verbal memory (Tumkaya et al. 2009; Lee et al. 2009). In a recent study (Schirmbeck et al. 2013), schizophrenia patients with antipsychotic-associated OCS had greater deficits in visuospatial perception and visual memory, executive functioning and cognitive flexibility compared to schizophrenia patients without OCS. These differences were found to be longitudinally stable over 12 months. A recent meta-analysis found higher impairment in abstract reasoning in schizo-obsessive patients compared to patients with schizophrenia with no difference in performance on other measures of executive function (Cunill et al. 2013). A recent study that attempted to examine whether candidate cognitive endophenotypes may be used to validate a schizo-obsessive subtype found no differential cognitive impairment in this group of patients (Meijer et al. 2013). In the context of these findings, it has been suggested that the majority of previous studies, which investigated the cognitive profile of schizophrenia patients with OCS, might have been confounded by a greater severity of psychosis. Hence, further research examining patients and their unaffected relatives is warranted to clarify the nature of genetic and environmental factors in schizophrenia with co-morbid obsessive-compulsive symptoms (Meijer et al. 2013).
9.5 Neurophysiological Findings in Schizo-Obsessive Disorder
Only one study examined the neurophysiological abnormalities in schizo-obsessive patients using event-related potentials (ERPs) during a discriminative response task. The study reported a distinct ERP pattern, with abnormally increased target activation and reduced P300 amplitudes in a schizo-obsessive group in comparison to a schizophrenia group and an OCD group (Pallanti et al. 2009).
9.6 Neurochemical Circuit Overlap in Schizophrenia and OCD
Several neurochemical systems interact in both OCS and psychotic disorders, most importantly serotonin, glutamate and dopamine.
Serotonin
Serotonergic abnormalities are documented in both schizophrenia and OCD; elevated levels of 5-HT2 receptors are demonstrated in the frontal cortex in schizophrenia, and lysergic acid diethylamide (LSD), a 5-HT2 agonist, is a well-known psychotomimetic (Busatto and Kerwin 1997). Moreover, serotonergic modulation of dopaminergic function provides a viable mechanism in schizophrenia (Agid et al. 2008). Serotonergic abnormalities play a pivotal role as indicated by the differential efficacy of serotonergic reuptake inhibitors in alleviating OCS (Murphy et al. 1989) over noradrenergic tricyclic antidepressants like desipramine. In addition, serotonin transporter and serotonin receptor (Bengel et al. 1999; Mundo et al. 2002) abnormalities are documented in OCD.
Glutamate
Glutamate abnormality, mainly NMDA receptor deficiency, is one of the influential hypotheses for schizophrenia pathogenesis (Sodhi et al. 2008). The phencyclidine model of schizophrenia symptoms and up-regulation of glutamate receptor expression in the frontal cortex after chronic exposure to clozapine or olanzapine (Tascedda et al. 2001) provide further support to glutamate abnormalities in schizophrenia. In OCD, reports from neuroimaging, genetic and cerebrospinal fluid (CSF) studies support involvement of glutamatergic system in the pathogenesis of OCD (Bhattacharyya and Chakraborty 2007): (a) neuroimaging studies using magnetic resonance spectroscopy (MRS) consistently have demonstrated increased glutamate in caudate and frontal cortex (Rosenberg et al. 2000; MacMaster et al. 2008); (b) genes involved in glutamate transmission (SLC1A1) have been implicated in association studies (Dickel et al. 2006); (c) a CSF study examining glutamate levels has reported increased glutamate in OCD patients (Chakrabarty et al. 2005); and (d) the glutamate antagonist riluzole is useful in treatment refractory OCD (Coric et al. 2005).
Dopamine
The revised dopaminergic hypothesis of schizophrenia postulates a regional abnormality in the dopaminergic system and dopamine as the final common pathway in the pathophysiology of schizophrenia (Keshavan et al. 2008; Kapur et al. 2005; Meyer-Lindenberg 2010). In its current form, the dopamine hypothesis of schizophrenia postulates a hyperdopaminergic state in the mesolimbic pathway resulting in psychotic symptoms and a hypodopaminergic state in the frontal cortical terminal fields of the mesocortical dopamine neurons as the basis of the ‘negative symptoms’ of schizophrenia (Duncan et al. 1999).
Dopamine and serotonin abnormalities have been demonstrated in patients with OCD (Marazziti et al. 1992), and several lines of evidence from preclinical and clinical investigations implicate dopamine in the mediation of certain types of repetitive behaviour (Goodman et al. 1990). Antipsychotic augmentation of treatment with serotonin reuptake inhibitors (SRI) suggests that dopamine receptor antagonism may further reduce OCS severity in SSRI-refractory OCD patients (Bloch et al. 2006). In summary, studies show abnormalities of serotonin, glutamate and dopamine in schizophrenia as well as in OCD. However, no study has examined neurochemical abnormalities in schizo-obsessive patients compared to schizophrenia and OCD which would provide further insights into the underlying neurochemical changes.
9.7 Summary
In summary, this review of neurobiological findings points towards significantly shared structural and functional brain abnormalities, namely, frontal lobe dysfunction and basal ganglia dysfunction in both schizophrenia and OCD. The preliminary evidence also suggests a greater deficit in schizo-obsessive patients than schizophrenia patients without OCS on neuroimaging, neuropsychological and neurophysiological measures. However, the number of studies investigating schizo-obsessive patients is limited and inconclusive and warrants further examination in longitudinal studies with bigger samples to delineate the underlying neurobiology.
References
Agid O, Kapur S, Remington G (2008) Emerging drugs for schizophrenia. Expert Opin Emerg Drugs 13(3):479–495. doi:10.1517/14728214.13.3.479 CrossRefPubMed
Andreasen NC (1997) The role of the thalamus in schizophrenia. Can J Psychiatry 42(1):27–33PubMed
Andreasen NC, Pierson R (2008) The role of the cerebellum in schizophrenia. Biol Psychiatry 64(2):81–88. doi:10.1016/j.biopsych.2008.01.003, S0006-3223(08)00049-8 [pii]CrossRefPubMedCentralPubMed
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