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Review Article
Neuroanatomical, Neurochemical, and
Neurodevelopmental Basis of Obsessive-Compulsive
Symptoms in Schizophrenia

Ganesan Venkatasubramanian, Naren P. Rao, Rishikesh V. Behere

ABSTRACT
The prevalence of the obsessive-compulsive symptoms in schizophrenia (OCSS) appears to be higher than that
expected on the basis of comorbidity rates. Review of brain abnormalities in schizophrenia and obsessive-compulsive
disorder (OCD) reveals involvement of similar regions namely the frontal lobe, the basal ganglia, the thalamus, and the
cerebellum, in both the disorders. Neurodevelopmental etiopathogenesis has been proposed to explain schizophrenia
as well as OCD. Significant overlap in neurotransmitter dysfunction (serotonin, glutamate, and dopamine) has been
documented between schizophrenia and OCD. The New-onset obsessive-compulsive (OC) symptoms have been
reported with the use of atypical antipsychotics in the schizophrenia patients In this background, OCSS is an emerging
area of recent interests. This article attempts to review the literature on the neurobiology of OCSS. Neuroimaging,
neuropsychological, and neuromotor abnormalities in OCSS discussed in the context of neurodevelopmental
etiopathogenesis suggest glutamate abnormalities in OCSS. Atypical antipsychotic induced OCSS points towards the
possible roles of glutamate and serotonin. Dopamine may be responsible for the beneficial role of antipsychotics
in the treatment of OCD. In summary, we propose that glutamate, serotonin, and dopamine abnormalities may be
the probable basis for OCSS.

Key words: Schizophrenia, obsessive-compulsive symptoms, neurodevelopment

INTRODUCTION the onset of OC symptoms can either precede

or be simultaneous with the onset of psychotic
The prevalence of obsessive-compulsive symptoms in symptoms. [6] We propose to label this group of
schizophrenia (OCSS) has been reported in the range of schizophrenia as DOCSS. Also, new-onset OC symptoms
8%–46%.[1,2] Considering the separate lifetime prevalence have been reported with atypical antipsychotics.[2,7] We
rates of the two illnesses [(1%–1.5% for schizophrenia[3] propose to label this group of schizophrenia as DIOCSS.
and 2%–3% for obsessive-compulsive disorder (OCD)[4]],
it seems that obsessive-compulsive (OC) symptoms and This review is divided into three sections. The first
schizophrenia coexist more often than chance.[5] section examines the relation between schizophrenia and
OCD in the context of neuroanatomical, neurochemical
For the purpose of this review, we have divided and neurodevelopmental abnormalities; second one
the OCSS into two groups: a) de-novo obsessive- reviews the neurobiological findings in OCSS; and
compulsive symptoms in schizophrenia (DOCSS), and the third attempts to explain the OCSS by proposing
b) drug induced obsessive-compulsive symptoms in a hypothetical neuroanatomical, neurochemical, and
schizophrenia (DIOCSS). In drug-naive schizophrenia, neurodevelopmental basis.

Department of Psychiatry, National Institute of Mental Health and Neurosciences, Bangalore, Karnataka, India

Address for correspondence: Dr. Ganesan Venkatasubramanian,

The Metabolic Clinic in Psychiatry, Department of Psychiatry, National Institute of Mental Health and Neurosciences, Hosur Road,
Bangalore-560 029, India. E-mail: venkat.nimhans@yahoo.com
DOI: 10.4103/0253-7176.53308

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Venkatasubramanian, et al.: Obsessive-compulsive symptoms in schizophrenia

Schizophrenia and OCD: Proposed neuroanatomical

Neuroanatomy circuits in schizophrenia

Proposed neuroanatomical circuits in OCD Recent concepts regarding the mechanisms of

Studies have shown abnormalities in the frontal schizophrenia postulate a disruption in distributed
cortex,[8,9] the basal ganglia,[10,11] the thalamus,[12,13] and functional circuits rather than an abnormality in a
the cerebellum in patients with OCD.[14] A functional single brain region such as, the prefrontal cortex.[25]
circuit for OCD involving the orbitofronto-striatal- In addition to the frontal cortex, brain abnormalities
thalamic pathway had been proposed. [15] Of the in schizophrenia have been demonstrated in the basal
ganglia, the thalamus and the cerebellum.[25-29]
most successful surgical operations for OCD, limbic
leukotomy combines bilateral cingulate lesions with Andreasen et al.,[23] have hypothesized a prefrontal-
lesions in the orbital medial frontal area, which contains thalamic-cerebellar-prefrontal pathway to explain the
fibres of the fronto-caudate-thalamic pathway.[16] The symptoms of schizophrenia. This approach highlights the
finding that OCD improves with ablation surgery of the importance of examining cortical-subcortical circuitry in
orbitofrontal area or the midline thalamic nuclei supports schizophrenia and examining the role of thalamus and
this hypothesized OCD circuit.[15] Abnormalities of the cerebellum in more detail.[23] It is argued that the thalamus
thalamus demonstrated in patients with OCD also filters out unnecessary information and forwards only
support the role of fronto-caudate-thalamic pathway relevant information and the deficit of this function may
in OCD.[13] Now, there is a substantial evidence from lead to positive symptoms in schizophrenia.[30] This theory
neuroimaging studies that, specific cortico-striatal- of “input overload” in schizophrenia appears very similar
thalamic-cortical circuits mediate OCD.[8,17] to that proposed for OCD.[5]

The OCD circuit arises in the orbital cortex and Neuroanatomical circuits
projects primarily on the ventromedial area of the in schizophrenia and OCD:
caudate nucleus, then the globus pallidus, the ventro- Conclusions
anterior and the mediodorsal thalamus, and back to the
cortex [18] The present functional theory of this OCD In summary, abnormalities of the frontal lobe, the basal
circuit depicts that increased excitatory output from ganglia, the thalamus, and the cerebellum have been
the orbitofrontal/cingulate cortex, or increased caudate demonstrated in schizophrenia and OCD. Thus, review
activity, causes inhibition of the dorsal thalamus, which of neuroanatomical circuits in schizophrenia and OCD
can lead to increased activation of the cortex due to loss reveals more similarities than differences. In fact, recent
of inhibition.[10] These findings are supported by the studies indicate similar abnormalities in schizophrenia
neuroimaging studies, which show increased activity in and OCD.[31,32] This similarity also emerges if one
the orbitofrontal cortex, the caudate, and the thalamus considers the gating or filtering of sensory information
and normalization after treatment.[19] as playing a role in either illnesses.

The fact that similar anatomical structures and parallel

The thalamus is an important component of this circuit
cortical-subcortical pathways have been independently
and plays an important role in filtering or “gating”
documented for both the illnesses, raises the possibility
sensory and motor information and, thus, in behaviour that a common functional aberration can lead to
modification. The multiple nuclei that constitute the the coexpression of what appears to be completely
thalamus have many diffuse projections to and from different symptoms. This is not to say that all patients
various regions of the cortex. Similar to the caudate, with schizophrenia and OCD share these aberrations,
the dorsal nucleus of the thalamus projects to the but it helps to explain the subgroup of patients who
orbitofrontal region and the mediodorsal nucleus share these symptoms and the relative frequency of
projects to the prefrontal cortex, although significant concurrent symptoms. In fact, it seems more plausible
overlap exists.[20,21] that these symptoms can often coexist than not.[5]
In conclusion, we propose probable fronto-caudate-
In addition to the fronto-strital-thalamic circuit, recent thalamic-cerebellar abnormalities in OCSS.
studies also suggest that cerebellum is involved in
the pathogenesis of OCD. Also, these studies provide Schizophrenia and OCD:
evidences for role of the cerebellum in OCD.[14,22] The Neurochemistry
cerebellum has connections with the thalamus[23] and
the basal ganglia,[24] and could play an important role Serotonin
in pathogenesis of OCD. In schizophrenia, serotonergic abnormalities in the

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Venkatasubramanian, et al.: Obsessive-compulsive symptoms in schizophrenia

form of elevation in the levels of 5-HT2 receptors have support the hyperglutamatergic state in pathogenesis
been demonstrated in the frontal cortex and LSD, a of OCD. This is in accord with proposed anatomical
5-HT2 agonist, is a well-known psychotomimetic.[33] substrates as glutamate is the primary excitatory
Serotonergic modulation of dopaminergic function neurotransmitter in fronto-striato-thalamic circuit.
provides a viable mechanism in schizophrenia.[34]
Dopamine
It is suggested that serotonergic abnormalities may The dopaminergic hypothesis of schizophrenia
play an important role in OCD and this is supported postulates that an aberration of the brain’s dopamine
by the observed differential efficacy of serotonergic transmitter systems is key to the pathophysiology of
reuptake inhibitors in alleviating OC symptoms.[35] schizophrenia.[25] In its current form, it assumess that
Drugs which lack serotonergic mechanism (for overactivity in the neurotransmission from dopamine
example, desipramine) are not effective in OCD. In cell bodies, located in the ventral tegmental area of
addition, studies have suggested association between the midbrain, results in the development of psychotic
OCD and serotonin transporter polymorphism as symptoms. In addition, a hypodopaminergic state in
well as serotonin receptor.[36,37] This evidence points the frontal cortical terminal fields of the mesocortical
towards role of serotonin in pathogenesis for OCD and dopamine neurons has been hypothesized to be the
schizophrenia. basis of the ‘negative symptoms’ of schizophrenia.[44]
Several lines of evidence from preclinical and clinical
Glutamate investigations implicate dopamine in the mediation of
Glutamate is increasingly implicated in pathophysiology certain types of repetitive behavior.[45] Dopamine and
of schizophrenia, and glutamate deficiency is one of the serotonin abnormalities have been demonstrated in
hypotheses, proposed to explain the pathophysiology patients with OCD.[46] Recent trials of combined SSRI
of schizophrenia.[38] Glutamate receptor expression and typical and atypical antipsychotic treatment suggest
was upregulated in the frontal cortex after chronic that dopamine receptor antagonism may further reduce
exposure to clozapine, and to a lesser extent to OC symptom severity in SSRI-refractory OCD patients,
olanzapine, but not with haloperidol.[39] The adaptive particularly for those with comorbid tic disorders.[47] It
mechanisms taking place in glutamatergic transmission may be also that some forms of OCD are associated
due to atypical antipsychotics might prove useful in with dysregulated dopaminergic function. In summary,
ameliorating some of the dysfunction observed in the studies show abnormalities of serotonin, glutamate, and
brain of schizophrenia.[39] dopamine in schizophrenia as well as in OCD.

However, not all patients respond to selective Schizophrenia and OCD:

serotonin reuptake inhibitors Selecive seretonergic
uptake inhibitors, and that indicates the involvement
Neurodevelopmental
of other neurotransmitters. Thus, the studies abnormalities
have examined various other neurotransmitters,
Schizophrenia and neurodevelopmental
dopamine and glutamate being the important.
abnormalities
Reports from neuroimaging, genetic, and
Several reasons have been advanced to support the view
course structure file (CSF) studies support the
that schizophrenia is a neurodevelopmental disorder.[48]
involvement of glutamate in the pathogenesis of
The primary reason is that the onset of schizophrenia
OCD. [40] Consistent use of neuroimaging studies
has a cumulative age incidence distribution, or
using MRS has demonstrated increased glutamate developmental function, that is nonlinear with a
in caudate and frontal cortex. [11,12] The glutamatergic peak change in slope or acceleration that usually
genes involved in glutamate transmission (SLC1A1) takes to occur during young adulthood. Given the
implicated in association studies.[41] It is important plausibility of the existence of brain abnormalities
to note that, till date none of the genes implicated in schizophrenia at the onset of the illness, [49] it
in serotonergic or dopaminergic transmission have further seems reasonable to conceive the onset of
attained significant value in genetic studies such as schizophrenia as a neurodevelopmental disorder.[50]
glutamatergic genes. The CSF studies examining the Further support has been provided by epidemiological
glutamate levels has reported increased glutamate in studies showing premorbid intellectual deficits dating
patients compared to the normal controls.[42] Recent back to early development[51,52] and neuropathological
open-label study using the glutamate, antagonist studies showing altered cerebral cytoarchitecture
Riluzole has shown efficacy of this agent in treatment of indicative of a developmental rather than an acquired
refractory OCD. [43] Overall, data from different studies encephalopathy. [53]

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OCD and neurodevelopmental with typical neuroleptics, a longer prodromal phase,

abnormalities and a predominance of negative symptoms. [59,61]
Neurodevelopmental etiology has been proposed in
Although OCD at times is episodic, with stress related schizophrenia with associated OC symptoms.[61]
exacerbations followed by partial remissions, there is
a substantial group of patients whose illness follows a Neuroimaging studies have demonstrated brain
chronic deteriorating course. These patients are more abnormalities in patients with schizophrenia and
likely to be men, with an early age of illness onset, and OCD. Neurodevelopmental abnormalities have been
comparatively severe symptoms. This is consistent with hypothesized to explain these brain abnormalities,
the predominance of males among childhood onset OCD, especially in patients with early-onset psychiatric illness.[62]
and the lower age of first admission and poorer outcome Patients with DOCSS have had their first professional
in males who develop OCD as adults.[54] Children with contact at a younger age compared to OCD patients.[63] In
OCD are also more likely to show neurological signs this context, the brain abnormalities in DOCSS suggest
than adults, with 80% exhibiting tics, and one-third probable neurodevelopmental etiopathogenesis.
displaying choreiform movements.[55] Neurological
soft signs such as involuntary movements, mirror Neuropsychology of DOCSS
movements, and disturbed fine motor coordination Berman et al., compared the neuropsychological
have been demonstrated in OCD.[56,57] OCD patients profile of schizophrenia patients with and without
with high soft sign scores have significantly increased OC symptoms.[64] Compared to non-OC schizophrenia
ventricular volumes compared to OCD patients with patients, those with OC symptoms performed worse
low soft sign scores and controled subjects.[58] These on visual-spatial skills, delayed nonverbal memory, and
data suggest the existence of a subgroup of patients, cognitive shifting abilities. In addition, the severity of
characterized by male sex, early onset, severe symptoms, OC scores correlated with poor performance in these
neurological signs, and a chronic course. Thus, this areas of cognition. Similarly, Lysaker et al.,[65] and Hwang
putative form of OCD, to a certain extent, resembles to et al.,[66] have demonstrated poorer executive function
neurodevelopmental disorders such as autism, dyslexia, in schizophrenia patients with OC symptoms than
and attention deficit disorder which has been termed those without OC symptoms. However, other studies
as ‘neurodevelopmental OCD’.[54] have not replicated these findings.[67] In an explorative
functional MRI study of schizophrenia patients with
varying degrees of OCD symptomatology, Levine et al.,[68]
Neurobiology of DOCSS: Is there have demonstrated negative relationship between OCD
a neurodevelopmental basis for symptomatology and activation of the left dorsolateral
DOCSS? prefrontal cortex, for a subgroup of patients.

Neuroimaging findings in DOCSS Together these findings suggest that patients with
In a Magnetic Resonance Imaging (MRI) study performed DOCSS may have poorer executive function, thus
on childhood- and adolescent-onset schizophrenia indicating poorer frontal lobe functioning compared
patients with OC symptoms, significant enlargement to patients with schizophrenia without OC symptoms.
of the anterior horn of the lateral ventricle, and the Frontal lobe dysfunction in schizophrenia could be
third ventricle had been demonstrated.[59] The ventricle- secondary to neurodevelopmental etiopathogenesis.
brain ratios (VBR) in male patients with schizophrenia Hence, we hypothesize that the poorer frontal lobe
or schizotypal personality disorder (SPD) who had functioning in patients with DOCSS may be secondary
prodromal symptoms of OCD, were compared to male to neurodevelopmental etiology.
patients with nonpsychotic OCD and normal male
comparison subjects using three-dimensional magnetic Neuromotor abnormalities in DOCSS
resonance imaging.[60] The VBR of the SPD group was In a study by Kruger et al,[69] schizophrenia patients
significantly larger, compared to nonpsychotic OCD group with OCD had more motor symptoms than non-OCD
or the comparison subjects. The patients with childhood- schizophrenic subjects. Tibbo et al,[70] have shown a trend
and adolescent-onset schizophrenia associated with OC in increased parkinsonian symptoms in schizophrenic
symptoms had significantly smaller left hippocampus patients with OCD than those without OCD. The
compared to schizophrenia patients without associated high prevalence of motor symptoms in these subjects
OC symptoms as well as healthy controls suggesting supports the hypothesis of a basal ganglia-frontal lobe
neurodevelopmental etiology in the former group.[61] connection linking OCD with schizophrenia.[70]
Childhood- and adolescent-onset schizophrenia patients
with prodromal OC symptoms were characterized by Basal ganglia dysfunction in schizophrenia has been
higher proportion of males, poor response of treatment hypothesized to be secondary to neurodevelopmental

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abnormalities.[71] In addition, neurodevelopmental state, [76] whereas schizophrenia is associated with

abnormalities have been hypothesized to explain glutamate deficiency. [75,77] As we have reviewed above,
neuromotor abnormalities in schizophrenia. [72] neurodevelopmental abnormalities may underlie
Fronto-striatal disorders have been explained by DOCSS. Since aberrant neurodevelopment is associated
neurodevelopmental etiopathogenesis. [73] Hence, with glutamate dysfunction, the paradoxical coexistence
we hypothesize that the fronto-striatal dysfunction (of OC symptoms and schizophrenia) could perhaps be
demonstrated in patients with DOCSS could be due to unstable prefrontal glutamate systems fluctuating
secondary to neurodevelopmental etiopathogenesis. between hyperactivity, producing OC symptoms, and
hypoactivity producing psychotic symptoms. Another
In summary, review of the neurobiological findings points possibility is that selected prefrontal glutamate
toward significantly increased, brain abnormalities, neurons are hyperactive while others are hypoactive
frontal lobe dysfunction, and basal ganglia dysfunction simultaneously. A third possibility is that prefronto-
(and thus fronto-striatal dysfunction) in DOCSS striatal glutamate neurons may be hyperactive initially
compared to schizophrenia patients without OC producing OC symptoms and may become intermittently
symptoms. Neurodevelopmental abnormalities have hypoactive due to exhaustion following periods of intense
been proposed to explain brain abnormalities, frontal hyperactivity. The first and the second possibilities may
lobe, and basal ganglia dysfunction in schizophrenia explain the simultaneous onset of DOCSS along with
(as reviewed above). In addition, fronto-striatal psychotic symptoms. The third possibility may explain
disorders have been explained by neurodevelopmental the onset of DOCSS preceding psychotic symptoms. This
etiopathogenesis.[73] Given this context, we hypothesize hypothesized model proposed to explain the paradox of
that the significantly excessive brain abnormalities and DOCSS is somewhat similar to the one proposed by
fronto-striatal dysfunction in patients with DOCSS may Carlsson,[76] to explain the paradoxical coexistence of
be secondary to neurodevelopmental etiopathogenesis. OCD and attention-deficit hyperactivity disorder.

It is possible that these neurodevelopmental abnormalities DIOCSS

demonstrated in the patients with DOCSS may simply
be reflective of the same in schizophrenia. However, It is still controversial whether antipsychotics ameliorate
schizophrenia patients with OC symptoms have or exacerbate OC symptoms.[78] The antipsychotics are
significantly more brain abnormalities than those useful as augmenting agents in treatment refractory
without OC symptoms. [61] Also, frontal lobe and OCD,[47] but at the same time, new-onset OC symptoms
basal ganglia dysfunction (and thus fronto-striatal have been reported with atypical antipsychotics.[2,7]
dysfunction) is more in schizophrenia patients with OC For the purpose of this review, we propose to label
symptoms than in schizophrenia patients without OC this as DIOCSS. Many case reports involve the use
symptoms.[65,66] Hence, we propose that DOCSS may of clozapine, risperidone, olanzapine,[2,7] quetiapine,[7]
indicate aberrant neurodevelopment. and clothiapine.[79] Larger trials have shown mixed
results,[80] with more recently, a positive correlations
with clozapine,[81] as well as a negative correlation
Neurodevelopment, glutamate, with olanzapine.[82] Most of the cases of DIOCSS
and DOCSS have involved schizophrenia patients on atypical
antipsychotics[7] and most commonly on clozapine.
Glutamatergic signaling is more than simply the
critical step in excitatory neurotransmission. The Serotonin and DIOCSS
spatial and temporal distribution of electrical activity The reports describing the beneficial effects of LSD,
is a key modulator of the constructive and destructive mescaline, psilocin, psilocybin, and peyote cactus in
processes that determine neuronal form and sculpt OCD, point to the beneficial role of 5-HT2A activation
the pattern of neural circuitry during ontogeny.[74] in improving OC symptoms.[83] DIOCSS have mostly
Glutamatergic receptors play an important role in been reported with atypical antipsychotics.[7] Atypical
regulating neuronal migration, neurite outgrowth, antipsychotics have an antagonistic effect at the 5-HT2
synaptogenesis, and the ‘pruning’ of supernumerary receptors.[84] Though, antipsychotic drugs such as
neurons by apoptosis.[75] Thus, glutamate plays a vital pimozide, haloperidol, fluphenazine, loxapine, and
role in neurodevelopment. thioridazine, have some antagonist activity at the
5-HT2A receptors,[85] exacerbation or induction of OC
The onset of DOCSS can precede the onset of symptoms has not been reported with these drugs.[86]
psychotic symptoms or be simultaneous with onset Furthermore, selective 5-HT reuptake inhibitors such
of psychotic symptoms.[6] The paradox of DOCSS as fluoxetine, paroxetine, fluvoxamine and citalopram,
is that OCD is associated with hyperglutamatergic also block the 5-HT2A receptors but they improve OC

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Venkatasubramanian, et al.: Obsessive-compulsive symptoms in schizophrenia

symptoms. 5-HT2c receptors have been implicated the treatment of OCD. Hence, in summary, we propose
in OCD.[87] Clozapine has the highest affinity for that glutamate, serotonin, and dopamine abnormalities
5-HT2c receptors among antipsychotic drugs.[88] In an may underlie the pathogenesis of OCSS.
in vivo electrophysiological study, Bergqvist et al.,[89]
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