Gray matter abnormalities in a drug resistant patient with early-onset schizophrenia: a case report and review of literature

doi:10.21203/rs.3.rs-1419874/v1

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Gray matter abnormalities in a drug resistant patient with early-onset schizophrenia: a case report and review of literature

https://doi.org/10.21203/rs.3.rs-1419874/v1

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Introduction. Neuroimaging studies have shown the presence of structural and functional brain anomalies at different stages of Schizophrenia. Structural and functional abnormalities affect the candidate brain areas for Schizophrenia and are associated with significant cognitive and behavioral impairment. Early-onset schizophrenia (EOS) is associated with poorer outcome if not diagnosed early and treated continuously.

Case presentation. We propose a detailed description of the volumetric variations in a 15-year-old female patient with Early-Onset Schizophrenia who developed drug resistance, and an overview of the main structural abnormalities reported in Schizophrenia. Moreover, we discuss the antipsychotic treatment effects and propose the possible consequences of drug resistance. Our clinical case shows a peculiar trend of volumetric variations probably due to drug resistance; furthermore, scientific findings converge on the presence of structural brain abnormalities at any age in Schizophrenia.

Conclusion. Based on the available findings so far, it is possible to affirm that, the antipsychotic treatment with atypical neuroleptics (especially if started early and effective on the first episode) might influence the development trajectories of cerebral nervous system in Early-Onset Schizophrenia.

structural MRI

early-onset schizophrenia

EOS

drug resistance

case report

The Early Onset Schizophrenia (EOS) represents 15% of all forms of psychosis. EOS occurs before the age of 18 and has a more severe prognosis as compared to Adult Onset Schizophrenia (AOS). Several studies have shown that the lack of early treatment in psychosis produces a longer duration of symptoms and represents an independent predictive factor for a worse prognosis [1, 2]. EOS is generally accepted as a chronic disorder with a heterogeneous genetic and neurobiological background, influencing early brain development and it is characterized by a combination of psychotic symptoms such as hallucination, delusions, disorganized thinking, loss of goal-directed behaviors, social withdrawal and cognitive deficits [3]. Several neuroimaging studies in Schizophrenia have revealed the presence of structural and functional brain anomalies at different stages of the disorder [4]. At structural MRI, compared to healthy controls, first episode drug-naive patients showed an enlarged lateral and third ventricles, an increased basal ganglia volume, a reduced gray matter (GM) volume of the whole brain, mainly on the hippocampus and the frontal and temporal lobes and a corpus callosum thinning [5, 6]. The most frequently reported functional alteration in the same patients are located in medial and dorsolateral prefrontal areas, thalamus and superior temporal gyrus [7, 8], as well as a resting-state fMRI study has found a focal area of functional anomaly in the left inferior frontal gyrus, also known as Broca’s area (or area 44 and 45 of Brodmann) [9]. Abnormalities in the frontal and temporal lobes, hippocampus, amygdala and basal ganglia were demonstrated in chronic patients at structural MRI [10]. Moreover, at functional MRI chronic patients showed cortical and sub-cortical functional alteration associated with cognitive and behavioral impairments [11] and mainly on the thalamus at a resting-state fMRI [9]. Overall, brain structural and functional alteration differentiate patients with Schizophrenia in different stages of their disorder from healthy controls with 80% sensitivity and specificity [12]. Here, we describe the peculiar trend of GM volumetric variations occurred in a 15-year-old female patient with EOS, that occurred after developing drug resistance due to incongruous interruption pharmacological treatment, previously treated successfully with risperidone at a dosage of 1.5mg/day. Furthermore, we propose a review of the literature concerning the structural anomalies and the effects that pharmacological treatment has on them.

Our patient is a 15 year old female born from term pregnancy with a history of normal motor, linguistic and cognitive development and good academic results. In January 2018, the patient presented a subtle change in her habitual behaviour with a decline in academic performance, social withdrawal, neglect in the person care and altered alimentary and sleep pattern. Cognitive assessment performed by the Standard Progressive Matrices showed a normal IQ (IQ = 105; average100 ± 15SD). The patient showed poor performance on measures of planning, short term verbal memory, working memory and attention. Moreover, evaluation of motor functioning performed by the Physical and Neurological Assessment of Subtle Signs (PANES) showed dysrhythmia and motor slowness in time motor tasks. Psychopathological evaluation performed by the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (K-SADS) showed the presence of acute psychotic symptoms, including visual and auditory hallucinations, paranoia, grossly disorganized speech and behaviour, associated with psychomotor agitation, anxiety and depressed mood. In February 2018, before starting the pharmacological treatment, a structural MRI was performed and subsequently the patient was treated with the administration of risperidone, gradually titrated up to the dose of 1.5mg/day and under pharmacological treatment her psychotic symptoms disappeared. In June 2018, following an incongruous interruption of pharmacological therapy by the patient due to poor parental care, a relapse of psychotic symptoms occurred. Risperidone (selective monoaminergic antagonist with high affinity for serotoninergic receptors 5-HT2A and dopaminergic D2 receptors) was introduced again at a dosage of 1.5mg/day without significant improvement in symptoms. Therefore, its dosage was increased up to 2mg/day without benefit. In July 2018, given the persistence of psychotic symptoms, risperidone was increased up to 3mg/day and lurasidone was added and titrated up to dose of the 74mg/day. Despite this, the patient continued to exhibit florid psychotic symptoms and consequently in August 2018 it was necessary to modify her pharmacological therapy. In fact, risperidone was gradually withdrawn and the suglopentixol was introduced and gradually titrated up to a dose of 10mg/day. The psychotic symptoms persistence imposed in September 2018 a new pharmacological treatment modification, consisting in gradually reducing lurasidone and introducing aripirazole, gradually titrated up to a dose of 15mg/day. Through this poly-pharmacotherapy, there was only a partial and transient psychotic symptoms reduction. Therefore, in November 2018 aripiprazole was reduced to a dose of 10mg/day and suglopentixol was increased to a dose of 15mg/day. In December 2018, the clinical course severity with hallucination, delusions, disorganized thinking and behavior, social withdrawal and cognitive impairment has imposed a further change in drug treatment. In fact, aripiprazole has been maintained at a dose of 10mg/day, suglopentixol has been reduced to a dose of 5mg/day and haloperidol has been added and gradually titrated up to a dose of 3mg/day in order to obtain a greater block of D2 receptors for dopamine. Despite this, our patient has not improved and her clinical history is suggestive of a significant pharmacological resistance, in which the use of clozapine is indicated. It was not possible to use this drug because of its complex management associated with the absence of a secure family support network. During this stage of the disorder, the patient was subjected to a second structural MRI.

In February 2018 (time T0) a first structural MRI was performed. Our patient was effectively treated with risperidone at a dosage of 1.5mg/day until June 2018. Following the incongruous suspension of antipsychotic treatment, a relapse of psychotic symptoms occurred and our patient showed resistance to treatment with both atypical and typical neuroleptics. In December 2018 (time T1), after 6 months of pharmacological resistance, a second structural MRI was performed. The cortical and subcortical areas brain analysis was performed through cortical surface-based analysis, consisting of automatic segmentation through the FREESUFER software. As per protocol, this segmentation used a high-contrast volumetric isotropic image between white and gray matter of the SIEMENS 3 Tesla tomograph. The neuroimaging data collected for our patient were compared with those of a control subject. 165 cortical and subcortical areas were considered, of which the volumetric difference between the first MRI at time T0 and the second MRI at time T1 was evaluated. Using the MINITAB v. 17, initially we have verified that these volumetric differences follow or not a normal distribution through the probability plot test for the normality evaluation. We found that considered volumetric (post-pre) differences distribution does not follow a normal distribution. Therefore, non-parametric tests have been chosen for statistical analysis. In particular, the Sign test for Median was used to verify that distribution of the volumetric differences was significantly different between our patient and the control subject. Furthermore, Mann-Whitney Test was used to verify that the volumetric differences distribution did not have the same median between our patient and the control subject. The differences distribution for the control subject does not have a significantly different median (p = 0.45 and median=-27 mm³). On the contrary, the differences distribution for our patient has a significantly different median from zero (p = 0.01 and median = 46 mm³). The two distributions have no equal median (p = 0.01). In our patient, we have found significant volumetric variations in specific brain regions before treatment and after drug resistance has been established. The POST-PRE difference is at least (in absolute value) of about 200 mm³ (value considered as a limit beyond which it cannot be a freesurfer segmentation error). The % POST-PRE difference is at least (in absolute value) 15% (value considered as a limit beyond which it cannot be a freesurfer segmentation error). The volumetric variations have a different trend depending on the brain areas considered and in particular some brain areas have a similar trend both on the left and on the right (in “WHITE” in Table 1) and others an opposite trend on the left and on the right (in “GREY” in the Table 1).

In our patient with regard to temporal cortex (superior and inferior temporal gyrus, superior and inferior temporal surface), frontal cortex (medial orbital surface, olfactory sulcus, rectum gyrus and subcallus gyrus), hippocampus, amygdala, thalamus, basal ganglia (caudate, putamen and pallidum) and cerebellum GM volumes decrease both on the left and on the right. On the contrary, with regard to other regions of frontal cortex (superior and inferior frontal gyrus, anterior and postero-dorsal cingulate cortex, inferior orbital cortex) and the precuneus of the superior parietal lobule GM volumes have an opposite trend on the left and on the right, or if they decrease to the left they increase to the right and vice versa (as an example see Figs. 1, 2, 3, 4 and 5).

Interestingly, in our patient the volumetric variations affect different brain areas that are candidates for Schizophrenia (SCZ). Several studies have shown that inside the temporal cortex the superior temporal gyrus (STG) represents a core cerebral cortical area for the pathophysiology of Schizophrenia [4, 13] and it is one of the most consistently reported region with reduced GM volumes in this disorder [14]. The STG play an important role in auditory processing, in language function, in auditory memory, in recognition of learned social-emotional values and non verbal cues [15–17]. The abnormality of STG-GM may be related to auditory and higher cognitive deficits in patients with Schizophrenia [18]. Moreover, STG connects to limbic system (hippocampus and amygdala), thalamus and the part of prefrontal cortex, which have been thought to be related to the pathophysiology of Schizophrenia, particularly in auditory hallucinations and disordered thoughts [19, 20]. Cortical thickness anomalies of the frontal lobe, interesting its various areas and specifically the prefrontal cortex, have been documented in Schizophrenia [21–23]. Frontal cortical areas are important for executive functioning and their volume reduction has often been reported to be associated with negative symptoms of Schizophrenia [24]. Hippocampal anomalies with an important role in the formation and emergence of Schizophrenia have been documented in this disorder: in fact, patients with Schizophrenia exhibit significant bilateral volume reduction and progressive hippocampal volume decrease in first-episode patients with Schizophrenia has been shown in many neuroimaging studies [25]. Moreover, inside the hippocampus smaller CA1 volumes and CA1 hyper-activation may be predictive of conversion in subjects at high risk of psychosis, as well as smaller CA1 and CA4/DG volumes in first-episode of Schizophrenia and more widespread smaller hippocampal sub-region volumes may be associated with longer duration of illness [26]. The thalamus holds a key anatomic position in the brain as part of the circuit that modulate perception, emotion and thinking and their integration in conscious experience [27]. Several studies have shown that the thalamic volume appeared to be reduced in patients with Schizophrenia [28]. The cerebellum is known to be involved with motor coordination, as well as with aspects of cognitive functioning such as attention, working memory and sensory discrimination [29] and this brain region has been implicated in the pathophysiology of Schizophrenia, especially with cortico-thalamo-cerbellar network [30]. In fact, decreased GM density in the vermis and tonsil of cerebellum [31] and decreased left cerebellar lobules VI and X volumes [32] are present at the early stage of Schizophrenia and appear to be associated respectively with nonverbal executive dysfunction and cognitive deficits [31, 32]. Numerous scientific evidence has documented the ability of antipsychotic medication to modulate brain morphology and produce volumetric change even over a short period of time [33]. Typical and atypical antipsychotics might affect brain structures differently due to their different pharmacological actions [34]. Based on our knowledge, studies on atypical antipsychotics seem to converge on their ability to maintain or increase the GM volume in Schizophrenia regardless of the age of onset of the disorder. Through structural RMI studies, some of which they have used region of interest technique and others voxel-based morphometry analysis, increased thalamus volumes in patients with schizophrenia was observed after use of atypical antipsychotics [13, 34–36]. It is believed that the thalamus can mediate the effects the clinical effects of antipsychotic drug due to its role in the integration and coordination of brain activity [37]. Moreover, exposure to antipsychotics has been shown to increase the expression levels of Fos-like protein in the midline thalamic nuclei and the use of atypical antipsychotics increases the thalamic N-acetyl-aspartate levels [38]. Increased frontal cortex volume, especially at the level of the prefrontal cortex, was found after atypical antipsychotic treatment in first episode of Schizophrenia [13, 39, 40]. Moreover, increased cortical thickness in the prefrontal cortex was associated with improvement of negative symptoms [39]. A decrease in negative symptoms has been related to dopamine release in the prefrontal cortex, which can be modulated by combined D2 and serotonin 5-HT2A receptor antagonism [41]. Atypical antipsychotics use has been found associated with an increased hippocampal volume and an increased BDNF levels in this brain region in patients at first episode of Schizophrenia [25]. Increased GM volume in cerebellum was found after atypical antipsychotic treatment in Schizophrenia [13, 41]. In a animal model atypical antipsychotics (clozapine) was associated with an increased NR2C expression in cerebellum relative to a typical antipsychotics (haloperidol) [29]. Findings from both cross-sectional studies of first-episode patients and longitudinal studies in Childhood-Onset and Adolescent-Onset Schizophrenia support the concept of EOS as a progressive neurodevelopmental disorder with both early and late brain abnormalities [42]. However, it is widely demonstrated that early antipsychotic treatment can significantly modify the course of the disease [43]. Despite this, the drug resistance issue cannot be overlooked. Kane and colleagues define drug resistance as the persistence of symptoms after at least three treatments with neuroleptic drugs of at least two different drug classes and last at least 6 weeks in the last 5 years [44]. Drug resistance may depend on several factors, such as pharmacokinetic and pharmacodynamic variables, neuro-immuno-endocrinological features, that could influence the subjective response to typical and atypical antipsychotics, duration of untreated psychosis (DUP), number of relapses, early onset of the disease and lack of treatment compliance [43]. In the case of our patient the drug resistance seems to be due to the lack of compliance with the treatment: in fact, it appeared after the risperidone incongruous interruption. This occurred during a critical period in the development of the central nervous system (CNS) and could explain the particular pattern of volumetric variations found in our patient through the structural MRI. In fact, GM volumes increase before puberty and decrease during adolescent through a competitive elimination of redundant synapses also known as synaptic pruning [42]. In a study of patients with Childhood-Onset Schizophrenia treated with clozapine compared to healthy subjects, no significant differences in cerebral volumes and lateral ventricles size were found [45]. Therefore, it appears that a clozapine successful treatment may lead to a convergence of the development trajectories of CNS between subjects suffering from EOS and healthy controls. Based on the clinical course of our patient, we hypothesize that early and effective treatment with risperidone and/or other atypical antipsychotic might have the same effect of clozapine on development trajectories of CNS. Therefore, the incongruous interruption of pharmacological treatment could have triggered a dysregulated pruning responsible for the drug resistance and volumetric variations observed in our patient by structural MRI.

Structural and functional brain abnormalities are now well documented in the EOS as well as in the AOS. This overview show that the structural anomalies consist mainly of a volumetric reduction the GM in the candidate brain regions for schizophrenia, such as superior temporal gyrus, prefrontal cortex, thalamus and cerebellum. Moreover, scientific evidence here summarized seems to support the hypothesis that atypical antipsychotics may favor the cerebral volumes normalization at the level of the candidate brain areas for Schizophrenia. Interestingly, the GM volume increase in some of these areas (e.g. prefrontal cortex and thalamus) secondary to exposure to atypical antipsychotics may be predictive of the pharmacological treatment efficacy. In this framework, the clinical case of our patient seems to show that the pharmacoresistance arosed in a critical period of the CNS development can lead to very particular trend of GM volumetric variations. Moreover, this particular pattern of GM volumetric variations also seems to coincide with a particularly unfavorable course of the disease. Although our data and our interpretative hypothesis need to be confirmed by further studies, it is possible to formulate at least two main reflections based on our clinical case, useful for improving management of patient with EOS and its therapy. Firstly, in the case of a positive response to neuroleptic treatment in the first episode, in order to prevent the drop-out would it be appropriate to switch to the administration of long acting injectable (LAI), which is still not widespread in children? Second, given the worse course and prognosis of EOS compared to AOS, would it be appropriate to review the criteria of drug resistance in developmental age?

Funding: No funds, grants, or other support was received.

Conflicts of interest/Competing interests: The authors declare that they have no conflicts of interest.

Ethics approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later

Consent to participate: Informed consent was obtained from the parent of the participant included in the study

Written Consent for Publication: Written consent for publication was obtained from the parent of the participant included in the study

Availability of data and material: Data are available on request from the corresponding author (SF)

Author Contribution: MBP and AP designed and coordinated the study. MBP, EB, VR and SS performed the clinical assessments. MM and MP performed MRI acquisitions; MM and SF performed statistical analyses. MBP wrote the first draft of the manuscript and AP and SF revised it. All authors made contributions in writing and discussing the manuscript. All authors have read and approved its final version.

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Gray matter abnormalities in a drug resistant patient with early-onset schizophrenia: a case report and review of literature

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