Baseline putamen volume as a predictor of positive symptom reduction in patients at clinical high risk for psychosis: A preliminary study

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Abstract

Objectives

Illness course in individuals at clinical high risk (CHR) status for psychosis is heterogeneous, which limits effective treatment for all CHR subgroups. Baseline predictors of positive symptom trajectory in the CHR group will reduce such limitations. We singled out the putamen, thought to be involved in the generation of the key schizophrenia symptoms early in the course of disease, as a potential predictor of positive symptom trajectory in CHR patients.

Method

We recruited 45 CHR patients and 29 age- and gender-matched healthy controls (HC). The CHR group was divided into patients with positive symptom reduction (CHR-R) and patients without positive symptom reduction (CHR-NR) at 6 months. Comparisons were made between the baseline putamen volumes of CHR-R, CHR-NR and HC groups. The relationship between baseline putamen volumes and clinical measures was investigated.

Results

Left putamen volumes of CHR-R patients were significantly smaller than those of HCs (p = 0.002) and of CHR-NR patients (p = 0.024). CHR-R patients had significantly reduced leftward laterality compared to HCs (p = 0.007). In the CHR-R group, bilateral putamen volumes were correlated with positive symptom severity at baseline (r =  0.552, p = 0.001) and at 6 months (r =  0.360, p = 0.043), and predicted positive symptom score change in 6 months at a trend level (p = 0.092).

Conclusion

Smaller left putamen volumes in CHR-R patients, and the correlation between positive symptom severity and putamen volumes suggest that putamen volume is a possible risk-stratifier and predictor of clinical course in the CHR population.

Introduction

The clinical high risk (CHR) state for psychosis is a heterogeneous population that is not only characterized by a heightened risk of transition to psychosis (Fusar-Poli et al., 2012a), but also by a range of comorbid psychiatric conditions (Fusar-Poli et al., 2014, Rietdijk et al., 2011, Rosen et al., 2006), as well as by cognitive (Fusar-Poli et al., 2012b), and functional deficits. Individuals who satisfy the criteria for the clinical high risk status have also been found to exhibit a number of structural (Meisenzahl et al., 2008, Nakamura et al., 2013, Peters et al., 2010, von Hohenberg et al., 2014) and functional brain changes (Dandash et al., 2014, Fornito et al., 2013, Lawrie et al., 2008), as reviewed previously (Fusar-Poli et al., 2011, Jung et al., 2012, Shim et al., 2010).

Recently, a trend of an increase in the proportion of CHR patients who never transition to psychosis has been observed (Simon and Umbricht, 2010, Simon et al., 2011). The majority of patients within the CHR cohort report a rapid improvement in their symptoms, and many undergo eventual remission (Lee et al., 2014) or report other residual psychiatric symptoms (Lin et al., 2015). Attempted early interventions include both nonpharmacological therapies such as intensive community care (Preti and Cella, 2010), cognitive behavioral therapy (de Koning et al., 2009), and pharmacological treatments such as antidepressants (Bowie et al., 2012, Fusar-Poli et al., 2014) and antipsychotics (Marshall and Rathbone, 2011, McGorry et al., 2009, Stafford et al., 2013). The heterogeneity in the CHR population and the low probability of transition, however, serve as deterrents in the development of optimal treatments for the entire spectrum of CHR patients. Stratification of the CHR population by identifying ways to predict the likely course that the symptoms of CHR patients will take will help uncover effective ways to treat even those help-seeking individuals who show persistent symptoms under current treatment regimens.

Presence and progression of positive symptoms, a hallmark in defining the onset of psychosis, are functionally (Agid et al., 2007a, Agid et al., 2007b, Sorg et al., 2013) and structurally (Taylor et al., 2005) tied to abnormalities in the striatum. Increased presynaptic dopamine synthesis (Howes et al., 2009, Kegeles et al., 2010) and altered functional connectivity (Dandash et al., 2014, Roiser et al., 2013) also precede the onset of psychosis and have been related to various measures of positive symptom severity. The role of the striatum in coding salience and value helps explain how striatal malfunction (i.e. misattribution of value or salience to irrelevant stimuli) results in the emergence of key symptoms such as delusions and hallucinations (Heinz and Schlagenhauf, 2010, Kapur, 2003). The striatum is ideally situated within the cortico-striato-thalamic circuitry in a spatially organized manner that makes the alterations in morphology of the striatum particularly revealing in disease states (Looi and Walterfang, 2013). A further role of the striatum underlying cognitive function also suggests the possibility that striatal morphology may already be abnormal in CHR individuals (Simpson et al., 2010).

The putamen, the dorsal portion of the input nuclei making up the striatum, principally receives inputs from the sensorimotor and associative cortices (Utter and Basso, 2008). Previous findings have highlighted abnormal dopaminergic function in sensorimotor and associative striatum in early stages of schizophrenia (Kegeles et al., 2010, Mizrahi et al., 2012). Volume changes in the putamen are closely related to response to antipsychotic treatment (Taylor et al., 2005), and to symptoms and course of disease in schizophrenia (Brandt and Bonelli, 2008). Additionally, the size of the putamen has been linked to severity of positive symptoms (Gur et al., 1998), treatment response (Li et al., 2012, Taylor et al., 2005), and outcome (Mitelman et al., 2009). Abnormalities in putamen volume are already apparent in patients experiencing the first episode of psychosis (Glenthoj et al., 2007), and healthy relatives with high genetic risk for psychosis (Dougherty et al., 2012, Seidman et al., 1997), in whom the putamen volume is decreased when compared to controls.

Whereas the exact neurobiological phenomena contributing to such volume changes remain obscure, the above findings single out abnormality in the structural measures of the putamen as a plausible candidate to predict course of the key symptoms, especially positive symptoms, of schizophrenia (Smieskova et al., 2010) early in the course of disease.

In our study, we first compared manually traced baseline putamen volumes of CHR patients who showed reduced positive symptoms (CHR-R) at 6 months, CHR patients who showed no positive symptom reduction (CHR-NR) at 6 months, and healthy controls (HC). Next, we investigated the relationship between putamen volume and other clinical variables in the CHR group. We hypothesized that baseline putamen volumes of CHR-R patients will be different from those of CHR-NR patients and HCs.

Section snippets

Subjects

We recruited 45 help-seeking individuals who visited the Seoul Youth Clinic from November 2004 to September 2014, and who met the criteria for a prodromal psychosis syndrome. History of psychiatric illnesses was screened by the Structured Clinical Interview for DSM-IV Axis I (SCID-I). Subjects with a diagnosis of a psychotic illness, substance dependence, neurological disorder, a history of significant traumatic brain injury, or any other significant medical condition possibly manifesting as a

Baseline demographic characteristics

There were no significant effects of group on age and parental social economic status (SES) among the CHR-R, CHR-NR, HC groups (Table 1). IQ and years of education differed among the three groups, with IQ being significantly lower in CHR-NR compared to HCs (p = 0.003) and in CHR-NR compared to CHR-R (p = 0.034), and years of education being significantly lower in CHR-R compared to HCs (p = 0.002). There were no significant differences in gender and handedness among the CHR-R, CHR-NR, and HC groups.

Clinical characteristics of the CHR group at baseline and at 6 months follow-up

Discussion

The main finding in this study is that left putamen volumes were significantly smaller in CHR patients who showed symptom reduction at 6 months of follow-up, compared to both healthy controls and CHR patients who did not show symptom improvement. In addition, we have found a significant negative correlation between putamen volume, and both baseline and follow-up PANSS positive symptom scores in the CHR-R group, whose baseline putamen volumes also predicted decrease of PANSS positive symptom

Conclusions

Abnormally small baseline putamen volumes, especially left putamen volumes, and reduced leftward laterality of putamen volumes were associated with positive symptom reductions at 6 months of follow up in our CHR patients, suggesting that such putamen volume abnormalities reflect a more favorable course of symptoms, possibly traceable to the presence of a neurological substrate of susceptibility to current treatment approaches before the onset of psychosis. Our study reveals the putamen as an

Contributors

Author Jun. Soo Kwon, Tae Young Lee were responsible for the design of the whole study and wrote the protocol. Author Sang Bin Hong wrote the manuscript. Author Sang Bin Hong, Tae Young Lee, Yoobin Kwak and Sung Nyun Kim supported the analysis, interpretation and manuscript revision. All authors contributed to and approved the final manuscript.

Role of the funding source

This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (Grant no. 2013R1A2A1A03071089).

Conflict of interest

All authors have declared that there are no conflicts of interest in relation to the subject of this article.

Acknowledgments

We special thanks go to the Min-Sub Shin, Soo-Hee Choi.

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