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Selective Estrogen Receptor Modulation IncreasesHippocampal Activity during Probabilistic Association Learningin Schizophrenia

Jochen Kindler1,2,3, Cynthia Shannon Weickert1,2,4, Ashley J Skilleter1,2,4, Stanley V Catts5,Rhoshel Lenroot1,2,4 and Thomas W Weickert*,1,2,4

1School of Psychiatry, University of New South Wales, Randwick, NSW, Australia; 2Neuroscience Research Australia, Randwick, NSW, Australia;3Department of Psychiatric Neurophysiology, University of Bern, Bern, Switzerland; 4Schizophrenia Research Institute, Darlinghurst, NSW, Australia;5School of Medical Science, University of Queensland, Brisbane, QLD, Australia

People with schizophrenia show probabilistic association learning impairment in conjunction with abnormal neural activity. The selectiveestrogen receptor modulator (SERM) raloxifene preserves neural activity during memory in healthy older men and improves memory inschizophrenia. Here, we tested the extent to which raloxifene modifies neural activity during learning in schizophrenia. Nineteen peoplewith schizophrenia participated in a twelve-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of theSERM raloxifene administered orally at 120 mg daily to assess brain activity during probabilistic association learning using functionalmagnetic resonance imaging (fMRI). Raloxifene improved probabilistic association learning and significantly increased fMRI BOLD activity inthe hippocampus and parahippocampal gyrus relative to placebo. A separate region of interest confirmatory analysis in 21 patients vs 36healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship inthe parahippocampal gyrus of healthy controls. Thus, selective estrogen receptor modulation by raloxifene concurrently increases activityin the parahippocampal gyrus and improves probabilistic association learning in schizophrenia. These results support a role for estrogenreceptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women withschizophrenia.Neuropsychopharmacology advance online publication, 22 April 2015; doi:10.1038/npp.2015.88

INTRODUCTION

Probabilistic association learning requires gradual learning ofprobabilistic-based cueoutcome associations that is depen-dent on frontalparietalstriatal neural activity in healthyadults (Fera et al, 2005; Poldrack et al, 1999). Probabilityestimation (ie, determining the likelihood that a particularevent will occur) is a form of inductive reasoning that isrelated to categorization (Smith, 1989), integral to normalthought processing, and central to daily function, forexample, when determining whether or not to prepare fora rainy day on the basis of dark clouds in the sky or whendetermining how to respond appropriately on the basis ofsocial cues displayed by other people (Behrens et al, 2008;Poldrack et al, 1999; Weickert et al, 2009). People withschizophrenia display impaired probabilistic associationlearning concurrent with a reduction in frontalparietalstriatal neural activity (Weickert et al, 2009, 2010). However,

people with schizophrenia who are capable of learning theprobabilistic associations at levels comparable to healthycontrols display increased activity in an alternate neuralnetwork that includes rostral prefrontal cortex, anteriorcingulate, and the parahippocampal gyrus (Weickert et al,2009). Identification of ways to increase activity in nodes ofthis alternative neural network may bring about learningbenefits in schizophrenia. As sex hormones can have potenteffects on cognition and brain physiology (Li and Singh,2014; Sherwin, 2003), we predicted that treatment with aselective estrogen receptor modulator (SERM) could increaselearning and memory-related brain activity in men andwomen with schizophrenia.Many convergent, indirect lines of evidence from clinical

behavioral data to molecular neuropathology suggest thatestrogen signaling may be altered in the brains of people withschizophrenia. First, the onset of schizophrenia typicallyoccurs in close proximity to puberty during late adolescence(Lieberman et al, 2001), suggesting that sex steroid-triggeredmaturational changes may unmask vulnerability. Addition-ally, gender differences in symptoms of psychosis (Goldsteinand Link, 1988), age of onset, and course of schizophreniahave been well documented (Gur et al, 1996; Hafner, 2003).Low estrogen/testosterone levels in females/males with

*Correspondence: Dr TW Weickert, School of Psychiatry, University ofNew South Wales, Neuroscience Research Australia, Barker Street,Randwick, NSW 2031, Australia, Tel: +61 2 9399 1730, Fax: +61 29399 1034, E-mail: t.weickert@unsw.edu.auReceived 2 December 2014; revised 14 February 2015; accepted 9March 2015; accepted article preview online 1 April 2015

Neuropsychopharmacology (2015), 110 2015 American College of Neuropsychopharmacology. All rights reserved 0893-133X/15

www.neuropsychopharmacology.org

http://dx.doi.org/10.1038/npp.2015.88mailto:t.weickert@unsw.edu.auhttp://www.neuropsychopharmacology.org

schizophrenia, respectively, are related to worse negativesymptoms and cognition (Ko et al, 2006; Moore et al, 2013).Significant genetic associations of estrogen receptor alpha(ESR1) polymorphisms with schizophrenia and changes inESR1 mRNA in the brains of people with schizophrenia havealso been reported (Perlman et al, 2005, 2004; Weickert et al,2008). Taken together, these findings suggest that there maybe blunted sex steroid responses in the brains of people withschizophrenia.In humans, circulating estrogen is a potent regulator of

emotional responses (Amin et al, 2005), working memory(Keenan et al, 2001), and frontal cortex activity (Bermanet al, 1997), all of which are altered in major mental illness.Estrogen therapy has been shown to improve recovery fromacute psychotic symptoms by reducing both positive andgeneral anxiety symptoms of schizophrenia primarily inolder females, and also in women of childbearing age(Kulkarni et al, 2014). In general, estrogen has been shown toimprove cognitive function in non-psychotic elderly women(Hogervorst et al, 2000; Matthews et al, 1999), particularlywhen postmenopausal treatment is initiated early (Andersonet al, 2004). However, the usefulness of hormone-based treat-ments to improve cognition in premenopausal women withschizophrenia and in men with schizophrenia is unknown.Raloxifene is an SERM approved for use as an osteoporosis

preventative at a daily oral dose of 60 mg. A daily dose of120 mg raloxifene has also been shown to be effective inpreserving brain activity and maintaining cognitive functionin older men and women (Goekoop et al, 2006; Yaffe et al,2005). Raloxifene supplementation has also been shown toreduce positive and negative psychotic symptom severity inpostmenopausal women with schizophrenia (Kulkarni et al,2010; Usall et al, 2011). Moreover, a recent study reportedbeneficial effects of raloxifene on memory and executivefunction in postmenopausal women with schizophrenia(Huerta-Ramos et al, 2014). Additionally, we have foundthat 120 mg per day of adjunctive raloxifene administrationimproved both verbal memory and attention in men andwomen with schizophrenia (Weickert et al, 2015).In the present study, adjunctive raloxifene was adminis-

tered to men and women with schizophrenia at a daily oraldose of 120 mg using a randomized, double-blind, placebo-controlled, cross-over design functional magnetic resonanceimaging (fMRI) study during probabilistic associationlearning. Our hypothesis was that administration of theSERM raloxifene would improve probabilistic associationlearning and reverse abnormal brain activity in people withschizophrenia. An additional confirmatory analysis in alarger sample of people with schizophrenia and healthycontrols was performed to show that altered regional brainactivity identified during raloxifene treatment was related tolearning in schizophrenia.

PARTICIPANTS AND METHODS

Treatment Trial: Effects of Raloxifene on Neural Activityin Schizophrenia

Participants. Twenty-five chronically ill adults with a dia-gnosis of schizophrenia or schizoaffective disorder wererecruited into the study. All patients met the Diagnosticand Statistical Manual of Mental Disorders, 4th edition

(DSM-IV) criteria for schizophrenia or schizoaffective dis-order on the basis of the Structured Clinical Interview forDSM-IV Axis 1 disorders (SCID) (First, 2007). All participantswere screened for exclusion criteria, which included a concur-rent DSM-IV Axis I diagnosis other than schizophrenia orschizoaffective disorder, history of uncontrolled diabetes orcardiovascular disease including hypertension, recent alcohol/substance abuse (within the past 5 years), head injury with lossof consciousness, epileptic seizures, structural brain abnorm-alities, developmental disorders, mental retardation, and/orcentral nervous system infection. A four subtest version of theWechsler Adult Intelligence Scale, 3rd Edition (WAIS-III)(Wechsler, 1997) and the Wechsler Test of Adult Reading(WTAR) (Wechsler, 2001) were administered to all participantsto obtain estimates of current IQ and premorbid IQ inschizophrenia. All people with schizophrenia were receivingantipsychotic medication (95% receiving second-generationantipsychotics) for at least 1 year before participation. Allparticipants had normal vision or their vision was corrected tonormal with MRI-compatible lenses.

Mean daily dose of antipsychotic medication for eachperson with schizophrenia was converted to approximatedaily mean chlorpromazine (CPZ) equivalents dose usingstandard guidelines (Leucht et al, 2003). Symptom severity inpeople with schizophrenia was assessed with the Positive andNegative Syndrome

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