Schizotypal Personality Disorder: a Current Review (2014)

PERSONALITY DISORDERS (C SCHMAHL, SECTION EDITOR)

Schizotypal Personality Disorder: A Current Review

Daniel R. Rosell & Shira E. Futterman &Antonia McMaster & Larry J. Siever

# Springer Science+Business Media New York 2014

Abstract The study of schizotypal personality disorder(SPD) is important clinically, as it is understudied, challengingto treat, often under-recognized or misdiagnosed, and associ-ated with significant functional impairment. SPD also repre-sents an intermediate schizophrenia-spectrum phenotype, andtherefore, can provide a better understanding of the genetics,pathogenesis, and treatment of related psychotic illnesses. Inthis review we discuss recent findings of SPD related toepidemiology and functional impairment, heritability and ge-netics, working memory and cognitive impairments, social-affective disturbances, and neurobiology. Additionally, weexamine the challenges associated with treating patients withSPD, as well as clinical recommendations. Finally, we addressfuture directions and areas in need of further exploration.

Keywords Schizotypal . Schizophrenia . Personalitydisorder . Frontal lobe . Temporal lobe . Dopamine .Workingmemory . Cognition . Social cognition . Affect processing .

Magical thinking . Perceptual aberration . Suspiciousness .

Paranoia . Social anhedonia

Introduction

Introduced in DSM-III, the diagnostic construct of schizotypalpersonality disorder was derived from two converging lines ofinvestigation: 1) borderline personality conditions, which rep-resented a clinically identified and heterogeneous population

of functionally impaired patients that manifested a variety ofpervasive disturbances of interpersonal function, cognition,affect, and behavioral control, many of whom exhibited atten-uated schizophrenia-spectrum traits; and, 2) studies of non-psychotic family members of patients with schizophrenia whoexhibited chronic peculiarities of thought and communication,as well as impoverished social function. Accordingly, earlystudies of the SPD construct were either related to: 1) confir-mation of its utility in identifying non-clinical individualscarrying a genetic vulnerability to schizophrenia; or, 2) clari-fication of its clinical validity, particularly in comparison withthe borderline personality disorder (BPD) construct. There-fore, the significance of defining the diagnosis of SPD wastwo-fold: It was an important step in the refinement of present-day severe personality disorder syndromes; and, it has yieldedan operational definition of an intermediate schizophrenia-spectrum phenotype that can be used to investigate the path-ogenesis, genetics, and development of therapeutics of majorpsychotic disorders. Studies of SPD have increasingly focusedon schizophrenia-spectrum issues, and there has been relative-ly less emphasis on SPD as a clinical syndrome, in and ofitself. In this review we will discuss recent findings in SPDand schizotypy related to epidemiology and functional impair-ment, pathogenesis, cognitive impairment, and neurobiologi-cal findings. Additionally, clinical topics will be addressedregarding phenomenology, differential diagnosis, multidi-mensionality, and treatment considerations.

Diagnostic Criteria, Psychometric Structure,and Multidimensionality

The SPD diagnostic criteria for DSM-5 are essentially un-changed from DSM-IV-TR, and consist of: ideas of reference;odd beliefs or magical thinking; unusual perceptual experi-ences and bodily illusions; odd thinking and speech;

This article is part of the Topical Collection on Personality Disorders

D. R. Rosell : S. E. Futterman :A. McMaster : L. J. SieverIcahn School of Medicine at Mount Sinai, New York, NY, USA

D. R. Rosell : S. E. Futterman :A. McMaster : L. J. Siever (*)James J. Peters Veterans Affairs Medical Center, 130 WestKingsbridge Road, Room 6A44, Bronx, NY 10468, USAe-mail: [email protected]

Curr Psychiatry Rep (2014) 16:452DOI 10.1007/s11920-014-0452-1

suspiciousness or paranoid ideation; inappropriate or con-stricted affect; behavior or appearance that is odd, eccentric,or peculiar; lack of close friends or confidants, other than first-degree relatives; excessive social anxiety that does not dimin-ish with familiarity and tends to be associated with paranoidfears. Five of nine criteria are required for a diagnosis of SPD.

SPD (as well as schizotypy in non-clinical populations) hasconsistently been shown to be a multi-dimensional construct.Although not all studies are in agreement, analyses of SPDhavemost consistently revealed a 3 factor solution:Cognitive-perceptual (odd beliefs, perceptual disturbances, ideas ofreference, and paranoia/suspiciousness), Interpersonal (noclose friends, social anxiety, +/- restricted affect), anddisorganized/oddness (odd speech/thought, odd behavior,-/+ restricted affect). Assignment of restricted/inappropriateaffect to either the interpersonal or oddness factor appears todepend on whether assessment was performed by 1) self-report in non-clinical populations, as opposed to 2) semi-structured interview of SPD or personality disordered patients,respectively [1]. Therefore, as our focus is on clinical pop-ulations, and given the greater validity of personality assess-ment from semi-structured interview compared to self-report,we favor the inclusion of restricted affect in the oddnessdomain. More recently, four dimensional factors were re-solved among non-psychotic family members of schizophre-nia probands, consisting of: Negative schizotypy, positiveschizotypy, interpersonal sensitivity, and social isolation/introversion [2]. This four factor solution is similar to onedescribed using a self-report measure of schizotypy amongnon-clinical participants [3].

Recent findings however have indicated that despite thevalidity of such a 3-factor solution among the nine diagnosticcriteria of SPD criteria, only the cognitive-perceptual andoddness factors persisted when examining the factor amongall DSM-IV personality disorder criteria [1]. Moreover,when all DSM-IV personality disorder criteria were exam-ined, paranoia/suspiciousness was associated with a factorthat essentially consisted of Paranoid Personality Disorder(PPD) criteria; no close friendswas associated with the samecriteria from Schizoid Personality Disorder (SCPD); and,social anxiety was not related to any clinically coherentfactor. Moreover, the social anxiety and no close friendscriteria of SPD were significantly correlated with a number ofpersonality disorder diagnoses. Thus, the interpersonal do-main (as well as the paranoia/suspiciousness criterion) didnot appear to be useful in discriminating SPD from otherpersonality disorders. Cognitive-perceptual criteria (namely,ideas of reference, odd beliefs, and perceptual disturbances)have been shown to exhibit high sensitivity and moderatepositive predictive value (PPV) in terms of diagnosis ofSPD; Oddness criteria (odd behavior, odd speech/thoughtprocess, and restricted affect) exhibited the highest PPV forthe SPD diagnosis.

Epidemiology and Functional Impairment

The lifetime prevalence of SPD in the United States (US) hasrecently been estimated to be just under 4 %, with slightlyhigher rates among men (4.2 %) than women (3.7 %). Like-lihood of SPD was greater among black woman, those with alow income, and people who were separated, divorced, orwidowed; and, odds of SPD were lower in Asian men. Afteradjusting for sociodemographic parameters and comorbidi-ties, SPD remained significantly associated with bipolar Iand II disorders, PTSD, BPD, and narcissistic personalitydisorder (NPD). Additionally, even after adjusting forsociodemographic parameters and axis I and II comorbidities,patients with SPD had significantly greater disability thanthose without SPD [4].

Among a large, Norwegian cohort of treatment-seekingpersonality disordered patients, 1.37 % of patients met criteriafor SPD, and 21 % reported at least 2 SPD symptoms. One-third of SPD patients were not comorbid with any otherpersonality disorder, one-third had only one additional comor-bid personality disorder, and one-third of SPD patients werediagnosed with two or more additional personality disorders.In addition to PPD, antisocial personality disorder (ASPD)also occurred with greater frequency among patients withSPD compared to the total sample of personality disorderedpatients. Although cognitive-perceptual criteria of SPD werestrongly associated with a diagnosis of BPD, BPD occurredwith no greater frequency among patients with SPD than thetotal sample of personality disordered patients. SPD exhibiteda stronger association with obsessive-compulsive disorder(OCD) than other personality disorders [1].

While it is clear that SPD is a clinically and functionallydisabling condition, the basis of functional impairment and itsrelation to other phenomenologically similar personality dis-orders has not been fully elucidated. In terms of real worldfunctioning, patients with SPD have been shown to be lesslikely to live independently or have obtained a Bachelorsdegree than patients with avoidant personality disorder(AvPD) and healthy control participants. Both patients withSPD and AvPD earned a lower hourly wage compared tohealthy control participants, however. Using an interview-based assessment of functional capacity (UCSDPerformance-Based Skills Assessment or UPSA), SPD pa-tients demonstrated lower functional capacity than patientswith AvPD and healthy control participants. Similar to therole of cognitive dysfunction (working memory, processingspeed, executive function) as a major determinant of function-al outcomes in schizophrenia, functional capacity in patientswith SPD was shown to be significantly correlated to a com-posite measure of cognitive function. Similar to previousreports, cognitive function among SPD patients was shownto be poorer than among healthy control participants andpatients with AvPD [5].

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Similar results have been found when examining patientswith SPD, PPD, and comorbid SPD/PPD, compared to par-ticipants without either of these diagnoses. A diagnosis ofSPD or PPD was associated with cognitive impairment, andcomorbidity of SPD and PPD was not associated with worsecognitive performance over and above either disorder, alone.While a diagnosis of either SPD or PPD was associated withless likelihood of employment than patients without either ofthese diagnoses, these differences were found to be primarilydetermined by cognitive impairment. Even after adjusting forcognitive function, however, a diagnosis of SPD was associ-ated with employment at jobs involving less social contact;and a diagnosis of PPD was associated with lower likelihoodof having a history of competitive work for more than a year[6].

Pathogenesis of SPD

Heritability of SPD

Early studies revealed that SPDwas more common among therelatives of schizotypal probands, compared to those of fam-ilies with non-cluster A personality disorders [7]. Twin studieshave provided evidence that SPD is determined by bothfamilial-genetic and unique environmental factors [8, 9]. Ithas also been observed that SPD can manifest in three differ-ent phenotypic classes, which are associated with differingetio-pathogenic paths [10]. A prominent genetic contributionwas associated with a phenotypic class of SPD that exhibitedexceptionally high levels of odd appearance/behavior, restrict-ed affect/aloofness, as well as lack of close friends. A secondSPD class, marked by high levels of magical ideation andperceptual disturbances, was also determined by familial-genetic and unique environmental influences. A third SPDclass, however, consisting of moderately high levels of ideasof reference, social anxiety, and suspiciousness, but low levelsof odd behavior, odd speech, and constricted affect, did notexhibit heritability, but rather, appeared to be determinedentirely by unique environmental influences. In addition tothe categorical diagnosis of SPD, the heritability of psycho-metric schizotypy and associated dimensions has been exam-ined in non-clinical populations [11, 12]. These reports havedemonstrated that there are both liability factors that arecommon and specific to the various schizotypy measures/dimensions, that are determined by genetic and unique envi-ronmental influences.

Environmental Factors

Unique environmental factors (i.e., those not shared among allsiblings) are strongly suggested to be involved in the devel-opment of SPD, schizotypy, and specific schizotypal

dimensions. Similar to findings in schizophrenia, prenatalinsults, such as influenza exposure during the 6th month ofgestation (specifically, week 23) have been associated withhigher scores of schizotypal traits in an adult male population[13]. A number of forms of psychological trauma [14, 15] andchronic stress [16] have been associated with SPD. The effectof trauma on the development of schizotypal symptoms, how-ever, appears to be dependent on genetic background. Forexample, self-reported traumawas associatedwith schizotypalsymptoms in first-degree relatives of schizophrenic, but notbipolar, patients [17]. Further, this effect was specific forpositive schizotypal symptoms [17], consistent with the pres-ence of specific liability factors for particular schizotypydimensions. Interestingly, among family members of patientswith bipolar disorder, self-reported trauma was associatedwith increased schizotypal symptoms, but only in those car-rying a variant of the catechol-O-methyl transferease (COMT)associated with greater dopamine degradation [18].

Molecular Genetics

The COMT Val158Met polymorphism is one of the beststudied candidate schizotypy genes. The Val allele, which isassociated with greater enzymatic activity than the Met allele,has been shown to be correlated with greater levels of self-reported schizotypy [19]. There is variability as to whethersusceptibility to the pro-schizotypy effects of the Val COMToccurs in non-clinical participants [19], only among schizo-phrenia proband family members [20], or among bipolarproband family members with high levels of psychologicaltrauma. Moreover, while it appears the Val allele is associatedwith specific schizotypal dimensions, findings are mixed, asthere is evidence for the interpersonal/negative symptoms [21,22], cognitive-perceptual/positive symptoms [21], social andphysical anhedonia [20]. Effects of the Val158Met COMTpolymorphism on disorganization symptoms have been par-ticularly mixed, with certain studies showing a positive rela-tionship with the Val allele [22], and others with the Met allele[23]. Lastly, multiple studies have also implicated theVal158Met COMT polymorphism in cognitive functions thathave are impaired in SPD and the schizophrenia spectrum[2325].

A number of genes, originally identified due to an associ-ation with schizophrenia, have been shown to be related tospecific schizotypy dimensions and endophenotypes. Variantsof the CACNA1C gene, which encodes for a protein involvedin the function of L-voltage gated calcium channels, havebeen associated with schizophrenia and bipolar disorder. Werecently performed a study determining the relationship be-tween a CACNA1C polymorphism and schizotypal symptomsand SPD [26]. We found that the A allele of the rs10067373CACNA1C polymorphism was associated with paranoid idea-tion among non-clinical, healthy participants; and it was more

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common among patients with SPD relative to healthy controlparticipants. Furthermore, among patients with SPD, this allelewas associated with symptoms of paranoia at the level of astatistical trend [26]. In a study of a healthy, non-clinicalpopulation, common variants of the zinc-finger proteinZNF804Awere associated with positive schizotypal symptoms,namely, paranoia and ideas of reference, but not negativeschizotypal symptoms nor cognitive performance [27]. On theother hand, the Disrupted In Schizophrenia 1 (DISC1) gene,which is involved in neural cell development, is associated withthe negative schizotypy dimension, social anhedonia, in healthyparticipants; this effect was specific, as other dimensions, suchas perceptual aberrations and physical anhedonia were not in-volved [28]. In healthy participants, the interpersonal schizotypyfactor has been shown to be related to variants of the p250GAPgene, which is involved in N-methyl-D-aspartate (NMDA) re-ceptor function [29].

Neuropsychological and Cognitive Characteristics

Cognitive deficits represent one of the most functionally,clinically, and neurobiologically significant manifestations ofSPD and schizotypy. Prefrontal-dependent cognitive process-es particularly, working memory and context processing have received particular focus in studies of the cognitiveimpairments of SPD. In many ways, the intense focus oncognitive dysfunction in SPD has been largely driven by thecritical role of working memory impairments on functionaloutcomes in schizophrenia and the lack of efficacy of standardtreatments on cognitive function. Thus, characterizing work-ingmemory and other cognitive domains in SPD can allow forthe assessment of novel therapeutic agents and identificationof neurobiological correlates of cognitive deficits, withoutmany of the confounds associated with such studies in schizo-phrenia, e.g., concurrent/past psychotropic medications, stageof illness and psychosis, chronic, severe functional impair-ment. However, as discussed earlier, attentional and memorydifficulties are common complaints of schizotypal patients inthe clinical setting, therefore, characterizing the nature ofcognitive dysfunction is important for improving treatmentoutcomes in SPD, as well.

Studies have sought to identify relationships betweenschizotypal symptoms dimensions and cognitive dysfunction.We have previously demonstrated a correlation between thePaced Auditory Serial Addition Test (PASAT), an auditory,verbal working memory task that is particularly affected inSPD, and the interpersonal symptom domain [30]. Further, ithas been described that omission errors in a sustained atten-tion span task were positively correlated with interpersonalschizotypal traits in a non-clinical population, whereasdisorganization traits were related to false-alarm or commis-sion errors of sustained attention [31]. However, findings have

been mixed, as working memory deficits have also beenshown to be related to higher levels of positive and lowerlevels of negative schizotypy [32].

Current pathophysiologic models of working memory im-pairment in SPD (and the schizophrenia-spectrum, morebroadly), involve a hypodopaminergic state, particularly, infronto-cortical regions, and subsequent understimulation ofdopamine D1 receptors in the dorsolateral prefrontal cortex(DLPFC) [33]. A significant body of literature implicates theD1 receptor as a key modulator of DLPFC-dependent work-ing memory function. Studies in neuroleptic-nave patientswith schizophrenia have described increased fronto-corticalD1 receptor availability, which is believed to reflect a com-pensatory, albeit insufficient, upregulation of D1 receptorsowing to understimulation [34]. A relationship between great-er working memory deficits and higher prefrontal D1 receptoravailability in patients with schizophrenia has also been de-scribed, which has been interpreted as impaired workingmemory as a function of D1 receptor understimulation [35].In a recent study by our group we found that while there are nodifferences in fronto-cortical D1 receptor availability betweenpatients with SPD and healthy controls, similar to what hasbeen observed in schizophrenia, poorer working memoryperformance, as indexed by the PASAT, was correlated withgreater prefrontal D1 receptor availability [36]. We have pre-viously demonstrated that the mixed D1/D2 receptor agonist,pergolide, improves working memory function in patientswith SPD [37]. Further unpublished findings from our groupsuggest that direct D1 receptor stimulation in SPD patients,using the high-affinity, full D1 receptor agonist,dihydrexidine, enhance working memory in patients withSPD. Although less well studied than dopaminergic mecha-nisms, the noradrenergic system may also be involved in thecognitive deficits of SPD. Accordingly, we have describedenhancement of context processing in patients with SPD usingthe alpha-2a adrenergic receptor agonist, guanfacine [38].

In terms of anatomical correlates of cognitive dysfunction,we have previously described that the relationship betweengreater spatial working memory performance and larger ven-trolateral prefrontal cortex size, observed in healthy controlparticipants, was absent in patients with SPD [39]. The caudateor dorsal striatum, which receives input primarily from dorso-lateral prefrontal regions and has been implicated in higher-order cognitive processes, appears to be involved in the cogni-tive abnormalities of SPD. Specifically, caudate volumes havebeen shown to be smaller in patients with SPD, and greatervolume reduction was related to poorer cognitive performance[40]. These findings have been extended to examining moresubtle changes in caudate shape abnormalities; greater aberrantmorphology of the right caudate in patients with SPD was alsorelated to cognitive impairment [41, 42].

Functional imaging studies have also begun to reveal theneural substrates associated with working memory difficulties


in SPD. We have previously observed attenuated workingmemory-associated activation of the left ventral prefrontalcortex, superior frontal gyrus, intraparietal cortex and posteri-or inferior gyrus in patients with SPD compared to healthycontrol participants [43]. In a more recent study, activation ofthe left posterior cingulate gyrus, and deactivation of thesuperior temporal gyrus, insula and middle frontal gyrus wereboth attenuated during a working memory task in patientswith SPD compared to healthy controls [44]. Neural networksynchronization, as assessed with EEG, during a visual work-ing memory task was decreased in a non-clinical group withhigh- vs. low-psychometric schizotypy [45].

Social/Interpersonal and Affective Processing

A significant literature is emerging characterizing the social/interpersonal and affective dimensions of SPD andschizotypy. Pflum et al. have compared performance of twoTheory of Mind (ToM) tasks in non-clinical participants se-lected for either high levels of positive schizotypy (ChapmansMagical Ideation and Perceptual Aberrations scales) or nega-tive schizotypy (Chapmans Social Anhedonia scale). Theyfound that only the positive schizotypy group exhibited ToMimpairments, but specifically in a Hinting Task a social-cogntive ToM task in which participants have to infer themeaning of a fictitious characters remark [46, 47]. No groupdifferences were observed for the Reading the Mind in theEyes Test (RMET) a social-perceptive ToM task in whichparticipants have to infer mental states based on static visualstimuli of facial expressions that only includes peri-orbitalfeatures [46]. A measure of referential thinking, however,which is related to positive schizotypy, but not specificallyMagical Ideation and Perceptual Aberrations, was associatedwith the RMET, such that greater levels of referential thinkingwere associated with poorer RMET performance [46].

Abbot et al. have performed studies similar to those de-scribed above in non-clinical participants with psychometri-cally determined schizotypy (using the SPQ rather thanChapmans scales) with two different tests of affect recogni-tion [48, 49]. In one study using pictures of faces withdifferent emotions, the interpersonal factor of the SPQ (whichconsists of social anhedonia, constricted affect, and socialanxiety) was associated with reduced accuracy of facial affectrecognition; moreover, the social anxiety component of theinterpersonal factor was particularly involved in this correla-tion [49]. No relationship was found, however, for thecognitive-perceptual SPQ factor (a measure of positiveschizotypy) and facial affect recognition [49]. The samegroup, however, found strikingly differing results when usingan affect identification task that involved more complex anddynamic stimuli, i.e., a brief audio/visual vignette of a socialinteraction [48]. Both total schizotypy (total SPQ score) and

positive schizotypy (cognitive-perceptual SPQ factor) wereassociated with poorer recognition of positive and negativeemotions [48]. However, negative schizotypy (interpersonalSPQ factor) was only associated with impaired recognition ofpositive emotions [48]. The disorganization SPQ factor wasnot related to emotion recognition [48].

We have recently reported a study using the EmpathicAccuracy task (EA) a multimodal, dynamic task whichassesses how well an individuals assessment of a targetsaffect is compared to the targets own assessment [50] inpatients with SPD compared to healthy controls [51]. Ourmain finding was that the group of patients with SPD exhib-ited poorer performance on the EA task when assessing neg-ative affect, compared to controls; but no group differenceswere observed for assessment of positive affect [51]. More-over, the two groups did not differ on the RMET [51]. Noclear association was found between severity of SPD symp-toms or SPQ total or individual factor scores with EA perfor-mance [51]. However, a significant effect was found, indi-cating greater impairment on negative valence EA perfor-mance was associated with poorer social support [51]; thus,identifying a correlate between a laboratory social cognitivetest and a real world social functional outcome.

In addition to understanding the mental states of others,studies have examined affect processing and regulation inpatients with SPD, and characterized the differential contribu-tion of the various schizotypy factors. For example, an earlystudy by Henry et al. examined emotion regulation strategiesin non-clinical participants with low and high levels of psy-chometric schizotypy (as assessed by the SPQ). Generallyspeaking, participants scoring high on the SPQ exhibitedimpairments in emotion amplification but not emotion sup-pression [52]. Moreover, it was the negative or interpersonalSQP factor particularly, blunted affect that was associatedwith impaired emotion augmentation [52]. Additionally,blunted affect was shown to be associated with an increaseduse of emotional regulatory process, suppression [52]. Using alaboratory task assessing the effect congruent vs. incongruentemotional primers have on identifying the correct emotionalvalence of a target, Martin et al. demonstrated that a non-clinical group scoring high on social anhedonia (a negative orinterpersonal schizotypy dimension) exhibited greater inter-ference from incongruency of emotional valence betweenprimer and target than did the controls or the schizotypy groupscoring high on cognitive-perceptual traits (a positiveschizotypy dimension) [53].

Brain imaging studies have begun to shed light on theneural substrates of social/interpersonal and affective process-es associated with SPD. We have recently demonstrated thatpatients with SPD exhibit exaggerated habituation of amyg-dala response to affectively valenced social visual stimulicompared to healthy control participants [54]. Premkumaret al. have characterized differences in neural activity patterns


in response to social rejection in low- vs. high-schizotypy,non-clinical participants. They found that in response to socialrejection activity in the dorsal anterior cingulate cortex(dACC), right superior frontal gyrus, and left ventral prefron-tal cortex increased and decreased in the low- vs. high-schizotypy group, respectively [55]. Using fMRI, Solimanet al. examined the activity of striatal, cortical, and limbicregions to laboratory induced psychological stress, and dem-onstrated that non-clinical participants scoring high on phys-ical anhedonia (a facet of negative schizotypy) exhibitedgreater stress-induced deactivation of striatal and limbic re-gions compared to control participants and those scoring highon perceptual aberration (a facet of positive schizotypy) [56].Additionally, across all participants, physical anhedonia wascorrelated with stress-associated striatal deactivation [56].Interestingly, as described in the Neurochemistry section, thissame group observed in a separate study that participantsscoring high for physical anhedonia exhibited greaterstress-induced release of presynaptic dopamine, com-pared to controls and participants with high levels ofperceptual aberrations [57].

Neurobiological Studies: Structural and NeurochemicalFindings

Structural Neuroanatomy

Numerous studies have examined differences in the size ofspecific brain regions in SPD and schizotypy in comparison tohealthy participants, patients with schizophrenia, and otherpersonality disorders. A number of recent reviews have com-prehensively discussed neuroanatomical findings in SPD,therefore, we will highlight overarching patterns and recentstudies, here.

Temporal Lobe One of the most consistent findings in SPDhas been temporal lobe volume reductions, possibly specificto the left hemisphere. Generally speaking, temporal lobevolume reductions in SPD are similar to those observed instudies of schizophrenia, but occur in a more restricted pattern[58, 59, 60]. Although not invariantly observed, reducedsize of the left superior temporal gyrus (STG) has receivedsignificant attention [60, 61]. However, the fusiform andmiddle temporal gyri have also been found to be reduced,but not the inferior temporal gyrus [59]. Recent studies havedemonstrated that not only do the temporal lobe volumereductions in SPD occur in a more anatomically restrictedmanner than they do in in schizophrenia, but temporal lobevolume reductions appear to be progressive over time inschizophrenia, whereas in SPD they are relatively stable[59, 60]. Generally speaking, involvement of the left tem-poral lobe suggests both auditory and language-related

processes may be affected. Studies have demonstrated corre-lations between lower temporal lobe size with poorer logicalmemory [62], the odd speech SPD diagnostic criterion [61],and possibly, cognitive-perceptual symptoms [58].

Frontal Lobe Frontal lobe findings in SPD are of particularinterest given the importance and recent focus on cognitiveand working memory impairments in the schizophrenia-spectrum. However, unlike temporal lobe differences in SPDwhich have been relatively consistent between studies andsimilar although narrower in scope relative to those of schizo-phrenia, frontal lobe findings in SPD have beenmore variable.For example, we have demonstrated prefrontal cortex graymatter volume reduction in schizophrenia compared to bothSPD patients and control participants; but, we did not observesignificant differences between the SPD and control groups.Moreover, we found volume differences of Brodmanns area(BA)10 a prefrontal region in SPD and schizophrenia werecontradistinctive. In other words, BA10 was increased inSPD, compared to controls and patients with schizophrenia,and decreased in schizophrenia compared to controls and SPDpatients. However, a recent study of neuroleptic-nave menwith SPD demonstratedwidespread reductions in cortical graymatter volumes, including the frontal lobe; and no regionswere identified with larger cortical volumes [63]. To com-plicate matters further, in studies of healthy, non-clinical par-ticipants those with high psychometric schizotypy demon-strated greater prefrontal [64] and global cortical gray mattervolumes [65]. This has led to the hypothesis that generalsparing of frontal lobe involvement in SPD, relative to thatof schizophrenia, represents a protective factor against thedevelopment of frank psychosis.

Striatum In addition to cortical regions, such as the temporaland frontal lobes, structural and anatomical differences of thestriatum have also been examined in patients with SPD. Thestriatum plays an essential role integrating cortical, thalamicand other subcortical processes in order to promote coherentsensori-motor, cognitive, and emotional/motivational func-tion. While findings have been inconsistent, some generalpatterns have begun to emerge. Regions composing the asso-ciative striatum most of the caudate and the pre-commissuralputamen have generally been implicated. Initial reports fromour group described smaller putamen volumes of patients withSPD compared to controls, whereas putamen size in patientswith schizophrenia was relatively larger than that of controlparticipants [66]. No differences of caudate volumes wereobserved, however. These findings suggested that smallerputamen volumes might reflect a compensatory changeagainst pathogenesis of an overt psychotic syndrome. How-ever, more recently, in a larger study of antipsychotic naveSPD patients, we observed increased putamen volumes, spe-cifically in the ventral and dorsal aspects [67]. Again, no


differences in caudate volumes were observed. Interestingly,greater putamen size correlated with less severe paranoidsymptoms. Therefore, it was proposed that increased putamenvolumes in SPD patients may be a protective factor againstdevelopment of psychosis. Discrepancy with our earlier studywas attributed to differences in sample size, gender ratios,medication history, or heterogeneity of the disorder. Never-theless, larger putamen size in SPD patients was consistentwith larger putamen volumes in schizophrenic patientswith better outcomes (possibly reflecting therapeuticsensitivity to antipsychotics) compared to poor-outcomeschizophrenia patients [68].

A separate group has also examined striatal neuroanatomyin patients with SPD, but have found abnormalities of caudate,rather than putamen, volume and morphology. They haveconsistently found smaller caudate volumes in SPD patientscompared to control participants. Moreover, they have foundglobal and regional morphological abnormalities of the cau-date nucleus in patients with SPD, most marked in the rightcaudate head. Generally speaking, these caudate volume dif-ferences correlated with cognitive impairments [4042, 69].

Other Regions and Structural Connectivity Structural abnor-malities of the cingulate gyrus, a limbic cortical region thatoverlays the internal capsule and is involved in a range ofcognitive/attentional and motivational/emotional functions,have also been described in SPD. We have previously ob-served reduced gray matter volumes in the anterior and pos-terior cingulate gyrus [58]. Findings in schizophrenia weresimilar to those of SPD patients, particularly with respect toreduced BA31 volumes [58]. Furthermore, we have found thatcomorbidity of SPD in patients with BPD was associated withaccentuated or additional gray matter loss of the posteriorcingulate, compared to BPD patients without SPD [70]. How-ever, not all studies have found volumetric differences in theanterior cingulate in SPD patients [71]. One group, however,has described that the right-greater-than-left asymmetry of theanterior cingulate observed in healthy female participants isabsent among female patients with SPD [72].

Studies have also begun to examine structural connectivity,using diffusion tensor imaging (DTI), which can be used toassess fiber tract integrity [73]. In patients with SPD, lowerfractional anisotropy (FA) of the uncinate fasciculus (UF),which is involved in fronto-temporal connectivity, was ob-served in SPD patients compared to healthy control partici-pants [74]. However, no differences in the integrity of thecingulum bundle (CB), another important fiber tract bundleinvolved in connectivity of prefrontal, temporal, and parietalcortices, were observed between SPD patients and healthycontrol participants. Finally, lower left UF cross-sectional areapredicted poorer cognitive performance, whereas lower rightUF area was correlated with greater SPD interpersonal symp-tomatology [74]. In accordance with these findings, FA of the

right UF has also been shown to correlate with the personalitytrait, extraversion, in patients with SPD but not in healthycontrol participants [75]. Our group recently examined theintegrity of the anterior limb of the internal capsule (ALIC)which carries fibers between the thalamus and frontal lobe inpatients with SPD. We found decreased volumes of the mid-ventral portion of the ALIC in SPD patients comparedto controls; and, fewer fiber tracts in the dorsal portionof the ALIC terminating in BA10 but not BA45. Fur-thermore, fewer dorsal-ALIC fibers correlated withgreater severity of total SPD symptomatology [76].

Dopamine Neurochemistry

Consistent with the role of the dopaminergic system in schizo-phrenia, studies have also begun to alterations in characterizedopamine neurochemistry in SPD using methods such aspositron emission tomography (PET) and single photon emis-sion computed tomography (SPECT) imaging. In an earlystudy from our group [77], we used SPECT imaging to char-acterize striatal presynaptic dopamine release by examiningthe degree of amphetamine-induced displacement of the D2receptor radioligand, [123I]IBZM: greater presynaptic dopa-mine releasing capacity is associated with greater decreases in[123I]IBZM binding after amphetamine challenge. No differ-ences in striatal [123I]IBZM binding were observed betweenSPD patients and healthy control participants, indicating nosignificant differences in striatal D2 receptor availability, it-self, in SPD patients. However, post-amphetamine decreasesin striatal [123I]IBZM binding SPD patients were almosttwice that of healthy control participants, suggestive of rela-tively greater presynaptic dopamine release in SPD patients.Moreover, the degree of presynaptic dopamine release in SPDpatients was similar to that observed in patients with remittedschizophrenia, but approximately half that of schizophrenicpatients with an acute exacerbation of symptoms [77].

Further published studies have examined dopaminergicneurochemistry in healthy, non-clinical participants character-ized with well validated self-report scales of schizotypy.Stress-induced striatal dopamine release, as indexed by com-paring striatal [11C]raclopride binding during a control and amental arithmetic task, was shown to be elevated only in agroup scoring high on a measure of negative schizotypy(Chapmanns Physical Anhedonia scale), but not in a groupscoring high on a measure of positive schizotypy group(Chapmanns Perceptual Aberration scale) nor in a controlgroup [57].

Examining amephtamine-induced changes in [11C]fallypridebinding, the association between presynaptic dopamine releaseand schizotypal traits was examined in healthy participantsassessed with the schizotypal personality questionnaire (SPQ)[78]. A positive correlation was found between totalschizotypy, as measured by the SPQ, and striatal presynaptic


dopamine release. This relationship was found to be primarilyrelated to presynaptic dopamine release in the associative stria-tum and the disorganized schizotypal traits [78]. Further ex-ploratory analyses indicated a positive correlation between pre-synaptic dopamine release in a number of other cortical andsubcortical regions [78]. In a separate study, disorganized traits,in non-clinical adults assessed with the SPQ, were positivelycorrelated with D2 dopamine receptor availability, as measuredby SPECT imaging with [123I]IBZM binding, in the rightstriatum [79]. Lastly, dopamine synthesis capacity in a non-clinical groupwith subclinical auditory hallucinatory phenomenadid not differ from a control group; and schizotypal and otherpsychosis-spectrum symptoms were not related to dopaminesynthesis capacity [80].

Unpublished preliminary studies from our group have exam-ined striatal dopamine release using amphetamine-induced[11C]raclopride displacement. These studies suggested greaterpresynaptic dopamine release, but specifically, in SPD patientsunder 40 years of age. Further, presynaptic dopamine release inSPD patients under 40 years old, appeared to be positivelycorrelated with cognitive-perceptual (or positive) symptomsand enhancedworkingmemory performance. Presynaptic striataldopamine, on the other hand, appeared to be inversely correlatedwith negative symptoms, such as interpersonal symptoms andsocial anhedonia in the under-40 SPD patients.

Clinical Perspectives

Identifying SPD and associated traits in the clinical setting can bechallenging as manifestations overlap with many other morewell-known psychiatric conditions, or may simply be qualifiedin colloquial terms (e.g., loner) without further diagnostic attri-bution. Common complaints of patients with SPD or schizotypaltraits are related to attentional/cognitive difficulties, social anxi-ety, difficulty connecting to others, and longstanding interper-sonal complications related to suspiciousness/paranoia. Superfi-cially healthier SPD patients may present with characteristicanxieties or neurotic conflicts that are, in a more latent manner,determined or exacerbated by underlying magical ideation, oddbeliefs, or overvalued ideas.

Therefore, schizotypal patients are not uncommonly di-agnosed with attention-deficit disorder (inattentive type);social anxiety disorder; autism-spectrum disorder; and dys-thymia. Additionally, the role of an underlying odd/magicalbelief as an aggravating factor of a concurrent symptomdisorder (e.g., anorexia, OCD) may be overlooked. Manyof the cognitive/perceptual disturbances that schizotypal pa-tients can bring to a clinicians attention can be quite dra-matic or alarming; despite exhibiting a fair degree of intactreality testing, these patients may nevertheless receive adiagnosis of a formal psychotic illness. Clinically significantschizotypy can exacerbate the treatment of other clinical

syndromes that may be the primary area of focus. For example,schizotypy has been shown to be a potential negative prognosticfactor in OCD. We have found that the underlying core beliefsassociated with certain disorders can have a more concretequality or be relatively refractory to insight in patients with SPD.

Medications can play either a primary or adjunctive role intreatment of patients with SPD or schizotypal traits. Impor-tantly, however, clinical trials for SPD or specific schizotypalsymptoms are rare, and therefore, our recommendations arebased on our clinical experience and discussions with col-leagues. We have found that attentional and cognitive diffi-culties are responsive to stimulants, such as those used to treatattention-deficit disorder. Although the use of stimulants inthose with a vulnerability to psychosis certainly requires closeclinical monitoring, we have not found stimulant use in SPDpatients to be problematic in this regard. On the contrary, wefind that the enhanced cognitive function may limit stress-induced impairment of executive function, and therefore, less-en the propensity more regressive forms of thought processes.Moreover, mood and social anxiety symptoms can also bealleviated during a course of stimulant treatment, however, wedo not recommend their use for indications other than atten-tional or cognitive difficulties. Early evidence from our groupalso supports a possible role for guanfacine, which also has anindication for attention-deficit disorder [38]. We did not ob-serve any benefit of the atypical antipsychotic, risperidone, oncognitive function in patients with SPD. Risperidone (0.25-2 mg), however, has been shown to improve both positive andnegative symptomatology in patients with SPD [81]. Antipsy-chotics should be used judiciously in SPD patients, especiallysince these symptoms are not necessarily the most disturbingto patients, nor are they necessarily the most problematic.Antipsychotics certainly play an important role when SPDpatients develop brief psychotic episodes, which they aresusceptible to during periods of elevated psychosocial stress.We have also found that benzodiazepines can play in impor-tant role in the treatment of anxiety in SPD, however, it is notuncommon that symptoms may only be partially relieved. Incontrast to the treatment of generalized anxiety, social anxiety,and panic disorder, we have not been impressed with theeffectiveness of serotonin reuptake inhibitors (SRIs) onSPD-associated anxiety. Moreover, we have not found anti-depressants to be particularly effective for the dysthymic andanhedonic symptoms of SPD.

The literature on psychotherapy for patients with SPD is closeto non-existent. Stones manuscript of his clinical experiencetreating schizotypal patients psychotherapeutically, althoughclose to 30 years old, remains highly relevant [82]. Psychother-apy with SPD patients can be limited by a variety of possibleinterpersonal complications. On the one hand, paranoia andlimited capacity/desire to form close personal relationships canbe a barrier for developing a therapeutic alliance. On the otherhand, in SPD patients with the capacity and desire to form


relationships, complications can arise during periods of treatmentintensification and separation. Patients with SPDmay experiencea blurring of the boundaries between themselves and the therapistas treatment advances. For example, a high functioning SPDpatient in psychotherapy began expressing a feeling that she andthe therapist knew each other from someplace else after thetherapist had linked the patient_s symptomatic, excessive consci-entiousness with her description of her siblings as being unreli-able during childhood. The patient's reaction was taken as anindication to the therapist that this standard psychotherapeuticintervention may not have suitable at that time. Additionally,SPD patients may either be unable to tolerate regular or extendedperiods of separation; alternatively, they may have difficultyexperiencing continuity between sessions as if the work ofeach session wasnt cumulative, but rather, was just anothernew session.

Peculiarities of thought and semantic processing make it verydifficult for SPD patients to be understood and/or communicatecomplex emotional and psychological states and concepts thatare typically required in psychotherapy. Furthermore, SPD pa-tients can have a limited capacity to think about their mentalstates abstractly; or, theymay find the process to be disconcertingor destabilizing. We have also noted that SPD patients exhibit astriking capacity for disavowal of certain realities, which furthercomplicates the process of psychotherapy as the anxiety associ-atedwith certain external consequences plays less of amotivatingrole for psychological change.

Vivid perceptual/dissociative disturbances that are associ-ated with elaborate magical beliefs require a delicate psycho-therapeutic approach, as SPD patients can simultaneously(albeit in an unintegrated manner) recognize these thoughtsand experiences as symptoms, yet at the same time, ascribethem to reality. Therefore, a challenge for the psychotherapistis to be able to tolerate and help the patient tolerate thesecomplicated and troubling experiences.

Lastly, there is significant individual variability in terms ofwhat types of psychotherapeutic interventions SPD patientscould benefit from; and, ultimately, this can only be assessedempirically during the initial and extended evaluation process.Therefore, once clinically significant schizotypy has beenidentified, this should prompt the clinician to pay particularlyclose attention to various factors, such as: the ability of thepatient to form a therapeutic alliance; the patients expectationof what are reasonable psychotherapeutic goals, and howpsychotherapy is supposed to work.

Conclusions

SPD is significant both as a clinical syndrome and, from aresearch perspective, as an intermediate schizophrenia-spectrum phenotype. From a clinical standpoint, SPD is rela-tively understudied, compared to other personality disorders,

and a great deal needs to be understood with respect to bothpharmacological and psychotherapeutic interventions. SPD canbe challenging to identify, as diagnostic phenomena may be a)difficult to elicit, b) attributed to more familiar diagnoses, or c)go unrecognized. Other important phenomena, namely, cogni-tive deficits (attentional, executive function, and working mem-ory impairments), may not lead one to consider a diagnosis ofSPD as they are not formally represented in theDSMdiagnosticcriteria. Nevertheless, such cognitive impairments are stronglyassociated with SPD and play an important role in determiningfunctional outcomes. Recognition of SPD may be aided byappreciation of its multidimensional nature, typically represent-ed in terms of cognitive-perceptual, oddness/disorganized, andinterpersonal/negative domains. SPD is a heritable condition,consisting of both genetic and environmental factors (e.g.,psychological trauma). There are factors that contribute to thedevelopment of SPD itself, as well as its component domains(e.g., cognitive-perceptual). In terms of the neurobiology ofSPD, there are shared and divergent elements with respect toschizophrenia. For example, both SPD and schizophrenia ex-hibit decreased left temporal lobe volumes; however, in SPD,temporal lobe volume abnormalities are anatomically morecircumscribed, and less progressive over time than in schizo-phrenia. Frontal lobe and striatal anatomical abnormalities havealso been identified in SPD; however, these findings have beenless consistent, and may also consist of compensatory or pro-tective factors that limit progression to full psychosis. Dopa-minergic neurochemistry in striatal and cortical regions appearsto play an important role in SPD and schizotypal traits in non-clinical participants. Areas in need of future focus includecharacterization of schizotypy in child and adolescent popula-tions, including further understanding of the relationship withautism-spectrum conditions; studies on psychopharmacologicaland psychotherapeutic treatments; characterization of the neuralcorrelates and therapeutics of cognitive impairment.

Compliance with Ethics Guidelines

Conflict of Interest Daniel R. Rosell has received support for traveland payment from writing or reviewing manuscript from the Departmentof Veterans Affairs.

Shira E. Futterman has received support from a grant from theNational Institute of Mental Health awarded to LJS.

Antonia McMaster has received a support from a grant from theNational Institute of Mental Health awarded to LJS.

Larry J. Siever has received grants and travel support from theNational Institute of Mental Health and the Department of VeteransAffairs. He also received travel support from theMental Illness Research,Education and Clinical Centers. Dr. Siever also has receive payment forwriting or reviewing manuscripts from the Department of Veterans Af-fairs, the Mental Illness Research, Education and Clinical Centers, andMount Sinai.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.


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Schizotypal Personality Disorder: A Current ReviewAbstractIntroductionDiagnostic Criteria, Psychometric Structure, and MultidimensionalityEpidemiology and Functional ImpairmentPathogenesis of SPDHeritability of SPDEnvironmental FactorsMolecular Genetics

Neuropsychological and Cognitive CharacteristicsSocial/Interpersonal and Affective ProcessingNeurobiological Studies: Structural and Neurochemical FindingsStructural NeuroanatomyDopamine Neurochemistry

Clinical PerspectivesConclusionsReferencesPapers of particular interest, published recently, have been highlighted as: Of importance Of major importance

Schizotypal Personality Disorder: a Current Review (2014)

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Transcript of Schizotypal Personality Disorder: a Current Review (2014)