Diagnosis and treatment of schizotypal personality disorder: evidence from a systematic review

The main objective of this review was to evaluate studies on the diagnosis, treatment, and course of schizotypal personality disorder and to provide a clinical guidance on the basis of that evaluation. A systematic search in the PubMed/MEDLINE databases was conducted. Two independent reviewers extracted and assessed the quality of the data. A total of 54 studies were eligible for inclusion: 18 were on diagnostic instruments; 22, on pharmacological treatment; 3, on psychotherapy; and 13, on the longitudinal course of the disease. We identified several suitable and reliable questionnaires for screening (PDQ-4+ and SPQ) and diagnosing (SIDP, SIDP-R, and SCID-II) schizotypal personality disorder. Second-generation antipsychotics (mainly risperidone) were the most often studied drug class and were described as beneficial. Studies on the longitudinal course described a moderate remission rate and possible conversion rates to other schizophrenia spectrum disorders. Because of the heterogeneity of the studies and the small sample sizes, it is not yet possible to make evidence-based recommendations for treatment. This is a systematic evaluation of diagnostic instruments and treatment studies in schizotypal personality disorder. We conclude that there is currently only limited evidence on which to base treatment decisions in this disorder. Larger interventional trials are needed to provide the data for evidence-based recommendations.


INTRODUCTION
Schizotypy is a heterogenous syndrome that is expressed across multiple dimensions, including cognitive-perceptual, disorganized, and interpersonal symptoms 1 or according to the symptomology of schizophrenia, positive, negative, and disorganized factors. [2][3][4] Raine 1 described two types of schizotypy: (1) neurodevelopmental schizotypy with relatively stable traits and significant brain and neurocognitive impairments that predispose to schizophrenia, and (2) pseudoschizotypy, a pronounced psychosocial entity with more symptom fluctuation that is unrelated to schizophrenia. Schizotypy, as a broader collection of both clinical and nonclinical traits, is assessed by psychometric inventories such as the Wisconsin Scales of Schizotypy. 3 The assessments for schizotypal traits are mainly used to define a high-risk group and its proneness to psychosis. 5 Mason described 16 different schizotypy scales that were based on clinical concepts or definitions and six scales for psychometric/personality measures of schizotypy. 5 According to the theoretical models of Meehl, 6,7 Lenzenweger, 8 Chapman, 9 and Kwapil, 10 schizotypy is a premorbid condition. The term schizotypy refers to both people with schizotypal personality disorder (STPD) and healthy individuals in the general population with certain personality traits and a latent liability for psychosis. 1 Consequently, research has been performed in both clinical patients and healthy schizotypal individuals. Several authors argue for a dimensional approach and a continuum between schizotypal traits and schizophrenia spectrum disorder 1,11,12 ; support for their argument is provided by genetic and linkage studies showing a considerable overlap between genetic association profiles in schizotypy and schizophrenia. 13,14 Since the introduction of the diagnosis of STPD in Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) in 1980, the diagnosis and treatment of STPD have remained difficult because of the lack of evidence-based algorithms. The original STPD item set was derived from the criteria of borderline schizophrenia seen in the relatives of schizophrenia patients. The differentiation between schizotypal traits and STPD is clinically important and reflects the degree of impairment in occupational and interpersonal functioning and the severity of symptom presentation. 14 This review focuses on the diagnosis of and therapeutic approaches in patients with a disease severity that fulfills the criteria of STPD not only as a premorbid condition or risk state but also as a separate diagnostic entity.
For years, the International Classification of Diseases (ICD) from the World Health Organization (WHO) and other classification instruments, e.g., the DSM from the American Psychiatric Association (APA), have differed in their classification of STPD (referred to as schizotypal disorder in the ICD): In ICD-9 and -10, it is listed under schizophrenia spectrum disorders, whereas in DSM-III to -5 it is classified as a personality disorder. In the forthcoming ICD-11, it will remain in the block of schizophrenia spectrum disorders. 15 In DSM-5, a diagnosis of STPD is defined by the following symptom categories: (1) general impairments in personality and self-functioning (identity and self-direction) and in interpersonal functioning (empathy, intimacy); (2) STPD-specific pathological personality traits, described as psychoticism, eccentricity, cognitive and perceptual dysregulation, and unusual beliefs and experiences, (3) detachment characterized by restricted affectivity and withdrawal, and (4) negative affectivity characterized by suspiciousness. In ICD-10, 16 and very likely in ICD-11, however, schizotypal disorder (F21) is characterized by eccentric behavior and changes in thinking and affect similar to those in schizophrenia; the evolution and course of the disease resemble those of a personality disorder (PD).
The prevalence of STPD has been described as ranging from 0.6% in a Norwegian sample to 4.6% in an American sample. 17 Men (4.2%) are more often affected than women (3.7%). 17 Common differential diagnoses are other PDs such as the borderline personality disorder (BPD), attention-deficit disorder (inattentive type), social anxiety disorder, autism-spectrum disorder, and dysthymia. 18 Comorbidities can complicate the disease course and treatment responses, and several studies focus on interventions for patients with comorbid obsessive-compulsive disorder (OCD) 19 and BPD. Schizotypy occurs more often in relatives of patients with schizophrenia or a Cluster A PD. Twin studies showed highly stable genetic factors and rather transient environmental factors for an increased risk for the schizotypal syndrome, 20 and genetic risk variants for schizophrenia could also be linked to STPD. [21][22][23] The conversion rates from STPD to schizophrenia spectrum disorders vary between 20 and >40%, depending on the follow-up interval. 1,24 Imaging studies detected numerous group-level differences in the size of specific brain regions in individuals with STPD or schizotypy in comparison with healthy participants, patients with schizophrenia, and patients with other PDs. 18 Despite these research efforts, evidence-based recommendations are still lacking for the diagnosis and treatment of STPD. National and international treatment guidelines for schizophrenia spectrum disorders (e.g., from the APA, the National Institute for Health and Care Excellence and World Federation of Societies of Biological Psychiatry (WFSBP)) do not discuss this topic, and specific guidelines for personality disorders pay only little attention to STPD. 25 Rosell et al. 18 recently published a nonsystematic literature review on the epidemiology, functional impairment, heritability and genetics, cognitive impairments, social-affective disturbances, and neurobiology of STPD. This detailed review provides a deeper insight into the pathophysiology of and experimental research on STPD and includes information on imaging and genetic and psychological testing. 18 Nevertheless, it remains unclear which diagnostic tools, medication, or psychotherapy are recommended. Therefore, the main objective of this systematic review, which was based in principle on the recommendation of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses group, 26 was to evaluate the literature on the diagnosis and treatment of patients seeking help for STPD. In addition, it offers some information on the longitudinal course of STPD and conversion rates to other schizophrenia spectrum disorders.

Articles on diagnostic instruments
Study characteristics. When examining the articles on diagnostic instruments, we focused on studies that tested disease criteria [27][28][29][30][31] and clinical diagnostic questionnaires for STPD. [32][33][34][35][36][37][38][39] One study did not specifically evaluate a diagnostic questionnaire but compared a factor analysis model with established questionnaires. 40 Individual outcomes. Five studies aimed at evaluating the variables of the diagnostic criteria, the shifts in diagnosis from DSM-III to -5 or ICD-8 to -10 and their effect on diagnostic sensitivity, specificity, and diagnostic overlap, 27,28,30,31,41 as indicated in Table 1. The reliability of the DSM-III criteria had an adequate mean kappa of 0.71. 27 In DSM-III, the diagnoses of BPD and STPD interacted on the symptom level. 27 In DSM-III-R, the threshold for an STPD diagnosis was raised, and the number of STPD diagnoses consequently decreased by 40%. This offered a sharper discrimination between STPD and related PDs, such as BPD and schizoid PD. 30 In the evolution of the ICD system, the threshold for meeting symptom criteria was also crucial for differential diagnosis: Whereas in ICD-8/-9 less patients would have been diagnosed with STPD, in ICD-10 the threshold was lowered and more patients were diagnosed with STPD. In the ICD system, the severity of the disease may mark the discrimination between STPD and schizophrenia, which would favor a dimensional diagnosis concept. 31 Most of the studies evaluated the inter-rater reliability (which ranged from 0.62 to 0.91) and test-retest reliabilities (which ranged from 0.64 to 0.84) of the diagnostic instruments; reliabilities were adequate (see Table 1). Among the diagnostic instruments, three were identified as being suitable for diagnosis because they had adequate reliabilities and validities for the respective diagnostic criteria: the Structured Interview for DSM-III Personality Disorder (SIDP), 33 the Semistructured Interview for DSM-III-R Personality Disorders (SIDP-R), 35 and the Structured Clinical Interview for DSM-IV (SCID-II) 37 (see Table 1). The self-report instruments Schizotypal Personality Questionnaire (SPQ) and Schizotypal Personality Questionnaire-Brief (SPQ-B) were designed as screening instruments for STPD. The SPQ-B shows adequate internal consistency (coefficient kappa = 0.87), 42 and the SPQ shows strong correlations between patients' responses and SCID-II-rated symptoms. 38,43 The Personality Diagnostic Questionnaire-4+ (PDQ-4+) is also a self-report instrument for diagnosing PD. It has more false-positive results than the SCID-II and is therefore only useful as a screening tool for PDs but not as a diagnostic tool. 44 The Minnesota Multiphasic Personality Inventory (MMPI) could not differentiate between individuals with STPD and schizophrenia. 45 However, a distinct profile (MMPI 2-7-8) showed an enrichment of diagnoses of Cluster A PDs when compared with SIDP-IV interviews. None of the instruments was designed to evaluate disease severity. Three studies compared diagnostic interviews with factor analysis models. 35,40,44 According to Battaglia et al. 35 , the three factors cognitive-perceptual, interpersonal, and oddness best describe the diagnosis of STPD; Fossati et al. 37 made the same statement, but these two studies had overlapping patient cohorts. Sanislow et al. 40 developed a four-factor model and argued that it was significantly better than the established unitary "generic" model. 40 Please see Table 1 for details.
Articles on interventional drug treatment trials Study characteristics. Most of the studies were prospective double-blind, placebo-controlled trials, [46][47][48][49][50][51][52][53][54][55][56] and all publications reported single-center results. We also identified one doubleblind, treatment-controlled trial; 57 one single-blind, placebocontrolled trial; 58 four open-label trials; 59-62 one retrospective study; 63 and four case reports. [64][65][66][67] Please see Table 2A, B and  Supplementary Table 3 and 4 for further study details and level of evidence (LoE) grading. In total, 16 individual drug treatments were studied. The most frequently studied drug was risperidone, 50,53,54,62 and the most frequently studied class of drugs were the antipsychotics, 47,48,50,53,54,[57][58][59][60]62,63,66 followed by the antidepressants. 46,61,64,65 Six studies tested other neuroactive drugs. 49,51,52,55,56,67 In most studies, the main outcome measurement was a general psychiatric symptom scale, such as the Brief Psychiatric Rating Scale, 60,63,67 the Hopkins Symptom Checklist, 48,61 and the Psychiatric Assessment Interview. 57 Three trials used interviews for specific psychotic symptoms, such as the Positive and Negative Symptom Scale (PANSS). 50,53,56 Some studies focused on patients with comorbidities of OCD or BPD and consequently measured outcome with the Yale-Brown Obsessive Compulsive Scale (YBOCS) 46,48,59,66 or the Self-Injurious Behavior scale. 47 One study used a specific tool, the SPQ, to assess the severity of STPD as an additional outcome measurement tool. 50 Common secondary outcome tools were      PDQ-4+ is a forced choice, self-report, 99-item questionnaire designed to measure the DSM-IV PDs. In these samples, schizophrenia-spectrum disorders, mental retardation, or dementia were excluded. The inter-rater reliability for diagnosis of SPD based on SCID II interviews of 25 subjects and 3 raters was kappa = 9.1. PDQ-4+ seems to predict falsepositive results. The factor model shows schizophrenia-related schizophrenia. PDQ-4+ scales do not identify subjects with definite personality disorder diagnoses. Reliability and predictive power improved when SPD was assessed by semi-structured, direct interviews that used all nine diagnostic criteria instead of through self-assessments of some dimensions of schizotypy. Considering SCID-II data, Raine's three-factor model of SPD features (Raine et al., 1994) was the best fitting model among those considered in study 1. Oddness was the factor that most sharply discriminated the SPD latent taxon from the complement in the clinical subjects of this study. The DIS-R is a diagnostic interview for Axis I disorders. 16 subjects (3.0%) in study 2 were diagnosed with DSM-III-R SPD; this was similar to the number of SPD subjects in study 1, 25 53 as a primary or secondary outcome.
Individual outcomes. Most of the studies on an antipsychotic drug intervention found a positive effect in STPD (see Table 2A). Thiothixine reduced general symptoms (especially illusions, ideas of reference, paranoid ideation, cognitive deficits, and anxiety) in cohorts of mixed BPD and STPD patients, but the respective studies found no significant relationship between diagnosis and outcome of treatment. 47,57 Risperidone was the only drug that was evaluated in studies that fulfilled relevant study quality criteria, such as reporting effect sizes, being randomized, and using quantitative measures and standardized questionnaires. It was evaluated in four independent studies: Koenigsberg et al. showed a reduction in the PANSS score in STPD but no difference in the STPD-specific SPQ; 50 62 In an open-label augmentation trial, a small cohort (n = 11) of patients with STPD had significant improvements in psychosis and depression ratings when treated with olanzapine. 60 In an openlabel study in patients with comorbid OCD and STPD, a combination of fluvoxamine and olanzapine showed beneficial effects, i.e., it reduced the YBOCS score, 59 and the concomitant diagnosis of STPD was significantly associated with a positive response. In a retrospective study, Di Lorenzo et al. reported a decrease of general symptoms when patients with schizophrenia spectrum disorder were treated with aripiprazole; patients with STPD were included, but no specific results were mentioned. 63 In one case report, clozapine treatment reduced symptoms in a patient with comorbid OCD and STPD. 66 Three studies investigating the use of antipsychotics analyzed mixed cohorts of STPD and BPD patients, 47,48,57 and one study analyzed patients with schizophrenia spectrum disorder. 63 Studies evaluating antidepressant treatment examined only mixed (BPD and STPD) or comorbid (OCD and STPD) cohorts (see Table 2B). In an open-label trial of fluoxetine, Markovitz et al. measured a reduction of general symptoms in patients with BPD, STPD, or both, 61 regardless of the diagnosis. In another study, clomipramine showed no significant effects on OCD symptoms in a cohort of patients with OCD and STPD, and the authors reported a worse treatment outcome in patients with comorbid STPD than in those with other PD diagnoses. 46 One case report described a patient with STPD who developed psychotic symptoms after treatment with fluoxetine, 64 and other case reports showed positive effects of clomipramine, paroxetine, and buspirone on depressive or OCD symptoms 46,65 (see Supplementary Tables 3C  and D). Five studies tested other substances and their effect on cognitive impairments in patients with STPD (see Supplementary  Table 3): On the basis of studies showing positive results of catecholamine agonistic treatment in schizophrenia-related disorders, Siegel et al. tested d-amphetamine in a cohort of patients with STPD and found an improvement in the Wisconsin Card Sorting Test (WCST); however, the authors found no effect of symptom change on the PANSS score. 56 Two studies tested dopamine agonists (pergolide and dihydrexidine) and showed improvements in working and verbal memory, executive functioning, information processing, and divided attention. 52,55 Two studies tested modulators of the autonomous nervous system (intravenous physostigmine, a cholinesterase inhibitor and Table 1 continued enhancer of the parasympathetic nervous system, and guanfacine, an α 2A receptor agonist and sympatholytic drug) and their effect on cognition. These studies showed improvements in verbal memory, visuospatial working memory, and context processing. 49,51 The sizes of the studies varied between 1 patient with STPD in a larger mixed cohort 63 and up to 31 patients with STPD 53 (see Supplementary Table 2).
Articles on psychotherapy Study characteristics. We identified one randomized clinical trial that compared integrated therapy with standard treatment, 68 one uncontrolled clinical trial, 69 and one case report of a patient with OCD and comorbid STPD. 70 The sizes of the studies varied from 1 70 to 79 68 patients with a diagnosis of STPD (see Supplementary  Table 2).
Individual outcomes. An uncontrolled prospective trial of a psychodynamic day-care treatment program found no benefit for STPD patients. 69 One case report showed a reduction of symptoms in a patient with STPD and OCD 70 after social skills training. Another trial also reported a positive effect of social skills training, i.e., STPD patients with this training had a lower transition rate from STPD to a psychotic disorder. 68 We found no trial that evaluated cognitive behavioral therapy in STPD (see Table 3).
Articles on longitudinal course and follow-up studies Study characteristics. We included eight studies of clinical cohorts. [71][72][73][74][75][76][77][78] Studies with mixed clinical and non-clinical cohorts were included if they predicted the development of an STPD diagnosis from childhood to adulthood or the conversion rate to psychotic illness. [79][80][81] One article focused of the stability of a diagnosis of STPD in young adult twins. 20 The study size depended on the investigated cohort (for details see Supplementary Table 2).
Individual outcomes. The follow-up periods of the studies ranged from a minimum of 1 year 81 to 27 years. 80 In a mixed cohort of healthy and mentally ill children, Bernstein et al. showed that an early STPD diagnosis during adolescence rarely persisted over a 2year follow-up period. 79 Along the same lines, in their study in adults Grilo et al. reported a remission of the STPD diagnosis in 61% of patients and suggested that, although maladaptive traits may persist, the severity of symptoms can change. 76 In contrast, Asarnow et al. showed that children with a diagnosis of STPD mostly kept the diagnosis, but 25% of them developed more severe schizophrenia spectrum disorders (schizophrenia or schizoaffective disorder). 81 Olin et al. evaluated the relationship between personality traits and disorders in a community-based cohort of healthy and mentally ill children and concluded that early traits can be predictive for the development of an STPD. Four studies evaluated longitudinal global functioning and impairment: [71][72][73][74] Impairments in global functioning and social impairment differed depending on the study sample, but, overall, patients with pure STPD had less impairment than patients with other comorbid PDs or SZ. In particular, patients with comorbid BPD had poor global functioning. Treatment with antipsychotic medication was common in STPD patients. 74,75 They were also frequently hospitalized and received psychotherapy. 75 Two studies evaluated the stability of symptoms over time: McGlashan et al. found paranoid ideation and unusual experiences to be the most stable, whereas oddness appeared to be the least prevalent and most changeable; 78 and Kendler et al. studied the stability of Cluster A PDs in twins and concluded that genetic risk factors lead to highly stable subtypes of the disorder, whereas shared environmental risk factors lead to rather transient symptoms 20 (see Table 4). Two studies focused on the conversion from STPD to a psychotic illness and found rates of 25-48%. 24,82 Quality of the studies The composition and size of the cohorts varied greatly across the studies, and all treatment studies were single center. Some studies in mixed samples of patients reported results on very few or only single STPD patients. It remains questionable whether the results of these studies can be applied to a larger group of patients with STPD. Most of the articles did not mention disease severity because of a lack of a suitable measurement tool. A variety of methods for evaluating the quality of diagnostic instruments, the outcome of clinical interventional studies (drug treatment or psychotherapy), or longitudinal outcome were applied across the studies, resulting in a high heterogeneity and hampering comparability.

DISCUSSION
We present a systematic review of diagnostic instruments and pharmacological and psychosocial treatment strategies for STPD. After performing a standardized and systematic literature search and analysis, we assessed 94 full-text articles for eligibility and evaluated 54 of them. At this point, it would be premature to make clear recommendations for the use of specific diagnostic instruments or drug or psychotherapy treatment approaches. Our evaluation of diagnostic instruments made clear that the diagnosis of STPD has changed over time. In each diagnostic system, the threshold for meeting symptom criteria seems to differentiate between related diseases, such as other PDs or schizophrenia. Nearly all the diagnostic instruments discussed for STPD have adequate inter-rater and test-retest reliability. Our review confirms that the SIDP for DSM-III, SIDP-R for DSM-III-R, and SCID-II for DSM-IV are suitable for diagnosing STPD, but we found that the diagnostic tool PDQ-4+ is more suitable for screening. Factor analysis models are frequently discussed as a diagnostic alternative to catalogs with rather arbitrary diagnostic criteria. A complete review of the scales used to access schizotypy as a broad concept can be found in the review by Mason, which focuses not only on the clinical diagnosis but also on psychometric measurements that assess schizotypal personality traits and define a high-risk group for schizophrenia. 5 Longitudinal studies examined the stability of the diagnostic entity and observed moderate-to-high remission rates between an early childhood onset and later adulthood. Patients suffering of comorbid BPD showed poorer social functioning than patients with pure STPD. 71,72 Yet, drug treatment responses in patients with comorbid BPD were regardless of the diagnosis. 47,57,61 Patients suffering of a comorbid OCD showed better response rates after treatment with olanzapine 59 and poorer responses after clomipramine treatment. 46 The articles on treatment clearly showed that antipsychotics are the most frequently used drugs. When we considered only studies that were of acceptable methodological quality (see LoEs in Tables 2 and 3 and Supplementary Table 3          14 years Diagnoses in this study were based on DSM-III criteria. Patients suffering from STPD without comorbid major affective disorder functioned better than patients with SZ. They had higher scores in global functioning (GAS) than SZ patients at baseline but not at follow-up. STPD patients with comorbid BPD were as impaired as schizophrenics at admission but significantly better at follow-up McGlashan 72 n total = 253 psychiatric patients, n STPD = 10, n STPD+SZ = 61, n STPD +SZ+BPD = 30, n STPD+BPD = 18 Range: 2-32 years STPD as defined by DSM-III criteria appeared to be common in the Chestnut Lodge follow-up study patients, although it was rare as a pure syndrome. From the perspective of follow-up, STPD seemed to be related to SZ but not to BPD. The mixed Axis II borderline syndrome (STPD+BPD) had a long-term profile closer to BPD than to STPD. The cohorts meeting STPD criteria had relatively poor social adjustments and fewer social contacts. The pure STPD cohort achieved the highest level on education compared to the mixed diagnoses. The pure STPD sample was mainly single (70%) and male (60%). Premorbid functioning was poor socially and good instrumentally Modestin et al. 73 n total = 39 psychiatric patients, n STPD = 14 (7 for follow-up), n SZ = 25 (17 for follow-up) 4 years Diagnosis of STPD was based on DSM-III, of SZ on ICD-9 and parts on DSM-III. A relationship not only between STPD and SZ but also between STPD and BPD could be detected. Pure STPD patients are rarely dysfunctional and less likely to require hospital care. Therefore, the clinical sample investigated is small and might not be representative for all STPD patients. On a blind examination, STPD patients in this cohort were found to be less socially adjusted and they tended to be more symptomatic. Compared with a small DSM-III schizophrenia subgroup, STPD patients undertook more suicide attempts. STPD patients were rating higher in social dissatisfaction. Patients with STPD were more anxious and they tended to suffer more from obsessive-compulsive symptoms and depression. Transient psychoses were frequent in STPD patients. The average neuroleptics dose was twice as low in STPD compared to SZ (92% of n total received neuroleptic medication) Mehlum et al. 74 n total = 97 patients with PD, n STPD = 13 at admission, n STPD = 9 at discharge range: 1.6-4.9 years STPD diagnoses were made according to DSM-III-R at index hospitalization and by SCID interview at follow-up. STPD patients displayed a moderate symptom reduction after 3 years of treatment but retained relatively poor global functioning. They were least socially adjusted, employed, and self-supporting of all diagnostic subgroups. STPD and BPD patients had far more inpatient treatment than other PDs Bernstein et al. 79 n total = 733 community-based adolescents

years
The overall prevalence of personality disorders peaked at age 12 years in boys and at age 13 years in girls and declined thereafter. STPD was the least prevalent Axis II disorder (moderate STPD 1.8%, severe STPD 1.2%). Children who met the criteria for STPD had increased social impairments, school or work problems, and a higher comorbidity with Axis I disorders. Longitudinal follow-up revealed that most Axis II disorders did not persist over a 2-year period. Subjects with disorders identified earlier remained at elevated risk for receiving a diagnosis again at follow-up (persistence after 2 years: for moderate STPD 9%, for severe STPD 11%) Olin et al. 80 n total = 232 children, n STPD = 36 children Range: 15-27 years, based on teachers' school reports The lifetime diagnoses used in the study are based on DSM-III-R. The first assessment was at age 15 years, the second at age 25 years, and the third between age 39 and 42 years. Those who later developed STPD were found to be more passive and unengaged and more hypersensitive to criticisms compared with the non-schizophrenia groups according to school reports. Males who developed STPD were found to be less disruptive and hyper-excitable compared with males with schizophrenia; females with STPD did not differ from females with schizophrenia. A receiver operating characteristic analysis found these factors to predict 73.5% of future STPDs. The three major factors accounting for 54.4% of the variance were labeled as "socially anxious and withdrawn," "disruptive and hyper-excitable," and "passive and unengaged." These findings suggest that pre-schizotypal traits may be identified in late childhood or adolescence Comparative groups: n comp1 = 31 SZ children, n comp2 = 37 nonpsychotic but mentally ill children, n comp3 = 68 children not mentally ill but schizophrenic mother, n comp4 = 60 healthy children Grilo et al. 76 n total = 633 patients, n PD = 544, n MDD = 89, n STPD = 78

years
The study examined the stability of different personality disorders over time. The STPD remission rate was 61% after 24 months. Remission rates after a more stringent definition with two or fewer criteria (by the DSM-IV Personality Disorders Follow Along Version, DIPD-FAV) after 12 consecutive months was 23% for STPD. Dimensionally, these findings suggest that PDs may be characterized by maladaptive trait constellations that are stable in their structure (individual differences) but can change in severity or expression over time In summary, our systematic review shows that the best evidence for efficacy in STPD is available for risperidone and to a limited extent for olanzapine. The literature on psychotherapy is sparse and does not allow us to make any recommendations, although social skills training seems to be effective and should be offered to patients with STPD. Large-scale naturalistic and interventional trials with defined diagnostic cohorts and strict study designs are needed to provide the data for more detailed evidence-based recommendations.

Study selection
This systematic review was conducted by searching the PubMed/ MEDLINE databases for papers published at any time. We conducted the final search on September 14, 2016, at which time the data source contained studies from April 1, 1947, to August 21, 2016. A total of 145 combinations of search terms were used to search the databases with the ENDNOTE X7 search tools (see Supplementary Information). Duplicates were removed by using the ENDNOTE X7 duplication detection feature. The publications (titles and abstracts) were then screened for relevance. To be included, the articles had to report on studies of original data and focus on the diagnosis, treatment, or follow-up of patients with STPD. Because including only studies with a Scottish Intercollegiate Guidelines Network (SIGN) LoE of 1− to 1++ would have limited the number of studies available for inclusion, we included not only randomized control trials but also cohort studies, retrospective non-analytical studies, and case studies (LoE 2++ to 3). Expert opinions (LoE 4) were not considered. Study designs and LoE grading are described in the Tables 2A, B, and 3, and  Supplementary Tables 3 and 4. Reviews, meta-analyses, and non-English publications were excluded. Two reviewers independently analyzed the full-text publications and retrieved data on clinical diagnosis and treatment. We searched also three additional databases (WHO Clinical Trials (http://apps.who.int/trialsearch/), ClinicalTrials (https://clinicaltrials.gov/), and the Cochrane Library (http://www.cochranelibrary.com/)) for ongoing or planned clinical trials and for systematic reviews or meta-analyses. Using the search term "schizotypal personality disorder," we identified 18 This study explores the extent to which relevant personality traits are stable in individuals diagnosed with four personality disorders (schizotypal, borderline, avoidant, and obsessive-compulsive personality disorders). The PDQ-IV was used for screening. The DIPD-IV was used for making the initial diagnosis based on DSM-IV criteria. The test-retest kappa for STPD was 0.64. There was an insufficient sample size in the inter-rater reliability sample to calculate the kappa for STPD, but diagnostic agreement was 100%. Participants were interviewed at 6 months, 1 year, and 2 years following the baseline assessment. Changes in personality traits were determined via a re-administration of the NEO-PI-R at the 1-and 2-year follow-up. The DIPD-IV was modified to record the presence of each criterion for the four PDs for each month of the follow-up interval. The standardized parameter estimates reflecting the stability for the latent trait variable across time were significant and quite large (β= 0.76 and β = 0.83, both ps < 0.01) as were the stability estimates for STPD (β = 0.90 and β = 0.81, both ps < 0.01).
The results demonstrate significant cross-lagged relationships between trait change and later disorder change for three of the four personality disorders studied Asarnow et al. 81 n STPD = 12 children, n SZ = 18 children range: 1-7 years There was significant continuity between SZ spectrum disorders in childhood and adolescence. The most common clinical outcome for children with STPD was continuing STPD, supporting the hypothesis of continuity between childhood and later STPD. However, 25% of the STPD sample developed more severe SZ spectrum disorders (schizophrenia or schizoaffective disorder, also supporting the hypothesis that STPD represents a risk or precursor state for more severe SZ spectrum disorders McGlashan et al. 78 n total = 474 patients with personality disorders, n STPD = 85 2 years In this study, a 24-month follow-up was obtained to evaluate the change of personality disorder criteria over time. For STPD, the most prevalent and least changeable criteria over 2 years were paranoid ideation, and unusual experiences. The least prevalent and most changeable criteria were odd behavior and constricted affect Woods et al. 82 n = 377 patients with prodromal syndrome, n HSC = 196, n FHR = 40, N STPD = 49 2.5 years 40% of prodromal patients converted to fully psychotic illness during 2.5 years of follow-up. Corresponding rates for help-seeking comparison (HSC) group, familial high-risk (FHR) group, and STPD subjects were correspondingly 4, 0, and 36%. Cox regression comparing distinguished prodromal patients from HSC but not from STPD subjects Debbane et al. 24 n = 376 patients by a clinically relevant expression of schizotypy (i.e., STPD, schizoid PD, or SD range: 2-20 years The conversion rates from STPD to a psychotic disorder varied between 25% and 48%. Suspected STPD in children, however, seldom led to the later emergence of a schizophrenic-spectrum psychotic disorder (only 6.25%) Kendler et al. 20 n total = 2282 twins range: 6-11 years The study examines the stability of genetic and environmental factors in paranoid and schizotypal PD. The stability over time of the criteria counts for STPD, estimated as polychoric correlations, was +0.40. 71% of the temporal stability derived from the effect of genetic factors. Shared genetic risk factors for two of the Cluster A PDs are highly stable in adults over a 10-year period while environmental risk factors are relatively transient. Over two thirds of the long-term stability of the common Cluster A PD liability can be attributed to genetic influences a The descriptions of outcome are direct citations or extracts from the referred publications Diagnosis and treatment of schizotypal personality disorder:. . . SK Kirchner et al.
clinical trials. Furthermore, we found two additional trials that had been completed; however, upon closer inspection it became clear that they did not meet the inclusion criteria for this systematic review. We identified one protocol 83 in the Cochrane Library, but it was withdrawn with no results in 2014. Our search strategy yielded 3420 unique studies, 3326 of which were excluded after we had screened the titles, abstracts, and article format reviews, resulting in 94 full-text articles. These 94 articles were scanned for the inclusion criteria of this systematic review-to be included, studies had to investigate diagnostic instruments for or the treatment or longitudinal course of STPD. After full-text screening, 38 articles had to be excluded because they did not include original data or were not about clinical patients with STPD. The remaining 56 articles were sorted into the following categories: clinical diagnostic instruments (18 studies), pharmacological treatment (22 studies), psychotherapy (3 studies), and longitudinal course and follow-up (13 studies) (see Supplementary Information). Publications on diagnostic questionnaires were only included if they evaluated diagnostic criteria or questionnaires as assessment tools. Articles on factor analysis models alone were excluded, and publications on drug treatment were excluded if there was no report of a clinical outcome. We identified three overlapping patient cohorts: one in the articles on diagnostic instruments (Battaglia et al. 35  General study characteristics We assumed a large heterogeneity in disease severity among the included patients who were recruited in outpatient and inpatient settings. Because of the inconsistent outcome measures in the interventional groups, in our view the available data were not suited to perform quantitative analyses, e.g., with a metaanalytical approach. Some study populations included also healthy and population-based individuals, but these studies were only taken into consideration when a clinical diagnosis of STPD was mentioned. 20,34,36,38,79,80 Most of the studies focused on adults, although three focused on children and the longitudinal course of their diseases. [79][80][81] The study sizes varied greatly, as indicated in Supplementary Table 2.

DATA AVAILABILITY
This is a systematic review. All data generated or analyzed during this study is included in this published article (or Supplementary Information). No other data are available.