695879

review-article2017
JOP0010.1177/0269881117695879Journal of PsychopharmacologyJakobsen et al.

Review Article

Antipsychotic treatment of schizotypy

and schizotypal personality disorder:
a systematic review Journal of Psychopharmacology
1­–9
© The Author(s) 2017
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DOI: 10.1177/0269881117695879
https://doi.org/10.1177/0269881117695879
Klaus Damgaard Jakobsen1,2, Eva Skyum2, Nasseh Hashemi2, journals.sagepub.com/home/jop
Ole Schjerning2, Anders Fink-Jensen3 and Jimmi Nielsen1,2,3

Abstract
Schizotypal personality disorder (SPD) is characterised by thought disorders, experiences of illusions, obsessive ruminations, bizarre or eccentric
behaviour, cognitive problems and deficits in social functioning – symptoms that SPD shares with schizophrenia. Efforts have been undertaken to
investigate the relationship between these conditions regarding genetics, pathophysiology, and phenomenology. However, treatment of SPD with
antipsychotics has received less scientific attention. Embase and PubMed databases were searched using all known generic names of antipsychotics as
search terms in combination with the following diagnostic terms: latent schizophrenia, schizotypal disorder, latent type schizophrenia, or SPD. Studies
were categorised according to evidence level on the basis of their methodology from A, being the best, to E, being the worst. Five hundred and nine
studies were retrieved and scrutinised. Sixteen studies, from the period 1972 to 2012, on antipsychotic treatment of SPD were extracted. Four studies
were categorised as evidence level A, two as level B, six as level C and three as level D, with one study level E. Only four randomised, double-blind,
placebo-controlled trials, on subjects with well-defined diagnoses, exists. Only amisulpride, risperidone and thiothixene have been studied according
to evidence level A. This result warrants further high quality studies of the effects of antipsychotic treatment of SPD.

Keywords
Antipsychotics, schizotypal personality disorder, schizotypy, review

Introduction
Schizotypy and schizotypal personality disorder (SPD) have their
nosological origin in the concepts of Bleulers (1911/1950) schizo-
phrenia latens, Hoch and Polatins (1949) pseudoneurotic schizo-
phrenia, Rados (1953) schizotypal, and Meehls (1962) schizotaxia.
Meehl (1989) thought that schizotaxia was the biological tem-
plate, i.e. endophenotype, behind the phenomenological manifes-
tations of schizophrenia spectrum disorders. The schizotaxic
condition is a genetically founded, neurointegrative defect, caus-
ing aberrant synaptic signal selectivity, which under normal social
conditions would cause schizotypy – a personality disorder char-
acterised by ambivalence, aversive drift, autism, cognitive slip-
page, and micro psychosis – and under influence of other genes
and aversive life events would cause schizophrenia. The concept
of SPD was mixed in the APA, Diagnostic and Statistical Manual
of Mental disorders, version II (DSM-II) with the psychodynamic
concept of borderline conditions (e.g. Kernberg, 1967; Gunderson,
1975) until Spitzer re-examined the Danish adoption studies of
Kety (1968) and Kety et al. (1994). This led to criteria that sepa-
rated SPD as a distinct entity in the DSM-III and thereafter in the
DSM-IIIR, -IV, and -V. Contrary to the DSM classification, schi-
zotypy has been classified as a psychosis-related disorder in the
WHO International Classification of Disease (ICD) system, pres-
ently the ICD-10. The present diagnostic criteria for SPD are
shown in Table 1. Much effort and many studies have since been
conducted in order to investigate the relationship between schizo-
taxia, SPD, and schizophrenia, e.g. with regard to genetics, patho-
physiology, and phenomenology, revealing that these conditions
are related, but separate entities (Ettinger et al., 2014; Rosell et al.,
2014). However, relatively few studies have been conducted con-
cerning the psychopharmacological treatment of SPD. Early clini-
cal trials were conducted under a biological, i.e. pharmacological,
paradigm as both diagnostic and pharmacological investigations,
using antidepressants and first generation antipsychotics (FGA),
in order to separate SPD from other borderline conditions, e.g.
histrionic/emotional unstable borderline personality disorders
(BPD) (Soloff et al., 1986b, 1989). Later studies with second gen-
eration antipsychotics (SGA), e.g. risperidone, have focused on
symptom reduction and effects on cognitive performance
(Koenigsberg et al., 2003; McClure et al., 2009). As the symp-
tomatology of SPD is broad and treatment with antipsychotics
may be beneficial in some of these domains, such as psychoticism
1Department of Clinical Medicine, Aalborg University, Aalborg,
Denmark
2Department of Psychiatry, Aalborg University Hospital, Aalborg,
Denmark
3Mental Health Centre Glostrup, University of Copenhagen,
Copenhagen, Denmark
Corresponding author:
Klaus Damgaard Jakobsen, Centre for Schizophrenia, Aalborg University
Hospital, Brandevej 5, 9220 Aalborg OE, Denmark.
Email: kdjakobsen@gmail.com
2 Journal of Psychopharmacology
Table 1.  Diagnostic criteria for schizotypal personality disorder.
DSM-V: SPD (301.22)
•  A
 pervasive pattern of social and interpersonal deficits marked by
acute discomfort with, and reduced capacity for, close relationships
as well as by cognitive or perceptual distortions and eccentricities
of behaviour, beginning in early adulthood and present in a variety
of contexts, as indicated by five or more of the following:
•  Ideas of reference (non-delusional)
•  Odd beliefs or magical thinking that influences behaviour
and is inconsistent with subcultural norms e.g. superstitions,
belief in clairvoyance, telepathy, sixth sense; in children or
adolescents, bizarre fantasies or preoccupations
•  Unusual perceptual experiences including bodily illusions
•  Odd thinking and speech e.g. vague, circumstantial,
metaphorical, over-elaborated or stereotype
•  Suspiciousness or paranoid ideation
•  Odd, eccentric or peculiar behaviour
•  Inappropriate or constricted affect
•  Lack of close friends or confidants other than first-degree
relatives
•  Excessive social anxiety that does not diminish with familiarity
and tends to be associated with paranoid fears rather than
negative judgments about self
•  Does not occur exclusively prior to onset of schizophrenia,
bipolar disorder, depression with psychotic features, other
psychoses or autism spectrum disorders
and hostility, we aimed to systematically review the effects of
antipsychotic treatment on SPD.
Methods
Search strategy
Embase and PubMed were searched on 11 January 2016 by the
use of a search protocol combining the following search terms:
1. Diagnoses – schizotypal equivalents
“SPD” [Mesh] OR (“latent schizophrenia” OR “schizotypal dis-
order” OR “latent type schizophrenia” OR “SPD”). Additionally,
(“casus limitares” OR “casus limitares pseudoneuroticae” OR
“casus limitares pseudopsychopaticae”) were not used as the
search term “Casus limit*” only gave one hit using a PubMed
search.
2. Antipsychotics
(“Antipsychotic Agents” [Mesh]) OR “Antipsychotic Agents”
[Pharmacological Action] OR (antipsychotics OR neurolep-
tics OR risperidone OR olanzapine OR aripiprazole OR que-
tiapine OR perospirone OR ziprasidone OR clozapine OR
amisulpride OR asenapine OR blonanserin OR clothiapine OR
iloperidone OR lurasidone OR mosapramine OR paliperidone
OR remoxipride OR sertindole OR sulpiride OR levomeprom-
azine OR tiapride OR chlorpromazine OR thioridazine OR
mesoridazine OR loxapine OR molindone OR perphenazine
OR thiothixene OR trifluoperazine OR haloperidol OR
ICD-10: Schizotypy (F21.9)
•  A
 condition characterised by eccentric and peculiarities in the way
of thinking and emotional life as can be seen in schizophrenia, but
definite symptoms of schizophrenia is not seen at any time. Symptoms
can include emotional coldness and anhedonia, bizarre behaviour,
social isolation, suspiciousness and bizarre ides that do not develop
into delusions. Obsessive rumination, disordered thinking, perceptual
disturbances and psychosis like episodes with intense illusions,
auditive or other hallucinations and paranoid ideas, without outer
cause, can be seen. The condition has no clear beginning and the
nature of the illness course is that of disordered personality:
•  For at least 2 years or at least four of the following:
•  Inadequate emotions or coldness
•  Eccentric, peculiar or bizarre looks or behaviour
•  Lack of contacts and tendency to social isolation
•  Bizarre or magical thinking, which influences behaviour and
is not part of a subcultural pattern
•  Suspiciousness or paranoid ideation
•  Obsessive rumination without inner resistance with
dysmorphophobic, sexual or aggressive content
•  Unusual perceptional experiences, somatosensory illusions,
depersonalisation and derealisation
•  Vague, metaphoric, artificial or stereotype thinking and speech
•  Micro psychotic episodes with intense illusions, hallucinatory
experiences or paranoid ideation, without outer cause
•  May never have meet the criteria for schizophrenia
fluphenazine OR droperidol OR zuclopenthixol OR pimozide
OR flupenthixol OR prochlorperazine OR promazine OR ace-
promazine OR triflupromazine OR cyamemazine OR chlor-
proethazine OR dixyrazine OR thiopropazate OR
acetophenazine OR thioproperazine OR butaperazine OR
perazine OR periciazine OR pipotiazine OR trifluperidol OR
melperone OR moperone OR pipamperone OR bromperidol
OR benperidol OR fluanisone OR oxypertine OR flupentixol
OR clopenthixol OR chlorprothixene OR tiotixene OR flus-
pirilene OR penfluridol OR clotiapine OR clothiapine OR sul-
topride OR veralipride OR levosulpiride OR prothipendyl OR
zotepine OR cariprazine).
For the search, the following keywords related to the review
subject combined with standard MeSH or Entree terms were
used, as shown in Table 2.
Duplicates were excluded using EndNote. Only articles writ-
ten in English, German or any Scandinavian language were
included. Articles that did not contain information on schizotypal
equivalents and/or antipsychotics in either title or abstract were
excluded.
3. The PubMed search
((((antipsychotics OR neuroleptics OR risperidone OR olanzap-
ine OR aripiprazole OR quetiapine OR perospirone OR ziprasi-
done OR clozapine OR amisulpride OR asenapine OR blonanserin
OR clothiapine OR iloperidone OR lurasidone OR mosapramine
OR paliperidone OR remoxipride OR sertindole OR sulpiride
OR levomepromazine OR tiapride OR chlorpromazine OR thior-
idazine OR mesoridazine OR loxapine OR molindone OR per-
phenazine OR thiothixene OR trifluoperazine OR haloperidol
Jakobsen et al. 3
Table 2.  Schizotypal equivalents used in the search strategy.
Schizotypal equivalents
Classification Year
ICD 7 1955
ICD 8 1965
ICD 9 1975
 
ICD 10 + R 1990
DSM II 1968
DSM III + III R 1980 + 1987
DSM IV + IV TR 1994 + 2000
DSM V 2013
ICD: International Classification of Diseases (World Health Organization (WHO)); DSM: Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric As-
sociation (APA)); Code: diagnostic code according to classification.
OR fluphenazine OR droperidol OR zuclopenthixol OR pimoz-
ide OR flupenthixol OR prochlorperazine OR promazine OR
acepromazine OR triflupromazine OR cyamemazine OR chlor-
proethazine OR dixyrazine OR thiopropazate OR acetophena-
zine OR thioproperazine OR butaperazine OR perazine OR
periciazine OR pipotiazine OR trifluperidol OR melperone OR
moperone OR pipamperone OR bromperidol OR benperidol OR
fluanisone OR oxypertine OR flupentixol OR clopenthixol OR
chlorprothixene OR tiotixene OR fluspirilene OR penfluridol OR
clotiapine OR clothiapine OR sultopride OR veralipride OR
levosulpiride OR prothipendyl OR zotepine OR cariprazine)) OR
((“Antipsychotic Agents”[Mesh]) OR “Antipsychotic Agents”
[Pharmacological Action]))) AND (((“latent schizophrenia” OR
“schizotypal disorder” OR “latent type schizophrenia” OR
“SPD”)) OR “SPD”[Mesh]).
4. The Embase search
(1) SPD/(2149), (2) exp neuroleptic agent/(238729), (3)
(antipsychotics OR neuroleptics OR risperidone OR olanzap-
ine OR aripiprazole OR quetiapine OR perospirone OR
ziprasidone OR clozapine OR amisulpride OR asenapine OR
blonanserin OR clothiapine OR iloperidone OR lurasidone
OR mosapramine OR paliperidone OR remoxipride OR sertin-
dole OR sulpiride OR levomepromazine OR tiapride OR
chlorpromazine OR thioridazine OR mesoridazine OR loxap-
ine OR molindone OR perphenazine OR thiothixene OR trif-
luoperazine OR haloperidol OR fluphenazine OR droperidol
OR zuclopenthixol OR pimozide OR flupenthixol OR
prochlorperazine OR promazine OR acepromazine OR triflu-
promazine OR cyamemazine OR chlorproethazine OR dixyra-
zine OR thiopropazate OR acetophenazine OR thioproperazine
OR butaperazine OR perazine OR periciazine OR pipotiazine
OR trifluperidol OR melperone OR moperone OR pipamper-
one OR bromperidol OR benperidol OR fluanisone OR
oxypertine OR flupentixol OR clopenthixol OR chlorprothix-
ene OR tiotixene OR fluspirilene OR penfluridol OR clotia-
pine OR clothiapine OR sultopride OR veralipride OR
levosulpiride OR prothipendyl OR zotepine OR cariprazine).
mp. (189775), (4) 2 or 3 (248851), (5) (latent schizophrenia or
schizotypal disorder or latent type schizophrenia or SPD).mp.
(2584), (6) 1 or 5 (2584), (7) 4 and 6 (288).
Code Diagnoses
300.5 Latent schizophrenia
295.5 Latent schizophrenia
295.5 Latent schizophrenia
301.22 SPD
F21/F21.9 Schizotypal disorder
295.5 Schizophrenia, latent type
301.22 SPD
301.22 SPD
301.22 SPD
Grading of the retrieved studies
The studies were indexed by year of publication, name of first
author and journal of publication. All studies were further
characterised by number of study subjects, age and gender of
these, use of diagnostic classification, use of psychometrics,
study design, antipsychotics used, study outcomes and study
limitations in order to provide a graduated level of evidence of
the studies. We adapted the grading of evidence, 2011 criteria
from the Centre for Evidence-Based Medicine, Oxford
University, UK. The grading of evidences consisted of five
levels, level A being placebo-controlled double-blind trials
with a diagnostically well-defined sample, level B being the
double blind trials with diagnostically well-defined samples
but without a placebo group, level C being the open trials with
diagnostically less well-defined samples, level D being case
studies or case series and level E being studies with low evi-
dence due to methodological problems, e.g. low number of
study subjects, unclear diagnostic criteria or unspecified out-
come measures.
Results
The PubMed and Embase searches revealed 303 and 288 hits,
respectively.
A total of 591 studies were found in the literature search and
82 were excluded based on language, leaving 509 for further
study of relevancy. This process resulted in 182 articles being
included. Five articles could not be retrieved via the Medical
Library of Aalborg University Hospital.
Of these, only 16 studies from the study period 1972 to 2012
on antipsychotics were retrieved as relevant for the issue of antip-
sychotic treatment of SPD. A flowchart of the search and selec-
tion process is shown in Figure 1. In total, four studies were
considered evidence level A, two studies level B, six studies level
C, three studies level D and one study level E. None of the studies
included used WHO/ICD criteria.
A review of the 16 selected studies is shown in detail in
Table 3.
Study 1 by Reyntjens (1972) was an open-label trial involving
120 subjects and DSM-II criteria, i.e. 102 subjects with mixed
personality disorders, 12 with bipolar disorder and 6 others
4 Journal of Psychopharmacology

Figure 1.  Flowchart of literature search and selection procedure.

medicated with pimozide 3 mg/day for 2 months. The study subjects across diagnoses with improved family, social and pro-
revealed that pimozide 3 mg daily had a resocialising effect in fessional function. Evidence level E.
Table 3.  Details of the 16 selected studies on antipsychotic treatment of SPD.

Study Author Journal No. of Classification and Diagnoses Design Antipsychotic drug Results Limitations Evidence
no. and year Subjects outcome measures level

1 Reyntjens Acta Psychiatrica 120 DSM-II 43 Schizoid, Open label Pimozide 3 mg, daily Resocialising effect with improved DSM-II Open label E
Jakobsen et al.

(1972) Belgica 31 Paranoid, 14 OCD, 14 familial, professional and social function

Hysterical, 12 BPD and 6
others
2 Brinkley Archives of General 5 DSM-II 1. Borderline with temper Case-series 1. Haloperidol 9 mg daily/ 1. Lucidity/control of anger attacks, 2. DSM-II Case-studies D
et al. (1979) Psychiatry outburst, 2. Borderline with perphenazine 16 mg daily, Remission of psychosis, without distinction
brief psychotic episodes, 2. Thiothixene 10 mg daily, 3. Remission of psychosis, 4. Remission between BPD and
3. Borderline with referential 3. Thiothixene 6 mg daily, of anxiety, 5. Remission of anxiety SPD
ideas, 4. Borderline with 4. Perphenazine 8 mg daily,
anxiety, 5. Borderline with 5. Thiothixene 25 mg daily
phobic anxiety
3 Serban American Journal of 52 DSM-III, structured 14 SPD, 16 BPD and 16 6-week to 3 months Haloperidol 3 mg daily, The difference in mean reduction of No placebo group C
and Siegel Psychiatry PSE, Borderline mixed BPD/SPD double blind trial range (2.2–3.8) and psychopathology was near significant (p DSM-III mixed group
(1984) syndrome index, with haloperidol and thiothixene 9.4 mg daily, < 0.08) favouring thiothixene. The study
Hamilton rating scale thiothixene range (1.8–17) concludes that small doses of thiothixene
of depression (HAM) have positive effects
4 Goldberg Archives of General 50 DSM-III, SIB, HSCL-90 BPD or SPD 12-week double blind Thiothixene 8.7 mg daily, No significant drug-placebo differences DSM-III mix of A
et al. (1986) Psychiatry study with thiothixene range (5–35 mg) between BPD and SDP groups. Using SIB BPD and SPD, trial
and placebo psychotic cluster, significant treatment used to propose a
differences were found on illusions and new antipsychotic
ideas of reference. Using the HSCL-90 responsive category
significant differences were found for
obsessive-compulsivity and psychoticism
5 Hymowitz Comprehensive 17 DSM-III, GAS, SIB, TDI SPD 2-week single blind Haloperidol 3.6 mg, range Overall improvement of schizotypal Small sample size C
et al. (1986) Psychiatry placebo period followed (2–12 mg) symptoms assessed by GAS, SIB and TDI Open label study
by a 6-week open trial without control
with haloperidol group in the active
trial phase
6 Soloff et al. Archives of General 64 DSM-III, BDI, GAS, 43.8% BPD, 50% BPD with 5-week double blind Haloperidol 7.24 mg daily, Using SCL-90, haloperidol produced DSM-III mixed C
(1986a, Psychiatry & HAM-17, IMPS, SADS, SPD and 6.2% SPD randomised trial with 20 range (4.05–10.43) a significant change in hostility and sample.
1986b) Psychopharmacology and SSI, SCL-90, Ward amitriptyline trials, 23 paranoid ideation and psychoticism
Bulletin scale of impulse action haloperidol trials and 21
controls
7 Soloff et al. Journal of Clinical 90 DSM-III 38.9% BPD, 56.7% mixed 5-week double blind Haloperidol range 4–16 Using IMPS and SCL-90 haloperidol DSM-III mixed B
(1989) Psychopharmacology GAS, SCL-90, Ham-D24, BPD/SPD and 4.4% SPD placebo with controlled mg daily. significantly improved hostility, sample
BDI, SSI, BDHI, BIS, trial with amitriptyline, psychoticism and reduced the schizotypal
IMPS and STIC haloperidol and placebo. factor in 65.2% of patients
8 Soloff et al. Archives of General 108 DSM-III, BDHI, BDI, 38.9% BPD and 61.1% mixed 21-week randomised Haloperidol 6 mg No significant interactions between DSM mixed sample B
(1993) Psychiatry GAS, SCL-90, IMPS, SSI BPD/SPD placebo-controlled medication and SPD on measures of
and HAM trial with haloperidol, schizotypal symptoms, psychoticism,
phenelzine and placebo. anger and hostility.
9 Schulz et al. Biological Psychiatry 11 DSM-III & R, SCL-90, BPD, 7 with SPD 8-week open-label study Olanzapine 7.73 mg daily, 14% symptom reduction on SIB, 55% Small sample, open C
(1999) BPRS, SIB, GAF, BIS, range (5.12–10.34) symptom reduction on SCL-90 and 29% label
SCID, SCID-II and BDHI improvement on GAF. SIB factor I and IV
was significantly reduced.

(Continued)
5
 6

Table 3.  (Continued)

Study Author Journal No. of Classification and Diagnoses Design Antipsychotic drug Results Limitations Evidence
no. and year Subjects outcome measures level

10 Bogetto Psychiatry Research 23 DSM-IV, Yale-Brown OCD, Tic-disorder or SPD 12-week open-label Fluvoxamine 300 mg daily/ 4 cases had SPD (17.4%). 4 (40%) Small sample size C
et al. (2000) Y-BOCS Scale, Ham-17 trial with olanzapine olanzapine 5 mg, daily augmentation responders had SPD. Open label study
and SCID-II augmentation for 6 Comorbid SPD was significantly correlated without control
months fluvoxamine with augmentation response group
treatment resistant
cases
11 Koenigsberg Journal of Clinical 25 DSM-IV, SCID-I, SIDP- SPD 9-week randomised, Risperidone up-titration to Significant lower PANNS scores in the Small sample A
et al. (2003) Psychiatry IV, SPQ, and PANNS double-blind, placebo- 2 mg, daily risperidone group than placebo group
Positive and negative controlled study with week 5 and 7
scale risperidone.
12 Keshavan Schizophrenia 11 DSM-IV, SCID, PDE SPD 26 week open-label Olanzapine 9.32 mg daily, Significant improvements were seen in Small sample size, C
et al. (2004) Research and OAS study with flexible dose range (6.57–11.07 mg) positive, negative and depressive and open-label and lack
design overall functioning of control group
13 Nagata et al. Psychiatry 1 DSM-IV Anorexia nervosa and SPD Case report Haloperidol 3 mg, daily After 2 weeks of treatment she improved Case report D
(2007) and Clinical both regarding SPD-symptoms and weight
Neurosciences gain
14 Kumar et al. Journal of Clinical 1 DSM-IV and SPQ SPD Case report, 8-week Aripiprazole 10 mg, daily 70% symptom reduction described. Single subject case D
(2008) Psychiatry follow up study
15 McClure Journal of Clinical 31 DSM-IV, SPD 2-week single-blind Risperidone up-titration to No significant differences on cognition Small study and A
et al. (2009) Psychopharmacology Neuropsychological placebo lead in 2 mg, daily between risperidone and placebo groups high dropout rate.
battery followed by a 10-week week 6 and 12.
double-blind trial with
risperidone or placebo
16 Koychev European 248 SPQ, N-back task, SWM, SPD Double-blinded Amisulpride 400 mg or Amisulpride improved cognitive measures Single-dose study. A
et al. (2012) Neuropharmacology VF and IQ. randomised placebo risperidone 2 mg in the high schizotypy group. All patients received
controlled trial nicotine
investigating the Study were not
effect on cognition of designed to assess
single-dose exposure effect of medication
to amisulpride, or
risperidone after initial
exposure to nicotine

SPD: schizotypal personality disorder; BPD: borderline personality disorders; DSM-II, III and IV: diagnostic and statistical manuals of mental disorders, version II, III, IV; SCID and SCID –II: structured clinical interview for DSM, axis
I & II; SIDP-IV: schedules for interviewing DSM-IV personality disorders; HAM, Ham-17, HAM-24: Hamilton rating scale of depression, version 17 or 24; GAS: global assessment scale; HSCL-90: Hopkins symptom checklist-90; SIB:
schedules for interviewing borderlines; TDI: thought disorder index; SADS: schedules for affective disorders and schizophrenia; BDI: beck depression inventory; IMPS: multidimensional psychiatric rating scale; SSI: schizotypal symptom
inventory; SCL-90: symptom checklist; DIB: diagnostic interview for borderlines; BDHI: Buss–Durkee hostility inventory; BIS: Barratt impulsiveness scale; STIC: self-report test of impulse control; BPRS: brief psychiatric rating scale;
Y-BOCS: Yale–Brown obsessive-compulsive scale; SPQ: schizotypal personality questionnaire; PANSS: positive and negative symptoms scale; PDE: personality disorder examination; OAS: overt aggression scale; spatial and verbal
working memory: neuropsychological battery testing; N-back Task: vigilance, spatial memory and word list learning, working memory; SWM Task: spatial working memory; VF: verbal fluency; IQ: task and national adult reading test.
Journal of Psychopharmacology
Jakobsen et al. 7
Study 2 by Brinkley et al. (1979) was a case series using
DSM-II on five subjects with borderline conditions. Case 1
(44-year-old woman) with temper outbursts was treated with
haloperidol 9 mg/day for 2 weeks followed by perphenazine 16
mg/day, which provided control of anger attacks. Case 2 (37-year-
old woman) with brief psychotic episodes was treated with thio-
thixene 10 mg/day for a month with remission of psychosis. Case
3 (37-year-old woman) with referential ideas was treated with
thiothixene 6 mg/day followed by remission of psychosis. Case 4
(34-year-old woman) with anxiety was treated with perphenazine
8 mg/day with total remission and case 5 (44-year-old woman)
with phobic anxiety was treated with thiothixene 25 mg/day for
12 months with remission. Evidence level D.
Study 3 by Serban and Siegel (1984) was a 6-week to
3-months double-blind study with 52 subjects diagnosed accord-
ing to DSM-III. Fourteen subjects had SPD, 16 subjects had BPD
and 16 subjects had mixed SPD/BPD. The study used haloperidol
3 mg/day and thiothixene 9.4 mg/day. Thirty-nine (84%)
improved moderately-markedly, the thiothixene group improved
more than the haloperidol group. Areas of response were cogni-
tion, derealisation, ideas of reference, anxiety and depression,
though not significantly. Evidence level C.
Study 4, by Goldberg et al. (1986) was a 12-week double-blind
placebo-controlled trial with 50 subjects with either BPD or SPD
characterised by the DSM-III criteria. The study tested thiothixene
8.7 mg/day against placebo. There were no significant drug–placebo
differences between BPD and SPD groups. Significant differences
were found regarding illusions, ideas of reference, psychoticism,
obsessive-compulsiveness and anxiety. Evidence level A.
Study 5 by Hymowitz et al. (1986) was a 2-week single-blind
trial followed by 6-week open-label trial with 17 subjects meet-
ing DSM-III criteria of SPD who was treated with haloperidol
3.6 mg/day. Ratings as displayed in Table 2 showed statistical
mild to moderate improvement in 50% of subjects, but the drop-
out effect was 50% due to side effects. Evidence level C.
Study 6 by Soloff et al. (1986a, 1986b) was a 5-week double-
blind randomised trial with haloperidol and amitriptyline. The 64
study subjects had DSM-III verified BPD (43.8%), BPD with
SPD (50%) and SPD (6.2%). Comorbidity was assessed using
The Schedule for Affective disorders and Schizophrenia (SADS).
Study subjects were treated with haloperidol 7.2 mg/day.
Significant medication effects with baseline scores as covariates
were found on self-rated measures: somatisation, interpersonal
sensitivity, anxiety, hostility, paranoid ideation psychoticism fac-
tors and the general severity index. Evidence level C.
Study 7 by Soloff et al. (1989) was a 5-week double blind pla-
cebo controlled with haloperidol and amitriptyline. The 90 study
subjects were assessed by DSM-III, 38.9% had BPD, 56.7% and
mixed BPD and SPD and 4.45 had SPD. Study subjects were
treated with haloperidol 10 mg/day. Haloperidol was superior to
amitriptyline and placebo by significantly improving hostility, psy-
choticism and the schizotypal factor by 65.2 %. Evidence level B.
Study 8 by Soloff et al. (1993) was a 21-week randomised
placebo-controlled trial with 108 subjects diagnostically classi-
fied using the DSM-III criteria. Thirty-eight point nine per cent
had BPD and 61.1% had mixed BPD/SPD. Study subjects were
treated with haloperidol and phenelzine. Haloperidol dosage was
6 mg/day. The study provides significant evidence for effects of
haloperidol on SPD, i.e. schizotypal symptoms, psychoticism,
anger and hostility. Evidence level B.
Study 9 by Schulz et al. (1999) was an 8-week open-label
study with 11 study subjects using DSM-III-R /IV criteria,
including the Structured Clinical Interview for Axis II (SCID-II).
Seven out of eleven subjects with BPD meet the criteria for SPD
as well. Study subjects were treated with olanzapine 7.7 mg/day.
The total score of each of the scales utilised in the study was
significantly reduced during treatment. Level of evidence C.
Study 10 by Bogotto et al. (2000) was a 12-week open-label
augmentation trial on 23 subjects with DSM-IV, including
SCID-II, diagnoses. All subjects had obsessive-compulsive dis-
order, of these 13% had a comorbid diagnosis of tic disorder and
SPD was present in 17.4% of subjects. Subjects were treated with
olanzapine 5 mg/day as augmentation to fluvoxamine. The study
found a significant association between having SPD and effect of
olanzapine augmentation. Evidence level C.
Study 11 by Koenigsberg et al. (2003) was a 9-week double-
blind randomised placebo-controlled trial on 25 study subjects
with DSM-IV SPD using SCID-I and The Schedule for
Interviewing DSM-IV personality disorders-IV (SIDP-IV).
Subjects were treated with risperidone up to 2 mg/day. Subjects
receiving risperidone had significant lower Positive and Negative
Symptom Scale (PANSS) scores on the general symptom scales
and PANSS positive and negative scales than subjects receiving
placebo. Evidence level A.
Study 12 by Keshavan et al. (2004) was a 26-week open-label
study on 11 subjects with DSM-IV diagnoses using the Structured
Clinical Interview for DSM-IV (SCID) and personality disorder
evaluation (PDE). Mean dose of olanzapine was 9.3 mg/day.
Diagnostic assessment and outcome measures were done as
shown in Table 2. The post treatment scores on the symptom
severity scales were significantly reduced as well as in overall
functioning. Evidence level C.
Study 13 by Nagata et al. (2007) is a 2-week case report with
DSM-IV chronic anorexia nervosa for 30 years with concomitant
SPD. After 2 weeks of treatment with haloperidol 3 mg/day, the
subject’s impulsiveness and SPD symptoms improved as well as
a weight gain was recorded. Evidence level D.
Study 14 by Kumar et al. (2008) is an 8-week case report with
a DSM-IV (SCID) SPD. The subjects were treated with aripipra-
zole 10 mg/day. A 70% symptom reduction was observed.
Evidence level D.
Study 15 by McClure et al. (2009) was a 10-week double-
blind placebo-controlled trial on 31 subjects with DSM-IV
verified SPD. A cognitive battery was used to assess neuropsy-
chological deficits. Risperidone was up titrated to 2 mg/day. No
significant differences could be found between the risperidone
and placebo-treated subjects. Evidence level A.
Study 16 by Koychev et al. (2012) was a single dose ran-
domised placebo-controlled trial of the effect on cognition of
nicotine, amisulpride 400 mg and risperidone 2 mg. Two hundred
and forty-eight subjects with SPD out of 13,275 possible candi-
dates were recruited. In the high SPD group, amisulpride was
found to improve neuropsychological performance. Evidence
level A.
Discussion
The main results of this review were that evidence supporting use
of antipsychotics in the treatment of SPD is sparse and any firm
clinical recommendations cannot be made. Only four studies met
8 Journal of Psychopharmacology
evidence level A criteria, with one of them being a single-dose
study by Koychev et al. (2012). Although this study found that,
especially, amisulpride could reverse some of the cognitive dys-
function in SPD, these results should be interpreted cautiously as
the effect of continuous exposure remains unknown.
Consequently, long-term studies investigating the effect of ami-
sulpride on level of functioning are warranted.
Although the results were not consistent throughout the whole
study period, Koenigsberg et al. (2003) found a positive effect of
2 mg risperidone on the PANSS total and all subscales.
Interestingly, some of these patients participated in a study inves-
tigating the effect of risperidone on cognitive measures and
found no effect (McClure et al., 2009). Thiothixene was also
studied in a double-blind design with negative results but an
effect was seen in patients with borderline features (Goldberg
et al., 1986).
Although, the overall effect of antipsychotics was not impres-
sive, several studies suggested that antipsychotics as a group
improved psychotic-like symptoms, such as illusions, psychoti-
cism, hostility and paranoid ideations (Goldberg et al., 1986;
Soloff et al., 1986a, 1986b, 1993).
The findings of this study should be interpreted within its
limitations. The 16 selected studies were published during the
period 1972–2012 and differed substantially in methodological
quality. Only four randomised, placebo-controlled trials have
been performed on diagnostically clear samples of considerable
size. Most studies were designed as open label or case series
testing the effect of either antidepressants or antipsychotics on
samples of small size with mixed diagnostic categories with
most of these studies being older. In contradiction to the large
amount of genetic, pathophysiological, neurocognitive, phe-
nomenological and diagnostic studies done on the relationship
between SPD, schizotaxia and schizophrenia – the published
data on pharmacological treatment aspect of SPD is sparse. A
diagnostic issue in future treatment trials of SPD is whether or
not SPD belongs to the schizophrenia spectrum disorders – as
micro psychoses are part of the WHO definition of SPD, but not
of the APA criteria. Another aspect is how SPD is regarded in
relation to schizophrenia. Danish studies has shown that the con-
version rate of ICD-10 schizotypy to schizophrenia is 25–50%,
2–5 years after the initial diagnose of schizotypy (Nordentoft
et al., 2006; Parnas et al., 2011), but both samples was biased
due to special selection procedures and/or small sample size.
Large-scale observational naturalistic studies on the conversion
rate of SPD to schizophrenia are missing. Lacking information
on the conversion rate of SPD to schizophrenia from large scale
observational studies leave researchers to use exclusion of SPD
as prodromal schizophrenia (Zhang et al., 2015) and therefore
preferably recruit study subjects that have passed the age of
onset of schizophrenia, i.e. 35 years of age. This may be the
cause of the sparse literature on antipsychotic treatment of SPD
because of the condition being seen as a schizophrenia prodrome
rather than a unique illness to study in its own right, also regard-
ing antipsychotic treatment.
SPD has primarily, previously, been studied as personality
disorder according to the DSM criteria, but not as a schizophre-
nia spectrum disorder according to ICD-criteria, in relation to
treatment with antidepressants, antipsychotics and mood-stabi-
lisers with the purpose to pharmacologically separate SPD from
BPD and to investigate the effect of different classes of psycho-
tropics (Herpertz et al., 2007; Ingenhoven et al., 2010; Ripoll
et al., 2011). These investigations have shown that antipsychotics
have a modest effect on cognition and perception and a better
effect on anger, hostility and impulsiveness. Antidepressants
seem not to have an effect on impulse-control and only a modest
effect on affect-regulation, while mood-stabilisers seem to have a
larger effect on impulsiveness. Nevertheless, studies investigat-
ing other core the features of SPD other than micro psychoses,
e.g. disordered and magical thinking, paranoid ideation, obses-
sive rumination, bizarre behaviour and low social functioning,
are missing.
Treatment of SPD is highly relevant, including from a public
health point of view, as SPD is heritable with a prevalence of
4–16% of non-psychotic first degree relatives of schizophrenics
and with a prevalence of 2–3% in the general population and is
associated with significant costs for the society (Torti et al.,
2013). Although not supported by the findings in this review,
treatment of SPD for transient/brief psychotic symptoms with
antipsychotics seems to be reasonable for obvious reasons.
Untreated psychoses can have devastating health consequences
for the individual and its surroundings, e.g. suicide or violent
behaviour towards others. However, continuous antipsychotic
treatment may also potentially be beneficial with regard to
improvement of cognitive and executive function, disorganised
and disordered thinking, behavioural oddness or bizarreness
and of overall general social functioning in SPD. As the double-
blind studies were few and most studies have questionable
methodology, the overall treatment-trend using antipsychotics
for SPD is reduction of psychoticism including impulsivity and
anger may still be indicated. Risks and benefits should be care-
fully evaluated and discussed with the patients before and dur-
ing the intervention. In cases where benefits are not clearly
outweighing the risks, treatment should be discontinued.
Investigation of interventions on these particular treatment-
domains in future clinical trials would overcome the diagnostic
discrepancy between APA (DSM-V) and WHO (ICD-10) crite-
ria regarding SPD. Such studies would determine whether cur-
rent clinical practice is appropriate.
Conclusion
The evidence supporting use of antipsychotics in the treatment of
SPD is sparse as randomised double blind placebo-controlled tri-
als are very few and the results are inconsistent. Minor evidence
supports an effect of risperidone; a strict evaluation, with the
patient, of risks and benefits are recommended before and during
treatment with antipsychotics are warranted. Further studies
investigating effects of antipsychotics on more specific domains
of SPD are warranted in order to enhance the evidence for treat-
ment of SPD with antipsychotics.
Declaration of conflicting interests
The author(s) declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this article:
Dr. Jakobsen has been a consultant for AstraZeneca, on an advisory board
for Bristol Myers Squibb and received speaker’s honoraria from
Lundbeck Pharma. Dr. Nielsen has received speaker honoraria from
Hemocue, Lundbeck, Sunovion and Bristol Myers Squibb and research
grants from H. Lundbeck and Pfizer. Dr. Fink-Jensen has received an
unrestricted research grant from Novo Nordisk. Dr. Schjerning has
received speaker honoraria from Lundbeck. BMsc Skyum and BMsc
Hashemi have no conflicts of interest.
Jakobsen et al. 9
Funding
The author(s) received no financial support for the research, authorship,
and/or publication of this article.
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