PERSONALITY DISORDERS

LITERATURE REVIEW Open Access

Review of pharmacologic treatment in cluster A personality

disorders

Jessa Koch, PharmD1; Taylor Modesitt, PharmD2; Melissa Palmer, PharmD2;

Sarah Ward, PharmD1; Bobbie Martin, PharmD, BCPP3; Robby Wyatt, MD4;
Christopher Thomas, PharmD, BCPP, BCPS5

How to cite: Koch J, Modesitt T, Palmer M, Ward S, Martin B, Wyatt R, Thomas C. Review of pharmacologic treatment in cluster A personality disorders. Ment Health Clin
[Internet]. 2016;6(2):75-81. DOI: 10.9740/mhc.2016.03.75.

Abstract
Introduction: A personality disorder is a pervasive and enduring pattern of behaviors that impacts an
individual’s social, occupational, and overall functioning. Specifically, the cluster A personality disorders
include paranoid personality disorder, schizoid personality disorder, and schizotypal personality disorder.
Patients with cluster A personality disorders tend to be isolative and avoid relationships. The quality of life
may also be reduced in these individuals, which provokes the question of how to treat patients with these
personality disorders. The purpose of this review is to evaluate the current literature for pharmacologic
treatments for the cluster A personality disorders.
Methods: A Medline/PubMed and Ovid search was conducted to identify literature on the psychopharma-
cology of paranoid personality disorder, schizoid personality disorder, and schizotypal personality disorder.
There were no exclusions in terms of time frame from article publication or country of publication, in order
to provide a comprehensive analysis; however, only articles that contained information on the cluster A
disorders were included.
Results: Minimal evidence regarding pharmacotherapy in paranoid and schizoid personality disorders was
found. Literature was available for pharmacologic treatment of schizotypal personality disorder. Studies
evaluating the use of olanzapine, risperidone, haloperidol, fluoxetine, and thiothixene did yield beneficial
results; however, treatment with such agents should be considered on a case-by-case basis.
Discussion: Most of the literature analyzed in this review presented theoretical ideas of what may constitute
the neurobiologic factors of personality and what treatments may address these aspects. Further research is
needed to evaluate specific pharmacologic treatment in the cluster A personality disorders. At this time,
treatment with pharmacologic agents is based on theory rather than evidence.

Keywords: schizotypal personality disorder, schizoid personality disorder, paranoid personality disorder,
cluster A, pharmacotherapy

1
PGY-2 Psychiatric Pharmacy Resident, Chillicothe VA Medical Center,
Chillicothe, Ohio; 2 PGY-1 Pharmacy Practice Resident, Chillicothe VA
Introduction
Medical Center, Chillicothe, Ohio; 3 Clinical Pharmacy Specialist in
Psychiatry, Chillicothe VA Medical Center, Chillicothe, Ohio; 4 Staff
Personality disorders are said to exist when a person’s
Psychiatrist, Chillicothe VA Medical Center, Chillicothe, Ohio; Clinical pattern of perceiving, relating to, and thinking about the
Assistant Professor of Psychiatry, Ohio University Heritage College of environment and oneself results in maladaptive behavior
Osteopathic Medicine, Athens, Ohio; 5 (Corresponding author) Clinical
and significant impairment in interpersonal relationships
Pharmacy Specialist in Psychiatry, PGY-1 and PGY-2 Residency Program
Director, Chillicothe VA Medical Center, Chillicothe, Ohio, cthcal@aol. and interactions. These patterns of inner experience and
com behavior are inflexible and pervasive, causing clinically
Q 2016 CPNP. The Mental Health Clinician is a publication of the College of Psychiatric and Neurologic Pharmacists. This is an
open access article distributed under the terms of the Creative Commons Attribution-NonCommercial 3.0 License, which
permits non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
significant distress or impairment in social, occupational, Methods
or other important areas of functioning.1
A literature review on the psychopharmacology of
Personality disorders are often characterized by symp- paranoid personality disorder, schizoid personality disor-
der, and schizotypal personality disorder was conducted
toms (eg, psychoticism in schizotypal personality disorder)
through PubMed and Ovid searches using combinations of
that are similar or nearly identical to pharmacotherapy-
the following search terms: schizotypal personality disorder
responsive symptoms seen in other mental disorders (eg,
treatment, pharmacotherapy schizotypal, antipsychotic
auditory hallucinations in schizophrenia). However, symp-
schizotypal, risperidone schizotypal, olanzapine schizotypal,
tomatic similarity does not equal etiologic or pathophys- aripiprazole schizotypal, quetiapine schizotypal, paliperidone
iologic similarity; therefore, similarity in response and schizotypal, clozapine schizotypal, ziprasidone schizotypal,
tolerability of pharmacotherapy cannot be assumed. It lurasidone schizotypal, asenapine schizotypal, iloperidone
was this presumed difference in etiology between schizotypal, haloperidol schizotypal, amitriptyline schizoty-
historically axis I (more biologic in origin) and axis II pal, fluoxetine schizotypal, guanfacine schizotypal, pergolide
(more psychological in origin) disorders that contributed schizotypal, schizoid personality disorder pharmacotherapy,
to previous recommendations discouraging the use of pharmacotherapy of personality disorders, paranoid person-
pharmacotherapy for personality disorders.2 ality disorder, and cluster a personality disorders. Only
papers that contained information on the cluster A
However, for certain dimensions of personality, such as personality disorders were included. There were no
impulsive-aggression, schizotypy, and novelty seeking, exclusions in terms of time frame from article publication
neurobiologic correlates have been demonstrated, sug- or country of publication, in order to provide a
gesting that some aspects of personality disorders may be comprehensive analysis. Of note, many of the articles
amenable to pharmacologic intervention.3-5 Based on included were based on Diagnostic and Statistical Manual
these findings and the results of efficacy studies, recent of Mental Disorders, 4th edition (DSM-IV) diagnostic
guidelines now recommend the judicious use of pharma- criteria. There were no changes made between DSM-IV
cotherapy as an adjunctive treatment in the overall and DSM-5 regarding the criteria for the personality
management of patients with severe personality disor- disorders.
der.6 There are currently no medications with US Food
and Drug Administration approval for use in personality
Paranoid Personality Disorder
disorders. All use of medications for symptoms of
personality disorders is considered off-label. This review Paranoid personality disorder is described as a pervasive
will focus on available evidence regarding the use of suspicion of others’ motives and behaviors in a variety of
pharmacotherapy for paranoid, schizoid, and schizotypal contexts. Individuals with this disorder may be considered
personality disorders, collectively known as the cluster A ‘‘odd’’ or ‘‘eccentric’’ by others and have a lack of close
personality disorders. relationships. The Table more thoroughly defines this
disorder and diagnostic criteria per DSM-5. The prevalence
Pharmacotherapy for personality disorders tends to be of paranoid personality disorder is not exactly known, but
symptom specific, focusing on dimensions of personality is estimated to be between 2% and 4% of the population.1
believed most likely to be responsive to pharmacotherapy This review intends to summarize the literature regarding
treatment for paranoid personality disorder, specifically
and that typically warrant the most clinical attention.
pharmacotherapy.
These dimensions include affective dysregulation (eg,
angry, anxious, depressed, labile mood), cognitive-per-
Overall, a review of the literature yields very little research
ceptual symptoms (eg, auditory, visual hallucinations), and
regarding pharmacotherapy options for the treatment of
impulsive aggression (eg, self-cutting, suicidality).2,6 The
paranoid personality disorder. The reason for this has been
use of pharmacotherapy is adjunctive, with the goal of theorized by multiple authors. The belief is that a paucity
providing enough stabilization to make it easier or of research exists because of the general lack of trust
possible for the patient to engage in psychosocial patients with paranoid personality disorder have for
interventions. The risks and benefits of pharmacotherapy others, with psychiatric providers being no exception.7,8
must be carefully considered, especially in a situation In reference to paranoid personality disorder, Angstman
where expected benefits may be modest.2,6 It is the goal and Rasmussen7 wrote, ‘‘These patients are difficult to
of this review to provide answers to questions regarding engage in a therapeutic relationship for medical or mental
the use of pharmacotherapy for cluster A personality health issues. . . Physicians should expect belittling com-
disorders and bring the reader up to date regarding what ments, accusations, and potentially litigious threats from
is known and unknown about the effectiveness of this these patients. . .’’ This behavior not only limits the
practice. likelihood of the patient seeking medical attention but

Ment Health Clin [Internet]. 2016;6(2):75-81. DOI: 10.9740/mhc.2016.03.75 76

TABLE: Diagnostic and Statistical Manual of Mental Disorders, 5th edition, personality disorders definitions and diagnostic
criteria

Personality
Disorder Definition Diagnostic Criteria

Paranoid Pattern of distrust and suspicion such A. 4 of the following:

that others’ intentions are (1) Questions if others are manipulating or deceiving him or her
interpreted as malignant
(2) Doubts the loyalty of friends and family
(3) Believes that confiding in others will lead to manipulation of given
information
(4) Interprets hidden meanings in nonthreatening remarks
(5) Bears grudges
(6) Believes personal assaults are being taken against his or her repute
(7) Distrusts the faithfulness of his or her significant other without
justification
B. Does not occur exclusively during the course of a psychotic disorder and
is not attributable to a medical condition
Schizoid Pattern of disengagement from social A. 4 of the following:
connections and a flattened range (1) Avoids or dislikes close relationships
of emotional articulation
(2) Prefers solitary activities
(3) Has minimal interest in sexual interactions with other
(4) Derives no enjoyment from activities
(5) Has few close friends, excluding family
(6) Apathetic to praise or criticism
(7) Displays emotional aloofness or flattened affectivity
B. Does not occur exclusively during the course of a psychotic disorder and
is not attributable to a medical condition
Schizotypal Pattern of severe discomfort in A. 5 of the following:
intimate relationships, mental or (1) Thoughts of reference
perceptual alterations, and
peculiarity of behavior (2) Strange beliefs or magical ideas
(3) Perceptual alterations
(4) Abnormal thinking and speech
(5) Paranoia
(6) Inappropriate or restricted affect
(7) Atypical behaviors
(8) Lack of close relationships, excluding family
(9) Presence of social anxiety
B. Does not occur exclusively during the course of a psychotic disorder and
is not attributable to a medical condition

also detracts from the collaborative therapeutic relation- Of the few articles written, a case series by Birkeland9
ship between provider and patient. Triebwasser et al8 retrospectively analyzed the psychiatric hospitalization
suggest that ambivalence in the diagnosis itself contrib- course of 15 patients in Denmark with paranoid person-
utes to the lack of research. Because the predominant ality disorder. Clinical Global Impression was rated at first
characteristic of paranoid personality disorder is paranoia admission and the last psychiatric visit in order to assess
itself—a common feature of numerous other psychiatric any clinical improvement. Birkeland9 found that a total of
conditions, such as posttraumatic stress disorder and 7 patients received an antipsychotic; the most commonly
schizophrenia—clinicians may be more apt to give prescribed one was flupentixol. Other antipsychotic
patients a diagnosis of a comorbid condition rather than medications prescribed included bromperidol and proma-
the personality disorder. Overall, the characteristics of zine. The median duration of treatment was 15 weeks. Of
paranoid personality disorder (ie, bearing grudges) likely the 15 patients, only 4 who received antipsychotic
have contributed to the dearth of research into the medication therapy were present for the 6-week follow-
treatment of this disorder. up. All 4 of these patients demonstrated improvement as

Ment Health Clin [Internet]. 2016;6(2):75-81. DOI: 10.9740/mhc.2016.03.75 77

measured by the Clinical Global Impression Improvement arthritis, obesity, and coronary artery disease.13 It has
(CGI-I) scale (CGI-I mean 1.8 compared with baseline CGI even been suggested by some researchers and clinicians
Severity [CGI-S] mean 5.5), over those who did not receive that patients with schizoid personality disorder may be
antipsychotic medication (CGI-I mean 4.0 compared with classified into two distinct classification groups of affect
baseline CGI-S mean 4.8). At the last follow-up visit, 3 of constricted or seclusive, and therefore could be classified
the 4 patients who received antipsychotic medications under other personality disorder diagnoses, such as
had improved, whereas 1 patient’s condition had wors- schizotypal personality disorder or avoidant personality
ened; however, the specific CGI-I values were not disorder, respectively.13
included. Additionally, of the 10 patients who were not
lost to follow-up, antidepressant medications had been Conducting a primary literature search for pharmacologic
administered to a total of 7 patients. Only 3 patients treatment in schizoid personality disorder yields no
demonstrated benefit as measured by a decrease in individual results and is typically categorized with all
depression symptoms; however, objective measures on other personality disorders. The focus of pharmacologic
this outcome were not included in the publication.9 treatment of personality disorders is based on patient-
specific symptoms—for example, many of the symptoms
Duggan et al10 conducted a systematic review of of schizoid personality disorder are similar to the negative
randomized controlled trials of the use of pharmacologic symptoms in schizophrenia.14
treatments for patients with personality disorders. The
meta-analysis of 35 trials favored the use of anticonvul- The lack of literature regarding pharmacotherapy is most
sants to reduce aggression and antipsychotics to reduce likely contributable to the reclusiveness of these patients
cognitive perceptual and mental disturbances. Paranoid and the difficulty in establishing and maintaining a
thinking and ideation fell under the cognitive perceptual therapeutic relationship.7 Overall, pharmacologic treat-
domain, yet no study included was actually conducted ment could be considered in patients with schizoid
with a patient who had paranoid personality disorder; personality disorder if there are other comorbid psychi-
rather, paranoid ideation was an outcome listed second- atric disorders requiring treatment.
ary to borderline personality disorder (a cluster B
personality disorder).
Schizotypal
Unfortunately, the extreme scarcity of research leaves the Individuals with schizotypal personality disorder often feel
question open as to what pharmacologic treatment may uncomfortable relating to other people, and although
or may not be effective for paranoid personality disorder. they may express displeasure about a lack of relationships,
At this time, perhaps the best option may be to treat the their behavior suggests a lack of desire for close
emergent symptomatology in patients with paranoid interactions (Table). These individuals are often anxious
personality disorder. Ongoing study is needed to further in social situations, especially with unfamiliar individuals,
direct pharmacotherapy for the treatment of paranoid which make large studies of patients with schizotypal
personality disorder. At this time, a Cochrane Review is personality disorder challenging. Although the reported
being conducted on the effectiveness of all pharmacologic rates of schizotypal personality disorder range from 0.6%
interventions used in the treatment of paranoid person- to 4.6% of the population, only an estimated 0% to 1.9%
ality disorder.11 Perhaps this review will offer guidance of individuals present to the health care setting.1
into further treatment options.
Literature regarding pharmacotherapy for schizotypal
personality disorder is limited to small studies that
Schizoid Personality Disorder examine olanzapine, risperidone, haloperidol, thiothixene,
Schizoid personality disorder is described in DSM-5 as a and fluoxetine. These studies were commonly confounded
pattern of detachment from social relationships and a by the addition of patients with borderline personality
restricted range of emotional expression (Table).1 Schizoid disorder.15-19
personality disorder is considered uncommon in clinical
settings and may be the least common of the cluster A Keshavan et al18 conducted an open-label study of
disorders.1,12 It is estimated that schizoid personality olanzapine in 11 patients with schizotypal personality
disorder is prevalent in 0.5% to 7% of the general disorder in 2004. Only 8 of 11 patients completed the 26-
population and up to 14% in the homeless population.7 week study; however, an intent-to-treat analysis was used.
Schizoid personality disorder has been associated with Study noncompletion was due to lack of follow-up and the
both psychiatric and medical disorders, including dysthy- need for multiple medications to stabilize the patient’s
mia, mania, panic disorder with agoraphobia, social psychiatric condition. Significant improvements were seen
phobia, generalized anxiety disorder, violent behavior, in positive and negative symptoms, depressive symptoms,

Ment Health Clin [Internet]. 2016;6(2):75-81. DOI: 10.9740/mhc.2016.03.75 78

and overall level of functioning based on the Brief from baseline to end point. Major limitations of the study
Psychiatric Rating Scale, Hamilton Depression (HAM-D) included the confounder of patients with borderline
scale, and Global Assessment Scale (GAS). No significant personality disorder and the lack of a control group.
extrapyramidal symptoms were observed. Additionally, no
significant changes in liver function tests, complete blood A double-blind, placebo-controlled study, conducted by
counts, or electrocardiograms were detected. However, Goldberg et al16 in 1986, examined thiothixene or placebo
significant weight gain was observed, with an average in 50 patients with borderline and/or schizotypal person-
gain of 7.33 6 9.6 kg. Major study limitations included the ality disorder during the course of 12 weeks. All patients
open-label design, inclusion of comorbid psychiatric had at least 1 psychotic symptom, and 40% of patients
disorders, small sample size, concomitant use of dival- had both schizotypal and borderline personality disorder.
proex and sertraline by a study subject, and lack of The Schedule for Interviewing Borderlines (SIB) was used
comprehensive evaluation of metabolic complications to evaluate patients weekly. The GAS was used to
(blood glucose, cholesterol, etc). evaluate patients as well. No significant differences were
seen in borderline or schizotypal clusters for the SIB or
Koenigsberg et al17 conducted a 9-week, randomized, GAS. Major limitations of this study were a small sample
double-blind, placebo-controlled trial of risperidone in 25 size and the inclusion of patients with borderline
patients with schizotypal personality disorder in 2003. This personality disorder. Additionally, the symptoms evaluat-
study excluded patients with borderline personality ed were clustered into 4 domains that included schizoty-
disorder as a primary diagnosis, as well as patients with pal criteria, borderline criteria, SIB criteria psychotic in
schizophrenia or bipolar disorder. However, patients nature, and miscellaneous. Therefore, the analysis was not
commonly had secondary personality disorders. Investi- designed to look at specific symptoms within these
gators obtained weekly symptom measurements by domains, which may have shown differences.
means of the Positive and Negative Syndrome Scale
(PANSS). The PANSS total score declined during the 9- A 12-week, prospective, nonblind study of fluoxetine in
week trial period in the treatment group but did not patients with borderline and/or schizotypal personality
decline in the placebo group. Patients in the treatment disorder was conducted in 1991.19 The study consisted of
group had significantly lower PANSS total scores than the individuals who presented to clinic on their own behalf
placebo group at weeks 3, 5, 7, and 9. Patients in the with symptoms of anxiety or depression. A total of 13
treatment group exhibited significantly lower PANSS patients had a diagnosis of Major Depressive Disorder
negative scores versus placebo at weeks 3, 5, and 7. (MDD), and 10 patients were receiving psychotherapy. A
However, the treatment group did not exhibit lower total of 12 patients reported self-mutilating behavior at
PANSS negative scores versus placebo at week 9. There baseline. By week 9 of the study, 50% fewer individuals
were several major limitations to the study, including a were self-injurious, and the total number of self-mutilative
high rate of secondary personality disorders, a small episodes had decreased by 74%. By week 12, only 2
sample size, an error in the randomization process, and a patients were still engaged in cutting behaviors, and these
high dropout rate. Additionally, because of the stepwise occurred less than one time per week. The Hopkins
dosing of risperidone, it was difficult to determine Symptom Checklist (HSCL) mean score was used to assess
whether improvement at certain weeks was due to an symptoms of depression and anxiety. The mean scores at
increase in dose or an increased length of treatment. weeks 3, 6, and 9 indicated a progressive decline in
symptom severity. However, it was not until week 12 that
A double-blind study conducted by Serban and Siegel15 in patients consistently noted improvement. The changes in
1984 examined either low-dose thiothixene or low-dose HSCL scores were similar across personality disorder
haloperidol in 52 patients with chronic schizotypal and/or diagnoses. The presence or absence of MDD did not
borderline personality disorder. The study demonstrated appear to affect scores at the end point. However, higher
efficacy of both drugs across all diagnoses, with baseline scores, indicating greater symptom severity, were
thiothixene exhibiting a greater response than haloperi- seen in the MDD group. There were many limitations of
dol. The Psychiatric Assessment Interview revealed this study, including the self-reported nature of all end
statistically significant symptom improvement from base- points, relevance of end points for schizotypal personality
line to end point within each treatment group for all disorder, nonblinded and per-protocol design, and use of
factors tested, which included general symptoms, anxiety, lorazepam and chloral hydrate to treat insomnia. Addi-
depression, derealization, paranoia, and ideas of refer- tionally, the inclusion of patients with borderline person-
ence. Thiothixene produced statistically significant im- ality disorder, concomitant MDD, and patients receiving
provement in general symptoms, depression, and psychotherapy can be considered study limitations.
paranoia compared with haloperidol. There was no
significant difference between the drugs on the HAM-D Interestingly, 3 studies have been conducted in schizotypal
scale, but each treatment group improved significantly patients examining the effect of pharmacotherapy on

Ment Health Clin [Internet]. 2016;6(2):75-81. DOI: 10.9740/mhc.2016.03.75 79

negative symptoms. The negative symptoms assessed in in developing a therapeutic relationship and continuity of
these studies included context processing, cognitive care.
deficits, and working memory. McClure et al20 conducted
a 4-week, randomized, double-blind, placebo-controlled Overall, most of the literature found was for the
study of the effects of guanfacine on context processing treatment for schizotypal personality disorder. As illus-
abnormalities. This study demonstrated that subjects in trated in ‘‘Methods,’’ the most search terms were used
the guanfacine group made less errors related to context when reviewing data for schizotypal personality disorder,
processing, to a statistically significant degree, compared which has the potential to bias the results. However, the
to the placebo group. The authors concluded that additional searches were completed after discovering
guanfacine may help improve some cognitive deficits information concerning schizotypal personality disorder
seen in the schizophrenia spectrum. McClure et al21 and specific medications. No specific medication informa-
conducted a 4-week, double-blind, placebo-controlled tion was found using the basic searches for paranoid
study on the effects of pergolide on cognitive deficits personality disorder or schizoid personality disorder, so
further search terms were not indicated. Even with the
associated with schizotypal personality disorder. Patients
greater number of articles for schizotypal personality
exhibited statistically significant improvements in pro-
disorder, the literature has limitations. The use of
cessing speed, executive functioning, working memory,
olanzapine, risperidone, haloperidol, fluoxetine, and thio-
and verbal learning and memory. Rosell et al22 conducted
thixene did yield beneficial results in patients with
a study of the effects of dihydrexidine, a selective D1
schizotypal personality disorder; however, treatment with
dopamine receptor agonist, on working memory in 16 such agents should be considered on a case-by-case basis.
patients with schizotypal personality disorder. This study
showed improved working memory during 1 of the 2 tests The literature review conducted on paranoid personality
administered. It is important to consider that pergolide is disorder and schizoid personality disorder yielded no
no longer available in the United States because of an controlled trials. There was a single case series of
increase in valvular heart defects. Additionally, dihydrex- treatment of paranoid personality disorder in Denmark,
idine is only available in intravenous formulation and has a but there were no conclusive results to guide future
short duration of action. Finally, all 3 of the medications treatment recommendations beyond the tentative con-
investigated in this area affect norepinephrine or dopa- clusion that an antipsychotic may be beneficial. Similarly,
mine in the prefrontal cortex, which poses the possibility because of the complete lack of evidence for schizoid
of interactions with antipsychotic medications. Limita- personality disorder, no recommendation for pharmaco-
tions of these studies include small sample size, adverse therapy treatment can be offered at this time.
effects of interventions, and lack of availability of agents.
In conclusion, most of the literature analyzed in this
Overall, olanzapine, risperidone, thiothixene, haloperidol, review presented theoretical ideas of what may constitute
and fluoxetine exhibited beneficial effects in patients with the neurobiologic factors of personality and what
schizotypal personality disorder. Unfortunately, many of treatments may address these aspects. Further research
the studies were confounded by the inclusion of patients is needed to evaluate specific pharmacologic treatment in
with borderline personality disorder. As described above, the cluster A personality disorders. At this time, treatment
the various limitations of the existing literature require with pharmacologic agents is based on theory rather than
practitioners to apply these findings to clinical practice evidence.
with caution.
Acknowledgments
Conclusion This material is the result of work supported with resources
and the use of facilities at the Chillicothe Veterans Affairs
Despite the impact that a cluster A personality disorder Medical Center in Chillicothe, Ohio. The contents of this paper
may have on an individual, limited research is available does not represent the views of the US Department of
regarding pharmacologic treatment. As noted in the Veterans Affairs or the US government.
paranoid personality disorder section, there are several
proposals for why there may be a lack of research.
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