TP Borderline - Tratam 1

CNS Drugs 2008; 22 (8): 671-692
REVIEW ARTICLE 1172-7047/08/0008-0671/$48.00/0
© 2008 Adis Data Information BV. All rights reserved.
Efficacy and Tolerability of

Pharmacotherapies for Borderline
Personality Disorder
Silvio Bellino, Erika Paradiso and Filippo Bogetto
Unit of Psychiatry, Department of Neurosciences, Service for Personality Disorders,
University of Turin, Turin, Italy
Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 671
1. Efficacy and Tolerability of Antidepressant Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673
1.1 MAOIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 673
1.2 Tricyclic and Heterocyclic Antidepressants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 674
1.3 SSRIs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 675
2. Efficacy and Tolerability of Mood Stabilizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
2.1 Lithium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 677
2.2 Carbamazepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 678
2.3 Oxcarbazepine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
2.4 Valproate Semisodium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 679
2.5 Lamotrigine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 680
3. Efficacy and Tolerability of Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681
3.1 First-Generation Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 681
3.2 Atypical Antipsychotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 683
4. Meta-Analyses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 687
Abstract Borderline personality disorder is a pervasive pattern of instability of inter-

personal relationships, affects and self-image, as well as marked impulsivity.
Although psychotherapy is needed to attain lasting improvements in a patient’s
personality and overall functioning, practice guidelines state that pharmacother-
apy is indicated to manage state symptoms and trait vulnerabilities. Three psycho-
pathological dimensions are the main targets for pharmacotherapy of borderline
personality disorder: affective dysregulation, impulsive-behavioural dyscontrol
and cognitive-perceptual symptoms. Guidelines recommend the use of antidepres-
sant agents and mood stabilizers for affective dysregulation and impulsive-
behavioural dyscontrol, and antipsychotics for cognitive-perceptual symptoms.
672 Bellino et al.
This review aims to report and discuss data from clinical trials, reviews and
meta-analyses concerning drug efficacy and tolerability in the treatment of
borderline personality disorder. Investigations that considered antidepressant
agents mainly focused on SSRIs, which are recommended as first-line treatments
for affective instability and impulse dyscontrol. Both open-label and randomized
controlled studies have been performed, predominantly concerning the efficacy of
fluoxetine and fluvoxamine. Other classes of antidepressants, such as TCAs and
MAOIs, were investigated as alternative treatments for borderline personality
disorder, but the risk of adverse effects and toxicity is a limitation to their use in
clinical practice. Increasing amounts of data have recently been collected on the
use of mood stabilizers to control mood instability and impulsivity in patients with
borderline personality disorder. More substantial data were derived from control-
led trials of valproate semisodium, although other drugs such as lithium, carbama-
zepine, oxcarbazepine and lamotrigine were tested with promising results. Several
first-generation antipsychotics were studied in open-label and controlled trials,
with good effects on behavioural dyscontrol and psychotic-like symptoms. Selec-
tion biases and heterogeneity of drugs and methods somewhat limited the value of
these results. More recent investigations have examined atypical antipsychotics,
with most of these studies being open-label trials with small sample sizes;
however, a few controlled studies have been performed using olanzapine, show-
ing improvements in impulsivity, anger and hostility.
In conclusion, a large number of different drugs have been evaluated in the
treatment of patients with borderline personality disorder. Initial findings are
encouraging for many of these drugs. However, data need to be replicated in
further controlled studies with head-to-head comparisons and long-term follow-
ups. Many questions remain to be answered.
The essential feature of borderline personality evidence that some personality dimensions of pa-
disorder is a pervasive pattern of instability of inter- tients appear to be mediated by dysregulation of
personal relationships, affects and self-image, as neurotransmitter physiology and are responsive to
well as marked impulsivity that begins by early medication.[5,6] Symptoms exhibited by patients
adulthood and appears in a variety of contexts.[1] with borderline personality disorder often fall within
Although psychotherapy is needed to attain and three psychopathological dimensions that are a tar-
maintain lasting improvements in a patient’s person- get for pharmacotherapy: affective dysregulation,
ality, interpersonal problems and overall function- impulsive-behavioural dyscontrol and cognitive-
ing,[2,3] American Psychiatric Association (APA) perceptual symptoms. APA guidelines[4] recom-
guidelines state that pharmacotherapy is indicated to mend choosing antidepressant agents, in particular
manage state symptoms during periods of acute SSRIs and MAOIs, and mood stabilizers for affec-
decompensation, as well as trait vulnerabilities.[4] tive dysregulation; SSRIs and mood stabilizers for
The pharmacological approach to the treatment impulsive-behavioural dyscontrol; and antipsychot-
of borderline personality disorder is based on the ics for cognitive-perceptual symptoms. Although
© 2008 Adis Data Information BV. All rights reserved. CNS Drugs 2008; 22 (8)
Pharmacotherapy of Borderline Personality Disorder 673
medications are widely used to treat patients with 1. Efficacy and Tolerability of
borderline personality disorder, the US FDA has not Antidepressant Agents
approved any medications specifically for the treat-
ment of this disorder.
This article reviews available data concerning 1.1 MAOIs
efficacy and tolerability of agents that have been
studied in the treatment of borderline personality Three placebo-controlled studies have tested the
disorder. A systematic search of published open- efficacy of MAOIs in the short-term treatment of
label and randomized, placebo-controlled trials con- borderline personality disorder.[7-9]
cerning pharmacotherapy of borderline personality In the trial by Cowdry and Gardner[7] tranyl-
disorder was performed on the online database cypromine, trifluoperazine, alprazolam and carba-
PubMed using the key words ‘borderline personality mazepine were compared with placebo in a group of
disorder’, ‘pharmacotherapy’, ‘antidepressants’, patients with borderline personality disorder and
‘mood stabilisers’, ‘anticonvulsants’ and ‘antipsy- concomitant hysteroid dysphoria. Tranylcypromine
chotics’. Data from open-label studies and from (40 mg/day) had significant effects on a variety of
randomized controlled studies were distinguished mood symptoms, such as depression, anger and sen-
for each class of drugs, in order to make clear the sitivity to rejection (table I). This drug also reduced
different level of evidence. the severity of impulsivity and suicide intentions,
Table I. Double-blind controlled trials of antidepressants in the treatment of borderline personality disorder
Drug and study Study design No. of Treatment Results with antidepressant drug
(comparator drugs) patients duration (wk)
MAOIs
Tranylcypromine
Cowdry and Gardner[7] db, pc (alprazolam, 16 6 ↓ Anger/hostility, ↓ depression,
trifluoperazine, ↓ impulsivity/suicidality vs placebo
carbamazepine)
Phenelzine
Soloff et al.[9] co, pc (haloperidol) 108 5 ↓ Anger/hostility vs placebo
TCAs
Amitriptyline
Soloff et al.[10] db, pc (haloperidol) 90 5 ↓ Depression, hostility, ↑ self-control vs
placebo
Desipramine
Links et al.[11] co, pc (lithium) 10 6 No significant differences between
desipramine and placebo
SSRIs
Fluoxetine
Coccaro and Kavoussi[12] db, pc 40 12 ↓ Irritability, ↓ aggressiveness vs placebo
Markovitz[13] db, pc 17 14 ↓ Anxiety/depression, ↓ global symptoms
vs placebo
Salzman et al.[14] db, pc 27 12 ↓ Anger/hostility, ↓ depression, ↑ global
functioning vs placebo
Fluvoxamine
Rinne et al.[15] co, pc 38 12 ↓ Affective instability vs placebo
co = crossover; db = double-blind; pc = placebo-controlled; ↓ indicates decreased; ↑ indicates increased.
674 Bellino et al.
while the effect on behavioural dyscontrol was close sonality disorder present high levels of impulsivity
to a significant level. and poor compliance; therefore, psychiatrists should
Parsons et al.[8] compared phenelzine (60 mg/ carefully explain the serious consequences of violat-
day) and imipramine (200 mg/day) in outpatients ing dietary restrictions, describe the picture of
with atypical depression and secondary co-morbidi- MAOI intoxication and give emergency instructions
ty with borderline personality disorder. Global im- in case a hypertensive crisis occurs.[4] Moreover,
provement was reported by 92% of patients admin- patients must be carefully informed that they must
istered phenelzine compared with 35% of patients discontinue an SSRI a long time (up to 5 weeks for
administered imipramine. fluoxetine) before beginning MAOI therapy, to
avoid the risk of serotonin syndrome.
Phenelzine was administered by Soloff and col-
leagues[9] in inpatients with borderline personality In summary, available controlled studies indicate
disorder and co-occurrence of major depression that MAOIs can be useful in treating borderline
(53%), hysteroid dysphoria (44%) or atypical de- personality disorder, with main effects on symptoms
pression (46%). The results of this controlled study of atypical depression, anger and impulsivity. These
indicated that phenelzine significantly decreased effects are considered to be independent of the an-
self-rated anger and hostility, but was not effective tidepressive action of these drugs,[9] although a
in reducing hysteroid dysphoria or atypical depres- study found that patients with a history of major
sion compared with haloperidol or placebo. depression or bipolar II disorder showed a non-
significant trend to a better response.[7]
The three reported studies of MAOIs in border-
line personality disorder had a short duration (5–6
1.2 Tricyclic and
weeks).[7-9] When a 5-week treatment with phen-
Heterocyclic Antidepressants
lezine 90 mg/day was continued for a further
16 weeks in a continuation study, only a modest The TCAs amitriptyline, imipramine and desi-
reduction of depression and irritability was obtained pramine have been tested in randomized controlled
in comparison with placebo.[16] trials of inpatients and outpatients with borderline
Concerning tolerability, phenelzine can provoke personality disorder.
weight gain,[9] but the most serious adverse event Soloff et al.[10] examined a group of inpatients
related to MAOI administration is hypertensive cri- with borderline personality disorder, comparing the
sis. Although hypertensive crises may be fatal, the effects of amitriptyline (mean dosage 149 mg/day)
risk of these events in patients with psychiatric with haloperidol and placebo. Amitriptyline was
disorders is estimated to be <1%,[17] and no cases of found to be superior to placebo in treating depres-
hypertensive episodes have been reported in patients sive symptoms and indirect hostility, and signifi-
with borderline personality disorder who failed to cantly improved self-control. It is notable that the
comply with tyramine dietary restrictions. MAOI core symptoms of the Hamilton Depression Rating
toxicity is characterized by delirium, agitation, Scale did not improve with amitriptyline, while the
hyper-reflexia, hallucinations, tachycardia, tachy- antidepressant was effective on the associated
pnoea, dilated pupils, diaphoresis and convulsions. symptoms of diurnal variation, depersonalization,
Hyperpyrexia is a very serious symptom associated paranoid symptoms, obsessive-compulsive symp-
with MAOI toxicity.[18] Adherence to dietary restric- toms, helplessness, hopelessness and worthlessness.
tions is of primary importance and must be the focus No significant differences were found between pa-
of patient education. Patients with borderline per- tients with and without co-morbid major depression.
On the contrary, schizotypal and paranoid symp- In conclusion, available data suggest that the
toms were associated with a poorer treatment res- response to TCAs in patients with borderline per-
ponse. sonality disorder appears modest. The risk of behav-
A few studies of TCAs in patients with borderline ioural toxicity and the potential lethality of TCAs in
personality disorder showed less favourable re- overdose support the preferential use of SSRIs or
sults.[8,11] related antidepressants for treating these patients.
Desipramine was not found to be better than

1.3 SSRIs
placebo in treating depression, anger and suicide
behaviours, when it was examined in a crossover A considerable number of studies have focused
comparison of this drug (mean dosage 162.5 mg/ on the central serotonergic system as a possible
day) with lithium carbonate (mean dosage target for psychopharmacological intervention for
985.7 mg/day) and placebo in outpatients with bor- impulsive-aggressive and suicidal patients.[12,20-25]
derline personality disorder and a low level of co- On the basis of these pharmacological hypo-
morbidity with mood disorders. Moreover, no dif- theses, open-label and randomized controlled trials
ferences were found between desipramine and pla- have been performed to test the efficacy of SSRIs in
cebo in the psychiatrist and patient perceptions of the treatment of symptoms of affective lability, im-
global improvement at 3 and 6 weeks.[11] pulsivity and aggressiveness of patients with border-
In a group of outpatients with atypical depression line personality disorder.[12-15,26-37] Findings of these
and concomitant borderline personality disorder, the trials showed that fluoxetine, sertraline and venla-
TCA imipramine was less efficacious than the faxine (a reuptake inhibitor of serotonin and norad-
MAOI phenelzine.[8] Imipramine 200 mg/day had a renaline [SNRI]) induced a significant decrease in
35% response rate, versus 92% for phenelzine.[8] symptoms of affective instability, dyscontrol of im-
Symptoms of borderline personality disorder pre- pulsivity, cognitive-perceptual abnormalities and
dicted a poor response to imipramine, but a good global functioning in patients with borderline per-
response to phenelzine. sonality disorder.[12-15,28,30,32,34,35,37] Fluoxetine (up
to 80 mg/day), sertraline (up to 200 mg/day) and
TCAs induce frequent adverse effects, such as
venlafaxine (up to 400 mg/day) produced effects on
sedation, dry mouth, constipation and weight gain.[1]
aggressiveness, depression, dysphoria and self-inju-
These drugs present a considerable risk of toxicity
rious tendencies after treatments of 8–12 weeks.[13]
and particular caution is needed when they are ad-
Some of these trials reported that improvement of
ministered in patients with suicidal intentions.[4] Fa- impulsivity occurred in a short time, usually in the
tal arrhythmias are possible in patients with first week of treatment, and was not related to ef-
heart conduction disturbances. Blood concentra- fects on depression or anxiety.[12] Furthermore,
tions should be measured to minimize the risk of some authors found that the lack of response to one
toxicity. SSRI was not a negative predictor of response for all
Some authors have reported that the use of ami- SSRIs. They suggested switching patients who did
triptyline in patients with borderline personality dis- not respond to a first trial with a serotonergic antide-
order may be associated with behavioural toxici- pressant to another drug of the same class.[26] In fact,
ty.[19] This term referred to the increase of such some patients who did not respond to fluoxetine
symptoms as impulsivity, aggressive behaviours, 80 mg/day had good results with sertraline
paranoia and suicidal intentions. 100–200 mg/day.[13] Other patients who did not
676 Bellino et al.
respond to SSRIs improved significantly after re- der were excluded, but dysthymic disorder, depres-
ceiving the SNRI venlafaxine. Higher doses of the sive disorder not otherwise specified, anxiety disor-
same SSRI and a longer duration of treatment (24 ders, and alcohol and substance abuse were
weeks instead of the usual 12 weeks) can also con- common. Fluoxetine had significant effects on ver-
vert a substantial proportion of patients from poor to bal aggression and aggression against objects after
good response, as was the case in a group of patients 10 weeks of treatment. However, global improve-
receiving sertraline.[13] ment was already significant at week 4 and irritabili-
To date, four double-blind, placebo-controlled ty decreased at week 6.[12]
studies are available on the efficacy and tolerability In a later study, Rinne et al.[15] tested the efficacy
of SSRIs in the treatment of borderline personality of fluvoxamine (mean dosage 166 mg/day) versus
disorder.[12-15] placebo in a sample of 38 women with borderline
Markovitz[13] conducted the first of these trials in personality disorder. Results of the study showed
a group of 17 patients with borderline personality that fluvoxamine, but not placebo, produced a robust
disorder and high co-occurrence of mood/anxiety and long-lasting reduction in the subscale scores for
disorders and somatic symptoms. The trial lasted 14 rapid mood shifts. In contrast, no difference between
weeks. Patients who received fluoxetine 80 mg/day the fluvoxamine and placebo groups was observed
had significantly better results in global symptoms, with regard to the effect on impulsivity and aggres-
depression and anxiety in comparison with patients sion scores. Rinne et al.[15] suggested that this latter
receiving placebo. Impulsivity and aggression were finding may be because of gender-specific differ-
not assessed. Some patients taking fluoxetine show- ences in impulsivity and aggression.
ed an improvement in somatic symptoms, such as In summary, SSRIs (particularly fluoxetine and
premenstrual symptoms and headache. fluvoxamine) were found to be efficacious in treat-
In the same period, a 12-week, double-blind trial ing borderline personality disorder in available con-
of fluoxetine (20–60 mg/day) was performed by trolled studies. The effects of these drugs concerned
Salzman and colleagues[14] in 27 patients with bor- symptoms of affective instability (depression,[13-15]
derline personality disorder or traits. Patients had a anxiety[12-14] and anger[14]), impulsive dyscontrol
good level of functioning (a mean score of 74 on the (verbal aggression and aggression against ob-
Global Assessment Scale) and did not present co- jects,[12] and global severity of the disorder[12-14]).
morbidity with Axis I or II disorders. Fluoxetine Concerning tolerability, SSRIs present a lower
induced a significant improvement in symptoms of incidence and milder severity of adverse effects than
anger and depression, and increased the level of tricyclic and heterocyclic antidepressants and
global functioning in the 22 patients completing the MAOIs. Risk of toxicity is also lower. The highly
trial. Reductions in anger and depression were inde- specific actions of SSRIs in enhancing serotonergic
pendent of each other. neurotransmission appear to explain their benefit,
In a 12-week, double-blind trial of fluoxetine while the lack of direct actions on other neurotrans-
(20–60 mg/day), Coccaro and Kavoussi[12] studied a mitter systems is responsible for their superior toler-
group of 40 patients with severe symptoms of im- ability profile compared with older antidepres-
pulsivity and aggression in the context of a personal- sants.[39,40]
ity disorder (approximately one-third had a DSM- Double-blind controlled trials of antidepressants
III-R[38] diagnosis of borderline personality disor- in the treatment of borderline personality disorder
der). Co-morbid major depression or bipolar disor- are summarized in table I.
2. Efficacy and Tolerability of ality disorder affective instability and bipolar disor-
Mood Stabilizers der rapid mood cycling could be a rationale for the
use of mood stabilizers in patients with borderline
The concept of mood stabilizers is widely applied
personality disorder.[48]
by clinicians and researchers to indicate a range of
To date, several open-label and controlled trials
compounds used in the treatment of bipolar disor-
have been performed to test the efficacy and tolera-
der, although international regulatory authorities do
bility of these agents in borderline personality disor-
not recognize mood stabilizing as a specific mecha-
der, and to specify their effects on different dimen-
nism of action.[41-46] A consensus definition of the
sions of borderline psychopathology (table II).
term has not yet been established.[47] Nevertheless,
mood stabilizers have been operationally described 2.1 Lithium
as agents that are efficacious in at least one of the
three phases of bipolar disorder (mania, bipolar de- In three reviews since the late 1980s,[54-56] lithium
pression or long-term maintenance), while not in- was reported to be an effective treatment for patients
creasing the frequency or severity of any of the other with borderline personality disorder. Its activity in-
phases of the illness.[41] No drugs used as mood volves three interacting systems: (i) modulation of
stabilizers have been approved by the FDA for the neurotransmitters, which may contribute to neuro-
treatment of borderline personality disorder; how- protection by readjusting excitatory and inhibitory
ever, these drugs are often prescribed off-label in activity balance; (ii) modulation of signals im-
clinical practice and are suggested by the APA pacting on the cytoskeleton, including glycogen
guidelines for the treatment of borderline personali- synthase kinase-3β, cyclic adenosine monophos-
ty disorder.[4] phate-dependent kinase and protein kinase C, which
Some investigators have suggested that a com- may be critical for the neural plasticity involved in
mon mechanism underlying both borderline person- mood stabilization; and (iii) regulation of second
Table II. Double-blind controlled trials of mood stabilizers in the treatment of borderline personality disorder
Drug and study Study design No. of Treatment Results with mood stabilizers
(comparator drugs) patients duration
Lithium
Links et al.[11] co (desipramine) 10 6 wk ↓ Irritability/anger, ↓ self-mutilation vs
desipramine
Carbamazepine
Gardner and Cowdry[49] co, pc 14 6 wk ↓ Behavioural dyscontrol vs placebo
Cowdry and Gardner[7] db, pc (alprazolam, 16 6 wk ↓ Behavioural dyscontrol vs placebo
trifluoperazine,
tranylcypromine)
Valproate semisodium
Hollander et al.[50] db, pc 16 10 wk ↓ Global symptomatology, ↓ irritability/
aggressivity, ↑ social functioning vs
placebo
Hollander et al.[51] db, pc 52 12 wk ↓ Impulsive aggression vs placebo
Frankenburg and Zanarini[52] db, pc 30 6 mo ↓ Interpersonal sensitivity, ↓ anger/
hostility, ↓ aggressiveness vs placebo
Lamotrigine
Tritt et al.[53] db, pc 24 8 wk ↓ Anger vs placebo
co = crossover; db = double-blind; pc = placebo-controlled; ↓ indicates decreased; ↑ indicates increased.
678 Bellino et al.
messengers, transcription factors and gene expres- thyroid function, ECG, blood counts and biochemis-
sion.[57] try, should be undertaken before treatment.
A review by Stein,[58] regarding lithium and the Periodic monitoring of plasma lithium concentra-
antiepileptic drug carbamazepine in the treatment of tions, as well as thyroid and kidney function, is
patients with borderline or antisocial personality indicated with prolonged lithium use.
disorder, suggested the effectiveness of both agents
2.2 Carbamazepine
on behavioural dysregulation and aggressiveness.
The only controlled trial of lithium in borderline Carbamazepine acts by blocking voltage-gated
personality disorder was a crossover comparison sodium channels and is indicated by the FDA for use
with desipramine performed in a group of ten pa- as an anticonvulsant drug.[63] Although this agent is
tients for 6 weeks.[11] Results showed the efficacy of commonly used by clinicians in the treatment of
lithium on core features of borderline personality borderline personality disorder, its use for this indi-
disorder psychopathology, such as irritability, anger cation has not been officially approved.
and self-mutilation.[11] A clinical practice survey performed by Denicoff
Lithium can be toxic to many organs, particularly and colleagues[64] compared carbamazepine with
after long-term use; however, most adverse effects many other agents (lithium, valproate sodium, anti-
are not severe and can be reduced or eliminated by psychotics, clonazepam, phenytoin, calcium chan-
lowering the dose or changing the dosage sched- nel antagonists) and electroconvulsive therapy in
1257 patients with different neurological and psy-
ule.[59] Metabolic adverse effects are particularly
chiatric disorders. These investigators reported that
dangerous and include hypothyroidism (up to 36%
carbamazepine led to significant global improve-
of patients in the study of bipolar I disorder patients
ment in the subgroup of patients with borderline
by Fagiolini et al.[60]), hyperparathyroidism and cal-
personality disorder.
cium level changes, weight gain and nephrogenic
In a crossover trial of carbamazepine in 14 fe-
diabetes insipidus (almost 20% of patients accord-
male outpatients with borderline personality disor-
ing to Van Gerven and Boer[61]). In addition, pa-
der, Gardner and Cowdry[49] demonstrated its effi-
tients may report other adverse effects related to the
cacy in decreasing the frequency and severity of
cardiovascular system (syncope, ECG abnormali-
behavioural dyscontrol. These preliminary findings
ties, circulatory failure), nervous system (blurred
were confirmed by further investigations: a 6-week
vision, tremors, vertigo, ataxia, nystagmus), kidney
placebo-controlled study comparing carbamazepine
(renal impairment) and gastrointestinal disturbance
(mean dosage 820 mg/day), alprazolam (4.7 mg/
(nausea, vomiting, diarrhoea).[62] Concomitant ad- day), trifluoperazine (7.8 mg/day) and tranyl-
ministration of NSAIDs, diuretics, renin-angioten- cypromine (40 mg/day) in the treatment of patients
sin inhibitors, theophylline and antibacterials has with borderline personality disorder and co-morbid
been reported to cause elevations in serum lithium hysteroid dysphoria;[7] and a review of double-blind
concentrations. Furthermore, lithium is potentially trials of drug therapy for personality disorders that
fatal in overdose, and current guidelines suggest that reported a marked improvement in impulsive ag-
it should be used with caution in patients at risk of gression following treatment with carbamaze-
suicide.[4] pine.[65]
A full medical history, as well as laboratory Further controlled trials suggested the effective-
investigations, including renal and liver function, ness of carbamazepine on a wider range of symp-
toms, including not only impulsive-aggressive be- Two patients withdrew from the study in the first 4
haviours[66] but also affective dysregulation,[67,68] weeks of treatment as a result of noncompliance. A
which is often the main goal of the use of mood statistically significant improvement was observed
stabilizers when treating patients with borderline in global psychopathology, anxiety, interpersonal
personality disorder. relationships and borderline personality disorder
Carbamazepine can induce several adverse ef- core features, including impulsivity, affective insta-
fects, including CNS disturbances (diplopia, blurred bility and outbursts of anger. These initial findings
vision, ataxia), fatigue and nausea.[69] Less common appear promising and provide preliminary evidence
are skin rash, mild leukopenia or thrombocytopenia, of a broad spectrum of action of this drug in patients
and hyponatraemia.[70] Idiosyncratic, potentially fa- with borderline personality disorder; however, con-
tal events have rarely been reported: agranulocyto- trolled trials of larger patient groups are needed to
sis, aplastic anaemia, exfoliative dermatitis, and se- replicate these data.
rious hepatic and pancreatic toxicity. Overdose of Concerning tolerability, the most frequent ad-
carbamazepine may have fatal effects. Periodic verse events during treatment with oxcarbazepine
measurement of the white blood cell count is recom- are dizziness, nausea, headache, somnolence and
mended.[4] fatigue.[86] Hyponatraemia may occur (albeit often
Data from a single study of patients with border- asymptomatically), particularly in the elderly. How-
line personality disorder related the use of carbama- ever, serum sodium level monitoring is not neces-
zepine to the onset of melancholic depression.[49] sary, unless relevant risk factors exist.[87] Severe
haematological dyscrasias have not been report-
2.3 Oxcarbazepine ed.[86] The enzyme-inducing interaction of ox-
carbazepine with ethinylestradiol and levonorgestrel
Oxcarbazepine is an antiepileptic agent structur- requires additional precautions for women using
ally related to carbamazepine, and shares the same hormonal contraception.[87]
mechanism of action of blocking voltage-gated so-
dium channels, but is less likely to induce cyto- 2.4 Valproate Semisodium
chrome P450 enzymes and to cause drug interac-
tions.[63] Valproate semisodium is an antiepileptic drug
Several trials have shown the efficacy of ox- facilitating the transmission of GABA.[88] This drug
carbazepine in the treatment of psychiatric disor- has been extensively studied in patients with border-
ders, such as bipolar disorder, substance abuse dis- line personality disorder.
order, resistant psychosis and schizoaffective disor- Initial findings regarding possible efficacy of this
der;[71-84] however, as in the case of carbamazepine, agent in treating patients with borderline personality
oxcarbazepine has been approved by the FDA for disorder came from open-label studies. Firstly, Wil-
treating seizure disorders only. cox[89] tested valproate semisodium in a group of
No randomized controlled trials are available that patients with psychomotor agitation due to different
investigate the use of oxcarbazepine in the treatment underlying psychiatric disorders and observed a
of borderline personality disorder. Initial data can be particularly marked reduction of agitation after
drawn from an open-label trial that was performed treatment in patients with bipolar disorder or border-
by our group, which investigated the 12-week treat- line personality disorder. Wilcox[90] then replicated
ment of 13 borderline personality disorder outpa- these data in a further trial that focused on borderline
tients with oxcarbazepine 1200–1500 mg/day.[85] personality disorder treatment.
680 Bellino et al.
Another 8-week, open-label trial of valproate tors found significant effects on interpersonal sensi-
semisodium (daily dose titrated to reach blood con- tivity, anger, hostility and aggressiveness.
centrations of 50–100 μg/mL) in 11 patients with Valproate semisodium causes dose-related ad-
borderline personality disorder by Stein and col- verse effects, such as gastrointestinal dysfunction
leagues[91] suggested the effect of the molecule on (nausea), mild transaminase elevations, tremor, se-
clinician-rated measures of overall psychopath- dation and weight gain.[93] Less common adverse
ology, mood, anxiety, anger, impulsivity and rejec- events are asymptomatic leukopenia and thrombo-
tion sensitivity in four of the eight patients who cytopenia. Idiopathic and potentially fatal events are
completed the study. represented by rare agranulocytosis, and hepatic and
Kavoussi and Coccaro[92] studied the efficacy of pancreatic toxicity.[94] Periodic monitoring of blood
8-week valproate semisodium therapy (up to 2000 cell count and hepatic function should be pro-
mg/day) in ten patients with several axis II diagno- vided.[4] After long-term treatment of women, poly-
cystic ovaries and hyperandrogenism can occur.
ses who had not responded to a previous trial with an
SSRI (two patients met the criteria for borderline
2.5 Lamotrigine
personality disorder). They reported a reduction in
irritability and impulsive aggressiveness after treat- The antiepileptic lamotrigine has recently been
ment. employed in the treatment of depressive episodes of
More reliable data derive from three placebo- bipolar disorder and in the prevention of recurrences
controlled trials.[50-52] of this disorder. This agent inhibits neuronal excita-
In a 10-week, double-blind trial of valproate bility and modifies synaptic plasticity by inhibiting
semisodium (medium plasma concentration 80 μg/ voltage-activated sodium channels. Indirectly, these
mL) in 16 patients with borderline personality disor- effects would be expected to regulate aberrant intra-
cellular and intercellular signalling in critical re-
der, Hollander and colleagues[50] found a marked
gions of the limbic forebrain.[95]
improvement in global symptomatology, social
functioning and borderline personality disorder fea- The use of lamotrigine in patients with borderline
personality disorder was firstly reported by Pinto
tures, such as depressive symptoms, aggressiveness,
and Akiskal[96] in a 1-year open-label trial of the
irritability and suicidal ideation or behaviour. How-
drug (daily dose up to 300 mg), suggesting an im-
ever, a high dropout rate (ten patients) precluded
provement in global functioning, sexual impulsive-
finding any significant differences between val-
ness, substance abuse and suicidal behaviour.
proate semisodium and placebo treatment groups.
A review by Green[97] of patients with mood
More recently, in a 12-week, double-blind trial, disorders also suggested the efficacy of this agent in
the same authors confirmed the efficacy of valproate treating mood instability of borderline personality
semisodium (mean daily dose 1325 mg) on impul- disorder.
sive aggression in 52 outpatients with borderline More recently, Preston and colleagues[98] investi-
personality disorder.[51] gated the frequency of co-morbid borderline person-
Frankenburg and Zanarini[52] performed a ality disorder in 35 patients with bipolar disorder
6-month, placebo-controlled study of valproate who had previously undergone two open-label trials
semisodium (plasma concentration 50–100 μg/mL) with lamotrigine, in order to evaluate the effects of
in 30 women with borderline personality disorder this drug on borderline personality disorder symp-
and co-morbid bipolar II disorder. These investiga- tom dimensions. Borderline personality disorder
was retrospectively diagnosed in 40% of the pa- symptoms (mood instability, anxiety, anger) and
tients. Lamotrigine was reported to be efficacious in somatic complaints.[4]
all borderline personality disorder-related symp-
toms, with a marked improvement of impulsivity 3.1 First-Generation Antipsychotics
and mood instability.
Early studies of antipsychotics targeted the
Only one double-blind trial of lamotrigine in
psychotic-like symptoms of patients with borderline
borderline personality disorder is currently avail-
personality disorder.
able. In 2005, Tritt and colleagues[53] compared the
Thioridazine was tested at a mean dosage of
efficacy of lamotrigine versus placebo in the treat-
92 mg/day in 13 patients with borderline personality
ment of aggression in 24 women with borderline
disorder. The open-label study lasted 12 weeks
personality disorder. A highly significant improve-
(with three patients withdrawing) and showed fa-
ment in anger was observed after 8 weeks of the
vourable effects on the global severity of symptoms,
trial.
overall borderline psychopathology and impulsive
The most common adverse events associated behaviours.[102] Flupentixol produced similar results
with lamotrigine are dizziness, diplopia and head- at the mean dosage of 3 mg/day in a group of
ache,[99] while the only serious adverse event is a adolescents with borderline personality disorder.[103]
rare hypersensitivity reaction primarily presenting In particular, there was a decrease in depressive and
as a rash (the Stevens-Johnson syndrome), which is impulsive symptoms and an improvement of global
potentially fatal (0.1% incidence in the study by functioning.
Bowden et al.[100]). Hirsch et al.[101] pointed out a
More reliable indications were provided by initial
correlation between lamotrigine serum concentra-
comparison trials of antipsychotics, which were
tion and tolerability: adverse effects requiring a dose
found to be effective on a wide range of symptoms.
change are uncommon with the most frequently
Loxapine (mean dosage 14.5 mg/day) and chlor-
encountered lamotrigine concentrations (<10 μg/
promazine (mean dosage 110 mg/day) were both
mL) and occur in only 7.4% of patients at concentra-
found to be effective in reducing depression, anxie-
tions obtained during the majority of clinical trials
ty, anger and suspiciousness.[104]
(<5 μg/mL). Lamotrigine did not appear to destabi-
A double-blind comparison of tiotixene (mean
lize mood and was not associated with sexual ad-
dosage 9.4 mg/day) and haloperidol (mean dosage
verse effects, weight gain or withdrawal symp-
3 mg/day) indicated that both drugs decreased the
toms.[101]
severity of a series of symptoms, including depres-
sion, anxiety, derealization, ideas of reference and
3. Efficacy and Tolerability overall borderline psychopathology (table III).[105]
of Antipsychotics More recent trials with a placebo control mostly
confirmed these data. Nevertheless, it should be
Antipsychotics are widely used in clinical prac- noticed that many studies of antipsychotics in pa-
tice for treating borderline personality disorder-re- tients with borderline personality disorder present
lated symptoms. Although this use has not been biases in sample selection that can affect both clin-
approved by the FDA, APA treatment guidelines ical picture and treatment outcome.
recommend the use of antipsychotics, primarily for In a 12-week, double-blind study of patients with
their effects on cognitive perceptual disturbances, borderline or schizotypal personality disorder and
but also for their efficacy in reducing affective concomitant psychotic-like symptoms, tiotixene
682 Bellino et al.
Table III. Double-blind controlled trials of first-generation antipsychotics in the treatment of borderline personality disorder
Drug and study Study design No. of Treatment Results with antipsychotics
Tiotixene
Serban and Siegel[105] db (haloperidol) 52 3 mo Tiotixene = haloperidol: ↓ global
symptomatology, ↓ depression/anxiety,
↓ paranoid ideation vs baseline
Goldberg et al.[106] db, pc 50 12 wk ↓ Psychotic symptoms, ↓ obsessive-
compulsive symptoms, ↓ phobic anxiety vs
placebo
Trifluoperazine
Cowdry and Gardner[7] db, pc (alprazolam, 16 6 wk ↓ Depression/anxiety, ↓ rejection sensitivity,
tranylcypromine, ↓ suicidal attempts vs placebo
carbamazepine)
Haloperidol
Soloff et al.[10] db, pc (amitriptyline) 90 5 wk ↓ Depression, ↓ hostility, ↓ schizotypal
symptoms, ↓ impulsiveness, ↑ global
functioning vs placebo
Soloff et al.[9] db, pc (phenelzine) 108 5 wk No significant differences vs placebo
db = double-blind; pc = placebo-controlled; ↓ indicates decreased; ↑ indicates increased; = indicates equivalent efficacy.
(mean dosage 8.7 mg/day) was significantly effec- age 4.8 mg/day) was significantly superior to place-
tive in treating illusions, ideas of reference, and self- bo on all symptom clusters,[19] including global se-
rated obsessive-compulsive and phobic symptoms, verity of symptoms, self- and clinician-rated depres-
but not depression and global functioning.[106] The sion, anger, impulsivity, schizotypal symptoms and
choice of patients with psychotic-like symptoms psychoticism.[10] In this group of patients, haloperi-
biased the effects of treatment towards cognitive- dol induced the same improvement of depression as
perceptual distortions. amitriptyline.
A placebo-controlled, crossover comparison was These results indicating the efficacy of haloperi-
performed by Cowdry and Gardner[7] in a group of dol on a wide range of symptoms of borderline
outpatients with borderline personality disorder. personality disorder were not replicated in another
Four drugs were administered in a 6-week trial: trial by the same authors.[9] In the second study, the
trifluoperazine, mean dosage 7.8 mg/day; alprazo- same design was used to compare haloperidol (mean
lam, mean dosage 4.7 mg/day; carbamazepine, dosage 3.9 mg/day) with phenelzine and placebo.
mean dosage 820 mg/day; and tranylcypromine, The antipsychotic had only modest and nonsignifi-
mean dosage 40 mg/day. Trifluoperazine significant effects on hostility and impulsive aggression.
cantly decreased depression, anxiety, rejection sen- A subgroup of patients in the above-cited trial of
sitivity and suicide attempts. As these patients had a haloperidol, phenelzine or placebo[9] who had re-
co-diagnosis of hysteroid dysphoria and a history of sponded to treatment received a 16-week continua-
impulsive dyscontrol, results could be biased to- tion of treatment.[16] Haloperidol treatment produced
wards affective symptoms and impulsivity. further significant improvement in irritability, but
A double-blind comparison of haloperidol and not hostility. Depression significantly increased in
amitryptyline was conducted by Soloff and col- severity during prolonged haloperidol treatment, in
leagues[10,19] in the 5-week acute treatment of a part as a consequence of akinesia. Global clinical
group of inpatients. Haloperidol (mean dos- improvement was of modest importance.
A 6-month continuation treatment was provided nin-2 (5-HT2) receptors, has been associated not
to patients with borderline or histrionic personality only with antipsychotic properties, but also with
disorder and a history of recurrent parasuicidal be- antimanic and antidepressant effects.[100] These ef-
haviours.[107] In this study, depot flupentixol 20 mg fects have been supported by the results of a number
was administered once monthly to control for of studies.[47,110-114] Early studies regarding treat-
nonadherence. A significant reduction in suicidal ment of borderline personality disorder with atypi-
behaviours was obtained compared with placebo cal antipsychotics suggested the efficacy of cloza-
Data on withdrawal rates in samples of outpa- pine. An initial report by Frankenburg and
tients with borderline personality disorder who re- Zanarini[115] concerned the beneficial effects of this
ceived treatment with antipsychotics depended on drug (mean dosage 253.3 mg/day) on positive and
the duration of the trial: 13.7% in a 6-week trial,[104] negative psychotic symptoms and overall function-
48.3% in a 12-week trial[106] and 87.5% in a 22-week ing in 15 patients with a co-diagnosis of borderline
continuation study.[16] In short-term treatments, lack personality disorder and psychotic disorder not oth-
of compliance can be a consequence of adverse erwise specified. Patients had been resistant or intol-
effects induced by typical antipsychotics, partic- erant to previous antipsychotic therapies. The relia-
ularly extrapyramidal symptoms (EPS), sedation bility of these results is limited as it is difficult to
and hypotension.[100,106,108,109] Some patients who ascertain whether psychotic symptoms were an ex-
have obtained a clinical improvement with low pression of borderline personality disorder or were
doses of antipsychotics in the acute treatment may due to co-morbidity with psychotic disorders.
withdraw when experiencing adverse effects in Benedetti and colleagues[116] tried to address this
longer continuation therapy.[4] Clinicians must take issue. They selected a sample of patients with bor-
into account the risk of tardive dyskinesia before derline personality disorder who were resistant to
deciding to administer first-generation antipsychot-
treatment (they had not responded to at least 4
ics for a long period.[4]
months of prior treatment with medication and psy-
Administration of thioridazine is not recommen- chotherapy) but did not meet the criteria for
ded as this drug increases the duration of the QT psychotic disorders. The open-label study focused
interval and can induce arrhythmias.[108,109] on psychotic-like symptoms, which were considered
A reassuring doctor-patient relationship that more typical of personality disorder. A combination
carefully considers problems related to adverse ef- of clozapine (mean dosage 43.8 mg/day) and psy-
fects and compliance can be useful to prevent with- chotherapy was administered for 4 months to 12
drawal during antipsychotic treatment.[4] patients, and induced an improvement in all symp-
Double-blind controlled trials concerning first- tom clusters – affective symptoms, impulsivity and
generation antipsychotics in the treatment of border- cognitive-perceptual distortions.
line personality disorder symptoms are summarized
Chengappa et al.[117] performed a similar investi-
in table III.
gation, administering clozapine to seven female in-
3.2 Atypical Antipsychotics patients with borderline personality disorder and
concomitant refractory psychosis, who had not re-
Atypical antipsychotics represent a new treat- sponded to previous treatment with other antipsy-
ment tool for borderline personality disorder. In fact, chotics. Patients were treated for up to 1 year and
their double mechanism of action, characterized by reported a reduction in self-destructive and aggres-
the antagonism of both dopamine-2 (D2) and seroto- sive behaviours, isolation, drug intake and abuse.
684 Bellino et al.
When considering the efficacy of risperidone in More extensive data have been reported for olan-
the treatment of borderline personality disorder, data zapine and quetiapine.
are sparse and derive from some case reports and Olanzapine is a thienobenzodiazepine with a high
two initial investigations.[118-122] affinity for D2 through D4 and 5-HT2A receptors,
In their 8-week, open-label trial of risperidone and a lower affinity for histamine (H1), muscarinic
(3.3 mg/day) in 15 outpatients with borderline per- (M1 through M5) and α1-adrenergic receptors. Ant-
sonality disorder, Rocca and colleagues[122] outlined agonism at D2 through D4 and 5-HT2A receptors is
thought to be the basis for its therapeutic efficacy,
the efficacy of this agent on aggressive behaviour,
while antagonism at H1, M1–M5 and α1-receptors is
affective instability and global psychopathology.
probably responsible for its adverse effects.[127]
Two patients discontinued treatment before the end
The first open-label study of olanzapine in bor-
of the trial because of lack of compliance.
derline personality disorder was conducted by
Szighethy and Schulz[119] published the initial Schulz and colleagues[120] in a sample of 11 outpa-
data of a double-blind comparison of risperidone tients with a co-diagnosis of dysthymic disorder.
(mean dosage 2.5 mg/day) and placebo. Twenty- The nine patients who completed the 8 weeks of
seven patients with borderline personality disorder treatment presented a decrease in impulsivity, hos-
were included and treated for 8 weeks (see table IV). tility, overall psychopathology and global function-
Risperidone was not more effective than placebo in ing.
increasing global functioning, but produced an im- Since the completion of this study, several con-
provement in psychoticism, paranoid ideas, phobias trolled trials have been published on this
and interpersonal sensitivity. drug.[37,123-125]
Table IV. Double-blind controlled trials of atypical antipsychotics in the treatment of borderline personality disorder
Drug and study Study design No. of Treatment Results with antipsychotics
Risperidone
Szighethy and Schulz[119] db, pc 27 8 wk No significant differences vs
placebo
Olanzapine
Zanarini et al.[37] db (fluoxetine, olanzapine 45 8 wk ↓ Impulsive aggression, ↓ chronic
+ fluoxetine) dysphoria vs baseline (olanzapine
= olanzapine + fluoxetine >
fluoxetine)
Zanarini and Frankenburg[123] db, pc 28 6 mo ↓ Anxiety/paranoid ideation,
↓ interpersonal sensitivity vs
placebo
Bogenschutz and Nurnberg[124] db, pc 40 12 wk ↓ Global symptomatology, ↓ anger
vs placebo
Soler et al.[125] db, pc (dialectical behaviour 60 12 wk ↓ Impulsive aggression,
therapy, olanzapine + ↓ depression/anxiety vs placebo
dialectical behaviour therapy)
Aripiprazole
Nickel et al.[126] db, pc 52 8 wk ↓ Global psychopathology,
↓ depression/anxiety, ↓ anger vs
placebo
db = double-blind; pc = placebo-controlled; ↓ indicates decreased; = indicates equivalent efficacy; > indicates better efficacy.
Two studies investigated the effects of olanza- of adverse events such as EPS, prolactin elevation
pine compared with placebo.[123,124] A 6-month and weight gain.[128-130]
double-blind, placebo-controlled trial of olanzapine Hilger and colleagues[131] described the effects of
(mean dosage 5.33 mg/day) in 28 women with bor- this agent (400–800 mg/day) on two women with
derline personality disorder was performed by borderline personality disorder with severe episodes
Zanarini and Frankenburg,[123] who pointed out the of self-mutilation, and found it to be efficacious in
efficacy of this agent on anxiety, paranoid ideation improving impulsive behaviour and overall func-
and interpersonal sensitivity. Bogenschutz and tioning.
Nurnberg[124] reported findings of a 12-week, doub-
A few pilot studies on quetiapine in the treatment
le-blind, placebo-controlled trial of olanzapine
of borderline personality disorder have recently
(5–10 mg/day) in 40 outpatients with borderline
been performed, with mostly concordant and prom-
personality disorder. From the fourth week of treat-
ising conclusions being reached. Adityanjee and
ment, these investigators observed a significant im- Schulz[132] tested the efficacy of quetiapine (25–300
provement in borderline psychopathology and an- mg/day) in ten patients who completed an 8-week
ger. open-label trial. Results showed an improvement in
Other studies considered combinations of olanza- overall symptomatology, hostility, impulsivity and
pine with another drug or psychotherapy. Zanarini functioning.
and colleagues[37] compared the efficacy of fluoxe- Villeneuve and Lemelin[133] replicated these find-
tine, olanzapine and the olanzapine-fluoxetine com- ings. They investigated the effects of quetiapine
bination in the treatment of 45 women meeting the (175–400 mg/day for 12 weeks) in a group of 23
criteria for borderline personality disorder. In their outpatients with borderline personality disorder and
8-week, randomized, double-blind study, the inves- found a significant improvement in impulsivity,
tigators found that all three treatment options signif- hostility, depression, anxiety and social functioning.
icantly improved chronic dysphoria and impulsive
Perrella et al.[134] recently tested open-label que-
aggression. However, olanzapine monotherapy and tiapine (400–800 mg/day) in 29 patients with bor-
the olanzapine-fluoxetine combination were found derline personality disorder for 12-weeks. Six pa-
to be superior to fluoxetine monotherapy in treating tients withdrew from the study because of adverse
both features of borderline psychopathology. Soler effects. In the final sample of 23 patients, these
et al.[125] recently compared the efficacy of olanza- investigators found a significant improvement in
pine and placebo in a combined treatment with global symptoms, depressive symptoms, hostility/
dialectical behavioural therapy. In their 12-week suspiciousness, aggressiveness and functioning.
double-blind study of a group of 60 outpatients with
Our group[135] performed a 12-week pilot study
borderline personality disorder, they found that
on the efficacy of quetiapine (mean dosage 309 mg/
olanzapine (mean dosage 8.83 mg/day) led to a
day) for the treatment of 14 patients with borderline
significant reduction of impulsive-aggressive beha-
personality disorder. Three patients withdrew from
viour, depression and anxiety compared with place-
the study because of noncompliance. Results were
bo.
mostly concordant with previous findings and con-
Quetiapine is a dibenzothiazepine characterized firmed the improvement of global symptomatology,
by low affinity for and rapid dissociation from post- impulsivity, outbursts of anger, anxiety and social
synaptic D2 receptors, which reduces the incidence functioning.
686 Bellino et al.
Aripiprazole, an atypical antipsychotic with par- use of growth factors can reduce the risk of infec-
tial agonist activity at D2 and 5-HT1A receptors, has tions. Transient leukocytosis and eosinophilia can
recently been introduced for the treatment of schizo- also be observed, but these do not usually have any
phrenia, schizoaffective disorder and bipolar disor- serious clinical effects.[145]
der.[136-140] Aripiprazole augmentation of various The incidence of EPS differs among the atypical
SSRIs has been reported to have good effects in antipsychotics, with risperidone being associated
refractory unipolar depression.[141,142] with the highest incidence, and clozapine and que-
Data concerning the use of aripiprazole in the tiapine with the lowest incidence.[146] The likelihood
treatment of borderline personality disorder are very of developing EPS depends not only on the specific
preliminary. agent chosen, but also on the rapidity of dose escala-
Three patients with borderline personality disor- tion, the target dose and the vulnerability of the
der and psychotic symptoms were treated with patient to this adverse effect.[146]
aripiprazole, with heterogeneous results shown in When taking into account metabolic effects, ris-
clinical response and tolerability.[143] peridone has a relatively low risk of causing obesity
Nickel et al.[126] performed a double-blind, place- and diabetes mellitus.[147]
bo-controlled trial of aripiprazole (15 mg/day) in 52 Data on the tolerability of atypical antipsychotics
patients with borderline personality disorder, find- specifically collected in samples of patients with
ing the molecule to be efficacious after 8 weeks in borderline personality disorder are limited. In the
reducing global psychopathology, depression, anxi- study by Soler and colleagues,[125] patients with
ety and anger. Drug therapy was well tolerated. In borderline personality disorder treated with olanza-
order to assess the long-term effects of the molecule pine experienced significant weight gain, but there
on borderline personality disorder, these investiga- was no dose-dependent relationship.
tors performed an 18-month follow-up trial[144] of Some data concerning the tolerability of que-
the sample of patients included in the previous in- tiapine in borderline personality disorder can be
vestigation.[126] According to the intent-to-treat ana- drawn from the study performed by our group,[135]
lysis, all scales of global psychopathology, depres- showing that the most common adverse effects were
sion and anxiety showed a significant improvement, somnolence, dry mouth and dizziness. Adverse ef-
suggesting that aripiprazole can be considered an fects were mild to moderate in most cases, but two
effective agent in the long-term treatment of patients patients discontinued treatment because of excess-
with borderline personality disorder. ive somnolence. The pattern of adverse effects ap-
Concerning adverse effects, the newer antipsy- peared to be in accordance with other investigations
chotics present a more favourable tolerability profile of quetiapine in patients with schizophrenia or bi-
compared with first-generation antipsychotics. polar disorder.[148,149]
Clozapine presents a serious risk of blood dyscra- More common adverse effects of aripiprazole are
sia. Neutropenia and agranulocytosis can occur in a headache, insomnia and anxiety. This pattern of
small percentage of patients (0.9% and 0.7%, re- adverse effects can be found in patients affected by
spectively, according to Lambertenghi De- other psychiatric disorders,[137,149,150] as well as in
liliers[145]), mainly during the first 18 weeks of clo- patients with borderline personality disorder.[143]
zapine treatment, and can lead to serious complica- Double-blind controlled trials of atypical anti-
tions. Drug discontinuation usually results in the psychotics in borderline personality disorder are
normalization of haematological parameters, and the summarized in table IV.
4. Meta-Analyses ity and psychotic symptoms. The only difference

seen between MAOIs and placebo was that patients
In recent years, a few reviews and meta-analytic receiving MAOIs were less hostile. The compari-
studies have evaluated the available pharmacologi- sons of MAOIs with antipsychotics did not show
cal interventions for borderline personality disorder, convincing differences, although some results were
with the aim of defining which evidence supports significant. Antipsychotics may have some benefits
the efficacy of pharmacotherapy on measures of for people with paranoid and psychotic symptoms,
symptoms and functional level. but there was little evidence for the advantage of one
To date, we found two meta-analyses of random- antipsychotic over another. Mood stabilizers, such
ized controlled trials of pharmacotherapy for pa- as valproate semisodium, may induce some change
tients with borderline personality disorder. Both in clinical global scores, but data are not conclusive.
studies pointed out that the evidence for efficacy is These authors concluded that well designed, clini-
very limited and a series of methodological limita- cally meaningful trials are needed and that the posi-
tions affect the reliability of results. tive effects of antidepressants could be considerable
The meta-analysis by Nosè et al.[151] included 20 and should be addressed first.
articles, reporting 22 placebo-controlled investiga-
tions: eight studies involved antipsychotics, seven 5. Conclusions
involved antidepressants and seven involved mood
stabilizers. Antidepressants and mood stabilizers Investigations on psychotropic agents in the
were found to be efficacious in reducing affective treatment of borderline personality disorder have
instability and anger, but did not produce significant recently tested several new drugs belonging to the
effects on impulsivity and aggression, unstable rela- classes of antidepressants, mood stabilizers and anti-
tionships, suicidality or functioning. Antipsychotics psychotics. Results are promising and suggest that
significantly improved impulsive aggression, inter- these medications can be useful in clinical practice,
personal relationships and global functioning. No particularly to control impulsive aggression and af-
difference was found between pharmacotherapy and fective instability.
placebo in terms of dropout rates. The authors con- However, available studies show a series of
cluded that pharmacotherapy has shown modest methodological limitations, such as small sample
beneficial effects on core traits of borderline person- sizes, the short duration of most trials, the lack of
ality disorder. long-term follow-up evaluations, the heterogeneity
Binks et al.[152] presented evidence from the of selection criteria and outcome measures, and the
Cochrane Database of Systematic Reviews, and in- high rates of dropouts. Sometimes, authors do not
cluded all randomized trials comparing psycho- describe the reasons for patients withdrawing from
active drugs with any other treatment for people trials, although a large proportion of withdrawals
with borderline personality disorder. They found ten appear to be related to insufficient compliance
small studies (n = 554) involving eight comparisons. among these patients. Furthermore, sponsorship
Data on antidepressants indicated that fluoxetine concerns might have led to a bias in the objective
may offer some improvement in ratings of anger. A evaluation of the effects of drugs. Considering these
study investigating the effects of mianserin on at- limitations, meta-analyses have concluded that
tempted suicide found no difference between drug pharmacological treatment of borderline personality
and placebo. Data indicated that haloperidol may disorder may be of use but is not currently based on
provide better results than antidepressants on hostil- good evidence from trials.
688 Bellino et al.
7. Cowdry RW, Gardner DL. Pharmacotherapy of borderline per-

Forthcoming investigations should therefore fo-
sonality disorder: alprazolam, carbamazepine, trifluoperazine,
cus on a series of relevant topics such as: pilot and tranylcipromine. Arch Gen Psychiatry 1988; 45: 111-9
studies of new agents; controlled trials of drugs 8. Parsons B, Quitkin FM, McGrath PJ, et al. Phenelzine, imipram-
ine, and placebo in borderline patients meeting criteria for
already tested in open-label case series; compari- atypical depression. Psychopharmacol Bull 1989; 25: 524-34
sons of new antiepileptic agents with better known 9. Soloff PH, Cornelius J, George A, et al. Efficacy of phenelzine
mood stabilizers, such as lithium or valproate semi- and haloperidol in borderline personality disorder. Arch Gen
Psychiatry 1993; 50 (5): 377-85
sodium; head-to-head comparisons of atypical and 10. Soloff PH, George A, Nathan S, et al. Amitriptyline versus
traditional antipsychotics to verify which differ- haloperidol in borderlines: final outcomes and predictors of
response. J Clin Psychopharmacol 1989; 9: 238-46
ences in clinical effects and adverse events specifi- 11. Links P, Steiner M, Boiago I, et al. Lithium therapy for border-
cally occur in borderline personality disorder; defi- line patients: preliminary findings. J Personal Disord 1990; 4:
nition of appropriate doses to treat borderline per- 173-81
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No sources of funding were used to assist in the prepara-
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CNS Drugs 2008; 22 (8): 671-692

REVIEW ARTICLE 1172-7047/08/0008-0671/$48.00/0

© 2008 Adis Data Information BV. All rights reserved.

Efficacy and Tolerability of

Abstract Borderline personality disorder is a pervasive pattern of instability of inter-

Desipramine was not found to be better than

4. Meta-Analyses ity and psychotic symptoms. The only difference

7. Cowdry RW, Gardner DL. Pharmacotherapy of borderline per-

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