Line 1. The mood dysregulation of the PD patient is
manifested by "positive'' symptoms such as lability, rejection
sensitivity, inappropriate intense anger, depressive "mood crashes,''
and temper outbursts. These are most characteristic of Cluster B patients.
"Negative mood states,'' including anhedonia and a "cold,
constricted affect,'' are more prevalent among the schizoid, paranoid, and
schizotypal patients of Cluster A. Excessive anxiety, as an affective state,
is ubiquitous across categories, though perhaps most commonly associated
with Cluster C patients. Dysregulation or disinhibition of affect may have a
basis in serotonergic function quite separate from the specific affect
expressed, whether anger, depression, or anxiety. It is important to
recognize the context in which affective dysregulation occurs. Anger, in the
context of cognitive-perceptual symptoms in a Cluster A patient, responds
well to dopamine blockade, that is, low-dose neuroleptics. In the context of
reactive depressive moods, as in the temper tantrums of a Cluster B patient,
enhancing serotonergic function may be the preferred mode of treatment
(i.e., SSRI antidepressants).
Line 2. The psychobiology of affective dysregulation
may involve disinhibition of emotional expression through diminished central
actions of serotonin in the prefrontal cortex. PD patients presenting with
syndromes of affective disinhibition. whether depressed, angry. or anxious.
should be treated initially with one of the SSRI antidepressants. Research
support for the efficacy of SSRI antidepressants against the depressive
moods and dysregulated anger of PD patients has been demonstrated in two
double-blind, randomized, placebo-controlled studies (Markovitz, 1995;
Salzman et al., 1995) and four open label case series (Cornelius et al.,
1990; Kavoussi et al. 1994; Markovitz et al., 19919 Norden, 1989), thus
warranting an "A'' level of support. SSRI antidepressants have the
additional advantages of a broad spectrum of therapeutic effects, relative
safety in overdose (e.g.. compared to the tricyclic or MAOI
antidepressants), and favorable side-effect profiles, supporting compliance.
Fluoxetine has been found useful against depressed mood. lability, rejection
sensitivity, impulsive behavior, self-mutilation, hostility, and even
psychoticism. Research trials have ranged in duration from 6 to 14 weeks for
acute treatment studies, with continuation studies up to 12 months.
Individual patients have retained improvement on maintenance treatment from
1 to 3 years. Studies have been reported with fluoxetine, in doses of 20-80
mg/day and sertraline, in doses of 100-200 mg/day or 200-600 mg/day
(Markovitz, 1995). A fair treatment trial of SSRI antidepressants is 4-6
weeks.
Research experience with tricyclic antidepressants
(TCAs) in PD patients has produced inconclusive results. Although patients
with comorbid major depression and PD improve with TCAS, the effects of both
TCA and MAOI antidepressants in patients with primary diagnoses of BPD have
been demonstrated to be independent of Axis I diagnoses of comorbid
depression (Cowdry & Gardner, 1988; Soloff, George, Nathan, Schulz,
Ulrich, & Perel, 1986b). In one placebo-controlled study, amitriptyline
was associated with a paradoxical behavioral toxicity in patients with BPD,
increasing suicidal ideation, paranoid thinking, and assaultiveness
significantly more than among placebo nonresponders (Soloff, George, Nathan,
Schulz, & Perel. 1986a).
Line 3. In studies of Axis I affective disorders,
acute treatment is usually 6-12 weeks, continuation is 4-9 months, and
maintenance is longer than 1 year. Since affective dysregulation is a
dimension of temperament in the PD patient, and not an acute illness, the
duration of continuation and maintenance phases of pharmacotherapy cannot
presently be defined. Significant improvement in the quality of the
patient's coping skills and interpersonal relationships may be required
before medication support can be discontinued.
Line 4. In the event of a suboptimal response, the
patient should be switched to a second SSRI or related antidepressant (i.e.,
the so-called "salvage'' strategy). Depressed patients who fail to
respond to one SSRI antidepressant may still respond to a second member of
the same family. In a study of borderline patients, half of patients who
failed to respond to fluoxetine responded to a trial of sertraline
(Markovitz, 199.5). Given the paucity of research on the question of
"salvage'' strategies with SSRI antidepressants in personality disorder
patients, this decision is supported only at the "C'' level. Among the
SSRl-related antidepressants, only venlafaxine has been studied in patients
with a primary diagnosis of PD in one open label trial (Markovitz &
Wagner, 1995). Efficacy was demonstrated against somatic complaints, which
were prominent in this sample, with robust effect sizes on overall global
improvement.
Lines 5, 6. As noted earlier, there are no empirical
guidelines for continuation or maintenance therapy when the target symptom
is part of temperament. Clinical experience suggests caution in
discontinuing a successful medication trial of antidepressants against
affective dysregulation when the patient has failed multiple prior
medication trials.
Line 7. When significant anxiety accompanies the
clinical presentation, the SSRI antidepressant may be insufficient, or, at
least, untimely. At this point, some consideration should be given to the
use of benzodiazepines. Anxiety in the PD patient may present as a chronic
and nonspecific complaint, the "pan-anxiety'' of older description, or
as an exaggerated response to a social stressor. The use of benzodiazepines
is problematic in the treatment of patients with PD, raising the risk of
abuse and even behavioral toxicity. The short-acting benzodiazepine
alprazolam has been associated with precipitating serious dyscontrol in one
placebo-controlled crossover study of patients with BPD (Gardner &
Cowdry, 1985). Abuse potential is significant and tolerance problematic over
time. Case reports demonstrate some efficacy in the PD patient for the long
half-life benzodiazepine clonazepam, which has anticonvulsant and antigenic
properties (Faltus, 1984; Freinhar & Alvarez, 1986). Clonazepam has very
high affinity for the benzodiazepine receptor and may be used in low doses.
It has been shown to increase serotonin synthesis and function in humans,
and unregulated the density of serotonin receptor sites in animals (Chouinard,
1987). These serotonin-enhancing properties may be involved in the efficacy
of clonazepam against agitation and increased motor activity in manic
patients and in its beneficial effects on anxiety and impassivity, including
violent outbursts, in the PD patient. Clonazepam is best used adjunctively
with the SSRI antidepressants. As research is generally lacking on the use
of benzodiazepines in the PD patient, support for these recommendations is
at the "C'' level.
Buspirone may offer some prophylactic benefit against
vulnerability to anxiety without the risk of abuse or tolerance; however,
the absence of an acute effect generally makes this drug less acceptable to
PD patients. Buspirone may confer some benefit against impulsive aggression
or enhance the efficacy of SSRI antidepressants through synergistic effects
on the serotonin system. At present, there is insufficient published
experience with buspirone in the PD patient to permit inclusion in a
clinical algorithm.
Where anger is the predominant affect, yet coexists
within an otherwise affective presentation, SSRI trials are still preferred
as the treatment of first choice. Salzman et al. (1995) have demonstrated
the efficacy of fluoxetine against anger in the BPD patient independent of
effects on depressed mood. Effects of fluoxetine on anger and impulsivity
may appear within days, much earlier than antidepressant effects. However,
if the patient presents in poor behavioral control, if risk of dyscontrol is
high and time is of the essence, low-dose neuroleptics can be added to the
regimen for rapid response. Low-dose neuroleptics confer the additional
benefit of diminishing the severity of affective symptoms. Augmentation with
neuroleptics should be considered before moving to the use of MAOI
antidepressants, which require more patient cooperation and compliance.
Line 8. MAOI antidepressants follow SSRI and related
antidepressants primarily because of concerns for safety, compliance with
diet, and a less favorable side-effect profile. Clinicians who wish to use
MAOI antidepressants as the second line of treatment should use the short
half-life SSRI antidepressants first, for example, sertraline or paroxetine,
avoiding the 35-day washout required for fluoxetine, before starting the
MAOI (i.e., 2-week washout of sertraline or paroxetine should be
sufficient). As a class, MAOI antidepressants have support for efficacy in
personality disorders from two placebo-controlled studies in which BPD was a
primary diagnosis (Cowdry & Gardner, 19889 Soloff et al., 1993) and in
studies of closely related diagnoses, that is, "hysteroid dysphoria''
and ''atypical depression,'' in which the diagnosis of personality disorder
was considered secondary (Parsons et al., 1989). The study of Cowdry and
Gardner (1988) demonstrated significant effects against behavioral
impulsively, mood reactivity, and rejection sensitivity, while the Cornelius
et al. (1993) study showed an effect against anger and hostility. Effects
against atypical depression or "hysteroid dysphoria'' are reported in
studies where the PD was secondary to the primary "atypical'' affective
disorder (Parsons et al. 1989). A "B'' level of support seems most
appropriate for this recommendation.
Lines 9, 10. If an MAOI antidepressant has
demonstrated no efficacy against lability. a mood stabilizer should replace
the MAOI antidepressant. If partial efficacy has been achieved with the MAOI
antidepressant, the mood stabilizer may be used as an augmenting agent.
Lithium carbonate, carbamazepine, and valproate are useful in the treatment
of labile mood in the context of Axis I bipolar disorders and have been used
empirically against the mood instability of Axis 11 patients. Among the
three mood stabilizers, lithium carbonate has the most research support in
double-blind, placebo-controlled studies with PD patients, although these
studies have focused on impulsive aggression rather than on mood regulation
and are reviewed in the next section. An early study of female adolescents
diagnosed as having "emotionally unstable character disorder'' (EUCD),
reported specific improvements in lability of mood with lithium treatment (Rifkin,
Levitan, Galewski, & Klein, 1972). The diagnostic validity of EUCD has
not withstood the test of time, resulting in the diagnosis being deleted in
DSM-III. A recent double-blind, placebo-controlled study comparing lithium
to desipramine and placebo against depressed mood in borderline patients
found no significant differences between the three against depressive
symptoms, although more patients on lithium (vs. placebo) tended to have
improvements in anger, suicidal symptoms, and impulse control. Global
assessments by therapists favored the lithium-treated patients because of
its effects on impulse control (Links, 1990). Lithium carbon- ate has the
disadvantages of a narrow margin of safety in overdose, the risk of
hypothyroidism in chronic use, and the need for monitoring blood levels.
Because of the close association between disinhibition of mood and impulse,
lithium is the preferred choice for affective lability among the three mood
stabilizers; however, support for efficacy specifically against affective
dysregulation is admittedly low (Level C).
Carbamazepine has demonstrated efficacy against
behavioral impulsivity, anger, suicidality, and anxiety in the context of
BPD patients with "hysteroid dysphoria'' in one double-blind,
placebo-controlled cross-over study (Cowdry & Gardner, 19879 Gardner
& Cowdry, 19#6b). However, a recent, well-controlled study of BPD
patients with no Axis I affective disorder found no significant benefit to
carbamazepine as compared to placebo (De La Fuenta & Lotstra, 1994). As
to behavioral toxicity. carbamazepine has precipitated melancholic
depression in borderline patients with a history of this disorder (Gardner
& Cowdry, 1986a). Medical precautions associated with the use of
carbamazepine include the risk of bone marrow suppression and the need to
follow hematologic parameters as well as blood levels of the drug.
Valproate has demonstrated some efficacy
in open label case studies of patients with BPD and may have some utility
against agitation, aggression, and anxiety among severely disturbed
inpatients (e.g.. less time in seclusion) (Wilcox, 1995). Among outpatients
with BPD, valproate is associated with modest overall improvement in mood,
anxiety, anger, impassivity, rejection sensitivity, irritability, and
overall symptom severity in half of patients studied (Stein, Simeon, Frenkel,
Islan, & Hollander, 1995). At this time, there is a paucity of research
data on the use of carbamazepine and valproate in the PD patient, warranting
a "C'' recommendation.
