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INFLUENTIAL PUBLICATIONS   |    
Evidence-Based Pharmacotherapy for Personality Disorders
Luis H. Ripoll; Joseph Triebwasser; Larry J. Siever
FOCUS 2013;11:225-248. doi:10.1176/appi.focus.11.2.225
Abstract

Patients with personality disorders are prescribed psychotropic medications with greater frequency than almost any other diagnostic group. Prescribing practices in these populations are often based on anecdotal evidence rather than rigorous data. Although evidence-based psychotherapy remains an integral part of treatment, Axis II psychopathology is increasingly conceptualized according to neurobiological substrates that correspond to specific psychopharmacological strategies. We summarize the best available evidence regarding medication treatment of personality disordered patients and provide optimal strategies for evidence-based practice. Most available evidence is concentrated around borderline and schizotypal personality disorders, with some additional evidence concerning the treatment of avoidant and antisocial personality disorders. Although maladaptive personality symptoms respond to antidepressants, antipsychotics, mood stabilizers, and other medications, evidence-based pharmacotherapy is most useful in treating circumscribed symptom domains and induces only partial improvement. Most available evidence supports use of medication in reducing impulsivity and aggression, characteristic of borderline and antisocial psychopathology. Efforts have also begun to reduce psychotic-like symptoms and improve cognitive deficits characteristic of schizotypy. Indirect evidence is also provided for psychopharmacological reduction of social anxiety central to avoidant personality disorder. Evidence-based practice requires attention to domains of expected clinical improvement associated with a medication, relative to the potential risks. The development of future rational pharmacotherapy will require increased understanding of the neurobiological underpinnings of personality disorders and their component dimensions. Increasing efforts to translate personality theory and social cognitive neuroscience into increasingly specific neurobiological substrates may provide more effective targets for pharmacotherapy.

(Reprinted with permission from Internationl Journal of Neuropsychopharmacology 2011;14:1257–1288) 

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Personality disorders are defined by an ‘enduring pattern of inner experience and behavior that… is inflexible and pervasive across a broad range of personal and social situations’, with symptomatic disturbances in cognition, affect, impulsivity, and interpersonal functioning leading to distress (APA, 1994). Until recently, guidelines recommended sparing use of pharmacotherapy, and expectations remained guarded regarding expected benefits from medications. Since then, distinctions between Axis I disorders, considered ‘ genetic … biological … brain disorders’ treated with medications; and Axis II disorders, alternatively considered ‘psychological’ and therefore treated with psychotherapy, has undergone a paradigm shift (Siever & Davis, 1991). In this atmosphere, clinicians must rely on the most up-to-date, evidence-based practices for pharmacotherapy to be effective.

Component dimensions of personality, such as impulsivity or aggressiveness, have demonstrable neurobiological correlates, as shown via a variety of endocrine, electrophysiological, and neuroimaging measures (Brambilla et al. 2004; Goodman et al. 2004; Houston et al. 2004; Juengling et al. 2003; Levitt et al. 2004; Minzenberg et al. 2006; New et al. 1997, 2004; Ogiso et al. 1993; Oquendo et al. 2005; Prossin et al. 2010; Rusch et al. 2003; Russ et al. 1991; Simeon et al. 1992; Soderstrom & Foresman, 2004). Identifying neurobiological substrates of personality has allowed for increasingly specific pharmacotherapy. Nevertheless, improvement from effective pharmacotherapeutic interventions is often transient and/or restricted to several symptom domains. In the USA, there are no FDA-approved medications for treating personality disorders. Thus, pharmacotherapy for personality disorders remains off-label, and psychopharmacological strategies for evidence-based practices remain lacking.

The majority of psychopharmacological research on personality disorders has focused on borderline personality disorder (BPD). In the most recent treatment guidelines for BPD, the American Psychiatric Association (APA, 2001), acknowledges that ‘pharmacotherapy has an important adjunctive role’, along with ‘extended psychotherapy to attain and maintain lasting improvement in … personality, interpersonal problems, and overall functioning’. Similarly, others have described psychopharmacological treatment of BPD as resulting only in ‘a mild degree of symptom relief’ (Paris, 2005). Moreover, there remains a dearth of evidence-based medication treatments for other personality disorders.

Often, pharmacotherapy for severe personality disorders is used to stabilize patients’ symptoms sufficiently in order to facilitate psychosocial interventions and foster reflective functioning. Close communication between psychotherapists and psychopharmacologists remains crucial. Although functional gains can be expected from medications, the magnitude and time-course vary. There is little evidence regarding distinctions between acute and maintenance pharmacotherapy, or how long to continue patients on a medication. Empirical data on recurrence or relapse is similarly scarce. Therefore, evidence-based practices must be judged case-by-case, weighing clinical risks and benefits.

Clinicians can refer to accompanying tables for the best available evidence regarding pharmacotherapy for personality disorders (see Tables 14). This data was compiled by searching the Medline database with the main combinations pharmacotherapy and each of the various DSM-IV personality disorder diagnoses. In addition, we paid particularly close attention to randomized, placebo-controlled trials (along with some lower-level evidence if this type of evidence was severely limited). We focused on studies published in the past 3 years, since the publication of the last World Federation of Societies of Biological Psychiatry Guidelines for the Biological Treatment of Personality Disorders (Herpertz et al. 2007). Additional research regarding medications for treating impulsive aggression was found via a similar Medline search on impulsivity, aggression, and pharmacotherapy.

 
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Table 1.Schizotypal personality disorder (SPD)
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PANSS, Positive and Negative Symptom Scale.

 
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Table 2.Antisocial personality disorder
 
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Table 3.Borderline personality disorder (BPD)
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AQ, Aggression Questionnaire; AsPD, antisocial personality disorder; AvPD, avoidant personality disorder; BDI, Beck Depression Inventory; BPD, borderline personality disorder; CGI, Clinical Global Impression; CGI-BPD, Clinical Global Impression for Borderline Personality Disorder; DPD, dependent personality disorder; GAS, Global Assessment Scale; HAMA, Hamilton Anxiety Scale; HAMD, Hamilton Depression Scale; HPD, histrionic personality disorder; MMPI, Minnesota Multiphasic Personality Inventory; OAS-M, Modified Overt Aggression Scale; PANSS, Positive and Negative Symptom Scale; PD, personality disorder; PTSD, post-traumatic stress disorder; SCL-90, Symptom Checklist-90; STAXI, State-Trait Anger Expression Inventory; ZAN-PBD, Zanarini Rating Scale for Borderline Personality Disorder.

 
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Table 4.Avoidant Personality Disorder (AvPD)
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For abbreviations in table see notes to Table 3.

Unfortunately, only a few novel trials of pharmacotherapy for personality disorders have been published during this recent period. Several recent meta-analyses have been published in this time, which we utilized to establish areas of consensus for evidence-based practice, and identify gaps that need to be addressed with future research. Many prior reviews cover only BPD, but we expanded our scope to include all personality disorders. Thus, we include a comprehensive summary of the best, current evidence, with commentary on recent consensus and recommendations for evidence-based practices, and future directions regarding pharmacotherapeutic strategies that have been insufficiently tested, but appear promising for further research. This situates this review as a nexus, compiling evidence-based practices for treating personality disorders for interested clinicians, as well as providing avenues for future psychopharmacological research.

SPD is characterized by interpersonal deficits and psychotic-like symptoms. Like schizophrenia patients, SPD patients often demonstrate cognitive deficits in working memory, particularly sustained attention and executive functioning (Bergida & Lenzenweger, 2006; McClure et al. 2007a; Parc & McTigue, 1997), as well as significant abnormalities in empathic understanding (Langdon & Coltheart, 2004; Pickup, 2006; Ripoll et al. unpublished data). Unlike schizophrenic patients, there is greater preservation of frontal volume in SPD (Siever & Davis, 2004).

Overall, clinical trials for SPD have been complicated by comorbidity, particularly with other personality disorders. Most early RCTs on BPD also included SPD patients (Goldberg et al. 1986; Serban & Siegel, 1984; Soloff et al. 1986c), because both SPD and BPD were considered rooted in ‘borderline’ schizophrenia; but psychotic symptoms in SPD and BPD are clinically distinguishable.

The conceptualization of SPD within the schizophrenia spectrum supports treatment with antipsychotic medications. Antipsychotics appear to be useful in the treatment of SPD, particularly in terms of psychotic-like symptoms (Goldberg et al. 1986; Koenigsberg et al. 2003). Open-label studies have suggested a role for antidepressants in treating self-injury, psychotic-like, and depressive symptomatology (Jensen & Andersen, 1989; Markovitz et al. 1991), but the evidence is weaker. Recent RCTs targeting cognitive deficits in SPD compared performance on neuropsychological tasks before and after treatment with medication or placebo. Both pergolide, a dopaminergic agonist active at both the D1 and D2 receptor (McClure et al. 2010), and the noradrenergic α2A agonist guanfacine (McClure et al. 2007b) improved SPD patients’ cognitive performance, on distinct neuropsychological measures. Whether this improvement extends to overall clinical functioning in SPD remains subject to future investigation.

In sum, SPD patients respond to low-dose, atypical antipsychotics, targeting psychotic-like symptoms and general functioning. First-generation antipsychotic medication and antidepressants may also play a role, although the evidence is not as reliable. Evidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential benefits. Cognitive enhancement via noradrenergic α2A or dopaminergic agonism may be future avenues of research, given that, by analogy with schizophrenia, the cognitive impairment in SPD may be responsible for the overall dysfunction observed in the disorder. Research efforts to understand neurobiological substrates of social cognitive dysfunction have heretofore mainly focused on BPD and schizophrenia. Because SPD involves social isolation, relational paranoia, and empathic deficits, research on pharmacotherapeutic effects on social cognition may also be fruitful.

Peer-reviewed trials of AsPD include studies on groups of individuals likely to have been antisocial based on histories of repeated violence and criminality and an absence of other stated causes for these behaviours. Lithium has been associated with decreases in serious rule infractions in incarcerated males (Sheard, 1971; Sheard et al. 1976). Prisoners treated with phenytoin committed fewer aggressive acts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility), and improvements in aggression appeared to be limited to impulsive (not pre-meditated) aggression (Barratt et al. 1991, 1997). At present, evidenced-based pharmacotherapy for AsPD is restricted to treatment of impulsive aggression. Future neurobiological research in AsPD and psychopathy will probably increase our understanding of the dysfunctional emotional empathy often seen in this disorder (Blair, 2005) and whether this may be susceptible to psychopharmacological intervention.

Most RCTs on personality disorders focused on BPD, which consists of several domains of dysfunction: affective instability, impulsivity and anger, transient psychotic or dissociative symptoms, and intense, unstable relationships (Lieb et al. 2004; Zanarini et al. 1990). BPD patients often demonstrate high comorbidity (Zanarini et al. 2004a, c) and make numerous suicide attempts and parasuicidal gestures, conferring significantly higher risk for completed suicide (Welch & Linehan, 2000).

Early studies employed a distinct nosology in characterizing subjects, some of whom actually had what might be called BPD today (Rifkin et al. 1972). In studies on suicidal or parasuicidal subjects, the majority often have BPD (Battaglia et al. 1999; Montgomery & Montgomery, 1982; Montgomery et al. 1983; Verkes et al. 1998). Early studies often included combinations of BPD and SPD subjects (Goldberg et al. 1986; Serban & Siegel, 1984; Soloff et al. 1986c), and studies recruiting a range of all personality disorders ultimately include BPD as the most frequent diagnosis (Coccaro & Kavoussi, 1997; Hollander et al. 2003).

Clinicians should exercise caution in attempting to apply research findings to severely ill BPD patients, as many RCTs recruited only outpatients, who further were excluded if they expressed acute suicidality (Frankenburg & Zanarini, 2002; Tritt et al. 2005; Zanarini & Frankenburg, 2003; Zanarini et al. 2004b) or had made a recent suicide attempt (Bogenschutz & Nurnberg, 2004). In addition, small sample sizes predominated, and most studies lasted ≤3 months. The few trials lasting ≥6 months suffered from high drop-out rates (Frankenburg & Zanarini, 2002; Zanarini & Frankenburg, 2001) or concomitant recruitment of subjects without BPD (Battaglia et al. 1999; Montgomery et al. 1983; Verkes et al. 1998). Moreover, RCTs with BPD subjects appear to be prone to high placebo response rates (Lieb et al. 2004; Salzman et al. 1995), meaning that open-label trial data should be interpreted with caution.

APA practice guidelines (APA, 2001) recommended a symptom-targeted approach in pharmacotherapy of BPD. This leaves open the possibility for patients to improve in some but not all symptom dimensions. Some clinicians have based their decision to implement polypharmacy on this, but there is actually little evidence as to the effectiveness of this strategy. The only study on combined pharmacotherapy in BPD (Zanarini et al. 2004b) found no superior efficacy for combination treatment compared to one medication alone. Using as few medications as possible to target central areas of clinical dysfunction, together with evidence-based psychotherapy, is usually the optimal treatment strategy. In light of this, although the 2001 guidelines suggest a prominent role for serotonergic pharmacotherapy, recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham & Calabrese, 2008; Mercer et al. 2009).

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Tricyclic antidepressants (TCAs)

Disturbances of serotonin have been associated with BPD, impulsive aggression, self-harm, and suicidality (Coccaro et al. 1995; Evenden, 1999; Malone et al. 1996; Pitchot et al. 2005). Low CSF levels of serotonin metabolites have been associated with suicide attempts and completion (Samuelsson et al. 2006; Traskman et al. 1981), impulsivity, aggression (Mehlman et al. 1994; Virkkunen et al. 1994), lifetime aggressiveness, and suicidal lethality (Placidi et al. 2001). Impulsive aggression with suicidality has been linked to blunted prolactin responses to the serotonergic probe fenfluramine (Coccaro et al. 1989). PET scans of personality-disordered subjects high in impulsive aggression have demonstrated reduced response to fenfluramine in orbitofrontal, ventromedial, and cingulate regions (Siever et al. 1999).

Nevertheless, early research on TCAs for BPD proved disappointing (Montgomery et al. 1983; Soloff et al. 1989). Amitryptiline has been associated with paradoxical increases in suicidality, paranoia, and behavioural dysregulation, attributed to ‘generalized disinhibition of cognitive and affective controls’ (Soloff et al. 1986a, 1987). Indeed, borderline patients have difficulty cognitively resolving conflict among stimulus dimensions (Posner et al. 2002), and prefrontal hypofunction can be seen after a serotonergic stimulus in subjects with prominent impulsive aggression (New et al. 2002). Thus, medications with adverse cognitive sequelae, including anticholinergic side-effects, may contribute to worsening impulsivity. As mentioned in prior reviews, the use of TCAs in treating BPD is discouraged (Abraham & Calabrese, 2008; Mercer et al. 2009). Their use is also associated with potentially significant risk of overdose.

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Monoamine oxidase inhibitors (MAOIs)

Despite hesitancy in prescribing MAOIs to patients with prominent impulsivity or self-injurious behaviour, some recommend these medications for BPD patients who can take them safely and reliably. Interest in MAOIs for BPD is rooted in their differential efficacy for conditions such as hysteroid dysphoria or atypical depression, viewed as being related to one other and BPD (Kayser et al. 1985; Liebowitz & Klein, 1981). In a crossover trial with multiple medication phases, only tranylcypromine was associated with higher patient-rated improvement scores and completion rates (Cowdry & Gardner, 1988).

Similarly, relative prominence of BPD symptoms predicted superiority of phenelzine (Parsons et al. 1989). Phenelzine is beneficial in the treatment of hostility, anxiety, and borderline symptoms (Soloff et al. 1993). In some patients, it could cause uncomfortable excitement and emotional reactivity (Cornelius et al. 1993). Thus, although there is evidence for their efficacy, many patients may not tolerate these medications. Other associated risks of MAOIs include toxicity in overdose and potentially fatal hypertensive crises or serotonin syndrome.

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Selective serotonin reuptake inhibitors (SSRIs)

SSRIs are thought to potentiate serotonergic neuromodulation but demonstrate more favourable side-effect profiles. Fluoxetine reduced anger in BPD independent of any antidepressant effect (Salzman et al. 1995). It also improved verbal and impulsive aggression, irritability, and overall functioning (Coccaro & Kavoussi, 1997). Similarly, a RCT with paroxetine demonstrated efficacy in preventing recurrent suicidal behaviour but no significant effect on depression, hopelessness, or anger (Verkes et al. 1998). By contrast, there was little added benefit from fluoxetine when added to dialectical behavioural therapy (DBT) (Simpson et al. 2004).

On the other hand, fluvoxamine decreased affective lability, but not scores of impulsivity or aggression (Rinne et al. 2002). Although SSRIs decrease impulsivity and aggression in BPD patients with comorbid intermittent explosive disorder (IED; Coccaro & Kavoussi, 1997; New et al. 2004), data from BPD subjects without comorbid IED are inconsistent (Rinne et al. 2002). Previous reviews have emphasized that effect sizes for antidepressant pharmacotherapy vary widely between classes and trials (Ingenhoven et al. 2010; Lieb et al. 2010; Mercer et al. 2009). Nevertheless, current evidence-based practice recommends use of SSRIs, due to potential benefits on impulsive aggression that may outweigh associated risks. There has been no evidence that antidepressants alleviate the chronic emptiness, shameful self-concept, and intrapsychic pain in BPD.

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First-generation antipsychotics

An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (e.g. Deutsch, 1942). Antipsychotics have demonstrated partial efficacy, reflecting underlying abnormalities in dopaminergic signalling. Borderline subjects demonstrate high levels of the dopamine metabolite, homovallinic acid, in both plasma and cerebrospinal fluid (Siever et al. unpublished data). Prior to more widespread use of SSRIs, antipsychotics demonstrated efficacy in decreasing psychotic-like symptoms (Goldberg et al. 1986; Soloff et al. 1986b), depression (Soloff et al. 1986b), irritability (Cornelius et al. 1993), and general symptom severity (Cowdry & Gardner, 1988; Soloff et al. 1986b).

A recent Cochrane review suggests haloperidol is efficacious in reducing anger in BPD, and treatment with flupenthixol decanoate reduced suicidal behaviour (Lieb et al. 2010). By contrast, evidence for efficacy of neuroleptics on affective symptoms, psychosis, and anxiety remains inconsistent. The dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower than schizophrenia. High drop-out rates are noted, and risk of extrapyramidal symptoms may further limit the utility of neuroleptics.

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Second-generation antipsychotics

Classical neuroleptics have largely been superseded by atypical antipsychotics, whose broader therapeutic benefits may be explained by activity beyond the D2 receptor. As mentioned in prior reviews, olanzapine has proven beneficial in treatment of BPD patients’ anxiety, anger, interpersonal sensitivity, and paranoia, but not depression (Zanarini & Frankenburg, 2001), as well as improving general clinical functioning and BPD symptomatology (Bogenschutz & Nurnberg, 2004). A recent, large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulz et al. 2008), although the authors suggested that patients may have been underdosed. A study comparing olanzapine to haloperidol showed no between-group differences except with respect to side-effects, with more weight gain associated with olanzapine and more extra-pyramidal side-effects with haloperidol (Shafti & Shahveisi, 2010).

Adding fluoxetine to olanzapine did not elicit further benefit, except that subjects receiving both medications gained less weight than those receiving only olanzapine (Zanarini et al. 2004b). The addition of olanzapine to DBT reduced depression, anxiety, and impulsive aggression, but the magnitude and timing of these benefits relative to DBT was difficult to interpret (Soler et al. 2005).

Aripiprazole has a novel mechanism of action (partial agonist at the dopamine D2 receptor and serotonin 5-HT1A receptor, antagonist at the 5-HT2A receptor). It may be more favourable than other atypicals with respect to metabolic side-effects. A longer half-life may be more effective for patients susceptible to non-adherence. In non-suicidal BPD patients, aripiprazole was effective in reducing aggression, anxiety, depression, psychosis, interpersonal symptoms, self-injurious behaviour, and subjective distress. There were no significant differences between groups in weight gain (Nickel et al. 2006). An 18-month, open-label follow-up showed sustained improvements and continued tolerability (Nickel et al. 2007).

Previously, open-label trials suggested possible efficacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al. 2004, 2006). The side-effect and psychopharmacological profiles of ziprasidone indicated lesser metabolic risks and antidepressant and anxiolytic effects thought to be independent of antidopaminergic activity (Keck et al. 1998; Tandon, 2000; Wilner et al. 2002). Despite such promise, a recent RCT with ziprasidone was negative (Pascual et al. 2008). Thus, evidence-based practice supports use of aripiprazole but not ziprasidone in treating BPD.

In meta-analyses, the class of antipsychotics had moderate effect in treating aggression, but no significant effect on depression, although aripiprazole and olanzapine may be exceptions (Lieb et al. 2010; Mercer et al. 2009). For aypicals, metabolic side-effects may limit clinical utility. Because 29-53% of borderline patients fulfil criteria for an eating disorder at some point in their lives (Lieb et al. 2004), and a significant number suffer from obesity (Frankenburg & Zanarini, 2006), iatrogenic metabolic risks must be regarded as serious. Although evidence-based practices have advanced in treating aggression associated with BPD; chronic emptiness, affective lability, and interpersonal dysfunction lack effective, evidence-based medication treatments.

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Mood stabilizers and anticonvulsants

Due to BPD patients’ affective dysregulation and comorbidity with bipolar disorder, some have classified BPD within the bipolar spectrum (Akiskal, 2004; Smith et al. 2004), although most continue to distinguish between the two, particularly with regard to interpersonal dysfunction (Bolton & Gunderson, 1996; Henry et al. 2001; Paris, 2004). Mood stabilizers are indeed becoming a more integral component of evidence-based treatment practices for BPD.

Lithium is beneficial in treating BPD, particularly in terms of quieting affective instability (Links et al. 1990; Rifkin et al. 1972). Lithium toxicity and/or non-compliance may be problematic, due to BPD patients’ characteristic impulsive, self-destructive behaviour.

However, anticonvulsants are more often recommended for treatment of rapid-cycling bipolar disorder, the variant most closely resembling BPD. Carbamazepine demonstrated ‘dramatic’ reductions in behavioural dyscontrol and improvements in global functioning, anxiety, anger, euphoria, impulsivity, and suicidality, but it was associated with worsening melancholic depression (Gardner & Cowdry, 1986a, b), and therapeutic benefits could not be replicated in in-patients (de la Fuente & Lotstra, 1994).

Although high drop-out rates were reported with divalproex (Hollander et al. 2001), it subsequently demonstrated benefits on interpersonal sensitivity, anger, and aggression in euthymic borderline women with bipolar II (Frankenburg & Zanarini, 2002). Divalproex reduced aggression, irritability, and overall disease severity in patients with Cluster B personality disorders and prominent impulsive aggression (Hollander et al. 2003). Differential treatment response in Cluster B subjects was enhanced by baseline trait impulsivity and state aggression, although not affective instability (Hollander et al. 2005).

Lamotrigine extends periods of euthymia in bipolar patients (e.g. Goodwin et al. 2004). Potential benefits also include pro-cognitive activity, as previously demonstrated in normal volunteers (Aldenkamp et al. 2002). Lamotrigine effectively reduced BPD patients’ anger (Tritt et al. 2005), and an 18-month follow-up demonstrated maintenance of this anti-aggressive effect (Leiberich et al. 2008). More recently, BPD patients without comorbid bipolar disorder but with prominent affective instability demonstrated reduced affective lability and impulsivity, but no change in other BPD symptoms, when treated with lamotrigine (Reich et al. 2009). Documented effects on impulsivity, anger, and affective lability in BPD thus make lamotrigine an attractive pharmacotherapeutic option. Nevertheless, the latter study reported higher rates of skin rash than reported elsewhere. Due to this life-threatening risk, clinicians should monitor patients closely and titrate the dose slowly.

Although topiramate’s utility in bipolar disorder is controversial, it is efficacious for BPD. Topiramate reduced anger in female BPD subjects (Nickel et al. 2004), and a similar RCT reported this effect in males with BPD (Nickel et al. 2005). A separate RCT conducted with female BPD patients taking topiramate also demonstrated improvements in somatization, anxiety, health-related quality of life, overall stress, interpersonal sensitivity, hostility, and other facets of interpersonal functioning (Loew et al. 2006). Although no drop-outs were due to side-effects; cognitive impairment, reduced appetite, and weight loss were commonly reported.

Open-label follow-up studies to these initial RCTs demonstrated maintenance of therapeutic gains and additional weight loss associated with topiramate, and the authors therefore encouraged longer-term use (Loew & Nickel, 2008; Nickel & Loew, 2008). The authors admit that the patients studied were not the most severe. Because cognitive side-effects of topiramate may more adversely affect severely impulsive or suicidal BPD patients, a careful risk/benefit analysis should be undertaken before prescribing.

Overall, mood stabilizers and anticonvulsants are effective in treating BPD, particularly symptoms of impulsivity and aggression. As a class, they also demonstrate a moderate effect in treating depression in BPD (Ingenhoven et al. 2010; Mercer et al. 2009). Although they are an important component of evidence-based practice, patients should be closely monitored, because some may not tolerate these medications. The relatively slow titration schedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinical effectiveness, particularly in a population often characterized by impulsive non-compliance. Although impulsivity and aggression appear to respond to treatment, there is little evidence of any effect from mood stabilizers in improving interpersonal dysfunction or disturbances of identity. Future research should focus more closely on these domains.

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Other medications

Although there have been case reports of improvement in BPD patients treated with alprazolam (Faltus, 1984), the class of benzodiazepines has been associated with disinhibition, worsening impulsivity, suicidal ideation, and behavioural dyscontrol in BPD (Cowdry & Gardner, 1988). Benzodiazepines are vehemently discouraged, due to these risks, as well as elevated risks of dependence. Patients may abuse benzodiazepines to self-medicate intrapsychic pain, interfering with progress in psychotherapy and adversely affecting cognition.

The omega-3 fatty acid, ethyl-eicosapentaenoic acid (E-EPA) decreased aggression and depression in women with moderate to severe BPD (Zanarini & Frankenburg, 2003). A similar anti-aggressive effect was observed in two other RCTs with healthy subjects (Hamazaki et al. 1996, 2002). Omega-3 fatty acids may act by inhibiting protein kinase C, a mechanism thought to be involved in lithium and valproic acid pharmacotherapy (Peet & Stokes, 2005).

Clonidine, a presynaptic α2 noradrenergic agonist, has been studied in a trial comparing two doses given to BPD patients amidst states of ‘acute aversive inner tension’. Although tension, dissociative symptoms, self-injurious urges, and suicidal ideation decreased for both doses, there was no difference between the two doses (Philipsen et al. 2004a). Ziegenhorn et al. (2009) conducted an RCT of clonidine with BPD subjects with prominent symptoms of hyperarousal. Most of them therefore also met criteria for comorbid PTSD, which limited generalizability of findings. In the total sample, clonidine treatment improved hyperarousal, subjective quality of sleep, and anxiety, but not borderline-specific symptoms, and these benefits were not seen in the minuscule non-PTSD subsample. Although clonidine and similar agents have been efficacious in the treatment of PTSD (e.g. Southwick et al. 1999; Strawn & Geracioti, 2008), their role in treating BPD remains unclear.

A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (e.g. bulimia, substance abuse), which may reflect disturbances in endogenous opioids. Some BPD patients become disinhibited and aggressive after receiving opiate medications (Saper, 2000), and morphine administration increased self-injurious behaviour in one patient with BPD (Thurauf & Washeim, 2000). Naloxone used during acute states of aversive tension and dissociation in BPD demonstrated no significant benefit (Philipsen et al. 2004b). Naltrexone has been used successfully in open-label trials to treat self-harm (Griengl et al. 2001; McGee, 1997; Roth et al. 1996) and dissociation (Bohus et al. 1999). Therefore, evidence for treatment of BPD with medications acting upon opioid receptors remains inconsistent. Treatment with full agonists or antagonists may be complicated by differences between chronic, effects on post-synaptic receptor density on the one hand, and distinct, acute effects of receptor agonism or antagonism on the other (Prossin et al. 2010; Stanley & Siever, 2010). The potential for abuse of full opioid agonists may pose too great a risk for an effective treatment. For both these reasons, future trials with partial opioid agonists may be more effective in reducing self-injury, interpersonal dysfunction, and intrapsychic pain.

AvPD is a common personality disorder (Loranger et al. 1994), existing as a comorbid condition in up to one-third of all patients with anxiety disorders (Alden et al. 2002). Up to 56% of AvPD patients continue to meet criteria after 2 years (Skodol et al. 2005). Nevertheless, distinguishing between this and generalized social phobia has been difficult, due to similarities in diagnostic criteria as well as frequently reported comorbidity. No neurobiological evidence indicates how the aetiology and psychopathology of AvPD differs from social phobia.

At present, clinicians should ‘extrapolate from data which are primarily related to anxiety disorders … to apply treatment strategies … that have primarily been developed for social phobia’ (Herpertz et al. 2007). Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as first-line agents. A potential caveat is mentioned for sertraline if symptoms began in childhood or adolescence, in which case lesser efficacy was reported (van Ameringen et al. 2004). Gabapentin (Pande et al. 1999) and pregabalin (Pande et al. 2004) have also demonstrated efficacy in social phobia. Second-line agents would include reversible MAOIs brofaromine and moclobemide, for which there is presently less robust evidence, and the irreversible MAOI phenelzine, which entails risk of serious side-effects.

Pharmacological research is strikingly absent from other personality disorders. In these cases, medication is particularly indicated in the treatment of comorbid Axis I disorders, particularly mood and anxiety disorders that frequently co-occur with narcissistic, histrionic, and dependent personality disorders. SSRIs may be of particular clinical benefit relative to TCAs, given their more favourable side-effect profile and the possibility of an independent effect on personality factors (Ekselius & von Knorring, 1998; Reich et al. 2002). With the advent of the next DSM, a greater emphasis on a dimensional diagnostic approach to personality disorders will probably cast greater importance upon pharmacotherapeutic interventions targeting dimensions common to a variety of current Axis II diagnoses.

One such dimension of personality dysfunction is impulsive aggression. Recent trials with levetiracetam and oxcarbazepine for impulsive aggression recruited individuals with IED without significant comorbidity (e.g. Mattes, 2005, 2008), while other trials recruited subjects with personality disorders and a history of impulsive aggression (e.g. Coccaro et al. 2009; Hollander et al. 2003). Coccaro et al. (2009) found an anti-aggressive effect of fluoxetine in patients with IED and personality disorders. Several anticonvulsants (most notably divalproex, oxcarbazepine, and phenytoin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al. 2010).

Although the past two decades of research have ushered a paradigm shift in personality disorders, most research has been limited to BPD and SPD. Future research should be directed towards the treatment of other Axis II diagnoses and dimensions of dysfunction across diagnoses. Although research has made great strides towards understanding impulsivity and aggression, similar neurobiological substrates should be sought for other dimensions of personality. Only by clarifying these gaps in the evidence base can clinicians anticipate more effective evidence-based psychopharmacological practices for the treatment of personality disorders.

Further efforts to understand to what extent AvPD differs from generalized social phobia are warranted. This may require understanding distinctions between these diagnoses in neurobiology of fear and social inhibition, and in the developmental trajectory of each disorder. For SPD, the effects of pro-cognitive interventions should be evaluated with respect to social isolation and overall functioning. More comprehensive efforts are needed to understand the underlying neurobiology of SPD to improve evidence-based practices. Further characterization of the interpersonal dysfunction and cognitive, sensory-gating abnormalities seen in SPD will probably improve the effect of treatment on general functioning. Efforts at understanding the neurobiology of schizophrenia and its prodrome will also assist in defining targets for pharmacotherapy. Clarifying the respective roles of genes and environment in shaping the course of the schizophrenia spectrum will also uncover future pharmacotherapeutic targets.

Within BPD, research has detailed more extensive evidence-based practices for treating impulsive aggression. Anticonvulsants and atypical antipsychotics are acquiring more prominent roles in the treatment of BPD, relative to SSRIs. Nevertheless, greater serotonergic specificity will probably improve the efficacy of treatments. For example, selective 5-HT2A antagonism, but not 5-HT2C antagonism, has been shown to decrease impulsivity (Higgins et al. 2003; Winstanley et al. 2004).

Future research will also focus on treating affective instability, intrapsychic pain, dissociation, and interpersonal dysfunction associated with BPD. BPD has been conceptualized as related to disturbed attachment (Fonagy & Luyten, 2009) and dysfunctional representations of self and other (Bender & Skodol, 2007), with other symptoms seen as sequelae to this core feature. Oxytocin, vasopressin, and opioids may therefore be of particular relevance for treating BPD (Stanley & Siever, 2010), given the developmental role of these neuropeptides in attachment and the relationship between attachment security and stable social cognitive representations of self and other (Fonagy & Luyten, 2009). Although these domains have been exclusively treated with psychotherapy, research in the neurobiology of affiliative behaviour (e.g. Depue & Morrone-Strupinsky, 2005) as well as self-injury and dissociation (Mauchnik & Schmahl, 2010) may eventually provide novel pharmacotherapeutic targets.

For all personality disorders, integrating psychopharmacology with neurobiological effects of psychotherapy may produce synergistic and long-lasting benefits. Evidence-based practice continues to recommend an approach that includes both psychotherapy and pharmacotherapy. Although experienced therapists’ contributions to personality theory and empirical research often continue to be at odds with one another, future research should attempt to connect theory with empirically-validated psychopharmacological targets. By understanding the neurobiology underlying increasingly complex behavior, pharmacotherapy can be optimized and targeted to personality dimensions previously considered susceptible only to psychotherapy.

Abraham  PF;  Calabrese  JR (2008).  Evidence-based pharmacologic treatment of borderline personality disorder: a shift from SSRIs to anticonvulsants and atypical antipsychotics? Journal of Affective Disorders 111, 21–30.
[CrossRef]
 
Akiskal  HS (2004).  Demystifying borderline personality: critique of the concept and unorthodox reflections on its natural kinship with the bipolar spectrum.  Acta Psychiatrica Scandinavica 110, 401–407.
[CrossRef]
 
Alden  LE;  Paosa  JM;  Taylor  CT;  Ryder  AG (2002).  Avoidant personality disorder: current status and future directions.  Journal of Personality Disorders 16, 1–29.
[CrossRef]
 
Aldenkamp  AP;  Arends  J;  Boorsma  HPR;  Diepman  L  et al. (2002).  Randomized double-blind parallel-group study comparing cognitive effects of a low-dose lamotrigine with valproate and placebo in healthy volunteers.  Epilepsia 43, 19–26.
[CrossRef]
 
Allgulander  C (1999).  Paroxetine in social anxiety disorder: a randomized placebo-controlled study.  Acta Psychiatrica Scandinavica 100, 193–198.
[CrossRef]
 
Allgulander  C;  Mangano  R;  Zhang  J;  Dahl  AA  et al. (2004).  Efficacy of venlafaxine ER in patients with social anxiety disorder: a double-blind, placebo-controlled, parallel-group comparison with paroxetine.  Human Psychopharmacology 19, 387–396.
[CrossRef]
 
APA (1994).  Diagnostic and Statistical Manual of Mental Disorders, 4th edn.  Washington DC :  American Psychiatric Association.
 
APA (2001).  Practice guideline for the treatment of patients with borderline personality disorder.  American Journal of Psychiatry 158 (October supplement), 1–52.
[CrossRef]
 
Baldwin  D;  Bobes  J;  Stein  DJ;  Scharwachter  I  et al. (1999).  Paroxetine in social phobia/social anxiety disorder. Randomised double-blind, placebo-controlled study. Paroxetine Study.  British Journal of Psychiatry 175, 120–126.
[CrossRef]
 
Barratt  ES;  Kent  TA;  Bryant  SG;  Felthous  AR (1991).  A controlled trial of phenytoin in impulsive aggression.  Journal of Clinical Psychopharmacology 11, 388–389.
[CrossRef]
 
Barratt  ES;  Stanford  MS;  Felthous  AR;  Kent  TA (1997).  The effects of phenytoin on impulsive and pre-meditated aggression: a controlled study.  Journal of Clinical Psychopharmacology 17, 341–349.
[CrossRef]
 
Battaglia  J;  Wolff  TK;  Wagner-Johnson  DS;  Rush  AJ  et al. (1999).  Structured diagnostic assessment and depot fluphenazine treatment of multiple suicide attempters in the emergency department.  International Clinical Psychopharmacology 14, 361–372.
[CrossRef]
 
Bender  DS;  Skodol  AE (2007).  Borderline personality as a self-other representational disturbance.  Journal of Personality Disorders 21, 500–517.
[CrossRef]
 
Bergida  H;  Lenzenweger  MF (2006).  Schizotypy and sustained attention: confirming evidence from an adult community sample.  Journal of Abnormal Psychology 115, 545–551.
[CrossRef]
 
Blair  RJR (2005).  Responding to the emotions of others: dissociating forms of empathy through the study of typical and psychiatric populations.  Consciousness and Cognition 14, 698–718.
[CrossRef]
 
Blomhoff  S;  Haug  TT;  Hellstrom  K;  Holme  I  et al. (2001).  Randomised controlled general practice trial of sertraline, exposure therapy and combined treatment in generalised social phobia.  British Journal of Psychiatry 179, 23–30.
[CrossRef]
 
Bogenschutz  MP;  Nurnberg  PH (2004).  Olanzapine vs. placebo in the treatment of borderline personality disorder.  Journal of Clinical Psychiatry 65, 104–109.
[CrossRef]
 
Bohus  MJ;  Landwehrmeyer  GB;  Stiglmayr  CE;  Limberger  MF  et al. (1999).  Naltrexone in the treatment of dissociative symptoms in patients with borderline personality disorder: an open-label trial.  Journal of Clinical Psychiatry 60, 598–603.
[CrossRef]
 
Bolton  S;  Gunderson  JG (1996).  Distinguishing borderline personality disorder from bipolar disorder: differential diagnosis and implications.  American Journal of Psychiatry 153, 1202–1207.
 
Brambilla  P;  Soloff  PH;  Sala  M;  Nicoletti  MA  et al. (2004).  Anatomical MRI study of borderline personality disorder patients.  Psychiatry Research 131, 125–133.
[CrossRef]
 
Coccaro  EF;  Kavoussi  RJ (1997).  Fluoxetine and impulsive aggressive behavior in personality-disordered subjects.  Archives of General Psychiatry 54, 1081–1088.
[CrossRef]
 
Coccaro  EF;  Kavoussi  RJ;  Hauger  RL (1995).  Physiological responses to d-fenfluramine and ipsapirone challenge correlate with indices of aggression in males with personality disorder.  International Clinical Psychopharmacology 10, 177–179.
[CrossRef]
 
Coccaro  EF;  Lee  RJ;  Kavoussi  RJ (2009).  A double-blind, randomized, placebo-controlled trial of fluoxetine in patients with intermittent explosive disorder.  Journal of Clinical Psychiatry 70, 653–662.
[CrossRef]
 
Coccaro  EF;  Siever  LJ;  Klar  HM;  Maurer  G  et al. (1989).  Serotonergic studies in patients with affective and personality disorders: correlates with suicidal and impulsive aggressive behavior.  Archives of General Psychiatry 46, 587–599.
[CrossRef]
 
Cornelius  JR;  Soloff  PH;  Perel  JM;  Ulrich  RF (1993).  Continuation pharmacotherapy of borderline personality disorder with haloperidol and phenelzine.  American Journal of Psychiatry 150, 1843–1848.
 
Cowdry  RW;  Gardner  DL (1988).  Pharmacotherapy of borderline personality disorder: alprazolam, carbamazepine, trifluoperazine, and tranylcypromine.  Archives of General Psychiatry 45, 111–119.
[CrossRef]
 
Davidson  J;  Yaryura-Tobias  J;  DuPont  R;  Stallings  L  et al. (2004b).  Fluvoxamine-controlled release formulation for the treatment of generalized social anxiety disorder.  Journal of Clinical Psychopharmacology 24, 118–125.
[CrossRef]
 
Davidson  JR;  Foa  EB;  Huppert  JD;  Keefe  FJ  et al. (2004a).  Fluoxetine, comprehensive cognitive behavioral therapy, and placebo in generalized social phobia.  Archives of General Psychiatry 61, 1005–1013.
[CrossRef]
 
de la Fuente  JM;  Lotstra  F (1994).  A trial of carbamazepine in borderline personality disorder.  European Neuropsychopharmacology 4, 479–486.
[CrossRef]
 
Depue  RA;  Morrone-Strupinsky  JV (2005).  A neurobehavioral model of affiliative bonding: implications for conceptualizing a human trait of affiliation.  Behavioral and Brain Sciences 28, 313–395.
 
Deutsch  H (1942).  Some forms of emotional disturbance and their relationship to schizophrenia.  Psychoanalytic Quarterly 11, 301–321.
 
Ekselius  L;  von Knorring  L (1998).  Personality disorder comorbidity with major depression and response to treatment with sertraline or citalopram.  International Clinical Psychopharmacology 13, 205–211.
[CrossRef]
 
Evenden  J (1999).  Impulsivity: a discussion of clinical and experimental findings.  Journal of Psychopharmacology 13, 180–192.
[CrossRef]
 
Fahlen  T (1995).  Personality traits in social phobia, II: changes during drug treatment.  Journal of Clinical Psychiatry 56, 569–573.
 
Faltus  FJ (1984).  The positive effect of alprazolam in the treatment of three patients with borderline personality disorder.  American Journal of Psychiatry 141, 802–803.
 
Fonagy  P;  Luyten  P (2009).  A developmental, mentalization-based approach to the understanding and treatment of borderline personality disorder.  Development and Psychopathology 21, 1355–1381.
[CrossRef]
 
Frankenburg  FR;  Zanarini  MC (2002).  Divalproex sodium treatment of women with borderline personality disorder and bipolar II disorder: a double-blind placebo-controlled pilot study.  Journal of Clinical Psychiatry 63, 442–446.
[CrossRef]
 
Frankenburg  FR;  Zanarini  MC (2006).  Obesity and obesity-related illnesses in borderline patients.  Journal of Personality Disorders 20, 71–80.
[CrossRef]
 
Gardner  DL;  Cowdry  RW (1986a).  Development of melancholia during carbamazepine treatment in borderline personality disorder.  Journal of Clinical Psychopharmacology 6, 236–239.
[CrossRef]
 
Gardner  DL;  Cowdry  RW (1986b).  Positive effects of carbamazepine on behavioral dyscontrol in borderline personality disorder.  American Journal of Psychiatry 143, 519–522.
 
Goldberg  SC;  Schulz  SC;  Schulz  PM;  Resnick  RJ  et al. (1986).  Borderline and schizotypal personality disorders treated with low-dose thiothixene vs. placebo.  Archives of General Psychiatry 43, 680–686.
[CrossRef]
 
Goodman  M;  New  A;  Siever  L (2004).  Trauma, genes, and the neurobiology of personality disorders.  Annals of the New York Academy of Sciences 1032, 104–116.
[CrossRef]
 
Goodwin  GM;  Bowden  CL;  Calabrese  JR;  Grunze  H  et al. (2004).  A pooled analysis of 2 placebo-controlled 18-month trials of lamotrigine and lithium maintenance in bipolar I disorder.  Journal of Clinical Psychiatry 65, 432–441.
[CrossRef]
 
Griengl  H;  Sendera  A;  Dantendorfer  K (2001).  Naltrexone as a treatment of self-injurious behavior – a case report.  Acta Psychiatrica Scandinavica 103, 234–236.
[CrossRef]
 
Hamazaki  T;  Sawazaki  S;  Itomura  M;  Asaoka  E  et al. (1996).  The effect of docosahexaenoic acid on aggression in young adults. A placebo-controlled double-blind study.  Journal of Clinical Investigation 97, 1129–1133.
[CrossRef]
 
Hamazaki  T;  Thienprasert  A;  Kheovichai  K;  Samuhaseneetoo  S  et al. (2002).  The effect of docosahexaenoic acid on aggression in elderly Thai subjects – a placebo-controlled double-blind study.  Nutritional Neuroscience 5, 37–41.
[CrossRef]
 
Heimberg  RG;  Liebowitz  MR;  Hope  DA;  Schneier  FR  et al. (1998).  Cognitive behavioral group therapy vs. phenelzine therapy for social phobia: 12-week outcome.  Archives of General Psychiatry 55, 1133–1141.
[CrossRef]
 
Henry  C;  Mitropoulou  V;  New  AS;  Koenigsberg  HW  et al. (2001).  Affective instability and impulsivity in borderline personality and bipolar II disorders: similarities and differences.  Journal of Psychiatric Research 35, 307–312.
[CrossRef]
 
Herpertz  SC;  Zanarini  M;  Schulz  CS;  Siever  L  et al. (2007).  World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Personality Disorders.  World Journal of Biological Psychiatry 8, 212–244.
[CrossRef]
 
Higgins  GA;  Enderlin  M;  Haman  M;  Fletcher  PJ (2003).  The 5-HT2A receptor antagonist M100,907 attenuates motor and ‘impulsive-type’ behaviours produced by NMDA receptor antagonism.  Psychopharmacology (Berlin) 170, 309–319.
[CrossRef]
 
Hollander  E;  Allen  A;  Lopez  RP;  Bienstock  CA  et al. (2001).  A preliminary double-blind, placebo-controlled trial of divalproex sodium in borderline personality disorder.  Journal of Clinical Psychiatry 62, 199–203.
[CrossRef]
 
Hollander  E;  Swann  AC;  Coccaro  EF;  Jiang  P  et al. (2005).  Impact of trait impulsivity and state aggression on divalproex vs. placebo response in borderline personality disorder.  American Journal of Psychiatry 162, 621–624.
[CrossRef]
 
Hollander  E;  Tracy  KA;  Swann  AC;  Coccaro  EF  et al. (2003).  Divalproex in the treatment of impulsive aggression: efficacy in cluster B personality disorders.  Neuropsychopharmacology 28, 1185–1197.
[CrossRef]
 
Houston  RJ;  Bauer  LO;  Hesselbrock  VM (2004).  Effects of borderline personality disorder features and a family history of alcohol or drug dependence on P300 in adolescents.  International Journal of’ Psychophysiology 53, 57–70.
[CrossRef]
 
Huband  N;  Ferriter  M;  Nathan  R;  Jones  H (2010).  Antiepileptics for aggression and associated impulsivity.  Cochrane Database for Systematic Reviews . Issue 2, Art. No. CD003499.
 
IMCTGMSP, Katschnig  H (1997).  The International Multicenter Clinical Trial Group on Moclobemide in Social Phobia. Moclobemide in social phobia: a double-blind, placebo-controlled clinical study.  European Archives of Psychiatry and Clinical Neuroscience 247, 71–80.
[CrossRef]
 
Ingenhoven  T;  Lafay  P;  Rinne  T;  Passchier  J  et al. (2010).  Effectiveness of pharmacotherapy for severe personality disorders: meta-analyses of randomized controlled trials.  Journal of Clinical Psychiatry 71, 14–25.
[CrossRef]
 
Jensen  HV;  Andersen  J (1989).  An open, noncomparative study of amoxapine in borderline disorders.  Acta Psychiatrica Scandinavica 79, 89–93.
[CrossRef]
 
Juengling  FD;  Schmahl  C;  Hesslinger  B;  Ebert  D  et al. (2003).  Positron emission tomography in female patients with borderline personality disorder.  Journal of Psychiatric Research 37, 109–115.
[CrossRef]
 
Kasper  S;  Stein  DJ;  Loft  H;  Nil  R (2005).  Escitalogram in the treatment of social anxiety disorder: randomised, placebo-controlled, flexible-dosage study.  British Journal of Psychiatry 186, 222–226.
[CrossRef]
 
Katzelnick  DJ;  Kobak  KA;  Greist  JH;  Jefferson  JW  et al. (1995).  Sertraline for social phobia: a double-blind, placebo-controlled crossover study.  American Journal of Psychiatry 152, 1368–1371.
 
Kayser  A;  Robinson  DS;  Nies  A;  Howard  D (1985).  Respons to phenelzine among depressed patients with features of hysteroid dysphoria.  American Journal of Psychiatry 142, 486–488.
 
Keck  P;  Buffenstein  A;  Ferguson  J;  Feighner  J  et al. (1998).  Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo-controlled trial.  Psychopharmacology 140, 173–184.
[CrossRef]
 
Koenigsberg  HW;  Reynolds  D;  Goodman  M;  New  AS  et al. (2003).  Risperidone in the treatment of schizotypal personality disorder.  Journal of Clinical Psychiatry 64, 628–634.
[CrossRef]
 
Lader  M;  Stender  K;  Burger  V;  Nil  R (2004).  Efficacy and tolerability of escitalopram in 12- and 24-week treatment of social anxiety disorder: randomised, double-blind, placebo-controlled, fixed-dose study.  Depression and Anxiety 19, 241–248.
[CrossRef]
 
Langdon  R;  Coltheart  M (2004).  Recognition of metaphor and irony in young adults: the impact of schizotypal personality traits.  Psychiatry Research 125, 9–20.
[CrossRef]
 
Leiberich  P;  Nickel  MK;  Tritt  K;  Pedrosa Gil  F (2008).  Lamotrigine treatment of aggression in female borderline patients, part II: an 18-month follow-up.  Journal of Psychopharmacology 22, 805–808.
[CrossRef]
 
Leone  NF (1982).  Response of borderline patients to loxapine and chlorpromazine.  Journal of Clinical Psychiatry 43, 148–150.
 
Lepola  U;  Bergtholdt  B;  St Lambert  J;  Davy  KL  et al. (2004).  Controlled-release paroxetine in the treatment of patients with social anxiety disorder.  Journal of Clinical Psychiatry 65, 222–229.
[CrossRef]
 
Levitt  JJ;  Westin  CF;  Nestor  PG;  Estepar  RS  et al. (2004).  Shape of caudate nucleus and its cognitive correlates in neuroleptic-naïve schizotypal personality disorder.  Biological Psychiatry 55, 177–184.
[CrossRef]
 
Lieb  K;  Vollm  B;  Rucker  G;  Timmer  A  et al. (2010).  Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomized trials.  British Journal of Psychiatry 196, 4–12.
[CrossRef]
 
Lieb  K;  Zanarini  MC;  Schmahl  C;  Linehan  MM  et al. (2004).  Borderline personality disorder.  Lancet 364, 453–461.
[CrossRef]
 
Liebowitz  MR;  Gelenberg  AJ;  Munjack  D (2005a).  Venlafaxine extended release vs. placebo and paroxetine in social anxiety disorder.  Archives of General Psychiatry 62, 190–198.
[CrossRef]
 
Liebowitz  MR;  Heimberg  RG;  Schneier  FR;  Hope  DA  et al. (1999).  Cognitive-behavioral group therapy versus phenelzine in social phobia: long-term outcome.  Depression and Anxiety 10, 89–98.
[CrossRef]
 
Liebowitz  MR;  Klein  DF (1981).  Interrelationship of hysteroid dysphoria and borderline personality disorder.  Psychiatric Clinics of North America 4, 67–87.
 
Liebowitz  MR;  Mangano  RM;  Bradwejn  J;  Asnis  G  et al. (2005b).  A randomized controlled trial of venlafaxine extended release in generalized social anxiety disorder.  Journal of Clinical Psychiatry 66, 238–247.
[CrossRef]
 
Liebowitz  MR;  Stein  MB;  Tancer  M;  Carpenter  D  et al. (2002).  A randomized, double-blind, fixed-dose comparison of paroxetine and placebo in the treatment of generalized social anxiety disorder.  Journal of Clinical Psychiatry 63, 66–74.
[CrossRef]
 
Links  PS;  Steiner  M;  Boiago  I;  Irwin  D (1990).  Lithium therapy for borderline patients: preliminary findings.  Journal of Personality Disorders 4, 173–181.
[CrossRef]
 
Lion  JR (1979).  Benzodiazepines in the treatment of aggressive patients.  Journal of Clinical Psychiatry 40, 70–71.
 
Loew  TH;  Nickel  MK (2008).  Topiramate treatment of women with borderline personality disorder, part II: an open 18-month follow-up.  Journal of Clinical Psychopharmacology 28, 355–357.
[CrossRef]
 
Loew  TH;  Nickel  MK;  Muehlbacher  M;  Kaplan  P  et al. (2006).  Topiramate treatment of women with borderline personality disorder: a double-blind, placebo-controlled study.  Journal of Clinical Psychopharmacology 26, 61–66.
[CrossRef]
 
Loranger  AW;  Sartorius  N;  Andreoli  A;  Berger  P  et al. (1994).  The international personality disorders examination. The world health organization/alcohol, drug abuse, and mental health administration international pilot study of personality disorders.  Archives of General Psychiatry 51, 215–224.
[CrossRef]
 
Lott  M;  Greist  JH;  Jefferson  JW;  Kobak  KA  et al. (1997).  Brofaromine for social phobia: a multicenter, placebo-controlled, double-blind study.  Journal of Clinical Psychophamacology 17, 255–260.
[CrossRef]
 
Malone  KM;  Corbitt  EM;  Li  S;  Mann  JJ (1996).  Prolactin response to fenfluramine and suicide attempt lethality in major depression.  British Journal of Psychiatry 168, 324–329.
[CrossRef]
 
Markovitz  PJ;  Calabrese  JR;  Schulz  SC;  Meltzer  HY (1991).  Fluoxetine in the treatment of borderline and schizotypal personality disorders.  American Journal of Psychiatry 148, 1064–1067.
 
Mattes  JA (2005).  Oxcarbazepine in patients with impulsive aggression: a double-blind, placebo-controlled trial.  Journal of Clinical Psychopharmacology 25, 575–579.
[CrossRef]
 
Mattes  JA (2008).  Levetiracetam in patients with impulsive aggression: a double-blind, placebo-controlled trial.  Journal of Clinical Psychiatry 69, 310–315.
[CrossRef]
 
Mauchnik  J;  Schmahl  C (2010).  The latest neuroimaging findings in borderline personality disorder.  Current Psychiatry Reports 12, 46–55.
[CrossRef]
 
McClure  MM;  Barch  DM;  Romero  MJ;  Minzenberg  MJ  et al. (2007b).  The effects of guanfacine on context-processing abnormalities in schizotypal personality disorder.  Biological Psychiatry 61, 1157–1160.
[CrossRef]
 
McClure  MM;  Harvey  PD;  Goodman  M;  Triebwasser  J  et al. (2010).  Pergolide treatment of cognitive deficits associated with schizotypal personality disorder: continued evidence of the importance of the dopamine system in the schizophrenia spectrum.  Neuropsychopharmacology 35, 1356–1362.
[CrossRef]
 
McClure  MM;  Romero  MJ;  Bowie  CR;  Reichenberg  A  et al. (2007a).  Visual-spatial learning and memory in schizotypal personality disorder: continued evidence for the importance of working memory in the schizophrenia spectrum.  Archives of Clinical Neuropsychology 22, 109–116.
[CrossRef]
 
McGee  MD (1997).  Cessation of self-mutilation in a patient with borderline personality disorder treated with naltrexone.  Journal of Clinical Psychiatry 58, 32–33.
[CrossRef]
 
Mehlman  PT;  Higley  JD;  Faucher  I;  Lilly  AA  et al. (1994).  Low CSF 5-HIAA concentrations and severe aggression and impaired impulse control in nonhuman primates.  American Journal of Psychiatry 151, 1485–1491.
 
Mercer  D;  Douglass  AB;  Links  PS (2009).  Meta-analyses of mood stabilizers, antidepressants and antipsychotics in the treatment of borderline personality disorder: effectiveness for depression and anger symptoms.  Journal of Personality Disorders 23, 156–174.
[CrossRef]
 
Minzenberg  MJ;  Grossman  R;  New  AS;  Mitropoulou  V  et al. (2006).  Blunted hormone responses to ipsapirone are associated with trait impulsivity in personality disorder patients.  Neuropsychopharmacology 31, 197–203.
 
Montgomery  SA;  Montgomery  D (1982).  Pharmacological prevention of suicidal behavior.  Journal of Affective Disorders 4, 291–298.
[CrossRef]
 
Montgomery  SA;  Nil  R;  Durr-Pal  N;  Loft  H  et al. (2005).  A 24-week randomized, double-blind, placebo-controlled study of escitalopram for the prevention of generalized social anxiety disorder.  Journal of Clinical Psychiatry 66, 1270–1278.
[CrossRef]
 
Montgomery  SA;  Roy  D;  Montgomery  DB (1983).  The prevention of recurrent suicidal acts.  British Journal of Clinical Pharmacology 15, 183S–188S.
[CrossRef]
 
New  AS;  Hazlett  EA;  Buchsbaum  MS;  Goodman  M  et al. (2002).  Blunted prefrontal cortical 18fluorodeoxyglucose positron emission tomography response to meta-chlorophenylpiperazine in impulsive aggression.  Archives of General Psychiatry 59, 621–629.
[CrossRef]
 
New  AS;  Trestman  R;  Mitropoulou  V;  Benishay  DS  et al. (1997).  Serotonergic function and self-injurious behavior in personality disorder patients.  Psychiatry Research 69, 17–26.
[CrossRef]
 
New  AS;  Trestman  R;  Mitropoulou  V;  Goodman  M  et al. (2004).  Low prolactin response to fenfluramine in impulsive aggression.  Journal of Psychiatric Research 38, 223–230.
[CrossRef]
 
Nickel  MK;  Loew  TH (2008).  Treatment of aggression with topiramate in male borderline patients, part II: 18-month follow-up.  European Psychiatry 23, 115–117.
[CrossRef]
 
Nickel  MK;  Loew  TH;  Pedrosa Gil  F (2007).  Aripiprazole in treatment of borderline patients, part II: an 18-month follow-up.  Psychopharmacology 191, 1023–1026.
[CrossRef]
 
Nickel  MK;  Muehlbacher  M;  Nickel  C;  Kettler  C  et al. (2006).  Aripiprazole in the treatment of patients with borderline personality disorder: a double-blind, placebo-controlled study.  American Journal of Psychiatry 163, 833–838.
[CrossRef]
 
Nickel  MK;  Nickel  C;  Kaplan  P;  Lahmann  C  et al. (2005).  Treatment of aggression with topiramate in male borderline patients: a double-blind, placebo-controlled study.  Biological Psychiatry 57, 495–499.
[CrossRef]
 
Nickel  MK;  Nickel  C;  Mitterlehner  FO;  Tritt  K  et al. (2004).  Topiramate treatment of aggression in female borderline personality disorder patients: a double-blind, placebo-controlled study.  Journal of Clinical Psychiatry 65, 1515–1519.
[CrossRef]
 
Noyes  R;  Moroz  G;  Davidson  JR;  Liebowitz  MR  et al. (1997).  Moclobemide in social phobia: a controlled dose-response trial.  Journal of Clinical Psychopharmacology 17, 247–254.
[CrossRef]
 
Ogiso  Y;  Moriya  N;  Ikuta  N;  Maher-Nishizono  A  et al. (1993).  Relationship between clinical symptoms and EEG findings in borderline personality disorder.  Japanese Journal of Psychiatry and Neurology 47, 37–46.
 
Oquendo  MA;  Krunic  A;  Parsey  RV;  Milak  M  et al. (2005).  Positron emission tomography of regional brain metabolic responses to a serotonergic challenge in major depressive disorder with and without borderline personality disorder.  Neuropsychopharmacology 30, 1163–1172.
[CrossRef]
 
Pande  AC;  Davidson  JR;  Jefferson  JW;  Janney  CA  et al. (1999).  Treatment of social phobia with gabapentin: a placebo-controlled study.  Journal of Clinical Psychopharmacology 19, 341–348.
[CrossRef]
 
Pande  AC;  Feltner  DE;  Jefferson  JW;  Davidson  JR  et al. (2004).  Efficacy of the novel anxiolytic pregabalin in social anxiety disorder.  Journal of Clinical Psychopharmacology 24, 141–149.
[CrossRef]
 
Parc  S;  McTigue  K (1997).  Working memory and the syndromes of schizotypal personality.  Schizophrenia Research 29, 213–220.
[CrossRef]
 
Paris  J (2004).  Borderline or bipolar? Distinguishing borderline personality disorder from bipolar spectrum disorders.  Harvard Review of Psychiatry 12, 140–145.
[CrossRef]
 
Paris  J (2005).  Borderline personality disorder.  Canadian Medical Association Journal 172, 1579–1583.
[CrossRef]
 
Parsons  B;  Quitkin  FM;  McGrath  PJ;  Stewart  JW  et al. (1989).  Phenelzine, imipramine, and placebo in borderline patients meeting criteria for atypical depression.  Psychopharmacological Bulletin 25, 524–534.
 
Pascual  JC;  Oller  S;  Soler  J;  Barrachina  J  et al. (2004).  Ziprasidone in the acute treatment of borderline personality disorder in psychiatric emergency services.  Journal of Clinical Psychiatry 65, 1281–1283.
[CrossRef]
 
Pascual  JC;  Madre  M;  Soler  J;  Barrachina  J  et al. (2006).  Injectable atypical antipsychotics for agitation in borderline personality disorder.  Pharmacopsychiatry 39, 117–118.
[CrossRef]
 
Pascual  JC;  Soler  J;  Puigdemont  D;  Perez-Egea  R  et al. (2008).  Ziprasidone in the treatment of borderline personality disorder: a double-blind, placebo-controlled, randomized study.  Journal of Clinical Psychiatry 69, 603–608.
[CrossRef]
 
Peet  M;  Stokes  C (2005).  Omega-3 fatty acids in the treatment of psychiatric disorders.  Drugs 65, 1051–1059.
[CrossRef]
 
Philipsen  A;  Richter  H;  Schmahl  C;  Peters  J  et al. (2004a).  Clonidine in acute aversive inner tension and self-injurious behavior in female patients with borderline personality disorder.  Journal of Clinical Psychiatry 65, 1414–1419.
[CrossRef]
 
Philipsen  A;  Schmahl  C;  Lieb  K (2004b).  Naloxone in the treatment of acute dissociative states in female patients with borderline personality disorder.  Pharmacopsychiatry 37, 196–199.
[CrossRef]
 
Pickup  GJ (2006).  Theory of mind and its relation to schizotypy.  Cognitive Neuropsychiatry 11, 177–192.
[CrossRef]
 
Pitchot  W;  Hansenne  M;  Pinto  E;  Reggers  J  et al. (2005).  5-Hydroxytryptamine 1A receptors, major depression, and suicidal behavior.  Biological Psychiatry 58, 854–858.
[CrossRef]
 
Placidi  GP;  Oquendo  MA;  Malone  KM;  Huang  YY  et al. (2001).  Aggressivity, suicide attempts, and depression: relationship to cerebrospinal fluid monoamine metabolite levels.  Biological Psychiatry 50, 783–791.
[CrossRef]
 
Posner  MI;  Rothbart  MK;  Vizueta  N;  Levy  KN  et al. (2002).  Attentional mechanisms of borderline personality disorder.  Proceedings of the National Academy of Sciences USA 99, 16366–16370.
[CrossRef]
 
Prossin  AR;  Love  TM;  Koeppe  RA;  Zubieta  JK  et al. (2010).  Dysregulation of regional endogenous opioid function in borderline personality disorder.  American Journal of Psychiatry 167, 925–933.
[CrossRef]
 
Reich  DB;  Zanarini  MC;  Bieri  KA (2009).  A preliminary study of lamotrigine in the treatment of affective instability in borderline personality disorder.  International Clinical Psychopharmacology 24, 270–275.
 
Reich  J (2002).  Drug treatment of personality disorder traits.  Psychiatric Annals 32, 590–596.
 
Rickels  K;  Mangano  R;  Khan  A (2004).  A double-blind, placebo-controlled study of a flexible dose of venlafaxine ER in adult outpatients with generalized social anxiety disorder.  Journal of Clinical Psychopharmacology 24, 488–496.
[CrossRef]
 
Rifkin  A;  Quitkin  F;  Carrillo  C;  Blumberg  AG  et al. (1972).  Lithium carbonate in emotionally unstable character disorder.  Archives of General Psychiatry 27, 519–523.
[CrossRef]
 
Rinne  T;  van den Brink  W;  Wouters  L;  van Dyck  R (2002).  SSRI treatment of borderline personality disorder: a randomized, placebo-controlled clinical trial for female patients with borderline personality disorder.  American Journal of Psychiatry 159, 2048–2054.
[CrossRef]
 
Roth  AS;  Rostroff  RB;  Hoffman  RE (1996).  Naltrexone as a treatment for repetitive self-injurious behavior: an open-label trial.  Journal of Clinical Psychiatry 57, 233–237.
 
Rusch  N;  van Elst  LT;  Ludaescher  P;  Wilke  M  et al. (2003).  A voxel-based morphometric MRI study in female patients with borderline personality disorder.  Neuroimage 20, 385–392.
[CrossRef]
 
Russ  MJ;  Campbell  SS;  Kakuma  T;  Harrison  K  et al. (1991).  EEG theta activity and pain insensitivity in self-injurious borderline patients.  Psychiatry Research 89, 201–214.
[CrossRef]
 
Salzman  C;  Wolfson  AN;  Schatzberg  A;  Looper  J  et al. (1995).  Effects of fluoxetine on anger in symptomatic volunteers with borderline personality disorder.  Journal of Clinical Psychopharmacology 15, 23–29.
[CrossRef]
 
Samuelsson  M;  Jokinen  J;  Nordstrom  AL;  Nordstrom  P (2006).  CSF 5-HIAA, suicide intent and hopelessness in the prediction of early suicide in male high-risk suicide attempters.  Acta Psychiatrica Scandinavica 113, 44–47.
[CrossRef]
 
Saper  JR (2000).  Borderline personality, opioids, and naltrexone.  Headache 40, 765–766.
[CrossRef]
 
Schneier  FR;  Gortz  D;  Campeas  R;  Fallon  B  et al. (1998).  Placebo-controlled trial of moclobemide in social phobia.  British Journal of Psychiatry 172, 70–77.
[CrossRef]
 
Schulz  SC;  Zanarini  MC;  Bateman  A;  Bohus  M  et al. (2008).  Olanzapine for the treatment of borderline personality disorder: variable-dose 12-week randomized double-blind placebo-controlled study.  British Journal of Psychiatry 193, 485–492.
[CrossRef]
 
Serban  G;  Siegel  S (1984).  Response of borderline and schizotypal patients to small doses of thiothixene and haloperidol.  American Journal of Psychiatry 141, 1455–1458.
 
Shafti  SS;  Shahveisi  B (2010).  Olanzapine vs. haloperidol in the management of borderline personality disorder: a randomized double-blind trial.  Journal of Clinical Psychopharmacology 30, 44–47.
[CrossRef]
 
Sheard  MH (1971).  Effect of lithium on human aggression.  Nature 230, 113–114.
[CrossRef]
 
Sheard  MH;  Marini  JL;  Bridges  CI;  Wagner  E (1976).  The effect of lithium on impulsive aggressive behavior in man.  American Journal of Psychiatry 133, 1409–1413.
 
Siever  LJ;  Buchsbaum  MS;  New  AS;  Spiegel-Cohen  J  et al. (1999).  D, L-fenfluramine response in impulsive personality disorder assessed with [18F]fluorodeoxyglucose positron emission tomography.  Neuropsychopharmacology 20, 413–423.
[CrossRef]
 
Siever  LJ;  Davis  KL (1991).  A psychobiological perspective on the personality disorders.  American Journal of Psychiatry 148, 1647–1658.
 
Siever  LJ;  Davis  KL (2004).  The pathophysiology of schizophrenia disorders: perspectives from the spectrum.  American Journal of Psychiatry 161, 398–413.
[CrossRef]
 
Simeon  D;  Stanley  B;  Frances  A;  Mann  JJ  et al. (1992).  Self-mutilation in personality disorders: psychological and biological correlates.  American Journal of Psychiatry 149, 221–226.
 
Simpson  EB;  Yen  S;  Costello  E;  Rosen  K  et al. (2004).  Combined dialectical behavior therapy and fluoxetine in the treatment of borderline personality disorder.  Journal of Clinical Psychiatry 65, 379–385.
[CrossRef]
 
Skodol  AE;  Gunderson  JG;  Shea  MT;  McGlashan  TH  et al. (2005).  The collaborative longitudinal personality disorders study (CLPS): overview and implications.  Journal of Personality Disorders 19, 487–504.
[CrossRef]
 
Smith  DJ;  Muir  WJ;  Blackwood  DH (2004).  Is borderline personality disorder part of the bipolar spectrum? Harvard Review of Psychiatry 12, 133–139.
[CrossRef]
 
Soderstrom  H;  Foresman  A (2004).  Elevated triiodothyronine in psychopathy – possible physiological mechanisms.  Journal of Neural Transmission 111, 739–744.
[CrossRef]
 
Soler  J;  Pascual  JC;  Campins  J;  Barrachina  J  et al. (2005).  Double-blind, placebo-controlled study of dialectical behavior therapy plus olanzapine for borderline personality disorder.  American Journal of Psychiatry 162, 1221–1224.
[CrossRef]
 
Soloff  PH;  Cornelius  J;  George  A;  Nathan  S  et al. (1993).  Efficacy of phenelzine and haloperidol in borderline personality disorder.  Archives of General Psychiatry 50, 377–385.
[CrossRef]
 
Soloff  PH;  George  A;  Nathan  RS;  Schulz  PM  et al. (1986a).