Chapter 9

Psychopharmacologie Management of Suicidality in Personality Disorders

Robert J Cardish, MD, FRCPC'

ABSTRACT
Objective: To review the evidence for the efficacy of pharmacotherapy and other biological treatments in suicidality associated with personality disorders, chiefly borderline personality disorder. Method: Systematic review ofthe literature. Results: Studies evaluating treatment of suicidality in personality disorders are absent. However, several studies examine the efficacy of pharmacotherapy for core symptom clusters that are closely associated with suicidal behaviour. Efficacy exists with transient psychotic episodes, fiashbacks and dissociations, affective dysregulation, impulsivity, and anger and hostility. Conclusions: Modest efficacy of pharmacologie treatments adjuvant to psychosocial treatments can be shown for clusters of symptoms related to borderline personality disorder.

RESUME
Objectif: Examiner les donnees probantes de l'efficacite de la phannacotherapie et d'autres traitements biologiques de la suicidabilite associee aux troubles de la personnalite, principalement au trouble de la personnalite limite. Methode : Une revue systematique de la documentation. Resultats : Les etudes evaluant le traitement de la suicidabilite dans les troubles de la personnalite sont absentes. Cependant, plusieurs etudes examinent l'efficacite de la pharmacotherapie pour les groupes de symptomes de base qui sont etroitement associes au comportement suicidaire. L'efficacite existe dans les episodes psychotiques transitoires, les recurrences et dissociations, le ddreglement affectif, l'impulsivite, et la colere et I'hostilite. Conclusions : L'efficacite modeste des traitements pharmacologiques adjoints aux traitements psychosociaux peut etre demontree pour les groupes de symptomes lies au trouble de la personnalite limite. (Can J Psychiatry 2007:52[6 Suppl 1]:115S-127S)

Key Words: borderline personality disorder, personality disorder, pharmacotherapy, suicidality, suicidal behaviour, impulsivity, affective dysregulation, transient psychotic episode

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S suicide in personality disorders a problem? Personality disorders (PDs) are common in the general population, with prevalence rates of up to 13,4%.' Among the personality disorders, borderline personality disorder (BPD) and antisocial personality disorder (APD) are particularly associated with suicidal behaviour. BPD is common, with a prevalence of about 1% in community samples.

commit suicide, PDs are common. Individuals who self-harm are at increased risk for completed suicide. This is true even if the suicide intent or the lethality of the attempt is low, BPD in particular is associated with a significant suicide rate of about 10%,

There is also evidence that PDs are more frequent among individuals who commit suicide. Psychological autopsy studies of people who commit suicide typically show a high proportion of them to have a PD, usually BPD, Up to 77% of suicides have a diagnosis of a PD,^ and in up to 34% this is the primary diagnosis,^

Pharmacotherapy and Other Somatic Treatments

The use of pharmacotherapy in the treatment of PDs has been extensively reviewed in recent years.''"^^ This systematic review (see "The Current Evidence Base for the Clinical Care of Suicidal Patients: Strengths and Weaknesses"^' for methodology and scope) summarizes that work, focusing on published studies relevant to the management of suicidal patients. Because of the paucity of studies that examined suicidal behaviour (that is, behaviour including deliberate self-harm and suicide attempts as well as suicide) as outcome variables, studies have been included that include known predictors of such behaviour (for example, impulsivity and anger) as surrogate outcomes,

What Is the Risk of Suicide in BPD?

Suicidal behaviour is a major challenge for people with BPD, Indeed, suicidal or self-harm behaviour is one ofthe 9 criteria that the DSM-IV lists for the diagnosis of BPD and is also more recognizable than some of the others. Long-term follow-up studies of inpatients diagnosed with BPD find suicide rates of about 10%.'' The diagnosis of BPD is associated with suicidal behaviour even when the suicide or self-harm criterion is excluded,^ BPD has also been found to have a higher association with suicidal behaviour than does major depression.^

Antidepressants
Selective Serotonin Reuptake Inhibitors Given the affective symptoms as well as the impulsivity associated with BPD, the use of selective serotonin reuptake inhibitors (SSRIs) for BPD has been well-studied. Serotonin is implicated in impulsive aggression and suicide, with many studies documenting low serotonin function.^^ There have been 7 randomized controlled trials (RCTs) of SSRIs in treating BPD. Fluoxetine Salzman and colleagues conducted a 13-week RCT of volunteer subjects with DSM-III BPD or "BPD traits" (meaning subthreshold BPD).^^ Subjects with recent suicidal behaviour were excluded, and they had to be free of self-mutilation for at least 4 years. Thirteen subjects received fluoxetine, and 9 received placebo. All subjects showed improvement, indicating a substantial placebo response. Subjects receiving fluoxetine showed greater reduction in overall distress and anger. The use of volunteers with no suicidality and not necessarily meeting criteria for BPD means this was a relatively high-functioning group and the results cannot be generalized to a more symptomatic patient population. Markovitz studied the use of fluoxetine in a sample of 17 subjects with DSM-III-R BPD.^" There was significant comorbidity, with 16 meeting criteria for a mood disorder (including bipolar I or II disorder). Subjects were randomly assigned to fluoxetine or placebo. There was significantly more improvement with medication in depression, anxiety.
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Do People Who Self-Harm Commit Suicide?

About 75% of people with BPD engage in self-harm behaviour.'' This includes self-injurious behaviour with and without suicidal intent. However, people who self-injure are at higher risk for eventual suicide regardless of motivation,^ PDs are present in 40% to 60% of individuals presenting to emergency departments with self-injury,^"'"

What About Suicide in Other PDs?

Cleckley stated that suicide was rarely carried out by psychopaths" (a diagnostic label similar to DSM-IV APD.) Subsequent studies have tended to confirm this, A high rate of suicide attempts in APD has been documented, but serious attempts are not common.'^ There have been no studies ofthe rate of suicide per se in APD, but mortality is higher in this group from nonnatural causes of death, including suicide, accidents, and homicide.'' Criminal offenders diagnosed with a personality disorder have a 5-year suicide rate of 3%'"*; however, the type of PD was not specified. Many of these individuals might have had BPD instead of, or along with, APD, Key Point: Suicide in patients with PDs is a major challenge, PDs are common in the general population and are frequently not recognized. Suicidal ideation is common in people with PDs, and among people who
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and global symptoms than with placebo. However, these results are hard to interpret because of the high degree of comorbidity. Suicidal behaviour was not examined as an outcome variable. Coccaro and Kavoussi examined the effectiveness of fiuoxetine on impulsive aggression in an RCT with 40 subjects diagnosed with DSM-IIl-R PD.^' About one-third ofthe subjects had BPD. While this study did not examine suicidality as an outcome measure, impulsive aggression is a predictor ofsuieidal behaviour and was prominent in the sample. Exclusion criteria included major depressive disorder (MDD) and bipolar disorder. Subjects were randomly assigned to fiuoxetine and placebo for 12 weeks. Subjects treated with fiuoxetine showed greater improvement in irritability and aggression. There was also a greater proportion of responders among the fiuoxetine group. One small study examined the effeet of fiuoxetine in treating BPD in subjects who were already receiving psychotherapy.^^ The sample consisted of 20 subjects receiving individual and group dialectical behaviour therapy (DBT). They were randomly assigned to fluoxetine or placebo, with 9 and 11 in each group respectively. After 12 weeks, there were no significant differences between the groups on any of the outcome measures. The authors concluded that there was no benefit in adding fluoxetine to a stable, efficacious psychotherapy. However, because they compared 2 active treatments in a very small sample the negative results should not be overinterpreted. Another study examined the role of pharmacotherapy combined with psychotherapy. Kool and eolleagues eonducted a 6-iTionth RCT comparing antidepressants and combined antidepressants and psychotherapy.^' This investigation was part of a larger study of 128 ambulatory patients with MDD. Of these patients, 85 (66%) had at least one personality disorder, and only 23 ofthe patients with PD (27%) had BPD, Ofthe 85 patients, 36 received medication alone and 49 combined therapy. Medication followed a protoeol allowing sequential ehanges in medication from fiuoxetine, to amitriptyline, and finally to moelobemide, in case of intoleranee or inefficacy. In addition to medication, the combined group also received 16 sessions of short-term psychodynamic supportive psychotherapy. Combined therapy was more effective than pharmaeotherapy alone for depressed patients with PDs. For patients without a PD, combined therapy was no more effective than phannacotherapy alone. This study did not look at suicidal behaviour as an outcome measure. It also did not compare combined therapy with psychotherapy alone, making it impossible to know whether the improvement in mood was related to the use of antidepressants.
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Paroxetine Verkes and colleagues conducted an RCT that examined the effieaey of paroxetine in preventing recurrent suicidal behaviour in a sample of 91 patients with reeent suicide attempts and who did not have a major Axis I diagnosis.^^ Subjects who had attempted suicide 5 or more times were tenned "major repeaters," according to Kreitman and Casey's definition, ^' Those who attempted suicide 1 to 4 times were called "minor repeaters." Subjects with major depressive disorder or a psyehotie disorder were excluded, as were those dependent on alcohol or drugs. Subjects were randomly assigned to receive paroxetine or plaeebo. All subjects reeeived supportive psychotherapy at 1- to 2-week intervals. All but 7 ofthe subjects met criteria for at least one DSM-IV PD, and 74 had at least one cluster B PD. Ofthe whole sample, 33% (15 of 46) ofthe paroxetine group, eompared with 47% (21 of 45) of the placebo group, made another attempt. This differenee was not statistically significant. However, within the minor repeater group, treatment with paroxetine was associated with significantly fewer reeurrences of suicidal behaviour. In this group, 5 of 30 patients (17%) receiving paroxetine, compared with 12 of 36 patients (33%) receiving plaeebo, made another attempt. The reeurrence rates in the major repeater group did not differ. They also found an interaction between drug and number of DSM-IV cluster B criteria met, Paroxetine was only effective in those patients meeting fewer than 15 eluster B eriteria. This study is important beeause it used suieide attempt as the main outeome measure in a sample of patients who were not depressed and who had recently attempted suieide. It directly addresses the question of whether treatment with an SSRI is effective in preventing suicide in patients with PDs seen in the emergency department after a suicide attempt. Overall, the answer is no. However, in the relatively lower risk group of minor attemptersthose with fewer than 5 attempts and meeting fewer cluster B criteriaparoxetine ean be effective,

Fluvoxamine
Finally, Rinne and colleagues investigated the efficacy of fiuvoxamine in a 6-week RCT of 38 women meeting DSM-IV criteria for BPD,'** Subjeets, who were between ages 18 and 50 years, were recruited from outpatient departments as well as the community. Exclusion criteria included diagnoses of bipolar disorder or sehizophrenia, Subjeets were randomly assigned to fluvoxamine or placebo in a double-blind design for 6 weeks. This was followed by a single-blind, half-crossover of 6 weeks in which all subjects received fiuvoxamine and then an open follow-up for another 12 weeks. Subjects treated with fiuvoxamine showed a reduction in the severity of rapid mood shifts that was statistieally significant
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and clinically relevant. This effect was noted within the first 6 weeks and persisted through the remaining 18 weeks of treatment. No difference was found for the ratings of anger and impulsivity, both of which improved equally in the medication and placebo groups. Side effects were common, but only nausea was more common in the medication group. This study is alone in showing improvement in rapid mood shifts in a group of patients with moderate-to-severe BPD, However, it was of short duration, and self-harm was not an outcome measure. It also showed a response to placebo in both anger and impulsivity.

Key Point: There is some evidence that SSRI antidepressants can be helpful in lessening symptoms of affective instability, anger, and impulsivity, although studies are inconsistent (Category B), Studies are also hampered by small sample sizes and short follow-up periods. Most studies do not include suicidal behaviour as an outcome measure, and some even exclude at inception patients with a history of suicide attempts. The one study that did specifically look at suicide attempts as an outcome had mixed results, with only the lower-risk group with fewer prior attempts showing a lower rate (Category A), Studies involving the combination of pharmacotherapy with psychotherapy support the use of psychotherapy. There is evidence that combining pharmacotherapy with psychotherapy is more effective than pharmacotherapy alone in patients with MDD and comorbid PD (Category A).

Fluphenazine Decanoate There was one attempt to duplicate the Montgomery study, using fiuphenazine decanoate. In an RCT, Battaglia and colleagues compared fiuphenazine in a "low" dose of 12,5 mg intramuscularly (equivalent to fiupenthixol 20 mg) with an "ultralow" dose of 1,5 mg (probably equivalent to placebo),'''' All patients were seen in an emergency department after attempting suicide, and all had a history of multiple suicide attempts. Eighty-five percent were diagnosed with BPD. Thirty patients received 12.5 mg monthly and 28 received 1,5 mg monthly for 6 months. Both groups showed a marked reduction in self-harm behaviour. While there was a trend for a greater effect in the low-dose group, compared with the ultralow-dose group, this difference was not significant statistically. Thiothixene Goldberg and colleagues studied the use of thiothixene (in a mean dosage of 8,7 mg daily) in an RCT with 50 outpatients who were diagnosed with DSM-III criteria for either BPD or schizotypal personality disorder,^" After 12 weeks of treatment, the investigators found improvement in subjects treated with medicadon only if they were experiencing brief psychotic episodes. Symptoms that improved included illusions, ideas of reference, and anxiety, but not depression. Unfortunately, self-harm was not examined as an outcome measure, Trifluoperazine (and Carbamazepine or Tranylcypromine) Cowdry and Gardner designed a randomized, double-blind, placebo-controlled crossover trial to study the effects of each of a broad range of psychotropic drugs: trifluoperazine, alprazolam, carbamazepine, and tranylcypromine, compared with placebo,'^ The subjects were patients with severe BPD with no present episode of MDD, but 50% had a history of MDD, which is typical, Suicidality was rated as significantly decreased, compared with placebo, during carbamazepine, tranylcypromine, and trifiuoperazine trials, Alprazolam was associated with significant worsening. This pioneering study did, however, have several fiaws, including relatively small numbers in each treatment arm combined with dropout rates averaging 55%, and the outcome measure of suicidality was subjective and vaguely defined. Nevertheless, their findings did achieve statistical significance and were reasonably interpreted as supporting a role for pharmacotherapy in treating BPD, particularly during periods of decompensation. There is no evidence from this study that permits or disallows extrapolation to other mood stabilizers, monoamine oxidase inhibitors (MAOI), or phenothiazines, Haloperidol Soloff and colleagues conducted a double-blind, placebocontrolled trial of haloperidol and amitriptyline in a sample of 61 inpatients diagnosed with BPD,^** Medications were given
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Neuroleptics
Fiupenthixol Decanoate In an early RCT, Montgomery and others studied the efficacy ofthe depot neuroleptic fiupenthixol in preventing recurrence of suicide attempts in 30 subjects, who were recruited from hospital inpatient units following a suicide attempt,^ ''^ About two-thirds were women and most had DSM-III BPD (23 of 30); patients with depression and schizophrenia were excluded. Subjects were randomly assigned to intramuscular fiupenthixol, at a dosage of 20 mg every 4 weeks, or placebo. After 6 months of treatment, there was a significant reduction in the number of suicidal acts in the fiupenthixol group, compared with the placebo group; 3 of 14 patients on medication made an attempt, compared with 12 of 16 on placebo. This study, although small, is important because it is the first study to report a positive effect of pharmacotherapy (or any other therapy) in reducing suicidal behaviour.
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in dose ranges of 4 to 16 mg for haloperidol and 100 to 175 mg for amitriptyline for 5-week periods. Haloperidol was superior to both amitriptyline and placebo on a composite measure of overall symptom severity, with no difference between amitriptyline and placebo. In a later study, the same group failed to replicate this finding.^^ They compared haloperidol with the MAOI phenelzine in a sample of 108 inpatients with DSM-III-R BPD. Patients were randomly assigned to haloperidol at an average dosage of 4 mg daily, phenelzine 60 mg daily, or placebo for 5 weeks of treatment. When outcome measures of anxiety, depression, impulsivity, and aggression were used, phenelzine was found to be more effective than haloperidol and placebo. Suicidality was not examined as an outcome. In another study, these researchers compared continuation therapy with haloperidol (up to 6 mg daily), phenelzine (up to 90 mg daily), and placebo in 14 men and 40 women with gp|-) 3s,39 Continuation medication trials lasted 16 weeks, following 5 weeks of acute therapy. They found that continuing haloperidol demonstrated efficacy only in treating irritability. Side effects were a problem in the haloperidol group, and there was a high dropout rate (64%, compared with 28% on placebo). Phenelzine led to only modest improvements in irritability and depression. Clozapine Clozapine is an atypical neuroleptic agent that has led to dramatic improvements in treatment-resistant schizophrenia and has been found to reduce the risk of suicide attempts in patients with schizophrenia.'"' Its use is limited because ofthe risk of agranulocytosis, requiring regular blood counts, and the risk of long-term cardiovascular effects. While there have been no controlled trials of clozapine in BPD, several case reports and open studies have documented dramatic results in seriously ill, hospitalized patients with BPD with severe self-mutilation who often had been resistant to other treatments.'""^^ In some cases improvement was enough that patients could be discharged. Despite the small samples and lack of control conditions, these results suggest that there may be a special role for clozapine in hospitalized patients with severe self-mutilation or psychotic symptoms, Olanzapine A placebo-controlled trial of olanzapine in BPD patients was conducted by Zanarini and Frankenburg in 2001 .''* They studied women with moderately severe BPD who were recruited from the community, excluding subjects with psychotic symptoms or MDD. Twenty-eight subjects (19 on olanzapine and 9 on placebo) entered the trial, which lasted 6 months. There was a high dropout rate in both groups. Olanzapine was
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associated with a significantly greater rate of change in measures of anxiety, interpersonal sensitivity, paranoia, and anger or hostility. There was no difference between the groups on depression. The mean daily dose (rounded) of olanzapine at the end of the trial was 5 mg. Weight gain associated with medication was about 1 kg. However, investigators noted that many of their subjects exercised regularly and paid careful attention to their nutrition. This is an important study suggesting that low-dose olanzapine can be effective in treating patients with BPD and that it is generally well-tolerated. However, the small sample size of relatively higher-functioning women with BPD may limit its generalization to more severe cases. In addition, suicidality was not examined as an outcome. Bogenschutz and George studied the use of olanzapine in patients with BPD recruited from the community and from outpatient clinics.'*^ Individuals with a serious suicide attempt within the previous 6 months were excluded, as were people with a psychotic disorder, MDD, or substance dependence not in at least partial remission. In a randomized placebocontrolled design, 40 patients (25 women and 15 men) were assigned to either olanzapine or placebo and followed for 12 weeks. Olanzapine was used in a dosage range of 2.5 to 20 mg daily. Patients treated with medication were significantly more improved than those on placebo in terms of BPD symptoms. There was significant weight gain in the medication group, with an average gain of about 4 kg. Weight gain and sedation were responsible for the premature termination of treatment in 2 ofthe medication-treated patients. This study suggests that olanzapine may be helpful in the short-term treatment of patients with BPD but that weight gain and sedation may limit its acceptance by patients. This is especially a concem in young female patients with BPD, many of whom are already concerned about weight. Self-harm was not examined as an outcome, and because subjects at higher risk of suicide attempts were excluded, it is not possible to draw conclusions about the usefulness of olanzapine in treating suicidal patients. As stated previously, many treatment-resistant patients with BPD are treated with an SSRI combined with a neuroleptic (a practice sanctioned by the American Psychiatric Association [APA] in its guidelines"**). In the first RCT of polypharmacy, Zanarini and colleagues'" compared the efficacy of fiuoxetine, olanzapine, and the olanzapine-fiuoxetine combination (OFC). The investigators recruited as subjects women from the community aged 18 to 40 years. Patients were excluded if they had current major depression. Forty-five subjects diagnosed with DSM-IV BPD were randomly allocated to fiuoxetine (n = 14), olanzapine (n = 16), and OFC (n = 15) and treated for 8 weeks. The mean dose at endpoint for
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fiuoxetine-treated subjects was 15 mg (range 10 to 30 mg) and for olanzapine-treated subjects 3 mg (range 2.5 to 7.5 mg); for the OFC group, the dose of fiuoxetine (rounded) was 13 mg (range 10 to 30 mg) and olanzapine was 3 mg (range 2.5 to 7.5 mg). Both olanzapine and OFC were more effective than fiuoxetine monotherapy in reducing both depression and aggression. Olanzapine was also superior to OFC in treating depressive symptoms. Subjects receiving fiuoxetine alone did not gain weight. The olanzapine-treated group gained about 3 kg, and the OFC group gained about 1 kg. The authors attributed the high retention rate (93% completed all 8 weeks) to their careful attention to the management of side effects. This study adds further evidence that low-dose olanzapine is beneficial for nonpsychotic symptoms of BPD. It also suggests that there is nothing to be gained by combining olanzapine with fiuoxetine apart from the lower weight gain. Unfortunately, there was no placebo control in this study. Subjects were women only, with BPD of moderate severity, limiting generalization to more severe cases. Similarly, suicidality was not examined. In another RCT, Soler and colleagues compared 30 patients with BPD treated with olanzapine and 30 patients given placebo.^" All subjects received a modified form of DBT (skills training and telephone access). After 12 weeks of treatment, the olanzapine-treated group had greater improvement in anxiety, depression, impulsiveness, and aggression. There was a significant weight gain in the medication group, with a mean gain of 3 kg. The dropout rate was 30% in both groups. An important weakness of this study was the fact that subjects could continue current medications, and 70% and 80% of subjects in the medication and placebo groups, respectively, were on antidepressants throughout the trial. Risperidone In an open-label trial, Rocca and colleagues treated 15 patients with BPD who had prominent histories of aggressive behaviour.^' Risperidone was started at 1 mg daily and increased as needed to a maximum of 4 mg daily. In the 13 patients who completed the 8-week trial, there was significant improvement in aggression. There was overall improvement, with reduced depression and increased energy and global functioning. The final mean dosage was 3 mg daily. Side effects were mild, and no subjects dropped out because of medication intolerance. Quetiapine Case reports suggest that quetiapine can be useful in reducing self-mutilation''^ and impulsive aggression. ^^ Villeneuve and colleagues treated 23 patients with BPD, who completed a 12-week trial of quetiapine, up to 400 mg daily.'"* They found a 20% reduction in impulsivity as well as
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improvement in symptoms of depression, anxiety, and hostility. While the medication was generally well-tolerated, one subject dropped out because of neutropenia and another because of possible neuroleptic malignant syndrome. In another open-label study, Bellino and colleagues treated 14 consecutive outpatients with BPD with quetiapine, up to 400 mg daily.'' There was significant improvement in ratings of impulsivity and fewer angry outbursts after the 12-week trial. Two subjects dropped out because of somnolence. Perrella and colleagues treated 29 subjects with BPD in an open-label trial with quetiapine, up to 800 mg daily, for 12 weeks.'^ There was improvement in hostility and aggression as well as depression. There was no change in ratings of suicidality. Six subjects dropped out because of side effects. Two subjects developed thrombocytopenia, one of whom had to discontinue the medication. Aripiprazole Aripiprazole is a newer atypical neuroleptic, not available in Canada, that has been reported to be only minimally associated with weight gain or changes in glucose or lipid levels." Nickel and colleagues studied the use of aripiprazole in subjects recruited from the community.'* They met DSM-III-R criteria for BPD, and while subjects with current suicidal ideation were excluded, those with self-injury were allowed. In an RCT, 26 subjects treated for 8 weeks with medication were compared with 26 on placebo. There was significant improvement in ratings of depression, anxiety, and anger in subjects treated with aripiprazole. The prevalence of self-injury dropped by 20% in the medication group, and increased slightly in the placebo group. No serious side effects were observed, and there was no significant weight gain. While the apparent lack of side effects is encouraging, this study is limited by the exclusion of subjects with suicidal ideation, the short trial, and the lack of measures of impulsivity. Key Point: There is evidence from one RCT that at least one traditional neuroleptic (trifiuoperazine) or mood stabilizer (carbamazepine) or MAOI (tranylcypromine) may lower suicidality (defined as proneness to act on suicidal feelings) in patients with PDs (Category A). One atypical neuroleptic, olanzapine, has been shown to be helpful in lowering anger or hostility and impulsive aggression, thought to be precursor correlates of suicidality in BPD (Category A), but suicidal behaviour per se was not used as an outcome variable. Significant rates of side effects, especially weight gain, limit its usefulness. Risperidone.(.Gategory B) and quetiapine (Category C) may also be helpful in BPD, but there is no evidence of an effect on siricidality. Special mention must be made of clozapine, which has
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been found helpful for severe self-harm in severely ill, hospitalized patients in a series of anecdotal reports (Category C).

reports and open-label studies with patients with RCTs have been reported. Hollander and colleagues studied the use of divalproex in 16 outpatients diagnosed with DSM-IV BPD,'''^ Patients were excluded if they had a psychotic disorder, current major depression, or current suicidal ideation. They were randomly assigned to 10 weeks of treatment at an approximate ratio of 2 to 1 (divalproex to placebo). The dose of divalproex was initially 250 mg at bedtime and gradually increased to obtain a blood level of 80 |ig/mL or the highest tolerable dose. Treatment with divalproex was associated with greater improvement on global measures of outcome. There was a high dropout rate (10 of 16), and the assignment ratio turned out to be 12:4 (divalproex to placebo). These factors severely limit the conclusions that can be obtained from this study. However, the authors note that the results were in the expected direction, and that none of the dropouts were owing to medication side effects. The exclusion of patients with suicidal ideation further limits the findings. In another small RCT, Frankenburg and Zanarini compared the efficacy and safety of divalproex and placebo in a group of women recruited through newspaper advertisements.''^ Thirty subjects meeting criteria for DSM-IV BPD and bipolar II disorder were randomly assigned to divalproex or placebo in a 2:1 ratio. Subjects were excluded if they were currently in a major depressive or hypomanic episode, were acutely suicidal, or had a history of a psychotic disorder. None ofthe subjects had continuous rapid-cycling bipolar II disorder. Treatment duration was 6 months. Divalproex was administered initially at a dosage of 250 mg twice daily and increased to reach a therapeutic serum level. Twenty subjects were assigned to medication and 10 to placebo, Divalproex was superior to placebo in reducing interpersonal sensitivity, anger and hostility, and impulsive aggression. There was no difference with regard to depression between the groups. There was a high attrition rate, but this was similar between the groups, with 35% ofthe medication group completing all 24 weeks, compared with 40% of the placebo group. Side effects were infrequent. Hollander and colleagues conducted a much larger placebocontrolled trial of divalproex in a sample of cluster B patients.** This was an industry-sponsored study designed to examine the usefulness of divalproex on impulsive aggression in a group of patients with diagnoses that included cluster B PD, intermittent explosive disorder (lED), and posttraumatic stress disorder (PTSD). All subjects had frequent physical or verbal outbursts. They excluded patients with psychotic disorders, current major depression of significant severity, or bipolar disorder, as well as those with "serious" suicidal or homicidal ideation. Patients on neuroleptics.
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Anticonvulsants
Carbamazepine Because of their effectiveness in bipolar disorder, anticonvulsants have been widely used in treating patients with BPD. Cowdry and Gardner included carbamazepine as part of a double-blind, crossover trial of placebo and 4 active medications in a small sample of 16 female outpatients with DSM-III BPD and prominent behavioural dyscontrol.^' Subjects with current major depression were excluded. Each trial lasted 6 weeks, and the dose of carbamazepine was titrated to therapeutic serum levels. Physicians rated patients as significantly improved on "suicidality" while receiving carbamazepine or tranylcypromine, compared with placebo. In a parallel study, 3 out of 17 subjects receiving carbamazepine developed melancholic depression that remitted when the drug was stopped.^" This finding was not supported in a small RCT of carbamazepine by de la Fuente and Lotstra.^' They used a sample of 20 inpatients with DSM-III-R BPD, of whom 14 were women. Subjects were excluded if currently in a major depressive episode. Carbamazepine was given in doses titrated to ensure therapeutic serum levels. After the trial of 32 days, there were no differences in outcome on the measures of anger, depression, behavioural dyscontrol, and global ratings between placebo and medication. These studies do not support the findings of Cowdry and Gardner^^ and suggest there is little evidence for a role for carbamazepine in treating patients with PDs who are at risk of suicide. However, the few studies available were small and none of them was specifically geared to evaluating suicidal behaviour per sethat is, the measures did not specifically count the incidences of suicide ideation, intentionally nonfatal self-harm, and suicide attempts. Oxcarbazepin e Oxcarbazepine is an anticonvulsant, structurally similar to carbamazepine but with fewer side effects and drug interactions.''^ Bellino and colleagues treated 17 consecutive outpatients for 12 weeks with oxcarbazepine at a dosage ranging from 1200 to 1500 mg daily.*' They found improvement in interpersonal difficulties, impulsivity, affective instability, and anger. However, there was no change in parasuicidal behaviour. Divalproex Divalproex is the best-studied anticonvulsant to date used in treating PDs. Following reports of its effectiveness in case
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Caring for the Suicidal Patient: An Evidence-Based Approach

benzodiazepines, or other mood stabilizers were exeluded, but some medications (for example, SSRIs) were allowed if patients were on a stable dosage that did not ehange during the trial. This was a large sample of 246 subjects, of whom 96 had cluster B PD, 116 had IED, and 34 PTSD, Ofthe cluster B group, 55% had BPD. Besides the broad range of diagnoses, this sample is remarkable for the number of men73%and the relatively older average age40 years. Only 15% had a history of psychiatrie hospitalization, while 46% had been arrested. This study used a randomized, placebo-controlled design over 19 sites. There was an initial screening period of up to 2 weeks, followed by 12 weeks of treatment, and then a 1-week period to taper off the medieation, Divalproex was given in an initial dosage of 500 mg daily. It was gradually increased to a therapeutic serum level. When the results were analyzed across all the diagnostic groups, there was no differenee between divalproex and plaeebo. There was also no improvement with divalproex in the IED and PTSD groups, but within the cluster B group there was clear improvement associated with divalproex on measures of aggression and irritability and in global ratings of severity. By the end of the trial, more than one-half the subjects were no longer eligible for the study, according to their aggression scores. Of subjects treated with divalproex, 72% were considered treatment responders (that is, much or very much improved), compared with 50% on placebo. Treatment-emergent adverse events were very common, with 93% in the medication group, compared with 81% with plaeebo. However, most of these were not considered serious. The dropout rate was similar between the medication and placebo groups (44% and 39% respectively). The most common adverse effects with medication were elevated liver enzymes, depression, nausea, and vomiting. Among the cluster B subjeets, 17% ofthe medication group discontinued participation in the study because of an adverse event, compared with 4% of the plaeebo group. In a subsequent analysis of this study, Hollander and colleagues compared 52 patients with BPD who had been randomly assigned to divalproex (M = 20) or placebo ( = 32).''' They found that divalproex was better than plaeebo in redueing impulsive aggression in patients with higher baseline impulsivity and aggression. In eonclusion, these studies suggest that divalproex may be helpful in reducing impulsive aggression in patients with BPD, and it is fairly well-tolerated. Unfortunately, the exclusion of subjeets with suicidal ideation and the lack of suicidality as an outcome measure again limit the generalization to suicidal patients.
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Topiramate In a pilot study. Nickel and colleagues eonducted a placebo-eontrolled, double-blind study comparing topiramate with plaeebo in 29 women with DSM-IV BPD. Subjects with complaints of moodiness, distrustfulness, impulsivity, and relationship difficulties were recruited through advertisements aimed at general praetitioners. They excluded subjects who were actively suieidal, who were abusing alcohol or drugs, or who had psyehotic disorders, MDD, or bipolar disorder. Subjects were randomized in a 2:1 ratio, with 21 assigned to topiramate and 10 to plaeebo. Medication was started at 50 mg daily and titrated to 250 mg daily by the sixth week. The duration ofthe study was 8 weeks. Significant improvement in the topiramate group was seen on measures of anger. Medication was associated with a signifieantly greater (but moderate) weight loss. Other side effects ineluded isolated cases of fatigue, dizziness, headaehe, and paresthesias. This study suggests that topiramate may be helpful in treating symptoms of anger, including impulsive aggression, in patients with BPD. However, it is a small pilot study of short duration, and included only moderately ill, nonsuicidal subjeets. The same group has published 2 RCTs of topiramate in subjeets with BPD. Nickel and eolleagues reeruited 44 men from outpatient departments and the community who were diagnosed with DSM-IV BPD.'' They excluded subjects who were actively suicidal. Twenty-two men were treated with topiramate up to 250 mg daily while 22 received placebo for the 8-week trial. They found significant improvement on most anger measures with topiramate, compared with placebo. There were no incidents of self-harm in either group. Treatment with topiramate was associated with a 5-kg weight loss. No other side effects were noted. In a similar study, Loew and colleagues studied the use of topiramate in 56 women recruited from the community from advertisements.'^ All subjects met DSM-IV BPD criteria; subjects were excluded who were currently suicidal or abusing alcohol or drugs. Twenty-eight women were treated with topiramate up to 200 mg daily, and 28 with plaeebo, for 10 weeks. There was significant improvement in the topiramate group on measures of anger, hostility, interpersonal sensitivity, phobie anxiety, and global severity. There was no improvement in depressive symptoms. They did not use an outcome measure speeifically designed to measure impulsivity or aggression. The average weight loss in the topiramate-treated group was over 4 kg more than observed with plaeebo. Other side effects included dizziness, fatigue, somnolence, cognitive impairment, and paresthesia, all described as mildly to moderately severe.
La Revue canadienne de psychiatrie, vol 52, supplement 1, juin 2007

Psychopharmacoiogic Management of Suicidaiity in Personaiity Disorders

Lamotrigine In open-label trials, lamotrigine has been useful in reducing suicidal behaviour" and other symptoms of BPD'"* in padents with BPD. Tritt and colleagues^^ studied the use of lamotrigine in an RCT of 27 women diagnosed with DSM-IV BPD, Exclusion criteria included major depression, being actively suicidal, and alcohol or drug abuse. According to a 2:1 rado, 18 subjects were assigned to lamotrigine up to 200 mg daily and 9 to placebo. After the 8-week trial, the lamotrigine group showed significant improvement on measures of anger. No serious side effects occurred; mild rash, dizziness, headache and nausea were the only side effects and were well-tolerated. There was moderate weight loss with no significant difference between groups. Key Point: There is evidence (Category A) supporting the use of divalproex in treating impulsive aggression in patients with PDs. It is also well tolerated, Topiramate (Category A) and lamotrigine (Category A) may be helpful for symptoms considered to be correlates of impulsive suicidality in BPD, but direct suicidal behaviour has not been used as an outcome variable. There is also mixed evidence (Category A) that carbamazepine is not useful in treating patients with PDs.

had not responded to trials of SSRIs, neuroleptics, or valproic acid. However, when naltrexone was added after he was on valproic acid for 6 weeks, the self-mudlation immediately stopped, and this result was maintained for 32 weeks. These results suggest that placebo-controlled trials of naltrexone are warranted in BPD padents who self-harm and self-mutilate, Electroconvulsive Therapy Electroconvulsive therapy (ECT) has been found to be highly effective in reducing acute suicide risk*"*' and is used in treating suicidality in patients with depressive illness concurrent with personality disorders. In a recent study, Feske and colleagues examined the acute outcome of ECT in depressed patients, comparing those with comorbid BPD, PD other than BPD, and no PD,^^ Compared with the other groups, the BPD padents had less symptomatic improvement. Patients with PD other than BPD responded as well to ECT as those with no PD, Remission of depression was seen in only 22% of BPD padents, compared with 56% and 70% of patients with other PD and no PD, respectively. This reinforces recent reviews concluding that depressed patients with comorbid PD, especially BPD, have a less robust response to ECT than do patients with MDD alone.'*''*'' Consistent with these findings, the APA practice guideline states that, in the absence of another indication for its use, ECT is not indicated for the treatment of suicidality in BPD,"*** Omega-3 Fatty Acids Several studies have examined the effectiveness of omega-3 fatty acids such as ethyl-eicosapentaenoic acid (E-EPA) on mood and behaviour. In an RCT, Gesch and colleagues found that prisoners taking vitamin and fatty acid supplements had significandy less antisocial (including violent) behaviour, compared with those taking placebo."^ Subjects were serving long terms for serious offences. While their psychiatric status was not determined, this may suggest a beneficial effect of fatty acids on impulsive aggression, Zanarini and Frankenburg used a double-blind, plaecbocontrolled design and compared the efficacy of E-EPA and placebo in treadng women padents with BPD in an 8-week trial,^^ Twenty subjects were given 1 g of E-EPA while 10 were given placebo. When baseline severity was controlled for E-EPA was superior to placebo in diminishing aggression and severity of depression. These findings are noteworthy because ofthe virtual lack of side effects of E-EPA. Clonidine Clonidine is a alpha2-adrenergic receptor agonist that suppresses the release of noradrenaline through actions at the presynapdc alpha2-autoreceptor, Nodng its usefulness in treating symptoms of PTSD, Philipsen and colleagues studied clonidine in an open pilot study,**' They administered
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Other Treatments
Opioid Receptor Antagonists Naltrexone has been used with some effect in treadng self-injurious behaviour in padents with mental retardadon,'* On the basis of this experience and the idea that dissociative symptoms may be related to alterations in the endogenous opiate system, opioid receptor antagonists have been used in patients with BPD. Using a double-blind, crossover design, Philipsen and colleagues compared naloxone and placebo in 9 patients with DSM-IV BPD treated intravenously when the patient was in an acute dissociative state,^' There was significant reduction on symptoms of dissociation and "aversive inner tension" after injecdon, with no difference between naloxone and placebo. In one small uncontrolled study, Bohus and colleagues gave naltrexone 25 to 100 mg 4 times daily to 13 patients with BPD and prominent dissociative symptoms, including flashbacks.'^ Patients rated symptoms for 1 week before and 1 week during treatment. Results showed a reduction in the duradon and intensity of dissociative symptoms as well as a reduction in the number of fiashbacks per day. Griengl and colleagues describe the use of naltrexone in a man with severe self-mutilation who met criteria for BPD," He
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Caring for the Suicidal Patient: An Evidence-Based Approach

clonidine to 14 women patients with DSM-IV BPD who were experiencing an acute state of "strong, aversive inner tension." All patients had chronic suicidal ideation, and 13 of them exhibited self-injurious behaviour. After administration of clonidine, aversive inner tension, dissociative symptoms, urge to self-injure, and suicidal ideation decreased. The drug was well tolerated with no severe adverse events. This finding needs to be confirmed with an RCT,

instability and anger (6 studies, 166 subjects) but no effect on impulsivity and aggression (3 studies, 142 subjects), interpersonal relationships (2 studies, 50 subjects), or global functioning(l study, 16 subjects). There was no effect on suicidality in the 3 studies that rated it: 1 antipsychotic trial (60 subjects), 1 antidepressant trial (25 subjects), and 1 mood stabilizer trial (16 subjects). The authors conclude that "pharmacotherapy can exert a modest beneficial effect" on traits of BPD.

Lithium
In a double-blind, placebo-controlled crossover study. Links and colleagues compared lithium carbonate with desipramine in patients with BPD,^^ Neither lithium nor desipramine were effective, compared with placebo, in depressive symptoms; however, therapists rated their patients as more improved on lithium, compared with placebo, on suicidal symptoms. Soloff' and Markovitz*' note that the need for monitoring blood levels, poorly tolerated side effects, and lethality in overdose limit the use of lithium in this impulsive population. Key Point: There is evidence (Category A) that omega-3 fatty acids are helpful in lowering aggression and depression in BPD. There may be some benefit from naltrexone and clonidine in self-harm behaviour (Category C). While lithium may be helpful (Category A), its use is limited. There is no role for ECT in treating PDs in the absence of any other indication (Category C).

Algorithms of Somatic Treatment in BPD

The APA has published guidelines for treating BPD."** It recommends using algorithms to choose medications, based on clusters of symptoms, including those relating to cognitive-perceptual difficulties, affective dysregulation, and impulsive-behaviour dysregulation. As noted above, suicidal behaviour is included in the impulsive-behaviour dyscontrol cluster. According to the APA algorithm, an SSRI is used as initial psychopharmaeologieal treatment. If there is partial efficacy, a low-dose neuroleptic is then added. With no efficacy, the patient is switched to a low-dose neuroleptic. The third step in the algorithm is to add (in the case of partial efficacy) or switch to (in the case of no efficacy) lithium carbonate or an MAOI, The next steps involve using carbamazepine or valproate, then adding an atypical neuroleptic. This approach has been severely criticized'""'^ because of limited research support beyond the first level. Links has suggested an alternative'^ to the symptom-specific algorithms recommended by the APA. He proposes an "outome-focused model" in which a patient-specific measurable outcome is chosen in collaboration with the patient, who is an active participant in the process. An example of an outcome is frequency or severity of self-cutting. By using an " of 1," medications can be tried in sequence. He notes that it is easy to start a drug in a patient with a PD but that it is often difficult to know when to stop it. This can lead to polypharmacy. In fact, many patients with BPD are on more than one drug,'' and it is often difficult to know which, if any, of the medications is helping them. Some acknowledged experts in the pharmacotherapy of PDs are not particularly enthusiastic about the use of medication. Soloff states that "medications do not cure character and are never the substitute for the work of a therapist."' He goes on to say that "treatment effects are modest in magnitude . . . Cure is not a realistic option. Reduction of symptom severity is a realistic goal." Similarly, Markovitz states that "data supporting the use of pharmacotherapy in personality dis- orders is limited" and points out that while symptom reduction is important, "the real key is whether this leads to improvements in a patient's life."''
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Metaanalyses and Systematic Reviews

Binks and colleagues systematically reviewed the pharmacotherapy of BPD for the Cochrane Collaboration.'^ Searching the literature up to 2002, they identified 10 RCTs. For binary outcomes, they calculated a standard estimation of relative risk. The authors conclude that the use of medication in BPD is not based on good evidence. They criticize the studies as being "small, short and poorly reported" and call for more research. Nose and colleagues conducted a metaanalysis of RCTs of medication for core traits of BPD.^" They found 22 studies, more than double the number found by Binks and colleagues, refiecting the growth of research in this area from 2002 to 2006. Antipsychotics had a positive effect against impulsivity and aggression (3 studies with 147 subjects), interpersonal relationships (3 studies with 136 subjects), and global functioning (7 studies with 342 subjects) but no effect on affective instability and anger (2 studies, 102 subjects). Antidepressants had a positive effect on affective instability and anger (4 studies, 125 subjects) but no effect on impulsivity and aggression (6 studies, 218 subjects), interpersonal relationships (1 study, 30 subjects), or global functioning (4 studies, 132 subjects). Mood stabilizers had a positive effect on affective
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Key Point: While medication can be used to ameliorate some ofthe symptoms (including suicidal behaviour) of patients with PDs (Category C), treatment effects are usually modest and unpredictable in the individual patient. Medication should be considered as adjunct to psychological treatment. When medication is used, it should follow a rational plan, such as the APA algorithtns, or a case-by-case methodology. It is useful to identify specific, measurable behavioural outcomes in advance, making it easier to decide whether to continue the drug or to stop it. When a drug proves to be of no added benefit, it should be discontinued and the residual supply collected from the patient to prevent the risk of accumulation.

contradictory. It is reasonable to try using carbamazepine or divalproex in cluster B disorders for affective instability and impulsive aggression on a case-by-case basis. Bear in mind that studies have found high attrition rates. If one is using these drugs, then it is also necessary to monitor the blood for bone marrow suppression and for changes in liver enzymes. Naltrexone may be tried on a case-by-case basis for self-mutilation. Similarly, clonidine and omega-3 fatty acids may also be given a trial in a particular case (all such advice is based on weak evidence from open studies). The evidence regarding lithium is similarly equivocal, and the drug is highly lethal in overdose and may therefore (despite the APA recommendations) be unsuitable with this population, given such a poor risk-reward equation. Notwithstanding this caveat, where there is clear evidence of comorbid nonrapid-cycling bipolar affective disorder, the clinician may employ lithium in a therapeutic trial or for maintenance, provided that the use of the drug is carefully monitored and precautions are taken against the stockpiling of lethal quantities ofthe drug.

Recommendations
We are seriously handicapped in interpreting the evidence of trials because there are no pharmacologie treatment studies on suicidality in PDs, including BPDwe are forced to make judgments based on the response of specific symptom clusters that are frequently associated with suicidal behaviour but are not true surrogates or proxies of this. In general, medication should not be viewed as the first line of treatment in working with patients with PDs, particularly BPD. However, there is modest evidence that they may sometimes be helpful in ameliorating specific symptom clusters, such as transitory psychotic episodes, periods of fiashbacks, dissociation, affective dysregulation, impulsivity, and anger or hostility. The first line of treatment with PDs is through psychological treatment modalities as outlined in "Effectiveness of Psychosocial Treatments on Suicidality in Personality Disorders,"'"* and medications may sometimes be complementary and make this treatment more feasible, particularly during times of acute crisis. Beware of polypharmacyreplace a drug that is not working. SSRIs may lessen symptoms of affective instability, anger, and impulsivity in some patients as well as improving depressed mood. Both typical and atypical neuroleptics may be tried (according to weak evidence) to lower proneness to act on suicidal feelings, anger or hostility, and impulsive aggression. Although the findings from studies with trifiuoperazine and olanzapine may not generalize to others in these categories, in practice, clinicians are using other drugs from the same groups as well, depending on their side effect profiles and other preferences. The evidence on mood stabilizers (divalproex and carbamazepine) and novel antieonvulsants (topiramate and lamotrigine) is also weak and sometimes
The Canadian Journal of Psychiatry, Vol 52, Supplement 1, June 2007

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Senior Psychiatrist, Borderline Personality Disorder Clinic, Centre for Addiction and Mental Health; Assistant Professor, University of Toronto, Toronto, Ontario. Address for correspondence: Dr RJ Cardish, CAMH, 1001 Queen Street West, Toronto, ON M6J 1H4; Robert_Cardish@catTih.net

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