Article2048 Am J Psychiatry 159:12, December 2002SSRI Treatment of Borderline Personality Disorder:A Randomized, Placebo-Controlled Clinical Trialfor Female Patients With Borderline Personality DisorderThomas Rinne, M.D., Ph.D.Wim van den Brink, M.D., Ph.D.Luuk Wouters, M.A.Richard van Dyck, M.D., Ph.D.Objective: Selective serotonin reuptakeinhibitors (SSRIs) are recommended fortreatment of affect lability, impulsivity,and aggression in patients with border-line personality disorder. This recommen-dation is based on positive findings in atleast 10 open studies and one small dou-ble-blind study of SSRIs for patients withborderline personality disorder and onestudy of impulsive aggressive patientswith different personality disorders. Arandomized, placebo-controlled SSRIstudy with borderline personality disor-der patients, however, provided inconclu-sive results because of a large response toplacebo. It was, therefore, decided to con-duct a new randomized trial with a largerstudy group.Method: A double-blind, placebo-con-trolled, randomized trial using the SSRIfluvoxamine for 6 weeks followed by ablind half-crossover for 6 weeks and anopen follow-up for another 12 weeks wasconducted with 38 nonschizophrenic,nonbipolar female patients with border-line personality disorder. The outcomemeasures were the rapid mood shift, im-pulsivity, and aggression subscales fromthe Borderline Personality Disorder Sever-ity Index.Results: Fluvoxamine but not placeboproduced a robust and long-lasting reduc-tion in the scores on the subscale forrapid mood shifts. In contrast, no differ-ence between the fluvoxamine and pla-cebo groups was observed in the effect onthe impulsivity and aggression scores.Conclusions: In this study, fluvoxaminesignificantly improved rapid mood shiftsin female borderline patients, but not im-pulsivity and aggression. This latter find-ing may be due to gender-specific differ-ences in impulsivity and aggression.(Am J Psychiatry 2002; 159:2048–2054)Patients suffering from borderline personality disorderconstitute a substantial proportion of the consumers ofmental health care and exhibit a broad spectrum of symp-toms and behaviors: affect lability with rapid mood shiftsfrom normal to depressive states, distinct irritability oranxiety, and impulsive, aggressive, and parasuicidal be-havior. A considerable number of studies (1–3) point to thecentral serotonergic system as a possible target for psy-chopharmacological intervention for impulsive, aggres-sive, and suicidal patients and thus for patients with bor-derline personality disorder. Several open studies (4–9) ofselective serotonin reuptake inhibitors (SSRIs) for smallgroups of borderline patients suggest that the prescriptionof an SSRI may be an effective pharmacological strategy toameliorate the pathology of borderline personality disor-der. However, we know of only one double-blind, placebo-controlled, randomized trial (10), which involved 14 fe-male and eight male borderline patients with mild tomoderate symptoms, and the results did not confirm thepositive results of the open studies because of a high rateof response to placebo. After post hoc refinement of theanalysis and the introduction of a measure of placebo re-sponse, statistically significant differences were obtainedwith respect to anger and aggression. A statistically signif-icant improvement in impulsive aggression was observedafter 12 weeks in another double-blind, randomized SSRIstudy (11), which included 28 male and 12 female subjectssuffering from a variety of impulsive DSM-III-R personal-ity disorders (13 subjects had borderline personality disor-der). However, the authors warned that the results of thisstudy must be interpreted with caution because of thesubstantial dropout rate (43%).Beyond these promising but controversial results withSSRIs, we know of no further double-blind, placebo-con-trolled studies using larger numbers of borderline patientswith severe borderline pathology. Moreover, on the basisof these findings from SSRI studies, SSRI treatment is rec-ommended for borderline personality disorder patientswith affect lability, impulsivity, and aggressiveness (12,13), a strategy also adopted in the practice guideline onborderline personality disorder of the American Psychiat-ric Association (14).Patients with borderline personality disorder are sus-ceptible to a broad spectrum of axis I disorders, such asaffective disorders, anxiety disorders (including post-traumatic stress disorder [PTSD]), eating disorders, andAm J Psychiatry 159:12, December 2002 2049RINNE, VAN DEN BRINK, WOUTERS, ET AL.substance use disorders (15). In all of the SSRI treatmentstudies of personality disorder patients that we know of,current major depressive disorder was an exclusion crite-rion because of the antidepressive effects of SSRIs. Such acriterion, however, does not allow for the fact that SSRIs arealso an effective treatment for many patients with anxietydisorders (including PTSD) and eating disorders (16–18).Furthermore, exclusion of all borderline patients with oneor more coexisting axis I disorders would reduce the studygroup to a marginal group with mild pathology. A clinicallymore relevant research strategy might, therefore, be a lessrigorous exclusion of comorbid axis I disorders and inclu-sion of them as a covariate in the statistical analysis.In addition to the preceding complications, the severityof borderline pathology raises some major ethical andpractical issues with regard to the use of long-term double-blind, placebo-controlled treatment. Taking this into ac-count, we decided to design the study in such a mannerthat the length of the placebo-controlled phase would bekept to a minimum but without the loss of statistical power.We believe that the present study includes the largestgroup (N=38) of well-diagnosed borderline personalitydisorder patients with moderate to severe pathology so farstudied in a pharmacotherapy trial. We conducted a dou-ble-blind, placebo-controlled, randomized trial using theSSRI fluvoxamine for 6 weeks followed by a blind half-crossover (with fluvoxamine replacing the placebo) for 6weeks and an open follow-up (in which all patients wereoffered fluvoxamine) for another 12 weeks. Following thementioned treatment recommendation, we investigatedthe effects of fluvoxamine on the borderline symptoms ofrapid mood shifts, impulsivity, and anger. Potential effectsof interactions with relevant axis I disorders were takeninto account in