Laboratory for Economic Management and Auctions Understanding Beta (A) “I don’t understand it! Yahoo has been such a winner, why has it collapsed so much?” bellowed Frank in the next cubicle. Sarah had endured Frank’s gloating over the success of his stock the year before last, but she suppressed a slight chuckle and decided to show him some pity. She felt she had to, since her
Doi:10.1016/j.psc.2008.03.013Clinical Trials of Treatmentfor Personality Disorders Joel Paris, MDInstitute of Community and Family Psychiatry, Sir Mortimer B. Davis Jewish General Hospital,Department of Psychiatry, McGill University, 4333 Cote Ste-Catherine Road,Montreal, QC H3T 1E4, Canada Untilrecently,thetreatmentofpatientswithpersonalitydisorderswas largely guided by clinical experience. However, in the past decade a se-ries of important clinical trials, both of pharmacotherapy and psycho- therapy, have been conducted. Almost all of this research deals withborderline personality disorder (BPD), a diagnosis that is common in clinicalsettings and that presents serious and worrisome challenges .
Personality disorders are chronic, but often improve with time . In fact, the prognosis for many personality disorders (PDs) is better than for most se-rious Axis I disorders. Since it difficult to determine whether improvement isnaturalistic or the result of any specific intervention, randomized controlled tri-als (RCTs) are crucial.
Another observation of importance for therapy is that depressed patients who also have PDs do not respond to the same treatment methods (whetherpharmacological or psychotherapeutic) as those without PDs Some havechallenged this conclusion in relation to antidepressants but a recentmeta-analysis supported it . The implication is that if clinicians avoid makingAxis II diagnoses, or only diagnose PD patients with comorbid Axis I condi-tions, they are likely to be disappointed with the results of drug treatment. Sim-ilarly, generic forms of psychotherapy may be less effective than methodsspecifically developed for PDs.
PSYCHOTHERAPIESDialectical Behavior TherapyDialectical behavior therapy (DBT) is an adaptation of cognitive behavioraltherapy, but is an eclectic mix of methods common to several other approaches. DBT is specifically designed to target the mood instability of BPD, but alsoaddresses impulsive behaviors. It applies behavioral analysis to incidents lead-ing to self-injury and overdoses, teaching patients alternative ways of handlingdysphoric emotions. DBT emphasizes empathic responses to distress that ª 2008 Elsevier Inc. All rights reserved.
provide ‘‘validation’’ for the inner experience of patients. The program consistsof individual therapy, group psychoeducation, and telephone availability for‘‘coaching.’’ DBT was the subject of one of the first randomized controlled trials of a psy- chotherapy designed for BPD . The results, published in 1991, showed thatit was clearly superior to ‘‘treatment as usual’’ (TAU, ie, outpatient therapy inthe community). After a year, patients receiving DBT were less likely to makesuicide gestures and spent less time in hospital. Although the gap narrowed at1-year follow-up , patients treated with DBT continued to have a higherfunctional level than those who were not treated with DBT.
In the 1991 study, more than 90% of patients treated with DBT stayed in therapy for the full year. That was a remarkable finding in a patient populationknown for a lack of treatment compliance. The highly structured nature ofDBT may be responsible. However, it should be noted that the patients inthis study received free treatment, while the cohort in treatment as usual didnot, and that replication studies in other centers have experienced higher ratesof attrition But these studies also confirmed the efficacy of DBT, whichis also effective in BPD patients with substance abuse .
The main limitation of the 1991 study was that it compared DBT to TAU, which tends to offer inconsistent follow-up. The advantage of DBT could havederived from its structure and consistency rather than from any specific form ofintervention.
To address this problem, Linehan and colleagues conducted a new clinical trial in which the comparison group was assigned to ‘‘treatment by communityexperts’’—therapists in the Seattle area who identified themselves as interestedin BPD, and whose fees were paid for by the research team. The results, publishedin 2006, found several outcomes that favored DBT: reductions in overdoses andsubsequent hospitalizations within the first year of treatment. But this time therewere no differences between the groups in the frequency of self-mutilation. Thus,DBT remained superior, even if its advantage was narrower.
While this research is highly encouraging, we need to determine whether its findings are generalizable to clinical settings. Selection biases affecting clinicalresearch tend to produce samples of patients who are compliant. Since not ev-ery BPD patient will follow through with DBT, we do not know whether thistreatment can be applied to all cases.
Another limitation concerns long-term efficacy. Linehan had suggested that a full course of treatment could take several years, but tested only the firststage (in which parasuicidal behaviors were targeted and brought under con-trol). We also do not know whether treated samples maintain their gainsand continue to improve or whether they might relapse. Although the originalcohort received therapy 15 years ago, there has been no follow up.
The largest problem for DBT is that it is resource-intensive and expensive.
For this reason, more than a decade after its introduction, implementation ofthis treatment has been spotty. Where available, it can produce long waitinglists—not surprising for a treatment whose initial phase lasts a full year. It remains to be seen whether DBT can be dismantled and streamlined for greaterclinical impact, but one recent study suggests that it can .
Other Forms of Cognitive TherapyLinehan developed DBT because of her experience that standard cognitivebehavioral therapy was not effective for this population. Nonetheless, CBT hasbeen subjected to clinical trials in these patients. Results using a method devel-oped by Beck (which focuses on correcting maladaptive cognitions) have beenpublished, but the trial was open and uncontrolled In a large RCT, Tyrerand colleagues , found that manualized cognitive behavioral therapy wassuperior to treatment as usual for the treatment of recurrent deliberate self-harm in PD patients, but was less effective for those with a diagnosis of BPD.
Recently, an RCT by Davidson and colleagues found standard CBT to be superior to treatment as usual for BPD. The average length of treatmentwas only 16 sessions, but CBT had a superior outcome. A report by Weinbergand colleagues of a 12-week clinical trial, found that that this brief treat-ment was superior to TAU in that it rapidly reduced self-harm behavior inBPD. All these findings suggest that CBT for BPD need not require severalyears of treatment.
Schema-focused therapy, developed by Young is a hybrid of CBT and psychodynamic therapy that focuses on maladaptive schema deriving from ad-verse experiences in childhood. A clinical trial found that improvementwas equivalent to a comparison group receiving transference-focused therapy(described later in this article).
The ‘‘STEPPS’’ program is another cognitive method providing psycho- education in a group format, designed to supplement standard therapy, and ithas been subjected to a successful clinical trial.
In summary, cognitive therapy is a strong contender to be considered a stan- dard treatment for BPD. A Cochrane review applying its usual high stan-dards of evidence, concluded that the data supporting this form of treatmentare promising.
While cognitive therapy has been proposed for the treatment of other per- sonality disorders , RCTs are rare and clinical guidelines unclear. Forexample, Emmelkamp and colleagues examined the use of CBT in avoi-dant personality disorder, comparing it to brief dynamic therapy, yet neithermethod was superior to a waiting list control group.
Psychodynamic TherapiesPsychoanalysts have long been interested in treating personality disorders, butpatients may not always do well with this approach. Thus, when BPD patientsare offered open-ended psychodynamic therapy, most will drop out withina few months .
In the first formal study of dynamic therapy in BPD, Stevenson and Meares reported improvement in 30 patients who received 2 years of a therapybased on self-psychology, and results remained stable after 5 years . Sincethere was no control group and outcome was compared with untreated patients on a waiting list (and to the overall course of the disorder), a replication waslater performed however, it was not clear how representative thesepatients were of clinical populations.
Mentalization-based therapy (MBT) has been tested with an RCT , and the good results were stable on 18-month follow-up MBT is derived fromattachment theory, and based on the idea that BPD patients need to taught to‘‘mentalize’’ (ie, to stand outside their feelings and accurately observe emotionsin self and others). MBT makes use of a number of cognitive methods, asacknowledged by Bateman and Fonagy . For example, mentalization re-sembles the concept of ‘‘decentering,’’ long applied by CBT Since the find-ings of the MBT trial were obtained to a day hospital, this milieu may haveaccounted for some of the improvement, and MBT is currently being testedin an outpatient setting .
Transference-focused psychotherapy (TFP) is a somewhat different psycho- dynamic method that aims to correct distortions in the patient’s perception ofsignificant others and of the therapist The method has been evaluated (ina comparison to DBT) in a randomized clinical trial, with results indicatingapproximately equivalent efficacy .
All these findings suggest that manualized dynamic therapies can also be suc- cessful for treating BPD, provided they are well structured. The most likelyreason why past therapies have often failed may be that they relied on unstruc-tured techniques, which leave patients adrift.
The findings also suggest that different forms of psychotherapy, based on different theories, can be effective.
Group TherapyGroups have been used either as a primary therapy, or as an adjunct to othertreatments. Only one controlled trial in BPD patients comparing long-termgroup to individual therapy has been published, with the finding that bothmethods achieved similar results .
PsychoeducationA recent RCT described the efficacy of brief psychoeducation for a mixedgroup of personality disorders. Education is also an essential element of DBTIt is useful to explain Axis II diagnoses to patients and to encourage them toread and browse on the Internet to obtain more information.
Whereas the families of patients have been, in the past, blamed for the de- velopment of personality disorders, therapists have come to realize they areburdened by their children’s psychopathology, and can be useful allies in treat-ment. Gunderson developed a program for psychoeducation of familymembers, paralleling previous work on expressed emotion in schizophrenia,but has not published data on its effectiveness.
PHARMACOTHERAPIESAlmost all the research on drugs for PDs has been on BPD.
NeurolepticsLow-dose neuroleptics have long been used for BPD, but have many sideeffects. Studies of haldoperidol show that patients tend to stop taking it, prob-ably for this reason, and that short-term effects are not maintained on 6-monthfollow-up Three studies of olanzapine found reductions inimpulsivity in short-term clinical trials. One study found that olanzapineadded to efficacy in patients also receiving DBT. However, all of these reportsused small samples. Moreover, clinical improvement did not translate intoremission.
Specific Serotonin Reuptake InhibitorsIt is unusual today to see a patient with BPD who is not on an antidepressant.
Yet this practice is not firmly based on controlled trials.
Specific serotonin reuptake inhibitors (SSRIs) have often been used for de- pressive symptoms in BPD. While one study reported that SSRIs reducemood swings in BPD, most suggest that SSRIs are most effectivein reducing anger and impulsive symptoms. High doses (eg, 60 to 80 mg of flu-oxetine) may produce reductions of self-mutilation , but patients can havedifficulty tolerating these levels.
Research has also examined MAO inhibitors and tricyclic antidepres- sants in BPD, but the side effects and potential lethality of these agents onoverdose have not encouraged their use.
Like neuroleptics, antidepressants ‘‘take the edge off’’ symptoms of BPD, but do not lead to remission of a personality disorder.
Mood StabilizersBPD is associated with marked affective instability, and has sometimes beenthought to lie in the bipolar spectrum . One reason for doubting this refor-mulation is that studies on mood stabilizers in BPD have produced unconvinc-ing results. The only controlled study of lithium in BPD failed todemonstrate clinical efficacy, and few clinicians would wish to use a drugthat is so dangerous on overdose. Carbamazepine can reduce impulsivitybut is also dangerous on overdose. Controlled trials of valproatehave shown only marginal efficacy in BPD, and the data suggestthat while this drug reduces impulsive aggression, it is less useful for affectiveinstability. The best results were obtained in a small-scale trial of valproate ,but this sample was limited to patients who were comorbid for bipolar II dis-order (ie, those with clear-cut hypomanic episodes), a very atypical groupthat may not even justify a BPD diagnosis. Lamotrigine and topiramatehave also been studied in small clinical trials in BPD patients, withsome effects in reducing anger and anxiety (but not depression).
In summary, mood stabilizers are more useful for impulsivity and aggression than for mood. As we have seen, the same effect can be obtained with SSRIsand low-dose neuroleptics. Although these agents are designated as ‘‘mood sta-bilizers,’’ their effects do not seem to extend very well to PDs. Efficacy is better documented in bipolar I and bipolar II; the emotional dysregulation in BPDpatients may be an entirely different phenomenon .
Other Pharmacological AgentsZanarini and Frankenburg reported that omega-3 fatty acids were helpfulfor BPD symptoms (in a small sample of patients obtained by advertisement).
Of course a single study is not sufficient evidence to recommend this agent fora clinical population.
PolypharmacyA wide variety of pharmacological agents reduce impulsivity in personalitydisorders, but none have ever been shown to produce clinical remission. Thesedrugs are of limited value because they were developed for other purposes,and are applied to Axis II diagnoses that probably have a differentpathophysiology.
Patients receiving medication usually remain unstable—in mood, impulsive actions, and relationships. This sometimes leads to the prescription of addi-tional agents, even if they have the same therapeutic effect (and limitations)as the original prescription. Thus, polypharmacy, a practice that is not evi-dence-based, is commonly applied to personality disorders, making it morelikely that patients will suffer from side effects. Patients with BPD are oftenon four to five drugs, with at least one from each major group . Unfortu-nately, algorithms for drug treatment in BPD, included in the American Psychi-atric Association guidelines for the treatment of BPD which are not basedon RCT evidence, lead directly to this practice.
A recent Cochrane report concluded that none of the clinical trials of drugs for BPD provides enough data to support their prescription. This beingthe case, it makes little sense to combine many drugs, none of which are specificto the disorder, when all of which do much the same thing.
SUMMARYThe treatment of patients with PDs is more hopeful than it was in the past.
However, we have become overly dependent on pharmacological treatments,neglecting psychotherapies even when they are evidence-based. Yet there ismuch stronger evidence for the effectiveness of psychotherapy in PDs thanfor any pharmacological intervention.
The main reasons psychological therapies are not more widely used is their cost and the length of time they need to be used. But several types of therapycan be effective, and some recent evidence suggests that we may be able to pro-vide these treatments in a briefer and more practical way .
Future research needs to answer other questions. First, since PDs are usually chronic, treatment research should move beyond short-term studies to examinelong-term effects, and treatment effects need to be shown to be superior to nat-uralistic remission. Second, the effective factors common to all psychotherapiesneed to be more specifically identified. Third, we need to develop entirely newgroups of drugs that specifically target the traits that underlie PDs.
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C l i n i c a l C a r e / E d u c a t i o n / N u t r i t i o n O R I G I N A L A R T I C L E Increased Intake of Calcium Reverses Vitamin B Malabsorption Induced by Metformin WILLIAM A. BAUMAN, MD ANN M. SPUNGEN, EDD SPENCER SHAW, MD VICTOR HERBERT, MD, JD ELIZABETH JAYATILLEKE, MS in vitamin B absorption because of altered RESEARCH DESIGN AND METHODS OBJECTIVE