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Issue 61, May 2017
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An effective, time-efficient way to screen for borderline personality disorder

Zimmerman M, Multach MD, Dalrymple K, Chelminski I. Clinically useful screen for borderline personality disorder in psychiatric outpatients. Br J Psychiatry. 2017 Feb;210(2):165-166. PubMed PMID: 27908898.


The importance of screening for borderline personality disorder was recently emphasized by Zimmerman et al. (2017). See

But how? In a busy clinical practice, which clinical feature could help us to most efficiently screen outpatients for the presence of borderline personality disorder?  


About 3700 patients attending a psychiatry outpatient clinic were evaluated.

A semi-structured diagnostic interview for DSM-IV borderline personality disorder was conducted.

There are nine diagnostic criteria for borderline personality disorder in DSM-IV and, based on them, the diagnosis of borderline personality disorder was identified.

The different diagnostic criteria were evaluated for their ability to “predict” the diagnosis of borderline personality disorder.  


The affective instability criterion had the highest sensitivity (93%). What this means is that of the persons who had borderline personality disorder, the affective instability criterion was present in 93% of them.

The negative predictive value of the affective instability criterion was 99%. This means that if the affective instability criterion was absent, there was a 99% chance that a diagnosis of borderline personality disorder was absent too.

The positive predictive value of the affective instability criterion was 38%. That is, only 38% of those with affective instability had a diagnosis of borderline personality disorder.

In case you are wondering, the criterion with the next highest sensitivity was inappropriate, intense anger or difficulty controlling anger.  


The authors recommended that clinicians screen for borderline personality disorder by enquiring about a single feature of the disorder--affective instability.

The presence of affective instability identified most patients with the disorder and its absence essentially ruled out the disorder in this study.

Clinical Commentary

Borderline personality disorder is a common and serious condition that is frequently missed. This is partly because the person presents with other problems like depression, anxiety, etc., and partly because its diagnosis is thought to require a detailed evaluation.

Thus, asking about affective instability should be done routinely in order to screen for possible borderline personality disorder.

That affective instability was the criterion with the highest sensitivity is not surprising because it is considered to be the central clinical feature of borderline personality disorder.

It should be kept in mind, though, that the negative predictive value of a screening question depends on the prevalence of the disorder. So, if a person presents with some features of borderline personality disorder (i.e., higher pre-test probability), additional questions may need to be asked even if affective instability is absent.

It is important to remember that the presence of affective instability does not mean that the borderline personality disorder is present; the positive predictive value is only 38%. However, if affective instability is absent, borderline personality disorder is very unlikely (at least in settings similar to those in which the study was done); the negative predictive value is 99%. This is exactly how a screening tool is supposed to work—identify persons who may have the disorder.

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Virtual reality exposure for social anxiety disorder

Bouchard S, Dumoulin S, Robillard G, Guitard T, Klinger É, Forget H, Loranger C, Roucaut FX. Virtual reality compared with in vivo exposure in the treatment of social anxiety disorder: a three-arm randomised controlled trial. Br J Psychiatry. 2016 Dec 15. pii: bjp.bp.116.184234. [Epub ahead of print] PubMed PMID: 27979818.


Exposure to social situations for the treatment of social anxiety disorder may cause excessive anxiety and patients may be reluctant to do it.

Can exposure to social situations in virtual reality (“in virtuo” exposure), as part of a broader cognitive-behavior therapy treatment plan, be an efficient alternative way of doing exposure?  


Participants in this study were randomly assigned to receive virtual reality exposure (n = 17), in vivo exposure (n = 22) or to be on a waiting list (n = 20).

Participants in both the virtual reality exposure and in vivo exposure groups also received 14 sessions of once-a-week individual cognitive-behavior therapy (CBT).

The outcome of treatment was evaluated using standard scales. A behavior avoidance test was also done by having patients do an impromptu speech before and after treatment that was video recorded and then systematically evaluated.  


Both the CBT with virtual reality exposure group and the CBT with in vivo exposure group showed greater improvement on all measures compared to the waiting list group.

The CBT with virtual reality exposure group did better than the CBT with in vivo exposure group on the primary outcome measure, the Liebowitz Social Anxiety Scale, but not on all measures.

Improvements in the active treatment groups were found to be maintained when the patients were followed up six months after end of the treatment.  


Using virtual reality exposure along with CBT can have the following advantages:

- Patients are less likely to avoid doing the exposure

- It can be less costly

- It is easier to implement

Clinical Commentary

While there has been excitement about using virtual reality in behavior therapy for various disorders, I have been skeptical about whether virtual reality environments meaningfully raise anxiety.

But, the environments of virtual reality and augmented reality are becoming more and more realistic. In this study, virtual reality exposure was at least as effective as in vivo exposure, if not better.

Please note that virtual reality exposure treatment for social anxiety disorder is not automated; it does not do away with the need for a therapist. This is because computers are not smart enough yet to know how to respond to what the patient says or does. What the virtual reality characters are saying to the patient is actually being triggered live by the therapist out of a set of potential things the virtual character could say. In fact, in this particular study, the therapist was in the same room as the patient. Thus, therapists were able to offer support and encouragement to both the virtual reality and in vivo exposure groups.  

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Why we must ask about childhood maltreatment

Nelson J, Klumparendt A, Doebler P, Ehring T. Childhood maltreatment and characteristics of adult depression: meta-analysis. Br J Psychiatry. 2017 Feb;210(2):96-104. PubMed PMID: 27908895.


Previous studies have found that being mistreated during childhood is a risk factor for clinical depression in adulthood.  


This study did a meta-analysis of all previous studies on this topic in order to describe how childhood maltreatment was related to the incidence, severity, age at onset, course, and treatment response of depression.

A total of 184 studies were included.


Of patients with clinical depression, 46% reported that they had suffered some form of childhood maltreatment.

This included sexual abuse in childhood (about 25% of patients with a depressive disorder), emotional neglect in childhood (about 46%), and more than one type of abuse (about 19%).

Persons who were maltreated in childhood:

Were 2.7 to 3.7 times more likely to develop clinical depression in adulthood, depending on the type of maltreatment

Had onset of depression earlier in life

Were twice as likely to develop chronic depression

Were twice as likely to have depression that did not respond to treatment

What type of maltreatment? Physical, sexual, and emotional maltreatment in childhood all increased the risk of depression in adulthood. However, among these three forms of maltreatment, emotional maltreatment most increased both the risk of depression during adulthood and the severity of depression. Physical maltreatment had the least effect of the three forms of maltreatment.

Having been maltreated in more than one way was even more closely associated with having clinical depression (odds ratio 3.7).  


Childhood maltreatment, especially emotional abuse and neglect, is a risk factor for clinical depression in adulthood.

Also, it is associated with depression that is more severe, has earlier onset, and is more likely to have poor response to treatment and to become chronic.

Clinical Commentary

What is the practical significance of this study? In general, our ability to predict who will or will not respond to our treatments is not great. So, any predictors of treatment response or features that guide choice of treatments are welcome.

In assessing any person with a depressive disorder, we should ask about maltreatment in childhood because a history of childhood maltreatment is associated with a decreased response not only to medications, but also to psychotherapy and to combination treatment.

Therefore, if a history of such maltreatment is present, this should tell us right at the initial assessment that this person probably needs more intensive treatment and use of a combination of modalities.  

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Why does he not look at me?

Moriuchi JM, Klin A, Jones W. Mechanisms of Diminished Attention to Eyes in Autism. Am J Psychiatry. 2017 Jan 1;174(1):26-35. PubMed PMID: 27855484.


A key clinical feature of autistic spectrum disorders is reduced attention to others' eyes.

But why do persons with autistic spectrum disorders have reduced eye contact? Two hypotheses have been put forward:

1. Gaze aversion: avoiding looking at others’ eyes in order to avoid overstimulating and negative hyperarousal. We can think of this as active avoidance of others’ eyes.

2. Gaze indifference: spending less time looking at others’ eyes because the eyes are not perceived as either engaging or informative. We can think of this as passive avoidance of others’ eyes.

These two hypotheses have different implications for the brain areas involved and for possible treatments.

For example, if the diminished eye contact in autism spectrum disorders is due to gaze aversion, treatment using an anxiolytic or behavioral exposure might work.

On the other hand if the decreased eye contact is due to gaze indifference, then we should explore non-pharmacological treatments that increase social engagement and the reinforcement value of social interaction.

The data supporting each of these hypotheses have been mixed. Also, previous research has focused on older children and on adults.

This study evaluated these hypotheses in 2-year-old children.  


A total of 86 two-year-old children were enrolled:

- 26 with autism

- 38 matched typically developing children, and

- 22 matched developmentally delayed children.

The children were shown video scenes of an actress looking directly into the camera. The actress was portraying the role of a caregiver and was speaking to the viewer in language appropriate to a toddler.

Eye-tracking was evaluated using a device that used reflections from the children’s eyes.

Two experiments were conducted. In the first, “direct cueing” by presentation of another stimulus was used to direct the attention of the toddler towards the lower face and then progressively towards the eyes of the person speaking. In the second, the toddlers’ eye gaze was evaluated without any additional stimulus other than the actress speaking to the toddler (“implicit cueing”).


Not surprisingly, looking at the eyes was reduced in children with autism spectrum disorder compared to both typically developing and developmentally delayed children.

However, the key finding was that this decreased looking at the eyes could be overridden by direct cueing to look at the eyes. When directly cued to look at the eyes, the children with autism did not look away faster than did typically developing children.

In fact, direct cueing had a stronger sustained effect on their amount of looking at the eyes than on that of the typically developing children. When cued to look at the eyes, they looked for longer at the eyes; when cued to look at the mouth, they looked for longer at the mouth.

When presented with implicit social cues to look at the eyes, 2-year-olds with autism did not either directly shift their gaze away or subtly look elsewhere.  


This study suggests that the gaze aversion hypothesis does not explain the diminished eye contact by children with autism spectrum disorders.

Rather, the study suggests that the diminished eye contact is due to passive insensitivity to the social signals in others' eyes.

Clinical Commentary

Eye contact is of the greatest importance in human social interaction. That is why it is important to address the diminished eye contact by children and adults with autistic spectrum disorder.

A better understanding, in each particular patient, of why he or she does not look people in the eye is essential for planning the treatment.

The authors noted that previous findings of atypical autonomic responses, atypical amygdala activation, and increased anxiety in response to looking at others’ eyes have been reported in older children and adults with autism spectrum disorders. Combined with the findings of this study, it is suggested that the atypical affective response to eye gaze seen in in older children and adults with autism spectrum disorder may be a consequence rather than the cause of atypical eye gazing behavior.

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If clozapine doesn’t work: What next?

Zheng W, Xiang YT, Yang XH, Xiang YQ, de Leon J. Clozapine Augmentation With Antiepileptic Drugs for Treatment-Resistant Schizophrenia: A Meta-Analysis of Randomized Controlled Trials. J Clin Psychiatry. 2017 Mar 28. [Epub ahead of print] PubMed PMID: 28355041.


Clozapine is an important treatment for persons with schizophrenia who have not responded to multiple trials of antipsychotic medication.

But, in one-third to two-thirds of cases, clozapine does not work or works only partially. What can be done in such cases?

There have been several randomized, controlled clinical trials that have evaluated the addition of various antiepileptic medications to clozapine in so-called “treatment-resistant schizophrenia”.  


A search of multiple databases was done to identify all relevant studies.

Twenty-two relevant randomized, controlled trials were identified.

Data were systematically extracted and evaluated, and a meta-analysis of the data was performed.


The 22 randomized, controlled clinical trials included a total of about 1200 patients.

Four antiepileptic medications were evaluated in these clinical trials as adjunctive treatments with clozapine: topiramate (5 studies), lamotrigine (8 studies), sodium valproate (6 studies), and magnesium valproate (3 studies).

Addition of sodium valproate reduced overall severity of symptoms (effect size 1.26), including positive symptoms and general psychopathology.

Addition of topiramate reduced overall severity of symptoms (effect size 0.89) including positive symptoms, negative symptoms, and general psychopathology.

However, addition of topiramate also led to significantly greater discontinuations of treatment (Number Needed to Harm was 7).

The efficacy of lamotrigine was marginal and not present in studies done outside China or when two outlier studies were removed from the analysis.

The efficacy of adding magnesium valproate was also not clear.


Addition of sodium valproate to clozapine was efficacious and safe.

While addition of topiramate to clozapine was efficacious, the discontinuation rate was high.  

Clinical Commentary

In my view, this meta-analysis is of great importance because in many persons, clozapine is not sufficiently effective for the treatment of schizophrenia and clinicians are left with the question of what to do next.

Among the antiepileptics, valproate seems to have the best evidence at this time and may be considered the first choice among the four antiepileptic medications evaluated in this meta-analysis.

However, a word of caution: we should not jump to augmentation strategies without first checking to make sure that the person is taking the clozapine and that the clozapine level is at least 350 ng/mL. Unfortunately, clozapine levels were not checked in many of the studies included in this meta-analysis and the possibility remains that valproate is effective due to increasing clozapine levels.  

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Rajnish Mago, MD
Medical Editor, GME Research Review

GME Research Review is a monthly newsletter edited by Rajnish Mago, MD, who is author of "The Latest Antidepressants" and "Side Effects of Psychiatric Medications: Prevention, Assessment, and Management." Dr. Mago selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry. 

We are always carefully evaluating which research papers to discuss in GME Research Review. Have come across a research paper published in the last 6 months that you thought is clinically relevant? Do you want me to analyze it for you and for the benefit of others? Please email Dr. Mago the citation at [email protected].

To contact GME, email us at [email protected]

GME does not provide medical advice. The website and articles are intended for informational purposes only. They are not a substitute for professional medical advice, diagnosis or treatment. Never ignore professional medical advice in seeking treatment because of something you have read on the GME Website. If you think you may have a medical emergency, immediately call your doctor or dial 911.

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