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Issue 73, May 2018
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Does lamotrigine work for borderline personality disorder?

Crawford et al; LABILE study team. The Clinical Effectiveness and Cost-Effectiveness of Lamotrigine in Borderline Personality Disorder: A Randomized Placebo-Controlled Trial. Am J Psychiatry. 2018 Apr 6:appiajp201817091006. [Epub ahead of print] PubMed PMID: 29621901.

Background

“Mood stabilizers” are often used off-label by clinicians for conditions other than bipolar disorder that are also characterized by mood instability.

For example, lamotrigine is often prescribed off-label to persons with borderline personality disorder.

This study evaluated whether lamotrigine is a clinically effective and cost-effective treatment for persons with borderline personality disorder.

Methods

This was a multicenter, randomized, double-blind, placebo-controlled clinical trial.

A total of 276 adults with borderline personality disorder were enrolled in the study. These participants were in contact with mental health services in the United Kingdom, i.e., came from clinical populations and not the community at large.

The diagnosis was established using the Structured Clinical Interview for DSM-IV Axis II Personality Disorders.

Persons with bipolar disorder or psychosis and those already taking any mood stabilizer were excluded from participating.

Participants were randomized to receive either lamotrigine or placebo for up to one year.

Lamotrigine was titrated up to 200 mg/day over 6 weeks based on tolerability and response. Women who were on oral contraceptives were titrated up to 400 mg/day of lamotrigine.

The primary outcome measure was the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) score after one year of treatment.

Results

About 71% of the participants could be followed up at the one-year mark.

Only 36% of the participants randomized to receive lamotrigine and 42% of those randomized to receive placebo were still taking it after one year. Only 34% of the participants took the study medication as per protocol throughout the study.

After three months of treatment, the mean ZAN-BPD score decreased equally in those who received lamotrigine or placebo.

After the first three months, the ZAN-BPD did not change much during the rest of the one-year period.

The mean ZAN-BPD score after one year of follow up was not different between the two groups.

In addition, secondary outcome measures like depressive symptoms, deliberate self-harm, social functioning, costs of direct care, etc., were also not different between the two groups.

Conclusions

Treatment of borderline personality disorder with lamotrigine is not clinically effective.

Clinical Commentary

Two previous smaller studies with short follow up had suggested that lamotrigine may be efficacious for borderline personality disorder. But, this study was much larger and followed patients for up to one year. Given the chronic nature of borderline personality disorder, longer-term outcomes are important.

We should note that even in the shorter-term (first three months) and when adherence to the study medications was much higher, lamotrigine was not more efficacious than placebo.

The findings of this study suggest that lamotrigine should not be used for the treatment of borderline personality disorder. The lesson for clinicians is that we should not choose treatments based on superficial similarities in disorders, for example, between bipolar disorder and borderline personality disorder.

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Do weight loss medications also improve cardiometabolic risk?

Khera et al. Effects of Weight-Loss Medications on Cardiometabolic Risk Profiles: A Systematic Review and Network Meta-analysis. Gastroenterology. 2018 Jan 3. [Epub ahead of print] PubMed PMID: 29305933.

Background

A few medications are specifically FDA-approved for weight loss.

This systematic review and network meta-analysis aimed to evaluate the extent to which these medications improve cardiometabolic risk factors in adults with obesity. It also aimed to compare these medications to each other in this regard.

Methods

A systematic literature search was done to identify relevant randomized controlled clinical trials that compared the weight loss medications to either placebo or another active drug.

These trials evaluated the use of (alphabetically) orlistat, lorcaserin, naltrexone-bupropion, phentermine-topiramate, and liraglutide when given to adults with obesity.

Only trials lasting for one year were included, which makes sense since the aim was to look at changes in cardiometabolic risk factors.

The cardiometabolic factors evaluated in these studies included changes in:

- Blood glucose (fasting blood glucose and hemoglobin A1c)

- Lipid profile (low-density lipoprotein and high-density lipoproteins)

- Blood pressure (systolic and diastolic), and

- Waist circumference.

Results

A total of 28 randomized controlled trials with about 29,000 participants were included in the analysis.

The median body mass index (BMI) was about 36 kg/m2. Note: A person with a BMI of 30 and above is considered to be obese.

The weight loss medications were associated with:

- A modest but statistically significant decrease in fasting blood glucose (weighted mean difference, 4 mg/dL), and

- A statistically significant decrease in waist circumference (weighted mean difference 3.3 cm).

But, the medications were not associated with clinically meaningful changes in systolic/diastolic BP or lipid profile.

The changes in cardiometabolic factors varied from one of the medications to another.

Phentermine-topiramate use was associated with:

  • A substantial decrease in waist circumference
  • A modest decrease in fasting blood sugar, hemoglobin A1c, and blood pressure
  • Minimal effect on lipid profile.

Liraglutide use was associated with:

  • A substantial decrease in fasting blood sugar, hemoglobin A1c, and waist circumference, but,
  • Minimal effect on blood pressure and lipid profile.

Naltrexone-bupropion use was associated with:

  • A moderate increase in high-density lipoprotein cholesterol, but,
  • Minimal effect on fasting blood sugar and waist circumference

Orlistat use was, not surprisingly, associated with:

  • A decrease in low-density lipoprotein, but also with
  • A decrease in high-density lipoprotein cholesterol, which is undesirable.

It is important to note that none of these medications improved all the cardiometabolic risk factors evaluated.

Conclusions

The FDA-approved weight-loss medications had only modest positive effects on cardiometabolic risk factors.

Clinical Commentary

The FDA-approved weight loss medications can lead to a 10% or greater decrease in body weight after one year of treatment in about 25 to 50% of patients.

To some extent, they also improve cardiometabolic risk factors, but this study shows that these improvements are modest for most patients.

In my opinion, on the one hand, persons with obesity may clearly benefit from these medications. On the other hand, medications alone will probably not be enough. They will need additional measures in order to produce more substantial weight loss and greater improvement in cardiometabolic risk factors. The weight loss medications should be considered to be only one part of the treatment plan.

The differential effects of the medications on various cardiometabolic risk factors suggest to me that the medication may be matched to the individual patients cardiometabolic profile.

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Sluggish Cognitive Tempo may predict medication response in children with ADHD

Froehlich et al. Sluggish Cognitive Tempo as a Possible Predictor of Methylphenidate Response in Children With ADHD: A Randomized Controlled Trial. J Clin Psychiatry. 2018 Feb 27;79(2). pii: 17m11553. PubMed PMID: 29489078.

Background

Many patients with attention deficit/hyperactivity disorder (ADHD) may also have sluggish cognitive tempo (SCT). This includes symptoms like excessive daydreaming, seeming like being in a fog, mental confusion, and underactivity (slowness, lethargy, drowsiness, etc.).

High sluggish cognitive tempo scores are estimated to occur in about half of children with ADHD.

This study aimed to assess whether sluggish cognitive tempo affects response to methylphenidate in children with ADHD and whether this effect is separate from the effect of ADHD subtypes on response to methylphenidate.

Methods

Children with ADHD, aged 7 to 11 years, who had never taken a stimulant medication, were included in this study.

Of the participants, 126 had ADHD predominantly inattentive type and 45 had ADHD combined type.

The evaluation of ADHD included structured interviews and the Vanderbilt ADHD Diagnostic Rating Scales. Both parent and teacher ratings were incorporated into the evaluations.

A randomized, double-blind, clinical trial of long-acting methylphenidate versus placebo was conducted.

The methylphenidate was given in escalating dose, i.e., each participant received a low, medium, or high dose.

A four-week crossover design was used. That is, the same patients received one intervention and then “crossed over” to receive the other intervention.

Sluggish Cognitive Tempo was assessed using a teacher-rated scale and its symptoms were divided into two groups (factors): Sluggish/Sleepy and Daydreamy.

Results

Participants with increased Sluggish/Sleepy factor scores were statistically significantly less likely to be responders to methylphenidate (odds ratio 0.67).

They were more likely to be either nonresponders to methylphenidate or responders to placebo.

Sluggish/Sleepy factor scores were also associated with a lack of a dose-response relationship based on parent and teacher ratings of inattention. That is, in participants with higher Sluggish/Sleepy factor scores, higher doses of methylphenidate were less likely to be associated with greater improvement in attention.

On the other hand, Daydreamy symptoms and the ADHD subtype (predominantly inattentive versus combined) were not associated with either response to methylphenidate or dose-response for inattentive symptoms.

Conclusions

Sluggish/Sleepy symptoms of sluggish cognitive tempo were associated with methylphenidate nonresponse. However, neither Daydreamy symptoms nor the ADHD subtype were associated with methylphenidate response.

Clinical Commentary

This study puts forth a new and interesting finding that pushes forward the research on sluggish cognitive tempo in children with ADHD.

But, it should be noted that even though the finding was statistically significant, there was a only a 30% reduction in response to methylphenidate. So, these findings should not be misinterpreted to mean that children with Sluggish/Sleepy symptoms should not be treated with methylphenidate (or other medications) for ADHD.

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Can aripiprazole worsen psychosis in schizophrenia?

Takeuchi et al. Can Aripiprazole Worsen Psychosis in Schizophrenia? A Meta-Analysis of Double-Blind, Randomized, Controlled Trials. J Clin Psychiatry. 2018 Mar 6;79(2). pii: 17r11489. [Epub ahead of print] PubMed PMID: 29570965.

Background

Several case reports have been published about worsening of psychotic symptoms in persons with schizophrenia whose antipsychotic was changed (switched) to aripiprazole or in whom aripiprazole was added to another antipsychotic.

This study is a meta-analysis combining previous data to more systematically evaluate this issue.

Methods

A systematic search of the literature was done to identify all double-blind, randomized, controlled clinical trials of switching to aripiprazole or adding aripiprazole in persons with schizophrenia spectrum disorders.  

From these clinical trials, the authors extracted:

  • The number of patients who experienced psychotic worsening, agitation, or anxiety
  • The number of patients who discontinued participation in the study due to “all causes,” lack of efficacy, or adverse events.
Results

A total of 22 studies with about 5800 participants were included in the meta-analysis.

Thirteen of these studies involved switching to aripiprazole and nine of them involved adding aripiprazole to another antipsychotic.

Psychotic worsening was reported as an adverse event in some patients in all of these studies. Note: an adverse event is simply an undesirable thing that happened during the study. It does not necessarily mean that the event was related to the medication.

There was no statistically significant difference in the risk of psychotic worsening, agitation, or anxiety between patients who were switched to aripiprazole or to another antipsychotic.

However, patients who were switched to aripiprazole were statistically significantly more likely to discontinue participation in the study due to lack of efficacy (relative risk 1.5).

Less data were available regarding adding aripiprazole to the previous antipsychotic. While no statistically significant increased risk was found in the available data, the authors concluded that the data were insufficient to provide definitive answers.

Conclusions

There was no evidence from randomized, controlled clinical trials that a switch to aripiprazole is associated with a risk of psychotic worsening in patients with schizophrenia spectrum disorders.

A switch to aripiprazole was associated with a higher risk of study discontinuation due to lack of efficacy.

Clinical Commentary

At least 24 case reports have been published of worsening of psychotic symptoms associated with either a switch to aripiprazole or addition of aripiprazole.

A hypothesis is that in persons who have received a D2 blocking agent for a while, the number of dopamine receptors may get upregulated. Then, when the person is switched to a D2 receptor partial agonist like aripiprazole, this may lead to worsening of psychosis.

This meta-analysis provides some reassurance that if there is, in fact, some risk of worsening of psychotic symptoms after a switch to aripiprazole, then at least the risk is small enough to not be detectable even in multiple studies in which patients were switched to aripiprazole.

On the other hand, the potential risks of adding aripiprazole to another antipsychotic will need further study.

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Do benzodiazepines work for tardive dyskinesia?

Bergman et al. Benzodiazepines for antipsychotic-induced tardive dyskinesia. Cochrane Database Syst Rev. 2018 Jan 20;1:CD000205. Review. PubMed PMID: 29352477.

Background

Tardive dyskinesia continues to be a problem even with the development of many second-generation antipsychotic medications.

One class of medications that has been used to treat tardive dyskinesia is benzodiazepines.

This systematic review by the Cochrane Collaboration is an update of a previously published review.

It aimed to evaluate whether benzodiazepines are efficacious for the treatment of tardive dyskinesia in persons with schizophrenia, schizoaffective disorder, or other chronic mental disorders.

Methods

A systematic search of the literature was done to identify all relevant randomized controlled clinical trials.

Data were systematically extracted from these studies and then analyzed.

Results

Four randomized controlled trials, in which a total of 75 persons participated, were identified. Yes—clinical trials in tardive dyskinesia were small studies until the recent commercial interest funded large studies.

Clinically important improvement was defined as more than 50% improvement on any of the tardive dyskinesia scales.  Theoretically, participants could have worsening, no improvement, improvement but not “clinically important”, or “clinically important improvement”. The primary outcome measure in this study was a combination of the first three of these categories into “no clinically significant improvement.” A bit strange, I know, but the authors noted that this approach best suited the available data. We’ll have to take their word for it.

There was no statistically significant difference between participants who received a benzodiazepine or a placebo in terms of having “no clinically significant improvement” in their tardive dyskinesia.

Similarly, there was no statistically significant difference in terms of worsening of tardive dyskinesia symptoms.

One study with 21 participants (Bobruff et al., 1981) that was included in this systematic review compared clonazepam to phenobarbital (active control group). In this study, clonazepam was statistically significantly more efficacious than phenobarbital for the treatment of tardive dyskinesia. That is, participants treated with clonazepam were statistically significantly less likely to have had “no clinically important improvement.” The relative risk was 0.4.  Remember that a relative risk of 1 means equal risk in both groups and a relative risk of less than 1 means that the risk was less than in the comparison group.

Conclusions

There is very limited research evidence about the use of benzodiazepines to treat antipsychotic-induced tardive dyskinesia.

The authors gave their opinion that:

- Benzodiazepines should not be used routinely to treat tardive dyskinesia.

- Due to the addiction potential of benzodiazepines, other treatments should be tried first.

Clinical Commentary

It is unfortunate that research on adverse effects has been tremendously neglected even though adverse effects are very important to patients and their families, affect quality of life, and are major contributors to the widespread problem of non-adherence to medications.

Clinically, benzodiazepines may appear to help in some cases when the patient is anxious because anxiety tends to worsen symptoms of tardive dyskinesia.

In the April issue of GME Research Review, we noted that anticholinergic medications are not efficacious for tardive dyskinesia. The systematic review discussed here shows that benzodiazepines are not proven treatments for tardive dyskinesia either, though one study did find clonazepam to be more efficacious than the control drug (phenobarbital).

Two new medications—valbenazine and deutetrabenazine—have been approved by the FDA in 2017 for the treatment of tardive dyskinesia. But, they are expensive and the great majority of patients around the world will not be able to access them. So, a systematic evaluation of other treatment options is important.

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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]


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