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Issue 49, May 2016
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What are the three types of suicide attempts?

Lopez-Castroman et al. Clustering suicide attempters: impulsive-ambivalent, well-planned, or frequent. J Clin Psychiatry. 2016 Mar 29. [Epub ahead of print] PubMed PMID: 27035768.

Suicidality is one of the most important problems that mental health professionals deal with. Suicide attempts are common and we are trained to assess the clinical significance of the events.

However, a better understanding of the different types of suicide attempts may help us as clinicians and may facilitate research into their management.


The most important thing for clinicians to remember is that nearly half of suicide attempts are preceded by a previous suicide attempt. Therefore, suicide prevention efforts focused on persons who have attempted suicide are of crucial importance. 

However, it has been very hard to predict suicidal behavior, even in persons who have attempted suicide.

One of the reasons for this is probably that, as every clinician knows, not all suicide attempts are the same. Previous research has focused on the severity of the suicide attempts and on the personality of the person attempting suicide. However, there has been little research using statistical methods to classify suicide attempts based on characteristics of the attempts.


1,009 hospitalized suicide attempters were included in the study.

Data on 11 clinically relevant items about the suicidal behavior were assessed.

These 11 items were statistically analyzed to identify subgroups (“clusters”) of suicidal behavior.


Three clusters were identified:

1. “Impulse-ambivalent” subgroup: This was the most common cluster. The means used were less lethal and there was less planning.

2. The “Frequent” subgroup: This cluster had the fewest number of persons. It included persons who reported a greater number of previous suicide attempts, who more often had serious or violent attempts, and who had an earlier age at the first suicide attempt. These persons were also less likely to have used alcohol or drugs prior to the suicide attempt. Many persons in the this cluster had experienced high levels of childhood abuse. The authors noted that, clinically, frequent attempters would be easily differentiated from the other clusters by the early onset, higher number of attempts, accompanying psychiatric morbidity, family history of suicidal behavior, and high levels of harm avoidance and childhood maltreatment. Thus, frequent attempters had many of the clinical characteristics of borderline personality disorder.

3. The “Well-planned” subgroup: Persons in this cluster had more carefully planned and prepared attempts, with more alcohol or drug use before the attempt, and more precautions to avoid interruptions or be rescued. High scores on severe emotional abuse in childhood were much more likely to be associated with the “Well-planned” group than with the “Impulsive-ambivalent” group.

The term harm avoidance refers to the tendency to inhibit behavior to avoid negative consequences. It has been associated with aggression against oneself and with the severity of suicide attempts.  The “Well-planned” suicide attempts were associated with one of the following two combinations:

a) High harm avoidance plus childhood emotional neglect

b) Low harm avoidance plus high hopelessness.


Cluster analysis showed three distinct clusters of persons who had attempted suicide. The specific clinical features of these persons and their suicidal behaviors may help us to plan suicide prevention strategies aimed at each subgroup.

Clinical Commentary

Every suicide attempt must be taken seriously. Categorizing suicide attempts into these three categories can help during clinical evaluation.  In addition to the characteristics of the suicide attempt itself, childhood emotional abuse or neglect, hopelessness, and harm avoidance should be evaluated.

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Which patients are more likely to benefit from adjunctive L-methylfolate?

Shelton et al. Association of obesity and inflammatory marker levels on treatment outcome: results from a double-blind, randomized study of adjunctive L-methylfolate calcium in patients with MDD who are inadequate responders to SSRIs. J Clin Psychiatry. 2015 Dec;76(12):1635-41. PubMed PMID: 26613389.

Some data have indicated that addition of L-methylfolate to antidepressants can reduce depression in a subset of persons who have not adequately responded to an antidepressant alone.

However, it is not clear which persons are most likely to benefit from addition of L-methylfolate and clinicians are left without any guidance about whom to prescribe L-methylfolate to.


This is a post hoc exploratory analysis of previously published randomized, controlled data of L-methylfolate for patients with major depressive disorder who had not adequately responded to an antidepressant alone (Papakostas et al., 2012).

In addition to body mass index, a variety of biochemical measures were evaluated as potential predictors of response to the addition of L-methylfolate. These included cytokines (various interleukins and tumor necrosis factor α), high-sensitivity C-reactive protein (hsCRP), insulin, adiponectin, and leptin.

For those who may wonder what the term “L-methylfolate calcium” in the title of the paper means, it simply refers to the proprietary form of L-methylfolate available in the US under the brand name Deplin®.


Adults with major depressive disorder who had had an inadequate response to a selective serotonin reuptake inhibitor (SSRI) were enrolled in the original trial and randomly given either L-methylfolate or placebo.

In the present analyses, outcomes were compared between patients who had values at baseline that were either above or below the median on each of the potential biomarkers evaluated.


Overall, persons who received L-methylfolate along with the antidepressant showed statistically significantly greater improvement than those who received antidepressant plus placebo.

When persons with a body mass index of 30 or more (i.e., those who were obese) were compared to those with a body mass index less than 30, addition of L-methylfolate was more efficacious than placebo only in those with a body mass index of 30 or more.

Greater improvements in depression with addition of L-methylfolate were found in those with higher values (i.e., above the median) of some biomarkers compared to those with lower values (i.e., below the median) even when controlling for obesity. These biomarkers were tumor necrosis factor α, interleukin 8, high sensitivity C-reactive protein, and leptin.

The presence together of both obesity and higher levels of these biomarkers predicted an even greater difference between L-methylfolate and placebo than either of them alone.


Presence of obesity and certain inflammatory markers, alone and in combination, were associated with greater improvement in depression with addition of L-methylfolate to an antidepressant in persons who had had an inadequate response to the antidepressant alone.

Clinical Commentary

In recent years, data have increasingly emerged indicating an association of clinical depression with obesity and with inflammatory markers. Obesity is associated with release of inflammatory cytokines from adipose tissue.

It is important to note that it is specifically intra-abdominal obesity that seems to be associated with increased risk of developing major depressive disorder, poorer response to antidepressant treatment, and, in this study, greater response to addition of L-methylfolate.

While it is not appropriate to measure these inflammatory markers in clinical practice, taking note of abdominal obesity is a simple measure that we should probably adopt as one factor in deciding whether or not to prescribe L-methylfolate.

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How to prevent postpartum relapse in bipolar disorder or postpartum psychosis

Wesseloo et al. Risk of Postpartum Relapse in Bipolar Disorder and Postpartum Psychosis: A Systematic Review and Meta-Analysis. Am J Psychiatry. 2016 Feb 1;173(2):117-27. PubMed PMID: 26514657.


An important clinical question is how to prevent postpartum relapse in women with a history of bipolar disorder or of postpartum psychosis, but without unduly exposing the pregnancy to medication.

This study provides helpful data to guide clinical practice.


Women with a history of bipolar disorder or of postpartum psychosis are at risk for relapse during the postpartum period. The exact degree of risk, with and without prophylactic medication, is uncertain.

This meta-analysis aimed to determine the risk of relapse during the postpartum period in these women.


A systematic and thorough search of the literature was done to identify relevant studies.

Data were combined using meta-analysis.


Thirty-seven articles that included a total of 4,023 patients were included.

Overall, the risk of relapse during the postpartum period was 35%.

Women with a history of bipolar disorder had a 37% risk of relapse. There was no difference in the risk of postpartum relapse in women with bipolar I or bipolar II disorder.

The risk of postpartum relapse was similar (31%) in women with a history of postpartum psychosis. However, women with a history of postpartum psychosis were more likely to develop severe episodes during the postpartum period than women with a history of bipolar disorder (29% vs. 17%).

In women with a history of bipolar disorder, postpartum relapse rates were significantly higher among those who did not take medication for bipolar disorder during pregnancy (66%) than in those who took medication (23%).  When these women used prophylactic medication during the postpartum period, relapse rates were lower (29%) than if they remained medication free (65%).

Two small studies suggested that starting lithium immediately after delivery was efficacious in preventing relapse in women with a history of postpartum psychosis.


The authors suggested that in women with bipolar disorder continuation of prophylactic medication during pregnancy should be considered since it seems to have a strong effect in reducing risk of relapse during the postpartum period.

On the other hand, in women who had a history of postpartum psychosis without other history of psychiatric illness, they suggest that it may be reasonable to start prophylactic medication immediately after delivery. This would minimize the risk of postpartum relapse while avoiding exposing the fetus to medication.

Clinical Commentary

The option of starting medication immediately after giving birth seems to be an attractive one, combining the benefit of prophylaxis with the avoidance of medication during the pregnancy.

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Meta-analyses no. 1: Flibanserin for Hypoactive Sexual Desire Disorder

Gao et al. Efficacy and Safety of Flibanserin in Women with Hypoactive Sexual Desire Disorder: A Systematic Review and Meta-Analysis. J Sex Med. 2015 Nov;12(11):2095-104. PubMed PMID: 26745616.

About 10% of pre-menopausal women are estimated to suffer from hypoactive sexual desire disorder.

Flibanserin (brand name Addyi) was approved by the FDA in 2015 as the first medication approved for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women.

Prior to and after approval of the drug, there have been concerns that the combination of limited benefit and potential adverse effects suggests a poor risk-benefit ratio.

These meta-analyses combine multiple studies on flibanserin to assess the benefit and potential harms due to flibanserin.

However, it is interesting to see how the two meta-analyses, published within months of each other, come to very different conclusions. I think that seeing this will help the clinician reader to appreciate that the conclusions of meta-analyses depend on the methodologies used and on the point of view of the authors.


Flibanserin is a postsynaptic agonist of serotonin receptor 1A and an antagonist of serotonin receptor 2A.

It has been shown to increase sexual desire and reduce distress in women with hypoactive sexual desire disorder (HSDD).

This study conducted a systematic review and meta-analysis of the efficacy, tolerability, and safety of flibanserin for the treatment of hypoactive sexual desire disorder (HSDD).


Medline, Embase, and the Cochrane Controlled Trials Register were searched to identify all published randomized, double-blind, placebo-controlled clinical trials of flibanserin for the treatment of HSDD.


Four randomized, placebo-controlled clinical trials were included. A total of 3,414 patients participated in these trials.

On the primary outcome measures, patients on flibanserin showed a statistically significantly greater improvement than those on placebo as follows:

1. “Satisfying sexual events”: standardized mean difference 0.59, which indicates a moderately large effect.

2. Sexual desire score: standardized mean difference 1.91, which indicates a large effect.

3. Female Sexual Function Index (FSFI) desire domain score: standardized mean difference 0.32, indicating a small effect.

Flibanserin was also more efficacious than placebo on the following key secondary efficacy endpoints: Female Sexual Function Index (FSFI) total score, Female Sexual Distress Scale-Revised (FSDS-R) total score, FSDS-R Item 13 score, Patient's Global Impression of Improvement score, and Patient Benefit Evaluation.

The authors state that the safety assessments “indicated that flibanserin was well tolerated.” However, adverse events were looked at only in the aggregate: proportion of women experiencing an adverse event (odds ratio 1.5), a nervous system event (odds ratio 2.6), or fatigue (odds ratio 1.7). So, stating that flibanserin was “well tolerated” does not appear to be supported by the data provided.


The authors stated that, “This meta-analysis indicates that flibanserin [is] an effective and safe treatment for HSDD in women.”

Clinical Commentary

It should be noted that the authors of this meta-analysis are in China and that they reported that they had no conflicts of interest to disclose.

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Meta-analyses no. 2: Flibanserin for Hypoactive Sexual Desire Disorder

Jaspers et al. Efficacy and Safety of Flibanserin for the Treatment of Hypoactive Sexual Desire Disorder in Women: A Systematic Review and Meta-Analysis. JAMA Intern Med. 2016 Feb 29. [Epub ahead of print] PubMed PMID: 26927498.


This study conducted a systematic review and meta-analysis of all randomized, controlled clinical trials of flibanserin for the treatment of hypoactive sexual desire disorder (HSDD) in women.


Three trial registries and 13 electronic databases (including Medline, Embase, and Psycinfo) were searched to identify relevant clinical trials. . The search strategy for each database was designed by an experienced medical information specialist.

Randomized, controlled clinical trials of flibanserin in premenopausal and postmenopausal women were included.


Five published and three unpublished studies were included.

A total of 5914 women were included in these clinical trials.

There was a statistically significantly greater improvement from baseline to end of treatment with flibanserin (100 mg/day) compared to placebo for:

1. Number of “satisfying sexual events” (mean increase 0.49 events)

2. eDiary desire item

3. Female Sexual Function Index (FSFI) desire item

When the women themselves rated their overall improvement, the ratings indicated minimal improvement to no change.

Women on flibanserin were 2.2 times more likely to discontinue due to adverse events.

Four adverse events were particularly looked at and the risk ratios for flibanserin vs. placebo were:

1. Dizziness -- 4.0 

2. Somnolence – 4.0

3. Nausea – 2.6

4. Fatigue – 1.6

Severe adverse events that occurred occasionally included syncope or hypotension.


Flibanserin treatment resulted in an average of one-half additional satisfying sexual event per month, though this does not rule out significantly greater benefit in some women.

There was a clinically significant increase in the risk dizziness, somnolence, nausea, and fatigue.

The authors suggested that before flibanserin can be recommended for clinical practice, studies on women from diverse populations should be conducted. In particular, they suggested studies in women with comorbid illnesses, use of other medications, or surgical menopause.

Clinical Commentary

One thing these two meta-analyses show is that we must be wary of meta-analyses looking at some of the studies and not others. We saw how inclusion of unpublished studies can significantly alter the conclusions one would draw from the literature. It is absolutely essential in any meta-analysis that the authors look for and include all studies on the topic, including unpublished studies.

Secondly, we should be cautious about general statements that a medication was “well-tolerated” that are commonly made. Rather, specific information about adverse events should be looked at, just as we look at specific information about efficacy.

Regarding flibanserin, further research is needed to identify subgroups of women with hypoactive sexual desire disorder (subsumed under Female Sexual Interest/Arousal Disorder in DSM-5) that are more likely to benefit from treatment with flibanserin.

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Rajnish Mago, MD
Professor of Psychiatry, Thomas Jefferson University

GME Research Review is a monthly newsletter edited by Rajnish Mago, MD, who is Professor of Psychiatry at Thomas Jefferson University and 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 you come across a research paper published in the last 6 months that you think is clinically relevant? If you would like to ask Dr. Mago to consider analyzing it, please email him 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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