Issue 66, Oct 2017
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Can ketamine rapidly decrease suicidal ideation?

Bartoli F, Riboldi I, Crocamo C, Di Brita C, Clerici M, Carrà G. Ketamine as a rapid-acting agent for suicidal ideation: A meta-analysis. Neurosci Biobehav Rev. 2017 Jun;77:232-236. Review. PubMed PMID: 28342764.

Background

Ketamine infusions have received a lot of attention as an exciting potential treatment for major depressive disorder that has not responded to other interventions.

Another major area of interest currently is the possible use of ketamine to acutely reduce suicidal ideation.

This meta-analysis evaluated the use of intravenous ketamine for the treatment of persons with current suicidal ideation.

Methods

A literature search was done to identify clinical trials that evaluated:

  • A single intravenous dose of ketamine (either as an infusion or as a bolus), and
  • Assessed changes in suicidal ideation within four hours of giving the ketamine

Patients were adults and were recruited from inpatient, outpatient, or emergency department settings.

Importantly, uncontrolled clinical trials were included. A placebo or active comparator was not present in any of the studies included.

A meta-analysis was then done to combine the results of the studies.

Results

Five clinical trials were included in the meta-analysis. They included a total of 99 participants.

Of these, 63 patients were treated with an IV bolus of ketamine 0.2 mg/Kg and 33 were treated with an IV infusion of ketamine 0.5 mg/Kg.

The decrease is suicidal ideation after giving the intravenous ketamine was large and statistically significant. The effect size, measured as the standardized mean difference, was 0.92.  So, intravenous ketamine was very effective in reducing suicidal ideation.

No statistically significant difference was identified in the effect of ketamine given as an infusion or as a bolus. That is, infusion and bolus seemed to work equally well.

Conclusions

Intravenous ketamine seems promising as a potential treatment for acute suicidal ideation.

However, for various reasons, the quality of the currently available research evidence was considered to be “very low” by the authors. Most importantly, none of the studies had a control group. 

Clinical Commentary

Intravenous ketamine may find a place in the management of persons with suicidal ideation.  But, randomized, controlled trials with larger numbers of participants are needed before firm conclusions can be drawn.

We may speculate whether ketamine’s ability to reduce suicidal ideation rapidly may allow some patients to avoid the need for hospitalization. But many questions remain.

1. A key question in this regard is whether the patients’ suicidal ideation could return in the next few days. If so, this may pose significant risks to the patient.

2. The risks of potential neurotoxicity or abuse with longer-term, repeated administration of ketamine will need to studied before its use can be recommended for clinical practice.

3. As the authors pointed out, suicidal ideation is a complex phenomenon involving both psychological and biological factors. So, ketamine may not be effective or appropriate for all persons with suicidal ideation.

Despite these limitations, this research raises the hope that in the future, similar rapid-acting anti-suicidal medications may be developed.

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Should melatonin be given to persons with Alzheimer’s disease?

Wang YY, Zheng W, Ng CH, Ungvari GS, Wei W, Xiang YT. Meta-analysis of randomized, double-blind, placebo-controlled trials of melatonin in Alzheimer's disease. Int J Geriatr Psychiatry. 2017 Jan;32(1):50-57. Review. PubMed PMID: 27645169.

Background

Sleep disturbance is an important symptom in persons with Alzheimer’s disease. It is troubling to both the patient and the caregivers.

One possible reason for the sleep disturbance may be that Alzheimer’s disease is associated with a lowering of plasma melatonin, which, in turn, may be due to disturbances in monoamine function.

Melatonin has been proposed as an intervention for the treatment of sleep disturbance in these patients.

This paper aimed to combine the results of previous studies on this topic.

Methods

A thorough search of the published literature was done to identify all published randomized controlled trials that evaluated the efficacy of melatonin for sleep disturbance in persons with Alzheimer's disease.

Total sleep time in these studies was assessed using actigraphy, not only by subjective report.

A meta-analysis of was done to combine the results of these studies.

Results

Seven clinical trials, conducted in many different countries, were identified. They included a total of 462 participants.

The duration of these clinical trials was very variable--from 10 days to 24 weeks.

Similarly, the dose of melatonin also varied--from 2 mg to 10 mg per day.

The primary outcome measure was sleep efficacy. The meta-analysis found that persons with Alzheimer’s disease who received melatonin did not have greater sleep efficacy than those who received placebo.

However, persons with Alzheimer’s disease who received melatonin had greater improvement in total sleep time at night compared to those who received placebo. But the effect size was small—a standardized mean difference of 0.26.

The sleep time during the day was not greater in those who received melatonin.

Melatonin did not improve cognitive functioning in these patients.

Conclusions

The authors concluded that melatonin appears to be effective and safe in improving the duration of sleep at night in persons with Alzheimer’s disease.

Clinical Commentary

While the benefit of melatonin was not large, it may be tried first rather than standard hypnotic medications because those medications can be associated with more significant adverse effects.

More data are needed about whether or not the benefit of melatonin in restoring nighttime sleep may potentially be enhanced by combining it with light therapy in the morning.

Whether or not the use of melatonin improves cognitive function remains unclear because most of the studies included in this meta-analysis were of relatively short duration. Evaluation of any potential benefit for cognitive functioning would require longer studies.

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Amantadine for antipsychotic-associated weight gain?

Zheng W, Wang S, Ungvari GS, Ng CH, Yang XH, Gu YH, Li M, Xiang YQ, Xiang YT. Amantadine for Antipsychotic-Related Weight Gain: Meta-Analysis of Randomized Placebo-Controlled Trials. J Clin Psychopharmacol. 2017 Jun;37(3):341-346. PubMed PMID: 28383359.

Background

Weight gain is one of the biggest problems associated with the use of antipsychotic medications.

Amantadine, which may increase the release of dopamine and norepinephrine, is used in the treatment of Parkinson’s disease. In the past, it was also used as an antiviral medication.

This paper aimed to combine the results of clinical trials of the use of amantadine for the treatment of weight gain associated with use of antipsychotic medications in persons with schizophrenia.

Methods

A literature search was done to identify randomized, double-blind, placebo-controlled clinical trials that evaluated the use of amantadine to treat weight gain in adults who had schizophrenia.

The results of these clinical trials were then combined using a meta-analytic approach.  

Results

Five relevant clinical trials were identified that included a total of 265 participants.

The average duration of the clinical trials was about 8 weeks.

How much amantadine? The dose ranged from 100 to 400 mg/day; the median dose was 236 mg/day.

Amantadine was more effective than placebo in reducing weight in these patients.

The effect size was moderate. The weighted mean difference (no pun intended) for the difference in weight reduction in persons receiving amantadine or placebo was about 5 lbs. Please note that this does not mean that amantadine leads to a 5 lbs weight loss. That is the average, so many patients lost much more or much less than that.

What about tolerability?

1. Rates of discontinuation of treatment were similar between amantadine and placebo.

2. Amantadine was significantly more likely to cause insomnia than placebo.

3. Other adverse events were similar between amantadine and placebo.

4. There was no worsening of either positive or negative symptoms.

Conclusions

Addition of amantadine appears to be effective for reducing antipsychotic-associated weight gain.

Clinical Commentary

Dealing with weight gain/metabolic syndrome is one of the most important issues related to use of second-generation antipsychotics. That is why this paper is important. It supports the use of amantadine as an option for the management of such weight gain.

I was concerned that amantadine, being pro-dopaminergic, may worsen psychotic symptoms, but this was not found to the case in these studies. However, at this time, I would be reluctant to use it in persons who had active positive symptoms.

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Is lavender oil a potential treatment for anxiety?

Generoso MB, Soares A, Taiar IT, Cordeiro Q, Shiozawa P. Lavender Oil Preparation (Silexan) for Treating Anxiety: An Updated Meta-Analysis. J Clin Psychopharmacol. 2017 Feb;37(1):115-117. PubMed PMID: 27861196.

Background

Lavender has been used for centuries as a medicinal plant and is believed to have calming and anxiolytic properties.

Lavender oil is derived from the flowers of this plant and contains more than 160 different chemical entities.

This paper aimed to combine the data from clinical trials that evaluated the efficacy of lavender oil for the treatment of “anxiety”.

Methods

A literature search was done to identify published clinical trials on the topic and the results were combined using meta-analytic techniques.

Five clinical trials were included in the meta-analysis. They had a total of 1165 participants.

Participants in these trials had generalized anxiety disorder (two studies), subsyndromal anxiety (one study), mixed anxiety and depressive disorder (one study), or anxiety-related restlessness (one study).

All five trials used a proprietary preparation of lavender oil developed in Germany (brand name Silexan®).  However, the authors of this meta-analysis are from Brazil and had no conflict of interest related to the product. The dose used was either 80 mg or 160 mg taken orally.

Four trials compared lavender oil to placebo while one compared it to lorazepam. Unfortunately, blinded assessment of outcome was not done and the inclusion criteria varied between the studies.

Lavender oil was statistically significantly more effective than placebo in reducing anxiety. The effect size was moderate to large (Hedge’s g 0.67). The benefit was greatest in participants who suffered from generalized anxiety disorder.

Conclusions

This preparation of lavender oil was associated with reduction in anxiety, especially in persons with generalized anxiety disorder.

Clinical Commentary

Given that our patients quite commonly use, or express interest in, complementary and alternative medications, mental health clinicians should have at least some familiarity with the literature on this topic. This paper was included for that reason and not to support or encourage the use of lavender oil as a treatment.

The methodology of the studies included was quite problematic. I hope that randomized, double-blind, placebo-controlled clinical trials in more narrowly defined subjects are conducted to further evaluate the potential use of lavender oil as a treatment for anxiety disorders.

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Should we order iron studies in persons with ADHD?

Wang Y, Huang L, Zhang L, Qu Y, Mu D. Iron Status in Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analysis. PLoS One. 2017 Jan 3;12(1):e0169145. Review. PubMed PMID: 28046016; PubMed Central PMCID: PMC5207676.

Background

We have a limited understanding of the pathophysiology of attention-deficit/hyperactivity disorder (ADHD).

Why iron? Iron is an important trace element and is involved in the regulation of dopaminergic activity, which is, of course, important in ADHD. Iron is an important cofactor for the tyrosine hydroxylase enzyme and so is important in the rate-limiting step in the production of dopamine.

Decreased iron concentration in the brain has been shown to be associated with changes in the conductivity of cortical fibers, in the serotonergic and dopaminergic systems, and in the formation of myelin.

Previous studies on the potential association between iron deficiency and ADHD have shown inconsistent results and no meta-analysis of these studies has previously been published.

This paper aimed to combine data from all published studies on this topic.

Methods

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

The results were combined using meta-analytic techniques.

Results

Eleven studies of children with ADHD were included. All of them used a case-control design and compared children with ADHD to controls.

Of these, ten studies (with 2191 participants of whom 1196 had ADHD) evaluated serum ferritin levels.

Six studies (with 617 participants of whom 369 had ADHD) evaluated serum iron levels.

The meta-analysis found that serum ferritin levels were statistically significantly lower in persons with ADHD than in controls.

The effect size was small-to-moderate (standardized mean difference 0.4).

This association was not found to be affected by age, gender, or hemoglobin levels.

Conclusions

ADHD in children is associated with lower serum ferritin levels, but not with lower serum iron levels.

Clinical Commentary

This data is intriguing and serum ferritin is certainly easy to check.

The authors pointed out some concerns about the apparent association between serum ferritin and ADHD as follows:  

1. While serum ferritin levels are a reliable indicator of iron stores in the body tissues, it is not clear if they similarly reflect iron stores in the brain.

2. Serum ferritin levels are affected not only by the iron stores, but also by factors like inflammation.

3. Although no difference between serum ferritin levels between treated and untreated patients were found in this study, it cannot be ruled out that children with ADHD have lower iron stores because they are picky eaters, their appetite is suppressed due to stimulant medications, etc.

Important: This paper and our inclusion of it should not be taken to mean that clinicians should recommend that children with ADHD take an iron supplement.  Unless, of course, a particular child has been found to have abnormally low serum ferritin levels. In that case, s/he should be referred to a primary care physician for evaluation regarding the cause of the iron deficiency and for appropriate treatment.  

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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].