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Issue 65, Sep 2017
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Ketamine: What is being given, by whom, and to whom?

Wilkinson ST, Toprak M, Turner MS, Levine SP, Katz RB, Sanacora G. A Survey of the Clinical, Off-Label Use of Ketamine as a Treatment for Psychiatric Disorders. Am J Psychiatry. 2017 Jul 1;174(7):695-696. PubMed PMID: 28669202.

Background

There has been a lot of excitement among researchers, clinicians, patients, and their families about the potential for ketamine treatment to help persons with major depressive disorder whose illness has not responded to other treatments.

Even though ketamine is not FDA-approved as a treatment for any mental disorder, many clinical facilities are using ketamine off-label. So-called “ketamine clinics” are cropping up all over the country.

The authors surveyed practitioners offering ketamine to find out about their clinical work.

This is the first published survey of practice patterns for ketamine as a treatment for mental disorders.  

Methods

Clinicians using ketamine were identified by three methods:

1. From September 2016 to January 2017, a web-based survey was sent to physicians in the US asking if they used ketamine for the treatment of psychiatric disorders.

2. An internet search was done to identify sites that advertised ketamine treatment for depression.

3. Academic and clinical colleagues of the authors were queried.  

Results

57 providers of ketamine treatment answered the survey.

74% were in private practice, only 14% in academic settings, and the rest in other settings.

67% of these clinicians were psychiatrists, 23% were anesthesiologists, and the rest were from other specialties.

74% of respondents reported that they administered ketamine in an office-based setting.

Most of the respondents had started providing ketamine treatment for psychiatric disorders only recently. The authors note that since 2012 there has been a substantial increase in the number of clinicians providing ketamine treatment.

  

For what diagnoses was ketamine being given? The three most common diagnoses were:

72% Major depressive disorder

15% Bipolar disorder

6% Posttraumatic stress disorder

  

And, it was not only being given intravenously (88% of respondents), but also orally (23%), or intranasally (19%).

The typical dose of ketamine used in research is 0.5 mg/kg given intravenously over about 45 minutes. But only 44% of respondents of those giving ketamine reported used that dose. Others reported using wider dose ranges that that.

During ketamine treatment, heart rate and pulse oximetry should be monitored. Most clinicians reported doing so, though how frequently these were checked varied.

Longer-term treatment with ketamine raises concern because there is little evidence to support such use and because there is concern about potential abuse or dependence. But, in this survey, 90% of the respondents reported offering ongoing ketamine treatment, i.e., for more than one month.

When used for maintenance, how often is ketamine given? There is wide variation in this:

once every 2 weeks (12%), once every 3 weeks (21%), monthly (30%), or less than monthly (16%).

Who is paying for this? Out of pocket -- 64% of patients, a portion reimbursed by insurance -- 23%, and “Other” -- 13%.  

Conclusions

There is a rapidly growing number of physicians in a variety of specialties and geographic locations who are offering ketamine treatment.

There is a need to adopt evidence-based treatment regimens.

The authors recommended that a registry should be developed to longitudinally follow patients who receive ketamine for a mental disorder.

Clinical Commentary

We might expect cutting edge treatments like ketamine to first become available in specialized mood disorders programs in academic settings and then gradually spread to other settings. But the great majority of clinicians providing ketamine are in private settings. How do we explain that? Since use of ketamine is such an exciting new development, why are most universities and research centers not offering it as an option?

On the other hand, since ketamine treatments are very expensive, in private settings there is a strong financial incentive to offer ketamine treatments to patients.  

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Does transcranial direct current stimulation (tDCS) work as well as an SSRI?

Brunoni AR, Moffa AH, Sampaio-Junior B, Borrione L, Moreno ML, Fernandes RA, Veronezi BP, Nogueira BS, Aparicio LVM, Razza LB, Chamorro R, Tort LC, Fraguas R, Lotufo PA, Gattaz WF, Fregni F, Benseñor IM; ELECT-TDCS Investigators. Trial of Electrical Direct-Current Therapy versus Escitalopram for Depression. N Engl J Med. 2017 Jun 29;376(26):2523-2533. PubMed PMID: 28657871.

Background

Transcranial direct-current stimulation (tDCS) seems to be an attractive treatment option in mental health because it is less expensive than transcranial magnetic stimulation (TMS) and is not associated with a risk of inducing a seizure.

Bust, is tDCS as effective as an SSRI?

Methods

This was a randomized, double-blind clinical trial that compared tDCS to escitalopram for the treatment of unipolar depressive disorder.

The study was designed to see if tDCS could be shown to be “noninferior” to escitalopram, a commonly used antidepressant medication.

  

Patients were randomized to receive one of the following:

1. tDCS plus oral placebo (“real” tDCS plus a placebo pill)

2. Sham tDCS plus escitalopram, or (“pretend” tDCS plus “real” escitalopram)

3. Sham tDCS plus oral placebo (neither the tDCS nor the antidepressant pill were “real”; both were placebos).

  

The tDCS was applied over the dorsolateral prefrontal cortex. It was given for 30-minutes daily (2-mA) for 15 consecutive weekdays, followed by 7 more treatments on a once a week basis.

Escitalopram was given at 10 mg/day for 3 weeks and then 20 mg/day.

“Noninferiority” of tDCS versus escitalopram was predefined by comparing the difference between tDCS and escitalopram to the difference between escitalopram and placebo. Noninferiority would be established if tDCS was associated with at least 50% of the superiority of escitalopram over placebo.  

Results

A total of 245 patients were randomized.

The mean reduction in score on the Hamilton Depression Rating Scale was about 11 points for those who received escitalopram, 9 points for those who received tDCS, and 6 points for those who received placebo.

Both escitalopram and tDCS were statistically significantly more efficacious than placebo.

But, based on the predefined criterion, tDCS was not found to be noninferior to escitalopram.

What were the side effects of tDCS? Patients who received tDCS were more likely to have skin redness, tinnitus, and nervousness than the other two groups. Also, two patients who received tDCS developed new-onset mania.

Despite the side effects, participants did not correctly guess whether they had received tDCS or sham tDCS.  

Conclusions

The authors concluded that tDCS did not show noninferiority to escitalopram for the treatment of unipolar depression and was associated with more adverse events.

Clinical Commentary

This clinical trial suggests that we cannot accept claims that tDCS is an option for “treatment-resistant” depression or that it is relatively free of adverse effects.

It is possible that tDCS may be helpful in combination with a standard antidepressant medication, as supported by a previous clinical trial published by the same research group (Brunoni et al., 2013). In this 2017 study, however, there was no treatment group that received the SSRI and tDCS.

Further study of tDCS as a potential treatment for mood and anxiety disorders is warranted, both as monotherapy and as an adjunct to antidepressant medications.

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Is it better to switch antidepressants or to augment?

Mohamed S, Johnson GR, Chen P, Hicks PB, Davis LL, Yoon J, Gleason TC, Vertrees JE, Weingart K, Tal I, Scrymgeour A, Lawrence DD, Planeta B, Thase ME, Huang GD, Zisook S; and the VAST-D Investigators. Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial. JAMA. 2017 Jul 11;318(2):132-145. PubMed PMID: 28697253.

Background

In the majority of patients, major depressive disorder does not remit with the first course of antidepressant treatment. But, it is not clear what the best next step is.

This study compared the effectiveness and safety of three commonly used next-step treatments for major depressive disorder.  

Methods

This was a randomized, controlled clinical trial that was single-blind.

Over 1500 patients from 35 Veterans Health Administration medical centers participated in this study.

These patients were diagnosed with major depressive disorder, did not have psychotic features, and had not responded to at least one adequate course of antidepressant treatment.

  

The participants were randomized to receive one of the following treatments for 12 weeks:

1. Switch to a different antidepressant, i.e., bupropion (“Switch group”)

2. Augment the current treatment with bupropion (“Augment-bupropion group”)

3. Augment the current treatment with an atypical antipsychotic, aripiprazole (“Augment-aripiprazole group”)

  

Bupropion sustained-release was started at 150 mg/day and increased if needed and tolerated to a maximum of 400 mg/day.

Aripiprazole was started at 2 mg/day and increased if needed and tolerated to a maximum of 15 mg/day.

After the 12 weeks of the main part of the study, the participants were also followed up for up to 36 weeks.

Results

The mean age of the participants was 54 years and 85% were men.

  

The primary outcome measure was remission. Remission rates at 12 weeks were as follows:

Switch group 22%

Augment-bupropion group 27%

Augment-aripiprazole group 29% (statistically significantly greater than the Switch group).

  

In addition to remission, another outcome measure is “response” (50% or more reduction in the severity of depression). Response rates were as follows:

Switch group 62%

Augment-bupropion group 66%

Augment-aripiprazole group 74% (statistically significantly greater than the both the other groups).

  

The relapse rates over 36 weeks were not statistically significantly different in the three groups.

Increased anxiety was more frequent among patients switched to bupropion (24%) or augmented with bupropion (23%) compared to those augmented with aripiprazole (17%).

But those augmented with aripiprazole were more likely to have somnolence, akathisia, and weight gain.

Conclusions

In this population, augmentation with aripiprazole led to a statistically significantly greater chance of response and remission of the depression compared to switching to bupropion.

However, the difference in remission rates was small (about 7%) and there were more side effects in patients who received aripiprazole.

So, the net utility of aripiprazole augmentation still needs further evaluation.

Clinical Commentary

This study addresses one of the commonest questions faced by clinicians who prescribe medications for major depression.

I agree with the authors’ concern about the relatively small difference in remission rates.

Thus, important questions remains for future studies: Who is more likely to respond to a particular treatment? Can subgroups be identified in which one treatment is much more likely to work than another?  

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Does lurasidone also work for maintenance treatment of bipolar disorder?

Calabrese JR, Pikalov A, Streicher C, Cucchiaro J, Mao Y, Loebel A. Lurasidone in combination with lithium or valproate for the maintenance treatment of bipolar I disorder. Eur Neuropsychopharmacol. 2017 Jul 6. pii: S0924-977X(17)30290-0. [Epub ahead of print] PubMed PMID: 28689688.

Background

Lurasidone is an FDA-approved treatment for acute bipolar depression—as monotherapy and as an adjunct to lithium or valproate.

But what about after the acute episode is over? Would it be helpful to continue lurasidone along with lithium or valproate?

This study aimed to evaluate the efficacy of lurasidone for preventing recurrences during the maintenance treatment of bipolar I disorder.

Methods

This was a 28-week clinical trial that used a randomized, placebo-controlled withdrawal design. What “withdrawal design” means will become clear below.

Patients with bipolar I disorder were enrolled if they had had at least one manic, mixed, or depressive episode in the previous two years.

In addition, the participants currently had significant manic or depressive symptoms based on standardized rating scales.

Those who had a history of substance abuse or of non-response to three or more adequate trials of antidepressants, antipsychotics, or mood stabilizers were excluded.

Stabilization phase: The participants first received lurasidone 20 to 80 mg along with either lithium or valproate for at least 12 weeks and up to 20 weeks.

At the end of 12 weeks, those who met specific stabilization criteria were randomized to receive double-blind treatment with either lurasidone 20 to 80 mg/day or placebo (along with either lithium or valproate). That is, participants who were stabilized on lurasidone were randomized to continue to be on lurasidone or for the lurasidone to be withdrawn and replaced with placebo.

Results

Nearly 500 patients were randomized.

The mean dose of lurasidone was 54 mg/day. The modal dose was 20 mg/day in 8%, 40 mg/day in 36%, 60 mg/day in 31%, and 80 mg/day in 26% of participants.

Lithium and valproate levels were not different between the lurasidone and placebo groups.

Those who were randomized to receive lurasidone had a 29% lower probability of recurrence of any mood episode than those who were randomized to receive placebo. However, this difference was not statistically significant (i.e., it was not sufficiently unlikely that this difference could have occurred due to chance alone).

The probability of recurrence of a mood episode by 28 weeks was 21% for those who received lurasidone versus 52% for those who received placebo but this difference was not statistically significant.

The estimated probability of recurrence of a depressive episode by week 28 was 13% in the lurasidone group versus 43% in the placebo group.

  

But in some subgroups of patients, the risk of recurrence was statistically significantly lower in patients who received lurasidone compared to those who received placebo:

1. Patients whose index episode was one of depression

2. Those whose illness was not rapid-cycling

3. Those whose symptoms were more severe.  

Conclusions

Lurasidone used along with lithium/valproate may be efficacious for prevention of recurrence of mood episodes in some patients.

Clinical Commentary

There are some reasons why this study and other such studies are more likely to find that the drug being studied to be efficacious compared to an unselected sample or real-world patients.

1. The sample was enriched. Only those who were able to tolerate lurasidone and did well on it (were “stabilized”) were included in this study.

2. Rather than the study drug, lurasidone, being added, it was withdrawn. That is, patients who were stable on lurasidone (along with lithium/valproate) had the lurasidone either stopped or not.

  

Still, I think the conclusion from this study is that at least for some patients, continuing the combination of lurasidone and lithium/valproate may be helpful. These patients seem to be those who get stabilized on this combination, don’t have rapid cycling, who present with bipolar depression, and whose symptoms are more severe.

As the authors noted, due to a study duration of only 6 months, relapse rates were relatively low, even on placebo. Also, the dose of lurasidone was limited to 80 mg/day, which was the maximum FDA-approved dose at that time. These factors may have reduced the ability of this study to identify the effectiveness of lurasidone with statistical confidence.

Given the important role of lurasidone for the treatment of bipolar depression, we need more research and more guidance as to how it should be used in the longer-term treatment of bipolar disorder.

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Deutetrabenazine for tardive dyskinesia?

Fernandez HH, Factor SA, Hauser RA, Jimenez-Shahed J, Ondo WG, Jarskog LF, Meltzer HY, Woods SW, Bega D, LeDoux MS, Shprecher DR, Davis C, Davis MD, Stamler D, Anderson KE. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: The ARM-TD study. Neurology. 2017 May 23;88(21):2003-2010. PubMed PMID: 28446646; PubMed Central PMCID: PMC5440239.

Background

Deutetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor and an isomer of tetrabenazine. It is FDA-approved for the treatment of chorea associated with Huntington’s disease.

It is also being developed for the treatment of tardive dyskinesia associated with use of dopamine-blocking drugs.

This clinical trial aimed to evaluate the efficacy and safety of deutetrabenazine as a treatment for tardive dyskinesia (TD).

Methods

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

117 patients with moderate to severe TD were randomized to receive either deutetrabenazine or placebo.

Patients were included if they had an Abnormal Involuntary Movement Scale (AIMS) score of six or more as assessed by blinded central video rating.

Their psychiatric illness was stable.

Medications, including antipsychotics, that were being taken at a stable dose could be continued. Patients who continued taking a dopamine receptor antagonist were equally randomized to receive deutetrabenazine or placebo.

Deutetrabenazine was given at 6 mg twice daily and titrated if needed and tolerated to a maximum of 48 mg/day.

Results

The diagnoses of the participants were schizophrenia (50%), “depression” (26%), bipolar disorder (23%), or schizoaffective disorder (19%).

Patients who were randomized to receive deutetrabenazine had a statistically significantly greater reduction in AIMS scores from baseline to week 12 compared to those randomized to receive placebo.

The difference between deutetrabenazine and placebo was statistically significant by 4 weeks.

Pre-defined response was obtained in 48% of patients on deutetrabenazine versus 40% of those on placebo. This difference was not statistically significant.

Importantly, psychiatric adverse effects were uncommon and not greater in patients on deutetrabenazine compared to those on placebo: anxiety (3% versus 7% on placebo), depressed mood/depression (2% in both groups), and suicidal ideation (0% versus 2% on placebo).  

Conclusions

Deutetrabenazine was efficacious and well tolerated for the treatment of tardive dyskinesia.

Clinical Commentary

At the time this research review is being published, a decision is expected from the FDA regarding a possible indication for deutetrabenazine for the treatment of tardive dyskinesia. This clinical trial was one of the two pivotal trials that supported the submission to the FDA.

If approved, deutetrabenazine would become the second medication to be FDA-approved for the treatment of tardive dyskinesia. The first was valbenazine.

Neither the clinician nor the patient should think that these new medications for tardive dyskinesia work for the majority of patients or that they produce complete improvement. The percentages of patients who were rated by clinicians as either “much improved” or “very much improved” at 12 weeks were 48% with deutetrabenazine versus 40% with placebo. When patients rated themselves, the corresponding percentages were 43% with deutetrabenazine versus 30% with placebo. These differences were not statistically significant, i.e., it is not sufficiently unlikely that they may have occurred by chance alone.

Rating on the Abnormal Involuntary Movement Scale (AIMS) requires training and experience. After randomization, based on central video rating of the severity of the tardive dyskinesia by experts, 14% of the participants in this study were found to have been wrongly included in the study. In the 86% of participants who did have an AIMS severity rating of 6 or more, the percentages of patients who were rated by clinicians as either “much improved” or “very much improved” at 12 weeks were 52% for deutetrabenazine versus 35% for placebo. What we can conclude from this is that the drug-placebo difference is greater in patients with greater severity of the tardive dyskinesia. This is similar to the drug-placebo difference being greater in antidepressant clinical trials with increasing baseline severity of depression.

Given the high cost of deutetrabenazine, it is good to know that at as early as four weeks there was statistically significantly greater improvement with deutetrabenazine than with placebo. But it would be very useful for clinicians to know the point at which deutetrabenazine is unlikely to work if no improvement has occurred so that additional cost can be avoided.  

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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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