Issue 70, Feb 2018
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Cannabidiol (CBD) may be a new adjunctive treatment for schizophrenia

McGuire et al. Cannabidiol (CBD) as an Adjunctive Therapy in Schizophrenia: A Multicenter Randomized Controlled Trial. Am J Psychiatry. 2017 Dec15:appiajp201717030325. [Epub ahead of print] PubMed PMID: 29241357.

Background

Recently, there has been a surge of interest in the potential utility of cannabidiol (CBD) for the treatment of many different mental health problems.

Previous research in both animals and humans has suggested that there may be some efficacy against psychotic symptoms.

This paper reports on a clinical trial evaluating the safety and effectiveness of CBD in persons with schizophrenia.

The study was funded by a pharmaceutical company that is developing cannabidiol as a potential medication.

Methods

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

Persons with schizophrenia whose illness had responded at least partially to treatment with an antipsychotic (i.e., was not “treatment-resistant”) were enrolled.

Participants were randomized to receive either CBD (1000 mg/day; N=43) or placebo (N=45) for six weeks. Their antipsychotic medication was also continued.

The CBD was given as 10 mL of a 100 mg/mL oral solution and in two divided doses.

Results

After six weeks of treatment, patients who received CBD had statistically significantly lower levels of positive symptoms (on the PANSS scale) than those who received placebo.

Negative symptoms and general psychopathology were not significantly different in the CBD and placebo groups.

Patients who received CBD were more likely to be rated on the Clinical Global Impression scale as being improved overall—79% versus 55%. This 24% difference is clinically quite significant.

The commonest adverse events were gastrointestinal—CBD 21%, placebo 7%.

There was no significant change in weight, serum prolactin or other laboratory tests.

No symptoms of Parkinsonism were noted in either group.

Conclusions

CBD may be useful as an adjunctive treatment for schizophrenia. It appears to be both effective and well-tolerated.

Since CBD is not a dopamine receptor antagonist, it may represent a new class of treatment for schizophrenia.

Clinical Commentary

There is a significant literature on the association of cannabis use and development of psychotic symptoms. But, those who may be apprehensive about CBD because it is derived from the Cannabis sativa plant should note that CBD does not have the psychotomimetic properties that tetrahydrocannabinol (THC) has. These are two very different chemicals.

Many clinical trials of CBD for a variety of mental health conditions are currently underway. So, in the next two to three years, we are likely to know a lot more about the potential role of CBD as a treatment in mental health.

One issue is that it is not clear what the dose of CBD for various conditions should be. The dose used in this study is several times that being tried for other mental health conditions.

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A way to significantly reduce suicidal ideation within one day?

Wilkinson ST, Ballard ED, Bloch MH, Mathew SJ, Murrough JW, Feder A, Sos P, Wang G, Zarate CA Jr, Sanacora G. The Effect of a Single Dose of Intravenous Ketamine on Suicidal Ideation: A Systematic Review and Individual Participant Data Meta-Analysis. Am J Psychiatry. 2017 Oct 3:appiajp201717040472. [Epub ahead of print] PubMed PMID: 28969441.

Background

Understandably, the field is excited about the apparent unique efficacy of ketamine for difficult-to-treat depression.

But ketamine may also have unique efficacy in reducing suicidal ideation.

This paper is a systematic review and individual participant data meta-analysis evaluating whether a single dose of intravenous ketamine can significantly reduce suicidal ideation.

What “individual participant data” meta-analysis means is that the authors did not only combine the results of the various studies on this topic as is done in most meta-analyses. Rather, they had access to the data for each patient in those studies. So, they were able to do a more powerful meta-analysis.

Methods

Eleven randomized, controlled clinical trials on this subject were identified that used either saline or midazolam as a control treatment.

Of these eleven studies, the authors were able to get individual participant data from ten studies.

This paper only focuses on participants who had suicidal ideation at baseline (N=167).

In the studies included in this meta-analysis, follow ups were done for up to one week.

Results

Patients who received ketamine showed a statistically significantly greater reduction in suicidal ideation compared to those who received the control intervention (either saline or midazolam).

This greater improvement was seen on both clinician-administered and self-report scales.

Importantly, the improvement occurred rapidly (within 1 day).

At all time points in the study, the effect sizes were moderate to large (Cohen's d=0.5-0.85). The effect size was largest on day 1 (0.7) and day 2 (0.8). What this suggests is that persons receiving placebo had gradual reduction in suicidal ideation too, but persons who received ketamine showed improvement within the first day or two.

After receiving ketamine, about 55% of participants were free of suicidal ideation on day 1 and about 60% on day 7.

Was the reduction in the suicidal ideation part of the reduction in the severity of depression in general? There was a statistically significant correlation between change in severity of depression and improvement in suicidal ideation. But, in addition to this strong correlation, statistically controlling for the change in severity of depression found that ketamine still had a statistically significantly greater benefit for suicidal ideation compared to control interventions.

The difference between ketamine and the comparison group was more modest when midazolam was the comparator rather than normal saline. For example, at day 1, the effect size was 0.9 in comparison with saline versus 0.6 in comparison with midazolam.

Conclusions

Treatment with intravenous ketamine was efficacious for reduction in suicidal thoughts in depressed patients with suicidal ideation that occurred within one day and lasted for up to one week. This effect on suicidal ideation appeared to be partially independent of its effects on depression.

The authors cautioned, however, that more studies of ketamine for suicidal ideation in persons with diagnoses other than depression are needed before we can say that ketamine has a specific effect on reducing suicidal ideation independent of reduction in depression.

The authors also cautioned that more research on ketamine's long-term safety and its efficacy in reducing suicidality is needed before its use can be implemented in clinical practice.

Clinical Commentary

To me, what is exciting about the rapid effects of ketamine on depression and suicidal ideation is not just that ketamine could be used for this purpose. It is that this shows that interventions can be developed that can do this.

It should be noted that the effect of ketamine is temporary. Ongoing treatment is essential and this may include continuation of ketamine treatments as one option.

But, it is not clear to what extent the reduction in suicidal ideation with ketamine will persist even if weekly ketamine treatments are continued. In a follow up study of 12 patients who responded to ketamine treatment, one died by suicide during follow up treatment with ketamine (Vande Voort et al., 2016).

So, ketamine or any other acute intervention should only be considered in the context of a wider treatment plan. It is not a panacea.

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Which clinical and genetic factors predict delay in remission from depression?

Falola MI, Limdi N, Shelton RC. Clinical and Genetic Predictors of Delayed Remission After Multiple Levels of Antidepressant Treatment: Toward Early Identification of Depressed Individuals for Advanced Care Options. J Clin Psychiatry. 2017 Nov 21. pii: 17m11448. [Epub ahead of print] PubMed PMID: 29178685.

Background

This study aimed to identify clinical and genetic factors that could be used to identify patients with major depressive disorder who are more likely to have delayed improvement despite multiple trials of different treatments.

Methods

This study used existing data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D), a very large study of multiple treatments for major depressive disorder. Patients in this study were treated with citalopram and if their depression did not remit, they were sequentially treated with alternative treatments.

Of the about 4000 patients who participated in the STAR*D study, DNA samples were available for about 2000 of them. Since this study aimed to evaluate both clinical and genetic predictors of improvement, it focused only on these 2000 patients.

For this study, remission after one or after several treatments was combined into a single variable and simply considered to be remission with treatment. The time to remission was measured from the start of treatment in the study irrespective of the type and number of treatments a participant had received before the illness remitted.

Multiple clinical variables and genetic polymorphisms were evaluated for their possible association with time to remission. Variables found to be associated with time to remission were then combined into a model to predict delayed remission.

Results

After one or a series of treatments, ultimately the depression remitted in about 66% of patients.

The median time to remission was about 11 weeks, but this varied considerably.

Predictors of delayed remission were:

  • Middle age
  • Less education (high school graduate or less)
  • Unemployment
  • Severe medical comorbidity
  • Severe baseline depression
  • Comorbid dysthymia (defined as more than four dysthymic symptoms)
  • Comorbid PTSD (defined as more than nine posttraumatic stress symptoms)
  • A/A or C/A genotypes of the serotonin receptor 1A (5-HT1A) genetic polymorphism rs 1364043
  • C/C genotype of the cytochrome P450 2D6 genetic polymorphism C2850T

These factors were combined together in a model that worked reasonably well to identify in advance those who were more likely to have a delay in remission of the depression.

Note that race was not a predictor of poor response to antidepressant treatment.

Conclusions

The findings of this study suggest that it may be possible to identify in advance persons with major depressive disorder whose clinical depression is more likely to have a delay in remission even after a series of treatments.

Clinical Commentary

Note that both the clinical and the genetic predictors of delay in remission found in this study are not amenable to being easily modified.

So, the point of having such predictors right at the start of treatment is to be more vigilant and more energetic in treating the depression in such patients.

But, in my opinion, we should use these findings as only one factor in clinical decision-making. The model combining the predictors found in this study had a sensitivity of 88%, but it had a low specificity of only 24%. This means that many persons who may not have delayed remission will also be identified by these predictors.

Also, what this study cannot tell us is what treatments to use when many of these predictors are present and whether these treatments would be likely to improve outcomes.

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A really simple thing we must do to help patients with psychosis or bipolar disorder

Lupu AM, Clinebell K, Gannon JM, Ellison JC, Chengappa KNR. Reducing Anticholinergic Medication Burden in Patients With Psychotic or Bipolar Disorders. J Clin Psychiatry. 2017 Nov 21. pii: 16m11269. [Epub ahead of print] PubMed PMID: 29178683.

Background

Anticholinergic medications are often prescribed to treat extrapyramidal side effects of antipsychotics.

But, anticholinergic medications often cause several side effects of their own.

These medications can often be discontinued later, during the maintenance phase of treatment with antipsychotics. In many, but not all, persons this can be done without return of the extrapyramidal side effects.

This paper reports on the findings of a quality improvement (QI) project that aimed to reduce anticholinergic medication burden and improve quality of life in patients with severe mental illness.

Methods

Patients were identified who had schizophrenia, schizoaffective disorder, or a bipolar disorder, were being treated in an outpatient psychiatric clinic, and were prescribed benztropine (a commonly used anticholinergic medication).

These patients were screened for anticholinergic side effects by the treating psychiatrist.

They were then referred to an on-site clinical pharmacist for a comprehensive medication review.

Anticholinergic side effects, cognitive impairment, and the effect of the anticholinergic side effects on quality of life were assessed using a questionnaire for anticholinergic side effecs and several Likert scales.

The pharmacist discussed recommendations for potential medication changes with the prescribing clinician.

Follow-up assessments were conducted over one to eight months later to evaluate patients for any improvements in side effects and in their quality of life.

Results

Twenty-nine patients were assessed for this study.

They were found to be receiving a median of three medications with anticholinergic properties (range one to six).

For 19 of the 29 patients, a medication change was recommended. In 13 patients, one or more medications with anticholinergic properties were stopped. In the other six patients, the dose of such a medication was reduced.

Note: Several patients in whom the anticholinergic was being reduced started to have extrapyramidal side effects. In these patients, the dose was reduced to the minimum effective dose rather than being stopped.

In these 19 patients, there was a statistically significant reduction in anticholinergic side effects. The scores on the Pittsburgh Anticholinergic Symptom Scale decreased by over half—from a median of 29 to a median of 14.

There were also improvements in memory (on the 5 word memory recall test) and in quality of life (on a 0 – 10 Likert scale).

Conclusions

In this interdisciplinary, collaborative quality improvement project, patients whose anticholinergic burden was reduced had an improvement in anticholinergic side effects, memory, and quality of life.

Clinical Commentary

What a simple thing to do and with beneficial effects! But, in my experience, so infrequently done.

Once an anticholinergic medication is started, patients tend to stay on it for years. But extrapyramidal side effects tend to occur mainly in the first few months of treatment with an antipsychotic. After that, unless the patient has extrapyramidal side effects, an attempt should be made to slowly taper off and stop the anticholinergic medication.

We should remember that centrally acting anticholinergic medications like benztropine not only cause peripheral anticholinergic side effects, but also cause impairment in cognitive functioning.  

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A treatment for insomnia in children with autism spectrum disorder

Gringras P, Nir T, Breddy J, Frydman-Marom A, Findling RL. Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children With Autism Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2017 Nov;56(11):948-957.e4. PubMed PMID: 29096777.

Background

Insomnia tends to be a troublesome symptom in children with autism spectrum disorder.

This study aimed to assess the efficacy and safety of prolonged-release melatonin for the treatment of insomnia in children and adolescents with autism spectrum disorder with or without attention-deficit/hyperactivity disorder (ADHD) and neurogenetic disorders (NGD).

Methods

The randomized, double-blind, placebo-controlled clinical trial enrolled 125 children and adolescents (2 to 17.5-years-old), 97% of whom had autism spectrum disorder and the remaining had a related syndrome.

The participants had insomnia that had not improved with behavioral intervention alone.

They were randomized to receive prolonged-release melatonin or placebo for 13 weeks.

The melatonin was started at 2 mg per day and increased if needed to 5 mg per day.

Results

After 13 weeks of double-blind treatment, participants who received prolonged-release melatonin had a greater improvement in total sleep time (an increase of 58 minutes compared to an increase of 9 minutes in those who received placebo).

Sleep latency (time to fall asleep) decreased by an average of about 40 minutes in persons who received prolonged-release melatonin compared to an average reduction of 12.5 minutes with placebo. The wake up time did not change, which is why the total sleep time increased.

The percentage of participants in whom there was a clinically meaningful improvement in total sleep time and/or sleep latency was 69% with prolonged-release melatonin and 39% with placebo. This 30% difference in response rate is a big difference.

Regarding side effects, somnolence was more commonly reported with prolonged-release melatonin than with placebo.

Conclusions

Prolonged-release melatonin was efficacious and safe for the treatment of insomnia in children and adolescents with autism spectrum disorder with or without ADHD or neurogenetic disorders.

This study used a pediatric formulation of melatonin in the form of a minitablet that was well accepted by these patients in whom difficulties in swallowing are known to be common.

Clinical Commentary

This study supports the use of melatonin for insomnia in this population. This is an important finding because these patients frequently suffer from insomnia.

But this study cannot show whether or not the prolonged-release, “pediatric-friendly” proprietary preparation is better than the cheap over-the-counter melatonin.

Also, the optimal dose of melatonin is not clear. In the study, participants could be increased from 2 mg to 5 mg, but in the open-label study that followed this trial, the dose could be increased further to 10 mg/day.

Similarly, this study did not specify the timing of melatonin with respect to bedtime. Experts in sleep medicine have suggested that the optimum timing for melatonin is 3 to 4 hours prior to bedtime. What the optimum time would be to take a prolonged-release preparation of melatonin is not clear.

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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].