GME Research Review
GME Research Review is a monthly newsletter edited by Rajnish Mago, MD, Associate Professor of Psychiatry at Thomas Jefferson University, who selects, summarizes, and provides a clinical commentary on the latest published research in psychiatry. Each summary has been derived from the relevant article’s abstract and the clinical commentary has been provided by Dr. Mago.
Issue 39, July 2015
In this month’s GME Research Review, I discuss five clinically useful research studies presented as posters at the annual meeting of the American Psychiatric Association in May 2015.
How can clinically available genetic testing explain why your patient had so many side effects on an antidepressant?
Mago et al. Genetic polymorphisms and antidepressant adverse effects.
Why is this study important?
- In the last couple of years, there is increased interest in pharmacogenetic testing, which has become available for clinical use. Clinicians are eager to know whether such testing can be useful in clinical practice and, if so, which patients may benefit the most from it.
- We all sometimes see patients who report that they had an unusual number and severity of adverse effects with one or more antidepressants. These patients are often suspected of having “personality disorder.” Is it really possible that for some of these patients genetic variations may explain why they had so many adverse effects?
- Aim: to find out whether genetic variations relevant to medications (“pharmacogenetic polymorphisms”) are associated with either increased adverse effects or non-response.
- This was tested with regard to certain antidepressants whose metabolism is highly dependent on any one specific CYP450 isoenzyme
- Patients with major depressive disorder or generalized anxiety disorder were enrolled.
- So far, 50 patients have been studied. The study is continuing and aims to enroll 100 patients.
- A Case Control design was used. That is, the study started with patients who did or did not have the particular problem of having more adverse effects.
- The two groups compared were:
a) Patients who had had increased adverse effects from specified antidepressants (Cases). One might expect that some of these patients may have had unexpectedly high serum levels of the antidepressant.
It is important to note that “increased adverse effects” did not mean just having had some adverse effects. It meant having had more than usual adverse effects. This was defined as either having five or more mild adverse effects, or having three or more moderate/severe adverse effects.
b) Patients in whom an antidepressant had failed to produce a response but also did not cause significant adverse effects (Controls). One might expect that some of these patients may have had unexpectedly low serum levels of the antidepressant.
- Genecept Assay™ (a battery of pharmacogenetic tests relevant to psychiatry) was obtained using saliva or cheek swab.
- One of the many things the test looks at is the level of activity of several cytochrome P450 isoenzymes. A patient in whom a particular cytochrome P450 isoenzyme has either poor or an intermediately low activity will probably have higher serum levels of a drug whose metabolism depends mainly on that isoenzyme. On the other hand, a patient in whom a particular cytochrome P450 isoenzyme has particularly high activity (ultrarapid metabolizer) will probably have lower than usual serum levels of the drug. Patients who have unusually high serum levels of the antidepressant may be more likely to have adverse effects. Similarly, patients with unusually low serum levels of the antidepressant may be less likely to respond to the antidepressant.
- For each antidepressant, one CYP450 isoenzyme was considered to be the most important metabolic pathway as follows: citalopram (2C19), duloxetine (2D6), escitalopram (2C19), paroxetine (2D6), venlafaxine (2D6).
- Importantly, 57% of Cases (patients with more side effects) were either poor or intermediate metabolizers on the specific CYP450 isoenzyme that is known to be primarily responsible for metabolizing that particular antidepressant. That is a very high percentage — 57%!
- Of Controls (patients who did not respond to the antidepressant), only 17% were poor or intermediate metabolizers. That’s a big difference (57% vs. 17%).
- So, the hypothesis turned out to be correct. The majority (57%) of this particular group of patients — those with unusually greater number/severity of adverse effects — were poor/intermediate metabolizers on the specific cytochrome P450 isoenzyme that metabolizes that particular antidepressant.
- Next, what if we raise the bar further and look at patients who had had even greater problems with adverse effects? Of patients who had two or more severe adverse effects on the antidepressant, 69% were found to be poor or intermediate metabolizers on the cytochrome P450 isoenzyme that metabolizes that particular antidepressant. That is a very high percentage! Presumably that is because this is a narrowly selected subgroup of patients.
- Patients on certain commonly used antidepressants who had more than usual adverse effects were very likely to be poor or intermediate metabolizers on the relevant CYP450 isoenzyme
- Shouldn’t pharmacogenetic testing be routinely considered in these patients?
- A key message of this study can be that when patients don’t improve on an antidepressant, pharmacogenetics may or may not be the explanation. But when patients on these particular antidepressants have a lot of side effects, the chances that they are poor or intermediate metabolizers on that particular isoenzyme are very high.
- In such patients, I always do pharmacogenetic testing because that can guide us to avoid prescribing medications — psychiatric and non-psychiatric — that are metabolized by that cytochrome P450 isoenzyme. Or to prescribe lower than usual doses.
A medication specifically studied for major depressive disorder with mixed features (a new category in DSM-5)
Suppes et al. Lurasidone for the treatment of major depressive disorder with mixed features: A randomized, double-blind, placebo-controlled 6-week trial
Why is this study important?
- We know about mixed episodes or mixed features in bipolar disorder, but DSM-5 has introduced a new subcategory in unipolar major depressive disorder: major depressive disorder with mixed features.
- This diagnosis is used when subthreshold manic or hypomanic features are present in an episode of major depressive disorder. These mixed features are reported to be fairly common.
- Standard antidepressants are less useful in these patients than in patients with major depressive disorder without mixed features, but there are no proven treatment alternatives.
- Lurasidone has been shown to work for bipolar depression, so it made sense for the manufacturer (Sunovion) to conduct a study of lurasidone for patients who had MDD with mixed features.
- Aim: To evaluate the efficacy and safety of lurasidone in patients with major depressive disorder with mixed features.
- This was the first placebo-controlled trial of any treatment for this subcategory of MDD.
- Patients in this study had major depressive disorder of at least moderate severity, defined as a Montgomery-Asberg Rating Scale (MADRS) score ≥26.
- In addition, they had two or three manic symptoms on most days over at least the two weeks prior to screening.
- This study was planned and conducted before the DSM-5 was officially introduced. I must point out that despite the title of the poster, the extent of mixed features required for inclusion in this study was not the same as that required for a DSM-5 diagnosis. In DSM-5, “At least three … manic/hypomanic symptoms are present nearly every day during the majority of days of a major depressive episode.” So, the DSM-5 has a higher threshold of symptoms required to diagnose MDD “with mixed features” than was used in this study.
- Patients with any lifetime history of bipolar I manic episodes, or any mixed manic episodes, were obviously excluded.
- Patients were randomized to six weeks of double-blind treatment with either flexible doses of lurasidone 20 to 60 mg/day (n=109) or placebo (n=100).
- Patients treated with lurasidone showed significantly greater improvement compared with placebo on the Montgomery-Asberg Depression Rating Scale (MADRS).
- To get an idea about how much of a difference there was, the simplest thing for a clinician to do is to look at the difference in the percentage of patients who responded. Response is defined as a 50% or greater reduction in the severity of depression.
- The percentage of responders was 68% on lurasidone versus 33% on placebo. Huge difference! Remember, it is widely accepted that a 10% difference in response rate is considered a minimum clinically useful difference. A 20% difference between drug and placebo is considered a very clinically useful advantage. Here, the drug-placebo difference is 35%.
- Common adverse events are usually defined as those occurring in 5% or more of patients. Common adverse events that occurred more often on lurasidone than on placebo were nausea (6% on lurasidone versus 2% on placebo) and somnolence/sedation (6% on lurasidone versus 1% on placebo).
- Other advents of interest to us with an antipsychotic are akathisia (4% on lurasidone versus 2% on placebo) and parkinsonism (3% on lurasidone versus 1% on placebo).
- What about metabolic parameters? With a second-generation antipsychotic, we are very interested in knowing about that.
- The poster shows only changes in the mean values of glucose, cholesterol, and triglycerides. These were small and similar on lurasidone and on placebo. But what we are more interested in are the percentages of patients who had a significant increase in each of these variables. That information was not provided in the poster.
- Lurasidone monotherapy was efficacious compared to placebo in reducing the severity of depression in patients with major depressive disorder with mixed features (as defined in this study).
- The inclusion of this subcategory in DSM-5, major depressive disorder with mixed features, will, no doubt, lead to disagreement and debate. Some will argue that these patients really have a form of bipolar disorders. DSM-5 notes that, “The presence of a ‘with mixed features’ specifier also increases the risk for future manic or hypomanic diagnosis.” However, only a minority of patients with major depressive disorder with mixed features, even if carefully followed for many years, will go on to develop bipolar disorder. So, yes, some of these patients probably really have a bipolar disorder, but that is probably a minority. That’s all I will say here about this controversy.
- Overall, the study is important because of being the first study of a treatment for this subgroup and because it was a relatively large, randomized, placebo-controlled clinical trial.
- The results of this study are impressive in terms of the large drug-placebo difference that was found.
- Unfortunately, due to when the patent will expire, I don’t think it will be feasible for the manufacturer to conduct further studies of lurasidone for this diagnostic subcategory in order to obtain an FDA indication for it.
Light therapy for non-seasonal major depression. Really?
Lam R. et al. A randomized, placebo-controlled study of light therapy, fluoxetine, and the combination for nonseasonal major depression.
Why is this study important?
- Fact A: Huge proportions of patients with major depressive disorder don’t respond adequately to standard antidepressants alone.
- Fact B: Huge proportions of patients with major depressive disorder find the side effects of standard antidepressants unacceptable. Many of these stop taking the medication.
- Fact C: Bright light therapy is a relatively simple and definitely benign treatment, but is greatly underutilized.
- There is some previous data to suggest that it could be helpful even in non-seasonal depression, but more data on this topic was needed.
- Aim: to determine if bright light therapy works for non-seasonal major depressive disorder — either alone or in combination with fluoxetine.
- A randomized, double-blind, placebo-controlled clinical trial was conducted at three sites in Canada
- The first author, Raymond Lam, MD, is a leading expert on the use of bright light therapy for depressive disorders.
- Patients with major depressive disorder of at least moderate severity were included.
- Patients with seasonal pattern or treatment-resistance were excluded.
- Patients were randomized to treatment for eight weeks with one of the following:
Group 1: Bright light therapy (fluorescent white light of 10,000 lux intensity for 30 minutes daily)
Group 2: Fluoxetine 20 mg/day
Group 3: Both bright light therapy and fluoxetine 20 mg/day
Group 4: Only placebo
- So, how is double-blind maintained in such studies where there are two treatments? The method is called “double dummy” and involves having two different placebos, corresponding to each of the two different treatments.
- And what about if one of the treatments is not a pill? Well, then you have to have placebo corresponding to that treatment as well. The placebo corresponding to bright light therapy used in this study was another machine, a negative ion generator. The placebo corresponding to the fluoxetine was a placebo pill that looked identical to the fluoxetine pill.
- So, Group 1 received bright light therapy plus a placebo pill; Group 2 received fluoxetine plus the negative ion generator; Group 3 received both active treatments; and Group 4 received both placebo treatments.
- 122 patients were randomized.
- The groups were compared primarily on reduction in severity of depression as measured on the Montgomery-Asberg Depression Rating Scale.
- Bright light therapy alone (Group 1) was more efficacious than placebo only (Group 4).
- Bright light therapy plus fluoxetine (Group 3) was more efficacious than placebo only (Group 4).
- Fluoxetine only (Group 2) was not more efficacious than placebo only (Group 4).
- Bright light plus fluoxetine (Group 3) was more efficacious than fluoxetine alone (Group 2).
- In secondary analyses, the percentage of patients showing a 50% or greater reduction in severity of depression was approximately 76% for bright light plus fluoxetine, 50% for bright light alone, 27% for fluoxetine alone, and 33% for placebo alone. 76% vs. 27 or 33%; we don’t usually see such a big difference between active treatment and placebo!
- Importantly, the combination treatment was statistically significantly more efficacious than any of the other three interventions.
- Bright light therapy, either alone or in combination with fluoxetine, was efficacious in the treatment of patients with non-seasonal major depressive disorder.
- The combination of bright light therapy and fluoxetine appeared to be the most efficacious treatment.
- Though not discussed here, there are other previous studies that also supported the use of bright light therapy for non-seasonal major depression.
- However, I wondered: will bright light therapy work mainly for depression with winter onset (even if the illness does not meet the criteria for seasonal pattern)? Or work better for persons who say that lower exposure to light in the winter affects their mood?
- In personal communication, Dr. Lam clarified, “We designed this study specifically to include patients with ‘garden variety’ MDD of the nonseasonal kind. We didn't ask about ‘sensitivity’ to light exposure, but there was no relationship of seasonality scores to outcome, or in season of year when the patients were studied.”
- Another issue that came to my mind was: Couldn’t it also be that patients who felt in some way that their depression was affected by the amount of light were the ones who volunteered for the study?
- I do think that we should consider bright light therapy much more frequently as a treatment for depressive disorders.
- Hopefully, further research will clarify which patients who do not meet the full criteria for seasonal pattern are most likely to respond to bright light therapy. In the meanwhile, I personally am more likely to consider bright light therapy for patients with a) seasonal pattern, b) seasonal worsening, or c) winter onset with patient report that the amount of light affects their mood.
Next, I will briefly summarize and discuss two randomized, placebo-controlled clinical trials of vilazodone for Generalized Anxiety Disorder that were presented as posters at the APA annual meeting 2015.
Vilazodone for Generalized Anxiety Disorder: the Sambunaris et al. poster
Sambunaris et al. Vilazodone in adult patients with generalized anxiety disorder: A double-blind, randomized, placebo-controlled, flexible-dose study.
Why is this study important?
- Serotonergic antidepressants are often considered the mainstay of pharmacotherapy for Generalized Anxiety Disorder (GAD). Buspirone, a 5-HT1A receptor partial agonist has also been used for treatment of Generalized Anxiety Disorder. So, a natural question occurs: would vilazodone, which combines the mechanisms of actions of SSRIs and buspirone, be a particularly good treatment for Generalized Anxiety Disorder?
- Note: vilazodone is approved by the US FDA for the treatment of major depressive disorder but not for the treatment of Generalized Anxiety Disorder.
- Aim: To evaluate the efficacy, safety, and tolerability of vilazodone for the treatment of Generalized Anxiety Disorder.
- A multicenter, randomized, double-blind, placebo-controlled clinical trial was conducted by the manufacturer of vilazodone.
- Vilazodone was given in flexible dose 20 to 40 mg/day for up to eight weeks. Note: this is the same as the recommended dose for the treatment of major depressive disorder.
- 398 patients, 18 to 70 years old, were studied.
- Patients on vilazodone had a statistically significantly greater reduction in severity of anxiety as measured on the Hamilton Anxiety Rating Scale total score.
- As usual, to get an idea of how big of an effect the medication has, let’s look at the percentage of responders, defined as a 50% or greater decrease in severity of anxiety as measured on the Hamilton Rating Scale for Anxiety. In this study, the response rate was 52% for patients on vilazodone and 42% for those on placebo.
- It is usual to consider a 10% or greater difference in response rates between drug and placebo as being the minimum threshold for a clinically useful effect. So, the drug-placebo difference in the study met the minimum threshold for a clinically meaningful effect, but no more than that. (The other clinical trial of vilazodone for Generalized Anxiety Disorder GAD, discussed below, did find a higher drug-placebo difference in the percentage of responders.)
- Was vilazodone associated with impairment in sexual functioning? For the Changes in Sexual Functioning Questionnaire, only limited information was provided in the poster. Changes in the mean values were small and were not different between vilazodone and placebo.
- However, we would be more interested in knowing the percentage of patients who had worsening of sexual functioning. That information was not provided in the poster.
- As in all clinical trials in psychopharmacology, “Treatment-Emergent Adverse Events (TEAEs)” were recorded. TEAEs are simply undesirable things that happened during the study whether or not they were related to the medication.
- As usual, let us focus on those Treatment-Emergent Adverse Events (TEAEs) that were reported spontaneously by 5% or more of patients on vilazodone and at least twice as often as on placebo. In decreasing order of incidence, these were: nausea (32%), diarrhea (31%), vomiting (7%), somnolence (6%), abnormal dreams (5%).
- Vilazodone was found to be statistically significantly more efficacious than placebo for the treatment of Generalized Anxiety Disorder.
- Note that there is no clinical trial that directly compared vilazodone to an SSRI for the treatment of Generalized Anxiety Disorder.
- Very limited information was provided in the poster about changes in sexual functioning. Therefore, I cannot comment on what this study concludes about vilazodone’s effects on sexual functioning.
- I did notice that sexual dysfunction was not among the adverse events reported by 5% or more of patients on vilazodone. However, see the study discussed below, in which it was.
Vilazodone for Generalized Anxiety Disorder: the Sheehan et al. poster
Sheehan et al. A double-blind, randomized, placebo-controlled, flexible-dose study of vilazodone in patients with generalized anxiety disorder.
Why is this study important?
- For the same reasons that were mentioned above while discussing the Sambunaris et al. poster.
- But why should we bother to look at two studies of the exact same topic? Well, replication is key to scientific inquiry. That is why the FDA requires for approval of a drug that at least two separate clinical trials should have demonstrated the efficacy of a drug.
- This clinical trial also aimed to evaluate the efficacy, safety, and tolerability of vilazodone for the treatment of GAD.
- The reason that pharmaceutical companies simultaneously conduct multiple similar clinical trials is that they need at least two positive clinical trials to get an FDA indication.
- The methodology of this trial was identical in every way to the one discussed above.
- 400 patients with GAD, 18 to 70 years old were studied.
- Vilazodone was statistically significantly more efficacious than placebo.
- The percentages of responders (patients who had a 50% or greater reduction in the severity of the anxiety as measured by the Hamilton Rating Scale for Anxiety total score) were 57% on vilazodone and 39% on placebo. The 18% difference in the response rates in this study was more than in the Sambunaris et al. paper discussed above and indicates a clearly clinically useful degree of efficacy.
- For the Changes in Sexual Functioning Questionnaire, only limited information was provided in the poster. The mean values worsened a little with vilazodone, while they improved a little with placebo.
- Treatment-emergent adverse events (TEAEs) reported spontaneously by 5% or more of patients on vilazodone and at least twice as often than on placebo were nausea (30%), diarrhea (28%), dizziness (11%), fatigue (5%), delayed ejaculation (5%), and erectile dysfunction (5%).
- Vilazodone was shown to be efficacious for the treatment of Generalized Anxiety Disorder with a clearly clinically meaningful benefit over placebo.
- Nausea and diarrhea were very common with vilazodone.
- Spontaneous reports of delayed ejaculation and/or erectile dysfunction occurred more often with vilazodone than with placebo.
- Vilazodone was shown to be efficacious for the treatment of Generalized Anxiety Disorder.
- The limited data provided in these two posters about the Changes in Sexual Functioning Questionnaire and from spontaneous reports from patients suggests that vilazodone appears to be associated with relatively low rates of sexual dysfunction.
- However, a number of methodological issues prevent me from drawing a more definitive conclusion on this point. I look forward to seeing more details of the data gathered in these trials and to results of ongoing research specifically aimed at assessing the extent to which vilazodone causes sexual dysfunction.
Did you find these research summaries clear and easy to understand? Did you find them clinically useful? Your feedback is very important! Please send me your thoughts at [email protected].
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