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 36, April 2015
Which patients with major depressive disorder more likely to benefit from adding L-methylfolate to a selective serotonin reuptake inhibitor?
Papakostas et al. Effect of adjunctive L-methylfolate 15 mg among inadequate responders to SSRIs in depressed patients who were stratified by biomarker levels and genotype: results from a randomized clinical trial. J Clin Psychiatry. 2014 Aug;75(8):855-63. PubMed PMID: 24813065.
Why is this article important?
- L-methylfolate (Deplin®) is commercially available and has been suggested as a potential add on when there is an inadequate response to an antidepressant alone in patients with major depressive disorder (MDD).
- However, we do need to know which patients are more likely to benefit from addition of L-methylfolate. It seems far-fetched to add it in every patient who does not show a full response to an SSRI.
- This paper aimed to identify some predictors of better response to L-methylfolate added to an antidepressant in patients with MDD.
- This paper describes post hoc analyses of a previously published randomized, placebo-controlled trial of L-methylfolate added to an SSRI after inadequate response in patients with MDD (Papakostas et al., 2012).
- The term “post hoc analyses” simply means that these analyses were not planned as part of the original study. Usually, post hoc analyses are considered more tentative and require a future, planned study to confirm their results.
- The original study (Papakostas et al., 2012) described a double-blind, randomized, placebo-controlled trial lasting for 60 days of L-methylfolate 15 mg/day versus placebo added to an SSRI.
- Outpatients with MDD who had not responded adequately with an SSRI were continued on the SSRI and in addition randomized into one of three groups: a) L-methylfolate 15 mg/day for 60 days, b) placebo for 30 days followed by L-methylfolate 15 mg/day for 30 days, or c) placebo for 60 days.
- The primary outcome measure was the 28-Item Hamilton Depression Rating Scale.
- Seventy-five patients were enrolled.
- Patients with following characteristics had greater improvement in depression on L-methylfolate compared to those on placebo:
- Body mass index ≥ 30 kg/m²
- Elevated plasma levels of high-sensitivity C-reactive protein
- Elevated plasma levels of 4-hydroxy-2-nonenal (4-HNE)
- Low S-adenosylmethionine/S-adenosylhomocysteine ratio
- Genetic markers related to methylation and L-methylfolate metabolism
- Most powerfully — combinations of the above markers
- The markers associated with inflammation or metabolism listed above and genomic markers associated with L-methylfolate synthesis and metabolism may help identify those patients with MDD and an inadequate response to SSRIs who may be more likely to benefit from addition of L-methylfolate to the SSRI.
- L-methylfolate is involved in the synthesis of monoamines relevant to the pathophysiology of at least some types of clinical depression.
- Various types of data support the role of folate metabolism in MDD and the clinical trial reported by Papakostas et al. (2012) suggested that addition of L-methylfolate 15 mg/day to the SSRI was efficacious.
- High BMI is commonly found in our patients and is easily determined. Therefore, this can be an useful consideration in deciding whether to add L-methylfolate to the SSRI.
- Regarding C-reactive protein, please think twice before you order it because many insurance companies refuse to pay for this test and it is expensive. The patient may get stuck with a significant bill. If you really want the test to be done, someone should call the insurance in advance to see if they will pay for the test.
- Of the genetic markers that were found to statistically significantly predict improvement with addition of L-methylfolate, some are available clinically. For example, the G>A intron polymorphism of the voltage-dependent calcium channel L-type, alpha 1c subunit (CACNA1C) and the 158 Val>Met polymorphism of catechol-o-methyltransferase (COMT) are commercially available.
- I have been using the C677T polymorphism of methylenetetrahydrofolate reductase (MTHFR) to decide which patients to give L-methylfolate to. My thought was that those who have the T/T polymorphism have a huge reduction in activity of the enzyme MTHFR that is in the pathway leading from folate to methylfolate, so these patients would benefit from being given L-methylfolate. Surprisingly, in this study, the C677T polymorphism was NOT significantly associated with benefit from add on L-methylfolate. It may seem that my hypothesis was wrong, but there is another possibility. Since the T/T polymorphism is present in only about 11% of the population, only a few patients in this study had the T/T polymorphism. The C/T and T/T groups were combined and compared to the C/C group. This may be an alternative explanation for why no significant association was found. I would like to see, in the future, a study with a larger sample size that would allow comparison between the T/T variation and the “normal” C/C alleles.
- At this time, it seems best to use a combination of predictors to predict which patients should receive addition of L-methylfolate.
What proportion of children treated with medications for ADHD also receives psychotherapy?
Gellad et al. Geographic variation in receipt of psychotherapy in children receiving attention-deficit/hyperactivity disorder medications. JAMA Pediatr. 2014 Nov;168(11):1074-6. PubMed PMID: 25243391.
Why this paper is important?
- It is not known what proportion of children on ADHD medications also receives psychotherapy.
- Mental health clinicians are often accused of “just medicating” children with ADHD and, therefore, need to know the facts.
- This paper should be make the mental health profession, our professional associations, and advocacy groups think more about whether these children are getting optimum treatment.
- ADHD is common and a lot of children are on ADHD medications.
- Non-pharmacological treatment may be preferred by many parents.
- A combination of medication and psychotherapy is probably best for most patients.
- This was a database study based on insurance claim data for commercially insured children.
- Children and adolescents, up to 17 years of age, were included if a prescription for an ADHD medication had been filled for them and they had been continuously enrolled in an insurance plan during a one year period.
- Individuals with comorbid autism or pervasive development disorder were excluded.
- County level data on supply of licensed psychologists was also obtained.
- Counties with very few children on ADHD medications (generally, smaller and more rural counties) were excluded.
- The primary outcome was the receipt of at least one outpatient psychotherapy visit (individual, group, or family) in that year, identified using current procedural terminology codes.
- In addition, the authors also looked at receipt of four or more therapy visits and at eight or more therapy visits.
- Statistical adjustments were made for age, sex, and the presence of comorbid psychiatric conditions.
- 301,530 children receiving ADHD medication were included in the analyses.
- The mean age was about 12 years and 70% were male.
- 25% of these children at least one psychotherapy visit in the same year that they had filled a prescription for an ADHD medication.
- This percentage variedly greatly from one county to another.
- 13% of children had at least four therapy visits.
- 7% of children had at least eight therapy visits.
- Interestingly, the percentage of children receiving psychotherapy was not closely associated with the number of licensed psychologists in that county.
- Only a quarter of commercially insured children receiving ADHD medication received any psychotherapy.
- In almost 200 counties, less than 10% of children receiving ADHD medication received therapy.
- Medication-only treatment is consistent with guidelines for school-aged children, but it may not be ideal for many patients.
- We need to be thoughtful in “triaging” children and adolescents with ADHD to the appropriate type of therapy. That is, we need to think about which patients with ADHD may be treated with medication alone and which ones must get psychotherapy in addition.
- When psychotherapy is provided, general supportive psychotherapy should not be considered to be adequate. The psychotherapy should be specific to the problems of that child or that family, and must be delivered with enough skill and frequency to have a clear benefit.
Why and for whom should we recommend combination treatment — an antidepressant and cognitive therapy — for major depressive disorder?
Hollon et al. Effect of cognitive therapy with antidepressant medications vs. antidepressants alone on the rate of recovery in major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2014 Oct;71(10):1157-64. PubMed PMID: 25142196
Why is this paper important?
- While we may say that the ideal is to provide all patients with both medication and psychotherapy, this is not realistic. Barriers include availability of well-trained therapists, cost of treatment, patients’ willingness to participate in psychotherapy, etc.
- Therefore, we need more data showing that addition of cognitive therapy is helpful, and about which patients are more likely to benefit from the addition of cognitive therapy.
- Antidepressant medications for the treatment of major depressive disorder have several limitations including limited rates of remission and recovery and low rates of adherence.
- This study aimed to assess the effects of combining cognitive therapy with an antidepressant versus an antidepressant alone in patients with major depressive disorder.
- A randomized, controlled trial was conducted at three universities in the US.
- 452 adult outpatients with chronic or recurrent MDD were recruited.
- Patients were randomly assigned to receive antidepressant medication alone or antidepressant medication along with cognitive therapy.
- Assessment of outcome was done by blinded raters.
- Remission was defined as 4 consecutive weeks with only minimal symptoms.
- Recovery was defined as another 26 weeks without relapse.
- Treatment was continued until recovery or a maximum of 42 months.
- While remission rates were not different between the groups, patients who received the combination of antidepressant medication and cognitive therapy were more likely to recover (73%) than patients who received antidepressant medication alone (63%).
- The benefit of the combined treatment was found in patients whose depression was severe and non-chronic (81% recovered versus 52% of the others).
- Of patients who received combined treatment, fewer patients dropped out (19% vs. 27%).
- In both groups, patients with comorbid Axis II disorders took longer to recover than did patients without comorbid Axis II disorders.
- Patients who received combined treatment had fewer adverse occurrences like hospitalizations; this was found to be because patients on combined treatment less time in major depression.
- Addition of cognitive therapy to antidepressant medication improves rates of recovery compared to treatment with an antidepressant medication alone.
- However, this benefit was limited to patients with severe, non-chronic depression.
- The 10% difference in rates of recovery overall is important. As a general rule of thumb, a difference between any two treatments of 10% or greater is considered clinically relevant.
- However, the difference in rates of recovery are much more impressive in patients who were more severely ill and had non-chronic depression. The 29% difference in rates of recovery is huge! We wish we had more treatments that could lead to a difference in treatment results of that magnitude.
- This difference is even more impressive when we note that the intervention is not being compared to placebo but to active treatment (antidepressant medication alone).
- Reduced hospitalizations! Well, that is some cost savings.
- It should be noted, however, that there was no control condition for the psychotherapy. That is, it was not a comparison between antidepressant medication plus cognitive therapy versus antidepressant medication plus supportive psychotherapy. Patients in the combination treatment were seen more frequently than patients who received antidepressant alone. Therefore, we know that patients in combined treatment did better but this study cannot say whether that benefit is specifically due to cognitive therapy. It may be that the benefit would have been less pronounced if patients in the medication only group were also seen frequently. Or that addition of general supportive psychotherapy may have been just as good.
- We must vigorously ensure that our patients with major depressive disorder, especially those whose depression is severe and/or showing an inadequate response to medication receive psychotherapy in addition to antidepressant medication.
Should patients with prolonged grief disorder receive exposure therapy focusing on memories of the deceased?
Bryant et al. Treating prolonged grief disorder: a randomized clinical trial. JAMA Psychiatry. 2014 Dec 1;71(12):1332-9. PubMed PMID: 25338187.
Why is this paper important?
- Prolonged grief refers to abnormal grief with persistent yearning for the deceased, associated emotional pain, difficulty in accepting the death, a sense of meaninglessness, bitterness about the death, and difficulty in engaging in new activities.
- It is considered to be present if these symptoms have persisted at least six months after the death.
- Prolonged grief occurs in about 10% of persons who are bereaved. That is, it is not a rare condition.
- It has been proposed for inclusion as a distinct diagnosis in the next edition of the International Statistical Classification of Diseases, i.e., the 11th Revision (ICD-11).
- Grief-focused cognitive behavior therapy (CBT) has been shown to be effective in treating prolonged grief disorder.
- Although treatment for prolonged grief disorder has included exposure therapy in the past, it is not clear whether exposure therapy is truly appropriate for this condition.
- This study aimed to compare the efficacy of CBT with exposure therapy to that of CBT alone in patients with prolonged grief disorder.
- A randomized clinical trial was conducted in 80 patients with prolonged grief disorder.
- The patients were attending an outpatient Traumatic Stress Clinic in Australia.
- All patients received ten sessions of group therapy that lasted two hours each and were held once a week.
- The group therapy was based on cognitive behavior therapy principles.
- In addition, all patients received four sessions of individual therapy. For this, they were randomized to receive either exposure therapy for memories of the death or supportive counseling.
- CBT with exposure led to greater improvement than CBT alone.
- At 6 month follow-up, CBT with exposure led to greater reductions in depression, in negative appraisals, and in functional impairment.
- Addition of exposure therapy that promotes emotional processing of memories of the death was helpful in reducing severity of the prolonged grief disorder
- Facilitating emotional responses to the death may promote greater changes in appraisals about the loss, which are, in turn, associated with symptom reduction.
- Promotion of emotional processing techniques in therapies to treat patients with prolonged grief disorder is recommended.
- When seeing patients with prolonged grief, we should watch for an understandable tendency to try to avoid painful memories. We should encourage patients to talk about the deceased person. In particular, we should encourage the patient to talk about those aspects of the death that seem to be causing the most distress.
Do second-generation (atypical) antipsychotics augment selective serotonin reuptake inhibitors in obsessive-compulsive disorder? Any of them or only specific ones?
Veale et al. Atypical antipsychotic augmentation in SSRI treatment refractory obsessive-compulsive disorder: a systematic review and meta-analysis. BMC Psychiatry. 2014 Nov 29;14(1):317. PubMed PMID: 25432131
Why is this paper important?
- Obsessive-Compulsive Disorder (OCD) is a common condition and notoriously tends to have limited response to treatment.
- It is, therefore, crucial for clinicians treating OCD to know about second steps if there is nonresponse to treatment with a selective serotonin reuptake inhibitor (SSRI).
- Second-generation antipsychotics are used more often now than first-generation antipsychotics. It is important to know if they are efficacious for augmenting SSRIs in OCD.
- Antipsychotic augmentation of SSRIs has been recommended by various practice guidelines for use in cases of nonresponse to SSRIs in patients with OCD.
- The authors aimed to systematically review and conduct a meta-analysis on the efficacy of second-generation antipsychotics for this use.
- Randomized, double-blind clinical trials comparing a second-generation antipsychotic to a placebo were included.
- Only studies lasting at least four weeks and in adults were included.
- Only studies in which patients had failed to respond to an SSRI were included.
- A thorough search of multiple sources was conducted in order to not miss any clinical trial that met the inclusion criteria.
- The primary outcome measure in all these studies was the Yale-Brown Obsessive Compulsive Scale (Y-BOCS).
- Patients were included in these studies if they had a Y-BOCS score of 16 or more and had at least one adequate trial of a SSRI or clomipramine for at least eight weeks prior to randomization.
- Fourteen studies met the inclusion criteria: five each with risperidone and quetiapine, and two each with aripiprazole and olanzapine. (Note though that the total number of patients in these fourteen studies combined was only 493!)
- Patients given risperidone were three times more likely to respond than those given placebo.
- The two studies that compared addition of aripiprazole to addition of placebo had only 79 patients in all, but a statistically and clinically significant benefit of aripiprazole augmentation was found.
- Quetiapine titrated up to 400 mg/day was the highest dose of quetiapine used in any of the studies. There was no significant difference between addition of quetiapine or placebo to an SSRI.
- For olanzapine, a total of only 70 patients were treated in the two studies combined. There was no difference between addition of olanzapine versus addition of placebo.
- The authors recommend that augmentation with cognitive behavior therapy (CBT) should be tried first for patients who don’t respond to an SSRI.
- For patients who do not respond to two trials of an SSRI or CBT, low dose risperidone (0.5 mg) or low dose aripiprazole (10 mg/day or less) may be tried.
- Efficacy of this augmentation should be assessed after four weeks. If it is efficacious, a risk-benefit analysis for continuing the treatment is recommended.
- As the authors acknowledge, the quality of the evidence for augmentation treatments in OCD reviewed in this paper is, on the whole, relatively poor.
- However, given how difficult it can be to treat OCD, it is important for us to be aware of antipsychotic augmentation as a reasonable strategy when initial treatment fails.
- It seems possible that other second-generation antipsychotics may not be efficacious for this purpose. It seems best to not use them to augment SSRIs in OCD until and unless future studies demonstrate their efficacy.
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