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Issue 83, Mar 2019
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The addition of mirtazapine to SSRI/SNRI for treatment resistant depression (TRD): What does the research suggest?

Kessler D et al. Heath Technol Assess 2018 Nov;22(63):1-136. Doi:10.3310/hta22630  PMID: 30468145

Background

Depression is one of the leading illnesses resulting in significant global morbidity. There remains an unmet need to develop treatments for TRD. In clinical practice the addition of mirtazapine to SSRI/SNRI is a commonly used strategy. This study focused on patient outcomes using the addition of mirtazapine to SNRI/SSRI for TRD.

Methods

This was a double-blind randomized controlled trial (N=480) conducted in the United Kingdom. Eligible participants were taking an SSRI or SNRI for at least 6 weeks and remained depressed. The Beck depression inventory-II (BDI-II) was used to measure outcomes. The study participants remained on the SSRI/SNRI and were randomized to mirtazapine 30 mg daily(started at 15 mg daily for 2 weeks and then increased to 30 mg) or placebo in a blinded fashion for 12 months duration. The primary outcome measurement of depressive symptoms was done using the BDI-II) The study also assessed for adverse events.

Results

431 participants (89.8%) were followed at 12 weeks. The BDI-II score declined in the mirtazapine group, however, the decline was not statistically significant compared with the placebo group. More participants withdrew in the mirtazapine group (N=46) compared with the placebo group (N=9) due to mild adverse events.

Conclusions

This was a negative study finding no benefit with addition of mirtazapine to SSRIs/SNRIs compared to placebo. 

Clinical Commentary

TRD remains a tough ailment to treat. Although the addition of mirtazapine is used commonly in clinical practice, this study does not suggest it to be efficacious as an augmenting agent for TRD.

  • There remains a need to develop new treatments to combat TRD.
  • Limitations: This study included voluntary unblinding at 12 weeks which made the interpretation of longer-term outcomes more difficult. In this study the researchers aimed to conduct face to face assessments at 12, 24, and 52 weeks. If face to face was not possible assessments were conducted over the phone. Assessments done over the phone may have been a limiting factor affecting results.
  • TRD remains an area of research to develop more effective treatments. Augmentation with atypical antipsychotics and the use of Transcranial Magnetic (TMS) stimulation (increased access now) are FDA approved treatments.
  • Intravenous ketamine has robust data for treating TRD but is not FDA approved. Intranasal esketamine is also being developed for TRD and is currently under review by the FDA.
  • Electroconvulsive therapy (ECT) remains a highly effective FDA approved treatment for TRD.
  • Tricyclic antidepressants and monoamine oxidase inhibitors are underutilized effective treatments. A generation of psychiatrists have been trained without utilizing these medications.
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Transcranial Magnetic Stimulation: Role in treatment-resistant depression (TRD): Results of a large US Veterans study.

Yesavage JA et al. JAMA Psychiatry. 2018 Sep1;75(9):884-893; doi: 10.1001/jama psychiatry. 2018.1483 . PMID:29955803

Background

Major depression remains a leading cause of morbidity. Suicide rates have also increased significantly in the last few years. Medication therapies have limited efficacy and a significant side-effect burden. Electroconvulsive therapy (ECT) is limited by the need for general anesthesia and as well as cognitive impairment. The FDA approved rTMS for the treatment of major depression in 2008. This large US Veterans study assessed rTMS for treatment resistant depression.

Methods

This was a large US Veterans study (N=164) conducted across 9 Veterans Affairs Medical Centers (VAMC). It was a sham-controlled double-blind randomized clinical trial conducted from September 2012 to December 2016. All participants received either left prefrontal rTMS treatment (10 Hz, 120% motor threshold, 4000 pulses/session) or sham (control) for up to 30 treatment sessions. The remission rate (Hamilton Rating Scale for Depression score < 10) was the primary outcome measure. A secondary analysis was conducted on other indices of posttraumatic stress disorder, depression, hopelessness, suicidality, and quality of life.

Results

The sample included 132 (80.5%) men and 126 (76.8%) were Caucasian. Sham rTMS was received by 83 participants and 83 received active rTMS. The primary analysis did not reveal any significant effect of treatment. In the active treatment group 33 of the 81 (40.7%) patients achieved remission compared with 31 of the 83 (37.4%) in the control group. Overall 64 of the 164 participants achieved remission. The results did not show statistical significance in the active group compared to the control group.

Conclusions

This was a negative study finding no difference between sham and active rTMS treatments.

Clinical Commentary

rTMS is a noninvasive procedure that uses magnetic fields to stimulate nerve cells in the brain. It is currently FDA approved for depression.  We need to continue developing new strategies for patients with TRD. This treatment is covered by Medicare and a limited number of commercial insurances. There is a need for prior authorizations. 

  • This study suggests that there is a high placebo response rate which questions the trial design and interrater reliability (not mentioned in the study). Depression studies are known to be associated with a high placebo response rate.
  • In reviewing this study, patients who did not have comorbid PTSD had a better response to rTMS.
  • rTMS has significant limitations. This may be a treatment for the mildly treatment resistant patient, one who has perhaps failed a trial of a couple of antidepressants. However, patients in this study had failed at least two antidepressants.
  • The clinician should be aware of the fact that the TMS equipment manufacturers are promoting this therapy in a big way, and psychiatrists need to do due diligence and evaluate claims made as part of the sales pitch.  
  • The population in this study had multiple comorbidities including history of substance abuse. rTMS protocols have also undergone many changes since this study was planned suggesting that the procedure may be more efficacious now.
  • TMS can still be used as a viable strategy for the civilian TRD patient. Patients in the VAMC have a higher rate of substance abuse disorder as well as PTSD. These factors suggest reduced efficacy of rTMS in this study.
  • Committing to 30 sessions can be difficult for patients.
  • FDA approval of intranasal esketamine may result in rTMS becoming obsolete.
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L-Methylfolate augmentation of Methylphenidate in ADHD: Does it work?

Surman C. et al. J Clin Psychopharmacol. 2019 Jan/Feb; 39(1):28-38. doi: 10.1097/JCP.0000000000000990. [Epub ahead of print] . PMID:30566416

Background

Attention-deficit/hyperactivity disorder (ADHD) treatment consists of medication therapy as well as behavioral interventions.  The response often reaches a plateau and patients feel they are only partially better. There is evidence of L-methylfolate augmenting antidepressants for treatment of depression. This study examined the role of L-methylfolate in augmenting methylphenidate partial responders in the treatment of ADHD.    

Methods

This study included N=44 adults with DSM-5 diagnosis of ADHD in a 12-week randomized, double-blind, placebo-controlled trial.  The participants received methylphenidate in combination with either 15 mg of L-methylfolate or placebo in a double-blind fashion. The investigators evaluated the effects on ADHD symptoms using a number of measures. These included the Behavioral Rating Inventory of Executive Function, Adult ADHD Self-report scale, methylphenidate dosing, emotional dysregulation, social adjustment, work productivity, autoantibodies to folate receptors, select genetic polymorphisms, as well as moderating effects of body mass index.

Results

No statistically significant differences were found in the L-Methylfolate group over the placebo group. L-Methylfolate was well tolerated and this group needed a significantly higher dose of Methylphenidate over time. Exploratory analyses suggested a variation in a guanosine triphosphate cyclohydrolase gene predicted a need for a higher dose of methylphenidate.

Conclusions

This study suggests that there is no additional value to adding L-Methylfolate to methylphenidate for treating ADHD. On the contrary, Methylphenidate efficacy is reduced when L-Methylfolate is added. This results in the need for a higher dosage of methylphenidate.

Clinical Commentary

L-Methylfolate has beneficial effects as an augmenting agent for antidepressants in a dose of 15 mg daily. Its effects occur in 2-4 weeks or it can be stopped as longer duration of therapy does not produce results. L-Methylfolate does not augment methylphenidate for ADHD. It reduces efficacy exposing the patient to a higher dose and hence side-effects.   

  • This is a negative study and is extremely important from the clinician’s perspective.
  • Complementary and alternative medicine (CAM) has become extremely popular. There is an increasing awareness of ADHD, as well as people seeking treatment. L-Methylfolate is a nutraceutical and hence considered harmless by many.
  • I would like to highlight that patients with mood disorders have persistent concentration impairment despite the mood disorder (bipolar/unipolar depression) being in remission. These patients often think they have ADHD and begin to seek stimulants. This group may be hard to exclude in studies and may be a limiting factor.
  • This study also has a small sample size once we look at exclusions and drop outs. 
  • Bottom line: L-Methylfolate augmentation is not ready for prime time in the clinical world. Even though a nutraceutical and considered harmless, it is a problematic as it increases the dose needed of methylphenidate, which was statistically significant compared with the placebo group. Increasing the methylphenidate dose leads to greater exposure to side-effects (Tourette syndrome, arrhythmias, and other cardiovascular events to name a few)
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Patients at imminent risk for suicide: Intranasal Esketamine?

Canuso CM et al.  Am J Psychiatry 2018 Jul1;175(7): 620-630. doi:10.1176/appi. ajp2018.17060720  PMID 29656663

Background

Depression is a widely prevalent illness and one-third of patients with major depressive disorder (MDD) do not respond to currently available antidepressants. Suicide is a major public health problem. This study assessed the efficacy and safety of intranasal esketamine in patients with major depression, including those at risk for suicide.

Methods

This double-blind, randomized, placebo-controlled study (N=68) involved participants receiving esketamine (84 mg) or placebo twice weekly for 4 weeks in addition to standard comprehensive treatment.  The primary efficacy endpoint was change in score from baseline to 4 hours after initial esketamine dose on the Montgomery-Asberg Depression rating scale (MADRS) total score. Clinician global judgement of suicide risk (from Suicide Ideation and Behavior Assessment Tool) was also assessed. Secondary endpoints included these measures at 24 hours and double-blind endpoint at day 25. This sample included severely depressed patients with suicidal ideation.

Results

The esketamine group had a statistically greater improvement in MADRS score compared with placebo at 4 hours and 24 hours but not at day 25. The MADRS suicidal thoughts item was improved significantly at 4 hours but not at 24 hours or day 25. Between group reductions in clinician global judgement of suicide risk scores were not significant at any time point. Common adverse events in the esketamine group were nausea, dizziness, dissociation, unpleasant taste, and headache.

Conclusions

This study indicates that intranasal esketamine given in addition to standard treatment may result in rapid reduction in depressive symptoms and some measures of suicidal ideation in patients at imminent suicide risk.  

Clinical Commentary

This is one of the earliest proof of concept studies in which a single 84 mg dose of inhaled esketamine was tested. Last month in this newsletter we reviewed a study which had tested the 28 mg, 56 mg, and 84 mg doses noting all to be efficacious, suggesting increasing response with dose escalation (GMERR Feb 2019). This is excellent news for both patients and providers. Intravenous ketamine infusions are currently being offered at various sites around the country, but are costly, not covered by insurance, and not FDA approved. There is a high likelihood of esketamine being approved by the FDA for depression and access will be easier for patients. FDA Advisory Panel recommended approval for TRD on 2/19/19. Final approval by FDA is expected in March 2019. FDA approval would lead to coverage from insurance plans. The side-effects are mild and manageable.

  • Inhaled esketamine once covered by insurance plans would take the management of treatment resistant depression (TRD) to another level. It would be user friendly and easier to administer in the office setting. The patients in this study were severely depressed with suicidal ideation.
  • This study revealed that esketamine has a rapid response with significant reduction in depression and suicidal ideation occurring rapidly but effects are not long lasting. This suggests that esketamine can be used for rapid reduction in symptoms, however a long-term comprehensive treatment plan including psychotherapy is needed, for which esketamine is not a substitute.
  • It is probably a first for psychiatry to have a medication that acts rapidly akin to medication for lowering high blood pressure and sugar rapidly.
  • We could possibly speculate that esketamine rapidly reduces “brain pressure” 
  • Intranasal ketamine used emergently in clinics for suicidal patients may reduce emergency room visits. Esketamine use in emergency room setting may avoid hospitalizations.
  • There is no long-term data as yet, for suicidal ideation.
  • Many patients with TRD may have comorbid drug and alcohol issues which may be a limitation to the use of esketamine.
  • Please note this drug has abuse potential.
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Autism spectrum disorder treatment: Does the diuretic bumetanide make a clinical difference?

James BJ, et al. Ann Pharmacother. 2018 Dec 2 160028018817304. :doi: 10. 1177/1060028018817304. [Epub ahead of print]  PMID 30501497

Background

Autism spectrum disorder (ASD) is being diagnosed increasingly, eight times more common in males than females. When it afflicts females, the symptoms are more profound and disability has greater severity.  ASD is characterized by restricted interests and deficits in social communication and interaction.

The cause is unclear but suspicions have ranged from genetic to environmental factors, including vaccinations (which has been debunked). Parents not getting children vaccinated has resulted in measles outbreaks around the country. Parents have desperately tried therapies ranging from gluten and casein free diets, chelation therapy, IVIG, as well as other behavior therapies. Applied behavior analyses (ABA) has been found to be beneficial but the efficacy is limited. Hence there is a huge unmet need to develop treatments that have a positive impact on outcome. There is no FDA approved clearly beneficial treatment. Antipsychotics such as risperidone and aripiprazole are FDA approved for aggression and agitation. Clinicians often struggle with these patients as they impact the entire family unit. In the case of milder cases of ASD early intervention is the key. In this this study oral bumetanide was studied for treatment of ASD.

Methods

This study reviewed human randomized controlled trials. The sample consisted of N=208 subjects, 2-18 years old with ASD. The oral bumetanide doses were low 0.5 mg bid in most cases (note maximum adult dose is 10 mg/day and the pediatric dose is 0.015-0.1mg/kg maximum of 10 mg/day) The Childhood Autism Rating Scale (CARS) was used to assess improvement in 90 days along with the Clinical Global Impression Scale (CGI). The focus was on key behavior issues such as social communication, interactions, and restricted interests. The studies also assessed bumetanide side-effects and tolerability issues.

Results

One trial had a statistically significant change on the CARS and two trials on the CGI. Behaviors most improved included social communication, interactions, and restricted interests. No dose effect correlation was noted in the dose-ranging trial. Side-effects noted were hypokalemia and polyuria associated with higher doses and resulted in withdrawal rates of 14-43%.

Conclusions

Low-dose oral bumetanide may be useful in patients with moderate to severe ASD. Behavioral therapies should also be tried in addition.

Clinical Commentary

ASD is an extremely distressing disorder for the family and the clinician. It often leads to a divorce due to interpersonal stress. The covered services available are extremely limited. The diagnosis is often missed by the pediatrician resulting in late detection and delayed intervention resulting in critical delays in treatment. Pediatricians often say “boys speak late and will improve with age”. Parents have to fight for services in school and after school the services drop off. There are no FDA approved treatments other than ABA (behavioral therapy with limited effects) resulting in desperation amongst parents often seeking non-standard unproven therapies.

Mechanism of action of Bumetanide: The neurotransmitter GABA plays an important role in the adult nervous system through its inhibitory actions assisting with sensory and cognitive functioning. In the fetus GABA has an excitatory role contributing to normal central nervous system development. Excitatory GABA signaling has been found to persist into adulthood in patients with ASD, chronic pain, brain trauma, epilepsy and other CNS disorders. There is an imbalance in excitatory-inhibitory activity resulting in defects in GABA signaling. Excitatory GABA is associated with high intracellular chloride levels. There is enhanced activity of the Na-K-Cl cotransporter1 leading to increased levels of intracellular chloride resulting in increased neuronal depolarization.

Bumetanide a loop diuretic and may attenuate symptoms of ASD as it is an antagonist of the Na-K-Cl cotransporter 1 reducing intracellular chloride and thus reducing aberrant excitatory GABA signaling.

  •  
  • The use of bumetanide is certainly a step in the right direction. The dose to try would be similar to the one in the study 0.5 mg bid for ninety days while monitoring for adverse events. I will be trying this strategy in my practice after parent/guardian consent.
  • When prescribing this drug for ASD, it is important to discuss the off-label use of bumetanide. I often give a journal reference when using drugs off-label as parents can then get accurate information from “Dr. Google”. It is then a more effective consent process.
  • The patients should be monitored for polyuria and hypokalemia as well as other adverse events.
  • The is no one medication treatment for ASD and hence this trial using bumetanide most importantly offers hope to these patients and their families which is so important for those afflicted with this debilitating condition.
  • References for ASD and treatment issues:

Annals of Clinical Psychiatry VOL 21 NO 3 August 2009 (full issue is on ASD)

Annals of Clinical Psychiatry VOL 21 NO 4 November 2009 (full issue is on ASD)

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Sanjay Gupta, MD
Clinical Professor of Psychiatry, SUNY Buffalo

GME Research Review is a monthly newsletter edited by Sanjay Gupta, MD, Clinical Professor of Psychiatry, SUNY Buffalo. Dr. Gupta 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. Gupta the citation at [email protected]

To contact GME, email us at [email protected]


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