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Issue 82, Feb 2019
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Treatment resistant depression (TRD): Addition of intranasal esketamine to antidepressant therapy

Daly EJ et al.  JAMA Psychiatry. 2018 Feb1;75(2): 139-148. doi:10.1001/jamapsychiatry.2017.3739  PMID 29282469

Background

Depression is a widely prevalent illness and one-third of patients with major depressive disorder (MDD) do not respond to currently available antidepressants. This study assessed the efficacy, safety, and dose-response of intranasal esketamine in patients with treatment resistant depression.

Methods

This double-blind, randomized, placebo-controlled study (N=126) was conducted at multiple sites between January 2014 and September 2015. The sample included patients with DSM-IV-TR diagnosis of MDD with inadequate response to 2 or more antidepressants. The study consisted of 4 phases. (1) screening, (2) double-blind treatment (days 1-15), (3) optional open-label treatment (days 15-74), and (4) posttreatment follow up (8 weeks). 67 patients were randomized and 60 completed the study. The participants were randomized (3:1:1:1) to placebo (n=33), esketamine 28 mg (N=11), 56 mg (N=11), or 84 mg (N=12) twice weekly in period 1. In the 2nd period, 28 placebo-treated participants with moderate to severe symptoms were rerandomized (1:1:1:1) to one of the 4 treatment arms; those with mild symptoms continued receiving placebo. The participants continued their antidepressant medication during the study.  The primary efficacy endpoint was change from baseline in the Montgomery-Asberg Depression rating scale (MADRS) total score.

Results

In all 3 esketamine groups there was a significant difference between drug and placebo. There was a significant ascending dose response relationship. Three of the participants in the 56 mg group (5%) during the double-blind phase and 1 of the 57 participants in the open-label phase had adverse events (syncope, headache, dissociative syndrome, and ectopic pregnancy).

Conclusions

In this first study of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. The response persisted for 2 months with lower dosing frequency. Results support further investigation in larger trials. 

Clinical Commentary

This is really good 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 approval would lead to coverage from insurance plans.

  • Inhaled esketamine once available and covered by insurance plans would take the treatment of TRD to a different level. It would be more user friendly and easier to administer in the office setting. This study had a high completion rate
  • This study tested three doses with an ascending dose relationship. Having a range of dosing options is extremely helpful.
  • Intranasal ketamine used emergently in clinics for suicidal patients may reduce emergency room visits. Additionally, used in emergency rooms may avoid hospitalizations.
  • 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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Prazosin: Off-Label uses other than PTSD associated nightmares!

Simpson TL et al.  Am J Psychiatry. 2018; 175:1216-1224; doi.10. 1176/appi.ajp.2018.17080913.  PMID: 30153753

Background

Prazosin (α-1 adrenoceptor antagonist) an antihypertensive medication, is now commonly used off-label to treat nightmares related to Post Traumatic Stress Disorder (PTSD). This study investigated the use of prazosin in alcohol use disorder (AUD), another condition involving elevated brain noradrenergic activity.

Methods

This was a double-blind randomized 12-week clinical trial (N=92) in which patients with a DSM-IV diagnosis of PTSD were excluded. The subjects met the DSM-IV criteria for alcohol dependence. The patients were randomized to placebo or prazosin dose of 4 mg in the morning, 4 mg in the afternoon, and 8 mg at bedtime (total prazosin dose 16 mg/day). The titration was completed by the end of week two. Daily alcohol consumption was monitored. The impact of prazosin was compared with placebo on the number of drinks per week, number of drinking days per week, and the number of heavy drinking days per week.

Results

The study was completed by eighty participants. There was a significant reduction in the number of drinks and number of heavy drinking days. The rate of drinking and the probability of heavy drinking was significantly decreased in the prazosin group over the placebo group. The participants in the prazosin group were more likely to report drowsiness and edema.

Conclusions

Prazosin holds promise as a pharmacologic treatment for alcohol use disorder.

Clinical Commentary

 Alcohol use disorder is a major public health problem and has a chronic relapsing nature. It is also comorbid with many psychiatric disorders, complicating their treatment. I have had good results using prazosin for PTSD related nightmares and this is another welcome use of prazosin based on this study. Replication studies in large samples are needed.

  • The FDA has approved treatments for alcohol use disorder such as naltrexone, disulfiram, and acamprosate, which have modest efficacy and low clinical utilization. Hence, the urgent need to find other effective treatments.
  • Naltrexone targets chronic alcohol-related brain opioid dysregulation. There is evidence to suggest that there is alcohol related brain noradrenergic system dysfunction. This affects stress regulation, arousal, and cognition.
  • Hence prazosin is a worthwhile choice particularly in those with PTSD and AUD.
  • This study dosed prazosin three time a day which affects compliance (prazosin was taken as directed 55% of the time and placebo 70% of the time in the trial). Despite the compliance issue, prazosin was still effective in reducing drinking frequency and heavy drinking.
  • Despite a high dose (16 mg/day) only one case of symptomatic orthostatic hypotension (decrease of 20 mm Hg or higher in systolic blood pressure from sitting to standing) was noted. I would still recommend blood pressure checks while using prazosin.
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Quetiapine safety in pregnancy: Prospective study of malformation risk, including first trimester exposure

Cohen LS et al. Am J Psychiatry. 2018 175:1225-1231; doi: 10.1176/appi.ajp.2018. 18010098. PMID:30111186

Background

In the last decade there has been an exponential increase in the use of antipsychotic drugs, including women of child bearing age group. The US Food and Drug Administration (FDA) has shifted the Pregnancy and lactation Labelling Rule from the previous system of category labelling to a more descriptive summary of outcomes of exposure to medications during pregnancy and lactation. Quetiapine has been widely used as monotherapy and in combination with other psychotropics by physicians both psychiatric and non-psychiatric due to its multiple psychiatric indications. It should be noted that approximately 50% of pregnancies are unplanned. This study was done to evaluate the risk of major malformations with quetiapine using a prospective design.

Methods

This research focused on extracting prospective data from The National Pregnancy Registry for Atypical Antipsychotics (NPRAA) at the Massachusetts General Hospital established in 2008. This database includes women ages 18-45 interviewed during pregnancy and the post-partum period. Obstetric, labor and delivery, and medical records from the first 6 months of life were screened for evidence of major malformations. In addition, women with first trimester exposure to quetiapine were compared with control subjects without exposure to second-generation antipsychotics.

Results

As of March 2017, 888 women were enrolled prospectively and 357 were deemed to be eligible for analysis. There were 152 women with first trimester exposure to quetiapine (most of the women were treated with quetiapine for bipolar disorder) compared with 205 controls without exposure to second-generation antipsychotics. There were 155 births in the exposed group (including three sets of twins), two major malformations were confirmed (1.3%), compared with three amongst the 210 infants born (1.8%) in the unexposed group (five sets of twins).

Conclusions

This study suggests that quetiapine is not a major teratogen based on this current database. Additional analyses based on ongoing data collection will be needed in the future.

Clinical Commentary

These results are reassuring as clinicians including myself use quetiapine widely, both as monotherapy and in combination with other psychotropics. The issues are often significant in the first trimester when fetal organogenesis occurs. Often patients come to a medical visit noting they had a positive pregnancy test and had already stopped their medications, not realizing that by this time fetal exposure has already occurred. However, antipsychotics in this case quetiapine, should be evaluated against the risk of exacerbation of psychiatric disease particularly depression and psychosis. Even though women develop psychiatric disorders in adolescence, pregnancy can be a trigger for psychiatric illness

  • Suicide can occur with untreated mental illness as could infanticide in untreated psychosis. Infanticide is a tragedy with an innocent victim, however the untreated perpetrator is often a victim too. Women who commit infanticide may receive a prison sentence in the United States unlike most other western nations.
  • It is often best to sit with both the would be mother as well as the father of the child and have a risk benefit discussion regarding the use of medications and obtain consent. I often ask the couple to consider if the mother was psychologically unstable “would the baby have good vibrations?” The psychiatric notes should be shared with the obstetricians as well as the primary care physicians, as well as other clinicians for care coordination. A phone call to the obstetrician is often the prudent way to proceed. Monthly visits are a suggested, and more frequently, if the situation demands.
  • I think it is important to provide a website and document it in the notes. I provide womensmentalhealth.org.  
  • Sometimes a second opinion from another colleague is helpful in difficult cases.
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Ropinirole augmentation for depression: Does it work?

Gershon AA et al. J Clin Psychopharmacol. 2018 Nov 26; doi: 10.1097/JCP.0000000000000984. [Epub ahead of print] . PMID:30489382

Background

Depression is a common illness which causes significant morbidity and increased risk suicide. Psychiatrists are always on the look out for newer strategies to treat depression. Ropinirole, a D2/D3 agonist, is one such agent used clinically as studies suggest a role of dopaminergic pathways in the treatment of depression. This clinical strategy was tested in a randomized trial pilot study.  

Methods

This was a double-blind, randomized, placebo-controlled trial of add-on ropinirole in depressed patients unresponsive to at least one antidepressant. The small sample included (N=32) unipolar and bipolar patients who remained depressed (21-item Hamilton Depression Rating Scale) after 4 weeks of treatment with an adequate dose of an antidepressant medication. Ropinirole or placebo 2 mg twice daily was added to the antidepressant for 7 weeks with weekly evaluations for depressive symptoms. Two commonly used scales in clinical trials, the Hamilton Depression Rating Scale (HDRS) and Montgomery-Asberg Depression Rating Scale (MADRS) were used for evaluation.

Results

No differences were found between the treatment and control groups.

Conclusions

The authors conclude there may be differences in pharmacological action between ropinirole and other dopaminergic agents such as pramipexole.

Clinical Commentary

In this study ropinirole did not separate from placebo for a mixed sample including patients with unipolar and bipolar depression. In the past both ropinirole and pramipexole have been used successfully to treat depression in other studies.

  • Ropinirole and other D2/D3 agonists have shown efficacy in previous studies when added to antidepressant therapy. Most studies have been conducted with pramipexole. There is dysregulation of opioid neurotransmission in depressed patients. Pramipexole blocks N-methyl-D-aspartate (NMDA) activation which may lead to antidepressant effects. These differences may explain the negative study with ropinirole. Ropinirole has opioid receptor affinity which is lacking with pramipexole.
  • This study also has a small sample and included both unipolar and bipolar patients (unipolar N=21; bipolar N=11) hence having low power. Additionally, this study had a high attrition rate.
  • Despite this being a negative study, I would not give up on ropinirole as this trial has several noted limitations which we should pay attention to when reviewing clinical research. 
  • Bottom line: In the real world it best to use medication strategies that are FDA approved before trying off-label approaches. 
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Postpartum depression and anxiety: Gut brain axis and the human microbiome

Slykerman RF et al. EBioMedicine. 2017 Oct;24: 159-165. : doi: 10.1016/ebiom.2017.09.013.EPub 2017 Sep14. PMID 28943228

Background

Postpartum depression (PPD) occurs in about 10-15% of women in the western world. This disorder is associated with significant morbidity for the mother and the newborn. It affects the ability of the mother to take care of the child and may also interfere with mother child bonding. PPD can also result in death by suicide. Most patients want to avoid psychotropic medications in pregnancy and the postpartum period. The gut brain axis has been thought to have a significant relationship with the brain and mood symptoms. Probiotics have been thought to have a role in the prevention of postpartum depression and anxiety, which has been explored by this study.

Methods

The aim of this study was to evaluate the effect of Lactobacillus rhamnoses HN001 (HN001) given in pregnancy and postpartum period on symptoms of depression and anxiety. The was a double-blind, randomized, placebo-controlled trial (N=423) conducted in New Zealand. The women recruited in the trial were at 14-16 weeks of gestation. The participants received either placebo or HN001 from enrollment till 6 months postpartum if breast feeding. The Edinburgh Postnatal Depression Scale and State Trait Anxiety Inventory were used to assess symptoms of depression and anxiety.

Results

380 women (89.9%) completed the questionnaires. This included 193 women (91%) in the placebo group and 187 (88.6%) in the treatment group. Mothers in the treatment group had significantly lower depression and anxiety scores.

Conclusions

Women who received HN001 had significantly lower depression and anxiety scores in the postpartum period. This probiotic may be useful for the prevention and treatment of depression and anxiety in the postpartum period.

Clinical Commentary

Pregnancy and postpartum period are a time when most individuals want to avoid medications not realizing that having depression and anxiety impairs their functioning as a new mother. The risk benefit analysis often is not heeded to by the patient. This is the first such study in a large sample with a double-blind placebo-controlled design that shows the probiotic HN001 to be beneficial compared with placebo. Complementary and alternative medication (CAM) is now very popular.

  • The microbiome is a complex microbial ecosystem containing some 100 trillion microorganisms. It functions to establish the intestinal lining and aids in its maintenance. It is influenced by several factors including genetics, age, sex, diet, and stress. There is evidence that there is a bidirectional relationship between the microbiome and emotional behavior (gut-brain axis).
  • Nutritional psychiatry is an emerging field exploring the relationship between dietary factors and mental health problems. Diet has become a compelling candidate in regulating mental health.
  • The mechanism of action of probiotics in mental disorders such as depression is via reduction of inflammation, increasing (BDNF) Brain Derived Neurotrophic factor (reduced in depression) and increasing serotonin neurotransmission. BDNF is like fertilizer for the brain. Probiotics have been shown to possess antioxidant and free radical scavenging abilities (reduces inflammation). Inflammatory markers such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFα) are known to be elevated in depression.
  • Probiotics are available, however, their use in PPD is off-label. The dose varies with the strain and the duration of treatment is not clearly known. The current research applies to the HN001 which has been tested in a randomized blinded study and may be used clinically. HN001 is to be administered up to 6 months postpartum.
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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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