Issue 105, Jan 2021
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Treatment of generalized anxiety disorder: RCT of yoga vs cognitive behavioral therapy vs stress education

Simon N M et al. JAMA Psychiatry.2020. Aug 12. doi:10.1001/jamapsychiatry.2020.2496 Online ahead of print

PMID:32805013

Background

Generalized anxiety disorder (GAD) is common, impairing, and undertreated. When comorbid with mood disorders, GAD causes them to be hard to treat. Although many patients with GAD seek complementary and alternative interventions, including yoga, data supporting yoga's efficacy or how it compares to first-line treatments are lacking. The aim of this study was to assess whether Kundalini yoga (KY) and cognitive behavioral therapy (CBT) for GAD are each more effective than a control condition (stress education) and whether KY is non-inferior to CBT for the treatment of GAD.

Methods

This was a randomized, 3-arm, controlled, single-blind clinical trial. The participants were recruited from two academic centers starting December 1, 2013, with an assessment ending October 25, 2019. Primary analyses included superiority testing of Kundalini yoga (KY) and CBT vs stress education and noninferiority testing of Kundalini yoga vs CBT.

 Participants were randomized to KY (n = 93), CBT for GAD (n = 90), or stress education (n = 43), which were each delivered to groups of 4 to 6 participants by 2 instructors during twelve 120-minute sessions with 20 minutes of daily homework.

Main outcomes and measures: The primary intention-to-treat outcome was acute GAD response (Clinical Global Impression-Improvement Scale score of much or very much improved) after 12 weeks as assessed by trained independent raters.

Results

Of 538 participants who were evaluated, 226 with a mean age, 33.4 years; 69.9% female with a primary diagnosis of GAD were included in the trial. A total of 155 participants (68.6%) completed the posttreatment assessment. Completion rates did not differ (Kundalini yoga, 60 [64.5%]; CBT, 67 [74.4%]; and stress education, 28 [65.1%]. Response rates were higher in the Kundalini yoga group (54.2%) than in the stress education group (33.0%); the number needed to treat, 4.59. In the CBT group, the response rates were 70.8% compared with 33.0% in the stress education group and the number needed to treat was 2.62. However, the noninferiority test did not find KY to be as effective as CBT.

Conclusions

In this trial, KY was efficacious for GAD, but the results support CBT remaining first-line treatment.

Clinical Commentary

It is great to see a RCT with nonmedication treatments for GAD, a condition where medication has limited long-term efficacy. Both CBT and KY were better than stress education (SE) for managing GAD however, CBT outperformed SE and KY. Stress education is a validated condition for GAD. The findings suggest that CBT is the first-line treatment for GAD. Kundalini yoga, though not as effective as CBT is also effective and may appeal to some patients.

In today's world, many individuals are looking for "natural treatments" and these treatments can be useful recommendations. While selective serotonin reuptake inhibitors and buspirone are medications used for GAD, they have limited efficacy and also have side-effects. Benzodiazepines have addiction potential and hence are not a good choice. The additional benefit of yoga being a group activity, it fosters camaraderie as well as emphasizes a healthy lifestyle, which are all in the patient's interest.

Summary:

In my clinical practice, I have better luck of sending patients for alternative therapies like yoga or meditation than CBT. It is great to see RCT with alternative therapies so as clinicians we can have confidence in alternative therapies also. In my practice, I do recommend yoga and meditation in addition to medications.

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Pharmacological treatments of generalized anxiety disorder: A review and meta-analysis

Slee A. Lancet. 2019 Feb 23;393 (10173):768-777. doi: 10.1016/S0140-6736 (18)31793-8. [Epub 2019 Jan 31]

PMID:30712879

Background

Generalized anxiety disorder (GAD) is associated with substantial dysfunction. Pharmacological treatment is often the first choice for clinicians because of the cost and access to psychological alternatives, but there is a paucity of comparative information for the multiple available medication choices.

Methods

A systematic review and network meta-analysis were performed on randomized trials in adult outpatients with a GAD.  MEDLINE, Web of Science, Cochrane Library, ClinicalTrials.gov, Chinese National Knowledge Infrastructure (CNKI), Wanfang data, [email protected], and commercial pharmaceutical registries were searched. Placebo and active control trials were included. Primary outcomes were efficacy including change in Hamilton Anxiety Scale Score and study discontinuations for any cause.

Results

Studies were published between Jan 1, 1994, and Aug 1, 2017, in which 1992 potential studies were screened. This analysis is based on 89 trials, which included 25 441 patients randomly assigned to 22 different active drugs or placebo. Duloxetine, pregabalin, venlafaxine, and escitalopram were more efficacious than placebo with relatively good acceptability. Mirtazapine, sertraline, fluoxetine, buspirone, and agomelatine were also found to be efficacious and well-tolerated but these findings were limited by small sample sizes. Quetiapine had the largest effect on HAM-A but it was poorly tolerated compared to placebo. Likewise, paroxetine and benzodiazepines were effective but also poorly tolerated compared with placebo. The risk of reporting bias was considered low.

Conclusions

There are several effective treatment choices for generalized anxiety disorder across classes of medications. The failure of initial pharmacological therapy might not be a reason to abandon a pharmacological treatment strategy.

Clinical Commentary

GAD has a lifetime prevalence of 5.7% with a higher prevalence in those over 65 years of age. This ailment may cause significant impairment in daily physical, psychological, and social functioning. The diagnosis of this disorder is often missed as the patient may not complain of specific symptoms. When treating individuals with a major psychiatric illness such as major depression and bipolar disorder we may miss the comorbid GAD resulting in a therapeutic impasse. This is one of the largest contemporary studies of GAD treatment. It included trials across a broad range of settings. Sixteen trials were published in Chinese and provided direct evidence for several comparisons that would not be available otherwise. This network meta-analysis assumes that the trials are similar. The exclusion of the Chinese trials did not make a difference in the findings.

A network meta-analysis is an extension of a pairwise meta-analysis which facilitates comparisons of multiple interventions that have not been studied in a head-to-head fashion.

Duloxetine, pregabalin, venlafaxine, and escitalopram were more efficacious than placebo based on a large sample size. Mirtazapine, sertraline, fluoxetine, buspirone, and agomelatine were also effective but the information was based on a smaller sample. This meta-analysis strengthens the case for using SSRIs and SNRIs for treating GAD. Benzodiazepines, due to their addiction potential and implications with alcohol and opiates should be avoided.

Quetiapine proved highly effective however, the side-effects such as sedation, tiredness, and the risk of tardive dyskinesia limit its use.

Please also consider the FDA indications while making a choice. Please note that pregabalin does not have any FDA indications for the treatment of psychiatric disorders.

This study strengthens the clinical basis for the use of duloxetine, venlafaxine, escitalopram, and pregabalin (not FDA approved in mental illness) as first-line choices for GAD treatment. Sertraline, fluoxetine, and buspirone are also first-line choices but the data was limited by small sample sizes. Vortioxetine and vilazodone are not effective for GAD. Mirtazapine has only been studied in China and has a risk of weight gain.

Speed: Buspirone and hydroxyzine are faster acting than most drugs in this analysis with reasonable effects.

Benzodiazepines get pushed to the back for the known reasons.

Summary:

In my opinion, we should use the GAD-7 scale to screen for anxiety routinely especially at the   initial evaluations. I would use the SSRIs first line followed by duloxetine. I would not give up on buspirone and would avoid hydroxyzine in older adults (anticholinergic effects). If patients have comorbid bipolar illness, I would try to avoid venlafaxine to avoid precipitating a manic episode. I would avoid the use of benzodiazepines except for emergencies. I always like to combine medication treatment with CBT or alternative treatments such as meditation or yoga.

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Generalized anxiety disorder in adolescents: RCT of escitalopram

Strawn JR et al. Jlin Psychiatry 2020 Aug 25; 81 (5):20m13396 doi: 10.4088/JCP.20m13396.

PMID:32857933

Background

Selective serotonin reuptake inhibitors (SSRIs) are commonly used to treat pediatric anxiety disorders, including generalized anxiety disorder (GAD). Their efficacy and tolerability are difficult to predict. This study evaluated the efficacy and tolerability of escitalopram in adolescents with GAD (DSM-IV-TR) and the impact of variants in HTR2A and serotonin transporter (SLC6A4) genes and cytochrome P450 2C19 (CYP2C19) phenotypes on the response as well as CYP2C19 phenotype on escitalopram pharmacokinetics.

Methods

Patients were treated with escitalopram (forced titration to 15 mg/d, then flexible titration to 20 mg/d) (n = 26, mean age 14.8 years) or placebo (n = 25, mean age14.9 years) for eight weeks. Outcomes were the change in scores on the Pediatric Anxiety Rating Scale (PARS) and Clinical Global Impressions (CGI) scales as well as vital signs and adverse events. Plasma escitalopram and desmethylcitalopram area under the curve during 24 hours (AUCO-24) and maximum concentration (Cmax) were determined and compared across CYP2C19 phenotypes.

Results

Escitalopram was superior to placebo for baseline-to-endpoint change in PARS and CGI scores, and increasing CYP2C19 metabolism was associated with decreases in escitalopram Cmax. Vital signs corrected QT interval, and adverse events were similar in patients who received escitalopram and placebo.

Conclusions

Escitalopram reduces anxiety symptoms and pharmacogenetics variables influence the trajectory and magnitude of improvement. Variation in CYP2C19 metabolism accounts for significant differences in escitalopram pharmacokinetics, raising the possibility that CYP2C19 phenotype should be considered when prescribing escitalopram.

Clinical Commentary

This is the first double-blind RCT of escitalopram in the treatment of pediatric patients with GAD. This study also suggests the potential predictive utility of pharmacogenetic markers of treatment response. This trial also links escitalopram pharmacokinetics with CYP2C19 metabolizer status and side-effects.

These findings are important as 40% of youth either do not respond to the pharmacological treatments of GAD or experience treatment-limiting side-effects.

This trial also had a low placebo response rate (24%).

Predictors of response to escitalopram: Response was predicted by intermediate CYP2C19 metabolizer status, having at least one long allele of SLC6A4, and having a G/G diplotype for HTR2A rs6311 allele.

Side-effects such as activation were associated with Cmax and AUC suggesting increased exposure leading to greater side-effects. This has also been noted with fluoxetine and fluvoxamine.

Ethnic differences: The "hypermetabolic" *17 allele is twice as common in African American (19%) and US white individuals (18%) compared to Hispanic individuals which can account for differences in efficacy and tolerability.

  

Summary:

In my opinion escitalopram, 15 to 20 mg has support for treating pediatric GAD. The pharmacogenetic status of the patient may influence the efficacy as well as the tolerability. Larger studies are needed to support the pharmacogenetic findings.

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Longitudinal course of pregnancy-related anxiety in parous and nulliparous women and association with social and generalized anxiety

Mudra S. et al.  J Affect Disord. Jan 1 2019; 260:(8): 111-118. doi:10.1016/j.jad.2019.08.033.[Epub 2019 Aug 19]

PMID 31494362

Background

There is evidence that pregnancy-related anxiety (PrA) has a negative impact on birth outcomes and infant development. However, little is known about the association of PrA with symptoms of social phobia (SP) and generalized anxiety disorder (GAD).

Methods

This German study assessed pregnant women (N=180) three times during pregnancy with the Pregnancy-Related Anxiety Questionnaire-Revised 2 (PRAQ-R2). Women 18 years and older pregnant in their 12-14th gestational week with a singleton child were included. The surveys were conducted 12th-14th (T0), 24th-26th week (T1) and 34th-36th as (T2) weeks of pregnancy   Those not speaking German were excluded. Statistical analyses were used to investigate the course of different PrA dimensions across pregnancy, and to relate PrA to symptoms of social and generalized anxiety.

Results

In this sample, 54% of the women were expecting their first child. A high percentage of the women were well educated with an average to high income.  PrA total score remained stable, but the different dimensions of PrA varied significantly over time. After controlling for obstetric and sociodemographic factors as well as depression, perceived social support, and self-efficacy, symptoms of SP significantly predicted higher levels of fear of childbirth, child-related worries, and concerns about mother´s appearance. Symptoms of GAD predicted higher child-related worries. Moreover, two distinct groups of women with either consistently higher or lower PrA scores were identified.

Conclusions

This study suggests that a longitudinal and differentiated investigation of specific forms of prenatal anxiety may improve our understanding of women at high risk for PrA and promote the development of individualized forms of interventions initiated during pregnancy.

Clinical Commentary

It is known that pregnancy is a time of uncertainty and there are often feelings of distress. Symptoms of anxiety occur in 27% of pregnancies. High levels of prenatal anxiety can negatively impact the health of mothers and children. The population-based study design is a strength of this sample along with a longitudinal assessment of the PrA. Limitations included a self-report questionnaire and a small sample size. This sample had a high educational level and was homogeneous regarding relationship status and socioeconomic background which could limit the generalizability of the results.

Some of the salient findings were significantly decreased child-related worries across pregnancy. This is related to the growing confidence of the mother as well as visualization of the baby with repeated ultrasounds as well as increasing recognition of the baby moving within.

Concerns about appearance decreased across pregnancy as there was a normal adaptation to bodily changes as the pregnancy progressed.

The other important finding was counterintuitive: SP symptoms indicate a significant association with all dimensions of PrA while GAD was only associated with worries of having a physically or mentally handicapped child (WaHC). Childbirth seemed to result in less fear if the expecting mother has a supportive network around her. Parity was a protective factor for birth and child-related fears.

The results suggest paying attention to anxiety disorders in the context of pregnancy.

Summary

I did not look at anxiety issues related to pregnancy in the way this study has helped me realize. This is especially important for social phobia. These individuals may benefit from therapy that is focused once pregnancy is diagnosed.  Questions for screening for SP to ask are below (Anxiety and depression association of America (ADAA):

https://adaa.org/screening-social-anxiety-disorder

  • Intense and persistent fear of a social situation in which people might judge you
  • Fear that you will be humiliated by your actions
  • Fear that people will notice that you are blushing, sweating, trembling, or showing other signs of anxiety
  • Knowing that your fear is excessive or unreasonable

I suggest the use of the generalized anxiety disorder questionnaire (GAD-7)  as a screen for generalized anxiety so psychotherapeutic options can be tailored.

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Prazosin for PTSD: Negative study in military veterans

Raskind MA et al. N Engl J Med. 2018 Feb 8; 378 (6):507-517. doi: 10.1056/NEJMMoa1507598.  [Online ahead of print]

PMID 29414272.

Background

In randomized trials, prazosin, an α1-adrenoreceptor antagonist, has been effective in alleviating nightmares associated with post-traumatic stress disorder (PTSD) in military veterans. This is a large multi-center study conducted to assess the efficacy of prazosin versus placebo for treating nightmares associated with PTSD.

Methods

Veterans from 13 Department of Veterans Affairs medical centers who had chronic PTSD and reported frequent nightmares were recruited for this study. Participants were randomly assigned to receive prazosin or placebo for 26 weeks; the drug or placebo was administered in escalating divided doses over 5 weeks to a daily maximum of 20 mg in men and 12 mg in women. After week 10, participants continued to receive prazosin or placebo in a double-blind fashion for an additional 16 weeks. The three primary outcome measures were the change in score from baseline to 10 weeks on the Clinician-Administered PTSD Scale (CAPS) item B2 ("recurrent distressing dreams"; scores range from 0 to 8, with higher scores indicating more frequent and more distressing dreams); the change in score from baseline to 10 weeks on the Pittsburgh Sleep Quality Index (PSQI; scores range from 0 to 21, with higher scores indicating worse sleep quality); and the Clinical Global Impression of Change (CGIC) score at 10 weeks (scores range from 1 to 7, with lower scores indicating greater improvement and a score of 4 indicating no change).

Results

A total of 304 participants underwent randomization; 152 were assigned to prazosin, and 152 to placebo. At 10 weeks, there were no significant differences between the prazosin group and the placebo group in the mean change from baseline in the CAPS item B2 score, in the mean change in PSQI score, or the CGIC score. There were no significant differences in these measures at 26 weeks (a secondary outcome) or in other secondary outcomes. At 10 weeks, the mean difference between the prazosin group and the placebo group in the change from baseline in supine systolic blood pressure was a decrease of 6.7 mm Hg. The adverse event of new or worsening suicidal ideation occurred in 8% of the participants assigned to prazosin versus 15% of those assigned to placebo.

Conclusions

In this large trial prazosin did not alleviate distressing dreams or improve sleep quality.

Clinical Commentary

What a surprise for us clinicians who regularly use prazosin for PTSD associated nightmares for both veterans as well as civilians. Prazosin is not FDA approved but has been considered a well-established off-label treatment for nightmares and PTSD symptoms by clinicians. Multiple previous studies and meta-analyses suggest that prazosin helps relieve symptoms of PTSD related to hyperarousal and nightmares. The issues are that this large VAMC study had a sample size equivalent to a combination of all previous studies (https://simpleandpractical.com). This study has led to a change in guidelines from the VA and DOD and the American Academy of sleep medicine. This created confusion in the field.

Subsequently, two additional meta-analyses have been published which have included the 2018 VA negative study we are discussing in this review (Reist et al., 2020; Zhang et al., 2020). Both revealed that prazosin works for nightmares but differed regarding the other PTSD symptoms https://simpleandpractical.com.

Mechanism: Hyperarousal is related to increased noradrenergic signaling responsible for PTSD pathophysiology. Hence an alpha 1 blocker is thought to be effective. So, the question is which subset of patients would respond to prazosin?

Based on the studies those with elevated blood pressure and pulse for the patient's age, and level of fitness, as well as those waking up distressed from trauma-related nightmares along with hypervigilance, tachycardia, and sweating may be more likely to respond.

This large trial used a maximum prazosin dose of 20 mg in males as well as 12 mg in females.

In Summary:

This study produced a controversy regarding the use of prazosin. It is a classic example of how clinicians, myself included, find a treatment effective but a large RCT is negative. I would still consider using prazosin as before as this study is related only to military veterans. Two subsequent meta-analyses found prazosin to be effective. In my practice, I have not used such high doses as in this trial, but now I would push up the dosage with BP and pulse monitoring. The patient needs to know the off-label nature of the use of prazosin.

Tip: When doing the eprescription I add off-label use in the communication box for the pharmacist to be aware.

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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]