What are the best medications for panic disorder?

 - Jennifer Middleton, MD, MPH

The COVID-19 pandemic is continuing to worsen mental health around the world; early studies from 2020 were already showing an increased prevalence of depression, anxiety, and panic disorder, and studies from 2021 demonstrate continued increasing rates of these mental health disorders. With several Food and Drug Administration (FDA) approved medications for panic disorder currently available in the United States, choosing an initial medication for patients with a new diagnosis can feel overwhelming. A newly published systematic review and network meta-analysis sought to identify the most effective medications for panic disorder and found that sertraline and escitalopram had the best balance of benefit and adverse events.

The systematic review and network meta-analysis examined the literature through June 2021 regarding pharmaceutical options for panic disorder. The researchers looked for randomized controlled trials (RCTs) that included adults aged 18 years and older and cited outcomes related to either benefit (remission rates) and/or harm (including somnolence, gastrointestinal problems, and cognitive impairment). They identified 87 studies with a total of 12,800 participants and followed appropriate systematic review methodology to extract and synthesize the data. Most of the studies compared medication treatment to placebo, so the authors conducted a network meta-analysis to compare outcomes among the various medication classes and medications identified in the systematic review:

Our network meta-analysis identified 11 current drug classes for the treatment of panic disorder, highlighting benzodiazepines, tricyclic antidepressants, and SSRIs as the highest ranked treatments for remission based on SUCRA values. Although benzodiazepines were associated with the lowest probability of dropout, they were also associated with the highest risk of adverse events. Overall, SSRIs provided high benefit (remission) with low risk of adverse events. Across individual SSRIs, sertraline and escitalopram were identified as the most efficacious agents with low risk of adverse events.

The researchers also evaluated included studies for risk of bias, and they noted that "[t]he findings were...based on studies of moderate to very low certainty levels of evidence, mostly as a result of within study bias, inconsistency, and imprecision of the findings reported." Nevertheless, this study's comprehensive and rigorous comparisons may still help guide treatment decisions for patients presenting with panic disorder.

Medications are a useful tool for treating panic disorder, but cognitive behavioral therapy is very effective as well (number needed to treat for complete remission of panic after 3-4 months = 2). Accessing support resources can be beneficial; I included a list of mental health resources developed during the pandemic in this blog post from 2020, and I especially like this one from the World Health Organization that emphasizes the importance of simple self-care habits. 

It's also important to precisely diagnose patients to guide treatment recommendations. This 2015 AFP article on "Diagnosis and Management of Generalized Anxiety Disorder and Panic Disorder in Adults" includes diagnostic criteria for both Generalized Anxiety Disorder and panic disorder along with an overview of treatment options - both pharmaceutical and non-pharmaceutical - to discuss with patients. There's also an AFP By Topic on Anxiety Disorders if you'd like to read more. 

Is COVID-19 vaccination beneficial in persons with past infection?

 - Kenny Lin, MD, MPH

Since the first COVID-19 vaccine received authorization for emergency use in December 2020, physicians and the public have vigorously debated whether infection-acquired ("natural") or vaccine-mediated immunity provides better protection against future infection and severe illness. The answer may never be known for certain, as observational studies are limited by confounding and it's hard to imagine a research ethics committee approving a trial that randomizes one group to intentional exposure to a potentially lethal infection. A more important clinical question is: does getting vaccinated after recovery from COVID-19 provide additional benefits? Currently, the Centers for Disease Control and Prevention recommends routine vaccination in all persons aged 5 years or older, regardless of their history of past infection.

Two large cohort studies published last week provided the strongest evidence to date that the answer is yes. The first study used electronic medical records from a health care organization covering more than half of the population of Israel to identify 149,000 patients age 16 years or older who had recovered from documented SARS-CoV-2 infection at least 100 days earlier and had not yet received COVID-19 vaccination as of March 1, 2021. 56% of these persons received at least one dose of BNT162b2 (Pfizer-BioNTech) vaccine by November 26, 2021. 2,168 of those who remained unvaccinated (3.3%) were reinfected during the study, compared to 354 of the vaccinated patients (0.4%). After adjustment for sociodemographic factors and coexisting illnesses, the estimated vaccine effectiveness was 82% for patients aged 64 years or younger and 60% for patients aged 65 years or older. A secondary analysis showed no difference in protection between one or two vaccine doses.

A second study in a highly vaccinated cohort of 35,768 health care workers in the United Kingdom tracked primary infections and reinfections between December 7, 2020 and September 21, 2021. Most participants received two doses of BNT162b2 (Pfizer-BioNTech) vaccine; 8% received the single-dose ChAdOx1 nCoV-19 vaccine (AstraZeneca). In previously uninfected participants who received the second dose of BNT162b2 six weeks or more after the first dose, adjusted vaccine effectiveness was 85% up to 73 days after the second dose but declined to 51% after 200 days. In comparison, adjusted effectiveness of the ChAdOx1 nCoV-19 vaccine was only 58% up to 73 days. In 6,169 participants who had COVID-19 prior to the study, long-term (>1 year) protection against re-infection was 69% in unvaccinated persons but remained high at 94% in persons who received one or two doses of BNT162b2.

Acknowledging some differences between the populations and the predominant variants circulating during the respective study periods, the results support the following conclusions. First, re-infection in unvaccinated persons is relatively uncommon during the first 9 months after a primary infection (1 in 30 in the Israeli study) but becomes more likely after 1 year (per the U.K. study). Similarly, the effectiveness of the initial two doses of BNT162b2 vaccine in preventing COVID-19 declines after 6-7 months, supporting booster doses. However, patients with past infections who subsequently receive one or two doses of BNT162b2 have sustained high levels of protection ("hybrid immunity") against re-infection for at least one year. In an editorial in The Guardian, Dr. Eric Topol recently argued that these and other data support re-defining "fully vaccinated" to include recovery from past infection plus a single dose of an mRNA vaccine.

COVID-19 vaccination in pregnancy may protect infants

 Jennifer Middleton, MD, MPH

COVID-19 vaccination is safe and beneficial in pregnant persons, a group that is especially vulnerable to complications from COVID-19 infection. Emerging research now suggests that these protections may extend to infants through at least the first 6 months of life. Building on earlier studies that demonstrated COVID-19 antibody transmission from mother to infant in utero and in breastmilk, a small study found antibodies against the SARS-CoV-2 spike protein persisted in infants whose mothers received COVID-19 vaccination in pregnancy. 

Researchers at Massachusetts General Hospital followed pregnant persons from their 2nd trimester who either received COVID-19 vaccination or had COVID-19 infection between weeks 20-32 of pregnancy. They chose this time frame because "previous studies have demonstrated superior transplacental transfer of antibodies during this window compared with vaccination closer to delivery." They then measured antibodies against the SARS-CoV-2 spike protein in the enrolled participants' infants for their first 6 months of life. 77 pregnant persons who received COVID-19 vaccination and 12 pregnant persons with symptomatic, documented COVID-19 infection were included in the study:

Vaccinated mothers had significantly higher titers at delivery with a mean (SD) of 2.03 (0.47) optical density (OD_450-570) compared with mothers after infection with a mean (SD) of 0.65 (0.76) OD_450-570 (P < .001)....Vaccination resulted in significantly greater antibody persistence in infants than infection. At 6 months, 57% (16 of 28) of infants born to vaccinated mothers had detectable antibodies compared with 8% (1 of 12) of infants born to infected mothers (P = .005). 

This study's findings suggest that "natural" immunity from disease is not superior, and may be inferior, to immunity induced by vaccination, though it's important to note that titer levels are a disease-oriented evidence (DOE) outcome. There is no evidence yet that COVID-19 vaccination in pregnancy reduces infants' risk of illness or hospitalization (POEM-level outcomes) compared to COVID-19 infection in pregnancy. Given that other established vaccines have demonstrated a link between infant titers and disease protection, however, this study offers hope that maternal COVID-19 vaccination may offer some protection to infants. 

Protecting infants is important despite conventional wisdom that COVID-19 infection is less severe in children than in adults. Infants appear to be at the highest risk of complications from COVID-19 among children under the age of 18 years. A study from China early in the pandemic (before vaccines were available), found that the prevalence of "severe" or "critical" COVID-19 complications in children under the age of 1 year was 8.8% and 1.9%, respectively. This information is important to share with pregnant persons and parents; yes, overall children have a lower risk of complications from COVID-19 infection, but infants have the highest risk among children under the age of 18 years.

No ongoing or planned COVID-19 vaccination trials include infants under the age of 6 months, so maternal vaccination - along with vaccination of all household members and close contacts - will likely be critical to protecting this age group from COVID-19 infection and its potential complications. Future studies are needed to establish maternal vaccination's benefit for preventing infections, hospitalization, and mortality in infants, but this newest study may inspire future research to answer those questions. In the meantime, we should continue to advise pregnant persons to receive COVID-19 vaccination, and perhaps the potential of benefit for their infant may sway some vaccine-hesitant individuals toward vaccination.

If you'd like to read more, the AFP By Topic on COVID-19 continues to be regularly updated, and this AFP editorial reviewing "Strategies for Addressing and Overcoming Vaccine Hesitancy" has many useful tips.

Screening for atrial fibrillation, revisited

 - Kenny Lin, MD, MPH

In 2018, the U.S. Preventive Services Task Force (USPSTF) concluded that there was insufficient evidence to assess the balance of benefits and harms of screening for atrial fibrillation (AF) with electrocardiography. However, the proliferation of wearable devices capable of detecting brief episodes of cardiac arrhythmias raised the question of whether screening high-risk patients outside of the office, analogous to home blood pressure monitoring, might prove beneficial. In a scientific statement, the American Heart Association discussed the knowledge gaps regarding the risk of stroke and benefits and harms of initiating long-term anticoagulation in persons with subclinical AF.

Two randomized screening trials published in 2021 provided a mixed picture. In the LOOP Study, 6004 Danish adults aged 70 to 90 years with stroke risk factors were randomized in a 1:3 ratio to receive an implantable loop recorder (ILR) or routine medical care. ILR participants were contacted if they had atrial fibrillation lasting for at least 6 minutes and recommended to start anticoagulation. Control participants received electrocardiography as needed from their primary care physicians. After a median follow-up of 64.5 months, 32% of patients in the ILR group and 12% of patients in the control group had atrial fibrillation detected, with similar proportions initiating oral anticoagulation. However, there was no significant difference in the primary outcome of stroke or systemic arterial embolism (4.5% of patients in the ILR group vs. 5.6% in the control group). Rates of major bleeding were not statistically different between the groups.

In the STROKESTOP trial, 28,768 Swedish adults aged 75 or 76 years were randomized to receive an invitation to screening with a handheld single-lead electrocardiogram twice daily for 2 weeks or usual care. After nearly 7 years of follow-up, a composite outcome of stroke, systemic embolism, hospitalization for bleeding, or all-cause mortality was slightly less likely to occur in the intervention group (NNT=93), but differences in individual outcomes were not statistically significant.

Reviewing these trial results and additional data, the USPSTF recently updated its 2018 statement and concluded that the evidence remains insufficient to make a recommendation. An accompanying editorial in JAMA Internal Medicine by Drs. John Mandrola and Andrew Foy (who authored a 2019 editorial on the downsides of detecting asymptomatic atrial fibrillation in AFP) noted that despite the potential benefits of widespread cardiac rhythm monitoring on cardiovascular and stroke risk, it "will also lead to misdiagnosis and downstream cascades of care" and that the "work-up of [arrhythmias] can lead to anxiety, iatrogenic harm, and excess health care costs."