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Primary Care Corner with Geoffrey Modest MD: Teens birthrate and sexual activity/contraception use

28 Jun, 17 | by gmodest

by Geoffrey Modest

2 related articles were recently published by the CDC.

1. In the United State from 1991 to 2014 the birth rate among teens age 15 to 19 hasdeclined by a dramatic 61%from 61.8 per 1000 to 24.2 per 1000, with larger % decreases in ethnic/racial minorities (see ). However the birth rate remained approximately twice as high for Hispanic and non-Hispanic black teens compared to non-Hispanic white teens. There are also significant geographic and socioeconomic disparities. See prior blog  for the full assessment . In brief:

— from 2006 to 2014, a 41% decline in birthrate overall, to 25.4 per 1000 female teens

— Hispanic: decreasing to 39.8 per 1000, a 51% decrease from 77.4 per 1000

— Black: decreasing to 37.0 per 1000, a 44% decrease, from 61.9 per 1000

— white: decreasing to 18.0 per 1000, a 35% decrease from 26.7 per 1000

— there is large geographic variability, for example the Hispanic birthrate in 2014 varied from 17.0 per 1000 in Maine to 58.0 per 1000 in Oklahoma; Black birthrate varied from 14.0 per thousand in New Hampshire to 54.6 per thousand in Arkansas; white birthrate varied from 4.8 per 1000 in New Jersey to 39.2 per 1000 in West Virginia. And, within states, sometimes the racial disparities remain very high: eg, in Nebraska the birth rate for whites was 16.2 (approx the national average) whereas the rates for black and Hispanic (42.6 and 53.9) were far above the national average for these groups.

–and, there was a higher birth rate in those who are unemployed, have lower levels of education and lower incomes.


–as a perspective, the overall US birth rate in 2011 for 15-19 years old females was 34.0 per 1000, vs 13 per 1000 the same year in Canada. And the rate in France was 7 per 1000 and in Germany 5 per 1000.


–very dramatic changes in teen birth rate, with a narrowing of the gap for racial/ethnic minorities as compared to whites. However, as noted, the gap remains significantly discordant.

–And, I suspect, a large part of the geographic gap reflects access to and quality of care. And there are major concerns about the future: the trump administration etc are pushing for decreased Planned Parenthood (potentially leading to even less access to care/contraception for poor and minority patients, with anticipated increases in pregnancy rates, and likely maternal and fetal death rates) and even cutbacks in maternity care. For example, another blog showed that a restrictive abortion law in Texas led to an 18.2% decline in abortions; and there have been a plethora of studies linking lack of prenatal care to poorer outcomes.

–and, the overall social environment, getting worse in the trump era, no doubt will add to the problem: lower incomes, cutbacks in social programs (including perhaps health insurance), fewer safety net programs overall, and social upheaval in general (including targeting immigrants) will predictably lead to even less access to care, less sense of hope for the future, lower self-esteem, and poorer health outcomes, including pregnancy rates.


2. Another CDC article evaluated sexual activity and contraceptive use among teens aged 15-19 in the US from 2011-2015 (see,finding:


–42.4% of never-married female teens (4.0 million) and 44.2% of never-married male teens (4.4 million) had sex at least once by the time of the interview; these numbers were similar to those from 2002 and 2006-2010, though looking back to 1988 there was a decline (downward trend, with p<0.05). By ethnicity/race, from 2002 to  2011-15:

–Hispanic female: 37.4% in 2002, 41.2% in 2011-15; Hispanic male: 54.8% to 45.7%

–non-Hispanic white female: 45.1% in 2002, 44.3% in 2011-15; non-Hispanic white male: 40.8% to 42.8%

–non-Hispanic black female: 56.9% in 2002, 45.7% in 2011-15; non-Hispanic black male: 63.3% to 58.6%

–of these, the differences in females in 2011-15 were not statistically significant; though the difference/decrease in non-Hispanic black males was significantly higher than the others

–assessing sexual activity by family structure at age 14: for females, a significantly lower % were sexually experienced if they lived with both parents (36.8% vs 50.8%) and for males (39.4% vs 51.9%); for males, if their mothers gave birth to first child by age >=20 (39.3% vs 56.7% if mothers younger). Also for males, less sexually experienced if mother had at least some college vs high school diploma or GED (41.0%​ vs 46.7%)

–by age: males more likely than females to have sex younger (age 15-16). Though probabilities were the same by age 17

–partners for first sexual experience: 74.1% of females but 51.1% of males were “going steady” with their partner; 13% of females and 27.3% of males with “just friends” (the latter especially true with younger teens)

–reasons for not having sex: most common: religion/morals (35.3% of females, 27.9% of males), then “not found right person yet” 21.7% females, 28.5% males; then “don’t want to get pregnant” 19.3% females, 21.2% males

–no change from 2002 in terms of % of teens who have had sex in past 3 months, though older teens (18-19 yo) were twice as likely as those 15-17.


–female teenager use of contraception at first sex:

–increased from 74.5% in 2002 to 81.0% in 2011-15, though lowest in non-Hispanic black teens at 62%, and higher in Hispanic (79%) and non-Hispanic white (87%) teens; overall, mostly using condoms (66.4% in 2002, increasing to 74.6% in 2011-15)

–dual protection (condom plus pill) also increased significantly from 13.1% in 2002 to 18.5% in 2011-15

–overall 5.8% of females had a long-acting reversible method (IUD in 2.8% or implant in 3.0%) in 2011-2015

–male teenager use of contraception at first sex:

–condom use increased from 70.9% in 2002 to 79.6% in 2006-10 and remained stable at 76.8% in 2011-2015

–emergency contraception use has increased significantly from 2002 (8% of female teens who ever used it) to 2011-15 (23%)

–no change in ever using condoms (97%), withdrawal (60%), pills (56%), depo-medroxyprogesterone (17%)

–feelings about hypothetical pregnancy (which does correlate with risk of teen birth, pregnancy risk behaviors): in 2011-15, more females would be very upset (60.5%) vs males (46.1%)

–teens who have sex at an earlier age are not only less likely to use contraceptives at time of first sex, but also at the last sex as well.



–although there are lots of statistics above, the report has even lots more….

–it is notable that 81% of females used contraception the first time they have sex, condoms were used by 77% of males the first time they have sex

–overall trends seem to confirm some decreases in sexual activity overall and increase in contraceptive usage since 1988, aligning with the observed decrease in teen pregnancy in the early 1990s (as above). though the contraceptive use largely plateaued or only decreased slightly since 2002, the types and effectiveness of contraceptives used has changed

–there is a general trend to promote long-acting reversible contraceptives (IUDs implants) in adolescents (eg, see ), and there is dramatically increasing use of emergency contraception

–one important potential utility of all of these statistics is to help us clinicians and public health people focus on teens where the statistical predictors point to those at highest risk of not using contraceptives or becoming pregnant (eg. family and social situation, education, age of first sex, ethnicity/race…)


–but, as noted in commentary after the first article, there are real concerns about the future, especially with access to high quality, affordable care (see above)

Primary Care Corner with Geoffrey Modest MD: physical activity and depression in childhood

2 Mar, 17 | by EBM

By Dr. Geoffrey Modest

And, perhaps the last blog on exercise, at least for now…

A Norwegian study assessed the relationship between physical activity, sedentary lifestyle, and DSM-IV defined major depressive disorder (MDD) in kids aged 6 to 10 years old (see DOI: 10.1542/peds.2016-1711​).


  • Community sample of 6-year-old children (n=795) in Trondheim, Norway were followed-up at 8 and 10 years of age.
  • Physical activity was recorded by accelerometry – wearing an accelerometer for 7 consecutive days, 24 hours a day, and only removing when bathing or showering; they assessed the time period of 6 AM till midnight and excluded periods of time where there were greater than 20 minutes of 0 counts (suggesting they were not wearing the unit); sedentary activity was <100 counts per minute; and moderate-to-vigorous physical activity, MVPA, was >2296 counts per minute). Major depression was assessed through semistructured clinical interviews of parents and children using the Preschool Age Psychiatric Assessment (PAPA), with a summed score creating the DSM-IV defined MDD; and the Child and Adolescent Psychiatric Assessment (CAPA) was used as well for children 8 and 10 years old.


  • DSM-IV defined MDD decreased from age 6 to 8 but then increase from age 8 to 10. (the prevalence of MDD was around 0.5% in all of the age groups)
  • Minutes of MVPA did not change from age 6 to 8 but decreased from age 8 to 10
  • Sedentary activity increased from age 6 to 8 and increased further from age 8 to 10
  • The symptoms of MDD and sedentary activity were modestly stable over this time. MVPA was more stable.
  • Cross-sectional findings
    • The symptoms of MDD were negatively correlated with MVPA at age 8 and 10, but were unrelated to sedentary activity.
    • At both ages of 6 and 8, higher levels of MVPA predicted fewer symptoms of MDD 2 years later, with a reduction of 0.2 symptoms of depression per daily hour spent in MVPA
    • There was no difference between males and females.
    • MVPA predicted reduced numbers of MDD symptoms from age 6 to 8, but depression did not predict later MVPA (i.e. it seems to be unidirectional). And there were no effects of sedentary activity on depression or vice versa


  • Some studies have found that physical activity may reduce the likelihood of the symptoms of major depressive disorder in adolescents and adults (see Craft LL. Prim Care Companion J Clin Psychiatry 2004; 6: 104, which includes meta-analyses showing exercise’s therapeutic benefit, on the order of cognitive therapy).It has been unclear whether this was related to the physical activity or the lack of sedentary behavior (these 2 are not perfectly correlated, and, for example, children may do periods of intense activity but have a lot of sedentary behavior time). This Norwegian study assessed these factors prospectively in younger children, finding that MVPA mattered but sedentary behavior time did not
  • One particular strength of this study is that they did look at symptoms of depression over time, since these often wax and wane. Also the study allows us to looks at the bi-directionality of the relationship between physical activity and depression, finding that the results were unidirectional from MVPA to MDD. Another advantage of the study over others is that they used a formal assessment of depression as well as a formal assessment of exercise.
  • The effect size of MVPA on MDD symptoms was small, but still on the order of magnitude of those of psychosocial intervention programs in children. And medications do not always work (and probably have more adverse effects than exercise…). So, exercise may well be an important therapeutic approach to treating depression in kids (i.e., not just preventative, as suggested in this study, and should probably be formally evaluated).
  • Some postulates as to why physical activity might decrease depressive symptoms include: these activities might distract children from thinking about negative events; physical activity in children also may bolster their self-esteem; and physically active children are more socially integrated into peer groups.
  • The mechanism by which physical activity might have helped include: higher availability of neurotransmitters which are depleted in people with depression and which may have antidepressant effects if augmented (e.g. serotonin, dopamine and norepinephrine); the potentially positive role for exercise-induced endorphins (see above cited article by Craft); also, there is evidence of increased cerebral blood flow and cognitive function with exercise. Other studies have shown that children taking exams in school do better when they are more physically active prior to taking those exams.
  • One quite concerning social evolution is that many schools have cut out physical education/activity in order to cram in more academic subjects. Unfortunately, this could not just lead to decrease school performance, but also reinforce future patterns of inadequate physical activity. It is concerning in this study that exercise decreased and sedentary time increased from ages 8 to 10.

So, MVPA did predict fewer future MDD symptoms in children, and such symptoms were relatively stable from ages 6 to 10. Sedentary activity however did not affect the risk of future symptoms of depression, and depression does not seem to influence the likelihood of MVPA or sedentary behavior. Their conclusion was that increasing MVPA at a population level may prevent depressive symptoms or MDD. And I think it makes sense for us in primary care to strongly encourage physical activity and advocate for more exercise in schools, and that exercise be considered an integral part of the curriculum, emphasized and promoted by the school system. And that there be more neighborhood-friendly and safe exercise venues, etc. Per the prior blogs and the myriad articles on the benefits of exercise, this is not just to prevent depression…

Primary Care Corner with Geoffrey Modest MD: Early Activity After Concussion?

26 Jan, 17 | by EBM

By Dr. Geoffrey Modest

A large Canadian study looked at outcomes in kids according to whether there was strict rest versus different levels of physical activity in the week after a concussion (see doi:10.1001/jama.2016.17396​ ).

Details at initial exam:

  • 2413 participants aged 5 to 18 with acute concussion completed the questionnaires in the emergency room, at day 7, and at day 28 post-injury. The researchers assessed persistent postconcussive symptoms (PPCS, defined as at least 3 new or worsening individual symptoms vs preconcussion status) to see how that varied according to the amount of physical activity begun within 7 days of the ED visit.
  • Mean age 11.8 years, 39% female, arrived at ED a median of 8.7 hours after injury, 24% lost consciousness (11% >3 minutes), 2% had seizure, 8% had prior concussions lasting more than a week.
  • 49% appeared dazed and confused, 41% answered questions slowly, 14% repeated the questions, 21% were forgetful.
  • Parental report of headache in 87%, nausea in 59%, balance problem in 44%, dizziness in 70%, drowsiness 73%, increased sleeping 35%, sensitivity to light or noise 37%, irritability 27%, sadness 40%, seemed mentally foggy 40%, increased fatigue 75%, poor concentration 37%, acts more emotional 40%


  • 1677 (69.5%) participated in early physical activity, 736 (30.5%) had no physical activity:
    • Light aerobic exercise (e.g. walking, swimming, or stationary cycling) in 795 (32.9%)
    • Sport-specific exercise (e.g. running drills in soccer or skating drills in ice hockey) in 214 (8.9%)
    • Noncontact drills (e.g. complex passing drills) in 143 (5.9%)
    • Full contact practice (e.g. normal training activities) in 106 (4.4%)
    • Full competition (e.g. normal game play) in 419 (17.4%)
  • PPCS at 28 days occurred in 733 people (30.4%)
  • The incidence of PPCS at 7:
    • Those who engaged in early physical activity: 523 (31.3%) were symptom-free and 803 (48%) had at least three persistent or worsening postconcussive symptoms.
    • Those not engaging in physical activity: 584 (79.5%) had at least three persistent or worsening postconcussive symptoms
  • The incidence of PPCS at 28 days, by propensity score matching:
    • Early physical activity: 28.7% versus 40.1% for no physical activity
    • Among those symptomatic at day 7, the incidence of PPCS:
      • Light aerobic activity: absolute risk benefit of 6.5% over no activity
      • Moderate activity: absolute risk benefit 14.3% over no activity
      • Full contact activity: absolute risk benefit 16.8% over no activity


  • Pediatric concussion guidelines uniformly recommend an initial period of cognitive as well as physical rest after a concussion. These recommendations include modification of school attendance and mental activities as well as avoidance of any physical activity until postconcussive symptoms have returned to baseline, and then a gradual resumption of activities. However, there is no actual evidence to support these recommendations: they reflect a concern for preventing harm.
  • It is, however, very clear from the literature, that re-injury and recurrent concussions are deleterious.
  • This study, though quite large, is an observational study. They did propensity score matching as a means to mathematically control for differences between the different groups of activity level, in an attempt to decrease the inherent bias in an observational study (by mathematically adjusting the groups for likely relevant variables). It was notable that of the 20 items that they asked parents initially (e.g. headache, balance problem, drowsiness, etc., as noted above), there really was not much difference between the groups that performed physical activity and those that did not. However, this study still does not rise to the same evidence quality as a randomized controlled trial (i.e., mathematically modeling is just not the same…). A further caveat is that they did not look at cognitive rest, and it is conceivable that those who did not do any physical activity had much more cognitive activity, and it was the cognitive activity actually caused an increase in PPCS (not so likely, but possible). Also, the cutpoint of beginning exercise within the first 7 days of injury is arbitrary. It would be useful to see data on when exercise was started, perhaps over the first 3 weeks post-concussion and stratified by the initial concussion scores, to see what was the optimal timing or degree of exercise postconcussion
  • It was also impressive that there was an apparent dose-response curve: those that did more activity seemed to benefit the most
  • There really are an array of reasons that might support the conclusions of the study: for some children having to avoid all activity creates significant dysphoria (being the parent of two kids who had concussions, I can attest that not participating in sports created a lot of unhappiness) which can account for some of the psychological symptoms such as fatigue, poor concentration, irritability, etc. As a contrary issue, it is quite clear in the literature that physical activity is important for skeletal health, cardiorespiratory fitness, improvement in symptoms of depression, anxiety, self-esteem, cognitive performance, and academic achievement. In addition, exercise may well lead to improved cerebral blood flow and promote neuro-plasticity,
  • The study is very important in challenging a long-held, though not rigorously demonstrated, view about dealing with injury, in this case concussion. Similarly, for a long time, we were all advised to limit any activity at all for patients with low back pain, for a minimum of two weeks. That also seemed prudent at the time, but turned out to be the antithesis of what we should have been doing. And in these cases, I think this conception that rest is the right prescription really undercuts the power of exercise in preserving and restoring health.

So, based on the study as well as some others, it seems to make sense to have a gradual resumption of physical activity as soon as tolerated after an acute concussion, but avoiding activities that might risk re-injury, given how much better kids did who resumed exercise within a week after a concussion. However, it certainly makes sense to have a real randomized controlled trial to assess the optimal degree of physical activity and its timing after concussion, as well as specific characteristics of the concussion which might dictate different exercise programs. And, also to look at the effect of cognitive rest (which, i think, may be nearly impossible in our technological era, given the intense cognitive stimulation of smartphones, electronic devices, etc.)

For prior blogs: for another study suggesting more rapid introduction of physical activity; or​ for a study looking at the time-course of postconcussive symptoms in kids seen in the Boston children’s hospital ED

Primary Care Corner with Geoffrey Modest MD: Sudden Cardiac Death in Young Athletes in the U.S.

2 Dec, 16 | by EBM

By Dr. Geoffrey Modest

A recent article looked at the demographics and epidemiology of sudden death in young athletes from the United States National Registry from 1982-2011 (see Maron BJ. Am J Med (2016) 129, 1170).


  • 2406 athlete deaths were reported to the registry, of whom 842 had confirmed cardiovascular causes associated with exercise, and with autopsy examination.


  • Mean age 18, 89% male, 46% white/43% African-American or other minority. 25% of deaths were during competition, 39% during practice, 17% during recreational activity, 18% unassociated with physical activity. 66% were junior high or high school, 19% in college. 35% playing basketball, 30% football.
  • Mortality rate in males exceeded females by 6.5-fold (1:121,691 and 1:787,392 athlete-years, respectively; p <0.001)
  • Cause of sudden death:
    • Hypertrophic cardiomyopathy (HCM): 302 athletes (292 males, 10 females), 36% of cases. 152 in African-American/138 in white
    • Congenital coronary anomalies: 158 athletes (127 males, 31 females), 19% of cases. 77 in African-American/72 in white
    • Indeterminate cause with left ventricular hypertrophy/possible HCM (autopsy finding abnormal hearts with increased heart weight and mild left ventricular thickening): 77 athletes (73 males, 4 females), 9% of cases. 31 in African-American/40 in white
    • Myocarditis: 57 athletes (46 male, 11 female), 7% of cases. 24 in African-American/30 and white
    • Arrhythmogenic right ventricular cardiomyopathy: 43 cases (31 male, 12 female). 8 in African-American and 35 in white


  • The US National Registry of Sudden Death in Athletes prospectively assembles data on the deaths of young athletes in competitive athletics, for those engaged in organized team or individual sports requiring regular training and competition, and have had sudden death. [not sure how inclusive this registry is for those just doing recreational sports — those in noncompetitive athletics may be significantly underreported]
  • This study confirms that hypertrophic cardiomyopathy was by far the single most common cause of sudden death in athletes in the US and was far more common in males and females. Coronary artery anomalies, arrhythmogenic right ventricular cardiomyopathy, and prolonged QT syndrome (though the latter only occurred in 18 individuals, 2.1% overall) were more frequent percentagewise in females.
  • Overall hypertrophic cardiomyopathy was more common in African-Americans than in whites and least common in white females.
  • The significant increase in cardiac deaths in males over females (greater than 6-fold) was also found in the French national registry (30-fold difference, though for marathon running it was 6-fold).
  • Structurally normal hearts were found in less than 5% of the athletes.
  • For a review of the American Heart Association and the American College of cardiology guidelines, see .
  • Given the relatively high percentage of athletes dying from hypertrophic cardiomyopathy (and especially if you include those with LVH but considered to be indeterminate in terms of the specific HCM criteria), these data reinforce the American Heart Association recommendations for pre-participation screening (see or Maron BJ. JACC. 2014; 64: 1479). A brief review of the criteria:
    • The 14-element recommended screen for preparticipation in competitive athletes includes 7 items on personal history (chest discomfort on exertion, unexplained syncope or near syncope, excessive dyspnea or palpitations on exertion, heart murmur, elevated blood pressure, prior restriction from participating in sports, and prior testing of the heart by a physician), 3 on family history (sudden death before age 50 in at least one relative, disability from heart disease in a close relative prior to the age of 50, known history of specific cardiac diseases including hypertrophic cardiomyopathy, long QT syndrome, ion channelopathies, Marfan syndrome, clinically significant arrhythmias), and 4 items on physical exam including heart murmur likely to be organic, femoral pulses to exclude aortic coarctation, physical stigmata of Marfan’s, hypertension)
    • However, it is noted that personal/family history is often insensitive in identifying cardiac abnormalities, physical exam is often unremarkable (with some abnormalities only detectable by EKG, such as WPW or channel ionopathies), and even HCM is only detected by a murmur at rest in 25%, with an additional 50% on by Valsalva or cardiac exam while standing.
    • The EKG is sensitive but not so specific, given the number of false positives in young athletes
      • 5% of elite athletes have EKGs indistinguishable from HCM
      • The EKG is abnormal in more than 90% of people with HCM but the EKG changes are typically nonspecific (the specificity is about 50 to 60%, as per
      • The sensitivity and specificity for HCM is also largely determined by the cutpoints of voltages used in defining HCM. As noted, false-negative results occur in more than 10% of patients with documented HCM as well as more than 90% with congenital coronary anomalies. (Though 40% of sudden deaths in athletes in the Minnesota study were from diseases that could reliably be picked up by EKG)
      • The guidelines are more circumspect about using screening EKGs. Prior guidelines I’ve seen have been more strongly against using EKG. This one suggests that there are real concerns about the availability of trained people to read EKGs in younger people, there are lots of false positives leading to lots of echocardiograms (and potentially scaring/medicalizing the kids and families), and the cost to the system is quite high, given the large number of EKGs that would be done. And the issue in the US is different, for example, from the Italian data showing potential benefit from EKG screening, since that area of Italy (Veneto) had a very large % of sudden death from arrhythmogenic right ventricular cardiomyopathy which can be found on EKG more easily
    • The recommendations: use the 14 point screening guideline as above. Screening with 12 lead EKG’s may be considered in young healthy people age 12 to 25, not necessarily limited to athletes, mandatory and universal mass screening with EKG is not recommended for anyone.

So, sudden cardiac death, not surprisingly, is a pretty devastating though infrequent outcome for young and basically healthy kids.  My concerns are that sudden death clearly happens to those who are not super-competitive athletes (66% happened in junior high or high school; overall only 25% during competition and 39% during practice – and I’m not sure how complete the above database is, especially in those not in competitive athletics), and that these deaths are potentially preventable, to the extent that the questionnaire is reliable. I would not be surprised, for example, if the mortality in a kid with HCM were as great in an unfit 7th grader working hard on the basketball court for 15 minutes vs the remarkably fit varsity player…. It seems to me, given this, that we really should be screening all young kids with the questionnaire, perhaps on entry to junior high school, which really means also interviewing parents/guardians since kids are likely quite unreliable in knowing the specifics of the family history.

Primary Care Corner with Geoffrey Modest MD: Fludrocortisone for Vasovagal Syncope

22 Sep, 16 | by EBM

By Dr. Geoffrey Modest

Vasovagal syncope is pretty common, but there are no documented effective treatments. Fludrocortisone has potential by improving venous return: its efficacy was evaluated in the Prevention of Syncope Trial 2 — POST 2 trial (see Sheldon R. JACC 2016; 68: 1).


  • 210 patients (71% female, median age 30, BMI 24, HR 70 bpm, BP 112/70) with a mean of 15 syncopal episodes over 9 years
  • Randomized to fludrocortisone at the highest tolerated doses (from 0.05-0.2 mg/d, titrated over 2 weeks, with most achieving the 0.2  mg dose) vs placebo and followed for 1 year
  • Inclusion criteria: >13 yo, >2 lifetime syncopal episodes; exclusions: diabetes, hepatic disease BP>135/85, “significant comorbidities”, or if when standing 5 minutes they had postural tachycardia of >30 bpm, or orthostatic hypotension of >20/10 mmHg.


  • 96 patients had at least 1 syncopal episode
  • Overall there was a 31% marginally non-significant reduction in syncope in those on fludrocortisone [HR 0.69 (0.46-1.03), p=0.069]: 44.0% vs 60.5%. the most benefit was in those with systolic BP<110, BMI>20, and syncope frequency >7/yr
  • But, in multivariable model, fludrocortisone conferred a significant 37% decrease [HR 0.63 (0.42-0.94), p=0.024]
  • And, when analysis was restricted to being on the fludrocorisone after dose stabilization, there was an even more significant 49% decrease [HR 0.51 (0.28-0.89), p=0.019]: approx 60% vs 30% in those achieving the 0.2 mg dose


  • There are a myriad of etiologies for syncope to consider, especially cardiac or neurologic (all excluded in the above study). And the preferred treatment for the syncope is to treat the underlying condition.
  • The above applies to those with classic “fainting” episodes: vasovagal syncope, which can happen even in patients with underlying cardiac or neuro morbidities, often triggered by stress, noxious stimuli, anxiety (including venipuncture, blood donation), prolonged standing or sitting, heat exposure, exertion, orthostasis,  (and in older people can be associated with micturition, defecation, cough), and clinically associated with the typical prodrome of light-headedness, along with vagal symptoms of nausea, pallor, diaphoresis. Symptoms typically gets better with lying down, though there can be some residual fatigue. And there can be brief episodes of myoclonic/involuntary esp. limb movements. But there should be no post-ictal state
  • Fludrocortisone seemed pretty effective when at the 0.2 mg dose, and likely more effective than midodrine (a few small studies finding effectiveness but less impressively)
  • Fludrocortisone has been used effectively in those with autonomic failure and orthostatic hypotension, presumably from its increased renal sodium absorption and plasma volume expansion.
  • In my experience, fludrocortisone is very well-tolerated in fragile patients with multiple comorbidities: I have prescribed fludrocortisone (sometimes with midodrine) very effectively in my reasonably large group of older patients with orthostatic hypotension, presumably from autonomic dysfunction (workup otherwise negative, or perhaps some diabetes, but often just from aging…). In this young group in the study above, without comorbidities and with just vasovagal syncope, there were no serious adverse events. And for those with orthostatic hypotension, of course, caffeine helps (1-3 cups of coffee/d, or 2-5 cups of tea). And, though I have not used them, NSAIDs can also help when used with fludrocortisone.
  • So, bottom line: vasovagal syncope is common (overall about 20-35% of syncope causes), a pretty high % (up to 34% in one study) have no warning symptoms prior to syncope, and can be associated with bad accidents (e.g., car crashes), so the above study may really prove to be clinically useful. One wonders if using the max dose of 0.3 mg might be even more useful, and I do have several elderly patients tolerating this dose well)

Primary Care Corner with Geoffrey Modest MD: USPSTF Recommendations on Lipid Screening in Adolescents

30 Aug, 16 | by EBM

By Dr. Geoffrey Modest

The USPSTF just came out with their lipid screening recommendations for children and adolescents (see JAMA 2016; 316(6): 625), giving them an “I” rating (current evidence insufficient to recommend screening). For full supporting documents of the USPSTF recommendations, see JAMA 2016; 316(6): 645). Their points:

  • They consider both dyslipidemia from genetic heterozygous familial hypercholesterolemia, FH, (1 in 200-500 people in North America and Europe), where there are really high cholesterol levels (LDL>190 mg/dl, often 2-3x that of unaffected people) and evidence of increased cardiovascular risk (though not typically until age 30: 1 in 6 men and 1 in 10 women have ischemic heart disease by age 40, 25% of women and 50% of men by age 50), as well as multifactorial dyslipidemia, MD, (may have genetic component as well as environmental, esp obesity, where the LDL is lower but >130). Several studies show that there is moderately good tracking of childhood hyperlipidemia into adulthood. But they comment that there are no long-term data that adolescent hyperlipidemia from MD leads to clinical cardiac events in adults. Or that treatment of the MD changes those hard clinical outcomes [i.e., no RCTs have been done, and it is hard to imagine that they ever will be. Would require lots of kids randomized into different treatment wings, maintaining those treatments for decades, and then being able to follow them until they were 50+ years old when more clinical events happen]
  • NHANES data suggest that 7.8% of children 8-17 yo have total cholesterol >200 mg/dl, and 7.4% of those 12-19 have LDL >130 [i.e., pretty common]
  • For those with FH there are data that short-term (<2 year) treatment leads to decreased LDL and decreases the early surrogate marker of carotid intima-media thickness [which actually seems to be a good predictor of future atherosclerotic disease, especially in kids]. There are no compelling data on the long-term benefit of statins through a randomized-controlled trial, since in those with FH it is considered unethical not to use statins. However, a retrospective analysis looked at children with FH who were put on statins for a mean of 10 years starting at age of 14, and compared them to the adults with FH not on statins (they predated the use of statins); they assessed outcomes by age 30 , finding that the adults had many more cardiovascular events at a younger age than the kids (at the age of 30, the cumulative CVD survival was about 90%, vs 100% in the kids, even though 28% of the kids were smokers. See Braamskamp MJ. Am J Coll Cardiol 2016; 67(4): 455). It was notable in this study that the youngest parent with an MI was 20 years old and died at age 23.
  • Harms of screening. Also inadequate evidence, though mostly concerns about medicalization (anxiety about diagnosis, labeling, potentially harmful therapy). Statins are well tolerated with transient adverse effects in kids (increased liver enzymes). And though cardiovascular disease is still the number one killer, there is concern about overdiagnosis (i.e., some people treated may never develop cardiovascular disease)
  • Therapy: statins are typically used, given the adult data. But no consensus on when to start in kids with FH (some say age 8-10, some age 20). No data on long-term use in kids [though there are potential issues concerning taking statins with pregnancy, which they did not mention….]
  • They do acknowledge the rationale for screening kids:
    • Atherosclerosis is a known progressive process which starts in kids, with autopsy studies showing that [my data, not in their document]:
      • Everyone has fatty streaks in their coronaries by age 15-34
      • Advanced atherosclerotic lesions are found in 2% of men and 0% of women aged 15-19, but
      • Advanced atherosclerotic lesions are found in 20% of men and 8% of women aged 30-34
      • The Bogalusa Heart Study found that in adolescents dying mostly from trauma at median age of 19.6, there was a strong correlation between the levels of cardiovascular risk factors (BMI, lipids, and BP) and the degree of atherosclerosis
    • Lipid levels in kids are associated with the extent of adult atherosclerosis
    • Familial hypercholesterolemia, FH, is associated with premature ischemic cardiovascular disease
    • Short-term treatment of patients with FH leads to substantially lower LDL levels and some evidence of improvement in atherosclerosis (see below)
    • Abnormal lipid levels in adults is strongly associated with coronary heart disease events
    • Early identification and intervention in adults can prevent such events
    • And, I would add, prevention of more advanced lesions upfront not only decreases mortality (still a significant number of patients die with their first MI, and more are chronically disabled), but also helps long-term, since statins do not reverse atherosclerosis (just stabilizes it and makes the plaques less likely to rupture), but the residual recurrent cardiac risk in those who sustain an MI (secondary prevention) even with statins remains much higher than in those on statins who are just at elevated cardiovascular risk (i.e., primary prevention)
  • Although there are some potential benefits of identifying and treating those with FH, there are no good data for those with multifactorial dyslipidemia. An Ohio universal screen program (n=6500) looked at nonfasting total cholesterol screening, finding elevated levels >200 in 8.5%. This cohort then had fasting lipids, finding 5.8% had LDL>130. The USPSTF review found that those with the highest likely yield for hyperlipidemia are kids with obesity (12.3%), overweight (8.9%), children 9-11yo (7.2%) and those 16-19 yo (7.2%) [There is an unexplained typical 10-15% decrease in cholesterol levels during puberty].


  • When reading guidelines, it is important to remember that USPSTF overall is an independent governmental agency (so less influenced by drug companies, etc., than some of the professional society recommendations), is very focused on rigorous data (so will not make recommendations if the issue has not been studied well. They say the same thing about blood pressure screening in kids: no data that screening leads to decreased future cardiovascular events, so an “I” rating). In fact, for pretty much the same reasons (lack of clearcut studies), USPSTF does not recommend screening average risk males until age 35 and women till 45. All of these USPSTF recommendations are much less aggressive than the Am Acad of Pediatrics (screen at age 2-10 in all obese kids or if family history of dyslipidemia, etc.), NCEP (screen at age 20), Am College of Physicians, etc.
  • And, as a perspective, we all screen for phenylketonuria in newborns, with a prevalence of 1 in 10,000, but not for familial hypercholesterolemia, with 50x the prevalence (>500,000 born each year)… though I do realize the rigor of studies showing benefit is different)
  • It is pretty clear that targeted screening of those considered to be high risk is not successful: in a few pediatric epidemiologic studies, 1/2 the kids would be missed by relying on parental information/ family history of dyslipidemia or premature cardiovascular disease (e.g., see Ritchie SK. Pediatrics 2010; 126(2):260). And, pretty surprisingly, only about 1/4 of FH patients receive their appropriate diagnosis by middle age (see Neil HA. BMJ 2000; 3212:148). From other organizations (e.g. Am Acad of Pediatrics), screening has been recommended as universal. Universal screening is also much easier to integrate into care than targeted screening.
  • I do definitely think that discussing diet and exercise is really important at all age groups (though adolescents may be the most resistant of them….). But I also do think, from my clinical experience, that this discussion is more effective, at least in some people, if there are personal specific markers that suggest that the individual may be at higher risk. And knowing the lipid levels of adolescents may be very helpful in changing behavior. For example, I think that knowing a person smokes helps individualize their treatment recommendations and is likely to be more effective than just telling everyone they should not smoke (of course, finding out that someone smokes is a bit less invasive than doing a blood test).
  • So, to me, the rationale to do testing wins out. One may pick up the relatively unusual cases of familial hypercholesterolemia, and it seems pretty intuitive that they need meds as supported by our understanding of their physiology and supplemented by some limited data. But one will mostly pick up the pretty common multifactorial hyperlipidemia, and I personally would pursue these patients aggressively with diet and exercise, based on logic but without definitive studies to prove it. I.e., I would use the found high lipid levels to talk with the patient (motivational interviewing) about diet and exercise and suggest much more aggressive follow-up than on their non-dyslipidemic peers. I would not start meds in this group, but if they were able to improve their lifestyle, would track their lipids and give them feedback. And, it turns out that most adolescents do not have optimal lifestyles (see next study)


Not so surprisingly to those in clinical practice with kids/adolescents, there are very impressive data that adolescents have pretty bad lifestyles in terms of cardiovascular health. A recent AHA scientific statement (see DOI: 10.1161/CIR.0000000000000441) noted:

  • 91% had poor diets, 9% intermediate diets: specifically, overconsumption of sodium, sugar, solid fats, refinded carbohydrates; under consumption of fruits, vegetables, whole grains, dairy, dietary fiber
  • Only 10% of boys and 5% of girls aged 16-19 years old had the recommended 60 minutes of moderate-to-vigorous exercise per day (including muscle-strengthening and bone-loading activities at least 3 days/week. [By the way, my untested hypothesis is that kids can use their cellphones, which seem to be pretty ubiquitous even in poorer communities, to track their “numbers of steps” they take each day, in order both to quantify an important aspect of exercise and give direct feedback to them]
  • 27% of12-19 year olds are obese (BMI>95th percentile)
  • This document does promote “early identification and control of dyslipidemia, including heterozygous familial hypercholesterolemia, throughout youth and into adulthood can reduce clinical cardiovascular disease risk beginning in young adult life”. Also it is typical that total cholesterol decreases 10-15% around puberty, independent of diet (suggesting that we should check lipids when kids are 9-11 yo, before these pubertal changes). Non-HDL is more predictive than any single lipid marker. NHANES data suggest that 26-35% of adolescents have “intermediate or poor” levels of total cholesterol overall (worst in Mexican-Americans, best in non-Hispanic whites)
  • Blood pressure. Use sex/height-specific percentile charts. 9-12% have intermediate or poor BP status
  • Fasting glucose <100 mg/dL. Part of the AHA’s Strategic Impact Goal Through 2020 and Beyond, though they note that this metric is not currently used in pediatric practice, misses the boat in obese children since hyperinsulinemia is the first sign of metabolic derangement, and does not adhere to the Am Diabetes Assn definitions (which are the same as for adults). By the fasting blood glucose <100 metric, 20-38% of 12-19 year olds have intermediate or poor levels in the NHANES study.
  • Smoking (twice as common in adolescents exposed to second-hand smoke: reinforcing the need to get parents/caregivers not to smoke, at least in the house). NHANES data suggest that about 1/3 of 12-19 year olds have tried cigarettes within the prior 30 days.


So, this all reinforces the approach of lipid screening in adolescents, despite the lack of clinical outcome data. To me, the reasons to screen younger people are not just to pick up the extreme cases of familial hypercholesterolemia (which typically requires meds) but to use the results as a concrete means to educate adolescents/families about the need for lifestyle changes, with a focus on diet, exercise and obesity, for anyone with hyperlipidemia.




A Response to: USPSTF Does Not Back Lipid Screening in Adolecents

See the response below, sent around with Holly’s permission. Her study (hyperlink below) in 3 sets of adolescents/young adults aged 17-21 and their parents (including some with familial hypercholesterolemia, obesity, and generally healthy) posited different cholesterol screening scenarios, finding that in each of these 3 groups, both the adolescents and the parents saw worse cholesterol results as signifying poorer health, with several commenting about the need to change their lifestyles. This provides support for universal cholesterol screening and using the results to try to influence behavior.  Even in adolescents.



Awesome summary Geoff about an issue near and dear to my heart (pun intended!).

I am interested in whether knowing about heart health/heart disease risk changes teens behavior.  Probably not but certainly gives us something to anchor our counseling on as you note.  You might find this qualitative study we did asking teens about their hypothetical response to lipid screening interesting –

Thanks as always for such an awesome blog!!!

Holly Gooding, MD, MSc

Division of Adolescent/Young Adult Medicine, Boston Children’s Hospital

Division of General Internal Medicine, Brigham and Women’s Hospital

Harvard Medical School, Boston, MA


Primary Care Corner with Geoffrey Modest MD: Dropping Teen Birthrates

18 May, 16 | by EBM

By Dr. Geoffrey Modest

MMWR found a decrease in teen birth rates and prior disparities for those aged 15-19, comparing 2013-14 with 2006-7  (see ).


  • From 1991-2014, the overall birth rate among those 15-19 yo declined 61% !!!, from 61.8 to 24.2 births/1000 women, and is currently the lowest ever recorded
  • Nationally, from 2006 – 2014 the teen birthrate decreased 41% overall, comparing 2006-7 and 2013-14:
    • 35% among whites (from 26.7 to 17.3/1000 teens)
    • 51% decrease among Hispanics (from 77.4 to 38.0/1000 teens), with the birth rate ratio vs whites declining from 2.9 to 2.2
    • 44% decrease among blacks (from 61.9 to 34.9/1000 teens), with the birth rate ratio vs whites declining from 2.3 to 2.0
  • By states, all had pretty dramatic decreases, the least in N Dakota at 13.4% and West Virginia at 14.9%, the most in Arizona at 47.8%, Connecticut at 47.6% and Colorado at 47.6%; almost all the other states are in the 30-40% range
  • There was huge variation of teen birth rates by county: from 3.1 to 119.0/1000 females aged 15-19. The highest birth rates being in Texas and much of the south (New Mexico, Oklahoma, Arkansas, Louisiana, Mississippi, Kentucky, Georgia)
  • For the states in the highest quintile of teen birth rates, the mean % of the population >15yo who are unemployed, mean % of population >24yo with an associates degree or higher, and mean family income were 10.5%, 19.9% and $46,005; in the lowest quintile, those numbers were 7.6%, 40.4%, and $73,967 and p<0.001 for all comparisons

So, a few observations:

  • It is certainly welcoming that the racial disparity gap is improving, but it has a long way to go
  • In some states this reflected a cross-ethnic consistency – e.g. in New Jersey: the teen birth rate in 2013-4 among whites was 4.8/1000 (below the national average of 18.0), for blacks was 27.4/1000 and Hispanics 31.3/1000 (also below the national averages of 37.0 and 39.8), though still a pretty staggering 6-7 fold higher than for whites
  • But in others, the disparities diverged: e.g. Nebraska, birth rate for whites was 16.2 (approx the national average) whereas the rates for black and Hispanic (42.6 and 53.9) were far above the national average for these groups.
  • The county-by-county map basically shows the highest teen birth rates are in the South, and largely coincides with those states there that refused to expand Medicaid through Obamacare
  • And, not so surprisingly, high teen birth rates also coincide with those states with the highest poverty rates and (somewhat less impressively, though pretty clearly) with highest numbers of African-Americans and Hispanics (see: map for poverty: ; map for racial disparities:….0…1ac.1.64.img..1.18.983…0j0i24.p9s7jYX4pj8#safe=active&tbm=isch&q=map+of+ethnicities&chips=q:map+of+ethnicities,g_1:usa&imgrc=WU9o2tjooIVI-M%3A )
  • The US Dept of Health and Human Services has been funding community-wide initiatives in 9 communities with some of the highest teen birth rates, focusing on black and Hispanic teens, with a goal to address the social determinants of health at the community level. Mostly these have focused on access to health care services and pregnancy prevention programs [but, not really looking at the fundamental issues of poverty, unemployment, inadequate education, etc.]
  • As a reference point, the adolescent birth rate is 34.2/1000 females in the US, 25.1 in the UK, 15.5 in Australia, and pretty much under 10 in the rest of Europe (see )
  • So, to put this together: teen pregnancy is clearly decreasing in the US, with decreasing racial/ethnic disparities, but the US overall has the highest rate as compared to other resource-rich countries, and there are large discrepancies in different regions of the US, largely tracking those areas of poverty, racial disparities, and fewer federal resources (which in some cases are those states have chosen to reject). Again, this really speaks to the need for a national, coherent approach to the inequities in our society, as a basis to improve public health outcomes overall.

Primary Care Corner with Geoffrey Modest: Adult and Pedi 2016 Immunization Schedules

11 Feb, 16 | by EBM

By Dr. Geoffrey Modest

The Advisory Committee on Immunization Practices and CDC just published their immunization recommendations for adults and kids.

  1. Adults. For those >18 years old, see  Ann Intern Med.2016;164(3):184, or go to for a nice color chart and the rather extensive footnotes, ideal for hanging in the immunization room by the refrigerator. Changes from 2015 include:
  • Simplification of the rather complex relationship between the pneumococcal vaccines: for immunocompetent people over 65yo, give PCV13 first, then at least one year later (had been 6-12 months), give PPSV23; if they already got PPSV23, wait one year at least to give the PCV13. In those immunocompromised (functional/anatomic asplenia, CSF leaks, cochlear implants, HIV, etc.), and >18yo, give PCV13 first, then can follow with PPSV23 at least 8 weeks later;  if they already got PPSV23, then wait at least one year for the single dose of PCV13.In those who should get a PPSV23 booster since they got the first dose <65 yo, they should wait at least 5 years to the next PPSV23 dose. They also note that those with immunocompromise/asplenia can receive up to a total of 3 doses of PPSV23. And they deleted the recommendation that adults 19-64 who are in nursing homes get PPSV23 (though, I wonder about the real utility of this: probably most have an indication for PPSV23 from asthma, COPD, diabetes, heart failure, alcoholism, smoking, etc. Also, I wonder about actual second-hand smoke exposure, though my understanding is that JCAHO requires some isolation of smoking areas. Sorry, but this simplification actually is simpler than last year’s…
  • Meningococcal B vaccine has been added: give to those >10 yo at increased risk of serogroup B infections (asplenia, complement deficiencies, local outbreaks of serogroup B). Can be given to adults aged 16-23 (preferably 16-18) to get short-term protection. A 2-dose series administered at least 1 months apart (the 2 different meningococcal B vaccines are not interchangeable). No recommendation about revaccination (vs the regular meningococcal vaccine for serogroups A,C,W,Y; where there should be revaccination every 5 years in those who remain at increased risk). See pedi schedule below for other details.
  • For the regular meningococcal vaccine, the conjugate A,C,W,Y (MenACWY) is preferred for adults <56yo, and for those >56 who have had prior meningococcal vaccine who need revaccination (whether they got the MenACWY or the polysaccharide MPSV4​ vaccine). The MPSV4 vaccine is preferred in those >56 who have never been vaccinated and need a single dose only (as with a recent outbreak). HIV is not an indication for meningococcal vaccine (despite outbreak in New York in 2014, which spurred some of us, like me, to vaccinate my HIV-positive patients)
  • HPV vaccine: they added the 9-valent vaccine (9vHPV). Can be used as the routine vaccine, given as 1 of the 3 recommended vaccines for females (others: 2vHPV and 4vHPV), or as 1 of the 2 for males (other: 4vHPV). The age recommendations have not changed: women beginning age 11-12 until age 26; men till age 21, though okay to give for 22-26 yo and recommended in that group for MSM.
  • And, they reinforce some of their newer recommendations, such as the importance of giving a Tdap to women for each pregnancy, preferably at 27-36 weeks’ gestation, and an influenza vaccine, to protect the woman and the to-be-born.


  1. Pedi. The updated 2016 pediatric immunization schedules were just released (see DOI: 10.1542/peds.2015-4531). For a chart of the immunizations as well as the catch-up schedule, see Also ideal to hang the color charts in the immunization room near the refrigerator.  Summary of changes in brief:
  • They added a blue bar to the already colorful chart, which indicates the range of recommended ages of a vaccine for certain high risk groups
  • See above re: the 9-valent HPV vaccine (9vHPV)
  • HPV: new purple bar (for ages of recommended vaccines in high risk groups), they added age 9-10 for children at high risk because of a history of sexual abuse (though, I wonder about the 5 year olds, etc……)
  • Meningococcal B vaccine (detailed above): begin at 10 years old if at increased risk, may otherwise consider in those 16-18.
  • Pneumococcal polysaccharide vaccine (PPSV23): moved to bottom of the list since not routinely indicated for anyone (but should be given to kids aged 6-18 with underlying immunocompromise, hemoglobinopathies, HIV, renal failure, nephrotic syndrome, etc.); in general, give PCV13 first, then PPSV23 at last 8 weeks later.
  • They clarified that in infants born to mothers with hepatitis B surface antigen (and the infant therefore gets immunized starting within 12 hours of birth), to check the infant for anti-HbsAg and HBsAg at least 1 months after final vaccine dose and between 9-18 months old (at time of regular well-child visit). They do not comment further, but I would suggest repeating the 3 doses again if there is a negative surface antigen and antibody in the kid, as we do with adults who are at high hepatitis B risk.
  • If a kid inadvertently gets a 4th DTaP early, but it was given at least 4 months but less than 6 months after the 3rd dose, no need to repeat (a logical correlate here, it seems to me, is that it might be reasonable to give this 4th dose earlier to a kid who will not be around for the usual 4th dose timing between 15-18 mos old, e.g. if they will be out of the country during that time)

Primary Care Corner with Geoffrey Modest MD: Re-Assessing a Ghost-Written Article on Paroxetine in Adolescent Depression

9 Feb, 16 | by EBM

By Dr. Geoffrey Modest

BMJ published an article finding the lack of benefit of either paroxetine or imipramine in adolescents with major depressive disorder (see BMJ 2015;351:h4320). To me, this study was really interesting because it resulted from an initiative called RIAT (Restoring Invisible and Abandoned Trials), an attempt by an international group to challenge the selective reporting of outcomes of randomized controlled trials, either because the results were never published or were misreported. In this case, the study (Study 329) was funded by a drug company (smithkline beecham), reported in 2001 in the Journal of the American Academy of Child and Adolescent Psychiatry, but “was largely ghostwritten, claimed efficacy and safety for paroxetine that was at odds with the data” (see Account Res 2008; 15: 152, which found that Study 329 showed “how ghostwriting of clinical trial results can contribute to the manipulation of data to favor the study medication. Study 329 of paroxetine pediatric use was negative for efficacy and positive for harm”). The concern was that this was an important article influencing the use of antidepressants, including paroxetine, in adolescents.  Details of the article, referred to as “Restoring study 329”:

  • The researches reanalyzed the reported study, using the drug company’s final clinical report, other publicly available documents, and 77,000 pages of de-identified individual case reports provided by the drug company. They adhered to the original protocol.
  • 275 adolescents aged 12-18 [mean age 15, 57% female, 85% white, mean duration of depression 13 months, 80% with 1 previous episode, 20% with concurrent anxiety, mean Hamilton depression scale (HAM-D)score of 19] who met DSM-IV criteria for a current episode of major depression of at least 8 weeks’ duration, in 12 study sites (10 in US, 2 in Canada) from 1994-1997; patients randomized to paroxetine, imipramine, or placebo in 1:1:1 ratio
  • Patients were titrated to paroxetine 20mg or imipramine 200mg over 4 weeks, independent of their response to the medications
  • Nonresponders at that point were titrated to a maximum dose of paroxetine 60mg or imipramine 300mg.
  • Patients had 45 minute weekly sessions of psychotherapy
  • Primary outcome: changes in HAM-D in the acute phase (1st 8 weeks), with a response defined as HAM-D score <=8 or >50% reduction in baseline score.


  • Mean paroxetine dose of 28 mg/d by week 8; mean imipramine dose of 206 mg/d
  • Paroxetine was no more effective than placebo (mean prespecified level for clinical significance was 4 points on HAM-D scale)
  • Review of the data showed no difference between placebo, paroxetine, or imipramine at any weekly assessment from week 1-8, or after multiple imputation modeling (this is a statistical technique to include missing data by different modeling methods, as opposed to just ignoring the missing data which could introduce a significant bias)
  • ​In terms of harms of therapies: they found that by reviewing the case report forms, the reported harms in the original article did not include 14% of the adverse events in the paroxetine group:
    • Paroxetine: 159 adverse events found by authors vs 136 reported; the additional events were mostly psychiatric ones (12/23)
    • Imipramine: 257 found vs 240 reported; mostly cardiovascular ones (5/17) not reported
    • Placebo: 77 found, 67 reported; mostly psychiatric (4/10) not reported
    • Of note, in terms of suicidal and self-injurious behavior (perhaps the most concerning adverse event):
      • The original paper reported 5 events with paroxetine, 3 with imipramine and 1 with placebo, and they were listed as “emotional lability”!!!
      • ​The case reports from the drug company reported 7 events with paroxetine, 3 with imipramine and 1 with placebo
      • The current RIAT analysis reported 11 events with paroxetine (i.e., more than twice that of the original paper), 4 with imipramine (3 definite, 1 possible) and 2 with placebo (1 definite, 1 possible)
    • And several instances were found with bias in interpreting these results (e.g. “an investigator, knowing the patient was on placebo, declared that a suicidal event was ‘definitely related to treatment”’ but of the 11 patients on paroxetine with serious adverse events, only one ”was considered by the treating investigator to be related to paroxetine treatment”)

So, a few issues:

  • The obvious one is that it is in the drug companies’ financial interests to mislead or misreport findings that might be harmful to their profits. The difficult-to-believe part of the above story was the extent of this malfeasance, with the drug company ghost-writing this article, exaggerating the positive effects of paroxetine, and hiding and minimizing the harmful ones (including suicide….). And, as in many, many of my blogs, this issue is increasingly critical: more and more articles in the most prestigious medical journals are funded by drug companies, the FDA is ceding more responsibility to the drug companies to do the studies and to do the followup postmarketing surveillance when drugs are approved (especially if approved early, or using surrogate markers), and it is clear that the FDA-required postmarketing studies are done pretty rarely by the drug companies.  It really makes it very hard for me to be an early or even middle-aged adopter of new drugs. I just don’t trust the process overall. For more details on this, including rigorous assessments of post-marketing surveillance studies, see several blogs in​ .
  • I essentially never use paroxetine for anything because of its relatively high frequency of potentially very serious withdrawal reactions. And I would really never use it with adolescents, who, as a group, are probably less likely to be assiduous medication takers.
  • I don’t think the above study should cast too much of a pall on the role of SSRIs in adolescent depression. There are many studies finding significant efficacy, mostly done with fluoxetine. And, though the studies are mixed, most show that the combo of SSRI and psychotherapy (esp. cognitive behavioral therapy) is even more effective.

Primary Care Corner with Geoffrey Modest MD: Zika Virus

29 Jan, 16 | by EBM

By Dr. Geoffrey Modest

The Zika virus has made the headlines of late. Some details:

  • Zika virus is a mosquito-born flavivirus, mostly transmitted by Aedes aegypti mosquitoes (which also seem proficient in transmitting dengue, chikungunya and yellow fever viruses)
  • Zika infections have been documented through intrauterine as well as intrapartum transmission from a viremic mother. RNA from the virus is also detected in breast milk though transmission has not been documented by breastfeeding
  • 80% of people are asymptomatic with the virusAedes_Albopictus
  • When symptomatic, there are usually only mild symptoms, with acute onset of fever, maculopapular rash, arthralgia, nonpurulent conjunctivitis. Lasting several days to 1 week. Fatalities are rare. But Guillan-Barre has been reported [note: there is a background incidence of Guillan-Barre. Not clear that the association with the Zika virus is causal, though a few cases have been found in Zika-infected individuals]
  • In Brazil outbreak, Zika RNA has been identified in brain tissue, placenta and amniotic fluid
  • Though there has been a dramatic increase in the numbers of infants with microcephaly or intracracial calcifications, it is unclear how many are associated with Zika
  • Testing: there are PCR tests for the viral RNA, and both IgM ELISA and PRNT (plaque reduction neutralization test) testing for antibodies.There can be cross-reacting antibodies causing false positives, but the PRNT is more specific to Zika. Contact the State Dept of Public Health for info
  • Since unclear which test is most reliable, CDC recommends both PCR and one of the antibody tests. All testing is done by the CDC or state labs.
  • PCR testing should be within 2 days of birth. Also CSF, if obtained for other studies, and maternal serum

Zika virus has been found largely in Africa and Southeast Asia in the past. In May 2015, the WHO reported lots in the Western Hemisphere, including travelers to the US (though no active transmission found so far). But almost all of Central and South America has active cases, including Puerto Rico, Mexico, and pretty much everywhere else except Costa Rica, Argentina, Chile, Uruguay. Also active transmission reported in Cape Verde (see for virus/travel updates)

See for the CDC guidelines on evaluation and testing of infants with possible congenital Zika infection. In brief:

  • Follow closely new mothers who were potentially exposed to Zika during pregnancy based on travel or residence in areas with Zika transmission
  • Review fetal ultrasounds and maternal testing for Zika
  • Test infants for the virus, if
    • Infant with microcephaly or intracranial calcifications
    • Infants born to mothers with positive or inconclusive test results for Zika virus
    • Also, Zika virus is a nationally notifiable condition
  • Infants with positive or inconclusive Zika tests: they should have ophthalmologic exam including retinal exam, within the first month of life, given reports of abnormal eye findings in those with possible congenital Zika. And repeat hearing screen at 6 months
  • Still look for other possible etiologies of microcephaly or intracranial calcifications if these findings present, and treat appropriately (including consultation with dysmorphologist, a new term to me…., as well as routine testing for syphilis, toxo, rubella, cmv, lymphocytic choriomeningitis virus infection, hsv) [even with appropriate training and interest, I’m not sure I would like the word “dysmorphologist” to be attached to my name]
  • In infants without any findings at birth but born to a Zika-positive mother, test the infant for Zika infection, and if possible infection, do routine exam with comprehensive neuro exam, check for hepatosplenomegaly and rashes, cranial ultrasound (unless normal in 3rd trimester check).
  • Only mothers who report symptoms suggestive of Zika within 2 weeks in an area with ongoing Zika virus transmission should get Zika testing. Then if positive or inconclusive, test the infant.
  • Management of Zika: nothing specific, no vaccines. Mothers should be encouraged to breastfeed, with apparent benefits outweighing potential risks
  • Prevention: just avoid mosquitoes

The CDC recommends that “all pregnant women consider postponing travel to areas where Zika virus transmission is ongoing”, and if she goes there, avoid mosquitoes (remember that this mosquito, unlike the dawn/dusk types that transmit malaria, is more around in the daytime. So, use lots of anti-mosquito protection — though I’m not sure that is so great for the infant, the CDC recommends DEET, picaridin and IR3535 as more likely to be safe)

The NY Times reported on possible risk of Zika sexual transmission. See . Basically, there is a “theoretical risk” of sexual transmission per the CDC.  A Tahitian man was exposed to the Zika virus in 2013, and a high level of virus was found in his semen and in his urine. Another was a malaria researcher in 2008, who was collecting mosquitoes for a malaria study in Senegal. He developed rash, fatigue, headaches, bloodshot eyes, and genital pain/likely hematospermia late in the illness. Tests for malaria, dengue and yellow fever were negative. After his return to the US, his wife who had remained in the US, developed several of these symptoms. Frozen serum from both the researcher and wife were subsequently positive for Zika virus, and no other family members were positive, suggesting sexual transmission.​

So, the clear concern here is yet another emerging infectious disease with potential dire consequences to those infected, unclear if there will be new and threatening modes of transmission, and lack of current vaccine or treatment. But overshadowing much of this is the effects of climate change. It turns out that even small degrees of warming lead to major changes in the territory for mosquitoes. New cases of dengue, for example, have migrated north to the US (sporadic new cases reported in Hawaii and Florida), though the range of the vector mosquito has spread considerably into the southern US

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