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Psych – depression

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​).

Details:

  • 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.

Results:

  • 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

Commentary:

  • 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: Depression – Drugs vs CBT

7 Nov, 16 | by EBM

By Dr. Geoffrey Modest

The Agency for Healthcare Research and Quality (AHRQ) just released their clinical review comparing nonpharmacological vs pharmacological treatments for patients with major depressive disorders (see https://www.effectivehealthcare.ahrq.gov/ehc/products/568/2155/major-depressive-disorder-report-151202.pdf for the full report, or https://www.effectivehealthcare.ahrq.gov/ehc/products/568/2303/major-depressive-disorder-clinician-160915.pdf for the summary).

Details:

  • They reviewed 44 trials from 1990-2015 of patients with mild to severe major depressive disorder (MDD)
  • Cognitive behavioral therapy (CBT) is as effective as second-generation antidepressants (SGAs, which for this review includes SSRIs, SNRIs, bupropion, mirtazapine, nefazodone, and trazodone) for mild to severe MDD, with moderate level of evidence. The evidence does not support SGAs plus CBT as being better than SGAs alone, though this was based on low quality of evidence
  • Therapy (SGA vs CBT) was discontinued at equal rates, for either SGAs or CBT, for adverse effects or patient dissatisfaction:
    • Common adverse effects:
      • For SGAs: nausea/vomiting, diarrhea, sleepiness/fatigue, headache, insomnia, weight gain
      • For psychotherapies: dissatisfaction with treatment
      • Black box warnings by FDA for SGAs: increased risk of suicidal thinking and behavior for kids and up to age 24, during initial treatment
      • “patients of all ages should be monitored appropriately and observed closely for clinical worsening, suicidal thinking and behavior, or unusual changes in behavior”
    • No statistically significant benefit of augmenting an SGA with another SGA or non-SGA med (low quality of evidence) or with CBT (moderate quality of evidence)
    • Limited evidence of benefits and adverse effects for the following, either alone or in combo with SGAs (only a few studies done). However, there is low-level evidence that these interventions may be similar to SGAs (except for the omega-3 fatty acids, which seem to be worse)
      • Interpersonal psychotherapy
      • Psychodynamic therapy
      • Acupuncture
      • Omega-3 fatty acids
      • S-adenosyl-L-methionine
      • St John’s wort
      • Exercise therapy
    • No eligible studies compared SGAs to other therapeutic modalities, such as yoga, humanistic therapy, or mindfulness interventions
    • Also very limited evidence regarding treatment efficacy in patient subgroups (eg by sex, age, race/ethnicity, medical comorbidities, coexisting psych conditions) and very few studies have looked at long term benefits or adverse effects treatments

Commentary:

  • MDD affects 16% of US adults over their lifetime, and 7% (17.5 million in 2014) have an episode of MDD each year
  • Approximately 1/3 of patients with MDD are severely depressed, as measured by their symptom severity, functional impairment and level of distress
  • But, about 40% of the patients do not respond to first-step treatment, and 70% do not achieve remission (reinforcing the need for a different treatment strategy, as mentioned in the document above)
  • Old numbers I have seen suggest that about 80% of depressed patients have their depression treated by primary care clinicians, with SGAs typically being the first option
  • There were a couple of studies finding superiority of third-wave CBT, which seems to involve acceptance and commitment treatment, behavioral activation, cognitive behavioral analysis, mindfulness based CBT,… These studies did find them better than SGAs, but were felt not to have sufficient strength of evidence. I should note that this document did not define third-generation CBT, though it seems that the studies on depression focused mostly on “behavioral activation”, which I gather is, in the great BF Skinner “operant conditioning” approach, mostly figuring out ways to increase environmental reinforcement and reduce environmental punishment (i.e., asking the patient what activities are hardest for them to do, then positively reinforcing patients as they try to perform these activities; another approach is to try to identify “depression loops”, when a coping strategy leads to increased depression, such as alcohol/drugs/escape/rumination, then try to identify and implement positive/reinforcing coping strategies)
  • My general approach for those patients who are severely depressed is to try an SSRI first (and I tend to use fluoxetine in those with lots of psychomotor retardation, sertraline otherwise, though this is NOT evidence-based and small studies I have seen suggest that this really is not a useful approach…..) And, given the possibility of a significant adverse event (e.g. suicide attempt, or perhaps worsening in those with an unmasked bipolar disorder), I do see patients back within 1-2 weeks to see how they are doing, realizing that it takes 3-4 weeks to really begin to see an anti-depressant effect. And I do promote counseling/CBT either as an alternative to SGAs or in combination (also, not supported by the literature, as above)
  • One very useful aspect of this report is that for us in primary care, we see only some of the studies on depression, since most don’t make it out of the psych literature (and probably a slanted cut of the studies at that, mostly the positive ones). My recollection over the years has been that there was some value to SSRI augmentation (e.g., adding another SGA such as bupropion, or adding psychotherapy or other non-med treatment, or adding buspirone, tricyclics or other non-SGA “augmenters”). But on review of this AHRQ compilation, it becomes clear that although there are a few smaller studies which show benefit to SSRI augmentation, this is not a uniform conclusion, and some of the big studies (e.g. STAR*D) did not have the correct groupings to allow for clear guidance (e.g., adding bupropion or buspirone seemed to help, but there was no way to know for sure if the small improvements were from adding the single new agent or from the combination/augmentation strategy). And given the large number of the recommendations in the “low strength-of-evidence” in the document, in some ways the real issue is that we just don’t have good enough studies to be able to promote a clear approach to patients with one of the most common and disabling conditions we treat. And, it would be great to have much more granular data: are there certain groups of patients who are more likely to respond to one drug over another, or some form of counseling vs drugs, or the combo of both???

Primary Care Corner with Geoffrey Modest MD: Adult Depression Guidelines

26 Feb, 16 | by EBM

By Dr. Geoffrey Modest

The American College of Physicians released a clinical practice guideline on nonpharmacologic vs pharmacologic treatment of adults with major depressive disorder–MDD (see file:///C:/Users/geoff/Downloads/AIME201603010-M152570.pdf ).

Details:

Background:

  • MDD, defined as in DSM-V: depressed mood or loss of pleasure or interest, along with other symptoms (changes in weight or appetite, insomnia or hypersomnia, psychomotor agitation or retardation nearly every day, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, indecisiveness or decreased ability to concentrate, and recurrent thoughts of death or suicide), lasting at least 2 weeks and affecting normal functioning
  • MDD has estimated lifetime prevalence of 16% in the US
  • 8 million ambulatory visits/year
  • Estimated economic cost to society and health care in 2000 was $83.1 billion (and probably higher today)
  • Definition of treatment response: a decrease of at least 50% in one of the tools [Patient Health Questionnaire-9 (PHQ-9) or Hamilton Depression Rating Scale (HAM-D); for meds, they only looked at second-generation antidepressants (i.e., not tricyclics, MAO inhibitors, which, by the way, are probably as effective in a few trials, but have more adverse effects and discontinuations); they also assessed nonpharmacologic approaches: psychological (acceptance and commitment therapy, cognitive behavioral therapy CBT, interpersonal therapy, psychodynamic therapy), complementary and alternative medicine (CAM) approaches (acupuncture, meditation, w-3 fatty acids, S-adenosly-L-methionine SAMe, St John’s wort, and yoga) and exercise

Results:

  • ​Meds vs CBT: no difference in outcome comparing the two after 8-52 weeks of treatment, for remission rates or functional capacity (mod quality evidence, 5 trials); 2 trials did not find benefit from combo therapy for remission after 12-52 weeks of therapy (low-quality evidence​)​, though perhaps some benefit in functional capacity.
  • Meds vs interpersonal therapy: no difference in response (3 trials, low-quality evidence​); no real evidence of combo therapy (only 1 low-quality trial which used nefazodone as the med).
  • Meds vs psychodynamic therapies: no difference for remission or functional capacity (3 trials, low-quality evidence).
  • Meds vs acupuncture: no diff comparing fluoxetine vs acupuncture after 6 weeks (1 trial, low-quality evidence​); combo fluoxetine or paroxetine with acupuncture found improved response after 6 weeks (2 trials, low-quality evidence​)
  • Meds vs w-3 fatty acids: meds better than w-3 fatty acids (1 trial, low-quality evidence​)
  • Meds vs SAMe: no diff in study with escitalopram (1 trial, low-quality evidence​)
  • Meds vs St John’s wort: no diff from 9 trials (low-quality evidence ​because meds not used at usual therapeutic dosage range. Other issues include non-regulation of St John’s wort by FDA and variable potency, important drug-drug interactions by inducing cytochrome P450 isoenzyme 3A4)
  • Meds vs yoga: no trials done
  • Meds vs exercise: no diff in response, including 2 trials with moderate quality of evidence for sertraline vs exercise after 16 weeks
  • ​Switching meds: no difference in response rate by switching from one med to another. Mod quality evidence [but very few studies evaluated: switching from bupropion vs sertraline or venlafaxine and sertraline vs venlafaxine], no diff in adverse events/discontinuation rates
  • Switching from med to different med vs switching to CBT: no difference, but 1 study with low-quality evidence
  • Augmenting one med with another: no difference in augmenting citalopram with bupropion vs buspirone (though adding bupropion decreased depression severity more than buspirone (1 trial with low-quality evidence)
  • Augmenting med with another vs augmenting with CBT: no difference in response, remission, depression severity if augment citalopram with buspirone or bupropion vs augmenting with CBT
  • ​In terms of harms overall: pretty mixed. Some trials with more discontinuation with meds vs psych therapies. Not much difference with (though acupuncture and St John’s wort did have fewer adverse events than meds)

Their conclusion: offer either CBT or med for patients with MDD after discussion treatment and adverse effects (strong recommendation; moderate quality evidence)

So, I’m not sure what to make of this. It is pretty clear that the studies evaluated did not create a basis for strong recommendations: in general only very few studies were included (reflecting the paucity of strict RCTs) and the majority had low-quality evidence. And several common management strategies were dismissed because of no formal studies being done (e.g., using the same med to retreat a person with depression who had previously responded to that med).

A few points:

  • There are several other common treatment strategies that were dismissed for lack of higher quality evidence, where in fact there are some supportive data:
    • Switching from one med to another when the first one does not work. I have seen a few studies (though do not have the reference handy) finding that switching SSRIs from one to another in nonresponders increases the response rate from a baseline group response rate to about 15-20% higher with a different SSRI. And, my clinical practice of trying one and, if no response, switching to another has been reasonably effective. If there is a partial response to the initial SSRI, I typically try either increasing the dose or augmentation (as in next point).
    • Adding an augmenting med to an antidepressant when there is suboptimal initial response. Again, the data are not great, and a systematic review overall did not find benefit for augmentation (though 2 or the 5 RCTs did). On the other hand, an impressive and pretty large trial (not a clean RCT) of patients with suboptimal response to citalopram did find benefit for augmentation with either bupropion or buspirone (somewhat better with bupropion) – see NEJM 2006; 354: 1243. And my personal experience pretty strongly supports augmentation with bupropion in those with partial responses to an SSRI.
    • Combining a med with psychotherapy. Several studies have confirmed an augmented effect of using this combined approach: e.g. World Psychiatry 2014; 13: 56 — a large meta-analysis of patients with MDD finding a clinically meaningful effect of combination therapy over meds alone.
  • Perhaps the biggest issue with these guidelines is the limitation of randomized controlled trials (RCTs) themselves, in terms of their generalizability to the patient sitting in front of you:
    • Structural issues: the RCT patients may be predominantly of a different gender, ethnicity, or have different comorbidities than your patient (and even in the best large RCTs with representation of many different types of people, any subgroup analysis looking at the factors most reflective of the patient you are treating are typically post-hoc analyses, which limit their statistical validity by introducing potential biases)
    • ​Exclusion criteria: RCTs have upfront exclusions which make the study data cleaner and easier to analyze; e.g. patients with cancer or renal failure, etc. are excluded (because of limited life expectancy, confounders with meds taken, other medical issues, etc.). But we still need to treat patients with these conditions…. Does the RCT really apply to them?
    • Inclusion criteria: a study may well find that meds vs psychotherapy are equivalent. But in order to be part of the study, those patients recruited must agree to be randomly assigned to either wing of the study, prior to randomization. but many patients (at least many of mine) are not good candidates for psychotherapy (not willing to go, too little insight for therapy to be useful, etc.), so there is a selection bias in terms of who participates in the RCT, and there may be real differences between those patients who would participate in a study and those who would not (i.e., their depression in the setting of who they are may respond differently to meds, for example).
  • Real-world applicability of RCT results: primary care providers do not have accessible study nurses who call the patients regularly, see if there are any problems, make sure they are taking their meds and perhaps do pill counts, make sure they make it to their psychotherapy appointments/etc., and have the drug company sponsors pay for all of the copays, transportation costs, and give the patient financial incentives to adhere to the protocol. Our real world patients may have little of these benefits, and may respond to treatments differently than the study patients as a result.
  • Placebo effect: an assumption in RCTs is that they are trying to prove that there is an incremental value of a new med, for example, over placebo. But maybe the placebo effect is clinically important???  There may be no trial showing that choosing a med based on either the patient’s prior success or that of a family member leads to a higher likelihood of success in the patient in front of you. BUT, first of all, there may be lack of recommendations about this just because the study was never done (i.e., there actually may be a benefit in choosing an SSRI based on this, we just don’t know). AND, even if there is a placebo effect, such that there is an increased response if the med worked before or in a family member, that’s clinically important and in the patient’s interest…..
  • So, this is not to say that there is no real use or even real importance of RCTs, just that there are limitations to their generalizability. And in the above case of depression, both the lack of studies to answer important questions and the assumption that we need to minimize the placebo affect should not necessarily undercut the applicability of treatments. Perhaps the main points of the guidelines are that there is reasonable equivalence overall to meds and psychotherapy (esp. CBT) overall, but that for such a really common problem as MDD, there are embarrassingly few high quality studies addressing the pressing clinical issues we see day-in and day-out…

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.

Results:

  • 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 http://blogs.bmj.com/ebm/category/pharmacy/​ .
  • 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: Phobias and Propranolol

28 Jan, 16 | by EBM

By Dr. Geoffrey Modest

There was a recent op-ed in the NY Times by the psychiatrist Richard Friedman on phobias and medical therapy (see http://www.nytimes.com/2016/01/24/opinion/sunday/a-drug-to-cure-fear.html?emc=edit_th_20160124&nl=todaysheadlines&nlid=67866768&_r=0 ).

His points:

  • 29% of Americans have some anxiety at some point in their lives
  • He cites a pretty remarkable study on using propranolol to block this anxiety, perhaps from blocking norepinephrine action (see article and review below)
  • He also raises the interesting contrary concern: stimulants (e.g. ritalin) can cause release of norepinephrine and could theoretically enhance fear/anxiety, or even PTSD in those exposed to trauma. He notes that soldiers exposed to stimulants did in fact have more

A small study was done looking at the effects of the b-blocker propranolol in inhibiting memory reconsolidation and decreasing the phobia (see Biological Psychiatry 2015; 78:880). The stimulus for the study was that fear memories are now considered not to be indelible memories, but ones which on reexposure to the object of fear, leads to neural protein synthesis and reconsolidation of that memory. Animal studies suggest that b-blockers can disrupt this process of reconsolidation and decrease anxiety. Based on this model, a small study was done of humans with arachnophobia. Wolf_spider_on_white

Details:

  • 15 people with arachnophobia (fear of spiders) received a single dose of propranolol, 40mg, vs 15 who received placebo, after a 2-minute exposure to a tarantula. An additional group received propranolol without the arachnid exposure
  • After the above treatment (propranolol or placebo), the patients stood in front of an open-caged tarantula at a distance of 60cm, then were asked to approach and attempt to touch the spider with their bare fingertips. Patients were tested at 16 days post-exposure, 3 months, and again at 1 year

Results:

  • ​The effect of the propranolol was striking and longstanding: patients were able to handle the tarantula after propranolol but not placebo, from the 16-day test to that at 1 year, without any falloff over time. In fact, all of the participants in the propranolol group were able to touch the tarantula 16 days later, 3 months later and 1 year later. In the other groups (both those on placebo and those on propranolol but not previously exposed to the tarantula), patients “barely touched the container” and demonstrated fears on approaching the container throughout the follow-up period. So, it was not just giving propranolol alone: taking propranolol without the tarantula exposure had no protective effect
  • In the group exposed to the tarantula, there was no effect of the propranolol in the patients’ self-declared fear of spiders at the 16 day post-exposure test (though, as noted, they were able to physically handle the spider at that time). But at 3 months there was less reported fear of spiders, and this persisted for the 1-year test

So, a few points:

  • Pretty remarkable that a single dose of propranolol can block the phobia for at least one year (though there were small numbers of patients in this study, propranolol certainly seems worth trying, it being a known and pretty innocuous med). Data from cognitive-behavioral therapy and extinction therapy (progressively increasing exposure to the feared object) show effectiveness, though that lasts only a brief time (personal testimony: I have some significant fear of heights. When I need to work on the roof of my house, it is really anxiety-provoking the first or second time up the ladder. But after a few times, I am fine going up and down, without concern — except that I am very careful. But then several months later, I am back to square one….)
  • And it is pretty interesting that the physiologic effect of propranolol is initially distinct from the cognitive effect, in that patients still stated they were still afraid of spiders at the day-16 test.
  • There are also some preliminary evidence that b-blockers decrease physiological responses to re-experiencing trauma in people with PTSD (it might be really interesting to try propranolol just after a person with PTSD has an experience which brings back memories of their trauma…). But, as a conceptual aside,​ I have seen several articles on the use of prazosin for PTSD (e.g., see AnnPharmacother 2007; 41: 1013)​, especially for decreasing the associated nightmares, and I have treated several patients with great, rather unexpected success. The concept is that sleep disorders are common with PTSD (70%), and that prazosin inhibits norepinephrine and perhaps thereby decreases the arousal in response to a stressor. In my experience, even very low dose prazosin has had dramatic results (e.g. 1-3 mg at night), though a recent article (Ther Adv Psychopharmacol 2014; 4: 43) notes that often higher doses are needed for full responses. These researchers also present 2 cases of patients of patients with psych comorbidities, one with PTSD and underlying major depressive disorder, but with a lot of daytime symptoms as well (hyperarousal, flashbacks, and re-experiencing the trauma) who responded pretty dramatically to prazosin 15mg in the am, 10mg at noon, and 20mg at night, and this high dose was very well-tolerated. The second patient with long-standing treatment-resistant major depressive disorder, PTSD and panic disorder and having failed a litany of meds, had lots of flashbacks, hypervigilance, reliving the experience, avoidance, nightmares, insomnia and concentration difficulties. She was titrated up to a dose of prazosin 15mg in am, 5mg at noon, and 10mg at night, and was also put on clomipramine for the depression, with a phenomenal response (PHQ-9 of 0 and asymptomatic PTSD).
  • So, as more studies unfold, the brain seems to be increasingly plastic/reprogrammable (i.e., it is not set for life at age 2, or 20, or ….)

Primary Care Corner with Geoffrey Modest MD: Drink Coffee and Live Longer

7 Dec, 15 | by EBM

By Dr. Geoffrey Modest

An analysis of the Nurses’ Health Studies (NHS, which began in 1976 with RNs aged 30-55 and  NHS2 which began in 1989 with RNs aged 25-42) and the Health Professionals Follow-up Study (HPFS, which began in 1986, with male health professionals aged 40-75) assessed total and cause-specific mortality in drinkers of caffeinated and decaffeinated coffee (see  or DOI: 10.1161/CIRCULATIONAHA.115.017341).

Details:

  • 74,890 women in NHS, 93,054 women in NHS2, and 40,557 men in HPFS, with extensive semi-quantitative food frequency questionnaires (131 items, administered every 4 years), and 4,690,072 person-years of follow-up. 95% white.
  • Up to 30 years of follow-up, with extensive data on known or suspected confounders (biennial questionnaires asking about age, weight, smoking, physical activity, medication use, fam history of diabetes, and self-reported diagnoses including hypertension, hypercholesterolemia, cardiovasc disease, and cancer), and 31,956 deaths

Results:

  • Never coffee drinkers, included 12% of those in NHS, 30% in NHS2, and 17% in HPFS
  • Drinkers of >5 cups/d, included 24% of those in NHS, 35% in NHS2, and 25% in HPFS
  • Compared to non-drinkers, coffee consumption of 1-5 cups/d was associated with decreased total mortality (HR for death was 0.95 for <=1cup/d, 0.91 for 1.1-3 cups/d, 0.93 for 3.1-5 cups/d, all of which were statistically significant, and a nonsignificant HR of  1.02 for >5 cups/d). No diff between caffeinated and decaffeinated coffee consumption
  • When analysis was restricted to never smokers (there were 10,505 deaths in 2,451,970 person-years in this group), compared to nondrinkers:
    • <=1cup/d, HR for mortality 0.94 (0.89-0.99)
    • 1-3 cups/d, HR for mortality 0.92 (0.87-0.97)
    • 1-5 cups/d, HR for mortality 0.85 (0.79-0.92)
    • >5 cups/d, HR for mortality 0.88 (0.78-0.99)
    • Overall p<0.001 for the trend
    • The association with total mortality was especially strong for those <70yo; no differences if stratify by diet quality (they calculated the Alternate Healthy Eating Index), BMI, physical activity, sex, and the cohort studied (NHS vs HPFS)
    • For caffeinated coffee, the trend had p<0.001. For decaffeinated coffee, the trend had p=0.022 (still significant)
    • Association with 1-cup increments of coffee/d found significant inverse associations for cardiovascular disease, neurological diseases, and suicide. No significant association with total cancer mortality

So, really great news…

  • Why does this make sense, especially since the association was not really with caffeine?
    • For cardiovascular disease: chlorogenic acid, lignans, quinides, trigonelline, and magnesium in coffee reduce insulin resistance and systemic inflammation
    • For neurological diseases (other studies have also found coffee consumption was associated with lower risk of Parkinson’s): for MPTP-induced Parkinson’s, there is loss of striatal dopamine transporter binding sites, and dopaminergic neurons, which is attenuated by caffeine
    • For suicides (also found in other studies): ???coffee has antidepressant effects, also it turns out that mice in stressful situations given caffeine have less stress-induced changes in their brains and behavior, but this doesn’t really answer the question about coffee or esp about decaffeinated coffee in humans
  • And, unfortunately, this study just reveals an association, so hard to say that this is causal. Though this was based on really long-term studies of people with extensive food diaries and controlling for many of the underlying possible confounders (and, perhaps the major confounder of smoking). But, then again, it is all self-reported/not verified, and is in a largely white population of professionals, limiting the generalizability of its conclusions.
  • But, at least coffee is not being demonized as being bad for your health….. In fact, it probably should be added to the food pyramid, and at the bottom (right next to the dark chocolate).

Primary Care Corner with Geoffrey Modest MD: SSRI use in pregnancy and birth defects

29 Jul, 15 | by EBM

By: Dr. Geoffrey Modest

A recent case-control analysis from the National Center on Birth Defects compared women who had children with birth defects to those without, to assess the association of the birth defects with specific SSRIs (selective serotonin reuptake inhibitors) taken from the month before pregnancy and through the third month of pregnancy ​(see BMJ 2015;350:h3190​).

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Details:

 –17952 mothers of infants with birth defects from US centers in 10 states were compared with 9857 who did not have infants with birth defects. they looked specifically at the birth defects previously reported to be associated with SSRIs, with data from the US National Birth Defects Prevention Study database. Excluded were mothers at higher risk for having children with birth defects for other reasons (diabetes, teratogenic drugs), or those not on SSRIs for psych conditions including depression, bipolar disorder, obsessive compulsive disorder.

–researchers looked at 5 SSRIs (citalopram, escitalopram, fluoxetine, paroxetine, and sertraline), controlling for maternal race/ethnicity, education, smoking and prepregnancy obesity.

Results:

–3.0% of mothers were on an SSRI (298 women)

–sertraline was the most commonly used SSRI (38.6% of controls), but there was no association with birth defects (assessed for the previously reported problems of anencephaly, septal defects, anal atresia, limb reduction, omphalocele)

–paroxetine (14.1% of controls) was associated with anencephaly [OR 3.2 (1.6-6.2)]; atrial septal defects [OR 1.8(1.1-3.0)]; right ventricular outflow tract obstruction defects [OR 2.4 (1.4-3.9)]; gastroschisis [OR 2.5 (1.2-4.8)]; and omphalocele [OR 3.5 (1.3-8.0)] (also assessed for previously reported hypospadias, cleft palate)

–fluoxetine (24.8% of controls) was associated with right ventricular outflow tract obstruction defects [OR 2.0 (1.4-3.1)] and craniosynostosis [OR 1.9 (1.1-3.0)] (also assessed for ventricular septal defects, esophageal atresia)

–citalopram (9.7% of controls) and escitalopram (8.7% of controls), no association with birth defects, except for marginal association between citalopram and neural tube defects [OR 1.8 (1.0-3.0)]. (citalopram also assessed for ventricular septal defects, cleft lip/palate, hypospadias; escitalopram assessed for septal defects)

So, this was a pretty large database, with presumably pretty thorough data collection, having a few conclusions (though should be confirmed in other large databases)

–Sertraline, which has evolved into being the most prescribed SSRI used in early pregnancy, seems to be pretty safe, not confirming any of the five previously reported birth defects

–Paroxetine should be avoided if possible. that being said, it is important to bear in mind that depression itself may have a significant morbidity an mortality (maternal and fetal), treating depression is very important and often needs meds, and one SSRI may work a lot better than others. so, the perspective here is that the likely very real  higher risk of fetal abnormalities that they found translates to pretty small absolute risks of anencephaly of 2-7/10,000; right ventricular outflow tract obstruction from 10-24/10,000 (assuming the associations are causal).

–The variability of the birth defect risks suggest that it risk is not intrinsic to the serotonin reuptake inhibition itself but to other structure or pharmacokinetic properties of the meds

–In terms of fetal effects of untreated maternal depression, there was a review and set of recommendations from the  American Psychiatric Association and the American College of Obstetricians and Gynecologists (see doi:10.1016/j.genhosppsych.2009.04.003​), with a few more recent studies. Overall,

–miscarriage rate: some suggestion in the literature of an association, but studies were small and methodologically limited. So, no clear-cut association.

–growth effects: some studies found increased risk of low-birth-weight and small-for-gestational-age infants, but again poor quality data. 2 more recent studies have found some evidence of decreased fetal weight gain and fetal growth restriction.  So, no clear-cut association.

–preterm delivery: again, overall not great studies. more recent ones have found modest effect in decreased breast-feeding and more preterm delivery.  So, no clear-cut association.

–neonatal effects: no clear association with congenital abnormalities. but more neonatal irritability, less activity and attentiveness, and fewer facial expressions; and, small studies have found increased blood cortisol levels and decreased dopamine and serotonin levels (as found in the depressed mothers), and greater neonatal right frontal EEG activation and lower vagal tone.

–longer-term effects: no data on mothers with Major Depressive Disorder (formally assessed), but instead in mothers with prenatal depressive symptoms, finding that kids at 18 months had greater developmental delay. other studies were less impressive.

Bottom line to me: good studies have not been done (that I know of) which assess pregnant women with Major Depressive Disorder (which is the group in the general population most responsive to SSRIs) and look at important maternal and fetal/childhood outcomes, including not just the “hard outcomes” of congenital abnormalities, in utero growth, preterm delivery, but also the short-term effects on the pregnant woman (coping skills, function, general sense of well-being) and the longer-term effects on the child (bonding, general assessment of function, happiness, developmental milestones, psychological effects, etc). In the meantime, I think it is important to treat depression in pregnancy, which may well include using medications (as well as support, counseling), and that the BMJ study provides reassurance that there are several antidepressants which are not associated with evident fetal congenital abnormalities, despite some reports to the contrary.

 

Primary Care Corner with Geoffrey Modest MD: Depression treatment in the elderly

4 Mar, 15 | by EBM

By: Dr. Geoffrey Modest

elderlyThe treatment of depression in the elderly can be very difficult. The usual meds (SSRIs) tend to be less effective in the elderly, with some studies not finding much difference from placebo. And psychotherapy, which does help some, is often also less effective, given that many elderly do not have much insight into their condition and many also find it difficult to change. There have been studies in the past showing significant efficacy of stimulants, especially in those with severe depression (eg, a study at Mass General Hosp of 129 geriatric inpatients with severe major depression found 66% with significant improvement within 1-2 days, and only 8% with adverse reactions and none with reduction in appetite. Average doses of dextroamphetamin was 8.2 mg and methylphenidate 8.2 mg (see J Geriatr Psychiatry Neurol. 1990;3(3):146). Other old studies have found an overall response rate of 81%.  I am unaware of newer studies).

In this context, a 16 week RCT was done of 143 geriatric outpatients with major depression, comparing methylphenidate to citalopram to the combination of the two (see doi: 10.1176/appi.ajp.2014.14070889). In brief:

–mean age 70, 1/2 women, 75% white, 16 years of education, age at depression onset mean 42 yo, duration of episode mean of 48 months and 80% with >24 months of depression.

–inclusion criteria: unipolar major depressive disorder, score >15 in Hamilton Depression Rating Scale HAM-D (mean in study was 18.9) and >25 on Mini-Mental State Exam (mean was 28.7)

–patients seen weekly for 4 weeks to titrate methyphenidate dose, then every 2 weeks for the 16-week study (ultimate methylphenidate range was 5-40 mg, with average of 16.3 mg in both groups). citalopram started at 20mg, then increased to 40mg after 1 months if insufficient improvement, then 60mg after 7-8 weeks if needed, with average dose of approx 35 mg in both groups.

Results:

–the HAM-D was significantly improved in the combo group within 2 weeks and maintained for the rest of the study (62% ​ remission rate at 16 weeks). the citalopram only group was intermediate (42% at 16 weeks), and the methylphenidate group did the least well (29% at 16 weeks). all of these results were significantly better than placebo for depression severity, assessment of global clinical improvement, and cognitive function (methylphenidate did not add to the improvement of cognitive function).

–the citalopram dose was significantly associated with achieving remission: 29.8% in those without citalopram, 41.9% in those on 20mg, 56.4% in those on 40mg, and 69.2% in those on 60mg. there was no clear dose-response curve in those on methylphenidate.

So, pretty impressive results. the combination therapy was pretty well-tolerated (did not increase the incidence of adverse reactions or the number of people who dropped out of the study — 45 dropped out, for a variety of reasons). The symptom response to the combination was faster (evident within a couple of weeks) and more profound. The issues that come up are:

–The FDA limits the citalopram dosing to 20mg for elderly. I did note in a blog post “there is a pretty dramatic increase in QTc with citalopram, but it is important to note that the actual clinical effect of this prolongation is NOT clear: the FDA looked at a large VA database and found that the risk of ventricular arrhythmias and mortality were LOWER in depressed patients on greater than 40mg citalopram/day, similar results to those found in patients on sertraline”.

–One other concern is that methylphenidate can increase citalopram levels

It would be great to have studies looking at the combo of another, perhaps safer SSRI (eg sertraline) with methylphenidate….

Primary Care Corner with Geoffrey Modest MD: Citalopram improves Alzheimer’s agitation

24 Feb, 14 | by EBM

JAMA this week reported on the use of citalopram for agitation in people with Alzheimer’s disease (see doi:10.1001/jama.2014.93). details:

–double-blind study of 186 pts with probable alzheimer’s and agitation (mean age 78, 46% women, 65% white, 70% on cholinesterase inhibitor and 42% on memantine) at 8 US and Canadian academic sites, all with 9 week psychosocial intervention, half with citalopram (began at 10mg, titrated up to 30mg over 3 weeks, and with 78% achieving the 30mg target). psychosocial intervention consisted of giving educational material, 24-hr availability for crisis management, and 20-30 minute counseling session at each visit, focusing on reviewing/adjusting supportive care plan, providing emotional support, counseling regarding specific caregiver skills, and assistance with problem solving on specific caregiver/patient issues.  At 9 weeks:

–18-point Neurobehavioral Rating Scale agitation subscale (NBRS-A) with 1 point improvement (felt by editorialist to be clinically significant) with citalopram.
–modified Alzheimer Disease Cooperative Study- Clinical Global Impression of Change (mADCS-CGIC) found 40% on citalopram to have moderate or marked improvement, vs 26% placebo. (OR 2.13)
–those on citalopram also had improved Cohen-Mansfield Agitation Inventory, Neuropsychiatric Inventory, and caregiver distress scores (but, no improvement in Neuropsychiatric Inventory scale, ability to complete ADLs, or in less use of rescue lorazepam,  AND there was worsening of cognition by 1 point on Mini Mental Status Exam (though unclear clinical relevance of this small a change; typically a 1.4 point change is considered significant) and increase in QTc by 18.1msec.

so, a few points of interest.

–neuropsych sx are really common in Alzheimer’s. antipsychotics have been used lots in the past, with unclear efficacy in the studies, and increased mortality (though they certainly seemed to work in some of my patients…) –given the FDA warning about citalopram dosing and increased QTc, lower doses and closer EKG monitoring seems reasonable. i had posted a previous blog confirming that there is a pretty dramatic increase in QTc with citalopram, but it is important to note that the actual clinical effect of this prolongation is NOT clear: the FDA looked at a large VA database and found that the risk of ventricular arrhythmias and mortality were LOWER in depressed patients on greater than 40mg citalopram/day, similar results to those found in patients on sertraline (i have largely shifted to sertraline as my “go-to” antidepressant overall, away from citalopram because of the QTc issue, but still use citalopram if sertraline not tolerated). anecdotally, a geriatric psychiatrist i know has been using sertraline for agitation in people with Alzheimers, with good effect. citalopram in this study was well-tolerated.
–overall, very impressive but short-term study. i would certainly prioritize nonpharmacologic management, but if insufficient, finding a 40% moderate to marked improvement with decreased agitation is very impressive.

geoff

Primary Care Corner with Geoffrey Modest MD: varenicline, combo Rx and use in mental illness

21 Jan, 14 | by EBM

there were a few important articles in the jan 8th JAMA on smoking — i will highlight 2 of them on varenicline, a partial agonist which binds with high affinity as well as specificity to neuronal acetylcholine receptors. smoking cessation in smokers is the most significant single intervention to decrease mortality, and 62% of deaths in female smokers/60% of deaths in male smokers are attributable to smoking.

 

1. i had postedt a general smoking cessation article about one year ago from JAMA which referenced some small study finding benefit of combining varenicline with bupropion. the current study (see  doi:10.1001/jama.2013.283185) was a 12-month multi-center RCT comparing varenicline with bupropion vs varenicline with placebo, with both medications dosed as is generally recommended.  results:

 

–500 patients (mean age 42, 94% white, 45% women, 78% completed at least some college — study done at Mayo clinic and univ minnesota), though only 62% completed the study (dropout rates similar in both groups)

–of those completing study:

–at 12 weeks: 53% in combo group achieved smoking abstinence and 56% 7-day point-prevalence smoking abstinence (ie, self-reported tobacco cessation for previous 7 days, confirmed by carbon monoxide level), vs 43% and 49% with varenicline alone

–at 26 weeks: 37% with prolonged and 38% with 7-day point prevalence abstinence in combo and 28% and 32% with varenicline alone

–at 52 weeks: 31% with prolonged and 37% with 7-day point prevalence abstinence in combo and 25% and 29% with varenicline alone

–adverse effects: combo with more anxiety (7% vs 3%) and depressive sx (4% vs 1%) — a bit surprising since the combo group had bupropion, a pretty potent anti-depressant….

–of the above, the only findings reaching statistical significance were: smoking abstinence at 12 and 26 weeks. no significance at 52 weeks, or any of the measures of 7-day point prevalence.

–subgroup analysis: for heavy smokers (>20 cigs/day), combo therapy assoc with statistically significant prolonged smoking abstinence at 12 weeks (50% vs 36%), 26 weeks (35% vs 19%) and 52 weeks (32% vs 17%), with similar numbers for those with high levels of nicotine dependence.

–less weight gain in combo group than in varenicline alone (1.1 vs 2.5kg at 12 weeks, 3.4 vs 3.8kg at 26 weeks, and 4.9 vs 6.1kg at 52 weeks)

 

this trial confirms the concept of combination therapy and extends it to varenicline plus bupropion. other studies have found improved abstinence rates with combo of bupropion and nicotine replacement therapy (NRT), and with using combo NRTs (eg patch for maintenance nicotine levels, with inhaler or lozenge for times of increased urge to smoke).  this study, though small numbers of patients and pretty high dropout rate, does suggest that the combo of bupropion and varenicline is effective, esp in those who are heavy smokers.

 

there are minimal studies of electronic cigarettes, as per a prior blog. mostly short-term (eg 12 weeks: 14% abstinence with e-cigarettes vs 4% with nicotine-free device; another study for 6 months found no statistical difference between e-cigarettes, nicotine patch or placebo). of note, the FDA has found important carcinogenic contaminants in 2 brands of e-cigarettes: polycyclic aromatic hydrocarbons and nitrosamines. (though my experience in a relatively small number of smokers is that the e-cigs did help them quit, and cigarettes have many more dangerous additives. however, i and others are concerned that e-cigarettes may change the rather pervasive anti-smoking ethic developed in this country over many years and make tobacco more acceptable and even chic for young people).

 

2. the above study excluded patients with major medical or psych illnesses, and there is concern that varenicline could exacerbate psych problems. in addition, the baseline smoking rates are significantly higher in people with mental illness (25% vs 19%, in 2011). not surprisingly, those with mental illness who received mental health treatment quit smoking at a higher rate than those who did not receive treatment (37% vs 33%). another JAMA article looked at patients with schizophrenia or bipolar disease who had quit smoking on varenicline and then were put on maintenance of varenicline plus cognitive behavioral therapy (CBT) vs CBT alone (see  doi:10.1001/jama.2013.285113), as follows:

 

–of 203 smokers (60% smoking more than 20 cigs/d) with medically-treated and stable schizophrenia or bipolar dz, then treated with varenicline in a 12-week open trial, 87 had at least 14 days of continuous abstinence by the end of this period (88% had schizophrenia, 12% bipolar)

–these 87 abstinent patients were randomized to continued varenicline to complete 52 weeks, along with tapering CBT sessions (median of 26 sessions), vs  placebo and CBT (24 sessions)

–at the end of the varenicline intervention (52 weeks), point prevalence abstinence rate of 60% with varenicline vs 19% placebo

–at the end of the study (76 weeks — ie, 24 weeks after stopping intervention), abstinence rates of 30% vs 11% (pretty impressive!!)

–and, perhaps most noteworthy, no difference in adverse events with varenicline in the open-label part of the study, and there were actually fewer reports of agitation or excitement with the maintenance varenicline than placebo (though more headaches)

 

so, small study, but does suggest that we can use varenicline in patients with schizophrenia or bipolar disease, which i think many of us were wary about.

 

geoff

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