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…
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