Tuesday, November 10, 2015

The Business of Psychological Questionnaires

Questionnaires are certainly in vogue in mental health research.  Often they are referred to in technical-sounding jargon, for example it is common to call a questionnaire an "instrument"  or a "measurement tool."

There are good reasons to have well-standardized questionnaires.  In research, it is useful if people across the world are all using a similar type of questionnaire, so that comparisons can be made more easily and clearly.

In psychotherapy or other mental health practice, there is evidence that obtaining regular feedback from patients or clients can be valuable to improve the quality of the therapy, and to prevent mistakes.  One of the leaders in showing the importance of this is Michael Lambert, an esteemed psychologist and psychotherapy researcher from Brigham Young University.  In a nutshell, his research shows us that problems can occur in psychotherapy without the therapist realizing it:  the patient or client could be developing new symptoms, detaching or losing interest in the therapy, feeling upset or disappointed with the therapist, or even developing a life-threatening emergency, but the therapist may not know this, because it is not talked about or asked about in the session.  This could be because the patient is inhibited to share this information, but it could also be simply because the problem was never inquired about.  In therapy sessions, just like with any other interaction, one can follow a certain narrative pathway habitually, therefore missing things that could be quietly going wrong in the background.

So Lambert has developed a questionnaire called the OQ-45, which consists of 45 simple questions covering everything from mood, anxiety, relationship satisfaction, loneliness, drinking, family life, work life, cognition, and physical health.  The idea is for patients or clients to fill in this questionnaire frequently, maybe even before every therapy appointment, so that no potential evolving problem area would be "missed."   The questionnaire would only take a few minutes to fill out, and could be done in the waiting room before an appointment.    Samples of the OQ-45 can be found in an internet search.  

I believe that this type of questionnaire is useful.  Certainly we have to respect Lambert's many years of research, to acknowledge that feedback of this type can improve therapy.

But the therapeutic benefit of this is not due to some special property of the questionnaire itself!  And the therapeutic benefit does not require the sophisticated statistical analysis that is offered to purchasers of the questionnaire!  The benefit of this is simply to do a review of symptoms regularly with patients or clients.  

Questionnaires in psychology have become a business.  For hundreds of dollars, one can sign up to receive copies of a questionnaire, scoring manuals, or perhaps an on-line entry and scoring package, which may produce attractive graphs of results.

I believe that it is absurd--in most cases--to have to pay for something like this.  The therapeutic principle here is of simply keeping track of a wide range of symptoms or problems systematically.   The technology here is not a sophisticated x-ray machine or microscope -- rather, they are sets of simple questions such as "I'm a good person" or "My body hurts" (to be rated from 0-4).

I have jokingly thought of creating a questionnaire, to be marketed, with a full statistical analysis package and online access, called the "How Are You Doing" instrument (the HAY-D-1).  It would consist of a single question, "How are you doing?"  with the opportunity to choose from one of 5 responses.    Perhaps there could be a published article demonstrating its reliability, validity, and correlations with other established research instruments. 

Understandably, many researchers have worked long and hard to show useful results from their work.  And it could be very desirable for them to have a way to earn a financial reward from the fruits of their labor.  I suppose, in a free society, it is quite reasonable for people to attempt to sell such things, if people are willing to buy them.

But when there is this type of marketing and financial dealing going on, it can increase biases on the part of both the seller and the buyer.  The buyer, having paid good money for questionnaires or "instruments," is more likely to think highly of their acquisition, due to cognitive bias (think again of Daniel Kahneman's work showing such effects).  Perhaps therapists are more likely to rely on such purchased questionnaires rather than simply creating their own.

I think it could be useful, if questionnaires are to be used at all, to create custom symptom review questions.  There is also some evidence that questions about the therapeutic alliance could be pertinent to therapeutic progress; these are absent from many symptom review surveys, including the OQ-45.

A nice idea in CBT is to have the clients or patients be actively involved in assessing and planning their own progress, instead of having the therapist be the "assessor."  So, it could be a useful therapeutic exercise for clients or patients to design their own questionnaires, using their own language, and their own scale!  The therapist could encourage and suggest a wide range of categories of questions to be followed, covering areas of physical, social, occupational, cultural, and psychological health, as well as a category about the therapeutic alliance, but the questions themselves could be designed by the client or patient!    If statistical analysis was felt to be interesting or useful, we could easily design a simple app to create graphs, or use a spreadsheet -- we would not have to pay an extra fee for this!

So I support the idea of regularly conducting broad symptom reviews in psychotherapy, but I do not believe it is necessary to buy questionnaire packages.  It could be even better to design one's own package, or collaborate with a patient or client to design a custom, personalized survey.  

Monday, November 9, 2015

Quetiapine for non-psychotic depression and anxiety

I read a recent review last week which warned against the use of quetiapine for treating non-psychotic mood disorders.

Yet, I believe there are a number of reasons to consider quetiapine and similar medications for non-psychotic states:

1) there is a much lower risk of the medication causing mania or psychosis.  With antidepressants, there is always the risk of mania induction.  Quetiapine not only would not cause mania, it could protect against it.

2) the use of quetiapine could reduce the likelihood of other sedatives, such as benzodiazepines, being used as often.  Benzodiazepine dependence is very common.  Quetiapine is less "addictive."

3) the doses of quetiapine in non-psychotic states can often be very low (under 100 mg) causing a much lower risk of metabolic side-effects than full doses of 400-600 mg per day or more.

What about research evidence?

Mezhebovsky et al (2013) published results of a multi-centre study involving about 450 elderly patients, showing that quetiapine 50-300 mg (mean = 168 mg) daily for 11 weeks, led to significant improvements in generalized anxiety symptoms, compared to placebo.
( http://www.ncbi.nlm.nih.gov/pubmed/23070803  )
 As with most effective treatments, the medication group had about twice as much improvement as the placebo group.  It is true that sleep improvement could account for a significant proportion of the overall symptom score improvement, but there was also improvement in the other symptom domains.   There were no major metabolic side effect problems in the quetiapine group.  The most common side effect was somnolence (sleepiness).

A 2012 review by Sanford and Keating ( http://www.ncbi.nlm.nih.gov/pubmed/22519923 ) showed an abundance of evidence that quetiapine is beneficial for treating bipolar depression (typically at doses of 300 mg/day) and for preventing recurrences of any mood episode.  For those who benefit acutely from quetiapine, there is evidence that it is a more effective mood stabilizer--on its own--than lithium. 

In unipolar depression, quetiapine would be most commonly used when a standard treatment such as an antidepressant was not working well.  In a study by El-Khalili et al (2010), quetiapine up to 300 mg per day was added as an adjunct to previous therapy for non-remitting depression:
( http://www.ncbi.nlm.nih.gov/pubmed/20175941).  They showed a modest benefit of adding the quetiapine, particularly at a higher dose of 300 mg/d.    A nice component of this article is the inclusion of symptom subtypes.   Many critics would argue that quetiapine might simply be sedating, and improve sleep, leading to most of its benefit over placebo.  These results confirm that quetiapine improves sleep symptoms.  But there were also symptom improvements in other categories, such as pessimism, inner tension,  and concentration impairment.

In conclusion, I think that quetiapine deserves to be considered as a medication option for non-psychotic conditions.   In many cases, there are comorbidities or diagnostic uncertainties, in cases of depression.  Many studies exclude patients who have comorbidities, or who do not neatly fit into diagnostic categories.   Quetiapine is unlikely to worsen comorbid conditions, and may be beneficial for many.  This makes it a safe option to think about if there is uncertainty or complexity in the diagnosis.  Standard antidepressants in this situation may carry a higher risk of causing new problems, including agitation or a manic state.

 The risks of metabolic side effects, etc. need to be watched for carefully, with consideration of stopping or changing the plan if problems of this type arise. 

Duloxetine (Cymbalta)

Duloxetine (Cymbalta) is another newer antidepressant, approved in the US in 2004, and in Canada in 2007.  It is a reuptake inhibitor of both serotonin and norepinephrine, and is most similar in this regard to venlafaxine (Effexor).  

In a study of medication treatment options for severe depression, a switch to duloxetine was compared with a dose increase of escitalopram.  The escitalopram group had better results, including a remission rate of 54% for escitalopram vs. 42% for duloxetine.  ( http://www.ncbi.nlm.nih.gov/pubmed/22559255 )

Another similar comparative study also favoured escitalopram 10-20 mg daily over duloxetine 60 mg, both in terms of effectiveness and side effect profile.  In this study 2% of the escitalopram group dropped out due to side effects, compared to 13% of the duloxetine group.
( http://www.ncbi.nlm.nih.gov/pubmed/17563128 )

In this well-done 2011 review by Schueler et al. comparing venlafaxine and duloxetine with SSRIs.  They concluded the following:
1) Venlafaxine had superior efficacy in response rates but inferior tolerability to SSRIs
2)  Duloxetine did not show any advantages over other antidepressants and was less well tolerated than SSRIs and venlafaxine.
( http://www.ncbi.nlm.nih.gov/pubmed/20831742 )

Another study, done in 2006, also showing evidence that venlafaxine is superior to duloxetine:  http://www.ncbi.nlm.nih.gov/pubmed/16867188

In one of the few well-designed comparative studies of venlafaxine vs. duloxetine, done by Perahia et al (2008), the two medications are found to have similar effectiveness, but with a higher dropout rate due to side effects in the duloxetine group. ( http://www.ncbi.nlm.nih.gov/pubmed/17445831 )   A look at graphs of symptom change show that the two medications appear identically effective.  But duloxetine caused more side effects, especially nausea.  It is true that discontinuing venlafaxine causes more side effects than discontinuing duloxetine, but this could be framed as a technical matter that just needs to be managed by very slow tapering.

This 2012 study (sponsored by the manufacturer!) by Martinez et al ( http://www.ncbi.nlm.nih.gov/pubmed/22027844 ) compares duloxetine with SSRI treatments for major depression, in a 12 week prospective trial.  Duloxetine performed well, but on the primary outcome measure there was no significant difference in response or remission rates.  On secondary measures there appeared to be some advantages for duloxetine, particularly for pain symptoms.  But the study was not intended to be for treating pain syndromes!  SSRIs are known to be ineffective for pain!
 Duloxetine is often touted as a good treatment for neuropathic pain.  And numerous studies do show that it can help.  But how does it actually compare to other options?  Specifically, how does it compare with a much cheaper and similar antidepressant, venlafaxine?   Rudroju et al (2013) looked at comparative effectiveness of various medications for treating neuropathic pain.  Many medications helped, including duloxetine.  But in this study, gabapentin and venlafaxine had the best odds ratio of helping, followed by pregabalin. Duloxetine was farther down the list.  With a benefit-risk analysis, which takes into account side effects and tolerability, gabapentin, pregabalin, and venlafaxine were once again at the top of the list of best agents, with duloxetine farther down.
 ( http://www.ncbi.nlm.nih.gov/pubmed/24284851)

Duloxetine (Cymbalta) costs about $4.23 for a 60 mg dose, compared to $0.38 for an equivalent 150 mg dose of Effexor XR.  So it is about 10 times more expensive than an alternative which is shown to work as well if not better. 

In conclusion, Cymbalta is yet another newer antidepressant which is not necessarily better than alternatives; in fact the alternatives such as Effexor XR are probably equally effective or more effective.   It is marketed intensely as a treatment for neuropathic and other pain syndromes, but alternatives such as Effexor XR work better, with fewer side effects, at a lower cost.   Therefore, just as with the other antidepressants mentioned in the previous posts, Cymbalta could be considered a third-line option, which might suit some people well if they have tried other things unsuccessfully.


Vortioxetine is one of the newest antidepressants on the market, released in the U.S. in 2013.  It has serotonin and norepinephrine reuptake inhibition effects, plus a variety of direct effects on serotonin receptors. 

This is a negative study of vortioxetine, showing that it did not lead to any difference in rating scores compared to placebo, when used at doses of 10 mg or 15 mg daily, to treat depression for 8 weeks:

In another study, by Jacobson et al (2015), looking at doses of 10 mg or 20 mg daily, they found slight improvements in the vortioxetine groups compared to placebo, with "significant" differences in the MADRS score only for the 20 mg dose ( http://www.ncbi.nlm.nih.gov/pubmed/26035185 ).  If you look at the symptom changes vs. placebo on a graph, the clinical relevance of the vortioxetine effect appears questionable.  Yet, typically with papers of this type, despite the results being very unimpressive, the authors try to frame it in a very positive way, as though they had discovered a fantastically effective new treatment.  Vortioxetine is supposed to be helpful for managing sexual side effects as well, but the measures of this done in the study once again do not show a spectacular benefit.  For those who did not have sexual side effects previously, about half in the vortioxetine group developed sexual side effects, at a rate 10-20% greater than placebo.   Here are the authors' final assertions at the end of their paper:   "In conclusion, vortioxetine 20 mg significantly reduced MADRS total score at 8 weeks in adults with MDD. Overall, vortioxetine was well tolerated in this study."   Perhaps a more fair conclusion could be "vortioxetine produced small differences compared to placebo in the MADRS score, but only at a dose of 20 mg daily.  The degree of improvement does not compare favourably with similar studies using other antidepressants.  Rates of side effects, including sexual side effects, were higher in the vortioxetine groups compared to the placebo groups."   

A 2015 meta-analytic review paper by Rosenblat et al (http://www.ncbi.nlm.nih.gov/pubmed/26209859 ) showed in general that antidepressants appear to help with cognitive function when used to treat depression.  But they conclude that "no statistically significant difference in cognitive effects was found when pooling results from head-to-head trials of SSRIs, SNRIs, TCAs, and NDRIs."

In this article by Llorca et al (2014), which is a "meta-regression analysis", it appears to favour vortioxetine as being better than other antidepressants.  (https://www.ncbi.nlm.nih.gov/pubmed/25249164)This article is then quoted elsewhere, such as on Wikipedia, as supporting the claim that vortioxetine is a superior antidepressant.  But the article shows indirect information only, there is no actual comparative study referred to at all.  And the findings, even from this study, really only show that vortioxetine is in the "same ballpark" in terms of effects, compared to other agents-- it certainly doesn't show superiority.

It was hoped that vortioxetine might help with generalized anxiety, but after several negative studies (https://www.ncbi.nlm.nih.gov/pubmed/24424707,
https://www.ncbi.nlm.nih.gov/pubmed/24341301 ), the latter of which showing that it was significantly inferior to another antidepressant (duloxetine), it is no longer claimed by anyone that it is an appropriate treatment for GAD.

Vortioxetine costs about $3.25 for a 20 mg dose.  This is about 10 times more than a 20 mg dose of citalopram.  

In conclusion, vortioxetine is another new option for treating depression.  It could be something to think about for treating anxious depression.  But there is no evidence that it is superior to other options, and is probably inferior in many cases.  There is no evidence of any specific benefit for treating anxiety disorders such as GAD.    I would consider it to be a third-line alternative at this point. 

Sunday, November 8, 2015

Desvenlafaxine (Pristiq)

Desvenlafaxine (Pristiq) is an antidepressant that has been available since 2008-2009.  It is another example, similar to escitalopram, of a new drug being marketed which is simply a chemical "tweak" of another very similar drug.  Pristiq is an active metabolite of another common antidepressant, venlafaxine (Effexor).  Effexor had been on the market since 1993.

Being new, many studies were done, usually comparing it with placebo, showing that it works.  Yet, very few studies were done comparing it with other antidepressants.

Laoutidis and Kioulos (2015) have recently published a review and meta-analysis of desvenlafaxine.   http://www.ncbi.nlm.nih.gov/pubmed/26205685
They found that while it clearly works better than placebo in short-term trials, it is significantly inferior to other agents in comparative studies (i.e. those studies in which desvenlafaxine is compared with a different antidepressant prospectively).

In a 2014 study by Maity et al., desvenlafaxine and escitalopram were found to be equally effective (actually with a non-statistically-significant" edge favouring escitalopram) for anxious depression.  But in this study, it caused more side-effects than escitalopram.  http://www.ncbi.nlm.nih.gov/pubmed/25097285

Soares et al (2010) similarly showed no advantage to using Pristiq instead of Cipralex for treating depression in post-menopausal women.  Once again, Cipralex had a non-statistically-significant advantage in effectiveness over Pristiq. http://www.ncbi.nlm.nih.gov/pubmed/20539246

(to be clear about what I mean by "non-significant," it is important to know that all statistical findings are probability statements.  "Significant" usually refers to a finding which has a less than 5% chance of being due to random variation alone.    For many findings, one measure might exceed another, but with a higher than 5%  likelihood of the difference being due to chance.  It should be considered, though, that from a Bayesian point of view, if you have results which differ, even at a so-called "non-significant" level of confidence, this finding still increases the likelihood somewhat that there is a significant difference.  For example, if we toss a coin 10 times, and find that we get 7 heads (instead of the expected 5), we know that there is 17% chance of getting 7 or more out of 10 heads from a fairly balanced coin.  Thus this would be "non-significant" with respect to showing that the coin was not fairly balanced.  But even so, if one indeed did see 7 heads in 10 tosses, it should increase one's suspicion (in a quantifiable way) that the coin is actually imbalanced.  Thus, one should not entirely dismiss "non-significant" results, they should optimally be considered in a large fund of data about an issue, each part of which should reasonably sway our judgment slightly)

In this interesting study by Liebowitz et al (2013)
( http://www.ncbi.nlm.nih.gov/pubmed/23517291 ), Pristiq was offered at two different doses (10 mg and 50 mg), compared with placebo, for treating depression.  Both doses were superior to placebo, but were equally effective to each other!   Yet, the "recommended dose" is 50 mg.  Pristiq is only available in 50 mg and 100 mg tablets!  

Pristiq costs about $3.00 per 50 mg pill.  A similar drug, Effexor XR, costs $0.75 for a similar dose.  Celexa at an equivalent dose costs $0.27, according to Pharmacy Compass (http://www.pharmacycompass.ca/).

So I do not see any reason to recommend Pristiq, except as one of a list of alternatives to try after other options have been tried.  There is no reason to expect that it would work better than any other antidepressant, unless a particular person just happens to prefer it (as is sometimes the case).  There is evidence to suggest that it has more side effects than alternatives.  I do not necessarily think it is a bad drug though:  I'm sure that there are some who might try it, and find it very helpful after exploring other options.  But based on current evidence it should not be included as a first-line agent. 

Escitalopam vs. Citalopram (Cipralex or Lexapro vs. Celexa)

It is interesting how professional opinion can be swayed by trends in practice.   Escitalopram (Cipralex, or Lexapro) is a newer antidepressant than citalopram (Celexa).   In fact, citalopram itself is a mixture of "enantiomers," which are molecules that are identical to each other except for being mirror-images of each other geometrically.  In many chemical processes, different enantiomers are formed in fairly equal amounts, as a mixture.   But escitalopram, unlike citalopram, consists of just one of these entantiomers, rather than being a mixture.   Citalopram is literally a mixture of escitalopram with an inactive enantiomer.  Therefore, you literally are taking escitalopram when you are taking citalopram.  You are also taking the inactive enantiomer of escitalopram. 

Here we have it again, that escitalopram has more recently been on patent, while citalopram has been available in a generic form for a longer time.  Of course, there would be many more industry-sponsored research studies done recently on escitalopram. 

There's no doubt about it, that escitalopram can be a good antidepressant.  But many professionals (including in one formal instructive report I recently read), assert that escitalopram is clearly "better" than citalopram.

I think this belief is mainly due to cognitive biases.   There has been much more marketing favouring escitalopram in the past decade.  The trends in practice among psychiatrists tend to favour the personal belief that "escitalopram is better."  Because it is used more often these days than citalopram, any positive report about escitalopram is likely to be more salient.  Also, with recurrent trials of antidepressants, any switch to almost any new agent has a reasonable probability of leading to some improvement, irrespective of the properties of the new agent.  For many people, a given antidepressant does not work well enough.  In this cohort, it is much more likely that a given person would have tried citalopram at some point in the past, and would now be looking at trying escitalopram.  There might be about a 30% chance of the escitalopram helping in this scenario.  For the thousands of people in this group, there would then be hundreds who would have the experience of escitalopram appearing to work better than citalopram.   This feeds the notion that escitalopram is in fact a better antidepressant.

The bias here is that very few people in this cohort would have tried escitalopram first, then tried citalopram later on.   This is because escitalopram is newer, more highly marketed, and is more likely to be used when other antidepressants have not worked.   But the prevailing evidence is that most any new antidepressant (or other therapy) trial has a similar chance of helping, when a previous trial has not helped.  Therefore, I predict that there would be an equal likelihood of citalopram working when escitalopram failed, compared to escitalopram working when citalopram failed.  It is possible that the only reason escitalopram appears to work more commonly is that it is simply used more often!

Some of my patients, over the years, have tried both of these medications.  Some have ended up preferring escitalopram.   Others have ended up preferring citalopram.  For most, there has been no difference, either in side effects or effectiveness. 

Are there any recent research studies which compare the two?  One recent study, by Li et al (2014), reviews and pools results from 3 previous clinical studies.  They conclude that there is no difference in response or remission rates between escitalopram and citalopram:

It is interesting to look at the data from previous studies, including a Cochrane review done in 2012, which conclude that escitalopram is better than citalopram: http://www.ncbi.nlm.nih.gov/pubmed/22786497   The authors slip in the caution that "As with most systematic reviews in psychopharmacology, the potential for overestimation of treatment effect due to sponsorship bias and publication bias should be borne in mind when interpreting review findings."  Yet the reader of this article is left with the impression that escitalopram is much better than citalopram.  

I note that escitalopram is about 30% more expensive than an equivalent dose of citalopram, according to PharmacyCompass, a Canadian service which helps people find the best local prices for medications at local pharmacies.   

In conclusion, I think that with respect to antidepressant choice, there is no doubt that escitalopram is appropriate and works at least as well as other available medications.  But it is not necessarily true that escitalopram is "better."  The problem with this biased view of "betterness" is that it could cause a person (a psychiatrist or patient) to overlook other options, and favour escitalopram as a first choice automatically, and unnecessarily.  It could also cause many to overlook citalopram as a possibility for someone who has unsuccessfully tried escitalopram in the past.