Showing posts with label Medications. Show all posts
Showing posts with label Medications. Show all posts

Tuesday, March 6, 2018

Depression Treatment Guidelines

I encourage having a look at the September 2016 issue of The Canadian Journal of Psychiatry, which summarizes treatment recommendations for major depressive disorder, based on a thoughtful review of the evidence available at the time.  The authors spent many hours of careful work preparing this authoritative set of articles, and I think they did a good job. 

Here is a brief summary:

1) Various antidepressants are beneficial for treating depression.  They may help with an acute episode, and may help prevent relapses if continued.  Some may work better than others, but the differences are small, and there are likely to be individual cases in which a so-called "second-line agent" works better than the first-line choices.    Some things are classified as "second-line" not because they are necessarily inferior, but because they have not been researched as much as the "first line" things.

2) Various types of psychotherapy are beneficial for treating depression.  These, too, can be helpful for acute episodes, as well as for preventing relapses, even after discontinuation.  CBT has particularly strong evidence for being effective. 

3) As to specifics, such as "which medication is best under which circumstances?" or "which type of psychotherapy is best under which circumstances?", the evidence often does not guide us clearly, aside from CBT in general being favoured. 

4) Various other types of treatment, including ECT, TMS, exercise, and light therapy, have evidence supporting their use.

I am concerned that there was not a lot of critical debate about these claims.  Many authors of review articles are proponents of a particular type of therapy (e.g. light therapy, CBT, etc.), and the content therefore may be biased, or at least lacking input or commentary from different points of view.   It could be argued that "the data speaks for itself," but often the verbal conclusions resulting from the data can be coloured significantly by the author's opinion.

There are some useful specific pointers:  for example, there is a lack of evidence that combining two different antidepressants is consistently helpful.  But "augmenting" strategies, such as adding an atypical antipsychotic medication to an antidepressant, are better supported by evidence. 

In general, for me, these guidelines are most useful as a very general introduction, to get an overview of common treatments, and of up-to-date research evidence.

Here are some ideas of my own to add about "treatment guidelines":

A very thorough understanding of a person's history is most important for care.  In many cases what appears to be "major depressive disorder" ends up being a more complicated story, upon spending time learning the history.  Many treatments such as antidepressants can be dangerous if given without thorough understanding of the history (for example, if there is a history of bipolar symptoms).  Obtaining a good history is not necessarily possible with a single visit, with a standardized interview, etc.  It takes time and a good therapeutic relationship to know a person's story.

There is some question about the validity of "major depressive disorder" as a construct.  Eiko Fried has a good summary of this issue on Twitter: https://twitter.com/EikoFried/status/935098850439847937
As I have written before, a great many patients do not have only one diagnosis (assuming we are focusing on a DSM-style diagnostic scheme).   It is therefore limited to focus only on the treatment of depression alone.  I realize that it is a convenience in research to define syndromes in this way, which can then help us to measure the effectiveness of treatments systematically.  But for a given individual, it is often necessary to step away from diagnostic constructs, and help the person in the specific ways they desire or need. 


There are many pathways towards nurturing mental health.  Finally it is reasonable for most people with depression to try various treatments, including medications, provided there is a good understanding of risks and potential benefits.  Psychotherapeutic ideas (such as CBT, but also other styles) are beneficial for most anyone, even those who do not have formally diagnosed mental illness.  Lifestyle and psychosocial factors are very important: exercise, healthy nutrition, healthy social, family, and community development, physical safety, career, education, stable finances, and the pursuit of meaning, should be an invited focus for everyone.    There is relatively little attention given to these issues in most published treatment guidelines (sometimes I get the feeling that some authors in the field are embarrassed to even approach them) yet for many people these issues are the most important of all.

In the 102 pages of this journal, which are devoted to approaching and treating depression--a disease of emotional and often existential suffering, loneliness, joylessness, and a crisis of meaning--here is a tally of individual words used in these pages:

1) love:  0 times.  The search engine found a reference to the author J. Glover as the only occurrence of "love"
2) compassion: 1 time
3) nutrition: 1 time
4) cooperation: 0 times, except as part of 7 references to an agency (the "Asia Pacific Economic Cooperation") which gave money to one of the authors
5) healing: 1 time
6) friendship: 0 times
7) encouragement: 1 time
8) pets: 0 times
9) nature: 1 time (referring to "nature of risk")
10) joy: 0 times
11) humour, laugh, laughter, smile, happy, happiness:  0 times for all
12) art, hobby, hobbies: 0 times
13) patience: 0 times
14) drug: 86 times
15) intervention: 91 times


While I love science (my alternative career would have been a mathematician or a statistician!) it is necessary in mental health care to also discuss issues or words that do not fit neatly into a science or data-based analysis.  These issues include compassion, meaning, love, and patience.  Another issue is finding ways to cope with, live with, or accept unremitting chronic illness or pain, while continuing an evidence-based, but uncertain and frustrating, search for relief or cure.  Algorithms and guidelines tend not to help very much with this existential struggle.    Educationally, I think it is more valuable to present case studies, with group engagement, perhaps with references made to treatment protocols, rather than to make the protocols themselves the subject of the lesson.   

I prescribe a lot of medication.  In some cases the medication appears to be incredibly helpful.  In many other cases, there is a small but significant benefit.  And in others still, there is not much benefit at all despite many, many trials of different medication.  And in a few cases, the medications are harmful.   Many of my patients benefit most from medications that are considered "second line." I can't think of any examples in my practice where guidelines of this type have been useful in determining the most helpful course, aside from being a very general roadmap to remind us of available options or the occasional new finding in the research.   But this roadmap would already be very familiar to most mental health professionals, part of an academic focus over years of training.   Specific treatment issues (such as choosing the best medication or psychotherapy combo etc.) are part of professional development: this requires ongoing familiarity with the broad research literature, and with experience in clinical practice, rather than reliance upon review articles.    Review articles of this type are  authored by research experts, whose work deserves respect; however, the authors represent a limited subset of expertise within the population of mental health workers.

My therapeutic style has included more and more ideas based on CBT, over the past 15 years.   Many of my patients work on structured CBT elsewhere as well.  As with medication, this is incredibly helpful for some, slightly helpful for many, and has little or no effect for a few others.  Arguably, some CBT groups could even be harmful for a few, if there is a large mismatch between what the person desires and needs and what is actually offered.   In many cases, people are familiar with these therapy styles, but have not yet really done the work necessary to derive benefit from them.  This lack of work is usually due to the depression or the psychosocial situation itself, but also can be due to a lack of continuity of care.  It can be a little bit like trying to learn a foreign language, and dabbling in it for a few months, learning a bit of grammar and vocabulary, but never really gaining fluency due to a lack of immersive focus,  and a lack of someone to speak the language with on a regular, long-term basis.


Many people, I think, simply benefit from knowing that they are being cared for, by a person or system which has time and attention for them as they need and desire, sometimes on a long-term, open-ended basis.  It is helpful for mental health care providers to be well-versed in a wide variety of therapeutic techniques, and to be able to adjust or tune the care to what each individual patient or client wants or needs.   Within a system, it is good to value the unique styles and abilities of different individuals within the group, rather than compelling everyone to follow an identical protocol.  Some caregivers are better-suited to using a CBT style, while others are naturally suited to IPT, meditation, or psychodynamic styles.    Some psychiatrists have a particular expertise and interest in medication management.  Most research protocols do not look at this issue in groups or systems.  These individual variations should be respected, but I do think it is also good for everyone to come together to learn from each other.  For example, psychodynamic therapists can adopt interesting, useful ideas from CBT therapists, and vice-versa.

Most of my patients would say that it was not some medication combo or therapeutic style or adherence to guidelines that ended up helping them, but was a combination of many factors, in conjunction with a system of care (such as a therapist, psychiatrist, or other support network) which was stable, consistent, compassionate, and long-term.





Tuesday, June 21, 2016

Feeling Trapped in a Life You Don't Want: Hopelessness & Chronic Depression

I originally published this post in March, 2009.  I was just looking at it again today, while browsing through my blog...I thought I would re-publish this, and maybe work on adding to it.   I have been reviewing treatment guidelines for mental illness, and have been asked to help prepare some official guidelines for my workplace...while I find this task, of preparing "guidelines,"  meaningful or useful in some ways, with some worthwhile observations and tips to be discovered in the existing research, I finally find the task a great source of weariness and frustration.  This particular post really represents something that is much, much closer to the "core" of who I am, or who I want to be, as a psychiatrist.  And it reflects more deeply--than any "guideline" could-- my beliefs about caring for people who are suffering.   


This post is in response to a comment on my previous post "What to expect from an antidepressant".

What is the purpose of a life?

What needs to be present in a life to make it worthwhile?

If a life is like a work of art, a giant canvas that you have been working on for decades--what if you feel that the canvas has already been wrecked? The damage may have been caused by "bad genes" (e.g. an inherited tendency to be depressed, etc.), which in the canvas metaphor might mean the canvas itself is fragile, thin, easily damaged, doesn't hold pigment very well, etc.

Or the damage may have been caused by "bad environment" (e.g. a traumatic childhood, lack of support, lack of opportunity, natural disasters, war, poverty, etc.), which in the canvas metaphor might mean the canvas itself has been damaged by others, or by environmental adversity, causing it to be very difficult or painful to work with in the present.

Or the damage may have been caused by your own past efforts (e.g. a history of spending years trying to develop oneself-- in school, in relationships, in work, etc.--but where these efforts have ended in failure, pain, breakups, sorrow, regret, guilt, or a sense of having burned your bridges--and where the past failures obstruct future opportunities, e.g. via a poor academic transcript, work record, etc.). In the canvas metaphor this might mean there is a lot of paint on the canvas, but none of it is what you want, none of it is where you wanted it to be, none of it you actually like, it all looks like a collection of mistakes. If it was a literal canvas, you might feel like the best action would be to just throw the painting away, and either start fresh, or give up painting altogether. You might feel like you never wanted to paint in the first place, that the task was forced upon you by the fact of your birth, and by the social expectation that you are supposed to live out your life.

For many people who struggle with chronic depression, I think there is some combination of all these three possibilities: genes, external environment, and personal efforts which haven't worked out, all contributing to a state of hopelessness, tiredness, exhaustion. It can feel like a daily struggle just to make it through the day, a yearning for time to pass just for things to be over. Life can feel like a trap, a life sentence to a prison term, a forced existence that you never really wanted, or have long since stopped wanting.

The idea of a medication somehow "treating" this problem can seem absurd. Or the idea of so-called "cognitive therapy" changing this problem can seem insulting. It is like observing a painting you don't like in an art gallery, and then being told that you have to do some exercises to change your thinking, so that you will start to like it, then have it up on your living room wall for the next 60 years. In some ways this dynamic reminds me of salesmanship, in which case it can feel like the therapist, or even the whole external world, is trying to "sell you" the idea that your life is supposed to be worthwhile, when all you see is something you hate and want to get rid of.

I don't have easy answers to this problem.

But here are some of my beliefs about approaching it:


There are people who will care about you, and who will sit with you through your suffering. A role of a therapist in this type of situation, I think, is to sit quietly, to be gently and consistently present.

The world is full of possibility. No matter how bad conditions have been--internally or externally, past or present--growth and change are possible. The brain is a dynamic structure. It is as powerful and consistently active when alive as is the heart. But the brain reinforces its own pathways. If these pathways give rise to feelings of despair, hopelessness, and futility, then every moment of life can become experiences of despair, hopelessness, and futility. If these pathways of thought, emotion, and felt experience, have been trodden for decades, it can be hard to forge new pathways within the mind.

Immense, profound life change is possible, regardless of how severe problems have been, how long they have been present, or how much damage the problems have caused.

Such changes may require an enormous amount of energy and time, and may require a lot of external support.

There are many individual life stories of profound life change, stories of journeys through chronic hopelessness towards meaning, energy, and joy. Historically, some of these stories are of mythical proportion, and are present in literature and the other creative arts. Many religious stories contain themes of this sort.

Contemporary examples include stories of individuals overcoming lifelong addictions which had devastated their previous life histories (here I am not saying chronic depression is an addiction, but that addictions and depression can both be characterized by feeling very stuck in something bleak and hopeless). The lore in addiction treatment has wisdom to share about making radical life change--in "12 step" models, for example, individuals are called upon to admit "powerlessness" over their problem, and to make a set of statements of faith about a "Power greater than ourselves", etc. While I am wary of the potential for dogmatic religiosity in such statements, I also see that if dogma can be set aside, the "12 steps" can be seen as a sort of "leap of faith", a new contract with life, to live--and work-- with the help of a supportive community. It admits, powerfully, that one must reach out to connect with the possibility of change, it is almost impossible to do alone (the "higher power" idea can simply be an admission that one needs external help).

Psychiatric medications in chronic depression usually do not lead to "profound life change" (sometimes they do, but really this is in a small minority of cases). However, often they help a small to moderate amount. Either to relieve some suffering or pain, or to potentiate energy that might then help to effect a new course in living. I do not feel that any effective treatment leads a person to become resigned to an unpleasant status quo, and then to learn how to "accept a bad life". I feel that effective treatments allow unpleasant circumstances to feel more bearable, then to facilitate the hope and actions that are necessary to improve the unpleasant circumstances.

Cognitive therapy can help. The goal, however, in cognitive therapy, cannot be simple "salesmanship". I think the goal has to be building a satisfying life, where there are healthy, stable relationships: meaningful work, meaningful love relationships, and meaningful activities that bring joy or happiness.

With any type of process that causes deep changes in the brain, the pathway may require you to go right back to the simplest foundations.

I'm reading Norman Doidge's book about "neuroplasticity" right now (The Brain that Changes Itself), which incidentally I recommend highly. The evidence he presents is quite convincing, to some degree surprising, but on another level intuitively very obvious--the brain can change itself, sometimes very radically.

But if new paths are to be formed in one's "mental forest" one may need to start with tasks that seem extremely simple, even infantile, perhaps even "insulting" in their simplicity. Cognitive therapy can seem extremely trite, or even a ridiculous exercise in mental manipulation--an exercise to comform oneself to how society as a whole expects you to think or feel, trying to convince you to think good thoughts about a bad situation.

The thing is, though, these seemingly ridiculous tasks (such as cognitive therapy, etc.) can start new paths forming. In conjunction with this, new connections can begin with the external world, in the form of new friendships, new involvements in creative work, new involvements in education, etc.

There may well be burned bridges, but there is a vast energy available to build new bridges, if you so wish. And your past experiences may eventually become more useful to you than they are right now.

Depression can be extremely tenacious. It is so extremely tenacious that in some cases it is almost like a character that wants to perpetuate itself. The depression itself, so to speak, sets up arguments in one's mind about why this or that action (e.g. medication, therapy, life change of other sorts) cannot or should not happen. In the forest path metaphor, it is like the depression not only has become an extremely well-trodden pathway in a dense forest, but it has also put high fences around the pathway, and a deep moat full of crocodiles on the other side of the fence too.

Once again, I emphasize that I have no easy answers. As I look at the above post, I see that it is rambling. Parts of it probably sound preachy or trite. Probably annoying to look at if you are feeling trapped in a depressive state. I think I come off sounding like a salesman myself, trying to convince you to buy that painting you don't really like.

My intention, though, is to convey my belief that change is possible. There is proof that change is possible. I see this proof in my own clinical experience, as well as in the stories of others. Deep change in a chronically unhappy life is possible, but may require a great deal of external help, and may require a type of commitment to change that is extremely difficult or exhausting to initiate. And your depression won't want you to make any such commitment.

Wednesday, March 9, 2016

Stimulant Medications for treating ADHD: A comparison

ADHD medication is a big business in the world today.  Annual sales of ADHD medication are projected to be 15-20 billion dollars by 2020, increasing at a rate of about 8% per year.   To put this in perspective, this is similar to the value of the worldwide market for fresh vegetables
 ( http://siteresources.worldbank.org/INTPROSPECTS/Resources/GATChapter13.pdf ).

 It is an amount of money that would pay for the salaries of
 400 000 teachers, each of whom paid $50 000 per year. 

 A relevant article to look at about this is by Alan Schwartz, published in the New York Times in 2013:
http://www.nytimes.com/2013/12/15/health/the-selling-of-attention-deficit-disorder.html?pagewanted=all&_r=0

I am not meaning this post to be a discussion of the controversies of ADHD diagnosis.  Instead, this post will focus mainly about ADHD medication.   I think the rising rate of ADHD diagnosis, and the rising rate of stimulant prescription,  is a very concerning trend, particularly if these diagnoses and treatments are offered without attending adequately to other biopsychosocial factors, and particularly if these treatments are being offered under the influence of un-recognized biases due to the financial power and influence of the manufacturers.

On the other hand, the rising awareness and acceptance of ADHD can allow those children, adults, and families who are dealing with ADHD-related issues to feel less stigmatized, judged, and unfairly treated.  In families, knowledge and acceptance of ADHD can help child-rearing practices to be adapted, so as to avoid a harshly punitive stance towards those children with attention problems.  


The newer ADHD medications are, not surprisingly, very popular, frequently prescribed, are often touted as being better than the older medications, and are listed first on medication advice guideline sheets (such as the CADDRA recommendations).

Here is a comparison of costs per day between the different ADHD drugs, looking at a typical full therapeutic dose for an adult.  These cost estimates come from a site called "Pharmacy Compass" which searches for the best local prices for medications at pharmacies.   

1. Newer drugs (CADDRA considers these to be the only "first line" medications):

Adderall XR 30 mg:$3.91 per day
Biphentin 80 mg:$4.36 per day
Concerta 72 mg:$5.92 per day
Vyvanse 60 mg:  $5.14 per day
Strattera 100 mg: $5.51 per day


2. Older drugs (CADDRA considers these "second line"):

Dexedrine spansules 40 mg: $3.59 per day

Ritalin (methylphenidate) 60 mg: $0.81 per day
 Ritalin SR 60 mg $0.66 per day


So we see that the least expensive option is methylphenidate or methylphenidate SR.  Dexedrine is over 5 times as expensive.  Concerta and Vyvanse are about 8 times as expensive, per day.

I mention these expense differences not necessarily in an effort to favour the cheaper medication, but rather to heighten your anticipation that there could be bias in any research results regarding these medications--especially if the research is sponsored by the manufacturers-- due to the huge profit motives involved.


It would be fair to look for studies which carefully and prospectively treat ADHD patients with Ritalin vs. one of the newer medications, in randomized comparisons.

1) Vyvanse vs. Ritalin.  Almost no studies in the literature!  In one study, all they looked at was whether patients stuck to a dosing regimen, in which case the Vyvanse group did "better." (http://www.ncbi.nlm.nih.gov/pubmed/23937642 ) But this measure had nothing to do with the patients actually feeling better or improving more!

A better study compared Vyvanse with Oros-MPH, a long-acting version of Ritalin (though not plain old Ritalin itself!)
[ http://www.ncbi.nlm.nih.gov/pubmed/23801529]

In this study, at first glance it certainly appears that Vyvanse is better!  But looking carefully, one finds statements such as this: "At endpoint, the difference between lisdexamfetamine and OROS-MPH in the percentage of patients with an ADHD-RS-IV total score less than or equal to the mean for their age was not statistically significant." (p.747)   This statement was tucked into the results section but left out of the conclusion.  Looking at side-effects, we find a lower total rate of adverse effects in the Ritalin group.  Reduced appetite, insomnia, and nausea were more common in the Vyvanse group.  Notably, there is a long list of conflicts of interest at the end of this paper, including some of the authors being employees of the Vyvanse manufacturer, and owning stocks in the company!


In conclusion here, there is no doubt that Vyvanse is an effective medication for ADHD.  The dosing regime is very convenient, which may be particularly effective and helpful for many.  But it is not necessarily superior to much cheaper alternatives.  For some people (including many patients I have seen), regular methylphenidate (Ritalin) allows better fine control of symptoms during the course of the day, without being "stuck" with a continuous sustained-release effect.  For others, they certainly do prefer the Vyvanse.  I just think that Vyvanse should not be assumed to be better, as the evidence is very weak that it is, while it is 8 times more expensive than Ritalin!

2) Concerta vs. Ritalin
http://www.ncbi.nlm.nih.gov/pubmed/11389303
This is a good early study, directly comparing the two medications, published in Pediatrics in 2001.  Here is the authors' concise summary: "On virtually all measures in all settings, both drug conditions were significantly different from placebo, and the 2 drugs were not different from each other."   The reason to choose Concerta over Ritalin would be convenience.  The authors do point out that "compliance" is more likely on a long-acting formulation.  But remember that "compliance" is a very, very indirect, and possibly irrelevant, measure of health and well-being!!  Why is it important that there be better "compliance?"   Should the only criteria not be well-being?   Certainly this is not a reason to classify Concerta as "better" or "first line".  Concerta is 9 times more expensive than Ritalin!

3) Adderall vs Ritalin
http://www.ncbi.nlm.nih.gov/pubmed/10103335
In this study, published in Pediatrics in 1999, Adderall comes out as looking better than Ritalin.  But, once again, the study was sponsored by the manufacturer.  On a close look, a couple of problems:  first, the doses of the medications were fixed.  The ritalin doses appear too low, so as not to match the equivalent doses of Adderall given.  At this point, one would usually give Ritalin doses at least twice that of Adderall (i.e. 100% higher) but in this study the Ritalin dose was only 40% higher than the Adderall dose.  In accordance with this under-dosing, the Adderall group not surprisingly had more side effects such as insomnia.

In conclusion, there is no doubt that Adderall XR is a good medication for ADHD.  Many of my patients have preferred it over other alternatives.  But it is not fair, once again, to assume that it is better.  It does not deserve to be considered "first line" while a similarly-effective alternative that is one-sixth the cost is considered "second line."

4) Meta-analytic comparison:
Faraone and Glatt (2010) have published a good meta-analytic review paper, which is worth reading in detail, with particular attention to the data tables and graphs:   http://www.ncbi.nlm.nih.gov/pubmed/20051220
In the conclusion of this paper, the authors state that they "found no significant differences between short- and long-acting stimulant medications."

Addendum:  a recent Cochrane review, published in February 2016 by Punja et al., concludes that there is a lot of evidence that amphetamines reduce core symptoms of ADHD, but cause a variety of problematic side-effects.  They note that there was evidence of a lot of bias in the studies they looked at, with the quality of evidence being low to very low.

Here is a direct quote from their conclusion:   "This review found no evidence that supports any one amphetamine derivative over another, and does not reveal any differences between long-acting and short-acting amphetamine preparations." 



Friday, February 19, 2016

Do Higher Doses of Antidepressants Work Better?

It is common practice in psychiatry to increase the dose of an antidepressant if the standard dose is not helping enough.  Sometimes doses are increased before even finding out if the lower dose is working. 

But it is interesting to consider evidence that higher doses actually do not necessarily work better:

RuhĂ© et al. (2009-2010) have published research on this issue, and conclude that SSRI dose increases do not improve effectiveness.  Their explanation for this is quite simple:  serotonin receptors are already well-occupied at standard doses, and this does not change with dose increases:  
http://www.ncbi.nlm.nih.gov/pubmed/18830236
http://www.ncbi.nlm.nih.gov/pubmed/20862644

In general, it is indeed interesting to see scanty evidence that increasing antidepressant doses lead to improved effectiveness, even for treatment-resistant cases.  

This issue came to my attention upon reading Lam's recent article about using light therapy to treat non-seasonal depression   ( http://www.ncbi.nlm.nih.gov/pubmed/26580307).  Their medication groups used only 20 mg of fluoxetine, without the possibility of increasing the dose.  They cited some old, dated references to support this, such as Altamura et al (1988), and  Beasley (1990):
http://www.ncbi.nlm.nih.gov/pubmed/2196623 
 
A better, more recent article reviewing antidepressant dose vs effectiveness is by Berney (2006):
http://www.ncbi.nlm.nih.gov/pubmed/16156383


In many studies, higher doses may appear to work better, mainly because the dose was increased before the lower dose had a chance to work fully.   The lower dose may well have worked just as well as the higher dose.  Controlled studies comparing different doses do not support the belief that higher doses work better.

So it should not be routine practice to increase antidepressant doses beyond a standard "full dose" which is usually one tablet or capsule daily.    In many cases, the different dosage regimes are likely to be equivalent.  It is relevant to consider that higher doses mainly benefit the pharmaceutical companies, since they are selling more product despite the effectiveness being the same.  Therefore, presentations of research data about antidepressant effectiveness may be biased in favour of higher doses.  An extremely common research design in antidepressant studies is to have "flexible dosing," usually leading to the antidepressant group averaging about twice the standard dose in the end.  This design, even when treatment effects are shown, biases the reader to have the specious conclusion that higher doses are better.

However, there are certainly many individual case reports of higher doses being more useful.  So dose increases may have a role in some cases.

The key point is to question dose increases as a reflexive, routine management strategy for inadequate antidepressant effects.  Alternative strategies include giving the lower dose a longer try, switching to something else, or using some form of augmentation.

Addendum:

Just days after posting this, I see there is a new meta-analysis by Jakubovski et al. in The American Journal of Psychiatry (173:2,pp. 174-183) which suggests that SSRI antidepressants do actually work slightly better at higher doses, peaking at 2.5 times the standard dose (e.g. 50 mg fluoxetine).   They admit that the data show a trade-off between slight improved effectiveness at higher doses, but accompanied by worsened tolerability. 

Yet, it is important to consider that higher doses could reflect a greater placebo effect; some of the research about active placebos show that agents which cause more side effects are likely to have a larger impact on symptoms than inert placebos.  Because antidepressants at higher doses have more side effects, there would be more of this "active placebo" effect.  See my previous post on this subject: http://garthkroeker.blogspot.ca/2009/03/active-placebos.html


It's hard to know what to make of this, other than to probably remain open-minded about the issue.  I think that a better study design for this type of issue is to look at dose comparisons within individual clinical trials, rather than to amass data meta-analytically.   Active placebo comparison groups would also be useful.  For example, agents which would cause very mild side-effects could be used instead of a totally inert placebo, so as to improve the blinding of the studies.    In many individual clinical trials of antidepressants (both new and old) which compare doses or dose ranges within the studies themselves, there are no significant differences in effectiveness.

Another issue, which the authors point out, is that most antidepressant studies have strict inclusion criteria which usually do not match the type of cases one would tend to see clinically most often.  Many studies require a major depressive disorder diagnosis, with limited comorbidities allowed, and with limited past treatment trials, etc.

Meanwhile, it remains reasonable to give a baseline dose of antidepressants an adequate length of time to work, without reflexively increasing the dose on a routine basis.   Dose increases remain an option, with some evidence-based support, but switching or augmentation could often be preferred, depending on patient preference and side-effects. 

Thursday, December 17, 2015

Antidepressants in Pregnancy: Autism Risk?

On December 14, 2015, Boukhris, Sheehy, Mottron, and Berard published a paper in JAMA Pediatrics which described their  study of the association between autism-spectrum disorders and exposure in utero to antidepressants.

They looked at all women who had pregnancies in Quebec between 1998 and 2009.  These 186 165 women have been followed prospectively in the Quebec Pregnancy Cohort (QPC).  The authors looked only at those infants born at full term; all antidepressant exposure was recorded, and there was up to 11 years of follow-up. 

They found that 3.2% of all infants born to this cohort were exposed to antidepressants in utero.  Of those infants who had this exposure, 46 later received a diagnosis of an autistic-spectrum disorder (1 %).  More specifically, among those exposed in the second or third trimester, there were 31 autistic-spectrum diagnoses (1.2 %).   Among those infants with no in utero antidepressant exposure, 1008 later received an autistic spectrum disorder diagnosis (0.7 %).

When the diagnoses were restricted to those made by a neurologist or psychiatrist, the findings remained positive, but with reduced statistical confidence.


Other factors, such as maternal history of psychiatric disorders, mother living alone, maternal gestational diabetes or hypertension, were also positively correlated with the infant later having an autistic-spectrum disorder diagnosis.

A major weakness of the study was that it did not have a detailed analysis or discussion of autistic-spectrum symptoms (even subsyndromally) in the parents or other relatives of the infants.  They state "although our sample size is large, the size decreased substantially in stratified analysis on family history of ASD, which led to decreased statistical power."  And they observe that "those using [antidepressants] were...more likely to have had another child with ASD than those not using ADs", but did not expand on this finding.      The most likely contributing factor towards autism-spectrum phenomena would be the presence of these same phenomena in the family, which would be heritable.   It is possible that the presence of this hereditary factor could have been an underlying cause for the heightened risk which they observed.   This same risk factor could theoretically have contributed to the mothers using antidepressants more frequently during the pregnancy.

Another weakness of the study concerns the use of the "autism spectrum disorder" diagnostic label.  The use of this label is more frequent nowadays.  The degree to which it is appropriately considered a "disorder" could be subject to debate about criteria or severity.  For example, with the "autism spectrum quotient" questionnaire,  criteria such as "I don't like reading fiction,"  "I am fascinated by numbers," and "I would rather go to a library than a party" increase the score towards an autism diagnosis!  It seems much more important to restrict such a label to some kind of marked social, behavioural, or communicative problem, rather than intellectual or recreational preferences.   Enjoyment of libraries should not lead to a DSM label! 

Another related confounding factor could be that someone who has taken antidepressants might be more likely to have their children assessed by someone able to "diagnose."   It could be that if an autism questionnaire was administered to every child in the cohort, then 1.2% (rather than 0.7%) of the entire cohort could meet some "autism spectrum" threshold.  Perhaps the increased incidence in the group who had taken antidepressants is simply due to these mothers having a higher likelihood of asking for their children to be assessed.   In order to determine whether this is true, we would have to ensure that every child in the cohort received the same type of assessment, including the same questionnaires (such as the "autism spectrum quotient").   But in this study, this was certainly not the case. 

While the authors find that SSRIs in particular were associated with increased ASD incidence, with minimal associations from other antidepressant classes, it is notable that there were far too few cases of  non-SSRI antidepressant exposure to make any reliable statement at all about non-SSRI antidepressants.   Therefore, they should remove the implied message that only SSRIs are involved with the association. 

Nevertheless, it is an important study with a very large cohort.  We must be vigilant about the possibility of risks for giving any medications, particularly in pregnancy.

If, in future studies, this difference in autism incidence is found to be directly caused by antidepressant exposure, the evidence here shows that the risk increases from 0.7% to 1.2%.  Posed differently, the probability of not having an autism-spectrum diagnosis changes from 99.3% to 98.8%.


In some cases, the risk of severe depression in pregnancy could outweigh the risk of a treatment causing harm, but this would need to be carefully evaluated and discussed.   A question to ask in this situation would be whether the antidepressant is specifically required for treatment of the depression.  In some cases, it might indeed be very helpful, with a much higher likelihood of depressive symptoms, and various adverse outcomes for mother and child, without it.  But in other cases, despite high depressive severity, the antidepressant might not clearly be an imperative component of the therapy.  Perhaps in some cases other treatment modalities could be sufficient, at least during the pregnancy.  It depends on the specific case or situation.  

I am bothered by the author's concluding remarks in their abstract; the remarks assert causation, despite the findings really being associative:  they say "use of antidepressants...increases the risk of ASD in children."  It would be more appropriate for them to have said, as they were more careful to do elsewhere in the body of the paper, that "there is an association between antidepressant exposure in utero and subsequent ASD diagnosis."

In any case, it is not controversial to assert that all possible non-medication strategies should be optimized in the treatment of depression, particularly in pregnancy.  This includes promotion of healthy lifestyle factors, careful attention to social and community support, and psychotherapy.   



Wednesday, December 9, 2015

Cochrane Review: ADHD medications have lower-quality evidence than most people believe

A new Cochrane review, published on November 25, 2015 by authors Storebø and Zwi, looked at the use of stimulants to treat childhood ADHD (specifically, methylphenidate).  Their conclusions included:

1.  "the low quality of the underpinning evidence means that we cannot be certain of the magnitude of the effects."
2. "the general perception of methylphenidate as an effective drug for all children with ADHD seems out of step with the new evidence."  

The authors found a great deal of industry sponsorship in existing studies, and found that "all 185 trials" had a high risk of bias.   I would add that more recent ADHD studies, involving newer, more expensive medications, are most likely at an even higher risk of similar biases.  

In general, the weaknesses of existing data are similar to the weaknesses in much other psychiatric research:  studies are usually brief, rather than long-term, despite  treatments often being given for many years or permanently.  

Other authors, such as Hinshaw (2015)[http://www.ncbi.nlm.nih.gov/pubmed/26262927] have reached similar conclusions, including
"the diminution of medication's initial superiority [was apparent] once the randomly assigned treatment phase turned into naturalistic follow-up. The key paradox is that while ADHD clearly responds to medication and behavioral treatment in the short term, evidence for long-term effectiveness remains elusive"

How should this information inform our understanding or management of ADHD?

First, I do not think it is necessary to stop using stimulants as a treatment.  However, I do think it is necessary to step away from the assumption that long-term stimulant use is appropriate for every person with ADHD symptoms.   Other ways of using stimulant medication could often be more appropriate for many, such as using stimulants sporadically, to manage attentional symptoms for brief periods of time.  

The evidence also does not strongly support the long-term effectiveness of behavioural therapies.  This, too, is not really surprising to me.  

I think that the answer lies in moving away from a highly medicalized, reductionistic approach entirely.  Phenomena such as ADHD have broad biopsychosocial underpinnings:  some factors exist within the individual, while many others exist in family, social, and educational structures.   In some ways this is similar to other public health issues, such as obesity or addictions:  a single medication or behavioural treatment is very unlikely to be a remarkably effective strategy to help with these problems.    Yet, each of these strategies has a role, provided that the role is not overvalued by those offering it.  Other larger social factors are extremely important as well, including factors relating to poverty, economic equality, community supports, provision of justice & public safety, etc. 

So in conclusion, I see -- not surprisingly -- that we must not have exaggerated expectations of medication for treating ADHD or any other psychiatric phenomena.  I do think stimulants have an important role, however, for many people, provided that the expectations are modest, and provided that side effect risks are not discounted by an over-enthusiastic prescriber with biased beliefs about long-term effectiveness vs. risk. 

It is also important not to be biased against any particular treatment.  In some cases, for example, balanced medication treatment of ADHD could reduce various types of risks, including substance use problems and traffic accidents, etc.   It is just that the magnitude of such protective effects are likely to be exaggerated in most practioners' minds, due to the biases described above. 

 As with other life issues, I believe it is necessary to have a very broad view about helping strategies, which includes other types of therapeutic support if desired, as well as attention given to community, educational, cultural, and family resources--not in isolation, but in a comprehensive and holistic way.


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

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:
http://www.ncbi.nlm.nih.gov/pubmed/26035186

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:
http://www.ncbi.nlm.nih.gov/pubmed/25401715


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.







Monday, April 27, 2015

Marijuana

Here's another update of this post, to account for studies between 2009 and 2015.

Marijuana use is quite common in the university population I see in my clinic.

It is my opinion that sporadic recreational marijuana use is less dangerous than alcohol use, for many people.  For others, it is more problematic, and the risks may be underestimated. 

Cannabis is an acute intoxicant, which could make activities such as driving much more dangerous. Also, smoking marijuana undoubtedly causes harm to the lungs, though probably not quite to the same degree as smoking tobacco cigarettes (see references below).

There is strong evidence that marijuana use increases the risk of developing a psychotic disorder, probably by about 40%.

People who have a psychotic illness, or who have a family history of psychotic illnesses, are at higher risk for having new or continuing psychotic symptoms if they use marijuana.

Also, based on some of the evidence cited below,  children and adolescents are probably much more vulnerable to negative, long-term emotional and cognitive effects from marijuana use. 

Many regular consumers of cannabis have problems with motivation. This may be reflected in poor grades in school, lack of success in building a career, etc.  This is possibly a non-causal association, but if someone has low motivation to begin with, the addition of cannabis is not likely to help.

There may be some selected exceptions.  For example, some have claimed that a culture of cannabis use has had a catalytic role in helping reclusive technical geniuses relax their social and creative inhibitions, to permit some examples of very successful scientific and business innovation, such as in Silicon Valley.

There is strong evidence that marijuana use is associated with more severe psychiatric symptoms, of almost every type; but much of this association could be due to the fact that those with more severe symptoms are more likely to use marijuana, not the other way around. In any case, those who choose to use marijuana more regularly as a cultural pursuit may be surrounding themselves with others who have more severe symptoms.   This is similar to the case  of alcohol:  part of the harmful effect of drinking heavily is due to proximity to places (such as rough bars) where there are a lot of other heavy drinkers -- in this environment, there is likely to be more physical danger, and much less breadth of social or cultural opportunity.  Ironically, decriminalization should probably reduce this effect, and therefore reduce some of the potential social harms.

There is some evidence that marijuana or other cannabinoids could be helpful to treat a variety of medical ailments. This evidence needs to be taken seriously.

Here is a brief survey of the very large literature on this subject:

Evidence of Risk and Harm

     Psychiatric Risks

This 2007 review from Lancet shows convincing evidence that marijuana use increases the risk of developing a psychotic disorder, and that the risk is dose-dependent (i.e. the more marijuana one uses, the higher the risk is of developing a psychotic disorder):
http://www.ncbi.nlm.nih.gov/pubmed/17662880

It concluded that the evidence is less clear linking marijuana to other problems, such as depression and anxiety: many of the studies looking at this did not sufficiently address non-causal reasons for the association between marijuana and other problems. For example, people who are more depressed or anxious may have a higher likelihood of using marijuana to treat their symptoms. Or, people whose cultural style may lead them away from conventional treatments for depression, may be more likely to use marijuana regularly.    Use of psychotherapy and antidepressants are also more common among those with depression, but this does not prove that psychotherapy and antidepressants cause depression! 

In this 2008 review from the British Journal of Psychiatry, the authors conclude that marijuana use is associated with worse outcome in psychotic disorders--but they say that the existing studies show only an association, not causality. Once again, confounding variables may cause this association to exist:
http://www.ncbi.nlm.nih.gov/pubmed/18978312


A significant cannabis withdrawal syndrome is described in the literature, particularly for heavy, long-term users. The syndrome involves about 2 weeks of irritability, restlessness, and insomnia, which could be quite destabilizing for someone struggling with mood symptoms, therefore leading to continued marijuana/cannabis use. Here is a 2006 review of the subject:
http://www.ncbi.nlm.nih.gov/pubmed/16612207

A few recent prospective studies have demonstrated increased dysphoria, anxiety, tiredness, ideas of reference, and schizotypal symptoms as a result of marijuana intoxication. In particular, individuals with pre-existing schizotypal personality traits had a more substantial increase in schizotypal symptoms following THC exposure. This adds to an evidence base suggesting that marijuana use carries a significant risk of exacerbating a variety of psychiatric symptoms, particularly psychosis-spectrum symptoms, and particularly in those with risk factors for psychotic illness.
Here are the references, which are both from Psychological Medicine in 2009:
http://www.ncbi.nlm.nih.gov/pubmed/19017430
http://www.ncbi.nlm.nih.gov/pubmed/19335936

This interesting study involved administration of THC to healthy volunteers who did not use THC.  Some members of the cohort experienced transient psychotic phenomena, while others did not.  These differences were associated with differences in cognitive impairment and functional MRI results. This supports the common-sensical observation that some individuals may be more vulnerable than others, to having adverse neuropsychiatric effects from THC use.  
http://www.ncbi.nlm.nih.gov/pubmed/23020923


Many other studies looked at populations who used different amounts of marijuana over time, and compared them in terms of various symptoms and intellectual functions, etc. Unfortunately, I find this type of retrospective analysis to be weak, and highly prone to confounding variables. In order to understand marijuana's long-term effects for sure, we would need to do a long-term, prospective, randomized, controlled study.

     Physical Risks

Here are some studies looking at risk to the lungs associated with marijuana smoking:

These studies show an increased risk of lung cancer in marijuana smokers:
http://www.ncbi.nlm.nih.gov/pubmed/19057263
http://www.ncbi.nlm.nih.gov/pubmed/18238947

These studies show a likely causal association between long-term marijuana smoking and obstructive lung disease:
http://www.ncbi.nlm.nih.gov/pubmed/18238947

http://www.ncbi.nlm.nih.gov/pubmed/17666437

     Prospective Animal Studies

Animal studies could add a little bit more information into the picture, since these have been done in a prospective, controlled fashion. Here is what I've found from the animal research literature:

This study showed that chronic marijuana exposure impairs spatial memory & learning in rats:
http://www.ncbi.nlm.nih.gov/pubmed/19179850

This study showed that chronic marijuana exposure impairs social and cognitive functions in rats, but especially when the period of exposure is during the pubertal ("adolescent") phase of development:
http://www.ncbi.nlm.nih.gov/pubmed/18782382

Another study showing that marijuana exposure may be particularly harmful to the "adolescent" brain in rats:
http://www.ncbi.nlm.nih.gov/pubmed/15582916

This study from UBC suggests that high-dose cannabinoids increase emotionality and "sensitize the stress axis" in rats:
http://www.ncbi.nlm.nih.gov/pubmed/16442741



Evidence of Benefits or Therapeutic Uses

This study shows that a synthetic cannabinoid promotes neurogenesis in the hippocampus, and may have antidepressant and anxiolytic effects:
http://www.ncbi.nlm.nih.gov/pubmed/16224541

Here is a reference to a good 2008 review of the pharmacology and potential therapeutic applications of cannabinoids such as marijuana:
http://www.ncbi.nlm.nih.gov/pubmed/18482430


     Neurological Diseases


Here's a 2012 study showing relief in muscle stiffness in multiple sclerosis patients, due to cannabis administration:
http://www.ncbi.nlm.nih.gov/pubmed/22791906

Another 2012 study from CMAJ showing relief of spasticity and pain in MS patients, following cannabis administration:
http://www.ncbi.nlm.nih.gov/pubmed/22586334


This study shows immediate relief of the symptoms of Parkinson's Disease following cannabis treatment: 

http://www.ncbi.nlm.nih.gov/pubmed/24614667

     Bowel Disease

This study, from a major journal of gastroenterology, shows that cannabis dramatically improved symptoms  of Crohn's disease (a type of inflammatory bowel disease), in a prospective, placebo-controlled trial.  
http://www.ncbi.nlm.nih.gov/pubmed/23648372

Another prospective study, showing that cannabis improves quality of life in inflammatory bowel disease:
http://www.ncbi.nlm.nih.gov/pubmed/22095142

     Pain Disorders


Here's a good 2013 study showing that cannabis compares favorably with other standard pharmacological treatments for neuropathic pain:
http://www.ncbi.nlm.nih.gov/pubmed/23237736

     Heart Disease

This 2005 study from the prestigious journal Nature suggests that cannabinoids could reduce the progression of atherosclerosis (the main cause of heart disease):
http://www.ncbi.nlm.nih.gov/pubmed/15815632
 
Conclusions

In conclusion, I think that marijuana use is dangerous, and harmful to your health in a variety of ways, due to acute intoxication, increased risk of psychosis, possible cognitive side-effects, and lung damage. It may be particularly harmful to adolescents. As a cultural pursuit, it may distract people from other life activities, or meaningful life roles, just as any habit or addictive behaviour can. But it may have beneficial effects for a variety of medical problems.

I have to admit, to be fair, that some people have psychological benefits from marijuana use -- certainly there are many testimonial accounts of this, but evidence beyond this is not clear on this point.  The few studies touting this application tend to be of short-duration, which leads to a similar criticism as that pertaining to mainstream pharmaceuticals:  short-term benefits for symptom relief do not always translate into long-term benefits, if the use continues for years.   More research is needed to gain a better understanding of the potential risks or benefits of cannabinoids, especially over longer-term use.

I have certainly seen people for whom cannabis appears to have a better benefit:risk profile than alternative treatments, for example to treat chronic pain symptoms and associated insomnia.    It may be preferable to use cannabis instead of a benzodiazepine, opiate, pregabalin, etc., particularly if these latter agents are causing a much higher load of side effects in a given person.

For some people, cannabis could be a relatively harmless entertainment, or even a catalyst for enjoying life more richly in various settings.  In this way, it could be analogous to having a glass of wine with meals, etc.

Another angle to the analysis is to consider relative risks of cannabis compared to other accepted intoxicants, such as alcohol.  With this type of risk analysis, one could often see greater risks with alcohol compared to cannabis, on a case-by-case basis, but we don't have good group data on this.  Suppose we had two adjacent similar countries, and prospectively allowed free access to alcohol in one country, and free access to cannabis in the other.  Then, suppose we were to assess health outcomes in these countries 20 years later.  I suspect we would have more examples of ruined families, criminal assaults or manslaughter, chronic diseases, and traffic fatalities, in the "alcohol" country compared to the "cannabis" country. 

The issue is complicated by the fact that those who are more apt to use cannabis are statistically also more apt to use alcohol and other street drugs.  It is possible that cannabis use could have "gateway" effects, leading people into a higher-probability zone of trying or using more dangerous drugs. But this is an open question. 

A proliferation of cannabis dispensaries have appeared in Vancouver in the past year.  While I do think that legalization is a positive step, in terms of the various pros and cons for public health,  I am not happy with the idea being touted by some, that cannabis is some kind of health food, or panacea.   There is an issue of cultural freedom as well, which I support, though I think that many in this "4-20" movement have an exaggerated view of the benefits of cannabis, with an underestimation of risks.


 

Monday, June 24, 2013

Ketamine in Psychiatry

I have just updated and edited this article over the past few days.

Ketamine is a drug which has been used in general anesthesia for decades.  It is a so-called "dissociative anesthetic," which means that it causes an altered state of sensory perception without loss of consciousness.  It is a blocker of NMDA receptors;  this blockade in turn boosts glutamate release through reduced presynaptic inhition.  From there the increased glutamate increases stimulation of AMPA receptors.  These effects occur only for a few hours after a dose.  The significance of these changes would be of some debate among neuroscientists, but the bottom line is that there is a brief but marked acute alteration in one of the core aspects of the brain's dynamics and metabolism, including those aspects responsible for the management of memory, learning, and emotional processing.   

Ketamine is used illictly as a recreational drug, a fact which might bias many of us against considering its potential benefit in medicine.  

The exciting news about ketamine recently is that a single dose can lead to a dramatic improvement in symptoms of depression, even in patients who have severe, chronic, treatment-refractory mood disorders.  Aside from these case reports, there have been a number of larger studies coming out, all of which look very promising. 

Here is my literature review on ketamine, I've selected what I have thought are the best or most representative articles:

I. Reviews
http://www.ncbi.nlm.nih.gov/pubmed/23759454
- A recent brief review from The Journal of Clinical Psychiatry (May 2013)  but in discussion of mechanism, a typical example of the divide between biological and non-pharmacologically based psychiatrists:  no mention was made of the impact of the environmental milieu during the ketamine treatment.  The treatment may have part of its effectiveness because of a very positive immediate experience, permitted by an interaction of the drug with a positive or meaningful therapeutic milieu.    The drug itself, if administered in a typical sterile or detached hospital clinic environment, may have much less benefit.  It reminds me of an old episode of The Twilight Zone in which a blind person is given a treatment which would restore his sight for a few hours.  But ironically when the sight is restored, there just happens to be a power failure, and the experience is wasted.   So, in describing mechanism, it is not just a question of receptor affinities and NMDA activity etc., it is the interaction of these with experience.

II. studies showing effects in mood disorders

http://www.ncbi.nlm.nih.gov/pubmed/22297150
bipolar depressed patients randomized to get IV ketamine 0.5 mg/kg or placebo, 2 infusions, 2 weeks apart. Around 70-80% response rates and 30% remission rates, with effects lasting several days on average. The placebo group had a 0% response rate.

http://www.ncbi.nlm.nih.gov/pubmed/22840761
ketamine 0.5 mg/kg IV 3 times per week x 2 weeks, in 24 patients with refractory depression. About 70% (17/ 24) of patients had a large, substantial improvement in depressive symptoms; improvement lasted an average of about 2-3 weeks.

http://www.ncbi.nlm.nih.gov/pubmed/20679587
Archives study, randomized add on of IV ketamine for bipolar depression. 13 of 17 patients in the ketamine group completed the study, vs. 15 of 16 patients in the placebo group. The patients were hospitalized, and had not responded to a mood stabilizer and antidepressant. Only 2 infusions, 2 weeks apart. But 50-60% response rates, 20-30% remission rates, lasting for 3-4 days, with a very large difference from placebo. Dissociative side effects occurred only acutely, for a few hours.

http://www.ncbi.nlm.nih.gov/pubmed/22297150
A similar study replicating the results of the above study.

http://www.ncbi.nlm.nih.gov/pubmed/23200737
ketamine 30-120 mg intranasally, used for severely symptomatic male bipolar patients, ages 6-17, every 3-7 days.  Marked symptom improvement in multiple domains, lasting 3-4 days after each dose.  side effects diminished with subsequent doses.  but still good clinical improvement.  Average of 20 weeks duration.  But this was a retrospective chart review.  Side effects such as transient dizziness etc. but no severe side effect problems. 

http://www.ncbi.nlm.nih.gov/pubmed/23182590
case series of 3 patients, treated with ketamine 0.5 mg/kg IV, every 1-2 weeks or so.  These patients had long complex histories of severe treatment-refractory depressions with comorbidities & axis II problems.  Varied response, one of the patients had marked improvement, the others had some benefit but not nearly so compelling. 

http://www.ncbi.nlm.nih.gov/pubmed/22854933
case series, 50-70 mg IM  ketamine q4 days for bipolar depression, marked improvement in one patient, slight improvement in another.  In these patients intranasal and/or oral ketamine did not help. 
Side effects of headache and irritability. 

http://www.ncbi.nlm.nih.gov/pubmed/23145560
bipolar depressed patients with a positive family history of alcoholism had better responses to ketamine.

http://www.ncbi.nlm.nih.gov/pubmed/20636166
a couple of cases of using oral ketamine 0.5 mg/kg to successfully treat anxiety and depressive symptoms in palliative care patients. Once again, good symptom improvement lasting about about a week. This study stands out for using oral ketamine, which would be much more convenient to use for outpatients.

III. effect on other psychiatric symptoms

http://www.ncbi.nlm.nih.gov/pubmed/22784486
no improvement in OCD symptoms with IV ketamine.

http://www.ncbi.nlm.nih.gov/pubmed/23245747
no exacerbation of PTSD symptoms in patients with trauma history exposed to a ketamine dose

IV. use for treating pain disorders on an outpatient basis

http://www.ncbi.nlm.nih.gov/pubmed/22833771
a chart review showing that transdermal ketamine can be useful for treating neuropathic pain.  I include this here to show that a transdermal route is possible, and also to show evidence of safety in other areas of outpatient medicine. 

http://www.ncbi.nlm.nih.gov/pubmed/21939497
another study looking at outpatient ketamine to treat chronic pain successfully. It was a 5-year retrospective study.    Here they used infusions, generally at a higher dose than the psychiatric studies (0.5-1 mg/kg), repeated every 3-4 weeks.   The treatments were successful and generally well-tolerated with no severe side effect problems.

This article (**) discusses ketamine use in palliative care, according to the authors' experience. In this population they suggest a starting oral dose of about 25 mg, up to 4 times daily, increasing if necessary to a maximum of 200 mg 4 times daily. As the first reference of my post suggests, it may be that IM ketamine is more effective than oral or nasal ketamine. 

http://www.ncbi.nlm.nih.gov/pubmed/20648208
a negative study, showing that adding ketamine to high-dose opioids for pain patients was not particularly useful in the long-term, in terms of reducing long-term high-dose opioid dose requirement. 


http://www.ncbi.nlm.nih.gov/pubmed/15322448
ketamine 20 mg orally twice daily, relieved neuropathic pain from MS

V. toxicity & risks

 http://www.ncbi.nlm.nih.gov/pubmed/21155941
 One of the clear long-term medical risks of ketamine use is vesicopathy.  Up to 20-30% of individuals who abuse ketamine recreationally have bladder symptoms, such as urinary frequency, urgency, and dysuria (pain). 

http://www.ncbi.nlm.nih.gov/pubmed/19919593
This 1-year longitudinal study shows substantial cognitive and functional impairment in heavy users of ketamine (many of whom using 20 doses per month). But there was no evidence of cognitive impairment in ketamine users who had less frequent use or lower doses.   

http://www.ncbi.nlm.nih.gov/pubmed/23145560
this study found that daily 1 mg/kg doses of IV ketamine caused signs of neurotoxicity after 6 months in monkeys.  Once again, this is a dose which is 14 times higher than the proposed weekly protocol for depression!   Consider how many other helpful agents (such as vitamins, water, oxygen, protein, etc.) would be dangerously toxic if taken at a dose 14 times higher than recommended! 


http://www.ncbi.nlm.nih.gov/pubmed/19133891
no cognitive deficits were found in ex-users of ketamine


http://www.ncbi.nlm.nih.gov/pubmed/10355218
In this review by Enarson (1999), he describes long-term use of oral ketamine in chronic pain patients.  3 patients out of 21 found ketamine very beneficial after over 1 year of daily use, with doses 100-240 mg per day, with improvements in pain, mood, energy, activity, and sleep.  Other patients did not like the ketamine due to short-term immediate effects, and discontinued early.  Others did not have much benefit but did not complain of side effect problems, even with over 100 mg/d for a year.  One patient was taking 500 mg/d for a year, with no side effect complaints.

http://www.ncbi.nlm.nih.gov/pubmed/12374726
case series following 4 neuropathic pain patients treated with oral ketamine 0.5 mg/kg up to 4 times per day for over 9 months.  No side effect problems or tolerance, and was effective for pain relief. 



According to Blonk et al. (2009), "Ketamine has been used in some patients for more than 1 year without observed tolerance or adverse effects associated with long-term use" (Enarson et al.,
1999; Furuhashi-Yonaha et al., 2002; Sakai et al., 2004).

V. Pharmacology (from the Monograph)**

Ketamine comes in 10, 50, or 100 mg/ mL solutions (the 100 mg/mL needs to be diluted for IV).
Parenteral use does not impair pharyngeal reflexes, therefore is safe for airway management. With IV administration, redistribution & metabolism causes duration of action of 45 minutes, and a half life of 10-15 minutes; a partially active metabolite has a half life of 2.5 hours.

There is a possible acute elevation in blood pressure with a rapid parenteral dose. Overall, it has a wide margin of safety in anesthesia.  There is respiratory depression only with rapid high-dose IV doses.

A dose of 2 mg/kg IV produces surgical anesthesia in 30 sec, lasting 5-10 minutes.  Doses of 9-13 mg/kg IM produce surgical anesthesia within 3-4 minutes, lasting 12-25 minutes. In surgery, low dose IV diazepam (under 20 mg) is used with the ketamine.

The LD50 in rats is about 20 times the equivalent human IM surgical dose.   

VI. Mode of Administration   **

Oral ketamine has about 20% the bioavailability of IV, but leads to equal bioavailability of the active metabolite.  So overall it would be conservative practice to start with the same dose orally as parenterally, and adjust (probably upwards) from there. An oral dose might need to be 3-4 times higher than a parenteral dose, to cause the same effect.  But an oral dose is likely to have an acute effect which lasts about twice as long as parenteral (approximately 4 hours of acute effects instead of 2 hours).   The qualitative difference of oral vs. parenteral effects may be due to the difference in levels of the metabolites.  The reference shown above suggest that IV doses may work better to treat mood symptoms, compared to non-parenteral dosing.   Yet, I see that this is not necessarily the case.  Some individuals may do just fine with oral dosing, so it makes sense to consider this the preferred initial mode of administration, since it is simpler, safer,  and more comfortable. 

Possible routes of administration include oral, intravenous (IV), intramuscular (IM), subcutaneous (SC), intranasal (nasal spray),  transdermal (skin creams or patches), and rectal. 


Some of the questions I have about ketamine use in psychiatry are:

1) how safe or useful is it in patients with strong histories of psychotic symptoms? 

2) to what degree does the environmental setting during the dose impact its effectiveness?  I wonder if the environment in the moment might act as a catalyst for its effects.  I suspect that a very positive, peaceful, meaningful environmental setting would consolidate the experience of symptom relief much more positively than exposure to the drug without any regard to the external situation.  This would be akin, I am thinking, to temporarily relieving a physical disability (as a prelude to working towards permanent improvement) being much more effective if the resources were in place during that temporary relief, to fully enjoy and appreciate the regained function in the moment.  This is why I suspect that the recreational use of agents such as ketamine in socially desolate or agitated settings (e.g. on the street, in a marginalized or socially impoverished situation, or in noisy parties, etc.) could have an emotionally harmful effect rather than any sustained benefit. 

3) if the ketamine is effective, what is the best long-term dosing interval?  (current studies suggest every 1-4 weeks, but not enough data to be sure)   My reading of the evidence suggests weekly dosing, with diminished frequency or dose  if symptoms remain stable.  Also, what is the role of other antidepressant therapies, including other antidepressants, in patients having ketamine treatments?  (some of the articles quoted above suggest that some drugs such as benzodiazepines may reduce ketamine's effects--I wonder if this is true for other drugs such as mood stabilizers)

4) if it is effective, does it remain effective for very long-term followup (over many years).  And if there is repeated use over this time, are there emergent side effect risks not appreciated in the present short-term studies?   

5) given that this is a new and exciting area of research, should this not warrant intense widespread research scrutiny, including large multicentre trials?  A new SSRI trial may well be more easy to fund and organize, due to the present funding and political structure of the research system, but perhaps a ketamine trial would be of greater good for patients. 

6) Ketamine has been used so far only in treatment-resistant severely ill patients.  Could ketamine have a role as a first-line agent for less severe cases? 

7) Could ketamine be useful as a component of therapy for other problems (e.g. personality disorders, eating disorders, relational disorders, etc.)

8) Because part of ketamine treatment is very immediate and acute (an effect lasting hours), could there be some type of psychotherapeutic activity during this time which might optimize its effect?



So, in conclusion, a very promising new area to be researched further.   I will be curious to find out more answers to these questions.