Foolproof, by Sander van der Linden: a recommendation, review, and analogy with psychotherapy

I strongly recommend a new book by Cambridge psychologist Sander van der Linden, entitled Foolproof: why misinformation infects our minds and how to build immunity.

I have followed van der Linden's research for several years, alongside other experts who are studying the psychology of persuasion, misinformation, and propaganda.    This area has been an interest of mine for many years, after discovering psychologists such as Cialdini and Kahneman.  

This is a subject that everyone needs to learn about!  Persuasive techniques (for good and for bad) have always been with us through history; the power and influence of these techniques will only continue to escalate, thanks to the internet era, and now the era of artificial intelligence (AI).  

I have discussed these issues in other posts, such as:

 Garth Kroeker: How Minds Change by David McRaney: a book review and discussion (August 18, 2022)

and 

Garth Kroeker: Political polarization, propaganda, conspiracy theories, misinformation, and vaccine hesitancy: a psychiatric approach to understanding and management).  (September 1, 2021) 

and 

Garth Kroeker: "GroupThink" (October 6, 2016) 

Van der Linden reviews the history and scope of misinformation.  Among the many current examples are conspiracy theorists impacting public opinion and policy, political influencers attempting to sway elections, propagandists from other countries defending violent or oppressive policies or sowing discord among their opponents, and of course the anti-vaccine community.  

There are a couple of acronyms he introduces: the word CONSPIRE can help us to recognize some of the common features of conspiracy theories:  

C = contradictory.  Most conspiracy theories feature contradictions.  For example, there could be a belief that some awful event is a hoax, but then also a belief that the awful event is real but was caused by evil conspirators.  

O = over-riding suspicion.    A sense of general distrust that goes beyond the topic of the conspiracy theory, particularly a distrust of official or mainstream explanations.  

N = nefarious plot.  A belief that there is a shadowy group of evildoers, such as government officials, corporations, or (at worst) a particular racial or ethnic group, who behind the scenes have caused some bad thing, perhaps with a motive to advance themselves.  

S = "something's wrong."  The belief that regardless of any acknowledged or corrected fact about an event, there's something going on that isn't right.  

P = persecuted individual.  The belief that someone is being deliberately harmed (most commonly, the believers in the conspiracy theory).  

I = immune to evidence.  Presentations of evidence often have little or no effect to change the opinion of people having conspiracy theory beliefs, in fact evidence could even "backfire" and cause the conspiracy theorist to become even more entrenched, or to believe that you or your sources of evidence are all biased or part of the conspiracy.   Such immunity to evidence is common among people who have limited expertise or knowledge about science, but could also be present in some highly educated people.  A conspiracy theorist who does have more scholarly expertise may understandably deploy statistical or psychological terminology to defend their beliefs; for example, by accusing other scholars of having psychological biases (such as confirmation bias).

Re = reinterpreting randomness.  This is creating a false causal story about random, unrelated events.   Humans in general are prone to doing this.   

It's interesting as a psychiatrist to reflect on the "CONSPIRE" factors above.  They are very often present in frank psychotic states, or in milder variants such as paranoid personality.  The tendency to have paranoid thoughts exists as a trait on a continuum in the population.  This trait has various environmental causes, but also has a high heritability.   It is a typical psychotic symptom to believe that there is a special, often ominous explanation behind pseudorandom events.    

Of course, sometimes there are explanations for events which differ from the mainstream understanding.  Through history there have always been maverick scientists,  who demonstrated something new and important, despite the objections or condemnation of their peers.  One example that has always bothered me was Alfred Wegener, who in 1912 was the first to propose the theory of continental drift; he was ridiculed and dismissed by his peers, who couldn't believe that entire continents could move across the face of the earth; Wegener tragically died before his theory was proved correct.   We have to be open to consider alternative theories.  However, maverick scientists, unlike conspiracy theorists, have clear evidence to support their claims; their reasoning does not contain contradictions; they are not immune to evidence, do not reinterpret randomness, and do not have ominous, over-riding suspicious beliefs about persecution.  

Van der Linden's next acronym is "DEPICT", to help remember features of manipulative communication:

  

D - discrediting.  The manipulative communicator will portray experts who disagree with them (such as scientific leaders, or even entire communities such as leading scientific journals), as biased, poorly qualified, incompetent, or having some nefarious agenda.  It is frustrating to have a scientific debate with someone who is engaging in such discrediting, since any sound evidence you raise with them will be dismissed as invalid.  

E - emotional.  Using strong emotional language to induce fear, anger, or disgust as a persuasive tool.  

P - polarization.  Framing issues, and people who have positions on these issues, in a "black or white" fashion, rather than as shades of grey.  This leads to a false sense of dichotomy, and encourages the formation of teams of opponents holding increasingly extreme positions, and increasing disrespect for those who disagree. 

I - impersonation.  Using fake experts to bolster a claim.   A variant of this is using an actual expert, but whose expertise has nothing to do with the issue at hand.  

C - conspiracy theories.  Encouraging conspiracy theory beliefs. 

T - trolling.  Attacking, insulting, or threatening opponents, usually in an online environment, such as on social media.  Such harassment has at times been so intense that scientists or policy experts (including in public health) have been afraid to speak out, fearing for their safety.  

Van der Linden's work focuses on how we can best deal with misinformation.  He concludes with an analogy:  misinformation must be dealt with by "immunizing" ourselves against it.  

In order to build immunity against an infectious disease, it is necessary to be exposed to a weakened version of the pathogen, in order to train the immune system, such that future doses of pathogens would be dealt with quickly.  

Infectious diseases are much easier to manage, with much less risk of harm or spread, by building immunity, rather than by only relying on treatment after infection.   

Similarly, it is much harder to "treat" misinformation after the fact.  Tactics to "treat" misinformation would be debate, education, and careful review of evidence.  But many people who have fallen into a misinformation "rabbit hole" are difficult to reach or persuade using reasoned debate.  Such debate may even cause the misinformed person to become even more angry or stubbornly adherent to their ideas.    

It is better to prevent people from falling into the rabbit hole in the first place--not by eliminating rabbit holes (which is impossible) but by teaching people how to identify and manage rabbit holes if they encounter them.  

The idea of "vaccination" is presented as an analogy throughout the book.  But beliefs and persuasion are not exactly like the body's immune system.  It's a very good analogy, but not perfect.  Much of the phenomenon van der Linden is talking about is explainable through learning theory:   we learn much better if we actually practice "hands on" with things, rather than just passively absorbing theory.  If you want to learn mathematics, you actually have to work through a lot of problems, not just read about how to do them.  If you want to learn how to ride a bike or drive a car, you have to practice cycling and driving, not just read about those things in a book!  As part of the practice, it is best to face challenging situations, and learn through experience how to overcome them.  

Similarly, to deal with emergencies, it is imperative to do behavioural practice many times as a preparation.  We have to do fire drills to prepare for a potential fire.  Pilots need to practice many times in a simulator how to manage engine failure.  If you only read about something, or learn about something, without practicing, you can't possibly become proficient, especially under pressure.  

To deal with misinformation, we have to practice, hands-on, dealing with misinformation, at first with "easy" examples, then more and more difficult ones.  

Applying these ideas to psychotherapy: CBT (cognitive-behavioural therapy) is very important and useful, but at worst it can be too passive.  Many people engaging in CBT do a lot of passive learning, they do written exercises in a workbook, but do not really practice deliberate exposure to uncomfortable stimuli.  The "vaccine" analogy could be useful to incorporate into CBT for treating depression or anxiety.   This is something that I have advocated for many years, mainly an emphasis on the "B" part of CBT.  To deal with panic attacks, it is most helpful to actually practice having panic attacks, in safe, controlled conditions!   To deal with depressive thoughts, it could be a useful exercise to invent simulated depressive thoughts, at first mild ones, then more challenging ones, to understand the mechanism by which they are created, and to practice facing them without being negatively affected.   This exposure therapy is like van der Linden's "vaccine."  But most therapists don't emphasize this enough, they only try to teach people to relax or cope with symptoms after they have occurred.  One of the purposes of talking about past emotional trauma is to recreate the painful events in the mind, but in a limited, controlled, "virtual" form, within the safe context of a therapy office.  In this way talking therapy has a vaccine-like effect.  

Linden's book is a must-read, not only for those interested in propaganda or misinformation, but also for anyone wanting a better understanding of the mind itself, with ideas that touch upon managing almost any life adversity, including mental illnesses.  

References: 

Linden, S. V. D. (2023). Foolproof: Why Misinformation Infects Our Minds and How to Build Immunity. WW Norton.

Supplements for Mental Health, Part 1: Folic Acid

The nutritional supplement industry has a global market size of over 300 billion US Dollars annually.   This is comparable to all the money spent in the world on fresh fruit and vegetables.  

People generally take supplements with the idea that they will improve health or vitality, or prevent disease.  

What is the current evidence that supplements could help improve mental health?  I'll start by looking at vitamin and mineral supplements.  

The vitamin with the most recent attention in the literature is folic acid.  This is a B vitamin found in leafy green vegetables, oranges, and other healthy foods.  It has been established for many years as an essential supplement for pregnant women, to help reduce the risk of birth defects.  

Supplementation of folic acid during pregnancy may modestly reduce the risk of post-partum depression, but there is a lack of rigorous randomized controlled trials (RCTs) to prove this.   

The most compelling recent study was published in JAMA Psychiatry in 2022, finding a strong association between folic acid supplementation at doses at 1 mg daily, and a substantially reduced risk of suicide.   

But a major negative study was published in 2018: this was an RCT showing no reduction in depression risk with high-dose folic acid supplementation over an amazing 7 years of follow-up.  But this study did not specifically look at using folic acid as an augmentation in the treatment of people who already have depression or other mental health problems.  

A 2015 meta-analysis found no significant benefit for short-term use of folic acid as an augmentation for treating depression.  

So in conclusion, there is some evidence of folic acid being useful in treating depression or reducing suicidal ideation, but the findings are by no means definitive, and there are negative studies in RCTs.  As with many of these issues, there should be better RCTs with standardized doses (probably 1 or 2 mg daily) and longer durations, looking at using folic acid as an augmentation in people with established mental health symptoms.  In the meantime, there is negligible risk to supplementing with folic acid 1 mg daily, so it is ok to do so.  

References:

Nutritional Supplements Market Size Report, 2030. (n.d.). Retrieved 28 December 2022, from https://www.grandviewresearch.com/industry-analysis/nutritional-supplements-market

Global Marketing Associates (2021, March 8). Global fruit and vegetable market: Export opportunity analysis. Global Marketing Associates. http://www.globalmarketing1.com/food-beverage/global-fruit-and-vegetable-market-export-opportunity-analysis/

Jin, X., Cheng, Z., Yu, X., Tao, Q., Huang, R., & Wang, S. (2022). Continuous supplementation of folic acid in pregnancy and the risk of perinatal depression–A meta-analysis. Journal of Affective Disorders, 302, 258–272. https://doi.org/10.1016/j.jad.2022.01.080

Gibbons, R. D., Hur, K., Lavigne, J. E., & Mann, J. J. (2022). Association Between Folic Acid Prescription Fills and Suicide Attempts and Intentional Self-harm Among Privately Insured US Adults. JAMA Psychiatry, 79(11), 1118–1123. https://doi.org/10.1001/jamapsychiatry.2022.2990

Okereke, O. I., Cook, N. R., Albert, C. M., Denburgh, M. V., Buring, J. E., & Manson, J. E. (2015). Effect of long-term supplementation with folic acid and B vitamins on risk of depression in older women. The British Journal of Psychiatry, 206(4), 324–331. https://doi.org/10.1192/bjp.bp.114.148361

Almeida, O. P., Ford, A. H., & Flicker, L. (2015). Systematic review and meta-analysis of randomized placebo-controlled trials of folate and vitamin B12 for depression. International Psychogeriatrics, 27(5), 727–737. https://doi.org/10.1017/S1041610215000046

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.

Mediterranean Diet for Treating Depression

Jacka et al. have just published in BMC Medicine (January 30, 2017) the results of a study showing that healthy dietary change leads to significant improvement in depression.

In their "SMILES" study (another astonishing acronym--it stands for "Supporting the Modification of Lifestyle in Lowered Emotional States" !!), they included 67 people with moderate to severe depression, who also had low dietary quality (e.g. they were not eating a lot of vegetables, fiber, fish, and nuts, but were eating a lot of processed foods and sweets).  The participants were randomized to receive 7 sessions of either nutritional counseling, or social support.  The nutritional counseling aimed to encourage a Mediterranean-style diet, including whole grains, nuts, fish, legumes, vegetables, and fruit, while avoiding sweets and processed foods.  The social support involved having neutral conversations or playing games ("befriending").

People in the nutritional counseling group dropped their depression rating scores by about 40%, while scores in the social support group dropped by only 20%, which was statistically different with a p-value of about .03.  That is, the difference in outcome was about 97% likely to be due to the treatment effect, rather than to chance.

Reflection and Conclusion

It goes without saying, in my opinion, that healthy diet must be emphasized for everyone, in order to improve all aspects of physical and mental well-being.  In depressive states, nutrition tends to be less healthy, for a variety of reasons:  people may have less energy to attend to good nutrition; their depression may cause reduced or increased appetite; there may be comorbid eating disorders; there may be medication-induced side effects affecting nutritional behaviour or metabolism; and the depression could be associated with negative economic and social factors, which are in turn related to poor nutrition.

In addition to this, it is possible that there is a direct biological effect of poor nutritional quality causing depression.

So, in order to manage depression, and all other illnesses, it is of course important to encourage healthy dietary change.

But in the case of this study, there are a few ways in which the results may seem to exaggerate the effect of the nutritional change:

First, it seems to me that any substantial positive lifestyle change could have an "active placebo" effect independent of its direct effect on mood.  Changing your diet in the ways suggested is, in my opinion, intrinsically healthy.  But in order for someone to actually make these changes, they would have to frequently make different decisions than usual in the course of their day (for example, they would eat broccoli and fish instead of a fast food burger).  It is clearly healthier to have that broccoli and fish, but the therapeutic impact of this decision may not be exclusively because of the better nutrition--it is also because the person is taking an active, disciplined step to choose something deliberately, in the name of changing their life for the better.  It is this positive intention which may be a significant part of the therapeutic impact.

People in the control group, who had conversations and card games during the 7 sessions, probably did not experience much of a sense of their lifestyle substantially changing.  I think a more interesting activity for the control group would involve something similarly "lifestyle changing" but not following the same nutritional guidelines.  

So I wholeheartedly affirm the practice of making positive dietary changes!  I have seen numerous patients who are feeling better as a result of making similar changes themselves.  But it is also important to question the conclusion of studies like this one...Here's a reason why:  suppose that there was another study which showed that buying an expensive nutritional supplement led to similar improvements in depression scores.  The supplement, in reality, could be inert, or could simply be flavoured water.  But taking the supplement would require a very active commitment on the part of participants, to alter their dietary behaviour in a consistent, disciplined way, with enthusiastic support from people claiming to be experts, over 12 weeks.  In this case, we could agree easily that the therapeutic impact of the apparent nutritional change was due to a change in disciplined habits, combined with positive expectancy, rather than due to the wholesome properties of the supplement itself.  If people were to assume, erroneously, that the supplement (and not the discipline involved to take the supplement) caused the benefit, then people would be at risk of being taken advantage of financially by the supplement manufacturers.
In conclusion,  I strongly encourage that people make positive, disciplined, healthy dietary change.  It quite probably will improve all aspects of health, including mental health.  But be careful not to overvalue the results of studies such as this one, since the same reasoning that would allow you to uncritically endorse this study's conclusions could make you vulnerable to the persuasive efforts of marketers selling products which also require disciplined adherence.

Audio and Video recordings of Positive Affirmations

In my last post, I was discussing a technique of practicing exposure to recordings of upsetting thoughts.

This same idea can be applied to positive thoughts too!

I encourage you to collect ideas, quotations, and encouragements.  Write them down, and then make an audio or video recording, using your own voice.

Choose a time when you are feeling calm and comfortable.  Make your recording a type of message to yourself, a message of support and encouragement.

Your encouragements could be quotations from a cognitive therapy exercise, in which you were reasoning or problem solving in response to negative thoughts.  Or they could be passages from a gratitude journal, in which you express thanks for any positives in your life.  Or they could be things you might say to someone else who has struggled or suffered in the same way that you did.  Or they could simply be simple, kind encouragements directed towards yourself.  For example, you could record something like "You are a beautiful person, full of kindness, love, and potential.  The world needs you. Take care of yourself...whatever hard times you are having now will pass..."   If you make a video, smile at yourself, and gaze at yourself with loving, compassionate eyes.

After you make your recording, it would be something to listen to or watch frequently.

Unlike the exposure therapy exercise, the goal here would not be to face a fear and strengthen yourself against it, but rather the goal would be to practice absorbing and accepting the positive messages.  If you listen to a piece of music frequently, the tune will eventually "play itself" in your mind, and your memory for this music will become more and more effortless.  Similarly, these positive recorded messages could become more naturally integrated into your memory.

I think that hearing your own voice, and seeing your own image, are more powerful influences on your mind and your thinking, compared to only working with your ideas using written text.  Hearing yourself speak is much more like experiencing your own thoughts, compared to reading your own written words.

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.

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:

Ruhé 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 

 http://www.ncbi.nlm.nih.gov/pubmed/3074862

 
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. 

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. 

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.

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.