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.   

Monday, December 14, 2015

Changes in Psychiatric Culture -- Wait Lists, "Efficiency," and Superficial Care

Psychiatrists are more commonly offering the following services:

1) "Assessment":  This is a single 1-hour interview, yielding an obligatory report with diagnostic label, and treatment advice.  In some places, this single interview is all the psychiatric input that is offered.

The single assessment has rich prececents in other areas of medicine.  For example, a visit to a dermatologist could yield a very accurate and fruitful diagnosis of a specific type of chronic skin disease, leading to a clear set of instructions for safe and effective treatments.  In many cases, it would  not be necessary to see the dermatologist regularly after this assessment, unless the treatment regime was going very poorly.

But psychiatry and dermatology are quite different!   Despite our attempts to have a reductionistic and medicalized diagnostic scheme in psychiatry (e.g. the DSM-V), we see that two different people with the exact same diagnosis frequently do not follow the same pathway of symptom progression. Identical treatments do not work in identical ways with different people.

Furthermore, I believe it is an act of significant hubris to assume that one can effectively "diagnose" someone, with respect to issues touching on a person's entire history of self, character, emotion, and intellect, following a single one-hour visit.   The "first impression" from a first interview can be very important to understand a person's life and problems, but as we all know, first impressions can very, very often be inaccurate or incomplete.  For some people, it could take weeks, months, or even years, to share their story. 

Yet, this pattern of assessments may, on paper, appear to be very efficient.  One could "manage" wait lists much more quickly.  The problem is that a single assessment is actually not very useful, despite yielding an official-looking report which appears useful.   Offering single assessments only is similar to a teacher offering a single day of school to each of 4 000 students, rather than a whole year of daily teaching for a classroom of 20.   Another insidious consequence of the apparently "efficient" pattern of doing multiple "assessments" is that the therapist, or teacher, who may have a great joy and talent for deeply helping people in an ongoing collaborative relationship, may instead not really get to help anyone very much, leading to sinking morale and rising cynicism.  Burnout would probably follow, much more often.  But the paycheque would not go down -- it would actually be higher (in psychiatry, the fees for assessments are about 25% higher than for spending the same length of time offering a follow-up therapy appointment).  

Many of the patients I have seen have had an incredible, audible sigh of relief, when they have discovered that I am actually going to make time to see them regularly!   There is often some sense of surprise that I do not focus on diagnostic labels.   The experience of mental health care, for many, has been one of shuttling between various short-term groups, superficial courses of CBT in a sort of group lecture format, brief one-on-one followup which ends just as a deeper sense of trust is forming, and medication trials with primary care doctors.   

2) "Medication management visits":  In many cases, psychiatrists do not offer what could be called "psychotherapy."  Instead, patients are seen for a few minutes,  to discuss medication doses.   These visits could possibly be more frequent if the patient is not doing as well.  It is understandable to have such visits, for people who are wishing to take medication.  In clinics serving those who have major mental illnesses, who are taking complex medication combinations, this type of service is undeniably important.   Other types of psychotherapy or health care may be happening elsewhere.  But if this is the only style of visit which psychiatrists are offering, it creates a frame in which medication use is implied as a norm.  Why would you have a "medication management visit" if you didn't want or need medication?  From the psychiatrist's point of view, why discuss other matters, such as relationships, goals, dreams for the future, etc. unless it pertains to the medication management plan?  The frame leads to an atrophy of therapeutic skill.  I think it is a serious problem if psychiatric visits are framed with an expectation of medication management, particularly when we know what an incredibly, strongly loaded set of biases exist around medication use and marketing.  The medication management visit framework is surely designed to "optimize" the use of psychiatry, in a setting of long wait lists and shortages of care, but in setting things up this way we are inviting a possible massive deterioration in the quality of care.  I note again, that psychiatrists using the provincial fee schedule receive a large financial gain by seeing larger numbers of patients for briefer, more superficial, medication-oriented visits.  The decrement in the quality of care may tragically not be noticed in the short term, because wait lists would be shorter, appearing to be beneficial. 

Also, "improved" wait list management may cause an external observer to assume that the system has been "fixed," therefore delaying more substantive systemic changes.  

In a further sort of game-theoretical analysis of these evolving trends, I believe that there are even more adverse consequences:   because of the changing culture of the type of psychiatric practice which is considered a norm, the profession itself will attract those who are most comfortable offering this style of service.  Those wishing to do more psychotherapeutic work, or having more skepticism about medicalized psychiatry, would feel ever more part of an eccentric minority, and might choose not to enter a psychiatry residency in the first place.    So psychiatry would become even more "medicalized" with time, in a form of evolutionary selection process.  

Ideas for Positive Change:

1) Wait list management.
a)  The public health system in Canada, and possibly private insurers elsewhere in the world, could simply fund private non-medical psychotherapists.  Therapy visits with a psychologist or other counselor could be covered under the public medical services plan.  This could reduce psychiatry wait lists dramatically, while also helping the many psychotherapists who are ironically struggling to make a living, despite there being a massive population need for their services.  For a large institution such as a university, if there were extra funds to spend on mental health, these funds could be spent on providing service availability with local therapists, personal trainers, music & art therapists, pet therapists, gym memberships, etc., rather than spending money on expensive new buildings and other infrastructure.   People help people.  Buildings don't help people much, despite appearing to do so.  

b) Non-medical psychotherapists could be allowed to prescribe medication, at least in a very limited way.    I am not meaning to suggest this as a way to increase medication use!  I suggest this to defuse the power dynamic which currently exists among psychiatrists and other physicians.   The basics of psychiatric medication prescription do not require many years of medical education to understand and manage safely.  In fact, the many years of  education may simply consolidate a culture of medication use as an often unnecessary norm.  If there would be less pressure on psychiatrists and other physicians as the sole prescribers of medication, then there could be an opportunity for psychiatrists to be less focused on medication, and therefore more focused on therapeutic alliance.

2) Style of Practice
Here, I think it is very simple:  make time for people!  Doctors, make time for your patients!  Be willing to see them!  I am less concerned about what style of psychotherapy or other tactics.   I am more concerned about being present, collaborative, empathic, and available.   We should be well-informed about medications, and about therapy styles such as CBT, but we should focus most of our attention on very basic matters of building rapport, trust, and working alliance, without fear of the relationship being cut off. 

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)[] 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.

Wednesday, December 2, 2015

Potentially Dangerous Biases in Policy Planning Meetings

Administrative meetings are are a common part of many people's professional lives.  Teachers, academics, health care workers, engineers...we all at times are required to attend meetings, some of which have a theme of planning for the future, and of changing the way things are done.

Quadrant 4
The importance of reflective, proactive planning is very high.  I often refer--with my patients-- to the four "quadrants" described by Stephen Covey (1989) in his very popular book, The 7 Habits of Highly Effective People.  He wisely points out that many people are devoted to what I call "quadrant 1", which is taking care of short-term, important tasks.  For many workers this could be answering calls, or dealing with emergencies.   While quadrant 1 is important, it often consumes so much time and energy that there is nothing left for long-term planning.

 It is an obvious problem when people are spending too much time in quadrants 2 and 3:  short-term or long-term unimportant tasks (such as engaging in unhealthy habits).

 But Covey's simple but great point of wisdom is that the highest priority ought to be setting aside time for "quadrant 4":  long-term, important tasks.  Many of us are too busy with the urgent matters of the day to make time for these things.   If more attention was given to long-term, creative, imaginative planning, the short-term important tasks could often be taken care of much more efficiently, leaving more time for deeper, higher quality, more meaningful work. 

So, reserving time for meetings, in order to plan for change, can be vitally important, even if they take us away from our important daily work.  

Meetings have Costs
However, meetings have costs!   Many meetings are unproductive and boring.    The cost of the meeting is not only financial (i.e. to pay for the salaries of those in attendance, plus any costs of using the space, or getting food, etc.), but more importantly there is a cost in terms of the work that could have been done if the meeting did not take place.   If there are 40 health care workers in a 3-hour meeting (which is really 4 hours, if we consider the time to get to the meeting place and back), this represents 160 patient-hours of health care which was not provided.   For some types of brief psychotherapy, which consist of 8 sessions over a 2-month period, the meeting has a cost of 20 suffering people not receiving help.    An added cost could be a decrement in morale caused by wasted, unrewarding, unproductive time.  

Cognitive Biases & Heuristics in Meetings
One of the biggest problems with meetings, in my opinion, has to do with the manner in which they occur.  Daniel Kahneman, the Nobel-laureate psychologist and behavioural economist, has written about the strong cognitive biases that occur in group interactions such as meetings.

If a meeting begins with a number of presentations which the rest of the group watches, then these presentations are likely to have more influence than is rationally expected.  This is particularly true if the presenters are seen as "experts."  This is in keeping with other social psychology work, such as that of Cialdini, looking at factors heightening pursuasion.  These six factors have strong, often unrecognized power to manipulate decision-making.  The factors are natural phenomena, and not necessarily "bad"--in fact, as Kahneman points out, these phenomena (heuristics) can help us make important decisions more quickly, because they are "cognitive short-cuts."  For example, if we have a trusted expert educating us about the use of a new technique, it may spare us from having to take a much longer time researching and learning about the technique on our own.  But unfortunately, these persuasive factors are also used manipulatively by marketers, and may also enchant us so much that we do not do the necessary critical thinking about ideas that are presented persuasively to us.  Furthermore, even if those involved with the heuristics do not have any negative or manipulative motive, the biases exist nevertheless.  They cause a potential harmful impairment in rational decision-making, even without anyone being aware of it! 

Cialdini's Elements of Persuasion
Here are five of Cialdini's six elements of persuasion, as manifest in a typical professional meeting:

1) Reciprocity (we are more likely to be persuaded if someone has just given us something of value, since we are likely to feel grateful and indebted):  meetings may begin with tasty snacks & coffee.  We may get our own personalized name tag, which makes us feel valued and important.  We may be entertained by a friendly, humorous, engaging presenter.  It makes us primed to cooperate!  Because we have invested time and effort to come to the meeting, we are probably more apt to be "receptive" to the ideas presented, so as to compensate ourselves for the effort.   This mechanism has been well-researched before in other studies of how people form allegiances to groups via strenuous tasks necessary to join, such as in fraternities or the military.

2) Consistency & Commitment (if we have already agreed to a certain component of an idea, we are more likely to be persuaded to go farther with it in the future, otherwise we could feel as though we are contradicting ourselves or being inconsistent).   This can happen when there are repeated meetings, perhaps spaced out weeks or months apart.  If people have agreed to certain aspects of a plan, they are much more likely to continue agreeing with the same plan, and to go farther with it, even though the plan may at this future point be inappropriate or worthy of questioning.  In sales, if you can convince someone to sign a petition, and to wear a sticker touting some kind of apparently wholesome idea, you are much more likely to be able to convince that person to contribute their time and money to the cause later on, even if that person would otherwise have had a lot of doubts about the plan.  In intimate relationships, if you have said "yes" to someone a number of times previously, it can be harder to say "no" to a similar future request; this often leads to people staying in an undesired relationship, or tolerating negative relationship behaviours, which they regret afterwards. In political movements, initial commitment to a group's policies can have an "inertia" which makes members go along with the group's subsequent negative actions (extreme examples of this phenomenon can be found in various political movements of the past century). 

3) Social Pressure (if other peers are conforming to an idea, we are more likely to as well).   Fellow members of the meeting may be smiling and nodding at the presenter's ideas.

In one meeting, in which electronic gadgets were discussed as a therapeutic modality (not only therapy apps, but also things such as covert monitoring of online activity to monitor health), one could notice that many people in the room had their heads buried in their laptop screens (an irony, speaking to the interpersonal detachment caused by electronic devices!)    Murmurings could be heard from nodding heads, of "yes, yes, therapy apps, yes, what a good idea!"   An objection to the idea of using electronic gadgetry this way would be perceived by the group as a jarring and unwelcome dissonance or even a disrespectful action. 

Also, another tactic in policy presentations can be to show that other large groups across the world are adopting the idea in question.  We may be shown that professional peers, perhaps in Australia, Germany, or Japan, have adopted some new policy, and are thriving with it.   It makes us feel like joining in, or even catching up to our Australian friends!  In an environment with a lot of social pressure, one would feel deterred from objecting to an idea, because of a concern that it might offend our friends, or that it might cause us to look reactionary or old-fashioned!  Clearly, it is important to learn about what our peers are doing, but the problem is when the social pressure becomes a biased cognitive short-cut, leading us to not question or think critically about the matter in question. 

4) Liking.  If the presenter is friendly, likable, humorous, and kind, we are more likely to be persuaded by his or her ideas.  Many salespeople and presenters are indeed friendly, likable people, which gives them a big persuasive advantage!  The trouble is, supposing we had some very shy or less social people in the group, who might have a more abrupt or chilly manner.  Yet, suppose these people had very, very good ideas to contribute to the discussion.  These voices would carry much less persuasive power because of the influence of this factor.    Sometimes quite harmful ideas have been "sold" to groups, because of the likable, engaging demeanour of the person presenting them.  Once again, one does not have to look far in political history to find unsettling or even frightening examples.  

5) Authority.  At the beginning of most presentations, we are usually shown a lengthy list of qualifications that the presenter has.  This might include degrees from major universities, academic awards, publications, etc.  Such a list conveys that the person we are listening to is an "expert," and that we should perhaps trust more strongly what is said.  Often, this is a useful cognitive short-cut.  But in many other situations, the qualifications may have nothing at all to do with the message being conveyed in the meeting.  I can think of some highly-paid professional experts who have much to say about clinical care of patients--but their area of expertise relates to extensive publication of research articles, and extensive attendance of international meetings.  The "expert" may actually have much less experience with clinical care than a humble colleague-- who lacks the impressive credentials-- in the next office, who spends his or her day seeing patients, while not publishing or attending meetings at all.   Qualifications should be respected, but we need to watch out for the impressiveness and "authority" of a presenter causing irrational biases and influence in our decision-making.   Another manifestation of the authority bias has to do with the sincere well-meaning nature of many presenters.  They may be very excited about their new idea.  They may be asked to give speeches and presentations about it across the country, and may even be getting famous as a result.  Their work may be grounded in a passion and commitment for their work, and also the enjoyment of getting acknowledgment and respect professionally.   The trouble is, this very excitement, ambition,  and the existence of professional credit and fame, could lead to a bias in which the presenter becomes overly attached to their ideas, and too eager to push the ideas without critique.  The audience may also really respect the presenter, and the integrity of the presenter's motives, but as a result may be too willing to agree respectfully with the ideas, instead of questioning them rationally. 

Behavioural Economic Biases

Other biases in meetings:  some of these biases are described in behavioural economics.

6) Joint vs Single comparison bias:  in many policy discussions, there may be a presenter excitedly showing results based on a new system or technique.  The results may be very positive.  But very often, there is no fair control group.  When we look at just one thing without comparing, it causes our assessment to be distorted.  Kahneman's classic example is of how people would value  sets of dishes:  in one set, there could be 10 plates in perfect condition, plus an eleventh plate which is defective.  In another set there would be just 10 plates in perfect condition, without the eleventh plate.  If people assess these two sets at the same time, they would value them identically, since they both contain 10 good plates.  But if people assess the sets individually, without comparison, they would give the first set a much higher value than the second.  The existence of the defective plate would make it seem like the whole set has something wrong with it.   In presentations, we often see only "one set of plates."

7) misuse of statistics.  There are many ways to misuse and misrepresent statistics (either deliberately or inadvertently) which ends up unfairly favouring a policy agenda.  A couple of simple, common examples occur to me, pertinent to mental health care:

a) no control group for self-limiting phenomena.    This type of data gathering often occurs in emergency services.  A person in crisis may present to an emergency room.  A symptom questionnaire is administered, showing very high symptom scores.  In the emergency room, the person may be lying on an uncomfortable stretcher in a noisy hallway for hours, be interviewed five or six times by nurses, ER physicians, residents, and then a psychiatrist.   Perhaps a different psychiatrist the next day.  The whole ordeal could be frightening, very uncomfortable, or even frankly traumatizing.    Yet, after three days, the same symptom questionnaire could be administered again, showing a dramatic reduction in symptom scores.  The person would be discharged home, and the data would appear to show that the emergency service was functioning very well.

 In this case,  the person improved mainly because of the passage of time.   Possibly the emergency room offered some measure of safety, and perhaps even some empathic support.  But mainly, it would have been the passage of time for an acute crisis to settle down.   Many of the features of the emergency room stay could have been frankly harmful, yet the data would not show this.   In order to show whether the emergency service was indeed helpful, one would need to have a comparison group, offering a different type of experience (for example, a comfortable, cozy, supportive, community-based environment which had rooms for people to stay overnight).    Probably, the alternative service would show better results, and also a much lower risk of severe adverse effects (such as a patient feeling traumatized).

b) short-sightedness.   Many treatment trials are short term, leading to rapid improvement in symptoms.  If we use potent sedatives to treat insomnia, for example, we are likely to see almost instantaneous improvement in symptom scores.  But if we follow this medicated group for a year, we would most likely see that the medication group was doing no better, or often worse, than a control group.   We see this type of bias all over our culture.  Evidence about the dangers of greenhouse gasses or other pollutants in the atmosphere require data spanning decades.  Short-term data may lull us into believing that there is no risk, or that a harmful policy is benign or beneficial.      In psychotherapy, there is indeed evidence that psychotherapy (of all types)  can have long-term beneficial effects for many people.  But a short-term view would unfairly discourage the use of longer-term psychotherapy.  It is technically easier to gather short-term data, and such data have less technical error (due, for example, to fewer patients lost to follow-up, etc.).   But just because some types of data are easier to gather, and appear to show a positive result, we should not be biased into thinking that long-term approaches are invalid. 

 Zimbardo's Work on the Social Causation of Negative Behaviour
 There are dramatic analogies to be made, looking at historical events.   Philip Zimbardo has written extensively about the manner in which disasterous, or even "evil" events can occur, due to the dynamics of a group context.    In groups, if there is a pre-existing majority position, the meeting can become a time in which the majority position becomes "celebrated" and pushed further, due to contagious group enthusiasm, particularly if the group features a type of hierarchy or a power differential.    A dissenter in such a meeting could be viewed as "negative" or "difficult," and there would be social pressures which discourage contrary points of view.  If one of themes in the meeting is "collaboration," then any comment which seems negative or "non-collaborating" may be seen to be violating the group ethos, even though the comment may be of high ethical import.     This phenomenon occurs in all human groups, including those in which the members are highly intelligent, sophisticated, and "civilized."   The decision making in groups leading to some of the world's great wars of the past centuries have often involved contagious enthusiasm from a strong majority view, in which dissenters were initially suppressed due to social pressure alone, then later due to threat of punishment.

The Brainstorming Myth

Another common event in policy planning meetings is "brainstorming."  This may be a process in which the attendees are split into groups of 5-7 people, and asked to freely, imaginatively, constructively express positive ideas for change, perhaps building on the ideas of others, with notes being taken, and with no criticisms allowed.  But more recent evidence has shown that brainstorming techniques could be inefficient in a variety of ways.  The same social dynamics outlined above could subvert the process, discourage dissent, and discourage a challenge to authority.   It could be much more fruitful, in a group dynamic, not to have "brainstorming," but rather to make strenuous efforts to permit a truly free debate, in which members have fully adequate time to prepare in advance.  In some meetings, there may be opportunity for debate, but the members have had no time to prepare.  This would be like having a court hearing for an important case, in which there would be ample opportunity for debate, but in which one side would be allowed weeks of preparation, while the other side would have to improvise on the spur of the moment with no preparation at all! 

Making Meetings Better

What can be done to improve meetings and to reduce unwelcome cognitive biases?

1) participants in meetings can be asked to contribute ideas before the meeting begins, perhaps anonymously.

2) free questioning, with uncensored feedback, must not only be encouraged, but the right to offer such feedback must be fiercely protected.   This is the foundation of a free society, and of a modern educational process as well. 

2) I do not believe that a decision-making meeting should feature educational presentations at all.  It is simply not possible for a group to critically appraise educational material in an unbiased fashion in the space of only a few hours.   If important group decisions are to be made in a meeting, the presence of a presenter causes very strong influence on this.  We assume that the presenter has good intentions, may be very wise, etc. -- but if there is no opportunity for detailed critical appraisal or debate, then the presenter is given automatic power to influence the group, through various mechanisms of psychological bias.

 Imagine attending a family meeting to decide on a vacation spot, or on a new school for the children, in which there is a presenter advocating some strong point of view on the matter who introduces and leads the meeting, complete with video display and free pastries! There is already a conflict of interest if a group facilitator already has a specific change agenda in mind.  The facilitator is then not really a facilitator anymore, but is a lobbyist.  It is especially harmful if the people attending the meeting assume that the facilitator is neutral, without knowing that there is a strong lobbying effect going on. 

The presenter in our hypothetical family meeting might argue a very convincing case for boarding schools, or home schooling, or on the wonderful possibilities of vacations in Mexico!   But would we want family decisions to be influenced by such a presentation?  My point here is not that presentations are bad -- in fact, they could be very useful and informative -- but the problem is when single presenters have the power to influence a group's decision-making agenda, without fair opportunity for critical analysis, and for other points of view to be fairly and thoroughly explored.   It is not enough to allow an hour during the meeting itself for critical debate!  Many of the arguments presented by a sophisticated lobbyist could require weeks to study.

One of the strengths of the modern legal system is of allowing a fair opportunity for free debate before a decision is made about a legal or ethical matter.  We would never have a situation in a legal proceeding in which the person running the meeting (e.g. the judge!) would give a sales presentation encouraging a particular decision, with no opportunity for the different groups to study the proposal in detail (usually, with weeks to prepare), before decisions are made. 

3) In many cases, meetings do not need to occur at all, as the cost of them (as outlined above) may greatly exceed the benefits.

4) Great care should be taken to minimize bias of all types, and to encourage any marginalized or "hidden" voices to be heard.  In mental health care debates, there are many with strong opinions on the matter.   In many public health analyses, there could be broad population surveys to decide upon future policy.  This is reasonable.  But in many cases, those who have actually accessed and benefited from long-term therapy are not heard from at all in the surveys.   This is analogous to making major decisions about cardiovascular health care by interviewing thousands of random members of the public, while not interviewing those who have actually had heart surgery.   People could conclude from such a survey that a rapid-access, short-term exercise program is what people really want for cardiac health, and that a heart surgery program is far too expensive and inefficient.  But this conclusion would be the result of numerous layers of bias, as well as from an inadequate understanding of the experiences of everyone involved intimately in the issue.  

5) "Pre-mortem"  Another of Kahneman's good ideas about decision making, particularly in group settings, is to have a "pre-mortem."  This means imagining that a particular decision has been made, but imagining further that the decision has led to very negative or even disastrous results in the future.  The exercise is to describe ways in which this negative result could have come to be.  The advantage of a pre-mortem could be to use the group's energy not simply to drift enthusiastically into contagious cognitive biases favouring a particular decision, but to work at exploring hidden risks which the group's enthusiasm would previously have been blind to. 

6) "Non-meeting" meetings:  I think it is a great idea to set aside and pay for times in which employees and colleagues can engage in structured healthy activities, such as an exercise class, a walk in the forest, a fine arts class, or a concert.  While this could seem wasteful and expensive, I think that the benefits for morale, group cohesiveness, enjoyment of work, reduced absenteeism, and work efficiency, could be substantial.  Also this would be an example of self-care on a group level, which I think is an important model for our patients to follow.  If we are doing healthy and enjoyable self-care activities as professionals, it is more likely that our patients will be willing to do the same.

5) Heroism.  Zimbardo concludes his thesis about negative group dynamics by calling for each of us to be a "hero."  The type of heroism he means is to be boldly willing to challenge authority, to speak up freely, even when there is a risk to doing so.  One of the best and strongest aspects of American culture is a respect for free speech (and certainly a respect for heroism).    But this wonderful cultural foundation needs to be constantly nurtured, exercised, and practiced, in order to prevent it from being eroded by other cultural forces.    Be heroic :  speak up!

Cialdini, R. B. (1984). The psychology of persuasion. New York: Quill William Morrow.

Covey Stephen, R. (1989). The 7 Habits of Highly Effective People. Simon & Shuster, USA.

Furnham, A. (2000). The brainstorming myth. Business strategy review, 11(4), 21-28.
Kahneman, D. (2011). Thinking, fast and slow. Macmillan.

Zimbardo, P. (2007). The Lucifer effect: Understanding how good people turn evil. New York.

Tuesday, November 10, 2015

The Business of Psychological Questionnaires

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Monday, November 9, 2015

Quetiapine for non-psychotic depression and anxiety

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

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

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

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

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

What about research evidence?

Mezhebovsky et al (2013) published results of a multi-centre study involving about 450 elderly patients, showing that quetiapine 50-300 mg (mean = 168 mg) daily for 11 weeks, led to significant improvements in generalized anxiety symptoms, compared to placebo.
(  )
 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 ( ) 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:
(  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.  ( )

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.
( )

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.
( )

Another study, done in 2006, also showing evidence that venlafaxine is superior to duloxetine:

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. ( )   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 ( ) 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.

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

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


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

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

In another study, by Jacobson et al (2015), looking at doses of 10 mg or 20 mg daily, they found slight improvements in the vortioxetine groups compared to placebo, with "significant" differences in the MADRS score only for the 20 mg dose ( ).  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 ( ) 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.  ( 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 (, ), 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.
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.

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.

(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)
( ), 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 (

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

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

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

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

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

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

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

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

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

It is interesting to look at the data from previous studies, including a Cochrane review done in 2012, which conclude that escitalopram is better than citalopram:   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


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):

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:

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:

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:

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.

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:

These studies show a likely causal association between long-term marijuana smoking and obstructive lung disease:

     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:

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:

Another study showing that marijuana exposure may be particularly harmful to the "adolescent" brain in rats:

This study from UBC suggests that high-dose cannabinoids increase emotionality and "sensitize the stress axis" in rats:

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:

Here is a reference to a good 2008 review of the pharmacology and potential therapeutic applications of cannabinoids such as marijuana:

     Neurological Diseases

Here's a 2012 study showing relief in muscle stiffness in multiple sclerosis patients, due to cannabis administration:

Another 2012 study from CMAJ showing relief of spasticity and pain in MS patients, following cannabis administration:

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

     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.

Another prospective study, showing that cannabis improves quality of life in inflammatory bowel disease:

     Pain Disorders

Here's a good 2013 study showing that cannabis compares favorably with other standard pharmacological treatments for neuropathic pain:

     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):

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.


Tuesday, January 6, 2015

CBT as a mental workout strategy

Many studies have shown that CBT is effective for treating depression and anxiety disorders.  The studies are convincing, and the effect sizes have been large, usually comparable to medication treatments.

CBT studies are also usually well-designed.  The therapy itself is very clear.  While some complain that a "manualized" therapy is too mechanical or detached, it is true that a very standardized therapy approach allows a much more reliable scientific study.  A less structured therapeutic style would be expected to show much more variability between one therapist and the next, or between one patient and the next.  This fact does not mean that standardized, manualized therapies are superior to less structured types, but it does mean that the standardized varieties give more meaningful research results showing without any doubt whether a psychological therapy works or not.

I believe that CBT is a type of "fitness training" focusing on psychological symptoms and goals.  The CBT therapist is an educator and coach.  Actual CBT sessions are analogous to having a workout with a personal trainer.

Just as with the literal situation of seeing a personal trainer, perhaps two or three times a week for 6 weeks, one could have a lot of fitness gains from the sessions alone. 

But most fitness gains--especially for skill-related activities such as learning tennis, skiing, skating, dance, or bowling--happen as a result of the hours of dedicated, earnest daily practice.  These practice hours would take place between training sessions with the coach!

Similarly, there is some improvement in symptoms due to CBT sessions alone.  But most of the gains, in my opinion, will occur as a result of focused daily practice and homework between the sessions.

Most CBT research does not clearly indicate the number of hours of practice the patients have done, and do not have any measure of the quality of the practice done.  Just as with children doing homework activities, it matters how much time is spent, but it matters even more how good the quality is.  Was the work done in a sloppy, bored, rushed, haphazard manner, or was there evidence that the work was done with care, attention, organization, and devotion?

Similarly, very little behavioural therapy research has looked specifically at exactly how long an exposure task needs to be in order to produce an optimal effect.

In my own look at these topics, I have reached the following conclusions:

1) Daily homework of high quality is necessary for CBT to work best.  This is no different from getting good results in a university class, or following music lessons.

2) Exposure tasks (which I believe are an essential part of all CBT) need to last 20 minutes in order to be most effective.  Many clinics advise 45-90 minutes at a time.  The difficulty of the exposure task has to be adjusted so that it is moderately challenging (not too easy, and not overwhelming), with some feeling of mastery when it is over.  Just as with physical workouts, at least 3-5 exposure tasks per week should be a goal.