Wednesday, January 9, 2013

Long-term clonazepam for panic disorder

The treatment of anxiety disorders, particularly panic disorder, should emphasize behavioural and cognitive therapy, exercise, lifestyle factors, etc. 

But medication treatments can often be very helpful if these other therapies are not helping.  The trend of thinking on this matter over the past few decades has been to preferentially use SSRI antidepressants, and to minimize the use of benzodiazepines such as clonazepam, due to concerns about side effects and dependence. 

This study challenges that notion:   It is a 3 year followup study (an excellent duration for a psychiatric study!) -- and compares paroxetine 40 mg/d with clonazepam 2 mg/d (all doses taken at bedtime) for treatment of panic disorder. 

The clonazepam alone group did very similarly well to the paroxetine group, with even a slight edge of superiority over paroxetine.  And there were fewer side effect complaints in the clonazepam group compared to paroxetine.  There was no advantage to combined therapy (clonazepam + paroxetine). 

While I still remain concerned about dependency and abuse problems with benzodiazepines, this type of study affirms that long-term benzodiazepine use may be helpful--and possibly superior to antidepressants--for some patients. 

Interesting Augmentations 2: L-methylfolate

L-methylfolate is an active form of folic acid which enters the brain.  Folic acid supplementation has been considered for decades in treating depression, with varying results (generally mildly positive).  The mechanism in the brain is generally as an indirect enhancer of the production of neurotransmitters, through its involvement in the metabolic pathway. 

Here are some recent studies looking at l-methylfolate as an augmentation:
Here, a dose of 15 mg/day of l-methylfolate (but not 7.5 mg) added to an SSRI led to a doubling of the response rate for depressed patients, after 30 days (about 30% vs. 15%).   These patients had previously been on the same SSRI alone without response.   There were no side effect problems.
Another positive study from 2011.  Again showing a significant improvement in response rate with l-methylfolate augmentation, with no side effect problems (probably fewer side effects in the folate group).  But this is a much weaker study due to it being retrospective. 

As I look further at this I see some controversy about whether there may be bias here, as the methylfolate is quite an expensive product.  I would want to see a comparison study between methylfolate and the much more inexpensive ordinary folic acid.    In discussions I've looked at pertaining to this issue, the argument is made that the dose of ordinary folic acid would be very high to match 15 mg of l-methylfolate.  Maybe so--but it would be very simple to do a comparison study, since if there is no clinical superiority of one over the other, then the more affordable product should be recommended. 

Tuesday, January 8, 2013

Interesting Augmentations 1: creatine + SSRI

From my annual review of articles from psychiatry journals, here is the first of a few which caught my eye: they're very simple studies looking at medication augmentations.  

An augmentation refers to adding some type of therapeutic agent (usually a medication) to help make another therapeutic modality work better.  Usually an augmentation would not be expected to help much on its own--the term implies that it must be used with something else.  Typical augmentations in common use are triiodothyronine (a form of thyroid hormone) or lithium added to antidepressants to treat depression. 

It's always nice to see an article which has an extremely simple premise (e.g. to try some new therapy or other), which could be readily applied in an attempt to help someone immediately. 

The first article is from a Korean group (Lyoo et al.) published in the American Journal of Psychiatry in September 2012. ( )   They looked at treating 52 women having a major depressive episode, with either escitalopram 10-20 mg/day plus placebo, or escitalopram 10-20 mg plus 5 grams of creatine monohydrate daily.  

From the second week of treatment onwards, the creatine group had better symptom improvement.  After 8 weeks, over 50% of the creatine group met criteria for remission, compared to only about 25% of the placebo group. 

Creatine has been used for years as a type of muscle-building supplement.  It may have some benefits for various neuromuscular and other neurological disorders.  Risks and side-effects are minimal, according to my reading of existing evidence, particularly at doses of 5 grams per day or less  (see this risk assessment review: ).    In the brain, the mechanism is of improving ATP availability, thereby improving cellular energy dynamics.  Humans obtain creatine from the diet (about 1 g/day) and from synthesis inside the body (another 1 g/day).  So it makes sense to have therapeutic doses well above the body's baseline supply of 2 g/day.   Here is a reference to an excellent review article by Persky (2001

Creatine is readily available wherever one would obtain nutritional supplements.  If one were to try creatine, I might suggest looking for pure creatine monohydrate, as opposed to some mixture (typically with protein powder), as the mixture would be more expensive, and would often contain unnecessary additives such as artificial sweeteners.  The creatine could be ingested as a partially dissolved suspension in warm water or juice.  The dosing regime could be debated somewhat, as creatine has quite a short half-life in plasma.  This current study used a single large dose daily, but the idea of using divided dosing should be explored. 

Monday, November 19, 2012

Prospect Theory and Psychiatry

Kahneman's most ingenious aspects of psychological theory have to do with quantifying psychological gains and losses.  These findings were the result of years of careful, clever, imaginative studies. 

The mind does not function according to the standard laws of economics.  In the mind, losses are weighted more heavily than equivalent gains.  This is due to the mind's tendency to form a personal attachment to an object or phenomenon associated with the present state.    In a sense, current possession is given extra value in the mind, even if there is no other rationale for it.  The value of any change is dependent on the initial baseline (so finding a quarter will seem much luckier if you are just short on bus fare home, compared to a different situation where your wallet is full of bus tickets).   We are willing to "pay" disproportionate amounts, psychologically or economically, for certainty, or for possibility.    People would "pay" an amount much more than 10% higher to have 100% instead of 90% certainty of safety or gain.  This is the basis on which the insurance industry thrives.  And people are willing to pay much more than 1% of a potential gain to raise the probability of gain from 0 to 1% (we see this phenomenon every day when people buy lottery tickets).

Psychologically, this means that we may distribute mental time, energy, or attachment irrationally.  We may chase irrationally after long shots, or invest an excess of energy into a task--perfectionistically--in a way which is unnecessary and depriving to other goals.  And the core mental property of loss aversion may cause us to hold onto aspects of the status quo too tenaciously, and cause us to be unreasonably unwilling to take small risks, if these risks involve letting go of something we currently have.

On the other hand, some of these phenomena could be viewed as intrinsic elements of what "makes us human."  While buying lottery tickets or doing other types of gambling activities are on the one hand irrational, they on the other hand could be viewed as game playing.  And we are willing to pay to play games.  (in the case of gambling, we pay with financial loss and lost time).  I think if such activities could be framed as play activities, it might help people to assign fair values to the activities.  The act of risk-taking might actually feel enjoyable, particularly if there are other positive cues associated (for the gambler, it might be the glitzy casino), even though the net result of the activity is loss.  The problem is, many people who gamble actually frame the activity as a profit-building venture, which is highly irrational and would be expected to lead to financial ruin if pursued to the fullest extent.  Also, the mind tends not to frame probabilities accurately, and is prone to see causal patterns in random sets; therefore many a gambler comes to believe that he or she is having some kind of exceptional luckiness that is different from average. 

Similarly, insurance purchasing is on the on hand an often inefficient use of money, but on the other hand it could be viewed as the cost of feeling more secure.  Or of paying someone else to take on some of your life risks.

The phenomenon of loss aversion is part of what helps us maintain stability in our relationships with people, belongings, and activities.

But sometimes this phenomenon can cause us to irrationally hold onto relationships, behaviours, commitments, or objects which would be healthier to let go of.   

Kahneman's research shows us that these phenomena cause extremely strong biases in decision making.  While some of these biases may be an intrinsic part of our humanity, I think that at the very least, his work invites us to think much more closely about the rationality of our decisions, when it comes to economic or psychological changes, acquisitions, or losses.  

Psychiatry & Decision Utility

In Kahnemann's chapter called "Two Selves" from Thinking, Fast and Slow, he discusses a very interesting bias having to do with how we feel about, value, or rate experiences having positive or negative attributes.

In a simple economic model, it would make sense to assume that a positive experience lasting 2 hours would be "worth" twice as much as a positive experience lasting only 1 hour.

Conversely, a negative or painful experience lasting 2 hours (or 2 months, or 2 years!) would be twice as bad as a negative or painful experience lasting only 1 hour (or 1 month, or 1 year).

One way to state this, is that if we were to graph painfulness vs. time, then it would make sense to say that the total negative impact of the pain should be the area under the curve.  

But this is not so!

The mind is not wired to make such evenly weighted evaluations.

Redelmeier's and Kahneman's 1996 study of colonoscopy pain showed that the negativity of patients' experiences depends on how severe the pain of the procedure was at its peak, and on how painful the procedure was when it was ending.  It DID NOT depend on how long the procedure lasted.  Other research has shown similar results. 

Therefore, if two painful events occur for an equal length of time, after which the pain of one of the events suddenly stops, while the pain of the other event gradually diminishes, people will rate the second event more favourably, because they experience gradual relief at the end of the event.   This is even though the second event technically involves a larger total amount of pain (since the painfulness continues for a longer time). 

Even if one painful event is much longer than another, it will be experienced in retrospect to have been more comfortable if the discomfort diminishes near the end.    Similarly, a brief but intensely painful experience will  have a more negative experiential impact compared to a much longer period of moderate painfulness.

As Kahneman shows so well, the mind exhibits "duration neglect"-- it tends not to calculate the goodness or badness of things according to adding up all the good or bad experiences over time.  Instead, the mind attends to the very worst moment, and to the period of time which is most recent.

 This bias could lead to a variety of problems in making healthy choices.  A problem which causes gradual health deterioration over many years could be preferred to another problem which would cause much less long-term harm, but which would be acutely more uncomfortable.  Addictions are an obvious example--the long term deterioration due to addictive behaviour may be barely noticeable, and quite tolerable in the moment.  Even the cumulative effect of the harm (the "area under the curve") might not be attended to experientially.  But acute withdrawal would be very uncomfortable, despite being much more favourable to long-term health.

In relationships, people might be tempted to stay in a chronically bad situation, if each time a severe problem occurs, there is a gentle apology or other positive relief afterwards.  The mind preferentially attends to the end of episodes, so if the ending is "positive" it may cause us to view an overall negative experience as much more positive than it warrants.

Similarly, we may undervalue long-term positives, if the ending happens to deteriorate.  A relationship which was thoroughly enjoyed in the moment every day for years might be remembered, and assimilated into retrospective experience, much, much more unfavourably if it ended in a negative way.  

This touches on the human tendency to view and experience life as we would a novel or other narrative:  we highly value the intense moments of the story, and we highly value the ending.  If the story is long and enjoyable, but has a disappointing, weak, or negative ending, then we are likely to devalue the entire story.

What implications does this have for psychiatric therapy?

First, I think it is important to acknowledge this fact about how the mind is "wired."  In a therapeutic environment, it may be especially important to work towards having positive endings to appointments if at all possible, particularly if there has been difficult or painful subject matter dealt with.

A converse point, one which I think Kahneman does not attend to very much in his work, is to consider whether the brain can be trained systematically to over-ride its biases.  Kahneman at times seems resigned to assume that nothing can over-ride these phenomena, as for example he observed that his well-informed psychology student subjects were just as vulnerable to biases as anyone else.  But Kahneman has not, in his current work, looked at ways to intensively train the mind to overcome specific biases.  I suspect that, as with any skill, it would take hundreds of hours of deliberate, focused practice to have any chance to change an ingrained mental habit.

I am therefore curious to explore the possibility of re-evaluating the "weighting" of experience as a sort of cognitive-behavioural exercise.  The mind tends to focus on peaks and endings, but perhaps through disciplined, prolonged mental effort (in a sort of CBT style), we could practice ways of emphasizing in our memory those points of experience between the peaks of pain, and before any endings.  This idea resonates with a sort of "positive psychology" or gratitude-journal approach, but in this case specifically recognizing that our brains may over-attend to strong negatives, therefore we should work at bolstering our attention to other points of experience.