Friday, July 16, 2010

Dopamine Agonists in Psychiatry

The dopamine agonists pramipexole and ropinirole are drugs used in the treatment of Parkinson Disease.

These drugs are now well-established in treating restless legs syndrome (RLS) and periodic limb movement disorder of sleep (PLMS), which are frequent problems afflicting about 10% of the population, and which can negatively impact quality of life & mood symptoms.

There is a small body of evidence showing possible benefits of dopamine agonists in the treatment of depression.

Unfortunately, dopamine agonists can exacerbate addictive/compulsive behaviour: 

Here are some references about the role of dopamine agonists in RLS and PLMS:

Here's a good review article on the use of ropinirole to treat these conditions:
Here's a recent review of dopamine agonists in general to treat RLS:
Here's a 2008 meta-analysis comparing ropinirole with pramipexole for treating RLS.  Pramipexole is shown to be slightly superior:

In this 2010 study, gabapentin was compared to ropinirole for treating RLS.  While ropinirole was superior in reducing objective measures of periodic limb movements, subjects taking gabapentin had a higher subjective benefit:

Here's a case study showing remission of depressive symptoms with ropinirole used as an augmenting agent: 

Here's a 2005 study looking at ropinirole augmentation in treating depression:
This 2010 review in Lancet showed a direct antidepressant effect of pramipexole in Parkinson Disease patients:
Here's a rather weak but positive 2010 paper describing a group of patients with bipolar depression who appeared to benefit from longer-term pramipexole treatment; doses averaged about 1 mg/d:

The side effects from these drugs include frequent nausea and dizziness, possibly some daytime sleepiness.  Psychiatric adverse effects can include hallucinations, and increased compulsive or impulse-control problems.

In summary, I think dopamine agonists have a role in selected psychiatric conditions, particularly if there are restless-legs symptoms contributing to insomnia or nocturnal discomfort.  They may help treat refractory depression, but there is a risk of causing impulse control problems or hallucinations in predisposed individuals. 

Potential adverse effects of group therapy

I encountered an article today about a subject I've often thought about:  does group therapy actually have a risk of worsening underlying problems?

Here's a link to the article:,8599,2003160,00.html

The mechanism could typically occur in the treatment of addictions, which is the subject of this article.  The same mechanism might operate in the treatment of behavioural problems, including conduct disorders, eating disorders, maybe even mood disorders.

Basically, the concern is that the individuals in the group might actually "teach" others in the group about tactics to engage more deeply in the problem behaviour.  The social bonds formed in the group might expand a person's network to engage in addictive behaviours.  If some members of an addiction treatment group are severely involved in the addiction, are perhaps ambivalently committed to therapy, and may be connected to convenient resources in the community to access their addiction, this may facilitate other less severely involved members of the group to broaden their access to addictions.

In eating disorders, members of the group might "compete" with each other to some degree with eating disorder behaviours.  If there are social leaders in the group who are still highly involved in the eating disorder, this may cause a negative peer pressure on others who are starting out.  

On the other hand, an opposing, positive force in group therapy is encountering others who have understanding and personal experience of similar problems.  This can be especially important for problems where a person often feels judged or misunderstood.  Also, members of the group can teach others tactics to deal with moment-to-moment manifestations of the addiction.  In order for these positive forces to be manifest, the group itself needs to be composed of individuals who are probably similar in terms of problem severity, and where there are individuals members of the group who are progressing.  This introduces a social learning effect, in which an individual can see and emulate another individual with similar problems who is starting to make progress.  The similar problem severity among members of the group would hopefully reduce the likelihood of mildly afflicted group members being drawn into more severe illness behaviours.

Since progress through problems is always a dynamic, individualized process, it may be that involvements with groups ideally need to change dynamically as well.  If  individuals are moving quickly away from addictive behaviours, they may ideally need to nurture group connections which are similarly healthy.

This poses another problem for many with long histories of addiction or other socially dynamic health problems:  relationships which have been strongly associated with the addiction may need to left behind, or at  least boundaried very carefully.

Thursday, June 10, 2010

Naturalistic study comparing quetiapine, ziprasidone, olanzapine, and risperidone

This study caught my eye recently (here's a link to the abstract:)

It's a naturalistic study, published in BMC Psychiatry in 2010, prospectively following 213 patients with symptoms of psychosis, who were randomized to receive one of four antipsychotic medications (quetiapine, ziprasidone, olanzapine, or risperidone), then apparently followed for up to 2 years.  

My prediction with such a study would be that all four medications would have similar effectiveness, with a slight edge in favour of olanzapine.

In fact, the results showed a slight edge in favour of quetiapine.  There were no substantial differences in tolerability.

The problems with this study, though, include the following:

1) Most of the data was actually for patients who had only been followed up for 6 weeks (not 2 years!).  Only 8 of the 213 patients were followed up for 2 years.  Of these 8, 5 were taking olanzapine, 2 were taking ziprasidone, and 1 was taking risperidone.  Perhaps one might be tempted to conclude that olanzapine is the drug that has the highest chance of being acceptable for long-term use.

 2) The results were presented in a type of "refined" fashion, for example the changes in symptom scores for each drug over time were presented as graphs with a single straight line for each drug, plotted over a 300-day period.  This type of graph omits a tremendous amount of relevant data:  first of all, there were very few patients who were actually followed for 300 days, most of them were only followed for 6 weeks.  A graph like this implies that there are strong data points stretching out over the entire period.  Secondly, the linear plots do not show the degree of scatter in the data points.  There were no direct reports of the raw data in the study, only refined statistical distillations.  It would be much more informative to show all of the data points plotted out over time:  then one could see the times where most of the data were derived, the various courses of symptom change for each individual in the study, etc.  It would be a messier graph! -- but it would not mislead the viewer to immediately conclude that one medication is obviously better than the others.

In conclusion, the study really grabbed my attention when I first looked at it, but I found it to be much weaker than I thought, after reading it closely.

It does, however, provide a little bit of support for the idea that any one of these four antipsychotic medications are reasonable to try, in the treatment of psychotic symptoms.  I agree that quetiapine is a reasonable first choice, though the others could be reasonable also, depending on personal preference, past experience, side effect risks, etc.  I would still lean towards olanzapine for anticipated long-term treatment of severe symptoms.

Wednesday, June 9, 2010

A Learning Model of Psychological Change: the necessity of work & practice

It requires a great deal of work to bring about psychological change.

The brain is a dynamic organ, its development influenced by genetic predisposition combined with environmental experience.  Repeated environmental experience sculpts the brain, altering the strength of neuronal connections, neuronal activity, neurochemistry, and even neuronal growth or survival.

Various environmental adversities obviously predispose the brain to generate psychological symptoms, including specific incidents of trauma or neglect.

The manner in which adversity changes the brain is similar to the manner in which the brain changes in response to any other sort of experience:  sometimes there is sudden, intense change which can happen in an instant (e.g. a traumatic brain injury), but most often the brain changes gradually, after many repetitions of similar stimuli or similar inner processes.

Some environmental adversities are repetitive over months or years.  But often times the repetition which does further harm is generated by the brain itself:  in response to a problem, the brain's repetitious analysis and revisiting of the problem ends up causing consolidated change and ongoing symptoms. A great deal of the harm caused by specific instants of trauma is caused by the brain's reaction months or years after the trauma is over.  This reaction is akin to an autoimmune disease, in which the body's attempts to fight off disease end up causing inflammation, pain, and tissue damage. 

A symptom, such as anxiety or depressed mood, once generated from any cause, may lead to a cascade of brain changes which perpetuate and intensify the symptom.  The behavioural withdrawal which results from anxiety or depression changes the potential experiences the brain may incorporate in order to heal itself.  Even without overt behavioural withdrawal, an anxious or depressive state may cause the brain to perceive normal or pleasurable stimuli as dangerous, negative, boring, or unpleasant.   Each time this experience occurs, the brain changes further into a state of more deeply consolidated anxious or depressive disorder.  The theory of cognitive-behavioural therapy insightfully recognizes the role of thoughts as part of a cascade of phenomena perpetuating psychological illness.  Recurrent hostile, reflexively critical, cynical, pessimistic or negative thinking may at times have intellectual or philosophical validity; however, such thoughts, if highly recurrent, teach and sculpt the brain to make such a style of thinking an entrenched habit.  Such habits of thought are obvious causes for depression and diminished quality of life.    

My point here is to describe the brain as a "teachable" organ.  It is changed and sculpted by experience.  The source of this experience may be from the external environment or from the self-generated inner environment of the brain.   The degree to which the brain is sculpted by experience depends on the intensity of the experiences, multiplied by the time or frequency the experiences repeat themselves.

 In this regard, as I've stated before, the brain and its experiences are analogous to a growing garden, or a forest:  changes require time, care, knowledge about requirements, and energy.

Therapeutically, it is very clear to me that much work must be done in order to effect significant, lasting brain change. Likewise, a growing garden requires frequent care, particularly if there are adverse conditions caused from within (e.g. depleted soil, weeds) or from without (e.g. harsh weather, vandalism).  

The neurochemical environment can be an obstacle to brain change, in the same sense that abnormal soil chemistry may thwart the most earnest efforts of a gardener.  The "abnormal soil chemistry" may itself have been caused by an imbalanced garden ecology over many years, perhaps by genetic predispositions of the plants, and may conceivably be remediated and prevented in the long term by healthy gardening practices, yet an immediate external aid could be an immensely helpful catalyst to help these changes occur more easily and quickly.   Likewise, psychiatric medications can often be helpful catalysts for change.

But the key ingredient for brain change is experiential.  The type of experience capable of changing the brain substantially must be strong enough (i.e. it must employ a significant degree of the brain's capacity for attention, thought, feeling, and sensation, rather than simply being a passive or background activity), and must be frequent enough (i.e. it must occur regularly over a long period of time).

These requirements for experiential change are, as I've claimed before, similar to the requirements needed for learning a new language, or a musical instrument.

Without daily practice, therapy experiences which involve only one, or a few, appointments per week, are unlikely to cause significant psychological change, for the same reason that a language or music class once or twice a week will not lead to much language or music learning without doing daily homework.   The classes may be helpful or inspiring guides, but most of the change or learning will occur due to many hours of hard work, practicing, in-between classes.

Studies of different therapeutic strategies for treating psychological symptoms usually neglect to assess the most obvious and powerful source for change:  the amount and quality of the practice done.  It seems to me that most any style of therapy could work quite well (some slightly better than others, depending on the situation), provided that a great deal of disciplined work and practice takes place to learn new skills, and to effect change in the brain.

The analogy of musical practice leaps to mind again, in which quantity and repetition are important for learning, but also "quality."  To practice something passively, carelessly, or inattentively is often ineffectual, or sometimes even counterproductive, since one may be inculcating an unwanted habit.  Also, some types of practice may be excessively mechanical, or may be veering off a desired course too easily.

I am reminded of the "Suzuki" method of music education, which I think is wonderful, for the following reasons:
1) it encourages one to start young (i.e. at any age or level of ability)
2) it strongly encourages "playing by ear", listening frequently to recordings with strong attention to perceiving sound and tonal quality; this leads to a stronger and more rapidly developed appreciation for esthetics, as well as less dependency on external cues such as printed music.   The therapeutic analogy could be of  inviting frequent indirect involvement from a therapist or therapeutic system, rather than doing all "homework" completely on ones' own.
3) it strongly encourages group practice & performance, right from the beginning. This teaches not only solo musicianship, but also following and playing well with others, enjoying others, cooperation, being in a leadership role, having confidence with performance, and sharing one's gifts with others.   Also, practice is encouraged to be not just a solitary activity, but something which can be done with family or loved ones.  Therapeutically, I think it is strongly desirable to incorporate psychological work into group, family, and community settings.  
4) it emphasizes the importance of good posture.  Therapeutically, I think a fairly strict and disciplined framework to practice psychological techniques is healthy and reduces the likelihood of acquiring unhelpful habits.  On a literal level, I think a balanced exercise routine is psychologically healthy, including cardiovascular or strength training, sports, or a "postural" exercise such as yoga. 
5) it emphasizes the need for a lot of repetition.  Therapeutically, it may be necessary to practice techniques thousands of times, over a period of months or years, in order for them to become fluent.   Repetition should never be undertaken in a dull, mechanical way -- it needs to be infused with careful, reverent attention -- but it is absolutely needed in order to master anything. 

I challenge all those wishing to change longstanding psychological problems to frequently renew commitments to work hard, and to translate these commitments into a disciplined schedule of daily practice.  It may be that there are symptoms of  tiredness, amotivation, apathy, or a very negative or painful reaction to a broad variety of daily life experiences; these symptoms can prevent engagement with commitments, and can hinder the capacity to engage in disciplined work habits.  Also, the life stressors (work, money, relationship problems, etc) can take up so much time and energy that there is not much left to do regular psychological work.  Perhaps part of the therapeutic process at this stage is to problem-solve around ways to reduce stresses, reduce some of the symptoms, bolster energy, etc. as prerequisites to establishing a work plan.  Another view of this issue is that the "work" alluded to here could take place within any type of life stressor, it does not necessarily require a lot of extra time separate from other activities of daily living.

Thursday, April 22, 2010

"Brain Training" ineffective?

Adrian Owen et al. published a letter in Nature this week, summarizing the results of a study examining the effects of playing "brain training" computer games.  Here is the link:

The format of the study is interesting, involving the BBC website, inviting mass public participation in ongoing on-line research projects (here's a link to that site, which has a variety of other entertaining surveys you can do:

In this case, over 11 000 subjects did various types of computer games on-line, aimed at developing various cognitive skills.  The subjects had to practice for at least 10 minutes per day, at least 3 days per week, for 6 weeks.  Some subjects practiced much more than others. 

The results are not very surprising to me:  basically, they showed that the skills developed while practicing a computer game do not "transfer" : they do not lead to generalized improvement in cognitive ability.   Even the subjects who practiced much more than the minimum requirement did not end up improving in a set of generalized cognitive tests afterwords.

Subjects improved significantly only in the specific tasks which were practiced.  This is intuitively obvious.   If you practice Tetris, you will become much better at Tetris, but are not likely to improve your mastery of French vocabulary!  Practicing volleyball will not help your guitar skills very much -- in some cases, such practice may in fact interfere with other skills acquisition, because one is procrastinating or redirecting energy away from one skill while practicing another.    Certainly it is true that computer games can be quite addictive:  if someone is spending many hours per week playing computer chess, or some other game, instead of reading, then overall educational performance is likely to decline rather than improve.

For participants in this study, it may be true that benefits occurred in "process" which were not adequately measured by the benchmark tests administered before and after the 6-week trial.  For example, playing a game which improves reflexes or visual memory might not immediately or directly "transfer" or  lead to improved performance in another reflex-based or memory-based benchmark test--but it might cause improvement in the rate at which another reflex-based or memory-based test, task, or game would be learned or mastered.  Analogously, if you have played a lot of volleyball, you might not immediately perform well in soccer--but you might learn to play and master soccer more quickly.  Or, if you have learned French and Spanish, you might not immediately perform well in a German vocabulary test, but you might be able to learn German much more quickly.  These types of benefits would not be picked up by the testing administered in this study. 

Here are some further ideas:

1) Is it possible that some particular cognitive games are more useful or generalizable than others?

-I think this is very possible.  I think that one should consider what type of gain is desired from the exercise you are doing.

A game which helps you practice learning and remembering faces and names could be quite helpful if such memory issues are problematic in your daily life.  Such a game would be inherently generalizable, since the daily behaviour and experience outside of the game would be similar to the game challenges. has examples of such games.

A game which helps you pay attention to reading texts closely, while monitoring and testing your speed, accuracy, memory, and comprehension of the text, could be very useful if you are having trouble reading or studying.

Games which teach and test general knowledge subjects could be obviously useful to gain general knowledge -- e.g. learning vocabulary, facts about nature, etc.

So, I think one should choose games carefully, with the knowledge that the game will train you to improve in a particular skill.  Is that particular skill likely to be useful or generalizable in your daily life?

2) Is it possible that some of the specific games used in this study could be generally useful to some particular individuals, even though they were not helpful to the group as a whole?

-I think this is very possible as well.  There are three main issues that leap to my mind about this:

First, the study looks at a large general population of volunteer subjects.  A great many of these subjects were probably already in pretty good shape cognitively, and were motivated and enthusiastic to participate in such a research project.  This would be like asking a bunch of fitness enthusiasts to do 10 minutes of calisthenics 3 times per week, and then checking to see if their overall fitness improved 6 weeks later.  It would not be surprising to see an absence of any effect.  However, if the participants were chosen because of having cognitive weaknesses, due to learning disabilities, dementia, other illnesses, or environmental deprivation, then perhaps there could have been a much more substantial and relevant improvement with such a regime.  People with a lower fitness level would be expected to benefit much more substantially from a simple calisthenic routine than those already in good shape.  Many people with depression might have low motivation or engagement with intellectual tasks -- in this case, games of this type might help people get their minds more active again, as a prelude to other types of learning or intellectual engagement. 

Second, I am reminded of some other requirements for change in the brain: an immersive or highly intensive environment can be required for the brain's plasticity to be harnessed.  This might require many hours per day, over many months.  These hundreds of hours of training would contrast with the total of 3 hours' minimum training which this study evaluated.   

Third, some of these game types could be useful, diagnostically, for evaluation or identification of particular cognitive or perceptual strengths and weaknesses.  If these problems are identified, then a specific recipe for improvement could be mapped out.

I do wish the authors of this study, given their interest in computer-based learning & cognitive testing, would invent some games which could help people develop ability in reading, comprehension, general knowledge, etc.  Also, there are game-like computerized exercises which can help people develop skills in recognizing emotions, empathizing, etc.  (examples can be found at the BBC site).   These exercises could be useful for dealing with social anxiety, relationship problems, Asperger's Syndrome, etc.