Thursday, November 3, 2011


Piracetam is a so-called "nootropic" drug, a substance which supposedly helps improve cognitive functioning.  It is available without prescription as a sort of supplement in many parts of the world.  In Canada it is not illegal, but must be imported (such as by ordering over the internet from U.S. suppliers).

The mechanism of action is not clear.   There is no obvious single receptor-mediated mechanism.  There may be various effects on ion channels, cell membrane characteristics, etc. but of course such statements are quite vague.

It is quite clear that there are few side-effect problems or toxicity risks with this agent.  Doses are typically 2-5 grams per day.

I became interested in this agent after encountering a case example of someone who reported quite a dramatic improvement in mood and overall functioning attributed to piracetam supplementation.

Here are the results of my survey through the research literature:  -- a 2005 review  -- a 1991 review looking specifically at its use  in treating  dementia; the data is really not impressive at all for dementia treatment.  -- a 2000 Japanese study affirming the effectiveness of piracetam combined with clonazepam  for treating myoclonus  (myoclonus is a neurological problem in which muscles are twitching involuntarily).  -- a 1996 study from Japan also showing benefit in treating myoclonus;  there were also improvements in motivation, attention, sleep, and mood (possibly secondary to improvement in the movement disorder). -- 2001 study from Archives of Neurology again affirming that piracetam is effective over 12 months of follow-up for treating myoclonic epilepsy. -- this 2000 Cochrane review stated that the data on piracetam are inconclusive, with studies not being of good quality - this 1999 article reviewed studies of piracetam for treating vertigo, concluding that it was useful for reducing frequency of recurrence, at doses of 2-5 grams per day.  -- this is a 2007 randomized placebo-controlled study from The Journal of Clinical Psychiatry,  in which piracetam 4800 mg/d for 9 weeks led to substantial improvements in tardive dyskinesia, with large differences from placebo.  -- piracetam has some antiplatelet function, which could be used in managing or preventing recurrences of vascular disorders.  This is a 1999 review of this subject.  -- this is a broad review of nootropics, published in 1994.  -- this 1987 study from The Journal of Clinical Psychopharmacology shows that children treated with piracetam may show improvements in dyslexia.
Doses were 3.3 grams daily x 36 weeks (dosed twice per day).  However, as I look at the results, I see that there is a statistical difference, but the numbers really look very similar between placebo and piracetam.    The placebo group improved substantially; the piracetam group improved only slightly more.  For example, the raw scores in the Grey Oral Reading Test increased from 17.1 to 22.5 in the placebo group; in the piracetam group it increased from 14.8 to 22.9.   It is true that the piracetam was well-tolerated, with minimal side-effect problems.
this is a 2002 study which attempted to show whether piracetam could prevent ECT-induced cognitive problems.   The dose was 7.2 g/day for a 2-week loading phase, then 4.8 g daily for the remaining 2 weeks.  They concluded that piracetam had no effect on cognition in this group; but the piracetam group did slightly better than the placebo group in terms of overall clinical improvement.
this 2006 study described anxiolytic effects of piracetam which were blocked by flumazenil (a benzodiazepine receptor blocker), suggesting that piracetam has some GABA-like activity.
a Hungarian study describing successful use of piracetam to treat alcohol withdrawal delirium
a 1993 Indian study showing that piracetam has anti-anxiety effects when administered on a longer-term basis in rats.
a 1979 article from Journal of Affective Disorders describing anti-anxiety effects from piracetam similar to a benzodiazepine, but without sedation.
in this 1983 study, piracetam 2.4 g/day or 4.8 g/day was compared with placebo in treating 60 elderly psychiatric patients; the 2.4 g/day group showed increased socialization, altertness, and cooperation, and had some improvement on memory and IQ tests, compared to the placebo group.
in this 1977 study, elderly psychiatric patients were given 2.4 g/day of piracetam or placebo, for 2 months.  The piracetam group did not improve in any cognitive tests or mood symptom scores compared to placebo, but interestingly 52% of subjects in the piracetam group showed overall improvement (CGI) compared to only 25% in the placebo group.
a Cochrane review from 2001 concluding that there is evidence that piracetam may improve the course of aphasia after stroke; however, the evidence was found to be weak.
this 1982 study shows that 40 g of IV piracetam caused greater reduction than placebo in antipsychotic-induced Parkinsonian side-effects.
a small 1979 study which showed that refractory depressed patients improved with the addition  of 2.4 g piracetam.
a look at toxicity risk due to piracetam, when given in higher doses (12 g/day) for 12 weeks, to stroke patients.  The paper concludes that there is no significant toxicity risk at this dose for this population.

In conclusion, piracetam appears to be clearly effective for a few uncommon conditions, such as myoclonus.  There is possible effectiveness for some other problems such as tardive dyskinesia.  The evidence for effectiveness as a "cognitive enhancer" appears to be quite shaky, but not absent.

I am particularly interested in some of the evidence which suggests that it could be useful as a safe, well-tolerated adjunct to treat depression or anxiety.  Some of the studies quoted above appear to support this possibility.  This theme also intersects with my recent thoughts about considering cognitive function in chronic mood, anxiety, ADHD, or personality disorders. A weakness in working memory capacity or executive functioning could substantially interfere with recovery from psychiatric illness; I suspect that a treatment which could specifically help with cognitive function could be a unique angle to augment treatments for these other psychiatric problems.  (see my previous post, which discusses an association between rumination & working memory dysfunction:  Here's another link about this:

I do think it would be worthwhile for research groups to consider doing some new, careful, large trials of piracetam as an augmentation for managing depression, anxiety disorders, etc.

Wednesday, October 26, 2011

Therapeutic approaches to irritability

Irritability can be a challenging symptom, often present in a wide range of different clinical settings.  Unipolar depression can present with irritable mood, as can the manic states of bipolar disorder.  Irritability is also a common problem in borderline personality disorder, as well as in various other populations, such as in those with autism, dementias, brain injury, conduct or oppositional disorders, and addiction disorders.  In some cases, arguably, irritability could be considered the primary problem for some people, which either exists on its own as a solitary symptom, or is the direct single cause of the person's other life problems (e.g. in relationships, employment, conflicts with the law, ability to work or study, etc.)

A variety of simple factors usually make irritability worse:
1) sleep problems.  Insomnia or deliberate reduction of sleep hours will magnify irritability.
2) hunger.  For some individuals especially, allowing a hungry state without eating healthily will magnify irritability.

In both cases above, a vicious cycle can arise, as greater irritability may prevent sleep or cause a further lack of appetite.   

3) multiple environmental or medical irritants which are not improving:  for example, crowding, noise, poor air quality, physical pains or discomforts

Therefore, in approaching irritability, it is essential to take steps to improve sleep, nutrition, pain, and environmental stimuli.

Further therapy for irritability should of course involve healthy lifestyle practices, such as exercise, relaxation, and meditative activity (if not formal "meditation" then something which accomplishes something similar, such as music listening or performance, biofeedback, hot baths, massage, etc.)  Reduction of caffeine intake, etc. could be important to try. Developing healthy philosophical practices can be very useful; for example, some type of calm or peace-oriented religious or other community involvement may add to one`s ability to manage irritability, especially since there could be group-based support and healthy cultural activities. 

Pharmacological treatment of irritability, if necessary, would  depend on obvious underlying causes.  In substance withdrawal states, for example, temporary appropriate sedation (e.g. with benzodiazepines, clonidine, or anticonvulsants such as gabapentin) could ease the irritability.    In manic states, mood stabilizers, antipsychotics, and benzodiazepines which ease the manic symptoms, would be expected to ease the irritability.  In major depression, an antidepressant of any sort, if it works for the individual, could dramatically improve the irritability.  ADHD can be a cause of irritability, which--seemingly paradoxically--could improve with stimulant therapy. 

In this post, I am particularly interested in looking at specific pharmacological treatments for idiopathic irritability, or irritability which has existed as a long-term emotional dynamic such as in those with borderline personality traits or disorder.

Here are a few pertinent links to abstracts in the research literature:
this 12 week randomized study shows modest benefits from divalproex to treat irritability in autistic children (ages 5-17)  gabapentin useful for borderline patients over a 6 month period (this is a good article, but it's in German)--  review of anticonvulsant effectiveness in personality disorders.  There is evidence in this paper to support trials of valproate, topiramate, and possibility also lamotrigine.  They describe some data on carbamazepine as well.  The level of evidence is such that I think these medications could be worth trying cautiously on an individual basis, particularly to target symptom domains such as irritability.  However, I think expectations should be modest, due to there most likely being a lot of variability in an individual's response. 

I am interested in the use of clonidine for irritability.  This drug is effective for treating withdrawal states (including one of the most unbearable withdrawal states possible, from opiates), but has also been used for many years to treat ADHD.  It can help with tic disorders as well, so could be a good choice for managing ADHD + tic comorbidity, a difficult problem often made worse by stimulants.  Clonidine was originally developed as a treatment for high blood pressure.  My main concern about clonidine is about how well its effects persist if taken continuously for more than a few months.  Here is an article about treating borderline personality patients with clonidine:

Here's a study looking at treating children with conduct or oppositional problems with stimulants and/or clonidine:

In conclusion, there are various options to try in the treatment of irritability from most causes.  While the evidence base is limited, there is support for attempting a variety of different pharmacological treatments for idiopathic irritability, particularly anticonvulsant medications.

Monday, October 3, 2011

Parental behaviours associated with offspring personality traits

Johnson et al. have published an interesting article in the August 2011 edition of The Canadian Journal of Psychiatry (pp. 447-456) in which they describe a nice longitudinal study of 669 families, correlating parenting behaviour with future personality traits in the offspring.

To some degree, studies of this type might seem to be re-examinations of the obvious -- that is, children of friendly, gentle, stable, involved parents are more likely to be healthy and stable themselves.  The thing is, much of this effect is arguably due to heredity rather than parenting.  The genetic factors which influence temperament, mood, personality, etc. are likely to be present in both parents and children--the impact of parenting behaviours themselves are therefore likely to be overestimated.

A good method to tease out these factors would be to study  families with adopted children, provided there is good data about psychological characteristics of the birth parents.  In general studies of this sort have led to the surprising conclusion that genetic factors are quite a bit higher than expected, and parenting factors quite a bit lower.

But this particular study is quite good.  It was longitudinal, following parents and offspring  at various ages during the offspring's childhood years (ages 6, 14, and 16), then following up in the offspring's young adulthood years (ages 22 and 33).  Most importantly, the study carefully assessed parental psychological traits and symptoms, which in my opinion would help control for inherited traits confounding the results.

This article has some problems with lack of clarity in the writing.  It was not exactly clear when the interviews were done (particularly the data from when the children were 6 years old).  Also, in the tables, various items (such as "high praise and encouragement" in Table 2) are listed twice, with different numbers!  I'm surprised that the writers and editors didn't address these things before publication.  

In any case, the results show that various positive parental behaviours led to substantially reduced risk of future psychological problems in the offspring ("reduced aggregate offspring personality disorder symptoms levels" and "elevated aggregate offspring personality resiliency").  Here are a few examples (some of these things may seem like obvious truths -- but it is important to be reminded about just how important these are):
1) speaking kindly to child
2) being calm, not reactive with child
3) attention and dedication to child
4) raised child without reliance on punishment
5) lots of time spent with child
6) shared enjoyable activities with child
7) high affection toward child
8) good communication with child
9) high praise and encouragement

A few findings might be surprising to some.  For example, "encouragement of offspring autonomy" from fathers actually was associated with a higher risk of offspring psychological problems.

Studies about parenting may seem to have limited relevance to those of us who are not parents, or who are not currently being parented.  But I believe these findings can be generalized:  in a psychodynamic sense, all relationships have at least a partial "parental" quality to them.  We all also have a "parenting role" with ourselves!  This role, and the behaviours or stance we take in this role, are undoubtedly coloured by the type of parenting we have experienced in our childhoods.

Findings of this type encourage us to change our "self-parenting":

1) Speak kindly to self!
2) Be calm and not reactive to self!
3) Be attentive and dedicated with yourself!
4) Be with yourself without reliance on punishment!
5) Spend lots of time with yourself! 
6) Share enjoyable activities with yourself!
7) Have high affection toward self!
8) Communicate well with self!
9) And give self praise and encouragement!

10) If you are accustomed to "encourage autonomy in yourself" a lot, maybe you can give this one a rest.

Friday, September 30, 2011

Pregabalin for generalized anxiety

There have been a variety of studies in the literature showing that pregabalin is effective for treating generalized anxiety.

The latest of such studies I have seen is published by Mark Boschen in the September 2011 issue of The Canadian Journal of Psychiatry (p.558-565).  

This article is a meta-analysis, and shows generally that pregabalin is effective compared to placebo, and has similar, if not greater, effectiveness than other medication options for treating generalized anxiety, such as SSRIs, venlafaxine, and benzodiazepines.

The most common doses have been in the 600 mg/day range, which I consider quite high, particularly since a reasonable dose range for pregabalin could be around 75-300 mg/day.  

The "limitations" admitted by the author include issues about dosing, and the fact that Pfizer has funded every published randomized study quoted in the article.

I believe that pregabalin could be a very useful option to try, if a medication trial is being considered for generalized anxiety treatment (of course, the first lines of therapy for generalized anxiety are CBT, relaxation-oriented therapies, meditation, exercise, etc.--but for many people these approaches are not sufficiently helpful).  Pregabalin has the advantage of having a quite different--and generally mild--side effect profile compared to other medications, and a what appears to be a fairly low (but I do not think zero) risk of addictiveness/dependence problems, particularly compared to benzodiazepines.

However -- the most obvious limitation of the literature findings is only mentioned briefly in passing by the author in the discussion:  it is hard to make a good conclusion about a treatment for anxiety when the duration of follow-up is only 4-8 weeks!  I believe that a study for this problem needs to extend for a year or more.  First of all, many treatments for anxiety can be acutely helpful, but then wear off substantially over time.  Arguably, having a beer every 4 hours could reduce GAD scores over a 4-week trial--but obviously this is not an acceptable long-term treatment!  (not only would there be multiple physical harms caused by this over a period of many months or years, but there would be substantial tolerance to anxiety reduction effects, which might only become apparent over many months; furthermore,there would be new psychiatric symptoms induced over a period of months and beyond).

It is not clear from the literature whether the acute benefits over 4-8 weeks from pregabalin would persist over a year or more, whether there would be tolerance, whether there would be longer-term emergent physical or psychiatric side-effects, dependence phenomena, trouble with withdrawal or discontinuation, etc.

Research of this type could be used --spuriously--to justify giving GAD patients benzodiazepines on a routine basis as well, despite the frequent and obvious problem of tolerance, dependence, cognitive problems, etc.  Most benzodiazepine studies are of similarly short duration, hence have very limited value to guide us for the long-term treatment decisions which are most important.

Yet, I do think that pregabalin is promising, and could be worth a cautious try, particularly if other approaches are not working well.

Thursday, September 29, 2011

Multi-dimensional nature of borderline personality symptom structure

Chmielewski et al. have published an article in the September 2011 edition of the Canadian Journal of Psychiatry in which they show that borderline personality is better described as having several separate symptom dimensions.

The benefit of having several dimensions instead of one could be illustrated by way of analogy:  suppose we are talking about heart disease.   One could simply describe all patients suffering a "heart attack" according to a single severity scale, perhaps including information of the amount of pain, degree of disability afterwards, etc.  This scale could be quite useful, but it would obscure a great deal of information about the group, and reduce the efficiency of treatment.   A multi-dimensional scale would instead look at several domains separately, such as perfusion abnormalities, rhythm abnormalities, and structural abnormalities.  Abnormal perfusion might be treated specifically with bypass surgery, rhythm problems with a pacemaker, and structural problems with a valve replacement etc.   Thus the management could become more meaningfully specific.

The authors of this paper about borderline personality show that a 3-factor model fit well to describe symptoms in borderline patients; a 1-dimensional model fit much more poorly.  The 3 factors are "affective dysregulation," "behavioural dysregulation," and "disturbed relations."    Affective dysregulation would refer to high intensity and lability of negative emotion, inappropriate anger, etc.   Behavioural dysregulation would refer to self-injurious behaviour, excessive or out-of-control behaviours such as binge eating, or I might add any sort of chemical or behavioural addiction.  Disturbed relations of course refers to interpersonal relationship problems.   One could see that these three domains would each influence the others, but part of a theoretical model is to consider to what degree problems in each domain could be considered primary.  (similarly, a blocked coronary artery would be a primary perfusion problem, but could in turn cause a secondary rhythm and structural problem in the heart). 

A particularly relevant remark from the authors comes in the discussion:  "...the current pattern of associations suggests that the glue that holds the BPD construct together may largely represent the general dysfunction or misery common across all forms of psychopathology and not just BPD."  So, the authors are hinting that we could perhaps do away with the BPD construct altogether, without any loss of insight,  and instead simply describe in succinct terms what the core symptoms are.  This makes sense to me.   I do believe that some of these core symptoms are extremely important to examine and address directly.  "Affective dysregulation" would be almost automatically addressed in any therapy environment, and "relationship dysfunction" is perhaps the most frequent topic of discussion (and perhaps transferential work) done in therapy.  But the "behavioural dysregulation"domain  I think is not quite so well-addressed in much therapeutic work.  I see this domain as the most common severe problem relatively more unique to those who fit into a "borderline personality" spectrum.  It is my own view to consider this domain through a type of addiction-medicine lens, as a set of problems which are highly destructive and addictive behavioural habits, often engaged in to cope with other symptoms, but which become independent problems with time.  This is similar to any other addiction;  alcoholism, for example,  may begin as alcohol consumption intended to calm nerves, deal with boredom, or to facilitate socialization, but in time becomes more and more a separate, self-contained behavioural and physiological addiction.

In my browsing through the literature as I was writing this post just now, I encountered a psychology master's thesis published online (by Edward Selby, M.Sc. 2007).  Here's a link:
Selby makes the case well that negative emotional cascades leading to behavioural dyregulation are strongly fuelled by rumination.  The events of behavioural dysregulation, such as self-injury, serve to distract one from the intense discomfort of rumination.  Here is a quote from the conclusion:
"the findings of this study provide preliminary evidence for an
emotional cascade model of dysregulated behavior. In this model high levels of rumination may cause extremely intense states of negative affect, which result in dysregulated behaviors that distract from rumination and reduce that state of negative affect. This study specifically linked rumination to drinking to cope, binge-eating behaviors, reassurance seeking, and urgency, and it is likely that rumination is linked to a variety of other deregulated behaviors. "

Rumination, of course, is another phenomenon common to much "general dysfunction or misery."  I am reminded how important it can be, as a practical therapeutic project with patients, to work on ways to move away from, or to let go of, rumination.  (see my previous post on rumination: