Scopolamine is an acetylcholine-receptor blocker, which is usually used to treat or prevent motion sickness. Some recent studies show that it might be useful to treat depression. Here is some background, followed by a few references to research studies:
The old tricyclic antidepressants (such as amitriptyline) were shown over many years to work very well for many people. Unfortunately, they are laden with side-effect problems and a significant toxicity risk (they can be lethal in overdose). The side effects are due to various different pharmacologic effects, particularly the blockade of acetylcholine and histamine receptors. Newer antidepressants, such as those in the SSRI group, have very few such receptor blockade effects.
In some studies, however, the old tricyclics actually are superior to newer antidepressants, especially for severely ill hospitalized depression patients.
It is interesting to consider whether some of the receptor blockade effects which were previously considered just nuisances or side-effect problems, could actually be part of the antidepressant activity. Or, in some cases, drugs which primarily have receptor blockade side effects may actually be indirectly modulating various other neurotransmitter systems.
A clear precedent exists in this regard: clozapine is undoubtedly the most effective antipsychotic, but it is loaded with multiple side effects and receptor blockades. It may be --at least in part-- because of the receptor blockades, not in spite of them, that it works so well.
Another example of this effect, quite possibly, is related to what I call the "active placebo" literature (I have referred to it elsewhere on this blog: http://garthkroeker.blogspot.com/2009/03/active-placebos.html) The active placebos used in these studies usually had side effects due to acetylcholine blockade, and the active placebo groups usually improved quite a bit more than those with inert placebos. This suggests another interpretation of the "active placebo" effect: perhaps it is not simply the existence of side-effects that psychologically boosts a placebo effect here, it is that the side-effects themselves are due to a pharmacologic action that is actually of direct relevance to the treatment of depression.
Here are some studies looking at scopolamine infusions to treat depression:
http://www.ncbi.nlm.nih.gov/pubmed/17015814
This 2006 study from Archives of General Psychiatry showed that 4 mcg/kg IV infusions of scopolamine (given in 3 doses, every 3-5 days) led to a rapid reduction in depression symptoms (halving of the MADRS score), with a pronounced difference from placebo. Of particular note is that the cohort consisted mainly of chronically depressed patients with comorbidities and unsuccessful trials of other treatments. Surprisingly, there were few side effect problems, aside from a higher rate of the expected anticholinergic-induced dry mouth and dizziness.
http://www.ncbi.nlm.nih.gov/pubmed/20074703
This is a replication of the study mentioned above, published in Biological Psychiatry in 2010.
http://www.ncbi.nlm.nih.gov/pubmed/20736989
Another similar study, this time showing a greater effect in women; again a 4 mcg/kg infusion protocol was used.
http://www.ncbi.nlm.nih.gov/pubmed/20926947
evidence from an animal study that scopolamine --or acetylcholine blockade in general-- affects NMDA-related activity, in general antagonizing the effects of NMDA. This is consistent with a theory that scopolamine may work in a similar manner to the NMDA-blocker ketamine (which has been associated with rapid improvement in depression symptoms) but without nearly as much risk of dangerous medical or neuropsychiatric side-effects.
http://www.ncbi.nlm.nih.gov/pubmed/21306419
This article looks at the pharmacokinetics of infused scopolamine, and also gives a detailed account of side-effects. There are notable cognitive side-effects, such as reduced efficiency of short-term memory.
http://www.ncbi.nlm.nih.gov/pubmed/16719539
This study looks at dosing scopolamine as a patch. The patch is designed to give a rapidly absorbed loading dose, then a gradual release to maintain a fairly constant level over 3 days. My own estimation, based on reviewing this information, is that a scopolamine patch would roughly approximate the IV doses used in the depression treatment studies described above, though of course the serum levels would be more constant.
Transdermal scopolamine (patches) are available in Canada from pharmacists without a physician's prescription.
While this is an interesting--though far from proven-- treatment idea, it is very important to be aware of anticholinergic side effects, which at times could be physically and psychologically unpleasant. At worst, cognitive impairment or delirium could occur as a result of excessive cholinergic blockade. Therefore, any attempt to treat psychiatric symptoms using anticholinergics should be undertaken with close collaboration with a psychiatrist.
Monday, February 6, 2012
Thursday, December 22, 2011
Mental health issues in the workplace
A frequent source of unhappiness I see has to do with a psychologically unhealthy work environment. I am interested to survey the research literature on this subject, but for starters here are a few thoughts:
1) many businesses simply do not seem to value the idea of simply treating employees well. Instead, a short-sighted view is taken, of attempting to maximize the work output or efficiency of the workers, while minimizing costs. On a short term basis (perhaps confirmed by mathematical models composed by the recent business or commerce graduate who is now in a managerial position), this leads to more profit for the business with fewer expenses. On a longer-term basis, however, this pattern leads to poor morale, loss of good or talented employees, higher rates of absenteeism, lower productivity, lower worker loyalty, which in turn must undoubtedly be perceived or intuited by customers, all of which would severely dampen the prosperity of the business.
2) counter-examples exist, of particular businesses which treat employees very well, allowing them more autonomy, healthy scheduling, security, non-authoritarian leadership, even paid time to attend fitness activities, etc. I can think of a few examples like this in which the business and the employees are prospering together, with a very positive public image as well.
3) I have to wonder if the current educational system biases the business world to perpetuate these types of problems. University programs in commerce, economics, or business may have a variety of biases: a money or wealth-acquisition-oriented value system may be very frequent in students drawn to these areas. The programs themselves, I observe, may be dealing with subject matter that involves very interesting, complex, and subtle interactions between human motivations, emotions, and behaviours. Yet the programs tend to have very little instruction or requirement for students to study the obviously related fields of psychology, sociology, ethics, history, political science, etc. Unfortunately this may equip graduates, who may be involved in group leadership and policy-making decisions affecting thousands of people, with strong profit-optimization skills, but very little wisdom or education about human nature or a foundation in altruistic values.
4) In any case, I think many employer-employee interactions are like a dysfunctional family: the "parents" either too authoritarian or enmeshed, or too detached and uninvolved. Usually there are problems with communication. Unfortunately, it is usually very difficult for this type of "family" to come for group therapy: it seems more common for these types of group problems to become more entrenched with time.
The field of "corporate psychology" seems to address some of these issues. I will be interested to survey this literature in the coming months, and hopefully add to this post in a helpful way. Aside from therapeutic ideas to make beneficial changes in business group dynamics, I wonder if it could be a useful trend in the future to allow free economic forces to help things along: if one is considering being a customer or an investor in a business, how about checking out how happy the employees are? It would be a service to the community, in the name of public and individual mental health, to support businesses which provide a healthy community not only to the public, but to their own employees.
1) many businesses simply do not seem to value the idea of simply treating employees well. Instead, a short-sighted view is taken, of attempting to maximize the work output or efficiency of the workers, while minimizing costs. On a short term basis (perhaps confirmed by mathematical models composed by the recent business or commerce graduate who is now in a managerial position), this leads to more profit for the business with fewer expenses. On a longer-term basis, however, this pattern leads to poor morale, loss of good or talented employees, higher rates of absenteeism, lower productivity, lower worker loyalty, which in turn must undoubtedly be perceived or intuited by customers, all of which would severely dampen the prosperity of the business.
2) counter-examples exist, of particular businesses which treat employees very well, allowing them more autonomy, healthy scheduling, security, non-authoritarian leadership, even paid time to attend fitness activities, etc. I can think of a few examples like this in which the business and the employees are prospering together, with a very positive public image as well.
3) I have to wonder if the current educational system biases the business world to perpetuate these types of problems. University programs in commerce, economics, or business may have a variety of biases: a money or wealth-acquisition-oriented value system may be very frequent in students drawn to these areas. The programs themselves, I observe, may be dealing with subject matter that involves very interesting, complex, and subtle interactions between human motivations, emotions, and behaviours. Yet the programs tend to have very little instruction or requirement for students to study the obviously related fields of psychology, sociology, ethics, history, political science, etc. Unfortunately this may equip graduates, who may be involved in group leadership and policy-making decisions affecting thousands of people, with strong profit-optimization skills, but very little wisdom or education about human nature or a foundation in altruistic values.
4) In any case, I think many employer-employee interactions are like a dysfunctional family: the "parents" either too authoritarian or enmeshed, or too detached and uninvolved. Usually there are problems with communication. Unfortunately, it is usually very difficult for this type of "family" to come for group therapy: it seems more common for these types of group problems to become more entrenched with time.
The field of "corporate psychology" seems to address some of these issues. I will be interested to survey this literature in the coming months, and hopefully add to this post in a helpful way. Aside from therapeutic ideas to make beneficial changes in business group dynamics, I wonder if it could be a useful trend in the future to allow free economic forces to help things along: if one is considering being a customer or an investor in a business, how about checking out how happy the employees are? It would be a service to the community, in the name of public and individual mental health, to support businesses which provide a healthy community not only to the public, but to their own employees.
Antidepressants = Psychotherapy = Placebo ?
Jacques Barber et al. have recently published the results of a randomized, controlled study conducted between 2001 and 2007, comparing antidepressant therapy, short-term dynamic psychotherapy, and placebo in a 16-week course of treatment for 156 depressed adults. Here is a link to the abstract: http://www.ncbi.nlm.nih.gov/pubmed/22152401
The bottom line in the study was that there was no significant difference between antidepressants, psychotherapy, or placebo. Response rates were 31% for medication, 28% for psychotherapy, and 24% for placebo -- which has a low probability of being statistically different. Remission rates were 26% for medication, 22% for psychotherapy, and 20% for placebo.
Critics trying to explain these findings might attempt to argue that the psychotherapy or the medication regime was not sufficient, etc. -- but I do not see this to be true. The medications (venlafaxine or sertraline) were given at quite sufficient doses for good lengths of time. The psychotherapy was not CBT (which has a larger research evidence base) but there is little reason, in my opinion, to believe that the therapy style was inferior.
The authors attempt to do some secondary analyses looking for explanations, but their conclusions seem quite weak to me (e.g. regarding race or gender). The fact that they spin these conclusions into a prominently framed set of "clinical points" seems quite inappropriate to me -- this is a negative study, there are no "clinical points" to be found here, unless they recommend placebos and cessation of other therapies!
There are a number of issues from this study that I do find very important to discuss:
1) despite a massive amount of data showing that various therapies (e.g. antidepressants or psychotherapy) are effective for various problems, there are examples of carefully-conducted negative studies, such as this one. These results cannot simply be explained away as statistical aberration: there must be a reason why one group of people responds to a treatment, while another does not. Many of these reasons are poorly understood. It may be that the diagnostic category of "major depressive disorder" is inadequate, in that it correlates poorly on its own with treatment responsiveness.
2) the subjects in this study had a high degree of comorbidity (e.g. substance abuse problems, anxiety disorders, and axis II problems). While the severity and chronicity of depression was not found to actually correlate with treatment responsiveness, I suspect that the comorbidities would substantially affect response to a relatively short-term course of therapy.
3) the subjects in this study were socioeconomically disadvantaged; while the effect of SES was also not found to "influence the initial findings," I believe that low SES is not necessarily a direct negative influence upon mental health; rather it is an indirect factor which for many people increases the likelihood of some profound mental health negatives (e.g. unemployment, lack of meaningful or satisfying employment, lack of healthy or safe community, lack of availability to do healthy or meaningful leisure activities, not enough money to eat healthily, etc.). I believe that the environmental adversities need to be looked at very closely in a study of this type.
This leads to what I believe is an obvious explanation for the findings here: there is no therapy for depression that is likely to help unless ALL contributing factors (including obvious environmental contributing factors) are addressed. By way of analogy, I believe it is pointless to treat insomnia using a powerful sedative if a person is sleeping in a room which is continuously noisy, cold, and prone to break-ins by violent intruders. The environmental issues need to be addressed first! Another analogy I have often used is of trying to repair a water supply system for a city: it is a waste of effort to pipe in more water from rivers, or to dig a deeper reservoir, if the walls of the reservoir and the pipes are leaking or bursting because of structural defects. In order for a therapeutic strategy to work, the "leaks" have to be repaired first. For a person with anemia, it is not an appropriate strategy to simply give a blood transfusion: while a transfusion may be necessary, it will not be sufficient--and could even make matters worse-- if the underlying cause of blood loss is not addressed and treated.
In the case of medications or psychotherapy, I believe these can be very helpful, but only if environmental adversity is also remedied. In some instances, of course, relief of a psychiatric symptom could help a person to improve the environmental circumstances. But in most other cases, I think the issue is broader, and could be considered a political or social policy matter.
Another related issue is that I do not believe "depression" can be treated on its own without addressing all psychiatric and medical comorbidities at the same time. Ongoing substance abuse, in my opinion, is often a powerful enough factor--psychologically as well as neurophysiologically--to completely dominate and dissolve the positive influences of psychotherapy or effective medication. In this study, 30-40% of the cohort reported substance use problems.
As a final thought, I think the "5 axis" model of diagnosis in the DSM system deserves some affirmation; many times, however, we only pay attention to Axis I (diagnoses such as depression or schizophrenia, etc.) or Axis II (personality disorder). I think that studies such as this one highlight the necessity to look closely at Axes III (medical illnesses) and IV (social, community, financial, and relational problems). It is likely that issues on these latter two axes can prevent any resolution of problems on the first two.
The bottom line in the study was that there was no significant difference between antidepressants, psychotherapy, or placebo. Response rates were 31% for medication, 28% for psychotherapy, and 24% for placebo -- which has a low probability of being statistically different. Remission rates were 26% for medication, 22% for psychotherapy, and 20% for placebo.
Critics trying to explain these findings might attempt to argue that the psychotherapy or the medication regime was not sufficient, etc. -- but I do not see this to be true. The medications (venlafaxine or sertraline) were given at quite sufficient doses for good lengths of time. The psychotherapy was not CBT (which has a larger research evidence base) but there is little reason, in my opinion, to believe that the therapy style was inferior.
The authors attempt to do some secondary analyses looking for explanations, but their conclusions seem quite weak to me (e.g. regarding race or gender). The fact that they spin these conclusions into a prominently framed set of "clinical points" seems quite inappropriate to me -- this is a negative study, there are no "clinical points" to be found here, unless they recommend placebos and cessation of other therapies!
There are a number of issues from this study that I do find very important to discuss:
1) despite a massive amount of data showing that various therapies (e.g. antidepressants or psychotherapy) are effective for various problems, there are examples of carefully-conducted negative studies, such as this one. These results cannot simply be explained away as statistical aberration: there must be a reason why one group of people responds to a treatment, while another does not. Many of these reasons are poorly understood. It may be that the diagnostic category of "major depressive disorder" is inadequate, in that it correlates poorly on its own with treatment responsiveness.
2) the subjects in this study had a high degree of comorbidity (e.g. substance abuse problems, anxiety disorders, and axis II problems). While the severity and chronicity of depression was not found to actually correlate with treatment responsiveness, I suspect that the comorbidities would substantially affect response to a relatively short-term course of therapy.
3) the subjects in this study were socioeconomically disadvantaged; while the effect of SES was also not found to "influence the initial findings," I believe that low SES is not necessarily a direct negative influence upon mental health; rather it is an indirect factor which for many people increases the likelihood of some profound mental health negatives (e.g. unemployment, lack of meaningful or satisfying employment, lack of healthy or safe community, lack of availability to do healthy or meaningful leisure activities, not enough money to eat healthily, etc.). I believe that the environmental adversities need to be looked at very closely in a study of this type.
This leads to what I believe is an obvious explanation for the findings here: there is no therapy for depression that is likely to help unless ALL contributing factors (including obvious environmental contributing factors) are addressed. By way of analogy, I believe it is pointless to treat insomnia using a powerful sedative if a person is sleeping in a room which is continuously noisy, cold, and prone to break-ins by violent intruders. The environmental issues need to be addressed first! Another analogy I have often used is of trying to repair a water supply system for a city: it is a waste of effort to pipe in more water from rivers, or to dig a deeper reservoir, if the walls of the reservoir and the pipes are leaking or bursting because of structural defects. In order for a therapeutic strategy to work, the "leaks" have to be repaired first. For a person with anemia, it is not an appropriate strategy to simply give a blood transfusion: while a transfusion may be necessary, it will not be sufficient--and could even make matters worse-- if the underlying cause of blood loss is not addressed and treated.
In the case of medications or psychotherapy, I believe these can be very helpful, but only if environmental adversity is also remedied. In some instances, of course, relief of a psychiatric symptom could help a person to improve the environmental circumstances. But in most other cases, I think the issue is broader, and could be considered a political or social policy matter.
Another related issue is that I do not believe "depression" can be treated on its own without addressing all psychiatric and medical comorbidities at the same time. Ongoing substance abuse, in my opinion, is often a powerful enough factor--psychologically as well as neurophysiologically--to completely dominate and dissolve the positive influences of psychotherapy or effective medication. In this study, 30-40% of the cohort reported substance use problems.
As a final thought, I think the "5 axis" model of diagnosis in the DSM system deserves some affirmation; many times, however, we only pay attention to Axis I (diagnoses such as depression or schizophrenia, etc.) or Axis II (personality disorder). I think that studies such as this one highlight the necessity to look closely at Axes III (medical illnesses) and IV (social, community, financial, and relational problems). It is likely that issues on these latter two axes can prevent any resolution of problems on the first two.
Saturday, December 10, 2011
Worksheets
Here's a good site that has many links to free therapy worksheets: http://therapyworksheets.blogspot.com/
Spending some focused time with a worksheet can be a healthy, useful, structured component of therapy or self-help. Worksheets can be especially useful if you want to build up healthy therapeutic habits, both in terms of inner reflection and external action, but find yourself in need of more clear structure to get started or to continue guiding you. I find this can be analogous to learning a subject at school, or a musical instrument, etc. : practicing is obviously important, but it can certainly help guide and discipline your practice efficiently to have a good textbook to work through.
Many thanks to the person who recommended this site to me!
Spending some focused time with a worksheet can be a healthy, useful, structured component of therapy or self-help. Worksheets can be especially useful if you want to build up healthy therapeutic habits, both in terms of inner reflection and external action, but find yourself in need of more clear structure to get started or to continue guiding you. I find this can be analogous to learning a subject at school, or a musical instrument, etc. : practicing is obviously important, but it can certainly help guide and discipline your practice efficiently to have a good textbook to work through.
Many thanks to the person who recommended this site to me!
Thursday, November 3, 2011
Piracetam
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:
http://www.ncbi.nlm.nih.gov/pubmed/16007238 -- a 2005 review
http://www.ncbi.nlm.nih.gov/pubmed/1794001 -- a 1991 review looking specifically at its use in treating dementia; the data is really not impressive at all for dementia treatment.
http://www.ncbi.nlm.nih.gov/pubmed/11084917 -- 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).
http://www.ncbi.nlm.nih.gov/pubmed/8914096 -- 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).
http://www.ncbi.nlm.nih.gov/pubmed/11346373 -- 2001 study from Archives of Neurology again affirming that piracetam is effective over 12 months of follow-up for treating myoclonic epilepsy.
http://www.ncbi.nlm.nih.gov/pubmed/10796585 -- this 2000 Cochrane review stated that the data on piracetam are inconclusive, with studies not being of good quality
http://www.ncbi.nlm.nih.gov/pubmed/10338110 - 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.
http://www.ncbi.nlm.nih.gov/pubmed/17685739 -- 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.
http://www.ncbi.nlm.nih.gov/pubmed/10338108 -- 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.
http://www.ncbi.nlm.nih.gov/pubmed/8061686 -- this is a broad review of nootropics, published in 1994.
http://www.ncbi.nlm.nih.gov/pubmed/3305591 -- 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.
http://www.ncbi.nlm.nih.gov/pubmed/12394531
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.
http://www.ncbi.nlm.nih.gov/pubmed/16878489
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.
http://www.ncbi.nlm.nih.gov/pubmed/12809069
a Hungarian study describing successful use of piracetam to treat alcohol withdrawal delirium
http://www.ncbi.nlm.nih.gov/pubmed/7906672
a 1993 Indian study showing that piracetam has anti-anxiety effects when administered on a longer-term basis in rats.
http://www.ncbi.nlm.nih.gov/pubmed/95599
a 1979 article from Journal of Affective Disorders describing anti-anxiety effects from piracetam similar to a benzodiazepine, but without sedation.
http://www.ncbi.nlm.nih.gov/pubmed/6415738
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.
http://www.ncbi.nlm.nih.gov/pubmed/360232
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.
http://www.ncbi.nlm.nih.gov/pubmed/11687079
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.
http://www.ncbi.nlm.nih.gov/pubmed/6128331
this 1982 study shows that 40 g of IV piracetam caused greater reduction than placebo in antipsychotic-induced Parkinsonian side-effects.
http://www.ncbi.nlm.nih.gov/pubmed/488520
a small 1979 study which showed that refractory depressed patients improved with the addition of 2.4 g piracetam.
http://www.ncbi.nlm.nih.gov/pubmed/10338106
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: http://garthkroeker.blogspot.com/2011/08/chronic-pain-rumination.html). Here's another link about this: http://www.ncbi.nlm.nih.gov/pubmed/21742932)
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.
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:
http://www.ncbi.nlm.nih.gov/pubmed/16007238 -- a 2005 review
http://www.ncbi.nlm.nih.gov/pubmed/1794001 -- a 1991 review looking specifically at its use in treating dementia; the data is really not impressive at all for dementia treatment.
http://www.ncbi.nlm.nih.gov/pubmed/11084917 -- 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).
http://www.ncbi.nlm.nih.gov/pubmed/8914096 -- 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).
http://www.ncbi.nlm.nih.gov/pubmed/11346373 -- 2001 study from Archives of Neurology again affirming that piracetam is effective over 12 months of follow-up for treating myoclonic epilepsy.
http://www.ncbi.nlm.nih.gov/pubmed/10796585 -- this 2000 Cochrane review stated that the data on piracetam are inconclusive, with studies not being of good quality
http://www.ncbi.nlm.nih.gov/pubmed/10338110 - 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.
http://www.ncbi.nlm.nih.gov/pubmed/17685739 -- 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.
http://www.ncbi.nlm.nih.gov/pubmed/10338108 -- 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.
http://www.ncbi.nlm.nih.gov/pubmed/8061686 -- this is a broad review of nootropics, published in 1994.
http://www.ncbi.nlm.nih.gov/pubmed/3305591 -- 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.
http://www.ncbi.nlm.nih.gov/pubmed/12394531
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.
http://www.ncbi.nlm.nih.gov/pubmed/16878489
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.
http://www.ncbi.nlm.nih.gov/pubmed/12809069
a Hungarian study describing successful use of piracetam to treat alcohol withdrawal delirium
http://www.ncbi.nlm.nih.gov/pubmed/7906672
a 1993 Indian study showing that piracetam has anti-anxiety effects when administered on a longer-term basis in rats.
http://www.ncbi.nlm.nih.gov/pubmed/95599
a 1979 article from Journal of Affective Disorders describing anti-anxiety effects from piracetam similar to a benzodiazepine, but without sedation.
http://www.ncbi.nlm.nih.gov/pubmed/6415738
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.
http://www.ncbi.nlm.nih.gov/pubmed/360232
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.
http://www.ncbi.nlm.nih.gov/pubmed/11687079
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.
http://www.ncbi.nlm.nih.gov/pubmed/6128331
this 1982 study shows that 40 g of IV piracetam caused greater reduction than placebo in antipsychotic-induced Parkinsonian side-effects.
http://www.ncbi.nlm.nih.gov/pubmed/488520
a small 1979 study which showed that refractory depressed patients improved with the addition of 2.4 g piracetam.
http://www.ncbi.nlm.nih.gov/pubmed/10338106
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: http://garthkroeker.blogspot.com/2011/08/chronic-pain-rumination.html). Here's another link about this: http://www.ncbi.nlm.nih.gov/pubmed/21742932)
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.
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