Ketamine in Psychiatry

I have just updated and edited this article over the past few days.

Ketamine is a drug which has been used in general anesthesia for decades.  It is a so-called "dissociative anesthetic," which means that it causes an altered state of sensory perception without loss of consciousness.  It is a blocker of NMDA receptors;  this blockade in turn boosts glutamate release through reduced presynaptic inhition.  From there the increased glutamate increases stimulation of AMPA receptors.  These effects occur only for a few hours after a dose.  The significance of these changes would be of some debate among neuroscientists, but the bottom line is that there is a brief but marked acute alteration in one of the core aspects of the brain's dynamics and metabolism, including those aspects responsible for the management of memory, learning, and emotional processing.   

Ketamine is used illictly as a recreational drug, a fact which might bias many of us against considering its potential benefit in medicine.  

The exciting news about ketamine recently is that a single dose can lead to a dramatic improvement in symptoms of depression, even in patients who have severe, chronic, treatment-refractory mood disorders.  Aside from these case reports, there have been a number of larger studies coming out, all of which look very promising. 

Here is my literature review on ketamine, I've selected what I have thought are the best or most representative articles:

I. Reviews
http://www.ncbi.nlm.nih.gov/pubmed/23759454
- A recent brief review from The Journal of Clinical Psychiatry (May 2013)  but in discussion of mechanism, a typical example of the divide between biological and non-pharmacologically based psychiatrists:  no mention was made of the impact of the environmental milieu during the ketamine treatment.  The treatment may have part of its effectiveness because of a very positive immediate experience, permitted by an interaction of the drug with a positive or meaningful therapeutic milieu.    The drug itself, if administered in a typical sterile or detached hospital clinic environment, may have much less benefit.  It reminds me of an old episode of The Twilight Zone in which a blind person is given a treatment which would restore his sight for a few hours.  But ironically when the sight is restored, there just happens to be a power failure, and the experience is wasted.   So, in describing mechanism, it is not just a question of receptor affinities and NMDA activity etc., it is the interaction of these with experience.

II. studies showing effects in mood disorders

http://www.ncbi.nlm.nih.gov/pubmed/22297150
bipolar depressed patients randomized to get IV ketamine 0.5 mg/kg or placebo, 2 infusions, 2 weeks apart. Around 70-80% response rates and 30% remission rates, with effects lasting several days on average. The placebo group had a 0% response rate.

http://www.ncbi.nlm.nih.gov/pubmed/22840761
ketamine 0.5 mg/kg IV 3 times per week x 2 weeks, in 24 patients with refractory depression. About 70% (17/ 24) of patients had a large, substantial improvement in depressive symptoms; improvement lasted an average of about 2-3 weeks.

http://www.ncbi.nlm.nih.gov/pubmed/20679587
Archives study, randomized add on of IV ketamine for bipolar depression. 13 of 17 patients in the ketamine group completed the study, vs. 15 of 16 patients in the placebo group. The patients were hospitalized, and had not responded to a mood stabilizer and antidepressant. Only 2 infusions, 2 weeks apart. But 50-60% response rates, 20-30% remission rates, lasting for 3-4 days, with a very large difference from placebo. Dissociative side effects occurred only acutely, for a few hours.

http://www.ncbi.nlm.nih.gov/pubmed/22297150
A similar study replicating the results of the above study.

http://www.ncbi.nlm.nih.gov/pubmed/23200737
ketamine 30-120 mg intranasally, used for severely symptomatic male bipolar patients, ages 6-17, every 3-7 days.  Marked symptom improvement in multiple domains, lasting 3-4 days after each dose.  side effects diminished with subsequent doses.  but still good clinical improvement.  Average of 20 weeks duration.  But this was a retrospective chart review.  Side effects such as transient dizziness etc. but no severe side effect problems. 

http://www.ncbi.nlm.nih.gov/pubmed/23182590
case series of 3 patients, treated with ketamine 0.5 mg/kg IV, every 1-2 weeks or so.  These patients had long complex histories of severe treatment-refractory depressions with comorbidities & axis II problems.  Varied response, one of the patients had marked improvement, the others had some benefit but not nearly so compelling. 

http://www.ncbi.nlm.nih.gov/pubmed/22854933
case series, 50-70 mg IM  ketamine q4 days for bipolar depression, marked improvement in one patient, slight improvement in another.  In these patients intranasal and/or oral ketamine did not help. 
Side effects of headache and irritability. 

http://www.ncbi.nlm.nih.gov/pubmed/23145560
bipolar depressed patients with a positive family history of alcoholism had better responses to ketamine.

http://www.ncbi.nlm.nih.gov/pubmed/20636166
a couple of cases of using oral ketamine 0.5 mg/kg to successfully treat anxiety and depressive symptoms in palliative care patients. Once again, good symptom improvement lasting about about a week. This study stands out for using oral ketamine, which would be much more convenient to use for outpatients.

III. effect on other psychiatric symptoms

http://www.ncbi.nlm.nih.gov/pubmed/22784486
no improvement in OCD symptoms with IV ketamine.

http://www.ncbi.nlm.nih.gov/pubmed/23245747
no exacerbation of PTSD symptoms in patients with trauma history exposed to a ketamine dose

IV. use for treating pain disorders on an outpatient basis

http://www.ncbi.nlm.nih.gov/pubmed/22833771
a chart review showing that transdermal ketamine can be useful for treating neuropathic pain.  I include this here to show that a transdermal route is possible, and also to show evidence of safety in other areas of outpatient medicine. 

http://www.ncbi.nlm.nih.gov/pubmed/21939497
another study looking at outpatient ketamine to treat chronic pain successfully. It was a 5-year retrospective study.    Here they used infusions, generally at a higher dose than the psychiatric studies (0.5-1 mg/kg), repeated every 3-4 weeks.   The treatments were successful and generally well-tolerated with no severe side effect problems.

This article (**) discusses ketamine use in palliative care, according to the authors' experience. In this population they suggest a starting oral dose of about 25 mg, up to 4 times daily, increasing if necessary to a maximum of 200 mg 4 times daily. As the first reference of my post suggests, it may be that IM ketamine is more effective than oral or nasal ketamine. 

http://www.ncbi.nlm.nih.gov/pubmed/20648208
a negative study, showing that adding ketamine to high-dose opioids for pain patients was not particularly useful in the long-term, in terms of reducing long-term high-dose opioid dose requirement. 


http://www.ncbi.nlm.nih.gov/pubmed/15322448
ketamine 20 mg orally twice daily, relieved neuropathic pain from MS

V. toxicity & risks

 http://www.ncbi.nlm.nih.gov/pubmed/21155941
 One of the clear long-term medical risks of ketamine use is vesicopathy.  Up to 20-30% of individuals who abuse ketamine recreationally have bladder symptoms, such as urinary frequency, urgency, and dysuria (pain). 

http://www.ncbi.nlm.nih.gov/pubmed/19919593
This 1-year longitudinal study shows substantial cognitive and functional impairment in heavy users of ketamine (many of whom using 20 doses per month). But there was no evidence of cognitive impairment in ketamine users who had less frequent use or lower doses.   

http://www.ncbi.nlm.nih.gov/pubmed/23145560
this study found that daily 1 mg/kg doses of IV ketamine caused signs of neurotoxicity after 6 months in monkeys.  Once again, this is a dose which is 14 times higher than the proposed weekly protocol for depression!   Consider how many other helpful agents (such as vitamins, water, oxygen, protein, etc.) would be dangerously toxic if taken at a dose 14 times higher than recommended! 


http://www.ncbi.nlm.nih.gov/pubmed/19133891
no cognitive deficits were found in ex-users of ketamine


http://www.ncbi.nlm.nih.gov/pubmed/10355218
In this review by Enarson (1999), he describes long-term use of oral ketamine in chronic pain patients.  3 patients out of 21 found ketamine very beneficial after over 1 year of daily use, with doses 100-240 mg per day, with improvements in pain, mood, energy, activity, and sleep.  Other patients did not like the ketamine due to short-term immediate effects, and discontinued early.  Others did not have much benefit but did not complain of side effect problems, even with over 100 mg/d for a year.  One patient was taking 500 mg/d for a year, with no side effect complaints.

http://www.ncbi.nlm.nih.gov/pubmed/12374726
case series following 4 neuropathic pain patients treated with oral ketamine 0.5 mg/kg up to 4 times per day for over 9 months.  No side effect problems or tolerance, and was effective for pain relief. 



According to Blonk et al. (2009), "Ketamine has been used in some patients for more than 1 year without observed tolerance or adverse effects associated with long-term use" (Enarson et al.,
1999; Furuhashi-Yonaha et al., 2002; Sakai et al., 2004).

V. Pharmacology (from the Monograph)**

Ketamine comes in 10, 50, or 100 mg/ mL solutions (the 100 mg/mL needs to be diluted for IV).
Parenteral use does not impair pharyngeal reflexes, therefore is safe for airway management. With IV administration, redistribution & metabolism causes duration of action of 45 minutes, and a half life of 10-15 minutes; a partially active metabolite has a half life of 2.5 hours.

There is a possible acute elevation in blood pressure with a rapid parenteral dose. Overall, it has a wide margin of safety in anesthesia.  There is respiratory depression only with rapid high-dose IV doses.

A dose of 2 mg/kg IV produces surgical anesthesia in 30 sec, lasting 5-10 minutes.  Doses of 9-13 mg/kg IM produce surgical anesthesia within 3-4 minutes, lasting 12-25 minutes. In surgery, low dose IV diazepam (under 20 mg) is used with the ketamine.

The LD50 in rats is about 20 times the equivalent human IM surgical dose.   

VI. Mode of Administration   **

Oral ketamine has about 20% the bioavailability of IV, but leads to equal bioavailability of the active metabolite.  So overall it would be conservative practice to start with the same dose orally as parenterally, and adjust (probably upwards) from there. An oral dose might need to be 3-4 times higher than a parenteral dose, to cause the same effect.  But an oral dose is likely to have an acute effect which lasts about twice as long as parenteral (approximately 4 hours of acute effects instead of 2 hours).   The qualitative difference of oral vs. parenteral effects may be due to the difference in levels of the metabolites.  The reference shown above suggest that IV doses may work better to treat mood symptoms, compared to non-parenteral dosing.   Yet, I see that this is not necessarily the case.  Some individuals may do just fine with oral dosing, so it makes sense to consider this the preferred initial mode of administration, since it is simpler, safer,  and more comfortable. 

Possible routes of administration include oral, intravenous (IV), intramuscular (IM), subcutaneous (SC), intranasal (nasal spray),  transdermal (skin creams or patches), and rectal. 


Some of the questions I have about ketamine use in psychiatry are:

1) how safe or useful is it in patients with strong histories of psychotic symptoms? 

2) to what degree does the environmental setting during the dose impact its effectiveness?  I wonder if the environment in the moment might act as a catalyst for its effects.  I suspect that a very positive, peaceful, meaningful environmental setting would consolidate the experience of symptom relief much more positively than exposure to the drug without any regard to the external situation.  This would be akin, I am thinking, to temporarily relieving a physical disability (as a prelude to working towards permanent improvement) being much more effective if the resources were in place during that temporary relief, to fully enjoy and appreciate the regained function in the moment.  This is why I suspect that the recreational use of agents such as ketamine in socially desolate or agitated settings (e.g. on the street, in a marginalized or socially impoverished situation, or in noisy parties, etc.) could have an emotionally harmful effect rather than any sustained benefit. 

3) if the ketamine is effective, what is the best long-term dosing interval?  (current studies suggest every 1-4 weeks, but not enough data to be sure)   My reading of the evidence suggests weekly dosing, with diminished frequency or dose  if symptoms remain stable.  Also, what is the role of other antidepressant therapies, including other antidepressants, in patients having ketamine treatments?  (some of the articles quoted above suggest that some drugs such as benzodiazepines may reduce ketamine's effects--I wonder if this is true for other drugs such as mood stabilizers)

4) if it is effective, does it remain effective for very long-term followup (over many years).  And if there is repeated use over this time, are there emergent side effect risks not appreciated in the present short-term studies?   

5) given that this is a new and exciting area of research, should this not warrant intense widespread research scrutiny, including large multicentre trials?  A new SSRI trial may well be more easy to fund and organize, due to the present funding and political structure of the research system, but perhaps a ketamine trial would be of greater good for patients. 

6) Ketamine has been used so far only in treatment-resistant severely ill patients.  Could ketamine have a role as a first-line agent for less severe cases? 

7) Could ketamine be useful as a component of therapy for other problems (e.g. personality disorders, eating disorders, relational disorders, etc.)

8) Because part of ketamine treatment is very immediate and acute (an effect lasting hours), could there be some type of psychotherapeutic activity during this time which might optimize its effect?



So, in conclusion, a very promising new area to be researched further.   I will be curious to find out more answers to these questions. 

Omega 3 update

Here is an update about omega-3 supplementation:

For a bit of background on omega-3 supplementation, see my other posts about this:
http://garthkroeker.blogspot.ca/2009/02/omega-3-supplementation.html
http://garthkroeker.blogspot.ca/2011/01/omega-3-deficiency-and-low-dietary.html

A meta-analysis from 2012 and some ensuing discussion has led to a few more recommendations (see http://www.ncbi.nlm.nih.gov/pubmed/22488258):


1) acute beneficial effects for mood may be present only for more severe symptoms.  However, I am curious about the preventative effects from continuous supplementation over a period of years; the data does not give us a clear answer about this yet. 

2) the EPA dose may need to be as high as 4 grams per day, certainly much higher than the 1 gram per day range frequently used in some of the studies. 

Risk factors for psychotic relapse

Alvarez-Jimenez et al. have done a good meta-analysis looking at risk factors for relapse of psychotic symptoms, published in Schizophrenia Research (2012;139-116-128).

The authors conclude that there are four major factors associated with increased risk of relapse in schizophrenia and other psychotic disorders:


1) non-compliance with meds (increases risk x4)
2) substance use (increases risk x3)
3) criticism from caregivers (increases risk x2.3) -- conversely better social support is associated with reduced risk of relapse
4) poorer premorbid adjustment (increased risk x2.2)


Interestingly, the authors conclude that factors such as diagnosis, length of illness, length of untreated symptoms, demographic variables, and cognitive function, are not associated with relapse risk.

Clearly, these findings add to the recommendations for helping patients who have had psychotic symptoms, and their families:
1) medication compliance is extremely important!
2) substance use must be avoided!
3) caregivers must work hard to avoid hostile or critical comments towards the patient


One question I have about these findings, however, is how causative some of these factors are.  It could be argued that an individual who is already more likely to relapse may be more likely to be non-compliant with medication, be more likely to engage in substance use, and may be more likely to behave in a way which elicits more criticism from other people.  The existence of these "risk factors" may indicate that the underlying disorder was more severe.  So, some or all of these risk factors may simply be non-causal associations.

In order to more definitively show that risk factors #1-#3 are causative (and therefore controllable or reversable), we would have to show evidence that externally improving medication compliance in a previously non-compliant person would clearly reduce relapse rate.  And we would need to show that a change in caregiver environment would produce a change in subsequent relapse rate. 

There is some such evidence, but I think it would be good to see a careful meta-analysis looking at risk-factor management in reducing relapse rate. 

Another thought I have about these findings is that the recommendations are appropriate not just for people who have had psychotic symptoms, but for all psychiatric conditions, and even for all members of the whole population!  That is, avoidance of substance abuse and having good social support with minimal hostility and criticism is probably good and protective for everybody's mental and physical health!   But we would have to look further at the research to see if this thought of mine has been proven. 

Lamotrigine review: bipolar depression, unipolar depression, borderline personality, OCD

Lamotrigine is a novel anticonvulsant.  Clearly it is useful for treating epilepsy, in terms of reducing seizure frequency in difficult cases, with a better side-effect profile than many other anti-seizure medications. 

It has been used in psychiatry for over 10 years, mainly to treat bipolar depression.  Initial studies were quite encouraging.  More recent studies have been a bit more mixed. 

Here are a few recent references:

http://www.ncbi.nlm.nih.gov/pubmed/21367355 
this was a large study of using lamotrigine as an augmentation to treat unipolar depression.  It did not show that lamotrigine was useful overall.  But it appeared much more effective in a subgroup of  patients with much more severe depression.  Average doses were about 200 mg/d, maximum 400 mg. 

http://www.ncbi.nlm.nih.gov/pubmed/19636254
this study showed improvements in affective lability with lamotrigine vs. placebo, in patients with borderline personality, using a flexible dose (average about 100 mg/day).

http://www.ncbi.nlm.nih.gov/pubmed/19200421  200 mg/d lamotrigine  helpful for bipolar depression as add-on with lithium x 8 wks

http://www.ncbi.nlm.nih.gov/pubmed/23107222
no difference in depression scores with lamotrigine vs placebo  as add on for bipolar patients 

http://www.ncbi.nlm.nih.gov/pubmed/22351381  adding lamotrigine 100 mg to an SSRI improved symptoms (about 30% reduction in YBOCS score) in OCD patients, compared to placebo, after 16 weeks.

In conclusion, I think lamotrigine is in the "why not give it a try" category for a variety of problems.  It might possibly help for treating depression in bipolar patients, or even as an augmentation in unipolar depression.  It might be useful in OCD patients, and in borderline personality.  It may be one of those agents which helps some individuals very well, even though the average effect for a group of similarly afflicted individuals may be unremarkable.  Another possibility is that it could help with certain symptom domains, such as obsessionality, ruminativeness, etc. which could occur more prominently in some but not all patients with mood or personality disorders. 

I think the big advantage of lamotrigine is that it is quite well-tolerated, with a benign side-effect profile, except for a small risk of a dangerous rash and a few other rare serious problems, which just need to be watched for carefully. 

N-acetylcysteine for OCD

I've written a post about N-acetylcysteine before (http://garthkroeker.blogspot.ca/2009/09/n-acetylcysteine-for-treatment-of.html), which suggested that it could be useful in treating compulsive behaviour disorders such as skin-picking. 

A recent 2012 study by Afshar et al. has shown that NAC is useful for treating obsessive-compulsive disorder (OCD).  Here's the reference: http://www.ncbi.nlm.nih.gov/pubmed/23131885

In this study, 48 patients with OCD who had not responded to an SSRI were given NAC up to 2400 mg/day or placebo, in addition to a continued dose of the same SSRI, for 12 weeks. 

The NAC group had about a 40% reduction in YBOCS score (a quantitative measure of OCD symptoms) after 12 weeks, compared to a 20% reduction in the placebo group.  This is a good, clinically relevant symptom change especially for a treatment-resistant group. 

Mild gastrointestinal complaints were more common in the NAC group, but there was not a big difference in drop-out rates between placebo and NAC. 

NAC works as as a glutamate-modulating agent, with possible anti-inflammatory effects.  It is metabolized to the amino acid cystine after entering the brain. 

So it appears that NAC could be a simple, low-risk, effective adjunct, or even a primary treatment modality, for obsessive-compulsive disorder. 

I would be curious to see more research looking at NAC for other anxiety disorders, or for ruminative depression. 

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:  http://www.ncbi.nlm.nih.gov/pubmed/22198456   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:

http://www.ncbi.nlm.nih.gov/pubmed/21311704
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. 

http://www.ncbi.nlm.nih.gov/pubmed/23212058
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. 

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. (  http://www.ncbi.nlm.nih.gov/pubmed/22864465 )   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:  http://www.ncbi.nlm.nih.gov/pubmed/16814437 ).    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 http://www.ncbi.nlm.nih.gov/pubmed/11356982

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. 

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.

Tests for Asperger's & Autism-Spectrum symptoms

Asperger Syndrome is an example of a mild autism-spectrum disorder.  Individuals with this condition have difficulty with social and communicative skills, particularly those skills requiring an understanding and awareness of others' emotional states, and those requiring emotional expressivity in speech and non-verbal gestures.  Usually individuals with an autistic-spectrum condition have a diminished interest in relationships with other people, and therefore prefer solitary activities. 

The possibility of Asperger Syndrome should be considered, in my opinion, when the history is of social difficulties & social withdrawal.  Often times these problems could be the result of social anxiety, depression, etc. but I think we realize these days that mild autistic symptoms are more common in the population.  This may indeed be due to an increase in the rate of autistic symptoms over time, but it could conceivably be due as well to being more aware of this syndrome, and therefore more able to recognize it.

I have found a site with some good tests for autism-spectrum syndromes, from the Cambridge Autism Research Centre.  Here is a link to the tests: http://www.autismresearchcentre.com/arc_tests

The particuar tests I find most useful are the Autism Spectrum Quotient, which is a symptom checklist.  Average scores on this checklist from a healthy population are about 15 for females and 18 for males, slightly higher for individuals in an analytical scientific profession such as mathematics (typically in the low 20's), but above 30 (typically 35 or higher) for individuals with an autistic spectrum disorder.

I have a few criticisms about some of the autism quotient questions, which I think cause the questionnaire to spuriously inflate the scores of people who are not autistic at all, but rather either socially anxious (e.g. the question "I find social situations easy") , socially more introverted but still very attuned to emotions and other people (e.g. the question "I would rather go to a library than a party"), or having particular intellectual interests (e.g. "I am fascinated by dates" or "I am fascinated by numbers").  Thus, shy people, historians, and mathematicians may have scores on the autism spectrum quotient which suggest that they are more "autistic" than they really are.  Here, I would define an autism-spectrum symptom to be much more specifically addressed by other questions having to do with reduced awareness of other people's emotional states, clear reduced interest in social engagement or communication, and impairment in understanding social norms in verbal and non-verbal interaction.  Yet, I think the questionnaire is sensitive, with a large difference in scores between Asperger patients and control patients without Asperger Syndrome.   

Also on this site there is an interesting set of tests having to do with accurately identifying emotions in pictures, sound clips, or film.  One particularly useful example is the "eyes test," in which you have to identify the emotion represented by a picture of someone's eyes.  Here again the mean in a non-Asperger population is about 26-28 correct, but an average of 22 in Asperger's patients.    If you try this test yourself, I suggest that you review the instructions first, and also make sure you are familiar with all the vocabulary words used in the test (these are all available in the downloads).   The test could be biased against individuals who are just a bit less familiar with the vocabulary words used.

It is on my list of things to write about to discuss the issue of autism-spectrum disorders further, since it is a theme that comes up not infrequently, especially in a university population.  Part of the discussion could include discussion about things that might help (such as social skills training, etc.) but also of understanding the issue, in its mild forms at least, as a character variant with a variety of positive aspects for the individual and for society, rather than as an overt "pathology."  In any case, I think understanding and discussion will help.

"The Lazy Controller" -- reflections about Kahneman's book

This is the first of a series of posts I've been planning based on Daniel Kahneman's book Thinking, Fast and Slow. 

I found this book to be excellent, an account of how the brain is very biased in its mode of forming decisions and judgments, loaded with very abundant solid research over 40-50 years in the social and cognitive psychology literature.

My purpose of reflecting on this book in detail is hopefully to add ideas about understanding the brain's biases in the context of psychiatric symptoms, and then to propose therapeutic exercises which could counter or resolve the biases, and strengthen cognitive faculties which may intrinsically be weak.

----

The first few chapters of this book are introductions to the idea that the brain can be understood as having two main modes of processing and responding to information; the author calls these "system 1" and "system 2."

System 1 is rapid, automatic, reflexive, and often unconscious.  It is the dominant system in most cases.  It is the foundation of "intuition."  It is built upon deeply engrained memory for similar situations.  It is a foundation of all talent and mastery of skills, in that it permits one to perform a difficult task with ease, without even having to "think" about it (e.g. for a master musician, athlete, surgeon, or really any other occupation).  But system 1 is extremely prone to biases.  Its mode of processing data is based on what it has experienced repeatedly in the past -- so it is a kind of autopilot -- and it can be very easily fooled  (yet, on the other hand, its rich set of past associations may be a fertile ground for imagination, creativity, and inspired insight). 

System 2 is a highly conscious, intellectually analytical mode.  It permits us to systematically solve a multi-step difficult problem of any sort.  It permits us to cope with situations which differ from an overlearned template.  It would be like the true pilot landing a plane in difficult or rapidly changing conditions, instead of letting the autopilot trying to land it.

One of Kahneman's main theses is that system 2 can be easily fooled too!  While system 2 is the only cognitive mechanism which could prevent biased interpretation of information, Kahneman shows that system 2 is intrinsically "lazy."  Because engaging system 2 is effortful -- it demands energy -- we are strongly drawn to intellectual processes which minimize the energy expenditure.  If system 1 has an automatic, "intuitive" answer for us, then we would tend not to engage system 2 at all.  And if a rapid engagement of system 2 appears to be sufficient to get an answer, we will usually not spend extra time or energy.  Thus system 2 can easily lead us to a premature and inaccurate conclusion.

Another of Kahneman's main theses has to do with the nature of phenomena, cause-and-effect, and data in general.  Accurate conclusions about cause and effect often require a type of statistical analysis (even a simple one, employing quite straightforward rules of probability), but Kahneman shows that the brain (both system 1 and system 2) are not intrinsically designed to think in a statistical fashion.  Therefore we tend to greatly distort the likelihood of various types of events.

An area I would want to extend beyond Kahneman's main theses is that I suspect both system 1 and system 2 could be very specifically trained to reduce biases.  Kahneman seems somewhat resigned to conclude that the brain simply can't resist the types of biases he describes (citing, for example, profoundly biased thinking in his psychology student subjects--or even in himself-- whose biases were evidently not reduced by understanding and education).  But I do not see that very much work has been done to very specifically and intensively train the mind to reduce biases -- I think that simply learning about bias is not enough, it is something that must be practiced for hundreds of hours, just like any other skill. (this reminds me of something said in psychotherapy:  "insight alone is not enough to effect change -- it must be accompanied by action.")

I believe this is relevant to psychiatry, in that all mental illnesses (such as depression, anxiety disorders, personality disorders, psychosis, and attention/learning disorders) contain symptoms which affect cognition.  In  cognitive therapy theory, it is assumed that depressive cognitions cause and perpetuate the mood disorder.    Many such "cognitive distortions" could be looked at through the lens of "system 1" and "system 2" problems.    For example, in many chronic symptom situations, system 2 may have developed a very deeply ingrained reflexively negative expectation about a great many situations, with many of these reflexes being unconscious.  These reflexes could possibly have been developed based on childhood experience of parents (consistent with a sort of psychoanalytic model), but I think the most prominent source of such reflexes would simply be due to having had a particular symptom frequently for years or decades at a time, regardless of that symptom's original cause.    Under such conditions the brain would change its expectation about the outcome of many events, based on the repeated negative experiences of the past (which could have been due to poor external environmental conditions, but also simply to the past chronicity of symptoms).

A proposed treatment for this phenomenon could very much be along the lines of cognitive therapy.  But I might suggest extending a specific focus on depressive "cognitive distortions" etc. to work on understanding and countering bias in systems 1 and 2 in general.  I propose that intellectual exercises to minimize biased interpretation of perceptions -- even if these exercises have little directly to do with psychiatric symptoms or depressive cognitions, etc. -- could be useful as a therapy for psychiatric disorders.

As outrageous as it seems, educating oneself about statistics, and practicing statistics problems repeatedly -- may be therapeutic for psychiatric illness!  

I'll try to continue this discussion with more specific examples in later posts.

Blueberries are good for your brain

Another study published in 2012 about dietary berry intake associated with slower rates of cognitive decline:
http://www.ncbi.nlm.nih.gov/pubmed/22535616

Here's a reference to a 2010 article by Krikorian et al. published in The Journal of Agriculture and Food Chemistry:
http://www.ncbi.nlm.nih.gov/pubmed/20047325

The article describes a randomized, placebo-controlled study in which 9 elderly adults were given about 500 ml/day of blueberry juice, with another 7 given a placebo fruit juice without blueberries. The study lasted 12 weeks, at which time cognitive and mood tests were administered.

The blueberry group clearly showed better memory performance than the placebo group, and the results had a robust level of statistical significance. The blueberry group also showed some improvement in depression symptoms.

Here's a reference to another review article on this:
http://www.ncbi.nlm.nih.gov/pubmed/18211020

The authors allude to other studies showing improved cognitive performance in animals given blueberry supplementation.

In the meantime, it seems quite sound advice to include more blueberries in your diet. An excellent snack food, a much healthier alternative than junk foods such as chips or candies, etc.

Statistics in Psychiatry & Medicine

This is a continuation of my thoughts about this subject. 

Statistical analysis is extremely important to understand cause & effect!  A very strong factor in this issue has to do with the way the human mind interprets data;  Daniel Kahneman, the Nobel laureate psychologist, is a great expert on this subject, and I strongly recommend a fantastic book of his called Thinking, Fast and Slow.  I'd like to review his book in much more detail later, but as a start I will say that it clearly shows how the mind is loaded with powerful biases, which cause us to make rapid but erroneous impressions about cause & effect, largely because a statistical treatment of information is outside the capacity of the rapid reflexive intuition which dominates our moment-to-moment cognitions.    And, of course, a lack of education about statistics and probability eliminates the possibility that the more rational part of our minds can overrule the reflexive, intuitive side.   Much of Kahneman's work has to do with how the mind intrinsically attempts to make sense of statistical information -- often with incorrect conclusions.  The implication here is that we must cooly calculate probabilities in order to interpret a body of data, and resist the urge to use "intuition," especially in a research study.    

I do believe that a formal statistical treatment of data is much more common now in published research.  But I am now going to argue for something that seems entirely contradictory to what I've just said above!  I'll proceed by way of a fictitious example:

Suppose 1000 people are sampled, (the sample size being carefully chosen using a statistical calculation, to elicit a significant effect size if truly present with a small probability of this effect being due to chance), all of whom with a DSM diagnosis of major depressive disorder, all of whom with HAM-D scores between 25 and 30.  And suppose they are divided into two groups of 500, matched for gender, demographics, severity, chronicity, etc.  Then suppose one group is given a treatment such as psychotherapy or a medication, and the other group is given a placebo treatment.  This could continue for 3 months, then the groups could be switched, so that every person in the study would at some point receive the active treatment and at another point the placebo. 

This is a typical design for treatment studies, and I think it is very strong. If the result of the study is positive, this is very clear evidence that the active treatment is useful. 

But suppose the result of the study is negative.  What could this mean?  Most of us would conclude that the active treatment is therefore not useful.   --But I believe this is an incorrect conclusion!-- 

Suppose, yet again, that this is a study of people complaining of severe headaches, carefully controlled for matching severity and chronicity, etc.  And suppose the treatment offered was neurosurgery or placebo.  I think that the results-- carefully summarized by a statistical statement--would show that neurosurgery does not exceed placebo (in fact, I'll bet the neurosurgery group would do a lot worse!) for treatment of headache. 

Yet -- in this group of 1000 people, it is possible that 1 or 2 of these headache sufferers was having a headache due to a surgically curable brain tumor, or a hematoma.  These 1 or 2 patients would have a high chance of being cured by a surgical procedure, and some other therapy effective for most other headache sufferers (e.g. a tryptan for migraine, or an analgesic, or relaxation exercises, etc.) would have either no effect or would have a spurious benefit (relaxation might make the headache pain from a tumor temporarily better -- and ironically would delay a definitive cure!) 

Likewise, in a psychiatric treatment study, it may be possible that subtypes exist (perhaps based on genotype or some other factor currently not well understood), which respond very well to specific therapies, despite the majority of people in the group sharing similar symptoms not responding well to these same therapies.  For example, some individual depressed patients may have a unique characteristic (either biologically or psychologically) which might make them respond to a treatment that would have no useful effect for the majority.

With the most common statistical analyses done and presented in psychiatric and other medical research studies, there would usually be no way to detect this phenomenon:  negative studies would influence practitioners to abandon the treatment strategy for the whole group.  

How can this be remedied?  I think the simplest method would be trivial:  all research studies should include in the publication every single piece of data gathered!  If there is a cohort of 1000 people, there should be a chart or a graph showing the symptom changes over time of every single individual.  There would be a messy graph with 1000 lines on it (which is a reason this is not done, of course!) but there would be much less risk that an interesting outlier would be missed!  If most of the thousand individuals had no change in symptoms, there would be a huge mass of flat lines across the middle of the chart.  But if a few individuals had a total, remarkable cure of symptoms, these individuals would stand out prominently on such a chart.  Ironically, in order to detect such phenomena, we would have to temporarily leave aside the statistical tools which we had intended to use, and "eyeball" the data.  So intuition could still have a very important role to play in statistics & research! 

After "eyeballing" the complete setof data from every individual, I do agree that this would have to lead to another formal hypothesis, which would subsequently have to be tested using a different study design, designed specifically to pick up such outliers, then a formal statistical calculation procedure would have to be used to evaluate whether the treatment would be effective for this group.  (e.g. the tiny group of headache sufferers specifically with a mass evident on a CT brain scan could enter a neurosurgery treatment study, to clearly show whether the surgery is better than placebo for this group).

I suspect that in many psychiatric conditions, there are subtypes not currently known about or well-characterized by DSM categorization.   Genome studies should be an interesting area in the future decades, to further subcategorize patients sharing identical symptoms, but who might respond very differently to specific treatment strategies. 

In the meantime, though, I think it is important to recognize that a negative study, even if done with very good study design and statistical analysis, does not prove that the treatment in question is ineffective for EVERYONE with a particular symptom cluster.  There might possibly be individuals who would respond well to such a treatment.  We could know this possibility better if the COMPLETE set of data results for each individual patient were published with all research studies.  

Another complaint I have about the statistics & research culture has to do with the term "significant."  I believe that "significance" is a construct that contradicts the whole point of doing a careful statistical analysis, because it requires a pronouncement of some particular probability range being called "significant" and others "insignificant."  Often times, a p value less than 0.05 is considered "significant".  The trouble with this is that the p value speaks for itself, it does not require a human interpretive construct or threshold to call something "significant" or not.  I believe that studies should simply report the p-value, and not call the results "significant" or not.  This way, 2 studies which yield p values of 0.04 and 0.07 could be seen to show much more similar results than if you called the first study "significant" and the second "insignificant."   There may be some instances in which a p-value less than 0.25 could still usefully guide a long-shot trial of therapy -- this p value would be very useful to know exactly, rather than simply reading that this was a "very insignificant" result.  Similarly, other types of treatments might demand that the p value be less than 0.0001 in order to safely guide a decision.   Having a research culture in which p<0.05="significant" dilutes the power and meaning of the analysis, in my opinion, and arbitrarily introduces a type of cultural judgment which is out of place for careful scientists. 

How long does it take for psychotherapy to work?

There are various research articles done in the past which describe rates of change in psychotherapy patients, some studies for example describing a plateau after about 25 sessions or so.  I find these studies very weak, because of the multitude of confounding factors:  severity and chronicity are obvious variables, also the type of follow-up assessments done.

In the CBT literature, a typical trial of therapy is perhaps 16-20 sessions.

In light of our evolving knowledge of neuroplasticity, and our breadth of understanding about education & learning, it seems to me that the most important variable of all is the amount of focused, deliberate practice time spent in a therapeutic activity.  Oddly, most psychotherapy studies--even CBT studies--do not look at how many hours of practice patients have done in-between therapy appointments.  This would be like looking at the progress of music students based on how many lessons they get, without taking into account how much they practice during the week. 

I have often compared psychological symptom change to the changes which occur, for example, with language learning or with learning a musical instrument.

So, I believe that a reasonable estimate of the amount of time required in psychotherapy depends on what one is trying to accomplish:

-Some types of therapeutic problems might be resolved with a few hours of work, or with a single feedback session with a therapist.  This would be akin to a musician with some kind of technical problem who needs just some clear instruction about a few techniques or exercises to practice.  Or it might be akin to a person who is already fluent in a foreign language, but needs a few tips from a local speaker about idioms, or perhaps some help with editing or grammar in a written text.

-Many more therapeutic problems could improve with perhaps 100 hours of work.  This would be like learning to swim or skate competently if you have never done these activities before.  Regular lessons ("therapy") would most likely speed up your rate of progress substantially.   But most of those 100 hours would be practice on your own, unless you're okay with the progress taking place over a year or more.   With the language analogy, think of how fluent you might become in a foreign language with 100 hours of focused, deliberate practice.  For most of us, this would lead to an ability to have a very simple conversational exchange, perhaps to get around in the most basic way in another country.  

-A much larger change is possible with 1000 hours of work:  with music, one could become quite fluent but probably not an expert.  With a foreign language, comfortable fluency would probably be possible, though probably still with an accent and a preference for the old language.
 
-With 5000-10000 hours of work (this is several hours per day over a decade or more) one could become an expert at a skill or a language in most cases.  

In psychotherapy, another confound though is whether the times in-between "practice sessions" lead to a regression of learning.  An educational analogy would be of practicing math exercises an hour per day with a good teacher, but then practicing another 8 hours a day with another teacher whose methods contradict the first.  Often times, learning will still take place with this paradigm, but it might be much less efficient.    Persistent mental habits, in the context of mental illnesses, can be akin to the "second teacher" in this metaphor, and unfortunately they do tend to plague people for many hours per day.

This reminds me of the evolving evidence about stroke rehabilitation & neuroplasticity:  substantial brain change can happen in as short a time as 16 days--but it requires very strict inhibition or constraint of the pathways which obstruct rehabilitation. (note: 16 days of continuous "immersion" = 16*24 = 384 hours!)  In stroke rehabilitation, the neuroplasticity effect is much more pronounced if the unaffected limb is restrained, compelling the brain to optimize improvement in function of the afflicted limb.  Here is a recent reference showing rapid brain changes following limb immobilization: http://www.ncbi.nlm.nih.gov/pubmed/22249495

In conclusion, I believe that it is important to have a clear idea about how much time and deliberate, focused effort are needed to change psychological symptoms or problems through therapeutic activities.  A little bit of meaningful change could happen with just a few hours of work.  In most cases, 100 hours is needed simply to get started with a new skill.  1000 hours is needed to become fluent.  And 5000-10000 hours is needed to master something.  These times would be much longer still if the periods between practice sessions are regressive.  In the case of addictions, eating disorders, self-harm,  or OCD, for example, relapses or even fantasies about relapse will substantially prolong the time it takes for any therapeutic effort to help.  Of course, it is the nature of these problems to have relapses, or fantasies about relapse--so one should let go of the temptation to feel guilty if there are relapses.   But if one is struggling with an addictive problem of this sort, it may help to remind oneself that the brain can change very substantially if one can hold onto to quite a strict behavioural pattern for the hundreds or thousands of hours which are needed.

As a visual reminder of this process, start with an empty transparent bottle, which can hold 250-500 mLof liquid (1-2 cups), and which can be tightly sealed with a small cap.  Add one drop of water every time you invest one hour of focused, deliberate therapeutic work.   The amount of time you need to spend in therapy depends on your goal.  If the goal is total mastery--then you must fill the entire bottle.  If simple competence in a new skill is an adequate goal, then you must fill just the cap of the bottle.  If there are activities in your day which contradict the therapeutic work, it would be like a little bit of water leaking out of your bottle.  So you must also attend to repairing any "leaks."  But every hour of your effort counts towards your growth.

Scopolamine for Depression

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.

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.

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.

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!

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.

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: 



http://www.ncbi.nlm.nih.gov/pubmed/20010551
this 12 week randomized study shows modest benefits from divalproex to treat irritability in autistic children (ages 5-17)

http://www.ncbi.nlm.nih.gov/pubmed/18273430  gabapentin useful for borderline patients over a 6 month period

http://www.ncbi.nlm.nih.gov/pubmed/19283647 (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:
http://www.ncbi.nlm.nih.gov/pubmed/19512980

Here's a study looking at treating children with conduct or oppositional problems with stimulants and/or clonidine: http://www.ncbi.nlm.nih.gov/pubmed/10660814

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.

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.

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.