Zinc supplements in mental health

Zinc is a trace mineral which is necessary for a variety of metabolic functions in the body.  The neuropharmacology of zinc certainly includes NMDA-blockade effects, as well as a probable collection of other effects such as increasing BDNF expression. 


There is evidence that zinc supplements could be helpful to treat depression.  Here is a brief review of some pertinent studies:

http://www.ncbi.nlm.nih.gov/pubmed/14730113
In this very simple Polish study published in 2003, 14 patients with unipolar depression were randomized to receive either antidepressant + placebo, or antidepressant  + 25 mg zinc, for 12 weeks.  Both groups improved, but the zinc group had about 40% greater symptom reduction than the placebo group.  I appreciate the fact that in this paper, the complete set of data was shown, for each individual patient in the study.  This allows one to do a custom analysis of the data:  in this case, for example, there were several patients who appeared to be treatment-resistant in the placebo group,  and it was interesting to look at the results with these patients excluded, since they would otherwise skew the results in favor of the zinc group.  But even with this adjustment, the zinc group still had a significant, clinically relevant improvement compared to placebo. 



http://www.ncbi.nlm.nih.gov/pubmed/19278731
This study done in 2009 looked at imipramine+ 25 mg/d zinc vs imipramine+placebo, for 12 weeks, in 60 unipolar depressed patients.  Here they found that for treatment resistant patients, the zinc group improved significantly more than the placebo group.  In effect, the zinc caused the treatment resistant group to respond as though it was no longer treatment resistant!   Yet, in this study, the zinc did not further improve symptoms in patients who were not treatment resistant. 

http://www.ncbi.nlm.nih.gov/pubmed/24130605
Another simple 12-week study, done in Iran, of 25 mg/d added zinc or placebo, in 44 patients with major depression.  It was quite recent, from 2013.   The zinc group once again improved substantially more than the placebo group.   The study stands out in looking carefully at dietary intakes of various nutrients in all of the patients, to control for various dietary confounds. 

http://www.ncbi.nlm.nih.gov/pubmed/23602205
another replication, from 2013


http://www.ncbi.nlm.nih.gov/pubmed/23806573
A 2013 meta-analysis, which concluded that zinc supplements have a clinically relevant effect in depression.  

http://www.ncbi.nlm.nih.gov/pubmed/21798601
Another meta-analysis, from 2012.  Again it affirms the possible usefulness of zinc, not only for treatment of depression, but for prevention as well.


http://www.ncbi.nlm.nih.gov/pubmed/23169472 
This meta-analysis looked at zinc in treating ADHD, and the conclusions were largely negative.  There have been a few studies suggesting benefit, but these results seem not to be consistent enough to make a recommendation.  It is tempting to consider a trial of zinc augmentation as a deliberate trial for a an individual though, given the negligible risk.

Here is a link to my previous posting about zinc, which outlines some other uses in psychiatry, such as in eating disorders.  Also my other posting reviews some information about toxicity risks.
http://garthkroeker.blogspot.ca/2009/07/zinc-eating-disorders.html

 http://www.ncbi.nlm.nih.gov/pubmed/23383172
This interesting study showed that high dose zinc supplements (corresponding to about 60 mg/d in humans) given to rats actually led to a reduction in zinc levels in the hippocampus, and an impairment in memory performance.  The mechanism may be that higher serum zinc levels reduces synaptic release of zinc, through a negative feedback mechanism.  The article can be taken as a warning that more is not necessarily better!  The low-dose zinc supplemented group in this study did better, corresponding to a human dose of about 15 mg/d.


In conclusion, I think zinc supplementation is a reasonable, safe, evidence-based augmentation strategy for treating or preventing depression.  Most of the studies used 25 mg elemental zinc; I think this is a reasonable dose for an initial 12-week trial.  After this point, if continued zinc supplementation is to be used, I would suggest bringing the dose down to the 15-20 mg per day range, to rule out toxicity risks.  

antidepressants in rapid cycling

http://bjp.rcpsych.org/content/202/4/251.abstract

In this short editorial by Michael Thase, the argument is made that  a diagnosis of bipolar II disorder is not necessarily a contraindication to antidepressant use for treating a depressive episode.

With these diagnostic categories, it is important to realize that there are relative risks of different management strategies, such as of antidepressants worsening rapid cycling.  But not all individuals necessarily will experience such an adverse effect.  We do not as yet have clear evidence ahead of time which can allow us to predict which patients with a particular diagnosis will experience benefit or adverse effect from a particular treatment. 

Part of the reason for this is that single diagnostic categories such as "bipolar II" or "rapid cycling" may represent a wide variety of ailments, which current diagnostic schemes cannot resolve, and may also represent numerous subsets of individuals, who may benefit or have adverse effects from different treatment strategies.

The best we can do, I think, is to use a type of Bayesian reasoning, in which current broad evidence should be our starting point to estimate risk or benefit.  In the case of rapid cycling, I think we must assume that there is a significant risk of adverse effects in rapid cycling bipolar patients.

But in an effort to treat a debilitating depressive state, there may be instances in which a riskier treatment could be warranted, as there is evidence that particular individuals can benefit.

Prazosin for PTSD update

In this article by Raskind et al. in the American Journal of Psychiatry (Sep. 2013), combat veterans with PTSD were given prazosin or placebo in a 15 week randomized study:

http://ajp.psychiatryonline.org/article.aspx?articleid=1712525

The prazosin was substantially beneficial for PTSD symptoms.  Dosing was on average about 5 mg in the mid-morning + 15 mg at bedtime.

There was a large, clinically relevant,  sustained difference from placebo, and the prazosin was well-tolerated.

The experience from this study differs from my own experience prescribing this drug, in that the doses were much higher.  Also, they used daytime doses, which I think shows acknowledgment that prazosin is not just useful for nightmares, but for all symptoms of PTSD, day and night.    I had previously prescribed in the 1-2 mg range, but I see there is a lot of room to move to higher doses, which could be much more effective without major safety or side-effect risks.

Journal Review 2013: 1. American Journal of Psychiatry

I'd like to summarize articles I found interesting during this past year's survey of journals--I'll start with The American Journal of Psychiatry.

1.  January 2013:  "Adding moderate-dose lithium does not help patients with bipolar disorder".  This is an editorial comment by Dunlop et al. about the "Litmus" study published by Nierenberg et al.   Basically, this randomized study showed that adding small doses of lithium to the other treatments (including medication) that bipolar patients are receiving, does not lead to any symptomatic benefit over 6 months of follow-up.

I would conclude from this study that either 1) larger doses of lithium are necessary to be consistently useful  or 2) subgroups may exist among the bipolar population which respond much better to such treatments, but such effects would not be noticed in a large cohort of patients sharing only the bipolar label as it is currently defined.

**an interesting alternate opinion is given in this article: http://www.ncbi.nlm.nih.gov/pubmed/21525518  Here, the authors show that trace lithium levels in drinking water (!) are inversely associated with suicide rates.   The amounts of lithium in drinking water could provide the equivalent of about 1-10 mg of oral intake (much less than the hundreds of milligrams per day which are typical in bipolar management).   Of note, small amounts of lithium could be absorbed not only orally but transdermally (e.g. from showering).  As I look at the authors' data graphs, I have to wonder how strong this result really is. Possibly a small number of outlier points have substantially boosted the apparent effect size.    Furthermore, despite the authors' attempts to control for obvious confounding factors (such as SES variation etc.) I have to wonder if this could be a non-causal association.  We would have to see more data about supplementing with tiny doses of lithium to be more sure of a protective effect.  At the very least, we need to see studies of this type replicated elsewhere.  The authors mention a study showing a similar result in Japan (http://www.ncbi.nlm.nih.gov/pubmed/19407280), but in this case there was no attempt to control for confounding factors.   A study of this type in England showed no association: http://www.ncbi.nlm.nih.gov/pubmed/21525523.  Other studies referred to were done in the early 70's or earlier, and are of questionable quality. 

Another positive line of evidence is typified by an article like this: http://www.ncbi.nlm.nih.gov/pubmed/22500970.  Here, the case is presented that lithium has neuroprotective effects and may even have a role in reducing the risk of dementia.   The evidence is based mostly on in vitro studies, but there are some randomized human studies coming out, such as  http://www.ncbi.nlm.nih.gov/pubmed/21525519, in which one year of lithium titrated to a low serum level of 0.25 - 0.5 mMol, led to improvements in cognition and biomarkers in Alzheimer Disease patients.  A small annoyance I have about this publication, as with many others, is that the precise information is not mentioned about exact doses of lithium each subject received, nor  about the exact serum levels of each subject (0.25 - 0.5 is within a low range, but the top end of this range is 100% higher than the low end!). 

A fair conclusion from existing evidence could be to consider a trial of low-dose lithium augmentation for patients with bipolar disorder, unipolar depression, or suicidal ideation from other causes.  The evidence would tell us that the most likely result of such a trial would be no symptomatic benefit.  But the possibility exists, with some reasonable support, that some patients may improve, perhaps because they are part of a subgroup who are more responsive to lithium effects.

This reminds me of another very interesting, albeit very controversial idea to research, which would be to look at population effects of various treatments.  I think something like this would be most appropriate and ethical if it was a vitamin or nutritional supplement, or obvious positive community resource such as a recreational facility available to all,  etc.  But the idea would be to give every individual in the population the same treatment, and to see if this could lead to reduced incidences of various symptoms over long periods of time.  Immunizations against infectious disease work on a similar principle:  there is some protection for each individual receiving an immunization, but there can be a massive reduction in disease prevalence if every person in the population is immunized.  Of course, psychological symptoms are obviously not the same as infectious diseases, but there is evidence that social factors strongly contribute to mental health events.

A benign study of this sort could, for example, be conducted in a prison environment, in which all inmates might receive access and formal time assigned to attend a new fitness facility.  Or all inmates could receive a vitamin supplement, etc. with their consent.

Similar studies could be possible on a university campus:  I think the most apt study could be to design better fitness facilities with much more convenient access, less crowding, and very low fees, as a giant public health experiment to reduce rates of depression and increase general health.   

Vitamin D update

Here`s a simple study, though one of the first of its type, showing a beneficial result from adding vitamin D supplementation to an antidepressant:
http://www.ncbi.nlm.nih.gov/pubmed/23093054

42 depressed subjects received fluoxetine 20 mg daily plus either 1500 IU of vitamin D or placebo, for 8 weeks.  

The vitamin D group had significantly better mood improvement!  

I think I would want to see this study replicated, but in the meantime I think it is reasonable to suggest vitamin D supplementation for most cases of depression, particularly in a region where there is a long, dark winter season.

Of note, in this study, the authors found that vitamin D levels were inversely correlated with depression severity ratings before the treatment trial began.  So it may be true that correcting vitamin D deficiency is the therapeutic mechanism, as opposed to supplementing vitamin D beyond the usual healthy range.  

The doses I suggest are 3000 IU per day.

Addendum:

On a contrary note, there was a large, important meta-analysis published in Lancet Diabetes & Endocrinology by Autier et al. on December 6, 2013, which closely reviewed existing evidence about Vitamin D status and supplementation.  

The authors conclude that low vitamin D status is a result of illness, not a cause of illness, in most clinical situations.    And they conclude that vitamin D supplementation had no effect on disease occurrence, except for a small effect in elderly women.

The full text is not yet available to me, so I am not sure what the authors looked at with respect to mood disorders and vitamin D.

But the findings are another example of the need to contain our excitement when we see strong correlations between variables.  In this case, low vitamin D has been correlated with higher incidences of various diseases, leading to the speculation that supplementation could be an effective treatment for the disease.  But this paper shows that much of this correlation is due to non-causal association.

The area of vitamin D supplementation remains important to research further, because this type of supplementation is quite safe, the prevalence of mild deficiency in the population is significant, and there are particular conditions which may indeed improve with higher-dose supplementation.

Furthermore, there have not been enough very simple augmentation studies, such as the first study mentioned above, which could show whether a simple supplement such as vitamin D could play a role in treating depression.

So, for now, I stand by the recommendation to try Vitamin D supplementation as a part of mood disorder treatment, unless there is some contraindication to this (such as hypercalcemia), but with the acknowledgment that the evidence for this is much weaker than I would like.

Ketamine update December 2013

http://www.ncbi.nlm.nih.gov/pubmed/24268616

This is one of the most recent studies on using ketamine in non-psychotic treatment-resistant depression.  The authors were Shiroma et al. from Minneapolis, published Oct 29, 2013. 

The study is unique in that the patients maintained their previous antidepressant regimen, with 0.5 mg/kg IV ketamine infusions added on to this regimen, three times per week, for 4 weeks.

11 of 14 patients had a treatment response, and 8 out of 14 had a remission of depressive symptoms. 

As one looks at the graphs showing symptom changes over time, it is very apparent that virtually all negative symptoms of depression diminished gradually, with progressive improvements over 3-4 successive infusions.  Measures of positive experience (calmness, happiness, and self-esteem) improved in tandem over the same time interval.

As with previous ketamine studies, patients had mild dissociative side effects during the infusion itself, which did not persist beyond a few hours, and which were not subjectively problematic.  Hemodynamic changes were minor.  One patient had nausea and vomiting.

It is pointed out in the discussion that an active placebo group would be a good idea in a study like this.  Giving a saline placebo infusion would be much less informative, because it would be obvious to the patients that they were not receiving ketamine.  So the authors discuss the possibility of giving a benzodiazepine active placebo (such as midazolam), etc.

 In fact, Murrough et al. have recently conducted a 2-site randomized controlled study of ketamine infusions for treatment-resistant depression patients, using an active placebo group who received IV midazolam ( http://www.ncbi.nlm.nih.gov/pubmed/23982301 )  This study used only one single IV infusion.  47 patients were randomized to receive ketamine, 25 received midazolam.   About 60% of the ketamine group had a good symptom response, compared to 30% in the midazolam group, with effects lasting about a week. 

So there is continuing evidence of ketamine being a useful antidepressant strategy for treatment-resistant patients.   I would like to see more studies using a more convenient dosing regime (e.g. oral or IM dosing) as most psychiatry offices would have a hard time safely administering a 40-minute IV infusion. 

I think there is good research data to support short-term trials-- the next big research focus should now be looking at the effectiveness and safety of using intermittent ketamine doses for long periods of time (e.g. every 1-4 weeks, over a period of years, just as we would use maintenance ECT).   Most clinicians who are nervous about ketamine as a mainstream treatment would be understandably concerned about long-term health risks.    Of course, in my opinion, the long term health risks of continuing treatment-resistant depression symptoms are very severe!  -- so even if there was established risk, I think it should be understood and be the patient's choice, just as is the case for so many other potentially dangerous medical treatments (such as immunosuppressants for autoimmune disease, anticonvulsants for epilepsy, antihypertensives for high blood pressure, etc.)


Ketamine vesicopathy:
One of the clear long-term risks of ketamine is lower urinary tract damage, including cystitis, with symptoms of urinary urgency, frequency, and dysuria (pain).  Here is the best reference I could find that relates the cumulative ketamine dose to a risk of having bladder symptoms:
http://www.ncbi.nlm.nih.gov/pubmed/21684556
The authors conclude that risk to the bladder was associated with having 3-5 doses per week of ketamine.  Typical doses in this population are at least 12 grams per week, which is at least 300 times more than a weekly dosing regimen used in psychiatry.   So the risk with the psychiatric dosing regimen appears to be low, but it is essential to watch very carefully for any evolving urinary tract symptoms.

Ketamine-induced memory dysfunction:
this is a good study warning of long-term cognitive dysfunction due to ketamine use: http://www.ncbi.nlm.nih.gov/pubmed/15500598

Once again, the group they looked at were involved in high-dose frequent recreational drug use, in conjunction with frequent use of alcohol, marijuana, and cocaine.  The doses of ketamine involved would probably have also been extremely high and frequent, although oddly the study does not actually even estimate the typical amounts used.   The ketamine group showed impairments in various memory functions, with partial improvement over several years of reduced use.

Other authors have shown clear neuropathological changes following 6 months of doses of 1 mg/kg per day. e.g. H. Yu, Q. Li, et al. Chronic ketamine abuse causes dysfunctions of different brain areas relevant to neurodevelopmental psychiatric disorders : Evidence from fMRI in a primate model.  This was a poster display (June 7, 2010).  This dosing is 14 times higher than the weekly maintenance regimen I would consider reasonable in psychiatry (0.5 mg/kg once per week).

The conclusion here, once again, would be that cognitive impairment is a possibility, but it is probably an issue with very high frequent doses far beyond what would be used in a psychiatric dosing schedule.  If ketamine is to be used in a medical setting, it is necessary to regularly assess cognitive functioning.

I am hesitant to consider dosing ketamine more than once per week, given these concerns, unless it was only for an initial 1-2 week course. 

Of note, depression itself causes severe cognitive dysfunction in many cases.  And other treatments for depression, including sedating antidepressants, antipsychotics, and ECT, have given rise to various cognitive side-effect complaints from patients.  I think these are risks to be aware of, to monitor, but then for patient & physician to together  make a careful clinical decision regarding risk vs. benefit.

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.