Thursday, April 3, 2014

Deep Pressure Stimulation for anxiety, ADHD, insomnia, or autism

Someone was telling me last week about a snug sweater that is available for your pet dog or cat, which is intended to soothe anxiety or phobic behaviour!  Here is an informational site for a business selling this:
The whole idea made me smile!   Maybe it’s gimmicky, but what if there’s something to this?

I think the idea is very simple, that pleasant, hug-like tactile stimuli can be emotionally comforting.  As with other sensory stimulus treatments for mental health symptoms, why not try tactile things?  We have, for example, bright light therapy, calming audio recordings, and aromatherapy, each of which have a reasonable evidence base.  Of course, there is massage therapy, but usually this would consist of  brief, fairly expensive sessions which would rarely be practical to arrange daily or continuously.  
Here are the results of my survey of this issue:
For children with autism or attention problems, there are weighted compression vests available on the market, which are supposed to help cognition, comfort, and behaviour.  These are simply vests which weigh about 10% of body weight:   This 2014 study in an occupational therapy journal showed significant improvement in ADHD symptoms in 110 children, average age 9 years.  The study had a randomized, crossover design, with subjects putting on the vest and immediately doing a CPT test.  The subjects were scored according to the CPT test result, and according to observations of behaviour during the trial.   Symptom improvement attributable to the vest was quite significant: about 20% improvement in being on-task, 50% reduction in fidgeting, and 20% reduction in CPT omission errors.  In this study, the 4 weighted vest subjects had 18-25 % improvement in on-task behaviour, also 3 of the 4 children asked to wear it more!  In this review article, they found insufficient evidence to recommend weighted vests. But most of the studies reviewed were looking at very young children (under 5) with autism.  It is of greater interest to me to look at the use of this strategy for older children and adults with anxiety or attention problems. 

This study showed that swaddling babies reduces the pain response to a blood test needle, compared to control.  
Temple Grandin is a famous autistic woman, with a BA in psychology and a PhD in animal science, who has been very open about her personal history; she has become an authority in the area of providing safe, ethical care and comfort to agricultural animals.    These are links to Grandin’s 1992 paper in Journal of Child and Adolescent Psychopharmacology in which she describes her own very beneficial experience of a device she built (“the squeeze machine”) which she used daily for many years.
She found this machine to be comforting, and to even improve her subsequent ability to tolerate other types of sensory and interpersonal stimuli as an adult.

Here is a very recent article with Grandin as co-author:  This is a case study of a woman with bipolar disorder who reported some benefit from deep pressure techniques.  Other adjuncts in this case were use of a squeeze ball, chewing gum, lightly tinted glasses, and a soft brush to rub against the skin. I'm a bit surprised this got published, though, since it seems they didn't really use any one technique systematically. 

Weighted blankets are another idea along these lines.  Here is a website selling items like this:   I see the weights are up to 20 pounds for a larger blanket, again with a recommendation of about 10% body weight.    It seems like a home-made version of this wouldn’t be too hard to make, or at least to experiment with.  The material used for the extra weight is often simply small, smooth stones.  
Sleeping in a mummy bag (a type of sleeping bag used for camping) is another similar idea.   

So, in summary, deep pressure stimuli of this sort could be worth a try to treat ADHD, anxiety, insomnia, or tactile hypersensitivity, with very little risk.  I suspect one could get an idea of results and tolerability quite quickly.  A key idea, that Grandin emphasizes, is that the stimulus should always be fully under your control, so it would be useful I think to be able to adjust the weight, and to remove it very easily. 

Tuesday, March 11, 2014

The obsolescence of paper journals and conferences

I was reading an editorial article the other day, entitled "A word to the wise about ketamine" by Alan Schatzberg (American Journal of Psychiatry, March 1, 2014).  

The article is a brief opinion piece cautioning psychiatrists about the use of ketamine as an antidepressant.  It includes such statements as this:
Without more data on what ketamine can do clinically, except to produce brief euphoriant effects after acute administration, and knowing it can be a drug of abuse, it is difficult to argue that patients should receive an acute trial of ketamine for refractory depression.
Of course, this is an important opinion, a valid point of debate!  If something like ketamine is indeed simply giving people a momentary high, then leading them into a dark pathway of addiction, then we need to acknowledge this risk and sound the warning!

The problem I have with this editorial is the nature of the debate that can take place in response to it.
Each statement in the editorial can be challenged in quite an engaging debate, for example:

 -benzodiazepines, antihistamines, opiates, and even antipsychotics such as Seroquel, are drugs of abuse as well, yet they have well-established medical benefits in many instances, independent of their "brief euphoriant effects."

-severe refractory depression which has not improved with multiple conventional treatments is a devastating condition; it does not seem "difficult to argue" at all, in favour of a simple agent administered weekly, in an office setting, with a drug level of zero shortly after the patient leaves the clinic, and which can produce profound relief and improved function lasting for a week at a time in a significant number of people.

-medications with potentially dangerous long-term side-effects, including lithium and antipsychotics, are routinely prescribed for refractory depression, often one after the other, even when previous similar trials have not helped at all!  An argument could be made that it should be time to stop this repetitive medication loading, after a dozen or more previous similar trials have done nothing except cause side effects!   It is interesting to consider the adverse consequences, psychologically and medically, of repeated ineffective psychotropic medication trials. 

Now, with this response I do not claim that ketamine is some kind of miracle drug.  I think it is promising, and deserves careful consideration.  It is entirely possible (probable, even) that there are risks associated with it that are not well-enough appreciated.  But in a refractory depressed population, the risks of continued symptoms are devastating!

I also do not mean to put down the value of other conventional medical therapies.  Lithium or antipsychotics or multiple conventional antidepressants may indeed be important, valuable, life-saving treatments, and I think we must keep an open mind about trying them, especially if they have not yet been tried in particular patients.  

Back to my main point, though, which is a process-related point:

-editorial writers in a major journal carry a lot of persuasive weight, which is certainly enhanced further by the editor's long list of publications and awards.   But when it comes to making decisions, it is ineffective to simply hear one person's opinion, even if that person is the leading expert in the world!  --especially, I might add, when this opinion comes from a position of obvious bias (for example, towards theoretical conservatism, lack of personal experience with the specific subject matter,  or "expert" status which is based on expertise in other subject areas than the issue at hand).   Every opinion should be heard, of course!  But in order for a productive understanding of an issue to take place, there needs to be debate!

In a journal such as The American Journal of Psychiatry one could certainly engage in a debate, for example by writing a letter in response to an article.  But, first of all, there is a huge time lag involved!  It could be a month or more before any response would be seen.  Even if the response was published, it would be located in the letter section, rather than in the prominent editorial section.  And imagine having a debate with someone professionally, but in a framework in which you could only exchange comments once per month!  I think the quality of the debate would suffer!  And I suspect many observers of such a debate would lose interest! 

We live in an era where it is possible to engage in an instantaneous debate online.  We can do this on most news websites.   Of course, on news sites, etc. a lot of the public commentary features quite extreme opinions, trolling, etc.  But in a professional on-line publication it would be quite easy to limit comments or discussion only to members of the psychiatric community.

It seems a puzzling and unnecessary relic at this point to observe an editorial of this sort, an opinion piece which has a great deal of room for discussion, but where no discussion can take place in a timely manner.  

There are several other reasons why paper journals in the sciences are obsolete:  first, they are a waste of paper!  Second, many advanced techniques of data presentation (for example, see Hans Rosling's work with health statistics) require a computer to be visualized.  A static 2-dimensional graph or photograph on paper conveys only a tiny fraction of the information which could be easily displayed online.  Similarly, I believe the entire data set should always be provided for any published study, so that the reader can conduct an independent analysis of the data.  This further reduces the possibility of bias in presentation, and conversely increases the possibility that another person could see something in the raw data that was missed by the authors!  Third, if one reads scientific papers online, one can instantly look at hyperlinked references to get a much richer and deeper understanding of the paper (including the paper's strengths and weaknesses). 

For many of the same reasons, I think lectures at professional conferences and meetings are obsolete as well, as least in their role as educational loci!  A professional conference may be a good place for social connections, networking, and tourism, or perhaps to attend a workshop to acquire a new hands-on skill, but it is wildly inefficient as a primary source of didactic education!  This is true for many of the same reasons described above for journals:  lectures are much more likely to be condensed opinion pieces on the part of the lecturer, usually without a lot of room for rich intellectual debate.   And another problem with conferences, in terms of persuasion and bias, is that they are designed to be luxurious!  If the experience of learning a possibly controversial or an outdated dogmatic idea takes place during a time which is simultaneously considered a vacation, in fancy hotels, with gourmet meals, in an exotic location, there is a much higher risk of biased persuasion taking place.   Didactic education does not require physical travel, it requires intellectual travel!

Friday, January 24, 2014

Tryptophan Depletion studies

The best review of tryptophan-depletion studies is by Moore et al. (2000).

 I think it is an accepted part of clinical psychiatric theory that serotonin obviously is related to mood, and the more serotonin there is, the better mood must be, and the less serotonin there is, the worse mood must be!  

With tryptophan-depletion, subjects are given a drink which results in a radical reduction in serotonin synthesis within hours.  It is strongly believed, though not rigorously proven, due to technical limitations, that such depletion results in a reduction of serotonin release by serotonergic neurons in the brain. 

The main consistent finding of these studies is that depressed patients who are treated with a serotonergic antidepressant, such as an SSRI, but who have not yet recovered fully from their depressive episode, are very sensitive to a sudden worsening in their depressive symptoms immediately after tryptophan-depletion. 

But, fully remitted patients tend not to have any depressive relapse following tryptophan depletion!

And depressed patients who have not yet received any antidepressant tend not to have worsening depressive symptoms following tryptophan depletion! 

And depressed patients treated with non-serotonergic antidepressants (such as desipramine) do not have worsened depressive symptoms following tryptophan depletion! 

There is little evidence that tryptophan depletion consistently affects panic or OCD symptoms. 

One study quoted in this review, by Delgado (1991), showed that in a group of untreated depressed patients given tryptophan-depletion, 37% actually improved following depletion, compared to 23% who got worse (by 10 points on the HDRS). 

It is obvious that momentary tryptophan depletion, and the resulting drop in serotonin synthesis, does not have consistent effects on psychiatric symptoms.  The effect is only reliable in partially treated patients taking SSRI's.  It may be that in these patients, it is a sudden induction of a withdrawal-like state which causes the sudden symptom change.  Or, it could be that in these patients in an early state of recovery, there is a temporary dependence on serotonin levels, which are working to "push"the patients towards recovery.  The tryptophan depletion suddenly removes the source of this "push", causing sudden relapse.  But serotonin clearly must not be the only possible way to "push"towards recovery, because depleting serotonin only has a negative effect on patients beginning SSRI treatment. 

Thursday, January 23, 2014

5-hydroxytryptophan (5-HTP)

The amino acid tryptophan is widely present in dietary proteins; it is metabolized, in a rate-limiting enzymatic step,  to 5-hydroxytryptophan in the brain, before being converted quickly into serotonin. 

5-hydroxytryptophan(5-htp) has been used as an antidepressant for many years, but little research apparently has been carried out recently, because it is not on a patent.

Cochrane reviews in 2001 and 2002 conclude that 5-htp probably is better than placebo for treating depression, but that the existing studies were of poor quality.

Here's a small randomized study comparing 5-htp with imipramine, with both groups showing similar improvements in depression symptoms. 
This 2004 study from the European Journal of Pediatrics shows that 5-htp given to children at a dose of 2 mg/kg at bedtime, led to a substantial reduction in night terrors over a 6-month period.  84% of the treatment group responded, compared to 29% of the placebo group.  The results were quite dramatic, with the average night terrors going down from 7 per month to 0.4 per month in the treated group, compared to a change from 7 to 3.4 in the placebo group.  There were no side effect problems.
This is an interesting opinion piece published in 2012.  However, there seem to be a lot of claims that are based on the authors' opinions, with references which look quite shaky and dated.  The main claim that I question is that 5-HTP causes a competitive inhibition of dopamine metabolism, thus leading in a longer-term basis to a hypodopaminergic state.  But another look at the basic science of this issue, such as described in this reference by Awazi (1978):, shows that serotonin itself relatively antagonizes dopamine function, but that exogenous 5-htp can actually cause a slight increase in dopaminergic activity, by displacing dopamine from storage sites and triggering a compensatory increase in dopamine synthesis. 

The bottom line about this dopamine issue should be to watch clinically for any signs of hypodopaminergic side effects (e.g. Parkinsonism) in any person using 5-htp supplements.  I actually don't see case reports along these lines. 

Wednesday, January 15, 2014

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:
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.
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.
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.
another replication, from 2013
A 2013 meta-analysis, which concluded that zinc supplements have a clinically relevant effect in depression.
Another meta-analysis, from 2012.  Again it affirms the possible usefulness of zinc, not only for treatment of depression, but for prevention as well. 
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.
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.