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.  http://www.ncbi.nlm.nih.gov/pubmed/336002

http://www.ncbi.nlm.nih.gov/pubmed/15146330 
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.


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3415362/
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): http://www.ncbi.nlm.nih.gov/pubmed/307696, 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:

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.  


Thursday, January 2, 2014

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.

Friday, December 20, 2013

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.