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.
Wednesday, January 15, 2014
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.
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.
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.
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.
Thursday, December 5, 2013
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.
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.
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