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:  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 (, but in this case there was no attempt to control for confounding factors.   A study of this type in England showed no association:  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:  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, 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:

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.


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

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 ( )  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:
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:

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.