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.
Friday, December 20, 2013
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.
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.
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.
Monday, June 24, 2013
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.
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.
Monday, June 3, 2013
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.
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.
Subscribe to:
Posts (Atom)