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.
Showing posts with label Bipolar. Show all posts
Showing posts with label Bipolar. Show all posts
Monday, June 24, 2013
Thursday, October 8, 2009
Is Seroquel XR better than generic quetiapine?
A supplement written by Christoph Correll for The Canadian Journal of Diagnosis (September 2009) was delivered--free--into my office mailbox the other day.
It starts off describing the receptor-binding profiles of different atypical antipsychotic drugs. A table is presented early on.
First of all, the table as presented is almost meaningless: it merely shows the concentrations of the different drugs required to block 50% of the given receptors. These so-called "Ki" concentrations have little meaning, particularly for comparing between one drug and another, UNLESS one has a clear idea of what concentrations the given drugs actually reach when administered at typical doses.
So, of course, quetiapine has much higher Ki concentrations for most receptors, compared to risperidone -- this is related to the fact that quetiapine doses are in the hundreds of milligrams, whereas risperidone doses are less than ten milligrams (these dose differences are not reflective of anything clinically relevant, and only pertain to the size of the tablet needed).
A much more meaningful chart would show one of the following:
1) the receptor blockades for each drug when the drug is administered at typical doses
2) the relative receptor blockade compared to a common receptor (so, for example, the ratio between receptor blockades of H1 or M1 or 5-HT2 compared to D2, for each drug).
The article goes on to explore a variety of other interesting differences between antipsychotics. Many of the statements made were theoretical propositions, not necessarily well-proven empirically. But in general I found this discussion valuable.
Despite apparent efforts for the author to be fair and balanced regarding the different antipsychotics, I note a few things:
1) there are two charts in this article showing symptom improvements in bipolar disorder among patients taking quetiapine extended-release (Seroquel XR).
2) one large figure appears to show that quetiapine has superior efficacy in treating schizophrenia, compared to olanzapine and risperidone (the only "p<.05 asterisk" was for quetiapine!) -- this figure was based on a single 2005 meta-analysis, published in a minor journal, before the CATIE results were published. No other figures were shown based on more recent results, nor was clozapine included in any figure.
I think quetiapine is a good drug. BUT -- I don't see any evidence that quetiapine extended release is actually any better, in any regard, than regular quetiapine. In fact, I have seen several patients for whom regular quetiapine suited them better than extended-release, and for whom a smaller total daily dose was needed.
Here is a reference to one study, done by Astra-Zeneca, comparing Seroquel with Seroquel XR, in healthy subjects: http://www.ncbi.nlm.nih.gov/pubmed/19393840 It shows that subjects given regular quetiapine were much more sedated 1 hour after dosing, compared to those given the same dose of Seroquel XR. It implies that the extended release drug was superior in terms of side-effects. Here is my critique of this study: first of all, sedation is often a goal in giving quetiapine, particularly in the treatment of psychosis or mania. Secondly, problematic sedation is usually the type that persists 12 hours or more after the dose, as opposed to one hour after the dose. In this study, the two different formulations did not differ in a statistically significant way with respect to sedation 7, 8 or 14 hours after dosing. In fact, if you look closely at the tables presented within the article, you can see that the Seroquel XR group actually had slightly higher sedation scores 14 hours after dosing. Thirdly, dosing of any drug can be titrated to optimal effect. Regular quetiapine need not be given at exactly the same dose as quetiapine XR--to give both drugs at the same dose, rather than at the optimally effective dose for each, is likely to bias the results greatly. Fourth, this study lasted only 5 days for each drug ! In order to meaningfully compare effectiveness or side-effects between two different drugs, it is necessary to look at differences after a month, or after a year, of continuous treatment. For most sedating drugs, problematic sedation diminishes after a period of weeks or months. Once again, if immediate sedation is the measure of side-effect adversity, then this study is biased in favour of Seroquel XR. Fifth, the study was done in healthy subjects who did not have active symptoms to treat. This reminds me of giving insulin to non-diabetic subjects, and comparing the side-effects of the different insulin preparations: the choice of population is an obvious strong bias!
Regular quetiapine has gone generic.
Quetiapine extended-release (Seroquel XR) has not.
I am bothered by the possibility of bias in Correll's article.
It is noted, in small print at the very end of this article, that Dr. Correll is "an advisor or consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Organon, Ortho McNeill-Janssen, Otsuka, Pfizer, Solvay, Supernus, and Vanda." AstraZeneca is the company which manufactures Seroquel XR.
In conlusion, I agree that there are obviously differences in receptor binding profiles between these different drugs. There are some side-effect differences.
Differences in actual effectiveness, as shown in comparative studies, are minimal. But probably olanzapine, and especially clozapine, are slightly better than the others, in terms of symptom control.
Quetiapine can be an excellent drug. Seroquel XR can be an excellent formulation of quetiapine, and might suit some people better.
BUT -- there is no evidence that brand-name Seroquel XR is superior to generic regular quetiapine.
One individual might respond better to one drug, compared to another.
The author, despite including 40 references, seems to have left out many important research studies on differences between antipsychotics, such as from CATIE and SOHO.
(see my previous post on antipsychotics: http://garthkroeker.blogspot.com/2008/12/antipsychotic-medications.html )
It starts off describing the receptor-binding profiles of different atypical antipsychotic drugs. A table is presented early on.
First of all, the table as presented is almost meaningless: it merely shows the concentrations of the different drugs required to block 50% of the given receptors. These so-called "Ki" concentrations have little meaning, particularly for comparing between one drug and another, UNLESS one has a clear idea of what concentrations the given drugs actually reach when administered at typical doses.
So, of course, quetiapine has much higher Ki concentrations for most receptors, compared to risperidone -- this is related to the fact that quetiapine doses are in the hundreds of milligrams, whereas risperidone doses are less than ten milligrams (these dose differences are not reflective of anything clinically relevant, and only pertain to the size of the tablet needed).
A much more meaningful chart would show one of the following:
1) the receptor blockades for each drug when the drug is administered at typical doses
2) the relative receptor blockade compared to a common receptor (so, for example, the ratio between receptor blockades of H1 or M1 or 5-HT2 compared to D2, for each drug).
The article goes on to explore a variety of other interesting differences between antipsychotics. Many of the statements made were theoretical propositions, not necessarily well-proven empirically. But in general I found this discussion valuable.
Despite apparent efforts for the author to be fair and balanced regarding the different antipsychotics, I note a few things:
1) there are two charts in this article showing symptom improvements in bipolar disorder among patients taking quetiapine extended-release (Seroquel XR).
2) one large figure appears to show that quetiapine has superior efficacy in treating schizophrenia, compared to olanzapine and risperidone (the only "p<.05 asterisk" was for quetiapine!) -- this figure was based on a single 2005 meta-analysis, published in a minor journal, before the CATIE results were published. No other figures were shown based on more recent results, nor was clozapine included in any figure.
I think quetiapine is a good drug. BUT -- I don't see any evidence that quetiapine extended release is actually any better, in any regard, than regular quetiapine. In fact, I have seen several patients for whom regular quetiapine suited them better than extended-release, and for whom a smaller total daily dose was needed.
Here is a reference to one study, done by Astra-Zeneca, comparing Seroquel with Seroquel XR, in healthy subjects: http://www.ncbi.nlm.nih.gov/pubmed/19393840 It shows that subjects given regular quetiapine were much more sedated 1 hour after dosing, compared to those given the same dose of Seroquel XR. It implies that the extended release drug was superior in terms of side-effects. Here is my critique of this study: first of all, sedation is often a goal in giving quetiapine, particularly in the treatment of psychosis or mania. Secondly, problematic sedation is usually the type that persists 12 hours or more after the dose, as opposed to one hour after the dose. In this study, the two different formulations did not differ in a statistically significant way with respect to sedation 7, 8 or 14 hours after dosing. In fact, if you look closely at the tables presented within the article, you can see that the Seroquel XR group actually had slightly higher sedation scores 14 hours after dosing. Thirdly, dosing of any drug can be titrated to optimal effect. Regular quetiapine need not be given at exactly the same dose as quetiapine XR--to give both drugs at the same dose, rather than at the optimally effective dose for each, is likely to bias the results greatly. Fourth, this study lasted only 5 days for each drug ! In order to meaningfully compare effectiveness or side-effects between two different drugs, it is necessary to look at differences after a month, or after a year, of continuous treatment. For most sedating drugs, problematic sedation diminishes after a period of weeks or months. Once again, if immediate sedation is the measure of side-effect adversity, then this study is biased in favour of Seroquel XR. Fifth, the study was done in healthy subjects who did not have active symptoms to treat. This reminds me of giving insulin to non-diabetic subjects, and comparing the side-effects of the different insulin preparations: the choice of population is an obvious strong bias!
Regular quetiapine has gone generic.
Quetiapine extended-release (Seroquel XR) has not.
I am bothered by the possibility of bias in Correll's article.
It is noted, in small print at the very end of this article, that Dr. Correll is "an advisor or consultant to AstraZeneca, Bristol-Myers Squibb, Cephalon, Eli Lilly, Organon, Ortho McNeill-Janssen, Otsuka, Pfizer, Solvay, Supernus, and Vanda." AstraZeneca is the company which manufactures Seroquel XR.
In conlusion, I agree that there are obviously differences in receptor binding profiles between these different drugs. There are some side-effect differences.
Differences in actual effectiveness, as shown in comparative studies, are minimal. But probably olanzapine, and especially clozapine, are slightly better than the others, in terms of symptom control.
Quetiapine can be an excellent drug. Seroquel XR can be an excellent formulation of quetiapine, and might suit some people better.
BUT -- there is no evidence that brand-name Seroquel XR is superior to generic regular quetiapine.
One individual might respond better to one drug, compared to another.
The author, despite including 40 references, seems to have left out many important research studies on differences between antipsychotics, such as from CATIE and SOHO.
(see my previous post on antipsychotics: http://garthkroeker.blogspot.com/2008/12/antipsychotic-medications.html )
Tuesday, February 10, 2009
Bipolar Depression
The depression which occurs in the context of bipolar disorder may have a variety of unique features (sometimes such a depression may occur BEFORE a clear manic episode has ever happened, so a depression with these features can sometimes be a warning sign of latent bipolarity, or a risk sign that bipolar disorder may develop in the future):
1) excessive sleep (rather than insomnia), along with marked physical lethargy
2) depression beginning early in life (during teenage or young adult years)
3) depressive episodes of short duration
4) depressive episodes having psychotic features (e.g. delusions)
5) other "atypical" depressive features, such as increased eating
6) Sometimes a very rapid response to antidepressants (e.g. within one or two doses)
Nevertheless, these features are not invariably present in bipolar depression; and many people may have depressive episodes with these features, who do not have bipolar disorder.
Conversely, in my opinion, there is one significant element from a person's history which points strongly away from a diagnosis of bipolar depression:
If a person has taken an antidepressant, especially at a high dose, and especially for a long period of time (over 3 months), and especially a tricyclic antidepressant or venlafaxine -- if a person has taken such an antidepressant on its own, without a mood stabilizer, and WITHOUT developing overt symptoms of mania, this is fairly strong evidence against underlying bipolarity.
Some of the recent evidence about treating bipolar depression leads us to question the role, value, or safety of antidepressants in the bipolar population.
http://www.ncbi.nlm.nih.gov/pubmed/18727689
(a 2008 review, showing little effect of antidepressants when added to mood stabilizers in treating bipolar disorder over at least 6 months of follow-up)
http://www.ncbi.nlm.nih.gov/pubmed/17392295
(this is from the New England Journal of Medicine--one of the world's leading medical journals--in 2007, and it showed, over 26 weeks of follow-up, that adding antidepressants to a mood stabilizer regime did not improve outcome, in fact the antidepressant group did not do quite as well)
Which treatments have an evidence base in bipolar depression?
1) Lamotrigine. It has the advantage of helping modestly with depressive symptoms with a low risk of causing mania. It may be true that some of the studies over the past few years have exaggerated the benefit of lamotrigine, however. In any case, it appears quite safe, and can be helpful for some people. There is a small risk of a very serious skin rash with this drug, otherwise it is quite safe and well-tolerated.
http://www.ncbi.nlm.nih.gov/pubmed/19200421
(a recent study looking at Lithium + Lamotrigine vs. Lithium + Placebo over 8 weeks of follow-up; the benefits of lamotrigine are significant but modest)
http://www.ncbi.nlm.nih.gov/pubmed/15003074
(this study also showed a benefit from lamotrigine, over a whole year, but there was no placebo group, so the results carry much less weight)
2) Other mood stabilizers, e.g. lithium, valproate, and carbamazepine. Unfortunately these drugs are probably more effective for preventing manic episodes than for preventing or treating depression. Yet, the combination of a standard mood stabilizer with another agent such as lamotrigine could be a valid step.
3) Atypical antipsychotics, e.g. olanzapine, quetiapine, and risperidone. These drugs undoubtedly are beneficial as mood stabilizers, possibly more so than the standard mood stabilizers such as lithium or valproate. There is evidence that antipsychotics + other mood stabilizers are additively effective in combination. They can be worth a try for treating bipolar depression. Unfortunately, if the bipolar depression is already characterized by excessive sleep, tiredness, and appetite, antipsychotics can sometimes make these symptoms worse. But if there are psychotic features with the depression, an antipsychotic can be an essential part of the treatment.
4) Omega-3 supplements : see my previous post
5) Light therapy: I have seen this be helpful at times. The light exposure may need to be carefully titrated (e.g. just a few minutes at a time), to prevent overstimulation or agitation. Light therapy requires the purchase of a 10 000 Lux light box, which could cost about $200-300.
http://www.ncbi.nlm.nih.gov/pubmed/18076544
6) Cognitive-behavioural therapy. Elements of CBT help with most anything, it seems to me (from learning to play the violin, to doing mathematics, to treating anxiety or depression from any cause). CBT can be adapted so as to be more tolerable and interesting (some of the workbooks can be hard to get through). I think its core features require daily written work, journaling, conducting a dialog with oneself about thoughts and emotions (hopefully to work at identifying forms of depressive thinking, and being willing to challenge such thoughts if they occur), and deliberately challenging oneself behaviourally to face fears, a little at a time. In bipolar disorder CBT may work best in conjunction with ideas that help to stabilize or structure daily behavioural rhythms (e.g. getting up regularly in the morning, having a routine, eating regularly, exercising, doing some intellectually challenging work, doing some creative work, going to bed around the same time, etc.). Of course, in depression of any sort, it can be extremely hard to initiate or maintain such lifestyle habits--if there is too much fatigue or lack of motivation to get started with very much, I encourage getting started with the very smallest of tasks or daily structures, and building from there; consistency is more important than amount.
http://www.ncbi.nlm.nih.gov/pubmed/18324665
7) Other psychotherapy: basic supportive care can be very important, provided there is a resilient, trusting therapeutic relationship
8) Antidepressants: despite the negative results of late, there are selected individuals for whom antidepressants may be very helpful. Over the past decade, bupropion has perhaps been the first antidepressant to consider, due to its lower rate of causing a manic switch, and possibly its higher likelihood of helping with the low energy states characteristic of bipolar depression. SSRI antidepressants have been the second-choice agents. MAOI's are probably lower risk with respect to causing manic switch, and the reversible MAOI moclobemide could be a good option. Venlafaxine and tricyclic antidepressants have been agents to avoid, due to their high risk of causing a manic switch.
References:
http://www.ncbi.nlm.nih.gov/pubmed/16449476
http://www.ncbi.nlm.nih.gov/pubmed/16880481
9) Stimulants: I have found that stimulants can be quite useful in bipolar depression, provided that they are not increasing psychotic symptoms or agitation. They have the advantage of working quickly, helping immediately with energy and attention, and often helping with mood. Furthermore, they can be withdrawn quickly if manic symptoms or agitation arises; if stimulants are withdrawn quickly, it causes a relative state of sedation. (Note that there is some evidence from a few older studies that stimulant treatment can actually reduce symptoms of mania) There are several older stimulants, such as methylphenidate (Ritalin), and dextroamphetamine (Dexedrine), and several newer formulations of these older drugs (e.g. Adderall). A newer, atypical stimulant called modafinil can be an option as well. However, modafinil is quite expensive and often not covered by medication plans in Canada.
References:
http://www.ncbi.nlm.nih.gov/pubmed/15383134
http://www.ncbi.nlm.nih.gov/pubmed/18980736
http://www.ncbi.nlm.nih.gov/pubmed/16974196
http://www.ncbi.nlm.nih.gov/pubmed/367183
http://www.ncbi.nlm.nih.gov/pubmed/3312177
(the above two references are to older, interesting studies showing that stimulant treatments actually helped REDUCE manic symptoms acutely--I cite this as evidence that stimulants are reasonable to use in bipolar patients, however I would not go so far as to recommend stimulants in the treatment of mania, as other anti-manic treatments are much more effective and accepted as a standard of care)
10) ECT:electroconvulsive therapy is unequivocally effective for treating both depression and mania. However, there may be a higher risk of mild but persistent cognitive side-effects in the bipolar population:
http://www.ncbi.nlm.nih.gov/pubmed/17653292
If there are "borderline" phenomena occuring in the context of bipolar depression, once again some of Dawson's ideas may be helpful (see my previous postings about borderline personality); these involve emphasizing the role and competence of the individual patient in choosing treatment options, and avoiding an authoritarian stance on the part of the therapist.
Other references:
http://www.ncbi.nlm.nih.gov/pubmed/18992784
(A recent study correlating early age of onset for depression with bipolarity, severity, recurrence, etc.)
http://www.ncbi.nlm.nih.gov/pubmed/18199233
(A review of diagnostic issues regarding bipolar depression)
1) excessive sleep (rather than insomnia), along with marked physical lethargy
2) depression beginning early in life (during teenage or young adult years)
3) depressive episodes of short duration
4) depressive episodes having psychotic features (e.g. delusions)
5) other "atypical" depressive features, such as increased eating
6) Sometimes a very rapid response to antidepressants (e.g. within one or two doses)
Nevertheless, these features are not invariably present in bipolar depression; and many people may have depressive episodes with these features, who do not have bipolar disorder.
Conversely, in my opinion, there is one significant element from a person's history which points strongly away from a diagnosis of bipolar depression:
If a person has taken an antidepressant, especially at a high dose, and especially for a long period of time (over 3 months), and especially a tricyclic antidepressant or venlafaxine -- if a person has taken such an antidepressant on its own, without a mood stabilizer, and WITHOUT developing overt symptoms of mania, this is fairly strong evidence against underlying bipolarity.
Some of the recent evidence about treating bipolar depression leads us to question the role, value, or safety of antidepressants in the bipolar population.
http://www.ncbi.nlm.nih.gov/pubmed/18727689
(a 2008 review, showing little effect of antidepressants when added to mood stabilizers in treating bipolar disorder over at least 6 months of follow-up)
http://www.ncbi.nlm.nih.gov/pubmed/17392295
(this is from the New England Journal of Medicine--one of the world's leading medical journals--in 2007, and it showed, over 26 weeks of follow-up, that adding antidepressants to a mood stabilizer regime did not improve outcome, in fact the antidepressant group did not do quite as well)
Which treatments have an evidence base in bipolar depression?
1) Lamotrigine. It has the advantage of helping modestly with depressive symptoms with a low risk of causing mania. It may be true that some of the studies over the past few years have exaggerated the benefit of lamotrigine, however. In any case, it appears quite safe, and can be helpful for some people. There is a small risk of a very serious skin rash with this drug, otherwise it is quite safe and well-tolerated.
http://www.ncbi.nlm.nih.gov/pubmed/19200421
(a recent study looking at Lithium + Lamotrigine vs. Lithium + Placebo over 8 weeks of follow-up; the benefits of lamotrigine are significant but modest)
http://www.ncbi.nlm.nih.gov/pubmed/15003074
(this study also showed a benefit from lamotrigine, over a whole year, but there was no placebo group, so the results carry much less weight)
2) Other mood stabilizers, e.g. lithium, valproate, and carbamazepine. Unfortunately these drugs are probably more effective for preventing manic episodes than for preventing or treating depression. Yet, the combination of a standard mood stabilizer with another agent such as lamotrigine could be a valid step.
3) Atypical antipsychotics, e.g. olanzapine, quetiapine, and risperidone. These drugs undoubtedly are beneficial as mood stabilizers, possibly more so than the standard mood stabilizers such as lithium or valproate. There is evidence that antipsychotics + other mood stabilizers are additively effective in combination. They can be worth a try for treating bipolar depression. Unfortunately, if the bipolar depression is already characterized by excessive sleep, tiredness, and appetite, antipsychotics can sometimes make these symptoms worse. But if there are psychotic features with the depression, an antipsychotic can be an essential part of the treatment.
4) Omega-3 supplements : see my previous post
5) Light therapy: I have seen this be helpful at times. The light exposure may need to be carefully titrated (e.g. just a few minutes at a time), to prevent overstimulation or agitation. Light therapy requires the purchase of a 10 000 Lux light box, which could cost about $200-300.
http://www.ncbi.nlm.nih.gov/pubmed/18076544
6) Cognitive-behavioural therapy. Elements of CBT help with most anything, it seems to me (from learning to play the violin, to doing mathematics, to treating anxiety or depression from any cause). CBT can be adapted so as to be more tolerable and interesting (some of the workbooks can be hard to get through). I think its core features require daily written work, journaling, conducting a dialog with oneself about thoughts and emotions (hopefully to work at identifying forms of depressive thinking, and being willing to challenge such thoughts if they occur), and deliberately challenging oneself behaviourally to face fears, a little at a time. In bipolar disorder CBT may work best in conjunction with ideas that help to stabilize or structure daily behavioural rhythms (e.g. getting up regularly in the morning, having a routine, eating regularly, exercising, doing some intellectually challenging work, doing some creative work, going to bed around the same time, etc.). Of course, in depression of any sort, it can be extremely hard to initiate or maintain such lifestyle habits--if there is too much fatigue or lack of motivation to get started with very much, I encourage getting started with the very smallest of tasks or daily structures, and building from there; consistency is more important than amount.
http://www.ncbi.nlm.nih.gov/pubmed/18324665
7) Other psychotherapy: basic supportive care can be very important, provided there is a resilient, trusting therapeutic relationship
8) Antidepressants: despite the negative results of late, there are selected individuals for whom antidepressants may be very helpful. Over the past decade, bupropion has perhaps been the first antidepressant to consider, due to its lower rate of causing a manic switch, and possibly its higher likelihood of helping with the low energy states characteristic of bipolar depression. SSRI antidepressants have been the second-choice agents. MAOI's are probably lower risk with respect to causing manic switch, and the reversible MAOI moclobemide could be a good option. Venlafaxine and tricyclic antidepressants have been agents to avoid, due to their high risk of causing a manic switch.
References:
http://www.ncbi.nlm.nih.gov/pubmed/16449476
http://www.ncbi.nlm.nih.gov/pubmed/16880481
9) Stimulants: I have found that stimulants can be quite useful in bipolar depression, provided that they are not increasing psychotic symptoms or agitation. They have the advantage of working quickly, helping immediately with energy and attention, and often helping with mood. Furthermore, they can be withdrawn quickly if manic symptoms or agitation arises; if stimulants are withdrawn quickly, it causes a relative state of sedation. (Note that there is some evidence from a few older studies that stimulant treatment can actually reduce symptoms of mania) There are several older stimulants, such as methylphenidate (Ritalin), and dextroamphetamine (Dexedrine), and several newer formulations of these older drugs (e.g. Adderall). A newer, atypical stimulant called modafinil can be an option as well. However, modafinil is quite expensive and often not covered by medication plans in Canada.
References:
http://www.ncbi.nlm.nih.gov/pubmed/15383134
http://www.ncbi.nlm.nih.gov/pubmed/18980736
http://www.ncbi.nlm.nih.gov/pubmed/16974196
http://www.ncbi.nlm.nih.gov/pubmed/367183
http://www.ncbi.nlm.nih.gov/pubmed/3312177
(the above two references are to older, interesting studies showing that stimulant treatments actually helped REDUCE manic symptoms acutely--I cite this as evidence that stimulants are reasonable to use in bipolar patients, however I would not go so far as to recommend stimulants in the treatment of mania, as other anti-manic treatments are much more effective and accepted as a standard of care)
10) ECT:electroconvulsive therapy is unequivocally effective for treating both depression and mania. However, there may be a higher risk of mild but persistent cognitive side-effects in the bipolar population:
http://www.ncbi.nlm.nih.gov/pubmed/17653292
If there are "borderline" phenomena occuring in the context of bipolar depression, once again some of Dawson's ideas may be helpful (see my previous postings about borderline personality); these involve emphasizing the role and competence of the individual patient in choosing treatment options, and avoiding an authoritarian stance on the part of the therapist.
Other references:
http://www.ncbi.nlm.nih.gov/pubmed/18992784
(A recent study correlating early age of onset for depression with bipolarity, severity, recurrence, etc.)
http://www.ncbi.nlm.nih.gov/pubmed/18199233
(A review of diagnostic issues regarding bipolar depression)
Omega-3 Supplementation
Omega-3 fatty acids are present in a variety of foods.
The fatty acids EPA and DHA are present mainly in fish such as salmon, herring, mackerel, anchovies, and sardines. These fatty acids, especially DHA, are probably important for brain function, and are also found in the retina of the eye.
Another omega-3 fatty acid, ALA, is present from plant sources such as canola oil, flax, and walnuts. ALA may be converted in the body to DHA.
There is some evidence that there are health benefits from diets higher in omega-3 fatty acids, or diets supplemented with extra omega-3.
Of interest for psychiatry, omega-3 supplementation may be a safe adjunct in the treatment of depression. Fish oil is probably the simplest source of extra EPA and DHA.
The only problem with increasing fish consumption is the exposure to environmental contaminants such as mercury and PCBs. Fish oil capsules may actually have less of these contaminants than pure fish, especially if the oil has been refined to remove contaminants. In any case, I think the benefit-risk ratio is very favourable, and that 1-3 capsules per day of fish oil is quite safe. And I feel confident to recommend increased fish intake in the diet. For vegetarians, increased intake of walnuts, canola, and flax could be recommended.
http://www.ncbi.nlm.nih.gov/pubmed/18183532
(a review of the studies over the past decade looking at omega-3 supplements in mood disorders)
http://www.ncbi.nlm.nih.gov/pubmed/16741195
(a nice review from The American Journal of Psychiatry in 2006, summarizing epidemiological data associating low fish consumption with higher rates of mood disorder, and summarizing some of the treatment studies showing antidepressant effects of omega-3 supplements in depression, bipolar disorder, and borderline personality)
http://www.ncbi.nlm.nih.gov/pubmed/19156158
(this is a recent study showing beneficial effects of omega-3 supplements in children with bipolar symptoms;but it was not a randomized or controlled study)
http://www.ncbi.nlm.nih.gov/pubmed/19200125
(this is a recent local study analyzing fish oil supplements for environmental pollutant levels, such as PCBs. Based on this study, one should avoid supplements of products such as seal or shark oils, which have much higher contaminant levels.)
http://www.ncbi.nlm.nih.gov/pubmed/19139352
(one of the articles summarizing evidence that omega-3 intake reduces the incidence or progression of macular degeneration, which is a common cause of visual loss in those over 65 years of age).
http://www.ncbi.nlm.nih.gov/pubmed/19064523
(a huge study, published in 2006, involving data from over
40 000 people over 18 years of follow-up--it shows a slight reduction in cardiac disease associated with higher fish consumption, but no change in overall "major chronic disease risk". But, incredibly, and unfortunately, they did not include mood or other psychiatric disorders in their assessment of "chronic disease" outcomes. Yet, studies of this type exemplify that The American Journal of Clinical Nutrition is an excellent journal, a valuable and practical source of evidence-based health information which could guide nutritional choices).
The fatty acids EPA and DHA are present mainly in fish such as salmon, herring, mackerel, anchovies, and sardines. These fatty acids, especially DHA, are probably important for brain function, and are also found in the retina of the eye.
Another omega-3 fatty acid, ALA, is present from plant sources such as canola oil, flax, and walnuts. ALA may be converted in the body to DHA.
There is some evidence that there are health benefits from diets higher in omega-3 fatty acids, or diets supplemented with extra omega-3.
Of interest for psychiatry, omega-3 supplementation may be a safe adjunct in the treatment of depression. Fish oil is probably the simplest source of extra EPA and DHA.
The only problem with increasing fish consumption is the exposure to environmental contaminants such as mercury and PCBs. Fish oil capsules may actually have less of these contaminants than pure fish, especially if the oil has been refined to remove contaminants. In any case, I think the benefit-risk ratio is very favourable, and that 1-3 capsules per day of fish oil is quite safe. And I feel confident to recommend increased fish intake in the diet. For vegetarians, increased intake of walnuts, canola, and flax could be recommended.
http://www.ncbi.nlm.nih.gov/pubmed/18183532
(a review of the studies over the past decade looking at omega-3 supplements in mood disorders)
http://www.ncbi.nlm.nih.gov/pubmed/16741195
(a nice review from The American Journal of Psychiatry in 2006, summarizing epidemiological data associating low fish consumption with higher rates of mood disorder, and summarizing some of the treatment studies showing antidepressant effects of omega-3 supplements in depression, bipolar disorder, and borderline personality)
http://www.ncbi.nlm.nih.gov/pubmed/19156158
(this is a recent study showing beneficial effects of omega-3 supplements in children with bipolar symptoms;but it was not a randomized or controlled study)
http://www.ncbi.nlm.nih.gov/pubmed/19200125
(this is a recent local study analyzing fish oil supplements for environmental pollutant levels, such as PCBs. Based on this study, one should avoid supplements of products such as seal or shark oils, which have much higher contaminant levels.)
http://www.ncbi.nlm.nih.gov/pubmed/19139352
(one of the articles summarizing evidence that omega-3 intake reduces the incidence or progression of macular degeneration, which is a common cause of visual loss in those over 65 years of age).
http://www.ncbi.nlm.nih.gov/pubmed/19064523
(a huge study, published in 2006, involving data from over
40 000 people over 18 years of follow-up--it shows a slight reduction in cardiac disease associated with higher fish consumption, but no change in overall "major chronic disease risk". But, incredibly, and unfortunately, they did not include mood or other psychiatric disorders in their assessment of "chronic disease" outcomes. Yet, studies of this type exemplify that The American Journal of Clinical Nutrition is an excellent journal, a valuable and practical source of evidence-based health information which could guide nutritional choices).
Monday, February 9, 2009
Lithium
I'd like to develop this post gradually, as there is a lot of evidence to summarize and refer to.
But here is a start:
"Mood stabilizers" are drugs which are thought to help treat the symptoms of bipolar disorder. It is hoped that these drugs might reduce manic symptoms, prevent recurrence of manic symptoms, while also reducing or preventing symptoms of depression.
The first treatments for manic episodes were sedatives, including barbiturates and antipsychotics.
The first "mood stabilizer" though, was lithium carbonate.
Lithium itself is the third-simplest element in the universe, after hydrogen and helium. It tends to form salts. It is structurally very similar to sodium, which is a salt-forming element essential to most every life function (that is why we find sodium ions abundantly in all body fluids, and in a similar concentration in the ocean; table salt consists of sodium and chlorine atoms which join together as crystals). Yet, lithium is not normally present in the human body, and is much less common in the universe as well, compared to hydrogen, oxygen, carbon, sodium, etc.
The mechanism of lithium's action in the body, when used as a drug, is still poorly understood. Its similarity to sodium is probably essential to its mechanism. I'll add to this commentary later, but for now I will say that the mechanism of lithium salts probably involves multiple actions inside of nerve cells; these actions may modulate cellular activity.
Here are some of the clinical actions of lithium carbonate, when used as a medication in those with bipolar disorder (I will list the actions in order of how clearly proven and substantial the effect is):
1) It reduces symptoms of mania
2) It may reduce the length of a manic episode (note that just because a treatment reduces symptom severity, it may not reduce the duration of the symptoms).
3) It may prevent the recurrence of manic symptoms
4) It may prevent the recurrence of depressive symptoms
5) It may reduce depressive symptoms when they occur
There are other uses for lithium carbonate as well:
1) It can be combined with an antidepressant to improve symptom control in unipolar depression
2) It may help treat specific symptoms such as irritability and rage
3) It helps prevent cluster headaches (a type of severe, recurrent headache)
Lithium is probably most useful in "classic bipolar disorder", in which individuals experience manic episodes with elevated mood (as opposed to irritable or "dysphoric" mood), and in which the mood episodes are not recurring frequently during an average year (i.e. there is no "rapid cycling").
Here are some of the side-effects of lithium:
1) thirst, increased urine production
2) tremor (shaky hands)
3) nausea
4) sedation -- usually it is a much less pronounced type of sedation compared to antipsychotics, benzodiazepines, or other "sleeping pills". But there can be feelings of reduced energy, reduced clarity of thinking, or lethargy
5) toxicity to the kidneys -- this is not common, but needs to be checked for regularly
6) inhibition of thyroid function -- this is not permanent, nor is it harmful to the thyroid gland (in fact, it may "rest" the thyroid gland); but diminished thyroid levels, if present, requires treatment with a thyroid supplement)
7) acne or other skin rashes
8) toxicity in overdose
There have been a few studies questioning the effectiveness of lithium, particularly in terms of its value in preventing recurrent mood episodes. But for many people it does appear to be very effective, both as an acute treatment and as a preventative agent. It probably works much better as an "anti-manic" agent than an "anti-depressant".
There are various forms of lithium, and various dosing regimes. In most cases, it can be dosed simply: once at bedtime. The concentration of lithium in the blood needs to be measured periodically. Levels which are too high can increase the likelihood of toxicity (mind you, excessive levels could usually be assessed on the basis of side-effect complaints); levels which are too low may not be effective.
In my experience, some people may benefit from staying on lithium, but adjusting the dose to a point that is more tolerable for them. It may not necessarily be true that everyone needs to have a full therapeutic concentration of lithium in order for it to work. For some people, the side effects may outweigh the benefit at full doses.
However, it is a frequent situation in an emergency room, or on a mood disorders hospital ward, that people with clear histories of bipolar disorder, stable on medication, end up having a recurrence of severe mania a few weeks or months after tapering or stopping their medication (often lithium). In some of these cases, the manic symptoms may have already been building up, leading the person to discontinue their medication (rather than the other way around). But in many of these cases, it seems to me that the lithium had been protecting them, and that the recurrence of mania happened because of medication discontinuation.
There is also some evidence that sudden lithium discontinuation can provoke increased mood instability. So, while there are no overt withdrawal symptoms from stopping lithium, it should be tapered slowly if possible (I would say over 1-2 months at least).
It should be emphasized that lithium is not a perfect drug, either in terms of side effects or in terms of effectiveness. Many people on full doses of lithium still experience relapses of mania. But it is quite clear, from decades of experience, that lithium can be helpful for many people with bipolar disorder.
References:
http://www.ncbi.nlm.nih.gov/pubmed/17547586
(a 2007 Cochrane review of mood stabilizers, showing good evidence for lithium, but also encouraging use of other mood stabilizers--which for some people could be superior to lithium-- such as valproate and atypical antipsychotics)
http://www.ncbi.nlm.nih.gov/pubmed/8120960
(a 1994 JAMA article showing the effectiveness of lithium and valproate, compared to placebo, in acute mania)
http://www.ncbi.nlm.nih.gov/pubmed/10807488
(a negative study, comparing lithium, valproate, and placebo; published in the major journal Archives of General Psychiatry in 2000--it shows very little difference between lithium, valproate, and placebo treatments with respect to relapses in bipolar patients over a 1-year period; however this study was probably biased in favour of high placebo effects and lower medication treatment effects, for a variety of reasons)
http://www.ncbi.nlm.nih.gov/pubmed/10891035
(a randomized, placebo-controlled study from Archives of General Psychiatry in 2000, showing a pronounced effect of lithium in reducing aggression in hospitalized children with conduct disorder)
http://www.ncbi.nlm.nih.gov/pubmed/16924942
http://www.ncbi.nlm.nih.gov/pubmed/3314489
(a Dutch review article from 2006, and an older article from a U.S. nephrology journal, summarizing the risk of kidney disease associated with lithium; about 15-20% of people taking lithium long-term may experience a decline in kidney function. While this decline is usually mild, I think that an alternative mood stabilizer should be strongly considered if someone is developing signs of reduced kidney function while on lithium).
But here is a start:
"Mood stabilizers" are drugs which are thought to help treat the symptoms of bipolar disorder. It is hoped that these drugs might reduce manic symptoms, prevent recurrence of manic symptoms, while also reducing or preventing symptoms of depression.
The first treatments for manic episodes were sedatives, including barbiturates and antipsychotics.
The first "mood stabilizer" though, was lithium carbonate.
Lithium itself is the third-simplest element in the universe, after hydrogen and helium. It tends to form salts. It is structurally very similar to sodium, which is a salt-forming element essential to most every life function (that is why we find sodium ions abundantly in all body fluids, and in a similar concentration in the ocean; table salt consists of sodium and chlorine atoms which join together as crystals). Yet, lithium is not normally present in the human body, and is much less common in the universe as well, compared to hydrogen, oxygen, carbon, sodium, etc.
The mechanism of lithium's action in the body, when used as a drug, is still poorly understood. Its similarity to sodium is probably essential to its mechanism. I'll add to this commentary later, but for now I will say that the mechanism of lithium salts probably involves multiple actions inside of nerve cells; these actions may modulate cellular activity.
Here are some of the clinical actions of lithium carbonate, when used as a medication in those with bipolar disorder (I will list the actions in order of how clearly proven and substantial the effect is):
1) It reduces symptoms of mania
2) It may reduce the length of a manic episode (note that just because a treatment reduces symptom severity, it may not reduce the duration of the symptoms).
3) It may prevent the recurrence of manic symptoms
4) It may prevent the recurrence of depressive symptoms
5) It may reduce depressive symptoms when they occur
There are other uses for lithium carbonate as well:
1) It can be combined with an antidepressant to improve symptom control in unipolar depression
2) It may help treat specific symptoms such as irritability and rage
3) It helps prevent cluster headaches (a type of severe, recurrent headache)
Lithium is probably most useful in "classic bipolar disorder", in which individuals experience manic episodes with elevated mood (as opposed to irritable or "dysphoric" mood), and in which the mood episodes are not recurring frequently during an average year (i.e. there is no "rapid cycling").
Here are some of the side-effects of lithium:
1) thirst, increased urine production
2) tremor (shaky hands)
3) nausea
4) sedation -- usually it is a much less pronounced type of sedation compared to antipsychotics, benzodiazepines, or other "sleeping pills". But there can be feelings of reduced energy, reduced clarity of thinking, or lethargy
5) toxicity to the kidneys -- this is not common, but needs to be checked for regularly
6) inhibition of thyroid function -- this is not permanent, nor is it harmful to the thyroid gland (in fact, it may "rest" the thyroid gland); but diminished thyroid levels, if present, requires treatment with a thyroid supplement)
7) acne or other skin rashes
8) toxicity in overdose
There have been a few studies questioning the effectiveness of lithium, particularly in terms of its value in preventing recurrent mood episodes. But for many people it does appear to be very effective, both as an acute treatment and as a preventative agent. It probably works much better as an "anti-manic" agent than an "anti-depressant".
There are various forms of lithium, and various dosing regimes. In most cases, it can be dosed simply: once at bedtime. The concentration of lithium in the blood needs to be measured periodically. Levels which are too high can increase the likelihood of toxicity (mind you, excessive levels could usually be assessed on the basis of side-effect complaints); levels which are too low may not be effective.
In my experience, some people may benefit from staying on lithium, but adjusting the dose to a point that is more tolerable for them. It may not necessarily be true that everyone needs to have a full therapeutic concentration of lithium in order for it to work. For some people, the side effects may outweigh the benefit at full doses.
However, it is a frequent situation in an emergency room, or on a mood disorders hospital ward, that people with clear histories of bipolar disorder, stable on medication, end up having a recurrence of severe mania a few weeks or months after tapering or stopping their medication (often lithium). In some of these cases, the manic symptoms may have already been building up, leading the person to discontinue their medication (rather than the other way around). But in many of these cases, it seems to me that the lithium had been protecting them, and that the recurrence of mania happened because of medication discontinuation.
There is also some evidence that sudden lithium discontinuation can provoke increased mood instability. So, while there are no overt withdrawal symptoms from stopping lithium, it should be tapered slowly if possible (I would say over 1-2 months at least).
It should be emphasized that lithium is not a perfect drug, either in terms of side effects or in terms of effectiveness. Many people on full doses of lithium still experience relapses of mania. But it is quite clear, from decades of experience, that lithium can be helpful for many people with bipolar disorder.
References:
http://www.ncbi.nlm.nih.gov/pubmed/17547586
(a 2007 Cochrane review of mood stabilizers, showing good evidence for lithium, but also encouraging use of other mood stabilizers--which for some people could be superior to lithium-- such as valproate and atypical antipsychotics)
http://www.ncbi.nlm.nih.gov/pubmed/8120960
(a 1994 JAMA article showing the effectiveness of lithium and valproate, compared to placebo, in acute mania)
http://www.ncbi.nlm.nih.gov/pubmed/10807488
(a negative study, comparing lithium, valproate, and placebo; published in the major journal Archives of General Psychiatry in 2000--it shows very little difference between lithium, valproate, and placebo treatments with respect to relapses in bipolar patients over a 1-year period; however this study was probably biased in favour of high placebo effects and lower medication treatment effects, for a variety of reasons)
http://www.ncbi.nlm.nih.gov/pubmed/10891035
(a randomized, placebo-controlled study from Archives of General Psychiatry in 2000, showing a pronounced effect of lithium in reducing aggression in hospitalized children with conduct disorder)
http://www.ncbi.nlm.nih.gov/pubmed/16924942
http://www.ncbi.nlm.nih.gov/pubmed/3314489
(a Dutch review article from 2006, and an older article from a U.S. nephrology journal, summarizing the risk of kidney disease associated with lithium; about 15-20% of people taking lithium long-term may experience a decline in kidney function. While this decline is usually mild, I think that an alternative mood stabilizer should be strongly considered if someone is developing signs of reduced kidney function while on lithium).
Wednesday, July 16, 2008
Bipolar Disorder
I have neglected so far to discuss a very important diagnostic category: bipolar disorder.
In bipolar disorder, there can be episodes of severe depression, in fact this may be the presenting or initial problem. Bipolar disorder is strongly heritable (it runs in families), even more strongly than other types of mental illness. Yet there are cases in which bipolar disorder can arise in an individual without an obvious family history.
The other "pole" in bipolar disorder is mania: this is a state in which mood is abnormally elevated or irritable, with a variety of other accompanying symptoms-
-increased energy (in its extreme form, severe uncontrollable physical agitation)
-decreased need for sleep (in its extreme form, no sleep at all despite high energy)
-racing thoughts or speech (in its extreme form, leading to incomprehensible speech)
-elevated self-esteem (in its extreme form, delusions of grandeur such as believing oneself to have supernatural powers)
-reckless and uncharacteristic behaviour (such as driving dangerously, taking other unusual risks such as substance use or gambling)
-uncharacteristic increase or change in social behaviour (e.g. promiscuity, socializing freely with strangers)
-increased spending (sometimes this leads to financial catastrophe, giving away one's savings, buying new cars, etc.)
-there may be psychotic symptoms such as hallucinations, paranoia, or severely disorganized thinking
-increased "goal-directed activity": many new plans, ideas, and actions, but often these are disorganized and chaotic
-usually these symptoms last for weeks or months at a time. For some people their symptoms fluctuate much more rapidly, sometimes between depressed symptoms and manic symptoms, or some combination simultaneously. This is so-called "rapid cycling".
A manic state can be very severe, leading to the police needing to bring the afflicted person to the hospital. There can be catastrophic life consequences, affecting relationships, finances, or physical health.
In other cases, though, a manic state can be quite mild (a so-called "hypomanic" state), and may even be quite a pleasant and productive period of time.
For any person seeking treatment for depression, it is extremely important to examine closely whether there have been any manic symptoms in the past--even mild ones--or if there is a family history of bipolar disorder. One important reason for this is that antidepressants can provoke manic episodes in persons with bipolar disorder. Treating depression in bipolar disorder requires extra care to prevent a manic episode from arising. This can involve a so-called "mood-stabilizer" drug such as lithium carbonate. Or, it can involve choosing a different type of treatment for the depression, such as a newer drug called lamotrigine, which can help with bipolar depression without causing mania.
In bipolar disorder, there can be episodes of severe depression, in fact this may be the presenting or initial problem. Bipolar disorder is strongly heritable (it runs in families), even more strongly than other types of mental illness. Yet there are cases in which bipolar disorder can arise in an individual without an obvious family history.
The other "pole" in bipolar disorder is mania: this is a state in which mood is abnormally elevated or irritable, with a variety of other accompanying symptoms-
-increased energy (in its extreme form, severe uncontrollable physical agitation)
-decreased need for sleep (in its extreme form, no sleep at all despite high energy)
-racing thoughts or speech (in its extreme form, leading to incomprehensible speech)
-elevated self-esteem (in its extreme form, delusions of grandeur such as believing oneself to have supernatural powers)
-reckless and uncharacteristic behaviour (such as driving dangerously, taking other unusual risks such as substance use or gambling)
-uncharacteristic increase or change in social behaviour (e.g. promiscuity, socializing freely with strangers)
-increased spending (sometimes this leads to financial catastrophe, giving away one's savings, buying new cars, etc.)
-there may be psychotic symptoms such as hallucinations, paranoia, or severely disorganized thinking
-increased "goal-directed activity": many new plans, ideas, and actions, but often these are disorganized and chaotic
-usually these symptoms last for weeks or months at a time. For some people their symptoms fluctuate much more rapidly, sometimes between depressed symptoms and manic symptoms, or some combination simultaneously. This is so-called "rapid cycling".
A manic state can be very severe, leading to the police needing to bring the afflicted person to the hospital. There can be catastrophic life consequences, affecting relationships, finances, or physical health.
In other cases, though, a manic state can be quite mild (a so-called "hypomanic" state), and may even be quite a pleasant and productive period of time.
For any person seeking treatment for depression, it is extremely important to examine closely whether there have been any manic symptoms in the past--even mild ones--or if there is a family history of bipolar disorder. One important reason for this is that antidepressants can provoke manic episodes in persons with bipolar disorder. Treating depression in bipolar disorder requires extra care to prevent a manic episode from arising. This can involve a so-called "mood-stabilizer" drug such as lithium carbonate. Or, it can involve choosing a different type of treatment for the depression, such as a newer drug called lamotrigine, which can help with bipolar depression without causing mania.
Monday, July 14, 2008
ECT
ECT (electroconvulsive therapy) is a hospital procedure in which the patient undergoes general anesthesia, after which an electric current is passed through the brain using externally-applied electrodes. In order for the treatment to work, a generalized seizure must be induced by the current.
This treatment arouses a lot of strong feeling and controversy in the public.
In my opinion, ECT can be almost miraculous in how well it works. There are a few instances in my career in which I have watched someone who had languished in a severe depressive state for months, wasting away, despite the intense caring efforts of family, nursing, perhaps many other types of treatment -- in these cases it appeared that the person was about to die from malnutrition. Sometimes it was believed that these individuals were in fact dying of "natural causes" or were simply elderly and terminally ill.
I can remember instances of clinical situations like this in which ECT caused the person to have a complete recovery from such a state. Truly miraculous. And no complaint of ECT-induced side-effects either.
ECT is used only for very treatment-resistant depression nowadays. It can also work particularly well for individuals who have depression with psychotic features (i.e. they have symptoms such as hallucinations or delusions with their depression). It can also work well to treat severe manic states.
Unfortunately, individuals in the treatment-resistant depressed group less frequently respond to any new therapy (though it is important to continue the search until something is found that works!). So when ECT is used in a treatment-resistant population, even ECT may not work. The people who have had ECT yet remain unwell may feel worse still. It is much like cardiac disease (in fact cardiology is one of the other branches of medicine in which a radically effective treatment, such as cardioversion, involves a carefully applied electric current passing through human tissue)--in chronic cardiac disease, the disease may worsen despite best efforts. The best treatment may not work, and the patient may even do worse afterwards. Likewise, with ECT, sometimes it does not work.
Yet the evidence does show that it has an important role in treating severe, resistant depression. It can sometimes work miraculously well. It is not without side-effects, but a careful look at the evidence will show that sustained measurable cognitive side-effects are uncommon. A recent article demonstrated some possible cognitive side-effects attributed to ECT in bipolar patients. Yet these side-effects were subtle, and quantitatively far less severe than the symptoms of the primary mental illness.
Ironically, ECT is also an anti-seizure treatment. ECT treatments cause the brain to subsequently be more resistant to having a seizure. It is sometimes used to treat seizure disorders. It is ironic this way. People need to acquaint themselves with what the research shows on this subject, and not assume in advance that an invasive treatment such as ECT must cause tissue damage. There is even some evidence that ECT treatments promote the growth of new nervous system tissue, rather than cause tissue destruction. Once again, I invite the reader to study the evidence. There is certainly no one who has an agenda to profit from giving or promoting ECT (independent of it being an actual helpful treatment), so I can't see any reason for bias in the evidence; ECT equipment is not expensive, there are no huge drug companies at play here, there is no one earning a fortune giving ECT, and there are long waits for patients needing anesthesia or psychiatric care for other reasons.
I do not mean to celebrate ECT as a perfect treatment. It certainly is not. But I think it has been demonized in the public, perhaps causing many people to rule out a therapeutic possibility that can be remarkably effective, often life-saving.
This treatment arouses a lot of strong feeling and controversy in the public.
In my opinion, ECT can be almost miraculous in how well it works. There are a few instances in my career in which I have watched someone who had languished in a severe depressive state for months, wasting away, despite the intense caring efforts of family, nursing, perhaps many other types of treatment -- in these cases it appeared that the person was about to die from malnutrition. Sometimes it was believed that these individuals were in fact dying of "natural causes" or were simply elderly and terminally ill.
I can remember instances of clinical situations like this in which ECT caused the person to have a complete recovery from such a state. Truly miraculous. And no complaint of ECT-induced side-effects either.
ECT is used only for very treatment-resistant depression nowadays. It can also work particularly well for individuals who have depression with psychotic features (i.e. they have symptoms such as hallucinations or delusions with their depression). It can also work well to treat severe manic states.
Unfortunately, individuals in the treatment-resistant depressed group less frequently respond to any new therapy (though it is important to continue the search until something is found that works!). So when ECT is used in a treatment-resistant population, even ECT may not work. The people who have had ECT yet remain unwell may feel worse still. It is much like cardiac disease (in fact cardiology is one of the other branches of medicine in which a radically effective treatment, such as cardioversion, involves a carefully applied electric current passing through human tissue)--in chronic cardiac disease, the disease may worsen despite best efforts. The best treatment may not work, and the patient may even do worse afterwards. Likewise, with ECT, sometimes it does not work.
Yet the evidence does show that it has an important role in treating severe, resistant depression. It can sometimes work miraculously well. It is not without side-effects, but a careful look at the evidence will show that sustained measurable cognitive side-effects are uncommon. A recent article demonstrated some possible cognitive side-effects attributed to ECT in bipolar patients. Yet these side-effects were subtle, and quantitatively far less severe than the symptoms of the primary mental illness.
Ironically, ECT is also an anti-seizure treatment. ECT treatments cause the brain to subsequently be more resistant to having a seizure. It is sometimes used to treat seizure disorders. It is ironic this way. People need to acquaint themselves with what the research shows on this subject, and not assume in advance that an invasive treatment such as ECT must cause tissue damage. There is even some evidence that ECT treatments promote the growth of new nervous system tissue, rather than cause tissue destruction. Once again, I invite the reader to study the evidence. There is certainly no one who has an agenda to profit from giving or promoting ECT (independent of it being an actual helpful treatment), so I can't see any reason for bias in the evidence; ECT equipment is not expensive, there are no huge drug companies at play here, there is no one earning a fortune giving ECT, and there are long waits for patients needing anesthesia or psychiatric care for other reasons.
I do not mean to celebrate ECT as a perfect treatment. It certainly is not. But I think it has been demonized in the public, perhaps causing many people to rule out a therapeutic possibility that can be remarkably effective, often life-saving.
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