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The Incredible, The Amazing, Lithium
It's an amazing metal. Not only does it treat acute mania, prevent recurrences, and treat refractory depression, but when consumed as LiCl, it tastes pretty good on vegetables. Or at least it did before the 1950s, when it was dropped from the list of acceptable salt-substitutes for hypertensives because of a nasty tendency to cause toxicity.
The history of lithium is colorful, and is covered elsewhere in this month's issue. In this article, TCR covers lithium from a clinical perspective, in the hopes of reminding you that it's easy to prescribe and to monitor, it's effective, and it's very cheap.
Lithium's benefits
In treating acute manic episodes, lithium's response rate is in the range of 70-80%. That's the good news. The bad news is that it takes up to two weeks to kick in, and thus is about a week slower than its main competitors, Depakote and the atypical antipsychotics. This is not a huge problem, however, because we will often use adjunctive neuroleptics or benzodiazepines for acute mania anyway.
Not only does lithium treat mania, but it is the only medication in the world that has been shown to be more effective than placebo in preventing recurrences of both mania and depression in bipolar disorder (1). Other medications may be effective for preventing specific problems in bipolar disorder. Thus, Lamictal (lamotrigine) prevents bipolar depression, and a recently reported but not yet peer-reviewed abstract reports that Zyprexa (olanzapine) was better than lithium at preventing relapse to mania in one trial (2). But lithium has been shown effective in bipolar disorder prophylaxis in study after study over the last 30 years.
Lithium is a good antidepressant, and is currently one of two drugs recommended in APA Guidelines for the treatment of bipolar depression (3). Lithium is the only psychiatric medication (other than clozapine) proven to prevent suicide. Meta-analytic studies have reported a 93% reduction in suicide acts in patients on lithium. Interestingly, lithium's antisuicide effect was most robust in recurrent major depression, although it was still a boon in both bipolar I and bipolar II disorders. Does this suicide data imply that we should be putting all our severely depressed patients on lithium, whether they have bipolar disorder or not? It's an arguable point!
There are a variety of allegations floating around related to certain supposed advantages of Depakote over lithium, especially in any manic presentation other than classic euphoric mania. Read the Depakote article in this issue for TCR's version of clarity on this topic.
How to Use Lithium
Now that you're chomping at the bit to start prescribing lithium, how should you do it? Start by getting baseline TSH, T4, and BUN/Cr levels drawn before the first dose, and then start with regular old Lithium Carbonate, 300 or 600 mg QHS. LiCO3 may cause a bit more initial GI distress than Eskalith CR or Lithobid but it's about half the price. Lithium's half life is 24 hours, so don't even think of dosing more than once a day, unless it becomes clear over time that your patient has fewer side effects with split dosing. Dosing it at night also has the beneficial effect of causing less polyuria.
Try to get the lithium level up to 0.8 meq/L or so. Comparative studies have shown that higher serum levels are more effective at preventing relapse, but on the down side, they lead to lower tolerability and more treatment drop-out. So shoot for 0.8, but if you have to drop down to 0.6 or 0.7 to maintain a happy camper, by all means do so. You'll probably end up at a dose between 900 mg - 1500 mg QHS for most patients.
Check lithium levels, TSH/T4, and BUN/Cr after one week, at one to two months, then every 6 to 12 months thereafter. The most common side effects are GI discomfort (remedies: split dosing, take with meals, switch to long-acting formulation, or switch to Li Citrate syrup), tremor (use Inderal LA 60 mg QAM or regular Inderal 20 mg BID-TID prn), polyuria/excessive thirst (dose it all at night, use low dose hydrochlorthiazide but watch lithium levels, which will often increase on this regimen), memory problems (no proven remedy, some try stimulants or acetylcholinesterase inhibitors), weight gain (diet and exercise and prayer).
Two side effect issues are confusing and controversial. First, can lithium actually damage the kidneys, beyond causing reversible polyuria? The answer is: probably, but it's quite rare. A ten-year prospective follow-up study of lithium's effects on the kidney found that declining kidney function was more related to age of the patient than duration of lithium use. One risk factor appears to be a history of frank lithium toxicity. Bottom-line is that kidney damage is unlikely, but caution dictates yearly BUN/Cr levels.
The second issue is lithium's effects on the heart. A Medline search reveals many case reports of lithium-induced sinus node dysfunction. Recall that the sinus node is our main cardiac pacemaker, and keeps our hearts beating in the 60-100 range. The usual symptoms of sinus node dysfunction are the results of bradycardia--fatigue, dizziness, and fainting. Studies that have bothered to measure sinus node functioning in large groups of patients on lithium have been pretty reassuring: severe, symptomatic sinus node dysfunction is quite rare (5). Based on this, a common sense approach would be to:
1) Get a pre-lithium EKG in patients with documented cardiac disease, especially in patients over 50, who have a higher rate of bradycardia due to age alone; and
2) Order an EKG in any lithium treated patient who has new onset dizziness or fainting.
TCR VERDICT: Don’t Neglect the Magic of Lithium!
1. Goodwin FK. Rationale for long-term treatment of bipolar disorder and evidence for long-term lithium treatment. J Clin Psychiatry. 2002;63[suppl 10]:5-12.
2. Tohen M. Olanzapine more effective for preventing mania relapse. Poster presentation, 5th International Conference on Bipolar Disorder, Pittsburg, 2003 (viewable on web at www.medscape. com/viewarticle/457508_print ).
3. American Psychiatric Association Practice Guidelines for the Treatment of Patients With Bipolar Disorder, Second Edition. 2002. Washington DC: APPI.
4. Baldessarini RJ, Tondo L, Hennen J. Lithium treatment and suicidal risk in major affective disorders: Update and new findings. J Clin Psychiatry 2003;64[suppl5]:44-52.
5. Rosenqvist M, Bergfeldt L, Aili H, et al. Sinus node dysfunction during long-term lithium treatment. Br Heart J. 1993;70:371- 375.
General PsychiatryThe history of lithium is colorful, and is covered elsewhere in this month's issue. In this article, TCR covers lithium from a clinical perspective, in the hopes of reminding you that it's easy to prescribe and to monitor, it's effective, and it's very cheap.
Lithium's benefits
In treating acute manic episodes, lithium's response rate is in the range of 70-80%. That's the good news. The bad news is that it takes up to two weeks to kick in, and thus is about a week slower than its main competitors, Depakote and the atypical antipsychotics. This is not a huge problem, however, because we will often use adjunctive neuroleptics or benzodiazepines for acute mania anyway.
Not only does lithium treat mania, but it is the only medication in the world that has been shown to be more effective than placebo in preventing recurrences of both mania and depression in bipolar disorder (1). Other medications may be effective for preventing specific problems in bipolar disorder. Thus, Lamictal (lamotrigine) prevents bipolar depression, and a recently reported but not yet peer-reviewed abstract reports that Zyprexa (olanzapine) was better than lithium at preventing relapse to mania in one trial (2). But lithium has been shown effective in bipolar disorder prophylaxis in study after study over the last 30 years.
Lithium is a good antidepressant, and is currently one of two drugs recommended in APA Guidelines for the treatment of bipolar depression (3). Lithium is the only psychiatric medication (other than clozapine) proven to prevent suicide. Meta-analytic studies have reported a 93% reduction in suicide acts in patients on lithium. Interestingly, lithium's antisuicide effect was most robust in recurrent major depression, although it was still a boon in both bipolar I and bipolar II disorders. Does this suicide data imply that we should be putting all our severely depressed patients on lithium, whether they have bipolar disorder or not? It's an arguable point!
There are a variety of allegations floating around related to certain supposed advantages of Depakote over lithium, especially in any manic presentation other than classic euphoric mania. Read the Depakote article in this issue for TCR's version of clarity on this topic.
How to Use Lithium
Now that you're chomping at the bit to start prescribing lithium, how should you do it? Start by getting baseline TSH, T4, and BUN/Cr levels drawn before the first dose, and then start with regular old Lithium Carbonate, 300 or 600 mg QHS. LiCO3 may cause a bit more initial GI distress than Eskalith CR or Lithobid but it's about half the price. Lithium's half life is 24 hours, so don't even think of dosing more than once a day, unless it becomes clear over time that your patient has fewer side effects with split dosing. Dosing it at night also has the beneficial effect of causing less polyuria.
Try to get the lithium level up to 0.8 meq/L or so. Comparative studies have shown that higher serum levels are more effective at preventing relapse, but on the down side, they lead to lower tolerability and more treatment drop-out. So shoot for 0.8, but if you have to drop down to 0.6 or 0.7 to maintain a happy camper, by all means do so. You'll probably end up at a dose between 900 mg - 1500 mg QHS for most patients.
Check lithium levels, TSH/T4, and BUN/Cr after one week, at one to two months, then every 6 to 12 months thereafter. The most common side effects are GI discomfort (remedies: split dosing, take with meals, switch to long-acting formulation, or switch to Li Citrate syrup), tremor (use Inderal LA 60 mg QAM or regular Inderal 20 mg BID-TID prn), polyuria/excessive thirst (dose it all at night, use low dose hydrochlorthiazide but watch lithium levels, which will often increase on this regimen), memory problems (no proven remedy, some try stimulants or acetylcholinesterase inhibitors), weight gain (diet and exercise and prayer).
Two side effect issues are confusing and controversial. First, can lithium actually damage the kidneys, beyond causing reversible polyuria? The answer is: probably, but it's quite rare. A ten-year prospective follow-up study of lithium's effects on the kidney found that declining kidney function was more related to age of the patient than duration of lithium use. One risk factor appears to be a history of frank lithium toxicity. Bottom-line is that kidney damage is unlikely, but caution dictates yearly BUN/Cr levels.
The second issue is lithium's effects on the heart. A Medline search reveals many case reports of lithium-induced sinus node dysfunction. Recall that the sinus node is our main cardiac pacemaker, and keeps our hearts beating in the 60-100 range. The usual symptoms of sinus node dysfunction are the results of bradycardia--fatigue, dizziness, and fainting. Studies that have bothered to measure sinus node functioning in large groups of patients on lithium have been pretty reassuring: severe, symptomatic sinus node dysfunction is quite rare (5). Based on this, a common sense approach would be to:
1) Get a pre-lithium EKG in patients with documented cardiac disease, especially in patients over 50, who have a higher rate of bradycardia due to age alone; and
2) Order an EKG in any lithium treated patient who has new onset dizziness or fainting.
TCR VERDICT: Don’t Neglect the Magic of Lithium!
1. Goodwin FK. Rationale for long-term treatment of bipolar disorder and evidence for long-term lithium treatment. J Clin Psychiatry. 2002;63[suppl 10]:5-12.
2. Tohen M. Olanzapine more effective for preventing mania relapse. Poster presentation, 5th International Conference on Bipolar Disorder, Pittsburg, 2003 (viewable on web at www.medscape. com/viewarticle/457508_print ).
3. American Psychiatric Association Practice Guidelines for the Treatment of Patients With Bipolar Disorder, Second Edition. 2002. Washington DC: APPI.
4. Baldessarini RJ, Tondo L, Hennen J. Lithium treatment and suicidal risk in major affective disorders: Update and new findings. J Clin Psychiatry 2003;64[suppl5]:44-52.
5. Rosenqvist M, Bergfeldt L, Aili H, et al. Sinus node dysfunction during long-term lithium treatment. Br Heart J. 1993;70:371- 375.
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