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Primary Care Providers' Resource Center

Primary Care Lithium Primer

For treatment of depression, primary care providers using the Texas Medical Algorithm (TMAP) got better results than those providing "treatment as usual".^Trivedi  What's in that algorithm that you aren't already doing?  For most of the PCP's I've talked with, here's a big one:  lithium. 

Can primary care providers really use lithium?  The TMAP says yes:  lithium augmentation is step 1A in that approach!  

Why be hesitant?  Some of your colleagues have said "hey, you can kill people with lithium, and it's hard to do that with an SSRI."  However, although lithium is more directly potentially lethal, it has also been shown to be "anti-suicidal" in many studies; e.g. see the excellent analysis by Baldessarini et al.   In a recent review, only lithium, not antidepressants, clearly reduced risk for suicide^Ernst  On this basis German reviewers suggested lithium prescription rates should be 10 times higher than at present.^{Muller-Oerlinghausen}

Certainly lithium is a "high-maintenance drug".  One must monitor lithium levels, thyroid and renal function, and weight.  Simple dehydration can raise lithium levels (though, interestingly, not via intense exercise, as sweating loses lithium 4 times faster than sodium^Jefferson), and a mere viral infection can cause a dramatic rise in lithium level.^{e.g. Abraham}

But you already use numerous drugs with narrow therapeutic indices, such as coumadin and gentamicin.  So it can't be just therapeutic drug monitoring that's holding you back.  Whatever it is, here are some data that may sway you, followed by some tips on using lithium.

Lithium Augmentation in Major Depression

Here are randomized trial data, presented courtesy of Dr. Michael Bauer, whose 2004 review with colleagues points out  that "...lithium augmentation is the best-documented approach in the treatment of refractory depression":  

(ellipse sizes indicate sample size in each trial, scale at lower right):    

Although it might take a moment to figure out the format of this picture, you can see that the response rates to lithium augmentation are generally around 45%, much higher than the placebo rates (if they were the same, they would lie on the diagonal line).  

In these 9 randomized trials of lithium augmentation in treatment-resistant depression, 4 were negative studies, probably because the sample size was too small to see a difference; because in a meta-analysis of those 9 trials,  Drs. Bauer and Doepfmer found this result:

Per their data, you'll need to treat about 4 patients with lithium to see one clear response in a patient who was otherwise "treatment resistant". 

Tips on Using Lithium as Augmentation in Major Depression

From Dr. Bauer's work:

• Shoot for a level between 0.6 and 0.8 mmol/L [by comparison, for optimal antimanic efficacy we shoot for around 1.0 or even higher sometimes -- JP].  At least 0.5 may be a critical minimum.^Bschor
• Give it at least 2 weeks at this level.
• If it works, continue at least 6 months, and consider 12 months.
• When you stop, taper it very slowly (see my recommendations below). 

Why the long course and slow taper?   Dr. Bauer and colleagues et al found that stopping lithium with a 1-week taper after 8-10 weeks of augmentation led to high relapse rates^Bauer, shown below.  Whether these results were due to stopping lithium after only about 2 months, or the abrupt taper, is not clear (stopping lithium quickly has been shown elsewhere^e.g.Cavanagh to produce this phenomenon). 

From my perspective (a little slower start than his, which follows below):

• Start with 300 mg pills, immediate release lithium carbonate (not slow release).
• Increase by one pill every 3 days, to a dose of 900 mg, less if poorly tolerated.
• Emphasize 600 mg might still help a lot, so continue the highest tolerable dose.
• May take all at night (or a.m.; i.e. a single dose per day is acceptable). 
• Lithium level 5 days after whatever dose the patient achieves; in the a.m. before a.m. lithium, if any ("trough" level). 
• For tremor, switch to slow release (generic is fine) and suggest bid dosing.
• For diarrhea on slow-release, switch back to immediate release and offer propranolol prn for tremor (10 to 40 mg prn or 40-80 LA).

Finally,

• Repeat TSH (you had a baseline, didn't you? of course) at 3 months;  monitor at least once in the interim for hypothyroid symptoms.
• Repeat TSH, lithium level, and creatinine at 6 months and 1 year.
• Tell patients: if you get the flu, and you're throwing up or having diarrhea, don't take lithium until those symptoms stop. 
• When you stop lithium, taper it; decrease by one pill per month (two unipolar patients in Bauer's continuation study relapsed with manic episodes when tapered over 1 week to placebo).  

For an even more rapid start, here are Dr. Bauer's recommendations (minor translations from European units):

*Note that the 450 mg version in the U.S. is a generic slow-release (no immediate release in that dose; watch for diarrhea with the slow-release).