Sunday, January 14, 2018

Lithium for Depression.....

I bought a copy of Manic Depressive Illness when it first came out in 1990.  One of the more interesting aspects of the book was the commentary on the use of lithium monotherapy for unipolar depression.  That discussion is limited to about three pages and reviewed the work to date.  In the opening paragraph there is this astonishing line:  "Overall, the result of open studies suggest that lithium is as effective in preventing unipolar illness as it is in preventing bipolar illness."  At the time there were 4 controlled studies (3-6) looking at the issue of maintenance therapy in mixed unipolar and bipolar groups.  Three of the four studies showed no difference between groups.  The fourth study was inconlusive due to a high dropout rate.  Subsequent analyses by Schou and Baldessarini and Tohen concluded that the protective effects of lithium in preventing recurrent depressive episodes was good.  In Schou's reanalysis he showed that the relapse rate in one year on lithium for unipolar depression was 22% (compared with a 20% relapse rate for bipolar disorder) and the rates for antidepressants at one year were 35% for unipolar depression and 65% for bipolar disorder (relative to placebo of 67-68% relapse rate).

Since that early open research there has been only randomized controlled clinical trial (RCT) of lithium versus placebo antidepressant augmentation (7).  In that study 7/15 patients treated with placebo relapsed and one suicided.  In the lithium treated group 0/14 relapsed.  The authors recommended that patients who respond to lithium augmentation be maintained on it for at least 6 months.  Additional clinical parameters of interest in the treated group was an average lithium dose of 980 mg, an average Li level of 0.65 mmol/L, and a response time of 17.5 days in acute treatment.  This is interesting because many psychiatrists using lithium augmentation were taught to stop at 600 mg/day and accept the associated lower levels.

My point in the introductory paragraph here is that it has been known for some time that lithium may have a role in maintenance of unipolar depression in addition to bipolar depression - even though it is hardly ever used that way int he United States.  In the US, patients typically endure a long series of antidepressant trials or augmentation strategies if the initial trails are ineffective.  There is always the problems of whether the antidepressant has lost its effect or not and the associated difficulty of trying to determine what other factors may be operative.  Lithium has been used for the past three decades as an augmenting agent - added to antidepressants.  Typically a lower dose is used (600 mg/day) and that may offer a lower chance of toxicity and less need for monitoring blood levels.

Against this backdrop, a very interesting paper by Tiihonen, et al came out last year (2). For reasons that will follow, I consider this to be one of the most important papers for clinical psychiatrists from 2017.  The authors provide a sound rationale for their study, specifically the advantages of a large scale epidemiological/observational study over an RCT or the Cochrane meta-analysis of RCTs.  That meta-analysis (like most Cochrane meta-analyses) concluded that the number of subjects included was too small to come to a statistically significant conclusion.

The study was conducted in Finland.  The authors point out that each citizen has a unique identifier that facilitates the design of large inclusive observational studies across health care databases.  The sample in this case was a study cohort (N= 123,712) of patients who had been admitted to a hospital for unipolar depression between January 1, 1987 and December 31, 2012.  They had a comparison incident cohort (N=30004) that looked at new patients beginning on December 31, 1996 with no mental health diagnosis, hospital admissions for depression, exposure to the medications of interest, or history of outpatient care in the year prior to the start.  The purpose of the incident cohort was to look at the issue of survival bias. The primary outcome measure was risk of readmission in all patients admitted  for unipolar depression at least once between 1987 and 2012.  All cause admissions were a secondary outcome measure.  Medication use was estimated using the PRE2DUP mathematical modelling of the patient medication purchasing.  Each patient was used as their own control to eliminate selection bias.  I did not have access to the appendices from this study, so I will forgo further discussion of the statistical methodology without that data.

Mean hospitalizations for people who had used lithium was 4.3 (SD 6.9) for psychiatric admission and 7.8 (SD 9.1) for all cause admissions compared to 2.2(SD 3.1) and 5.8(SD 7.0) for those who had not indicating the lithium treated patient were more severely ill.  Using lithium significantly decreased the relapse risk.  Mean daily lithium dose was noted to be 765 mg.  Forest plots are contained in the body of the article looking at the hazard rations of readmission for several pharmacological treatments in both the study cohort and the incident cohort.  Forest plots looked at benzodiazepines, hypnotics, antipsychotics, and lithium +/- antidepressants.

Lithium monotherapy was superior to all other studied pharmacotherapies in preventing hospital readmissions.  Older antidepressants (amitriptyline and doxepin) and antipsychotics (clozapine sulpride, aripiprazole, and quetiapine) showed some efficacy in preventing hosptializations.  Benzodiazepines did not.  In the incident cohort where (survival bias was eliminated) the lithium effect on decreased rehospitalizations was more robust suggesting the effect size was more valid than for the total cohort.  They also did a secondary mortality assessment and showed that both lithium and antidepressants were associated with decreased overall mortality and no difference was observed for antipsychotics.

The authors recognize that there are significant adverse effects and limitations with the use of lithium.  They point out there are also possible advantages outside the treatment of mood disorders but there is a significant burden associated with taking it.  They recommend that is be considered for maintenance of a broader group of patients with unipolar depression.  In our antidepressant-centric society, I agree with their conclusion.  The effects in this study really cannot be ignored.  Lithium augmentation of antidepressants has been around for over 30 years.  It surfaced again the the STAR*D protocol.  I see patients who have been exclusively been treated by other physicians or prescribers and in the past 8 years I have seen exactly 1 patient with unipolar depression who was being treated with lithium augmentation.  It is far more common to see patient taking 2-4 antidepressants (typically SSRI + bupropion + trazodone or mirtazapine) or an antidepressant plus lamotrigine as the augmentation strategy.  A similar study with a cohort of American patients would be very useful to look at questions about the efficacy of lithium versus the antidepressant polypharmacy or lamotrigine - but my concern would be that there would not be a large enough sample of patients taking lithium.

It may be up to clinicians who are used to lithium therapy and the application to unipolar depression to reintroduce the practice and collect data on what the outcomes are relative to standard antidepressant augmentation strategies. Overall this study from a group of pharmacoepidemiologists provides compelling data to take a second look at an old strategy instead of just adding more antidepressants.  The data looks so good, lithium is so inexpensive, and in the USA we are in an absolute vacuum of lithium non-use for unipolar depression.   Inpatient treatment for depression has become so atrocious that it has never been more important to help people stay out of the hospital. That is why I considered this to be an important paper. 

George Dawson, MD, DFAPA



1:   Goodwin, FK, Jamison, KR. Manic-depressive illness. New York: Oxford University Press, 1990: pp.693-696.

2: Tiihonen J, Tanskanen A, Hoti F, Vattulainen P, Taipale H, Mehtälä J,Lähteenvuo M. Pharmacological treatments and risk of readmission to hospital for unipolar depression in Finland: a nationwide cohort study. Lancet Psychiatry. 2017 Jul;4(7):547-553. doi: 10.1016/S2215-0366(17)30134-7. Epub 2017 Jun 1. PubMed PMID: 28578901.

3: Prien RF, Klett CJ, Caffey EM Jr. Lithium carbonate and imipramine inprevention of affective episodes. A comparison in recurrent affective illness. Arch Gen Psychiatry. 1973 Sep;29(3):420-5. PubMed PMID: 4579507.

4: Prien RF, Caffey EM Jr, Klett CJ. Prophylactic efficacy of lithium carbonate in manic-depressive illness. Report of the Veterans Administration and National Institute of Mental Health collaborative study group. Arch Gen Psychiatry. 1973 Mar;28(3):337-41. PubMed PMID: 4569674.

5: Coppen A, Noguera R, Bailey J, Burns BH, Swani MS, Hare EH, Gardner R, MaggsR. Prophylactic lithium in affective disorders. Controlled trial. Lancet. 1971 Aug 7;2(7719):275-9. PubMed PMID: 4104974.

6: Baastrup PC, Poulsen JC, Schou M, Thomsen K, Amdisen A. Prophylactic lithium: double blind discontinuation in manic-depressive and recurrent-depressive disorders. Lancet. 1970 Aug 15;2(7668):326-30. PubMed PMID: 4194439.

7: Bauer M, Bschor T, Kunz D, Berghöfer A, Ströhle A, Müller-Oerlinghausen B.Double-blind, placebo-controlled trial of the use of lithium to augment antidepressant medication in continuation treatment of unipolar major depression. Am J Psychiatry. 2000 Sep;157(9):1429-35. PubMed PMID: 10964859.


Figure 1 above is directly from reference 2 with permission from Elsevier.  Licensing agreement #4270040486127.


  1. Key publications in this story were your references 5 and 6. The Coppen study (5) was very persuasive. It was done prospectively on the heels of the Baastrup discontinuation study (6), which in turn was spurred by the misguided critiques of Blackwell and Shepherd (who had never treated a single patient with Li). The US studies done in the early 1970s (3,4) came from the Psychopharmacology Research Branch within NIMH. Sadly, that exemplary unit was terminated in the late 1980s, and no corporate entity had any interest in pursuing, much less promoting, the effectiveness of Li in both recurrent unipolar and bipolar affective disorders.

    1. Barney,

      Thanks for the commentary from the research side at the time.

      I remember the Psychopharmacology Research Branch and recall attending one of their conferences a couple of years before it was terminated. Your point about the lack of commercial support is well taken. There seems to be no end to the combinatorics of medications that are soon off patent or in a generic form that still has pricing power.

    2. Dr. Carroll, glad I found you here, I have not conversed with you on a BB since Mickey's unfortunate passing. Sorry for the off topic nature of this post but Dr. Carroll understands inflammation and psych more than just about anyone.

      I saw your recent Twitter comment on biomarkers and was wondering if you thought any were ready for prime time, meaning practical clinical application in depression short of melancholia which is most of the depression I see. Specifically I am wondering about CRP and IL-6 although I realize they are not specific. Even if not markers for disease itself, are these useful baseline markers that would document clinical response?

      I'm increasingly convinced of an inflammatory/epigenetic/glucose-related subtype and the role of cytokines. I simply can't ignore the fact that small d depression seems to have massively exploded at the same time that metabolic syndrome did (1980) and when people went from eating 20 lbs of sugar a year to their own body weight in sugar. Doubtless some of this is due to the nosology mischief of DSM but it appears that within the depressive spectrum we are seeing less pure melancholia and more small d disorder.

      Also, the fact that interferon notoriously leads to depression seems to provide strong evidence of an inflammatory process.

      Diet, exercise and psychotherapy seem to be as effective in mild to moderate cases as SSRI/SNRI drugs so isn't it time for a major paradigm reassessment?

      Also interested in any comments on Vitamin D screening (deficiencies appear to be high in psych populations) and the role of keto diet and/or intermittent fasting. My own N=1 experiments with intermittent fasting (I've gone up to 5 days on bone broth and coffee) and keto completely eliminated my 2 PM fatigue so it stands to reason that interventions that improve alertness would have to affect mood and energy level in general. I was never depressed when I did this but I have to admit caloric restriction (protein matters too because of mTOR expression), particularly carbs has a really positive effect on physical and mental energy level, which makes sense when you think about the role of BDNF.

  2. As much as Lithium is probably the only real "mood stabilizer" medication to fit that term, I still don't see many patients really having sustained avoidance of depressive episodes who are truly Bipolar patients. That is 25 years of providing care mostly in Community Mental Health Clinics making this observation. But, I have seen a few. Still have not met a person who has true Bipolar disorder, that being presentations of mania and depression in the patient's history, who have had sustained stability just on an antiseizure med like Depakote, tegretol, or other similar medication.

    Oh, and it is a shame the word Bipolar has been so dumbed down these past 15 or more years just to give false validation to overmedicate with antipsychotics. Psychiatry is to blame for this egregious failure. To this day, antipsychotics to treat primary mood disorders should be tapered to an effort to discontinue, slowly and per stability in psychosocial matters mind you, but, never to maintain at high dosages for years.

    Sorry, I look forward to reading of colleagues successfully sued for negligence, malfeasance, and sheer incompetence to leave patients on high dosages of meds like Seroquel, Zyprexa, Rispderal, even Abilify, that have overt consequences. Why give flagrant ammunition to anti-psychiatry zealots who hit the random chance right moment in their criticism of the over prescribing of these medications for alleged indications well outside their intended mark when seeking FDA approval?

    So much for alleged gold in them their hills, colleagues! Fools gold, and then taken by lawyers who's agenda isn't much better than careless colleagues, hmm???

    Joel Hassman, MD

    1. James O'Brien, M.D.January 20, 2018 at 9:07 AM

      The traction of the newer epilepsy drugs and SGAs over Lithium is a matter of financial incentive over clinical efficacy. There's not a lot of interest in Lithium now because there's no money to be made from it. I'm with you on the SGA for bipolar issue...for all the supposed interest in neuroprotection, why give neurotoxic drugs over something that is truly neuroprotective?

      I go by a general rule in life...if a therapeutic option that makes someone a lot of money is marginally better or equal to an option that doesn't, the second option probably is in fact a lot better. This is why intermittent fasting or portion control works better than expensive diet programs although the latter claims to be better. Once one develops this insight into what's motivating therapies, your options in life both as a patient and clinician become a lot cheaper and more effective.

    2. I generally agree - but given the diagnostic uncertainty involved and my experience acknowledge that there are many exceptions. The best example I can think of is people who were stabilized in state hospitals on very early APs like chlorpromazine, who probably had good prognosis bipolar disorder and were part of the first wave of discharged patients.

      I have personally seen unsuccessful efforts to get them off of the CPZ and onto lithium that failed. They were put back on the CPZ and did very well again.

      In order to be certain that we are applying the correct treatment - we need a lot more diagnostic certainty than the DSM indexing system. I expect that one day we will be able to know ahead of time who will be respond to which medication.

      The current way around that is to prescribe the best treatment early in the course and not lose sight of it. I see that as the major current problem and I see it frequently.

    3. Actually, and I have hesitation writing this, but, the alleged Bipolars who have equal Axis 2 qualities per the irritability and role of some anxiety or PTSD to their lability, I have found LOW doses of clonazepam ALONG with an antimanic med like Lithium or low dose Depakote have achieved some if not much stability, BUT along with consistent ongoing psychotherapy.

      Never will know how much the therapy is impacting, but if I have the luxury of working with said patients for more than 9 mos (remember much of my professional life of late has been as a temp for avg of 4 mos an assignment since 2010), and the patient stays at dosages of less than 2mg a day of clonazepam, a taper leads to more function and insight.

      Yeah, the few times benzos really have a place. This from a clinician who basically hates this drug class, especially alprazoloam and diazepam. By the way , who the hell writes for diazepam in 2018???

      Joel Hassman, MD

  3. I have also treated skewed samples like the one that you describe and have actually seen it happen in my family. My mother had severe bipolar disorder that was progressively destabilized by years of treatment by primary care physicians giving her (in those days) tricyclic antidepressants and benzodiazepines. The severity of manic episodes as well as the frequency of those spells increased dramatically with that treatment. By the time she saw a psychiatrist and was put on lithium it was probably too late to alter the course of chronic illness. Even then she still came back under the care of physicians who treated her with antidepressants and antipsychotics. I was called at one point because she "couldn't talk she could only whisper." I talked to her on the phone and she clearly had hypophonic dysarthria from haloperidol. The last years of her life were well into the atypical era and I called her physician and asked why haloperidol was being used and of course why this complication was not diagnosed. My mother and the entire history of my family would have been different with more informed treatment of bipolar disorder.

    I have seen that pattern repeated time and time again. Young women who I treated for post partum bipolar disorder with psychosis and stabilized on lithium - continuously destabilized and readmitted to the point that they were rediagnosed as schizoaffective disorder and treated with antipsychotics and antidepressants. When they were readmitted to my service, I would change the diagnosis, restabilize them, reeducate them and their family about the illness and what needed to be done.

    It can be a frustrating process. If I had the time to start over, I would run my own specialty clinic and treat these problems the way they need to be treated. That is consistently, over time, and never losing sight of the fact that if you don't do things the right way - somebody's life may be ruined. Too many people think psychiatry is easy.

  4. Great post - lithium is definitely underrated these days. I think the research of lithium in unipolar depression should extend to cover questions about antidepressant treatment emergent bipolarity. There are patients that get such a bad reaction to their first 1 or 2 antidepressants (such as increased agitation, restlessness, disinhibition) that you wonder about bipolar disorder but it never really reaches a level severe enough to hang your hat on it.. and by then the drug has been swiftly discontinued anyway, so who knows. Lithium would be a good choice in these patients, I suspect, but there is no literature on it...

  5. Thanks Victor - agree the research on people who do not tolerate antidepressants is weak.

    For a while there was a bipolar 3 designation that indicated antidepressant induced mania. That diagnosis fell out of favor because the DSM committee decided there was not much evidence to say this was a unique phenomenon versus undiagnosed bipolar patients presenting initially with depression.

    I think about 1/6 patients has a difficult time with SSRIs, but that seems largely due to serotonergic effects to me. Lithium does have serotonergic effects and I have diagnosed at least one case of serotonin syndrome in a bipolar patient who was acutely admitted to a hospital and restarted a the full maintenance dose of lithium that he was taking. I warn patient on SSRI that serotonin syndrome is a possibility.

    It is also interesting that there are a subgroup of patients with agitation, anger, and in some cases overt aggression that respond to SSRIs. Figuring out this dimension and whether there is any bipolar diathesis can be very difficult at time.

    Lithium can also have a paradoxical effect and cause agitation in some patients, but it is rarer than occurs with antidepressants.