Lithium for Bipolar I and II:  Part Two



This is section is from my first book “An Insider’s View of Bipolar Disease.” It is fact base and referenced.

Lithium is the primary drug used in the treatment of Bipolar Disease (BPD), although new drugs are made available all the time. Lithium is the first in a class of drugs known as Mood Stabilizers. Mood stabilizers lengthen the interval between episodes of mania and depression, and maintain the patient in a normal (euthymic) state.

The mechanism of action Lithium has an interesting history. In the 19th century, it was discovered that water from certain mineral springs in Texas, when ingested, caused improvement in manic patients. These “crazy waters” contained high levels of lithium carbonate. (Fowler, G. Crazy Water: The Story of Mineral Wells and Other Texas Health Resorts. Fort Worth: Texas Christian University Press: 1991)

In 1847 a British physician, Alfred Garrod, discovered that uric acid was present in excess in patients with gout or gout kidney stones. To dilute the urine, Garrod used lithium. (Garrod, AB. The Nature and Treatment of Gout and Rheumatic Gout. London: Walton: 1859).

The modern use of lithium to treat mania can be pinpointed to 1949 when John Cade, reviewing Garrod’s work, felt that uric acid had a connection to mania and started using lithium carbonate and lithium citrate on 46 manic patients. He had remarkable success, with some patients being able to be discharged from institutions after years of unsuccessful treatment. (Cade, J., et al, Lithium salts in the treatment of psychotic excitement. Med J Aust. 1949; 2:349-352).

Many case reports of success in many countries led to the use of lithium carbonate for the mania aspect of bipolar disease. By 1954 studies showed equal efficacy to ECT with the mere prophylactic use of a pill.

The administration was tricky until blood levels could be measured, which was achieved in 1958. (National Institutes of Health. Office of NIH history. Laboratory instructions Collection. Museum of Medical Research, October 2006).

Lithium’s use in the U.S. was slow to take on but by the late 1960’s, as blood levels could be easily measured, it became the treatment of choice for prevention and treatment of the manic side of bipolar disease as a ‘mood stabilizer.’ (See my article on Eugene O’Neill 1956)

Lithium’s side-effects include tremor, uncommon cardiac arrhythmia, thyroid dysfunction and renal insufficiency over many years if kidney function is not monitored. The latter will be discussed in length and in fact is a main reason for this article.

The importance of frequent blood level checks cannot be overstated as the difference between a therapeutic versus toxic level is very small. (Canada, final publication PubMedCentral, Bipolar disorder Jun 2009; 11 Supp. 2:4-9)

The mechanism of action in Lithium remains elusive. It seems to affect various parts of the central nervous system neurons. An enzyme inhibited by lithium is involved restoring the body’s clock known as circadian rhythm and Lithium can also raise serotonin levels. (Rao, JS et al; Mol. Psychiatry 13 (6)585-596). Now it has been shown that Lithium prevents swings in both directions, manic and depressive.

Renal Insufficiency

The reason for this article is largely due to a statement at this year’s California NAMI conference held in Monterrey. One of the speakers, a nephrologist, made a statement that has been very distressing to “consumers” on lithium for bipolar disease. The statement was that inevitably lithium will cause loss of kidney function over ten to twenty years. The angst created from this erroneous suggestion has led to many folks on lithium to contact me to allay their fears.

I will digress here to relate a nugget of my personal story regarding lithium. I was diagnosed with major depression disease (MDD) in 1973 during medical school when I had my first depression which was associated with psychosis.

Luckily, this occurred at Washington University School of Medicine in St. Louis. After many weeks before I sought care and several weeks after outpatient medication trials, I had a psychotic break and ended up at Renard Hospital the psychiatric hospital of Barnes Hospital at the medical school.

As the old medications were mostly ineffective I was magically put in remission by electroconvulsant therapy (ECT). After three treatments I was back to Paul. I had four more as an outpatient and then back to my hospital rotations.

Three years later while in my second year of internal medicine residency in San Francisco I recognized another depression coming on. Another two weeks later I abruptly left outpatient cardiology clinic at SFGH and flew back to St. Louis.

Seven treatments later I was back in San Fran. It was not until 1988 that I had my first obvious manic episode after starting my practice in Modesto, California in 1979. My psychiatrist here in Modesto already me on Zoloft for MDD. Retrospectively, I had had small episodes of hypomania going back to college.

Lithium was the magic bullet for me from 1988 to 2013. My psychiatrist here in Modesto, my internist and I all knew to follow my Creatinine on a yearly panel.

When over six months my Cr began rising from 1.1 slowly to 1.6 we stopped the Lithium and started Lamictal. The Cr returned to 1.2 over several months and now it runs 1.2.

With that background I am going to present fact based material about the REVERSABLE effect of Lithium on kidney function. I will drawing mostly from Redford and Goodwin’s second edition, Manic – Depressive Illness: Bipolar Disorders and Recurrent Depression, Oxford Press, 2007.

In the U.S. in the 90s Depakote became the primary mood stabilizer used in the U.S. The authors believe, since this is not the case in other developed countries, that this was due to the intense marketing of this drug by the original manufacturer (virtually impossible to determine since generics released) which has huge profit compared to lithium carbonate. The main, and fatal, side effect of Depakote combined with Lamictal (Stevens-Johnson’s rash).

This discussion relates to maintenance therapy for BPD not acute crisis in which IM Haldol or IM new age atypicals such as Risperdal, Zyprexa and Geodon. A new atypical, Invega has been released in a long acting IM preparation.

The recommendation by the authors in the first edition, 1999) and now are the mood stabilizer of choice for maintenance therapy is lithium carbonate.

“Continuation Treatment and the Transition to Maintenance Therapy.”

The authors state — “With careful monitoring of the therapeutic benefits as well as the side effects of treatment, titration of the lithium, anticonvulsant, or antipsychotic along with a gradual decrease in the dose of any typical antipsychotic medication can be substantially accompanied with 1-2 weeks of initiation of treatment. By the third week, some patients can be maintained on lithium and anticonvulsant or an atypical antipsychotic alone.”

“As detailed in the first edition of this volume, early placebo-controlled studies established lithium as effective, although not rapidly acting, treatment of choice for mania. Many of these studies varied as to dosage, serum levels and rapidity of dosage titration, making it difficult to establish the precise time to onset or lithium’s antimanic action.”

Newer studies of treatment of acute manic crisis with rapid titration of lithium plus IM Ativan were as effective as IM Haldol plus or the three new atypicals IM.

Then and now treatment is based on the blood level of lithium not the dose. Maintenance blood levels should be kept in the 0.6-0.8 mEq/L level.

The largest number of studies showed equal efficacy of lithium and Depakote. Although many psychiatrists have tried maintenance of BPD with an atypical antipsychotic this has not been shown to as effective as lithium combined with the newer anticonvulsants (Depakote or Lamictal) plus an oral atypical antipsychotic.

As far as electroconvulsant therapy (ECT) this has not been shown to be more effective than medications for treatment of bipolar mania. This is not the case for ECT and bipolar depression. Treatment refractory bipolar depression or MDD is best treated by ECT.

(Note that in the first edition the only available medications for either BPD, bipolar depression or bipolar mania were tricyclics, Wellbutrin, lithium, MAO inhibitors and ECT.”)

The issue of adding an antidepressant to the maintenance therapy discussed above is controversial. In general avoidance is the rule. However, if major depression is the more severe manifestation in an individual patient with BPD addition of a low dose antidepressant such as SSRI or SNRI is appropriate while watching for early signs of mania

As far as renal function and lithium: “As the long-term effects of lithium on the kidney have become clearer, earlier concerns about its nephrotoxicity have eased significantly. While the risk of reduced glomerular function with lithium appears to be very low, a small number of patients appear to develop glomerular and tubulointerstitial nephropathy that can progress to renal insufficiency and be irreversible if not detected early enough. It appears that in this small group of vulnerable patients, lithium interacts with other medical condition (e.g., hypertension) or familial or environmental problems to cause progressive renal failure. In a review of such cases, the reversibility of renal insufficiency after discontinuation of lithium appeared to be associated with serum creatinine levels lower than 2.5 mg/dl further highlighting the need for monitoring of renal function in patients taking lithium.

Creatinine clearance determinations are no longer recommended for routine monitoring; obtaining serum creatinine determinations every 3 to 12 months, depending on such factors as age and general medical conditions, is reasonable. Patients who have serum creatinine levels consistently greater than 1.6 mg/dl (or whose level is 25% or more above the pretreatment baseline) should be referred for medical evaluation, which should start with a creatinine clearance determination. The more common lithium associated renal problem is nephrogenic diabetes insipidus (reflected in “creeping creatinine”), seen in about 20 percent of those taking lithium for 15 to 20 years or longer which is caused by lithium-induced reductions in the capacity of the distal tubules to reabsorb electrolytes. This condition is accompanied by a mild but significant decrease in urine-concentrating ability, which has been demonstrated in most (though not all) longitudinal studies of lithium’s effect on the kidney. …More recent longitudinal studies have not found a progressive decrease over time, however, suggesting that there is a decrease in urine-concentrating ability during the first few years of lithium treatment and little or no further progression in ensuing decades.” (N.B the need to stay hydrated particularly if on diuretics or from dehydration due to gastroenteritis or other acute illnesses.)

The nephrologist should periodically ask about polyuria or excessive urination particularly noticeable at night.

Written by paul