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Editorial

Lithium therapy at the millennium: a

revolutionary drug used for 50 years faces

competing options and possible demise

History

Numerous articles in the scientific literature give historical accounts of lithium’s discovery and devel- opment in psychiatry. As the year 2000 approaches, lithium is still the first-choice drug for treating mania and for prophylaxis of bipolar disorder.

Lithium’s discovery in Australia and its develop-

ment first in Europe and then the US has been most thoroughly researched and is reviewed in F. Neil

Johnson’s classic book The History of Lithium

Therapy (1). Johnson’s account documents the de-

tails of John Cade’s initial discovery, followed by the early and extremely important clinical and

metabolic studies of the Australians, CH Noack and EM Trautner, and Trautner, Morris, Noack and

Gershon (2–4). Later, in 1959, Gershon was to

spend a year’s fellowship in the US and write a

review on the specificity of the lithium ion (5). On a second trip to the US, Gershon eventually joined New York University and began trials published in

1968 comparing lithium to chlorpromazine – thus

providing the Australian–US connection (6). The

spread of lithium from Australia to Europe, with

isolated reports from France, Italy, Czechoslovakia, England, and finally North America, is well

documented.

A major turning point in the history of lithium

occurred in 1954, when Danish researcher Mogens

Schou and colleagues published their first double- blind study of lithium in mania, initiating Schou’s lifelong passionate pursuit of lithium research and teaching (7). Schou personally disseminated the

evolving information on lithium with his prolific

writings and lecturing over the next 40 years, by

travelling from country to country and stimulating thousands of investigators and clinicians on all

continents worldwide. Schou has been the single

most important psychiatrist in the history of lithium therapy, following Cade’s discovery.

The spread of lithium therapy to the US – the

Danish connection

In 1958, at the New York State Psychiatric Institute

(NYSPI) and Columbia Presbyterian Medical Cen-

ter, while still a second-year resident, I was stimu- lated to begin lithium research after discussions with Lawrence Kolb, then Director of the Institute. Kolb had recently returned from a visit with Cade in

Australia, and he encouraged me to begin lithium

trials, knowing of my strong background in internal medicine and my skepticism about continuing in

psychiatry at a time when the psychoanalytic model was so dominant. At that time, Heinrich Waelsch,

Chief of Research in Biochemistry at NYPSI, first

directed my attention to Cade’s and Schou’s work.

Schou had previously (1949–1950) worked as a

Fellow under Waelsch at the NYPSI, and Waelsch

had followed Schou’s work with lithium when he

returned to Denmark, and remained in constant

communication with him, thus providing the

NYPSI–Danish connection.

Simultaneously, Waelsch helped me set up flame

photometry equipment in the laboratory to measure

lithium levels in the blood of lithium patients on the acute ward, where I was a resident, working under

Shervert Frazier. There, I began my first clinical trials administering lithium carbonate to seriously disturbed manic patients, most of whom were failing and straitjacketed on large doses of chlorpromazine. Over the next 5 or 6 years (beginning in 1958), these early studies, which later evolved, with resident

Ralph Wharton, into the use of behavioral ratings

and biochemical indices, including serum lithium

levels, constituted the first systematic lithium re- search trials in the US on acute psychotic manic

patients. The response of these patients on the acute ward to lithium carbonate at therapeutic doses was, I found, remarkable, and paralleled the results

already published by Cade, Schou, and others.

In 1964, George Schlagenhauf, Joseph Tupin, and

Robert White, at the University of Texas, had heard of our lithium trials in New York, but had not yet begun their own. Schlagenhauf phoned me and

asked if they could send up a manic Texas professor to our research unit for a clinical trial on lithium. The professor was working on 20 books and 50

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Editorial

papers simultaneously, talking nonstop, not sleep- ing, with clear-cut manic delusions and wild eupho- ria. He was in a Texas hospital, still uncontrolled despite massive doses of chlorpromazine. I treated the manic professor with lithium carbonate and

after several weeks he calmed down remarkably. I

sent him back to Texas completely stabilized on

lithium carbonate therapy.

In 1965, our trials and those of the Texas group

were presented at the American Psychiatric Associ- ation’s annual meeting, and later both series were published in the American Journal of Psychiatry in 1966 (8, 9). In the 1960s and early 1970s, the

National Institute of Mental Health and a number

of university centers in a multicenter trial led by Robert Prien, as well as individual trials by our

group and a number of other groups in the US and

worldwide continued the expansion of clinical re-

search on lithium. Published reports of large multi- center and smaller carefully controlled lithium trials during this period, as well as laboratory:metabolic research on lithium, took place (10, 11).

At the NYSPI, I was early on able to convince the

New York State Commissioner to set up the first

specially funded lithium clinic in the US, and it

continued as a highly cost-effective method of treat- ing these patients, until closure in 1995. I was also able to acquire private funds to establish a Lithium Foundation for Depression and Manic-Depression

in New York City. Additionally, Lawrence Kolb

and I established a Metabolic Ward at the NYSPI,

modeled after the one I had observed at the Maud-

sley Hospital in London, to study electrolyte

metabolism and behavior in bipolar patients. Subse- quently a newly named Department of Lithium

Studies and Manic Depression was set up at the

NYSPI and Columbia for me to direct.

In 1970, the Lithium Task Force of America

(William Bunney, Irvin Cohen, Jonathan Cole,

Ronald Fieve, Samuel Gershon, Robert Prien, and

Joseph Tupin), after repeated meetings over 2 years, advised the FDA to approve the use of lithium

carbonate for the treatment of mania, and lithium

officially became available in the pharmacy. (In the 1940s, lithium chloride had been used as a dietary salt substitute, but was removed from the market

when it was found to be toxic, causing several deaths in cardiac patients when the need for lithium plasma monitoring was still not well understood.)

The overall impact of lithium at this point was to revolutionize diagnosis and treatment in psychiatry. Since lithium was used to treat patients in 1949,

before chlorpromazine, it was the first drug to truly spark the psychopharmacologic revolution, and it

significantly influenced the development of the Di- agnostic and Statistical Manual (DSM) II through

the DSM-IV. In my psychiatric experience then and

now, lithium is the only medication I know that is a specific treatment for a specific major mental

illness, and it revolutionized psychiatric thinking. Unlike most other psychopharmacologic agents,

lithium seemed to work directly on the core of the illness, whereas phenothiazines worked around the

illness, suppressing it but also causing major side effects.

Specificity

The idea of specificity of the lithium ion for mania has preoccupied clinical researchers over time and has been debated since Cade’s original study. Cade himself believed lithium to be specific for mania, as do Samuel Gershon and myself to this very day. Is

lithium as specific for manic-depression as penicillin is for the streptococcus? Probably not, but it is as specific as many forms of highly selective treatments in medicine. One can ask, ‘‘Is digitalis specific for heart disease?’’ Obviously there are many different cardiac conditions that exist, and a genetic spectrum also exists for manic-depression and most other

illnesses in psychiatry.

Lithium, in my experience, after treating or super- vising the treatment of over 5000 bipolar and unipo- lar patients over 41 years, is very specific in the uncomplicated classic bipolar manic patient, when

the patient is medically well, compliant as to dosage and frequency of blood levels, and it also helps to have a positive family history of mania.

The issues of lithium’s effectiveness in bipolar

depression and its long-term prophylaxis of bipolar illness remain less clear cut and more debatable,

despite many long-term, double-blind controlled

studies that were carried out in the 1970s. To date, there are also insufficient long-term double-blind controlled studies of anti-epileptic drug prophylaxis in bipolar illness, and an insufficient number of

long-term studies comparing lithium to the anti-

epileptics.

However, although lithium is highly specific and

effective in 70–80% of pure bipolar patients who

have all the factors predictive of lithium success

(classic bipolar symptoms, medically well, compli- ant with dosage and blood levels, and family his-

tory), patients may fail because the treating

psychiatrist lacks adequate training.

Inadequate psychiatric residency training in lithium therapy

As important as the ideal profile of the bipolar

patient for a high degree of lithium responsiveness is the ideal training for the psychiatrist administer- 68

Editorial

ing lithium therapy. He or she must have received

expert training during the residency or later from a psychopharmacologist:lithium expert experienced

in treating the acute phases of mania with lithium as a first-line treatment, and in using lithium with: without anti-depressants to treat the acutely de-

pressed phase of bipolar illness. Also, the resident needs to observe long-term therapy with lithium

with:without anti-depressants and with secondary

and alternative use of anti-epileptics in atypical patients and:or benzodiazapines when appropriate.

Adequate training with lithium requires following

bipolar patients for at least 8–12 months, and

preferably more in the residency or thereafter, with weekly and monthly contact with the actual patients and blood chemistries and often the patient’s rela- tives. Most residencies do not provide this essential training to psychiatric residents, and most bipolar patients only have one to two episodes annually.

Learning the clinical subtleties of lithium treatment requires that the psychiatric resident see many pa- tients over long periods of time. Most residents

graduate having seen only a limited number of

bipolar patients for a limited elected period of 2–4 months. Therefore, on graduation they are poorly

equipped and tend to underuse lithium as the first line of treatment. Instead, they begin the new bipo- lar patient on an anti-epileptic, since it is easier to use and requires less knowledge.

Furthermore, anti-epileptics are also marketed

much more vigorously by the pharmaceutical indus-

try than is the non-patentable lithium. Thus, it is not surprising for the inexperienced or inadequately

trained resident to gravitate in the direction of

choosing an anti-epileptic over lithium, even though lithium would most likely prove a superior treat-

ment for that patient. There are fewer risks of

toxicity with anti-epileptics than with lithium, but the price is too often poor results with the patient, and polypharmacy may occur early on.

In such a setting, despite receiving lithium, val- proic acid, carbamazapine, clonazapine, and:or the anti-psychotics, the bipolar patient too often re- mains psychotic, poorly stabilized, or drugged, and the family reports that they are astounded by the

polypharmacy and the patient’s failure within weeks or months to return to normal functioning.

At this point, the family, if not the patient, often seeks a consultant. For years, in an average week I have seen four to six new bipolar patients in consul- tation who have been given smatterings of all the

above drugs for a few weeks to 2 years, by one to

five psychiatrists. The patient and family report that lithium has not been used, or was used for a short time and has not worked. Likewise, the anti-epilep- tics, anti-psychotics, and benzodiazapines also have not worked.

In my estimation, the above scenario today results in 40–50% of bipolar patients being inadequately

treated. If this is the case even in our top university hospitals, then lack of training for psychiatrists in lithium and alternative bipolar therapies in local hospitals and clinics is even more alarming. Perhaps as the year 2000 approaches it is no longer econom- ically feasible to train residents thoroughly in the use of lithium and the proper place for alternative

anti-epileptic and anti-psychotic therapies in treat- ing the bipolar patient.

Lithium therapy in health maintenance

organizations:managed care

From an economic standpoint, the social and finan- cial impact of lithium therapy for manic-depressive illness in the US over the last two decades has been impressive. According to the Pharmaceutical Re-

search and Manufacturers of America 1998 survey,

the use of lithium has saved the US $145 billion since 1979, and has dramatically decreased the suicide

rate, divorce, car accidents, violent acts, and loss of productivity in the workforce and community (12).

However, despite lithium’s obvious benefits, sev-

eral recent papers on the use of lithium in health maintenance organizations (HMOs) (one such study

was carried out at Kaiser–Permanente in Portland,

OR) suggest that a high percentage of HMO psychi-

atrists prescribe lithium sporadically rather than continuously as a maintenance therapy for long-

term prophylaxis (13). HMOs also have large prob-

lems with patient compliance, and the frequent

discontinuation and starting up again of lithium and its alternatives is associated with multiple

hospitalizations.

Lithium is thus not being used cost effectively in our present health care system. The highly cost-ef- fective lithium clinic, a delivery model I and others originated in the 1970s at Columbia-Presbyterian

Medical Center and the NYSPI, is being gradually

phased out in most university hospitals, to be

replaced by the general psychiatric outpatient psy- chopharmacology clinic (14). The Kaiser–Perma-

nente study in an isolated HMO is probably

representative of what is going on in the country, in many hospitals and hallowed university settings,

where lack of proper training accounts for the

haphazard use of lithium, anti-epileptics, anti-psy- chotics, and other drugs.

Anti-epileptics developed to date are indicated for patients who have failed on lithium, or as first-line treatment for atypical, rapid-cycling, schizoaffective forms of bipolar illness. They are also the first choice for patients who on lithium develop serious rash,

allopecia, or may have impaired kidney function.

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Editorial

Anti-epileptics’ present and future development is important, therefore, for the general field of psy- chopharmacology. Currently, studies are in progress with lamotragine, which appears to be particularly beneficial for the depressed phase of bipolar illness, and topiramate, which seems to be the first anti-

epileptic that not only shows promise in bipolar

illness, but is also accompanied by weight loss.

Gabapentin is another effective anti-epileptic

medication, whose potential as a mood stabilizer

is now being examined. Valproic acid and car-

bamazapine, although used by many psychiatrists

for a number of years, have not been rigorously

tested to a sufficient degree to give a final opinion as to how they compare in long-term prophylaxis

for bipolar disorder, or what their antidepressant effect is.

Possible demise of a first-line treatment?

Lithium is, for a large number of patients who are not receiving it, the drug of choice. Ironically, 15 years ago, before the anti-epileptics arrived, there was a brief period when lithium was being over-pre- scribed for patients who diagnostically did not even have mood disorders. The pendulum has now

swung, and anti-epileptics are often incorrectly used as a first-line treatment in the bipolar patient. Due to the rather bleak situation that exists in the proper use of lithium in HMOs, outpatient psychiatric

clinics, and private practice, combined with the

inadequate training of residents, as well as polyphar- macy and the disappearance of the lithium clinic

model, lithium carbonate – this non-patentable

drug – may fall into disuse.

If industry can produce entirely new compounds

that have decided benefits over lithium, then lithi- um’s status as the first-line treatment in bipolar manic-depression will decline. But to date, lithium usage is declining for the wrong reasons. Today, it is very difficult and expensive for industry and:or the National Institute of Mental Health to demonstrate long-term efficacy with proprietary anti-epileptics and other new compounds. Compared to the metic-

ulous prophylactic studies of bipolar illness carried on in the 1970s in our lithium clinic at Columbia and other academic centers, studies lasting up to 4 years, the cost to the pharmaceutical industries today to carry out comparable studies is enormous and

almost prohibitive.

However, lithium carbonate, after 50 years, re-

mains the first-line treatment for most bipolar pa- tients. Hopefully the many spectacular examples of lithium’s success in normalizing bipolar mania,

which so impressed the early investigators in the

1940s throughout the 1970s, and still impress me

when I treat bipolar patients today, will continue to provide enough motivation to psychiatrists to retain lithium as a first-line treatment for most patients with acute mania, and for long-term prophylaxis of bipolar patients.

Ronald R Fieve, MD

Professor of Clinical Psychiatry

Columbia University.

Chief of Psychiatric Research

Manic Depressive Studies

New York State Psychiatric Institute.

Medical Director

Fieve Clinical Services, Inc.

952 Fifth Avenue, Suite 1A

New York, NY 10021

Tel: 1-212-***-****

Fax: 1-212-***-****

Website: www.fieve.com

E-mail: ******@***.***

References

1. Johnson FN. The History of Lithium Therapy. London: Macmillan, 1984.

2. Cade JFJ. Lithium salts in the treatment of psychotic excitement. Med J Aust 1949; 14: 349–352.

3. Noack CH, Trautner EM. Lithium treatment of maniacal psychosis. Med J Aust 1951; 18: 219–222.

4. Trautner EM, Morris R, Noack CH, Gershon S. The excretion and retention of ingested lithium and its effects on the ionic balance of man. Med J Aust 1955; 2: 280–291. 5. Gershon S, Yuwiler A. A specific pharmacological approach to the treatment of mania. J Neuropsych 1960; 1: 229–241. 6. Johnson G, Gershon S, Hekemian L. Controlled evaluation of lithium and chlorpromazine in the treatment of manic states: an interim report. Comprehen Psychiatry 1968; 9 (6): 563–573.

7. Schou M, Juel-Neielsen N, Stromgren E, Voldby H. The treatment of manic psychoses by the administration of lithium salts. J Neurol Neurosurg Psychiatry 1954; 17: 250–260.

8. Wharton R, Fieve R. The use of lithium and affective psychoses. Am J Psychiatry 1966; 123 (6): 706–712. 9. Schlagenhauf C, Tupin J, White RB. The use of lithium carbonate in the treatment of manic psychosis. Am J Psychiatry 1966; 123: 201–206.

10. Fieve RR, Platman SR, Plutchik RR. The use of lithium in affective disorders: I. Acute endogenous depression. Am J Psychiatry 1968; 125: 487–491.

11. Prien RF, Daffey EM, Klett CJ. Comparison of lithium carbonate and chlorpromazine in the treatment of mania. Arch Gen Psychiatry 1972; 26: 146–153.

12. Pharmaceutical Research and Manufacturers of America. 1998 Survey: New Medicines in Development. 1100 15th Street NW, Washington DC 20005.

13. Johnson RE, McFarland BH. Lithium discontinuation in a health maintenance organization. Am J Psychiatry 1996; 153

(8): 993–1000.

14. Fieve R. The lithium clinic: a new model for the delivery of psychiatric services. Am J Psychiatry 1975; 132 (10): 1018– 1022.

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