Thomas A.Ban, editor. Lithium in Psychiatry in Historical Perspective.


William E. Bunney Jr’s comments

Contributions to Psychiatry Research with Lithium



        In 1871 William Hammond, Professor of Diseases of the Mind and Nervous System at the Bellevue Hospital Medical College in New York, became the first physician to prescribe lithium for mania.  In 1894 Danish psychiatrist Frederick Lange used lithium in the treatment of depression. 

        However, lithium was not referred to until 1949 when John Cade from Melbourne successfully treated manic patients.  In 1951 C. H. Noack, also in Melbourne, conducted an open trial of over 100 patients in the treatment of mania.  In 1952 Danish psychiatrist Mogens Schou conducted a randomly controlled trial of lithium in mania and published the results in 1954.  He showed that many patients could be kept in a normal state by administration of a maintenance dose.  In the United States the use of lithium was studied in the 1960s;  Samuel Gershon published the first paper on the use of lithium and the treatment of mania.  In 1962 George Winokur utilized lithium in the treatment of mania at Barnes Hospital, St. Louis. 

        I became actively involved with Fred Goodwin, John Davis and Jan Fawcett at the Intramural Program of the NIMH in clinical trials of lithium in mania and depression and published more than 20 papers investigating the mode of action of lithium over the next two decades (two of these papers were published in Science and two were published in Nature.

        In the mid-1960s, while I was still at the Intramural Program of the NIMH, along with Ron Fieve at New York Columbia Presbyterian Medical Center, we initiated studies using lithium in manic-depressive illness.  In 1968 Fred Goodwin and I conducted a longitudinal double-blind study of two manic patients treated in a random fashion with lithium carbonate and placebo. Daily ratings of mania were recorded independently by a trained psychiatric nursing team and by a psychiatrist. The major finding was a definite increase in mania, reflected in the daily ratings, during placebo periods within 24 hours of the withdrawal of lithium.  Placebo was substituted for lithium on five occasions, resulting in a rapid increase in mania.  Then lithium was administered and there was a complete decrease in manic symptomatology.  This publication on the double-blind consistency of the repeated relapses of manic symptoms on placebo and the subsequent therapeutic response on lithium, along with the research of Gershon and Fieve, helped convince many clinicians and researchers in the United States of the efficacy of lithium in the treatment of mania (Bunney WE Jr, Goodwin FK, Davis JM, Fawcett JA. A behavioral-biochemical study of lithium treatment. Am J Psychiatry. 1968; 125:91-104).


Published Papers on the Clinical Use of Lithium in the Treatment of Mania and Depression, and Studies of the Mechanisms of Action of Lithium


1. Colburn RW, Goodwin FK, Bunney WE Jr, Davis JM. Effect of lithium on the uptake of noradrenaline by synaptosomes. Nature 1967; 215:1395-8. 

The effect of lithium on NE is several-fold.  We demonstrated that acute lithium treatment increases labeled NE update by rat brain synaptosomes.

2. Greenspan K, Goodwin FK, Bunney WE Jr, Durell J. Lithium ion retention and distribution. Patterns during acute mania and normothymia. Arch Gen Psychiatry. 1968; 19:664-73.  

Unlike the phenothiazines, Lithium is believed to control the mood state at plasma levels which do not cause general sedation, and which have virtually no subjective effects in normal subjects. This high degree of specificity suggests that lithium salts will prove to be important pharmacological tools for the study of the pathophysiology of manic-depressive disorders.  We embarked on studies of the mechanism of action of the lithium salts, and confirmed that acutely manic patients retain more lithium ion than normal subjects.

3. Goodwin FK, Murphy DL, Bunney WE Jr. Lithium-carbonate treatment in depression and mania. A longitudinal double-blind study. Arch Gen Psychiatry. 1969; 21:486-96.  

This paper presented the clinical results of an intensive longitudinal double-blind study in 30 manic-depressive and depressed patients.  The therapeutic use of lithium-carbonate in affective disorders has recently been the focus of considerable interest, particularly in light of clinical evidence that it may have beneficial effects not only in mania but also in some cases of depression. We showed that the unique feature of this drug in these patients demonstrates long-term mood-stabilizing properties when used prophylactically.

4. Murphy DL, Goodwin FK, Bunney WE Jr. Aldosterone and sodium response to lithium administration in man. Lancet. 1969; 2:458-61.  

Administration of lithium carbonate to 16 manic-depressive and depressed patients was found to lead to an initial 1-2 days of sodium and water diuresis. In the subsequent 4-5-day period of treatment, sodium retention associated with a 50% increase in aldosterone excretion occurred.  In the next several days there was a return towards pre-lithium levels. These changes occurred in all patients and were apparently not related to the initial clinical state of the patient nor the presence or absence of symptomatic improvement with lithium.

5. Murphy DL, Colburn RW, Davis JM, Bunney WE Jr. Stimulation by lithium of monoamine uptake in human platelets. Life Sciences. 1969; 8:1187-93.

Blood platelets share with monoamine-containing nerve endings from brain and peripheral organs the capacity to transport and store serotonin. In vitro, platelets concentrate serotonin up to 1000-fold from the incubation medium. The amine concentrating mechanism in both platelets and nerve endings depends on metabolism, exhibits saturation kinetics, and is inhibited by ouabain and other drugs including the tricyclic antidepressants. In addition, there are morphological similarities between platelets and nerve endings in that they both contain amine storage vesicles and mitochondria enclosed within a limiting membrane. Pretreatment with lithium was found to increase the uptake of noradrenaline into nerve endings (synaptosomes) isolated from rat brain.  In the present study platelets obtained from manic-depressive patients receiving lithium showed a similar increase of monoamine uptake.

6. Murphy DL, Colburn RW, Davis JM, Bunney WE Jr. Imipramine and lithium effects on biogenic amine transport in depressed and manic-depressed patients. Am. J. Psychiatry 1970; 127:339-45.

It is often risky to extrapolate to man the results of animal studies on the mechanism of action of psychoactive drugs. In this study, platelets obtained from patients before and during treatment with imipramine and lithium were used to determine whether the effects of these drugs suggested by animal studies to be involved in cell membrane transport could be identified in these human cells. Imipramine was found to inhibit and lithium to stimulate amine transport in platelets. confirming that the cellular effects of these drugs in man are similar to their effects on brain cells from animals.

7. Murphy DL, Goodwin FK, Bunney WE Jr. Leukocytosis during lithium treatment. Am J Psychiatry. 1971; 127:1559-61.

An increase in circulating leukocytes accompanied lithium treatment in 28 consecutively studied manic-depressive patients. Acutely manic patients showed the most marked changes and maintained leukocyte counts of 10,000 to 14,000 during the first two to four weeks of lithium administration. Leukocyte counts returned to pre-lithium levels within one week after discontinuation of the drug. In 11 patients receiving lithium for longer periods the elevation in white cell count persisted throughout treatment.

8. Murphy DL, Bunney WE Jr. Total body potassium changes during lithium treatment. J Nerv Ment Dis. 1971; 152:381-9.

Total body potassium decreased after 2 weeks of lithium administration in 12 of 13 depressed patients but increased in 6 of 7 manic patients treated with lithium under identical conditions. These opposite changes were statistically significant for each group of patients. In a smaller group of depressed patients followed for longer periods during lithium treatment, the potassium levels returned to pre-lithium values. The dependence of the direction of potassium change on the clinical state of the patient may be related to some previously described differences between manic and depressed patients and also to differences in the therapeutic response to lithium between the two groups.

9. Goodwin FK, Murphy DL, Dunner DL, Bunney WE Jr. Lithium response in unipolar versus bipolar depression. Am. J. Psychiatry. 1972; 129:44-7.

The antidepressant effects of lithium carbonate were evaluated in a group of 52 hospitalized depressed patients, using a longitudinal double-blind design that involved alternating drug and placebo periods in the same patient. Thirty-six of the 52 patients showed some improvement on lithium, including 15 who had complete remission of symptoms. Virtually all of the antidepressant responses occurred in patients with a past history of mania or hypomania.

10. Bunney WE Jr, Murphy DL. Neurobiological considerations on the mode of action of lithium carbonate in the treatment of affective disorders. Pharmakopsychiatr Neuropsychopharmakol. 1976; 9:142-7.

The effects of lithium on membrane function and cellular processes are considered in relation to lithium's physiochemical properties. Several cellular regulatory functions, including cyclic AMP formation and metabolism and biogenic amine neurotransmitter metabolism, are examined as possible mechanisms whereby lithium might exert its mood stabilizing actions. The necessity for understanding lithium's interactions with "receptors" - the molecular sites affected by lithium - in considering its pre-and post-synaptic effects in stressed.

11. Jasinsky DR, Nutt JG, Haertzen CA, Griffith JD, Bunney WE Jr.  Lithium: Effects on subjective functioning and morphine-induced euphoria. Science. 1977; 195:582-4.

The therapeutic usefulness of lithium in decreasing the euphoria and other symptoms associated with manic behavior and the hypothesis of a common final mechanism for elevations in mood have led to speculation that lithium may block the euphoria induced by drugs of abuse. In this study, lithium alone was anti-euphoric in drug-free opiate addicts and, further, did not block morphine-induced euphoria.

12. Gallager DW, Pert A, Bunney WE Jr. Haloperidol-induced presynaptic dopamine supersensitivity is blocked by chronic lithium. Nature. 1978; 273:309-12.

Several groups have theorized that alterations in catecholamine receptor sensitivity may be a factor in the etiology of affective disorders, especially manic-depressive illness. As lithium therapy has been shown to be effective in preventing recurrent episodes of mania and depression in manic-depressive illness, it is of interest to determine whether, at the level of individual DA neurones in the CNS, chronic lithium treatment could also affect the development of presynaptic supersensitivity. We provide here electrophysiological evidence for the blockade of presynaptic supersensitivity development following chronic lithium treatment.

13. Pert A, Rosenblatt JE, Sivit C, Pert CB, Bunney WE Jr. Long-term treatment with lithium prevents the development of dopamine receptor supersensitivity. Science. 1978; 201:171-3.

Long-term treatment of rats with haloperidol produced an increased sensitivity to the locomotor and stereotypic effect of apomorphine. This behavioral dopaminergic supersensitivity was accompanied by increased binding of [3H] spiroperidol in the striatum. Rats treated concurrently with lithium and haloperidol failed to develop both behavioral sensitivity to apomorphine and increased striatal dopamine receptor binding. The ability of lithium to prevent recurrent manic-depressive episodes may be related, in part, to its ability to stabilize dopaminergic receptor sensitivity.

14. Rosenblatt JE, Pert CB, Tallman JF, Pert A, Bunney WE Jr. The effect of imipramine and lithium on alpha- and beta-receptor binding in rat brain. Brain Res. 1979; 160:186-91.

Lithium is an efficacious prophylactic agent for preventing unipolar and bipolar mania and depression. Its mechanism of action is unknown, but it is assumed to interact at cellular sites normally designated for sodium. A recent proposal is that lithium's action is due to its ability to stabilize and, hence halt the development of receptor super- and subsensitivity which is postulated to accompany the various psychotic states. We have recently tested this hypothesis in an animal model in which chronic haloperidol treatment was used to induce dopamine receptor supersensitivity. In that study, we found that lithium administered concurrently with haloperidol blocked the development of haloperidol-induced dopamine receptor supersensitivity as measured both behaviorally and biochemically.

Chronic treatment with lithium rather than acute exposure of rat brain membranes to lithium ion appears to be responsible for the effects we have observed. Acute exposure of rat brain membranes to lithium concentrations ranging between 0.03 and 3.0 mM, the concentrations of lithium expected to be carried over into the test tube from the brain levels which we have routinely noted, failed to alter the binding to either a-, fl- or dopamine receptors. However, we found that lithium is able to block the supersensitivity of a-and fl-receptors which develops after 6-hydroxydopamine lesions.

This was the first report of lithium's ability to alter the sensitivity of adrenergic receptors in brain. Could this be due to a non-specific 'toxic' effect of lithium? Rats maintained on lithium for 3-5 weeks in our laboratory show a 15 ~ weight loss but no overt differences in behavior from controls. The effects of lithium on adrenergic receptors are highly reproducible, but it is impossible to rule out a 'stress' effect. These alterations in receptor sensitivity may relate to lithium's therapeutic effect. It will be important to demonstrate concomitant behavioral alterations in receptor sensitivity accompanying the biochemical changes observed here.

15. Alexander PE, van Kammen DP, Bunney WE Jr. Antipsychotic effects of lithium in schizophrenia. Am. J. Psychiatry. 1979; 136:283-7.

The lithium carbonate therapy of 13 psychotic schizophrenic patients was evaluated in a placebo-controlled three-week study that was double-blind. Seven of the 13 patients were less psychotic while receiving lithium; 4 of these 7 patients relapsed after lithium withdrawal. Patients who improved during the third week on lithium could be differentiated from nonresponders on the basis of their improvement during the first week. Clinical factors such as diagnosis, prognosis, and symptoms failed to predict responders from nonresponders. To the authors' knowledge, this is the first controlled study to yield positive results with schizophrenic patients treated with lithium alone.

16. Gallager DW, Bunney WE Jr. Effects of chronic lithium administration on the development of supersensitivity in CNS amine systems. A microiontophoretic study.  In: Usdin E, Kopin, IJ, Barchas JD, editors. Catecholamines. Basic and Clinical Frontiers. New York. Pergamon Press, 1979, pp. 669-71. 

A supersensitive response of the activity of DA-containing cells in the zona compacta of the substantia nigra to microiontophoretically applied DA and to intravenously administered apomorphine was produced by chronic haloperidol treatment in rats. Animals treated concurrently with lithium and haloperidol failed to develop this presynaptic DA supersensitivity. However, lithium's ability to block the development of supersensitivity in the DA system may not be generalized to other amine systems since chronic lithium treatment did not prevent the development of supersensitivity to 5HT in hippocampal pyramidal cells following chronic tricyclic antidepressant administration.

17. Pert CB, Pert A, Rosenblatt JE, Tallman JF, Bunney WE Jr. Catecholamine receptor stabilization. A possible mode of lithium's anti-manic action. In: Usdin E, Kopin IJ, Barchas JD, editors. Catecholamines. Basic and Clinical Frontiers. New York. Pergamon Press, 1979, pp. 583-5.

Chronic administration of lithium to rats treated with repeated doses of haloperidol prevents the dopamine receptor supersensitivity that normally develops when haloperidol is administered alone. Lithium's prevention of dopamine receptor supersensitivity has been documented by behavioral, neurophysiological, and biochemical receptor binding techniques. Chronic lithium treatment alone in rats has small but reproducible effects: an increase in α-receptor binding, a decrease in β-receptor binding and no alteration in dopamine receptor binding. In preliminary experiments, lithium is able to block the development of the α- and β receptor sensitivity that normally accompanies brain norepinephrine depletion by 6-hydroxydopamine.

18. Bunney WE Jr, Pert A, Rosenblatt J, Pert CB, Gallager D. Mode of action of lithium. Some biological considerations. Arch Gen Psychiatry. 1979; 36:898-901.

This communication will review some of the properties of lithium and four possible cellular sites of interaction between lithium and other cations. It will emphasize the observation that lithium interacts with cyclic adenosine monophosphate (AMP)-mediated processes and, finally, will review a hypothesis that the onset of mania may be associated with the development of supersensitivity of catecholamine receptors. New evidence will be reported that lithium can block the development of supersensitivity in CNS neuronal receptors in rats.

19. Rosenblatt JE, Pert A, Layton B, Bunney WE Jr. Chronic lithium reduced [3H] spiroperidol binding in rat striatum. Eur J Pharmacol. 1980; 67:321-2. 

The efficacy of lithium in the acute treatment and prophylaxis of mania is well established. Although the mechanism of lithium's anti-manic effects is not entirely understood, it is thought to involve central nervous system catecholamine neurotransmission.  Recently we reported that lithium prevented development of both the behavioral supersensitivity to apomorphine and the increase in [3H] spiroperidol binding following chronic haloperidol treatment in rats.  We confirmed these findings with electro- physiological techniques. In the present study we report that chronic treatment with lithium alone decreases dopamine receptor density in the corpus striatum in a rapidly reversible manner.

20. van Kammen DP, Alexander P, Bunney WE Jr. Lithium treatment in post-psychotic depression. Brit J Psychiatry. 1980; 136:479-85.

Six of eleven drug-free schizophrenic patients who were depressed following remission of their illness showed a significant decrease in their depressive symptomatology during a double-blind, placebo substitution lithium trial. Traditional indicators of prognosis did not predict lithium response in this small sample; the schizophrenic patients tolerated the lithium well. Lithium should be studied further in a larger patient sample as an adjunct in the treatment of post-psychotic depression, which frequently is treatment resistant.

21. Bunney WE Jr, Garland BL. Possible receptor effects of chronic lithium administration. Neuropharmacology. 1983; 22(3B):367-72.

Evidence suggests that lithium pretreatment might be effective in blocking the development of pharmacologically-induced behavioral dopamine supersensitivity although alterations in receptor binding may not be directly correlated to behavioral changes. Experimental results indicate that the effect of lithium may not be consistent throughout the brain, may be related to specific methods of sensitivity-induced alterations and may simultaneously alter several receptor systems.

22. Bunney WE Jr, Garland BL. Lithium and its possible modes of action. In: Post RM, Ballenger JC, Uhde TW, Bunney WE Jr, editors. Neurobiology of the Mood Disorders. Baltimore. Williams and Wilkins, 1984, pp. 731-43.

This review covers biological effects of lithium electrolytes, the neurotransmitters dopamine, norepinephrine and serotonin, acetylcholine, c-AMP, effect of lithium on receptor sensitivity, cholinergic muscarinic receptor binding, and GABA. 

23. Cohen IM, Bunney WE Jr, Cole JO, Fieve RR, Gershon S, Prien RF. The current status of lithium therapy. Report of the APA Task Force. Am J Psychiatry. 1975; 132:997-1001.  

In 1969 the American Psychiatric Association appointed a Task Force on Lithium and assigned to it the charge of providing “an appraisal of current knowledge about efficacy and safety of lithium therapy in psychiatry.”  In its report to the Council on Research and Development in the 1970s, the task force recommended that APA continue to critically evaluate lithium therapy; this resulted in the appointment of the present task force in 1973.  The following report responds to the charge given to this task force to reappraise lithium therapy after it had been generally available for several years.  In it the task force proposes to assess the value of lithium in the indications that have been suggested for its use, to describe and explain the procedures used in administering it therapeutically and prophylactically, to review the undesirable effects and complications of the treatment and their significance and management, and to bring to the attention of the membership those issues about lithium therapy that remain unresolved.


Note: Lithium was approved by the FDA for the treatment of mania in 1970.


October 22, 2020