Lithium Withdrawal Research Articles

Enhancement of granulopoiesis by lithium carbonate in a patient with hairy cell leukemia

A 73-year-old patient with hairy cell leukemia and profound granulocytopenia both before and after splenectomy was treated with lithium carbonate. With serum lithium level maintained in the therapeutic range, granulocyte count steadily increased from a level below 200/ mm 3 to 800/mm 3 over a two-week period. This trend reversed upon withdrawal of lithium. A second hematologic response occurred when the drug was reintroduced. The data support the contention that lithium carbonate may effectively stimulate granulopoiesis on a long-term basis, and this pharmacologic approach may be a useful adjunct to the management of hairy cell leukemia.

Is There a Lithium Withdrawal Syndrome?

Patients who discontinued lithium after a mean of 29 +/- 21 months prophylaxis were compared with a similar group who were not taking the drug; all had only been in hospital once, and satisfied DSM-III criteria for mania. During the first three months following withdrawal of lithium, significantly more patients relapsed than in the control group; after this period, the rate was identical. These findings suggest that lithium withdrawal exists as a clinical phenomenon and that a period of lithium treatment does not improve the long-term prognosis, once the drug has been stopped.

Reactions to withdrawal of antidepressants, antiparkinsonian drugs, and lithium

Withdrawal reactions to antidepressants, antiparkinsonian drugs, and lithium are rarely considered as a source of morbidity in psychiatric patients. The author reviews the somewhat limited information available for these three drug categories. Possible neurotransmitter mechanisms underlying these reactions are discussed, along with recommendations for clinical management and areas for future research.

Kinetics of the uptake of monoamines into synaptosomes from rat brain: Consequences of lithium treatment and withdrawal

The uptake systems for noradrenaline (NA) and 5-hydroxytryptamine (5-HT) into synaptosomal preparations from rat brain were found to consist of two components, a low-capacity and a high-capacity process. Administration of lithium (2 mequiv./kg) for 12 days was found to cause an increase in the activity of the low-capacity uptake process for NA, but to markedly inhibit the high-capacity system for this neurotransmitter. Following withdrawal of lithium, the activity of the low-capacity system returned to control values, but there was a profound enhancement of the high-capacity uptake process for NA. Both the low- and the high-capacity uptake systems for 5-HT were found to be inhibited by the administration of lithium. The reduced activity of the high-capacity system resulting from administration of lithium was still present 2 days after the cessation of treatment with the drug, whereas the low-capacity process was found to be further depressed. The uptake of dopamine (DA) into synaptosomal preparations appeared to be more complex than that of NA and 5-HT, since the shape of the substrate-velocity curve implied some form of multiple and co-operative process. The administration of lithium resulted in an enhancement of the uptake of DA in all regions of the brain examined, while 2 days of withdrawal from the drug caused a reduction to below control values in the amount of DA taken up. It therefore seems that alterations in monoaminergic uptake processes play a part in the mode of action of lithium, and may be involved in the genesis of the lithium-withdrawal phenomenon.

Myocardial changes in rats with lithium-induced uraemia.

The possible effects of lithium on myocardial morphology were studied at the light-microscopic level in three different rat models: (i) rats with chronic renal failure due to lithium administration for 8-16 weeks after birth, (ii) normal, adult rats treated with lithium for 16 weeks, and (iii) new-born rats exposed to lithium in their prenatal life. Morphological changes were found in 57% of the male rats with lithium-induced uraemia after lithium administration for 16 weeks postnatally. The changes comprised myocytic degeneration and necrosis associated with infiltration of lymphocytes, histiocytes and plasma cells. This morphological picture is different from the myocardial changes associated with chronic renal failure. Male rats with chronic uraemia after withdrawal of lithium 8 weeks postnatally showed no myocardial changes after 16 weeks. Also, male rats with normal renal function had no myocardial changes after 16 weeks on lithium, but these rats had a significantly lower plasma level of lithium than the lithium-uraemic rats (0.8 vs. 1.4 mmol/l). It is suggested that myocarditis was a consequence of persistent high plasma levels of lithium maintained in the lithium-uraemic rats and that cardiotoxic effects of lithium may be potentiated by concomitant renal failure.

Recurrence of affective illness after withdrawal of long‐term lithium treatment

Clinical outcome following discontinuation of long-term maintenance therapy with lithium and manic-depressive patients was studied. Although the majority showed recurrence of affective episodes, the relapses tended to be spread over a period of months. There was no evidence of immediate and inevitable "rebound" of psychotic episodes following lithium withdrawal. This finding is discussed in the light of results from other lithium discontinuation studies.

Lithium treatment and thyroid function. A survey of 237 patients in long-term lithium treatment.

In a cross-sectional study of 237 patients treated with lithium for more than six months, 10 patients had serum thyroid stimulating hormone (TSH) values above 35 mU/l and concomitantly low triiodothyronine (T3) and abnormally low serum thyroxine (T4). Eight patients had TSH values of 10.0-34.9 mU/l, while T3 and T4 were within or close to the normal ranges. Most of the patients had TSH values of 0.9-9.9 mU/l and normal or close to normal T3 and T4 values. Three male patients had TSH below 0.9 mU/l, but normal T3 and T4 values. A retrospective investigation three years later showed that all patients with TSH above 35 mU/l had clinically diagnosed overt hypothyroidism and treated accordingly with either replacement therapy with thyroxine or discontinuation of the lithium treatment. The thyroid parameters normalized spontaneously in 2 out of 3 patients who had their lithium treatment discontinued, while one still needed replacement therapy 1 1/2 years after withdrawal of lithium. Five patients had been put on replacement therapy before the cross-sectional study. The frequency of overt hypothyroidism thus indicated a prevalence about ten times as high as should be expected. An overrepresentation of women was found in the group with TSH values above 10 mU/l, whereas the group with TSH values of 0.9-10.0 mU/l showed no such sex predomination. The age distribution was equal in all groups. TSH appeared to be the most efficient parameter in revealing undetected hypothyroidism in the present investigation of patients in long-term lithium treatment.

Lithium and drug interactions.

The mutual enhancement of the side effects of muscular tremor and rigidity caused by lithium and neuroleptic drugs should be recognised. However, at present the 'case' for a neuroleptic-lithium interaction producing severe organic brain syndrome is arguably weak; in the absence of standardised sampling for monitoring lithium serum concentrations such reports may simply reflect 'pure' lithium intoxication rather than a drug interaction. Certainly it seems unwarranted in this connection to ascribe specific properties to haloperidol. A potentially high risk of interaction should be recognised between lithium and natriuretic diuretics, and other drugs and therapeutic measures affecting sodium balance. Such interactions may disturb stable treatment monitoring and give rise to the start of self-increasing lithium intoxication. The practical clinical importance of lithium interactions with neuromuscular blocking agents, phenytoin, carbamazepine, iodide salts and methyldopa is only weakly supported by the data available at this time. However, if simple prophylactic measures are available when such drugs are to be used in patients receiving lithium, for example temporary withdrawal of lithium, it may be prudent to take such steps.

Abrupt lithium discontinuation in manic-depressive patients.

Prophylactic lithium was abruptly discontinued (under double-blind conditions and using placebo) in 18 manic-depressive patients for 15 days. Following lithium withdrawal tremor of hands, polyuria, general muscular weakness, polydipsia and dryness of mouth were significantly reduced. No withdrawal symptoms were noted. Three patients relapsed within 4 days of lithium discontinuation. The questions arising from these findings are discussed and the possibility of a rebound phenomenon produced by lithium is considered.

Functional and Structural Changes in the Rat Kidney by Long-Term Lithium Treatment

The relation between functional and structural renal changes induced by lithium was studied in rats during long-term treatment and after withdrawal of lithium. Administration of LiCl in the diet for up to 21 weeks caused marked polyuria associated with a significant lowering of renal concentrating ability assessed by dehydration and vasopressin tests. Plasma creatinine and plasma urea were not significantly changed by the treatment. Upon withdrawal of lithium water intake and concentrating ability were normalized within 4--8 weeks. Lithium caused focal light microscopic changes in the distal convoluted tubule and the collecting duct, consisting of nuclear and cellular polymorphism and, after prolonged treatment, dilatation of tubular lumens with tubular cell atrophy. These changes appeared later than the concentrating defect and persisted when lithium was withdrawn after prolonged treatment. No significant correlation was found between the degree of tubular changes and water intake or concentrating ability. It is concluded that the reversible diabetes insipidus induced by lithium in rats cannot be explained directly by the light microscopical changes observed in the distal part of the nephron, although the structural changes may be secondary to the polyuric state induced by lithium.

Effect of lithium treatment and withdrawal on uptake of noradrenaline into rat brain synaptosomes: A kinetic study

Abstract 1. Changes in noradrenaline uptake into synaptosomes prepared from various regions of rat brain were examined using a kinetic approach following treatment with and withdrawal from lithium. 2. A two-component uptake mechanism for noradrenaline was found in synaptosomes of control animals. 3. Lithium treatment enhanced noradrenaline uptake at low ligand concentrations, but abolished the high-capacity uptake mechanism. Lithium withdrawal returned uptake at low ligand concentrations to control values, but resulted in a “rebound” increase in the uptake due to the high-capacity system. 4. It is thought that these changes may be consequences of alterations in noradrenaline release following lithium treatment and withdrawal.

Monoamine uptake into synaptosomes from various regions of rat brain following lithium administration and withdrawal

The uptake of monoamines into synaptosomes from various regions of rat brain was examined following lithium (Li) treatment (2 mequiv/kg/day) and subsequent withdrawal. In control animals, regional differences were noted in the amount of NA, DA and 5-HT taken up. The consequences of Li administration were found to depend upon the monoamine examined. Dopamine uptake was enhanced, while that of 5-HT was depressed in all regions studied. The effects on NA uptake were seen to be regionally variable, being enhanced in the hypothalamus and striatum and depressed in the midbrain and cortex. Lithium withdrawal resulted in a return towards control values for all regions and substrates except striatum (DA and 5-HT) and midbrain (5-HT), where the uptake remained unaltered or was enhanced with respect to the Li-treated rats. It is suggested that part of the therapeutic effect of Li in mania is due to alterations in the uptake processes for the monoamines, and that the “rebound” mania seen clinically following Li withdrawal may be associated with dopaminergic and tryptaminergic systems, particularly in the striatum and midbrain.

Brain gabaergic and dopaminergic systems following lithium treatment and withdrawal

1. 1. Changes in dopaminergic and GABAergic systems were examined in several brain regions following short-term lithium administration and subsequent withdrawal. 2. 2. Lithium administration appears to cause a reduction in turnover of dopamine in most regions examined. In addition, there may be increased turnover of GABA in the midbrain, with decreased GABA outflow in other regions. 3. 3. Lithium withdrawal resulted in enhanced striatal dopamine turnover, together with a further decrease in dopamine content in other brain regions. With the exception of striatum, GABAergic parameters returned towards control.

Renal concentrating capacity in long-term lithium treatment and after withdrawal of lithium.

The urinary concentrating capacity was estimated with the DDAVP test in 87 patients receiving lithium therapy, which was discontinued in all patients. The test was repeated three and eight weeks after withdrawal of lithium in 75 patients and one year after withdrawal in 27 patients. Of the 87 patients, 52 were also treated with neuroleptics, which treatment was continued throughout the study. Two control groups, consisting of 30 patients receiving only neuroleptics and 30 healthy subjects, were studied on one occasion with the DDAVP test. Lithium-treated patients had significantly lower concentrating capacity and higher serum creatinine than healthy subjects at all examinations. Small but statistically significant correlations were found between urinary osmolality and total dose of lithium, between urinary osmolality and duration of lithium treatment, between the highest serum lithium concentration recorded and urinary osmolality after withdrawal of lithium and between the daily dose of lithium and urinary osmolality, while patients were still on lithium. The concentrating capacity improved significantly during the first two months after withdrawal of lithium, but not later. One year after withdrawal of lithium, 17 of 27 patients still had a concentrating capacity below 800 mOsm/kg. Patients receiving lithium and neuroleptics had lower concentrating capacity than patients treated with lithium alone, and patients treated with neuroleptics alone had lower concentrating capacity than healthy subjects.

Antipsychotic effects of lithium in schizophrenia

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.

Reversibility of Lithium-Induced Impairment of Renal Concentrating Ability in Rats

Male Wistar rats were treated with lithium added to their food for 11 weeks followed by a withdrawal period of 4 weeks. Urine flow and osmolality were recorded daily. Renal concentrating ability was evaluated from the maximal urine osmolality recorded by the DDAVP test (5 ng/kg s.c.) and dehydration test (28 h or until 8% loss of body weight) after lithium treatment for 1,3 and 9 weeks, and 1, 2, 3 and 4 weeks after withdrawal of lithium. During lithium treatment, the rats developed massive polyuria with severe impairment of renal concentrating ability. After withdrawal of lithium, urine flow and osmolality and renal concentrating ability were reversed to control levels within 2-3 weeks. There was a highly significant correlation between the results obtained with the two tests for renal concentrating ability. Lithium treatment did not cause irreversible changes of endogenous creatinine clearance or plasma creatinine concentration. It is concluded that the impairment of renal concentrating ability caused by prolonged lithium administration is a reversible condition.

Impairment of vigilance and performance under lithium-treatment. Studies in patients and normal volunteers.

Subtle changes of adaptive behaviour under lithium treatment may possess interest not only as side-effects, but also as a possible explanation for the mechanism of action of lithium salts. - In 18 patients under long-term lithium treatment and 10 normal volunteers before and after one week of lithium application the EEG was recorded and performance as well as psychophysiological tests were carried out. The results, particularly of the d-2-test point to a considerably reduced performance in patients and normal volunteers. The EEG data in both groups suggest reduced vigilance until stage B3 or C (in the sense of Head of Bente); CFF was significantly elevated only during the first days of lithium application in the normal volunteers. Whereas EEG changes persist, other symptoms as CFF reduction, fine hand tremor, or reduced performance resolved at least partially 7 days after lithium withdrawal in the normal volunteers.

A study of abrupt lithium withdrawal

Twelve patients were abruptly switched from lithium to placebo as part of a double-blind cross-over study. In contrast to other drugs effective in mood disorders, lithium produced no withdrawal syndrome.

Iodine and lithium-induced hypothyroidism: Documentation of synergism

Signs and symptoms of hypothyroidism were noted in a patient receiving lithium carbonate for 2 years as prophylaxis against recurrence of mania and depression. When lithium therapy was stopped, the hypothyroidism resolved; but it recurred with the administration of potassium iodide. When potassium iodide therapy was discontinued, the patient became euthyroid. In a second patient chemical evidence of hypothyroidism (fall in circulating thyroid hormone levels, elevation of serum thyrotropin) was noted after he had received 3 weeks of lithium therapy. With the addition of potassium iodide, laboratory evidence of hypothyroidism became more pronounced, and clinical signs of hypothyroidism developed. All abnormalities resolved promptly following the withdrawal of lithium and iodine. These observations suggest that lithium and iodine can act synergistically to produce hypothyroidism and that the combined use of these agents should be avoided.

Experimental Withdrawal of Lithium in Recovered Manic-Depressive Patients: A Report of Five Cases

The authors conducted a single-blind study to determine whether patients with manic-depressive disease who responded favorably to lithium would show significant change when placebo was substituted. Symptoms recurred in all subjects within six weeks of placebo substitution, and clinical stability returned when lithium treatment was resumed. These findings are discussed in relation to the question of the prophylactic influence of long-term maintenance on lithium.