Erythrocyte lithium efflux in bipolar patients and control subjects: the question of reproducibility

The reproducibility of in vitro erythrocyte lithium efflux and lithium efflux in the presence of selected membrane transport inhibitors (phloretin, ouabain, 4,4'-diisothiocyano-2,2'-disulphonic acid stilbene, and p-chloromercury-benzene sulphonate) was investigated in bipolar patients and age- and sex-matched control subjects. Efflux experiments were repeated three times in each patient-control pair within a period of 14 days. No differences were detected between patients and control subjects in any of the parameters measured. All components of lithium efflux showed wide day-to-day variation in the same subject in both patients and control subjects. Intersubject variability, however, was significantly greater than intrasubject variation. Since intraindividual variation of phloretin-inhibited lithium efflux was found to be considerable, and no real patient-control differences could be detected, the significance of this in vitro parameter in bipolar affective illness seems somewhat questionable and should be carefully reconsidered. The relevance of these findings to the putative cell membrane dysfunction in this disease is discussed.     

Elevation of erythrocyte glycine levels during lithium treatment of affective disorders

An elevation of erythrocyte (RBC) glycine was observed in a group of patients with bipolar affective disorder who were being treated with lithium (Li) carbonate. A maximal increase of 90% or more was generally attained after about 100 days of Li intake and was maintained for 2 years or longer. After 3 or more years of Li therapy, the RBC glycine had often returned to the normal range. Abrupt withdrawal of Li in such a case produced an immediate, dramatic, and paradoxical increase in RBC glycine which lasted for 100 days. Plasma glycine was not affected by Li.     

Serum and red cell folate and affective morbidity in lithium prophylaxis

Serum and red cell folate concentrations were estimated in 68 affective disorder patients taking lithium prophylactically, 65 of whom had bipolar disorder. The number of hospital admissions, the frequency of use of additional mood altering treatments and the Affective Morbidity Index were calculated for the 2 years of the study. Contrary to other findings, there were no differences between the folate concentrations for different severities of affective morbidity. These results question the rationale of prescribing folic acid preparations for lithium-treated bipolar disorder patients, but the authors indicate that folate concentrations may be low in lithium-treated unipolar depressives.     

Repression and reactivation of lithium efflux from erythrocytes.

Efflux of lithium from human erythrocytes was studied in patients before, during, and after discontinuation of administration of lithium carbonate. Onset of lithium-induced repression of efflux took approximately 10 days and was significantly shorter in patients who had had lithium therapy previously. Reactivation took a longer period of time--approximately 2 week--and was found to be related to duration of lithium therapy. Theoretical pathways of lithium flow through membranes are discussed.     

Interdependency of lithium ratio, plasma lithium level and clinical state in patients with affective disorders

The interrelationship between lithium ratio, lithium plasma level and the different clinical phases of 31 patients with bipolar affective disorder has been investigated. the interdependency of these variables was followed longitudinally during different phases of the illness while under lithium therapy. Although positive correlations between lithium ratio and lithium plasma levels were evident, the lithium ratio values in the euthymic group were significantly higher than those in the manic and depressive groups, independently of the plasma lithium level. Our data suggested that RBC/plasma lithium ratio might be a sensitive state dependent index in affective bipolar illness.     

The course of affective disorders

Summary All patients suffering from affective psychoses (ICD 296) who were admitted to the Psychiatric University Clinic of Zurich between 1959 and 1963 were studied in a follow-up investigation until 1975. Of 254 affective psychoses, 95 were bipolar patients (37.4%) and 159 were monopolar (62.6%). The sample of bipolar patients was complemented with all patients who had been admitted in the period 1959–1963 because of manic or mixed manicdepressive syndromes.This paper describes the change of diagnosis in the two diagnostic groups. In 10% (N= 20) of monopolar depression cases there was a change of diagnosis to bipolar affective illness. An analysis shows that the diagnosis of patients with three or more depressive episodes (unipolar depressives) was especially prone to change.A mathematical correction of some diagnostic errors leads to the conclusion that the ratio of unipolar depression to bipolar illness may be about 11.A major source of diagnostic error lies in the change of affective to schizoaffective illness. Up to now, no clinical criterion exists that would exclude this error, which was found in 6% (n=12) of the monopolar but also in 7.5% (n=3) of the bipolar index patients.It is recommended that studies of affective disorders should be based on truly representative samples of the illness, including patients with one or two episodes, and that the term unipolar depression be used synonymously with the term monopolar depression, originally created by Kleist (1947) and Leonhard (1957).     

Psychopathology during long-term lithium treatment of patients with major affective disorders. A prospective study

Thirty-seven patients with major affective disorders according to DSM-III and on continuous lithium treatment were followed during a 7-year period. Outcome was assessed by use of the Comprehensive Psychopathological Rating Scale and by the need for additional psychotropic medication and for hospital and outpatient care. Anamnestic variables and patient's attitudes to their lithium medication were also included in the analysis of outcome, as were laboratory data, including lithium parameters. An increase in psychopathology was demonstrated in a significant number of patients and was attributed mainly to an increase in the depressive symptoms, with a significant increase in the rated scores for fatiguability, pessimistic thoughts, reduced sleep, and inner tension. Suicidal thoughts were common, but no suicide attempts were made. A significant number of patients complained of failing memory, but no significant progression was demonstrated during the 7-year study period. The increase in the depressive symptoms was closely correlated with the number of hospital admissions for depressive recurrence and with the number of days in hospital. The following factors showed a significant relationship with the increase in depressive symptoms: serum lithium levels, large increase in the elimination half-life of lithium, low level of social functioning, low TSH values, and need of concomitant administration of antidepressants and benzodiazepines.     

Prediction of affective psychoses response to lithium prophylaxis. The role of socio-demographic, clinical, psychological and biological variables

A set of socio-demographic, clinical, psychological and biological variables was examined in 100 patients diagnosed according to Perris as bipolar affective psychotics or unipolar depressive psychotics, maintained on prophylactic lithium for 2 years and divided into responders and non-responders to this treatment on the basis of strict criteria. The results confirmed the potential role of four indices as predictors of response to prophylaxis: a positive family history of bipolar affective illness and a high red blood cell/plasma lithium ratio (positive predictors) and the presence of the HLA-A3 antigen and a high score on the Neuroticism Scale of the Eysenck Personality Questionnaire (negative predictors). A stepwise discriminant analysis showed that neuroticism score, lithium ratio and HLA-A3 antigen, taken together, correctly classified 74.6% of responders and 68.3% of non-responders. It is hypothesized that these variables as a group may be of practical value in predicting response to lithium prophylaxis, and that pharmacogenetic and, perhaps, personality factors may be involved in treatment failures.     

Outcome of lithium prophylaxis: a prospective follow-up of affective disorder patients assigned to high and low serum lithium levels

The purpose of the study was to examine the outcome of long-term lithium treatment in consecutively admitted affective disorder patients assigned to high and low serum lithium levels. A total of 91 patients were diagnosed according to DSM-III criteria and randomly allocated to two open treatment groups in which prophylactic lithium was administered in high (serum lithium 0.8-1.0 mmol L^-1) and low (serum lithium 0.5-0.8 mmol L^-1) doses, respectively. The patients were followed for 2 years or until discontinuation of lithium treatment or readmission to hospital for recurrence of affective illness. The main outcome of the treatment groups was compared with Kaplan-Meier survival curves and by Cox regression analysis. A total of 31 patients (34%) completed 24 months of prophylactic lithium treatment without recurrence and readmission to hospital. In total, 18 patients (20%) suffered a recurrence on lithium, and 42 patients (46%) discontinued lithium or were lost to follow-up. No effect of treatment group was seen, either for the total patient group or for the large subgroup of bipolar patients when analysed separately. A number of patients did not maintain their original assignment to the high serum lithium levels group. The results were analysed both according to assignment and according to actual serum lithium levels. Abuse of alcohol or medication was associated with a poor outcome. Only one third of the patients completed 2 years of lithium prophylaxis successfully. No difference in the protection against recurrences was observed between patients maintained on high and low serum lithium levels.     

Cognitive and affective functions in patients with affective disorders treated with lithium AN ASSESSMENT BY QUESTIONNAIRE

A questionnaire of 19 items was devised to assess subtle changes in affective and cognitive function in patients with affective disorders under long-term lithium therapy. Of 147 patients, 138 (93.9%) answered the questionnaire. The function of the hypothalamic-pituitary-thyroid axis was also analysed by biochemical investigations, and the interrelations between the function of this axis and affective and cognitive functions were studied. The patients under lithium maintenance therapy showed no clearcut changes in affective and cognitive functions. Some statistically significant correlations were found between rising thyrotropin levels and improved affective function. Patients who admitted periods of depression under lithium therapy showed highly significantly greater variance both in free thyroxine index and in thyrotropin levels than patients denying such periods. We may conclude that successful prophylactic lithium therapy against depression is linked to a stabilizing effect on the hypothalamic-pituitary-thyroid axis.     

Mood-independent aberrancies in associative processes in bipolar affective disorder: an apparent stabilizing effect of lithium

Forty-eight patients from an affective disorders clinic were tested twice with a word association test. They gave significantly fewer repetitions of common responses than did 29 normal controls. This difference was not related to subgroup diagnosis (bipolar I, bipolar II, unipolar, schizoaffective, and cyclothymic personality), to mood state at the time of testing, or to cycling frequency. The total number of repeated responses was directly correlated with serum lithium level (r = 0.44, p less than 0.01, especially in those judged good lithium responders (r = 0.71, p less than 0.05). This finding may reflect a normalizing effect of lithium on associative processes in affective illness.     

Testing competing path models linking the biochemical variables in red blood cells from Li+-treated bipolar patients

Objectives: Red blood cells (RBCs) from Li⁺‐treated bipolar patients have shown abnormalities in intracellular Li⁺ concentration ([Li⁺]_i), Na⁺/Li⁺ exchange rates, and membrane phospholipid levels. Based on Li⁺‐loaded RBC studies, we hypothesized that Li⁺‐treated bipolar patients also have varied intracellular free Mg²⁺ concentrations ([Mg²⁺]_f) as compared with normotensive patients. We addressed how these experimentally determined values are intercorrelated. Assuming that Li⁺ treatment alters these biochemical parameters, we provide hypothetical pathways based upon structural equation modeling statistics. Methods: In RBCs from 30 Li⁺‐treated bipolar patients, we determined [Li⁺]_i, serum [Li⁺] ([Li⁺]_e), Na⁺/Li⁺ exchange parameters, membrane phospholipid levels, [Mg²⁺]_f, and Li⁺ membrane binding affinities. Comprehensive statistical analyses assessed correlations among the biochemical data. We used path analysis statistics to propose potential pathways in which the data were correlated. Results: We found significant correlations within the three Na⁺/Li⁺ exchange parameters and percentage composition of the membrane phospholipids. Additional correlations existed between [Mg²⁺]_f and V_std, K_m, or phospholipid composition, between [Li⁺]_i and percentage of phosphatidylcholine, and between percentage of phosphatidylserine and K_m. Based on these findings, we hypothesized and statistically determined the most probable pathway through which these parameters were intercorrelated. Conclusions: Significant correlations existed between the biochemical parameters that describe the cell membrane abnormality and the Li⁺/Mg²⁺ competition hypotheses. Using path analysis statistics, we identified a biochemical pathway by which Li⁺ may assert its cellular effects. This study serves as an illustrative example how path analysis is a valuable tool in determining the direction of a certain biochemical pathway.     

RBC-choline: changes by lithium and relation to prophylactic response

ABSTRACT– Red blod cell (RBC)- and plasma-choline levels were measured in patients on lithium (n= 96), antidepressants (n - 32) and nenroleptics (n= 51), and in 25 healthy drug-free controls. Lithium patients exhibited highly increased RBC- and slightly increased plasma-choline levels compared with controls (P < 0.001 and P < 0.05, respectively); the choline ratio (RBC-/plasma-choline) was elevated almost to the same extent as RBC-choline (P < 0.001). With antidepressants RBC-choline and choline ratios were slightly reduced (P < 0.05), whereas neuroleptics showed no effect on choline levels. 79 % of lithium patients were responders (reduction in hospitalizations with lithium), 21 % were non-responders (no reduction or increase in hospitalizations]. Choline ratio exhibited a significant relation to prophylactic lithium response, but lithium ratio did not. The percentage of nori-responders was significantly higher in patients with a choline ratio exceeding 100 than in patients with a choline ratio below this cut-off (P < 0.01). Thus, the increase of RBC-choline and choline ratios appears to be an effect specific for lithium and might be related to the outcome of lithium prophylaxis.     

Course of illness and pattern of recurrences in patients with affective disorders during long-term lithium prophylaxis: a retrospective analysis over 15 years

Berghöfer A, Kossmann B, Müller-Oerlinghausen B. Course of illness and pattern of recurrences in patients with affective disorders during long-term lithium prophylaxis: a retrospective analysis over 15 years. Acta Psychiatr Scand 1996: 93: 349–354. © Munksgaard 1996. We analysed the recurrences of 86 patients with monopolar and bipolar mood and schizoaffective disorders treated with lithium over a period of 8.2 years on average in a specialized out-patient clinic. Lithium medication was discontinued by 24% of patients. Diagnosis, age and gender had no influence on the mean morbidity index. Bipolar and schizoaffective patients suffered from more severe recurrences, resulting in hospital admissions, than monopolar patients. A significant decrease in intensity of manic episodes and a significant shortening of depressive episodes was observed over a 10-year treatment period. However, the percentage of manic episodes among all episodes remained constant. There was no indication of a loss of the prophylactic effect in a subgroup of 30 patients who had been treated for a minimum of 10 years. The morbidity index also remained constant over 10 years in the whole sample. Furthermore, the mean lithium blood levels as well as the additional medication in this subgroup could be lowered in the second half of the treatment decade as compared to the initial 5 years.     

Thyrotoxicosis after complete or partial lithium withdrawal in two patients with bipolar affective disorder

Objectives: To highlight and discuss thyrotoxicosis after lithium withdrawal as a potential complication of lithium therapy for bipolar disorder.
Case Reports: Both patients presented developed thyrotoxicosis, the first patient after stopping the lithium completely, and the second patient after a reduction in the lithium dose.
Conclusions: Clinicians should be alert to the possibility of thyrotoxicosis emerging when lithium is being completely or partially withdrawn. Such withdrawal could unmask a latent hyperthyroidism.     

Sodium-dependent calcium efflux from single Aplysia neurons

⁴⁵Ca²⁺ efflux from single Aplysia somata was measured. Replacement of external Na with Tris caused a reduction in the efflux following a transient increase. CCMP, a metabolic poison, caused a reversible increase in the efflux. The results suggest that Na⁺/Ca²⁺ exchange and mitochondrial uptake can act to regulate Ca²⁺ inAplysia neurons.     

Carbamazepine versus lithium in the prophylaxis of bipolar affective disorder.

A 12-month double-blind trial of carbamazepine vs lithium, given as sole treatment for the prophylaxis of bipolar affective disorder, was carried out in 31 patients. All were previously stable on lithium; 15 were switched over to carbamazepine and 16 remained on lithium. Although the overall relapse rate was similar in the 2 groups (6 on carbamazepine, 8 on lithium), nearly all the relapses in carbamazepine occurred in the first month, probably precipitated by lithium withdrawal. Two patients on carbamazepine developed a rash and were withdrawn. More side effects were noted during the early stages on carbamazepine. Patients on lithium tended to gain weight (+4 kg) compared with carbamazepine (-3.1 kg). It is concluded that carbamazepine is as effective as lithium in the prophylaxis of bipolar affective disorder; changeover from lithium to carbamazepine should be done slowly.     

Hyperthyroxinemia in major affective disorders

Ninety-nine patients fulfilling DSM-III criteria for primary major affective disorder, either bipolar or unipolar, were studied. A 12% prevalence of elevated thyroxine levels was found. Three of the 12 hyperthyroxinemia patients also had elevated free thyroxine index. No statistically significant difference in response to antidepressant treatment was observed between the hyperthyroxinemia group and the normal serum thyroxine group.     

Haloperidol and lithium carbonate treatment did not influence serum immunoglobulin levels in schizophrenic and affective patients

Serum immunoglobulin levels were studied in 153 psychiatric patients (87 schizophrenic, 48 bipolar and 18 unipolar patients), and 35 healthy controls. Psychotropic treatments (haloperidol in the schizophrenic patients and lithium in the bipolar affective patients) did not alter serum immunoglobulin levels. Decreased mean IgM serum level was detected in the major affective patients (unipolar and bipolar) compared with normal controls. Nonspecific environmental, infectious, autoimmune and emotional factors that can play a role in the alterations obtained in psychiatric patients are discussed.