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Predicting lithium response prior to treatment could both expedite therapy and avoid exposure to side effects. Since lithium responsiveness may be heritable, its predictability based on genomic data is of interest. We thus evaluate the degree to which lithium response can be predicted with a machine learning (ML) approach using genomic data. Using the largest existing genomic dataset in the lithium response literature (n = 2210 across 14 international sites; 29% responders), we evaluated the degree to which lithium response could be predicted based on 47,465 genotyped single nucleotide polymorphisms using a supervised ML approach. Under appropriate cross-validation procedures, lithium response could be predicted to above-chance levels in two constituent sites (Halifax, Cohen's kappa 0.15, 95% confidence interval, CI [0.07, 0.24]; and Würzburg, kappa 0.2 [0.1, 0.3]). Variants with shared importance in these models showed over-representation of postsynaptic membrane related genes. Lithium response was not predictable in the pooled dataset (kappa 0.02 [- 0.01, 0.04]), although non-trivial performance was achieved within a restricted dataset including only those patients followed prospectively (kappa 0.09 [0.04, 0.14]). Genomic classification of lithium response remains a promising but difficult task. Classification performance could potentially be improved by further harmonization of data collection procedures.

The paper presents the current state of knowledge on lithium treatment. The history of the therapeutic application of lithium began in 1859 and its introduction to modern psychiatry took place 90 years later. Since the early 1960s, lithium became a precursor of mood-stabilizing drugs and nowadays is the drug of choice for the prevention of manic and depressive recurrences in mood disorders. It remains a valuable drug for the treatment of acute episodes of mania and depression, especially for the augmentation of antidepressant drugs in treatment resistant depression. The factors of prophylactic efficacy of lithium in the context of the so-called excellent lithium responders and the efficacy in affective episodes were discussed. Among mood-stabilizing drugs, lithium exerts the biggest effect on preventing suicidal behaviors. It also shows antiviral (mainly against herpes viruses) and immunomodulatory activity. The evidence has recently been gathered on neuroprotective and ‛antidementia' properties of lithium, which prompted its use in neurodegenerative disorders. The biochemical mechanism of lithium is associated mainly with the inhibition of glycogen synthase kinase-3 and an effect on intracellular signaling. The recommendations for managing lithium-induced adverse effects both in the early and late period of treatment as well as for lithium use in pregnancy and perinatal period were given. The necessity of overcoming negative perceptions of lithium was pointed out to increase the number of possible beneficiaries of lithium treatment. Both introduction of lithium into modern psychiatry and its therapeutic effects have been reflected in literature and art.

The third part of the triptych of my 50-year activity in psychiatry is about psychopharmacology. This way of treatment changed the picture of contemporary psychiatry. The introduction of neuroleptic (antipsychotic) drugs and tricyclic antidepressants in the 1950s resulted in a therapeutic revolution and contributed to the ‛medicalization' of psychiatry and its therapeutic similarity to other non-surgical specialties. Adiscovery of prophylactic lithium activity in the1960s initiated the mood-stabilizing drugs.During the last half-century, the most dynamic was the 1990s when most antipsychotic and antidepressant drugs of the so-called new generation were introduced. The twenty-first century marks a debut of next antidepressant and antipsychotic drugs, some of the latter having long-acting injectable preparations. An interesting event was a demonstration of the antidepressant activity of ketamine. My research domain in psychopharmacology was lithium treatment of affective illnesses. Lithium makes the topic of many papers I authored, more than 150 of them are in the PubMed database. Many clinical and research aspects related to lithium administration have been reported as first in Polish literature and some are pioneering in the world. Recently, I wrote the book Lithium - the amazing drug in psychiatry which has also its English version. I have carried much research on antidepressant drugs, pharmacotherapy of treatment-resistant depression, and mood-stabilizing drugs for which I proposed a modern classification. I participated in European projects EUFEST and OPTIMISE on the optimization of using antipsychotic drugs in schizophrenia. I also performed much research on the antidepressant effect of ketamine and electroconvulsive therapy.

Objectives: There is still debate about whether the quality of long-term efficacy of lithium in patients with bipolar disorders is influenced by atypical features. Extended Cox regression models allow for the use of all follow-up data on diseases with multiple episodes. The aim of the present analysis was to apply the best suited of these models to analyze the influence of atypical features on the widely used outcome measure of time to recurrence in a large multicenter cohort of lithium responders established by the International Group for the Study of Lithium Treated Patients., Methods: A conditional extended Cox model with a random frailty term was applied to the data of 336 bipolar I and II disorder patients, all of whom were responders to lithium with treatment for up to 30 years., Results: Differences were found in the long-term outcome, even in patients who have demonstrated a relatively good response to lithium treatment. The hazard for recurrence was negatively influenced by the presence of atypical features, mainly mood-incongruent psychotic symptoms, interepisodic residual symptomatology, and rapid cycling., Conclusions: As a result of the findings, physicians should regularly reassess the quality of response in bipolar disorder patients with atypical features and, if necessary, modify treatment. Extended Cox regression models are well suited for evaluating long-term outcome and should be used more extensively to analyze treatment outcome in psychiatric and somatic disorders.

Introduction: Brain-derived neurotrophic factor (BDNF) has been involved in the pathogenesis of bipolar mood disorder and in the mechanism of mood-normalizing action of lithium. The aim of this study was to find a possible association between lithium prophylactic effect in bipolar patients and two polymorphisms of BDNF gene., Methods: Eighty-eight patients (35 males, 53 females) with bipolar illness were studied. Duration of lithium prophylaxis ranged between 5-27 years (mean 15 years). Three categories of prophylactic lithium response were delineated: excellent responders (ER), partial responders (PR) and non-responders (NR). All patients were genotyped for two polymorphisms of BDNF gene: Val66Met and -270C/T., Results: The Val/Met genotype of Val66Met polymorphism occurred more frequently (p = 0.037) and there was a trend for a higher incidence of Met allele (p = 0.076), in ER than in NR. A trend for C/T genotype and T allele of -270C/T polymorphism was observed to occur more frequently in ER than in NR (p = 0.057 and p = 0.065, respectively)., Conclusion: The data obtained suggest that polymorphism of BDNF gene may be connected with a quality of lithium prophylaxis.

Objectives: The aim of the study was to assess the prophylactic effect of long-term lithium administration in patients with bipolar mood disorders entering treatment in the 1970s and 1980s at the outpatient clinic of the Department of Psychiatry, University of Medical Sciences, Poznan, Poland., Methods: The clinical characteristics of two groups of patients before and during lithium therapy were compared, namely, the 60 bipolar patients who entered lithium prophylaxis in the 1970s and 49 patients who entered in the 1980s. Both groups received the drug over a 10-year period., Results: The patients who entered lithium in the 1970s had fewer previous episodes of depression and more of mania than the patients who entered the therapy in the 1980s, although the total number of affective episodes was similar in both groups. The overall prophylactic efficacy of lithium over a 10-year period of administration was similar in both groups, except for a trend towards a greater number of depressive episodes in the first year of lithium prophylaxis in the 1980s group. The excellent lithium responders constituted 35% of the 1970s patients and 27% of those in the 1980s group. The 1970s patients were maintained on a higher level of serum lithium compared to the patients in the 1980s group and had more lithium-induced side effects., Conclusions: A decrease in lithium prophylactic efficacy in consecutive decades was not observed. Small differences between the bipolar patients entering lithium therapy in the 2 decades were observed in terms of the previous history of illness and during the course of lithium administration.

The influence of lithium, carbamazepine or valproate treatment on the cognitive functions is presented.

Experimental and clinical data pointing to antiviral and immunomodulatory effects of lithium have been reviewed in the context of new information accumulated in the last recent two decades, indicating a possible pathogenic role of viral infection and/or immune dysfunction in affective illness. Antiviral effects of lithium, particularly against herpes viruses, was demonstrated in both experimental and clinical conditions. Patients with affective illness taking lithium for prophylactic purposes have a greatly reduced frequency of labial herpes recurrences. The therapeutic action of oral and topical lithium administration on labial and genital herpes was also demonstrated in non-affective subjects. In both experimental conditions and in clinical studies with affective patients, lithium was shown to exert favorable effects on many parameters of cellular and humoral immunity. The evidence was also presented that lithium may alleviate the immune-endocrine component concomitant to an acute affective episode, such as acute phase reaction, cytokine secretion and hyperactivation of hypothalamic-pituitary-adrenal axis. It is speculated that the antiviral and immunomodulatory properties of lithium may contribute to psychotropic actions of this ionic drug, especially prevention of recurrences in affective illness.

Fifty-nine patients with treatment-resistant depression were randomly allocated an addition of either lithium (Li; 31 patients) or carbamazepine (CBZ; 28 patients) to ongoing antidepressant treatment. The therapeutic efficacy of both strategies, assessed after 28 days, was not significantly different. In the Li group, clinical improvement significantly correlated with decrease in thyroxine concentration. Also, a decrease in cortisol level in Li responders and an increase in nonresponders was observed, suggesting a regulatory effect of Li on the hypothalamic-pituitary-adrenal axis activity. CBZ responders had lower baseline severity of depression than CBZ nonresponders and clinical improvement significantly correlated with increase in erythrocyte ATPase activity in the CBZ group.

This study was performed on 32 patients with refractory depression in whom lithium was added to antidepressant treatment in order to potentiate the therapeutic effect, and in 20 healthy controls. Plasma concentration of three acute-phase proteins (APPs): C-reactive protein, alpha-1-acid glycoprotein (AGP) and alpha-1-antichymotrypsin (ACT) as well as microheterogeneity of AGP and ACT were measured, before and after 4 weeks of lithium addition to antidepressants. Before Li addition, all patients studied had elevated values of APPs, which suggested the existence of immunological activation. A significant decrease in plasma levels of all APPs and the decrease of glycosylation values of AGP and ACT was observed after Li potentiation. A favorable clinical effect of lithium potentiation after 4 weeks was found in 24 patients (75%). Nonresponders to Li potentiation differed from responsers by their immunological indices prior to Li addition. They had higher values of reactivity coefficients, which means more inflammatory patterns.

In the beginning of 1960s, initial reports appeared pointing to a possibility of preventing depressive and manic recurrences in affective illness by means of long-term administration of lithium salts. Subsequent several years of controlled studies confirmed such prophylactic effect of lithium in affective illness beyond any doubt. Some patients in whom lithium administration was started in the beginning of 1970s may, by now, have received lithium for more than twenty years. The patient reported in the present paper, had began lithium treatment on April 1, 1971, after her third depressive episode since 1965. During 25 years of uninterrupted lithium carbonate administration in daily dose 1000 mg (for 5 years-750 mg) and with mean serum lithium concentration 0.6 mmol/l, the recurrences have not been observed, mental status was normal and professional (physician-ophthalmologist) and family functioning was good. Either somatic or mental side-effects have not occurred. Twenty five years of the patient's lithium treatment, was paralleled by important events for lithium therapy such as, i.a., autobiographies of prominent persons receiving lithium for porphylactic purposes, definition of a new category of psychotropic drugs (normothymic) with lithium as a prototype, establishing some mechanism of lithium action on intracellular transmission, discovery of antiviral and immunomodulatory effect of lithium as well as finding of decreased mortality of patients receiving long-term lithium therapy.

The authors review recent findings concerning biological mechanisms of drug-resistant depression. Treatment-resistant depression may result from the inability of antidepressants to normalize serotonergic transmission. Efficacy of therapeutic strategies enhancing serotonergic function such as potentiation of tricyclic antidepressants with lithium or fluoxetine as well as effectiveness of selective serotonin reuptake inhibitors in drug-resistant depression may support this hypothesis. Limbic-hypothalamic-pituitary-adrenal axis hyperactivity may be also an important factor of the persistence of depression, and so treatment with inhibitors of steroid biosynthesis may bring about readjustment of this axis and remission of depression in some cases of drug-resistant depression with hypercortisolemia. Another subtype of drug-resistant depression may be related to a dysfunction of hypothyroidism. Some evidence suggests also a relationship between drug resistance in depression and changes in the immune system. Research on biological mechanisms of drug-resistant depression may help clinicians to decide on the most appropriate treatment strategy in resistant depression as well as to shed light on the pathomechanism of depression.

Lithium augmentation of antidepressant drugs was studied in 51 patients with endogenous refractory depression. The remission after 28 days of lithium was obtained in 28 patients (55%). Better effect of lithium was shown in bipolar than unipolar patients, with subjects with lower pre-lithium severity of depression and in those with rapid improvement (within 7 days) on lithium addition. Factors such as age, gender, number of prior antidepressant (or ECT) treatments, type of preceding antidepressant, mean plasma lithium concentration and the results of DST did not show any association with the outcome of lithium augmentation. The 'priming' effect of lithium may contribute to the mechanism of lithium potentiation in a proportion of depressed patients.

Three mechanisms of lithium transport across erythrocyte membrane [lithium-sodium countertransport (LSC), lithium-potassium cotransport (LPC), and passive lithium diffusion (PLD)] were estimated in 27 acutely schizophrenic patients, 27 acutely depressed affective patients and in 18 control subjects. The activities of all mechanisms studied were significantly lower in both schizophrenic and depressed patients compared with controls. Analysis by gender showed that in control subjects, mean values of erythrocyte LSC and LPC were significantly higher in males compared with females. The decrease of LSC and LPC in depression and LSC in schizophrenia compared with control subjects was observed only in male patients but not in female ones. The results obtained suggest that lithium transport abnormalities during acute psychotic episodes are not specific to affective patients where lithium exerts its therapeutic action, but are also observed in schizophrenia. These abnormalities are more evident in male patients.

The effect of lithium (Li) and carbamazepine (CBZ) on erythrocyte lithium transport in vivo was investigated in 28 patients with affective or schizoaffective illness (14 given Li and 14 given CBZ). In 12 of them, Li or CBZ were added to current psychotropic treatment. The activities of erythrocyte lithium-sodium countertransport (LSC), lithium-potassium cotransport (LPC) and passive lithium diffusion (PLD) were assayed before and after 28 days of treatment. The administration of Li caused a significant decrease of LPC as well as PLD activity. The administration of CBZ resulted in a significant increase of the activity of LPC system. No systematic relationship was observed between Li or CBZ-induced alterations in erythrocyte transport and changes in clinical state of patients. The possible clinical implications of the dissimilar effect of Li and CBZ on erythrocyte lithium transport are discussed.

There has been considerable interest in the possibility that some psychotropic medications may possess antiviral activity. Several clinical observations suggest that lithium may inhibit the reactivation of latent herpes simplex virus, thereby reducing the number of recurrent infections. We performed a retrospective study examining the putative antiviral activity of various psychotropic agents in 177 subjects receiving lithium prophylaxis and a comparison group of 59 subjects receiving other antidepressant drugs for affective illness. Chronic lithium administration resulted in a significant reduction in the mean rate of recurrent labial herpes infections when compared to the pretreatment period (p less than 0.001). In contrast, the mean rate of herpes infections was unchanged in patients taking other antidepressants (p = 0.53). Although the overall reduction in herpes infections was not significantly different between groups, the proportion of subjects reporting a reduction in infection rate was greater in the lithium group (71%) compared with those receiving other antidepressants (52%) (p = 0.07). These data compliment prior in vitro and clinical studies demonstrating a potential antiviral activity for lithium carbonate.

The relative prophylactic efficacy of lithium against manic and depressive recurrences was examined in 61 patients (22 males, 39 females) with bipolar manic-depressive disorders by comparing the number of manic and depressive episodes for each patient during equally long periods before and during lithium treatment. In all the patients, the percentage of depressive episodes during lithium was smaller than that of manic episodes. The better antidepressive than antimanic prophylactic effect of lithium was significant only in male patients, while the reduction of manic episodes during lithium was greater in females. The fraction of patients without depressive episodes on lithium was greater in the male group. The results obtained with this study design indicate that lithium is an effective antidepressive prophylactic agent in bipolar patients. Sex differences are also implicated in response to lithium prophylaxis.

Erythrocyte lithium transport mechanisms--lithium-sodium countertransport (LSC), lithium-potassium cotransport (LPC) and passive lithium efflux (PLE)--were measured in 46 patients with bipolar affective disorder on prophylactic lithium therapy and in 20 healthy control subjects. Maximal velocity of LSC measured at saturating intracellular lithium concentration was lower in the patients than in the controls; this may concur with previous reports on possible links between impaired activity of LSC and bipolar affective illness. When measured at therapeutic lithium concentration, LSC was 4 times lower and Km for LSC was 5 times higher in lithium-treated affective patients than in control subjects. The in vivo erythrocyte:plasma lithium ratio was inversely correlated with LSC in lithium-treated patients; higher ratios were found in females than in males. No differences were found between affective patients and control subjects in other erythrocyte lithium transport measurements. The values for lithium transport were not related to age, duration of lithium therapy, concomitant neuroleptic treatment, hypertension or obesity. Lower activity of LSC was found in patients with lithium-induced thyroid enlargement than in the other patients. The results obtained are discussed in the light of contemporary findings concerning erythrocyte lithium transport mechanisms in affective disorders and other conditions.

The personality trait of alexithymia was assessed in 95 patients (35 male, 60 female) with affective illnesses, receiving lithium prophylactically, by means of Schalling-Sifneos Personality Scale (SSPS). The mean SSPS score was similar to that of the healthy population: only 8 patients had a score below 50 points. No relationship was observed between alexithymia score and age, diagnostic category (bipolar I, bipolar II, unipolar) and the duration of lithium therapy. Lower SSPS scores (i.e. high alexithymia) were found in subgroups of male patients with essential hypertension and female patients with lithium-induced obesity. The results suggest that alexithymic traits have no relationship to the pathogenesis of affective illness but may play some role in somatic symptoms emerging in affective patients on lithium prophylaxis.

Clinical and biochemical factors related to the activity of the erythrocyte lithium-sodium countertransport (LSC) system were investigated during lithium prophylaxis in 27 patients (13 male, 14 female) with bipolar affective illness. No relationship was found between erythrocyte LSC and such factors as age, gender, duration of lithium prophylaxis, quality of prophylactic lithium response, and family history of affective illness. There was a significant negative correlation between the activity of LSC and the magnitude of the erythrocyte lithium ratio both in whole group and in female patients. In seven patients with concomitant hypertension, the relationship between high activity of LSC and hypertension was not demonstrated. The levels of total cholesterol, HDL cholesterol, triglycerides, and potassium related neither to LSC activity nor to hypertension. Erythrocyte LSC in patients with lower TSH levels were significantly reduced compared to patients with higher TSH. The values of TSH were negatively correlated with T4 but not with T3. Concentrations of T3 were positively correlated with plasma total cholesterol levels. These results are discussed in the view of recent findings on erythrocyte LSC.

When lithium carbonate is administered to individuals, there is considerable intersubject variation in the extent of accumulation of Li+ by erythrocytes. The primary reason for this is differences in the activity of a Li+-Na+ counterflow system, which, under clinical conditions, removes Li+ from the cell. It appears that some bipolar patients accumulate more Li+ in their red cells than either unipolar depressives or normal controls. The precise clinical characteristics of the bipolar patients who accumulate relatively large amounts of erythrocyte Li+ need to be clarified in future research. Finally, the measurement of red cell concentrations of Li+, in addition to the usual plasma measurement, can be used as an indicator of patient compliance.

The active cation transport mechanisms (ouabain-dependent fluxes of sodium; ODS) and potassium (ODK), sodium-potassium adenosine triphosphatase ([Na+-K+]-ATPase) activity as well as lithium-sodium countertransport (LSC) reflecting sodium exchange diffusion, were studied in erythrocytes of forty-four patients with endogenous depression both in acute episode and in remission, and compared with thirty healthy control subjects. During depressive episodes, the activities of all mechanisms studied were significantly lower than those of control subjects. In female depressives the values of ODS and LSC were lower than in males. In remission, the activity of all mechanisms rose, reaching in most patients the values of control subjects. In female patients, activities of ODS and LSC were still lower than in male patients and female controls. The activities of ODS and LSC had the highest discriminating power between depressive patients and control subjects. It appears that membrane pathology may be an aetiologic factor in endogenous depression. A disturbance in erythrocyte transport presents most conspicuously during depressive episodes and in some patients may also persist to the normothymic period.

The authors investigated lithium and magnesium levels in serum and RBC in 30 patients with affective disorders during lithium prophylaxis. No differences in magnesium levels were found in relation to diagnosis (unipolar, bipolar), sex and age. Mean RBC lithium index was higher in females than in males, particularly in bipolar patients. Magnesium levels in erythrocytes showed a significant negative correlation with RBC lithium and RBC lithium index. Serum magnesium levels did not correlate of lithium concentrations. It was concluded that RBC magnesium may play a role in lithium penetration of RBC and this was discussed in relation to clinical and pathogenetic factors.

The effect of lithium administration on cation transport processes in erythrocytes was investigated in 26 patients with affective illnesses. The measures of ouabain-dependent sodium and potassium transport, Na+K+ATP-ase activity and lithium-sodium countertransport in erythrocytes were taken before and after 14 days of lithium therapy. In eleven patients an additional assay was made, following 3-12 months of continuous lithium administration. A significant increase in sodium and potassium transport as well as Na+K+ATP-ase activity was found after 14 days of lithium therapy, while the intensity of lithium-sodium countertransport markedly decreased. Maintenance treatment with lithium tended to stabilize these changes on the altered level. A role of cation transport in the mechanism of lithium action is discussed. It is suggested that an increment of erythrocyte active cation transport may accompany the normothymic effect of lithium.

The activity of the lithium--sodium countertransport system in erythrocytes was estimated in 16 control subjects and 28 patients suffering from affective disorders (11 bipolar, 17 unipolar) during depression, mania and remission. In all the patients studied, mean estimates of countertransport were significantly lower during an episode than after remission, with low values occurring more frequently in mania than in depression in bipolar patients. The mean values in patients with affective disorders but who were in remission remained lower than those of control subjects. Lowest values occurred more frequently in patients with bipolar than in those with unipolar illness. the possible physiological significance of reductions in the activity of the lithium--sodium countertransport mechanism in red cells was discussed.

The movement of the lithium ion (Li+) across the membrane of intact erythrocytes incubated in vitro was assessed under two different experimental conditions in which such transfer occurred primarily due to the activity of a lithium-sodium countertransport system. The 13 subjects on whom the in vitro procedures were done subsequently received lithium carbonate for 14 to 56 days, and the extent of accumulation of Li+ by erythrocytes in vivo was measured. While both in vitro procedures yielded data that correlated with the extent of accumulation of Li+ by erythrocytes in vivo, a system measuring the efflux of Li+ from Li+-loaded cells produced a much higher correlation (0.976). The magnitude of this correlation suggests that this in vitro system can be used for further investigations into the relevance of the erythrocyte accumulation of Li+ to the pathogenesis and treatment of affective disorders.

Previous investigations have elucidated an erythrocyte lithium-sodium countertransport (LSC) system as the primary mechanism for extruding lithium from the cell, and this activity has been described in terms of Michaelis-Menten kinetics. In most clinical studies the maximum velocity (Vmax) of the LSC has been measured by estimating the rate of lithium efflux from lithium-loaded cells. To date, few studies have examined whether the affinity (Km) of the LSC for lithium might be altered in patients with affective disorders. In the present study we examined LSC kinetic parameters (Vmax, leak, Km, and in vitro lithium ratio) at baseline in 80 patients with affective disorder and 25 healthy control subjects, and after 6 weeks of lithium administration in 33 of the patients. No differences in Vmax were observed between any patient and control group, although Vmax was significantly lower in unipolar depressed men compared to bipolar men (P = 0.043). The affinity (Km) of the transport 'carrier' for lithium did not differentiate between patient and control groups. Chronic lithium administration caused a decreased Vmax in bipolar men (P = 0.015), an increase in the in vitro lithium ratio in bipolar men (P = 0.002) and bipolar women (P = 0.002), and a marginal increase in Km in bipolar men (P = 0.08) and bipolar women (P = 0.06). Although the present data do not demonstrate an underlying difference for Km between affectively ill patients and controls, they do indicate a decrease in the affinity of the transport 'carrier' for lithium after chronic lithium administration.

Lithium pharmacokinetics after a single dose and pharmacokinetic prediction of optimal lithium carbonate dose in steady-state, were investigated in 15 patients with affective illness. In nine patients the course of plasma concentration after a single dose was characteristic for two-compartment and in six patients for one-compartment model. Patients fitting the two-compartment model required higher daily lithium dose to achieve steady-state therapeutic lithium level than patients fitting the one-compartment model. A significant correlation was found between plasma lithium level 12 and 24 h after a single dose and the daily dose required for achieving optimal lithium level in the course of subsequent lithium administration.

In 10 psychiatric patients marrow granulocyte reserve, marginal granulocyte pool, granulocyte mobilization into skin chamber, serum lysozyme activity was estimated before and ten days after the lithium treatment. In all patients the peripheral neutrophil count rose significantly. The marrow granulocyte reserve did not change markedly. Moreover, the marginal granulocyte pool as expressed in percentages diminished. Serum lysozyme activity, total leukocyte mobilization, and blood granulocyte clearance remained unchanged. However, the serum lysozyme activity index fell significantly. The in vitro addition of lithium to the suspension of granulocytes obtained from healthy persons reduce the granulocyte adherence especially in concentrations similar to those induced in treated patients. Our findings suggest that lithium in vivo may diminish the granulocyte adherence resulting in the prolonged intravascular half-life time of the cells. Thus, the cell accumulation in the vascular bed seems to be the main reason for lithium induced granulocytosis rather than the intensification of marrow granulocyte system proliferation.