Ongoing lithium treatment prevents relapse after total sleep deprivation.

Forty bipolar depressed inpatients underwent three consecutive cycles of total sleep deprivation (TSD). At the beginning of the study, 20 patients were free of psychotropic drugs and 20 had been receiving lithium medication for at least 6 months. Mood was rated on the Hamilton Rating Scale for Depression before and after TSD; perceived mood changes during treatment were evaluated with self-administered visual analog scales. Patients undergoing long-term lithium treatment showed a significantly better response to TSD as rated on both scales: 13 of 20 patients (vs. 2 of 20 patients without lithium) showed a sustained response during a follow-up period of 3 months. This preliminary evidence of a positive interaction of TSD and long-term lithium treatment could be explained by a synergistic effect of both treatments on brain serotonergic function, possibly via a desensitization of 5-hydroxytryptamine-1A inhibitory autoreceptors.     

Effect of chronic lithium and withdrawal from chronic lithium on presynaptic dopamine function in the rat

Bipolar affective disorders can be successfully treated with long-term use of the mood stabilizer lithium. However, discontinuation of lithium treatment is followed by a high incidence of manic episodes. In the present study, we attempted to identify neurobiological changes that might mediate this rebound mania. In vivo microdialysis in the anaesthetized rat and in situ hybridization histochemistry were used to study the effect of chronic lithium treatment and withdrawal from chronic lithium treatment on presynaptic dopamine (DA) function. Rats were maintained for 28 days on a lithium diet or control diet. The lithium-withdrawn treatment group had their lithium diet substituted for control diet from day 25 of the treatment period. Microdialysis probes were implanted in the shell of the nucleus accumbens and both basal extracellular DA levels and DA levels in the presence of the DA uptake inhibitor bupropion (1 microM) were collected. Basal DA levels did not differ between any of the treatment groups. However, during local perfusion of bupropion, the increase in DA was significantly attenuated in the lithium-treated animals compared to controls or lithium-withdrawn animals. In situ hybridization of DA transporter mRNA in the ventral tegmental area revealed no difference in the abundance of this mRNA in any of the groups. These data suggest that there is impaired DA release in rats during chronic lithium treatment, but DA release returns to normal levels on withdrawal from lithium treatment, and is therefore unlikely to underlie the rebound mania associated with lithium withdrawal.     

Ten-year follow-up of thyroid function in lithium patients.

The objective of this paper was to study prospectively the course of clinically relevant thyroid dysfunction in a cohort of patients on long-term lithium treatment. Patients (N = 150) who had undergone a cross-sectional evaluation of their thyroid function in 1989, when they were at different stages of lithium treatment, were followed up for the presence of thyroid autoimmunity, hypothyroidism, and goiter during a further period of lithium exposure of up to ten years. The following annual rates of newly developed thyroid dysfunction were observed: autoimmunnity (1.4%), subclinical hypothyroidism (1.7%), and goiter (2.1%). Subjects with thyroid autoimmunity had a higher chance of requiring substitution treatment with levothyroxine for subclinical hypothyroidism compared with subjects with no evidence of thyroid autoimmunity (13/32 = 41% versus 7/118 = 6%). Subjects (N = 15) who were prescribed carbamazepine in addition to lithium showed a significant decrease of TSH concentrations. In patients already being treated with lithium for several years, the overall incidence of hypothyroidism, goiter, and thyroid autoimmunity were comparable with those reported for the general population. However, lithium exposure may represent an additional risk factor for hypothyroidism in women and/or in the presence of thyroid autoimmunity.     

Bilateral hippocampal volume increases after long-term lithium treatment in patients with bipolar disorder: a longitudinal MRI study

Rationale The majority of volumetric magnetic resonance imaging (MRI) studies of the hippocampus in patients with bipolar disorder (BD) show no differences in hippocampal volume between patients and healthy controls. Significant variability, however, exists in the medication status of patients included in these studies. In particular, treatment with lithium may exert long-term effects on hippocampal volume, influencing cognitive outcomes in BD patients. Objectives To our knowledge, no longitudinal volumetric study has been performed in patients with BD, which would allow for an examination of whether lithium therapy used to treat BD can exert a long-term effect on hippocampal volume. Materials and methods We examined the effects of lithium on hippocampal volumes and recollective memory performance over a period of 2 to 4 years in 12 patients with BD who had never received pharmacotherapy before lithium initiation. Results We found bilateral increases in volume of the hippocampus over time. We also found some evidence of improvement in verbal memory performance over the 4-year measurement period as assessed by the California Verbal Learning Test. Conclusions Consistent with preclinical literature supporting the neuroprotective effects of lithium, long-term treatment is associated with preservation of recollective memory function and increased hippocampal size in vivo.     

Chronic treatment with lithium,but not sodium valproate,increases cortical N-acetyl-aspartate concentrations in euthymic bipolar patients

Previous studies have found that treatment with lithium over a 4-week period may increase the concentration of N-acetyl-aspartate (NAA) in both bipolar patients and controls. In view of other findings indicating that NAA concentrations may be a good marker for neuronal viability and/or functioning, it has been further suggested that some of the long term benefits of lithium may therefore be due to actions to improve these neuronal properties. The aim of the present study was to utilize H magnetic resonance spectroscopy ( H MRS) to further examine the effects of both lithium and sodium valproate upon NAA concentrations in treated euthymic bipolar patients. In the first part of the study, healthy controls (n =18) were compared with euthymic bipolar patients (type I and type II) who were taking either lithium (n =14) or sodium valproate (n =11), and NAA : creatine ratios were determined. In the second part, we examined a separate group of euthymic bipolar disorder patients taking sodium valproate (n =9) and compared these to age- and sex-matched healthy controls (n =11), and we quantified the exact concentrations of NAA using an external solution. The results from the first part of the study showed that bipolar patients chronically treated with lithium had a significant increase in NAA concentrations but, in contrast, there were no significant increases in the sodium valproate-treated patients compared to controls. The second part of the study also found no effects of sodium valproate on NAA concentrations. These findings are the first to compare NAA concentrations in euthymic bipolar patients being treated with lithium or sodium valproate. The results support suggestions that longer-term administration of lithium to bipolar patients may increase NAA concentrations. However, the study suggests that chronic administration of sodium valproate to patients does not lead to similar changes in NAA concentrations. These findings suggest that sodium valproate and lithium may not share a common mechanism of action in bipolar disorder involving neurotrophic or neuroprotective effects.     

Carbamazepine augmentation in lithium-refractory bipolar patients: a prospective study on long-term prophlyactic effectiveness

Twenty-two patients affected by bipolar or schizoaffective disorder, in whom carbamazepine was added to lithium after recurrence when on maintenance with lithium alone, were followed up prospectively for 2 to 13 years. The number of episodes, hospitalizations, and cumulative affective morbidity was markedly reduced after carbamazepine augmentation. Seventeen patients presented a better course during combined treatment than during lithium alone, and of these 15 had no further recurrences. Four patients did not appear to improve after carbamazepine augmentation, whereas one featured reemergence of affective episodes after having derived satisfactory benefit from combination for 7 years (delayed tolerance). Carbamazepine augmentation was associated with a reduction of lithium doses in some patients, including a subgroup who had not tolerated lithium at usual therapeutic levels. Carbamazepine significantly reduced serum thyrotropin concentrations, which were abnormally high in approximately one half of patients when on lithium alone. Total serum thyroxine concentrations were also decreased after carbamazepine augmentation, but free thyroid hormone concentrations did not change. Other significant carbamazepine-induced changes in laboratory tests included increases in total cholesterol concentrations and decreases in white blood cell counts.     

Recurrence risk in bipolar manic-depressive disorders after discontinuing lithium maintenance treatment: an overview

Lithium remains unequaled in its research support as a standard maintenance treatment for bipolar manic-depressive disorders. It has important beneficial effects on recurring bipolar depression as well as mania, and in both types I and II bipolar syndromes, with powerful antisuicide effects not demonstrated with alternative mood-stabilisers. Data collected from numerous studies indicate that discontinuing lithium maintenance treatment is followed by sharply increased morbidity and possibly mortality, particularly in the first 6 to 12 months. However, we found that gradual discontinuation markedly reduced, and not merely delayed, recurrences of mania or depression after discontinuing lithium, with an even stronger effect in bipolar type II than type I patients. Secondary long-term retreatment with lithium following discontinuation yielded only minor average losses of benefits. Increased early recurrence risk may also arise after stopping long-term treatment with other neuropsychotropic drugs. Such reactions probably reflect physiological adaptations of the brain to pharmacodynamic effects, and their impact may be limited by slow drug discontinuation. The phenomenon of high early post-treatment discontinuation recurrence risk has clinical and scientific implications for the design, management and interpretation of treatment protocols that involve discontinuing long-term treatments in disorders requiring maintenance pharmacotherapy with centrally neuropharmacologically active drugs.     

On the elimination half-life of lithium in long-term treatment of patients with affective disorders

The elimination half-life of lithium was investigated in 55 patients on long-term treatment in 1980, when their mean treatment time was 7·5 years. Twenty-seven of the patients were reinvestigated 7 years later, at which point their mean treatment time was 15 years. An approximate method for determining the elimination half-life of lithium was used, and this variable was tested in eight chronic psychotic patients on lithium treatment, in whom the elimination half-life was also determined by a conventional technique. The elimination half-life was 32 h in 1980 and varied between 15 and 128 h. The elimination half-life was significantly increased 7 years later, with a median increase of 8 h. The elimination half-life of lithium was closely correlated to age and to daily weight-related dose of lithium when the patients entered the study in 1980, but this was not seen at the time of the reinvestigation in 1987. The elimination half-life did not vary with serum creatinine, maximal urine osmolality, or with the concomitant neuroleptic medication. Further studies are needed to clarify the clinical significance of the prolonged elimination half-life with time.     

Addition of lithium to haloperidol in non-affective,antipsychotic non-responsive schizophrenia: a double blind,placebo controlled,parallel design clinical trial

This double-blind placebo controlled, parallel design clinical trial compared the therapeutic effects of the addition of lithium or placebo to haloperidol in 21 seriously ill state hospital patients with DSM-III-R schizophrenia, who did not have concurrent affective disorders and who had not responded to previous trials of conventional antipsychotic medication. During a baseline period of 6 weeks, patients were switched to a stable dose of haloperidol (mean ± SD dose=13.6±8.1 mg/day). Patients were then randomized to receive either lithium or placebo in addition to haloperidol for 8 weeks (mean ± SD lithium level =0.98±0.13 mEq/1). Symptoms and side effects were assessed weekly. Improvement in symptoms correlated with the non-blind adjustment of antipsychotic dose, but not with lithium or placebo treatment. Side effects ratings did not differ between the two groups, but one patient developed a reversible delirium associated with combined lithium/haloperidol treatment. For these long-term, severely ill patients, combined treatment afforded no advantage over treatment with haloperidol alone.Supported by Grant MH 46700 from the National Institute for Mental Health. Lithium and lithium placebo capsules were supplied by Lilly Pharmaceuticals     

Fluoxetine treatment of bipolar II depression

We have previously reported on the familial aggregation of bipolar II affective disorder and have speculated that new treatment approaches might be required for this difficult disorder. Based on Reimherr's report that fluoxetine responders were more likely to have poor prior responses to tricyclics and to have chronic depressions with "atypical" clinical features, we used fluoxetine to treat the chronic atypical depression in selected bipolar II outpatients. The 16 bipolar II patients in our series had been depressed for an average of 5.3 years prior to starting fluoxetine and had had poor responses to tricyclics, MAOIs, and lithium. All but one have had some response to fluoxetine. Ten of the 13 patients who have been taking fluoxetine for 10 or more months have had a good to very good response and the other 3 have had a fair response. Only one patient discontinued fluoxetine because of side effects. These findings should encourage further treatment research using fluoxetine and other serotonin reuptake blockers as well as research into the pathophysiologic identity of bipolar II as a possible distinct form of affective disorder.     

Use of topiramate in treatment-resistant bipolar spectrum disorders

To evaluate the effectiveness and safety of topiramate as add-on, long-term therapy for treatment-resistant bipolar-spectrum disorders, 34 DSM-IV bipolar-spectrum patients, including bipolar I (n = 28), bipolar II (n = 3), bipolar not otherwise specified (n = 2), and schizoaffective disorder bipolar type (n = 1), considered to be resistant to treatment with lithium, carbamazepine, and valproate, received increasing doses of topiramate as adjunctive therapy for their manic (n = 17), depressive (n = 11), hypomanic (n = 3), or mixed (n = 3) symptoms. Outcome measures included the Young Mania Rating Scale (YMRS), the Hamilton Rating Scale for Depression (HAM-D), and the Clinical Global Impression (CGI) for Severity. Patients were followed up for 6 months. Twenty-five patients (74%) completed the 6-month follow-up. Nine patients (26%) dropped out early due to lost of follow-up (n = 4), worsening of symptoms (n = 2), side effects (n = 1), hospitalization due to intercurrent illness (n = 1), and noncompliance (n = 1). By intent-to-treat analysis, there was a significant reduction in YMRS, HAM-D, and CGI scores (p < 0.0001 for all measures at the endpoint) after the introduction of topiramate. Most therapeutic effects appeared between weeks 2 and 6. Fifty-nine percent of manic patients and 55% of depressed patients were considered to be responders to the drug, which was well tolerated; only one patient discontinued due to side effects. The most common side effect was paraesthesia (n = 2). Ten patients experienced moderate weight loss during the follow-up period. The mean topiramate dose at endpoint was 202 +/- 65 mg/day. These preliminary results indicate that adjunctive topiramate may be useful in the long-term treatment of bipolar spectrum disorders, even in the most difficult-to-treat patients.     

Decreased anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder.

This project was designed to compare differences in brain proton spectra between children and adolescents with bipolar disorder (BPD) and gender and age-matched normal controls, and to measure changes in myo-inositol levels following lithium therapy, utilizing in vivo proton magnetic resonance spectroscopy (1H MRS). A single voxel (2x2x2 cm3) was placed in brain anterior cingulate cortex for acquisition of the 1H spectra at baseline and after acute (7 days) lithium administration in 11 children (mean age 11.4 years) diagnosed with BPD, and in 11 normal controls. Acute lithium treatment was associated with a significant reduction in the myo-inositol/creatine ratio. This decrement was also significant in lithium-responders when analyzed separate from non-responders. Compared to normal controls, BPD subjects showed a trend towards a higher myo-inositol/creatine during the manic phase. These preliminary data provide evidence that a significant reduction in anterior cingulate myo-inositol magnetic resonance may occur after lithium treatment, especially among responders. Follow-up studies involving a larger sample may allow us to confirm whether changes in myo-inositol associated with acute lithium therapy persist in long-term clinical response of patients with and without lithium compliance.     

Neutrophil mobilization in lithium-induced neutrophilia

Twenty patients on long-term treatment with lithium who had persistently elevated neutrophil counts were challenged with adrenalin and hydrocortisone to measure their marginal and bone marrow granulocyte pools. Compared with normal controls the results suggest that the absolute numbers of granulocytes in each pool are not increased, although the percentage change is diminished because of the greater baseline values in the experimental group. These data suggest that lithium acts on granulopoiesis within the bone marrow, and are in keeping with the concept that the granulocyte reserve has a finite size. There is no apparent connection between lithium-induced neutrophilia and either the therapeutic or unwanted effects of lithium.     

Lithium augmentation of venlafaxine: an open-label trial

The authors conducted an open-label study of the efficacy and tolerability of venlafaxine and of lithium augmentation in outpatients with depression who were not responding to venlafaxine. Outpatients aged 18 to 70 years were eligible if they had a minimum baseline score of 16 on the 17-item Hamilton Rating Scale for Depression (HAM-D). Patients were started on venlafaxine 37.5 mg twice daily for 1 week. For weeks 2 through 4, the dose of venlafaxine was increased to 75 mg twice daily, and for weeks 5 through 7, the dose was further increased to 75 mg three times daily. At the end of the 7-week treatment period, patients with a <50% decrease in their HAM-D scores from baseline were given lithium carbonate 600 mg once daily. The dose of lithium carbonate was adjusted to maintain plasma levels in the range of 0.6 to 1.0 mmol/mL. Efficacy was assessed with the 17-item HAM-D, Montgomery-Asberg Depression Rating Scale, and the Clinical Global Impressions Scale. Data were analyzed on an intent-to-treat basis. At the end of the 7-week treatment period, 35% of patients showed a > or = 50% decrease in their HAM-D scores from baseline. Lithium augmentation was initiated in 23 patients. The results showed that the addition of lithium was well-tolerated and led to a further decrease in the HAM-D scores, with eight patients responding and two of them presenting a remission. The addition of lithium to venlafaxine was found to be a well-tolerated strategy in treatment-resistant patients.     

Routine EEG examinations accompanying lithium therapy over two years (author's transl)]

In 15 lithium-treated psychotic patients, the following variables were examined over two years at 6-monthly intervals; seru lithium levels, serum electrolytes, thyroid function, urinary creatinine and urea, and clinical EEG. The mean serum lithium level was 0.64 mval/l and did not change during the two years. When compared to the pretreatment EEG, visual analysis did not indicate any specific potentials, focal signs, or asymmetrical phenomena such as have been reported in the literature. Only at the beginning of treatment could a small increase in unspecific, abnormal changes be demonstrated, which, however, decreased during the following 18-month period of investigation.     

A controlled trial of lithium augmentation in fluvoxamine-refractory obsessive-compulsive disorder: lack of efficacy.

Two- and 4-week double-blind placebo-controlled trials of lithium augmentation of ongoing fluvoxamine treatment trials were conducted in 20 and 10 patients, respectively, with primary obsessive-compulsive disorder (OCD) who had failed to respond to fluvoxamine alone. Although 2 weeks of double-blind lithium augmentation produced a small but statistically significant reduction in obsessive-compulsive symptoms, most patients did not have a clinically meaningful response. Furthermore, there was no statistical or clinical improvement in obsessive-compulsive symptoms during the subsequent 4-week double-blind, placebo-controlled trial of lithium augmentation. On the basis of treatment response criteria, only 18% and 0% of the patients responded to lithium augmentation of fluvoxamine during the 2- and 4-week treatment trials, respectively. In light of the previously reported 44% response rate to lithium augmentation in treatment-resistant depressed patients on fluvoxamine, the results of this study suggest that pathophysiological differences may exist between OCD and depression. The routine use of lithium augmentation in the management of patients with OCD who are refractory to serotonin reuptake inhibitors is not supported by these findings.     

Lithium poisoning from a poison control center perspective

The purpose of this study was to evaluate the severity of lithium poisoning from a poison control center-based population and the correlation of the Hansen and Amdisen classification with outcome and lithium levels in that setting. All lithium overdoses brought to the attention of the poison control center were prospectively observed during 1 year. Demographic data, amount ingested, coingestants, symptoms and signs, lithium levels, treatment, and outcome were recorded. There were 12 acute lithium overdoses: 5, 5, and 2 with grade 0, 1, and 2, respectively. No patients required hemodialysis or had sequelae or died. There were 174 acute-on-chronic overdoses: 66, 85, 15, and 8 with grade 0, 1, 2, and 3, respectively. Six patients underwent hemodialysis; none had sequelae but one died. There were 19 chronic poisonings: 9, 9, and 1 with grade 1, 2, and 3, respectively. Three patients underwent hemodialysis; one had sequelae and one died. Patients classified as grade 2 had higher lithium levels than those with grade 1 in patients with only lithium poisoning (3.08 +/- 0.77 vs. 2.09 +/- 0.91 mmol/L P = 0.03). The study concluded that morbidity (0.5%) and mortality (1%) associated with lithium poisoning are rarely observed. The Hansen and Amdisen classification does not appear to be a useful clinical tool to predict either morbidity or mortality and does not correlate well with lithium levels.     

Olanzapine: new indication. Prevention of bipolar disorder: unconvincing trials

(1) Lithium, the standard preventive treatment for patients with bipolar disorder, reduces the number of relapses and suicide attempts. (2) Olanzapine is the first neuroleptic to be approved in France for prevention of relapse in patients with bipolar disorder. Many neuroleptics are already used for this indication but their efficacy has not been established in comparative clinical trials. (3) One placebo-controlled double-blind trial involved 361 patients who were treated just after recovering from a manic episode. The trial was supposed to last 48 weeks, but only 146 patients were treated for more than 8 weeks. Therefore, the trial results, including an observed effect on mania, cannot be interpreted to imply long-term prevention. (4) One double-blind trial compared olanzapine plus a mood stabiliser with placebo plus a mood stabiliser in 344 patients who had recovered from an acute episode. Only 21 patients completed the 12-month trial, and the percentage of patients who had relapses (manic or depressive) did not differ significantly between the groups. (5) In a third double-blind trial, 431 patients in remission from a manic episode after treatment with olanzapine + lithium were treated for 12 months with lithium or olanzapine. This trial suggested that olanzapine was more effective in preventing depressive and manic relapses (30% of patients, compared to 38.8% with lithium), but only 171 patients completed the trial. Most dropouts were due to adverse events (19% with olanzapine, 26% with lithium). The impact of treatment on suicide risk was not studied. (6) In a fourth study, 101 patients in remission from a mixed or manic episode continued their initial treatment with olanzapine or sodium divalproate in double-blind manner for 11 months. The risk of relapse was not significantly different between the groups, but the study sample size was too small to tell whether or not the treatments were equally effective. (7) Trials focusing on prevention of relapse in patients with bipolar disorder confirmed the known adverse effects of olanzapine, including weight gain and QTc prolongation. Olanzapine was associated with more weight gain and sedation than lithium. Hyperglycaemia occurring on olanzapine can cause life-threatening ketoacidosis. (8) Lithium remains the standard treatment for preventing recurrent bipolar disorder. There is no firm evidence that olanzapine is more effective than a mood stabiliser after lithium failure, or that it boosts the efficacy of lithium.     

Maintenance efficacy of divalproex in the prevention of bipolar depression.

Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recently published, double-blind, placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients. This report describes, in further detail, the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder. A randomized, double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance period. Bipolar I patients, who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode, were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase. Outcome measures were the rate of early discontinuation for depression, time to depressive relapse, proportion of patients with depressive relapse, mean change in Depressive Syndrome Scale score, proportion of patients receiving antidepressants, and time in the study. Among patients taking an antidepressant, a higher percentage of patients on placebo than divalproex discontinued early for depression. Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period. Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance. Indices of severity of prestudy illness course predicted worse outcome in all treatment groups. Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder, particularly in patients who had responded to divalproex when manic, and among patients with a more severe course of illness.