Lithium therapy in patients on dialysis: A systematic review.

BACKGROUND: Lithium is a first-line pharmacotherapy for the treatment of bipolar disorder, but long-term use is associated with nephrotoxicity. However, as dialysis effectively eliminates lithium, it remains a pharmacotherapeutic option for patients on dialysis. This systematic review seeks to evaluate the dosing, safety, efficacy, and monitoring of lithium in patients receiving dialysis. METHOD: A PubMed database search performed May 5th, 2020, identified 535 article titles. After exclusion criteria were applied, a total of 15 articles were included in this systematic review. RESULTS: In 18 patients receiving dialysis, lithium was primarily used for the treatment of mood disorders. The majority of patients received 300-900 mg lithium carbonate thrice-weekly following dialysis, but several alternative lithium salts and dosing strategies were utilized. The pharmacokinetic properties of lithium in dialysis are not well understood and can be complicated by a serum lithium "rebound effect" following dialysis, due to a two-compartment volume of distribution. Additionally, presence of residual diuresis in some patients may be reason to administer lithium more frequently than thrice-weekly following dialysis. Lithium was shown to be an effective pharmacotherapy in all patients, with many demonstrating rapid improvement after drug initiation. Five patients experienced an adverse event on lithium, but only one patient required lithium discontinuation. CONCLUSION: Lithium may be used in patients on dialysis, with close monitoring of pre-dialysis serum lithium concentrations for at least two weeks after treatment initiation, followed by a lower frequency after stabilization to ensure therapeutic concentrations and reduce toxicity risk.

Lithium Is Likely to Persist in the Brain: Clinical Implications for Electroconvulsive Therapy.

ABSTRACT: Electroconvulsive therapy and concomitant lithium therapy remain a matter of debate because of increased rates of adverse events. Current recommendations include monitoring lithium levels and reducing lithium to minimally effective dose. We present a report on protracted effects of lithium intoxication as electroconvulsive therapy 8 days after intoxication and under normal lithium serum levels resulted in a prolonged seizure. Electroencephalogram recordings before stimulation showed electroencephalogram correlates of subsiding lithium intoxication most likely due to protracted lithium influx and efflux of the central nervous system.

Lithium toxicity with prolonged neurologic sequelae following sleeve gastrectomy: A case report and review of literature.

RATIONALE: Lithium is the first-line medication for bipolar disorder, given a narrow therapeutic window of 0.8 to 1.2 mEq/L. Change of lithium pharmacokinetics following bariatric surgery may lead to lithium toxicity, which is particularly concerned. PATIENT CONCERNS: We presented a 39-year-old man with morbid obesity and bipolar affective disorder for 20 years, who was treated with lithium. He developed serious lithium toxicity following sleeve gastrectomy and prolonged neurologic sequelae. DIAGNOSES: He suffered from persistent watery diarrhea, general weakness, and then drowsy consciousness. Lithium level was checked immediately to be 3.42 mEq/L and lithium toxicity was diagnosed. INTERVENTIONS: After 3 courses of hemodialysis, his serum lithium level subsequently declined to 0.63 mEq/L, while his consciousness returned normal. Lithium was replaced by lamotrigine. OUTCOMES: The patient was discharged thirty-five days after admission, while his serum lithium declined to 0.06 mEq/L. Neurologic sequelae were noted by muscle weakness and pain sensation in both feet. The nerve conduction test revealed sensorimotor polyneuropathy with conduction block. He was advised to keep a passive range of motion exercise. LESSONS: Although the consensus guideline remains lacking, our report reviewed cases of relevance in the literature and highlighted the awareness of the potential risk of lithium toxicity following bariatric surgery. We suggest close monitoring of the lithium levels and perhaps a dosage adjustment for the postoperative period.

Combination of Olanzapine and Samidorphan Has No Clinically Significant Effect on the Pharmacokinetics of Lithium or Valproate.

BACKGROUND AND OBJECTIVE: Olanzapine is an atypical antipsychotic indicated for the treatment of schizophrenia and, either as monotherapy or as an adjunct to lithium or valproate, for bipolar I disorder. Multiple daily doses of olanzapine do not affect the pharmacokinetics of lithium or valproate; therefore, concomitant olanzapine administration does not require dosage adjustment of lithium or valproate. ALKS 3831, a combination of olanzapine and the opioid receptor antagonist samidorphan (OLZ/SAM), is currently under development to provide the established antipsychotic efficacy of olanzapine while mitigating olanzapine-induced weight gain. Olanzapine is recognized as one of the most efficacious antipsychotics; however, the benefits of olanzapine are offset by its propensity to cause significant weight gain, which may lead to long-term metabolic sequelae. This study evaluated the effects of multiple daily doses of OLZ/SAM on the pharmacokinetics of lithium or valproate in healthy subjects. METHODS: This was an open-label, single-sequence, two-cohort study (ALKS3831-B101) conducted at a single center in the USA. Thirty-four healthy adult subjects were assigned (1:1) to receive lithium carbonate 300-mg tablets (cohort 1) or divalproex sodium 500-mg tablets (cohort 2), once every 12 h on days 1-7. Once-daily oral doses of OLZ/SAM (olanzapine 10 mg/samidorphan 10 mg) bilayer tablets were administered on days 8-18. Subjects resumed every 12-h doses of lithium or valproate concomitantly with the once-daily oral doses of OLZ/SAM on days 12-18. Plasma concentrations of lithium and valproic acid (valproate) were quantified in blood samples collected prior to and up to 12 h after lithium or valproate dose administration on days 7 and 18. Pharmacokinetic parameters of lithium and valproate, including maximum plasma concentration and area under the plasma concentration-time curve over a 12-h dosing interval, were calculated. The ratio of geometric means of maximum plasma concentration and area under the plasma concentration-time curve over a 12-h dosing interval in the presence and absence of OLZ/SAM, and its two-sided 90% confidence intervals, were derived from a mixed-effects model. Adverse events were monitored throughout the study. RESULTS: The 90% confidence intervals for the ratios of geometric means, in the presence vs. absence of OLZ/SAM, were within the equivalence interval of 80-125% for both maximum plasma concentration and area under the plasma concentration-time curve over a 12-h dosing interval of lithium and of valproate. The safety profiles of lithium or valproate co-administered with OLZ/SAM were consistent with what has been previously reported for lithium or valproate. The safety profile of OLZ/SAM was consistent with that observed in previous clinical studies with OLZ/SAM. CONCLUSIONS: Consistent with previously reported findings on olanzapine, administration of multiple doses of OLZ/SAM did not have a clinically significant effect on the pharmacokinetics of lithium or valproate. Co-administration of OLZ/SAM and lithium or valproate was generally well tolerated; the safety profile of OLZ/SAM was consistent with that observed in previous clinical studies.

Factors influencing lithium pharmacokinetics in patients with acute mania: A population pharmacokinetic analysis.

OBJECTIVE: The objective of this study was to conduct a population pharmacokinetic model of lithium in Thai patients with acute mania. METHODS: Lithium concentrations from 222 acute manic patients were included in this study. The population pharmacokinetic model was developed using NONMEM 7.3 software. Influences of potential covariates including body size, age, renal function, and gender were evaluated through a stepwise approach. Bootstrap analysis and an external validation approach were used to evaluate the robustness and predictability of the final model. RESULTS: A one-compartment model adequately described lithium pharmacokinetics. Body weight and age were significant predictors for lithium clearance, with the following relationship: CL/F (L/hr) = 1.43 * (WT/65)0.425  * (age/38)-0.242 . The population estimates of lithium clearance, volume of distribution, and absorption rate constant of the final model were 1.43 L/hr, 54 L (fixed), and 0.426 hr-1 (fixed), respectively. Model evaluation showed that the final model was predictive and robust. CONCLUSIONS: A population pharmacokinetic model of lithium with good performance was developed in Thai patients with acute mania. This model can be used to assist clinicians in individualized lithium therapy.

Population pharmacokinetic modeling of sustained release lithium in the serum, erythrocytes and urine of patients with bipolar disorder.

PURPOSE: Lithium (Li), the first-line treatment of bipolar disorder, was first developed as an immediate-release form with a routine therapeutic drug monitoring 12 h after the last dose. In Europe, the most commonly prescribed form is a sustained release (srLi). Yet no pharmacokinetics (PK) study has been published of srLi, administered once a day, in adults. The present study describes srLi PK in the serum and erythrocytes of bipolar patients. METHODS: To assess srLi PK, we studied prospectively 17 French bipolar patients on a median dose of 1000 mg (600-1600) for at least 2 years. Serum (S), erythrocyte (E) concentrations, and urinary (U) amount were collected over 8 h after 15 days of morning intake using monitoring electronic medical system (MEMs). Population PK parameters were estimated using the SAEM algorithm (MONOLIX 4.3.3 software). RESULTS: Using a population approach, we built a PK population model of srLi including one S compartment (VS = 23.0 L, ClS = 1.21 L h-1), one E compartment (VE = 64.7 L, ClSE = 3.63 L h-1, ClES = 9.46 L h-1), and one U compartment (F = 0.62) and estimate the ratio of concentrations to Li in E over S at 0.38 with 27% between-subject variability. CONCLUSION: This is a PK model of srLi once a day in bipolar patients using a population approach simultaneously describing Li concentrations in serum, erythrocytes, and urine which provide an estimate of the ratio of concentration in erythrocyte over serum and its between-subject variability (BSV).

Population Pharmacokinetics and Exposure-Response of Lithium Carbonate in Patients Based on Tubular Reabsorption Mechanisms.

BACKGROUND AND OBJECTIVE: Lithium, which is used to treat bipolar disorder, has a narrow therapeutic blood concentration range and quickly reaches clinically toxic levels. We performed a population pharmacokinetic analysis with a lithium tubular reabsorption model including urinary pH and investigated the relationship between blood lithium concentration and tremor as a side effect. METHODS: Routine clinical data, including 389 serum concentrations, were collected from 214 patients orally administered an adjusted amount of lithium carbonate. Pharmacokinetics were described using a one-compartment distribution model with first-order absorption and elimination. The fractions of the MID (Li+ + LiCO3-) and ION (2Li+ + CO32-) forms were calculated using the Henderson-Hasselbalch equation, and the influences of these fractions on clearance (CL) were evaluated. The rate of tremor development was analyzed using a logit model. RESULTS: Oral apparent CL (CL/F) was explained by nonrenal CL and renal CL, and renal CL was varied by the fractions of lithium forms influenced by urinary pH. The contribution of MID to CL was slightly larger than that of ION. The rate of tremor development was estimated to be more than 30% when the trough lithium concentration was greater than 1.26 mEq L-1. CONCLUSION: Renal function and urinary pH are important indices in lithium treatment, so the serum concentration of lithium may be predicted based on the renal function and urinary pH.

Lithium therapeutic dose monitoring in human saliva.

BACKGROUND: Lithium carbonate is valuable and effective agent in the treatment and prophylaxis of mood disorders, particularly bipolar disorder (BD). Due to its narrow therapeutic range, frequent serum lithium estimation is necessary. To avoid the discomfort of frequent venipuncture, a non-invasive method for serum lithium concentration is needed. An alternative method of determining lithium level could be saliva or urine. Literature data regarding the reliability of saliva lithium levels is not conclusive. MATERIAL AND METHODS: The aim of this study is to provide an overview of possibility to replace blood serum with saliva look through research in that field. RESULTS: Some authors conclude that there is constant ratio between serum and saliva lithium level and they suggest that saliva can replace serum for estimation lithium level. Other revealed that saliva/serum lithium ratio is constant individually, so saliva/serum lithium ratio should be estimated individually. Finally there are studies excluding the possibility of replacement serum with saliva. CONCLUSIONS: There is little number of studies on saliva clinical use in lithium level monitoring. Further studies should base on current data including methods of obtaining saliva and its biochemical analysis, collecting samples in a specific time frame from the last dosage of lithium, as well as inter-subject or intra-subject measurements.

Lithium in Paediatric Patients with Bipolar Disorder: Implications for Selection of Dosage Regimens via Population Pharmacokinetics/Pharmacodynamics.

BACKGROUND: Lithium is a well-established treatment for bipolar I disorder in adults. However, there is a paucity of information on its pharmacokinetics/pharmacodynamics in children and adolescents. We aimed to develop the first lithium dosage regimens based on population pharmacokinetics/pharmacodynamics for paediatric patients. METHODS: Lithium concentrations, Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Improvement (CGI-I) scores over 24 weeks were available from 61 paediatric patients with bipolar I disorder. The population pharmacokinetics/pharmacodynamics were co-modelled. Concentrations and clinical effects following several dosage regimens were predicted by Monte Carlo simulations. RESULTS: The pharmacokinetics were well characterised by a two compartment model with linear elimination. Including the effect of total body weight (TBW) or lean body weight (LBW) on clearance and volume of distribution decreased the unexplained inter-individual variability by up to 12 %. The population mean (inter-individual variability) clearance was 1.64 L/h/53 kg LBW0.75 (19 %) and central volume of distribution 23.6 L/53 kg LBW (6.8 %). The average lithium concentration over a dosing interval required for a 50 % reduction in YMRS was 0.711 mEq/L (59 %). A maintenance dose of 25 mg/kg TBW/day lithium carbonate in two daily doses was predicted to achieve a ≥50 % reduction in YMRS in 74 % of patients, while ~8 % of patients would be expected to have trough concentrations above the nominal safety threshold of 1.4 mEq/L. Therefore, therapeutic drug monitoring will still be required even with these dosing strategies. CONCLUSIONS: When accounting for body size, the pharmacokinetic parameters in paediatric patients were within the range of estimates from adults. Pharmacokinetic/pharmacodynamic modelling supported development of practical scientifically-based dosage regimens for paediatric patients.

Step-wise loss of antidepressant effectiveness with repeated antidepressant trials in bipolar II depression.

OBJECTIVE: This study examined the relationship between the number of prior antidepressant treatment trials and step-wise increase in pharmacodynamic tolerance (or progressive loss of effectiveness) in subjects with bipolar II depression. METHODS: Subjects ≥18 years old with bipolar II depression (n=129) were randomized to double-blind venlafaxine or lithium carbonate monotherapy for 12 weeks. Responders (n=59) received continuation monotherapy for six additional months. RESULTS: After controlling for baseline covariates of prior medications, there was a 25% reduction in the likelihood of response to treatment with each increase in the number of prior antidepressant trials (odds ratio [OR]=0.75, unstandardized coefficient [B]=-0.29, standard error (SE)=0.12; χ2 =5.70, P<.02], as well as a 32% reduction in the likelihood of remission with each prior antidepressant trial (OR=0.68, B=-0.39, SE=0.13; χ2 =9.71, P=.002). This step-wise increase in pharmacodynamic tolerance occurred in both treatment conditions. Prior selective serotonin reuptake inhibitor (SSRI) therapy was specifically associated with a step-wise increase in tolerance, whereas other prior antidepressants or mood stabilizers were not associated with pharmacodynamic tolerance. Neither the number of prior antidepressants, nor the number of prior SSRIs, or mood stabilizers, were associated with an increase in relapse during continuation therapy. CONCLUSIONS: The odds of responding or remitting during venlafaxine or lithium monotherapy were reduced by 25% and 32%, respectively, with each increase in the number of prior antidepressant treatment trials. There was no relationship between prior antidepressant exposure and depressive relapse during continuation therapy of bipolar II disorder.

A case of lithium intoxication induced by an antihypertensive angiotensin 1 subtype-specific angiotensin II receptor blocker in an elderly patient with bipolar disorder and hypertension.

Lithium carbonate is considered to be a first-line treatment for bipolar disorder; however, this drug has a narrow therapeutic window, and lithium intoxication is commonly induced by various drugs interaction and situations. We herein report a case of lithium intoxication induced by the administration of an antihypertensive agent targeting the angiotensin 1 (AT1) subtype of the angiotensin II receptor in a 65-year-old woman with a 40-year history of bipolar disorder type 1, and 1-year history of essential hypertension. Her bipolar disorder had been well-controlled with 600 mg/day of lithium carbonate for more than 10 years. She was later diagnosed with hypertension and the AT1 receptor blocker, azilsartan was thereafter administrated on a daily basis. After 3 weeks of azilsartan administration, she presented with progressive action tremor and showed a gradual deterioration of her physical state. Four months after the start of azilsartan administration, she presented with alternating episodes of diarrhea and constipation. Two weeks before admission to our hospital, she presented with mild consciousness disturbances, myoclonus, truncal ataxia, and appetite loss. She was diagnosed to have lithium intoxication based on an elevated serum lithium concentration of 3.28 mEq/l.It is therefore important to evaluate the serum lithium concentration after the administration of antihypertensive agents, and consider lithium-antihypertensive agent interactions when selecting antihypertensive agents in elderly patients receiving long-term lithium carbonate treatment.

Population Pharmacokinetics of Lithium Carbonate in Young Male Healthy Chinese Volunteers.

Aim: To investigate the population pharmacokinetics (PK) model of lithium carbonate in young male healthy Chinese subjects. Methods: This study was conducted using a 2-period crossover design. 20 healthy male subjects received lithium carbonate tablets from 2 different Chinese pharmaceutical manufacturers. Plasma samples were obtained by blood sampling over 72 h in each period. Population PK analysis was performed using nonlinear mixed-effects model (NONMEM) software. The final models were validated using bootstrap and visual predictive check (VPC) approaches. Results: The final PK model was a two-compartment model. The population PK parameters, clearance (CL/F), apparent distribution volume of the central compartment (V2/F), inter-compartmental clearance (Q/F) and apparent distribution volume of the peripheral compartment (V3/F), were 9.39 L/h, 10.4 L, 22.1 L/h, and 216 L, respectively. Conclusion: Population PK models for lithium carbonate have been developed and considerable inter-subject variability was found in healthy young male Chinese subjects. It takes a long time to achieve the steady state in conventional therapy. This may provide guidelines for future use of lithium carbonate in China.

[Potentiation strategies]. / Dépression résistante : les stratégies de potentialisation.

Lithium is among the most classically recommended add-on therapeutic strategy for the management of depressive patients showing unsuccessful response to standard antidepressant medications. The effectiveness of the add-on strategy with lithium requires achieving plasma levels above 0.5 mEq/L. Mood-stabilizing antiepileptic drugs such as carbamazepine, valproate derivatives or lamotrigine have not demonstrated conclusive therapeutic effects for the management of depressive patients showing unsuccessful response to standard antidepressant medications. Thyroid hormones are considered among the currently recommended add-on therapeutic strategy for the management of depressive patients showing unsuccessful response to standard antidepressant medications. The effectiveness of the add-on strategy with thyroid hormones requires achieving plasma concentration of TSH close to the lower limits at the normal range (0.4 µUI/L) or even below it. Second-generation antipsychotics such as aripiprazole or quetiapine have consistently demonstrated significant therapeutic effects for the management of depressive patients showing unsuccessful response to standard antidepressant medications. Second-generation antipsychotics however require the careful monitoring of both cardiovascular and metabolic adverse effects.

The Effects of Lithium Administration on Oxidant/Antioxidant Status in Rats: Biochemical and Histomorphological Evaluations.

Present study was planned to determine possible dose-dependent effects of lithium (Li) on oxidant-antioxidant status and histomorphological changes in liver and kidney tissues. For this purpose, twenty-four Wistar male rats were equally divided into three groups: the rats in group I served as controls, drinking tap water without lithium. Groups II and III received 0.1 and 0.2 % lithium carbonate (Li2CO3) through their drinking water, respectively, for 30 days. At the end of the experimental period, lithium concentrations, levels of malondialdehyde (MDA) and glutathione (GSH) and superoxide dismutase (SOD) activities were measured in considered tissues. Histomorphological study was also performed on liver and kidney tissues. Compared to controls, MDA was significantly higher but GSH level lower in groups II and III. SOD activity was higher in group III, but no difference was determined in group II in liver tissue. In kidney tissue, there was no difference determined in MDA and GSH levels between control and experimental groups but SOD activity in groups II and III was significantly higher. In histologic sections of both experimental liver and kidney tissues, specific degenerations were observed. The results of the present study show that treatment with lithium carbonate may result in liver and kidney tissue abnormalities and oxidative damage.

Study of blood and brain lithium pharmacokinetics in the rat according to three different modalities of poisoning.

Lithium-induced neurotoxicity may be life threatening. Three patterns have been described, including acute, acute-on-chronic, and chronic poisoning, with unexplained discrepancies in the relationship between clinical features and plasma lithium concentrations. Our objective was to investigate differences in plasma, erythrocyte, cerebrospinal fluid, and brain lithium pharmacokinetics using a multicompartmental approach in rat models mimicking the three human intoxication patterns. We developed acute (intraperitoneal administration of 185 mg/kg Li2CO3 in naive rats), acute-on-chronic (intraperitoneal administration of 185 mg/kg Li2CO3 in rats receiving 800 mg/l Li2CO3 in water during 28 days), and chronic poisoning models (intraperitoneal administration of 74 mg/kg Li2CO3 during 5 days in rats with 15 mg/kg K2Cr2O7-induced renal failure). Delayed absorption (4.03 vs 0.31 h), increased plasma elimination (0.65 vs 0.37 l/kg/h) and shorter half-life (1.75 vs 2.68 h) were observed in acute-on-chronically compared with acutely poisoned rats. Erythrocyte and cerebrospinal fluid kinetics paralleled plasma kinetics in both models. Brain lithium distribution was rapid (as early as 15 min), inhomogeneous and with delayed elimination (over 78 h). However, brain lithium accumulation was more marked in acute-on-chronically than acutely poisoned rats [area-under-the-curve of brain concentrations (379 ± 41 vs 295 ± 26, P < .05) and brain-to-plasma ratio (45 ± 10 vs 8 ± 2, P < .0001) at 54 h]. Moreover, brain lithium distribution was increased in chronically compared with acute-on-chronically poisoned rats (brain-to-plasma ratio: 9 ± 1 vs 3 ± 0, P < .01). In conclusion, prolonged rat exposure results in brain lithium accumulation, which is more marked in the presence of renal failure. Our data suggest that differences in plasma and brain kinetics may at least partially explain the observed variability between human intoxication patterns.

Lithium dosing equations: are they accurate?

BACKGROUND: Several equations are used to predict lithium doses necessary to attain therapeutic serum concentrations. A number of studies have evaluated these equations; however, few equations were compared simultaneously. OBJECTIVE: To assess the accuracy and precision of published dosing equations in predicting daily lithium doses and to evaluate if pertinent laboratory tests were performed prior to initiation. METHODS: A retrospective analysis was performed of patients who received lithium at the Medical University of South Carolina Institute of Psychiatry between July 2010 and July 2012. Using dosing equations, expected lithium doses were calculated based on corresponding serum concentrations identified in patient charts. Expected doses were then compared with actual lithium doses. The primary end point was to assess the accuracy and precision of dosing equations using mean differences in daily lithium doses and standard deviations. Secondary end points included presence of pertinent laboratory tests and use of concomitant interacting drugs . RESULTS: Of 155 patients identified, 59 were eligible for analysis. Equations developed by Abou-Auda et al and Pepin et al did not predict doses that were significantly different from actual doses. Conversely, equations by Jermain et al, Terao et al, and Zetinet al did predict statistically different doses. CONCLUSIONS: Abou-Auda et al developed a predictive lithium dosing equation that was more accurate than equations developed by Jermain et al, Terao et al, and Zetin et al and more precise than the Pepin et al equation. Further study evaluating the influence of equations on clinical outcomes is warranted.

[Ramadan and bipolar disorder: Example of circadian rhythm disturbance and its impact on patients with bipolar disorders]. / Ramadan et trouble bipolaire : exemple de perturbation du rythme circadien et son impact sur la maladie.

INTRODUCTION: Fasting during the Ramadan month is a cornerstone of Islam. Several disorders of the chronobiological rhythms occur during this month and impact on mood. Through this paper the authors provide a literature review of the impact of fasting on patients with bipolar disorders. MATERIALS AND SUBJECTS: A literature review using Mesh keywords through Medline database. From 1970 to 2011, articles in French and English were selected. RESULTS: Circadian rhythm refers to the approximately 24-hour cycles that are generated by an organism. Most physiological systems demonstrate circadian variations. Many hormones and other metabolisms, such as gastric pH, insulin, glucose, calcium and plasmatic gastrine, have been shown to exhibit circadian oscillation. The role of social rhythm in behaviors and its influence on circadian rhythms in humans is now obvious. It has been shown that the lack of concentration and irritability increased continuously during Ramadan month and reached its peak at the end of the month. Mood and vigilance are significantly decreased during the fasting month. Several authors have stated that the course of bipolar illness may be affected by the changes in social rhythm that occur during Ramadan (fasting month). Studies which have been devoted to this topic are sparse. Kadri et al., in 2000, studied 20 bipolar patients during the fasting month of Ramadan of 1417 (Hegirian calendar, corresponding to January 1997). Diagnosis of bipolar disorder was made according to ICD-10 criteria. Patients were assessed during the week before Ramadan, the second and the fourth weeks of the fasting month and the first week after its end, with the Hamilton Depression and Bech-Rafaelsen scales. The plasma concentration of lithium was also assessed. The main finding of the study was that 45% of the patients relapsed, 70% during the second week, and the remaining patients at the end of Ramadan. These relapses were not related to plasma concentration of lithium. Most of the relapses were manic (71,4%). Patients who did not relapse had more insomnia and anxiety during the second and third weeks of the study. The side effects of lithium increased and were seen in 48% of the sample, mostly dryness of the mouth with thirst and tremor. However, Farooq et al. in 2006 studied 62 bipolar patients during the fasting month of Ramadan 1427 (from 25 September to 24 October 2006). Serum lithium, electrolytes, Hamilton Depression Rating Scale (HDRS) and Young Mania Rating Scale (YMRS) were assessed, one week before Ramadan, mid Ramadan and one week after Ramadan. The side effects and toxicity were measured by symptoms and signs checklist. There was no significant difference in mean serum lithium levels at three time points. The scores on HDRS and YMRS showed significant decrease during Ramadan (F=34,12, P=0,00, for HDRS and F=15,6, P=0,000 for YMRS). Also the side effects and toxicity did not differ significantly at the three point's assessment. CONCLUSION: All physiologic parameters are influenced by the circadian rhythm, which is influenced in its turn by the food rhythm. So far, the results of these two main studies, with opposite results, do not help us advise bipolar patients to fast or not to fast. Other studies in this field are badly needed.

Short TE (7) Li-MRS confirms Bi-exponential lithium T2 relaxation in humans and clearly delineates two patient subtypes.

PURPOSE: (i) To develop an MRS technique to measure (7) Li levels in human brain in a reasonable scan time, (ii) to develop a technique to quantify (7) Li T2 relaxation times as measured from human brain in patients taking lithium for the treatment of their bipolar disorder, and (iii) to confirm or refute the presence of bi-exponential (7) Li T2 relaxation in human brain. MATERIALS AND METHODS: We modified a spin-echo MRS pulse sequence to decrease its minimum echo time. With IRB approval, we performed lithium MRS with the modified pulse sequence on 13 euthymic bipolar patients stable on long-term lithium to treat their disease. RESULTS: We were able to achieve a total scan time per sample of 8:20; total scan time including imaging, calibration and MRS was approximately 1 h 15 min. We observed bi-exponential T2 relaxation in the majority of patients, with an average short decay time of 5.3 ± 1.4 ms and an average long decay time of 68.2 ± 10.2 ms. However, in two patients we observed strongly mono-exponential T2 relaxation with an average decay time of 47.4 ± 1.3 ms. CONCLUSION: (7) Li relaxation patterns may prove useful to distinguish between lithium-responsive and lithium nonresponsive bipolar patients.

[Complete atrioventricular block during lithium therapy within therapeutic range]. / Kompletter AV-Block unter Lithiumtherapie im therapeutischen Bereich.

HISTORY AND CLINICAL FINDINGS: A 69-year-old man came to the emergency unit because of vertigo and presyncope. A bipolar disorder - known since an age of 15 years - has been treated with 2 × 450 mg lithium and 100 mg perazine per day for several years (no other medications). With the exception of a low heart rate (36/min) clinical examination findings were unremarkable. INVESTIGATIONS: Electrocardiography revealed a permanent complete atrioventricular block with a heart rate of 36/min. Echocardiography showed a normal left ejection fraction (EF 65 %). Laboratory tests were mainly unremarkable, particularly the lithium levels (0,7 mmol/l) were within the therapeutic range. TREATMENT AND COURSE: Continuous treatment with orciprenaline stabilized the heart rate at an average of 52/min. After pacing with a provisional pacemaker a permanent pacemaker was implanted without complications, and the symptoms of vertigo and dizziness disappeared. Pacemaker checkup on the following day still showed a complete atrioventricular block with a heart rate of 28/min. CONCLUSION: Complete atrioventricular block secondary to chronic lithium therapy even in therapeutic levels is a rare complication with poor prognosis. Therefore it should be treated consequently.

[A comparative analysis of the influence of different types of Carbopol on the release rate of lithium-carbonate from matrix tablets].

BACKGROUND/AIM: Hydrophilic matrix tablets represent the most commonly used oral dosage form. Carbomers used in the concentration of 10%-30% for preparation of matrix tablets, may significantly affect the profile of drug release due to the formation of hydrogel matrix tablets. The aim of this study was to compare the influence of different types of Carbopol (carbomers in the pharmacopoeia) on the release rate of lithium-carbonate and other pharmaceutical, technological, physical and chemical properties of the prepared formulations of matrix tablets. METHODS: Three different formulations of matrix tablets were made according to direct compression method. The tablets were of the following composition: carbomer, lactose monohydrate, magnesium-stearate, lithium-carbonate in the proportion 75:120: 5 : 300. The first formulation was made with Carbopol 971P NF, the second one with Carbopol 974 P NF and the third one with Carbopol 71G NF. The quantity of lithium-carbonate was determined according to the BP 2009, pharmaceutical and tecnological properties were examined in accordance with the regulations of Ph. Jug. V, whereas the release rate of lithium-carbonate from the formulations was examined by the application of dissolution test, prescribed in the monography 'Lithium Carbonate Extended-Release Tablets' in USP 26. RESULTS: The profile of lithium-carbonate release from matrix tablets with Carbopol 974P NF entirely complies with the regulations of USP 26, whereas the values obtained from the analysis of matrix tablets with Carbopol 971P NF and Carbopol 71G NF were considerably lower than the prescribed ones. In all the investigated formulations the content of the drug, mass variation and tablet hardness comply with the regulations set in pharmacopoeia. CONCLUSION: In the formulation of matrix tablets with lithium-carbonate, by the application of carbomers in the concentration of 15%, with Carbopol 974 P NF a favourable lithium-carbonate release profile was achieved, whereas in the formulations with Carbopol 971P NF and Carbopol 71G NF, the release rate was significantly lower than that given in the USP 26 monography.