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.

Lipid peroxidation, antioxidant activities and stress protein (HSP72/73, GRP94) expression in kidney and liver of rats under lithium treatment.

The present work was aimed at studying the effects of a subchronic lithium treatment on rat liver and kidneys, paying attention to the relationship between lithium toxicity, oxidative stress, and stress protein expression. Male rats were submitted to lithium treatment by adding 2 g of lithium carbonate/kg of food for different durations up to 1 month. This treatment led to serum concentrations ranging from 0.5 mM (day 7) to 1.34 mM (day 28) and renal insufficiency highlighted by an increase of blood creatinine and urea levels and a decrease of urea excretion. Lithium treatment was found to trigger an oxidative stress both in kidney and liver, leading to an increase of lipid peroxidation level (TBARS) and of superoxide dismutase and catalase activities. Conversely, glutathione peroxidase activity was reduced. Constitutive HSP73 (heat shock protein 73) expression was not modified by lithium treatment, whereas inducible HSP72 was down-regulated in kidney. GRP94 (glucose regulated protein 94) appeared as two isoforms of 92 and 98 kDa: the 98-kDa protein being overexpressed in kidney by lithium treatment whereas 92-kDa protein was underexpressed both in kidney and liver.

[Catatonic dilemma in a schizoaffective patient with combined lithium-risperidone administration]. / Katatones Dilemma unter Kombinationsbehandlung mit Lithium und Risperidon.

OBJECTIVE: The case of a schizoaffective patient suffering from a malignant catatonic syndrome following combined lithium-risperidone therapy is explored. METHOD: A case report and relevant deliberations regarding pathophysiology of the catatonic dilemma are discussed. CONCLUSIONS: There are two critical transitions in the development of a malignant catatonic syndrome. Dopaminergic system and psychopharmacological factors are supposed to play a key role. However, other neurotransmitter systems and the individual predisposition must be considered.

Lithium normalizes elevated intracellular sodium.

BACKGROUND: Both mania and bipolar depression are characterized by elevations of intracellular sodium concentrations. This observation has been purported to be central to the pathophysiology of abnormal moods in bipolar illness. Reduction of sodium influx is a proposed shared mechanism of action of effective mood stabilizers, but direct documentation of this effect for lithium has never been demonstrated. METHODS: Flame spectroscopic determinations of intracellular sodium concentration were performed in the human glioma cell line, LN292, after treatment with the sodium pump inhibitor, ouabain, and co-treatment with ouabain and lithium. RESULTS: Ouabain 0.1 microM doubles the intracellular sodium concentration after 3 days. Pretreatment with lithium 1 mM for 1 week normalizes intracellular sodium. CONCLUSION: This is the first demonstration that lithium can normalize abnormally elevated intracellular sodium levels. This may be an important mechanism of lithium action.

Biological predictors of lithium response in bipolar disorder.

In order to prescribe lithium appropriately to patients with bipolar disorder, predictors of lithium response are helpful. The present paper reviews the biological predictors of lithium response. As a positive predictor of lithium response, the following have been reported: strong loudness dependence of the auditory-evoked N1/P2-response; higher brain lithium concentration; lower inositol monophosphatase (IMPase) mRNA expression; higher serotonin-induced calcium mobilization; increased N-acetyl-aspartate peak and decreased myo-inositol peak; white matter hyperintensity; decreased intracellular pH; higher frequency of phospholipase C gamma-1 (PLCG1)-5 repeat and PLCG1-8 repeat; and C973A polymorphism in the inositol polyphosphate 1-phosphatase gene. In contrast the following have been reported as a predictor of negative lithium response: epileptiform abnormality of electroencephalography; human leukocyte antigen type A3; decreased phosphocreatine peak area after photic stimulation; and homozygotes for the short variant of the serotonin transporter gene. Most of the possible biological predictors of better lithium response, such as lower IMPase mRNA levels, white matter hyperintensity, lower brain intracellular pH, enhanced calcium response, and PLCG1-5 repeat had been detected as risk factors for bipolar disorder, suggesting that bipolar disorder responding well to maintenance lithium treatment is a distinct category having a certain neurobiological basis, although these findings need further replication. The search for biological predictors of lithium response is still in its infancy. Most of the laboratory or neuroimaging techniques used in these studies are not easily performed in clinical settings, so the development of an easy and useful laboratory test is needed.

The use of lithium clearance measurements as an estimate of glomerulo-tubular function.

Lithium clearance measurements are based on the observation that lithium undergoes isoosmotic reabsorption in the proximal renal tubule to the same extent as salt and water, but undergoes neither reabsorption nor secretion elsewhere in the nephron. Consequently, lithium clearance values estimate the delivery of isoosmotic fluid to the loop of Henle and hence provide an assessment of proximal tubular reabsorption of isoosmotic fluid. If sodium clearance and urinary flow rate are also measured, then this allows the derivation of a number of parameters relating to both the absolute and relative renal handling of isoosmotic fluid in the proximal and distal regions of the kidney. Consequently, lithium clearance techniques can be used in both experimental and clinical studies to evaluate glomerulo-tubular function and provide information regarding the handling of sodium and water by the proximal and distal nephron in both health and disease. The use of lithium clearance measurements in the assessment of glomerulo-tubular function in patients treated with rIL2 for colorectal cancer is described and its application to both drug-induced toxicity and other disease states discussed.

El uso de medicamentos durante el embarazo: 1 parte / The use of medicaments during pregnancy: part 1

Existen medicamentos que, por la enfermedad, ameritan su uso durante el embarazo, algunos otros fármacos, dependiendo de la necesidad, pueden prescribirse y otro grupo de drogas está contraindicado durante la gestación. A continuación se describen, principalmente, las drogas de mayor importancia para tratar, en pacientes embarazadas, enfermedades crónicas tales como: depresión, epilepsia, hipertensión, etc. También se describen los riesgos teratogénicos de las drogas que se prescriben y la problemática que implica el dejar la enfermedad sin tratamiento. Además se resumen los diversos agentes y causas dismorfogénicas, así como los cambios farmacocinéticos que se producen durante el embarazo

The effects of lithium on neurulation stage mouse embryos.

The aim of this study was to evaluate the maternal toxicity and teratogenicity of lithium following intraperitoneal injection (i.p.) with lithium carbonate (Li2CO3) in pregnant CD-1 mice at the developmental stage of neurulation (E8; day of vaginal plug, E0). Light (LM) and electron (TEM) microscopic studies were also done to document the tissue and cellular changes occurring in embryonic tissues during the 48 h following treatment with 300 mg/kg body wt. Li2CO3. Controls were untreated or given equimolar amounts of NaCl or Na2CO3. A pharmacokinetic study showed that lithium was rapidly absorbed from the peritoneal cavity after the above-stated dose, achieved peak serum levels of 9.8 mmol/l within 1 h, had a half-life in the blood of 5 h and was completely cleared by 16 to 24 h after injection. Doses of Li2CO3 > 300 mg/kg body wt. were toxic to adult CD-1 mice. The latter dose had no detectable maternal toxicity but caused a 19% resorption rate and 2% incidence of open cranial neural tube defect in gestations terminated on E18. The malformation and resorption rates in gestations terminated on E11, E12 and E14 were not significantly different from those of E18. A strong litter effect was seen both for the resorption and malformation rates at all stages examined. At 3 h after treatment cell death became evident in the neuroepithelium. Cells continued to die for approximately 17 h and all necrotic debris had been cleared by 48 h. Also at 3 h after treatment small densely stained inclusions began to appear in mesodermal cells. TEM showed these to be non-membrane bound with an irregular shape and variable size; the lack of staining for acid phosphatase indicated a non-lysosomal structure; the ultrastructural features suggested a lipoid basis. At 24 h after treatment vascular ruptures and surface ectodermal ruptures were seen in the cranial mesoderm. These ruptures with extravascated blood were also seen at 48 h after treatment. A litter effect was also noted with respect to the tissue and cellular changes. These experiments suggest that the developing vascular system may be a target for lithium. In addition, the possibility is discussed that lithium induced cell death in the neuroepithelium may lead to neural tube defects.

Reduced renal fractional excretion of lithium in cystic fibrosis.

We hypothesized that patients with cystic fibrosis would have abnormal lithium handling because the genetic defect in cystic fibrosis encodes an ion channel which causes a generalized electrolyte transport disorder in epithelial membranes. Eight patients with cystic fibrosis and eight age-sex matched healthy subjects ingested 600 mg lithium carbonate and had urine and serum lithium levels assessed 24 h later. Compared with healthy subjects, the patients with cystic fibrosis had higher serum lithium levels (0.071 +/- 0.038 vs 0.113 +/- 0.055 mmol l-1, P = 0.03) and had lower fractional renal excretion of lithium (27.5 +/- 14.8 vs 18.8 +/- 9.3%, P = 0.03). Caution should be used in prescribing standard doses of lithium to patients with cystic fibrosis until more definitive data are available.

Rational polypharmacy in the bipolar affective disorders.

Bipolar affective illness represents a syndrome not readily treated by single agents. Approximately 50% of patients are inadequately responsive to lithium and the majority of patients require supplemental antidepressants, antimanic, antipsychotic or hypnotic medications. These traditional adjunctive medications are associated with potential problems. Antidepressants may precipitate mania (at a rate about double that of placebo) or cause cycle acceleration. Neuroleptics may be associated with either more profound or longer depressive phases, and clearly increase the risk of tardive dyskinesia, to which bipolar patients appear particularly predisposed. Moreover, there are subgroups of patients who are known to be poorly responsive to lithium. These include patients with rapid cycling, dysphoric mania, co-morbid drug or alcohol abuse, a pattern of depression-mania-well interval (D-M-I as opposed to the M-D-I pattern), and patients without a family history of bipolar illness in first-degree relatives. There is increasing recognition that the anticonvulsants carbamazepine and valproate are effective alternatives or adjuncts to lithium in the acute and long-term treatment of bipolar illness. Ideally, one would want to assess whether patients who were unresponsive to lithium were responsive to an anticonvulsant alone prior to utilizing lithium in addition to anticonvulsant combination therapy. However, from the clinical perspective, it is often more expedient to use an anticonvulsant adjunctively to lithium to assess the efficacy of this combination and establish mood stabilization. When lithium is not discontinued, the increased morbidity during lithium withdrawal also would not occur and would not confound the evaluation of the new agent. We suggest the initial use of acute adjuncts to lithium with the anticonvulsants carbamazepine or valproate (instead of neuroleptics) so that their efficacy can be assessed in the individual's acute episode, with the likelihood of a positive response in longer-term prophylaxis. Hypnotic benzodiazepines with anticonvulsant properties, such as clonazepam or lorazepam, are often used to help to induce sleep in escalating bipolar patients, and may be useful adjuncts as well. Patients who were inadequately responsive to either carbamazepine or valproate alone may be responsive to the anticonvulsant combination. In a similar fashion, one can also utilize several mood-stabilizing drugs (lithium and an anticonvulsant such as carbamazepine or valproate) in the treatment of depressive breakthroughs, and then augment this combination (if necessary) with a catecholamine-active antidepressant such as bupropion or a serotonin-selective reuptake inhibitor (SSRI) such as fluoxetine, paroxetine, sertraline or if necessary a monoamine oxidase inhibitor (MAOI). Once the patient has responded to a combination of drugs, it becomes problematic to decide whether the last agent added was the crucial ingredient in helping the patient achieve remission or that remission might have occurred with this agent alone. A conservative approach would have merit in patients who are finally stabilized on complex polypharmacy regimens only after many years of sequential trials; in this instance, the potential risk of re-exacerbating the illness with a taper of one of the drugs in the regimen. Rational polypharmacy should thus be implemented with careful delineation of the prior course of illness (typically using life chart methodology) and targeted treatment outcomes titrated against side effects, using sequential clinical trials in individual patients who have not adequately responded to monotherapy. In this fashion, it is hoped that pharmacodynamic differences among agents can be maximized and pharmacokinetic and side effects minimized.

Successful preoperative preparation for thyroidectomy in Graves' disease using lithium alone: report of two cases.

To elucidate the effect of lithium carbonate in the preoperative preparation of patients with Graves' disease, it was given without any other antithyroid medication to two patients as an alternative to thionamide, which had caused adverse effects. The initial dose of lithium carbonate was 600 mg/day, and the final doses were 1200 and 900 mg/day, while the periods of administration were 67 and 27 days, respectively. The highest serum concentrations of lithium during the administration period were 0.83 and 0.43 mEq/l, respectively. This preoperative preparation lowered serum thyroid hormone levels and clinical improvement. A subtotal thyroidectomy was performed uneventfully in both patients, after which the serum lithium levels decreased rapidly and the thyroid hormone levels increased only slightly for a few days. No adverse effects of lithium carbonate were observed. Thus, we conclude that the administration of lithium carbonate alone is an effective and safe method for the preoperative management of Graves' disease when conventional antithyroid drugs show adverse effects.

Lithium clearance measurements during recombinant interleukin 2 treatment: tubular dysfunction in man.

Renal tubular function was evaluated in nine patients undergoing recombinant interleukin 2 (rIL2) treatment for metastatic colorectal carcinoma. A lithium clearance technique was used and the activities of the lysosomal enzyme N N-acetyl-beta-D-glucosaminidase were also measured in the patients' urine, before treatment, during treatment, and then 2 days and 23 days after rIL2 therapy had finished. Significant reductions in clearances of creatinine, sodium, and lithium were observed. The fractional excretions of sodium and lithium were also reduced. Twenty-three days following cessation of rIL2 treatment, there was still a significant reduction in creatinine clearance compared with pretreatment values (p < .01). The clearances of sodium and lithium were also reduced compared with pretreatment values although this did not achieve significance. The fractional reabsorption of sodium and water by the proximal nephron increased during rIL2 treatment, from 0.707 +/- 0.030 (pretreatment) to 0.793 +/- 0.043. This increased reabsorption of sodium and water persisted, rising to 0.849 +/- 0.029, 2 days following cessation of treatment (p < .001, means +/- SEM). Twenty-three days later this had returned toward the pretreatment value, being 0.781 +/- 0.036. The fractional reabsorption of sodium by the distal nephron was also significantly elevated, both during and 2 days after completing rIL2 treatment. Twenty-three days after cessation of rIL2, this value had returned to the pretreatment value. However, in contrast, the fractional reabsorption of water by the distal nephron demonstrated no change during rIL2 treatment, but 2 days posttreatment was significantly reduced and remained low for a further 3 weeks.

Renal tubular sodium and water metabolism in brain tumour patients submitted to craniotomy.

PURPOSE: To evaluate the effect of Brain Tomour (BT) and Neurosurgery (NS) on the renal handling of H2O and Na, and the clinical importance of SIADH in this setting. METHODS: Fourteen patients with BT pre-op for NS and 6 controls (C) pre-op for general surgery, were assessed in a controlled prospective trial. All patients were normovolaemic, with normal renal function. They received 400 mg of lithium carbonate (Li) 8 hours before each of two test periods (I and II) and a standard water load only before period II. Clearances studies were performed pre-op (period I) and 24 hours post-op (period II). RESULTS: Serum Na was normal at all times. Despite normovolaemia, a 1% decrement in serum osmolality and the water load, ADH dramaticaly increased from time I to II mainly in the BT group (36.2 +/- 9.4 vs 7.1 +/- 0.6 pmol/L, p = 0.02). FENa, FELi and FEUricA were significantly more elevated in the BT group pre and post-op (at time II respectively 4.6 +/- 1.6 vs 1.1 +/- 0.3%; 29.3 +/- 4.9 vs 22.6 +/- 5.5; 26.0 +/- 8.1 vs 11.3 +/- 2.2, p = 0.03). Proximal and distal H2O re-absorption and distal fractional Na re-absorption were identical in both groups pre and post-operatively. CONCLUSIONS: 1-BT and NS always induce a SIADH. 2-There was a primary Na loss at the proximal tubule level not explained by ADH increment, that did not significantly changed H2O handling. 3-To prevent hyponatraemia, hypotonic I.V. fluids should be avoided, but more importantly saline must be provided to this potentially salt-wasting condition.

The first lithium clinic in Hong Kong: a Chinese profile.

A study of 50 Chinese patients referred to the first lithium clinic in Hong Kong revealed a high prevalence of recurrent mania and rarely unipolar depression. A history of delusions and hallucinations, and re-diagnosis from schizophrenia to manic depressive psychosis, were common. Lithium was prescribed after 3.9 episodes of illness, and at a dosage of 1,191 mg despite a moderate serum level of 0.63 mmol/l. Laboratory monitoring was haphazard, and polypharmacy was common. This might pose unnecessary risks to some patients.

Gender differences in pharmacokinetics and pharmacodynamics of psychotropic medication.

OBJECTIVE: This review explores the theoretical background for and empirical evidence supporting gender-related differences in pharmacokinetics and pharmacodynamic properties of psychotropic medications. METHOD: The authors reviewed all English-language articles on this topic that involved original research using human subjects. RESULTS: Limited evidence suggests that young women seem to respond better to and require lower doses of antipsychotic agents and benzodiazepines than young men. The administration of exogenous hormones interacts with medications, changing plasma levels and possibly conferring greater risks for toxicity. Young women may have an enhanced response to nontricyclic antidepressants. CONCLUSIONS: Too little basic and clinical research has been conducted on sex differences in therapeutic effects and side effects of psychopharmacological treatments. Addressing these differences as well as similarities will lead to safer and more effective treatment for all patients.

PIP: A review of the English-language literature on original research with human subjects concerning sex differences in pharmacokinetics and psychotropic agents was attempted. With respect to absorption and bioavailability, women may secrete less gastric acid, and progesterone in the luteal phase slowed gastric emptying. Drugs with high affinity for adipose tissue (diazepam) would be distributed more in females with a lower ratio of lean body mass to adipose tissue. Yet, over time half-life may be prolonged with higher serum levels in patients with less lean body mass. The 1st-pass metabolism of drugs and later extensive metabolizing for systemic circulation are carried out in the liver. The menstrual cycle also affects gastric motility as dilution via fluid retention results in lower plasma levels. Estrogen may reduce monoamine oxidase activity and progesterone may increase it. Women taking oral contraceptives and diazepam during menstruation become relatively intoxicated. With respect to antipsychotic agents higher fluphenazine levels were found in women, and they required 1/2 the dose of fluspiriline as men. Women improved more after pimozide and chlorpromazine treatment than men. The incidence of severe tardive dyskinesia was higher in postmenopausal women possibly attributable to estrogen loss. Oral contraceptives reduced the clearance of benzodiazepines resulting in slower peak levels of diazepam while being off pills led to impairment of cognitive and psychomotor tasks. Temazepam and oxazepam also cleared more slowly in women. Among antidepressant agents MAO inhibitors produced better results in women than did tricyclic antidepressants. Lithium-induced hypothyroidism predominates in women as does thyroid disease, and possibly rapid-cycling bipolar illness is also linked to this condition.

Glomerulotubular function in patients undergoing moderate surgical stress.

Glomerular function and renal tubular function assessed by measurements of creatinine clearance rates (CCR), lithium clearance rates (CLi, and N-acetyl-beta-D-glucosaminidase (NAG) enzymuria were measured immediately prior to and within 24 h of operation (average operative time 150 min) in 16 patients undergoing a moderate surgical stress. Although serum creatinine concentrations and CCR were similar pre- and postsurgery at 105 +/- 21 and 108 +/- 21 mumol/L and 108 +/- 67 and 110 +/- 59 mL/min/100 kg body weight (mean +/- SD), respectively, both CLi and NAG were significantly increased following the surgical insult. CLi was increased from 19.7 +/- 6.1 to 31.7 +/- 16.7 mL/min/100 kg (p less than 0.01) and NAG from 71 +/- 58 to 164 +/- 10 U/mmol urinary creatinine (p less than 0.001). In addition, the absolute distal tubular reabsorption of sodium and water increased from 18.3 +/- 5.9 and 15.8 +/- 9.7 to 30.6 +/- 16.4 and 27.6 +/- 12.2 mL/min/100 kg body weight (both p less than 0.05), respectively. These results indicate early postoperative renal tubular dysfunction following a moderate surgical stress, undetected by conventional screening.

Impaired diluting segment chloride reabsorption in patients with cystic fibrosis.

Clearance studies were performed in 12 patients with cystic fibrosis (CF) during maximum water diuresis. The fractional diluting segment reabsorption was calculated from chloride clearance (CCl) and maximum free water clearance (CH2O) as 'CH2O/CCl+CH2O'. Fractional delivery to the diluting segment and from the proximal tubules was estimated by maximum urine flow during water diuresis (Vmax/GFR) and lithium clearance (CLi/GFR), respectively. The data were compared with results obtained in young healthy subjects. To estimate free water generation beyond the medullary diluting segment, CH2O/GFR was also measured during acute furosemide administration in 5 patients. Values for the term CH2O/CCl+CH2O were significantly lower in patients with CF (79.1 +/- 5.1%) as compared with healthy controls (89.4 +/- 4.4%). This was also true for the terms Vmax/GFR (CF: 9.5 +/- 1.6%; control subjects: 13.8 +/- 2.5%) and CLi/GFR (CF: 22.2 +/- 4.1%; control subjects: 30.7 +/- 5.1%). Compared to data derived from the literature, the solute-free water generation during administration of furosemide (CH2O/GFR) was significantly reduced in patients with CF (6.8 +/- 1.5%) as compared with healthy subjects (13.3 +/- 6.1%). We conclude that reabsorption in the diluting segment is impaired in patients with CF, perhaps at a site beyond the thick ascending limb of Henle's loop. Enhanced proximal reabsorption, suggested by reductions in Vmax/GFR and CLi/GFR, appears to be a compensatory phenomenon to maintain sodium and chloride balance.