Comparative efficacy of lithium carbonate loading dose versus standard dosing, each combined with quetiapine, in acute mania of bipolar I disorder: a randomized single-blind controlled trial.

Objective To analyze effects of lithium carbonate on thyroid function in patients with bipolar affective disorder. Methods Thirty patients with bipolar disorder and depressive episode treated in Shenzhen Kangning hospital from April 2016 to November 2017 were selected as observation group. Another 30 healthy persons in the same period were selected as control group, and the thyroid function of the two groups was compared. Results The thyroxine 4(T4), free thyroxine 3(FT3) and free thyroxine 4(FT4) in observation group were significantly lower than those in control group before treatment (P 0.05). In observation group, FT4 was significantly decreased after using lithium carbonate (P<0.05). Conclusions Lithium carbonate in the treatment of bipolar affective disorder can reduce the patients’ thyroid function in a certain degree. Key words: Bipolar affective disorder; Lithium carbonate; Thyroid function

Patients with comorbid cancer and bipolar affective disorder require psychiatric symptom stabilization to continue cancer treatment, and mood stabilizers, including lithium carbonate, are often administered during cancer treatment. However, the risk of lithium carbonate-induced consciousness disturbance seems not to be well recognized among medical professionals involved in cancer treatment. A woman in her 70s was diagnosed with bipolar affective disorder at approximately 28 years of age and was hospitalized twice for worsening manic depressive episodes. Lithium carbonate (600 mg/day, orally) was administered. At X-3 years, she was diagnosed with left breast cancer (cT2N2M0, Stage IIIA) and received preoperative chemotherapy (doxorubicin, cyclophosphamide, and paclitaxel) following total mastectomy and axillary lymph node dissection. At X years, she was hospitalized because of a consciousness disturbance. Brain metastasis and lithium carbonate overdose were eliminated, and renal function was normal. However, the blood lithium level was 1.74 mEq/L, and lithium carbonate intoxication due to dehydration was most suspected. Her level of consciousness improved with adequate intravenous fluid, and she recovered with no adverse effects. In patients with comorbid cancer and bipolar affective disorder, the stabilization of psychiatric symptoms is necessary, and lithium carbonate is an important medication. However, oncologists and liaison psychiatrists need to consider the possible risk of consciousness disturbance due to lithium carbonate intoxication.

In an 18 hospital study, 205 patients hospitalized with a diagnosis of manic-depressive illness, manic type, were treated upon discharge with lithium carbonate or placebo for a two-year period. Lithium carbonate was significantly more effective than placebo in preventing relapses (ie, affective episodes severe enough to require hospitalization or use of nonstudy drugs). The difference in treatment outcome between lithium carbonate and placebo was due mainly to the lower incidence of manic relapses on lithium carbonate. Patients on lithium carbonate also had a lower incidence of depressive relapses than patients on placebo but the limited incidence of severe depression in this sample makes it difficult to draw any conclusions regarding the prophylactic efficacy of lithium carbonate in depressive illness. The results from this trial coupled with those from other studies indicate that lithium carbonate combined with regular clinical appraisals is a safe and effective treatment for preventing relapse in manic-depressive illness.

To the Editor: Lithium is one of the commonly used drugs for the treatment of bipolar affective disorders. Its use is associated with various side effects, dermatologic side effects being one of them. Dermatologic side effects can be one of the reasons for poor compliance and are reported in 3%–45% of the population receiving lithium. Mohandas and Rajmohan1 found acneiform eruptions, psoriasis, maculopapular eruptions, and follicular eruptions to be most commonly reported. However, fixed drug eruption due to the use of lithium carbonate has not been reported. We report one such case in a patient with bipolar mania. Case report. Mr A, a 16-year-old male diagnosed with bipolar affective disorder as the second episode of mania with psychotic symptoms according to ICD-10 criteria, reported for follow-up. A maintenance dose of tablet lithium carbonate 900 mg/d was effective until the past year. At this visit, he reported blisters over the dorsal aspects of the hands and foot, with lesions extending to the mouth and genitalia. After 2–3 days, the blisters had subsided and were now seen to have been replaced by a hypopigmented patch surrounded by hyperpigmented border over the same areas (Figure 1). The lesions were associated with itching and disappeared after a few days of treatment with povidone-iodine (Betadine) application and multivitamin capsules. Figure 1. Fixed Drug Eruption Over the Wrist Mr A attributed the lesions to the antidiarrheal medication taken during one of those instances and continued taking lithium carbonate in the same dose. His serum lithium level was within the therapeutic range at this visit. However, the lesions recurred in a similar manner a month later on 2 successive occasions. On consultation, lithium carbonate therapy was stopped because lithium carbonate was considered the possible precipitant. A rechallenge was done in a low dose, after which the lesions appeared again, thereby confirming lithium to be the likely cause. The Naranjo Adverse Drug Reaction Probability Scale2 was applied with a score of 6, suggesting that lithium carbonate was the probable cause of the side effect. Mr A was subsequently started on tablet sodium valproate (1,000 mg/d) and olanzapine (10 mg/d). He was maintaining well for 4 months after the change in medications but was lost to follow-up. The exact cause for the cutaneous side effects associated with lithium is not known, but the role of stress and psychological factors has been proposed. Kansal et al3 state that the decrease in cyclic adenosine monophosphate and inositol that results from lithium treatment has also been considered as a possible cause. The low intracellular levels of calcium, the lack of differentiation of keratinocytes, and enhanced phagocytic activity of leukocytes have been suggested as the possible mechanisms of action. Reduction in the dosage apart from specific intervention for the lesions has been suggested as a possible treatment strategy.

832: Comparison of magnesium sulfate regimens for prevention of eclampsia: A network meta-analysis

Why do patients with manic-depressive illness stop their lithium?

In a double-blind, long-term follow-up study, 117 bipolar patients received lithium carbonate, imipramine hydrochloride, or both and 150 unipolar patients received lithium carbonate, imipramine, both lithium carbonate and imipramine, or placebo. With bipolar patients, lithium carbonate and the combination treatment were superior to imipramine in preventing manic recurrences and were as effective as imipramine in preventing manic recurrences and were as effective as imipramine in preventing depressive episodes. The combination treatment provided no advantage over lithium carbonate alone. With unipolar patients, imipramine and the combination treatment were more effective than lithium carbonate and placebo in preventing depressive recurrences. The combination treatment provided no advantage over imipramine alone. The lithium carbonate-treated group had fewer manic episodes than the other groups. Treatment outcome, which was evaluated primarily in terms of the occurrence of major depression or manic episodes, was significantly related to characteristics of the index episode, ie, the episode that brought the patient into the study.

Objective To evaluate the efficacy and safety of quetiapine fumarate as mono-therapy for acute mania in patients with bipolar disorder.Methods The study design was randomized,double blind,double dummy.lithium controlled.multicenter trial.Patients with bipolar disorder were hospitalized for the treatment of an acute manic episode according to the Chinese Classification of Mental Disorders 3rd edition criteria.and with the Young Mania Rating Scale(YMRS)total score≥20 were randomized to receive quetiapine(twice daily up to 800 mg/d)or lithium(twice daily up to 2000 mg/d).The primary endpoint was the change of YMRS total score from baseline to Day 28(last observation carried forward;LOCF).The safety was evaluated with the rate of adverse events(AEs),laboratory test and ECG.Results The ITTincluded 154 subjects.with 77 in each treatment group.Mean doses were 642.9 mg/d and 1377.7 mg/d for quetiapine and lithium respectively.Changes of YMRS total score from baseline to Day 28 in quetiapine and lithium group were-18.2 and-15.9,respectively.At Day 28,the response rate was significantly higher in quetiapine-treated patients(78%vs.60%;P=0.013).Quetiapine was well tolerated up to doses of 800 mg/d,and 78%of patients in quetiapine group and 69%in lithium group reported AEs.The most frequently reported AEs in quetiapine group were constipation(35%),dizziness(15%),and diarrhea (10%),and in lithium group were nausea(17%),constipation(13%),and vomiting(13%).Three subjects in lithium group but none in quetiapine group withdrew due to AEs.Conclusions The study resuhs support that quetiapine monotherapy is effective and well tolerated in the treatment of acute mania. Key words: Bipolar disorder; Lithium carbonate; Randomized controlled trials; Quetiapine

To the Editor: Lamotrigine is currently used for treatment of bipolar depression alone or as an adjunct to other drugs. The exact mechanism of the antidepressant action of lamotrigine is not known. Lamotrigine used as an adjuvant mood stabilizer has been reported to induce mania1 and hypomania2 in case reports. Here we present 2 cases of lamotrigine-induced switch, 1 in which lamotrigine was used as a single agent and another in which it was added in a very small dose as an adjuvant. Case 1. Mr A, a 24-year-old single male university graduate, had a family history of bipolar affective disorder in a grandfather and unspecified psychosis in a maternal uncle. He presented in 2008 with a 2-year history of episodic illness characterized by an episode of mania (DSM-IV criteria) lasting for 6 months treated with olanzapine (10 mg/d) and risperidone (2 mg/d) and an episode of moderate depression with somatic symptoms lasting for 11.5 months characterized by pervasive low mood, anhedonia, loss of interest in pleasurable activities, hopelessness, wish to die, somatic symptoms, and disturbed biofunctions. Results of routine investigations and workup for organicity were within normal limits. He was started on lamotrigine 25 mg at bedtime, and the dose was gradually increased to 200 mg. Two weeks after initiation of the drug, he developed irritability and anger outbursts on a dose of 150 mg. When the dose was increased to 200 mg/d, he developed mania along with mood-congruent psychotic symptoms (his Young Mania Rating Scale3 [YMRS] score was 20). As a result, lamotrigine was tapered and stopped over 2 weeks and lithium was added (300–1,200 mg/d) along with risperidone (2–3 mg/d). His symptoms improved over 2 weeks. He has remained well after discharge from the hospital. Case 2. Mr B, a 23-year-old single man, had a family history of alcohol dependence syndrome in his father and past history of childhood oppositional defiant disorder, cannabis dependence syndrome (currently abstinent), and harmful alcohol use. He presented with an episodic illness since 19 years of age characterized by 1 manic episode (DSM-IV criteria) without psychotic symptoms lasting 3 months treated with risperidone 4 mg/d and clonazepam 1.5 mg/d. He discontinued these medications after 1 year. He had another episode of mania (DSM-IV criteria) lasting for 3 months at 21 years of age and was treated with lithium carbonate 1,600 mg/d, risperidone 8 mg/d, and trihexyphenidyl 4 mg/d. He continued taking lithium, and risperidone was tapered off. He most recently presented in 2008 with pervasive low mood, loss of interest in pleasurable activities, hopelessness, somatic symptoms, and disturbed biofunctions of 3 weeks’ duration. He was diagnosed with bipolar affective disorder, current episode moderate depression with somatic symptoms. Lamotrigine 25 mg/d was added to lithium. A week later, he started to exhibit elated mood, overactivity (goal directed), overfamiliarity with people, grandiose plans of starting a business, increased cigarette smoking, and decreased need for sleep. He was admitted and diagnosed with bipolar affective disorder, current episode mania (lamotrigine induced). Urine cannabis screen was negative. He rated 13 on the YMRS and was started on sodium valproate 1,000 mg/d and tablet clonazepam 3 mg/d along with the lithium carbonate he was receiving. His symptoms improved over a duration of 3 weeks, and he was discharged. He has remained well after discharge on regular medications. In the first case, manic symptoms developed when lamotrigine was gradually hiked to 200 mg/d. The patient was not on any other medications during this time, and lamotrigine was the sole agent that might have induced a manic switch. This is possibly the first such case reported. In the second case, the patient developed a manic switch on the addition of a very small dose of lamotrigine. Lamotrigine may induce a switch through its ability to decrease glutamate release, thereby reducing binding to the N-methyl-D-aspartate receptor complex.4

Simplified dosing regimens of teicoplanin for patient groups stratified by renal function and weight using Monte Carlo simulation

Purpose: In ST elevation myocardial infarction (STEMI) patients a suboptimal degree of platelet inhibition for the first 2 hours has been described following the standard (180 mg) ticagrelor loading dose (LD). We aimed to compare the pharmacodynamic effect of double (360mg) vs standard LD of ticagrelor in STEMI patients undergoing primary percutaneous coronary intervention (PCI). Methods: We performed a prospective, non-randomized, 2-center study in 42 consecutive, P2Y12 inhibitor naïve STEMI patients. Following blood sampling (Hour 0), patients were administered a 360 mg of ticagrelor, immediately before PCI. Platelet reactivity (PR) was assessed at Hour 0, 0.5, 1, 2 and 4 with the VerifyNow assay. PR was assessed at the same time-points in a control group of 32 STEMI patients, who received standard ticagrelor LD. Results: In the high LD group, PR in PRU (least-squares estimates, 95% CIs) tended to increase from Hour 0 (221.5, 200.5-242.4) to Hour 0.5 (257.8, 236.9-278.7), p=0.08. PR at Hour 1 (217.7, 196.8-238.6) did not differ compared to Hour 0 (p>0.99). PR observed at Hour 2 (110.5, 89.6-131.4) and Hour 4 (43.7, 22.8-64.6) was significantly decreased compared to Hour 0 (P<0.001 for both). The high PR rates (threshold 230 PRU) at Hour 0.5, 1, 2 and 4 were 78.6%, 52.4%, 23.8% and 2.4% respectively. In 22 propensity-matched pairs of patients, PR did not differ significantly between standard and high LD group at any time point (Table). Table 1. Platelet reactivity (VerifyNow PRU) at 0.5, 1, 2 and 4 hours post ticagrelor LD Conclusions: In STEMI patients treated with primary PCI, double the standard LD of ticagrelor results in no significant PR change at Hour 1 compared to baseline. At Hour 2, the double LD of ticagrelor achieves high platelet inhibition in the majority of patients. Double LD of ticagrelor did not appear superior to the standard LD in reducing PR the early hours after intake in STEMI.

BackgroundIDSA guidelines recommend the usage of a loading dose when using vancomycin for seriously ill patients to rapidly achieve adequate trough concentrations. While the relationship between vancomycin and nephrotoxicity is the focus of many studies, and with the strength of that relationship still debated, few studies have examined the relationship between vancomycin loading doses and nephrotoxicity.MethodsWe performed a retrospective cohort study examining vancomycin dosing for internal medicine teaching services’ patients over the 2014–15 academic year at one academic medical center. We generated a list of all hospitalized patients aged 18–85 who received vancomycin and were admitted to a teaching service. Patient data were extracted from the inpatient EMR via manual chart review. Patients were excluded if their pretreatment calculated glomerular filtration rate (GFR) was less than 50 mL/minute, if they received less than three doses of vancomycin, or if their initial dose was subtherapeutic (<10 mg/kg). Nephrotoxicity was determined by 7-day acute kidney injury (AKI) rate. Patients in the loading dose (>20 mg/kg) cohort were compared with those in the standard dose cohort (10–20 mg/kg). Our primary modeling used multi-variable logistic regression with AKI as our outcome of interest.Results438 of the initial 804 patients were enrolled. The loading dose (n = 365, 83%) and standard dosing (n = 73, 17%) cohorts were not significantly different regarding demographics, GFR, nephrotoxic drug exposure, total vancomycin received, trough levels, or comorbidities, and were only significantly different regarding body mass index (BMI). The 7-day AKI rate was not significantly different between the two arms (6.3% in the standard dosing arm and 8.2% in the loading dose arm P = 0.6). AKI rate significantly increased in both arms in the setting of concurrent piperacillin–tazobactam and vancomycin administration (OR 2.5, P = .04). There was no association between BMI and AKI.ConclusionFew studies have examined the relationship between nephrotoxicity and vancomycin loading doses. The results of this study provide evidence that the use of loading doses is not significantly associated with increased 7-day AKI rate.DisclosuresAll authors: No reported disclosures.

A multihospital collaborative study evaluated prophylactic lithium carbonate therapy in 205 patients with bipolar manic-depressive illness. Factors associated with poor lithium carbonate response are the following: (1) a recent history of frequent affective episodes requiring hospitalization, and (2) previous failure of lithium carbonate treatment. Results also suggest that lithium carbonate response may be related to the presence of schizo-affective illness and a family history of bipolar affective illness, but the small numbers of patients in these groups limit interpretation. Most failures on lithium carbonate therapy occur during the first year. Ability to remain on the maintenance schedule with no episodes for a year may be the most potent predictor of ultimate prophylactic success. There are important implications in these findings for the clinician selecting patients for prophylactic treatment.

Bloodstream infections (BSIs) caused by KPC-producing Klebsiella pneumoniae (KPC-Kp) remain associated with high mortality, even outside intensive care units (ICUs). Optimizing early β-lactam exposure through a loading dose (LD) of ceftazidime-avibactam or meropenem-vaborbactam may improve outcomes, but evidence in non-ICU settings is limited. We conducted a retrospective single-centre study (January 2023-June 2025) including adult non-ICU inpatients with genotypically confirmed KPC-Kp BSI. The control group received standard dosing (ceftazidime-avibactam 2 g/0.5 g q8h or meropenem-vaborbactam 2 g/2 g q8h, both over 3 h). The LD group received either one standard dose infused over 30 min (Scheme A) or one standard dose + 50% infused over 2-3 h (Scheme B), followed by the standard regimen q8h. Primary outcomes were 7- and 30-day all-cause mortality; secondary outcomes included microbiological clearance ≤72 h, ICU transfer and/or vasopressor use, adverse events (AEs ≥ grade 2), hospital stay, and recurrence ≤30 days. A total of 189 patients were included (140 controls, 49 LD). Groups were comparable in age (median 74 years), comorbidities (Charlson 5), and renal function (eGFR ≈45 mL/min/1.73 m²). LD was associated with faster blood-culture clearance (78% versus 55%; RR 1.26, 95% CI 1.03-1.61, P = 0.02) and lower ICU/vasopressor requirement (7.5% versus 23%; RR 0.60, 95% CI 0.29-0.93, P = 0.02). Median hospital stay was shorter (33 versus 37 days, P = 0.3). Thirty-day mortality was lower in LD (16.3% versus 21.0%; adjusted RR 0.62, 95% CI 0.39-1.29, P = 0.23), indicating a non-significant but clinically relevant trend. No increase in adverse events or nephrotoxicity was observed. In non-ICU KPC-Kp BSIs, a β-lactam loading dose regimen was associated with faster microbiological clearance, reduced ICU transfer and shorter hospital stay, without added toxicity. Mortality showed a non-significant trend towards improvement. Pragmatic LD strategies may enhance early β-lactam exposure where therapeutic drug monitoring (TDM) is unavailable. Prospective PK/PD-guided studies are warranted.

In the midst of recent preparations to move the Phipps Psychiatric Clinic at Johns Hopkins University School of Medicine in Baltimore to a new building, Joseph H. Stephens opened an unused locked closet and, much to his surprise, stepped into the lives of thousands of former psychiatric patients. Stephens, a Hopkins psychiatrist, discovered more than 10,000 5-by-8-inch cards neatly filed in the closet. The cards were the remnants of a project conducted from 1936 to 1950, in which detailed clinical descriptions and follow-ups were prepared for all patients admitted to the Phipps Clinic between 1913 and 1940. A rare opportunity was at hand individuals unexposed to the modern arsenal of psychoactive drugs could be tracked over decades for clues to the natural ebb and flow of psychiatric symptoms. Stephens and his colleagues sorted the 8,172 patients portrayed on the cards into eight groups based on current psychiatric diagnoses. The long-term outlook for those who were manic depressive was examined first, reported Stephens at the recent American Psychiatric Association meeting in Chicago. And the results were not encouraging. As many as 2 million people in the United States are estimated to suffer from manic depression, a condition marked by periods of severe depression interspersed with episodes of uncontrollable elation, restlessness, racing thoughts and delusions of grandeur. There are indications that specific genes may predispose some people to manic depression (SN: 2/28/87, p.132). For more than 30 years, the basic treatment for this disorder has been lithium carbonate, a drug that often dampens manic and depressive mood swings. In the past decade, research has suggested that, even with lithium, manic depression is usually more persistent and severe than depression alone. Among 234 pre-lithium manic depressives followed for an average of 15 years after discharge from the Phipps Clinic, the Hopkins researchers found that one-third continued to suffer from severe symptoms and ended up back in the hospital for long stretches. Another 39 percent were moderately disturbed and reentered the hospital once or twice. The remaining 28 percent were not rehospitalized, but only half of them suffered no further episodes of mania or depression.