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PubMed2002

Genetic analysis of high-risk e6 in episomal maintenance of human papillomavirus genomes in primary human keratinocytes.

Papillomaviruses possess small DNA genomes that encode five early (E) proteins. Transient DNA replication requires activities of the E1 and E2 proteins and a DNA segment containing their binding sites. The E6 and E7 proteins of cancer-associated human papillomavirus (HPV) transform cells in culture. Recent reports have shown that E6 and E7 are necessary for episomal maintenance of HPV in primary keratinocytes. The functions of E6 necessary for viral replication have not been determined, and to address this question we used a recently developed transfection system based on HPV31. To utilize a series of HPV16 E6 mutations, HPV31 E6 was replaced by its HPV16 counterpart. This chimeric genome was competent for both transient and stable replication in keratinocytes. Four HPV16 E6 mutations that do not stimulate p53 degradation were unable to support stable viral replication, suggesting this activity may be necessary for episomal maintenance. E7 has also been shown to be essential for episomal maintenance of the HPV31 genome. A point mutation in the Rb binding motif of HPV E7 has been reported to render HPV31 unable to stably replicate. Interestingly, HPV31 genomes harboring two of the three p53 degradation-defective E6 mutations combined with this E7 mutation were maintained as replicating episomes. These findings imply that the balance between E6 and E7 functions in infected cells is critical for episomal maintenance of high-risk HPV genomes. This model will be useful to dissect the activities of E6 and E7 necessary for viral DNA replication.

Amino Acid Sequence↗
PubMed2002

Chromosome binding site of latency-associated nuclear antigen of Kaposi's sarcoma-associated herpesvirus is essential for persistent episome maintenance and is functionally replaced by histone H1.

Latency-associated nuclear antigen 1 (LANA1) of Kaposi's sarcoma-associated herpesvirus (KSHV; human herpesvirus 8) persistently maintains a plasmid containing the KSHV latent origin of replication (oriP) as a closed circular episome in dividing cells. In this study, we investigated the involvement of chromosome binding activity of LANA1 in persistent episome maintenance. Deletion of the N-terminal 22 amino acids of LANA1 (DeltaN-LANA) inhibited the interaction with mitotic chromosomes in a human cell line, and the mutant concomitantly lost activity for the long-term episome maintenance of a plasmid containing viral oriP in a human B-cell line. However, a chimera of DeltaN-LANA with histone H1, a cellular chromosome component protein, rescued the association with mitotic chromosomes as well as the long-term episome maintenance of the oriP-containing plasmid. Our results suggest that tethering of KSHV episomes to mitotic chromosomes by LANA1 is crucial in mediating the long-term maintenance of viral episomes in dividing cells.

Antigens, Viral↗
PubMed2005

Episomal maintenance of plasmids with hybrid origins in mouse cells.

Bovine papillomavirus type 1 (BPV1), Epstein-Barr virus (EBV), and human herpesvirus 8 genomes are stably maintained as episomes in dividing host cells during latent infection. The mitotic segregation/partitioning function of these episomes is dependent on single viral protein with specific DNA-binding activity and its multimeric binding sites in the viral genome. In this study we show that, in the presence of all essential viral trans factors, the segregation/partitioning elements from both BPV1 and EBV can provide the stable maintenance function to the mouse polyomavirus (PyV) core origin plasmids but fail to do so in the case of complete PyV origin. Our study is the first which follows BPV1 E2- and minichromosome maintenance element (MME)-dependent stable maintenance function with heterologous replication origins. In mouse fibroblast cell lines expressing PyV large T antigen (LT) and either BPV1 E2 or EBV EBNA1, the long-term episomal replication of plasmids carrying the PyV minimal origin together with the MME or family of repeats (FR) element can be monitored easily for 1 month under nonselective conditions. Our data demonstrate clearly that the PyV LT-dependent replication function and the segregation/partitioning function of the BPV1 or EBV are compatible in certain, but not all, configurations. The quantitative analysis indicates a loss rate of 6% per cell, doubling in the case of MME-dependent plasmids, and 13% in the case of FR-dependent plasmids in nonselective conditions. Our data clearly indicate that maintenance functions from different viruses are principally interexchangeable and can provide a segregation/partitioning function to different heterologous origins in a variety of cells.

Animals↗
PubMed1999

Trithorax- and Polycomb-group response elements within an Ultrabithorax transcription maintenance unit consist of closely situated but separable sequences.

In Drosophila, two classes of genes, the trithorax group and the Polycomb group, are required in concert to maintain gene expression by regulating chromatin structure. We have identified Trithorax protein (TRX) binding elements within the bithorax complex and have found that within the bxd/pbx regulatory region these elements are functionally relevant for normal expression patterns in embryos and confer TRX binding in vivo. TRX was localized to three closely situated sites within a 3-kb chromatin maintenance unit with a modular structure. Results of an in vivo analysis showed that these DNA fragments (each approximately 400 bp) contain both TRX- and Polycomb-group response elements (TREs and PREs) and that in the context of the endogenous Ultrabithorax gene, all of these elements are essential for proper maintenance of expression in embryos. Dissection of one of these maintenance modules showed that TRX- and Polycomb-group responsiveness is conferred by neighboring but separable DNA sequences, suggesting that independent protein complexes are formed at their respective response elements. Furthermore, we have found that the activity of this TRE requires a sequence (approximately 90 bp) which maps to within several tens of base pairs from the closest neighboring PRE and that the PRE activity in one of the elements may require a binding site for PHO, the protein product of the Polycomb-group gene pleiohomeotic. Our results show that long-range maintenance of Ultrabithorax expression requires a complex element composed of cooperating modules, each capable of interacting with both positive and negative chromatin regulators.

Animals↗
PubMed1998

Erosive oesophagitis: outcome of repeated long term maintenance treatment with low dose omeprazole 10 mg or placebo.

AIMS: To investigate the efficacy of daily maintenance treatment with omeprazole 10 mg in reducing the relapse rate of healed erosive oesophagitis. METHODS: Three hundred patients with erosive oesophagitis (grade 2 or greater) received omeprazole 20 mg daily for 12 weeks, followed by 40 mg daily for a further 12 weeks if required. After healing, patients were randomised to double blind treatment with omeprazole 10 mg daily or placebo for up to 18 months. On relapse the treatment cycle was repeated. RESULTS: The cumulative healing rate at 12 weeks in the initial healing period was 95%, and 96% and 98% on rehealing courses after relapse in the first and second maintenance periods respectively. After 12 weeks of treatment, 98% of patients were free from heartburn and 97% were free of all reflux related symptoms. Relapse in the subgroup of patients who relapsed in both maintenance periods was infrequent on omeprazole 20 mg daily: only 9% at two years. Gastrin concentrations rose above normal in one third of patients. One patient had linear hyperplasia of endocrine cells and another had micronodular hyperplasia. There were no side effects definitely attributable to omeprazole. CONCLUSION: Maintenance treatment with omeprazole 10 mg daily keeps about 60% of patients with erosive oesophagitis in prolonged remission. Patients relapsing once are likely to do so again; they can subsequently be treated effectively with omeprazole 20 mg daily.

Anti-Ulcer Agents↗
PubMed1986

Determinants of Ca2+-dependent stress maintenance in skinned swine carotid media.

Ca2+-dependent stress maintenance without proportional myosin light chain (MLC) phosphorylation was demonstrated in the detergent-skinned swine carotid media when [Ca2+] was reduced from high to intermediate concentrations (Chatterjee, M., and R. A. Murphy. Science Wash. DC 221: 464-466, 1983). In this study of the same preparation, we examined the influence of the initial [Ca2+] and MLC phosphorylation levels on the formation of a stress maintaining state (the "latch" state). Fibers were contracted with 0.82, 1.3, 2.1, or 7.2 microM Ca2+ and then exposed to a lower [Ca2+] to determine the magnitude and Ca2+ sensitivity of stress maintenance. MLC phosphorylation levels were measured in all strips. The magnitude of the stress that rapidly developed was dependent on the initial activating [Ca2+]. The Ca2+ sensitivity of stress maintenance appeared to be independent of the initial levels of stress and MLC phosphorylation. However, the magnitude of the maintained stress was dependent on the initial levels of Ca2+. Only two values for half-maximal responses were evinced in all Ca2+-dependent stress curves: 1.4 X 10(-6) M Ca2+ for rapid stress development and 3.1 X 10(-7) M for stress maintenance. Cumulative [Ca2+]-response curves were shown to result in a decreased maximal stress response and an increase in the apparent Km compared with curves determined by responses to single [Ca2+] exposures. This was associated with a time- and stress-related deterioration of the preparation. The latter was not prevented by exogenous calmodulin or leupeptin (an effective inhibitor of an endogenous Ca2+-dependent protease shown to disrupt the cellular cytoskeleton).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effect of lung volume maintenance during sleep in nocturnal asthma.

Previous studies have shown that lung volume decreases and airway resistance increases during sleep in patients with nocturnal asthma. To determine whether the fall in lung volume per se causes the overnight decrement in forced expiratory volume in 1 s (FEV1) and/or increase in bronchial responsiveness, we investigated the effect of preventing this nocturnal decrease in lung volume. The mean volume change on a baseline night was -16.3 +/- 1.6% from presleep values and on the volume maintenance night +7.1 +/- 3.0% (P = 0.0001). However, this maintenance of lung volume did not alter the overnight decrement in FEV1 (-29.6 +/- 5.2% baseline vs. -30.2 +/- 5.8% volume maintenance). Similarly, the increase in bronchial responsiveness was also unaltered from baseline to volume maintenance nights, with presleep provocative concentrations of methacholine producing a 20% decrement in FEV1 of 0.28 +/- 0.15 vs. 0.22 +/- 0.7 mg/ml, respectively, and postsleep values of 0.07 +/- 0.03 vs. 0.04 +/- 0.02 mg/ml, respectively. Thus the fall in lung volume during sleep in the nocturnal asthmatic patient is a result, not a cause, of the overnight worsening of lung function.

Adult↗
PubMed2004

Presynaptic activity and Ca2+ entry are required for the maintenance of NMDA receptor-independent LTP at visual cortical excitatory synapses.

We have shown that some neural activity is required for the maintenance of long-term potentiation (LTP) at visual cortical inhibitory synapses. We tested whether this was also the case in N-methyl-d-aspartate (NMDA) receptor-independent LTP of excitatory connections in layer 2/3 cells of developing rat visual cortex. This LTP occurred after 2-Hz stimulation was applied for 15 min and always persisted for several hours while test stimulation was continued at 0.1 Hz. When test stimulation was stopped for 1 h after LTP induction, only one-third of the LTP instances disappeared, but most did disappear under a pharmacological suppression of spontaneous firing, indicating that LTP maintenance requires either evoked or spontaneous activities. LTP was totally abolished by a temporary blockade of action potentials with lidocaine or the removal of extracellular Ca(2+) after LTP induction, but it persisted under a voltage clamp of postsynaptic cells or after a temporary blockade of postsynaptic activity with the glutamate receptor antagonist kynurenate, suggesting that LTP maintenance requires presynaptic, but not postsynaptic, firing and Ca(2+) entry. More than one-half of the LTP instances were abolished after a pharmacological blockade of P-type Ca(2+) channels, whereas it persisted after either L-type or Ni(2+)-sensitive Ca(2+) channel blockades. These results show that the maintenance of NMDA receptor-independent excitatory LTP requires presynaptic firing and Ca(2+) channel activation as inhibitory LTP, although the necessary level of firing and Ca(2+) entry seems lower for the former than the latter and the Ca(2+) channel types involved are only partly the same.

Anesthetics, Local↗
PubMedDate not supplied

Adjustable maintenance dosing with budesonide/formoterol reduces asthma exacerbations compared with traditional fixed dosing: a five-month multicentre Canadian study.

BACKGROUND: Adjustable maintenance dosing with budesonide/formoterol in a single inhaler (Symbicort, AstraZeneca, Lund, Sweden) may provide a convenient means of maintaining asthma control with the minimum effective medication level. OBJECTIVES: To compare adjustable and fixed maintenance dosing regimens of budesonide/formoterol in asthma. METHODS: This was an open-label, randomized, parallel-group, multicentre, Canadian study of asthma patients (aged 12 years or older, postbronchodilator forced expiratory volume in 1 s 70% or greater of predicted normal). Following a one-month run-in on budesonide/formoterol (100/6 µg or 200/6 µg metered doses, two inhalations twice daily), 995 patients were randomly assigned either to continue on this fixed dosing regimen or to receive budesonide/formoterol adjustable dosing (step down to one inhalation twice daily if symptoms were controlled or temporarily step up to four inhalations twice daily for seven or 14 days if asthma worsened). The primary efficacy variable was the occurrence of exacerbations (requiring oral or inhaled corticosteroids, emergency department treatment, serious adverse events or added maintenance therapy because of asthma). RESULTS: With adjustable dosing, significantly fewer patients experienced exacerbations compared with fixed dosing (4.0% versus 8.9%, P=0.002; number needed to treat=21 [95% CI 13 to 59]). Patients required 36% fewer overall doses of budesonide/formoterol (2.5 versus 3.9 inhalations/day, P<0.001), and total costs per patient were lower (difference over five months -141 Canadian dollars [95% CI -162 Canadian dollars to -116 Canadian dollars]). Asthma symptom severity (modified National Heart, Lung, and Blood Institute stage) was maintained or improved in 97% or greater of patients in both groups (pre-run-in to end of treatment). Both treatments were well tolerated. CONCLUSIONS: Budesonide/formoterol adjustable maintenance dosing provided more effective asthma control than fixed dosing, with a lower overall drug dose and reduced total cost.

Administration, Inhalation↗
PubMed2006

[Maintenance electroconvulsive therapy in elderly psychotic unipolar depression].

BACKGROUND AND OBJECTIVE: This study was designed to assess the safety and efficacy of continuation/maintenance electroconvulsive therapy (ECT) in elderly psychotic major depressed patients after ECT remission. PATIENTS AND METHOD: Using a longitudinal randomized single-blind design, we compared the two-year outcome of two subgroups of psychotic unipolar depressed elderly patients who were ECT remitters: one treated with a maintenance nortriptyline regimen (n = 13) and one treated with combined maintenance ECT plus nortriptyline (n = 6). RESULTS: During 2 years of maintenance treatment in elderly psychotic unipolar depressed ECT remitters, relapse/recurrence rates were significantly higher in the nortriptyline subgroup than in the combined ECT plus nortriptyline subgroup. The tolerability of both treatments was similar. CONCLUSIONS: This study supports the use of combined maintenance ECT and antidepressant treatment in elderly psychotic unipolar depressed patients who are ECT remitters.

Aged↗
PubMed2001

Maintenance electroconvulsive therapy in affective and schizoaffective disorder.

Twenty-one patients (13 depressives and 8 schizoaffectives) who underwent maintenance electroconvulsive therapy (M-ECT) were compared with controls who received maintenance pharmacotherapy alone. Measures of effectiveness and safety of maintenance treatment were prospectively obtained during a 1-year follow-up. Survival analysis demonstrated a significantly better outcome defined by time to rehospitalization for all patients of the M-ECT group. Regarding the subgroups, depressives of the M-ECT group had markedly decreased rehospitalization rates compared to depressive controls. Furthermore, M-ECT in depressives resulted in a significant reduction in hospitalization rates and duration during follow-up. In schizoaffective patients, a significant difference in survival time was found in favor of the M-ECT group. In both groups, schizoaffectives had a markedly poorer outcome compared to depressive subjects. Our results indicate that in selected patients M-ECT, at least in combination with supporting medication, may be an efficient and safe alternative to pharmacological continuation or maintenance therapy alone.

Adult↗
PubMed2004

Resumption and maintenance of employment after a first acute myocardial infarction: sociodemographic, vocational and medical predictors.

In a community cohort of 833 women and men aged <60 years, employed at the time of a first acute myocardial infarction (AMI), the relation of sociodemographic, vocational, and medical variables to the following three aspects of employment was investigated longitudinally: resumption of employment anytime within 5 years after AMI, resumption of employment within 3 months of the AMI, and maintenance of employment 5 years after AMI. Different sets of characteristics of persons with a first AMI were related to the different criteria of employment. Only sociodemographic and vocational variables were related to early resumption of employment, whereas maintenance of employment 5 years after AMI was influenced by both medical and nonmedical variables. These results support the importance of examining different aspects of resumption and maintenance of employment after AMI. They also suggest that early resumption of employment after AMI and employment anytime 5 years after AMI are more a function of the sociodemographic and vocational characteristics of the person with the AMI than of that person's medical condition, whereas long-term maintenance of employment after an AMI is also related to the person's medical condition.

Age Factors↗
PubMed2005

Maintenance of remission in Crohn's disease.

When remission of Crohn's disease is achieved, the next goal is to maintain long-term remission. Aminosalicylates may be recommended for maintenance remission, even though the results are less consistent than those observed in ulcerative colitis. The benefit is mainly observed in the post-surgical setting and in patients with ileitis, and with a prolonged disease duration. Corticosteroids are not effective in maintaining remission and should not be used for this indication. Azathioprine and 6-mercaptopurine are effective in maintaining remission. Maintenance benefits remain significant for patients who continued with the therapy for up to 5 years. Methotrexate has also been found to be effective in maintaining remission in Crohn's disease in patients who have responded acutely to methotrexate. Cyclosporine has not been found to be an effective maintenance agent. Mycophenolate mofetil could be considered a therapy in patients who are either allergic to azathioprine or in whom azathioprine failed to induce remission. The use of infliximab may change the future approach to maintenance therapy for Crohn's disease. Patients who responded clinically to infliximab have maintained their clinical response when receiving repeat infusions at 8-week intervals. In patients refractory to other therapies, infliximab may be effective in maintaining remission.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1976

Haemoglobin and serum iron responses to periodic intravenous iron-dextran infusions during maintenance haemodialysis.

Patients with chronic renal failure who were on maintenance haemodialysis, were given monthly 600 mg iron intravenously as iron-dextran complex to a body replacement total of 5-6 g iron. Those patients who had been on maintenance haemodialysis for a long period and had received numerous blood transfusions failed to show a rise in haemoglobin levels. Those patients who received iron from the commencement of maintenance dialysis, and who had not received blood transfusions, showed a significant increase in haemoglobin concentrations which has been maintained for more than 18 months after iron therapy ceased, despite a concurrent decrease in serum iron concentrations. Pre-treatment and post-treatment levels of serum iron are not of predictive value for the success of iron treatment, neither for the haemoglobin nor the serum iron response. A body replacement dose of iron given intravenously over a year benefits the majority of patients on maintenance haemodialysis and is recommended for the treatment of their anaemia.

Anemia↗
PubMed2004

Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin.

Knowledge of pharmacogenetics may help clinicians predict their patients' therapeutic dose of warfarin, thereby decreasing the risk of bleeding during warfarin initiation. Our goal was to use pharmacogenetics to develop an algorithm that uses genetic, clinical, and demographic factors to estimate the warfarin dose a priori. We collected a blood sample, demographic variables, laboratory values, smoking status, names of medications, and dietary history from 369 patients who were taking a maintenance dose of warfarin. Using polymerase chain reaction, we genotyped each participant for the presence of 8 polymorphisms in the cytochrome P450 2C9 system. Using multiple regression, we quantified the association between warfarin dose and all factors. Advanced age, lower body surface area (BSA), and the presence of cytochrome P450 2C9 *2 or *3 single nucleotide polymorphisms were strongly associated (P < 0.001) with lower warfarin dose: the maintenance dose decreased by 8% per decade of age, by 13% per standard deviation decrease in BSA, by 19% per 2C9*2 allele, and by 30% per 2C9*3 allele. Warfarin doses were 29% lower in patients who took amiodarone, 12% lower in patients who took simvastatin, 21% lower in patients whose target INR was 2.5 rather than 3.0, and 11% lower in white rather than African-American participants (P < 0.05 for these comparisons). An algorithm that included these factors and one of borderline significance (sex), explained 39% of the variance in the maintenance warfarin dose. Use of this pharmacogenetic model had potential to prevent patients from being overdosed when initiating warfarin: we estimate that only 24 (6.5%) patients would have been over- dosed by >2 mg/day with pharmacogenetic dosing compared to 59 (16%) patients who would have been overdosed if they had been prescribed the empirical dose of 5 mg/day (P < 0.001). In conclusion, the maintenance warfarin dose can be estimated from demographic, clinical, and pharmacogenetic factors that can be obtained at the time of warfarin initiation.

Aged↗
PubMed1988

Prevention of coronary artery reocclusion and reduction in late coronary artery stenosis after thrombolytic therapy in patients with acute myocardial infarction. A randomized study of maintenance infusion of recombinant human tissue-type plasminogen activator.

Sixty-eight patients with acute "transmural" myocardial infarction presenting within 6 hours (range, 1.3-5.8 hours) of onset of chest pain were given intravenous recombinant tissue-type plasminogen activator (rt-PA) at a dosage of 1 mg/kg during 90 minutes. Coronary angiography at 90 minutes revealed a patent infarct-related coronary artery in 52 patients (76%). These patients were randomized either to treatment by continuous infusion of heparin alone (27 patients) or to treatment by heparin and a maintenance infusion of rt-PA at a dosage of 0.8 mg/kg during 4 hours (25 patients). Coronary angiography was repeated 60 minutes after the start of the maintenance infusion and again after 8-14 days. Acute symptomatic reocclusion of the infarct-related artery occurred during the 1-hour observation period in five (19%) patients treated with heparin alone but in none of the patients treated with rt-PA (p = 0.05). The measured residual stenosis of the patent infarct-related coronary artery was similar in the heparin-treated and the rt-PA-treated groups at 90 minutes infusion: 66 +/- 14% versus 68 +/- 13% diameter stenosis, respectively (mean +/- SD) and 1.1 +/- 1.1 mm2 versus 0.82 +/- 0.7 mm2 area (p = 0.35). At 8-14 days after infusion, residual stenosis was unchanged in the heparin-treated group, but it improved to 55 +/- 17% (p = 0.001) and 1.6 +/- 1.2 mm2 (p = 0.003) in the rt-PA-treated group. At 90 minutes of infusion, residual intraluminal thrombus was observed in 29 of the 52 patients (56%) with a comparably measured distribution in the two groups (p = 0.43). At 150 minutes, however, the extent of intraluminal thrombus was significantly reduced in the rt-PA-treated group as compared with the heparin-treated group (p = 0.03). In-hospital ischemic events (symptomatic reocclusion, unstable angina, or cardiovascular death) occurred in 12 patients of the heparin-treated group but only in three patients of the rt-PA-treated group (p = 0.03). Fibrinogen levels decreased to 65 +/- 21% of baseline at 90 minutes of rt-PA infusion. During the rt-PA maintenance infusion, fibrinogen fell slightly from 63 +/- 26 to 57 +/- 28% (p = 0.18). This study shows that after successful reperfusion with 1 mg/kg rt-PA during 90 minutes, a maintenance infusion of 0.8 mg/kg rt-PA during 4 hours prevents acute symptomatic coronary artery reocclusion, and it reduces the frequency of ischemic events and the severity of residual coronary artery stenosis at hospital discharge.

Aged↗
PubMed1976

Overview: maintenance therapy in psychiatry: II. Affective disorders.

In the first part of this overview the author reviewed the clinical literature on prophylactic treatment of schizophrenia with maintenance antipsychotic drugs. In this second part he reviews the literature on maintenance treatment of affective disorders with lithium and tricyclics. He concludes that the growing realization that maintenance treatment is necessary to prevent recurrences of both mania and depression in bipolar disease and depression in unipolar disease is one of the most important advances in psychiatric therapeutics. The effectiveness of maintenance treatment provides the potential for a truly preventive approach to the treatment of affective disorders.

Affective Symptoms↗
PubMed2002

Effect of abrupt change from standard to low serum levels of lithium: a reanalysis of double-blind lithium maintenance data.

OBJECTIVE: Growing evidence suggests that abrupt lithium discontinuation increases the risk of recurrence for patients with bipolar disorder. To assess the effect of abrupt change in lithium dose, the authors reanalyzed data from a previously reported, randomized, double-blind trial of standard- versus low-dose lithium for maintenance therapy in bipolar disorder. METHOD: In the original study, serum lithium levels were obtained during a 2-month open stabilization period for 94 patients with bipolar disorder who were then randomly assigned to be maintained on a low (serum level=0.4-0.6 meq/liter) or a standard (0.8-1.0 meq/liter) level of lithium therapy. Patients were then followed for up to 182 weeks. This reanalysis examined the potential confounding influence of prerandomization lithium level and change in lithium level on the outcome of subjects assigned to a standard or low maintenance dose of lithium. RESULTS: In a Cox proportional hazards model incorporating pre- and postrandomization lithium levels and the interaction of these factors, only the interaction term remained significantly associated with time to recurrence. CONCLUSIONS: The findings indicate that change in serum lithium level may be a more powerful predictor of recurrence of bipolar disorder than the absolute assignment to a low or a standard dose of lithium and suggest that an abrupt decrease in lithium level should be avoided. This reanalysis did not directly address optimal maintenance lithium levels but raises questions about the original study's finding of superiority for lithium levels > or =0.8 meq/liter. The results underscore the importance of accounting for the possible confounding effects of changes in the intensity of pharmacotherapy in studies of maintenance therapies for bipolar disorder.

Adult↗