Prediction of lithium response using clinical data.

OBJECTIVE: Promptly establishing maintenance therapy could reduce morbidity and mortality in patients with bipolar disorder. Using a machine learning approach, we sought to evaluate whether lithium responsiveness (LR) is predictable using clinical markers. METHOD: Our data are the largest existing sample of direct interview-based clinical data from lithium-treated patients (n = 1266, 34.7% responders), collected across seven sites, internationally. We trained a random forest model to classify LR-as defined by the previously validated Alda scale-against 180 clinical predictors. RESULTS: Under appropriate cross-validation procedures, LR was predictable in the pooled sample with an area under the receiver operating characteristic curve of 0.80 (95% CI 0.78-0.82) and a Cohen kappa of 0.46 (0.4-0.51). The model demonstrated a particularly low false-positive rate (specificity 0.91 [0.88-0.92]). Features related to clinical course and the absence of rapid cycling appeared consistently informative. CONCLUSION: Clinical data can inform out-of-sample LR prediction to a potentially clinically relevant degree. Despite the relevance of clinical course and the absence of rapid cycling, there was substantial between-site heterogeneity with respect to feature importance. Future work must focus on improving classification of true positives, better characterizing between- and within-site heterogeneity, and further testing such models on new external datasets.

Trajectories of adherence to mood stabilizers in patients with bipolar disorder.

BACKGROUND: Nonadherence with mood stabilizers is a major problem that negatively impacts the course of bipolar disorder. Medication adherence is a complex individual behavior, and adherence rates often change over time. This study asked if distinct classes of adherence trajectories with mood stabilizers over time could be found, and if so, which patient characteristics were associated with the classes. METHODS: This analysis was based on 12 weeks of daily self-reported data from 273 patients with bipolar 1 or II disorder using ChronoRecord computer software. All patients were taking at least one mood stabilizer. The latent class mixed model was used to detect trajectories of adherence based on 12 weekly calculated adherence datapoints per patient. RESULTS: Two distinct trajectory classes were found: an adherent class (210 patients; 77%) and a less adherent class (63 patients; 23%). The characteristics associated with the less adherent class were: more time not euthymic (p < 0.001) and female gender (p = 0.016). No other demographic associations were found. CONCLUSION: In a sample of motivated patients who complete daily mood charting, about one quarter were in the less adherent class. Even patients who actively participate in their care, such as by daily mood charting, may be nonadherent. Demographic characteristics may not be useful in assessing individual adherence. Future research on longitudinal adherence patterns in bipolar disorder is needed.

Solar insolation in springtime influences age of onset of bipolar I disorder.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

Treatment of lithium intoxication: facing the need for evidence.

Lithium has been used as the gold standard in the treatment of major depressive and bipolar disorders for decades. Due to its narrow therapeutic index, lithium toxicity is a common clinical problem. Although risk factors for lithium intoxication seem to be well-described, lacking patient education and inexperience of treatment are assumed to contribute to the probability of lithium intoxication. A review of literature shows that the treatment of lithium intoxication has not been adequately studied or standardized. The aim of this literature review is to compile and present current evidence on the treatment of lithium intoxication and contribute to a standardization regarding general treatment recommendations as well as evidence on indication for extracorporeal methods. Against the background of this common and potentially life-threatening condition, the standardization of the treatment of lithium intoxication is definitely a task for the future.

Regularity in daily mood stabilizer dosage taken by patients with bipolar disorder.

OBJECTIVE: The aim of this study was to investigate regularity in the daily mood stabilizer dosage taken by patients with bipolar disorder, and identify factors associated with irregularity. METHODS: Self-reported daily mood and medication data were available from 206 patients who took the same mood stabilizer for ≥100 days. Approximate entropy (ApEn) was used to measure serial regularity in daily mood stabilizer dosage. Generalized estimating equations (GEE) were used to estimate if demographic or clinical variables were associated with ApEn. RESULTS: There was a wide range of regularity in the daily mood stabilizer dosage. The mean percent of days of missing doses was 13.6%. The number of psychotropic medications (p=0.007), pill burden (p=0.004) and percent of days with depressed mood (p=0.013) were associated with more irregularity, while the percent of days euthymic (p=0.014) was associated with less irregularity. The percent of days missing doses was not associated with the number of medications, pill burden or mood ratings. DISCUSSION: Patients may have irregularity in daily dosage in spite of a low percent of days missing doses. Psychotropic medication regimen complexity and depression are associated with increased dosage irregularity. Research is needed on how irregularity in daily dosage impacts the continuity of drug action of mood stabilizers.

Attachment and temperament profiles among the offspring of a parent with bipolar disorder.

INTRODUCTION: Attachment is associated both with the risk of developing a mood disorder and temperamental profile. Relatively little is known about these associations in children of a parent with bipolar disorder (BD). The present study is a preliminary analysis of the association between attachment, temperament and psychopathology among high-risk offspring. METHODS: As part of an ongoing prospective cohort study, offspring from families with one parent with BD (HR) and offspring from families with unaffected parents (C) were clinically assessed using KSADS-PL format interviews annually. Validated self-report measures of perceived attachment and temperament were completed. RESULTS: Perceived attachment did not differentiate HR from C offspring and did not predict psychopathology or mood disorder in particular. However, high emotionality significantly predicted the risk of psychopathology in HR offspring, where 1 standard deviation increase in emotionality significantly increased the hazard of psychopathology by a factor of 1.36 (p=0.0009) and mood disorder by a factor of 1.24 (p=0.02). LIMITATIONS: Use of retrospective measures and low sample size for some models. CONCLUSIONS: There may be no gross abnormalities in attachment among HR compared to C offspring. It remains unclear if emotionality is a barometer of illness or a true risk factor in this population. More longitudinal research is needed to advance understanding of the influential pathways by which psychosocial risk factors impact the development of BD. This research has implications for targeted early interventions in HR youth.

Comparison of pre-episode and pre-remission states using mood ratings from patients with bipolar disorder.

Daily self-reported mood ratings from patients with bipolar disorder were analyzed to see if the 60 days before an episode of hypomania or depression (pre-episode state) could be distinguished from the 60 days before a month of euthymia (pre-remission state), and if a pre-hypomanic state could be distinguished from a pre-depressed state. Data were available from 98 outpatients with bipolar disorder, who returned about one year of daily data, and received treatment as usual. The approximate entropy (ApEn), mean mood and mood variability (standard deviation) were determined for 53 pre-hypomanic states, 42 pre-depressive states, and 65 pre-remission states.There was greater serial irregularity (ApEn) and greater variability in mood in the pre-episode than the pre-remission state. There was greater serial irregularity (ApEn) but no difference in variability in mood in the pre-hypomanic state when compared to the pre-depressed state. ApEn can distinguish between the pre-episode, pre-remission, pre-hypomanic and pre-depressive states. Using daily mood ratings, pre-episode changes were detected before the episode onset. Further investigation to relate the pre-episode and pre-remission states to other clinical and biological data is indicated.

Lithium response across generations.

OBJECTIVE: To describe and integrate observations from bipolar patients responsive to lithium stabilization and their children. METHOD: Selected findings are described from the clinical and biological investigations of adults meeting research criteria for bipolar disorder and for responsiveness to lithium stabilization; and from prospective studies of the children of lithium responders and non-responders. RESULTS: Response to prophylactic lithium identifies a valid subtype of bipolar disorder, however the search for biological markers of lithium response, while promising, has so far remained inconclusive. Adult responders to lithium stabilization exhibit definable clinical features which are also observable in their affected children. In prospective studies the children of bipolar parents develop symptoms earlier than reported previously, with marked differences between the offspring of lithium responders and non-responders. The illness evolves in predictable clinical stages, first from non-specific sleep and anxiety disorders to mood symptoms and then, often starting in adolescence, major depressive and later activated episodes. CONCLUSION: Investigating and comparing unequivocal responders and non-responders to long-term lithium treatment and their offspring is a fertile research strategy for addressing a multitude of clinical and research questions.

Characterization of liposomal vesicles encapsulating rhodanese for cyanide antagonism.

The major mechanism of removing cyanide from the body is its enzymatic conversion by a sulfurtransferase, e.g. rhodanese, to the less toxic thiocyanate in the presence of a sulfur donor. Earlier results demonstrated that externally administered encapsulated rhodanese significantly enhances the in vivo efficacy of the given sulfur donor. Present studies are focused on liposomal carrier systems encapsulating rhodanese. Physicochemical properties, e.g. membrane rigidity, size distribution, surface potential, osmolarity, and viscosity, were determined for various liposomal lipid compositions and hydrating buffers to establish in vitro stability and in vivo fate. Lipid composition was also optimized to achieve maximum encapsulation efficiency.

Liposomal oxytetracycline and doxycycline: studies on enhancement of encapsulation efficiency.

Liposomal encapsulations of oxytetracycline (OTC) and doxycycline (DC) with various lipid compositions and hydrating solutions have been studied in order to develop a new liposomal formulation to treat bacterial infections. Encapsulation efficiencies as a function of pH (pH 4.0-8.0) in ionic (phosphate buffers) and non-ionic (mannitol or glucose) hydrating solutions with various lipid compositions (lecithin or α-L-dipalmitoylphosphatidylcholine, with or without cholesterol) were determined and compared to the character of lipid vesicles. Based on our encapsulation efficiency studies and on the drug stability considerations it can be concluded that for OTC/DC encapsulation the use of non-ionic solutions is the most promising.

Do antidepressants influence mood patterns? A naturalistic study in bipolar disorder.

This prospective, longitudinal study compared the frequency and pattern of mood changes between outpatients receiving usual care for bipolar disorder who were either taking or not taking antidepressants. One hundred and eighty-two patients with bipolar disorder self-reported mood and psychiatric medications for 4 months using a computerized system (ChronoRecord) and returned 22,626 days of data. One hundred and four patients took antidepressants, 78 did not. Of the antidepressants taken, 95% were selective serotonin or norepinephrine reuptake inhibitors, or second-generation antidepressants. Of the patients taking an antidepressant, 91.3% were concurrently taking a mood stabilizer. The use of antidepressants did not influence the daily rate of switching from depression to mania or the rate of rapid cycling, independent of diagnosis of bipolar I or II. The primary difference in mood pattern was the time spent normal or depressed. Patients taking antidepressants frequently remained in a subsyndromal depression. In this naturalistic study using self-reported data, patients with bipolar disorder who were taking antidepressants--overwhelmingly not tricyclics and with a concurrent mood stabilizer--did not experience an increase in the rate of switches to mania or rapid cycling compared to those not taking antidepressants. Antidepressants had little impact on the mood patterns of bipolar patients taking mood stabilizers.

Re-evaluation of randomized control trials of lithium monotherapy: a cohort effect.

OBJECTIVE: The reported reduction of lithium's efficacy in the prophylaxis of bipolar illness has been attributed to various factors, including diagnostic changes and heterogeneous study designs. We attempted to quantify the impact of pre-randomization enrichment designs and diagnostic drift on randomized controlled trials (RCTs) of lithium maintenance therapy. METHODS: Using the Cochrane RCT search filter, MEDLINE, EMBASE, and PSYCHINFO were searched (1966 to June 2004) for all available randomized studies using the text word 'lithium'. Studies of 1 year minimum duration in bipolar disorder involving lithium and placebo arms were identified. Superiority trials without a placebo arm, discontinuation and mirror image studies were excluded. Standardized scales were used to assess randomization and allocation concealment. RESULTS: Nine RCTs enrolling 1432 bipolar I and II patients, randomizing 341 to lithium and 386 to placebo were identified, with 705 reported pre-randomization dropouts. The pooled odds of remaining recurrence free in two non-enriched RCTS using Research Diagnostic Criteria (RDC) or Feighner criteria were 3.2:1 (95% CI 0.65--15.46) trending in favor of lithium over placebo, and 22.0:1 (95% CI 7.0--68.7) for three trials using lithium enrichment and excluding atypical bipolar disorder. The odds of remaining recurrence free using DSM-IV criteria and lamotrigine enrichment were 1.9:1 (95% CI 1.2-2.8). CONCLUSION: Lithium maintenance RCTs differ in patient selection, design, and outcome. A cohort effect can be associated with the use of pre-randomization enrichment phases and, to a lesser extent, with diagnostic drift, compromising straightforward comparisons across three decades of lithium monotherapy in bipolar illness.

Studies on molecular interactions between nalidixic acid and liposomes.

The interaction between nalidixic acid sodium salt (NANa) and liposomes prepared from alpha-L-dipalmitoyl-phosphatidylcholine (DPPC) or from its binary mixture with dioleoyl-phosphatidylcholine (DOPC) was studied with differential scanning calorimetry (DSC) and electron paramagnetic resonance (EPR) spectroscopy. We evaluated the role of broadband ultraviolet-B (UV-B) irradiation on the molecular interactions between the lipids and the NANa, and determined the decay-kinetics of the incorporated spin labeled fatty-acid free radicals. Multilamellar and unilamellar vesicles were prepared by sonication and extrusion. The entrapment efficiencies were determined spectrophotometrically. The size-distribution of the liposomes and its change in time was checked by dynamic light scattering (DLS). Our results indicate that NANa mainly interacts with lipid head groups. However, its effect and presumably the formation of the free radicals, induced by broadband ultraviolet-B, is not localized only to the head group region of the lipid molecules. Depending on DOPC content, interaction between the NANa and the lipids modifies the phase-transition parameters of the liposome dispersions.

Biological UV dosimeters in simulated space conditions.

Polycrystalline uracil thin layers participate in the phage and uracil response (PUR) experiment, assigned to the biological dosimetry of the extraterrestrial solar radiation on the International Space Station (ISS). In ground based experiments (experiment verification tests), the following space parameters were simulated and studied: temperature, vacuum and short wavelength UV (UV-C, down to 200 nm) radiation. The closed uracil samples proved to be vacuum-tight for 7 days. In the tested temperature range (from -20 to +40 degrees C) the uracil samples are stable. The kinetic of dimer formation (dimerization) and reversion (monomerization) of uracil dimers due to short wavelength UV radiation was detected, the monomerization efficiency of the polychromatic deuterium lamp is higher than that of the germicidal lamp. A mathematical model describing the kinetic of monomerization-dimerization was constructed. Under the influence of UV radiation the dimerization-monomerization reactions occur simultaneously, thus the additivity law of the effect of the various wavelengths is not applicable.

The electronic assessment of the longitudinal course of bipolar disorder: the ChronoRecord software.

Longitudinal studies are the optimal approach when investigating the highly variable course of bipolar disorder, but such studies are expensive, prone to reporting errors and to missing data. Automation of data collection may reduce such errors and improve data quality. The ChronoRecord, validated software that patients can install on a home computer to report mood, medications, sleep, life events, weight and menstrual data, has been designed to achieve such automation. In the trial of the ChronoRecord reported here, 80 of 96 (83 %) patients with bipolar disorder showed high acceptance of this computer-based system for self-report, entering daily recordings for a period of 3-months. This new technology, in addition to providing an accurate longitudinal record for research purposes, also facilitates on-going patient feedback and accurate study monitoring.

Does prophylaxis-delay in bipolar disorder influence outcome? Results from a long-term study of 147 patients.

OBJECTIVE: This study investigated the impact of latency (the time between illness onset and initiation of prophylactic treatment) on the outcome of prophylaxis in bipolar disorders. METHOD: The effect of prophylaxis delay (latency) on the course of illness was assessed in 147 patients. Dependent variables were: reduction of days spent in the hospital (prior to vs. during prophylaxis), time to first recurrence, and Morbidity-Index during prophylaxis (lithium or carbamazepine). Latency and other independent variables were tested using a multivariate approach. RESULTS: Latency (9.3 years on average) had no significant effect on the subsequent response. Illness severity prior to prophylaxis, however, did predict the relative response. The course of illness during treatment could not be predicted by any one factor. CONCLUSION: The delay in initiating prophylaxis appears to have no influence on prophylaxis outcome. Instead, those whose illness was more severe were treated earlier and these patients subsequently showed a relatively greater response. If severity is not controlled for as part of the analysis, latency may be mistaken as an important predictor for response.

Biological UV dosimeters in quality control of tanning tubes.

Although according to the International Radiological Protection Association-International Non-Ionizing Radiation Committee recommendation (1991) the use of sunbeds for cosmetic purposes is not recommended, tanning devices are used widely. Ten different types of commercially available sunbed tubes have been studied using a uracil biological UV dosimeter, and three of them were analyzed in detail. Dimerization effectiveness of the tubes was measured directly, whereas efficiency of erythema induction was calculated weighting the emission spectra by the Commission Internationale de l'Eclairage erythema action spectrum. The data obtained demonstrate that quality control of sunbed tubes has to include not only the determination of the UV doses administered but also the assessment of the health risk due to the UVB and UVA components of the lamp. A method of quality control using the uracil biological dosimeter was elaborated, and the estimation of the "acceptable" exposure time was checked/controlled on 15 volunteers by assessing individually the erythema induction threshold. A correct classification of the sunbed tubes is proposed by characterizing the erythema induction versus DNA-damaging effectiveness of tubes.

Stability of nucleic acid under the effect of UV radiation.

Nucleic acids (combined with protein molecules) are essential constituents of the living systems playing an important role in the early evolution of life as well. A specific feature of these molecules has been found and directly confirmed recently: under the influence of short-wavelength UV radiation bipyrimidine photoproducts (cyclobutane dimers and 6-4 bipyrimidines) are induced and the reversion of them can be provoked by the same photons. However, reversion is preferred by the shorter wavelengths. With increasing ratio of the longer wavelength components of the radiation (using artificial UV sources and solar light on the Earth's surface) the impact of the reversible photoproducts in the harmful biological effect decreases and other photoproducts are dominant. Assuming the photoinduced reactions (dimerisation and reversion) are statistical events, during the irradiation the chance for a number of nucleoprotein molecules to survive the radiation damage can be reality. The theoretical and experimental basis of these assumptions will be discussed in the case of bacteriophage T7 nucleoprotein.