Disturbances of basic self and prodromal symptoms among non-psychotic help-seeking adolescents.

BACKGROUND: The goal of this study was to explore the notion that anomalies of self-experience (ASE) are a core, 'not-yet-psychotic' clinical phenotype of emerging schizophrenia and its spectrum. Method To accomplish this goal, we examined the relationship between ASE and commonly accepted risk markers in a sample of 87 help-seeking, non-psychotic adolescents (aged 14-18 years). ASE were assessed with the Examination of Anomalous Self-Experience (EASE), subclinical psychotic symptoms were assessed with the Prodromal Questionnaire and the Structured Interview for Prodromal Syndromes, deterioration in psychosocial functioning was assessed with the Social and Role Functioning Scales, and level of distress with the Mood and Anxiety Symptoms Questionnaire. RESULTS: About 82 participants completed the entire EASE interview. The number of participants who reported ASE at a clinically meaningful level (n = 18, 22%) was smaller than that who met diagnostic criteria for a prodromal syndrome (n = 28, 34%). The degree of overlap between the two conditions was moderate but statistically significant (χ2 (1) = 7.01, p = 0.008). An exploratory factor analysis revealed that ASE load on a different factor than prodromal symptoms and deterioration in functioning, but that there is a moderate correlation between the three factors. CONCLUSIONS: These results suggest that ASE are prevalent among non-psychotic help-seeking adolescents, yet at a considerably lower rate than prodromal symptoms. In addition, they suggest that ASE and prodromal symptoms constitute distinct but moderately related dimensions of potential risk. Taken together, they provide preliminary support for the clinical usefulness of supplementing and refining the methods of early detection of risk with assessment of ASE.

Compliance declines between clinic visits.

Adherence to prescribed drug dosing regimens declined substantially during the interval between clinic visits and drug level tests. Using microelectronic monitors to observe pill-taking habits, 20 patients averaged 88% compliance before and 86% compliance after the visit, but this dropped to 67% compliance a month later. These data indicate that spot drug levels do not represent long-term "steady-state" drug serum concentrations.

Clinical and electrographic effects of acute anticonvulsant withdrawal in epileptic patients.

We retrospectively investigated the effects of acute antiepileptic drug (AED) withdrawal on seizure symptomatology--including frequency, clinical features, and electrical onset--by studying 35 patients during evaluation for epilepsy surgery. The highest risk for both partial and secondary generalized seizures occurred during absent or subtherapeutic, and not during rapidly falling, AED levels. AED withdrawal had minimal effect on clinical symptomatology or electrographic onset.

Measurement of carbamazepine and carbamazepine epoxide in the human brain using in vivo microdialysis.

We report the first study of carbamazepine and carbamazepine-10,11-epoxide concentrations determined by using intracerebral microdialysis in three patients undergoing depth electrode studies for the evaluation of medically intractable epilepsy. Very small microdialysis catheters, affixed to and inserted with the depth electrodes, sampled drug concentration in the extracellular environment. We perfused artificial extracellular fluid continuously, and varied the perfusion rate to permit estimation of the absolute drug concentration in the extracellular space. Serum samples were obtained simultaneously. The relation between dialysate and extracellular concentration (recovery fraction) depended, in vivo but not in vitro, on the relative lipophilicity of the compounds, suggesting that diffusion of the drug within the brain is a major determinant of microdialysate drug concentration. When this is taken into account, the steady-state extracellular concentrations of these compounds closely mirror their unbound serum concentrations.

Phenytoin concentrations in the human brain: an in vivo microdialysis study.

We report the first human study of phenytoin concentration using in vivo microdialysis, which permits sampling the extracellular environment of the brain. This technique has been applied to patients undergoing intracranial electrode investigation for intractable epilepsy. By varying the rate of perfusion (from 2.5 to 0.25 microliters/min), it is possible to quantify the concentration of drug in the extracellular fluid (ECF), which reflects the concentration on the outer neuronal cell membrane. Samples were obtained from four catheters in two patients, in whom serum phenytoin (PHT) concentrations were held constant. Unbound serum concentrations were measured following ultrafiltration at 37 degrees C. In one patient, with left and right hippocampal probes, steady state ECF/unbound serum ratios were 87 and 84% respectively. In the second patient, with hippocampal and frontal probes, ECF/unbound serum ratios were 87 and 85% respectively. Flow rate for 50% maximal recovery averaged 1.65 microliters/min (1.5-1.7 microliters/min). We found that steady state ECF PHT concentrations corresponded closely to unbound serum concentrations. No differences are observed between different sites within the brain. Flow rates needed for equilibration of dialysate with the extracellular space were slower than reported for carbamazepine, but faster than those we found for carbamazepine-epoxide and valproate.

Novel methods for studying new antiepileptic drug pharmacology.

A number of new antiepileptic drugs act by indirect mechanisms and thus produce effects that may not best be measured by traditional blood studies of the drugs and their metabolites. Study of the indirect action of these drugs on GABA-mediated inhibition by microdialysis and nuclear MR spectroscopy has proved more relevant. These new investigative techniques may also prove valuable as compounds affecting glutamate or other excitatory neurotransmitters are developed.

A pharmacodynamic approach to the estimate of carbamazepine autoinduction.

Population-based pharmacokinetic prediction algorithms have been developed for several medications. A fundamental assumption has been that the kinetics remain constant over time. Carbamazepine (CBZ), however, induces its own metabolism in a concentration- and time-dependent manner. A Bayesian estimation program is presented that models the changing catabolic enzyme activity, linearly related to hepatic microsomal enzyme concentration, along with the serum drug concentration. An Emax model is used for enzyme formation with respect to drug concentration: elimination of enzyme activity is modeled as a first-order process. This program was tested in 22 drug-naive outpatients begun on CBZ monotherapy. The 1 week concentrations were used to prospectively predict concentrations at 1 month of therapy and were very close to actual measurements: prediction bias (mean error of prediction) = -0.1 micrograms/mL and precision (median absolute error of prediction) = 1.2 micrograms/mL. Comparison estimates, made by assuming a constant concentration/dose ratio, had bias = 2.6 micrograms/mL (p < 0.001) and precision = 2.2 micrograms/mL (p = 0.01). We conclude that (1) CBZ autoinduction is not complete after 1 week of therapy and (2) the methodology permits accurate estimation of CBZ pharmacokinetics.

A Phase II study of the safety and efficacy of teriflunomide in multiple sclerosis with relapses.

BACKGROUND: Teriflunomide, a dihydro-orotate dehydrogenase inhibitor, has immunomodulatory effects, including the ability to suppress experimental allergic encephalomyelitis. In this randomized, double-blind, placebo-controlled Phase II study, the authors examined the safety and efficacy of oral teriflunomide in multiple sclerosis (MS) with relapses. METHODS: Patients (n = 179) with relapsing-remitting MS (n = 157) or secondary progressive MS with relapses (n = 22) were randomized to receive placebo, teriflunomide 7 mg/day, or teriflunomide 14 mg/day for 36 weeks. MRI brain scans were performed every 6 weeks. The primary endpoint was the number of combined unique active lesions per MRI scan. Secondary endpoints included MRI-defined disease burden, relapse frequency, and disability increase. RESULTS: The median number of combined unique active lesions per scan was 0.5, 0.2, and 0.3 in the placebo, teriflunomide 7 mg/day (p < 0.03 vs placebo), and teriflunomide 14 mg/day (p < 0.01 vs placebo) groups during the 36-week double-blind treatment phase. Teriflunomide-treated patients also had significantly fewer T1 enhancing lesions per scan, new or enlarging T2 lesions per scan, and new T2 lesions. Patients receiving teriflunomide 14 mg/day had significantly reduced T2 disease burden. Teriflunomide treatment resulted in trends toward a lower annualized relapse rate and fewer relapsing patients (14 mg/day only) vs placebo. Significantly fewer patients receiving teriflunomide 14 mg/day vs placebo demonstrated disability increase. Treatment was well tolerated; numbers of adverse events and serious adverse events were similar in all treatment groups. CONCLUSION: Oral teriflunomide was effective in reducing MRI lesions and was well tolerated in patients with relapsing multiple sclerosis.

A method for prediction of phenytoin levels in the acute clinical setting.

Phenytoin (PHT) administration is complicated by saturation kinetics within the therapeutic range, causing marked changes in drug concentration with small changes in dose. The "half-life" increases with concentration, varying from 8-24 hr up to weeks, making it difficult to obtain the steady state levels needed by most prediction algorithms and nomograms. A Bayesian prediction program (Epidose) is presented which explicitly models PHT absorption and elimination kinetics in the non-steady state. The algorithm accounts for the interdependency of closely spaced sequential samples. Estimates of future PHT concentration were made on 20 hospital inpatients, most of whom were acutely ill and received other medications. Future (mean = 4 day) PHT concentrations were predicted over a range from 4 to 22 micrograms/ml (mean 13.9 micrograms/ml) with a median absolute error of 1.0 microgram/ml. These data demonstrate that the program can be used for accurate PHT concentration predictions in sick patients.

Near-patient rapid assay of phenytoin concentration.

The Biotrack 516 is a simple, automated whole blood phenytoin (PHT) assay that reports corresponding total serum concentrations in 3 min. We compared Biotrack results in 58 patients with the total and unbound serum PHT concentrations measured by the standard TDx fluorescence polarization immunoassay. Correlation with total TDx concentration was high (r = 0.98); median absolute error was 1.4 micrograms/ml. Correlation of unbound PHT with Biotrack (r = 0.95) was comparable to correlation of unbound and total TDx (r = 0.94). The Biotrack assay is a promising method for clinical monitoring of PHT concentrations.

Differentiation of temporal lobe ictal behavior associated with hippocampal sclerosis and tumors of temporal lobe.

Ictal behavioral characteristics may reflect seizure spread patterns and provide a clue to seizure onset location, between or within specific cerebral lobes. Sequential symptomatology might therefore distinguish patients with hippocampal sclerosis from patients with temporal lobe tumors. To determine ictal behavioral differences in patients of these groups, we analyzed 145 seizures of 33 patients with hippocampal sclerosis (group I) and 79 seizures of 22 patients with temporal lobe tumors (group II). First appearance of a variety of ictal behavioral characteristics was determined in three phases (first 5 s, 5-60 s, and from 60 s to mental clearing) for patients in both groups. Ipsilateral hand automatisms were significantly more frequent in the first 60 s in group I (p < 0.005). Onset of contralateral head turning was observed in the first 5 s only in group II (p < 0.05). First appearance of leg automatisms in group I and of oral automatisms in group II were very rare in phase 2 (p < 0.01, p < 0.005). Time of onset of other ictal behavioral characteristics and duration of seizures were not statistically different between the two groups. Ictal behavioral characteristics varied among and within patients and patient groups, but certain behavioral characteristics were helpful in differentiating these two groups of temporal lobe epilepsy (TLE) patients.

How often is medication taken as prescribed? A novel assessment technique.

The evaluation of the efficacy of medication is confounded when patients do not adhere to prescribed regimens. Overdosing, underdosing, and erratic dosing intervals can diminish drug action or cause adverse effects. Using a new method with epilepsy as a model, we assessed compliance with long-term medications among newly treated and long-term patients. Medication Event Monitor Systems (Aprex Corporation, Fremont, Calif) are standard pill bottles with micro-processors in the cap to record every bottle opening as a presumptive dose. Compliance rates averaged 76% during 3428 days observed: 87% of the once daily, 81% of the twice daily, 77% of the three times a day, and 39% of the four times a day dosages were taken as prescribed. Coefficients of variation of drug serum concentrations had no significant relationship to compliance rates. Pill counts overestimated compliance increasingly as compliance with the prescribed regimen declined. Neither drug serum concentrations nor pill counts would have identified the frequency of missed doses that were revealed with continuous dose observations.

In vivo determination of valproate binding constants during sole and multi-drug therapy.

Valproate (VPA) is present in humans and is largely bound to protein. Only free drug is metabolized, and antiepileptic and toxic effects are probably related to free concentrations. By measuring serial free and total serum VPA levels after routine oral doses, we have determined individual in vivo protein binding parameters for 37 patients after a total of 49 separate drug administrations. Binding site concentrations and dissociation constants were fitted using a nonlinear algorithm. On sole VPA (n = 28) the mean dissociation constant was 91 mumol/L, and the mean concentration of binding sites was 1,176 mumol/L. Evidence suggests a second, nonsaturable binding site. Fraction of unbound VPA ranged from 5.4% at low levels up to 38.7%, rising with increasing total concentration. Concurrent therapy with phenytoin (n = 7) or carbamazepine (n = 8) did not cause displacement of VPA. Changes in free fraction were consistently observed during the interdose interval. The data demonstrate that the binding changes are not a factor in decreased VPA levels during coadministration of other antiepileptic drugs.