The definition and assessment of adherence vary considerably across studies. Increasing consensus regarding these issues is necessary to improve our understanding of adherence and the development of more effective treatments. We review the adherence literature over the past 3 decades to explore the definitions and assessment of adherence to oral antipsychotics in schizophrenia patients. A total of 161 articles were identified through MEDLINE and PsycINFO searches. The most common method used to assess adherence was the report of the patient. Subjective and indirect methods including self-report, provider report, significant other report, and chart review were the only methods used to assess adherence in over 77% (124/161) of studies reviewed. Direct or objective measures including pill count, blood or urine analysis, electronic monitoring, and electronic refill records were used in less than 23% (37/161) of studies. Even in studies utilizing the same methodology to assess adherence, definitions of an adherent subject varied broadly from agreeing to take any medication to taking at least 90% of medication as prescribed. We make suggestions for consensus development, including the use of recommended terminology for different subject samples, the increased use of objective or direct measures, and the inclusion in all studies of an estimate of the percentage of medication taken as prescribed in an effort to increase comparability among studies. The suggestions are designed to advance the field with respect to both understanding predictors of adherence and developing interventions to improve adherence to oral antipsychotic medications.

The authors report the CYP2D6 inhibitory effects of fluoxetine, paroxetine, sertraline, and venlafaxine in an open-label, multiple-dose, crossover design. Twelve CYP2D6 extensive metabolizers were phenotyped, using the dextromethorphan/dextrorphan (DM/DX) urinary ratio, before and after administration of fluoxetine 60 mg (loading dose strategy), paroxetine 20 mg, sertraline 100 mg, and venlafaxine 150 mg. Paroxetine, sertraline, and venlafaxine sequences were randomized with 2-week washouts between treatments; fluoxetine was the last antidepressant (AD) administered. Comparing within groups, baseline DM/DX ratios (0.017) were significantly lower than DM/DX ratios after treatment (DM/DXAD) with fluoxetine (0.313, p < 0.0001) and paroxetine (0.601, p < 0.0001) but not for sertraline (0.026, p = 0.066) or venlafaxine (0.023, p = 0.485). Between groups, DM/DXAD ratios were significantly higher for fluoxetine and paroxetine compared to sertraline and venlafaxine. No differences between DM/DXAD ratios were found for fluoxetine and paroxetine although more subjects phenocopied to PM status after receiving the latter (42% vs. 83%; chi 2 = 4.44, p = 0.049, df = 1). Similarly, no differences between DM/DXAD ratios were found for sertraline and venlafaxine. Of note, the DM/DXAD for 1 subject was much lower after treatment with paroxetine (0.058) compared to fluoxetine (0.490), while another subject exhibited a much lower ratio after treatment with fluoxetine (0.095) compared to paroxetine (0.397). Significant correlations between AD plasma concentration and DM/DXAD were found for paroxetine (r2 = 0.404, p = 0.026) and sertraline (r2 = 0.64, p = 0.002) but not fluoxetine or venlafaxine. In addition, DM/DXAD correlated with baseline isoenzyme activity for paroxetine, sertraline, and venlafaxine groups. These results demonstrate the potent, but variable, CYP2D6 inhibition of fluoxetine and paroxetine compared to sertraline and venlafaxine. CYP2D6 inhibition may be related, in part, to dose, plasma concentration, and baseline isoenzyme activity, and these correlations merit further investigation.

Cognitive adaptation training (CAT) is a psychosocial treatment that uses environmental supports such as signs, checklists, alarms, and the organization of belongings to cue and sequence adaptive behaviors in the home. Ninety-five outpatients with schizophrenia (structured clinical interview for diagnosis, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) were randomly assigned to (1) Full-CAT (CAT focused on many aspects of community adaptation including grooming, care of living quarters, leisure skills, social and role performance, and medication adherence), (2) Pharm-CAT (CAT focused only on medication and appointment adherence), or (3) treatment as usual (TAU). Treatment lasted for 9 months, and patients were followed for 6 months after the withdrawal of home visits. Medication adherence (assessed during unannounced, in-home pill counts) and functional outcomes were assessed at 3-month intervals. Results of mixed-effects regression models indicated that both CAT and Pharm-CAT treatments were superior to TAU for improving adherence to prescribed medication (P < .0001). Effects on medication adherence remained significant when home visits were withdrawn. Full-CAT treatment improved functional outcome relative to Pharm-CAT and TAU (P < .0001). However, differences for functional outcome across groups decreased following the withdrawal of home visits and were no longer statistically significant at the 6-month follow-up. Survival time to relapse or significant exacerbation was significantly longer in both CAT and Pharm-CAT in comparison to TAU (.004). Findings indicate that supports targeting medication adherence can improve and maintain this behavior. Comprehensive supports targeting multiple domains of functioning are necessary to improve functional outcomes. Maintenance of gains in functional outcome may require some form of continued intervention.

Normal renal function is important for the excretion and metabolism of many drugs. Renal diseases which affect glomerular blood flow and filtration, tubular secretion, reabsorption and renal parenchymal mass alter drug clearances and lead to the need for alterations in dosage regimens to optimise therapeutic outcome and minimise the risk of toxicity. Renal disease is increasing and the cost of care has risen progressively over the past decade. Part of these costs is related to inappropriate drug therapy and excessive drug use. Although there are a variety of methods for evaluating the various aspects of renal function, the most practical and commonly used clinical measure of renal function is estimated creatinine clearance (CLCR) as a marker for glomerular filtration. This is useful since alterations in drug clearance are proportional to alterations in CLCR, and this relationship is used as the basis for changing doses and dosage intervals for drugs which are largely renally excreted. Two populations, neonates and the elderly, are at risk of inappropriate drug dosage due to physiological changes in renal function. Estimated CLCR may not be the best method of evaluating renal function in these patients, and dosage regimens should be carefully considered. Renal insufficiency and concurrent drug therapy used in these populations can either increase or decrease drug absorption, depending on the particular agent. Drug distribution may be altered in renal insufficiency due to pH-dependent protein binding and reduced protein (primarily albumin) levels. Interestingly, renal disease may affect hepatic as well as renal drug metabolism; the exact mechanisms for these changes are not well understood. The most important quantitative pharmacokinetic change is excretion. Glomerular filtration and tubular process may both be affected but not to the same extent, and the type of renal disease may differentially affect filtration and excretion. Drug removal by dialysis is dependent on a number of factors, including the characteristics of a particular drug and the type of dialysis and equipment used. Therapeutic outcomes may be evaluated using end-points such as plasma concentrations, patient outcomes such as reduction in fever or negative cultures, and system-wide changes such as drug-use or laboratory-use patterns.

The selective serotonin reuptake inhibitors (SSRIs) and venlafaxine display the following rank order of in vitro potency against the cytochrome P450 (CYP) isoenzyme CYP2D6 as measured by their inhibition of sparteine and/or dextromethorphan metabolism: paroxetine > fluoxetine == norfluoxetine ~ sertraline ~ fluvoxamine > venlafaxine. On this basis, paroxetine would appear to have the greatest and fluvoxamine and venlafaxine the least potential for drug interactions with CYP2D6-dependent drugs.In vivo, inhibitory potency is affected by the plasma concentration of the free (unbound) drug, a potentially important consideration since many CYP2D6-metabolised drugs exhibit nonlinear (saturable) kinetics, and by the presence of metabolites, which might accumulate and interact with the CYP system. Under steady-state conditions, paroxetine and fluoxetine are approximately clinically equipotent inhibitors of CYP2D6 in vivo (as determined through their effects on desipramine metabolism); sertraline, in contrast, shows lower steady-state plasma concentrations than fluoxetine and, hence, a less pronounced inhibition of CYP2D6.Of the drugs that are metabolised by CYP2D6, secondary amine tricyclic antidepressants, antipsychotics (e.g. phenothiazines and risperidone), codeine, some antiarrhythmics (e.g. flecainide) and ~-blockers form the focus of clinical attention with regard to their potential interactions with the SSRIs. Coadministration of desipramine and fluoxetine (20 mg/day) at steady-state produced an"" 4-fold elevation in peak plasma desipramine concentrations, while the long half-life of the active metabolite norfluoxetine was responsible for a significant and long lasting ("" 3 weeks) elevation of plasma desipramine concentrations after discontinuation of fluoxetine. Similarly, coadministration of desipramine with paroxetine produced an "" 3-fold increase in plasma desipramine concentrations. In contrast, coadministration of desipramine and sertraline (50 mg/day) for 4 weeks resulted in a considerably more modest ("" 30%) elevation in plasma desipramine concentrations. Coadministration offluoxetine (60 mg/day, as a loading dose) [equivalent to serum concentrations obtained with 20 mg/day at steadystate] with imipramine or desipramime resulted in "" 3-to 4-fold increases in plasma area under the curve (AUC) values for both imipramine and desipramine (illustrating a significant drug interaction potential at multiple isoenzymes). Consistent with its minimal in vitro effect on CYP2D6, fluvoxamine shows minimal in vivo pharmacokinetic interaction with desipramine, but does interact with imipramine ("" 3-to 4-fold increase in AUC) through inhibi-

Patients and physicians were not able to identify adherence. The inability of physicians to accurately identify adherent individuals is likely to have important consequences for prescribing behavior, health care costs, and patient outcomes.

The objective of this study was to investigate pharmacokinetic and pharmacodynamic interactions between midazolam and fluoxetine, fluvoxamine, nefazodone, and ketoconazole. Forty healthy subjects were randomized to receive one of the four study drugs for 12 days in a parallel study design: fluoxetine 60 mg per day for 5 days, followed by 20 mg per day for 7 days; fluvoxamine titrated to a daily dose of 200 mg; nefazodone titrated to a daily dose of 400 mg; or ketoconazole 200 mg per day. All 40 subjects received oral midazolam solution before and after the 12-day study drug regimen. Blood samples for determination of midazolam concentrations were drawn for 24 hours after each midazolam dose and used for the calculation of pharmacokinetic parameters. The effects of the study drugs on midazolam pharmacodynamics were assessed using the symbol digit modalities test (SDMT). The mean area under the curve (AUC) for midazolam was increased 771.9% by ketoconazole and 444.0% by nefazodone administration. However, there was no significant change in midazolam AUC as a result of fluoxetine (13.4% decrease) and a statistical trend for fluvoxamine (66.1% increase) administration. Pharmacodynamic data are consistent with pharmacokinetic data indicating that nefazodone and ketoconazole resulted in significant increases in midazolam-related cognition impairment. The significant impairment in subjects' cognitive function reflects the changes in midazolam clearance after treatment with ketoconazole and nefazodone. These results suggest that caution with the use of midazolam is warranted with potent CYP3A4 inhibitors.

Haloperidol has been used extensively for the treatment of psychotic disorders, and it has been suggested that the monitoring of plasma haloperidol concentration is clinically useful. Different assay methodologies have been used in research and clinical practice to examine the relationship between response and plasma concentration of the drug. Chemical assays such as high pressure liquid chromatography (HPLC) and gas-liquid chromatography (GLC) have good precision and sensitivity; radioimmunoassay (RIA) is generally more sensitive, but less precise and specific. Radioreceptor assay quantifies dopaminereceptor blocking activity but does not provide results comparable with those of HPLC, GLC and RIA. Large doses of haloperidol can safely be given intravenously and intramuscularly for rapid neuroleptisation; the bioavailability of this agent administered orally ranges from 60 to 65%. However, there is large interindividual, but not intraindividual, variability in plasma haloperidol concentrations and most pharmacokinetic parameters. This interindividual variability could be partially explained by the reversible oxidation/reduction metabolic pathway of haloperidol: it is metabolised via reduction to reduced haloperidol, which is biologically inactive. Different extents of enterohepatic recycling, and ethnic differences in metabolism, could also account for the observed variability in haloperidol disposition. Although not conclusive from different clinical studies, it appears that a plasma haloperidol concentration range of 4 micrograms/L to an upper limit of 20 to 25 micrograms/L produces therapeutic response. The role of reduced haloperidol in determining clinical response is not clear, although in some studies a high reduced haloperidol/haloperidol concentration ratio has been suggested to be associated with therapeutic failure. Measurements of red blood cell or cerebrospinal fluid haloperidol concentration have also been proposed as determinants of therapeutic response, but results from different studies are inconsistent, and do not seem to provide a significant advantage over plasma concentration monitoring. Physiological parameters such as prolactin and homovanillic acid levels have been evaluated, with the latter showing some promise that warrants further investigation. Haloperidol decanoate can be characterised by a flip-flop pharmacokinetic model because its absorption rate constant is slower than the elimination rate constant. Its plasma concentration peaks on day 7 after intramuscular injection. The elimination half-life is about 3 weeks, and the time to steady-state is about 3 months.