Karen E. Bremner

Selective serotonin reuptake inhibitors and CNS drug interactions: A critical review of the evidence

SummaryThe potential for drug-drug interactions in psychiatric patients is very high as combination psychopharmacotherapy is used to treat comorbid psychiatric disorders, to treat the adverse effects of a medication, to augment a medication effect or to treat concomitant medical illnesses. Interactions can be pharmacodynamic or pharmacokinetic in nature. This paper focuses on the metabolic kinetic interactions between selective serotonin reuptake inhibitors (SSRIs) and other central nervous system (CNS) drugs. The evidence for and clinical significance of these interactions are reviewed, with special emphasis on antipsychotics, tricyclic anti-depressants and benzodiazepines.Many psychotropic medications have an affinity for the cytochrome P450 (CYP) enzymes which promote elimination by transforming lipid soluble substances into more polar compounds. SSRIs serve both as substrates and inhibitors of these enzymes. In vitro studies provide a screening method for evaluating drug affinities for substrates, inhibitors or inducers of CYP enzymes. Although in vitro data are important as a starting point for predicting these metabolic kinetic drug interactions, case reports and controlled experimental studies in humans are required to fully evaluate their clinical significance. Several factors must be considered when evaluating the clinical significance of a potential interaction including: (a) the nature of each drugs’ activity at an enzyme site (substrate, inhibitor or inducer); (b) the potency estimations for the inhibitor/inducer; (c) the concentration of the inhibitor/inducer at the enzyme site; (d) the saturability of the enzyme; (e) the extent of metabolism of the substrate through this enzyme (versus alternative metabolic routes); (f) the presence of active metabolites of the substrate; (g) the therapeutic window of the substrate; (h) the inherent enzyme activity of the individual, phenotyping/genotyping information; (i) the level of risk of the individual experiencing adverse effects (e.g. the elderly) and (j) from an epidemiological perspective, the probability of concurrent use.This paper systematically reviews both the in vitro and in vivo evidence for drug interactions between SSRIs and other CNS drugs. As potent inhibitors of CYP2D6, both paroxetine and fluoxetine have the potential to increase the plasma concentrations of antipsychotic medications metabolised through this enzyme, including perphenazine, haloperidol, thioridazine and risperidone in patients who are CYP2D6 extensive metabolisers. Controlled studies have demonstrated this for perphenazine with paroxetine and haloperidol with fluoxetine. Fluvoxamine, as a potent inhibitor of CYP1A2, can inhibit the metabolism of clozapine, resulting in higher plasma concentrations.Drug interactions between the SSRIs and tricyclic antidepressants (TCAs) can occur. Fluoxetine and paroxetine, as potent inhibitors of CYP2D6, can increase the plasma concentrations of secondary and tertiary tricyclic antidepressants. Sertraline and citalopram are less likely to have this effect. Fluvoxamine can increase the plasma concentrations of tertiary TCAs.Fluvoxamine inhibits, via CYP3A, CYP2C19 and CYP1A2, the metabolism of several benzodiazepines, including alprazolam, bromazepam and diazepam. Fluoxetine increases the plasma concentrations of alprazolam and diazepam by inhibiting CYP3A and CYP2C19, respectively. The clinical importance of the interaction with diazepam is attenuated by the presence of its active metabolite. Sertraline inhibits these enzymes only mildly to moderately at usual therapeutic doses. Therefore the potential for interactions is less; however, the in vivo evidence is minimal. Paroxetine and citalopram are unlikely to cause interactions with benzodiazepines.The evidence is conflicting for an interaction between carbamazepine and the SSRIs fluoxetine and fluvoxamine. These combinations should be used cautiously, and be accompanied by monitoring for adverse events and carbamazepine plasma concentrations. A lack of interaction between paroxetine or sertraline and carbamazepine has been documented.The SSRIs are not equivalent in their potential for drug interactions when combined with other CNS medications. Each combination must be assessed individually. Several factors must be considered when predicting the outcome of a potential interaction based on in vitro data (e.g. active metabolites and concentration ranges). In vivo studies are required to evaluate their clinical significance. Generally, sertraline and citalopram at the lower therapeutic dosage range appear to have less propensity for interactions. Anticipated pharmacokinetic interactions can usually be managed with careful monitoring and appropriate adjustments in dosage and titration.

Citalopram decreases desirability, liking, and consumption of alcohol in alcohol‐dependent drinkers

In previous studies serotonin uptake inhibitors such as citalopram decreased alcohol consumption in alcoholics. The mechanism of the effect is not fully understood. This study tested the hypothesis that it is mediated by changes in desire to drink and alcohol effects. After a 1‐week baseline period, subjects (13 men and three women; aged 26 to 69 years; healthy, nondepressed, alcohol‐dependent drinkers [mean, 6.6 drinks per day]) were randomized in a double‐blind fashion to receive 40 mg/day citalopram and placebo for 1 week each, separated by a 1‐week washout period. Daily standard alcoholic drinks (13.6 gm ethanol), nonalcoholic drinks, and tobacco use were recorded; evening urine samples were taken; and interest, desire, craving, and liking for alcohol were rated. Medical status, depression, and anxiety were assessed weekly, but no other treatment or advice was given. Daily alcoholic drinks significantly decreased during citalopram treatment (mean ± SEM = 4.6 ± 0.6) compared with placebo (5.7 ± 0.8; p = 0.01), and the average decrease was 17.5%. Percentage of days abstinent increased during citalopram administration (27.7% ± 5.7%) compared with placebo (15.5% ± 3.7%; p < 0.01). Citalopram decreased interest, desire, craving, and liking for alcohol (all p < 0.05). There was clear internal validation of these measures in that variations in each correlated with alcohol consumption (all r > 0.5, p < 0.05). Nonalcoholic drinks, self‐reports of cigarettes smoked (daily smokers), and body weight did not change significantly. In experimental bar sessions, after the citalopram and placebo periods, subjects were required to consume as many of 18 minidrinks as possible (equivalent to six standard drinks) at 5‐minute intervals. Subjects rated their desire for alcohol, intoxication, and mood. Citalopram had no significant effects on the desirability of alcohol or subjective feelings of intoxication. The findings indicate that serotonin uptake inhibitors may act by decreasing the urge to drink and the reinforcing effects of alcohol. Also, a naturalistic outpatient trial is a sensitive, simple, and economic procedure for detecting these drug effects.

Healthcare costs associated with prostate cancer : estimates from a population-based study

Study Type – Health Economic (multiway sensitivity analyses)
Level of Evidence 2b

A Review and Meta-Analysis of Prostate Cancer Utilities

Background. Health-related quality of life is a key issue in prostate cancer (PC) management. The authors summarized published utilities for common health-related quality of life outcomes of PC and determined how methodological factors affect them. Methods. In their systematic review, the authors identified 23 articles in English, providing 173 unique utilities for PC health states, each obtained from 2 to 422 respondents. Data were pooled using linear mixed-effects modeling with utilities clustered within the study, weighted by the number of respondents divided by the variance of each utility. Results. In the base model, the estimated utility of the reference case (scenario of a metastatic PC patient with severe sexual symptoms, rated by non-PC patients using time tradeoff) was 0.76. Disease stage, symptom type and severity, source of utility, and scaling method were associated with utility differences of 0.10 to 0.32 (P < 0.05). Utilities from PC patients rating their own health were 0.14 higher than those from the reference case, but utilities from PC patients rating scenarios were lowest. Time tradeoff yielded the highest utilities. Computer administration yielded lower utilities than personal interview (P = 0.02). Neither the scales high anchor nor study purpose had significant effects on utilities. Conclusions. This study provides pooled utility estimates for common PC health states and describes how clinical and methodological factors can significantly affect these values. When possible, utility estimates for a modeling application should be derived similarly. Formal data synthesis methods might be useful to researchers integrating utility data from heterogeneous sources. Further exploration of these methods for this purpose is warranted.

Fluoxetine attenuates alcohol intake and desire to drink.

Several serotonin uptake inhibitors, including the long-acting fluoxetine, have been found to decrease alcohol intake in moderately dependent alcoholics. While the mechanism of their effect is not fully elucidated, a previous study with citalopram indicated that decreased desire to drink may be an important factor. Therefore, we tested fluoxetine effects on alcohol intake and desire to drink in a placebo-controlled study. Subjects, recruited by advertisement, were mildly/moderately dependent alcoholics 112 male, four female, aged 19–59 years, healthy, non-depressed) who did not believe they had a drinking problem and were not requesting treatment. After a 1 week baseline they received, single-blind, 2 weeks placebo followed by 2 weeks fluoxetine 60 mg/day. As out-patients, subjects recorded daily standard drinks (13.6 g ethanol) and rated interest, desire, craving and liking for alcohol biweekly. Each out-patient period was immediately followed by a double-blind experimental drinking session. Out-patient daily drinks slightly decreased during fluoxetine to 6.6 ± 0.9 (x ± S.E.M.) compared with during placebo (7.16 ± 0.95, p = 0.07, N.S.) and baseline (7.18 ± 1.0, p > 0.1, N.S.). Desire, interest and craving for alcohol decreased during fluoxetine vs placebo baseline (p < 0.05), but not vs placebo. Appetite loss and decrease in food intake (p < 0.01, fluoxetine vs placebo) correlated with each other (r = 0.91, p < 0.01) but neither correlated with decrease in alcohol intake (appetite: r = 0.26, N.S.; food intake: r = 0.22, N.S.). Weight loss occurred during fluoxetine (p < 0.05 vs placebo) but did not correlate with decrease in alcohol intake (r = 0.1, N.S.). In the experimental drinking sessions after placebo and fluoxetine treatments subjects rated their desire for each of 18 mini-drinks (each one-third of a standard drink) offered at 5 min intervals. Fluoxetine decreased desire to drink throughout the sessions; both mean and maximum desire ratings were lower after fluoxetine than after placebo (ANOVA, p < 0.05). Therefore, fluoxetine seems to have a robust effect on decreasing desire for alcohol. We propose that in the absence of intention by subjects to reduce drinking, their habitual drinking patterns mitigated against reduced consumption in the out-patient phase. However, fluoxetine could be a useful adjunct for patients in a treatment context who are motivated to reduce their drinking.

End-of-Life Care for Lung Cancer Patients in the United States and Ontario

BACKGROUND Both the United States and Canada offer government-financed health insurance for the elderly, but few studies have compared care at the end of life for cancer patients between the two systems. METHODS We identified care for non-small cell lung cancer (NSCLC) patients who died of cancer at age 65 years and older during 1999-2003. Patients were identified from US Surveillance, Epidemiology, and End Results (SEER)-Medicare data (N = 13,533) and the Ontario Cancer Registry (N = 8100). Health claims during the last 5 months of life identified chemotherapy and emergency room use, hospitalizations, and supportive care. We estimated rates per person-months (PM) for short-term survivors (died <6 months after diagnosis) and longer-term survivors (died ≥6 months after diagnosis), adjusting for demographic differences. To test whether monthly rates in Ontario were statistically significantly different from the United States, standardized differences were computed, and a 99% confidence interval (CI) was constructed to account for the multiple tests performed. All statistical tests were two-sided. RESULTS Rates of chemotherapy use were statistically significantly higher for SEER-Medicare patients than Ontario patients in every month before death (short-term survivors at 5 months before death: SEER-Medicare, 33.2 patients per 100 PM vs Ontario, 9.5 per 100 PM, rate difference = 23.7 per 100 PM, 99% CI = 18.3 to 29.1 per 100 PM, P < .001; longer-term survivors at 5 months before death: SEER-Medicare, 24.4 patients per 100 PM vs Ontario, 14.5 per 100 PM, rate difference = 9.9 per 100 PM, 99% CI = 7.7 to 12.1 per 100 PM, P <. 001). During the last 30 days of life, fewer SEER-Medicare than Ontario patients were hospitalized (short-term survivors, 49.9 vs 78.6 patients per 100 PM, rate difference = 28.6 per 100 PM, 95% CI = 22.9 to 34.4 per 100 PM, P <. 001; longer-term survivors, 44.1 vs 67.1 patients per 100 PM, rate difference = 23.0 per 100 PM, 95% CI = 18.5 to 27.5 per 100 PM, P < .001). CONCLUSIONS NSCLC patients in both Ontario and the United States used extensive end-of-life care. Limited availability of hospice care in Ontario and differing attitudes between the United States and Ontario regarding end-of-life care may explain the differences in practice patterns.

Health utilities and psychometric quality of life in patients with early‐ and late‐stage hepatitis C virus infection

Background and Aim:  Hepatitis C virus (HCV) infection is associated with impairment in health‐related quality of life (HRQOL). The purpose of this study was to evaluate HRQOL across the HCV disease spectrum using preference‐based (utility) and non‐preference‐based (psychometric) methods, adjusting for sociodemographic factors and co‐morbidity.

Using fuzzy logic to predict response to citalopram in alcohol dependence

The prediction of patient response to new pharmacotherapies for alcohol dependence has usually not been successful with standard statistical techniques. We hypothesized that fuzzy logic, a qualitative computational approach, could predict response to 40 mg/day citalopram and 40 mg/day citalopram with a brief psychosocial intervention in alcohol‐dependent patients.

Impact of rituximab on treatment outcomes of patients with diffuse large b-cell lymphoma: a population-based analysis.

We conducted a multi‐institutional population‐based analysis of the survival and toxicity associated with the addition of rituximab to chemotherapy for patients with diffuse large B‐cell lymphoma (DLBCL), including patients aged ≥80 years, who were excluded from published randomized trials. Using population‐based registries in Ontario, we identified 4021 patients who received chemotherapy with or without rituximab (R‐CHOP [rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone] or CHOP) for DLBCL between 1996 and 2007, including 397 patients aged ≥80 years. After propensity score matching, the overall survival (OS) and significant toxicities for R‐CHOP and CHOP treatment groups were compared. R‐CHOP was associated with a significant increase in 5‐year OS compared to CHOP alone (62% vs. 54%; hazard of death = 0·78, P = 0·0004). Survival benefit was seen in all age groups, including those aged ≥80 years. Patients treated with rituximab did not have a significant increase in 1‐year hospitalization rates for cardiac, pulmonary, gastrointestinal or neurological diagnoses compared to those treated with CHOP alone. The addition of rituximab to CHOP improves survival in the general population of patients with DLBCL and produces early survival benefit for very elderly patients, without any significant increase in the risk of serious toxicity.

Utility and health-related quality of life in prostate cancer patients 12 months after radical prostatectomy or radiation therapy.

This study aims to examine and compare changes in quality of life after two common treatments for prostate cancer (PC), radical prostatectomy (RP) and radiation therapy (RT). Patients newly diagnosed with localized PC, scheduled to receive RP (n=68) or RT (n=66), completed three cancer/PC-specific psychometric instruments and three PC-specific utility instruments before treatment, and 2 and 12 months after treatment. We assessed the magnitude and time course of changes in psychometric and utility measures, and differences between treatments. The results showed that RP was associated with significant urinary and sexual dysfunction; RT caused bowel problems. Fatigue and pain were common to both. RP patients reported more problems with physical, role and social function. Utilities decreased significantly after both treatments. Effects were most severe 2 months post treatment, and then showed some recovery, but many endured for 1 year. After 1 year, 30–60% of patients had utility scores that were clinically significantly worse than at baseline. Secondary androgen deprivation therapy also significantly decreased psychometric and utility measures of quality of life. Many adverse symptoms reported 2 months after RP and RT endure for 1 year. Despite different symptom profiles, RP and RT result in similar utility decrements.