Long-term health care costs for prostate cancer patients on androgen deprivation therapy.

BACKGROUND: Comparing relative costs for androgen deprivation therapy (adt) protocols in prostate cancer (pca) requires an examination of all health care resources, not only those specific to pca. The objective of the present study was to use administrative data to estimate total health care costs in a population-based cohort of pca patients. METHODS: Patients in Ontario with pca who started 90 days or more of adt at age 66 years or older during 1995-2005 were selected from cancer registry and health care administrative databases. We classified patients (n = 21,818) by regimen (medical castration, orchiectomy, anti-androgen monotherapy, medical castration with anti-androgen, orchiectomy with anti-androgen) and indication (neoadjuvant, adjuvant, metastatic disease, biochemical recurrence, primary nonmetastatic). Using nonparametric regression methods, with inverse probability weighting to adjust for censoring, and bootstrapping, we computed mean 1-year, 5-year, and 10-year longitudinal total direct medical costs (2009 Canadian dollars). RESULTS: Mean first-year costs were highest for metastatic disease, ranging from $24,400 for orchiectomy to $32,120 for anti-androgen monotherapy. Mean first-year costs for all other indications were less than $20,000. Mean 5-year and 10-year costs were lowest for neoadjuvant treatment: approximately $43,000 and $81,000 respectively, with differences of less than $4,000 between regimens. Annual costs were highest in the first year of adt. Orchiectomy was the least costly regimen for most time periods, but was limited to primary and metastatic indications. Outpatient drugs, including pharmacologic adt, accounted for 17%-65% of total first-year costs. CONCLUSIONS: Compared with combined therapies, the adt monotherapies, particularly orchiectomy when clinically feasible, are more economical. Our methods exemplified the use of algorithms to elucidate clinical information from administrative data. Our approach can be adapted for other cancers to expand the range of studies using Canadian administrative data.

Population-based trends in systemic therapy use and cost for cancer patients in the last year of life.

BACKGROUND: The use of systemic therapy near the end of life can expose cancer patients to severe toxicity for minimal survival gain and comes with a high cost. Early palliative care is recommended, but there is evidence that aggressive care remains common. To better understand those patterns, the present study set out to describe trends in systemic therapy use and cost for cancer patients in the last year of life. METHODS: Using the BC Cancer Registry, a retrospective population-based cohort of cancer decedents (2002-2007) was identified and linked to systemic therapy records. The outcomes of interest were any systemic therapy use and total systemic therapy costs during the last year of life. Multiple logistic regression (systemic therapy use) and generalized linear regression (costs) were conducted, adjusting for age, sex, and survival. Subgroup analyses were performed for patients with primary colorectal, lung, prostate, or breast cancer. RESULTS: From 2002 to 2007, use of systemic therapy in the last 12-4 months of life increased by 21% (95% ci: 10% to 33%); no significant change in use in the last 3 months of life was observed. Costs for both periods increased over time, by 48% (95% ci: 36% to 63%) and by 33% (95% ci: 19% to 49%) respectively. The trends varied across cancer sites, with the greatest increases being observed for lung and colorectal cancer patients. CONCLUSIONS: The use and costs of systemic therapy have generally been increasing, putting pressure on health care providers and payers, but the quality-of-life implications for patients must be better understood.

Health care costs for prostate cancer patients receiving androgen deprivation therapy: treatment and adverse events.

BACKGROUND: Serious adverse events have been associated with androgen deprivation therapy (adt) for prostate cancer (pca), but few studies address the costs of those events. METHODS: All pca patients (ICD-9-CM 185) in Ontario who started 90 days or more of adt or had orchiectomy at the age of 66 or older during 1995-2005 (n = 26,809) were identified using the Ontario Cancer Registry and drug and hospital data. Diagnosis dates of adverse events-myocardial infarction, acute coronary syndrome, congestive heart failure, stroke, deep vein thrombosis or pulmonary embolism, any diabetes, and fracture or osteoporosis-before and after adt initiation were determined from administrative data. We excluded patients with the same diagnosis before and after adt, and we allocated each patient's time from adt initiation to death or December 31, 2007, into health states: adt (no adverse event), adt-ae (specified single adverse event), Multiple (>1 event), and Final (≤180 days before death). We used methods for Canadian health administrative data to estimate annual total health care costs during each state, and we examined monthly trends. RESULTS: Approximately 50% of 21,811 patients with no pre-adt adverse event developed 1 or more events after adt. The costliest adverse event state was stroke ($26,432/year). Multiple was the most frequent (n = 2,336) and the second most costly health state ($24,374/year). Costs were highest in the first month after diagnosis (from $1,714 for diabetes to $14,068 for myocardial infarction). Costs declined within 18 months, ranging from $784 per 30 days (diabetes) to $1,852 per 30 days (stroke). Adverse events increased the costs of adt by 100% to 265%. CONCLUSIONS: The economic burden of adverse events is relevant to programs and policies from clinic to government, and that burden merits consideration in the risks and benefits of adt.

Predicting utility scores for prostate cancer: mapping the Prostate Cancer Index to the Patient-Oriented Prostate Utility Scale (PORPUS).

BACKGROUND: The Prostate Cancer Index (PCI) is a health profile instrument that measures health-related quality of life with six subscales: urinary, sexual, and bowel function and bother. The Patient-Oriented Prostate Utility Scale (PORPUS-U) measures utility (0=dead and 1=full health). Utility is a preference-based approach to measure health-related quality of life, required for decision analyses and cost-effectiveness analyses. We developed a function to estimate PORPUS-U utilities from PCI scores. METHODS: The development data set included 676 community-dwelling prostate cancer (PC) survivors who completed the PCI and PORPUS-U by mail. We fit three linear regression models: one used original PORPUS-U scores and two used log-transformed PORPUS-U scores, one with a hierarchy constraint and one without. The model selection was performed using stepwise selection and fivefold cross validation. The validation data included 248 PC outpatients with three assessments on the PCI and PORPUS-U. Scores were retransformed for validation, with Duan's smearing estimator applied to correct potential bias. The predictive ability of the models was assessed with R(2), root mean square error (RMSE) and by comparing predicted and observed utilities. RESULTS: The best-fitting model used the log-transformed PORPUS-U with no hierarchy constraint. The R(2) was 0.72. The RMSE ranged from 0.040 to 0.061 for the three validation data sets. Differences between predicted and observed utilities ranged from 0.000 to 0.006 but predicted utilities overestimated the lowest 5% of observed PORPUS-U scores and underestimated the highest observed scores. CONCLUSIONS: Our algorithm can calculate PORPUS-U utility scores from PCI scores, thus supplementing descriptive quality of life measures with utility scores in PC patients. Utilities derived from mapping algorithms are useful for assigning utility to groups of patients but are less accurate at predicting utility of individual patients. We are exploring statistical methods to improve the mapping of utilities from descriptive instruments.

Cost-effectiveness of intensity-modulated radiotherapy in prostate cancer.

AIMS: To compare the costs and effectiveness of intensity-modulated radiotherapy (IMRT) with three-dimensional conformal radiotherapy (3DCRT) for the radical treatment of localised prostate cancer at elevated doses (>70 Gy). MATERIALS AND METHODS: A cost-effectiveness analysis model was developed using clinical effectiveness estimates from a systematic review. The base case analysis assumes equal biochemical survival for IMRT and 3DCRT, but lower frequency of gastrointestinal toxicity for IMRT. The costs of IMRT and 3DCRT were estimated through activity-based costing, incorporating input from radiation oncologists, physicists and treatment planners. RESULTS: The delivery of IMRT produced 0.023 more quality-adjusted life-years (QALY) than 3DCRT at an additional cost of $621 (QALY and costs discounted at 5% per year), yielding an incremental cost-effectiveness ratio of $26 768 per QALY gained. The treatment cost of IMRT was $1019 more than 3DCRT, but IMRT resulted in less frequent gastrointestinal toxicity, thus avoiding $402 in the treatment of toxicity. In the scenario that compared a higher dose of IMRT (75.6 Gy) to 3DCRT (68.4 Gy), IMRT improved disease control with equal toxicity incidence, and the IMRT strategy dominated (less costly and more effective). In the base case scenario (no survival difference), the cost-effectiveness of IMRT was most sensitive to the treatment cost difference between IMRT and 3DCRT. CONCLUSION: For radical radiation treatment (>70 Gy) of prostate cancer, IMRT seems to be cost-effective when compared with an equivalent dose of 3DCRT.

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.

Variations in response to citalopram in men and women with alcohol dependence.

OBJECTIVE: To examine the differential effects of citalopram on alcohol consumption in nondepressed women and men with mild to moderate alcohol dependence. DESIGN: Prospective, placebo-controlled study. PARTICIPANTS: Sixty-one subjects (34 men and 27 women). INTERVENTIONS: After a 2-week baseline, subjects were randomly assigned to 12 weeks of citalopram (40 mg per day) (n = 15 women, 16 men) or placebo (n = 12 women, 18 men). All received brief standard psychosocial interventions. OUTCOME MEASURES: Alcohol Dependence Scale, Montgomery-Asberg Depression Scale, Michigan Alcohol Screening Test, State-Trait Anxiety Inventory and daily alcohol intake. RESULTS: Pretreatment sex differences were evident in alcohol consumption, alcohol dependence, alcohol-related problems and on anxiety and depression measures. After treatment, analyses of covariance with depression and anxiety scores as covariates revealed a differential benefit of citalopram for men. Men receiving citalopram reduced average drinks per day by 44%, whereas women exhibited a 27% decrease (p < 0.05). CONCLUSIONS: Men may benefit more than women from citalopram in the treatment of alcohol dependence. These findings highlight the importance of examining sex as a significant variable in evaluating response to pharmacotherapy.

Long-term benzodiazepine therapy does not result in brain abnormalities.

Studies on the association between long-term benzodiazepine use and brain abnormalities have yielded conflicting results. The computed tomographic (CT) scans of 20 long-term users of benzodiazepine (65% men; mean age +/- SD [range], 42 +/- 12.1 years [23-59]; mean daily benzodiazepine dose [diazepam equivalents], 19.5 +/- 16.2 mg [2.5-70]; mean cumulative benzodiazepine exposure, 55.2 g [1.8-198]) were compared with 36 age- (+/-3 years) and sex-matched controls. Controls were prospectively recruited from 96 patients attending a neurology clinic and were interviewed to screen for alcohol and substance use disorders and other conditions possibly leading to brain atrophy. Three neuroradiologists blindly assessed each CT scan for atrophy and measured ventricles (V1, V2, V3), sulci, fissures, cisterns, and folia. Reliability among observers ranged from 0.92 to <0.1, in which case deleting one observer increased all reliabilities to >0.45. No difference in atrophy was found between benzodiazepine users and controls. V1 measures were significantly higher for benzodiazepine users than for controls (mean +/- SD, 12.1 +/- 1.3 vs. 11.1 +/- 2.0;p = 0.02), but measures of third and fourth largest sulci were significantly higher in controls than in benzodiazepine users. Right third and fourth largest sulci (mean +/- SD), respectively, were the following: controls, 0.72 +/- 0.4 and 0.74 +/- 0.7; benzodiazepine users, 0.51 +/- 0.3 and 0.46 +/- 0.3 (p < 0.02). Left third and fourth largest sulci, respectively, were the following: controls, 0.77 +/- 0.6 and 0.65 +/-0.3; benzodiazepine users, 0.53 +/- 0.3 and 0.5 +/- 0.3 (p < 0.02). Long-term benzodiazepine therapy does not result in brain abnormalities that can be demonstrated on CT scans.

Safety of ipsapirone treatment compared with lorazepam: discontinuation effects.

OBJECTIVE: To determine discontinuation effects of ipsapirone, a novel azapirone and partial 5-HTIA agonist that has anxiolytic effects clinically and has not caused dependence or withdrawal symptoms in animals, and to compare these effects with those of the benzodiazepine lorazepam, owing to concern about dependence or withdrawal symptoms following use of these drugs. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial. SETTING: Outpatient and inpatient treatment. PARTICIPANTS: Sixty-five healthy male volunteers who had experience with sedative-hypnotics or anxiolytics and did not meet DSM-III-R criteria for abuse or dependence. INTERVENTIONS: Participants were randomized to receive ipsapirone 15 mg per day (n = 17), ipsapirone 22.5 mg per day (n = 16), lorazepam 3 mg per day (n = 16), or placebo (n = 16) as outpatients for 36 days (treatment) followed by single-blind placebo as inpatients for 3 days and as outpatients for 6 days (withdrawal). OUTCOME MEASURES: Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Scale (HAM-D), Spielberger State Anxiety Scale, Sleep Quality Questionnaire, General Symptom Checklist, self-rated intoxication, Clinical Institute Withdrawal Assessment--Benzodiazepines (CIWA-Benzo), psychomotor testing and urine drug screen. RESULTS: Only 45 subjects completed the study; discontinuation rates did not significantly differ among treatment groups. At day 39, fewer and less severe symptoms (e.g., insomnia and fatigue) were found on the CIWA-Benzo scale after treatment with ipsapirone or placebo than after treatment with lorazepam (p < 0.05). Subjects reported longer sleep latency and poorer sleep quality after receiving lorazepam than after receiving ipsapirone or placebo. Scores on the HAM-D, Spielberger State Anxiety and HAM-A scales did not change from baseline. CONCLUSIONS: Withdrawal symptoms were detected after discontinuation of therapeutic doses of lorazepam. Significantly fewer symptoms were observed after withdrawal from anxiolytic doses of ipsapirone.

Using fuzzy logic to predict response to citalopram in alcohol dependence.

INTRODUCTION: 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. METHODS: Two data sets were formed with patients from our studies who received 40 mg/day citalopram alone (n = 34) or 40 mg/day citalopram and a brief psychosocial intervention (n = 28). The output variable, "response," was the percentage decrease in alcohol intake from baseline. Input variables included age, gender, baseline alcohol intake, and levels of anxiety, depression, alcohol dependence, and alcohol-related problems. RESULTS: A fuzzy rulebase was created from the data of 26 randomly chosen patients who received 40 mg/day citalopram and was used to predict the responses of the remaining eight patients. Eight rules related response with depression, anxiety, alcohol dependence, alcohol-related problems, age, and baseline alcohol intake. The average magnitude of the error in the predictions (RMSE) was 2.6 with a bias (ME) of 0.6. Predicted and actual response correlated (r = 0.99; p < 0.001). A fuzzy rulebase was created from the data of 28 randomly chosen patients who received 40 mg/day citalopram and a brief psychosocial intervention and was used to predict the responses of the remaining five patients. Six rules related response with age, anxiety, depression, alcohol dependence, and baseline alcohol intake with good predictive performance (RMSE = 6.4; ME = -1.5; r = 0.96; p < 0.01). CONCLUSIONS: This study indicates that fuzzy logic modeling can predict response to pharmacotherapies for alcohol dependence.

Long-acting injectable bromocriptine does not reduce relapse in alcoholics.

Dopamine is one of several neurotransmitters that may mediate alcohol intake and dependence. A randomized, double-blind, placebo-controlled international, multicentre study was conducted to assess the effects of a long-acting injectable preparation of bromocriptine, a dopamine agonist, (Parlodel-LAR) in reducing relapse in 366 moderately/severely dependent alcoholics (DSM-III-R), drinking approximately 200 g alcohol (14.5 standard drinks) per day. After detoxification they were randomized to receive six monthly injections of bromocriptine 25 mg (n = 120), bromocriptine 50 mg (n = 124), placebo (n = 122). Brief psychosocial treatment was allowed. At 6 months there were no significant differences between treatment groups in rates of relapse to any drinking or to drinking > or = 5 days per month and > or = 3 drinks per day. Pre-treatment alcohol intake did not determine response. Efficacy ratings by subjects and investigators and adverse events, reported by 51% of subjects, did not differ between treatments. The results of this large study, in which compliance was enhanced by Parlodel-LAR, do not indicate that bromocriptine is efficacious in the maintenance of abstinence or reduced drinking. Possible reasons for the discrepancy between these conclusions and those of some previous clinical trials, in which bromocriptine was reported to reduce symptoms of alcohol withdrawal and dependence, are discussed.

Pharmacotherapy of late life mood disorders.

The pharmacotherapy of elderly patients with affective illnesses presents clinicians with a number of challenges. Changes associated with normal aging, as well as concomitant medical illnesses and their treatment, can affect the pharmacokinetics and pharmacodynamics of psychotropic drugs. Furthermore, the relative paucity of controlled trials with elderly patients necessitates a reliance on studies done on younger populations, which may be inappropriate. This review attempts to highlight how knowledge of the effects of aging on pharmacokinetics and pharmacodynamics can help clinicians optimize therapy for their older patients with affective disorders.

Research strategies to assess pharmacotherapies for alcoholism.

1. The development and implementation of standardized basic and clinical research strategies is necessary for the discovery and testing of new and effective pharmacotherapies for alcohol dependence. While many animal studies have indicated the involvement of central serotonin, endogenous opioids and dopamine, their exact mechanisms of action have not been fully discerned. One problem is the use of various animal models, making it difficult to compare or replicate results from different laboratories. 2. Once a drug appears to decrease alcohol intake in animals, assessing its effects in humans can be even more challenging. 3. Most drugs were developed and may be even registered for another indication, so Phase I trials must be repeated in heavy alcohol users in case the drug has behavioural, pharmacokinetic or pharmacodynamic interactions with alcohol. 4. Phase II trials, assessing the effects of the drug on alcohol intake, are usually radically different from the animal models: most are long (> 6 months), use varied designs, and accept only abstinence as successful outcome. Moderately dependent alcoholics, who comprise the majority of patients, prefer a goal of nonhazardous drinking. 5. In Phase III multicentre trials, especially international ones, it is almost impossible to control for potentially confounding variables, such as patient characteristics and concomitant psychosocial treatment. 6. Also, research in pharmacotherapies for alcoholism is influenced by external factors such as sources of funding and other resources. Thus, this methodical progression from Phase I to Phase III clinical trials is often abbreviated. 7. The authors developed a brief early Phase II clinical paradigm to assess pharmacotherapies for moderately dependent alcoholics, and conducted 3 studies with the serotonin uptake inhibitors, citalopram and fluoxetine, and a serotonin antagonist, ritanserin. This paradigm, which includes a short (1 to 2 weeks) outpatient phase and two experimental drinking sessions, measures alcohol intake, desire to drink, alcohol's subjective effects, and intoxication. While it may have limited relevance to a goal of abstinence, it is efficient and economical to screen drug effects on alcohol intake and suggest mechanisms (desire to drink, subjective effects). It is also the only human model concordant with results in animals. 8. Development of new pharmacotherapies for alcoholism may benefit from acceptance of both abstinence and moderation of drinking as acceptable treatment goals.

Recent advances in geriatric psychopharmacology.

Psychopharmacotherapy of the elderly must take into account the effects of age-related changes in the structure and function of the brain and various organs. In general, older people are more sensitive than young people to both the therapeutic and toxic effects of psychotropic medications, necessitating lower doses and longer dosage intervals. This holds true for the treatment of 5 major types of psychiatric illness (depression, bipolar disorder, anxiety, psychotic disorders and dementia). The tricyclic antidepressants, although efficacious, inexpensive, and backed by 30 years of experience, are less well tolerated by the elderly than are newer antidepressants such as the selective serotonin uptake inhibitors. Problems with monoamine oxidase (MAO) inhibitors, including orthostatic hypotension and restrictions in diet and other medication use, have been overcome by the advent of reversible selective inhibitors of MAO-A, but the efficacy of these in the elderly has yet to be proven in clinical trials. Lithium remains the mainstay for the treatment of bipolar disorder. However, careful dosing and monitoring of plasma lithium concentrations are required in the elderly due to changes in pharmacokinetics and pharmacodynamics which make older patients very sensitive to the toxic effects of this medication. Similarly, age-related changes in the pharmacokinetics and pharmacodynamics of the benzodiazepines, the most frequently prescribed medications for anxiety in the elderly, result in recommendations for lower doses and preferential use of those agents metabolised by conjugation (e.g. oxazepam). Buspirone, a partial serotonin 5-HT1A-agonist which is better tolerated than benzodiazepines in the elderly, may be used as an alternative. The elderly are extremely sensitive to extrapyramidal adverse effects which the typical antipsychotics (neuroleptics) exhibit to varying extents. The selection of a suitable agent for the treatment of a psychotic disorder should be based upon the adverse effect profile of the drug and the specific symptoms and situation of the patient. The newer atypical antipsychotics, clozapine and risperidone, have yet to be well-studied in the elderly. Dementia, exemplified by Alzheimer's disease, is almost exclusively an illness of the elderly. Only one medication, tacrine, has been approved for its treatment, based on extensive basic research and positive results of several clinical trials. Its long-term benefits have yet to be determined and it has several adverse effects, including a tendency to increase liver enzymes to the extent that the medication has to be discontinued.(ABSTRACT TRUNCATED AT 400 WORDS)

Ritanserin, a central 5-HT2 antagonist, in heavy social drinkers: desire to drink, alcohol intake and related effects.

Ritanserin, a 5-HT2 receptor antagonist, decreased alcohol intake in some, but not all, animal studies and in an open clinical study. We tested the short-term effects of ritanserin in 39 (35 male, four female) heavy social drinkers (consuming at least 28 drinks/week), aged 19-63 years, who were not seeking treatment. After an intake assessment, they received placebo for 7 days in a single-blind baseline. They were then randomly assigned to one of three double-blind treatments for 14 days: ritanserin 5 mg/day (n = 12), ritanserin 10 mg/day (n = 13) or placebo (n = 14). Subjects recorded daily outpatient alcohol intake. Feelings of intoxication and interest, desire, craving and liking for alcohol were rated retrospectively at each weekly study visit. Experimental drinking sessions were conducted after baseline (EDS1) and treatment (EDS2); in each session subjects were offered 18 mini-drinks (total = six standard) and rated their desire to drink, intoxication and mood (POMS). Outpatient results: ritanserin 5 mg/day decreased desire and craving for alcohol (vs. baseline, p < 0.05) but not alcohol intake. Liking of alcohol decreased from baseline with ritanserin 10 mg/day (p = 0.01) and placebo (p = 0.05). Changes in alcohol intake from baseline with ritanserin 10 mg/day (increase, p > 0.05) and placebo (decrease, p > 0.05) were different (p < 0.05). EDS results: in EDS2, desire ratings for the first three mini-drinks were lower after ritanserin 5 mg/day than after ritanserin 10 mg/day (p < 0.05), but the decreases were not statistically significant when EDS1 desire ratings were controlled for. Ritanserin 10 mg/day increased alcohol-induced feelings of intoxication and friendliness, compared with placebo (p < 0.05). Both ritanserin 5 mg/day and 10 mg/day enhanced alcohol-induced decreases in fatigue, compared with placebo (p < 0.05). These results indicate that ritanserin may have differential effects on alcohol intake, desire, craving and liking, intoxication and some of alcohol's effects on mood. However, they suggest that ritanserin has limited efficacy in reducing alcohol intake in heavy drinkers.

Effects of citalopram and a brief psycho-social intervention on alcohol intake, dependence and problems.

Citalopram (C) decreased alcohol intake and desire to drink in short-term (2-4 weeks) studies with no other treatment. We tested the long-term effects of C combined with a brief psycho-social intervention. After a 2-week baseline, mildly/moderately dependent alcoholics (35 males, 27 females) were randomized, double-blind to 12 weeks of C 40 mg/day (n = 31) or placebo (P) (n = 31) and a brief psycho-social intervention with follow-ups at 4 and 8 weeks post-treatment. Alcohol intake was monitored daily and alcohol dependence (ADS) and problems (MAST) were assessed at intake and post-treatment. During the first week, the decrease (%) from baseline daily alcoholic drinks (mean +/- SEM) was greater with C (47.9 +/- 5.1 from 6.5 +/- 0.6) than with P (26.1 +/- 4.2 from 5.8 +/- 0.4) (p < 0.01). However, the 12-week decreases with C (35.1%) and P (38.8%) were similar. There were gender differences within the C group. The males had higher MAST scores at intake (mean +/0 SEM = 10.4 +/- 0.8; n = 15) than the females (6.4 +/- 0.9, n = 16) (p < 0.01) and were slightly heavier drinkers during baseline (7.1 +/- 0.9 vs. 5.9 +/- 0.9 drinks/day, NS). The response to C was greater in males (44% decrease) than females (26%) (p < 0.05) and correlated with MAST scores (r = 0.44, p = 0.01), but not with baseline alcohol intake (r = 0.2, NS). Craving and liking for alcohol and alcohol dependence (ADS) and problems (MAST) decreased similarly with C and P (p < 0.01). Thus, the short-term effects of C were replicated but no long-term effect was detected. Tolerance to citalopram, perhaps through some adaptive neurobiological changes, may have developed. The potential therapeutic use of C as a useful pharmacological adjunct in alcoholics remains to be determined.

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 (12 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 (mean +/- 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.

Treatment of alcohol withdrawal syndrome.

Treatment of the alcohol withdrawal syndrome is the first step towards the rehabilitation of alcohol-dependent patients. The objectives of treatment are relief of symptoms, prevention of complications and a smooth transition into a long-term rehabilitation programme. Recently, progress has been made in the clinical management of the alcohol withdrawal syndrome through standardization of the assessment using the CIWA-A scale and frequent monitoring of clinical findings, recognition of the efficacy of non-pharmacological interventions (i.e. standardized supportive care) and simplification of pharmacotherapy by optimizing the use of long-acting benzodiadepines via a loading dose technique. Benzodiazepines, because of their cross-tolerance with ethanol, wide margin of safety and low potential for physical dependence and tolerance, are very effective and are the drugs of choice for the treatment of the alcohol withdrawal syndrome.

Serotonin-altering medications and desire, consumption and effects of alcohol-treatment implications.

The relationship between serotonin neurotransmission and alcohol consumption (AC) was first determined in preclinical studies. AC generally increases following treatments which decrease serotonin activity, and levels of 5-HT and metabolites are low in some brain regions of alcohol-preferring rats. Pharmacological treatments which enhance serotonergic neurotransmission (uptake inhibitors, releasers, agonists) consistently reduce AC in rats. Serotonin uptake inhibitors (SUI; e.g., citalopram, fluoxetine) have been studied extensively in humans. In several double-blind randomized, placebo-controlled trials, SUI consistently decreased short-term (2-4 weeks) AC by averages of 15% to 20% in nondepressed mildly/moderately dependent alcoholics who received no other treatment. Some subjects decreased AC by up to 60%. The effects of SUI on AC were dose-dependent and not related to side effects (few and mild) or changes in anxiety or depression (not observed). SUI decreased desire to drink and liking for alcohol, suggesting a mechanism of action, to be considered in the development of treatments to reduce AC and prevent relapse. However, while an adjunctive brief psychosocial intervention enhanced the short-term effect of a SUI, the long-term (12-week) effects of SUI and placebo were similar. Other drugs acting on the 5-HT system have been tested in humans, but results are inconclusive. For example, buspirone, a 5-HT1A receptor partial agonist, reduced anxiety and alcohol craving, but not AC; a 5-HT partial agonist, m-CPP, increased craving in abstinent alcoholics; modest reductions in AC were observed with a 5-HT3 antagonist, ondansetron (0.5 mg/day, but not 4 mg/day). Ritanserin, a 5-HT2 antagonist, reduced desire to drink and prevented relapse in a small (n = 5) study, and there was some indication that it reduced desire to drink and enhanced alcohol effects without reducing AC, in another study. The therapeutic potential of these medications is being studied. SUI and other serotonin-altering medications are promising new neuropharmacological treatments for AC.

Behavioural correlates of alcohol intoxication.

Alcohol is used in most cultures despite knowledge of the physical, psychological and social problems associated with its abuse. Behavioural impairment is a function of several factors, including blood alcohol concentration (BAC) and the rate of alcohol metabolism by alcohol dehydrogenase and the microsomal ethanol-oxidizing system. Their availability and activity depend upon alcohol use history, ethnicity, other drug use and gender. Adverse social consequences related to alcohol intoxication include impaired driving, acts of aggression and violence towards self and others, and various types of accidents. About 40% of all fatal traffic accidents in Canada and the US in 1986-1987 were alcohol-related. Similar statistics have been reported in the UK and Europe (e.g. Sweden). The risk of a fatal car accident increases exponentially with a driver's BAC, prompting recommendations to lower the legal BAC limit for driving and piloting aircraft. Risks of falls, drownings, and fires and burns may also be increased by alcohol intoxication. At least 22% of work-related accidents may have involved alcohol use. These data are probably conservative estimates as under-reporting of alcohol use is likely. Alcohol facilitates aggressive behaviours, but it is difficult to separate the pharmacological effect from psychosocial effects or some other common factor (e.g. low CSF levels of the serotonin metabolite 5-H1AA have been reported in alcoholics, suicide attempters, violent offenders). In addition, alcohol interacts with other drugs to increase or decrease their behavioural and therapeutic effects. An acutely high BAC inhibits the metabolism of other CNS depressants (e.g. benzodiazepines), but long-term alcohol use increases the metabolism of most drugs. A potential amethystic agent, to block or reverse alcohol's effects, has been identified in preclinical studies (Ro15-4513, an imidazobenzodiazepine). Some clinical studies indicated that naloxone, lithium, ibuprofen, zimeldine and catecholamine agonists may reduce ethanol-induced behavioural or cognitive effects but the results have not been consistently replicated. More research is needed to determine the potential clinical use of amethystic agents and other pharmacotherapies in the prevention and treatment of problem behaviours associated with alcohol abuse and intoxication.