Direct and indirect interactions between antidepressant drugs and CYP2C6 in the rat liver during long-term treatment

The aim of the present study was to investigate the influence of tricyclic antidepressants (TADs: imipramine, amitriptyline, clomipramine, desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline) and novel antidepressant drugs (mirtazapine, nefazodone) on the activity of CYP2C6 measured as a rate of warfarin 7-hydroxylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as well as in microsomes of rats treated intraperitoneally (i.p.) for one day or two weeks with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone at 10 mg/kg i.p.; desipramine, fluoxetine, sertraline at 5 mg/kg i.p.; mirtazapine at 3 mg/kg i.p.), in the absence of the antidepressants in vitro. Some of the investigated antidepressant drugs added to liver microsomes of control rats inhibited the rate of 7-hydroxylation of warfarin. The obtained K_i values indicated that nefazodone and fluoxetine were the most potent inhibitors of the studied reaction (K_i = 13 and 23 μM, respectively), while tricyclic antidepressants and sertraline were weak in this respect (K_i = 70–127 μM). A one-day (i.e. 24 h) exposure to fluoxetine and mirtazapine resulted in a significant increase in the rate of the 7-hydroxylation of warfarin in rat liver microsomes. The other studied antidepressants did not significantly affect the rate of the CYP2C6-specific reaction. After two-week treatment with the investigated antidepressants, the increase in CYP2C6 activity observed after 24-h exposure to fluoxetine and mirtazapine was more pronounced. Moreover, unlike after one-day exposure, imipramine and sertraline significantly increased the activity of the enzyme. The other tricyclic antidepressants or nefazodone did not produce any significant effect when administered in vivo. The above-described enhancement of CYP2C6 activity correlated positively with the simultaneously observed increases in the enzyme protein level, which indicates the enzyme induction. The studied antidepressants increased the CYP2C6 protein level in the liver microsomes of rats after chronic treatment: imipramine to 174.6 ± 18.3%, fluoxetine to 159.1 ± 13.7%, sertraline to 135.3 ± 11.2% and mirtazapine to 138.4 ± 10.2% of the control. In summary, two different mechanisms of the antidepressant–CYP2C6 interaction have been found to operate in the rat liver: 1) direct inhibition of CYP2C6 shown in vitro mainly for nefazodone and fluoxetine, with their inhibitory effects being somewhat more potent than their action on human CYP2C9; 2) the in vivo induction of CYP2C6 by imipramine, fluoxetine, sertraline and mirtazapine.     

A double-blind, placebo-controlled study of sertraline with naltrexone for alcohol dependence

IntroductionSignificant preclinical evidence exists for a synergistic interaction between the opioid and the serotonin systems in determining alcohol consumption. Naltrexone, an opiate receptor antagonist, is approved for the treatment of alcohol dependence. This double-blind placebo-controlled study examined whether the efficacy of naltrexone would be augmented by concurrent treatment with sertraline, a selective serotonin receptor uptake inhibitor (SSRI).MethodsOne hundred and thirteen participants meeting DSM IV alcohol dependence criteria, who were abstinent from alcohol between 5 and 30 days, were randomly assigned to receive one of two treatments at two sites. One group received naltrexone 12.5 mg once daily for 3 days, 25 mg once daily for 4 days, and 50 mg once daily for the next 11 weeks, together with placebo sertraline. The other group received naltrexone as outlined and simultaneously received sertraline 50 mg once daily for 2 weeks, followed by 100 mg once daily for 10 weeks. Both groups received group relapse prevention psychotherapy on a weekly basis.ResultsCompliance and attendance rates were comparable and high. The groups did not differ on the two primary outcomes, time to first drink and time to relapse to heavy drinking, or on secondary treatment outcomes. With the exception of sexual side effects which were more common in the combination group, most adverse events were similar for the two conditions.ConclusionsAs the doses are tested in combination with specialized behavioral therapy, this study does not provide sufficient evidence for the combined use of sertraline and naltrexone above naltrexone alone.     

Escitalopram versus sertraline in the treatment of major depressive disorder: a randomized clinical trial*

ABSTRACT

Objective: This trial was conducted to compare the efficacy and tolerability of a fixed dose of escitalopram 10?mg/day with sertraline optimally dosed within its recommended dose range (50–200?mg/day) for the treatment of major depressive disorder.

Methods: In this multicenter trial, depressed patients (DSM?IV defined; baseline Montgomery–Asberg Depression Rating Scale [MADRS] ≥ 22) aged 18–80 years were randomly assigned to 8 weeks of double-blind treatment with escitalopram (10?mg/day) or sertraline (50–200?mg/day) following a 1?week single-blind placebo lead-in period. There was no placebo comparison arm. Sertraline was initiated at 50?mg/day, and could be increased by 50?mg/day at weekly intervals based on clinical need and tolerability at the lower dose level. The blind was maintained with matching double-blind placebo capsules for the escitalopram group. Change from baseline to endpoint in MADRS total score (last observation carried forward) was the primary efficacy measure.

Results: A total of 212 patients received double-blind medication. At week 8, the mean sertraline dosage was 144?mg/day (median = 150?mg/day). Mean changes from baseline to endpoint in MADRS scores were –19.1 and –18.4 for the escitalopram and sertraline groups, respectively. At endpoint, 75% and 70% of escitalopram- and sertraline-treated patients, respectively, were responders (≥ 50% improvement from baseline in mean MADRS scores). Both treatments were generally well tolerated; only 2% and 4% of patients prematurely discontinued escitalopram and sertraline treatment, respectively, due to adverse events.

Conclusion: No differences in efficacy were observed for fixed-dose escitalopram 10?mg/day and sertraline flexibly dosed from 50–200?mg/day. At these doses, both escitalopram and sertraline were generally well tolerated.     

Placebo-controlled, multicenter study of sertraline treatment for obsessive-compulsive disorder

The safety and efficacy of sertraline versus placebo were examined in a group of nondepressed outpatients with obsessive-compulsive disorder (OCD). Patients with moderate-to-severe OCD were recruited at 10 sites. After a 1-week placebo lead-in, patients were treated in a double-blind fashion for 12 weeks with sertraline or placebo. Sertraline was administered at a starting dose of 50 mg/day, with flexible titration up to 200 mg/day. The efficacy measures were the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the National Institute of Mental Health Global Obsessive Compulsive Scale (NIMH), and the Clinical Global Impression Scale (CGI) Severity of Illness and Improvement subscales. One hundred sixty-seven patients were randomly assigned and received at least one dose of double-blind medication: 86 received sertraline and 81 received placebo. All efficacy measures showed significantly greater improvement in the sertraline group from the end of week 8 until the end of week 12. Significantly greater improvement (p < 0.05) in the sertraline group first became apparent by the end of week 3 on the Y-BOCS and the CGI Improvement scale, and by the end of weeks 6 and 8, respectively, on the NIMH and CGI Severity scale. Sertraline was well tolerated, without serious adverse effects. In conclusion, sertraline was safe and effective in the treatment of patients with OCD.     

Fluvoxamine but not sertraline inhibits the metabolism of olanzapine: evidence from a therapeutic drug monitoring service

Therapeutic drug monitoring data of the new atypical neuroleptic drug olanzapine were used to study interactions with the selective serotonin reuptake inhibitors fluvoxamine and sertraline. The distribution of the ratio of concentration/daily dose (C/D; ng/mL per mg/d) of olanzapine was compared in three groups: patients treated with olanzapine (n = 134), patients treated with olanzapine plus fluvoxamine (n = 10) concomitantly, and patients treated with olanzapine plus sertraline (n = 21) concomitantly. No significant difference was seen between the olanzapine and the olanzapine plus sertraline groups. Patients receiving fluvoxamine in addition to olanzapine had C/D ratios that were in the mean 2.3-fold higher than patients receiving olanzapine without additional fluvoxamine. This indicated that fluvoxamine inhibits the metabolism of olanzapine, probably because of inhibition of cytochrome P450 (CYP) 1A2, whereas sertraline is unlikely to interfere with the metabolism of olanzapine. Combination therapy of olanzapine and fluvoxamine should be used cautiously, and therapeutic drug monitoring should be instituted to avoid olanzapine-induced adverse effects or intoxications.     

Excretion of citalopram in breast milk

Aims The objective of this study was to measure the secretion of the selective serotonin uptake inhibitor citalopram in breast milk.
Methods The excretion of citalopram in breast milk was studied at steady-state conditions in two patients with depression and in one healthy volunteer after ingestion of a single dose citalopram.
Results Milk/serum concentration ratios based on single pairs of samples from the two patients ranged from 1.16 to 1.88. Based on milk concentration data from the patients, the absolute dose ingested by a suckling infant would be 4.3–17.6  μg  kg⁻¹ day⁻¹, and the relative dose 0.7–5.9% of the weight-adjusted maternal dose. Based on area-under-the-time-concentration curves from the healthy volunteer, the milk/serum ratio was 1.00, the absolute dose to the infant during steady-state conditions would be 11.2  μg  kg⁻¹ day⁻¹ and the relative dose 1.8% of the weight-adjusted maternal dose.
Conclusion The study shows that the relative dose to a suckling infant is close to that reported for fluoxetine, and higher than reported for fluvoxamine, paroxetine and sertraline.     

Cost–utility comparison of escitalopram and sertraline in the treatment of major depressive disorder

ABSTRACT

Objective: To construct a cost–utility model comparing escitalopram with sertraline in the treatment of major depressive disorders.

Methods: A decision analytic model was created to compare the cost–utility of these two antidepressants from the perspective of a managed-care organization. The model was designed to compare 10–20?mg/day of escitalopram to 50–200?mg/day of sertraline. Benefits (utility) scores were calculated based on clinical and utility data obtained from the literature. Direct medical costs included costs of the antidepressants, titration, treatment failures, and adverse events. Costs and benefits were modeled for a 6-month period and the model was subjected to thorough sensitivity analyses.

Results: The estimated 6-month total cost was $919 for escitalopram and $1351 for sertraline. The estimated QALYs were 0.40296 for escitalopram and 0.39268 for sertraline. These differences were mostly due to differences in drug acquisition costs and adverse events. The robustness of the cost–utility model results were tested in a Monte Carlo simulation of 10?000 patients and it indicated an 88.5% probability that escitalopram was the dominant therapy, suggesting both lower costs and greater QALYs.

Conclusion: This cost–utility model that incorporated the costs of titration and impact of side-effects comparing escitalopram 10–20?mg per day and sertraline 50–200?mg per day shows that escitalopram appeared to be less costly and produced efficacy (utility) at least as good as and maybe slightly better than that of sertraline.     

Addition of risperidone to sertraline improves sertraline-resistant refractory depression without influencing plasma concentrations of sertraline and desmethylsertraline

In the present study, we examined the efficacy of risperidone addition on sertraline-resistant depressed patients and the effects of risperidone on the metabolism of sertraline. Ten patients (M/F: 4/6, age: 54 +/- 10 years) met the DSM-IV criteria for major depressive disorder enrolled the study. Hamilton Dating Scale for Depression (HAM-D) scores (mean +/- SD) in all 10 patients significantly decreased from 19 +/- 4 (before risperidone addition) to 11 +/- 3 (4 weeks after risperidone addition). Plasma levels of sertraline and desmethylsertraline did not change after risperidone addition. Serum BDNF levels in responders to risperidone addition were changed from 8.1 +/- 2.7 ng/ml (before risperidone addition) to 11.5 +/- 0.9 ng/ml (4 weeks after risperidone addition); in contrast, those in nonresponders changed from 7.8 +/- 2.2 ng/ml (before risperidone addition) to 7.9 +/- 2.4 ng/ml (4 weeks after risperidone addition). These results suggest that the addition of risperidone to sertraline is effective and well tolerated for sertraline-resistant depressive patients, which is accompanied with the increase in serum BDNF levels in responders to the risperidone addition, and the addition of risperidone to sertraline does not seem to influence sertraline metabolism.     

A double-blind,placebo-controlled trial of sertraline for depressive symptoms in patients with stable,chronic schizophrenia

There have been no studies specifically examining the efficacy of selective serotonin reuptake inhibitor antidepressants for the symptoms of depression in schizophrenia. This study aimed to determine the efficacy and safety of sertraline as a treatment for depressive symptoms in patients with stable, chronic schizophrenia. The Beck Depression Inventory (BDI) was used as the principal outcome measure and other measures of depressive symptoms as secondary outcome measures. Twenty-six patients were entered into a double-blind, placebo-controlled, 8-week trial of sertraline and were included in the intent-to-treat (ITT) analysis (13 in each group). Eight patients in the sertraline group and 12 in the placebo group completed at least four weeks in the study and were considered to have had adequate treatment. On the ITT analysis, the mean score on the BDI fell 14.5% for the sertraline group and 5.6% for the placebo group (p > 0.05); the mean score on the Hamilton Depression Rating Scale (HDRS) fell 16.99% for the sertraline group and 8.3% for the placebo group (p > 0.05). When the analysis was repeated for those who had received adequate treatment, the mean BDI score fell by 28% for the sertraline group and 6% for the placebo group (p = 0.1); the mean HDRS score fell 31% for the sertraline group and 8.6% for the placebo group (p = 0.02). On the Clinical Global Impression-Improvement Scale, 10 of the 13 patients on sertraline improved against four of the 13 in the placebo group (p = 0.05). Sertraline-treated patients showed a significant improvement on the anxiety/ depression subscale of the BPRS on ITT analysis (F = 10.1, p = 0.004). There was no significant effect on negative or positive symptoms. Sertraline was well tolerated. The results suggest that sertraline is useful as a treatment for depressive symptoms in schizophrenia.     

Treatment strategies in patients with major depression not responding to first-line sertraline treatment

RATIONALE: A large proportion of patients with major depression do not respond sufficiently to any first-line treatment. OBJECTIVES: The aim of this study was to compare a strategy of sertraline dose increase with a strategy of adding mianserin in patients with major depression insufficiently responding to 6 weeks of open treatment with sertraline, controlling for the effect of an extended duration of treatment. METHODS: One thousand six hundred and twenty-nine patients, 18-65 years of age, with major depression scoring at least 18 on the 17-item Hamilton depression scale (HDS) were treated openly with 50 mg/day sertraline, and patients who after 4 weeks had not responded (achieving at least a 50% reduction in score on the HDS) were treated with 100 mg/day sertraline for an additional 2-week period. The patients who had still not responded were then randomised to double-blind treatment for an additional 5 weeks with either 100 mg/day sertraline plus placebo, 200 mg/day sertraline plus placebo or 100 mg/day sertraline plus 30 mg/day mianserin. RESULTS: After 6 weeks of open treatment, 60% had responded and 22% had dropped out, leaving 295 non-responding patients (18%) for randomisation. In the intention-to-treat-analysis, continuing the treatment with 100 mg/day sertraline resulted in response in 70% of the non-responders, similar to the response rate (67%) obtained in the patients who had mianserin added. However, increasing the sertraline dose to 200 mg/day resulted in a lower response rate at 56% ( P<0.05). Similar results were seen in the completers. A substantial increase in the accumulated response rate from week 6 to week 8 was seen. There was no influence of baseline variables, including the presence of melancholic features on the overall post-randomisation response rate. CONCLUSION: After 6 weeks of insufficient antidepressant treatment with 50-100 mg/day sertraline, a continued treatment with 100 mg/day sertraline can be considered until at least week 8 before considering changing strategy, unless the condition deteriorates.     

Plasma risperidone concentrations during combined treatment with sertraline

The effect of sertraline on the steady-state plasma concentrations of risperidone and its active metabolite 9-hydroxyrisperidone (9-OH-risperidone) was studied in 11 patients with schizophrenia or schizoaffective disorder. To treat concomitant depressive symptoms, additional sertraline, at the dose of 50 mg/d, was administered for 4 weeks to patients stabilized on risperidone (4-6 mg/d). Mean plasma concentrations of risperidone, 9-OH-risperidone, and the active moiety (sum of the concentrations of risperidone and 9-OH-risperidone) did not change significantly during combined treatment with sertraline. At the end of week 4, sertraline dosage was adjusted in some patients on the basis of the individual response and then maintained until the end of week 8. At final evaluation, mean plasma levels of risperidone active moiety were not modified in the 4 patients who were still receiving the initial sertraline dose, but concentrations were slightly but not significantly increased (by a mean 15% over pretreatment) in the subgroup of 5 subjects treated with a final dose of 100 mg/d. In the 2 patients receiving the highest dose of sertraline, 150 mg/d, at week 8 total plasma risperidone concentrations were increased by 36% and 52%, respectively, as compared with baseline values. Sertraline coadministration with risperidone was well tolerated, and no patient developed extrapyramidal symptoms. These findings indicate that sertraline at dosages up to 100 mg/d is not associated with clinically significant changes in plasma risperidone concentrations. However, higher doses of sertraline may elevate plasma risperidone levels, presumably as a result of a dose-dependent inhibitory effect of sertraline on CYP2D6-mediated 9-hydroxylation of risperidone.     

In Vivo Genotoxicity Assessment of Sertraline by Using Alkaline Comet Assay and the Cytokinesis‐Block Micronucleus Assay

Sertraline, a leading antidepressant in the selective serotonin reuptake inhibitor (SSRI) group of medicine, is the most frequently prescribed drug. In this study, the alkaline comet assay and the cytokinesis‐block micronucleus (CBMN) assay were used to investigate genotoxicity potential of sertraline in the peripheral blood lymphocytes (PBLs) of acute and chronic sertraline‐treated Wistar albino rats. Male Wistar albino rats (n = 48) were administered low, medium and high doses of sertraline (10, 40, 80 mg/kg) for acute and chronic treatment by employing the gavage method to investigate genotoxicity of the administered drug. The data (tail length, tail intensity and tail moment) were analysed and indicated that there was no statistically significant difference between sertraline‐treated groups and the negative control group with respect to DNA damage (p > 0.05). However, it was observed that acute sertraline administration had caused much more DNA damage in comparison with chronic treatment (p < 0.05). According to the data obtained from the CBMN test, an increase in the micronucleus (MN) frequency was detected at chronic and high‐dose acute sertraline treatment. Based on the outcome of comet assay, detection of statistically insignificant DNA damage may be due to the fact that sertraline did not cause damage on DNA. Also, increase in frequency of MN in chronic sertraline treatment suggests that chronic sertraline administration might influence some mechanisms of cell division. Therefore, dose adjustment in depressed patients seems significant as it may help prevent further prognosis of the diseases.     

Role of serotonin receptors in the effect of sertraline on feeding behaviour

The effect of sertraline, a serotonin (5-HT) uptake inhibitor, on 1 h food intake of food-deprived rats was studied in male rats treated intraperitoneally with 1 and 2.5 mg/kg metergoline, a 5-HT₁ and 5-HT₂ receptor antagonist, 0.5 mg/kg GR 38032F, a 5-HT₃ receptor antagonist, or intracerebroventricularly with 6-hydroxy-dopamine to destroy catecholamine-containing neurons. The feeding-suppressant effect of 10 mg/kg sertraline was not significantly modified by any treatment. At 1 and 2.5 mg/kg metergoline did not significantly modify the reduction in total intake and meal size induced by sertraline in slightly-deprived rats whereas at 1 mg/kg the 5-HT receptor antagonist completely blocked the effect of 1.5 mg/kgd-fenfluramine, a 5-HT releaser and uptake inhibitor. In a runway test, metergoline at 1 but not 2.5 mg/kg significantly attenuated the effect of 10 mg/kg sertraline on starting speed in the first and second trial blocks. Both doses tended to attenuate the effect of sertraline on running speed but the interaction was not significant. The reduction in food intake induced by sertraline was antagonized only by 1 mg/kg metergoline in the last trial block. The bulk of these findings argues against an important role of 5-HT receptors in the effect of sertraline on feeding behaviour.     

Sertraline effects on cerebrospinal fluid monoamines and species-typical socioemotional behavior of female cynomolgus monkeys

Rationale

Although widely prescribed, little is known about the effects of selective serotonin reuptake inhibitors (SSRIs) on social behavior and cerebrospinal fluid (CSF) monoamines in female primates.

Objective

The objective of this study was to determine the effects of sertraline on agonistic and affiliative behavior.

Methods

Twenty-one adult female cynomolgus monkeys were housed in small, stable social groups, trained to participate in oral dosing, and began a 5-week cumulative dose–response study. Serial doses of 0, 5, 10, 15, and 20 mg/kg of sertraline were administered orally for 1 week each. Behavior was recorded daily during 10-min observations before and 4 h after dosing. On the seventh day of dosing, circulating sertraline/desmethylsertraline and CSF monoamines/metabolites were determined 4 h after the last dose.

Results

At 20 mg/kg, circulating sertraline/desmethylsertraline was in the therapeutic range. CSF 5-hydroxyindole acetic acid decreased by 33 % (p?<?0.05). Overall aggression, submission, locomotion, and time alone decreased, whereas affiliative behaviors (body contact, grooming) increased (all p values <0.05). Effects of sertraline on aggression and submission were social status-dependent, reducing aggression in dominants and submission in subordinates.

Conclusions

A clinically relevant oral dose of sertraline resulted in CSF metabolite changes similar to those observed in patients and altered the socioemotional behavior of female monkeys. Changes in CSF 5-HT and dopamine are novel observations that may be sex-specific. The robust effects of sertraline on aggression and affiliation may explain the efficacy of SSRIs on a range of human behavioral pathologies that share the characteristics of increased aggression and decreased sociality.     

Spotlight on sertraline in the management of major depressive disorder in elderly patients

Sertraline is a selective serotonin reuptake inhibitor (SSRI) with well established antidepressant and anxiolytic activity. Results from several well designed trials show that sertraline (50-200 mg/day) is effective in the treatment of major depressive disorder in elderly patients (> or =60 years of age). Primary endpoints in most studies included the Hamilton Depression Rating Scale (HDRS), Clinical Global Impression score and the Montgomery-Asberg Depression Rating Scale. Sertraline was significantly more effective than placebo and was as effective as fluoxetine, nortriptyline and imipramine in elderly patients. During one trial, amitriptyline was significantly more effective than sertraline (mean reduction from baseline on one of six primary outcomes [HDRS]), although no quantitative data were provided. Subgroup analysis of data from a randomised, double-blind trial in elderly patients with major depressive disorder suggests that vascular morbidity, diabetes mellitus or arthritis does not affect the antidepressant effect of sertraline. Secondary endpoints from these clinical trials suggest that sertraline has significant benefits over nortriptyline in terms of quality of life. In addition, significant differences favouring sertraline in comparison with nortriptyline and fluoxetine have been recorded for a number of cognitive functioning parameters. Sertraline is generally well tolerated in elderly patients with major depressive disorder and lacks the marked anticholinergic effects that characterise the adverse event profiles of tricyclic antidepressants (TCAs). The most frequently reported adverse events in patients aged > or =60 years with major depressive disorder receiving sertraline 50-150 mg/day were dry mouth, headache, diarrhoea, nausea, insomnia, somnolence, constipation, dizziness, sweating and taste abnormalities. The tolerability profile of sertraline is generally similar in younger and elderly patients. Sertraline has a low potential for drug interactions at the level of the cytochrome P450 enzyme system. In addition, no dosage adjustments are warranted for elderly patients solely based on age. CONCLUSION: Sertraline is an effective and well tolerated antidepressant for the treatment of major depressive disorder in patients aged > or =60 years. Since elderly patients are particularly prone to the anticholinergic effects of TCAs as a class, SSRIs such as sertraline are likely to be a better choice for the treatment of major depressive disorder in this age group. In addition, sertraline may have advantages over the SSRIs paroxetine, fluoxetine and fluvoxamine in elderly patients because of the drug's comparatively low potential for drug interactions, which is of importance in patient groups such as the elderly who are likely to receive more than one drug regimen.     

Sertraline: a review of its use in the management of major depressive disorder in elderly patients

Sertraline is a selective serotonin reuptake inhibitor (SSRI) with well established antidepressant and anxiolytic activity. Results from several well designed trials show that sertraline (50 to 200 mg/day) is effective in the treatment of major depressive disorder in elderly patients (> or =60 years of age). Primary endpoints in most studies included the Hamilton Depression Rating Scale (HDRS), Clinical Global Impression (CGI) score and the Montgomery-Asberg Depression Rating Scale (MADRS). Sertraline was significantly more effective than placebo, and was as effective as fluoxetine, nortriptyline and imipramine in elderly patients. During one trial, amitriptyline was significantly more effective than sertraline [mean reduction from baseline on one of six primary outcomes (HDRS)], although no quantitative data were provided. Subgroup analysis of data from a randomised, double-blind trial in elderly patients with major depressive disorder suggests that vascular morbidity, diabetes mellitus or arthritis does not affect the antidepressant effect of sertraline. Secondary endpoints from these clinical trials suggest that sertraline has significant benefits over nortriptyline in terms of quality of life. In addition, significant differences favouring sertraline in comparison with nortriptyline and fluoxetine have been recorded for a number of cognitive functioning parameters. Sertraline is generally well tolerated in elderly patients with major depressive disorder, and lacks the marked anticholinergic effects that characterise the adverse event profiles of tricyclic antidepressants (TCAs). The most frequently reported adverse events in patients aged > or =60 years with major depressive disorder receiving sertraline 50 to 150 mg/day were dry mouth, headache, diarrhoea, nausea, insomnia, somnolence, constipation, dizziness, sweating and taste abnormalities. The tolerability profile of sertraline is generally similar in younger and elderly patients. Sertraline has a low potential for drug interactions at the level of the cytochrome P450 enzyme system. In addition, no dosage adjustments are warranted for elderly patients solely based on age. CONCLUSION: Sertraline is an effective and well tolerated antidepressant for the treatment of major depressive disorder in patients aged > or =60 years. Since elderly patients are particularly prone to the anticholinergic effects of TCAs as a class, SSRIs such as sertraline are likely to be a better choice for the treatment of major depressive disorder in this age group. In addition, sertraline may have advantages over the SSRIs paroxetine, fluoxetine and fluvoxamine in elderly patients because of the drug's comparatively low potential for drug interactions, which is of importance in patient groups such as the elderly who are likely to receive more than one drug regimen.     

Comparing effects of methylphenidate, sertraline and placebo on neuropsychiatric sequelae in patients with traumatic brain injury

BACKGROUND: This study aimed to investigate the effects of methylphenidate and sertraline compared with placebo on various neuropsychiatric sequelae associated with traumatic brain injury (TBI). METHODS: This was a 4 week, double-blind, parallel-group trial. Thirty patients with mild to moderate degrees of TBI were randomly allocated to one of three treatment groups (n = 10 in each group) with matching age, gender and education, i.e. methylphenidate (starting at 5 mg/day and increasing to 20 mg/day in a week), sertraline (starting at 25 mg/day and increasing to 100 mg/day in a week) or placebo. At the baseline and at the 4 week endpoint, the following assessments were administered: subjective (Beck Depression Inventory) and objective (Hamilton Depression Rating Scale) measures of depression; Rivermead Postconcussion Symptoms Questionnaire for postconcussional symptoms; SmithKline Beecham Quality of Life Scale for quality of life; seven performance tests (Critical Flicker Fusion, Choice Reaction Time, Continuous Tracking, Mental Arithmetic, Short-Term memory, Digit Symbol Substitution and Mini-Mental State Examination); subjective measures of sleep (Leeds Sleep Evaluation Questionnaire) and daytime sleepiness (Epworth Sleepiness Scale). All adverse events during the study period were recorded and their relationships to the drugs were assessed. RESULTS: Neuropsychiatric sequelae seemed to take a natural recovery course in patients with traumatic brain injury. Methylphenidate had significant effects on depressive symptoms compared with the placebo, without hindering the natural recovery process of cognitive function. Although sertraline also had significant effects on depressive symptoms compared with the placebo, it did not improve many tests on cognitive performances. Daytime sleepiness was reduced by methylphenidate, while it was not by sertraline. CONCLUSIONS: Methylphenidate and sertraline had similar effects on depressive symptoms. However, methylphenidate seemed to be more beneficial in improving cognitive function and maintaining daytime alertness. Methylphenidate also offered a better tolerability than sertraline.     

米氮平与舍曲林治疗抑郁症伴有焦虑疗效比较

目的 :比较米氮平与舍曲林对抑郁症伴焦虑的疗效及其安全性。方法 :1 1 1例抑郁症分为 2组。米氮平组 56例 [男性 30例 ,女性 2 6例 ,年龄(39±s 1 3)a,本次抑郁病期 (3± 5)mo]予米氮平30～ 45mg ,po,qd;舍曲林组 55例 [男性 2 9例 ,女性 2 6例 ,年龄 (40± 1 2 )a,本次抑郁症病期 (4± 4)mo]予舍曲林 50～ 1 0 0mg,po,qd;均 6wk为一个疗程。结果 :对抑郁症状的治疗 ,米氮平组显效率73 % ,舍曲林组显效率 67% ,疗效差异无显著意义(P >0 .0 5) ;对焦虑症状的治疗 ,米氮平组显效率79 % ,舍曲林组显效率 44 % ,疗效差异有显著意义(P <0 .0 5)。整体药物不良反应发生率 2组相当。结论 :米氮平与舍曲林是安全有效的治疗抑郁症的药物 ,但抗焦虑作用米氮平优于舍曲林     

Clinical trial: a phase II, randomized study evaluating the safety, pharmacokinetics and anti-viral activity of clevudine for 12 weeks in patients with chronic hepatitis B

Background  Clevudine is a polymerase inhibitor that has the unusual feature of delayed viral rebound after therapy in some patients which may be related to its pharmacokinetics.
Aim  To characterize pharmacokinetic and pharmacodynamic profile of clevudine, a potent hepatitis B polymerase inhibitor.
Methods  A multicenter, randomized study comparing 10, 30 and 50 mg clevudine once daily for 12 weeks with 24 weeks off-treatment follow-up. Patients had chronic HBV infection, were nucleoside-naïve without co-infection. HBV viral load (VL) was assayed using Digene Hybrid Capture II with a lower limit of detection of 4700 copies/mL (940 IU/mL). Clevudine levels were measured using a liquid chromatography/mass spectrometery method.
Results  A total of 31 patients were enrolled into the 10 mg ( n  = 10), 30 mg ( n  = 11) and 50 mg ( n  = 10) groups, respectively. At week 12, the median VL change was −3.2, −3.7 and −4.2 log₁₀ copies/mL (−0.64, −0.74 and −0.84 log₁₀ IU/mL) in the 10, 30 and 50 mg groups, respectively ( P  = 0.012). At week 12, one of 10, five of 11 and two of 10 patients had VL below the assay lower limit of detection. Clevudine was well tolerated with no severe/serious adverse events. The mean plasma half-life of clevudine was 70 h and consequently is not the cause of the delayed viral rebound seen in some patients. Through modelling, 97% of the maximal treatment effect was reached with a 30 mg daily dose. Six patients had genomic changes without viral rebound.
Conclusion  Clevudine appears to be a potent and tolerable (over 12 weeks) anti-viral and the optimal dosage appears to be 30 mg once daily.     

Effectiveness and acceptability of sertraline and citalopram in major depressive disorder: pragmatic randomized open-label comparison

OBJECTIVE: Citalopram and sertraline are widely prescribed selective serotonin reuptake inhibitors (SSRIs). There is no conclusive evidence to show superiority of citalopram or sertraline in terms of efficacy or tolerability. Hence this study was designed to compare short term efficacy and safety of citalopram and sertraline in major depressive disorder (MDD) in Indian patients. METHODS: In an open, randomized study, 100 patients were divided into two groups. In Group A (n = 50) patients received citalopram (20-60 mg/day) for 6 weeks. In Group B (n = 50) patients received sertraline (50-150 mg/day) for 6 weeks. Patients were evaluated at baseline and then at 1, 2, 3, 4, 5, and 6 weeks. RESULTS: There was significant improvement in Hamilton depression rating scale (HDRS), Montgomery and Asberg depression rating scale (MADRS) and Amritsar depressive inventory (ADI) scores (p < 0.05) with both the drugs. However, the decrease in score was more with citalopram (p < 0.05). Onset of action of citalopram was earlier as compared to sertraline (p < 0.05). The number of responders and remitters was also more with citalopram (p < 0.05). No serious adverse event was reported in either of the groups. CONCLUSION: Citalopram had shown better efficacy, earlier onset of action and more number of responders and remitters as compared to sertraline in MDD in Indian patients.