RESUMEN

According to both in vitro and in vivo data P-glycoprotein (P-gp) may restrict the uptake of several antidepressants into the brain, thus contributing to the poor success rate of current antidepressant therapies. The therapeutic activity of citalopram resides in the S-enantiomer, whereas the R-enantiomer is practically devoid of serotonin reuptake potency. To date, no in vivo data are available that address whether the enantiomers of citalopram and its metabolites are substrates of P-gp. P-gp knockout (abcb1ab (-/-)) and wild-type (abcb1ab (+/+)) mice underwent acute (single-dose) and chronic (two daily doses for 10 days) treatment with citalopram (10mg/kg) or escitalopram (5mg/kg) Serum and brain samples were collected 1-6h after the first or last i.p. injection for subsequent drug analysis by an enantioselective HPLC method. In brain, 3-fold higher concentrations of S- and R-citalopram, and its metabolites, were found in abcb1ab (-/-) mice than in abcb1ab (+/+) mice after both acute and chronic citalopram treatments. After escitalopram treatment, the S-citalopram brain concentration was 3-5 times higher in the knockout mice than in controls. The results provide novel evidence that the enantiomers of citalopram are substrates of P-gp. Possible clinical and toxicological implications of this finding need to be further elucidated.

Asunto(s)

RESUMEN

Venlafaxine (VEN) is an antidepressant drug mainly metabolized by the cytochrome P450 (CYP) enzyme CYP2D6 to the active metabolite O-desmethylvenlafaxine (ODV). VEN is also metabolized to N-desmetylvenlafaxine (NDV) via CYP3A4. ODV and NDV are further metabolized to N,O-didesmethylvenlafaxine (DDV). VEN is a racemic mixture of the S- and R-enantiomers and these have in vitro displayed different degrees of serotonin and noradrenaline reuptake inhibition. The aim of the study was to investigate if an enantioselective analysis of VEN and its metabolites, in combination with genotyping for CYP2D6, could assist in the interpretation of forensic toxicological results in cases with different causes of deaths. Concentrations of the enantiomers of VEN and metabolites were determined in femoral blood obtained from 56 autopsy cases with different causes of death. The drug analysis was done by liquid chromatography tandem mass spectrometry (LC/MS/MS) and the CYP2D6 genotyping by PCR and pyrosequencing. The mean (median) enantiomeric S/R ratios of VEN, ODV, NDV and DDV were 0.99 (0.91), 2.17 (0.93), 0.92 (0.86) and 1.08 (1.03), respectively. However, a substantial variation in the relationship between the S- and R-enantiomers of VEN and metabolites was evident (S/R ratios ranging from 0.23 to 17.6). In six cases, a low S/R VEN ratio (mean 0.5) was associated with a high S/R ODV ratio (mean 11.9). Genotyping showed that these individuals carried two inactive CYP2D6 genes indicating a poor metabolizer phenotype. From these data we conclude that enantioselective analysis of VEN and ODV can predict if a person is a poor metabolizer genotype/phenotype for CYP2D6. Knowledge of the relationship between the S- and R-enantiomers of this antidepressant drug and its active metabolite is also important since the enantiomers display different pharmacodynamic profiles.

Asunto(s)

RESUMEN

Pharmacokinetics of antidepressant drugs (ATDs), in terms of steady-state and trough values, in patients from Child and Adolescent Psychiatry centers in the midsouth-eastern part of Sweden, were evaluated, and the use of ATDs in this population were described. Patients to be prescribed an ATD were studied between 2002 and 2004. Two hundred eleven children, 64% girls and 36% boys (ages 8-20 years) were evaluated. The primary indication for the antidepressant treatment was depression in 69% of subjects. The median body mass index was 20.2 kg/m² (range, 12.4-38.6 kg/m²). Suspected adverse drug reactions were spontaneously reported in 31% (no serious). Monotherapy was indicated in 49% of request forms. The most common drug combination with the ATD was oral contraceptives. The concentrations of drugs in the patient evaluated population to referenced data for adults from the dose administered were as expected in 63%, higher than expected in 26% and lower than expected in 11%. The most prescribed ATD was sertraline (SERT). Dose-concentration relationships for SERT and metabolite desmethylsertraline (DSERT) were seen, rs = 0.48 and rs = 0.5, respectively. No relationship was found between dose and ratio DSERT/SERT. The median daily dose was 50 mg (range, 12.5-150 mg), SERT concentration 16 ng/mL (range, 3-88 ng/mL), and DSERT 33 ng/mL (range, 0-253 ng/mL). CYP2D6*4 was the most common poor metabolizer allele. Therapeutic drug monitoring may provide support to prescribing physicians to individual dose optimizing and to assess drug compliance, above all when ATDs are not well studied in pediatric patients before approval for general prescription.

Asunto(s)

RESUMEN

The female Sprague-Dawley (SD) and Dark Agouti (DA) rats are considered the animal counterparts of the human extensive and poor metabolizer cytochrome P450 (CYP) 2D6 phenotypes, respectively. The aim of this work was to study possible rat strain differences in the steady-state pharmacokinetics of the (+)-(S)- and (-)-(R)-enantiomers of citalopram and its demethylated metabolites. A chronic drug treatment regimen (15 mg/kg daily) was implemented for 13 days in separate groups of SD (n = 9) and DA (n = 9) rats by using osmotic pumps. The concentrations of citalopram and two major metabolites in serum and two brain regions were analyzed by an enantioselective high-performance liquid chromatography assay. Higher serum and brain levels of citalopram and demethylcitalopram, but lower levels of didemethylcitalopram, were observed in DA rats when compared with SD rats. The enantiomeric (S/R) concentrations ratios of citalopram were lower in the DA rats when compared with the SD rats (0.53 ± 0.05 vs. 0.80 ± 0.03, P < 0.001), indicating a possibly decreased capacity in the metabolism of the (-)-(R)-enantiomer in the DA rats. This study shows that CYP2D deficiency results in steady-state pharmacokinetic differences of the enantiomers of citalopram and its metabolites.

Asunto(s)

RESUMEN

RATIONALE: P-glycoprotein (P-gp) plays an important role in the efflux of drugs from the brain back into the bloodstream and can influence the pharmacokinetics and pharmacodynamics of drug molecules. To our knowledge, no studies have reported pharmacodynamic effects of any antidepressant drug in the P-gp knockout mice model. OBJECTIVE: The aim of this study was to investigate the enantiomeric venlafaxine and metabolite concentrations in serum and brain of abcb1ab⁻/⁻ mice compared to wild-type mice upon chronic dosing, and to assess the effect of venlafaxine treatment on open-field behavior. METHODS: P-gp knockout and wild-type mice received two daily intraperitoneal injections of venlafaxine (10 mg/kg) over ten consecutive days. Locomotor and rearing activities were assessed on days 7 and 9. After 10 days, drug and metabolite concentrations in brain and serum were determined using an enantioselective LC/MS/MS method. RESULTS: The brain concentrations of venlafaxine and its three demethylated metabolites were two to four times higher in abcb1ab⁻/⁻ mice compared to abcb1ab+/+ mice. The behavioral results indicated an impact on exploration-related behaviors in the open-field as center activity was increased, and rears were decreased by venlafaxine treatment. CONCLUSION: Our results show that P-gp at the blood-brain barrier plays an important role in limiting brain entry of the enantiomers of venlafaxine and its metabolites after chronic dosing. Taken together, the present pharmacokinetic and pharmacodynamic findings offer the possibility that the expression of P-gp in patients may be a contributing factor for limited treatment response.

Asunto(s)

RESUMEN

According to in vitro studies the enantiomers of venlafaxine display different degrees of serotonin and noradrenaline reuptake inhibition. Therefore, clarification of the enantiomeric drug distribution between serum and brain is highly warranted. To elucidate if P-glycoprotein (P-gp) in a stereoselective manner transports venlafaxine and its metabolites out of the brain we used abcb1ab double-knockout mice that do not express P-gp. A single dose of racemic venlafaxine (10 mg/kg bw) was intraperitoneally injected to knockout (-/-) and wildtype (+/+) mice. Serum and brain samples were collected 1, 3, 6 and 9 h following drug administration for analysis by LC/MS/MS. One to six hours post-dose, the brain concentrations of venlafaxine, O-desmethylvenlafaxine and N-desmethylvenlafaxine were 2-3, 2-6 and 3-12 times higher in abcb1ab (-/-) mice compared to abcb1ab (+/+) mice, respectively. No major differences in the serum and brain disposition of the S- and R-enantiomers of venlafaxine and its metabolites were found between the groups. We conclude that P-gp decreases the penetration of the S- and R-enantiomers of venlafaxine and its major metabolites into the brain. No evidence of a stereoselective P-gp mediated transport of these substances was observed.

Asunto(s)

Asunto(s)

Asunto(s)

RESUMEN

A stereoselective method is described for simultaneous determination of the S- and R-enantiomers of venlafaxine and its three demethylated metabolites in human plasma and whole blood samples. This validated method involved LC/MS/MS with positive electrospray ionization and solid phase extraction. Chromatographic separation was performed on a 250 mm x 2.1mm Chirobiotic V column with a total run time of 35 min. In plasma, calibration curves were in the range of 1-1000 nM for the S- and R-enantiomers of venlafaxine and O-desmethylvenlafaxine, and 0.5-500 nM for N-desmethylvenlafaxine and N,O-didesmethylvenlafaxine. In whole blood the corresponding concentrations were 10-4000 and 5-2000 nM, respectively. The intra-day precision was <6.3% and the inter-day precision was <9.9% for plasma and <15% and <19% for whole blood. LLOQ ranged between 0.25 and 0.5 nM. No ion suppression/enhancement or other matrix effects were observed. The method was successfully applied for determination of venlafaxine and its metabolites in plasma from patients and whole blood samples from forensic autopsy cases.

Asunto(s)

RESUMEN

Citalopram is marketed as a racemate (50:50) mixture of the S(+)-enantiomer and R(-)-enantiomer and the active S(+)-enantiomer (escitalopram) that possess inhibitory effects. Citalopram was introduced in Sweden in 1992 and is the most frequently used antidepressant to date in Sweden. In 2002, escitalopram was introduced onto the Swedish market for treatment of depression and anxiety disorders. The main objective of this study was to investigate S(+)-citalopram [i.e., the racemic drug (citalopram) or the enantiomer (escitalopram)] present in forensic autopsy cases positive for the presence of citalopram in routine screening using a non-enantioselective bioanalytical method. Fifty out of the 270 samples found positive by gas chromatography-nitrogen-phosphorus detection were further analyzed using enantioselective high-performance liquid chromatography. The 50 cases were genotyped for CYP2D6 and CYP2C19, as these isoenzymes are implicated in the metabolism of citalopram and escitalopram. In samples positive for racemic citalopram using the screening method for forensic autopsy cases, up to 20% would have been misinterpreted in the absence of an enantioselective method. An enantioselective method is thus necessary for correct interpretation of autopsy cases, after the enantiomer has been introduced onto the market. The percentage of poor metabolizers was 6% for CYP2D6 and 8% for CYP2C19.

Asunto(s)

RESUMEN

BACKGROUND AND OBJECTIVE: Mirtazapine is a tetracyclic antidepressant drug available as a racemic mixture of S(+)- and R(-)-mirtazapine. These enantiomers have different pharmacological properties, and both contribute to the clinical and adverse effects of the drug. Cytochrome P450 (CYP) 2D6 has been implicated in the metabolism of S(+)-mirtazapine. However, the effect of CYP2D6 on serum concentrations of the enantiomers of mirtazapine and its metabolites has not been assessed in patients on long-term treatment. The main objective of the study was to evaluate the effect of the CYP2D6 genotype on enantiomeric steady-state trough serum concentrations of mirtazapine and its metabolites N-desmethylmirtazapine and 8-hydroxymirtazapine. The effects of sex, age and smoking behaviour were also assessed. SUBJECTS AND METHODS: The study included 95 patients who had depression according to the Diagnostic and Statistical Manual of Mental Disorders-4th Edition and were treated for 4 weeks with a daily dose of mirtazapine 30 mg. The serum concentrations of the enantiomers of mirtazapine and its metabolites were analysed by liquid chromatography-mass spectrometry, and the subjects were genotyped for CYP2D6 alleles *3, *4, *5 and *6 and gene duplication. RESULTS: Three subjects (3%) were classified as ultrarapid metabolizers (UMs), 56 (59%) as homozygous extensive metabolizers (EMs), 30 (32%) as heterozygous EMs and 6 (6%) as poor metabolizers (PMs) of CYP2D6. The median trough serum concentrations of S(+)-mirtazapine were higher in PMs (59 nmol/L, p = 0.016) and in heterozygous EMs (39 nmol/L, p = 0.013) than in homozygous EMs (28 nmol/L). PMs and heterozygous EMs also had higher mirtazapine S(+)/R(-) ratios (0.4) than homozygous EMs (0.3, p = 0.015 and 0.004, respectively). The S(+)-N-desmethylmirtazapine concentration was higher in PMs (16 nmol/L) than in homozygous EMs (7 nmol/L, p = 0.043). There was an association between the CYP2D6 genotype and the ratio between S(+)-8-hydroxymirtazapine and S(+)-mirtazapine, with a significantly higher ratio in homozygous EMs than in heterozygous EMs (0.11 vs 0.05, p = 0.007). The influence of the CYP2D6 genotype on S(+)-mirtazapine, the mirtazapine S(+)/R(-) ratio and S(+)-N-desmethylmirtazapine remained significant after correction for the influence of sex, age and smoking. Smokers had significantly lower concentrations of S(+)-mirtazapine (23 vs 39 nmol/L, p = 0.026) and R(-)-N-desmethylmirtazapine (39 vs 51 nmol/L, p = 0.036) and a significantly lower mirtazapine S(+)/R(-) ratio (0.28 vs. 0.37, p = 0.014) than nonsmokers, and the effect of smoking remained significant after multivariate analysis. CONCLUSIONS: This study is the first to show the impact of the CYP2D6 genotype on steady-state serum concentrations of the enantiomers of mirtazapine and its metabolites. Our results also support the role of CYP1A2 in the metabolism of mirtazapine, with lower serum concentrations in smokers than in nonsmokers.

Asunto(s)

RESUMEN

Several studies suggest that serotonin reuptake inhibitors (SRIs) exert a more rapid effect when used for the treatment of symptoms such as anger and irritability then when used for depression, obsessive-compulsive disorder, or anxiety. In line with this, premenstrual irritability can be effectively dampened by intermittent administration of an SRI, from ovulation to menstruation, indicating an onset of action of 10 days or less. How fast this effect appears, in terms of hours or days, is of considerable theoretical interest, but has previously not been studied in detail. To explore this issue, 22 women with marked premenstrual irritability, who previously had responded to paroxetine, were given this compound during two menstrual cycles and placebo during one cycle in a double-blind, cross-over fashion. The women were asked to start medication in the midst of the luteal phase when irritability had been intense for 2 days. The paroxetine cycles differed significantly from the placebo cycle as early as 14 h after drug intake with respect to the number of subjects experiencing sustained reduction in irritability. When the different cycles were compared with respect to irritability-rating scores for each time of assessment, the difference was significant at day 3. The side effect nausea had an even more rapid onset (4 h), but usually disappeared within 4 days. To summarize, this controlled trial shows that an SRI reduces premenstrual irritability already within a few days after the onset of treatment.

Asunto(s)

RESUMEN

There is limited information on the pharmacokinetics ofziprasidone (ZIP) in naturalistic clinical settings. The objective of this study was to investigate the concentrations of ZIP and its active metabolite S-methyl-dihydroziprasidone (SMDZ), and the dose-normalized concentrations, using routine therapeutic drug monitoring (TDM) data. A high-performance liquid chromatographic method for determining serum concentrations of these substances for routine clinical use was established at the TDM Laboratory in Linköping, Sweden. This analytical service was available to all physicians in Sweden. Between January 2001 and December 2004, 545 analyses, representing samples from 370 patients, were performed. The median daily ZIP dose was 120 mg (range 20 -320 mg). In all, 121 steady-state trough specimens with essential clinical information were included in the pharmacokinetic evaluation. The median (25th to 75th percentile) serum concentration of ZIP was 125 nmol/L (82-188 nmol/L). The SMDZ:ZIP ratio decreased with increasing serum concentration of ZIP. The median (25th to 75th percentile) dose-normalized concentrations (nmol L(-1) mg(-1) d(-1) forZIPand SMDZ were 1.13 (0.74-1.77) and 0.62 (0.45-0.86), respectively,with SMDZ:ZIP ratio of 0.57 (0.42-0.79). The overall coefficients of variation for dose-normalized serum concentrations of ZIP, SMDZ, andSMDZ:ZIP ratio were 62%, 56%, and 57%, respectively (n = 121). Smoking women had lower normalized ZIP concentrations than nonsmoking women. Twenty-eight patients with repeated eligible TDM analyses were studied for intraindividual variance over time. In summary, great interindividual and intraindividual differences in ZIPconcentrations were observed. TDM of ZIP maybe used for individual dose adjustments and monitoring medication adherence.

Asunto(s)

RESUMEN

The aim of the study was to investigate the use of antidepressant drugs among elderly people in nursing homes. Elderly residents who where found to have been prescribed at least one antidepressant drug according to the specific medication dispensing system were identified in 8 nursing homes in the county of Ostergötland, Sweden. Data were collected from the medical record forms at the nursing home. Blood samples were drawn for the assessment of drug concentration, blood chemistry parameters and cytochrome P450 expression. At least one antidepressant drug was prescribed to 38% of elderly people in the nursing home studied. A total of 71 patients were evaluated, 80% women and 20% men. The median age was 84 years (range, 71-100 years). Indications for antidepressant drug treatment were found on 96% of medical record forms (depression, 60%); however, information relating to when treatment was initiated could not be found on 34% of medical record forms and a clear time schedule for how long this drug treatment was planned to continue could not be found either. A possible adverse effect of antidepressant drug treatment was retrieved in at least 77% of patients. Polypharmacotherapy was common; median number of drugs per patient was 11. Concentrations of drugs were higher than expected in 73%. Most patients were medicated with citalopram (n = 44). A clear interindividual variability of concentrations at each dose level was found for citalopram and for the metabolites desmethylcitalopram and didesmethylcitalopram. A significant correlation was found between the estimation of creatinine clearance and concentration-dose ratio of citalopram. Poor metabolizers, who had been prescribed an antidepressant drug that are substrate for the cytochrome P450 isoenzyme examined, have higher concentrations of prescribed antidepressant drug than do non-poor metabolizers in relation to dose. An increase in quality contribution to follow-up at antidepressant medications is needed. A more frequent clinical use of therapeutic drug monitoring and pharmacogenetic tests in addition to therapeutic drug monitoring may be one important tool in this process.

Asunto(s)

RESUMEN

INTRODUCTION: Poor adherence to antidepressant treatment is common, and results in increased disability and costs. Several factors are thought to influence patients' ability and willingness to adhere. So far, however, consensus is lacking regarding patient characteristics that predict nonadherence. The purpose of this study was to identify predictors of nonadherence to antidepressant treatment that can be ascertained at treatment start. METHOD: The present study used data from a randomized controlled trial with the main objective of studying the effect of two different compliance-enhancing programs on treatment adherence and treatment response in 1031 primary care patients with major depression. In this study, logistic regression analyses were performed to examine patient- and illness-related characteristics potentially associated with nonadherence. RESULTS: Nonadherence to antidepressant treatment was predicted by age under 35 or over 64 years, presence of personality disorder, sensation-seeking personality traits, substance abuse, and absence of concomitant medications. CONCLUSION: Certain patient- and illness-related characteristics may imply an increased risk of nonadherence to antidepressant treatment. Giving special attention to subjects with such characteristics may improve adherence.

RESUMEN

The main objectives of this study were to outline the inter- and intraindividual and overall pharmacokinetic variability of S-citalopram, S-desmethylcitalopram, and S-didesmethylcitalopram in serum by means of therapeutic drug monitoring; and to investigate potential correlations between the serum concentration and simultaneously collected clinical data. The study was conducted on outpatients in Sweden in 2002 to 2005. Included in the pharmacokinetic evaluation were 155 patients (68% women and 32% men) aged 17 to 95 years (average, 51 years). One serum sample per patient, taken as a trough value in steady state, was assessed. For the inter- and intraindividual variation calculation, 16 patients were included with two eligible samples each. The median daily dose was 20 mg/day (range, 5-40 mg). Extensive overall serum concentration variability was seen for all dose levels. The interindividual coefficient of variation for dose-normalized concentrations was 71% for S-citalopram, 36% for S-desmethylcitalopram, and 50% for S-didesmethylcitalopram. The intraindividual variations over time for the same parameters were approximately 30%, except for the ratio S-desmethylcitalopram/S-citalopram, which was 23%. The median S-desmethylcitalopram level was approximately 60% of the parent substance and the S-didesmethylcitalopram level approximately 9%. Higher age was correlated with higher serum concentrations, but no gender-related concentration differences were found. A majority (76%) of the patients took one or more drugs in addition to escitalopram, but concomitant medication did not seem to interact with escitalopram. However, women taking oral contraceptives showed a lower metabolic ratio compared with age-matched women. As a result of the wide range of the ratio in this population, these findings are not considered of clinical relevance.

Asunto(s)

RESUMEN

Patients with chronic hepatic encephalopathy often display altered diurnal rhythm as well as other affective disturbances which motivate treatment with antidepressants. We investigated the effects of sustained treatment with citalopram (10 mg/kg daily, 10 days) on 24-hr behavioural open-field activities in portacaval-shunted (PCS) rats and sham-operated control rats. In addition, the daytime and nighttime serum melatonin levels, as well as the serum concentrations of the enantiomers of citalopram and its metabolites, were analyzed. Untreated PCS rats showed reduced locomotor and rearing activities during nighttime. Citalopram treatment resulted in elevated behavioural activity in the PCS rats during night, indicative of an improved entrainment to the light-dark cycle, whereas no behavioural effect could be observed in sham rats. Higher melatonin levels in both PCS and sham rats were observed during nighttime compared with daytime, but the untreated PCS rats also showed higher daytime melatonin level than the corresponding sham group. Citalopram treatment seemed not to have any major effect on the melatonin levels. Higher serum levels of both citalopram and metabolites were observed in PCS rats as compared to sham rats. An altered ratio between the S- and R-enantiomers could also be observed in the PCS rats. In conclusion, the present data support the contention of a disturbed diurnal rhythm, and that the melatonin activity may be altered, in chronic hepatic encephalopathy. The citalopram treatment resulted in similar behavioural performances and daytime serum melatonin levels in PCS rats and controls, although pharmacokinetic differences were present between the groups.

Asunto(s)

RESUMEN

BACKGROUND: It is well known that portacaval shunting ultimately leads to a decrease in liver volume and hepatic function, but the mechanism is uncertain. The aim of the present study was to evaluate the effect of portacaval shunting (PCS) upon the morphological changes that occur in the liver in rats after port caval anastomosis. MATERIALS AND METHODS: Sixty-six male rats underwent either PCS (n = 35) or sham operations (n = 31). Hormone levels were determined in blood samples taken just before removal and weighing of the livers. Hematoxylin and eosin-stained sections were used for quantitative morphometric analysis. Apoptosis, mitosis, and cellular organelles also were assessed quantitatively. RESULTS: There was a significant reduction in the liver mass together with testosterone levels in PCS rats in comparison with sham rats. The distance between presinusoidal and postsinusoidal vessels was reduced from 500 mum in the sham rats to 299 mum in the PCS rats (P = 0.000001). Within the same group, there was a significant reduction in the area of hepatocyte nuclei in zone 3 in comparison with zone 1. Electron microscopy revealed a highly significant (P = 0.0007) reduction in the membrane-bound cytoplasmic organelles of zone 3 hepatocytes in PCS rats in comparison with the sham rats. Apoptosis was increased in zone 3 in PCS rats (P = 0.00001), whereas in zone 1 of the same group, there was an associated increased in mitosis (P = 0.000001). Overall, the degree of apoptosis was in excess of mitosis, resulting in a general loss of liver mass. CONCLUSION: Morphometric analysis at cellular and subcellular levels confirms the morphological findings of liver atrophy in PCS rats. The mechanism of atrophy is a complex one. Portacaval shunting leads to hepatic atrophy that, in turn, results in microcirculatory and hormonal changes that further contribute to liver cell loss in this animal model.

Asunto(s)

RESUMEN

Non-adherence to antidepressant drug treatment is common. In a recent study in depressed primary care patients, we reported a strong relationship between adherence and response after 6 months. With the use of a naturalistic design, the patients in that study were prospectively followed for 2 years. The purpose of the present study was to investigate the patients' long-term outcome and, in particular, to examine the impact of patients' treatment adherence on response, remission and relapse. Of the 1031 patients in the intent-to-treat (ITT) sample, 835 completed the study. After 2 years, the overall remission rate defined as a Montgomery-Asberg Depression Rating Scale score of nine or less was 68% in the ITT sample analysed with the last observation carried forward (LOCF) technique, and 75% in observed cases. In total, 34% of the responders experienced at least one relapse. Response rates (LOCF) were significantly higher in adherent compared to non-adherent patients at week 24 [95% confidence interval (CI) = 21.4-32.1], year 1 (95% CI = 12.3-22.2) and year 2 (95% CI = 9.2-19.0). Remission rates (LOCF) were also significantly higher in the group of adherent patients at week 24 (95% CI = 9.6-21.5), year 1 (95% CI = 10.0-21.5) and year 2 (95% CI = 11.0-22.0). No relationship between adherence and relapse rate was observed, although the mean time from response to first sign of relapse was significantly longer in the adherent patients (95% C I= 9-97 days). In conclusion, this 2-year follow-up study showed superior long-term recovery in patients who were adherent to antidepressant medication compared to non-adherent patients.

Asunto(s)

RESUMEN

OBJECTIVE: To study how implementation of a naturalistic trial design for mirtazapine treatment in major depressive disorder for six (up to 12) months could be used and evaluated by means of clinical efficacy and safety. METHOD: An open-labelled, prospective, multicenter, non-comparative trial was conducted during a 2-year period in patients with major depression according to DSM-IV treated in psychiatric departments and primary care in Sweden. Minimal inclusion and exclusion criteria were used in order to diminish the potential patient selection bias. Maximum flexibility of the dosage of mirtazapine was allowed, and clinical assessments included MADRS, CGI, vital signs and spontaneous reporting of adverse events. RESULTS: 192 patients were found eligible and enrolled in the study. A significant improvement in depressive symptoms according to MADRS and CGI was observed including particularly marked sleep improvement early in the treatment. Slight increases in body weight and BMI were observed. The investigational drug was well tolerated overall. CONCLUSION: The clinical efficacy and safety of mirtazapine found in this naturalistic setting is in line with previously reported data on mirtazapine in traditional controlled clinical trials. The results confirm that the naturalistic study design facilitated conduct of the trial. The authors suggest that this type of study design should also be applied to other antidepressant drugs that are frequently prescribed in the general population.

Asunto(s)