Mirtazapine

Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA). The antidepressant efficacy of mirtazapine has been established in randomised, double-blind comparative studies. Mirtazapine has generally shown similar efficacy to other antidepressants. There is evidence for a faster onset of action with mirtazapine than with the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) on the basis of mean depression rating scale scores.

Data from a long term (mean 240 days) clinical trial that was subsequently used in pharmacoeconomic analyses showed that mirtazapine was associated with significantly higher sustained remission rates and rates of discontinuation because of improvement than amitriptyline and placebo. Although differences were not statistically significant, mirtazapine had higher response rates at 6weeks than the SSRI fluoxetine in an analysis that was also used as the basis of pharmacoeconomic studies.

Mirtazapine improved quality of life to a similar extent to fluoxetine, citalopram and paroxetine in unpublished studies of 6 and 8 weeks’ duration. Pooled analyses suggest that mirtazapine may be associated with greater improvement than fluoxetine and citalopram in quality of life after 2 and 4 weeks, although confirmation is required.

In a decision analytical model of ≈6 months’ duration, mirtazapine was associated with a higher proportion of successfully treated patients and lower total direct costs than amitriptyline. The direct cost per successfully treated patient with mirtazapine was lower than that with amitriptyline by 33 112 Austrian schillings (S; year of costing not stated), 24 212 French francs (FF; 1995/1996 values), 13 851 Swedish kronor (SEK; 1997 values) and £553 (1997/1998 values) in Austrian, French, Swedish and UK analyses, respectively.

Compared with fluoxetine, mirtazapine was associated with higher per-patient costs in all 4 countries but a higher proportion of successfully treated patients. Mirtazapine was more cost effective than fluoxetine: the direct cost per successfully treated patient was lower by S32 046 in Austria, FF25 914 in France, SEK9796 in Sweden and £327 in the UK. The additional cost of mirtazapine versus fluoxetine for each additional successfully treated patient at 6 months was S11 732, SEK17 229, £750 and FF3342 in the Austrian, Swedish, UK and French analyses, respectively.

Mirtazapine was generally associated with lower indirect costs (for lost productivity of employed patients) than amitriptyline and similar indirect costs to fluoxetine in the analyses.

Major depression is a common psychiatric disorder which results froma complex interaction between environmental and genetic factors. Estimates of the lifetime prevalence of major depression vary greatly; however, the disease is generally thought to be underdiagnosed and undertreated. Depression is a disabling condition that impairs health-related quality of life and increases all-cause mortality. The condition places a great burden on the health and productivity of society which, when measured in Disability-Adjusted Life Years, is exceeded only by ischaemic heart disease in established market economies.

Studies assessing the direct and indirect costs of depression highlight the enormous impact the illness has on society. For example, available cost-of-illness analyses have estimated total annual costs to be $US43.7 billion in the US (1990 values) and £3 billion in England and Wales (1990/1991 values). Studies have generally concluded that depression is associated with a greater proportion of indirect than direct costs; a ratio of 7:1 was found in 2 studies. Drug costs were a low proportion of the direct costs (≈10 to 12%) and total costs (≈1 to 2%).

The antidepressant efficacy of mirtazapine has been established in randomised, double-blind comparative studies.

Meta-analyses of data from comparative trials demonstrated that significant improvements in depression rating scale scores were apparent within 1 or 2 weeks in recipients ofmirtazapine or amitriptyline. Improvementsweremaintained throughout 6 weeks of treatment, at which time remission and response rates were similar in patients treatedwithmirtazapine or amitriptyline and significantly greater than among placebo recipients.

Mirtazapine was effective in maintaining remission and preventing relapse in a long term, double-blind, placebo-controlled study in patients with major depression. Sustained remission rates at end-point were significantly greater in mirtazapine-treated patients (77%) than in recipients of either amitriptyline (57%) or placebo (43.9%). These data, in addition to withdrawal rates because of improvement,which were also significantly betterwith mirtazapine than amitriptyline or placebo, were used in pharmacoeconomic analyses of mirtazapine. In addition, relapse rates were significantly lower and sustained response rates were significantly higher among recipients of mirtazapine or amitriptyline compared with placebo recipients. Importantly, mirtazapine was better tolerated than amitriptyline in this study.

The antidepressant efficacy of mirtazapine has also been compared with that of the selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) citalopram, fluoxetine and paroxetine in randomised, double-blind, multicentre studies. Mirtazapine had a faster onset of action than the SSRIs on the basis of mean depression rating scale scores in clinical trials and post-hoc pooled analyses. At the end of the studies (6 or 8 weeks) there were no statistically significant differences between mirtazapine and SSRIs in the percentages of patients classified as responders or in remission. In a 6-week trial used as the basis for pharmacoeconomic analyses, response rateswere 67%with mirtazapine and 46%with fluoxetine.

The percentage of responders was more than 2-fold greater among recipients of mirtazapine (18%) than venlafaxine (7%) after 1 week in a randomised, doubleblind, multicentre study in severely depressed hospitalised patients with melancholia. Although the differences were not statistically significant for this or the following variables, a greater proportion of mirtazapine than venlafaxine recipients were categorised as responders (≥62 vs ≥52%), or were considered to be in remission after 8 weeks of treatment (≥38 vs ≥29%).

Data from meta-analyses of placebo-controlled trials indicate that dry mouth, drowsiness/sedation, increased appetite and bodyweight gain are the most common adverse events with short term (5 to 6 weeks) mirtazapine therapy. Typical SSRI adverse events were generally less common with mirtazapine than with fluoxetine, paroxetine and citalopram, although overall mirtazapine appeared to have a similar tolerability profile to those of the SSRIs. Mirtazapine appeared to be better tolerated than venlafaxine. Increased appetite and bodyweight have been reported to be more common with mirtazapine than with antidepressant comparators.

Improvements in health-related quality of life, as assessed on the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), were similar between mirtazapine and fluoxetine or citalopram.Mean improvements from baseline to endpoint in Q-LES-Q total scores with mirtazapine were 7.5 or 12.2 at 6 or 8 weeks, respectively, as reported in 2 unpublished trials. Unpublished pooled analyses of data from the 2 trials showed that a significantly greater proportion of mirtazapine than SSRI recipients had ≤50% improvement in their total score at days 14 and 28. When compared with each SSRI individually, the same result was observed for mirtazapine versus citalopram, but there were no significant differences between mirtazapine and fluoxetine.

Mirtazapine and paroxetine produced equivalent improvements from baseline on the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) in total quality-of-life scores in a 6-week trial.

A decision analysis model of the cost effectiveness of mirtazapine versus amitriptyline and fluoxetine in patientswith moderate and severe depression has been developed and applied to Austria, France, Sweden and the UK. Primarily, the perspective of the national health funder was taken, but indirect costs were also estimated separately.

Although mirtazapine was associated with higher per-patient costs versus fluoxetine in each country, the drug had better efficacy and was more cost effective than fluoxetine when modelled over a 26-week period. The proportion of successfully treated patients was greater with mirtazapine (19.1%) versus fluoxetine (15.6%) in the model. The direct cost per successfully treated patient with mirtazapine was lower than that with fluoxetine by S32 046, FF25 914, SEK9796 and £327 in Austria, France, Sweden and the UK, respectively. The additional cost of mirtazapine versus fluoxetine for each additional successfully treated patient at 6 months was S11 732 in the Austrian analysis, SEK17 229 in the Swedish analysis, £750 in the UK study and FF3342 (calculated using available data) in the French analysis.

Mirtazapine was generally associated with lower indirect costs (for lost productivity of employed patients) than amitriptyline and similar indirect costs to fluoxetine in the analyses.