Does mirtazapine help treat treatment-resistant depression?

Relevance

Depression is one of the main factors that determine our health.
Unfortunately, more and more individuals are susceptible to this disease and, according to preliminary data, by 2030 depression will become the leading cause of disability in countries with a high level of economic development. Typically, the first step in drug therapy for depression is the prescription of antidepressants. But monotherapy is not effective in all cases. Researchers in the UK conducted a multicentre phase 3 trial to evaluate the effectiveness of combining mirtazapine (a tricyclic antidepressant) with a serotonin reuptake inhibitor (SSRI) or a serotonin-noradernaline reuptake inhibitor (SNRI) in the treatment of treatment-resistant depression.

Study design

The study involved 106 general practices in the UK. 480 patients aged 18 years or older had a Beck Depression Inventory score of 14 or more. All patients were treated with an SSRI or SNRI for at least 6 weeks, but symptoms of depression persisted.

Of the 480 patients, 241 were randomized to mirtazapine and 239 to placebo. All patients continued to receive SSRIs or SNRIs.

Primary endpoint of the study

Beck Depression Inventory severity at 12 weeks was selected.
Secondary endpoints
included quality of life, anxiety, and incidence of side effects assessed at weeks 12, 24, and 52.

Treatment regimen

◊ Dosage and dose selection

• For depression: 15-45 mg/day
• Initial dose – 15 mg in the evening; increase every 1-2 weeks until the effect is achieved; maximum – 45 mg/day
• Sedation will not increase with increasing dose
• Crushing the 15 mg tablet into two halves will increase sedation [1].
• For hot flashes: 7.5 mg-60 mg
• Insomnia/PTSD: 15-45 mg
• If anxiety, insomnia, agitation, or akathisia occur at the beginning of treatment or after interruption of treatment, the possibility of bipolar disorder should be considered and switched to a mood stabilizer or an atypical antipsychotic

◊ How quickly it works

• In patients with insomnia and anxiety, it may take immediate effect.
• Begins to act after 2-4 weeks
• If there is no effect after 6-8 weeks, you need to increase the dose or switch to another drug
• To prevent relapse, it can be taken for many years.

◊ Expected result

• Complete remission.
• After the symptoms of depression disappear, you should continue taking it for one year if this was the treatment of the first episode. If this is to treat a recurrent episode, treatment can be extended indefinitely.
• Use in the treatment of anxiety may be indefinite.

◊ If it doesn't work

• Change the dose, switch to another medicine or add an auxiliary drug;
• Connect psychotherapy;
• Review the diagnosis by identifying comorbid conditions;
• In patients with undiagnosed bipolar affective disorder, the effectiveness of treatment may be low, in which case it is necessary to switch to a mood stabilizer [1].

◊ How to stop taking it

It can be reduced gradually, but there is no need [1].

◊ Treatment combinations

• For fatigue, drowsiness, loss of concentration: modafinil [3].
• Use combinations with other antidepressants with caution because they may precipitate bipolar disorder and suicidal ideation.
• Combination with venlafaxine (“California Rocket Fuel”) is a strong combination, but watch for risk of bipolar disorder and suicidal ideation [1]
• Benzodiazepines
• For bipolar depression, psychotic depression, treatment-resistant depression, treatment-resistant anxiety disorder: mood stabilizers, atypical antipsychotics
• For anxiety disorder: gabapentin, tiagabine

results

• At week 12, Beck score was 18.0 (12.3) in the mirtazapine group and 19.7 (12.4) in the placebo group (adjusted mean difference, −1.83 (95% CI −3.92 to 0.27). ); P=0.09).
• At weeks 24 and 52, there were also no significant differences in depressive symptoms between the study groups (difference, −0.85 (95% CI −3.12 -1.43) at week 24 and 0.17 (95% CI −2 .13-2.46) at 52 weeks).
• Side effects were more common in the mirtazapine group. It was noteworthy that 46 patients from the main group stopped treatment due to adverse events, while only 9 in the placebo group.

Efficacy of mirtazapine therapy in patients with depression and affective disorders

The transition of new drugs from the laboratory to everyday medical practice is always a difficult and partly contradictory process. A balanced attitude towards a medicine comes only at the stage when the doctor has a good idea of ​​the limits of the medicine’s capabilities, based on an understanding of its advantages and disadvantages, and assigns it a stable place in his arsenal. The time it takes for a doctor to adapt to a new drug is reduced if the doctor has the opportunity to study in more detail the features of its action, using individual techniques from scientific research itself. This allows the doctor to more accurately summarize his experience and compare it with the experience of colleagues, and critically evaluate the literature data. This article is devoted to the results of one of these projects. The new drug chosen was mirtazapine, an antidepressant that is active in both the serotonergic and noradrenergic systems and selectively blocks a2 noradrenergic and 5-HT2 and 5HT3 serotonergic receptors. This neurochemical profile distinguishes mirtazapine from all currently known drugs in this group. According to the literature, mirtazapine has a powerful antidepressant effect with low severity of side effects characteristic of both tricyclic and serotonergic antidepressants [1,2].

Materials and methods

The study included 63 patients suffering from various types of affective disorder and experiencing moderate to severe depression.

The total score on the Hamilton Depression Scale (17 points) was chosen as a criterion for the severity of the condition. Severe depression was considered if this indicator was more than 25, moderate severity was more than 18, but less than 25. According to this criterion, patients were divided almost equally: with severe depression - 34 patients (average indicator on the Hamilton scale 31.6 ± 0.8 , moderate depression - 29 patients (average Hamilton scale 19.8±0.7).

The distribution of patients by diagnostic groups, as well as the average severity of depression on an objective and subjective scale by group, is shown in Table 1.

As can be seen from the table, the greatest severity of depression was observed in patients with bipolar disorder, and the least - with chronic depressive disorder, that is, dysthymia and cyclothymia.

The research project included 12 psychiatric hospitals in Moscow, St. Petersburg and other Russian cities. There were no strict inclusion or exclusion criteria: physicians were asked to prescribe mirtazapine to all patients hospitalized for depression who were clearly eligible for antidepressant therapy. Of the antidepressants, only mirtazapine was used. Freedom was also provided in the dosage of the drug within the instructions, where the therapeutic dose varied from 15 to 45 mg. The duration of the project for each patient was 42 days.

In order to formalize the data obtained, it was proposed to use the following scales:

• Hamilton Depression Scale (17 items) [3];

• Global Clinical Impression Scale;

• Beck Self-Rating Inventory for Depression (21 items) [4].

Results and discussion

The analysis of the results was carried out in two directions: the dynamics of the condition in patients of various nosological groups and the dynamics of the condition in patients with severe and moderate depression, regardless of their nosological affiliation.

All patients, except 1 patient from the group of patients with chronic affective disorder (dysthymia), who interrupted the study due to ineffectiveness of therapy, completed the study. The percentage of responders (50% reduction on the Hamilton scale) at the end of the study, depending on the course of affective psychosis, is presented in Table 2.

Bipolar affective disorder

Statistically significant changes in the Hamilton scale were observed already by the end of the first week (p < 0.001). By the end of the study, the average total score on the scale showed the absence of depression (7.4±1.9) (Fig. 1). By the end of the first week of therapy, the most significant changes were observed in such symptoms as depressive mood, sleep disturbance and mental anxiety, while changes in the severity of depressive symptoms such as guilt, suicidal thoughts, and lethargy underwent insignificant dynamics. By the end of the study, almost all symptoms assessed by the Hamilton scale had virtually disappeared. Only the mean performance and gastrointestinal disturbance scores were 1 (the mildest degree of disturbance). According to the global clinical impression scale, this group of patients progressed from “moderate severity of the disease” (average score 4.0±0.1) through “mild severity of the disease” (average score 3.4±0.1) to “the condition borders on normal” "(average value 2.1±0.2) (p<0.001). On the self-assessment scale, statistically significant changes were also detected by the end of the first week, but were less pronounced than on the Hamilton scale (Fig. 1). By the end of the study, the Beck scale showed an even more significant improvement (p < 0.001), but still its severity remained significantly less than on the Hamilton scale.

Recurrent depression

A similar picture was observed in the group of patients with recurrent depression (Fig. 2). The difference concerned a number of symptoms that decreased in severity in the first week of therapy. The following symptoms responded most quickly to treatment by the end of the first week: depressive mood (p<0.05), suicidal thoughts (p<0.05), sleep disorder (p<0.05), gastrointestinal dysfunction (p<0.05) and weight change (p<0.01). By the end of the study, almost all symptoms had completely disappeared. The exception was the indicators of performance and depressive mood, the average values ​​of which were still slightly greater than one, which corresponds to a mild degree of severity of the disorder.

Depressive episode

The diagnosis of “depressive episode” was given to patients if the type of course at the current stage of the disease could not be determined. In the vast majority of cases, these were patients with a very short follow-up. The general nature of the dynamics of the Hamilton, Beck and global clinical impression scales was the same as in the two previous groups of patients: statistically significant changes on all scales were detected by the end of the first week of therapy. Improvement continued to increase during treatment. However, some differences were also revealed: along with the symptom of “depressed mood” (p<0.01), the symptom of “decreased performance” (p<0.05) responded most strongly to therapy (by the end of the first week). During the same period, the weight of patients changed statistically significantly (p<0.05). That is, the primary response to therapy combined both signs of a bipolar and monopolar course. Changes in other signs of the Hamilton scale were statistically insignificant in the first period of therapy, but were almost completely reduced by the end of the study (p<0.001).

Improvement on the physician-completed scale outpaced improvement on the patient-completed scale.

Chronic mood disorder

Of the variety of chronic mood disorders, only patients with dysthymia were represented here. Unlike other groups of patients, in these patients a pronounced improvement in condition was detected later, only at the end of the study, both on an objective and subjective scale (the first week of therapy - changes in indicators on the Hamilton and Beck scale are statistically insignificant, the end of the study - p<0.001 ). Despite this, the nature of changes on the Hamilton and Beck scales practically repeated the dynamics of scale indicators in other groups (Fig. 3). According to the Hamilton scale, in the first week of therapy, a statistically significant change was observed only in relation to the symptom “decreased performance” (p<0.05). It is interesting to note that the symptom “depressive mood” was no less pronounced here than in other groups (F34 - 3.1±0.2, F33 - 3.0±0.1, F32 - 3.0±0.1, F31 – 3.3±0.2) and responded to therapy more slowly. By the end of the study, in this group there was not a single average Hamilton scale score that exceeded 1, that is, all symptoms without exception underwent reverse development.

Summarizing the above, it can be noted that, regardless of the form of affective disorder, the nature of changes in the Hamilton and Beck indices during mirtazapine therapy was the same. In all groups, the dynamics of improvement on the Hamilton scale was faster and more pronounced than on the Beck scale. In other words, the Hamilton scale turned out to be more sensitive to changes in the condition of patients than the Beck scale, which is fully consistent with the literature data [6]. However, the Beck scale also well reflected the improvement in the patients’ condition, which complemented the clinical impression. At the end of the study, there were no differences in individual symptoms recorded by the Hamilton scale. However, a significant difference was found in the set of most quickly responsive symptoms in groups with different types of disease. It is interesting that in three out of four groups the symptom “depressive mood” was statistically significantly reduced already in the first week of therapy, while in none of the groups by this time was there a reduction in feelings of guilt, a symptom that, together with a depressed mood, forms the core of depression . In two of the four groups, a rapid increase in the performance of patients was noted, and in the group of patients with dysthymia this symptom was the only one that responded to treatment in the first week; in patients with bipolar and monopolar disease, on the contrary, this symptom responded later and persisted at the end of the study.

Dynamics of the condition of patients with moderate and severe depression

Among practitioners, based on everyday clinical experience, an opinion has formed that there is a difference in the nature of the response to therapy of patients with severe and milder depression. In some cases, severe depression is associated with resistant depression. It is assumed that for the treatment of patients with such severity of the disease it is necessary to use drugs with a less selective neurochemical effect (mainly tricyclic antidepressants), doses of antidepressants should be higher, and preference should be given to intramuscular and intravenous forms. In this regard, it was especially interesting to compare the dynamics of therapeutic response rates in patients with severe and moderate depression. It was found that according to the Hamilton and Beck scales, in both groups of patients, statistically significant changes occurred already in the first week of treatment and continued to increase thereafter (Fig. 4). In the first week of therapy, changes on the Hamilton scale in the group of patients with severe depression were even slightly greater than in the group with moderate depression (the percentage of changes was 39.9% versus 37.3%, the difference did not reach the level of statistical significance). In the next therapeutic period, the dynamics were reversed: by the end of the study, the percentage of changes in the first group was 27.5%, and in the second - 35.9% (p<0.05). In other words, patients with severe depression responded more quickly to therapy, but this rate subsequently decreased, while the improvement of patients with moderate depression was more uniform. According to the Beck scale, the situation looked different: the percentage of improvement in patients with severe depression was slightly greater throughout the study than in patients with milder depression (in patients of the first group, the percentage of improvement was 17.8% in the first week and 28.9% in the second week, in patients of the second group - 14.3% and 25.3%, respectively, but the difference did not reach the level of statistical significance). That is, there was a tendency for patients with severe depression to perceive the improvement in their condition more vividly than patients with moderate depression. It should be noted that, despite the absence of restrictions on the dosage of the drug, both in the first and in the other group of patients, the doses were the same and amounted to 30 mg. Thus, in some respects, the response to therapy in patients with severe depression was even more pronounced; the oral form of the drug was not an obstacle to obtaining a high therapeutic effect in patients with severe depression; the dose of the drug did not change depending on the severity of the condition.

Side effects

Side effects were observed in a small number of patients and were mild. The most common side effects were dry mouth (6 cases), drowsiness (2 cases), hypotension (2 cases). In isolated cases, the following were observed: a feeling of weakness, insomnia, anxiety and inversion of affect. Increased appetite and weight gain, known to be the most common side effects of mirtazapine therapy (7), were not listed as side effects in this study, although the Hamilton scale items showed changes in these symptoms.

Conclusion

Analysis of the results of the study allows us to draw two blocks of conclusions. The first concerns the technique of conducting this unusual study, the second concerns its results.

1. Results based on data obtained by practitioners rather than researchers are essentially the same as results based on data obtained under the special conditions of controlled studies:

• Not only the objective Hamilton scale, but also the Beck self-rating scale were sensitive to changes that occurred during mirtazapine therapy.

• The Beck Scale has been successfully used in patients with severe depression, although according to some authors, the severity of depression limits the use of this tool [4].

2. The study showed that mirtazapine was an effective antidepressant for various forms of mood disorder:

• the general nature of the dynamics of the therapeutic response was similar in patients with different types of course, but the immediate response (the first week of therapy) was significantly different, revealing the most “sensitive” signs to mirtazapine in patients with different types of affective disorder.

• Mirtazapine was found to be equally effective as an antidepressant for severe and moderate depression (5).

• greater severity of depressive disorders did not require an increase in dose.

The list of references can be found on the website https://www.rmj.ru

Mirtazapine –

Remeron (trade name)

(Organon)
Literature
1. Mosolov S.N., Kostyukova E.G., Serditov O.V. et al. Clinical efficacy and tolerability of the new antidepressant mirtazapine (Remeron) in severe depression. Social and Clinical Psychiatry, 1, 2000, pp. 55-60.

2. Kolyutskaya E.V., Yastrebov D.V. Use of mirtazapine in the treatment of depression. Russian medical journal N19, vol. 2, N2-3, 1999, pp. 50-52

3. Hamilton M. Development of a rating scale for primary depressive illness. Brit.J, of Soc.Clin.Psychol., 1967; 6: 278-296.

4. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961; 4: 561-571

5. Gorman JM. Mirtazapine: clinical overview Journ Clin Psychiatry 1999;60 (suppl 17),pp9-13

6. Moller HJ, von Zerssen D. Self-ration procedures in the evaluation of antidepressants. Psychopathology 1995; 28: 291-306

7. Guelfi JD, Ansseau M, Timmerman L et al. Efficacy and tolerability of mirtazapine vs venlafaxine in hospitalized, severely depressed patients with melancholia. Abstracts ECNP, Brussels, 2000.