How helpful is tianeptine for bipolar
Guideline-compliant pharmacotherapy for depression
Pharmacotherapy of depression according to guidelines
In the case of depressive illnesses, antidepressants are generally effective. Due to the high proportion of placebo effects and unspecific effects as well as marginal superiority over placebo in milder depression, the general indication according to the S3 guideline unipolar depression is only given in severe depression. Almost all antidepressants work in a similar way. They increase the intrasynaptic serotonin and / or noradrenaline concentration via various mechanisms. After successful acute therapy, the obligatory transition to maintenance therapy follows for several months. If the indication is given, recurrence prophylaxis can then be carried out for several years. In the case of non-response to antidepressant monotherapy despite adequate duration and dose, various strategies can be chosen for further treatment: discontinuation, therapeutic drug monitoring, dose increase (not with SSRIs), combination of specific antidepressants, augmentation with lithium or a second-generation antipsychotic. For the success of pharmacotherapy, the procedure according to an antidepressive step-by-step plan (therapy algorithm) is of great importance.
Principally, antidepressants are effective for the treatment of depressive disorders. Due to a large extent of placebo and unspecific effects and because of an only marginal superiority over placebo in mild to moderate depressions the use of antidepressants is recommended only for the treatment of severe episodes (according to the German National S3 Guideline). Nearly all antidepressants share a similar mode of action, namely to increase the intrasynaptic concentration of serotonin and / or nor¬epinephrine. After a successful acute treatment, antidepressants should be continued for maintenance therapy for several months. If indicated, prophylactic treatment for several years can be added. In case of non-response different treatment strategies exist: stopping medication, therapeutic drug monitoring, dose increase (not with SSRI), combination of certain antidepressants, and augmentation with lithium or second generation antipsychotics. For a successful pharmacotherapy treatment should be conducted in accordance with a therapy algorithm.
Depression is common. In the EU, the one-year prevalence of depression is 6.9% of the population (1). In 15–25% of those affected, the course is chronic (i.e. longer than two years) (2), and all psychiatric interventions have a high non-responder rate (3). Since 1995 there has been a five-fold increase in the number of antidepressant prescriptions in Germany (4). H. the prevalence rates are constant (1).
Therapy for depression is based on three pillars: pharmacotherapy, psychotherapy and, in the case of chronic courses, sociotherapy. The pharmacotherapy of depression should be presented clearly in the following overview and based on the S3 guideline Unipolar Depression (5) (www.leitlinien.de/nvl/depression). The article deals exclusively with depressive episodes that occur as single episodes or in the context of a unipolar recurring course, but not with depression in the context of bipolar affective diseases (so-called bipolar depression).
A - indication
Antidepressants are effective drugs for depression. However, it has been shown consistently that 50–75% of the effect is due to placebo and unspecific effects (6). Antidepressants have no protective effect against suicide or attempted suicide (7).
The more severe the depression, the greater the superiority over placebo (8; 9). For this reason, the S3 guideline unipolar depression (5) recommends antidepressants for moderate depressive episodes as an equal alternative to psychotherapeutic treatment, while for severe depressive episodes a general recommendation is made for antidepressants (in combination with psychotherapy). For mild depressive episodes, however, antidepressants should not generally be used for initial treatment (5). In this case, the patient should be actively considered and advised on the basis of the relevant spontaneous remission rate. According to ICD-10, the severity of depressive episodes is based on the number of symptoms (Table 1).
B - choice of antidepressant
Almost all 30 antidepressants approved in Germany cause an increase in the intrasynaptic serotonin and / or noradrenaline concentration in the synaptic gap, albeit via different mechanisms. However, there are considerable doubts that this intrasynaptic influence is related to the antidepressant effect, since this theory shows various contradictions (6; 10). For example, no serotonin or norepinephrine deficit (which could be corrected by antidepressants) could be found in depressed patients. The intrasynaptic changes occur within hours of taking an antidepressant, which leaves no explanation as to why the clinical effect is delayed by several weeks. Finally, antidepressants without (bupropion) or with an opposite (tianeptine) effect on the intrasynaptic serotonin concentration have an equally strong antidepressant effect.
The approximately 30 antidepressants are also clinically similar. The onset of action is delayed by about three weeks and the response rate is only between 50 and 70%, with about half of the patients experiencing only a partial response and not a complete remission (6). However, there are clear differences in the side effect profile, so that the choice of antidepressant is largely dependent on this (11).
C - application
The pharmacological treatment of depression is divided into three treatment phases (Figure 1).
The first treatment stage of acute therapy (Figure 2) includes the start of drug treatment for depression. Any additional dosing phase that may be necessary should be kept as short as possible. The aim is to achieve the standard dose, as efficacy has been sufficiently well documented for this alone. After the standard dose has been reached, an effective latency of three to four weeks (up to six weeks in older patients) must be waited for in order to be able to assess the effectiveness of the drug on the decision day.
A dichotomous decision (addressing = response: yes / no) is required. To make this possible, it is essential to document the patient's symptoms in a suitable form before starting medication, which can be done, for example, in the form of psychopathological findings, a third-party assessment scale or a self-assessment scale. When assessing based solely on the doctor's or patient's memory, the partial improvements are easily overlooked in the frequent case that the patient has not yet achieved a full remission, but has achieved a response (example: the mood is still depressed, but the brooding has been reduced to just two hours in the morning.)
Procedure in response to the antidepressant
If the patient responds to the medication, further treatment takes place until remission and the obligatory transition to maintenance therapy for six to nine months to prevent an early relapse. The medication should be continued unchanged, also with regard to the dose.
After the maintenance therapy has ended, the question arises whether the patient should also be recommended an indefinite period of recurrence prophylaxis. This is usually carried out with the same antidepressant - provided that it is well tolerated. The indication for relapse prophylaxis depends on the individual risk of relapse, which can be estimated from the previous course. If a patient had an initial depressive phase or the previous depressive phase was many years ago, long-term psychotropic therapy is usually not indicated. If, on the other hand, the patient has already had three depressive phases in the last five years, for example, a new phase is likely soon and long-term recurrence prevention is recommended.
Procedure in the event of non-response to the antidepressant
In the event of a non-response to antidepressant monotherapy despite adequate duration and dose, there are different strategies for how to proceed (Figure 3).
a - stop pharmacotherapy
This is an important and rarely used strategy, especially with the frequent mild and moderate degrees of severity. In view of the similarity of all antidepressants (see above), non-response to an antidepressant can also be viewed as an indication of a generally poor pharmacotherapeutic treatability. Further treatment can take place through supportive discussions with a GP, daily structuring, targeted planning of positive experiences, guided self-help (books, online), sport, waking therapy (sleep deprivation therapy) or specific psychotherapy.
b - check blood levels of the antidepressant
The determination of the serum level and the subsequent dose adjustment (therapeutic drug monitoring, TDM) is useful in the case of non-response (12). The Working Group for Neuropsychopharmacology and Pharmacopsychiatry (AGNP) prepared a comprehensive overview of the therapeutic serum levels and the degree of scientific evidence (13; can also be found in the S3 guideline on Unipolar Depression). There is no reliable knowledge about the relationship between therapeutic serum levels and clinical efficacy for all antidepressants (especially not for tranylcypromine and agomelatine).
c - Dose up the antidepressant
Another option that can be considered is the addition of the previously ineffective antidepressant above the standard dose. An indication for this is for tricyclic antidepressants, venlafaxine and tranylcypromine, for which comparative studies show a better effectiveness of a higher dose. However, no dose increase is indicated for SSRIs, since comparative studies consistently show no better efficacy in high doses than in standard doses (14; 15). For this reason, the S3 guideline on unipolar depression advises against increasing the dose of SSRIs (5).
d - switch antidepressant
According to the current S3 guideline on unipolar depression, changing the antidepressant in the case of non-response is not the treatment strategy of first choice, as there is no superiority between the change and simply continuing treatment with the previously ineffective antidepressant. This has recently been confirmed by a systematic review and meta-analysis (10). A possibly observable effect does not go beyond the time savings achieved in this way. This is presumably due to the general similarity of all antidepressants discussed above, so that (in contrast to, for example, an augmentation with lithium) a new antidepressant does not establish a real new therapeutic strategy.
e - Combine two antidepressants
When combining two antidepressants, the only recommended option is to administer an α2 autoreceptor blocker such as mianserin or mirtazapine on the one hand with a reuptake inhibitor (SSRI, SNRI or TZA = NSMRI [non-selective monoamine reuptake inhibitor]) on the other. Systematic reviews and meta-analyzes have shown that this combination is superior to monotherapy (16). This empirical finding is consistent with the pharmaco-theoretical rationale, according to which an inhibition of reuptake via the increased neurotransmitter concentration via the α2 autoreceptor causes a negative feedback, which weakens the desired effect. The simultaneous administration of an α2-autoreceptor blocker then prevents the negative feedback. With combination therapy, alternating and potentiated side effects are feared. However, there was no higher drop-out rate in patients with combination therapy than with monotherapy (16).
f - augmentation
The augmentation (= reinforcement) of the antidepressant medication with lithium is of central importance in the guideline-compliant pharmacotherapy of unipolar depression, since the principle of action of lithium augmentation differs completely from the similar mechanisms of action of antidepressants (17; 18). Lithium is added in the acute treatment of depression after non-response to antidepressant monotherapy. A rather rapid increase in dosage should be aimed for in order to achieve a serum level similar to that of prophylactic treatment (0.6 to 0.9 mmol / l). This level must be maintained for at least two weeks. In response, the continuation of lithium and antidepressant for at least six months as maintenance therapy (see above) is indicated (19). A second possibility of augmentation are second-generation antipsychotics. Although four drugs (olanzapine, risperidone, aripiprazole, quetiapine) are more effective than placebo augmentation (20), only quetiapine is approved for augmentation in Germany.
D - therapy algorithm for unipolar depression
The pharmacotherapy of depression is particularly successful if it is based on a step-by-step plan (antidepressant therapy algorithm). This has been shown repeatedly by randomized studies in comparison to treatment without guidelines (21). The S3 guideline on unipolar depression provides an example based on current scientific knowledge (5) (Figure 4). The procedure according to a clear concept, an appropriate duration of the treatment stages and the systematic evaluation of the effectiveness at the end of each stage are central elements of such a stage plan (3).
conclusion for practice
- For antidepressants, a relevant superiority over placebo could only be shown for severe depressive episodes.
- After three to four weeks of antidepressant medication at the standard dose, the effectiveness must be checked.
- In the event of non-response, discontinuing the antidepressant is a rational strategy.
- Other strategies in the case of non-response include determining the serum level, increasing the dose (not with SSRIs), combining specific antidepressants or augmentation e.g. B. with lithium.
Conflicts of Interest
The authors deny any conflict of interest.
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4 Schwabe U, Paffrath D (Ed.): Drug Ordinance Report 2015. Berlin, Heidelberg: Springer-Verlag, 2015.
5 DGPPN, BÄK, KBV, AWMF, AkdÄ, BPtK, BApK, DASGHG, DEGAM, DGPM, DGPs, DGRW (ed.) For the guideline group Unipolar Depression: S3 Guideline / National Care Guideline Unipolar Depression - long version. 2nd edition, version 5. 2015 [cited: 2018-06-13]. DOI: 10.6101 / AZQ / 000364. www.depression.versorgungsleitlinien.de.
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7 Bschor T, Müller-Oerlinghausen, B: Antidepressants do not reduce the risk of suicides or suicide attempts in depressed patients. A response to the press release of the German Society for Psychiatry, Psychotherapy, Psychosomatics and Neurology (DGPPN). Drug Ordinance in Practice (AVP), 2014, 41: 2-5.
8 Kirsch I, Deacon BJ, Huedo-Medina TB et al .: Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration. PLoS Med 2008; 5: e45.
9 Fournier JC, DeRubeis RJ, Hollon SD et al .: Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA 2010; 303: 47-53.
10 Bschor T, Kern H, Henssler J, Baethge C: Switching the antidepressant after nonresponse in adults with major depression: a systematic literature search and meta-analysis. J Clin Psychi-atry 2016; 79: 16r10749.
11 Bschor, T, Adli, M: Therapy of depressive illnesses. CME certified training. Dtsch Arztebl 2008, 105: 782-792.
12 Busche, M, Bschor, T: Guideline-compliant pharmacotherapy for therapy-resistant depression. DNP 2017, 18 (5): 36-43.
13 Hiemke C, Baumann P, Bergemann N et al .: AGNP consensus guidelines for therapeutic drug monitoring in psychiatry: update 2011. Pharmacopsychiatry 2011; 44: 195-235.
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16 Henssler J, Bschor T, Baethge C: Combining antidepressants in acute treatment of depression: a meta-analysis of 38 studies including 4511 patients. Can J Psychiatry 2016; 61: 29-43.
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21 Adli M, Berghofer A, Linden M et al .: Effectiveness and feasibility of a standardized stepwise drug treatment regimen algorithm for inpatients with depressive disorders: results of a 2-year observational algorithm study. J Clin Psychiatry 2002; 63: 782-790.
The article relates to antidepressant therapy in adults and does not apply to children and adolescents.
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