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Stopping antidepressants can cause withdrawal (discontinuation) symptoms, the return of the original illness, and rebound. The latter means that the disease will return stronger, faster, or with greater likelihood than if it had not been treated with medication. The Psychiatry Working Group of the Drug Commission of the German Medical Association (Akda) presents the scientific findings and provides practical recommendations for action. Withdrawal symptoms are multiform; unspecific physical symptoms are predominant. Distinguishing them from the recurrence of depressive symptoms can be difficult. Most of them are mild and self-limiting. There is insufficient evidence on the extent and frequency of rebound depression. The rebound risk implies that when establishing the medication, the short-term benefit must be weighed against the possible long-term risk of chronic depression or the possible need for long-term medication. Patients should be informed about the risk of withdrawal both as early as the joint decision-making process about treatment initiation and regularly during the course of treatment. Withdrawal should take place gradually, except in emergency situations, whereby small steps should be taken, especially in the low-dose range.

Background German S3 guidelines are subject to the highest methodological standards. This includes that they are only valid for a certain time period. Following the first edition in 2012 the first update of the S3 guidelines on bipolar disorder has now been published (2019). Objective What has changed in the field of pharmacological recommendations comparing the first edition with the update in 2019? Material and methods Comparison of the 1st edition from 2012 with the update from 2019 of the S3 guidelines for the diagnostics and treatment of bipolar disorders. Results The three principle treatment targets of acute treatment of bipolar depression, acute treatment of mania and phase prophylaxis (maintenance treatment) can be distinguished. For acute treatment of bipolar depression, for the first time a medication has received a level A recommendation: quetiapine. For the acute treatment of mania, several drugs are still recommended with the same level of recommendation (B). Asenapine has been added as the tenth substance. Lithium is still the only drug with a level A recommendation for maintenance and prophylactic treatment and is also the only drug approved for this indication without restrictions. A new recommendation is that in the absence of contraindications, phase prophylaxis with a serum level of at least 0.6x202f;mmol/l should be carried out. With a B recommendation, quetiapine has been added to the drugs for phase prophylactic treatment. Conclusion The S3 guidelines make recommendations at the highest scientific level. In view of these findings, lithium is clearly underutilized for maintenance therapy. In the absence of clear contraindications (advanced renal insufficiency), every patient with bipolar disease should be given the chance of lithium prophylaxis for an adequately long period.

Objective Recent meta-analyses on dose-response relationships of SSRIs are largely based on indirect evidence. We analyzed RCTs directly comparing different SSRI doses. Method Systematic literature search for RCTs. Two raters independently screened articles and extracted data. Across SSRIs, doses defined as low, medium, and high doses, based on drug manufacturers' product monographs, were analyzed in pairwise random-effects meta-analyses and in a sensitivity network meta-analysis with regard to differences in antidepressive efficacy (primary outcome). We also analyzed all direct comparisons of different dosages of specific SSRIs. (Prospero CRD42018081031). Results Out of 5333 articles screened, we included 33. Comparisons of dosage groups (low, medium, and high) resulted in only small and clinically non-significant differences for SSRIs as a group, the strongest relating to medium vs low doses (SMD: -0.15 [95%-CI: -0.28; -0.01) and not sustained in a sensitivity analysis. Among different doses of specific SSRIs, no statistically significant trend emerged for efficacy at higher doses, but 60 mg/day fluoxetine are statistically significantly inferior to 20 mg/day. Paroxetine results are inconclusive: 10 mg/day are inferior to higher doses, but 30 and 40 mg/day are inferior to 20 mg/day. Meaningful effects cannot be ruled out for certain drugs and dosages, often investigated in only one trial. Dropout rates increase with dose-particularly due to side effects. Network meta-analyses supported our findings. Conclusions There is no conclusive level I or level II evidence of a clinically meaningful dose-response relationship of SSRIs as a group or of single substances. High SSRI doses are not recommended as routine treatment.

Background German S3 guidelines are subject to the highest methodological standards. This includes that they are only valid for a certain time period. Following the first edition in 2012 the first update of the S3 guidelines on bipolar disorder has now been published (2019). Objective What has changed in the field of pharmacological recommendations comparing the first edition with the update in 2019? Material and methods Comparison of the 1st edition from 2012 with the update from 2019 of the S3 guidelines for the diagnostics and treatment of bipolar disorders. Results The three principle treatment targets of acute treatment of bipolar depression, acute treatment of mania and phase prophylaxis (maintenance treatment) can be distinguished. For acute treatment of bipolar depression, for the first time a medication has received a level A recommendation: quetiapine. For the acute treatment of mania, several drugs are still recommended with the same level of recommendation (B). Asenapine has been added as the tenth substance. Lithium is still the only drug with a level A recommendation for maintenance and prophylactic treatment and is also the only drug approved for this indication without restrictions. A new recommendation is that in the absence of contraindications, phase prophylaxis with a serum level of at least 0.6x202f;mmol/l should be carried out. With a B recommendation, quetiapine has been added to the drugs for phase prophylactic treatment. Conclusion The S3 guidelines make recommendations at the highest scientific level. In view of these findings, lithium is clearly underutilized for maintenance therapy. In the absence of clear contraindications (advanced renal insufficiency), every patient with bipolar disease should be given the chance of lithium prophylaxis for an adequately long period.

Objective Recent meta-analyses on dose-response relationships of SSRIs are largely based on indirect evidence. We analyzed RCTs directly comparing different SSRI doses. Method Systematic literature search for RCTs. Two raters independently screened articles and extracted data. Across SSRIs, doses defined as low, medium, and high doses, based on drug manufacturers' product monographs, were analyzed in pairwise random-effects meta-analyses and in a sensitivity network meta-analysis with regard to differences in antidepressive efficacy (primary outcome). We also analyzed all direct comparisons of different dosages of specific SSRIs. (Prospero CRD42018081031). Results Out of 5333 articles screened, we included 33. Comparisons of dosage groups (low, medium, and high) resulted in only small and clinically non-significant differences for SSRIs as a group, the strongest relating to medium vs low doses (SMD: -0.15 [95%-CI: -0.28; -0.01) and not sustained in a sensitivity analysis. Among different doses of specific SSRIs, no statistically significant trend emerged for efficacy at higher doses, but 60 mg/day fluoxetine are statistically significantly inferior to 20 mg/day. Paroxetine results are inconclusive: 10 mg/day are inferior to higher doses, but 30 and 40 mg/day are inferior to 20 mg/day. Meaningful effects cannot be ruled out for certain drugs and dosages, often investigated in only one trial. Dropout rates increase with dose-particularly due to side effects. Network meta-analyses supported our findings. Conclusions There is no conclusive level I or level II evidence of a clinically meaningful dose-response relationship of SSRIs as a group or of single substances. High SSRI doses are not recommended as routine treatment.

ObjectiveTo evaluate the efficacy and tolerability of baclofen vs. placebo for long-term treatment of alcohol use disorder. MethodSystematic review and meta-analysis following methods of the Cochrane Collaboration Handbook (PROSPERO registration: CRD42017073663). Primary outcome was the random-effects summary estimate of all standardized mean differences (SMDs), as calculated from the primary outcomes of each study. ResultsFourteen double-blind RCTs (1522 patients) were included. Heterogeneity was substantial for most analyses (I-2 about 75%). Baclofen showed a small, but not statistically significant superiority over placebo: SMD=0.22 ([95% CI: -0.03; 0.47], P=0.09). This result was supported by a leave-one-out-analysis, and Orwin's fail-safe N, by predefined secondary analyses (on abstinence rates and amount of drinking), and by a post hoc-analysis of high-dose studies (>80mg/day). An analysis of low risk of bias studies (SMD=0.10 [-0.20; 0.41], P=0.51, I-2=43.3%) found no effect. Exclusion of four studies focusing on patients with comorbidity yielded a small positive effect. Drop-out rates were similar. ConclusionOur results question baclofen's utility in the long-term treatment of alcohol use disorder at both normal and high doses. While the confidence intervals indicate that marginally harmful or moderately beneficial effects of baclofen remain a possibility, the most likely effect size is slightly above placebo effects.

ObjectiveTo evaluate the efficacy and tolerability of baclofen vs. placebo for long-term treatment of alcohol use disorder. MethodSystematic review and meta-analysis following methods of the Cochrane Collaboration Handbook (PROSPERO registration: CRD42017073663). Primary outcome was the random-effects summary estimate of all standardized mean differences (SMDs), as calculated from the primary outcomes of each study. ResultsFourteen double-blind RCTs (1522 patients) were included. Heterogeneity was substantial for most analyses (I-2 about 75%). Baclofen showed a small, but not statistically significant superiority over placebo: SMD=0.22 ([95% CI: -0.03; 0.47], P=0.09). This result was supported by a leave-one-out-analysis, and Orwin's fail-safe N, by predefined secondary analyses (on abstinence rates and amount of drinking), and by a post hoc-analysis of high-dose studies (>80mg/day). An analysis of low risk of bias studies (SMD=0.10 [-0.20; 0.41], P=0.51, I-2=43.3%) found no effect. Exclusion of four studies focusing on patients with comorbidity yielded a small positive effect. Drop-out rates were similar. ConclusionOur results question baclofen's utility in the long-term treatment of alcohol use disorder at both normal and high doses. While the confidence intervals indicate that marginally harmful or moderately beneficial effects of baclofen remain a possibility, the most likely effect size is slightly above placebo effects.

In clinical practice, there is a need for a more individualized selection of antidepressants and adequate dosage. The investigation of pharmacokinetically relevant genes is a promising approach to assist this selection. In the past 2 years, two commercially available tests have been subject of advertisement, a test from Stada, which analyses variants of the cytochrome P450 isoenzymes CYP2D6 and CYP2C19 and a test from HMNC Brain Health, which analyses variants of the ABCB1 gene. The costs for both kits are not covered by the statutory health insurance and it is therefore proposed that the patients are invoiced directly in the form of individual healthcare payment. The companies claim that by applying the tests antidepressant treatment failure can be avoided and that patients will respond faster to the antidepressant used. These claims are not based on appropriate clinical trials, which are either lacking or reveal conflicting results. Hence, the routine use of these tests is not recommended. In accordance with the German S3 Guideline for unipolar depression, therapeutic drug monitoring (TDM) of serum levels should be carried out in cases of non-response to an antidepressant with adequate dosage and duration. As a rule the costs for TDM are covered by the statutory health insurance. Cytochrome P450 genotyping is only indicated when the serum level is not within the expected range and other reasons to explain this discrepancy are excluded. Many laboratories provide these analyses and in individual cases the costs are reimbursed by the statutory health insurance. Further research should be carried out to investigate the importance of the ABCB1 gene for the treatment with antidepressants.

In clinical practice, there is a need for a more individualized selection of antidepressants and adequate dosage. The investigation of pharmacokinetically relevant genes is a promising approach to assist this selection. In the past 2 years, two commercially available tests have been subject of advertisement, a test from Stada, which analyses variants of the cytochrome P450 isoenzymes CYP2D6 and CYP2C19 and a test from HMNC Brain Health, which analyses variants of the ABCB1 gene. The costs for both kits are not covered by the statutory health insurance and it is therefore proposed that the patients are invoiced directly in the form of individual healthcare payment. The companies claim that by applying the tests antidepressant treatment failure can be avoided and that patients will respond faster to the antidepressant used. These claims are not based on appropriate clinical trials, which are either lacking or reveal conflicting results. Hence, the routine use of these tests is not recommended. In accordance with the German S3 Guideline for unipolar depression, therapeutic drug monitoring (TDM) of serum levels should be carried out in cases of non-response to an antidepressant with adequate dosage and duration. As a rule the costs for TDM are covered by the statutory health insurance. Cytochrome P450 genotyping is only indicated when the serum level is not within the expected range and other reasons to explain this discrepancy are excluded. Many laboratories provide these analyses and in individual cases the costs are reimbursed by the statutory health insurance. Further research should be carried out to investigate the importance of the ABCB1 gene for the treatment with antidepressants.

Objectives. This 2013 update of the practice guidelines for the biological treatment of unipolar depressive disorders was developed by an international Task Force of the World Federation of Societies of Biological Psychiatry (WFSBP). The goal has been to systematically review all available evidence pertaining to the treatment of unipolar depressive disorders, and to produce a series of practice recommendations that are clinically and scientifically meaningful based on the available evidence. The guidelines are intended for use by all physicians seeing and treating patients with these conditions. Methods. The 2013 update was conducted by a systematic update literature search and appraisal. All recommendations were approved by the Guidelines Task Force. Results. This first part of the guidelines (Part 1) covers disease definition, classification, epidemiology, and course of unipolar depressive disorders, as well as the management of the acute and continuation phase treatment. It is primarily concerned with the biological treatment (including antidepressants, other psychopharmacological medications, electroconvulsive therapy, light therapy, adjunctive and novel therapeutic strategies) of adults. Conclusions. To date, there is a variety of evidence-based antidepressant treatment options available. Nevertheless there is still a substantial proportion of patients not achieving full remission. In addition, somatic and psychiatric comorbidities and other special circumstances need to be more thoroughly investigated. Therefore, further high-quality informative randomized controlled trials are urgently needed. © 2013 Informa Healthcare.

Objective: Alcohol-dependent patients in early abstinence show an impairment of cognitive functions which can be seen in poor implement atio n of newly learned skills for avoiding relapse. Executive dysfunction may persist during abstinence in alcohol-dependent persons, thus mitigating long-term abstinence. This study assessed visual memory function and choice of organizational strategies in alcoholics, as these are major factors necessary to implement ongoing behavior changes which are required for maintaining abstinence.Methods: We investigated 25 severely alcohol-dependent male patients between days 7 to 10 of abstinence, immediately after clinical withdrawal symptoms have ceased, compared to 15 healthy age, sex, and education matched controls. Pharmacological therapy had been terminated at least four half-lifes before inclusion into the study. Visual perceptual learning and organizational strategies were assessed with the Rey-O ster rieth Complex Figure Test (R-OCF).Results: There were no group differences in copying or recalling the figure, but time differences occurred. Alcoholics and healthy controls performed worse in recalling than in copying. But, alcoholics used less effective organizational strategies.Conclusions: There was a deficit in choice of organizational strategy in newly abstinent and unmedicated alcohol-dependent patients. Due to the imperfect organizational strategies, alcoholics might need auxiliary therapeutic care to strengthen their cognitive ability., Hintergrund: Alkoholabhängige Patienten in der frühen Abstinenzphase zeigen Einbußen in ihren kognitiven Funktionen, welche in der geringen Anwendung neu erlernter Fertigkeiten deutlich werden, um einen Rückfall zu verhindern. Exekutive Dysfunktionen können bei Alkoholikern in dieser Phase der Abstinenz überdauern und somit eine Langzeit-A bsti nenz beeinträchtigen. Die vorliegende Studie erfasst visuelle Gedächtnisfunktionen und die Wahl der Organisationsstrategie bei Alkoholikern. Diese Faktoren sind bei der Anwendung neu erlernter Verhaltensweisen notwendig, um die erlangte Abstinenz aufrecht zu erhalten. Methoden: Wir verglichen 25 alkoholabhängige männliche Patienten zwischen dem 7. und 10. Tag der Abstinenz, direkt nachdem die klinischen Entzugssymptome aufhörten, mit einer gesunden für Alter, Geschlecht und Bildung abgeglichenen Kontrollgruppe (n=15). Eine Pharmakotherapie wurde mindestens vier Halbwertszeiten vor Einschluss in die Studie beendet. Visuelles Wahrnehmungslernen und Organisationsstrategien wurden mit dem Rey-Osterrieth Complex Figure Test (R-OCF) erhoben.Ergebnisse: Es wurden keine Gruppenunterschiede in der visuellen Gedächtnisleistung und der Wahl der Organisationsstruktur bei abstinenten, unmedizierten alkoholabhängigen Patienten im Vergleich zu gesunden Kontrollpersonen gefunden. Beide Gruppen erreichten weniger gute Werte in der Reproduktions-Aufgabe als in der Kopier-Aufgabe. Jedoch zeigten abstinente Alkoholiker weniger effektive Organisationss trate gien als gesunde Kontrollpersonen. Schlussfolgerung: Es bestand ein Defizit in der Wahl der Organisationss trateg ie bei abstinenten, unmedizierten Alkoholikern. Aufgrund der weniger effektiven Organisationsstrategien könnten Alkoholiker von einem zusätzlichen therapeutischen Angebot profitieren, um ihre kognitiven Fertigkeiten zu stärken.

Im Bereich der medikamentösen antidepressiven Therapie ist die Bedeutung von erblichen Polymorphismen arzneistoffmetabolisierender Enzyme bereits in vielen Studien untersucht und gezeigt worden. Die meisten Antidepressiva werden über polymorphe Cytochrom-P450-Enzyme verstoffwechselt. Diese Arbeit befasst sich mit der Fragestellung, ob die Häufigkeitsverteilung der CYP2D6-, CYP2C19- und CYP2C9-Allele in der an Depression erkrankten Studienpopulation sich von der in der Normalbevölkerung unterscheidet und ob Veränderungen in der Pharmakokinetik, wie sie durch Cytochrom-P450-Polymorphismen verursacht werden, unter normalen klinischen Bedingungen Auswirkungen auf die Wirksamkeit der antidepressiven Therapie, die Nebenwirkungsrate und den Verlauf der Erkrankung haben. Im Rahmen dieser Arbeit wurden 334 Patienten auf die häufigsten CYP2D6-Allele (*3,*4,*5,*6 und Duplikation) und CYP2C19- und CYP2C9-Allele *2 und *3 mittels Genotypisierung untersucht. Die Bestimmung der seltener auftretender CYP2D6-Allele (*8,*9,*10,*17,*2 und *41) erfolgte zusätzlich bei 200 Patienten. Die entsprechenden klinischen Fragebögen mit Angaben zur Anamnese, Schwere der Erkrankung, Therapieverlauf und Nebenwirkungsprofil wurden von 233 Patienten in Abhängigkeit des CYP2D6- und CYP2C19-Genotyps ausgewertet. Für die Beurteilung des Langzeittherapieverlaufs standen jedoch deutlich weniger Patientendaten zur Verfügung, so dass die Ergebnisse zum Teil nur für den CYPD6-Genotyp ausgewertet werden konnten. Die genetischen Analysen ergaben, dass die Häufigkeitsverteilung der CYP2D6-, CYP2C19- und CYP2C9-Polymorphismen in der untersuchten Studienpopulation keine signifikante Änderung im Vergleich zur Normalbevölkerung aufwies. Während der Einfluss der CYP2D6-Genotypen auf pharmakokinetische Parameter eindeutig nachgewiesen ist, konnten die Ergebnisse dieser Arbeit weitestgehend keinen Zusammenhang zwischen der Schwere der Depression, der Therapieresponse, der Häufigkeit und Schwere der Nebenwirkungen und, The importance of genetic polymorphisms of drug metablizing enzymes have been already investigated und proved in many studies before. Most of antidepressants are metabolized by cytochrome P450 enzymes. The aim of this study was to determine if there is a difference in the distribution of CYP2D6-, CYP2C19- and CYP2C9-allels in inpatients with major depression in comparison to the healthy population and if changes in the pharmacokinatic, created by cytochrome P450 polymorphisms, can be have effects on the efficacy of antidepressant therapy, rate of intolerable side effects and development of the depression. We examined 334 patients by genotyping for the most important CYP2D6-allels (*3,*4,*6,*5 und duplication) and the CYP2C19- and CYP2C9-allels *2 and *3. Further 200 patients were tested for the more infrequent CYP2D6-allels (*8,*9,*10,*17,*2 and *41). The corresponding clinical questionnaires containing informations about the anamnesis, severity of the desease, therapeutic outcome and intolerable side effects have been evaluated of 233 patients in dependence of the CYP2D6- and CYP2C19-genotype. There were significant less clinical datas for the evaluation of long term therapy response be available, so that the results could be partially only analysed for the CYP2D6-genotype. The genetic analysis detected that the distribution of the CYP2D6-, CYP2C19- and CYP2C9-polymorphismen in the study population didn´t reached significant changes in comparison to the healthy population. While the influence of CYP2D6-genotypes on pharmacokinatic parameters is clear demonstrated, the results of this study mainly couldn´t establish a relation between the severity of depression, therapeutic response, frequency and severity of side effects and the CYP2D6 and CYP2C19-genotype.

Im Bereich der medikamentösen antidepressiven Therapie ist die Bedeutung von erblichen Polymorphismen arzneistoffmetabolisierender Enzyme bereits in vielen Studien untersucht und gezeigt worden. Die meisten Antidepressiva werden über polymorphe Cytochrom-P450-Enzyme verstoffwechselt. Diese Arbeit befasst sich mit der Fragestellung, ob die Häufigkeitsverteilung der CYP2D6-, CYP2C19- und CYP2C9-Allele in der an Depression erkrankten Studienpopulation sich von der in der Normalbevölkerung unterscheidet und ob Veränderungen in der Pharmakokinetik, wie sie durch Cytochrom-P450-Polymorphismen verursacht werden, unter normalen klinischen Bedingungen Auswirkungen auf die Wirksamkeit der antidepressiven Therapie, die Nebenwirkungsrate und den Verlauf der Erkrankung haben. Im Rahmen dieser Arbeit wurden 334 Patienten auf die häufigsten CYP2D6-Allele (*3,*4,*5,*6 und Duplikation) und CYP2C19- und CYP2C9-Allele *2 und *3 mittels Genotypisierung untersucht. Die Bestimmung der seltener auftretender CYP2D6-Allele (*8,*9,*10,*17,*2 und *41) erfolgte zusätzlich bei 200 Patienten. Die entsprechenden klinischen Fragebögen mit Angaben zur Anamnese, Schwere der Erkrankung, Therapieverlauf und Nebenwirkungsprofil wurden von 233 Patienten in Abhängigkeit des CYP2D6- und CYP2C19-Genotyps ausgewertet. Für die Beurteilung des Langzeittherapieverlaufs standen jedoch deutlich weniger Patientendaten zur Verfügung, so dass die Ergebnisse zum Teil nur für den CYPD6-Genotyp ausgewertet werden konnten. Die genetischen Analysen ergaben, dass die Häufigkeitsverteilung der CYP2D6-, CYP2C19- und CYP2C9-Polymorphismen in der untersuchten Studienpopulation keine signifikante Änderung im Vergleich zur Normalbevölkerung aufwies. Während der Einfluss der CYP2D6-Genotypen auf pharmakokinetische Parameter eindeutig nachgewiesen ist, konnten die Ergebnisse dieser Arbeit weitestgehend keinen Zusammenhang zwischen der Schwere der Depression, der Therapieresponse, der Häufigkeit und Schwere der Nebenwirkungen und, The importance of genetic polymorphisms of drug metablizing enzymes have been already investigated und proved in many studies before. Most of antidepressants are metabolized by cytochrome P450 enzymes. The aim of this study was to determine if there is a difference in the distribution of CYP2D6-, CYP2C19- and CYP2C9-allels in inpatients with major depression in comparison to the healthy population and if changes in the pharmacokinatic, created by cytochrome P450 polymorphisms, can be have effects on the efficacy of antidepressant therapy, rate of intolerable side effects and development of the depression. We examined 334 patients by genotyping for the most important CYP2D6-allels (*3,*4,*6,*5 und duplication) and the CYP2C19- and CYP2C9-allels *2 and *3. Further 200 patients were tested for the more infrequent CYP2D6-allels (*8,*9,*10,*17,*2 and *41). The corresponding clinical questionnaires containing informations about the anamnesis, severity of the desease, therapeutic outcome and intolerable side effects have been evaluated of 233 patients in dependence of the CYP2D6- and CYP2C19-genotype. There were significant less clinical datas for the evaluation of long term therapy response be available, so that the results could be partially only analysed for the CYP2D6-genotype. The genetic analysis detected that the distribution of the CYP2D6-, CYP2C19- and CYP2C9-polymorphismen in the study population didn´t reached significant changes in comparison to the healthy population. While the influence of CYP2D6-genotypes on pharmacokinatic parameters is clear demonstrated, the results of this study mainly couldn´t establish a relation between the severity of depression, therapeutic response, frequency and severity of side effects and the CYP2D6 and CYP2C19-genotype.