[Stopping antidepressants: withdrawal symptoms and rebound effects : Review and practical recommendations]. / Absetzen von Antidepressiva ­ Absetzsymptome und Rebound-Effekte : Übersicht und praktische Empfehlungen.

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 (AkdÄ) 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.

In search of a dose-response relationship in SSRIs-a systematic review, meta-analysis, and network meta-analysis.

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.

[German S3 guidelines on bipolar disorders-first update 2019 : What is new in pharmacotherapy?] / S3-Leitlinie Bipolare Störungen ­ 1. Update 2019 : Was ist neu in der Pharmakotherapie?

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 0.6 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.

[A review of the update of the German S3-guideline on diagnostics and therapy of bipolar disorders 2019]. / Überblick über Neuerungen der überarbeiteten und aktualisierten Leitlinie zur Diagnostik und Therapie bipolarer Störungen 2019.

Since the first publication of the guideline in 2012, which included critically reviewed evidence up to 2010, several hundred articles with new evidence were published and some topics of the clinical consensus needed to be reconsidered. Therefore, it was urgently necessary to revise the guideline to bring them up to date. In this article important revisions and updates are presented and the chances and limitations of the development of the guidelines and their implementation are discussed.

Baclofen for alcohol use disorder-a systematic meta-analysis.

OBJECTIVE: To evaluate the efficacy and tolerability of baclofen vs. placebo for long-term treatment of alcohol use disorder. METHOD: Systematic 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. RESULTS: Fourteen double-blind RCTs (1522 patients) were included. Heterogeneity was substantial for most analyses (I2 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 (>80 mg/day). An analysis of low risk of bias studies (SMD = 0.10 [-0.20; 0.41], P = 0.51, I2  = 43.3%) found no effect. Exclusion of four studies focusing on patients with comorbidity yielded a small positive effect. Drop-out rates were similar. CONCLUSION: Our 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.

[Psychotherapy of depressive disorders : Procedures, evidence and perspectives]. / Psychotherapie depressiver Störungen : Verfahren, Evidenz und Perspektiven.

BACKGROUND: Depressive disorders are associated with a high burden of suffering and significantly reduce the well-being and the self-esteem of affected patients. Psychotherapy is one of the main treatment options for depressive disorders. OBJECTIVE: The aim of this article is to present the current evidence for antidepressive psychotherapeutic treatments. MATERIAL AND METHODS: During the revision of the German S3- and National Disease Management Guideline (NDMG) on unipolar depression in 2015, a comprehensive and systematic evidence search was conducted. The results of this search along with a systematic update are summarized. RESULTS: The most intensively investigated psychotherapeutic method is cognitive behavioral therapy (CBT), which proved to be effective in many trials. Evidence also exists for psychodynamic psychotherapy and interpersonal therapy (IPT), followed by systemic therapy and client-centered psychotherapy; however, the evidence is less robust. CONCLUSION: Psychotherapy alone or in combination with pharmacotherapy was shown to be an effective treatment option. Psychotherapy represents a key element in the treatment of depressive disorders.

[Psychotherapy of depressive disorders: Evidence in chronic depression and comorbidities]. / Psychotherapie depressiver Störungen: Evidenz bei chronischer Depression und bei Komorbidität.

BACKGROUND: Psychotherapy has been shown to be an effective treatment option for depressive disorders; however, its effectiveness varies depending on patient and therapist characteristics and the individual form of the depressive disorder. OBJECTIVES: The aim of this article is to present the current evidence for psychotherapeutic antidepressive treatments for patients with chronic and treatment-resistant depression as well as for patients with mental and somatic comorbidities. MATERIAL AND METHODS: During the revision of the currently valid German S3- and National Disease Management Guideline (NDMG) on unipolar depression published in 2015, a comprehensive and systematic evidence search including psychotherapy for specific patient groups was conducted. The results of this search along with a systematic update are summarized. RESULTS: Psychotherapy has been shown to be effective in reducing depressive symptoms in patients suffering from chronic and treatment-resistant depression and in patients with mental and somatic comorbidities. The evidence is insufficient particularly for patients with mental comorbidities. CONCLUSION: Based on the current evidence and clinical expertise the NDMG recommends psychotherapy alone or in combination with pharmacotherapy to treat most of these depressive patient groups. Evidence gaps were identified, which highlight the need for further research.

Adverse events of group psychotherapy in the in-patient setting - results of a naturalistic trial.

OBJECTIVE: Adverse events of psychotherapy have often been neglected in research. In this study, potential adverse events of group psychotherapies in a psychiatric hospital were systematically assessed, explored for predictors and linked to treatment outcome. METHOD: A naturalistic trial was conducted in 180 in-patients attending different group psychotherapies. Adverse events were assessed using three different measures: (i) weekly reporting of unwanted treatment reactions, (ii) mood changes in response to every single group session and (iii) premature group termination. RESULTS: Different measures of adverse events were weakly associated. Deterioration of mood state and/or unwanted treatment reactions were experienced by 60-65% of all patients. Reports of unwanted treatment reactions decreased over time and were negatively associated with symptom improvement. However, mood state deterioration was constant and unrelated to treatment outcome. The rate of premature group termination was 34%. Significant predictors of adverse events included patient characteristics as well as disadvantageous group conditions. CONCLUSIONS: For the majority of patients, group psychotherapy in the in-patient setting is associated with adverse events. Changes over time and a strong correlation with general symptom severity must be considered in the assessment and interpretation of adverse events. Predictors should be considered as potential risk factors in future research.

[Genetic tests for controlling treatment with antidepressants]. / Genetische Tests zur Steuerung der Behandlung mit Antidepressiva.

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.

The challenge of treatment in bipolar depression: evidence from clinical guidelines, treatment recommendations and complex treatment situations.

Bipolar depression and its clinical presentation is a frequent but complex psychiatric disease. Despite the high prevalence and the clinical and economic relevance of bipolar depression, few treatments are proven to be highly and consistently effective. In practice, the treatment of bipolar depression typically includes complex treatment decision-making. The best evidence for a pharmacological treatment exists for quetiapine. Alternatives with limitations are lamotrigine (also in the combination with lithium), carbamazepine and olanzapine. The effectiveness and recommendation of antidepressants in the treatment of bipolar depression remains controversial. Initially, depressive episodes should been treated with one of the named substances with antidepressant properties. In non-responders, a combination of lithium and lamotrigine, or antidepressants in combination with either lithium, an antiepileptic drug or atypical antipsychotics, may be necessary. If a depressive episode occurs under ongoing mood-stabilizing treatment, combination treatments of different substances, even with antidepressants, can be necessary. In the case of treatment-resistant depressive episodes, complex treatment strategies (combination therapies, MAO inhibitors) should be considered. This review describes the treatment recommendations of different guidelines for bipolar depression and emphasizes their differences. Furthermore, alternative pharmacological treatment strategies and complex treatment situations are discussed.

[Pharmaceutical treatment of bipolar depression. Evidence from clinical guidelines and treatment recommendations]. / Pharmakologische Behandlung der bipolaren Depression. Evidenz aus klinischen Leitlinien und Behandlungsempfehlungen.

Treatment of bipolar depression requires complex treatment decisions in daily routine care. The best evidence for pharmacological treatment is given for quetiapine and with limitations also in off-label use for lamotrigine, especially in combination with lithium, carbamazepine and olanzapine. Effectiveness and recommendation of antidepressants in treatment of bipolar depression remain controversial because of insufficient data. Initially, in depressive episodes a phase prophylactic treatment should be initiated or (if already existing) optimized and more severe episodes should be treated with the substances described before. In case of non-response, the combination of lithium and lamotrigine or antidepressants in combination with lithium, antiepileptics or atypical antipsychotics may be necessary. If depressive episodes occur in the course of pharmacological treatment with prophylactic agents, combination therapies of different substances, even with antidepressants, are necessary. In case of treatment-resistant depressive episodes, complex treatment strategies (e.g. combination therapies and MAO inhibitors) should be considered.

[New facts of long-term prophylaxis for bipolar affective disorder]. / Neue Fakten zur Phasenprophylaxe der bipolar affektiven Erkrankung.

Lithium and with restrictions, carbamazepine, valproic acid, lamotrigine, olanzapine, aripiprazole and quetiapine, are approved in Germany for maintenance treatment of bipolar disorder. Lithium is the only drug that (I) proved to be effective for the prevention of depressive as well as manic episodes in state-of-the-art studies without an enriched design and that (II) is approved for the maintenance treatment of bipolar disorders without restrictions. It (III) is also the only drug which is recommended for maintenance treatment by the current German S3 guidelines on bipolar disorders with the highest degree of recommendation (A) and (IV) is the only drug with a well proven suicide preventive effect. Hence, lithium is the mood stabilizer of first choice. No patient should be deprived of lithium without a specific reason. Side effects and risks are manageable if both the physician and the patient are well informed. Detailed and practical information on a safe use of lithium can be found in the S3 guidelines on bipolar disorders. For patients who do not respond sufficiently to lithium, have contraindications or non-tolerable side effects, other mood stabilizers should be used. Restrictions in their respective approval as well as specific side effects and risks have to be taken into account. Because maintenance treatment is a long-term treatment, particular concern should be paid to drugs with the potential risk of a metabolic syndrome, particularly atypical antipsychotics.

Comparing augmentation with non-antidepressants over sticking to antidepressants after treatment failure in depression: a naturalistic study.

INTRODUCTION: Non-response to an antidepressant monotherapy in unipolar depression is quite common. Therefore strategies for subsequent treatment steps are necessary. However, there is a lack of direct comparisons of these different strategies. In this naturalistic study we compared the outcome to different strategies after failure of the primary antidepressant treatment. METHODS: Failure of primary antidepressant monotherapy occurred in 135 patients. 98 of these patients have been administered 4 treatment strategies of the physicians' choice: lithium augmentation (Li-Augm), switching to another antidepressant (AD-Switch), combination of 2 antidepressants (AD-Comb) or augmentation with second generation antipsychotic (SGA-Augm). Primary outcome measure was the 17-item Hamilton rating scale for depression (HRSD). RESULTS: Patients who received Li-Augm or augmentation with SGAs showed significantly greater improvement in HRSD and BDI compared to patients with antidepressant switch or antidepressant combination. Remission rates for Li-Augm and SGA-Augm were 89.3% and 86.2% compared to 40.7% for AD-Switch and 42.9% for AD-Comb. DISCUSSION: Changing to another pharmacological class (Li-Augm or augmentation with SGAs) showed better treatment results than sticking to the class of antidepressants (AD-Switch and AD-Comb) after primary failure in response to antidepressant monotherapy in unipolar depression. The lack of randomization and absence of a non-response definition are design flaws. Controlled studies are required to confirm the findings of this trial.

[Side effects and risk profile of lithium: critical assessment of a systematic review and meta-analysis]. / Nebenwirkungs- und Risikoprofil von Lithium : Kritische Bewertung einer systematischen Übersicht und Metaanalyse.

Lithium is the only drug that obtained the highest level of recommendation for maintenance therapy in the recent German S3 guidelines on bipolar disorders. In addition it is the only drug with proven efficacy for the prevention of manic as well as depressive episodes in studies with a non-enriched design. Therefore, it is highly welcomed that The Lancet recently published a systematic review and meta-analysis on the risks and side effects of lithium. This is the most comprehensive review on this topic so far.The glomerular filtration rate and maximum urinary concentration ability are slightly reduced under lithium. More patients suffered from renal failure compared to controls; however, renal failure remains a very rare event. The review confirmed the well known suppressive effects of lithium on the thyroid. An increase of serum calcium could be observed relatively frequently, therefore, regular control of serum calcium under lithium therapy is recommended. A relevant increase in body weight is more frequent under lithium than under placebo but less frequent than under olanzapine. No statistically significant increase could be found for hair loss, skin disorders or major congenital abnormalities.Lithium treatment is a safe therapy when clinicians follow the established recommendations. Data indicate that a risk for renal failure exists especially in patients without regular monitoring or with too high lithium serum levels. A (subclinical) hypothyroidism is not an indication to stop administration of lithium but is an indication for l-thyroxin substitution therapy. In pregnancy the risks of continuing lithium should be balanced against the risks of stopping lithium together with the patient.

[Antipsychotics for treatment of neuropsychiatric disorders in dementia]. / Antipsychotika zur Behandlung neuropsychiatrischer Störungen bei Demenz.

Antipsychotics, when used to treat neuropsychological symptoms associated with dementia, are associated with low effectiveness but a high risk of side effects. Some of these unwanted effects are severe and include an increased rate of cerebrovascular events and increased mortality. Although neuropsychiatric symptoms are frequently associated with dementia, it appears that antipsychotics are often used without clear indications and for too long time periods. Antipsychotics should be used only when all non-pharmacological strategies have failed. A clear definition of the treatment target in advance and a continuous monitoring of the therapy are mandatory.

No correlation between lithium serum levels and psychopathological features during the euthymic interval of patients with recurrent affective disorder.

INTRODUCTION: The aim of this prospective study was to investigate the influence of lithium serum levels on subclinical psychopathological features during the euthymic interval in patients with an affective disorder. METHODS: The study included 54 patients with a recurrent affective disorder undergoing a continuous prophylactic lithium treatment (31 unipolar, 23 bipolar). The observation period lasted for 2 years and included 332 visits. Visits consisted of a detailed interview, a continuous measurement of lithium levels and the collection of validated scales including HAMD, YMRS, CGI, VAMS and the SCL-90R. Several correlations between lithium serum levels and different psychopathological features during the euthymic interval were calculated on an individual patient basis and on a group basis to reveal generally occurring correlations. RESULTS: No generally occurring significant correlations between lithium serum levels and specific psychopathological features were found. Only on a single patient level, 32 significant correlations between lithium level and specific psychopathological features were found, partly indicating a negative and partly indicating a positive influence of higher lithium levels on psychopathological symptoms. Nevertheless, in the group analyses no significant correlations were found. DISCUSSION: Higher lithium levels were not associated with an improved psychopathological status, but they were not associated with a worse status (due to a higher burden of side effects) either. According to the literature there is currently no strong evidence to treat patients with a higher lithium level. It is recommended to start with a lower level and to continue with individual adjustments in accordance to prophylactic efficacy and tolerability.

[S3 guidelines on diagnostics and therapy of bipolar disorders: development process and essential recommendations]. / S3-Leitlinie zur Diagnostik und Therapie bipolarer Störungen: Entwicklungsprozess und wesentliche Empfehlungen.

Bipolar disorders are severe psychiatric disorders with extensive individual and health economic consequences. Starting in 2007 the first German evidence and consensus based guideline for diagnostics and treatment of bipolar disorders was developed which holds the potential of increasing confidence of therapists, patients and relatives in the decision-making process and improving healthcare service experiences of patients and relatives. Apart from recommendations for diagnostics and treatment the guidelines provide those for trialogue action, knowledge transfer and self-help and for strategies for healthcare provision of this complex disorder. In the present article the methodology and essential recommendations are outlined and complemented in specific topics by corresponding articles in this special issue. Due to restrictions of the length of this presentation there is the need to refer to the comprehensive version of the guidelines at several points also regarding a detailed discussion of the limitations.

No evidence for switching the antidepressant: systematic review and meta-analysis of RCTs of a common therapeutic strategy.

OBJECTIVE: Switching antidepressants is a common strategy for managing treatment-resistant depressed patients. However, no systematic reviews have been conducted to date. METHOD: We systematically searched MEDLINE/EMBASE/Cochrane Central Register of Controlled Trials and additional sources. We included double-blind studies of patients with depressive symptomatology who were not responding to initial antidepressant monotherapy and were subsequently randomized to another antidepressant or to continue the same antidepressant. Results were pooled for meta-analysis of response + remission rates using a fixed-effects model. RESULTS: A total of three studies were included. Switching to another antidepressant was not superior to continuing the initial antidepressant in any of these studies. Our meta-analysis showed no significant advantages to either strategy and no significant heterogeneity of results [OR for response rates: 0.85 (95% CI: 0.55-1.30) favoring continuing]. CONCLUSION: There is a discrepancy between the published evidence and the frequent decision to switch antidepressants, indicating an urgent need for more controlled studies. Pending such studies we recommend that physicians rely on more thoroughly evaluated strategies.