Incidence of antidepressant discontinuation symptoms: a systematic review and meta-analysis.

BACKGROUND: Antidepressant discontinuation symptoms are becoming an increasingly important part of clinical practice, but the incidence of antidepressant discontinuation symptoms has not been quantified. An estimate of antidepressant discontinuation symptoms incidence could inform patients and clinicians in the discontinuation of treatment, and provide useful information to researchers in antidepressant treatments. We aimed to assess the incidence of antidepressant discontinuation symptoms in patients discontinuing both antidepressants and placebo in the published literature. METHODS: We systematically searched Medline, EMBASE, and CENTRAL from database inception until Oct 13, 2022 for randomised controlled trials (RCTs), other controlled trials, and observational studies assessing the incidence of antidepressant discontinuation symptoms. To be included, studies must have investigated cessation or tapering of an established antidepressant drug (excluding antipsychotics, lithium, or thyroxine) or placebo in participants with any mental, behavioural, or neurodevelopmental disorder. We excluded studies in neonates, and those using antidepressants for physical conditions such as pain syndromes due to organic disease. After study selection, summary data extraction, and risk of bias evaluation, data were pooled in random-effects meta-analyses. The main outcome was the incidence of antidepressant discontinuation symptoms after discontinuation of antidepressants or placebo. We also analysed the incidence of severe discontinuation symptoms. Sensitivity and meta-regression analyses tested a selection of methodological variables. FINDINGS: From 6095 articles screened, 79 studies (44 RCTs and 35 observational studies) covering 21 002 patients were selected (72% female, 28% male, mean age 45 years [range 19·6-64·5]). Data on ethnicity were not consistently reported. 16 532 patients discontinued from an antidepressant, and 4470 patients discontinued from placebo. Incidence of at least one antidepressant discontinuation symptom was 0·31 (95% CI 0·27-0·35) in 62 study groups after discontinuation of antidepressants, and 0·17 (0·14-0·21) in 22 study groups after discontinuation of placebo. Between antidepressant and placebo groups of included RCTs, the summary difference in incidence was 0·08 [0·04-0·12]. The incidence of severe antidepressant discontinuation symptoms after discontinuation of an antidepressant was 0·028 (0·014-0·057) compared with 0·006 (0·002-0·013) after discontinuation of placebo. Desvenlafaxine, venlafaxine, imipramine, and escitalopram were associated with higher frequencies of discontinuation symptoms, and imipramine, paroxetine, and either desvenlafaxine or venlafaxine were associated with a higher severity of symptoms. Heterogeneity of results was substantial. INTERPRETATION: Considering non-specific effects, as evidenced in placebo groups, the incidence of antidepressant discontinuation symptoms is approximately 15%, affecting one in six to seven patients who discontinue their medication. Subgroup analyses and heterogeneity figures point to factors not accounted for by diagnosis, medication, or trial-related characteristics, and might indicate subjective factors on the part of investigators, patients, or both. Residual or re-emerging psychopathology needs to be considered when interpreting the results, but our findings can inform clinicians and patients about the probable extent of antidepressant discontinuation symptoms without causing undue alarm. FUNDING: None.

Differential Outcomes of Placebo Treatment Across 9 Psychiatric Disorders: A Systematic Review and Meta-Analysis.

Importance: Placebo is the only substance systematically evaluated across common psychiatric diagnoses, but comprehensive cross-diagnostic comparisons are lacking. Objective: To compare changes in placebo groups in recent high-quality randomized clinical trials (RCTs) across a broad spectrum of psychiatric disorders in adult patients. Data Sources: MEDLINE and the Cochrane Database of Systematic Reviews were systematically searched in March 2022 for the latest systematic reviews meeting predetermined high-quality criteria for 9 major psychiatric diagnoses. Study Selection: Using these reviews, the top 10 highest-quality (ie, lowest risk of bias, according to the Cochrane Risk of Bias tool) and most recent placebo-controlled RCTs per diagnosis (totaling 90 RCTs) were selected, adhering to predetermined inclusion and exclusion criteria. Data Extraction and Synthesis: Following the Cochrane Handbook, 2 authors independently carried out the study search, selection, and data extraction. Cross-diagnosis comparisons were based on standardized pre-post effect sizes (mean change divided by its SD) for each placebo group. This study is reported following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline. Main Outcome and Measure: The primary outcome, pooled pre-post placebo effect sizes (dav) with 95% CIs per diagnosis, was determined using random-effects meta-analyses. A Q test assessed statistical significance of differences across diagnoses. Heterogeneity and small-study effects were evaluated as appropriate. Results: A total of 90 RCTs with 9985 placebo-treated participants were included. Symptom severity improved with placebo in all diagnoses. Pooled pre-post placebo effect sizes differed across diagnoses (Q = 88.5; df = 8; P < .001), with major depressive disorder (dav = 1.40; 95% CI, 1.24-1.56) and generalized anxiety disorder (dav = 1.23; 95% CI, 1.06-1.41) exhibiting the largest dav. Panic disorder, attention-deficit/hyperactivity disorder, posttraumatic stress disorder, social phobia, and mania showed dav between 0.68 and 0.92, followed by OCD (dav = 0.65; 95% CI, 0.51-0.78) and schizophrenia (dav = 0.59; 95% CI, 0.41-0.76). Conclusion and Relevance: This systematic review and meta-analysis found that symptom improvement with placebo treatment was substantial in all conditions but varied across the 9 included diagnoses. These findings may help in assessing the necessity and ethical justification of placebo controls, in evaluating treatment effects in uncontrolled studies, and in guiding patients in treatment decisions. These findings likely encompass the true placebo effect, natural disease course, and nonspecific effects.

[Depression: Low-threshold Cardinal Measures as a Complement or Alternative to Pharmacological or Psychotherapeutic Interventions]. / Depression: Niedrigschwellige Kardinalmaßnahmen als Basis jeder Behandlung.

The third edition of the German National Clinical Practice Guideline for Depression emphasizes the significance of cardinal measures much more strongly than before. Low-threshold cardinal measures are an indispensable component of every depression treatment, regardless of severity and setting. They are suitable as a standalone treatment for mild and moderate depression. If inadequate improvement is observed, additional therapies should be supplemented. They should be implemented immediately after diagnosis to enhance the success rate.Regarding cardinal measures, among other things, comprehensive patient education in understandable language is essential. Patients with depressive disorders require guidance on structuring their day and building healthy activities. Patients with depression-related sleep disturbances benefit from sleep hygiene rules. Wake therapy constitutes an excellent and low-risk treatment method with immediate effect, which is a standard component of adequate depression treatment. Patients with a seasonal pattern of depression should be advised on light therapy. All patients should be encouraged to engage in regular physical activity with moderate intensity.

Antidepressants and Social Functioning in Patients with Major Depressive Disorder: Systematic Review and Meta-Analysis of Double-Blind, Placebo-Controlled RCTs.

INTRODUCTION: Social functioning (SF) is the ability to fulfil one's social obligations and a key outcome in treatment. OBJECTIVE: The aim of the study was to estimate the effects of antidepressants on SF in patients with major depressive disorder (MDD). METHODS: This meta-analysis and its reporting are based on Cochrane Collaboration's Handbook of Systematic Reviews and Meta-Analyses and PRISMA guidelines (protocol registration at OSF). We systematically searched CENTRAL, Medline, PubMed Central, and PsycINFO for double-blind RCTs comparing antidepressants with placebo and reporting on SF. We computed standardized mean differences (SMDs) with 95% CIs and prediction intervals. RESULTS: We selected 40 RCTs out of 1,188 records screened, including 16,586 patients (mean age 46.8 years, 64.2% women). In 27 studies investigating patients with MDD (primary depression), antidepressants resulted in a SMD of 0.25 compared to placebo ([95% CI: 0.21; 0.30] I2: 39%). In 13 trials with patients suffering from MDD comorbid with physical conditions or disorders, the summary estimate was 0.24 ([0.10; 0.37] I2: 75%). In comorbid depression, studies with high/uncertain risk of bias had higher SMDs than low-risk studies: 0.29 [0.13; 0.44] versus 0.04 [-0.16; 0.24]; no such effect was evident in primary depression. There was no indication of sizeable reporting bias. SF efficacy correlated with efficacy on depression scores, Spearman's rho 0.67 (p < 0.001), and QoL, 0.63 (p < 0.001). CONCLUSIONS: The effect of antidepressants on SF is small, similar to its effect on depressive symptoms in primary MDD, and doubtful in comorbid depression. Strong correlations with both antidepressive and QoL effects suggest overlap among domains.

Antidepressants and quality of life in patients with major depressive disorder - Systematic review and meta-analysis of double-blind, placebo-controlled RCTs.

BACKGROUND: Quality of Life (QoL) is an important outcome in mental disorders. We investigated whether antidepressant pharmacotherapy improved QoL vs. placebo among patients with MDD. METHODS: Systematic literature search in CENTRAL, Medline, PubMed Central, and PsycINFO of double-blind, placebo-controlled RCTs. Screening, inclusion, extraction, and risk of bias assessment were conducted independently by two reviewers. We calculated summary standardized mean differences (SMD) with 95%-CIs. We followed Cochrane Collaboration's Handbook of Systematic Reviews and Meta-Analyses and PRISMA guidelines (protocol registration at OSF). RESULTS: We selected 46 RCTs out of 1807 titles and abstracts screened, including 16.171 patients, 9131 on antidepressants and 7040 on placebo, a mean age of 50.9 years, with 64.8% women. Antidepressant drug treatment resulted in a SMD in QoL of 0.22 ([95%-CI: 0.18; 0.26] I2 39%) vs. placebo. SMDs differed by indication: 0.38 ([0.29; 0.46] I2 0%) in maintenance studies, 0.21 ([0.17; 0.25] I2 11%) in acute treatment studies, and 0.11 ([-0.05; 0.26], I2 51%) in studies focussing on patients with a physical condition and major depression. There was no indication of subtstantial small study effects, but 36 RCTs had a high or uncertain risk of bias, particularly maintenance trials. QoL and antidepressive effect sizes were associated (Spearman's rho 0.73, p < 0.001). CONCLUSIONS: Antidepressants' effects on QoL are small in primary MDD, and doubtful in secondary major depression and maintenance trials. The strong correlation of QoL and antidepressive effects indicates that the current practice of measuring QoL may not provide sufficient additional insights into the well-being of patients.

Acute effects of lithium augmentation on the kidney in geriatric compared with non-geriatric patients with treatment-resistant depression.

INTRODUCTION: Lithium augmentation (LA) of antidepressants is a first-line therapy option for treatment-resistant depression (TRD). Nevertheless, it is rarely used in geriatric patients mostly because of the fear of kidney toxicity. The purpose of this study is to investigate estimated glomerular filtration rate (eGFR) changes and number of acute kidney injuries (AKI) using LA in geriatric compared with non-geriatric patients. METHODS: In a prospective multicenter cohort study, eGFR changes were measured in 201 patients with unipolar depression (nage≥65years  = 29; nage<65years  = 172) at baseline and over 2-6 weeks of LA. We used linear mixed models to investigate changes in eGFR upon LA and assessed the number of AKIs, according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. RESULTS: Both age groups showed a significant eGFR decline over the course of treatment with lower eGFR in geriatric patients. The lithium serum level (interpretable as "effect of LA") had a significant effect on eGFR decline. Both effects (age group and lithium serum level) on eGFR decline did not influence each other, meaning the effect of LA on eGFR decline did not differ between age groups. Two AKIs were observed in the geriatric age group when serum lithium levels exceeded the therapeutic range of >0.8 mmol/L. CONCLUSION: This is the first study investigating eGFR change and AKI upon LA for TRD in geriatric compared with non-geriatric patients. Our data suggest that LA, as an effective treatment option in geriatric patients, should be closely monitored to avoid AKIs.

Hyperthyroidism and clinical depression: a systematic review and meta-analysis.

Hyperthyroidism and clinical depression are common, and there is preliminary evidence of substantial comorbidity. The extent of the association in the general population, however, has not yet been estimated meta-analytically. Therefore we conducted this systematic review and meta-analysis (registered in PROSPERO: CRD42020164791). Until May 2020, Medline (via PubMed), PsycINFO, and Embase databases were systematically searched for studies on the association of hyperthyroidism and clinical depression, without language or date restrictions. Two reviewers independently selected epidemiological studies providing laboratory or ICD-based diagnoses of hyperthyroidism and diagnoses of depression according to operationalized criteria (e.g. DSM) or to cut-offs in established rating scales. All data, including study quality based on the Newcastle-Ottawa Scale, were independently extracted by two authors. Odds ratios for the association of clinical depression and hyperthyroidism were calculated in a DerSimonian-Laird random-effects meta-analysis. Out of 3372 papers screened we selected 15 studies on 239 608 subjects, with 61% women and a mean age of 50. Relative to euthyroid individuals, patients with hyperthyroidism had a higher chance of being diagnosed with clinical depression: OR 1.67 ([95% CI: 1.49; 1.87], I2: 6%; prediction interval: 1.40 to 1.99), a result supported in a number of sensitivity and subgroup analyses. The OR was slightly less pronounced for subclinical as opposed to overt hyperthyroidism (1.36 [1.06; 1.74] vs. 1.70 [1.49; 1.93]). This comorbidity calls for clinical awareness and its reasons need investigation and may include neurobiological mechanisms, common genetic vulnerability and a generally heightened risk for clinical depression in patients with chronic somatic disorders.

Dose effects of tricyclic antidepressants in the treatment of acute depression - A systematic review and meta-analysis of randomized trials.

BACKGROUND: Tricyclic antidepressants (TCA) continue to be an important group of drugs, but it is unclear whether a dose-response relationship is supported by high-level evidence. METHODS: Systematic review in the Cochrane Collaboration's Central Register of Controlled Trials (CENTRAL) of studies randomizing patients to at least two doses of one TCA, complemented by searches in Medline, Embase, and PsycInfo. In multilevel regression, we calculated the standardized mean difference (SMD) in antidepressant efficacy per mg TCA dose increase, and we analyzed drop-outs due to adverse events. Finally, we computed random effects meta-analyses of all dose comparisons investigated in a minimum of two studies. RESULTS: Out of 5365 studies screened, we included 15 randomized trials on 24 comparisons of 14 different dose contrasts. We found a statistically non-significant positive effect of increasing the dose: 0.34 SMD with 100 mg/d dose increase ([-0.03; 0.70] p = 0.073). While several comparisons showed no clear signal of a dose gradient, 300 mg of imipramine/desipramine is statistically significantly superior to 150 mg (SMD: 0.80 [0.28; 1.33], p = 0.003, I2: 0%). Drop-outs increased with higher doses, albeit not statistically significantly: Odds ratio (OR) of 1.44 with 100 mg dose increase [0.54; 3.86]. Overall, risk of bias was high. LIMITATIONS: Limited number of studies with mainly high risk of bias. CONCLUSIONS: So far, data on a dose-response relationship in TCAs from direct dose comparisons are inconclusive. Clinically, escalation to high doses may be justified if side effects are bearable.

Combining Antidepressants vs Antidepressant Monotherapy for Treatment of Patients With Acute Depression: A Systematic Review and Meta-analysis.

IMPORTANCE: Combining antidepressants is frequently done in the treatment of acute depression, but studies have yielded conflicting results. OBJECTIVE: To conduct a systematic review and meta-analysis assessing efficacy and tolerability of combination therapy. Combinations using presynaptic α2-autoreceptor antagonists or bupropion were investigated separately. DATA SOURCES: MEDLINE, Embase, PsycINFO, and the Cochrane Central Register of Controlled Trials were systematically searched from each database inception through January 2020. STUDY SELECTION: Randomized clinical trials (RCTs) comparing combinations of antidepressants with antidepressant monotherapy in adult patients with acute depression were included. DATA EXTRACTION AND SYNTHESIS: Following guidelines from Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) and recommendations from the Cochrane Handbook, 2 reviewers independently performed a literature search, study selection, data extraction, and evaluation of risk of bias. Data were pooled in random-effects analyses. MAIN OUTCOMES AND MEASURES: Primary outcome was efficacy measured as standardized mean difference (SMD); secondary outcomes were response, remission, change from baseline in rating scale scores, number of dropouts, and number of dropouts due to adverse events. RESULTS: Thirty-nine RCTs including 6751 patients were eligible. Combination treatment was statistically significantly associated with superior treatment outcomes relative to monotherapy (SMD = 0.31; 95% CI, 0.19-0.44). Combining a reuptake inhibitor with an antagonist of presynaptic α2-autoreceptors was superior to other combinations (SMD = 0.37; 95% CI, 0.19-0.55). Bupropion combinations were not superior to monotherapy (SMD = 0.10; 95% CI, -0.07 to 0.27). Numbers of dropouts and dropouts due to adverse events did not differ between treatments. Studies were heterogeneous, and there was indication of publication bias (Egger test result was positive; P = .007, df = 36), but results remained robust across prespecified secondary outcomes and sensitivity and subgroup analyses, including analyses restricted to studies with low risk of bias. CONCLUSIONS AND RELEVANCE: In this meta-analysis of RCTs comparing combinations of antidepressants with antidepressant monotherapy, combining antidepressants was associated with superior treatment outcomes but not with more patients dropping out of treatment. Combinations using an antagonist of presynaptic α2-autoreceptors may be preferable and may be applied as a first-line treatment in severe cases of depression and for patients considered nonresponders.

Clinical manifestations and immunomodulatory treatment experiences in psychiatric patients with suspected autoimmune encephalitis: a case series of 91 patients from Germany.

Autoimmune encephalitis (AE) can rarely manifest as a predominantly psychiatric syndrome without overt neurological symptoms. This study's aim was to characterize psychiatric patients with AE; therefore, anonymized data on patients with suspected AE with predominantly or isolated psychiatric syndromes were retrospectively collected. Patients with readily detectable neurological symptoms suggestive of AE (e.g., epileptic seizures) were excluded. Patients were classified as "probable psychiatric AE (pAE)," if well-characterized neuronal IgG autoantibodies were detected or "possible pAE" (e.g., with detection of nonclassical neuronal autoantibodies or compatible cerebrospinal fluid (CSF) changes). Of the 91 patients included, 21 (23%) fulfilled our criteria for probable (autoantibody-defined) pAE and 70 (77%) those for possible pAE. Among patients with probable pAE, 90% had anti-NMDA receptor (NMDA-R) autoantibodies. Overall, most patients suffered from paranoid-hallucinatory syndromes (53%). Patients with probable pAE suffered more often from disorientation (p < 0.001) and impaired memory (p = 0.001) than patients with possible pAE. Immunotherapies were performed in 69% of all cases, mostly with high-dose corticosteroids. Altogether, 93% of the patients with probable pAE and 80% of patients with possible pAE reportedly benefited from immunotherapies (p = 0.251). In summary, this explorative, cross-sectional evaluation confirms that autoantibody-associated AE syndromes can predominantly manifest as psychiatric syndromes, especially in anti-NMDA-R encephalitis. However, in three out of four patients, diagnosis of possible pAE was based on nonspecific findings (e.g., slight CSF pleocytosis), and well-characterized neuronal autoantibodies were absent. As such, the spectrum of psychiatric syndromes potentially responding to immunotherapies seems not to be limited to currently known autoantibody-associated AE. Further trials are needed.

Dose-Response Relationship in Selective Serotonin and Norepinephrine Reuptake Inhibitors in the Treatment of Major Depressive Disorder: A Meta-Analysis and Network Meta-Analysis of Randomized Controlled Trials.

INTRODUCTION: Selective serotonin and norepinephrine reuptake inhibitors (SNRI) are among the most prescribed antidepressants, and dose escalation is a frequently applied strategy after non-response to an initially prescribed dose. OBJECTIVE: This meta-analysis aimed to find evidence of a dose-response relationship or to the contrary in direct comparisons of different SNRI doses in patients with major depressive disorder. METHODS: A systematic literature search for RCTs comparing at least two doses of SNRIs was carried out in CENTRAL, PubMed, PsycINFO, and EMBASE. Doses were classified as high, medium, and low according to manufacturers' product monographs and analyses at the level of SNRIs as a group and for single substances, accompanied by sensitivity network meta-analyses (Prospero CRD42018081031). RESULTS: From 2,070 studies screened, we included 26 studies with a total of 10,242 patients. Comparisons of medium versus low and high versus medium doses resulted in clinically and statistically non-significant standardized mean differences of -0.06 (-0.16 to 0.04) and -0.06 (-0.16 to 0.03) in favor of higher doses. In the analyses of single substances, no statistically significant results emerged, and many contrasts yielded very small effect sizes. Dropouts due to side effects tended to be more frequent with higher doses. Heterogeneity was low. Network meta-analyses of direct comparisons supported the findings, as did a risk of bias analysis. CONCLUSION: Based on the lack of positive evidence for a dose-response relationship in SNRIs as a group and in single SNRIs, we recommend prescribing medium doses. In case of insufficient response, we do not recommend increasing the dose of SNRIs.

Electrocardiographic Changes During Initiation of Lithium Augmentation of Antidepressant Pharmacotherapy.

PURPOSE/BACKGROUND: Lithium augmentation of antidepressants represents a common strategy to overcome treatment resistance in patients with major depressive disorder. The use of lithium has been associated with cardiovascular adverse effects such as QTc prolongation and tachyarrhythmia. Although the previous studies investigated monotherapy with lithium, the aim of this study was to investigate electrocardiographic changes in LA. METHODS/PROCEDURES: A 12-lead surface electrocardiogram (ECG) was obtained from 38 patients with major depressive disorder before and during LA. Changes in heart rate, PQ, QRS and QTc interval, QT dispersion, ST segment, and T- and U-wave alterations were analyzed using a linear mixed model. FINDINGS/RESULTS: The ECG readings of 33 patients were evaluated. Lithium augmentation was not significantly associated with changes in heart rate, QTc, PQ, or QRS interval. We found a significant decrease in QT dispersion. These results were independent of sex, age, stable comedication, and comorbidities. During LA, we observed 9 cases of T-wave alterations and 2 cases of new U waves. CONCLUSIONS: Our data provide no evidence for serious ECG abnormalities at therapeutic serum lithium levels in patients treated with LA. In particular, we did not find evidence for QTc time lengthening or tachyarrhythmia, such as torsades des pointes. The recommended intervals for ECG checks should be considered to detect long-term effects of LA.

Association of Hypothyroidism and Clinical Depression: A Systematic Review and Meta-analysis.

Importance: Hypothyroidism is considered a cause of or a strong risk factor for depression, but recent studies provide conflicting evidence regarding the existence and the extent of the association. It is also unclear whether the link is largely due to subsyndromal depression or holds true for clinical depression. Objective: To estimate the association of hypothyroidism and clinical depression in the general population. Data Sources: PubMed, PsycINFO, and Embase databases were searched from inception until May 2020 for studies on the association of hypothyroidism and clinical depression. Study Selection: Two reviewers independently selected epidemiologic and population-based studies that provided laboratory or International Statistical Classification of Diseases and Related Health Problems diagnoses of hypothyroidism and diagnoses of depression according to operationalized criteria (eg, Diagnostic and Statistical Manual of Mental Disorders or International Statistical Classification of Diseases and Related Health Problems) or cutoffs in established rating scales. Data Extraction and Synthesis: Two reviewers independently extracted data and evaluated studies based on the Newcastle-Ottawa Scale. Summary odds ratios (OR) were calculated in random-effects meta-analyses. Main Outcomes and Measures: Prespecified coprimary outcomes were the association of clinical depression with either hypothyroidism or autoimmunity. Results: Of 4350 articles screened, 25 studies were selected for meta-analysis, including 348 014 participants. Hypothyroidism and clinical depression were associated (OR, 1.30 [95% CI, 1.08-1.57]), while the OR for autoimmunity was inconclusive (1.24 [95% CI, 0.89-1.74]). Subgroup analyses revealed a stronger association with overt than with subclinical hypothyroidism, with ORs of 1.77 (95% CI, 1.13-2.77) and 1.13 (95% CI, 1.01-1.28), respectively. Sensitivity analyses resulted in more conservative estimates. In a post hoc analysis, the association was confirmed in female individuals (OR, 1.48 [95% CI, 1.18-1.85]) but not in male individuals (OR, 0.71 [95% CI, 0.40-1.25]). Conclusions and Relevance: In this systematic review and meta-analysis, the effect size for the association between hypothyroidism and clinical depression was considerably lower than previously assumed, and the modest association was possibly restricted to overt hypothyroidism and female individuals. Autoimmunity alone may not be the driving factor in this comorbidity.

Faster speed of onset of the depressive episode is associated with lower cytokine serum levels (IL-2, -4, -6, -10, TNF-α and IFN-γ) in patients with major depression.

INTRODUCTION: Cytokines might play a key role in the pathophysiology of major depressive disorder (MDD). The speed of onset of depressive episodes has been discussed as an important clinical parameter in MDD. The aim of this study was to investigate a potential influence of the speed of onset of the depressive episode on cytokine serum levels. METHOD: Serum level of the cytokines interleukin (IL)-2, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), interferon-gamma (IFN-γ) granulocyte and monocyte colony stimulating factor (GM-CSF) were measured in a total of 92 patients with MDD that did not respond to at least one previous antidepressant treatment. Patients were retrospectively divided in two groups: Faster (≤4 weeks) and slower (>4 weeks) onset of the depressive episode defined as the time passing from the first depressive symptoms to a full-blown depressive episode by using information from a clinical interview. RESULTS: We found significantly lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ in patients with a faster onset compared to patients with a slower onset of the depressive episodes. Furthermore, lower cytokine serum levels of IL-2, IL-8, IL-10 and IFN-γ were found in patients with a shorter duration (less than 6 months) compared to a longer duration (6-24 months) of the current depressive episode. This effect on cytokines was independent from the effect of the speed of onset of the depressive episode. CONCLUSIONS: Patients with faster onset of the depressive episode might represent a biological subtype of MDD with lower serum levels of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ.

Suicide risk with selective serotonin reuptake inhibitors and other new-generation antidepressants in adults: a systematic review and meta-analysis of observational studies.

BACKGROUND: There is ongoing controversy whether antidepressant use alters suicide risk in adults with depression and other treatment indications. METHODS: Systematic review of observational studies, searching MEDLINE, PsycINFO, Web of Science, PsycARTICLES and SCOPUS for case-control and cohort studies. We included studies on depression and various indications unspecified (including off-label use) reporting risk of suicide and/or suicide attempt for adult patients using selective serotonin reuptake inhibitors (SSRI) and other new-generation antidepressants relative to non-users. Effects were meta-analytically aggregated with random-effects models, reporting relative risk (RR) estimates with 95% CIs. Publication bias was assessed via funnel-plot asymmetry and trim-and-fill method. Financial conflict of interest (fCOI) was defined present when lead authors' professorship was industry-sponsored, they received industry-payments, or when the study was industry-sponsored. RESULTS: We included 27 studies, 19 on depression and 8 on various indications unspecified (n=1.45 million subjects). SSRI were not definitely related to suicide risk (suicide and suicide attempt combined) in depression (RR=1.03, 0.70-1.51) and all indications (RR=1.19, 0.88-1.60). Any new-generation antidepressant was associated with higher suicide risk in depression (RR=1.29, 1.06-1.57) and all indications (RR=1.45, 1.23-1.70). Studies with fCOI reported significantly lower risk estimates than studies without fCOI. Funnel-plots were asymmetrical and imputation of missing studies with trim-and-fill method produced considerably higher risk estimates. CONCLUSIONS: Exposure to new-generation antidepressants is associated with higher suicide risk in adult routine-care patients with depression and other treatment indications. Publication bias and fCOI likely contribute to systematic underestimation of risk in the published literature. REGISTRATION: Open Science Framework, https://osf.io/eaqwn/.