Fluoxetine

We did a systematic review and network meta-analysis. We searched the Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, AMED, the UK National Research Register, and PSYNDEX from the date of their inception to Jan 8, 2016, with no language restrictions. We used the search terms “depress*” OR “dysthymi*” OR “adjustment disorder*” OR “mood disorder*” OR “affective disorder” OR “affective symptoms” combined with a list of all included antidepressants.
We included double-blind, randomised controlled trials (RCTs) comparing antidepressants with placebo or another active antidepressant as oral monotherapy for the acute treatment of adults (≥18 years old and of both sexes) with a primary diagnosis of major depressive disorder according to standard operationalised diagnostic criteria (Feighner criteria, Research Diagnostic Criteria, DSM-III, DSM-III-R, DSM-IV, DSM-5, and ICD-10). We considered only double-blind trials because we included placebo in the network meta-analysis, and because this study design increases methodological rigour by minimising performance and ascertainment biases.⁷ (link) Additionally, we included all second-generation antidepressants approved by the regulatory agencies in the USA, Europe, or Japan: agomelatine, bupropion, citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, venlafaxine, vilazodone, and vortioxetine. To inform clinical practice globally, we selected the two tricyclics (amitriptyline and clomipramine) included in the WHO Model List of Essential Medicines). We also included trazodone and nefazodone, because of their distinct effect and tolerability profiles. Additionally, we included trials that allowed rescue medications so long as they were equally provided among the randomised groups. We included data only for drugs within the therapeutic range (appendix pp 133, 134). Finally, we excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness.
The electronic database searches were supplemented with manual searches for published, unpublished, and ongoing RCTs in international trial registers, websites of drug approval agencies, and key scientific journals in the field.⁸ For example, we searched ClinicalTrials.gov using the search term “major depressive disorder” combined with a list of all included antidepressants. We contacted all the pharmaceutical companies marketing antidepressants and asked for supplemental unpublished information about both premarketing and post-marketing studies, with a specific focus on second-generation antidepressants. We also contacted study authors and drug manufacturers to supplement incomplete reports of the original papers or provide data for unpublished studies.
Six pairs of investigators (ACi, TAF, LZA, SL, HGR, YO, NT, YH, EHT, HI, KS, and AT) independently selected the studies, reviewed the main reports and supplementary materials, extracted the relevant information from the included trials, and assessed the risk of bias. Any discrepancies were resolved by consensus and arbitration by a panel of investigators within the review team (ACi, TAF, LZA, EHT, and JRG).
The full protocol of this network meta-analysis has been published.⁸

A total of 62 participants (38 women and 24 men) were examined in this study. Of these, 31 patients fulfilled the criteria of OCD [ICD-10 F42.X: mean age 35.2 (SD = 10.7) years] and 31 subjects formed the healthy control group [mean age 39.1 (SD = 15.0) years]. A detailed description of the groups can be found in Table 1.Table 1

Sociodemographic and clinical characteristics

Trait	OCDN = 31	HCN = 31	p-value*
Age, mean (SD), years	38,7 (11,9)	39,6 (13,1)	n. s
Gender
Female n,	19 (61,3%)	19 (61,3%)	n. s
Male n,	12 (38,7%)	12 (38,7%)
Marital status
Single, n	17 (54,8%)	12(38,7%)
Married, n	9 (29,0%)	19 (61,3%)	p = 0.009
Divorced, n	5 (16,1%)	0
Current Partnership
- No	13 (41,9%)	7 (22,6%)	n. s
- Yes	18 (58,1%)	24 (77,4%)
Graduation
High school, n	25 (80,7%)	24 (77,4)
Junior high school, n	3 (9,7%)	5 (16,1%)	n. s
Low school., n	3 (9,7%)	2 (6,5%)
Occupational status
Current employment (Including be a student), n	22 (71,0%)	27 (87,1%)	n. s
No current Job,	9 (29,0%)	4 (12,9%)
Diagnosis (ICD-10)
F42.0, n	5 (16,1%)	/
F42.2, n	26 (83,9%)
Age of onset
mean (SD), years	23,2 (9,1)	/
Duration of illness
mean (SD), years	15,8 (10,8)	/

^*x²-Test/ t-Test; n. s. non-significant, OCD Obsessive–compulsive disorder, HC Healthy controls

All OCD patients were recruited and examined during their treatment at the Department of Psychiatry (LWL-University Hospital of the Medical Faculty of Ruhr-University Bochum, special outpatient clinic for OCDs). Examination of the healthy volunteers also took place at the LWL-University Hospital Bochum and recruitment was via notices and flyers.
Patients and healthy volunteers aged 18–67 years were included. Further inclusion criteria were a verbal IQ > 70, sufficient German language skills and the ability to give informed consent according to the Helsinki and ICH-GCP declarations. Exclusion criteria for the study were: severe somatic diseases; other mental diseases, such as reduced intelligence (ICD10 F70–F70.9), schizophrenia (ICD10 F20–F20.9) or organic brain disorders (ICD10 F06–F06.9, dependence on illegal drugs); acute suicidal tendencies or behaviour endangering others; and lack of informed consent to participate in the study.
Furthermore, psychopharmacotherapy was not an exclusion criterion for patients with OCD. In this respect, 96.8% of the patients (n = 30) received monotherapy, whereby antidepressants from the selective serotonin reuptake inhibitor group [e.g. sertraline (n = 21), escitalopram, paroxetine, fluoxetine] but also clomipramine (a tricyclic antidepressant) were predominantly used. Moreover, seven of the patients received a combination treatment (mainly a sedating antipsychotic medication, e.g. promethazine or quetiapine). At the time of inclusion in the study, 12 patients were receiving psychotherapeutic treatment (validation therapy: n = 9; deep psychology: n = 3). Only five of the patients (16.1%) with OCD had not received psychotherapy at the time of study inclusion, either currently or in the past. A detailed anamnesis was taken from all OCD patients and healthy volunteers in a semi-structured interview (duration 45–60 min). The psychometric characteristics, including shame and guilty proneness, were gathered using various questionnaires.
The study was approved by the local Ethics Committee (No. 20–6883) of the Medical Faculty of Ruhr-University Bochum.

We identified the following potential confounders a priori using directed acyclic graphs^{28 (link)}: age at pregnancy, primiparous, marital status, smoking during pregnancy, and Charlson Comorbidity Index (calculated based on 19 conditions; definition in the eMethods in Supplement 1). We used a history of self-harm (definition in the eMethods in Supplement 1) and psychiatric diagnoses at any time before pregnancy, including schizophrenia, bipolar disorder, depression, other mood disorders, and others (International Classification of Diseases, Eighth Revision [ICD-8] and Tenth Revision [ICD-10] codes listed in eTable 2 in Supplement 1); number of psychiatric emergencies; and coprescribed medications (opioid analgesics, antiseizure medications, antipsychotics, benzodiazepine/z-hypnotics, or anxiolytics; ATC codes listed in eTable 3 in Supplement 1) in the 6 months before pregnancy as a proxy for disease severity. In addition, we included filling prescriptions for 2 or more classes of antidepressants and having an average daily dose of an antidepressant greater than 1 fluoxetine dose equivalent (ie, 40 mg fluoxetine)^{29 (link)} in the 6 months before pregnancy as an additional proxy of the severity of mental illnesses.

A total of 30 female Swiss albino mice were chosen and segregated into five different groups (n = 6). Animals were grouped as follows: normal control (group 1), LPS control (group 2), pretreatment group in low-dose treatment (4-MESC + LPS; group 3), pretreatment group in high-dose treatment (4-MESC + LPS; group 4), and standard group (fluoxetine + LPS; group 5). The experimental plan was carried out for 28 days. Mice of group 1 received normal water. The pretreatment of 4-MESC with low doses (25 mg/kg) and high doses (50 mg/kg) were administered orally to the third and fourth groups, respectively, for 28 days. Fluoxetine (20 mg/kg p.o.) was administered to mice for 28 days as a standard drug. On the 28th day, all mice except those in the control group received a single injection of lipopolysaccharide (0.83 mg/kg i.p.). The day after LPS administration, all mice in each group were evaluated behaviorally using an open-field test (OFT), an immobility test using a tail-suspension test (TST), and a forced swim test (FST). All animals were anesthetized, and retro-orbital blood was withdrawn. Then, the animal was decapitated. The serum and brains of mice were stored at −80°C for biochemical estimations.