Citalopram

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The electronic database searches were supplemented with manual searches for published, unpublished, and ongoing RCTs in international trial registers, websites of drug approval agencies, and key scientific journals in the field.⁸ For example, we searched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

Inclusion criteria for GP practices were: (a) up to one GP/practice participating at any time; located within one of the study’s South East London areas; and (b) using EMIS electronic health record software. Inclusion criteria for patients in addition to being registered at one of the participating practices were: (a) age ≥18, (b) at least moderately severe major depressive syndrome on Patient Health Questionnaire (PHQ-9; a score of ≥15),8 (link) (c) no plans to change GP practice, (d) able to complete self-report scales orally or in writing, (e) no previous prescription of mirtazapine or vortioxetine, (f) evidence of early treatment resistance as defined by (i) current or recent prescription (in the last 2 months) of any of the following antidepressants listed: citalopram, fluoxetine, sertraline, escitalopram, paroxetine, venlafaxine or duloxetine, and (ii) previous prescription of at least one other antidepressant out of the same list of antidepressants.
Exclusion criteria for patients were: (a) inability to consent to the study, (b) unstable medical condition (assessed based on in-depth screening visit), (c) currently being treated by mental health specialist, (d) high suicide risk (assessed with Mini International Neuropsychiatric Interview suicidality screen),9 (e) past diagnosis of schizophrenia or schizo-affective disorder, (f) current psychotic symptoms (three clinical screening questions validated in our previous work to exclude schizophreniform disorders),10 11 (link) (g) bipolar disorder on WHO Composite International Diagnostic Interview12 (link) at prescreening or using the Structured Clinical Interview for DSM-513 at screening including Bipolar Otherwise Specified categories, (h) currently at risk of being violent (assessed on in-depth screening visit), (i) drug (modified PHQ) or alcohol abuse (PHQ)8 (link) over the last 6 months, (j) suspected central neurological condition (eg, dementia, stroke, assessed on in-depth screening visit), (k) (planned) pregnancy or insufficient contraception in women of childbearing age (assessed on in-depth screening visit and prescreening), (l) breast feeding or within 6 months of giving birth, (m) has already been prescribed both escitalopram and sertraline.

Families were recruited through internet and newspaper services, local clinics, and patient support groups in Montréal, Québec. Families were mostly of white, middle-class, intact, and French-Canadian. Inclusion criteria for all families consisted of having at least one child between the ages of 6 and 11 years, and fluency in either English or French. General demographic information presented by risk status can be found in Table 1. Control families were excluded if either parent presented with a current axis-I disorder or reported a history of affective disorders. Inclusion criteria for families having a parent with BD consisted of have one parent with a BD1 or BD2 diagnosis. Psychopathology in parents was assessed with the Structured Clinical Diagnostic Interview for DSM-IV-R (SCID-I; 24). The sample consisted of 25 families with a parent having BD (72% mothers) and 28 families with parents having no mental disorders (90% mothers).Table 1

Demographic characteristics presented by risk-status

Variable	OBD	Control Offspring
Offspring age at first timepoint	7.77 years (SD = 1.74)	8.67 years (SD = 1.68)
Offspring sex
Girls	17	18
Boys	17	14
Family ethnicity
Aboriginal (e.g., First Nations, Inuit, Metis, Native American, Native Australian)	1	0
Black (e.g., African–American, Nigerian, Haitian, Jamaican, Somali)	0	4
East Asian, South-East Asian, Pacific Islander (e.g., Chinese, Japanese, Korean, Vietnamese, Thai, Filipino, Indonesian)	1	2
Hispanic/Latino/Latin-American (e.g., Brazilian, Chilean, Mexican, Cuban)	1	3
Middle Eastern, North African, Central Asian (e.g., Jordanian, Saudi, Egyptian, Moroccan, Iranian, Afghan, Tajikistani)	2	3
White (Caucasian)	20	16
Parental marital status
Single	5	2
Married	18	18
Separated	2	5
Divorced	0	3
Parental educational attainment
Highschool Diploma	1	0
CÉGEP Diploma	4	4
Some university achievement	1	3
University Degree	19	21
Family annual income
Less than $25,000	4	4
$25,001 to $50,000	8	8
$50,001 to $75,00	5	5
$75,001 to $100,000	1	7
More than $100,000	7	3
Family SES compositea	9.44 (SD = 2.10)	9.48 (SD = 1.67)

^aSES Composite = socioeconomic composite score, which combines both parental educational attainment and family annual income

Within families having a parent with BD, most affected parents presented with BD-I (90%), and all reported a history of depression. At the start of the study, most parents with BD were asymptomatic, while two were in a current manic episode. While the latter two individuals were included in the study on the basis of their diagnosis, it was their partners who completed the RUSH program and all accompanying assessments. For the other 23 families, the affected parents attended the program and completed all assessments. All parents with BD were receiving pharmacological treatment at the time of the study, which included various combinations of antidepressant (bupropion, citalopram, escitalopram, sertraline, venlafaxine; n = 6), anticonvulsant (divalproex, lamotrigine, topiramate, valproate, n = 12), antipsychotic (chlorpromazine, lurasidone, olanzapine, quetiapine, ziprasidone; n = 12) and mood stabilizing medication (lithium; n = 9).
There were 66 children across the 53 families (34 OBD; 32 control; 48% female), aged between 6 and 11 years (M = 8.20 years, SD = 1.20 years). None of the control offspring met criteria for a psychological disorder, while ten OBD had a current diagnosis at T1, including an anxiety disorder (n = 1), enuresis (n = 2), oppositional defiant disorder (n = 1), and attention deficit/hyperactivity disorder (n = 6; all of whom were being treated with psychostimulants). None of the OBD were receiving any psychosocial treatments throughout the duration of the study. Psychopathology in offspring was assessed with the parent-version of the Kiddie-Schedule of Affective Disorders and Schizophrenia-Present and Lifetime Version [K-SADS-PL; (Kaufman and Schweder 2004 ). Children were excluded on the basis of presenting with pervasive developmental disorder, an intellectual or chronic physical disorder, or any history of an affective or psychotic disorder. Groups of children did not significantly differ on any key demographic variable (e.g., sex, ethnicity, or socioeconomic status) (all p > 0.05).
Of the initial 25 families having a parent with BD who underwent the T1 assessment, 20 completed the RUSH program. Of the 20 families who completed the RUSH program, all returned for T2 and T3 assessments, but only 17 families were retained at T4. Families most commonly reported a lack of time as the reason for dropping out at T4. No differences were observed between the original sample and those who dropped out prior to participating in the RUSH program or at T4 with regards to various demographic variables (offspring and parent sex and age, socioeconomic status), parental diagnosis (BD-I v. BD-II), offspring psychopathology at T1, as well as parents’ baseline scores across all four scores of parenting stress (all p > 0.05).

Retrospective results from TDM analysis of antidepressants and antipsychotics were extracted from the LIMS system of the three participating Danish laboratories. These were the Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus (AUH); the Laboratory of the Danish Epilepsy Centre–Filadelfia, Dianalund (EHL); and the Department of Clinical Biochemistry, Rigshospitalet (RH), Copenhagen. Approvals were obtained from the respective hospital boards, prior to downloading the data.
Therapeutic drug monitoring at AUH is carried out by using LC-MS/MS technology and assays that have been developed in-house. The analyses are all accredited according to ISO:15189:2013, and the quality is externally monitored by proficiency testing. Results were extracted for the following drugs covering a period from 1 January 2014 to 31 December 2018: amitriptyline/nortriptyline (metabolite), aripiprazole/dehydroaripiprazole (metabolite), citalopram/escitalopram, clomipramine/desmethylclomipramine (metabolite), clozapine, duloxetine, fluoxetine/norfluoxetine (metabolite), imipramine/desipramine (metabolite), mirtazapine, olanzapine, perphenazine, quetiapine, risperidone/paliperidone (metabolite), sertraline, venlafaxine/o-desmethyl-venlafaxine (metabolite), ziprasidone, and zuclopenthixol.
All the assays performed at EHL have been developed in-house by using LC-MS/MS technology. These include the same drugs as are analysed at AUH and in addition flupentixol, haloperidol, and paroxetine. Although part of the laboratory production, fluoxetine/norfluoxetine, mianserine, and ziprasidone were excluded, owing to a low number of samples (<100). The assays (n = 26) are accredited according to ISO15189:2013, with the exception of aripiprazole/dehydroaripiprazole, and mirtazapine. The quality is externally monitored by proficiency-testing programmes, covering all analytes. For this study, data were collected from the laboratory LIMS system spanning a period from 1 January 2012 to 30 March 2022.
The analyses for therapeutic drugs at RH is performed by HPLC using UV-detection. The following drugs are included in the laboratory repertoire: amitriptyline/nortriptyline, clomipramine/desmethylclomipramine, clozapine, dosulipine/northiaden, and imipramine/desipramine, of which amitriptyline, nortriptyline, clozapine, and imipramine/desipramine are accredited according to ISO 15189:2013. The quality of the assays is monitored by external proficiency-testing schemes. For the calculations, data were collected covering the period from 9 May 2011 to 26 April 2022.