Stop or Go? Relapse prevention training with guided tapering of antidepressants during pregnancy. A pragmatic multicenter RCT to investigate risk and benefits for mother and child.

Rationale:

About 2% women in the Netherlands use Selective Serotonin Reuptake Inhibitors (SSRIs) during their pregnancy for symptoms of depression and/or anxiety. SSRI use in pregnancy is controversial. On the one hand SSRIs may be toxic to the intrauterine developing child, while on the other hand, relapse of depression and/or anxiety during pregnancy holds risks for both mother and child. Among patients and professionals there is an urgent need for evidence from randomized studies to make rational decisions regarding continuation or tapering of SSRIs during pregnancy. No such studies exist to date.



Objective:

The aim of this study is to investigate the effect of preventive cognitive therapy with guided tapering of SSRIs in early pregnancy as compared to continuation of SSRIs during pregnancy. We will study effects on both mother and child with a pragmatic approach.

Our hypotheses are:

1) Tapering of SSRIs with added preventive cognitive therapy (CT) increases the risk of clinically relevant maternal relapse of depression in excess of [absolute] 15% compared to continuation of SSRIs. If rejected, then discontinuation is deemed non-inferior with regard to relapse risk;

2) Tapering of SSRIs is better than continuation of SSRIs with respect to child development;

3) Assuming no relevant effects of discontinuation on the mother and no effects on the child, discontinuation decreases total costs per woman and child on a 3 months and projected long term base.

In absence of clinical differences between the two options, tapering of SSRIs will be declared preferential during pregnancy.



Study design:

A nationwide pragmatic multi-center randomized controlled non-inferiority trial (RCT).



Study population:

The study population consists of 200 women who are between 8-16 weeks pregnant and use SSRIs without clinically relevant depressive symptoms.



Intervention:

After informed consent, women will be randomly allocated into two groups:

1. Preventive cognitive therapy with gradual, guided discontinuation of SSRI under clinical management (intervention group);

2. Continuation of SSRI (control group).



Main study parameters/endpoints:

Primary outcome:

Risk (cumulative incidence) of relapse of maternal depressive disorder (as defined by the Structured Clinical Interview for DSM disorders) during pregnancy and up to 3 months postnatal.



Secondary outcomes:

1. Child condition at birth (Apgar, gestational age, birth weight, head circumference);

2. Child neurodevelopmental outcome at 3 months (General Movements);

3. Child behaviour (CBCL) at 18 months;

4. Cost effectiveness (including indicated second echelon care, hospital delivery and clinical child observation in case of SSRI use).



Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

All participants in the study receive regular check up on the potential return of their depressive symptoms. The main risk in this study involves the tapering of medication in women who are mentally stable. Although tapering of antidepressant medication in mentally stable patients is part of evidence based clinical practice, it could introduce relapse of previous depressive symptoms. We realize that in pregnant women this involves risks for the mother and her unborn child. Therefore, each patient will be critically evaluated by an experienced psychiatrist/clinical psychologist at inclusion, to judge whether it is clinically justified to taper antidepressant medication. If so, antidepressants will be tapered with close monitoring by a general practitioner or psychiatrist, and additional preventive CT will be provided. The provision of preventive CT in addition to tapering medication is in accordance with (inter)national guidelines (Multidisciplinary Dutch guidelines 2013, APA 2010, NICE 2009)1,2,3.
Of note is that in both randomized groups concomitant therapy is allowed in this pragmatic trial, e.g. the administration of benzodiazepines.
Additional burdens without risks will be:

1. Blood sampling of the woman at inclusion;

2. A structured psychiatric interview of the woman at inclusion (30-90 minutes) and at 12 weeks after delivery (+/- 30 minutes);

3. Questionnaires at fixed time points: inclusion, 24 and 36 weeks pregnancy, 4 and 12 weeks and 18 months after delivery (+/- 30 minutes);

4. Collection of meconium of the newborn by the parents;

5. Collection of breast milk when breastfeeding;

6. Collection of placenta and cord blood (if possible);

7. Collection of hair (+/- 1 cm2) and a buccal swab at 3 months after delivery of both mother and child;

8. The child born from the included woman will be videotaped in a non-invasive home observation at 3 months of age (30-60 minutes) to measure general movements of the child. The mother is allowed to be present during the assessment.



A potential benefit of participating in this study might be the superiority of the intervention (i.e. tapering of SSRI with additional preventive CT) compared to treatment as usual with respect to maternal and child health outcome. The study guarantees access to preventive CT therapists without additional costs and waiting lists for participants who are allocated to the intervention arm.

1) Tapering of SSRIs with added preventive cognitive therapy (CT) increases the risk of clinically relevant maternal relapse of depression in excess of [absolute] 15% compared to continuation of SSRIs. If rejected, then discontinuation is deemed non-inferior with regard to relapse risk.

2) Tapering of SSRIs is better than continuation of SSRIs with respect to child development.

3) Assuming no relevant effects of discontinuation on the mother and no effects on the child, discontinuation decreases total costs per woman and child on a 3 months and projected long term base.

In absence of clinical differences between the two options, tapering of SSRIs will be declared preferential during pregnancy.

T0: Inclusion: SCID, HAM-D, Mind2Care, STAI, EPDS, PSS, TIC-P, EQ-5D-5L, bloodsample;

T1: 24 weeks: CTQ, EPDS, STAI 6-item, PSS, EQ-5D-5L;

T2: 36 weeks: HAM-D, EPDS, PSS, STAI 6-item, TIC-P, EQ-5D-5L;

T3: Delivery: registered details;

T4: 4 weeks after delivery: EPDS, PSS, STAI 6-item, TIC-P, EQ-5D-5L;

T5: 12 weeks after delivery: SCID, HAM-D, EPDS, PSS, STAI 6-item, TIC-P, EQ-5D-5L, GM, hair cortisol;

T6: 18 months after delivery: CBCL, C-TRF, LDS;

T7: 24 months after delivery: information of the CJG.

After informed consent, women will be randomly allocated into two groups:

1) Preventive cognitive therapy with gradual, guided discontinuation of SSRI under clinical management (intervention group);

2) Continuation of SSRI (control group).