Depressive disorders represent the major cause of disability worldwide (1, 2). These disorders are prevalent in the perinatal period and about 12% of women are affected (3). However, prevalence rates of perinatal depression (PD) should be cautiously considered since this disorder is frequently underdiagnosed, mainly because patients experience delays and difficulties in help-seeking due to feelings of guilty and fear of stigmatization (4, 5). PD poses a significant burden on affected women, their families and on society at large; moreover, it carries serious long-term consequences on the mental health of the new born (6, 7). In particular, PD can have several detrimental effects including low birth weight, preterm birth, small development for gestational age, early childhood developmental delays, poor maternal fetal attachment, impairments in cognitive functioning, behavioral disturbances, and development of depressive disorders in the childhood or adolescence (8–16).

Different risk factors have been identified for PD, including low socioeconomic status (17–19), being a single mother (17, 20), poor social support (21), general life stress (17), and unplanned pregnancies (22). Indeed, PD is associated with a dysregulation and hyperactivity of the hypothalamic-pituitary-adrenal axis activity (HPA) (23), with an increased exposition to the corticotrophin-releasing hormone (CRH) during intrauterine development.

Several interventions have been developed for reducing the impact of risk factors and for preventing the development of PD (24), including professionally-based home visits, postpartum peer-based telephone support, interpersonal psychotherapy (25), and cognitive behavioral therapy (26). Although several of these interventions have been made available in clinical practice, research is needed in order to confirm their efficacy (27).

Symptoms of perinatal depression often include anxiety, irritability, sleep disturbance, low mood, and excessive concern for the child's care (28), in fact, PD is a multi-faceted and complex condition which can have heterogeneous clinical presentations (15). In particular, a significant number of women with PD experience comorbid anxiety (29, 30), obsessive-compulsive symptoms and post-traumatic stress disorders (31).

One of the main debated issues regarding the optimal prevention and treatment of perinatal depression is related to the opportunity to early detect the disorder through screening procedures (32, 33). In particular, it has been argued that screening programmes can be effective in reducing burden and disability associated with the disorder (34), although there is the risk to create false-positives (35). Screening procedures aim to detect people at high risk to develop a full-blown disorder, and therefore the clinical utility of the screening process is greatly influenced by the ability to accurately identify those patients (33–35).

However, screening programmes are considered acceptable and even desirable by most pregnant women, both depressed and non-depressed (36). Therefore, available guidelines (37, 38) recommend that healthcare professionals (including midwives, obstetricians, health visitors, and general practitioners) ask questions about past or present mental illness, family history of perinatal mental illness and previous psychiatric treatments including inpatient care. Moreover, the American Academy of Pediatrics also recommend that pediatricians screen new mothers for depression during their visits in the 6 months following childbirth (39).

According to a recent review (40), treatment of PD depends on symptom severity and functional impairment (41, 42). Cognitive behavioral therapy (43), interpersonal psychotherapy, and psychoeducation (44, 45) are usually adopted in case of mild to moderate forms of PD; while antidepressants, more often selective serotonin reuptake inhibitors (SSRI), are used for severe cases (46–51).

When available, pregnant women with PD prefer psychotherapy (52) and the effectiveness of psychological and psychosocial treatments for PD has been explored (53).

Several initiatives have been proposed worldwide in order to assess the efficacy and feasibility of psychoeducational interventions for women with PD. A recent meta-analysis by Sockel (26) found only one study (54) evaluating the efficacy of a psychoeducational programme for women with PD in improving depressive symptoms. More recently, other programmes have been proposed also in low-middle income countries (55).

Psychoeducational interventions are effective in reducing affective symptoms and the levels of stress, with low costs for the mental health department (56).

Based on these premises, the Department of Psychiatry of the University of Campania “Luigi Vanvitelli” is carrying out a study to develop and test the efficacy of a psychoeducational family intervention in pregnant women with perinatal depression and their close relatives.

To our knowledge no randomized controlled trial has been carried out so far in Italy on the effectiveness of psychoeducational interventions for women affected by perinatal depression, although psychoeducational intervention has demonstrated its efficacy in a wide range of severe mental disorders, such as bipolar disorder (57), schizophrenia (58), major depression (59), obsessive compulsive disorder (60), and eating disorders (61).

The present trial aims to evaluate the efficacy and feasibility of a new psychoeducational family intervention compared to the Best Treatment Option (BTO) in a sample of women affected by perinatal depression and their family members. The Best Treatment Option (BTO) is provided according to the NICE guidelines (62). In particular, mild to moderate forms of depression may be addressed with self-help or psychological counseling. For moderate or severe forms of PD, high-intensity psychological intervention, or pharmacological treatments are recommended.

The secondary aims are to: (1) improve mental health literacy on the topic of perinatal depression, with a specific focus on risk and protective factors as well as on available therapeutic strategies for the management of perinatal depression; (2) identify clinical, socio-cultural, and pregnancy-related predictive factors for the development of perinatal depression; (3) improve coping strategies and family functioning of family members participating to the intervention; (4) evaluate the long-term effects of the intervention.

Recruitment for the RCT will be conducted adopting a multistep strategy, as reported in Figure 1:

- Step 1. All pregnant women attending the outpatient unit of Gynecology and Obstetrics of the University of Campania “Luigi Vanvitelli” will be invited to participate in the study through the use of informative leaflets on perinatal depression (i.e., characteristics of the disorder, risks, long-term consequences, available treatments). Those interested in having more information will be referred to a research team member presenting a brief overview of study procedures and time commitment in order to obtain their informed consent. Once informed consent is obtained, patients will be officially enrolled in the study and will undergo the screening procedure, compiling the Edinburgh Postnatal Depression Scale (EPDS) (64).

Starting from January 2019, patients attending the outpatient unit of Gynecology and Obstetrics of the University of Campania “Luigi Vanvitelli” will be invited to participate to the study. The eligibility criteria will be: (1) gestation age > 3 months or within 3 days of childbirth; (2) age ≥ 18 years; (3) absence of any disabling physical condition; (4) living with a relative for at least 9 months in the last year and continuously in the last 3 months.

Exclusion criteria will be: (1) intellectual disability; (2) diagnosis of schizophrenia, schizoaffective disorder, delusional disorder, or other not specified psychosis-spectrum disorder; (3) having experienced depressive symptoms before pregnancy.

Three mental health professionals (at least one will be a psychiatrist) will receive an ad-hoc training course for the provision of the experimental intervention. Supervision meetings will be organized during the study period in order to ensure fidelity to the procedure.

This study is being conducted in accordance with globally accepted standards of good clinical practice, in agreement with the Declaration of Helsinki and with national and local regulations. The study investigators ensure that all mental health professionals involved in the study are qualified and informed about the protocol, interventions, and trial-related duties. The study protocol has been submitted to the Ethical Review Board of the University of Campania “Luigi Vanvitelli.”

Researchers participating to the study are blinded to patient allocation. All patients are assessed at the following time points: baseline (T0); 3 months post-randomization (T1); 6 months post-randomization (T2); 9 months post-randomization (T3); 12 months post-randomization (T4) (Table 2).

The following questionnaires and schedules will be used during the study:

The Edinburgh Postnatal Depression Scale (EPDS) (64) is a simple and short 10-items self-report screening questionnaire initially developed for use in postnatal women to improve detection of postnatal depression. The EPDS allows health professionals to detect women who might need help and require a referral for a full diagnostic assessment. EPDS has satisfactory sensitivity and specificity values and it is also sensitive to changes in severity of depression over time. For the purpose of the present study, the cut-off threshold has been set at ≥ 10 (66). In validation studies, different cut-off points have been found due to clinical, social, cultural and economic diversities (70). The cut-off score for possible depression (i.e., a positive screening result) is ≥13 points but, as suggested by Hewitt et al. (71), a cut-off score ≥ 10 can be used in order to identify patients with both major or minor depression. Moreover, given the observed variability in the performance of the test, the screening procedure could produce both false positives and negatives (72). Therefore, it is essential that this screening tool is complemented by the clinical judgment (73).

At baseline the following information will be collected: (1) sociodemographic data (age, nationality, educational level, marital status, employment status, number of family members, duration of the illness, time in charge at the mental health center (months), number of (voluntary and involuntary) hospitalizations, suicide attempts (numbers); (2) clinical features related to pregnancy (gestational period, previous pregnancies, in vitro fertilization, clinical conditions of the fetus, and the pregnant); (3) social context, such as relationship with the partner, family conflicts, socio-economic stressors, history of any psychiatric disorder (Table 3).

From month 1 to 6, the following phases have been carried out: (1) development of the work plan for data collection; (2) training course for mental health professionals on the interventions; (3) training course for researchers on assessment tools. From month 7 to 12, patients' recruitment will be implemented. From month 7 to 18, interventions will be provided to participating patients. From month 7 to 20, patients' follow-up assessments are being made. From month 20 to 24, statistical analyses will be performed as well as findings will be disseminated through scientific papers, posters and conference participation. A specific plan for dissemination will be developed, including institutional newsletters, press and media release, flyers, training course throughout the national context in order to promote the implementation of the intervention on a large scale. Moreover, users and carers will be involved in the process of dissemination organizing thematic conferences for presenting the characteristics of the intervention.

The stepwise procedure is summarized in Figure 2.

Pregnancy is a stressful period for women, which can be further complicated by an early postnatal hospital discharge (85, 86). Risk factors for PD include previous mental disorders, low socioeconomic status, being a single mother, general life stress (12), unwanted and unplanned pregnancies (22), conflicts with the partner, lack of support, limited information, and stigma (87).

Despite many scientific associations and task forces, including the United States' Preventive Services Task Force (USPSTF) (88), the National Institute for Health and Care Excellence (62), the Canadian Task Force on Preventive Health Care (CTFPHC) (89) and the American College of Obstetricians and Gynecologists (68), have highlighted the importance of developing screening and treating programs for PD, there are still many unsolved issues, such as efficacy and the availability of those programs, whose efficacy has been demonstrated by RCTs.

One of the main strengths of our study is represented by the adaption of a well-known family psychoeducational model to the treatment of perinatal depression. In particular, the Falloon psychoeducational intervention was developed for the community management of schizophrenia (63, 90) and has been subsequently adapted to the management of major depression (59, 91) and bipolar disorder (57, 92–94). Perinatal depression may represent an ideal target for this kind of interventions, since it is highly dependent from stressful life events and from family context. Moreover, peripartum is a period of women's life in which pharmacological treatments should be used very cautiously and only in a limited situations. Another strength of our study is the rigorous methodology adopted, which will allow us to understand the impact of the experimental intervention on patient's outcome through a randomized controlled approach. Moreover, the main outcome is the reduction of depressive symptoms at 3-months after randomization. This is an ambitious outcome, since many confounding variables can impact on it. In particular, in some cases the childbirth represents itself an event associated with a reduction of depressive symptoms (95), thus biasing the effectiveness of the experimental intervention. Moreover, other contextual factors (such as support by family members, changes in the daily routine following the childbirth, or starting a pharmacological treatment) can have an impact on the long-term outcome. We aim to control for such variables using a statistical procedure, in order to accommodate for the impact of all these confounding variables.

Furthermore, the postnatal psychoeducation programme is suitable for clinical use as it is relatively brief and can be delivered by postnatal unit nurses and midwives after a short period of training.

Another strength of this study is the use of the EPDS as screening measure, which will allow comparisons with data from other international studies.

In order to detect patients affected by both major and minor depression, the cut-off at EPDS of ≥10 has been selected (71) and it will have to be complemented by the clinical judgment (96).

The assessment tools have been selected on the basis of their wide use in clinical practice and in clinical trials (84). Therefore, the adoption of these instruments will give us the opportunity to compare our findings with those of other previous studies. Moreover, the HAM-A and HAM-D are well-known, validated, reliable, and easy to use scales, and have been selected in order to not overburden the researchers and mental health professionals involved in the study with a specific training on the use of assessment tools (84).

Our study has some limitations. The first is the fact that the study will be carried out in one center only, with a consequent reduced generalizability of findings. However, this can be considered as a pilot study representing the basis for a larger multicentric study that our research group is planning.

Another possible limitation is the exclusion from the study of women with psychotic disorders or women with depressive disorders before pregnancy. This methodological choice was due to the need to assess and treat only patients with an onset of depression during pregnancy. Another possible limitation is the lack of a standardized pharmacological treatment for women that will be recruited for the RCT phase. Despite a standardized pharmacological treatment could be useful to assess more precisely the efficacy of the experimental psychoeducational intervention, we decided not to standardize the pharmacological treatment in order to treat women with PD under ordinary conditions. In any case, the pharmacological management of pregnant women will follow the NICE guidelines (62).

Perinatal depression represents a serious threat for mental health, also considering the detrimental consequences for children. Therefore, it is an ethical imperative to identify new strategies for adequately treat such conditions and reduce the long-term negative impact on the mothers as well as their babies and family members. We hope that the study we will carry on will help to improve the clinical, psychosocial, and family management of perinatal depression.

LS, VC, ML, MT, GS, and AF designed the study and wrote the protocol. AF, VDV, ML, and LS organized the training and supervision for mental health professionals. ADC, GF, VC, FZ, and VG performed the literature search. GS developed the plan of statistical analyses. LS, AF, MT, and ML coordinated the study.