Results of the search

The database searches identified 7767 records. This resulted in 5631 records after removing duplicates. Based on titles and abstracts, we excluded 5555 irrelevant records, resulting in retrieving 76 records (left side of PRISMA Flowchart). Additionally, from 16 identified reviews (Supplementary Material, Table S6), we identified 27 primary studies - five of them met our eligibility criteria [1, 6, 9, 27, 46].

Altogether (after database and snowball searches), we included 29 studies published in 31 papers [1, 3, 6, 8,9,10, 13, 15, 16, 18, 20, 24,25,26,27, 30, 32, 33, 35, 37, 40, 41, 43, 44, 46, 47, 49, 52, 53]. The PRISMA flow diagram is presented in Figure 1.

Figure 1

In total, we could not retrieve 13 full texts of studies therefore we labeled them as awaiting classification (Supplementary Material, List S3) and they will be checked during each update of the search. We excluded 11 studies: eight due to the wrong context and three due to the wrong concept (Supplementary Material, List S4). We identified three protocols of studies and nine abstracts which we labeled as ongoing studies (Supplementary Material, List S5).

Included studiesGeneral characteristics

The general characteristics regarding study types, funding, conflict of interests, ethical approval, and consent from participants are presented in Supplementary Material, Table S7.

We included 29 studies which were published between 1999 [9] and 2023 [18]. Nine of the research were conducted in the US (32.14%), three in Iran (10.71%), two in each country: the UK, China, Sweden, Israel, Portugal, and Brazil (7.14%), and one in each: Italy, Turkey, Denmark, Japan, and the Netherlands (3.57%).

Population

The total number of participants was 746,659 (median 74; from 1 to 575,921) — 745,749 (99.88%) women and 910 (0.12%) men. Age of the participants was presented in a heterogeneous way making it difficult to synthesize, however, in all studies if reported, the people were in early 30 to 45 years. In two studies [28,43], the population involves centers of specialists. The characteristics of the participants are presented in Table 1.

Table 1 General characteristics of participants included in studies (N=29)

All participants included in the reviewed studies had documented infertility. None of the studies focused on individuals merely at risk of infertility. One abstract (labelled as an ongoing study) included a sample of 26 transgender women, but no outcomes were yet reported.

Medication

Altogether, psychiatric medications occurred 83 times: 45 times (54.2%) medications for depression, 16 times (19.3%) - for anxiety, 9 times (10.8%) - for psychosis, 5 times (6%) mood stabilizers and 8 times (9.6%) other drugs. Regarding the time of use of the medication, most of them were used during ART (n=20/29, 68.97%), before ART (n=13/29, 44.83%), and after ART (n=7/29, 24.14%). In 3 papers (6.98%) this information was not provided.

Medications for depression

Serotonin reuptake inhibitor (SERT) constitutes the most frequently explored group of drugs for depression (n=15/29, 51.72%) with fluoxetine the most common medication (n=8/29, 27.59%). While, the second most frequently tested group was serotonin and norepinephrine reuptake inhibitors (SERT and NET) (n=4/29, 13.79%) with venlafaxine on the top (n=3/29, 10.34%) (Table 2).

Table 2 List of antidepressants examined in studies (N=29) Medications for anxiety

The most frequently examined medications were GABA Positive Allosteric Modulators with midazolam the most commonly discussed (n=6/29, 20.69%). Within this group were also diazepam (n=3/29, 10.34%), temazepam (n=2/29, 6.90%), and oxazepam, clonazepam, lorazepam which were examined once (n=1/29, 3.45%). Additionally, the general ‘benzodiazepines’ and ‘anxiolytics’ were tested once too (n=1/29, 3.45%).

Medications for psychosis

There were several antipsychotics examined in primary studies: olanzapine (dopamine, serotonin receptor antagonist (D2, 5-HT2)), clozapine, risperidone (dopamine, serotonin, noradrenaline receptor antagonist (D2, 5-HT2, NE alpha-2)), quetiapine (dopamine, serotonin, noradrenaline MM; receptor antagonist (D2, 5-HT2) and reuptake inhibitor (NET)), aripiprazole (dopamine, serotonin receptor partial agonist (D2, 5-HT1 A)), haloperidol (dopamine receptor antagonist (D2)), and promethazine (histamine, dopamine receptor antagonist (H1,D2)). None of the medicine was investigated more than once.

Medications for relapse prevention

Among medications that could be used in bipolar disorder, there were: valproic acid (acting on glutamate in unknown yet mode of action), lithium (acting on enzyme interactions), lamotrigine (acting on glutamate via voltage-gated sodium channel blocker), and general mood stabilizers.

Others

The remaining medications involved medication in sleep disturbances, opioid use disorder, or toxicology: zolpidem (GABA Positive Allosteric Modulator (GABA-A receptor, benzodiazepine site)), flumazenil (GABA receptor antagonist), ketamine (glutamate receptor antagonist), naloxone (opioid receptor antagonist), methadone (opioid receptor agonist), and other (hypnotics, not specified sedatives).

The indication for using a specific medication

A) Psychiatric indications are presented in Table 3.

Table 3 Map of psychiatric indications of medications

In 7 full texts, the indications were not reported. It regards to use of antidepressants (in 4 cases); fluoxetine, sertraline, and citalopram (each twice); and escitalopram; paroxetine; venlafaxine; nefazodone, SSRI (once).

b) Non-psychiatric indications of psychopharmacology are presented in Table 4.

Table 4 Map of non-psychiatric indications of medications described in studiesDosages of medications

The reported dosages together with the duration of treatment are presented in Tables 3 and 4. Dosages were not reported 43 times: antidepressants (n=6), SSRI (n=3), citalopram (n=2), fluoxetine (n=2), lithium (n=2), venlafaxine (n=2), sertraline (n=2), anxiolytics (n=1), antipsychotics (n=1), sedatives (n=1), mood stabilizers (n=1), escitalopram (n=1), nefazodone (n=1), paroxetine (n=1), SNRI (n=1), tricyclic (n=1), benzodiazepines (n=1), atypical antipsychotics (n=1), clozapine (n=1), olanzapine (n=1), quetiapine (n=1), risperidone (n=1), lamotrigine (n=1), valproic acid (n=1), flumazenil (n=1), hipnotics (n=1), naloxone (n=1), zolpidem (n=1).

Outcomes

The outcomes analyzed in certain studies are presented in Supplementary Material, Table S8.

Related to ART

Semen: In 26 studies semen outcomes were not considered. In the two remaining studies among outcomes were: initial total motile sperm count and final total motile sperm count — twice examined, initial total volume (ml), initial concentration (M/ml), initial motility (%), final total volume (ml), final concentration (M/ml), and final motility (%) tested once.

Cycle: In six studies number of oocytes was reported.

Efficacy: fertilization rate/pregnancy/positive conception was examined most frequently (10 times), and then number of embryos biopsied (3 times), and implantation rate (twice). Among single outcomes were: blastulation rate, number of usable blastocysts, number of euploid embryos, cycle cancellation rate, top quality embryos presence, and percentage of zygotes developing to 8-cell embryos,

Other: number of follicles punctured, transvaginal ultrasound-guided oocyte retrieval duration, number of harvested oocytes, number of initiated ART, day of transfer, day 13 hCG value, day 15 hCG value.

Related to birth

Live birth rate was examined in six studies. Multiple pregnancy rates were tested in one paper. Additionally, a spontaneous abortion rate was examined three times, together with early pregnancy loss, and miscarriage.

Related to mental state

Among outcomes related to mental states the most common one was severity of symptoms (psychotic, anxious, and depressive). The other outcomes include: sedation level, satisfaction level, TNF-α levels, cortisol levels, relapse rate, inflammatory biomarker predictors of relapse, relation between stress, incidence of side effects, time taken to achieve Aldrete score=10, and oxygen saturation.