Paragraph 11 of the German Medicinal Products Act requires that either drug class or indication group or mechanism of action (Bundesministerium der Justiz 2019) be stated in the package insert. All 311 package inserts examined fulfil this requirement. In 59% (185 package inserts in absolute terms) only the substance or indication group is mentioned and in the remaining 41% (126 package inserts in absolute terms) the mode of action is also described (Fig. 2). However, this is not a detailed explanation, but just a very rough outline in 2 to 3 sentences. Whether the substance group or the effect, meaning the mode of action is stated, is usually standardised within a substance class. Exceptions to this are the active substances risperidone, citalopram, and escitalopram. For the PIs of the mGPCR antagonists haloperidol, clozapine, melperone, opipramol and quetiapine, the mode of action is mentioned, but not the substance group. In the case of olanzapine, both are mentioned (Fig. 3). The PIs of risperidone explain the mode of action of the substance in 87% (identification numbers 188–220), the remaining 13% (identification numbers 221–225) are limited to naming the substance group (Fig. S2). The modes of action of moclobemide and sertraline are not mentioned in the NE/5-HT enhancers, whereas they are mentioned for venlafaxine. 29% of the PIs of citalopram (identification numbers 251–254 and 259–262) contain an explanation of the mode of action, and 71% (identification numbers 255–258 and 263–274) contain only a mention of the substance or indication group (Fig. S3), 88% of the PIs of escitalopram (identification numbers 275–292 and 296–299) contain an explanation of the mode of action and 12% (identification numbers 293–295) contain only a mention of the substance or indication group (Fig. S4). It is striking that pharmacologically very similar drugs differ significantly in PIs (Fig. 3, Fig. S3, Fig. S4).

Effect-overall. This diagram shows the distribution of all 311 PI between PI in which the substance or indication group is mentioned (blue) and PI with the mode of action mentioned (orange)

Effect of the respective drugs. This diagram shows how many PIs contain a description of the mode of action (orange) plotted against the active substances, as well as how many PIs only contain the substance or indication group (blue) plotted against the active substances

“The suicide rates among people with serious mental illness [are already …] high” (Fu et al. 2023). Treatment with NE/5-HT enhancers can further increase this risk, as the various effects often only occur in a staggered manner when a new patient is prescribed the drug. As a rule, there is an increase in drive at the beginning and only after a time delay does the mood improve. The patient is therefore particularly at risk during this initial time interval and must be explicitly informed about this. No increased risk has been proven to date for treatment with mGPCR antagonists, but the extent to which a potential risk is pointed out was also examined. The analysis points out that 43% of all PIs analysed refer to an increased risk of suicide. In the other 57%, the topic is not mentioned. 100% of the PIs of NE/5-HT enhancers and 33% of the PIs of mGPCR antagonists refer to the increased risk (Fig. 4). Under 25-year-olds and patients who have already shown suicidal or auto-aggressive behaviour in the past are mentioned as particularly suicidal risk in all PIs of NE/5-HT enhancers and in those of quetiapine. If one searches the literature for the suicide risk associated with quetiapine use, “there is no evidence of treatment-emergent suicidality with quetiapine” (Weisler et al. 2014).

Suicidal risk. The diagram shows the suicidal risk in regard to the respective drugs. It distinguishes between active substances with no elevated risk (blue) and active substances for which an elevated suicidal risk is mentioned in the PI (orange)

Many PIs often include a long list of medications with which the preparation may interact. This fact often leads to uncertainty on the part of the patient. The patient may not be aware that many of the drugs listed are hardly relevant on the German market or in some cases are no longer authorised and, therefore, no longer pose a risk. The 55 irrelevant drugs mentioned belong, among others to the group of antibiotics (antibacterial drugs), anticoagulants, antihypertensives, diuretics, and psychotropic drugs (Table S2). The drugs are not listed in the drug prescription report of 2022 and 2023 or have no prescriptions (Ludwig et al. 2023).

In addition to the many drugs that are irrelevant, there is also at least one spelling mistake when mentioning the name of an active ingredient. For example, “thioridazine” becomes “thiorizadine”. A patient who does not recognise “their” medication could be at risk from potential interactions.

In addition to interactions with co-medications, interactions with food and stimulants can also occur (Table 2). Whether and which interactions are to be expected is standardised in the PI of an active substance. According to the PI, there are no interactions with the drugs haloperidol, olanzapine, opipramol, venlafaxine, citalopram and escitalopram. As stated in the PIs clozapine, on the other hand, interacts with both caffeine and tobacco. The plasma concentrations are increased by caffeine consumption. This means that dose changes of clozapine may be necessary after a change in the usual caffeine intake (Kämmerer 2011). Tobacco consumption, on the other hand, leads to enzyme induction, which is associated with a faster breakdown of clozapine. The serum concentrations of clozapine achievable with a standard dose are considerably reduced in smokers and there may be a total loss of efficacy. An increase in dose is therefore necessary in smokers. Quitting tobacco smoking can lead to a sharp increase in the plasma level of clozapine. Patients should therefore be sure to inform their doctor of any plans to stop smoking. In such cases, the dose of clozapine should be reduced accordingly (Kämmerer 2011). Although the PI of clozapine indicates that a change in smoking behaviour can have an effect, the exact course of events is not explained, so that it remains unclear when and whether an under- or overdose can occur. For the intake of melperone, the PI does refer to interactions with milk, coffee, and tea, but this information has not been substantiated by scientific articles (search keywords on PubMed: melperone AND milk, melperone AND coffee, melperone AND tea). Quetiapine and sertraline are known to interact with grapefruit via cytochrome P450 3A4 metabolism. “Grapefruit juice has been shown to be an inhibitor of CYP3A4 [… and] there are many reports suggesting that grapefruit juice can inhibit the pharmacokinetics of drugs that are metabolized by CYP3A4. [A corresponding] increase [in] the plasma level” can thus be associated with an overdose (Ueda et al. 2009). When taking risperidone, the PIs differentiate between the solution and tablet form about the interaction. The tablets do not interact with food and stimulants, whereas the solution interacts with tea. The tea catechins, especially epifallocatechinallate (EGCg), form insoluble complexes with the risperidone solution, which reduce the efficacy of the drug (Goromaru et al. 2023; Ikeda et al. 2010, 2012). According to PI, the active ingredient moclobemide interacts with tyramine-rich foods such as mature cheese or red wine. Although the “hypertensive crisis after ingestion of tyramine-rich food [… only] becomes clinically relevant from a moclobemide dosage above 900 mg/d” (Bonnet 2003) or in combination with other drugs that interact with tyramine-rich food, the interaction should not be challenged regardless of the dosage.

Interactions between the psychotropic drug and alcohol are generally always warned against, regardless of scientific evidence. The only difference is the urgency of the wording. The information in the package inserts for haloperidol, clozapine, olanzapine, melperone, quetiapine, risperidone, venlafaxine, and escitalopram is standardised regardless of manufacturer and dose. For opipramol, moclobemide and sertraline, the information provided by the individual manufacturers varies slightly but is independent of the dose. The same applies to venlafaxine, where there is an additional warning about extreme tiredness and unconsciousness. For the intake of citalopram, different information is given even for different dosages from one manufacturer. In 27.97% of PIs, it is advised to avoid alcohol, and in 28.20% of PIs, it is recommended to “pay attention” to it. According to 27.33% of PIs, the combination of alcohol with psychotropic drugs is prohibited. In 10.89% of the PIs, it is stated that no interactions are to be expected, but that the combination should nevertheless be avoided. Other formulations are “abstain” (2.24%), “advise against” (1.92%) or “give with caution” (0.64%). Only in 0.64% of the package inserts is the section on interaction with alcohol completely missing (Fig. 5, Fig. S5).

Various general formulations that warn against the additional intake of alcohol. This diagram shows the distribution of different formulations concerning the warning against the additional intake of alcohol during the therapy with psychotropic drugs

The interaction between alcohol and psychotropic drugs occurs either via pharmacodynamics or pharmacokinetics (Weathermon and Crabb 1999). However, no information on mechanisms of action can be found for the drugs melperone, opipramol, risperidone, and escitalopram. Haloperidol, olanzapine, citalopram, and sertraline interact via pharmacodynamics. For olanzapine, it has been proven that the combination with alcohol increases the depressant effect on the central nervous system, which can ultimately lead to a drop in oxygen saturation (Callaghan et al. 1999; Wilson et al. 2012). The combination of alcohol with citalopram or sertraline can result in changes in EEG waves (Pietrzak and Czarnecka 2003). Clozapine, quetiapine, moclobemide, and venlafaxine interact with alcohol via the pharmacokinetic mechanism. In the case of clozapine, “the concomitant use of alcohol is associated with a significant[ly potentiated] risk of severe adverse reactions” (Monroy-Jaramillo et al. 2022). In contrast, the combination of quetiapine with alcohol leads to a decrease in the serum level of the drug and to an increase in the effect of alcohol (Aburamadan et al. 2021; Gujjar et al. 2016). For moclobemide and venlafaxine, it is known that the interaction is pharmacokinetic, but no or only a few specific interactions with alcohol are mentioned (Tiller 1990; Troy et al. 1997; Uzbay et al. 1995).

The reproductive topics covered in the PI relate to pregnancy, breastfeeding, fertility, and sexual dysfunction. Although the information in the PI is standardised, it is very general and therefore appears to be more of a legal safeguard. In addition, they do not correspond to the current scientific status of Embryotox. Embryotox was founded in 1988 and is dedicated to the professional exchange and harmonisation of counselling procedures as well as the scientific evaluation of exposed pregnancies since 1990 (Embryotox Redaktion, n). In 2004, the advisory centre became the Pharmacovigilance and Advisory Centre for Embryonal Toxicology (Embryotox Redaktion, n). The internet portal used was developed in 2008 and focuses on drug therapy during pregnancy and breastfeeding. The information on the respective active substance pages may differ from the information in the Information for healthcare professionals, the Red List and on the package leaflet. They take into account relevant study results from specialist journals as well as the current state of discussion in relevant professional associations (Embryotox Redaktion, a).

About pregnancies, the PIs for clozapine, olanzapine, risperidone and moclobemide only advise informing the doctor. This information, with the addition that the medication should be discontinued, can also be found in the PIs for haloperidol, melperone, opipramol, and quetiapine. The PIs for venlafaxine, citalopram, escitalopram, and sertraline advise to inform your doctor and discontinue the medication. There is also a warning about vaginal bleeding. In addition to the paragraph on pregnancy itself, all PIs, except those for opipramol and moclobemide, warn that continuous use of the medication can lead to withdrawal symptoms in the newborn within 24 h of delivery. These would then manifest themselves in the form of drowsiness, agitation, drinking difficulties and breathing difficulties, as well as hyper- and hyporeflexia (Fig. 6, Fig. S6).

Package insert recommendations during pregnancy—overall. This diagram shows the distribution of different recommendations given in all 311 PIs for the time during the pregnancy

Embryotox provides much more specific instructions than the package inserts. Haloperidol may be taken during pregnancy if no more tolerable antipsychotics, such as quetiapine or risperidone, can be considered (Embryotox Redaktion, e). In the case of clozapine, it is not necessary to switch patients who are well-controlled. However, readjustment should be carried out with better-proven mGPCR antagonists such as quetiapine, possibly risperidone or, if necessary, haloperidol (Embryotox Redaktion, c). If melperone was taken before pregnancy, a switch should be made to a better-proven sedative. Promethazine and, in the case of sleep disorders, amitriptyline, and diphenhydramine are suitable for this purpose (Embryotox Redaktion, f). The use of olanzapine can also be continued in well-adjusted patients, but a new adjustment to this medication should not be made during pregnancy, but rather started with quetiapine. In general, quetiapine, risperidone and haloperidol are better alternatives during pregnancy (Embryotox Redaktion, h). Opipramol therapy can be continued in well-adjusted patients, but an alternative medication should be chosen depending on the indication in the case of a new adjustment (Embryotox Redaktion, i). The mGPCR antagonist quetiapine can be taken in any case (Embryotox Redaktion, j). Treatment with risperidone may be continued in well-adjusted patients, but should be replaced by quetiapine in new patients (Embryotox Redaktion, k).

According to Embryotox, the use of NE/5-HT enhancers may generally be continued during pregnancy. When taking moclobemide, a switch should be urgently prevented. However, a readjustment, especially before a planned pregnancy, should be made directly with an active substance of the tricyclic antidepressants (TCA) or the selective serotonin reuptake inhibitors (SSRI) (Embryotox Redaktion, g). The prescription of venlafaxine does not have to be changed, but the new setting should rather be with citalopram or sertraline (Embryotox Redaktion, m). The SSRI escitalopram may continue to be taken during pregnancy, although citalopram and sertraline are also better alternatives here. According to Embryotox, the latter is the drug of choice for treating depression during pregnancy anyway and should therefore not be changed (Embryotox Redaktion, b; Embryotox Redaktion, d; Embryotox Redaktion, l).

Whenever psychotropic drugs are taken during pregnancy, close psychiatric and gynaecological monitoring should be carried out. When taking clozapine, olanzapine, quetiapine and risperidone, the risk of gestational diabetes must be considered. In addition, close ultrasound examinations, especially in the first trimester, should document unremarkable foetal development. If possible, the delivery should take place in a clinic with a neonatology unit, as postnatal adjustment disorders cannot be ruled out (Embryotox Redaktion, b; Embryotox Redaktion, c; Embryotox Redaktion, d; Embryotox Redaktion, e; Embryotox Redaktion, f; Embryotox Redaktion, g; Embryotox Redaktion, h; Embryotox Redaktion, i; Embryotox Redaktion, j; Embryotox Redaktion, k; Embryotox Redaktion, l; Embryotox Redaktion, m). When taking mGPCR antagonists, adaptation disorders can manifest themselves in the form of neurological, gastrointestinal, respiratory, or extrapyramidal-motor symptoms; very rarely, seizures can also occur. Due to the risk of agranulocytosis, the use of clozapine requires additional blood tests of the newborn child (Embryotox Redaktion, c; Embryotox Redaktion, e; Embryotox Redaktion, f; Embryotox Redaktion, h; Embryotox Redaktion, i;Embryotox Redaktion, j; Embryotox Redaktion, k). Taking the NE/5-HT enhancers moclobemide and venlafaxine can also lead to neurological, gastrointestinal, and respiratory disorders in the newborn after birth. In rare cases, the previous intake of venlafaxine can also lead to seizures or myoclonus in the newborn. In general, the use of SSRIs can lead to hyperexcitability, tremor, drinking disorders, respiratory distress syndrome, hypoglycaemia and sleep or behavioural abnormalities in newborns. It is therefore advisable to reduce the dose of the respective NE/5-HT enhancer one to two weeks before delivery and to increase it again postpartum to minimise withdrawal symptoms in the newborn as much as possible (Embryotox Redaktion, b; Embryotox Redaktion, d; Embryotox Redaktion, g; Embryotox Redaktion, l; Embryotox Redaktion, m). Table 3 shows a comparison of the information given in the package inserts and by the Embryotox website.

The PIs also provide only vague information for the breastfeeding phase. For the use of haloperidol, risperidone, moclobemide and venlafaxine, the only advice given is to consult a doctor. This recommendation is supplemented in the PI of citalopram by the advice not to breastfeed. A specific ban on breastfeeding is issued for the use of clozapine, melperone, olanzapine, quetiapine and sertraline. The PIs for escitalopram state that the medication can pass into breast milk, but there are no more specific instructions (Fig. 7, Fig. S7). Embryotox gives more differentiated recommendations here. Haloperidol can be taken during breastfeeding in low doses and as monotherapy, but attention should be paid to developmental delays, sedation, drinking difficulties, restlessness, extrapyramidal motor disorders and gastrointestinal symptoms (Embryotox Redaktion, e). The same applies to the use of clozapine, although this is viewed somewhat more critically, as the risk of agranulocytosis in the child cannot be ruled out (Embryotox Redaktion, c). Melperone and opipramol can also be taken during the breastfeeding phase, but here too attention must be paid to possible drinking difficulties, restlessness, extrapyramidal motor disorders and gastrointestinal symptoms (Embryotox Redaktion, f; Embryotox Redaktion, i). Olanzapine, quetiapine, and risperidone are permitted in low doses and in monotherapy, but the newborn should also be closely monitored here (Embryotox Redaktion, h; Embryotox Redaktion, j; Embryotox Redaktion, k). Breastfeeding is also acceptable in the context of antidepressant therapy with moclobemide, venlafaxine, citalopram and escitalopram, provided there are no signs of sedation, drinking difficulties or restlessness (Embryotox Redaktion, b; Embryotox Redaktion, d; Embryotox Redaktion, g; Embryotox Redaktion, m). According to Embryotox, however, the drug of choice during breastfeeding is sertraline (Embryotox Redaktion, l).