Psychotropic drugs

Destroy Depression

Depression Causes and Treatment

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Christof Schaefer

4.9.1

Antidepressants in general

708

4.9.2

Tri- and tetracyclic antidepressants

709

4.9.3

Selective serotonin reuptake inhibitors

714

4.9.4

Other antidepressants

718

4.9.5

Phenothiazine and thioxanthene neuroleptics

720

4.9.6

Butyrophenones

724

4.9.7

Atypical neuroleptics

724

4.9.8

Antimanic drugs

727

4.9.9

Benzodiazepines

727

4.9.10

Other anxiolytics

730

4.9.11

Other hypnotics

731

4.9.12

Psychoanaleptics

732

4.9.13

Parkinson drugs

732

4.9.1 Antidepressants in general

Occurring with a frequency of approximately 10-15°/o, depression represents a significant problem after delivery. Women delivering their first child are overrepresented. The symptomatology ranges from slight depression as a reaction to the new situation and pressures after delivery, to deep depression with melancholic characteristics - or even to psychotic depression. Untreated pronounced depression can lead, just like other psychiatric illness, to a disturbance in the early mother-child relationship, and impairment of early behavioral development.

Under such circumstances, psychotherapeutic and (if necessary) psychopharmacological therapy should be considered. Apart from tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI) arc predominantly used. Among tricyclics, tertiary amines with pronounced anticholinergic and sedating characteristics (arnitriptylin, imipramine, clomipramin, doxepin) are distinguished from secondary (desipramin, nnrtriptylin) and primary (amoxapin) amines, where these properties are less strong. Recently, 95 women with postpartum depression were treated with cither tricyclic nortriptyline or the SSRI sertraline. The proportions of women who responded and remitted did not differ between the drugs at 4, 8 or 24 weeks. The total side-effect burden of each drug was similar, although side-effect profiles differed between agents. Breastfed infant serum levels were near or below the level of quantifiability for both agents (Wisner 2006).

In so far as they have been studied, the M/P ratios of antidepressants lie between I and 2. However, there are considerable individual variations. For most antidepressants, only traces were dctectcd in the scrum of breastfed children. Toxic symptoms (mostly moderate) have only been observed in breastfed infants whose mothers were being treated with citalopram, doxepin, and fluoxetin (overview in Weissman 2004).

With SSRIs in particular, the highest drug concentration in the milk can be expected up to 8 hours after intake - and thus brief interruptions of breastfeeding for a few hours do not necessarily limit the baby's exposure. However, it might be advisable to take the medication after the last feed at night.

Combination therapy using several psychoactive drugs should be viewed very critically while breastfeeding. When combination therapy is unavoidable, decisions about possible limitations on breastfeeding need to be made on a case-by-case basis. Basically, accumulation in young infants under 8 weeks of age, especially in those born prematurely, cannot be ruled out under long-term medication.

Long-term effects of antidepressants used during breastfeeding have barely been studied. The WHO Working Group on Drugs and Human Lactation (Bennett 1996) classifies most of the tricyclic antidepressants and some of the SSRI as "probably safe", as does the American Academy of Pediatrics (2001).

4.9.2 Tri- and tetracyclic antidepressants

Amitriptyline

Up to 95% of amitriptyline is protein-bound and is rapidly metabolized to nortriptyline, which is also pharmacologically active. Six breastfeeding women taking 75-175 mg amitriptyline a day were studied (survey in Weissman 2004). The M/P ratio was 1; the relative dosage for a fully breastfed baby, including the active metabolites, should not, in light of current experience, exceed 2.5%. Amitriptyline and nortriptyline could not be detected in the infants' serum. The children had no acute clinical symptoms. Among the 10 infants breastfed while their mothers were taking tricyclic antidepressants, development in the first year of life did not differ from that of the artificially fed infants in a control group (Yoshida 1997A).

Amoxapine

Galactorrhea was reported with a daily intake of 250 mg amoxap ine. The patient was neither pregnant nor breastfeeding. Less than 20fig/l amoxapine plus 140|ig/i of the metabolite 8-hydroxy-amoxapine were excreted in the milk. An M/P ratio of about 0.3 and a relative dosage of 0.7% can be calculated with the available data (cited in Spigset 1998).

Clomipramine, half-life 32 hours, increases the prolactin levels and can stimulate lactation. The pharmacologically active metabolites are N-desmethylclomipramine and two hydroxy-metabolites - 8-OH-clomipramine and 8-OH-desmethylclomipramine. Based on seven published mother-child pairs, the average relative dosage is 1.3% (overview in Weissman 2004). After birth, 267|ig/l were measured in the plasma of an infant who had been exposed prenatally (the mother took 125 mg clomipramine a day). From the seventh day postpartum, the dosage was increased to 150 mg daily. The maternal plasma concentration rose from 355[ig/l on day 10 to 510 jig/l on day 35. The milk concentration was between 270 and 624|ig/l. In the same period of time, concentrations decreasing from 45|ig/l to 9.8(ig/l were measured in the infant's serum (this was due to the breakdown of the drug transferred prenatally). Assuming the highest value reported in the milk, the dosage for a fully breastfed baby -without considering the metabolites - would seem to be 4% of the maternal weight-related dosage (Schimmell 1991).

In a further study, four mother-child pairs were studied. The mothers took between 75 mg and 125 mg¡of clomipramine daily. Milk samples were not studied. Neither clomipramine nor its metabolites (detection level 10 ng/1) could be detected in the infants' serum (Wisner 1995). A newer study showed concentrations in the milk of two women, that were similar to those reported by Schimmell in 1991 (Yoshida 1997A). The infants did not show any signs of effects from the medication.

Desipramine, with a half-life ranging from 12 to 54 hours, is the pharmacologically active metabolite of imipramine. Up to 95% is bound to plasma protein.

On the basis of five published mother-child pairs, an average relative dose of 1.6% can be expected (overview in Weissman 2004).

In a case report, 381 [ig/l were measured in the milk with a dosage of 300mg/day. An infant would get up to 2.4% of the maternal weight-adjusted dose, when the metabolite 2-hydroxydesipramine is included (Stancer 1986). Only slight traces (if any) of imipramine could be measured in the serum of four further examined children. The babies did not show symptoms.

Dosutepine (= dothiepin), half-life 9 hours, is metabolized in the liver into the three pharmacologically active metabolites nordo-sulepine, dosulepine sulfoxide, and nordosulepiue sulfoxide. One study examined eight women (Ilett 1993). In a further study, 20 breastfeeding mothers received dosulepine (Buist 1993A). The M/P ratio of dosulepine is about 1. With treatment of up to 225 mg daily, a maximum of 475(ig/l dosulepine plus 1200|ig/l of the metabolites was measured. The highest values on the same order of magnitude were reported in another study of two women (Yoshida 1997A). Based on these data, a maximum of 7% of the maternal weight-related dosage is calculated for the infant when the metabolites are included. However, on average it is below 1% (survey in Weissman 2004). For one child, only traces of the active ingredient (4 ng/l) were detected in the serum; the maternal serum level was 2623|tg/l (Yoshida 1997A). No effects were observed in the newborns. In a further study, prenatally exposed children aged 3 and 5 years were followed up. There was nothing remarkable about them compared to a non-exposed control group (Buist 1995).

Doxepin

Up to 80% of doxepin and its active metabolite N desmethvldox-epin is bound to the plasma protein. The half-life of doxepin ranges from 8 to 25 hours; that of N-desmethyldoxepin is 33-81 hours. In a study of two breastfeeding mothers, one of whom received 150 mg and the other 75 mg of doxepin daily, an average of 0.3-1% of the maternal weight-related dosage (including the metabolite N-dcsmethyldoxepin) was reported for the infant (Kemp 1985), One of the infants had to be treated for depressed breathing and sedation. Values of 2.2[ig/l doxepin and - corresponding to the maternal concentration - 66|ig/l JV-desmethyldoxepin - were measured in his serum (Matheson 1985). Symptoms improved after changing to artificial feeding. It would seem that accumulation must be expectcd in an infant. A further case report describes a 9-day-oid boy with a weak suck, muscular hypotonia, and vomiting. His mother took 35 mg doxepin a day. Doxepin was found in the infant's serum just at detection level (lOpg/i); the metabolite could not be detected. The symptoms disappeared 48 hours after changing to artificial feeding (Frey 1999).

Imipramine has a half-life of 6-20 hours. Up to 95% is bound to plasma protein. With a dose of 200 mg imipramine a day, a maximum of 29|ig/i of imipramine and 35|ig/l of desipramine (metabolite) were measured in the milk (Sovner 1979). By contrast, in four mothers in a newer study taking 75-150 mg daily, active ingredient concentrations of up to 600(ig/l were measured in the milk. Most of the values, however, were significantly under 300|ig/l (Yoshida 1997A). Based on these data, a maximum of 90 ng/kg per day, or 7% of the maternal weight-related dosage, could be calculated for the baby. However, on average, it is below 2% (survey in Weissman 2004).

Maprotiline

Following treatment with 100-150 mg daily of maprotiline, a tetracyclic antidepressant, a relative dosage of 1.6% was reported in an older study; however, this did not take into account active metabolites (survey in Bennett 1996).

Mianserin is also a tetracyclic antidepressant. Up to about 90% of it is bound to plasma protein, and it has a half-life of around 22 hours. The primary active metabolite is desmethylmianserin. Two breastfeeding women, one of whom took 40 mg and the other 60 mg of mianserin daily, were studied; levels of 20[ig/l and SO^g/l, respectively, of mianserin were measured in the milk. For desme-thylmianserin, these figures were 20pg/l and 10|ig/l respectively. Including the metabolites, a maximum of 1.5% of a weight-related dosage for an infant was calculated. No medication could be detected in the scrum of the first baby; when the urine of the second baby was examined, 12 ng/1 of mianserin and 14[ig/l of dcsmethyl-mianserin were reported (Buist 1993B).

Nortriptyline, half-life 37 hours, is the active metabolite of amitriptyline. Experience with a total of 27 mother-infant pairs, where the mothers were taking 50-175 mg nortriptyline a day, indicated that no acute toxic symptoms would be expectcd among the breastfed infants. The M/P ratio (about 1) and the relative dosage (not over 2-3%) correspond to the experience with amitriptyline mentioned above (survey in Weissman 2004, Spigset 1998). Only in the case of a 4-week-old baby, whose mother took 60 mg a day and had a serum concentration of just 42|ig/l, could 10|ig/l nortriptyline be detected in the infant's serum. In other studies, infant serum levels were near or below the level of quantifiability (Wisner 2006). With some of the other children, only very minute amounts of nortriptyline's 10-hydroxy-metabolite were found.

Opipramol

There is an older study of 10 women on opipramol, which indicates an M/P ratio of 0.1 and a relative dosage of only 0.3% (Herrmann 1970).

There are either no or insufficient data on the substances diben-zepin, lofepramine, and trimipramine.

Recommendation. When drug treatment for depression is urgently needed, monotherapy with amitriptyline, clomipramine, nortriptyline, imipramine, desipramine or dosulepine is the treatment of choice during breastfeeding. With compelling indications, other tricyclics are also acceptable. Doxepin should be avoided. In cases of symptoms potentially associated with drug therapy, a pediatrician and a teratology information center should be contacted to decide individually upon measuring drug values in the infant's serum, supplementary formula feeding, weaning, and/or changing therapy. There is insufficient information on the long-term effects of antidepressant medication taken during breastfeeding.

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