Tricyclic antidepressants in pregnancy and puerperium.

Review

Tricyclic antidepressants in pregnancy and puerperium Salvatore Gentile 1.

Introduction

2.

General considerations

3.

Studies investigating the reproductive safety of single TCAs

Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Laval on 06/22/14 For personal use only.

4.

Studies investigating the reproductive safety of TCAs as a group

5.

Conclusions

6.

Expert opinion

Mental Health Center Cava de’ Tirreni - Vietri sul Mare, Department of Mental Health, ASL Salerno, Cava de’ Tirreni (Salerno), Italy

Introduction: Several concerns have been raised regarding the reproductive safety of the antidepressants most frequently used in clinical practice, such as selective serotonin reuptake inhibitors (SSRIs). Areas covered: This article aims to assess the risk/benefit ratio of the use of alternative pharmacological options, specifically tricyclic antidepressants (TCAs) in pregnancy and puerperium. Expert opinion: Although TCAs have been prescribed for several decades, their own teratogenic potential to cause structural defects remains undetermined. However, some signals seem to exist suggesting that prenatal clomipramine exposure may increase the risk of cardiac defects. Moreover, TCAs have been associated with the risk of prenatal antidepressant exposure syndrome. Among TCAs, clomipramine seems to be associated with more severe and prolonged neonatal symptoms. However, some findings of this syndrome reported with SSRI use, such as persistent pulmonary hypertension of the newborn, necrotizing enterocolitis and QT prolongation, have not been described after TCA exposure. Hence, current evidence suggests that, as a group, a preference of TCAs over SSRIs in early pregnancy is not justified. In contrast, there appears to be a small gain in safety if TCAs (with the exception of clomipramine) are used in late pregnancy. Among this class of antidepressants, nortriptyline seems to be safest medication for use during breastfeeding. Keywords: breastfeeding, pregnancy, safety, tricyclic antidepressants Expert Opin. Drug Saf. (2014) 13(2):207-225

1.

Introduction

Although pregnancy is considered a time of emotional wellbeing for women, a number of epidemiological studies have shown that pregnancy does not protect from mood disorders. Indeed, in community samples, about 10% of women show perinatal depressive symptoms [1,2]. Moreover, when women with a past history of major depressive disorder discontinue their medication during pregnancy, the risk of relapse is as high as 65%, whereas only 25% of women who continue pharmacological treatment experience recurrence of mood symptoms [3]. Antenatal depression is an important clinical problem because it is associated with various adverse consequences for mothers and children [4], such as suboptimal obstetric outcomes (including increased rates of premature births and babies small for gestational date) [5,6]. Moreover, many untreated women continue to show depressive symptoms after parturition, and thus, they are at risk of impaired interaction with their infant at a time when the child is in a particularly sensitive developmental period [7,8]. As in the general population, the most frequently prescribed antidepressants in pregnancy are selective serotonin reuptake inhibitors (SSRIs) [9]. Whether these compounds lead to any increase in the rate of congenital anomalies and perinatal problems has been the matter of several epidemiological and case-control studies. 10.1517/14740338.2014.869582 © 2014 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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Article highlights. . .

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Clomipramine may be associated with an increased risk of cardiovascular defects. Current evidence suggests that, as a group, a preference of TCAs over SSRIs in early pregnancy is not justified. TCAs have the potential to cause the PAES, although no cases of PPHN, necrotizing enterocolitis or QT prolongation (described with SSRI exposure) have been reported. There appears to be a gain in safety if TCAs (with the exception of clomipramine) are used in late pregnancy. Among this class of antidepressants, nortriptyline seems to be safest medication in breastfeeding.

This box summarizes key points contained in the article.

So far, results are conflicting: several reports indicate that the overall rate of congenital malformations is not increased compared to that detectable in the general population [10-15], whereas other studies show a modest increase in the risk of cardiovascular defects or other congenital malformations with SSRIs as a group or specific SSRIs, such as citalopram, fluoxetine, paroxetine and sertraline [16-19]. An emerging concern about the reproductive safety of SSRIs has been raised by case-control studies which have reported an increased risk of a potentially life-threatening condition, such as persistent pulmonary hypertension of the newborn (PPHN), after exposure to SSRIs during late pregnancy; however, this finding remains controversial [20-22]. Conversely, it has been known for some years that infants prenatally exposed to SSRIs are more likely to suffer from a complex constellation of symptoms included under the definition of prenatal antidepressant exposure syndrome (PAES) [23,24]. In the USA and Australia, existing pregnancy labels for antidepressants do not indicate a differential assessment of the teratogenic risks posed by SSRIs (except for paroxetine) and tricyclic antidepressants (TCAs) [25,26]. However, the US FDA and Health Canada advised prescribers of the potential for neonatal adverse reactions after third trimester exposure to SSRIs and serotonin--noradrenalin reuptake inhibitors (SNRIs) [27,28]. In contrast, no warnings have been issued for TCAs. In the UK the National Teratology Information Service recommends two TCAs, namely, amitriptyline and imipramine, as first-line agents for antenatal depression [29]. The clinical guidelines of the National Institute for Health and Clinical Excellence in England and Wales also states that prescribers ‘should take into account that tricyclic antidepressants (TCAs), such as amitriptyline, imipramine, and nortriptyline, have lower known risks during pregnancy than other antidepressants’ [30]. The lack of uniformity in the existing guidelines makes it difficult for clinicians to choose the best available option for female patients of childbearing age. Hence, this systematic 208

review aims to provide an up-to-date analysis of the available evidence on the safety of TCAs in early and late pregnancy, and during breastfeeding. The implications for the choice of the safest pharmacological option in this population of patients will be also discussed. Data source, study selection and data extraction are available in Appendix 1. 2.

General considerations

Pregnancy Physiological changes occurring during pregnancy may alter pharmacokinetics of drugs [31]. Plasmatic levels of TCAs may actually decrease during the second trimester. Such a decrease may be the result of increased plasma volume, drug-metabolizing enzyme activity and renal clearance [32]. Thus, especially during the third trimester, the need for an increase in the daily medication dose to maintain therapeutic blood levels may occur [33,34]. Whether these changes play any role in influencing the reproductive safety of medications is not known. 2.1

Breastfeeding All TCAs are excreted into breast milk. Almost all of them are weak bases, and thus, are likely to show milk-to-plasma (M/P) ratios (the ratio of drug concentration in breast milk to drug concentrations in maternal plasma) > 1, a historical notional level of concern [35]. However, the clinical implications of this finding remains uncertain: in fact, in infants exposed to other classes of antidepressants, unwanted reactions have often been described with M/P ratio values < 1 [36]. 2.2

Studies investigating the reproductive safety of single TCAs

3.

Imipramine and desipramine Imipramine, desipramine and pregnancy 3.1.1.1 Fetal malformations 3.1

3.1.1

During the early 1970s, in the light of preliminary investigations [37,38], reports in Canadian and British press, radio and television warned not only about the risk of limb anomalies [39] but also other types of fetal malformations [40-42] associated with in utero exposure to imipramine. In 1973, on the basis of this safety signals, the Australian Drug Evaluation Committee (ADEC) requested the manufacturer of the drug to provide details of all published and unpublished data on outcomes of imipramine-exposed pregnancy. The ADEC also asked major maternity hospitals in Australia, as well as other Committees on Safety of Medications in several American and European countries, to make available information about any suspected cases of imipramine-associated fetal malformations. After analyzing this information, the ADEC concluded that ‘current assessment proves no causal relationship’ between imipramine exposure during early pregnancy and an increase in the risk of congenital birth defects [43].

Expert Opin. Drug Saf. (2014) 13(2)

Tricyclic antidepressants in pregnancy and puerperium

A number of published reports have actually described healthy fetal outcomes after exposure to imipramine during various stages of pregnancy [44-48]. As regards desipramine, there are no published reports describing the timing of exposure during pregnancy. Perinatal complications Small case-series studies and case reports suggest that late pregnancy exposure both to imipramine and desipramine might be associated with the risk of perinatal complications, mainly due to withdrawal phenomena [47-49]. Published data on the use of imipramine and desipramine during pregnancy are summarized in Table 1A. Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Laval on 06/22/14 For personal use only.

3.1.1.2

(nortriptyline and 10-hydroxynortriptyline) into breast milk widely varies, depending on maternal dosage, time of investigation after parturition and whether fore- or hind-milk were analyzed. Until now, there have been no reports describing detrimental reactions in infants exposed to the medication through maternal milk (Table 2B) [62-64]. As summarized in Table 2B, seven studies (including a total of 28 cases) investigated the safety of nortriptyline for the breastfed infant, and showed no clinically adverse outcomes [47,51,65-69]. When measured, the serum levels of the parent drug and its metabolites in the breastfed infant were either below the detection limits or very low. Clomipramine Clomipramine and pregnancy 3.3.1.1 Fetal malformations 3.3

3.1.2

Imipramine, desipramine and breastfeeding

Research on imipramine includes case reports and case-series studies, overall investigating 21 mother--infant pairs. Serum concentration were measured in a few cases [50-52]. However, the infant clinical outcome was reassuring [47,50,52]. Seven infants have been described whose mothers were taking desipramine while breastfeeding. No detrimental effects were observed [47,51,53]. In six of these cases, plasma levels of the parent drug and/or its metabolite (2-hydroxydesipramine) were found to be below the detection limit [51,53]. Published data on the use of imipramine and desipramine during breastfeeding are shown in Table 1B. Amitriptyline and nortriptyline Amitriptyline, nortriptyline and pregnancy 3.2.1.1 Fetal malformations 3.2

3.2.1

Database analyses and cohort studies failed to demonstrate an increase in the risk of fetal malformations after exposure to amitriptyline and its metabolite nortriptyline during various stages of pregnancy [44,54]. Conversely, anecdotal clinical observations, as well as signals from prospective studies, reported some cases of fetal malformations (mainly including not only limb anomalies but also a variety of other defects) following in utero exposure to both drugs are available [41-43,55-57]. Main limitation of such studies was that approximately two-thirds of the mothers were on polypharmacotherapy [41,42]. Perinatal complications A number of case reports suggested that late in utero exposure to both amitriptyline and nortriptyline might be associated with perinatal complications [42,58-60]. However, neonatal problems were usually associated with long-term polypharmacotherapy. Table 2A shows studies investigating the safety of amitriptyline and nortriptyline in pregnancy. 3.2.1.2

Amitriptyline, nortriptyline and breastfeeding Although the first case report on amitriptyline exposure via maternal milk dates back to almost 3 decades ago [61], there have only been seven additional cases reported since [47,50,58,62-64]. Secretion of amitriptyline and its metabolites 3.2.2

3.3.1

One case series and one prospective study failed to show an increase in the structural teratogenic risk after in utero exposure to clomipramine [42,70]. However, a large prospective investigation (including 1029 cases from the Swedish Medical Birth Register) demonstrated a statistically significant association between clomipramine use during pregnancy and cardiovascular anomalies, (especially atrial and ventricular septal defects) [71]. These results replicated those emerging from a previous case-control study [72]. However, both studies suffer from methodological limitations. Indeed, as highlighted by the authors themselves, there may have been undetected confounders in the analysis. Among these is maternal alcoholism, which is known to be associated with an increased risk for cardiac defects [72]. A second problem in this typology of studies is the multiple comparison situation. A large number of drugs were studied, and infants with cardiovascular defects were divided into a number of subgroups. Thus, the number of statistical tests performed was large and some may randomly reach statistical significance [72]. For this reason, the authors concluded that further studies on independent materials are needed to verify or reject this association [72]. Perinatal complications Several descriptions of perinatal complications of various degrees of severity associated with late in utero exposure to clomipramine, principally attributed to discontinuation phenomena, are available [42,48,70,73-78]. Recently, a small case-series study demonstrated relatively high rates of severe complications in neonates exposed prenatally to this specific antidepressant. Interestingly, the study also found that half-life of clomipramine is longer in neonates than in adults [79]. Table 3A shows published data on the use of clomipramine during early and/or late pregnancy. 3.3.1.2

Clomipramine and breastfeeding In the case-series study by Schimmell et al. [70], one baby was breastfed by a mother who continued clomipramine therapy 3.3.2


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Table 1A. Pregnancy exposure to imipramine and desipramine: structural teratogenic risks and perinatal complications.


Study/drug/ sample size

Timing of exposure

Daily dose (mg)

Presence and type of birth defects

Pregnancy and perinatal outcomes

McBride 1972 [39] Case report (Imipramine, n = 1) Barson 1972 [40] Case report (Imipramine, n = 1)

First trimester

Not available

Bilateral amelia

Not available

First month

20 (fixed dose)

Death of the fetus

Ida¨npaä¨n-Heikkila¨ and Saxen 1973 [41] Case-control study (Imipramine, n = 3)

First trimester

Not available

McElhatton et al. 1996 [42] Prospective study (Imipramine, n = 30)

Not specifically stated but timing included first trimester in all TCA exposures First 10 weeks (in all but one patient)

Not available

Multiple deformities, including neural tube defects, cleft palate, multiple rib defects, diaphragmatic hernia, adrenal hypoplasia Two cases of cleft lip/palate One case of meningocele and renal cystic degeneration The mothers took concomitant medications 1 case of extra digit 1 case of omphalocele

Between days 4 and 28 after conception

Not available

Beyond the 27th week

Kuenssberg and Knox 1972 [43] Database analysis (Imipramine, n = 17) Australian Drug Evaluation Committee 1973 [44] Computerized search (1971 -- 1973) of records from two Australian hospitals (case of limb defects recorded: n = 23) Crombie et al. 1972 [45] Database analysis (Imipramine, n = 19) Ware and DeVane 1990 [46] Case-series (Imipramine, n = 2) Misri and Sivertz 1991 [47] Case-series (Imipramine, n = 8 with known timing of exposure) Eggermont et al. 1972 [48] Case-series (Imipramine, n = 3) Webster 1973 [49] Case report (Desipramine, n = 1)

Not available

3 cases of spontaneous abortion

One case of defective abdominal muscles One case of diaphragmatic hernia None of the affected infants was exposed in utero to tricyclics

Not available

Not available

No

Not available

Early pregnancy

10 (case 1) 50 (case 2)

No

No adverse effects reported

Throughout pregnancy (n = 1) Late pregnancy (n = 7)

125 -- 250 (range)

No

1 case of hypotonia and irritability 6 cases of withdrawal symptoms 1 case with healthy outcome

Throughout pregnancy

50 -- 150 (range)

No

3 cases of respiratory, circulatory, and neurological complications


Not available

Not available

Sweating, feeding problems, weight loss, respiratory distress, tachycardia

during lactation. Maternal plasma and milk concentrations of the drug, infant serum levels, and the M/P ratio widely varied depending on the day of estimation after parturition. Although the baby’s plasma levels of the drug or its metabolite 210

Not available Stillbirth

Not available

(desmethylclomipramine) were at some time points as high as the mother’s plasma levels, the infant showed no untoward reactions. Conversely, infant plasma levels were low in the infants described by Yoshida et al. [50]. Where clinical outcomes were



Table 1B. Infant safety with imipramine and desipramine therapy in breastfeeding.


Study/drug/ sample size Misri and Sivertz 1991 [47] Case-series (Imipramine, n = 14) Yoshida et al. 1997 [50] Case series (Imipramine, n = 4) Birnbaum et al. 1999 [51] Case series (Imipramine, n = 2) Sovner and Orsulak 1979 [52] Case report (Imipramine, n = 1) Misri and Sivertz 1991 [47] Case report (Desipramine, n = 1) Birnbaum et al. 1999 [51] Case series (Desipramine, n = 5) Stancer and Reed 1986 [53] Case report (Desipramine, n = 1)

Maternal daily dose (mg)

Maternal serum levels (ng/ml)

Milk levels (ng/ml)

Milk/plasma ratio

Infant’s serum levels (ng/ml)

Infant’s outcome

125 -- 225 (range)

Not available

Not available

Not available

Not available

No adverse effects

75 -- 150 (range)

29 -- 340 (range)

Fore-milk: 40 -- 509 (range) Hind-milk 110 -- 610 (range)

Fore-milk: 0.4 -- 2.0 (range) Hind-milk 0.9 -- 3.8 (range)

Measured in 2 infants: 0.6 and up to 7.4, respectively

No acute toxic effects

10 case 1 (range) 75 case 2 (range)

Not available

Not available

Not available

Imipramine/ Not available Desipramine: below detection limits

200 (fixed dose)

Imipramine 21 Desipramine 41

Imipramine 4 -- 29 (range) Desipramine 17 -- 30 (range)

Not available

Not available

No adverse effects

100 (fixed dose)

Not available

Not available

Not available

Not available

No adverse effects

37 -- 200 (range)

Not available

Not available

Not available

Below the detection limits

Not available

300 (fixed dose)

Desipramine 257 -- 271 (range) 2-OH-Desipramine 234 -- 253 (range)

Desipramine 316 -- 328 (range) 2-OH-Desipramine 327 -- 381 (range)

Desipramine Below the 1.12 -- 1.21 (range) detection limits 2-OH-Desipramine 1.29 -- 1.62 (range)

reported (8/10 cases Table 3B) no adverse effects were observed [48,50,70,80]. Dothiepin (dosulepin) and doxepin 3.4.1 Dothiepin, doxepin and pregnancy 3.4.1.1 Fetal malformations and perinatal complications 3.4

A small prospective study failed to demonstrate fetal malformations after in utero exposure to doxepin [42], whereas one case of birth defects was described after dothiepin exposure [42]. Anecdotal reports described transient perinatal complications associated with late in utero exposure to both medications [81]. Studies on the use of dothiepin and doxepin during pregnancy are reassumed in Table 4A.

No adverse effects

Dothiepin (dosulepin), doxepin and breastfeeding

3.4.2

Data are available on a total of 30 breastfed infants whose mothers were treated with dothiepin (dosulepin) during lactation [50,82,83], but infant serum levels were only measured in three cases. One infant had high levels of the parent compound and its metabolites (nordothiepin, dothiepin-S-oxide, and nordothiepin-S-oxide) [50], whereas the serum levels were relatively low or below the detection levels in other two infants [50,83]. Two out of three single case reports described adverse reactions in infants exposed to doxepin through maternal milk [84,85]. This finding may be due to the liability of the active metabolite of doxepin (N-methyldoxepin) to accumulate in the infant’s serum. However, this finding remains


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Table 2A. Pregnancy exposure to amitriptyline and nortriptyline: structural teratogenic risks and perinatal complications.



Timing of exposure during pregnancy

Daily dose (mg)

Presence and type of fetal malformation


Crombie et al. 1972 [45] Database analysis (Amitriptyline, n = 28) Maschi et al. 2008 [54] Prospective study (Amitriptyline, n = 26) Ida¨npaä¨n-Heikkila¨ and Saxen 1973 [41] Case-control study (Amitriptyline, n = 2)

From 6 weeks before to 22 weeks after the last menstrual period

Not available

No

Not available

Various stages of pregnancy

Not available

No

No

First trimester Third trimester

Not available 30 mg (fixed dose)

Not available Subarachnoid hemorrhage/infant’s death

McElhatton et al. 1996 [42] Prospective study (Amitriptyline, n = 118)

Timing included first trimester in 97% of all tricyclic exposures

Not available

Personal communication by McBride to the Australian Drug Evaluation Committee, 1973 (see ref [43]) Case report (Amitriptyline, n = 1) Freeman 1972 [55] Case report (Amitriptyline, n = 1) Rafla and Meehan 1990 [56] Case report (Amitriptyline, n = 1)

Between days 4 and 28 after conception

Not available

One case of micrognathia, one-sided anomalous mandible and pes equinovarus One case of hydrocephalus Both mothers received concomitant medication with perphenazine 1 case of pyloric stenosis, inguinal hernia, and ectopic testis 1 case of hydrocephalus 1 case of small ventricular septal defect 1 case of single palmar crease and small palpebral fissure 1 case of facial angioma and unilateral hydrocele 1 case of facial muscle asymmetry 1 case of hydroamnios, cardiomegaly, premature closure of the ductus arteriosus (neonatal death) In 3 of these cases, the mother took concomitant medication Limb reduction deformities

First trimester

30 (fixed dose)

Hypoplastic right tibia and foot, absence of fibula

Not available


> 150 (fixed dose)

Thanatophoric dwarfism The mother also took phenytoin and phenobarbital

Death of the fetus

212


10 cases of spontaneous abortion 2 cases of stillbirth 5 cases of perinatal complications, ranging from drowsiness to neurodevelopmental impairment In all cases, the mothers took concomitant medication

Not available


Table 2A. Pregnancy exposure to amitriptyline and nortriptyline: structural teratogenic risks and perinatal complications (continued).


Study/drug/ sample size Golden and Perman 1980 [57] Case report (Amitriptyiline, n = 1) Breyer-Pfaff et al. 1995 [58] Case report (Amitriptyiline, n = 1) Personal communication by McBride to the Australian Drug Evaluation Committee, 1973 Case report (see ref [43]) (Nortriptyiline, n = 1) McElhatton et al. 1996 [42] Prospective study (Nortriptyiline, n = 4) Hendrick and Altshuler 1999 [59] Case report (Nortriptyiline, n = 1) Shearer et al. 1972 [60] Case report (Nortriptyiline, n = 1)


Daily dose (mg)


4 weeks post conception

50 (fixed dose)

Bilateral anophthalmia The mother took several concomitant medications

Not specified


175 (fixed dose)

No

Respiratory distress

During the critical period of limb development

Not available

Limb anomalies No further clinical details available

Not available

Timing include first trimester in 97% of all tricyclic exposures

Not available

No

1 case of prematurity


85 -- 120 (range)

No



100 (fixed dose)

No

Urinary retention

controversial [86]. Studies that analyzed the safety of such antidepressants for the breastfed infant are summarized in Table 4B.

Studies investigating the reproductive safety of TCAs as a group

4.

4.1


TCAs as a group and pregnancy Fetal malformations

4.1.1

Studies investigating the reproductive safety of TCAs as a group include much larger samples than those of single TCAs. However, their results should be interpreted with great caution. Indeed, the medications included in this group show different receptorial profiles and, thus, may have different, specific impacts on the developing fetus. Although a retrospective study [13] hypothesized that early pregnancy exposure to TCAs might be associated with a statistically significant increase in the risk of spina bifida (however, the finding should be interpreted with great caution, since it was merely based on a single

TCA-exposed case), most of these investigations did not find any association between early in utero exposure to such medications and an increase in the rate of congenital birth defects [87-89]. A matched cohort study [90], based on information included in the UK’s General Practice Research Database, also provided reassuring results. In contrast, progressively updated information from the Swedish Medical Birth Register suggests that the risks for a relatively severe malformation, for any cardiovascular defect and for ventricular or atrial septal defects were significantly increased for TCAs exposure (primarily clomipramine) [71,72,91]. However, as pointed out by the authors, these typologies of studies carry the risk of exposure misclassification, as it is not certain that a woman who had bought a drug did in fact use it during the organogenesis. Moreover, some confounders, such as alcohol use, which may interfere with the analysis, remained uninvestigated. Moreover, the study design was unable to distinguish between the effects of depression and drug treatment of depression.


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Table 2B. Infant safety with amitriptyline and nortriptyline therapy in breastfeeding.





Milk levels (ng/ml)

Milk/plasma ratio


Infant’s outcome

Misri and Sivertz 1991 [47] Case report (Amitriptyiline, n = 1) Yoshida et al. 1997 [50] Case series (Amitriptyiline, n = 2) Breyer-Pfaff et al. 1995 [58] Case report Amitriptyiline, n = 1)

150 (fixed dose)

Not available

Not available

Not available

Not available


100 case 1 (fixed dose) 175 case 2 (fixed dose)

1443 7156

No acute toxic effects reported

27 -- 71 (range) (Amitriptyline) 20 -- 87 (range) (Nortriptyline) 127 ± 50 (median) (10-OHNortriptyline)

Fore-milk: 0.1 Hind-milk: 0.5 Fore-milk: Not available Hind-milk: 0.6 Not specified

7.5 Not available

175 (fixed dose)

>1

No adverse effects reported (despite previous symptoms of poor adaptation following in utero exposure to Amitriptyline)

Bader and Newman 1980 [61] Case report (Amitriptyiline, n = 1) Brixen-Rasmussen

100 (fixed dose)

83 -- 141 (range) (Amitriptyline) 59 -- 86 (range) (Nortriptyline)

Fore-milk: 185 Hind-milk: 707 Fore-milk: Not available Hind-milk:4077 54% of serum levels (Amitriptyline) 74% of serum levels (Nortriptyline) 70% of serum levels (10-OHNortriptyline) 135 -- 151 (range) (Amitriptyline) 52 -- 59 (range) (Nortriptyline)



75 (fixed dose)

50 -- 54 (range) (Amitriptyiline) 61 -- 67 (range) (Nortriptyline)




100 (fixed dose)



Not available

Not specified

150 (fixed dose)

90 (Amitriptyiline) 146 (Nortriptyline)

Not available

1.07 -- 1.62 (range) (Amitriptyline) 0.68 -- 0.88 (range) (Nortriptyline) 1.44 -- 1.92 (range) (Amitriptyiline) 1.03 -- 1.12 (range) (Nortriptyline) 0.50 -- 1.30 (range) (Amitriptyiline) 0.50--0.70(range) (Nortriptyline) Not available


Not specified


Not available

Not available

Not available

Not available


60 -- 75 (range)

Not available

Not available

Not available


Not available

50 -- 80 (range)

47 -- 160 (range) (Nortriptyline)

Not available

Not available

Below the detection limits in all infants or low (5 -- 10, range)


et al. 1982 [62] Case report (Amitriptyiline, n = 1) Pittard and O’Neal 1986 [63] Case report (Amitriptyiline, n = 1) Erickson et al. 1979 [64] Case report (Amitriptyiline, n = 1) Misri and Sivertz 1991 [47] Case series (Nortriptyiline, n = 2) Birnbaum et al. 1999 [51] Case series (Nortriptyiline, n = 4) Wisner and Perel 1991 [65] Case series (Nortriptyiline, n = 7)

214



Table 2B. Infant safety with amitriptyline and nortriptyline therapy in breastfeeding (continued).



Wisner and Perel 1996 [66] Case series (Nortriptyiline, n = 5) Wisner et al. 1997 [67] Case series (Nortriptyiline, n = 7) Matheson and Skjaeraasen, 1988 [68] Case report (Nortriptyline, n = 1) Mammen et al. 1997 [69] Case series (Nortriptyline, n = 2)

4.1.2



Milk levels (ng/ml)


Infant’s outcome

60 -- 110 (range)


Not available

Not available



60 -- 150 (range)


Not available

Not available

0 -- 17 (range)


125 (fixed dose)


101--404(range) (Nortriptyline)

0.87 -- 2.03 (range)

Not available


Not available

66 -- 95 (range) (Nortriptyline) 174 -- 330 (range) (10-OHNortriptyline)

Not available

Not available

< 4 (median)


Gestational complications

A retrospective study [92] identified, through the analysis of the US nationwide Medicaid Analytic eXtract, a large cohort of pregnant women with depression. Pharmacy dispensing records were used to ascertain antenatal exposure to SSRIs, SNRIs, TCAs, bupropion and other antidepressant monotherapy or polytherapy during the first half of the third trimester and the second trimester of pregnancy. Main study findings were that both SNRIs and TCAs were associated with a higher risk of preeclampsia than SSRIs. Perinatal complications No difference in specific delivery outcomes (prematurity, birth weight, head circumference and Apgar scores) between exposed and unexposed infants were found in the retrospective study by Simon et al. [89]. However, a further retrospective and one prospective study suggested that late pregnancy exposure to TCAs may increase the rate of poor neonatal adaptation symptoms [13,93]. However, in the report by Ka¨lleń [93] the exact time of administration of the drugs was not specified in about 40% of the cases. 4.1.3

Neurodevelopmental outcome TCA exposure during various stages of pregnancy was not associated with language, motor and IQ impairment in the infants [88,89,94]. However, further findings [95] raised potential concerns regarding an increased risk of autism spectrum disorders associated with antenatal TCA exposure. However, several limitations of this study need to be acknowledged. One of the most severe limitations was that the study design did 4.1.4

Milk/plasma ratio

not allow to conclude whether the association between antidepressant use and autism spectrum disorder reflects severe depression during pregnancy or is a direct effect of the drug. Also, depression was identified using specialist psychiatric care records and therefore was certainly under-ascertained, since most people with depressive disorders do not seek help or are managed in primary care. The under-ascertainment of depression may have led to partial control for confounding in the relation between antidepressant use and autism spectrum disorder in the offspring. Table 5 shows reviewed studies investigating the safety of TCAs as a group in pregnancy. TCAs as a group and breastfeeding The study by Nulman et al. [94] included a relatively large number of infants breastfed by mothers on TCA therapy. However, no information is available about the infants’ outcome. 4.2

5.

Conclusions

Congenital anomalies Published literature does not confirm the hypothesized association between pregnancy exposure to TCAs (either as a group or as single antidepressants) and an increase in the risk of limb defects, despite this association, originally supposed on the basis of only four cases [39,43,55], received further confirmation [13]. Moreover, exhaustive medical records are available for only four cases of limb 5.1


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Table 3A. Pregnancy exposure to clomipramine: structural teratogenic risks and perinatal complications.


Study/sample size


Daily dose (mg)


Perinatal complications

1 case of bilateral talipes 1 case of Harlequin syndrome In both cases, the mothers took concomitant medications No malformations reported

22 spontaneous abortions 9 cases of poor neonatal adaptation syndrome In 5 cases, the mothers took concomitant medication Tremors, seizures, feeding problems, laryngeal spasm 1 case of hypotonia 1 case of transient tachypnea 1 case of hypotonia, respiratory problems, jitteriness Not available

McElhatton et al. 1996 [42] Prospective study (n = 134 pregnancies)


Not available

Eggermont et al. 1972 [48] Case report (n = 1) Schimmell et al. 1991 [70] Case series (n = 6, 5 live births)

Last 5 months of pregnancy

75 (fixed dose)


75 -- 250 (range)

No malformations reported

Ka¨lleń and Otterblad Olausson, 2006 [71] Prospective analysis of the Swedish Medical Birth Register (n = 1029, live births, n = 35394) Ka¨lleń and Otterblad Olausson 2003 [72] Case-control study (n = 5015 cases with cardiac defects, n = 577370 control infants) Ben Musa and Smith 1972 [73] Case report (n = 1) Cowe et al. 1982 [74] Case report (n = 2)

Early pregnancy

Not available

Increased risk of cardiovascular defects (mostly atrial or ventricular septum defects) (odds ratio: 1.87; 95% CI: 1.16 -- 2.99)

Early pregnancy

Not available

Increased risk of cardiovascular defects (odds ratio: 2.03; 95% CI: 1.22 -- 3.40)

Not available


75 (fixed dose)

Not available

Hypothermia, jitteriness

Late/entire pregnancy

Not available

Not available

Østergaard and Pederesen 1982 [75] Case report (n = 2) Singh et al. 1989 [76] Case report (n = 1)


100 (case 1) (fixed dose) 200 (case 2) (fixed dose) 125 (range)

No

1 infant with seizures, jitteriness, hypertonia, ankle clonus 1 infant with premature delivery, convulsions, myoclonic jitteriness (co-medication with flurazepam) Hyper/hypotonia, hypothermia, lethargy, cyanosis, feeding problems, tachypnea Hypertonia, tachypnea, diaphoresis Mother had concomitant medication with lorazepam

216

From week 31

Not available



Table 3A. Pregnancy exposure to clomipramine: structural teratogenic risks and perinatal complications (continued).


Study/sample size Bromiker and Kaplan, 1994 [77] Case report (n = 1) Bloem et al. 1999 [78] Case report (n = 1) ter Horst et al. 2012 [79] Case series (n = 11)


Daily dose (mg)



From week 12 to 32

100 -- 150 (range)

Not available

Hypertonia, seizures, respiratory distress


100 (fixed dose)

Not available

Generalized myoclonic state

Not available

25 -- 125 (range)

No

10 cases of withdrawal reactions (the most frequently observed withdrawal symptoms were: shortened period of sleep after feeding, poor feeding, tremors hyperactive Moro reflex, tachypnea, tachycardia and cyanosis

Table 3B. Infant safety with clomipramine therapy in breastfeeding. Study/sample size



Milk levels (ng/ml)

Misri and Sivertz, 1991 [48] Case report (n = 1) Yoshida et al. 1997 [50] Case series (n = 2)

175 (fixed dose)

Not available

Not available

Not available

Not available



69 -- 163 (range)


100 case 1 (fixed dose) 150 case 2 (fixed dose) 125 -- 150 (range)

Not available

Fore-milk: 0.1 -- 2.4 (range) Hind-milk: 0.7 -- 1.5 (range) Not available

1.1 -- 3.8 (range)

Birnbaum et al. 1999 [51] Case series (n = 2) Schimmell et al. 1991 [70] Case report (n = 1) Wisner et al. 1995 [80] Case series (n = 4)

Fore-milk: 48 -- 200 (range) Hind-milk: 61 -- 283 (range) Not available

Below the detection limit

Not available

208 -- 510 (range)

216 -- 624 (range)

0.76 -- 1.62 (range)

9.8 -- 266.6 (range)


75 -- 125

60 -- 254 (range)

Not available

Not available

Below the detection limit


malformations. However, analogous risks were never hypothesized for SSRI. Further, two studies on single TCAs with improved methodology indicated an increased risk of cardiac malformations [71,72] and, specifically, of atrial and ventricular

M/P ratio


Infant’s outcome

septum defects associated with maternal clomipramine therapy. Whereas the first study reported that the risk concerned particularly relatively mild cardiac defects (although the 2 cases of transposition of the large vessels among the 18 recorded cases of cardiac malformations should be taken


217

S. Gentile

Table 4A. Pregnancy exposure to dothiepin (dosulepin) and doxepin: structural teratogenic risks and perinatal complications.




McElhatton et al. 1996 [42] Prospective study (Doxepin, n = 14) McElhatton et al. 1996 [42] Prospective study (Dothiepin, n = 9) Prentice and Brown, 1989 [81] Case report (Dothiepin, n = 1)

Daily dose (mg)




Not available

No

1 case of spontaneous abortion 1 case of late fetal death


Not available

No


25 -- 75 (range)

One of twins with esophageal atresia and tracheoesophageal fistula (other twin normal) No

Tachyarrhythmia

Table 4B. Infant safety with dothiepin (dosulepin) and doxepin therapy in breastfeeding. Study/drug/ sample size



Yoshida et al. 1997 [50] Case series (Dothiepin, n = 2)


180 -- 2623 (range)

Ilett et al. 1993 [82] Case series (Dothiepin, n = 8)

25 -- 225 (range)

Buist et al. 1993 [83] Case series (Dothiepin, n = 20)

75 -- 225 (range)

11 -- 170 (range) (Dothiepin) 3 -- 68 (range) (Nordothiepin) 18 -- 682 (range) (Other Metabolites) 56.4 (Dothiepin) 71.8 (Nordothiepin) (means of 12 women taking daily dose of 150 mg)

Matheson et al. 10 (fixed dose) 1985 [84] Case report (Doxepin, n = 1)

0 -- 21 (range) (Doxepin) 0 -- 66 (range) (Metabolites)

35 (fixed dose) Frey et al. 1999 [85] Case report (Doxepin, n = 1)

31 (Doxepin) 25 (Metabolites)

150 (fixed dose) Kemp et al. 1985 [86] Case report (Doxepin, n = 1)

35 -- 68 (range) (Doxepin) 65 -- 131 (range) (Metabolites)

218

Milk levels (ng/ml) Fore-milk: 124 -- 3730 (range) Hind-milk: 309 -- 4737 (range) 5 -- 475 (range) (Dothiepin) 3 -- 56 (range) (Nordothiepin) 30 -- 617 (range) (Other Metabolites) 95.3 (Dothiepin) 40.2 (Nordothiepin) (means of 12 women taking daily dose of 150 mg) 7 -- 29 (range) (Doxepin) 0 -- 11 (range) (Metabolites) 60 -- 100 (Doxepin + Metabolites) Split data unavailable Not specified

Milk/plasma ratio


Fore-milk: Infant 1 0.6 -- 1.4 (range) 4.1 Infant 2 Hind-milk: Not available 1.7 -- 2.8 (range) Not available Not available

Infant’s outcome No adverse effects reported


Not available

Infant 1 below detection limits Infant 2: 34 (Dothiepin) 22 (Nordothiepin)


0.3 -- 0.9 (range) (Doxepin) 0.12 -- 0.17 (range) (Metabolites) 1.0 -- 1.7

3 (Doxepin) 58 -- 66 (range) (Metaboli-tes)

Respiratory depression

~ 10 (Doxepin) < 10 (Metabolites)

Poor sucking and swallowing, hypotonia, vomiting

0.51 -- 2.39 (range) (Doxepin) 0.54 -- 2.35 (range) (Metabolites)

Below the No adverse detection limits -15 effects reported



Table 5. Tricyclic antidepressants as a group: structural teratogenic risks and perinatal complications.


Study/sample size


Daily dose (mg)


Perinatal-gestational complications/ neurodevelopmental outcome Increased risk of: Respiratory distress and other respiratory conditions (relative risk: 2.02, 95% CI: 1.33 -- 3.06) Endocrine and metabolic disturbances (relative risk: 2.15, 95% CI: 1.04 -- 4.44) Temperature instability (relative risk: 2.36, 95% CI: 1.08 -- 5.16) Not available

Davis et al. 2007 [13] Retrospective study of automated health system databases (Tricyclics: first trimester exposures: n = 167; third trimester exposures: n = 136; unexposed controls: n = 49669 Pastuszak et al. 1993 [87] Prospective controlled study (Live births: n = 60 exposed to tricyclics, 58 to fluoxetine, 76 to non-teratogen agents) Nulman et al. 1997 [88] Prospective study (Live births: n = 80 exposed to tricyclics, n = 84 exposed to non-teratogen agents) Simon et al. 2002 [89] Retrospective investigation of a prepaid health plan (infants exposed to tricyclics : n = 209 extensively matched unexposed infants: n = 209) Vasilakis-Scaramozza, 2013 [90] Matched cohort study (n = 1608 births)

First trimester Third trimester

Not available Not available

Increased risk of: Spina bifida (relative risk: 12.43, 95% CI: 1.70 -- 90.66) Limb anomalies (relative risk: 2.55, 95% CI: 1.23 -- 5.29) Not available

First trimester

Not available

No cases of fetal malformations reported

All exposed in first trimester, varying durations in second and third trimester

Not available

1 ventricular septum defect, 1 hypospadias 1 pyloric stenosis

Perinatal complications: no available data No increased risk of impaired IQ and language development at 16 -- 86 months

Various stages of pregnancy

Not available

No significant difference in the rate of fetal anomalies compared to controls but data were not clear as to how many children were exposed in first trimester

First trimester

Not available

Reis and Ka¨lleń, 2010 [91] Retrospective study (n = 2444)

Before the first antenatal visit or prescribed during pregnancy

Not available

n = 42 Crude relative risk: 0.9 (95% CI: 0.7 -- 1.1) No significant difference in the rate of fetal anomalies compared to controls Relatively severe malformation n = 77 (odds ratio: 1.36, 95% CI: 1.07 -- 1.72) Any cardiovascular defect n = 30 (odds ratio: 1.63, 95% CI: 1.12 -- 2.36) Atrioventricular septal defects n = 17 (odds ratio: 1.84, 95% CI: 1.13 -- 2.97

No difference in prematurity, birth weight, head circumference, Apgar scores vs controls and early vs late pregnancy exposure Neonatal adaptation: no available data No difference in motor or speech delay up to 2 years Not available


Not available

219

S. Gentile

Table 5. Tricyclic antidepressants as a group: structural teratogenic risks and perinatal complications (continued).


Study/sample size


Daily dose (mg)


Perinatal-gestational complications/ neurodevelopmental outcome

Palmsen et al. 2013 [92] Matched cohort study (n = 441 exposed to tricyclic monotherapy) Ka¨llen, 2004 [93] Prospective study (n = 395 births, comparison with total population of n > 560000 births)

Second trimester/ first half of the third trimester

Not available

No

Increased risk of preeclampsia in TCA-exposed women vs SSRI-exposed women

Late pregnancy

Not available

Not available

Nulman et al. 2002 [94] Prospective, controlled study (n = 46 exposed; n = 36 unexposed controls) Rai et al. 2013 [95] Population based nested case-control study (n = 6/20 -5/13)


Not available

Not available

Increased risk of: Preterm delivery (odds ratio: 2.50; 95% CI: 1.87 -- 3.34) Low birth weight (odds ratio: 1.88; 95% CI: 1.28 -- 2.76) (finding attributed to premature births) Respiratory distress (odds ratio: 2.20; 95% CI: 1.44 3.35) Hypoglycemia (odds ratio: 2.07; 95% CI: 1.36 -- 3.13) Low Apgar scores (odds ratio: 2.99; 95% CI: 1.58 -- 5.65) Seizures (odds ratio: 6.8; 95% CI: 2.2 -- 16.0) Perinatal complications: N/A No difference in global IQ and language development at 15 -- 71 months of age


N/A

N/A

into consideration [71]), the second study demonstrated an increased risk of both severe and less severe cardiac defects [72], with marginally increased odds ratios, however. Retrospective records also suggested that early pregnancy exposure to TCAs and, especially, clomipramine, may increase the risk of cardiac anomalies [91]. Nevertheless, as reported above, all studies suggesting an increased cardiac teratogenicity of TCAs are not devoid of intrinsic, severe limitations, such as the lack of a control group of untreated depressed mothers. Hence, potential detrimental effects of the underlying maternal disorder on the developing fetus cannot definitively be ruled out. Nonetheless, a possible association between antenatal clomipramine exposure and fetal cardiovascular malformations cannot be ruled out. On the other hand, the absence of clomipramine fetal effects described in the study by McElhatton et al. [42] may be due to the small sample size. 220

Increased risk of autism spectrum disorders (odds ratio: 4.15 (95% CI: 1.44 to 11.96)

Gestational/perinatal complications TCA exposure during late pregnancy seems to be associated definitively with increased risks of the PAES (which include both poor pregnancy outcomes -- preterm birth and low birth weight and perinatal complications -- body temperature instability, poor feeding, respiratory distress, cardiac rhythm disturbance, lethargy, muscular tone anomalies, jitteriness, jerky movements and seizures) [13,42,47-49,58,60,70,7379,81,88,93,96]. From a clinical point of view, such problems seem to be particularly severe in the case of clomipramine exposure [79]. Currently, the pathogenesis of these phenomena remains unclear. Some theories suggest interference with placental perfusion and withdrawal effects (related to reduced serotonergic functions or increased cholinergic activity) [94]. It is also possible that the PAES may be due to a prolonged neonatal hepatic immaturity and/or to a genetically determined, reduced metabolizing aptitude [95]. 5.2



If used during the second trimester and the first half of third trimester, TCAs have also been associated with an increase in the risk of preeclampsia [92], a clinical condition that can seriously compromise maternal and offspring health, since it may cause intrauterine growth restriction and medically indicated preterm delivery. However, the same risk has also been reported with SNRI and SSRI exposure [92].

If used in late pregnancy, TCAs may increase the risk of preeclampsia and induce a usually mild, transient PAES. Neonatal symptoms seem to be more severe and prolonged for clomipramine exposure. However, until now there have been no report of three potentially severe complications (PPHN, QT prolongation and necrotizing enterocolitis) described with SSRI exposure [20,21,99,100].

Neurodevelopmental outcomes Antenatal exposure to TCAs seems devoid of effects on the main neurodevelopmental milestones [88,89], although a preliminary report (which requires further, urgent confirmations) linked antenatal TCA exposure to increased risks of autism spectrum disorder [94]. Of note, this risk has also been associated with SSRI exposure [95].

6.2


5.3

Breastfeeding Overall, 107 cases described the outcome of infants exposed to TCAs through maternal milk. However, the calculation of the Breastfed Infant-Antidepressant Safety Index (BI-ASI) was not feasible because no each single agent reached the theoretical threshold for its quantification (50 cases, at least) [97]. The largest number of cases was reported for dothiepin (dosulepin). The relatively high levels of the parent compound and its metabolite in the plasma of one of the three infants in whom drug levels were measured is of concern. Moreover, unwanted events have been reported with doxepin exposure [84,85]. In one of these cases, the baby needed to be admitted to neonatal care unit [84]. Studies of nortriptyline included the second largest sample (n = 28). Drug and metabolite levels were measured in 23 infants: both were undetectable or relatively low. Until now, available data on other TCAs are too limited to draw conclusions about their safety in puerperium. 5.4

6.

Expert opinion

Early and late pregnancy Although TCAs have been prescribed for several decades, data on infant outcomes after early pregnancy exposure are limited and include much smaller sample sizes than those in SSRI studies. This applies to the studies on TCAs as a class and, with the exception of clomipramine, to individual tricyclic agents. Sample sizes of 600 -- 1200 exposed cases are needed to test for an only two-fold increase of congenital malformations above the general population rate of 2 -- 4% [98]. The sample sizes of all existing studies of TCAs as a group and for individual tricyclics (excluding the studies by Ka¨lleń, Reis, and Otterblad Olausson [71,72,91]) do not reach this threshold. However, some signals seem to exist suggesting that prenatal clomipramine exposure may increase the risk of cardiac defects. 6.1

Breastfeeding Available data are too limited to consider TCAs as first choice agents in breastfeeding mothers. However, nortriptyline shows limited but concordant reassuring information. In summary, reviewed information suggests that a preference of TCAs over SSRIs in early pregnancy is not justified. In contrast, there appears to be a small gain in safety if TCAs are used in late pregnancy. In fact, although TCAs, as the other classes of antidepressants, are likely to induce gestational complications, such as preeclampsia, and neonatal withdrawal and/or toxic symptoms, until now there have been no reports of PPHN and/or QT prolongation or necrotizing enterocolitis associated with prenatal TCA exposure. Moreover, antenatal TCA exposure has not been associated with later impaired neurodevelopment. The potential and modest increase in risk of autism spectrum disorders, which also involves SSRIs, is far for being definitively confirmed. During lactation, two SSRIs (sertraline and paroxetine) should still be considered as first-line agents [97]. Among TCAs, nortriptyline is a suitable option. Whereas these findings may be helpful in choosing the antidepressant agent with the ‘least worst’ safety profile during the perinatal period, they do not imply that treatment should be changed during pregnancy and/or puerperium. In fact, in choosing the most appropriate pharmacological option for individual patients, it is important to also take into account: quality and severity of mood symptoms, past and current response to treatments, and degree of severity of maternal side effects. This may mean that, sometimes, clinicians may be forced to identify a satisfactory agreement/compromise between fetal/ neonatal adverse effects and maternal clinical factors.

Acknowledgments S Gentile wishes to thank A Wieck, FRCPsych, for her precious contribution and suggestions during the early phase of the preparation of this manuscript.

Declaration of interest The authors have no competing interests to declare and have received no funding in preparation of the manuscript.


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Gentile S. On categorizing gestational birth, and neonatal complications following late in utero exposure to antidepressants. The prenatal antidepressant exposure syndrome. CNS Spectrums 2010;15(3):167-85 A systematic review on the risk of gestational and neonatal complications associated with antidepressant exposure during pregnancy. Gentile S. Use of contemporary antidepressants during breastfeeding. A proposal for a specific safety index. Drug Saf 2007;30:107-21 A clinical method to assess the safety of psychotropic drugs for the breastfed infant. BI-ASI is a specific safety-index reassuming frequency and degree of severity of adverse events in the infants associated with maternal treatment with last generation-antidepressants. This Index could be also applicable to TCAs. However, for each drug of this class of antidepressants, the overall number of reports describing the outcome of infants exposed to antidepressant monotherapy electively via maternal milk is lower than the theoretical threshold of 50. Hence, in accordance with the BI-ASI, the safety of TCAs for the breastfed infant should be considered unknown.

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Affiliation Salvatore Gentile1,2 MD PhD 1 Mental Health Center Cava de’ Tirreni - Vietri sul Mare, Department of Mental Health, ASL Salerno, Cava de’ Tirreni, Piazza Galdi, 841013 Cava de’ Tirreni (Salerno), Italy Tel: +39 089 4455439; Fax: +39 089 4455440; E-mail: [email protected] 2 University of Naples, Medical School “Federico II”, Department of Neurosciences, Naples, Italy


Appendix 1. Data source, study selection and data extraction


The literature search was conducted using the databases MEDLINE/PubMed, TOXNET, EMBASE, and The Cochrane Library. Additional reports were identified from the reference lists of published articles. The search terms ‘tricyclic’ and ‘antidepressant’ were combined with ‘treatment/pregnancy/postpartum/neonate/newborn/ lactation/breastfeeding’ and each of the following: ‘malformation/anomaly/discontinuation/withdrawal/and poor neonatal adaptation.’ The same search was carried out for

individual tricyclic antidepressants, including amitriptyline, clomipramine, desipramine, dosulepin (dothiepin), doxepin, imipramine and nortriptyline. Identified articles were searched for additional references. All articles published in English and reporting original data on the reproductive safety of tricyclic antidepressants in case reports, case series, controlled trials, pregnancy registers or epidemiological studies were obtained. The electronic search provided 450 articles. However, studies investigating the risk of birth defects were only selected if the timing of the exposure was stated. Forty-four articles met the inclusion criteria. Searches were last updated on November 15, 2013.


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Tricyclic antidepressants.

Poisoning with tricyclic antidepressants.

Poisoning with tricyclic antidepressants.

Dysarthria with tricyclic antidepressants.

Tricyclic antidepressants and tryptophan in unipolar depression.

Intrapatient responses to ECT and tricyclic antidepressants.

Individualised dosage of tricyclic antidepressants.

Dyskinesias associated with tricyclic antidepressants.

Inappropriate use of tricyclic antidepressants.

Letter: Do tricyclic antidepressants work?

Letter: Suicide with tricyclic antidepressants.

Letter: Suicide with tricyclic antidepressants.

Tricyclic antidepressants and opioids-better together?

Drowsiness, impaired performance and tricyclic antidepressants drugs.

Reversal of neuromuscular blockade and tricyclic antidepressants.

Tricyclic antidepressants in nine heart transplant recipients.

Altered pharmacokinetics of tricyclic antidepressants in burns.

Enhancement of morphine analgesia by tricyclic antidepressants.

Cerebrovascular complications in pregnancy and puerperium.

Osteoporosis presenting in pregnancy, puerperium, and lactation.

Rapid intramuscular administration of tricyclic antidepressants.

The analgesic effect of tricyclic antidepressants.

Memory Impairment following Acute Tricyclic Antidepressants Overdose.

Do tricyclic antidepressants enhance adrenergic transmission?