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Bipolar disorder in adults: Teratogenic and postnatal risks of pharmacotherapy Author Victoria Hendrick, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Oct 2013. | This topic last updated: Abr 17, 2013. INTRODUCTION Among women with an established pregnancy, surveys estimate that psychotropic drugs are taken by 21 to 33 percent [1,2]. Although these medications are often necessary to control a psychiatric illness that predates or emerges during pregnancy, pharmacotherapy entails risks of structural malformations, neonatal toxicity and withdrawal, and adverse developmental effects. This topic reviews the teratogenic and postnatal effects of pharmacotherapy for bipolar disorder. The principles of teratology; treatment of mania, hypomania, major depression, and mixed episodes during pregnancy; preconception and prenatal maintenance pharmacotherapy for bipolar patients; and preconception counseling for patients with bipolar disorder are discussed separately: (See "Principles of teratology".) (See "Bipolar disorder in pregnant women: Treatment of mania and hypomania".) (See "Bipolar disorder in pregnant women: Treatment of major depression".) (See "Bipolar disorder in women: Preconception and prenatal maintenance pharmacotherapy".) (See "Bipolar disorder in women: Contraception and preconception assessment and counseling".) DEFINITIONS Bipolar disorder Bipolar disorder is a mood disorder that is characterized by episodes of mania (table 1), hypomania (table 2), and major depression (table 3), as well as mixed episodes (major depression concurrent with mania) [3]. The subtypes of bipolar disorder include bipolar I and bipolar II. Patients with bipolar I disorder experience manic and mixed episodes, and nearly always experience major depressive and hypomanic episodes. Bipolar II disorder is marked by at least one hypomanic episode, at least one major depressive episode, and the absence of manic and mixed episodes. Additional information about the clinical features and diagnosis of bipolar disorder is discussed separately. (See "Bipolar disorder in adults: Epidemiology and pathogenesis".) Teratogen Teratogens are factors that can alter normal intrauterine development of fetal growth, anatomic structures, physical functioning, and postnatal development. This definition encompasses environmental exposures, maternal medical disorders, infectious agents, and genetic conditions. Most discussions of teratogens usually center on drug exposures. In determining whether a drug is a teratogen, many authorities stipulate that the exposure causes a pattern of defects [4]. Thus, if exposure is associated with an increase in birth defects greater than that expected in the general population, but the defects vary and there is no discernible pattern, the drug is generally not considered teratogenic. The principles of teratology are discussed separately. (See "Principles of teratology".) GENERAL PRINCIPLES All psychotropic drugs presumably cross the placenta and are present in the amniotic fluid [5]. Embryonic and fetal exposure to maternal pharmacotherapy can cause [2,6-8]: Miscarriage Major and minor structural malformations Fetal growth restriction and low birth weight Preterm delivery Neonatal toxicity and withdrawal Section Editor Paul Keck, MD Deputy Editor David Solomon, MD

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Postnatal developmental effects upon behavior, cognition, and emotional regulation Medication effects upon the fetus vary according to gestational age [2,6,8]. As an example, the fetus is most vulnerable to major morphologic teratogenesis during organogenesis in the embryonic period of the first trimester, between the third and eighth week of gestation (weeks of gestation are counted from the first day of the last menstrual period) (figure 1 and figure 2). Organogenesis occurs 5 to 10 weeks from the first day of the last menstrual period, or 3 to 8 weeks from conception (conception occurs approximately two weeks after the first day of the last menstrual period). By contrast, neonatal toxicity and withdrawal are the result of third trimester exposure. The estimated risk of major congenital malformations appears to vary among the medications that are most commonly used to treat bipolar disorder. The rank order from greatest to least teratogenic risk is [9-14]: Valproate Carbamazepine Lithium Lamotrigine Antipsychotics Antidepressants In discussing teratogenic effects, patients should be informed that the base rate for congenital defects in the general population is approximately two to five percent [15-18]. The incidence of defects is two to three percent at birth but increases to five to six percent after one year when hidden defects are discovered. The estimated risks of congenital defects from pharmacotherapy are typically based upon birth registry and observational studies [7]. Although these studies probably provide the best evidence of the risks, the accuracy of these estimates is uncertain due to ascertainment bias. In addition, information about teratogenic effects is usually presented in terms of monotherapy, whereas many studies are confounded due to concomitant exposure to multiple psychotropic and nonpsychotropic medications [19], and acutely ill pregnant bipolar patients often require medication combinations [20-23]. Further, it is often not possible to separate the effects of drugs from the psychiatric illness itself, and studies often do not control for comorbid substance use disorder, maternal age, maternal body mass index, and prior miscarriages. Although a drug may significantly increase the risk of a congenital anomaly, the absolute risk may be low [24]. As an example, the estimated risk of Ebsteins anomaly (abnormalities of the tricuspid valve and right ventricle) in the general population is 1 in 20,000 live births [25-27]. Following first-trimester exposure to lithium, the risk increases 20-fold to approximately 1 in 1000, which many authorities consider low [6,24,28]. Resources Current information about the possible teratogenic effects of medications is available from several resources; these are discussed separately. (See "Principles of teratology", section on 'Resources'.) In addition, the possible teratogenic effects of drugs and suggestions for managing them can be found for all drugs included in the UpToDate drug database: search on the drug name, choose the drug information topic for that drug, and click on the Pregnancy Implications section of the topic outline. Clicking on the name of a drug cited within any UpToDate topic will also bring you to the drug information topic. ANTIPARKINSONIAN DRUGS USED FOR TREATING EXTRAPYRAMIDAL SYMPTOMS Among the antiparkinsonian drugs that are used to treat extrapyramidal symptoms secondary to antipsychotics, reviews suggest that the risk of teratogenicity with antihistamines (eg, diphenhydramine) appears to be low [29], and that organ malformation appears to be less likely with diphenhydramine than amantadine, benztropine, and trihexyphenidyl [24,30]. As an example, a study of 270 infants exposed to diphenhydramine during the first trimester found no association with congenital defects [31]. However, studies have found that prenatal use of diphenhydramine was associated with congenital malformations [5], including a case-control study in which prenatal exposure to diphenhydramine was significantly greater among children with oral clefts (N = 599) than controls (N = 500) [32]. ANTIDEPRESSANTS Nearly all of the evidence about the teratogenic and postnatal developmental effects of antidepressants is based upon treatment of pregnant patients with unipolar major depression. Most studies have not found that selective serotonin reuptake inhibitors (SSRIs) in the first trimester increase the risk of birth defects,

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with the possible exception of paroxetine [33]. In addition, tricyclic antidepressants [24,34,35], bupropion [36], mirtazapine [37], nefazodone [38], trazodone, and venlafaxine [39] are generally not associated with congenital malformations. The teratogenic and postnatal effects of antidepressants are discussed separately. (See "Depression in pregnant women: Management".) ANTIEPILEPTICS Teratogenic and neurobehavioral effects have been identified in children exposed to valproate, and less frequently, carbamazepine [14]. Although most studies suggest that the estimated rate of major congenital malformations with lamotrigine appears to be comparable to the rate in the general population, some studies suggest that lamotrigine may possibly cause orofacial clefts [40]. The known risks of prenatal exposure to antiepileptics are based primarily upon observations of epilepsy patients, and are discussed separately. (See "Risks associated with epilepsy and pregnancy", section on 'Effect of antiepileptic drugs on the fetus'.) ANTIPSYCHOTICS Most studies have found that prenatal exposure to first- and second-generation antipsychotics did not appear to increase the risk of major physical malformations above rates observed in the general population [4,41]. Although one birth registry found that the risk of congenital malformations was significantly increased in newborns exposed to antipsychotics during pregnancy compared with unexposed infants, the risk was not significant when the analyses excluded concomitant exposure to anticonvulsants [42]. Use of antipsychotics during pregnancy may increase maternal weight. A population-based birth registry of 958,729 pregnancies found that a body mass index 26 (overweight or obesity) was significantly more probable in patients treated with antipsychotics than untreated women (odds ratio = 2) [42]. Fetal exposure to antipsychotics may vary due to differences in placental permeability to these drugs. A prospective observational study of 50 pregnant patients examined the placental passage of antipsychotics, defined as the ratio of umbilical cord serum drug concentration to maternal serum drug concentration [22]. (Umbilical cord and maternal plasma concentrations were drawn at delivery; drugs cross the placenta more readily late in pregnancy). The placental passage ratios were as follows: Olanzapine 72 percent Haloperidol 66 Risperidone 49 Quetiapine 24 The ratio for quetiapine was significantly lower than that for olanzapine and haloperidol. First-generation antipsychotics have been more widely used and studied during pregnancy than second-generation antipsychotics [2,42]. In addition, the risks of prenatal exposure to antipsychotics have been examined primarily in patients with hyperemesis gravidarum who received low doses of antipsychotics as antiemetics and were presumed to not have a psychiatric disorder, and secondarily in patients with psychotic disorders and mood disorders [24,42]. Postnatal effects Neonatal toxicity and withdrawal Chronic administration of antipsychotics during the third trimester may cause symptoms of neonatal toxicity and withdrawal, including [1,6,24,41,43,44]: Abnormal movements (dyskinesia) Abnormally increased or decreased muscle tone Motor restlessness Hyperreflexia Agitation Hyperactivity Tremor Sedation Irritability Crying Tachycardia Hypotension Difficulty breathing

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Difficulty feeding Gastrointestinal dysfunction (eg, functional bowel obstruction) Many of the symptoms of toxicity and withdrawal were described in a United States Food and Drug Administration warning [44]. Although the incidence of these symptoms is not known, extrapyramidal symptoms (eg, abnormal movements, restlessness, and tremor) may be more likely to occur with first-generation antipsychotics and risperidone than with other second-generation antipsychotics [4]. Symptoms typically subside within hours to days, but may persist for weeks to months after birth [4]. Specific treatment is usually not necessary, but more severely affected newborns may require longer hospital stays [44]. Developmental effects Intrauterine exposure to antipsychotics may adversely affect neuromotor functioning during infancy. A prospective observational study that controlled for maternal psychiatric status and other variables found significantly poorer neuromotor performance (eg, posture, muscle tone, and reflexes) six months postpartum in babies with prenatal antipsychotic exposure (N = 22) compared to babies with no prenatal psychotropic exposure (N = 85) [23]. However, assessment at six months may not predict long-term outcome. In addition, information processing and learning were comparable for the two groups. First-generation The reproductive safety risks of first-generation antipsychotics are generally regarded as low, based upon a literature that extends back to the 1960s [2,5,22]. Use of first-generation antipsychotics during pregnancy does not appear to increase perinatal mortality. A prospective observational study found that the frequency of stillbirths and neonatal deaths were each similar in patients treated with typical antipsychotics (N = 3056) and in untreated patients (N = 38,281) [45]. Perinatal mortality is discussed separately. (See "Perinatal mortality".) Most studies have not found an increased risk of birth defects following prenatal exposure to first-generation antipsychotics, including chlorpromazine, haloperidol, perphenazine, prochlorperazine, and trifluoperazine [1,4,5]. Although a 1996 meta-analysis of three prospective observational studies and one retrospective chart review (2591 live birth infants exposed during pregnancy to first-generation antipsychotics and 71,746 unexposed infants) found a significantly increased risk of congenital malformations (odds ratio 1.21) [24], subsequent studies have not. As an example, a prospective observational study found that the rate of congenital malformations did not differ significantly between newborns exposed to haloperidol or penfluridol (N = 128) and unexposed newborns (N = 581) (3.1 versus 3.8 percent) [43]. It is not clear if prenatal exposure to first-generation antipsychotics adversely affects birth weight. Two prospective observational studies (N = 846 and 83) each found that birth weights were significantly less (approximately 220 grams) in babies exposed to typical antipsychotics compared with unexposed babies [43,46]. However, a third prospective observational study found that birth weights were comparable for infants exposed to first-generation antipsychotics (N = 2860) and for unexposed infants (N = 35,353) [45]. Reviews have found that prenatal exposure to first-generation antipsychotics does not appear to adversely affect behavioral, cognitive, or emotional development [2,47,48]. As an example, a prospective observational study found that intelligence quotient scores measured at four years of age were comparable in children exposed during pregnancy to typical antipsychotics (N = 2141) and in unexposed children (N = 26,217) [45]. Second-generation Second-generation antipsychotics usually do not appear to be associated with fetal deaths or teratogenic effects, based upon reviews of the limited available data [1,4]. As an example, a prospective observational study compared pregnancy outcomes in 151 pregnant patients treated during the first trimester with atypical antipsychotics (primarily olanzapine, risperidone, and quetiapine) and a comparison group of 151 unexposed pregnant women. The rate of spontaneous abortions, stillbirths, and major congenital malformations was comparable for the two groups [20]. The reported rates of fetal death and congenital malformations for specific second-generation drugs do not exceed rates in the general population: Aripiprazole A review found three case reports of treatment with aripiprazole during pregnancy, including one in which the drug was used during conception and the first trimester [49]. Outcome was normal for all three cases.

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Clozapine The manufacturer has received 523 reports about use of clozapine during pregnancy; congenital anomalies occurred in 4 percent and there was no pattern of defects [4] Olanzapine The manufacturer has received 144 reports about prospective use of olanzapine during pregnancy; the frequency of congenital malformations was consistent with the rate in the general population [4] Quetiapine The manufacturer has received 298 reports about prospective and retrospective use of quetiapine during pregnancy (most reports involved patients who took other medications); congenital anomalies occurred in 5 percent and there was no pattern of defects [4] Risperidone The manufacturer has received 713 reports about use of risperidone during pregnancy. Among the 68 prospectively reported pregnancies with a known outcome, organ malformations occurred in 4 percent and spontaneous abortions in 17 percent [50] Ziprasidone The manufacturer has received 57 reports about use of ziprasidone during pregnancy; normal outcomes occurred in 50 cases, spontaneous abortions in 5, malformation in 1, and stillbirth in 1 [4] The association between exposure to second-generation antipsychotics during pregnancy and birth weight is not clear. One prospective observational study found that large for gestational age births occurred significantly more often in newborns exposed during pregnancy to second-generation antipsychotics (primarily olanzapine, risperidone, quetiapine, or clozapine; N = 25), compared with control infants (N = 38) (20 versus 3 percent) [46]. Another prospective observational study found that exposure during pregnancy to olanzapine (N = 12) was associated with significantly higher infant birth weights, compared with exposure to other psychotropic drugs (N = 13) (3310 versus 2921 grams) [51]. By contrast, a prospective observational study found that low birth weight occurred in significantly more infants following prenatal exposure to second-generation antipsychotics (olanzapine, risperidone, or quetiapine; N = 151), compared with control infants (N = 151) (10 versus 2 percent) [20]. In addition, a prospective observational study of 13 infants exposed to olanzapine during pregnancy found that low birth weight occurred in 31 percent [22]. There do not appear to be any high quality studies that have examined fetal exposure to second-generation antipsychotics and behavioral, cognitive, and emotional effects in these children [4,48]. BENZODIAZEPINES It is not clear if exposure to benzodiazepines or to hypnotic, benzodiazepine receptor agonists (eg, zaleplon, zolpidem, or zopiclone) during pregnancy increases the risk congenital malformations. To the extent that benzodiazepines are teratogenic, many authorities consider the absolute risk small [6,19,24]. Several studies suggest that benzodiazepines may not be associated with birth defects, including [52-54]: A birth registry study that found congenital malformations were comparable for infants exposed during pregnancy to hypnotic, benzodiazepine receptor agonists (N = 1341) and control infants (N = 1,125,734) (4.3 versus 4.7 percent) [55] A meta-analysis of seven cohort studies (1090 infants exposed during pregnancy to benzodiazepines and 71,776 controls) found that there was no relationship between fetal exposure to benzodiazepines and major malformations [19] By contrast, other studies suggest that benzodiazepines or hypnotic, benzodiazepine receptor agonists may be associated with congenital malformations, including oral cleft [24,56]: A meta-analysis of six heterogeneous case-control studies (285 cases with fetal exposure to benzodiazepines and 14,686 controls) found that exposure was significantly associated with a significantly elevated risk of oral cleft (odds ratio 1.8) [19] A birth registry study found that congenital malformations were significantly increased in newborns exposed during pregnancy to benzodiazepines or hypnotic benzodiazepine receptor agonists (N = 1979), compared with all newborns (N = 873,879) (OR 1.2) [57]. In particular, the risk of pylorostenosis was nearly three times greater than expected and alimentary tract atresia nearly four times greater.

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A meta-analysis of four case-control studies (166 cases with fetal exposure to benzodiazepines and 5970 controls) found that major malformations were significantly associated with the use of benzodiazepines during pregnancy (odds ratio 3.0) [19] Based upon case-control studies, fetal exposure to benzodiazepines may increase the risk of oral cleft from the general population base rate of 6 in 10,000 births to 11 in 10,000 births [6]. However, retrospective case-control studies may be subject to recall bias [52]. In addition, compared with pregnant patients who do not use benzodiazepines or hypnotic benzodiazepine receptor agonists, patients using these drugs may be older and more likely to smoke and use other drugs (eg, anticonvulsants) [58]. An increased risk of preterm birth and low birth weight were reported by a birth registry for infants exposed in late pregnancy to benzodiazepines or hypnotic benzodiazepine receptor agonists [57]. Chronic administration of benzodiazepines proximal to delivery can cause neonatal toxicity and withdrawal, including [2,6,52,57]: Hypothermia Low Apgar scores Apnea Lethargy Hypotonia or hypertonia Restlessness Tremor Hyperreflexia Irritability Poor feeding Vomiting Diarrhea This toxicity and withdrawal is widely reported [5], and may occur more often in preterm infants than term infants [59]. Symptoms may persist for up to three months [5]. It is not clear if using benzodiazepines during pregnancy adversely affects neurobehavioral development, due to conflicting results among studies [2,48]. However, in the largest prospective study, motor and cognitive functioning were comparable at age three years for children exposed in utero to benzodiazepines (N = 1870) and unexposed children (N = 48,412) [60]. LITHIUM Use of lithium during pregnancy does not appear to increase perinatal mortality. A prospective observational study found that the frequency of miscarriages and stillbirths were each similar in patients treated with lithium (N = 138) and in controls (N = 148) [61]. Perinatal mortality is discussed separately. (See "Perinatal mortality".) Lithium appears to cause teratogenic effects that primarily involve the fetal heart [2,6]. The estimated incidence of major congenital anomalies among children of women treated with lithium during the first trimester is between 4 and 12 percent [62]. Cardiac malformations that have been observed include Ebsteins anomaly (abnormalities of the tricuspid valve and right ventricle), coarctation of the aorta, and mitral atresia [6,62-64]. Ebsteins anomaly may be the most common fetal cardiac defect caused by lithium. The estimated risk of the anomaly in the general population is 1 in 20,000 live births [25-27]; following first-trimester exposure to lithium, the risk appears to increase 20-fold to approximately 1 in 1000 [65], which many authorities consider low [2,6,24,28,66]. A meta-analysis of six case control studies (N = 264) found that the odds of exposure to lithium in cases of Ebsteins anomaly did not differ significantly from controls without the defect; however, the estimates were unstable because the number of events (exposure to lithium) was low [67]. Ebsteins anomaly is discussed separately. (See "Ebstein's anomaly of the tricuspid valve".) Birth weight may be increased in newborns exposed to lithium during pregnancy. A prospective observational study found that birth weights were significantly greater in babies exposed to lithium during pregnancy, compared with controls (3475 versus 3383 grams) [61].

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Use of lithium during the second and third trimester can result in neonatal complications, including [5,7,8,41,68-70]: Premature labor Polyhydramnios Cardiomegaly Hepatomegaly Nephrogenic diabetes insipidus Goiter and hypothyroidism Gastrointestinal bleeding Shock Lithium toxicity can also occur in newborns with late pregnancy exposure; symptoms include [5,7,8,41,68-70]: Low Apgar scores Shallow respirations, apnea, and cyanosis Bradycardia or tachycardia Cardiac arrhythmias and abnormal electrocardiogram (ECG) Seizures Lethargy or coma Muscle flaccidity and hypotonia Twitching Poor suck, grasp, and Moro reflexes Difficulty feeding Neonatal lithium toxicity and complications are more common in newborns with higher serum lithium concentrations. In a study of 24 infants exposed in utero to lithium, significantly lower Apgar scores, higher rates of central nervous system and neuromuscular complications, and longer hospital stays were observed in infants born with umbilical cord serum lithium concentrations >0.6 mEq/L (0.6 mmol/L), compared to infants with lower concentrations [71]. Lithium toxicity generally resolves in one to two weeks. Birth weight may be increased in babies exposed in utero to lithium. An observational study found that birth weight was significantly greater in lithium-exposed babies (N = 138) than unexposed babies (N = 148) (3475 versus 3383 grams) [61]. Maternal lithium dose was not correlated with birth weight. Available studies suggest that prenatal lithium exposure does not adversely affect developmental outcomes: A prospective study found that major developmental milestones (eg, smiling, lifting head, sitting, crawling, standing, talking, and walking) were achieved at comparable ages for lithium-exposed children (N = 22) and unexposed controls (N = 148) [61] A retrospective study found that behavioral measures of development were comparable for children exposed to lithium prenatally (N = 60) compared with their unexposed siblings (N = 57) [72] Lithium appears to completely equilibrate across the placenta. An observational study of 27 infant-mother pairs found that the ratio of lithium serum concentrations in umbilical cord blood to maternal blood was 1.1, across a wide range of maternal concentrations [71]. ELECTROCONVULSIVE THERAPY Neither the number nor pattern of congenital malformations in children exposed in utero to electroconvulsive therapy (ECT) implicates it as a causal factor in organ dysgenesis [6]. A review of 300 case reports of ECT during pregnancy found five reports of congenital anomalies, including hypertelorism, talipes equinovarus (clubfoot), optic atrophy, anencephaly, and pulmonary cysts [73]. The review concluded that these malformations were not the result of ECT, and that there was no evidence of postnatal developmental effects. In addition, there is little or no evidence that fetal exposure to ECT adversely affects intrauterine growth, or causes neonatal toxicity or adverse developmental effects [6]. The most common adverse effects of ECT in the mother are premature contractions and labor, and in the fetus bradyarrhythmias [74]. The risk of teratogenic effects and neonatal toxicity posed by ECT anesthetic drugs appears to be low [68,73-75]: Glycopyrrolate The anticholinergic glycopyrrolate does not readily cross the placenta, and there do not

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appear to be any reports of teratogenesis with the injected solution Methohexital Although the general anesthetic methohexital crosses the placenta, there do not appear to be any reports of teratogenesis with the drug Propofol Although the general anesthetic propofol crosses the placenta, there do not appear to be any reports of teratogenesis with the drug Succinylcholine The muscle relaxant succinylcholine generally does not appear to significantly affect the fetus; typically only a small amount at most crosses the placenta In addition, it is unlikely that these drugs cause congenital malformations and toxicity because of the infrequent and brief exposure that occurs during a course of ECT. INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, The Basics and Beyond the Basics. The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on patient info and the keyword(s) of interest.) Basics topics (See "Patient information: Bipolar disorder (The Basics)" and "Patient information: Reducing the costs of medicines (The Basics)".) Beyond the Basics topics (See "Patient information: Bipolar disorder (manic depression) (Beyond the Basics)" and "Patient information: Reducing the costs of medicines (Beyond the Basics)".) These educational materials can be used as part of psychoeducational psychotherapy. (See "Bipolar disorder in adults: Maintenance treatment", section on 'Psychoeducation'.) The National Institute of Mental Health also has educational material explaining the symptoms, course of illness, and treatment of bipolar disorder in a booklet entitled "Bipolar Disorder," which is available online at the website http://www.nimh.nih.gov/health/publications/bipolar-disorder/complete-index.shtml or through a toll-free number, 866-615-6464. The web site also provides references, summaries of study results in language intended for the lay public, and information about clinical trials currently recruiting patients. More comprehensive information is provided in many books written for patients and family members, including The Bipolar Disorder Survival Guide: What You and Your Family Need to Know, written by David J. Miklowitz, PhD (published by The Guilford Press, 2002); An Unquiet Mind: A Memoir of Moods and Madness, written by Kay Jamison, PhD (published by Random House, 1995); and Treatment of Bipolar Illness: A Casebook for Clinicians and Patients, by RM Post, MD, and GS Leverich, LCSW (published by Norton Press, 2008). The Depression and Bipolar Support Alliance (http://www.dbsalliance.org or 800-826-3632) is a national organization that educates members about bipolar disorder and how to cope with it. Other functions include increasing public awareness of the illness and advocating for more research and services. The organization is administered and maintained by patients and family members, and has local chapters. The National Alliance on Mental Illness (http://www.nami.org or 800-950-6264) is a similarly structured organization devoted to education, support, and advocacy for patients with any mental illness. Bipolar disorder is one of their priorities. SUMMARY AND RECOMMENDATIONS Bipolar disorder is a mood disorder that is characterized by episodes of mania (table 1), hypomania (table

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2), and major depression (table 3), as well as mixed episodes (major depression concurrent with mania or hypomania). (See 'Bipolar disorder' above and "Bipolar disorder in adults: Epidemiology and pathogenesis".) Teratogens are factors that can alter normal intrauterine development of fetal growth, anatomic structures, physical functioning, and postnatal development. This definition encompasses environmental exposures (eg, drugs), maternal medical disorders, infectious agents, and genetic conditions. (See 'Teratogen' above and "Principles of teratology".) The estimated risk of major congenital malformations appears to vary among the medications that are most commonly used to treat bipolar disorder. The rank order from greatest to least teratogenic risk is: (See 'General principles' above.) Valproate Carbamazepine Lithium Lamotrigine Antipsychotics Antidepressants Among the antiparkinsonian drugs that are used to treat extrapyramidal symptoms secondary to antipsychotics, reviews suggest that organ malformation appears to be less likely with diphenhydramine than amantadine, benztropine, or trihexyphenidyl. (See 'Antiparkinsonian drugs used for treating extrapyramidal symptoms' above.) Most studies have not found that selective serotonin reuptake inhibitors (SSRIs) in the first trimester increased the risk of birth defects, with the possible exception of paroxetine. In addition, tricyclic antidepressants, bupropion, mirtazapine, nefazodone, trazodone, and venlafaxine are generally not associated with congenital malformations. (See "Depression in pregnant women: Management".) Teratogenic and neurobehavioral effects have been identified in children exposed to valproate, and less frequently, carbamazepine. Although most studies suggest that the estimated rate of major congenital malformations with lamotrigine appears to be comparable to the rate in the general population, some studies suggest that lamotrigine may possibly cause orofacial clefts. (See "Risks associated with epilepsy and pregnancy", section on 'Effect of antiepileptic drugs on the fetus'.) Most studies have found that exposure during pregnancy to first and second-generation antipsychotics does not appear to increase the risk of major physical malformations above rates observed in the general population. However, chronic administration of antipsychotics during the third trimester may cause symptoms of neonatal toxicity and withdrawal. (See 'Antipsychotics' above.) It is not clear if exposure to benzodiazepines or to hypnotic, benzodiazepine receptor agonists during pregnancy increases the risk of congenital malformations. Chronic administration of benzodiazepines proximal to delivery can cause neonatal toxicity and withdrawal. (See 'Benzodiazepines' above.) Lithium appears to cause teratogenic effects that primarily involve the fetal heart. The estimated incidence of major congenital anomalies among children of women treated with lithium during the first trimester is between 4 and 12 percent. Ebsteins anomaly may be the most common fetal cardiac defect caused by lithium; the absolute risk in newborns exposed to lithium in utero is approximately 1 in 1000, compared with an estimated risk in the general population of 1 in 20,000 live births. In addition, use of lithium during the second and third trimester can result in neonatal complications and lithium toxicity. (See 'Lithium' above.) Neither the number nor pattern of congenital malformations in children exposed in utero to electroconvulsive therapy (ECT) implicates it as a causal factor in organ dysgenesis. The risk of neonatal toxicity and adverse developmental effects posed by ECT also appears to be low. (See 'Electroconvulsive therapy' above.)

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GRAPHICS DSM-IV-TR diagnostic criteria for mania


A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary). B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:
1) Inflated self-esteem or grandiosity 2) Decreased need for sleep (eg, feels rested after only 3 hours of sleep) 3) More talkative than usual or pressure to keep talking 4) Flight of ideas or subjective experience that thoughts are racing 5) Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli) 6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation 7) Excessive involvement in pleasurable activities that have a high potential for painful consequences (eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

C. The symptoms do not meet criteria for a mixed episode. D. The mood disturbance 1) is sufficiently severe to cause marked impairment in occupational functioning, usual social activities, or relationships with others, 2) necessitates hospitalization to prevent harm to self or others, or 3) has psychotic features. E. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism).
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Text Revision, Fourth Edition (Copyright 2000). American Psychiatric Association.

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DSM-IV-TR diagnostic criteria for hypomania


A. A distinct period of persistently elevated, expansive, or irritable mood, lasting at least 4 days, that is clearly different from the usual nondepressed mood. B. During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree:
1) Inflated self-esteem or grandiosity 2) Decreased need for sleep (eg, feels rested after only 3 hours of sleep) 3) More talkative than usual or pressure to keep talking 4) Flight of ideas or subjective experience that thoughts are racing 5) Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli) 6) Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation 7) Excessive involvement in pleasurable activities that have a high potential for painful consequences (eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

C. The episode is associated with an unequivocal change in functioning that is uncharacteristic of the person when not symptomatic. D. The disturbance in mood and the change in functioning are observable by others. E. The episode 1) is not severe enough to cause marked impairment in social or occupational functioning, 2) does not necessitate hospitalization, and 3) does not have psychotic features. F. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse, a medication, or other treatment) or a general medical condition (eg, hyperthyroidism). Note: Hypomanic-like episodes that are clearly caused by somatic antidepressant treatment (eg, medication, ECT, light therapy) should not count toward a diagnosis of bipolar II disorder.
Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Text Revision, Fourth Edition (Copyright 2000). American Psychiatric Association.

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DSM-IV-TR diagnostic criteria for major depression


A. Five (or more) of the following symptoms have been present during the same 2-week period, and represent a change from previous functioning. At least one of the symptoms is either depressed mood or loss of interest or pleasure.
(Note: Do not include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions or hallucinations.) Depressed mood most of the day, nearly every day (or alternatively can be irritable mood in children and adolescents) Markedly diminished interest or pleasure in all, or almost all, activities, nearly every day Significant weight loss while not dieting, weight gain, or decrease or increase in appetite Insomnia or hypersomnia nearly every day Psychomotor agitation or retardation nearly every day Fatigue or loss of energy nearly every day Feelings of worthlessness or excessive or inappropriate guilt nearly every day Diminished ability to think or concentrate, or indecisiveness, nearly every day Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide

B. The symptoms do not meet criteria for a Mixed Episode. C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. D. The symptoms are not due to the direct physiological effects of substance or a general medical condition. E. The symptoms are not better accounted for by Bereavement, ie, after the loss of a loved one, the symptoms persist for longer than two months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.
Adapted from American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th ed, Text Revision. American Psychiatric Association, Washington, DC 2000.

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Periods of sensitivity during development

Reproduced with permission from: Unborn Patient: Prenatal Diagnosis and Treatment. Harrison, Golbus, Filly (eds). Philadelphia, Saunders, 1990. p. 44. Copyright 1990 Elsevier.

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The developing fetus

Reproduced with permission from: Moore, K. The developing human: Clinically oriented embryology, WB Saunders, Philadelphia 1982. Copyright 1982 Elsevier.

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