Bipolar disorder in pregnant women: Treatment of mania and hypomaniaAuthorVictoria Hendrick, MDAll topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Oct 2014. | This topic last updated: Jul 24, 2014.INTRODUCTION — Medications are commonly used to treat pregnant patients, including those with manic and hypomanic episodes [1]. At least one prescription drug is taken by more than 60 percent of pregnant patients [2], and psychotropic drugs are taken by 21 to 33 percent [3,4].

This topic discusses pharmacotherapy for pregnant patients with mania or hypomania. Treatment of bipolar major depression during pregnancy, prenatal maintenance pharmacotherapy for bipolar disorder, the teratogenic and postnatal risks of medications used for bipolar disorder, and the general treatment of mania and hypomania is discussed separately.

DEFINITION OF BIPOLAR DISORDER — Bipolar disorder is characterized by episodes of mania (table 1), hypomania (table 2), and major depression (table 3) [5]. The subtypes of bipolar disorder include bipolar I and bipolar II. Patients with bipolar I disorder experience manic 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 episodes. Additional information about the clinical features and diagnosis of bipolar disorder is discussed separately. (See "Bipolar disorder in adults: Clinical features" and "Bipolar disorder in adults: Assessment and diagnosis".)

INDICATIONS — Pharmacotherapy is indicated for pregnant patients with manic and hypomanic episodes that are characterized by [6]:

●Suicidal or homicidal ideation or behavior●Aggressive behavior●Psychotic features (delusions or hallucinations)●Poor judgement that places the patient or others at imminent risk of being harmed●Moderate to severe impairment of social or occupational functioning●Involvement in pleasurable activities that have a high potential for painful consequences (eg, unrestrained buying sprees or sexual indiscretions)

Medications may not be indicated for some episodes of hypomania. However, it is not clear which untreated hypomanic episodes will progress to mania that requires pharmacotherapy.

MANAGEMENT

General principles — Bipolar mood episodes during pregnancy are usually treated by perinatal or general psychiatrists in collaboration with obstetricians and

primary care clinicians [4,7-10].

For manic and hypomanic pregnant patients, treatment is based upon randomized trials that excluded pregnant patients [11], as well as observational studies, birth registries, and clinical experience [12].

For pregnant bipolar patients treated with pharmacotherapy, clinicians should attempt to use [1,4,13,14]:

-Drugs with fewer known teratogenic effects-Monotherapy-Doses at the low end of the therapeutic range

The risks of teratogenic effects from medications commonly used to treat bipolar disorder are discussed separately. (See "Teratogenic and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy".)

For pregnant patients with bipolar mood episodes that occur during maintenance pharmacotherapy, we favor increasing the dose within the therapeutic dose range rather than starting a second medication [4,15,16]. This includes ensuring serum concentrations are in the therapeutic range for medications such as lithium, as well as increasing the dose to achieve a higher serum level within the therapeutic range, provided that side effects do not intervene. However, many patients require medication combinations [9,17-19].

Following recovery from prenatal bipolar mood episodes with pharmacotherapy, we suggest that patients receive maintenance treatment. For patients who decline maintenance pharmacotherapy, abrupt discontinuation of medications should be avoided. Rather, clinicians should attempt to taper and discontinue drugs over the course of at least 15 days to minimize the risk of relapse, based upon observational studies [20]. Prenatal maintenance pharmacotherapy and the risk of abruptly discontinuing pharmacotherapy are discussed separately. (See "Bipolar disorder in women: Preconception and prenatal maintenance pharmacotherapy" and "Bipolar disorder in women: Contraception and preconception assessment and counseling", section on 'Relapse after discontinuing pharmacotherapy'.)

Setting — The setting for prenatal treatment of bipolar mood episodes depends upon the type and severity of symptoms, level of psychosocial functioning, and available support [15,21,22]:

●Inpatient hospitalization is often required for safety and stabilization of patients with severe symptoms (eg, suicidal ideation with a specific plan or intent)

●Partial hospital (day) treatment may be feasible for managing moderate symptoms (eg, suicidality that does not pose an imminent risk, such as fleeting thoughts of killing oneself with vague or nonexistent plans and no intent)

●Outpatient treatment may be suitable for patients with less acute symptoms (eg, thoughts that family members would be better off if the patient was dead, with no plan or intent to commit suicide)

Monitoring the patient — The psychiatric status of pregnant bipolar patients should be regularly monitored, with particular attention to suicidal ideation and psychosis [7,23]. Patients taking medications are also assessed for therapeutic and adverse effects. In addition, serum concentrations of medications with established therapeutic levels (eg, lithium) should be checked. Monitoring pregnant patients who take lithium is discussed separately. (See "Bipolar disorder in women: Preconception and prenatal maintenance pharmacotherapy", section on 'Refractory patients'.)

The frequency of assessing pregnant bipolar patients generally ranges from daily to monthly, depending upon the type and severity of symptoms. Hospitalized patients are monitored daily, and patients with active suicidal ideation, a specific plan, and intent to kill themselves typically require constant observation. Outpatients who have not achieved substantial improvement in the number, intensity, and frequency of symptoms are generally seen weekly; patients who have improved substantially may be seen every two to four weeks until they remit.

Duration of individual drug trial — We suggest treating pregnant patients with mania and hypomania for three weeks before determining whether a specific drug is beneficial, based upon the duration of most randomized trials (which excluded pregnant patients) [11]. Response is defined as stabilizing the patient’s safety and substantial improvement in the number, intensity, and frequency of symptoms.

SPECIFIC TREATMENTS — Despite clinical differences between mania and hypomania (eg, hypomania is less severe than mania), for the purpose of treatment these mood elevated syndromes are considered to be similar and thus treated with the same medications [15,21,22].

First line medications — For manic and hypomanic pregnant patients, we suggest first-generation antipsychotics, which have been widely used during pregnancy [4,24]. We prefer haloperidol, based upon its demonstrated efficacy in randomized trials (which excluded pregnant patients) [11], and other studies that suggest haloperidol is not associated with an increased risk of congenital anomalies [3,25]. Using haloperidol is consistent with practice guidelines from the United Kingdom National Institute for Health and Clinical Excellence [23,26], and haloperidol is preferred by many authorities [1,18,27]. Other first-generation antipsychotics that are reasonable alternatives to haloperidol include chlorpromazine, fluphenazine, perphenazine, thiothixene, and trifluoperazine [28]. Clinicians can expect that response to a first-generation antipsychotic will occur in approximately 50 percent of patients, based upon trials in nonpregnant patients [29].

The efficacy of haloperidol for treating mood elevated syndromes appears to be comparable to risperidone and olanzapine, and superior to quetiapine and lithium [11]. In addition, there is more experience using haloperidol during pregnancy compared with second-generation antipsychotics, and the reproductive safety profile of haloperidol is generally regarded as superior to lithium. The efficacy of haloperidol, risperidone, olanzapine, quetiapine, and lithium (in randomized trials that excluded pregnant patients) is discussed separately, as is the reproductive safety profile of these drugs, and the dose, side effect profile (table 4), and pharmacology of haloperidol. (See "Bipolar disorder in adults: Pharmacotherapy for acute mania and hypomania" and "Teratogenic and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy" and "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects".)

For pregnant bipolar patients who cannot tolerate the usual minimal therapeutic dose of haloperidol (5 to 10 mg per day) because of extrapyramidal symptoms (EPS), we suggest cautiously reducing the dose (eg, by 1 to 2 mg per day), while closely monitoring the patient for exacerbation of mood elevated symptoms. If decreasing the dose is unfeasible or inadequate, we suggest tapering and discontinuing haloperidol over one to two weeks and at the same time starting and titrating up a low-potency agent (eg, chlorpromazine) [30]. Haloperidol is tapered by the same amount for each dose decrease. As an example, haloperidol 8 mg per day is decreased by 2 mg per day every one to three days. The dose and side effects of chlorpromazine are discussed separately. (See "First-generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Chlorpromazine'.)

For pregnant patients receiving haloperidol who develop Parkinsonism or dystonia, a reasonable alternative to switching drugs is to add diphenhydramine. Reviews suggest that the risk of teratogenicity with antihistamines such as diphenhydramine appears to be low [31], and that fetal organ malformation appears to be less likely with diphenhydramine than amantadine, benztropine, and trihexyphenidyl [30,32]. Additional information about the treatment of extrapyramidal symptoms and the teratogenic risks of antiparkinsonian drugs is discussed separately. (See "Pharmacotherapy for schizophrenia: Side effect management", section on 'Extrapyramidal symptoms' and "Teratogenic and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy", section on 'Antiparkinsonian drugs used for treating extrapyramidal symptoms'.)

Resistant patients — In our clinical experience, pregnant patients with manic and hypomanic episodes often do not respond to or tolerate haloperidol. (Response is defined as stabilizing the patient’s safety and substantial improvement in the number, intensity, and frequency of symptoms.) For these resistant patients, we suggest in order of preference risperidone, quetiapine, or olanzapine, based upon their efficacy and side effects in randomized trials (that excluded pregnant patients) [11], as well as study findings that suggest these drugs are not associated with an increased risk of major malformations [19,33,34]. Using second-generation

antipsychotics during pregnancy is consistent with the practice of many perinatal psychiatrists [18]. Up to 50 to 60 percent of patients may respond, based upon trials in nonpregnant patients [29].

The efficacy of risperidone and olanzapine appears to be superior to quetiapine and lithium; quetiapine appears to be better tolerated than olanzapine; and although the efficacy of quetiapine and lithium appear comparable, quetiapine may be better tolerated [11]. In addition, study findings suggest that second-generation antipsychotics are not associated with an increased risk of major malformations [18,19,33,34], whereas lithium is generally regarded as teratogenic [35-37]. The preference for treating pregnant bipolar patients with risperidone, quetiapine, or olanzapine rather than lithium is consistent with practice guidelines from the United Kingdom National Institute for Health and Clinical Excellence [23,26].  

However, second-generation antipsychotics, particularly olanzapine, may cause metabolic complications (eg, hyperglycemia and obesity) that are associated with risks to the mother and fetus [38,39]. These risks are discussed separately, as is monitoring of metabolic parameters in pregnant patients taking second-generation antipsychotics. (See "Bipolar disorder in women: Preconception and prenatal maintenance pharmacotherapy", section on 'Metabolic complications'.)

To switch drugs, haloperidol is tapered and discontinued over one to two weeks while at the same time risperidone is started and titrated up. We generally taper haloperidol by the same amount for each dose decrease. As an example, haloperidol 8 mg per day is decreased by 2 mg per day, every one to three days. For resistant pregnant bipolar patients who do not respond to or tolerate treatment with one second line medication, we suggest tapering and discontinuing the failed medication over one to two weeks at the same time that another second-line medication is started and titrated up. The failed medication is generally tapered by the same amount for each dose decrease. As an example, risperidone 6 mg per day is decreased by 1 to 2 mg per day, every one to three days.

The efficacy of risperidone, quetiapine, and olanzapine for treating mood elevated syndromes (in randomized trials that excluded pregnant patients) is discussed separately, as are the doses, side effects (table 4), pharmacology, and reproductive safety profiles. (See "Bipolar disorder in adults: Pharmacotherapy for acute mania and hypomania" and "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Individual medications' and "Teratogenic and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy", section on 'Second-generation'.)  

Refractory patients — Based upon clinical experience, prenatal manic and hypomanic episodes generally respond to sequential trials of haloperidol, risperidone, quetiapine, and olanzapine. (Response is defined as stabilizing the safety of the patient, as well as substantial improvement in the number, intensity, and frequency of symptoms.) However, for refractory patients who do not respond to antipsychotics, we suggest in order of preference lithium and electroconvulsive

therapy (ECT) [40]. For patients unresponsive to sequential trials of lithium and ECT, other options include lithium plus an antipsychotic, carbamazepine, and valproate.

Lithium — For pregnant patients with manic episodes that do not respond to multiple antipsychotics, we suggest lithium, based upon its efficacy and side effects in randomized trials (which excluded pregnant patients) [11]. Although lithium is generally regarded as teratogenic due to increased risks of cardiac defects (eg, Ebstein’s anomaly) [35-37], many authorities consider the absolute risk small [1,4,17,32,41]. Clinicians can expect that up to approximately 50 percent of patients will respond, based upon trials in nonpregnant patients [29].

The dose schedule for lithium, use of serum concentrations to establish the proper dose, and lithium toxicity are discussed separately, as are using lithium during pregnancy and lithium’s reproductive safety profile. (See "Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects" and "Bipolar disorder in women: Preconception and prenatal maintenance pharmacotherapy", section on 'Refractory patients' and "Teratogenic and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy", section on 'Lithium'.)

Electroconvulsive therapy — For pregnant patients with moderate to severe manic episodes that do not respond to sequential trials of antipsychotics and lithium, we suggest electroconvulsive therapy (ECT), which is generally regarded as efficacious and safe [42,43]. The use of ECT for pregnant bipolar patients is consistent with recommendations in multiple practice guidelines [7,26,44-46]. Evidence for the efficacy of ECT includes studies that found ECT is effective for mania in patients who are not pregnant. (See "Bipolar disorder in adults: Indications for and efficacy of electroconvulsive therapy (ECT)", section on 'Mania'.)

In addition, a review of observational studies of pregnant patients treated for mood or psychotic disorders with ECT found that among 68 cases with outcome data, at least partial remission occurred in 78 percent [47]. Among the seven patients with bipolar disorder, remission occurred in five and partial remission in one.

ECT during pregnancy is generally regarded as safe for the mother and fetus [43,48,49]. Many authorities think that ECT poses fewer risks than untreated bipolar mood episodes and medications that are potentially teratogenic (eg, valproate and carbamazepine, and to a lesser extent lithium) [1,43,47,50,51]. The reproductive safety profile of ECT is discussed separately. (See "Teratogenic and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy", section on 'Electroconvulsive therapy'.)

ECT is typically well tolerated and there are no absolute contraindications to ECT, even among patients whose general medical status is compromised [43]. However, safety concerns regarding ECT necessitate preprocedure obstetric consultation (consistent with guideline recommendation), with emphasis upon assessing risk factors for spontaneous abortion, preterm labor, abruption, and uteroplacental

insufficiency due to the association of ECT with transient increases or decreases in blood pressure and uterine contractions. The patient’s general medical status is also evaluated; medical consultation prior to ECT is discussed separately, as is the use of ECT for patients with general medical conditions. (See "Medical consultation for electroconvulsive therapy" and "Overview of electroconvulsive therapy (ECT) for adults", section on 'Patients with comorbid general medical illness'.)

A review of observational studies found that the most frequent maternal complication from ECT during pregnancy is induction of premature labor [47]. Among 339 pregnant patients treated with ECT, there were 20 maternal complications, of which 18 were thought to be related to ECT:

●Status epilepticus – one case●Placental abruption – one case (possibly related to acute hypertension)●Vaginal bleeding – two cases●Uterine contractions and/or preterm labor – 12 cases●Hematuria – one case●Abdominal pain – one case

The general adverse effects of ECT include cardiopulmonary events, aspiration pneumonia, fractures, dental and tongue injuries, headache, nausea, and cognitive impairment [43]. (See "Overview of electroconvulsive therapy (ECT) for adults", section on 'Adverse effects'.)

Common general adverse effects after each ECT treatment are usually treated as follows [43]:

●Headache and/or myalgia – Acetaminophen (nonsteroidal anti-inflammatory drugs may alter maternal and fetal hemostasis, and lead to early constriction or closure of the fetal ductus arteriosus)

●Nausea – Meclizine, metoclopramide, or prochlorperazine

A review found that the most frequent fetal complication from prenatal ECT is bradyarrhythmia [47]. Among 339 pregnant patients treated with ECT, there were 25 fetal or neonatal adverse events, of which 11 were thought to be related to ECT:

●Fetal death due to maternal status epilepticus – one case●Miscarriage 24 hours post-ECT – one case●Multiple brain infarctions after multiple ECT courses during pregnancy – one case●Transient fetal arrhythmias (typically bradycardia, thought to be the result of hypoxia) – eight cases  

ECT is generally given three times per week on alternate days. Most patients regardless of indication remit with 6 to 12 treatments, but some patients require 20

or more. A review of prenatal ECT found that the mean number of treatments per ECT course was 11 [47]. The number and frequency of treatments in the general use of ECT is discussed separately, as are the adjustments in ECT technique for pregnant patients. (See "Overview of electroconvulsive therapy (ECT) for adults", section on 'Treatment course' and "Technique for performing electroconvulsive therapy (ECT) in adults", section on 'Pregnancy'.)

Following a course of ECT, clinicians usually prescribe maintenance pharmacotherapy. (See "Bipolar disorder in women: Preconception and prenatal maintenance pharmacotherapy", section on 'Specific drugs'.)

Other options — For pregnant bipolar patients with moderate to severe manic episodes that do not respond to sequential trials of antipsychotics, lithium, and ECT, we suggest in order of preference:

●Lithium plus an antipsychotic – For patients who do not respond to lithium monotherapy and decline or do not have access to ECT, we suggest adding either a first or second-generation antipsychotic to lithium, based upon randomized trials that excluded pregnant patients. (Response is defined as stabilizing the safety of the patient, as well as substantial improvement in the number, intensity, and frequency of symptoms.) For patients who do not respond to antipsychotics, lithium, and ECT, we concurrently start lithium plus an antipsychotic. No head-to-head trials have compared medication combinations consisting of lithium plus an antipsychotic; we typically use lithium plus haloperidol, risperidone, quetiapine, or olanzapine. The choice of an antipsychotic is based upon factors including past response to medications, side effect profiles, comorbid general medical conditions, potential for drug-drug interactions, patient preference, and cost. As an example, if the patient previously showed a modest response to haloperidol and no response to risperidone, quetiapine, or olanzapine, we would choose lithium plus haloperidol. The efficacy of lithium plus an antipsychotic in randomized trials (that excluded pregnant patients) is discussed separately, as are the doses, side effects, pharmacology, and reproductive safety profiles. (See "Bipolar disorder in adults: Pharmacotherapy for acute mania and hypomania" and "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Individual medications' and "Teratogenic and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy".)Specific medication interactions that can occur may be determined using the drug interactions tool (Lexi-Interact Online) included in UpToDate. This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section on Drug interactions.Refractory patients who do not respond to or tolerate one lithium/antipsychotic combination should be treated with a second combination. We usually taper and discontinue the failed antipsychotic at the same time that a different antipsychotic is started and titrated up. The failed antipsychotic is generally tapered over one to two weeks by the same amount for each dose decrease (eg, haloperidol 8 mg per day is decreased by 2 mg per day, every one to three days).  

●Carbamazepine or valproate (divalproex) – For pregnant patients with manic episodes, we typically avoid carbamazepine and valproate because of the risks of teratogenic and postnatal developmental effects [1]. However, for patients who do not respond to sequential treatment with antipsychotics, lithium, ECT, and lithium plus antipsychotics, and have previously responded to carbamazepine or valproate for preconception mood episodes, it is reasonable to use either of these antiepileptics [23,26], both of which have demonstrated efficacy in randomized trials that did not include pregnant patients [11]. The evidence of efficacy, dose, side effects, and pharmacology of carbamazepine and valproate are discussed separately, as is the management of pregnant patients receiving these drugs, and the risks of teratogenic and postnatal effects; much of this information is based upon treatment of epilepsy. (See "Bipolar disorder in adults: Pharmacotherapy for acute mania and hypomania" and "Pharmacology of antiepileptic drugs" and "Management of epilepsy and pregnancy", section on 'Management during pregnancy and delivery' and "Risks associated with epilepsy and pregnancy", section on 'Effect of antiepileptic drugs on the fetus'.)Patients treated with valproate or carbamazepine during pregnancy should also receive folic acid 4 mg per day, which may prevent neural tube defects [52]. In addition, the obstetrician should be informed to screen for teratogenic effects [23]. (See "Management of epilepsy and pregnancy", section on 'Management during pregnancy and delivery' and "Folic acid supplementation in pregnancy", section on 'Anticonvulsant therapy' and "Prenatal screening and diagnosis of neural tube defects".)Valnoctamide (not available in the United States) is an analogue of valproate that appears to be less teratogenic in mice than valproate, and may possibly benefit acutely manic, pregnant patients [53]. A randomized trial compared adjunctive valnoctamide (400 mg three times daily) with placebo in 32 nonpregnant, manic patients treated with risperidone (1 to 4 mg per day); manic symptoms improved significantly more with adjunctive valnoctamide [54].SUMMARY AND RECOMMENDATIONS

●Bipolar disorder is characterized by episodes of mania (table 1), hypomania (table 2), and major depression (table 3). (See 'Definition of bipolar disorder' above and "Bipolar disorder in adults: Clinical features", section on 'Clinical presentation' and "Bipolar disorder in adults: Assessment and diagnosis", section on 'Diagnosis'.)

●Pharmacotherapy is indicated for pregnant patients with manic or hypomanic episodes that are characterized by (see 'Indications' above):

•Suicidal or homicidal ideation or behavior•Aggressive behavior•Psychotic features (delusions or hallucinations) •Poor judgement that places the patient or others at imminent risk of being harmed•Moderate to severe impairment of social or occupational functioning•Involvement in pleasurable activities that have a high potential for painful consequences (eg, unrestrained buying sprees or sexual indiscretions)

●Clinicians treating pregnant patients with manic or hypomanic episodes should attempt to use drugs with fewer known teratogenic effects, monotherapy, and doses at the low end of the therapeutic range. An individual drug trial typically lasts three weeks before determining the medication is beneficial. (See 'General principles' above.)●For manic and hypomanic pregnant patients, we suggest first-generation antipsychotics rather than other medications (Grade 2B). We prefer haloperidol, but reasonable alternatives include chlorpromazine, fluphenazine, perphenazine, thiothixene, and trifluoperazine. (See 'First line medications' above)●For pregnant patients with manic or hypomanic episodes who do not respond to or tolerate first-generation antipsychotics, we suggest in order of preference risperidone, quetiapine, and olanzapine, rather than other drugs (Grade 2C). (See 'Resistant patients' above.) ●Pregnant patients with refractory manic or hypomanic episodes that do not respond to antipsychotics are often treated with lithium, electroconvulsive therapy (ECT), or lithium plus an antipsychotic. (See 'Refractory patients' above.)

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Bipolar disorder in pregnant women: Treatment of major depressionAuthorVictoria Hendrick, MDLiterature review current through: Oct 2014. | This topic last updated: Apr 16, 2014.INTRODUCTION — Medications are commonly used to treat pregnant patients, including those with bipolar major depression [1]. At least one prescription drug is taken by more than 60 percent of pregnant patients [2], and psychotropic drugs are taken by 21 to 33 percent [3,4].

This topic discusses treatment of pregnant patients with bipolar major depression. Treatment of manic and hypomanic episodes during pregnancy, prenatal maintenance pharmacotherapy for bipolar disorder, the teratogenic and postnatal risks of pharmacotherapy for bipolar disorder, and the general treatment of bipolar major depression are discussed separately.

DEFINITION OF BIPOLAR DISORDER — Bipolar disorder is characterized by episodes of mania (table 1), hypomania (table 2), and major depression (table 3) [5]. The subtypes of bipolar disorder include bipolar I and bipolar II. Patients with bipolar I disorder experience manic 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 episodes. Additional information about the clinical features and diagnosis of bipolar disorder is discussed separately. (See "Bipolar disorder in adults: Clinical features" and "Bipolar disorder in adults: Assessment and diagnosis", section on 'Diagnosis'.)

INDICATIONS — Pharmacotherapy is indicated for pregnant patients with bipolar major depression that is characterized by [6]:

●Suicidal or homicidal ideation or behavior●Aggressive behavior●Psychotic features (delusions or hallucinations)●Poor judgement that places the patient or others at imminent risk of being harmed●Moderate to severe impairment of social or occupational functioning

GENERAL PRINCIPLES AND MANAGEMENT — Bipolar mood episodes during pregnancy are usually treated by perinatal or general psychiatrists in collaboration with obstetricians and primary care clinicians [4,7-10].

For pregnant patients with bipolar major depression, treatment is based upon randomized trials that excluded pregnant patients [11-14], as well as observational studies, birth registries, and clinical experience [15].

Additional information about the general principles and management of treating bipolar mood episodes during pregnancy are discussed separately, as is the general treatment of bipolar major depression. (See "Bipolar disorder in pregnant women: Treatment of mania and hypomania", section on 'Management' and "Bipolar disorder in adults: Pharmacotherapy for acute depression".)          

Duration of individual drug trial — We suggest treating pregnant patients with bipolar major depression for six to eight weeks before determining whether a specific drug is beneficial, based upon the duration of most randomized trials (which excluded pregnant patients) [11-13,16]. Response is defined as stabilizing the patient’s safety and substantial improvement in the number, intensity, and frequency of symptoms.

SELECTING TREATMENT — Bipolar major depression during pregnancy is typically treated with pharmacotherapy because it is easier to administer, more widely available, and more acceptable to patients than electroconvulsive therapy (ECT). However, refractory patients may benefit from ECT.

First line treatment — For pregnant patients with bipolar major depression, we suggest lamotrigine as first line treatment, based upon efficacy in a meta-analysis of randomized trials that excluded pregnant patients [14]. Up to 40 to 50 percent of patients may respond (defined as stabilizing the patient’s safety and substantial improvement in the number, intensity, and frequency of symptoms). In addition, the reproductive safety profile of lamotrigine is generally regarded as favorable [4,17,18]. The efficacy of lamotrigine and quetiapine appear to be comparable, but there is more experience using lamotrigine during pregnancy than quetiapine. In addition, there is more evidence supporting the efficacy of lamotrigine compared with fluoxetine plus olanzapine or lamotrigine plus lithium, and prenatal treatment with monotherapy is preferable to treatment with drug combinations due to concerns about teratogenic effects.

The efficacy of lamotrigine, quetiapine, fluoxetine plus olanzapine, and lamotrigine plus lithium; reproductive safety profile of these drugs; and the dose schedule, side effects (table 4 and table 5) (including life-threatening skin rash), and pharmacology of lamotrigine are discussed separately. (See "Bipolar disorder in adults: Pharmacotherapy for acute depression" and "Teratogenic and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy" and "Pharmacology of antiepileptic drugs", section on 'Lamotrigine' and "Bipolar disorder in adults: Maintenance treatment".)

Treatment resistance — For pregnant patients with bipolar major depression who do not respond to lamotrigine or cannot tolerate it, we suggest quetiapine [19], based upon randomized trials that excluded pregnant patients [20-23]. Up to 50 to 60 percent of patients may respond (defined as stabilizing the patient’s safety and substantial improvement in the number, intensity, and frequency of symptoms). In addition, other studies suggest that quetiapine is not associated with teratogenic effects [24], and use of quetiapine for bipolar major depression during pregnancy is consistent with practice guidelines from the United Kingdom National Institute for Health and Clinical Excellence [25,26]. There is more evidence supporting the efficacy of lamotrigine compared with fluoxetine plus olanzapine or lamotrigine plus lithium, and prenatal treatment with monotherapy is preferable to treatment with drug combinations due to concerns about teratogenic effects.

We generally taper and discontinue lamotrigine at the same time that quetiapine is started and titrated up. Lamotrigine is usually tapered by the same amount for each dose decrease over a one to two week period. As an example, lamotrigine 200 mg per day is decreased by 50 mg per day every three to four days.

Second-generation antipsychotics may cause metabolic complications (eg, hyperglycemia and obesity) that are associated with risks to the mother and fetus [27,28]. These risks are discussed separately, as are monitoring of metabolic parameters in pregnant patients taking second-generation antipsychotics and the efficacy, dose, reproductive safety, pharmacology, and side effects of quetiapine. (See "Bipolar disorder in women: Preconception and prenatal maintenance pharmacotherapy", section on 'Metabolic complications' and "Bipolar disorder in adults: Pharmacotherapy for acute depression" and "Teratogenic and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy", section on 'Second-generation' and "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects", section on 'Quetiapine'.)

Refractory patients — Pregnant patients with bipolar major depression often do not respond to sequential trials of lamotrigine and quetiapine. For these refractory patients, we suggest tapering and discontinuing quetiapine over one to two weeks at the same time that another medication regimen is started and titrated up. (Response is defined as stabilizing the safety of the patient and others, as well as substantial improvement in the number, intensity, and frequency of symptoms.) Quetiapine is generally tapered by the same amount for each dose decrease. As an example, quetiapine 600 mg per day is decreased by 50 to 100 mg per day, every one to two days.

We suggest using the following treatments in sequence for pregnant patients with refractory bipolar major depression, based upon their efficacy in randomized trials (which excluded pregnant patients), reproductive safety profiles, and adverse effects. Although the benefit of fluoxetine plus olanzapine and the combination of lamotrigine and lithium appear to be comparable, neither fluoxetine nor olanzapine appear to be associated with teratogenic effects. By contrast, lithium is generally regarded as teratogenic [29-31]. The proportion of patients who respond to any of

the following treatment regimens may be as high as approximately 50 percent, based upon trials in nonpregnant patients [11,12].

●Fluoxetine plus olanzapine – Fluoxetine plus olanzapine is efficacious for bipolar major depression in nonpregnant patients [12,32]. However, second-generation antipsychotics, especially olanzapine, may cause metabolic complications (eg, hyperglycemia and obesity) that are associated with risks to the mother and fetus [27,28]. These risks are discussed separately, as are monitoring of metabolic parameters in pregnant patients taking second-generation antipsychotics and the efficacy, dose, reproductive safety, pharmacology, and side effects of fluoxetine and olanzapine. (See "Bipolar disorder in women: Preconception and prenatal maintenance pharmacotherapy", section on 'Metabolic complications' and "Teratogenic and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy" and "Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects" and "Second-generation antipsychotic medications: Pharmacology, administration, and comparative side effects" and "Bipolar disorder in adults: Pharmacotherapy for acute depression".)Specific medication interactions that can occur may be determined using the drug interactions tool (Lexi-Interact Online) included in UpToDate. This tool can be accessed from the online search page or through the individual drug information topics in the section on Drug Interactions.  

●Lamotrigine plus lithium – For pregnant patients with bipolar major depression who do not respond to or tolerate fluoxetine plus olanzapine, we suggest lamotrigine plus lithium [11]. Fluoxetine plus olanzapine are usually tapered and discontinued concurrently over a period of one week, and subsequently lamotrigine and lithium are started and titrated up. Fluoxetine is generally tapered by the same amount for each dose decrease, as is olanzapine. As an example, fluoxetine 40 mg per day is decreased by 10 mg per day every two days, and olanzapine 15 mg per day is decreased by 5 mg per day every three days. Although lithium is generally regarded as teratogenic due to increased risks of cardiac defects (eg, Ebstein’s anomaly) [29-31], many authorities consider the absolute risk small [1,4,18,33,34]. The reproductive safety profile of lamotrigine is generally regraded as favorable [4,17,18], based primarily upon studies of patients with epilepsy. (See "Teratogenic and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy", section on 'Lithium' and "Risks associated with epilepsy and pregnancy", section on 'Lamotrigine'.)The dose schedule, side effects (table 4 and table 5) (including life-threatening skin rash), and pharmacology of lamotrigine are discussed separately; as are the use of lithium during pregnancy, dose, use of serum concentrations to establish the proper dose, side effects, and pharmacology of lithium. (See "Pharmacology of antiepileptic drugs", section on 'Lamotrigine' and "Bipolar disorder in women: Preconception and prenatal maintenance pharmacotherapy", section on 'Refractory patients' and "Bipolar disorder in adults and lithium: Pharmacology, administration, and side effects" and "Bipolar disorder in adults: Maintenance treatment".)Specific medication interactions that can occur may be determined using the drug interactions tool (Lexi-Interact Online) included

in UpToDate. This tool can be accessed from the online search page or through the individual drug information topics in the section on Drug Interactions.

●Electroconvulsive therapy (ECT) – For refractory pregnant patients with bipolar major depression that does not respond to sequential trials of lamotrigine, quetiapine, fluoxetine plus olanzapine, and lamotrigine plus lithium, we suggest electroconvulsive therapy (ECT). Lamotrigine and lithium are tapered and discontinued over a period of one to two weeks prior to starting ECT. Lamotrigine is generally tapered by the same amount for each dose decrease, as is lithium. As an example, lamotrigine 200 mg per day is decreased by 50 mg per day every three to four days, and lithium 1200 mg per day is tapered by 300 mg per day every three to four days.Reviews have found that ECT is efficacious and safe for patients with bipolar major depression who are not pregnant, as well as patients who are pregnant [35,36]; ECT is thus recommended by several practice guidelines [7,37-40]. The efficacy, adverse maternal and fetal effects, and reproductive safety of ECT are discussed separately, as is the technique for performing ECT during pregnancy. (See "Bipolar disorder in adults: Indications for and efficacy of electroconvulsive therapy (ECT)", section on 'Bipolar major depression' and "Bipolar disorder in pregnant women: Treatment of mania and hypomania", section on 'Electroconvulsive therapy' and "Teratogenic and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy", section on 'Electroconvulsive therapy' and "Technique for performing electroconvulsive therapy (ECT) in adults", section on 'Pregnancy'.)

ADJUNCTIVE TREATMENT

Psychotherapy — For pregnant patients with bipolar major depression who are treated with pharmacotherapy, we suggest adjunctive psychotherapy based upon randomized trials in nonpregnant patients [2,6,41]. As an example, a one-year randomized trial compared intensive psychotherapy plus pharmacotherapy with brief psychoeducation plus pharmacotherapy in 293 nonpregnant patients with bipolar major depression [42]. Intensive psychotherapy consisted of family therapy, cognitive-behavioral therapy, or interpersonal and social rhythm therapy, with up to 30 sessions (50 minutes each) administered over nine months; brief psychoeducation included three 50-minute sessions instructing patients about the clinical features and treatment of bipolar disorder. Recovery occurred in more patients who received adjunctive intensive psychotherapy compared with brief psychoeducation (64 versus 52 percent), and outcome did not differ significantly among the three intensive therapies. Using psychotherapy is also supported by randomized trials in pregnant patients with unipolar major depression [43], and is consistent with treatment guidelines [26].

Omega-3 fatty acids — For pregnant patients with bipolar major depression, dietary supplementation with omega-3 fatty acids (eg, eicosapentaenoic acid 1 to 2 grams per day) as adjunctive treatment is reasonable, based upon limited evidence in meta-analyses of randomized trials (which excluded pregnant patients) [44,45]

and the apparent lack of serious side effects. In addition, prenatal intake of omega-3 fatty acid supplements may have modest beneficial effects on fetal neurodevelopment, and do not have known harmful effects. The efficacy of omega-3 fatty acids and the risks and benefits during pregnancy are discussed separately. (See "Bipolar disorder in adults: Pharmacotherapy for acute depression" and "Fish consumption during pregnancy".)

RESIDUAL INSOMNIA — Bipolar major depression in pregnant patients often includes insomnia, which may persist despite resolution of the depressive syndrome. For patients with residual insomnia, we suggest behavioral therapy, including education about sleep hygiene (table 6) and stimulus control (table 7). Patients unresponsive to behavior therapy typically receive additional treatment with low dose doxepin. Treatment of insomnia is discussed separately. (See "Treatment of insomnia".)

SUMMARY AND RECOMMENDATIONS

●Bipolar disorder is characterized by episodes of mania (table 1), hypomania (table 2), and major depression (table 3). (See 'Definition of bipolar disorder' above and "Bipolar disorder in adults: Assessment and diagnosis", section on 'Diagnosis'.)

●Pharmacotherapy is indicated for pregnant patients with bipolar major depression that is characterized by (see 'Indications' above):

•Suicidal or homicidal ideation or behavior•Aggressive behavior•Psychotic features (delusions or hallucinations)•Poor judgement that places the patient or others at imminent risk of being harmed•Moderate to severe impairment of social or occupational functioning

●An individual drug trial for pregnant patients with bipolar major depression typically lasts six to eight weeks before determining whether treatment is beneficial. (See 'General principles and management' above.)●For pregnant patients with bipolar major depression, we suggest lamotrigine as first line treatment rather than other medications (Grade 2C). (See 'First line treatment' above.)

●For pregnant patients with bipolar major depression who do not respond to lamotrigine or cannot tolerate it, we suggest quetiapine rather than other medications (Grade 2C). (See 'Treatment resistance' above.)●Pregnant patients with refractory bipolar major depression that does not respond to lamotrigine or quetiapine are often treated with fluoxetine plus olanzapine, lamotrigine plus lithium, or electroconvulsive therapy. (See 'Refractory patients' above.)●For pregnant patients with bipolar major depression who are treated with

pharmacotherapy, we suggest adjunctive psychotherapy (Grade 2B). (See 'Psychotherapy' above.)

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