Effects of Antimanic Mood-Stabilizing Drugs on Fetuses, Neonates, and Nursing Infants

Mohammad Masud Iqbal, MD, MPH, MSPH, DTM; Sai Prakash Gundlapalli, MD, William G. Ryan, MD, Thad Ryals, MD, Birmingham, Ala; Terry E. Passman, MD, Department of Psychiatry and Behavioral Neurobiology, the Regional Neonatal Intensive Care Unit, and the Department of Epidemiology and International Health, University of Alabama at Birmingham School of Medicine; and the Harbor Unit, Thomas Hospital, Fairhope, Ala

South Med J. 2001;94(3) 

In This Article

Abstract and Introduction

Abstract

Pregnancy presents a special problem to the clinician treating bipolar disorders in women. Since the first episode of mania typically occurs before the age of 30, many women in their prime childbearing years may be exposed to potentially teratogenic mood-stabilizing agents. This exposure may also continue for the nursing infant during lactation. Pregnancy itself can exacerbate bipolar symptoms and also alter the pharmacokinetics of mood-stabilizing drugs. Risks to mother and fetus can be reduced with a number of simple strategies, including monotherapy with the lowest effective dose of a drug for the shortest period necessary, periconceptional use of multivitamins with folate, prescription of drugs with established safety records, and avoidance of exposure to antimanic agents during the first trimester of pregnancy. In this article, we review existing evidence on the risks to fetuses and nursing infants of mothers taking specific mood-stabilizing agents, and we present appropriate management guidelines designed to minimize these risks.

Introduction

Untreated bipolar disorder can place a pregnant woman and her unborn infant in significant danger. It may cause a serious disruption of functioning that requires a need for prolonged hospitalization; a vulnerability to suicidal ideation and violence; or loss of employment, housing, and social support. Other risks include malnutrition, attempts at premature self-delivery, fetal abuse or infanticide, noncompliance with prenatal care, and a higher risk of postpartum psychosis.

The patient's clinician must make a risk-benefit assessment that weighs the risks of untreated mental illness against the potential harm of using psychotropic medications to manage this condition in both fetus and mother. The clinician should discuss these risks with the patient in a way that considers the wishes of the patient and the experience and level of comfort of the clinician.

All major classes of psychotropic medications, including antimanic drugs, can be assumed to diffuse readily across the placenta to the fetus or to be excreted into milk. The mechanism of this transfer depends on a number of pharmacokinetic factors, such as (1) the drug's lipid solubility, (2) its molecular weight, (3) maternal blood levels, (4) plasma protein binding, (5) oral bioavailability in the mother and the infant, (6) the pKa (pH at which the drug is 50% ionized),[1] and (7) the half-life of the drug in maternal and neonatal circulation. Of these many factors, perhaps the two most important and useful are the lipid solubility and the molecular weight of the drug. The transfer of a drug across the placenta is directly proportional to its lipid solubility and inversely proportional to its molecular weight. Compounds with a molecular weight less than 600 are relatively permeable, and those with a molecular weight greater than 1,000 are considered relatively impermeable.[2]

Antimanic agents are indicated for treatment of acute manic episodes and maintenance of remission in bipolar disorders and make up several classes of pharmacologic agents ( Table ), including lithium, the first-generation anticonvulsants (carbamazepine and valproic acid [VPA]), the second-generation anticonvulsants (gabapentin, lamotrigine, and topiramate), conventional antipsychotic medications (chlorpromazine, haloperidol, fluphenazine, and thiothixene), atypical antipsychotics (clozapine, risperidone, and olanzapine), and the benzodiazepines (clonazepam).

Patients with bipolar disorder often show fluctuations in mood during long-term maintenance. Although conventional antipsychotics can be used to control these episodes, these agents are associated with several concerns.[3,4] First, no compelling data from controlled trials support the efficacy of these agents as maintenance therapy.[5,6] Second, maintenance with antipsychotic drugs may be associated with the exacerbation of depressive symptoms in some patients.[7,8] Third, the risk for development of extrapyramidal movement disorders appears to be higher in patients with bipolar disorder than in schizophrenics.[9,10]

Lithium, the first modern antimanic agent, was approved in 1970 by the United States Food and Drug Administration (FDA) for treatment of acute mania and for maintenance in bipolar disorder and is widely regarded as the standard antimanic therapy, whether it is used alone or in combination with other anticonvulsant drugs.[11] It is different from other psychotropic agents in that it is not a sedative, depressant, or euphoriant.

The two first-generation anticonvulsants, valproate and carbamazepine, have also been shown to be effective in the treatment of acute mania.[12] Valproate was approved in the United States in 1978 and has poor to moderate antidepressant properties in addition to its antimanic properties.[13] Bipolar patients with anxiety disorder are best treated often with VPA. Open- label and case study data also support the use of VPA in panic disorder,[14,15] obsessive-compulsive disorder,[16,17] and posttraumatic stress disorder.[18] Carbamazepine has been in use for more than 27 years but has been acknowledged as a first-line antiepileptic drug only in the past decade.[19] It has also been found to produce therapeutic responses in manic-depressive patients, including those resistant to lithium. Both VPA and carbamazapine have limited antidepressant effects and may have a tendency to induce mania or decrease cycle lengths.

Second-generation anticonvulsants (gabapentin, lamotrigine, topiramate, vigabatrin, tiagabin, felbamate, and fosphenytoin) approved by the FDA are recommended as adjunctive therapy for seizures.[20] Gabapentin, lamotrigine, and topiramate are thought to have possible antidepressant effects in addition to their mood-stabilizing properties with fewer adverse side effects and are used as adjunctive therapy for manic symptoms.[21,22,23,24]

The atypical antipsychotics such as clozapine, risperidone, and olanzapine may possess thymoleptic properties different from those of the conventional antipsychotics. These atypical agents are commonly used in treating bipolar disorders in the United States. Open trials suggest that clozapine may have acute and long-term mood-stabilizing effects in patients with mixed mania or rapid cycling and in those who are refractory to other mood stabilizers, electroconvulsive therapy, and conventional antipsychotics.[25,26] A recent placebo-controlled trial suggested that olanzapine has antimanic activity, especially in rapid cycling disorder.[27,28] A small number of open trials and case reports have also described the efficacy of risperidone in the treatment of acute mania and in rapid cycling.[29,30,31,32]

Clonazepam, a high-potency benzodiazepine, is a useful adjunct in the treatment of acute mania because it aids sleep and decreases agitation. It may be used in conjunction with antimanic agents and to replace or permit lower doses of antipsychotic medications. It has been suggested that continued use of clonazepam might have mood-stabilizing effects with improvement in sleep, possibly preventing some manic relapses, though this is not well established.[33]

This review will deal primarily with the various effects of specific antimanic drugs on fetuses, neonates, and nursing infants when these drugs are administered during pregnancy and lactation, considering available data from both human and animal models.

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