CLINICAL HANDBOOK OF SCHIZOPHRENIA

476 VI. SPECIAL POPULATIONS AND PROBLEMSAs newer agents, second-generation antipsychotic agents (SGAs) are less well studiedduring pregnancy than FGAs. One prospective study compared pregnancy and neonataloutcomes for women taking the SGAs olanzapine, risperidone, quetiapine, andclozapine, and for demographically comparable women who were taking medicationsknown not to be teratogenic. There was no significant difference in rates of malformations,reported labor complications, or mean gestational age between exposed andcomparison infants.The SGA side effects posing the highest risk during pregnancy are obesity and diabetes.Obesity during pregnancy increases the risk of hypertension, preeclampsia, neuraltube defects, and need for caesarean section. Infants born to mothers with obesity have ahigher risk of macrosomia or low birthweight. Gestational diabetes doubles the rate ofspontaneous abortion and increases the rate of birth defects by three- to fourfold. Weightgain and increased risk of diabetes are particularly pronounced for clozapine andolanzapine. Weight gain can also occur with risperidone and quetiapine; data aboutwhether these agents increase diabetes risk are equivocal. Ziprasidone and aripiprazoleare usually weight-neutral and do not appear to increase the risk of diabetes.A prospective, comparative study of SGAs in human pregnancy indicated thatwomen taking quetiapine during pregnancy had significantly higher body mass indices(BMIs) than pregnant women not taking psychotropic medication. No significant differencesin BMI were found between pregnant women taking olanzapine and comparisonpregnant women taking no psychotropic medication. Although there are case reports ofnew-onset or worsening gestational diabetes in women taking clozapine during pregnancy,a prospective study indicated no significant difference in rates of diabetes, hypertension,or caesarean section between pregnant women taking SGAs and pregnantwomen taking no psychotropic agents.Postpartum, sedation is an especially problematic medication side effect. Somewomen report being unable to awaken to their babies’ cries due to altered sleep qualityfrom antipsychotic medication. Others report that medication-induced sedation saps theenergy they need for parenting. Clozapine, quetiapine, and olanzapine have higher reportedrates of sedation than risperidone, ziprasidone, and aripiprazole.Few data are available regarding exposure of breast-feeding infants to SGAs. Somebreast-feeding babies whose mothers were taking olanzapine were noted to have sedation,poor suck reflex, jaundice, shaking, diarrhea, sleep problems, tongue protrusion,cardiomegaly, and heart murmur. However, no causal connection was established.Clozapine, which is highly lipophilic, is found in relatively high concentrations in breastmilk and can accumulate in breast-feeding babies.Dosing Strategies during PregnancyPregnancy affects medication absorption, distribution, and metabolism. The most significantchange appears to be effects on hepatic cytochrome P450 (CYP450) systems. Pregnancyincreases the activity of CYP450 3A4 and 2D6. Most antipsychotic agents are predominantlymetabolized by CYP450 3A4 (aripiprazole, haloperidol, quetiapine, andziprasidone) and/or CYP450 2D6 (aripiprazole and risperidone). Pregnancy may thereforelower the levels of each of these medications at a given dose. Breakthrough symptomsmay necessitate a dose increase. By contrast, pregnancy decreases the activity ofCYP450 1A2, the primary metabolizer of olanzapine and clozapine. At a given dose,these medications may have higher levels in the pregnant than in the nonpregnant state,resulting in additional side effects.