Guidelines for prescribing antipsychotics during pregnancy and lactation include the following:

1.  Consider nondrug options
2.  Avoid drugs if possible during weeks 6–10
3.  Use antipsychotics about which most is known during pregnancy
4.  Keep doses low before delivery
5.  Increase dose postpartum
6.  Have patient take medications just before infant’s longest sleep of the day
7.  Consult with pediatrician

Optimal prescription of antipsychotics during pregnancy is complicated by altered pharmacokinetics across the three trimesters, fear of teratogenesis, need to safeguard the smooth progress of labor and delivery,  need to prevent withdrawal effects in the neonate,  and concerns about subtle effects on the infant’s neurodevelopment. The latter concerns are also present during breast-feeding.  Plasma volume increases by about 50% during pregnancy and body fat also increases, expanding the volume of drug distribution. Blood flow to the kidneys rises, as does the glomerular filtration rate, thus speeding renal elimination.  Many liver enzymes are activated during pregnancy,  so drugs are metabolized more quickly, consequently increasing the rate of clearance.

The end result is that plasma drug concentration is lowered during pregnancy. At the same time, because of increasing titers of sex steroids acting on neurotransmitter receptors,  some pregnant women may not require high drug concentrations in order to stay symptom-free. Changes in physiology begin in early gestation and are most pronounced in the third trimester of pregnancy. Further changes occur during labor, with some returning to baseline within 24 hours of delivery, while others remain for up to 12 weeks postpartum (15, 17, 22). There are relatively few specific data on pharmacokinetics/ dynamics in pregnancy, so therapeutic guidelines must be based on observational studies and basic principles.

The use of medications during pregnancy and lactation requires critical attention to the timing of exposure,  the dose and duration of use,  and fetal susceptibility.  Essentially all psychotropic drugs pass through the placenta. The aim of management of women with schizophrenia during pregnancy and the postpartum period is to achieve an optimal balance between minimizing fetal and neonatal exposure to drugs and the deleterious consequences of a psychotic mother. Usually monotherapy with the lowest effective dose of a drug for the shortest period necessary is the best strategy.  If possible, drug exposure during the first trimester is best avoided (19).  The use of low-potency phenothiazines during the first trimester probably increases the risk of congenital abnormalities by an additional four cases per 1,000.

A recent study of over 2,000 births to mothers diagnosed with schizophrenia compared to over a million births to women without schizophrenia found significantly increased risks for stillbirth, infant death, preterm delivery, low birth weight, and small size for gestational age among t he offspring of women with schizophrenia. Women with an episode of schizophrenia during pregnancy had the highest risks. Control for a higher incidence of smoking during pregnancy among the subjects as well as for single motherhood,  maternal age,  parity,  maternal education and country of birth,  and pregnancy-induced hypertensive diseases in a multiple regression model reduced the risk. But even after adjustments, there was a doubled risk for women with an episode of schizophrenia during pregnancy in relation to women in the comparison group.  The risks for preterm delivery and low birth weight were significantly elevated for all subjects. It is impossible to tell from this study how much of the poorer outcome can be attributed to antipsychotic treatment.

Another study of over 2,000 children of women with schizophrenia found that these infants had an increased   risk   of   postneonatal   death   largely explained by an increase in sudden infant death syndrome. They also had a marginally statistically significant increase in the risk of congenital malformations.  The same study found that women with schizophrenia had fewer antenatal care visits than pregnant women in the general population and that their babies tended to have lower Apgar scores. Subjects were at increased risk of interventions such as cesarean section,  assisted vaginal delivery, amniotomy, and pharmacological stimulation of labor. The authors concluded that their findings must be interpreted against a backdrop of presumed differences in socioeconomic status, substance abuse, smoking, and medication use between subjects with schizophrenia and comparison subjects.

Fetal circulation, compared with maternal circulation, contains less protein, leaving more of the drug unbound—i.e., facilitating entry into the brain. Liver enzymes are relatively inactive in the fetus, increasing the possibility of toxic effects. Excretion is relatively prolonged.  In addition,  the blood-brain barrier is incomplete, and the nervous system is immature and, therefore, it is more sensitive to drug effects.

Teratogenic effects are both dose and time dependent,  with organs at the greatest risk during their period of fastest development. Week 6 to week 10 is the most vulnerable period. Besides organ malformation,  potential risks to the fetus are spontaneous abortion, growth retardation, and immediate neonatal effects,  such as extrapyramidal and withdrawal symptoms.  Neurodevelopmental effects of antipsychotic drugs have never been demonstrated in humans but remain a theoretical concern.

Not much is yet known about the newer drugs.

Clozapine poses special potential risks for the fetus: seizure and agranulocytosis.  Thus far,  olanzapine appears relatively safe.  Twenty-three prospectively and 11 retrospectively ascertained pregnancy reports on pregnant women treated with olanzapine were collected in the Lilly Worldwide Pharmacovigilance Safety Database. Spontaneous abortion occurred in 13%, stillbirth in 5%, and prematurity in 5%—all within the range of normal historic control rates. There were no major malformations.

Most experts suggest minimal use—no use,  if possible—of antipsychotics during weeks 6–10 of gestation to prevent teratogenesis and low doses before expected delivery to prevent toxicity and withdrawal in the infant, with immediate resumption of a full dose after delivery because of the high risk of the mother’s decompensation postpartum (12, 13, 16, 20).

Mary V. Seeman, M.D.

REFERENCES
1. Anthony M, Berg MJ: Biologic and molecular mechanisms for sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics, part I. J Womens Health Gend Based Med 2002; 11:601 - 615
2. Anthony M, Berg MJ: Biologic and molecular mechanisms for sex differences in pharmacokinetics, pharmacodynamics, and pharmacogenetics, part II. J Womens Health Gend Based Med 2002; 11:617 - 629
3. Harris RZ, Benet LZ, Schwartz JB: Gender effects in pharmacokinetics and pharmacodynamics. Drugs 1995; 50:222 - 239
4. Kashuba AD, Nafziger AN: Physiological changes during the menstrual cycle and their effects on the pharmacokinetics and pharmacodynamics of drugs. Clin Pharmacokinet 1998; 34: 203 - 218
5. Beierle I, Meibohm B, Derendorf H: Gender differences in pharmacokinetics and pharmacodynamics. Int J Clin Pharmacol Ther 1999; 37:529 - 647
6. Flores Perez J, Juarez Olguin H, Flores Perez C, Perez Guille G, Guille Perez A, Camacho Vieyra A, Toledo Lopez A, Carrasco Portugal M, Lares Asseff I: Effects of gender and phase of the menstrual cycle on the kinetics of ranitidine in healthy volunteers. Chronobiol Int 2003; 20:485 - 494
7. Haddad L, Milke P, Zapata L, de la Fuente JR, Vargas-Vorackova F, Lorenzana-Jimenez M, Corte G, Tamayo J, Kaplan M, Marquez M, Kershenobich D: Effect of the menstrual cycle in ethanol pharmacokinetics. J Appl Toxicol 1998; 18:15 - 18
8. Kamimori GH, Joubert A, Otterstetter R, Santaromana M, Eddington ND: The effect of the menstrual cycle on the pharmacokinetics of caffeine in normal, healthy eumenorrheic females. Eur J Clin Pharmacol 1999; 55:445 - 449
9. Rowan JP: "Estrophasic" dosing: a new concept in oral contraceptive therapy. Am J Obstet Gynecol 1999; 180:302 - 306
10. Balant-Gorgia AE, Gex-Fabry M, Balant LP: Therapeutic drug monitoring and drug-drug interactions: a pharmacoepidemiological perspective. Therapie 1996; 51:399 - 402
11. Gex-Fabry M, Balant-Gorgia AE, Balant LP: Therapeutic drug monitoring databases for postmarketing surveillance of drug-drug interactions. Drug Saf 2001; 24:947 - 959
12. American Academy of Pediatrics Committee on Drugs: Use of psychoactive medication during pregnancy and possible effects on the fetus and newborn. Pediatrics 2000; 105:880 - 887
13. Boyle RJ: Effects of certain prenatal drugs on the fetus and newborn. Pediatr Rev 2002; 23:17 - 24
14. Craig M, Abel K: Drugs in pregnancy: prescribing for psychiatric disorders in pregnancy and lactation. Best Pract Res Clin Obstet Gynaecol 2001; 15:1013 - 1030
15. Dawes M, Chowienczyk PJ: Drugs in pregnancy: pharmacokinetics in pregnancy. Best Pract Res Clin Obstet Gynaecol 2001; 15:819 - 826
16. Ernst CL, Goldberg JF: The reproductive safety profile of mood stabilizers, atypical antipsychotics, and broad-spectrum psychotropics. J Clin Psychiatry 2002; 63(suppl 4):42 - 55
17. Frederiksen MC: Physiologic changes in pregnancy and their effect on drug disposition. Semin Perinatol 2001; 25:120 - 123
18. Gjere NA: Psychopharmacology in pregnancy. J Perinat Neonatal Nurs 2001; 14:12 - 25
19. Patton SW, Misri S, Corral MR, Perry KF, Kuan AJ: Antipsychotic medication during pregnancy and lactation in women with schizophrenia: evaluating the risk. Can J Psychiatry 2002; 47: 959 - 965
20. Shehata HA, Nelson-Piercy C: Drugs in pregnancy: drugs to avoid. Best Pract Res Clin Obstet Gynaecol 2001; 15:971 - 986
21. Winans EA: Antipsychotics and breastfeeding. J Hum Lact 2001; 17:344 - 347
22. Wyska E, Jusko WJ: Approaches to pharmacokinetic/pharmacodynamic modeling during pregnancy. Semin Perinatol 2001; 25:124 - 132
23. Peralta V, Cuesta MJ, Caro F, Martinez-Larrea A: Neuroleptic dose and schizophrenic symptoms: a survey of prescribing practices. Acta Psychiatr Scand 1994; 90:354 - 357
24. Miller MA: Gender-based differences in the toxicity of pharmaceuticalsthe Food and Drug Administration's perspective. Int J Toxicol 2001; 20:149 - 152
25. Kaasinen V, Kemppainen N, Nagren K, Helenius H, Kurki T, Rinne JO: Age-related loss of extrastriatal dopamine D(2)-like receptors in women. J Neurochem 2002; 81:1005 - 1010
26. Lindamer LA, Lohr JB, Harris MJ, McAdams LA, Jeste DV: Gender-related clinical differences in older patients with schizophrenia. J Clin Psychiatry 1999; 6:61 - 67
27. Goldstein JM, Kennedy DN, Caviness VS Jr: Brain development, XI: sexual dimorphism (image, neuro). Am J Psychiatry 1999; 156:352
28. Maccoby EE, Jacklin CN: Psychological sex differences, in Scientific Foundations of Developmental Psychiatry. Edited by Rutter M. London, Heinemann Medical, 1980, pp 92 - 100
29. Earls F: Sex differences in psychiatric disorders: origins and developmental influences. Psychiatr Dev 1987; 1:1 - 23
30. Usall J, Araya S, Ochoa S, Busquets E, Gost A, Marquez M (Assessment Research Group in Schizophrenia [NEDES]): Gender differences in a sample of schizophrenic outpatients. Compr Psychiatry 2001; 42:301 - 305
31. Hafner H: Gender differences in schizophrenia. Psychoneuroendocrinology 2003; 28(suppl 2):17 - 54
32. Castle DJ: Epidemiology of women and schizophrenia, in Women and Schizophrenia. Edited by Castle DJ, McGrath J, Kulkarni J. Cambridge, UK, Cambridge University Press, 2000, pp 19 - 33
33. Benes FM, Tutle M, Khan Y, Farol P: Myelination of a key relay zone in the hippocampal formation occurs in human brain during childhood, adolescence, and adulthood. Arch Gen Psychiatry 1994; 51:477 - 484
34. Kirov G, Jones PB, Harvey I, Lewis SW, Toone BK, Rifkin L, Sham P, Murray RM: Do obstetric complications cause the earlier age at onset in male than female schizophrenics? Schizophr Res 1996; 20:117 - 124
35. Seeman MV: Psychopathology in women and men: focus on female hormones. Am J Psychiatry 1997; 154:1641 - 1647
36. Medland SE, Geffen G, McFarland K: Lateralization of speech production using verbal/manual dual tasks: meta-analysis of sex differences and practice effects. Neuropsychologia 2002; 40:1233 - 1239
37. Lalloo R, Sheiham A: Risk factors for childhood major and minor head and other injuries in a nationally representative sample. Injury 2003; 34:261 - 266
38. Marneros A, Pillmann F, Haring A, Balzuweit S, Bloink R: Features of acute and transient psychotic disorders. Eur Arch Psychiatry Clin Neurosci 2003; 253:167 - 174
39. Jarbin H, Ott Y, Von Knorring AL: Adult outcome of social function in adolescent-onset schizophrenia and affective psychosis. J Am Acad Child Adolesc Psychiatry 2003; 42:176 - 183
40. Bottlender R, Sato T, Jager M, Wegener U, Wittmann J, Strauss A, Moller HJ: The impact of the duration of untreated psychosis prior to first psychiatric admission on the 15-year outcome in schizophrenia. Schizophr Res 2003; 62:37 - 44
41. Harrigan SM, McGorry PD, Krstev H: Does treatment delay in first-episode psychosis really matter? Psychol Med 2003; 33: 97 - 110
42. Antelman SM, Levine J, Gershon S: Time-dependent sensitization: the odyssey of a scientific heresy from the laboratory to the door of the clinic. Mol Psychiatry 2000; 5:350 - 356
43. Howard R, Rabins PV, Seeman MV, Jeste DV (International Late-Onset Schizophrenia Group): Late-onset schizophrenia and very-late-onset schizophrenia-like psychosis: an international consensus. Am J Psychiatry 2000; 157:172 - 178
44. Seeman MV: Interaction of sex, age, and neuroleptic dose. Compr Psychiatry 1983; 24:125 - 128
45. Meltzer HY, Rabinowitz J, Lee MA, Cola PA, Ranjan R, Findling RL, Thompson PA: Age at onset and gender of schizophrenic patients in relation to neuroleptic resistance. Am J Psychiatry 1997; 154:475 - 482
46. Torgalsboen AK: Full recovery from schizophrenia: the prognostic role of premorbid adjustment, symptoms at first admission, precipitating events and gender. Psychiatry Res 1999; 88: 143 - 152
47. Mortensen P, Juel K: Mortality and causes of death in first admitted schizophrenic patients. Br J Psychiatry 1993; 163:183 - 189
48. Jeste DV, Lindamer LA, Evans J, Lacro JP: Relationship of ethnicity and gender to schizophrenia and pharmacology of neuroleptics. Psychopharmacol Bull 1996; 32:243 - 251
49. Szymanski S, Lieberman JA, Alvir JM, Mayerhoff D, Loebel A, Geisler S, Chakos M, Koreen A, Jody D, Kane J, Woerner M, Cooper T: Gender differences in onset of illness, treatment response, course, and biologic indexes in first-episode schizophrenic patients. Am J Psychiatry 1995; 152:698 - 703
50. Melkersson KI, Hulting AL, Rane AJ: Dose requirement and prolactin elevation of antipsychotics in male and female patients with schizophrenia or related psychoses. Br J Clin Pharmacol 2001; 51:317 - 324
51. Pollock BG: Gender differences in psychotropic drug metabolism. Psychopharmacol Bull 1997; 33:235 - 241
52. Robinson DG, Woerner MG, Alvir JMJ, Geisler S, Koreen A, Sheitman B, Chakos M, Mayerhoff D, Bilder R, Goldman R, Lieberman JA: Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 1999; 156:544 - 549
53. Robinson D, Woerner MG, Alvir JM, Bilder R, Goldman R, Geisler S, Koreen A, Sheitman B, Chakos M, Mayerhoff D, Lieberman JA: Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry 1999; 56:241 - 247
54. Pinals DA, Malhotra AK, Missar CD, Pickar D, Breier A: Lack of gender differences in neuroleptic response in patients with schizophrenia. Schizophr Res 1996; 22:215 - 222
55. Magharious W, Goff DC, Amico E: Relationship of gender and menstrual status to symptoms and medication side effects in patients with schizophrenia. Psychiatry Res 1998; 77:159 - 166
56. Kashuba AD, Nafziger AN, Kearns GL, Leeder JS, Shirey CS, Gotschall R, Gaedigk A, Bertino JS Jr: Quantification of intraindividual variability and the influence of menstrual cycle phase on CYP2D6 activity as measured by dextromethorphan phenotyping. Pharmacogenetics 1998; 8:403 - 410
57. Kashuba AD, Bertino JS Jr, Rocci ML Jr, Kulawy RW, Beck DJ, Nafziger AN: Quantification of 3-month intraindividual variability and the influence of sex and menstrual cycle phase on CYP3A activity as measured by phenotyping with intravenous midazolam. Clin Pharmacol Ther 1998; 64:269 - 277
58. Kashuba AD, Bertino JS Jr, Kearns GL, Leeder JS, James AW, Gotschall R, Nafziger AN: Quantitation of three-month intraindividual variability and influence of sex and menstrual cycle phase on CYP1A2, N-acetyltransferase-2, and xanthine oxidase activity determined with caffeine phenotyping. Clin Pharmacol Ther 1998; 63:540 - 551
59. Salokangas RK, Saarijarvi S, Taiminen T, Lehto H, Niemi H, Ahola V, Syvalahti E: Effect of smoking on neuroleptics in schizophrenia. Schizophr Res 1997; 23:55 - 60
60. Goff DC, Henderson DC, Amico E: Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects. Am J Psychiatry 1992; 149:1189 - 1194
61. Pan L, Vander Stichele R, Rosseel MT, Berlo JA, De Schepper N, Belpaire FM: Effects of smoking, CYP2D6 genotype, and concomitant drug intake on the steady state plasma concentrations of haloperidol and reduced haloperidol in schizophrenic inpatients. Ther Drug Monit 1999; 21:489 - 497
62. Shimoda K, Someya T, Morita S, Hirokane G, Noguchi T, Yokono A, Shibasaki M, Takahashi S: Lower plasma levels of haloperidol in smoking than in nonsmoking schizophrenic patients. Ther Drug Monit 1999; 21:293 - 296
63. Ohara K, Tanabu S, Yoshida K, Ishibashi K, Ikemoto K, Shibuya H: Effects of smoking and cytochrome P450 2D6*10 allele on the plasma haloperidol concentration/dose ratio. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27:945 - 949
64. Brockmoller J, Kirchheiner J, Schmider J, Walter S, Sachse C, Muller-Oerlinghausen B, Roots I: The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment. Clin Pharmacol Ther 2002; 72:438 - 452
65. Kelly DL, Conley RR, Tamminga CA: Differential olanzapine plasma concentrations by sex in a fixed-dose study. Schizophr Res 1999; 40:101 - 104
66. Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM: Olanzapine: pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet 1999; 37:177 - 193
67. Carrillo JA, Herraiz AG, Ramos SI, Gervasini G, Vizcaino S, Benitez J: Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol 2003; 23:119 - 127
68. Skogh E, Reis M, Dahl ML, Lundmark J, Bengtsson F: Therapeutic drug monitoring data on olanzapine and its N-demethyl metabolite in the naturalistic clinical setting. Ther Drug Monit 2002; 24:518 - 526
69. Gex-Fabry M, Balant-Gorgia AE, Balant LP: Therapeutic drug monitoring of olanzapine: the combined effect of age, gender, smoking, and comedication. Ther Drug Monit 2003; 25:46 - 53
70. Lane HY, Chang YC, Chang WH, Lin SK, Tseng YT, Jann MW: Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics. J Clin Psychiatry 1999; 60:36 - 40
71. Palego L, Biondi L, Giannaccini G, Sarno N, Elmi S, Ciapparelli A, Cassano GB, Lucacchini A, Martini C, Dell'Osso L: Clozapine, norclozapine plasma levels, their sum and ratio in 50 psychotic patients: influence of patient-related variables. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26:473 - 480
72. Wilner KD, Tensfeldt TG, Baris B, Smolarek TA, Turncliff RZ, Colburn WA, Hansen RA: Single- and multiple-dose pharmacokinetics of ziprasidone in healthy young and elderly volunteers. Br J Clin Pharmacol 2000; 49(suppl 1):15S - 20S
73. Yukawa E, Ichimaru R, Maki T, Matsunaga K, Anai M, Yukawa M, Higuchi S, Goto Y: Interindividual variation of serum haloperidol concentrations in Japanese patients "clinical considerations on steady-state serum level-dose ratios. J Clin Pharm Ther 2003; 28:97 - 101
74. Linnet K, Olesen OV: Free and glucuronidated olanzapine serum concentrations in psychiatric patients: influence of carbamazepine comedication. Ther Drug Monit 2002; 24:512 - 517
75. Miceli JJ, Anziano RJ, Robarge L, Hansen RA, Laurent A: The effect of carbamazepine on the steady-state pharmacokinetics of ziprasidone in healthy volunteers. Br J Clin Pharmacol 2000; 49(suppl 1):65S - 70S
76. Gorski JC, Wang Z, Haehner-Daniels BD, Wrighton SA, Hall SD: The effect of hormone replacement therapy on CYP3A activity. Clin Pharmacol Ther 2000; 68:412 - 417
77. Belle DJ, Callaghan JT, Gorski JC, Maya JF, Mousa O, Wrighton SA, Hall SD: The effects of an oral contraceptive containing ethinyloestradiol and norgestrel on CYP3A activity. Br J Clin Pharmacol 2002; 53:67 - 74
78. Muirhead GJ, Harness J, Holt PR, Oliver S, Anziano RJ: Ziprasidone and the pharmacokinetics of a combined oral contraceptive. Br J Clin Pharmacol 2000; 49(suppl 1):49S - 56S
79. Wang Z, Gorski JC, Hamman MA, Huang SM, Lesko LJ, Hall SD: The effects of St John's wort (Hypericum perforatum) on human cytochrome P450 activity. Clin Pharmacol Ther 2001; 70: 317 - 326
80. Balant-Gorgia AE, Gex-Fabry M, Genet C, Balant LP: Therapeutic drug monitoring of risperidone using a new, rapid HPLC method: reappraisal of interindividual variability factors. Ther Drug Monit 1999; 21:105 - 115
81. Brosen K, Skjelbo E, Rasmussen BB, Poulsen HE, Loft S: Fluvoxamine is a potent inhibitor of cytochrome P450 1A2. Biochem Pharmacol 1993; 45:1211 - 1214
82. Back DJ, Orme ML: Pharmacokinetic drug interactions with oral contraceptives. Clin Pharmacokinet 1990; 18:472 - 484
83. Altamura AC, Sassella F, Santini A, Montresor C, Fumagalli S, Mundo E: Intramuscular preparations of antipsychotics: uses and relevance in clinical practice. Drugs 2003; 63:493 - 512
84. Daniel WA: Mechanisms of cellular distribution of psychotropic drugs: significance for drug action and interactions. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27:65 - 73
85. Koyama H, Mori S, Sugioka N, Nishihara T, Nakajima K: Age-related alteration of haloperidol-serum protein binding. J Pharm Pharmacol 2003; 55:77 - 83
86. Casey D: Neuroleptic drug-induced extrapyramidal syndromes and tardive dyskinesia. Schizophr Res 1991; 4:109 - 120
87. Morgenstern H, Glazer W: Identifying risk factors for tardive dyskinesia among long-term outpatients maintained with neuroleptic medication. Arch Gen Psychiatry 1993; 50:723 - 733
88. Yassa R, Jeste D: Gender differences in tardive dyskinesia: a critical review of the literature. Schizophr Bull 1992; 18:701 - 715
89. Kamijo Y, Soma K, Nagai T, Kurihara K, Ohwada T: Acute massive pulmonary thromboembolism associated with risperidone and conventional phenothiazines. Circ J 2003; 67:46 - 48
90. Priori SG, Schwartz PJ, Napolitano C, Bloise R, Ronchetti E, Grillo M, Vicentini A, Spazzolini C, Nastoli J, Bottelli G, Folli R, Cappelletti D: Risk stratification in the long-QT syndrome. N Engl J Med 2003; 348:1866 - 1874
91. Hatta K, Takahashi T, Nakamura H, Yamashiro H, Asukai N, Matsuzaki I, Yonezawa Y: The association between intravenous haloperidol and prolonged QT interval. J Clin Psychopharmacol 2001; 21:257 - 261
92. Seeman MV: Schizophrenic men and women require different treatment programs. J Psychiatr Treat Eval 1983; 5:143 - 148
93. Russell JM, Mackell JA: Bodyweight gain associated with atypical antipsychotics: epidemiology and therapeutic implications. CNS Drugs 2001; 15:537 - 551
94. Homel P, Casey D, Allison DB: Changes in body mass index for individuals with and without schizophrenia, 1987 - 1996. Schizophr Res 2002; 55:277 - 284
95. Allison DB, Mentore JL, Heo M, Chandler LP, Cappelleri JC, Infante MC, Weiden PJ: Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156: 1686 - 1696
96. Baptista T, Kin NM, Beaulieu S, De Baptista EA: Obesity and related metabolic abnormalities during antipsychotic drug administration: mechanisms, management and research perspectives. Pharmacopsychiatry 2002; 35:205 - 219
97. Hedenmalm K, Hagg S, Stahl M, Mortimer O, Spigset O: Glucose intolerance with atypical antipsychotics. Drug Saf 2002; 25: 1107 - 1116
98. Sernyak MJ, Leslie DL, Alarcon RD, Losonczy MF, Rosenheck R: Association of diabetes mellitus with use of atypical neuroleptics in the treatment of schizophrenia. Am J Psychiatry 2002; 159:561 - 566
99. Jin H, Meyer JM, Jeste DV: Phenomenology of and risk factors for newonset diabetes mellitus and diabetic ketoacidosis associated with atypical antipsychotics: an analysis of 45 published cases. Ann Clin Psychiatry 2002; 14:59 - 64
100. Jensen DM, Damm P, Sorensen B, Molsted-Pedersen L, Westergaard JG, Ovesen P, Beck-Nielsen H: Pregnancy outcome and prepregnancy body mass index in 2,459 glucose-tolerant Danish women. Am J Obstet Gynecol 2003; 189:239 - 244
101. Watkins ML, Rasmussen SA, Honein MA, Botto LD, Moore CA: Maternal obesity and risk for birth defects. Pediatrics 2003; 111:1152 - 1158
102. Kuruvilla A, Peedicayil J, Srikrishna G, Kuruvilla K, Kanagasabapathy AS: A study of serum prolactin levels in schizophrenia: comparison of males and females. Clin Exp Pharmacol Physiol 1992; 19:603 - 606
103. Naidoo U, Kinon BJ, Gilmore JA, Liu H, Halbreich UM: Hyperprolactinemia in response to antipsychotic drugs: characterization across comparative clinical trials. Psychoneuroendocrinology 2003; 28(suppl 2):69 - 82
104. Wieck A, Haddad PM: Antipsychotic-induced hyperprolactinaemia in women: pathophysiology, severity and consequences: selective literature review. Br J Psychiatry 2003; 182: 199 - 204
105. Becker D, Liver O, Mester R, Rapoport M, Weizman A, Weiss M: Risperidone, but not olanzapine, decreases bone mineral density in female premenopausal schizophrenia patients. J Clin Psychiatry 2003; 64:761 - 766
106. Abraham G, Paing WW, Kaminski J, Joseph A, Kohegyi E, Josiassen RC: Effects of elevated serum prolactin on bone mineral density and bone metabolism in female patients with schizophrenia: a prospective study. Am J Psychiatry 2003; 160:1618 - 1620
107. Goff DC, Klibanski A: Hyperprolactinemia and bone mineral density: the potential impact of antipsychotic agents. Psychoneuroendocrinology 2003; 28(suppl 2):97 - 108
108. Aizenberg D, Sigler M, Weizman A, Barak Y: Anticholinergic burden and the risk of falls among elderly psychiatric inpatients: a 4-year case-control study. Int Psychogeriatr 2002; 14: 307 - 310
109. Hankinson SE, Willett WC, Michaud DS, Manson JE, Colditz GA, Longcope C, Rosner B, Speizer FE: Plasma prolactin levels and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1999; 91:629 - 634
110. Wang PS, Walker AM, Tsuang MT, Orav EJ, Glynn RJ, Levin R, Avorn J: Dopamine antagonists and the development of breast cancer. Arch Gen Psychiatry 2002; 59:1147 - 1154
111. Oksbjerg Dalton S, Munk Laursen T, Mellemkjaer L, Johansen C, Mortensen PB: Schizophrenia and the risk for breast cancer. Schizophr Res 2003; 62:89 - 92
112. Compton MT, Miller AH: Sexual side effects associated with conventional and atypical antipsychotics. Psychopharmacol Bull 2001; 35:89 - 108
113. Compton MT, Miller AH: Antipsychotic-induced hyperprolactinemia and sexual dysfunction. Psychopharmacol Bull 2002; 36:143 - 164
114. Compton MT, Miller AH: Priapism associated with conventional and atypical antipsychotic medications: a review. J Clin Psychiatry 2001; 62:362 - 366