|Ahead of print publication
Treatment-resistant schizophrenia with high-risk pregnancy: Challenges in management
Prerna Balkrishen Khar1, Smita Panse2, Nishant Das3
1 Department of Psychiatry, TNMC and BYL Nair Charitable Hospital, Mumbai, Maharashtra, India
2 Department of Psychiatry, PCMC's PGI, YCM Hospital, Pune, Maharashtra, India
3 Department of Psychiatry, BJGMC and SGH, Pune, Maharashtra, India, India
|Date of Submission||23-Jul-2020|
|Date of Decision||10-Sep-2020|
|Date of Acceptance||22-Sep-2020|
|Date of Web Publication||31-Mar-2021|
Prerna Balkrishen Khar,
104, Magic Carpet CHS, Juhu Verosova Link Road, Andheri West, Mumbai - 400 053, Maharashtra
Source of Support: None, Conflict of Interest: None
Managing a severe treatment-resistant psychiatric illness in the context of pregnancy has always been a challenge for psychiatrists, especially with a comorbid medical illness. We present a case of an elderly primigravida having schizophrenia of 22 years, with high-risk pregnancy, who suffered from an acute psychotic exacerbation during pregnancy. She was managed with clozapine, aripiprazole, and amisulpiride, after a failed trial of olanzapine and electroconvulsive therapy. This case highlights the challenges in managing an elderly primigravida with comorbid gestational diabetes mellitus and fibroid who required prolonged hospitalization throughout her pregnancy. A strong liaison with an obstetrician goes a long way in ensuring smooth management.
Keywords: Clozapine, high-risk pregnancy, schizophrenia
|How to cite this URL:|
Khar PB, Panse S, Das N. Treatment-resistant schizophrenia with high-risk pregnancy: Challenges in management. Ann Indian Psychiatry [Epub ahead of print] [cited 2021 Apr 20]. Available from: https://www.anip.co.in/preprintarticle.asp?id=312770
| Introduction|| |
Managing a severe treatment-resistant psychiatric illness in the context of pregnancy has always been a challenge for psychiatrists, especially if associated with comorbid medical illness. This case highlights challenges in managing an elderly primigravida with comorbid gestational diabetes mellitus (GDM) and uterine fibroid who required prolonged hospitalization throughout her pregnancy.
| Case Report|| |
A 36-year-old female with a history of schizophrenia of 22 years duration was well maintained on clozapine 200 mg for 2 years when she conceived over the same dose. In view of her gestational status, clozapine was down-titrated to 25 mg/day by her treating psychiatrist in her 1st trimester. In her 4th month of gestation, she was admitted in our Psychiatry ward after an acute psychotic exacerbation, characterized by withdrawn behavior, disturbed sleep, and hallucinatory conduct of 3 days onset.
On mental status examination (MSE), she was ill-kempt, agitated, and abusive. She had increased psychomotor activity and hallucinatory conduct. Her effect was irritable and thinking revealed formal thought disorder in the form of word salad. She was uncooperative for formal MSE and had lack of social judgement and insight. Her Brief Psychiatric rating scale (BPRS) score was 67. She had to be given injectable neuroleptics (Haloperidol) for a week due to extreme agitation. After baseline investigations and medical fitness evaluation, in view of refusal to accept medication, extreme agitation, and impaired self-care, she was started on a course of electroconvulsive therapy (ECT). With high-risk written informed consent of the caregiver, ECTs were given in the presence of a stand-by Obstetrician. Left-lateral position was maintained during the ECTs. After 4 ECTs, as she became amenable to oral medications, she was started on olanzapine 5 mg which was gradually uptitrated to 20 mg. She received 8 ECTs over 3 weeks.
Antenatal monitoring was kept and ultrasonography (including fetal anomaly scan) was done at regular intervals which did not reveal any fetal anomaly. In view of high-risk pregnancy (large intrauterine fibroid and elderly primigravida), she was started on depot Injection Hydroxyprogesterone 500 mg by her treating team of obstetricians, given at weekly intervals for 6 weeks along with micronized progesterone 200 mg daily once she started accepting medications orally.
With the above management, her self-care improved, biofunctions stabilized, and she began to accept medications orally. However, she continued to have hallucinatory conduct, formal thought disorder (word salad), abusive behavior,and rapport could not be established.
After reviewing her past treatment records brought by her father and husband, treatment resistance (failure to respond to haloperidol, risperidone, olanzapine, and ECTs) was established. In view of past good response to clozapine, written informed consent was obtained from her husband and father after discussion of the risk-benefit ratio. She was restarted on tablet clozapine 25 mg HS, which was gradually uptitrated to 400 mg as per NICE guidelines. Clozapine monitoring was kept (Haemogram, liver function tests, lipid profile, and blood sugar) and no side effects were noted. BPRS score decreased to 43 after 8 weeks
However, on day 65 of admission, she developed hyperglycemia and was diagnosed with ? GDM versus ? drug-induced hyperglycemia. Injection insulin 10 IU was started in divided doses after the physician opinion. Hence, further uptitration of clozapine was deferred and treatment was augmented with aripiprazole 5 mg OD after obtaining written informed consent of her husband. It was gradually uptitrated to 20 mg.
In view of her fluctuating symptoms and need for continuous monitoring of her physical and mental status, she was kept hospitalized and her medications were continued till term. She delivered a healthy baby girl through a planned cesarean section after 36 weeks of gestation. No withdrawal symptoms were noted in the neonate. The baby was fed through top feeds as the mother was on clozapine. Breast milk secretion was stopped with tablet cabergoline 1 mg. Supervised baby care was ensured. Her psychotic symptoms exacerbated on the 3rd postpartum day, in the form of disruptive behavior and agitation. Hence, she was started on amisulpiride 50 mg, gradually uptitrated to 400 mg. Clozapine was increased to 600 mg and aripiprazole decreased to 10 mg (low dose continued to reduce the metabolic side effects of clozapine). Clinical improvement was seen with a decline in psychotic symptoms and the patient starting to enquire into the well-being of her neonate. Insulin was discontinued after good glycemic control (second day postpartum). She was discharged after a total of 163 days (postpartum-day 30) of inpatient management. She continues to follow-up regularly in the OPD. She is currently maintained well on clozapine 600 mg and aripiprazole 10 mg. Amisulpiride was gradually down-titrated and omitted after 1 year of attaining symptom remission. The patient was also explained regarding the possible side effects in the infant and advised to have a close follow-up with the pediatrician. No developmental deficits have been noted in the baby so far who is 2 years old at present.
| Discussion|| |
Clozapine is a second-generation antipsychotic, which does not increase serum prolactin levels and hence is considered to be fertility sparing in women., Our understanding of using clozapine during pregnancy is limited to case reports and case series as ethical concerns forbid randomized controlled trials.
The rates of gestational diabetes in pregnant women on clozapine are twice as high as those not receiving the drug., However, many confounding factors cannot be ignored, such as a family history of diabetes mellitus, and a higher Body Mass Index (BMI) in these women. Plasma concentrations of clozapine may diminish during pregnancy due to a higher hepatic metabolism and distribution volume, explaining the exacerbation of psychosis and the need for higher doses in management in our patient, leading to GDM.
Safety, course, and outcome of pregnancy in women treated with clozapine have been described in a number of case studies with some reporting spontaneous abortions and some fetal malformations. A review of case reports of pregnant women on antipsychotics done by Gentile et al. in 2008 mentioned macrosomia, cardiac malformations, floppy infant syndrome, and neonatal seizures among the neonatal side effects. However, some had an uneventful pregnancy with a good fetal outcome.
Breastfeeding in women on clozapine has many complications such as agranulocytosis and bone marrow suppression in the infant. The accumulation in breast milk has been attributed to the lipophilic properties of clozapine and the high lipid concentration of breast milk.
McCauley-Elsom et al. and Grover et al., in their review on the effects of psychotropics during pregnancy have also mentioned that there is no conclusive evidence regarding the safety or risks associated with clozapine use for pregnant women as it is very difficult to ascertain whether the fetal malformations are due to clozapine or due to the maternal mental illness and other confounding factors.
Our case was challenging in terms of management as the pregnancy was high risk and the treatment resistance required high doses of clozapine and augmentation with aripiprazole and amisulpiride to ensure behavioral management, leading to a viable pregnancy
| Conclusion|| |
Managing a psychotic exacerbation in the background of medical illness in pregnancy requires a multidisciplinary approach. One must always assess the risk-benefit ratio before down-titrating psychotropic agents during pregnancy. It is advisable to continue the same medication during pregnancy to which the patient had earlier responded. A strong liaison with the patient's caregivers along with the treating obstetrician and physician goes a long way in ensuring smooth management.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
The authors would like to thank the treating obstetrician Dr Megha Karnik for her assistance in patient management and the Head of the department of Psychiatry, Dr Manjeet Santre for his support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Volavka J, Czobor P, Cooper TB, Sheitman B, Lindenmayer JP, Citrome L et al
. Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychiatry 2004;65:57-61.
Nguyen T, Mordecai J, Watt F, Frayne J. Obstetric and neonatal outcomes of clozapine exposure in pregnancy: A consecutive case series. Arch Womens Ment Health 2020;23:441-5.
Bodén R, Lundgren M, Brandt L, Reutfors J, Kieler H. Antipsychotics during pregnancy: Relation to fetal and maternal metabolic effects. Arch Gen Psychiatry 2012;69:715-21.
Gupta N, Grover S. Safety of clozapine in 2 successive pregnancies. Can J Psychiatry 2004;49:863.
Mehta TM, Van Lieshout RJ. A review of the safety of clozapine during pregnancy and lactation. Arch Womens Ment Health 2017;20:1-9.
Desai G, Babu GN, Rajkumar RP, Chandra PS. More questions than answers! Clinical dilemmas in psychopharmacology in pregnancy and lactation. Indian J Psychiatry 2009;51:26-33.
] [Full text]
Gentile S. Antipsychotic therapy during early and late pregnancy. A systematic review. Schizophr Bull 2010;36:518-44.
Sethi S. Clozapine in pregnancy. Indian J Psychiatry 2006;48:196-7.
] [Full text]
Parikh T, Goyal D, Scarff JR, Lippmann S. Antipsychotic drugs and safety concerns for breast-feeding infants. South Med J 2014;107:686-8.
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.
McCauley-Elsom K, Gurvich C, Elsom SJ, Kulkarni J. Antipsychotics in pregnancy. J Psychiatr Mental Health Nurs 2010;17:97.
Grover S, Dutt A, Avasthi A. Indian research: Focus on clozapine. Indian J Psychiatry 2010;52:168-73.
] [Full text]