Prevention of mania in a primigravida at ultra‐high risk of postpartum recurrence

A 29-year-old primigravida was referred to our clinic for pre-pregnancy counselling. She had recently discontinued the birth control pill in preparation for conception. She was being treated with quetiapine 200 mg daily for bipolar I disorder. She denied having had any mood episodes for approximately 9 months. She reported that quetiapine had been effective in preventing recurrences of bipolar disorder and denied any side effects except mild drowsiness in the morning. As shown in the Life Chart (Figure 1), she first developed mood symptoms when she was 18 years old. She did not have any other current or lifetime psychiatric or physical disorders. She had been hospitalized twice for manic/mixed episodes with psychotic features including delusions, hallucinations, catatonia and grossly disorganized behaviour. Family history was notable for suspected bipolar disorder in her father, anxiety in a brother and unspecified psychiatric illness in paternal grandmother. Using the DSM-5 criteria, we confirmed a diagnosis of bipolar I disorder, severe with mood-incongruent psychotic features-in full remission. Due to various risk factors including primiparity, personal and possibly a family history of bipolar disorder, she was thought to be at an ultra-high risk of recurrence of manic/mixed episodes (the dominant polarity). As part of pre-pregnancy counselling, we discussed the following topics: effect of pregnancy and postpartum on the course of bipolar I disorder, risks and benefits of drug use during and after pregnancy, and modifiable risk factors of mood/psychotic episodes such as sleep loss.1 Continuation of current dose of quetiapine was recommended for maintenance treatment of bipolar disorder during pregnancy. Six months after the initial consultation, she was referred again to our clinic. She indicated that a couple of months prior to pregnancy, the quetiapine dose had been increased to 300 mg daily due to racing thoughts and insomnia in the context of work-related stress. She described having had transient symptoms such as sadness, crying spells and irritability during early pregnancy. Otherwise, she had been free of hypo/manic or psychotic symptoms thus far in pregnancy. We recommended continuation of quetiapine in the current dose and to take additional 25 mg once daily prn for insomnia, anxiety or hypo/mania. The first-trimester exposure to quetiapine is not associated with a substantially increased risk of congenital malformations. We were cognizant that the current dose was likely insufficient to prevent postpartum recurrence of mood episodes. Instead of increasing the quetiapine dose and risking postural hypotension, we decided to use olanzapine for treatment/prevention of emerging symptoms of mania. She was also recommended to use a mood tracker daily to rate her mood, sleep, medication use and stressful events. During regular follow-up appointments, psychoeducation about the detection of emerging symptoms, proactive management of these symptoms, treatment adherence and regulation of sleep–wake cycle was routinely emphasized. Due to the COVID-19 pandemic, the care was provided virtually, initially every 4 weeks and then on a biweekly basis. The pregnancy was unremarkable except for hypothyroidism requiring levothyroxine 25 mcg daily. In late pregnancy, she was prescribed olanzapine 5 mg nocte prn for prevention of symptoms of hypo/mania.2 Due to the effect of pregnancy-related metabolic changes on serum quetiapine levels, dose increases are usually needed to prevent recurrences of bipolar disorder. We decided against optimizing quetiapine dose because she was already experiencing restlessness of in her legs. Moreover, we were concerned about falls due to potential postural hypotension. She had a spontaneous vaginal delivery at term and gave birth to a healthy female child weighing 7 lbs. and 15 oz. During the postpartum appointments, her husband was regularly in attendance. When assessed day 3 postpartum, the patient reported euphoria, mood fluctuations, racing thoughts and poor sleep beginning immediately after delivery. On examination, she was alert and oriented, however, her speech was mildly pressured. She denied feeling sad or having thoughts of harm to self or the new born. Similarly, there were no current psychotic symptoms. She indicated that she had started writing down her thoughts. Collateral information was regularly elicited from her husband. In order to facilitate uninterrupted sleep at night, we discussed the pros and cons of breastfeeding vs. pumping. She decided to pump milk and her husband agreed to provide nocturnal child care. In order to minimize stimulation, the first couple of appointments were intentionally kept short. We also recommended that visits by family and friends should be brief and kept to a minimum. Olanzapine dose was increased to 10 mg at bedtime. When contacted via phone on day 4 postpartum, she reported that she had a restful sleep the previous night and denied any current symptoms except racing thoughts. On examination, her speech was still pressured. She was encouraged to take olanzapine 5 mg od prn during the day. As she continued to have occasional irritability, interrupted sleep and increased goal-directed activity, the olanzapine bedtime dose was increased to 15 mg. By 4 weeks postpartum, the manic symptoms had remitted but she developed mild depression including sadness, crying spells, tiredness and increased sleep requirement. Due to daytime drowsiness, the olanzapine dose was reduced gradually to 10 mg at bedtime. We discussed pharmacologic options for treatment of depression. She had had a trial of lurasidone a few years earlier but she did not find it effective. She agreed to try lithium but was concerned about its use during lactation. The depression was short-lived and remitted with psychosocial interventions alone. Due to sustained improvement in her mood, she was referred back to her psychiatrist for follow-up care. She has not had a recurrence of hypo/mania or depression and has been euthymic for 8 months. She is currently being treated with quetiapine 300 mg only. According to the patient, the combination of expert psychiatric care, pharmacotherapy, family support and her faith was instrumental in preventing recurrence of postpartum mania. She is breastfeeding and supplementing it with formula feeding. Her menstrual periods have resumed and she has not had any premenstrual exacerbation of mood symptoms. The patient provided written informed consent after reviewing the contents of this report. Awareness of the heightened risk of recurrence during and after pregnancy led to this patient's timely referral to our clinic. The pre-pregnancy psychiatric consultation provided an opportunity for a detailed discussion about the risks and benefits of medication use during pregnancy and lactation. Based on individualized risk assessment, we estimated that she was at an extremely high risk of recurrence of mania or psychosis, however, we also noted mitigating factors such as prolonged euthymic intervals, absence of rapid cycling, acceptance of bipolar disorder diagnosis, medication adherence, sustained employment and a supportive relationship with her husband. Moreover, she and her husband had an excellent therapeutic relation with the clinical team and both participated actively in discussions about her care. During joint sessions with the patient and her spouse, we emphasized the importance of modification of risk factors to reduce the risk of peripartum recurrence. Since she had not had a mood episode for several months prior to conception, we decided to keep her on the same dose of quetiapine. Moreover, first-trimester exposure to quetiapine is not associated with a substantially increased risk of congenital malformations. Due to sustained mood stability and the absence of intolerable side effects, the quetiapine dose was kept unchanged during pregnancy. However, we were cognizant that the current dose will likely be insufficient to prevent postpartum recurrences. Instead of increasing the quetiapine dose and risking postural hypotension, we decided to use olanzapine for prevention of emerging symptoms of hypo/mania. Lithium is commonly recommended for women with bipolar disorder or postpartum psychosis who are at high risk of postpartum recurrence. Since lithium has a longer onset of action compared to olanzapine, it is unclear whether it would have been as effective as olanzapine in controlling hypo/manic symptoms that appeared on day 1 postpartum. Moreover, olanzapine was particularly effective for treatment of sleep loss which was a prominent early symptom of hypo/mania. The drug treatment was targeted at prevention of mania for several reasons. First, preponderance of manic/mixed episodes suggested she was at greater risk of recurrence of these episodes rather than of depression. Second, episodes of hypo/mania generally occur earlier than depression after delivery. Third, the mania-depression-euthymic interval (MDI) course suggested that prevention of mania might also prevent ensuing depression. Evidence in support of this clinical approach comes from a small study in which the addition of olanzapine to mood stabilizers was more effective than mood stabilizers alone in preventing recurrences of postpartum mania/psychosis. And finally, patients with psychotic features or an MDI course are more likely to have excess time spent in mania. Among women with mood disorders, a diagnosis of bipolar I disorder is associated with the highest risk of recurrence during both pregnancy and postpartum.3 A study by Di Florio et al. found that among women with bipolar I disorder, approximately 20% of deliveries were followed by an episode of postpartum mania or psychotic depression.4 Another study by the same group found that episodes of mania or psychosis within 6 weeks of delivery were overrepresented among primiparous women. A retrospective study of medication-free pregnant women from Italy found 75% had a history of one or more mood episodes postpartum.5 Currently, there are no data on the risk of postpartum recurrence among primiparous women with mania-preponderant bipolar disorder. Dr Subramanian has no conflict of interest to disclose. Dr Sharma has received grant support from, participated on scientific advisory boards for, or served on speakers' bureaus of Assurex, Genome Canada, Neurocrine Biosciences, Sage Therapeutics, Stanley Medical Research Institute and Sunovion Pharmaceuticals. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.