Chapter 6 140 gradually increased to the maximum of the recommended dose range of 2500mg/day, still resulting in a low tVPAc of 30 mg/l as shown in Figure 1 (day 49). Liver function tests were all within reference range (supplemental file) and there were no drug interactions that could induce a low tVPAc. The patient shifted from hypomania towards mania. To treat the mania, lithium reintroduction was attempted alongside VPA. Reintroduction failed twice as a result of concurrent deliria due to an infection (day 66) and urinary retention (day 70). As her mania worsened during subtherapeutic tVPAc and while awaiting planned admission to a psychmed-unit for lithium reintroduction, VPA was increased to 4000mg/day (day 77) exceeding the maximum approved dose of 60 mg/kg/day by 700mg. The VPA dose increase resulted in a tVPAc of 59 mg/l (day 81). Upon admission she exhibited cognitive dysfunctions (day 88). She was disorientated; answering questions sometimes inadequately or only tangentially and was not structurable. Besides her mania, considered causes included the recent alleged lithium intoxications or a post-delirium state. Based on clinical symptoms she hadmoderate cognitive impairment comparable to Global Deterioration Scale (GDS) 4 (Reisberg et al., 1982). Lithium 400mg/day was reintroduced (day 90) and increased to 800mg/day after one week. Two days thereafter, she clinically worsened with hypotension, disorientation and somnolence. Due to the severity of her symptoms, she was transferred to the internal medicine department (day 98).Cyclophosphamide was stopped due to a pancytopenia. A lithium level of 1.3 mmol/l led to the decision to halt the lithium reintroduction (day 99). Her MoCA had declined to 15/30 and Mini-Mental State Examination (MMSE) was 20/30 (day 109). Her cognitive function further deteriorated to severe cognitive impairment (GDS 5) following lithium cessation. A CT scan revealed no evidence of cerebral pathology besides mild atrophy. As a precaution, VPA 4000mg/day (tVPAc 68mg/l) was reduced to 3000mg/day (day 118) below the maximum dose of 60 mg/kg/day. The free concentration of the 3000mg VPA as well as that of the previous 4000mg blood sample was extracted by ultrafiltration, using centrifugation at 1000-2000g at 25C as the driving force for the ultrafiltration. The free VPA in the ultra filtrate was measured by an immuno-assay technique (Abbott ARCHITECT). Albumin had dropped to 14g/L (day 124). In themeantime, the patient severely deteriorated with conative function deficits and activities of daily living dependency (GDS 6). She became apathetic, could barely be motivated to eat or drink and was in need of a wheelchair. She lost the motivation to continue living, spending most of her time in the fetal position. VPA was stopped immediately (day 126) after the laboratory result of the VPA 3000mg/day indicated a free fraction of 66%, with a free concentration of 15.8 mg/l (reference range 4 - 12mg/l) (Sriboonruang et al., 2011), and tVPAc of 24 mg/l. The sample of VPA 4000mg/day of day 113, which was determined retrospectively, showed a toxic unbound VPA concentration of 37.8 mg/l, with a tVPAc of 68mg/l (free fraction 56%). After VPA withdrawal, she switched to a hyperactive delirium and suffered a seizure (day 130). Olanzapine 5mg was started
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