A 35 years aged married male patient, educated till postgraduate level and belonging to a Hindu joint family of upper socioeconomic status, with a family history of bipolar affective disorder in second-degree relative, presented to the Psychiatry outpatient department in March 2021 with relapse of manic episode. The patient is a known case of bipolar affective disorder-I for 16 years and was under our follow-up since 2017. In the past, there were 9 manic episodes, starting from 2004 with incomplete inter-episodic remission. The current episode was sub-acute in onset and characterized by irritable mood, decreased need for sleep, over religiosity, increased libido, a delusion of grandiosity, over talkativeness, emotional lability, overfamiliarity, increased goal-directed activities, verbal aggression, overplanning, and hallucinatory behavior.
At the time of admission, the patient was on clozapine 350 mg, lithium 1200 mg, rifaximin 1000 mg and lactulose 90 mL (due to raised serum ammonia), L carnitine 1000 mg (due to raised serum creatine phosphokinase (CPK), and Levothyroxine 75 microgram. In addition to this, patient was also receiving modified electroconvulsive therapy (mECT) sessions once per week (a total of 19 mECT sessions were administered and seizure duration was adequate in all sessions). The Young mania rating scale (YMRS) score was 38 and the Auditory and visual hallucination rating scale score was 31. Additionally rising serum ammonia and CPK levels limited the option of further increasing the dose of clozapine. Considering existing condition and the past history of inadequate control of symptoms post-treatment with olanzapine 20 mg, quetiapine (400-800mg), sodium valproate (1200–1500 mg), it was decided to give a trial of endoxifen which is a novel anti-manic agent acting through a different mechanism.
After reviewing the available literature, it was initially decided to give a 3-weeks trial of endoxifen 8 mg in combination with clozapine 350 mg and lithium 1200 mg, for acute symptomatic control of mania. There was an improvement in the clinical symptoms after the initiation of 3-weeks of endoxifen therapy, the score on YMRS was reduced to 11. Subsequently, endoxifen was stopped and only clozapine 350 mg was continued. The symptoms which persisted were overplanning, elevated mood, increased psychomotor activity, and hallucinatory behavior. The patient would report hearing voices of multiple people mostly having non-threatening content and non-distressing. Due to persisting hallucinatory behavior, the clozapine dose was increased gradually by 12.5 mg up to 382.5 mg. After stopping endoxifen, there was the reappearance of manic symptoms in 10-days and the score on YMRS increased to 32. Serum ammonia increased to 185.5 microgram/dl and serum CPK level increased to 182U/l. As reported in medical literature, this impairment in ammonia and CPK levels can be attributed to clozapine treatment (Takahashi, 2016; Wu Chou et al., 2014). Endoxifen 8 mg was re-started subsequently with careful monitoring of complete blood count including platelet count, liver function test, renal function test including serum electrolytes, vision, prothrombin time, INR, and ECG weekly (Table 1).
Table 1
Complete blood count, liver function, and kidney function tests values of the patient
Complete blood count (27/03/2021)
|
|
Total Leukocyte Count (TLC) (mm3)
|
9.21
|
Red blood cell (RBC) Count (million/ mm3)
|
5.10
|
Platelet Count (10^3) (mcL)
|
270
|
Differential Leukocyte Count (DLC)
|
N65/L25/M06/E03/B01
|
Mean corpuscular volume (MCV) (fl)
|
89.2
|
Mean corpuscular hemoglobin (MCH) (pg)
|
29.4
|
Mean cell hemoglobin concentration (MCHC) (g/dL)
|
33.0
|
Liver function tests (27/03/2021)
|
|
Bilirubin (mg/dL)
|
0.59
|
Alanine aminotransferase (ALT) (U/L)
|
25
|
Aspartate aminotransferase (AST) (U/L)
|
17
|
Alkaline phosphatase (ALP) (U/L)
|
109
|
Prothrombin time (PT) (secs)
|
11.9
|
activated partial thromboplastin time (aPTT) (secs)
|
27.2
|
International normalized ratio (INR)
|
1.018
|
Kidney function tests (27/03/2021)
|
|
Urea (mg/dL)
|
14
|
Creatinine (mg/dL)
|
0.9
|
Uric acid (mg/dL)
|
7.3
|
Na (mmol/L)
|
139
|
K (mmol/L)
|
4.1
|
Ca (mg/dL)
|
8.4
|
Miscellaneous (21/03/2021)
|
|
GGT (U/L)
|
26
|
LDH (U/L)
|
208
|
To rule out urea cycle enzyme defects, quantitative estimation of all amino acids in serum was done, which came out to be within normal limits
|
Serum ammonia and CPK monitoring were done on every alternate day (Table 2). Ultrasonography of whole abdomen, fibroscan, and CECT portography were done in consultation with a gastroenterologist to rule out causes of raised serum ammonia but all were within normal limits. Serum amino acid assay was done to rule out urea cycle enzyme defects that were within normal limits. The score on YMRS reduced to 10 in the next 3-weeks and the patient was planned for discharge (Fig. 1). After finishing 3-weeks of re-trial, endoxifen was continued on alternate days for another 3-weeks with biweekly serum ammonia and CPK monitoring. At the end of the treatment period, the YMRS score reduced to 8 (Fig. 1) and the AVHRS score to 11. However persistent hallucinatory behavior required increasing the dose of clozapine very gradually up to 450 mg, with regular monitoring. The patient presently has undergone complete remission of manic symptoms and is under regular follow-up. Mild hallucinatory behavior is present but the patient has not reported any auditory hallucinations.
Table 2
Serum ammonia and creatine phosphokinase (CPK) levels of the patient during treatment
DATE
|
S. AMMONIA (microgram/dL)
|
S. CPK (U/L)
|
13/03/2021
|
154.9
|
51.0
|
14/03/2021
|
101.06
|
525.4
|
15/03/2021
|
139.80
|
629.8
|
16/03/2021
|
124
|
-
|
19/03/2021
|
92
|
199.0
|
23/03/2021
|
87
|
73.0
|
25/03/2021
|
58
|
66.0
|
31/0 3/2021
|
46
|
103
|
05/04/2021
|
57
|
71
|
12/04/2021
|
125
|
-
|
13/04/2021
|
89
|
-
|
14/04/2021
|
185.5
|
182
|
22/04/2021
|
-
|
179
|