|Year : 2015 | Volume
| Issue : 3 | Page : 110-112
Can the combination of lithium and olanzapine be an effective treatment strategy in the management of bipolar disorder with Wilson's disease?
Praveen Tripathi1, Priyanka Goyal1, Abhisek Pratap Singh1, Sujita Kumar Kar2, Ashish Pundhir3
1 Department of Psychiatry, Institute of Human Behavior and Allied Sciences, Delhi, India
2 Department of Psychiatry, King George's Medical University, Lucknow, Uttar Pradesh, India
3 Department of Community Medicine, Subharti Medical College, Meerut, Uttar Pradesh, India
|Date of Submission||05-Mar-2015|
|Date of Acceptance||05-Apr-2015|
|Date of Web Publication||8-Jun-2015|
Dr. Sujita Kumar Kar
Department of Psychiatry, King George's Medical University, Lucknow - 226 003, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Wilson's disease is a disorder of copper metabolism, which frequently has neurobehavioral manifestations due to the involvement of the central nervous system (CNS). Depression is the commonest neuropsychiatric manifestation; however, recent studies have revealed the association of bipolar disorder with Wilson's disease. Lithium is a safe and efficacious medication in the management of bipolar disorder in Wilson's disease. Our case report highlights the efficacy of the combination of lithium and olanzapine in the management of bipolar disorder in the context of Wilson's disease.
Keywords: Bipolar disorder, lithium, olanzapine, Wilson′s disease
|How to cite this article:|
Tripathi P, Goyal P, Singh AP, Kar SK, Pundhir A. Can the combination of lithium and olanzapine be an effective treatment strategy in the management of bipolar disorder with Wilson's disease?. Int J Nutr Pharmacol Neurol Dis 2015;5:110-2
|How to cite this URL:|
Tripathi P, Goyal P, Singh AP, Kar SK, Pundhir A. Can the combination of lithium and olanzapine be an effective treatment strategy in the management of bipolar disorder with Wilson's disease?. Int J Nutr Pharmacol Neurol Dis [serial online] 2015 [cited 2022 May 27];5:110-2. Available from: https://www.ijnpnd.com/text.asp?2015/5/3/110/158376
| Introduction|| |
Wilson's disease is a heritable disorder of copper metabolism that follows an autosomal recessive pattern.  Neuronal tissue damage due to the accumulation of copper gives rise to diverse neurobehavioral symptoms.  The basal ganglia, especially the caudate nucleus and putamen, are usually involved in Wilson's disease, and in later stages there may be cavitation in the putamen as well as frontal lobes.  A variety of psychiatric manifestations have been reported in patients of Wilson's disease, with depression being the most common.  Almost every patient of Wilson's disease suffers from one or more behavioral symptoms at some point of time during the course of illness.  One recent study revealed a strong association of bipolar affective disorder with Wilson's disease and this opens new channels for research. 
Recent studies in the pathophysiology of bipolar disorder have pointed toward abnormalities in the structure and function of key emotional control networks in the human brain. It has been suggested that there are disturbances in the early development of brain networks that modify emotional behavior, leading to abnormal connections between ventral prefrontal networks and limbic brain regions, especially the amygdala. 
The existing literature supports the use of mood stabilizers for the treatment of bipolar disorder in patients with Wilson's disease. ,
| Case report|| |
A 32-year-old male presented with sadness of mood, irritability, lethargy and easy fatigability, decreased interest in work, death wishes, and disturbed sleep and appetite for 1 month. The patient's history was suggestive of three manic episodes and one depressive episode in the past, with the last episode being that of mania, occurring 1 year earlier and successfully treated with lithium monotherapy. The patient had developed jaundice at the age of 12 years. He was diagnosed with Wilson's disease after the relevant investigations. He has been on chelating agents since then and is doing well on medications, with no symptoms suggestive of chronic liver disease or neurological deficits. There was no history of any renal impairment, pancreatitis, or joint involvement. There was no family history of any psychiatric illness. The general physical examination and systemic examination [including detailed central nervous system (CNS) examination] did not reveal any deficits. The routine blood investigations (including liver function tests) were also within normal limits. The patient's abdominal computed tomography (CT) scan revealed chronic liver disease with a few abdominal collaterals, and magnetic resonance imagining (MRI) brain was suggestive of mild cerebellar, brainstem, and basal ganglia (especially putamen) atrophy. On comparison with a previous MRI brain (which was done 2 years earlier), no progression of brain lesions was observed.
The mental status examination had revealed depressed affect with ideas of hopelessness, helplessness, and worthlessness. The physical examination revealed slurring of speech and Kayser-Fleischer ring More Details (on slit-lamp examination). Investigations revealed serum ceruloplasmin 5 mcg/dL, serum copper 83 mcg/dL, and 24-h urine copper 58 mcg/dL. His other hematological investigations including liver function test were within normal limits. The patient was on trientene 1500 mg per day, zinc 150 mg per day, and pyridoxine 40 mg per day for the management of Wilson's disease. The psychiatric diagnosis of "bipolar affective disorder, current episode moderate depression" was made as per the International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) Diagnostic Criteria for Research (DCR) criteria.
The patient was started on lithium 600 mg per day, which was later increased to 900 mg per day and in view of poor response after 6 weeks; augmentation was done with olanzapine (5 mg per day). The patient had shown significant improvement in depressive symptoms. He was discharged after 1 month of hospitalization and did well in follow-up.
| Discussion|| |
In our patient, the index episode was a moderate depressive episode with history of multiple episodes of mania in the last 5 years. Lithium was started in view of a history of good response in the previous episodes and existing favorable evidences regarding its use in Wilson's disease. , The patient had shown poor response to lithium alone and features of irritability were persistent, so we thought of starting antipsychotics in low dose. When olanzapine was added, the patient had shown significant improvement.
Lithium is a mood stabilizer, a first-line agent in the management of bipolar affective disorder.  Even after more than half a century of use, the exact mechanism of its action is still mysterious.  Evidences suggest lithium's interference in the intracellular signaling pathway by inhibiting the glycogen synthase kinase-3beta (GSK-3β), which is a pro-apoptotic enzyme.  Lithium's neuroprotective role is mediated by its anti-apoptotic activity (inhibition of pro-apoptotic enzyme).  Lithium also decreases the stimulation of brain protein kinase C (PKC), which may be attributable to its mood-stabilizing property in bipolar affective disorder.  Recent evidences suggest the possible role of lithium in gene expression as well as post-translational modification of stress proteins, which is also responsible for its neuroprotective effect.  Due to its narrow therapeutic index, side effects are more likely to occur.  Lithium treatment possesses the risks of multisystemic side effects such as the following: Neurological (tremor, dysarthria, ataxia, confusion, seizure, coma), gastrointestinal (dyspepsia, nausea, metallic taste), metabolic (weight gain, impaired glucose tolerance), endocrinal (hypothyroidism), renal (impaired glomerular filtration, renal failure, diabetes insipidus), dermatological (acneiform eruptions), and cardiac (arrhythmia).  Olanzapine is a second-generation antipsychotic, which has antagonistic activity on dopamine, serotonin, histamine as well as the alpha-1-adrenergic receptors.  Olanzapine is effective in bipolar affective disorder, particularly in the manic and mixed episodes.  Several side effects, such as weight gain, dyslipidemia, hyperglycemia, metabolic syndrome, extrapyramidal side effects (rare), and sedation, are reported with olanzapine treatment. 
Carta et al. 2012, in their systematic review analyzed different possible associations between bipolar disorder and Wilson's disease.  The possibility of trace element accumulation in the brain may be an explanation of the pathogenesis of bipolar disorder, which is quite similar to the pathogenesis of Wilson's disease.  However, another possibility may be related to genetic linkage, as both Wilson's disease and bipolar disorder share common chromosomal involvement. Chromosome 13 is involved in Wilson's disease,  as well as in bipolar affective disorder. , Hence, the explanation of association between Wilson's disease and bipolar disorder may extend beyond trace element deposition, which needs to be studied further.
So far as the management aspect is concerned, it is too early to generalize the pharmacological management of this case; however, further studies are required to observe the safety and efficacy of the combination of lithium and olanzapine in depressive episodes of bipolar disorder associated with Wilson's disease.
| References|| |
Carta MG, Sorbello O, Moro MF, Bhat KM, Demelia E, Serra A, et al
. Bipolar disorders and Wilson's disease. BMC Psychiatry 2012; 12:52.
Lorincz MT. Neurologic Wilson's disease. Ann N Y Acad Sci 2010;1184:173-87.
Scheinberg IH, Sternlieb I. Treatment of the neurologic manifestations of Wilson's disease. Arch Neurol 1995;52:339-40.
Strakowski SM, Adler CM, Almeida J, Altshuler LL, Blumberg HP, Chang KD, et al
. The functional neuroanatomy of bipolar disorder: A consensus model. Bipolar Disord 2012;14:313-25.
Loganathan S, Nayak R, Sinha S, Taly AB, Math S, Varghese M. Treating mania in Wilson's disease with lithium. J Neuropsychiatry Clin Neurosci 2008;20:487-9.
Rybakowski JK, Litwin T, Chlopocka-Wozniak M, Czlonkowska A. Lithium treatment of a bipolar patient with Wilson's disease: A case report. Pharmacopsychiatry 2013;46:120-1.
Werneke U, Ott M, Renberg ES, Taylor D, Stegmayr B. A decision analysis of long-term lithium treatment and the risk of renal failure. Acta Psychiatr Scand 2012;126:186-97.
Li X, Bijur GN, Jope RS. Glycogen synthase kinase-3beta, mood stabilizers, and neuroprotection. Bipolar Disord 2002;4:137-44.
DiazGranados N, Zarate CA Jr. A review of the preclinical and clinical evidence for protein kinase C as a target for drug development for bipolar disorder. Curr Psychiatry Rep 2008;10:510-9.
Nciri R, Bourogaa E, Jbahi S, Allagui MS, Elfeki A, Vincent C, et al
. Chronic neuroprotective effects of low concentration lithium on SH-SY5Y cells: Possible involvement of stress proteins and gene expression. Neural Regen Res 2014;9:735-40.
Jefferson JW, Greist JH. Lithium. In: Sadock BJ, Sadock VA, Ruiz P, editors. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9 th
ed. Vol. 2. Philadelphia: Lippincott Williams & Wilkins; 2009. p. 3133-45.
Marder SR, Hurford IM, van Kammen DP. Second-generation antipsychotics. In: Sadock BJ, Sadock VA, Ruiz P, editors. Kaplan and Sadock's Comprehensive Textbook of Psychiatry. 9 th
ed. Vol. 2. Philadelphia: Lippincott Williams & Wilkins; 2009. p. 3207-40.
Carta M, Mura G, Sorbello O, Farina G, Demelia L. Quality of life and psychiatric symptoms in Wilson's disease: The relevance of bipolar disorders. Clin Pract Epidemiol Ment Health 2012;8:102-9.
Badenhop RF, Moses MJ, Scimone A, Mitchell PB, Ewen KR, Rosso A, et al
. A genome screen of a large bipolar affective disorder pedigree supports evidence for a susceptibility locus on chromosome 13q. Mol Psychiatry 2001l;6:396-403.
Maziade M, Chagnon YC, Roy MA, Bureau A, Fournier A, Mérette C. Chromosome 13q13-q14 locus overlaps mood and psychotic disorders: The relevance for redefining phenotype. Eur J Hum Genet 2009;17:1034-42.