Medication Change To Aripiprazol Biology Essay

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Olanzapine is a second generation antipsychotic medication that is widely used in patients with schizophrenia, schizoaffective, bipolar disorder and treatment-resistant depression. The drug is also used off-label in other psychotic disorders, behavioral disturbances in dementia, children and adolescents, impulse control disorders and borderline personality disorder.(1, 2) Results of the randomized-controlled and pragmatic trials strongly support its efficacy and effectiveness. Results of CATIE study strengthened its use in patients with schizophrenia. Olanzapine proved its efficacy in all phases of CATIE trial. Olanzapine and clozapine had the greatest liability to induce side effects.(3, 4) Olanzapine has a well-known propensity to induce metabolic side effects like: clinically significant weight gain, hyperglycemia, lipid abnormalities which altogether can lead to metabolic syndrome. We will introduce a patient with schizophrenia, who has been treated with olanzapine and showed severe hypertriglyceridemia after medication initiation and which resolved after its cessation and medication change to aripiprazole. Here, we will show the changes in levels of triglyceride (TG), glucose, weight, cholesterol, waist circumference, blood pressure before and at 1 week and 2 weeks after the cessation of olanzapine.

Case Raport

27-year-old man, single, with secondary education, employed as printing machine operator, living with his mother, with no significant medical history, was diagnosed with schizophrenia paranoid type according do DSM-IV-TR criteria. He was put on antipsychotic medication (risperidone). The dosage was gradually increased to 3 mg of that medication given in the evening. The medication was well tolerated. During hospitalization patient's blood was drawn for laboratory tests. Table 1 describes laboratory findings before treatment with risperidone was initiated (time point - t0). No significant deviations from the normal range was seen apart from mildly increased total cholesterol (CHOL) and triglycerides (TG) level. Treatment with risperidone resulted in almost complete symptomatic and functional recovery. Patient's psychic state has substantially improved, the patient regained disease insight and positive symptoms have subsided. The patient showed signs of blunted affect and complied with amotivation, anhedonia and lack of energy. One month after admission the patient was discharged from the hospital. Came back to work and was functioning normally in his usual roles.

Subsequently the patient was consulted in the out-patient department of our hospital. Two months after being discharged from psychiatric unit the patient decided to stop treatment without consultation with his psychiatrist. One month after risperidone discontinuation psychotic symptoms recurred. After psychiatric consultation risperidone was started again. The dosage was gradually increased to 5 mg a day. The medication was stopped after six weeks course due to lack of efficacy and extrapyramidal side effects (akathisia) and persistence of depressive symptoms. Consulting psychiatrist decided to start treatment with olanzapine. Table 1 summarizes the results of laboratory tests before olanzapine therapy was started (time point - t1). Olanzapine dosage was slowly increased to 15 mg given at bedtime. Psychotic symptoms resolved in less than a month of olanzapine therapy, however the patient was complaining of sedation during the day, lack of energy, nausea and concentration difficulties and episodes of abdominal pain. No evident pathology was seen on physical examination. The existence of the above symptoms and the need to monitor side effects of antipsychotics according to the Polish guidelines made the psychiatrist to order laboratory tests. The results are summarized in table 1 in the column described as time point - t2. Evident hypertriglyceridemia was observed with triglycerides level above 700 mg/dl and 900 mg/dl in the subsequent analysis (t3). Total cholesterol was also increased to 390 mg/dl. Transaminases activity was 6-7 times above the upper limit of the normal range and bilirubin level was nearly 3 mg/dl.

Other common causes of hypertriglyceridemia were excluded on the basis of additional laboratory tests and past medical history. Olanzapine-induced mixed dyslipidemia with a predominance of hypertriglyceridemia was diagnosed. Antipsychotic medication was changed. Olanzapine was gradually withdrawn while aripiprazole therapy was initiated and the dosage was slowly increased to reach 30 mg a day given in the morning. Olanzapine discontinuation and treatment with aripiprazole resulted in decrease of triglyceride levels nearly to normal range. The patient was advised to follow a Mediterranean diet and have a regular monitoring of the lipid profile.

Table 1 summarizes laboratory test results 1week (t4) and 2 weeks (t5) after olanzapine discontinuation. No significant deviations from the reference range of metabolic profile and liver function tests were seen. CHOL and TG were slightly increased, 226.4 mg/dl and 156.2 mg/dl respectively. Severe hypertriglyceridemia was revealed after 12 weeks of olanzapine therapy and it subsided 1 week after olanzapine discontinuation and 3 weeks after aripiprazole introduction.

Discussion

Olanzapine is a second generation antipsychotic that is structurally similar to clozapine. Both medications share to same extent their side-effects profile. Olanzapine therapy can lead to a wide range of metabolic side effects, like weight gain(2, 5), glucose dysregulation(6, 7), diabetes mellitus(8, 9), hyperglycemic non-ketonic coma(10, 11) and diabetic ketoacidosis(12, 13). Apart from these metabolic adverse effects, olanzapine can induce life-threatening conditions, like acute hepatocellular-cholestatic liver injury(14) as well as venous thromboembolism(15) and acute pancreatitis.(16, 17) Olanzapine was also found to be one of the four antipsychotics inducing liver damage most frequently in the Polish study.(18) Hypertriglyceridemia was also observed in the course of olanzapine therapy.(19, 20) MHRA Public Assessment Report for olanzapine summarizes the frequency of side effects.(21) According to that document the most frequent metabolic side effects of olanzapine include: weight gain (>10%), hypertriglyceridemia and hypercholesterolemia (1-10%), hyperglycemia (1-10%), glucosuria (1-10%), transient, asymptomatic elevations of aminotransferases (ALT, AST), especially in early treatment (1-10%). Pancreatitis, diabetic coma with ketoacidosis, venous thromboembolism are regarded as potentially life-threatening but relatively rare conditions seen in less than 1% of cases.(21)

Osser et al. observed metabolic and lipid profile changes during 12-week olanzapine therapy in 24 patients (mainly men) with schizophrenia.(22) Mean olanzapine dose used was 13.8 mg. The authors observed a mean increase of body weight (5.4 kg), with the accompanying mean fasting TG elevation of 60 mg/dL to 222 ± 135 mg/dL (mean ± SD). The association between weight gain and TG elevation was so strong that after controlling for weight, analysis of covariance showed no independent increase in triglycerides. Yamamoto et al. described a case of an adolescent male patient who developed hypertriglyceridemia during olanzapine therapy and found a relationship between propensity for triglycerides elevation, weight gain and decreased lipoprotein lipase (LPL) activity.(23) The authors suggested that weight gain and hypertriglyceridemia induced by olanzapine were due to decrease in LPL activity.

Different data was obtained by other authors. Adachi et al. described a case of 40-year-old male patient referred due to severe hypertriglyceridemia (TG: 1,598 mg/dl) induced by olanzapine.(24) TG elevation in that patient was not connected with body weight gain nor fasting glucose level increase. To understand which TG-rich lipoprotein is important for olanzapine-induced hypertriglyceridemia, the authors measured each lipoprotein fraction by the anion-exchange high-performance liquid chromatography. They found that very-low density lipoprotein (VLDL-C) was the most important lipoprotein for olanzapine-induced hypertriglyceridemia. VLDL level was remarkably high during olanzapine therapy and it promptly decreased after olanzapine cessation. The level of VLDL almost paralleled decreasing TG level. Adachi et al. found also a positive correlation between olanzapine-induced TG elevation and high-sensitivity C-reactive protein (hs-CRP). Cessation of olanzapine lead to decrease of hs-CRP and increase of adiponectine. Unlike Osser et al., these authors did not observe significant LPL activity changes after discontinuation of olanzapine. VLDL is a TG rich lipoprotein. It is composed of 55% TG, 20% of cholesterol and 15% of protein. VLDL is produced in the liver and transports lipids to muscles and fat tissue.(25, 26) Adachi et al. speculated that olanzapine might induce inflammation and reduce adiponectin, leading to activation of hormone-sensitive lipase which hydrolyzes TG to free fatty acids (FFA). Increased circulating FFA may enter the liver, resulting in hepatic overproduction of VLDL and hepatic steatosis.

The patient described in the present case report developed a severe elevation of TG which was evident 12 weeks after initiation of olanzapine therapy. Secondary causes of hypertriglyceridemia, which are summarized in table 2, were also ruled out. Primary and genetic causes of hypertriglyceridemia could be excluded on the basis of family history and lack of significant deviations from reference range observed before olanzapine treatment was introduced. Since all other primary and secondary causes were excluded, the metabolic abnormalities could only be attributed to olanzapine. Temporal relationship also points to olanzapine as a probable cause of metabolic changes described above.

The described patient did not experience significant body weight nor fasting glucose level increase during olanzapine therapy. Hypertriglyceridemia was correlated with signs of the liver damage (aminotransferase elevation) which resolved after olanzapine discontinuation and initiation of therapy with aripiprazol. The latter medication was chosen because lower propensity to induce metabolic and hepatic side effects. Aripiprazole has good overall safety profile. Keck et al. conducted a 100 week bipolar maintenance treatment study using aripiprazole in comparison with placebo.(27) The following metabolic or cardiovascular side effects were seen in that study: hypertension in 7.8 % (placebo 3.6 %) and weight gain in 6.5% (placebo 0%) of patients, while aripiprazole had no effect on QTc interval of the ECG, total cholesterol, LDL or HDL cholesterol, triglycerides, or glucose levels. Long-term trial conducted in 555 patients with schizophrenia revealed that weight changes and weight related quality of life were better with aripiprazole, compared to olanzapine, quetiapine and risperidone.(28) However, there are also rare case reports describing hypertriglyceridemia induced by aripiprazol.(29) That is why despite its good overall safety profile, clinical monitoring of metabolic side effects is still recommended in patients treated with aripiprazole. The patient described in our report had his antipsychotic treatment changed from olanzapine into aripiprazole and this led to symptomatic and functional remission of schizophrenia symptoms as well as normalization of metabolic changes and resolution of liver damage induced earlier by olanzapine.

Aripiprazole was compared with placebo as the add-on antipsychotic in olanzapine-treated stable schizophrenia patients with obesity.(30) During the 4 weeks of aripiprazole treatment (15 mg/d), there were significant decreases in weight and body mass index compared with placebo. The authors did not observe significant differences in cholesterol level between groups. However, total serum triglycerides decreased significantly during the aripiprazole treatment phase. There was a decrease in C-reactive protein comparing aripiprazole treatment to placebo, although it did not reach statistical significance level.

To authors best knowledge this is the first case report of hypertriglyceridemia and liver damage induced by olanzapine which were successfully treated with medication discontinuation and change to aripiprazole with a good clinical outcome and side effects relief.

Conclusions

Olanzapine may induce hypertriglyceridemia and liver damage in susceptible individuals.

Aripiprazole may be used with success instead of olanzapine in cases of hypertriglyceridemia.

Patients' lipid profile should be checked during olanzapine therapy to avoid serious complications.

Acknowledgment

This paper was supported by a grant N N402 243435 from the Polish Ministry of Science and Higher Education.

Table 1. Changes of metabolic parameters observed during the course of olanzapine treatment

Time point

Variable

T0

T1

T2

T3

T4

T5

Conversion factor

SI Units

Treatment

Before risperidone

risperidone

olanzapine

olanzapine

aripiprazole

aripiprazole

Triglycerides [mg/dl]

154

156.2

761.3

936.1

166.8

191.7

0.0113

mmol/l

Total Cholesterol [mg/dl]

212.5

226.4

390

300.7

243.5

249.7

0.0259

mmol/l

HDL Cholesterol [mg/dl]

44.1

66.2

38.4

19.7

41.7

43.3

0.0259

mmol/l

LDL Cholesterol [mg/dl]

137.6

108.9

-

-

168.4

168.0

0.0259

mmol/l

Glucose [mg/dl]

91.9

88.7

104.7

85.9

92.4

94.9

0.0555

mmol/l

ALT [U/l]

33.0

-

237

248.0

48.0

-

1

U/l

AST [U/l]

36.0

-

307

329.0

28.0

-

1

U/l

Bilirubin [mg/dl]

0.8

-

2.4

2.7

0.6

-

17.1

µmol/L

Weight [kg]

79.7

76.5

76.5

75.1

-

78.4

1

kg

BMI [kg/m2]

24.06

23.97

23.1

22.7

-

23.7

1

kg/m2

Waist circumference [cm]

97

95

95

93

-

96

0.01

m

Systolic BP [mmHg]

137

133

136

134

-

128

7.5006-10−3

Pa

Diastolic BP [mmHg]

87

85

88

82

-

82

7.5006-10−3

Pa

T0 - Before risperidone initiation; T1 - risperidone (10 weeks ) 4 mg/d; T2 - olanzapine (12 weeks) 15 mg/d; T3 - olanzapine (13 weeks) 20 mg/d; T4 - 1 week after olanzapine discontinuation; aripiprazole (3 weeks); 30 mg/d; T5 - 2 weeks after olanzapine discontinuation, aripiprazole (4 weeks); 30 mg/d; ALT - alanine aminotransferase; AST - aspartate aminotransferase

Table 2. Secondary causes of hypertriglyceridemia which were ruled out in the described patient on the basis of medical history and laboratory findings.

Type of cause

Cause

Metabolic causes

Diabetes mellitus type 1 and 2

Obesity

Hypothyroidism

Nephrotic syndrome and end-stage renal disease

Medications

High-dose thiazide diuretics

High-dose beta-adrenergic blocking agents, excluding those with intrinsic sympathomimetic activity

Unopposed oral estrogen replacement therapy

Oral contraceptives with high estrogen content

Tamoxifen

Glucocorticoids

Oral isotretinoin

Antiretroviral therapy

Other causes

Excessive alcohol intake

High-carbohydrate diets

Acute pancreatitis

Pregnancy

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