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Olanzapine

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Olanzapine is an efficacious and well-tolerated atypical antipsychotic indicated for the symptomatic treatment and management of schizophrenia. Schizophrenia is a chronic, often debilitating and relapsing mental illness that impairs the functioning of a person’s mental and social ability (Gupta & Kulhara, 2010, p. 21). Schizophrenia remains one of the most abtruse and costliest mental disorders, affecting around 1% of the general population and is equally common in men and women (Van Os & Kapur, 2009, p. 635). This chronic psychosis disrupts the person’s life as well as the lives of their family and friends often making it difficult to cope (Van Os & Kapur, 2009, p. 635). Currently, there is no cure for schizophrenia, but the illness can be successfully treated and managed. Antipsychotic drugs remain the pharmacological choice in treating the symptoms of schizophrenia, in particular the atypical antipsychotic olanzapine (Neal, 2009, p. 141).

Reports suggest that a chemical transmitter imbalance could explain the pathophysiology of schizophrenia. This imbalance involves anomalies within the synaptic dopamine neurotransmission (Neal, 2009, p. 142). The mesocorticolimbic pathway which has an association with the control of behaviour and emotions reveals elevated dopaminergic activity (Bullock & Hales, 2013, p. 321). This particular pathway starts in the midbrain and connects to different areas of the limbic system and cerebral cortex. It also involves the parahippocampal gyrus, hippocampus and amygdale, temporal and frontal lobe cortex (Neal, 2009, p. 142). The overactivity of this pathway is reported to be responsible for the disordered thought process, unusual behaviour and altered emotions (Bullock & Hales, 2013, p. 321). Family history is one of the most significant risk factors in developing schizophrenia. A first degree relative ie: a parent or sibling has a 6% to 17% incidence and a monozygotic twin has a 50% approximate lifetime incidence of developing schizophrenia (Schultz, S., North, S., & Shields, C. 2007. p. 1822). Schizophrenia may also be induced by illicit drugs, such as cannabis and marijuana that increase dopaminergic activity in the brain (Galbraith, A., Bullock, S., & Manias, E. 2004, p. 316). Schizophrenia is characterized by positive and negative symptoms. Positive symptoms may include hallucinations, voices that speak to or about the person and delusions that are often paranoid. Negative symptoms include a flattened effect, where the person has a loss of a sense of pleasure, loss of will or drive and social withdrawal (Schultz et al., 2007, p. 1821). The signs and symptoms of schizophrenia generally develop over weeks to months, no single sign or symptom is pathognomonic of schizophrenia (Schultz et al., 2007, p. 1823). By utilizing appropriate research, the proceeding segments of this paper will attempt to substantiate the claim that olanzapine is the most effective atypical antipsychotic medication to treat and manage the symptoms of schizophrenia. This paper will draw comparisons between atypical antipsychotic medications currently available for the symptomatic treatment of schizophrenia and demonstrate why olanzapine is the first choice for symptom treatment and management.

Antipsychotic medications are the pharmacological choice for treatment and management of symptoms associated with schizophrenia, of which olanzapine is the most efficious. These medications are generally referred to as typical and atypical antipsychotics or first and second generation antipsychotics (Kane, 2010, p. 345). Typical antipsychotics, have a higher risk of extrapyramidal side effects, such as dystonic reactions, parkinsonian symptoms, sexual dysfunction, akathisia, and are therefore not a first choice for treatment. The newer atypical antipsychotics such as olanzapine exhibit fewer unwanted side effects and are therefore the preferred choice for symptom management (Schultz et al., 2007, p. 1824).

Schizophrenia is a leading cause of functional disability. Patients with schizophrenia not only suffer from the symptoms but also occupational functioning and low levels of productivity (Liu-Seifert, Ascher-Svanum, Osuntokun, Jen & Gomez, 2011, p. 2). The choice of antipsychotic medication also plays a role in adherence and persistence. Olanzapine is associated with a better rate of adherence and persistence, compared to other atypical antipsychotics such as risperidone (Zhao, Tunis & Lage, 2002, p. 746). Adherence to olanzapine in particular has also been linked to less psychiatric hospitalizations, as per figure One below (Liu-Seifert et al., 2011, p. 2)

Figure 1. Shows the relapse resulting from inpatient hospitalization by adherence to specified medication. adherence category for each medication (Furiak, Asher-Svanum, Klein, Smolen, Lawson, Conley & Culler, 2009, p. 6).

The most commonly used atypical antipsychotic medications currently prescribed to treat and manage symptoms of schizophrenia are: olanzapine, risperidone, quetiapine, ziprasidone or aripiprazole, of these olanzapine remains the most effective for symptomatic therapy (Zhao et al., 2002, p. 746). Reported evidence suggests that treatment with olanzapine provides significantly greater improvements in negative and positive symptoms, compared to the other atypical antipsychotic medication currently available (Edgell, E., Anderson, S., Johnstone, B., Dulisse, B., Revicki, D., & Breier, A. 2000. p. 567).

Olanzapine has shown to have an affinity across a number of receptor systems, binding to the following: serotonin 5HT2A/2C,5HT3, 5HT6; dopamine D1,D2,D3,D4,D5; cholinergic muscarinic receptors m1-m5; alpha1 adrenergic; and histamine H1 receptors (Ellenbroek, 2012, p. 1374; Mims online, 2013). The antipsychotic activity of olanzapine is due to antagonism at D2 receptors in the mesolimbic pathway and 5HT2A/2C receptors in the frontal cortex. Antagonism at D2 receptors relieves positive symptoms while antagonism at 5HT2A receptors relieves negative symptoms of schizophrenia (Callaghan, Bergstrom, Ptak & Beasley, 1999, p. 178).

Electrophysiological studies show that olanzapine selectively reduced the firing of mesolimbic (A10) dopaminergic neurons, while having little effect on the striatal (A9) pathways involved in motor function, this reduces motor side effects (Catalyst, 2013). An additional Single Photon Emission Computed Tomography (SPECT) imaging study found that patients treated with olanzapine had lower striatal D2 occupancy than other patients treated with other antipsychotic medication such as risperadone. Treatment with olanzapine continues to show significant improvements in the negative and positive symptoms of schizophrenia compared to risperadone (Mims Online, 2013).

Olanzapine is well absorbed following oral administration, where it reaches peak plasma concentrations within 5 to 8 hours and requiring generally just a daily dose. Comparing Olanzapine to risperadone which reaches peak plasma within 1 to 2 hours and requires multiple doses, olanzapine again comes out as the preferred pharmacological treatment (Mims Online, 2012). Olanzapine is metabolised in the liver by conjugative and oxidative pathways. The main circulating metabolite N-10-glucuronide does not pass the blood brain barrier (Catalyst, 2013). The elimination half life in healthy individuals is approximately 33 hours and the plasma clearance is 26L/hr, these ranges are dependent on age, gender and smoking status. Males and smokers tend to have a higher plasma clearance of olanzapine than women and non smokers (Callaghan, Bergstrom, Ptak & Beasley, 1999, p.178).

The recommended commencement dose of olanzapine is 5mg – 10mg per day, administered in a single dose. The daily dosage may be adjusted depending on the individual’s clinical status. The dose may be adjusted within the range of 5mg – 20mg daily. Absorption is not affected by food, so this medication can be taken without regard to meals (Mims Online, 2013). Olanzapine is available as an oral medication by way of a tablet or soluble wafer, it is also available as an intramuscular injection as well as a depot injection. The depot injection is generally reserved for patients who refuse or are non compliant with the oral medication regimes. Compared to other antipsychotic medication such as ziprasidone, olanzapine is available in a variety of preparations, this means it’s accessible to a wider population ie: those that can take it orally and those that require a depot injection. (Mims Online, 2013). The efficiency of olanzapine has been confirmed through an international, multicentre, double blind clinical trial, comparing Olanzapine and risperidone. 150 patients were randomized to therapy using either olanzapine 10mg to 20mg per day or risperidone 4mg to 12mg in multiple doses per day for a maximum of 28 weeks (Edgell, Anderson, Johnson, Dulisse, Revicki & Breier, 2000, p. 567). Edgell et al., reported that a larger number of patients treated with olanzapine maintained their response compared to risperidone treated patients. The incidence of hyperprolactinaemia, sexual dysfunction and adverse events were reported as less by olanzapine treated recipients compared to those treated with risperidone, this adds to the confirmation that olanzapine is the medication of choice. (Edgell et al., 2000, p. 568). Functional activities such as employment, being a student or volunteer and general housekeeping were improved, showing moderately high and high levels of productivity with olanzapine treated patients compared to risperidone and other antipsychotic treatment. Figure 1 below shows a higher incidence of productivity level with olanzapine treatment compared to other available antipsychotic medications (Liu-Seifert et al., 2011, p. 4).

Figure 2

Figure 2 shows a comparison between olanzapine and other available antipsychotics--aripiprazole, haloperidol, risperidone, quetiapine, and ziprasidone. This graph demonstrates that olanzapine is consistently associated with a higher productivity level compared to other antipsychotic medications available (Liu-Seifert et al. 2011, p. 4)
The CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study involved almost 1500 participants with chronic schizophrenia. The main point of this trial was to measure the overall clinical effectiveness of a range of antipsychotics. Figure 3 shows a significantly higher proportion of patients treated with olanzapine had the most significant improvement in symptom treatment. Olanzapine also had the least amount of dropouts compared to perphenazine, risperidone and ziprasidone during the trial (Levine, Rabinowitz, Faries, Lawson & Ascher-Svanum, 2012, p. 145).

Figure 3. Percent of patients by best and worst treatment response trajectory by medication
Note. O: olanzapine, P: perphenazine, Q: quetiapine, R: risperidone, Z: ziprasidone.
(Levine, Rabinowitz, Faries, Lawson & Ascher-Svanum, 2012, p. 145)

Olanzapine, a serotonin-dopamine receptor antagonist, has shown to be effective against the positive and negative symptoms of schizophrenia with significantly fewer treatment-emergent extrapyramidal symptoms (Conley & Meltzer, 2000, p. 27). In relation to extrapyramidal symptoms, a larger percentage of people treated with haloperidol experienced parkinsonism or akathisia compared to those treated with olanzapine. All adverse effects need to be regularly assessed, these effects may include: sleeping difficulties, sexual and reproductive system problems, involuntary movements, abnormalities in blood pressure, blood lipids, liver enzymes due to asymptomatic elevations and glucose levels (Kane & Correll, 2010, p. 352). Compared to other atypical antipsychotic medication olanzapine has shown only a few adverse effects such as dry mouth, sedation, and increase in appetite. Olanzapine also displays less hyperprolactinemia compared to risperidone (Conley & Meltzer, 2000, p. 26).

Differences among antipsychotic medication on tolerability, safety, efficacy, cost and adherence all have cost effectiveness implications for treating schizophrenia. The use of olanzapine results in better clinical outcomes and lower total direct health care costs to the individual and the community compared to risperidone, ziprasidone, aripiprazole and quetiapine. Olanzapine is therefore the more cost effective therapeutic option for treatment and management of symptoms of schizophrenia, as displayed in figure 4 (Furiak, Asher-Svanum, Klein, Smolen, Lawson, Conley & Culler, 2009, p.15).

Figure 4 Shows mean medical costs in treating schizophrenia as well as the various medication costs. This also shows that olanzapine is the most cost effective treatment (Furiak, Asher-Svanum, Klein, Smolen, Lawson, Conley & Culler, 2009, p. 14).

Symptom severity has been examined by PANSS (Positive and Negative Syndrome Scale Values), these studies have shown that patients treated with olanzapine showed improvement in their general mental state compared to those patients treated with risperidone (Levine et al, 2012, p. 142). Patients taking olanzapine experienced less acute dystonia, bradykinesia, hypokinesia, akathisia, hypertonia, new onset parkinsonism, tremor and rigidity compared to those taking risperidone (
Komossa, K., Rummel-Kluge, C., Hunger, H., Schmid, F., Schwarz, S., Duggan, L., Kissling, W., & Leucht, S. 2010, p. 13).

In summary, schizophrenia is a highly complex disorder, exhibiting multiple symptoms and complexities. Given these complexities, olanzapine is currently the most efficious drug for the management and treatment of symptoms of schizophrenia. Treatment with olanzapine is associated with more favourable medication use patterns than treatment with risperidone. Patients treated with olanzapine compared to risperidone also had a decreased likelihood of using anti-parkinsonian medications (Zhao et al., 2002, p. 745-747). Olanzapine has shown to have an efficacy over and above other atypical antipsychotic medications such as risperidone and ziprasidone in relation to side effects, cognitive and mood symptoms (Keks, 2004, p. 148). Olanzapine may be a costlier choice of atypical antipsychotic compared to ziprasdone but it could be argued that the benefits of having reduced extrapyramidal effects and a better quality of life overall would justify the expense.

REFERENCES

Callaghan, J., Bergstrom, R., Ptak, L., & Beasley, C. (1999). Olanzapine: Pharmacokinetic and pharmacodynamics profile. Clinical Pharmacokinetics, 37(3), 177-193.

Catalyst. (2013). Catalyst [Online]. Retrieved from: http://catalyst.hen.com.au.ezproxy.csu.edu.au/productInformation.hen?file=p03177

Conley, R., & Meltzer, H. (2000). Adverse events related to olanzapine. The Journal of Clinical Psychiatry(61) suppl 8, 26-29. Retrieved from http://europepmc.org/abstract/MED/10811240

Coyle, J. (2012) NMDA Receptor and Schizophrenia: A Brief History. Schizophrenia Bulletin, 38(5), pp.920-926. doi: 10.1093/schbul/sbs076.

Edgell, E., Andersen S., Johnstone, B., Dulisse, B., Revicki, D., & Breir, A. (2000). Olanzapine versus Risperidone: A prospective comparison of clinical and economic outcomes in schizophrenia. Pharmacoeconomics, 18(6), 567-579. Retrieved from http://ezproxy.csu.edu.au/login?url=http://search.ebscohost.com/login.aspx?direct=true&db =heh&AN=9526736&site=ehost-live

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Furiak, N., Ascher-Svanum, H., Klein, R., Smolen, L., Lawson, A., Conley, R. & Culler, S. (2009). Cost-effectiveness model comparing olanzapine and other oral atypical antipsychotics in the treatment of schizophrenia in the United States. Cost Effectiveness and Resource Allocation, 7:4, 1-22. doi:10.1186/1478-7547-7-4.

Grace, A. (2011). Dopamine system dysregulation by the hippocampus: Implications for the pathophysiology and treatment of schizophrenia. Journal of Neuropharmacology. doi:10.1016/j.neuropharm.2011.05.011.

Guo, X., Zhai, J., Wei, Q.,Twamley, E., Jin, H., Fang, M., Hu, M. & Zhao, J. (2011). Neurocognitive effects of first and second generation antipsychotic drugs in early stage schizophrenia: A naturalistic 12 month follow up study. Journal of Neuroscience Letters. doi: 10.1016/j.neulet.2011.08.027

Gupta, S., & Kulhara, P. (2010). What is schizophrenia: A neurodevelopmental or neurodegenerative disorder or a combination of both? A critical analysis. Indian Journal of Psychiatry, 52(1). 21-27. doi:10.4103/0019-5545.58891.

Hong, L., Ascher-Svanum, H., Osuntokun, O., Kai Yu, J., & Gomez, J. (2011). Change in level of productivity in the treatment of schizophrenia with olanzapine or other antipsychotics. BMC Psychiatry, 11(1), 87-95. doi: 10.1186/1471-244X-11-87.

Kahn, R., Fleischhacker, W., Boter, H., Davidson, M., Vergouwe, Y., Keet, I., Gheorghe, M., Rybakowski, J., Galderisi, S., Libiger, J., Hummer, M., Dollfus, S., Lopez-Ibor, J., Hranov, L., Gaebel, W., Peuskens, J., Lindefors, N., Riecher-Rossler, A. & Grobbee, D. (2008) Effectiveness of antipsychotic drugs in first episode schizophrenia and schizophreniform disorder: an open randomised clinical trial. The Lancet, 371, 1085-1097. doi. 10.1016/S0140-6736(08)60486-9

Kane, J., & Correll, C. (2010). Pharmacologic treatment of schizophrenia. Retrieved from http://www.ncbi.nim.nih.gov/pmc/articles/PMC3085113

Keshavan, J., Nasrallah, H. & Tandon, R. (2011). Schizophrenia, “Just the Facts” 6. Moving ahead with the schizophrenia concept: From the elephant to the mouse. Journal of Schizophrenia Research. doi: 10.1016/j.schres.2011.01.011.

Komossa, K., Rummel-Kluge, C., Hunger, H., Schmid, F., Schwarz, S., Duggan, L., Kissling, W., & Leucht, S. (2010). Olanzapine versus other atypical antipsychotics for schizophrenia. Cochran Schizophrenia Group. doi: 10.1002/14651858.CD006654.pub2.

Levine, S., Rabinowitz, J., Faries, D., Lawson, A. & Ascher-Svanum, H. (2012). Treatment response trajectories and antipsychotic medications: Examination of up to 18 months of treatment in the CATIE chronic schizophrenia trial. Journal of Schizophrenia Research, 137, 141-146. doi:10.1016/j.schres.2012.01.014

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Neal, M. (2012). Medical Pharmacology at a glance, (7th ed). London: Wiley-Blackwell. Retrieved from CSU EBook Library.

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Tandon, R., Nasrallah, H. & Keshavan, S. (2010). Shizophrenia, “Just the Facts” 5. Treatment and prevention: Past, present & future. Journal of Schizophrenia Research. doi:10.1016/j.schres.2010.05.025.

Van Os, J & Kapur, S. (2009). Schizophrenia. The Lancet, 374(9690), 635-645. doi. 10.1016/S0140-6736(09)60995-8

Zhao, Z., Tunis, S., & Lage, M. (2002). Medication treatment patterns following initiation on Olanzapine versus Risperidone: A retrospective analysis. Clinical Drug Investigation, 22(11), 741-749. Retrieved from http://ezproxy.csu.edu.au/login?url=http://search.ebscohost.com/login.aspx?direct=true&db =s3h&AN=7728271&site=ehost-live

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