1. Maria

2.  19 year old Maori female with a diagnosis of paranoid schizophrenia presenting for re-admission to the acute inpatient mental health unit with an exacerbation of psychotic symptoms.  Disorganised thoughts, auditory hallucinations of a persecutory nature, paranoid delusions.  Recently discharged from the unit on a combination of olanzapine and haloperidol after a long admission for first presentation schizophrenia and failure to respond to risperidone and quitiepine  History of heavy marijuana use and occasional use of methamphetamine  Smokes 20 cigarettes per day

4.  First presented to the mental health service 4 months ago with acute psychotic symptoms and recent heavy use of Marijuana and occasional methamphetamine  An extensive physical examination, cognitive assessment and range of blood tests and a CT head scan were completed to rule out physical causes.  All investigations were within normal range apart from a positive urine drug screen for THC.

5.  The presence of more than 2 of the DSM-4 criteria for paranoid schizophrenia for more than one month, in the absence of continued marijuana use, led to a final diagnosis of first presentation schizophrenia, paranoid type.  After failing to respond to treatment with risperidone and then quitiepine she eventually responded well to olanzapine 15mg daily supplemented by frequent doses of PRN Haloperidol to manage periods of distress and agitation. On this basis the haloperidol was moved to a regular dose of 10mg daily.  Discharged to community care on olanzapine 5mg Mane and 10mg Nocte and haloperidol 5mg BD.

6.  Visited by her community mental health nurse (CMHN) a week after discharge and found to be presenting with a range of extra pyramidal side effects (EPSE). She complained of tremor and muscular rigidity and was observed to have slurred speech and an unsteady gait.  Knowing that these are common side effects of haloperidol (MIMS, 2014) her CMHN discussed the issue with her treating psychiatrist and her haloperidol was reduced from 10mg to 5mg daily.  A stat dose of benztropine 2mg and PRN up to 4mg per day was provided to treat the EPSE.  On review the following day she had taken a further two doses of Benzropine and reported no further uncomfortable side effects.  Visited again by her CMHN one week later and found to be experiencing an acute exacerbation of psychotic symptoms.

7.  Olanzapine 5mg Mane and 10mg Nocte  Haloperidol 5mg daily  Benzropine 1 – 2mg PRN (up to 4mg daily)

8.  Atypical anti-psychotic dopamine and serotonin antagonist agent (MIMS, 2014).  Smoking induces the CYP-1A2 metabolism of olanzapine. Clearance of Olanzapine is therefore greater in tobacco smokers than in non-smokers (Eli Lilly, 2013)  Approximately 93% protein bound (Eli Lilly, 2013)

9.  Butyrophenone dopamine (D2) antagonist anti-psychotic agent.  92% protein bound (Healthcare Logistics, 2012).  Extra pyramidal (EPSE) side effects, including tremor, unsteady gait, muscular rigidity and slurred speech, often occur at moderate to high doses (MIMS, 2014).  Increased risk when combined with olanzapine due to competition for albumin and increased availability of active metabolite.  Co-administration of haloperidol and olanzapine can lead to increased risk of EPSE due to cytochrome P450 inhibition of haloperidol metabolism and enhanced D2 receptor blockade (Healthcare Logistics, 2012).

10.  Acetylcholine blocking anticholinergic agent used in the treatment of parkinsonism and for extra-pyramidal side effects from anti- psychotic agents (AFT pharmaceuticals, 2012).  Common side effects include dry mouth, constipation and nausea while less commonly it can lead to exacerbation of psychotic symptoms (AFT pharmaceuticals, 2012).

12. Exacerbation of psychotic symptoms possibly caused by:  Recent reduction in dose of haloperidol  Benztropine can cause exacerbation of psychotic symptoms, especially when taken in high doses (MIMS, 2014).  Maria has a history of illicit drug use and benztropine is known to be abused by used by some patients (AFT pharmaceuticals, 2012)  Could therefore be an adverse effect either at prescribed dose or due to taking too much benztropine  Marijuana or other drug induced exacerbation (ruled out via negative urine drug screen)  Tobacco mediated induction of CYP-450 enzyme system and subsequent reduction of olanzapine serum level.  Other (psychosocial or physical/medical cause)

14.  Effective treatment for schizophrenia with greater efficacy and lower risk of EPSE than haloperidol (Leucht, Pitschel-Walz, Abraham & Kissling, 1998)  Available as a long acting intra-muscular depot preparation  Risk of metabolic side effects (MIMS, 2014), such as weight gain, dyslipidaemia and insulin resistance, in a young woman who already has a BMI of 30

15.  More effective than traditional anti-psychotics in treatment resistant schizophrenia and greater efficacy than other newer anti- psychotics when switching from another atypical anti-psychotic (McEvoy, Lieberman & Stroup et al, 2006)  Even though Clozapine is a highly efficacious drug in treating the symptoms of schizophrenia is also is associated with many potential side effects, some very serous such as agranulocytosis. It also requires quite extensive monitoring including weekly blood tests during the early phase of titration (Novartis, 2014).

16.  May be an effective treatment option but all traditional anti-psychotics are associated with EPSE and Maria has been sensitive to this group of side effects.

17. Even though clozapine may offer the greatest efficacy it is also associated with greater risks than olanzapine. Switching to another traditional anti-psychotic is not a desirable option due to the risk of further EPSE. Following consultation with Maria and other relevant health professionals it is proposed that we treat Maria with olanzapine alone and clozapine is kept as a contingency plan if this fails to adequately treat Maria’s psychosis:  Stop haloperidol to minimise the risk of further EPS  Increase olanzapine to 5mg BD and 10mg Nocte (keeps the higher dose at night time to minimise sedation during the day) and review daily for two weeks to monitor sedation and other immediate adverse effects  Stop Benztropine. An anti-cholinergic shouldn’t be necessary because EPS with olanzapine monotherapy is very rare (MIMS, 2014).  Consider depot olanzapine later if compliance becomes an issue

18.  Metabolic monitoring (baseline weight, waist measurement, BMI, blood lipids, HbA1c) and regular monitoring at 3 month intervals. Repeat earlier if visible signs of weight gain are evident.  Educate regarding healthy lifestyle (diet and exercise)  Educate re smoking (in regard to its health risks generally and its potential effect on liver enzyme system and serum levels of olanzapine)  Daily mental state assessment and weekly standardised assessment tool, such as the brief psychiatric rating scale (BPRS) (Overall and Gorham, 1962) to monitor clinical efficacy  Adjust dose of olanzapine as required according to response aiming for the lowest dose that is effective.

19. If olanzapine monotherapy is successful then Maria will need to be monitored in the community in regard to:  Any adverse effects that might emerge and related dose adjustments (Commonly sedation, constipation, and metabolic anomalies such as weight gain, dyslipidaemia and insulin resistance (MIMS, 2014).  Monitor for exacerbation of psychotic symptoms that could occur as a result smoking induced CYP-450 enzyme system and decreased serum Olanzapine  On-going smoking cessation education  On-going metabolic monitoring  Continue regular mental state assessment and BPRS to monitor clinical efficacy of treatment

20. Maria is a young woman recently diagnosed with Schizophrenia who has proven difficult to treat due to sensitivity to extra-pyramidal side effects and possibly adverse reaction to benztropine or other cause of relapse of psychosis. Pharmacokinetic principles of protein binding and associated increased effects and side effects have been considered as has the potential for smoking to induce the CYP-450 liver enzyme system to potentially cause a drop in serum olanzapine levels. Olanzapine is a drug that has demonstrated a high degree of efficacy in the treatment of schizophrenia and EPSE is rare with this agent. If metabolic side effects can be avoided via close monitoring and education in regard to healthy lifestyle then this drug could give Maria the opportunity of a greatly improved quality of life that is free of the distressing symptoms of psychosis. If Olanzapine does not turn out to be the answer for Maria then Clozapine can be considered as the next option

21. AFT Pharmaceuticals (2012). Retrieved from http://www.medsafe.govt.nz/searchResults.asp?q=Benzropinehttp://www.medsafe.govt.nz/searchResults.asp?q=Benzropine Eli Lilly (2013). Retrieved from http://www.medsafe.govt.nz/searchResults.asp?q=Olanzapinehttp://www.medsafe.govt.nz/searchResults.asp?q=Olanzapine Healthcare Logistics (2012). Retrieved from http://www.medsafe.govt.nz/searchResults.asp?q=haloperidolhttp://www.medsafe.govt.nz/searchResults.asp?q=haloperidol Leucht, S., Pitschel-Walz, G., Abraham, D., and Kissling, W (1998) Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials, Schizophrenia Research, 35, 51–68 McEvoy, J P., Lieberman, J A., Stroup, T C., Davies, S M., Meltzer H Y., Rosenheck M D., et al (2006). Effectiveness of Clozapine Versus Olanzapine, Quetiapine, and Risperidone in Patients With Chronic Schizophrenia Who Did Not Respond to Prior Atypical Antipsychotic Treatment, American Journal of Psychiatry 163: 600–610 MIMS online [electronic resource]. Published: Auckland: MediMedia New Zealand Ltd Novartis (2014). Retrieved from www. medsafe.govt.nz/profs/datasheet/c/ Clozaril tab.pdf www. medsafe.govt.nz/profs/datasheet/c/ Clozaril tab.pdf Overall, J E., Gorham, D R. (1962). The Brief Psychiatric Rating Scale, Psychological Reports, 10, 799-812.