References

1. Stahl SM, Lamotrigine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 259–652. Stahl SM, Clozapine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 113–83. Stahl SM, Risperidone, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 475–814. Stahl SM, Olanzapine, in Stahl’s Essential Psychopharmacology The Prescriber’s Guide, 3rd edition, Cambridge University Press, New York, 2009, pp 387–925. Citrome L, Kantrowitz JT, Olanzapine dosing above the licensed range is more efficacious than lower doses: fact or fiction? Expert Reviews Neurother 2009; 9: 1045–586. Citrome L, Quetiapine: dose response relationship to schizophrenia. CNS Drugs 2008; 22: 69–727. Lindenmayer J-P, Citrome L, Khan A, Kaushik S, A randomized double-blind, parallel-grou, fixed dose, clinical trial of quetiapine 600 mg/day vs 1200 mb/day for patients with treatment-resistant schizophrenia or schizoaffective disorder. Abstracts of the Society for Biological Psychiatry, 2010, New Orleans Louisiana8. Stahl SM, Antipsychotics, in Stahl’s Essential Psychopharmacology, 3rd edition, Cambridge University Press, New York, 2008, pp 327–4529. Goff DC, Keefe R, Citrome L, Davy K, Krystal JH, Large C, Ghompson TR, Volavka J, Webster E, Lamotrigine as add-on therapy in schizophrenia. J Clin Psychopharmacol 2007; 27: 582–910. Stahl SM, Grady MM. A critical review of atypical antipsychotic utilization: Comparing monotherapy with polypharmacy and augmentation. Cur Med Chem 11, 313–26

Patient FileLightning RoundThe Case: The elderly man with schizophrenia and Alzheimer’s disease

The Question: How do you treat a patient with schizophrenia who is poorly responsive to antipsychotics and then develops Alzheimer’s dementia?

The Dilemma: Can you give an antipsychotic for one disorder when this is relatively contraindicated for another disorder in the same patient at the same time?

Pretest Self Assessment Question(answer at the end of the case) Which of the following is a reasonable approach to treating an aging patient with schizophrenia who then develops Alzheimer’s dementia?

A. Risk of cardiovascular events and death associated with the diagnosis of Alzheimer disease generally mean that antipsychotics should not be given even though the patient has long standing schizophrenia

B. Generally the needs for treating schizophrenia and the benefits of antipsychotic treatment of this condition outweigh the risks associated with antipsychotics when given in the presence of the additional condition of Alzheimer’s disease

C. Cholinesterase inhibitors can be combined with antipsychotics

D. Best to treat a patient like this with cholinesterase inhibitors alone

Patient Intake 65-year-old man with a psychotic disorder since age 26 currently diagnosed as paranoid schizophrenia, with multiple hospitalizations for auditory hallucinations, ideas of reference, persecutory delusions, disorganization of thinking and aggressive behavior

He has exhibited episodes of psychomotor agitation and aggressive behavior but has never met full criteria for either mania or major depression, but has carried the diagnosis of schizoaffective disorder at times in the past

About 18 years ago stabbed the manager of his board and residential care facility during an argument and was convicted of attempted murder but found not criminally responsible by reason of insanity and admitted to a forensic facility

Now developing deficits in cognition and short term memory consistent with early Alzheimer’s disease and confirmed on neuropsychological testing

Psychiatric History Currently, his psychosis is out of control plus he now has worsening cognitive symptoms superimposed

He was previously controlled on olanzapine (Zyprexa) 40 mg/day prior to the onset of progressive cognitive decline over the past year

He refused medication for about a week recently, and his mental status declined with increasing confusion, more difficult to direct and more threatening

Involuntary medication administration procedures were approved and the patient has been doing better, but still perseverates and seems confused with poor short term memory

Also taking valproate (Depakote) 1000 mg in the morning and 1250mg at night

Not only is there a question as to whether olanzapine can be given to a patient with Alzheimer’s disease due to the black box warning for increased risk of cardiovascular events and death in elderly dementia patients, but there is even the consideration that his olanzapine dose may need to be increased beyond what even younger psychotic patients without Alzheimer’s disease normally take in order to gain behavioral control

Of the following choices, what would you do?

Taper his valproate

Taper his olanzapine

Increase olanzapine dose (after obtaining plasma drug levels)

Start a cholinesterase inhibitor

Case Outcome Plasma drug levels were measured and proved to be in the low to normal range despite the high dose of olanzapine 40 mg/day

Olanzapine dose was thus increased slowly to 20 mg in the morning and 40 mg at night with good response

IM olanzapine was given prn a few times during the tapering up to manage behavioral disturbances

A good response was seen to his uncooperativeness and threatening behaviors, but he still perseverates and seems confused

Donepezil (Aricept) 5 mg was started with perhaps a slight improvement in cognition

If this does not work, the plan is either to increase the donepezil dose or try a cautious lowering of his valproate dose

Case Debrief It appears as though this patient has a long-standing psychotic illness now complicated by Alzheimer’s disease, with somewhat mutually contradictory treatment requirements

The patient cannot even withstand a few days discontinuation of his antipsychotic without behavioral decompensation, and standard to high doses of olanzapine are only partially effective

Despite his age and the controversy of giving very high antipsychotic doses and the added controversy of administering antipsychotics to an Alzheimer’s patient, the risks, and benefits were weighed and found in favor of trying very high olanzapine doses with good results, at least short-term

Given the severity of his long standing psychotic condition, which is still the most disabling condition for him, and few other options since many antipsychotics have failed, the cautious step wise increase of olanzapine doses to heroic levels seems to have been empirically effective

He may be partially noncompliant or partially failing to absorb his drug, thus necessitating higher than normal oral doses

There is almost no written documentation in the literature for treating cases at these doses of olanzapine, especially at his age and, in particular, in the presence of comorbid Alzheimer’s disease

The dilemma is whether to risk cardiovascular events and premature death in order to control psychosis

A treatment committee with a patient advocate reluctantly approved this treatment approach, with quarterly reviews, and the patient agreed to this treatment plan

Posttest Self Assessment Question: Answer Which of the following is a reasonable approach to treating an aging patient with schizophrenia who then develops Alzheimer’s dementia?

A. Risks of cardiovascular events and death associated with the diagnosis of Alzheimer disease generally mean that antipsychotics should not be given even though the patient has long standing schizophrenia

– Such risks are low and generally documented in patients with Alzheimer disease alone and not in elderly schizophrenics, for whom antipsychotics are still indicated

B. Generally the needs for treating schizophrenia and the benefits of antipsychotic treatment of this condition outweigh the risks associated with antipsychotics when given in the presence of the additional condition of Alzheimer’s disease

– Although this is an individual determination, this is generally true for patients with continuing active symptoms of psychosis convincingly improved by antipsychotics

C. Cholinesterase inhibitors can be combined with antipsychotics

– This is true and may even improve the cognitive symptoms associated with schizophrenia as well as the cognitive symptoms associated with Alzheimer’s disease

D. Best to treat a patient like this with cholinesterase inhibitors alone

– This approach is not likely to be successful as it will leave psychosis untreated

Answer: B and C