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Keywords:

  • antipsychotic drug;
  • behavioral and psychological symptoms of dementia (BPSD);
  • ethics;
  • evidence;
  • off-label use

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CURRENT SITUATION REGARDING THE APPROVAL OF ANTIPSYCHOTICS IN GERIATRIC PSYCHIATRY IN JAPAN
  5. EXPERT OPINION ON THE USE OF ANTIPSYCHOTICS IN OLDER PATIENTS OUTSIDE JAPAN
  6. EXPERT OPINION ON ANTIPSYCHOTIC USE IN OLDER PATIENTS IN JAPAN
  7. EVIDENCE IN FAVOR OF THE PRESCRIPTION OF ATYPICAL ANTIPSYCHOTICS FOR THE TREATMENT OF BPSD
  8. DISCUSSION
  9. ACKNOWLEDGMENT
  10. REFERENCES

The term ‘off-label use’ is generally taken to mean the prescription of a drug without approved official authorization. The present article deals with ethical problems associated with the off-label use of antipsychotic drugs for the treatment of behavioral and psychological symptoms of dementia (BPSD) in Japan. Before the introduction of the Law of Protection of Private Information, the off-label use of antipsychotics was an almost open secret in Japan. Indeed, users of mental health care make strong requests that they receive the best and newest treatment available. Here, a huge gap exists between what psychiatrists consider ‘best’ and what the health service authority approves. For the sake of patients' interest, psychiatrists cannot help prescribing a drug for an unapproved indication or in a dose outside the usual range, otherwise they are unable to effect a therapeutic outcome. Although thioridazine and vegetamin are officially approved for the treatment of geriatric psychosis in Japan, they are not used commonly compared with atypical neuroleptics. Clinicians' preference for atypical agents over conventional neuroleptics is based on ethical motivation regarding the safe use of the drug rather than profitability. The failure to follow the information on the drug label should not necessarily preclude a psychiatrist from making a good clinical judgment in the interest of the patient. Even so, the psychiatrist should be aware that the patient retains the right to redress for possible medical malpractice. Japanese psychiatrists should take into account the evidence concerning the effectiveness of the drug for any unlicensed indication when they prescribe it off-label. They should also inform patients of the fact that the prescription is off-label and of any risks and benefits involved in the prescription of that particular drug. Whenever there is evidence of benefit, a trial of the drug should always be performed under careful clinical monitoring.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CURRENT SITUATION REGARDING THE APPROVAL OF ANTIPSYCHOTICS IN GERIATRIC PSYCHIATRY IN JAPAN
  5. EXPERT OPINION ON THE USE OF ANTIPSYCHOTICS IN OLDER PATIENTS OUTSIDE JAPAN
  6. EXPERT OPINION ON ANTIPSYCHOTIC USE IN OLDER PATIENTS IN JAPAN
  7. EVIDENCE IN FAVOR OF THE PRESCRIPTION OF ATYPICAL ANTIPSYCHOTICS FOR THE TREATMENT OF BPSD
  8. DISCUSSION
  9. ACKNOWLEDGMENT
  10. REFERENCES

The term ‘off-label use’ is generally taken to mean the prescription of a drug without approved official authorization. The present article deals with ethical problems associated with the off-label use of antipsychotic drugs for the treatment of behavioral and psychological symptoms of dementia (BPSD) in Japan.

Arai1 once indicated that the off-label use of antipsychotics is a matter of concern for all psychiatrists, citing complex issues, such as informed consent, information disclosure and malpractice. Three years later, the Law of Protection of Private Information was instituted and, as a consequence, these matters have become much more serious.2 The fact that psychiatrists prescribe a drug without approved official authorization can be publicly disclosed.

CURRENT SITUATION REGARDING THE APPROVAL OF ANTIPSYCHOTICS IN GERIATRIC PSYCHIATRY IN JAPAN

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CURRENT SITUATION REGARDING THE APPROVAL OF ANTIPSYCHOTICS IN GERIATRIC PSYCHIATRY IN JAPAN
  5. EXPERT OPINION ON THE USE OF ANTIPSYCHOTICS IN OLDER PATIENTS OUTSIDE JAPAN
  6. EXPERT OPINION ON ANTIPSYCHOTIC USE IN OLDER PATIENTS IN JAPAN
  7. EVIDENCE IN FAVOR OF THE PRESCRIPTION OF ATYPICAL ANTIPSYCHOTICS FOR THE TREATMENT OF BPSD
  8. DISCUSSION
  9. ACKNOWLEDGMENT
  10. REFERENCES

The Japanese Ministry of Health and Labor officially approves very few drugs in geriatric psychiatry: donepezil for Alzheimer's disease, but not for other types of dementia; tiapride for delirium as a consequence of cerebral infarction; amantadine for the loss of motivation due to cerebral infarction; nicergorine for the loss of motivation due to poor circulation as a consequence of cerebral infarction; and thioridazine and vegetamin for geriatric psychosis.

It is suspected that Japanese psychiatrists commonly prescribe antipsychotics for the control of BPSD, such as agitation, anxiety, night-time disturbed behavior, delusions and hallucinations. Such prescriptions are the use of a drug outside the terms of its marketing authorization, except those for thioridazine and vegetamin, the latter including chlorpromazine.

EXPERT OPINION ON THE USE OF ANTIPSYCHOTICS IN OLDER PATIENTS OUTSIDE JAPAN

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CURRENT SITUATION REGARDING THE APPROVAL OF ANTIPSYCHOTICS IN GERIATRIC PSYCHIATRY IN JAPAN
  5. EXPERT OPINION ON THE USE OF ANTIPSYCHOTICS IN OLDER PATIENTS OUTSIDE JAPAN
  6. EXPERT OPINION ON ANTIPSYCHOTIC USE IN OLDER PATIENTS IN JAPAN
  7. EVIDENCE IN FAVOR OF THE PRESCRIPTION OF ATYPICAL ANTIPSYCHOTICS FOR THE TREATMENT OF BPSD
  8. DISCUSSION
  9. ACKNOWLEDGMENT
  10. REFERENCES

Alexopolous et al.3 surveyed expert opinion on the use of antipsychotics in older patients (65 years of age or older) for recommendations concerning indications for antipsychotics, the choice of antipsychotic for different conditions (e.g. delirium, dementia, schizophrenia, delusional disorder, psychotic mood disorders) and for patients with comorbid conditions or a history of side-effects, dosing strategies, duration of treatment and medication combinations.

Alexopolous et al.3 found that the expert panel did not recommend using antipsychotics in panic disorder, generalized anxiety disorder, non-psychotic major depression, hypochondria, hostility or in sleep disturbance in the absence of a major psychiatric syndrome. However, they favored the prescription of antipsychotics for several other disorders. For agitated dementia with delusions, the experts' first-line recommendation was risperidone (05–2.0 mg/day) followed by quetiapine (50–100 mg/day) and olanzapine (5.0–7.5 mg/day). For late-life schizophrenia, the experts recommended risperidone (1.25–3.5 mg/day) as the first-line therapy and quetiapine (100–300 mg/day), olanzapine (7.5–15 mg/day) and aripiprazole (15–30 mg/day) as second-line treatments. For older patients with delusional disorders, an antipsychotic was the only treatment recommended. For agitated non-psychotic major depression in older patients, the experts' first-line recommendation was a single antidepressant; second-line options included an antidepressant plus an antipsychotic, an antidepressant plus a benzodiazepine and an antidepressant plus a mood stabilizer.

EXPERT OPINION ON ANTIPSYCHOTIC USE IN OLDER PATIENTS IN JAPAN

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CURRENT SITUATION REGARDING THE APPROVAL OF ANTIPSYCHOTICS IN GERIATRIC PSYCHIATRY IN JAPAN
  5. EXPERT OPINION ON THE USE OF ANTIPSYCHOTICS IN OLDER PATIENTS OUTSIDE JAPAN
  6. EXPERT OPINION ON ANTIPSYCHOTIC USE IN OLDER PATIENTS IN JAPAN
  7. EVIDENCE IN FAVOR OF THE PRESCRIPTION OF ATYPICAL ANTIPSYCHOTICS FOR THE TREATMENT OF BPSD
  8. DISCUSSION
  9. ACKNOWLEDGMENT
  10. REFERENCES

Four Japanese experts in geriatric psychiatry have discussed this issue. Indeed, Arai4 took the recent safety warning issued by the US Food and Drug Administration (FDA)5 seriously. However, he basically favored atypical antipsychotics prescribed for BPSD on the conditions that patients are fully informed of the fact that the prescription is off-label, as well as any risks and benefits involved in the prescription. Ikeda6 also admitted that there are demented patients with BPSD who require treatment with atypical antipsychotics.

Conversely, Kudo and Taketa7 maintained that the first choice of treatment for BPSD is non-pharmacological intervention. They warned careless prescribers of antipsychotics against the increased likelihood of serious cerebrovascular adverse events. In Takita's opinion,8 it is possible to control BPSD without prescribing atypical antipsychotics. He proposed alternative therapies for BPSD, such as sodium valproate and Yi-Gan San, the traditional Chinese medicine.

EVIDENCE IN FAVOR OF THE PRESCRIPTION OF ATYPICAL ANTIPSYCHOTICS FOR THE TREATMENT OF BPSD

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CURRENT SITUATION REGARDING THE APPROVAL OF ANTIPSYCHOTICS IN GERIATRIC PSYCHIATRY IN JAPAN
  5. EXPERT OPINION ON THE USE OF ANTIPSYCHOTICS IN OLDER PATIENTS OUTSIDE JAPAN
  6. EXPERT OPINION ON ANTIPSYCHOTIC USE IN OLDER PATIENTS IN JAPAN
  7. EVIDENCE IN FAVOR OF THE PRESCRIPTION OF ATYPICAL ANTIPSYCHOTICS FOR THE TREATMENT OF BPSD
  8. DISCUSSION
  9. ACKNOWLEDGMENT
  10. REFERENCES

Although no atypical antipsychotics are officially approved in Japan, there is considerable evidence concerning both the benefits and risks of using these drugs to treat BPSD.

Risperidone

The following three studies are in favor of the prescription of risperidone to patients with BPSD.

Katz et al.9 conducted the first large double-blind, placebo-controlled study to evaluate the efficacy and safety of risperidone in the treatment of psychotic and behavioral symptoms in patients with severe dementia. They found significantly greater reductions in psychosis and aggressive behavior in patients on resperidone compared with those on the placebo. Because more adverse events were reported by patients receiving 2 mg/day risperidone than by patients on 1 mg/day, the authors concluded that 1 mg/day risperidone is an appropriate dose for most elderly patients with dementia.

Brodaty et al.10 attempted a randomized, double-blind, placebo-controlled trial examining the efficacy and safety of risperidone in the treatment of aggression, agitation and psychosis in elderly nursing-home patients with dementia. They found a significant reduction in aggressive behavior following treatment with risperidone compared with placebo. Brodaty et al.10 found a similar improvement in agitation and psychotic symptoms. In addition, somnolence and urinary tract infection were found to be more commonly reported in patients receiving risperidone treatment.

Cruz-Jentoft et al.11 conducted a multicenter, open-label, prospective study treating 75 patients with vascular or mixed-type dementia and concomitant behavioral and psychological symptoms with risperidone for up to 6 months. Risperidone decreased the frequency and severity of overall behavioral and psychological symptoms. Although adverse events, such as hypotension, somnolence and paresthesia, were reported, extrapyramidal symptoms decreased transiently over the course of the study. The authors concluded that risperidone was effective and well tolerated in the treatment of BPSD with vascular or mixed-type dementia.

The following two studies from far-eastern countries are of particular importance to the Japanese population because of the ethnic and cultural similarities of the samples with Japan.

Chan et al.12 conducted a 12 week double-blind, randomized comparison of haloperidol and risperidone treatment in 58 Chinese patients diagnosed with DSM-IV dementia of Alzheimer's type or vascular dementia. They found that low-dose haloperidol and risperidone were well tolerated and associated with reductions in the severity and frequency of BPSD. In their opinion, resperidone may have a more favorable risk–benefit profile in view of its lower propensity to induce extrapyramidal symptoms.12

Sub et al.13 made a randomized, double-blind crossover comparison of risperidone and haloperidol in Korean dementia patients with behavioral disturbances. In that study, 120 patients received flexible doses (0.5–1.5 mg/day) of risperidone or haloperidol for 18 weeks. Sub et al.13 found that patients receiving risperidone benefited from reductions in aggressiveness and anxieties/phobias compared with patients on haloperidol. The risk of antipsychotic-induced parkinsonism was significantly lower with risperidone than with haloperidol.

Olanzapine

The efficacy and safety of olanzapine in treating psychosis with behavioral and psychological symptoms have been reported by Street et al.,14 De Deyn et al.,15 Edell and Tunis,16 Walker et al.17 and Cummings et al.18

Street et al.14 conducted a multicenter double-blind, placebo-controlled 6-week study in 206 Alzheimer's disease (AD) patients with psychological and behavioral symptoms. They found low-dose olanzapine (both 5 and 10 mg/day) produced significant improvement compared with placebo in agitation/aggression, hallucinations and delusions. In contrast, olanzapine at 15 mg/day did not produce significantly greater improvement compared with placebo. No significant cognitive impairment, increase in extrapyramidal symptoms or central anticholinergic effects were found at any dose of olanzapine used relative to placebo. Street et al.14 concluded that the low doses of olanzapine (5 and 10 mg/day) were significantly superior to placebo and well tolerated in treating behavioral symptoms of AD.

De Deyn et al.15 conducted a 10 week double-blind treatment of 625 patients with Alzheimer's dementia with placebo or fixed-dose olanzapine (1.0, 2.5, 5.0 and 7.5 mg/day). Although 1.0 mg olanzapine did not show significant differences from placebo, end-point Clinical Global Impression of Change (CGI-C) scores showed that the greatest improvement was found for the group treated with olanzapine 2.5 mg. Olanzapine at a dose of 7.5 mg significantly decreased psychosis and overall behavioral disturbances and was well tolerated.15

Edell and Tunis16 examined change in BPSD for dementia patients from hospital admission to discharge. Patients were prescribed haloperidol (n = 289), olanzapine (n = 209) or risperidone (n = 500). Olanzapine showed significantly greater overall improvement in BPSD than risperidone or haloperidol. In particular, olanzapine was effective in improving individual BPSD, such as active, verbal and passive aggression, delusions/hallucinations etc.16

Whether atypical neuroleptics can be a treatment option is of particular importance in dementia with Lewy bodies (DLB). This is because this form of dementia, although commonly characterized by varieties of psychological and behavioral symptoms, poorly tolerates treatment with conventional neuroleptics.

Walker et al.17 presented the results of eight DLB patients with associated psychotic and behavioral difficulties. All patients were given olanzapine 2.5–7.5 mg and monitored at 2 weekly intervals. Three of the eight patients could not tolerate olanzapine even at the lowest dose available, two patients showed clear improvement and three patients were able to tolerate olanzapine but gained only minimal benefit. Walker et al.17 concluded that olanzapine conferred little advantage over conventional neuroleptics.

In contrast, Cummings et al.18 conducted a post hoc analysis of a subgroup of patients with DLB and included a larger double-blind, placebo-controlled, randomized parallel group trial of olanzapine for the treatment of AD that found that patients with DLB treated with 5 mg/day olanzapine showed significant reductions in delusions and hallucinations. Patients treated with 10 mg/day olanzapine showed a significant reduction in delusions. No significant exacerbation of parkinsonian symptoms was found. Preliminary analysis suggested that olanzapine (5 or 10 mg/day) reduces psychosis in patients with DLB without worsening parkinsonism.18

Moretti et al.19 performed a controlled open-label study investigating the treatment of behavioral symptoms in vascular dementia. They followed (for 12 months) a group of 346 consecutive outpatients with a diagnosis of subcortical vascular dementia or multi-infarctual dementia. Moretti et al.19 found that patients receiving olanzapine (2.5–7.5 mg/day) showed significantly improved BPSD. In addition, the patients were receiving numerous medications for the treatment of concomitant medical conditions. Given the potential complications associated with these medications, these patients tolerated olanzapine quite well. Moretti et al.19 concluded that olanzapine could be a safe and effective treatment for BPSD due to vascular dementia when given in suitable doses and adequately followed up.

Quetiapine

The following study supports the prescription of quetiapine to patients with BPSD. Fujikawa et al.20 attempted an 8 week, open-label study of 25–200 mg/day quetiapine for the treatment of behavioral and psychological symptoms of AD. The authors found a significant reduction in agitation, delusions, behavioral problems and other associated problems, without any exacerbation of extrapyramidal symptoms.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CURRENT SITUATION REGARDING THE APPROVAL OF ANTIPSYCHOTICS IN GERIATRIC PSYCHIATRY IN JAPAN
  5. EXPERT OPINION ON THE USE OF ANTIPSYCHOTICS IN OLDER PATIENTS OUTSIDE JAPAN
  6. EXPERT OPINION ON ANTIPSYCHOTIC USE IN OLDER PATIENTS IN JAPAN
  7. EVIDENCE IN FAVOR OF THE PRESCRIPTION OF ATYPICAL ANTIPSYCHOTICS FOR THE TREATMENT OF BPSD
  8. DISCUSSION
  9. ACKNOWLEDGMENT
  10. REFERENCES

Before the introduction of the Law of Protection of Private Information, the off-label use of antipsychotics was an almost open secret in Japan. Psychiatrists have not dared to point out the ethicolegal problems in treating patients with an approved drug for unapproved purposes. Indeed, in most cases they have known that the drug being used is off-label. However, due to no legally prescribed obligation to disclose this information, Japanese psychiatrists were able to draw the veil over those actions they feared people would criticize. For purely therapeutic purposes, practically all Japanese psychiatrists felt no reluctance in doing this to achieve their ends. When prescribing off-label, they considered the evidence that the drug is likely to be effective for the unapproved indication.

Such a disregard for the official label of approval can be best illustrated by a well-known quote from Kitano Takeshi, one of the greatest film directors in Japan: ‘We hesitate at nothing to go through a stop sign without stopping, if we go together’.

However, from a psychiatrist's point of view, there is still a need for justification. Indeed, users of mental health care make strong requests that they receive the best and newest treatment available. Here, a huge gap exists between what psychiatrists consider as ‘best’ and what the health service authority approves. For the sake of patients' interest, psychiatrists cannot help prescribing a drug for an unapproved indication or in a dose outside the usual range; otherwise, they are unable to effect a therapeutic outcome. For this reason, Japanese psychiatrists have dared to turn a blind eye to what is approved officially.

Although thioridazine and vegetamin are officially approved for the treatment of geriatric psychosis in Japan, they are not used commonly compared with atypical neuroleptics. There is an ethical reason for this: elderly patients with dementia are susceptible to drug-induced extrapyramidal symptoms and considerable evidence shows a correlation between the higher incidence of extrapyramidal symptoms and conventional neuroleptics, such as chlorpromazine and thioridazin, compared with atypical neuroleptics. Hence, clinicians' preference of atypical agents to conventional neuroleptics is based on ethical motivation regarding the safe use of the drug rather than profitability.

At the same time, atypical agents still give rise to serious motor side-effects in elderly patients, due mainly to these patients' increased susceptibility to movement disorders. Consequently, compared with the common dose for usual adult patients, far more conservative doses of atypical drugs are recommended for elderly demented patients.

The failure to follow the information on the drug label should not necessarily preclude a psychiatrist from making a good clinical judgment in the best interests of the patient. Even so, the psychiatrist should be aware that the patient retains the right to redress for possible medical malpractice.

Japanese psychiatrists should take into account the evidence concerning the effectiveness of the drug for the unlicensed indication when they prescribe it off-label. They should also inform patients of the fact that the prescription is off-label and of any risks and benefits involved in the prescription. Whenever there is evidence of benefit, a trial of the drug should always be performed under careful clinical monitoring.

It is certain that some patients have difficulty understanding the concept of ‘off-label’. In addition, psychiatrists may be concerned that the information given about a drug's off-label use could adversely effect the patient's adherence to his/her pharmacotherapy.

Nevertheless, patients should be given full information about their medication. Pharmacists and nurses, as well as psychiatrists, should take the time and energy to ensure that this occurs.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. CURRENT SITUATION REGARDING THE APPROVAL OF ANTIPSYCHOTICS IN GERIATRIC PSYCHIATRY IN JAPAN
  5. EXPERT OPINION ON THE USE OF ANTIPSYCHOTICS IN OLDER PATIENTS OUTSIDE JAPAN
  6. EXPERT OPINION ON ANTIPSYCHOTIC USE IN OLDER PATIENTS IN JAPAN
  7. EVIDENCE IN FAVOR OF THE PRESCRIPTION OF ATYPICAL ANTIPSYCHOTICS FOR THE TREATMENT OF BPSD
  8. DISCUSSION
  9. ACKNOWLEDGMENT
  10. REFERENCES
  • 1
    Arai H. The official approval of antipsychotics reconsidered. Seishinigaku 2002; 44: 366367 (in Japanese).
  • 2
    Arai H. The treatment of BPSD. Clinician 2005; 52: 881885 (in Japanese).
  • 3
    Alexopoulos GS, Streim J, Carpenter D et al. Expert consensus panel for using antipsychotic drugs in older patients. J Clin Psychiatry 2004; 65 (Suppl 2): 599.
  • 4
    Arai H. Atypical antipsychotics may be prescribed with careful clinical monitoring and full informed consent for demented patients with BPSD. Seishinigaku 2006; 48: 11621164 (in Japanese).
  • 5
    US Food and Drug Administration. FDA issues Public Health Authority for antipsychotic drugs used for treatment of behavioral disorders in elderly patients. FDA Talk Paper T05-13, April 11 2005. Rockville, MD: US Food and Drug Administration, 2005. Available online from http://www.fda.gov/bbs/topics/ANSWERS/2005/ANS01350.html
  • 6
    Ikeda M. Considering the use of atypical antipsychotics for patients with BPSD. Seishinigaku 2006; 48: 11651167 (in Japanese).
  • 7
    Kudo T, Taketa M. Considering the use of atypical antipsychotics for demented patients with BPSD. Seishinigaku 2006; 48: 11711175 (in Japanese).
  • 8
    Takita M. Is it possible to control BPSD without prescribing atypical antipsychotics? Seishinigaku 2006; 48: 11681170.
  • 9
    Katz IR, Jeste DV, Mintzer JE et al. Comparison of risperidone and placebo for psychosis and behavioral disturbances associated with dementia: A randomized, double-blind trial: J Clin Psychiatry 1999; 60: 107115.
  • 10
    Brodaty H, Arnes D, Snowdon J et al. A randomized placebo-controlled trial of risperidone for the treatment of aggression, agitation and psychosis of dementia. J Clin Psychiatry 2003; 64: 134143.
  • 11
    Cruz-Jentoft AJ, Burón J-A, Diago JI et al. Risperidon in the treatment of behavioural and psychological symptoms in patients diagnosed with vascular or mixed-type dementia. Int J Psychiatry Clin Pract 2005; 9: 4551.
  • 12
    Chan WC, Lam LC, Choy CN et al. A double-blind randomized comparison of risperidone and haloperidol in the treatment of behavioural and psychological symptoms in Chinese dementia patients. Int J Geriatr Psychiatry 2001; 16: 11561162.
  • 13
    Sub GH, Son HG, Ju YS et al. A randomized, double-blind, crossover comparison of risperidone and haloperidol in Korean dementia patients with behavioral disturbances. Am J Geriatr Psychiatry 2004; 12: 509516.
  • 14
    Street JS, Clark WS, Gannon KS et al. Olanzapine treatment of psychotic and behavioral symptoms in patients with Alzheimer disease in nursing care facilities: A double blind, randomized, placebo-controlled trial. The HGEU Study Group. Arch Gen Psychiatry 2000; 57: 968976.
  • 15
    De Deyn PP, Carrasco MM, Deberdt W et al. Olanzapine versus placebo in the treatment of psychosis with or without associated behavioral disturbances in patients with Alzheimer's disease. Int J Geriatr Psychiatry 2004; 19: 115126.
  • 16
    Edell WS, Tunis SL. Antipsychotic treatment of behavioral and psychological symptoms of dementia in geropsychiatric inpatients. Am J Geriatr Psychiatry 2001; 9: 289297.
  • 17
    Walker Z, Grace J, Overshot R et al. Olanzapine in dementia with Lewy bodies: A clinical study. Int J Geriatr Psychiatry 1999; 14: 459466.
  • 18
    Cummings JL, Street J, Masterman D et al. Efficacy of olanzapine in the treatment of psychosis in dementia with Lewy bodies. Dement Geriatr Cogn Disord 2002; 13: 6773.
  • 19
    Moretti R, Torre P, Antonello RM et al. Olanzapine as a possible treatment of behavioral symptoms in vascular dementia: Risks of cerebrovascular events. A controlled, open-label study. J Neurol 2005; 252: 11861193.
  • 20
    Fujikawa T, Takahashi T, Kinoshita A et al. Quetiapine treatment for behavioral and psychological symptoms in patients with senile dementia of Alzheimer type. Pharmacopsychiatry 2004; 49: 201204.