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Keywords:

  • atypical antipsychotics;
  • delirium;
  • elderly;
  • quetiapine

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Background:  A recent study reported that patients with delirium responded well to the administration of atypical antipsychotic agents. In the present study we administered quetiapine to patients with delirium and obtained good results.

Methods:  This study included 24 patients (10 men, 14 women), referred to the psychiatry department during admission to other hospital departments, who were diagnosed as having delirium according to the diagnostic and statistical manual of mental disorders (4th edition) (DSM-IV) between April 2001 and September 2002. The mean age of the patients was 76.5 years (men 71.0 years; women 80.5 years). An initial dose of quetiapine was established at 25–50 mg/day. Depending on the symptoms, the dose and frequency were increased as required. According to Trzepacz's delirium rating scale (DRS), the treatment response was evaluated prior to the administration of quetiapine and 1, 3, 5 and 7 days after administration began.

Results:  Prior to the administration of quetiapine, the mean DRS score was 18.1. The mean scores were 12.2, 10.8, 9.7 and 8.9 after 1, 3, 5 and 7 days of quetiapine administration, respectively. These values were significantly lower than the value before administration (P < 0.001). Seven days after the administration of quetiapine commenced, the total DRS score was lower than the cutoff point (12) in 20 patients (83.3%). In 18 patients (75.0%), delirium was clinically relieved. Doses ranged from 25 mg/day to 125 mg/day, with a mean dose of 54.7 mg/day. With respect to the administration method, the majority of patients (i.e. 13 patients) received quetiapine once per day (after dinner). Somnolence was observed in three patients as a side-effect of quetiapine administration. However, this side-effect improved after 1–2 days, without decreasing the dose.

Conclusions:  Quetiapine may be useful for controlling delirium and concerning side-effects and extrapyramidal symptoms were not recorded in the present study. Thus, it is appropriate to trial quetiapine in the treatment of delirium.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

The treatment for delirium plays an important role in liaison consultation. Previously, butyrophenone antipsychotic agents, such as haloperidol, have been prescribed as a first-choice agent in the treatment of delirium. However, side-effects such as extrapyramidal symptoms and oversedation frequently developed. A recent study has reported that patients with delirium respond to the administration of atypical antipsychotic agents such as risperidone1 and olanzapine.2,3 In this study, we administered quetiapine to patients with delirium and obtained good results.

SUBJECTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

This study included 24 patients (10 men and 14 women), referred to the psychiatry department during admission to other hospital departments, who were diagnosed with delirium according to the DSM-IV between April 2001 and September 2002. The mean age of the patients was 76.5 years (men 71.0 years; women 80.5 years). Initial daily doses of quetiapine were established at 25–50 mg/day. The agent was administered once per day (after dinner). In accordance with patient symptoms, the dose and frequency of quetiapine were increased as required. According to Trzepacz's delirium rating scale (DRS),4 the treatment response was evaluated before administration of quetiapine (day 0) and 1, 3, 5 and 7 days after administration was started. As the symptoms of delirium can change over a 24 h period, treatment responses were evaluated by obtaining information from the hospital nurses in addition to a medical examination. Furthermore, the DRS is not considered appropriate when items 1 (time course after onset) and 7 (physical disorder) are serially evaluated.4 Thus, some studies employing the DRS exclude these two items. However, in the present survey all 10 items were evaluated.

In addition, before we began the study we explained to the patients and/or their family that using this medication would not have insurance benefits. We also outlined the potential side-effects of quetiapine use. After we obtained consent, the medical treatment was initiated.

The patients’ backgrounds are shown in Table 1.

Table 1.  Patient background
Itemn = 24
  • Mean (SD).

  • Dementia was diagnosed according to the DSM-IV criteria based on patient information before admission, which was obtained from the patients’ family and information obtained from nurses after admission in addition to consultation.

  • §

    Eight of nine patients with fractures were enrolled in the present study after surgery.

  • Fractures consisted of a pubic fracture in one patient, femoral neck fractures in four patients and femoral trochanteric fractures in four patients.

Mean age (years)
 Total76.5 (9.0)
 Men71.0 (9.1)
 Women80.5 (7.4)
Dementia
 Yes12 (50.0%)
 No12 (50.0%)
Department from which the patient was referred
 Internal medicine 9 (37.5%)
 Orthopedics10 (41.7%)
 Urology 2 (8.3%)
 Neurosurgery 2 (8.3%)
 Dermatology 1 (4.2%)
Physical disease§
 Infection 5 (20.8%)
 Malignant tumor 4 (16.7%)
 Cerebral infarction 2 (8.3%)
 Fracture 9 (37.5%)
 Others 4 (16.7%)

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Effects on delirium

Prior to the administration of quetiapine, the mean ± SD DRS score was 18.1 ± 3.7. Scores were 12.2 ± 5.2, 10.8 ± 4.7, 9.7 ± 4.0 and 8.9 ± 3.9 after 1, 3, 5 and 7 days of quetiapine administration, respectively. These values were significantly lower than the value recorded before administration (P < 0.001). Seven days after administration, the mean DRS score was significantly lower than the score recorded after 1 day of administration (P < 0.05) (Fig. 1). Furthermore, 7 days after administration, the total DRS score was lower than the cutoff point (12) in 20 patients (83.3%). Eleven of these 20 patients did not have dementia. In addition, delirium was clinically relieved in 18 patients (75.0%). Eleven of these patients did not have dementia.

image

Figure 1. Mean ± SD changes in the delirium rating score. (□), Significant to 0th (P < 0.001).

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Dose and administration method

The daily dose of quetiapine ranged from 25 mg to 125 mg, with a mean dose of 54.7 mg. Most patients (10) received a daily dose of 25 mg. Four patients each received 50 mg, 75 mg and 100 mg and two patients received 125 mg. Thirteen patients received the agent once per day (after dinner), comprising the highest percentage. In six patients with daytime psychomotor excitation and aggressiveness, quetiapine was administered three times per day. Four of these six patients also had dementia. In five patients, nocturnal alertness was noted and the agent was administered twice per day (after dinner and before retiring to bed).

Side-effects

Somnolence was observed in three patients. However, in these patients, this side-effect improved after 1–2 days, without decreasing the dose. None of our patients developed extrapyramidal symptoms, hypotension, oversedation or hyperglycaemia.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Effects of quetiapine

The first choice medication for delirium is haloperidol;5 however, theoretical research supporting the validity and safety of haloperidol is rare6 and the effects of haloperidol on delirium are rarely reported.

Haloperidol is frequently associated with side-effects, such as extrapyramidal symptoms, which are more frequent in elderly and seriously medically ill patients. Atypical antipsychotics, such as quetiapine, risperidone and olanzapine are particularly suitable for elderly patients because of the lower incidence of extrapyramidal symptoms.7 In recent years, studies have reported on the treatment of delirium using atypical antipsychotics such as quetiapine,4,8,9 risperidone1 and olanzapine.2,3 It has been reported that five of 11 patients with delirium improved after treatment with olanzapine.2 Another report showed that risperidone was useful in the treatment of 12 (from a total of 13) elderly patients with delirium.1

In the present study, the DRS score significantly decreased 1 day after the administration of quetiapine, and the total DRS score was lower than the cutoff point (12) in 20 patients (83.3%) 7 days after administration began. In addition, delirium was clinically relieved in 18 patients (75%). These findings suggest that quetiapine may be useful in the treatment of delirium and that the efficacy of this agent is rapid, as has been previously reported,3,4 although it is possible that the improvements recorded may have been spontaneous. Further clinical research is necessary to determine the efficacy of quetiapine in the treatment of delirium.

Dose and administration method

In the present study, the mean dose of quetiapine was 54.7 mg/day, which is similar to a value previously reported (46.8 mg/day).6 In addition, the agent was effective at low doses ranging from 25 mg/day to 125 mg/day, as previously shown.8,9

Some studies have reported that quetiapine should be administered before retiring to bed. However, delirium is often exacerbated after dinner and tmax = 1.3 ± 0.6 h.10 Thus, maximal blood concentration may be obtained at the time of retiring, and sleep may be rapidly secured if the agent is orally administered after dinner. We initially administered quetiapine after dinner. In 13 patients (54.2%) this postdinner administration was effective. However, in patients with nocturnal alertness, who did not respond to postdinner administration alone, an additional dose was given before the patient retired to bed. As a result, sleep duration was prolonged. Furthermore, in patients with daytime excitation, quetiapine was administered three times per day and sedation was achieved.

Side-effects

Haloperidol is frequently associated with side-effects including extrapyramidal symptoms. Although adding an anticholinergic agent may decrease these extrapyramidal symptoms, this approach is not ideal because it may exacerbate delirium in the patients.

Previous reports have shown that the appearance of extrapyramidal symptoms with the use of quetiapine is low.7,11,12 In a study comparing quetiapine, haloperidol and a placebo, the rate of the appearance of extrapyramidal symptoms was 4–8% with quetiapine, 37% with haloperidol and 18% with the placebo.11 A comparison with atypical antipsychotics, such as risperidone, reported extrapyramidal symptom appearance rates of 7% with quetiapine and 20.5% with risperidone.12 A study examining quetiapine treatment in elderly patients (over 65 years) with psychotic disorders resulted in infrequent reports of extrapyramidal-related events in 13% of the patients overall and any single extrapyramidal symptom occurred in less than 3% of the patients.7 Thus, the use of quetiapine results in very low rates of extrapyramidal symptoms.

One previous report showed that three of 11 patients with delirium who were treated with haloperidol had extrapyramidal symptoms.2 However in the present study, no patients showed extrapyramidal side-effects.

In the present study, somnolence was observed in three patients (12.5%); however, this side-effect disappeared 1–2 days after the administration of quetiapine began. Although transient somnolence may be characteristic of quetiapine administration, no other side-effects occurred, thus quetiapine can be considered to result in very few side-effects (including very few extrapyramidal symptoms).2,4

Pharmacological discussion

The etiology of delirium varies and the pathogenesis of delirium remains to be clarified. Previous studies suggest that the D2-blocking actions of antipsychotic agents, such as haloperidol, the antihistaminergic actions of an antidepressant, mianserin, α1receptor-blocking actions and 5-HT2 receptor-blocking actions are effective in controlling delirium. Atypical antipsychotic agents exhibit antihistaminergic actions, α1receptor-blocking actions, 5-HT2receptor-blocking actions and D2receptor-blocking actions, as demonstrated for the above agents. The rate and strength of receptor blocking can vary among the agents; however, the efficacy of quetiapine for delirium may be characterized by the rate of receptor blocking by quetiapine.13

CONCLUSIONS

We administered the atypical antipsychotic agent, quetiapine, to 24 patients with delirium. The effects of the agent were rapid and quetiapine can be considered to be useful in treating delirium.

Very few side-effects (extrapyramidal symptoms) were recorded with quetiapine compared to haloperidol. Thus, it is appropriate to trial quetiapine in the treatment of delirium, although it remains controversial as to whether health insurance will cover the use of quetiapine in the treatment of delirium.

Formal clinical trials are necessary to thoroughly examine the efficacy and safety of quetiapine in the treatment of delirium.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. SUBJECTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
  • 1
    Kuniyosi M, Norimasa M, Kazutoyo I et al. Koreisya no sennmounitaisuru risperidone no rinnsyoukouka. Rinsyoutolennkyuu 1998; 75: 228230 (in Japanese).
  • 2
    Sipahimalani A & Masand PS. Olanzipine in the treatment of delirium. Psychosomatics 1998; 39: 422429.
  • 3
    Passik SD & Cooper M. Complicated delirium in a cancer patient successfully treated with olanzapine. J Pain Symptom Manage 1999; 17: 219223.
  • 4
    Trzepacz PT, Baker RW, Greenhous J. A symptom rating scale for delirium. Psychaiatry Res 1988; 23: 8997.
  • 5
    American Psychiatric Association. Practice Guideline For Treatment of Patients with Delirium. Washington: American Psychiatric Association; 1999.
  • 6
    Sasaki Y, Matuyama T, Inoue S et al. Treatment of delirium with quetiapine 2002; 5: 325334 (in Japanese with English abstract).
  • 7
    Tariot PN, Salzaman D, Yeung PP et al. Long-term use of quetiapine in elderly patients with psychotic disorders. Clin Ther 2000; 22: 10681084.
  • 8
    Nakajima M, Nakamura J, Etho Y et al. Clinical effects of quetiapine on delirium with dementia. Rinshoseisinyakuri 2002; 5: 6370 (in Japanese with English abstract).
  • 9
    Sasaki Y, Denda K, Koyama T. Quetiapine for delirium: a three-case study. Seisinigaku 2001; 43: 12531255 (in Japanese with English abstract).
  • 10
    Murasaki K, Simada E, Yosimoto Y et al. Phase I study of quetiapine fumarate (CIC 204,636,Zeneca) on healthy male volunteers. Clin Eval 1999; 27: 101144.
  • 11
    Arvanitis LA & Miller BG. Mulitple fixed doses of seroquel (Quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with Haloperidol and Placebo. Biol Psychiatry 1997; 42: 233246.
  • 12
    Mullen J, Jibson MD, Sweitzer D. A comparison of the relative safety, efficacy, and tolerability of quetiapine and risperidone in outpatients with schizophrenia and other psychotic disorders: the quetiapine experience with safety and tolerability (QUEST) study. Clin Ther 2001; 23: 18391854.
  • 13
    Saller CF & Salama AI. Seroguel: biochemical profile of a potential antipsychotic. Psychopharmacology 1993; 112: 285292.