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Keywords:

  • antipsychotics;
  • aspiration pneumonia;
  • schizophrenia;
  • smoking;
  • substance P

Abstract

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

Aspiration pneumonia is a serious health concern in older patients with schizophrenia. In this study, we examined clinical and demographic variables that could impact the plasma substance P level, which is a useful predictive biomarker of aspiration. Thirty-four patients were included (mean age ± SD: 70.9 ± 10.8 years). A greater number of cigarettes/day and a higher antipsychotic dosage were found to be associated with a lower plasma substance P level, while age showed a trend-level effect. This finding suggests the need for intensive observation for prevention of aspiration pneumonia in heavy smokers who are receiving a higher antipsychotic dose in this senior population.

CASES OF ASPIRATION pneumonia are common, but they generate serious health concerns, especially in patients with schizophrenia, due to the use of antipsychotic drugs that often result in a diminished swallowing reflex.1 Cough and swallowing reflexes are an important defense mechanism to counteract aspiration,2 and substance P is a neuropeptide that plays a principal role in these reflexes.3 Impairments in these reflexes are reportedly correlated with the incidence of pneumonia in post-stroke patients.4 Hence, this substance has been suggested to be a useful predictive biomarker of aspiration,3 and possibly aspiration pneumonia. Consistent with this fact is that the exposure to antipsychotic drugs has been reported as disturbing the swallowing reflex in humans1 and decreasing the plasma substance P level in guinea pigs.5 Furthermore, a recent cross-sectional survey showed that the use of haloperidol was associated with a diminished swallowing reflex and lower plasma substance P level in patients with chronic schizophrenia.5 In addition, smoking has also been reported to disturb the cough reflex.6 Given long-term antipsychotic treatment and the high smoking rate in schizophrenia patients,6 this is expected to be especially important in senior patients who are subject to age-related physiological changes. As an initial step for effective monitoring and successful intervention for aspiration, we conducted a cross-sectional study to examine clinical and demographic variables that could impact the plasma substance P level in older patients with chronic schizophrenia.

METHODS

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

Subjects

Inpatients at Sakuragaoka Memorial Hospital were included if they were 60 years of age and older, met the DSM-IV criteria for schizophrenia, had been treated with a stable medication regimen for at least 1 week, and were capable of providing informed consent.

Thirty-four patients were included in this study. Mean age ± SD and duration of illness were 70.9 ± 10.8 years and 45.5 ± 13.7 years, respectively.

Procedures

A plasma sample was taken between 06.00 and 07.00 hours and centrifuged at 3000 rpm for 8 min within 1 h. Within 30 min after centrifugation, plasma was mixed with a stabilizing agent and frozen at −30°C. The plasma substance P level was then assayed, using enzyme-linked immunosorbent assay, at Kyowa Medex Assay Center. Demographic and clinical variables collected included age, sex, duration of illness, smoking status, and antipsychotic dosage.

Daily doses of antipsychotics were converted to chlorpromazine equivalents (CPZE).7 Subjects who received <300 mg/d and ≥600/d mg CPZE were considered to belong to low- and high-dose groups, respectively, while others were sorted to a standard dose group, in accordance with the Schizophrenia Patient Outcomes Research Team Treatment Recommendations.8

This study was approved by the institutional review board of Sakuragaoka Memorial Hospital, and all participants provided informed consent.

Statistical analysis

Statistical analyses were carried out using spss 17.0 (spss Inc., Chicago, IL, USA). To examine the effects of various characteristics altogether, a univariate general linear model was used with the following variables: antipsychotic dosage (i.e. high-, standard- and low-dose groups), class of main antipsychotics (i.e. first- and second-generation antipsychotics), cigarettes/day and age on the plasma substance P level. The model was generated with main effects and significant 2-way interaction terms. Pearson's r was calculated to examine the correlation between the primary variables of interest. A P-value <0.05 was considered statistically significant and all tests were two-tailed.

RESULTS

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

Mean CPZE antipsychotic dose ± SD was 361 ± 337 mg/day; 17, eight, and nine patients were grouped into the low-, middle-, and high-dose groups, respectively.

A univariate general linear model showed significant effects of antipsychotic dose groups (F(2,21) = 3.72, P = 0.04) and cigarettes/day (F(1,21) = 4.77, P = 0.04) on the plasma substance P level (Corrected Model: F(7,21) = 3.01, P = 0.02, R2 = 0.50). The plasma substance P level was higher in the standard-dose group (47.9 ± 22.0 pg/mL) than in the high-dose group (31.1 ± 13.0 pg/mL) and the low-dose group (24.2 ± 4.6 pg/mL). The plasma substance P level was inversely correlated with the number of cigarettes/day (Pearson's r = −0.386, P = 0.024) (Fig. 1). No statistically significant difference was found in the substance P level between patients treated with first-generation antipsychotics and those with second-generation antipsychotics (F(1,21) = 0.40, P = 0.54).

image

Figure 1. The plasma substance P level was inversely associated with the number of cigarettes/day (Pearson's r = −0.386, P = 0.024).

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DISCUSSION

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

The main findings of this study are: (i) the number of cigarettes per day was inversely associated with the plasma substance P level; and (ii) plasma substance P level was lower in the high-dose group than that in the standard-dose group.

Although smoking has been shown to diminish the cough reflex,6 the mechanisms are still unknown. In light of the finding that the plasma substance P level was low in heavy smokers in the present study, this substance may be one of the potential mechanisms underlying cough suppression in smokers. As the smoking rate is very high in patients with schizophrenia,9 smoking secession is expected to be beneficial to prevent aspiration pneumonia in this population.

An antipsychotic drug, haloperidol, has been shown to be associated with a diminished swallowing reflex and a lowered plasma substance P level in schizophrenia.10 Consistent with this observation, the high-antipsychotic-dose group showed a lower plasma substance P level than the standard-dose group, suggesting that excessive antipsychotic dosing might disturb substance P production and therefore cough and swallowing reflexes. This might highlight the need for careful observation for potential aspiration pneumonia in senior patients with chronic schizophrenia who are receiving higher antipsychotic dosage. On the other hand, paradoxically, the plasma substance P level in the low-dose group was lower than that in the standard-dose group. However, it is more likely that a subgroup of older individuals have a low substance P level already at the baseline. Moreover, clinicians tend to prescribe lower doses to these patients in response to the observed clinical sensitivity, resulting in the lower plasma substance P level in the low-dose group. In fact, five out of the six patients who had suffered aspiration pneumonia within the previous year were receiving low antipsychotic doses. Still, given the methodological limitations as described below, these preliminary findings need to be confirmed in future investigations.

There are several limitations in this cross-sectional study. First, although significant effects of antipsychotic dosage and smoking status on the plasma substance P level were observed, a small sample size is a major concern, which warrants further investigations. Second, due to the nature of the cross-sectional study design, a causal correlation between the substance P level and antipsychotic dosage cannot be determined. Third, this study did not evaluate the actual incidence of aspiration pneumonia, which needs to be addressed in prospective trials. Fourth, the number of cigarettes was evaluated on a daily consumption and not cumulative (pack-years) basis. Finally, a failure to find a significant age effect on the level could be due to a type II error. Given these limitations, proactive results of this study should be interpreted as preliminary.

In conclusion, a greater number of cigarettes/day and a higher antipsychotic dosage were found to be associated with a lower plasma substance P level in senior patients with chronic schizophrenia, emphasizing the need for intensive observation for aspiration pneumonia in heavy smokers who are receiving a high antipsychotic dosage. Further investigations, including a prospective study to examine associations among reflex activities, cigarette smoking, and incidence of pneumonia with a larger sample size, are warranted to elucidate the effects of plasma substance P level on clinical outcomes in patients with schizophrenia.

ACKNOWLEDGMENTS

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

Some of these data were presented at the 19th annual meeting of the Japanese Society of Clinical Neuropsychopharmacology, Kyoto, Japan, 14 November 2009.

The authors gratefully acknowledge Drs Satoru Iwashita, Sachiko Irie, and Yuki Kikuchi for their continuous support and insightful advice.

REFERENCES

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