Department of Anthropology, University of Auckland, Auckland, New Zealand
Division of Cognitive Neuroscience & Behavioral Neurology, Department of Neurology, University of Iowa Hospitals & Clinics, Iowa City, IA, USA and Department of Anthropology, University of Iowa
Ministry of Health, Koror, Republic of Palau
Behavioral Health Division, Belau National Hospital, Koror, Republic of Palau
Department of Anthropology, University of Auckland, Auckland, New Zealand
Correspondence: John S. Allen, Division of Cognitive Neuroscience & Behavioural Neurology, Department of Neurology - 2RCP, University of Iowa Hospitals & Clinics, Iowa City, IA 52242, USA
Declaration of interest Supported by grants from the University of Auckland Research Council and the New Zealand Schizophrenia Fellowship.
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ABSTRACT |
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Aims To compare the primary and extrapyramidal symptom profiles and substance-using habits of betel chewing v. non-chewing people with schizophrenia.
Method A cross-sectional study of 70 people with schizophrenia. Symptom ratings measured by the Positive and Negative Syndrome Scale (PANSS) and Extrapyramidal Symptom Rating Scale (ESRS), and demographic and substance-use data, were compared for 40 chewers and 30 non-chewers of betel nut.
Results Betel chewers with schizophrenia scored significantly lower on the positive (P=0.001) and negative (P=0.002) sub-scales of the PANSS than did non-chewers. There were no significant differences in extrapyramidal symptoms or tardive dyskinesia.
Conclusions Betel chewing is associated with milder symptomatology and avoidance of more harmful recreational drugs. These initial results indicate that longitudinal research is merited.
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INTRODUCTION |
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Nine alkaloids constitute the active ingredients of betel nut (Farnworth, 1976), the most abundant of which is arecoline - a potent muscarinic agonist that rapidly crosses the blood-brain barrier and induces a range of parasympathetic effects (Asthana et al, 1996). Such cholinergic agents are again receiving attention as potential treatments for psychosis (Bodick et al, 1997; Tandon, 1999). Our principal hypothesis is that the muscarinic action of betel nut may exert a beneficial effect on the symptoms of people with schizophrenia. Since millions of people with schizophrenia live in betel-chewing regions, an increased understanding of the interaction between betel chewing and schizophrenia should benefit clinical treatment.
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METHOD |
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Subjects
Following ethical approval, the study was carried out at the Belau National
Hospital between June and October 1998. The inclusion criteria were chronic
schizophrenia or schizoaffective disorder (with mainly schizophrenic course),
with an established DSM-III or DSM-IV (American Psychiatric Association,
1980,
1994) diagnosis.
Seventy-six informed and consenting out-patients, all indigenous Palauans, completed the study and were paid for their participation. Five subjects with bipolar disorder and one with acute schizophrenia were excluded, leaving a final pool of 70 subjects (49 men and 21 women). Fifty-four subjects were being treated with either haloperidol or fluphenazine (mainly by depot injection) and 48 were receiving anticholingeric medication. No participants were treated with atypical medications.
A recently completed genetic epidemiological study had identified and diagnosed 160 people with strictly defined schizophrenia in Palau (Myles-Worsley et al, 1999). A number of these people were now deceased or off-island, leaving 122 people from the original group; the study sample therefore includes about 57% of the known Palauan schizophrenia population.
Fifty-two subjects (74.3% of the sample) chewed betel nut. However, this group included a proportion of casual users. The serious betel chewer carries a kit of ingredients and is readily distinguishable from the social user, who does not carry chewing paraphernalia but accepts a quid from peers in social situations. The casual users were included in the non-chewing group. After local advice on defining casual user, an arbitrary cut-off point was made at two or fewer betel nuts per day as the criterion for inclusion in the non-chewing group. This cut-off produced a chewing group of 40 and a non-chewing group of 30.
A subgroup of 16 subjects (10 chewers and 6 non-chewers) were not receiving antipsychotic pharmacotherapy and were used as a comparison group to control for the effects of medication.
Instruments
The symptomatology of betel chewers was compared with non-chewers using the
Positive and Negative Syndrome Scale (PANSS;
Kay et al, 1992), the
Extrapyramidal Symptom Rating Scale (ESRS;
Chouinard & Ross-Chouinard,
1979) and a self-report questionnaire of substance-using habits.
In conjunction with demographic details, the substance-use questionnaire asked
about consumption of betel nut, cigarettes, alcohol and marijuana.
Self-reports were supplemented with reference to chart histories of substance
misuse and consultation with case workers.
All rating was carried out by R.J.S. To avoid rater bias, the interviewer was blind to the chewing status of subjects until symptom rating was completed. The test batteries were conducted in English with the assistance of the study participant's case worker - either a psychiatric nurse or social worker. English is the language of instruction in Palauan schools and all subjects spoke English with varying degrees of fluency. The case worker helped each participant to complete the substance-use questionnaire and acted as interpreter when required during the PANSS interview and ESRS assessment that followed. Background information on the participant's social functioning required for the PANSS was obtained from the participant's chart, case worker and family.
Palauan case workers were consulted on the range of PANSS items as they related to each subject, particularly delusional content, communication and cognitive agility, and interpretation of affect. The Structured Clinical Interview for the PANSS (SCI-PANSS; Kay et al, 1992) was translated into Palauan, then back-translated into English to provide a transcultural reference text for the rater and case workers. The westernised similarities and proverbs items of the abstract thinking section of the PANSS were substituted with Palauan expressions and proverbs.
Statistical tests
Differences in scale scores between sample groups were compared using the
independent samples t-test. Non-parametric data were assessed using
the 2-test and the independent samples Mann-Whitney
U-test. Correlations between continuous variables were assessed using
Pearson's r. All tests were two-tailed. The 95th percentile (0.05)
was considered the minimum level of statistically significant difference in
all tests.
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RESULTS |
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Among chewers the average betel nut consumption was 10.6 (5.7 s.d.) whole nuts (18.8 (11.1 s.d.) quids) per day. This figure is probably conservative, as an uncharacteristic dry season, attributed popularly to El Niño, resulted in a shortage of betel nut over the first few months of the study period: 29 members of the chewing group (72.5%) said that they were chewing less frequently than usual.
With the exception of the positive and negative sub-scales (r=0.18), the PANSS sub-scales and total score are significantly intercorrelated. Therefore, although all PANSS sub-scale and symptom cluster data are reported with associated P values, statistically valid scale comparisons should be limited to those between the positive and negative sub-scales.
The mean PANSS scores for the chewing group were significantly lower than those for the non-chewing group on the positive, negative and general psychopathology sub-scales, as was the total score (Table 2). This trend was repeated in symptom cluster measurements of thought disturbance, paranoid belligerence and anergia. Scores on the ESRS of extrapyramidal symptoms (EPS) and tardive dyskinesia (TD) were not significantly different between the two groups. In comparison to a normative United States PANSS sample of 240 medicated North American patients with schizophrenia (Kay et al, 1992), the positive and negative scale scores of non-chewers were average, and those of chewers were slightly below to below average, suggesting that these group-symptomatology profiles are broadly comparable transculturally.
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In the unmedicated subgroup, chewers scored significantly lower on the scale for negative symptoms and the anergia symptom cluster, on the general psychopathology scale and in total score (Table 3). There were no significant between-group differences in positive symptoms. The unmedicated chewers consumed more betel nut than medicated chewers (24.2 v. 18.8 quids/day) with an associated increase in estimated chewing time from 4.7 to 6 h/day (Table 1). No significant differences in EPS or TD scores emerged between the two groups.
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Other substances
Betel chewing was not associated with the use of other recreational
substances, whereas nicotine, alcohol and marijuana consumption were
significantly positively correlated (Table
4).
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A significant negative correlation between cigarette smoking and betel chewing was found, that is, subjects tended to be either exclusively chewers or smokers (Table 4). However, most betel chewers included tobacco as an ingredient of their chewing quid, resulting in a majority of subjects (91.4%) consuming tobacco either as part of a chewing quid or as smoked cigarettes. Smokers, none the less, consumed more tobacco, at an average of 13.8 cigarettes/day v. 6.1 for those who included tobacco in the betel quid.
Alcohol and marijuana consumption were not significantly related to PANSS symptom scores. The relationship between cigarette smoking and schizophrenia symptoms was a reversal of the betel data: the total PANSS score of the smoking group was significantly higher than that of the non-smoking group (t=3.13, P=0.002).
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DISCUSSION |
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Our results indicated that betel chewing is associated with less severe
symptoms of schizophrenia as measured by the PANSS. Chewers scored
significantly lower than non-chewers on the positive and negative symptom
measures of the PANSS. The symptom score differences between groups were
modest for the total group and balanced between positive and negative
symptoms. When only subjects not receiving medication were considered, the
group difference was substantial, mainly for negative symptoms. Among all
subjects, the group total scores of chewers were significantly lower than
those of non-chewers (60.5 v. 77.3, t= -4.1,
P0.001) and among unmedicated subjects the difference in mean
total PANSS score between chewers and non-chewers was dramatic (57.7
v. 84.0, t= -2.3, P=0.04).
Muscarinic agonists in schizophrenia
The main study hypothesis, that betel chewing may exert a beneficial effect
on the primary symptoms of schizophrenia, is supported by these results, and
the muscarinic agonist action of the most abundant betel nut alkaloid,
arecoline (Farnworth, 1976),
provides the most promising pharmacological explanation for this effect.
Despite ambiguous results in early research (Davis et al, 1978), a number of researchers propose that cholinergic agents may modulate dopaminergic hyperactivity and prevent the emergence of positive symptoms (Friedhoff & Alpert, 1973; Davis et al, 1978; Tandon & Greden, 1989; Tandon, 1999). Research suggests that muscarinic agonist derivatives of arecoline may exert an atypical-like action, ameliorating both negative and positive symptoms. Bodick et al (1997) report that the selective M1 agonist xanomeline, a thiadiazole derivative of arecoline (Moltzen & Bjornholm, 1995), produced dose-dependent reductions in delusions, hallucinations and other psychotic behaviours in a clinical trial with patients diagnosed with Alzheimer's disease. Shannon et al (1998) performed preclinical rodent studies assessing the use of xanomeline as an antipsychotic and produced results consistent with the performance of atypical agents. They conclude that "xanomeline may provide a novel approach to the treatment of psychosis with potential for a rapid onset of action, efficacy against positive and negative symptoms, and with little or no liability to produce extra-pyramidal side-effects" (see also studies on other muscarinic agents by Bymaster et al (1998) and Shannon et al (1999)).
Betel nut arecoline may have similar effects to those of its derivatives described above. Betel chewers hold the betel quid in the buccal cheek cavity, utilising an absorption route that avoids first-pass metabolism and maintaining betel alkaloids in the blood stream for extended periods. The non-selective agonist action of arecoline may exert a crude atypical-like antipsychotic effect, in conjunction with the parasympathetic effects routinely tolerated by habitual users. Such an action may explain the favourable effect on negative symptoms and the generally mild EPS and TD among betel-chewing subjects with schizophrenia.
Extrapyramidal symptoms and tardive dyskinesia
Extrapyramidal symptoms resulting from betel nut consumption have been
reported previously (Deahl,
1989). As discussed above, no significant differences emerged in
ratings of EPS or TD between chewers and non-chewers. Additionally, no
significant differences emerged in dosages of neuroleptic or anticholinergic
medication.
Despite compliant (i.e. mainly depot) long-term neuroleptic medication with substantial dosages for many subjects, symptoms of TD were fairly infrequent among the study participants. Unambiguous TD symptoms, such as choreoathetoid or bucco-lingual movements, were seen in only 7 of the 70 participants (10%). In comparison, a previous analysis of 76 studies (n=39187) has reported a TD prevalence of 24.2% cross-culturally (Yassa & Jeste, 1992).
Other substances
In accordance with findings reported elsewhere
(Chong & Choo, 1996), our
results show that smokers' PANSS scores were significantly higher than
non-smokers'. The possibility that the favourable association between PANSS
score and betel chewing is an artefact of non-smoking is unlikely, because
most chewers consumed tobacco in their quid.
Similarly, the finding that betel nut tends to be used to the exclusion of other substances is of interest, but is unlikely to explain the favourable association between betel chewing and milder symptoms of schizophrenia, as neither marijuana nor alcohol consumption were significantly related to group PANSS scores.
Social variability
Betel chewing is a social activity in Micronesia and it may be associated
with milder symptomatology simply because the practice itself is indicative
of, or marks a return to, normal social functioning
(Wilson, 1979). However, a
social functionality explanation for group differences in scale scores is not
supported by the data, since there were no significant chewing v.
non-chewing group differences in regard to demographic indicators of social
functionality - marital status, number of children, living situation or
employment status. Additionally, an assessment of social functioning is
implicit in the structure of the PANSS instrument via input from family
members and case workers. However, a suitable social functioning instrument is
recommended in any subsequent research to more directly clarify associations
between social functioning and betel chewing.
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CLINICAL IMPLICATIONS AND LIMITATIONS |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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REFERENCES |
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Received for publication September 6, 1999. Revision received February 21, 2000. Accepted for publication February 24, 2000.