Blog del Profesor Manuel Gurpegui - Catedrático en psiquiatría.

Nicotine dependence and symptoms in schizophrenia

Publicaciones / Profesor Manuel Gurpegui

Blog: Profesor Manuel Gurpegui – Catedrático y Director del Departamento de Psiquiatría de la Universidad de Granada.

Fecha: 05-03-2005

Autor:

M.Carmen Aguilar

Manuel Gurpegui

Francisco J. Diaz

José de León

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Nicotine dependence and symptoms in schizophrenia

Naturalistic study of complex interactions

Background

Smoking may have a beneficial effect on either schizophrenic symptoms or antipsychotic side-effects, but studies are hampered by the lack of control of confounding factors.

Aims

To explore the self-medication hypothesis in a large sample of stable out-patients with schizophrenia.

Method

Symptoms, assessed with the Positive and Negative Syndrome Scale (PANSS), and number of hospitalisations were compared in 250 out-patients with DSM–IV schizophrenia classified into three categories: highly dependent smokers, mildly dependent smokers and non-smokers. Log-linear analysis was used to control for potential confounding and interacting variables.

Results

High PANSS total scores and positive symptoms were less frequent in mildly dependent smokers than in non-smokers or highly dependent smokers. The highly dependent smokers had the worst outcome.

Conclusions

The data do not generally support the self-medication hypothesis but rather suggest a complex interaction between nicotine dependence and schizophrenic symptoms.

Declaration of interest

None. Funding detailed in Acknowledgements.

Schizophrenia is associated worldwide with a higher rate of smoking than that observed among the general population or those with other severe mental illnesses (McCreadie, 2002; Llerena et al, 2003). This association persists after correcting for such confounding factors as antipsychotic medication, institutionalisation or alcohol and drug use (de Leon et al, 1995, 2002a ; Llerena et al, 2003). Smoking might be a marker of a more severe illness or might have a beneficial effect in schizophrenia by improving its symptoms and/or decreasing extrapyramidal side-effects of antipsychotics – ‘the self-medication hypothesis’ (Lohr & Flynn, 1992; Ziedonis et al, 1994; Dalack et al, 1998). This study explores both the self-medication hypothesis and the hypothesis that severe forms of schizophrenia are associated with high levels of nicotine dependence.

METHOD

Patients

The study was located at two community mental health centres and their rehabilitation unit, covering the catchment area of the city of Granada (southern Spain). All participants received free psychiatric treatment from the national health system. The sample included the first 250 consecutive patients with a diagnosis of DSM–IV (American Psychiatric Association, 1994) schizophrenia who provided written informed consent after a complete description of the study (18 of 278 patients refused to participate; 10 additional excluded patients had a chart diagnosis of schizophrenia but did not meet the DSM–IV diagnosis). The diagnosis was made with the clinician version of a structured diagnostic interview (First et al, 1994). All 250 patients were Caucasians. The mean age was 36.1 (s.d.=9.5) years and the mean age at diagnosis was 21.9 (s.d.=6.0) years. There were 195 males (78%); this male overrepresentation is typical of treatment samples from many countries (Hambrecht et al, 1993), including Granada (Salize et al, 1999).

Twenty per cent had not completed their primary education; 45% had completed primary, 25% secondary and 10% a university education. Most patients (94%, 236/250) were taking antipsychotics, with a mean dose of chlorpromazine equivalents of 550 mg/day (s.d.=459). The frequency of patients taking depot antipsychotics was 45% (113/250); risperidone, 33% (82/250); olanzapine, 6% (14/250); and clozapine, 4% (10/250). There is no reason to believe that the self-reported smoking of these patients was unreliable, because until recently smoking has been socially acceptable in Spain. Moreover, a reliable self-report of smoking or non-smoking status was provided by a subsample of 99 participants (of the 250 studied) whose cotinine in saliva was measured by radioimmunoassay.

Variables

All ratings were conducted by a research psychiatrist (M.C.A.). Table 1 describes the variables used in statistical analyses. In order to avoid bias in the assessment, the clinical evaluation was conducted first, and information concerning medication and substance use, including tobacco and nicotine dependence, was gathered afterwards.

Table 1

All variables were dichotomised except nicotine dependence, which was given three categories. On the basis of the Fagerström Test for Nicotine Dependence (FTND), smokers were classified as very highly dependent (FTND > 47; smoking a median of 40 cigarettes/day) or not very highly dependent (FTND ≤47; median of 20 cigarettes/day) (Fagerström et al, 1990). The three categories will be called highly dependent smokers, mildly dependent smokers and non-smokers. Schizophrenic symptomatology was assessed with the Spanish version of the Positive and Negative Syndrome Scale (PANSS; Peralta & Cuesta, 1994). The PANSS total scores were divided into high (≥45) and low scores. The negative, positive, disorganised, excited, anxious and depressed factors of the PANSS were calculated by adding the scores of the items with a loading higher than 0.50 in the factor (Peralta & Cuesta, 1994), and dividing by the number of those items. Subjects with a score ≥2 for a factor were considered to have clinically significant symptoms (except for the excited factor, see Table 1 footnote). In summary, the presence of symptoms with regard to a factor (e.g. positive symptoms) in these clinically stable out-patients suggests that despite treatment they continue to have sufficient positive symptoms to be identified through a standardised assessment.

The Simpson & Angus (1970) Neurological Rating Scale was used to measure parkinsonian side-effects. Akathisia was assessed with the Barnes Akathisia Scale (Barnes, 1989). Some patients might have extrapyramidal side-effects previously corrected by antiparkinsonian drugs, therefore vulnerability to extrapyramidal side-effects was defined as the occurrence of at least one of the three following conditions: current treatment with antiparkinsonian medication; a score of >0 on the neurological rating scale; or a score of > 0 on the Barnes Akathisia Scale (presence of akathisia).

A high antipsychotic dose was defined as a chlorpromazine equivalent of ≥ 10 mg/kg per day. Current alcohol and caffeine intake was assessed by interview and verified by chart review and collateral information from the family (with whom most patients live in Spain). Owing to the small number of patients using illegal drugs (7%, 17/250), a drug-use variable was not included in the analysis.

Finally, a high number of hospitalisations after correcting for duration of illness was used for the longitudinal definition of the severity of psychiatric symptoms.

Statistics

The Statistical Package for the Social Sciences (version 11.0) was used for calculations (SPSS, 1997). Initially, the three groups were compared by univariate parametric or non-parametric tests, as appropriate. Then, log-linear analyses of the data were performed (Agresti, 1990; SPSS, 1997); the log-linear analyses had two main purposes: they tested the hypothesis of a significant association of nicotine dependence with schizophrenic symptomatology, as measured by either the PANSS total score (or each one of its factors) or the number of hospitalisations; and they described the strength and direction of such association across different combinations of levels of potential interacting variables such as gender, antipsychotic dose/type and caffeine and alcohol intake. Strength and direction of associations were measured with odds ratios and their 95% confidence intervals from cross-tabulations.

In a first analysis, the association between nicotine dependence and PANSS total score was tested while controlling for gender, antipsychotic dose/type and caffeine and alcohol intake. This was performed by including the seven variables in a saturated log-linear model. Table 2 shows the significant interactions that were obtained. The significances of interaction were tested using partial χ²(SPSS, 1997). A significant interaction between two variables was interpreted as evidence that the two variables were associated, even when controlling for the other variables in the model. Analyses similar to that of the PANSS total score were repeated for number of admissions (Table 3) and for negative, positive, disorganised, excited, anxious and depressed PANSS factors (results not presented).

img tab 2

img tab 3

A second purpose of the statistical analyses was to describe the association between nicotine dependence and schizophrenic symptomatology across different combinations of levels of other variables. One difficulty was that the relatively high number of variables considered in this study produced many possible combinations. Some variables represented a small sample size; for instance, the five dichotomous variables (gender, antipsychotic dose and type and caffeine and alcohol intake) produced 2⁵=32 possible combinations of levels. It is not practical or statistically advisable to perform so many cross-tabulations. Because odds ratios are rather inaccurate with small sample sizes, a systematic methodology that discarded irrelevant variables was used (SPSS, 1997). This methodology was based on the collapsibility conditions (Agresti, 1990); the rationale behind the collapsibility conditions is that variables that do not affect an association can be excluded from the analysis of that association (group B of variables in Tables 2 and 3), even if those variables have an effect on one of the variables involved in the association. The above analyses were repeated by including vulnerability to extrapyramidal side-effects as an additional variable.

RESULTS

Among the 250 patients there were 173 (69%) current smokers and 77 (31%) non-smokers (including 7 (4%) former smokers and 70 (27%) that had never smoked daily). As expected, the rate of smoking was higher in our sample than among the Spanish general population (Pinilla & González, 2001) for both males (75% v. 45%) and females (49% v. 27%).

Table 1 shows the variable distribution across the three groups of nicotine dependence. There were no significant differences in current age, age at diagnosis or educational level. The mean (s.d.) PANSS total score was 45.7 (10.7) for non-smokers, 41.7 (9.2) for mildly dependent smokers and 47.9 (14.1) for highly dependent smokers (Kruskal–Wallis χ²=12.0, d.f.=2, P<0.01); had this comparison been made between smokers and non-smokers, no significant difference would have been found: 44.6 (12.1) v. 45.7 (10.7) (Mann–Whitney χ²=1.3, d.f.=1, P=0.25). The mean (s.d.) number of hospital admissions was 2.8 (4.0) for non-smokers, 3.0 (3.0) for mildly dependent smokers and 6.4 (6.3) for highly dependent smokers (Kruskal–Wallis χ²=27.9, d.f.=2, P<0.0001). The levels (median) of cotinine (ng/ml) in saliva in the 99 participants for whom it was determined were: 551 in highly dependent smokers (n=31), 423 in mildly dependent smokers (n=29) and 0.6 in non-smokers (n=29).

Symptom score and nicotine dependence

Table 2 shows results from the log-linear model that included nicotine dependence and the variables listed in the first column. The interaction between nicotine dependence and PANSS total score was significantly different from zero, indicating that these two variables were significantly associated when controlling for the other variables (gender, antipsychotic dose and type, caffeine and alcohol intake). Nicotine dependence was significantly associated with other variables (gender, antipsychotic dose and type, and caffeine intake). Two groups of variables can be identified from Table 2: group A, comprising PANSS total score and antipsychotic dose and type; and group B, comprising gender and caffeine and alcohol intake. Nicotine dependence was associated significantly with all the variables of group A and some variables of group B. However, the variables of group A were not associated with the variables of group B. In fact, no significant interactions simultaneously involving variables of A and variables of B were found. By virtue of the collapsibility conditions, the strength and direction of the association between PANSS total score and nicotine dependence do not vary across the levels of caffeine or alcohol intake, gender or across combinations of those levels. Thus, this association can be studied by controlling only for antipsychotic dose and type.

The association between PANSS total score and nicotine dependence was therefore studied with cross-tabulations for each of the four combinations of antipsychotic doses and types. The association was most significant among those on a low dose of typical antipsychotics (Fig. 1). In these subjects, mildly dependent smokers included the lowest number of subjects with clinically meaningful symptoms in the total PANSS. Among those on a low dose of a typical antipsychotic, non-smokers have an odds ratio of 2.7 of having a high PANSS total score when compared with mildly dependent smokers (Fig. 1). In other words, the percentage of patients with high total scores was significantly lower in mildly dependent smokers than among non-smokers or highly dependent smokers.

Fig. 1

Fig. 1 High Positive and Negative Syndrome Scale (PANSS) total score (≥45, presence of symptoms) among non-smokers (NS, □), mildly dependent smokers (MDS, □) and highly dependent smokers (HDS, □). Numbers above bars indicate percentages. Group 1, all participants. Significance of simultaneous comparisons of the three dependence groups: χ²=7.4, d.f.=2, P<0.02. Odds ratio (95% CI): 2.0 (1.1-8.4) for NS v. MDS; 2.1 (1.9-3.9) for HDS v. MDS. Group II, participants with a low dose of typical antipsychotics: χ²=9.9, d.f.=2, P=0.007. Odds ratio (95% CI) 2.7 (1.1-6.6) for NS v. MDSS; 3.7 (1.6-8.9) for HDS v. MDS. Group III, participants with a low dose of typical antipsychotics and vulnerability to extrapyramidal symptoms: χ²=5.8, d.f.=2, P=0.06.

When vulnerability to extrapyramidal side-effects was also included in the log-linear model, the significant interactions were the same as in Table 2; additionally, a significant interaction between antipsychotic type and vulnerability to extrapyramidal side-effects, and a significant interaction between PANSS total score and vulnerability to extrapyramidal side-effects were found (see footnote to Table 2). The association between PANSS total score and nicotine dependence was close to significant for those on a low dose of typical antipsychotic medication who showed vulnerability to extrapyramidal side-effects (Fig. 1); among these, mildly dependent smokers included the lowest number with clinically meaningful symptoms in the PANSS total score.

The analysis of the positive factor was very similar to the analysis of the PANSS total score and supported the self-medication hypothesis for those on a low dose of typical antipsychotics who are mildly dependent smokers.

Negative, depressive or anxious symptoms were not significantly associated with nicotine dependence (Table 1). Thus, the analyses of these symptoms did not support the self-medication hypothesis. Neither the disorganised nor the excited PANSS factor, after analysis, supported the self-medication hypothesis. Moreover, disorganised residual symptoms were associated with heavy smoking (see next section).

Number of admissions and nicotine dependence

Table 1 shows that highly dependent smokers had the highest proportion of hospital admissions compared with mildly dependent smokers (odds ratio=3.0) and non-smokers (odds ratio=3.9) (see also Fig. 2).

Fig. 2

Fig. 2 High number of hospital admissions among non-smokers (NS, □), mildly dependent smokers (MDS, □) and highly dependent smokers(HDS, □). Numbers above bars indicate percentages. Group I, all participants. Significance of simultaneous comparisons of the three dependence groups: χ²=19.6, d.f.=2, P<0.01. Odds ratio (95% CI) 3.9 (2.0-7.7) for HDS v. NS; 3.0 (1.6-5.7) for HDS v. MDS. Group II, participants without disorganised symptoms: χ²=15.0, d.f.=2, P<0.01. Odds ratio (95% CI) 4.2 (1.9-9.1) for HDS v. NS; 2.6 (1.3-5.2) for HDS v. MDS.

When the disorganised symptom variable was considered in the analysis, the association between nicotine dependence and number of admissions was significant only for those without disorganised symptoms (Fig. 2).

DISCUSSION

The self-medication hypothesis of smoking in schizophrenia

There is a discrepancy in the literature, with numerous animal studies suggesting that nicotine should help negative symptoms but scarce clinical data suggesting that this may be true in those with schizophrenia (Hughes, 2000). Two main sub-hypotheses are usually included in the self-medication hypothesis: smoking reduces the side-effects of antipsychotics; and nicotine may improve schizophrenic symptoms, particularly the negative, cognitive and/or depressive symptoms (Taiminen et al, 1998).

Two mechanisms have been implicated in the reduction of antipsychotic side-effects: a release of dopamine resulting from the administration of nicotine, a notion supported by both acute administration of nicotine in animal models (Drew et al, 2000) and in vivo human studies (Salokangas et al, 2000); and a decrease in antipsychotic blood levels through enzymatic induction. Individuals with schizophrenia who smoke tend to receive consistently higher doses of antipsychotics than non-smokers (Ziedonis et al, 1994; de Leon et al, 1995, 2002a ). The inductive effect of smoking in antipsychotic metabolism therefore is inadvertently corrected by psychiatrists, because smokers tend to be treated with higher daily doses of antipsychotics than non-smokers. When compared with others with severe mental illness in three epidemiological studies in psychiatric hospitals, the effect of antipsychotic medication did not explain the association between schizophrenia and smoking (de Leon et al, 1995, 2002a ; Llerena et al, 2003). Some cross-sectional studies have suggested that smoking reduces antipsychotic side-effects and others have not (Dalack et al, 1998); yet all of these studies are hampered by the lack of control for confounding factors. Longitudinal studies with small samples suggest that, when compared with atypical antipsychotics, typical antipsychotics are associated with increased smoking in some individuals (McEvoy et al, 1995) and with a greater difficulty for quitting smoking (George et al, 2000). Anticholinergic medication was not associated significantly with smoking in this or in previous studies (de Leon et al, 1995, 2002a , b ).

In spite of the hypothesis from animal studies (Drew et al, 2000), very limited clinical data support an association between smoking and a reduction in negative symptoms (Dalack et al, 1998). Data indicating that nicotine may improve sensory gating abnormalities and smooth pursuit eye movements in schizophrenia or cognitive abnormalities induced by antipsychotics are somewhat stronger. Nicotine may have antidepressant qualities in individuals with depression (Salin-Pascual et al, 1996), but this is not well established in those with schizophrenia.

The literature appears to suggest that those with severe forms of schizophrenia may smoke more frequently, and more heavily, than those with less severe forms (Lohr & Flynn, 1992). The possible beneficial effect of nicotine (and smoking) on schizophrenic symptoms and antipsychotic side-effects may be obscured by this association between smoking and severe forms of schizophrenia. In summary, a critical reading of the literature lends very limited support to the self-medication hypothesis, but this effect may be obscured by the association between severe forms of schizophrenia and heavy smoking.

Limitations and strengths of this study

The limitations of the cross-sectional design make it impossible to prove definitively or to deny that smoking has beneficial effects on schizophrenia. It is not ethical to conduct long-term studies by (ideally) randomising patients to heavy or mild smoking. However, our study – involving a great number of stable out-patients with schizophrenia – like other naturalistic studies, may help to select which individuals are more likely to improve their schizophrenic symptoms and/or extrapyramidal side-effects using nicotine patches or other nicotine agonists. Because experimental designs with randomisation (to different levels of smoking and lack of smoking) are not admissible, other naturalistic studies with large samples, refined assessments and sophisticated statistical techniques to control for confounders are needed to confirm these findings.

Our findings suggest that nicotine dependence and schizophrenic symptomatology might be statistically dependent in out-patients with schizophenia, but the data imply a complex interaction between these two variables. Our large sample size and the use of a sophisticated statistical technique, log-linear analysis, made it possible to control for potential confounding and interacting variables (Agresti, 1990). In contrast with other statistical techniques such as multiple linear or logistic regression, the log-linear methodology provides a clearer way to identify and deal with multiple interactions among several variables. In addition, as explained in the statistics section, the methodology used allows the systematic identification of variables affecting the association between nicotine dependence and schizophrenic symptoms, and the identification of subgroups where this association exists. Finally, the log-linear methodology does not imply the assumption of linear relationships among the variables analysed. The results of this study in stable out-patients with low levels of symptoms suggest that such an assumption is unsustainable. One apparent drawback of log-linear methodology is the need to transform continuous variables into categorical ones. Nonetheless, the amount of information that a log-linear analysis produces compensates for the possible loss of some information in the transformation (Agresti, 1990).

One may argue that the association between increased frequency of hospitalisation and high nicotine dependence may be partly explained by institutionalisation. However, this is not likely. Our cross-cultural studies suggest that, although the prevalence of current smoking in the general population is influenced by social pressure, high nicotine dependence among smokers with severe psychiatric illness appears to be similar across countries and remarkably resistant to social pressure (de Leon et al, 2002b ).

Support for the self-medication hypothesis in mildly dependent smokers

The analysis of the PANSS total score, as well as the analysis of its positive symptom factor, supported the self-medication hypothesis for mildly dependent smokers, especially for those taking low doses of typical antipychotics. Those with low levels of total symptoms are overrepresented among mildly dependent smokers compared with non-smokers. It may be that mild levels of smoking were associated with a reduction of schizophrenic symptoms, especially among those taking a low dose of typical antipsychotics (and particularly those showing vulnerability to extrapyramidal side-effects). The differential effect of typical and atypical antipsychotics on smoking behaviour is consistent with other studies with different designs suggesting that those with schizophrenia on typical antipsychotics may smoke more (McEvoy et al, 1995) and have more difficulties in quitting smoking (George et al, 2000).

The possible alleviation of positive symptoms by chronic nicotine administration could be explained by a potential correction of the cortical–subcortical dissociation of dopamine activity, which may be associated with schizophrenia (Dalack et al, 1998). However, in certain cases of schizophrenia (perhaps the most severe), ‘self-medication’, even with higher amounts of nicotine – as in our highly dependent smokers – would not be effective.

In summary, if there is any beneficial effect of nicotine it may be restricted to mildly dependent smokers, and particularly to those on low dosages of typical antipsychotics who are sensitive to the extrapyramidal side-effects. Such a benefit appears to affect only certain symptoms. Our study does not support the self-medication hypothesis for highly dependent smokers, who have poorer outcomes despite their heavy smoking.

Other symptom differences do not support the self-medication hypothesis

In contrast to the positive symptoms, the analyses of negative, anxious and depressive symptoms in our sample do not support the self-medication hypothesis. This does not necessarily refute the hypothesis; the assessment may not have been sensitive enough or the effect size too small to be apparent with the statistical power in our sample. Taiminen et al (1998) similarly found no differences in negative symptoms according to smoking behaviour. Although these two naturalistic studies do not rule out the possibility of beneficial effects of nicotine on negative symptoms, they certainly suggest that the alleviation of other schizophrenic symptoms is more likely. Ziedonis et al (1994) described lower levels of negative symptoms in heavy smokers (and higher levels of positive symptoms), in comparison with light smokers and non-smokers with schizophrenia. Goff et al (1992) found higher levels of both negative and positive symptoms in smokers than in non-smokers, whereas Kelly & McCreadie (1999) were not able to demonstrate significant differences between smokers and non-smokers.

The presence of disorganised symptoms was associated with a high dependence on nicotine in our sample and did not support the self-medication hypothesis.

Poor outcome and heavy smoking

Our results suggest that severe forms of schizophrenia with poor outcome, manifested by either residual disorganised symptoms or a greater number of hospital admissions without residual disorganised symptoms, were associated with heavy smoking. Certainly if nicotine has some beneficial influence in schizophrenia, it is not evident in those with a poor outcome. There are no clear-cut theories to explain the association between highly dependent smoking and poor long-term outcome in schizophrenia. The most likely underlying reason is that these individuals may have vulnerability to both high nicotine dependence and schizophrenia with poor outcome.

Clinical Implications and Limitations

CLINICAL IMPLICATIONS

In out-patients with schizophrenia, smoking behaviour may be related to symptoms, dose and type of medication and vulnerability to extrapyramidal side-effects.
This study provided very limited support for a beneficial effect of nicotine (a beneficial effect is possible in total and positive symptoms in midly dependent smokers when compared with non-smokers). smokers when compared with non-smokers).
High nicotine dependence is associated with poor-outcome schizophrenia.

LIMITATIONS

The limitations of the cross-sectional design make it impossible to prove definitively or to deny a beneficial effect of smoking on schizophrenia.
Although the interviewer made every effort to avoid bias, including the assessment of nicotine dependence at the end of the interview, she was not always blind regarding the smoking status of the patient.
Nicotine dependence assessment was based on patient self-reporting.

Acknowledgements

The authors are grateful to patients and staff of the Granada-South and. Granada-North Community Mental Health Centres and their Out-patient. Rehabilitation Unit, for their collaboration, and to the Institutional Review. Boards of the San Cecilio and Virgen de las Nieves University Hospitals, who. approved this protocol. Juan Rivero helped with data collection. M.C.A.’s work in this study was supported by a grant from the Spanish. Agency for International Cooperation (AECI).

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Caffeine Intake in Outpatients With Schizophrenia

Publicaciones, Blog / Profesor Manuel Gurpegui

Blog: Profesor Manuel Gurpegui – Catedrático y Director del Departamento de Psiquiatría de la Universidad de Granada.

Fecha: 30-04-2004

Autor:

Manuel Gurpegui

M. Carmen Aguilar

José M. Martínez-Ortega

Francisco J. Díaz

José de León

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Abstract

Several studies suggest that caffeine intake is high in patients with schizophrenia and a few of them suggest that caffeine may contribute to schizophrenia symptomatology. None of these studies control for the effect of tobacco smoking, which is associated with induction of caffeine metabolism. Therefore, the high amount of caffeine intake among patients with schizophrenia may be due to their high prevalence of smoking. This is the first large study to explore whether caffeine

intake in patients with schizophrenia is related to tobacco (or alcohol) use or to the severity of schizophrenia symptomatology. The sample included 250 consecutive consenting outpatients with a diagnosis of DSM-IV schizophrenia from Granada, Spain. Fiftynine percent (147/250) of patients consumed caffeine. Current caffeine intake was associated with current smoking and alcohol use. As none of the females used alcohol, the association with alcohol was only present in males with schizophrenia. Among caffeine consumers, smoking was associated with the amount of caffeine intake. Cross-sectional schizophrenia symptomatology was not associated with caffeine intake.

Keywords: Caffeine, coffee, schizophrenia, tobacco smoking, nicotine, alcohol.

Schizophrenia Bulletin, 30(4):935-945,2004.

Caffeine is potentially addictive and is the most widely used psychoactive substance in the world. Caffeine is a competitive adenosin receptor antagonist. Adenosin is a modulator of intracellular signaling that reduces cell excitability. In the central nervous system (CNS), adenosine inhibits the release of acetylcholine, gammaaminobutyric acid (GABA), glutamate, dopamine, norepinephrine, and serotonin. Adenosine Al receptors mediate inhibition of the adenylate cyclase. Adenosine A2 receptors stimulate the adenylate cyclase. Caffeine is an equipotent and nonselective Al and A2 adenosine receptor antagonist. Caffeine releases dopamine (and other amines) in the brain (Benowitz 1990; Donovan and DeVane 2001). Some articles have suggested that selective adenosin agonists may have a role as adjunct therapy in schizophrenia (Ferre 1997; Dixon et al. 1999). Missak (1991) proposed that an endogenous caffeine-like substance may be deficient in schizophrenia.

Caffeine and Schizophrenia

An early review suggested that schizophrenia may be associated with increased use of caffeine (Schneier and Siris 1987). Some early anecdotal reports in institutionalized patients with schizophrenia suggested that some patients were prone to unusual behaviors such as coffee eating (Benson and David 1986; Zaslove et al. 1991Z?) or had exacerbations of their symptoms after increased caffeine intake (Mikkelsen 1978; Hyde 1990; Zaslove et al. 1991b; Kruger 1996). Since institutionalization in other settings, such as prisons, may be associated with an increased caffeine use (Hughes and Bolland 1992; Hughes et al. 1998), it cannot be ruled out that some of these behaviors may be associated with hospital institutionalization.

Polydipsia is also a frequent behavior in severe cases of schizophrenia patients admitted to long-term psychiatric hospitals (de Leon et al. 1994, 1996, 2002a). Polydipsic patients tend to drink high quantities of any liquids and can drink large volumes of caffeinated beverages if they have access to them. A high caffeine intake appears to contribute to the complications of hyponatremia in some polydipsic patients (Kirubakaran 1986). In a 5-year followup of 89 long-term schizophrenia inpatients, Koczapski et al. (1990) found 7 patients with a clear caffeine intoxication (some ate coffee) of whom 3 also had polydipsia with water intoxication. Moreover, water intoxication was only present in the heaviest caffeine consumers.

There are several cross-sectional studies suggesting that caffeine intake is high in patients with schizophrenia (table 1) and that caffeine may contribute to schizophrenia symptomatology (table 2). None of these studies control for the effect of tobacco smoking or alcohol drinking. As described below, tobacco smoking is associated with an induction of caffeine metabolism, and smokers tend to need two to three times more caffeine than nonsmokers to reach the same plasma caffeine levels. Therefore, the high amount of caffeine intake noted among schizophrenia patients may be due to their high prevalence of smoking. As a matter of fact, tobacco smoking is very prevalent in schizophrenia patients worldwide. By combining results from eight studies in several countries, it was estimated that the odds for a patient with schizophrenia to be a current smoker was two times higher than the odds for a patient with other severe mental illness (LLerena et al. 2003). There may be a biological association between schizophrenia and tobacco smoking (Freedman et al. 1997; Dalack et al. 1998). Heavy smoking among smokers may be particularly prevalent in schizophrenia patients (de Leon et al. 1995, 2002fc; Olincey et al. 1997). Therefore, when reviewing studies of caffeine intake in the literature, one needs to take into account that the intake of heavy amounts of caffeine by schizophrenia patients may be associated with smoking and its metabolic effects. Similarly, studies relating caffeine intake with schizophrenia symptomatology should correct for the effects of the association between caffeine intake and smoking. Another confounding factor is alcohol intake, which may be associated with caffeine intake.

In summary, although there are no systematic caffeine surveys controlling for confounding factors in patients with schizophrenia, the available literature suggests that schizophrenia may be associated with caffeine intake. The presence of high prevalences of alcohol drinkers, smokers, and polydipsic subjects among patients with schizophrenia may contribute to this association. Unfortunately, the literature has not distinguished well whether the association between schizophrenia and caffeine intake means that schizophrenia is associated with a higher prevalence of current caffeine intake, with a higher amount of caffeine intake among caffeine consumers, or with both. The association between caffeine intake and schizophrenia symptomatology has not been well established and published studies do not take into account confounding factors (table 2). On the other hand, caffeine intake may confound biological studies in patients with schizophrenia (Hughes and Howard 1997).

Caffeine and Antipsychotics

Previous studies suggested that typical antipsychotics should not be administered at the same time as coffee or tea because they may precipitate (Hirsch 1979). This precipitation is not explained by the presence of caffeine (Cheeseman and Neal 1981; Lasswell et al. 1984). More importantly, recent studies have suggested that caffeine may cause drug interactions with antipsychotics metabolized by cytochrome P450 1A2 (CYP1A2). Clozapine is also metabolized by CYP1A2, therefore caffeine may increase clozapine levels and contribute to side effects (White and de Leon 1996; Carrillo et al. 1998). Without taking this pharmacokinetic interaction into account, it is difficult to interpret changes in caffeine intake in patients taking clozapine (Marcus and Snyder 1995). In summary, patients and physicians should be aware that caffeinated beverages can decrease the metabolism of CYP1A2- dependent antipsychotics (clozapine and olanzapine).

Caffeine Intake in the General Population

In the United States, where caffeine has been better studied, 85 percent of adults drink coffee, tea, or caffeinated sodas daily (Barone and Roberts 1996; Hughes and Oliveto 1997). A great majority of U.S. subjects may have detectable plasma caffeine levels even foods such as peanuts or chocolate have caffeine (de Leon et al. 2003). In the general population, caffeine intake is weakly related to alcohol intake but is moderately to strongly related to tobacco smoking (Istvan and Matarazzo 1984). This relationship between caffeine, alcohol, and nicotine intake may be partly explained by genetic factors(Hettema et al. 1999). When exploring associations with caffeine intake, it is important to distinguish between current caffeine intake, which is a dichotomous variable (consumed or not consumed currently), and amount of caffeine intake, which is a continuous variable. While the former variable is usually described in a group of people by a prevalence, the latter is described by a mean or a median. Some factors may be associated with only one of these variables, while others may be associated with both of them.

Caffeine and Alcohol Drinking

Alcohol intake appears to be associated with caffeine intake and is therefore a potential confounding factor in caffeine studies (Istvan and Matarazzo 1984; Hughes 1996; Hays et al. 1998). Heavy caffeine intake is associated with heavy alcohol intake, but the relationship appears to be weak (Istvan and Matarazzo 1984). Patients with present and past history of alcohol abuse/dependence report high caffeine intake (Istvan and Matarazzo 1984;

Hughes 1996). Besides this epidemiological information, a few animal studies suggest that caffeine treatment is associated with increases in alcohol consumption. It is possible that caffeine may decrease alcohol’s sedating effects, although there is no agreement on this issue (Hughes 1996). In a study exploring the use of alcohol and caffeine in relation to depressive symptoms, alcoholics did not differ from other psychiatric patients in the use of caffeine (Leibenluft et al. 1993).

Caffeine and Smoking

Smokers have a higher caffeine intake than nonsmokers (Swanson et al. 1994), have plasma caffeine concentrations that are two to three times lower than nonsmokers with the same caffeine intake (de Leon et al. 2003), and have increased plasma caffeine concentrations after smoking cessation (Benowitz et al. 1989). The polycyclic aromatic hydrocarbons found in tobacco smoke appear to be inducers of CYP1A2, the caffeine main metabolic pathway (Bertz and Granneman 1997).

In rats, chronic consumption of caffeine accelerates the acquisition of nicotine self-administration, and the exclusión of caffeine from the drinking water of animals maintained on nicotine results in a dramatic response reduction during the first caffeine-free session (Shoaib et al. 1999). Both nicotine and caffeine contribute to psychomotor stimulant effects, but through different neurotransmitter systems. The effects of nicotine appear to be mediated by mesolimbic dopamine systems (Pontieri et al. 1996), whereas the effects of caffeine appear to be mediated by the antagonism of adenosine A2 receptors. The adenosine A2 receptors are located on the same postsynaptic neurons as the D2 dopamine receptors. Adenosin receptors modulate dopaminergic function by regulating dopamine release in presynaptic neurons and intracellular signaling in postsynaptic striatal neurons (Kim and Palmiter 2003). Besides the modulating effects through adenosin receptors, it is posible that caffeine may have some dopamine agonist properties, including agonist actions at D, receptors (Ferre et al. 1991 ;Casasetal. 2000).

In summary, in the general population, smoking is clearly associated with a higher amount of caffeine intake among caffeine drinkers. This may be mainly explained by a pharmacokinetic (metabolic) effect. Current tobacco smoking also appears to be associated with an increased prevalence of current caffeine intake. It is possible that this is related to pharmacodynamic factors (interactions at receptor level) and/or genetic factors.

To conclude this introduction, although there is no agreement on the matter, some cross-sectional studies have suggested that caffeine intake may be associated with schizophrenia symptomatology (table 2). However, the literature provides no systematic surveys of caffeine in patients with schizophrenia controlling for the effects of smoking or alcohol drinking, which are associated with schizophrenia. This current, large study explores whether caffeine intake in patients with schizophrenia is related to the severity of schizophrenia symptomatology, controlling for tobacco and alcohol use. The hypotheses explored in this study are as follows: in patients with schizophrenia, (1) caffeine intake is associated with smoking, (2) caffeine intake is associated with alcohol drinking, and (3) caffeine intake is associated with severity of schizophrenia symptoms. These hypotheses will be explored by using two different variables: current caffeine intake and amount of caffeine intake.

Methods

Sample. The location of the study was at the two Community Mental Health Centers and an outpatient rehabilitation program that cover the catchment area of the city of Granada, in the south of Spain. All patients receive free psychiatric treatment from the national health system. The sample included the first 250 consecutive patients with a diagnosis of DSM-IV (APA 1994) schizophrenia who provided written informed consent after a complete description of the study. The diagnosis was made with the clinician version of a structured diagnostic interview (First et al. 1994). During the recruitment process, a total of 278 consecutive patients were considered to participate in the study. Ten of these patients had a chart diagnosis of schizophrenia but did not meet the DSM-IV diagnosis. Therefore, they were excluded from the study by the research psychiatrist. In addition, 18 DSM-IV schizophrenia patients refused to consent. This left us with the 250 patients. All of the patients were Caucasians, like the majority of the Spanish population. The number of hospitalizations, corrected by illness duration, was used as a historical measure of prognosis.

Scales. Schizophrenia symptomatology was assessed with the Spanish version of the Positive and Negative Symptoms Scale (PANSS), which can be used to provide factor scores (Peralta et al. 1994). The Simpson-Angus Neurological Rating Scale (SANRS; Simpson and Angus 1970) and the Barnes Akathisia Scale (BAS; Barnes 1989) were used to measure extrapyramidal side effects. Those patients treated with anticholinergics or those with a score > 0 in either the SANRS or the BAS scales were considered as having a vulnerability to extrapyramidal side effects. Only one rater, a research psychiatrist (M.C.A.) rated all scales in all patients.

Assessment of Substance Use. Heavy smoking among smokers was defined as smoking 1.5 packs or more per day according to patient’s report (de Leon et al. 1995). The frequency of current smoking among all patients and of heavy smoking among smokers was studied. Nicotine dependence was assessed in smokers by using the Fagerstrom Test for Nicotine Dependence (FTND; Heatherton et al. 1991). Prior studies have found that the FTND has two underlying latent factors: the Smoking Pattern and Morning Smoking factors (Haddock et al. 1999). The Smoking Pattern factor was calculated by adding FTND items 1, 2, 4, and 6. Because the daily number of cigarettes smoked (item 1) loads this factor, it is a measure of nicotine dependence associated with heavy smoking. The Morning Smoking factor was calculated by adding FTND items 3 (“hate to give up morning cigarette”) and 5 (“smoking more in first hours after awaking”) and may be a measure of nicotine dependence that is not influenced by heavy smoking and therefore may be independent of the metabolic effects of heavy smoking. The current use of alcohol and illegal drugs was assessed by patient interview and verified by chart review and collateral information from the family. Patients were asked about their consumption of caffeinated beverages. As in U.S. epidemiological surveys, average weekly amount of caffeine intake was determined by estimating caffeine content in caffeinated beverages and then converting it to mg/kg/day Barone and Roberts 1996; Hughes and Oliveto 1997). In this Spanish sample, the standard caffeine content used for coffee was 100 mg in a 150-cc cup of drip coffee (Bedate 1981). This is a little higher than the U.S. standard of 85 mg in a 5-oz cup of brewed coffee (Barone and Roberts 1996; Hughes and Oliveto 1997). Other European studies considered that European cups of coffee have greater amounts of caffeine than U.S. cups (Rihs et al. 1996). In this study, the standard caffeine content used for caffeinated sodas was 23 mg in a 200-cc glass of soda. This is equivalent to the U.S. standard of 40 mg in a 12-oz cup (Hughes and Oliveto 1997). A high amount of caffeine intake was defined as consuming more than two cups of coffee per day or more tan 200 mg of caffeine/day.

Statistics. The Statistical Package for Social Sciences (SPSS; SPSS, Inc., Chicago, IL) was used for calculations. Odds ratios (ORs) were computed from two-way crosstabulations for univariate analyses. The 95 percent confidence intervals (CIs) for ORs were calculated. The presence-absence of current caffeine intake was the dichotomous dependent variable for a logistic regression analysis using several dichotomous independent variables: current smoking, high dose of antipsychotic medication (> 10 mg/kg/day chlorpromazine equivalents), typical antipsychotics, vulnerability to extrapyramidal side effects, high total PANSS score (> 45), age > 35 years, gender, and alcohol use. A similar analysis was performed for a high amount of caffeine intake (> 200 mg/day) among caffeine consumers. All logistic models fit well according to the Hosmer-Lemeshow Goodness-of-Fit test. Caffeine intake across levels of severity of smoking and schizophrenia symptomatology was studied using Kruskal-Wallis tests.

Results

Sample Description. The mean (SD) age was 36.1 (9.5) years, and mean age at diagnosis was 21.9 (6.0). Seventyeight percent (195/250) were males. The mean (SD) PANSS factor scores were 1.8 (0.7) for the negative, 1.6 (0.9) for the positive, 1.3 (0.5) for the disorganized, 1.1 (0.4) for the excited, 1.7 (0.7) for the anxious, and 1.6 (0.5) for the depressive factor. These scores were low and reflected that patients were stable outpatients. In Spain, patients are not discharged from acute admissions until they are doing well and can live in the community (almost always with their family).

Ninety-four percent (236/250) of patients were taking antipsychotics with a mean (SD) dose of 550 (459) mg/day of chlorpromazine equivalents. Typical antipsychotics were prescribed in 71 percent (177/250) and antiparkinsonians in 37 percent (92/250) of patients. Sixty-nine percent (172/250) of the patients had a vulnerability to extrapyramidal side effects.

The frequency of current smokers was 69 percent (173/250) and the mean (SD) number of packs per day among current smokers was 1.5 (0.7). Heavy smoking was present in 57 percent (98/173) of smokers. Among smokers, the mean (SD) FTND score was 6.8 (2.3). The means (SD) of the Smoking Pattern and Morning Smoking factors were 5.8 (2.0) and 1.0 (0.8), respectively. Current use of alcoho and illegal drugs was present in 21 percent (52/250) and 7 percent (17/250), respectively.

Current Caffeine Intake and Associated Variables in Univariate Analysis. No subjects were consuming tea or over-the-counter medications containing caffeine. Coffee was consumed by 51 percent (127/250) of the patients and caffeinated sodas by 23 percent (58/250). These two percentages overlapped because some patients consumed both types of caffeinated beverages. ifty-nine percent (147/250) consumed at least one type of caffeinated beverage.

Current caffeine intake was reported by 64 percent (125/195) of male and 40 percent (22/55) of female patients. Thus, caffeine intake was significantly associated with male gender (table 3). Current caffeine intake was reported by 69 percent (120/173) of smokers and 35 percent {21 HI) of nonsmokers. Thus, current caffeine intake was significantly associated with current smoking (table 3).

Current caffeine intake was reported by 90 percent (47/52) of alcohol drinkers and 51 percent (100/198) of nondrinkers. Thus, current caffeine intake was significantly associated with current alcohol use (table 3). Current caffeine intake was also significantly associated with treatment using typical antipsychotics (table 3), but vulnerability to extrapyramidal side effects was not significant.

In males, current caffeine intake was present in 36 percent of nonsmokers who did not consume alcohol and in 62 percent of smokers who did not consume alcohol (X2 = 8.5, df= 1, p = 0.004). A further significant increase from 62 percent to 91 percent occurred among males who smoked and used alcohol (x2 = 12.5, df= 1, p = 0.001). None of the female patients consumed alcohol. Therefore, it was not possible to study the association between alcohol and current caffeine intake in females.

Logistic Regression of Current Caffeine Intake.

Current caffeine intake was significantly associated with current smoking and alcohol use (table 3). None of the other independent variables were significant in the logistic regression, although the effect of typical neuroleptics was almost significant (table 3).

High Amount of Caffeine Intake in Caffeine

Consumers. In our sample, 38 percent (94/250) of patients had a high amount of caffeine intake. In the logistic regression within caffeine consumers, the only variable associated with a high amount of caffeine intake was current smoking (corrected OR = 3.8, Cl 11.5, 9.6], x2 = 8.1, df= 1, p < 0.01). The analyses of the median amount of caffeine intake for caffeine consumers in nonsmokers, non-heavy smokers, and heavy smokers suggested a dose effect: the median amount of caffeine intake was 1.3 mg/kg/day in nonsmokers, 2.7 in non-heavy smokers, and 3.4 in heavy smokers (Kruskal-Wallis was x2 = 23.1, df = 2, p < 0.001 for three populations, x2 = 10.3, df = 1, p = 0.001 for nonsmokers and non-heavy smokers; and x2 = 3.0, df = 1, p = 0.08 for non-heavy smokers and heavy smokers).

Caffeine Intake and Schizophrenia Symptomatology. Neither in the total sample nor in caffeine consumers was the amount of caffeine intake associated with scores in the 6 PANSS factors. All mean factor scores were very similar, and far from significant, when compared across high, non-high, and null amount of caffeine intake. The correlations between factor scores and the amount of caffeine intake were not significant and very low (r < 0.1). In the total sample, the nonsignificant correlation between the amount of caffeine intake and the total PANSS score was r = 0.04 (p = 0.6). In current caffeine consumers, the correlation was r = 0.02 (p = 0.9). Similarly, the amount of caffeine intake was not related to the historical prognosis measured by the number of hospitalizations, corrected by the illness duration. In current caffeine consumers who were taking antipsychotics, the nonsignificant correlation between amount of caffeine intake and dose of antipsychotic medication was r – 0.1 (p = 0.2).

Amount of Caffeine Intake and Nicotine Dependence. An attempt was made to xplore whether nicotine dependence might have an effect on the amount of affeine intake independent from the metabolic effect in the liver of smoking. In the 173 smokers, the FIND was significantly correlated with the amount of caffeine intake (r = 0.24, p = 0.002). The metabolic effects of smoking may explain this correlation. As a matter of fact, the significance of the correlation disappeared when controlling for the daily number of cigarettes (partial r = 0.04, p – 0.6). The correlation between the amount of caffeine intake and the FTND Morning Smoking factor (possibly a measure of nicotine dependence independent of heavy smoking) was r = 0.09 (p = 0.2). In summary, both analyses suggest that in smokers, the association between the amount of caffeine intake and nicotine dependence may simply reflect that more dependent smokers smoke more cigarettes, have greater CYP1A2 induction, and therefore may need a higher amount of caffeine intake to deliver caffeine to their brains.

Discussion

Association Between Caffeine Intake and Smoking. Current caffeine intake was associated with current tobacco smoking. Smoking also appeared to have an increasing metabolic effect. Heavy smokers appear to consume more caffeine than non-heavy smokers; nonheavy smokers consume more caffeine than nonsmokers. Once the metabolic effect of smoking was controlled for, nicotine dependence in smokers did not appear any longer to be associated with caffeine intake. Association Between Caffeine and Alcohol Intake. Current caffeine intake was related to current alcohol intake. This was a male effect. In males, the frequency of current caffeine consumers increased with smoking and further increased with alcohol consumption. This complex interaction among current caffeine intake, tobacco smoking, and alcohol use may or may not be present in the general population but has not been appropriately examined by studies investigating the three substances simultaneously (Istvan and Matarazzo 1984).

Lack of Association Between Caffeine Intake and Schizophrenia Symptomatology. The severity of schizophrenia symptomatology was not significantly associated with current caffeine intake or the amount of caffeine intake. This finding appears to be in agreement with three of five prior studies (table 2). The two other studies did not control for confounding effects of smoking, which is associated with caffeine intake.

Because of the cross-sectional nature of our study, it is not possible to rule out that changes in caffeine intake may be associated with changes in schizophrenia symptomatology. Unfortunately, longitudinal studies have not provided clear answers. In a double-blind study, Lucas and Pickar (1990) found that caffeine increased psychotic symptoms in 13 schizophrenia patients in spite of the antipsychotic treatment. Four studies compared the effects of switching from caffeinated to decaffeinated beverages (DeFreitas et al. 1979; Koczapski et al. 1989; Zaslove et al. 1991a; Mayo et al. 1993). In 14 U.S. male long-term inpatients (12 with schizophrenia), the switch to decaffeinated coffee was associated with a decrease in hostility and suspiciousness, and the improvement was reversed when caffeinated coffee was reintroduced (DeFreitas et al. 1979). In 33 Canadian schizophrenia inpatients, 4-week periods of decaffeinated coffee did not consistently improve behavior when alternated with 4- week periods of caffeinated coffee for 16 weeks (Koczapski et al. 1989). In a double-blind crossover study of 26 long-stay English schizophrenia patients there were no changes when patients were switched to decaffeinated beverages (Mayo et al. 1993). In a 1,200- bed U.S. State hospital, the ban of the sale of caffeinated beverages appeared to be associated with a decrease in assaultive behavior (Zaslove et al. 1991a). Due to the lack of control of other variables, it is possible that the decrease in assaultive behavior may reflect other hospital changes (Carmel 1991).

Lack of a Clear Association Between Caffeine Intake and Antipsychotic Treatment. In our study, neither current caffeine intake nor the amount of caffeine intake among caffeine consumers was significantly associated with a presence of extrapyramidal side effects or high doses of antipsychotic medication (typical antipsychotics had an effect in the border of significance in some analyses).

Comparison With the Spanish General Population. Unfortunately, systematic surveys of caffeine intake in Spain are scarce, so comparisons of our patients with the general population are limited. Two areas of Spain conducted systematic and representative health surveys of the population (Anitua and Aizpuru 1996; Jane et al. 2002). These area surveys (Gonzalez-Pinto et al. 1998; Jane et al. 2002) and a national survey (Pinilla and Gonzalez 2001) provide data on tobacco smoking but no data on caffeine intake. After an extensive computer search and inquiring in several universities, only two caffeine surveys could be identified. One included a control group of 1,086 subjects for a study of bladder cancer (Escolar-Pujolar et al. 1993). The other survey was performed by a consumer organization and has very limited data posted in a Web page (Organizaci6n de Consumidores y Usuarios [OCU] 2002). According to these surveys, 60 percent of the Spanish population consumed coffee at least once daily (Escolar-Pujolar et al. 1993) and 66 percent consumed coffee in the previous month (OCU 2002). In our sample, 49 percent (123/250) of patients reported to consume coffee daily and 51 percent (127/250) in the previous month. Caffeinated sodas were consumed by 45 percent of Spaniards in the previous month (OCU 2002). In our sample, 14 percent (36/250) reported to consume caffeinated sodas daily and 23 percent (58/250) in the previous month.

In our sample, 38 percent of patients had a high amount of caffeine intake (> 2 cups of coffee or 200 mg of caffeine/day). In the available Spanish surveys, 27 percent (Escolar-Pujolar et al. 1993) and 24 percent (OCU 2002) of Spaniards had more than two cups of coffee per day. However, these surveys did not measure other caffeinated beverages.

Conclusions

To conclude, this study suggests that in schizophrenia both current caffeine intake and amount of caffeine intake in caffeine consumers may be associated with tobacco smoking. Thus, the apparently excessively high intake of caffeine in schizophrenia patients reported in the literatura may reflect the well-known large percentage of smokers and heavy smokers in schizophrenia patients. In males, current caffeine intake was also significantly associated with current alcohol intake. Current alcohol intake and current smoking may have some kind of interaction, since among male smokers, the prevalence of current caffeine intake was higher among current alcohol drinkers tan among non-current drinkers. In caffeine consumers, a high amount of caffeine intake was not significantly associated with current alcohol intake. Another conclusion of this study is that neither current caffeine intake nor the amount of caffeine intake was significantly associated with the severity of schizophrenia symptomatology, not even after controlling for alcohol or tobacco use. However, owing to the cross-sectional nature of our data, we still cannot rule out the possibility of an association between caffeine intake and schizophrenia symptomatology. Longitudinal studies have to be carried out to address this issue. This is the first systematic survey of caffeine intake in schizophrenia patients that simultaneously takes into account smoking, alcohol intake, and schizophrenia symptomatology. New studies using repeated plasma caffeine levels in patients with schizophrenia and controls will also be needed to better investigate the above observations.

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Acknowledgments

The authors are grateful to patients and staff of the Granada-South and Granada-North Community Mental Health Centers and their outpatient rehabilitation unit for their collaboration and to Institutional Review Boards of the San Cecilio and Virgen de las Nieves University Hospitals who approved this protocol. We wish to thank Juan Rivero, R.N., who works at the Granada-Sur Mental Health Center, for his help with data collection and Margaret T. Susce, R.N., M.L.T., who works at the Mental health Research Center at Eastern State Hospital, Lexington, KY, for her help with editing of this article. M. Carmen Aguilar’s work in this study was supported by a grant from the Spanish Agency for International Cooperation (A.E.C.I.). Dr. Diaz was partially supported by a grant from the Dirección de Investigaciones de la Universidad Nacional, Medellin, Colombia.

The Authors

Manuel Gurpegui, M.D., is affiliated with the Department of Psychiatry and Institute of Neurosciences University of Granada, Granada, Spain, in a position that would be equivalent to U.S. Associate Professor. M. Carmen Aguilar, M.D., rotated through the Department of Psychiatry and Institute of Neurosciences, University of Granada, Granada, Spain, in a position that would be equivalent to a U.S. psychiatry fellowship. This study was part of her doctoral dissertation (an academic requirement in Spain for physicians who want to extend their training). Jose M. Martinez-Ortega, M.D., is a doctoral student for the doctoral program for physicians at the Institute of Neurosciences, University of Granada, Granada, Spain. Francisco J. Diaz, Ph.D., is affiliated with the Department of Statistics, Universidad nacional, Medellin, Colombia, in a position that is equivalent to U.S. Associate Professor. Jose de Leon, M.D., is Medical Director, Mental Health Research Center, Eastern State Hospital, Lexington, KY.

* Estimado lector, este es un blog de divulgación científica dirigido al profesional, estudiante, y en general, a toda persona interesada en el campo de la psiquiatría. La información aquí expuesta, no constituye una recomendación para que usted realice ningún tipo de tratamiento médico o psiquiátrico, ni sustituye la visita a un especialista. Ante cualquier patología, consulte siempre a un profesional de la medicina o de la psiquiatría.

Caffeine Intake in Outpatients With Schizophrenia Leer más »

Psicosis inducida por cannabis una comparación transversal con esquizofrenia aguda.

Psicosis inducida por cannabis: una comparación transversal con esquizofrenia aguda.

Noticias / Profesor Manuel Gurpegui

Blog: Profesor Manuel Gurpegui – Catedrático y Director del Departamento de Psiquiatría de la Universidad de Granada.

Fecha: 3-3-2002

Autor:

Núñez LA, Gurpegui M

Fuente: https://www.ncbi.nlm.nih.gov/pubmed/11939970

OBJETIVO:

La existencia de psicosis inducida por cannabis (CP) sigue siendo controvertida, en parte debido a problemas metodológicos. Hipotetizamos que la esquizofrenia aguda (AS) y la CP pueden tener distintas características demográficas, premórbidas y clínicas.

MÉTODO:

Comparamos a 26 pacientes con PC a 35 con AS, luego de que su estado de consumo de cannabis se confirmó mediante repetidas pruebas de orina. Los pacientes con CP fueron evaluados después de al menos 1 semana pero no más de 1 mes de abstinencia. Los síntomas se evaluaron con el Examen estatal actual (PSE).

RESULTADOS:

En el grupo CP, el sexo masculino, el estado de ánimo expansivo y la ideación, la desrealización / despersonalización, las alucinaciones visuales y las alteraciones del sensorio fueron más frecuentes que en el grupo AS. Los rasgos de personalidad esquizoide premórbidos se asociaron con mayor frecuencia a AS y rasgos de personalidad antisocial a CP.

CONCLUSIÓN:

El uso intenso continuo de cannabis puede inducir un trastorno psicótico distinto de AS. Estas dos entidades clínicas comparten algunas características pero difieren en otras.

* Estimado lector, este es un blog de divulgación científica dirigido al profesional, estudiante, y en general, a toda persona interesada en el campo de la psiquiatría. La información aquí expuesta, no constituye una recomendación para que usted realice ningún tipo de tratamiento médico o psiquiátrico, ni sustituye la visita a un especialista. Ante cualquier patología, consulte siempre a un profesional de la medicina o de la psiquiatría.

Psicosis inducida por cannabis: una comparación transversal con esquizofrenia aguda. Leer más »

Procesamiento visuo-perceptivo en los pacientes con esquizofrenia tratados con antipsicóticos típicos y los tratados con atípicos

Publicaciones / Profesor Manuel Gurpegui

Blog: Profesor Manuel Gurpegui – Catedrático y Director del Departamento de Psiquiatría de la Universidad de Granada.

Fecha: 29-01-2001

Autor:

ROMERA, M. I.* y GURPEGUI, M.**

* Servicio de Psiquiatría. Hospital Universitario Virgen de las Nieves. Granada.

** Departamento de Psiquiatría e Instituto de Neurociencias, Universidad de Granada.

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Procesamiento visuo-perceptivo en los pacientes con esquizofrenia tratados con antipsicóticos típicos y los tratados con atípicos.

Visuo-perceptual processing in patients with schizophrenia treated with typical or atypical antipsychotics

Resumen

Objetivo: Estudio piloto para explorar la posible asociación entre un régimen particular de medicación antipsicótica (AP) y las características clínicas y visuo-perceptivas. Sujetos y método: Una serie de 32 pacientes (25 varones; edad_ DE = 28,1_ 5,1 años, límites 20-39) con esquizofrenia desde hacía al menos dos años (promedio_ DE = 6,0_ 3,6 años), y mantenidos con la misma medicación antipsicótica durante al menos un año, se dividieron en cuatro grupos según su medicación de mantenimiento. La evaluación incluía el empleo de la Escala de los Síndromes Positivo y Negativo (PANSS), la Figura Compleja de Rey, y la Escala BELS de Leff (habilidades de la vida diaria).

Resultados: No hubo diferencias significativas en características demográficas ni en habilidades de la vida diaria. Los pacientes con APs clásicos por vía oral puntuaron significativamente más alto en el factor desorganizativo que quienes tomaban clozapina. En general, los pacientes con APs atípicos obtuvieron mejor resultado en las tareas de percepción y memoria visual (los peores fueron los de decanoato de flufenazina). En el conjunto de los 32 pacientes, el tiempo de copia aumenta con la edad, con puntuaciones más altas en los factores negativo y depresivo, y con más bajas en memoria visual. En la regresión lineal múltiple, sólo la puntuación en memoria visual y la edad siguen siendo significativas.

Conclusiones: A pesar del pequeño tamaño de la muestra, los pacientes con APs atípicos parecen estar mejor, tanto en síntomas como en capacidades visuo-espaciales. La reproducción visual está_ influida por la memoria visual y por la edad.

Palabras clave: Esquizofrenia. Medicación antipsicótica, Tareas visuo-espaciales.

Summary

Objective: This is a pilot study exploring the possible association between a particular antipsychotic (AP) medication regime and both clinical and visuo-perceptual features.

Subjects and method: A series of 32 patients (25 males; mean age± SD = 28.1± 5.1 years, range 20-39) suffering from schizophrenia for at least two years (mean± SD duration of illness = 6.0± 3.6 years), and maintained on the same antipsychotic medication for at least one year, were divided into four groups according to their maintenance medication. Their assessment included the Positive and Negative Syndrome Scale (PANSS), the Rey’s Complex Figure test (visual perception and memory), and Leff’s BELS scale (skills of daily living).

Results: There were not significant differences in demographic features or daily living skills. The patients on oral classical APs scored ignificantly higher on the disorganization factor than those on clozapine. In general, patients on atypical APs did better on the visual perception and memory tasks, with those on fluphenazine decanoate being the poorest. In the whole series of the 32 patients, the copy time increased with age, with higher scores on the negative and the depressive factors, and with lower scores in visual memory. On multiple linear regression, only visual memory score and age remained significant.

Conclusions: In spite of the small sample size, patients on atypical APs seem to be in a better condition, both in symptoms and in visuo-spatial abilities. Visual reproduction is influenced by both visual memory and age.

Key words: Schizophrenia. Antipsychotic medication. Visuospatial tasks.

Actas Españolas de Psiquiatría 2001;29(1): 19-24

La elección correcta del fármaco antipsicótico en el tratamiento de la esquizofrenia se debe basar, en primer lugar, en la respuesta al tratamiento previo, si lo hubo, y en segundo lugar, en el perfil de acción del medicamento (tanto en los efectos terapéuticos como en los secundarios) (1, 2). En la práctica clínica diaria se suelen elegir preparados depot para los pacientes no cumplidores, y clozapina para los refractarios a tratamiento. A veces, características no explicitadas en la historia clínica hacen que se elija un medicamento determinado. Por otra parte, el fármaco que se prescribe puede influir en ciertas características de los pacientes: en el déficit neuropsicológico, particularmente en el procesamiento visuo- perceptivo (3) y en las manifestaciones psicopatológicas, e indirectamente en las habilidades de la vida diaria, moduladas por el deterioro cognitivo (4).

imagen 1 Procesamiento visuo-perceptivo en los pacientes con esquizofrenia tratados con antipsicóticos típicos y los tratados con atípicos

En los pacientes con esquizofrenia es frecuente encontrar un enlentecimiento general de las funciones cognitivas, con particular afectación de los procesos de atención y memoria y de la organización temporal de la conducta (síndrome disejecutivo) (3, 5, 6). También muestran peores resultados en las tareas de percepción y reconocimiento visual (5); en pacientes sin predominio de síntomas negativos se ha detectado un mayor deterioro de la memoria visual en el campo visual derecho, así como un mayor tiempo de reacción en la realización de pruebas específicas, asimetría que confirma la observada en algunos estudios, pero no en otros (3).

En el presente trabajo se describen las características de una serie de casos con esquizofrenia tratados con diferentes regímenes de medicación antipsicótica: antipsicóticos clásicos por vía oral, un antipsicótico depot , los antipsicóticos atípicos olanzapina y risperidona, y el antipsicótico atípico clozapina (reservado a casos «resistentes»). Nos ha interesado analizar particularmente el tiempo de evolución de la enfermedad, la sintomatología actual y el funcionamiento de la percepción y la memoria visual.

PACIENTES Y MÉTODO

Pacientes

Se comparan cuatro grupos de pacientes en función del tratamiento. Grupo 1: nueve pacientes tratados con antipsicóticos clásicos (siete con haloperidol y dos con tioridazina). Grupo 2: siete tratados con decanoato de flufenazina. Grupo 3: ocho tratados con antipsicóticos atípicos (cinco con olanzapina y tres con risperidona). grupo 4: ocho casos resistentes tratados con clozapina. Criterios de inclusión: a) pacientes diagnosticados de esquizofrenia (según criterios DSM-IV y CIE-10), en cualquiera de los subtipos, que estuvieran en tratamiento ambulatorio con antipsicóticos; b) un tiempo de evolución de la enfermedad de al menos dos años; y c) un tiempo de tratamiento con el actual fármaco antipsicótico de al menos un año. Todos los pacientes eran mayores de 18 años y dieron su consentimiento informado.

Criterios de exclusión: a) tener una enfermedad neurológica clínicamente relevante; b) déficit sensorial visual; c) trastorno por uso de sustancias; d) trastorno psicótico breve, trastorno psicótico debido a enfermedad médica o inducido por sustancias; y e) tomar, como tratamiento coadyuvante, fármacos estabilizadores del humor o antidepresivos.

De los 32 pacientes, 25 eran varones (78,1%); su edad media era de 28,1 años (DE= 5,1) y todos tenían una edad comprendida entre 20 y 39 años. El tiempo de evolución medio de la enfermedad era de 6,0± 3,6 años. Dos pacientes habían alcanzado estudios medios y el resto sólo tenían estudios primarios. De los 32 pacientes, 21 habían estado alguna vez incluidos en un programa de rehabilitación.

La dosis diaria de medicación antipsicótica se expresa en mg equivalentes de clorpromazina (2); para el cálculo, 1 mg de risperidona se ha considerado equivalente a 100 mg de clorpromazina; de olanzapina, 3 mg; y de clozapina, 50 mg; para el cálculo de la dosis equivalente de la medicación depot se aplicó la fórmula de Hollister (7). Nueve pacientes tomaban anticolinérgicos, todos ellos biperideno en dosis de 4 mg/día (tabla I).

Procedimiento de evaluación

Los primeros 32 pacientes consecutivamente atendidos que cumplieron los requisitos de inclusión y exclusión fueron entrevistados por la misma profesional (IR). Se les administró la prueba de la Figura Compleja de Rey (8), que evalúa la percepción y la memoria visuoespacial.

imagen 2 Procesamiento visuo-perceptivo en los pacientes con esquizofrenia tratados con antipsicóticos típicos y los tratados con atípicos

Se trata de una prueba no verbal y prácticamente libre de influencias culturales. La figura reúne las siguientes propiedades: ausencia de significado evidente, fácil realización gráfica y una estructura de conjunto lo suficientemente complicada para exigir una actividad analítica y organizadora. Se pide a cada sujeto que realice dos tipos de tareas: primero, copiar la figura que se le presenta; y segundo, después de aproximadamente tres minutos, reproducir la figura sin tenerla a la vista y sin recibir ningún tipo de ayuda.

La evaluación psicopatológica se realizó por medio de la escala PANSS (The Positive and Negative Síndrome Scale ), en la versión española de Peralta y Cuesta (9). Además de la información recogida a partir de la entrevista con el paciente, en algunos casos se entrevistó también a algún familiar que le acompañaba. Los datos psicopatológicos se refieren a la semana previa. Para clasificar a los pacientes en la escala compuesta se utilizó el sistema inclusivo. La puntuación en los factores de la escala PANSS se obtuvo según la fórmula ofrecida por el estudio de validación de la escala en población española (10); es decir, para calcular cada factor, la suma de los elementos con carga superior a 0,50 (en dicho estudio) se dividió por el número de elementos contribuyentes al factor.

El funcionamiento de los pacientes se registró por medio de la escala de habilidades específicas básicas de la vida diaria (escala BELS, de Leff) (11); esta escala valora las habilidades para la convivencia de personas que sufren una enfermedad mental de larga duración. Sólo se utilizó la segunda parte de la escala, que evalúa el nivel real de realización de cada actividad de la vida diaria. La puntuación posible oscila desde la máxima independencia hasta la completa dependencia de otras personas.

Análisis estadístico

Las variables continuas y las ordinales se compararon por medio de la prueba H de Kruskall-Wallis entre los cuatro grupos; en caso de observarse diferencias significativas, se hicieron comparaciones de dos en dos por medio de la prueba U de Mann-Whitney. La distribución de las variables cualitativas se analizó por medio de la prueba de c2 , y los grupos se compararon de dos en dos por medio de la prueba exacta de Fisher. Finalmente, se estudió la relación de las variables dependientes entre sí, y la de éstas con el tiempo de evolución y la edad por medio de la correlación ordinal de Spearman (rs). Para aclarar la relación entre diversas variables, se hicieron cálculos de regresión lineal múltiple. Se utilizó el paquete estadístico SPSS, versión 8.0.

RESULTADOS

Los cuatro grupos no eran significativamente distintos (tabla I) en cuanto a edad, sexo, educación, tiempo de evolución de la enfermedad, estar o no asistiendo a dispositivos de rehabilitación, y dosis de medicación antipsicótica (medida en equivalentes de clorpromazina).

No existían diferencias en las habilidades específicas de la vida diaria. En general, los pacientes eran más independientes en autocuidado y habilidades comunitarias: en autocuidado, 31 de los pacientes eran independientes; en habilidades comunitarias, lo eran 28; y en las actividades y relaciones sociales, 13.

Con respecto a la sintomatología medida con la PANSS, los pacientes se situaban en los percentiles 17-20 de la subescala P, 19-35 de la subescala N, y 20-27 de la subescala PG; en la escala compuesta, en los percentiles 35-43; los pacientes, en general, se encontraban en un rango de gravedad medio-bajo. La puntuación total de la escala PANSS y de sus distintos factores se muestra en la tabla II. Sólo en el factor desorganizativo se observaron diferencias significativas entre los grupos.

En la ejecución de la Figura Compleja de Rey, se encontraron diferencias significativas entre los grupos en exactitud/riqueza de copia, calidad de la copia y patrón de copia. En general, rinden peor los pacientes tratados con decanoato de flufenazina (tabla III). Sólo tres sujetos (dos tomaban haloperidol y uno risperidona) cambian la posición del papel en la prueba, lo que indica torpeza e inmadurez al copiar la figura.

imagen 3 Procesamiento visuo-perceptivo en los pacientes con esquizofrenia tratados con antipsicóticos típicos y los tratados con atípicos

Sólo en dos sujetos (uno en tratamiento con risperidona y otro con olanzapina) la reproducción de memoria es superior a la copia, lo que puede indicar una cierta lentitud en orientarse en un complejo visuo-espacial.

Cuando se comparan los 16 pacientes que tomaban antipsicóticos típicos (grupos 1 y 2) con los que tomaban atípicos (grupos 3 y 4), se ponen de manifiesto diferencias significativas en las siguientes variables: factor desorganizativo de la PANSS (2,79± 1,26 vs 1,76± 0,61; U = 6,50; p = 0,011), número de pacientes con calidad superior de copia (7 vs 14; prueba exacta de Fisher, c2 = 6,79; p = 0,023), puntución en copia (28,7± 3,5 vs 33,2± 3,4; U = 9,59; p = 0,002) y puntución en memoria (14,9± 5,5 vs 20,3± 6,2; U = 5,94; p = 0,015); también se aprecia una tendencia a diferir en el número de pacientes con perseveración al realizar el dibujo (9 vs 3; prueba exacta de Fisher, c2 = 4,80; p = 0,066).

En el conjunto de los 32 pacientes, a mayor tiempo de evolución menor dosis de antipsicótico reciben (rs = –0,38; p= 0,040). Los pacientes utilizan mayor tiempo para la copia cuanto mayor es su edad (rs = 0,35; p= 0,047) y cuanto más alta es su puntuación en el factor negativo de la PANSS(rs = 0,45; p= 0,009) y en el factor depresivo( rs = 0,36; p= 0,030), y cuanto menor es la puntuación de la memoria(rs = –0,43; p= 0,015). Cuanto mejor es la puntuación de la memoria mejor es la puntuación de la copia(rs = 0,45; p= 0,009).

Al tratar de predecir, por medio de regresión lineal múltiple, el tiempo de copia a partir de la puntuación en memoria, los factores negativo y depresivo de la PANSS y la edad, ambos factores de la PANSS dejan de ser significativos y quedan como variables predictoras la puntuación en memoria (coeficitente b estandarizado= –0,510; p= 0,001) y la edad (b = 0,468; p= 0,002).

DISCUSIÓN

Este estudio es un intento de averiguar en qué se distinguen los pacientes con esquizofrenia colocados bajo distinto régimen de medicación antipsicótica. Se puede considerar como estudio piloto y tiene la limitación del reducido número de pacientes incluidos. Por otro lado, tiene la virtud de estudiar pacientes estables en cuanto al tratamiento.

Dado el carácter transversal del trabajo, la atribución de la causalidad siempre será especulativa y poco segura. En concreto, no se puede determinar si las diferencias proceden de la medicación o si características no explicitadas de los pacientes hacen que se les mantenga con uno u otro tratamiento. Por ejemplo, los pacientes no cumplidores tienen más probabilidad de ser tratados con decanoato de flufenazina, o los casos resistentes de ser tratados con clozapina.

La eficacia del tratamiento farmacológico de la esquizofrenia se valora generalmente según la reducción de la sintomatología; sin embargo, los fármacos antipsicóticos pueden producir efectos sobre los déficits neuropsicológicos (12-15), mejorando a su vez el funcionamiento social del paciente. Por tanto, el tratamiento del déficit neuropsicológico debería ser, en lo posible, un objetivo prioritario. Los fármacos antipsicóticos atípicos, debido principalmente a su mecanismo de acción (antagonismo sobre receptores 5HT2 , interacción con las vías glutamatérgicas) y a los menores efectos extrapiramidales, pueden mejorar los síntomas negativos y el deterioro cognitivo en la esquizofrenia (16, 17). Hagger et al (18) observaron, en 36 pacientes tratados con clozapina, mejoría en la memoria verbal a las seis semanas de tratamiento, mejoría que se incrementó a los seis meses, y que entonces alcanzó también a la función ejecutiva y a la atención. Algunos autores (3) recomiendan un tiempo no inferior a un año para evaluar el efecto de un fármaco antipsicótico sobre la función cognitiva; por ello, en nuestro estudio incluimos sólo sujetos que llevaban como mínimo un año en tratamiento.

Los efectos de los fármacos antipsicóticos sobre la función cognitiva están todavía en discusión. En la mayoría de los estudios se ha descrito cómo los fármacos antipsicóticos convencionales pueden mejorar el rendi miento cognitivo en diversas tareas. Sin embargo, los nuevos antipsicóticos (risperidona, olanzapina, clozapina) parecen tener un efecto más favorable sobre los déficits cognitivos que los típicos o convencionales (12- 15,19). Algunos estudios, pero no otros, encuentran diferencias significativas entre unos antipsicóticos atípicos y otros (12). No se conoce hasta qué punto la mejoría cognitiva se debe a efecto directo o indirecto de la medicación antipsicótica (3). Los efectos anticolinérgicos de los antipsicóticos pueden disminuir el rendimiento en las pruebas de memoria; a ello hay que añadir que la toma de biperideno en nuestra serie de casos se concentraba sobre todo en el grupo de decanoato de flufenazina, por lo que no hay que excluir su efecto en el rendimiento de la memoria. No obstante, el hecho de que también la copia está más afectada en ese grupo hace pensar que su menor rendimiento proceda de otros factores.

En nuestros casos estudiados, existe mayor deterioro neuropsicológico en los pacientes tratados con decanoato de flufenazina (que suelen ser previamente pacientes no cumplidores) que en los demás grupos (en la integración de los estímulos visuo-perceptivos y en la realización del análisis visuo-espacial y menor facilidad de construcción gráfica). No encontramos diferencias significativas entre los distintos grupos en memoria visual, que en la mayoría de los casos se encuentra deteriorada.

Son múltiples los estudios (12) que encuentran que los pacientes con esquizofrenia tratados con antipsicóticos atípicos presentan menor sintomatología que los tratados con típicos. En nuestra muestra, sólo encontramos diferencias con respecto al factor desorganizativo: los tratados con clozapina puntuaban menos que los tratados con haloperidol o tioridazina y, en conjunto, los tratados con antipsicóticos atípicos menos que los tratados con neurolépticos clásicos.

El deterioro cognitivo (4, 20) podría tener consecuencias en la calidad de vida del paciente con esquizofrenia, influyendo sobre las habilidades de las que dispone para adaptarse al medio social. No observamos, en la serie de casos analizada, diferencias significativas en las habilidades específicas de la vida diaria; sin embargo, sí hallamos algunas diferencias entre los grupos en cuanto a la integración de los estímulos visuoperceptivos, el análisis espacial y la construcción gráfica de la Figura Compleja de Rey, por lo cual parece que los déficits que afectan a estas funciones no llegan a mostrar su repercusión en el funcionamiento social. Pero no hay que olvidar que nuestro estudio está limitado por el diseño transversal y el pequeño tamaño de la serie de casos (n= 32).

Los déficits neuropsicológicos modulan el funcionamiento social y comunitario del paciente con esquizofrenia (4, 21, 22) y, por tanto, la calidad de vida de éste. Se desconoce si estos déficits influyen en menor o mayor medida que los propios síntomas de la enfermedad: según algunos autores, la función cognitiva predice la adaptación social del paciente en mayor medida que la propia sintomatología; otros concluyen que son los síntomas los que marcan el pronóstico del funcionamiento en la comunidad (23, 24). Tampoco hay datos consistentes que delimiten qué déficits producen de manera más específica una mayor limitación en el funcionamiento social, aunque se han encontrado en diversos estudios relaciones significativas con la memoria verbal, la vigilancia y la función ejecutiva (4, 25).

BIBLIOGRAFÍA

Schatzberg AF, Cole JO, DeBattista C. Manual of Clinical Psychopharmacology. 3ª ed. Washington DC: American Psychiatric Press; 1997. p. 128-30.
American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. Am J Psychiatry 1997;154(Supl 4):1-63.
Bustillo JR, Thaker G, Buchanan RW, Moran M, Kirkpatrick B, Carpenter WT. Visual information processing impairments in deficit and nondeficit schizophrenia. Am J Psychiatry 1997;154:647-54.
Green MF. What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 1996;153:321-30.
O’Donnell BF, Swearer JM, Smith LT, Nestor PG, Shenton ME, McCarley RW. Selective deficits in visual perception and recognition in schizophrenia. Am J Psychiatry 1996;153:687-92.
Keefe RSE, Leesroitman SE, Dupre RL. Performance of patients with schizophrenia on a pen and paper visuospatial working memory task with short delay. Schizophr Res 1997;26;9-14.
Hollister LE. Farmacología clínica de drogas psicoterapéuticas. Madrid: Editorial Médica Panamericana; 1986.
Rey A. Rey – Test de copia y reproducción de memoria de figuras geométricas complejas, ed 6 (versión española de De la Cruz MV, Seisdedos M, Cordero A). Madrid: TEA Ediciones; 1997.
Peralta V, Cuesta MJ. Validación de la escala de los síndromes positivo y negativo (PANSS) en una muestra de esquizofrénicos españoles. Actas Luso-Esp Neurol Psiquiatr 1994;21:44-50.
Peralta V, Cuesta MJ. Psychometric properties of the positive and negative syndrome scale (PANSS) in schizophrenia. Psychiatry Res 1994;53:31-40.
Leff J. Habilidades específicas básicas de la vida diaria. Sevilla: Servicio Andaluz de Salud, Dirección General de Asistencia Sanitaria, Programa de Salud Mental; 1985-1993.
Green MF, Marshall BD, Whirsing WC, Ames D, Marder SR, McGurk S, et al. Does risperidone improve verbal working memory in treatment-resistant schizophrenia? Am J Psychiatry 1997;154:799-804.
Breier A. Cognitive deficit in schizophrenia and its neurochemical basis. Br J Psychiatry 1999;178(Supl 37):16-8.
Friedman JI, Temporini H, Davis KL. Pharmacologic strategies for augmenting cognitive performance in schizophrenia. Biol Psychiatry 1999;45:1-16.
Rosenheck R, Cramer JX, Thomas J, Henderson W, Frisman L, Fye C, Charney D. Department of Veterans Affairs Cooperative Study Group on Clozapine in Refractory Schizophrenia. A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia. N Engl J Med 1997;337: 809-15.
Moore NA. Behavioral pharmacology of the new generation of antipsychotics agents. Br J Psychiatry 1999;174(Supl 38):5-11.
Harrison PJ. Neurochemical alterations in schizophrenia affecting the putative receptor targets of atypical antipsychotics. Br J Psychiatry 1999;174(Supl 38):12-22.
Hagger C, Buckley P, Kenny JT, Friedman L, Ubogy D, Meltzer HY. Improvement in cognitive functions and psychiatric symptoms in treatment-refractory schizophrenic patients receiving clozapine. Biol Psychiatry 1993;34:702-12.
Sharma T. Cognitive effects of conventional and atypical antipsychotics in schizophrenia. Br J Psychiatry 1999;174(Supl 38):44-51.
Citrome L. New antipsychotic medications: What advantages do they offer? Postgrad Med 1997;101:207- 10, 213-4.
Fernández A, González J. Rehabilitación psicosocial en los trastornos esquizofrénicos. En: Sáiz Ruiz J, ed. Esquizofrenia: enfermedad del cerebro y reto social. Barcelona: Masson; 1999.
MacDonald EM, Jackson HJ, Hayes RL, Baglioline AJ, Madden C. Social skill as a determinant of social networks and perceived social support in schizophrenia. Schizophr Bull 1998;29:275-86.
Penn DL, Mueser KT. Research update on the psychosocial treatment of schizophrenia. Am J Psychiatry 1996;153:607-17.
Norman RMG, Malla AK, Cortese L, Cheng S, Díaz K, McIntosh E, et al. Symptoms and cognition as predictors of community functioning: A prospective analysis. Am J Psychiatry 1999;156:400-5.
Velligan DI, Mahurin RK, Diamond PL, Hazleton BC, Eckert SL, Miller AL. The functional significance of symptomatology and cognitive function in schizophrenia. Schizophr Res 1997;25:21-31.

* Estimado lector, este es un blog de divulgación científica dirigido al profesional, estudiante, y en general, a toda persona interesada en el campo de la psiquiatría. La información aquí expuesta, no constituye una recomendación para que usted realice ningún tipo de tratamiento médico o psiquiátrico, ni sustituye la visita a un especialista. Ante cualquier patología, consulte siempre a un profesional de la medicina o de la psiquiatría.

Procesamiento visuo-perceptivo en los pacientes con esquizofrenia tratados con antipsicóticos típicos y los tratados con atípicos Leer más »

Entorno escolar y experiencia docente como factores de riesgo de síntomas depresivos en docentes.

Noticias / Profesor Manuel Gurpegui

Blog: Profesor Manuel Gurpegui – Catedrático y Director del Departamento de Psiquiatría de la Universidad de Granada.

Fecha: 28-1-1998

Autor:

Jurado D ¹ , Gurpegui M , Moreno O , de Dios Luna J .

Fuente: https://www.ncbi.nlm.nih.gov/pubmed/19698603

Una muestra representativa de docentes que trabajan en el nivel primario o secundario en escuelas públicas y privadas respondió a un cuestionario anónimo sobre información sociodemográfica y completó la Escala de Evaluación de Depresión del Centro de Estudios Epidemiológicos (CES-D). Los maestros se clasificaron como deprimidos cuando anotaron 16 en el CES-D; El 27.5% de los sujetos estaban por encima de este puntaje de corte.

La regresión logística se utilizó para calcular un modelo multivariado con las variables propiedad de la escuela, nivel de grado y experiencia docente. Trabajar en una escuela pública, enseñar en el nivel primario y una experiencia docente más larga aumentaron el riesgo de sintomatología depresiva.

* Estimado lector, este es un blog de divulgación científica dirigido al profesional, estudiante, y en general, a toda persona interesada en el campo de la psiquiatría. La información aquí expuesta, no constituye una recomendación para que usted realice ningún tipo de tratamiento médico o psiquiátrico, ni sustituye la visita a un especialista. Ante cualquier patología, consulte siempre a un profesional de la medicina o de la psiquiatría.

Entorno escolar y experiencia docente como factores de riesgo de síntomas depresivos en docentes. Leer más »

Suicidio en Andalucía: resultados epidemiológicos preliminares

Publicaciones / Profesor Manuel Gurpegui

Blog: Profesor Manuel Gurpegui – Catedrático y Director del Departamento de Psiquiatría de la Universidad de Granada.

Fecha: 01-04-1991

Autor:

M. Gurpegui, R. Fernández Villamor, A. Medina, R.A. Palacios, A. González Iglesias

M.J. Moreno, M.A. Muñoz, J. E. Callejas, V. Elvira, E. Fernández Romero, R. Ibáñez

Descargar PDF:

Suicidio en Andalucía: resultados epidemiológicos preliminares

Gurpegui, R. Fernández Villamor, A. Medina, R.A. Palacios,
González Iglesias, M.J. Moreno, M.A. Muñoz, J. E. Callejas, V. Elvira, E. Fernández Romero y R. Ibáñez

RESUMEN

En una zona montañosa del interior de Andalucía se confirmaron altas tasas de incidencia de suicidio consumado, que oscilan entre 27 y 39 por cien mil habitantes y año en las zonas consideradas de riesgo, y entre O y 217 en zonas testigo. Se demuestra la existencia de un pico de incidencia entre los adolescentes, el predominio en la edad tardía y en el sexo masculino y la preferencia, en el conjunto de la población, por el procedimiento de suspensión mecánica.

Palabras clave: Suicidio, epidemiología; Factores de riesgo.

SUMMARY

Suicide in Andalusia: preliminary epidemiological results

High incidence rates of suicide, ranging from 27 to 39 per hundred thousand inhabitants within the risk areas, and from O to 22 within the control areas, were confirmed in certain montainous region of inner Andalusia. In addition to an incidence peak in adolescente, later age and gender male were observed to be risk factors. Hanging was the procedure most frequently used.

Key words: Suicide, epidemiology; Risk factors.

INTRODUCCION

La incidencia del suicidio varía mucho de unos lugares a otros de Andalucía: según datos oficiales (Anuario Estadístico de España, 1985), en 1983 las tasas de suicidio consumado (por cien mil habitantes y año) fueron de 10,1 en la provincia de Almería, 6,1 en la de Córdoba, 8,7 en la de Granada y 8,9 en la de Jaén; 3,2 en la de Cádiz, 3,1 en la de Huelva, 5,6 en la de Málaga y 4,8 en la de Sevilla. Aunque, como en todas partes, las cifras oficiales quedan probablemente por debajo de las reales, queda patente la desigual distribución del suicidio entre las provincias andaluzas (Tabla 1). Además, dentro de cada provincia hay zonas a las que popularmente se atribuye una mayor incidencia de suicidio; para confirmar este supuesto, se ha obtenido información, a través de los registros civiles, acerca de las causas de muerte en áreas a las que se atribuye tal riesgo (zona S) y en otras neutras, que sirven de testigo o grupo control (zona T), entre los años 1980 y 1989. Se han recogido también algunas características sociodemográficas de las personas muertas por suicidio, por accidente o por enfermedad.

Trabajo presentado al VII Congreso de la Sociedad Andaluza de Psiquiatría. Granada, abril de 1991.

* En el trabajo han participado, en Córdoba, E. Fernández Romero, A. Medina y M.J. Moreno; en Granada, J.E. Callejas, M. Gurpegui, R. Ibáñez, M.A. Muñoz, R.A. Palacios; y en Jaén, V. Elvira, R. Fernández-Villamor y A. González Iglesias. El diseño del estudio ha sido realizado por M. Gurpegui, a quien ha de dirigirse la correspondencia: Departamento de Psiquiatría, Facultad de Medicina, Universidad de Granada, E-18071 Granada.

Tabla 1. Suicidios en Andalucía (1983)^*

Provincias	incidencia (por 100.000 hab./año)
Almería	10,1
Jaén	8,9
Granada	8,7
Córdoba	6,1
Málaga	5,6
Sevila	4,8
Cádiz	3,2
Huelva	3,1

^*Datos calculados del Anuario Estadístico de España, 1985, a partir del número de muertes por suicidio y del número de habitantes.

En un estudio posterior, se tratará de esclarecer la participación de factores genéticos o de factores culturales, y la posible interacción entre ellos, en el exceso de riesgo de suicidio consumado. Tales áreas geográficas de presuntas tasas altas de suicidio, podrían servir de manera ideal para analizar la relación entre los factores genéticos y la cultura, incluida la subcultura familiar. De entre estas áreas, en este estudio se ha elegido para análisis la región de los Montes Orientales, que incluye territorios del Sur-Este de la provincia de Córdoba, del Oeste de la de Granada y del Sur-Oeste de la de Jaén. Paralelamente, se han recogido datos de localidades cercanas a las que se atribuye una menor incidencia.

La zona de los Montes Orientales está enclavada en el sistema subbético, se caracteriza por una elevada altitud media y por lo quebrado y sinuoso del terreno. En ella, los recursos económicos proceden de una agricultura relativamente minifundista de olivo y cereal, del trabajo temporero en la hostelería de costas turísticas españolas y en la vendimia francesa y de subsidios de desempleo agrario (Compón et al., 1989).

Los pueblos que componen este área geográfica se caracterizan en general por baja renta per capita y escasez de población. Además, su especial ubicación dificulta la comunicación con el exterior y los mantiene relativamente aislados. No es zona de paso, de modo que, para visitarlos, hay que ir expresamente a ellos; las carreteras de acceso son tortuosas, estrechas y de firme ondulado. De entre los municipios del Sur peninsular, son aquellos en los una mayor proporción de población vive en un habitat disperso, en el que, además, se dan mayores condiciones de marginación que en otras zonas rurales del Sur (en muchos cortijos, falta luz eléctrica y teléfono). Las condiciones y expectativas de vida se mantienen en niveles que en otras zonas de Andalucía son propias del pasado, y la mentalidad de la gente adopta patrones culturales peculiares de la SubBética. Aquí los procesos migratorios se han desarrollado tardíamente, en comparación con otras zonas de cortijos (Compán et al., 1989).

METODO

Los datos incluidos en este estudio se han obtenido directamente de los registros civiles municipales de algunas localidades seleccionadas por su ubicación en la zona considerada popularmente como de elevada frecuencia de suicidios, así como de otras cercanas pero externas a la zona marcada.

La recogida de datos, en la que han participado varios equipos, ha estado guiada por un procedimiento común y presidida por el esquema que a continuación se expone (Tabla 2), cuyos últimos apartados quedan pendientes para fases posteriores del estudio.

Tabla 2. Esquema del protocolo de estudio sobre el suicidio consumado: incidencia y características asociadas

Esquema para la recogida de datos:

Municipios seleccionados (comparación):

1.1. Los de una zona en la que el suicidio se considera endémico (zona S).

1.2. Los de otra zona (testigo) a la que no se atribuye tal característica (zona T) .

Registro anual (1980-89) de fallecimientos en cada municipio, con la catalogación: 1. Por suicidio.

2.2. Por accidente.

2.3. Por enfermedad.

Comparación de los fallecidos, clasificados por la causa de muerte.

3.1. Características sociodemográficas: edad, sexo, nivel educativo, ocupación, clase social, habitat, red social.

3.2. Antecedentes familiares de suicidio y de enfermedad mental.

3.3. Utilización de servicios médicos y de otros servicios de ayuda.

3.4. Estudio cualitativo de la representación mental de la muerte y el suicidio en una
muestra de familias de individuos muertos por suicidio, por accidente o por enfermedad.

Los datos se tabularon de forma que, en la estratificación por sexo, edad y estado civil, los porcentajes se agregaron no por la causa de muerte sino por la característica sociodemográfica; es decir, se alcanzaba el 100 por ciento al sumar, por ejemplo, la proporción de mujeres o la de solteros que murieron por suicidio, por accidente o por enfermedad, en lugar de distribuir el suicidio por sexo, edad o estado civil; así es más directa la posible identificación de las características sociodemográficas como factores de riesgo.

La categoría «por accidente» es posible que incluya, como se reconoce en la mayoría de los estudios epidemiológicos sobre el suicidio, una proporción de casos que podrían constituir suicidio encubierto.

Dado que las poblaciones estudiadas son relativamente pequeñas, los datos de los diez años objeto de estudio se han acumulado para hacer las comparaciones; obviamente, se ha tenido después que dividir por diez para expresar la incidencia en número de casos por cien mil habitantes y año.

RESULTADOS

Se observa tasas de suicidio muy elevadas, que en algunas localidades están en torno a 40/100.000 habs./año (Tabla 3). No en todas las localidades consideradas de alto riesgo se alcanzas tasas tan altas; y en una población del grupo testigo, Fuentevaqueros, situada en la Vega de Granada, sorprende una tasa de 21,7.

Tabla 3. Incidencia de suicidio en algunos lugares de Andalucía, comparada con la de algunos países europeos

Lugar	Incidencia (por 100.000 hab./año)
Países Europeos*
Hungría	40
Reino Unido	10
España	4
Grecia	3
Provincias Andaluzas
Córdoba
Iznajar	39,8
Zuheros	0,0
Jaén
Frailes	44,4
Castillo de Locubín	29,7
Alcalá la Real	25,5
Alcaudete	14,2
Mancha Real	8,3
Granada
Montefrío	35,9
Íllora	13,6
Fuentevaqueros	21,7

*Tomado de Gelder et al. (1989).

En general, la proporción de muertes por suicidio es superior en los varones que en las mujeres, aunque hay en esto alguna llamativa excepción (Tabla 4).

Tabla 4. Distribución de las muertes por suicidio según el sexo*

Provincia		Proporción de muertes por suicidio
Provincia	Total	Varones	Mujeres
Córdoba
Iznájar	5,7	10,4	1,2
Zuheros
Granada
Fuentevaqueros	2,6	3,6	1,8
Íllora	1,8	2,5	1,1
Montefrío	5,7	5,2	6,2
Jaén
Alcalá la Real	3,4	4,7	2,0
Alcaudete	1,7	2,7	0,6
Castillo de Locubín	3,5	3,6	3,4
Frailes	3,6	5,2	2,2
Mancha Real	1,2	2,5	0,0

*Proporción de muertes por suicidio entre el total de muertes, distribuidas por sexo. Los nombres en cursiva corresponden a localidades de la zona testigo.

La proporción de muertes por suicidio es especialmente alta en adultos jóvenes y en adolescentes en algunas localidades (Tabla 5); sin embargo, este fenómeno no es universal, pues no se observa en los municipios de la zona T (Mancha Real, Fuentevaqueros) ni en algunos de la zonas (Alcaudete, Frailes). En edades más avanzadas, la proporción de muertes por suicidio, que no son menos frecuentes, se va diluyendo en un número mayor de muertes por otras causas.

Tabla 5. Distribución de las muertes por suicidio según la edad.

Edad (años)			Localidad
Edad (años)	Alcalá la Real			Iznájar	Mancha Real
0-15	2	(9,0%)	1	(100%)	0	(0,0%)
16-30	3	(11,1%)	5	(38, 5%)	0	(0,0%)
31-40	6	(35,2%)	5	(45,5%)	1	(16,6%)
41-50	7	(15,2%)	6	(24,0%)	1	(11,1%)
51-60	8	(6,9%)	4	(8,9%)	3	(8,3%)
61-70	14	(6,0%)	2	(2,9%)	1	(1,6%)
71-80	10	(2,0%)	4	(3,0%)	1	(0,5%)
81+	4	(0,6%)	2	(0,9%)	0	(0,0%)

En cuanto a la proporción de muertes por suicidio según el estado civil, se aprecia un gradiente descendente entre solteros, casados y viudos, tal como muestran los datos de la provincia de Jaén (Tabla 6); el número de personas divorciadas es escaso para hacer generalizaciones.

El procedimiento preferentemente utilizado es el de suspensión mecánica (ahorcamiento), que en las tres provincias representa las tres cuartas partes de los casos (Tabla 7).

Tabla 6. Distribución de las muertes por suicidio según el estado civil en algunas localidades de la provincia de Jaén.

Proporción de muertes por suicidio

Localidad	Total	Solteros	Casados	Viudos	Divorciados
Alcalá la Real	3,4	8,3	4,7	1,0	0,0
Alcaudete	1,7	4,9	2,1	0,7	0,0
Castillo de Locubín	3,5	9,5	4,9	0,9	0,0
Frailes	3,6	5,5	4,9	0,9	100
Mancha Real	1,2	6,8	1,1	0,3	0,0

Tabla 7. Procedimientos utilizados en la ejecución del suicidio.

		Provincias
Procedimientos	Córdoba	Granada	Jaén
Ahorcadura	72,4	72,2	77,6
Sumersión	10,3	7,4	9,2
Arma de fuego	13,8	13,0	6,1
Degollamiento	3,4	–	–
Precipitación (1)		3,7	3,1
Ingestión (2)		1,9	3,1
Inhalación de gas		1,9	1,0

Incluye también el procedimiento de colocarse en las vías fdrras al paso del tren.
Incluye la ingestión de cáusticos y otro tipo de sustancias.

Como datos particulares, merecen resaltarse los siguientes:

En la provincia de Córdoba, en lznájar el 5,7% de las personas (10,4% de los varones y 1,2% de las mujeres) mueren por suicidio, cuya incidencia en esa población es de 39,8 habitantes/año; en Zuheros, por el contrario, no hubo muerte alguna por suicidio durante los diez años estudiados. En la provincia de Granada, en Montefrío, también el 5,7% de los fallecidos lo fueron por suicidio (el 5,2% de los varones y el 6,2% de las mujeres); su incidencia de suicidio es de 35,9; en Fuentevaqueros, que tiene una incidencia de 21,7, el 2,6% de la población murió por suicidio (3,6% de los varones y 1,8 de las mujeres). En la provincia de Jaén, un 3,4% de los fallecidos en Alcalá la Real lo fueron por suicidio (4,7% de los varones y 2,0 de las mujeres); la tasa de suicidio en este municipio fue, de 27,0%; en Mancha Real, cuya tasa de suicidio fue de 8,3, los suicidios, todos ocurridos en varones, representaron un 1 ,2% del total de muertes.

DISCUSION

La incidencia de suicidio en la zona de riesgo estudiada alcanza índices, según se muestra en la Tabla 3, muy superiores a los globales de España y son comparables a los más altos del mundo (Klerman, 1987; Gelder et al., 1989). El predomino en el sexo masculino, el aumento de frecuencia con la edad y la especial relevancia que en época reciente ha adquirido en la adolescencia son también coincidencias de los datos de este estudio con el consenso general (Klerman, 1987; Gelder et al., 1989). En el suicidio del adolescente, la impulsividad, o el deficiente control de los impulsos, parece desempeñar un importante papel y últimamente se ha observado asociación con el abuso de sustancias (Rich et al., 1986).

Estos resultados preliminares aseguran que la zona objeto de atención reúne excelentes características para analizar los factores genéticos y culturales que facilitan el trágico desenlace por el que una persona se quita su propia vida. Está comprobado que la historia familiar de suicidio se asocia a un mayor riesgo de intento de suicidio (que en muchos casos lleva a la consumación) en personas con muy distintos diagnósticos psiquiátricos (Roy, 1983). Junto al importante peso de la genética, tal como indican los estudios en la comunidad de los Amish (Egeland y Sussex, 1 985), diversos factores individuales y sociales, que han recibido especial atención desde el trabajo pionero de Durkheim en 1892 (Durkheim, 1 969; Klerman, 1987; Tejedor et al, 1988), pueden también tener una importante contribución en un acto de conducta cuya predicción y prevención (Murphy, 1983) merecen cualquier esfuerzo investigador.

BIBLIOGRAFIA

Anuario Estadístico de España (1985). Madrid: Instituto Nacional de Estadística.

Compán D, Rodríguez A, Cabrera MJ (1989). Sistema educativo escolar y marginación en áreas rurales periféricas. El aprovechamiento escolar en el municipio de Montefrío (Granada). En: Asociación de Geógrafos Españoles. Actas del XI Congreso Nacional de Geografía. Madrid: Universidad Complutense de Madrid; pp 51-60.

Durkheim E (1969). Le suicide. Paris: P.U.F.

Egelan JA, Sussex JN (1 985). Suicide and family loading for affective disorders. JAMA, 254: 915-918.

Gelder M, Gath D, Mayou R (1989). Oxford Textbook of Psychiatry, ed. 2. Oxford: Oxford University Press, pp 478-506.

Klerman GI (1987). Clinical epidemiology of suicide. J Clin Psychiatry, 48 (12, Suppl): 3338

Murphy GE (1983). On suicide prediction and prevention. Arch Gen Psychiatry, 40: 343344.

Rich CL, Young D, Fowler RC (1986). San Diego suicide study: I. Young vs old subjects. Arch Gen Psychiatry, 43: 577-582.

Roy A (1983). Family history of suicide. Arch Gen Psychiatry, 40: 971-974.

Tejedor MC, Pericay JM, Castillón JJ (1988). Epidemiología del suicido: factores individuales y sociales. Monografías Médicas Jano, 2: 649-654.

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