Department of Psychiatry, University of Granada
Department of Psychiatry and Institute of Neurosciences, University of Granada, Granada, Spain
Department of Statistics, Universidad Nacional, Medellin, Colombia
Mental Health Research Center at Eastern State Hospital, Lexington, KY, USA
Correspondence: Manuel Gurpegui, Department of Psychiatry and Institute of Neurosciences, Faculty of Medicine, Av. Madrid 11, E-18071 Granada, Spain. Tel: +34 958240704; Fax: +34 958246187; e-mail: gurpegui{at}ugr.es
Funding detailed in Acknowledgements.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 nicotine dependence and schizophrenic symptoms.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
METHOD |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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.
|
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 2 (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).
|
|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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
(KruskalWallis 2=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)
(MannWhitney
2=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
(KruskalWallis
2=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.
|
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).
|
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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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 corticalsubcortical 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 |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
LIMITATIONS
![]() |
ACKNOWLEDGMENTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders (4th edn) (DSM-IV). Washington, DC: APA.
Barnes, T. R. E. (1989) A rating scale for drug-induced akathisia. British Journal of Psychiatry, 154, 672 -676.[Abstract]
Dalack, W., Healy, D. & Meador-Woodruff, J. H.
(1998) Nicotine dependence in schizophrenia: clinical
phenomena and laboratory findings. American Journal of
Psychiatry, 155, 1490
-1501.
de Leon, J., Dadvand, M., Canuso., C., et al (1995) Schizophrenia and smoking: an epidemiological survey in a state hospital. American Journal of Psychiatry, 152, 453 -455.[Abstract]
de Leon, J., Tracy, J., McCann, E., et al (2002a) Schizophrenia and tobacco smoking: a replication study in another US psychiatric hospital. Schizophrenia Research, 56, 55 -65.[CrossRef][Medline]
de Leon, J., Becoña, E., Gurpegui, M., et al (2002b) The association between high nicotine dependence and severe mental illness may be consistent across countries. Journal of Clinical Psychiatry, 63, 812 -816.[Medline]
Drew, A. E., Derbez, A. E. & Werling, L. L. (2000) Nicotinic receptor-mediated regulation of dopamine transporter activity in rat prefrontal cortex. Synapse, 38, 10 -16.[CrossRef][Medline]
Fagerström, K. O., Heatherton, T. F. & Kozlowski, L. T. (1990) Nicotine addiction and its assessment. Ear Nose and Throat Journal, 69, 763 -765.[Medline]
First, M. B., Spitzer, R. L., Gibbon, M., et al (1994) Structured Clinical Interview for DSM-IV Axis I Disorders (Clinician Version). Washington, DC: American Psychiatric Association.
George, T. P., Ziedonis, D. M., Feingold, A., et al
(2000) Nicotine transdermal patch and atypical antipsychotic
medications for smoking cessation in schizophrenia. American
Journal of Psychiatry 157, 1835
-1842.
Goff, D. C., Henderson, D. C. & Amico, E. (1992) Cigarette smoking in schizophrenia: relationship to psychopathology and medication side effects. American Journal of Psychiatry, 149, 1189 -1194.[Abstract]
Hambrecht, M., Maurer, K. & Hafner, H. (1993) Evidence for a gender bias in epidemiological studies of schizophrenia. Schizophrenia Research, 8, 223-231.[CrossRef][Medline]
Hughes, J. F. (2000) Evidence for and against the self-medication hypothesis for smoking. International Journal of Neuropsychopharmacology, 3 (suppl. 1), S58-S59.
Kelly, C. & McCreadie, R. G. (1999) Smoking
habits, current symptoms, and premorbid characteristics of schizophrenic
patients in Nithsdale, Scotland. American Journal of
Psychiatry, 156, 1751
-1757.
Llerena, A., de la Rubia, A., Peñas-Lledó, E. M., et al (2003) Schizophrenia and tobacco smoking in a Spanish psychiatric hospital. Schizophrenia Research, 60, 313 -317.[Medline]
Lohr, J. B. & Flynn, K. (1992) Smoking and schizophrenia, Schizophrenia Research, 8, 93-102.[CrossRef][Medline]
McCreadie, R. G., on behalf of the Scottish Comorbidity Study
Group (2002) Use of drugs, alcohol and tobacco by people with
schizophrenia: case-control study. British Journal of
Psychiatry, 181, 321
-325.
McEvoy, J. P., Freudenreich, O., Levin, E. D., et al (1995) Haloperidol increases smoking in patients with schizophrenia. Psychopharmacology, 119, 124 -126.[Medline]
Peralta, V. & Cuesta, M. (1994) Psychometric properties of the Positive and Negative Syndrome Scale (PANSS) in schizophrenia. Psychiatry Research, 53, 31-40.[CrossRef][Medline]
Pinilla, J. & Gonzáalez, B. (2001)
Profile of the population of Spain with respect to the smoking habit, period
1993-1997. European Journal of Public Health,
11, 346
-351.
Salin-Pascual, R. J., Rosas, M., Jimenez-Genchi, A., et al (1996) Antidepressant effect of transdermal nicotine patches in nonsmoking patients with major depression. Journal of Clinical Psychiatry, 57, 387 -389.[Medline]
Salize, H. J., Küstner, B. M., Torres-Gonzalez, F., et al (1999) Needs for care and effectiveness of mental health care provision for schizophrenic patients in two European regions: a comparison between Granada (Spain) and Mannheim (Germany). Acta Psychiatrica Scandinavica, 100, 328 -334.[Medline]
Salokangas, R. K., Vilkman, H., Ilonen, T., et al
(2000) High levels of dopamine activity in the basal ganglia
of smokers. American Journal of Psychiatry,
157, 632
-634.
Simpson, G. M. & Angus, J. W. S. (1970) A rating scale for extrapyramidal side effects. Acta Psychiatrica Scandinavica, 212 (suppl.), 11 -19.
SPSS (1997) SPSS Advanced Statistics 7.5. Chicago, IL: SPSS Inc.
Taiminen, T. J., Salokangas, R. K., Saarijarvi, S., et al (1998) Smoking and cognitive deficits in schizophrenia: a pilot study. Addictive Behaviors, 23, 263 -266.[CrossRef][Medline]
Ziedonis, D. M., Kosten, T. R., Glazer, W. M., et al (1994) Nicotine dependence and schizophrenia. Hospital and Community Psychiatry, 45, 204 -206.[Medline]
Received for publication February 25, 2004. Revision received September 9, 2004. Accepted for publication September 10, 2004.
HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Psychiatric Bulletin | Advances in Psychiatric Treatment | All RCPsych Journals |