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BRITISH JOURNAL OF PSYCHIATRY (2006),(2006),188,122^127 188, 122^127

Schizophrenia, neuroleptic examined 1–6 weeks later by the Mobile Clinic of the Social Insurance Institution and mortalityy (SII) in two phases: a screening phase and a diagnostic (clinical) phase. The measure- ments of the screening phase, the methods MATTI JOUKAMAA, MARKKU HELIOHELIOVAARA,«VA AR A, PAUL KNEKT, used for studying chronic diseases and the ARPO AROMAA, RAIMO RAITASALO and VILLE LEHTINEN basic results of the Mini-Finland Health Survey have been previously described in detail (Aromaa et aletal, 1989; MaMakela¨kela¨ et aletal,, 1993). People with a disease history, symp- toms or findings suggestive of chronic dis- eases were asked to participate in the Background There is an excess of Excess mortality among people with schizo- diagnostic (clinical) phase, which was on death from natural causes among people phrenia is partly a result of suicide (Brown, average 3.5 months after the screening 1997; Harris & Barraclough, 1998; Heila¨ examination. Cardiovascular and respira- with . &Lo& Lonnqvist,¨ nnqvist, 2003) but is also attributable tory diseases, diabetes and other somatic Aims Schizophrenia and its treatment to natural deaths (Brown, 1997; Morten- conditions were diagnosed on the basis of sen, 2003), obviously explained by dietary medical history, symptoms, physical with neuroleptics were studied for their and lifestyle factors (Brown, 1997) and examination and findings of the screening prediction of mortalityinmortality in a representative possibly by use of neuroleptics (Montout phase (Aromaa et aletal, 1989; MaMakela¨kela¨ et aletal,, population sample of 7217 Finns aged 553030 et aletal, 2002; Ray & Meador, 2002). Most 1993).1993). years. studies have included small and non- representative series of patients, short Screening procedure MethodMethod A comprehensive health follow-up and no control for confounding The methods used and the basic findings factors. In a representative population examination was carried out at baseline. concerning mental disorders in the Mini- sample over a long follow-up period, we Schizophrenia was determined using the Finland Health Survey have been described found schizophrenia to be associated with in detail elsewhere (Lehtinen et aletal,, Present State Examination and previous excess mortality. In males this was owing 19901990aa,,bb). The screening for mental dis- medicalrecords. to cardiovascular diseases (especially orders comprised several parts. We tried coronary disease), suicides and respiratory to make the screen as sensitive as possible ResultsResults During a17-year follow-up, 39 diseases and in females to cerebrovascular in order to minimise the number of false- oftheof the 99 people with schizophrenia died. and respiratory diseases (Joukamaa et aletal,, negative cases, as no screen-negative people 2001). In the present study schizophrenia Adjusted for age and gender, the relative were invited to participate in the clinical and its treatment with neuroleptic medi- mortalityriskbetweenthose with schizo- phase of the study. The most important cation were studied for their prediction of phrenia and others was 2.84 (95% CI part of the screen was the 36-item version mortality. We aimed to assess the effects of the General Health Questionnaire (Gold- 2.06^3.90),andwas2.06^3.90),andwas2.25(95%CI1.61^3.15) 2.25(95% CI1.61^3.15) of socio-demographic and lifestyle factors berg, 1972). People were also invited to after further adjusting for somatic and somatic health on the mortality participate in the clinical phase if the differentials. diseases,bloodpressure, bloodpressure,cholesterol,bodycholesterol,body records in the SII indicated that they were mass index, smoking, exercise, alcohol receiving a disability pension because of a mental disorder or were entitled to re- intakeandeducation.Thenumberofneuro- METHOD lepticslepticsused used atatthe the time ofofthe the baseline imbursement for medication for such dis- orders (according to the National Health The current study was based on the Mini- survey showed a graded relationrelationto to Insurance Scheme in Finland, all psychoses Finland Health Survey (Aromaa et aletal,, mortality.Adjusted for age, gender, entitle the individual to free medication 1989). This comprehensive survey, carried somatic diseases and other potential risk for their treatment). People were also se- out between 1978 and 1980, was designed lected if they reported having used health factors for premature death, the relative to assess the health of adult Finns. The services (including those provided by a gen- riskwasrisk was 2.50 (95% CI1.46^4.30) per study population was a two-stage cluster eral practitioner) for a mental disorder or sample drawn from the population register increment of one neuroleptic. there was a self-perceived mental disorder. and stratified to represent Finns aged 30 A total of 35% of those who participated Conclusions Thereis anurgentneedto years or over. The first stage comprised in the screening phase were identified by the selection of 40 representative areas. In ascertainwhetherascertain whether thehighmortalityinthe high mortalityin various screening instruments; 95% of the second stage a systematic sample of schizophreniais attributabletothe disorder these agreed to participate in the clinical inhabitants was drawn from each area. phase of the health examination. itself or the medication. The sample size was 8000 persons, of whom 7217 (90%) participated in the Declaration of interest None. health examination (Aromaa et aletal, 1989).,1989). Case-finding procedure The participants were first interviewed The most important method of psychiatric ySee invited commentary,p.128, thisissue. at home by local public health nurses and case identification in the clinical phase

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was use of the short version of the ninth schizophrenia was also recorded in the RESULTSRESULTS edition of the Present State Examination screening phase and was categorised (PSE; Wing et aletal, 1974), which was admi- according to the number prescribed. At At baseline a number of lifestyle-related nistered by a psychiatric nurse. Training the time of the baseline assessment the factors and chronic diseases were asso- in the use of the PSE was provided by those following conventional neuroleptics were ciated with the prevalence of schizophrenia. who developed the method. The diagnoses the only neuroleptic drugs in use in Finland: Since some of the associations seemed to were obtained via the computer program with an aliphatic side-chain differ between men and women, all these CATEGO–ID (Wing et aletal, 1978). Diag- (, , levome- results were stratified according to gender nostic information was also obtained from: promazine); phenothiazines with a methyl- (Tables 1 and 2). Heavy smoking and case notes of participants in in-patient psy- side-chain (, obesity were significantly associated with chiatric care; SII records on disability pen- ); phenothiazines with a schizophrenia in both men and women, sions granted because of a mental disorder piperazine-ethanol side-chain (perphen- whereas being underweight proved to be a and on reimbursement for medication to azine, , ); phe- significant determinant only in men, and treat psychoses; examination by the physi- nothiazines with a piperidine side-chain diabetes and other somatic diseases in cian in the clinical phase of the survey; (, pericyazine, ); women. Inverse associations with schizo- and assessment by the psychiatric nurse (, clopen- phrenia emerged for alcohol intake and conducting the PSE interview. A panel of thixol, flupenthixol, thiothixene); butyro- serum HDL cholesterol in both men and two psychiatrists reviewed the case notes phenones (, , women; in women there was an inverse of in-patients and the psychiatric records ); (); benza- association for exercise and in men for entitling individuals to SII benefits (disabil- mides (); and indoles (oxyperine). systolic pressure. ity pensions and reimbursement for medi- A number of factors may be associated The age- and gender-adjusted relative cines) to validate the diagnoses. For the both with schizophrenia and mortality and risk of total mortality between people with final diagnostic assessments, a special com- could therefore confound the analysis. schizophrenia and others was 2.84 (95% CI puter program was designed that combined Age, gender, level of education, smoking, 2.06–3.90). The risk of mortality was in- information from various sources, taking alcohol intake, exercise, body mass index, creased among people with schizophrenia into account the degree of certainty and systolic and diastolic pressure, serum total even after controlling for potential risk eliminating mutually incompatible and HDL cholesterol, diabetes, cardio- factors for premature death (low level of assessment combinations. There were 99 vascular and respiratory diseases and other education, smoking, alcohol intake, exer- people with a diagnosis of schizophrenia, somatic diseases were therefore considered cise, body mass index, systolic and diastolic giving an age-adjusted prevalence of 1.3% potential confounders or effect modifiers pressure, and total and HDL cholesterol) with no gender difference (Lehtinen et aletal,, in the present study (Brown, 1997; and coexistent somatic diseases (Table 3). 19901990aa); this was in accordance with an ear- Mortensen, 2003). As there was no difference between men lier population study in Finland (Vaisanen, and women in the association between 1975).1975). schizophrenia and mortality, they were The mortality of those examined has combined in these analyses. been systematically monitored since the There were only four unnatural deaths baseline assessment. This information was Statistical analysis among those with schizophrenia. Adjusted obtained from the Central Statistical Office Logistic regression was used to estimate the for age and gender, the relative risk of of Finland. The principal causes of death associations between the potential con- natural death between people with schizo- were coded according to ICD–8 (World founding and effect-modifying factors and phrenia and others was 2.80 (95% CI Health Organization, 1974). During a the prevalence of schizophrenia. The gener- 2.00–3.93). follow-up from 1978 until 1994 the al linear model was used to compute multi- Of the 99 people with schizophrenia, numbers of deaths (in parentheses deaths of ple partial correlation ratios between those 20 were taking no neuroleptic drug at base- people with schizophrenia) were as follows factors and the number of neuroleptic drugs line, 31 one drug, 34 two drugs and 14 (see Joukamaa et al, 2001): a total of 1597 among participants with schizophrenia. three or more drugs. The most commonly (39) deaths occurred; 876 (17) were caused Cox’s proportional hazards regression used neuroleptic was thioridazine (34%), by any cardiovascular disease; 130 (8) by model (Cox, 1972) was used to estimate followed by (20%), chlor- respiratory diseases; 341 (7) by cancers; the strength of the association between promazine (19%), (14%), 72 (2) by injuries; and 20 (2) by suicides. schizophrenia and mortality and between chlorprothixene (13%) and haloperidol The definitions and measurement of neuroleptic drug use for schizophrenia and (12%); use of other neuroleptics was less lifestyle and related factors (level of edu- mortality. The number of neuroleptic drugs than 10%. Among participants with schizo- cation, exercise, smoking, alcohol intake, for schizophrenia was included both as a phrenia, there was a strong inverse re- body mass index, systolic and diastolic categorical variable and as a continuous lationship between serum HDL cholesterol blood pressure, serum total and high- variable in the model. Potential confound- and the number of neuroleptic drugs pre- density lipoprotein (HDL) cholesterol) have ing and effect-modifying factors were scribed (correlation coefficient¼770.41,0.41, been described in more detail elsewhere entered into the Cox models. Adjusted rela- PP550.001) thatremained statistically (Aromaa(Aromaa et aletal, 1989; MaMakela¨kela¨ et aletal, 1993).,1993). tive risks and their 95% confidence inter- significant after adjustmentadjustment for age, gender, Participants were asked about drugs pre- vals (CIs) were estimated based on this all lifestyle-related factors and coexistent scribed by their physician. The use of model. The SAS software package version somatic diseases (partial corre- neuroleptic drugs among people with 6.12 (SAS Institute, 1997) was used. lationlation¼770.31,0.31, PP¼0.007). Smoking was

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Ta b l e 1 Relative risk for schizophrenia according to putative determinants of premature death and coexistent somatic diseases

VariableMen Women

nn Schizophrenia, nn RR95% CI nn Schizophrenia, nn RR95% CI

Age, yearsyearsAge, 30^44 134315 1.001.00 11 137316 1.00 11 45^5445^54 78116 1.85 0.91^3.77 828 21 2.21 1.15^4.251.15^4.25 55^64 60310 1.49 0.67^3.34 745 80.92 8 0.920.39^2.16 65^74 43643630.61 3 0.610.18^2.13 642 70.93 7 0.93 0.38^2.280.38^2.28 557575 159 21.132 1.13 0.26^5.00.26^5.0 307307 11 0.280.280.04^2.10 Education Lower 224535 1.00 2660266041 1.00 AverageAverage 69280.72 8 0.72 0.33^1.590.33^1.59814 10 0.710.710.34^1.46 Higher 38530.48 3 0.480.15^1.60 421 22 0.260.260.06^1.11 Smoking Never 98010 1.00 302938 1.00 Quit 1136 90.759 0.75 0.30^1.870.30^1.87369 40.86 4 0.860.30^2.44 Pipe, cigar or 5520 cigarettes per day677 14 2.04 0.90^4.62 385 51.03 5 1.030.40^2.67 5520 cigarettes per day 52913 2.502.501.08^5.76 112 64.416 4.41 1.77^10.971.77^10.97 Alcohol intake NoneNone 91527 1.00 238147 1.00 1^99 g/week 16661666 1212 0.220.220.11^0.44 1414 60.176 0.170.07^0.40 100^249 g/week 23723710.12 1 0.120.02^0.91 48 0 55250g/week250 g/week 50450460.35 6 0.35 0.14^0.860.14^0.8652 0 Body mass index (kg/m22)) 5520.020.0 12410 9.51 4.11^22.01 235 31.37 3 1.370.39^4.75 20.0^24.920.0^24.9 1346 1515 1.001.00 160017 1.00 25.0^29.9 146414 0.81 0.38^1.68 1351 12 0.85 0.40^1.82 30.0^34.930.0^34.9 35135151.19 5 1.190.43^3.32 558 12 2.24 1.03^4.85 5535.0 3724.84 2 4.841.06^22.19 151 95.989 5.982.54^14.04 Exercise NoneNone 108519 1.00 1551155133 1.00 Low level or occasional 164221 0.72 0.38^1.35 1835 18 0.42 0.23^0.76 High level and regular 59150.47 5 0.470.17^1.28 50350320.16 2 0.160.04^0.69 Chronic diseases Cardiovascular No 219632 1.00 2628262834 1.00 YesYes 112614 0.82 0.42^1.62 1267 19 1.32 0.69^2.53 Respiratory No 249230 1.00 348849 1.00 YesYes 83016 1.64 0.88^3.06 407 40.70 4 0.700.25^1.97 DiabetesDiabetes No 314743 1.001.00 3658365844 1.00 YesYes 1753 1.261.26 0.38^4.210.38^4.21237 94.15 9 4.151.85^9.32 OtherOther No 257033 1.00 2728 28281.00 YesYes 75213 1.36 0.70^2.640.70^2.641167 25 2.33 1.32^4.11

RR, relative risk. 1. Unadjusted.

also associated with the number of neuro- multifactorial analysis (partial correlation was related to the subsequent mortality. Of leptics prescribed (correlation coefficient¼ ¼0.27,0.27, PP¼0.14).0.14). people with schizophrenia taking one, two 0.35,0.35, PP¼0.007), but the association did The number of neuroleptic drugs and three or more neuroleptic drugs, 11 not reach statistical significance in the prescribed at the time of the baseline survey (35%), 15 (44%) and 8 (57%) respectively

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Ta b l e 22Tab Odds ratio for schizophrenia according to blood pressure and cholesterol levels

Variable Men Women

Means.d. OR 95% CI11 Means.d. OR 95% CI95%CI11

Diastolic pressure, mmHg 88.611.8 0.82 0.61^1.110.61^1.1186.1 11.711.7 1.221.220.92^1.60 Systolic pressure, mmHg 144.821.2 0.53 0.37^0.770.37^0.77147.8 26.0 0.82 0.57^1.18 HDL cholesterol, mmol/l 1.590.4 0.70 0.50^0.980.50^0.98 1.791.790.4 0.470.470.34^0.65 Total cholesterol, mmol/l 6.91.3 1.041.040.78^1.39 7.0 1.4 1.17 0.88^1.55

OR, odds ratio; HDL, high-density lipoprotein. 1. Per an increment of 1 s.d.

Ta b l e 33Tab Relative risk of mortality in people with schizophrenia (nn¼99) compared with others (nn¼7118) afterafter7118) estimates were 1.69 (0.42–6.80), 4.75 adjustment for potential confounding factors (1.95–11.53), 2.53 (0.63–10.21) and 5.35 (1.33–21.55). Factors adjusted for RR95% CI DISCUSSION None (unadjusted) 2.011.46^2.76 Age, gender 2.84 2.06^3.902.06^3.90 Main findings Age, gender, level of education, systolic pressure, diastolic pressure, 2.212.21 1.58^3.081.58^3.08 The present study demonstrated a graded total and HDL cholesterol, body mass index, smoking, alcohol intake relationship between the number of neuro- and exercise leptic drugs prescribed and mortality of Age, gender, cardiovascular disease, respiratory disease, diabetes and 2.89 2.10^3.982.10^3.98 those with schizophrenia. This relationship other somatic disease and the excess mortality among people with schizophrenia could not be explained All the factors and diseases above 2.252.251.61^3.15 by coexistent somatic diseases or other RR, relative risk; HDL, high-density lipoprotein. known risk factors for premature death. To our knowledge this was the first study Ta b l e 44Tab Relative risk of mortality among people with schizophrenia (nn¼99) per an increment of one to analyse such associations in the general neuroleptic drug after adjustment for potential confounding factors population using a prospective design. Although the excess mortality of people Factors adjusted for RR95% CI with schizophrenia was first demonstrated before the Second World War, the causes None (unadjusted) 1.431.03^1.99 have varied over the years, especially before Age, gender 1.701.20^2.41 the neuroleptic era (see Brown, 1997). It Age, gender, level of education, systolic pressure, diastolic pressure, 2.291.38^3.80 has been claimed that the contemporary total and HDL cholesterol, body mass index, smoking, alcohol intake high natural mortality in schizophrenia and exercise results from a variety of lifestyle factors Age, gender, cardiovascular disease, respiratory disease, diabetes 1.691.17^2.45 (Brown, 1997; Mortensen, 2003). Of these factors we were able to consider several and other somatic disease (smoking, exercise, body mass index, blood All the factors and diseases above 2.502.501.46^4.30 pressure, serum total and HDL cholesterol), RR, relative risk; HDL, high-density lipoprotein. but not all (e.g. dietary factors). However, after adjustment for these factors the excess died during follow-up, whereas the drugs in the whole of the study population, mortality of people with schizophrenia corresponding rate was 5 (20%) among the 68 people taking neuroleptics for other persisted. Similarly, comorbid somatic those without neuroleptic medication. psychoses were excluded. Adjusted for age diseases did not account for the mortality. Table 4 shows the relative risk of dying and gender, people with schizophrenia tak- Obviously there are other factors associated among those with schizophrenia per incre- ing no neuroleptic, one, two and three or with mortality in schizophrenia and the ment of one neuroleptic drug adjusted for more neuroleptic drugs had relative risks association with neuroleptic drugs was very age, gender, lifestyle-related factors and (95% CI) of 1.29 (0.53–3.11), 2.97 (1.64– clear. This remained after adjustment for chronic somatic diseases. Irrespective of 5.38), 3.21 (1.93–5.35) and 6.83 (3.40– many different potentially confounding the factors modelled, the relationship 13.71) respectively compared with those factors. At the time of the baseline survey between number of neuroleptic drugs and without schizophrenia or any antipsychotic only classic neuroleptic drugs were in use mortality remained strong and statistically treatment with neuroleptics. The associa- in Finland.inFinland. significant.significant. tion remained stable throughout the obser- It is now well known that most or all To assess the combined effect of schizo- vation period. Even after excluding the first classic neuroleptics can cause prolongation phrenia and the number of neuroleptic 10 years of follow-up, the corresponding of the QT interval of the electrocardiogram

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which is associated with the potentially fatal arrhythmia torsade de pointes CLINICAL IMPLICATIONS (Witchel(Witchel et aletal, 2003). Recently, in a large study RaystudyRay et aletal (2001) showed that && The somatic health of people with schizophrenia is an important issue. prescription of moderate doses of antipsy- chotics was associated with large relative && The use of classical neuroleptic drugs is associated with mortality in schizophrenia. and absolute increases in the risk of sudden && A combination of neuroleptic drugs seems to increase the risk of mortality. cardiac death. It has been proposed that antipsychotic drugs might also be asso- LIMITATIONS ciated with venous thrombosis, pulmonary embolism (Thomassen et aletal, 2001) and && The statistical power of the present study was insufficient for subgroup analyses. asthma mortality (Joseph et aletal, 1996). These && associations could explain at least some of Since the baseline assessment was completed in the1970s, it was not possible to the deaths from respiratory diseases in the use standardised criteria for schizophrenia. present study. && We were not able to analyse the total period of neuroleptic use and the total dosage.dosage. Neuroleptic polypharmacy The risk of dying increased in our study if the participants were taking more than one neuroleptic drug. This is in line with previous findings. Waddington et aletal MATTI JOUKAMAA, MD,PhD,Tampere School of Public Health,University of Tampere and Department of « (1998) found that receiving more than one Psychiatry,TamperePsychiatry,TampereUniversityHospital,Tampere;MARKKUHELIOVAARA,MD,PhD,PAULKNEKT,PhD, University Hospital,Tampere; MARKKUHELIOVAARA,MD,PhD,PAULKNEKT,PhD, ARPO AROMAA, MD, PhD, National Public Health Institute, Helsinki; RAIMO RAITASALO, PhD, Social antipsychotic concurrently was associated Insurance Institution, Helsinki; VILLE LEHTINEN, MD,PhD,NationalMD, PhD, National Research and Development Centre for with reduced survival in a 10-year follow- Welfare and Health, Helsinki, Finland up of 88 people with schizophrenia. In a French study the mortality among patients CorrespCorrespondence:Drondence:Dr Matti Joukamaa,DepartmentofJoukamaa,Department of SoSocialcial Psychiatry,Tampere School of Public Health, with chronic schizophrenia was associated University of Tampere, FIN-33014, Finland. E-mail: matti.joukamaa@@uta.fiuta.fi with the dosage of neuroleptics (Bralet etet (First received 28 October 2004, final revision 15 March 2005, accepted 18 May 2005) alal, 2000). Why is more than one neuro- leptic drug prescribed? We can presume that one reason might be the lack of re- sponse to a single antipsychotic, possibly Because of the comprehensive nature of Conclusions related to the severity of the illness. Is it also the Mini-Finland Health Survey we were More attention should be paid to the possible that the most severe forms of able to take many potential confounding somatic health of people with schizo- schizophrenia carry a higher risk of dying factors into account. The main screening phrenia. Our results indicate a need to than less severe schizophrenia. However, instrument used, the General Health modify the deleterious lifestyle factors of it must be borne in mind that antipsychotic Questionnaire, is most suitable for screen- patients with schizophrenia previously polypharmacy can also lead to increased ing for non-psychotic psychiatric illnesses recommended by Brown et aletal (2000). The side-effects because of the potential influ- such as anxiety and mood disorders. recognition and medical management of ence on many receptors in addition to brain However, other aspects of our screening somatic diseases among people with schizo- DD receptors (Waddington et aletal,, 22 procedure, especially review of the SII phrenia is a challenge to psychiatrists. Fu- 1998).1998). records concerning disability pensions and ture research needs to determine whether If classic neuroleptics were the cause of reimbursement for medicines used to treat the high mortality among those with premature deaths among people with severe mental disorders, identified those schizophrenia is mainly attributable to the schizophrenia it could be assumed that the with psychotic disorders. Another limita- disorder per se or to the antipsychotic medi- excess mortality would have decreased with tion was that we were not able to define cation. Study of the association between the the introduction of the newer atypical anti- the total period of neuroleptic use or total newer antipsychotic drugs and mortality psychotics. However, a Swedish study dosage or to assess the impact of prior in patients with schizophrenia will be found an increase in mortality in patients treatment. In addition, the number of important after a sufficient period of treat- with schizophrenia (Osby et aletal, 2000).,2000). people with schizophrenia was relatively ment has elapsed to allow long-term The newer agents low, only 99, of whom 39 died during follow-up.follow-up. can affect somatic health in different ways follow-up. In spite of these limitations we (Wirshing(Wirshing et aletal, 2003).,2003). consider the results valid. The association of the use of neuroleptic drugs and REFERENCES Study strengths and limitations mortality poses questions which could not be answered in this study. A careful quanti- Aromaa, A., HelioHeliovaara,«vaara, M., Impivaara, O., et aletal The strengths of the present study included tative analysis of the association of neuro- (19 8 9) Aims, methods and study population. Part 1.In The Execution of the Mini-Finland Health Survey (eds A. a long follow-up and a representative leptic drug dosage and mortality would be Aromaa, M. HelioHeliovaara,O.Impivaara,«vaara,O.Impivaara, et al). Publication sample with a high participation rate. especially interesting. no. ML:88. Helsinki: Social Insurance Institution.

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