Early death and CSF monoamine metabolites in schizophrenia spectrum psychosis

Abstract

Introduction: Patients with schizophrenia have higher rates of mortality than the general population. Lower concentrations of the cerebrospinal fluid (CSF) monoamine metabolites homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA) have been associated with suicidal, aggressive and impulsive behavior. Mortality has been suggested as a measure of impulsivity and a relationship between early death and lower concentrations of CSF monoamine metabolites has been reported but the studies are few with short periods of follow-up and small numbers. Aim: The objective of this study was to investigate a relationship between early death and concentrations of CSF 5-HIAA and HVA. Methods: Three hundred and eighty-five inpatients with schizophrenia spectrum psychosis were lumbar punctured in a standardized manner and followed for a median of 26 years. Patients were searched to identify those who had died. Causes of death were obtained from the Causes of Death Register. Results: During the time of follow-up, 97 patients died. Schizophrenia spectrum psychosis patients died at an earlier age from both natural and unnatural causes of death. No significant associations were found between CSF 5-HIAA and HVA concentrations and non-suicidal death. Attempted suicide was not a risk factor for non-suicidal death at younger age. Conclusion: Patients with schizophrenia spectrum psychosis die at an earlier age from both natural and unnatural causes of death. Attempted suicide is not a risk factor for non-suicidal death at younger age. Low concentrations of CSF HVA and 5-HIAA were not a risk factor for non-suicidal death at younger age in schizophrenia spectrum psychosis.

• Early death
• CSF monoamine metabolites
• Mortality
• Psychosis
• Schizophrenia

Patients with schizophrenia die on average younger than people in general. This excess mortality is mainly associated with suicide but also with increased mortality from other causes (1–4). Patients with schizophrenia have also higher rates of mortality from natural causes than patients with other mental disorders (5).

The mortality gap between the general population and schizophrenia patients has worsened in recent decades (6). Although the natural causes of death are the same, the higher mortality in schizophrenia patients may relate to causes that reflect a dimension of poor judgment, risk-taking and impulsivity (7). Lifestyle factors such as smoking, lack of exercise and unhealthy diet may contribute (8), as well as other factors such as side-effects from medication (9). Impulsiveness may be an important factor affecting mortality, both from suicides (10) and non-suicidal deaths such as accidents. High levels of impulsivity might influence the choices one makes, making one more prone to suicidal behavior (11), as well as to general risk taking behavior such as an unhealthy lifestyle involving use of tobacco, alcohol and drugs, risk taking behavior in traffic, and an unhealthy diet. Low concentrations of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA), the major serotonin metabolite, have been related to impulsive and aggressive behavior in different mental disorders (12–15). However there is no consensus concerning a relationship between concentrations of CSF homovanillic acid (HVA), the major dopamine metabolite, and impulsivity and aggression (16).

Impulsivity is a difficult construct to measure in retrospect. However, mortality may represent a reliable and objective dichotomization of impulsivity and correlations between CSF 5-HIAA and HVA concentrations and age of death in a sample of patients with various psychiatric disorders has been reported (7).

Aim

The aim of the present study was to investigate whether low concentrations of CSF 5-HIAA and HVA could predict early death from other causes than suicide in a long-term cohort of patients with schizophrenia spectrum psychosis.

Materials and Methods

Subjects

This study was approved by the Stockholm regional ethics committee (NO. 2006/408-31/4). The cohort has been described and investigated (17–19). Briefly, patients (n=385, 153 men and 232 women) were admitted to psychiatric clinics in Stockholm between 1973 and 1987 with symptoms of psychosis. The cohort consisted of those patients who consented to participate in studies involving a lumbar puncture irrespective of being their first treatment episode or representing a relapse. Patients with active substance abuse were excluded (20–23). Preliminary diagnosis at admittance was schizophrenia. Mean age±standard deviation (s) at index admission was 29.8±7.9 for men and 33.8±10.3 for women (P<0.0001).

Lumbar puncture

Lumbar puncture was performed in a standardized manner within 2 weeks after admittance between 08:00 and 09:00 h after the subject had been at bed rest for at least 8 h. Drug treatment was withheld until lumbar puncture had been performed. Twelve milliliters of CSF were drawn (24) and immediately centrifuged and stored at below −20°C. CSF 5-HIAA and HVA concentrations were determined by mass fragmentography (25).

Data abstraction

Follow-up for every patient started at index admission and ended in July 2006 or at the time of death. Mean±(s) and median follow-up time was 24.4±7.6 and 26.1 years, respectively. Information about prior suicide attempt was retrieved from the medical records. Suicide attempt was defined according to the definition of the National Strategy for Suicide Prevention for suicidal acts (26). All patients were searched for in the Central Bureau of Statistics to identify those who had died. The reported causes of death were obtained from the Causes of Death Register at the National Board of Health and Welfare. Patients’ diagnosis were based on register data for all hospitalization periods and assessed in retrospect. Every patient was given a lifetime diagnosis using a hierarchy earlier described (27, 28). None of the patients was lost to follow-up.

Statistical analysis

Statistical analyses were performed using the JMP statistical package version 7 (SAS Inc., 2007). T-tests were used to analyze the unpaired data and regression analysis for the multiple variable testing. Significance level was set at P<0.05.

Results

During follow-up, 97 (27%) of the 385 patients died, 26 (7%) by suicide, six (2%) by accidents, three (0.8%) from undetermined causes and 62 (16%) patients died from natural causes. Median age at death was 54.6 years for all deceased patients. Results with regard to death by suicide have been published earlier and these patients were therefore excluded in the present analysis (17). The remaining deceased patients (n=71) were divided by the median age into two groups (Tables 1 and 2). Median age at death for non-suicidal deceased patients was 59.2 years (mean 60.1 years, n=71, 21 men and 50 women). The majority of these patients died from natural causes (Table 1) and received a lifetime diagnosis of schizophrenia (Table 2). There was no significant difference in follow-up time between the younger and older deceased.

Table 1. Causes of death for patients below and above median split.

Causes of death	Deceased below median split ≤age 59.2, n	Deceased above median split >age 59.2, n
Cardiovascular	6	18
Cancer	11	6
Infectious	4	4
Gastrointestinal	3	5
Respiratory	2	2
Neurological	1	0
Accidents	6	0
Undetermined	3	0

Table 2. Lifetime diagnosis for patients above and below median split.

Lifetime diagnosis	Deceased below median split ≤age 59.2, n	Deceased above median split >age 59.2, n
Schizophrenia	29	20
Schizophreniform disorder	0	3
Schizoaffecive disorder	0	4
Psychosis not otherwise	3	3
specified
Personality disorder	1	0
Bipolar disorder	1	0
Delusional disorder	0	3
Other	2	2

CSF 5-HIAA and HVA concentrations (mean±s) for the younger deceased (107±39 and 177±82 nM, respectively) were significantly lower than for the old deceased (125±36 and 240±111 nM, P=0.04 and P=0.008, respectively). However, no significant correlations between CSF 5-HIAA and HVA concentrations and age at death below median split were found taking age and height into account (Table 3). CSF 5-HIAA and HVA concentrations were higher in the female patients as expected. Thus our finding could be explained by these confounders that are known to influence the concentrations of monoamine metabolites in CSF.

Table 3. Statistical results analyzing (a) concentrations (nM) of the monoamine metabolites 5-hydroxyindole acetic acid (5-HIAA) and homovanillic acid (HVA) and death by non-suicidal causes before and after the median age of death, and (b) age at death for attempters and non-attempters.

(a) Monoamine metabolite	Deceased before age 59.2 years	Deceased after age 59.2 years	Uncorrected statistics	Statistics corrected for age and height
5-HIAA (mean±s)	107±39	125±36	t=−2, df=1, P=0.04	t=0.34, df=3, P=0.74
HVA (mean±s)	177±82	240±111	t=−2.25, df=1, P=0.008	t=0.62, df=3, P=0.54
(b)	Age at death (mean±s)	Uncorrected statistics	Statistics corrected for age
Suicide attempt	56±14	t=2, df=1, P=0.046	t=−0.48, df=2, P=0.6
No suicide attempt	64±14

s, standard deviation.

No significant difference in CSF 5-HIAA and HVA concentrations (mean±s) was found between accidental (n=6, 106±40 and 168±85, respectively), undetermined (n=3, 92±46 and 181±104, respectively) and natural (n=27, 108±40 and 212±51, respectively) deaths for the younger deceased (P=0.8 and P=0.5, respectively).

Information about suicide attempt were obtained from medical records for 55 (57%) of the deceased patients (suicide attempters n=18, non-attempters n=37). There was no significant difference in time of follow-up between attempters and non-attempters. Attempted suicide was not a risk factor for non-suicidal death at younger age (Table 3).

Discussion

In the present long-term study of 385 inpatients with schizophrenia spectrum psychosis, 97 patients died during the 24-year follow-up. Patients who died at age 59 or younger died mostly of suicide (n=24) confirming the high suicide risk reported in this patient population, especially in the earlier years of disease (29). A high number of the patients died from accidents (n=6), not surprisingly given several previous reports of a high mortality from unnatural causes aside from suicide in schizophrenia spectrum psychosis (1, 3, 4). The main natural cause of death in our study was cardiovascular disease (25%) and cancer (18%). These findings are well in line with epidemiological data (4, 30).

There were no significant CSF 5-HIAA and HVA concentration differences between younger and older non-suicidal deceased patients when height and age of the participants were taken into account. This is in contrast with Faustman et al. (7) who reported lower CSF 5-HIAA and HVA concentrations among those who died early in a cohort of male inpatient veterans with mixed psychiatric diagnosis. The present sample was much larger and involved both men and women but was limited to a diagnosis within the schizophrenia spectrum psychosis, which may explain parts of the discrepant results between the studies. However, we were only able to retrieve 57% of the medical records to obtain information about prior suicide attempt. The use of neuroleptic medication with metabolic side-effects increasing the risk of cardiovascular disease is a major concern among psychotic patients and warrants for close follow-up of somatic health (31). Serotonin reuptake inhibitors and other drugs involving the serotonin system may be helpful decreasing the mortality from cardiovascular disease, as suggested for depressed patients (32) but this remains to be scrutinized in patients with schizophrenia spectrum psychosis. The general decrease in inpatient care capacity during the last few decades (33, 34) with less structure, observation and investigations of the patients may be a contributing factor affecting the general health.

Among the younger deceased, no significant difference was found in monoamine metabolites levels between undetermined, accidental and natural deaths. Lower concentrations of CSF 5-HIAA has been associated with higher risk of suicidal and aggressive behavior (10). However, most of the studies involve small samples of patients and few studies analyzed patients with schizophrenia spectrum psychosis.

Suicidal behavior, related to impulsivity and aggression, has been suggested to increase the risk of early death, maybe reflecting an impaired decision making concerning the lifestyle (7). However, in the present study, attempted suicide was not a risk factor for non-suicidal deaths at younger age. With a median age at death of 59.2 years the investigated patients approximately lost 20 years of life compared with estimated life expectancy of the general population in Sweden (35).

Conclusion

In the present study, there was a high rate of deaths from suicide, accidents and undetermined causes at an early age and the age at death was 20 years younger than expected. Attempted suicide was not found to be a risk factor from non-suicidal deaths. No significant association was found between CSF 5-HIAA and HVA concentrations and early non-suicidal deaths in schizophrenia spectrum psychosis. The increased mortality from natural and unnatural causes in schizophrenia spectrum psychosis (4, 30, 36), in many ways correlated to the unhealthy lifestyle (8), deserves further attention. Treating physicians need an integrated approach to the psychiatric and medical treatment of these patients.

Acknowledgement

Financial support was provided through the regional agreement on medical training and clinical research between Stockholm County Council and the Karolinska Institutet, the Swedish Research Council (nos. K2007-62X-15078-04-3, K2008-62P-20597-01-3), the Wallenberg Foundation and the HUBIN project.

Disclosure of interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.