HARMFUL DRINKING IN MILITARY VETERANS WITH POST-TRAUMATIC STRESS DISORDER: ASSOCIATION WITH THE D2 DOPAMINE RECEPTOR A1 ALLELE

R. McD. Young, B. R. Lawford1,3, E. P. Noble4,*, B. Kann5, A. Wilkie3, T. Ritchie4, L. Arnold2 and S. Shadforth3

Discipline of Psychiatry, Southern Clinical Division, School of Medicine, The University of Queensland, Brisbane, Queensland,
1 Hospital Alcohol and Drugs Service and
2 Department of Haematology, Royal Brisbane Hospital, Brisbane,
3 Greenslopes Private Hospital, Brisbane, Australia,
4 Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, CA, USA and
5 Nambour Hospital, Nambour, Queensland, Australia

Received 10 May 2001; in revised form 14 August 2001; accepted 22 February 2002


    ABSTRACT
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Aims: The frequency of the Taq I A alleles (A1 and A2) of the D2 dopamine receptor (DRD2) gene was examined in Caucasian post-traumatic stress disorder (PTSD) patients and controls. Results: In 91 PTSD patients, the frequency of the A1 allele was higher (P = 6.12 x 10-3) than in the 51 controls. In the 38 PTSD harmful drinkers (>=60 g alcohol/day), A1 allelic frequency was higher (P = 3.91 x 10-2) than in the 53 non-harmful drinkers (<60 g alcohol/day), the former being also higher (P = 3.76 x 10-4) than in controls. However, there was no difference between non-harmful drinkers and controls. Based on DRD2 allelic association, the 35 PTSD patients with the A1+ (A1A1, A1A2) allele consumed more than twice the daily amount of alcohol than the 56 patients with the A1- (A2A2) allele (P = 1.94 x 10-3). When the hourly rate of alcohol consumed was compared, A1+ allelic patients consumed twice the rate of the A1- allelic patients (P < 10-7). Conclusion: The DRD2 A1 allele was associated with PTSD. However, this association was found only in the harmful drinkers. PTSD patients with the A1+ allele consumed more alcohol than patients with the A1- allele. The importance of determining alcohol consumption in DRD2 association studies with PTSD is suggested.


    INTRODUCTION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Post-traumatic stress disorder (PTSD) follows the occurrence of severe stress or trauma. A variety of conditions can lead to PTSD, with stress in military combat being a common experience. Although PTSD is classified among the anxiety disorders, a number of features of the disorder suggest a relationship with other conditions. Among some of these are: antisocial behaviour, depressed mood, insomnia, alcohol and other substance misuse and incidence of other co-morbid psychiatric disorders (Brady, 1997Go; Davis et al., 1997Go; Fichtner et al., 1997Go). The relationship between PTSD and alcohol problems may be especially important as a growing body of studies shows the high co-occurrence of PTSD and alcohol dependence (Schmitt and Nocks, 1984; Druley and Pashko, 1988Go; McFall et al., 1992Go; Kofoed et al., 1993Go). Indeed, a recent study of PTSD in Vietnam combat veterans has found that the increase in use of alcohol and illicit drugs paralleled the increase in number of PTSD symptoms (Bremner et al., 1996Go).

Substantial evidence, derived from family, adoption and twin studies, suggests a genetic influence on PTSD (Davidson et al., 1985Go, 1989Go; True et al., 1993Go; Reich et al., 1996Go) and alcohol dependence (Goodwin, 1985Go; Pickens et al., 1991Go; Heath et al., 1997Go; Kendler et al., 1997Go). Moreover, twin studies suggest that PTSD and alcohol dependence have common genetic contributions (True et al., 1993Go; Xian et al., 2000Go). The molecular genetic bases of these disorders are currently under active investigation.

A number of studies have now implicated the D2 dopamine receptor (DRD2) gene in alcohol dependence. Specifically the DRD2 A1 allele has been associated with this disorder, particularly its severe form (e.g. Neiswanger et al., 1995Go; Lawford et al., 1997Go; Noble et al., 2000Go; for review see Noble, 2000Go). The DRD2 A1 allele has also been associated with other substance use disorders including cocaine (Noble et al., 1993Go), nicotine (Noble et al., 1994Go; Comings et al., 1996aGo; Spitz et al., 1998Go) and opioid (Lawford et al., 2000Go) dependence and psychostimulant (Persico et al., 1996Go) and polysubstance abuse (Smith et al., 1992Go).

Few studies have been undertaken to identify the molecular genetic basis of PTSD. All three available (Comings et al., 1991Go, 1996bGo; Gelernter et al., 1999Go) have considered the role of the DRD2 gene in this disorder. Two of these studies (Comings et al., 1991Go, 1996bGo) have implicated the DRD2 A1 allele in this disorder, whereas the third (Gelernter et al., 1999Go) has not. The findings of Comings et al. (1996b) are particularly striking since they studied Vietnam veterans who had been exposed to severe combat conditions and examined the prevalence of the DRD2 Taq I A allele in those who developed PTSD versus those who did not. The prevalence of the A1 allele was 60% in those with PTSD compared to 5% in those without PTSD (P < 0.001). However, in these previous studies, the combat veterans’ substance use patterns were not presented and the control groups employed were not screened for substance use. Therefore the possible confounding effect of substance misuse in extant studies examining the association of the DRD2 A allele with PTSD cannot be estimated.

The primary aim of this study was therefore to determine whether or not the amount of alcohol consumed was a factor in DRD2 A1 allelic association with PTSD. It compared the frequency of the DRD2 A1 allele in PTSD patients and in controls without PTSD. Moreover, the frequency of this allele was assessed in subgroups of PTSD patients who drank or did not drink alcohol at harmful levels. Further, the daily amount and hourly rate of alcohol consumed were ascertained in PTSD patients with and without the presence of the DRD2 A1 allele.


    MATERIALS AND METHODS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Subjects
Ninety-one unrelated Caucasian veterans in the Australian armed forces, hospitalized for treatment of PTSD, were recruited for the study. Patients were assessed for PTSD using DSM-IV criteria (American Psychiatric Association, 1994Go) by a consultant psychiatrist (B.L.) or a senior psychiatric registrar (B.K.). PTSD caseness was confirmed by all patients exceeding the clinical cut-off on the Mississippi Scale for Combat-Related Posttraumatic Stress Disorder (Zatzick et al., 1997Go). The validity and reliability of this scale in veterans are well-established (Keane et al., 1988Go). In addition, patients had a psychiatric history taken (B.L or B.K.) or were assessed by a clinical nurse (A.W.). Demographic data and daily amount of alcohol consumed whilst on active combat service and during the 12-month period prior to the patients’ recruitment into the study were obtained. The amount of alcohol consumed was converted to grams of pure ethanol per day. Rate of alcohol consumed during each drinking occasion in the past 12 months was also ascertained and expressed as grams of pure ethanol per hour. In addition, patients’ use of cigarettes and illicit drugs was obtained, as well as first-degree family history of alcoholism.

Fifty-one unrelated Australian Caucasian controls were recruited from several Brisbane hospitals. Information obtained from these subjects included demographic data, and an assessment was made of their current and past use of alcohol, cigarettes and illicit drugs. In addition, first-degree family history of alcoholism was ascertained.

The interviews of both the PTSD patients and controls were conducted blind to their DRD2 allelic status. All participants provided informed consent and were able to terminate participation in the study without prejudice. Institutional ethics approval was obtained from Greenslopes Private Hospital and the Royal Brisbane Hospital.

Genotyping
A 10-ml blood sample was drawn from each subject. Genomic DNA was extracted employing standard techniques and used as a template for determination of Taq I A DRD2 alleles by the polymerase chain reaction (Grandy et al., 1993Go). The amplification of DNA was carried out using a Perkin Elmer GeneAmp 9600 thermocycler. Approximately 500 ng of amplified DNA was digested with 5 U of Taq I restriction enzyme (New England Biolabs) at 65°C overnight. The resulting products were separated by electrophoresis in a 2.5% agarose gel containing ethidium bromide and visualized under ultraviolet light. The A1A2 genotype is revealed by three fragments: 310, 180 and 130 bp; the A2A2 genotype is revealed by two fragments: 180 and 130 bp. The A1A1 genotype is shown by the uncleaved 310 bp fragment.

Data analysis
Information coded from the interviews was entered into a computer database. {chi}2-Test (Yates-corrected) was employed to compare DRD2 A1 allelic differences between the various groups studied. Within the clinical sample, differences between the two PTSD drinking groups (i.e. those who drank alcohol at harmful and non-harmful levels) and two allelic groups [A1+ (A1A1, A1A2) and A1– (A2A2)] in alcohol consumption (grams per day and grams per hour) were examined using a one-way analysis of variance. Values are expressed as means ± SEM. P <= 0.05 was considered to be statistically significant.


    RESULTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
The ninety-one PTSD patients and 51 controls were Australian Caucasians of European descent and none reported Aboriginal, Asian, Polynesian, African or other ethnic background.

The PTSD patients were males with an average age (± SEM) of 52.0 ± 0.7 years. All patients met DSM-IV criteria of PTSD and had a score of >94 on the Mississippi Scale for Combat-Related Posttraumatic Stress Disorder (Zatzick et al., 1997Go). These veterans reported drinking alcohol at harmful levels (>=60 g/day) (Australian National Health and Medical Research Council, 1992Go) on military bases whilst off duty during active service in Vietnam. Thirty-eight (41.8%) patients currently (i.e. during the past 12 months) consumed alcohol at harmful levels (>=60 g/day), whereas 53 (58.2%) patients currently consumed alcohol at non-harmful levels (<60 g/day). The non-harmful drinkers smoked 8.85 ± 2.19 cigarettes/day, while the harmful drinkers smoked 16.9 ± 3.33 cigarettes/day (F = 4.40, P = 0.039). The average ages of the harmful and non-harmful drinkers were 50.8 ± 0.5 years and 52.9 ± 1.0 years respectively (F = 2.54, P = 0.115). Thirty-three of 89 patients (37.1%) were current cigarette smokers and 70 of 91 patients (76.9%) were current alcohol users, but none was an illicit drug user. The primary drug of choice was therefore alcohol. Of the total sample of patients, 38 (41.8%) had a positive first-degree family history of alcoholism. There was no significant difference in the percentage of patients with a first-degree family history of alcoholism between harmful drinkers vs non-harmful drinkers (52.8 vs 35.9%, {chi}2 = 1.87, P = 0.171).

In the 51 controls (18 males, 33 females; age: 38.9 ± 1.9 years), none currently or in the past drank >40 g of alcohol/ day, a low risk level of alcohol consumption (Australian National Health and Medical Research Council, 1992Go). None was a current or past smoker or illicit drug user. Furthermore, none reported first-degree family history of alcoholism.

The DRD2 genotypes of the 91 PTSD patients were: A1A1, n = 1; A1A2, n = 34; A2A2, n = 56. This genotype distribution did not deviate from Hardy–Weinberg equilibrium (Yates-corrected {chi}2 = 2.00, P = 0.157). The genotypes of the harmful drinkers were: A1A1, n = 1; A1A2, n = 19; A2A2, n = 18. The genotypes of the non-harmful drinkers were: A1A1, n = 0; A1A2, n = 15; A2A2, n = 38. The genotypes of the control subjects were: A1A1, n = 1; A1A2, n = 5; A2A2, n = 45. This genotype distribution also did not deviate from Hardy– Weinberg equilibrium ({chi}2 = 0.442, P = 0.506).

Figure 1Go shows the frequency of the DRD2 A1 allele in the total PTSD group and in the control group. The frequency of the A1 allele in the PTSD group (19.8%) was significantly higher ({chi}2 = 7.51, P = 6.12 x 10-3) than in the control group (6.9%).



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Fig. 1. Frequency of the DRD2 A1 allele in post-traumatic stress disorder (PTSD) patients and in controls, and in PTSD non-harmful and harmful drinkers. All PTSD patients vs controls, P = 6.12 x 10-3; PTSD harmful drinkers vs non-harmful drinkers, P = 3.91 x 10-2; PTSD non-harmful drinkers vs controls, P = 0.138; PTSD harmful drinkers vs controls, P = 3.76 x 10-4.

 
Figure 1Go also shows the frequency of the DRD2 A1 allele in the two PTSD subgroups. A1 allelic frequency in the harmful drinkers (27.6%) was significantly higher ({chi}2 = 4.26, P = 3.91 x 10-2) than in the non-harmful drinkers (14.2%) and was significantly higher ({chi}2 = 12.6, P = 3.76 x 10-4) than in the controls (6.9%). However, the frequency of the A1 allele was not significantly different when the non-harmful drinkers group was compared to the controls ({chi}2 = 2.20, P = 0.138). A linear trend analysis showed a significant A1 allelic frequency increase in the order of controls, non-harmful drinkers and harmful drinkers ({chi}2 = 14.2, P = 1.64 x 10-4).

Figure 2Go shows the average grams of alcohol consumed/ day in the PTSD patients during the previous 12 months. The harmful drinkers consumed 190.2 ± 20.3 g of alcohol/day, whereas the non-harmful drinkers consumed 14.8 ± 2.5 g of alcohol/day (F = 101.9, P < 10-10). Based on DRD2 allelic association, PTSD patients with the A1+ (A1A1, A1A2) allele consumed 136.1 ± 25.9 g of alcohol/day, while the A1- (A2A2) allelic PTSD patients consumed 58.1 ± 10.6 g of alcohol/day (F = 10.2, P = 1.94 x 10-3).



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Fig. 2. Average grams of alcohol consumed per day by post-traumatic stress disorder (PTSD) harmful and non-harmful drinkers and by PTSD patients with and without the DRD2 A1 allele. Harmful drinkers vs non-harmful drinkers, P < 10-10; A1+ allele vs A1- allele, P = 1.94 x 10-3.

 
Figure 3Go displays the average rate at which alcohol was consumed, in grams per hour, in PTSD patients during the past 12 months. The harmful drinkers consumed 44.2 g of alcohol/h, whereas the rate for the non-harmful drinkers was 32.1 ± 3.6 g of alcohol/h. The rate of alcohol consumption was significantly higher in the harmful drinkers compared to the non-harmful drinkers (F = 6.04, P = 1.62 x 10-2). Based on DRD2 allelic association, PTSD patients with the A1+ allele consumed 51.7 ± 3.7 g of alcohol/h, whereas A1- allelic patients consumed 26.8 ± 2.5 g of alcohol/h (F = 34.3, P = 9.9 x 10-8).



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Fig. 3. Average grams of alcohol consumed per hour by post-traumatic stress disorder (PTSD) harmful and non-harmful drinkers and by PTSD patients with and without the DRD2 A1 allele. Harmful drinkers vs non-harmful drinkers, P = 1.62 x 10-2; A1+ allele vs A1- allele, P < 10-7.

 

    DISCUSSION
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
Alcohol problems are common among returned Australian (O’Toole et al., 1998Go) and American (Zatzick et al., 1997Go) combat veterans with PTSD. Alcohol use disorders following combat appear to have a mixed aetiology, being a product of both pre-morbid risk factors and combat exposure (O’Toole et al., 1998Go). The veterans examined in this study all consumed alcohol at harmful levels whilst serving on military bases in Vietnam, a social setting known to be associated with heavy alcohol use (Kaplan et al., 1994Go). Thirty years after returning from combat service, a substantial number of these subjects (42%) still continued to drink alcohol at harmful levels.

Alcoholics are a heterogeneous group consisting of at least two types: a more severe ‘genetic’ type characterized by an inability to abstain and a less severe ‘environmental’ type characterized by an ability to abstain (Cloninger, 1987Go; Babor et al., 1992Go). In the present study, the DRD2 A1+ allelic PTSD veterans, many years after returning from combat service, exhibited more extreme drinking behaviour, consuming twice the amount of alcohol per day at nearly twice the hourly rate, than PTSD veterans without the DRD2 A1 allele. Whereas many previous studies have associated the DRD2 A1 allele with alcoholism per se (for review see Noble, 2000Go), this is the first study that has associated the DRD2 A1 allele with differences in specific alcohol consumption behaviours.

PTSD commonly co-occurs with anxiety, depressive and substance use disorders (O’Toole et al., 1997). In this respect, alcohol has a role, as it positively reinforces drinking by elevating mood and is negatively reinforcing via its anxiolytic effects (Young et al., 1990Go; Holdstock et al., 2000Go). A number of studies have shown that individuals who experience primarily alcohol’s stimulant effects also report greater drug-liking and euphoria than individuals who experience mostly alcohol’s sedative effects (de Wit et al., 1987Go, 1989Go; Chutuape and de Wit, 1994Go; Duka et al., 1998Go). Interestingly, heavy drinkers experience greater stimulant and fewer sedative and aversive subjective effects after alcohol than do light drinkers (Holdstock et al., 2000Go). These differences occur in the absence of any group differences in breath alcohol levels. The evidence suggests that there may well be intrinsic biological differences between heavy and light drinkers.

What might some of these differences be that account for differential drinking behaviour in PTSD patients? There is growing evidence that DRD2 A1+ allelic carriers have reduced brain dopaminergic function. Autopsy studies using [3H]spiperone (Noble et al., 1991Go) and [3H]raclopride (Thompson et al., 1997Go), D2 dopamine receptor ligands, found significant reductions (30–40%) in the numbers of D2 dopamine receptors in the brains of A1+, compared with A1-, allelic carriers. The density of D2 dopamine receptors was progressively lower in A2A2, A1A2 and A1A1 genotypes (Noble et al., 1991Go). Similarly, positron emission tomography (PET) studies in healthy individuals, using [11C]raclopride, found a significant decrease in brain D2 dopamine receptor density in A1+, compared with A1-, allelic carriers (Pohjalainen et al., 1998Go). Another study, using the D2 dopamine receptor radiotracer [123I] iodobenzamide in controls and schizophrenics (Laruelle et al., 1998Go), could not find a significant difference in D2 dopamine binding potential between A1+ and A1- allelic subjects. However, an editorial in the same journal issue where these two prior studies were published (Hitzemann, 1998Go), reviewed their merits. It found the Laruelle et al. study had insufficient power to detect a significant difference between the A1+ and A1- allelic subjects, although it showed a non-significant trend amongst the healthy controls. Moreover, the editorial asserted that the D2 dopamine receptor binding potential and allelic association in that study may have been confounded in the schizophrenics by prior neuroleptic treatment. Indeed, a recent report (Silvestri et al., 2000Go) did find increased D2 dopamine receptor binding in schizophrenics after treatment with antipsychotics. However, a more recent study (Jönsson et al., 1999Go) of healthy individuals, using [11C]raclopride, also found a significant decrease in brain D2 dopamine receptor density in A1+ compared to A1- allelic carriers.

It has been hypothesized that low levels of brain D2 dopamine receptors predispose individuals to use alcohol and other drugs as a means of compensating for the decrease in activation of reward circuits activated by these receptors (Noble, 1996Go). In support of this view is a recent PET study (Volkow et al., 1999Go), which showed that methylphenidate, a dopamine transporter inhibitor, produced a pleasant response in subjects with low brain D2 dopamine receptors but an aversive response in subjects with high D2 dopamine receptors. Moreover, treatment with bromocriptine, a D2 dopamine receptor agonist, resulted in reduced anxiety and better retention in treatment of alcoholics with the DRD2 A1+ allele (i.e. those who have fewer D2 dopamine receptors), than alcoholics without this allele (Lawford et al., 1995Go). Given these considerations, it is suggested that PTSD patients with the DRD2 A1+ allele may find alcohol highly reinforcing as a means of alleviating anxiety and other dysphoric effects, leading them to self-medicate their symptoms by consuming alcohol rapidly and at excessive harmful levels.

There is growing evidence for the involvement of the dopaminergic system in response to stress (Kreek and Koob, 1998Go; Pani et al., 2000Go). More recently and specifically, studies are showing an important gene (DRD2)–environment (stress) interaction in human cognitive functioning and alcohol problem outcome. Stress, in pre-adolescent children, differentially affected cognitive markers, including visuospatial ability (Benton’s Line Orientation) and event-related potential (P300 amplitude), in subjects with the DRD2 A1+ and A1- alleles (Berman and Noble, 1997Go). Specifically, increasing stress was negatively correlated with cognitive functioning in DRD2 A1+ allelic children, but no such correlation was found in children with the DRD2 A1- allele. These findings have been supported and extended in subsequent investigations. In a sample of alcoholic patients, stress-related variables were significantly associated with severity of physiological dependence in patients with the DRD2 A1+ allele, but not in patients without this allele (Bau et al., 2000Go). Another study (Madrid et al., 2001Go) ascertained the relationship between stress, severity of alcohol problems and the DRD2 alleles. It found that alcohol problems increased significantly with increasing stress in DRD2 A1+ allelic subjects, but not in A1- allelic subjects.

Given the above considerations, it is possible that the sensitivity of DRD2 A1+ allelic subjects to stress, and the likelihood of dopamine-induced reinforcement in such individuals when drinking, may account for the greater and more harmful alcohol use amongst DRD2 A1+ allelic PTSD patients of the present study. It is also possible that the greater alcohol use by DRD2 A1+ allelic patients may have a deleterious effect on PTSD symptoms and the course of this disorder, as the misuse of this drug often generates further stress through health problems and social, emotional, interpersonal and financial dislocation. A cycle of deterioration may be experienced by DRD2 A1+ allelic subjects involving a synergistic effect of stress and subsequent alcohol consumption to alleviate stress (Bau et al., 2000Go). This combined influence may be important in an attempt to cope acutely with the stress of combat and in subsequent protracted drinking with exposure to ongoing stressors.

In the current sample, which is the largest number of PTSD subjects studied with respect to the DRD2 gene so far, stratification of the subjects based on alcohol use data has resulted in a more definitive exploration of the relationship between the DRD2 A1 allele and PTSD. This has not been possible on the basis of evidence published to date, where smaller samples of clinical subjects were studied (Comings et al., 1991Go; Gelernter et al., 1999Go) or where a stress test methodology was employed (Comings et al., 1996bGo). The difference in DRD2 A1 allelic frequency between PTSD and control subjects was not sustained when harmful drinkers were excluded from the PTSD group. The implications of our findings are that those patients with the DRD2 A1+ allele may have an enhanced vulnerability to develop serious alcohol problems. As such, they may be at greater risk in a military environment and are more likely to have a poorer prognosis to treatment. Prospective research of recruits is needed which assesses cognitive functioning both before and after exposure to trauma and DRD2 A1+ allelic genetic risk, because of the potentially long-standing and debilitating consequences of these factors in combination.

There are some limitations to the present study. A larger number of controls would have been desirable. Whilst the study entailed only men, the relationship between the DRD2 A1 allele, drinking behaviour and PTSD in females remains to be determined. Many of the drinking measures required self-reported data; additional assessments would have strengthened the patient reports. The study is cross-sectional in design and longitudinal investigations would be beneficial to ascertain if DRD2 A1 allelic status can predict problem drinking in PTSD patients over time.

In conclusion, the DRD2 A1+ allele in servicemen with PTSD is associated with markedly more persistent and harmful drinking behaviour than in servicemen without this allele. The increased DRD2 A1+ allelic frequency found in PTSD veterans was not independent of drinking behaviour.


    ACKNOWLEDGEMENTS
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
We would like to thank Adele C. Smithers-Fornaci, the Christopher D. Smithers Foundation, NY, the Greenslopes Private Hospital Veterans’ Research Foundation, Brisbane, for their generous support, and the staff and patients of Greenslopes Private Hospital for their cooperation. The excellent editorial assistance of Lesley Jenkin is gratefully acknowledged.


    FOOTNOTES
 TOP
 FOOTNOTES
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
 REFERENCES
 
* Author to whom correspondence should be addressed at: UCLA Neuropsychiatric Institute, 760 Westwood Plaza, Los Angeles, CA 90024-1759, USA. Back


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 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ACKNOWLEDGEMENTS
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