DRD2) Gene Is Associated with Co-Morbid Depression, Anxiety and Social Dysfunction in Untreated Veterans with Post-Traumatic Stress Disorder

European Psychiatry 21 (2006) 180–185 http://france.elsevier.com/direct/EURPSY/ Original article

The D2 dopamine receptor (DRD2) gene is associated with co-morbid depression, anxiety and social dysfunction in untreated veterans with post-traumatic stress disorder

Bruce R. Lawford, M.D. a,b, Ross Young, Mc.D. Ph.D. b,c, Ernest P. Noble, Ph.D. M.D. b,d,*, Burnett Kann, M.D. e, Terry Ritchie, Ph.D. b

a Greenslopes Private Hospital, Brisbane, Qld., Australia b Alcohol Research Centre, Neuropsychiatric Institute, UCLA, Los Angeles, CA, USA c School of Psychology and Counselling, Queensland University of Technology, Carseldine, Brisbane, Qld., Australia d Brain Research Institute, UCLA, Los Angeles, CA, USA e Nambour Hospital, Nambour, Qld., Australia

Received 19 August 2004; accepted 14 January 2005

Available online 24 March 2005

Supported by The Greenslopes Private Hospital Research Foundation, Australia, Queensland University of Technology, Australia and the Adele C. Smithers-Fornaci and Christopher D. Smithers Foundation, United States

Abstract

Objective. – To identify clusters of patients with post-traumatic stress disorder (PTSD) according to symptom profile and to examine the association of the A1 allele of the D2 dopamine receptor (DRD2) gene with these clusters. Method. – Fifty-seven untreated Caucasian Vietnam veterans with PTSD were administered the General Health Questionnaire-28 (GHQ) and the Mississippi Scale for combat-related PTSD. DRD2 allelic status was determined by PCR. Results. – Subjects with the DRD2 Al allele compared to those without this allele had significantly higher scores on GHQ 2 (anxiety/insomnia), GHQ 3 (social dysfunction) and GHQ 4 (depression). Cluster analysis of the GHQ data identified two primary groups. A high psychopathology cluster (cluster 3), featured by high co-morbid levels of somatic concerns, anxiety/insomnia, social dysfunction and depression, and a low psychopathology cluster (cluster 1), manifested by the reverse pattern. Scores in each of the four GHQ groups were significantly higher in cluster 3 than cluster 1, as was Mississippi Scale PTSD score. DRD2 A1 allele veterans compared to those without this allele were significantly more likely to be found in the high than the low psychopathology cluster group. Conclusions. – DRD2 variants are associated with severe co-morbid psychopathology in PTSD subjects. © 2005 Elsevier SAS. All rights reserved.

Keywords: PTSD; DRD2 polymorphism; Anxiety; Depression; Social dysfunction

1. Introduction [39]. Equally, the symptom profile in those that develop PTSD varies considerably. A genetic influence on symptomatology Post-traumatic stress disorder (PTSD) does not develop in remains significant after accounting for the extent of combat all persons subjected to traumatic stress indicating consider- exposure and contributes 13–34% of the variance in liability able individual differences in susceptibility to this disorder for PTSD symptoms [43]. The risk of developing PTSD following combat trauma in Vietnam was higher in those with a history of parental depression [43]. A family history of psy- * Corresponding author. Present address: Pike Professor of Alcohol Stu- dies, Alcohol Research Centre, Neuropsychiartric Institute (NPI), UCLA, chiatric illness is found more frequently in combat veterans Westwood, CA 90024, USA. with co-morbid depression and PTSD than in those with E-mail address: [email protected] (E.P. Noble). PTSD alone [24]. This co-morbidity is not associated with

0924-9338/$ - see front matter © 2005 Elsevier SAS. All rights reserved. doi:10.1016/j.eurpsy.2005.01.006 B.R. Lawford et al. / European Psychiatry 21 (2006) 180–185 181 stressor severity or number of traumatic events [24]. These thermore, every patient exceeded the clinical cut-off score of data suggest a possible genetic pre-morbid risk in the devel- 94 on the Mississippi Scale for combat-related PTSD [49]. opment of co-morbid disorders in those with PTSD. The validity and reliability of the Mississippi scale are well Combat-related PTSD is a highly debilitating condition established in veterans [20]. Patients then provided a clinical with a chronic course. The quality of life of PTSD patients is history. Demographic data including ethnic background were frequently compromised by a variety of co-morbid condi- obtained. tions including social anxiety disorder, panic disorder, gen- The General Health Questionnaire-28 (GHQ) was admin- eralised anxiety disorder, dysthymia and major depressive dis- istered. The GHQ measures four psychopathological factors order [17,49,31]. Both animal [38,13] and human [37,22] relevant to PTSD co-morbidity: somatic concerns (GHQ1), studies implicate the D2 dopamine receptor (DRD2) gene in anxiety/insomnia (GHQ2), social dysfunction (GHQ3) and the pathogenesis of anxiety and depression. Taq 1A variants depression (GHQ4). The GHQ has been widely validated of the DRD2 gene are associated with marked differences in internationally as a means of detecting psychiatric caseness D2 receptor density and are therefore good candidates to and is sensitive to change [32]. The GHQ has utility as a investigate the genetic contributions to the symptoms of follow-up measure of veteran mental health following expo- PTSD. sure to combat [9] and is sensitive to changes in combat- An in vitro post-mortem study using (3H)spiperone [30] related PTSD symptoms [47]. It has been used to assess symp- as a D2 dopamine receptor ligand, found a significant decrease tom severity [12,25]. in the number of D2 dopamine receptors in the brains of those After the procedure had been fully explained, all partici- with DRD2 A1+ (A1A1 and A1A2 genotypes) allelic status pants provided written informed consent. They were able to than in those with A1– (A2A2 genotype) status. Similarly, an terminate their involvement at any time during the interview in vivo autoradiographic study [41] using (3H) raclopride as without prejudice. Institutional ethics approval was obtained a D2 dopamine receptor ligand confirmed this finding, as have from the Greenslopes Private Hospital. subsequent positron emission tomography (PET) studies 2.2. Genotyping [34,18]. The developmental impact of A1+ status is evident early in life. The A1+ allele is associated with social dysfunc- A 10 ml blood sample was drawn from each patient. tion in children [27]. In adolescents, an interaction between Genomic DNA was extracted employing standard tech- A1+ allelic status and family stress results in compromised niques and used as a template for determination of TaqI A visuo-spatial functioning [4]. DRD2 alleles by the polymerase chain reaction [14]. The As differences in D2 dopamine receptor density have been amplification of DNA was carried out using a Perkin Elmer associated with depression, anxiety and impaired social func- GeneAmp 9600 Thermocycler. Approximately 500 ng of tion and Taq1A variants are also associated with differences amplified DNA was digested with five units of TaqI restric- in D2 dopamine receptor density, we examined whether tion enzyme (New England Biolabs) at 65 °C overnight. The Taq1A allelic status was associated with symptom severity resulting products were separated by electrophoresis in a 2.5% (anxiety, depression and social function) in a sample of com- agarose gel containing ethidium bromide and visualised under bat veterans with PTSD. The association of these variants ultraviolet light. Three genotypes are obtained: the A1A2 with PTSD per se was not investigated. genotype is revealed by three fragments: 310, 180 and 130 bp. The A2A2 genotype is shown by two fragments: 180 and 130 bp. The A1A1 genotype is revealed by the uncleaved 2. Method 310 bp fragment.A1+ allele subjects are those that have either the A1A1 or A1A2 genotype; A1– allele subjects have the 2.1. Subjects A2A2 genotype only.

Fifty-seven unrelated male Caucasian patients diagnosed 2.3. Analysis using DSM IV criteria for PTSD were recruited for study. All subjects were Vietnam combat veterans who had served in Information coded from the interviews, GHQ, Mississippi Scale and genotyping results were entered into a computer the Australian Defence Force. None were being treated with 2 psychotropic medication. Patients were excluded from the database. Nominal data were analysed by Yates corrected v study if they had a diagnosis of psychosis, bipolar disorder, test and continuous data were analysed by analysis of vari- obsessive–compulsive disorder, or organic brain syndrome ance (ANOVA). A “joining tree” cluster analysis was em- including dementia. All subjects had sufficient comprehen- ployed to identify various symptom cluster groups [11]. P ≤ sion of English and could understand the administered ques- values 0.05 were considered statistically significant. tionnaires. Patients were assessed for PTSD by a consultant psychia- 3. Results trist (B.L.) or a senior psychiatric registrar (B.K.) using Diag- nostic and Statistical Manual of Mental Disorders (DSM-IV) The mean age of the 57 participants was 51.4 years; criteria. PTSD diagnosis was confirmed for all subjects. Fur- (S.D. = 5.3). They had the following genotypes: A1A2 (A1+ 182 B.R. Lawford et al. / European Psychiatry 21 (2006) 180–185 allele), n = 21; and A2A2 (A1– allele), N = 36. There were no patients with the A1A1 genotype. This genotype distribu- tion did not deviate from Hardy–Weinberg equilibrium (v2 =2.86,df=1,P = 0.09). There was no significant difference in age between A1+ and A1– allele subjects (50.9 years (S.D. = 3.6) vs. 51.6 years (S.D. = 6.0), F = 0.30 df = 1, 55, P = .59). GHQ and allelic data are shown in Table 1. ANOVA did not reveal a significant difference in GHQ 1 scores between A1+ and A1– allele patients. However, significantly higher scores in A1+ compared to A1– allele patients were found in GHQ2(F = 7.32 df = 1,55, P = .009), GHQ 3 (F = 7.75 df = 1,55 P = 0.007) and GHQ 4 (F = 12.9 df = 1,55, P = .0007) scores. These differences remain significant after Bonferroni correction. The GHQ data were analysed using “joining tree” cluster analysis [11] in order to determine subgroups of patients that Fig. 1. The Mississippi scale scores for combat-related PTSD of each of the differed according to co-morbid symptom profile. This analy- four psychopathology clusters. sis was conducted blind to allelic status. Four clusters were The four cluster groups scores were significantly different (F (3,52) = 6.62, P = 7.0 × 10–4), with cluster 3 having a significantly higher score than clus- evident, with the GHQ factor scores in each of the clusters ter1(F (1,45) = 18.8, P = 8.2 × 10–5). shown in Table 2. Table 3 contains Z-transformed GHQ cluster scores. Cluster 1 was characterised by low scores on all pared to cluster 1 had significantly higher Z scores in GHQ 1 –7 four GHQ factors; cluster 2 revealed low scores on somatic (F = 36.2 df = 1,46, P =2.7×10 ), GHQ 2 (F = 193 –10 concerns and social dysfunction. Cluster 3 was characterised df = 1,46, P <10 ), GHQ 3 (F = 56.5 df = 1,46, –9 –10 by raised scores on all GHQ factors, whereas cluster 4 showed P =1.5×10 ) and GHQ 4 (F = 82.1 df = 1,46, P <10 ). raised somatic concerns and anxiety/insomnia scores but The Mississippi scale score for combat-related PTSD of lower social dysfunction and depression scores. Only two each of the four clusters are shown in Fig. 1. ANOVA indi- clusters, the low psychopathology cluster 1 and the high psy- cated a significant difference in the Mississippi Score among chopathology cluster 3 had sufficient numbers of patients for the four clusters (F (1, 52) = 6.62, P = .0007). Again, only statistical analyses.ANOVArevealed that cluster 3 when com- cluster 1, the low psychopathology cluster, and cluster 3, the high psychopathology cluster contained a sufficient number Table 1 of patients to be subjected to further analyses. The results GHQ scores in patients with the DRD2 A1+ and A1– allele* showed that the Mississippi Score was significantly higher in GHQ number A1+ allele A1– allele cluster 3 than in cluster 1 (143.3 ± 3.4 vs. 121.3 ± 3.2, (N = 21) (N = 36) GHQ 1 (somatic concerns) 11.3 ± 1.1 10.2 ± 0.7 NS F = 18.8 df = 1, 45, P < .0001). GHQ 2 (anxiety/insomnia) 14.4 ± 1.1 11.0 ± 0.7 P = 0.009 The final analysis examined the allelic status of subjects GHQ 3 (social dysfunction) 14.4 ± 1.0 11.3 ± 0.6 P = 0.007 within the low and high psychopathology clusters. In the low GHQ 4 (depression) 13.1 ± 1.2 7.8 ± 0.9 P = 0.0007 psychopathology cluster 1, eight patients had the A1+ allele, * A1+ allele represents A1A1 or A1A2 genotype A1– allele represents whereas 24 patients carried the A1– allele. On the other hand, A2A2 genotype. in the high psychopathology cluster 3, 12 patients had the

Table 2 GHQ cluster scores Cluster scores GHQ number 1 (N =32) 2(N =3) 3(N =16) 4(N =6) GHQ 1 (somatic concerns) 7.91 ± 0.62 10.00 ± 1.16 14.31 ± 0.86 15.33 ± 1.26 GHQ 2 (anxiety/insomnia) 8.53 ± 0.37 13.67 ± 2.33 17.88 ± 0.59 16.50 ± 0.56 GHQ 3 (social dysfunction) 10.19 ± 0.60 9.00 ± 1.53 17.38 ± 0.61 13.00 ± 0.68 GHQ 4 (depression) 6.59 ± 0.70 17.67 ± 0.67 16.38 ± 0.58 4.67 ± 1.38

Table 3 GHQ cluster scores (Z-transformed) Cluster scores Signiﬁcance GHQ number 1 (N =32) 2(N =3) 3(N = 16) 4 (N = 6) Cluster 1 vs. cluster 3 GHQ 1 (somatic concerns) –0.581 ± 0.133 -0.129 ± 0.249 0.803 ± 0.186 1.023 ± 0.271 P <10–6 GHQ 2 (anxiety/insomnia) –0.767 ± 0.077 0.288 ± 0.479 1.153 ± 0.121 0.870 ± 0.116 P < 10–6 GHQ 3 (social dysfunction) –0.516 ± 0.138 –0.788 ± 0.350 1.131 ± 0.140 0.129 ± 0.157 P <10–6 GHQ 4 (depression) –0.524 ± 0.118 1.331 ± 0.112 1.115 ± 0.097 –0.846 ± 0.232 P <10–6 B.R. Lawford et al. / European Psychiatry 21 (2006) 180–185 183

A1+ allele, whereas four patients carried theA1– allele.Yate’s inversely proportional to D2 dopamine receptor binding corrected v2 statistic revealed that cluster 3 had a signifi- [44,45]. This suggests that depression is associated with cantly higher prevalence of A1+ allele participants than clus- decreased brain D2 dopamine receptor density. Similarly, sub- ter1(v2 = 9.01, df = 1, P < .003). jects with schizophrenia treated with typical antipsychotic drugs show a worsening of depressive symptoms with increas- ing D2 dopamine receptor occupancy [7]. Moreover, a PET 4. Discussion study of patients with schizophrenia treated with the atypical antipsychotics olanzapine or risperidone demonstrated that The A1+ allele of the DRD2 was associated with increased D2 dopamine receptor occupancy was proportional to sub- GHQ anxiety, depression and social dysfunction scores in jective experience of depression [8]. untreated Veterans with PTSD. The association between GHQ There is considerable overlap between the pharmacothera- depression scores and DRD2 status is consistent with a large peutic treatment of depression and anxiety disorders and the body of research that supports the association between dopam- beneficial effects of many of these agents may be mediated ine deficiency and mood disorders [33]. Equally, the associa- via the D2 dopamine receptor. For example, selective seroto- tion between the GHQ scores of social dysfunction and anxi- nin reuptake inhibitors are effective treatments for both anxiety withA1+ allelic status, and thus low D2 dopamine receptor ety and depressive disorders [3,35]. Fluoxetine causes an density, in PTSD, is consistent with social anxiety disorder increase in nucleus accumbens shell D2 dopamine receptor and detachment being linked to dopamine hypoactivity [36]. mRNA resulting in increased D2 dopamine receptor postsyn- More broadly, the association of A1+ allelic status with the aptic binding in the nucleus accumbens [1]. Similarly, the processing of environmental rewards has been postulated [48]. SSRI citalopram increases D2 dopamine receptor mRNA in Previous research has proposed an association between the the striatum and nucleus accumbens [10]. This effect of cit- A1+ allele and harm avoidance, a personality trait composed alopram on increased transcription of the DRD2 gene is likely of worry, pessimism and shyness [16]. to be mediated by increased serotonin levels induced by In addition to the associations of the A1+ allele with indi- SSRIs, as 5-hydroxytryptophan also increases D2 dopamine vidual GHQ scores, A1+ allelic status was also strongly over- receptor mRNA transcription [19]. D2 dopamine receptor represented with a severe psychopathology PTSD cluster binding increases in SSRI treatment responders and decreases featuring more intense co-morbid symptoms of somatic prob- in non-responders [23] suggesting that induction of D2 lems, anxiety, social dysfunction, and depression. The two dopamine receptor gene expression is likely to be an impor- main symptom clusters found in this study are similar to those tant mechanism by which SSRIs exert therapeutic effects. This identified in other research of veterans mental health. For is a possible explanation for the finding that PTSD patients example, Hallman et al. [15] studied 1161 Gulf War veterans with the A1+ allele treated with the SSRI paroxetine, showed using cluster analysis and identified a group reporting good more significant improvements in social functioning than health and few moderate or severe symptoms. The second PTSD A1– allele patients [25]. group was characterised by fair or poor health and increased Dopamine receptor ligands also have both anxiolytic and frequency of moderate or severe symptoms. Equally two of antidepressant effects [2,40]. A double-blind placebo con- the three PTSD clusters identified by Miller et al. [28] were a trolled study [26] examined the effects of a DRD2 agonist, low psychopathology cluster and a cluster characterised by bromocriptine (BRO) and placebo (PLA) on treatment out- severe anxiety and depressive symptoms. come in alcoholism. The results showed that in the four groups Epidemiological studies and clinical experience show that of alcoholics studied (BRO A1+ allele, BRO A1– allele, PLA the co-morbidity of anxiety and depressive disorders is fre- A1+ allele, PLA A1– allele) the greatest and most significant quent [5]. There is considerable evidence that genetic risk for decreases in craving and anxiety were found in A1+ allele anxiety and depression is probably accounted for by similar alcoholics treated with bromocriptine (BROA1+ allele). Bro- or substantially overlapping genes [29]. The association of mocriptine has similar efficacy as imipramine and amitrip- A1+ status with a cluster of severe co-morbid depression, tyline for the treatment of endogenous depression [6,46]. The anxiety and social dysfunction symptom individuals in a clini- pharmacogenetic application of SSRI’s and D2 dopamine cal sample with PTSD suggests that the Taq 1A polymor- receptor agonists may have considerable potential in the future phism of the DRD2 is one of these genes. treatment of PTSD and other anxiety/depressive disorders in A1+ allelic status is associated with decreased D2 dopam- A1+ allele individuals. ine receptor binding [30,41,34,18]. In non-clinical subjects, Although this study has a number of strengths there are a significant relationship was found between low D2 dopam- also some weaknesses. The numbers of patients recruited were ine receptor binding and the NEO personality trait of depres- small; however the differences between cluster groups in sion [21]. Regarding clinical depression, depressed patients terms of DRD2 allelic status were marked. The current study exhibit a hypersensitive response to dextroamphetamine with recruited male patients only and the results may not be gen- severity of depression correlating highly with the rewarding eralisable to female patients or patients who were exposed to effects of this agent [42]. In the laboratory, subjects adminis- trauma other than combat (for example, trauma related to tered intravenous methylphenidate experience reward that is sexual abuse). The age range of patients was also restricted 184 B.R. Lawford et al. / European Psychiatry 21 (2006) 180–185 and there was a period of several decades between traumatic [13] Gingrich B, Liu Y, Cascio C, Wang Z, Insel TR. Dopamine D2 recep- exposure and recruitment for this research. The implications tors in the nucleus accumbens are important for social attachment in Microtos orchogaster of DRD2 A1+ allele status for the acute response to trauma female prairie voles ( ). Behav Neurosci 2000; 114:173–83. are yet to be established. 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